Synthesis of a novel farnesyl transferase inhibitor, ABT-100; selective preparation of a stereogenic tertiary carbinol

• Published in: Tetrahedron Vol. 61; no. 18; pp. 4419 - 4425
• Main Authors: Rozema, Michael J., Kruger, Albert W., Rohde, Bridget D., Shelat, Bhadra, Bhagavatula, Lakshmi, Tien, James J., Zhang, Weijiang, Henry, Rodger F.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 02.05.2005; Elsevier
• Subjects: Asymmetric addition; Chemistry; Chemistry, Organic; Chiral keto-ester; Chiral quaternary alcohol; Chiral tertiary alcohol; Farnesyl-transferase; FTI; Inhibitor; Lewis acid; Organozinc reagent; Palladium coupling; Physical Sciences; Science & Technology; Suzuki coupling; Lewis acid; Suzuki coupling; Chiral quaternary alcohol; Chiral tertiary alcohol; Chiral keto-ester; Organozinc reagent; Palladium coupling; Farnesyl-transferase; FTI; Inhibitor; Asymmetric addition; chiral keto-ester; ENANTIOSELECTIVE SYNTHESIS; farnesyl-transferase; CHIRAL AUXILIARIES; organozinc reagent; asymmetric addition; NUCLEOPHILIC-ADDITION; CROSS-COUPLING REACTIONS; PHENYLGLYOXALATE; palladium coupling; inhibitor; ALPHA-HYDROXY ACIDS; DERIVATIVES; chiral tertiary alcohol; chiral quaternary alcohol; CYCLOPEPTIDE ALKALOIDS
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2005.02.072

A stereoselective synthesis of ABT-100 1 , a novel farnesyl transferase inhibitor, is described. The key step involves a stereoselective addition of the heterocyclic zinc reagent 10 to chiral α-keto ester 9 in >10:1 diastereoselectivity using menthol as the chiral auxiliary. Crystallization of the product as the dimeric zinc complex facilitates isolation of product in >99:1 dr. The biaryl linkage is formed by the use of a Suzuki coupling employing only 0.06 mol% of the catalyst. Coupling of the two fragments is accomplished using a S NAr reaction between diol 5 and arylfluoride 4 . The overall yield for the five step sequence is 37% on kilogram scale. The development of an asymmetric synthesis of farnesyl transferase inhibitor ABT-100 is presented. The preparation features the asymmetric addition of a heterocyclic organozinc reagent to set the tertiary carbinol and a regioselective S NAr reaction to prepare the phenolic ether linkage.