Application of the asymmetric aminohydroxylation reaction for the syntheses of HIV-protease inhibitor, hydroxyethylene dipeptide isostere and γ-amino acid derivative

Article abstract of DOI:10.1016/j.tetlet.2004.05.057

An enantioselective synthesis of lactone 1, a precursor to the (2R,4S,5S) hydroxyethylene dipeptide isostere and amino acid AHPPA 2 has been accomplished from the common intermediate 5 employing Sharpless asymmetric aminohydroxylation as the key step.

Full text of DOI:10.1016/j.tetlet.2004.05.057

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5477–5479
Application of the asymmetric aminohydroxylation reaction for the
syntheses of HIV-protease inhibitor, hydroxyethylene dipeptide
isostere and c-amino acid derivative
Nagendra B. Kondekar, Subba Rao V. Kandula and Pradeep Kumar*
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India
Received 1 April 2004;revised 30 April 2004;accepted 7 May 2004
Abstract—An enantioselective synthesis of lactone 1, a precursor to the (2R,4S,5S) hydroxyethylene dipeptide isostere and amino
acid AHPPA 2 has been accomplished from the common intermediate 5 employing Sharpless asymmetric aminohydroxylation as
the key step.
Ó 2004 Elsevier Ltd. All rights reserved.
The last two decades have witnessed a considerable
upsurge of interest in the use of enzyme inhibitors as
therapeutic agents.1 The advent of acquired immuno-
deficiency syndrome (AIDS) and the discovery of its
causative agent, human immunodeficiency virus (HIV-
1),2 has given an impetus to the development of efficient
inhibitors of viral enzymes, in particular of the trans-
criptase and more recently of the proteinase (HIV-PR).3
inhibitor, pepstatin.6 AHPPA has also been employed
for the design of HIV protease inhibitors.7 While the
majority of the earlier syntheses of isosteres and AH-
PPA use optically active amino acids as chiral pool
material,8;9 reports in which all the stereogenic centres
are constructed by asymmetric synthesis are rather
scarce.10 As part of our research programme aimed at
developing enantioselective syntheses of naturally
occurring amino alcohols,11 the Sharpless asymmetric
aminohydroxylation (AA)12 was envisioned as a pow-
erful tool, offering considerable opportunities for syn-
thetic manipulations. We have now developed a new
and enantioselective synthesis of lactone 1 and AHPPA
2 utilising Sharpless asymmetric aminohydroxylation as
the key step (Fig. 1).
Consequently numerous potent and selective HIV pro-
tease inhibitors have been designed based upon the
transition state mimetic concept, incorporating
hydroxyethylene and hydroxyethylamine dipeptide
isosteres as the scissile site.4 In view of this, a highly
enantioselective synthesis of the isostere unit is still
desirable.
The development of new approaches to the stereo con-
trolled synthesis of c-amino b-hydroxy acids has been a
subject of immense interest within the context of bio-
logically active peptide mimics.5 The two well known
examples are AHPPA (4-amino-3-hydroxy-5-phenyl-
pentanoic acid) 2 and statin. They are the key constit-
uents of microbially produced aspartic peptidase
Ph
OH
H
N
H
N
O
O
Ph
Hydroxyethylene Phe-Phe isostere
O
NH2
Ph
O
Ph
COOH
BocHN
Ph
OH
NHCOCH3
2
1
Keywords: HIV-protease inhibitor;Hydroxyethylene dipeptide iso-
stere; c-Amino acid derivative;Sharpless asymmetric aminohydroxy-
lation.
Ph
COOEt
OH
5
* Corresponding author. Tel.: +91-20-25893300x2050;fax: +91-20-
25893614;e-mail: tripathi@dalton.ncl.res.in
Figure 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.057

5478
N. B. Kondekar et al. / Tetrahedron Letters 45 (2004) 5477–5479
NHCOCH3
i
iii
ii
COOEt
Ph
Ph
Ph
CHO
COOEt
Ph
iv
5
3
4
OH
N
COOEt
Ph
Ph
COOMe
NHBoc
v
COOMe
O
8
N
O
7
6
Boc
OH
Boc
O
COOEt
vii
O
Ph
vi
viii
Ph
O
O
N
O
BocHN
BocHN
9
Boc
1
10
Ph
Ph
Scheme 1. Reagents and conditions: (i) Ph3P@CHCO2Et, THF, 0 °C to rt, 85%;(ii) (DHQ) 2PHAL, K2[OsO2(OH)2], LiOH, N-bromoacetamide,
t-butanol–H2O (1:1), 0 °C to rt, 64%;(iii) 0.5 M HCl in MeOH, reflux, then Boc 2O, Et3N, DCM, 0 °C to rt, 87%;(iv) 2,2-DMP, p-TSA, DCM, rt,
89%;(v) (a) DIBAL-H, DCM, )78 °C to rt, 76%, (b) Ph3P@CHCO2Et, THF, 0 °C to rt, 60%;(vi) H 2, 10% Pd–C, EtOAc–MeOH, 90%;(vii) AcOH,
PhMe, reflux;67%;(viii) LiHMDS, BnBr, THF, )78 °C, 79%.
The synthesis (Scheme 1) of lactone 1 started from
phenyl acetaldehyde 3, a readily available starting
material. Thus, treatment of 3 with (ethoxycarbonyl-
methylene)triphenylphosphorane in THF under reflux
gave the Wittig product 4 in 85% yield. In the next,
Sharpless aminohydroxylation step, it was envisioned
that N-bromoacetamide would be the best nitrogen
source of all those available at present12b for an easy
chromatographic separation of the product and sub-
sequent synthetic manipulation. Thus the asymmetric
amino hydroxylation of the olefin 4 with potassium
osmate (4 mol %) as oxidant in tert-butanol–water (1:1)
in the presence of (DHQ)2PHAL (5 mol %) as chiral
ligand and freshly prepared N-bromoacetamide13 as the
nitrogen source, afforded the desired amino alcohol 514
amine with concomitant transesterification to the methyl
ester. The successive conversion of amine into the Boc
protected amino alcohol 6 followed by further protec-
tion as acetonide using 2,2-dimethoxypropane in the
presence of a catalytic amount of p-toluenesulfonic acid
afforded 7 in 89% yield. Reduction with DIBAL-H to
the corresponding aldehyde and subsequent Wittig
reaction with (ethoxycarbonylmethylene)triphenylphos-
phorane afforded the olefin 8 in good yield. The olefin
reduction by hydrogenation using 10% Pd–C gave 9 in
90% yield, which on acetonide deprotection using acetic
acid followed by reflux in toluene underwent smooth
lactonisation to furnish 10 in 67% yield. The lactone 10
was alkylated with benzyl bromide using LiHMDS as a
base to furnish the desired compound 1 in excellent
20
20
in 10:1 regioisomeric ratio and 64% yield with 89% ee,
yield, ½aŠ )41.7 (c 0.32, CHCl3), lit.8b ½aŠ )40.0
D
D
20
D
½aŠ )56.08 (c 0.8, CHCl3).15
(c 0.10, CHCl3) along with a small amount (5%) of cis-
alkylated product. This step completes the formal syn-
thesis of the isostere since transformation of 1 to the
isostere has been reported previously.8b
Further, in order to achieve the synthesis of target
compound 1 from 5, we required a suitable amino
protecting group for further synthetic manipulation. To
this end the amide 5 was subjected to hydrolysis using
0.5 M HCl in methanol under reflux to furnish free
Scheme 2 summarises the synthesis of (3S,4S)-4-amino-
3-hydroxy-5-phenylpentanoic acid (AHPPA) from the
NH2
NHCOCH3
COOEt
NBn2
i
Ph
Ph
vii
COOMe
iii
ii
Ph
COOMe
Ph
11
14
5
OH
NBn2
12
OBn
OH
NBn2
O
NBn2
N2
Ph
COOH
v
iv
Ph
COOH
13
OBn
OBn
15
OBn
O
NH2
HN
vi
Ph
Ph
COOH
2
OH
16
OH
Scheme 2. Reagents and conditions: (i) 0.5 M HCl in MeOH, reflux, 87%;(ii) BnBr, K 2CO3, DCM, 91%;(iii) LiOH, MeOH–H 2O (3:1), 76%;
(iv) Et3N, ClCO2Et, THF, CH2N2, 50%;(v) Ag 2O, THF–H2O, 60%;(vi) H 2, 10% Pd–C, EtOAc, rt, 85%;(vii) concd HCl, 80 °C, 73%.

N. B. Kondekar et al. / Tetrahedron Letters 45 (2004) 5477–5479
5479
6. (a) Umezawa, H.;Aoyagi, T.;Morishima, H.;Matsuzaki,
common intermediate 5. The cleavage of the N-acetyl
group of 5 to the free amine was accomplished using
0.5 M HCl in methanol under reflux with concomitant
transesterification to afford 11 in excellent yield. N- and
O-benzylation of 11 was followed by base hydrolysis of
the ester to the corresponding acid 13 in good yield. For
one carbon homologation of the acid 13 to 15, we at-
tempted the following sequence. Acid 13 was first con-
verted into a mixed anhydride and subsequently treated
with excess of diazomethane to furnish the diazo com-
pound 1416 in moderate yield. Further treatment with
silver oxide resulted in the desired acid 15 via Wolff
rearrangement. Debenzylation of 15 led to the forma-
tion of the lactam 16, which on ring opening with
concd HCl furnished the target compound 2 in 73%
M.;Hamada, M.;Takeuchi, T. J. Antibiot. 1970, 23, 259–
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Yamazaki, Y.;Masuma, R.;Takahashi, Y.;Tanaka, H.;
Huang, L.;Woodruff, H. J. Antibiot. 1986, 39, 1079–1092.
7. Moore, M. L.;Bryan, W. M.;Fakhury, S. A.;Magaard,
V. W.;Huffan, W. F.;Dayton, B. D.;Meek, T. K.;
Hyland, L. J.;Dreyer, G. B.;Metcalf, B. W.;Gorniak, J.
G.;Debouck, C. Biochem. Biophys. Res. Commun. 1989,
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9. (a) Reetz, M. T.;Drewes, M. W.;Matthews, B. R.;
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20
20
yield {½aŠ )22.3 (c 0.36, H2O), lit.17 ½aŠ )24.0 (c 0.44,
D
D
H2O)}. The physical and spectroscopic data were in full
agreement with the literature.17
10. Evans, D. A.;Bartroli, J.;Shih, T. L. J. Am. Chem. Soc.
1981, 103, 2127–2129.
In conclusion, enantioselective syntheses of lactone 1
and AHPPA 2 have been accomplished from a common
intermediate 5 for the first time utilising Sharpless cat-
alytic aminohydroxylation as the key step. A short
reaction sequence and high overall yield of the target
compounds render our strategy a good alternative to the
known methods.
11. (a) Fernandes, R. A.;Kumar, P. Tetrahedron: Asymmetry
1999, 10, 4797–4802;(b) Fernandes, R. A.;Kumar, P. Eur.
J. Org. Chem. 2000, 3447–3449;(c) Fernandes, R. A.;
Kumar, P. Tetrahedron Lett. 2000, 41, 10309–10312;(d)
Pandey, R. K.;Fernandes, R. A.;Kumar, P. Tetrahedron
Lett. 2002, 43, 4425–4426;(e) Naidu, S. V.;Kumar, P.
Tetrahedron Lett. 2003, 44, 1035–1037;(f) Kandula, S. V.;
Kumar, P. Tetrahedron Lett. 2003, 44, 1957–1958;(g)
Gupta, P.;Fernandes, R. A.;Kumar, P. Tetrahedron Lett.
2003, 44, 4231–4232;(h) Pandey, R. K.;Upadhyay, P. K.;
Kumar, P. Tetrahedron Lett. 2003, 44, 6245–6246.
12. (a) Li, G.;Chang, H. T.;Sharpless, K. B. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 451–454;For a review on the
Sharpless asymmetric aminohydroxylation, see: (b)
Bodkin, J. A.;McLeod, M. D. J. Chem. Soc., Perkin
Trans. 1 2002, 2733–2746.
Acknowledgements
N.B.K. and S.V.K. thank CSIR, New Delhi for research
fellowships. We are grateful to Dr. M. K Gurjar, Head,
Organic Chemistry: Technology Division for his support
and encouragement. This is NCL communication No
6662.
13. Oliveto, E. P.;Gerold, C. Org. Synth. Coll. Vol. IV, 1963,
104.
14. During the column purification of 5, the corresponding
dihydroxy compound (12%) was also isolated as side
product.
1
15. The regioisomeric ratio of 5 was determined based on H
NMR spectra and the enantiomeric excess (ee) was
calculated using Mosher analysis by converting ester 7
into the the corresponding alcohol and then derivatising it
References and notes
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20
D
3390–3360, 2983, 2361, 1738, 1657; H NMR (500 MHz,
data 5: ½aŠ )56.08 (c 0.8, CHCl3) IR (CHCl3, cmÀ1):
1
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CDCl3): d 1.26–1.28 (t, J ¼ 7:2 Hz, 3H), 2.12 (s, 3H), 2.85–
2.97 (m, 2H), 4.17–4.22 (q, J ¼ 6:8 Hz, 2H), 4.35–4.39 (m,
1H), 4.72–4.74 (dd, J ¼ 9:1, J ¼ 1:9 Hz, 1H), 6.48–6.50 (d,
J ¼ 9:1 Hz, 1H), 7.22–7.34 (m, 5H), 13C NMR (50 MHz,
CDCl3): d 14.01, 22.89, 37.87, 40.44, 52.83, 55.88, 61.56,
62.05, 72.73, 126.69, 128.49, 137.28, 170.94. GC–MS: 266
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20
16. Spectral data 14: ½aŠ )2.87 (c 1.60, CHCl3) IR (neat,
D
cmÀ1): 2964, 2361, 2106, 1813, 1749, 1680; 1H NMR
(500 MHz, CDCl3): d 2.9–3.04 (t, J ¼ 11:5 Hz, 1H), 3.20–
3.26 (m, 1H), 3.57–3.59 (d, J ¼ 12:8 Hz, 2H), 4.13–4.16 (d,
J ¼ 13:3 Hz, 2H), 4.22–4.31 (m, 2H), 4.74–4.77 (m, 2H),
5.36 (s, 1H), 7.2–7.44 (m, 20H); 13C NMR (125 MHz,
CDCl3): d 14.24, 55.17, 64.67, 126.53, 127.09, 128.13,
128.56, 128.68, 128.82, 128.99, 129.25, 139.88;GC–MS:
490 (M+1).
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