Published on Web 07/18/2002
Enantioselective Total Synthesis of (+)-Testudinariol A Using a New
Nickel-Catalyzed Allenyl Aldehyde Cyclization
Kande K. D. Amarasinghe and John Montgomery*
Department of Chemistry, Wayne State UniVersity, Detroit, Michigan 48202
Received June 3, 2002
Testudinariols A and B are epimeric triterpene marine natural
products that were originally isolated from the skin and the mucus
of the marine mollusc Pleurobranchus testudinarius by Spinella
(eq 1).1 Testudinariol A (1) possesses C2 symmetry, whereas
aldehyde by LiAlH4 reduction and Swern oxidation afforded
aldehyde 7 in 64% yield over three steps.
With substrate 7 in hand, we considered the development of a
new cyclization process to prepare the requisite functionalized
cyclopentanol core. In analogy to nickel-catalyzed ynal cyclizations
previously developed in our laboratory,6 we anticipated that the
analogous nickel-catalyzed cyclization of an allenyl aldehyde with
dimethylzinc would afford the desired core structure. After some
optimization, the desired cyclization was developed with exception-
ally high stereocontrol. Accordingly, substrate 7 was treated
with dimethylzinc, Ti(O-i-Pr)4, and 10 mol % Ni(COD)2 in THF
to afford cyclopentanol 10 in 62% yield in >97:3 diastereo-
selectivity. Ti(O-i-Pr)4 is not a required additive in this reaction,
although its use leads to higher yields and diastereoselectivities.
We propose that the mechanism of this novel process involves
formation of a Ni(0) π-complex 8 with the aldehyde and proximal
allene π-systems coordinating to nickel in an eclipsed fashion with
a pseudoequatorial orientation of the side chain (Scheme 2).
Oxidative cyclization to metallacycle 9, followed by dimethylzinc
transmetalation and reductive elimination, would afford the observed
stereochemistry of product 10.7,8 This combination of an asymmetric
anti aldol reaction to control the acyclic stereochemistry and a
nickel-catalyzed cyclization to control the cyclic stereochemistry
provides a powerful combination for the construction of ring
systems such as 10.
testudinariol B (2) lacks symmetry. The structures possess a highly
functionalized cyclopentanol framework with four contiguous
stereocenters appended to a central 3-alkylidene tetrahydropyran.
Total syntheses of testudinariols A and B were recently ac-
complished by Mori,2 and a formal synthesis of testudinariol A
was published by Kodama.3 Given the difficulties in efficiently
controlling the stereochemical issues presented by these structurally
intriguing natural products, we have developed a novel strategy
for the preparation of testudinariol A. In the context of this effort,
we have developed a new nickel-catalyzed reaction for the
cyclization of allenyl aldehydes, and we have utilized complex
applications of the Abiko-Masamune asymmetric aldol reaction4
and the Overman oxocarbenium ion/vinyl silane condensation
process.5 The combination of these procedures has provided an
efficient total synthesis of (+)-testudinariol A.
We chose to investigate an asymmetric anti aldol reaction to
control the critical acyclic C-6/C-7 relative and absolute stereo-
chemistry.4 Functionalization of allenyl acid chloride 3 with the
norephedrine-derived chiral auxiliary 4 provided ester 5 in 99%
yield (Scheme 1). According to the conditions reported by Abiko
and Masamune, enolization of 5 with (c-hex)2BOTf and triethyl-
amine in dichloromethane followed by treatment with 3-benzyl-
oxypropionaldehyde afforded aldol adduct 6 as a 97:3 ratio of
anti:syn diastereomers in 72% yield. Diastereoselectivity within the
anti manifold was 90:10. Interestingly, the original reports from
Abiko and Masamune were restricted to the preparation of
propionate aldols, but the synthesis of the more functionalized
substrate 5 similarly proceeded cleanly with very good control of
stereochemistry. Protection of 6 as the methoxyethoxymethyl
(MEM) ether followed by conversion of the ester linkage to an
Protection of alcohol 10 as the TIPS ether, followed by Li0/NH3
debenzylation and conversion of the resulting primary hydroxyl to
the iodide with PPh3/I2 and imidazole, allowed the formation of
11 in 75% yield over three steps. Assembly of the C2-symmetrical
core structure then required preparation of bis(vinyl bromide) 13
(Scheme 3). Bromination of 1,5-hexadiene, followed by elimination
with LDA and silylation, afforded bis(silyl acetylene) 12.9 DIBAL
reduction and bromination resulted in the formation of bis(vinyl
bromide) 13.10 Metal-halogen exchange with s-BuLi in THF
afforded a dianion which was alkylated with primary iodide 11.11
By employing a 3:1 stoichiometry of iodide 11 to the dianion of
13, a 38% yield of bis(vinyl silane) 14 was obtained along with
13% of monoalkylated material and a 54% recovery of 11.
To complete the synthesis, a two-directional oxocarbenium
ion/vinyl silane cyclization was carried out.5 A 0.1 M, -78 °C
dichloromethane solution of bis(vinyl silane) 14 was treated with
10 equiv of Et2AlCl, and the mixture was allowed to warm to
room temperature. Upon cooling of the mixture back to -78 °C
and quenching with 2 M NaOH, clean conversion to the bis-
tetrahydropyran was observed. To our knowledge, this represents
the first two-directional oxocarbenium ion cyclization of this
type.12 The crude material was then treated with n-Bu4NF to
afford (+)-testudinariol A (1) in 55% yield over two steps. NMR
spectral data were identical to those previously reported {[R]25
)
D
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9366
J. AM. CHEM. SOC. 2002, 124, 9366-9367
10.1021/ja027148y CCC: $22.00 © 2002 American Chemical Society