Biomimetic total synthesis of (+)-himbacine

Article abstract of DOI:10.1021/ol047676+

(Chemical Equation Presented) On treatment with trifluoroacetic acid butenolide 14 undergoes N-Boc deprotection and condensation followed by an iminium ion activated intramolecular Diels-Alder cycloaddition to give the (+)-himbacine precursor 11 on reduct

Full text of DOI:10.1021/ol047676+

ORGANIC
LETTERS
2
005
Vol. 7, No. 4
85-588
Biomimetic Total Synthesis of
)-Himbacine
5
(+
Kirill Tchabanenko, Robert M. Adlington, Andrew R. Cowley, and
Jack E. Baldwin*
Chemistry Research Laboratory, UniVersity of Oxford, Mansfield Road,
Oxford OX1 3TA, United Kingdom
jack.baldwin@chem.ox.ac.uk
Received November 11, 2004
ABSTRACT
On treatment with trifluoroacetic acid butenolide 14 undergoes N-Boc deprotection and condensation followed by an iminium ion activated
intramolecular Diels
−
Alder cycloaddition to give the (
+
)-himbacine precursor 11 on reductive work up. Compound 11 was converted into
(
+
)-himbacine in four synthetic steps.
2
In 1956, Ritchie and Taylor reported isolation of the
Galbulimina family alkaloids from the bark of Himantandra
baccata.11 Overall 28 new alkaloids were isolated, which
were divided into 4 classes. Class 1 consisted of four
tetracyclic lactones.
effects. More recently though, himbacine has been shown
to be a selective muscarinic antagonist and thus a potential
3
new lead in the treatment of Alzheimer’s disease. Conse-
quently himbacine 1 has attracted much synthetic attention,4
and three successful total syntheses of this molecule have
been reported to date. Quite remarkably an intramolecular
Diels-Alder reaction was involved in the construction of
the tricyclic core unit of himbacine in all the synthetic efforts
published, however these approaches do not describe a
5-7
(
2) Collins, D. J.; Culvnor, C. C. J.; Lamberton, J. A.; Loder, J. W.;
Price, J. R. Plants for Medicines; C.S.I.R.O.: Melbourne, 1990.
3) Kozikowski, A. P.; Fauq, A. H.; Miller, J. H.; McKinney, M. Biol.
Med. Chem. Lett. 1992, 2, 797.
4) De Baecke, G.; De Clercq, P. J. Tetrahedron Lett. 1995, 36, 7515.
Hofman, S.; De Baecke, G.; Kenda, B.; De Clercq, P. J. Synthesis 1998,
79. Hofman, S.; Gao, L.-J.; Van Dingenen, H.; Hosten, N. G. C.; Van
Haver, D.; De Clercq, P. J.; Milanesio, M.; Viterbo, D. Eur. J. Org. Chem.
(
(
4
Within its class, himbacine (1) was the first and major
isolated representative. It was originally shown to exhibit
anti-spasmodic activity with low toxicity and few side
2
001, 2851. Wong, L. S.-M.; Sherburn, M. S. Org. Lett. 2003, 5, 3603.
(5) Hart, D. J.; Wu, W.-L.; Kozikowski, A. P. J. Am. Chem. Soc. 1995,
17, 9369. Hart, D. J.; Li, J.; Wu, W.; Kozikowski, A. P. J. Org. Chem.
997, 62, 5023.
1
1
(
6) Chackalamannil, S.; Davies, R. J.; Asberom, T.; Doller, D.; Leone,
(
1) Brown, R. F. C.; Drummond, R.; Fogerty, A. C.; Hughes, G. K.;
D. J. Am. Chem. Soc. 1996, 118, 9812. Chakalamannil, S.; Davies, R. J.;
Wang, Y.; Asberom, T.; Doller, D.; Wong, J.; Leone, D. J. Org. Chem.
1999, 64, 1932.
(7) Takadoi, M.; Katoh, T.; Ishiwata, A.; Terashima, S. Tetrahedron Lett.
1999, 40, 3399. Takadoi, M.; Katoh, T.; Ishiwata, A.; Terashima, S.
Tetrahedron 2002, 58, 9903.
Pinhey, J. T.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1956, 9, 284. Ritchie,
E.; Taylor, W. C. The Galibulimina Alkaloids. In The Alkaloids; Manske,
R. H. F., Ed.; Academic Press: New York, 1967; Vol. 9, p 529. Ritchie,
E.; Taylor, W. C. The Galibulimina Alkaloids. In The Alkaloids; Manske,
R. H. F., Ed.; Academic Press: New York, 1973; Vol. 13, p 227.
1
0.1021/ol047676+ CCC: $30.25
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Published on Web 01/20/2005

general biomimetic synthesis for all members of the class 1
Galbulimina alkaloids.
the iminium species 7 or 8. The compound 14 would be
obtained from a known aldehyde 15 via a Horner-Emmons
type olefination as outlined in Scheme 2.
Our proposed biogenesis of all members of the class 1
8
Galbulimina alkaloids is outlined in Scheme 1.
Scheme 2. Synthetic Plan
Scheme 1. Biogenesis of the Class 1 Galbulimina Alkaloids
Probably the most elegant approach to the aldehyde 15
5
was reported by Hart and we have adopted this sequence
in our synthesis. According to the published procedures
cycloheptene was converted into the aldehyde 16 in six
synthetic steps and 49% overall yield (Scheme 3). A number
Scheme 3. Synthesis of the Horner-Emmons Precursors
9
The polyketide derivative 5 would undergo reductive
lactonisation to produce the butenolide 6, which on reductive
amination followed by methylation or protonation would give
the iminium species 7 or 8. Intramolecular Diels-Alder
reaction via the endo transition state would afford tricycles
9
or 10, which on hydride reduction of the iminium ion from
either R or â face would finish the cis- or trans-piperidine
rings of the himbacine precursor 2, himbeline precursor 11
and himandravine precursor 13. It was previously shown that
mild reduction affords quantitative conversion of himgravine
into himbacine,1 which coupled with the fact that him-
gravine is found in significantly smaller quantities leads to
a proposal that himgravine is a precursor on the biosynthetic
pathway to himbacine.
010
8
Previously we have demonstrated evidence of the pos-
sibility of an iminium ion activated biological Diels-Alder
reaction of the type shown above. The core tricyclic unit of
himgravine was constructed via a Gassman-type11 oxonium
ion activated Diels-Alder cycloaddition. To obtain un-
ambiguous evidence in support of our iminium ion proposal
we decided to investigate the reaction of the dienone 14,
which on Boc removal should provide after condensation
of different homologation methods in order to obtain the
aldehyde 15 were tried, including the use of commercially
available stabilized phosphorane Ph
3
PdCHCHO and arsenic
5
ylide Ph
3
AsdCHCHO, which was prepared according to
1
2
published procedure. In our hands, these Wittig-type
procedures resulted in low yields of the product, which was
always contaminated with small amounts of over homolo-
gated material. On the contrary, the use of the aldimine 1713
gave a satisfactory isolated yield of the homologated alde-
hyde 15 (Scheme 3).
(
8) Baldwin, J. E.; Chesworth, R.; Parker, J. S.; Russell, A. T.
Tetrahedron Lett. 1995, 36, 9551.
9) 5 itself would most probably be derived from nine acetates and one
(
pyruvate by standard polyketide biosynthesis, as previously postulated by
Mander et al.; see: Mander, L. N.; Prager, R. H.; Rasmussen, M.; Ritchie,
E.; Taylor, W. C. Aust. J. Chem. 1967, 20, 1705.
The synthesis of the chiral phosphonate 18 was ac-
complished in three steps. 2-Methyl piperidine was resolved
(
10) Pinhey, J. T.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1961, 14,
06.
11) Gassman, P. G.; Singleton, D. A.; Wilwending, J. J.; Chavan, S. P.
J. Am. Chem. Soc. 1987, 109, 2182.
1
(12) Huang, Y.-Z.; Shi, L.; Yang, J.; Cai, Z. J. Org. Chem. 1987, 52,
3558.
(13) Bellasoued, M.; Majidi, A. J. Org. Chem. 1993, 58, 2517.
(
586
Org. Lett., Vol. 7, No. 4, 2005

Scheme 4. Completion of Synthesis
1
4
5
via crystallization with L-tartaric acid, which was followed
by Boc protection and oxidation.15 Treatment of the piperi-
dinone with a small excess of the lithiated dimethyl meth-
ylphosphonate produced the desired Horner-Emmons re-
agent 18 in 54% yield after column chromatography (Scheme
tection and N-methylation of 20 afforded the synthetic (+)-
himbacine (Scheme 4), whose structure was confirmed via
a doping NMR experiment with an authentic sample17 of
the natural product.
The structure of the himandravine precursor 21 was
established after Boc deprotection followed by formation of
a dinitrobenzoate derivative 22 (Scheme 5) (which was
3
).
Olefination of the aldehyde 15 and Horner-Emmons
reagent 18 was achieved in acetonitrile using H u¨ nig’s base
and an excess of lithium chloride. The cyclization precursor
4 was then treated with trifluoroacetic acid in dichlo-
16
1
Scheme 5. Preparation of the Himandravine Analogue 22
romethane at 0 °C and the reaction was allowed to slowly
warm to room temperature. After stirring for an hour it was
quenched by addition of an access of sodium cyanoborohy-
dride almost immediately followed by addition of saturated
aqueous sodium bicarbonate. To our delight the crude NMR
spectrum of the reaction mixture showed complete conver-
sion of the starting material along with the appearance of
two characteristic peaks at 6.62 and 6.69 ppm corresponding
to the resonances of the protons of the R,â-unsaturated double
bond of two epimeric products 11 and 13 derived from
consecutive N-Boc deprotection, condensation, cycloaddition
and iminium ion reduction (Scheme 4).
The reduction proved to be nonfacial selective and both
proton peaks had identical integration in the 500 MHz 1H
NMR. We found that direct separation of the diastereomeric
mixture of 11 and 13 from the complex crude reaction
mixture was impossible and required N-Boc protection
followed by a highly selective reduction of the trisubstituted
double bond10 in order to separate the N-Boc protected
himbeline 20 and himandravine 21 derivatives. Boc depro-
crystallized by a slow evaporation of an ethyl acetate
solution). The results of the single-crystal X-ray analysis of
(
14) Doller, D.; Davies, R.; Chackalamannil, S. Tetrahedron: Asymmetry
997, 7, 1275.
15) Occhiato, E. G.; Prandi, C.; Ferrali, A.; Guarna, A.; Venturello, P.
J. Org. Chem. 2003, 68, 9728.
16) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
2
2 are presented in Figure 1.
1
(
It is notable that all four representatives of the class 1
Galbulimina alkaloids can be accessed from the cyclization
products 11 and 13.
(
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 2183.
Org. Lett., Vol. 7, No. 4, 2005
587

Scheme 6. Attempted Cyclization of Des-methyl 14
Figure 1. Crystal structure of the himandravine analogue 22.
consecutive N-Boc deprotection, condensation and iminium
ion activated intramolecular Diels-Alder cycloaddition
process. This provides support for our proposed biogenesis
of the class 1 Galbulimina alkaloids.
Interestingly, in an earlier model study on an analogue of
14 lacking the stereogenic center R to the nitrogen, cycliza-
tion was not achieved when the Boc-protected nitrogen was
methylated; higher temperatures and longer reaction times
did not lead to the formation of the tetracycle (Scheme 6).
This is consistent with a more facile condensation from a
primary rather than a secondary amine in order to access a
key iminium ion intermediate.
In summary, we have demonstrated a single step bio-
mimetic transformation of 14 into a tetracyclic himbacine
precursor 11, which was transformed into the natural product
in four simple steps. We believe this proceeds via a
Acknowledgment. We would like to thank the NMR staff
of the Chemistry Research Laboratory, especially Dr. Barbara
Odell, for their help with structure elucidation.
Supporting Information Available: 1H and 13C NMR
spectra for compounds 1, 3, 4, 14, 18, and 20-22. Tables
of crystal data, fractional coordinates and thermal parameters,
and interatomic distances with standard deviation for the
himandravine derivative 22. This material is available free
of charge via the Internet at http://pubs.acs.org.
(17) The ref 1 mg sample was obtained from Fisher Scientific UK (Acros
cat. no. 32912 0010).
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Org. Lett., Vol. 7, No. 4, 2005