The bromopentadienyl acrylate approach to himbacine.

Article abstract of DOI:10.1021/ol0259746

[reaction: see text] The syntheses of 4,4a-didehydrohimbacine and 4,4a-didehydrohimandravine are presented. Key steps include an intramolecular Diels-Alder reaction of a bromopentadienyl acrylate and Suzuki-Miyaura and Stille coupling reactions.

Full text of DOI:10.1021/ol0259746

ORGANIC
LETTERS
2002
Vol. 4, No. 11
1955-1957
The Bromopentadienyl Acrylate
Approach to Himbacine
Leon S.-M. Wong, Lisa A. Sharp, Natacha M. C. Xavier, Peter Turner,† and
Michael S. Sherburn*
School of Chemistry, UniVersity of Sydney, Sydney NSW 2006, Australia
m.sherburn@chem.usyd.edu.au
Received April 5, 2002
ABSTRACT
The syntheses of 4,4a-didehydrohimbacine and 4,4a-didehydrohimandravine are presented. Key steps include an intramolecular Diels−Alder
reaction of a bromopentadienyl acrylate and Suzuki−Miyaura and Stille coupling reactions.
The structures of himbacine (1) and himandravine (2) (Figure
1) were reported by Pinhey, Ritchie, and Taylor in 1961.1
These alkaloids were extracted from Galbulimima baccata,
a species of tree found in Northern Australia and Papua New
Guinea. Himbacine was subsequently found to exhibit strong,
selective binding to muscarinic receptors of the M2 subtype.2
Speculation that selective presynaptic muscarinic receptor
antagonists might find application in the treatment of
neurodegenerative disorders such as Alzheimer’s disease3 has
provoked extensive synthetic efforts toward Galbulimima
alkaloids by many groups.4-8
(Figure 1). Of all possible Diels-Alder-based disconnections
that can be applied to the himbacine framework, a ring B
Reported synthetic work toward himbacine to date involves
the construction of ring B by way of a Diels-Alder reaction
† To whom correspondence should be addressed regarding the crystal
structure.
(1) Pinhey, J. T.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1961, 14
106-134.
(2) (a) Anwar-ul, S.; Gilani, H.; Cobbin, L. B. Naunyn-Schmiedeberg’s
Arch. Pharmacol. 1986, 332, 16-20. (b) Wang, J. X.; Roeske, W. R.; Wang,
W.; Yamamura, H. I. Brain Res. 1988, 446, 155-158.
(3) Kozikowski, A. P.; Fauq, A. H.; Miller, J. H.; McKinney, M. Bioorg.
Med. Chem. Lett. 1992, 2, 797-802.
(4) (a) Hart, D. J.; Wu, W.-L.; Kozikowski, A. P. J. Am. Chem. Soc.
1995, 117, 9369-9370. (b) Hart, D. J.; Li, J.; Wu, W.-L.; Kozikowski, A.
P. J. Org. Chem. 1997, 62, 5023-5033.
(5) (a) De Baecke, G.; De Clercq, P. J. Tetrahedron Lett. 1995, 36, 7515-
7518. (b) Hofman, S.; De Baecke, G.; Kenda, B.; De Clercq, P. J. Synthesis
1998, 479-489. (c) 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. 2001, 2851-2860.
Figure 1. Synthetic approaches to himbacine involving a Diels-
Alder reaction to construct the B-ring.
10.1021/ol0259746 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/07/2002

disconnection of 4,4a-didehydrohimbacine appeared to us as
the most synthetically attractive, since such a disconnection
reveals an intramolecular Diels-Alder (IMDA) reaction
involving an acrylate ester derivative of either a [3]-
dendralene9 or a bromodiene. We recently reported the results
of a joint synthetic-computational investigation into the
feasibility of the latter approach for the preparation of
himbacine,10 and herein we disclose an extension of this work
to 4,4a-didehydrohimbacine and 4,4a-didehydrohimandra-
vine.11 The appearance of a paper by De Clercq and co-
workers12 prompts this preliminary report.
in high selectivity. Deprotection of the silyl ether and
esterification of the resulting bromodienol with acryloyl
chloride gave IMDA precursor 7. Dilute (10 mM) solutions
of 7 in chlorobenzene undergo a highly stereoselective IMDA
reaction upon heating to 132 °C for 5 days at ambient
pressure to afford two cycloadducts 8 and 9 in an 86:14 ratio.
Both cycloadducts possess the C3,C3a-anti-stereochemistry
required for himbacine. The stereochemical outcome of the
IMDA reaction of 7 mirrors that seen with the acyclic
precursor 10.10 This close similarity in reaction outcome
strongly suggests that the same stereocontrolling influences
are at play. Thus, π-diastereofacial selectivity in these
reactions is dominated by the development of destabilizing
1,3A strain in transition states leading to the unseen C3,C3a-
syn isomers. Of the two observed C3,C3a-anti products,
trans-fused exo-isomer 8 (cf. 11) is preferred over its cis-
fused endo-congener 9 (cf. 12) as a result of the presence of
a destabilizing eclipsing interaction between the CH3 group
and H3a in the transition state leading to the latter. The major
cycloaddition product 8 is readily converted into the required
cis-fused isomer 9 in essentially quantitative yield on
exposure to DBU.10
Scheme 1. Synthesis of Bromotricycle 9a
The D-ring-appended vinylstannane side chains required
for himbacine and himandravine, 16 and 19, respectively
(Scheme 2), were prepared from the known N-Boc piperidine
Scheme 2. Synthesis of D-Ring-Appended Vinyl Stannanesa
a (a) Pd(PPh3)4 (0.10 equiv), Ba(OH)2 (1.8 equiv), THF-
MeOH-H2O, 25 °C, 15 h, 70%; (b) Bu4NF (1.5 equiv), THF, 25
°C, 3 h, 94%; (c) CH2dCHCOCl (1.6 equiv), Et3N (2.1 equiv),
CH2Cl2, 25 °C, 0.5 h, 81%; (d) PhCl ([7]initial ) 10 mM), BHT
(0.05 equiv), reflux, 112 h, 81%; 8:9 ) 86:14; (e) DBU (1.1 equiv),
CH2Cl2, reflux, 16 h, 97%; (f)10 PhCl ([10]initial ) 10 mM), BHT
(0.05 equiv), reflux, 156 h, 83%; 11:12 ) 81:19.
a (a) (Ph3PCHBr2)Br (2.0 equiv), t-BuOK (1.9 equiv), THF, RT,
10 min, 81%; (b) LiHMDS (1.2 equiv), THF, -78 °C - RT, 7 h,
90%; (c) Bu3SnH (2.2 equiv), Pd2dba3 (0.005 equiv), PPh3 (0.04
equiv), THF, RT, 6 h, 77%; (d) (Ph3PCHBr2)Br (2.0 equiv), t-BuOK
(1.9 equiv), THF, RT, 7 h, then n-BuLi (5.0 equiv), -78 °C, 10
min, 78%; (e) Bu3SnH (1.1 equiv), AIBN (0.05 equiv), PhH, reflux,
11 h, 61%.
Our synthesis begins (Scheme 1) with a Suzuki-Miyaura
coupling between (S)-lactic acid derived dibromoalkene 413
and cyclohexene-1-boronic acid 3,14 which, in line with
earlier observations by Roush,15 gave the Z-bromodiene 5
aldehydes 1316 and 177c,16a through related two- and three-
step sequences.17 In the case of the 2,5-trans diastereomer
16, modified Corey-Fuchs reaction18 of aldehyde 13 gave
(6) Baldwin, J. E.; Chesworth, R.; Parker, J. S.; Russell, A. T.
Tetrahedron Lett. 1995, 36, 9551-9554.
(7) (a) Chackalamannil, S.; Davies, R. J.; Asberom, T.; Doller, D.; Leone,
D. J. Am. Chem. Soc. 1996, 118, 9812-9813. (b) Chackalamannil, S.;
Davies, R. J.; Wang, Y.; Asberom, T.; Doller, D.; Wong, J.; Leone, D.;
McPhail, A. T. J. Org. Chem. 1999, 64, 1932-1940. (c) Chackalamannil,
S.; Davies, R.; McPhail, A. T. Org. Lett. 2001, 3, 1427-1429.
(8) Takadoi, M.; Katoh, T.; Ishiwata, A.; Terashima, S. Tetrahedron Lett.
1999, 40, 3399-3402.
(9) Fielder, S.; Rowan, D. D.; Sherburn, M. S. Angew. Chem., Int. Ed.
2000, 39, 4331-4333.
(10) Cayzer, T. N.; Wong, L. S.-M.; Turner, P.; Paddon-Row, M. N.;
Sherburn, M. S. Chem. Eur. J. 2002, 8, 739-750.
(11) Portions of this work were presented by L.S.-M.W. at the Royal
Australian Chemical Institute Organic Group 21st Annual Symposium,
University of Wollongong, Australia, 29 November 2000.
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Org. Lett., Vol. 4, No. 11, 2002

Scheme 3. Synthesis of 4,4a-Didehydrohimbacine 22 and
4,4a-Didehydrohimandravine 23a
a (a) Pd(PPh3)4 (0.20 equiv), CuCl (5.0 equiv). LiCl (6.0 equiv),
DMSO, 60 °C, 32 h, 73% for R = R-H; 65% for R = â-H; (b)
CF3COOH (80 equiv), CH2Cl2, RT, 10 min, then CH2O (17 equiv),
NaBH3CN (6 equiv), CH3CN, RT, 16 h, 65% for R = R-H; 60%
for R = â-H.
the 1,1-dibromoalkene 14, which was converted to the
E-vinylstannane 16 via the 1-bromoalkyne 15 according to
Pattenden’s hydrostannylation-reductive debromination pro-
tocol.19 Interestingly, better yields were obtained in the 2,5-
cis series by adopting a one-pot Corey-Fuchs reaction-
dehydrobromination-debromination sequence18 (17 f 18)
followed by radical hydrostannylation (18 f 19).
Figure 2. ORTEP diagram of 4,4a-didehydrohimandravine 23.
Acknowledgment. We thank Dr. Ian Luck (University
of Sydney) for assistance with NMR experiments and the
Australian Research Council and the University of Sydney
for funding.
Cuprous chloride accelerated Stille coupling of vinylstan-
nanes 16 and 19 with bromotricycle 9 proceeded in 73%
and 65% yields under conditions reported by Corey and co-
workers (Scheme 3).20
Deprotection and reductive methylation of the tetracyclic
products 20 and 21 gave 4,4a-didehydrohimbacine 22 and
4,4a-didehydrohimandravine 23 in overall yields of 65% and
60%, respectively. The structure of the latter was confirmed
by single-crystal X-ray analysis (Figure 2).21
Supporting Information Available: Experimental pro-
cedures and product characterization data for key steps (3
1
+ 4 f 5; 7 f 8 + 9; 16 + 9 f 20; 20 f 22), H and 13C
NMR spectra of all new compounds, and X-ray crystal-
lographic details for 4,4a-didehydrohimandravine 23. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0259746
In summary, a short and modular approach to didehydro
analogues of biologically important Galbulimima alkaloids
has been developed. Current efforts involve the application
of this general strategy to the synthesis of himbacine.
(15) Roush, W. R.; Moriarty, K. J.; Brown, B. B. Tetrahedron Lett. 1990,
31, 6509-6512
(16) (a) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109-1117. (b)
Chackalamannil, S.; Davies, R. J.; Wang, Y.; Asberom, T.; Doller, D.;
Wong, J.; Leone, D.; McPhail, A. T. J. Org. Chem. 1999, 64, 1932-1940.
(17) Attempts to carry out this conversion directly (Hodgson, D. M.;
Boulton, L. T.; Maw, G. N. Tetrahedron 1995, 51, 3713-3724) have thus
far proven unsuccessful.
(12) Cauwenberge, G. V.; Gao, L.-J.; Van Haver, D.; Milanesio, M.;
Viterbo, D.; De Clercq, P. J. Org. Lett. 2002, 4, 1579-1582.
(13) (a) Marshall, J. A.; Xie, S. J. Org. Chem. 1995, 60, 7230-7237.
(b) Smith, N. D.; Kocienski, P. J.; Street, S. D. A. Synthesis 1996, 652-
666.
(14) This known compound (Renaud, J.; Ouellet, S. G. J. Am. Chem.
Soc. 1998, 120, 7995-7996) was prepared on large scale from 1-lithio-1-
cyclohexene (Brandsma, L.; Verkruijsse, H. D. Synth. Commun. 1990, 20,
3367-3369) by boronate ester formation and hydrolysis.
(18) Michel, P.; Gennet, D.; Rassat, A. Tetrahedron Lett. 1999, 40,
8575-8578.
(19) Boden, C. D. J.; Pattenden, G.; Ye, T. J. Chem. Soc., Perkin Trans.
1 1996, 2417-2419.
(20) Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121,
7600-7605.
(21) See Supporting Information for full details.
Org. Lett., Vol. 4, No. 11, 2002
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