[en] A new asymmetric synthesis of 2-substituted chiral chromanes has been achieved. The key step is the intramolecular conjugate addition of a phenolic nucleophile on a alpha,beta-unsaturated ester catalyzed by Cinchona alkaloids. The high ee's obtained with cinchonine and its derivatives have been rationalized by ab initio quantum chemistry calculations of transition state structures. (C) 2004 Elsevier Ltd. All rights reserved.
Disciplines :
Chemistry
Author, co-author :
Merschaert, Alain
Delbeke, Pieter
Daloze, Désiré
Dive, Georges ; Université de Liège - ULiège > Centre d'ingénierie des protéines
Language :
English
Title :
The rational design of modified cinchona alkaloid catalysts. Application to a new asymmetric synthesis of chiral chromanes
Publication date :
07 June 2004
Journal title :
Tetrahedron Letters
ISSN :
0040-4039
Publisher :
Pergamon-Elsevier Science Ltd, Oxford, United Kingdom
Despite using the optimized conditions described in Ref. [10a], we obtained up to 20 mol % of the unwanted 3-epimer
A large excess of the Wittig reagent is required to achieve complete conversion of the aldehyde
Catalyst 28 was prepared by reduction of 12 with NaBH4 in methanol followed by deprotection with K2CO3. 29 was obtained by refluxing 12 with NH2OH·HCl in formic acid for 1 h followed by deprotection as above. 27 was obtained by decarbonylation of 12 with (Ph 3P)3RhCl in toluene at 70°C for 20 h followed by deprotection as above
Introduction of electron-withdrawing groups ot carbon-3 has a very significant effect on quinuclidinic nitrogen basicity. See: Drzewiczak C., Suszko-Purzycka A., Skolik J. Pol. J. Chem. 67:1993;45-52. Calculated (ACD/Log D Suite software, Adv. Chem. Dev. Inc.) pKa values for 27, 28, 29, and 30 are, respectively, 10.09, 9.29, 6.79, and 9.02 (±0.4)
The Z methyl ester 3a was selected as it is readily obtained by reaction of 1 with bis(2, 2, 2-trifluoroethyl)(methoxycarbonyl-methyl)phosphonate according to Still W.C., Gennari C. Tetrahedron Lett. 24:1983;4405-4408. It offered also the best peaks resolution in our chiral HPLC method
These conditions were selected based on our initial studies. We often observed significant decrease of ee above 100°C
Calculated (ACD) pKa values: 9.99 for 24 and 9.18 for 5
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The calculations were performed with GAUSSIAN94. For all the systems, a full geometry optimization was performed at the Hartree-Fock level within the minimal basis set MINI-1′. For the starting models involving water or simple amino-alcohols as catalysts, a full optimization within the double 6-31G basis set was also performed. The transition states (TS) were first optimized and the related minima were obtained by following the intrinsic reaction coordinate (IRC) from this TS. For details on similar approaches, see: Dive G., Dehareng D. Int. J. Quant. Chem. 73:1999;161-174
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