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Emetine and Related Alkaloids
Chapter 2 3 / E M E T I N E A N D RELATED ALKALOIDS
Occurrence: Alangiaceae and Rubiaceae N u m b e r : 14 Structures: C H 30 ^
OCH* OR 1
( - ) - E m e t i n e , R = CH 3 (+)-Psychotrine, R = Η 3 (-)-Cephaeline, R =Η (+) - O-Methylpsychotrine, R = C H 3 2 4 ( - ) - A l a n g a m i d e = N - 2 ' - C O - N H - C H 3 (+)-Alangicine*s 1 1 - H y d r o x y p s y c h o t r i n e emetine
CH,
(+)-Emetamine
(+) - D e m e t h y l p s y c h o t r i n e
4
427
II. CHEMICAL INTERRELATIONSHIPS
(—) - P r o t o e m e t i n e
(—) - I p e c o s i d e
Protoemetinol ( C H O r e p l a c e d b y C H 2O H )
H-Dihydroprotoemetine, R " Η 5 6 (-)-Ankorine, * R = OH '
5
-g H-Alangiside
H
* Stereochemistry not yet established.
I. INTRODUCTION
The original or classical emetine alkaloids consist of five bases: emetine, cephaeline, psychotrine, O-methylpsychotrine, and emetamine, obtained mainly from ipecac or ipecacuanha — the roots of the South American straggling bush Cephaelis ipecacuanha (Brotero) Rich, or the Central American Psychotria granadensis Benth, ex Oerst 1 (Rubiaceae). To this group have been added protoemetine and ipecoside, both of which are also found in ipecac. The alkaloids of ipecac, especially emetine, are im portant because of their antiamebic activity. The Indian plant Alangium lamarckii Thw. (Alangiaceae) has recently been found to contain emetine, cephaeline, and psychotrine, as well as the new alkaloids alangicine, desmethylpsychotrine, alangamide, dihydroprotoemetine and ankorine. II. CHEMICAL INTERRELATIONSHIPS BETWEEN THE IPECAC BASES
Emetine is levorotatory a n d has four methoxyl groups. Although the alkaloid contains one tertiary and one secondary nitrogen, n o ΛΓ-methyl function is present in it or in any of its immediately related bases. The chemical relationship between emetine and the remaining original ipecac alkaloids have been summarized in Scheme I. In the catalytic reductions of psychotrine to cephaeline and of O-methylpsychotrine to emetine, isocephaeline a n d isoemetine are also produced. These two reduction products, not found in natural sources and not shown in Scheme I, are diastereoisomeric at C - Γ with cephaeline a n d emetine, respectively.
428
23. EMETINE AND RELATED ALKALOIDS
OCH
-^rV
N
^ ^ ^ O C H
3 3
C H 30 CH3O
„OCH 3 "OCH3 ( + ) - 0-Methylpsychotrine ( i c H 2N 2
(—) -Cephaeline
(+) - P s y c h o t r i n e Scheme I
III. DEGRADATION OF EMETINE
Crude emetine was first isolated in 1817 by Pelletier, but the correct empirical formula of C 29 H 4 o 0 4 N 2 was not established until 1914 due to insufficient purification. Despite its early discovery, emetine was not obtained in crystalline form until 1953. Initial studies on the oxidation of emetine with potassium permanganate under a variety of experimental conditions led to the isolation of such fragments as 1 to 4. C H 3c \
C H 3O S^ ^ C O O H
CHaO^
C H 3 C / ^ A COOH :
CH,
C H
3
0 " ^ ^ 0
COOH
4 m -Hemipinic acid All of these c o m p o u n d s pointed to the presence of the 6,7-dimethoxyisoquinoline system in emetine. But the extremely high yield (96%) of m-hemipinic acid (2) obtained
429
Scheme II
III. DEGRADATION OF EMETINE
430
23. EMETINE AND RELATED ALKALOIDS
in one of the oxidations indicated that more than one moiety capable of yielding this product was present in the molecule. Hesse, Pyman, Karrer, Späth, Reichstein, Pailer, and others carried out extensive Hofmann and Emde degradations on emetine. F r o m such work it became obvious that the secondary nitrogen in the alkaloid is monocyclic, while the tertiary nitrogen belongs to two rings. The correct structure for emetine, first tentatively suggested in 7 1948 by Robinson on biogenetic grounds, was confirmed independently in 1949 by 8 9 Battersby and O p e n s h a w and by Pailer and Porschinski. The main lines of the extensive degradative work carried out by Battersby and Openshaw is presented in Schemes I I and I I I . Although certain compounds in these schemes were not completely characterized, the isolation of such shards as 6-ethylveratric acid (Schemes I I and I I I ) , 5-ethylpyridine-2,4-dicarboxylic acid (Scheme I I ) , formaldehyde and the conjugated diene 5 (Scheme I I I ) , all served to define the correct 8 structure for emetine.
6-Ethylveratric acid
Emetine hexahydrotris*methine
Scheme I I I
I V . T H E POSITION OF THE PHENOLIC F U N C T I O N IN CEPHAELINE
The position of the phenolic function in cephaeline was settled conclusively when Pailer a n d Porschinski converted O-ethylcephaeline into the intermediate 6 by a series of Hofmann degradations and catalytic reduction. Ozonization of this salt then gave
431
VI. THE STEREOCHEMISTRY OF EMETINE
2-ethyl-4-ethoxy-5-methoxybenzaldehyde, so that cephaeline must have the phenolic 9 function at C-6'.
2-Ethyl-4-ethoxy5-methoxybenz aldehyde
6
Ö-Ethylcephaeline
V. PROTOEMETINE
Q9H27O3N,
( —)-Protoemetine, an ipecac alkaloid of biogenetic interest, was isolated in 1957. The compound is tricyclic and bears two methoxyl groups, as well as a single tertiary nitrogen function and an aldehyde group. Its structural elucidation rests mainly 10 u p o n its conversion to the naturally occurring O-methylpsychotrine (Scheme I V ) .
(+) - 0 - M e t h y l p s y c h o t r i n e
COC1
Scheme IV Since O-methylpsychotrine has been reduced to emetine, the above conversion also constitutes a partial synthesis of emetine. Additionally, protoemetine has been condensed with 3-hydroxy-4-methoxyphenylethylamine to produce cephaeline and some iso1 0 - 21 cephaeline. The former product can be O-methylated to e m e t i n e .
VI. T H E STEREOCHEMISTRY OF EMETINE
Emetine possesses the thermodynamically stable irafw-quinolizidine arrangement delineated in which all the substituents are equatorially situated. The more salient reasons for this assignment of configuration at the four asymmetric centers may be summarized as follows:
23. EMETINE AND RELATED ALKALOIDS
432
C H 30 (—)-Emetine
Isoemetine
13
The O R D curves of emetine and its salts depend primarily u p o n the benzylic centers of asymmetry at C-l l b and at C - Γ . Van Tamelen pointed out that these two centers must be antipodal to one another, since emetine hydrobromide exhibits negligible rota tional change in the 300 to 700 πιμ range, indicating that the contributions of the two
Homoveratrylamine
trans - 3 , 4 - D i e t h y l cyclopentanone
1. L i B H 4 2. p - T o l u e n e sulfonyl chloride 3. Thiourea 4. Ni(R)
Several
(±)-Emetine
<
s t e sp
Scheme V
433
VI. THE STEREOCHEMISTRY OF EMETINE
centers essentially cancel each other. O n the other hand, isoemetine hydrobromide, which is epimeric with emetine at C - Γ , exhibits increasing rotation down to 300 ηιμ 1 4 16 because of optical reinforcement of the two asymmetric c e n t e r s . " The hydrogen atoms at C-2 and C-3 must be trans to each other, and the C-11 b hydrogen must be eis to that at C-2. This conclusion was reached after the synthesis of the tricyclic base 7 of known relative stereochemistry, starting with iraH£-3,4-diethylcyclopentanone. Base 7 proved to be identical with material derived from the lactam ester 8 through the immonium salt 9 by steps not involving any change in stereochemistry. Since the lactam ester 8, as will be seen in Section VII, A, had previously been converted by Preobrazenskii et al. into racemic emetine, the relative configurations at C-2, C-3, 1 5 17 and C-11 b in emetine were established (Scheme V ) . " The final step in the preparation of the tricyclic base 7 from the lactam ester 8 by reduction of the immonium salt 9 under a variety of experimental conditions including catalytic hydrogenation, mixed metal hydrides, or sodium in alcohol, always resulted in the formation of only one isomer of 7. This fact implies that the C-1 l b hydrogen in emetine is axial, by analogy with similar reductions in the yohimbine series in which, 18 for example, the immonium salt 10 is reduced to y o h i m b a n e . If the thermodynamically less stable isomer of the tricyclic base 7 is desired, it may be obtained together with 7 by reduction of the salt 9 with either zinc or tin in hydrochloric acid.
10
Yohimbane
The foregoing conclusions regarding the stereochemistry of emetine are reinforced l by the presence in 2'-benzoylemetine of I R Bohlmann bands around 3.65 ηιμ (2740 c m " ) characteristic of iraws-quinolizidine systems, indicating that the pair of electrons on N-5 and the hydrogen a t o m at l i b in emetine exist primarily in a trans-diaxial rela 19 tionship. The absolute configuration of emetine at C-11 b was settled by means of a comparative study of the molecular rotations of N-2 '-benzoyl- and 7V-2'-acetylemetine versus that 20 for the corresponding 5-1 l b dehydroemetinium s a l t s . It was observed that the axial hydrogen at l i b in natural (—)-emetine makes a large negative contribution: N-2'y acetylemetine exhibits [M]£ — 401.4°, and the corresponding dehydro (immonium) salt y lacking asymmetry at C-1 l b has [M]£ + 6 2 5 . 5 ° . This situation is analogous to that prevailing in the (— )-tetrahydroprotoberberine series, represented here by ( —)-norcoralydine, in which, due to the presence of the 14-a-H, the molecular rotation values usually lie near —1000°. Therefore the corresponding asymmetric centers in the two alkaloidal series must be identical, and the C-11 b hydrogen in emetine is alpha. Battersby and co-workers employed the diene 11, obtained by sequential Hofmann degradation of 7V-acetylemetine, to study the absolute configuration at C - Γ . C o m p o u n d
434
23. EMETINE AND RELATED ALKALOIDS
(-) - N o r c o r a l y d i n e
11 is actually related to the diene 5 obtained during the degradative studies on emetine. Oxidation of 11 first with ozone and then either with potassium permanganate or peracetic acid furnished, besides methyl ethyl ketone, the bicyclic (—)-acid amide 12. The latter was then chemically interrelated with the alkaloid (+)-calycotomine of 21 known absolute configuration. i.o3
11
^ ^ * X > C H
12
3
(+)-Calycotomine
The stereochemistry of the remaining classical ipecac alkaloids follows from that 12 of emetine. The O R D curve of psychotrine has been r e c o r d e d ; and a chemical 22 correlation has been established between the ipecac and indole alkaloids.
V I I . SYNTHESES OF EMETINE
More than a dozen syntheses of emetine are known, which make this compound the most synthesized alkaloid known. The study of these syntheses constitutes an interesting and worthwhile intellectual exercise in the laboratory-induced transformation of organic materials, so that most of these preparations will be considered here. A. The Preobrazhenskii
Synthesis
The first synthesis of emetine was reported by Preobrazhenskii and his group in 1950. The sequence was later expanded and modified, and the Russian work in its 23 final form may be summarized as shown in Scheme V I . * Since several steps in the synthesis, including the initial Michael condensation with diethyl glutaconate, lacked stereochemical control, diastereoisomeric intermediates were obtained which had to be separated in the course of the synthesis. * The structural assignments made for some of the intermediates obtained in this synthesis 2 4 25 had to be modified. '
435
VII. SYNTHESES OF EMETINE
COOC 2H 5
C=N +
C 2H 5OOC
N a O C 2H 5
c i2 i
S
C O O C 2H 5
COOCoH. COOC 2H 5
COOC 2H 5 Diethyl glutaconate C 2H 5OOC
C2H3I,
C=N
N
Ethyl cyanoacetate 1.
C=N
C 2H 5OOC
OH",
C=N Homoveratry lamine,
controlled
COOC 2H 5
COOC2H5
saponification
2. Δ, - c o 2
C H 3O v ^
H 2, N i ( R )
' COOC 2H 5
CH3O
1. H o m o v e r a t r y l a m i n e ,
2. POCI3
1. POCI3
CH.
2. [ H ]
3. [H]
CH3O'
COOC 2H 5
•> (±)-Emetine
COOC 2H 5
or a l t e r n a t i v e l y : Homoveratry l a m i n e in e x c e s s ,
C2H5OOC
CSN
H 2 , Ni(R)
3'
C
H
1. pocij 2.[H]
(+) - E m e t i n e
CH3O'
COOC 2H 5
Scheme VI B. The Batter shy-Turner
Synthesis
A clean stereospecific synthesis was devised by Battersby and Turner utilizing the 26 jß-ketolactam 13 originally prepared by B a n . Michael condensation of the unsaturated lactam 14 with malonic ester gave after work-up the thermodynamically favored trans compound 15, and subsequent catalytic reduction to the tricyclic ester 16 also proceeded to yield the more stable isomer. The tricyclic ester 16 was found to be identical with that derived from protoemetine, except for the optical activity, so that the remainder of the synthesis essentially followed the conversion of protoemetine to emetine (Scheme 27 VII). C. The Burgstahler-Bithos
Synthesis 28
A synthesis of emetine reminiscent of the van Tamelen yohimbine synthesis has been carried out by Burgstahler and Bithos utilizing the c o m m o n reagent gallic acid
436
23. EMETINE A N D RELATED ALKALOIDS
xTV
CHgO.^ HC OH,
°Υ ν ^Ί
0Η3
ί?
/
^JL
m T
C H
3
J
+
irxr
0 ^ /
2
HOOC^f^
C H
ethanol ^
COOH
3
0 ^
/
*N
(Mannich)
N H
HOOC
C \ O O^H
Carbethoxyβ
ο Η , ο . ^ / ν
I.A,-CO2 2. E t h a n o l , Η +
»° *
1
C H 3 OA ' J
N<
C 2 H 5 O O C< S o
;
'
CHaO^jSv^^
»y'«°e
.
1
CH3O,
ύ
Γ
3
II
H
CHsCV^Q^N^
^
C 2H 5O O C ^ c ^ o ^ H 5
" I
H 2, P t ,
CH CX^x\
3 θ +Λ
' ·
3
-CO2 ,
[\\\
3
NaBH4 .
c^o^^V ^
C H 3O — s ^ c y N .
Ο
1
ο 1. Diethyl malonate,
CHaO^^^X Υ
|f
CHgO^,;^^ f
ΟΗ θ"^^°γ" ^ Ν
3
l . A c 20
2.
N a O C 2H 5 f
Τ
Τ
N a O C 2H 5 J
r^n-^xU^Nv.
(Michael)
2. H3O+, A, - c o 2
OH
Scheme VII as starting material. This approach is nonstereospeciflc and diastereoisomeric compounds had to be separated at proper intervals. Cleavage of the triol 17 with periodic acid produced a mixture of the lactol 18 and the corresponding hydroxyaldehyde, which, without separation, was cyclized to the lactam aldehyde 19 (Scheme V I I I ) .
Gallic acid
All-eis
isomer
29
437
VII. SYNTHESES OF EMETINE
Scheme VIII
D. The van Tamelen
Synthesis
In the synthesis of emetine achieved by van Tamelen, Schiemenz, and Arons, the keto triester 2 0 was first obtained by Michael condensation of methyl acetoacetate with dimethyl glutaconate. Mannich-type condensation of 2 0 with homoveratrylamine and formaldehyde then provided the key intermediate 2 1 . The remainder of the synthesis follows straightforward lines, especially since the tricyclic ester 2 2 had already 30 been converted to emetine by Preobrazhenskii and other workers (Scheme I X ) .
-
i butyi C H
3
0 ^ ^
2
N
H
Y Y
C
Ct>OCH 3
H 3
20
Scheme IX
C H 3O v
— JOCX "C"CH3
(Mannich)
21
CÜOCH^
23. EMETINE AND RELATED ALKALOIDS
438
E. The Glaxo
Synthesis
Clark, Meredith, Ritchie, and Walker have carried out a stereospecific preparation of emetine that follows unusual lines. Condensation of the imine 23 with acetonedicarboxylic acid in dilute aqueous sulfuric acid was found to yield the required meso diamino ketone 24, while if the condensation were carried out in aqueous pyridine the undesired racemic diastereoispmer of 24 resulted. One amino function of 24 was protected through monobenzylation, and a Michael-aldol condensation with methyl vinyl ketone gave rise, after acid-catalyzed dehydration, to the critical intermediate 25. Reduction of the conjugated double bond with lithium in liquid ammonia followed by equilibration with acid gave the more stable trans-fused ketone 26. Following removal of the ketonic function, reductive debenzylation yielded emetine. The main 31 advantage of this approach is that no isoemetine is obtained as a by-product (Scheme X ) .
1. E t h a n e d i t h i o l ,
1. L i / N H 3
H
+
2 . Ni(R)
2 . Hot H +
3 . H 2,
(equilibration
Pd/C
(debenzylation)
at C-3)
(±) - E m e t i n e
Ph-CH
Scheme Χ F. The First Roche Basle Synthesis 32
The aim of this approach was to prepare the tricyclic ketone 2 9 , which after homolo 13 gation to the acid 30 would be convertible into emetine (Scheme X I ) .
VII. SYNTHESES OF EMETINE
439
HC OH, ethylmalonic
CHgO
1. CH 2N 2 2. NaOCH 3 (Dieckmann) 3. H 30 + A, -C02
CH3O. CH3O'
C 2H 5O O C -
C 2H 5O O C ' HOOC
CH2 ?
28
2
°Τ^1Γ^
0Η3
Malononitrile, NH 4OAc, HOAc
COOH
CH3O.
NC"
N
C N
CH3O. Homoveratrylamine
30
CH3O
COOH
CH3O. 1. H 2, Pd 130°, 100 atm 2. Separation of diastereoisomers
CH3O
1. POCI3 2. H 2, Pt H
-N^O|Py
\ ^ ^ O C H
Also:
(±)-Emetine
O C H
3 3
CH3O CH3O 31
pocij
OCH3
OCH,
"OCH3 ( ± ) - 2 J3 - D e h y d r o e m e t i n e
OCH3 (±) - 2 , 3 - D e h y d r o i s o e m e t i n e ( D e v o i d of a m e b i c i d a l a c t i v i t y )
Scheme XI
440
23. EMETINE AND RELATED ALKALOIDS
The a m i n o ester 27 yielded the diacid ester 28 through a Mannich-type reaction with formaldehyde and ethylmalonic acid. Esterification, Dieckmann cyclization, hydrolysis, and then decarboxylation produced the required tricyclic ketone 29. H o m o logation to 30 was accomplished by condensation with malononitrile followed by hydrolysis and decarboxylation. The acid 30 was condensed with homoveratrylamine and the resulting amide reduced catalytically to a separable mixture of eis and trans isomers. The trans species after Bischler-Napieralski cyclization and reduction afforded emetine. Alternatively, the amide 31 could be cyclized to ( ± )-2,3-dehydro-0-methylpsychotrine, and succeeding reduction afforded a separable mixture of ( ± ) - d e h y d r o e m e t i n e and (±)-dehydroisoemetine. Dehydroemetine is comparable to emetine in amebicidal 1 3 , 33 activity, so that this synthesis is of commercial i m p o r t a n c e . Diethyl
P h - C H
2
- 0 ^
P h
Z!ZZ%
" C H 2- < V ) C 2H 5OOC
X O O C 2H 5
Benzyl a - b r o m o b u t y r a t e CK^O
1 . H 2, P d / C 2. S Q C 1 2
C 2H 5OOCf ^COOC 2H 5 32 1. N a O H (saponification) . Δ -CO
1-Carbethoxy-
6,7-dimethoxy-
Ο Κ
Ο γ ^ γ ^
3
tetrahydro-
I
^ i n c l i n e
,
0 Η
II
Jj
Ν
Ο
Ο ^ ^ γ C 2H 5OOC C 2H 5O O C X O O C 2H 5
4 . N a O C 2H 5 (Dieckmann)
3
H
"
33 C H 30
1. H 2, P d 2 . CH3SO2CI,
CH;
pyridine
34
CH; CH3O'
C H 3- S 0 2- 0
COOC 2H 5
COOC 2H 5
1. s o c i 2 C
l . P h C H 2S - N a +
2 . C H 2N 2
H
3
3.
2. Ni(R) n
3. NaOH
^
A g 20
CH 30>
(Arndt-Eistert)
(
4. Κ Ο Η
3
35
COOH Scheme XII
2
+ ( e s t eHr i f i c a t i o n )
^
Hl
C H 30 ' 36
• N ^y O LH
COOH
VII.
441
SYNTHESES OF EMETINE
G. The Second Roche Basle
Synthesis
The acid chloride of a-ethyl-ß,ß-dicarbethoxypropionic acid ( 3 2 ) was first prepared by the condensation of benzyl α-bromobutyrate with malonic ester, followed by de benzylation over palladium and treatment with thionyl chloride. This acid chloride was then used to acylate l-carbethoxy-6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline to form the amide 3 3 . The latter material was converted to the keto lactam 3 4 by the sequence indicated, and further transformation provided the tricyclic acid 3 5 as a pair of diastereoisomers. O n e isomer, u p o n homologation, gave the key homotricyclic 34 lactam acid 3 6 , which was converted to emetine by the usual sequence (Scheme X I I ) .
C O O C 2H 5 a
CH, Y^CH CH 2
C O O C 2H 5
+
jm^
HCy^yOH
N=C^Y^CH CH
NSCT
3
H3Q+, A,^
2
C
3
~ °
H O ^ ^ O H
2
SCH, ^
C H
2CH3
CH3 1. A q . HBr (hydrolysis)
Potassium
CL^N^Cl POCli
γ
37
Ύ
Homoveratryl i o d i d e , KOH,
t-butyl
ny
alcohol
^
CH0, CH0'
S ^ C|ΓH 2 C H 3
^ y ^ C H 2^ x i 3 CH 3
3
Diethyl
3
3
Pd/C,
^XH-O^Nv^Cl
m e t h o x i d e ^ Ph
^ ^ C H 2C H CH 3
NIOC^S^
39
NaOAc
C
H
3f
3
CH 3C/
CH0-V0N. r
COOH
COOH
Y^V^i V
CH30
CH 0 ^^ ^ I
diastereoisomers
>
J
Q
I
3
2. Ethyl chloroformate 3. H o m o v e r a t r y l a m i n e
—»•
| r
I
n
NU
^
^Y^CH CH 2
/
S
38
lΝ
CH 3 H 2O 2>
\ ^ CH 2 C O - C O O C 2H 5
3
1. S e p a r a t i o n of
S
i
ΟΗ0-^^^γ^| ° y
^CH 2CH 3 CH3
CH0,
40
^
(hydrogenolysis)
C H 3Q
3
Η
2 . H 2,
*l
diph
I
H'
Scheme XIII
LA Η -.
3
442
2 3 . EMETINE A N D RELATED ALKALOIDS
H. The Roche Welwyn
Synthesis
The application of pyridone chemistry to the synthesis of emetine has been success fully exploited by Barasch, Osbond, a n d Wickens. T h e known dichloropyridine 37 was converted t o the pyridone 38, a n d JV-alkylation with homoveratryl iodide led t o the derivative 39. Since the C-methyl group on the pyridone system is activated through conjugation with t h e carbonyl group, it was possible t o homologate 39 t o the acid 40. Catalytic reduction of 40 produced a separable pair of diastereoisomers, one of which was treated first with ethyl chloroformate a n d then with homoveratrylamine t o give rise t o the lactam amide 41, which was taken to emetine via Bischler-Napieralski 35 cyclization a n d subsequent reduction (Scheme X I I I ) .
/. The Burroughs-Wellcome
Synthesis
Openshaw a n d Whittaker have developed a commercially applicable synthesis of emetine in which the required optically active intermediate ( —)-44 is obtained by a 3 6 38 highly efficient a n d unusual process (Scheme X I V ) . " Water, room
CH3O,
(-)-Camphor-lOsulfonic acid,
CH3O'
ethyl acetate
H 3O
Η-44 Salt p r e c i p i t a t e s out from hot solution C H ( P h ) 3P = C H - C O O C 2H 5
3
C L ^
C H
C H 30 "
H 2, P t
3
( X ^
C H 30 '
CH
45
COOC2H5
Scheme XIV
46
C O O C 2H
5
VIII. IPECOSIDE, A MONOTERPENOIDAL ISOQUINOLINE GLUCOSIDE
443
Condensation of the imine hydrochloride 4 2 with the Mannich base 4 3 afforded the amino ketone 4 4 in almost quantitative yield. Resolution of this product with ( —)-camphor-10-sulfonic acid resulted in crystallization of the salt of the desired levorotatory base. Since ring C of the amino ketone 4 4 can be readily opened in the manner shown in Scheme XIV, the dextrorotatory amino ketone 4 4 kept being racemized while the levorotatory enantiomer continuously precipitated out as the salt. The net result was an almost total conversion of the racemic amino ketone 4 4 into its levorota tory form, epimerization also having occurred at the site of attachment of the ethyl side chain. Homologation with ethoxycarbonylmethylenetriphenylphosphorane yielded only one geometric isomer of 4 5 and subsequent catalytic reduction provided the optically active ester 4 6 which can readily be taken to emetine. Whenever the intermediate 4 6 is prepared in any of the aforementioned syntheses in either the levorotatory or the racemic form, condensation with homoveratrylamine succeeded by Bischler-Napieralski cyclization and reduction always leads to a mixture of emetine and isoemetine. Isoemetine is inactive as an amebicide, but it can be TVchlorinated on the secondary nitrogen using sodium hypochlorite, and treatment with base leads to O-methylpsychotrine by loss of hydrogen chloride. 0-Methyl3 6 , 73 psychotrine may then be reduced again to a mixture of emetine and i s o e m e t i n e . A significant observation of Openshaw and Whittaker is that condensation of the ester 4 6 with homoveratrylamine is appreciably accelerated by the presence of 2-hydroxypyridine, which acts as a bifunctional catalyst in the condensation of strongly basic amines with esters. F r o m the practical point of view, 2-hydroxypyridine can easily 39 be removed from the resulting amide because of its high solubility in w a t e r . The Openshaw and Whittaker synthesis can also be modified so as to produce the 40 effective amebicides ( + )- as well as ( —)-2,3-dehydroemetine. J. The Zymalkowski-Frahm
Synthesis
The key (5-lactone carboxylic acid 5 0 required for a synthesis of emetine was prepared as shown in Scheme XV. The aziridine obtained by the condensation of the acid chloride of 4 7 with ethylenimine was not isolated, but was forthwith reduced with lithium aluminum hydride to the aldehyde 4 8 . Homologation using ethoxycarbonylmethylenetriphenylphosphorane yielded in this instance a mixture of geometric isomers which was condensed in a Michael reaction with malonic ester. Hydrolysis, decarboxylation, 4 1 and lactonization subsequently gave the desired product 5 0 Finally, condensation of the lactone 5 0 with 2 moles of homoveratrylamine followed by hydrogenation and isomer separation yielded ( + )-emetine. VIII. IPECOSIDE, A MONOTERPENOIDAL ISOQUINOLINE GLUCOSIDE
The neutral glucoside ipecoside, C 2 7 H 3 5 N 0 1 2, was obtained in 1952 from ipecac 42 root, and its chemistry has been described so far mainly in communication f o r m . The glucoside consists of an N-acetylated tetrahydroisoquinoline moiety, a C-10 terpenoidal unit, and glucose. Since the term "alkaloid" has never been rigorously
444
23. EMETINE AND RELATED ALKALOIDS
Choromethyl methyl ether, η
1. O H ~
Na, ether
2.
C 2H 5OOC
CH 3
COOC 2H 5 i.soci 2
C 2H 5OOC
Δ,
-C0
2
COOC2H5
CH 3
50
Scheme XV defined, ipecoside can be considered to be alkaloidal even though it is a neutral compound. 1
Ipecoside exhibits an amide carbonyl at 6.13 μ (1630 c m " ) and a band at 5.92 μ - 1 (1690 c m ) which was assigned to the C H 3 O O C - C = C — O - system which had been shown to be present in several of the indole alkaloids. The U V data were also in accord with a tetrahydroisoquinoline component, Xmax 285 ιημ with a bathochromic shift in base due to the presence of the phenolic groups, and also with the presence of the C H 3 O O C - C = C - 0 - - chromophore with /lmax 238 πιμ. Catalytic hydrogenation gave dihydroipecoside, which showed unchanged U V and IR spectra (carbonyl region) since only the terminal double bond had been reduced. Mild acid hydrolysis of ipecoside yielded D-glucose, while acetic acid was liberated under conditions sufficiently vigorous to cleave the amide linkage (Scheme XVI). Ipecoside gave only acetic acid upon K u h n - R o t h oxidation, whereas dihydro ipecoside afforded propionic and acetic acids. The enzyme ß-glucosidase hydrolyzes ipecoside so that a ß-glucosidic linkage was assigned to the anomeric center. The enzyme also hydrolyzes 0,0-dimethyldihydroipecoside, though more slowly, to yield an aglycone, probably 5 1 , which undergoes isomerization with acid to a second, more stable, diastereoisomeric aglycone which
445
VIII. IPECOSIDE, A M O N O T E R P E N O I D A L I S O Q U I N O L I N E G L U C O S I D E
,0
Dihydroipecoside
(-) - I p e c o s i d e
I
"cr v-cr HO-
HO
Mild a c i d hydrolysis Acetic
D-Glucose
acid
Scheme XVI has been formulated as 52. Oxidation of the aglycone 52 furnished the enol ^-lactones - 1 53 and 54, both of which exhibit carbonyl absorption at 5.64 ηιμ (1773 c m ) (Scheme XVII).
3°^V^
C H
Ipecoside
Two steps
CH
II
CH3O
ß-Glucosidase Η'Ί
Ο,
'
V
^C-CH
C H3
[Ό-glucose
Ο-Dimethyldihydroipecoside
ft Ν
3Q^Sv^S
'
CH
[ο]
>H
3
a
C H
•
Ο
O ^ V
3 3
52
r
X>CH
C H 30 ^
3 +
Η
C H
3
0 ^
53
54
Scheme XVII C H 3O
0,
O-Dimethyldihydro-
H3O+ Δ
N
CH30
ipecoside
HO
55
56
CHgO [Η]
CH30
Χ Ή 2Ο Η (—) - D i h y d r o p r o t o e m e t i n e
Scheme XVIII
'CHO
3
23. EMET N IE AND RELATED ALKALO D IS
446
Final proof of structure came from the vigorous acid hydrolysis of 0 , 0 - d i m e t h y l dihydroipecoside, which yielded the aldehydes 55 and 56. Reduction of the latter product gave (— )-dihydroprotoemetine, identical with authentic material (Scheme XVIII).
IX. ALANGS ID IE
( — )-Alangiside is a-,monoterpenoidal lactam recently isolated from A. lamarckii. The molecular formula, C 2 5 H 3 1O 1 0N , as well as spectral data seemed to indicate that alangiside was closely related to desacetylipecoside. The enzyme /?-glucosidase cleaved alangiside to D-glucose and the aglycone C 1 9H 2 i 0 5 N . Additionally, alangiside could undergo the following changes: Acetlation
(a) Alangiside ° - r > Alangiside penta-O-acetate C a t J[ H A c e t l a l i no > Dihydroalangiside " - r > Dihydroalangisidepenta-O(b) Alangiside acetate C H l K A c e t y l a nt i o (c) Alangiside > O-Methylalangiside ° " > O-Methylalangiside t e t r a d acetate The actual correlation with desacetylipecoside was carried out by treating desaceiylipecoside hydrochloride with a weak base to induce lactamization. O-Methylation 4 2a then provided O-methylalangiside (Scheme XVIII a ) . The exact position of the phenolic function in alangiside has not yet been settled.
O-glucose
Desacetylipecoside hydrochloride N a 2C 0 3 orTMH 3
C H 2N 2
Ö-glucose
O-Methyl alangiside
Scheme XVIII a
O-glucose Alangiside
447
X. BIOSYNTHESIS
Χ . BIOSYNTHESIS
Using feeding experiments, Battersby and Gregory have firmly established that in Cephaelis ipecacuanha geraniol is converted into loganin which can then act as a precursor for ipecoside and cephaeline. The Q unit of the ipecac alkaloids and the 4 3 ,4 C 1 0 unit of ipecoside are, therefore, of monoterpenoid o r i g i n .
Ipecoside
Cephaeline
Further studies by Arigoni, Battersby, and their co-workers using mostly Menyanthes trifoliata Linn. (Gentianeae), Vinca rosea Linn. (Apocynaceae), and Rauwolfia serpentina Benth. (Apocynaceae), the last two yielding a variety of indolic alkaloids, have de 45 4 9 monstrated t h a t " : (1) Geraniol is first oxidized to 10-hydroxygeraniol within the biogenetic locus. (2) Nerol and 10-hydroxynerol are almost as efficient as geraniol and 10-hydroxygeraniol as precursors for loganin. (3) Carbon atoms 9 and 10 in 10-hydroxy geraniol and 10-hydroxynerol must equili brate and become essentially identical by introduction of oxygen at both centers. (4) 10-Hydrogeraniol or 10-hydroxynerol go to deoxyloganin, which is then oxidized to loganin. (5) Loganin is cleaved to secologanin, which is a pivotal intermediate. Depending upon the amino acids and the enzymes available in the plant, secologanin can either act as a precursor for desacetylipecoside so as to yield ipecoside and the emetine-type bases, or, alternatively, it can condense to give vincoside, which is a precursor of the indolic iboga, corynanthe, and aspidosperma alkaloids (Scheme XIX). All of the intermediates mentioned here have been isolated as natural products from plants, some only in trace amounts. Turning again to C. ipecacuanha, it has recently been possible to demonstrate that loganin is changed into secologanin which undergoes conversion to desacetylipecoside and desacetylisoipecoside. It is desacetylipecoside and not desacetylisoipecoside which
448
23. EMETINE A N D RELATED ALKALOIDS
T
iCH3 ^ C H 2O H 9
H
3
C ^ C H
CH.3
: H 2O H 10
3
" H 3C r " C H 2 O H
Geraniol
10 - H y d r o x y g e r a n i o l
: H 2O H
Ή 3 0 ' ^ C H 2O H
H 3C f
10- H y d r o x y n e r o l
^CH3
Nerol
O-glucose C H 3O O C Deoxyloganin
Loganin
Secologanin
Η
O-glucose C H 3O O C Desacetylipecoside
Emetine -type alkaloids
Ipecoside
De sac etylis oipec oside
Ibogatype alkaloids
Vincoside
Corynanthetype alkaloids
Aspidospermatype alkaloids
Scheme XIX can be converted biologically into ipecoside, cephaeline, and emetine. The mechanism of the interesting C-5 C-l 1 b inversion in going from desacetylipecoside to cephaeline 4 93 remains to be e s t a b l i s h e d . Finally, experiments with C. ipecacuanha using labeled glycine and sodium acetate have shown that glycine can act as a specific two-carbon precursor of the C 9 unit of cephaeline, delivering 15 — 1 8 % of the activity incorporated to C - l 5 and none t o C-14. On the other hand, radioactive acetic acid did not label this unit with any specificity or efficiency but was incorporated instead into the sterol ^-sitosterol that is also present in the plant. T h e oxidation state of a two-carbon c o m p o u n d may, therefore, exert 50 a major effect upon its utilization in biosynthesis (Scheme X X ) .
449
XI. T H E P A R T I A L S Y N T H E S I S O F S E C O L O G A N I N A N D IPECOSIDE
Labeled
glycine Labeled
sodium
cephaeline
acetate Labeled
ß-sitosterol
Scheme X X
X I . T H E P A R T I A L SYNTHESIS OF S E C O L O G A N I N A N D IPECOSIDE
Controlled mild alkaline hydrolysis of the interesting naturally occurring glucoside 51 menthiafolin, obtained from Menyanthes trifoliata L i n n . , followed by methylation
(—) - S e c o l o g a n i n Menthiafolin
Desacetylipecoside
Desacetylisoipecoside
hydrochloride
hydrochloride
Countercurrent distribution
Desacetylipecoside * hydrochloride
A c 20 ,
τ
τ
Hexa-O-acetyl* ipecoside Scheme X X I p y r i de i n
N a O C H 3, hm ae nt o i
*
^ecoside
450
23. EMETINE AND RELATED ALKALOIDS
with diazomethane, afforded secologanin. Subsequent Mannich condensation with 3,4-dihydroxyphenylethy lamine hydrochloride yielded two products, desacetylipecoside and desacetylisoipecoside hydrochlorides, which were separated by countercurrent distribution. Desacetylipecoside was then polyacetylated, and Zemplen deacetylation 4 5 , 25 furnished ( —)-ipecoside, identical with the natural product (Scheme X X I ) .
XII. RUBREMETINE SALTS
Mild oxidation of emetine with ferric chloride, bromine, iodine, or mercuric acetate gives reddish, optically active compounds known as rubremetine salts. As a result of this transformation one nitrogen atom loses its basic character while the other becomes quaternary. The structure assigned to the rubremetine cation incorporates a nonbasic nitrogen within a pyrrole ring, a quaternary nitrogen as part of the original isoquinoline system, and asymmetry about C-3 where the ethyl group is attached 5 3 55 (Scheme X X I I ) . " Catalytic reduction of rubremetine chloride readily furnishes two basic and colorless diastereoisomers, A- and B-dihydrorubremetine, which are epimeric at C-l l b . The starting material as well as the products exhibit positive color tests for pyrrole, and spectral data indicate that both A- and B-dihydrorubremetines possess cis-fused 5 6 57 quinolizidine s y s t e m s . ' The dihydrorubremetines can be hydrogenated further very slowly, but the reaction is appreciably catalyzed by acid. The product from either isomer is optically active tetrahydrorubremetine which still shows pyrrole reactions and contains n o Ν —Η function. Tetrahydrorubremetine is formed through the intermediacy of the immonium salt 5 7 whose formation from the dihydrorubremetines is acid-catalyzed. In line with this reasoning, the dihydrorubremetines undergo mutarotation in acid solution via 5 6 57 the salt 5 7 (Scheme X X I I ) . ' Several syntheses of the rubremetine cation are available.
XIII. P H A R M A C O L O G Y
33
Ipecac was the standard treatment of the South American Indians before the advent of the white m a n for what is now recognized as amebic dysentery caused by the micro organism Entamoeba histolytica. In 1912 it was recognized that the alkaloid responsible for this drug action is emetine, which is less toxic and more effective than the accom panying base cephaeline. Emetine is effective only against amebic and not bacillary infections, and the drug is still useful in efforts at eradication of the extraintestinal trophozoites and in the treatment of acute amebic intestinal or extraintestinal infections. Emetine is toxic and cumulative, and it must not be given beyond a 10-day period. Poisoning by emetine is characterized by muscular tremors and weakness and pains, especially in the extremities. The alkaloid has also been used as a mild emetic, but this is not a common treatment.
451
XIII. P H A R M A C O L O G Y
C H 30 * ÖCH3 Rubremetine
cation H 2, P t
CHL OCH3
OCH3
Β -Dihydrorubremetine
A -Dihydrorubremetine
C H 30 ' OCH3 Tetrahydrorubremetine
Scheme XXII
(±)-2,3-Dehydroemetine is almost equal to emetine in amebicidal activity, the ( — )-enantiomer being the biologically active component. T h e racemic compound is usually used a n d it has been found that it is better tolerated and more readily excreted than ( —)-emetine. T h e absence of the C-3 ethyl group of emetine results in a partial loss of antiamebic activity. The pharmacological usefulness of emetine and 2,3-dehydroemetine may be related to the fact that they inhibit protein synthesis in mammalian cells. Emetine also has antiparasitic activity in certain lung diseases and in sheep infected 1 with Fasciola hepatica. As pointed o u t earlier, (— )-emetine, identical with the natural product, is produced commercially by Burroughs Wellcome & Co. in England, while ( + )-2,3-dehydroemetine is manufactured at Hoffmann-La Roche in Switzerland. Since an optical resulution is
452
23. EMETINE AND RELATED ALKALOIDS
not involved in the production of ( + )-2,3-dehydroemetine, it is more readily available than synthetic (— )-emetine. Emetine has also shown potential in initial tests as an anticancer drug and is currently 58 undergoing clinical evaluation at the National Institutes of Health. The benzoquinolizidine derivative tetrabenazine (Nitoman, Hoffmann-La Roche) has been extensively tested because of its psychotropic activity. It exerts a reserpine-like sedative action and has a beneficial effect on various symptoms of schizophrenia as well as in Huntington's chorea. Like reserpine, tetrabenazine decreases the 5-hydroxytryptamine and catechol amine content in the brain. It is less potent than reserpine 5 9 5 9a but of shorter duration and faster onset of action. > It is presently in use in some of the Scandinavian countries.
Ο Tetrabenazine
When Af-2'-benzyloxycarbonylemetine was quaternized with 3,3-ethylenedioxy-lp-toluenesulfonate and the salt reduced with lithium in liquid ammonia, fission of the N-5 to C-l l b bond was accompanied by cleavage of the benzyloxycarbonyl group, so that the product was the secoemetine 5 8 which was-de-AT-alkylated to the derivative 60 5 9 . Compound 5 9 is less potent as an amebicide than the parent alkaloid.
Ν - 2' -Benzyloxycarbonylemetine
58
59
453
XIV. MASS S P E C T R O S C O P Y
XIV.
M A S S SPECTROSCOPY
The mass spectral cleavage pattern of the emetine-type alkaloids is dependent on the degree of saturation of ring D . The two most intense peaks in the spectrum of cephaeline are at m/e 192 and 178 and are due to ions 60 — 62.
60 m/e
192
61 m/e
62 m/e
192
178
O-Methylpsychotrine, which incorporates an imine function in ring D , exhibits a totally different cleavage pattern, with two discernible modes of fragmentation (Scheme XXIII). In type (i) cleavage, the very intense peak at m/e 273 and the strong m/e 205 peak are produced through cleavage of the allylic C-2 to C-α bond. Type (ii) 3 fission affects primarily ring C and produces the stable ions of m/e 190 and 230.
m/e
O - M e t h y l p s y c h o t r i n e , M®
Type (ii)
m/e
190
Scheme X X I I I
273
m/e
205
454
23. EMETINE AND RELATED ALKALOIDS
In the spectrum of ankorine, the base peak at m/e 334 corresponds to the ( Μ — 1) ion. Other intense peaks are seen at m/e 320, 318, 262, 221, 207, and 192, and these 5 are interpreted in Scheme X X I V . C H 30 . CH3O'
OH e
HOH 2C^ Ankorine
2 26
m /
M®, m/e 335
CH3O,
CH 0 ^y ^ ^CH <
A
3
N
OH
3
m/e 221 -CH2
m/e 207 -CH3
m/e 192 m/e 320
[-
2H
m/e 318 Scheme XXIV
XV. N M R
SPECTROSCOPY
It is difficult to m a k e specific assignments for the proton chemical shifts of the classical 12 emetine b a s e s . T h e N M R spectrum for the simpler alkaloid ankorine is more readily 5 interpreted and the chemical shifts are quoted below.
NMR s p e c t r a l values for ankorine
455
REFERENCES
X V I . U V SPECTROSCOPY 1 3 61
Emetine d i h y d r o c h l o r i d e ' Psychotrine
12
4
Desmethylpsychotrine 4
Alangicine 62 Emetamine
Protoemetine P e r c h l o r a t e Ankorine
5 61
Rubremetine c h l o r i d e (not a natural product)
10
Η
Λ*° Χ 230 and 283 πιμ (4.23 and 3.87) ^ P " 256 τημ (3.11) N H 1C l°mL 240, 288, 306, and 356 τημ (4.14, 3.76,3.80, and 3.83) 0 Η Λ* Χ 223, 277, 310, and 410 τημ (3.95, 3.83, 3.34, and 3.96) Η Α*° Χ 275, 312, and 408 τημ (3.84, 3,42, and 4.09) Η λ £ £ 236 and 283 τημ (4.85 and 3.86) H ^ J S 217, 262, 303, and 321 πιμ (4.28, 3.72, 3.36, and 3.48) H ^ a ° x 232 and 283 πιμ (3.92 and 3.61) H / S 220 and 254 πιμ (3.85 and 2.68) λ*™ 272 πιμ (2.96) AS? 257, 286, 300, and 437 πιμ (4.28, 4.24, 4.26, and 4.47).
REFERENCES 1. For reviews on the ipecacuanha alkaloids, see Η. T. Openshaw, in "Chemistry of the Alkaloids" (S. W. Pelletier, ed.), p. 85. Van Nostrand, Princeton, New Jersey, 1970; and A. Brossi, G. V. Parry, and S. Teitel, in "The Alkaloids" (R. F. H. Manske, ed.), Vol. 13, p. 189. Academic Press, New York, 1971; and Cs. Szäntay in Recent Developments in the Chemistry of Natural Carbon Compounds, Vol. 2, 63 (1967), Akademiai Kiado, Budapest. 2. S. C. Pakrashi and E. Ali, Indian J. Chem. 7, 635 (1969). 3. H. Budzikiewicz, S. C. Pakrashi, and H. Vorbrüggen, Tetrahedron 20, 399 (1964). 4. S. C. Pakrashi and E. Ali, Tetrahedron Lett. p. 2143 (1967). 5. A. R. Battersby, R. S. Kapil, D. S. Bhakuni, S. P. Popli, J. R. Merchant, and S. S. Salgar, Tetrahedron Lett. p. 4965 (1966). 6. B. Dasgupta, / . Pharm. Sei. 54, 481 (1965). 7. R. Robinson, Nature (London) 162, 524 (1948). 8. A. R. Battersby and Η. T. Openshaw, J. Chem. Soc., London pp. 3207 andS 59 (1949). 9. M. Pailer and K. Porschinski, Monatsh. Chem. 80, 94 and 101 (1949). 10. A. R. Battersby and B. J. T. Harper, J. Chem. Soc, London p. 1748 (1959). 11. Cs. Szantay, L. Töke, and P. Kolonits, J. Org. Chem. 31, 1447 (1966). 12. S. Teitel and A. Brossi, J. Amer. Chem. Soc. 88, 4068 (1966). 13. A. Brossi, M. Baumann, and O. Schnider, Helv. Chim. Acta 42, 1515 (1959). 14. Ε. E. van Tamelen, P. E. Aldrich, and J. B. Hester, Jr., J. Amer. Chem. Soc 79, 4817 (1957). 15. Ε. E. van Tamelen and J. B. Hester, Jr., / . Amer. Chem. Soc 81, 507 (1959). 16. Ε. E. van Tamelen, P. E. Aldrich, and J. B. Hester, Jr., J. Amer. Chem. Soc. 81, 6214 (1959). 17. For a closely related sequence, see A. R. Battersby and S. Garratt, / . Chem. Soc, London p. 3512(1959). 18. Ε. E. van Tamelen and M. Shamma, / . Amer. Chem. Soc. 76, 950 (1954). 19. Y. Ban, M. Terashima, and O. Yonemitsu, Chem. Ind. (London) pp. 568 and 569 (1959).
456
20. 21. 22. 23.
23. EMETINE A N D RELATED ALKALOIDS
M. Terashima, Chem. Pharm. Bull. 8, 517 (1960). A. R. Battersby, R. Binks, and T. P. Edwards, J. Chem. Soc., London p. 3474 (1960). A. R. Battersby, S. W. Breuer, and'S. Garratt, / . Chem. Soc, C p . 2467 (1968). R. P. Evstigneeva, R. S. Livshits, L. I. Zakharin, M. S. Bainova, and N. A. Preobrazhenskii, Dokl. Akad. Nauk SSSR1S, 539 (1950); R. P. Evstigneeva and N. A. Preobrazhenskii, Tetrahedron 4, 223 (1958). See also L. I. Zakharin and N. A. Preobrazhenskii, Z. Obshch. Khim. 22, 1890 (1952); 23, 153 (1953). 24. J. A. Weisbach, J. L. Kirkpatrick, E. L. Anderson, K. Williams, B. Douglas, and H. Ra poport, J. Amer. Chem. Soc 87, 4221 (1965). 25. A. W. Frahm, Arch. Pharm. (Weinheim) 301, 621 (1968). 26. Y. Ban, Pharm. Bull. 3, 53 (1955). 27. A. R. Battersby and J. C. Turner, Chem. Ind. (London) p. 1324 (1958); / . Chem. Soc, London p. 717 (1960). 28. Ε. E. van Tamelen, M. Shamma, A. W. Burgstahler, J. Wolinsky, R. Tamm, and P. E. Aldrich, / . Amer. Chem. Soc 80, 5006 (1958); 91, 7315 (1969). 29. A. W. Burgstahler and Z. J. Bithos, / . Amer. Chem. Soc. 82, 5466 (1960). 30. Ε. E. van Tamelen, G. P. Schiemenz, and H. L. Arons, Tetrahedron Lett. p. 1005 (1963); Ε. E. van Tamelen, C. Placeway, G. P. Schiemenz, and I. G. Wright, / . Amer. Chem. Soc 91, 7359 (1969). 31. D. E. Clark, R. F. K. Meredith, A. C. Ritchie, and T. Walker, J. Chem. Soc, London p. 2490 (1962). 32. A. R. Battersby, Η. T. Openshaw, and H. C. S. Wood, / . Chem. Soc, London p. 2463 (1953). 33. A. Brossi, Pure Appl. Chem. 19, 171 (1969). 34. A. Grüssner, E. Jaeger, J. Hellerbach, and O. Schnider, Helv. Chim. Acta 42, 2431 (1959). 35. M. Barasch, J. M. Osbond, and J. C. Wickens, / . Chem. Soc, London p. 3530 (1959). 36. Η. T. Openshaw and N. Whittaker, J. Chem. Soc, London pp. 1449 and 1461 (1963). 37. N. Whittaker, J. Chem. Soc, C p. 85 (1969). n 38. For a related approach, see Szäntay et al. 39. Η. T. Openshaw and N. Whittaker, / . Chem. Soc, C p. 89 (1969). 40. N. Whittaker, J. Chem. Soc, C p. 94 (1969). 41. F. Zymalkowski and A. W. Frahm, Arch. Pharm. (Weinheim) 297, 219 (1964); Chem. Abstr. 60, 15727b (1964). 42. A. R. Battersby, B. Gregory, H. Spencer, J. C. Turner, M.-M. Janot, P. Potier, P. Francois, and J. Levisalles, Chem. Commun. p. 219 (1967). For the X-ray determination of 0,0-dimethylipecoside sesquihydrate see O. Kennard, P. J. Roberts, N. W. Isaacs, F. H. Allen, W. D. S. Motherwell, Κ. H. Gibson, and A. R. Battersby, Chem. Commun. p. 899 (1971). 42 a. R. S. Kapil, A. Shoeb, S. P. Popli, A. R. Burnett, G. D. Knowles, and A. R. Battersby, Chem. Commun. p. 904 (1971). 43. A. R. Battersby and B. Gregory, Chem. Commun. p. 134 (1968); see also A. R. Battersby, R. S. Kapil, and R. Southgate, ibid. p. 131. 44. For related experiments, see S. Brechbühler-Bader, C. J. Coscia, P. Loew, C. von Szczepanski, and D. Arigoni, Chem. Commun. p. 136 (1968); also P. Loew and D. Arigoni, ibid. p. 137. 45. A. R. Battersby, A. R. Burnett, and P. G. Parsons, / . Chem. Soc, C p. 1187 (1969). 46. A. R. Battersby, A. R. Burnett, and P. G. Parsons, / . Chem. Soc, C p. 1193 (1969). 47. S. Escher, P. Loew, and D. Arigoni, Chem. Commun. p. 823 (1970). 48. A. R. Battersby, A. R. Burnett, and P. G. Parsons, Chem. Commun. p. 826 (1970). 49. A. R. Battersby, S. H. Brown, and T. G. Payne, Chem. Commun. p. 827 (1970). 49 a. A. R. Battersby and R. J. Parry, Chem. Commun. p. 901 (1971). 50. A. K. Garg and J. R. Gear, Tetrahedron Lett. p. 4377 (1969). 51. A. R. Battersby, A. R. Burnett, G. D. Knowles, and P. G. Parsons, Chem. Commun. p. 1277 (1968).
REFERENCES
52. 53. 54. 55.
457
A. R. Battersby, A. R. Burnett, and P. G. Parsons, Chem. Commun. p. 1280 (1968). A. R. Battersby, Η. T. Openshaw, and H. C. S. Wood, Experientia 5, 114 (1949), Η. T. Openshaw and H. C. S. Wood, J. Chem. Soc., London p. 391 (1952). A. Brossi, M. Gerecke, A. R. Battersby, R. S. Kapil, Y. Ban, and M. Terashima, Experientia 22, 134 (1966). 56. K.-A. Kovar, H. Ehrhardt, and H. Auterhoff,.,4rc/z. Pharm. (Weinheim) 302, 220 (1969). 57. K.-A. Kovar, Arch. Pharm. (Weinheim) 303, 579 (1970). 58. R. Ε. Perdue, Jr. and J. L. Hartwell, Morris Arbor. Bull. 20, 35 (1969). 59. A. Pletscher, A. Brossi, and K. F. Gey, Int. Rev. Neurobiol. 4, 275 (1962). 59 a. D. E. Schwartz, H. Bruderer, J. Rieder, and A. Brossi, Biochem. Pharmacol. 15, 645 (1966). 60. J. P. Yardley, R. W. Rees, and H. Smith, / . Med. Chem. 10, 1088 (1967). 61. A. Brossi and O. Schnider, Helv. Chim. Acta 45, 1899 (1962). 62. A. R. Battersby, G. C. Davidson, and J. C. Turner, J. Chem. Soc, London p. 3899 (1961).
Occurrence: Alangiaceae and Rubiaceae N u m b e r : 14 Structures: C H 30 ^
OCH* OR 1
( - ) - E m e t i n e , R = CH 3 (+)-Psychotrine, R = Η 3 (-)-Cephaeline, R =Η (+) - O-Methylpsychotrine, R = C H 3 2 4 ( - ) - A l a n g a m i d e = N - 2 ' - C O - N H - C H 3 (+)-Alangicine*s 1 1 - H y d r o x y p s y c h o t r i n e emetine
CH,
(+)-Emetamine
(+) - D e m e t h y l p s y c h o t r i n e
4
427
II. CHEMICAL INTERRELATIONSHIPS
(—) - P r o t o e m e t i n e
(—) - I p e c o s i d e
Protoemetinol ( C H O r e p l a c e d b y C H 2O H )
H-Dihydroprotoemetine, R " Η 5 6 (-)-Ankorine, * R = OH '
5
-g H-Alangiside
H
* Stereochemistry not yet established.
I. INTRODUCTION
The original or classical emetine alkaloids consist of five bases: emetine, cephaeline, psychotrine, O-methylpsychotrine, and emetamine, obtained mainly from ipecac or ipecacuanha — the roots of the South American straggling bush Cephaelis ipecacuanha (Brotero) Rich, or the Central American Psychotria granadensis Benth, ex Oerst 1 (Rubiaceae). To this group have been added protoemetine and ipecoside, both of which are also found in ipecac. The alkaloids of ipecac, especially emetine, are im portant because of their antiamebic activity. The Indian plant Alangium lamarckii Thw. (Alangiaceae) has recently been found to contain emetine, cephaeline, and psychotrine, as well as the new alkaloids alangicine, desmethylpsychotrine, alangamide, dihydroprotoemetine and ankorine. II. CHEMICAL INTERRELATIONSHIPS BETWEEN THE IPECAC BASES
Emetine is levorotatory a n d has four methoxyl groups. Although the alkaloid contains one tertiary and one secondary nitrogen, n o ΛΓ-methyl function is present in it or in any of its immediately related bases. The chemical relationship between emetine and the remaining original ipecac alkaloids have been summarized in Scheme I. In the catalytic reductions of psychotrine to cephaeline and of O-methylpsychotrine to emetine, isocephaeline a n d isoemetine are also produced. These two reduction products, not found in natural sources and not shown in Scheme I, are diastereoisomeric at C - Γ with cephaeline a n d emetine, respectively.
428
23. EMETINE AND RELATED ALKALOIDS
OCH
-^rV
N
^ ^ ^ O C H
3 3
C H 30 CH3O
„OCH 3 "OCH3 ( + ) - 0-Methylpsychotrine ( i c H 2N 2
(—) -Cephaeline
(+) - P s y c h o t r i n e Scheme I
III. DEGRADATION OF EMETINE
Crude emetine was first isolated in 1817 by Pelletier, but the correct empirical formula of C 29 H 4 o 0 4 N 2 was not established until 1914 due to insufficient purification. Despite its early discovery, emetine was not obtained in crystalline form until 1953. Initial studies on the oxidation of emetine with potassium permanganate under a variety of experimental conditions led to the isolation of such fragments as 1 to 4. C H 3c \
C H 3O S^ ^ C O O H
CHaO^
C H 3 C / ^ A COOH :
CH,
C H
3
0 " ^ ^ 0
COOH
4 m -Hemipinic acid All of these c o m p o u n d s pointed to the presence of the 6,7-dimethoxyisoquinoline system in emetine. But the extremely high yield (96%) of m-hemipinic acid (2) obtained
429
Scheme II
III. DEGRADATION OF EMETINE
430
23. EMETINE AND RELATED ALKALOIDS
in one of the oxidations indicated that more than one moiety capable of yielding this product was present in the molecule. Hesse, Pyman, Karrer, Späth, Reichstein, Pailer, and others carried out extensive Hofmann and Emde degradations on emetine. F r o m such work it became obvious that the secondary nitrogen in the alkaloid is monocyclic, while the tertiary nitrogen belongs to two rings. The correct structure for emetine, first tentatively suggested in 7 1948 by Robinson on biogenetic grounds, was confirmed independently in 1949 by 8 9 Battersby and O p e n s h a w and by Pailer and Porschinski. The main lines of the extensive degradative work carried out by Battersby and Openshaw is presented in Schemes I I and I I I . Although certain compounds in these schemes were not completely characterized, the isolation of such shards as 6-ethylveratric acid (Schemes I I and I I I ) , 5-ethylpyridine-2,4-dicarboxylic acid (Scheme I I ) , formaldehyde and the conjugated diene 5 (Scheme I I I ) , all served to define the correct 8 structure for emetine.
6-Ethylveratric acid
Emetine hexahydrotris*methine
Scheme I I I
I V . T H E POSITION OF THE PHENOLIC F U N C T I O N IN CEPHAELINE
The position of the phenolic function in cephaeline was settled conclusively when Pailer a n d Porschinski converted O-ethylcephaeline into the intermediate 6 by a series of Hofmann degradations and catalytic reduction. Ozonization of this salt then gave
431
VI. THE STEREOCHEMISTRY OF EMETINE
2-ethyl-4-ethoxy-5-methoxybenzaldehyde, so that cephaeline must have the phenolic 9 function at C-6'.
2-Ethyl-4-ethoxy5-methoxybenz aldehyde
6
Ö-Ethylcephaeline
V. PROTOEMETINE
Q9H27O3N,
( —)-Protoemetine, an ipecac alkaloid of biogenetic interest, was isolated in 1957. The compound is tricyclic and bears two methoxyl groups, as well as a single tertiary nitrogen function and an aldehyde group. Its structural elucidation rests mainly 10 u p o n its conversion to the naturally occurring O-methylpsychotrine (Scheme I V ) .
(+) - 0 - M e t h y l p s y c h o t r i n e
COC1
Scheme IV Since O-methylpsychotrine has been reduced to emetine, the above conversion also constitutes a partial synthesis of emetine. Additionally, protoemetine has been condensed with 3-hydroxy-4-methoxyphenylethylamine to produce cephaeline and some iso1 0 - 21 cephaeline. The former product can be O-methylated to e m e t i n e .
VI. T H E STEREOCHEMISTRY OF EMETINE
Emetine possesses the thermodynamically stable irafw-quinolizidine arrangement delineated in which all the substituents are equatorially situated. The more salient reasons for this assignment of configuration at the four asymmetric centers may be summarized as follows:
23. EMETINE AND RELATED ALKALOIDS
432
C H 30 (—)-Emetine
Isoemetine
13
The O R D curves of emetine and its salts depend primarily u p o n the benzylic centers of asymmetry at C-l l b and at C - Γ . Van Tamelen pointed out that these two centers must be antipodal to one another, since emetine hydrobromide exhibits negligible rota tional change in the 300 to 700 πιμ range, indicating that the contributions of the two
Homoveratrylamine
trans - 3 , 4 - D i e t h y l cyclopentanone
1. L i B H 4 2. p - T o l u e n e sulfonyl chloride 3. Thiourea 4. Ni(R)
Several
(±)-Emetine
<
s t e sp
Scheme V
433
VI. THE STEREOCHEMISTRY OF EMETINE
centers essentially cancel each other. O n the other hand, isoemetine hydrobromide, which is epimeric with emetine at C - Γ , exhibits increasing rotation down to 300 ηιμ 1 4 16 because of optical reinforcement of the two asymmetric c e n t e r s . " The hydrogen atoms at C-2 and C-3 must be trans to each other, and the C-11 b hydrogen must be eis to that at C-2. This conclusion was reached after the synthesis of the tricyclic base 7 of known relative stereochemistry, starting with iraH£-3,4-diethylcyclopentanone. Base 7 proved to be identical with material derived from the lactam ester 8 through the immonium salt 9 by steps not involving any change in stereochemistry. Since the lactam ester 8, as will be seen in Section VII, A, had previously been converted by Preobrazenskii et al. into racemic emetine, the relative configurations at C-2, C-3, 1 5 17 and C-11 b in emetine were established (Scheme V ) . " The final step in the preparation of the tricyclic base 7 from the lactam ester 8 by reduction of the immonium salt 9 under a variety of experimental conditions including catalytic hydrogenation, mixed metal hydrides, or sodium in alcohol, always resulted in the formation of only one isomer of 7. This fact implies that the C-1 l b hydrogen in emetine is axial, by analogy with similar reductions in the yohimbine series in which, 18 for example, the immonium salt 10 is reduced to y o h i m b a n e . If the thermodynamically less stable isomer of the tricyclic base 7 is desired, it may be obtained together with 7 by reduction of the salt 9 with either zinc or tin in hydrochloric acid.
10
Yohimbane
The foregoing conclusions regarding the stereochemistry of emetine are reinforced l by the presence in 2'-benzoylemetine of I R Bohlmann bands around 3.65 ηιμ (2740 c m " ) characteristic of iraws-quinolizidine systems, indicating that the pair of electrons on N-5 and the hydrogen a t o m at l i b in emetine exist primarily in a trans-diaxial rela 19 tionship. The absolute configuration of emetine at C-11 b was settled by means of a comparative study of the molecular rotations of N-2 '-benzoyl- and 7V-2'-acetylemetine versus that 20 for the corresponding 5-1 l b dehydroemetinium s a l t s . It was observed that the axial hydrogen at l i b in natural (—)-emetine makes a large negative contribution: N-2'y acetylemetine exhibits [M]£ — 401.4°, and the corresponding dehydro (immonium) salt y lacking asymmetry at C-1 l b has [M]£ + 6 2 5 . 5 ° . This situation is analogous to that prevailing in the (— )-tetrahydroprotoberberine series, represented here by ( —)-norcoralydine, in which, due to the presence of the 14-a-H, the molecular rotation values usually lie near —1000°. Therefore the corresponding asymmetric centers in the two alkaloidal series must be identical, and the C-11 b hydrogen in emetine is alpha. Battersby and co-workers employed the diene 11, obtained by sequential Hofmann degradation of 7V-acetylemetine, to study the absolute configuration at C - Γ . C o m p o u n d
434
23. EMETINE AND RELATED ALKALOIDS
(-) - N o r c o r a l y d i n e
11 is actually related to the diene 5 obtained during the degradative studies on emetine. Oxidation of 11 first with ozone and then either with potassium permanganate or peracetic acid furnished, besides methyl ethyl ketone, the bicyclic (—)-acid amide 12. The latter was then chemically interrelated with the alkaloid (+)-calycotomine of 21 known absolute configuration. i.o3
11
^ ^ * X > C H
12
3
(+)-Calycotomine
The stereochemistry of the remaining classical ipecac alkaloids follows from that 12 of emetine. The O R D curve of psychotrine has been r e c o r d e d ; and a chemical 22 correlation has been established between the ipecac and indole alkaloids.
V I I . SYNTHESES OF EMETINE
More than a dozen syntheses of emetine are known, which make this compound the most synthesized alkaloid known. The study of these syntheses constitutes an interesting and worthwhile intellectual exercise in the laboratory-induced transformation of organic materials, so that most of these preparations will be considered here. A. The Preobrazhenskii
Synthesis
The first synthesis of emetine was reported by Preobrazhenskii and his group in 1950. The sequence was later expanded and modified, and the Russian work in its 23 final form may be summarized as shown in Scheme V I . * Since several steps in the synthesis, including the initial Michael condensation with diethyl glutaconate, lacked stereochemical control, diastereoisomeric intermediates were obtained which had to be separated in the course of the synthesis. * The structural assignments made for some of the intermediates obtained in this synthesis 2 4 25 had to be modified. '
435
VII. SYNTHESES OF EMETINE
COOC 2H 5
C=N +
C 2H 5OOC
N a O C 2H 5
c i2 i
S
C O O C 2H 5
COOCoH. COOC 2H 5
COOC 2H 5 Diethyl glutaconate C 2H 5OOC
C2H3I,
C=N
N
Ethyl cyanoacetate 1.
C=N
C 2H 5OOC
OH",
C=N Homoveratry lamine,
controlled
COOC 2H 5
COOC2H5
saponification
2. Δ, - c o 2
C H 3O v ^
H 2, N i ( R )
' COOC 2H 5
CH3O
1. H o m o v e r a t r y l a m i n e ,
2. POCI3
1. POCI3
CH.
2. [ H ]
3. [H]
CH3O'
COOC 2H 5
•> (±)-Emetine
COOC 2H 5
or a l t e r n a t i v e l y : Homoveratry l a m i n e in e x c e s s ,
C2H5OOC
CSN
H 2 , Ni(R)
3'
C
H
1. pocij 2.[H]
(+) - E m e t i n e
CH3O'
COOC 2H 5
Scheme VI B. The Batter shy-Turner
Synthesis
A clean stereospecific synthesis was devised by Battersby and Turner utilizing the 26 jß-ketolactam 13 originally prepared by B a n . Michael condensation of the unsaturated lactam 14 with malonic ester gave after work-up the thermodynamically favored trans compound 15, and subsequent catalytic reduction to the tricyclic ester 16 also proceeded to yield the more stable isomer. The tricyclic ester 16 was found to be identical with that derived from protoemetine, except for the optical activity, so that the remainder of the synthesis essentially followed the conversion of protoemetine to emetine (Scheme 27 VII). C. The Burgstahler-Bithos
Synthesis 28
A synthesis of emetine reminiscent of the van Tamelen yohimbine synthesis has been carried out by Burgstahler and Bithos utilizing the c o m m o n reagent gallic acid
436
23. EMETINE A N D RELATED ALKALOIDS
xTV
CHgO.^ HC OH,
°Υ ν ^Ί
0Η3
ί?
/
^JL
m T
C H
3
J
+
irxr
0 ^ /
2
HOOC^f^
C H
ethanol ^
COOH
3
0 ^
/
*N
(Mannich)
N H
HOOC
C \ O O^H
Carbethoxyβ
ο Η , ο . ^ / ν
I.A,-CO2 2. E t h a n o l , Η +
»° *
1
C H 3 OA ' J
N<
C 2 H 5 O O C< S o
;
'
CHaO^jSv^^
»y'«°e
.
1
CH3O,
ύ
Γ
3
II
H
CHsCV^Q^N^
^
C 2H 5O O C ^ c ^ o ^ H 5
" I
H 2, P t ,
CH CX^x\
3 θ +Λ
' ·
3
-CO2 ,
[\\\
3
NaBH4 .
c^o^^V ^
C H 3O — s ^ c y N .
Ο
1
ο 1. Diethyl malonate,
CHaO^^^X Υ
|f
CHgO^,;^^ f
ΟΗ θ"^^°γ" ^ Ν
3
l . A c 20
2.
N a O C 2H 5 f
Τ
Τ
N a O C 2H 5 J
r^n-^xU^Nv.
(Michael)
2. H3O+, A, - c o 2
OH
Scheme VII as starting material. This approach is nonstereospeciflc and diastereoisomeric compounds had to be separated at proper intervals. Cleavage of the triol 17 with periodic acid produced a mixture of the lactol 18 and the corresponding hydroxyaldehyde, which, without separation, was cyclized to the lactam aldehyde 19 (Scheme V I I I ) .
Gallic acid
All-eis
isomer
29
437
VII. SYNTHESES OF EMETINE
Scheme VIII
D. The van Tamelen
Synthesis
In the synthesis of emetine achieved by van Tamelen, Schiemenz, and Arons, the keto triester 2 0 was first obtained by Michael condensation of methyl acetoacetate with dimethyl glutaconate. Mannich-type condensation of 2 0 with homoveratrylamine and formaldehyde then provided the key intermediate 2 1 . The remainder of the synthesis follows straightforward lines, especially since the tricyclic ester 2 2 had already 30 been converted to emetine by Preobrazhenskii and other workers (Scheme I X ) .
-
i butyi C H
3
0 ^ ^
2
N
H
Y Y
C
Ct>OCH 3
H 3
20
Scheme IX
C H 3O v
— JOCX "C"CH3
(Mannich)
21
CÜOCH^
23. EMETINE AND RELATED ALKALOIDS
438
E. The Glaxo
Synthesis
Clark, Meredith, Ritchie, and Walker have carried out a stereospecific preparation of emetine that follows unusual lines. Condensation of the imine 23 with acetonedicarboxylic acid in dilute aqueous sulfuric acid was found to yield the required meso diamino ketone 24, while if the condensation were carried out in aqueous pyridine the undesired racemic diastereoispmer of 24 resulted. One amino function of 24 was protected through monobenzylation, and a Michael-aldol condensation with methyl vinyl ketone gave rise, after acid-catalyzed dehydration, to the critical intermediate 25. Reduction of the conjugated double bond with lithium in liquid ammonia followed by equilibration with acid gave the more stable trans-fused ketone 26. Following removal of the ketonic function, reductive debenzylation yielded emetine. The main 31 advantage of this approach is that no isoemetine is obtained as a by-product (Scheme X ) .
1. E t h a n e d i t h i o l ,
1. L i / N H 3
H
+
2 . Ni(R)
2 . Hot H +
3 . H 2,
(equilibration
Pd/C
(debenzylation)
at C-3)
(±) - E m e t i n e
Ph-CH
Scheme Χ F. The First Roche Basle Synthesis 32
The aim of this approach was to prepare the tricyclic ketone 2 9 , which after homolo 13 gation to the acid 30 would be convertible into emetine (Scheme X I ) .
VII. SYNTHESES OF EMETINE
439
HC OH, ethylmalonic
CHgO
1. CH 2N 2 2. NaOCH 3 (Dieckmann) 3. H 30 + A, -C02
CH3O. CH3O'
C 2H 5O O C -
C 2H 5O O C ' HOOC
CH2 ?
28
2
°Τ^1Γ^
0Η3
Malononitrile, NH 4OAc, HOAc
COOH
CH3O.
NC"
N
C N
CH3O. Homoveratrylamine
30
CH3O
COOH
CH3O. 1. H 2, Pd 130°, 100 atm 2. Separation of diastereoisomers
CH3O
1. POCI3 2. H 2, Pt H
-N^O|Py
\ ^ ^ O C H
Also:
(±)-Emetine
O C H
3 3
CH3O CH3O 31
pocij
OCH3
OCH,
"OCH3 ( ± ) - 2 J3 - D e h y d r o e m e t i n e
OCH3 (±) - 2 , 3 - D e h y d r o i s o e m e t i n e ( D e v o i d of a m e b i c i d a l a c t i v i t y )
Scheme XI
440
23. EMETINE AND RELATED ALKALOIDS
The a m i n o ester 27 yielded the diacid ester 28 through a Mannich-type reaction with formaldehyde and ethylmalonic acid. Esterification, Dieckmann cyclization, hydrolysis, and then decarboxylation produced the required tricyclic ketone 29. H o m o logation to 30 was accomplished by condensation with malononitrile followed by hydrolysis and decarboxylation. The acid 30 was condensed with homoveratrylamine and the resulting amide reduced catalytically to a separable mixture of eis and trans isomers. The trans species after Bischler-Napieralski cyclization and reduction afforded emetine. Alternatively, the amide 31 could be cyclized to ( ± )-2,3-dehydro-0-methylpsychotrine, and succeeding reduction afforded a separable mixture of ( ± ) - d e h y d r o e m e t i n e and (±)-dehydroisoemetine. Dehydroemetine is comparable to emetine in amebicidal 1 3 , 33 activity, so that this synthesis is of commercial i m p o r t a n c e . Diethyl
P h - C H
2
- 0 ^
P h
Z!ZZ%
" C H 2- < V ) C 2H 5OOC
X O O C 2H 5
Benzyl a - b r o m o b u t y r a t e CK^O
1 . H 2, P d / C 2. S Q C 1 2
C 2H 5OOCf ^COOC 2H 5 32 1. N a O H (saponification) . Δ -CO
1-Carbethoxy-
6,7-dimethoxy-
Ο Κ
Ο γ ^ γ ^
3
tetrahydro-
I
^ i n c l i n e
,
0 Η
II
Jj
Ν
Ο
Ο ^ ^ γ C 2H 5OOC C 2H 5O O C X O O C 2H 5
4 . N a O C 2H 5 (Dieckmann)
3
H
"
33 C H 30
1. H 2, P d 2 . CH3SO2CI,
CH;
pyridine
34
CH; CH3O'
C H 3- S 0 2- 0
COOC 2H 5
COOC 2H 5
1. s o c i 2 C
l . P h C H 2S - N a +
2 . C H 2N 2
H
3
3.
2. Ni(R) n
3. NaOH
^
A g 20
CH 30>
(Arndt-Eistert)
(
4. Κ Ο Η
3
35
COOH Scheme XII
2
+ ( e s t eHr i f i c a t i o n )
^
Hl
C H 30 ' 36
• N ^y O LH
COOH
VII.
441
SYNTHESES OF EMETINE
G. The Second Roche Basle
Synthesis
The acid chloride of a-ethyl-ß,ß-dicarbethoxypropionic acid ( 3 2 ) was first prepared by the condensation of benzyl α-bromobutyrate with malonic ester, followed by de benzylation over palladium and treatment with thionyl chloride. This acid chloride was then used to acylate l-carbethoxy-6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline to form the amide 3 3 . The latter material was converted to the keto lactam 3 4 by the sequence indicated, and further transformation provided the tricyclic acid 3 5 as a pair of diastereoisomers. O n e isomer, u p o n homologation, gave the key homotricyclic 34 lactam acid 3 6 , which was converted to emetine by the usual sequence (Scheme X I I ) .
C O O C 2H 5 a
CH, Y^CH CH 2
C O O C 2H 5
+
jm^
HCy^yOH
N=C^Y^CH CH
NSCT
3
H3Q+, A,^
2
C
3
~ °
H O ^ ^ O H
2
SCH, ^
C H
2CH3
CH3 1. A q . HBr (hydrolysis)
Potassium
CL^N^Cl POCli
γ
37
Ύ
Homoveratryl i o d i d e , KOH,
t-butyl
ny
alcohol
^
CH0, CH0'
S ^ C|ΓH 2 C H 3
^ y ^ C H 2^ x i 3 CH 3
3
Diethyl
3
3
Pd/C,
^XH-O^Nv^Cl
m e t h o x i d e ^ Ph
^ ^ C H 2C H CH 3
NIOC^S^
39
NaOAc
C
H
3f
3
CH 3C/
CH0-V0N. r
COOH
COOH
Y^V^i V
CH30
CH 0 ^^ ^ I
diastereoisomers
>
J
Q
I
3
2. Ethyl chloroformate 3. H o m o v e r a t r y l a m i n e
—»•
| r
I
n
NU
^
^Y^CH CH 2
/
S
38
lΝ
CH 3 H 2O 2>
\ ^ CH 2 C O - C O O C 2H 5
3
1. S e p a r a t i o n of
S
i
ΟΗ0-^^^γ^| ° y
^CH 2CH 3 CH3
CH0,
40
^
(hydrogenolysis)
C H 3Q
3
Η
2 . H 2,
*l
diph
I
H'
Scheme XIII
LA Η -.
3
442
2 3 . EMETINE A N D RELATED ALKALOIDS
H. The Roche Welwyn
Synthesis
The application of pyridone chemistry to the synthesis of emetine has been success fully exploited by Barasch, Osbond, a n d Wickens. T h e known dichloropyridine 37 was converted t o the pyridone 38, a n d JV-alkylation with homoveratryl iodide led t o the derivative 39. Since the C-methyl group on the pyridone system is activated through conjugation with t h e carbonyl group, it was possible t o homologate 39 t o the acid 40. Catalytic reduction of 40 produced a separable pair of diastereoisomers, one of which was treated first with ethyl chloroformate a n d then with homoveratrylamine t o give rise t o the lactam amide 41, which was taken to emetine via Bischler-Napieralski 35 cyclization a n d subsequent reduction (Scheme X I I I ) .
/. The Burroughs-Wellcome
Synthesis
Openshaw a n d Whittaker have developed a commercially applicable synthesis of emetine in which the required optically active intermediate ( —)-44 is obtained by a 3 6 38 highly efficient a n d unusual process (Scheme X I V ) . " Water, room
CH3O,
(-)-Camphor-lOsulfonic acid,
CH3O'
ethyl acetate
H 3O
Η-44 Salt p r e c i p i t a t e s out from hot solution C H ( P h ) 3P = C H - C O O C 2H 5
3
C L ^
C H
C H 30 "
H 2, P t
3
( X ^
C H 30 '
CH
45
COOC2H5
Scheme XIV
46
C O O C 2H
5
VIII. IPECOSIDE, A MONOTERPENOIDAL ISOQUINOLINE GLUCOSIDE
443
Condensation of the imine hydrochloride 4 2 with the Mannich base 4 3 afforded the amino ketone 4 4 in almost quantitative yield. Resolution of this product with ( —)-camphor-10-sulfonic acid resulted in crystallization of the salt of the desired levorotatory base. Since ring C of the amino ketone 4 4 can be readily opened in the manner shown in Scheme XIV, the dextrorotatory amino ketone 4 4 kept being racemized while the levorotatory enantiomer continuously precipitated out as the salt. The net result was an almost total conversion of the racemic amino ketone 4 4 into its levorota tory form, epimerization also having occurred at the site of attachment of the ethyl side chain. Homologation with ethoxycarbonylmethylenetriphenylphosphorane yielded only one geometric isomer of 4 5 and subsequent catalytic reduction provided the optically active ester 4 6 which can readily be taken to emetine. Whenever the intermediate 4 6 is prepared in any of the aforementioned syntheses in either the levorotatory or the racemic form, condensation with homoveratrylamine succeeded by Bischler-Napieralski cyclization and reduction always leads to a mixture of emetine and isoemetine. Isoemetine is inactive as an amebicide, but it can be TVchlorinated on the secondary nitrogen using sodium hypochlorite, and treatment with base leads to O-methylpsychotrine by loss of hydrogen chloride. 0-Methyl3 6 , 73 psychotrine may then be reduced again to a mixture of emetine and i s o e m e t i n e . A significant observation of Openshaw and Whittaker is that condensation of the ester 4 6 with homoveratrylamine is appreciably accelerated by the presence of 2-hydroxypyridine, which acts as a bifunctional catalyst in the condensation of strongly basic amines with esters. F r o m the practical point of view, 2-hydroxypyridine can easily 39 be removed from the resulting amide because of its high solubility in w a t e r . The Openshaw and Whittaker synthesis can also be modified so as to produce the 40 effective amebicides ( + )- as well as ( —)-2,3-dehydroemetine. J. The Zymalkowski-Frahm
Synthesis
The key (5-lactone carboxylic acid 5 0 required for a synthesis of emetine was prepared as shown in Scheme XV. The aziridine obtained by the condensation of the acid chloride of 4 7 with ethylenimine was not isolated, but was forthwith reduced with lithium aluminum hydride to the aldehyde 4 8 . Homologation using ethoxycarbonylmethylenetriphenylphosphorane yielded in this instance a mixture of geometric isomers which was condensed in a Michael reaction with malonic ester. Hydrolysis, decarboxylation, 4 1 and lactonization subsequently gave the desired product 5 0 Finally, condensation of the lactone 5 0 with 2 moles of homoveratrylamine followed by hydrogenation and isomer separation yielded ( + )-emetine. VIII. IPECOSIDE, A MONOTERPENOIDAL ISOQUINOLINE GLUCOSIDE
The neutral glucoside ipecoside, C 2 7 H 3 5 N 0 1 2, was obtained in 1952 from ipecac 42 root, and its chemistry has been described so far mainly in communication f o r m . The glucoside consists of an N-acetylated tetrahydroisoquinoline moiety, a C-10 terpenoidal unit, and glucose. Since the term "alkaloid" has never been rigorously
444
23. EMETINE AND RELATED ALKALOIDS
Choromethyl methyl ether, η
1. O H ~
Na, ether
2.
C 2H 5OOC
CH 3
COOC 2H 5 i.soci 2
C 2H 5OOC
Δ,
-C0
2
COOC2H5
CH 3
50
Scheme XV defined, ipecoside can be considered to be alkaloidal even though it is a neutral compound. 1
Ipecoside exhibits an amide carbonyl at 6.13 μ (1630 c m " ) and a band at 5.92 μ - 1 (1690 c m ) which was assigned to the C H 3 O O C - C = C — O - system which had been shown to be present in several of the indole alkaloids. The U V data were also in accord with a tetrahydroisoquinoline component, Xmax 285 ιημ with a bathochromic shift in base due to the presence of the phenolic groups, and also with the presence of the C H 3 O O C - C = C - 0 - - chromophore with /lmax 238 πιμ. Catalytic hydrogenation gave dihydroipecoside, which showed unchanged U V and IR spectra (carbonyl region) since only the terminal double bond had been reduced. Mild acid hydrolysis of ipecoside yielded D-glucose, while acetic acid was liberated under conditions sufficiently vigorous to cleave the amide linkage (Scheme XVI). Ipecoside gave only acetic acid upon K u h n - R o t h oxidation, whereas dihydro ipecoside afforded propionic and acetic acids. The enzyme ß-glucosidase hydrolyzes ipecoside so that a ß-glucosidic linkage was assigned to the anomeric center. The enzyme also hydrolyzes 0,0-dimethyldihydroipecoside, though more slowly, to yield an aglycone, probably 5 1 , which undergoes isomerization with acid to a second, more stable, diastereoisomeric aglycone which
445
VIII. IPECOSIDE, A M O N O T E R P E N O I D A L I S O Q U I N O L I N E G L U C O S I D E
,0
Dihydroipecoside
(-) - I p e c o s i d e
I
"cr v-cr HO-
HO
Mild a c i d hydrolysis Acetic
D-Glucose
acid
Scheme XVI has been formulated as 52. Oxidation of the aglycone 52 furnished the enol ^-lactones - 1 53 and 54, both of which exhibit carbonyl absorption at 5.64 ηιμ (1773 c m ) (Scheme XVII).
3°^V^
C H
Ipecoside
Two steps
CH
II
CH3O
ß-Glucosidase Η'Ί
Ο,
'
V
^C-CH
C H3
[Ό-glucose
Ο-Dimethyldihydroipecoside
ft Ν
3Q^Sv^S
'
CH
[ο]
>H
3
a
C H
•
Ο
O ^ V
3 3
52
r
X>CH
C H 30 ^
3 +
Η
C H
3
0 ^
53
54
Scheme XVII C H 3O
0,
O-Dimethyldihydro-
H3O+ Δ
N
CH30
ipecoside
HO
55
56
CHgO [Η]
CH30
Χ Ή 2Ο Η (—) - D i h y d r o p r o t o e m e t i n e
Scheme XVIII
'CHO
3
23. EMET N IE AND RELATED ALKALO D IS
446
Final proof of structure came from the vigorous acid hydrolysis of 0 , 0 - d i m e t h y l dihydroipecoside, which yielded the aldehydes 55 and 56. Reduction of the latter product gave (— )-dihydroprotoemetine, identical with authentic material (Scheme XVIII).
IX. ALANGS ID IE
( — )-Alangiside is a-,monoterpenoidal lactam recently isolated from A. lamarckii. The molecular formula, C 2 5 H 3 1O 1 0N , as well as spectral data seemed to indicate that alangiside was closely related to desacetylipecoside. The enzyme /?-glucosidase cleaved alangiside to D-glucose and the aglycone C 1 9H 2 i 0 5 N . Additionally, alangiside could undergo the following changes: Acetlation
(a) Alangiside ° - r > Alangiside penta-O-acetate C a t J[ H A c e t l a l i no > Dihydroalangiside " - r > Dihydroalangisidepenta-O(b) Alangiside acetate C H l K A c e t y l a nt i o (c) Alangiside > O-Methylalangiside ° " > O-Methylalangiside t e t r a d acetate The actual correlation with desacetylipecoside was carried out by treating desaceiylipecoside hydrochloride with a weak base to induce lactamization. O-Methylation 4 2a then provided O-methylalangiside (Scheme XVIII a ) . The exact position of the phenolic function in alangiside has not yet been settled.
O-glucose
Desacetylipecoside hydrochloride N a 2C 0 3 orTMH 3
C H 2N 2
Ö-glucose
O-Methyl alangiside
Scheme XVIII a
O-glucose Alangiside
447
X. BIOSYNTHESIS
Χ . BIOSYNTHESIS
Using feeding experiments, Battersby and Gregory have firmly established that in Cephaelis ipecacuanha geraniol is converted into loganin which can then act as a precursor for ipecoside and cephaeline. The Q unit of the ipecac alkaloids and the 4 3 ,4 C 1 0 unit of ipecoside are, therefore, of monoterpenoid o r i g i n .
Ipecoside
Cephaeline
Further studies by Arigoni, Battersby, and their co-workers using mostly Menyanthes trifoliata Linn. (Gentianeae), Vinca rosea Linn. (Apocynaceae), and Rauwolfia serpentina Benth. (Apocynaceae), the last two yielding a variety of indolic alkaloids, have de 45 4 9 monstrated t h a t " : (1) Geraniol is first oxidized to 10-hydroxygeraniol within the biogenetic locus. (2) Nerol and 10-hydroxynerol are almost as efficient as geraniol and 10-hydroxygeraniol as precursors for loganin. (3) Carbon atoms 9 and 10 in 10-hydroxy geraniol and 10-hydroxynerol must equili brate and become essentially identical by introduction of oxygen at both centers. (4) 10-Hydrogeraniol or 10-hydroxynerol go to deoxyloganin, which is then oxidized to loganin. (5) Loganin is cleaved to secologanin, which is a pivotal intermediate. Depending upon the amino acids and the enzymes available in the plant, secologanin can either act as a precursor for desacetylipecoside so as to yield ipecoside and the emetine-type bases, or, alternatively, it can condense to give vincoside, which is a precursor of the indolic iboga, corynanthe, and aspidosperma alkaloids (Scheme XIX). All of the intermediates mentioned here have been isolated as natural products from plants, some only in trace amounts. Turning again to C. ipecacuanha, it has recently been possible to demonstrate that loganin is changed into secologanin which undergoes conversion to desacetylipecoside and desacetylisoipecoside. It is desacetylipecoside and not desacetylisoipecoside which
448
23. EMETINE A N D RELATED ALKALOIDS
T
iCH3 ^ C H 2O H 9
H
3
C ^ C H
CH.3
: H 2O H 10
3
" H 3C r " C H 2 O H
Geraniol
10 - H y d r o x y g e r a n i o l
: H 2O H
Ή 3 0 ' ^ C H 2O H
H 3C f
10- H y d r o x y n e r o l
^CH3
Nerol
O-glucose C H 3O O C Deoxyloganin
Loganin
Secologanin
Η
O-glucose C H 3O O C Desacetylipecoside
Emetine -type alkaloids
Ipecoside
De sac etylis oipec oside
Ibogatype alkaloids
Vincoside
Corynanthetype alkaloids
Aspidospermatype alkaloids
Scheme XIX can be converted biologically into ipecoside, cephaeline, and emetine. The mechanism of the interesting C-5 C-l 1 b inversion in going from desacetylipecoside to cephaeline 4 93 remains to be e s t a b l i s h e d . Finally, experiments with C. ipecacuanha using labeled glycine and sodium acetate have shown that glycine can act as a specific two-carbon precursor of the C 9 unit of cephaeline, delivering 15 — 1 8 % of the activity incorporated to C - l 5 and none t o C-14. On the other hand, radioactive acetic acid did not label this unit with any specificity or efficiency but was incorporated instead into the sterol ^-sitosterol that is also present in the plant. T h e oxidation state of a two-carbon c o m p o u n d may, therefore, exert 50 a major effect upon its utilization in biosynthesis (Scheme X X ) .
449
XI. T H E P A R T I A L S Y N T H E S I S O F S E C O L O G A N I N A N D IPECOSIDE
Labeled
glycine Labeled
sodium
cephaeline
acetate Labeled
ß-sitosterol
Scheme X X
X I . T H E P A R T I A L SYNTHESIS OF S E C O L O G A N I N A N D IPECOSIDE
Controlled mild alkaline hydrolysis of the interesting naturally occurring glucoside 51 menthiafolin, obtained from Menyanthes trifoliata L i n n . , followed by methylation
(—) - S e c o l o g a n i n Menthiafolin
Desacetylipecoside
Desacetylisoipecoside
hydrochloride
hydrochloride
Countercurrent distribution
Desacetylipecoside * hydrochloride
A c 20 ,
τ
τ
Hexa-O-acetyl* ipecoside Scheme X X I p y r i de i n
N a O C H 3, hm ae nt o i
*
^ecoside
450
23. EMETINE AND RELATED ALKALOIDS
with diazomethane, afforded secologanin. Subsequent Mannich condensation with 3,4-dihydroxyphenylethy lamine hydrochloride yielded two products, desacetylipecoside and desacetylisoipecoside hydrochlorides, which were separated by countercurrent distribution. Desacetylipecoside was then polyacetylated, and Zemplen deacetylation 4 5 , 25 furnished ( —)-ipecoside, identical with the natural product (Scheme X X I ) .
XII. RUBREMETINE SALTS
Mild oxidation of emetine with ferric chloride, bromine, iodine, or mercuric acetate gives reddish, optically active compounds known as rubremetine salts. As a result of this transformation one nitrogen atom loses its basic character while the other becomes quaternary. The structure assigned to the rubremetine cation incorporates a nonbasic nitrogen within a pyrrole ring, a quaternary nitrogen as part of the original isoquinoline system, and asymmetry about C-3 where the ethyl group is attached 5 3 55 (Scheme X X I I ) . " Catalytic reduction of rubremetine chloride readily furnishes two basic and colorless diastereoisomers, A- and B-dihydrorubremetine, which are epimeric at C-l l b . The starting material as well as the products exhibit positive color tests for pyrrole, and spectral data indicate that both A- and B-dihydrorubremetines possess cis-fused 5 6 57 quinolizidine s y s t e m s . ' The dihydrorubremetines can be hydrogenated further very slowly, but the reaction is appreciably catalyzed by acid. The product from either isomer is optically active tetrahydrorubremetine which still shows pyrrole reactions and contains n o Ν —Η function. Tetrahydrorubremetine is formed through the intermediacy of the immonium salt 5 7 whose formation from the dihydrorubremetines is acid-catalyzed. In line with this reasoning, the dihydrorubremetines undergo mutarotation in acid solution via 5 6 57 the salt 5 7 (Scheme X X I I ) . ' Several syntheses of the rubremetine cation are available.
XIII. P H A R M A C O L O G Y
33
Ipecac was the standard treatment of the South American Indians before the advent of the white m a n for what is now recognized as amebic dysentery caused by the micro organism Entamoeba histolytica. In 1912 it was recognized that the alkaloid responsible for this drug action is emetine, which is less toxic and more effective than the accom panying base cephaeline. Emetine is effective only against amebic and not bacillary infections, and the drug is still useful in efforts at eradication of the extraintestinal trophozoites and in the treatment of acute amebic intestinal or extraintestinal infections. Emetine is toxic and cumulative, and it must not be given beyond a 10-day period. Poisoning by emetine is characterized by muscular tremors and weakness and pains, especially in the extremities. The alkaloid has also been used as a mild emetic, but this is not a common treatment.
451
XIII. P H A R M A C O L O G Y
C H 30 * ÖCH3 Rubremetine
cation H 2, P t
CHL OCH3
OCH3
Β -Dihydrorubremetine
A -Dihydrorubremetine
C H 30 ' OCH3 Tetrahydrorubremetine
Scheme XXII
(±)-2,3-Dehydroemetine is almost equal to emetine in amebicidal activity, the ( — )-enantiomer being the biologically active component. T h e racemic compound is usually used a n d it has been found that it is better tolerated and more readily excreted than ( —)-emetine. T h e absence of the C-3 ethyl group of emetine results in a partial loss of antiamebic activity. The pharmacological usefulness of emetine and 2,3-dehydroemetine may be related to the fact that they inhibit protein synthesis in mammalian cells. Emetine also has antiparasitic activity in certain lung diseases and in sheep infected 1 with Fasciola hepatica. As pointed o u t earlier, (— )-emetine, identical with the natural product, is produced commercially by Burroughs Wellcome & Co. in England, while ( + )-2,3-dehydroemetine is manufactured at Hoffmann-La Roche in Switzerland. Since an optical resulution is
452
23. EMETINE AND RELATED ALKALOIDS
not involved in the production of ( + )-2,3-dehydroemetine, it is more readily available than synthetic (— )-emetine. Emetine has also shown potential in initial tests as an anticancer drug and is currently 58 undergoing clinical evaluation at the National Institutes of Health. The benzoquinolizidine derivative tetrabenazine (Nitoman, Hoffmann-La Roche) has been extensively tested because of its psychotropic activity. It exerts a reserpine-like sedative action and has a beneficial effect on various symptoms of schizophrenia as well as in Huntington's chorea. Like reserpine, tetrabenazine decreases the 5-hydroxytryptamine and catechol amine content in the brain. It is less potent than reserpine 5 9 5 9a but of shorter duration and faster onset of action. > It is presently in use in some of the Scandinavian countries.
Ο Tetrabenazine
When Af-2'-benzyloxycarbonylemetine was quaternized with 3,3-ethylenedioxy-lp-toluenesulfonate and the salt reduced with lithium in liquid ammonia, fission of the N-5 to C-l l b bond was accompanied by cleavage of the benzyloxycarbonyl group, so that the product was the secoemetine 5 8 which was-de-AT-alkylated to the derivative 60 5 9 . Compound 5 9 is less potent as an amebicide than the parent alkaloid.
Ν - 2' -Benzyloxycarbonylemetine
58
59
453
XIV. MASS S P E C T R O S C O P Y
XIV.
M A S S SPECTROSCOPY
The mass spectral cleavage pattern of the emetine-type alkaloids is dependent on the degree of saturation of ring D . The two most intense peaks in the spectrum of cephaeline are at m/e 192 and 178 and are due to ions 60 — 62.
60 m/e
192
61 m/e
62 m/e
192
178
O-Methylpsychotrine, which incorporates an imine function in ring D , exhibits a totally different cleavage pattern, with two discernible modes of fragmentation (Scheme XXIII). In type (i) cleavage, the very intense peak at m/e 273 and the strong m/e 205 peak are produced through cleavage of the allylic C-2 to C-α bond. Type (ii) 3 fission affects primarily ring C and produces the stable ions of m/e 190 and 230.
m/e
O - M e t h y l p s y c h o t r i n e , M®
Type (ii)
m/e
190
Scheme X X I I I
273
m/e
205
454
23. EMETINE AND RELATED ALKALOIDS
In the spectrum of ankorine, the base peak at m/e 334 corresponds to the ( Μ — 1) ion. Other intense peaks are seen at m/e 320, 318, 262, 221, 207, and 192, and these 5 are interpreted in Scheme X X I V . C H 30 . CH3O'
OH e
HOH 2C^ Ankorine
2 26
m /
M®, m/e 335
CH3O,
CH 0 ^y ^ ^CH <
A
3
N
OH
3
m/e 221 -CH2
m/e 207 -CH3
m/e 192 m/e 320
[-
2H
m/e 318 Scheme XXIV
XV. N M R
SPECTROSCOPY
It is difficult to m a k e specific assignments for the proton chemical shifts of the classical 12 emetine b a s e s . T h e N M R spectrum for the simpler alkaloid ankorine is more readily 5 interpreted and the chemical shifts are quoted below.
NMR s p e c t r a l values for ankorine
455
REFERENCES
X V I . U V SPECTROSCOPY 1 3 61
Emetine d i h y d r o c h l o r i d e ' Psychotrine
12
4
Desmethylpsychotrine 4
Alangicine 62 Emetamine
Protoemetine P e r c h l o r a t e Ankorine
5 61
Rubremetine c h l o r i d e (not a natural product)
10
Η
Λ*° Χ 230 and 283 πιμ (4.23 and 3.87) ^ P " 256 τημ (3.11) N H 1C l°mL 240, 288, 306, and 356 τημ (4.14, 3.76,3.80, and 3.83) 0 Η Λ* Χ 223, 277, 310, and 410 τημ (3.95, 3.83, 3.34, and 3.96) Η Α*° Χ 275, 312, and 408 τημ (3.84, 3,42, and 4.09) Η λ £ £ 236 and 283 τημ (4.85 and 3.86) H ^ J S 217, 262, 303, and 321 πιμ (4.28, 3.72, 3.36, and 3.48) H ^ a ° x 232 and 283 πιμ (3.92 and 3.61) H / S 220 and 254 πιμ (3.85 and 2.68) λ*™ 272 πιμ (2.96) AS? 257, 286, 300, and 437 πιμ (4.28, 4.24, 4.26, and 4.47).
REFERENCES 1. For reviews on the ipecacuanha alkaloids, see Η. T. Openshaw, in "Chemistry of the Alkaloids" (S. W. Pelletier, ed.), p. 85. Van Nostrand, Princeton, New Jersey, 1970; and A. Brossi, G. V. Parry, and S. Teitel, in "The Alkaloids" (R. F. H. Manske, ed.), Vol. 13, p. 189. Academic Press, New York, 1971; and Cs. Szäntay in Recent Developments in the Chemistry of Natural Carbon Compounds, Vol. 2, 63 (1967), Akademiai Kiado, Budapest. 2. S. C. Pakrashi and E. Ali, Indian J. Chem. 7, 635 (1969). 3. H. Budzikiewicz, S. C. Pakrashi, and H. Vorbrüggen, Tetrahedron 20, 399 (1964). 4. S. C. Pakrashi and E. Ali, Tetrahedron Lett. p. 2143 (1967). 5. A. R. Battersby, R. S. Kapil, D. S. Bhakuni, S. P. Popli, J. R. Merchant, and S. S. Salgar, Tetrahedron Lett. p. 4965 (1966). 6. B. Dasgupta, / . Pharm. Sei. 54, 481 (1965). 7. R. Robinson, Nature (London) 162, 524 (1948). 8. A. R. Battersby and Η. T. Openshaw, J. Chem. Soc., London pp. 3207 andS 59 (1949). 9. M. Pailer and K. Porschinski, Monatsh. Chem. 80, 94 and 101 (1949). 10. A. R. Battersby and B. J. T. Harper, J. Chem. Soc, London p. 1748 (1959). 11. Cs. Szantay, L. Töke, and P. Kolonits, J. Org. Chem. 31, 1447 (1966). 12. S. Teitel and A. Brossi, J. Amer. Chem. Soc. 88, 4068 (1966). 13. A. Brossi, M. Baumann, and O. Schnider, Helv. Chim. Acta 42, 1515 (1959). 14. Ε. E. van Tamelen, P. E. Aldrich, and J. B. Hester, Jr., J. Amer. Chem. Soc 79, 4817 (1957). 15. Ε. E. van Tamelen and J. B. Hester, Jr., / . Amer. Chem. Soc 81, 507 (1959). 16. Ε. E. van Tamelen, P. E. Aldrich, and J. B. Hester, Jr., J. Amer. Chem. Soc. 81, 6214 (1959). 17. For a closely related sequence, see A. R. Battersby and S. Garratt, / . Chem. Soc, London p. 3512(1959). 18. Ε. E. van Tamelen and M. Shamma, / . Amer. Chem. Soc. 76, 950 (1954). 19. Y. Ban, M. Terashima, and O. Yonemitsu, Chem. Ind. (London) pp. 568 and 569 (1959).
456
20. 21. 22. 23.
23. EMETINE A N D RELATED ALKALOIDS
M. Terashima, Chem. Pharm. Bull. 8, 517 (1960). A. R. Battersby, R. Binks, and T. P. Edwards, J. Chem. Soc., London p. 3474 (1960). A. R. Battersby, S. W. Breuer, and'S. Garratt, / . Chem. Soc, C p . 2467 (1968). R. P. Evstigneeva, R. S. Livshits, L. I. Zakharin, M. S. Bainova, and N. A. Preobrazhenskii, Dokl. Akad. Nauk SSSR1S, 539 (1950); R. P. Evstigneeva and N. A. Preobrazhenskii, Tetrahedron 4, 223 (1958). See also L. I. Zakharin and N. A. Preobrazhenskii, Z. Obshch. Khim. 22, 1890 (1952); 23, 153 (1953). 24. J. A. Weisbach, J. L. Kirkpatrick, E. L. Anderson, K. Williams, B. Douglas, and H. Ra poport, J. Amer. Chem. Soc 87, 4221 (1965). 25. A. W. Frahm, Arch. Pharm. (Weinheim) 301, 621 (1968). 26. Y. Ban, Pharm. Bull. 3, 53 (1955). 27. A. R. Battersby and J. C. Turner, Chem. Ind. (London) p. 1324 (1958); / . Chem. Soc, London p. 717 (1960). 28. Ε. E. van Tamelen, M. Shamma, A. W. Burgstahler, J. Wolinsky, R. Tamm, and P. E. Aldrich, / . Amer. Chem. Soc 80, 5006 (1958); 91, 7315 (1969). 29. A. W. Burgstahler and Z. J. Bithos, / . Amer. Chem. Soc. 82, 5466 (1960). 30. Ε. E. van Tamelen, G. P. Schiemenz, and H. L. Arons, Tetrahedron Lett. p. 1005 (1963); Ε. E. van Tamelen, C. Placeway, G. P. Schiemenz, and I. G. Wright, / . Amer. Chem. Soc 91, 7359 (1969). 31. D. E. Clark, R. F. K. Meredith, A. C. Ritchie, and T. Walker, J. Chem. Soc, London p. 2490 (1962). 32. A. R. Battersby, Η. T. Openshaw, and H. C. S. Wood, / . Chem. Soc, London p. 2463 (1953). 33. A. Brossi, Pure Appl. Chem. 19, 171 (1969). 34. A. Grüssner, E. Jaeger, J. Hellerbach, and O. Schnider, Helv. Chim. Acta 42, 2431 (1959). 35. M. Barasch, J. M. Osbond, and J. C. Wickens, / . Chem. Soc, London p. 3530 (1959). 36. Η. T. Openshaw and N. Whittaker, J. Chem. Soc, London pp. 1449 and 1461 (1963). 37. N. Whittaker, J. Chem. Soc, C p. 85 (1969). n 38. For a related approach, see Szäntay et al. 39. Η. T. Openshaw and N. Whittaker, / . Chem. Soc, C p. 89 (1969). 40. N. Whittaker, J. Chem. Soc, C p. 94 (1969). 41. F. Zymalkowski and A. W. Frahm, Arch. Pharm. (Weinheim) 297, 219 (1964); Chem. Abstr. 60, 15727b (1964). 42. A. R. Battersby, B. Gregory, H. Spencer, J. C. Turner, M.-M. Janot, P. Potier, P. Francois, and J. Levisalles, Chem. Commun. p. 219 (1967). For the X-ray determination of 0,0-dimethylipecoside sesquihydrate see O. Kennard, P. J. Roberts, N. W. Isaacs, F. H. Allen, W. D. S. Motherwell, Κ. H. Gibson, and A. R. Battersby, Chem. Commun. p. 899 (1971). 42 a. R. S. Kapil, A. Shoeb, S. P. Popli, A. R. Burnett, G. D. Knowles, and A. R. Battersby, Chem. Commun. p. 904 (1971). 43. A. R. Battersby and B. Gregory, Chem. Commun. p. 134 (1968); see also A. R. Battersby, R. S. Kapil, and R. Southgate, ibid. p. 131. 44. For related experiments, see S. Brechbühler-Bader, C. J. Coscia, P. Loew, C. von Szczepanski, and D. Arigoni, Chem. Commun. p. 136 (1968); also P. Loew and D. Arigoni, ibid. p. 137. 45. A. R. Battersby, A. R. Burnett, and P. G. Parsons, / . Chem. Soc, C p. 1187 (1969). 46. A. R. Battersby, A. R. Burnett, and P. G. Parsons, / . Chem. Soc, C p. 1193 (1969). 47. S. Escher, P. Loew, and D. Arigoni, Chem. Commun. p. 823 (1970). 48. A. R. Battersby, A. R. Burnett, and P. G. Parsons, Chem. Commun. p. 826 (1970). 49. A. R. Battersby, S. H. Brown, and T. G. Payne, Chem. Commun. p. 827 (1970). 49 a. A. R. Battersby and R. J. Parry, Chem. Commun. p. 901 (1971). 50. A. K. Garg and J. R. Gear, Tetrahedron Lett. p. 4377 (1969). 51. A. R. Battersby, A. R. Burnett, G. D. Knowles, and P. G. Parsons, Chem. Commun. p. 1277 (1968).
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52. 53. 54. 55.
457
A. R. Battersby, A. R. Burnett, and P. G. Parsons, Chem. Commun. p. 1280 (1968). A. R. Battersby, Η. T. Openshaw, and H. C. S. Wood, Experientia 5, 114 (1949), Η. T. Openshaw and H. C. S. Wood, J. Chem. Soc., London p. 391 (1952). A. Brossi, M. Gerecke, A. R. Battersby, R. S. Kapil, Y. Ban, and M. Terashima, Experientia 22, 134 (1966). 56. K.-A. Kovar, H. Ehrhardt, and H. Auterhoff,.,4rc/z. Pharm. (Weinheim) 302, 220 (1969). 57. K.-A. Kovar, Arch. Pharm. (Weinheim) 303, 579 (1970). 58. R. Ε. Perdue, Jr. and J. L. Hartwell, Morris Arbor. Bull. 20, 35 (1969). 59. A. Pletscher, A. Brossi, and K. F. Gey, Int. Rev. Neurobiol. 4, 275 (1962). 59 a. D. E. Schwartz, H. Bruderer, J. Rieder, and A. Brossi, Biochem. Pharmacol. 15, 645 (1966). 60. J. P. Yardley, R. W. Rees, and H. Smith, / . Med. Chem. 10, 1088 (1967). 61. A. Brossi and O. Schnider, Helv. Chim. Acta 45, 1899 (1962). 62. A. R. Battersby, G. C. Davidson, and J. C. Turner, J. Chem. Soc, London p. 3899 (1961).