A short approach to the synthesis of the ritonavir and lopinavir core and its C-3 epimer via cross metathesis

Article abstract of DOI:10.1016/j.tetasy.2009.09.003

A short synthesis of hydroxyethylene dipeptide isostere, a core unit of the HIV-protease inhibitors ritonavir and lopinavir, its C-3 epimer and C₂ symmetric diamino diol is described. The crucial aspects of the synthesis are self-cross metathesis and exploitation of C₂-symmetric of the metathesis product 8 to obtain the required skeleton.

Full text of DOI:10.1016/j.tetasy.2009.09.003

Tetrahedron: Asymmetry 20 (2009) 2201–2204
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A short approach to the synthesis of the ritonavir and lopinavir core
and its C-3 epimer via cross metathesis
*
Errabelli Ramu, B. Venkateswara Rao
Organic Division III, Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A short synthesis of hydroxyethylene dipeptide isostere, a core unit of the HIV-protease inhibitors riton-
avir and lopinavir, its C-3 epimer and C2 symmetric diamino diol is described. The crucial aspects of the
synthesis are self-cross metathesis and exploitation of C2-symmetric of the metathesis product 8 to
obtain the required skeleton.
Received 15 June 2009
Accepted 2 September 2009
Available online 14 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Ph
1. Introduction
N
S
O
OH
S
H
H
AIDS, a degenerative disease of the immune system, is one of
the most challenging problems in medicine. Aspartyl protease
plays a vital role not only in HIV but also in the development
and propagation of several disease states.1 The human immunode-
ficiency virus protease (HIV-PR) is an essential enzyme for the rep-
lication of the virus responsible for AIDS.
O
N
N
N
N
N
H
O
O
Ph
Ritonavir 1
Ph
A number of peptidomimetic protease inhibitors in combina-
tion with reverse transcriptase inhibitors have now been approved
for the treatment of AIDS.2,3 Ritonavir 14 and lopinavir 24 (Fig. 1)
are the protease inhibitors, which are selective, potent and clini-
cally effective.2a Therefore several approaches have been devel-
oped for the synthesis of the core unit.4 Both ritonavir 1 and
lopinavir 2 consist of the unique dipeptide mimic 3 (Fig. 2) evolved
from the structure-based design strategies.5 The utility of dipep-
tide isosteres in the design and synthesis of potent and selective
HIV protease inhibitors has been well documented.6
Incorporation of C2 symmetry has become a useful paradigm in
the design of active site inhibitors for HIV-1 protease (HIV PR) and
has led to the design of a series of highly potent, C2 symmetry-
based diol containing inhibitors of HIV PR. The symmetric
molecule inhibited both the protease activity and the acute HIV-
1 infection in vitro, and was at least 10,000-fold more potent
against HIV-1 protease than against related enzymes and appeared
to be stable to degradative enzymes.7 All diastereomers of the
C2-symmetric diaminodiol core 5 are active against HIV proteases8
and the diol 5 is a basic structural motif of Kalanchosine8b which is
an anti-inflammatory agent. Therefore several synthetic ap-
proaches have been developed to make this core unit. Due to the
importance of this molecule, our interest in this area4a and the
OH
O
H
N
N
NH
N
H
O
O
O
Ph
Lopinavir 2
Figure 1.
metathesis reaction,9 we herein report a short and efficient synthe-
sis of the ritonavir and lopinavir isostere and diamino diol com-
pound 5 utilizing the self cross metathesis10 as the key step.
2. Results and discussion
As illustrated in Scheme 1, our synthesis started from commer-
cially readily available L-phenyl alanine. L-Phenyl alanine was con-
verted to its corresponding Boc-amino alcohol 6 easily using
standard procedures. Alcohol 6 was subjected to Swern oxidation
conditions using (COCl)2, DMSO in CH2Cl2 to give the aldehyde,
which was taken as such to the next step without purification.
The one carbon extension of aldehyde to olefin compound 7 was
unsuccessful under standard Wittig protocols. Finally olefin 7
was obtained using Takai–Nozaki11 olefination conditions in 55%
overall yield (for two steps). The key cross metathesis reaction of
olefin 7 using Grubbs’ second generation olefin metathesis catalyst
* Corresponding author. Tel./fax: +91 40 27193003.
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B. Venkateswara
Rao).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.09.003

2202
E. Ramu, B. Venkateswara Rao / Tetrahedron: Asymmetry 20 (2009) 2201–2204
Ph
Ph
Ph
OH
OH
OH
BocHN
Ph
BocHN
Ph
BocHN
Ph
NHBoc
NHBoc
NHBoc
OH
4
3
5
Figure 2.
c
Chelation control
Na
Felkin Anh control
a, b
Ph
L-Phenylalanine
Ph
OH
NHBoc
NHBoc
BocHN
O
O
R1
7
6
BocHN
NHBoc
Ph
R1
H
[H]
H
e
R2
R2
d
4
3
+
[H]
Ph
syn-isomer major
R1 = Bn, R2 = CH2-CH(NHBoc)-Bn
anti-isomer major
NHBoc
8
Figure 3.
Scheme 1. Reagents and conditions: (a) (i) AcCl, MeOH, reflux, 3 h; (ii) (Boc)2O,
TEA, THF, rt, 7 h (95% for two steps); (b) LiCl, NaBH4, EtOH, THF, rt, 16 h 82%; (c) (i)
DMSO, (COCl)2, CH2Cl2, ꢁ78 °C, 2 h then TEA; (ii) Zn, CH2I2, Ti (OiPr)4, THF, rt, 1 h,
55% (for two steps); (d) 10 mol % Grubbs’ second generation catalyst, CH2Cl2, 40 °C,
14 h, 87%; (e) BH3–SMe2, H2O2, NaOH, THF, 0 °C to rt, 8 h, 70%.
5 exclusively; its spectroscopic data were in good agreement with
the reported values.14 Compounds 3 and 5 were selectively
converted to ritonavir and lopinavir and other derivatives using re-
ported procedures.4k,n,14b
(10 mol %) afforded C2-symmetric dimer 84i as the E-isomer exclu-
sively, whereas a first generation Grubbs’ catalyst failed to give the
product in our hand.12 Although alkene 8 was synthesized by Gur-
jar et al. using Julia olefination, it involves more steps using re-
agents such as n-butyllithium, Na/Hg amalgam and Na in liquid
ammonia, which resulted in low yields of the product. Therefore
their approach has limitation to large scale synthesis. Hydrobora-
tion of olefin 8 with BH3ꢀSMe2 in THF gave the required alcohols
3 and 4 in a 3.8:1 ratio as a separable mixture; its spectroscopic
data are in good agreement with the reported values.4l
3. Conclusions
In conclusion, we demonstrated a short synthesis of phe-phe
hydroxyethylene isostere 3, a core unit of ritonavir and lopinavir,
its C-3 epimer 4 and diol 5 from C2 symmetric dimer 8, which
a single monomer using self-metathesis,
hydroboration and sharpless asymmetric dihydroxylation.
was obtained from
4. Experimental section
In order to obtain good diastereoselectivity in the formation of 3
and 4, an oxidation and reduction protocol was applied to the mix-
ture of 3 and 4 (Scheme 2). Dess–Martin periodinane oxidation of
the secondary alcohol function of 3 and 4 in CH2Cl2 led to ketone
9. Reduction of the 9 with NaBH4 in MeOH gave anti-alcohol 4 as
the major isomer in a 9:1 ratio. The formation of the major trans-iso-
mer can be explained by a chelation control model consistent with
TLC was performed on Merck Kiesel gel 60, F254 plates (layer
thickness 0.25 mm). Column chromatography was performed on
silica gel (60–120 mesh) using ethyl acetate and hexane mixture
as eluent. Melting points were determined on a Fisher John’s melt-
ing point apparatus and are uncorrected. IR spectra were recorded
on a Perkin–Elmer RX-1 FT-IR system. 1H NMR and 13C NMR spec-
tra were recorded using Varian Gemini-200 MHz or Bruker
Avance-300 MHz spectrometer. 1H NMR data are expressed as
chemical shifts in ppm followed by multiplicity (s-singlet; d- dou-
blet; t- triplet; q- quartet and m- multiplet), number of proton(s)
and coupling constant(s) J (Hz). 13C NMR chemical shifts are ex-
pressed in ppm. Optical rotations were measured with Horiba-
SEPA-300 digital polarimeter. Accurate mass measurement was
performed on Q STAR mass spectrometer (Applied Biosystems,
USA).
Hoffman’s explanation of the reduction of
a
-amino ketone16
(Fig. 3). Reduction with ZnBH4 in THF afforded the syn-alcohol 3 as
the major isomer in an 8:2 ratio, which can be explained by a Felkin
Anh model16 (Fig. 3). To obtain the C2 symmetric diol, we subjected
olefin 8 to dihydroxylation4i under Sharpless asymmetric condi-
tions13 with an AD Mix-b in t-BuOH/H2O (1:1) to afford the anti-diol
g
3
O
NHBoc
Ph
f
3 + 4
Ph
4.1. (S)-tert-Butyl 1-phenylbut-3-en-2-yl carbamate 7
NHBoc
h
4
To a stirred solution of oxalyl chloride (0.7 mL, 8.0 mmol) in dry
CH2Cl2 (5 mL) under nitrogen atmosphere, was added DMSO
(1.13 mL, 16 mmol) slowly at ꢁ78 °C and stirred for 30 min at
ꢁ78 °C. Alcohol 6 (1.0 g, 3.9 mmol) in dry CH2Cl2 (10 mL) was
added slowly over 10 min and stirred further for 2 h after which
Et3N (3.35 mL, 24.0 mmol) was added. The temperature was slowly
raised to room temperature over 20 min and the reaction mixture
was diluted with CH2Cl2 (50 mL). The organic layer was washed
with brine and water, and dried over anhydrous Na2SO4. The sol-
vent was removed on a rotary evaporator to give the aldehyde,
9
OH
NHBoc
NHBoc
Ph
Ph
i
Ph
Ph
NHBoc OH
NHBoc
8
5
Scheme 2. Reagents and conditions: (f) Dess–Martin periodinane, CH2Cl2, 0 °C to rt,
3 h, 80%; (g) ZnBH4, THF, 0 °C to rt, 5 h, 75%; (h) NaBH4, MeOH, 0 °C to rt, 3 h, 80%; (i)
AD mix-b, H2O/t-BuOH (1:1) 0 °C, 12 h, 85%.

E. Ramu, B. Venkateswara Rao / Tetrahedron: Asymmetry 20 (2009) 2201–2204
2203
which was used as such for the next reaction without any
purification.
1H). 7.1–7.4 (m, 10H); 13C NMR (100 MHz, CDCl3): d 28.26, 35.44,
39.67, 41.4, 47.94, 55.11, 69.24, 79.0, 79.95, 126.0, 126.56, 128.25,
128.51, 129.19, 129.51, 137.34, 138.12, 155.63, 157.1; ESIMS: 485
[M+1]+; HRMS: calcd for C28H40N2O5 [M+Na]+ 507.2834, found
507.2845.
To the stirred suspension of Zn (2.4 g, 36.10 mmol) in freshly
dried THF was added CH2I2 (1.61 mL, 20.0 mmol) at 25 °C. After
30 min of stirring, Ti (OiPr)4 (4.0 mL, 4.0 mmol, 1 M solution in
THF) was added and the resulting mixture was stirred at 25 °C
for 30 mins. A solution of aldehyde (1.0 g, 4.0 mmol) in THF
(10 mL) was added dropwise after being stirred for 1 h and the
reaction mixture was diluted with ether (20 mL), washed with
1 M HCl (2 ꢂ 20 mL), NaHCO3 (25 mL) and brine (25 mL), dried
over Na2SO4, filtered, concentrated in vacuo and purified by col-
umn chromatography (hexane/ethyl acetate, 4:1) to afford com-
pound 7 (0.48 g, 55% for two steps) as a white solid. Mp: 71–
4.4. tert-Butyl (2S,5S)-3-oxo-1,6-diphenylhexane-2,5-diyl
dicarbamate 9
To the stirred solution of alcohol mixtures 3 and 4 (0.2 g,
0.41 mmol) in CH2Cl2 (10 mL) at 0 °C was added Dess–Martin peri-
odinane (0.26 g, 0.61 mmol) and stirred for 3 h. The reaction mix-
ture was diluted with ether (20 mL) followed by washing with
saturated NaHCO3 solution (2 ꢂ 25 mL) and brine (2 ꢂ 25 mL).
The organic layer was dried over Na2SO4 and evaporated under re-
duced pressure. The crude product was purified by column chro-
matography using ethyl acetate/petroleum ether (2:8) to afford
the keto compound 9 (0.16 g, 80%) as a white solid. Mp: 145–
73 °C; ½a 2D5
ꢃ
¼ þ13:8 (c 0.5, CHCl3), {lit15
½
a 2D5
ꢃ
¼ 15:0 (c 0.6, CHCl3)};
IR m ;
max 3339, 3025, 2978, 1682, 1527, 1358, 1169, 1018, 692 cmꢁ1
1H NMR (CDCl3, 300 MHz) d .4 (s, 9H), 2.82 (m, 2H), 4.38 (br s, 2H),
5.08 (dd, J = 11.7, 17.3 Hz, 2H), 5.77 (m, 1H), 7.11–7.29 (m, 5H); 13C
NMR (50 MHz) in CDCl3: d 155.1, 137.9, 137.3, 129.4, 128.3, 126.3,
114.6, 79.2, 53.4, 41.3, 28.2; ESIMS: 248 (M++H).
148 °C; ½a 2D5
¼ þ15:5 (c 2.0, CHCl3); IR (KBr): mmax 3370, 3028,
ꢃ
2980, 1687, 1517, 1251, 1170, 700; 1H NMR (300 MHz, CDCl3): d
.4 (s, 18H), 2.45–3.0 (m, 6H), 4.05 (m, 1H), 5.03 (d, 1H), 7.05–
7.28 (m, 10H); ESIMS: 505 [M+Na]+; HRMS: calcd for C28H38N2O5
[M+Na]+ 505.2678, found 505.2671.
4.2. tert-Butyl (2S,5S,E)-1,6-diphenylhex-3-ene-2,5-diyl
dicarbamate 8
Olefin 7 (0.65 g, 2.63 mmol) was dissolved in dry CH2Cl2 (10 mL).
Grubbs’ second generation catalyst (0.22 g, 0.26 mmol) was added.
The reaction mixture was stirred at 40 °C for 14 h, then concen-
trated under reduced pressure and the residue was purified by
column chromatography using ethyl acetate: petroleum ether
(3:7) to afford the compound 8 (0.21 g, 87%) as a white solid. Mp:
4.5. Reduction with ZnBH4
4.5.1. tert-Butyl (2S,3S,5S)-3-hydroxy-1,6-diphenylhexane-2,5-
diyldicarbamate 3
To a stirred suspension of NaBH4 (0.018 g, 0.4 mmol) in dry THF
(15 mL) was added anhydrous ZnCl2 (0.035 g, 0.24 mmol) solution
in THF (3 mL) at 0 °C and stirred overnight. The solid in the reaction
mixture was allowed to settle for 4 h and the clear solution was
used for the reaction.
To a stirred solution of ketone 9 (0.1 g, 0.20 mmol) in dry THF
(2 mL) was added the above prepared Zn(BH4)2 (3 mL, mmol) solu-
tion at 0 °C and stirred for 5 h after which the reaction was
quenched with saturated solution of NH4Cl (2 mL). Next, THF was
removed under vacuum and the residue was extracted with ethyl
acetate (2 ꢂ 10 mL). The organic portion was separated, dried over
anhydrous Na2SO4 and concentrated. Silica gel column purification
(hexane/ethyl acetate 4:1) of the residue gave the syn alcohol 3
(50 mg, 60%) as the major isomer and the anti-isomer 4 (12 mg,
15%) in an 8:2 ratio as a white solid.
132–136 °C; ½a 2D5
¼ ꢁ12:3 (c 1.2, CHCl3); I.R mmax 3371, 3027,
ꢃ
2978, 1689, 1526, 1251, 1170, 700; 1H NMR (CDCl3, 200 MHz) d .4
(s, 18H), 2.76 (m, 4H), 4.31 (br s, 4H), 5.41 (br s, 2H), 7.0–7.28 (m,
10H); 13C NMR (75 MHz) in CDCl3: d 155, 137.3, 130.7, 129.6,
128.3, 126.4, 79.4, 52.7, 41.6, 28.3; ESIMS: 489 (M++Na); HRMS:
calcd for C28H38N2O4 [M+Na]+ 489.2729, found 489.2739.
4.3. tert-Butyl (2S,3S,5S)-3-hydroxy-1,6-diphenylhexane-2,5-
diyl dicarbamate 3 and tert-butyl (2S,3R,5S)-3-hydroxy-1,6-
diphenylhexane-2,5-diyl dicarbamate 4
To the solution of 8 (0.2 g, 0.42 mmol) in THF (5 ml), BH3.Me2S
(0.1 ml, 0.51 mmol) was added dropwise at ꢁ10 °C. Stirring was
continued for 8 h at room temperature. The reaction was quenched
by the addition of 10% NaOH (1 mL) followed by 30% H2O2 (2 mL) at
0 °C and then the reaction mixture was allowed to return to room
temperature, and stirring was continued for another 2 h. The reac-
tion mixture was extracted with ethyl acetate (2 ꢂ 50 mL) and
water (50 mL). The combined organic layers were washed with
brine, dried over Na2SO4 and concentrated under reduced pressure.
The crude product was purified by column chromatography using
ethyl acetate/petroleum ether (1:3) to afford compound 3 (0.12 g,
50%) as a white solid. Further elution with ethyl acetate/petroleum
ether (1:3) afforded compound 4 (0.035 g, 20%) as a white solid.
4.6. Reduction with NaBH4
4.6.1. tert-Butyl (2S,3R,5S)-3-hydroxy-1,6-diphenylhexane-2,5-
diyldicarbamate 4
To a stirred solution of ketone 9 (0.1 g, 0.41 mmol) in dry MeOH
(2 mL) was added NaBH4 at 0 °C and stirred for 3 h. Next, MeOH
was removed under vacuum and the residue was treated with sat-
urated aqueous solution of NH4Cl (2 mL) and extracted with ethyl
acetate (2 ꢂ 10 mL). The organic layer was separated, dried over
anhydrous Na2SO4 and concentrated. Silica gel column purification
(hexane/ethyl acetate 3:1) of the residue gave the anti-alcohol 4
(65 mg, 72%) as the major isomer and the syn-isomer (7 mg, 10%)
as a solid in a 9:1 ratio.
Compound 3: Mp: 192–196 °C; ½a D25
ꢃ
¼ ꢁ14:25 (c 1, CHCl3). IR
(KBr); mmax 3369, 2977, 1688, 1528, 1170, 700 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d 1.3–1.4 (s, 18H), 1.55–1.65 (m, 2H), 2.6–2.9
(m, 4H), 3.6–3.7 (m, 2H), 3.85 (m, 1H), 4.5 (br s, 1H), 4.8 (d, 1H).
7.05–7.4 (m, 10H); 13C NMR (75 MHz, CDCl3): d 28.35, 38.5,
39.76, 41.62, 50.12, 56.0, 69.97, 79.26, 79.6, 126.24, 126.44,
128.41, 129.34, 129.41, 137.58, 138.54, 155.93, 156.14; ESIMS:
485[M+1]+; HRMS: calcd for C28H40N2O5 [M+Na]+ 507.2834, found
4.6.2. tert-Butyl (2S,3S,4S,5S)-3,4-dihydroxy-1,6-
diphenylhexane-2,5-diyl dicarbamate 5
To a stirred solution of compound 8 (0.1 g, 1.63 mmol) in a 1:1
mixture of tBuOH and water (5 mL) was added Ad-mix-b (0.3 g) at
0 °C and stirred for 12 h. After completion of the reaction Na2SO3
(0.5 g) was added to the reaction mixture and extracted into ethyl
acetate (2 ꢂ 10 mL). The organic layer was separated, dried over
anhydrous Na2SO4 and the solvent was concentrated under re-
507.2838. Compound 4: Mp: 156–160 °C; ½a D25
¼ ꢁ11:2 (c 0.5,
ꢃ
CHCl3); IR (KBr): mmax 3309, 2976, 2930, 1665, 1535, 1275, 1168,
700 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.35 (s, 9H), 1.39 (s, 9H),
;
1.62 (m, 2H), 2.72–2.93 (m, 4H), 3.47 (m, 1H), 3.76 (m, 1H), 4.11
(m, 1H), 4.3 (br s, OH), 4.4 (d, J = 8.6 Hz, 1H), 4.55 (d, J = 9.45 Hz,

2204
E. Ramu, B. Venkateswara Rao / Tetrahedron: Asymmetry 20 (2009) 2201–2204
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Haight, A. R.; Scarpetti, D.; Allen, M. S.; Menzia, J. A.; Robbins, T. A.; Parekh, S. I.;
Langridge, D. C.; Tien, J.-H. J.; Pariza, R. J.; Kerdesky, F. A. J. J. Org. Chem. 1994, 59,
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A.; Sham, H. L.; Zhao, C.; Vasavanonda, S.; Kohlbrenner, W. E.; Wideburg, N. E.;
Saldivar, A.; Green, B. E.; Herrin, T.; Norbeck, D. W. Bioorg. Med. Chem. 1994, 2,
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Green, E. B.; McDonald, E.; Vasavanonda, S.; Saldivar, A.; Wideburg, E. N.; Kati,
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duced pressure. The crude product was purified by column chro-
matography using ethyl acetate/petroleum ether (2:8) to afford
diol compound 5 (0.70 g, 85%) as a white solid. Mp: 181–185 °C.
½
a 2D5
ꢃ
¼ ꢁ12:2 (c 0.5, CHCl3) {lit14b
½
a 2D5
ꢃ
¼ ꢁ13:4 (c 1.0, CH2Cl2}; IR
(KBr): mmax 3345, 2977, 1661, 1537, 1275, 1168, 1020; 1H NMR
(300 MHz, CDCl3): d 1.41 (s, 18H), 2.96 (dd, J = 4.5, 13.97 Hz, 2H),
3.15–3.25 (m, 4H), 4.03 (m, 2H), 4.39 (m, 4H), 7.15–7.3 (m, 10H);
13C NMR (75 MHz, CDCl3): d 28.3, 36.24, 50.68, 70.09, 80.22,
126.49, 128.58, 129.81, 137.0, 156.94; ESIMS: 523[M+Na]+; HRMS:
calcd for C28H40N2O6 [M+Na]+ 523.2784, found 523.2794.
Acknowledgements
5. Erickson, J. W.; Fesik, S. W. Annu. Rep. Med. Chem. 1992, 26, 271. and references
cited therein.
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D. W.; Plattner, J. J.; Rittenhouse, J. W.; Turon, M.; Wideburg, N.;
Kohlbrenner, W. E.; Simmer, R.; Helfrich, R.; Paul, D. A.; Knigge, M.
Science 1990, 249, 527.
E. Ramu thanks the CSIR-New Delhi for research fellowship. The
authors also thank Dr. J. S. Yadav, Dr. A. C. Kunwar and Dr. T. K.
Chakraborthy for their help and encouragement, and also thank
DST (SR/S1/OC-14/2007), New Delhi for financial support.
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