Iminium ion cascade reaction in the total synthesis of (+)-vincadifformine

Article abstract of DOI:10.1021/ol201892j

An iminium ion triggered cascade reaction is described in the total synthesis of (+)-vincadifformine by the coupling of 3,3-substituted tetrahydropyridine and indole derivative. The strategy allows simultaneous construction of two new rings, three new sigma bonds, and two new stereogenic centers in one pot with complete stereochemical control.

Full text of DOI:10.1021/ol201892j

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4672–4675
Iminium Ion Cascade Reaction in the Total
Synthesis of (þ)-Vincadifformine
Ganesh Pandey* and Prasanna Kumara C
Division of Organic Chemistry, National Chemical Laboratory, Pune-411008, India
gp.pandey@ncl.res.in
Received July 13, 2011
ABSTRACT
An iminium ion triggered cascade reaction is described in the total synthesis of (þ)-vincadifformine by the coupling of 3,3-substituted
tetrahydropyridine and indole derivative. The strategy allows simultaneous construction of two new rings, three new sigma bonds, and two new
stereogenic centers in one pot with complete stereochemical control.
Asymmetric synthesis of biologically active complex
natural products involving cascade reactions with the
formation of multiple bonds or multiple rings has been
the subject of intense research in recent years.1 The design
In continuation with our interest in the synthesis of
alkaloids,2 we became interested in developing a new and
nonbiogenetic route for the synthesis of Aspidosperma
alkaloids. Vincadifformine (1), tabersonine (2) and jeran-
tinine (3) belonging to this class have caught the attention
of synthetic chemists over the past several years due to
their unique structural features and cytotoxic activities
against human cancer cell lines (Figure 1).3 In particular,
1 has significant value because it is a valuable precursor for
pharmaceutically important vincamine, vincamone and
Cavinton.4 In addition, it is also suggested to be a possi-
ble biogenetic and synthetic precursor for the cytotoxic
leucophyllidine and rhazinilam alkaloids, respectively.5
(2) (a) Pandey, G.; Banerjee, P.; Kumar, R.; Puranik, V. G. Org. Lett.
2005, 7, 3713. (b) Pandey, G.; Gupta, N. R.; Pimpalpalle, T. M. Org.
Lett. 2009, 11, 2547.
(3) (a) Saxton, J. E. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: New York, 1998; Vol. 50, Chapter 9. (b) Saxton, J. E. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1998; Vol. 51,
Chapter 1. (c) Lim, K. H.; Hiraku, K.; Komiyama, K.; Koyano, T.;
Hayashi, M.; Kam, T. S. J. Nat. Prod. 2007, 70, 1302. (d) Feng, T.; Li, y.;
Cai, X. H.; Wang, Y. Y.; Luo, X. D. Org. Lett. 2010, 12, 968. (e) Lim,
K. H.; Hiraku, K.; Komiyama, K.; Kam, T. S. J. Nat. Prod 2008, 71,
1591.
(4) (a) Szantay, C. Pure. Appl. Chem. 1990, 62, 1299. (b) Danieli, B.;
Lesma, G.; Palmisano, G. J. Chem. Soc., Chem. Commun. 1981, 908–
909. (c) Sapi, J.; Szabo, L.; Baitz-Gacs, E.; Kalaus, G.; Szantay, C.
Tetrahedron 1988, 44, 4619–4629. (d) Calbi, L.; Danieli, B.; Lesma, G.;
Palmisano, G. J. Chem. Soc., Perkin Trans. 1 1982, 1371.
Figure 1. Representatives of Aspidosperma alkaloids.
of cascades to obtain specific biologically active structu-
rally complex natural products poses a significant intellec-
tual challenge and can be one of the most impressive
activities in natural product synthesis.
(1) (a) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem.,
Int. Ed. 2006, 45, 7134. (b) Nicolaou, K. C.; Chen, J. C. Chem. Soc. Rev.
2009, 38, 2993. (c) Padwa, A. Pure Appl. Chem. 2003, 75, 47. (d) Tietze,
L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967. (e) Amorde,
S. M.; Jewett, I. T.; Martin, S. F. Tetrahedron 2009, 65, 3222.
(5) (a) Gan, C. Y.; Robinson, W. T.; Etoh, T.; Hayashi, M.;
Komiyama, K.; Kam, T. S. Org. Lett. 2009, 11, 3962. (b) Szabo, L. F.
ARKIVOC (Gainesville, FL, U.S.) 2008, No. iii, 167. (c) David, B.;
Sevenet, T.; Thoison, O.; Awang, k.; Pais, M.; Wright, M.; Guenard, D.
Biorganic. Med. Chem. Lett. 1997, 7, 2155.
r
10.1021/ol201892j
Published on Web 08/04/2011
2011 American Chemical Society

This alkaloid displays a complex pentacyclic conforma-
tionally rigid skeleton due to the cis-relationship of the
three contiguous stereocenters in the cyclohexyl ring at
C-7, C-21 and C-20. Owing to the challenge associated
with the construction of these structural frame works
including a quaternary carbon center, extensive synthetic
efforts have been made to obtain 1 both in racemic6 as well
as in optically pure form.7 Majority of these approaches
have relied on intramolecular DielsꢀAlder (DA) type
cycloaddition reaction of a biogenetically postulated seco-
dine intermediate.8 However, auxiliary controlled or chiral
substrate controlled cycloaddition of secodine intermedi-
ate have generally led to the formation of mixture of
diastereomers.7b
The synthetic design of crucial precursor 4 was visua-
lized through Birch reduction-alkylation of the chiral
nicotinic acid derivative 8. Although enantioselective con-
struction of all carbon quaternary stereocenter in the
cyclohexane ring employing Birch reduction-alkylation
of benzoic acid derivatives9 is known, to the best of our
knowledge, no report is found for similar transformation
for generating substituted piperidine system.
Scheme 2. Synthesis of 11
In an effort to develop a nonbiogenetic route to 1 in
optically pure form, we looked at the problem entirely
from a different angle and devised a cascade strategy as
outlined retrosynthetically in Scheme 1. This strategy was
envisioned to provide two new rings, two new stereogenic
centers and three new sigma bonds in a single operation
through the sequential involvement of reactive intermedi-
ates 6 and 7. We are happy to disclose herein our successful
endeavor of accomplishing the total synthesis of (þ)-1 in
overall 4% yield and >99% ee.
Scheme 1. Retrosynthetic Analysis
On the simple premise that Birchreduction-alkylation of
8, obtained by the reaction of 2-chloronicotininc acid and
(S)-prolinol, followed by simple chemical transformation
would give 4, we subjected 8 to Birch reduction-alkylation
at ꢀ78 °C using ethyl iodide, but to our utter surprise,
it gave the expected product only in ∼6% yield. Therefore,
we used more electrophillic allyl bromide for alkyla-
tion reaction and succeeded in getting 9 in 46% yield
(de= 97.9%).10a Single crystallization in dichloromethane-
n-pentaneafforded9 as(colorlesscrystals, mp 105ꢀ106 °C)
a single diastereomer. The stereochemistry of 9 was con-
firmed unambiguously through X-ray crystallographic
analysis.10b The excellent diastereoselectivity in the forma-
tion of 9, presumably, results from the involvement of
rigid molecular architecture of enolate intermediate where
proline stereocenter directs the alkylation preferentially
at β-face.
(6) (a) Ziegler, F. E.; Bennett, B. G. J. Am. Chem. Soc. 1973, 95, 7458.
(b) Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1998, 120, 13523. (c)
Takano, S.; Hatakeyama, S.; Ogasawara, K. J. Am. Chem. Soc. 1979,
101, 6414. (d) Kuehne, M. E.; Roland, D. M.; Hafter, R. J. Org. Chem.
1978, 43, 3705. (e) Kuehne, M. E.; Matsko, T. H.; Bohnert, J. C.;
Kikemo, C. L. J. Org. Chem. 1979, 44, 1063. (f) Barsi, M. C.; Das, B. C.;
Fourrey, J. L.; Sundaramoorthi, R. J. Chem. Soc. Chem. Commun. 1985,
88. (g) Kobayashi, S.; Peng, G.; Fukuyama, T. Tetrahedron Lett. 1999,
40, 1519. (h) Kuehne, M. E.; Wang, T.; Seaton, P. J. J. Org. Chem. 1996,
61, 6001. (i) Kalaus, G.; Greiner, I.; Kajtar-Peredy, M.; Brlik, J.; Szabo,
L.; Szantay, C. J. Org. Chem. 1993, 58, 1434. (j) Kutney, J. P.; Chan,
K. K.; Failli, A.; Fromson, J. M.; Gletsos, C.; Nelson, V. R. J. Am.
Chem. Soc. 1968, 90, 3891. (k) Coldham, I; Burrell, A. J. M.; White,
L. E.; Adams, H.; Oram, N. Angew. Chem., Int. Ed. 2007, 46, 6159. (l)
Laronze, J.-Y.; Laronze-Fontaine, J.; Levy, J.; Le Men, J. Tetrahedron
Lett. 1974, 15, 491.
Our initial attempt to remove chiral auxiliary from 9
by stirring with a mixture of 80% H2SO4/MeOH (1:8) gave
(9) (a) Schultz, A. G.; Macielag, M.; Sundararaman, P.; Taveras,
A. G.; Welch, M. J. Am. Chem. Soc. 1988, 110, 7828. (b) Donohoe, T. J.;
McRiner, A. J.; Helliwell, M.; Sheldrake, P. J. Chem. Soc., Perkin.
Trans. 1 2001, 1435.
(10) (a) Diastereomeric excess of 9 was measured by HPLC analysis
using Atlantis RP-18 column, CH3CN/H2O (40:60), λ = 224 nm. (b)
CCDC 783953 contains the supplementary crystallographic data for 9.
(c) Enantiomeric purity of 11 was determined by HPLC using Chiralcel
OD-H column; i-PrOH/petroleum ether (10:90) as eluent, λ = 220 nm.
(7) (a) Kuehne, M. E.; Podhorez, D. E. J. Org. Chem. 1985, 50, 924.
(b) Kuehne, M. E.; Bandarage, U. K.; Hammach, A.; Li, Y. L.; Wang, T.
J. Org. Chem. 1998, 63, 2172. (c) Yuan, Z. Q.; Ishikawa, H.; Boger, D. L.
Org. Lett. 2005, 7, 741.
(8) (a) Scott, A. I. Acc. Chem. Res. 1970, 3, 151. (b) Scott, A. I. Bioorg.
Chem. 1974, 3, 398.
Org. Lett., Vol. 13, No. 17, 2011
4673

11 in low enantiopurity (19% ee)10c as well as yield (46%,
Scheme 2). The loss of chirality results due to the involve-
ment of intermediate 10, formed by further methanolysis
of 11 followed by recylization. Further, we also attempted
a sequential approach of cleaving first the ether moiety of 9
(stirring with CH3COOH/H2O/THF (1:1:8, rt)) to obtain
12 (89% yield), followed by methanolysis using sodium
methoxide in methanol. However, this effort also gave
undesired achiral 13. Finally, we succeeded in transform-
ing 12 to required 11 in excellent yield (87%) as well as
high enantiopurity (>99% ee) by stirring with copper(II)
triflate11 in methanol.
obtained in 61% yield starting from 3-(2-chloroethyl)-
1H-indole in a single step operation (Scheme 4).17
Scheme 4. Synthesis of Indole Fragment 5
Since, the central feature of our proposed synthetic
strategy for stereoselective formation of the aspidosperma
skeleton rests on the iminium ion triggered cascade cycli-
zations by coupling of (ꢀ)-4 and 5, we proceeded to test
our hypothesis by heating a mixture of 4 (0.4 mmol) and 5
(0.4 mmol) in the presence of NaI (2.8 mmol) in anhydrous
acetonitrileatreflux. Toour dismay, after 12h, onlya trace
amount of product was noticed by TLC. Several experi-
ments using other solvents such as HMPA, NMP along with
additives like sodium bicarbonate, DMAP, TBAI etc. also
failed to give satisfactory result. After several optimization
studies, we found that the reaction proceeded in refluxing
DMF in the presence of potassium iodide and produced 1
{[R]28D = þ550 (c 0.2, EtOH); lit7a {[R]28D = þ542 (c 0.04,
EtOH)} in 35% yield (>99% ee).18 All spectral data of 1
were found in good agreement with the literature report.7b
Scheme 3. Synthesis of Imine (ꢀ)-4
One carbon reductive degradation of terminal olefinic
moiety of 11 by following the sequence of oxidative-
cleavage (OsO4/NaIO4),12 dithioacetalization of the re-
sultant aldehyde followed by reductive desulfurization
(Raney Nickel, H2, EtOH, reflux) afforded 14 in 53%
yield. Reduction of 14 under the Luche’s condition13
followed by tosylation of the primary alcohol moiety
produced 15 in 73% yield. N-Boc protection followed by
amide reduction using DIBAL-H resulted in the corre-
sponding hemiaminal, which on treatment with trifluor-
oacetic acid in dichloromethane afforded chiral imine 4 in
83% yield (>99% ee, Scheme 3).14,15 The required indole
segment 5, though reported in few steps,16 was easily
Scheme 5. Synthesis of (þ)-Vincadifformine
(11) Niklas, N.; Hampel, F.; Liehr, G.; Zahl, A.; Alsfasser, R.
Chem.;Eur. J. 2001, 7, 5135.
(12) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6,
3217.
(13) Kim, S.; Ko, H.; Lee, T.; Kim, D. J. Org. Chem. 2005, 70, 5756.
(14) Enantiomeric excess of (ꢀ)-4 was determined by HPLC analysis:
Chiralcel OJ-H column, i-PrOH/petroleum ether (15:85), λ = 254 nm.
(15) Several protocols were evaluated to synthesize 4 in shorter steps,
but poor enantiomeric excess even at key steps led us to proceed with this
present approach. We continue to attempt to find an alternative route
for its synthesis.
(16) (a) Wenkert, E.; Dave, K. G.; Gnewuch, C. T.; Sprague., P. W.
J. Am. Chem. Soc. 1968, 90, 5251. (b) Kutney, J. M.; Brown, R. T.; Piers.,
E. J. Am. Chem. Soc. 1964, 86, 2286. (c) Hudlicky, T.; Reed, J. W. The
way of synthesis: Evolution of design and methods for natural products;
Wiley-VCH: Weinheim, 2007; Part 4, p 759. (d) Kutney, J. P.; Badger,
R. A.; Beck, J. F.; Bosshardt, H.; Matough, F. S.; Redaura-Sanz, V. E.;
So, Y. H.; Sood, R. S.; Worth, B. R. Can. J. Chem. 1979, 57, 289.
(17) Parsons, R. L.; Berk, J. D.; Kuehne, M. E. J. Org. Chem. 1993,
58, 7482.
4674
Org. Lett., Vol. 13, No. 17, 2011

Presumably, the formation of 1 in this reaction involves
a diastereomeric mixture of intermediate 7. To provide
support for the intermediacy of 7 in this cascade sequence,
we carried out the reaction at a lower temperature (90 °C,
12 h) and observed the formation of diastereomeric mixture
of 7a and 7b along with some amount of 1, evidenced by
HPLC and LCꢀMS analysis.19 Since the formation of both
diastereomers of 7 was always accompanied by some amount
of 1, we could not determine the exact ratio of 7a and 7b. Our
attempt to isolate pure diastereomers through column chro-
matography (silica gel and neutral alumina) for characteriza-
tion purposes was found unsuccessful due to their poor
stability. Molecular models suggest that 7a, in which the
nucleophilic carbon center of enamine and electrophilic car-
bon center of iodomethylene group is in close proximity
(Scheme 5), may get transformed to 1 faster compared to
7b. The fate of presumed 7b could not be ascertained as this
could give 1via 7a through CurtinꢀHammett equilibration or
may decompose to some other compounds. The moderate
yield of 1 through this cascade reaction may be due to the
combined effect of parallel transformation of 5 to 16 (20%)
and decomposition of (ꢀ)-4 and 7b.
In conclusion, the synthesis of pentacyclic Aspidosperma
alkaloid (þ)-vincadifformine is achieved with good enan-
tiopurity (>99% ee) by a convergent route through an
iminiumꢀenamine cascade reaction. Further studies to
synthesize some other alkaloids of this class and show
optimization of the yield during a cascade sequence are in
progress and will be revealed in due course.
Acknowledgment. We thank DST, New Delhi for fi-
nancial support and P.K.C. thanks CSIR, New Delhi, for
the award of research fellowship.
Supporting Information Available. Experimental details
as well as characterization data and copies of the NMR
spectra of all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(18) The enantiomeric excess was measured and compared with
racemic 1 by HPLC analysis using Chiralcel OD-H column (250 ꢁ
4.6 mm), ethanol/petroleum ether/TFA (15:85:0.1), λ = 220 nm.
(19) HPLC-Mass analysis of 7: Kromasil RP-18 (150 ꢁ 4.6 mm)
column, MeOH/H2O (85:15), λ = 254 nm. See Supporting Information.
Org. Lett., Vol. 13, No. 17, 2011
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