A general strategy for the synthesis of vincamajine-related indole alkaloids: Stereocontrolled total synthesis of (+)-dehydrovoachalotine, (-)-vincamajinine, and (-)-11-methoxy-17-epivincamajine as well as the related quebrachidine diol, vincamajine diol,

A General Strategy for the Synthesis of Vincamajine-Related

Indole Alkaloids: Stereocontrolled Total Synthesis of

(+)-Dehydrovoachalotine, (-)-Vincamajinine, and

(-)-11-Methoxy-17-epivincamajine as Well as the Related

Quebrachidine Diol, Vincamajine Diol, and Vincarinol¹

Jianming Yu,^†Xiangyu Z. Wearing, and James M. Cook*

Department of Chemistry, University of WisconsinsMilwaukee, Milwaukee, Wisconsin 53201

capncook@uwm.edu

Received November 8, 2004

The highly convergent stereocontrolled total synthesis of (-)-vincamajinine (7), (-)-11-methoxy-

17-epivincamajine (9), and the oxygen-bridged (+)-dehydrovoachalotine (22) are described. Key steps

in the synthesis of 7 and 9 involved the stereospecific enolate-driven palladium-catalyzed cross-

coupling reaction, a Tollens reaction, an acid-assisted intramolecular cyclization to form the C(7)-

C(17) quaternary center, and two stereospecific reductions. The efficiency of this strategy is

illustrated by the completion of the synthesis of 7 and 9 in 16 [from ^D-(+)-tryptophan methyl ester

17] and 17 (from the Scho¨llkopf chiral auxiliary 27) reaction vessels, respectively. This constitutes

the first total synthesis of these indole alkaloids and provides the first regiospecific route to 11-

methoxy-substituted ajmaline/vincamajine-related alkaloids. The synthesis of 22 required a novel

DDQ-mediated cyclization to furnish the C(6)-O(17) bond, executed in stereospecific fashion.

Completion of these syntheses illustrates a concise and versatile strategy for the synthesis of

vincamajine-related alkaloids, which has also been employed to prepare the related compounds

quebrachidine diol (53), vincamajine diol (56), and vincarinol (59).

Introduction

While more than 84 ajmaline/vincamajine/quebrachi-

dine indole alkaloids have been isolated, which includes

the bisindoles which contain at least one monomeric

ajmaline/vincamajine/quebrachidine unit, those which

contain a carbomethoxy group at C(16) form a unique

series (Figure 1).⁵Studies by Houghton et al.⁶have

demonstrated that a number of alkaloids from various

parts of Alstonia scholaris, A. macrophylla, and A.

glaucescens, collected from Thailand, exhibited pro-

nounced antiplasmodial activity. (+)-Alstomacroline (1),

a bisindole alkaloid, was isolated from the root bark of

A. macrophylla collected in Thailand and exhibited potent

activity against drug-resistant strains of malaria para-

Indole alkaloid natural products are an important

source of biologically active compounds.^2,3Ajmaline-

related indole alkaloids contain the polycyclic ajmaline

ring system, the E-olefinic C(19)-C(20) unsaturated

members of which belong to the sarpagine, vincamajine,

and quebrachidine series.⁴

^†Current address: FMC Corp., P.O. Box 8, Princeton, NJ 08543.

(1) Portions of this work were communicated earlier; see: (a) Yu,

J.; Wearing, X. Z.; Cook, J. M. J. Am. Chem. Soc. 2004, 126, 1358-

1359. (b) Yu, J.; Wearing, X. Z.; Cook, J. M. Tetrahedron Lett. 2004,

45, 3937-3940.

(2) Wright, C. W.; Phillipson, J. D. Phytother. Res. 1990, 4, 127-

139.

(3) Hamaker, L. K.; Cook, J. M. The Synthesis of Macroline Related

Alkaloids. In Alkaloids: Chemical and Biological Perspectives; Pelle-

tier, S. W., Ed.; Elsevier Science: New York, 1995; Vol. 9, pp 23-84.

(4) The “biogenetic numbering” of indole alkaloids is used in the text;

see: Le Men, J.; Taylor, W. I. Experientia 1965, 21, 508-510.

(5) For a recent review, see: Lounasmaa, M.; Hanhinen, P. The

Ajmaline Group of Indole Alkaloids. In The Alkaloids; Cordell, G. A.,

Ed.; Academic Press: San Diego, 2001; Vol. 55, Chapter 1, pp 1-87.

(6) Keawpradub, N.; Kirby, G. C.; Steele, J. C.; Houghton, P. J.

Planta Med. 1999, 65, 690-694.

Published on Web 04/19/2005

J. Org. Chem. 2005, 70, 3963-3979

3963

Yu et al.

basified ground leaves of Aspidosperma quebracho-

blanco¹¹and later from many other species.^10,12The

related (-)-vincamajine (4), an N_a-methyl analogue of

(+)-quebrachidine, has also been obtained from many

species.^12e,g,j,l,13Both (-)-11-methoxyvincamajine (5)^9band

10-methoxyvincamajine (6)^12d,14have only been isolated

from Alstonia species. The isolation of (-)-vincamajinine

(7, 17-epivincamajine) from the aerial parts of Vinca

major was reported by Zhukovich and Vachnadze in

1985.¹⁵(+)-Vincarine (8), an N_a-H analogue of (-)-

vincamajinine, was isolated from Vinca erecta, Vinca

herbacea, and Vinca major.¹⁶The constitution and rela-

tive configuration of these indole alkaloids were deter-

mined on the basis of NMR studies and chemical corre-

lation or confirmed by chemical conversion and spectral

data.^9-16These indole alkaloids typically possess a unique

rigid, caged hexacyclic carbon skeleton which contains

seven stereogenic centers (carbons 2, 3, 5, 7, 15, 16, and

17) as well as the key olefinic bond at C(19)-C(20) in

the E-configuration. However, the configuration of the

C(17)-hydroxyl group in 3-6 [17(S)] is different from that

in 7-9 [17(R)]. Due to the paucity of these natural

(10) Lyon, R. L.; Fong, H. H. S.; Farnsworth, N. R.; Svoboda, G. H.

J. Pharm. Sci. 1973, 62, 218-221.

(11) Gorman, M.; Burlingame, A. L.; Biemann, K. Tetrahedron Lett.

1963, 39-46.

(12) (a) Atta-ur-Rahman; Qureshi, M. M.; Ali, S. S.; De Silva, K. T.

D.; Silva, W. S. J. Fitoterapia 1990, 61, 91-92. (b) Martinez, P. J. A.;

Rodriguez, A. M. R.; Dehesa, G. M.; Machua, V. M. Rev. Cubana Quim.

1988, 4, 43-51. (c) Allam, K.; Beutler, J. A.; Le Quesne, P. W. J. Nat.

Prod. 1987, 50, 623-625. (d) Caron, C.; Yachaoui, Y.; Massiot, G.; Le

Men-Olivier, L.; Pusset, T.; Se´venet, T. Phytochemistry 1984, 23, 2355-

2357. (e) Vercauteren, J.; Massiot, G.; Se´venet, T.; Le´vy, J.; Le Men-

Olivier, L.; Le Men, J. Phytochemistry 1979, 18, 1729-1731. (f)

Bruneton, J.; Cave´, A.; Moretti, C. Fitoterapia 1979, 50, 123-126. (g)

Titeux, F.; Richard, B.; Debray, M. M.; Le Men-Olivier, L.; Le Men, J.

Phytochemistry 1975, 14, 1648-1649. (h) Bombardelli, E.; Bonati, A.;

Danieli, B.; Gabetta, B.; Mustich, G. Fitoterapia 1974, 45, 183-187.

(i) Douzoua, L.; Mansour, M.; Debray, M. M.; Le Men-Olivier, L.; Le

Men, J. Phytochemistry 1974, 13, 1994-1995. (j) Aynilian, G. H.;

Farnsworth, N. R. Lloydia 1974, 37, 299-308. (k) Burke, D. E.; Cook,

G. A.; Cook, J. M.; Haller, K.; Lazar, H. A.; Le Quesne, P. W.

Phytochemistry 1973, 12, 1467-1474. (l) Hart, N. K.; Johns, S. R.;

Lamberton, J. A. Aust. J. Chem. 1972, 25, 2739-2741. (m) Combes,

G.; Fonzes, L.; Winternitz, F. Phytochemistry 1966, 5, 1065-1073.

(13) (a) Kam, T.-S.; Iek, I.-H.; Choo, Y.-M. Phytochemistry 1999, 51,

839-844. (b) Che´rif, A.; Massiot, G.; Le Men-Olivier, L.; Pusset, J.;

Labarre, S. Phytochemistry 1989, 28, 667-670. (c) Ghedira, K.; Ze´ches-

Hanrot, M.; Richard, B.; Massiot, G.; Le Men-Olivier, L.; Se´venet, T.;

Goh, S. H. Phytochemistry 1988, 27, 3955-3962. (d) Ratnayake, C.

K.; Arambewela, L. S. R.; De Silva, K. T. D.; Atta-ur-Rahman; Alvi,

K. A. Phytochemistry 1987, 26, 828-829. (e) Ratnayake, C. K.;

Arambewela, L. S. R.; De Silva, K. T. D.; Atta-ur-Rahman; Alvi, K. A.

Phytochemistry 1987, 26, 868-870. (f) Lewin, G.; Tamini, O.; Cabalion,

P.; Poisson, J. Ann. Pharm. Fr. 1981, 39, 273-275. (g) Aliev, A. M.;

Babaev, N. A. Farmatsiya 1976, 25, 30-32. (h) Mamatas-Kalamaras,

S.; Se´venet, T.; Thal, C.; Potier, P. Phytochemistry 1975, 14, 1849-

1854. (i) Cosson, J. P. The´se d’Universite´ de Paris-Sud, Orsay, 1975.

(j) Crow, W. D.; Hancox, N. C.; Johns, S. R.; Lamberton, S. Aust. J.

Chem. 1970, 23, 2489-2501. (k) Patel, M. B.; Poisson, J.; Pousset, J.

L.; Rowson, J. M. J. Pharm. Pharmacol. 1965, 17, 323-324. (l) Plat,

M.; Lemay, R.; Le Men, J.; Janot, M. M.; Djerassi, C.; Budzikiewicz,

H. Bull. Soc. Chim. Fr. 1965, 2497-2501. (m) Strouf, O.; Kavkova, K.

Chem. Listy 1962, 56, 987-1028. (n) Gosset, J.; Le Men, J.; Janot, M.

M.; Djerassi, C. Bull. Soc. Chim. Fr. 1961, 1033-1035.

FIGURE 1. Vincamajine-related group of indole alkaloids.

FIGURE 2. Formation of (+)-alstomacroline (1).⁸

sites (IC₅₀of 1.12 µM against the K1 strain of Plasmo-

dium falciparum).^6,7A partial synthesis of 1 was reported

by Le Quesne et al.⁸via a biomimetic coupling process

by condensation of the two components, (+)-quebrachi-

dine (3) and macroline (10) (Figure 2). The related

bisindole alkaloid (-)-11-methoxy-10-(11′-vincorinyl)-17-

epivincamajine (2) was isolated in 1992 from the leaves

of Tonduzia pettieri (Alstonia pettieri),^9aaccompanied by

the monomeric base (-)-11-methoxy-17-epivincamajine

(9).⁹The latter two alkaloids have not been evaluated

for antimalarial activity to date. (+)-Quebrachidine (3),

reported to show psychosedative and adrenergic activ-

ity,¹⁰was first isolated in 1963 from the extract of the

(14) (a) Lewin, G.; Kunesch, N.; Poisson, J.; Se´venet, T. J. Indian

Chem. Soc. 1978, 55, 1096-1098. (b) Lewin, G.; Kunesch, N.; Cave´,

A.; Se´venet, T.; Poisson, J. Phytochem. 1975, 14, 2067-2071.

(15) Zhukovich, E. N.; Vachnadze, V. Yu. Khim. Prir. Soedin. 1985,

5, 720.

(16) (a) Yuldashev, P. K.; Yunusov, S. Y. Dokl. Akad. Nauk SSSR

1964, 154, 1412-1413. (b) Yuldashev, P. K.; Yunusov, S. Y. Khim. Prir.

Soedin. 1965, 1, 110-113. (c) Vachnadze, V. Y.; Malikov, V. M.;

Mudzhiri, K. S.; Yunusov, S. Y. Soobshch. Akad. Nauk Gruz. SSR 1972,

66, 97-99. (d) Zhukovich, E. N.; Vachnadze, V. Y. Khim. Prir. Soedin.

1984, 4, 533-534.

(7) Keawpradub, N.; Houghton, P. J. Phytochemistry 1997, 46, 757-

762.

(8) Burke, D. E.; Cook, J. M.; Le Quesne, P. W. J. Am. Chem. Soc.

1973, 95, 546-552.

(9) (a) Morfaux, A.-M.; Mouton, P.; Massiot, G.; Le Men-Olivier, L.

Phytochemistry 1992, 31, 1079-1082. (b) Morfaux, A.-M.; Mouton, P.;

Massiot, G.; Le Men-Olivier, L. Phytochemistry 1990, 29, 3345-3349.

3964 J. Org. Chem., Vol. 70, No. 10, 2005

Synthesis of Vincamajine-Related Indole Alkaloids

SCHEME 1. Retrosynthetic Analysis of

(-)-Vincamajinine (7)

FIGURE 3. Postulated biogenesis of the vincamajine-related

indole alkaloids.

compounds isolated to date, biological activity has not

been reported for alkaloids 4-9.

The complex architecture of the above-mentioned in-

dole alkaloids, coupled with their largely unexplored

potential in medicine or as tools for biological studies,

rendered these indoles as attractive targets for total

synthesis. An approach to the synthesis of (-)-3 has been

described by Martin et al.;¹⁷however, no total synthesis

of 1-9 has yet been reported. Herein, we provide a

detailed account of the first synthesis of (-)-vincamaji-

nine (7), the 11-methoxy analogue (-)-9, and (+)-dehy-

drovoachalotine (22)¹⁸as well as the preparation of the

related compounds, (+)-quebrachidine diol (53), (+)-

vincamajine diol (56), and (+)-vincarinol (59).

indole nucleus and the electrophilic aldehyde following

the elegant work of Bartlett, Taylor, and van Tamelen.^20,21

Results and Discussion

Synthetic Plan. Close inspection of the structures of

these indole alkaloids (1-9) indicated the major chal-

lenges for the syntheses included the generation of the

C(16) quaternary carbon center, complete control of the

stereochemistry at C(2) and C(17), stereospecific genera-

tion of the C(19)-C(20) ethylidene function in the E-

configuration, and development of an efficient route for

the preparation of the rigid caged hexacyclic system

which contained a C(16) carbomethoxy group. Most

notably, a biogenetic scheme for formation of the these

indole alkaloids has been reviewed by Lounasmaa et al.¹⁹

which included the proposals of Bartlett, Taylor,²⁰and

van Tamelen,²¹amenable perhaps to formation of the

quaternary C(7)-C(17) bond. As illustrated in Figure 3,

cyclization of polyneuridine aldehyde (11) was postulated

to occur by intramolecular cyclization to furnish the

hexacyclic ring system in indolenine (12) which could

stereoselectively be reduced by an NAD(P)-H-assisted

process from the si face to provide (+)-3.¹⁹As a means to

construct the strained hexacyclic framework, this biomi-

metic intramolecular cyclization was attractive as long

as a stereospecific means to introduce the C(17) hydroxyl

group could be developed. It was believed that experi-

mental conditions could be found to take advantage of

the vicinal location of the nucleophilic â-position of the

The disconnection strategy summarized in Scheme 1

(for vincamajinine 7) envisioned here involved oxidation

of the C(16)-hydroxymethyl function of diol (13) available

from the acid-assisted reductive cyclization of 14 via the

previous contributions of Bartlett, Taylor, and van

Tamelen.^20,21The latter aldehyde 14 contained four of the

seven stereogenic centers in 7 as well as the olefinic bond

at C(19)-C(20) in the E configuration. Since the synthetic

strategy for the formation of the C7-C17 bond of 13 was

based on the treatment of aldehyde 14 under acidic

conditions, the presence of an aldehydic group at the

desired axial position (C-17) and a quaternary carbon

center at C(16) in 14 rendered the formation of the

quaternary carbon center at C(16) a pivotal process in

this strategy. As illustrated, disconnection of aldehyde

14 unveiled N_a-methylvellosimine 16 (via 15) as a puta-

tive synthetic precursor. It was believed that the qua-

ternary center of aldehyde 14 could be obtained from

aldehyde 16 via the Tollens reaction²²in one step and

the diol 15, which resulted, might be selectively oxidized

to give 14 in a stereoslective fashion. The required 16,

in turn, had earlier been constructed in our laboratories.²³

Efforts that resulted in completion of this strategy are

described below.

Construction of the Hexacyclic Core 13 Required

for the Synthesis of (-)-Vincamajinine (7). The

stereocontrolled total synthesis of (-)-13 began with the

readily available N_a-methylvellosimine 16 obtained from

D-(+)-tryptophan methyl ester in stereospecific fashion

in eight reaction vessels in 39% overall yield.²³This had

been previously achieved via a combination of the asym-

metric Pictet-Spengler reaction, Dieckmann cyclization,

(17) For an approach to the synthesis of (+)-3, see: Chen, X.; Martin,

S. F. 214th ACS National Meeting, Las Vegas, NV, Sep 9-11, 1997;

American Chemical Society: Washington, DC, 1997; ORGN 204.

(18) For the isolation of (+)-dehydrovoachalotine (22), see: (a)

Pinchon, T.-M.; Nuzillard, J.-M.; Richard, B.; Massiot, G.; Le Men-

Olivier, L.; Se´venet, T. Phytochemistry 1990, 29, 3341-3344. (b)

Gabetta, B.; Martinelli, E. M.; Mustich, G. Fitoterapia 1974, 45, 32-

36. (c) Tirions, G.; Kaisin, M.; Braekman, J. C.; Pecher, J.; Martin, R.

H. Chimia 1968, 22, 87-88.

(19) Koskinen A.; Lounasmaa, M. Planta Med. 1982, 45, 248-249.

(20) Bartlett, M. F.; Sklar, R.; Taylor, W. I.; Schlittler, E.; Anai, R.

L. S.; Beak, P.; Bringi, N. V.; Wenkert, E. J. Am. Chem. Soc. 1962, 84,

622-630.

(21) van Tamelen, E. E.; Haarstad, V. B.; Orvis, R. L. Tetrahedron

1968, 24, 687-704.

(22) (a) Munoz, S.; Gokel, G. W. J. Am. Chem. Soc. 1993, 115, 4899-

4900. (b) Parry-Jones, R.; Kumar, J. Educ. Chem. 1985, 22, 114-116.

(23) (a) Yu, J.; Wang, T.; Liu, X.; Deschamps, J.; Flippen-Anderson,

J.; Liao, X.; Cook, J. M. J. Org. Chem. 2003, 68, 7565-7581. (b) Yu,

J.; Wearing, X. Z.; Cook, J. M. Tetrahedron Lett. 2003, 44, 543-547.

J. Org. Chem, Vol. 70, No. 10, 2005 3965

Yu et al.

TABLE 1. Reaction Conditions for the Formation of Diol 15 via the Tollens Reaction

entry

condition

reaction time (h)

isolated yield (%)

1

37% aq HCHO (5 equiv), KOH (2 N, 10 equiv), MeOH, rt

37% aq HCHO (15 equiv), KOH (2 N, 10 equiv), MeOH, rt

37% aq HCHO (25 equiv), KOH (2 N, 10 equiv), MeOH, rt

37% aq HCHO (123 equiv), Na₂CO₃(3 equiv), MeOH/CH₂Cl₂(2:1), rt

(HCHO)_n(8 equiv), K₂CO₃(8 equiv), MeOH, reflux

60

40

10

60

85

2

88

3

90

4²⁸

5²⁹

no reaction

SCHEME 2. Stereocontrolled Synthesis of the

(-)-Vincamajinine (7) Core

intermediate 19. This increase in the concentration of

formaldehyde accelerated the reaction rate (Table 1,

entries 2 and 3), as expected, and also slightly increased

the yield. While this work was in progress, conditions

appeared for two other recent examples of the Tollens

reaction.^28,29Examination of these new conditions (entries

4²⁸and 5²⁹), unfortunately, resulted in no reaction in this

system. As illustrated in Table 1, use of the conditions

reported here (entries 1-3, Table 1) provided excellent

yields of the C(16) quaternary diol 15.

With the success of the synthesis of diol 15, the

synthesis of many sarpagine-related indole alkaloids

which contain a C-16 quaternary center might be real-

ized.³⁰Herein an example for the voachalotine series is

illustrated which resulted in the stereospecific synthesis

of the C(6)-O(17) oxygen-bridged alkaloid (+)-dehydro-

voachalotine (22).^1bOxidative cyclization of diol 15 ef-

fected by DDQ^18c,31-35in THF afforded ether 20 in 95%

yield (Scheme 3). The remaining hydroxyl moiety of cyclic

ether 20 was converted into the corresponding aldehyde

21 via intramolecular oxidation with (PhSeO)₂O/PhCl

analogous to previous work of Barton et al.³⁶and Trudell

et al.³⁷The aldehyde so formed was further oxidized with

KOH/I₂/MeOH by the procedure of Yamada, Yamamoto,

et al.³⁸to deliver the methyl ester 22 in 90% yield. The

optical rotation [[R]²⁶_D+125.0 (lit.¹⁸[R]²⁶_D[R]²⁶_D+124(2)]

and spectroscopic properties of synthetic (+)-22 were in

excellent agreement with those of natural (+)-dehydro-

voachalotine.¹⁸

and stereocontrolled intramolecular enolate driven pal-

ladium-mediated cross-coupling reaction (Scheme 2). The

latter was reported in the total synthesis of vellosimine

by Wang et al.²⁴This synthetic strategy was executed

efficiently to provide intermediate 16 in gram quanti-

ties.²³Alternatively, Martin et al.²⁵reported an enantio-

selective route for the synthesis of 16 via a biomimetic

pathway. With gram quantities of (-)-16 in hand,

numerous efforts (aldolizations, alkylations, and acyla-

tions) were originally carried out to construct the qua-

ternary carbon center at C-16, but they were not suc-

cessful.^26,27Gratifyingly, it was found that the aldehydic

group at C-16 could be converted into diol 15 in 85% yield

via the Tollens reaction²²with 37% aqueous formalde-

hyde (5 equiv) and KOH (10 equiv) in methanol, as shown

in Table 1. The prochiral quaternary carbon center at

C-16, which contained the structurally hindered diol in

15, was constructed in one step. More importantly,

because of the symmetry of the two diol moieties at C-16,

generation of a new chiral center with expensive reagents

was avoided. Encouraged by this result, attention turned

toward reduction of the reaction time for the Tollens

process. The amount of 37% aqueous formaldehyde was,

therefore, increased to facilitate the formation of 15 from

(28) Sung, M. J.; Lee, H. I.; Lee, H. B.; Cha, J. K. J. Org. Chem.

2003, 68, 2205-2208.

(29) Shimada, K.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc.

2003, 125, 4048-4049.

(30) Lounasmaa, M.; Hanhinen, P.; Westersund, M. The Sarpagine

Group of Indole Alkaloids. In The Alkaloids; Cordell, G. A., Ed.;

Academic Press: San Diego, 1999; Vol. 52, Chapter 2, pp 103-195.

(31) (a) Oikawa, Y.; Yoshioka, T.; Kunihiko, M.; Yonemitsu, O.

Heterocycles 1979, 12, 1457-1462. (b) Oikawa, Y.; Yonemitsu, O. J.

Org. Chem. 1977, 42, 1213-1216.

(32) Campos, O.; DiPierro, M.; Cain, M.; Mantei, R.; Gawish, A.;

Cook, J. M. Heterocycles 1980, 14, 975-984.

(33) Wang, T.; Xu, Q.; Yu, P.; Liu, X.; Cook, J. M. Org. Lett. 2001,

3, 345-348.

(24) Wang, T.; Cook, J. M. Org. Lett. 2000, 2, 2057-2059.

(25) For a biomimetic approach to N_a-methylvellosimine (16), see:

Deiters, A.; Chen, K.; Eary, T.; Martin, S. F. J. Am. Chem. Soc. 2003,

125, 4541-4550.

(26) Wang, T. Ph.D. Thesis. University of WisconsinsMilwaukee,

2001.

(27) For excellent reviews on the formation of quaternary carbon

centers, see: (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int.

Ed. 1998, 37, 389-401. (b) Fuji, K. Chem. Rev. 1993, 93, 2037-2066.

(c) Martin, S. F. Tetrahedron 1980, 36, 419-460.

(34) Walker, D.; Hiebert, J. D. Chem. Rev. 1967, 67, 153-195.

(35) Yu, J.; Wang, T.; Wearing, X. Z.; Ma, J.; Cook, J. M. J. Org.

Chem. 2003, 68, 5852-5859.

(36) Barton, D. H. R.; Brewster, A. G.; Hui, R. A. H. F.; Lester, D.

J.; Ley, S. V.; Back, T. G. J. Chem. Soc., Chem. Commun. 1978, 952-

954.

(37) Trudell, M. L.; Cook, J. M. J. Am. Chem. Soc. 1989, 111, 7504-

7507.

(38) Yamada, S.; Morizano, D.; Yamamoto, K. Tetrahedron Lett.

1992, 33, 4329-4332.

3966 J. Org. Chem., Vol. 70, No. 10, 2005

Synthesis of Vincamajine-Related Indole Alkaloids

SCHEME 3. Total Synthesis of

(+)-Dehydrovoachalotine (22)

SCHEME 4. Stereocontrolled Synthesis of the

Core Structure of (-)-Vincamajinine (7)

With the key C(16) bis-hydroxymethyl intermediate 15

in hand, selective conditions for the oxidation of the 16-

hydroxymethyl group present in the axial (â) position,

in contrast to oxidation of the equatorial (R) hydroxy-

methyl group, were required. This was realized on

stirring 15 with tetrapropylammonium perruthenate

(TPAP)³⁹to provide the desired aldehyde 23 with >10:1

diastereoselectivity in 78% yield. This oxidation was a

key process required for synthesis of 7 or 9. When

â-aldehyde 23 was dissolved in a mixture of TFA/Ac₂O,

the conjugate acid of the aldehyde was sufficiently

electrophilic to cyclize to the indoleninium salt, which

was trapped as the diacetate 24 by Ac₂O.⁴⁰This cycliza-

tion stereospecifically provided the 17(S) stereochemistry

in 24 in 84% yield. The use of trifluoroacetic acid was

key to the stereoselectivity in this process. This reagent

provided the kinetic product while cyclization of 23 with

Ac₂O/HCl(g) gave the thermodynamic 17(R) isomer,

although the ds was not 100%. Acid-assisted reduction

of the carbinolamine function in 24 with Et₃SiH/TFA⁴¹

furnished the C2(R)-H stereochemistry in indolinine 25

from the bottom face as the sole product in 90% yield.

Thus, the required caged congested hexacyclic ring

system, which contained the desired 17(R) hydroxyl

function, and the C2(R)-H were efficiently constructed

from 15 in three steps. To this end, further hydrolysis of

diacetate 25 under basic conditions gave diol 13 in 85%

yield (Scheme 4).

metric induction would be prepared from the inexpensive

L-valine. As shown in Scheme 5, iodoaniline 26 and the

propargyl unit 27,⁴²which had been prepared on a 200 g

scale with high diasteroselectivity from the readily avail-

able Scho¨llkopf chiral auxiliary, underwent Larock het-

eroannulation⁴³in the presence of Pd(OAc)₂, K₂CO₃, and

LiCl in DMF at 100 °C to provide the protected 6-meth-

oxytryptophan 28 in 77% yield on 300 g scale. The N_a-

methyl analogue 29 was obtained in 95% yield simply

by methylation of the indole N_a-H function with MeI and

NaH. Hydrolysis of the Scho¨llkopf chiral auxiliary in 29

in aqueous 2 N HCl in EtOH, accompanied by concomi-

tant loss of the indole-2-silyl group, provided optically

active N_a-methyl-6-methoxy-D-tryptophan ethyl ester 30

in 93% yield. Since the 2-iodo-5-methoxyaniline 26 and

the propargyl unit 27 could be readily prepared on a large

scale (>200 g), this provided an efficient route to syn-

thesize 6-methoxy-^D-tryptophan with high diastereose-

lectivity.⁴⁴With N_a-methyl-6-methoxy-D-tryptophan ethyl

ester 30 in hand, the 11-methoxy tetracyclic ketone 35

was prepared, as illustrated in Scheme 6. The primary

amine in 30 was converted into the N_b-benzyl ester 31

by reductive amination in high yield. The optical purity

of this N_b-benzyltryptophan 31 was determined to be

greater than 98% ee by comparison of the optical rotation

with that of an authentic sample.⁴⁵The Pictet-Spengler

condensation between the aldehyde 32 and the N_b-

benzylamine 31 was carried out in the presence of the

catalyst (acetic acid/CH₂Cl₂) to afford a mixture (at C-1)

of trans (33b) and cis (33a) diesters in nearly quantitative

yield in a ratio of 72:28. If TFA/CH₂Cl₂was employed in

this process, significant decomposition of the starting

6-methoxytryptophan 31 was observed. In keeping with

the mechanistic studies on the carbocation-mediated cis/

trans isomerization,^44,46-48when the Pictet-Spengler was

Construction of the Hexacyclic Core 45 Required

for the Synthesis of (-)-11-Methoxy-17-epivincama-

jine (9). Since the hexacyclic core of 13 was efficiently

synthesized from ^D-(+)-tryptophan methyl ester, the

6-methoxy-D-tryptophan ethyl ester (30) was chosen as

the chiral transfer agent and starting material for the

synthesis of 9. Because of the ^D-stereochemistry in 30

required for the asymmetric Pictet-Spengler reaction,

the Scho¨llkopf chiral auxiliary required for the asym-

(42) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook, J.

M. J. Org. Chem. 2001, 66, 4525-4542.

(43) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689-

6690.

(44) (a) Liu, X.; Deschamps, J. R.; Cook, J. M. Org. Lett. 2002, 4,

3339-3342. (b) Wearing, X. Z.; Cook, J. M. 225th ACS National

Meeting, New Orleans, LA, March 23-27, 2003; American Chemical

Society: Washington, DC, 2003; ORGN 412.

(45) Liu, X. Ph.D. Thesis, University of WisconsinsMilwaukee,

2002.

(39) For a review on TPAP/NMO oxidations, see: Ley, S. V.;

Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639-666.

(40) The first example of the intramolecular cyclization to form the

hexacyclic ring system in the presence of Ac₂O/HCl(g)/AcOH was

reported in the synthesis of ajmaline-related alkaloids; see: Bartlett,

M. F.; Lambert, B. F.; Werblood, H. M.; Taylor, W. I. J. Am. Chem.

Soc. 1963, 85, 475-477. These conditions did not work, however, in

this case even after stirring for 5 days.

(41) (a) Li, J.; Wang, T.; Yu, P.; Peterson, A.; Weber, R.; Soerens,

D.; Grubisha, D.; Bennett, D.; Cook, J. M. J. Am. Chem. Soc. 1999,

121, 6998-7010. (b) Li, J.; Cook, J. M. J. Org. Chem. 1998, 63, 4166-

4167.

(46) Cox, E. D.; Hamaker, L. K.; Li, J.; Yu, P.; Czerwinski, K. M.;

Deng, L.; Bennett, D. W.; Cook, J. M.; Watson, W. H.; Krawiec, M. J.

Org. Chem. 1997, 62, 44-61.

(47) Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797-1842.

J. Org. Chem, Vol. 70, No. 10, 2005 3967

Yu et al.

SCHEME 5. Synthesis of N_a-Methyl-6-methoxy-D-tryptophan Ethyl Ester (30)

SCHEME 6. Synthesis of the 11-Methoxy Tetracyclic Ketone (35)

SCHEME 7. Synthesis of

(+)-N_a-Methyl-16-epigardneral (40)

completed, a small amount of TFA was added to the

reaction mixture after which epimerization of the ste-

reocenter at C(1) of this cis diastereomer 33a took place

to give the desired trans diastereomer 33b as the single

isolable diastereomer. This isomerization took place in

10 h at a much faster rate than the parent 11-(H) ana-

logue.^44,48Dieckmann cyclization of the trans diester 33b,

followed by base-mediated hydrolysis/decarboxylation in

a one-pot process then provided the key tetracyclic ketone

35 in 85% overall yield. The synthesis of this key ketone

35 could then be carried out in a two-pot fashion (from

28) and was accomplished (from iodoaniline 26) in five

reaction vessels in an overall yield of 46%.

With an efficient synthesis of the 11-methoxytetracyclic

ketone 35 in hand, attention turned to the synthesis of

16-epi-N_a-methyl gardneral 40, a base previously ob-

tained by Sakai from the degradation of gardnerine.⁴⁹As

illustrated in Scheme 7, the N_b-benzyl group of 35 was

removed via catalytic hydrogenation, and was followed

by alkylation with (Z)-1-bromo-2-iodo-butene 37 to pro-

vide ketone 38 in an overall yield of 74% (two steps).

When this ketone 38 was subjected to the conditions of

the enolate driven palladium-catalyzed intramolecular

cyclization, the 11-methoxy pentacyclic ketone 39 was

obtained in 82% yield in stereospecific fashion. This

ketone 39 was then converted into 16-epi-N_a-methyl

gardneral 40 in 90% yield via a Wittig reaction followed

by hydrolysis.⁴⁴The aldehyde 40 so formed, was subjected

(48) Zhao, S.; Liao, X.; Wang, T.; Flippen-Anderson, J.; Cook, J. M.

J. Org. Chem. 2003, 68, 6279-6295.

(49) Sakai, S.; Yamamoto, Y.; Hasegawa, S. Chem. Pharm. Bull.

1980, 28, 3454-3456.

3968 J. Org. Chem., Vol. 70, No. 10, 2005

Synthesis of Vincamajine-Related Indole Alkaloids

SCHEME 8. Stereocontrolled Synthesis of the

Core of (-)-11-Methoxy-17-epivincamajine (9)

SCHEME 9. Stereocontrolled Synthesis of the Key

16-Hydroxymethyl-17-aldehydo Intermediate 50

to the conditions of the Tollens reaction to afford diol 41

in 87% yield. This diol was selectively oxidized to give

the desired â-aldehyde 42 via the TPAP-oxidation devel-

oped earlier in 77% yield (>8:1 dr), as depicted in Scheme

8. The acid-assisted cyclization of â-aldehyde 42 with

TFA/Ac₂O stereospecifically provided the 17(S) stereo-

chemistry in diacetate 43 in 85% yield. Further ste-

reospecific reduction of carbinolamine 43 with Et₃SiH in

the presence of TFA was executed in high yield and

provided the crucial diacetate 44 in 85% yield. Hydrolysis

of 44 with K₂CO₃in MeOH furnished diol 45 in 90% yield,

which contained the required seven stereogenic centers

and the C(19)-C(20) E-olefinic bond. It is worthy of note

that the E-configuration of this olefinic function is the

thermodynamically less stable isomer, consequently the

palladium-mediated cyclization was critical to its ste-

reospecific formation.^23a

SCHEME 10. Stereocontrolled Synthesis of

(+)-Quebrachidine Diol 53

Construction of the Hexacyclic Cores 53, 56, and

59 Necessary for the Synthesis of (+)-Quebrachi-

dine (3), (-)-Vincamajine (4), and (+)-Vincarine (8).

Since the synthesis of the congested hexacyclic cores 13

(for the synthesis of 7) and 45 (for the synthesis of 9)

was successfully completed, attention turned to extension

of this strategy to the synthesis of the hexacyclic cores

of 3, 4, and 8. As shown in Scheme 9, (+)-vellosimine

(46) was chosen as the intermediate for the synthesis of

the hexacyclic core of quebrachidine 3. Thus, (+)-vello-

simine (46), available in enantiospecific fashion in seven

reaction vessels in 27% overall yield from ^D-(+)-tryp-

tophan methyl ester,^23,50was protected as the N_a-Boc

intermediate in the presence of DMAP to afford 47 in

85% yield. The N_a-Boc-protected vellosimine 47 was next

converted into the C(16)-quaternary diol 48 via the

Tollens reaction, and this was followed by the TPAP

oxidation to provide the desired â-aldehyde 49 with >8:1

diastereoselectivity in 69% overall yield for the two steps.

The Boc group in 49 was removed using TFA in dichlo-

romethane under standard conditions⁵¹to provide alde-

hyde 50 in 84% yield. The intramolecular cyclization of

50 occurred under modified conditions [Ac₂O/HCl(g)]^20,21,40

to give the desired diacetate 51 [17(R)] with >2:1 dia-

stereoselectivity in 52% yield (Scheme 10). The imine

moiety of this intermediate was stereospecifically reduced

using NaBH₃CN in the presence of acid⁵²and the acetate

functions were hydrolyzed with aqueous K₂CO₃to provide

diol 53 in 77% overall yield (two steps). As anticipated,

the spectroscopic data and optical rotation ([R]²⁶_D+59.2,

(50) Wang, T.; Cook, J. M. 219th ACS National Meeting, San

Francisco, CA, March 26-30, 2000; American Chemical Society:

Washington, DC, 2000; ORGN 752.

(51) Hanessian, S.; Faucher, A.-M. J. Org. Chem. 1991, 56, 2947-

2949.

(52) Bornmann, W. G.; Kuehne, M. E. J. Org. Chem. 1992, 57, 1752-

1760.

J. Org. Chem, Vol. 70, No. 10, 2005 3969

Yu et al.

SCHEME 11. Stereocontrolled Synthesis of

(+)-Vincamajine Diol 56

SCHEME 13. Completion of the Total Synthesis of

(-)-Vincamajinine (7)

more, analysis indicated the proton signal at 17-H

appeared at 4.10 ppm in diol 59 [17(R)] in contrast to

the 17(S) stereochemistry (δ 4.30) of quebrachidine diol

53. Thus, the hexacyclic cores contained in quebrachidine

diol 53, vincamajine diol 56, and vincarinol 59 have been

synthesized in an efficient manner, and these caged

systems are available for the synthesis of the correspond-

ing (+)-quebrachidine (3), (-)-vincamajine (4), and (+)-

vincarine (8), respectively.

SCHEME 12. Stereocontrolled Synthesis of

Vincarine Diol 59

Completion of the Total Synthesis of (-)-Vinca-

majinine (7). The final steps required for the synthesis

of vincamajinine (7) are shown in Scheme 13. Unexpect-

edly, diol 13 was labile to some conditions of oxidation

[e.g., (PhSeO)₂O/Ph,^36,37TPAP/NMO,³⁹TEMPO/BAIB/

CH₂Cl₂⁵⁴] which ultimately resulted in cleavage of the

C(7)-C(17) bond. Careful treatment of diol 13, however,

with Dess-Martin periodinane⁵⁵furnished the ketone 60

with the C(16) primary alcohol moiety intact. After

isolation, further oxidation of ketone 60 with Dess-

Martin periodinane provided the desired aldehydoketone

61 (78% for two steps). These sequential oxidations were

important steps in the synthesis of 7 and attempts to

execute them in a one-pot process, resulted in low yields

of aldehydoketone 61.⁵⁶The C-16(S) aldehydic group of

61 was converted into the methyl ester 62 upon treat-

ment with KOH/I₂in 92% yield.³⁸The stereochemical

issue of the C(17) hydroxyl group which now remained

was resolved by simple reduction of ketone 62 with

NaBH₄. Attack occurred exclusively from the least hin-

dered face to provide (-)-vincamajinine (7) in 90% yield.

Analysis of the proton NMR spectrum indicated the

characteristic singlet at 17-H(R) appeared at 3.98 ppm

in (-)-7 in contrast to the 17(S) stereochemistry (δ 4.21)

in (-)-vincamajine (4).^12e,g,j,l,13The structure of (-)-7 was

c 0.24, MeOH) of diol 53 were virtually identical to that

of diol 53 ([R]²⁶+60.6, c 0.17, MeOH) obtained from

D

reduction of natural (+)-quebrachidine (3) with LiAlH₄.⁵³

This strategy was also employed for the synthesis of the

diol 56 in the vincamajine series (Scheme 11). Intramo-

lecular cyclization of 23 using Ac₂O/HCl(g) (>3:1 dr),

followed by reduction (Et₃SiH, TFA) and hydrolysis under

basic conditions provided the diol 56 in 60% overall yield

(three steps). Again, the spectral data and optical rotation

of the synthetic diol 56 ([R]²⁶_D+10.5, c 0.51, MeOH) were

in excellent agreement with an authentic sample of 56

([R]²⁶+10.6, c 0.17, MeOH) obtained via the reduction

D

of natural (-)-vincamajine (4) with LiAlH₄.⁵³

Under the modified conditions (TFA/Ac₂O) developed

for the synthesis of the hexacyclic cores of 13 and 45,

which contained the C-17(R) stereochemistry of the

monol, treatment of aldehyde 50 with TFA/Ac₂O exclu-

sively afforded the desired imine 57 in 82% yield (Scheme

12). The imine moiety of 57 was stereospecifically reduced

using Et₃SiH/TFA and the acetate functions were hydro-

lyzed with aqueous K₂CO₃to give diol 59 in 78% overall

yield (two steps). The structure of vincarinol 59 was

established with full characterization by ¹H and ¹³C

NMR, NOESY, NOE, MS, and IR spectroscopy. Further-

1

fully characterized by H and ¹³C NMR, NOESY, NOE,

MS, and IR. This completed the first stereocontrolled

total synthesis of (-)-7 in 16 reaction vessels from ^D-(+)-

tryptophan methyl ester in an overall yield of 11.8%.

(54) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,

G. J. Org. Chem. 1997, 62, 6974-6977.

(55) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,

7277-7287. (b) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48,

4155-4156.

(53) Authentic samples of both (+)-quebrachidine (3) and (-)-

vincamajine (4) were kindly provided by Professor Toh-Seok Kam

(University of Malaya) and Professor Monique Zeches-Hanrot (Uni-

versity of Reims).

(56) In the absence of the isolation of ketone 60, further oxidation

of 60 with Dess-Martin periodinane at room temperature resulted in

the decomposition of ketone 60 and isolation of only a small amount

of aldehydoketone 61.

3970 J. Org. Chem., Vol. 70, No. 10, 2005

Synthesis of Vincamajine-Related Indole Alkaloids

SCHEME 14. Completion of the Total Synthesis of

(-)-11-Methoxy-17-epivincamajine (9)

alkaloids including alkaloids in the 10- and 12-methoxy

series, heretofore difficult to obtain regiospecifically.

Further work on the synthesis of these monomeric- and

bis-indole alkaloids is underway and will be reported in

due course.

Experimental Section

Microanalysis was performed on an F and M Scientific Corp.

model 185 carbon, hydrogen, and nitrogen analyzer. Melting

points were taken on a Thomas Hoover melting point ap-

paratus and are reported uncorrected. Proton and carbon NMR

spectra were recorded on 250 and 300 MHz NMR spectrom-

eters. The analytical TLC plates used were UV-active silica

gel on plastic. The TLC plates were visualized under UV light

or developed with spray reagents. Alkaloids were visualized

with Dragendorf’s reagent or a saturated solution of ceric

ammonium sulfate in 50% sulfuric acid or an aqueous solution

of 2,4-dinitrophenylhydrazine in 30% sulfuric acid. Chroma-

tography refers to flash chromatography using 230-400 mesh

60 A silica gel, grade 60. Methanol was dried by distillation

over magnesium metal/I₂. Tetrahydrofuran, benzene, and

toluene were dried by distillation from sodium-benzophenone

ketyl. Methylene chloride was dried over MgSO₄and then was

distilled from P₂O₅.

Completion of the Total Synthesis of (-)-11-

Methoxy-17-epivincamajine (9). Once the synthesis of

vincamajinine (7) was realized, attention turned to the

construction of 11-methoxy-17-epivincamajine (9) to il-

lustrate the versatility of this approach. The desired diol

45, available by the efficient process described in Schemes

6-8, was subjected to the condition of Dess-Martin

oxidation. Gratifyingly, it was found that oxidation of 45

under the Dess-Martin periodinane conditions was much

faster than that of the parent 13 (Scheme 14). Both

primary and secondary alcohol functions of diol 45 were

simultaneously converted into the corresponding alde-

hyde and ketone moieties to give aldehydoketone 63 in

65% yield. The aldehydic group in 63 was converted into

the methyl ester 64 in 91% yield by the elegant procedure

of Yamamoto et al.³⁸The C(17) ketone which remained

was stereoselectively reduced from the top face to furnish

the synthetic (-)-11-methoxy-17-epivincamajine (9) in

93% yield with NaBH₄in EtOH. The spectroscopic

properties and optical rotation [[R]²⁶-10.5 (lit.^9b[R]²⁶

Preparation of Voachalotinol (15). To a solution of

aldehyde 16²³(306 mg, 1.0 mmol) in MeOH (10 mL) were

added formaldehyde [(25 equiv, 25 mmol) 1.9 mL of a 37% w/w

solution in water] and 85% KOH (10 equiv, 659 mg, 10 mmol)

in MeOH (10 mL). The reaction mixture was stirred at rt for

10 h, diluted with brine, and extracted with CH₂Cl₂(2 × 50

mL). The combined organic extracts were washed with brine,

dried (Na₂SO₄), filtered, and concentrated under reduced

pressure. The residue that resulted was purified by column

chromatography (silica gel, MeOH/CHCl₃) 1:12) to provide

diol 15 as a white solid (304 mg, 90%): FTIR 3330, 2911, 1470

1

cm^-1; H NMR (300 MHz, DMSO-d₆) δ 1.54 (d, J ) 6.6 Hz, 3

H), 1.76 (m, 2 H), 2.68 (m, 3 H), 3.01 (dd, J ) 10.4, 5.0 Hz, 1

H), 3.07 (d, J ) 5.4 Hz, 1 H), 3.23 (dd, J ) 9.8, 5.0 Hz, 1 H),

3.41 (t, J ) 4.8 Hz, 1 H), 3.50 (m, 3 H), 3.61 (s, 3 H), 4.04 (t,

J ) 4.7 Hz, 1 H), 4.12 (dd, J ) 9.7, 3.7 Hz, 1 H), 4.46 (t, J )

4.9 Hz, 1 H), 5.26 (q, J ) 6.7 Hz, 1 H), 6.98 (t, J ) 7.7 Hz, 1

H), 7.08 (t, J ) 7.0 Hz, 1 H), 7.39 (m, 2 H); ¹³C NMR (300

MHz, DMSO-d₆) δ 12.7, 22.9, 27.8, 28.7, 29.3, 43.5, 48.1, 49.0,

56.2, 57.1, 58.0, 66.2, 105.4, 109.5, 113.6, 118.0, 118.7, 120.0,

137.0, 139.8, 140.2; EIMS (m/e, relative intensity) 338 (M⁺,

100), 321 (10), 307 (23), 263 (11), 182 (25); HRMS calcd for

C₂₁H₂₆N₂O₂338.1994, found 338.1993. This material was used

directly in the next step.

D

-12.0)] of synthetic (-)-9 were in excellent agreement

with those of natural (-)-11-methoxy-17-epivincamajine

(9). See the Experimental Section and the Supporting

Information for details. This synthesis required 17 reac-

tion vessels from the Scho¨llkopf chiral auxiliary 27 and

was completed in an overall yield of 5.4%.

Conclusion

In summary, a stereocontrolled total synthesis of (+)-

dehydrovoachalotine (22), (-)-vincamajinine (7), and (-)-

11-methoxy-17-epivincamajine (9) was accomplished by

combination of the highly practical asymmetric Pictet-

Spengler reaction, a Tollens reaction, an acid-assisted

intramolecular cyclization, and two stereospecific reduc-

tions that provided the required hexacyclic ring systems

in stereocontrolled fashion. This constitutes the first total

synthesis of these alkaloids and provided the first re-

giospecific route to 11-alkoxy substituted ajmaline-

related alkaloids. In particular, alteration of the acidic

conditions during formation of the C(7)-C(17) quaternary

center can be employed to stereospecifically control the

intramolecular cyclization to provide the 17(R) configu-

ration. This strategy was concise and versatile since the

three hexacyclic cores of (+)-quebrachidine (3), (-)-

vincamajine (4), and (+)-vincarine (9) have been synthe-

sized in a similar manner as well. This stereocontrolled

approach will permit extension of this strategy to the

synthesis of many vincamajine/ajmaline-related indole

Preparation of (2aS,3S,4E,7S,12cR,12dR)-4-Ethylidene-

4,5,7,8,12c,12d-hexahydro-8-methyl-3,7-methano-2H-furo-

[4,3,2-ij]indolo[3,2-b]quinolizine-2a(3H)-methanol (20).

To a solution of diol 15 (34 mg, 0.10 mmol) in THF (2 mL)

was added DDQ (46 mg, 0.20 mmol). The mixture which

resulted was heated to reflux for 2 h. The mixture was then

diluted with CH₂Cl₂(25 mL), washed with a saturated solution

of aq NaHSO₃(5 mL) and brine (2 × 10 mL), and dried (K₂-

CO₃). The solvent was removed under reduced pressure and

the residue which resulted was chromatographed (silica gel,

CHCl₃/MeOH ) 9:1) to provide the cyclic ether 20 as a white

solid (32 mg, 95%): FTIR 3382, 2922, 1469, 1011 cm^-^{1 1}H

;

NMR (300 MHz, CDCl₃) δ 1.68 (3 H, d, J ) 6.8 Hz), 1.95 (m,

2 H), 3.00 (t, J ) 2.7 Hz, 1 H), 3.14 (d, J ) 7.5 Hz, 1 H), 3.46

(s, 2 H), 3.50-3.74 (m, 7 H), 4.11 (dd, J ) 8.5, 5.3 Hz, 1 H),

5.45 (q, J ) 6.7 Hz, 1 H), 5.67 (d, J ) 7.5 Hz, 1 H), 7.17 (td,

J ) 7.8, 1.1 Hz, 1 H), 7.24 (td, J ) 7.9, 1.1 Hz, 1 H), 7.30 (t,

J ) 8.0 Hz, 1 H), 7.70 (d, J ) 7.5 Hz, 1 H); ¹³C NMR (75.5

MHz, CDCl₃) δ 12.8, 28.7, 29.1, 29.2, 45.9, 47.4, 55.4, 62.9,

66.7, 68.1, 72.0, 103.3, 108.9, 116.2, 118.7, 119.8, 121.4, 126.1,

136.3, 137.3, 143.0; EIMS (m/e, relative intensity) 336 (M⁺,

36), 319 (24), 305 (9), 196 (43), 182 (100); HRMS calcd for

J. Org. Chem, Vol. 70, No. 10, 2005 3971

Yu et al.

C₂₁H₂₄N₂O₂336.1837, found 336.1822. This material was

employed directly in the next step.

(dd, J ) 10.3, 4.7 Hz, 1 H), 3.49 (s, 2 H), 3.54 (s, 3 H), 3.66 (m,

1 H), 4.22 (dd, J ) 18.3, 7.9 Hz, 1 H), 4.79 (t, J ) 4.6 Hz, 1 H),

5.34 (q, J ) 6.8 Hz, 1 H), 6.99 (t, J ) 7.1 Hz, 1 H), 7.09 (td,

J ) 8.1, 1.0 Hz, 1 H), 7.39 (t, J ) 7.5 Hz, 2 H), 9.04 (s, 1 H);

¹³C NMR (75.5 MHz, DMSO-d₆) δ 13.0, 23.5, 26.4, 27.1, 29.4,

48.7, 53.1, 55.3, 58.0, 66.2, 103.9, 109.7, 115.5, 118.0, 119.0,

120.7, 125.9, 137.5, 138.4, 139.8, 202.6; EIMS (m/e, relative

intensity) 336 (M⁺, 16), 307 (29), 263 (22), 183 (100); HRMS

calcd for C₂₁H₂₄N₂O₂336.1838, found 336.1823. This material

was used directly in the next step.

Preparation of (2R,17S,19E)-17-Aceto-16-[(acetyloxy)-

methyl]-19,20-didehydroajmalan-2,17-diol (24). The TFA

(2 mL) was added to a solution of 23 (80 mg, 0.23 mmol) in

Ac₂O (5 mL). The reaction mixture was stirred in a sealed

vessel at rt for 6 h, at which time it was concentrated under

reduced pressure. The residue was diluted with CH₂Cl₂(20

mL), and a solution of 10% aq NH₄OH was added to bring the

pH to 8. The organic layer was extracted with CH₂Cl₂(20 mL),

which was washed with brine (2 × 20 mL), dried (Na₂SO₄),

filtered, and evaporated under reduced pressure. The residue

that resulted was purified by preparative TLC on silica gel

(CHCl₃/MeOH ) 9:1) to provide 24 (84.5 mg, 84%): FTIR 2941,

1742, 1473, 1241 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 1.48 (m,

1 H), 1.57 (d, J ) 6.7 Hz, 3 H), 1.72 (s, 3 H), 2.00 (s, 3 H), 2.04

(dd, J ) 18.6, 4.4 Hz, 1 H), 2.45 (d, J ) 12.3 Hz, 1 H), 2.76 (m,

4 H), 2.93 (dd, J ) 13.5, 4.6 Hz, 1 H), 3.46 (m, 4 H), 3.90 (m,

2 H), 5.35 (s, 1 H), 5.40 (q, J ) 6.4 Hz, 1 H), 6.54 (d, J ) 7.8

Hz, 1 H), 6.76 (t, J ) 7.4 Hz, 1 H), 7.06 (d, J ) 7.2 Hz, 1 H),

7.13 (t, J ) 7.7 Hz, 1 H); ¹³C NMR (75.5 MHz, CDCl₃) δ 12.8,

20.5, 20.7. 22.8, 28.5, 29.4, 29.9, 43.8, 55.6, 58.7, 59.0, 62.0,

67.7, 82.0, 97.4, 107.6, 116.8, 118.6, 122.9, 126.8, 128.5, 137.0,

152.1, 169.2, 170.9; EIMS (m/e, relative intensity) 438 (M⁺,

64), 422 (100), 406 (34), 378 (43), 319 (46), 253 (34), 182 (76);

HRMS calcd for C₂₅H₃₀N₂O₅438.2154, found 438.2148. This

material was used directly in the next step.

Preparation of (2aR,3S,4E,7S,12cR,12dR)-4-Ethylidene-

4,5,7,8,12c,12d-hexahydro-8-methyl-3,7-methano-2H-furo-

[4,3,2-ij]indolo[3,2-b]quinolizine-2a(3H)-carboxalde-

hyde (21). The benzeneseleninic anhydride (6.6 mg, 0.025

mmol) was added to a solution of dry chlorobenzene (5 mL)

and cyclic ether 20 (17 mg, 0.05 mmol). The mixture was

heated to 115 °C (oil bath temperature) for 30 min. The orange

solution which resulted was cooled to rt, and the solvent was

removed under reduced pressure. The oil which resulted was

dissolved in EtOAc (25 mL) and poured into a solution of aq 1

N NaOH (20 mL). The mixture was then extracted with EtOAc

(2 × 20 mL). The combined organic extracts were washed with

brine and dried (Na₂SO₄), and the solvent was removed under

reduced pressure to afford an oil. The oil was chromatographed

(silica gel, CHCl₃/MeOH ) 15:1) to provide aldehyde 21 as a

pale yellow solid (15 mg, 92%): FTIR 2938, 1720, 1468 cm^-1

;

¹H NMR (300 MHz, CDCl₃) δ 1.64 (dt, J ) 6.8, 1.9 Hz, 3 H),

2.08 (m, 2 H), 3.19 (t, J ) 2.7 Hz, 1 H), 3.65 (s, 3 H), 3.68 (m,

2 H), 3.70 (d, J ) 15.5 Hz, 2 H), 3.86 (d, J ) 10.3 Hz, 1 H),

4.26 (d, J ) 7.3 Hz, 2 H), 5.42 (q, J ) 6.8 Hz, 1 H), 5.81 (d,

J ) 7.6 Hz, 1 H), 7.15-7.32 (m, 2 H), 7.68 (d, J ) 7.7 Hz, 1

H), 9.59 (s, 1 H); ¹³C NMR (75.5 MHz, CDCl₃) δ 12.7, 28.4,

28.8, 29.2, 47.5, 55.2, 57.3, 59.4, 65.1, 72.8, 103.0, 109.0, 117.7,

118.9, 120.0, 121.8, 125.8, 133.3, 137.4, 142.1, 201.3; EIMS

(m/e, relative intensity) 334 (M⁺, 34), 305 (43), 196 (41), 182

(100); HRMS calcd for C₂₁H₂₂N₂O₂334.1681, found 334.1684.

This material was employed directly in the next step.

Preparation of (+)-Dehydrovoachalotine (22). Alde-

hyde 21 (6.7 mg, 0.02 mmol) was dissolved in anhydrous

MeOH (2 mL), and a solution of 85% KOH (2.6 equiv, 3.4 mg,

0.052 mmol) and iodine (1.3 equiv, 6.6 mg, 0.026 mmol) in

anhydrous MeOH (each 0.5 mL) were successively added to

21 at 0 °C. After 30 min, the reaction mixture was quenched

by addition of glacial acetic acid to bring the pH to 7. The

solution was diluted with CH₂Cl₂, washed with a 10% aq

solution of NaHSO₃(20 mL) brine (2 × 20 mL), and dried (Na₂-

SO₄). The solvent was removed under reduced pressure, and

the residue which resulted was purified by chromatography

on silica gel (CHCl₃/MeOH ) 20:1) to provide dehydrovoacha-

lotine 22 as a pale yellow solid (5 mg, 90%): [R]_D) +125.0 (c

0.08, MeOH) [lit.¹⁸[R]_D) +124 ( 2 (c 0.90, MeOH)]; IR 1736,

Preparation of (2r,17R,19E)-17-Aceto-16-[(acetyloxy)-

methyl)]-19,20-didehydroajmalan-17-ol (25). The TFA (2

mL) and Et₃SiH (3 mL) were added to a solution of 24 (45 mg,

0.10 mmol) in CH₂Cl₂(2 mL). The reaction mixture which

resulted was stirred in a sealed vessel at rt for 3 d, at which

time it was concentrated under reduced pressure. The residue

was dissolved in CH₂Cl₂(30 mL), and a solution of 10% aq

NH₄OH was added to bring the pH to 8. The organic layer

was separated, washed with brine (2 × 20 mL), dried (Na₂-

SO₄), filtered, and evaporated under reduced pressure. The

residue that resulted was purified by preparative TLC on silica

gel (CHCl₃/MeOH ) 15:1) to provide 25 (38 mg, 90%): FTIR

1

1467, 1238 cm^-1; H NMR (300 MHz, CDCl₃) δ 1.60 (d, J )

7.9 Hz, 3 H), 2.03 (m, 2 H), 2.29 (t, J ) 2.9 Hz, 1 H), 3.65 (s,

3 H), 3.72 (3 H, s), 3.71-3.76 (m, 3 H), 3.94 (d, J ) 10.1 Hz,

1 H), 4.07 (dd, J ) 9.4, 4.2 Hz, 1 H), 4.52 (d, J ) 7.7 Hz, 1 H),

5.36 (q, J ) 7.6 Hz, 1 H), 5.78 (d, J ) 7.7 Hz, 1 H), 7.14-7.33

(m, 3 H), 7.70 (d, J ) 7.5 Hz, 1 H); ¹³C NMR (75.5 MHz, CDCl₃)

δ 12.6, 29.1, 29.3, 31.0, 47.1, 52.2, 53.9, 55.4, 61.4, 68.3, 72.6,

103.4, 109.1, 116.5, 119.2, 120.1, 121.8, 126.4, 135.7, 137.7,

143.3, 175.9; EIMS (m/e, relative intensity) 364 (M⁺, 26), 333

(10), 196 (30), 182 (100); HRMS calcd for C₂₂H₂₄N₂O₃364.1786,

found 364.1765. The spectral data of this material were in

excellent agreement with that of the literature.¹⁸

2941, 1749, 1422, 1241 cm^-^{1 1}H NMR (300 MHz, CDCl₃) δ

;

1.50 (dd, J ) 13.6, 10.4 Hz, 1 H), 1.60 (d, J ) 6.8 Hz, 3 H),

1.76 (s, 3 H), 1.79 (d, J ) 12.0 Hz, 1 H), 2.02 (s, 3 H), 2.30 (dd,

J ) 11.8, 4.6 Hz, 1 H), 2.67 (s, 3 H), 2.71 (d, J ) 4.7 Hz, 1 H),

2.78 (d, J ) 4.4 Hz, 1H), 2.98 (dd, J ) 13.4, 4.8 Hz, 1H), 3.32

(d, J ) 4.7 Hz, 1 H), 3.50 (m, 1 H), 3.54 (t, J ) 2.2 Hz, 1 H),

3.69 (dd, J ) 9.5, 4.8 Hz, 1 H), 3.92 (m, 2 H), 5.33 (s, 1 H),

5.39 (q, J ) 6.7 Hz, 1 H), 6.63 (d, J ) 7.9 Hz, 1 H), 6.78 (td,

J ) 7.4, 0.8 Hz, 1 H), 7.10 (dd, J ) 7.3, 0.7 Hz, 1 H), 7.15 (td,

J ) 7.8, 1.2 Hz, 1 H); ¹³C NMR (75.5 MHz, CDCl₃) δ 12.8, 20.6,

20.7, 22.3, 28.8, 34.9, 36.5, 45.2, 53.3, 54.1, 55.8, 62.0, 68.0,

75.1, 82.7, 108.9, 116.3, 119.1, 122.5, 128.4, 128.9, 137.9, 154.9,

169.4, 171.0; EIMS (m/e, relative intensity) 422 (M⁺, 100), 379

(6), 363 (20); HRMS calcd for C₂₅H₃₀N₂O₄422.2204, found

422.2206. This material was used directly in the next step.

Preparation of (6S,7R,9E,10S,11S,11aS)-9-Ethylidene-

5,6,8,9,10,11,11a,12-octahydro-11-(hydroxymethyl)-5-meth-

yl-6,10-methanoindolo[3,2-b]quinolizine-11-carboxalde-

hyde (23). The TPAP (1.8 mg, 0.005 mmol) was added to a

mixture of 15 (34 mg, 0.10 mmol), 4 Å MS (50 mg, 500 mg/

mmol), and NMO (18 mg, 0.15 mmol) in CH₂Cl₂(10 m L) under

a N₂atmosphere. The reaction mixture was stirred at rt for

12 h, at which time it was passed through a pad of Celite and

washed with CH₂Cl₂(20 mL). The filtrate was washed with

brine (2 × 20 mL), dried (Na₂SO₄), filtered, and concentrated

under reduced pressure. The residue that resulted was purified

by preparative TLC on silica gel (CHCl₃/MeOH ) 9:1) to

provide 23 and its C-16 epimer in >10:1 ratio (26 mg, 78%).

23: FTIR 2941, 1692, 1469 cm^-1; ¹H NMR (300 MHz, DMSO-

d₆) δ 1.67 (d, J ) 6.7 Hz, 3 H), 1.80 (t, J ) 10.4 Hz, 1 H), 1.90

(m, 1 H), 2.82 (dd, J ) 15.5, 4.6 Hz, 1 H), 2.91 (d, J ) 2.4 Hz,

1 H), 3.03 (d, J ) 4.2 Hz, 1 H), 3.16 (d, J ) 15.5 Hz, 1 H), 3.40

Preparation of (+)-(2r,17R,19E)-19,20-Didehydro-17-

hydroxyajmalan-16-methanol (13). A solution of 20% aq K₂-

CO₃(2 mL) was added to a solution of 25 (42 mg, 0.10 mmol)

in MeOH (2 mL) at rt. The mixture was stirred at rt for 24 h

and concentrated under reduced pressure to remove the

MeOH, after which time it was diluted with CH₂Cl₂(20 mL)

and separated. The aqueous phase was extracted with CH₂-

Cl₂(2 × 15 mL). The combined organic extracts were washed

with brine, dried (Na₂SO₄), filtered, and evaporated under

reduced pressure. The residue that resulted was purified by

3972 J. Org. Chem., Vol. 70, No. 10, 2005

Synthesis of Vincamajine-Related Indole Alkaloids

preparative TLC on silica gel (CHCl₃/MeOH ) 9:1) to provide

diol 13 as a white solid (29 mg, 87%): [R]_D) +8.84 (c 0.52,

121.2, 124.2, 124.6, 132.3, 140.6, 156.7, 162.7, 163.9; MS (CI,

CH₄) m/e (relative intensity) 500 (M⁺+ 1, 100), 470 (16), 386

(14), 288 (21). Anal. Calcd for C₂₈H₄₅N₃O₃Si: C, 67.29; H, 9.08;

N, 8.41. Found: C, 67.49; H, 9.16; N, 8.34.

MeOH); FTIR 3405, 2951, 1638 cm^-^{1 1}H NMR (300 MHz,

;

CDCl₃) δ 1.51 (m, 1 H), 1.66 (d, J ) 6.8 Hz, 3 H), 1.77 (d, J )

11.8 Hz, 1 H), 2.21 (dd, J ) 11.8, 4.6 Hz, 1 H), 2.66 (s, 3 H),

2.80 (d, J ) 3.7 Hz, 1 H), 2.96 (m, 2 H), 3.40 (d, J ) 6.8 Hz, 1

H), 3.43 (m, 1 H), 3.52 (m, 1 H), 3.54 (t, J ) 2.1 Hz, 1 H), 3.60

(d, J ) 10.2 Hz, 1 H), 3.73 (dd, J ) 9.6, 5.0 Hz, 1 H), 4.10 (1

H, s), 5.36 (q, J ) 6.6 Hz, 1 H), 6.74 (d, J ) 7.9 Hz, 1 H), 6.87

(t, J ) 7.4 Hz, 1 H), 7.11 (d, J ) 7.2 Hz, 1 H), 7.22 (td, J ) 7.7,

1.2 Hz, 1 H); ¹³C NMR (75.5 MHz, CDCl₃) δ 13.0, 22.7, 28.2,

34.9, 35.8, 47.6, 53.7, 54.6, 55.6, 62.2, 67.0, 76.1, 85.8, 109.7,

116.2, 119.9, 121.6, 128.3, 130.7, 137.8, 154.7; EIMS (m/e,

relative intensity) 338 (M⁺, 76), 321 (9), 194 (83), 157 (100);

HRMS calcd for C₂₁H₂₆N₂O₂338.1994, found 338.1993. This

material was used in a later step.

To a solution of optically pure (-)-3-{[(2R,5S)-2,5-dihydro-

5-(1-methylethyl)pyrazinyl]methyl}-6-methoxy-1-methyl-2-(tri-

ethylsilyl)-1H-indole (29) (50 g, 0.1 mol) in THF (1000 mL) at

0 °C was slowly added a cold solution of 2 N aq HCl (875 mL).

The mixture was allowed to warm to rt and stirred for 2 h.

Ice (800 g) was added to the solution, and the pH of the

reaction mixture was adjusted to 8 with 10% aq NH₄OH

(concd) at 0 °C. The mixture was then extracted with CH₂Cl₂

(4 × 1000 mL). The combined organic layers were dried (Na₂-

SO₄), and the solvent was removed under reduced pressure.

After all of the solvent had been removed, the residue was

subjected to Kugelrohr distillation at 80 °C (0.3 mmHg) to

remove ^L-valine ethyl ester while pure 1-methyl-6-methoxy-

D-tryptophan ethyl ester 30 (25.7 g, 93%) remained. An

analytical sample was obtained by flash chromatography (silica

gel, EtOAc) to afford 30 as a light yellow oil: [R]_D) -7.21 (c

2.01, CHCl₃) [lit.⁴⁹[R]_D) -7.09 (c 2.06, CHCl₃)]; IR (NaCl)

3374, 3311, 2980, 1736, 1623 cm^-1; ¹H NMR (300 MHz, CDCl₃)

δ 1.30 (t, J ) 7.1 Hz, 3 H), 1.62 (bs, 2 H), 2.99 (dd, J ) 14.4,

7.7 Hz, 1H), 3.24 (dd, J ) 14.3, 4.7 Hz, 1 H), 3.65(s, 3 H), 3.79

(dt, J ) 7.4, 2.6 Hz, 1 H), 3.89 (s, 3 H), 4.18 (q, J ) 7.1 Hz, 2

H), 6.75-6.83 (m, 3 H), 7.48 (d, J ) 8.6 Hz, 1 H); ¹³C NMR

(75.5 MHz, CDCl₃) δ 14.1, 30.6, 32.5, 55.2, 55.8, 60.6, 93.1,

108.9, 109.8, 119.6, 122.6, 126.5, 137.8, 156.6, 175.0; MS (EI)

m/e (relative intensity) 276 (M⁺, 4), 174(100), 159(11). Anal.

Calcd for C₁₅H₂₀N₂O₃: C, 65.18; H, 7.30; N 10.14. Found: C,

64.96; H, 7.36; N, 10.24. This material was used directly in

the next step.

Preparation of N_b-Benzyl-6-methoxy-1-methyl-D-tryp-

tophan Ethyl Ester (31). Benzaldehyde (46 g, 0.435 mol) was

added to a solution of tryptophan ethyl ester 30 (100 g, 0.36

mol) in dry ethanol (2 L) at rt under nitrogen. The solution

which resulted was stirred at this temperature for 5 h, cooled

to -10 °C, and treated portionwise with NaBH₄(16.5 g, 0.435

mol) to keep the temperature below -5 °C (about 3 h). After

the mixture was allowed to stir for an additional 1 h, ice-

water (75 mL) was added, and the mixture was allowed to

warm to rt. The ethanol was removed under reduced pressure,

and the aqueous residue was extracted with EtOAc (3 × 1.8

L). The combined organic layers were washed with brine and

dried (Na₂SO₄). After removal of the solvent under reduced

pressure, the residue was purified by flash chromatography

(ethyl acetate/hexanes ) 3:1) to afford 31 as an oil (125 g,

93%): ¹H NMR (250 MHz, CDCl₃) δ 1.14 (t, J ) 7.1 Hz, 3 H),

1.77 (bs, 1 H), 3.08 (dd, J ) 6.9, 2.7 Hz, 2H), 3.61 (m, 2 H),

3.65 (s, 3 H), 3.80 (d, J ) 13.2 Hz, 1H), 3.84 (s, 3 H), 4.07 (q,

J ) 7.1 Hz, 2 H), 6.72 (m, 3 H), 7.25 (m, 5 H), 7.40 (d, J ) 9.0

Hz, 1 H); ¹³C NMR (75.5 MHz, CDCl₃) δ 14.12, 29.21, 32.54,

52.01, 55.63, 60.49, 61.27, 92.64, 108.66, 109.73, 119.59,

122.40, 126.28, 126.86, 128.11, 128.22, 137.54, 139.72, 156.29,

174.78; CIMS m/e 367 (M⁺+ 1, 100). Anal. Calcd for

C₂₂H₂₆N₂O₃: C, 72.11; H, 7.15; N, 7.64. Found: C, 71.93; H,

7.10; N, 7.53. This material was used directly in the next step.

Preparation of (-)-3-{[(2R,5S)-2,5-Dihydro-5-(1-meth-

ylethyl)pyrazinyl]methyl}-6-methoxy-2-(triethylsilyl)-

1H-indole (28). To a three-neck flask (5 L) equipped with an

overhead stirrer were charged 2-iodo-5-methoxyaniline 26 (300

g, 1.20 mol) and the Scho¨llkopf derivative 27 (530 g, 1.45 mol),

as well as lithium chloride (5.1 g, 0.12 mol), sodium carbonate

(318 g, 3.0 mol), palladium(II) acetate (3.50 g, 0.0156 mol),

and dry DMF (4 L). The mixture was then degassed with a

vacuum pump three times at rt with argon. The suspension

which resulted was heated for 36 h at 100 °C under an

atmosphere of Ar. After examination of the mixture by TLC

(silica gel) indicated the iodoaniline 26 had been consumed,

the reaction mixture was cooled to rt and the DMF was

removed under reduced pressure. Methylene chloride (4 L) was

added to the residue, and the suspension which resulted was

filtered to remove unwanted salts. After removal of the CH₂-

Cl₂, the crude product was purified by flash chromatography

(silica gel, 2% EtOAc/hexanes) to give the desired 6-methoxy

substituted indole 28 (450 g, 77%): [R]_D) - 21.4 (c 1.58,

CHCl₃); IR (NaCl) 3388, 2944, 1683 cm^-1; ¹H NMR (300 MHz,

CDCl₃) δ 0.67 (d, J ) 6.8 Hz, 3 H), 0.85-1.05 (m, 18 H), 1.20

(t, J ) 7.1 Hz, 3 H), 1.30 (t, J ) 7.1 Hz, 3 H), 2.25 (m,1 H),

2.80 (dd, J ) 13.5, 10.6 Hz, 1 H), 3.46 (dd, J ) 14.1, 3.1 Hz, 1

H), 3.84 (s, 3 H), 3.88 (t, J ) 3.9 Hz, 1 H), 4.01-4.21 (m, 5 H),

6.70 (dd, J ) 8.7, 2.2 Hz, 1 H), 6.82 (d, J ) 2.1 Hz, 1 H), 7.60

(d, J ) 8.7 Hz, 1 H), 7.77 (bs, 1 H); ¹³C NMR (75.5 MHz, CDCl₃)

δ 4.1, 7.9, 14.7, 14.8, 17.1, 19.5, 32.1, 32.5, 56.0, 59.3, 60.9,

61.0, 61.1, 93.9, 109.3, 121.8, 124.4, 124.7, 130.5, 139.5, 157.0,

163.1, 164.2; MS (CI, CH₄) m/e (relative intensity) 486 (M⁺

+

1, 100), 456 (13), 372 (51), 274 (27); exact mass calcd for

C₂₇H₄₃N₃O₃Si 485.3074, found 485.3055. This material was

employed directly in the next step.

Preparation of (-)-1-Methyl-6-methoxy-^D-tryptophan

Ethyl Ester (29). Sodium hydride (60% in mineral oil, 12.4

g) in several portions was added to a mixture of indole 28 (100

g, 0.21 mol), methyl iodide (44 g, 0.31 mol), and anhydrous

DMF (1000 mL) at 0 °C. After this mixture was stirred for 2

h, analysis by TLC (silica gel) indicated the absence of starting

material. The reaction solution was quenched with water (8

mL), and the mixture which resulted was subsequently poured

into hexanes (5000 mL) to precipitate out sodium hydroxide

which was removed by filtration. The solvent was then

removed under reduced pressure and the residue was crystal-

lized from hexanes at 0 °C to afford the N_a-methyl derivative

29 as white needlelike crystals in several crops. The product

in the mother liquor was purified by flash chromatography

(silica gel, EtOAc/hexanes ) 3:97). The combined material 29

(99 g) was obtained in 95% yield: [R]_D) -17.5 (c 0.81, CHCl₃);

mp 91-92 °C; IR (NaCl) 2945, 1688, 1613 cm^-1; ¹H NMR (300

MHz, CDCl₃) δ 0.63 (d, J ) 6.8 Hz, 3 H), 0.95 (m, 15 H), 0.98

(d, J ) 6.9 Hz, 3 H), 1.14 (t, J ) 7.1 Hz, 3 H), 1.23 (t, J ) 7.1

Hz, 3 H), 2.23 (m, 1 H), 2.80 (dd, J ) 14.0, 4.5 Hz, 1 H), 3.45

(dd, J ) 14.0, 3.5 Hz, 1 H), 3.73 (s, 3 H), 3.84 (s, 3 H), 3.85 (m,

1 H), 3.90-4.15 (m, 5 H), 6.65 (m, 2 H), 7.50 (d, J ) 9.2 Hz, 1

H); ¹³C NMR (75.5 MHz, CDCl₃) δ 4.8, 7.6, 14.3, 14.4, 16.7,

19.1, 31.6, 31.9, 33.1, 55.7, 59.2, 60.4, 60.5, 60.7, 91.9, 108.2,

Preparation of (-)-(1S,3R)-N_b-Benzyl-3-(ethoxycar-

bonyl)-2,3,4,9-tetrahydro-7-methoxy-9-methyl-1H-pyrido-

[3,4-b]-1-propanoic Acid Methyl Ester (33b). The methyl

4-oxobutanoate 32 (24 g, 0.208 mol) and HOAc (8.25 g, 0.138

mol) were added to a round-bottom flask (2 L) which contained

a solution of optically active N_b-benzyl-6-methoxy-1-methyl-

D-tryptophan ethyl ester 31 (50 g, 0.138 mol) in dry CH₂Cl₂

(300 mL) at 0 °C. The reaction mixture which resulted was

stirred at rt overnight. A mixture of trans and cis diastereo-

mers (72:28) was present at this stage. The TFA (23.75 g, 0.208

mol) in CH₂Cl₂(500 mL) was then added at 0 °C. The reaction

mixture which resulted was stirred at rt for 12 h and then

cooled in an ice bath. The pH was brought to 8 with a solution

of 10% aq NH₄OH_.The aqueous layer was separated and

extracted with CH₂Cl₂(3 × 500 mL). After the combined

J. Org. Chem, Vol. 70, No. 10, 2005 3973

Yu et al.

organic layers were washed with brine and dried (K₂CO₃), the

solvent was removed under reduced pressure. The residue

which resulted was purified by flash chromatography (silica

resulted was allowed to stir at rt under an atmosphere of H₂

for 24 h. Analysis by TLC (silica gel plate was exposed to NH₃

vapors) indicated the existence of only a very small amount of

starting material 33. The catalyst was removed by filtration

(Celite) and was washed with EtOH (3 × 100 mL). The solvent

was removed under reduced pressure. The residue was dis-

solved in a mixture of CHCl₃and aq NH₄OH (5:1, 500 mL).

The aqueous layer was extracted with CHCl₃(3 × 200 mL).

The combined organic layers were washed with brine (100 mL)

and dried (K₂CO₃). The solvent was removed under reduced

pressure to afford the crude amine which was chromato-

graphed (flash) on silica gel (CHCl₃/EtOH ) 9:1) to provide

pure N_a-Me, N_b-H, tetracyclic ketone 36 (4.56 g, 87%): FTIR

gel, EtOAc/hexanes ) 1:4) to provide 33b (57 g, 90%): [R]_D

)

-34.7 (c 0.3, CHCl₃); FTIR (CDCl₃) 2950, 2846, 1735, 1624

1

cm^-1; H NMR (250 MHz, CDCl₃) δ 1.35 (t, J ) 7.1 Hz, 3 H),

1.89 (m, 2 H), 2.43 (m, 2 H), 3.02 (m, 2 H), 3.36 (d, J ) 13.2

Hz, 1 H), 3.45 (s, 3 H), 3.57 (s, 3 H), 3.78 (d, J ) 13.2 Hz, 2 H),

3.87 (s, 3 H), 4.02 (dd, J ) 10.5, 5.4 Hz, 1 H), 4.22 (m, 2 H),

6.77 (s, 1 H), 6.80 (d, J ) 2.2 Hz, 1 H), 7.21-7.44 (m, 6 H); ¹³

C

NMR (62.5 MHz, CDCl₃) δ 14.36, 20.47, 28.21, 29.75, 51.20,

52.69, 53.63, 56.32, 60.81, 93.57, 106.46, 108.66, 118.71,

126.96, 128.17, 129.35, 134.66, 139.54, 156.47, 172.90, 173.94;

EIMS(70 eV) m/e (relative intensity) 464 (M⁺, 7.4), 377 (100.0),

213 (37.5). Anal. Calcd for C₂₇H₃₂N₂O₅: C, 69.81; H, 6.94; N,

6.03. Found: C, 70.11; H, 6.94; N, 5.90. This material was used

directly in the next step.

1

(CHCl₃) 1700, 1619 cm^-1; [R]_D) -147.16 (c 0.43, CHCl₃); H

NMR (300 MHz, CDCl₃) δ 2.10-2.22 (m, 2 H), 2.46-2.55 (m,

2 H), 2.81 (d, J ) 16.6 Hz, 1 H), 3.13 (dd, J ) 16.6, 6.8 Hz, 1

H), 3.65 (s, 3 H), 3.90 (s, 3 H), 3.96 (d, J ) 6.8 Hz, 1 H), 4.40

(bs, 1 H), 6.78 (m, 2 H), 7.36 (d, J ) 9.2 Hz, 1 H); ¹³C NMR

(75.5 MHz, CDCl₃) δ 25.68, 29.32, 31.37, 34.84, 44.89, 55.75,

59.68, 93.10, 106.39, 108.53, 118.65, 120.89, 133.84, 137.69,

156.30, 210.64; EIMS (m/e, relative intensity) 270 (M⁺, 23),

213 (100). Anal. Calcd for C₁₆H₁₈N₂O₂: C, 71.09; H, 6.71; N,

10.36. Found: C, 70.89; H, 6.77; N, 10.25. This material was

used directly in the next step.

Preparation of (6S,10S)-5,6,7,8,10,11-Hexahydro-12-(Z-

2′-iodo-2′-butenyl)-3-methoxy-5-methyl-6,10-iminocyclooct-

[b]indol-9-one (38). A solution of N_a-methyl, N_b-H tetracyclic

ketone 36 (4.0 g, 14.8 mmol) and Z-1-bromo-2′-iodo-2-butene

37 (5.35 g, 20.6 mmol) was dissolved in THF (200 mL), and

K₂CO₃(13.3 g) was added. The mixture was heated to 60 °C

for 24 h. Analysis by TLC (silica gel, CHCl₃/C₂H₅OH ) 4:1)

indicated the absence of tetracyclic ketone 36. The K₂CO₃was

removed by filtration and was washed with EtOAc (3 × 100

mL). After removal of the solvent under reduced pressure, the

crude product was purified by flash chromatography (silica gel,

EtOAc/hexanes ) 1:9) to provide N_b-Z-2′-iodo-2′-butenyl tet-

racyclic ketone 38 (5.66 g, 85%): FTIR (CHCl₃) 1710, 1618

cm^-1; [R]_D) -81.96 (c 1.36, CHCl₃); ¹H NMR (300 MHz,

CDCl₃) δ 1.83 (d, J ) 6.36 Hz, 3 H), 1.96-2.18 (m, 2 H), 2.48-

2.59 (m, 2 H), 2.68 (d, J ) 16.9 Hz, 1 H), 3.12 (dd, J ) 16.9.

6.9 Hz, 1 H), 3.37 (bs, 2 H), 3.60 (s, 3 H), 3.70 (d, J ) 6.5 Hz,

1 H), 3.91 (s, 3 H), 4.09 (bs, 1 H), 5.85 (q, J ) 6.3 Hz, 1 H),

6.80 (m, 2 H), 7.37 (d, J ) 9.2 Hz, 1 H); ¹³C NMR (75.5 MHz,

CDCl₃) δ 20.54, 21.71, 29.36, 29.75, 34.27, 48.75, 55.82, 63.52,

63.93, 93.17, 105.82, 108.59, 118.68, 120.79, 132.00, 132.65,

137.83, 139.28, 156.32, 209.97; EIMS (m/e, relative intensity)

450 (M⁺, 20), 393 (89), 213 (100), 212 (69). Anal. Calcd for

C₂₀H₂₃N₂O₂I: C, 53.34; H, 5.15; N, 6.22. Found: C, 53.66; H,

5.29; N, 6.03. This material was used directly in the next step.

Preparation of 11-Methoxy-1-methyl-17-norsarpagan-

16-one (39). A mixture of N_b-Z-2′-iodo-2′-butenyl tetracyclic

ketone 38 (2 g, 4.44 mmol), Pd(OAc)₂(50 mg, 0.22 mmol), Bu₄-

NBr (1.45 g, 4.44 mmol), PPh₃(250 mg, 0.95 mmol), and K₂-

CO₃(2.47 g, 17.76 mmol) in a solution of DMF-H₂O (9:1, 200

mL) was degassed under reduced pressure at rt with argon.

The mixture was then heated to 70 °C (oil bath temperature)

under an atmosphere of argon for 24 h. The mixture was cooled

to rt, diluted with EtOAc (1000 mL), washed with H₂O (5 ×

100 mL), and dried (Na₂SO₄). The solvent was removed under

reduced pressure, and the oil which resulted was chromato-

graphed (silica gel, EtOAc/hexanes ) 3:7) to provide penta-

cyclic ketone 39 (1.18 g, 82%): ¹H NMR (300 MHz, CDCl₃) δ

1.68 (d, J ) 6.9 Hz, 3 H), 2.16 (dt, J ) 12.6, 3.3 Hz, 1 H), 2.52

(t, J ) 11.7 Hz, 1 H), 2.97 (dd, J ) 15.6, 6.2 Hz, 1 H), 3.28 (d,

J ) 15.5 Hz, 1 H), 3.40 (bs, 1 H), 3.56 (s, 3 H), 3.58 (m, 1 H),

3.84 (m, 2 H), 3.89 (s, 3 H), 4.34 (d, J ) 9.3 Hz, 1 H), 5.54 (q,

J ) 6.9 Hz, 1 H), 6.77 (m, 2 H), 7.38 (d, J ) 8.2 Hz, 1 H); ¹³C

NMR (75.5 MHz, CDCl₃) δ 12.58, 22.50, 29.28, 36.01, 44.34,

49.66, 55.50, 55.73, 64.09, 93.09, 104.43, 108.29, 119.02,

120.87, 121.00, 132.40, 136.44, 138.18, 156.13, 217.29; CIMS

(m/e, relative intensity) 323 (M⁺+ 1, 100); HRMS calcd for

Preparation of (-)-(6S,10S)-5,6,7,8,10,11-Hexahydro-3-

methoxy-5-methyl-6,10-imino-9H-cyclooct[b]indol-9-

one (35). Sodium hydride (4.8 g of 60% NaH in mineral oil,

0.12 mol) was added to a solution of trans diester 33b (20 g,

0.04 mol) in dry toluene (40 mL) under argon. Dry methanol

(4.0 mL) was added carefully to the above mixture (a large

amount of H₂was evolved at this point). The mixture which

resulted was stirred at rt for 0.5 h and then heated to reflux

for an additional 4 h. The reaction mixture was then allowed

to cool to rt and treated with a saturated aqueous solution of

NaHCO₃(40 mL). The organic layer was separated, washed

with brine, and dried (Na₂SO₄). After removal of solvent under

reduced pressure, the residue was purified by flash chroma-

tography (hexanes/ethyl acetate ) 3:1) to afford the â-ketoester

34 (14.4 g, 85%) as a yellow colored solid: mp 168-169 °C;

FTIR (CHCl₃) 3053, 2924, 1660 cm^-^{1 1}H NMR (250 MHz,

;

CDCl₃) δ 2.27 (d, J ) 15.5 Hz, 1 H), 2.84 (dd, J ) 15.5, 5.5 Hz,

1 H), 2.87 (d, J ) 15.5 Hz, 1 H), 3.14 (dd, J ) 16.2, 5.8 Hz, 1

H), 3.53 (s, 3 H), 3.66 (s, 3 H), 3.74 (d, J ) 15.5 Hz, 2 H), 3.75

(m, 1 H), 3.66 (s, 3 H), 4.04 (d, J ) 5.3 Hz, 1 H,), 6.76-6.80

(m, 2 H), 7.25-7.39 (m, 6 H), 11.97 (s, 1 H); ¹³C NMR (75.5

MHz, CDCl₃) δ 22.21, 28.13, 29.39, 48.82, 51.42, 54.97, 55.95,

56.02, 93.25, 93.99, 105.32, 108.55, 118.76, 121.07, 127.28,

128.43, 128.74, 133.18, 137.68, 138.29, 156.21, 171.90, 172.54;

EIMS (70 eV) m/e (relative intensity) 418 (M⁺, 57), 303 (100.0),

295 (69). Anal. Calcd for C₂₅H₂₆N₂O₄: C, 71.75; H, 6.26; N,

6.69. Found: C, 71.98; H, 6.22; N, 6.74. This material was used

directly in the next step.

A solution of â-ketoester 34 prepared above (4.0 g, 9.6 mmol)

was dissolved in 1,4-dioxane (40 mL). The 40% aqueous

solution of KOH was then added to the above mixture. The

reaction mixture which resulted was heated to reflux for 3 d.

The solution was allowed to cool to rt. The 1,4-dioxane was

removed under reduced pressure. The mixture which remained

was extracted with CH₂Cl₂(3 × 20 mL). The organic layer was

separated, washed with brine, and dried (Na₂SO₄). The solvent

was removed under reduced pressure and the residue was

purified by flash chromatography (hexanes/ethyl acetate ) 3:1)

to afford 35 as white crystals (2.9 g, 85%): mp 77-78 °C;

[R]_D) -176.2 (c 0.30, CHCl₃); FTIR (CDCl₃) 1713, 1625 cm^-1

;

¹H NMR (250 MHz, CDCl₃) δ 1.89-2.17 (m, 2 H), 2.43 (m, 2

H), 2.63 (d, J ) 16.9 Hz, 1 H), 3.20 (dd, J ) 16.9, 6.7 Hz, 1 H),

3.52 (s, 3 H), 3.64 (s, 2 H), 3.67 (s, 3 H), 4.01 (bs, 2 H), 6.76-

6.80 (m, 2 H), 7.24-7.39 (m, 6 H); ¹³C NMR (75.5 MHz, CDCl₃)

δ 20.55, 29.32, 29.85, 34.30, 49.04, 55.97, 56.31, 64.94, 93.54,

105.84, 108.70, 118.78, 121.12, 127.32, 128.44, 128.65, 132.10,

138.12, 138.42, 156.55, 209.98; EIMS (70 eV) m/e (relative

intensity) 360 (M⁺, 31.9), 303 (100.0). Anal. Calcd for

C₂₃H₂₄N₂O₂: C, 76.64; H, 6.71; N, 7.77. Found: C, 76.61; H,

6.90; N, 7.63. This material was used directly in the next step.

Preparation of (-)-(6S,10S)-5,6,7,8,10,11-Hexahydro-3-

methoxy-5-methyl-6,10-imino-9H-cyclooct[b]indol-9-

one (36). Tetracyclic ketone 35 (7.0 g, 19.4 mmol) was

dissolved in anhydrous ethanolic HCl (5%, 100 mL), after

which Pd/C (10%, 1.5 g) was added. The mixture which

3974 J. Org. Chem., Vol. 70, No. 10, 2005

Synthesis of Vincamajine-Related Indole Alkaloids

C₂₀H₂₂N₂O₂322.1681, found 322.1681. This material was

employed directly in the next step.

under a N₂atmosphere. The reaction mixture which resulted

was stirred at rt for 12 h, at which time it was passed through

a pad of Celite and washed with CH₂Cl₂(50 mL). The filtrate

was washed with brine (2 × 50 mL), dried (Na₂SO₄), filtered,

and concentrated under reduced pressure. The residue that

resulted was purified by preparative TLC on silica gel (CHCl₃/

MeOH ) 9:1) to provide 42 and its C-16 epimer in >8:1 ratio

Preparation of (+)-11-Methoxy-1-methylsarpagan-17-

al (40). A mixture of anhydrous potassium tert-butoxide (6.73

g, 0.06 mol) and methoxymethyl triphenylphosphonium chlo-

ride (17.1 g, 0.05 mol) in dry benzene (500 mL) was allowed

to stir at rt for 1 h. The pentacyclic ketone 39 (2.0 g, 6.9 mmol)

in THF (160 mL) was then added into the above orange

solution dropwise at rt. The mixture which resulted was stirred

at rt for 24 h (the reaction progress was monitored by ¹H NMR

spectroscopy). The mixture was diluted with EtOAc (3 × 700

mL), washed with H₂O (3 × 50 mL) and brine (50 mL), and

dried (K₂CO₃). The solvent was removed under reduced pres-

sure to afford an oil. The baseline materials were removed by

a rapid wash column on silica gel. The solvent was removed

under reduced pressure and the residue was dissolved (without

further purification) in a solution of aq HCl (2 N) in H₂O-

THF (1:1, 400 mL). The solution which resulted was stirred

at 55 °C (oil bath temperature) under an atmosphere of argon

for 6 h (the reaction progress was monitored by ¹H NMR

spectroscopy). The reaction mixture was cooled to 0 °C and

extracted with ethyl ether (5 × 100 mL) to remove phosphorus-

based byproducts, and the water layer was then brought to

pH 8 with an ice-cold aqueous solution of NaOH (1 N). The

aqueous layer was extracted with CH₂Cl₂(3 × 1 L), and the

combined organic layers were washed with H₂O (3 × 100 mL),

brine (100 mL) and dried (K₂CO₃). The solvent was removed

under reduced pressure to provide N_a-methyl-16-epi-gardneral

(186 mg, 77%). 42: FTIR 2923, 1700, 1625, 1489 cm^-^{1 1}H

;

NMR (300 MHz, DMSO-d₆) δ 1.63 (d, J ) 8.0 Hz, 3 H), 1.96

(m, 1 H), 2.10 (dt, J ) 13.2, 3.4 Hz, 1H), 2.91 (d, J ) 15.6 Hz,

1 H), 3.02 (d, J ) 4.8 Hz, 1 H), 3.06 (m, 1 H), 3.10 (d, J ) 5.0

Hz, 1 H), 3.55 (s, 3 H), 3.56 (m, 1 H), 3.64 (m, 2 H), 3.72 (m,

1 H), 3.89 (s, 3 H), 4.25 (dd, J ) 9.8, 1.8 Hz, 1 H), 5.42 (q, J )

6.8 Hz, 1 H), 6.76 (m, 2 H), 7.31 (d, J ) 11.0 Hz, 1 H), 9.18 (s,

1 H); ¹³C NMR (75.5 MHz, DMSO-d₆) δ 12.8, 24.0, 27.2, 27.6,

29.2, 49.2, 53.8, 55.7, 55.8, 61.3, 66.7, 93.2, 104.3, 108.2, 117.1,

118.7, 120.1, 135.8, 137.3, 138.4, 156.2, 203.8; EIMS (m/e,

relative intensity) 366 (M⁺, 53), 337 (64), 293 (34), 213 (100),

198 (29), 79 (36). This material was employed directly in the

next step.

Preparation of (2r,17S,19E)-17-Aceto-16-[(acetyloxy)-

methyl]-19,20-didehydro-11-methoxyajmalan-2,17-diol

(43). The TFA (3 mL) was added to a solution of aldehyde 42

(100 mg, 0.27 mmol) in Ac₂O (3 mL). The reaction mixture

was stirred in a sealed vessel at rt for 8 h, at which time it

was concentrated under reduced pressure. The residue was

diluted with CH₂Cl₂(20 mL), and a cold solution of an aq 10%

NH₄OH was added to bring the pH to 8. The organic layer

was diluted with CH₂Cl₂(20 mL), washed with brine (2 × 20

mL), dried (Na₂SO₄), filtered, and evaporated under reduced

pressure. The residue that resulted was purified by prepara-

tive TLC on silica gel (CHCl₃/MeOH ) 9:1) to provide 43 (108.7

40 (1.88 g, 90%): FTIR (CHCl₃) 1710, 1618, 1484 cm^-1; [R]_D

)

+30.93 (c 1.05, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 1.62 (d,

J ) 6.9 Hz, 3 H), 1.78 (ddd, J ) 12.4, 3.7, 2.6 Hz, 1 H), 2.13

(ddd, J ) 12.2, 9.8, 1.8 Hz, 1 H), 2.52 (d, J ) 7.6 Hz, 1 H),

2.57 (d, J ) 15.6 Hz, 1 H), 3.13 (dd, J ) 15.5, 5.2 Hz, 1 H),

3.22 (m, 1 H), 3.59 (s, 3 H), 3.61-3.66 (m, 3 H), 3.89 (s, 3 H),

4.25 (d, J ) 8.4 Hz, 1 H), 5.38 (q, J ) 6.7 Hz, 1 H), 6.77 (m, 2

H), 7.35 (d, J ) 7.8 Hz, 1 H), 9.65 (s, 1 H); ¹³C NMR (75.5

MHz, CDCl₃) δ 12.57, 26.48, 27.17, 29.33, 32.29, 49.33, 50.47,

54.75, 55.76, 56.06, 93.18, 102.92, 108.17, 116.90, 118.68,

121.53, 134.23, 137.88, 138.05, 155.95, 202.71; EIMS (70 eV,

m/e, relative intensity) 336 (M⁺, 95), 307 (100), 277 (97), 213

(50). This material was employed directly in the next step

without further purification.

1

mg, 85%): FTIR 2938, 1741, 1624, 1239 cm^-1; H NMR (300

MHz, CDCl₃) δ 1.56 (m, 1 H), 1.60 (d, J ) 6.8 Hz, 3 H), 1.78

(s, 3 H), 2.02 (s, 3 H), 2.04 (m, 1 H), 2.53 (d, J ) 12.4 Hz, 1 H),

2.72 (s, 3 H), 2.76 (d, J ) 4.6 Hz, 1 H), 2.88 (d, J ) 4.0 Hz, 1

H), 2.97 (dd, J ) 13.5, 4.7 Hz, 1 H), 3.52 (m, 2 H), 3.64 (d,

J ) 10.2 Hz, 1 H), 3.78 (s, 3 H), 3.92 (m, 2 H), 5.35 (s, 1 H),

5.43 (q, J ) 6.7 Hz, 1 H), 6.15 (d, J ) 2.1 Hz, 1 H), 6.29 (dd,

J ) 8.1, 2.2 Hz, 1 H), 6.96 (d, J ) 8.0 Hz, 1 H); ¹³C NMR (75.5

MHz, CDCl₃) δ 12.8, 20.6, 20.7, 22.7, 28.3, 29.4, 30.0, 43.8,

55.3, 55.6, 58.1, 58.8, 62.0, 67.8, 77.1, 81.9, 95.9, 97.8, 102.4,

116.7, 119.2, 123.3, 137.2, 153.6, 160.8, 169.4, 171.0; EIMS

(m/e, relative intensity) 468 (M⁺, 5), 452 982), 349 (5), 283

(100), 224 (94), 212 (32). This material was employed directly

in the next step.

Preparation of (6S,7R,9E,10S,11aS)-9-Ethylidene-5,8,9,-

10,11a,12-hexahydro-3-methoxy-5-methyl-6,10-methanoin-

dolo[3,2-b]quinolizine-11,11(6H)-dimethanol (41). To a

solution of aldehyde 40 (336 mg, 1.0 mmol) in MeOH (10 mL)

were added formaldehyde [(25 equiv, 25 mmol) 1.9 mL of a

37% w/w solution in water] and 85% KOH (10 equiv, 659 mg,

10 mmol) in MeOH (10 mL). The reaction mixture which

resulted was stirred at rt for 10 h, diluted with brine, and

extracted with CH₂Cl₂(2 × 50 mL). The combined organic

extracts were washed with brine, dried (Na₂SO₄), filtered, and

concentrated under reduced pressure. The residue that re-

sulted was purified by column chromatography (MeOH/CHCl₃

) 1:12) to afford 41 (320 mg, 87%): FTIR 3329, 2931, 1625,

Preparation of (2r,17R,19E)-17-Aceto-16-[(acetyloxy)-

methyl]-19,20-didehydro-11-methoxyajmalan-2,17-diol

(44). The TFA (5 mL) and Et₃SiH (5 mL) were added at rt to

a solution of 43 (50 mg, 0.106 mmol) in CH₂Cl₂(5 mL). The

reaction mixture was stirred in a sealed vessel at rt for 3 d, at

which time it was concentrated under reduced pressure. The

residue was dissolved in CH₂Cl₂(10 mL), and cold 10% aq NH₄-

OH was added to bring the pH to 8. The organic layer was

diluted with CH₂Cl₂(20 mL), washed with brine (2 × 20 mL),

dried (Na₂SO₄), and filtered and the solvent removed under

reduced pressure. The residue that resulted was purified by

preparative TLC on silica gel (CHCl₃/MeOH ) 15:1) to provide

44 (41 mg, 85%): FTIR 2944, 1742, 1232 cm^-1; ¹H NMR (300

MHz, CDCl₃) δ 1.53 (dd, J ) 13.7, 10.4 Hz, 1 H), 1.60 (d, J )

6.8 Hz, 3 H), 1.80 (s, 3 H), 1.82 (m, 1 H), 2.03 (s, 3 H), 2.27

(dd, J ) 12.0, 4.6 Hz, 1 H), 2.65 (s, 3 H), 2.73 (d, J ) 4.5 Hz,

1 H), 2.81 (d, J ) 3.4 Hz, 1H), 2.98 (dd, J ) 13.4, 4.8 Hz, 1 H),

3.36 (d, J ) 4.6 Hz, 1 H), 3.54 (m, 2 H), 3.72 (dd, J ) 9.6, 4.5

Hz, 1 H), 3.82 (s, 3 H), 3.93 (m, 2 H), 5.31 (s, 1 H), 5.39 (q,

J ) 6.8 Hz, 1 H), 6.21 (d, J ) 2.2 Hz, 1 H), 6.32 (dd, J ) 8.1,

2.2 Hz, 1 H), 6.98 (d, J ) 8.1 Hz, 1 H); ¹³C NMR (75.5 MHz,

CDCl₃) δ 12.8, 20.8, 22.2, 28.8, 29.6, 34.7, 36.4, 45.0, 52.7, 54.0,

55.3, 55.6, 61.8, 68.0, 77.1, 82.6, 96.5, 103.0, 116.4, 121.4, 122.8,

137.6, 156.3, 160.6, 169.5, 171.0; EIMS (m/e, relative intensity)

452 (M⁺, 100), 409 (6), 393 (22). This material was used

directly in the next step.

1

1491 cm^-1; H NMR (300 MHz, CDCl₃) δ 1.67 (d, J ) 6.8 Hz,

3 H), 1.84-2.00 (m, 2 H), 2.66 (m, 1 H), 3.01 (m, 3 H), 3.46 (d,

J ) 10.9 Hz, 1 H), 3.54 (s, 3 H), 3.60 (d, J ) 10.9 Hz, 1 H),

3.71 (m, 4 H), 3.90 (s, 3 H), 4.25 (d, J ) 9.2 Hz, 1 H), 5.41 (q,

J ) 6.4 Hz, 1 H), 6.77 (m, 2 H), 7.33 (dd, J ) 7.2, 1.9 Hz, 1 H);

¹³C NMR (75.5 MHz, CDCl₃) δ 12.8, 22.2, 27.5, 28.3, 29.2, 48.2,

48.9, 55.7, 55.9, 56.8, 63.6, 70.2, 93.1, 104.8, 108.3, 117.0, 118.8,

120.2, 135.3, 135.8, 138.1, 156.1; EIMS (m/e, relative intensity)

368 (M⁺, 100), 351 (23), 337 (57), 293 (23), 213 (69); HRMS

calcd for C₂₂H₂₈N₂O₃368.2100, found 368.2087. This material

was employed directly in the next step.

Preparation of (6S,7R,9E,10S,11aS)-9-Ethylidene-5,6,-

8,9,10,11,11a,12-octahydro-11-hydromethyl-3-methoxy-5-

methyl-6,10-methanoindolo[3,2-b]quinolizine-11-carbox-

aldehyde (42). The TPAP (12.3 mg, 0.034 mmol) was added

to a mixture of 41 (250 mg, 0.68 mmol), 4 Å MS (340 mg, 500

mg/mmol), and NMO (123.1 mg, 1.02 mmol) in CH₂Cl₂(50 mL)

J. Org. Chem, Vol. 70, No. 10, 2005 3975

Yu et al.

Preparation of (+)-(2r,17R,19E)-19,20-Didehydro-17-

hydroxy-11-methoxyajmalan-16-methanol (45). The 20%

aq K₂CO₃(5 mL) was added to a solution of 44 (30 mg, 0.066

mmol) in MeOH (5 mL) at rt. The mixture was stirred at rt

for 6 h and concentrated under reduced pressure to remove

the MeOH. It was then diluted with CH₂Cl₂(20 mL) and

separated. The aqueous phase was extracted with CH₂Cl₂

(2 × 15 mL). The combined organic extracts were washed with

brine, dried (Na₂SO₄), filtered, and evaporated under reduced

pressure. The residue that resulted was purified by prepara-

tive TLC on silica gel (CHCl₃/MeOH ) 9:1) to provide 45 (21.6

mg, 90%): [R]_D) +24.8 (c 1.75, MeOH); FTIR 3372, 2915,

1618, 1489, 1459, 1262, 1227, 1077 cm^-1; ¹H NMR (300 MHz,

CDCl₃) δ 1.53 (m, 1 H), 1.67 (d, J ) 6.8 Hz, 3 H), 1.75 (d, J )

11.9 Hz, 1H), 2.18 (dd, J ) 11.9, 4.5 Hz, 1 H), 2.65 (s, 3 H),

2.81 (d, J ) 4.2 Hz, 1 H), 2.93 (m, 2 H), 3.42 (d, J ) 6.7 Hz, 1

H), 3.44 (m, 1 H), 3.54 (m, 1 H), 3.57 (t, J ) 2.2 Hz, 1 H), 3.63

(d, J ) 10.2 Hz, 1 H), 3.74 (dd, J ) 9.7, 5.1 Hz, 1 H), 3.82 (s,

3 H), 4.07 (s, 1 H), 5.37 (q, J ) 6.8 Hz, 1 H), 6.32 (d, J ) 2.1

Hz, 1 H), 6.40 (dd, J ) 8.0, 2.2 Hz, 1 H), 7.01 (d, J ) 8.0 Hz,

1 H); ¹³C NMR (75.5 MHz, CDCl₃) δ 13.0, 22.6, 28.1, 34.7, 35.8,

47.3, 53.2, 54.6, 55.4, 55.5, 62.1, 67.1, 76.2, 85.8, 97.2, 104.2,

116.3, 122.0, 122.7, 137.5, 156.1, 160.7; EIMS (m/e, relative

intensity) 368 (M⁺, 72), 351(8), 187 (100), 174 (78). This

material was used in a later step.

mixture of 48 (161 mg, 0.38 mmol), 4 Å MS (190 mg, 500 mg/

mmol), and NMO (69 mg, 0.57 mmol) in CH₂Cl₂(30 mL) under

a N₂atmosphere. The reaction mixture which resulted was

stirred at rt for 12 h, at which time it was passed through a

pad of Celite and washed with CH₂Cl₂(30 mL). The filtrate

was washed with brine (2 × 30 mL), dried (Na₂SO₄), filtered,

and concentrated under reduced pressure. The residue that

resulted was purified by preparative TLC on silica gel (CHCl₃/

MeOH ) 9:1) to provide 49 and its C-16 epimer in >8:1 ratio

(120 mg, 75%). The TFA (2 mL) was added to a solution of

pure 49 prepared above (120 mg, 0.28 mmol) in CH₂Cl₂(5 mL)

at rt. The reaction mixture was stirred at rt for 3 h. After

removal of the solvent under reduced pressure, the residue

was brought to pH 9 with a cold solution of 10% aq NaOH.

The mixture which resulted was extracted with CH₂Cl₂(2 ×

20 mL), the combined organic extracts were washed with brine

(2 × 20 mL), dried (Na₂SO₄), and filtered, and the solvent was

removed under reduced pressure. The residue that resulted

was purified by column chromatography on silica gel (CHCl₃/

MeOH ) 20:1) to afford aldehyde 50 (76 mg, 84%): FTIR 3374,

1

2906, 1680, 1452 cm^-1; H NMR (300 MHz, DMSO-d₆) δ 1.57

(d, J ) 6.7 Hz, 3 H), 1.69 (t, J ) 11.4 Hz, 1 H), 1.96 (m, 1 H),

2.82 (dd, J ) 15.6, 4.6 Hz, 1 H), 2.90 (d, J ) 3.0 Hz, 1 H), 3.02

(d, J ) 3.7 Hz, 1 H), 3.16 (d, J ) 5.4 Hz, 1 H), 3.38 (dd, J )

10.2, 4.6 Hz, 1 H), 3.47 (dd, J ) 7.9, 1.7 Hz, 1 H), 3.65 (dd,

J ) 10.4, 4.9 Hz, 1 H), 4.11 (d, J ) 10.2 Hz, 1 H), 4.79 (t, J )

4.6 Hz, 1 H), 5.32 (q, J ) 6.7 Hz, 1 H), 6.94 (t, J ) 7.8 Hz, 1

H), 7.02 (td, J ) 8.8, 1.2 Hz, 1 H), 7.25 (d, J ) 8.0 Hz, 1 H),

7.36 (d, J ) 7.5 Hz, 1 H), 8.99 (s, 1 H), 10.87 (s, 1 H); ¹³C NMR

(75.5 MHz, DMSO-d₆) δ 13.0, 23.6, 26.9, 28.1, 50.0, 53.1, 55.6,

58.4, 66.2, 104.2, 111.4, 115.3, 117.9, 118.6, 121.0, 126.1, 136.8,

138.7, 139.0, 202.2; EIMS (m/e, relative intensity) 322 (M⁺,

195), 293 (72), 263 (44), 249 (53), 169 (100); HRMS calcd for

C₂₀H₂₂N₂O₂322.1681, found 322.1670. This material was used

directly in the next step.

Preparation of N_a-Boc-vellosimine (47). To a solution

of vellosimine 46 (100 mg, 0.34 mmol) and Boc₂O (100 mg, 0.47

mmol) in dry CH₃CN (1 mL) was added DMAP (5 mg). The

mixture which resulted was allowed to stir at rt for 4 h. The

solvent was removed under reduced pressure and the oil was

chromatographed (silica gel, EtOAc/hexanes ) 2:3) to provide

47 (113 mg, 85%): FTIR (NaCl) 1726, 1369 cm^-^{1 1}H NMR

;

(300 MHz, CDCl₃) δ 1.58 (d, J ) 6.82 Hz, 3 H), 1.66 (s, 9 H),

1.78 (dt, J ) 12.9, 3.1 Hz, 1 H), 2.22 (m, 1 H), 2.39 (d, J ) 7.5

Hz, 1 H), 2.53 (dd, J ) 16.1, 1.0 Hz, 1 H), 3.08 (ddd, J ) 16.1,

5.4, 1.2 Hz, 1 H), 3.16 (t, J ) 1.9 Hz, 1 H), 3.53-3.65 (m, 3 H),

4.71 (d, J ) 7.4 Hz, 1 H), 5.32 (q, J ) 6.9 Hz, 1 H), 7.17-7.28

(m, 2 H), 7.38 (d, J ) 7.0 Hz, 1 H), 8.08 (d, J ) 7.6 Hz, 1 H),

9.62 (s, 1 H); ¹³C NMR (75.5 MHz, CDCl₃) δ 12.6, 26.7, 27.2,

28.2, 33.4, 49.4, 51.3, 55.3, 56.0, 84.0, 110.7, 115.8, 116.8, 118.0,

122.7, 124.0, 129.4, 134.4, 136.0, 138.7, 150.1, 202.8; EIMS

(m/e, relative intensity) 392 (M⁺, 21), 336 (25), 321 (14), 307

(100), 293 (22), 263 (18), 213 (26), 169 (38); HRMS calcd for

C₂₄H₂₈N₂O₃392.2100, found 392.2079. This material was used

directly in the next step.

Preparation of (2r,17S,19E)-17-Aceto-16-[(acetyloxy)-

methyl]-19,20-didehydro-1-demethylajmalan-17-ol (52).

The Ac₂O (3 mL) which was presaturated with HCl (g) was

added to a solution of 50 (92 mg, 0.28 mmol). The reaction

mixture was heated at 55 °C in a sealed vessel for 5 d. After

cooling, the solvent was removed under reduced pressure. The

residue was diluted with CH₂Cl₂(20 mL), and cold 10% aq

NH₄OH was added to bring the pH to 8. The organic layer

was diluted with CH₂Cl₂(20 mL), washed with brine (2 × 20

mL), dried (Na₂SO₄), filtered, and evaporated under reduced

pressure. The residue that resulted was purified by prepara-

tive TLC on silica gel (CHCl₃/MeOH ) 9:1) to provide a

mixture of 51 and its C-17 epimer in >2:1 ratio (90 mg, 78%).

To a solution of 51 prepared above (81 mg, 0.20 mmol) in AcOH

(2 mL) was added NaBH₃CN (20 mg, 0.30 mmol) at rt. The

reaction mixture was stirred at rt for 1 h and then cooled in

an ice bath. The 10% aq NH₄OH was added to bring the pH to

8 and the mixture was extracted with CH₂Cl₂(2 × 20 mL).

The combined organic extracts were washed with brine (2 ×

20 mL), dried (Na₂SO₄), and filtered, and the solvent was

removed under reduced pressure. The residue that resulted

was purified by preparative TLC on silica gel (CHCl₃/MeOH

) 9:1) to provide 52 (49 mg, 60%) and its C-17 epimer (24 mg,

Preparation of N_a-Boc-17-hydroxysarpagan-16-metha-

nol (48). To a solution of aldehyde 47 (392 mg, 1.0 mmol) in

MeOH (10 mL) were added formaldehyde [(25 equiv, 25 mmol)

1.9 mL of a 37% w/w solution in water] and 85% KOH (10

equiv, 659 mg, 10 mmol) in MeOH (10 mL). The reaction

mixture was stirred at rt for 10 h, diluted with brine, and

extracted with CH₂Cl₂(2 × 50 mL). The combined organic

extracts were washed with brine, dried (Na₂SO₄), filtered, and

concentrated under reduced pressure. The residue that re-

sulted was purified by column chromatography (MeOH/CHCl₃

) 1:12) to afford diol 48 (390 mg, 92%): FTIR 3070, 2923, 1726

1

cm^-1; H NMR (300 MHz, CDCl₃) δ 1.60 (d, J ) 6.7 Hz, 3 H),

1.68 (s, 9 H), 1.81 (dt, J ) 13.6, 3.3 Hz, 1 H), 2.01 (td, J )

10.5, 2.2 Hz, 1 H), 2.81 (m, 4 H), 3.43 (d, J ) 10.7 Hz, 1 H),

3.54 (m, 4 H), 3.70 (d, J ) 10.7 Hz, 1 H), 4.61 (dd, J ) 10.3,

3.4 Hz, 1 H), 5.30 (q, J ) 6.6 Hz, 1 H), 7.29 (m, 3 H), 8.12 (d,

J ) 7.9 Hz, 1 H); ¹³C NMR (75.5 MHz, CDCl₃) δ 12.7, 22.3,

27.9, 28.1, 28.1, 28.1, 29.2, 42.5, 50.6, 55.4, 55.9, 64.4, 70.6,

83.9, 112.6, 115.6, 115.9, 117.9, 122.6, 123.9, 128.4, 135.8,

136.9, 137.5, 149.9; EIMS (m/e, relative intensity) 424 (M⁺,

100), 368 (94), 351 (49), 337 (92), 323 (30), 293 (51), 213 (52),

169 (78); HRMS calcd for C₂₅H₃₂N₂O₄424.2362, found 424.2356.

This material was used directly in the next step.

30%). 52: FTIR 3423, 1642, 1243 cm^-^{1 1}H NMR (300 MHz,

;

CDCl₃) δ 1.52 (m, 1 H), 1.58 (d, J ) 6.6 Hz, 3 H), 1.77 (d, J )

11.7 Hz, 1 H), 1.87 (s, 3 H), 2.00 (s, 3 H), 2.45 (dd, J ) 11.7,

4.7 Hz, 1 H), 2.71 (m, 2 H), 3.10 (d, J ) 4.2 Hz, 1 H), 3.46 (t,

J ) 1.8 Hz, 1 H), 3.56 (dd, J ) 9.4, 4.0 Hz, 1 H), 3.86 (m, 2 H),

3.92 (d, J ) 10.9 Hz, 1 H), 4.11 (d, J ) 10.9 Hz, 1 H), 5.38 (q,

J ) 6.4 Hz, 1 H), 5.63 (s, 1 H), 6.76 (m, 2 H), 7.08 (m, 2 H); ¹³

C

NMR (75.5 MHz, CDCl₃) δ 12.7, 20.6, 20.7, 21.6, 28.5, 36.2,

49.8, 55.1, 55.4, 57.1, 62.3, 64.3, 68.4, 74.7, 110.9, 117.2, 119.1,

123.8, 128.3, 128.8, 137.4, 151.5, 168.7, 170.9; EIMS (m/e,

relative intensity) 408 (M⁺, 100), 349 (71), 278 (19), 218 (27),

176 (57), 130 (94); HRMS calcd for C₂₄H₂₈N₂O₄408.2049, found

408.2049. This material was used directly in the next step.

Preparation of (6S,7R,9E,10S,11S,11aS)-9-Ethylidene-

5,6,8,9,10,11,11a,12-octahydro-11-(hydroxymethyl)-5H-

6,10-methanoindolo[3,2-b]quinolizine-11-carboxalde-

hyde (50). The TPAP (6.9 mg, 0.019 mmol) was added to a

3976 J. Org. Chem., Vol. 70, No. 10, 2005

Synthesis of Vincamajine-Related Indole Alkaloids

Preparation of (+)-(2r,17S,19E)-19,20-Didehydro-17-

hydroxy-1-demethylajmalan-16-methanol (53). A 20% aq

solution of K₂CO₃(2 mL) was added to a solution of 52 (8.2

mg, 0.02 mmol) in methanol (2 mL) at rt. The mixture which

resulted was stirred at rt for 24 h and concentrated under

reduced pressure to remove MeOH, diluted with CH₂Cl₂(10

mL), and separated. The aqueous phase was extracted with

CH₂Cl₂(2 × 10 mL). The combined organic extracts were

washed with brine, dried (Na₂SO₄), and filtered, and the

solvent was removed under reduced pressure. The residue that

resulted was purified by preparative TLC on silica gel (CHCl₃/

MeOH ) 9:1) to provide diol 53 as a pale yellow powder (5.5

mg, 85%): [R]_D) +59.2 (c 0.24, MOH); FTIR: 3395, 2925,

Hz, 1 H), 7.02 (dd, J ) 7.2, 0.9 Hz, 1 H), 7.17 (td, J ) 7.7, 1.3

Hz, 1 H); ¹³C NMR (75.5 MHz, CDCl₃) 12.7, 20.6, 21.6, 28.6,

29.9, 30.1, 48.9, 55.2, 58.8, 62.1, 62.7, 63.9, 75.3, 96.6, 108.7,

118.3, 118.7, 123.9, 127.0, 128.7, 135.5, 151.5, 168.6, 170.7;

EIMS (m/e, relative intensity) 438 (M⁺, 100), 422 (76), 379 (34),

319 (22), 289 (12), 182 (28); HRMS calcd for C₂₅H₃₀N₂O₅

438.2154, found 438.2148. This material was used directly in

the next step.

Preparation of O,O-Diacetylvincamajinol (55). TFA (3

mL) and Et₃SiH (3 mL) were added to a solution of 54 (66 mg,

0.15 mmol) in CH₂Cl₂(4 mL). The reaction mixture which

resulted was stirred in a sealed vessel at rt for 2 d, at which

time the solvent was removed under reduced pressure. The

residue was dissolved in CH₂Cl₂(10 mL) and brought to pH 7

with cold 10% aq NH₄OH. The organic layer was diluted with

CH₂Cl₂(20 mL), washed with brine (2 × 20 mL), and dried

(Na₂SO₄). The solvent was removed under reduced pressure,

and the residue that resulted was purified by preparative TLC

on silica gel (CHCl₃/MeOH ) 15:1) to provide diacetate 55 (57.6

1

1632, 1462 cm^-1; H NMR (300 MHz, CDCl₃) δ 1.52 (dd, J )

9.9, 4.1 Hz, 1 H), 1.71 (d, J ) 6.8 Hz, 3 H), 1.75 (m, 1 H), 2.48

(m, 1 H), 2.52 (d, J ) 7.0 Hz, 1 H), 2.74 (d, J ) 4.6 Hz, 1 H),

3.00 (d, J ) 4.8 Hz, 1 H), 3.46 (m, 2 H), 3.55 (m, 1 H), 3.67 (m,

2 H), 3.92 (d, J ) 5.1 Hz, 1 H), 4.30 (s, 1 H), 5.42 (q, J ) 6.8

Hz, 1 H), 6.82 (m, 2 H), 7.15 (m, 2 H); ¹³C NMR (75.5 MHz,

CDCl₃) δ 12.9, 21.8, 28.5, 35.2, 51.5, 55.1, 55.4, 58.1, 62.7, 64.4,

68.2, 75.1, 111.1, 117.3, 119.7, 123.9, 128.5, 129.3, 137.0, 151.7;

EIMS (m/e, relative intensity) 324 (M⁺, 66), 307 (10), 194 (100),

176 (29), 130 (87); HRMS calcd for C₂₀H₂₄N₂O₂324.1838, found

324.1835. This material was identical to that obtained from

an authentic sample of quebrachidine (3) described below.

Preparation of (+)-(2r,17S,19E)-19,20-Didehydro-17-

hydroxy-1-demethylajmalan-16-methanol (53) from the

Reduction of Natural (+)-Quebrachidine (3). The LiAlH₄

(4 equiv, 2.6 mg, 0.064 mmol) was added to a solution of

natural (+)-quebrachidine (5.6 mg, 0.016 mmol) in THF (2 mL)

at 0 °C. After the mixture was stirred for 10 min at 0 °C, the

reaction was warmed to rt and stirred for an additional 4 h. it

was then cooled in an ice bath. Water (0.5 mL) was slowly

added to this mixture, and the mixture was extracted with

CH₂Cl₂(2 × 15 mL). The combined organic extracts were

washed with brine, dried (Na₂SO₄), filtered, and evaporated

under reduced pressure. The residue that resulted was purified

by preparative TLC on silica gel (CHCl₃/MeOH ) 9:1) to

provide authentic diol 53 as a pale yellow powder (4.2 mg,

82%): [R]_D) +60.6 (c 0.165, MeOH); FTIR 3326, 2922, 1608,

1456 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 1.53 (dd, J ) 9.9, 4.1

Hz, 1 H), 1.71 (d, J ) 6.8 Hz, 3 H), 1.75 (m, 1 H), 2.48 (m, 1

H), 2.53 (d, J ) 7.0 Hz, 1 H), 2.74 (d, J ) 4.6 Hz, 1 H), 3.01 (d,

J ) 4.7 Hz, 1 H), 3.46 (m, 2 H), 3.55 (m, 1 H), 3.67 (m, 2 H),

3.92 (d, J ) 5.0 Hz, 1 H), 4.30 (s, 1 H), 5.41 (q, J ) 6.8 Hz, 1

H), 6.83 (m, 2 H), 7.16 (m, 2 H); ¹³C NMR (75.5 MHz, CDCl₃)

δ 12.9, 21.9, 28.6, 35.2, 51.5, 55.2, 55.5, 58.2, 62.7, 64.3, 68.3,

75.2, 111.1, 117.3, 119.7, 123.9, 128.5, 129.3, 137.3, 151.7;

EIMS (m/e, relative intensity) 324 (M⁺, 85), 307 (6), 194 (100),

176 (28), 130 (89); HRMS calcd for C₂₀H₂₄N₂O₂324.2838, found

324.1837.

1

mg, 91%): FTIR 2950, 1744, 1477, 1244 cm^-1; H NMR (300

MHz, CDCl₃) δ 1.52 (m, 1 H), 1.56 (d, J ) 6.7 Hz, 3 H), 1.75

(d, J ) 11.8 Hz, 1 H), 1.85 (s, 3 H), 1.98 (s, 3 H), 2.41 (dd, J )

6.9, 3.9 Hz, 1 H), 2.53 (dd, J ) 14.3, 5.0 Hz, 1 H), 2.65 (s, 3 H),

2.68 (d, J ) 4.7 Hz, 1 H), 3.08 (d, J ) 4.6 Hz, 1 H), 3.20 (d,

J ) 4.9 Hz, 1 H), 3.43 (m, 1 H), 3.45 (t, J ) 2.1 Hz, 1 H), 3.57

(dd, J ) 10.0, 4.9 Hz, 1 H), 3.90 (d, J ) 10.9 Hz, 1 H), 4.09 (d,

J ) 10.9 Hz, 1 H), 5.39 (q, J ) 6.8 Hz, 1 H), 5.58 (d, J ) 0.9

Hz, 1 H), 6.65 (dd, J ) 7.4, 3.6 Hz, 1 H), 6.73 (td, J ) 7.5, 0.6

Hz, 1 H), 7.01 (dd, J ) 7.2, 0.8 Hz, 1 H), 7.15 (td, J ) 7.7, 1.2

Hz, 1 H); ¹³C NMR (75.5 MHz, CDCl₃) 12.7, 20.5, 20.6, 21.1,

28.3, 34.0, 35.9, 49.8, 53.6, 55.4, 56.3, 62.3, 64.2, 74.6, 75.1,

109.1, 117.3, 118.6, 123.3, 128.4, 129.2, 137.1, 154.2, 169.5,

170.9; EIMS (m/e, relative intensity) 422 (M⁺, 100), 379 (12),

363 (39), 319 (7); HRMS calcd for C₂₅H₃₀N₂O₄422.2206, found

422.2181. This material was used directly in the next step.

Preparation of (+)-(2r,17S,19E)-19,20-Didehydro-17-

hydroxyajmalan-16-methanol (56). The 20% aq solution of

K₂CO₃(2 mL) was added to a solution of diacetate 55 (21 mg,

0.05 mmol) in methanol (2 mL) at rt. The mixture which

resulted was stirred at rt for 2 d and concentrated under

reduced pressure to remove MeOH, after which it was diluted

with CH₂Cl₂(15 mL), and separated. The aqueous layer was

extracted with CH₂Cl₂(2 × 10 mL). The combined organic

extracts were washed with brine, dried (Na₂SO₄), and filtered,

and the solvent was removed under reduced pressure. The

residue that resulted was purified by preparative TLC on silica

gel (CHCl₃/MeOH ) 9:1) to provide diol 56 as a pale yellow

oil (15 mg, 88%): [R]_D) +10.5 (c 0.51, MeOH); FTIR 2943,

1

1607, 1476 cm^-1; H NMR (300 MHz, CDCl₃) δ 1.50 (dd, J )

13.8, 9.8 Hz, 1 H), 1.61 (m, 1 H), 1.67 (d, J ) 6.7 Hz, 3 H),

2.34 (dd, J ) 14.0, 5.0 Hz, 1 H), 2.48 (dd, J ) 11.8, 4.8 Hz, 1

H), 2.65 (s, 3 H), 2.71 (d, J ) 5.8 Hz, 1 H), 2.94 (d, J ) 4.7 Hz,

1 H), 3.23 (d, J ) 4.9 Hz, 1 H), 3.42 (m, 2 H), 3.52 (m, 1 H),

3.69 (m, 2 H), 4.24 (s, 1 H), 5.39 (q, J ) 6.7 Hz, 1 H), 6.67 (d,

J ) 7.8 Hz, 1 H), 6.83 (td, J ) 7.5, 0.6 Hz, 1 H), 7.15 (dd, J )

7.2, 0.7 Hz, 1 H), 7.20 (td, J ) 7.8, 1.2 Hz, 1 H); ¹³C NMR

(75.5 MHz, CDCl₃) 12.9, 21.5, 28.4, 34.1, 35.2, 51.5, 54.0, 55.3,

57.4, 62.7, 64.5, 74.6, 75.5, 109.2, 117.0, 119.0, 123.6, 128.5,

130.0, 137.3, 154.5; EIMS (m/e, relative intensity) 338 (M⁺,

100), 321 (10), 194 (67), 157 (71), 144 (88); HRMS calcd for

C₂₁H₂₆N₂O₂338.1994, found 338.1990. This material was

identical to that obtained from an authentic sample of (-)-

vincamajine (4) described below.

Preparation of (2r,17R,19E)-17-Aceto-16-[(acetyloxy)-

methyl]-19,20-didehydroajmalan-2,17-diol (54). Aldehyde

23 (80 mg, 0.23 mmol) was dissolved in Ac₂O (5 mL) which

was presaturated with HCl gas. The reaction mixture was

stirred in a sealed vessel at rt for 3 d, at which time it was

concentrated under reduced pressure. The residue was dis-

solved in CH₂Cl₂(20 mL), and cold 10% aq NH₄OH was added

to bring the pH to 8. The organic layer was diluted with CH₂-

Cl₂(20 mL), washed with brine (2 × 20 mL), dried (Na₂SO₄),

filtered, and concentrated under reduced pressure. The residue

that resulted was purified by preparative TLC on silica gel

(CHCl₃/MeOH ) 12:1) to provide 54 (60 mg, 60%) and its C-17

epimer (18 mg, 18%). 54: FTIR 2950, 1743, 1477 cm^-^{1 1}H

;

Preparation of (+)-(2r,17S,19E)-19,20-Didehydro-17-

hydroxyajmalan-16-methanol (56) from the Reduction

of Natural (-)-Vincamajine (4). To a solution of natural (-)-

vincamajine (4.4 mg, 0.012 mmol) in THF (2 mL) at 0 °C was

added LiAlH₄(4 equiv, 2.6 mg, 0.064 mmol). After the mixture

was stirred for 10 min at 0 °C, the reaction solution was

allowed to warm to rt and stirred for an additional 1 h. The

reaction mixture was then quenched by slow addition of water

(0.5 mL). The mixture was extracted with CH₂Cl₂(2 × 15 mL),

NMR (300 MHz, CDCl₃) δ 1.59 (d, J ) 6.8 Hz, 3 H), 1.68 (dd,

J ) 14.3, 3.7 Hz, 1 H), 1.87 (s, 3 H), 2.00 (s, 3 H), 2.24 (dd,

J ) 12.6, 4.5 Hz, 1 H), 2.57 (d, J ) 12.6 Hz, 1 H), 2.67 (dd,

J ) 15.0, 5.0 Hz, 1 H), 2.74 (s, 3 H), 2.78 (d, J ) 4.6 Hz, 1 H),

3.12 (d, J ) 4.6 Hz, 1 H), 3.20 (d, J ) 4.7 Hz, 1 H), 3.53 (m, 2

H), 3.73 (d, J ) 10.1 Hz, 1 H), 3.90 (d, J ) 10.9 Hz, 1 H), 4.10

(d, J ) 10.9 Hz, 1 H), 5.49 (q, J ) 6.8 Hz, 1 H), 5.62 (d, J )

1.5 Hz, 1 H), 6.62 (d, J ) 7.8 Hz, 1 H), 6.75 (td, J ) 7.9, 0.7

J. Org. Chem, Vol. 70, No. 10, 2005 3977

Yu et al.

washed with brine, and dried (Na₂SO₄). The solvent was

removed under reduced pressure, and the residue that resulted

was purified by preparative TLC on silica gel (CHCl₃/MeOH

) 9:1) to provide authentic diol 56 as a pale yellow oil (3.9

mg, 87%): [R]_D) +10.6 (c 0.17, MeOH); FTIR 2943, 1607, 1476

cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 1.53 (dd, J ) 13.9, 9.9 Hz,

1 H), 1.61 (m, 1 H), 1.68 (d, J ) 6.7 Hz, 3 H), 2.36 (dd, J )

13.9, 4.9 Hz, 1 H), 2.49 (dd, J ) 11.8, 4.8 Hz, 1 H), 2.67 (s. 3

H), 2.71 (d, J ) 5.8 Hz, 1 H), 2.99 (d, J ) 4.7 Hz, 1 H), 3.27 (d,

J ) 4.9 Hz, 1 H), 3.47 (m, 2 H), 3.64 (m, 3 H), 4.28 (s, 1 H),

5.40 (q, J ) 6.7 Hz, 1 H), 6.69 (d, J ) 7.4 Hz, 1 H), 6.83 (t,

J ) 7.5 Hz, 1 H), 7.15 (d, J ) 7.1 Hz, 1 H), 7.23 (td, J ) 1.0,

7.8 Hz, 1 H); ¹³C NMR (75.5 MHz, CDCl₃) 12.9, 21.6, 28.4, 34.1,

35.2, 51.5, 53.9, 55.4, 57.5, 62.7, 64.4, 74.8, 75.7, 109.3, 116.9,

119.1, 123.3, 128.6, 129.9, 137.8, 154.5; EIMS (m/e, relative

intensity) 338 (M⁺, 61), 321 (5), 194 (80), 157 (100), 144 (97);

HRMS calcd for C₂₁H₂₆N₂O₂338.1994, found 338.1994.

Preparation of (17R,19E)-17-Aceto-16-[(acetyloxy)meth-

yl]-1,2,19,20-tetradehydro-1-demethylajmalan-17-ol (57).

The TFA (5 mL) was added to a solution of 50 (161 mg, 0.50

mmol) in Ac₂O (5 mL). The reaction mixture was stirred in a

sealed vessel at rt for 8 h, at which time the solvent was

removed under reduced pressure. The residue was dissolved

in CH₂Cl₂(40 mL), and a cold solution of 10% aq NH₄OH was

added to bring the pH to 8. The organic layer was diluted with

CH₂Cl₂(40 mL), washed with brine (2 × 30 mL), dried (Na₂-

SO₄), and filtered and the solvent removed under reduced

pressure. The residue that resulted was purified by prepara-

tive TLC on silica gel (CHCl₃/MeOH ) 9:1) to provide diacetate

57 (184 mg, 80%): FTIR 3421, 2938, 1737, 1332 cm^-1; ¹H NMR

(300 MHz, CDCl₃) δ 1.63 (d, J ) 7.0 Hz, 3 H), 1.68 (s, 1 H),

1.82 (s, 3 H), 2.05 (m, 2 H), 2.09 (s, 3 H), 2.15 (d, J ) 13.5 Hz,

1 H), 2.43 (m, 2 H), 2.86 (d, J ) 4.8 Hz, 1 H), 2.93 (d, J ) 4.4

Hz, 1 H), 3.62 (m, 2 H), 4.14 (m, 2 H), 4.37 (d, J ) 9.4 Hz, 1

H), 5.45 (q, J ) 6.7 Hz, 1 H), 6.01 (s, 1 H), 7.28 (td, J ) 6.6,

0.8 Hz, 1 H), 7.37 (td, J ) 7.7, 1.2 Hz, 1 H); ¹³C NMR (75.5

MHz, CDCl₃) δ 12.7, 20.7, 20.7, 27.4, 29.3, 35.9, 46.3, 54.1,

56.3, 61.1, 64.7, 67.9, 77.8, 117.2, 120.6, 122.5, 125.4, 128.5,

134.9, 136.7, 156.4, 169.4, 170.8, 183.9; EIMS (m/e, relative

intensity) 406 (M⁺, 100), 363 (39), 347 (87), 333 (44), 303 (25),

182 (30), 169 (40); HRMS calcd for C₂₄H₂₆N₂O₄406.1893, found

406.1879. This material was used directly in the next step.

0.10 mmol) in methanol (4 mL) at rt. The mixture which

resulted was stirred at rt for 2 d and concentrated under

reduced pressure to remove MeOH. It was then diluted with

CH₂Cl₂(30 mL) and separated. The aqueous layer was

extracted with CH₂Cl₂(2 × 20 mL). The combined organic

extracts were washed with brine, dried (Na₂SO₄), and filtered,

and the solvent was removed under reduced pressure. The

residue that resulted was purified by preparative TLC on silica

gel (CHCl₃/MeOH ) 9:1) to provide diol 59 as a pale yellow

solid (28 mg, 87%): [R]_D) +66.7 (c 0.21, MeOH); FTIR 3402,

1

2922, 1638 cm^-1; H NMR (300 MHz, CDCl₃) δ 1.52 (dd, J )

13.4, 9.9 Hz, 1 H), 1.66 (d, J ) 6.7 Hz, 3 H), 1.78 (d, J ) 11.9

Hz, 1 H), 2.18 (m, 1 H), 2.22 (d, J ) 4.6 Hz, 1 H), 2.79 (d, J )

4.3 Hz, 1 H), 2.91 (d, J ) 4.8 Hz, 1 H), 3.06 (dd, J ) 13.5, 5.0

Hz, 1 H), 3.41 (d, J ) 10.2 Hz, 1 H), 3.52 (dt, J ) 9.7, 2.0 Hz,

1 H), 3.60 (d, J ) 10.2 Hz, 1 H), 3.72 (m, 1 H), 4.08 (d, J ) 6.3

Hz, 1 H), 4.10 (s, 1 H), 5.35 (q, J ) 6.7 Hz, 1 H), 6.86 (m, 2 H),

7.14 (m, 2 H); ¹³C NMR (75.5 MHz, CDCl₃) δ 12.9, 23.0, 28.3,

35.9, 47.5, 54.5, 55.4, 56.1, 62.1, 67.0, 69.6, 85.9, 111.6, 116.2,

120.3, 122.1, 128.2, 130.2, 137.6, 151.9; EIMS (m/e, relative

intensity) 324 (M⁺, 64), 307 (10), 194 (100), 176 (29), 143 (55),

130 (100); HRMS calcd for C₂₀H₂₄N₂O₂324.1838, found

324.1839.

Preparation of (2r,19E)-19,20-Didehydro-16-hydroxy-

methylajmalan-17-one (60). The Dess-Martin periodinane

(7.76 mg, 0.018 mmol) reagent was added to a solution of 25

(5.0 mg, 0.015 mmol) in CH₂Cl₂(3 mL) at 0 °C, and the mixture

was stirred at rt for 1 h. Solutions of saturated aq NaHCO₃(1

mL) and saturated aq Na₂S₂O₃(1 mL) were added to the

mixture, and this was followed by the addition of CH₂Cl₂(10

mL). The organic layer was separated, and the aqueous phase

was extracted with CH₂Cl₂(2 × 10 mL). The combined organic

extracts were washed with brine, dried (Na₂SO₄), and filtered,

and the solvent was removed under reduced pressure to give

a residue which was purified by preparative TLC on silica gel

(CHCl₃/MeOH ) 9:1) to provide ketone 60 (4.3 mg, 87%): FTIR

3560, 2945, 1735 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 1.68 (dd,

J ) 3.6, 1.8 Hz, 1 H), 1.70 (d, J ) 6.8 Hz, 3 H), 2.05 (d, J ) 4.4

Hz, 1 H), 2.12 (d, J ) 11.7 Hz, 1 H), 2.45 (dd, J ) 12.0, 4.6 Hz,

1 H), 2.65 (s, 3 H), 2.98 (d, J ) 4.1 Hz, 1 H), 3.04 (d, J ) 4.9

Hz, 1 H), 3.44 (d, J ) 4.5 Hz, 1 H), 3.60 (m, 2 H), 3.63 (d, J )

11.4 Hz, 1 H), 3.77 (d, J ) 11.0 Hz, 1 H), 3.78 (m, 1 H), 5.47

(q, J ) 6.8 Hz, 1 H), 6.72 (d, J ) 7.9 Hz, 1 H), 6.91 (t, J ) 6.7

Hz, 1 H), 7.20 (d, J ) 6.3 Hz, 1 H), 7.24 (d, J ) 6.4 Hz, 1 H);

¹³C NMR (75.5 MHz, CDCl₃) δ 12.92, 23.41, 27.32, 34.02, 35.61,

54.38, 54.96, 56.12, 59.03, 61.23, 63.73, 76.66, 109.23, 118.21,

119.58, 123.36, 127.02, 128.82, 135.54, 154.39, 218.13; EIMS

(m/e, relative intensity) 336 (M⁺, 25), 308 (20), 291 (6), 277

(5), 144 (100); HRMS calcd for C₂₁H₂₄N₂O₂336.1838, found

336.1834. This material was used directly in the next step.

Preparation of (2r,17R,19E)-17-Aceto-16-[(acetyloxy)-

methyl]-19,20-didehydro-1-demethylajmalan-17-ol (58).

The TFA (3 mL) and Et₃SiH (3 mL) were added to a solution

of 57 (61 mg, 0.15 mmol) in CH₂Cl₂(4 mL) at rt. The reaction

mixture which resulted was stirred in a sealed vessel at rt for

2 d, at which time the solvent was removed under reduced

pressure. The residue was dissolved in CH₂Cl₂(10 mL) and

brought to pH 7 with 10% aq NH₄OH. The organic layer was

diluted with CH₂Cl₂(20 mL), washed with brine (2 × 20 mL),

and dried (Na₂SO₄). The solvent was removed under reduced

pressure, and the residue that resulted was purified by

preparative TLC on silica gel (CHCl₃/MeOH ) 15:1) to provide

Preparation of (2r,19E)-19,20-Didehydro-17-oxoajma-

lan-16-carboxaldehyde (61). To a solution of keto alcohol

60 (6.0 mg, 0.018 mmol) in CH₂Cl₂(3 mL) was added Dess-

Martin periodinane (11.8 mg, 0.027 mmol) at rt, and the

mixture was stirred at rt for 30 min. Solutions of saturated

aq NaHCO₃(1 mL) and saturated aq Na₂S₂O₃(1 mL) were

then added to the mixture, and this was followed by the

addition of CH₂Cl₂(10 mL). The organic layer was separated,

and the aqueous phase was further extracted with CH₂Cl₂

(2 × 10 mL). The combined organic extracts were washed with

brine, dried (Na₂SO₄), filtered, and concentrated in vacuo to

give a residue which was purified by preparative TLC on silica

gel (CHCl₃/MeOH ) 9:1) to provide 61 (5.4 mg, 90%): FTIR

diacetate 58 (55 mg, 90%): FTIR 3345, 2920, 1736, 1236 cm^-1

;

¹H NMR (300 MHz, CDCl₃) δ 1.52 (dd, J ) 13.3, 10.2 Hz, 1

H), 1.59 (d, J ) 6.7 Hz, 3 H), 1.79 (s, 3 H), 1.85 (d, J ) 9.5 Hz,

1 H), 2.02 (s, 3 H), 2.30 (dd, J ) 11.8, 4.7 Hz, 1 H), 2.73 (d,

J ) 4.6 Hz, 1 H), 2.77 (d, J ) 4.4 Hz, 1 H), 3.09 (dd, J ) 13.5,

4.9 Hz, 1 H), 3.50 (m, 2 H), 3.66 (m, 1 H), 3.93 (d, J ) 4.7 Hz,

2 H), 4.01 (d, J ) 4.8 Hz, 1 H), 5.32 (s, 1 H), 5.37 (q, J ) 6.7

Hz, 1 H), 6.74 (d, J ) 7.6 Hz, 1 H), 6.82 (t, J ) 7.4 Hz, 1 H),

7.09 (m, 2 H); ¹³C NMR (75.5 MHz, CDCl₃) δ 12.8, 20.6, 20.8,

22.7, 29.0, 36.5, 45.2, 54.1, 55.6, 61.9, 68.0, 69.4, 83.0, 110.8,

116.3, 119.8, 123.0, 128.2, 128.6, 137.8, 152.0, 169.4, 171.0;

EIMS (m/e, relative intensity) 408 (M⁺, 94), 349 (60), 278 (15),

218 (25), 176 (62), 130 (100); HRMS calcd for C₂₄H₂₈N₂O₄

408.2049, found 408.2045. This material was used directly in

the next step.

1

3414, 2940, 1735 cm^-1; H NMR (300 MHz, CDCl₃) δ 1.59 (d,

J ) 6.8 Hz, 3 H), 1.60 (m, 1 H), 2.19 (m, 1 H), 2.28 (m, 1 H),

2.66 (s, 3 H), 3.42 (m, 2 H), 3.60 (m, 3 H), 3.73 (d, J ) 4.2 Hz,

1 H), 3.82 (m, 1 H), 5.41 (q, J ) 6.8 Hz, 1 H), 6.73 (d, J ) 7.9

Hz, 1 H), 6.88 (m, 1 H), 6.98 (d, J ) 6.8 Hz, 1 H), 7.25 (m, 1

H), 9.74 (s, 1 H); ¹³C NMR (75.5 MHz, CDCl₃) δ 12.6, 23.2,

29.0, 34.1, 35.0, 54.1, 55.3, 55.4, 61.1, 66.8, 75.6, 109.4, 118.8,

119.8, 123.3, 126.2, 129.1, 132.8, 154.4, 196.4, 208.8. EIMS

(m/e, relative intensity) 334 (M⁺, 20), 306 (36), 277 (11), 183

Preparation of (2r,17R,19E)-19,20-Didehydro-17-hy-

droxy-1-demethylajmalan-16-methanol (59): The solution

of 20% aq K₂CO₃(4 mL) was added to a solution of 58 (41 mg,

3978 J. Org. Chem., Vol. 70, No. 10, 2005

Synthesis of Vincamajine-Related Indole Alkaloids

(24), 157 (32), 144 (100); HRMS calcd for C₂₁H₂₂N₂O₂334.1681,

found 334.1687. This material was used directly in the next

step.

9.67 (s, 1 H); ¹³C NMR (75.5 MHz, CDCl₃) δ 13.1, 23.3, 29.0,

33.8, 35.4, 54.0, 54.2, 55.3, 55.8, 59.2, 66.8, 76.6, 97.0, 103.9,

118.2, 118.5, 124.0, 133.3, 155.7, 161.0, 196.8, 209.1; EIMS

(m/e, relative intensity) 364 (M⁺, 9), 336 (42), 307 (14), 213

(18), 187 (37), 174 (100). This material was employed directly

in the next step.

Preparation of (2r,19E)-19,20-Didehydro-17-oxoajma-

lan-16-carboxylic Acid Methyl Ester (62). Aldehydoketone

61 (8.0 mg, 0.024 mmol) was dissolved in anhydrous MeOH

(1 mL), and a solution of 85% KOH (2.6 equiv, 4.1 mg, 0.062

mmol) and iodine (1.3 equiv, 7.8 mg, 0.031 mmol) in anhydrous

MeOH (each 0.25 mL) was successively added at 0 °C. The

mixture which resulted was stirred at rt for 1 h, and glacial

acetic acid was then added dropwise to bring the pH to 8. The

solution was diluted with CH₂Cl₂(10 mL), the organic layer

was washed with 10% Na₂S₂O₃(10 mL) and brine (2 × 10 mL),

dried (Na₂SO₄), and filtered, and the solvent was removed

under reduced pressure. The residue that resulted was purified

by preparative TLC on silica gel (CHCl₃/MeOH ) 12:1) to

provide 62 (7.8 mg, 92%): FTIR 2949, 2358, 1752, 1718, 1239

cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 1.68 (dd, J ) 10.9, 9.8 Hz,

1 H), 1.71 (dt, J ) 6.8, 1.7 Hz, 3 H), 2.17 (m, 2 H), 2.64 (s, 3

H), 2.73 (dd, J ) 12.1, 4.6 Hz, 1 H), 3.42 (d, J ) 4.5 Hz, 1 H),

3.56 (d, J ) 4.1 Hz, 1 H), 3.61 (m, 2 H), 3.69 (m, 2 H), 3.75 (s,

3 H), 5.35 (q, J ) 6.7 Hz, 1 H), 6.71 (d, J ) 7.9 Hz, 1 H), 6.89

(td, J ) 7.5, 0.8 Hz, 1 H), 7.03 (dd, J ) 7.4, 0.8 Hz, 1 H), 7.25

(td, J ) 7.8, 1.3 Hz, 1 H); ¹³C NMR (75.5 MHz, CDCl₃) δ 13.1,

23.7, 29.2, 34.0, 35.7, 52.4, 53.8, 55.9, 59.2, 60.5, 61.6, 76.6,

109.3, 118.2, 119.7, 123.4, 126.9, 128.9, 134.4, 154.5, 169.0,

207.4. EIMS (m/e, relative intensity) 364 (M⁺, 19), 336 (37),

144 (100); HRMS calcd for C₂₂H₂₄N₂O₃364.1787, found

364.1779. This material was used directly in the next step.

Preparation of (-)-Vincamajinine (7). To a solution of

62 (7 mg, 0.019 mmol) in EtOH (1 mL) at 0 °C was added

NaBH₄(1.1 mg, 0.029 mmol). The reaction mixture was stirred

at rt for 1 h. To this mixture, water (0.1 mL) was added slowly.

The solution which resulted was diluted with CH₂Cl₂(5 mL),

the organic layer was washed with brine (2 × 10 mL), dried

(Na₂SO₄), filtered, and the solvent was removed under reduced

pressure. The residue that resulted was purified by prepara-

tive TLC on silica gel (CHCl₃/MeOH ) 9:1) to provide 7 as a

pale yellow solid (6.4 mg, 90%): [R]_D) -4.00 (c 0.30, CHCl₃);

FTIR 2919, 1726, 1453, 1255 cm^-1; ¹H NMR (300 MHz, CDCl₃)

δ 1.50 (dd, J ) 13.7, 10.2 Hz, 1 H), 1.56 (dt, J ) 6.8, 1.6 Hz,

3 H), 1.74 (d, J ) 11.9 Hz, 1 H), 2.54 (dd, J ) 11.9, 4.7 Hz, 1

H), 2.63 (s, 3 H), 2.90 (dd, J ) 13.4, 4.9 Hz, 1 H), 3.37 (d, J )

4.9 Hz, 1 H), 3.41 (d, J ) 4.7 Hz, 1 H), 3.48 (m, 3 H), 3.63 (dd,

J ) 9.2, 4.9 Hz, 1 H), 3.68 (s, 3 H), 3.98 (s, 1 H), 5.23 (q, J )

6.7 Hz, 1 H), 6.76 (d, J ) 7.9 Hz, 1 H), 6.83 (td, J ) 7.4, 0.8

Hz, 1 H), 7.04 (dd, J ) 7.4, 0.8 Hz, 1 H), 7.18 (td, J ) 7.7, 1.3

Hz, 1 H); ¹³C NMR (75.5 MHz, CDCl₃) δ 12.9, 23.1, 29.9, 34.9,

36.1, 51.9, 53.6, 53.8, 54.1, 55.6, 61.7, 76.2, 86.3, 109.8, 115.9,

120.1, 121.6, 128.6, 130.3, 136.7, 154.7, 175.3; EIMS (m/e,

relative intensity) 366 (M⁺, 76), 222 (9), 190 (83), 157 (100),

144 (78); HRMS calcd for C₂₂H₂₆N₂O₃366.1943, found 366.

1928

Preparation of (2r,19E)-19,20-Didehydro-11-methoxy-

17-oxoajmalan-16-carboxylic Acid Methyl Ester (64). The

11-methoxyaldehydoketone 63 (5.0 mg, 0.0137 mmol) was

dissolved in anhydrous MeOH (1 mL), and a solution of 85%

KOH (2.6 equiv, 2.35 mg, 0.0356 mmol) and iodine (1.3 equiv,

4.5 mg, 0.0178 mmol) in anhydrous MeOH (each 0.5 mL) was

successively added at 0 °C. The mixture was stirred at rt for

1 h, and glacial acetic acid was added dropwise to bring the

pH to 8. The solution which resulted was diluted with CH₂Cl₂

(10 mL), the organic layer was washed with 10% Na₂S₂O₃(10

mL) and brine (2 × 10 mL), dried (Na₂SO₄), and filtered, and

the solvent was removed under reduced pressure. The residue

that resulted was purified by preparative TLC on silica gel

(CHCl₃/MeOH ) 12:1) to provide 64 (4.9 mg, 91%): FTIR 2916,

1

1750, 1727, 1614, 1458, 1229; H NMR (300 MHz, CDCl₃) δ

1.60 (dd, J ) 12.1, 11.7 Hz, 1 H), 1.70 (d, J ) 6.7 Hz, 3 H),

2.17 (m, 2 H), 2.64 (s, 3 H), 2.69 (dd, J ) 8.5, 4.7 Hz, 1 H),

3.47 (m, 2 H), 3.58 (d, J ) 4.1 Hz, 1 H), 3.65 (m, 2 H), 3.70 (m,

1 H), 3.75 (s, 3 H), 3.82 (s, 3 H), 5.38 (q, J ) 6.5 Hz, 1 H), 6.29

(d, J ) 2.2 Hz, 1 H), 6.41 (dd, J ) 8.1, 2.2 Hz, 1 H), 6.92 (d,

J ) 8.1 Hz, 1 H); ¹³C NMR (75.5 MHz, CDCl₃) δ 13.1, 23.4,

29.1, 34.0, 35.4, 52.6, 53.8, 55.3, 55.7, 56.2, 59.2, 61.3, 76.5,

97.0, 104.1, 118.7, 123.8, 124.9, 137.9, 155.8, 160.0, 168.7,

207.1; EIMS (m/e, relative intensity) 394 (M⁺, 10), 366 (55),

174 (100). This material was employed directly in the next

step.

Preparation of (-)-11-Methoxy-17-epivincamajine (9).

The NaBH₄(1.0 mg, 0.026 mmol) was added to a solution of

64 (4 mg, 0.010 mmol) in EtOH (1 mL) at 0 °C. The reaction

mixture was stirred at rt for 1 h. Water (0.1 mL) was added

slowly to this solution. The mixture which resulted was diluted

with CH₂Cl₂(5 mL), washed with brine (2 × 10 mL), dried

(Na₂SO₄), and filtered and the solvent removed under reduced

pressure. The residue that resulted was purified by prepara-

tive TLC on silica gel (CHCl₃/MeOH ) 9:1) to provide 9 as a

pale yellow foam (3.5 mg, 93%): [R]_D) -10.5 (c 0.15, CHCl₃)

[lit.^9b[R]_D) -12 (c 0.5, CHCl₃)]; FTIR 3300, 2918, 1720, 1612,

1

1461, 787 cm^-1; H NMR (300 MHz, CDCl₃) δ 1.52 (dd, J )

14.1, 10.0 Hz, 1 H), 1.62 (d, J ) 6.8 Hz, 3 H), 1.73 (m, 1 H),

2.27 (dd, J ) 12.1, 4.5 Hz, 1 H), 2.68 (s, 3 H), 2.99 (dd, J )

13.2, 5.2 Hz, 1 H), 3.41 (d, J ) 4.7 Hz, 1 H), 3.44 (d, J ) 4.6

Hz, 1 H), 3.47 (m, 2 H), 3.48 (d, J ) 4.8 Hz, 1 H), 3.60 (m, 1

H), 3.72 (s, 3 H), 3.82 (s, 3 H), 4.00 (s, 1 H), 5.29 (q, J ) 6.8

Hz, 1 H), 6.33 (d, J ) 2.2 Hz, 1 H), 6.40 (dd, J ) 8.1, 2.2 Hz,

1 H), 6.97 (d, J ) 8.0 Hz, 1 H); ¹³C NMR (75.5 MHz, CDCl₃) δ

12.9, 22.7, 29.6, 34.9, 35.8, 52.1, 53.3, 53.7, 54.1, 55.4, 56.0,

61.7, 76.5, 85.9, 97.4, 104.5, 116.4, 122.0, 122.8, 136.6, 156.4,

160.7, 175.0; EIMS (m/e, relative intensity) 396 (M⁺, 100), 365

(17), 222 (87), 190 (83), 187 (64), 174 (29). The spectral data

of 9 were in excellent agreement with the literature values.^9b

Preparation of (2r,19E)-19,20-Didehydro-11-methoxy-

17-oxoajmalan-16-carboxaldehyde (63). To a solution of

diol 45 (15.0 mg, 0.041 mmol) in CH₂Cl₂(5 mL) was added

Dess-Martin periodinane (44.6 mg, 0.10 mmol) at 0 °C, and

the mixture was stirred at 0 °C for 1 h. Solutions of saturated

aq NaHCO₃(1 mL) and saturated aq Na₂S₂O₃(1 mL) were

then added to the mixture, and this was followed by the

addition of CH₂Cl₂(10 mL). The organic layer was separated,

and the aqueous phase was further extracted with CH₂Cl₂

(2 × 10 mL). The combined organic extracts were washed with

brine, dried (Na₂SO₄), and filtered, and the solvent was

removed in vacuo to give a residue which was purified by

preparative TLC on silica gel (CHCl₃/MeOH ) 9:1) to provide

63 (9.6 mg, 65%): FTIR 2927, 1738, 1710, 1622, 1462, 1230

cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 1.62 (m, 1 H), 1.70 (d, J )

4.0 Hz, 3 H), 2.15 (m, 1 H), 2.24 (m, 1 H), 2.62 (s, 3 H), 3.40

(m, 2 H), 3.60 (m, 3 H), 3.68 (d, J ) 2.5 Hz, 1 H), 3.80 (s, 3 H),

3.81 (m, 1 H), 5.38 (q, J ) 6.1 Hz, 1 H), 6.29 (d, J ) 2.2 Hz, 1

H), 6.41 (dd, J ) 8.1, 2.2 Hz, 1 H), 6.92 (d, J ) 8.1 Hz, 1 H),

Acknowledgment. We thank NIMH for support (in

part) of this work. We also thank Dr. Tohru Fukuyama

(The University of Tokyo) for helpful discussions as well

as Professor Toh-Seok Kam (University of Malaya) and

Professor Monique Zeches-Hanrot (University of Reims)

for generous gifts of authentic (+)-quebrachidine and

(-)-vincamajine, respectively.

Supporting Information Available: ¹H and ¹³C NMR

comparison of natural (-)-11-methoxy-17-epivincamajine (9)

as well as diols 53 and 56, derived from natural materials,

with synthetic 9, 53, and 56, respectively. This material is

available free of charge via the Internet at http://pubs.acs.org.

JO040282B

J. Org. Chem, Vol. 70, No. 10, 2005 3979

Article Doi

A general strategy for the synthesis of vincamajine-related indole alkaloids: Stereocontrolled total synthesis of (+)-dehydrovoachalotine, (-)-vincamajinine, and (-)-11-methoxy-17-epivincamajine as well as the related quebrachidine diol, vincamajine diol,

DOI: 10.1021/jo040282b

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Article abstract of DOI:10.1021/jo040282b

Full text of DOI:10.1021/jo040282b

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