Synthesis of a chiral aziridine derivative as a versatile intermediate for HIV protease inhibitors.

Article abstract of DOI:10.1021/ol016147s

[reaction: see text] Chiral aziridine derivative 1 was prepared from D-tartaric acid. This compound could be utilized as a common intermediate for the synthesis of hydroxyethylamine class HIV protease inhibitors such as saquinavir, amprenavir, or nelfinavir.

Full text of DOI:10.1021/ol016147s

ORGANIC
LETTERS
2001
Vol. 3, No. 15
2349-2351
Synthesis of a Chiral Aziridine
Derivative as a Versatile Intermediate for
HIV Protease Inhibitors
,†
B. Moon Kim,* Sung Jin Bae,† Soon Mog So,† Hyun Tae Yoo,† Sun Ki Chang,‡
Jung Hwan Lee,‡ and JaeSung Kang‡
Center for Molecular Catalysis, School of Chemistry & Molecular Engineering,
Seoul National UniVersity, Seoul, 151-747, Korea, and Samchully Pharmaceutical Co.,
Ltd., Seoul, 135-280, Korea
kimbm@snu.ac.kr
Received May 21, 2001
ABSTRACT
Chiral aziridine derivative 1 was prepared from D-tartaric acid. This compound could be utilized as a common intermediate for the synthesis
of hydroxyethylamine class HIV protease inhibitors such as saquinavir, amprenavir, or nelfinavir.
Inhibitors of human immunodeficiency virus protease (HIV
PR) have been developed as one of the most promising
chemotherapeutic agents for the treatment of acquired
immune deficiency syndrome (AIDS).1,2 The HIV PR inhibi-
tors often exhibit complex structures equipped with multiple
stereogenic centers. Thus, development of an efficient and
practical synthetic route for these inhibitors presents a
challenge for synthetic organic chemists. HIV PR inhibitors
such as saquinavir (4),3 amprenavir (5),4 and nelfinavir (6)5
all belong to the hydroxyethylamine (HEA) class of inhibi-
tors,6 and there are many reports on the synthesis of this
class of inhibitors.7 However, general synthetic methodolo-
gies that provide access to a common intermediate for all
three of the inhibitors are rare, since most of the HEA
inhibitors are derived from phenylalanine derivatives, af-
fording access to 4 and 5 only. The thiophenyl moiety in 6
has to be introduced from sources other than the phenyl-
alanine derivative.7g,j,k We envisioned that if one had access
(5) Kaldor, S. W.; Kalish, V. J.; Davies, J. F.; II; Shetty, B. V.; Fritz, J.
E.; Appelt, K.; Burgess, J. A.; Campanale, K. M.; Chirgadze, N. Y.;
Clawson, D. K.; Dressman, B. A.; Hatch, S. D.; Khalil, D. A.; Kosa, M.
B.; Lubbehusen, P. P.; Muesing, M. A.; Patick, A. K.; Reich, S. H.; Su, K.
S.; Tatlock, J. H. J. Med. Chem. 1997, 40, 3979.
(6) For the definition and various structures of HIV PR transition state
isosteres, see ref 2.
(7) (a) Ghosh, A. K.; McKee, S. P.; Lee, H. Y.; Thompson, W. J. Chem.
Commun. 1993, 273. (b) Parkes, K. E. B.; Bushnell, D. J.; Cracjeff, P. H.;
Dunsdon, S. J. Freeman, A. C.; Gunn, M. P.; Popkins, R. A.; Lambert, R.
W.; Thomas, G. J. J. Org. Chem. 1994, 59, 3656. (c) Gurjar, M. K.; Devi,
N. R. Tetrahedron: Asymmetry 1994, 5, 755-758. (d) Beaulieu, P. L.;
Wernic, D. J. Org. Chem. 1996, 61, 3635-3645. (e) Shibata, N.; Katoh,
T.; Terashima, S. Tetrahedron Lett. 1997, 38, 619. (f) Beaulieu, P. L.;
Lavalle´e, P.; Abraham, A.; Anderson, P. C.; Boucher, C.; Bousquet, Y.;
Duceppe, J.-S.; Gillard, J.; Gorys, V.; Grand-Maˆıtre, C.; Grenier, L.;
Guindon, Y.; Guse, I.; Plamondon, L.; Soucy, F.; Valois, S.; Wernic, D.;
Yoakim, C. J. Org. Chem. 1997, 62, 3440-3448. (g) Rieger, D. L. J. Org.
Chem. 1997, 62, 8546-8548. (h) Ghosh, A. K.; Fidanz, S. J. Org. Chem.
1998, 63, 6146-6152. (i) Corey, E. J.; Zhang, F.-Y. Angew. Chem., Int.
Ed. 1999, 38, 1931. (j) Inaba, T.; Yamada, Y.; Abe, H.; Sagawa, S.; Cho,
H. J. Org. Chem. 2000, 65, 1623-1628. (k) Zook, S. E.; Busse, J. K.;
Borer, B. C. Tetrahdron Lett. 2000, 41, 7017.
† Seoul National University.
‡ Samchully Pharmaceutical Co., Ltd.
(1) Flexner, C. New Engl. J. Med. 1998, 338, 1281-1292.
(2) For reviews on the development of HIV PR inhibitors, see: (a) Huff,
J. R. J. Med. Chem. 1991, 34, 2305. (b) Meek, T. D. J. Enzymol. Inhib.
1992, 5, 65. (c) Wlodwer, A.; Erickson, J. W. Annu. ReV. Biochem. 1993,
543. (d) Martin, J. A. AntiViral Res. 1992, 17, 265. (e) Tomasselli, A. G.;
Heinrikson, R. L. Biochim. Biophys. Acta 2000, 189-214.
(3) Roberts, N. A.; Martin, J. A.; Kinchington, D.; Broadhurst, A. V.;
Craig, J. C.; Duncan, I. B.; Galphin, S. A.; Handa, B. K.; Krohn, A.;
Lambert, R. W.; Merrett, J. H.; Mills, J. S.; Parkes, K. E. B.; Redshaw, S.;
Ritchie, A. J.; Taylor, D. L.; Thomas, G. J.; Machin, P. J. Science 1990,
248, 358.
(4) Kim, E. E.; Baker, C. T.; Dwyer, M. D.; Murcko, M. A.; Rao, B.
G.; Tung, R. D.; Navia, M. A. J. Am. Chem. Soc. 1995, 117, 1181-1182.
10.1021/ol016147s CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/29/2001

to a 1,4-dielectrophilic chiron (A) as shown in Figure 1, a
common synthetic intermediate could be obtained. The two
terminal electrophilic sites of structure A should of course
Scheme 1a
a (a) (i) SOCl2, MeOH; (ii) 2,2-dimethoxypropane, p-TsOH,
dichloromethane or 2,2-dimethoxypropane, p-TsOH, benzene,
MeOH, azeotropic removal of water; (b) NaBH4, MeOH; (c)
methanesulfonyl chloride, LiCl, Et3N, CH3CN, 55 °C; (d) SOCl2,
CCl4 then RuCl3(3H2O), NaIO4, CCl4-CH3CN-H2O or SO2Cl2,
imidazole, CH2Cl2; (e) potassium phthalimide, DMF; (f) (i)
NH2NH2, EtOH; (ii) (Boc)2O, aqueous NaOH; (g) for 13a, TBSCl,
imidazole, DMF; for 13b, dihydropyran, catalytic p-TsOH‚H2O,
CH2Cl2; (h) NaH, THF.
Figure 1.
be distinguishable, and we expected that this could be
accomplished through introduction of an aziridine and an
epoxide functionality sequentially from the corresponding
1,4-dielectrophile. Herein we report on the efficient synthesis
of the new chiral aziridine derivative (1), which could be
utilized as a versatile core intermediate for the preparation
of diverse HEA class HIV protease inhibitors.
2(S),3(S)-butanediol 9 was accomplished through treatment
with triethylamine, lithium chloride, and methanesulfonyl
chloride in acetonitrile (50% yield).
With dichlorodiol 9 in hand, 1,4-dichlorobutane-2(S),3-
(S)-diol sulfate was prepared either from a two-step se-
quence12 involving thionyl chloride in chloroform followed
by oxidation using ruthenium chloride and sodium periodate
in ∼95% yield or from sulfuryl chloride5b with imidazole
as a base in carbon tetrachloride (∼80-85% yield). As we
had reported earlier,8 the former two-step method gave higher
yields (∼93%) of the desired product. Though opening of
this cyclic sulfate with LiN3 proceeded smoothly,8 a safer
alternative was sought for a possibly large scale operation,
and the use of potassium phthalimide was found to be quite
efficient for this purpose. Thus, the cyclic sulfate of
4-dichloro-2(S),3(S)-butanediol was treated with potassium
phthalimide in DMF to provide N-[1,4-dichloro-2(S)-hy-
droxy-3(R)-butyl]phthalimide (11) in quantitative yield.
Deprotection of the phthalimide group was accomplished by
treating 11 with 80% hydrazine monohydrate in 2-propanol
followed by treatment with methanolic HCl, and the resulting
free amine was converted to 2(R)-((tert-butyloxycarbonyl)-
amino)-1,4-dichloro-3(S)-hydroxybutane (12) upon reaction
with (Boc)2O in the presence of triethylamine in THF (75%
from 11). Reaction of 12 with either tert-butyldimethyl-
chlorosilane or dihydropyran provided the protected amino
alcohol 13a or 13b, respectively.13 The desired aziridine
functionality was installed from 13 upon reaction with
sodium hydride in THF in an almost quantitative yield.
We previously reported the preparation of 3(R)-(N-(tert-
butyloxycarbonyl)amino)-2(S)-hydroxy-1,4-dichlorobutane (12)
through efficient desymmetrization of 1,4-dichloro-2(S),3-
(S)-hydroxybutane cyclic sulfate (10).8 This four-carbon
chiron with a 2,3-anti-aminohydroxy and 1,4-dielectrophile
arrangement could be utilized for the synthesis of the
common intermediate 1 for HIV PR inhibitors. Although the
cyclic sulfate 10 could be derived from diol 9, which was
prepared from asymmetric dihydroxylation of 1,4-dichloro-
trans-2-butene,9 we searched for more economical ways to
generate the diol. Toward this goal, D-tartaric acid was a
very convenient and economical solution. Scheme 1 outlines
the preparation of chiral aziridine 1 from D-tartaric acid.10
D-Tartaric acid was converted to acetonide diester 7 in an
almost quantitative yield through either a two-step method
involving conversion to dimethyl ester followed by acetonide
formation or in one-step using 2,2-dimethoxypropane in the
presence of p-toluenesulfonic acid.11 Reduction of 7 using
NaBH4 in methanol produced 2,3-O-isopropylidene-D-threitol
8 in 85% yield. A one-pot conversion of 8 to 1,4-dichloro-
(8) Kim, B. M.; Bae, S. J.; Seomoon, G. Tetrahedron Lett. 1998, 39,
6321.
(9) (a) Vanhessche, K. P. M.; Wang, Z. M.; Sharpless, K. B. Tetrahedron
Lett. 1994, 35, 3469. (b) Vanhessche, K. P. M.; Sharpless, K. B. Chem.
Eur. J. 1997, 3, 517.
1
(10) All compounds showed satisfactory H and 13C and/or IR spectro-
scopic data and/or mass values.
(11) Mash, E. A.; Nelson, K. A.; Van Deusen, S.; Hemperly, S. B.
Organic Syntheses; Wiley: New York, 1993; Collect. Vol. VIII, pp 155-
156.
(12) (a) Yun, G.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538.
(b) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1989, 30, 655. (c) Lohray,
B. B.; Sharpless, K. B. Tetrahedron Lett. 1989, 30, 2623.
2350
Org. Lett., Vol. 3, No. 15, 2001

With the chiral aziridine 1 in hand, we investigated
opening of the aziridine moiety with the proper alkyl or
thioaryl group. Opening of an aziridine functionality with
lithium dialkylcuprates has been documented,14 and reaction
of 1a or 1b with lithium diphenylcuprate proceeded smoothly
to the corresponding ring-opened product 14a or 14b,
respectively, in about 75% yield, which could be used as a
precursor for the synthesis of amprenavir and saquinavir (eq
1). To obtain an intermediate for nelfinavir, opening of the
Scheme 2a
a (a) TBAF, THF; (b) i-BuNH2, i-PrOH; (c) p-nitrobenzene-
sulfonyl chloride, Et3N, CH2Cl2; (d) (i) HCl(g), CH2Cl2; (ii) 19,
Et3N, CH2Cl2; (e) SnCl2‚2H2O, EtOAc.
aizirdine with thiophenoxide was also carried out to provide
phenyl sulfide 15a in 82% yield.
With proper installation of the necessary residues at the
R′ position of compounds 14 and 15, we carried out a
synthesis of a complete HIV PR inhibitor taking Amprenavir
as a target molecule as depicted in Scheme 2. Deprotection
of the protecting group of 14a or 14b and concomitant
epoxide ring formation was accomplished through the use
of tetrabutylammonium fluoride (TBAF) or p-TsOH‚H2O
followed by KOH/MeOH, respectively, and the epoxide 16
was obtained in good yield. Opening of the epoxide with
isobutylamine (90% yield) followed by reaction with p-
nitrobenznesulfonyl chloride provided 18 in 88% yield.
Removal of the Boc protecting group followed by treatment
with N-hydroxysuccinimidyl carbonate of 3(S)-hydroxytet-
rahydrofuran (19) furnished 20 in 85% yield. Reduction of
the nitro group of 20 to the corresponding amino group using
SnCl2‚2H2O (90% yield) completed the synthesis to furnish
amprenavir.
In summary, an efficient synthetic method was devised
to prepare the chiral aziridine derivative 1, a versatile
synthetic intermediate for the synthesis of HEA class HIV
PR inhibitors. Through opening of the aziridine ring with
either carbon or sulfur nucleophiles, this intermediate could
be used for the synthesis of intermediates for either saquinavir
and amprenavir or nelfinavir. Investigation of the aziridine-
opening reaction with a variety of other carbon and hetero-
atom nucleophiles for the preparation of important synthetic
intermediates for other biologically active compounds is in
progress.
Acknowledgment. We thank Samchully Pharmaceutical
Co., Inc. ,for generous financial support. S.J.B. and S.M.S.
thank the Ministry of Education, Republic of Korea, for their
BK 21 fellowship.
(13) Protection of the alcohol of 12 as the tetrahydropyranyl (THP) ether
13b provided a more economical reaction sequence. Using this protocol,
up to 30 mol scale reactions have been carried out to provide epoxide 16
in ∼30% overall yield from D-tartaric acid.
Supporting Information Available: Experimental pro-
cedure and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(14) Kozikowski, A. P.; Ishida, H.; Isobe, K. J. Org. Chem. 1979, 44,
2788.
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