136 7
[Reprinted from the Journal of Organic Chem istry, 38, 2496 (1973).] ,
Copyright 1973 by the American Chemical Society and reprinted by perm ission of the copyright owner.
S y n t h e s is o f Y o h im b in e s . I. T o t a l S y n t h e s i s o f A llo y o h im b in e ,
a -Y o h im b in e , a n d T h e ir E p ijn e r s . R e v is e d S t r u c t u r e o f N a t u r a l A llo y o h im b in e
Lá s z l ó Tö k e,* Ka t a l i n Ho n t y, La j o s Sz a b ó, Gá u o r Bl a s k ó, a n d Cs a b a Sz á n t a y
Institute o f Organic Chemistry, Technical University, Budapest, X I . Gellert ter. 4, Hungary Received February 13, 1973
T he first to ta l synthesis of alloyohim bine (6a) and its isomers 4i, 4j, an d 8b has been accom plished. Sodium borohydride reduction of th e keto n itrile 3 yielded alcohols 4a and 4b, epim eric a t C n. T he diastereoisom ers 4i and 4j belonging to th e epiallo series were derived from 4a and 4b. E pim erization of 4i a t C3 furnished 6a which proved to be identical w ith jm turally occurring alloyohim bine except for m elting p o in t and optical activity.
Com pound 6a could be converted to a-yohim bine u n d er m ild conditions, characteristic of those used for epi
m erization a t C16. On th e basis of these facts, th e stru ctu res for alloyohim bine and epialloyohim bine should be revised to 6a an d 4i, respectively. T he hydroxy ester 4j does n o t lend itself to facile epim erization a t C3, and has not y e t been found in nature.
Two products had been obtained from the catalytic reduction of the unsaturated nitrile ester 1 which had been prepared in the course of the total syn th esis of yohim bine.1 The main product, the trans 2,3-di- substituted nitrile ester, was used for the syn th esis of yohimbine. It stood to reason, therefore, to utilize the cis fused isomer 2, w hich was the minor product, for the preparation of yohim bines of the alio series, especially so since such bases had not been heretofore synthesized.
The nitrile ester 2 was converted in alm ost quanti
tative yield to the pentacyclic ketone 3 using potassium íerí-butoxide in D M SO . T his ketone is strongly enolized both in th e solid and dissolved states, and on the basis of its spectral properties m ust exist m ainly in the epiallo-trans (E t) conform ation.2
In the course of the earlier sodium borohydride reduc
tion of the analogous ketone nitrile belonging to the normal series, three diiferent nitrile alcohols were isolated out of the theoretically possible four. Under similar conditions (D M F -m eth an ol), 3 furnished only tw o products, 4a and 4b, in a ratio of about 2:3.
From spectral evidence, both 4a and 4b m ust exist in the E t conformation (Table I). It is also possible to establish the stereochem istry of the Cn hydroxyl function from the chemical shift of the C17 proton.3
(1) C t. S íiltitu y , L . T ö k e , (Mil K . 11 o n ly . T etra h ed ro n L e tt., 1665 ( IUU5);
L , T ö k e , K . ll u n t y , a m i C a, Hy.ánm y, V h tm , H er., 102, 324H (1Ö6B), (2) (ft) W . F . T r ä g e r , C . M . L ee, u n d A . 1{. B e c k e t, T e tr a h e d r o n, 2 3 , ¡105 (1 9 6 7 ). (b ) F o r th e m e a n in g o f th e s y m b o ls fo r t h e c o r r e s p o n d in g c o n fo r
m a tio n s o f y o h im b a n d e r i v a ti v e s , s e e C s. S z á n ta y , M a n y . K é m , L a p ja , 2 6 , 4 90 (1971),
(3) J . D . A lb r ig h t. L . A . M lts c h e r , a n d I.. G o ld m a n , ./. Oru. C h em ., 2 8 , 38 (1963).
T a d l e I
N m k a n d I k D a t a
■N m r," 6---.
C,7 C|7 Ir,6 cl»"' „—-Conformation---s proton hydroxyl Bohlmann Cl7 C17 Skele
!ompd multiplet doublet bands H OH ton
4a 4.05 5.25 2815, 2775,»
2700
e c a LV
4b 3.5 . 5 5.45 2815,2775 ac e E t
4c 5.15 2815, 2775 e E t
4d 4.85 2815, 2780 a E ,
0 In D M S O -d6 a t 60 M H z. b In pyridine. c a = axial, e = equatorial. J See ref 2b.
In isom er 4a the equatorial Cn proton is at 5 4.05, w hile in 4b th e axial Cn proton is located higher up
held at 5 3.55. In view of the stab le E t conformation of the tw o isom ers, it follow s th a t the hydroxyl group in 4a is a w hile in 4b it is j3. T he corresponding O -acylated derivatives 4c and 4d were also prepared, and their spectra confirmed th e correctness of the Cn assignm ents since Hie signals for the a protons are now shifted to 5 5.15 and 4.85, respectively. In accordance with the steric assignm ents, the rate of O -acctylation of 4b was larger by an order of m agnitude than that for the sim ilar reaction of 4a.
It had been observed in the course of the yohimbine synthesis' that the analogs of 4a and 4b belonging to th e normal series readily epimerized at- C-l(>, bearing the nitrile group, in th e presence of aqueous alcoholic alkali at room tem perature or under gentle heating.
T h e A<l value calculated from t he equilibrium constants was in good agreem ent with the energy difference of a
Sy n t h e s i s o f Al l o y o h i m b i n e a n d « - Yo s h i m b i n e J. Org. Chem., Vol. 38, No. 14, 1973 2497
CH2 CN N COOCH3 2
N C ^ H ^
COOCH,
4 R. R* r3 4 Ri r2 r3
a CN H OH f CN OTs H
b CN OH H g CONH, H OH
c CN OH OAc h CONH2 OH H
a
CN OAc H i c o2c h3 H OHe CN H OTs i COvCHj OH H
nitrile group in the axial and equatorial positions of a cyclohexanc system.4 On the other hand, isom ers 4a and 4b belonging to the epiallo series could not be epimerized w ith alcoholic alkali. T his result can be readily rationalized by the realization that, if the nitrile group were to epimerize to the /3 position, it would interact w ith the axial hydrogens at C3 and C2i in the E t conformation (Chart I). If the m olecule were to take the epiallo-cis (E 0J) conformation to evade such
Ch a r t I
(4) E . L. E liel, N . L . A llin g er, S. J . A n g y a l, a n d G . A. M o r r is o n , “ C o n f o r m a tio n a l A n a ly s is ," W iley , N e w Y o rk , N . Y ., 1965, p 44.
steric interaction, then th e indole ring would be placed in an axial position. One can see, then, that the energy difference betw een the a and /3 nitrile epimers would be m uch larger than the value of ~ 0.‘2 k cal/m ol observed in the normal series.
It should be m entioned, by w ay of comparison, th at 3-epi-a-yohim bine (9b) in which the Ci6 substituent is (3 exists entirely in the epiallo-cis ( E C1) conforma
tion, and Bohlm ann bands indicative of the E t con
form ation arc com pletely absent.
N either can th e epimerizatiorx of the nitrile alcohols be brought about by hot m ethanolic alkali. However, 4a is converted relatively quickly, in about 30 min, to the unsaturated nitrile 5, w heteas 4b undergoes this
a H OH b OH H
dehydration over a period of about 8 hr. This differ
ence in rates of elim ination is again in agreement with the structural assignm ents made.
T he difference in th e elim ination rates when the to sy la tes 4e and 4f are heated in D M F parallels th at for their hydroxyl precursors. T his trend can also be ob
served in the m ass spectra. In contradistinction to the spectrum of 4f, the molecular peak of 4e is not observed;
nither only the ion for the dehydro species 5 is recorded.
B y analogy with the behavior of the tosylate of 3-epi-a-yohim bine,5 it was expected th at in pyridine a quaternary salt could be derived from 4e. The fact th a t such a transform ation did not occur may be attributed to the elim ination reaction in the nitrile pro
ceeding at a considerably faster rate than that for the corresponding ester, so th a t quaternization does not appear as a concurrent reaction.
An answer can now be given as to why only tw o isom ers are formed in th e reduction of the ketone 3 belonging to th e epiallo series, w hile it will be recalled th at three alcohols are formed in the corresponding re
action in the normal series.
Considering the stereochem istry depicted in Chart I, in the ketone 3 the nitrile group can occupy solely an a position, contrary to th e analogous keto nitrile be
longing to the normal series where the nitrile in a 0 configuration is also present at equilibrium. It follows th at attack by sodium borohydride leads to two alcohols, with a Hlight preference for attack from the convex side of the m olecule.
As a further step in the synthesis, the nitrile groups in 4a and 4b were converted to ester functions. Sim
ilarly, in th e normal series, direct hydrolysis did not yield the required results. R ather, the acid amides 4g and 4h were prepared using hydrogen peroxide in
(5) P . E . A ld ric h , P . A. D ia s s i, D . F . D ick o l, C . M . D y lio n , P . I) . H an ce, C . F . I lu o b n e r , 15. K o r z u n , M . E . K u e h n e , H . L iu , H . B. M c P h illa m y , E . W . I to b b , D . K . R o y o h a u d h u r i , E , S c h li ttl e r , A . F . A n d ré , E . V an T a m e - le n , F . L . W e is e n b o rn , E . W e n k e r t, a n d O . W in le r a te in e r , J . A m e r . Chem . S o c., 8 1 , 2481 (1 9 5 9 ).
2498 J . Org. Chem.., Vol. 38, No. 14, 1973 Tö k e, Ho n t y, Sz a b ó, Bl a s k ó, a n d Sz á n t a y
alkaline m ethanol, and from them the free acids were obtained by boiling with aqueous hydrochloric acid, Estérification of the two acid w ith diazom ethane gave rise to esters 4i and 4j. N otew orthy was the observa
tion that the isomers containing the Cm, Oii sub
stituents in th e cis relationship (4a, 4g) hydrolyse mere rapidly than in the trans com pounds (4b, 4h) on account of the effect of the hydroxyl group.
However, in the course of the hydrolysis of the acid amide 4g with hydrochloric acid, epim erization at the C3 site also occurred, so th a t in addition to 4i belonging to the epiallo series, a smaller quantity of 6a of th e alio configuration was also formed. T h at 4i and 6a actually differ only at Ca was proven by mercuric acetate oxidation, which furnished th e same, im m onium salt, 7b. R eduction of this salt with sodium borohydride gave 6a as the main product, while 4i was recovered from the zinc in acetic acid reduction.
Boiling with acid of 6a with the alio configuration and subsequent m éthylation provided a 1:3 mixture of 6a and 4i, identical with that derived from the boiling with acid and m éthylation of the am ide 4g.
Following all of these transform ations, it was som e
what unexpected to find th a t the chrom atographic, spectral, and chem ical properties of 6a were identical with those of natural alloyohim bine to w hich the structure 8a had been attributed in th e literature.6 The original structural assignm ent had been based on the finding that on boiling w ith potassium te?'£-butoxide alloyohimbine was converted to a-yohim bine (8b), the
7, 8, 9, R, R.
a OH H
b H OH
structure of which had been firmly established.7 Indeed, under such conditions, epim erization of th e Cn hydroxyl can occur, as for exam ple in the prepa
ration of /3-yohimbine from yohim bine. Thus, allo
yohim bine was considered to bo the Cn epimer of a-yohim bine.
To elim inate this apparent contradiction, we tried to bring about under m ild conditions the epim erization of natural alloyohim bine, as well as of 6a which we had synthesized. It was found th at alloyohim bine can be
(6) J . E . S a x to n in “ T h e A lk a lo id s , C h e m is tr y a n d P h y s io lo g y ,” V ol. V I I , R . II . F . M a n s k e , E d ., A c a d e m ic P re s s , N e w Y o rk , N . Y ., 1960, p 5 5 , a n d R . H . F . M a n s k e , ib id ., V o l. V I I I , 1965, p 705, a n d re fe re n c e s c ite d th e r e in .
(7) M . M . J a n o t, I t. G o u ta r e l, E . W . W a rn h o ff, a n d A . L e H ir , B u ll. Soc.
C h im . F r ., 6 37 (1 9 6 1 ).
readily converted to a-yohim bine a t room temperature using sodium mothoxide as base. Under such mild conditions, only the more aejdio Cx8 hydrogen a to the carbom ethoxy group can be pulled. For instance, yohim bine cannot epimerize under such conditions to 0-yohim bine.
I t follows then th at th e structural assignm ent for alloyohim bine, also strongly supported by nmr data, m ust be revised to 6a. A corollary is that 3-epialloyo- him bine is now correctly represented by expression 4i.
According to the literature, 3-epialloyohim bine should be represented by expression 9a. The ir spectrum7 of this alkaloid clearly shows Bohlm ann ir bands, so that the molecule would then exist in the E t conformation.
Such a steric arrangement, however, would mean th at the /3 carbom ethoxy group would strongly interfere with the hydrogens at C3, Ci8, and C2i.
In support of our new assignm ents, it should be noted th a t W eisenborn indicated8 as early as 1957 that epim erization at C « of 3-epi-a-yohim bine (9b) occurred upon treatm ent w ith sodium m ethoxide to afford 3-epi- 16-epi-a-yohim bine. The latter compound should be renamed 3-epialloyohim bine and m ust be represented by 4i. U sing W eisenborn’s conditions, we have found th at 9b could be com pletely isomerized to the natural antipode of 4i.
It is interesting to note th at in the original literature9 on alloyohim bine structure 6a was considered as a possibility for the alkaloid, but was then rejected.
Another result of our stereochem ical revisions con- perns the nom enclature of th e depyrroloalloyohimbine earlier synthesized by u s. 10 T he proper name for this berban derivative should now be 10,1 1-dim ethoxyde- pyrrolo-14-epi-a-yohim bine.
From the hydroxy nitrile 4b, we have also prepared, through the interm ediacy of th e am ide 4h, the m ethyl ester 4j, which proved to be a very stable material, and did not epimerize even on boiling with concentrated acid. Sodium borohydride reduction of its A-3 im
m onium salt yielded, in addition to 6b, which possesses the alloyohim bine skeleton, a substantial quantity of the isom er 4j. Such a result could be expected since in 6b either the indole ring (AC1 conformer) or the Cm and Cr? substituents on ring E (At conformer) must be in axial positions.
Following the present synthesis of alloyohimbine and 3-epialloyohim bine the total synthesis of all known yohim bine alkaloids can now be considered to have been achieved, especially since the conversions alloyohimbine a-yohim bine7 and a-yohim bine — 3-epi-a-yohim - b ine11 are already known from the literature.
Experim ental Section
Infrared sp ectra were determ ined on a Perkin-E lm er 221 and UR-10 spectrom eter. N uclear m agnetic resonance spectra were ob tain ed on a P erkin-E lm er R 12 (60 M H z) and on a Varian 300- M H z in stru m en t located in Belgium, an d are given in 6 units downfield from internal tetram eth y lsilan e. Mass spectra were recorded a t 70 eV on A E I MS-902 double-focusing instrum ent
(8) F . L . W e is e n b o r n , J . A m e r . C hem . S o c ., 7 9 , 48 1 8 (1957).
(9) A. L e H ir , M . M . J a n o t , a n d R . G o u ta r e l, B u ll. Soc. C h im . F r ., 1027 (1 9 5 3 ).
(10) L . S z a b ó , K . H o n ty , L . T ö k e , a n d C s. S z á n t a y , Chem . B er., 105, 3231 (1 9 7 2 ).
(11) F . L. W e is e n b o r n a n d P . A. D ia s s i, J . A m e r . Chem . Soc., 7 8, 2022 (1 9 5 6 ).
Sy n t h e s i s o f Al l o y o h i m b i n e a n d o- Yo s h i m b i n e J. Org. Chem., Vol. 38, No. 14, 1973 2499 using direct insertion probe a t 120-150°. H igh-resolution mass
m easurem ents were accurate to w ithin 2 ppm .
Thin layer chrom atography (tic) was perform ed on silica gel G, E . M erck AG; silica gel P Fzm+m, E . M erck AG, was used for preparative layer, an d silica gel (0.05-0.2 m m ), E . M erck AG, for colum n chrom atography, unless otherwise noted.
A nhydrous m agnesium sulfate was employed as the drying ag en t. All reactions utilizing strongly basic reagents were con
ducted in an oxygen-free d ry nitrogen atm osphere. M elting points are uncorrected.
17-Oxo-3-epialloyohimban-16«-carbonitrile (3 ).—A solution of 3.35 g (9.5 m m ol) of 2 (previously dried in vacuo w ith boiling toluene over phosphorus pentoxide for 12 h r) and 3.14 g (28 m m ol) of sublimed potassium icrt-butoxide in 15 ml of dry DMSO was allowed to stan d a t room tem p eratu re for 12 hr, in a carefully dried apparatus under nitrogen. In the m eantim e th e potassium sa lt of 3 began to separate. T he reaction m ixture was poured into 100 ml of ice w ater m ade acidic to p H 7.5. T h e precipitate was collected, washed w ith w ater an d th en w ith m ethanol, and dried to give 2.95 g (97% ) of crude p ro d u ct of satisfacto ry p u rity for use in th e next step w ithout fu rth er purification. RecrystaJ- lization from D M F -w a te r gave an an aly tical sam ple, m p 285°
dec.
A nal. Calcd for C20H2,N3O: C , 75.21; H , 6.83; N , 13.16.
F ound: C, 74.94; H , 6.60; N , 12.99.
I r (K B r) 3450-3050 (OH.vNH), 2170 ( C = N conj), 2220 ( C = N , w), 1720 ( C = 0 , w), and 2750 an d 2810 c m- 1 (B ohlm ann bands);
ir (D M F ) 2200 cm- 1 ( C = N ) .
17tt-Hydroxy-3-epialloyohimban-16«-carbonitrile (4a) an d 17/3- H ydroxy-3-epialloyohim ban-16a-carbonitrile (4b).—To a stirred suspension of 0.73 g (2.29 m m ol) of 3 in 40 ml of D M F -m eth an o l (1 :1 ) under nitrogen was added 0.17 g (4.5 m m ol) of sodium borohydride in sm all portions during 1 h r. Stirring was continued for an additional 3 h r and the progress of th e reaction was fol
lowed by tic (chloroform -m ethanol 5 .0 :0 .7 , Hi 4b > 3 > 4a).
T he excess of sodium borohydride was decomposed w ith acetic acid and th e solvent was rem oved in vacuo. T he residue was dissolved in water and basified w ith co ncentrated am m onium hydroxide to pH 8.5. T he solid separating on cooling was washed w ith w ater to give 0.70 g (95% ) of a m ixture of 4a and 4b which was chrom atographed over alum ina (B rockm ann, activity I I —II I). E lution w ith chloroform -m ethanol (9 9:1) afforded 0.27 g (37% ) of 4b w hich upon recrystallization from ethanol gave colorless crystals, m p 275° dec.
A nal. Calcd for C20H23N3O: C , 74.73; H , 7.21; N , 13.07.
Found: C, 74.77; 11,7.29; N , 13.25.
Ir (K B r) 3500-3100 (O H , N H ), 2820, 2760 (B ohlm ann bands), 2240 cm-1 ( C = N ) ; ir (pyridine) 2815, 2775 (B ohlm ann bands), 2245 cm-* ( C h N ) ; n m r (DMSO-de) 5 10.80 (s, 1, N H ), 5.45 (d, 1, OH, J = 6H z, C „ O H ), 3.55 (m , l , C n H ).
F u rth er elution w ith chloroform -m ethanol (98:2) gave 0.22 g (30% ) of 4a which was recrystallized from ethanol to give w hite needles, mp 265° dec.
A nal. Calcd for C20H23N3O: C , 74.73; H , 7.21; N , 13.07.
F ound: C, 74.61; H , 7.31; N , 13.49.
I r (K B r) 3420 (O H ), 3340 (N H ), 2820, 2760 (B ohlm ann bands), 2250 cm-1 ( C = N ) ; ir (pyridine) 2815, 2775, 2760 (Bohlm ann bands), 2243 cm“ 1 ( C s N ) ; nm r (DMSO-<4) S 10.85 (s, 1, N II), 5.25 (d, 1, J = 0 H z), Cn O H ), 4.05 (m , 1, C „ H ).
17a-H ydroxy-3-epialloyolum ban-16a-carbonitrile O-Acetate (4c).—A m ixture of 0.10 g (0.31 m m ol) of 4a, 3.0 ml of anhydrous pyridine, and 0.3 ml (2.9 m m ol) of acetic anhydride w as allowed to stand a t room tem p eratu re for 48 h r under nitrogen. T he solid which separated was rem oved by filtration and washed w ith 2 ml of ether-petroleum eth er (bp 3 0-60°) (1 :1 ) to give 74 mg (68%). C rystallization frciln 15 ml of dioxarie-w ater (1 :1 ) gave 40 mg (30% ) of 4c: m p 200° dee; ir (K B r) 3300 ( N il) , 2813, 2780 (Bohlm ann bands), 2245 (Ca N ), 1740, 1230 c m“ 1 (OCO- C11?.); ir (pyridine) 2815, 2774 (B ohlm ann bands), 2245 c m-1 (C ssN ); nm r (DMSO-d„) S 10.95 (s, 1, N H ), 5.15 (m , 1, C n H ), 2.05 (s, 3, O C O C Il3); mass spectrum (70 eV) m /e (rel intensity) 363 (100, M+), 362 (95), 320 (14), 304 (30), 303 (15), 302 (22), 277 (1.8), 276 (2.8), 184(15), 170(30), 169(23), 150(21).
17/3-Hydroxy-3 -epialloyohim ban-16a-carbonitrile O-Acetate (4d).—A m ixture of 0.10 g (0,31 m m ol) of 4b, 3.0 ml of anhydrous pyridine, and 0.3 ml (2.9 mm ol) of acetic anhydride was allowed to stand a t room tem perature for 24 h r under nitrogen. T he dark solution was diluted w ith ice w ater and m ade basic w ith concentrated am m onium hydroxide. T he solid was filtered and
crystallized from ethanol to give 70 m g (68% ) of 4d: m p 268- 270° dec; ir (K B r) 3350 (N H ), 2815, 2770 (B ohlm ann bands), 2245 ( C = N ) , 1745, 1245 c m- 1 (OCOCH*); ir (pyridine) 2815, 2780 (B ohlm ann bands), 2250 c m- 1 ( ( ' N ); n m r (DM SO-de) S 10.85 (s, 1, N H ), 4.85 (m , 1, C,7 H ), 2.0 (s, 3, O CO C H 3); mass spectrum (70 eV) m /e (rel in ten sity ) 363 (100, M +), 362 (77), 320 (2.3), 304 (28), 303 (1.8), 302 (16), 277 (1.7), 276 (2.7), 184 (9.5), 170(17), 169(16), 156(13).
17a-H y droxy-3-epialloy ohim ban-16a-carbonitrile O-T osy late (4e).— A solution of 24.8 m g (0.077 m m ol) of 4a an d 40 m g (0.21 m m ol) of p-toluenesulfonyl chloride in 2 m l of d ry pyridine was allowed to sta n d a t room tem p e ra tu re for 1 2 h r u n d er nitrogen.
T h e p roduct was sep arated by p re p a ra tiv e tic (m ethylene chloride-m ethanol (100:8), Ri 4e > 4a), yielding 9.5 mg of 4e, m p 290° dec, w hich could n o t be o b tain ed crystalline: m ass spec
tru m (70 eV) m /e (rel in ten sity ) 303 (90.3, M +), 302 (100), 288 (2.4), 275 (2.7), 274 (2.9), 235 (1.5), 221 (3.6), 211 (6.7), 209 (6.2), 197 (5.2), 184 (13.8), 170 (11), 169 (17.6), 156 (27.2).
Boiling 4e (2 m g) in 1 ml of d ry pyridine for 3 h r gave no change, while during th e reflux in D M F for 1 h r elim ination occurred an d 5 was o btained as the sole p ro d u ct [tic, chloroform -m ethanol (5 .0 :0 .2 ), lit 4e > 5 > 4 a ].
17/3-Hydroxy-3-epiaIloyohimban-16a-carbonitrile O-Tosylate (4f).—T he conversion of 34.4 m g (0.107 mm ol) of 4b to 4f was accom plished under th e sam e conditions as for th e p rep aratio n of 4e. T h e yield of 4f was 10 m g, m p 310° dec, which could n o t be obtained crystalline: m ass spectrum (70 eV) m /e (rel in ten sity ) 475 (1.4, M +), 303 (94.9), 302 (100), 288 (2.3), 275 (2.8), 274 (3.2), 221 (3.7), 211 (6.7), 209 (6.2), 198 (4.1), 197 (5.5), 184 (13.2), 170 (10.7), 169 (16.5), 156 (26.4).
4f (2 m g) was refiuxed in pyridine (1 m l). N o product was form ed after 3 hr. Reflux was continued in D M F . Analysis of th e m ixture by tic show ed th a t it consisted of 4f and S in the ratio 4 :6 after 11 h r [chloroform -m ethanol (5 .0 :0 .2 ), R i 4f > 5 > 4 b )].
16,17-D ehydro-3-epialloyohim ban-16-carbonitrile (5 ).—A solu
tion of 10 mg (0.031 m m ol) of 4a in 5 ml of I N ethanolic p o tas
sium ethoxide solution was refluxed under nitrogen for 3 hr. A fter cooling th e sep arated crystals were collected an d reciystallized from eth an o l to give S as colorless needles (8 m g, 85% ): m p 233-235°; ir (K B r) 3340 (N H ), 2210 ( C = N conj), 1630 c m' 1 ( C = C ) ; m ass spectrum (70 eV) m /e (rel in ten sity ) 303 (100, M +), 302 (98), 288 (2.4), 275 (2.6), 274 (2.5), 221 (3), 211 (5.8), 209 (5.6), 198 (3.9), 197 (4.8), 184 (12), 170 (8.5), 169 (13.6), 156 (25).
17«-H ydroxy-3-epialloyohim ban-16«-caiboxam ide (4g).—To a stirred m ixture of m ethanol (28 m l), 1 N sodium hydioxide (5.0 m l), an d 15% hydrogen peroxide solution (1.7 m l) was added 0.23 g (0.71 m m ol) of 4a. T he suspension was refiuxed under nitrogen to the disappearing of th e sta rtin g m aterial [about 75 m in, tic chloroform -m ethanol (5 .0 :1 .5 ), lit 4a > 4 g ]. T he excess of th e reag en t was destroyed w ith sodium borohydride an d the solvent was evaporated i n vacuo. T h e ta n residue was ta k e n up w ith ice w ater (1.5 m l), filtered, an d w ashed w ith w ater (2 X 0.5 m l), giving 0.20 g (79% ) of w hite crystals of 4g. An analytical sam ple was p repared by recrystallization from chloroform - m ethanol (1 0 0 :1 .5 ), m p 280-285° dec.
A nal. Calcd for C2,H25N302- I I20 : C , 67.21; H , 7.61; N , 11.75. F ound: C , 67.01; H , 7.38; N , 11.95.
I r (K B r) 3450-3150 (O H , N II), 2820, 2760 (B ohlm ann bands), 1665, 1590 c m- 1 (C O N H 2); mass spectrum (70 eV) m /e (rel in ten sity ) 339 (10 0, M +), 338 (52), 321 (5), 295 (16), 277 (14), 267 (2.2), 235 (3.6), 223 (7.4), 221 (7), 209 (6), 197 (6), 184 (12), 170(13), 169(17), 156(10).
17/'j-Hvdroxy-3-epialloyohimban-16tt-r,arboxamide (4h).—A solution of 4b (0.24 g, 0.74 m m ol) in m ethanol (23 m l), 1 N sodium hydroxide (7.0 m l), and 15% hydrogen peroxide (1,6 ml) was stirred an d refluxed for a b o u t 75 min, after which time tic showed th e com plete disappearance of 4b [chloroform -m ethanol (5 .0 :1 .5 ), R i 4b > 4 h]. Sodium borohydride was added to the solution to decompose excess hydrogen peroxide. M ost of the solvent w as th en rem oved under reduced pressure, and the residue o btained was ta k e n in cold w ater, w ashed, an d filtered to give 0.19 B (73% ) of 4h. R ecrystallization from chloroform - petroleum e th er gave colorless crystals, m p 256 -259° dec.
A nal. Calcd for CmI I Si N , 0 , • H >0: O, 67.21; H , 7.61; N , 11.75. F ound: C , 67.64; 11, 7.36; N , 11.40.
I r (K B r) 3450-3150 (O H , N H ), 2800, 2760 (B ohlm ann b an d s), 1660, 1615 c m-1 (C O N H 2); mass sp ectru m (70 eV) m /e (rel in ten sity ) 339 (100, M +), 338 (65), 321 (6), 295 (12), 277 (8),
2500 J. Org. Chem., Vol. 38, No. 14, 1973 Tö k e, Ho n t y, Sz a b ó, Bl a s k ó, a n d Sz á n t a y
207 (2.2), 235 (3.6), 223 (10), 221 (0.2), 209 (5.8), 197 (0.5), 184 (15), 170(15), 169(18.5), 156(11).
M ethyl 17/S-Hydroxy-3-epintloyohlmban-16o-carbojfylate (4j).
—A solution of 0.25 g (0,70 m m ol) of 4h in 40 ml of 18% hydro- chlorio acid was refluxed for 7 -8 h r under nitrogen (tin, b e i^ e n e - methanol (4 .0 :1 .7 ), /if 4h > th e a c id j. T he solvent was removed in vacuo and after azeotropic rem oval of w ater w ith benzene and crude acid was suspended in m ethanol (5 m l) and treated w ith an excess of at) ethereal solution of diazoinethane.
A fter 60 min th e excess of the reagent w as decomposed w ith acetic acid and th e solvent was rem oved again. T he rtmidue was refluxed with 2 X 25 ml of chloroform an d filtered and the com
bined extracts wero concentrated to a sm all volum e. T he crude product was purified by chrom atography on silica. E lu tio n w ith m ethylene chloride-m ethanol (9 8:2) yielded 0.10 g (40,5% ) of 4j which upon recrystallization from m ethanol afforded colorless needles, m p 232-233°.
A nal. Calcd for CS,H26N20 3: C , 71.16; H , 7.40; N , 7.92.
Found; C , 71.10; H , 7 .4 4 ;.N , 8.03.
Ir (K B r) 3500-3200 (O il, NIT), 2820, 2780 (B ohlm ann bands), 1740 (C 02C II3), 1060 c m- 1 (C O II); ir (C H C l,) 3620 (O H ), 3470 (N H ), 2815, 2775 (B ohlm ann bands), 1730 (C 02C II3), 1050 c m' 1 (CO H ); nm r (CDC1,, a t 300 M H z) S 7.76 (s, 1, N H ), 7.42 (d, 1, C9II ), 7.27 (d, 1, C ,2TI), 7.12-7.0 (m , 2, Cio, and Cn H ), 3.83 (m , 1, C i,I I ) , 3.80 (s, 3, C O jC II,), 3.55 (m , 3 ,C ,H ) ; mass spectrum (70 eV) m /c (rel in ten sity ) 354 (100, M +), 353 (99), 339 (12), 337 (3.1), 335 (1.6), 325 (2.5), 323 (1.3), 305 (4.5), 295 (2.7), 277 (2.0), 184 (1.5), 170(15), 169 (19), 156(11), 144 (8.5).
M ethyl 17«-Hydroxy-3-epialloyohimban-16«-carboxylate (4i) and M ethyl 17«-Hydroxyalloyohim ban-16a-carboxylate [6a, ( ± ) - Alloyohimbine].— 4g (0.11 g, 0.31 m m ol) w as refluxed in 20 ml of 18% hydrochloric acid for 4 h r [tic, chloroform -m ethanol (5 .0:1.5), Hi 4g > acid] under nitrogen an d th en evaporated to dryness. T he residue was d eh y d rated b y azeotroping w ith benzene. T he solid, w hich show ed two spots on tic, was taken up w ith m ethanol (5 m l) an d tre a te d w ith excess of an ethereal solution of diazom ethane. A fter 60 m in th e excess reagent was destroyed w ith acetic acid. T h e residue a fte r rem oval of sol
vents was treated w ith boiling chloroform (2 X 25 m l) an d a sm all am ount of insoluble m aterial filtered off. T he filtrate was taken to dryness in vacuo, leaving th e m ixture of 4i an d 6a, which was separated by chrom atography on silica'; elution w ith m eth y lene chloride-acetone (80:20) yielded 6a (15 m g, 13% ). R e
crystallization from ethyl acetate following from e th er gave an analytical sam ple of 6a: m p 136-137°; ir (K B r) 3550-3200 (O H, N H ), 2805, 2750 (B ohlm ann bands), 1725 ( C 02C II3), 1050 c m- 1 (CO H); ir (CHC13) identical w ith th a t of an a u th en tic sam ple of n atu ral alloyohim bine, 3615 (O H ), 3470 (N H ), 2805, 2760 (Bohlm ann bands), 1715 (C 02C II3), 1050 c m" 1 (C O H );
nm r (CDC13) 8 8.57 (s, 1, N II), 7,65-7.05 (m , 4, arom atic p ro tons), 3.80 (axial C17 I I signal coincident w ith m ethoxycarbonyl signal to ta l intensity equivalent to four p ro to n s), 3.25 (m , 1, C3 H ); mass spectrum (70 eV) m /c (rel in ten sity ) 354 (100, M +), 353 (95), 339 (4.8), 337 (1.9), 335 (1.4), 323 (4.9), 295 (7.3), 277 (1.5), 267 (1.7), 184 (6.7), 170 (12), 169 (14), 156 (9.0), 144 (9.6).
F u rth e r elution w ith m ethylene chloride-acetone (65:35) afforded 4i (50 mg, 43.7% ). An an aly tical sam ple w as recry stal
lized from ethyl acetate: m p 223-224° (sublim ed a t 226.5°); ir (K B r) 3550-3350 (O H , N II), 3460 (N II), 2815, 2775 (B ohlm ann bands), 1720 (C 02C H 3), 1060 c m“ 1 (C O H ); ir (CIIC1,) 3650- 3500 (O H , N II), 3480 (N H ), 2815, 2775 (B ohlm ann b an d s), 1725 (C 02CH3), 1050 cm“ 1 (C O H ); nm r (CDC1S a t 300 M H z) S 7.72 (s, 1, N H ), 7.45 (d, 1, C9H ), 7.28 (d, 1, C,2 H ), 7.14 7.04 (m , 2, Cm and Cn II), 4.23 (s, 1 ,C „ H ) , 3.82 (s, 3, C 02C II3), 3.48 (m , 1, C3II ); mass spectrum (70 eV) m /c (rel in ten sity ) 354 (100, M +), 353 (98), 339 (8.5), 337 (2.1), 335 (1.4), 323 (4.6), 295 (8.4), 277 (1.9), 267 (2.0), 184 (8.4), 170 (18), 169 (21), 156 (13), 144 (12).
3-Epi-a-yohimbine (9 b ).11—To a solution of 60 m g (0.17 m m ol) of n atu ral a-yohim bine (8b) in 4 ml of glacial acetic acid held a t 60° was added 215 mg (0.67 m m ol) of m ercury ( I I ) a cetate. T he course of th e oxidation was followed by tic [chloroform -m ethanol (5 .0 :0 .5 ), under an am m onia atm osphere, R 18b > th e im m onium s a lt of 8b). A fter com pletion of the reaction (ca. 90 m in) th e m ercury(I) acetate was rem oved by filtration and washed w ith acetic acid (5 m l). T he filtrate was heated to boiling, hydrogen sulfide gas was introduced, and th e sulfides were filtered off.
Zinc d u st (0.30 g) w as added to the solution, th e reflux was continued for 2.5 hr, and the solution was filtered an d evaporated to dryness in vacuo. T he residue was dissolved in w ater.
Basification w ith concentrated am m onia followed by ethereal extraction yielded a crude p ro d u ct w hich was purified by chrom a
to graphy op silica. E lu tio n w ith chloroform sav e I!},5 mg of a- yohim bine (8b). T hen chloroform -m ethanol (90:10) eluted a 3,4-secoyohimbine fraction. F u rth e r oljition w ith «hlorofprrjt- m ethanol (85:15) afforded 10 .8 mg of ,'S-epi-a-yohunbine (9b),
8b had m p 235-236°; niass sp ectru m (70 eV) m /e (rel intensity) 354 (100, M +), 353 (93), 339 (5.5), 337 (2), 336 (1.5), 335 (1.9), 323 (6), 295 (7.1), 184(10), 170(12), 169(13), 156(8.4),
9b had m p 225°; mass spectrum (70 eV) m /e (rel intensity) 354 (100, M +), 353 (94), 339 (10), 337 (3.9), 335 (2.6), 323 (6.3), 297 (9.3), 295 (10), 184(18), 170(19), 169 (21).
3,4-Secoyohim bine had m ass spectrum (70 eV) m /a (rel inten
sity ) 356 (100, M +), 355 (40), 341 (5.1), 339 (6.8), 335 (49), 325 (8), 297 (53), 264 (8.5), 250 (12), 225 (23), 223 (14).
O xidation-R eduction of 4i an d 4j. A.— M e rc u ry (II) acetate (71 m g, 0,22 m m ol) was added in sm all portion over a period of 10 m in to a solution of 4i (10 m g, 0.028 m m ol) in glacial acetic acid (9 m l). T he m ixture was k e p t a t 60° for 10 h r under nitro
gen an d th en filtered. T he filtrate w as heated to boiling, hydro
gen sulfide gas was introduced, th e insoluble sulfides were filtered off, an d th e solvent was evap o rated in vacuo, giving a yellow oil (7b) which was halved.
(1) A suspension of th e 3-dehydro com pound and a large excess of zinc d u st (five to six tim es the w eight of the 3-dehydro com pound) in glacial acetic acid was refluxed for 2 hr. T he m ixture was filtered, th e solvent was rem oved in vacuo, an d the residue was dissolved in w ater an d m ade basic w ith concentrated am m onia. T he base was ex tracted exhaustively w ith chloro
form , an d th e e x tra c t was w ashed, dried, and evaporated. T he residue w as sep arated b y p rep arativ e tic [benzerie-ethanol (40:
10), developed tw ice, Ri 6a > 4 i[. I t consisted of 4i and 6a in th e ratio of 3 :2 .
(2) Sodium borohydride w as added gradually to a solution of 7b a c e ta te in m ethanol till th e sta rtin g m aterial disappeared.
A nalysis of th e reaction m ixture b y tic [m ethyl ethyl k eto n e- hexane-m ethanol (1 .5 :3 :0 .5 ), R i 6a > 4 io r A1203-G, chloroform - m ethanol (5 .0 :0 .1 5 ), Ri 6a > 4iJ show ed th a t it consisted m ostly of 6a.
B .—T he oxidation was carried o u t on 10 m g of 4j by th e m ethod described above to 7b. T he m aterial o b tain ed (7a) was reduced w ith sodium borohydride. Analysis of th e m ixture by tic [AUOa G , chloroform -m ethanol (5 .0 :0 .1 5 )], show ed th a t it consisted of 4j and 6b in th e ratio of 4 :1.
E pim erization of Alloyohimbine (6a ) to a-Y ohim bine (8b ).—
N a tu ra l alloyohim bine (15 m g) in 3 ml of 2 N m ethanolic sodium m ethoxide solution was allowed to sta n d a t room tem perature under nitrogen for 4 days. Separation of th e m ixture by prepara
tive tic [chloroform -m ethanol i 100:16), R t 8b > 6a] gave 5.6 mg of a-yohim bine (8b ). T he p ro d u ct w as shown to be identical in all respects (ir, m ass spectrum , tic sp o ts) w ith the authentic n atu ral a-yohim bine.
Epim erization of 3-Epi-a-yohim bine (9b) to 3-Epialloyohimbine (4i).— 3-Epi-a-yohim bine (9b) ( 1 m g) in 1.5 ml of 2 N m ethanolic sodium m ethoxide solution was h eated a t 60° under nitrogen.
T he isom erization was followed b y tic [chloroform -m ethanol (5 .0 :0 .5 ), R i 4i > 9b]. A fter 80 m in th e ratio of 9b and 4i was 3 :2 and in 2 h r 9b was com pletely converted to one of th e enantio- mers of 4i.
R egistry N o .—2, 40085-19-6; 3, 40085-20-9; 4a, 40085-21-0; 4b, 40085-22-1; 4c, 40085-23-2; 4d, 40085-24-3; 4 e , 40085-25-4; 4f, 40085-26-5; 4g, 40085- 27-0; 4h , 40085-28-7; 4i, 40085-29-8; 4j, 40085-30-1;
5, 40085-31-2; 6a, 40085-32-3; 8b, 131-03-3; 9b, 483-09-0; 3,4-seco-a-yohim bine, 39990-62-0.
Acknow ledgm ents. —T he authors w ish to thank the Hungarian A cadem y o f Sciences for financial support;
Professor M . Shamma, The P ennsylvania State U niversity, Pennsylvania, and Professor R. Goutarel, G if-sur-Y vette, France, for providing samples of natural alloyohim bine; Professor M . Anteunis, Gent, Belgium , for the 300-M H z nmr spectra and Dr. P.
K olonits for the 60-M H z nmr spectra; and Dr. J.
T am fe for the high-resolution mass spectra.
[Reprinted from the Journal of Organic Chem istry, 38, 2501 (1973).]
Copyright 1973 by the American Chemical Society and reprinted by perm ission of the copyright owner.
S y n t h e s is o f Y o h im b in e s . I I .
A n A lt e r n a t iv e R o u t e to A llo y o h im b in e A lk a lo id s
Lá s z l ó Tö k e,* Zs u z s a Go m b o s, Gá b o r Bl a s k ó, Ka t a l i n Ho n t v, La j o s Sz a b ó, Jó z s e f Ta m á s, a n d Cs a b a Sz á n t a y
Institute of Organic Chemistry, Technical University, Budapest, X I . Gellert tér 4, Hungary Received February 13, 1973
S tartin g from th e readily available keto ester 1, through interm ediates 3, 6a, 6b, 6j, and 6k, a stereospecific to tal synthesis of d isubstituted alloyohim banes of ty p e 7 was accomplished. A lloyohimbine (8m ), a-yohim bine (8n), and th e o th er two possible stereoisomers (8h and 8i) were also prepared. In th e course of these tran sfo r
mations, the first example of imino ether-enam ine tautom erism , neighboring-group participation in th e hydrolysis of compounds 6a and 6b, and a Knoejyenagel condensation under extrem ely mild experim ental conditions were observed and studied.
The route to the synthesis of alkaloids of the allo
yohimbine type described in our previous com m unica
tio n 1 utilized a by-product of a catalytic hydrogenation as starting material. Our aim was now to elaborate a high-yield, practical synthesis of alloyohim bine bases.
Condensation of the K eto E ster 1 with M ethyl Cyanoacetate and M àlononitrile. —The readily avail
able2 keto ester 1 was the starting material, and the improved mode of preparation of the salt 2 required in its preparation is described in the Experim ental Section.
The ketone 1 was condensed with m ethyl cyano
acetate. It was expected that this reaction would be accompanied by epimerization at C3, since such a change had been observed earlier in th e case of benzo[a]- quinolizidine derivatives,3 and had in fact been used successfully by us in the realization of th e stereoselective synthesis of corynantheidine.4 However, under the experimental conditions (N H jO A c-H O A c, azeotropic removal of water w ith benzene) w hich had proven successful with the analog of 1 possessing a C3 ethyl substituent, the vinyl lactam 4 was obtained instead of the required cyano ester 3a. R ing E of th is lactam m ay be opened through acid-catalyzed hydrolysis, and the initial ester 1 can be recovered following esterification.
Lactam 4 could also be generated by th e reaction of the cyano ester 3a with am m onium acetate.
Using triethylam m onium acetate as catalyst, no vinyl lactam 4 was formed. Rather, the desired cyano ester 3a was produced in low yield, w hile the dienam ine 5a formed through oxidation was the main product.
The structure assigned to the dienam ine 5a was con
sistent with the spectral data, and could be; supported chemically since mercuric acetate oxidation of 3a yielded 5a. The behavior of 5a is similar in m any respects to that of its benzo \a jquinolizidine analog prepared and studied earlier.6 It is a yellow substance, resistant to catalytic hydrogenation. On the basis of the temperature dependence of its ntnr spectrum , it must bo a mixture of E and Z isomers. Owing to the reduced energy of activation caused by the extensive conjugation, these tw o isomers are readily interconverti
ble,6 the coalescence of th e tw o indole N H signals occurring at 180°.
(1) L. T ö k e , K . H o n ty , L . S zab ó , G . B la sk ó , a n d C s. S z á h ta y , J . Org.
Chem ., 38, 2496 (1 0 7 3 ).
(2) C ». S z á n ta y , L. T ö k e , K . l l o n t y , an il d y . K a la u s , J . Org. C h em ., 32, 423 (1007).
(3) A. B ro ssi a n d O. B ch n id er, li d o . C h im . Actu, 4 5 , 1899 (1 0 0 2 ).
(4) C s. S z á n ta y a n d M . B á rc z a i-B e k e , C hem . B e r., 1 0 2 , 3ŐÖ3 ( l ‘J0 tí).
(5) M . B á rc z a i-B e k e , G . D ö rn y e i, G . T ó th , a n d C s. S z á n ta y , T etra h ed ro n , in p ress.
A fter a thorough study of the reaction conditions, we finally succeeded in preparing th e desired cyano ester 3a in good yield by carrying out th e reaction in triethyl- am m onium acetate as solvent in the presence of phos
phorus pentoxide. Under such conditions the reac
tion proceeded rapidly at room temperature, and there was no need for azeotropic rem oval of the water formed.
R eduction of 3a w ith sodium borohydride gives 6a in good yield. T h e nmr spectrum of th is product show s th a t the m ethoxyl m ethyl of the Ri ester group is split into tw o peaks w hich are independent of tem perature. T h is phenom enon is a consequence of the new asym m etric center formed following the reduc
tio n .4 There is 110 need to separate the diastereo- isom ers, however, since the new asym metric center disappears in th e course of further reactions.
As an alternative to the condensation of 1 with m ethyl cyanoacetate, the reaction was performed with malono- nitrile. T he product, 3b, was sim ilarly easy to reduce to 6b, while its mercuric acetate oxidation product, 5b, was the analog of the dienam ine 5a.
The rem arkably stable; im ino ether 6c could be derived from th e dinitrile 6b using base catalysis in an alcoholic medium. T he properties of this base, which include the new im ino ether-enam ine tautom erism observed in association w ith it, have been reported elsew here.6 In an aprotic solvent, 6c can be converted w ith 1 mol of water to th e ester 6a. Al
ternatively, in dry m ethanol saturated with hydrogen chloride, the acid am ide 6e is obtained. The latter reaction is so easily controlled that, in the preparation of the ester nitrile 6a from the dinitrile 6b, it was found expedient to prepare the amide 6e first, which was sub
sequently converted to the ester using the dry meth- anol-hydrogen chloride treatm ent. The imino ether to am ide conversion is presum ably an Aai process.
T his assum ption is supported by th e fact th a t in D M F solution 6c alkylates carboxylic acids, thus, e.g.,
6g
to 6a, at room tem perature w hile converting itself to the acid am ide 6e.T he triester 6f can be prepared either from the amide 6e or the ester 6a. B oth ester groups of the ester 6a hydrolyzed with remarkable ease, by simply
(6) (a) L . T ö k e , G . B la s k ó , L . S z a b ó , a n d C s. S z á n t a y , T etra h ed ro n L ett., 2 4 5 9 (1 9 7 2 ). (b ) F o llo w in g o u r p r e lim in a r y c o m m u n ic a tio n o n th e im in o e t h e r - e n a m iíi ö t a u to m e r iz a t lo n ,0“ P ro fe s s o r II. A h lb r e c h t o f G ie sse n , West
G e r m a n y , >VW k in d e n o u g h to d r a w o u r a t t e n t i o n to s o m e of his aiiU unpub-
1 in h ud w o rk r o ta tin g to th e as s ig n m e n t» o f N H i a n d C = N H p r o to n peaks
in th e n m r s p e c t r a . F u r t h e r s tu d ie s o n o u r p a r t in i tia te d b y th e s e c o m m e n ts h a v e s h o w n t h a t th e s p e c t r a l a s s ig n m e n ts fo r th e tw o f u n c tio n a litie s m u s t b e c o n t r a r y to th o s e g iv e n b y us e a rlie r, so t h a t th e r a t io o f th e t a u to - m e rs s h o u ld a lso b e re v e r s e d .
2502 J. Or g. Chem., Vol. 38, No. 14, 1973 Tö k e, Go m b o s, Bl a s k ó, Ho n t y, Sz a b ó, Ta m á s, a n d Sz á n t a y
c h3c — c h c h2c h2c o2c h3 O CHoN(CH3)3F
2
CH2 / C\ c h2c o2c h3
R CN
/ \ c \ c h2c o2c h3
R CN
Hi R2
5 6
3,5 R 6 R i r2 R3
a COsCHs a c o , c h3 CN c o2c h3
b CN b CN CN c o2c h3
N H
c
c
✓ C N c o2c h3\ o c h3 N H
d C✓ CN c o2c h ,
\ OC2H5
e C O N H2 CN c o2c h3
f c o2c h3 c o2c h3 c o2c h3
g c o2h CN c o2h
h c o n h2 CN c o2h
i h CN c o2h
j H CN C 0 2CHa
k H c o2c h3 C 02CH3
dissolving in alkali at 0° and then acidifying. The precipitate formed is diacid 6g. T his exceedingly rapid hydrolysis could be due to neighboring group participation. A similar behavior is also shown toward alkali by the dinitrile 6b. However, in this case, the amide 6h is also present besides the dicar- boxylic acid 6g.
Short boiling of a solution of the diacid 6g in D M F led, as expected, to decarboxylation and form ation of the carboxylic acid nitrile 6i, which could in turn be converted to the ester nitrile 6j w ith diazom ethane, or alternatively to the diester 6k w ith dry m ethanol and hydrogen chloride.
Preparation of the Alloyohimbine S keleton from the Nitrile Ester 6j. —The nitrile ester 6j can be converted in good yield by potassium ¿ert-butoxide in D M SO into the pentacyclic ketone 7a, which exists as a mixture of keto-enol tautom ers both in the solid phase and in solution. Prom spectral data, the com pound m ust exist in the trails (At) conformation. In the alio series, the stefic interaction between the Cm H, the C3 H, and the Cu substituent, present in the epiallo an alogs,1 is not a factor. There is, therefore, only a minimal
difference in energy between an axial and an equatorial Cie cyano group in 7a, so th a t in an equilibrium m ix
ture both isomers could be present. Accordingly, sodium borohydride reduction of 7a yielded a 4 :1 mixture of the isom eric nitrile alcohols 8a and 8b.
11. R2
a CN H
b II c o2c h3
c H H
d COjC H , H
8 Ri k2 r 3 R. R5
a CN H o h H H
b H CN OH H H
c CN H OAc H H
d H CN OAc II H
e 11 CN H OH 11
f c o n h2 H OH H H
g H C O N Il2 OH H H
h c o2c h3 H OH H H
i II C 02CI13 OH H H
j H H OH H C 02C H3
k H H H OH C 02C H3
1 H 1 1 OH H c h2o h
m 11 C 02C H3 1 1 OH II
n c o2c h3 1 1 H OH 1 1
T he spectral characteristic s of isomers 8a and 8b (Table I) indicate th a t both exist in the A t conforma-
Ta b l e I
Sp e c t r a l Va l u e s ,---N m r ,° b--- s
C17 proton hydroxyl Ir,6 cm*1, Compd multiplet doublet Bohlmann band»
8a 3.95 5.05 2815, 2765
8b 3.93 5.15 2810,2770
8c 5.10 2810, 2760
8d 4.95 2805, 2760
0 In D M S O -* a t 60 M H z. h In pyridine.
tion so th a t the C17 OH group can occupy only an axial site. T he correctness of this assignm ent is corroborated by the nmr spectra of the aeetylated derivatives 8c and 8d (Table I). It can thus be concluded unequiv
ocally th a t the OH groups in 8a and 8b are p, so that attack by borohydride m ust occur from the convex side of the m olecule and is subject to “steric approach control.”
The above conclusions are also supported by the chem ical behavior of th e two com pounds. Either isom er when dissolved in alcoholic alkali at room tem
perature yields a nearly 1:1 mixture of 8a and 8b.
Under such mild conditions only the carbon atom, adjacent to th e nitrile group, can be epimerized. It should be m entioned here th a t 8a and 8b must be pri
mary products of th e reduction of the ketone 7a be
cause no epim erization occurs under the conditions of the induction. A dditionally, the ratio of the reduc
tion products remains unchanged when th e reaction w ith sodium borohydride is carried out in acetic acid.
Al t e r n a t i v e Ro u t e t o Al l o y o h i m b i n e Al k a l o i d s J. Org. Client., Vol. 38, No. 14, 1973 2503 Further confirmation of the steric assignm ents can
be obtained through correlation w ith the nitrile al
cohols 9a and 9b of the epiallo series synthesized
nV n s
h h* T i.* 'H H " ’T
c n'r?Kl»,
% 9
Hi R*
OH H
H OH
earlier.1 Thus, when the product 9a was epimerized at C- 3 by oxidation w ith mercuric acetate and sub
sequent reduction, a product com pletely identical w ith 8b was obtained, proving th a t in both com pounds the Cn OH group m ust be On the other hand, sim ilar epimerization of 9b led to an alio nitrile alcohol which was identical w ith neither 8a nor 8b. For this new nitrile alcohol, structure' 8e can be written.
It will be recalled th a t the nitrile group in the penta- cyclic indole bases could be hydrolyzed in tw o ste p s.1’7 In the first step, treatm ent of the nitrile w ith hydrogen peroxide furnished the amide. W hen the reaction was carried out at room tem perature, th is transform ation occurred at a faster rate than Cib isom erization. The unsaturated amide 10b, w hich was formed in substan
tial quantities at higher temperature, was present only in trace amounts.
In pyridine solution, the ir spectrum of th e amide 8g show s only weak Bohlm ann bands so th a t th e allo- cis (Ad) conform ation m ust predom inate. In th e A t conformation both the carboxam ide and th e h y droxyl groups m ust be axial, while in th e A ci arrange
ment th ey are equatorial.
The hydroxy esters 8h and 8i can be prepared from the amides using hydrogen chloride in dry m ethanol.
A by-product of th is reaction is apo-a-yohim bine.
T he chromatographic behaviors of both esters 8h and 8i differ from th at of natural a-yohim bine or allo
yohim bine.
The importance of th e syn th esis of 8h and 8i lies primarily in the fact th at all the yohim bine isom ers w ith the alio configuration are now available, thus further enhancing our earlier view s on the revision of the stereochem istry of alloyohim bine.
The main spectral features of the isomers in ques
tion have been sum marized in T able II. For clarity’s sake, Table II also includes the data for alloyohim bine (8m) and a-yohim bine (8n) discussed earlier.1
(7) L . T o k e , K , H o n ty , a n d C s. S z iin ta y , C h em . B e r., 102, 3 2 4 8 (1 9 6 9 ).
T.UlIiR I I
Sp e c t r a l Va l u e s
'— —»C onform ation --- » /--- N r a r , 6--- % I r , ' c m -1 , C.
Cl7 C . B o h lm a n n C„ in d o le S kele
C o m p el p r o to n p r o to n band9 OH rin g to n
8h 4.26» 3 .0 5 2810, 2760 ax eq A,
8i 3.75» 3 .9 5 V ery weak eq ax Aci
8m (alloyo-
him bine) 3.80* 3,2 5 280.5,2760 eq eq A,
8n (a-yohim -
bine) 3.99» 3 .1 5 2805, 2765 eq eq At
» In C D C lj a t 300 M H z. <• In CDC1, a t 60 M H*. • In pyri
dine.
Epimerization of Yohim bine Isom ers. —We have studied the epim erization of yohim bine isomers in 2 N m ethanolic sodium m ethoxide at room temperature.
Under these conditions, only the Cm site, adjacent to the earbom ethoxy group, can epimerize. Starting w ith 8h, its isomer 8i appeared after a few hours, si
m ultaneously w ith th e elim ination product 10c. Com
p lete equilibration was achieved after about 3 days, w ith an 8h :8i ratio of about 1:1. Upon further stand
ing, the quantity of 10c increased. The behavior of the ester alcohols thus bears som e sim ilarity to that of the nitrile alcohols 8a and 8b, but on the basis of spectral data no full analogy prevails. The transfor
m ation 8a - * ■ 8b occurs betw een compounds possessing the A t conform ation, and the equilibrium ( ~ 1 :1) is determ ined by th e sm all difference in energy between the axial and equatorial positions of the nitrile group (Chart I). It should also be added that the A t -*• A C1 conform ational equilibrium also plays an im portant role (Chart I). Species 8i is one of those rare sub
Ch a r t I
OH
2504 J . Org. Chem., Vol. 38, No. 14, 1973 Tö k e, Go m b o s, Bl a s k ó, Ho n t y, Sz a b ó, Ta m á s, a n d Sz á n t a y
stances w ith the alloyohim bine skeleton whose C /D ring annelation is cis.
Synthesis of the Alloyohimbine Skeleton from the D iester 6 k .—The direction of the Dieckmarm cycliza- tion of 6k was predicated on the conditions used as already established earlier7 in the case of compounds of analogous structures. When the reaction was carried out in hot toluene in the presence of sodium m etli- oxide or sodium hydride, the enolic pentacyclic ketone 7b was isolated as the sole product. The compound was readily decarboxylated to the known8 ( ± )-alloy o- himbone (7c). A lternatively, sodium borohydride reduction of 7b yielded alcohols 8j and 8k in a 20:1 ratio, together with a sm all am ount of th e diol 81.
Since neither 8j nor 8k was identical w ith any of the previously prepared yohim bine isomers, the ester func
tion must be linked to Cis. T he steric arrangement of the hydroxyl group in 8j and 8k was not extensively investigated. Rather, w ith the' assum ption th a t “steric approach control” is operative, we attributed struc
ture 8j to the substance formed in larger quantity.
When the cyclization was carried out at room tem perature, the isomer 7d, alloyohim biuone, was isolated in about 30% yield in addition to 7b. K etone 7d, in analogy to 7b, is also subjected to k eto-en ol tautom - erism, and again leads to (± )-a llo y o h im b o n e (7c) upon hydrolysis and decarboxylation.
The optically active form of aloyohim binone (7d) is known9 from the oxidation of a-yohim bine, and it is reported that it exists com pletely in th e enolic form.
This statem ent, however, is valid only in the solid phase, since in pyridine or chloroform solution the keto form predominates by about 80%. Spectral data indicate that 7d exists both in th e solid phase and in solution as the At conformer.
Reduction of 7d with sodium borohydride furnished three hydroxy esters. The main product proved to be identical with the unnatural base 8h. T he second product was ( ± ^ alloyohim bine1 (8m), while the third product was (± )-a -y o h im b in e (8ft). The ratio of th e alkaloids was 8 h : 8 m : 8n = 7 : 3: 2.
Taking into consideration our earlier investigations in the normal yohim bane,7 epialloyohim bane,1 and berbane series,10 it can be stated th a t the structures and relative quantities of the stereoisom eric alcohols obtained from the sodium borohydride reduction of yohimbinones and their analogs containing nitrile are in accordance w ith th e concept of “steric approach control” in the reduction.
Experim ental Section
The infrared spectra were determ ined on Perkin-E lm er 221 and UR-10 spectrom eters. N uclear m agnetic resonance spectra were obtained on a Perkin-Elm er R 12 (60 M H z), V arian A-60, and Varian-300 M Hz instrum ents a t G en t and are given in S units downfield from internal tetram ethylsilane. M ass spectra were recorded a t 70 eV on a A EI-M S-902 double-focusing in stru m en t using direct insertion probe a t a tem perature of 120-150°. High*
resolution m aw measurem ents were acMiirate to within 2 ppm . Thin layer chrom atography (tic) was perform ed on silica gel G , E . M erck AG, unless otherwise noted. Silica gel PFam+a««
(8) P . G . F h ilp o t t a n d A. M . P a r s o n s , J . C h em . S o c ., 3 0 1 8 (1 9 5 8 ).
(9) J . D . A lb r ig h t a n d L. G o ld m a n , J . Ora. C h em ., 3 0 , 1107 (1965); J. 1).
A lb rig h t a n d L . G o ld m a n , J , A m e r . C hem . S o c., 8 9 , 241Ü (11/07).
(10) L. S zab ó , K . H o n ty , I, T ó th , L . T ő k e , a n d C s. Szántay, C hem . B e r., 105, 3215 (1972); L . S z a b ó , K . Honty, L. T ö k e , a n d C s. Szántay, ib id ., 105, 3231 (1972).
and A12Oj P F 25i+366, E . M erck AG, were used for p rep arativ e layer chrom atography. Silica gel (0.05-0.2 m m , E . M erck, AG) was used for colum n chrom atography, unless otherw ise noted.
A nhydrous m agnesium sulfate was em ployed as th e drying ag en t.
All reactions utilizing strongly basic reagents were conducted under oxygen-free d ry nitrogen atm osphere.
4-Dim ethylam inom ethyt-5-oxocaproic Acid M ethyl E ste r M eth- iodide (2) an d 4-M ethylene-S-oxocaproic Acid M ethyl E s te r .2— A suspension of 138 g (0.6 mol) of diethyl a -a c e ty lg lu ta ra te in 600 ml of 2 A' sodium hydroxide solution w as stirred vigorously for 3 h r a t room tem p eratu re and the unchanged sta rtin g m aterial was extracted w ith ether (2 X 100 m l). A solution of 61 g (0.75 m ol) of diethylam ine hydrochloride in 102 m l of 22% aqueous form al
dehyde (0.75 m ol) was added dropw ise w ith stirring in to the aqueous phase obtained above. A fter the reaction m ixture was allowed to sta n d for 48 hr a t room tem p eratu re it was acidified to p i I 3 w ith concentrated hydrochloric acid and evaporated to dryness in vacvo. T he resulting viscous oil, which contained sodium chloride, was dissolved in 100 ml of h o t ethanol, an d the salt was filtered and washed w ith eth an o l (3 X 50 m l). T he com bined alcoholic solution was dehy d rated by azeotroping w ith benzene (200 m l). T he process was repeated several tim es w ith a m ixture of benzene-ethanol (2 :1 ) while th e w ater c o n te n t decreased to 3 -8 % (checking by K arl-F isch er m ethod). T he am o u n t of phosphorus pentoxide necessary for the esterification was calculated by th e form ula
„ w ater c o n te n t (% ) X w eight of crude m aterial , (m,,1) “ --- 18 X 100 ... ... + mol of sta rtin g m aterial T h e solution of crude m aterial in 300 ml of m ethanol was added portionw ise to the calculated a m o u n t of phosphorus pentoxide in 600 ml of m ethanol w ith cooling. A fter the reaction m ixture was allowed to sta n d a t room tem p eratu re for 24 hr, th e solvent was rem oved in vacuo, an d th e residue was rendered to pH 3 dissolving in sa tu ra te d sodium bicarbonate solution and extracted w ith ether (5 X 200 m l). T he com bined ex tracts were washed, dried, ev ap o rated , an d distilled to give 27 g (28% ) of 4-m ethylene-5- oxocaproic acid m ethyl ester, bp 70-72° (2 m m ).J
T he above aqueous solution, which was extracted w ith ether, was cooled an d m ade alkaline w ith sa tu ra te d sodium bicarbonate solution an d ex tracted im m ediately w ith eth er (5 X 500 m l).
T he com bined ex tracts were dried an d evaporated. T he obtained oil (38 g) in 10 ml of d ry m ethanol was tre a te d w ith m ethyl iodide (19 m l, 0.3 m ol) an d allowed to sta n d overnight. T he precipi
ta te d crystals were collected an d w ashed w ith dry ether, giving 50 g (25% ) of 2, m p 118-119°.
15,20-Dehydro-16-azayohim bone (4 ).—T o th e solution of 1.25 g (3.82 m m ol) of 1 in 300 ml of dry toluene was added 0.8 g (10.4 m m ol) of am m onium a c e ta te and 2 ml of glacial acetic acid, and the m ixture was refluxed for 4 h r. T he reaction was followed by tic [benzene-m ethanol (8 .5 :1 .5 )], Rt 1 > 4. T he cooled solution was neutralized w ith sodium m ethoxide, w ashed w ith w ater, and dried, an d th e solvent was evaporated in vacuo under nitrogen.
T he residue (0.95 g, 84% ) was crystallized twice from ethanol to give 0.72 g (64% ) of 4, m p 261-262°.
A nal. C alcd for C,8Iii,,NaO: C, 73.69; H , 6.53; N , 14.33.
P ound: C, 73.41; H , 6.54; N , 14.55.
I r (K B r) 3370 (lactam N H ), 3320 (indole N II), 2815, 2750 (B ohlm ann bands), 1665 (lactam C —O), 1630 c m -1 ( C = C ) ; nm r (D M SO -d6) 8 8.95 (s, 1, lactam N H ), 7.45-0.50 (m , 4, arom atic protons).
H ydrolysis an d S ubsequent M ethylation of 4 to 1.—T he solution of 12 m g (4.5 X 10 6 m ol) of 4 in 5 ml of 0.005% aqueous HC1 was refluxed for 4 hr, the solvent was evaporated in vacuo, and th e residue was dried by azeotroping w ith benzene-ethanol.
T h e sa lt o btained was suspended in 10 ml of m ethanol and allowed to sta n d for 30 m in w ith all excess of ethereal diazo- m ethatte, tic, benzene-m ethanol (8 .5 :1 .5 ). T he residue (12.2 mg, 91% ) a fter rem oval of th e solvent was crystallized from m ethanol, m p 207-208°. T he id en tity of th e m aterial as 1 was established by ir, tic, and m ixture m elting p o in t.’
A nal. C alcd for C ,oH «N 20 3: C , 69.61; H , 6.79; N , 8.58.
F ound: C , 69.53; 11,6.86; N , 8.65.
Ir (K B r) 3380 (N H ), 1721 (C O .C H j), 1710 c m “ 1 ( C = 0 ) . M ethyl 3/M 2-M ethoxycarbonylethyl)-l,3,4,7,12,12bai-hexahy- dro-2//,6//-indolo[2,3-a]quinolizin-2-ylidenecyanoacetate (3a).
—T o th e solution of 10.4 g (31.7 m m ol) of 1 in 42 ml of glacial acetic acid was added 64 ml (460 m m ol) of triethylam ine, 1.8 g
