Merck + Co., Inc.

Todd K Jones

David J Mathre

Thomas J Blacklock

Lyndon C Xavier

Sander G Mills

Ralph P Volante

Ichiro Shinkai

David Askin

Robert A Reamer

Richard Desmond

Cheryl A Grice

Helmut H Mrozik

Edward J Grabowski

David M Tschaen

Lin Chu

Paul Sohar

F Edward Roberts

Julie J Mohan

Dong-Hui Wang

Olivia D Weber

Justin S Cisar

A process is described for the total synthesis of the macrolide immunosuppressant, FK-506, and important tricarbonyl process intermediates thereof. The tricarbonyl intermediates can be produced by the mild oxidation of 2,3-dihydroxy carboxylate compounds containing olefin moieties.

Process for synthesis of FK-506 and tricarbonyl intermediates

The chiral catalyst of general structure 1, or its enantiomer ##STR1## is prepared by treating the corresponding N-carboxy anhydride of structure 2 ##STR2## with an aryl metal, especially a phenyl metal such as an aryl magnesium halide, aryl lithium, aryl zinc or aryl cesium, to form a 1,1-diaryl- methanol of structure 3 ##STR3## followed by treatment with a compound of structure, 4 ##STR4## The catalyst, wherein R is aromatic, is novel and in some cases superior to the catalyst wherein R is alkyl or aralkyl in directing the chirality of diborane, borane-dimethyl sulfide or borane-tetrahydrofuran reductions of ketones to secondary alcohols.

Chiral catalysts for reduction of ketones and process for their

Avermectin compounds are substituted at the 4a-position: the 4a-methyl group is first derivatized with a hydroxy group which is then substituted with a variety of alkyl, alkoxy alkyl, or polyalkoxy alkyl groups and derivatives thereof. The compounds are potent antiparasitic and anthelmintic agents and compositions for such uses are also disclosed.

4.alpha.-substituted avermectin derivatives

Chiral boron catalysts for reduction of ketones and process for their

5,6-Dihydro-4-(R-amino)-4H-thieno[2,3-b]-thiopyran-2-sulfonamide-7,7-dioxid e is a potent carbonic anhydrase inhibitor useful in the treatment of ocular hypertension and glaucoma. The S-(+)-enantiomer of that compound, the more active enantiomer, is prepared by a process involving an intermediate step of an enantioselective reduction of a carbonyl group employing an oxazaborolidine chiral catalyst.

Enantiospecific synthesis of

A process is described for the improved synthesis of the optically pure C.sub.10 -C.sub.18 fragment of the macrolide structure of the immunosuppressant FK-506. This compound is also useful as an intermediate for preparing FK-506 derivatives.

FK-506 C10-C18 process intermediates

The chiral catalyst of general structure 1, or its enantiomer ##STR1## is prepared by treating the corresponding N-carboxy anhydride of structure 2 ##STR2## with an aryl metal, especially a phenyl metal such as an aryl magnesium halide, aryl lithium, aryl zinc or aryl cesium, to form a 1,1-diaryl-methanol of structure 3 ##STR3## followed by treatment with a compound of structure, 4 ##STR4## The catalyst, wherein R is aromatic, is novel and in some cases superior to the catalyst wherein R is alkyl or aralkyl in directing the chirality of borane-dimethyl sulfide reductions of ketones to secondary alcohols.

Arylation process for preparation of chiral catalysts for ketone

A process is described involving an alkaline rearrangement of FK-506 producing a new decarbonylated 22-membered macrocycle rearrangement derivative of FK-506, i.e. C.9, nor-keto FK-506.

Hydroxide mediated FK-506 rearrangement product

Process for synthesis of FK-506 C10-C18 intermediates

Novel hydroxide mediated FK-506 rearrangement process

Growing community of inventors

Edison, NJ, United States of America

Todd K Jones