A new asymmetric 1,4-addition method: Application to the synthesis of the HIV non-nucleoside reverse transcriptase inhibitor DPC 961

Tetrahedron Letters

Volumn 41, Issue 17, 2000, Pages 3015-3019

  Magnus, Nicholas A ^a   Confalone, Pat N ^a   Storace, Louis ^a  

^a DUPONT COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

6 CHLORO 4 CYCLOPROPYLETHYNYL 3,4 DIHYDRO 4 TRIFLUOROMETHYL 2(1H) QUINAZOLINONE; EFAVIRENZ; RNA DIRECTED DNA POLYMERASE INHIBITOR;

ARTICLE; CHIRALITY; DRUG ACTIVITY; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; STEREOCHEMISTRY;

EID: 0034701536     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(00)00331-2     Document Type: Article

References (13)

1. (a) Corbett, J. W.; Ko, S. S.; Rodgers, J. D.; Bacheler, L. T.; Diamond, S.; Lai, C.-M.; Jeffery, S.; Klabe, R. M.; Rabel, S. R.; Saye, J. A.; Adams, S. P.; Trainor, G. L.; Anderson, P. S.; Erickson-Viitanen, S. K. Antimicrob. Agents Chemother. 1999, 43, 2893.
2. (b) Asymmetric syntheses of dihydroquinazolinones have been reported which involve the use of chiral amino alkoxides to mediate the enantioselective addition of acetylides to cyclic N-acyl ketimines. Huffman, M. A.; Yasuda, N.; DeCamp, A. E.; Grabowski, E. J. J. J. Org. Chem. 1995, 60, 1590.
3. (a) Young, S. D.; Britcher, S. F.; Tran, L. O.; Payne, L. S.; Lumma, W. C.; Lyle, T. A.; Huff, J. R.; Anderson, P. S.; Olsen, D. B.; Carroll, S. S.; Pettibone, D. J.; O'Brien, J. A.; Ball, R. G.; Balani, S. K.; Lin, J. H.; Chen, I.-W.; Schleif, W. A.; Sardana, V. V.; Long, W. J.; Byrnes, V. W.; Emini, E. A. Antimicrob. Agents Chemother. 1995, 39, 2602.
4. (b) Pierce, M. E.; Parsons Jr., R. L.; Radesca, L. A.; Young, S. L.; Silverman, S.; Moore, J. R.; Islam, Q.; Choudhury, A.; Fortunak, J. M. D.; Nguyen, D.; Luo, C.; Morgan, S. J.; Davis, W. P.; Confalone, P. N. J. Org. Chem. 1998, 63, 8536 and references cited therein.
5. (c) Patel, M.; Ko, S. S.; McHugh, R. J.; Markwalder, J. A.; Srivastava, A. S.; Cordova, B. C.; Klabe, R. M.; Erickson-Viitanen, S. K.; Trainor, G. L.; Seitz, S. P. Bioorg. Med. Chem. Lett. 1999, 9, 2805.
6. (d) Patel, M.; McHugh, R. J.; Cordova, B. C.; Klabe, R. M.; Erickson-Viitanen, S. K.; Trainor, G. L.; Ko, S. S. Bioorg. Med. Chem. Lett. 1999, 9, 3221.
7. (e) Thompson, A. S.; Corely E. G.; Huntington, M. F.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 8937.
8. (f) Tan, L.; Cheng-Yi, C.; Tillyer, R. D.; Grabowski, E. J. J.; Reider, P. J. Angew. Chem., Int. Ed. Engl. 1999, 38, 711.
9. Sternbach, L. H.; Metlesics, W.; Silverman, G.; Toome, V. J. Org. Chem. 1966, 31, 1007.
10. Britcher, S. F.; Lumma Jr., W. C.; Goldman, M. E.; Lyle, T. A.; Huff, J. R.; Payne, L. S.; Quesada, M. L.; Young, S. D.; Sanders, W. M.; Tucker, T. J.; Sanderson, P. E. Merck & Co., Inc.: USA Patent. International Publication Number: WO 93/04047; International Application Number: PCT/US92/06576; International publication date: 4 March 1993.
11. (a) Reissert, A.; Schaaf, H. Chem. Ber. 1926, 39, 2494.
12. (b) Gheorghui, C. V. Chem. Ber. 1943, 76, 994.
13. 2, the hemiaminal 9 (1.0 g, 2.70 mmol) is suspended in toluene (10 mL) and treated with triethylamine (TEA) (1.88 mL, 13.49 mmol) to give a colorless homogeneous mixture. The resulting mixture is cooled to 0°C, and thionyl chloride (206 μL, 2.83 mmol) added slowly. This produces a bright orange mixture with TEA hydrochloride salt as a precipitate. After 1 h at 0°C, the mixture is cooled to -50°C. A 2N cyclopropylacetylene magnesium chloride solution in THF (6.47 mL, 10.79 mmol) is added to the mixture over 0.5 h. The resulting mixture is quenched into 12% aqueous citric acid (10 mL). The organic phase is concentrated via distillation and the remaining solvent subsequently exchanged for methanol employing azeotropic distillation. This induces crystallization of the product 11 in 86% (970 mg) isolated yield. The de of 11 in the crude reaction mixture was determined to be 92% by HPLC using a Zorbax RX-C18 column.