Tetrahydrocephalostatin

The next results reported by the Fuchs group concerned cephalostatin 7. The ability to form the 5/5 spiroketal of the right half and the 6/5 spiroketal of the left half from a common advanced intermediate would be advantageous from a practical standpoint. The feasibility of this approach can be seen in the work on tetrahydrocephalostatin 12 (Scheme 18, vide supra). 

A more detailed study27 was carried out of the spiroketalization reaction. Compounds obtained by C-23 deoxygenation of intermediates in the tetrahydrocephalostatin 12 synthesis were used, with various permutations differing in their C-20 stereochemistry and also the presence or absence of benzylation at C-26. These compounds were subjected to a series of acid-catalyzed cyclizations. 

The right half of cephalostatin 7 was synthesized32 in an analogous manner to that of tetrahydrocephalostatin 12. The silyl ether of 55 was dihydroxylated to give a pair of inseparable diastereomers in a 4 1 ratio, the major product 57 corresponding to the natural C-25 stereochemistry (Scheme 26). However, no reaction was observed with conditions used for spiroketalization (Scheme 22, vide supra), while harsher conditions led to undesired products. As in the earlier work, the brominated derivative 58 of the desired 5/5 spiroketal was formed by treatment with NBS. A diastereomeric byproduct was also obtained, occurring from cyclization of the minor epimer of 57. 

On the synthetic front, the discovery of these alkaloids has sparked interest in the construction of unsymmetrical pyrazines, and the methods developed will be useful in other settings as well. The Fuchs group has successfully accomplished landmark syntheses of tetrahydrocephalostatin 12, cephalostatin 7, cephalostatin 12, and ritterazine K and is clearly close to a synthesis of dihydrocephalostatin 1. These efforts have added significantly to the areas of steroid and spiroketal chemistry. 

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