[reaction: see text]. A novel variant of the atom-economical Passerini reaction between suitably protected argininal, dipeptide isonitrile, and proline components afforded adduct 13. Orthogonal N-deprotection of 13 led, via a smooth O- to N-acyl migration, to 14, which constitutes the N(10)-C(17) fragment of the cyclotheonamide family of serine protease inhibitors. Each reaction in this three-step protocol proceeds in good yield and under very mild conditions.

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Thrombin, a serine protease with trypsin-like specificity, plays a central role in the coagulation cascade by mediating both the final conversion of fibrinogen to fibrin and the activation of platelets. 1 The prominent anticoagulant therapeutic agents currently available, heparin and its low molecular weight derivatives, and the indirectly acting orally bioavailable coumarins suffer from many side effects and limited efficacy. 2 Considerable efforts to develop safer and novel thrombin inhibitors are presently underway. 3 Recently, in our laboratories, compound 1 (CVS 1123) was identified as a potent transition-state thrombin inhibitor which demonstrated good oral bioavailability and selectivity profiles (see Figure 1). 4 Molecularmodeling considerations and structure-activity relationship (SAR) studies on 1 and related serine protease inhibitors led to the design of compounds 2 (CVS 1578) and 3 (CVS 1778), 5 which incorporated a six-and a seven-membered lactam sulfonamide moiety at P 3 -P 4 , 6 respectively. The lactam template was based upon the pioneering work of Freidinger. 7 Both molecules displayed a high degree of selectivity for the inhibition of thrombin over trypsin (Table 1).

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