Epoxyalcohol route to hydroxyethylene dipeptide isosteres: A new synthesis of the diaminoalcohol core of HIV-protease inhibitor ABT-538 (Ritonavir)

Article abstract of DOI:10.1039/b005804l

A stereoselective synthesis of the diaminoalcohol core of Ritonavir illustrates a novel approach to hydroxyethylene dipeptide isosteres, based on the regioselective reduction of amino acid-derived epoxyalcohols.

Full text of DOI:10.1039/b005804l

Epoxyalcohol route to hydroxyethylene dipeptide isosteres: a new synthesis of
the diaminoalcohol core of HIV-protease inhibitor ABT-538 (Ritonavir)
Fabio Benedetti* and Stefano Norbedo
Department of Chemical Sciences, University of Trieste, Via Giorgieri 1, 34127 Trieste, Italy.
E-mail: benedett@univ.trieste.it; Fax: +39 040 6763903; Phone: +39 040 6763919
Received (in Liverpool, UK) 13th July 2000, Accepted 8th December 2000
First published as an Advance Article on the web
A stereoselective synthesis of the diaminoalcohol core of
Ritonavir illustrates a novel approach to hydroxyethylene
dipeptide isosteres, based on the regioselective reduction of
amino acid-derived epoxyalcohols.
obtained in a single step by treating the diol with 3 equiv. of
methanesulfonyl chloride and 6 equiv. diisopropylethylamine
(DIPEA) in 1,2-dichloroethane, at 80 °C for 6 h. The dimesylate
6 initially obtained spontaneously cyclizes via SN2 attack of the
carbonyl oxygen of Boc on the neighbouring sulfonate ester to
give the inverted oxazolidinone 7. Displacement of the second
mesylate was obtained by treating crude 7 with 1.5 equiv. NaN3
in DMSO for 18 h at 50 °C, in the presence of 1 equiv. of
18-crown-6, affording the azide 8 [[a]2D5 = 235 (c 0.2, MeOH)]
in which all the stereocenters have the correct configuration
(50% for the two steps). The stereochemistry of the ox-
azolidinone 8 was established from NOE experiments. These
show a 3% enhancement between the ring H4 and H5,
consistent with a trans relationship between these protons,
while in the cis-oxazolidinone 12 (Scheme 2) a 11% enhance-
ment is detected between the same protons. The Boc-protected
amino group was then restored by treatment of 8 with equimolar
amounts of Boc2O and NaH in THF, at 25 °C for 12 h, followed
by hydrolysis of the resulting N-Boc heterocycle with Cs2CO3
in MeOH–water at 25 °C for 2 h.9 Finally, hydrogenation of the
azide, in MeOH over 10% Pd/C, gave the monoprotected (S,S,S)
hydroxyethylene dipeptide isostere 9 {[a]2D5 = 219 (c 0.2,
MeOH)} in 20% overall yield from the epoxyalcohol 4.
Ritonavir (1), approved in 1996,1 is a potent and clinically
effective peptidomimetic inhibitor of the protease of HIV, with
high oral bioavailability.2 The structure of Ritonavir was
designed to target the enzyme’s active site and is based on the
hydroxyethylene dipeptide isostere 2.2a In the original synthesis
of the inhibitor,3 the diaminoalcohol 2 was obtained from the
corresponding diaminodiol 3 by a multi-step deoxygenation
The synthetic approach shown here can be expanded to
obtain the epimeric Phe-Phe dipeptide isostere 13 with the
opposite configuration at the alcoholic carbon (Scheme 2). In
this case the diol 5 is treated with sodium hydride in THF at
25 °C for 12 h to give, in 85% yield, the cis-oxazolidinone 10
arising from a normal acyl transfer cyclization10 {[a]D25 = 242
(c 0.2, MeOH)}. The NOE enhancement between the ring
approach.4 The core 2 was then statistically monoacylated to
introduce the first side chain while the second flanking residue
was introduced in the final step. This strategy has some
drawbacks: loss of 2 through undesired bis-acylation, im-
possibility of introducing different residues on the isostere’s C1
and C4, which originate from the Ca of the same aminoacid via
the reductive dimerization of the corresponding aminoalde-
hyde,4 and a less than optimal stereocontrol in the synthesis of
3. Several approaches have been proposed to overcome these
limitations, based on aminoacids as precursors from the chiral
pool5 or on enantioselective synthetic strategies.6 In this
communication we describe a short and efficient synthesis of
the monoprotected Ritonavir core 9 which utilizes the amino-
acid derived epoxyalcohol 4 as key intermediate (Scheme 1).
The epoxyalcohol 4 was obtained from phenylalanine, in four
steps and 40% overall yield, as described previously.7
2,3-Epoxyalcohols are regioselectively converted into the
corresponding 1,3-diols by Red-Al;8 accordingly, when the
epoxyalcohol 4 was treated with this reagent (3 equiv.) in THF
at 50 °C for 24 h, attack of hydride took place selectively to give
the Boc-protected aminodiol 5 {[a]2D5 = 218 (c 0.2, MeOH)} in
60% yield after chromatography. In order to convert this
compound into the required diaminoalcohol 9, it is necessary to:
i) selectively activate the hydroxy group on C4 towards
displacement by a suitable precursor of the aminogroup and ii)
invert the configuration of C2 which is opposite to that of 9.
Differentiation of the two secondary hydroxy groups, selective
activation and inversion of the configuration of C2 were
Scheme 1 Reagents and conditions: (a) Red-Al, THF, 50 °C, 60%; (b)
MsCl, DIPEA, 80 °C; (c) NaN3, DMSO, 18-crown-6, 50 °C, 50%, 2 steps;
(d) NaH, Boc2O, THF; (e) Cs2CO3, MeOH–H2O, 67%, 2 steps; (f) 1 atm H2,
10% Pd/C, MeOH, 100%.
DOI: 10.1039/b005804l
Chem. Commun., 2001, 203–204
This journal is © The Royal Society of Chemistry 2001
203

yaminoalcohols 4 has been described previously;7,12 the present
extension to the synthesis of monohydroxyethylene isosteres
further demonstrates the synthetic utility of these inter-
mediates.
This work was supported by Istituto Superiore di Sanità,
National Research Program on AIDS and the University of
Trieste.
Notes and references
1 http://www.niaid.nih.gov/daids/dtpdb/
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Scheme 2 Reagents and conditions: (a) NaH, THF, 25 °C, 85%; (b) MsCl,
Et3N, CH2Cl2, 0 °C; (c) NaN3, DMSO, 18-crown-6, 50 °C, 75%, 2 steps; (d)
NaH, Boc2O, THF; (e) Cs2CO3, MeOH–H2O, 58%, 2 steps; (f) 1 atm H2,
10% Pd/C, MeOH, 100%.
protons (11%) is consistent with the cis stereochemistry of the
ring substituents. With the first hydroxy group thus protected,
the second OH can be activated as mesylate, in CH2Cl2 at
0 °C,11 and the resulting oxazolidinone 11 is then converted into
the selectively protected (S,R,S) isostere 13 {[a]2D5 = +1.0 (c 2,
MeOH)} by the same sequence of reactions seen before for the
synthesis of 9 (Scheme 2). The overall yield of 13 is 22%, from
the epoxyalcohol 4.
We have thus described a novel approach to the synthesis of
the (S,S,S) dipeptide isostere of Ritonavir 9 and its (S,R,S)
epimer 13, based on the regioselective ring opening of an
epoxyalcohol with aluminium hydride. This strategy leads to a
mono-protected diaminoalcohol from which peptidomimetic
protease inhibitors can be directly obtained by coupling with
different peptide, or non-peptide, residues. The approach is not
limited to isosteres with identical side chains, and it should thus
be possible to extend this methodology to the synthesis of a
repertoire of isosteres with different residues, starting from the
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Chem. Commun., 2001, 203–204