Chapter 11 The Erythrina Alkaloids

CHAPTER11

The Erythrina Alkaloids V. BOEKELHEIDE University of Rochester, Rochester, New York I. Introduction ...................................................... 11. Elucidation of Structure ............................................ 1. Correlation of the Aromatic Erythrina Alkaloids with a- and P-Erythroidine and a Uniform Style of Presentation.. ................... 2. Hexahydroapoerysotrine and Correlation of the Eryso- nncl ErythraAlkaloids ...................................................... 3. The Apo Rearrangement.. .............. ............. 4. The Apo-Isoapo Rearrangement. ................................. 5 . Synthesis of the Dimethyl Ether of Apoerysopine.. . . . . . . . . . . . . . . . . . 6. Hofmann Degradations and Aromatization of Ring A . . . . . . a. p-Erythroidine Series.. ....................................... b. m-Erythroidine Series. ............................. c. Arrangement of the Lactone Ring in a-Erythroidine.. . 7. von Braun Degradation with Aromatization of Ring A.. ............ 8. Aromatization of Ring A during Hydrogenation of Desmethoxy-/3........ Erythroidine ....................................... 9. Position of the Aliphatic Methoxyl Group. ........................ 10. Deduction of the Spiro Structure.. ............................... 11. Erysonine and Erythratine. ........................ 111. Syntheses of the Spiro Amine System.. . . . . . . . . . . . . . . . . . . IV. Possible Biogenetic Relationships. ...................... V. Pharmacology ........................................ VI. Tables of Physical Constants.. ...................................... 1. Table 1. The Basicity of the Erythrina Alkaloids and Sonw of Their Derivatives.. ................................................... 2. Table 2. Ultraviolet Absorption Maxima (and VII. References.. ................................ VIII. Addendum .......................................................

Page 201 202 202 203 205 206 207 209 213 214 215 216

225 225 227

I. Introduction At the time when the chapter on the Erythr~nualkaloids was written, the isolation and characterization of the members of this family was essentially complete. Only two new alkaloids have since been discovered and both of these are simple derivatives of erysodine. Thus, Lapiere found the glucoside of erysodine, glucoerysodine, to be a constituent of Erythrina abyssinica Lam. (46, 47), and quite possibly this is the form in which erysodine is generally present in species of Erythrina. The second discovery was that of dihydroerysodine, which Tomita found to 201

202

1 ' . BOEKELHEIDE

be present in Cocculus laurifolius D C . a member of the Menispermaceae (48). Its identity was established by comparison with an authentic sample of dihydroerysodine obtained by catalytic hydrogenation of erysodine. This observation is gratifying because it is in full accord with the scheme of biogenesis proposed for the Erythrina alkaloids. I n the early chapter the discussion of the chemistry of the Erythrina alkaloids was mainly concerned with the pioneering work of Folkers and his collaborators. Around 1949 there was a revival of interest in these alkaloids, with a number of laboratories becoming quite active. The extensive degradation studies which were carried out have led to structures for all the Erythrina alkaloids, which are now generally accepted. The elucidation of structure of the aromatic Erythrina alkaloids was a contribution of the Zurich Laboratory and the structures of a- and /3-erythroidine came from work in the Rochester Laboratory (49-51). The following discussion will be concerned entirely with these new structures and the experimental basis for their deduction. 11. Elucidation of Structure*

Erythrina ALKALOIDS WITH UNIFORM STYLEOF PRESENTATION I n the early investigations discussed in Chapter 14 of Volume 11 it was concluded that the aromatic Erythrina alkaloids and the erythroidines represented two distinct groups which differed rather markedly in their chemical nature. This influenced the degradation studies such that the chemical work done on the two groups was almost entirely independent, even to the style of presentation used to represent the structures finally deduced. Thus, the general structure first drawn to represent the aromatic Erythrina alkaloids is given by IX, whereas that first used for 6-erythroidine is shown by X. 1.

CORRELATION OF THE AROMATIC

a- AND /3-ERYTHROIDINE AND A

:&

R R2O IOQ+ f \

R3O

IX

/

X

Although there is still no direct experimental evidence to prove a correlation between the two groups of compounds, it is now accepted that they are closely related and, disregarding stereochemical relationships, differ only in that the erythroidines have a 6-lactone ring where * This material is supplementary to Volume 11, pages 502-508.

203

THE ERYTHRINA ALKALOIDS

the benzenoid ring occurs in the aromatic Erythrina alkaloids. For ease of presentation and to avoid needless duplication, we propose to use the style of presentation shown by structures XIa-g for all the Erythrina alkaloids. These structures emphasize the indole portion of the molecule which is the feature common to both groups.

Xlf

XI Xla,

R, and R, = -CH,--,

Xlb,

Rl = R,

=

-H,

Erysopine

R, or R,

=

-H,

Erysodine

R, o r R,

=

-CH,,

R, = R,

= -CH,,

Xlc, and

Xld, Xle,

1

Erythraline

!

8-Erythroidine

and

Erysovine Erysotrine 0

X'9 a-Erythroidine

Erysotrine (XIe), shown above, does not occur naturally but is the trivial name given to a common transformation product, included for purposes of reference. The other Erythrina alkaloids, the structures of which are not shown, include dihydroerysodine; erythramine, which is identical with dihydroerythraline obtained by catalytic hydrogenation of erythraline; and erythratine and erysonine, the structures of which are discussed later. With these structures in mind, we can discuss the experimental evidence leading to their deduction. 2. HEXAHYDROAPOERYSOTRINE AND CORRELATION OF

THE

ERYTHRA-ALKALOIDS One of the outstanding features of structures XIa-g is the heteroannular diene system present in rings A and B. Its presence is surmised from the fact that all these alkaloids have an absorption maximum in the ultraviolet around 235 mp (see Table 2). Hydrogenation to the corresponding di- and tetrahydro derivatives occurs readily and drastically lowers the absorption in this region. From the extensive studies on ERYSO- AND

204

V. BOEKELHEIDE

ultraviolet absorption spectra of conjugated dienes (51, 52), it seems evident that the conjugated diene is of the type shown. The presence of the aliphatic methoxyl group in the neighborhood of the conjugated diene system is revealed by the behavior of erysodine (XIc), erythraline (XIa), and a- and /?-erythroidine (XIf, g) on treatment with acid under mild conditions. All these alkaloids (52a, 53-55) lose the elements of methanol with lengthening of the diene to a conjugated triene system, which has a strong absorption maximum around 313 mp (see Table 2 ) . Again, by analogy from the spectra of known conjugated trienes (52), it can be deduced that the products of these acid-catalyzed eliminations are best represented by the type of triene system present in structures XIIa,c,f,g.

& -

0

CH,

XI *

XI1

I n the case of erythraline and erysodine, the desmethoxy derivatives,

Pt

0 OH CH,

Apoerysodine

Hexahydroapoer.ysotrine

O\

P

CHI

Apoeryt hraline

*

Generalized formulas are used in this and subsequent illustrations, in which the bracket indicates ring D and addition of the alphabetical letter to the roman numeral of the formula indicates which particular ring D is being discussed.

THE ERYTHRINA ALKALOIDS

205

XIa,c, are known as apoerysodine and apoerythraline (despite their unfortunate names they should not be confused with the true apo derivatives resulting from skeletal rearrangement to be discussed later). When apoerysodine and apoerythraline are hydrogenated followed by the conversion in each case of the oxygen functions in ring D to methyl ether linkages, the resulting hexahydroapoerysotrine is the same from each series (53). It follows therefore that erysodine and erythraline must have not only the same carbon skeletons but also the same stereochemistry at the spiro atom 5. 3. THEAeo REARRANGEMENT

When the original alkaloids (XIa,c,f) or their desmethoxy derivatives (XIIa,c,f) are subjected to acid treatment under stronger conditions, i.e., boiling hydrobromic acid or polyphosphoric acid at 125", a rearrangement with aromatization of ring A occurs (52a, 53-55). This reaction, known as the apo-rearrangement, leads to a dihydroindole derivative as shown by XIVb,f. If an intermediate carbonium ion, XIIIb,f, is assumed, the overall course of the rearrangement becomes clear.

XI1

n+

;i7

Y

XIV

Xlll

In the case of the aromatic Erythrina alkaloids, the apo-rearrangement is accompanied by cleavage of the aromatic ether linkages in ring D so that the product in each case is apoerysopine (XIVb). Also, since the apo-rearrangement results in destruction of both asymmetric atoms, apoerysopine and apo-/3-erythroidineare optically inactive. Proof for the indoline structures, XIVb,f, is now quite abundant. The spectral and physical properties, particularly the weak basicity, of these molecules are in agreement with the assigned structures. Further, apo-/3-erythroidineis readily dehydrogenated to a true indole derivative, XV (56, 57). When apo-,%erythroidineis oxidized with permanganate, it yields 7-carboxyisatin (XVI) and 2-aminoisophthalic acid (XVII), showing the points of attachment to be at the 1 and 7 positions of the indoline nucleus.

206

V . BOEKELHEIDE

Both apo-/3-erythroidine and the dimethyl ether of apoerysopine have been carried through the Hofmann exhaustive methylation procedure (57-60), and these reactions are illustrated below. The infrared absorption spectra were particularly valuable in showing that the intermediate olefins, XVIIIe,f and XXe,f, are of the type, RCH = CH,. I n the apoerysopine series, dehydrogenation of X I X to give X X I I demonstrates again the presence of an indole nucleus.

xvnl

XIX

C H,O

XXll

4. THEAPO-ISOAPO REARRANGEMENT

I n the case of p-erythroidine (XIf), the aliphatic double bond in Ring D appears to be stable and does not isomerize into conjugation with the lactone carbonyl as long as the spiro amine system is intact. However, with aromatization of ring A, as in the apo-rearrangement, the double bond becomes unstable and is readily isomerized into conjugation by even such mild conditions as chromatography over alumina. This isomerization is illustrated below by the conversion of apo-8-erythroidine, XIVf, to isoapo-p-erythroidine, X X I I I (69).

THE ERYTHRINA ALKALOIDS

3

207

0 0

XlVf

XXlll

Again, in the case of apo-/3-erythroidine, this isornerization was useful to show that the first stage of the Hofmann exhaustive methylation of apo-/3-erythroidine resulted in cleavage of the seven-membered ring rather than the five. Thus, chromatography of XVIIIf results in isomerization to the yellow compound, XXIV. Since ozonolysis of XVIIIf gives formaldehyde whereas XXIV gives acetaldehyde, the Hofmann reaction must have cleaved the seven-membered ring as shown (59).

Me

0

CH=CH,

XVlllf

0

XXIV

5. SYNTHESIS OF THE DIMETHYL ETHEROF APOERYSOPINE

Of the various degradation products isolated in the structural studies, the optically inactive apo derivatives appeared to represent the most attractive choice for obtaining synthetic confirmation of the structural proposals. Recently, Wiesner and his collaborators have accomplished this important objective by preparing XIVe and showing that it is indeed identical with the dimethyl ether of apoerysopine from natural sources (61, 62). Their method of synthesis is outlined below.

CH,

208

V. BOEKELHEIDE

2 OH

XIV

Synthetic studies directed toward the apo-p-erythroidine structure, XIVf, have led to model compounds such as XXV, which show similar chemical and spectral properties (63-65). However, direct synthetic confirmation is still lacking in this case.

e CH,

H3

x xv

6. HOFMANN DEGRADATIONS AND AROMATIZATION OF RINGA Although the Hofmann exhaustive methylation procedure has been used extensively in degrading the Erythrina alkaloids, there are relatively few instances in which the reaction proceeds in a straightforward fashion with simple introduction of a double bond. With the tetrahydro derivatives, XXVIa,e, the reaction follows a normal course t o give XXVITa,e:(66).

62

Hotmann

CH, U

XXVl

XXVll

THE ERYTHRINA ALKALOIDS

209

However, with the less highly saturated derivatives the Hofmann reaction is accompanied by aromatization of ring A and frequently elimination of functional groups may occur as well. Since the Hofmann reaction has been particularly important in the case of the dihydro a- and /3-erythroidines in establishing not only the carbon skeleton but the lactone ring arrangements as well, these will be discussed separately. a. 8-Erythroidine Series. When dihydro-/3-erythroidine (XXVIII) is converted to the corresponding quaternary betaine (XXIX) and this is subjected to thermal decomposition, aromatization occurs with elimination of both oxygen-containing functional groups to give XXX (54,67). To avoid the decarboxylation and maintain marking groups to indicate

21 MeI_ OH-

-

CYO

& cH,

0

XXVlll

0

CH,

CH20H

co; XXIX

CH,

CH,

xxx

the point of attachment of the lactone ring, dihydro+erythroidine was reduced with lithium aluminum hydride to give the corresponding diol (XXXI), and this in turn was subjected to the exhaustive methylation procedure (68). I n this case aromatization of ring A was accompanied by loss of methanol but the diol function remained intact as shown by XXXII. The further steps in the exhaustive methylation procedure with the diol are summarized in the reaction scheme below.

OH

XXXI

OH

XXXll

J

0

210

V. BOEKELHEIDE

on

Again, through ozonolysis and infrared spectral studies the intermediate methine bases were shown to be of the type, RCH=CH,. Also, the final oxidation product, o-ethylbenzoic acid, was identified by comparison with synthetic material. The arrangement of the diol function derived from the lactone ring was found when attempts to hydrogenate the aliphatic double bond present in XXXI led to hydrogenolysis of the allylic alcohol group rather than reduction. That the allylic alcohol was a t the position shown was established by taking the hydrogenolysis product, XXXIII, and carrying it through a similar Hofmann degradation series to give XXXIV. This, by ozonolysis, yielded methyl ethyl ketone. This result leads to the deduction that the only compatible arrangement of the &lactone ring present in p-erythroidine is that shown by XIf.

b. a-Erythroidine Series. A similar series of Hofmann degradations was attempted in the case of a-erythroidine but, owing to the different location of the aliphatic double bond, the reaction sequence took a

THE ERYTHRINA ALKALOIDS

21 1

somewhat different course (69). As illustrated, dihydro-a-erythroidine (XXXV) is converted by lithium aluminum hydride to the corresponding diol (XXXVI), which in turn undergoes the Hofmann reaction with aromatization of ring A and elimination of the elements of methanol to give XXXVII. I n contrast to the corresponding product in the ,f?-erythroidineseries, XXXVII retains optical activity and undergoes catalytic reduction of the aliphatic double bond without hydrogenolysis of the allylic alcohol. It is also of interest that, in the final stage of the exhaustive methylation procedure, elimination of the trimethyhmino group occurs through internal displacement forming a tetrahydrofuran ring rather than by the normal introduction of a double bond.

o

CHCH, :H,bH

xxxv

bH

XXXVI

Confirmation of the structure of the final degradation product, XXXVIII, has been sought through independent synthesis. Recently,

212

V. BOEKELHEIDE

the synthesis of racemic jl-(0-ethylbenzoy1)-tetrahydrofuran (XXXVIII) has been accomplished following the scheme shown below (70). Since the racemic and natural samples of XXXVIII have superimposable infrared spectra, it is reasonably certain that the postulated structures for the a-erythroidine degradation sequence are correct.

0

XXXVlll C. Arrangement of the Lactone Ring in a-Erythroidine. The Hofmann degradation sequence in the case of 8-erythroidine leads to an unambiguous assignment of the lactone ring as shown in structure XIf. However, although the corresponding sequence for a-erythroidine places the double bond at the 13-14 position, it does not distinguish between having the carbonyl group a t C,, or Cl,. I n the original discussion of this point (69), the assignment of the lactone carbonyl to C1,,as shown by XXXIX, was made on the basis that the ultraviolet and infrared spectra of a-erythroidine were not in agreement with the presence of a conjugated carbonyl.

XXXIX

Further investigation (70) has cast doubt on the validity of the spectral argument and has led to a reinvestigation of this point. When dihydro-a-erythroidine was converted to the corresponding betaine (XL) and this was slowly decomposed thermally, a mixture of products resulted, one of which was identical with the oxygen-free product (XXX) obtained in a similar way from the betaine (XXIX) of dihydro/3-erythroidine. Since the degradation of a- and B-erythroidine to this common product involves removal of the lactone carbonyl through decarboxylation, the only rational explanation for this result is that the

THE ERYTHRINA ALKALOIDS

213

carbonyl function occupies the same position in both a- and /3-erythroidine and the difference between the two relates to the difference in position of the carbon-carbon double bond.

$;,

+ CO,+ CH,OH

CH,CH,

,COY

xxx

XL

On the basis of the above argument that a- and 13-erythroidine are simply double bond isomers, it should be possible to effect an interconversion providing the stereoehemical relationships are the same for both. This has now been done (70). As shown below, dihydro-a-erythroidine is isomerized in base to give dihydro-/3-erythroidine, identical in all respects with authentic material. Thus a- and p-erythroidine are exactly alike, stereochemically and otherwise, with the exception of the location of the double bond in the D ring. It is of interest that the equilibrium in the above isomerization lies almost entirely on the side of the nonconjugated isomer, dihydro-8-erythroidine. As discussed under the apo-isoapo rearrangement, when the spiro ring is not present, the position of equilibrium is reversed.

c't,

CHI

-

-

OH-

~

0 0

D i hydro oc -er ythroidine

Dihydro

0

- fi -cry t hroidine

7. VON BRAWN DEGRADATION WITH AROMATIZATION OF RINGA Although a comparable Hofmann-aromatization reaction has not, as yet, been demonstrated with the aromatic Erythrina alkaloids, a very similar aromatization was encountered in studies of the reaction of dihydroerysotrine (XLI) with cyanogen bromide (71). In this case the initial product was not isolated but was treated directly with lithium aluminum hydride to give a compound having the chemical and spectral properties to be expected for the biphenyl derivative (XLII). This has been interpreted as shown below.

214

V. BOEHELHEIDE

0 0

CH, CH,

XLI

0

0

CH, CH,

3.

n

XL II

8.

RINGA DURING HYDROGENATION OF DESMETHOXY -/~-ERYTHROIDINE

AROlMATIZATION O F

A final example of the ease with which aromatization of ring A occurs is provided by studies on the catalytic hydrogenation of desmethoxyB-erythroidine (XIIf).I n neutral solution hydrogenation of desmethoxy8-erythroidine over platinum yields an optically inactive, aromatic substance the properties of which are in agreement with those to be expected for the tetrahydroisoquinoline structure, XLV. This unusual transformation has been interpreted as shown below (72). I n the initial stage it is presumed that the labile allylic amine linkage suffers hydrogenolysis with aromatization of ring A to give XLIII. This, in turn, can undergo the apo-isoapo rearrangement to XLIV which, when followed by addition of the secondary amine, gives the postulated product, XLV.

qy 0

Xllf

XLlll

-*

THE ERYTHRINA ALKALOIDS

0

0

215

0

c

Support for this postulation is found in the fact that catalytic reduction of desmethoxy-/3-erythroidinol methochloride (XLVI) results in hydrogenolysis yielding XXXII, identical with the Hofmann degradation product discussed previously (72).

OH

XXXll

9. POSITION OF THE ALIPHATIC METHOXYLGROUP

A t present, chemical evidence regarding the position of the aliphatic methoxyl group is available only for 13-erythroidine. As shown below, when p-erythroidinol (XLVII)is subjected to the Hofmann degradation, aromatization occurs in this case without loss of the methoxyl group and the product is XLVIII. Permanganate oxidation of XLVIII yields 4-methoxyphthalic anhydride, establishing that the methoxyl group in p-erythroidine must be either at position 2 or 3. That position 3, and not 2, is the correct one can be decided from several pieces of evidence. If the methoxyl group were at position 2, p-erythroidine

216

V. BOEKELHEIDE

should behave as an enol ether, which it does not. Secondly, the methoxyl group at position 3 is allylic and, therefore, might be expected to be eliminated during reduction following the Birch procedure (73); this is found to be the case (54). As mentioned earlier, the interconversion of dihydro-a- and dihydro8-erythroidine (see p.213) establishes that the position of the methoxyl group in a-erythroidine is also at C,. In the aromatic series the evidence, aside from analogy and biogenesis, is based on an X-ray analysis of erythraline hydrobromide (74) which places the methoxyl likewise at the 3-position. 10. DEDUCTION OF THE SPIRO STRUCTURE

From the degradative evidence it can be seen that the Erythrina alkaloids give rise to two important series of products in which ring A has become aromatized. On the one hand, these alkaloids go over to an indoline-type structure (XIV) and, on the other, t o an ortho disubstituted benzenoid structure (XXXII). To explain the origin of these two series of products, the spiro structure proposed for these alkaloids appears to be not only a satisfactory solution but a necessary requirement.

63x IV

J

XXXll

11. ERYSONINE AND ERYTHRATINE

From a comparison of their physical properties, it seems quite likely that erysonine is identical with desmethylerysodine, a degradation product of erysodine (53). On this basis Prelog and associates have suggested formula XLIX for erysonine. Similarly, from the evidence of Folkers et al. (74a, 75) it seems very likely that erythratine has structure L. However, conclusive proof for both these structures is still lacking.

q

THE ERYTHRINA ALKALOIDS

217

/ /

0 0

k, R,

XLlX

III. Syntheses of the Spiro Amine System I n the previous discussion, all the syntheses mentioned were of degradative products the relationship of which to the original alkaloids involved rearrangements destroying the spiro amine system. It was highly important, therefore, to obtain a correlation between synthetic material and natural material in which this system is still intact. Although a number of preliminary experiments in this direction were made (76-78), the first successful synthesis of a compound containing the desired spiro amine system was that of Belleau (79). This elegant synthesis is illustrated below for the parent compound (LIII, R = H), to which the trivial name erythrinane has been given.

aO1 LIV

L"

218

V.

BOEKELHEIDE

Later, Bellean (SO) repeated the synthesis using the corresponding dimethoxy derivative and obtained racemic hexahydroapoerysotrine (LIII, R = OCH,). The infrared spectrum of the picrate of this racemic mixture proved to be superimposable with the spectrum of the picrate of natural hexahydroapoerysotrine obtained from the degradations described earlier. Recently. Mondon (81) has demonstrated that cyclization to form the spiro amine system occurs even more readily when the lactam carbonyl is placed in the potential five-membered ring instead of the six. When the ketal acid (LIV) is warmed with 3,4-dimethoxyphenethylamine (LV) in the presence of acid, a condensation-cyclizationreaction occurs very smoothly and in excellent yield to give the amide (LVI, R = OCH,). This, on reduction with lithium aluminum hydride, gives the same racemate of hexahydroapoerysotrine obtained previously by Belleau. Contrary to the original report (82, 83) it is necessary that catalytic amounts of acid be added or the initial condensation stops at the stage of the ketal-amide (LVII). However, the ketal-amide in turn is readily cyclized by acid to give LVI (R = OCH,). .O

LVII

0 0 CH,CH,

From the method of cyclization employed in the Belleau and Mondon syntheses, it is not possible to predict with certainty the stereochemistry of the product. If the cyclization were a concerted process, the expected product would be LVIII. On the other hand, if there were a relatively stable carbonium ion as an intermediate, the thermodynamically more stable product would be expected, which is probably LIX. From the fact that natural hexahydroapoerysotrine is obtained through a hydrogenation step which must fix the stereochemistry of its spiro ring fusion in the same manner as shown by LVIII, it seemed evident that the cyclization must therefore be a concerted process. Since the establishment of identity by spectral comparison may be open to question when diastereoisomers are involved, it was desirable to obtain unequivocal proof that the synthetic sample was indeed identical with natural hexahydroaposerysotrine. The racemic base

219

THE ERYTHRWA ALKALOIDS

CH,CH,

CH, CH,

LVlll

LIX

corresponding to LIII (R = -0CHJ has been prepared by the Mondon procedure and resolved through the use of optically active dibenzoyltartaric acid (84). Of the two enantiomers, the base recovered from the (-) dibenzoyl-L-tartrate proved t o be identical with natural hexahydroapoerysotrine. Thus, the fact that the synthetic and natural isomers have the same mode of ring fusion is beyond question. Of the two syntheses, the cyclization in the Mondon procedure occurs appreciably more readily than that in Belleau’s. Exactly why this should be so is not clear. However, this difference is quite evident in the application of these methods to nonaromatic analogs. Thus, the preparation of LX by the Mondon route using cyclohexenylamine occurred smoothly in good yield (84). On the other hand, attempts to prepare LX by Belleau’s method gave a different product in poor yield. That LX has the structure assigned was established by preparing it independently through the Birch reduction of erythrinane, LIII (85).

Et NH,

a LX

Llll

Two other routes leading to the spiro amine system with oxygen present in ring A have been devised. Thus, Wiesner and his collaborators (86) prepared a compound which may be LXI by the route shown below.

T:

CH,

+

H,N

0 CH,

2oooc_ CH,=CHCH,

0 CH,

+$% CH,-CH,OH

0

0

CH, CH,

220

V . BOEKELHEIDE

0 0 CH,CH,

0 0

CH,CH1

LXI

Likewise, Prelog (87) has prepared a compound having structure

LXII. As yet neither compound LXI nor LXII has been related to a degradative product from the a.roniatic alkaloids.

P

+

ct

9 q -

n,

pH12

0

0

0 0 CH,CH,

LXll

0 0

IV. Possible Biogenetic Relationships Although there have been a number of speculations on the biogenesis of the Erythrina alkaloids (49-51, 88-90), there is no experimental basis on which to judge these proposals and their usefulness lies in the extent to which they correlate and predict structural relationships. The spiro amine system, being new in the alkaloid field, might be

THE ERYTHRINA ALKALOIDS

221

expected to arise through a new type of variation in biogenesis. As outlined below, the most satisfactory scheme envisions a combination of two molecules of 3,4-dihydroxyphenylalanineto give an indole nucleus. Since indole alkaloids are usually considered to arise through incorporation of tryptophan as a building block and condensation of 3,4-dihydroxyphenylalaninewith itself is the accepted scheme for producing isoquinoline alkaloids, the outstanding feature of the present scheme is that it represents an overlap of the two great biogenetic pathways for forming indole and isoquinoline alkaloids. CH, HCO,H 4

uo

HO

OH

HO HO

OH

OH

Er ysopinc

o<-and@-Erythroidinc

OH

222

V.

BOEKELHEIDE

I n this scheme erysopine appears as a key intermediate for the elaboration of the various aromatic alkaloids as well as for U - and 8-erythroidine. Since these further alterations do not affect the stereochemistry a t C, and C,, it would be expected that all the Erythrina alkaloids would have the same spatial arrangement at these asymmetric atoms. As yet no stereochemical correlations have been established between the aromatic Erythrina alkaloids and the erythroidines, and this remains as one of the outstanding problems in this field. Actually, the most important insight into the stereochemistry of the Erythrina alkaloids has come from the X-ray studies of Nowacki and Bonsma on erythraline hydrobromide (91). On the basis of their results erythraline has either the spatial configuration shown below or its mirror image.

Stereochemical Formulation for Erythraline

V. Pharmacology The early work of Unna on the curariform activity of the Erythrina alkaloids has been summarized in Volume V, page 281. More recently, though, Slater and his colleagues (92, 93) have published a more definitive study on 8-erythroidine and its derivative in which testing was done for both peripheral and central nervous effects. These results are presented in Tables A and B. As can be seen, all the spiro amine derivatives show either neuromuscular or ganglionic blocking effects, or both. The peculiar fact that quaternization of these tertiary amines lowers the intensity of their neuromuscular blocking action is again verified. However, the effect of quaternization on ganglionic blockade is much smaller, and ganglionic blockade usually becomes predominant in such quaternary salts. The central effects observed included both depressant and convulsant activity, although the intensity of action was considerably lower than that observed in the case of peripheral activity. It is of interest that whereas structural alterations frequently changed the nature of the physiological response, rarely did complete loss of activity occur.

TABLE A PERIPHERAL EFFECTS

Compound

1. 8-Erythroidine

2. j3-Erythroidine methiodide 3. 8-Erythroidinol 4. 8-Erythroidinol methiodide 5. Dihydro-j3-erythroidine 6. Dihydro-j3-erythroidine me thiodide 7. Dihydro-p-erythroidinol

8. 8-Tetrahydro-p-erythroidine

9. P-Hexahydrodesmethoxy8-erythroidine

Structure

XIf XIf . Me1 XLVII XLVII * Me1 XXVIII XXVIII . Me1

9 9

XXXI

CH,O

Intraperitoneal LD,, (mice)

ED. 50 Rat diaphragm

(mg./kg.) 29.5+ 2.0 32.2k 6.0 46.1* 3.3

(mMil.1 0.4

4.5f 0.5 160 *I2

0.08

178 k 2 0

1

1

Blocking dose in cst Neuromuscular

Ganglionic

20

(mg./kg.) 20 5 10 5 0.5 7

10

5

(mg./kg.) 10 15 20 15 0.5

10.6 f1.7

0.12

1

0.5

72.0f

9.6

0.7

5

5

14.0* 0.8

0.3

6

5

0

10. Apo-8-erythroidine methiodide

XIVf * Me1

224

5:

2

E x

3

V. BOE KEL HEI DE

1 9 0

*

19 0

u3

0

om8

V

c:

”” P

&,

W

0 19

m 0

0 In

H H

x x

W

0 rn

P

0

CJ In

I” V

P

225

THE ERYTHRINA ALKALOIDS

VI. Tables of Physical Constants TABLE

1

BASICITY OF THE ERYTHRINA ALKALOIDS AND SOME O F THEIR DERIVATIVES

Compound 1. Erysodine 2. Erysovine 3. Erysopine 4. Erythraline 5. Erysonine 6. Dihydroerysodine 7. Dihydroerythraline (Erythramine) 8. a-Erythroidinol 9. 8-Erythroidinol 10. Dihydro-a-erythroidinol 11. Dihydro-p-erythroidinol

12. 13. 14. 15.

PKa of hydrochloride

Structure

Desmethoxy-8-erythroidinol Apoerysodine Apoerythraline Apoerysopine

I n methylcellosolve as solvent (51). * I n water 8 s solvent (69).

XIc or X I d XIc or XId XIb XIa XLIX XIc or d + 2 H XIa 2H See below XLVII XXXVI XXXI See below XI10 or d XIIa XIVe

+

I

1

6.290 6.45a 6.600 6.970 6.500 7.02a 6.65' 1.19b 7 .SO6 8.42b 8.69b 7.71b 6.540 6.590 3.600

4

0

CH,

CHCH CH,OH'

6H

Dermethoxy -@

o( -Erythroidinol

TABLE

-

erythroidinol

2

ULTRAVIOLET ABSORPTION MAXIMA

(AND LOO E VALUES)

Compound 1. 8-Erythroidine 2. or-Erythroidine 3. Desmethoxy-perythroidine 4. Erysodine 5. Erysovine 6. Erysopine 7 . Erythraline 8. Apoerysodine 9. Apoerythraline

10. Apoerysopine P

Structure

Maxima (log E )

Reference

XIf XIg

238 (4.4) 224 (4.5)

64 69

XIIf XIc or d XIc or d XIb XIa XIIc or d XIIa

312 (3.6) 285 (3.5); 235 (4.3) 285 (3.5); 239 (3.8) 292 (3.6); 240 (4.3) 292 (3.6); 238 (4.3) 315 (3.7); 290 (3.7); 239 (4.0) 315 (inflection, 3.7); 295 (3.8); 240 (inflection, 3.8) 301 (4.0); 268 (4.0); 235 (4.3)

54 93a 51 51 22 53 53

XIVb

53

226

V. BOEKELHEIDE

VII. References 46. 47. 48. 49. 50. 51. 52.

C. Lapibre, “Contribut,ion A 1’6tude des alcaloides des ErythrinBes,” LiBge, 1952. C. Lapihe, J . Pharm. Belg. 6, 71 (1952). M. Tomita, Phamt. Bull. ( T o k y o ) 4, 225 (1956). V. Boekelheide and V. Prelog, Progr. i n Org. Chem. 3, 242 (1955). V. Boekelheide, Record of Chem. Progr. Kresge-Hooker Sci. Lib. 16, 227 (1955). V. Prelog, Angew. Chem. 69, 33 (1957). L. Fieser and M. Fieser, “Natural Products Related to Phenanthrene,” Reinhold, New York, 1949, p. 185. 52a. G. L. Sauvage and V. Boekelheide, J . Ant. Chem. Soc. 7 2 , 2062 (1950). 53. M. Carmack, B. C. McKusick, and V. Prelog, Helv. Chim. Actn 34, 1601 (1951). 54. V. Boelrelheide, J. Weinstock, M. F. Grundon, G. L. Sauvage, and E. J. Agnello, J . A m . Chem. SOC.75, 2550 (1953). 55. V. Boekelheide and M. F. Grundon, J . A m . Chem. SOC.75, 2563 (1983). 56. C. Lapibre and R.. Robinson, Chem. & Ind. (London) 30, 650 (1951). 57. M. F. Grundon and V. Boekelheide, J . A m . Chem. SOC.74, 2637 (1952). 58. J. R. Merchant, Ph.D. Thesis, Eidgenossische Technische Hochschule, Ziirich, 1963. 59. M. F. Grundon and V. Boekelheide, J . A m . Chem. SOC.75, 2537 (1953). 60. M. F. Grundon, G. L. Sauvage, andV. Boekelheide,J. Am. Chem.Soc. 75,2541 (1953). 61. Z. Valenta and K. Wiesner, Chem. & Ind. (London) p. 402 (1954). 62. I(. Wiesner, Z . Valenta, A. J. Mason, and F. W. Stonner, J . A m . Chern. Sac. 77, 675 (1955). 63. 13. D. Astill and V. Boekelheide, J . Am. Chem. Soc. 7 7 , 4079 (1955). 64. W. G . Gall, B. D. Astill, and V. Boekelheide, J . Org. Chem. 20, 1538 (1955). 65. W. G. Gall and V. Boekelheide, J . Org. Chem. 19, 504 (1954). 66. G. W. Kenner, H. G. Khorana, and V. Prelog, Helv. Chim. Acta 34, 1969 (1951). 67. 1 7 . Boekelheidc and E. J. Agnello, J . Am. Chem. SOC.73, 2286 (1951). 68. J. Weinstock and V. Boekelheide, J . A.m. Chem. SOC.7 5 , 2546 (1953). 69. J. C. Godfrey, D. S. Tarbell, and V. Boekelheide, J . A m . Chem. SOC.77, 3342 (1966). 70. G. C. Morrison and V. Boekelheide, unpublished work. 71. V. Prelog, B. C. McKusick, J. R. Merchant, 8 . Julia, and M. Wilhelm, HeZv. Chim. Acta 39, 498 (1956) 72. V. Boekelheide, A. E. Anderson, and G. L. Sauvage,J. A m . Chem.Soc. 75,2558 (1953). 73. G. Stork, J . A m . Chem. Soc. 74, 768 (1952). 74. W. Nowacki and G. F. Bonsma, unpublished work as quoted in reference 71. 74a. K. Folkers, F. Koniuszy, and J. Shavel, Jr., J . A m . Chem. SOC.64, 2146 (1942). 75. K. Folkers, F. Koniuszy, and J . Shavel, Jr., J . Am. Chem. SOC.73, 589 (1951). 76. A. J. Manson and K. Wiesner, Chenz. & Ind. (London) p. 641 (1953). 77. S. Chiavarelli, E. F. Rogers, and G. B. Rfarini-Bettolo, Qazz. chim. itul. 83,347 (1953). 78. J. Jack and V. Boekelheide, unpublished work. i9. B. Belleau, J . Am. Chem. SOC.75, 5765 (1953). 80. B. Belleau, Chem. & I n d . (London) p. 410 (1956). 81. A. Mondon, Angew. Chem. 68, 578 (1956). 82. A. Mondon, Abstract, Nordwestdeutsche Chemiedozenten-Tagung, Miinster, April 1-3, 1957. Private communication. 83. V. Boekelheide and M. Chang, unpublished work. 84. M. Muller and 1’. Boekelheide, unpublished work. 85. V. Boekelheide and T. T. Grossnickle, unpublished work. 86. K . W-iesner, Z. Valenta, A. J. Manson and F. W. Stonner, J . A m . Chem. SOC.7 7 , 675 (1955).

THE ERYTHRINA ALKALOIDS

227

67. V. Prelog, M. Ternbah, and 0. Rodig, unpublished work. Cf. reference 51. 88. E. Wenkert, Chem. & I n d . ( L o n d o n ) p. 1088 (1953). 89. R. Robinson, C h e m & I n d . ( L o n d o n ) p. 1317 (1953).

90. B. Witkop and S. Goodwin, Ezpericntia 8, 377 (1952). 91. W. Nowacki and G. F. Bonsma. Cf. reference 71. 92. D. Megirian, D. E. Leary, and I. H. Slater, J . Pharmaeol. Exptl. Themap. 113, 212 (1955). 93. D. Megirian, Ph.D. Thesis, University of R,ochester, Kochester, New York, 1953. 94a. V. Prelog, K. Wiesner, H. G. Khorana, and G. W. Kenner, Hclv. Chim. Aeta 32, 453 (1949). 04. B. Uelleau, Can. J . Chem. 35, 651 (1957). 95. B. Belleau, Can. J. Chem. 35, 663 (1957). 96. M. Miiller, T. T. Grossnickle, and V. Boekelheide, J . Am. Chem. Soc. in Press. 97. V. Boekelheide and G. C. Morrison, J . Am. Chem. SOC.80, 3905 (1958). 98. D. H. R. Barton andT. Cohen, “Festschrift A. Stoll,” p. 127. Birkhauser, Basel, 1957. 99. A. Mondon, Angew. Chern. 70, 406 (1958).

VIII. Addendum Since the writing of the manuscript for the preceding article, progress has been made in elaborating the chemistry of the erythrina alkaloids. 1. Belleau has reported the details of his synthesis and resolution of 15,16-dimethoxyerythrinane(LVIII)and the proof of the identity of the levorotatory enantiomorph with hexahydroapoerysotrine (94). Also, he has reported the synthesis of an isomer (presumably a diastereisomer) of 14,15,16,17-tetra-hydroerythrinane (LX) (95). 2. The synthesis and resolution of 14,15,16,17-tetra-hydro-16-oxaerythrinane has been accomplished and it has been shown that the levorotatory enantiomorph is identical with anhydro-a-hexahydrodesmethoxy-p-erythroidine (96). This synthesis establishes the presence of the spiro amine system for a- and /i-erythroidine. 3. The details of the interconversion of a- and p-erythroidine have been published (97). 4. Barton and Cohen have proposed a biogenetic scheme for the erythrina alkaloids based on the radical coupling of phenols (98). 5. Mondon has extended his previous synthesis of 15,16-dimethoxyerythrinane to permit the introduction of a double bond a t C,-C, (99).