Total synthesis of himandravine.

Article abstract of DOI:10.1021/ol010038w

[reaction: see text] The first total synthesis of (+)-himandravine (1) is described, starting from (2S,6S)-cis-2-formyl-6-methyl-N-Boc-piperidine (8) in 11 linear steps and 17% overall yield. The key step involves a highly diastereoselective intramolecula

Full text of DOI:10.1021/ol010038w

ORGANIC
LETTERS
2001
Vol. 3, No. 10
1427-1429
Total Synthesis of Himandravine
Samuel Chackalamannil* and Robert Davies
Schering-Plough Research Institute, 2015 Galloping Hill Road,
Kenilworth, New Jersey 07033
Andrew T. McPhail
P. M. Gross Chemistry Laboratory, Duke UniVersity,
Durham, North Carolina 27708-0346
samuel.chackalamannil@spcorp.com
Received February 28, 2001
ABSTRACT
The first total synthesis of (+)-himandravine (1) is described, starting from (2S,6S)-cis-2-formyl-6-methyl-N-Boc-piperidine (8) in 11 linear
steps and 17% overall yield. The key step involves a highly diastereoselective intramolecular Diels−Alder reaction of the key intermediate 5
that contains the entire latent carbon framework and functional group substitution of himandravine.
Himandravine (1) is a complex tetracyclic piperidine alkaloid
isolated from the bark of Galbulimima baccata, a species of
the magnolia family found in New Guinea and northern
Queensland regions of Australia.1 Himandravine shares its
piperidine ring, connected to each other via a trans-ethylene
unit. Himandravine is diastereomeric to himbeline, being
epimeric at the carbon bearing the alkenyl unit of piperidine.
While himbacine has enjoyed much synthetic2 and medicinal
chemistry attention lately by virtue of its potent antimusca-
rinic activity,3 the synthetic and biological properties of
himandravine remain unexplored.4 It has been postulated that
(2) For the total synthesis of himbacine, see: (a) Chackalamannil, S.;
Davies, R. J.; Wang, Y.; Asberom, T.; Doller, D.; Wong, J.; Leone, D. J.
Org. Chem. 1999, 64, 1932. Also see: Chackalamannil, S.; Davies, R. J.;
Asberom, T.; Doller, D.; Leone, D. J. Am. Chem. Soc. 1996, 118, 9812.
(b) Hart, D. J.; Wu, W.-L.; Kozikowski, A. P. J. Am. Chem. Soc. 1995,
117, 9369. Also see: Hart, D. J.; Li, J.; Wu, W.-L.; Kozikowski, A. P. J.
Org. Chem. 1997, 62, 5023. (c). Takadoi, M.; Katoh, T.; Ishiwata, A.;
Terashima, S. Tetrahedron Lett. 1999, 40, 3399. For studies directed toward
the total synthesis of himbacine, see: (d) Baldwin, J. E.; Chesworth, R.;
Parker, J. S.; Russell, A. T. Tetrahedron Lett. 1995, 36, 9551. (e) Hofman,
S.; De Baecke, G.; Kenda, B.; De Clercq, P. J. Synthesis 1998, 479.
(3) (a) Darroch, S. A.; Taylor, W. C.; Choo, L. K.; Mitchelson, F. Eur.
J. Pharmacol. 1990, 182, 131. (b) Malaska, M. J.; Fauq, A. H.; Kozikowski,
A. P.; Aagaard, P. J.; McKinney, M. Bioorg. Med. Chem. Lett. 1995, 5, 61
and references therein. (c) Kozikowski, A. P.; Fauq, A. H.; Miller, J. H.;
McKinney, M. Bioorg. Med. Chem. Lett. 1992, 2, 797.
structural traits with its congeners himbacine and himbeline
in that these alkaloids possess the same tricyclic perhy-
dronaphthofuranone ring system and a 2,6-disubstituted
(1) (a) Pinhey, J. T.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1961, 14,
106. (b) Brown, R. F. C.; Drummond, R.; Fogerty, A. C.; Hughes, G. K.;
Pinhey, J. T.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1956, 9, 283. (c)
Ritchie, E.; Taylor, W. C. In The Alkaloids; Manske, R. H. F., Ed.; Academic
Press: New York, 1967; Vol. 9, p 529.
(4) Himandravine and N-methylhimandravine are reportedly less active
in guinea-pig ileal longitudinal muscle and electrically stimulated left
atrium.3a However, the Ki value for himandravine in cloned human
muscarinic M2 receptors has not been reported, which is required for a
meaningful comparison.
10.1021/ol010038w CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/21/2001

the chirality of the substituted piperidine moiety might be
important to the potency and receptor selectivity of
himbacine.3a Since himandravine has the (S)-absolute chiral-
ity at the C2 piperidine carbon, which is opposite to that of
himbacine, its synthesis constitutes an important step in the
structure-activity relationship study (SAR) of this important
class of molecules. Reported here is the first total synthesis
of (+)-himandravine in 11 linear steps and 17% overall yield
starting form (S)-2-methyl-N-Boc-piperidine (6). Also, this
total synthesis confirms the structure as well as the absolute
stereochemistry of himandravine.
The synthesis of (+)-himandravine is outlined in Scheme
2. We have previously reported an efficient synthesis of
Scheme 2a
The retrosynthetic analysis is presented in Scheme 1 which
bears close analogy to our previously reported synthesis of
Scheme 1
himbacine. The key step of the synthesis is a highly
enantioselective intramolecular Diels-Alder reaction5 of
tetra-ene intermediate 5 which bears the entire latent carbon
framework of himandravine and functional group substitu-
tion. The facial selectivity of the C3a-C9a bond formation
in the intramolecular Diels-Alder reaction is dictated by the
preferred conformation A of the intermediate 5 which
minimizes A1,3 strain.6 The preexisting absolute chirality at
C3 would be translated into the R-configuration at C3a which,
in turn, would produce the required absolute configurations
at C4 and C4a and, after epimerization, at C9a. The stereo-
selective reduction of the internal double bond from the
convex face was expected to produce the required R-
configuration at C8a as reported before.2a
a Reagents and conditions: (a) (i) sec-BuLi, Et2O, TMEDA, -78
°C; (ii) DMF; (b) silica gel, Et3N:EtOAc:hexane (3:10:90, v/v/v),
22 h; (c) CrCl2, CHI3, THF; (d) PdCl2(PhCN)2, CuI, piperidine,
THF 10, rt; (e) Lindlar, H2, MeOH:CH2Cl2 (1:4, v/v), quinoline
(45 wt % equiv); (f) 13, 1-(3-dimethylaminopropyl)-3-ethylcarbo-
diimide hydrochloride, DMAP, TEMPO (1 wt % equiv), CH2Cl2;
(g) toluene, TEMPO (1 wt % equiv), 186 °C, 8 h; (h) DBU; (i)
(Boc)2O, NaOH (20%);(j) RaNi, H2, MeOH; (k) TFA:CH2Cl2 (1:
10, v/v).
(2R,6S)-trans-2-formyl-6-methyl-N-Boc-piperidine2a (7) from
(S)-2-methylpiperidine7 (6) using Beak’s method.8 The
corresponding (2S,6S)-cis-2-formyl-6-methyl-N-Boc-piperi-
dine (8) needed for the total synthesis of (+)-himandravine
was efficiently generated from trans-substituted piperidine
7 by triethylamine-catalyzed epimerization on silica gel in
83% yield. Homologative iodovinylation of formyl derivative
(5) For reviews on intramolecular Diels-Alder reaction, see: (a) Roush,
W. R. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 4, p 513. (b) Ciganek, E. In Organic
Reactions; Dauben, W. G., Ed.; John Wiley & Sons: New York, 1984;
Vol. 32, p 1. (c) Craig, D. Chem. Soc. ReV. 1987, 16, 87. (d) Weinreb, S.
W. Acc. Chem Res. 1985, 18, 16. (e) For a discussion of the substituent
effect on intramolecular Diels-Alder reactions of enoates, see: Jung, M.
E. Synlett 1990, 4, 186.
(6) (a) Hoffmann, R. W.Chem. ReV. 1989, 89, 1841. (b) Adam, W.;
Glaser, J.; Peters, K.; Prein, M. J. Am. Chem. Soc. 1995, 117, 9190 and
references therein. (c) Mulzer, J.; Bock, H.; Eck, W.; Buschman, J.; Lugar,
P. Angew. Chem., Int. Ed. Engl. 1991, 30, 414.
(7) Doller, D.; Davies, R.; Chackalamannil, S. Tetrahedron: Asymmetry
1997, 8, 1275.
(8) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109.
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Org. Lett., Vol. 3, No. 10, 2001

8 using Takai protocol gave the trans-vinyl iodide 9 in 63%
yield.9 Sonogashira coupling10 of vinyl iodide 9 and com-
mercially available propargylic alcohol 10 gave the ene-ynol
11 in 73% yield. Selective reduction of the alkyne unit of
11 using Lindlar catalyst followed by esterification with
dienoic acid 132a,11 gave the Diels-Alder precursor 5 in a
combined 83% yield. Intramolecular Diels-Alder reaction
of tetra-ene derivative 5 at 186 °C, followed by in situ
epimerization at C9a by treatment with DBU, and reprotection
of the partially deprotected piperidine nitrogen, gave tricyclic
intermediate 14 in 60% isolated yield. Selective hydrogena-
tion12 of the internal double bond of 14 mediated by Raney
nickel followed by hydrolytic removal of the Boc protecting
group gave (+)-himandravine which showed spectroscopic
properties identical to those of a sample of natural product
and a comparable optical rotation.13,14 Definitive proof of
the structure of synthetic himandravine was derived from
the X-ray crystallographic analysis of its hydrochloride salt
(Figure 1).
Figure 1. X-ray crystallographic structure of himandravine
hydrochloride. Chloride anion not shown.
ture and absolute chirality of himandravine. The biological
data of himandravine and related compounds will be
published in the future.
In conclusion, the first total synthesis of (+)-himandravine
has been accomplished in 11 linear steps and 17% overall
yield. The current synthesis corroborates the reported struc-
Acknowledgment. The authors thank Drs. Ashit Ganguly,
William J. Greenlee, and Michael Czarniecki for helpful
discussions. We also thank Dr. Pradip Das for mass spectral
data, Dr. Mohindar Puar for NMR data, and Prof. W. C.
Taylor, University of Sydney, Australia for an authentic
sample of (+)-himandravine.
(9) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408.
(10) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467. (b) Alami, M.; Linstrumele, G. Tetrahedron Lett. 1991, 6109. For
reviews on the Sonogashira reaction, see: (d) Rossi, R.; Carpita, A.; Bellina,
F. Org. Prep. Proc. Int. 1995, 27(2), 127. (e) Sonogashira, K. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 3, p 521.
Supporting Information Available: 1H and 13C NMR
spectra for compounds 1, 5, 8, 9, 11, 14, and 15. Tables of
crystal data, fractional coordinates and thermal parameters,
and interatomic distances with standard deviation for the
hydrochloride of himandravine (1a). This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(11) Tanikaga, R.; Nozaki, Y.; Tamura, T.; Kaji, A. Synthesis 1983, 134.
(12) The hydrogenation product 15 was contaminated with a trace amount
of side product, presumed to be the C8a epimer, that could not be separated
by flash chromatography.
20
(13) Specific rotation of himandravine: [R]D +19.8 (c 1.08, CHCl3);
lit.1b +23 (c 1.89, CHCl3). Himandravine hydrochloride melted at 218-
220 °C (dec).
(14) All intermediates were characterized by 1H and 13C NMR, IR, and
mass spectroscopic methods.
OL010038W
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