ORGANIC
LETTERS
2013
Vol. 15, No. 3
678–681
syn-Selective Kobayashi Aldol Reaction
Using Acetals
Hiroyuki Tsukada, Yuki Mukaeda, and Seijiro Hosokawa*
Department of Applied Chemistry, Faculty of Advanced Science and Engineering,
Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
Received December 22, 2012
ABSTRACT
The Kobayashi aldol reaction has been used to construct anti-aldol products by remote stereoinduction. Since the product of the Kobayashi aldol
reaction has a typical polyketide structure, this reaction has been applied to the total synthesis of natural products. By varying this reaction, it was
found that the reaction with acetals in the presence of Lewis acid proceeded to give syn adducts in high stereoselectivity. This is the first example
of the stereoselective reaction of the chiral dienol ether and acetals.
The Kobayashi aldol reaction, avinylogous Mukaiyama
aldol reaction using chiral silyl dienol ethers and alde-
hydes, has been used to construct anti-aldol products by
remote stereoinduction (Scheme 1).1 This reaction allows
construction of two stereogenic centers and introduction
of the multifunctional C5 unit including R,β-unsaturated
imide. Since the product of the Kobayashi aldol reaction
has a typical polyketide structure, this reaction has been
applied to the total synthesis of natural products.2 Some
cases of this reaction have been reported to give syn
adducts predominantly (Scheme 2). Kobayashi’s group
found that R-heteroatom substituted aldehyde a provided
syn adducts selectively by switching the facial selectivity of
the aldehyde (Scheme 2, eq 1).3 Chen’s group reported
that syn adducts were obtained by aldehydes capable of
chelation in Kobayashi aldol reactions (eq 2).4 Kalesse
published that the (1E,3Z)-ketene N,O-acetal 4 gave syn
adducts 5 in a highly stereoselective manner (eq 3).5
Recently, we also reported a syn-selective Kobayashi aldol
reaction using excess amount of Lewis acid (eq 4), of which
the stereochemistry is different from that of Kalesse’s
adducts.6 These efforts have realized stereoswitching by
using the same chiral synthon. However, the reactions of
the chiral dienol ether and acetals to prepare the protected
aldoladductshavebeenunprecedented. Herein, wepresent
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r
10.1021/ol303519y
Published on Web 01/18/2013
2013 American Chemical Society