X Z COOH 1 X=Y=Z=α-OH,H 2 X=Z=α-OH,H; Y=H,H 3 X=Y=Z=O Y (enantiopure)-host + (RS)-guest (enantiopure)-host (R)-guest (S)-guest TETRAHEDRON: ASYMMETRY Tetrahedron: Asymmetry 12 (2001) 1479–1483 Pergamon Enantioselective inclusion in bile acids: resolution of cyclic ketones Valerio Bertolasi, Olga Bortolini, Marco Fogagnolo, Giancarlo Fantin* and Paola Pedrini Dipartimento di Chimica, Universita ` di Ferrara, Via Borsari 46, 44100 Ferrara, Italy Received 10 May 2001; accepted 25 May 2001 Abstract—Cholic and deoxycholic acids were found to form inclusion compounds with various racemic cyclic ketones enabling direct and straightforward enantiomer separation. The X-ray structure of the 2:1 inclusion complex between (-)-bicyclo[3.2.0]- hept-2-en-6-one and cholic acid is reported. © 2001 Elsevier Science Ltd. All rights reserved. 1. Introduction The resolution of racemates by enantioselective inclu- sion in suitable chiral hosts is an interesting branch of organic stereochemistry that is receiving renewed inter- est in recent years. 1 This technique is based on the ability of a chiral host to incorporate enantioselectively the racemic guest within its molecular or crystal lattice cavities (Scheme 1). The major advantages of this methodology are its efficiency and simplicity, the mild conditions employed, the quantitative recovery of both guest and host com- pounds and the wide applicability of the method. 2 A number of inclusion procedures have been described in the literature that may be grouped in: (i) absorption methods 3 in which the insoluble host was simply left in the presence of the guest, or vice versa, for a given time, (ii) crystallization methods 4 in which the host is dis- solved and recrystallized from the guest and (iii) solid- state inclusions 5 consisting of a co-grinding of the two solid components in an agate mortar. Steroids are one of the best sources of chiral host compounds due to their multi-functional and rigid, although flexible, structure. Among steroids, bile acid derivatives have often been used for this purpose on account of their ability to recognize and resolve impor- tant organic substrates such as lactones, 6 alcohols, 4 sulfoxides 7 and epoxides, 8 which are otherwise difficult to resolve. These substrates have been shown to form inclusion compounds with derivatives of cholic 1, deoxycholic 2 and dehydrocholic acid 3, affording enriched or resolved racemates (e.e. up to 99%). The efficiency of bile acids as host compounds is associ- ated with two additional peculiarities. The majority of the bile acids are commercially available compounds, obtainable at low cost and easy to handle. Further- more, the carboxylic function present on the steroid lateral chain permits ready removal of the host from the reaction mixture by direct acid–base treatment and facilitates recycling. 7,8 Taking into account these con- siderations, all classes of ‘neutral’ organic molecules lacking acid–base functions that are not suited to classi- cal resolution via preparation of diastereoisomeric salts 9 are ideal candidates for host–guest resolution Scheme 1. * Corresponding author. Fax: +39-0532-240709; e-mail: fnn@unife.it 0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII:S0957-4166(01)00243-9