Angewandte
Chemie
DOI: 10.1002/anie.200901992
Asymmetric Catalysis
Rhodium-Catalyzed Asymmetric Enyne Cycloisomerization of
Terminal Alkynes and Formal Total Synthesis of (ꢀ)-Platensimycin**
K. C. Nicolaou,* Ang Li, Shelby P. Ellery, and David J. Edmonds
The development of efficient cyclization methods for five-
membered ring formation constitutes a continuing challenge
in natural and designed molecule construction. Among these
methods, the cycloisomerization of 1,6-enynes to form cyclo-
pentane rings has evolved into a powerful technology in
chemical synthesis in the past few years. A number of
transition metal complexes, such as those of palladium,[1]
ruthenium,[2] rhodium,[3] and iron,[4] have proven to be
effective catalysts in this transformation. Rhodium-based
catalytic systems have attracted particular attention as they
demonstrated excellent reactivity and enantioselectivity when
applied to internal alkyne substrates.[3] However, in some
instances an exocyclic methylene group (as opposed to a
Scheme 1. Proposed mechanism of rhodium-catalyzed asymmetric
cycloisomerization of terminal enynes.
substituted olefinic bond) is needed on the resulting inter-
mediates for direct elaboration to more advanced products, a
condition that requires terminal alkynes as substrates.
Although “capped” alkynes with disposable groups have
been utilized in this regard, their removal can be laborious
and inefficient. Herein we report a rhodium-catalyzed
asymmetric enyne cycloisomerization reaction using terminal
alkynes as substrates and its application to a formal total
synthesis of (ꢀ)-platensimycin.
Table 1: Catalyst screening.[a]
Entry
Catalyst
Yield of 1a [%]
ee [%][b]
Scheme 1 shows the proposed mechanism for the rho-
dium-catalyzed cycloisomerization of the terminal acetylene I
into a cyclopentane derivative (IV) through transient species
II and III.
1
2
3
4
[Rh(cod)(MeCN)2]BF4,(S)-binap
[{Rh(cod)Cl}2], (S)-binap, AgOTf
[{Rh(cod)Cl}2], (S)-binap, AgSbF6
[Rh((S)-binap)]SbF6
36
60
65
86
90
91
95
>99
Employing 1,6-enyne 1 as a substrate we examined a
number of rhodium-based complexes to find the optimum
catalytic system; our results are summarized in Table 1. Thus,
while the reactivity of [Rh(cod)(MeCN)2]BF4 in the presence
of (S)-binap was rather modest (36% yield of product 1a,
[a] Reactions were run in 1,2-dichloroethane (DCE; 0.4m) in the presence
of 5–10 mol% catalyst at 238C for 12–16 h. [b] Measured by chiral HPLC
methods (OD-H column) after derivatization to the corresponding
p-bromobenzoate
ester.
binap=2,2’-bis(diphenylphosphino)-1,1’-
binaphthalene, cod=1,5-cyclooctadiene, Tf=trifluoromethanesulfonyl,
Ts =para-toluenesulfonyl.
[*] Prof. Dr. K. C. Nicolaou, A. Li, S. P. Ellery, Dr. D. J. Edmonds
Department of Chemistry and
after 12 h at 238C), the product was obtained with a promising
ee value (90%, Table 1, entry 1). The complex generated in
situ by mixing [{Rh(cod)Cl}2] and AgOTf in the presence of
(S)-binap led to a 60% product yield and a comparable
ee value (91%, Table 1, entry 2), whereas the combination of
[{Rh(cod)Cl}2], AgSbF6, and (S)-binap employed by Zhang
et al. with internal alkynes[3] gave 1a in 65% yield and 95% ee
(Table 1, entry 3). Finally, it was found that the preformed
rhodium catalyst [Rh((S)-binap)]SbF6[5] gave the best results,
furnishing product 1a in 86% yield and greater than 99% ee
(Table 1, entry 4).
The absolute configuration of product 1a was determined
by X-ray crystallographic analysis of its p-bromophenyl
carbamate derivative[6] (1b, m.p. 99–1018C, EtOAc/hexanes
1:1) prepared from 1a through sequential NaBH4 reduction
and treatment with p-bromophenyl isocyanate in the presence
of Et3N, as shown in Scheme 2.
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[**] We thank Drs. D. H. Huang, R. Chadha, and G. Siuzdak for NMR
spectroscopic, X-ray crystallographic, and mass spectrometric
assistance, respectively. We also gratefully acknowledge A. Nold for
assistance with chiral HPLC, and Dr. J. S. Chen for helpful
discussions. Financial support was provided by a grant from the
Skaggs Institute for Research, and graduate fellowships from
Bristol-Myers Squibb and Eli Lilly (to A.L.), and Novartis (to S.P.E.).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2009, 48, 6293 –6295
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6293