A concise, convergent multikilogram synthesis of CI-1034 (1), a potent endothelin receptor antagonist, is described. A 15-step preparation from commercially available o-vanillin and benzenesulfonyl chloride employs a remarkably robust Suzuki coupling between a boronic acid and an aromatic sulfonate ester as the key synthetic step. A scalable route capable of producing multikilogram quantities of CI-1034 with no chromatographic steps is described in this contribution. Improvements to the process included using a 4-fluorobenzenesulfonate ester as a suitable substitute for the triflate group in the Suzuki reaction and the use of MgCl 2 as a substitute for TiCl 4 in a Dieckmann condensation to provide the benzothiazine dioxide core.

[reaction: see text] Mucohalic acids (mucochloric acid (1, 3,4-dichloro-5-hydroxy-5H-furan-2-one) and mucobromic acid (2, 3,4-dibromo-5-hydroxy-5H-furan-2-one)) are inexpensive, commercially available starting materials with multiple functional groups. These compounds have been modified by way of reduction followed by Suzuki cross-coupling reactions involving arylboronic acids to afford highly functionalized alpha,beta-unsaturated gamma-butyrolactones in excellent yield. The synthetic utility of these building blocks was effectively demonstrated through preparation of the antiinflammatory drug Vioxx.

Convergent synthesis of 8-fluoronaphthalen-1-ylamine (6) was achieved through the reaction of 1H-naphtho [1,8-de][1,2,3]triazine (15) with HF-pyridine under mild conditions. This new synthesis for the preparation of 6 overcame many scale-up challenges that exist in the methods reported in the literature and provided a practical alternative synthesis of 1-(8-fluoronaphthalen-1-yl) piperazine (1).

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The dolastanes are marine diterpenes whose molecular array of fused 6-7-5 alicyclic rings is distinctive. As part of a program directed toward the synthesis of representatives of these bioactive natural products, the possibility of elaborating their framework by intramolecular cyclization to form the central seven-membered ring has been examined. An expedient two-step route to keto ester 8 was developed. This intermediate proved receptive to copper-promoted conjugate addition of allylmagnesium bromide and [ (£) -2-(trimethylsilyl)vinyl] lithium. The acetal 21 to be subsequently derived from these adducts could be conveniently crafted into the highly functionalized 2-cyclopentenones 27. Central to the synthetic strategy was the need for intramolecular C-C bond formation within 27. Because we were singularly unsuccessful in achieving the desired end result, this particular approach appears unsuited for gaining access to the dolastanes.