Synthesis of (+)-Allopumiliotoxins 267A, 339A, and 339B
J. Am. Chem. Soc., Vol. 122, No. 29, 2000 6951
Table 1
Results and Discussion
Development of an Ynal Reductive Cyclization Procedure.
Transition metal-catalyzed reductive cyclizations of dienes,
enynes, and diynes have been widely developed with numerous
catalyst systems.9 The corresponding cyclizations of carbonyls
with alkenes and alkynes, however, are less well developed.
Early metals are effective at promoting the coupling of carbonyls
with alkenes and alkynes via the formation of oxametallacycles,
but catalytic turnover in these systems is often difficult due to
the strength of the early metal-oxygen bond.10 While very
efficient stoichiometric procedures have been developed that
are quite broad in scope,7 the corresponding catalytic procedures
have been somewhat elusive. This limitation was partially
overcome by Buchwald11 and Crowe,12 who demonstrated that
titanocene-catalyzed reductive cyclizations of enones and ynones
were effective when silanes were employed as the reducing
agent. However, the titanium-catalyzed methods were unsuc-
cessful in the formation of rings larger than five-membered and
in couplings involving terminal alkynes. A number of late-metal-
catalyzed reductive cyclizations involving carbonyls have also
been reported. Of particular note are the studies from Mori and
Tamaru that described the efficient nickel-catalyzed coupling
of diene-aldehydes with triethylsilane,13 triethylborane,14 or
diethylzinc14 as the reducing agent. The scope of this procedure
is quite broad, and several complex synthetic applications have
been reported.15
suited for preparation of the allopumiliotoxin indolizidine
framework. However, we quickly found that direct addition of
the organozinc to the aldehyde was impossible to suppress as
the ynal substrate complexity increased.
We then examined triethylsilane as a less nucleophilic
reducing agent.17 In contrast to the diethylzinc-promoted process,
reductive cyclizations employing triethylsilane were very ef-
ficient across a broad range of substrate classes. The quinolizi-
dine ring system18 6 was first targeted, via cyclization of ynals
5a-d which possess a piperidine ring in the tether chain (Table
1). Cyclizations proceeded cleanly in several hours at 45 °C in
THF to afford high yields and very good diastereoselectivities.
Typical catalyst loadings were 10-20 mol % with a 2:1 to 4:1
phosphine-nickel ratio, and substrate concentrations typically
ranged from 0.02 to 0.05 M. Upon lowering the reaction
temperature to 0 °C, cyclizations required 18-48 h under
otherwise identical conditions. At 0 °C, diastereoselectivities
were uniformly outstanding across the range of substrates
examined. The quinolizidine framework was efficiently pro-
duced from ynals that possessed a variety of acetylenic
substituents, including aromatic (entry 3) and aliphatic (entry
4) internal alkynes, terminal alkynes (entry 5), and alkynylsilanes
(entry 6). The equatorial hydroxyl was selectively produced in
all cases. No evidence was obtained for competing reduction
of the aldehyde or alkyne without cyclization.
Our group recently reported a procedure for nickel-catalyzed
aldehyde-alkyne reductive and alkylative cyclizations involving
organozincs.16 In cyclizations involving a simple ynal and
diethylzinc, Ni(COD)2 catalyzed formation of the alkylative
cyclization product 4a, whereas Ni(COD)2/PBu3 catalyzed
formation of the reductive cyclization product 4b (eq 1). The
The [3.3.0] bicyclic framework of pyrrolizidine alkaloids19
was next examined (Table 2). The requisite ynals were quite
unstable, and attempts to purify the adducts from Swern
oxidation led to extensive decomposition. However, Swern
oxidation of alcohols 8a-c followed by simple extraction and
concentration afforded aldehydes of sufficient purity to ef-
ficiently participate in the nickel-catalyzed cyclizations. The
overall two-step procedure of oxidation and cyclization cleanly
Ni(COD)2/PBu3 catalyzed procedure appeared to be ideally
(9) (a) For an extensive review, see: Ojima, I.; Tzamarioudaki, M.; Li,
Z. Y.; Donovan, R. J. Chem. ReV. 1996, 96, 635-662. (b) For an early
example of this reaction class, see: Trost, B. M.; Rise, F. J. Am. Chem.
Soc. 1987, 109, 3161.
(10) Hewlett, D. F.; Whitby, R. J. J. Chem. Soc., Chem. Commun. 1990,
1684.
(11) (a) Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1995, 117,
6785-6786. (b) Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1996,
118, 3182-3191.
(12) Crowe, W. E.; Rachita, M. J. J. Am. Chem. Soc. 1995, 117, 6787-
6788.
(13) (a) Sato, Y.; Takimoto, M.; Hayashi, K.; Katsuhara, T.; Takagi,
K.; Mori, M. J. Am. Chem. Soc. 1994, 116, 9771. (b) Sato, Y.; Takimoto,
M.; Mori, M. Tetrahedron Lett. 1996, 37, 887. (c) Takimoto, M.; Hiraga,
Y.; Sato, Y.; Mori, M. Tetrahedron Lett. 1998, 39, 4543.
(14) (a) Kimura, M.; Ezoe, A.; Shibata, K.; Tamaru, Y. J. Am. Chem.
Soc. 1998, 120, 4033. (b) Kimura, M.; Fujimatsu, H.; Ezoe, A.; Shibata,
K.; Shimizu, M.; Matsumoto, S.; Tamaru, Y. Angew. Chem., Int. Ed. 1999,
38, 397.
(17) For other transition metal-catalyzed cyclizations involving hydrosi-
lanes, see: (a) Ojima, I.; Zhu, J. W.; Vidal, E. S.; Kass, D. F. J. Am. Chem.
Soc. 1998, 120, 6690. (b) Trost, B. M.; Rise, F. J. Am. Chem. Soc. 1987,
109, 3161-3163. (c) Tamao, K.; Kobayashi, K.; Ito, Y. J. Am. Chem. Soc.
1989, 111, 6478. (d) Takacs, J.; Chandramouli, S. Organometallics 1990,
9, 2877. (e) Widenhoefer, R. A.; DeCarli, M. A. J. Am. Chem. Soc. 1998,
120, 3805. (f) Molander, G. A.; Nichols, P. J. J. Am. Chem. Soc. 1995,
117, 4415.
(18) (a) Michael, J. P. Nat. Prod. Rep. 1999, 16, 675. (b) Kinghorn, A.
D.; Balandrin, M. F. In Alkaloids: Chemical and Biological PerspectiVes;
Pelletier, S. W., Ed.; Wiley: New York, 1984; Vol. 2, Chapter 3. (c) Herbert,
R. B. In Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S.
W., Ed.; Wiley: New York, 1985; Vol. 3, Chapter 6. (d) Pearson, W. H.;
Suga, H. J. Org. Chem. 1998, 63, 9910.
(15) (a) Sato, Y.; Saito, N.; Mori, M. Tetrahedron Lett. 1997, 38, 3931.
(b) Sato, Y.; Saito, N.; Mori, M. Tetrahedron 1998, 54, 1153. (c) Sato, Y.;
Takimoto, H.; Mori, M. Synlett 1997, 6, 734.
(16) (a) Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119,
9065-9066. (b) Montgomery, J. Acc. Chem. Res. In press.
(19) (a) Liddell, J. R. Nat. Prod. Rep. 1999, 16, 499. (b) Hartmann, T.;
Witte, L. In Alkaloids: Chemical and Biological PerspectiVes; Pelletier,
S. W., Ed.; Wiley: New York, 1995; Vol. 9, Chapter 4. (c) Broggini, G.;
Zecchi, G. Synthesis 1999, 6, 905. (d) Li, Y. W.; Marks, T. J. J. Am. Chem.
Soc. 1998, 120, 1757.