Sintese estereosseletiva do tamoxifeno, um agente antiestrogenico na terapia do cancer de mama

AUTOR(ES)
DATA DE PUBLICAÇÃO

2002

RESUMO

Tamoxifen is a non-steroidal antiestrogenic agent largely used in breast cancer therapy, particularly, in pacients with high risk to develop the disease after removal of the primary tumor. The structure of tamoxifen is relatively simple and could be reduced for synthetic purpose to a tetrasubstituted olefin. The (Z)-isomer (1) has antiestrogenic activity, while the (E)-isomer (2) acts like estrogen, stimulating the proliferation of breast cancer cells. The relationships between double bond geometry and antitumoural activity makes the development of stereoselective synthesis of (Z)-tamoxifen an interesting and important subject. The first part of this work involved the of elimination in basic media of derivated of alcohol (1R*,2S*)-5A, prepared via the Grignard reaction between ketone (+/-)-3 and phenylmagnesium bromide (4). The best isomeric ratio achieved in there studies (Z:E = 1:3 with the corresponding mesylated) led us to investigate the behavous of the derivatives of alcohol (1S*,2S*)-5B under the same reaction conditions, which afforded a 3:1 mixture of the Z and E isomers of tamoxifen. The second approach for the stereoselective preparation of (Z)-tamoxifen involved Pd(0)-catalysed double cross-coupling between organometallic compounds and vinylic dibromides. Tamoxifen was obtained as a 2,3:1 mixture of the Z and E isomers through the Suzuki or Negishi coupling reactions. During our study, we stereoselectively prepared E-substituted vinylic dibromides 38a-f through the bromination of acetylenes 37a-f with pyridinium bromide perbromide in carbon tetrachloride and methanol as the solvent mixture. The vinylic dibromides were subjected to double cross-coupling reaction with phenylzinc chloride acoording Negishi s protocol, to afford the corresponding tri- and tetrasubstituted olefins in good yields.

ASSUNTO(S)

acoplamentos mamas compostos organometalicos

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