An efficient asymmetric hydrogenation approach to the synthesis of the Crixivan® piperazine intermediate

Tetrahedron Letters

Volumn 39, Issue 38, 1998, Pages 6823-6826

  Rossen, K ^a   Pye, P J ^a   DiMichele, L M ^a   Volante, R P ^a   Reider, P J ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

INDINAVIR; PIPERAZINE DERIVATIVE; PROTEINASE INHIBITOR;

ARTICLE; CHEMICAL REACTION; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN IMMUNODEFICIENCY VIRUS; HYDROGENATION; STEREOCHEMISTRY;

HUMAN IMMUNODEFICIENCY VIRUS;

EID: 0032541686     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(98)01484-1     Document Type: Article

References (15)

1. 1. (a) Vacca, J.P.; Dorsey, B.D.; Schleif, W.A.; Levin, R.B.; McDaniel, S.L.; Darke, P.L.; Zugay, J.; Quintero, J.C.; Blahy, O.M.; Sardana, V.V.; Schlabach, A.J.; Graham, P.I.; Condra, J.H.; Gotlib, L.; Holloway, M.K.; Lin, J.; Chen, I.-W.; Vastag, K.; Ostovic, D.; Anderson, P.S.; Emini, E.A.; Huff, J.R. Proc. Natl. Acad. Sci. USA 1994, 91, 4096.
2. (b) Idem., J. Med. Chem. 1994, 37, 3443.
3. (c) Askin, D.; Eng, K.K.; Rossen, K.; Purick, R.M.; Wells, K.M.; Volante, R.P.; Reider, P.J. Tetrahedron Lett. 1994, 35, 673.
4. (d) Maligres, P.E.; Upadhyay, V.; Rossen, K.; Cianciosi, S.J.; Purick, R.M.; Eng, K.K.; Reamer; R.A. Askin, D.; Volante, R.P.; Reider, P.J. Tetrahedron Lett. 1995, 36, 2195.
5. (e) Maligres, P.E.; Weissman, S.A.; Upadhyay, V.; Cianciosi, S.J.; Purick, R.M.; Eng, K.K; Reamer, R.A.; Sager, J.; Rossen, K.; Askin, D.; Volante, R.P.; Reider, P.J. Tetrahedron 1996, 52, 3327.
6. (f) Rossen, K.; Reamer, R.A.; Volante, R.P.; Reider, P.J. Tetrahedron Lett., 1996, 37, 6843.
7. (g) Rossen, K.; Volante, R.P.; Reider, P.J. Tetrahedron Lett. 1997, 38, 777.
8. 2. Rossen, K.; Weissman, S.A.; Sager, J.; Reamer, R.A.; Askin, D.A.; Volante, R.P.; Reider, P.J. Tetrahedron Lett. 1995, 36, 6419.
9. 3. (a) Rossen, K.; Sager, J.; DiMichele, L.M. Tetrahedron Lett. 1997, 38, 3183.
10. (b) Ugi, I.; Lohberger, S.; Karl, R. in Comprehensive Organic Chemistry: Selectivity for Synthetic Efficiency, Vol. 20. (Eds. B.M. Trost, C.H. Heathcock), Pergamon, Oxford 1991, P. 1083.
11. 13C NMR δ 164.3, 162.2, 156.4, 137.5, 126.2, 79.1, 52.5, 43.7, 38.9, 28.2(6C), minor rotamer-164.0, 163.8, 156.4, 136.3, 125.0, 79.7, 52.4, 47.5, 39.0, 28.2(6C). The Z-stereochemistry of 8 is base on the observed nOe (represented by the curved arrow) from the vinyl proton to the t-butyl amide proton. Dichloroacetaldehyde hydrate is commercially available from TCI, N-Boc-ethylenediamine is commercially available from Aldrich, but is readily prepared in high yield from ethylenediamine.
12. 13C NMR δ 163.7, 161.9, 151.7, 118.0, 116.2, 82.5, 52.0, 43.5,35.8, 28.4 (3C), 27.8 (3C),
13. 2 and 40°C for 24 h to give (S)-10. The absolute stereochemistry is determined by preparation of authetic (S)-10 from (S)-2 of known absolute stereochemistry (EDC, HCOOH).
14. 4NI, <1% conv., 21% ee. The poor performance of the [2.2]PHANEPHOS ligand is suprising, since the ligand gives a highly active hydrogenation catalyst for a closely related tetrahydropyrazine: Pye, P.J.; Rossen, K.; Reamer, R.A.; Tsou, N.N.; Volante, R.P.; Reider, P.J. J. Am. Chem. Soc. 1997,119, 6207.
15. 4 and evaporated to dryness to give 273 mg of 2 (91%) as a white crystalline material. An aliquot of the product was formylated (EDC, HCOOH) and its ee was determined as 98% using the SFC.