Stereocontrolled elaboration of quaternary carbon centers through the asymmetric Michael-type alkylation of chiral imines/secondary enamines: Enantioselective synthesis of (+)-vincamine

Article abstract of DOI:10.1021/jo9622690

An enantioselective synthesis of (+)-vincamine (1) has been developed. The key strategic element was the stereocontrolled elaboration of a quaternary carbon center (future C-20 center of 1) by using the asymmetric Michael reaction involving chiral imines/secondary enamines under neutral conditions. Thus, addition of enaminolactam (S)-12, derived from ketolactam 7 (itself prepared in four steps from commercially available tryptamine) and (S)-1-phenylethylamine, to methyl acrylate led, after hydrolytic workup, to adduct (R)-6 with a 90% stereoselectivity. The critical removal of the additional keto group of 6 was then examined. After extensive experimentation, we finally established that the most efficient deoxygenation procedure was the Wolff-Kishner reduction of the corresponding keto acid, which proceeded with a 55% yield. The cornerstone [ABD]-tricyclic lactam ester 38 thus obtained was next cyclized under Bischler-Napieralski reaction conditions to afford, after catalytic hydrogenation of the intermediary iminium perchlorate salt, a mixture of the desired, known indoloquinolizidine 5 and its epimer 39, in a ratio of 6:1, respectively. Basic treatment of 5 led to (+)-homoeburnamonine 4, which was finally converted, according to a known procedure, into our goal (+)-vincamine (1). Thus, synthesis of (+)-vincamine (1) has been achieved by a linear sequence of 15 chemical operations, starting from tryptamine, with an overall yield of 1.2%.

Full text of DOI:10.1021/jo9622690

3890
J . Org. Chem. 1997, 62, 3890-3901
Ster eocon tr olled Ela bor a tion of Qu a ter n a r y Ca r bon Cen ter s
th r ou gh th e Asym m etr ic Mich a el-Typ e Alk yla tion of Ch ir a l
Im in es/Secon d a r y En a m in es: En a n tioselective Syn th esis of
(+)-Vin ca m in e
Didier Desmae¨le, Khalid Mekouar, and J ean d’Angelo*
Unite´ de Chimie Organique Associe´e au CNRS, Centre d’EÄ tudes Pharmaceutiques, Universite´ Paris-Sud,
5 rue J .-B. Cle´ment, 92296 Chaˆtenay-Malabry, France
Received December 5, 1996X
An enantioselective synthesis of (+)-vincamine (1) has been developed. The key strategic element
was the stereocontrolled elaboration of a quaternary carbon center (future C-20 center of 1) by
using the asymmetric Michael reaction involving chiral imines/secondary enamines under neutral
conditions. Thus, addition of enaminolactam (S)-12, derived from ketolactam 7 (itself prepared in
four steps from commercially available tryptamine) and (S)-1-phenylethylamine, to methyl acrylate
led, after hydrolytic workup, to adduct (R)-6 with a 90% stereoselectivity. The critical removal of
the additional keto group of 6 was then examined. After extensive experimentation, we finally
established that the most efficient deoxygenation procedure was the Wolff-Kishner reduction of
the corresponding keto acid, which proceeded with a 55% yield. The cornerstone [ABD]-tricyclic
lactam ester 38 thus obtained was next cyclized under Bischler-Napieralski reaction conditions
to afford, after catalytic hydrogenation of the intermediary iminium perchlorate salt, a mixture of
the desired, known indoloquinolizidine 5 and its epimer 39, in a ratio of 6:1, respectively. Basic
treatment of 5 led to (+)-homoeburnamonine 4, which was finally converted, according to a known
procedure, into our goal (+)-vincamine (1). Thus, synthesis of (+)-vincamine (1) has been achieved
by a linear sequence of 15 chemical operations, starting from tryptamine, with an overall yield of
1.2%.
Ch a r t 1
In tr od u ction
Vinca alkaloids comprise a large group of biologically
active, naturally occurring bases, isolated from several
plants of the Vinca species.1 Among these bases, (+)-
vincamine (1), the major alkaloid encountered in peri-
winkle (Vinca minor L., Apocynaceae), appears to be a
particularly attractive synthetic target. In man, the best
established pharmacological property of vincamine (1)
and semisynthetic derivatives, such as ethyl apovincami-
nate (2) (vinpocetine, Cavinton),2 is the cerebroprotective
activity, caused by a dilation of brain arteries, improving
the global cerebral blood flow. Thus, vinpocetine has
been proposed for the treatment of certain vascular
dementia, by enhancing oxygen release of hemoglobin,3
of the sensorineural impairment of hearing,4 in ophthal-
mological therapy.5 Recent investigations have shown
that pharmacon 2 also exhibits a protective effect against
brain damage caused by ischemia,6 a gastroprotective
action,7 and a remarkable promising activity in removing
tumoral calcinosis,8 effects possibly related to the power-
ful hydroxyl radical-scavenging capability of this mol-
ecule (close to that of vitamin E)9 (Chart 1).
Several strategies for the synthesis of vincamine (1)
(the “biogenetic” numbering system was used here)10 and
analogs have been developed. The common feature in
these approaches was to establish first the [ABCD]-type
octahydroindolo[2,3-a]quinolizine system of this alkaloid,
starting from an indole subunit, and to achieve the
synthesis by creating the fifth ring E. Thus, strategically,
the elaboration of vincamine (1) and related alkaloids
reduced to four main methodologies for establishing the
requisite gem-disubstituted tetracyclic indoloquinolizi-
dine moieties 3 bearing two controlled stereogenic carbon
X Abstract published in Advance ACS Abstracts, May 15, 1997.
(1) Atta-ur-Rahman; Sultana, M. Heterocycles 1984, 22, 841-858.
Eburnamine-vincamine alkaloids: Lounasmaa, M.; Tolvanen, A. In
The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1992;
Vol. 42, p 1. Saxton, J . E. Nat. Prod. Rep. 1996, 13, 327-363.
(2) Ka´rpa´ti, E.; Szporny, L. Arzneim.-Forsch. (Drug Res.) 1976, 26,
1908-1911. Biro´, K.; Ka´rpa´ti, E.; Szporny, L. Ibid. 1976, 26, 1918-
1919. Bencsa´th, P.; Debreczeni, L.; Taka´cs, L. Ibid. 1976, 26, 1920-
1922. Rosdy, B.; Bala´zs, M.; Szporny, L. Ibid. 1976, 26, 1923-1925.
(3) Tohgi, H.; Sasaki, K.; Chiba, K.; Nozaki, Y. Ibid. 1990, 40, 640-
643.
(8) Ueyoshi, A.; Ota, K. J . Int. Med. Res. 1992, 20, 435-443.
(9) Ola´h, A.; Balla, G., Balla, J .; Szabolcs, A.; Karmazsin, L. Acta
Pædiatr. Hung. 1990, 30, 309-316.
(10) Le Men, J .; Taylor, W. I. Experientia 1965, 21, 508-510.
(11) (a) Kuehne, M. E. Lloydia 1964, 27, 435-439. (b) Kuehne, M.
E. J . Am. Chem. Soc. 1964, 86, 2946. (c) Wenkert, E.; Wickberg, B.
Ibid. 1965, 87, 1580-1585. (d) Gibson, K. H.; Saxton, J . E. J . Chem.
Soc., Chem. Commun. 1969, 799. (e) Gibson, K. H.; Saxton, J . E. J .
Chem. Soc., Perkin Trans. 1 1972, 2776-2787. (f) Kalaus, G.; Gyo¨ry,
P.; Kajta´r-Peredy, M.; Radics, L.; Szabo´, L.; Sza´ntay, C. Chem. Ber.
1981, 114, 1476-1483. (g) Irie, K.; Ban, Y. Heterocycles 1982, 18, 255-
258. (h) Takano, S.; Sato, S.; Goto, E.; Ogasawara, K. J . Chem. Soc.,
Chem. Commun. 1986, 156-158. (i) Lounasmaa, M.; J okela, R.
Heterocycles 1986, 24, 1663-1965. (j) Gmeiner, P.; Feldman, P. L.; Chu-
Moyer, M. Y.; Rapoport, H. J . Org. Chem. 1990, 55, 3068-3074.
(4) Riba´ri, O.; Zelen, B.; Kolla´r, B. Ibid. 1976, 26, 1977-1979.
(5) Kaha´n, A.; Ola´h, M. Ibid. 1976, 26, 1969-1974.
(6) (a) Krieglstein, J .; Rischke, R. Eur. J . Pharmacol. 1991, 205,
7-10. (b) Rischke, R.; Krieglstein, J . J apan J . Pharmacol. 1991, 56,
349-356. (c) Iiono, T.; Katsura, M.; Kuriyama, K. Eur. J . Pharmacol.
1992, 224, 117-124.
(7) Nosa´lova´, V.; Machova´, J .; Babulova´, A. Arzneim.-Forsch. (Drug
Res.) 1993, 43, 981-985.
S0022-3263(96)02269-4 CCC: $14.00 © 1997 American Chemical Society

Enantioselective Synthesis of (+)-Vincamine
J . Org. Chem., Vol. 62, No. 12, 1997 3891
Ch a r t 2
Sch em e 1
atoms, namely the crucial quaternary center at C-20 and
the adjacent methine at C-21: the Pictet-Spengler
cyclization,11 the Bischler-Napieralski (B-N) cycliza-
tion,12 the Michael-type alkylation of the so-called “Wen-
kert’s enamine”,13 and the annulation reaction of a
dihydro-â-carboline14-17 (Chart 2).
Syn th etic P la n , Resu lts a n d Discu ssion
Our own strategy for the enantioselective synthesis of
(+)-vincamine (1) is outlined in the retrosynthetic path-
way depicted in Scheme 1.18 The basic approach featured
a general methodology for the stereocontrolled elabora-
tion of quaternary carbon centers as key step in the
construction of the [ABD]-type subunit 6 from keto
lactam 7. The latter compound was efficiently prepared
in four steps, starting from tryptamine. Synthesis of the
requisite tricycle 6, in its desired R configuration, in-
volved the asymmetric Michael addition of the chiral
enaminolactam, prepared from 7 and (S)-1-phenylethyl-
amine, to methyl acrylate. Wolff-Kishner (W-K) reduc-
tion of the additional keto group of 6, followed by B-N
cyclization, led to the indoloquinolizidine derivative 5,
having established during the events the correct stereo-
chemical relationship between C-20 and C-21. Base-
induced cyclization of 5 finally gave (+)-homoeburnamo-
nine 4, a direct, known precursor of (+)-vincamine (1).
Alternatively, compound 5 can be converted into 1 by the
efficient two-step procedure recently reported by Nemes.13i
As mentioned above, the key step in the synthesis of
our goal 1 was the stereocontrolled creation of a quater-
nary carbon center (step 7 f 6) by using the asymmetric
Michael reaction involving chiral imines/secondary enam-
ines, derived from 1-phenylethylamine, which we re-
ported a decade ago.19 We were confident that this
methodology might be applied to the peculiar â-keto
lactam topology of 7, having previously established that
addition of a chiral enaminolactam, derived from a â-keto
lactam model, to methyl acrylate, led to the expected
adduct with a good yield and an excellent stereoselec-
tivity (94%).20 The requisite tricyclic ketolactam 7 was
elaborated in four steps with an overall yield of 43%, as
follows.21 Conjugate addition of tryptamine to ethyl
acrylate (THF, 12 h at 20 °C, 83%) gave adduct 8, which
was next condensed with ethylmalonic acid monoethyl
ester (DCC, cat. DMAP, CH2Cl2, 18 h at 20 °C, 83%) to
furnish diester 9. Dieckmann cyclization of 9 (NaH,
THF, 4 h at 20 °C, 79%) afforded 10, which upon
decarbethoxylation (LiBr, 2 equiv of water, 12 h at reflux
in DMF, 79%), finally gave the desired keto lactam 7
(Scheme 2).
(12) (a) Herrmann, J . L.; Cregge, R. J .; Richman, J . E.; Semmelhack,
C. L.; Schlessinger, R. H. J . Am. Chem. Soc. 1974, 96, 3702-3703. (b)
Pfa¨ffli, P.; Oppolzer, W.; Wenger, R.; Hauth, H. Helv. Chim. Acta 1975,
58, 1131-1144. (c) Herrmann, J . L.; Cregge, R. J .; Richman, J . E.;
Kieczykowski, G. R.; Normandin, S. N.; Quesada, M. L.; Semmelhack,
C. L.; Poss, A. J .; Schlessinger, R. H. J . Am. Chem. Soc. 1979, 101,
1540-1544. (d) Ono, K.; Kawakami, H.; Katsube, J . Heterocycles 1980,
14, 411- 414. (e) Govindachari, T. R.; Rajeswari, S. Indian J . Chem.
1983, 22B, 531-537. (f) Langlois, Y.; Pouilhe`s, A.; Ge´nin, D.; Andri-
amialisoa, R. Z.; Langlois, N. Tetrahedron 1983, 39, 3755-3761. (g)
Lounasmaa, M.; Tolvanen, A. J . Org. Chem. 1990, 55, 4044-4047.
(13) (a) Thal, C.; Sevenet, T.; Husson, H.-P.; Potier, P. C. R. Acad.
Sc. 1972, 275, 1295-1297. (b) Warnant, J .; Farcilli, A.; Toromanoff,
E. Ger. Offen. 2, 115, 718, 14 Oct 1971; Chem. Abstr. 1972, 76, 34462
m. (c) Sza´ntay, C.; Szabo´, L.; Kalaus, G. Tetrahedron Lett. 1973, 191-
192. (d) Sza´ntay, C.; Szabo´, L.; Kalaus, G. Tetrahedron 1977, 33, 1803-
1808. (e) Rossey, G.; Wick, A.; Wenkert, E. J . Org. Chem. 1982, 47,
4745-4749. (f) Szabo´, L.; Sa´pi, J .; Kalaus, G.; Argay, G.; Ka´lma´n, A.;
Baitz-Ga´cs, E.; Tama´s, J .; Sza´ntay, C. Tetrahedron 1983, 39, 3737-
3747. (g) Szabo´, L; Kalaus, G; Sza´ntay, C. Arch. Pharm. (Weinheim)
1983, 316, 629-638. (h) Lounasmaa, M.; J okela, R. Heterocycles 1986,
24, 1663-1665. (i) Nemes, A.; Czibula, L.; Visky, G.; Farkas, M.; Kreidl,
J . Ibid. 1991, 32, 2329-2338.
(14) (a) Oppolzer, W.; Hauth, H.; Pfa¨ffli, P.; Wenger, R. Helv. Chim.
Acta 1977, 60, 1801-1809. (b) Ge´nin, D.; Andriamialisoa, R. Z.;
Langlois, N.; Langlois, Y. J . Org. Chem. 1987, 52, 353-356.
(15) For another approach to vincamine: Hakam, K.; Thielmann,
M.; Thielmann, T.; Winterfeldt, E. Tetrahedron 1987, 43, 2035-2044.
(16) Semisynthetic routes to vincamine. (a) Hugel, G.; Le´vy, J .; Le
Men, J . C. R. Acad. Sc. 1972, 274, 1350-1352. (b) Hugel, G.; Massiot,
G.; Le´vy, J .; Le Men, J . Tetrahedron 1981, 37, 1369-1375. (c) Danieli,
B.; Lesma, G.; Palmisano, G. J . Chem Soc., Chem. Commun. 1981,
908-909. (d) Hugel, G.; Le´vy, J . Tetrahedron 1984, 40, 1067-1073.
(17) Syntheses of alkaloids related to vincamine (selected papers).
Eburnamonine: (a) Bartlett, M. F.; Taylor, W. I. J . Am. Chem. Soc.
1960, 82, 5941-5946. (b) See ref 11c. (c) Buzas, A.; Herisson, C.;
Lavielle, G. C. R. Acad. Sc. 1976, 283, 763-765. (d) Wenkert, E.;
Hudlicky, T.; Showalter, H. D. H. J . Am. Chem. Soc. 1978, 100, 4893-
4894. (e) Bo¨lsing, E.; Klatte, F.; Rosentreter, U.; Winterfeldt, E. Chem.
Ber. 1979, 112, 1902-1912. (f) Buzas, A.; J acquet, J .-P.; Lavielle, G.
J . Org. Chem. 1980, 45, 32-34. (g) Irie, K.; Ban, Y. Heterocycles 1981,
15, 201-206. (h) Wenkert, E. ; Halls, T. D. J .; Kwart, L. D.; Magnusson,
G.; Showalter, H. D. H. Tetrahedron 1981, 37, 4017-4025. (i) Magnus,
P.; Pappalardo, P.; Southwell, I. Ibid. 1986,42, 3215-3222. (j) Node,
M.; Nagasawa, H.; Fuji, K. J . Org. Chem. 1990, 55, 517-521. (k)
Kaufman, M. D.; Grieco, P. A. J . Org. Chem. 1994, 59, 7197-7198. (l)
Da Silva Goes, A.; Ferroud, C.; Santamaria, J . Tetrahedron Lett. 1995,
36, 2235-2238. Homoeburnamonine: (m) See ref 11d, e. (n) Laronze,
J .; Laronze, J . Y.; Le´vy, J .; Le Men, J . Bull. Soc. Chim. Fr. 1977, 1195-
1206. (o) Buzas, A.; Retourne, C.; J acquet, J . P.; Lavielle, G. Tetrahe-
dron 1978, 34, 3001-3004. (p) Szabo´, L.; Sa´pi, J .; No´gra´di, K.; Kalaus,
G.; Sza´ntay, C. Ibid. 1983, 39, 3749-3753. Apovincaminic acid
esters: (q) Lo¨rincz, C.; Sza´sz, K.; Kisfaludy, L. Arzneim.-Forsch. (Drug
Res.) 1976, 26, 1907. (r) Danieli, B.; Lesma, G.; Palmisano, G. Gazz.
Chim. Ital. 1981, 111, 257-267. (s) Danieli, B.; Lesma, G.; Palmisano,
G. Tetrahedron Lett. 1981, 22, 1827-1828. (t) Christie, B. D.; Rapoport,
H. J . Org. Chem. 1985, 50, 1239-1246.
F ir st Rou te: Use of Meth yl 2-Acetoxya cr yla te a s
Mich a el Accep tor . Strategically, it became apparent
(19) d’Angelo, J .; Desmae¨le, D.; Dumas, F.; Guingant, A. Tetrahe-
dron: Asymmetry 1992, 3, 459-505. d’Angelo, J .; Cave´, C.; Desmae¨le,
D.; Dumas, F. Trends in Organic Synthesis; Pandalai, S. G., Ed.; Tri-
vandrum: India, 1993; Vol. 4, pp 555-615.
(20) Ambroise, L.; Chassagnard, C.; Revial, G.; d’Angelo, J . Tetra-
hedron: Asymmetry 1991, 2, 407-410.
(21) Sugasawa, S.; Fujii, T. Pharm. Bull. (J apan) 1955, 3, 47-52.
Ban, Y. Ibid. 1955, 3, 53-59. Barash, M.; Osbond, J . M.; Wickens, J .
C. J . Chem. Soc. 1959, 3530-3543.
(18) For a preliminary account of this work see: Mekouar, K.;
Ambroise, L.; Desmae¨le, D.; d’Angelo, J . Synlett, Special Issue May
1995, 529-532.

3892 J . Org. Chem., Vol. 62, No. 12, 1997
Desmae¨le et al.
Sch em e 2
Sch em e 4
Sch em e 3
lizidine of type 3. However, all attempts at B-N cycliza-
tion of 14 (POCl3, 24 h in MeCN at reflux and then
NaBH3CN; POCl3, 24 h in toluene at reflux and then
NaBH4; or 24 h in neat POCl3 at reflux and then H2/Pd-
C)12 proved to be invariably unsuccessful. Having sus-
pected the presence of the keto group at C-15 in com-
pound 14 to be responsible for the failure, we then
decided to examine the B-N cyclizations of model keto
lactam 15, and of its derivative 17, lacking the interfering
keto group. As anticipated, the attempted B-N cycliza-
tion of 15 (prepared in 62% yield by condensing 7 with
EtI, Triton B, MeOH-CH3CN, 4 days at 20 °C) was
fruitless. Conversion of 15 into 17 was accomplished by
using the Barton-McCombie radical-induced deoxygen-
ation procedure.23 For this purpose, keto lactam 15 was
first reduced into alcohol 16a (NaBH4, MeOH, 1 h at 20
°C, 90%), which was converted into xanthate 16b ((i) NaH
in THF, 30 min at 20 °C; (ii) CS2, 30 min at 20 °C; (iii)
MeI, 15 min at 20 °C, 50%). Reduction of this xanthate
(n-Bu3SnH, AIBN, 4 h in toluene at reflux) finally gave
the desired lactam 17 with a 73% yield. B-N cyclization
of this lactam now proceeded in a straightforward manner
((i) 4 h in POCl3 at reflux; (ii) anion exchange with
aqueous LiClO4; (iii) NaBH4, MeOH, 12 h at 20 °C) to
furnish the expected tetracyclic derivative 1817a in 60%
yield (Scheme 4).
The precedent series of experiments clearly established
that the failure of the B-N cyclization of keto lactam 15
(and very likely 14) was due to the presence of the keto
group. Removal of the interfering keto group of 14 was
therefore examined. W-K reduction of the R-hydroxy
acid, obtained by saponification of 14 ((i) LiOH in MeOH,
2 h at 20 °C; (ii) hydrazine hydrate, diethylene glycol,
30 min at 160 °C; (iii) KOH, 4 h, 220 °C) was first
attempted.11c However, this reaction proved to be un-
satisfactory, delivering the desired “deoxygenated” de-
rivative in only very low yield (3%).24 The above,
alternative methodology involving the reduction of a
xanthate was therefore tried next. The first step in this
sequence required the chemoselective reduction of the
keto group of 14, a somewhat tricky problem due to the
presence of four carbonyl functions in this molecule. This
transformation was efficiently realized by using LiAIH(O-
t-Bu)3 as reducing agent (THF, 48 h, 20 °C, 85%).
that a concise, direct construction of the future ring E of
vincamine 1 from the tricyclic precursor 7 should require
the presence, at the subsequently created quaternary
carbon center, of a “masked” pyruvic acid ester side chain.
In this respect, the use of methyl 2-acetoxyacrylate
(13)13c,d as electrophilic partner in the above-mentioned
asymmetric Michael reaction would achieve two goals,
namely the installation of a quaternary stereocenter with
predictable configuration and simultaneous introduction
of an R-acetoxypropanoate appendage, equivalent, through
simple oxidation, to the desired pyruvic acid ester moiety.
Thus, we began our investigation by condensing enamino
lactam 12, prepared from 7 and (S)-1-phenylethylamine
(11) (of 96% ee) (12 h at reflux in toluene, with azeotropic
removal of water, catalytic p-TsOH, quantitative), with
methyl 2-acetoxyacrylate (13) (neat, hydroquinone, 24 h
at 60 °C, then 20% aqueous AcOH, 24 h at 40 °C).
Adduct (16S,20R)-14 was thus obtained in 66% yield as
1
a single diastereomer, as evidenced by H and 13C NMR
1
spectroscopy, and with a 96 ( 1% ee [determined by H
NMR, having added Eu (hfc)3 as chiral shift reagent].
Taking into account that the ee of the starting chiral
auxiliary amine 11 was 96%, the efficiency of the asym-
metric induction in the present Michael process was
therefore 99 ( 1%. The relative configuration at the two
newly created stereogenic centers C-16 and C-20 was
determined at the level of the pentacyclic lactone deriva-
tive 21 (vide infra).18 The portrayed absolute configura-
tion of adduct 14, although not definitely established,
paralleled the stereochemical outcome observed in the
condensation of acceptor 13 with the chiral imine derived
from 2-methylcyclohexanone and amine 11 (Scheme 3).22
With the necessary adduct 14 in hand, we next
envisaged the construction of a tetracyclic indoloquino-
(23) Barton, D. H. R.; Mc Combie, S. W. J . Chem. Soc., Perkin Trans.
1 1975, 1574-1585. Hartwig, W. Tetrahedron 1983, 39, 2609-2645.
(24) Unexpectedly, compound 17 (6%) was also isolated in this
reaction, along with unidentified indolic derivatives.
(22) Ambroise, L.; Desmae¨le, D.; Mahuteau, J .; d’Angelo, J . Tetra-
hedron Lett. 1994, 35, 9705-9708.

Enantioselective Synthesis of (+)-Vincamine
J . Org. Chem., Vol. 62, No. 12, 1997 3893
Sch em e 5
Sch em e 6
Sch em e 7
reduction of 22 (NaBH4 in AcOH, or catecholborane25)
proved to be unsuccessful. By contrast, treatment of 22
with LiH (48 h in toluene at reflux)26 gave the expected
unsaturated lactam 23 in 55% yield. Unfortunately, all
efforts at reducing selectively the hindered double bond
of the lactam ring of 23 invariably failed because of the
competitive reduction of the indole nucleus (Scheme 6).
An alternative way for reducing the keto group of 6
employed alcohols 24, obtained as a 3:1 epimeric mixture
by treating 6 with LiAIH(O-t-Bu)3 (THF, 4 h at 20 °C,
74%). However, derivatization of these alcohols was
again impeded by their marked propensity to cyclize into
lactones. This cyclization was thus accomplished with a
78% yield by heating major alcohol 24a for 3 h in benzene
at reflux, in the presence of amberlyst R15. B-N
cyclization of the resulting trans lactone 25 gave a 3:1
epimeric mixture of pentacyclic derivatives 26 ((i) POCl3
at reflux 5 h; (ii) anion exchange with aqueous LiClO4;
(iii) 1 bar of H2, 10% Pd-C, DMF, 40%). Unfortunately,
However, derivatization of the alcohols 19 thus obtained
was thwarted by their propensity to cyclize into lactones
20 (this partial, spontaneous cyclization was ended by
heating 19 for 24 h at reflux in benzene in the presence
of amberlyst R15, 72%). Epimeric lactones 20 (3:1
mixture) were separated by chromatography over silica
gel. Unfortunately, treatment of major trans isomer 20a
under B-N cyclization conditions ((i) POCl3, 14 h in
refluxing MeCN; (ii) 1 bar of H2, Pd-C) gave with a low
yield (20%) the pentacyclic derivative 21, exhibiting the
“unnatural” trans relationship between the ethyl sub-
stituent at C-20 and the H atom a C-21 (cleavage of the
acetoxy group took place during this operation). The
depicted relative stereochemistry in 21 was assigned by
1H NMR spectroscopy, including NOE experiments
(Scheme 5). In view of the above results, this route was
abandoned.
1
examination of the H NMR data of 26 revealed that, as
Secon d Rou te: Use of Meth yl Acr yla te a s a
Mich a el Accep tor . Having thus been forcibly diverted
from the “direct” route involving the introduction, in
enaminolactam 12, of an R-acetoxypropanoate side chain,
equivalent to a pyruvic acid ester moiety, an alternative
plan was devised, in which the key step was the Michael
addition of 12 to methyl acrylate. Indeed, it was our hope
that the propanoate appendage thus introduced in adduct
6 might be less prone to interfere with the subsequent
synthetic steps than the R-acetoxypropanoate side chain
of related adduct 14. Addition of 12 of 96% ee to methyl
acrylate proceeded smoothly (THF, hydroquinone, 48 h
at 60 °C, then 20% aqueous AcOH, 3 days at 40 °C) to
furnish adduct (R)-6 with a 70% yield and an ee of 89 (
1%, corresponding to an asymmetric induction of 92 (
1%, after correction of the optical purity of the chiral
auxiliary. The ee of adduct 6 was determined by 1H NMR
spectroscopy [after adding Eu(hfc)3 as chiral shift re-
agent], and its absolute configuration was unambiguously
established through the completion of the synthesis of
natural (+)-vincamine (1) (vide infra). In view of the
difficulties encountered in the first route, our next
synthetic efforts were focused upon the removal of the
keto group of adduct 6. In this respect, the reduction of
the corresponding p-tosylhydrazone 22 (prepared from
6, TsNHNH2, 10 days in MeOH at reflux, in 80% yield)
seemed particularly attractive. However, attempted
observed for the conversion 20a f 21, the major isomer
26a exhibited the undesired trans relationship between
the ethyl substituent at C-20 and the H atom at C-21
(Scheme 7).
In view of these results, we decided to reduce first the
interfering carbomethoxy group of 6. For this purpose,
6 was saponified into acid 27 (LiOH, H2O2, 5 h at 20 °C,
76%), which was then transformed into diols 28a ((i)
i-BuOCOCl, Et3N, 30 min at 0 °C; (ii) NaBH4, MeOH, 24
h at 20 °C, 75%). Selective protection of the primary
alcohol group of 28a (t-BuPh2SiCl, imidazole, DMF, 12
h at 20 °C, 68%) furnished the corresponding tert-
butyldiphenylsilyl ether derivatives 28b, which were next
converted into xanthates 29 ((i) NaH, THF, 20 min at 20
°C; (ii) CS2, 30 min; (iii) MeI, 15 min at 20 °C, 50%).27
Reduction of these xanthates (n-Bu3SnH, AIBN, 2 h in
toluene at reflux, 85%) finally gave the pivotal derivative
30 (Scheme 8).
At this juncture, two strategies have evolved for the
subsequent construction of an indolo[2,3-a]quinolizidine
(25) Kabalka, G. W.; Baker, J . D., J r. J . Org. Chem. 1975, 40, 1834-
1835.
(26) Caglioti, L.; Grasselli, P.; Selva, A. Gazz. Chim. Ital. 1964, 537-
551.
(27) The exact amount of HNa should be used in this reaction, in
order to minimize the condensation of the indole nitrogen atom with
CS2.

3894 J . Org. Chem., Vol. 62, No. 12, 1997
Desmae¨le et al.
Sch em e 8
Sch em e 10
homoeburnamonine 4 by using pyridinium dichromate,11h
this new access to these molecules constitutes a signifi-
cant improvement for transforming 33 into 4. Inciden-
tally, an unexpected result was obtained in the Dess-
Martin periodinane oxidation of alcohol 33 (CH2Cl2, 2 h
at 20 °C): R,â-unsaturated aldehyde 36 (4:1 mixture of
E/ Z stereomers) was the only compound isolated, al-
though with a modest yield (32%) (Scheme 10).
Sch em e 9
The alternative approach for converting 30 into vin-
camine 1 first involved the restoration of the propanoate
appendage. Preliminary experiments having established
that a “free” indole nucleus was not stable to the
conditions required for the direct oxidation of a primary
alcohol group into a carboxylic function (J ones reagent
or pyridinium dichromate), the indole nitrogen atom of
compound 30 was first protected as tert-butoxycarbonyl
(BOC) derivative 37a [NaH, (t-BuOCO)2O, THF, 3 h at
20 °C, 69%]. Selective deprotection of the tert-butyl-
diphenylsilyl group then gave primary alcohol 37b (n-
Bu4NF, THF, 2 h at 20 °C, 77%), which was transformed
into ester 38 ((i) pyridinium dichromate, DMF, 12 h at
20 °C; (ii) CH2N2, Et2O; (iii) HCO2H, 12 h at 20 °C, 46%).
of type 3: an approach in which compound 30 was
subjected to B-N cyclization prior to the restoration of
the correct oxidation state of the three-carbon appendage
and an alternative one, in which the order of these two
reactions was inverted. During the course of the first
approach, it became apparent that the tert-butyldiphen-
ylsilyl protecting group of 30 was too labile under the
B-N cyclization conditions. The related transformation
was therefore effected on the more robust pivaloate 31,
prepared from 30 ((i) n-Bu4NF, THF, 2 h at 20 °C; (ii)
t-BuCO2H, DCC, catalytic DMAP, CH2Cl2, 24 h at 20 °C,
65%). When exposed to the B-N cyclization conditions
((i) POCl3 at reflux, 6 h; (ii) anion exchange with LiClO4;
(iii) 1 bar of H2, Pd-C, DMF), 31 gave a 3:1 epimeric
mixture of tetracyclic derivatives 32 (45% yield), sepa-
rated by flash chromatography over silica gel. To our
delight, the major isomer 32b exhibited the “natural” cis
relationship between the ethyl appendage at C-20 and
the H group at C-21, as evidenced through its correlation
with authentic (+)-homoeburnamonine 4 (vide infra)
(Scheme 9).
With the requisite tetracycle 32b in hand, we next
examined its conversion into our goal vincamine 1.
Removal of the pivaloyl group of 32b (DIBAH, CH2Cl2, 2
h at -78 °C, 89%) furnished alcohol 3317n of 90%
enantiomeric purity, which proved to be identical in all
respects with an authentic sample prepared by reduction
of (+)-homoeburnamonine 4, a correlation that definitely
established the relative and absolute configuration of 33.
In other respects, since the transformation of 33 into
homoeburnamonine 4 has been accomplished, its present
preparation constitutes a formal synthesis of (+)-4, and
therefore of (+)-vincamine (1). However, considering the
modest yields reported for conversion 33f 4 (20-26%),17n
we decided to reexamine this transformation. After
extensive experimentation, we discovered that DMSO/
SO3-pyridine oxidation of 33 (Et3N, 30 min at 20 °C)14b
furnished with a 60% yield aldehyde 34, in equilibrium
with epimeric carbinolamines 35.17n In view of the fact
that compounds 34/35 have been efficiently oxidized into
B-N cyclization of 38 next afforded the iminium per-
13g
chlorate salt
((i) POCl3 at reflux, 3 h; (ii) anion
exchange with aqueous LiClO4), which, upon catalytic
hydrogenation (1 bar of H2, 10% Pd-C, DMF), furnished
with a 52% combined yield the cornerstone derivative (-)-
5,13g,h,14a of 91% enantiomeric purity, along with its
epimer 39, in a ratio of 6:1, respectively, which were
easily separated by chromatography over alumina. Com-
pound 5 was then enantiomerically enriched to ca. 100%
ee through the recrystallization of its (+)-dibenzoyl-D-
tartarate salt derivative.13g Physical and spectroscopic
data of upgraded 5 proved to be identical in all respects
with those reported in the literature. Moreover, base-
induced cyclization of 5 (NaHMDS, THF-toluene, 2 h
at 20 °C, 70%)14a gave enantiomerically pure (+)-homoe-
burnamonine 4, indistinguishable in all respects from an
authentic sample. Finally, compound 4 has been trans-
formed by using Oppolzer’s protocol (NaHMDS, t-
BuONO, toluene, 1 h at 50 °C, 65%)14a into a mixture of
syn/ anti oximes 40a , which were next converted through
the R-keto lactam intermediate 40b, according to the
Szantay procedure ((i) AcOH, p-TsOH, paraformalde-
hyde, 100 °C, 5 h; (ii) MeOH, t-BuOK, 2 h at 20 °C, 40%
overall yield),13g into our goal (+)-vincamine (1). Our
synthetic sample of (+)-1 also proved to be identical in
all respects with the natural material (Scheme 11).

Enantioselective Synthesis of (+)-Vincamine
J . Org. Chem., Vol. 62, No. 12, 1997 3895
Sch em e 11
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were recorded on a
capillary tube melting point apparatus and are uncorrected.
Infrared (IR) spectra were obtained as neat films between
NaCl plates or KBr pellets. The 1H NMR and 13C NMR spectra
were recorded in CDCl3, unless otherwise stated. Recognition
of methyl, methylene, methine, and quaternary carbon nuclei
in 13C NMR spectra rests on the J -modulated spin-echo
sequence or 2D-HMQC spectroscopy. Mass spectra analyses
were recorded by electron impact at 70 eV. Optical rotations
were measured at 589 nm in a 1 dm cell at specified temper-
ature. Analytical thin-layer chromatography was performed
on Merck silica gel 60F254 glass precoated plates (0.25 mm
layer). All liquid chromatography separations were performed
using Merck silica gel 60 (230-400 mesh ASTM). Diethyl
ether and tetrahydrofuran (THF) were distilled from Na-
benzophenone ketyl. Methanol was dried over magnesium and
distilled. Benzene and CH2Cl2 were distilled from calcium
hydride, under a nitrogen atmosphere. All reactions involving
air- or water-sensitive compounds were routinely conducted
in glassware that was flame-dried under a positive pressure
of nitrogen. Organic layers were dried over anhydrous MgSO4.
Chemicals obtained from commercial suppliers were used
without further purification. Elemental analyses were ob-
tained from the Service de microanalyse, Centre d’Etudes
Pharmaceutiques, Chaˆtenay-Malabry, France.
Ep ilog a n d Con clu sion
Although the present enantioselective synthesis of
(+)-1 realizes our original objective, it nevertheless
suffers from a vexing drawback, namely a poor overall
yield (0.16%), reflecting a lenghty experimental endeavor
(23 chemical steps from commercially available tryp-
tamine). This was essentially due to the transient
change of oxidation state of the ester group of adduct 6
(reduction, then reoxidation of the resulting alcohol into
the requisite carboxyl function), dictated by its interfer-
ence with the subsequent steps devoted to the removal
of the keto group. With a view to simplify the above
synthetic scheme, we recently sought an alternative route
for the direct removal of the keto group of 6, but
preserving the oxidation state of the ester function. The
W-K reduction of 6, a methodology that was a priori
postponed, considering the disappointing result obtained
in the related reduction of adduct 14 (vide supra), was
thus examined. To our delight, W-K reduction of keto
acid 27, derived from 6, ((i) hydrazine hydrate, diethylene
glycol, 30 min at 160 °C; (ii) KOH, 4 h at 220 °C; (iii)
acidification with 12 N HCl; (iv) CH2N2) furnished the
desired keto ester 38 with a satisfactory yield (55%).
Thus, this alternative constitutes a remarkable improve-
ment of our synthetic scheme, since the removal of the keto
group of adduct 6, which was originally accomplished in
11 steps with a 5% yield, now proceeded in only three
steps, with a 37% yield.
3-[[2-(1H-In d ol-3-yl)eth yl]a m in o]p r op a n oic Acid Eth yl
Ester (8). To a stirred solution of tryptamine (10 g, 62.5
mmol) in THF (20 mL) was added dropwise at 20 °C ethyl
acrylate (6.25 g, 62.5 mmol). After being stirred for 12 h, the
reaction mixture was concentrated under reduced pressure,
and the residual oil was directly chromatographed on silica
gel (CH2Cl2-MeOH, 9:1) to give adduct 8 (13.5 g, 83%) as a
yellow oil: IR (neat) 3428, 1729, 1623 cm-1 1H NMR (200
;
MHz) δ 1.20 (t, J ) 7.1 Hz, 3 H), 1.56 (broad s, 1H), 2.50 (t, J
) 6.6 Hz, 2H), 2.93 (t, J ) 6.6 Hz, 2H), 2.97 (s, 4H), 4.08 (q, J
) 7.1 Hz, 2H), 7.01 (d, J ) 2.3 Hz, 1H), 7.07-7.23 (m, 2H),
7.31 (d, J ) 6.4 Hz, 1H), 7.62 (d, J ) 6.4 Hz, 1H), 8.30 (broad
s, 1H); 13C NMR (50 MHz) δ 14.0 (CΗ3), 25.4 (CΗ2), 34.4 (CH2),
44.7 (CH2), 49.5 (CH2), 60.3 (CH2), 111.0 (CH), 113.2 (C), 118.6
(CH), 119.0 (CH), 121.8 (CH), 122.0 (CH), 127.2 (C), 136.4 (C),
172.5 (C); MS m/ e (rel intensity) 261 [(M + 1)•+, 3], 260 (M•+
3), 173 (9), 144, (16), 130 (100).
,
2-[[[3-(E t h oxyca r b on yl)p r op yl][2-(1H -in d ol-3-yl)et h -
yl]a m in o]ca r bon yl]bu ta n oic Acid Eth yl Ester (9). To a
mixture of amino ester 8 (12 g, 46.1 mmol), ethylmalonic acid
monoethyl ester (8.11 g, 50.7 mmol), and 1,4-bis(methylami-
no)pyridine (0.61 g, 5 mmol) in CH2Cl2 (100 mL) was added
1,3-dicyclohexylcarbodiimide (10.5 g, 51 mmol). The reaction
mixture was stirred at 20 °C for 18 h, and then the solid was
filtered off and washed with three 20 mL portions of CH2Cl2.
The combined fitrates were evaporated, and the residue was
chromatographed on silica gel (ethyl acetate-hexane, 1:1) to
yield amido ester 9 as an oil (15.4 g, 83%): IR (neat) 3400,
3350, 1731, 1640 cm-1 1H NMR (200 MHz) (due to amide
;
resonance most signals are splitted into two sets in a 60:40
ratio) δ 0.69 and 0.98 (2 t, J ) 7.4 Hz, 3H), 1.20-1.30 (m, 6H),
1.50-2.20 (m, 2H), 2.50-2.60 (m, 2H), 2.95-3.10 (m, 2H), 3.31
(t, J ) 7.2 Hz, 1H), 3.40-3.90 (m, 4H), 3.95-4.20 (m, 4H),
6.99 (d, J ) 1.9 Hz, 1H), 7.05-7.20 (m, 2H), 7.36 (t, J ) 6.6
Hz, 1H), 7.58 and 7.69 (2 d, J ) 7.3 Hz, 1H), 8.59 and 8.76 (2
broad s, 1H); MS m/ e (rel intensity) 402 (M•+, 0.35), 357 (1.3),
260 (5), 214 (7), 144 (20), 143 (100), 130 (43).
5-E t h yl-1-[2-(1H -in d ol-3-yl)e t h yl]-4-h yd r oxy-6-oxo-
1,2,5,6-tetr a h yd r o-3-p yr id in eca r boxylic Acid Eth yl Ester
(10). In a two-necked flask equipped with a magnetic stirrer,
a dropping funnel, and a reflux condenser was placed sodium
hydride (60% in mineral oil, 2.76 g, 69 mmol). The solid was
washed with hexane under nitrogen (2 × 15 mL) and covered
with THF (15 mL). A solution of amido ester 9 (14.5 g, 36.08
mmol) in THF (50 mL) was added dropwise at 20 °C, and the
resulting mixture was stirred for 4 h. After the mixture was
cooled to 0 °C, ethanol (20 mL) was cautiously added, and the
reaction mixture was poured into water (50 mL), acidified to
pH 5-6 with 2 N HCl, and extracted with CH2Cl2 (3 × 100
A concise, direct approach for the total enantioselective
synthesis of (+)-vincamine (1) has thus been developed.
The key tactical element was the asymmetric Michael
addition of chiral enamino lactam 12 to methyl acrylate
to create stereoselectively the crucial quaternary carbon
center at C-20. Thus, according to the strategy that was
ultimately adopted, involving the W-K reduction of the
keto group of adduct 6, (+)-vincamine (1) has been
synthesized by a linear sequence of 15 chemical opera-
tions, with an overall yield of 1.2% (mean yield per step:
74%), from commercially available tryptamine. In this
respect, this approach constitutes an efficient enantiose-
lective synthesis of (+)-1. Further extensions of the
present strategy are currently under investigation in our
laboratory.

3896 J . Org. Chem., Vol. 62, No. 12, 1997
Desmae¨le et al.
mL). The combined organic layers were dried and concen-
trated in vacuo. Chromatography (hexane-ethyl acetate, 40:
60) gave lactam 10 (10.2 g, 79%) as a white solid: mp 140-
142 °C (Et2O); IR (neat) 3500, 3300, 1679, 1642 cm-1; 1H NMR
(200 MHz) δ 0.86 (t, J ) 7.4 Hz, 3H), 1.30 (t, J ) 7.1 Hz, 3H),
1.80-2.20 (m, 2H), 3.08 (t, J ) 7.6 Hz, 2H), 3.17 (m, 1H), 3.60-
3.90 (m, 2H), 3.91 (dd, J ) 15.4, 3.0 Hz, 1H), 4.02 (dd, J )
15.4, 2.5 Hz, 1H), 4.24 (q, J ) 7.1 Hz, 2H), 7.04 (d, J ) 2.2 Hz,
1H), 7.00-7.20 (m, 2H), 7.36 (dd, J ) 7.0, 1.4 Hz, 1H), 7.69
(d, J ) 7.0 Hz, 1H), 8.36 (broad s, 1H), 11.93 (s, 1H); 13C NMR
(50 MHz) δ 9.8 (CH3), 14.2 (CH3), 23.0 (CH2), 23.9 (CH2), 45.1
(CH2), 46.2 (CH), 47.7 (CH2), 60.9 (CH2), 93.8 (C), 111.1 (CH),
112.6 (C), 118.7 (CH), 119.3 (CH), 122.0 (2 CH), 127.4 (C),
136.3 (C), 168.2 (C), 168.8 (C), 169.5 (C). Anal. Calcd for
C20H24N2O4: C, 67.41; H, 6.74; N, 7.86. Found: C, 67.35; H,
6.83; N, 7.89.
pressure, and 1 N HCl (5 mL) was added to the residual oil.
The mixture was extracted with CH2Cl2 (5 × 20 mL), and the
collected organic phases were washed with brine, dried, and
concentrated in vacuo. Chromatography on silica gel (cyclo-
hexane-ethyl acetate, 4:1) afforded keto ester 21 as a yellow
gum (0.99 g, 66%): [R]22 -11.9 (c ) 1.7; EtOH); IR (neat)
D
1
3420, 1747, 1710, 1635 cm-1; H NMR (400 MHz) δ 0.78 (t, J
) 7.5 Hz, 3H), 1.81 (q, J ) 7.5 Hz, 2H), 2.01(s, 3H), 2.37 (dd,
J ) 13.9, 8.9 Hz, 1H), 2.46-2.55 (m, 3H), 3.09 (t, J ) 7.1 Hz,
2H), 3.28 (dt, J ) 12.9, 6.2 Hz, 1H), 3.38 (ddd, J ) 12.9, 7.8,
5.7 Hz, 1H), 3.71(s, 3H), 3.75 (dt, J ) 13.3, 6.9 Hz, 1H), 3.93
(dt, J ) 13.3, 7.1 Hz, 1H), 4.92 (dd, J ) 13.9, 8.8 Hz, 1H), 7.09
(d, J ) 2.3 Hz, 1H), 7.13 (td, J ) 7.5, 1.1 Hz, 1H), 7.20 (td, J
) 7.5, 1.2 Hz, 1H), 7.36 (d, J ) 7.4 Hz, 1H), 7.67 (d, J ) 7.0
Hz, 1H), 8.10 (broad s, 1H); 13C NMR (100 MHz) δ 9.2 (CH3),
20.6 (CH3), 23.6 (CH2), 32.6 (CH2), 36.1 (CH2), 38.9 (CH2), 42.6
(CH2), 48.7 (CH2), 52.4 (CH3), 58.5 (C), 70.2 (CH), 111.3 (CH),
112.6 (C), 118.6 (CH), 119.5 (CH), 122.2(CH), 122.3 (CH), 127.2
(C), 136.3 (C), 169.9 (C), 170.0 (C), 170.1 (C), 207.7 (C). No
satisfactory microanalytical data could be obtained for that
uncrystalline material.
3-E t h yl-1-[2-(1H -in d ol-3-yl)e t h yl]-2,4-p ip e r id in e d i-
on e (7). To a stirred solution of keto ester 10 (4.0 g, 11.2
mmol) in DMF (20 mL) were successively added LiBr (1.07 g,
12.3 mmol) and water (0.40 mL, 22.4 mmol). The reaction
mixture was refluxed for 12 h. After cooling, the DMF was
removed under reduced pressure (0.1 Torr), and the residue
was suspended in water (30 mL) and extracted with EtOAc (3
× 30 mL). The combined organic phases were washed with
brine, dried over MgSO4, and evaporated. The crude residue
was chromatographed on silica gel (hexane-ethyl acetate, 40:
60) and further purified by recrystallization in Et2O to give
pure 7 (2.51 g, 79%) as white crystals: mp 132 °C; IR (KBr)
[3S-(3â,4a r,8a â)]-3-Acet oxy-4a -et h yl-6-[2-(1H -in d ol-3-
yl)eth yl]octa h yd r o-2,5-p yr a n o[3,2-c]p yr id in ed ion e (20a ).
To a solution of keto lactam 14 (3.50 g, 8.18 mmol) in THF
(70 mL) was added portionwise lithium tri-tert-butoxyalumi-
nohydride (4.16 g, 16.4 mmol). After the solution was stirred
for 48 h at 20 °C, 1 N HCl was added (70 mL), and the reaction
mixture was extracted with ethyl acetate (5 × 30 mL). The
collected organic phases were washed with brine, dried, and
concentrated in vacuo to leave crude epimeric alcohols 19 (2.99
g, 85% yield) as a yellow viscous oil. The above mixture of
alcohols was dissolved in benzene (30 mL) and placed in a
round-bottom flask equipped with a Dean-Stark trap filled
with 3 Å molecular sieves. Amberlyst R15 (2 g) was added,
and the reaction mixture was refluxed for 12 h. After cooling,
the reaction mixture was filtered, concentrated under reduced
pressure, and chromatographed on silica gel. Elution with
hexane-ethyl acetate (20:80) gave the less polar lactone 20a
(1.49 g, 54%); further elution afforded lactone 20b (0.50 g,
18%). Only the major isomer 20a is described: oil; IR (neat)
1
3320, 1720, 1650 cm-1; H NMR (300 MHz) δ 0.99 (t, J ) 7.4
Hz, 3H), 1.85-2.15 (m, 2H), 2.23 (ddd, J ) 17.4, 8.7, 5.8 Hz,
1H), 2.37 (dt, J ) 17.4, 5.0 Hz, 1H), 3.00-3.10 (m, 2H), 3.21
(dt, J ) 13.4, 5.5 Hz, 1H), 3.42 (ddd, J ) 13.4, 8.8, 5.1 Hz,
1H), 3.70-3.92 (m, 2H), 7.01 (d, J ) 2.2 Hz, 1H), 7.12 (td, J )
7.0, 1.2 Hz, 1H), 7.20 (td, J ) 7.0, 1.1 Hz, 1H), 7.36 (d, J ) 7.8
Hz, 1H), 7.64 (d, J ) 7.6 Hz, 1H), 8.28 (broad s, 1H); 13C NMR
(75 MHz) δ 11.8 (CΗ3), 18.9 (CH2), 23.7 (CH2), 38.0 (CH2), 43.5
(CH2), 48.9 (CH2), 58.7 (CH), 111.3 (CH), 112.7 (C), 118.5 (CH),
119.4 (CH), 122.1 (2 CH), 127.2 (C), 136.3 (C), 168.2 (C), 205.5
(C); MS m/ e (rel intensity) 284 (M•+, 9), 144 (13), 143 (100),
130 (48). Anal. Calcd for C17H20N2O2: C, 71.83; H, 7.04; N,
9.86. Found: C, 71.71; H, 7.07; N, 9.77.
1
3426, 1747, 1640 cm-1; H NMR (400 MHz) δ 1.03 (t, J ) 7.6
Hz, 3H), 1.50 (q, J ) 7.6 Hz, 2 H), 1.92 (dd, J ) 13.3, 11.7 Hz,
1H), 2.03 (m, 2H), 2.18 (s, 3H), 2.85 (dd, J ) 13.3, 7.6 Hz, 1H),
2.95-3.10 (m, 2H), 3.15-3.30 (m, 2H), 3.44-3.50 (m, 1H),
3.75-3.82 (m, 1H), 4.57 (dd, J ) 12.3, 5.1 Hz, 1H), 5.05 (dd, J
) 11.6, 7.6 Hz, 1H), 7.01 (d, J ) 2.3 Hz, 1H), 7.13 (td, J ) 7.4,
1.1 Hz, 1H), 7.20 (td, J ) 7.5, 1.0 Hz, 1H), 7.35 (d, J ) 8.2 Hz,
1H), 7.62 (d, J ) 7.4 Hz, 1H), 8.05 (broad s, 1H); 13C NMR (50
MHz) δ 8.2 (CH3), 20.6 (CH3), 21.4 (CH2), 22.7 (2 CH2), 31.7
(CH2), 44.4 (2 CH2), 47.9 (C), 67.0 (CH), 79.1 (CH), 111.3 (CH),
112.6 (C), 118.5 (CH), 119.4 (CH), 122.0 (CH), 122.1 (CH),
127.3 (C), 136.3 (C), 167.3 (C), 169.6 (C), 169.9 (C).
(S)-3-Eth yl-4-[(1-p h en yleth yl)a m in o]-1-[2-(1H-in d ol-3-
yl)eth yl]-5,6-d ih yd r o-2(1H)-p yr id in on e (12). A solution of
keto lactam 7 (3.60 g, 12.7 mmol) in toluene (20 mL) was
placed in a round-bottom flask equipped with a Dean-Stark
trap. (S)-(+)-1-Phenylethylamine (1.70 g, 14.0 mmol, [R]22
D
+39.1, neat, ee 96%) was added, followed by p-toluenesulfonic
acid (0.05 g, 0.26 mmol). The reaction mixture was refluxed
for 12 h with azeotropic removal of water. After cooling, the
reaction mixture was concentrated under reduced pressure to
give enamino lactam 12 as a pale yellow solid (4.90 g,
quantitative). Recrystallization in EtOAc afforded an analyti-
cal sample of 12 as white crystals: mp 158 °C; [R]22 +16.0 (c
[ 2 S -( 2 â,4 a â,1 4 b â,1 4 c r) ] -2 -H y d r o x y -1 4 c -e t h y l -
2,3,4a ,5,6,8,9,14,14b,14c-d eca -h yd r o-3-1H-in d olo[2,3-a ]p y-
r a n o[2,3-h ]qu in olizin on e (21). To a solution of lactam 20a
(100 mg, 0.25 mmol) in acetonitrile (7 mL) was added freshly
distilled POCl3 (1.10 g, 7.2 mmol), and the reaction mixture
was heated at reflux for 14 h. After evaporation to dryness,
the amorphous brown solid obtained was dissolved in ethyl
acetate (10 mL) and DMF (1 mL). Pd/C (10%, 50 mg) was
added, and the resulting suspension was stirred under hydro-
gen atmosphere (1 bar) for 12 h. The reaction mixture was
filtered through Celite and the solid residue washed with ethyl
acetate. The filtrate was evaporated, and the crude residue
was treated with a 30% ammonia solution. The mixture was
extracted with CH2Cl2, and the collected organic phases were
washed with brine, dried, and concentrated in vacuo. Chro-
matography on silica gel (cyclohexane-ethyl acetate, 1:1) gave
indoloquinolizidine 21 (17 mg, 20%) as an amorphous solid:
D
) 1.3, CHCl3); IR (KBr) 3425, 3190, 2969, 1614, 1591 cm-1
;
1H NMR (300 MHz) δ 1.11 (t, J ) 7.4 Hz, 3H), 1.50 (d, J ) 6.7
Hz, 3H), 1.85-2.05 (m, 1H), 2.18-2.35 (m, 1H), 2.30-2.55 (m,
2H), 2.91-3.20 (m, 4H), 3.62 (t, J ) 7.1 Hz, 2H), 4.23 (d, J )
6.9 Hz, 1H), 4.41-4.55 (m, 1H), 6.95 (d, J ) 2.5 Hz, 1H), 7.10
(t, J ) 7.3 Hz, 1H), 7.20 (t, J ) 7.5 Hz, 1H), 7.25-7.40 (m,
6H), 7.65 (d, J ) 7.2 Hz, 1H), 8.40 (broad s, 1H); 13C NMR (50
MHz) δ 12.9 (CH3), 17.3 (CH2), 24.0 (CH2), 24.9 (CH2), 25.0
(CH3), 44.6 (CH2), 47.9 (CH2), 52.5 (CH), 103.9 (C), 111.7 (CH),
113.6 (C), 118.8 (CH), 119.0 (CH), 121.7 (CH), 122.1 (CH),
125.2 (2 CH), 127.1 (CH), 128.4 (C), 128.8 (2 CH), 136.3 (C),
145.1 (C), 149.5 (C), 167.5 (C); MS m/ e (rel intensity) 387 (M•+
,
42), 358 (6), 257 (60), 245 (59), 244 (94), 143 (52), 130 (30),
105 (100). Anal. Calcd for C25H29N3O: C, 77.51; H, 7.49; N,
10.85. Found: C, 77.32; H, 7.68; N, 10.69.
[R -(R *,S *)]-r-(Ac e t y lo x y )-3-e t h y l-1-[2-(1H -in d ol-3-
yl)eth yl]-2,4-d ioxo-3-p ip er id in ep r op a n oic Acid Meth yl
Ester (14). A mixture of enaminolactam 12 (1.36 g, 3.51
mmol), freshly distilled methyl 2-acetoxyacrylate 13 (1.01 g,
7.0 mmol), and hydroquinone (20 mg) in THF (10 mL) was
stirred at 60 °C for 24 h. THF (20 mL) was added, followed
by 20% aqueous acetic acid (10 mL). The mixture was stirred
for 24 h at 40 °C. The solvent was removed under reduced
1
IR (neat) 3437, 2753, 1744 cm-1; H NMR (400 MHz) δ 0.44
(t, J ) 7.6 Hz, 3H), 1.30 (m, 1H), 1.89 (m, 1H), 1.95 (dd, J )
11.6, 11.3 Hz, 1H), 2.10 (qd, J ) 12.4, 5.0 Hz, 1H), 2.47 (m,
1H), 2.59 (m, 2H), 2.67 (ddd, J ) 14.9, 1.0, 0.5 Hz, 1H), 2.90
(m, 1H), 3.02 (ddd, J ) 10.4, 4.8, 1.4 Hz, 1H), 3.10 (dd, J )
11.6, 7.4 Hz, 1H), 3.15 (m, 1H), 3.19 (s, 1H), 3.25 (broad s,
1H), 4.23 (dd, J ) 12.4, 4.7 Hz, 1H), 4.38 (dd, J ) 11.3, 7.4

Enantioselective Synthesis of (+)-Vincamine
J . Org. Chem., Vol. 62, No. 12, 1997 3897
Hz, 1H), 7.11-7.22 (m, 2H), 7.34 (d, J ) 7.3 Hz, 1H), 7.48 (d,
J ) 7.8 Hz, 1H), 7.78 (broad s, 1H).
7.6 Hz, 2H), 7.03 (d, J ) 2.3 Hz, 1H), 7.06-7.22 (m, 2H), 7.35
(dd, J ) 7.2, 1.6 Hz, 1H), 7.68 (d, 1H, J ) 6.8 Hz), 8.27 (broad
s, 1H); MS m/ e (rel intensity) 298 (M•+, 6), 269 (65), 213 (12),
168 (20), 143 (100); HRMS calcd for C19H26N2O 298.2045, obsd
298.2054.
3,3-Diet h yl-1-[2-(1H -in d ol-3-yl)et h yl]-2,4-p ip er id ion e
(15). To a solution of keto lactam 7 (2.60 g, 9.15 mmol) in
anhydrous CH3CN (30 mL) were added dropwise at 0 °C
benzyltrimethylammonium hydroxide (Triton B, 40% methanol
solution, 9 mL, 20 mmol) and iodoethane (3.12 g, 20 mmol).
The reaction mixture was stirred at 20 °C. After 2 days,
additional portions of Triton B (2.25 mL, 5 mmol) and ethyl
iodide (0.78 g, 5.0 mmol) were added, and the stirring was
continued for 2 days. The reaction mixture was concentrated
in vacuo, and the residue was taken up into CH2Cl2 (50 mL)
and washed with 1 N HCl, sodium bicarbonate, and finally
brine. The collected organic phases were dried and concen-
trated in vacuo. Chromatography on silica gel (cyclohexane-
ethyl acetate, 1:1) afforded lactam 15 as a viscous oil (1.77 g,
62%): IR (neat) 3309, 1723, 1629 cm-1; 1H NMR (200 MHz) δ
0.74 (t, J ) 7.4 Hz, 6H), 1.84 (q, J ) 7.4 Hz, 4H), 2.46 (t, J )
6.4 Hz, 2H), 3.09 (t, J ) 7.2 Hz, 2H), 3.32 (t, J ) 6.4 Hz, 2H),
3.85 (t, J ) 7.3 Hz, 2H), 7.04 (d, J ) 2.3 Hz, 1H), 7.00-7.20
(m, 2H), 7.35 (d, J ) 7.4 Hz, 1H), 7.67 (d, J ) 7.5 Hz, 1H),
8.30 (s, 1H); 13C NMR (50 MHz) δ 9.7 (2 CΗ3), 23.6 (CH2), 30.7
(2 CH2), 40.0 (CH2), 42.7 (CH2), 49.0 (CH2), 62.3 (C), 111.4
(CH), 112.2 (C), 118.5 (CH), 119.2 (CH), 121.9 (CH), 122.1
(CH), 127.1 (C), 136.4 (C), 171.8 (C), 209.9 (C). Anal. Calcd
for C19H24N2O2: C, 73.05; H, 7.74; N, 8.97. Found: C, 72.89;
H, 7.76; N, 8.85.
(()-1,1-Dieth yl-1,2,3,4,6,7,12,12b-octa h yd r oin d olo[2,3-
a ]qu in olizin e (18). A mixture of lactam 17 (286 mg, 0.96
mmol) and freshly distilled POCl3 (4 mL) was heated at reflux
for 4 h. After evaporation to dryness, the brown gum obtained
was dissolved in CH2Cl2 (15 mL) and treated by a 1 M aqueous
solution of LiClO4 (5 mL). After the mixture was stirred for
10 min, the organic layer was separated and the aqueous phase
extracted with CH2Cl2 (2 × 10 mL). The collected organic
phases were washed with an aqueous solution of LiClO4, dried,
and concentrated in vacuo. The amorphous solid obtained was
dissolved in MeOH (5 mL) and cooled to 0 °C, and sodium
borohydride (400 mg, 10.6 mmol) was added portionwise. The
reaction mixture was stirred for 12 h and quenched with
aqueous sodium sulfate. The mixture was extracted with ethyl
acetate (4 × 20 mL), and the combined organic phases were
washed with brine, dried, and concentrated in vacuo. Chro-
matography on silica gel (cyclohexane-ethyl acetate, 60:40)
afforded indoloquinolizidine 18 (162 mg, 60%) as a viscous
yellow oil: 1H NMR (400 MHz) δ 0.69 (t, J ) 7.7 Hz, 3H), 1.10
(m, 1H), 1.17 (t, J ) 7.7 Hz, 3H), 1.40-1.59 (m, 3H), 1.76 (q,
J ) 7.7 Hz, 2H), 1.86 (m, 1H), 1.98 (dq, J ) 14.4, 7.7 Hz, 1H),
2.35 (td, J ) 11.9, 2.5 Hz, 1H), 2.59 (td, J ) 11.2, 7.5 Hz, 1H),
2.61-2.66 (m, 1H), 2.95-3.10 (m, 3H), 3.34 (s, 1H), 7.08 (td, J
) 7.4, 1.0 Hz, 1H), 7.14 (td, J ) 7.5, 1.1 Hz, 1H), 7.28 (d, J )
7.6 Hz, 1H), 7.47 (d, J ) 7.6 Hz, 1H), 7.83 (broad s, 1H); 13C
NMR (50 MHz) δ 7.3 (CH3), 8.0 (CH3), 21.9 (CH2), 22.1 (CH2),
25.5 (CH2), 29.9 (CH2), 31.4 (CH2), 39.4 (C), 54.2 (CH2), 56.9
(CH2), 66.5 (CH), 110.5 (CH), 111.4 (C), 117.8 (CH), 119.1 (CH),
121.3 (CH), 126.8 (C), 133.9 (C), 135.8 (C).
(()-3,3-Dieth yl-1-[2-(1H-in d ol-3-yl)eth yl]-4-h yd r oxy-2-
p ip er id in on e (16a ). To a solution of keto lactam 15 (1.76 g,
5.6 mmol) in ethanol (20 mL) was added portionwise 0.38 g
(10 mmol) of sodium borohydride. The mixture was stirred
at 20 °C for 1 h, poured into saturated aqueous ammonium
chloride (20 mL), and extracted with ethyl acetate (4 × 50 mL).
The combined organic extracts were driedm and the solvents
were removed under reduced pressure. The residue was
chromatographed on silica gel (hexane-ethyl acetate, 1:4) to
afford alcohol 16a (1.59 g, 90%), which crystallized on stand-
(R)-3-E t h yl-1-[2-(1H -in d ol-3-yl)et h yl]-2,4-d ioxo-3-p ip -
er id in ep r op a n oic Acid Meth yl Ester (6). A mixture of
enamino lactam 12 (4.8 g, 12.4 mmol), methyl acrylate (2.23
mL, 24.8 mmol), and hydroquinone (50 mg) in THF (10 mL)
was heated at 60 °C for 2 days. After the mixture was cooled
to 20 °C, 20% aqueous acetic acid (20 mL) and THF (50 mL)
were added, and the mixture was stirred for 72 h at 40 °C.
The solvents were removed under reduced pressure, and 1 N
HCl (100 mL) was added to the residual oil. The mixture was
extracted with CH2Cl2 (5 × 100 mL), and the collected organic
phases were washed with brine, dried, and concentrated in
vacuo. Chromatography on silica gel (hexane-ethyl acetate,
ing: mp 65 °C (Et2O); IR (neat) 3420-3250, 1610 cm-1
;
1H
NMR (200 MHz) δ 0.85 (t, J ) 7.4 Hz, 3H), 0.91 (t, J ) 7.4
Hz, 3H), 1.45 (m, 1H), 1.55-2.00 (m, 5H), 2.60 (broad s, 1H),
2.98 (t, J ) 7.4 Hz, 2H), 3.07-3.40 (m, 2H), 3.42-3.70 (m, 2H),
3.92 (t, J ) 5.8 Hz, 1H), 6.99 (d, J ) 2.3 Hz, 1H), 7.05-7.20
(m, 2H), 7.33 (d, J ) 7.4 Hz, 1H), 7.64 (d, J ) 8.4 Hz, 1H),
8.70 (s, 1H); 13C NMR (50 MHz) δ 8.9 (CH3), 9.0 (CH3), 23.0
(CH2), 24.3 (CH2), 26.5 (CH2), 27.3 (CH2), 44.0 (CH2), 48.4
(CH2), 49.7 (C), 69.0 (CH), 111.2 (CH), 113.1 (C), 118.7 (CH),
119.2 (CH), 121.9 (CH), 122.0 (CH), 127.4 (C), 136.3 (C), 172.9
(C). Anal. Calcd for C19H26N2O2: C, 72.58; H, 8.33; N, 8.90.
Found: C, 72.19; H, 8.36; N, 8.61.
4:1) gave keto lactam 6 (3.20 g, 70%) as a pale yellow oil: [R]22
D
+12.1 (EtOH, c ) 2.5); IR (neat) 3320, 1730, 1635 cm-1 1H
;
NMR (200 MHz) δ 0.75 (t, J ) 7.4 Hz, 3H), 1.84 (q, J ) 7.4
Hz, 2H), 2.08-2.22 (m, 4H), 2.46 (t, J ) 6.4 Hz, 2H), 3.08 (t,
J ) 7.1 Hz, 2H), 3.32 (t, J ) 6.4 Hz, 2H), 3.63 (s, 3H), 3.73-
3.91 (m, 2H), 7.08 (d, J ) 2.3 Hz, 1H), 7.12 (td, J ) 7.5, 1.0
Hz, 1H), 7.20 (td, J ) 7.5, 1.0 Hz, 1H), 7.36 (dd, J ) 7.4, 1.3
Hz, 1H), 7.68 (d, J ) 7.4 Hz, 1H), 8.40 (broad s, 1H); 13C NMR
(50 MHz) δ 9.3 (CH3), 23.4 (CH2), 29.6 (CH2), 30.1 (CH2), 30.5
(CH2), 39.1 (CH2), 42.6 (CH2), 48.8 (CH2), 51.5 (CH3), 60.5 (C),
111.3 (CH), 112.1 (C), 118.4 (CH), 119.2 (CH), 121.9 (CH),
122.2 (CH), 127.1 (C), 136.2 (C), 170.8 (C), 173.1 (C), 208.7
(C); MS m/ e (rel intensity) 370 (M•+, 8), 339 (3), 199 (3), 196
(3), 144 (15) 143 (100), 130 (28). Anal. Calcd for C21H26N2O4:
C, 68.09; H, 7.07; N, 7.56. Found: C, 67.91; H, 7.16; N, 7.55.
(R)-3-Eth yl-1-[2-(1H-in d ol-3-yl)eth yl]-2-oxo-4-[[(4-m eth -
ylp h en yl)su lfon yl]h yd r a zon o]-3-p ip er id in ep r op a n oic
Acid Meth yl Ester (22). A mixture of keto lactam 6 (2.00 g,
5.4 mmol) and (p-toluenesulfonyl)hydrazine (2.00 g, 10.8 mmol)
in MeOH (10 mL) was heated at reflux. After the mixture
was stirred for 2 days, an additional portion of (p-toluene-
sulfonyl)hydrazine (1.00 g, 5.4 mmol) in MeOH (2 mL) was
added. The operation was repeated each 48 h during 10 days.
The mixture was then concentrated under reduced pressure,
and the residue was chromatographed on silica gel (hexane-
ethyl acetate, 1:1) to give pure p-tosylhydrazone 22 (2.30 g,
80%) as a yellow amorphous solid: IR (neat) 3420, 1730, 1644,
3,3-Diet h yl-1-[2-(1H -in d ol-3-yl)et h yl]-2-p ip er id in on e
(17). In a 50 mL round-bottom flask was placed sodium
hydride (80% in mineral oil, 0.50 g, 16.6 mmol). The solid was
washed with hexane under nitrogen (2 × 5 mL) and covered
with THF (7 mL). A solution of alcohol 16a (1.0 g, 3.18 mmol)
and imidazole (0. 05 g, 0.7 mmol) in THF (4 mL) was added
dropwise at 20 °C. After the solution was stirred for 30 min
at 20 °C, carbon disulfide (1.25 mL, 20.9 mmol) was added,
the reaction mixture was stirred for 30 min, methyl iodide
(0.76 mL, 12 mmol) was then added, and the mixture was
stirred for a further 15 min period. The reaction mixture was
poured into 1 N HCl, (10 mL), extracted with CH2Cl2 (3 × 30
mL), dried, and concentrated in vacuo. Chromatography on
silica gel (hexane-ethyl acetate, 70:30) gave xanthate 16b
(0.62 g, 50%) as a pale yellow oil: IR (neat) 3426, 1626, 1226,
1057 (-OCS2Me) cm-1. To a solution of the above xanthate
16b (0.62 g, 1.6 mmol) and AIBN (10 mg) in degassed toluene
(15 mL), was added dropwise over 30 min tri-n-butyltin
hydride (1.40 g, 4.8 mmol). The reaction mixture was heated
at reflux for 4 h. After cooling, the solution was concentrated
in vacuo and the residue partitioned between acetonitrile and
petroleum ether. The separated acetonitrile layer was dis-
tilled, and the crude product was chromatographed on silica
gel (cyclohexane-ethyl acetate, 70:30) to give lactam 17 (0.35
g, 73%): IR (neat) 3312, 1612 cm-1; 1H NMR (200 MHz) δ 0.85
(t, J ) 7.4 Hz, 6H), 1.38-1.57 (m, 2H), 1.60-1.87 (m, 6H),
3.01 (t, J ) 7.6 Hz, 2H), 3.22 (t, J ) 5.7 Hz, 2H), 3.65 (t, J )
1621 cm-1
;
1H NMR (200 MHz) δ 0.57 (t, J ) 7.1 Hz, 3H),
1.75 (q, J ) 7.1 Hz, 2H), 1.96-2.08 (m, 4H), 2.21 (t, J ) 6.1
Hz, 2H), 2.43 (s, 3H), 3.01 (t, J ) 6.8 Hz, 2H), 3.14 (t, J ) 5.9

3898 J . Org. Chem., Vol. 62, No. 12, 1997
Desmae¨le et al.
Hz, 2H), 3.62 (s, 3H), 3.63-3.77 (m, 2H), 7.00 (d, J ) 2.3 Hz,
1H), 7.04 (td, J ) 7.6, 1.2 Hz 1H), 7.16 (td J ) 7.5, 1.2 Hz,
1H), 7.30 (d, J ) 8.4 Hz, 2H), 7.34 (d, J ) 7.6 Hz, 1H), 7.39 (s,
1H), 7.58 (d, J ) 7.5 Hz, 1H), 7.81 (d, J ) 8.4 Hz, 2H), 8.10
(broad s, 1H); 13C NMR (50 MHz) δ 8.9 (CH3), 21.6 (CH3), 23.6
(CH2), 25.3 (CH2), 29.3 (CH2), 31.1 (CH2), 31.5 (CH2), 43.2
(CH2), 49.0 (CH2), 51.5 (CH3), 54.0 (C), 111.3 (CH), 112.7 (C),
118.6 (CH), 119.4 (CH), 122.1 (CH), 122.4 (CH), 127.3 (C),
128.1 (2 CH), 129.5 (2 CH), 135.0 (C), 136.4 (C), 144.3 (C), 157.9
(C), 170.9 (C), 173.7 (C); Anal. Calcd for C28H34N4O5S: C,
62.45; H, 6.31; N, 10.40. Found: C, 62.28; H, 6.50; N, 10.31.
(R)-3-Eth yl-1-[2-(1H-in d ol-3-yl)eth yl]-2-oxo-1,2,3,6-tet-
r a h yd r o-3-p yr id in ep r op a n oic Acid Meth yl Ester (23). To
a suspension of LiH (70 mg, 8.80 mmol) in toluene (5 mL) was
added p-tosylhydrazone 22 (1.0 g, 1.86 mmol). The mixture
was heated at reflux for 48 h. After being cooled to 20 °C, the
mixture was poured into crushed ice and extracted with
CH2Cl2. The collected organic phases were washed with brine,
dried, and concentrated in vacuo. Chromatography on silica
gel (hexane-ethyl acetate, 1:1) gave unsaturated lactam 23
(362 mg, 55%) as a pale yellow oil: IR (neat) 3410, 1731, 1619,
through Celite and the solid residue washed with ethyl acetate.
The filtrate was evaporated, and the crude residue was treated
by a 30% ammonia solution. The mixture was extracted with
CH2Cl2, and the collected organic phases were washed with
brine, dried, and concentrated in vacuo. Chromatography on
silica gel (cyclohexane-ethyl acetate, 1:1) afforded indolo-
quinolizidine 26b (35 mg, 10%); further elution gave indolo-
quinolizidine 26a (105 mg, 30%). Only the major isomer 26a
is described: IR (neat) 3423, 2847, 2813, 1730 cm-1; 1H NMR
(200 MHz) δ 0.52 (t, J ) 7.6 Hz, 3H), 1.60 (m, 1H), 1.80-2.30
(m, 4 H), 2.40-3.20 (m, 9H) 3.16 (s, 1H), 4.52 (dd J ) 12.0,
4.8 Hz, 1H), 7.05-7.20 (m, 2H), 7.31 (d, J ) 7.2 Hz, 1H), 7.48
(d, J ) 7.2 Hz, 1H), 7.72 (broad s, 1H); 13C NMR (50 MHz) δ
8.6 (CH3), 19.5 (CH2), 21.9 (CH2), 27.0 (CH2), 27.3 (CH2), 27.4
(CH2), 40.8 (C), 52.9 (CH2), 53.9 (CH2), 67.4 (CH), 84.0 (CH),
110.8 (CH), 111.9 (C), 118.0 (CH), 119.6 (CH), 121.9 (CH),
126.7 (C), 132.2 (C), 135.9 (C), 171.2 (C).
(R)-3-E t h yl-1-[2-(1H -in d ol-3-yl)et h yl]-2,4-d ioxo-3-p ip -
er id in ep r op a n oic Acid (27). To a solution of keto lactam 6
(5.45 g, 20 mmol) in methanol (100 mL) was added dropwise
at 0 °C 680 mg (20 mmol) of lithium hydroxide in 30%
hydrogen peroxide (20 mL). After being stirring for 5 h at 20
°C, the reaction mixture was cooled to 0 °C and acidified to
pH 3 with 1 N HCl. The aqueous solution was extracted with
ethyl acetate (3 × 100 mL). The combined extracts were
cautiously washed with saturated aqueous sodium bisulfite,
dried, and evaporated in vacuo. The residue was chromato-
graphed on silica gel (CH2Cl2-MeOH, 9:1) to give acid 27 as a
viscous yellow oil (4.10 g, 76%): IR (neat) 3500-2500, 1725,
1494 cm-1 1H NMR (300 MHz) δ 0.80 (t, J ) 7.4 Hz, 3H),
;
1.22-1.35 (m, 1H), 1.58-1.68 (m, 2H),1.95-2.07 (m, 1H),
2.15-2.32 (m, 3H), 3.06 (t, J ) 7.8 Hz, 2H), 3.63 (s, 3H), 3.74
(dd J ) 7.8, 7.3 Hz, 2H), 3.85 (s, 2H), 5.35 (dt, J ) 10.2, 2.0
Hz, 1H), 5.79 (dt, J ) 10.2, 3.0 Hz, 1H), 7.06 (d, J ) 2.2 Hz,
1H), 7.12 (td, J ) 7.6, 1.0 Hz, 1H), 7.19 (td, J ) 7.8, 1.2 Hz,
1H), 7.36 (d, J ) 7.8 Hz, 1H), 7.69 (d, J ) 7.6 Hz, 1H), 8.18
(broad s, 1H); 13C NMR (75 MHz) δ 9.4 (CΗ3), 23.0 (CH2), 30.2
(CH2), 33.3 (CH2), 34.9 (CH2), 47.2 (C), 47.7 (CH2), 49.3 (CH2),
51.5 (CH3), 111.1 (CH), 113.0 (C), 118.8 (CH), 119.4 (CH), 122.0
(CH), 122.1 (CH), 122.2 (CH), 127.4 (C), 130.3 (CH), 136.3 (C),
171.1 (C), 173.8 (C).
1633 cm-1 1H NMR (200 MHz) δ 0.71 (t, J ) 7.3 Hz, 3H),
;
1.80 (q, J ) 7.3 Hz, 2H), 2.09 (broad s, 4H), 2.38 (t, J ) 6.2
Hz, 2H), 3.04 (t, J ) 6.7 Hz, 2H), 3.15-3.30 (m, 2H), 3.70 (dt,
J ) 13.3, 6.8 Hz, 1H), 3.90 (dt, J ) 13.3, 6.8 Hz, 1H), 7.00 (s,
1H), 7.05-7.21 (m, 2H), 7.33 (d, J ) 7.3 Hz, 1H), 7.61 (d, J )
7.1 Hz, 1H), 8.63 (broad s, 1H); 13C NMR (50 MHz) δ 9.3 (CH3),
23.3 (CH2), 29.8 (CH2), 30.1 (CH2), 30.4 (CH2), 39.0 (CH2), 42.6
(CH2), 48.8 (CH2), 60.6 (C), 111.4 (CH), 112.0 (C), 118.3 (CH),
119.3 (CH), 121.9 (CH), 122.5 (CH), 127.1 (C), 136.3 (C), 171.2
(C), 176.5 (C), 208.7 (C). No satisfactory microanalytical data
could be obtained for that uncrystalline material.
[4a R-(4a r,8a â)]-4a -E t h yl-6-[2-(1H -in d ol-3-yl)et h yl]oc-
ta h yd r o-2,5-p yr a n o[3,2-c]p yr id in ed ion e (25). To a solu-
tion of keto lactam 6 (1.10 g, 2.97 mmol) in THF (10 mL) was
added portionwise lithium tri-tert-butoxyaluminohydride (1.51
g, 5.95 mmol). After the solution was stirred for 4 h at 20 °C,
1 N HCl was added (20 mL), and the reaction mixture was
extracted with ethyl acetate (5 × 40 mL). The collected organic
phases were washed with brine, dried, and concentrated in
vacuo to leave crude epimeric alcohols 24a ,b (820 mg, 74%
yield) as a colorless viscous oil. The pure R-isomer 24a (610
mg, 1.64 mmol) obtained by chromatography on silica gel (ethyl
acetate-MeOH 98:2) was dissolved in benzene (10 mL),
Amberlyst R15 (0.1 g) was added, and the reaction mixture
was refluxed for 12 h with azeotropic removal of water. After
cooling, the mixture was filtered, concentrated under reduced
pressure, and chromatographed on silica gel. Elution with
ethyl acetate gave 25 (435 mg, 58%) as white crystals: mp
[3R-(3R*,4R*)]- a n d [3R-(3R*,4S*)]-3-Eth yl-1-[[2-(1H-
in d ol-3-yl)e t h yl]-3-[[3-(1,1-d im e t h yle t h yl)d ip h e n ylsi-
lyl]oxy]p r op yl]-4-h yd r oxy-2-p ip er id in on es (28b). To a
solution of acid 27 (2.20 g, 6.18 mmol) in THF (20 mL) were
added triethylamine (1.3 mL, 9.27 mmol) and isobutyl chlo-
roformate (1.27 g, 9.27 mmol). After being stirred for 30 min
at 0 °C, the solid was filtered off and washed with three 5 mL
portions of THF. The combined fitrates were cooled to 0 °C,
and NaBH4 (4.00 g, 0.1 mol) was added portionwise, followed
with 10 mL of methanol. After the mixture was stirred for 24
h at 20 °C, 3 N HCl (100 mL) was added, and the resulting
mixture was extracted with CH2Cl2 (4 × 100 mL). The
collected organic phases were washed with brine, dried, and
concentrated in vacuo. Chromatography on silica gel (CH2Cl2-
MeOH, 9:1) gave diols 28a (1.60 g, 75%) as a 3:1 mixture of
diastereomers: HRMS calcd for C20H28N2O3 344.209 99, found
344.209 69. The above mixture of diols (1.60 g, 4.65 mmol)
was dissolved into DMF (6 mL), and imidazole (1.60 g, 4.64
mmol) was added, followed by tert-butyldiphenylsilyl chloride
(1.40 mL, 4.80 mmol). The reaction mixture was stirred at
20 °C for 12 h, and then water was added and the mixture
extracted with ethyl acetate (3 × 20 mL). The collected organic
phases were dried and concentrated in vacuo. Chromatogra-
phy on silica gel (hexane-ethyl acetate, 1:1) afforded silyl
ethers 28b (1.84 g, 68%, 3:1 mixture of diastereomers) as a
pale yellow oil: IR (neat) 3435, 1618 cm-1; 1H NMR (200 MHz)
δ 0.90 (t, J ) 7.5 Hz, 3H), 1.06 (s, 9H), 1.30-2.10 (m, 8H),
2.98 (t, J ) 7.4 Hz, 2H), 3.12 (m, 1H), 3.32 (m, 1H), 3.50 (m,
1H), 3.65 (t, J ) 5.8 Hz, 2H), 3.70 (m, 1H), 3.89 (dd, J ) 7.0,
3.8 Hz, 1H), 6.95 (d, J ) 2.3 Hz, 1H), 7.10-7.20 (m, 2H), 7.29
(d, J ) 7.6 Hz, 1H), 7.35-7.45 (m, 7H), 7.60-7.75 (m, 5H),
8.13 (broad s, 1H); 13C NMR (50 MHz) δ 8.6 (CH3), 19.2 (C),
22.9 (CH2), 24.1 (CH2), 26.3 (CH2), 26.9 (3 CH3), 27.6 (CH2),
29.9 (CH2), 30.7 (CH2), 43.9 (CH2), 48.2 (CH2), 49.0 (C), 64.4
(CH2), 69.3 (CH), 111.1 (CH), 113.1 (C), 118.7 (CH), 119.2 (CH),
121.9 (CH), 122.1 (CH), 127.5 (C), 127.6 (4 CH), 129.6 (2 CH),
210 °C (ethyl acetate); IR (neat) 3440, 1741, 1640 cm-1
;
1H
NMR (200 MHz) δ 0.95 (t, J ) 7.5 Hz, 3H), 1.58 (q, J ) 7.5
Hz, 2 H), 1.90 (dt, J ) 14.1, 8.8 Hz, 1H), 2.00-2.20 (m, 2H),
2.25-2.50 (m, 1H), 2.50-2.80 (m, 2H), 2.90-3.10 (m, 2 H),
3.20-3.40 (m, 1H), 3.45 (dt, J ) 6.4, 6.9 Hz, 1H), 3.80 (dt, J )
6.4, 6.9 Hz, 1H), 4.37 (dd, J ) 12.0, 5.3 Hz, 1H), 7.02 (d, J )
2.2 Hz, 1H), 7.07-7.20 (m, 2H), 7.35 (d, J ) 7.3 Hz, 1H), 7.65
(d, J ) 7.3 Hz, 1H), 8.15 (s, 1H); 13C NMR (50 MHz) δ 8.3
(CH3), 21.6 (CH2), 22.7 (CH2), 23.0 (CH2), 24.7 (CH2), 27.8
(CH2), 42.9 (CH2), 44.3 (CH2), 47.9 (C), 78.3 (CH), 111.2 (CH),
112.5 (C), 118.4 (CH), 119.2 (CH), 121.9 (2 CH), 127.3 (CH),
136.2 (C), 170.7 (C), 171.3 (C);
[14b S-(14b â,14cr)]-14c-E t h yl-2,3,4a ,5,6,8,9,14,14b ,14c-
d eca h yd r o-3-1H-in d olo[2,3-a ]p yr a n o[2,3-h ]qu in olizin o-
n e (26a ). A mixture of lactam 25 (370 mg, 1.09 mmol) and
freshly distilled POCl3 (9 mL) was heated at reflux for 6 h.
After evaporation to dryness, the brown gum obtained was
dissolved in CH2Cl2 (15 mL) and treated by a 1 M aqueous
solution of LiClO4 (5 mL). After the solution was stirred for
10 min, the organic layer was separated and the aqueous phase
extracted with CH2Cl2 (2 × 10 mL). The collected organic
phases were washed with an aqueous solution of LiClO4, dried,
and concentrated in vacuo. The amorphous solid obtained was
taken up in DMF (3 mL), 10% Pd/C (200 mg) was added, and
the resulting suspension was stirred under hydrogen atmo-
sphere (1 bar) for 4 h. The reaction mixture was filtered

Enantioselective Synthesis of (+)-Vincamine
J . Org. Chem., Vol. 62, No. 12, 1997 3899
134.0 (2 C), 135.6 (4 CH), 136.3 (C), 172.9 (C); MS m/ e (rel
intensity) 582 (M•+, 3), 525 (24), 507 (2), 440 (4), 382 (3), 199
(35), 143 (100); HRMS calcd for C36H46N2O3Si 582.327 62,
found 582.327 77.
at reflux for 6 h. After evaporation to dryness, the brown gum
obtained was dissolved in CH2Cl2 (15 mL) and treated with a
1 M aqueous solution of LiClO4 (5 mL). After the mixture was
stirred for 10 min, the organic layer was separated and the
aqueous phase extracted with CH2Cl2 (2 × 10 mL). The
collected organic phases were washed with an aqueous solution
of LiClO4, dried, and concentrated in vacuo to give a brown
amorphous solid (560 mg, 93%). The crude iminium salt
obtained was dissolved in DMF (5 mL), 10% Pd/C (250 mg)
was added, and the resulting suspension was stirred under
hydrogen atmosphere (1 bar) for 4 h. The reaction mixture
was filtered through Celite and the solid residue washed with
CH2Cl2. The filtrate was evaporated, and the crude residue
was treated by a 30% ammonia solution. The mixture was
extracted with CH2Cl2, and the collected organic phases were
washed with brine, dried, and concentrated in vacuo. Chro-
matography on silica gel (cyclohexane-ethyl acetate, 60:40)
afforded trans-indoloquinolizidine 32a (57 mg, 12% from
lactam 31) as a viscous oil: IR (neat) 3445, 2801, 2753, 1721
(S)-3-Eth yl-1-[2-(1H-in d ol-3-yl)eth yl]-3-[3-[[1,1-d im eth -
yleth yl)d ip h en ylsilyl]oxy]p r op yl]-2-p ip er id in on e (30). In
a 50 mL round-bottom flask was placed sodium hydride (80%
in mineral oil, 100 mg, 3.33 mmol). The solid was washed with
hexane under nitrogen (2 × 5 mL) and covered with THF (7
mL). A solution of alcohols 28b (1.30 g, 2.23 mmol) and
imidazole (0.05 g, 0.7 mmol) in THF (10 mL) was added
dropwise at 20 °C. After the solution was stirred for 30 min
at 20 °C, carbon disulfide (0.4 mL, 6.65 mmol) was added, the
reaction mixture was stirred for 30 min, iodomethane (0.54 g,
3.80 mmol) was then added, and the mixture was stirred for
a further 15 min period. The reaction mixture was poured
into 1 N HCl (10 mL), extracted with CH2Cl2 (3 × 30 mL),
dried, and concentrated in vacuo. Chromatography (hexane-
ethyl acetate, 60:40) gave epimeric xanthates 29 (0.75 g,
50%): IR (neat) 3447, 1627, 1217, 1060 (-OCS2Me) cm-1; MS
m/ e (rel intensity) 672 (M•+, 0.15), 657 (0.25), 615 (0.8), 564
(2), 549 (10), 535 (8), 507 (35), 344 (10), 143 (100). To a solution
of xanthates 29 (0.75 g, 1.12 mmol) in degassed toluene (15
mL) containing AIBN (10 mg) was added dropwise over 30 min
tri-n-butyltin hydride (1.62 g, 5.58 mmol). The reaction
mixture was heated at reflux for 2 h. After cooling, the
solution was concentrated in vacuo and the residue partitioned
between acetonitrile and petroleum ether. The acetonitrile
layer was evaporated, and the crude product was chromato-
graphed on silica gel (cyclohexane-ethyl acetate, 80:20) to give
lactam 30 (0.54 g, 85%) as a colorless oil: IR (neat) 3485, 1635,
1
cm-1; H NMR (200 MHz) δ 0.67 (t, 3H, J ) 7.6 Hz), 1.28 (s,
9H), 1.08-2.10 (m, 12H), 2.35 (ddd, J ) 12.2, 12.0, 2.5 Hz,
1H), 2.40-2.80 (m, 2H), 2.85-3.10 (m, 3H), 3.29 (s, 1H), 4.21
(t, J ) 6.0 Hz, 2H), 7.07-7.24 (m, 2H), 7.30 (d, J ) 8.8 Hz,
1H), 7.46 (d, J ) 8.0 Hz, 1H), 8.01 (s, 1H), 13C NMR (50 MHz)
δ 7.4 (CH3), 22.1 (CH2), 22.2 (CH2), 23.3 (CH2), 25.5 (CH2), 27.4
(3 CH3), 32.4 (CH2) 35.2 (CH2), 39.2 (C), 39.3 (CH2), 54.1 (CH2),
56.9 (CH2), 65.2 (CH2), 67.2 (CH), 110.7 (CH), 111.8 (C), 117.8
(CH), 119.2 (CH), 121.4 (CH), 126.8 (C), 134.0 (C), 135.9 (C),
178.5 (C). Further elution gave cis-indoloquinolizidine 32b
(160 mg, 33% from lactam 31) as an oil: IR (neat) 3515, 3458,
2800, 2751, 1715 1467 cm-1 1H NMR (400 MHz) δ 1.08 (s,
;
1235 cm-1
;
1H NMR (200 MHz) δ 0.86 (t, J ) 7.4 Hz, 3H),
9H), 1.17 (t, J ) 7.5 Hz, 3H), 1.35-1.65 (m, 4H), 1.65-2.05
(m, 6H), 2.34 (td, J ) 12.4, 2.8 Hz, 1H), 2.45-2.80 (m, 2H),
2.80-3.10 (m, 3H), 3.32 (s, 1H), 3.88 (t, J ) 6.8 Hz, 2H), 7.07-
7.24 (m, 2H), 7.31 (d, J ) 8.8 Hz, 1H), 7.48 (d, J ) 8.0 Hz,
1H), 7.80 (broad s, 1H); 13C NMR (50 MHz) δ 8.0 (CH3), 21.9
(CH2), 22.1 (CH2), 22.5 (CH2), 27.1 (3 CH3), 29.0 (CH2), 31.4
(CH2), 32.2 (CH2), 38.7 (C), 39.3 (CH2), 54.1 (CH2), 56.9 (CH2),
65.0 (CH2), 66.4 (CH), 110.6 (CH), 111.8 (C), 117.9 (CH), 119.2
(CH), 121.4 (CH), 126.8 (C), 133.6 (C), 135.9 (C), 178.5 (C). No
satisfactory microanalytical data could be obtained for that
uncrystalline material.
1.06 (s, 9H), 1.44-1.88 (m, 10H), 3.01 (t, J ) 7.4 Hz, 2H), 3.28
(m, 2H), 3.50-3.80 (m, 4H), 6.95 (d, J ) 2.3 Hz, 1H), 7.05-
7.25 (m, 2H), 7.30-7.50 (m, 7H), 7.60-7.70 (m, 5H), 8.20
(broad s, 1H); 13C NMR (50 MHz) δ 8.7 (CH3), 19.2 (C), 20.0
(CH2), 23.2 (CH2), 26.9 (3 CH3), 27.6 (CH2), 29.3 (CH2), 31.4
(CH2), 34.8 (CH2), 44.6 (CH2), 48.6 (CH2), 48.9 (C), 64.5 (CH2),
111.1 (CH), 113.1 (C), 118.7 (CH), 119.1 (CH), 121.8 (CH),
122.1 (CH), 127.6 (C and 4 CH), 129.5 (2 CH), 134.1 (2 C),
135.5 (4 CH), 136.3 (C), 174.5 (C). No satisfactory microana-
lytical data could be obtained for that uncrystalline material.
(S)-2,2-Dim eth ylp r op a n oic Acid 3-[3-Eth yl-1-[2-(1H-
in d ol-3-yl)eth yl]-2-oxop ip er id in e-3-yl]p r op yl Ester (31).
To a solution of lactam 30 (3.22 g, 5.7 mmol) in dry THF (6
mL) was added dropwise a 1 M solution of tetra-n-butylam-
monium fluoride in THF (12 mL, 12 mmol). After the mixture
was stirred for 4 h, saturated NaCl was added, and the mixture
was extracted with CH2Cl2 (3 × 15 mL), dried, and concen-
trated in vacuo. To the crude residue dissolved in CH2Cl2 (20
mL) were successively added pivalic acid (0.70 g, 6.9 mmol),
4-(dimethylamino)pyridine (0.12 g, 1.0 mmol), and 1,3-dicy-
clohexylcarbodiimide (1.42 g, 6.9 mmol). The reaction mixture
was stirred at 20 °C for 24 h, and then the solid was filtered
off and washed with three 20 mL portions of CH2Cl2. The
combined filtrates were evaporated, and the residue was
chromatographed on silica gel (ethyl acetate-hexane, 1:1) to
(1S,cis)-1-Eth yl-1,2,3,4,6,7,12,12b-octa h yd r oin d olo[2,3-
a ]qu in olizin e-1-p r op a n ol (33). To a solution of ester 32b
(110 mg, 0.28 mmol) in CH2Cl2 (3 mL) was added dropwise at
-78 °C diisobutylaluminum hydride (1.25 mL, 1 M solution
in CH2Cl2). After 2 h, ethyl acetate (1 mL) was added, followed
by addition of saturated aqueous sodium/potassium tartrate
solution. After being stirred for 0.5 h, the reaction mixture
was filtered, and the aluminum salts collected were washed
with several portions of CH2Cl2. The organic layer was
separated and the aqueous phase extracted with CH2Cl2. The
combined extracts were dried and concentrated in vacuo. The
crude product was purified by flash chromatography on silica
gel (CH2Cl2/MeOH: 94/6) to give gave lactam 33 (75 mg, 89%)
as a pale yellow oil: [R]22 -97.2 (EtOH, c ) 1.7); IR (neat)
D
1
3515, 3380, 2947, 2805 cm-1; H NMR (200 MHz) δ 1.16 (t, J
yield amido ester 31 (1.52 g, 65% overall yield): [R]22 +30.9
) 7.6 Hz, 3H), 1.20-1.50 (m, 2H), 1.51-1.62 (m, 3H), 1.64-
2.0 (m, 6H), 2.36 (td J ) 11.4, 2.6 Hz, 1H,), 2.50-2.70 (m, 2H),
2.80-3.10 (m, 3H), 3.60 (s, 1H), 3.46 (td, J ) 6.8, 2.4 Hz, 2H),
7.06-7.20 (m, 2H), 7.32 (dd, J ) 6.8, 1.8 Hz, 1H), 7.48 (dd, J
) 6.6, 1.8 Hz, 1H), 7.94 (broad s, 1H); 13C NMR (50 MHz) δ
8.0 (CH3), 21.7 (CH2), 22.0 (CH2), 26.3 (CH2), 29.2 (CH2), 31.2
(CH2), 32.0 (CH2), 39.3 (C), 54.2 (CH2), 56.5 (CH2), 63.6 (CH2),
66.4 (CH), 110.7 (CH), 111.5 (C), 117.8 (CH), 119.2 (CH), 121.3
(CH), 126.9 (C), 133.6 (C), 135.9 (C).
D
(c ) 0.8, EtOH); IR (neat) 3291, 1728, 1615 cm-1
;
1H NMR
(200 MHz) δ 0.86 (t, J ) 7.4 Hz, 3H), 1.21 (s, 9H), 1.42-1.82
(m, 10H), 3.02 (t, J ) 7.4 Hz, 2H), 3.22 (t, J ) 5.6 Hz, 2H),
3.57-3.80 (m, 2H), 4.03 (t, J ) 5.6 Hz, 2H), 7.04 (d, J ) 2.3
Hz, 1H), 7.07-7.24 (m, 2H), 7.56 (d, J ) 7.4 Hz, 1H), 7.68 (d,
J ) 7.4 Hz, 1H), 8.20 (broad s, 1H); 13C NMR (50 MHz) δ 8.6
(CH3), 20.0 (CH2), 23.1 (CH2), 23.8 (CH2), 27.2 (3 CH3), 29.4
(CH2), 31.4 (CH2), 34.7 (CH2), 38.7 (C), 44.5 (CH2), 48.4 (CH2),
48.7 (C), 64.7 (CH2), 111.1 (CH), 113.1 (C), 118.7 (CH), 119.2
(CH), 121.8 (CH), 122.1 (CH), 127.5 (C), 136.3 (C), 174.2 (C),
178.0 (C). Anal. Calcd for C25H36N2O3: C, 72.78; H, 8.79; N,
6.79. Found: C, 72.55; H, 8.68; N, 6.68.
(S)-3-Eth yl-1-[2-[1-(ter t-bu toxyca r bon yl)-1H-in d ol-3-yl-
]et h yl]-3-(3-h yd r oxyp r op yl)-2-p ip er id in on e (37b ). So-
dium hydride (80% in mineral oil, 90 mg, 3.00 mmol) was
washed with hexane under nitrogen (2 × 5 mL) and covered
with THF (2 mL). Lactam 30 (520 mg, 0.92 mmol) in THF (5
mL) was added dropwise at 20 °C. After the mixture was
stirred for 10 min at 20 °C, di-tert-butyl dicarbonate (240 mg,
1.10 mmol) in THF (2 mL) was added, and the resulting
mixture was stirred for 3 h. The mixture was poured into
saturated ammonium chloride and extracted with ethyl acetate
(1S,tr a n s)-2,2-Dim eth ylp r op a n oic Acid 3-[1-Eth yl-1-
[1,2,3,4,6,7,12,12b-octah ydr oin dolo[2,3-a ]qu in olizin e]]pr o-
p yl Ester (32a ) a n d (1S,cis)-2,2-d im eth ylp r op a n oic Acid
3-[1-Eth yl-1-[1,2,3,4,6,7,12,12b-octah ydr oin dolo[2,3-a ]qu in -
olizin e]]p r op yl Ester (32b). A mixture of lactam 31 (500
mg, 1.21 mmol) and freshly distilled POCl3 (10 mL) was heated

3900 J . Org. Chem., Vol. 62, No. 12, 1997
Desmae¨le et al.
(3 × 10 mL). The collected organic phases were dried and
concentrated in vacuo to leave protected indole 37a (422 mg,
69%) as a viscous oil that was used in the next step without
further purification. To a solution of the above lactam 37a
(422 mg, 0.63 mmol) in dry THF (5 mL) was added dropwise
at 0 °C a 1 M solution of tetra-n-butylammonium fluoride in
THF (1.0 mL, 1.00 mmol). After the mixture was stirred for
4 h at 20 °C, saturated NaCl was added, and the resulting
mixture was extracted with CH2Cl2 (3 × 20 mL), dried, and
concentrated in vacuo. The residue was chromatographed on
silica gel (ethyl acetate-cyclohexane, 1:4) to give alcohol 37b
(208 mg, 77%) as a viscous oil: IR (neat) 3449, 1731, 1622
nitrogen evolution was observed. The reaction mixture was
then concentrated in vacuo, and chromatography on silica gel
(ethyl acetate-hexane, 70:30) gave pure lactam 38 (1.90 g,
55%).
(1S,tr a n s)-1-Eth yl-1,2,3,4,6,7,12,12b-octah ydr oin dolo[2,3-
a ]qu in olizin e-1-p r op a n oic Acid Meth yl Ester (39) a n d
(1S,cis)-1-E t h yl-1,2,3,4,6,7,12,12b -oct a h yd r oin d olo[2,3-
a ]qu in olizin e-1-p r op a n oic Acid Meth yl Ester (5). To a
solution of lactam 38 (1.21 g, 3.4 mmol) in acetonitrile (4 mL)
was added freshly distilled POCl3 (8 mL). The mixture was
heated at 100 °C until no more starting material could be
detected by TLC (4 h). After evaporation to dryness, the brown
gum obtained was dissolved in CH2Cl2 (15 mL), 1 M aqueous
LiClO4 (5 mL) was added, and stirring was continued for 10
min. The organic layer was separated and the aqueous phase
extracted with CH2Cl2 (2 × 10 mL). The collected organic
phases were washed with an aqueous solution of LiClO4, dried,
and concentrated in vacuo to give a brown amorphous solid
(1.39 g): IR (neat) 3600, 1742, 1630, 1540 cm-1; 1H NMR (200
MHz) δ 0.68 (t, J ) 7.2 Hz, 3H), 1.50-2.60 (m, 10 H), 3.15 (m,
2H), 3.65 (s, 3H), 3.94 (m, 2H), 4.07 (m, 2H), 7.16 (t, J ) 7.7
Hz, 1H), 7.40 (t, J ) 7.6 Hz, 1H), 7.55 (d, J ) 8.1 Hz, 1H),
7.78 (d, J ) 8.5 Hz, 1H), 10.70 (broad s, 1H); 13C NMR (DMSO-
d6, 50 MHz) δ 8.0 (CH3), 17.3 (CH2), 18.2 (CH2), 25.7 (CH2),
28.1 (CH2), 29.5 (CH2), 31.5 (CH2), 43.1 (C), 51.5 (CH3), 53.7
(CH2), 54.5 (CH2), 113.3 (CH), 121.3 (C and CH), 121.5 (CH),
122.8 (C), 124.8 (CH), 128.4 (C), 140.3 (C), 170.2 (C), 172.7
(C). The crude iminium salt obtained above was dissolved in
DMF (10 mL). Pd/C (10%, 600 mg) was added, and the
resulting suspension was stirred under hydrogen atmosphere
(1 bar) for 5 h. The reaction mixture was filtered through
Celite and the solid residue washed with CH2Cl2. The filtrate
was evaporated, and the residue was treated by a 30%
ammonia solution. The mixture was extracted with CH2Cl2,
and the collected organic phases were washed with brine,
dried, and concentrated in vacuo. Chromatography on silica
gel (cyclohexane-ethyl acetate, 60:40) afforded a 6:1 mixture
of cis- and trans-indoloquinolizidine 5 and 39 (600 mg, 52%).
Separation was achieved by chromatography on alumina
(CH2Cl2-MeOH, 90:10) to give in the first fractions the trans
isomer 39 (86 mg) [IR (neat) 3366, 2800, 2755, 1731 cm-1; 1H
NMR (200 MHz) δ 0.69 (t, J ) 7.4 Hz, 3H), 1.01-1.60 (m, 9H),
1.70-2.70 (m, 11H), 2.90-3.10 (m, 3H), 3.34 (s, 1H), 3.81 (s,
3H), 7.00-7.20 (m, 2H), 7.37 (d, 1H, J ) 7.2 Hz), 7.55 (d, 1H,
J ) 6.9 Hz), 8.90 (broad s, 1H); 13C NMR (50 MHz) δ 7.2 (CΗ3),
21.9 (2 CH2), 25.3 (CH2), 28.2 (CH2), 31.9 (CH2), 33.0 (CH2),
39.4 (C), 52.1(CH3), 54.0 (CH2), 56.9 (CH2), 66.4 (CH), 110.9
(CH), 111.6 (C), 117.6 (CH), 119.0 (CH), 121.1 (CH), 126.6 (C),
133.0 (C), 136.2 (C), 175.8. (C)]; further elution gave cis-
1
cm-1; H NMR (200 MHz) δ 0.85 (t, J ) 7.4 Hz, 3H), 1.64 (s,
9H), 1.40-1.86 (m, 10H), 2.32 (s, 1H), 2.92 (t, J ) 7.2 Hz, 2H),
3.21 (m, 2H), 3.45-3.70 (m, 4H), 7.23 (td, J ) 7.4, 1.4 Hz, 1H),
7.30 (td, J ) 7.4, 1.4 Hz, 1H), 7.40 (s, 1H), 7.62 (d, J ) 7.4 Hz,
1H), 8.10 (d, J ) 7.4 Hz, 1H); 13C NMR (50 MHz) δ 8.6 (CH3),
19.9 (CH2), 22.8 (CH2), 27.7 (CH2), 28.2 (3 CH3), 29.0 (CH2),
31.8 (CH2), 34.2 (CH2), 44.6 (C), 48.1 (CH2), 49.0 (CH2), 62.8
(CH2), 83.4 (C), 115.1 (CH), 117.8 (C), 119.0 (CH), 122.4 (CH),
123.2 (CH), 124.3 (CH), 130.4 (C), 135.4 (C), 149.9 (C), 175.0
(C).
(S )-3-E t h yl-1-[2-(1-H -in d ol-3-yl)e t h yl]-2-oxo-3-p ip e -
r id in ep r op a n oic Acid Meth yl Ester (38). F r om th e
Oxid a tion of Alcoh ol 37b. To a stirred solution of pyri-
dinium dichromate (0.75 g, 2 mmol) in DMF (2 mL) was added
rapidly at 20 °C alcohol 37b (170 mg, 0.4 mmol) in DMF (1
mL). After 12 h, the reaction mixture was diluted with CH2Cl2
(50 mL) and filtered through Florisil. The solid was washed
twice with 10 mL portions of CH2Cl2. The combined filtrates
were evaporated to leave a yellow oil that was used directly
in the next step. To a cooled solution of the crude acid in a
1:3 mixture of CH2Cl2-Et2O (10 mL), was added an etheral
solution of diazomethane until no more nitrogen evolution was
observed. The reaction mixture was then concentrated in
vacuo. The residue was dissolved in formic acid (5 mL), and
the reaction mixture was stirred at 20 °C for 12 h. The
reaction mixture was then concentrated in vacuo. The residue
was taken into CH2Cl2 (20 mL), washed with sodium bicarbon-
ate, dried, and concentrated. Purification by chromatograpy
on silica gel (ethyl acetate-hexane, 30:70) gave ester 38 (65
mg, 46% overall yield from 37b) as a viscous yellow oil: [R]22
D
+15.3 (c ) 1.9, EtOH); IR (neat) 3283, 1738, 1616 cm-1 1H
;
NMR (400 MHz) δ 0.84 (t, J ) 7.4 Hz, 3H), 1.45-1.60 (m, 1H),
1.65-1.95 (m, 6H), 2.28-2.40 (m, 2H), 3.00 (t, J ) 7.4 Hz 2H),
3.19 (t, J ) 5.7 Hz, 2H), 3.57-3.70 (m, 2H), 3.66 (s , 3H), 7.05
(s, 1H), 7.13 (t, J ) 6.9 Hz, 1H), 7.16 (t, J ) 7.0 Hz, 1H), 7.35
(d, J ) 8.0 Hz, 1H), 7.67 (d, J ) 7.8 Hz, 1H), 8.10 (broad s,
1H); 13C NMR (50 MHz) δ 8.4 (CH3), 19.6 (CH2), 23.0 (CH2),
29.5 (CH2), 30.8 (CH2), 33.1 (CH2), 44.0 (CH2), 48.6 (CH2), 48.7
(C), 51.4 (CH3), 111.2 (CH), 112.5 (C), 118.5 (CH), 118.9 (CH),
121.6 (CH), 122.2 (CH), 127.3 (C), 136.3 (C), 173.6 (C), 174.2
(C); MS m/ e (rel intensity) 356 (M•+, 6), 325 (2), 214 (4), 182
(11), 171 (6), 143 (100); HRMS calcd for C21H28N2O3 356.20999,
obsd 356.20975. Anal. Calcd for C21H28N2O3: C, 70.76; H,
7.92; N, 7.85. Found: C, 70.62; H, 7.99; N, 7.75. F r om th e
Wolff-Kish n er Red u ction of Keto Acid 27. To a degassed
solution of acid 27 (3.56 g, 10 mmol) in diethylene glycol (75
mL) placed in a round flask equipped with a short distillation
path was added hydrazine hydrate (12 mL, 0.38 mmol). The
temperature of the reaction mixture was raised to 160 °C over
a 1 h period, allowing the distillation of water and hydrazine
excess. The reaction mixture was cooled to 20 °C, and crushed
molten KOH (13 g, 0.23 mol) was added in one portion. The
mixture was then heated to 220-225 °C until no nitrogen
evolution could be observed. After 4 h, the reaction mixture
was cooled to 150 °C, and the major part of the solvent was
removed under reduced pressure (0.05 Torr). The residue was
cooled to 0 °C, taken up into water (50 mL), and partially
neutralized with concentrated HCl (30 mL). The mixture was
extracted twice with CH2Cl2 (20 mL). The aqueous phase was
then acidified to pH 2 with 3 N HCl. The mixture was
extracted with CH2Cl2, and the collected organic phases were
washed with brine, dried, and concentrated in vacuo. The
residue was dissolved in Et2O (10 mL) and cooled to 0 °C, and
an etheral solution of diazomethane was added until no more
indoloquinolizidine 5 (514 mg) as a viscous oil: [R]22 -113 (c
D
) 2, CH2Cl2). Recrystallization of the dibenzoyl-D-tartarate
salt13g gave enantiomerically pure 5: [R]22 -124 (c ) 2,
D
CH2Cl2) (lit.13g [R]22D -121 (c ) 2.02, CH2Cl2)); IR (neat) 3511,
1
2801, 2753, 1730 cm-1; H NMR (400 MHz) δ 1.18 (t, J ) 7.6
Hz, 3H), 1.40-1.60 (m, 4 H), 1.69 (dq, J ) 15.7, 7.6, 1H), 1.81
(dq, J ) 15.7, 7.6 Hz, 1H), 1.90 (m, 1H), 2.05-2.15 (m, 2H),
2.20 (m, 1H), 2.36 (ddd, J ) 12.1, 12.0, 2.4 Hz, 1H), 2.55 (ddd,
J ) 11.0, 10.9, 3.6 Hz, 1H), 2.65 (m, 1H), 2.90 (m, 1H), 3.00
(m, 2H), 3.34 (s, 1H), 3.57 (s, 3H), 7.08 (td, J ) 6.8, 1.5 Hz,
1H), 7.14 (td,J ) 6.8, 1.5 Hz, 1H), 7.31 (d, J ) 7.9 Hz, 1H),
7.47 (d, J ) 7.6 Hz, 1H), 7.81 (broad s, 1H); 13C NMR (50 MHz)
δ 8.1 (CH3), 21.9 (2 CH2), 28.6 (2 CH2), 30.9 (CH2), 32.2 (CH2),
39.3 (C), 51.5 (CH3), 54.1 (CH2), 56.7 (CH2), 66.2 (CH), 110.7
(CH), 111.8 (C), 117.8 (CH), 119.2 (CH), 121.4 (CH), 126.8 (C),
133.4 (C), 135.8 (C), 174.7 (C), MS (IC, CH4) m/ e (rel intensity)
341 ((M + H).+, 100). Anal. Calcd for C21H28N2O2: C, 74.08;
H, 8.29; N, 8.22. Found: C, 73.86; H, 8.42; N, 8.04.
D-Hom oebu r n a m en in -14(15H)-on e (4). To a stirred
solution of enantiopure ester 5 (295 mg, 0.87 mmol) in
anhydrous toluene (5 mL) was added dropwise at 0 °C a
solution of sodium bis(trimethylsilyl)amide (2 M in THF, 1.5
mL, 3 mmol). After being stirred for 2 h at 20 °C, the reaction
mixture was cooled to 0 °C, and saturated NaHCO3 solution
(4 mL) was added. The organic layer was separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The
collected organic phases were washed with brine, dried, and

Enantioselective Synthesis of (+)-Vincamine
J . Org. Chem., Vol. 62, No. 12, 1997 3901
concentrated in vacuo to leave a solid that was purified by
chromatography (hexane-ethyl acetate, 50:50, Rf 0.43). Crys-
tallization in methanol gave pure homoeburnamonine 4 (188
and potassium tert-butoxide (10 mg) was added. After being
stirred at 20 °C for 2 h, the reaction mixture was poured into
brine (4 mL) and extracted with CH2Cl2 (3 × 10 mL). The
collected organic phases were dried and concentrated in vacuo
to leave a white solid. Crystallization in methanol gave pure
(+)-vincamine (1) (39 mg, 40%) as white crystals: mp 230-
mg, 70%) as white crystals: mp 154-155 °C; [R]22 +20.3 (c
D
) 1.4, DMF) (lit.14a mp 154-155 °C; [R]22D +20.7 (c ) 1, DMF));
IR (KBr): 2934, 2860, 2805, 1699 cm-1; 1H NMR (400 MHz) δ
0.89 (t, J ) 7.5 Hz, 3H), 1.03 (td, J ) 13.6, 3.7 Hz, 1H), 1.42
(dt, , J ) 12.8, 3.1 Hz, 1H), 1.50-1.63 (m, 3H), 1.68 (dddd, J
) 13.1, 12.8, 12.8, 3.8 Hz, 1 H), 2.05-2.20 (m, 2H), 2.46 (ddd,
J ) 16.0, 4.1, 2.3 Hz, 1H), 2.66 (m, 1H), 2.71 (m, 1H), 2.76 (m,
1H), 2.80 (m, 1H), 3.00 (ddd, J ) 12.4, 12.4, 4.5 Hz, 1H), 3.11
(dddd, J ) 16.0, 16.0, 5.0, 3.0 Hz, 1H), 3.32 (dd, J ) 13.0, 5.3
Hz, 1H), 4.08 (s, 1H), 7.27-7.35 (m, 2H), 7.44 (d J ) 6.9 Hz,
1H), 8.46 (d, J ) 7.8 Hz, 1H); 13C NMR (50 MHz) δ 7.6 (CH3),
17.3 (CH2), 21.2 (CH2), 28.4 (CH2), 31.9 (2 CH2), 32.5 (CH2),
37.6 (C), 46.3 (CH2), 51.5 (CH2), 62.4 (CH), 117.5 (2 CH and
C), 123.5 (CH), 124.6 (CH), 130.1 (C), 133.1 (C), 136.1 (C), 173.2
(C). Anal. Calcd for C20H24N2O: C, 77.88; H, 7.84; N, 9.08.
Found: C, 77.66; H, 7.78; N, 9.06. The thus obtained (+)-
lactam 4 was shown to be identical with an authentic sample
provided by Roussel-Uclaf, on the basis of a mixed melting
point and the specific rotation.
232 °C; [R]22 +44.0 (c ) 1.4, pyridine) (lit.13i mp 234-235 °C;
D
[R]22D +44.5 (c ) 1, pyridine)); IR (KBr) 3400-2400, 1748 cm-1
;
1H NMR (200 MHz) δ 0.91 (t, J ) 7.5 Hz, 3H), 1.30-1.80 (m,
5H), 2.10 (d, J ) 14.3, 1H), 2.24 (d, J ) 14.2, 1H), 2.27 (m,
1H), 2.42-2.70 (m, 3H), 2.90-3.10 (m, 1H), 3.20-3.40 (m, 2H),
3.82 (s, 3H), 3.92 (s, 1H), 4.64 (s, 1H), 7.08-7.18 (m, 3H), 7.45-
7.52 (m, 1H); 13C NMR (50 MHz) δ 7.6 (CH3), 16.8 (CH2), 20.8
(CH2), 25.1 (CH2), 28.9 (CH2), 35.1 (C), 44.4 (CH2), 44.6 (CH2),
50.9 (CH2), 54.2 (CH3), 59.1 (CH), 81.9 (C), 105.9 (C), 110.3
(CH), 118.4 (CH), 120.2 (CH), 121.6 (CH), 129.0 (C), 131.4 (C),
134.4 (C), 174.4 (C). Anal. Calcd for C21H26N2O3: C, 71.16;
H, 7.33; N, 7.90. Found: C, 71.05; H, 7.40; N, 7.80. The
obtained (+)-vincamine (1) was shown to be identical with an
authentic sample provided by Pr. J ean Le´vy (Faculte´ de
Pharmacie de Reims, France), on the basis of a mixed melting
point and the specific rotation.
(+)-Vin ca m in e (1). To a solution of D-homoeburnamonine
4 (130 mg, 0.42 mmol) in toluene (0.8 mL) were successively
added tert-butyl nitrite (950 mg, 9.2 mmol) and sodium
bis(trimethylsilyl)amide (2 M in THF, 0.6 mL, 1.2 mmol). The
reaction mixture was stirred for 1.5 h at 50 °C. After cooling,
the solution was poured into saturated ammonium chloride.
The organic layer was separated, and the aqueous phase was
extracted with ethyl acetate. The collected organic phases
were washed with brine, dried, and concentrated in vacuo.
Purification by chromatography (hexane-ethyl acetate, 50:50)
gave a mixture of isomeric oximes 40a (92 mg, 65%) as an
amorphous solid. To a solution of the above mixture of oximes
(90 mg, 0.26 mmol) in glacial acetic acid (2 mL) were added
dry p-TsOH (100 mg, 0.26 mmol) and paraformaldehyde (100
mg, 0.26 mmol). The reaction mixture was heated at 100-
105 °C for 5 h under stirring. After cooling, the solution was
poured into 10 mL of ice-water, treated with 25% NH4OH to
pH 9, and extracted with CH2Cl2 (3 × 10 mL). The combined
extracts were dried, filtered, and evaporated to dryness. The
residue (40b) was dissolved in anhydrous methanol (2 mL),
Ack n ow led gm en t. The following colleagues of the
Centre d’EÄ tudes Pharmaceutiques of Chaˆtenay-Malabry
are gratefully acknowledged: Dr. Lydia Ambroise for
performing preliminary experiments, Dr. J acqueline
Mahuteau for valuable assistance with NMR studies,
and Mrs. Sophie Mairesse-Lebrun for elemental analy-
ses. We would like to thank also Dr. J ean Buendia
(Socie´te´ Roussel-Uclaf, Romainville, France) for a gen-
erous gift of (+)-homoeburnamonine and Pr. J ean Le´vy
(Faculte´ de Pharmacie de Reims, France) for a sample
of (+)-vincamine.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H or 13C
NMR spectra (32 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current mastehead page for ordering information.
J O9622690