Organic Chemistry of Drug Synthesis. Volume 7

inhibitor antiviral drugtiprinavir( 52 ) notably departs from this pattern as
it omits the peptide-like moiety present in the earlier agents; this drug is
also as a result said to be active against HIV strains that have developed
resistance to the peptidomimetic agents. The convergent synthesis begins
with the addition of the enolate from methyl acetate to the carbonyl
group in 39. The product ( 40 ) is then saponified and the resulting acid
resolved by way of its ephedrine salt. Treatment of the desired enantiomer
with chloromethylp-hydroxybiphenyl gives the doubly alkylated deriva-
tive 41. Reaction of that compound with DIBAL-H results in reduction
of the ester to an alcohol ( 42 ). This function is then back-oxidized with
hypochlorite in the presence of tetramethylpiperidolN-oxide to give the
aldehyde ( 43 ).

O

39

1. CHBuLi 3 CO 2 CH 3
   2. NaOH
   3. Resolve

OH

CO 2 H

OCH 2 OR

CO 2 CH 2 OR

ROCH 2 Cl

R = C 6 H 5 C 6 H 4 -

40 41

DIBAL-H

OCH 2 OR

42

OH

NaOCl

N

OH

O

OCH 2 OR

43

O

Preparation of the other major fragment begins with Knoevenagel con-
densation ofm-nitrobenzaldehyde with dimethyl malonate to yield diester
45. Treatment of intermediate bromide 45 with diethyl zinc in the presence
of cupric iodide leads to conjugate addition of an ethyl group ( 46 ). The
diacid obtained on saponification of that product then spontaneously dec-
arboxylates on warming. The product obtained on esterifying the remain-
ing carboxylic function acid is next resolved by chromatography over a
chiral column. Condensation of the enolate from treatment of 47 with
the aldehyde in the other fragment affords the adduct ( 48 ). The newly
introduced hydroxyl group is oxidized to the ketone by means of pyridi-
nium chlorochromate to afford theb-ketoester ( 49 ). The biphenoxy pro-
tecting group on the tertiary alcohol is then removed by acid hydrolysis.

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