Diastereoselective synthesis of a core fragment of ritonavir and lopinavir

Article abstract of DOI:10.1016/j.tetlet.2011.10.087

A novel approach to the synthesis of Boc-core, a key starting material for ritonavir and lopinavir involving an unprecedented diastereoselective nitroaldol reaction on β-amino aldehyde is disclosed.

Full text of DOI:10.1016/j.tetlet.2011.10.087

Tetrahedron Letters 52 (2011) 6968–6970
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diastereoselective synthesis of a core fragment of ritonavir and lopinavir
Arnab Roy, Lekkala Amarnath Reddy, Namrata Dwivedi, Jyothirmayi Naram, Rodda Swapna,
Golla China Malakondaiah, Mylavarpu Ravikumar, Dinesh Bhalerao, Taduri Bhanu Pratap,
⇑
Padi Pratap Reddy, Apurba Bhattacharya, Rakeshwar Bandichhor
API, R&D, IPDO-Innovation Plaza, Dr. Reddy’s Laboratories Ltd, Bachupalli, Qutubullapur, R. R. District, 500 072 Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel approach to the synthesis of Boc-core, a key starting material for ritonavir and lopinavir involving
an unprecedented diastereoselective nitroaldol reaction on b-amino aldehyde is disclosed.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 1 August 2011
Revised 15 October 2011
Accepted 17 October 2011
Available online 20 October 2011
Keywords:
Asymmetric nitroaldol reaction
Henry reaction
Diastereoselective synthesis
HIV protease inhibitors
b-Amino aldehyde
A key element present in many HIV protease inhibitors for
example, ritonavir and lopinavir (Fig. 1) contains a chiral 1,4-dia-
mino-3-hydroxy architecture.1 In general, stereoselective manipu-
lation at two stereogenic centers, in the presence of a systemic
predisposed chirality, in a convergent fashion imposes a formida-
ble challenge. The direct nitroaldol reaction between protected
amino alcohol and aldehyde is recognized as an economical means
to construct chiral C–C bond.2 However, despite the proven poten-
tial, so far, apart from the methodology disclosed by Piantner
et al.2a that employs nitromethane, there is no precedence of asym-
metric version describing the reaction of an enantiopure protected
b-amino aldehyde with a substituted nitroalkane derivative in or-
der to access 1,4-diamino-3-hydroxy framework. In particular, the
S
H
N
HN
N
N
N
O
O
O
OH HN
O
N
HN
OH
4
3
1
HN
O
HN
O
S
O
O
1
2
Figure 1. Structure of ritonavir 1 and lopinavir 2.
development of
nitroaldol reaction yielding a key component of the biologically ac-
tive molecules presents a vital pursuit.
a catalyst-controlled highly diastereselective
Synthesis of 6 starts with the reduction of (S)-phenyl alanine 10
with the use of NaBH4/H2SO4 system to afford amino alcohol 11
in 74% of yield and 98% of purity.6 Subsequent chlorination of alco-
hol 11 led to obtain chlorinated product 12 in excellent yield and
purity (79% and 93%) by following the literature procedure7 that
utilizes thionyl chloride for such kind of transformations.
Protection of amino group present in 12 with Boc by using
(Boc)2O and NaOH afforded advanced intermediate 13.8 Second or-
der nucleophilic substitution reaction with the use of NaCN on 13
afforded homologated product 149 which was further treated with
Raney Ni/Na2HPO4/pyridine/AcOH/H2O10 to obtain 6 in 61% yield
and 90% of purity as shown in Scheme 1. Synthesis of 5 was accom-
plished by using modified procedure reported in literature.11
As outlined in Scheme 2, the 1,4-diamino-2-hydroxy derivative
[(2S,3S,5S)-2-amino-3-hydroxy-5-tert-butyloxycarbonylamino-1,6-
Herein, we report the design, synthetic development, and appli-
cation of an asymmetric nitroaldol procedure for the C–C bond for-
mation to obtain 1,4-diamino-3-hydroxy all syn functionalized
central core of HIV protease inhibitors ritonavir (1)3 and lopinavir
(2).4
We embarked our study on the synthesis of 6 which was almost
free from protection–deprotection and the innovative approach
that we adopted adds to the expediency of our method to synthe-
size valuable b-amino aldehydes in an unprecedented manner.
⇑
Corresponding author.
E-mail address: rakeshwarb@drreddys.com (R. Bandichhor).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.087

A. Roy et al. / Tetrahedron Letters 52 (2011) 6968–6970
6969
1.7 eq. NaBH4
0.23 eq. H2SO4
12.5 mol%
Raney Ni, H2
5 mol% isopropyl bioxazoline
Bn
Bn
Bn
CO2H
NH2
1.18 eq. SOCl2
DME, 85 °C, 4 h
OH
6
5 mol% Cu(OAc)2,1 eq of
Bn
NO2
4
NH2
MeOH, 100 psi
25 °C, 18 h
THF, 27 °C, 18 h
IPA, 25 °C, 48 h
5
10
11, 74%
1.1 eq. (Boc)2O
2.2 eq. NaOH
OH HNBoc
HO2C
1/2
1.25 eq. succinic
acid
Bn
3.0 eq. NaCN
Cl
Cl
3
NH2
THF, 26 °C, 20 h
NHBoc
DMF,100 °C
30 min
IPA, 70 °C (30 min)
25 °C, 12 h
NH2
CO2H
40%
12, 79%
13,
95%
3
200% Ra Ni
Bn
6.05 eq. Na2HPO4
Scheme 3. End game strategy to access 3 hemisuccinate salt.
CN
NHBoc
, 89%
6
, 61%
pyridine:AcOH:H2O
25 °C, 22 h
14
In another campaign, (R)-BINOL-La-Li heterobimetallic catalytic
system was employed to obtain enhanced diastereoselectivity. The
catalyst displays basic as well as Lewis acid properties. In general,
such kind of catalytic system, in the absence of base, catalyzes
nitroaldol reaction of aldehydes with nitroalkanes in an excellent
enantio/diastereoselective manner.5
With our substrates, the S configuration at both the newly
generated stereogenic centers reflects that the nitronate reacted
preferably on the Si face of aldehydes in the presence of (R)-BI-
NOL-La-Li system that preferentially afforded syn selective product
4 which could be attributed to the sterically hindered transition
state (9) as shown in Scheme 2. As shown in Table 1, we achieved
higher dastereomeric ratio (entry 6) than that with bisoxazoline
system.
A nitroaldol reaction of aldehyde 6 with phenyl nitroethane 5
was catalyzed in the presence of 5 mol % of (R)-BINOL-La-Li at
À38 °C, affording nitroaldol product 4 in 53% yield and with diaste-
reoselectivity (80:9:10:1) under stirring for 24 h. Reaction of 6
with 5 was also alternatively performed by using the (SS)-isopropyl
bisoxazoline and Cu(OAc)2 to obtain 4 in situ in 76% of yield and
with dr (62:29:4:5). We purified the major all syn pair of the nitro-
aldol adduct 4 and characterized. The anti pair, being minor, was
not possible to isolate. Conversion of the nitro derivative 4
(in situ), into the desired core 3 (in situ) was achieved by the
hydrogenation with Ra Ni under H2 atmosphere in methanol. After
removal of the Ra Ni and distillation of the methanol, the reaction
mixture was diluted with isopropanol and subsequently succinic
acid was added to obtain hemisuccinate salt of 3 with 40% of yield
and 98% of purity as shown in Scheme 3.
Scheme 1. Synthesis of b-amino aldehyde 6.
Bn
NO2
OH HN
Boc
5
catalyst
solvent
NHBoc
CHO
Bn
NO2
6
4
OH HN
Boc
reduction
1
2
&
NH2
3
Li
R
O
*
*
O
O
O
N
N
O
OtBu
R
Bn
O
O
O
Li
Cu
AcO
La
Li
O
O
N
O
H N
O
O
*
O
O
N
NHBoc
Bn
Bn
Bn
OH
OH
=
8
*
9
R = Pr, tBu, Bn
i
moderate dr
higher dr
Scheme 2. Diasteroselective nitroaldol approach and plausible TS to access 4.
diphenylhexane] 3 may be obtained by employing the nitroaldol
strategy. To access the nitroaldol product 4, catalyst controlled
intermolecular nitroalkane 5 (nitronate) additions to the protected
b-amino aldehyde 6 were envisioned. In one of the campaigns, C2
symmetric bisoxazoline ligands 7 were screened. As shown in
Scheme 2, the stereochemical outcome is plausibly due to the
transition state 8 that afforded the desired 3, 4-syn product with
S configuration at newly generated stereogenic centers.
It can be envisaged that the existing functional group may cause
steric hindrance in stereo space with the group(s) present in the
catalyst leading to a moderate diastereoselectivity. As shown in
Table 1, none of the bisoxazoline variants as a ligand offered excel-
lent diastereoselectivity in the nitroaldol step. The best result in
the first screen was obtained with the combination of 5 mol % iso-
propyl bisoxazoline ligand/Cu(II) catalyst (entry 3) and isopropanol
as a solvent affording the desired nitro derivative 4 in promising
yield and diastereoselectivity.
In conclusion, we have developed an efficient and operationally
simple method for the directed nitroaldol of b-amino acid 6 with
nitroderivative 5 to give enatiomerically pure diastereomer, 1,4-
diamino-3- hydroxy derivative 3 as a core structure of the HIV pro-
tease inhibitors
1
and
2
in good chemical yields and
diastereoselectivities.
This approach presents the first example of nitroaldol citing the
reaction of an enantiopure protected b-amino aldehyde with a
substituted nitroalkane derivative to access 1,4-diamino-3-hydro-
xy framework. We believe that this strategy will find applications
in synthetic organic chemistry.
Acknowledgment
We thank the management of Dr. Reddy’s Laboratories Ltd. for
supporting this work.
Table 1
Asymmetric nitroaldol of aldehyde 6 with 5
Yield (%) of 4a
References and notes
No.
Catalyst
Sol.
°C/h
dr (HPLC)
1
2
3
4
5
6
—
IPA
IPA
IPA
IPA
IPA
THF
25/24
25/24
25/48
25/48
25/48
À38/24
No reaction
No reaction
62:29:4:5
52:38:01:9
55:35:5:5
80:9:10:1
—
—
76
71
62
53
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