A highly efficient total synthesis of (+)-himbacine

Full text of DOI:10.1021/ja962542f

9812
J. Am. Chem. Soc. 1996, 118, 9812-9813
Scheme 1
A Highly Efficient Total Synthesis of (+)-Himbacine
Samuel Chackalamannil,* Robert J. Davies,
Theodros Asberom, Dar´ıo Doller, and Daria Leone
Schering-Plough Research Institute
2015 Galloping Hill Road
Kenilworth, New Jersey 07033
ReceiVed July 23, 1996
Himbacine (1), a tetracyclic piperidine alkaloid isolated from
the bark of the Australian pine tree of Galbulimima species,1,2
has attracted considerable attention due to its interesting
structural features and promising biological property as a
muscarinic receptor antagonist.3 Positive modulation of synaptic
acetylcholine levels by selective inhibition of presynaptic
muscarinic receptors is a promising therapeutic approach for
the treatment of senile dementia associated with Alzheimer’s
disease.4 Himbacine is a potent inhibitor of the muscarinic
receptor of M2 subtype with 20-fold selectivity toward the M1
receptor.5 However, the paucity of natural himbacine as well
as the inherent structural complexity of this molecule has
precluded exhaustive optimization of its biological properties
by structural modification. Hart, Wu, and Kozikowski have
published a total synthesis of himbacine in 20 linear steps.6a
A
short, practical synthesis of himbacine would greatly facilitate
research in the therapeutic application of this compound. We
wish to report a highly convergent and concise synthesis of (+)-
himbacine (Scheme 2) in 11 linear steps and 9.7% yield starting
from readily accessible (S)-2-methylpiperidine L-tartrate (3).
Our approach envisions, as the key step, an enantioselective,
all-encompassing intramolecular Diels-Alder reaction7 of the
appropriately functionalized molecular ensemble 11, which bears
the entire latent carbon framework and functional group
substitution of himbacine (Scheme 1). Several points are worth
noting regarding this approach. First, we expected that the
vinylcyclohexenyl region of 11 would act as the diene moiety
in the intramolecular Diels-Alder reaction in preference to the
piperidinyl substituted diene, since it is more likely to adopt
the required cisoid conformation. The methyl group at C3 would
serve to confer the s-cis orientation to the ester linkage, thereby
facilitating the cyclization.8 The face selectivity of the C3a-
C
9a bond formation in the intramolecular Diels-Alder reaction
would be dictated by the preferred conformation B of the
intermediate 11, which avoids A1,3 strain. During the Diels-
Alder process, the absolute chirality at C3 would be translated
to R-configuration at C3a which, in turn, would engender the
required absolute configurations at C4 and C4a and, after
epimerization, at C9a.9 Finally, considering the fact that the
pendent trans double bond is sterically encumbered by the
presence of the tricyclic ring system and the N-Boc-substituted
piperidine, we expected to achieve regioselective reduction of
the internal double bond.10 This reduction would occur ste-
reoselectively from the less hindered R-face to produce the
required R-configuration at C8a.
The implementation of the above plan is outlined in Scheme
2. Commercially available 2-methylpiperidine was resolved
using L-tartaric acid.11,12 The tartrate salt 3 was directly
converted to N-Boc-protected (S)-2-methylpiperidine by treat-
ment with excess of Boc anhydride in 96% yield.13 Treatment
of piperidine derivative 4 with sec-butyllithium followed by
quenching with dimethylformamide according to the Beak
procedure14 yielded the trans-substituted piperidinyl aldehyde
5 in 86% yield. Homologative iodovinylation of aldehyde 5
(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.
(2) For X-ray crystallographic studies on himbacine, see: Fridrichsons,
J.; Mathieson, A. M. Acta Crystallogr. 1962, 15, 119.
(3) (a) Malaska, M. J.; Fauq, A. H.; Kozikowski, A. P.; Aagaard, P. J.;
McKinney, M. Bioorg. Med. Chem. Lett. 1995, 5, 61 and references cited
therein. (b) Kozikowski, A. P.; Fauq, A. H.; Miller, J. H.; McKinney, M.
Bioorg. Med. Chem. Lett. 1992, 2, 797. (c) Darroch, S. A.; Taylor, W. C.;
Choo, L. K.; Mitchelson, F. Eur. J. Pharmacol. 1990, 182, 131.
(4) (a) Miller, J. H.; Aagaard, P. J.; Gibson, V. A.; McKinney, M. J.
Pharmacol. Exp. Ther. 1992, 263, 663. (b) Dodds, H. N. Drugs Future
1995, 20, 157.
(5) Five muscarinic receptor subtypes have been reported. See: Levey,
A. I. Life Sci. 1993, 52, 441 and references cited therein. Himbacine has
been reported to bind to M2 receptor with a Ki value of 4.6 nM and with
20-fold selectivity against M1 receptor (ref 3b).
(9) (a) For a discussion of A1,3 strain induced facial selectivity of
intermolecular Diels-Alder reactions, see: Adam, W.; Glaser, J.; Peters,
K.; Prein, M. J. Am. Chem. Soc. 1995, 117, 9190 and references cited
therein. (b) For a review on A1,3 strain induced stereoselectivity, see:
Hoffmann, R. W. Chem. ReV. 1989, 89, 1841.
(10) It has been reported that reduction of himbacine to dihydrohimbacine
required catalytic hydrogenation over platinum oxide in glacial acetic acid
for 16 h (ref 1a).
(6) For the total synthesis of himbacine, see: (a) Hart, D. J.; Wu, W.-
L.; Kozikowski, A. P. J. Am. Chem. Soc. 1995, 117, 9369. For studies
directed toward the total synthesis of himbacine, see: (b) Baldwin, J. E.;
Chesworth, R.; Parker, J. S.; Russell, A. T. Tetrahedron Lett. 1995, 36,
9551. (c) Baecke, G. D.; De Clercq, P. Tetrahedron Lett. 1995, 36, 7515.
(7) For reviews on intramolecular Diels-Alder reactions, 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, Inc.: 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.
(11) The resolution of 2-methylpiperidine was carried out according to
the procedure given by Marckwald. Marckwald, W. Ber. 1896, 29, 43. Also,
see: (a) Craig, J. C.; Roy, S. K. Tetrahedron 1965, 21, 401. (b) Munchof,
M. J.; Meyers, A. I. J. Org. Chem. 1995, 60, 7084. (c) Tallent, W. H.;
Stromberg, V. L.; Horning, E. C. J. Am. Chem. Soc. 1955, 77, 6361.
(12) The optical purity of (S)-2-methylpiperidine was measured using
O-acetylmandelic acid as a chiral solvating agent. Integration of the methyl
doublet indicated >99% optical purity after four recrystallizations. See:
Parker, D.; Taylor, R. J. Tetrahedron 1987, 43, 5451.
(13) The workup procedure involved addition of excess of ammonium
hydroxide. This step converted the unreacted reagent, which coeluted with
the product, to more polar tert-butylurethane.
(8) For a discussion of the substituent effect on intramolecular Diels-
Alder reactions of enoates, see: Jung, M. E. Synlett 1990, 4, 186.
(14) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109.
S0002-7863(96)02542-5 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 40, 1996 9813
Scheme 2
steps according to the reported procedure20 (eq 1). Esterification
of alcohol 9 with the acid 10 yielded the Diels-Alder precursor
11 in 91% yield.19 Thermal cyclization of a solution of
compound 11 in toluene at 186 °C for 8 h generated exclusively
the exo adduct 12 which, under reaction conditions, underwent
partial isomerization to the cis lactone 13.21
A brief treatment of the reaction mixture with excess of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) effected complete isomer-
ization of 12 to the cis lactone 13. Regioselective reduction of
the internal double bond of 13 occurred stereoselectively from
the less hindered R-face under catalytic hydrogenation over
Raney nickel22 to yield the previously reported N-Boc-himbeline
derivative 14.6a,23 N-Deprotection of compound 14 yielded (+)-
himbeline (2). Direct conversion of compound 14 to (+)-
himbacine was achieved in a one-pot procedure by deprotection
with trifluoroacetic acid followed by reductive methylation6a
using aqueous formaldehyde and sodium cyanoborohydride.
Both synthetic himbeline and himbacine showed spectroscopic
properties identical to those reported for the natural products
as well as comparable optical rotations.24,25
In conclusion, we have completed the total synthesis of
himbacine in 11 linear steps from readily accessible (S)-2-
methylpiperidine L-tartrate (3) in 9.7% yield. With this practical
synthesis of himbacine now in hand, the continuing exploration
of the promising biological property of this class of compounds
will be aided.
Acknowledgment. The authors thank Drs. Ashit K. Ganguly,
Michael Czarniecki, William J. Greenlee, and Michael J. Green for
helpful discussions. We also thank Dr. Jesse Wong and Mr. Robert
Tiberi for preparation of intermediate 10, Dr. Pradip Das for mass
spectral data, Dr. Mohindar Puar and Dr. T.-M. Chan for NMR analysis,
and Prof. W. C. Taylor, University of Sydney, Australia for an authentic
sample of (+)-himbacine.
according to the Takai protocol15 using chromous chloride16 and
iodoform yielded the vinyl iodide 6 in 50% yield. Palladium-
mediated coupling17 of vinyl iodide 6 with commercially
available18 (S)-3-butyn-2-ol (7) gave the enyne derivative 8 in
81% yield. Selective reduction of the triple bond of 8 was
achieved using catalytic hydrogenation over Lindlar catalyst in
the presence of quinoline.19
Supporting Information Available: Spectral data and procedures
for compounds 1, 2, 5, 6, 8, 9, 11, 13, and 14 and 1H NMR (400 MHz)
and 13C NMR (100 MHz) spectra of compounds 1, 2, 6, 13, and 14,
1
and H NMR (400 MHz) for natural (+)-himbacine (19 pages). See
any current masthead page for ordering and Internet access instructions.
The carboxylic acid derivative 10 was readily prepared from
cyclohexane carboxaldehyde in an overall 66% yield in three
JA962542F
(15) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.
(16) The technical grade chromous chloride (95%) available from Aldrich
was used. Chromous chloride of high purity (99.9%), purchased from Strem
Chemicals, gave inferior yields.
(17) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467. (b) Alami, M.; Linstrumele, G. Tetrahedron Lett. 1991, 6109. For
reviews on Sonogashira reaction, see: (d) Rossi, R.; Carpita, A.; Bellina,
F. Org. Prep. Proced. 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.
(21) Prolonged reaction time resulted in substantial amount of N-
deprotection of 12. The corresponding free amine could be readily converted
to 13 by treatment of the crude reaction mixture with Boc anhydride in the
presence of 20% aqueous sodium hydroxide. Thermolytic deprotection of
tert-butoxycarbonyl protecting group on indoles and pyrroles has been
reported: Rawal, V. H.; Cava, M. P. Tetrahedron Lett. 1985, 26, 6141.
(22) Large excess (8-12 wt equivs) of Raney nickel was necessary.
Commercially available (Aldrich) Raney nickel was washed four times with
water and four times with methanol prior to use.
(23) N-Boc-(+)-himbeline showed 1H and 13C NMR data identical to
those reported.6a Specific rotation: [R]D20 +66.7 (c 0.19, CHCl3); lit.6a [R]D
20
(18) (S)-3-Butyn-2-ol was purchased from Chiroscience Ltd, Cambridge
Science Park, Milton Rd, Cambridge, CB4 4WE, England. It is also available
from DSM Fine Chemicals, 217 Rte 46 W., Saddle Brook, NJ 07663-6253.
(19) The crude product, which was used for the next step without further
purification, was contaminated with a small amount (5-10%) of saturated
alcohol generated from the over-reduction of dienol 9. This side product
underwent esterification at the next step to generate the corresponding ester
which coeluted with the desired product 11. However, the presence of this
side product did not affect the subsequent intramolecular Diels-Alder
reaction.
+60.6 (c 0.55, CHCl3).
(24) The 13C and 1H NMR spectra of himbeline were identical to those
reported (ref 6a, supporting information). The melting point of synthetic
himbeline hydrochloride was 261-263 °C (dec) (lit.1b 265-266 °C) and
the specific rotation was [R]D + 22.4 (c 0.33, CHCl3); lit.6a,1b [+17.1 (c
20
0.56, CHCl3)6a, +19 (2.4% in CHCl3)1b].
(25) Synthetic himbacine was identical to the natural product by 1H NMR,
13C NMR, and TLC. Synthetic himbacine melted at 129-130 °C (lit.6a 129-
130 °C). A 1:1 mixture of synthetic himbacine and authentic natural
20
himbacine melted undepressed. Specific rotation: [R]D +59.4 (c 0.35,
(20) Tanikaga, R.; Nozaki, Y.; Tamura, T.; Kaji, A. Synthesis 1983, 134.
CHCl3); lit.6a,1b [+51.4 (c 1.01, CHCl3)6a, +63 (1.04% in CHCl3)1b].