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An efficient and general synthesis of homochiral alpha-amino substituted bromo-heteroaromatics B using a diastereoselective 1,2-addition has been developed. The obtained heteroaromatic intermediates allow for a rapid two-dimensional exploration of a new series of histone deacetylase inhibitors, through Suzuki-Miyaura cross-coupling reactions for the introduction of a second aromatic element, followed by global deprotection and derivatization of the amino group. (C) 2009 Published by Elsevier Ltd.

Glycine anion (4) and glycine cation (8) synthons are used in efficient syntheses of 4-substituted analogues of HA-966 (1). A stereospecific route to cis derivatives involves hydrogenation of enamines such as 16. Introduction of a chiral auxiliary leads to an enantioselective synthesis of 2a (L-687, 414).

The stoichiometric silyl-cupration of allene 7, followed directly by treating the intermediate cuprate with a proton, with a range of carbon electrophiles, and with chlorine gives the vinylsilanes 8–13. Alternatively, when iodine is the electrophile, the product is the vinyl iodide 16. This can then be metallated and treated with a proton or a range of carbon electrophiles to give the allylsilanes 18–21. More-substituted allenes also undergo silyl-cupration followed by protonation, phenylallenes giving vinylsilanes, and alkylallenes giving, on the whole, allylsilanes. Stoichiometric stannyl-cupration of allenes takes place, with similar but less reliable regiocontrol to that of the corresponding silyl-cupration.

The cyclopentane-forming reaction (20–43) of (4 RS ),5 SR )-2, 2,4-trimethyl-5-trimethylstannylhexanal takes place with retention of configuration at the carbon atom undergoing electrophilic substitution, in contrast to similar cyclopropane-forming reactions (e.g. 47–48), which take place with inversion of configuration. The hydride transfer (24–45) of the 4 RS ,5 RS diastereoisomeric hexanal takes place from a conformation with hydride anti to the stannyl group. In the case of reactions which might have formed four-membered rings, fragmentation takes place (16–28 and 17–30). The presence of a phenyl ring on the carbon carrying the stannyl group interferes with the reactions designed to test the stereochemistry of the SE2 reaction, diverting the reaction to the formation of tetralins (10–26 and 34–38) or benzcycloheptenes (34–37).