Scheme III TBAF = (n-Bu)4NF Synthesis of /S-Furanone 2. Compound 1 (226 mg, 1 mmol) was dissolved in 8 mL of anhydrous diethyl ether, placed in a flask equipped with a dry argon inlet, and cooled at -15 °C. To the stirred solution was added 0.63 mL (1 mmol) of a 1.60 M ethereal solution of methyllithium. After 1.30 h at -15 °C, 1.5 mL of anhydrous hexamethylphosphoric triamide and 0.7 mL (8.8 mmol) of freshly distilled chloroacetyl chloride were added. The mixture was reacted 30 min at -15 °C and 1 h at room temperature.The reaction mixture was poured into a slurry of ammonia and crushed ice, stirred for 20 min, and then extracted three times with 20 mL of diethyl ether. The combined extracts were washed with water and dried (Na2S04). After evaporation at reduced pressure, 200 mg of product was obtained which was chromatographed on a Florisil (6 g) column. By elution with n-pentaneethyl acetate (95:5 v/v) there was obtained 160 mg (82% yield) of pure 2: oil; IR (liquid film) 1700,1640 cm"1; NMR (CDC13)4.50 (s, 2 H, OCH2CO), 0.95 (s, 9 H, (CH3)3C).

With the bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-C1) coupling reagent, synthesis of the cyclosporine A 8-11 tetrapeptide has been carried out utilizing both Fmocand Cbz-N-protection of the intermediates. The former protecting group allows a very time efficient sequence where isolation of the free imino fragment is obviated and demonstrates the potential for applications to solid phase. Cbz protection is more economical for larger scale synthesis, however, and provides more stable intermediates. In both cases remarkable chemical efficiency was achieved, the fully protected tetrapeptide being obtained in 66% and 73% yields, respectively, from the constituent protected amino acids. By means of the Fmoc procedure, diastereomers at each stage of coupling have been separately prepared. HPLC analysis, using these compounds as internal standards, has shown that racemization in all cases was less than 1 %.The cyclosporines are a family of extensively Nmetabolites, a number of which possess strong, orally active methylated cyclic undecapeptides, first isolated as fungal immunosuppressive properties.1 Due to the recent FDA

A high-throughput screen against human DGAT-1 led to the identification of a core structure that was subsequently optimized to afford the potent, selective, and orally bioavailable compound 14. Oral administration at doses ≥0.03 mg/kg significantly reduced postprandial triglycerides in mice following an oral lipid challenge. Further assessment in both acute and chronic safety pharmacology and toxicology studies demonstrated a clean profile up to high plasma levels, thus culminating in the nomination of 14 as clinical candidate ABT-046.

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