J. Am. Chem. Soc. 1997, 119, 3627-3628
3627
140690.7 In this communication we describe the first asym-
metric synthesis of the unique non-peptidic HIV protease
inhibitor PNU-140690.
Asymmetric Syntheses and Absolute
Stereochemistry of 5,6-Dihydro-r-pyrones, A New
Class of Potent HIV Protease Inhibitors
T. M. Judge, G. Phillips, J. K. Morris, K. D. Lovasz,
K. R. Romines, G. P. Luke, J. Tulinsky, J. M. Tustin,
R. A. Chrusciel, L. A. Dolak, S. A. Mizsak, W. Watt,
J. Morris, S. L. Vander Velde, J. W. Strohbach, and
R. B. Gammill*
Structural, Analytical and Medicinal
Chemistry Research, Pharmacia & Upjohn, Inc.
Kalamazoo, Michigan 49001
ReceiVed October 1, 1996
The synthetic challenge presented by 1 (PNU-140690) was
clearly to devise a means of firmly controlling the two remote
asymmetric centers present in the molecule. In an earlier
synthesis of R-pyrones, we successfully used the addition of
an organocuprate to a chiral unsaturated acylimide to establish
the C3R center.8 That strategy resulted in high chemical and
enantiomeric yields and thus provided a logical starting point
for the current campaign. The successful extension of that
strategy would ultimately depend on conversion of the readily
available Michael adduct to a 3,6-disubstituted 4,5-dihydro-R-
pyrone in a stereocontrolled manner to yield the necessary
chirality at C6 in the final product.
Addition of the lithium salt of (R)-4-phenyl-2,5-oxazolidinone
(2) to pentenoyl chloride afforded the unsaturated imide 3 in
95% yield as a crystalline solid (Scheme 1). Addition of the
aryl cuprate derived from [3-[bis(trimethylsilyl)amino]phenyl]-
magnesium bromide (4)9 to 3 afforded the Michael adduct as a
single diastereomer.10 The trimethylsilyl protecting groups
could be removed under mildly acidic conditions to yield an
aniline intermediate, which was subsequently bisbenzylated to
afford crystalline 5 in 78% overall yield. Introduction of an
acetyl group to 5 required a two step protocol11 involving first
generation of the titanium enolate, followed by the addition of
2-methyl-2-methoxy-1,3-dioxolane (6). Subsequent acid hy-
drolysis of the resulting ketal provided methyl ketone 7 as a
single diastereomer in 95% yield over the two steps. We first
investigated the aldol chemistry of 7 using Ti(OiPr)Cl3 as the
Lewis acid and Hunig’s base to generate the enolate species.14
Treatment of the resultant enolate with 4-heptanone (8) cleanly
afforded aldol adduct 10 in 91% isolated yield. Treatment of
that same enolate with the 1-phenylhexan-3-one (9) afforded a
3/2 mixture of diastereomeric aldol adducts 11 and 12 in 73%
yield.12 Aldol adduct 10 and the major diastereomer 11 from
the reaction with unsymmetrical ketone 9 were independently
lactonized to yield dihydro-R-pyrones 13 and 14, respectively.
Debenzylation and subsequent sulfonylation of 13 and 14
Inhibition of the HIV protease enzyme, which plays a key
role in viral maturation, represents a promising therapeutic
strategy for treatment of the escalating problem of HIV
infection.1-4 At Pharmacia & Upjohn we have developed two
classes of low molecular weight HIV protease inhibitors,
R-pyrones (PNU-969885 and PNU-1030176) and 5,6-dihydro-
R-pyrones (PNU-140690). The latter class of compounds
represents the first nonpeptide HIV protease inhibitors which
possess the antiviral potency of their peptide counterparts and
importantly have therapeutically useful pharmaceutical proper-
ties.7 Moreover, HIV-1 isolates highly resistant to ritonavir and
broadly cross-resistant to a number of other protease inhibitors,
including saquinavir and indinavir, remain sensitive to PNU-
(1) (a) Pillay, D.; Bryant, M.; Getman, D.; Richman, D. D. ReV. Med.
Virol. 1995, 5, 23-33. (b) West, M. L.; Fairlie, D. P. Trends Pharmacol.
Sci. 1995, 16, 67-75. (c) Darke, P. L.; Huff, J. R. AdV. Pharmacol. 1994,
25, 399-454.
(2) Thaisrivongs, S. Annu. Rep. Med. Chem. 1994, 17, 133-144.
Redshaw, S. Exp. Opin. InVest. Drugs 1994, 3, 273-286.
(3) For a discussion on the pharmaceutical properties of protease
inhibitors, see: Plattner, J. J.; Norbeck, D. W. In Drug DiscoVery
Technologies; Clark, C. R., Moos, W. H., Eds.; Ellis Horwood: Chichester,
England, 1990; pp 92-126; Olson, G. L.; Bolin, D. R.; Bonner, M. P.;
Bo¨s, M.; Cook, C. M.; Fry, D. C.; Graves, B. J.; Hatada, M.; Hill, D. E.;
Kahn, M.; MAdison, V. S.; Rusieck, V. K.; Sarabu, R.; Sepinwall, J.;
Vincent, G. P.; Voss, M. E. J. Med. Chem. 1993, 36, 3039-3049.
(4) For recent examples describing the synthesis of protease inhibitors
see: 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, 2195-2198. Parkes, K. E. B.; Bushnell, D. J.;
Crackett, P. H.; Dunsdon, S. J.; Freeman, A. C.; Gunn, M. P.; Hopkins, R.
A.; Lambert, R. W.; Martin, J. A.; Merrett, J. H.; Redshaw, S.; Spurden,
W. C.; Thomas, G. J. J. Org. Chem. 1994, 59, 3656-3664. Baker, W. R.;
Condon, S. L. J. Org. Chem. 1993, 58, 3277-3284.
(5) Thaisrivongs, S.; Tomich, P. K.; Watenpaugh, K. D.; Chong, K.-T.;
Howe, W. J.; Yang, C.-P.; Strohbach, J. W.; Turner, S. T.; McGrath, J. P.;
Bohanon, M. J.; Lynn, J. C.; Mulichak, A. M.; Spinelli, P. A.; Hinshaw, R.
R.; Pagano, P. J.; Moon, J. B.; Ruwart, M. J.; Wilkinson, K. F.; Rush, B.
D.; Zipp, G. L.; Dalga, R. J.; Schwende, F. J.; Howard, G. M.; Padbury, G.
E.; Toth, L. N.; Zhao, Z.; Koeplinger, K. A.; Kakuk, T. J.; Cole, S. L.;
Zaya, R. M.; Piper, R. C.; Jeffrey, P. J. Med. Chem. 1994, 37, 3200-3204.
(6) Romines, K. R.; Watenpaugh, K. D.; Howe, W. J.; Tomich, P. K.;
Lovasz, K. D.; Morris, J. K.; Janakiraman, M. N.; Lynn, J. C.; Horng, M.-
M.; Chong, K.-T.; Hinshaw, R. R.; Dolak, L. A. J. Med. Chem. 1995, 38,
4463-4473. Skulnick, H. I.; Johnson, P. D.; Howe, W. J.; Tomich, P. K.;
Chong, K.-T.; Watenpaugh, K. D.; Janakiraman, M. N.; Dolak, L. A.;
McGrath, J. P.; Lynn, J. C.; Horng, M.-M.; Hinshaw, R. R.; Zipp, G. L.;
Ruwart, M. J.; Schwende, F. J.; Zhong, W.-Z.; Padbury, G. E.; Dalga, R.
J.; Shiou, L.; Possert, P. L.; Rush, B. D.; Wilkinson, K. F.; Howard, G.
M.; Toth, L. N.; Williams, M. G.; Kakuk, T. J.; Cole, S. L.; Zaya, R. M.;
Lovasz, K. D.; Morris, J. K.; Romines, K. R.; Thaisrivongs, S.; Aristoff, P.
A. J. Med. Chem. 1995, 38, 4968-4971.
(8) Gammill, R. B.; Judge, T. M.; Phillips, G.; Zhang, Q.; Sowell, C.
G.; Cheney, B. V.; Mizsak, S. A.; Dolak, L. A.; Seest, E. P. J. Am. Chem.
Soc. 1994, 116, 12113-12114.
(9) Available from Aldrich Chemical Co.
(10) For reviews see: Tomioka, K.; Koga, K. In Asymmetric Synthesis;
Morrison, J. D., Ed.; Academic Press: New York, 1983; Vol. 2, p 201.
Rossiter, B. E.; Swinge, N. M. Chem. ReV. 1992, 92, 771. Nicolas, E.;
Russell, K. C.; Hruby, V. J. J. Org. Chem. 1993, 58, 766.
(11) Evans, D. A.; Urpi, F.; Somers. T. C.; Clark, J. S.; Bilodeau, M. T.
J. Am. Chem. Soc. 1990, 112, 8215.
(12) The assignment of the absolute stereochemistry in 11 and 12 was
established using an X-ray crystal structure of lactone intermediate in the
diastereomeric C3S series.
(7) Thaisrivongs, S.; Skulnick, H. I.; Turner, S. R.; Strohbach, J. W.;
Tommasi, R. A.; Johnson, P. D.; Aristoff, P. A.; Judge, T. M.; Gammill,
R. B.; Morris, J. K.; Romines, K. R.; Chrusciel, R. A.; Hinshaw, R. R.;
Chong, K. T.; Tarpley, W. G.; Poppe, S. M.; Slade, D. E.; Lynn, J. C.;
Horng, M. M.; Tomich, P. K.; Seest, E. P.; Dolak, L. A.; Howe, W. J.;
Howard, G. M.; Schwende, F. J.; Toth, L. N.; Padbury, G. E.; Wilson, G.
J.; Shiou, L.; Zipp, G. L.; Wilkinson, K. F.; Rush, B. D.; Ruwart, M. J.;
Koeplinger, K. A.; Zhao, Z.; Cole, S.; Zaya, R. M.; Kakuk, T. J.;
Janakiraman, M. N.; Watenpaugh, K. D. J. Med. Chem. 1996, 39, 4349-
4353.
S0002-7863(96)03434-8 CCC: $14.00 © 1997 American Chemical Society
Judge
