IMDA-radical cyclization approach to (+)-himbacine

Article abstract of DOI:10.1021/ol0353058

(Equation presented) A formal total synthesis of the selective muscarinic receptor antagonist himbacine is presented. Key C-C bond-forming steps include an intramolecular Diels-Alder reaction, Stille coupling reactions, and a 6-exo-trig acyl radical cycli

Full text of DOI:10.1021/ol0353058

ORGANIC
LETTERS
2003
Vol. 5, No. 20
3603-3606
IMDA-Radical Cyclization Approach to
)-Himbacine
(+
Leon S.-M. Wong and Michael S. Sherburn*
Research School of Chemistry, Australian National UniVersity, Canberra ACT 0200,
Australia, and School of Chemistry, UniVersity of Sydney, Sydney NSW 2006, Australia
sherburn@rsc.anu.edu.au
Received July 16, 2003
ABSTRACT
A formal total synthesis of the selective muscarinic receptor antagonist himbacine is presented. Key C−C bond-forming steps include an
intramolecular Diels
−Alder reaction, Stille coupling reactions, and a 6-exo-trig acyl radical cyclization to a conjugated enyne. An unexpected
secondary alcohol to chloride conversion is witnessed during attempted thionocarbonate formation.
Himbacine (1) (Figure 1) is an alkaloid extracted from
Galbulimima baccata, a tree found in Northern Australia and
Papua New Guinea.1 Himbacine exhibits strong, selective
In efforts toward this end, we recently described concise
syntheses of 4,4a-didehydrohimbacine 6 and N-methyl-4,-
4a-didehydrohimandravine.10 Whereas this approach allowed
binding to muscarinic receptors of the M2 subtype,2
a
property that has potential medicinal applications.3 The
unique architecture of Galbulimima alkaloids, coupled with
himbacine’s promising biological activity, has provoked the
synthetic efforts of several groups.4-8 These approaches have
delivered many analogues of himbacine for biological
evaluation.9 To date, however, no analogue has been reported
with both higher potency and M2-selectivity than himbacine.
(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. Takadoi, M.; Katoh, T.; Ishiwata, A.; Terashima, S.
Tetrahedron 2002, 58, 9903-9923.
(9) (a) Darroch, S. A.; Taylor, W. C.; Choo, L. K.; Mitchelson, F. Eur.
J. Pharmacol. 1990, 182, 131-136. (b) Kozikowski, A. P.; Aagaard, P. J.;
McKinney, M. Bioorg. Med. Chem. Lett. 1993, 3, 1247-1252. (c) Malaska,
M. J.; Fauq, A. H.; Kozikowski, A. P.; Aagaard, P. J.; McKinney, M. Bioorg.
Med. Chem. Lett. 1995, 5, 61-66. (d) Doller, D.; Chackalamannil, S.;
Czarniecki, M.; McQuade, R.; Ruperto, V. Bioorg. Med. Chem. Lett. 1999,
9, 901-906. (e) Gao, L.-J.; Waelbroeck, M.; Hofman, S.; Van Haver, D.;
Milanesio, M.; Viterbo, D.; De Clercq, P. J. Bioorg. Med. Chem. Lett. 2002,
12, 1909-1912. (f) Takadoi, M.; Terashima, S. Bioorg. Med. Chem. Lett.
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Bioorg. Med. Chem. Lett. 2002, 12, 3271-3273. (h) Takadoi, M.;
Yamaguchi, K.; Terashima, S. Bioorg. Med. Chem. 2003, 11, 1169-1186.
(10) Wong, L. S.-M.; Sharp, L. A.; Xavier, N. M. C.; Turner, P.;
Sherburn, M. S. Org. Lett. 2002, 4, 1955-1957. For an almost identical
approach, see: Van Cauwenberge, G.; Gao, L.-J.; Van Haver, D.; Milanesio,
M.; Viterbo, D.; De Clercq, P. J. Org. Lett. 2002, 4, 1579-1582. Gao,
L.-J.; Van Cauwenberge, G.; Hosten, N.; Van Haver, D.; Waelbroeck, M.;
De Clercq, P. J. ARKIVOC 2003, 22-45.
(1) 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, 283-287.
Pinhey, J. T.; Ritchie, E.; Taylor, W. C.; Binns, S. D. 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.
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P. J. Org. Chem. 1997, 62, 5023-5033.
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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.
10.1021/ol0353058 CCC: $25.00
© 2003 American Chemical Society
Published on Web 09/09/2003

regiocontrolled anti-1,2-addition of hydrogen to the more
substituted alkene moiety of a conjugated diene would be
necessary (i.e., 6 f 1). Herein we report a total synthesis of
himbacine that circumvents this problem.
The essence of this new approach is the utilization of the
alkene moiety generated by the IMDA reaction as the site
for intramolecular radical addition (Figure 1). Thus, an
IMDA reaction on a [3]dendralene,11 or a synthetic equivalent
thereof, would generate the B/C bicyclic lactone 3. A
subsequent 6-exo-trig acyl radical addition12 to the resulting
semicyclic diene would install the A ring of 2. The requisite
stereochemistry at C4 would be obtained by hydrogen atom
delivery to the convex face of 5. An epimerization at C4a
and functional group interconversions would complete the
synthesis.
Selenoate ester 3 was prepared to investigate this proposal
(Scheme 1). The synthesis of 3 begins with a Stille coupling
between (S)-lactic acid-derived dibromoalkene 713 and (E)-
vinylstannane 8,14 which proceeded smoothly to give the (Z)-
bromodiene 9 in high selectivity.15 Protection of the primary
alcohol as the MOM ether followed by desilylation and
esterification with acryloyl chloride gave Diels-Alder
precursor 10. Bromopentadienyl acrylate 10 underwent an
IMDA reaction in refluxing chlorobenzene over 6 days at
ambient pressure to afford two cycloadducts 11 and 12 in
Figure 1. Intramolecular Diels-Alder/radical cyclization approach
to himbacine.
rapid access to himbacine analogues, it is not amenable to
the preparation of the natural product since a stereo- and
Scheme 1. Synthesis and Cyclization of Diene-Appended Radical Precursor 3a
a Reaction conditions: (a) dibromide 7 (1.00 equiv), vinylstannane 8 (1.05 equiv), Pd2dba3 (0.0125 equiv), AsPh3 (0.10 equiv), THF, 50
°C, 20 h, 72%; (b) MOM-Cl (5.0 equiv), i-Pr2NEt (5.0 equiv), DMAP (0.1 equiv), CH2Cl2, 0 °C to rt, 3 h, 96%; (c) TBAF (1.5 equiv),
THF, 0 °C to rt, 30 min, 94%; (d) CH2dCHCOCl (1.5 equiv), Et3N (2.1 equiv), CH2Cl2, 0 °C, 1 h, 91%; (e) PhCl ([10]initial ) 10 mM),
BHT (0.05 equiv), reflux, 140 h, 75%, 11:12 ) 84:16; (f) DBU (1.1 equiv), CH2Cl2, reflux, 17 h, 99%; (g) vinylstannane 13 (1.5 equiv),
Pd(PPh3)4 (0.1 equiv), CuCl (5.0 equiv), LiCl (6.0 equiv), DMSO, 60 °C, 21 h, 86%; (h) PPTS (1.1 equiv), t-BuOH, reflux, 48 h; Boc2O,
CH2Cl2, rt, 17 h, 81%; (i) (COCl)2 (2.1 equiv), DMSO (4.2 equiv), CH2Cl2, -78 °C, 1 h then Et3N (10 equiv), 94%; (j) NaClO2 (3 equiv),
NaH2PO4 (3 equiv), 2-methyl-2-butene (8 equiv), THF/t-BuOH/H2O (3:3:1), rt, 1 h, 93%; (k) Ph2Se2 (2 equiv), n-Bu3P (2 equiv), DMF, rt,
18 h, 60%; (l) Ph3SnH (1.5 equiv), Et3B (1.2 equiv), air, PhH, reflux, 2 h, 65%, 15:16 ) 20:80; 16E:16Z ) 40:60.
3604
Org. Lett., Vol. 5, No. 20, 2003

Scheme 2. Synthesis and Cyclization of Enyne-Appended Radical Precursor 19a
a Reaction conditions: (a) bromoalkene 12 (1.0 equiv), alkynylstannane 17 (1.5 equiv), Pd(PPh3)4 (0.1 equiv), CuCl (5.0 equiv), LiCl
(6.0 equiv), DMSO, 60 °C, 21 h, 85%; (b) PPTS (1.1 equiv), t-BuOH, reflux, 48 h; Boc2O, CH2Cl2, rt, 17 h, 75%; (c) (COCl)2 (2.1 equiv),
DMSO (4.2 equiv), CH2Cl2, -78 °C, 1 h then Et3N (10 equiv), 95%; (d) NaClO2 (3 equiv), NaH2PO4 (3 equiv), 2-methyl-2-butene (8
equiv), THF/t-BuOH/H2O (3:3:1), rt, 1 h, 94%; (e) Ph2Se2 (2 equiv), n-Bu3P (2 equiv), DMF, rt, 18 h, 76%; (f) Bu3SnH (1.5 equiv), AIBN
(0.1 equiv), PhH, reflux, 18 h, 90%, 20:21 ) 48:52; (21 C1′S:R ) 50:50); (g) DBU (1.1 equiv), CH2Cl2, reflux, 7 h, 94%; (h) NaBH4 (1.4
equiv), CeCl3‚7H2O (1 equiv), MeOH, -78 °C, 4 h, 97% (R-OH:â-OH ) 77:23); (i) C6F5OC(S)Cl (9 equiv), DMAP (10 equiv), CH3CN,
reflux, 20 h, 87%; (j) Bu3SnH (5.1 equiv), AIBN (cat.), PhMe, reflux, 7 h, 82%.
an 84:16 ratio, a stereochemical outcome consistent with
previous investigations conducted with related precursors.16
The desired cis-fused adduct 12 was obtained in essentially
quantitative yield after exposure of the IMDA product
mixture to DBU.
(11) Fielder, S.; Rowan, D. D.; Sherburn, M. S. Angew. Chem., Int. Ed.
2000, 39, 4331-4333.
The (E)-vinylpiperidine side chain was installed in high
yield using Corey’s cuprous chloride-accelerated Stille
coupling procedure17 between 12 and known vinylstannane
13.10 To complete the sequence, the primary MOM ether 14
was transformed into the phenylselenoate ester 3 by depro-
tection,18 Swern oxidation,19 Pinnick oxidation,20 and esteri-
(12) For a review of acyl radical reactions, see: Chatgilialoglu, C.; Crich,
D.; Komatsu, M.; Ryu, I. Chem. ReV. 1999, 99, 1991-2069. See also:
Boger, D. L.; Mathvink, R. J. J. Org. Chem. 1992, 57, 1429-1443.
(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. (c) Trost, B. M.; Muller, T. J. J.; Martinez, J. J. Am. Chem. Soc. 1995,
117, 1888-1899.
(14) Vinyl stannane 8 was prepared by Bu3SnH addition to 1-hexynol
(92% isolated yield, E:Z ) 87:13 by GC): Kalivretenos, A.; Stille, J. K.;
Hegedus, L. S. J. Org. Chem. 1991, 56, 2883-2894.
(17) Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121,
7600-7605.
(15) Shen, W., Wang, L. J. Org. Chem. 1999, 64, 8873-8879.
(16) For a detailed analysis of reactions of this type, see: Cayzer, T.
N.; Wong, L. S.-M.; Turner, P.; Paddon-Row: M. N.; Sherburn, M. S. Chem.
Eur. J. 2002, 8, 739-750.
(18) Exposure to PPTS in refluxing t-BuOH caused partial loss of the
N-Boc protecting group. The crude product from this reaction was treated
with Boc2O to re-install the amine protecting group.
(19) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651-1660.
Org. Lett., Vol. 5, No. 20, 2003
3605

fication.21 The 6-exo-trig radical cyclization of selenoate ester
3 was examined with a range of radical mediators (Bu3SnH,
(Me3Si)3SiH, and Ph3SnH) under a variety of different
conditions. The most fruitful of these gave the desired
product in isolated yields of only 13%. The regioselectiVity
of H-atom delivery to allyl radical 5 (Figure 1) was the
problem, as evidenced by isolation of the more highly
substituted alkene 16 as the major product. Indeed, the ratio
of 15:16 was 1:4 at best. Nevertheless, the C4 epimer of 15
could not be detected, an encouraging result that demon-
strated a high degree of stereocontrol during H atom delivery
to the more substituted end of the allylic radical.
Since the yield of the desired product 15 could not be
improved by either switching the radical mediator or modify-
ing of the reaction conditions, an alternative approach was
necessary. We reasoned that a conjugated enyne should solve
the problem, since delocalized allenic/propargylic radicals
appear to react almost exclusively at the propargylic site.22
Thus, selenoate ester 19, an alkynic congener of 3, was
prepared from bromoalkene 12 as shown in Scheme 2. Stille
coupling between vinyl bromide 12 and alkynylstannane 1723
was best performed once again in the presence of cuprous
chloride. The protected primary alcohol 18 was elaborated
into the acyl selenide 19 in good yield through the four-step
sequence described earlier. Intriguingly, the reductive 6-exo-
trig radical cyclization furnished a ca. 1:1 mixture of alkynic
(20) and allenic (21) products under all conditions examined,
the best isolated yields being obtained with Bu3SnH in
refluxing benzene. Once again, the desired C4 trapping
product 20 was produced as a single diastereoisomer, whereas
the two allenes 21 were produced in equal amounts.
Evidently, the regiochemistry of H atom delivery to allenic/
propargylic radicals is sensitive to substitution.
Epimerization at C4a (20 f 22) was accomplished in
excellent yield with DBU. We planned to remove the ketone
group by reduction to the alcohol and then Barton-
McCombie deoxygenation via thionocarbonate 24. Luche
reduction of the ketone at low temperature gave the axial
alcohol 23 in excellent yield with high stereoselectivity. No
reaction occurred upon attempted thionocarbonate formation
at ambient temperature. Under more forcing conditions,
however, we were surprised to witness a very clean conver-
sion to the axial chloride (25). To our knowledge, such a
transformation is without precedent in the thionocarbonate
series; related conversions have, however, been witnessed
with xanthates.24 Reductive dechlorination of 25 with
Bu3SnH completes the formal total synthesis of himbacine.25
We wonder whether some previously reported “deoxygen-
ations” via the Barton-McCombie method have instead
involved the removal of chlorine.
In summary, a novel route to himbacine has been
developed. The route has allowed access to new analogues
of the natural product, compounds that should shed light on
the structural requirements for optimal potency and selectivity
with muscarinic receptors.
Acknowledgment. We thank the Australian Research
Council, the University of Sydney, and the Australian
National University for funding.
(20) Bal, B. S.; Childers Jr., W. E.; Pinnick, H. W. Tetrahedron 1981,
37, 2091-2096.
Supporting Information Available: Experimental pro-
cedures and product characterization data for key steps
(10 f 11 + 12, 3 f 15 + 16, 19 f 20 + 21, 23 f 25) and
1H and 13C NMR spectra of advanced intermediates 15, 16,
20-22, 25, and 26. This material is available free of charge
via the Internet at http://pubs.acs.org.
(21) Masamune, S.; Hayase, Y.; Schilling, W.; Chan, W. K.; Bates, G.
S. J. Am. Chem. Soc. 1977, 99, 6756-6758.
(22) When propargyl bromide is treated with Bu3SnH, propyne and allene
are formed in an 84:16 ratio: Menapace, L. W.; Kuivila, H. G. J. Am.
Chem. Soc. 1964, 86, 3047-3051. Studies on substituted systems: (a)
Fantazier, R. M.; Poutsma, M. L. J. Am. Chem. Soc. 1968, 90, 5490-5498.
(b) Srikrishna, A.; Sharma, G. V. R.; Hemamalini, P. J. Chem. Soc., Chem.
Commun. 1990, 1681-1683. (c) Wartenberg, F.-H.; Junga, H.; Blechert,
S. Tetrahedron Lett. 1993, 34, 5251-5252. (d) Quiclet-Sire, B.; Zard, S.
Z. J. Am. Chem. Soc. 1996, 118, 1209-1210. (e) Denieul, M.-P.; Quiclet-
Sire, B.; Zard, S. Z. Tetrahedron Lett. 1996, 37, 5495-5498. (f) Bogen,
S.; Fensterbank, L.; Malacria, M. J. Org. Chem. 1999, 64, 819-825. (g)
Boutillier, P.; Zard, S. Z. Chem. Commun. 2001, 1304-1305.
(23) Prepared from the alkyne (ref 10) by deprotonation (n-BuLi (1.1
equiv), THF, -78 °C, 10 min) and then stannylation with Bu3SnCl (1.1
equiv, rt, 40 h) in 90% yield.
OL0353058
(24) (a) Cristol, S. J.; Seapy, D. G. J. Org. Chem. 1982, 47, 132-136.
(b) Barany, G.; Schroll, A. L.; Mott, A. W.; Halsrud, D. H. J. Org. Chem.
1983, 48, 4750-4761. (c) Kozikowski, A. P.; Lee, J. Tetrahedron Lett.
1988, 29, 3053-3056.
(25) Alkyne 26 (prepared by a different approach) was converted into
himbacine by De Clercq and co-workers. See refs 5c and 9e.
3606
Org. Lett., Vol. 5, No. 20, 2003