HIV-1 protease inhibitors based on acyclic carbohydrates

Article abstract of DOI:10.1021/jo971562c

A series of acyclic C₂-symmetric HIV protease inhibitors readily accessible from D-mannitol have been developed. Several of the compounds synthesized showed significant in vitro activity against HIV-1 protease.

Full text of DOI:10.1021/jo971562c

4898
J . Org. Chem. 1998, 63, 4898-4906
HIV-1 P r otea se In h ibitor s Ba sed on Acyclic Ca r boh yd r a tes
Guido Zuccarello,† Abderrahim Bouzide,† Ingemar Kvarnstro¨m,† Gunilla Niklasson,†
Stefan C. T. Svensson,† Magnus Brisander,† Helena Danielsson,‡ Ulrika Nillroth,‡
Anders Karle´n,∇ Anders Hallberg,∇ Bjo¨rn Classon,§ and Bertil Samuelsson*,§
Department of Chemistry, Linko¨ping University, S-581 83 Linko¨ping, Sweden, Departments
of Biochemistry and Organic Pharmaceutical Chemistry, Uppsala University, BMC,
S-751 23 Uppsala, Sweden, and Department of Organic Chemistry, Arrhenius Laboratory,
Stockholm University, S-106 91 Stockholm, Sweden
Received August 21, 1997
A series of acyclic C2-symmetric HIV protease inhibitors readily accessible from D-mannitol have
been developed. Several of the compounds synthesized showed significant in vitro activity against
HIV-1 protease.
Ch a r t 1. F DA-Ap p r oved HIV-1 P r In h ibitor s
In tr od u ction
Human immunodeficiency virus (HIV), the etiologic
agent of acquired immune deficiency syndrome (AIDS),
is spreading at an alarming rate.1 Progress in the
treatment of AIDS leading to an effective therapy has
been slow, but recent results with new AIDS drugs,
notably the HIV-1 protease inhibitors, allow for cautious
optimism.2
The HIV-1 protease (PR) is a virally encoded ho-
modimeric aspartyl protease3 responsible for the process-
ing of the gag and gag/pol gene products which enables
the proper organization of core structural proteins and
the release of viral enzymes. Inhibition of HIV PR leads
to the production of immature, noninfectious viral par-
ticles.4 There are today four HIV-1 protease inhibitors
approved by the U.S. FDA for the treatment of AIDS:
Roche’s saquinavir (1), Abbott’s ritonavir (2), Merck’s
indinavir (3), and Agouron’s nelfinavir (Chart 1).
* Additional for correspondence: Astra Ha¨ssle AB, S-431 83 Mo¨ln-
dal, Sweden.
† Linko¨ping University.
‡ Department of Biochemistry, Uppsala University.
∇ Department of Organic Pharmaceutical Chemistry, Uppsala Uni-
versity.
§ Stockholm University.
(1) (a) Barre-Sinoussi, F.; Chermann, J .-C.; Rey, F.; Nugeyre, M.
T.; Chemaret, S.; Gruest, J .; Dauguet, C.; Axler-Blin, C.; Brun-Vezinet,
F.; Rouzioux, C.; Rozenbaum, W.; Montagnier, L. Science 1983, 220,
868-871. (b) Popovic, M.; Sarngadharan, M. G.; Read, E.; Gallo, R. C.
Science 1984, 224, 497-500. (c) Gallo, R. C.; Salahuddin, S. Z.; Popovic,
M.; Shearer, G. M.; Kaplan, M.; Haynes, B. F.; Plaker, T. J .; Redfield,
R.; Oleske, J .; Safai, B.; White, G.; Foster, P.; Markham, P. D. Science
1984, 224, 500-503. (d) Gallo, R. C.; Montagnier, L. Sci. Am. 1988,
259 (4), 25-32. (e) Greene, W. C. Sci. Am. 1993, ISBN 0-7167-2547-9.
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1996, 271, 755-756.
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63, 2550-2556.
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Moss, B.; Sawyer, T. K.; Heinrikson, R. L.; Tarpley, W. G. Science 1990,
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Invest. Drug 1996, 5, 153. (b) De Clercq, E. J . Med. Chem. 1995, 38,
2491-2517. (c) Redshaw, S. Exp. Opin. Invest. Drug 1994, 3, 273-
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Huff, J . R. J . Med. Chem. 1991, 34, 2305-2314.
A number of reports on the design and synthesis of HIV
PR inhibitors have been published.5 In general in these
inhibitors, the scissile bond has been replaced by a
nonhydrolyzable transition-state isostere. Unfortunately,
most of these peptidomimetic HIV PR inhibitors retain
a substantial amount of peptide character, and as a
result, their oral bioavailability is low and a short plasma
half-life is observed.6 In addition, it has been demon-
S0022-3263(97)01562-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/07/1998

Acyclic Carbohydrate HIV PR Inhibitors
J . Org. Chem., Vol. 63, No. 15, 1998 4899
Ch a r t 2. Str u ctu r es of Com p ou n d s 4 a n d 5
strated in clinical trials that doses in excess of 1 g daily
are necessary to suppress viral replication7 and that
selection of resistance due to multiple mutations in the
HIV PR genome takes place as a result of exposure to
HIV PR inhibitors.8 Results from combination therapies
involving HIV PR inhibitors as one component are now
beginning to emerge showing promising results.9
There is today a need for the development of new
generations of HIV PR inhibitors with high potency, with
improved oral bioavailability, and with reduced selection
for resistance. The high cost of HIV-1 therapy has also
emphasized the importance of chemically readily acces-
sible inhibitors.
Sch em e 1. Syn th esis of Com p ou n d 10a (R ) P h )
The carbohydrates are a diverse, chiral pool of natural
compounds. They are in general inexpensive and have
thus frequently been used as starting materials. In the
design and synthesis of new types of peptidomimetic
HIV-1 protease inhibitors, we have developed acyclic
carbohydrate alditol-based transition-state mimetics as
replacements for the scissile dipeptide bond of the
substrate. The carbohydrate alditol serves as a struc-
tural matrix for placing the appropriate side chains in
the appropriate spatial positions, with the backbone
chirality selected to provide the spatial topology of the
desired isostere. Several reports have described the use
of commercially available and inexpensive D-mannitol for
the convenient synthesis of potent acyclic HIV-1 protease
inhibitors.10 Hirschmann has earlier reported on the
development of a cyclic glucose derivative as a soma-
tostatin peptidomimetic.11
Researchers at Abbott have previously reported on the
elegant design of symmetric acyclic inhibitors that capi-
talize on the unique C2 symmetry of the dimeric HIV
PR.12 In this paper we have used D-mannitol to synthe-
size a series of compounds of the general structure 4
(Chart 2) with the 3R,4R, 3R,4S and 3S,4S chirality of
the central diols that have been evaluated in antiviral
assays and whose structure-activity relationships (SAR)
have been compared with that of the related Abbott
compound 5. In addition, we have also synthesized the
3S,4-deoxy and 3R,4-deoxy analogues of 4 and the
unsymmetrical 1-phenoxy-6-phenyl diol-related to both
structures 4 and 5. The comparative ease by which
different aryl and to some extent alkyl groups corre-
sponding to the P1/P1′ substituents of the carbohydrate
alditol HIV-1 protease inhibitor can be introduced at the
1-O and 6-O positions is also demonstrated for selected
examples.
(6) (a) Navia, M. A.; Chaturvedi, P. R. DDT 1996, 1, 179. (b)
Plattner, J . J .; Norbeck, D. W. Drug Discovery Technol. 1990, 92. (c)
Adang, A. E. P.; Hermenkens, P. H. H.; Linders, J . T. M.; Ottenheijm,
H. C. J .; van Staveren, C. J . Recl. Trav. Chim. Pays-Bas 1994, 113,
63-70.
Resu lts a n d Discu ssion
(7) (a) Steele, F. Nature Med. 1995, 1, 285-286. (b) Scrip 1995, Feb
17, 2000, 25.
For the synthesis of HIV PR inhibitors, R-amino
aldehydes have frequently been used as synthetic inter-
mediates where the precursor R-amino acid side chains
correspond to the selected P1/P1′ substituents of the
inhibitor. To obtain diversity for the P1/P1′ substituents
of the inhibitor, unnatural and frequently novel amino
acids in isomerically pure form have been prepared and
assembled in a nonconvergent synthesis to produce the
compounds of interest.
The use of acyclic carbohydrates as peptidomimetic
HIV PR inhibitors can allow for the facile access to sets
of stereochemically diverse compounds that can be as-
sembled in a convergent way.
Ch em istr y. For the synthesis of 10a , the diepoxide
6 (Scheme 1), readily available from D-mannitol in four
steps and in 23% overall yield,13 was heated with phenol
in DMF at 110 °C in the presence of potassium carbonate
to give the diol 7a in 81% yield. Compound 7a was
converted into the corresponding diazide 8a in 91% yield,
(8) King, R. W.; Garber, S.; Winslow, D. L.; Reid, C.; Bacheler, L.
T.; Anton, E.; Otto, M. J . Antiviral Chem. Chemother. 1995, 6, 80-88.
(9) (a) Scrip 1996, Feb. 19, 2101, 21. (b) Scrip 1996, 2100, 17.
(10) (a) Ghosh, A. K.; McKee, S. P.; Thompson, W. J . Tetrahedron
Lett. 1991, 32, 5729-5732. (b) Chenera, B.; Boehm, J . C.; Dreyer, G.
B. Bioorg. Med. Chem. Lett. 1991, 1, 219-222. (c) J adhav, P. K.;
Woerner, F. J . Bioorg. Med. Chem. Lett. 1992, 2, 353-356. (d) J adhav,
P. K.; Man, H.-W. Tetrahedron Lett. 1996, 37, 1153-1156. (e) Yoko-
matsu, T.; Suemune, K.; Shibuya, S. Heterocycles 1993, 35, 577-580.
(11) (a) Hirschmann, R. Angew. Chem., Int. Ed. Engl. 1991, 30,
1278-1301. (b) Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Salvino,
J .; Leahy, E. M.; Sprengeler, P. A.; Furst, G.; Smith, A. B., III. J . Am.
Chem. Soc. 1992, 114, 9217-9218. (c) Hirschmann, R.; Nicolaou, K.
C.; Pietranico, S.; Leahy, E. M.; Salvino, J .; Arison, B.; Cichy, M. A.;
Spoors, P. G.; Shakespeare, W. C.; Sprengeler, P. A.; Hamley, P.; Smith,
A. B., III; Reisine, T.; Raynor, K.; Maechler, L.; Donaldson, C.; Vale,
W.; Freidinger, R. M.; Cascieri, M. R.; Strader, C. D. J . Am. Chem.
Soc. 1993, 115, 12550-12568.
(12) (a) Kempf, D. J .; Norbeck, D. W.; Codacovi, L.; Wang, X. C.;
Kohlbrenner, W. E.; Wideburg, N. E.; Paul, D. A.; Knigge, M. F.;
Vasavanonds, S.; Craig-Kennard, A.; Saldivar, A.; Rosenbrook, W., J r.;
Clement, J . J .; Plattner, J . J .; Erickson, J . J . Med. Chem. 1990, 33,
2687-2689. (b) Greer, J .; Erickson, J . W.; Baldwin, J . J .; Varney, H.
D. J . Med. Chem. 1994, 37, 1035-1054. (c) Hosur, M. V.; Bhat, T. N.;
Kempf, D. J .; Baldwin, E. T.; Liu, B.; Gulnick, S.; Wideburg, N. E.;
Norbeck, D. W.; Appelt, K.; Erickson, J . W. J . Am. Chem. Soc. 1994,
116, 847-855. See also (d) Budt, K.-H.; Peyman, A.; Hansen, J .; Knolle,
J .; Meichsner, C.; Paessens, A.; Ruppert, D.; Stowasser, B. Bioorg. Med.
Chem. 1995, 3, 559-571.
(13) Le Merrer, Y.; Dure´ault, A.; Greck, C.; Micas-Languin, D.;
Gravier, C.; Depezay, J .-C. Heterocycles 1987, 25, 541-548.

4900 J . Org. Chem., Vol. 63, No. 15, 1998
Zuccarello et al.
Sch em e 2. Syn th esis of th e C-3 a n d C-4
Ta ble 1. Yield s for th e Syn th esis of Com p ou n d s 7b-ja
Dia ster eoisom er s of 10a
ound
C
a
Method A: ROH, K2CO3, DMF, 110 °C, 16 h. Method B: ROH,
Mg(CIO4)2, CH3CN, 82 °C, 16 h.
using Mitsunobu conditions with DIAD, triphenylphos-
phine, and diphenyl phosphorazidate.14 Hydrolysis of the
isopropylidene group in 8a by 3 N HCl in methanol gave
diazido diol 9a in 96% yield from which the final product
10a was obtained in 92% yield by reduction of the azide
groups and simultaneous protection of the resulting
diamine using catalytic hydrogenation over 10% pal-
ladium on carbon in the presence of di-tert-butyl dicar-
bonate (Boc2O).15
dure was used to prepare 10b-e utilizing triphenylphos-
phine in tetrahydrofuran/water for the azide reduction
followed by reacting the resulting diamine with di-tert-
butyl dicarbonate.
Many reports have shown that the stereochemistry at
the core of the HIV protease inhibitor has a major effect
on the potency of the inhibitors. The P1/P1′ groups
usually have the chirality corresponding to that of the
L-amino acids, whereas the stereochemistry of the central
diols can vary.
Compound 11, corresponding to compound 10a but
having the hydroxyls of the central diol inverted, was
prepared starting from L-mannonic 1,4-lactone (Scheme
2). The monoisopropylidene intermediate 12, prepared
from L-mannonio-1,4-lactone,19 was selectively benzoy-
lated at the primary hydroxyls, using benzoyl chloride,
tosylated at the secondary hydroxyls, and subsequently
treated with potassium carbonate in methanol to give
epoxide 1320 in 21% yield from 12.13 Compound 13 was
heated with phenol in DMF at 110 °C in the presence of
potassium carbonate to give the diol 1420 in 96% yield,
which was converted into the corresponding diazide 1520
in 53% yield, using Mitsunobu conditions. The isopro-
pylidene group in 15 was hydrolyzed using 3 N HCl in
methanol to give the corresponding diazido diol in 66%
yield. In situ reduction of the azide groups by hydroge-
nation over 10% palladium on carbon followed by protec-
tion of the resulting diamino groups with di-tert-butyl
dicarbonate gave the desired product 11 in 58% yield.
Preparation of compound 16, corresponding to com-
pound 10a having one of the hydroxyls of the central diol
The synthesis of compound 10a provides ready access
to variations of the P1/P1′ groups starting from diepoxide
6 (Scheme 1). Heating various substituted phenols with
diepoxide 6 at 110 °C in DMF in the presence of
potassium carbonate gave diols 7b-h in yields ranging
from moderate to good (Table 1). However, when alcohols
were used to effect this epoxide opening the reaction
failed. Varying the base (KOtBu, NaH), solvent (toluene,
DMSO, THF), or temperature (-10 f 110 °C) did not
lead to improvements either giving unreacted starting
material or resulting in the decomposition of the di-
epoxide. When Lewis acids such as boron trifluoride
diethyl etherate,16 cerium ammonium nitrate,17 magne-
sium triflate, or calcium chloride were used in the
reaction, low and variable yields (<20%) of the desired
diepoxide-opened products were obtained. However, with
magnesium perchlorate (potentially explosive)18 in re-
fluxing acetonitrile, diols 7i,j were obtained in reproduc-
ible yields (25% and 89%, respectively). Diols 7b-j were
readily converted to the corresponding diazides 8b-j in
fair to excellent yields (32-100%), using Mitsunobu
conditions. Hydrolysis of the isopropylidene group either
in 90% aqueous trifluoroacetic acid or with 3 N HCl in
methanol afforded the diazido diols 9b-j in good to
excellent yields (46-85%). Compounds 10f-j were ob-
tained from catalytic hydrogenation of the corresponding
diazido diols over 10% palladium on carbon in the
presence of di-tert-butyl dicarbonate. A two-step proce-
(14) Hughes, D. L. Org. React. 1992, 42, 335-656.
(15) Saito, S.; Nakajima, H.; Inaba, M.; Moriwake, T. Tetrahedron
Lett. 1989, 30, 837-838.
(16) (a) Brandes, A.; Eggert, U.; Hoffmann, H. M. R. Synlett 1994,
745-747. (b) Guivisdalsky, P. N.; Bittman, R. J . Am. Chem. Soc. 1989,
111, 3077-3079. (c) Guivisdalsky, P. N.; Bittman, R. J . Org. Chem.
1989, 54, 4637-4642.
(17) Iranpoor, N.; Baltork, I. M. Synth. Commun. 1990, 20, 2789-
2797.
(18) Chini, M.; Crotti, P.; Gardelli, C.; Macchia, M. Synlett 1992,
673-676.
(19) (a) Lam, P. Y. S.; Eyermann, C. J .; Hodge, C. N.; J adhav, P.
K.; Delucca, G. V. World Patent Application 9307128, 1993; p 182. (b)
Nugiel, D. A.; J acobs, K.; Worley, T.; Patel, M.; Kaltenbach, R. F., III;
Meyer, D. T.; J adhav, P. K.; De Lucca, G. V.; Smyser, T. E.; Klabe, R.
M.; Bacheler, L. T.; Rayner, M. M.; Seitz, S. P. J . Med. Chem. 1996,
39, 2156-2169.
(20) Hulte´n, J .; Bonham, N. M.; Nillroth, U.; Hansson, T.; Zuccarello,
G.; Bouzide, A.; A° qvist, J .; Classon, B.; Danielson, U. H.; Karle´n, A.;
Hallberg, A.; Kvarnstro¨m, I.; Samuelsson, B. J . Med. Chem. 1997, 40,
885-897.

Acyclic Carbohydrate HIV PR Inhibitors
J . Org. Chem., Vol. 63, No. 15, 1998 4901
Sch em e 3. In ver sion of th e C-4 Hyd r oxyl of 10a
Sch em e 4. Mon od eoxygen a tion of Diol 10a
inverted, was attempted from the monoacetylated diol
9a . The mono-O-acetate or mono-O-benzoate having a
single unprotected hydroxyl group was then subjected to
standard Mitsunobu inversion conditions or exposed to
chromium(VI)-based oxidants. Surprisingly this hy-
droxyl group was inert to these reaction conditions,
probably due to steric shielding.
Sch em e 5. In ver sion of th e Hyd r oxyl
Ster eoch em istr y of 19
Instead, compound 9a was hydrogenated using pal-
ladium on carbon (10%) to give the corresponding di-
amine which was reacted with benzyl chloroformate in
the presence of excess triethylamine to give the cyclic
carbamate 17, in 28% yield, having one unprotected
hydroxyl group (Scheme 3). Oxidation of the hydroxyl
group to the corresponding ketone using chromium(VI)
oxide-acetic anhydride-pyridine21 followed by reduction
with sodium borohydride in methanol gave the desired
epimer 18 along with 17 in 77% total yield (0.85:1 ratio).
Hydrolysis of the carbamate in 18 using barium hydrox-
ide and Boc protection of the amino groups using di-tert-
butyl dicarbonate gave the desired compound 16 in 42%
yield from 18.
For the synthesis of compound 19, compound 10a was
reacted with thiocarbonyldiimidazole to give the cyclic
thiocarbonate 20 in 70% yield, which was subjected to
radical deoxygenation conditions (Scheme 4). Addition
of tributyltin hydride and 2,2′-azobis(isobutyronitrile) to
the cyclic thiocarbonate 20 over 20 min gave the desired
deoxygenation product 19 in 68% yield along with minor
amounts of compounds 21-23. Yields were comparable
when benzyloxycarbonyl was used instead of tert-butoxy-
carbonyl as amino protecting group in 20. Addition of
tributyltin hydride and 2,2′-azobis(isobutyronitrile) to the
cyclic thiocarbonate 20 over a short time (15 min) gave
as the main products the desulfurization compound 21
(22% yield) and the cyclic carbamate 22 (17% yield).
Compound 22 could be converted to the desired product
19 in 56% overall yield by hydrolysis with barium
hydroxide followed by reaction of the resulting diamine
with di-tert-butyl dicarbonate. Applying longer addition
times (50 min) or high dilution conditions (7 mM) in the
radical deoxygenation reaction led to the rearranged
product 2322 (15% yield). The trans stereochemistry of
the oxathiolone ring in 23 was determined by the large
coupling between the ring hydrogens (J ) 8.5 Hz).
The hydroxyl epimer of 19 was synthesized using
4-nitrobenzoic acid23 in the Mitsunobu reaction followed
by hydrolysis of the 4-nitrobenzoate with lithium hy-
droxide to give 24 in 82% yield (Scheme 5).
The unsymmetrical inhibitor 25, which has structural
similarity to both compounds 5 and 10a , was also
synthesized (Scheme 6). Diepoxide 6 was heated with 2
equiv of phenol at 90 °C in dimethylformamide in the
presence of potassium carbonate. The monoaddition
product 26 was isolated in 31% yield (45% based on
recovered starting material) along with 7a . Reacting the
monoepoxide 26 with phenyllithium and CuBr‚SMe2
afforded the unsymmetrical diol 27, in 86% yield. Con-
version of 27 to the corresponding diazide using the
Mitsunobu reaction was accompanied by elimination.10
The isopropylidene group of the diazide was hydrolyzed
using HCl in methanol, and 28 was isolated in 18% yield
from 27. Catalytic hydrogenation over 10% palladium
on carbon in the presence of di-tert-butyl dicarbonate gave
the unsymmetrical inhibitor 25, in 85% yield.
HIV-1 P r otea se In h ibition . The inhibitory effect of
the synthesized compounds was determined with purified
HIV-1 protease in a standardized assay. The results are
presented as IC50 values, i.e., the concentration of inhibi-
tor resulting in 50% inhibition in this assay.24
Str u ctu r e-Activity Rela tion sh ip . The enzyme in-
hibitory activity (Table 2) of compound 10a is 5-8 times
(23) Dodge, J . A.; Trujillo, J . I.; Presnell, M. J . Org. Chem. 1994,
59, 234-236.
(24) Nillroth, U.; Besidsky, Y.; Classon, B.; Chattopadhyaya, J .; Ugi,
I.; Danielsson, U. H. Drug Des. Discovery 1995, 13, 43-54.
(21) Garegg, P. J .; Samuelsson, B. Carbohydr. Res. 1978, 67, 267.
(22) Tsuda, Y.; Kanemitsu, K.; Kakimoto, K.; Kikuchi, T. Chem.
Pharm. Bull. 1987, 35, 2148-2150.

4902 J . Org. Chem., Vol. 63, No. 15, 1998
Zuccarello et al.
Ta ble 2. Va lu es for th e In h ibition of HIV-1 P r
Sch em e 6. Syn th esis of th e Un sym m etr ica l
In h ibitor 25
ound
C
a
Values from ref 12a.
Mg(ClO4)2 (0.50 g, 2.24 mmol). The reaction mixture was
heated to reflux for 7.5 h and then added to Et2O (50 mL) and
saturated aqueous NaHCO3 (30 mL). The organic phase was
washed with H2O (30 mL) and saturated aqueous NaCl (30
mL), dried (MgSO4), and concentrated. The residue was
purified by flash column chromatography (9:1 f 2:1 PhCH3/
EtOAc) to give 7i (0.104 g, 24% yield) as a colorless liquid along
with the monoaddition product (39% yield) as a colorless
liquid: 1H NMR (250 MHz, CDCl3) δ 3.91 (m, 2H), 3.79 (m,
2H), 3.74 (dd, J ) 10.6, 2.8 Hz, 2H), 3.52 (dd, J ) 10.2, 7.0
Hz, 2H), 3.46 (d, J ) 3.0 Hz, 2H), 3.30 (tt, J ) 8.9, 3.8 Hz,
2H), 1.92 (m, 4H), 1.75 (m, 4H), 1.52 (m, 2H), 1.37 (s, 6H),
1.34-1.20 (m, 10H); 13C NMR (63 MHz, CDCl3) δ 109.2 (s),
79.9 (d), 78.3 (d), 71.9 (d), 69.1 (t), 32.3 (t), 32.1 (t), 27.0 (q),
25.8 (t), 24.1 (t).
less active than that of the Abbott compound 5, whereas
the unsymmetrical inhibitor 25 is equipotent with 5.
Inversion of both the hydroxyls in 10a gives, in contrast
to that observed for the isomers of compound 5, the
inactive compound 11,12a,c whereas inversion of one
hydroxyl gives inhibitor 16, which is equipotent with
inhibitor 10a . Notably however, when one of the hy-
droxyls in diol 10a is deoxygenated, giving inhibitor 19,
an increase in activity is observed as previously
described,12c resulting in an inhibitor equipotent with
Abbott compound 5. The hydroxyl epimer of inhibitor
19, compound 24, is inactive which demonstrates the
importance of the interaction of the hydroxyl group with
the catalytic aspartic acids in the active site of the HIV-1
protease. Modification of the P1/P1′ substituent of 10a
did not improve on the antiviral activity compared to 10a
(unpublished data).
Mon oa d d ition P r od u ct: 1H NMR (250 MHz, CDCl3) δ 4.05
(dd, J ) 6.7, 4.2 Hz, 1H), 3.89 (t, J ) 7.0 Hz, 1H), 3.79 (ddd,
J ) 10.3, 6.9, 3.6 Hz, 1H), 3.68 (dd, J ) 9.6, 3.4 Hz, 1H), 3.50
(dd, J ) 9.6, 6.4 Hz, 1H), 3.31 (tt, J ) 8.8, 3.8 Hz, 1H), 3.19
(q, J ) 3.6 Hz, 1H), 2.84 (s, 1H), 2.84 (d, J ) 3.5 Hz, 1H), 2.73
(d, J ) 3.9 Hz, 1H), 1.89 (m, 2H), 1.73 (m, 2H), 1.52 (m, 1H),
1.38-1.20 (m, 5H), 1.42 (s, 3H), 1.41 (s, 3H); 13C NMR (63
MHz, CDCl3) δ 109.8 (s), 78.5 (d), 78.3 (d), 78.2 (d), 71.5 (d),
68.7 (t), 52.2 (d), 44.9 (t), 32.2 (t), 32.0 (t), 27.0 (q), 26.7 (q),
25.8 (t), 24.1 (t), 24.0 (t).
1,6-Di-O-isobu tyl-3,4-O-isop r op ylid en e-D-m a n n itol, 7j.
Synthesized by the same method as for 7i in 89% yield: 1H
NMR (250 MHz, CDCl3) δ 3.91 (dd, J ) 5.9, 1.9 Hz, 2H), 3.78
(m, 2H), 3.69 (dd, J ) 9.8, 2.8 Hz, 2H), 3.58 (d, J ) 3.1 Hz,
2H), 3.51 (dd, J ) 9.8, 6.3 Hz, 2H), 3.28 (dd, J ) 10.1, 7.6 Hz,
2H), 3.25 (dd, J ) 10.1, 7.6 Hz, 2H), 1.90 (nonet, J ) 6.7 Hz,
2H), 1.37 (s, 6H), 0.91 (d, J ) 6.7 Hz, 12H); 13C NMR (63 MHz,
CDCl3) δ 109.3 (s), 79.9 (d), 78.5 (t), 72.0 (d), 71.9 (t), 28.3 (d),
26.9 (q), 19.3 (q).
Con clu sion
It has been demonstrated that potent HIV-1 protease
inhibitors can be obtained by employing carbohydrate
alditols as templates. Work is in progress to optimize
this new class of inhibitors using X-ray crystal structures
of protease-inhibitor complexes and molecular modeling.
Exp er im en ta l Section
2,5-Dia zid o-2,5-d id eoxy-3,4-O-isop r op ylid en e-1,6-d i-O-
p h en yl-L-id itol, 8a . To a cooled (-5 °C) solution of diisopro-
poxy azodicarboxylate, DIAD (7.9 g, 93 mmol) in THF (5 mL)
were added 7a (7.06 g, 18.7 mmol) in THF (50 mL) and Ph3P
(10.3 g, 39.1 mmol). After 15 min, diphenyl phosphorazidate
(DPPA; 12.86 g, 46.77 mmol) was added and the reaction
mixture allowed to warm to room temperature. After stirring
overnight, the solvent was removed in vacuo to give a yellow
oil. The crude material was purified by flash column chro-
matography (2:1 petroleum ether/PhCH3 f 9:1 PhCH3/EtOAc)
to give 8a (7.28 g, 91% yield) as a colorless oil: [R]D +40.4 (c
3,4-O-Isop r op ylid en e-1,6-d i-O-p h en yl-D-m a n n itol, 7a .
To 1,2:5,6-dianhydro-3,4-O-isopropylidene-D-mannitol, 6 (5.0
g, 26.9 mmol), and phenol (10.3 g, 110 mmol) in DMF (100
mL) was added K2CO3 (1.8 g, 13.4 mmol). The reaction
mixture was heated at 110 °C for 7 h. After cooling, it was
added to saturated aqueous NH4Cl (200 mL) and extracted
with Et2O (200 mL). The organic phase was washed with H2O
(2 × 100 mL), dried (MgSO4), and concentrated to give a solid.
Purification by flash column chromatography (4:1 PhCH3/
EtOAc) gave 7a as a white solid (8.18 g, 81% yield): mp 116-
117 °C; [R]D +44.9 (c ) 1.52, CHCl3); 1H NMR (250 MHz,
CDCl3) δ 7.27 (t, J ) 8.0 Hz, 4H), 6.96 (t, J ) 7.2 Hz, 2H),
6.94 (d, J ) 8.2 Hz, 4H), 4.23 (d, J ) 8.3 Hz, 2H), 4.09-4.04
(m, 6H), 3.81 (s, 2H), 1.38 (s, 6H); 13C NMR (63 MHz, CDCl3)
δ 158.6 (s), 129.4 (d), 121.1 (d), 114.7 (d), 109.8 (s), 79.7 (d),
71.7 (d), 69.5 (t), 26.9 (q). Anal. Calcd for C21O6 H26: C, 67.36;
H, 7.00. Found: C, 67.17; H, 7.18.
1
) 1.35, CHCl3); H NMR (250 MHz, CDCl3) δ 7.28 (dd, J )
8.2, 7.6 Hz, 4H), 6.98 (t, J ) 7.4 Hz, 2H), 6.91 (d, J ) 8.2 Hz,
4H), 4,33 (s, 2H), 4.25-4.20 (m, 4H), 3.73 (dd, J ) 6.4, 5.9 Hz,
2H), 1.47 (s, 6H); 13C NMR (62 MHz, CDCl3) δ 157.9 (s), 129.6
(d), 121.7 (d), 114.7 (d), 110.9 (s), 76.9 (d), 67.8 (t), 59.6(d),
26.9 (q). Anal. Calcd for C21O4 H24N6: C, 59.42; H, 5.70; N,
19.80. Found: C, 59.64; H, 5.57; N, 19.76.
1,6-Di-O-cycloh e xyl-3,4-O-isop r op ylid e n e -D-m a n n i-
tol, 7i. To a solution of 6 (0.206 g, 1.11 mmol) and cyclohex-
anol (2.30 mL, 22.1 mmol) in acetonitrile (2.2 mL) was added
2,5-Dia zid o-2,5-d id eoxy-1,6-d i-O-p h en yl-L-id itol, 9a . To
8a (0.896 g, 2.11 mmol) was added a cold (0 °C) solution of
acetyl chloride (3.5 mL, 49.2 mmol) in MeOH (75 mL) which

Acyclic Carbohydrate HIV PR Inhibitors
J . Org. Chem., Vol. 63, No. 15, 1998 4903
had been stirring for 10 min. After stirring for 24 h at room
temperature, the reaction mixture was concentrated in vacuo
to give an oil. The crude product was purified by flash column
chromatography (4:1 PhCH3/EtOAc) to give 9a (0.79 g, 96%
yield) as a colorless oil: 1H NMR (250 MHz, CDCl3) δ 7.28
(dd, J ) 8.3, 7.6 Hz, 4H), 6.98 (t, J ) 7.3 Hz, 2H), 6.90 (d, J )
8.1 Hz, 6H), 4.25 (m, 4H), 3.93 (br s, 4H), 3.03 (d, J ) 2.6 Hz,
2H); 13C NMR (62 MHz, CDCl3) δ 157.9 (s), 129.6 (d), 121.7
(d), 114.6 (d), 70.9 (d), 68.0 (t), 62.4 (d).
2,5-Bis[N-(ter t-bu toxyca r bon yl)a m in o]-2,5-d ideoxy-1,6-
d i-O-p h en yl-L-id itol, 10a . To 9a (0.77 g, 2.00 mmol) and tert-
butoxycarbonyl anhydride (Boc2O; 0.80 g, 3.6 mmol) in EtOAc
(15 mL) was added Pd/C (10%, 0.12 g). Hydrogen was added
(with flushing) at atmospheric pressure to the system and the
reaction mixture stirred for 3 h. The suspension was then
filtered through Celite and concentrated in vacuo to give a
colorless solid. This was purified by flash column chromatog-
raphy (4:1 PhCH3/EtOAc) to give 10a (0.98 g, 92% yield) as a
colorless oil: mp 115-116 °C; [R]D -26.4 (c ) 1.42, CHCl3);
1H NMR (250 MHz, CDCl3) δ 7.27 (ddd, J ) 8.2, 7.3, 2.2 Hz,
6H), 6.96 (t, J ) 7.3 Hz, 2H), 6.88 (d, J ) 8.0 Hz, 4H), 5.17 (d,
J ) 7.7 Hz, 2H), 4.15 (m, 6H), 3.91 (s, 2H), 3.53 (br s, 2H),
1.43 (s, 18H); 13C NMR (62 MHz, CDCl3) δ 158.3 (s), 156.3 (s),
129.5 (d), 121.3 (d), 114.7 (d), 80.1 (s), 71.5 (d), 68.2 (t), 51.0
(d), 28.3 (q). Anal. Calcd for C28O8H40N2: C, 63.14; H, 7.57;
N, 5.26. Found: C, 63.25; H, 7.47; N, 5.08.
2,5-Bis[N-(ter t-bu toxyca r bon yl)a m in o]-2,5-d ideoxy-1,6-
bis-O-(4′-n itr op h en yl)-L-id itol, 10b. To 9b (0.462 g, 0.97
mmol) in MeOH (25 mL) was added Ph3P (0.639 g, 2.43 mmol).
After stirring overnight, the solvent was removed in vacuo.
The residue was dissolved in EtOAc (40 mL) and Boc2O (0.491
g, 2.26 mmol) added. After stirring for 3 days at room
temperature, the reaction mixture was concentrated. The
reaction mixture was purified by crystallization (petroleum
ether/acetone) to give 10b (0.422 g, 70% yield): [R]D +37.0 (c
) 0.40, CHCl3); 1H NMR (100 MHz, CDCl3) δ 8.17 (d, J ) 9.2
Hz, 4H), 7.00 (d, J ) 9.3 Hz, 4H), 5.43 (d, J ) 8.7 Hz, 2H),
4.52-3.88 (m, 10H), 1.44 (s, 18H); 13C NMR (25 MHz, CDCl3)
δ 163.1 (s), 155.9 (s), 141.2 (s), 125.5 (d), 114.3 (d), 80.0 (s),
70.2 (d), 68.0 (t), 50.1 (d), 28.2 (q). Anal. Calcd for
CHCl3); 1H NMR (250 MHz, CDCl3) δ 6.93 (dd, J HH ) 9.2 Hz,
J HF ) 7.7 Hz, 4H), 6.78 (dd, J HH ) 9.2 Hz, J HF ) 4.6 Hz, 4H),
5.29 (d, J ) 8.0 Hz, 2H), 4.24-3.68 (m, 10H), 1.40 (s, 18H);
13C NMR (63 MHz, CDCl3) δ 157.4 (d, J CF ) 238.7 Hz), 156.3
(s), 154.4 (s), 115.8 (dd, J CF ) 24.5 Hz), 115.6 (dd, J CF ) 6.8
Hz), 80.2 (s), 71.2 (d), 68.6 (t), 50.9 (d), 28.2 (q). Anal. Calcd
for C28O8H38N2F2: C, 59.14; H, 6.74; N, 4.93. Found: C, 59.35;
H, 6.84; N, 4.85.
2,5-Bis[N-(ter t-bu toxyca r bon yl)a m in o]-2,5-did eoxy-1,6-
bis-O-(p en ta flu or op h en yl)-L-id itol, 10g. Synthesized by
the same method as for 10a in 70% yield: mp 190-192 °C;
[R]D +13.90 (c ) 0.41, CHCl3); 1H NMR (250 MHz, DMSO-d6)
δ 6.63 (d, J ) 8.8 Hz, 2H), 4.60 (s, 2H), 4.26-3.97 (m, 6H),
3.16 (s, 2H), 1.34 (s, 18H); 13C NMR (63 MHz, DMSO-d6) δ
156.3 (s), 144.6 (s), 140.9 (s), 136.4 (s), 133.6 (s), 78.7 (s), 76.6
(d), 71.4 (t), 51.7 (d), 29.1 (q). Anal. Calcd for C28O8H30N2F10
:
C, 47.19; H, 4.24; N, 3.93. Found: C, 47.22; H, 4.30; N, 3.82.
2,5-Bis[N-(ter t-bu toxyca r bon yl)a m in o]-2,5-d id eoxy-1,6-
d i-O-(1′-n a p h th yl)-L-id itol, 10 h . Synthesized by the same
method as for 10a in 45% yield: [R]D -6.61 (c ) 1.18, CHCl3);
1H NMR (100 MHz, CDCl3) δ 8.06 (m, 2H), 7.79 (m, 2H), 7.50-
7.15 (m, 8H), 6.76 (m, 2H), 5.40 (d, J ) 7.2 Hz, 2H), 4.52-
4.04 (m, 8H), 1.41 (s, 18H); 13C NMR (25 MHz, CDCl3) δ 160.0
(s), 157.3 (s), 134.1 (s), 127.0 (d), 126.6 (d), 125.8 (d), 125.4 (s),
125.0 (d), 121.4 (d), 120.1 (d), 105.0 (d), 80.0 (s), 74.5 (d), 70.3
(t), 48.2 (d), 28.3 (q). Anal. Calcd for C36O8H44N2: C, 68.33;
H, 7.01; N, 4.43. Found: C, 68.56; H, 7.09; N, 4.31.
2,5-Bis[N-(ter t-bu toxyca r bon yl)a m in o]-1,6-d i-O-cyclo-
h exyl-2,5-d id eoxy-L-id it ol, 10i. Synthesized by the same
method as for 10a in 36% yield: 1H NMR (250 MHz, CDCl3)
δ 5.13 (d, J ) 7.7 Hz, 2H), 3.98 (m, 2H), 3.80 (s, 2H), 3.64 (m,
6H), 3.27 (m, 2H), 1.88 (m, 4H), 1.71 (m, 4H), 1.44 (br s, 20H),
1.23 (m, 10H); 13C NMR (63 MHz, CDCl3) δ 156.0 (s), 79.4 (s),
78.0 (d), 72.0 (d), 69.0 (t), 50.7 (d), 31.9 (t), 28.4 (q), 25.7 (t),
23.8 (t).
2,5-Bis[N-(ter t-bu toxyca r bon yl)a m in o]-2,5-did eoxy-1,6-
d i-O-isobu tyl-L-id itol, 10j. Synthesized by the same method
as for 10a in 36% yield: 1H NMR (250 MHz, CDCl3) δ 5.12 (d,
J ) 8.9 Hz, 2H), 3.99 (br s, 2H), 3.77 (s, 2H), 3.64-3.49 (m,
6H), 3.21 (d, J ) 6.7 Hz, 4H), 1.85 (nonet, J ) 6.7 Hz, 2H),
1.44 (s, 18H), 0.89 (d, J ) 6.7 Hz, 12H); 13C NMR (63 MHz,
CDCl3) δ 156.0 (s), 79.5 (s), 78.3 (d), 72.0 (t), 50.5 (d), 28.3 (q,
d), 19.3 (q).
1,2:5,6-Dia n h yd r o-3,4-O-isop r op ylid en e-D-id itol, 13. To
a cooled (-80 °C) solution of 3,4-O-isopropylidene-L-mannitol,
12 (20.0 g, 90 mmol), in pyridine/CH2Cl2 (1:1, 1.0 L) was added
benzoyl chloride (20 mL, 172 mmol) in CH2Cl2 (20 mL)
dropwise. After stirring for 1.5 h, the reaction mixture was
allowed to slowly warm to 0 °C. The reaction mixture was
then added to cold (0 °C) 6 N HCl (500 mL) and the aqueous
layer extracted with CH2Cl2 (150 mL). The combined organic
layers were washed with 3% aqueous Na2CO3 (100 mL), dried
(MgSO4), and concentrated in vacuo to give a syrup that was
used without further purification.
To a cooled (0 °C) solution containing the crude dibenzoate,
triethylamine (25 mL, 180 mmol), and N,N-dimethyl-4-ami-
nopyridine (2.2 g, 18 mmol) in dichloromethane (150 mL) was
added tosyl chloride (34.3 g, 180 mmol) portionwise. The
reaction mixture was stirred at 0 °C for 1 h and then allowed
to warm to room temperature and stirred for 16 h. It was then
added to cold (0 °C) 3 N HCl (50 mL) and the aqueous layer
extracted with CH2Cl2 (50 mL). The combined organic layers
were washed with saturated aqueous NaCl (50 mL), dried
(MgSO4), and concentrated in vacuo to give a syrup that was
used without further purification.
The syrup was dissolved in CH2Cl2/MeOH (5:6, 550 mL) and
K2CO3 (62 g, 449 mmol) added. After 2.5 h, H2O (300 mL)
was added and the aqueous layer extracted with CH2Cl2 (150
mL). The combined organic layers were washed with satu-
rated aqueous NH4Cl (100 mL), dried (MgSO4), and concen-
trated in vacuo. The syrup was purified by flash column
chromatography (4:1 PhCH3/EtOAc) to give 3.50 g of 13 (21%
yield): 1H NMR (100 MHz, CDCl3) δ 3.83 (dd, J ) 3.3, 1.5 Hz,
2H), 3.08 (m, 2H), 2.84 (dd, J ) 5.1, 4.1 Hz, 1H), 2.63 (ddd, J
C
28O12H38N4: C, 54.01; H, 6.15; N, 9.00. Found: C, 53.70; H,
5.77; N, 8.08.
2,5-Bis[N-(ter t-bu toxyca r bon yl)a m in o]-2,5-dideoxy-1,6-
bis-O-(3′-n itr op h en yl)-L-id itol, 10c. Synthesized by the
same method as for 10b in 62% yield: [R]D +42.7 (c ) 0.89,
1
CHCl3); H NMR (100 MHz, CDCl3) δ 7.86 (ddd, J ) 7.9, 1.8,
1.3 Hz, 2H), 7.73 (t, J ) 2.2 Hz, 2H), 7.45 (t, J ) 7.9 Hz, 2H),
7.23 (ddd, J ) 8.2, 2.3, 1.3 Hz, 2H), 5.02 (d, J ) 7.3 Hz, 2H),
4.97 (br s, 2H), 4.53-4.23 (m, 2H), 4.11-4.19 (m, 4H), 1.47 (s,
18H); 13C NMR (25 MHz, CDCl3) δ 157.9 (s), 155.3 (s), 148.8
(s), 129.9 (d), 121.1 (d), 116.5 (d), 108.9 (d), 81.2 (s), 77.4 (d),
66.9 (t), 50.0 (d), 28.1 (q). Anal. Calcd for C28O12H38N4: C,
54.01; H, 6.15; N, 9.00. Found: C, 54.21; H, 5.99; N, 7.80.
2,5-Bis[N-(ter t-bu toxyca r bon yl)a m in o]-2,5-d ideoxy-1,6-
bis-O-(2′-n itr op h en yl)-L-id itol, 10d . Synthesized by the
same method as for 10b in 45% yield: [R]D +22.76 (c ) 1.16,
1
CHCl3); H NMR (100 MHz, CDCl3) δ 7.90 (dd, J ) 8.3, 1.9
Hz, 2H), 7.53 (ddd, J ) 9.1, 6.7, 1.8 Hz, 2H), 7.14-6.98 (m,
4H), 5.18-5.02 (4H), 4.65-4.19 (m, 6H), 1.45 (s, 18H); 13C
NMR (25 MHz, CDCl3) δ 154.9 (s), 151.0 (s), 139.0 (d), 134.4
(s), 125.9 (d), 121.1 (d), 114.2 (d), 80.8 (s), 77.5 (d), 67.3 (t),
50.6 (d), 28.0 (q). Anal. Calcd for C28O12H38N4‚0.25C7H8: C,
55.34; H, 6.24; N, 8.68. Found: C, 55.17; H, 6.26; N, 8.50.
2,5-Bis[N-(ter t-bu toxyca r bon yl)a m in o]-2,5-d ideoxy-1,6-
bis-O-(4′-m eth oxyp h en yl)-L-id itol, 10e. Synthesized by the
same method as for 10a in 81% yield: [R]D +14.89 (c ) 1.90,
1
CHCl3); H NMR (100 MHz, CDCl3) δ 7.16 (s, 8H), 5.54 (d, J
) 8 Hz, 2H), 4.48-4.06 (m, 10H), 3.95 (s, 6H), 1.50 (s, 18H);
13C NMR (25 MHz, CDCl3) δ 156.0 (s), 153.6 (s), 152.2 (s), 115.4
(d), 114.3 (d), 79.7 (s), 71.1 (d), 68.5 (t), 55.5 (q), 50.7 (d), 28.2
(q). Anal. Calcd for C30O10H44N2: C, 60.79; H, 7.48; N, 4.73.
Found: C, 60.56; H, 7.52; N, 4.60.
2,5-Bis[N-(ter t-bu toxyca r bon yl)a m in o]-2,5-d ideoxy-1,6-
bis-O-(4′-flu or op h en yl)-L-id itol, 10f. Synthesized by the
same method as for 10a in 86% yield: [R]D +9.90 (c ) 1.77,

4904 J . Org. Chem., Vol. 63, No. 15, 1998
Zuccarello et al.
) 5.2, 2.6, 0.8 Hz, 1H), 1.41 (s, 6H); 13C NMR (25 MHz, CDCl3)
δ 110.2 (s), 77.8 (d), 50.8 (d), 43.5 (t), 26.5 (q).
triethylamine (1.1 g, 10.8 mmol) were added. The reaction
mixture was stirred overnight at room temperature, and the
solution was washed with water (10 mL), dried (MgSO4), and
concentrated in vacuo. Purification by flash column chroma-
tography (1:1 PhCH3/EtOAc) gave 0.110 g of the product (28%
yield): [R]D -33.51 (c ) 0.57, CHCl3); 1H NMR (250 MHz,
CDCl3) δ 7.25-7.12 (m, 9H), 6.92 (t, J ) 7.3 Hz, 1H), 6.91 (t,
J ) 7.4 Hz, 1H), 6.84 (d, J ) 9.6 Hz, 2H), 6.80 (d, J ) 9.2 Hz,
2H), 6.46 (s, 1H), 5.71 (d, J ) 8.9 Hz, 1H), 5.05 (d, J ) 12.1
Hz, 1H), 4.99 (d, J ) 12.5 Hz, 1H), 4.40 (t, J ) 5.2 Hz, 1H),
4.33 (d, J ) 5.3 Hz, 1H), 4.17 (m, 1H), 4.03 (m, 4H), 3.85 (m,
2H); 13C NMR (63 MHz, CDCl3) δ 159.1 (s), 158.2 (s), 158.0
(s), 156.6 (s), 136.2 (s), 129.5 (d), 128.5 (d), 128.2 (d), 128.0
(d), 121.5 (d), 121.3 (d) 114.7 (d), 79.5 (d), 70.6 (d), 68.7 (t),
67.1 (t), 66.8 (t), 53.7 (d), 51.2 (d). Anal. Calcd for
3,4-O-Isop r op ylid en e-1,6-d i-O-p h en yl-D-id itol, 14. To
1,2:5,6-dianhydro-3,4-O-isopropylidene-D-iditol, 13 (0.50 g, 2.69
mmol), and phenol (1.03 g, 10.9 mmol) in DMF (20 mL) was
added K2CO3 (0.18 g, 1.4 mmol). The reaction mixture was
heated to 110 °C for 16 h. The reaction mixture was then
diluted with Et2O (120 mL), washed with saturated aqueous
NH4Cl (30 mL) and H2O (30 mL), dried (MgSO4), and concen-
trated in vacuo. The residue was purified by flash column
chromatography (4:1 PhCH3/EtOAc) to give 0.96 g of the
product (96% yield): 1H NMR (250 MHz, CDCl3) δ 7.25 (t, J
) 7.6 Hz, 4H), 6.94 (t, J ) 7.3 Hz, 2H), 6.89 (d, J ) 8.5 Hz,
4H), 4.33 (s, 2H), 4.08-4.00 (m, 6H), 2.66 (d, J ) 5.5 Hz, 2H),
1.46 (s, 6H); 13C NMR (63 MHz, CDCl3) δ 158.4 (s), 129.6 (d),
121.3 (d), 114.6 (d), 110.1 (s), 77.1 (d), 69.4 (d), 68.6 (t), 27.2
(q).
C
27O7H28N2: C, 65.84; H, 5.73; N, 5.69. Found: C, 66.09; H,
5.89; N, 5.83.
2,5-Dia zid o-2,5-d id eoxy-3,4-O-isop r op ylid en e-1,6-d i-O-
p h en yl-L-m a n n itol, 15. To a cooled (-5 °C) solution of DIAD
(0.54 mL, 2.7 mmol) in THF (0.5 mL) were added 3,4-O-
isopropylidene-1,6-di-O-phenyl-L-iditol (0.50 g, 1.34 mmol) in
THF (5 mL) and Ph3P (0.70 g, 2.67 mmol). After 15 min, DPPA
(0.67 mL, 3.11 mmol) was added and the reaction mixture
allowed to warm to room temperature. After stirring over-
night, the solvent was removed in vacuo to give a yellow oil.
The crude material was purified by flash column chromatog-
raphy (PhCH3) to give 0.30 g of the diazide (53% yield) as a
colorless oil: 1H NMR (250 MHz, CDCl3) δ 7.30 (t, J ) 7.8 Hz,
4H), 6.98 (t, J ) 7.2 Hz, 2H), 6.93 (d, J ) 8.4 Hz, 4H), 4.36
(dd, J ) 3.6, 10.2 Hz, 2H), 4.20 (dd, J ) 1.8, 5.4 Hz, 2H), 4.11
(dd, J ) 7.2, 9.6 Hz, 2H), 3.97 (m, 2H), 1.44 (s, 6H); 13C NMR
(63 MHz, CDCl3) δ 158.0 (s), 129.6 (d), 121.5 (d), 114.6 (d),
111.2 (s), 78.0 (d), 68.1 (t), 62.6 (d), 27.4 (q).
2,5-Diazido-2,5-dideoxy-1,6-di-O-ph en yl-L-m an n itol. To
2,5-diazido-2,5-dideoxy-3,4-O-isopropylidene-1,6-di-O-phenyl-
D-mannitol (0.10 g, 0.24 mmol) was added a cold (0 °C) solution
of acetyl chloride (0.142 mL, 2.00 mmol) in MeOH (5 mL)
which had been stirring for 10 min. After stirring for 24 h at
room temperature, the reaction mixture was diluted with H2O
(10 mL), extracted with Et2O (20 mL), dried (MgSO4), and
concentrated in vacuo to give an oil. The crude product was
purified by flash column chromatography (4:1 PhCH3/EtOAc)
to give 0.060 g of the diazide diol (66% yield) as a colorless oil:
1H NMR (250 MHz, CDCl3) δ 7.31 (dd, J ) 8.1, 7.6 Hz, 4H),
7.00 (t, J ) 7.2 Hz, 2H), 6.95 (d, J ) 8.7 Hz, 4H), 4.41 (dd, J
) 9.8, 2.8 Hz, 2H), 4.23 (dd, J ) 9.9, 5.9 Hz, 2H), 3.95 (m,
4H), 2.82 (d, J ) 5.8 Hz, 2H); 13C NMR (63 MHz, CDCl3) δ
158.0 (s), 129.7 (d), 121.7 (d), 114.7 (d), 69.3 (d), 68.3 (t), 61.7
(d).
2,5-Bis[N-(ter t-bu toxyca r bon yl)a m in o]-2,5-d ideoxy-1,6-
d i-O-p h en yl-L-m a n n itol, 11. To 2,5-diazido-2,5-dideoxy-1,6-
di-O-phenyl-D-mannitol (0.10 g, 0.26 mmol) and Boc2O (0.1154
g, 0.529 mmol) in EtOAc (4 mL) was added Pd/C (10%, 0.0612
g). Hydrogen was added (with flushing) at atmospheric
pressure to the system and the reaction mixture stirred for 4
h. The suspension was then filtered through Celite and
concentrated in vacuo to give a colorless solid. This was
purified by flash column chromatography (4:1 PhCH3/EtOAc)
to give 0.078 g of 11 (58% yield) as a solid: mp 125 °C; [R]D
+48.20 (c ) 0.4, CHCl3); 1H NMR (250 MHz, CDCl3) δ 7.26
(dd, J ) 8.2, 7.2 Hz, 4H), 6.96 (t, J ) 7.2 Hz, 2H), 6.89 (d, J )
8.2 Hz, 4H), 5.32 (d, J ) 8.7 Hz, 2H), 4.60 (d, J ) 7.7 Hz, 2H),
4.31 (d, J ) 4.6 Hz, 2H), 4.09-3.92 (m, 4H), 3.76 (dd, J ) 10.3,
4.9 Hz, 2H), 1.43 (s, 18H); 13C NMR (63 MHz, CDCl3) δ 158.6
(s), 157.2 (s), 129.5 (d), 121.1 (d), 114.5 (d), 80.7 (s), 68.3 (t),
66.8 (d), 50.7 (d), 28.3 (q). Anal. Calcd for C28O8H40N2: C,
63.14; H, 7.57; N, 5.26. Found: C, 63.32; H, 7.49; N, 5.13.
5-N-(Ben zyloxycar bon yl)-2,3-N,O-car bon yl-2,5-diam in o-
2,5-d id eoxy-1,6-d i-O-p h en yl-L-id itol, 17. To 9a (0.303 g,
0.79 mmol) in EtOAc (20 mL) was added Pd/C (10%, 0.087 g).
Hydrogen was added (with flushing) at atmospheric pressure
to the system and the reaction mixture stirred for 16 h. The
suspension was then filtered through Celite and concentrated
in vacuo to give a colorless solid. This was dissolved in CH2-
Cl2 (10 mL), and benzyl chloroformate (3.0 g, 17.5 mmol) and
5-N-(Ben zyloxycar bon yl)-2,3-N,O-car bon yl-2,5-diam in o-
2,5-d id eoxy-1,6-d i-O-p h en yl-L-a ltr itol, 18. To CrO3 (0.0195
g, 0.195 mmol) and acetic anhydride (0.02 g, 0.20 mmol) in
CH2Cl2 (5 mL) was added pyridine (0.031 g, 0.39 mmol). After
5 min, the alcohol (0.044 g, 0.089 mmol) in CH2Cl2 (10 mL)
was added. The reaction mixture was stirred for 3 h and the
solvent removed in vacuo. The residue was filtered through
a SiO2 column (EtOAc) to give 0.050 g of the crude ketone.
This crude product was dissolved in MeOH (5 mL) and
NaBH4 (0.0152 g, 0.40 mmol) added. After 1 h, the reaction
mixture was partitioned between H2O (20 mL) and EtOAc (30
mL). The organic layer was washed with H2O (20 mL), dried
(MgSO4), and concentrated in vacuo. The residue was purified
by flash column chromatography (1:1 PhCH3/EtOAc) to give
0.034 g of an inseparable mixture of 18 and 17 (∼0.85:1 by
NMR, 77% yield): 1H NMR (250 MHz, CDCl3) δ 7.25-7.12
(m, 9H), 6.92 (t, J ) 7.3 Hz, 1H), 6.91 (t, J ) 7.4 Hz, 1H), 6.84
(d, J ) 9.6 Hz, 2H), 6.80 (d, J ) 9.2 Hz, 2H), 6.15 (s, 1H), 5.58
(d, J ) 9.9 Hz, 1H), 5.04 (s, 1H), 4.99 (s, 1H), 4.50 (t, J ) 4.3
Hz, 1H), 4.33 (m, 1H), 4.17 (m, 1H), 4.03 (m, 4H), 3.85 (m,
2H); 13C NMR (63 MHz, CDCl3) δ 158.7 (s), 158.2 (s), 158.0
(s), 156.6 (s), 136.0 (s), 129.5 (d), 128.5 (d), 128.2 (d), 128.0
(d), 121.5 (d), 121.3 (d) 114.7 (d), 78.5 (d), 71.3 (d), 69.3 (t),
67.3 (t), 66.8 (t), 52.7 (d), 51.1 (d). Anal. Calcd for C27O7H28N2‚
0.5H2O: C, 64.65; H, 5.83; N, 5.59. Found: C, 64.43; H, 5.73;
N, 5.35.
2,5-Bis[N-(ter t-bu toxyca r bon yl)a m in o]-2,5-did eoxy-1,6-
d i-O-p h en yl-L-a ltr itol, 16. To the mixture of alcohols (0.034
g, 0.069 mmol) in dioxane (2.0 mL) was added Ba(OH)2‚8H2O
(0.107 g, 0.34 mmol) in water (1.3 mL). The reaction mixture
was heated to 80 °C for 24 h. The suspension was then
filtered, and the solids were washed with acetone (20 mL). The
organic solvents were removed in vacuo and the aqueous
remainder was diluted with H2O (20 mL) and extracted with
EtOAc (2 × 30 mL) and CH2Cl2 (2 × 30 mL). The combined
organic layers were dried (K2CO3) and concentrated in vacuo.
The residue was dissolved in EtOAc (3.5 mL) and Boc2O (0.079
g, 0.036 mmol) added. After 4 h, the solvent was removed in
vacuo. The residue was purified by flash column chromatog-
raphy (2:1 PhCH3/EtOAc) to give 0.015 g of 16 (91% yield)
along with 0.012 g of the 10a : [R]D +32.60 (c ) 0.8, CHCl3);
1H NMR (250 MHz, CDCl3) δ 7.28 (t, J ) 7.9 Hz, 4H), 6.97 (t,
J ) 7.3 Hz, 1H), 6.97 (t, J ) 7.5 Hz, 1H), 6.90 (d, J ) 7.6 Hz,
2H), 6.87 (d, J ) 7.6 Hz, 2H), 5.32 (d, J ) 8.9 Hz, 1H), 5.15 (d,
J ) 9.2 Hz, 1H), 4.32 (m, 2H), 4.24 (m, 4H), 4.10 (s, 2H), 4.00
(m, 1H), 3.70 (m, 1H), 1.46 (s, 9H), 1.45 (s, 9H); 13C NMR (63
MHz, CDCl3) δ 158.2 (s), 157.5 (s), 155.8 (s), 129.6 (d), 121.5
(d), 121.4 (d) 114.7 (d), 80.7 (s), 79.9 (s), 72.7 (d), 71.6 (d), 69.0
(t), 67.0 (t), 51.2 (d), 50.3 (d), 28.3 (q), 27.4 (q). Anal. Calcd
for C28O8H40N2: C, 63.14; H, 7.57; N, 5.26. Found: C, 63.22;
H, 7.62; N, 5.27.
2,5-Bis[N-(ter t-bu toxyca r bon yl)a m in o]-2,5-d id eoxy-1,6-
d i-O-p h en yl-3,4-O-th ioca r bon yl-L-id itol, 20. To a stirred
solution of 10a (0.572 g, 1.10 mmol) in THF (10 mL) was added
N,N’-thiocarbonyldiimidazole (0.317 g, 1.78 mmol). The reac-
tion mixture was stirred at 55 °C for 22 h and then concen-
trated in vacuo. The residue was purified by flash column
chromatography (19:1 PhCH3/EtOAc) to give 0.433 g of 20 (70%

Acyclic Carbohydrate HIV PR Inhibitors
J . Org. Chem., Vol. 63, No. 15, 1998 4905
yield) along with 0.075 g of the corresponding carbonate (12%
yield): 1H NMR (250 MHz, CDCl3) δ 7.27 (dd, J ) 8.2, 7.6 Hz,
4H), 6.97 (t, J ) 7.3 Hz, 2H), 6.88 (d, J ) 8.1 Hz, 4H), 5.18 (s,
2H), 4.88 (d, J ) 9.5 Hz, 2H), 4.39 (m, 2H), 4.07 (m, 4H), 1.46
(s, 18H); 13C NMR (63 MHz, CDCl3) δ 190.7 (s), 157.7 (s), 155.6
(s), 129.6 (d), 121.7 (d), 114.7 (d), 82.8 (d), 81.0 (s), 66.3 (t),
50.4 (d), 28.2 (q). Anal. Calcd for C29O8H38N2S: C, 60.61; H,
6.66; N, 4.88; S, 5.58. Found: C, 60.83; H, 6.50; N, 4.87; S,
5.34.
2,5-Bis[N-(ter t-bu toxyca r bon yl)a m in o]-3,4-O-ca r bon yl-
2,5-d id eoxy-1,6-d i-O-p h en yl-L-id itol. 1H NMR (250 MHz,
CDCl3) δ 7.28 (t, J ) 7.8 Hz, 4H), 6.98 (t, J ) 7.4 Hz, 2H),
6.89 (d, J ) 7.8 Hz, 4H), 4.95 (s, 2H), 4.86 (d, J ) 9.4 Hz, 2H),
4.34 (m, 2H), 4.11 (td, J ) 9.4, 7.2 Hz, 2H), 4.04 (td, J ) 9.6,
7.8 Hz, 2H), 1.46 (s, 18H); 13C NMR (63 MHz, CDCl3) δ 157
0.8 (s), 155.6 (s), 153.9 (s), 129.6 (d), 121.7 (d), 114.7 (d), 80.9
(s), 77.9 (d), 66.6 (t), 50.5 (d), 28.2 (q).
2,5-Bis[N-(ter t-bu toxyca r bon yl)a m in o]-2,4,5-tr id eoxy-
1,6-d i-O-p h en yl-L-id itol, 19. A solution of 20 (0.176 g, 0.314
mmol), tributyltin hydride (0.20 mL, 0.74 mmol), and ΑΙΒΝ
(0.011 g, 0.067 mmol) in dry toluene (5 mL) was added
dropwise to refluxing toluene (6.5 mL) over 25 min. After an
additional 45 min, the reaction mixture was allowed to cool,
and the solution was concentrated in vacuo. The residue was
dissolved in acetonitrile (20 mL) and washed with hexane (4
× 10 mL). The acetonitrile layer was dried (MgSO4) and
concentrated in vacuo. The residue was purified by flash
column chromatography (4:1 PhCH3/EtOAc) to give 0.093 g of
19 (59% yield) along with small amounts of 21-23: [R]D
+21.59 (c ) 0.91, CHCl3); 1H NMR (250 MHz, CDCl3) δ 7.31-
7.24 (m, 4H), 6.95 (t, J ) 7.5 Hz, 2H), 6.91-6.85 (m, 4H), 5.40
(d, J ) 7.7 Hz, 1H), 5.23 (d, J ) 9.2 Hz, 1H), 4.25 (dd, J ) 9.5,
3.4 Hz, 1H), 4.16-3.96 (m, 5H), 3.84 (m, 1H), 3.11 (dd, J )
9.1, 6.3 Hz, 1H), 1.98 (m, 2H), 1.44 (s, 18H); 13C NMR (63 MHz,
CDCl3) δ 158.0 (s), 155.8 (s), 155.5 (s), 129.3 (d), 121.0 (d), 114.4
(d), 79.7 (s), 79.6 (s), 69.5 (d), 69.2 (t), 68.7 (t), 53.1 (d), 48.3
(d), 36.6 (t), 28.4 (q). Anal. Calcd for C28O7H40N2: C, 65.09;
H, 7.80; N, 5.42. Found: C, 65.26; H, 7.82; N, 5.60.
2,5-Bis[N-(ter t-bu toxyca r bon yl)a m in o]-2,5-d ideoxy-3,4-
O-m et h ylen e-1,6-d i-O-p h en yl-L-id it ol, 21: 1H NMR (250
MHz, CDCl3) δ 7.28 (t, J ) 7.9 Hz, 4H, H2′, H6′), 6.98 (t, J )
7.3 Hz, 2H, H4′), 6.93 (d, J ) 8.2 Hz, 4H, H3′, H5′), 5.04 (s,
2H, OCH2O), 4.99 (d, J ) 8.8 Hz, 2H, NH), 4.37 (d, J ) 7.3
Hz, 2H, OCH), 4.24 (m, 2H, OCHaHb), 4.07 (m, 4H, OCHaHb,
NCH), 1.48 (s, 18H, CH3); 13C NMR (63 MHz, CDCl3) δ 158.4
(s), 155.4 (s), 129.5 (d), 121.2 (d), 114.5 (d), 94.5 (t), 80.0 (s),
77.2 (d), 66.9 (t), 51.3 (d), 28.4 (q).
2-Am in o-5-[N-(ter t-bu toxycar bon yl)am in o]-2,3-N,O-car -
bon yl-2,4,5-tr id eoxy-1,6-d i-O-p h en yl-L-id itol, 22: 1H NMR
(250 MHz, CDCl3) δ 7.29 (t, J ) 7.7 Hz, 2H, H3′), 7.27 (t, J )
7.9 Hz, 2H, H3′′), 6.97 (t, J ) 7.3 Hz, 2H, H4′, H4′′), 6.89 (d,
J ) 7.7 Hz, 2H, H2′), 6.87 (d, J ) 7.5 Hz, 2H, H2′′), 5.94 (s,
1H, C2NH), 5.04 (d, J ) 8.9 Hz, 1H, C5NH), 4.52 (td, J ) 6.5,
4.0 Hz, 1H, COOCH), 4.15 (td, J ) 8.5, 4.0 Hz, 1H, NC5H),
4.07-3.92 (m, 5H, OCH2, NC2H), 2.10-2.30 (m, 2H, CH2), 1.45
(s, 9H, CH3); 13C NMR (63 MHz, CDCl3) δ 158.5 (s, C2NHCO),
158.3 (s, C1′), 158.0 (s, C1′′), 155,5 (s, (CH3)3COCO), 129.6 (d,
C3′, C3′′), 121.6 (d, C4′), 121.4 (d, C4′′), 114.6 (d, C2′, C2′′),
80.1 (s, (CH3)3CO), 76.8 (d, C3), 69.5 (t, C2), 69.2 (t, C5), 56.9
(d, C5), 46.9 (d, C2), 37.1 (t, C4), 28.3 (q, CH3).
2,5-Bis[N-(ter t-bu toxyca r bon yl)a m in o]-3,4-O,S-ca r bo-
n yl-2,4,5-tr id eoxy-1,6-d i-O-p h en yl-4-th io-L-id itol, 23: 1H
NMR (250 MHz, CDCl3) δ 7.31 (t, J ) 8.4 Hz, 2H, H3′′), 7.26
(t, J ) 8.2 Hz, 2H, H3′), 6.99 (t, J ) 7.2 Hz, 1H, H4′′), 6.97 (t,
J ) 7.4 Hz, 1H, H4′), 6.90 (d, J ) 8.1 Hz, 2H, H2′′), 6.87 (d, J
) 8.3 Hz, 2H, H2′), 5.29 (dd, J ) 8.9, 1.3 Hz, 1H, C5NH), 4.88
(d, J ) 9.5 Hz, 1H, C2NH), 4.76 (d, J ) 8.6 Hz, 1H, COOCH),
4.62-4.49 (m, 2H, NCH), 4.32 (dd, J ) 8.4, 1.6 Hz, 1H, SCH),
4.07 (m, 3H, OCH2), 3.98 (dd, J ) 9.5, 2.8 Hz, 1H, OC1HaHb),
1.48 (s, 9H, CH3), 1.45 (s, 9H, CH3); 13C NMR (63 MHz, CDCl3)
δ 172.2 (s, SCOO), 158.1 (s, C1′′), 157.7 (s, C1′), 155.9 (s,
OCOO), 155.4 (s, OCOO), 129.7 (d, C3′′), 129.5 (d, C3′), 121.8
(d, C4′′), 121.5 (d, C4′), 114.8 (d, C2′′), 114.4 (d, C2′), 82.1 (d,
C3), 80.7 (s, C(CH3)3), 69.7 (t, C1), 67.4 (t, C6), 53.0 (d, C4),
50.2 (d, C5), 49.0 (d, C2), 28.3 (q, CH3). Anal. Calcd for
C29O8H38N2S: C, 60.61; H, 6.66; N, 4.88; S, 5.58. Found: C,
60.76; H, 6.57; N, 4.75; S, 5.43.
2,5-Bis[N-(ter t-bu toxyca r bon yl)a m in o]-2,4,5-tr id eoxy-
3-O-(4-n it r ob en zoyl)-1,6-d i-O-p h en yl-L-m a n n it ol. To a
solution of 19 (0.029 g, 0.058 mmol), Ph3P (0.067 g, 0.26 mmol),
and p-nitrobenzoic acid (0.0415 g, 0.248 mmol) in THF (1 mL)
was added DEAD (0.040 mL, 0.254 mmol). After stirring
overnight, the solvent was removed in vacuo to give a yellow
oil. The crude material was purified by flash column chro-
matography (9:1 PhCH3/EtOAc) to give 0.052 g of the crude
p-nitrobenzoate ester which was used in the next step: 1H
NMR (250 MHz, CDCl3) δ 8.21 (d, J ) 8.7 Hz, 2H), 8.12 (d, J
) 8.6 Hz, 2H), 7.26 (t, J ) 7.7 Hz, 4H), 6.97 (t, J ) 7.3 Hz,
1H), 6.95, J ) 7.3 Hz, 1H), 6.86 (d, J ) 8.6 Hz, 4H), 5.50 (m,
1H), 5.25 (d, J ) 9.2 Hz, 1H), 4.89 (d, J ) 9.6 Hz, 1H), 4.46
(m, 1H), 4.25-4.00 (m, 5H), 2.25 (m, 2H), 1.42 (s, 9H), 1.36 (s,
9H); 13C NMR (63 MHz, CDCl3) δ 164.3 (s), 158.5 (s), 158.1
(s), 155.4 (s), 155.2 (s), 150.4 (s), 135.8 (s), 130.8 (d), 129.6 (d),
128.9 (d), 121.5 (d), 121.2 (d), 114.5 (d), 114.4 (d), 80.1 (s), 79.7
(s), 73.2 (d), 70.2 (t), 67.0 (t), 52.0 (d), 46.6 (d), 33.0 (t), 28.3
(q).
2,5-Bis[N-(ter t-bu toxyca r bon yl)a m in o]-2,4,5-tr id eoxy-
1,6-d i-O-p h en yl-L-m a n n itol, 24. To a solution of the crude
ester (0.038 g theoretical, 0.058 mmol) in a mixture of EtOH/
H2O/THF (5 mL, 2:1:2) was added LiOH (0.0086 g, 0.36 mmol).
After 1 h, the reaction mixture had turned yellow, and it was
added to Et2O (20 mL) and saturated aqueous NH4Cl (10 mL).
The organic phase was dried (MgSO4) and concentrated. The
residue was purified by flash column chromatography (9:14:1
PhCH3/EtOAc) to give 0.024 g of 24 (82% yield): [R]D +2.63 (c
) 0.99, CHCl3); 1H NMR (250 MHz, CDCl3) δ 7.26 (m, 4H),
6.96 (t, J ) 6.6 Hz, 2H), 6.88 (d, J ) 7.7 Hz, 2H), 6.86 (d, J )
7.7 Hz, 2H), 5.17 (d, J ) 8.8 Hz, 1H), 5.15 (d, J ) 7.3 Hz, 1H),
4.35 (dd, J ) 9.2, 3.0 Hz, 1H), 4.29 (m, 1H), 4.22 (m, 1H), 4.05
(dd, J ) 9.0, 3.0 Hz, 1H), 3.96 (dd, J ) 9.1, 3.0 Hz, 1H), 3.86
(m, 2H), 1.70 (m, 2H), 1.43 (s, 9H), 1.43 (s, 9H); 13C NMR (63
MHz, CDCl3) δ 158.7 (s), 158.4 (s), 157.3 (s), 155.6 (s), 129.5
(d), 129.5 (d), 121.3 (d), 121.0 (d), 114.5 (d), 114.4 (d), 80.3 (s),
79.6 (s), 70.3 (d), 67.8 (t), 66.9 (t), 53.9 (d), 47.1 (d), 37.4 (t),
28.4 (q), 28.3 (q). Anal. Calcd for C28O7H40N2: C, 65.09; H,
7.80; N, 5.42. Found: C, 65.21; H, 7.95; N, 5.39.
1,2-An h yd r o-3,4-O-isop r op ylid en e-6-O-p h en yl-D-m a n -
n itol, 26. To 6 (0.50 g, 2.7 mmol) and phenol (0.58 g, 6.2
mmol) in DMF (20 mL) was added K2CO3 (0.13 g, 1.3 mmol).
The reaction mixture was heated to 90 °C and stirred
overnight. After cooling, the reaction mixture was added to
saturated aqueous NH4Cl (20 mL) and extracted with Et2O
(20 mL). The organic phase washed with H2O (2 × 10 mL),
dried (MgSO4), and concentrated to give a solid. Purification
by flash column chromatography (4:1 PhCH3/EtOAc) gave 26
(0.23 g, 31% yield, 45% yield based on recovered starting
material) along with 7a (0.23 g, 23% yield) and 6 (0.16 g, 31%
yield): 1H NMR (250 MHz, CDCl3) δ 7.29 (t, J ) 8.0 Hz, 2H),
6.97 (m, 3H), 4.29 (d, J ) 8.0, 1H), 4.11-4.00 (m, 4H), 3.20
(m, 1H), 2.89 (m, 1H), 2.83 (dd, J ) 4.9, 2.7 Hz, 1H), 1.45 (s,
3H), 1.43 (s, 3H); 13C NMR (63 MHz, CDCl3) δ 158.5 (s), 129.5
(d), 121.2 (d), 114.7 (d), 110.2 (s), 79.0 (d), 78.3 (d), 71.1 (t),
69.0 (d), 52.1 (d), 45.6 (t), 27.0 (q), 26.7 (q). Anal. Calcd for
C
15O5H20‚0.15 C7H8: C, 65.54; H, 7.26. Found: C, 67.20; H,
6.11.
1-Deoxy-3,4-O-isop r op ylid en e-1-p h en yl-6-O-p h en yl-D-
m a n n itol 27. To a cold (-78 °C) suspension of 26 (0.50 g,
1.8 mmol) and CuBr‚SMe2 (0.18 g, 0.9 mmol) in THF (10 mL),
was added dropwise PhLi (1.0 M in benzene, 7.1 mmol). After
stirring for 1 h at -78 °C, the reaction mixture was allowed
to warm to room temperature. After an additional hour,
saturated aqueous NH4Cl (10 mL) was added. The organic
layer was washed with H2O (2 × 10 mL), and the aqueous
layers were back-extracted with Et2O (30 mL). The combined
organic layers were dried (MgSO4) and concentrated. The
residue was purified by flash column chromatography (9:1 f
4:1 PhCH3/EtOAc) to give 27 (0.55 g, 86% yield): 1H NMR (250
MHz, CDCl3) δ 7.32-7.24 (m, 7H), 6.98-6.91 (m, 3H), 4.26
(d, J ) 8.3 Hz, 1H), 4.02 (dd, J ) 9.4, 2.3 Hz, 1H), 3.97 (m,

4906 J . Org. Chem., Vol. 63, No. 15, 1998
Zuccarello et al.
2H), 3.85 (m, 2H), 3.55 (s, 1H), 3.18 (dd, J ) 14.4, 2.4 Hz, 1H),
3.11 (s, 1H), 2.74 (dd, J ) 13.8, 8.2 Hz, 1H), 1.43 (s, 3H), 1.41
(s, 3H).
2,5-Bis[N-(ter t-bu toxyca r bon yl)a m in o]-1,2,5-tr id eoxy-
1-p h en yl-6-O-p h en yl-L-id itol, 25. To 28 (0.21 g, 0.57 mmol)
and Boc2O (0.28 g, 1.3 mmol) in EtOAc (6 mL) was added Pd/C
(10%, 0.062 g). Hydrogen was added (with flushing) at
atmospheric pressure to the system and the reaction mixture
stirred for 3 h. The suspension was then filtered through
Celite and concentrated. The crude product was purified by
flash column chromatography (6:1 PhCH3/EtOAc) to give 25
(0.245 g, 85% yield) as an oil: 1H NMR (250 MHz, CDCl3) δ
7.29-7.16 (m, 7H), 6.94 (t, J ) 7.4 Hz, 1H), 6.87 (d, J ) 8.0
Hz, 2H), 5.09 (d, J ) 8.0 Hz, 1H), 4.91 (d, J ) 8.5 Hz, 1H),
4.01 (br s, 3H), 3.93-3.83 (m, 3H), 3.66 (br s, 1H), 3.51 (br s,
1H), 3.04-2.87 (m, 2H), 1.38 (s, 18H); 13C NMR (63 MHz,
CDCl3) δ 158.3 (s), 156.1 (s), 138.5 (s), 129.5 (d), 129.3 (d), 128.4
(d), 126.3 (d), 121.2 (d), 114.6 (d), 79.9 (s), 72.2 (d), 68.5 (t),
53.1 (d), 50.5 (d), 38.1 (t), 28.3 (q). Anal. Calcd for: C28O7H40N2
‚ 0.5 H2O: 63.98; H, 7.86; N, 5.33. Found: C, 63.68; H, 7.20;
N, 6.02.
2,5-Diazido-1,2,5-tr ideoxy-3,4-O-isopr opyliden e-1-ph en -
yl-6-O-p h en yl-L-id itol. To a cooled (-5 °C) solution of DIAD
(0.43 g, 2.5 mmol) in THF (1 mL) was added 27 (0.40 g, 1.1
mmol) in THF (5 mL) and Ph3P (0.64 g, 2.5 mmol). After 15
min, DPPA (0.77 g, 2.8 mmol) was added and the reaction
mixture allowed to warm to room temperature. After stirring
overnight, the solvent was removed in vacuo to give a yellow
oil. The crude material was purified by flash column chro-
matography (2:1 petroleum ether/PhCH3 f 9:1 PhCH3/EtOAc)
to give a mixture of the product and the elimination product
1
(0.297 g, ∼2:3 by H NMR) which was used in the next step.
2,5-Dia zid o-1,2,5-t r id eoxy-1-p h en yl-6-O-p h en yl-L-id i-
tol, 28. To cold (0 °C) methanol (10 mL) was added acetyl
chloride (0.52 g, 6.6 mmol). After stirring for 10 min, the
solution was added to the crude diazide (0.297 g, ∼0.29 mmol)
and stirred overnight at room temperature. The reaction
mixture was concentrated, diluted with H2O (20 mL), and
extracted with Et2O (20 mL). The organic phase was dried
(MgSO4) and concentrated in vacuo to give an oil. This oil was
purified by flash column chromatography (4:1 PhCH3/EtOAc)
to give 28 (0.075 g, 18% yield for two steps): 1H NMR (250
MHz, CDCl3) δ 7.32-7.22 (m, 7H), 6.99 (td, J ) 7.3, 0.7 Hz,
1H), 6.89 (dd, J ) 7.9, 0.8 Hz, 2H), 4.24 (m, 2H), 3.94-3.82
(m, 2H), 3.65 (m, 2H), 3.10 (dd, J ) 5.6, 13.6 Hz, 1H), 3.01-
2.93 (m, 3H); 13C NMR (63 MHz, CDCl3) δ 157.9 (s), 136.7 (s),
129.6 (d), 129.3 (d), 128.8 (d), 127.1 (d), 121.7 (d), 114.6 (d),
72.1 (d), 71.4 (d), 68.0 (t), 64.8 (d), 62.3 (d), 36.7 (t).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for compounds 7b-h , 8b-j and 9b-j (6 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O971562C