Chapter 1 Erythrina and Related Alkaloids

-CHAPTER

1-

ER YTHRINA AND RELATED ALKALOIDS S. F. DYKE*AND S. N. QUESSY~ School o/Chei?iisfry.The Uniuersitj. of Bath. Bath, A t o i l , Encqland I. Introduction . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . , , . . . . . . . . . . , , , . . . . . , 11. Erythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Occurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......................... B. Isolation and Detection . . . . . . . . . . . . . . . . C. Structure Determination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111. Homoerythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Occurrence and Isolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Structure Determination . . . . . . . . . . . . . , . . . . . . . . . . , . . . . . . . . IV. Cephalotasus Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Occurrence and Isolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Structure Determination . . . . . . ...... . .. ... . .. V. Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Erythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Homoerythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Cephalotasus Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . , , . . . . . . . . , . VI. ..... ...... ..... .. ..... . ..... .............................................. B. Homoerythrina Alkaloids . . . . _ . _ . . _ . . ., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Cephalotasus Alkaloids . . . . . . . . .............. ............. V11. Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1

2 2 6

1 21 21 30 31 42 42 45 51 51 58 59 61 61 12 16 91 93

1. Introduction The last review in this series (1)covered the literature to the end of October, 1966. At that time 10 Erythrina alkaloids were known, and the structures and stereochemistries of most of them had been established. The total synthesis of erysotrine had been described by Mondon’s group in a preliminary communication (2),but nothing was known about the biosynthesis of these alkaloids, although some speculations had been reported. * Present address: Department of Chemistry. Queensland Institute of Technology, Brisbane. Queensland, Australia. ’ CSIRO postdoctoral fellow, 1979. Present addrcss: Research and Dcvclopment Department. Riker Laboratories, Thornleigh, New South Wales, Australia. THE ALKALOIDS. VOL. X V l l l

Copyright @ I Y 8 1 by Academic Press. Inc. All rights of reproduction an any rorin reserved.

ISBN 0-12-469SlR-3

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S . F. DYKE AND S. N. QUESSY

Frc;. 1. The structures and accepted numbering system for A : 1,6-diene skeleton and B : A1(6)-alkene skeleton.

In the intervening 13 years the subject has expanded dramatically; over 60 compounds are now classified as Erythrina alkaloids, and the structures of most of these have been deduced from a combination of mass spectral fragmentation analysis, H-NMR spectral interpretations, and chemical correlations with alkaloids of known structures. Some ‘‘unusual’’ alkaloids have been obtained from certain Cocculus species and a new, as yet small, subgroup, the Homoerythrina alkaloids, has been recognized. The biosynthetic pathway from tyrosine through the aromatic bases to the erythroidines has been elucidated, and some significant advances have been made in methods of total synthesis. Reviews of the Erythrina alkaloids since 1966 have appeared (3-6). Because of the postulated biosynthetic derivation of the Cephalotaxus alkaloids from the Homoerythrina bases, the former, relatively new group is included in this chapter. Anticancer activity has been found in certain members of the Cephalotaxus group, so the subject has already been reviewed several times (7-9). Annual coverage is given to the Erythrina, Homoerythrina, and Cephalotaxus alkaloids in the Specialist Periodical Reports of the Chemical Society (20-ZZa). The Erythrina alkaloids are conveniently divided into two main structural groups: the 1,6-diene group and the A1(6)-alkene group (see Fig. 1). The biogenetically important alkaloid erysodienone cannot be classified in this way. The present chapter covers the literature from November 1966 to the end of May 1979. 11. Evythvitza Alkaloids

A. OCCURRENCE There are now over 60 Erythrina alkaloids of known structure 1-61 (see Figs. 2-4) and several more, the structures of which are yet to bz assigned (12). The alkaloids occur in species of Erythrina (Leguminosae), a genus of wide distribution in tropical parts of the world, and in species of Cocculus

1

2 3 4 5 6 7 8 9 10

11 12 13 14

1s* 16 17*

R' Erysotrine Erysotramidine Erythravine Erythraline Erysovine Erysoline Erysodine Erysonine Erysopine Erysothiovine Glucoerysodine Eryso thiopine Erysophorine Coccuvinine Coccolinine Coccuvine Coccoline

CH30 CH,O CH30 -OCH2CH30 CH,O HO HO HO CH30 h U

CH30 H H H H

R2

R3

R'

X

2H 0 2H 2H 2H 2H 2H 2H 2H 2H 2H 2H 2H 2H 0 0 0

FIG.2. Erj,llrrina alkaloids: 1,6-diene series. a : H0,CCH2S0,-,

18 19 20 21 22 23 24 25 26 27 28 29 30 31

Erythrartine Erythristemine Erythrascine Erythrinine 1 I -Methoxyerythraline 1 I-Oxoerythraline I I-Hydroxyerysovine I I-Methoxyerysovine 1 I-Oxoerysovine 1 I-Hydroxyerysodine 1 I-Methoxyerysodine 1 I-Oxoerysodine I I-Methuxyerysopine 1 1-0xoerysopine

CH, CH, CH 3

-CH,-~-CH, CH,

R2

R3

CH3 CH 3 CH,

OH OCH OAc OH OCH -0 OH OCH, -0 OH OCH, -0

~~

CH, CH, CH, H H H H H

H H H CH.3 CH 3 CH, H H

,

0ch3 -0

b : I-/~-glucosyl,c: hypaphorine ester, d : alkaloid is possible artifact.

R1orJp

4

S. F. DYKE AND S. N. QUESSY

RZO

" ' oR

-

CH,O"

CH,O' R'

32" 33" 34* 35*

Erythrabine Crystamidine 10,ll-Dehydroerysovine 10,ll-Dehydroerysodine

R2

X

36 Isococculidine R

CH, CH, -CH2CH, H CH, H

0 0 2H 2H

37 Isococculine R = H

* means an alkaloid is a possible artifact.

X R' 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54

Dihydroerysotrine Erythratidine Erythratidinone Erythramine Erythratine Erythratinone Dihydroerysovine Erysosalvine Erysosalvinone Dihydroerysodine Erysotine Eryso tinone Erysopitine Erysoflorinone Coccutrine Erythroculine Cocculidine

H H H H H H H H H H H H H H CH,O H H

R2

R3

CH,O CH,O CH,O CH,O CH,O CH,O -OCH,O-OCH20-OCH,OCH,O HO HO CH,O CH,O HO HO CH,O HO CH,O HO CH,O HO HO HO HO H OH CH,O CH,O,C H CH ,O

FIG.3 . Erythrinu alkaloids: Al(6) alkene series.

X H OH =O H OH =O H OH =O H OH =O OH =O H H H

= CH,

1.

E R Y T H R I N A AND RELATED ALKALOIDS

5

CH,O

CH 3

0

0

0

57 3-Demethoxyerythratidinone

59 r-Erythroidine

58 Erysodienone

60 [I-Erythroidine

61 Cocculolidine

FIG.4. Erythrina alkaloids: miscellaneous

(Menispermaceae), a genus of more limited distribution in tropical areas (13). A conspectus of the genus Erythrina was published by Krukoff who listed 108 species and 9 hybrids (14), and over half of these have been examined for their alkaloidal content. Attention must be drawn to the fact that Krukoff has reclassified several species. Notably, E. lithosperma has been subdivided such that E. lithosperma Blume is now a synonym for E. variegata L., wherer.5 E. lithosperma Miguel is a synonym for E. subumbrans Merril. In addition, E. orientalis, E. variegata uar. orientalis, and E. indica are synonyms for E. variegata L. (14).This reclassification has resulted in some misleading claims and doubtful identifications in the literature (15). Most studies have concentrated on examination of the seeds, which typically contain 0.1% alkaloids, although alkaloids have been isolated from the leaves, stalks, stems, bark, roots, pods, and flowers of Erythrina species. An extensive survey of Erythrina species has been made by two groups using combined GC-MS; Rinehart and co-workers at Illinois have examined American species (15, 16) and Jackson and co-workers at Cardiff examined old world species (12, 17). Other major investigations have been carried out by Barton and co-workers (18-21), by Ito and co-workers in Japan (22-32), and by Ghosal and co-workers (33-37), and Singh and Chawla in India (38-41). From the results of these studies it is apparent that individual species are often distinctive in their alkaloid profile, although the sections and subgenera are not clearly marked. Several patterns do emerge, however. Erysovine (5)and erysodine (7) are ubiquitous, although

6

S. F. DYKE AND S. N. QUESSY

they do not occur in all parts of each plant (12, 15-17); the sections Breviflora and Edules are low in alkaloid but high in amino acid content (13,42); the major alkaloids of E. folkersii are of the 1,6-diene type whereas those of E. salvizjlora are of the l(6)-alkene type ( 1 5 ) ; the American species do not contain 1 1-oxygenated alkaloids and presumably lack the capacity to hydroxylate ring C (12, 21). However, Ito has reported the isolation of erythrinine (21) from E. crysta galli L., an American species (30). The hybrid species E. x bidwillii elaborated two new alkaloids, erythrinine (21) (24, 25) and the dibenzo[e,f]azonine base erybidine (62), (23, 26) which had not been found in the parent species E. crysta galli and E. herbacea (13). Erythrinine has since been isolated from E. crysta galli (30) and erybidine has been isolated from several other Erythrina species (12, 27, 30,31). Although the alkaloidal profile of Erythrina species is often characteristic, there is considerable quantitative variation in different samples (17). Differences have been noted in the content of the bark, seed, and leaves of the plant (33, 35, 43, 4 4 , and some striking variations have been reported. In their GC-MS examination of E. folkersii, Rinehart’s group (15) failed to detect erythraline (4),which had been reported in an earlier study of this plant (45),although 4 could be detected in other species (16).Ghosal et al. reported erysotrine (1) to be the major component by far in the bark of E. variegata var. orientalis, with only minor amounts of 5 present (33), whereas Singh et al. (41) in a more recent investigation reported only 5 from the bark of the same species. Whereas some of the variation may result from the location of the plant or its age at harvest, there is some evidence for chemical variants within species. Barton et al. (21)reported a thorned variety of E. lithosperma Blume (E. variegata L.) that contained only erysotrine and a smooth variety that contained 1 along with erythratidinone (40), 3-demethoxyerythratidinone (57), and traces of erythraline (4).Letcher referred to two varieties of E. lysistemon harvested in Southern Rhodesia which contained either 1 or 1 1-methoxyerythraline (22) but not both. Although erythristemine (19) had been isolated from E. lystistemon from South Africa none was found in the varieties from Southern Rhodesia, and no change in the nonpolar alkaloids present in the leaves could be detected over a period of four months. It was therefore suggested that there are at least three chemical variants of E. lysistemon (46). B. ISOLATION AND DETECTION

The procedure of Folkers, where the ground plant material is extracted with hexane to remove fats, is widely used; but Rinehart and co-workers (16) pointed out that a significant quantity of alkaloid could be detected

1.

ERYTHRI.VA AND RELATED ALKALOIDS

7

by GC-MS analysis of the hexane fraction, so that earlier examinations where this fraction was discarded must be regarded as incomplete. Alcoholic extraction of the remaining marc gave the “free” alkaloids, whereas acid hydrolysis gave rise to the liberated alkaloids (usually the largest fraction). Ghosal(35) has described a detailed flow chart for the isolation of a variety of alkaloids from E. variegata. The greatest advance in the isolation and identification of Erythrina alkaloids has come from the powerful combination of GC-MS, which has provided a methodology for comprehensive taxonomic investigation of the whole genus. Its value derives from the facile identification of the alkaloids from their fragmentation patterns, the speed and accuracy of the method, the avoidance of large-scale extraction and chromatography, and the requirement of only milligram quantities of crude alkaloid extract. The power of the technique has been demonstrated by the number of new alkaloids detected and the number of species investigated using it (12, 15, 16). There are rarely more than eight alkaloids present in a species, and the possibility of the same GC retention time is not normally a problem. In cases where overlap has been observed it has proved possible to identify both components from the mass spectrum of the mixture. The crude alkaloid extracts are treated with trimethylsilyldiethylamine to form volatile TMS derivatives of the hydroxylated components. The presence of a free phenolic or hydroxyl group is then detected by an ion with mje 73 [(CH,),Si+]. Positional isomers [e.g., erysovine (5) and erysodine (7)] are resolved although u- and 8-erythroidine are not. The presence of perythroidine (60) can be estimated since it shows some enol content under the silylation conditions and gives rise to a monotrimisyl derivative with m/e 345 (15). As a supplement to electron impact MS, field ionization MS, which allows identification of the alkaloids by their molecular formula, has been introduced (47). The combination of HPLC-field desorption MS, which utilizes the greater resolving power of HPLC over GC, has been applied; and the presence of alkaloids not detected by GC-MS was revealed in one case (12). Various other alkaloids have been found concurrently with the Erythrina group. Hypaphorine is by far the most common, but choline, N-nororientaline, and erybidine (62) are not uncommon. C. STRUCTURE DETERMINATION

I . X-Ray Crystal Structures and Absolute Stereochemistry The absolute stereochemistry of the aromatic Erythrina alkaloids has been determined. An X-ray analysis of the 2-bromo-4,6-dinitrophenolate

8

S. F. DYKE AND S. N. QUESSY

salt of erythristemine confirmed the assumption that the 3R,5S configuration of the erythroidines exists in the aromatic group. This result also confirms the common biosynthetic origin of the two types. The configuration of the methoxyl group at C-11 was found to be S. The use of 2-bromo4,6-dinitrophenol for the preparation of a heavy-atom derivative was novel and may be applicable in other cases (20,48). The absolute stereochemistry of the A1(6)-alkene alkaloids cocculine (56) and coccutrine (52) has also been established by X-ray analysis. It was found that the cyclohexene ring A exists preferentially in an approximate half-chair conformation in the free base, but this was altered to an envelope conformation on protonation of the nitrogen atom (49). R I

CH,O'19 Erythristemine

56 R = H Cocculine 52 R = CH,O Coccutrine

The crystal structures of the alkaloids containing a hydroxyl group at C-2 have not been determined. The stereochemistry of erythratine (42) was established as 2R,3R,5S by Barton et al. (19) and that of erythratidine (39) as 2S,3R,5S by the same group (21)on the basis of optical rotation and N MR data for both pairs of C-2 epimers (see Section II,C,4b). The configuration at C-2 for erysosalvine (45), erysotine (48), and erysopitine (50) has not been defined. The absolute stereochemistry of other alkaloids rests on comparison of their CD and NMR characteristics with those of alkaloids of known stereochemistry as well as on chemical interconversions. 2. Spectral Characteristics a. Infrared and UV Spectra. The 1,6-diene alkaloids show IR absorbances a t 1610 cm-' and UV absorbances around 285 (dioxygenated aromatic ring) and 230-235 nm (diene). The 8-0~0-1,6-dienegroup exhibits a lactam absorbance at 1665 cm-' and an additional UV absorbance at 256 nm arising from the dienone chromophore (21). The Al(6)-alkene group absorb in the UV around 225 nm, whereas the enone group usually shows UV absorbance around 230 nm and IR absorbance in the region of 1675-1698 cm-'. Erysodienone (58) exhibits UV

1.

E R Y ? . H R / N A AND RELATED ALKALOIDS

9

absorbances at 240-242 and 285nm and IR bands at 1672, 1655, and 1614 cm-' (34). b. Circular Dichroism. The 1,6-diene alkaloids exhibit strong positive Cotton effects and previous attempts to relate this to the absolute configuration, using diene rules, have led to assignments of configuration opposite to that found by X-ray analysis. An explanation for the failure of the diene rules for Erythrina and other systems has been advanced. The allylic methoxyl system (at C-3) has helical chirality opposite to that of the diene chromophore, and it appears that the sign of the diene Cotton effect is determined by the former group (50). Members of the A1(6)-alkene group also show a positive Cotton effect, and this was used to assign the absolute configuration of cocculine (56) and cocculidine (54), later supported by X-ray analysis (51, 52). c. Mass Spectrometric Characteristics. Because of the heavy reliance on MS identification of Erythrina alkaloids, several studies of their fragmentation patterns have been made. A comprehensive analysis of the fragmentations of erythrinanes was described by Migron and Bergmann (53)but is not discussed here. The MS of a variety of Erythrina alkaloids were studied by Boar and Widdowson (54) who proposed fragmentation schemes based on the usual techniques of accurate mass measurement of major ions and on metastable analysis. Further elaboration was made through the use of deuterium-labeled samples. Only the general MS features will be discussed here, as several detailed schemes can be found in the literature (15, 21, 54). All the 1,6-diene structures show a simple fragmentation pattern, summarized in Scheme 1. The main pathway involves loss of the allylic substituent at C-3 which allows distinction between the isomeric groups. For example, erythravine (3) can be distinguished from erysovine (5) and erysodine (7) by the nature of RO. However, distinction between pairs isomeric in ring D, that is, between 5 and 7 or between 6 and 8, cannot be made by MS alone.

+ m 2m~ ~ .c trj CY

IcJn71+. RO

SCHEME I . Mujor

l+.

RO

M S ~ f r a g i ~ ~ c ~ t ~ tpatterii u t i o r i fhr

1.h-drene srries (R = H,CH, or TMS)

The A1(6)-alkene alkaloids show a more complex fragmentation pattern in which loss of the allylic substituent is of only minor importance. A major

10

S. F. DYKE AND S. N. QUESSY

fragmentation pathway involves a retro-Diels-Alder reaction (path a in Scheme 2), and an alternative pathway involves loss of the C-2-C-3 unit (path b in Scheme 2). Each ion subsequently loses a hydrogen atom. The nature of the substituent at C-3 is readily established from path a and for all known Al(6)-alkene types is methoxyl. The substituent at C-2 is then defined by M + -C3H,0R, where R is usually H or OH (15, 16, 54). Distinction between A1(6)-alkene types and the isomeric A2( I)-alkene types [e.g., isococculine (37)] can be made by MS. For example, 37 exhibits a fragmentation pattern similar to the l ,6-diene types.

/ -C,I!,O

q7’+

\b -C,H ,OR\

//

HC SCHEME 2. Mujor M S Jkugmentutionpatiern for A1(6)-aNceneseries (R = H or OH)

The enone alkaloids, such as erythratidinone (40), do not undergo fragmentation by path b in Scheme 2, but exhibit loss of CO as shown in Scheme 3 (21, 54). Alkaloids containing 1 I-hydroxyl or 11-methoxyl groups show additional ions arising from loss of H,O or CH30H, respectively, from the

C * , O V

C

0

I1

0

CHO SCHEME

3. Frugmenmthn puirern .for enone f?‘pes

1.

ER YTHRIiVA A N D RELATED ALKALOIDS

11

parent ion (12, 20, 22, 46). The 1 1-oxoalkaloids show a characteristic fragmentation ion resulting from cleavage at ring C. For example, the TMS derivative of 11-oxoerysodine (29) exhibits a characteristic ion with m/e 222 (12)(see Scheme 4).

SCHEME 4

d. NMR Characteristics. Once the erythrinane skeleton is established, it is possible to deduce the complete structure from detailed NMR data with the aid of decoupling, NOE, and INDOR techniques. Assignments of stereochemistry at C-2, C-3, and C-11 have been made from the values of coupling constants by comparison with data from related alkaloids in the group, for which crystal structures have been determined (19-21,43,55-58). In a review of the NMR of the alkaloids (59) coverage is given to the Erythrina group. Protons attached to C-14 and C-17 in the aromatic ring can be readily distinguished. Irradiation in the benzylic region causes a sharpening in the signal due to H-17 (19),whereas irradiation of the axial C-3 proton produces about 15% NOE for the signal due to H-14 (57). The NOE effect arises because H-14 lies over ring A and spatially near the axial C-3 proton. The INDOR technique can also be used to locate H-14 (58). Combinations of these techniques have been used to determine the position of substituents in the aromatic ring (43,56-58). For example, dihydroerysovine (44)was found to contain methoxyl and hydroxyl groups at C-15 and C-16, and their relative positions were determined by NMR. The resonance for the proton at C-14 (6 6.99) was located by INDOR and confirmed by NOE. When the other aromatic proton (6 6.30) was monitored a NOE and decoupling effect was observed at the aromatic methoxyl signal (6 3.27), but this effect was not observed when the C-14 proton was monitored. This established that the methoxyl group was near C-17, i.e., at C-16 (57). The usefulness of the technique has also been demonstrated with cocculidine (54), which is of firmly established structure (60).The position of the aromatic methoxyl group could be established using INDOR by monitoring each aromatic proton in turn. It was found that the aromatic proton (6 6.93) with J value of 2.5 Hz was spatially near the C-3 axial proton,

12

S. F. DYKE AND S. N. QUESSY

hence the methoxyl group was at C- 15 (58).This was supported by synthesis of the alternative C-16 methoxyl isomer (63) and comparison of its NMR spectrum using INDOR and NOE techniques (58).

HO

44 Dihydroerysovine

54 R' 63 R'

= =

H , R Z = CH,O Cocculidine CH,O, RZ = H

The stereochemistry at C-3 in the 1,6-diene series can be determined from the value of J 2 , 3 . In all cases this value is small, about 2 Hz, suggesting that the proton at C-3 is quasi-axial and hence that the methoxyl group is equatorial. This assignment is supported by the observation of diaxial couplings (J3ax,4ax z 10 Hz) between protons at C-3 and C-4 (19-21,55, 56). The stereochemistries at C-2 and C-3 in erythratine (42) and erythratidine (39) were established partly by NMR (19, 21). With the aid of INDOR the value of J3,4was found to be 5.5 and 12 Hz for both alkaloids, suggesting that the C-3 proton was axial in both cases, This was supported by interconversion studies (see Section II,C,4b). In erythratine (42) the value of was found to be 7.5 Hz and in its C-2 epimer 3-4 Hz. This suggested stereochemistries A and B, respectively (as shown in Fig. 5), for erythratine and its C-2 epimer. The values off,,, (4.25 Hz) and 52,3(4.25 Hz) in erythratidine (39) suggested that the proton at C-2 is equatorial and that the stereochemistry is that of B in Fig. 5. Thus, 42 and 39 have opposite stereochemistry at C-2. The position of the extra methoxyl group in erythristemine (19) was established at C-11 when it was found that irradiation of the proton at C-17 caused slight narrowing of the methine signal at 6 3.94. The shift of this

OH A

B

FIG.5 . Stereochemistries in ring A

1.

ER YTH-HRINA A N D RELATED ALKALOIDS

13

methine suggested an attached methoxyl group, thus identifying the methoxyl group at C-l 1. This was confirmed by X-ray analysis, which also gave the absolute configuration. The value of J,,,, (4 Hz) was found with the aid of INDOR since the methoxyl signals partly obscured the methine signal. The stereochemistry at C-1 1 in the other 11-oxygenated alkaloids have been related to erythristemine by comparison of the value J,,,,,, which all lie around 4 Hz, suggesting the same configuration at C- 11 (43).

,

3. 1,6-Diene Series

a. Simple Types. Resolution of the final ambiguities in the structures of erysodine (7), erysovine (5), and erysonine (8) was discussed in the previous review (1)of this treatise on the basis of a preliminary communication (18). The complete details of this work have now been published (19). Erysotrine (l),long known only as a synthetic product, was isolated from E. suberosa Roxb. in 1969 (38,39) and has since been identified in a large number of Erythrina species (12, 16, 17, 31, 33, 44). An investigation of E. folkersii by Krukoff and Moldenke by GC-MS (15) revealed the existence of two new 1,6-diene alkaloids erythravine (C,,H,,NO,) and erysoline (C,,H,,NO,). Erythravine was identified as 3-desmethylerysotrine (3) from its MS fragmentation pattern. Erysoline appeared to bear a similar relationship to either 5 or 7. Demethylation of samples of both 5 and 7 resulted in the identification of erysoline with 3-desmethylerysovine (6) (see Scheme 5), from GC retention time and spectroscopic comparisons. R'O

R20

CH,O"

5 R' 7 R'

= CH,, = H,

R2 = H Erysovine

R Z = CH, Erysodine

HO' 6 R' 8 R'

= CH,, = H,

R2 = H Erysoline R 2 = CH, Erysonine

SCHEME 5

Erysophorine (13)was isolated from the water-soluble extract of the seeds of E. arborescens Roxb. (37). The molecular formula C,,H,8N,0,C1 was established by analysis. The mass spectrum of 13 gave no molecular ion but exhibited fragments consistent with a 1,6-diene Erythrina alkaloid and a carboxylated indole-3-alkylamine. Erysophorine appeared to be a combined alkaloid, and its UV spectrum was similar to that of an equimolar mixture

14

S. F. DYKE AND S. N. QUESSY

13 R = Hypaphorine

64 Hypaphorine

of 5 and hypaphorine (64). The presence of three quaternary N-methyl groups and two methoxyl groups was evident from the NMR spectrum. Hydrolysis of 13 in dilute hydrochloric acid proceeded readily affording 5 and 64, and erysophorine was deduced to be erysovine linked by esterification at C-15 to hypaphorine. This was the first example of a phenolic Erytkrinu alkaloid esterified to an acid other than sulfoacetic or hexuronic acids. Recently, another combined alkaloid has been isolated, this time from the seeds of E. oariegata L. (43).Hydrolysis of the alkaloid yielded 7 ; and since 64 was also positively identified in the extracts, it is possible that this alkaloid could be the complementary positional isomer of erysophorine. b. 8-0x0Types. Ito's group isolated two new alkaloids, erythrabine (C,,H,,NO,) (32)and erysotramidine (C,,HzlNO4) (2), from E. arborescens Roxb., which were both of higher oxidation level than the 1,6-diene types (27,28).The structures were assigned on the basis of spectroscopic and chemical investigations. Later, a similar alkaloid, crystamidine (C, *HI,NO,), was isolated from E. crysta galli L.; and MS data indicated an alkaloid of the 1,6-diene type. The NMR spectroscopic data established the presence of a methylenedioxy group, a methoxyl group, and two para-oriented aromatic protons. The UV and IR data suggested a heteroannular conjugated system, and the carbonyl group ( v ,,,1695 cm-I) was placed at C-8 after detailed examination of the NMR spectrum. The structure of crystamidine (33)was proved by correlation with erythraline (4), (see Scheme 6). Catalytic reduction of 33 gave a product (65) identical to that obtained by oxidation

33 Crqstdmidinr

65

SCHEME 6

4 Erjthralme

1.

E R Y T H R I N A A N D RELATED ALKALOIDS

15

of 4 with potassium permanganate, followed by catalytic reduction (32).This also established the stereochemistry at C-5 and C-3 in crystamidine. Two other 8-0x0 derivatives [coccoline (17) and coccolinine (15)] have been isolated from Cocculus species, and these are discussed separately later (see Section 11,C,5). It has been recognized that, since oxidation at C-8 is relatively facile, the 8-0x0 derivatives are probably artifacts produced in the drying process (55). Both 10,ll-dehydroerysovine (34) and 10,lldehydroerysodine (35), which have been detected in GC-MS studies, are thought to be artifacts produced by an elimination reaction from 11-methoxyor 11-hydroxyalkaloids (12).

c. C-11 Oxygenated Types. The first Erythrina alkaloid with oxygenation at C-11 was isolated from E. lysistemon Hutchinson and given the name erythristemine (20). The molecular formula C,oH25N04was established by analysis and confirmed by high resolution MS. The IR spectrum showed no hydroxyl nor carbonyl absorbances and the UV spectrum was almost identical to that of erythraline 4. The MS data were consistent with a 1,6-diene structure containing an additional methoxyl group in ring C or D. Careful examination of the NMR spectrum with the aid of INDOR (see Section II,C,2d) suggested that the methoxyl group was at C-11. Structure 19 was proposed and confirmed by X-ray analysis of the 2-bromo-4,6dinitrophenolate salt (20,48),which also established the complete stereochemistry shown in structure 19.

19 Erythristemine

A little later 11-methoxyerythraline (22), isolated as a pale yellow gum, was obtained from the same species (46).The spectroscopic properties of 22 were similar to those of erythristemine except that a methylenedioxy group was present instead of the two aromatic methoxyl groups in 19. The NMR spectrum of 22 could be interpreted completely without the necessity of INDOR, as the signals did not obscure one another. The coupling data were consistent with H-3 being quasi-axial, as in 19. At about the same time, Ito et al. (22) reported the isolation of an alkaloid C,,HIgNO4 from E. indica Lam. (now classified as E. variegata L.) to which

16

S. F. DYKE AND S. N. QUESSY

they gave the name erythrinine. The IR spectrum showed a hydroxyl function, which was further demonstrated by the preparation of an 0-acetate, and the UV and MS data suggested a 1,6-diene structure. Catalytic reduction of erythrinine followed by hydrogenolysis over Palladium black in aqueous hydrobromic acid gave tetrahydroerythraline (66) (see Scheme 7). This established the basic structure and the stereochemistry at C-5 and C-3. The hydroxyl group was placed at C-1 1 because of the ease of hydrogenolysis, and since oxidation gave a ketone in conjugation with the aromatic ring (vmaX1680 cm- I ) . Therefore, structure 21 was established for erythrinine although the configuration at C-1 1 was not determined. Erythrinine has since been isolated from E. x bidwillii (24, 25), E. crysta galli (30, 32), Eryrhrina species from Singapore (31),and old world species (12). OH (iJPtO,-H,

(ii) P d ~H , HBr ,

66 Tetrahydroerythraline

21 Erythrinine

SCHEME I

The name erythrinine had been assigned to an alkaloid isolated in 1969 from E. lithosperma (61). The formula for this alkaloid was found to be C30H,,N,0,, and little structural information was known except that it contained four methoxyl groups and one amide function and that all four nitrogen atoms were present in rings. No further elaboration of the structure has been reported. Erythrascine (C,,H,,NO,) was isolated from the seeds of E. arborescens Roxb. collected in India (36).The MS fragmentation pattern was typical of a 1,6-diene type, and the IR spectrum exhibited an absorbance at 1728 cmwith no hydroxyl absorption. The MS and NMR spectroscopic data were consistent with erythrascine being 11-acetoxyerysotrine (20). Soon afterwards the Japanese group reported the isolation of 1 I-hydroxyerysotrine (CI9Hz3NO,)from the seeds of the same species (27). Structure 18 was established from spectroscopic and chemical correlation studies. It is not clear whether both alkaloids 18 and 20 are natural products, since the possibility that erythrascine was an artifact was not discussed and since no other 11-acetoxyalkaloids have been reported. Further studies by Ito and co-workers (31) have resulted in the isolation of erythrinine (21) and 11hydroxyerysotrine (18) from other Erythrina species. Recently, examination

1.

E K Y T H R I . Y A A N D RELATED ALKALOIDS

17

CH,O’ 20 R 18 R

= CH,CO Erythrascine = H ll-Hyroxyerysotrine

(erythrartine)

of the flowers of E. uariegata L. collected in Egypt resulted in the isolation of an alkaloid (CI9H,,NO,) to which the name erythrartine was given. Erythrartine was deduced to be 1l-hydroxyerysotrine (18) on spectroscopic evidence (43).The authors were unable to compare their sample with that reported by the Japanese group. The statement that 18 is the first example of an ll-oxygenated Erythrina alkaloid from E. variegata (43) is incorrect since erythrinine (21) was isolated by Ito et al. in 1970 from E. indica Lam (22),a synonym for E. variegata L. (14). It has been suggested (43) that the absolute configurations of the 11oxyerythrina alkaloids 18, 20, 21, and 22 are the same as that of erythristemine (19), that is llj? (or 1lS), on the basis of correlation of optical rotations and since the value of J,,,,, is the same. Examination of old world Erytlzrina species by GC-MS has revealed the existence of a larger variety of 1 1-oxygenated alkaloids 23-31 (see Fig. 2), including examples with 1I-0x0 functions. The assignment of the structures of these compounds rests entirely on MS evidence (12)(see Section II,C,2c). 4. A1(6)-Alkene Series a. Without C-2 Oxygenation. Dihydroerysovine (44) and dihydroerysodine (47) have been isolated from Cocculus species (see Section II,C,5), although dihydroerysotrine (38) is still known only as a reduction product of erysotrine (1). Erythramine (47), previously known as a reduction product of erythraline (4) (62).was detected in E. crysta galli and in E. glauca Willd. (now classified as E. fusca Loureiro) (19). Since there was insufficient sample isolated, erythramine was prepared from erythraline and its structure established by NMR. In addition, erythramine was prepared by an alternative route from erythratine (42) (see Scheme 8) by chlorination and reduction. Since 42 could also be converted to erythraline (19),an alkaloid of known stereochemistry (631, the position of the double bond as well as the configurations a t C-3 and C-5 in erythramine were firmly established.

18

S. F. DYKE AND S. N. QUESSY

41 Erythramine

42 Erythratine SCHEME 8

Several other alkaloids like 41 but with abnormal substitution pattern in ring D, have been isolated from Cocculus species and are discussed in Section II,C,5. b. With C-2 Oxygenation. Erythratinone (43), which was synthesised by oxidation of 42 (19), has been isolated by Barton et al. (19) as a major alkaloid in E. crysta galli. Further work by the same group has resulted in the isolation of a similar alkaloid erythratidinone (C, 9H23N04)from E. lithosperma Blume (now classified as E. variegata L.) (21). This alkaloid exhibited spectroscopic data similar to those,of 43 and erythratidinone was established as a 1(6)-en-2-one structure. The NMR data established the presence of three methoxyl groups and the dpbstitution pattern of ring D. With the aid of INDOR it was concluded that the proton at C-3 was axial from coupling values of 5.5 Hz with H-4e, and 12.0 Hz with H-4a. Structure 40 was proposed for erythratidinone since borohydride reduction (see Scheme 9) gave the known erythratidine (39, [a],, 273-) and its C-2 epimer ([.ID 142"). Erythratidine had been isolated earlier from E.Jufcata Bentham (64),but its stereochemistry was unknown. By application of Mills' rule (65)39 was assigned the 2 s configuration (as 39), which was opposite to that established for erythratine (42)by the same group (19). Further evidence

+

+

0 40 Ervthratidinone

OH

39 Erqthratidine ( + C-2 epimer)

SCHEME 9

1 Erysotrine

1.

ERYTHRINA AND RELATED ALKALOIDS

19

for the configuration at C-2 in 39 came through the analysis of its NMR spectrum (see Section II,C,2d). The absolute configuration at C-5 in both 39 and 40 was established by dehydration of 39 to give erysotrine (1) (see Scheme 9) along with 2-chlorodihydroerysotrine. A second enone alkaloid (CI8H,,NO,) was isolated from E. lithospernza Blume in the same study and identified as 3-desmethoxyerythratidinone (57) by the similarity of its spectroscopic properties to those of erythratidinone (40). In the first GC-MS examination of Erythrina species, several new A1 (6)alkene-type alkaloids were discovered in E. salvi$ora Krukoff and Barneby (15). Erysotinone (49), previously known only as a synthetic racemate (66), was identified from its MS fragmentation pattern. The substitution pattern in ring D was established by conversion of the isolated alkaloid to dihydroerysodine (47)which was prepared from a sample of erysodine (7)(see Scheme 10). Another G C fraction which gave an identical MS to that of 49 was assigned the isomeric structure 46 and given the name erysosalvinone. A further fraction exhibiting a n enone fragmentation pattern similar to both 46 and 49 but with a molecular ion at 58 amu higher, due to an extra TMS (67) and one fewer CH, (15) group, was assigned structure 51 and named erysoflorinone. Fractions with MS fragmentation patterns similar to that of erythratidine were isolated and one identified with the reduction product of erysotinone (49). This product 48 was previously prepared from 49 by Barton et al. (68) and given the name erysotine, but neither erysotine (48) nor erysotinone (49) had been previously obtained from natural sources. Erysotine was found to have an N M R spectrum similar to that of erythratidine (39),and methylation of 48 using diazomethane gave a product that had identical melting point and G C retention time to that of 39 (see Scheme 11). In view of the fact that the structure given by Millington et al. (15) was that of 2-epierythratidine rather than 39, their stereochemistry for erysotine was also incorrect. This would seem to suggest that erysotine, like erythratidine, has the 2 s configuration; however the structures given by Millington et al. for both erysotine and erythratidine (Fig. 6 in ref. 1 5 ) were of the 2R configuration [as in erythratine (42)]. The alternative positional isomer [related to erysosalvinone (46)] was also identified in this study and named erysosalvine (45). Erysopitine (C,,H,,NO,) was isolated from E. uariegata L. and its structure (50) assigned from spectroscopic evidence (35).Conversion of 50 to erysotrine (1) (see Scheme 12) established the stereochemistry at C-3 and C-5, but the configuration at C-2 has not yet been defined. Of biogenetic interest (see Section V,A) was the isolation of erysodienone (58) along with N-norprotosinomenine (67) and protosinomenine (68) from E. lithosperma Blume (now E. variegata L.) (34,35).Erysodienone had been previously synthesised (54, 66, 6H), but this was the first report of its isolation

0 49 R’ 46 R’ 51 R’

= = =

H, RZ = CH, Erysotinone CH,, R Z = H Erysosalvinone R 2 = H Erysoflorinone

47 Dihydroerysodine

7 Erysodinc

SCHEME 10

49 Erysotinone

48 Erysotine

(

+ C-2 epimer) SCHEME 11

39 Erythratidine

1.

E R Y T H R I N A AND RELATED ALKALOIDS

21

CH,O

HO

OH 50 Erysopitine

1 Erysottine

SCHEME 12 HO

0

CH30 cH30?R OH

58 Erysodienone

67 R = H 68 R = C H 3

from plant material. Identification of 58 was made by comparison of its melting point and spectroscopic properties with the reported data and by reduction to the known transformation product erysodienol(35). 5. Abnormal Alkaloids from Cocculus Species Only 3 of the 12 species of Cocculus (Menispermaceae) have been examined for alkaloids and most studies have concerned C. laurifolius, which has yielded the greatest number of alkaloids (see Table I) (51, 55-58,60, 69-76). The Erythrina-type alkaloids obtained from Cocculus are abnormal in the sense that they contain no oxygen function at C-16, the only exceptions being dihydroerysovine (44), dihydroerysodine (47), and erythroculine (53). Erythroculine is, however, unusual in that it has a methoxycarbonyl group at C-16. The two alkaloids isococculidine (36) and isococculine (37) are of the A2( 1)-alkene type rather than the A1 (6)-alkene type. The insecticidal alkaloid cocculolidine (61), a lower homolog of B-erythroidine (60) (see Fig. 4), was mentioned in the previous review ( 1 ) where its isolation from C. trilobus DC was reported. It has now been isolated from C. carolinus DC, a species native to the Southeastern United States (69).

22

S. F. DYKE A N D S. N. QUESSY

TABLE I ERYTHRIXA ALKALOIDS FROM Alkaloid

mP( C )

Cocculine Isococculine Cocculidine Isococculidine Coccutrine Coccoline Coccolinine Coccuvine Coccuvinine Erythroculine Cocculitine Dihydroerysovine Dihydroerysodine Cocculolidine

217-218

~

86-87 (93-95) 95-96 263 -265 245-246 174- 175 137-1 38 103- 104 193-196b.C 142-1 43 h

208-209 144- 146

COCCLLUS SPECIES

[.ID

Plant source‘

A B C A A A B

+271

+ 260 + 124 + 232 + 233

A

A A A A A B A B C

~

+ 194 + 93 + 233 + 224 + 273

Ref. 51,55

60 h9

70 51, 55, 58

55 60 55

71 72 56

73 74 57 75 76 69

“A. C. luurfolius DC (leaves); B, C. trilobus DC (leaves); C, C. carolinus DC (fruits). Oil. Styphnate.

Cocculine (C, , H 2 , N 0 2 ) and cocculidine (Cl8H2,NO,) were isolated from C. laurijolius in 1950 (77) but escaped mention in previous reviews of this treatise because only a partial structure, unrelated to the Erythrina alkaloids, had been advanced (78). On the basis of the spectroscopic properties of the alkaloids and their Hofmann degradation products, structures 56 and 54 (without stereochemistry) were proposed for cocculine and cocculidine, respectively (79); however, a different group (80) proposed structures 69 and 70, respectively, on the basis of similar evidence. The

CH,O’ 56 R = H Cocculine 54 R = CH, Cocculidine

69 R = H 70 R = C H ,

1.

E R ) TliRI,\ A A N D RELATED ALKALOIDS

23

AcO

56 Cocculine

71

SCHEME13

former group established the spiro structure of 56 by conversion to the 0 , N diacetate 71 (51) (see Scheme 13), and X-ray analysis of the hydrobromide salts of 56 and 54 established the structures originally proposed (51, 52). Although the absolute stereochemistry was stated to be 3 R 3 the structures were ambiguously represented as the mirror image of this configuration. A rigorous definition of the absolute configuration of cocculine was reported by McPhail and Onan in 1977 (49) whereby stereostructure 56 (i,e., 3R,5S9 was established for cocculine. It follows that cocculidine has stereostructure 54 since it has been demonstrated that methylation of cocculine using diazomethane gives cocculidine (77). Cocculine has also been isolated from C. trilobus (60)and C. carolinus (69).

52 Coccutrine

53 Erythroculine

A related alkaloid coccutrine (CI8H,,NO,) was isolated from C. trilobus (60)and structure 52 established spectroscopically, with the positions of the aromatic hydroxyl and methoxyl groups being defined by X-ray analysis. Coccutrine is the only example of an Erythrinu alkaloid containing an oxygen function at C- 17. An unusual alkaloid, erythroculine (C,,H,, NO,) was obtained from the leaves of C. luurifolius (67)and its structure (53) deduced from spectroscopic and degradative evidence (73). The MS data were consistent with a Al(6)alkene structure and the IR spectrum exhibited an absorbance at 1710 cm-'. The N M R spectrum established the presence of three methoxyl groups and two para-oriented aromatic protons. Reduction of 53 gave erythroculinol

53 Erythroculine

I

BC'I, CH,CI,

74

72 Erythroculinol

!

(I) AC,O ( i t ) yon Braun (iii) L A H (iv) CH,O,'NaBH,

&

NCH3

73

SCHEME 14

75

1.

25

E R Y T H R l N A A N D RELATED ALKALOIDS

(72) (see Scheme 14) which contained an IR absorption attributable to a hydroxyl group, but no carbonyl band was observed. Since one of the methoxyl groups in the NMR spectrum had disappeared, a methoxycarbonyl group was established. Demethylation of 53 gave a phenolic base 73 (Scheme 14)which showed a large bathochromic shift in the UV spectrum. This led to the assignment of the methoxyl function in 53 ortho to the methoxycarbonyl group, and the position of these groups was made on the basis of detailed NMR studies, including the observation of deuterium exchange ortho to the methoxyl group in erythroculinol. The environment of the nitrogen atom was established by Hofmann degradation of 72 (Scheme 14) and spectroscopic analysis of the degradation product 74. Erythroculinol was degraded by a combination of von Braun and Hofmann methods (see Scheme 14) to the biphenyl 75, whose structure was proved by an unambiguous synthesis. Finally, the stereochemistry at C-3 and C-5 was established by transformation of erythroculine (53) to tetrahydroerysotrine (76) as shown in Scheme 15. The presence of the methoxycarbonyl group in 53 is interesting from a biogenetic point of view.

i

53

performic acid

76 Tetrahydroerysotrine SCHEME 15

Continued examination of the pharmacologically interesting species C. laurifolius, particularly by Singh et al. (55,56,70-72, 74) has led to the isolation of more Erythrina alkaloids that have structures related to cocculine (56) and cocculidine (54). Coccuvine (C, 7H19N02) and coccuvinine (C,,H,,NO,) were found to be of the 1,6-diene type (56, 72) and the structures 16 and 14, respectively, were established on the basis of spectroscopic evidence and chemical interconversions. Methylation of coccuvine (16) (see

26

S. F. D Y K E AND S. N. QUESSY

Scheme 16) gave coccuvinine (141, which was reduced catalytically to give cocculidine, the structure and absolute stereochemistry of which was already established. The 8-0x0 counterparts of both coccuvine and coccuvinine were also isolated and given the names coccoline and coccolinine. Structures 17 and 15 (see Fig. 2) were assigned on the basis of spectroscopic studies including detailed examination of NMR spectra (55, 71). In addition methylation of 17 gave 15. The stereochemistry at C-3 was determined from coupling-constant data (see Section II,C,2d)and the configuration at C-5 was assumed. It was suggested, however, that 17 and 15 were artifacts produced during the drying process.

HO

9% CH,O p

&izHH1,

-

CH,O~’

’

16 Coccuvine

-

CH,O-’

’

CH,O

-;I CH,O,’

14 Coccuvinine

54 Cocculidine

SCHEME16

Two further alkaloids, isococculine (C, ,H2 NO2) and isococculidine (C, sH2,N02),were isolated and found to be isomeric with cocculine 56 and cocculidine (54), but were discovered to have novel structures with respect to the position of the double bond (55, 70). Structures 37 and 36 for iso-

37 R = H Isococculine 36 R = CH, Isococculidine

55 Cocculitine

cocculine and isococculidine, respectively. followed from the analysis of the physical data. For example, the UV spectrum of 36 showed an isolated double bond, but the MS fragmentation pattern was similar to that of the 1,6-diene Erythrina structure rather than the A1(6)-alkene type. The A2(1)alkene structure was supported by the NMR spectrum which exhibited two olefinic protons at 6 6.06 and 5.85 ppm ( J , , 2 = 10.5 Hz). The absolute stereochemistry was not determined since a correlation between 36 and cocculidine (54) through their dihydro derivatives was not possible because

1. t R > THRl.tA

A N D RELATED ALKALOIDS

27

of the resistance of 54 to hydrogenation (55).However, the configurations at C-3 and C-6 were supported by coupling-constant data obtained from the NMR spectrum. A new alkaloid cocculitine (C,,H,,NO,) was isolated recently from C. laurijolius (74). The IR spectrum indicated the presence of a hydroxyl group (3460 cm- ’) which was further established by the formation of a mono-O-acetate (1715 cm-I). The NMR spectrum of cocculitine was very similar to that of erythratine (42),except in the aromatic region. The aromatic methoxyl group was located at C-15 on the basis of detailed decoupling experiments, and the stereochemistry at C-3 was determined from the coupling data, which suggested that the proton at C-3 was axial. A value of 8.5 Hz for J,,, suggested that the proton at C-2 was also axial and hence structure 55 was proposed for cocculitine. Only two “normal” Erythrina alkaloids have been isolated from Cocculus species, dihydroerysodine (47) (75) and dihydroerysovine (44), the latter recently from C. trilobus (57).Neither alkaloid has been found in Erythrina species. The structure 44 for dihydroerysovine was deduced from the spectroscopic evidence and by methylation using diazomethane to give the known dihydroerysotrine (38). The positions of the aromatic substituents were determined by detailed N M R experiments using NOE and INDOR techniques (see Section II,C,2d).

47 Dihydroerysodine

44 Dihydroerysovine

111. Homoerythrina Alkaloids

A. OCCURRENCE AND ISOLATION The C-Homoerythrina alkaloids are a relatively recently identified group, the first examples being isolated and identified from Schelharnnzera ~ ~ ~ u F. ~MueI1. c uin /I968 ~ (81). ~ ~Homoerythrina alkaloids have been isolated from all three species of Schelhanziwera (Liliaceae), in which they constitute a further addition to the various biosynthetically related alkaloids within the family Liliacea (82-85); from the leaves of species of Phelline (Ilicacea), where their presence raises some doubts about the taxonomic classification of the genus (86-88); and from the roots and stems of species

28

S . F. DYKE AND S . N. QUESSY

of Cephalotaxus (Cephalotaxaceae), particularly C. wilsoniana Hayata in which they are the major alkaloids (89-91) (see Table 11). Many members of the Homoerythrina group occur with their C-3 epimers, in contrast to the Erythrina group, and despite the fact that they appear in relatively few plant species, over 20 individual Homoerythrina alkaloids have been isolated, although the structures of two of them remain incomplete because of insufficient amounts of samples. Those alkaloids of known strucTABLE I1 PHYSICAL PROPERTIES OF HOMOERYTHRINA ALKALOIDS Alkaloid

Formula

m P ( C)

88 89 8-Oxoschelhammeridine 1 la-Oxoschelhammeridine Schelhammeridine 3-Epischelhammeridine 86 (Alkaloid 6) Schelhammericine 3-Epischelhammericine

186-1 88 133 170-171 151 -173 118 131-133 126 76-77 169-172' 170- 17I'

Ma (Alkaloid A)

188-1 89c 260d 173- 174 182-185 184-185 e 152-153 150-152 150-151 244 decd e e I43 -145' 100-1 01

~

84b (Alkaloid 1) Schelhammerine 3-Epischelhammerine 96 83 (Alkaloid B)

Wilsonine 3-Epiwilsonine 82a 82b 85 (Alkaloid 2) 97 (Alkaloid 5)

[.I; f 143

+ 140

+ 35

- 41

108 f24 f63 +I22 f 123 +98 I23 - 100 15 186 + I67 172 f76r +I11 +115 -51 58 +I18 + 122 72 +91

-

+ + + +

+ +

Plant sourceh (Ref.) E E A A A A D A A, B, C D F, G A D A A D F A, C F G D F F, G D D

Solvent: chloroform. A, S . peduncula/a F. Muell: B, S. niul/iflora R. Br.; C , S. Uiidulatu R. Br.. D. P. coniosa Labill: E. P. billardieri; F. C. harringroiria K. Koch var. hurr.iiiy/oiiiu: G, C. wilsoniuna Hay. Picrate. Hydrochloride. Noncrystalline. Doubtful value due to impure sample.

1.

29

ERYTHRINA AND RELATED ALKALOIDS

ture are shown in Figs. 6 and 7. Within the three genera, the alkaloid profile is fairly distinctive, with only 3-epischelhammericine (81b) occurring in all three. The alkaloids have been isolated either by alcohol extraction of the dried plant material (82,90) or by ether extraction of the basified plant material (87). The crude mixture is then fractionated by countercurrent distribution, followed by chromatographic purification and recrystallization. The Homoerythrina alkaloids have not been reviewed before, except briefly in conjunction with Cephalotaxus alkaloids, with which they occur in Cephalotaxus species (9). Y

R' 77a 77b 78 79

Schelhammeridine 3-Epischelhammeridine 8-Oxoschelhammeridine 1 la-Oxoschelhammeridine

R2

-CH2-CH2-CH2-CH2-

R3

R4

X

Y

CH,O H CH,O CH,O

H CH,O H H

H, H2 0 H2

H2 H, H2 0

PIG. 6a. Homoerythrina alkaloids: 1,6 diene series

R2

80a 80b 81a

81b 82a 82b 83

Schelhammerine 3-Epischelhammerine Schelhammericine 3-Epischelhammericine 3-Epi-2,7-dihydrohomoerysotrine 2,7-Dihydrohomoerysotrine 2.7-Dihydrohomoerysovine

R2

CH2 -CH,-CH2-CH,CH, CH, CH, CH, CH, H ~~

R3

R4

X

CH,O H CH,O H CH3O H H

H CH,O H CH,O H CH,O CH,O

OH OH H H H H H

FIG.6b. Homoerythrina alkaloids: Al(6) alkene series.

30

S. F. DYKE AND S.

N. QUESSY

RZO

k4 R1 84a 84b 85

R2

3-Epi-6~,7-dihydrohomoerythraline -CH,6~,7-Dihydrohomoerythraline -CH CH, CH, 6a,7-Dihydrohomoerysotrine

R3

R4

CH30 H H

H CH,O CH,O

FIG.7a. Homoerythrina alkaloids: A2(1) alkene series

R4 R' 86 87a 87b

R2

3~-Methoxy-l5,16-methylenedioxy-6,7-epoxy- -CH2C-homoerythrinan-2(1)-em CH, CH, Wilsonine CH, CH, 3-Epiwilsonine

R3

R4

H

CH,O

CH,O H

H CH,O

FIG.7b. Homoerythrina alkaloids: epoxy- A2( 1) series

88 R = H 89 R = CH,

90 Phellibiline'

FIG.7c. Homoerythrina alkaloids : the homoerythroidines.

B. NOMENCLATURE Nomenclature for the Homoerythrina group is a problem because only a few of the alkaloids have been given trivial names. Since the structures of the Homoerythrina group parallel those of the Erytlzrina group we have

1.

31

EK > 7 H R I . V A A N D RELATED ALKALOIDS

decided to refer to the unnamed members as homo analogs of the corresponding Erythrina alkaloid. This has the advantage of illustrating the structural relationship between the two groups (as they are biogenetically related) and keeps the names relatively simple. When this is not possible the Chemical Abstracts system, which is based on the C-homoerythrinan ring 91, is used. We have used the Chemical Abstracts numbering system for the sake of consistency, even though it differs from that used in the literature (cf. 92).

11 6 % :s

14

7

3 2

91

2

92

C. STRUCTURE DETERMINATION 1. Spectroscopic Characteristics

In many ways the spectroscopic properties of the Homoerythrina group parallel those of the Erythrina series (cf. Section II,C,2). The UV and NMR characteristics are similar, particularly in rings A and B. The mass spectra of the 1,6-diene series show a simple fragmentation pattern, similar to that in the Erythrina 1,6-diene series, with the major fragmentation pathway involving loss of the allylic substituent (see Scheme 17). The A1(6)-alkene series shows a more complex fragmentation pattern, as do their A1(6)-alkene Erythrina counterparts. The same retro-Diels-Alder fragmentation occurs, but other important modes of fragmentation are initiated in ring C (see Scheme 18). As in the Erythrina group, the stereochemistry at C-3 may be assigned from coupling constant data; however, chemical shift data can also be used as an indicator of stereochemistry. For example, in the schelhammericine (81a) series (3S-methoxyl), the methoxyl resonance occurs at 6 2.74 ppm

32

S. F. DYKE AND S . N. QUESSY

Ic SCHEME

I

-CH,OH

18. Major fiagmentation pathway f o r A I ( 6 ) d k e n e - t y p eHomoerythrina alkaloids

with a quartet for the axial C-4 proton near 6 1.78 ppm. In the 3-epischelhammeridine (81b) series (3R-methoxyl), the methoxyl resonance occurs at 6 3.17 ppm, with an apparent triplet for the axial C-4 proton around 6 1.52 ppm. 2. Schelhammerine, Schelhammeridine, and Their C-3 Epimers The structural determination of the first Homoerythrina alkaloids, obtained from Schelhammera, was the subject of an elegant series of papers by the CSIRO group in Australia (81-85). Two major alkaloids from S. peduncufata F. Muell. were named Schelhammerine (C, ,H,,NO,) and ~ c h e l ~ a ~ ~ (CI9H2,NO3) e ~ ~ ~ i n e(82). The alkaloids had similar NMR characteristics in that both exhibited resonances attributable to a methylenedioxy group, a nonaromatic methoxyl group, and two para-aromatic protons ; but schelhammeridine contained two olefinic protons in its N M R spectrum and exhibited an isolated alkene absorption in the UV spectrum, whereas schelhammerine showed absorption arising from only one olefinic proton in the NMR spectrum, and the extra oxygen atom was found to be in a hydroxyl group. Furthermore, treatment of schelhammerine in pyridine with methanesulfonyl chloride gave schelhammeridine in 20% yield (see Scheme 19), revealing that the two alkaloids were structurally related. Since the nitrogen atom was tertiary, and evidence for N-methyl was not observed, a tetracyclic system was considered. The possibility that the fused heterocyclic rings were both six-membered was excluded through analysis

1.

E R Y 7 H R / , C A A N D RELATED ALKALOIDS

80a Schelhammerine

33

77a Schelhammeridine (20"f; yield based on recovered 80a)

SCHEME 19

of the signals for the C-7 and C-8 protons in the NMR spectrum of schelhammeridine, which clearly indicated a five-membered ring. The complete structure of schelhammerine (except for stereochemistry at C-2 and C-5) was deduced as 80a from a careful analysis of its 100-MHz NMR spectrum, with the aid of decoupling experiments. Values of 5.0 Hz and 3.2 Hz for J3,4ax suggested that the proton at C-3 was equafor J3,4eq torial; but a value of 3.0 Hz for J 2 , 3did not allow definitive assignment of the stereochemistry at C-2, although it suggested that the proton at C-2, was also equatorial. The absolute stereochemistry (as shown in 80a) was established by X-ray analysis of schelhammerine hydrobromide (92). The stereochemical assignments made from the NM R spectrum were further supported by the isolation of an alkaloid (alkaloid H) isomeric with schelhammerine, with similar UV and identical MS spectra. A value of 12 Hz for J3,4ah indicated that the proton at C-3 was axial, but lack of large transdiaxial couplings for J 2 , 3 suggested that the hydroxyl group at C-2 was axial, as in 80a. The alkaloid therefore had the structure 80b and is 3-epischelhammerine. The assignment of structure 77a for schelhammeridine followed from the NMR analysis and from the interconversion reaction (Scheme 19), which also established the absolute configuration at C-3 and C-5. In addition, a minor constituent (alkaloid G) was isolated, isomeric with 77a, having identical UV and MS spectra but with a value of 11 Hz for J3,4ax. The alkaloid therefore appeared to be 3-epischelhammeridine (77b), demonstrated by a series of interconversions summarized in Scheme 20. Vigorous hydrolysis of 77a in acid gave a complex mixture of products, the major one being the alcohol 93, That epimerization at C-3 had occurred was evident from the values of 3.5 and 12 Hz for J3,4in the N M R spectrum. A minor product with values of 2.0 and 4.8 Hz for J3,4was found to be the alcohol, with retention of configuration at C-3. Methylation of 93 gave 77b, and conversely acid hydrolysis of 77b gave 93 thus establishing the configurations at C-3 and C-5 in 77b (83).

34

S. F. D Y K E AND S.

77a

N. QUESSY

93 (70“,) ( + C-3 epirner lo“,)

77b

SCHEME 20

The two isomeric alcohols 94a and 94b were isolated and identified among the minor products of the hydrolysis reaction. This finding revealed that

94a R’ = OH, R 2 = R 3 = H 94b R’ = R’ = H, R 2 = OH 94c R’ = OAc, R 2 = H, R3 = AC

the “apo rearrangement,” which occurs on acid hydrolysis of the Erythrina alkaloids, does not occur with the Homoerythrina group, where a bridged biphenyl system is formed. The ease of cleavage of the N-C-5 bond in schelhammeridine is also unparalleled in the Erythrina series. When schelhammeridine was heated at reflux in acetic anhydride a single stereoisomer 94c was obtained. It was then shown that the stereochemical outcome of the acid-hydrolysis reaction was temperature-dependent, because of limited rotational freedom of the biphenyl system. Hydrogenation of schelhammeridine (77a) in acetic acid gave rise to five products, and the structures of four of them were determined spectroscopically (83). The two major products were the 2,7-dihydro- and the tetrahydro derivatives 81a and 95, respectively (see Scheme 21). Hydrogenolysis and N-C-5 bond cleavage products were also observed. It was found that the yield of the dihydro derivative 80a was increased when ethanol was used as the solvent for the hydrogenation. The 6a-configuration in 95 was assigned on the assumption that hydrogenation would occur from the less hindered a-side of the molecule. In the Erythrina group, this assumption proved to be incorrect ( I ) , so the configuration at C-6 in 95 and in the A2( 1)dihydro series (Section 111,C,5) remains to be proved.

1.

E R Y T H R I V A A N D RELATED ALKALOIDS

77a

35

81a (30',,) (Schelhammencine)

SCHEME21

3. Oxoschelhammeridines Two alkaloids (C,,H,,NO,) were isolated from S. pedunculata, of which one was a base and the other was nonbasic (84). The base (alkaloid J) exhibited an IR absorbance at 1665 c m p l and UV absorbances at 232 (3,100), 277 (4,600) and 313 nm (5,000), suggesting an aryl ketone. Comparison of its NMR spectrum with that of schelhammeridine revealed a lack of C-1 1 methylene protons and a downfield shift of the C-17 proton. The ketone function was therefore located at C-lla. The stereochemistry at C-3 was and the configuration at C-5 was assigned from the value of 4.0 Hz for J3,4ax assumed. Structure 79 was proposed for the basic alkaloid, which is therefore 1 1a-oxoschelhammeridine.

The NMR spectrum of the nonbasic alkaloid (alkaloid K) showed the C-7 olefinic signal as a singlet, in contrast to the usual multiplet, and there were no signals attributable to the protons at C-8. A downfield shift observed for the protons at C-10 was consistent with the expected deshielding effect of a carbonyl group at C-8, which also accounted for the nonbasic nature of the alkaloid. An intense IR band at 1685 c m p l also supported the lactam structure 78. The value of 5.0 Hz for J3,4ax supported the stereochemical assignment at C-3, but rigorous proof of the structure 78 was obtained by oxidation of schelhammeridine using mangenese dioxide to give 8-oxoschelhammeridine (78) (see Scheme 22). This established the configuration at C-5 and proved the stereochemistry at C-3.

36

S. F. D Y K E A N D S. N. QUESSY

CH,O

CH,O

77a Schelhammeridine

78

SCHEME 22

4. Schelhammericine and the A l(6)-Alkene Series Schelhammericine ( C ,,H,,NO,) was recognized as a A1(6)-alkene structure from its MS fragmentation pattern (see Section III,C,l) and structure 81a was determined through analysis of its NM R spectrum. Values of 3.5 and 5.0 Hz for J3,4 suggested that the proton at C-3 was equatorial. Schelhammericine was identified as the dihydro product 81a obtained on catalytic hydrogenation of schelhammeridine (refer to Scheme 2 1) (84). An isomeric alkaloid (alkaloid E) was isolated from S. pedunculata and found to be the major alkaloid in 5’. rnultzj2ora R.Br. (85). Values of 4.0 and 11 Hz for J3,4suggested that it was the C-3 epimer 81b of schelhammericine. Structure 81b was proved by identification of 3-epischelhammericine with 2,7-dihydro-3-epischelhammeridine(see Scheme 23) (84). Later on, another group reported the isolation of 81b from P.comosa, and was able to convert 3-epischelhammerine (80b) to 81b by chlorination and reduction, as shown in Scheme 23 (87). Cephalotaxus harringtonia var. harring ton ia has also yielded 3-epischelhammericine ( 9I ) .

(9 -.::-::Cy+ 0

-

CH,O,-

’

77b 3-Epischelhammeridine

CH,O,’

CH,O,’

,

OH Slb 3-Epischelhammericine

80b 3-Epischelhammerine

SCHEME 23

Other alkaloids in the Al(6)-alkene series have been reported. Two isomeric alkaloids (C,,H,,NO,) were obtained from Cephalotaxus harringtonia K. Koch var. harringtonia. Their spectroscopic properties closely resembled those of schelhammericine except that their NMR spectra revealed the presence of two aromatic methoxyl groups in place of the methylenedioxy group of schelhammericine. The alkaloids were therefore 3-epihomo-2,7-

1.

E R YTHR/.\ 1 A N D RELATED ALKALOIDS

37

dihydroerysotrine and homo-2,7-dihydroerysotrine, with structures 82a and 82b, respectively. Distinction between the two epimers was made on the basis of the NMR data (see Section III,C,l). The configuration at C-5 was considered the same as that in schelhammericine, since their optical rotations were of the same sign and magnitude (89).

R4

82a R ' = R 2 = CH,, R3 = CH,O, R 4 = H 82b R' = R Z = CH,, R 3 = H, R4 = CH,O 83 R ' = CH,, R2 = R' = H, R4 = CH,O

An alkaloid (C,,H,,NO,, alkaloid B) isolated from S. pedunculutu exhibited UV characteristics similar to those of schelhammerine (80a) and an IR absorbance at 3600 cm-' suggested a phenolic hydroxyl group. The NMR spectrum was similar to that of 3-epischelhammericine and revealed the presence of one aromatic methoxyl group, a phenolic proton, and paraoriented aromatic protons. The position of the phenol group was located at C-15 by an NMR experiment that involved deuterium exchange of the aromatic proton ortho to the phenol group. The remaining aromatic proton was broadened because of benzylic coupling and was therefore at C-17. The stereochemistry at C-3 was deduced from the observation of a large value and the configuration at C-5 was assigned by the sign and magfor J3,4ax, nitude of the optical rotation. The data were consistent with structure 83 for this alkaloid, which is therefore homo-2,7-dihydroerysovine (84). This same alkaloid was found in S. undulutu (85)and has also been isolated from C. harringtoniu var. hurringtoniu along with a similar base which, from its NMR spectrum was epimeric at C-3. However, the positions of the aromatic methoxyl and hydroxyl groups could not be defined because of a lack of pure sample, and partial structure 96 was proposed (89). H

CH,O' 96

97

38

S . F. D Y K E A N D S . N. QUESSY

An alkaloid (C2,H19N04, alkaloid 5 ) , isolated from Plicllinr c o m u a Labill., has a MS fragmentation of the A1(6)-alkene type. The N M R spectrum revealed the presence of three aromatic methoxyl groups, and the methoxyl group at C-3 was found to be equatorial from the large value of J3,4ax(1 1.5 Hz). The configuration at C-5 was assumed to be 5s on the basis of the sign and magnitude of the optical rotation. The partial structure 97 was proposed and it was suggested, on steric and biogenetic grounds, that the aromatic substitution pattern was 15,16,17-trimethoxy.

5. A2(1)-Alkene Series The first alkaloid of the A2(1)-alkenetype was obtained from S.peduncufata

(84). An alkaloid (CI9H,,NO3, alkaloid A) was isolated that was isomeric

with both schelhammericine (81a) and 3-epischelhammericine (Sib), but which clearly contained an allylic methoxyl group, as indicated by the NMR spectrum and the ease of hydrolysis of the methoxyl group. Hydrolysis proceeded with inversion of configuration at C-3 to give alcohol 98 (see Scheme 24), the structure of which was supported by its NMR spectrum. Structure 84a was proposed for the alkaloid, and this was further supported by its reduction to a product identical with tetrahydroschelhammeridine 95 (see Scheme 25), which fixed the configurations a t C-3 and C-5, but the 6ci-configuration was assumed. The alkaloid 84a is therefore 3-epi-6~,7dihydrohomoerythraline. The C-3 epimer 84b ( 6 4 7-dihydrohomoerythraline) was not reported in S. pedunculata but was later isolated from P. C O ~ O S U(87). From its NMR 10" HCI

10"" HCI

A

(35"")

0

'H

'H 84a

98

84b

SCHEME 24. Relationship bertveen 84a and 84b.

84a

77a

95 SCHEME

25

1.

39

ER YTHRI.VA A N D RELATED ALKALOIDS

spectrum this alkaloid (alkaloid 1) was found to contain an allylic methoxyl group, and the coupling data suggested that the C-3 proton was axial. Hydrolysis of 84b gave the allylic alcohol 98 as the major product; this product had properties identical to those reported for the demethylation product of 84a (84)(see Scheme 24). The interconversion reactions outlined in Schemes 24 and 25 allowed the complete stereochemistry of 84b to be assigned. In addition, it was found that the von Braun degradation product of 84b was identical to that of 3-epischelhammeridine 81b (87),as shown in Scheme 26.

84b

81b

SCHEME 26

From the same plant a similar alkaloid (C,,H,,NO,, alkaloid 2) was isolated and found to differ from 84b in that it contained two aromatic methoxyl groups in place of the methylenedioxy group. The C-3 proton was, from the N M R coupling constants, found to be axial, and structure 85 was consistent with the data. The configuration at C-5 was assumed, although its CD curve was the inverse of that of 84b in the region 235 nm. Structure 85 corresponds to 6~~,7-dihydrohomoerysotrine. Two alkaloids, C,,H,,NO, and C,,H,,NO, (alkaloids 6 and 7), isolated from P.comosa exhibited similar NMR characteristics (87).Both contained an allylic methoxyl group, a disubstituted double bond, and para-oriented aromatic protons ; however, the former contained a methylenedioxy group and the latter two aromatic methoxyl groups. Their IR spectra showed the absence of hydroxyl or carbonyl functions, which suggested that the fourth oxygen atom was contained in a ring. The MS fragmentation patterns of the two alkaloids were almost identical, showing that they differed only in the aromatic substituents. Structures 86 and 87b, respectively, were assigned

CH,O. 85

R' 86

87a R' = CH,O. R Z = H 87b R' = H , R 2 = CH,O

40

S. F. DYKE A N D S. N. QUESSY

to the two alkaloids from the spectroscopic evidence and on the basis of the transformations summarized in Schemes 27 and 28. Reduction of 87b using LAH gave the tertiary alcohol 99 with preservation of the double bond (Scheme 27). The position of both the double bond and the hydroxyl group was clear from the NMR and MS data of 99. The downfield shift experienced by the proton at C-14 (A6 1.36 ppm) could be accounted for if the hydroxyl group had the 68-configuration as this would place it spatially near the aromatic proton at C-14. Similar reduction of 86 gave the corresponding tertiary alcohol 100. Catalytic reduction of 87b gave rise to a secondary alcohol 101 as the major product. The MS and NMR data clearly revealed that isomerization of the double bond to the A1(6)-position had occurred. The signal for the methine to which the hydroxyl group was attached (i.e., C-7 proton) was located at 6 4.53 ppm by the use of N M R experiments involving deuterium exchange and acetylation. Irradiation of this signal produced a small (< 1 Hz) decoupling effect on the olefinic signal and a significant decoupling effect at the methylene protons attached to C-8. The data were consistent only with the hydroxyl group being attached at C-7, but the coupling values of 5.0 and 6.7 Hz for J7,* did not permit assignment of configuration. A similar reduction of 86 gave the secondary alcohol 102 which exhibited spectroscopic properties similar to those of 101. Further support for the structure of 102 was obtained from its

86 R + R = C H z 87b R = CH,

RO

CH,O” 99 R = C H ,

/

100 R + R = C H ,

OH

OH 101 R = CH,

102 R

+ R = CH2

1.

41

E R Y T H R l N A A N D RELATED ALKALOIDS I,) SOCI, 111)

LAH

A

(9 CH,O"

81b 3-Epischelhammericine

102 SCHEME 28

transformation to 3-epischelhammericine (Slb), as outlined in Scheme 28, which established the configurations at C-3 and C-5. That the original alkaloids 86 and 87b contained a 6,7-epoxy group was an inescapable conclusion of the reduction experiments; and the presence of such a group poses an interesting biogenetic problem. The stereochemistry of the epoxide remains uncertain. The alkaloid 87b was later isolated from C. wilsoniunu along with its C-3 epimer 87a (90). The name wilsonine has been given to 87a and 3-epiwilsonine to 87b. Since the alkaloid 86 has no trivial name and is not related to any members of the Erythrinu group, it is referred to here as 6,7-epoxy-3a-methoxy-15,16-methylenedioxy-C-homoerythrinan2(1)-ene.The structure of wilsonine was established in the way just described. 6. Homoerythroidines The two major alkaloids from P . billurdieri were found to have the chemical compositions C,,H2,N03 and C1,H2,N03. Their NMR spectra were similar, both contained a trisubstituted double bond but no aromatic protons. The former alkaloid exhibited one exchangeable hydroxyl proton, whereas the latter contained an aliphatic methoxyl group. The relationship between the two alkaloids was established when demethylation of the C,, alkaloid gave the C,, alkaloid. An absorbance at 1745 cm-' in the IR spectra suggested a 6- or elactone, an observation which was supported by LAH reduction to a diol (v,,,3450 cm-') in quantitative yield. The MS data suggested a A1(6)-alkene structure, and from the combined spectroscopic and degradative data the partial structures 103a and 103b were proposed

RO

-

103a R 103b R

=H = CH,

90

104

42

S. F. DYKE AND S. N . QUESSY

for the alkaloids. It was found that 103a isomerized on column chromatography to a product for which either the partial structure 90 (without the stereochemistry) or 104 was deduced. Structure 90 was favored on biogenetic grounds and on consideration of the N M R spectrum (88). The complete structure of this base, named phellibiline, was established by X-ray analysis, which revealed the absolute configurations at C-3, C-5, and C-12 as shown in stereostructure 90 (93).Since 90 was derived from the naturally occurring hydroxylic alkaloid and since this alkaloid has been related to its 0-methyl analog, structures 88 and 89 could be assigned to them. Alkaloid 89 is therefore 2,7-dihydrohomo-P-erythroidine, and the two major

88 R = H 89 R = CH,

alkaloids from P. billardieri are the only examples of the homoerythroidine series yet isolated.

IV. Cephalotaxus Alkaloids A. OCCURRENCE AND ISOLATION Cephalotaxus is a genus of plum yew natural to Eastern Asia, although it is now cultivated in many parts of the world (94). There are about seven species and most have been examined for alkaloids, which have been obtained from all parts of the plants. Since the alkaloidal extracts were reported in 1969 to exhibit antitumor activity (95), an intense investigation of the Cephalotaxus alkaloids has followed (8, 9). Most of the isolation work, structural elucidation, and pharmacological assay has come from the Northern Regional Research Laboratory in Illinois (8). The alkaloids were best isolated from the ethanol extract of the plant material, partially fractionated by counter-current distribution, and subsequently purified by preparative chromatography. Of the 11 known Cephalotasus alkaloids (105-115 in Figs. 8 and 9), cephalotaxine (105a)is ubiquitous and the most abundant (up to 64% of the total alkaloid extract) in all species examined. C. wilsoniana Hay., which yields only minor quantities of cephalotaxine, is the exception, however ; it is rich in Homoerythrina alkaloids,

1.

43

E R Y T H R I Y A AND RELATED ALKALOIDS

OR3

Cephalotaxine Epicephalotaxine Acetylcephalo taxine Harringtonine Homoharringtonine Isoharringtonine Deox yharringtonine Desme thylcephalotaxine Cephalotaxinone

105a 105b 106 107 108 109 110 111 112

R’

R2

R3

HO H CH,CO a b

H HO H H H H H H

CH, CH, CH, CH, CH3 CH, CH, H CH3

C

d HO

co-o-

“ t

a = CH,-C-(CH,),

OH

CH,

0 OH

b

= CH,-C-(CH,),+OH

I

CH,CO,CH,

CH,COzCH,

CH, b

U

CO-O-

H

= CH,-~--(CH,),&OH

CH,

CO-O-

H

H d

9

CO-O-

= CH,-C-(CH,),-OH

OH

I

CH,

CH,COzCH3

CO,CH, d

1

F I ~8.. Ceptiaiofa.xus alkaloids.

OCH, 113 Desmethylcephalotaxinone

OCH, 114 1I-Hydroxycephalotaxine

FIG.9. Ceplialotauus alkaloids.

OCH, 115 Drupacine

44

S. F. DYKE AND S. N. QUESSY

companion alkaloids in Cephalotaxus species (90).Seven Homoerythrina alkaloids have been identified in Cephalotaxus, including 3-epischelhammericine (Sob), wilsonine (87a), 3-epiwilsonine (87b), and structures 82a, 82b, 83, and 96 (8). The other Cephalotaxus alkaloids are structurally related to cephalotaxine (105a)and the most important group are the harringtonines 107-1 10, which are C-3 esters of cephalotaxine, since they have antitumor activity (see Section VII). The harringtonines constitute less than 10% of the total alkaloid extract and are in greatest abundance in C. harringtonia K. Koch var. harringtonia (89). The demand for the harringtonines for use in clinical trials has exceeded their supply from natural sources, resulting in many attempts to synthesize them from the more abundant cephalotaxine (see Section V1,C). In a very recent examination of C. msnii Hook., a new antitumor alkaloid was isolated but found to be structurally unrelated to the usual Cephalotaxus alkaloids. In view of the chemical results the botanical classification of the plant is being reexamined (96). Recently, a GC-MS method for the separation and quantitative identification of extracts from Cephalotaxus species (97)has been described. Most of the alkaloids were resolved, particularly the biologically active esters. The seven Homoerythrina alkaloids were only resolved into two groups of five and two components, respectively, under the conditions described. Acetylcephalotaxine (106), 1 1-hydroxycephalotaxine (114), and desmethylcephalotaxinone (113) were not resolved by retention time, but could be identified within the mixture by their MS fragmentation patterns. Cephalotaxinone (112) gave two GC peaks after silylation, presumably due to a contribution from the enol component. The artifact peak overlaps partly with the peak for drupacine (115) and hence introduces a slight error for this component and makes it difficult to quantify cephalotaxinone. It has been observed that the melting points and optical rotations of several alkaloids differ by more than can be attributed to experimental variation and must thus depend on the plant source (9,89,98).The most striking example is cephalotaxinone which has [mID-57" (0.3 c/g cmP3, CHCI,), from C. harringtonia var. drupacea and [.ID - 125' (0.6 c/g cm-,, CHC1,) from C. harringronia var. harringtonia, but that obtained by oxidation of cephalotaxine has [.I, -155" (0.63 c/g ern-,, CHCI, (89, 98). It has been suggested that Cephalotaxus alkaloids may occur as partial racemates. Although cephalotaxine is optically active ([.], - 183"),its crystalline methiodide is racemic. The amorphous residue was found to be optically active ( [ a ] , 1127, and it was suggested that racemization occurred during recrystallization from hot methanol (99).It is not clear whether Cephalotaxus alkaloids do occur as partial racemates or whether some racemization occurs

+

1.

ER YTHRINA AND RELATED ALKALOIDS

45

during the isolation and purification procedures. It has been noted that cephalotaxine obtained by transesterification of deoxyharringtonine (110) has the same optical rotation as natural cephalotaxine, and yet the harringtonines do not occur as diastereomers. If cephalotaxine does occur as a partial racemate, then the acyl portion of the harringtonines should also be partly racemic, and this would have some significance in structure-activity studies (9, 100).

B. STRUCTURE DETERMINATION 1. Cephalotaxine and Epicephalotaxine Pure cephalotaxine was first isolated from C. fortunei Hook. and C. harringtoniu var. drupacea [formerly referred to as C. drupacea ( I O l ) ] (102). The pioneering work on the structure of cephalotaxine (C,,H,,NO,) was reported in 1963 by Paudler et ul. (102, 103), and on the basis of chemical and spectroscopic evidence structure 116 was tentatively proposed. The fact that the olefinic proton appeared as a singlet in the NMR spectrum was rationalized by proposing a dihedral angle with the adjacent proton of 90" and hence zero coupling. Powell et al. (104) reexamined the structure of cephalotaxine and suggested two structures, 105 and 117, which accommodated all the data, although the former structure was favored on biogenetic grounds.

116

OCH, 105

117

46

S . F. DYKE AND S . N. QUESSY

In an accompanying publication (105), the X-ray crysial structure of cephalotaxine methiodide, which proved structure 105 for cephalotaxine, was reported. Although the methiodide was prepared from optically active ([.ID - 183”) cephalotaxine, the crystalline product was racemic, so that only the relative stereochemistry was obtained. It appears that all four chiral sites in the methiodide undergo inversion, presumably by facile cleavage and re-formation of the N-C-5 bond. This could also explain the early difficulties in the structural elucidation by chemical transformation. Recently, the absolute configuration has been established by X-ray analysis of cephalotaxine p-bromobenzoate (99, 106) as 3S,4S,5R (as shown in 105a). The seven-membered heterocyclic ring exists in a boat conformation with the nitrogen atom at the prow. 17

11

OCH, 105a Cephalotaxine

A minor alkaloid from C. fortunei (98) showed an IR spectrum identical to that of cephalotaxine, but its melting point was depressed by it. The physical properties of this alkaloid were found to be identical to the minor product obtained by reduction of cephalotaxinone (112) using LAH (102). The alkaloid was therefore 3-epicephalotaxine (105b). Although a small amount of 105b was produced on reduction of cephalotaxinone with LAH, the use of borohydride or DIBAL-H gave only cephalotaxine (98). 2. Esters of Cephalotaxine During the structure elucidation work, cephalotaxine was shown to form a mono-0-acetate (106) (102), and this compound was later found as a minor alkaloid in C.fortunei (98).An impure sample of acetylcephalotaxine was also obtained from C. wilsoniana Hay. (90). When the alkaloidal extracts of C. harringtonia var. harringtonia were found to possess antileukemia properties, a search for the responsible alkaloids was initiated, since the major component, cephalotaxine, was inactive. Four alkaloids (the harringtonines) that exhibited anticancer properties were isolated. The structures of harringtonine, isoharringtonine, and homoharringtonine were reported in 1970 (107),and that of deoxyharringtonine was reported in 1972 (108).

1.

47

E R Y T H R I N A A N D RELATED ALKALOIDS

Examination of the NMR spectra of the harringtonines revealed a spectrum nearly identical to that of cephalotaxine as well as the presence of signals arising from a side chain. This observation led to the discovery that alkaline hydrolysis of the harringtonines gave cephalotaxine in each case, plus a complex dicarboxylic acid. This was further supported by the MS data, since each alkaloid exhibited a prominent fragmentation ion with nz/e 298, due to loss of the side chain (M' -OR). The same peak was observed in the MS of cephalotaxine (M' -OH). It was therefore established that the harringtonines were C-3 esters of cephalotaxine, differing only in the nature of the ester side chain. The structures of these side chains were deduced from a careful examination of the NMR spectra of their dimethyl esters, obtained from the natural alkaloids by transesterification using sodium methoxide in methanol (100, 107, 108). The number and nature of free hydroxyl groups was determined by examination of the NMR spectra in DMSO-d, before and after deuterium exchange. The N M R spectra of the esters obtained from harringtonine and homoharringtonine exhibited two equivalent methyl groups and two different carboxymethyl signals, two tertiary hydroxyl groups, and an isolated methylene group. The spectra were consistent with structures 118 and 119, respectively, for these diesters. The spectrum of the diester obtained from isoharringtonine differed in that it contained an isopropyl function, a singlet due to an isolated methine bearing a hydroxyl group, and only one tertiary hydroxyl group. Structure 120 was proposed for this diester. By a combination of IR and NMR evidence the diester obtained from deoxyharringtonine was found to contain only one hydroxyl group, which was tertiary, and structure 121 was consistent with the data. The structures of these diesters were confirmed by synthesis (see Section V1,C). C0,CH3

OH

CH,OZCpCH,-C~~(CH,),pCpCH,

OH

CH 3

118

H

C02CH3

CH,O,C-C-C-(CH,),

OH

OH 120

CO,CH, CHAOIC

CH,

7

OH

ICHZ),pCpCHA

OH

CHS

119

H -C-CH, CH,

C0,CH3

H

CH,O,C-CH,~C~(CH~),~~~CH; OH

CH,

121

The problem now remained as to which carboxyl group was attached to the cephalotaxine skeleton. The two possible half-esters, 122 and 123, were synthesized (see Section VI,C), and esterification of cephalotaxine with 122 gave rise to a mixture of diastereomers, neither of which was

48

S. F. DYKE AND S . N. QUESSY

CO,CH,

HO,C-CH,--C

(CH,), OH

H C - CH3

CH30,C-CHZ

CH3

122

CO,H

H

C-(CH2),

C -CH,

OH

CH,

123

CH,02C-CH,

H

CO

-

C

(CH,),-C-CH,

,

OH

CH3

124

identical to deoxyharringtonine (108). This result suggested that the tertiary carboxyl group was linked to cephalotaxine in deoxyharringtonine ; but all attempts to esterify cephalotaxine with the half-ester 123 failed, and it was concluded that both reactants were sterically hindered. It was found that in the MS fragmentation patterns of the half-esters, cleavage at the tertiary center was preferred. Thus, 122 and 123 exhibited M-CO,H (m/e 173) and M-CO,CH, (m/e 159) fragmentation ions in the ratios 1 :8 and 3: 1, respectively. Deoxyharringtonine showed a ratio ofmle 1731159 of 3:1, suggesting linkage through the tertiary carboxyl group (108). The structures of deoxyharringtonine and the other harringtonines have been proved by partial syntheses from cephalotaxine and are discussed in Section V1,C. The absolute configurations of the acyl side chains are also discussed in that section as they depend, in part, on stereospecific synthesis. Recently, tissue cultures of C. harringtonia var. harringtonia were found to yield Cephalotaxus alkaloids in the same ratio as the parent plant, although in lower total yield. It was hoped that this method would help to offset the shortage of harringtonines, since the alkaloids could be obtained after six months, whereas the Cephalotaxus tree was slow to mature. A new harringtonine was discovered in the culture. The GC-MS evidence suggested that it was a homolog of deoxyharringtonine, and structure 124 was proposed for the side chain from the MS data. The name homodeoxyharringtonine was suggested for the alkaloid (109). 3. 11-Hydroxycephalotaxine and Drupacine Two minor alkaloids (C1,H,,NO,), obtained from C. harringtonia var. drupacea (Sieb and Zucc) Koidz., were deduced to be 1 l-hydroxycephalotaxine (114) and its related ketal drupacine (115) (101, 104). The NMR spectrum of the former exhibited features similar to that of cephalotaxine, with the addition of a triplet at 6 4.78 ppm, which was part of an ABX system. The alkaloid formed a diacetate wherein the position of the methine

1.

49

ER YTHR1,VA A N D RELATED ALKALOIDS

triplet in the NMR spectrum shifted to 6 6.09 ppm. The AB part at b 3.26 ppm was assigned to the protons at C-10, hence the hydroxyl group was located at C-1 1. It did not prove possible to prepare 1 l-hydroxycephalotaxine from cephalotaxine because of the sensitivity of the C-3 hydroxyl group to oxidation, and therefore the configurations at C-4 and C-5 were assumed. Drupacine also exhibited an ABX pattern in its NMR spectrum, with a triplet centered at 6 4.87ppm. The position of this signal remained unchanged upon acetylation, which gave a mono-0-acetate. There was no olefinic signal in the NMR spectrum but geminal coupling in the methylene signals attributable to C-1 was observed. That drupacine is the 2,ll-bridged structure 115 was demonstrated by its preparation under mild acid conditions from 1 1-hydroxycephalotaxine (see Scheme 29). Furthermore, treatment of 114 with tosyl chloride in pyridine gave the 3,ll-bridged ether 125. These reactions require a cis relationship between the 1 1-hydroxyl group and the cyclopentene ring, so that the stereochemistry of the hydroxyl group in 11-hydroxycephalotaxine must be as shown in 114, where the hydroxyl groups are in close proximity. Further support for this assignment came from the finding that the diacetate of 114 could be readily epimerized at C-1 1, a reaction which obviously relieves the steric congestion.

OCH,

OCH,

114

11s

I OCH, 12s

SCHEME 29

50

S. F. DYKE AND S. N. QUESSY

The ready conversion of 114 to 115 suggested that drupacine might be an artifact produced during the isolation procedure. However, it was demonstrated that the isolation conditions could not account for all the material, so that some drupacine must be present in the plant (101). Both alkaloids are unique to C. harringtonia var. drupacea, and an alkaloid with properties similar to those of drupacine was also reported by Asada in the same species, although no structure was given (110). 4. Cephalotaxinone, Desmethylcephalotaxine, and Desmeth ylcephalo taxinone Cephalotaxinone (C, ,H ,NO,) was first isolated and characterized from C. harringtonia var. harringtonia (89) and later from C. fortunei (98). In the IR spectrum of this material, the hydroxyl group of cephalotaxine was absent but a carbonyl absorbance at 1720 cm-' was present. A shift in the olefinic absorbance from 1665 to 1625 cm-' suggested an enone structure. Cephalotaxinone was found to be identical to the product 112 formed by Oppenauer oxidation of cephalotaxine (105a) (see Scheme 30). This also established the stereochemistry of 112 at C-4 and C-5.

OCH,

OCH,

105a Cephalotaxine

112 Cephalotaxinone

SCHEME 30

Desmethylcephalotaxine (111) was first prepared by mild acid hydrolysis of cephalotaxine, during the early structure elucidation work (102). The same workers later identified this material as a minor constituent of C. fortunei (98). Desmethylcephalotaxine is not an artifact, since pure cephalotaxine can be subjected to the isolation procedure without loss. It was noted that chromatography of Ceplra~otasus alkaloid fractions over neutral alumina resulted in considerable losses (111). Further elution with dilute aqueous acetic acid resulted in the isolation of a new alkaloid, desmethylcephalotaxinone ([.ID + 2.3"). The IR spectrum of this alkaloid was consistent with the presence of a vinylic hydroxyl group (3520 cm-l) and a conjugated carbonyl group (1690 cm-I). The NMR spectrum obtained in deuterochloroform contained features of the cephalotaxine structure, but included a singlet attributable to an isolated methylene (6 2.54 ppm). In DMSO-d, this resonance appeared as an AB quartet. Acetylation

1.

51

ER Y 7 H R I N A A N D RELATED ALKALOIDS

produced an enol acetate, which exhibited a signal due to an isolated methylene at 6 2.59 ppm in the NMR spectrum. Structure 113 was established by interconversion reactions. Cephalotaxine was oxidized to cephalotaxinone (112) (as in Scheme 30) which, on vigorous hydrolysis in acid, gave desmethylcephalotaxinone ([.ID 40") in less than 30% yield after 3 hr at 80' (see Scheme 31). This material was identical to the natural product except for its optical rotation. It appeared that the natural product was nearly racemic since methylation gave optically inactive cephalotaxinone (see Scheme 31) plus a small quantity of the isomeric ether 126. The spectroscopic evidence suggested that desmethylcephalotaxinone exists in the tautomeric structure 113. The possibility that 113 was an artifact was considered unlikely under the conditions of isolation. The alkaloid has been found as a minor component in C. harringtonia var. harringtonia and in C. harringtonia var. drupacea ( I l l ) .

+

vigorous H *

'CH ,CH,CHIOCH,), , H

> +

OCH,

0 113 R = H Desmethoxycephalotaxinone 126 R = CH,

112 Cephalotaxinone

SCHEME 31

V. Biosynthesis A.

E R Y T H R ~ N AALKALOIDS

At the time of the last review in this treatise ( I ) very little was known about the biosynthesis of the Erythrina alkaloids. The essential postulate was that the aromatic bases are derived from tyrosine, with a phenolic coupling as a key step (Scheme 32) involving the symmetrical intermediate (127a) derived from 3,4-dihydroxyphenylalanine (DOPA). In one suggestion. oxidation of 127a to 128 (route 1, Scheme 32) and ring closure to 129, followed by cyclization to 132a was envisaged, whereas in the alternative proposal (route 2, Scheme 32) 127a undergoes phenolic coupling to 130a, followed by oxidation to the diphenoquinone (131a) and cyclization to 132a. The overall scheme was supported by the observation (66,112) that when 127a was oxidized with alkaline potassium ferricyanide ( )-erysodienone (58) was isolated in 35% yield. Mondon and Ehrhardt (66) also described the further in aitro conversion of (58)to ( f)-erysodine (7) via 133.

+

Tyrosine

L

DOPA

I

OH

R20

OH

OH

130

128

I

RZO 0

steps

131

HO 0

129 0

132

a : R, = R, = H b : R, = R, = Me

Me0

H R'O 7

OH 133

SCHEME 32. A postulated biosynrhetic whet?ir.forErythrinu alkaloids

Hoq-$H 1.

58

-

53

E R YTHRf.VA A N D RELATED ALKALOIDS

%: :M

Me0

< H

Me0

/

Me0

QH 133

7

Since that time dramatic advances have been made in our understanding of the biosynthetic pathways to these alkaloids, almost entirely as a result of I4C-labeled feeding experiments. In an early study (113) [2-14C]tyrosine (34)was found to be incorporated equally at C-8 and C-10 of /l-erythroidine (60),a type of Erythrina alkaloid always believed (114)to arise from aromatictype compounds. This observation was regarded as a strong piece of evidence in favor of Scheme 32. Barton et al. (115) found acceptable levels of incorporation of 134 into erythraline (4), but when 127b, tritiated in the otherwise unsubstituted

mH;zH

HO

---+

o%*

-

MeO,'

134

60

4

positions ortho and para to the phenolic hydroxyl groups, was fed to E. crista galli very low levels of incorporation were found. It was concluded that a secondary amine such as 127 is not a precursor of the aromatic Erythrina alkaloids and an alternative biosynthetic route (Scheme 33) was proposed (115). In a key experiment (115) it was shown that (+)-(S)-norprotosinomenine (135) was incorporated into 4 100 times more efficiently than its enantiomer, strong evidence that 135 is a specific precursor of 4 (19,61,116).The intermediacy of 130b was also established (68).Interestingly, dibenzazonine alkaloids have been isolated from various erythrina species (21, 23). Furthermore, erysodienone (58) has been isolated (22, 23,34),

DOPA

Tyrosine

OMe

OH 136

135

I

OH

OH

M

e/

Me0

\

o

g

H

Meox& /

Me0

OH

\

OH

130b

137

Me0 Me0 58 Erysodienone

138

Me0 OH SCHEME 3 3 . The biosynthetic route to the Erythrina alkaloids

1.

55

E R YTHRlh'A A N D RELATED ALKALOIDS

Me0

Me0

MeO"

0

Me0

0 48 Erysotrine

Me0 MeO'

MeO'

OH 42 Erythratine

140

I

I

i

J

Erythraline (4)

Erysovine (5)

+ Erysopine (9) + etc.

SCHEME 33 (continued)

together with (S)-norprotosinomenine, from E. lithosperma (but see Section II,A about this species). When ['4C]4-methoxynorprotosinomenine was fed to E. crista galli, the erythraline (4) that was isolated was found to be equally labeled at the methoxyl and methylenedioxy group carbon atoms, thus confirming the involvement of a symmetrical intermediate such as 130b.

56

S. F. DYKE A N D S. N. QUESSY

The important point concerning stereochemistry was also considered by Barton et al. (117, 118), who pointed out that the conversion of chiral 136 to 130b, thence into chiral erysodienone (as 139), must either involve an

139

inversion of configuration or a symmetrical intermediate. They showed (118) that chiral 130b is very rapidly racemized at room temperature and that only (-)-(55’)-erysodienone is the precursor of erythraline and of both a- and P-erythroidine. The biosynthesis of the “unusual” Erythrina alkaloids such as isococculidine (36), cocculidine (54),and cocculine (56) proceeds (119, 120) from (+)-

54 R = M e 56 R = H

(S)-norprotosinomenine (135).This was established (120) in feeding experiments with C. laurifolius DC. The proposed route is summarized in Scheme 34, where reduction of 136 to 141 was originally thought to occur, followed by a dienol-benzene rearrangement to 142. However, cyclization of 142 to isococculidine (36) is hard to visualize, although intermediate 143 was postulated. An alternative route (11a) involves reduction of the diphenoquinone 144 to 145, followed by cyclization to 146 and further elaboration to 36. The biosynthesis of z-and p-erythroidines has been investigated (118)by feeding 17-rnonotritioerysodine, 14,17-ditritioerysopine, and 1,17-ditritioerysodienone, when high levels of incorporation were observed, thus confirming that these lactonic alkaloids are derived in vivo from the aromatic compounds. The remaining point of ambiguity concerns the position of cleavage of ring D; the feeding experiments are compatible with either C-15-C-16 or C-16-C-17 cleavage, with the loss of C-16 and retention of tritium at C-17.

135

I

4

Me0

Me0

0 144

OH 141

I

/

M Meo%H e0

\ OH 142

J.

/

M eO

0 143

MeO,' 36

58

S . F. DYKE AND S.

N. QUESSY

B. HOMOERYTHRINA ALKALOIDS The first two homoerythrina alkaloids to be isolated (82)were schelhammerine (80a) and schelhammeridine (77a), and since various species of

OH

80a

17a

Lilaceae also contain 1-phenethylisoquinoline alkaloids, it was suggested (82) that the homoerythrina derivatives are biosynthesized along a pathway analogous to that followed by the Erythrina alkaloids themselves (Scheme 35). Some preliminary results from feeding experiments (121) support this view; ( +)-[2-14C]tyrosine causes specific labeling of C-8 in 77a. Me0

?H

OH

I

OH

1.

59

E R Y T H R I N A AND RELATED ALKALOIDS

C. C E P H A L O T AALKALOIDS XCS Arguing from structural similarities, it was originally suggested (10)that the Cephalotaxus alkaloids could be derived in viuo from the same precursor as the aromatic erythrina bases, but since Cephalotaxus and homoerythrina alkaloids have been isolated (90)from E. wilsoniana, it has been postulated (lob, 89) that both groups have a 1-phenethyltetrahydroisoquinoline as a common precursor (Scheme 36). Tyrosine is incorporated (122)into cephalotaxine, but the labeling pattern did not seem to be consistent with a

benzilic

rearrangement

RO

HO CO,H

0 .L

etc

SCHEME 36. Possible biosynrhetic route to the Ci~phulotaxusalkaloids.

60

S. F. D Y K E A N D S. N. QUESSY

OMe 105a

CO,H OH

0

acetyl-Co A

*C02H

&COZH

CO,H cephalotaxine

1

\COZH 110

S C H ~37. M ~Bios.vnthrsi3 uf dro.iy/turrittylottirtr

0

1.

E R YTHRl’VA AND RELATED ALKALOIDS

61

l-phenethylisoquinoline intermediate. Thus, [3-14C]tyrosine gave cephalotaxine (105a) with 68% of the activity at C-11 and 32% at C-4, but [2-14C]tyrosine labeled C-10 (37% of the activity); no label was found at C-7 or C-8. However, it was realized subsequently (123) that tyrosine was being catabolized, and the aromatic ring was not being incorporated into cephalotaxine. It was found (123)that phenylalanine is the precursor, in line with the derivation of other l-phenethylisoquinolines,and that ring D is derived from the aromatic ring of phenylalanine with the loss of one carbon atom. The biosynthesis of the acyl side chain of deoxyharringtonine (110) has been found (124) to involve L-leucine (Scheme 37).

VI. Synthesis A. ERYTHRINA ALKALOIDS A synthesis of erysotrine (1) was achieved by Mondon and his associates and reported in preliminary form in the previous review in this treatise (1). This work, which has now been published in full (125-129), is summarized in Scheme 38. Condensation of homoveratrylamine with the glyoxalate derivative of 4-methoxycyclohexanone gave the enamide (147) which, with phosphoric acid, was cyclized to the tetracyclic material (148). Reduction with Raney nickel followed by treatment with sulfuric acid gave the oxide (149) in which the rings A/B must be cis-fused. When 149 was subjected, after O-acetylation, to acid treatment, a mixture of two alkenes (150) was formed. These were separated and the correct one epoxidized to 151. Ring opening of 151 with dimethylamine yielded 152 which, on Cope elimination from the derived N-oxide, gave the alkene (153). Allylic rearrangement occurred when 153 was treated with acidified methanol to yield 154 as a mixture of epimers. These were separated by chromatography and each was carried through the remainder of the synthesis. Reduction of the amide carbonyl group of 154 gave 155, and this was followed by dehydration to 1. Finally, resolution of 1 was effected with dibenzoyltartaric acid to provide the (+)-isomer, identical with erysotrine obtained from natural sources. Mondon (125) was also able to convert the isomers (150), where the cis-A/B ring junction is established, to the dihydro derivative (156). This was then reduced to 157, where the A/B ring junction must be cis. Later, Kametani et al. (130, 131) reported that the tetracyclic compound (160) could be obtained as a mixture of cis-trans isomers merely by heating together the amine (158) and the ketoester (159). However, Mondon (132, 133) has cast doubt on this work and concludes that Karnetani’s product is

62

S. F. D Y K E A N D S. N. QUESSY

147 \

149

150

148

151

Me0

,

'OH

NMe,

153

152 SCHEME38. The ,first sythesis of erysotrine

1.

63

ER Y T H R I X A A N D RELATED ALKALOIDS

1.53

HC I !&OH

A

Me0 M e O ‘ U

154

I

( 1 1 separation 01 cpimeis

(111

LAH

Me0

“OH 155

1

SCHEME 38 (continued)

150

% Meo% Me0 ‘OH

Me0 Meo%

156

157

a mixture of the cis isomer (157) and the uncyclized material (161). Kametani et al. (131) also described the condensation of 158 with 162 and with 163 to form 164 and 165, respectively, but Mondon (132) concludes that these structures too are incorrectly assigned. HO Me0

159

160

64

S. F. DYKE AND S. N. QUESSY

Me0

U 161 158

164

165

A new approach to the synthesis of the Erythrina alkaloids involves (134) a Birch reduction of the amide (166) to 167, followed by cyclization, first to 168 with sulfuric acid in DMF, then to the ketolactam (169) with formic BzO

HO

Me0

Me0

T

N

M eO d

Me0 166

H

M

167

I

H,SO, DMF

98" HCO H

&

Me0

169

168

0

Y

e

1.

65

ER Y T H R I X A A N D RELATED ALKALOIDS

acid. When the isomeric amide (170)was subjected (135)to a similar sequence, the overall yield of 172 reached 90%. Ketalization of 172 with ethylene

Me0

170

Me0e

O

171

y

$

I

+K;z:xFJ

MHe 0

(

H,SO,. DM F

O

0

0

L/

/ M e0

172

173

(il Li+NR, lii) 0,

3'"' '

e

0

THF

(I)

f;":',

9 H

Oxidation

Me0

Me0

OH

H "OAc 0

LJ

175

174

Me0

V

i

e

0

-9

+---

35""

MeO% Me0 'OAc

MeO"

/

1 Erysotrine

/

176

(I,) ill

m+ Meo%

HC'I MeSO,CI dcelone

Me0

Me0 OS0,Me

OH

O w 0

O w 0

177

174

85",,

!

NdOH MeOH

178

180

\

Zn HOAc

";"-::6,.

PhSeCl

Me0

Y

Me0 CI

w

0

SePh C

I SCH,Ph

179

182

*

15"" H,Oi ps

loo", 4gYO. MrOH

I

W

SCH,Ph

181

182

I

i

Me0

Me0 RdNl

MeO"

MeO"

1.

67

ER YTHRINA A N D RELATED ALKALOIDS

glycol followed by 0-methylation gave 173, the lithium enolate of which was hydroxylated with oxygen to yield 174, which has the wrong stereochemistry at C-7. Epimerization was achieved by oxidation followed by reduction. Acetylation of the hydroxyl group and deketalization then yielded the ketoamide (175), which was reduced and dehydrated to 176. The conversion of 176 to erysotrine had been reported previously by Mondon and Nestler (136). The total synthesis of (+)-Erysotramidine (2) has been described by Ito et al. (137) starting from the amide (174) (Scheme 39). After 0-mesylation to 177, base-catalyzed reaction gave the cyclopropane derivative (178) which with zinc in acetic acid was reduced to 179, which was identical to the product (135) of 0-methylation of 172. Conversion of 178 to the thioketal(l80) was followed by reaction with phenylselenyl chloride. A mixture of two compounds, 181 and 182, was produced; the former could be transformed quantitatively to the latter. Finally, treatment of 182 with silver nitrate in methanol gave 183, which was then desulfurized to yield erysotramidine (2). An interesting short synthesis of the erythrane skeleton has been achieved by Wilkens and Troxler (138). Ethyl cyclohexanone-2-carboxylate was MeO.

L

M

o

e

w

,

Et 184

185

alkylated with ethyl bromoacetate, followed by condensation with homoveratrylamine to yield 184. Cyclization of 184 with phosphoric acid yielded 185. Stevens and Wentland (139) have prepared the erythrane derivative (187) by reacting the endocyclic enamine (186) with methyl vinyl ketone.

Me Meor rn i Meo”i-. -Meo +M e 0

Me0

O

POCI,

Me0

Me0

H

0 187

186

f

l

68

S. F. D Y K E AND S. N. QUESSY

The enamine (186) was itself prepared from homoveratrylamine and y butyrolactone. Yet another approach to the erythrane skeleton (140)involved Birch reduction of 6-methoxyindoline to 188, followed by N-acylation with 3,4-dimethoxyphenylacetyl chloride to yield 189. When this product was reacted with POCl, the ketoamide (190) was obtained in poor yield; the major product was 191.

Me0

rn 188

I 189

191

Synthetic studies along the biosynthetic route have attracted considerable attention. A very early success mentioned in the previous review ( I ) and in the biosynthesis section of this chapter (Section V,A) involved the oxidation of the diphenol(127a) with alkaline potassium ferricyanide to erysodienone (132a) via the benzocene (13Oa) and the diphenoquinone (131a) (Scheme 32). The mechanism of this reaction has been discussed by Barton et al. (68).The

1.

69

E R Y T H R I N A AND RELATED ALKALOIDS

dienone (132a) has been converted to erythratine and dihydroerysodine (see Section V,A). A particularly interesting and useful synthesis of 130b has been described by Kupchan et al. (141-143), who oxidized the l-bemyltetrahydroisoquinoline (192, R = COCF,) with vanadium oxyfluoride (Scheme 40). Earlier Kametani et al. (144) had oxidized 192 (R = C0,Et) with potassium ferricyanide and had obtained 193 (R = C0,Et) in 2% yield. HO Me0

R

OH

OH

192

193

I

NaOH

130b

NaBH,

194

SCHEME 40. Kupchan's sjnthesis of bcvrxcenes

Oxidation of the 1-benzyltetrahydroisoquinoline(195) with VOCl, (145) yielded the dienone (196) in 34% yield; reaction of this with boron trifluoride etherate provided 197, and this was converted, as shown in Scheme 41, to 14-methoxyerysodienone (199). Oxidation of the secondary amine (200) gave (146)the methoxyerysodienone (201) in only 6% yield. The alternative mode of oxidation, leading to 202, was not observed.

70

S. F. DYKE AND S.

N. QUESSY

HO

Ms

Me0

Me0

OH

OH

195

196

I

63",, BF,IEt,O

Meek

OH

?H

Me0

M

e

o

w

\ Ms

w OH

OH 198

197

J

I99 SCHEME 41. Preparation of 14-metho~q.erq.sodienone.

A photochemical method has been employed by Ito and Tanaka (147) to synthesize erybidine (62) (Scheme 42). Irradiation of the bromoamide (203) gave a mixture of lactams 204 and 205. After chromatographic separation, the former was reduced and N-methylated to erybidine. Alkaloids of the erythroidine type have not yet been synthesized, but the parent ring system has been obtained (148) by the method summarized in Scheme 43.

1.

71

E R YTHRI.CA A N D RELATED ALKALOIDS

K,FelCNI,

Me0

Hoq Me0

OH 200

OMe

201

Me0 \

0 202

OH I

Me0

Me0

\

Me0

72

S. F. DYKE AND S. N. QUESSY

C:r

C0,Et

I

PhCHO

(iiJ HCILMeOH

v

SCHEME 43. Preparation oj rlir e r j tliroidiiie skelerori.

B. HOMOERYTHRINA ALKALOIDS The ring system of the homoerythrina alkaloids has been prepared (149)by oxidative coupling of the 1-phenethyltetrahydroisoquinoline (206, R = COCF,) (Scheme 44). The diphenol (208) was obtained in 76% yield from 207, but all attempts to oxidize the N-trifluoroacetate of 208 to a diphenoquinone failed-probably because the two aromatic rings are orthogonal to each other. However, oxidation of the secondary arnine (208) itself with potassium ferricyanide gave a mixture of 209 (45”/d yield) and 210 (15%);

1.

73

ER YTHRINA AND RELATED ALKALOIDS

5?M:e

‘OCF3

Me0 Me0

\

‘ OH

OH 201

206

I

(I) NaOH (11)

(111)

HCI NdBH,

OH

208

0 209

HO

M

e

00

9

210

SCHEME 44. Preparatiori of’ a honioer~.rl~ritia bF ozridarice coupling

these were separated by preparative thin layer chromatography. Sometime previously, Kametani and Fukumoto (150) described the oxidation of 206 (R = H) with potassium ferricyanide and assigned structure 210 to the product, but later they (151)altered this to 209.

74

S. F. DYKE AND S. N. QUESSY

The dienone (210) has also been prepared (152, 153) by oxidation of the amide (211) with potassium ferricyanide, when 212 was obtained in 67% yield. After protection of the phenolic hydroxyl group, reduction with LAH

211

212

removed the amide carbonyl and reduced the dienone to the dienol. Reoxidation and removal of the 0-benzyl group then yielded 210. An alternative preparation of 209 was described (152) in which 210 was converted (I) (11) (111)

BrCl LAH CrO,

Me0 210 89"o

eH

?H

I

chromous chloride

\

209 SCHEME 45. A n alternative preparation of 209

1.

75

E R Y T H R I N A A N D RELATED ALKALOIDS

to the amide (213)in 89% yield by reaction with chromous chloride; the amide (213), after 0-benzylation, reduction with LAH, and de-0-benzylation, gave the amine (208) in 53% yield. Finally, a 60% yield of 209 was realized when the diphenol 208 was oxidized with alkaline potassium ferricyanide (Scheme 45). Interestingly, when the dienone (207) is treated with BF,/etherate (154), rearrangement occurs to give the homoaporphine (214). Oxidation of the tetramethoxy-1-phenethyl-1,2,3,4-tetrahydroisoquinoline (215) with VOF, gave (142) a little of the dienone (210, together with a 64% yield of 217. However, when each was treated with acid, rearrangement occurred to give 218 and 219, respectively.

M::ycoc Me0Y Me0

Me0

\

OH

Me0

.6' OMe

215

214

OMe 0

M:Ip M e 0P \ C

O

217

216

M

e

o

COCF,

Me0 OMr 218

C

OMe

OMe

OMe 219

w

F

3

76

S. F. DYKE AND S. N. QUESSY

c. CEPH.4LOTAXL.S

ALKALOIDS

1. Cephalotaxine The total synthesis of alkaloids of the cephalotaxine type has attracted considerable attention (75) because of the anticancer activity reported for certain derivatives (100) (see Section IV,A). The first synthesis of cephalotaxine (105a) was reported by Auerbach and Weinreb (155,156),closely

OMe 105a

followed by that of Semmelhack et al. (157-159) by a very different route. The former method can be conveniently divided into two stages, with the tricyclic enamine (225) as the first target; the route adopted is summarized

220

224

\

225 SCHEME 46. The prc'paration of the tricyclic enamine (225).

1.

77

ER Y T H R I N A A N D RELATED ALKALOIDS

in Scheme 46. Acylation of 1-prolinol (221) with 3,4-methylenedioxyphenacetyl chloride (220) at - 20" in acetonitrile solution gave the N-acylated compound (222), with only minor amounts of the 0-N-diacyl derivative. Oxidation of 222 to 223 was effected with dimethyl sulfoxide, dicyclohexylcarbodiimide, and dichloracetic acid. Cyclization of 223 to the tricyclic amide (224) was achieved using boron trifluoride etherate. The required enamine (225) was obtained in quantitative yield by reducing 224 with lithium aluminium hydride. The second phaseof the synthesis by Auerbach and Weinreb wasconcerned with the construction of ring D. This proved to be rather difficult and initial attempts failed. Thus, alkylation of 225 with propargyl bromide gave 226, which upon hydration with aqueous mercuric sulfate yielded the expected ketone 227. However, all attempts to cyclize 227 failed. In a modified

(9 (9 225

0

226

I

Me0

C0,Et

228

0A C H ,

227

approach, 225 was alkylated with 4-bromo-3-methoxycrotonate, but again the alkylated material (228) could not be cyclized. The a-dicarbonyl compound (230)was prepared (Scheme 47) by acylating 225 with a 2-acetoxypropionyl chloride in acetonitrile to give 229, which, after hydrolysis with potassium carbonate, was oxidized to 230 with lead dioxide. In a better procedure, wherein 230 was obtained directly in 73% yield, the tricyclic enamine (225) was treated with the mixed anhydride obtained from the interaction of pyruvic acid with ethyl chloroformate. An intramolecular Michael addition was achieved by treating 230 with magnesium methoxide,

78

S. F. DYKE AND S. N. QUESSY

(yq-&-
0

AcO

P-

229

&Me 0 230 52“,

I

Mg(OMe),

0

231

112 Cephalotaxinone

SCHEME 47. Auerharh and Weinreb‘s synthesis of rrp/ialora\-ine.

leading to demethylcephalotaxinone (113). A study of the N MR spectrum revealed that none of the tautomer (231) was present. Demethylcephalotaxinone has been isolated from C. harringtonia ( I l l ) , and the synthetic product was found to be identical to the natural product. However, when 113 was heated under reflux with an excess of 2,2-dimethoxypropane in methanol/ dioxan, cephalotaxinone (112) was formed and isolated in 40% yield. Finally, reduction of 112 with sodium borohydride proceeded in a stereospecific fashion to give racemic cephalotaxine (105a). An alternative route (Scheme 48) was used by Dolby et al. (160)to prepare the tricyclic enamine (225).A Vilsmejer reaction between 3,4-methylenedioxyN,N-dimethylbenzamide (232),and pyrrole gave the amide (233)in 80% yield. Reduction with sodium borohydride provided the benzyl pyrrole (234),which

1.

ER YTHRINA AND RELATED ALKALOIDS

232

233

235

234

236

79

231

lLAH 238

SCHEME 48. Dolbj's preparation o/ enaminc2 225.

was further reduced to 235 catalytically over a rhodium-alumina catalyst. N-Acylation with chloroacetyl chloride gave 236 which on irradiation was cyclized to the tricyclic amide (237). Reduction with 1ithiu.m aluminium hydride yielded the saturated amine (238), and this was converted to the required enamine (225)by treatment with mercuric acetate. A chelating ionexchange resin was used to remove excess of mercuric acetate-a procedure superior to precipitation of the sulfide with hydrogen sulfide. Attempted annulation of 225 with ethyl x-bromoacetoacetate led to the rearranged tetracyclic compound 239 (R = C0,Et) and not to the expected product (240). Hydrolysis and decarboxylation of 239 (R = C0,Et) gave the ketone (239, R = H) which on further reduction yielded the amine (241). identical to the material prepared some years ago (161) by an independent route.

80

S. F. DYKE AND S. N. QUESSY

240

241

239

Alkylation of 225 with bromoacetone (160)gave the expected product 227, but attempts to cyclize this material gave the rearranged compound 239 (R = H) once more. It was postulated by Dolby et al. that the initially formed product was the desired compound 240 which then rearranged to the observed product 239 (R = C0,Et) by the mechanism summarized in Scheme 49. 0

I1

225

BrCH,~-C--CH,CO,El f

240

0

I

0

239 R = C0,Et

SCHEME 49. Dolby's mec~huiiisnt.fbr reurraizgeimwt of' 240

to

239.

1.

81

ER )ITHRI.VA AND RELATED ALKALOIDS

242

243 (I)

TFAA

(iil SnCI,

238

1

244

Hg(OAc1,

225

SCHEME 50. A n alternatice preparation of enaminr 225

Yet another method has been described (162)(Scheme 50) for the preparation of the tricyclic enamine (225). N-Alkylation of ethyl pyrrole-2-carboxylate with 242 in the presence of sodium hydride gave, after hydrolysis, the amino acid (243). This was cyclized to 244, reduced to 238, then oxidized to 225. Alkylation of 225 with propargyl bromide, followed by hydration with a mercuric salt gave the ketone (227), but this could not be cyclized, thus confirming the observation made by Weinreb and Auerbach (156)but contrasting with the report of Dolby et al. (160). A photochemical route to the key amine (238) has been described by Tse and Snieckus (163) (Scheme 51). The maleimide (245) was iodinated in the

245

246

241 SCHEME 5 1. A photochemical prc,parution of tricyclic amine 238

82

S . F. DYKE AND S . N. QUESSY

presence of silver trifluoroacetate at the 6-position, then treatment with methyl magnesium iodide, followed by dehydration gave 246. A 40% yield of 247 was obtained on irradiation of the alkene 246, and reduction then gave 238. The second total synthesis of cephalotaxine (157-159) was very different conceptually since it was a convergent synthesis involving the two intermediates 248 and 249. The azabicyclic intermediate (248) was prepared from pyrrolidone (250) (Scheme 52), which with the Meerwein reagent gave 251. The latter was treated with an excess of ally1 Grignard reagent to yield 252.

249a X = C1 249b X = I

248

251

250

n

254 Me,SiCI

Me,SiO

OSiMe,

L

255

1

i

253

+H

Z 0 -

3

248

J

256

SCHEME 52 Seriimelhach's synthesis of cephalota.uine

1.

ER Y T H R I N A AND RELATED ALKALOIDS

83

N-Acylation with tert-butoxycarbonyl azide to 253 was followed by oxidative ozonolysis and esterification to 254. The yield of 254 from 252 was 61% in a procedure whereby the intermediates were not isolated. The diester (254) was subjected to the acyloin condensation with a potassium-sodium alloy and the product was isolated as the O,O,N-trisilyl compound (255). This was oxidized immediately with bromine to 256 and treatment with diazomethane gave 248. The yield of 248 from 254 was 55%. Intermediates 249a and 249b were obtained from piperonal by standard methods. The essential intermediate 257 required for ring closure to the cephalotaxus skeleton was obtained (about 60% yield) by combining 248 and 249 in acetonitrile solution. A number of methods of cyclization of 257 was studied (Scheme 53). In the first approach 257a was treated with sodium triphenylmethide, when a 13-16% yield of cephalotaxinone (112) could be isolated

257a X 257b X

= C1

112

=I

7

258 SCHEME 53. The cyc1i;atiorr rcvictions t o cephalotasinone

NCOCF,

'$

*

NCOCF,

"OF,

BzO

/

\

OMe

\

BzO

OMe 26 1

260

INaOH

OMe

GMe

OMe

OMe

263

M

e

O

I

( I ) TFA In) CH,N,

g

/ (1)

262

OMe Meo$~

Pd C H,

1111 K K O ,

NCOCF,

HO

/

BzO

\

OMe

\

265

OMe 264

.i

266 SCHEME 54. A hii~genriicull.vputteriicd approach to cc~phali~rurinr.

1.

E R Y T H R I X A AND RELATED ALKALOIDS

85

from the complex mixture. The reaction was presumed to involve the benzyne anion (258) as an intermediate. No improvement in yields could be gained by using the iodo compound (257b) or by variation of the conditions. The yield of 112 was raised to 35% when the anion (259) derived from 257b was treated with a Ni(0) complex to induce nucleophilic displacement of iodine. In an alternative procedure, the anion (259) was treated with a sodiumpotassium alloy to form cephalotaxinone (112) in 45% yield. However cephalotaxinone was obtained in 94% yield when 25713 was treated with potassium tert-butoxide in refluxing ammonia with simultaneous irradiation with a Hanovia 450-W medium pressure lamp. These conditions caused radical cleavage of the aromatic ring-iodine bond in the anion (259),followed by coupling of the aromatic radical with the nucleophilic center. Finally, reduction of 112 with diisobutyl aluminium hydride gave ( -t)-cephalotaxine (105a) An approach to the cephalotaxine skeleton, based upon the presumed biogenetic route, has been reported (164) and involves the oxidation of the I-phenethylisoquinoline derivative (260) with VOF, (Scheme 54). Alkaline cleavage of the dienone (261)gave 262 which, as the hydrochloride salt, was reduced 263. N-trifluoroacetylation followed by 0-methylation yielded 264 which, after hydrogenolysis to 265, was oxidized with potassium ferricyanide to give the dienone (266). 2. Esters of Cephalotaxine Although cephalotaxine itself exhibits no significant antileukemic activity, a number of naturally occurring esters of the alkaloid, the harringtonines (107-110), are active against L1210 and P388 leukemias in mice (89, 100, 108), and so some attention has been devoted to the synthesis of the dicarboxylic acid side chains (see also Section IV,A). The hydroxydicarboxylic acid (270), derived by hydrolysis of deoxyharringtonine, was synthesized by the method shown in Scheme 55 to confirm the structure deduced by spectral methods (see Section IV,A). Conventional chemistry was employed; methyl isopentyl ketone (267)was reacted with diethylcarbonate in the presence of sodium hydride to yield the ketoester (268).Addition of HCN gave 269, hydrolysis of which provided the hydroxydicarboxylic acid (270). The overall yield was 48%. Esterification with diazomethane gave the diester, which was partially hydrolyzed to the halfester (122), the most hindered ester function remaining intact. This, after conversion to the half-ester acid chloride, was used to acylate cephalotaxine. A pair of diastereomorphs was produced, neither of which proved to be identical to deoxyharringtonine. It was concluded that the latter must have structure 110 in which the ester linkage to cephalotaxine involves the tertiary,

86

S. F . DYKE AND S. N. QUESSY

0

261

268

OMe 0 %OH 122

0

123

SCHEME 55. S.vnthetic proof of structure of deoxyharringtonine.

rather than the primary carboxyl group. However, when the isomeric halfester (123) was prepared, acylation of cephalotaxine could not be achieved, presumably because of steric hindrance at the carboxyl group. An alternative synthesis of 123 (165) (Scheme 56) started from the commercially available dimethyl itaconate (271, R = Me). Epoxidation to 272 (R = Me) was achieved with trifluorperacetic acid, and this, with isobutyllithium and cuprous iodide, gave the diester (273, R = Me). The benzyl ester (273, R = CH,Ph) was prepared in a similar way from 271 (R = CH,Ph) and 272 (R = CH,Ph). Catalytic hydrogenolysis of 273 (R = CH,Ph) gave the required half-ester (123). Finally 123 was resolved with ephedrine. Auerbach et d. (165)also failed in their attempts to acylate cephalotaxine to deoxyharringtonine. However, deoxyharringtonine (110)has been synthesized (166-168) by the method summarized in Scheme 57. The lithium salt (274) of 3-methyl-lbutyne was condensed with ethyl tert-butyloxalate to give 275 which, after

1.

87

E R Y T H R I X A AND RELATED ALKALOIDS

CF,CO,H

'C0,Me 271

272

C0,Me 273 ( R = Me = 121) 273 (R = H = 123)

SCHEME 56. A n alternatioe synthesis of the acid 123.

reduction and hydrolysis, yielded the cc-ketoacid (276). Conversion of 276 to the acid chloride followed by reaction with cephalotaxine provided the ester (277). Deoxyharringtonine (110)was produced when 277 was condensed Ll+-C-c

i i

EtO CC0,t-Bu

0

P

o=c-c-c= 1

0-t-Bu

274

275

+ 1

(i) HJPdiC (ii) TFA

(i) SOCI, (ii) cephalotaxine

276

"

I -c'

HO,C

/I

OMe

0 277

\

MeC0,Me;LDA

110

SCHEME 57. Synthesis of deoxyharringtonine

88

S. F. DYKE AND S. N. QUESSY

with the lithium salt of methyl acetate. The mixture of diastereomorphs was separated by thin layer chromatography. The hydroxyacid (118) obtained by the hydrolysis of harringtonine was synthesized (169) by the route shown in Scheme 58. Condensation of the lithium salt (278) with ethyl tert-butyloxalate gave 279, which with the lithium salt of methyl acetate was converted to 280. Hydrolysis with trifluoracetic acid yielded 281 (R = H) which with diazomethane gave the dimethyl ester (281, R = Me). Catalytic hydrogenation and hydrogenolysis with 10% palladium on carbon yielded 118 which, apart from optical rotation, was found to be identical to material obtained from harringtonine, thus confirming the structure of harringtonine deduced by spectral methods (see Section IV,A). When the half-ester (281, R = H) was treated with hydrogen over palladium on charcoal, the lactone (282)was produced. Harringtonine (107) has been synthesizcd (170) by the method shown in Scheme 59. Claisen condensation between 283 and ethyl oxalate in the presence of NaH gave 284 which, when heated under reflux with aqueous HCl, was converted to a mixture from which the oxide (285) was isolated. Without purification, 285 was treated with HCl/MeOH to yield 286, saponification of which yielded the unsaturated acid as its sodium salt 287. After conversion to the acid chloride, reaction with cephalotaxine yielded 288. Li+-Cec 218

4Me,COCOCO,Et

t-Bu0,C

"--J?

1

C=C

219

MeCO:g,LDA

OBz

OH

OBz +

t-BuOZC \CO,Me

281

280

H, Pd C EtOAc

w

0

2

M

e

&H

C0,Me 118

C0,Me 282

SCHEME58. Synthetic proof o j structure of harrinytonine

1.

E R YTHRINA A N D RELATED ALKALOIDS

89

Hydration of the double bond of 288 gave 289, on which a Reformatski reaction was performed to yield harringtonine (107) together with epiharringtonine (because of the two modes of hydration of the double bond in 288) (Scheme 59). The required ester (283) was prepared by first condensing isobutyraldehyde with malonic acid to form 290, followed by isomerizing with CHCH2C02Et

283

286

(CO,Et), NaH

’

0

I1

)

I

CHCHCC0,Et C02Et 284

285

LCO*Me 107 SCHEME 59. S?;nthesis of harringronine

90

S. F. DYKE A N D S. N. QUESSY

base to 291 and then by esterifying to 283. A very similar route to harringtonine has been described by Chinese workers (171).

: i-x CHO

CH=CHCO,H 290

1 -

283

BF, EtOH

KOH H,O

>,:HCH2COzH 29 1

In the structural analysis of isoharringtonine (109),the relative configuration of the diacid side chain was solved (172) by a synthesis (Scheme 60).

_j____l_

C0,Et COMe

-!(LL!?KOH %,

WCozH

292

/ *o

293

H

C0,Me

d%C02Me =5 . 8 5 3

CO,H

C0,Me

0 294

H? 6 = 6.8

295

297

I

.."..x

OSO, H,O,

0 5 0 ,

0,Me

, C0,Me OH

296

I

MeO,C&H OH 298

SCHEME 60. Relatiue configuration of side chain of i.so/zarringtorzine.

H,O,

1.

ERYTHRI,VA AND RELATED ALKALOIDS

91

Trans-esterification of the alkaloid with sodium methoxide gave a single dimethyl ester which possessed either the threo (298) or the erythro configuration (296). Ethyl isoamylacetoacetate (292) was converted to 293 by a method developed by Vaughn and Anderson (173). Esterification of 293 gave the trans-dimethyl ester (297) which, with osmium tetroxide and hydrogen peroxide, yielded the single diol (298). This was assigned the threo configuration, in view of the known cis-hydroxylation achieved by osmium tetroxide. In an alternative sequence, the diacid (293)was dehydrated with P,O, to the anhydride (294), which in turn was esterified to the cisdiester (295). The vinyl proton absorption at 6 5.85 for 295 compares with the value of 6 6.8 for the trans structure (297). Cis-hydroxylation of the cis-diester (295) yielded the erythro compound (296). The PMR spectrum of 296 was found to be identical with that of the diol diester derived from isoharringtonine. The absolute configuration of the side chain of isoharringtonine has been deduced (174)to be 2R,3S(299)by comparing the C D spectra of its molybdate complexes with those of piscidic acid (300)of known absolute configuration.

COzH

CO,H

299

300

An alternative synthesis of 295 involves (175)the addition of diisoamyllithium cuprate to dimethylacetylene dicarboxylate. The major product (89%) was the required 295 together with some 297. The mixture was separated by chromatography.

VII. Pharmacology Many Erythrina alkaloids possess curare-like action. Alkaloidal extracts from different parts of Erythrina species have been used in indigenous medicine, particularly in India ( 176).Many pharmacological effects, including astringent, sedative, hypotensive, neuromuscular blocking, CNS depressant, laxative, and diuretic properties, have been recorded for total alkaloid extracts, although not all these properties can be associated with the erythrinane structure alone (38, 177, I78). A few purified Erythrina alkaloids have been shown to have useful pharmacological properties. Cocculine (56) and cocculidine (54) nitrates have been

92

S . F. DYKE AND S . N. QUESSY

reported to show hypotensive action in dogs, due mainly to ganglionic blocking action. Neither alkaloid had a significant effect on the CNS (179). Isococculidine (37)was shown to be a weak blocking agent at the cholinergic receptor in frogs (180).The juice of the leaf and bark of E. suberosa Roxb. was reported to have antitumor activity and the major alkaloid isolated was erysotrine (1)(181).Erysotrine was found to exhibit properties consistent with those of a competitive neuromuscular blocking agent in anaesthetized dogs (182). Cocculolidine (61) was reported to be an insecticidal alkaloid (76). Analogs of Erythrina alkaloids that lack the aromatic ring have been prepared for structure-activity studies (183). Antitumor activity in P388 and L1210 experimental leukemia systems was detected in extracts from the seeds of C. harringtonia K. Koch var. harringtonia (8,95).It was soon discovered that the major component, cephalotaxine (105a), was inactive and that the activity resided in the esters 107-110 (the harringtonines) ( 184187). Harringtonine (107) and homoharringtonine (108) had about the same activity in the P388 system and both were more active than deoxyharringtonine (110) and isoharringtonine (109).The latter two were only marginally active in the L1210 system (8).The optimum dose (for mice) was in the range 2-12 mg/kg by intraperitoneal injection over a period of 9 days (186, 187). Harringtonine appears to be the most effective agent and recent studies in the People’s Republic of China have shown that it is effective against L615 leukemia, L7212 leukemia, sarcoma 180, and Walker carcinosarcoma 256 (188).Harringtonine also appeared to be effective in the treatment of acute and chronic myelocytic leukemia in humans (189). The mode of action of the harringtonines has been investigated. All inhibit protein synthesis in eukaryotic cells (190-192). The principal effect of harringtonine was inhibition of protein biosynthesis in HeLa cells (193). Homoharringtonine, a potential antineoplastic alkaloid ( 194, was cytotoxic in HeLa, KB, and L cells growing in monolayer cell cultures (194). In view of the difficulty in obtaining a sufficient supply of the active esters for biological screening, considerable effort has been applied to the problem of preparing the esters from the more readily available cephalotaxine (105a) (see Section V1,C). This effort has also resulted in the preparation of many analogs containing ester groups that do not occur in the natural alkaloids and that have been used to obtain structure-activity relationships (168, 171, 195). Although some degree of structural variation must be tolerated, since homo-, iso-, and deoxyharringtonine show activity, most of the synthetic esters were found to be inactive (195).From a large number of cephalotaxine esters, the only synthetic ones to show significant activity in the P388 systems are those having the side-chain structures 301-304 (196).There appears to be little rationality in the structure-activity relationship.

1.

E R Y T H R l N A AND RELATED ALKALOIDS

93

OCH, 301 R = COC(=CH,)CH,CO,Me 302 R = COCH=CHCO,Me(trans) 303 R

=

H ,,,, ,OCO,CH2CC1, CO-C, Ph

304 R = CO2CH2CCI3

REFERENCES 1. R. K. Hill, in “The Alkaloids“ (R. H. F. Manske, ed.), Vol. 9, p. 483. Academic Press, New York, 1967. 2. A. Mondon and K. F. Hansen, Tet. Lett. 5 (1960). 3. T. Kametani, “The Chemistry of the Isoquinoline Alkaloids,” p. 167. Elsevier, Amsterdam, 1969. 4. A. Mondon, in “Chemistry of the Alkaloids” (S. W. Pelletier, ed.), p. 173. Van NostrandReinhold, Princeton, New Jersey, 1970. 5. T. Kametani and K. Fukumoto, Synthesis 657 (1972). 6. A. McL. Mathieson, Int. Ret;. Sci.: Phys. Chem., Ser. Two 11, 177-216 (1975). 7. S. M. Weinreb and M. F. Semmelhack, Acc. Chem. Res. 8, 158 (1975). 8. C. R. Smith, R. G . Powell, and K. L. Mikolajczak, Cancer Treat. Rep. 60,1157 (1976). 9. J. A. Findlay, Int. Rev. Sci.: Ory. C/7em., Ser. Two 9, 23 (1976). 10. V. A. Snieckus, Alkaloids (London) 1, 145 (1970). 10a. V. A. Snieckus, Alkaloids (London) 2, 199 (1971). lob. V. A. Snieckus, Alkaloids (London)3, 180 (1972). 1Oc. V. A. Snieckus. Alkaloids (London) 4, 273 (1973); 5. 176 (1974): 7, 176 (1976); S. 0. De Silva and V. A. Sneickus, ibid. 8, 144 (1977). 11. R. B. Herbert, Alkaloids (London) 1, 22 (1970); 5, 24 (1974): 8, 10 (1977). 1 la. R. B. Herbert, Alkaloids (London)6, 23 (1975). 12. D. E. Games, A. H. Jackson, N. A. Khan, and D. S. Millington, Lloydia 37, 581 (1974). 13. P. H. Raven, Lloydia 37. 321 (1974). 14. B. A. Krukoff and R. C. Barneby, Lloydia 37,332 (1974); 40,407 (1977). 15. D. S. Millington, D. H. Steinman, and K. L. Rinehart, Jr., J . Am. C/iem. Soc. 96, 1909 (1974). 16. R. T. Hargreaves, R. D. Johnson, D. S. Millington, M. H. Mondal, W. Beavers, L. Becker, C. Young, and K. L. Rinehart, Jr., Llojdia 37, 569 (1974). 17. I. Barakat, A. H. Jackson, and M. I. Abdulla, Lloydia 40,471 (1977). 18. D. H. R. Barton, R. James, G . W. Kirby, D. W. Turner, and D. A. Widdowson, Chem. Conmzun. 294 (1966). 19. D. H. R. Barton. R. James. G. W. Kirby. D. W. Turner. and D. A . Widdowson. J . Chem. SOC.C 1529 (1968).

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