It has recently been disclosed that certain substituted cyclobutane analogs of purine nucleosides possess anti-viral activity. See Zahler, et al., European Patent Application No. EP322854, published Jul. 5, 1989; Ichikawa, et al., European Patent Application No. EP330992, published Sep. 6, 1989; Slusarchyk, et al., European Patent Application No. EP335355, published Oct. 4, 1989; and Norbeck, et al., European Patent Application No. EP366059, published May 2, 1990. In particular, the (1'.alpha., 2'.beta., 3'.alpha.)-isomer of (I) is disclosed to be a useful anti-viral compound. ##STR1##
The (1'.alpha.,2'.beta.,3'.alpha.)-isomer of (I) and related bishydroxymethylcyclobutyl substituted purines have been prepared via intermediates such as the trans-isomer of (II). See Slusarchyk, et al., EP335355; Honjo, et al., Chem. Pharm. Bull. 37 1413 (1989); and Norbeck, et al., EP366059. ##STR2## However, the processes used to prepare the trans-isomer of (II) provide a racemic compound which leads to preparation of the racemic (1'.alpha.,2'.beta.,3'.alpha.)-isomer of (I).
Katagiri, et al., Chem. Pharm. Bull. 38 288 (1990), disclose intermediates such as the racemic (1.alpha.,2.beta.,3.alpha.)-isomer of (III), which are also useful for the preparation of the racemic (1'.alpha.,2'.beta.,3'.alpha.)-isomer of (I). ##STR3##
It is sometimes the case that the (+)-enantiomer and the (-)-enantiomer of a compound will have different biological activities. Therefore, it would be useful to have a method for preparing the substantially pure enantiomers of the (1'.alpha.,2'.beta.,3'.alpha.)-isomer of (I).
A process for the preparation of a precursor (trans-(IV)) to the substantially pure enantiomers of trans-(II) has been disclosed by Hayashi, et al. (Chemistry Letters, 793 (1989). This process involves an asymmetric [2+2] cycloaddition reaction between 3-(3-(methoxycarbonyl)acryloyl)-1,3-oxazolidin-2-one and 1,1-bis(methylthio)ethylene which is catalyzed by a chiral titanium reagent. ##STR4## This process has been applied to the preparation of the (+)-enantiomer of the (1'.alpha.,2'.beta.,3'.alpha.)-isomer of (I) (Ichikawa, et al., European Patent Application No. EP358154, published Mar. 14, 1990).
Norbeck, et al. (EP366059), disclose the use of the (+)-enantiomer of (1R,2R)-1,2-bis(methoxycarbonyl)-3-methylenecyclopropane as a precursor for the preparation of the (+)-enantiomer of the (1'.alpha.,2'.beta.,3'.alpha.)-isomer of (I).
USPTO Backgrounds
USPTO Backgrounds