Asymmetric dihydroxylation route to a dipeptide isostere of a protease inhibitor: Enantioselective synthesis of the core unit of ritonavir

Article abstract of DOI:10.1039/a902518i

An enantioselective synthesis of the dipeptide isostere of ritonavir has been accomplished utilizing Sharpless asymmetric hydroxylation as the key step.

Full text of DOI:10.1039/a902518i

Asymmetric dihydroxylation route to a dipeptide isostere of a protease
inhibitor: enantioselective synthesis of the core unit of ritonavir
Arun K. Ghosh,* Dongwoo Shin and Packiarajan Mathivanan
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, USA.
E-mail: arunghos@uic.edu
Received (in Corvallis, OR, USA) 29h March 1999, Accepted 22nd April 1999
An enantioselective synthesis of the dipeptide isostere of
ritonavir has been accomplished utilizing Sharpless asym-
metric hydroxylation as the key step.
with NaN3 in DMF at 90 °C and (3) catalytic hydrogenation of
the resulting azide over 10% Pd/C in EtOAc in the presence of
Boc2O (overall 73% yield). The benzyl side chain at C-2 in
isostere 2 was installed by a stereoselective alkylation of lactone
derivative 6 as described previously.8 Thus, generation of the
enolate of lactone 6 with LiHMDS in THF at 278 °C, and
subsequent reaction with BnI afforded the alkylated product 7
as a single diastereomer along with a small amount (4%) of
dialkylated product. Alkylated lactone 7 was separated (70%
yield) by silica gel chromatography. Saponification of lactone 7
by LiOH followed by protection of the resulting hydroxy acid
with TBDMSCl, imidazole in DMF afforded the TBDMS
protected acid derivative 8.5a Curtius rearrangement of the acid
8 with (PhO)2PON3 and Et3N in refluxing toluene followed by
addition of BnOH as described previously provided the Z-
The utility of dipeptide isosteres in the design and synthesis of
potent and selective HIV protease inhibitors has been well
documented.1 A number of peptidomimetic protease inhibitors
in combination with reverse transcriptase inhibitors have now
been approved for treatment of AIDS, and early indications are
very promising.2, 3 Ritonavir 1 is one such protease inhibitor
which is potent, selective and clinically effective.2a Ritonavir
consists of a unique dipeptide mimic 2 evolved from structure-
based design strategies (Fig. 1).4 Most syntheses of the ritonavir
isostere start with N-protected l-amino acids and are therefore
limited to natural amino acid-derived substitutents.5 Herein we
report an enantioselective synthesis of the ritonavir isostere
utilizing the Sharpless’ catalytic asymmetric dihydroxylation
reaction as the key step.
As illustrated in Scheme 1, g,d-unsaturated ester 4 was
prepared by addition of vinyl magnesium bromide to phenyl-
acetaldehyde 3, followed by Claisen rearrangement of the
resulting allylic alcohol with triethyl orthoacetate in the
presence of propionic acid at 145 °C.6 Ethyl ester 4 was
converted to lactone 5 utilizing Sharpless protocol.7 Thus, ester
4 was treated with AD-mix-b and MeSO2NH2 in a mixture
(1:1) of ButOH and H2O at 0 °C for 36 h and the resulting
hydroxy ester was lactonized in the presence of a catalytic
amount of AcOH in refluxing toluene for 6 h. The desired
hydroxy lactone 5 was obtained in 87% yield after silica gel
chromatography [[a]2D3258, (c 1.81, CHCl3)]. The hydroxy
lactone 5 was transformed into protected amino lactone
derivative 6 in the following three steps sequence: (1) formation
of the mesylate with MsCl and Et3N in the presence of a
catalytic amount of DMAP; (2) displacement of the mesylate
O
O
i,ii
Ph
Ph
H
OEt
3
6
7
4
iii
O
O
O
O
iv–vi
H
HO
Ph
Boc-N
Ph
5
vii
O
Ph
TBDMS
H
CO2H
Ph
O
O
viii
H
Boc-N
Boc-N
H
H
Ph
N
OH
C4
O
H
N
C5
C2
Ph
O
Ph
ix
N
H
S
8
O
H-N
O
Ph
H
N
N
N-Boc
N-Z
HO
RO
Me
H
Boc-N
H
Boc-N
Ritonavir 1
vi
S
Ph
Ph
Ph
Ph
11
9 R = TBDMS
10 R = H
x
Ph
OH
C4
O
Scheme 1 Reagents and conditions: i, CH2NCHMgBr, Et2O, 0 °C, 57%; (ii)
MeC(OEt)3, MeCH2CO2H (cat), 145 °C, 86%; (iii) AD-Mix-b, Me-
SO2NH2, ButOH, H2O, 0 °C, then PhMe, 115 °C, 87%; iv, MsCl, DMAP,
Et3N, CH2Cl2, 0 °C; v, NaN3, DMF, 87%; vi, H2, 10% Pd-C, Et3N, Boc2O,
EtOAc, 23 °C, 84%; vii, LiHMDS, THF, BnI, 278 °C, 70%; viii, aq. LiOH,
DME, 23 °C, H3O+, then imidazole, TBDMSCl, DMF, 23 °C, quant. ix,
(PhO)2PON3, Et3N, PhMe, then BnOH, 130 °C, 65%; x, TBAF, THF, 23
°C, 75%.
H
N
C5
C2
N
H
O
Ph
Ritonavir core structure 2
Fig. 1 Dipeptide mimetic of ritonavir 1
Chem. Commun., 1999, 1025–1026
1025

O
Financial support of this project was provided by the National
Institutes of Health (GM 53386). We thank Ms Hanna Cho for
the protease inhibition assay.
H
NZ
O
NHZ
HO
H
Hb
H-N
i
Boc-N
Ha
Ph
Ph
Ph
Ph
Notes and references
10
12
1 S. Thaisrivongs, Annu. Rep. Med. Chem., 1994, 29, 133; P. L. Darke
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ii,iii
iv,v
2 (a) D. J. Kempf, K. C. Marsh, J. F. Denissen, E. McDonald, S.
Vasavononda, C. A. Flentge, B. G. Green, L. Fino, C. H. Park,
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G. L. Drusano, AIDS, 1996, 10, 485; J. M. Schapiro, M. A. Winters, F.
Stewart, B. Efron, J. Norris, M. J. Kozal and T. C. Merigan, Ann. Intern.
Med., 1996, 124, 1039 and references cited therein.
4 J. W. Erickson and S. W. Fesik, Annu. Rep. Med. Chem., 1992, 26, 271
and references cited therein.
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Zugay, J. Org. Chem., 1993, 58, 1025; (b) T. L. Stuk, A. R. Haight, D.
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6 R. I. Trust and R. E. Ireland, Org. Synth., 1988, Coll. Vol. 6, 606.
7 Z.-M. Wang, X.-L. Zhang, K. B. Sharpless, S. C. Sinha, A. Sinha-
Bagchi and E. Keinan, Tetrahedron Lett., 1992, 33, 6407; K. B.
Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino, J. Hartung, K. S.
Jeong, H.-L. Kwong, K. Morikawa, Z.-M. Wang, D. Xu and X.-L.
Zhang, J. Org. Chem., 1992, 57, 2768.
H
N-Boc
H
NZ
HO
HO
H
H
Boc-N
Boc-N
Ph
Ph
Ph
Ph
14
13
Scheme 2 Reagents and conditions: i, SOCl2, THF, 23 °C, 73%; ii, KOH,
EtOH–H2O (1:1), 70 °C; iii, THF, Boc2O, NaHCO3, 23 °C, 52%; iv,
Boc2O, Et3N, DMAP (cat), THF, 23 °C, 93%; v, Cs2CO3, PriOH–MeOH
(6:1), 23 °C, 60%.
derivative 9 (overall 65% yield from 7).9 Removal of the silyl
group by treatment with TBAF in THF at 23 °C afforded the
dipeptide isostere 10 with (4R)-configuration. Catalytic hydro-
genation of 10 over 10% Pd/C in the presence of Boc2O and
Et3N furnished the Boc derivative 11 in 72% yield after silica
gel chromatography.
In the ritonavir isostere, the (4S)-configuration of the
hydroxy group is known to be essential for effective enzyme
inhibitory properties.2a, 5, 10 Therefore, the C-4 hydroxy group
stereochemistry was inverted as depicted in Scheme 2. Reaction
of 10 with SOCl2 in THF at 23 °C furnished the oxazolidinone
12 (73%). The vicinal coupling constant of oxazolidinone 12 is
consistent with an anti stereochemical relationship (JAB 4.8
Hz).11 Treatment of the oxazolidinone 12 with KOH in EtOH–
H2O (1:1) resulted in the cleavage of the Z group and the
oxazolidinone ring. Boc protection of the free amines afforded
the biologically active dipeptide mimetic 13. Differentially
protected dipeptide mimic 14 was prepared by protection of
oxazolidinone 12 with Boc2O and Et3N in the presence of a
catalytic amount of DMAP in THF followed by selective
cleavage of the oxazolidinone ring by treatment with Cs2CO3 in
PriOH–MeOH (6:1) at 23 °C for 6 h.12 Consistent with the
previous report, dipeptide mimic 11 with (4R)-hydroxy config-
uration has shown enzyme inhibitory potency (IC50 value)
greater than 2 mM in the assay protocol developed by Toth and
Marshall.13, 14 Inversion of the C-4 hydroxy configuration of 10
resulted in derivatives 13 and 14 with inhibitory potencies of
118 nM and 75 nM respectively. Dipeptide isostere 14 has been
previously converted to ritonavir and its derivatives.2a
In conclusion, we have developed an enantioselective
synthesis of the core unit of ritonavir by utilizing Sharpless’
catalytic asymmetric dihydroxylation reaction as the key step.
The present route provides access to a diverse array of protease
inhibitors containing designed functionalities. Synthesis and
biological evaluation of novel protease inhibitors are currently
in progress.
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references therein.
9
T. Shioiri, K. Ninomiya and S. Yamada, J. Am. Chem. Soc., 1972, 94,
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Matsunaga, T. Ishizuka and T. Kunieda, Tetrahedron, 1997, 53, 1275.
13 M. V. Toth and G. R. Marshall, Int. J. Pept. Protein Res. 1990, 36,
544.
14 In-house prepared saquinavir [ref. 2(c)] exhibited an IC50 value of 1.6
nM in the same assay.
Communication 9/02518I
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Chem. Commun., 1999, 1025–1026