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Tetrahedron Letters 50 (2009) 1236–1239

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Tetrahedron Letters
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Stereoselective construction of an anti-b-alkoxy ether by Ireland–Claisen rearrangement for medium-ring ether synthesis
Kenshu Fujiwara a,*, Natsumi Kawamura a, Hidetoshi Kawai a,b, Takanori Suzuki a
a b

Division of Chemistry,Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan

a r t i c l e

i n f o

a b s t r a c t
The asymmetric synthesis of an acyclic anti-b-alkoxy ether was achieved by the Ireland–Claisen rearrangement of Z-3-alkoxy-2-propenyl glycolate ester, prepared from Garner’s aldehyde, aglycolic acid derivative, and ethynyl N,N-diisopropylcarbamate. The resulting acyclic ether was facilely converted to seven- and eight-membered cyclic ethers via processes involving ring-closing olefin metatheses. Ó 2009 Elsevier Ltd. All rights reserved.

Article history: Received 1 December 2008 Revised 5 January 2009 Accepted 8 January 2009 Available online 10 January 2009 Keywords:Stereoselective synthesis Cyclic ethers Ireland–Claisen rearrangement Ring-closing olefin metathesis

Natural medium ring ether compounds, which are often bioactive, have attracted synthetic interest due to their particular structural features, such as medium-sized ring systems or stereochemical complexity around the ether linkage.1 While a large number of synthetic methods have been developed by manyresearch groups,2 ring-closing olefin metathesis (RCM)3 based approaches have been extensively explored,4,5 because RCM realizes efficient ring-closure under mild catalytic conditions and tolerates a wide variety of functional groups in its substrates. However, the construction of the stereochemically complex ether linkage in the diene substrates of RCM for medium ring ethers is still difficult.6Therefore, approaches toward these systems have focused on the establishment of an efficient method for the stereoselective synthesis of acyclic ethers. In our recent studies on the construction of medium ring ethers using RCM,7 we found that the Ireland–Claisen rearrangement of an acyclic Z-3-alkoxy-2-propenyl glycolate ester stereoselectively produced an acyclic anti-b-alkoxy ether, corresponding to anether moiety of a natural trans-fused polycyclic ether.7a Here, we describe the development of an improved variant of this rearrangement, which accomplishes the asymmetric synthesis of an acyclic anti-b-alkoxy ether from easily available starting materials for efficient medium ring ether synthesis. The goal of this project was to devise a facile method to construct a terminal medium ring in atrans-fused polycyclic ether system (1) (Scheme 1). Toward this goal, a synthetic route was
* Corresponding author. Tel.: +81 11 706 2701; fax: +81 11 706 4924. E-mail address: (K. Fujiwara). 0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2009.01.011





CO2Me Medium-RingOR

Formation (by RCM)


O H H trans-Fused Polycyclic Ether (1) O OH H O H O H 5 O H 4 H O O Z
1 3

anti H 2

Chirality-Transferring Ireland-Claisen Rearrangement









OZ R1O SiR3 3


Lindlar Hydrogenation R2 R2

R2-Assisted 1 Stereoselective OR Addition

OR1 + R2 CHO 8 R3 OCb 9


OR 6


HO 7

O O O 10

i-Pr OH Me Cb O NBoc Me i-Pr N O O CHO 11 12


O n H 13: n=1, R3=CO2Me 14: n=0, R3=CH2OBn

Scheme 1.

K. Fujiwara et al. / Tetrahedron Letters 50 (2009) 1236–1239


designed that relied on RCM for the ring closure of the terminal medium ring of 1 and chirality-transferring Ireland–Claisen rearrangement for setting up the anti-b-alkoxy ether substrate (2) stereoselectively. Based on our...