Acceleration of hetero-Michael reaction by symmetrical pentacyclic guanidines Kazuo Nagasawa, p Angelina Georgieva, Hiroki Takahashi and Tadashi Nakata RIKEN The Institute of Physical and Chemical Research), Hirosawa 2-1, Wako-shi, Saitama 351-0198, Japan Received 19 July 2001; accepted 7 September 2001 Abstract ÐSymmetrical pentacyclic guanidines 1a ± c and 2 which contain the core skeleton of 13,14,15-isocrmbescidine 800, have been synthesized. In the presence of catalytic amounts of these guanidines 1, the reaction rate of the conjugate addition of pyrrolidine 9) to g-crotonolactone 10) could be enhanced depending upon the size of the cavities and substituents on tetrahydropyran rings of 1 and 2. q 2001 Elsevier Science Ltd. All rights reserved. 1. Introduction The guanidine group present in the side chain of arginine is ubiquitous in an enzyme that binds anionic substrates and also contributes to the stabilization of protein's three- dimensional structures by forming salt with carboxylate function. 1 In nature a variety of guanidine-containing natural products have been isolated which have attracted much attention because of their interesting activities, mostly arising from the two peculiar parallel interactions including hydrogen bonding of the guanidinium ion with phosphate- containing biomolecules. 2 Due to the strong ability of guani- dine to set a pair of zwitter ionic hydrogen bonds with anionic compounds and to stabilize their anionic transition state, the guanidine-contained molecules suggest to us their use as a new reaction vessel. In addition, the partial proto- nation from guanidine-containing molecules hosts) through the substrate molecules guests) can be expected to in¯uence the guests reactivities by changing the electronic properties. 3 As a consequence, several synthetic applica- tions have appeared using not only guanidines but also amidines as a catalyst. For example, Strecker reaction, 4a,b acylataion, 4c silylation, 4d Wittig and Horner±Emmons reac- tions, 4e Diels±Alder reaction, 4f Henry reaction, 4g epoxida- tion, 4h and Michael reaction. 4i±l Inspired by these recent advances in guanidine and amidine-mediated reactions, we decided to investigate the possibilities of developing the cyclic compounds an non-metal containing organic chiral catalyst, which are not considered to have much unfavorable environment effect. We planned to synthesize four new symmetric pentacyclic guanidines 1a ± c and 2 for the achievement of new chiral catalysts on the basis of our recent studies 5 concerning the synthesis of ptilomycalin A 6 and its analogs. 7 The sus- tituents on the tetrahydropyran rings of guanidine 1 and 2 can be expected to control the conformation of the core structure around the guanidine moiety through their favor- able equatorial position and provide us with a variety cavity of sizes around the guanidine. 2. Results and discussion Following the procedure in our previous paper, 5 we synthe- sized a family of new symmetrical pentacyclic guanidine analogs 1a ± c and 2, which can be seen in the core structure of 13,14,15-isocrambescidine 800 Scheme 1). The 1,3- dipolar cycloaddition reaction of the optically active nitrone 3, 8 obtained from l-1)-tartaric acid, and ole®n 4 9 in toluene at 1108C, stereoselectively gave isoxazolidine 6 in 50±70% yield. The isoxazolidine 7 was treated with m-CPBA to regenerate the nitrone regioselectively, 10 which was subjected to the second 1,3-dipolar cycloaddition reaction with an ole®n 4 9 to provide isoxazoline 7 in 40± 60% yield. After hydrogenation of 7 with Pd±C, the pyrro- lidine 8 was subjected to bis N-Boc thiourea with HgCl 2 11 Tetrahedron 57 2001) 8959±8964 Pergamon TETRAHEDRON 0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved. PII: S0040-402001)00907-3 Keywords: pentacyclic guanidine; organic chiral catalysts; 1,3-dipolar cycloaddition reaction; hetero-Michael reaction. p Corresponding author. Present address: Institute of Molecular and Cellu- lar Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Tel.: 181-3-5841-7848; fax: 181-3-5841- 8495; e-mail: nagasawa@iam.u-tokyo.ac.jp