Epoxyalcohol route to hydroxyethylene dipeptide isosteres. Stereodivergent synthesis of the diamino alcohol core of ritonavir and its C-2 epimer

Article abstract of DOI:10.1021/jo025616g

A stereoselective synthesis of hydroxyethylene dipeptide isosteres based on the 1,4-diamino-2-hydroxybutane structure is described. Horner - Emmons olefination of phosphonates derived from α-amino acids, stereoselective reduction of the resulting enones to allylic alcohols, and syn epoxidation of the latter lead to enantiomerically pure 1-amino-2-hydroxy-3,4-epoxybutanes, key intermediates in the synthesis. Reductive cleavage of the epoxy alcohols with Red-Al proceeds in a highly regioselective way, giving 1-amino-2,4-dihydroxybutanes, from which diamino alcohol hydroxyethylene isosteres are obtained by selective protection of the secondary 2-hydroxy group, via cyclization to 1,3-oxazolidinone, and further elaboration of the 4-hydroxy. Both C-2 epimers of 1,4-diamino-2-hydroxybutanes are accessible by appropriate choice of the conditions for cyclization. The approach is demonstrated by the synthesis of a series of six hydroxyethylene dipeptide isosteres, including the diamino alcohol core of potent HIV-protease inhibitor ritonavir 18 and its C-2 epimer 11a.

Full text of DOI:10.1021/jo025616g

Ep oxya lcoh ol Rou te to Hyd r oxyeth ylen e Dip ep tid e Isoster es.
Ster eod iver gen t Syn th esis of th e Dia m in o Alcoh ol Cor e of
Riton a vir a n d Its C-2 Ep im er
Fabio Benedetti,* Federico Berti, and Stefano Norbedo
Department of Chemical Sciences, University of Trieste, Via Giorgieri 1, I-34127 Trieste, Italy
benedett@univ.trieste.it
Received February 24, 2002
A stereoselective synthesis of hydroxyethylene dipeptide isosteres based on the 1,4-diamino-2-
hydroxybutane structure is described. Horner-Emmons olefination of phosphonates derived from
R-amino acids, stereoselective reduction of the resulting enones to allylic alcohols, and syn
epoxidation of the latter lead to enantiomerically pure 1-amino-2-hydroxy-3,4-epoxybutanes, key
intermediates in the synthesis. Reductive cleavage of the epoxy alcohols with Red-Al proceeds in
a highly regioselective way, giving 1-amino-2,4-dihydroxybutanes, from which diamino alcohol
hydroxyethylene isosteres are obtained by selective protection of the secondary 2-hydroxy group,
via cyclization to 1,3-oxazolidinone, and further elaboration of the 4-hydroxy. Both C-2 epimers of
1,4-diamino-2-hydroxybutanes are accessible by appropriate choice of the conditions for cyclization.
The approach is demonstrated by the synthesis of a series of six hydroxyethylene dipeptide isosteres,
including the diamino alcohol core of potent HIV-protease inhibitor ritonavir 18 and its C-2 epimer
11a .
In tr od u ction
inhibitors of reverse transcriptase, another retroviral
enzyme. These combination therapies suppress viral
replication for prolonged periods and have led to a
significant decline in mortality related to AIDS.4
Peptidomimetic inhibitors based on hydroxyethylene
dipeptide isosteres A show great efficacy against HIV-
PR.1-3,5 Ritonavir6 and lopinavir,7 both containing the
1,4-diamino-2-hydroxybutane core A, are among the
most potent anti-AIDS drugs discovered so far, with
excellent oral bioavailability, particularly when admin-
istered as an association of the two drugs (Kaletra).4
Aspartyl proteases play a crucial role in the develop-
ment and propagation of several disease states.1 Renin
for example, which is responsible for the conversion of
angiotensinogen into angiotensin I, is involved in the
development of hypertension, and cathepsin D, another
endogenous protease, is thought to be involved in cancer
and Alzheimer’s disease. Among exogenous enzymes,
plasmepsins are believed to be involved in the degrada-
tion of human hemoglobin, which is the main source of
food for the malarial parasite Plasmodium falciparum.
The human immunodeficiency virus protease (HIV-PR)
is an essential enzyme for the replication of the virus
responsible for AIDS, and aspartic proteases secreted into
the host organism by strains of Candida may be con-
nected with some of the effects caused by infections by
these yeasts. The availability of structural information
for many enzymes of this class has made them attractive
targets for the rational design of potent and selective
inhibitors, many of which show great promise as drugs.1a,2
In particular, a number of designed inhibitors of HIV-
PR have rapidly reached the market and are currently
used in the therapy of AIDS,3 in combination with
(4) For comprehensive and updated information on FDA-approved
anti-AIDS drugs see the URL: http://www.niaid.nih.gov/daids/dtpdb/
fdadrug.htm.
(5) (a) Lebon, F.; Ledecq, M. Curr. Med. Chem. 2000, 7, 455-477.
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H.; Kong, X. P.; Plattner, J . J .; Leonard, J . M.; Norbeck, D. W.;
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10.1021/jo025616g CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/08/2002
J . Org. Chem. 2002, 67, 8635-8643
8635

Benedetti et al.
SCHEME 1
Nanomolar inhibitors of renin based on isosteres A have
also been reported.8
This route, however, is practical only for C2-symmetric
diaminodiols, with identical R, R′ groups, the only case
in which deoxygenation cannot lead to multiple products,
due to the equivalency of the two symmetry-related
hydroxy groups.
Another approach to diamino alcohols A (Scheme 1,
route b) starts from hydroxyethylene isosteres C (5-
amino-4-hydroxyacids), which are converted into A via
the Curtius rearrangement of the corresponding acyl
azides.8,14 4-Amino-3-hydroxybutyric acids C are acces-
sible by a number of stereoselective strategies from chiral
precursors such as R-amino acids15 and sugars16 or from
achiral precursors by asymmetric synthesis.17
Despite the considerable synthetic effort in this area,
however, few direct syntheses of the diamino alcohol core
A have been reported and are limited to the dibenzyl
derivative (R, R′ ) CH2Ph) mimicking the Phe-Phe
dipeptide.18 In this paper we describe a direct and general
approach to diamino alcohol dipeptide isosteres A start-
ing from R-amino acids (route c, Scheme 1).19 The key
Due to the presence of the isolated chiral center on C-4,
the synthesis of the diamino alcohol core A is not
straightforward, and these isosteres are in general
obtained by transformation of other, more accessible,
dipeptide isosteres.9 Thus, for example, the approach
followed in the original synthesis of the diamino alcohol
core of ritonavir10 was based (route a, Scheme 1) on the
deoxygenation of dihydroxyethylene isosteres B (diamino-
diols), which, in turn, can be readily obtained by the
pinacol homocoupling of R-aminoaldehydes11 and from
other chiral precursors such as sugars12 or tartaric acid.13
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Chem. 1992, 35, 1735-1746.
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Kennard, A.; Sham, H. L.; Zhao, C.; Vasavanonda, S.; Kohlbrenner,
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Budt, K. H.; Peyman, A.; Hansen, J .; Knolle, J .; Meichsner, C.;
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4898-4906. (b) Kang, S. H.; Ryu, D. H. Chem. Commun. 1996, 355-
356. (c) Dreyer, G. B.; Boehm, J . C.; Chenera, B.; DesJ arlais, R. C.;
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Darke, P. L.; Zugay, J . C. J . Org. Chem. 1993, 58, 1025-1029. (c)
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Ghosh, A. K.; Shin, D.; Downs, D.; Koelsch, G.; Lin, X.; Ermolieff, J .;
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8636 J . Org. Chem., Vol. 67, No. 24, 2002

Ritonavir and Its C-2 Epimer
nate.21 Horner-Emmons olefination of the phosphono-
ketones 2 with the appropriate aldehyde under the
conditions described by Mikolajczyk22 (EtOH/K2CO3) gave
the trans enones 3 characterized by a 15.5-16 Hz
coupling constant between the vinyl protons. No cis
isomers were detected, in agreement with the high
stereoselectivity generally reported for this reaction.22b
The N-Boc aminoketones were then reduced with
sodium borohydride in methanol, giving the syn-amino
alcohols 4. Hydride addition takes place according to
Cram’s model (BocNH ) medium; R ) large) with
stereoselectivity ranging from 75% in the reduction of 3a
to over 95% in the reduction of aminoketones 3b-e
containing a branched substituent on the R-carbon.20,23
In the latter case a single crystallization was sufficient
to obtain amino alcohols 4 as single diastereoisomers. The
enantiomeric purity was checked at this stage, by con-
verting the N-Boc amino alcohols into the corresponding
Mosher’s esters and was found in every case to be the
same as in the starting aminoesters 1, indicating that
no epimerization adjacent to the carbonyl takes place
during the synthesis. Syn epoxidation24 of the allylic
alcohols 4 with m-chloroperoxybenzoic acid was the next
step, giving the epoxyalcohols 5 as single stereoisomers.
By this sequence of stereoselective reactions epoxyalco-
hols 5b, 5d , and 5e were obtained in 32%, 40%, and 50%
yield from the methyl esters of valine (1b), isoleucine
(1d ), and (S)-phenylglycine (1e), respectively; epoxides
5a and 5c were available from our previous investigation,
in which the stereochemical course of this reaction
sequence was analyzed and discussed in detail.20
Conversion of the epoxy alcohol intermediates 5 to
hydroxyethylene isosters 11 was then carried out in four
passages, as shown in Scheme 2. A regioselective reduc-
tive cleavage of the epoxide ring was required in order
to set the correct functionalization on the four-carbon
skeleton (Scheme 2). Red-Al is known to selectively
transfer a hydride to the C-2 of 2,3-epoxy alcohols to give
1,3-diols;25 accordingly, the reductive ring cleavage of
epoxy alcohols 5 with this reagent proceeded successfully
to give the syn,syn-aminodiols 6 in 60-76% isolated yield.
Regioisomers derived from hydride attack at C-3 were
never detected, irrespectively of the size of the R′ sub-
stituent. We have shown previously that, with a variety
of nucleophiles under nonchelating conditions, ring open-
ing of epoxides 5 takes place preferentially at the distal
SCHEME 2 a
a
(a) CH3PO(OCH3)2, n-BuLi, THF; 95%. (b) R′CHO, K2CO3,
EtOH, 25 °C; 80%. (c) NaBH4, MeOH, 0 °C; 67-79%. (d) mCPBA,
CH2Cl2, 25 °C; 65-70%. (e) Red-Al, THF, 25 °C; 60-76%. (f) NaH,
THF, 25 °C; 78-85%. (g): (i) MsCl, Et3N, CH2Cl2, 0 °C; (ii) NaN3,
18-crown-6, DMSO, 50 °C; 75-83% overall. (h): (i) Boc2O, NaH,
THF, 25 °C; (ii) K2CO3, MeOH/H2O, 25 °C; 70-85% overall. (i) 1
atm H2, 10% Pd/C, MeOH, 25 °C; 95-100%.
step in the synthesis is the reductive ring opening of
epoxyalcohols D, which allows installing the isolated
chiral center with the proper stereochemistry. Complete
control of stereoselectivity in the formation of the isolated
chiral center, access to both epimers at C-2, and the
possibility to differentiate between R and R′ residues and
between the two amino groups are the key features of
this novel synthesis of the 1,4-diamino-2-hydroxybutane
core unit.
(20) (a) Benedetti, F.; Miertus, S.; Norbedo, S.; Tossi, A.; Zlatoidzky,
P. J . Org. Chem. 1997, 62, 9348-9353. (b) Benedetti, F.; Miertus, S.;
Norbedo, S. Croatica Chem. Acta 2001, 74, 763-777.
(21) (a) Deziel, R.; Plante, R.; Caron, V.; Grenier, L.; Llinas-Brunet,
M.; Duceppe, J .-S.; Malenfant, E.; Moss, N. J . Org. Chem. 1996, 61,
2901-2903. (b) Chakravarty, P. K.; Combs, P.; Roth, A.; Greenlee, W.
J . Tetrahedron Lett. 1987, 28, 611-612.
(22) (a) Mikolajczyk, M.; Balczewski, P. Synthesis 1987, 659-661.
(b) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863-927.
(23) (a) Albeck, A.; Persky, R. Tetrahedron 1994, 21, 6333-6346.
(b) Dufour, M.-N.; J ouin, P.; Poncet, J .; Pantaloni, A.; Castro, B. J .
Chem. Soc., Perkin Trans. 1 1986, 1895-1899. (c) See also: Koskinen,
A. M. P.; Koskinen, P. M. Tetrahedron Lett. 1993, 34, 6765-6768.
(24) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,
1307-1370.
(25) For leading references see: (a) Finan, J . M.; Kishi, Y. Tetra-
hedron Lett. 1982, 23, 2719-2722. (b) Viti, S. M. Tetrahedron Lett.
1982, 23, 4541-4544. (c) Minami, N.; Ko, S. S.; Kishi, Y. J . Am. Chem.
Soc. 1982, 104, 1109-1111. (d) Ma, P.; Martin, V. S.; Masamune, S.;
Sharpless, K. B.; Viti, S. M. J . Org. Chem. 1982, 47, 1378-1380. (e)
Kirshenbaum, K. S.; Sharpless, K. B. Chem. Lett. 1987, 11-14. For a
recent example see: (f) Marshall, J . A.; Lu, Z. H.; J ohns, B. A. J . Org.
Chem. 1998, 63, 817-823.
Resu lts a n d Discu ssion
The initial part of the synthesis (Scheme 2) is the
preparation of the amino epoxyalcohol intermediates 5,
starting from R-amino acids and following a general
approach that we developed as part of our work on
dihydroxyethylene isosteres.20 Aminoesters 1 were ini-
tially converted into the corresponding ketophosphonates
2 by reaction with lithiated methyl dimethylphospho-
(18) (a) Haight, A. R.; Stuk, T. L.; Allen, M. S.; Bhagavatula, L.;
Fitzgerald, M.; Hannick, S. M.; Kerdesky, F. A. J .; Menzia, J . A.;
Parekh, S. I.; Robbins, T. A.; Scarpetti, D.; Tien, J . J . Org. Proc. Res.,
Dev. 1999, 3, 94-100. (b) Stuk, T. L.; Haight, A. R.; Scarpetti, D.; Allen,
M. S.; Menzia, J . A.; Robbins, T. A.; Parekh, S. I.; Langridge, D. C.;
Tien, J . J .; Pariza, R. J .; Kerdesky, F. A. J . J . Org. Chem. 1994, 59,
4040-4041. (d) Gurjar, M. K.; Pal, S.; Rao, A. V. R.; Pariza, R. J .;
Chorghade, M. S. Tetrahedron 1997, 53, 4769-4778.
(19) Preliminary communication: Benedetti, F.; Norbedo S. Chem.
Commun. 2001, 203-204.
J . Org. Chem, Vol. 67, No. 24, 2002 8637

Benedetti et al.
SCHEME 3
Having accomplished the differentiation between the
two secondary hydroxy groups, the next step in the
synthesis was the conversion of the hydroxy group of 7,
activated as mesylate, into amino. This passage actually
proved harder than expected due to the propensity of the
intermediate mesylate to eliminate giving the alkene 9.
This was the main or sole product when direct displace-
ment of the mesylate was attempted with concentrated
NH3 in THF or when sodium azide was used as the
nucleophile in either aqueous methanol or DMSO. How-
ever, carrying out the displacement with sodium azide
in dimethyl sulfoxide, in the presence of 18-crown-6,
compounds 8 (Scheme 2) where obtained in 80-85% yield
for the two passages. A small amount (8%) of elimination
product 9 accompanied the formation of 8b and 8d , in
which a bulky residue (R′ ) isopropyl) is present on the
carbon adjacent to the reaction center and partially
hinders displacement of the leaving group by the nucleo-
phile, while in the synthesis of benzyl derivatives 8a ,c
and methyl derivative 8e elimination to the alkene was
not observed. The hydroxy and amino groups were then
regenerated by treatment of the oxazolidinones 8 with
di-tert-butyl dicarbonate, followed by hydrolysis of the
more labile N-Boc-oxazolidinones thus obtained with
potassium or cesium carbonate in aqueous methanol29 to
give N-Boc amino alcohols 10. Finally, catalytic hydro-
genation of the azides 10 gave the selectively monopro-
tected hydroxyethylene isosteres 11a -e. Diamino alco-
hols 11 were obtained by this route in 27-38% yield from
the epoxyalcohols 5, while the overall yield from the
starting N-Boc-aminoesters 1 was 11-17%. In view of
the well-known preference of aspartic proteases for
hydrophobic cleavage sites, dipeptide isosteres with
aliphatic or aromatic side chains were selected as targets
of the present study. However, the methodology is quite
general and can be easily extended to other residues.
Dibenzyl diamino alcohol 11a (Scheme 2) possesses the
same structure of the diamino alcohol core of ritonavir
and lopinavir, but has the opposite configuration at the
alcoholic carbon, which is R in 11a and S in ritonavir.
Thus, an inversion of configuration at this carbon was
required to extend our synthesis from the syn,syn to
the anti,anti series of isosteres. The feasibility of this
approach was demonstrated by the synthesis of the
diamino alcohol core of ritonavir.
carbon.20,26 The complete C-2 selectivity observed in this
case is in agreement with the hypothesis that, in the
reductive ring opening by Red-Al, selectivity is controlled
by coordination of aluminum to the epoxy alcohol followed
by intramolecular delivery of hydride onto C-2.25a-e
Furthermore, the reduction of methyl epoxide 5e clearly
demonstrates that the scope of the reaction is not limited
to substrates possessing bulky R′ substituents.
After establishing the desired functionalization on the
butane skeleton, it was necessary to selectively protect
the 2-hydroxy group in order to convert the newly formed
4-hydroxy into amine. The logical way to differentiate
between the two secondary hydroxy groups was to exploit
their different positional relationships with respect to the
Boc-protected amino group in the formation of a cyclic
N,O-protected derivative. In a first attempt, the amino-
diol 6b was treated with excess 2,2-dimethoxypropane
(DMP) in the presence of p-toluenesulfonic acid; under
these conditions, however, the 1,3-dioxane 13 was ob-
tained rather than the desired oxazolidine 12 (Scheme
3). Although useless for the purpose of the synthesis,
compound 13 allowed the confirmation of the syn stereo-
chemistry of the parent 1,3-diol 6b. In particular, in the
13C NMR spectrum of 13 the large difference between the
chemical shifts of the isopropylidene methyl groups (19.5
and 30.1 ppm, respectively) and the value of 98.3 ppm
for the acetal quaternary carbon are diagnostic of a syn
relationship between the two hydroxy groups.27
The desired intramolecular N,O-protection was even-
tually obtained by treating the N-Boc aminodiols 6 with
sodium hydride in THF (Scheme 2), whereupon an
intramolecular acyl transfer cyclization takes place
smoothly, giving oxazolidinones 7 in good yields. Values
of 7.3-8.0 Hz for the coupling constant J (H4,H5) between
the vicinal oxazolidinone ring protons were measured in
the 1H NMR spectra of 7, consistent with a cis disposition
of the ring substituents.28 Oxazolidinones 7 derive from
L-amino acids via the epoxy alcohols 5, and no racem-
ization is observed in the early stages of the synthesis;20
therefore, the syn-relationships between the ring sub-
stituents of 7 and between the oxygens of 13 (Scheme 3)
unambiguously confirm the stereochemical assignments
shown in Scheme 2.
An initial attempt to invert the configuration of C-2
at a late stage in the synthesis was unsuccessful: when
the azido alcohol 10a was made to react with benzoic
acid, under Mitsunobu conditions,30 a mixture of products
was formed, probably due to the presence of the reactive
azido group. The solution, eventually, came again from
oxazolidinone chemistry. We,31 and others,10,32 have
shown that when the hydroxy group of chiral N-Boc-â-
amino alcohols is converted into a suitable leaving group,
cyclization to oxazolidinones can take place with inver-
sion of configuration, by an SN2 intramolecular displace-
ment (Scheme 4) with concomitant loss of isobutene. The
C-5 configuration of the resulting oxazolidinone is op-
posite with respect to that of the corresponding product
(26) Benedetti, F.; Magnan, M.; Miertus, S.; Norbedo, S.; Parat, D.;
Tossi, A. Bioorg. Med. Chem. Lett. 1999, 20, 3027-3030.
(27) (a) Chan, T. H.; Nwe, K. T. J . Org. Chem. 1992, 57, 6107-
6111. (b) Evans, D. A.; Rieger, D. L.; Gage, J . R Tetrahedron Lett. 1990,
31, 7099-7100. (c) Rychnovsky, S. D.; Skalitzky, D. J . Tetrahedron
Lett. 1990, 31, 945-948.
(28) (a) Armbruster, J .; Grabowski, S.; Ruch, T.; Prinzbach, H.
Angew. Chem., Int. Ed. Engl. 1998, 37, 2242-2245. (b) Fa¨ssler, A.;
Bold, G.; Steiner, H. Tetrahedron Lett. 1998, 39, 4925-4928. (c)
Shinozaki, K.; Mizuno, K.; Oda, H.; Masaki, Y. Bull. Chem. Soc. J pn.
1996, 69, 1737-1745. (d) Baker, W. R.; Pratt, J . K. Tetrahedron 1993,
49, 8739-8756. (e) Herranz, R.; Castro-Pichel, J .; Vinuesa, S.; Garcia-
Lopez, M. T. J . Org. Chem. 1990, 55, 2232-2234. (f) Raddatz, P.;
J onczyk, A.; Minck, K.; Schmitges, C. J .; Sombroek, J . J . Med. Chem.
1991, 34, 3267-3280. (g) Kempf, D. J . J . Org. Chem. 1986, 51, 3921-
3926. See also refs 11d, 13a, and 15c.
(29) Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1987, 28, 4185-4188.
(30) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Hsu, C. T.; Wang,
N.-Y.; Latimer, L. H.; Sih, C. J . J . Am. Chem. Soc. 1983, 105, 593-601.
(31) Benedetti, F.; Norbedo, S. Tetrahedron Lett. 2000, 41, 10071-
10074.
8638 J . Org. Chem., Vol. 67, No. 24, 2002

Ritonavir and Its C-2 Epimer
tion31 directly to the N-Boc aminodiol 6a , a precursor of
the azide 10a , which was also available from the syn-
thesis of the hydroxyethylene isostere 11a . When 6a was
treated with excess methanesulfonyl chloride and diiso-
propylethylamine, in 1,2-dichloroethane at 80 °C, the
activated oxazolidinone 15 was smoothly obtained by
cyclization of the intermediate bis-mesylate 14 (Scheme
5). It was thus possible, in a single step, to obtain (i) the
desired inversion of configuration at the diol C-2; (ii) the
selective protection of the first hydroxy group; and (iii)
the activation of the second hydroxy group. The crude
mesylate 15 was then subjected to the reaction with
sodium azide and 18-crown-6, under the same conditions
already described for the 2R series, to give the azide 16
with an overall yield of 50% for the two steps (Scheme
5). Although the yield for the cyclization step was
somewhat lower in this case, the route is more direct and
overall yields are better (50% for the pathway 6a f 15
f 16 against 36% for the pathway 6a f 10a f 16). The
final steps of the synthesis, viz., Boc-protection and
hydrolysis of the oxazolidinone 16 to give the protected
amino alcohol 17 and catalytic hydrogenation of the azide
to the (S,S,S)-diamino alcohol 18 (Scheme 5), are analo-
gous to those already described for the epimeric (S,R,S)-
isostere 11a. By this route the Boc-monoprotected ritonavir
core 18 was obtained from the diol 6a in 35% and 25%
overall yields for the two pathways described.
SCHEME 4
SCHEME 5 a
Con clu sion s
We have described a novel, stereoselective synthesis
of diamino alcohol dipeptide isosteres based on epoxy
alcohol intermediates (5) that can be obtained in good
yields from R-amino acids. The high level of asymmetric
induction observed in all steps ensures that the stereo-
chemical information is efficiently transferred from the
first stereogenic center, derived from the amino acid
precursor, to the epoxide ring of intermediates 5. Reduc-
tive cleavage of these epoxy alcohols is highly regiose-
lective and generates 1-amino-2,3-diols, which are then
elaborated to give the diamino alcohol isosteres, via the
selective protection of the 2-hydroxy group as oxazolidi-
none. By tuning the conditions for N-Boc amino alcohol
cyclization to 1,3-oxazolidinone it is further possible to
control the configuration of the alcoholic carbon, thus
giving access to both syn,syn and anti,anti isosteres. The
possibility to introduce nonidentical R, R′ side chains,
corresponding to natural and nonnatural amino acids,
and the selective monoprotection of the amino groups are
other valuable features of this approach, particularly for
the synthesis of inhibitors in which the isostere is coupled
to different peptide residues.34
Recently we have described the synthesis of dihydroxy-
ethylene isosteres, based on the 1,4-diamino-2,3-dihy-
droxybutane20 and 4-amino-2,3-dihydroxybutyrate26 cores,
via the ring opening of epoxyalcohols 5. The extension
of this approach to the 1,4-diamino-2-hydroxy iso-
stere, described in this work, further demonstrates the
utility of epoxy alcohols 5 as intermediates for the
synthesis of building blocks of peptidomimetic aspartic
protease inhibitors.
a
(a) MsCl, DIPEA, 1,2-dichloroethane, reflux. (b) NaN3, 18-
crown-6, DMSO, 50 °C; 50% for two steps. (c) SOCl2, THF, 25 °C;
80%. (d) (i) Boc2O, NaH, THF, 25 °C; (ii) K2CO3, MeOH/H2O, 25
°C; 74%. (e) 1 atm H2, 10% Pd/C, MeOH, 25 °C; 95%.
obtained by the more conventional base-catalyzed intra-
molecular acyl transfer mechanism.33
To apply this approach to the synthesis of the ritonavir
core, the azide 10a was treated with thionyl chloride, as
recently described by Ghosh,32a to give the C-5 inverted
oxazolidinone 16 in 80% yield (Scheme 5). The trans
stereochemistry of this oxazolidinone was clearly estab-
lished from a NOE experiment, which showed a 3%
enhancement between the ring H-4 and H-5 against a
10% enhancement observed for the same protons in the
corresponding cis oxazolidinone 8a .
A more efficient synthesis of 16 was obtained by
applying our conditions for N-Boc amino alcohol cycliza-
(32) (a) Ghosh, A. K.; Shin, D.; Mathivanan, P. Chem. Commun.
1999, 1025-1026. (b) Williams, L.; Zhang, Z.; Shao, F.; Carroll, P. J .;
J oullie´, M. M. Tetrahedron 1996, 52, 11673-11694. (c) Curran, T. P.;
Pollastri, M. P.; Abelleira, S. M.; Messier, R. J .; McCollum, T. A.; Rowe,
C. G. Tetrahedron Lett. 1994, 35, 5409-5412. (d) Bach, T.; Schro¨der,
J . Tetrahedron Lett. 1997, 38, 3707-3710. (e) Agami, C.; Couty, F.;
Hamon, L.; Venier, O. Tetrahedron Lett. 1993, 28, 4509-4512. (f) Lago,
M. A.; Samanen, J .; Elliott, J . D. J . Org. Chem. 1992, 57, 3493-3496.
(33) Ager, D. J .; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96,
835-875.
(34) In the original synthesis of ritonavir, approximately 50% of the
isostere was lost through statistical formation of the undesired product
during the acylation of the unprotected diamino alcohol core. See ref
10.
J . Org. Chem, Vol. 67, No. 24, 2002 8639

Benedetti et al.
(c 0.2); IR (Nujol) 3417, 1721, 1688, 1630 cm-1; 1H NMR δ 1.39
(s, 9H), 1.79 (dd, 3H, J ) 1.5, 7.0 Hz), 5.43 (d, 1H, J ) 6.6
Hz), 5.97 (d, NH, J ) 6.6 Hz), 6.10 (dd, 1H, J ) 1.5, 15.4 Hz),
6.98 (dq, 1H, J ) 7.0, 15.4 Hz), 7.26-7.35 (m, 5H, Ph); 13C
NMR 18.5, 28.4, 62.6, 79.8, 128.1, 128.2, 128.3, 129.1, 137.2,
145.2, 155.0, 194.3; ES-MS m/z 276 [MH]+. Anal. Calcd for
Exp er im en ta l Section
Moisture-sensitive reactions were carried out in oven-dried
vessels under a positive argon pressure. THF was predried
over KOH, fractionated, and redistilled from sodium benzo-
phenone before use. Dichloromethane was dried over CaCl2
and fractionated. Flash column chromatography was per-
formed on silica gel 60 (230-400 mesh); silica gel 60F254 coated
plastic sheets were used for TLC and developed with I2 or with
aqueous KMnO4/H2SO4. Melting points were determined in an
open capillary apparatus and are uncorrected. 1H NMR spectra
(400 MHz) and 13C NMR spectra (100.4 MHz) were recorded
for CDCl3 solutions containing Me4Si as an internal standard.
Mass spectra were obtained by electron impact (MS) and/or
electrospray ionization (ES-MS) at the University of Trieste
Central Facility for Mass Spectrometry. Elemental analyses
were obtained in-house at the Department of Chemical Sci-
ences. Optical rotations were measured at 589 nm for MeOH
solutions. Known phosphonates 2a -d were obtained as de-
scribed.20,21 The synthesis of epoxyalcohols 5a and 5c has been
reported previously.20
C
16H21NO3: C 69.8, H 7.69, N 5.09. Found: C 69.5, H 8.01, N
5.01.
ter t-Bu tyl (1S,2R,3E)-2-Hyd r oxy-1-isop r op yl-5-m eth -
ylh ex-3-en ylca r ba m a te (4b). NaBH4 (563 mg, 14.8 mmol)
was added in small portions over 10 min, at 0 °C, to a stirred
solution of enone 3b (4.00 g, 14.8 mmol) in methanol (50 mL).
After 1 h at 0 °C the solution was neutralized with glacial
acetic acid, the solvent was rotary evaporated, and the residue
was partitioned between ethyl acetate and saturated aqueous
NaHCO3. The aqueous phase was extracted with ethyl acetate,
and the combined organic phases were washed with brine and
dried over sodium sulfate. The solvent was rotary evaporated
to give the crude product, which was recrystallized from
isopropyl ether (2.69 g, 67%): mp 105-106 °C; [R]25 -31.5 (c
D
0.5); IR (Nujol) 3365, 1684 cm-1; H NMR δ 0.89 (d, 3H, J )
1
Dim eth yl [(3S)-3-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-3-
p h en yl-2-oxop r op yl]p h osp h on a te (2e). Following a re-
ported procedure20,21 and starting from 8.91 g (33.6 mmol) of
(S)-N-Boc-2-phenylglycine methyl ester, 67.0 mL (168 mmol)
of 2.5 M BuLi in hexane, and 18.2 mL (168 mmol) of dimethyl
methylphosphonate, a crude oil was obtained, which was
crystallized from isopropyl ether to afford 11.41 g (31.9 mmol,
95%) of white crystals; mp 89 °C; [R]25D +130 (c 0.2); IR (Nujol)
6.9 Hz), 0.92 (d, 3H, J ) 6.8 Hz), 0.94 (d, 6H, J ) 6.8 Hz),
1.37 (s, 9H), 1.71 (m, 1H), 2.24 (m, 1H), 2.61 (bs, OH), 3.46
(m, 1H), 4.07 (m, 1H), 4.38 (d, NH, J ) 9.5 Hz), [5.34 (ddd, J
) 15.4, 7.0, 1.1 Hz), 5.64 (dd, J ) 15.4, 5.5 Hz), 2H]; 13C NMR
δ 18.2, 20.1, 22.2, 28.3, 28.9, 30.8, 60.4, 73.6, 79.4, 125.4, 141.1,
157.0; ES-MS m/z 272 [MH]+, 216, 172. Anal. Calcd for C15H29
-
NO3: C 66.4, H 10.8, N 5.18. Found: C 66.9, H 11.1, N 5.27.
ter t-Bu t yl (1S,2R,3E)-2-H yd r oxy-5-m et h yl-1-[(1S)-1-
m eth ylp r op yl]h ex-3-en ylca r ba m a te (4d ). With the same
procedure, 3d (3.00 g, 10.6 mmol) gave 2.39 g (8.37 mmol, 79%)
3242, 1703 cm-1 1H NMR δ 1.38 (s, 9H), 2.86 (dd, 1H, J )
;
14.3, 21.6 Hz), 3.17 (dd, 1H, J ) 14.3, 22.0 Hz), 3.61 (d, 3H, J
) 11.0 Hz), 3.75 (d, 3H, J ) 11.4 Hz), 5.44 (m, 1H), 5.88 (m,
NH), 7.28-7.37 (m, 5H, Ar); 13C NMR δ 28.3, 38.0 (d, J ) 133
Hz), 53.2, 64.9, 80.1, 128.2, 128.8, 129.4, 136.1, 154.7, 197.6;
ES-MS m/z 358 [MH]+. Anal. Calcd for C16H24NO6P: C 53.8,
H 6.77, N 3.92. Found: C 53.9, H 6.38, N 3.92.
of a white solid: mp 72-74 °C, from isopropyl ether; [R]25
D
-28.1 (c 0.4); IR (Nujol) 3382, 1683 cm-1
;
1H NMR δ 0.87-
1.01 (m, 12H), 1.09 (m, 1H), 1.44 (m, 10H), 1.56 (m, 1H), 2.29
(m, 1H), 2.75 (bs, OH), 3.59 (m, 1H), 4.20 (m, 1H), 4.45 (d,
NH, J ) 9.3 Hz), [5.39 (dd, J ) 15.5, 6.9 Hz), 5.72 (dd, J )
15.5, 6.2 Hz), 2H]; 13C NMR δ 11.1, 16.1, 22.2, 24.8, 28.3, 30.8,
35.6, 59.7, 73.4, 79.4, 125.1, 141.1, 157.1; ES-MS m/z 286
[MH]+, 230, 186. Anal. Calcd for C16H31NO3: C 67.31, H 10.95,
N 4.93. Found: C 67.3, H 11.2, N 4.92.
ter t-Bu t yl (1S,3E)-1-Isop r op yl-5-m et h yl-2-oxoh ex-3-
en ylca r ba m a te (3b). Oven-dried K2CO3 (3.66 g, 26.5 mmol)
was added in small portions, over 15 min, to a stirred solution
of phosphonoketone 2b (R ) CH(CH3)2)20,21 (8.57 g, 26.5 mmol)
and isobutyric aldehyde (2.10 g, 29 mmol) in absolute ethanol
(50 mL). After 3 h the reaction mixture was filtered and the
solution was neutralized with glacial acetic acid. The solvent
was rotary evaporated, and the residue was partitioned
between ethyl acetate and saturated aqueous NaHCO3. The
aqueous phase was extracted with ethyl acetate, and the
combined organic phases were washed with brine and dried
over sodium sulfate. The solvent was rotary evaporated, and
the crude oily product was purified by flash chromatography
with 1:1 diethyl ether/petroleum ether as eluant (5.71 g,
ter t-Bu tyl (1S,2R,3E)-2-Hyd r oxy-1-p h en ylp en t-3-en yl-
ca r ba m a te (4e). With the same procedure, 3e (2.66 g, 9.67
mmol) gave 2.41 g (8.70 mmol, 90%) of a white solid: mp 128
°C, from isopropyl ether; [R]25 +31 (c 0.2); IR (Nujol) 3359,
D
1684 cm-1; H NMR δ 1.40 (s, 9H), 1.65 (d, 3H, J ) 6.6 Hz),
1
2.17 (bs, OH), 4.32 (m, 1H), 4.71 (m, 1H), 5.29 (ddd, 1H, J )
1.5, 7.0, 15.4 Hz), 5.68 (dq, 1H, J ) 6.6, 15.4 Hz), 7.25-7.34
(m, 5H, Ph); 13C NMR δ 17.8, 28.4, 59.6, 75.5, 79.8, 127.6,
127.8, 128.4, 129.2, 129.5; ES-MS m/z 278 [MH]+. Anal. Calcd
for C16H23NO3: C 69.3, H 8.36, N 5.05. Found: C 69.3, H 8.80,
N 5.07.
80%): [R]25 +3.6 (c 0.4); IR (neat) 3427, 3335, 1716, 1693,
D
1626 cm-1; 1H NMR δ 0.71 (d, 3H, J ) 7.0 Hz), 0.93 (d, 3H, J
) 6.6 Hz), 1.01 (d, 6H, J ) 6.6 Hz), 1.37 (s, 9H), 2.04 (m, 1H),
2.42 (m, 1H), 4.46 (dd, 1H, J ) 4.0, 8.8 Hz), 5.22 (d, NH, J )
8.8 Hz), 6.08 (d, 1H, J ) 15.7 Hz), 6.88 (dd, 1H, J ) 6.6, 15.7
Hz); 13C NMR δ 16.6, 19.8, 21.1, 28.2, 30.9, 31.2, 61.9, 79.4,
124.7, 155.3, 155.9, 198.7; ES-MS m/z 270 [MH]+, 214, 170.
ter t-Bu tyl (1S,3E)-5-Meth yl-1-[(1S)-1-m eth ylp r op yl]-2-
oxoh ex-3-en ylca r ba m a te (3d ). With the same procedure, the
phosphonoketone 2d 20 (8.00 g, 23.7 mmol) and isobutyric
aldehyde (1.95 g, 27 mmol) gave 5.37 g (19.0 mmol, 80%) of
ter t-Bu tyl (1S,2S,3R,4R)-3,4-Ep oxy-2-h yd r oxy-1-isop r o-
p yl-5-m eth ylh exylca r ba m a te (5b). 60% m-Chloroperoxy-
benzoic acid (3.17 g, 11.1 mmol) was added to a stirred solution
of alkene 4b (2.5 g, 9.21 mmol) in dichloromethane. After 24
h at room temperature, the solution was washed with 10%
aqueous sodium metabisulfite, saturated aqueous NaHCO3,
and brine and dried over sodium sulfate. The solvent was
rotary evaporated, and the crude product was purified by flash
chromatography eluting with ethyl acetate/dichloromethane
mixtures (1.72 g, 65%). Analytical samples were obtained by
recrystallization from isopropyl ether/hexane: mp 80-81 °C;
oily 5d : [R]25 +1.1 (c 0.9); IR (neat) 3429, 3349, 1702, 1690,
D
1623 cm-1; 1H NMR δ 0.87 (d, 3H, J ) 7.3 Hz), 0.96 (d, 3H, J
) 6.8 Hz), 1.08 (d, 6H, J ) 6.8 Hz), 1.08-1.32 (m, 2H), 1.43
(s, 9H), 1.82 (m, 1H), 2.49 (m, 1H), 4.52 (dd, 1H, J ) 4.4, 8.3
Hz), 5.26 (d, NH, J ) 8.3 Hz), 6.15 (d, 1H, J ) 15.7 Hz), 6.94
(dd, 1H, J ) 15.7, 6.5 Hz); 13C NMR δ 11.6, 16.0, 21.1, 24.1,
28.3, 31.2, 37.7, 61.8, 79.4, 124.9, 155.2, 155.8, 198.9; ES-MS
m/z: 284 [MH]+, 228, 184.
[R]25 +11.5 (c 0.7); IR (Nujol) 3371, 1686 cm-1 1H NMR δ
;
D
0.84 (d, 3H, J ) 7.0 Hz), 0.89-0.93 (m, 9H), 1.37 (s, 9H), 1.49
(m, 1H), 2.02 (m, 1H), 2.49 (bs, OH), 2.70 (m, 1H), 2.85
(m, 1H), 3.43 (m, 1H), 3.61 (m, 1H), 4.54 (d, NH, J ) 10.3 Hz);
13C NMR δ 16.0, 17.3, 17.9, 19.1, 27.3, 27.6, 29.0, 57.2, 57.6,
61.0, 70.0, 78.4, 155.2; ES-MS m/z 288 [MH]+, 232, 188. Anal.
Calcd for C15H29NO4: C 62.7, H 10.2, N 4.87. Found: C 62.5,
H 10.3, N 4.90.
ter t-Bu tyl (1S,3E)-1-P h en yl-2-oxop en t-3-en ylca r ba m -
a te (3e). With the same procedure, the phosphonoketone 2e
(9.50 g, 26.5 mmol) and acetaldehyde (7.90 g, 180 mmol) gave
6.11 g (22.3 mmol, 84%) of 3e: needles, mp 80 °C; [R]25D +171
ter t-Bu tyl (1S,2S,3R,4R)-3,4-Ep oxy-2-h yd r oxy-5-m eth -
yl-1-[(1S)-1-m eth ylp r op yl]h exylca r ba m a te (5d ). With the
8640 J . Org. Chem., Vol. 67, No. 24, 2002

Ritonavir and Its C-2 Epimer
same procedure, 4d (2.00 g, 7.01 mmol) gave 1.48 g (4.91 mmol,
70%) of a white solid: mp 95-97 °C, from isopropyl ether/
16.2, 17.5, 18.2, 24.3, 28.3, 34.1, 34.4, 34.8, 60.0, 73.9, 77.5,
79.7, 157.2; ES-MS m/z 304 [MH]+, 248, 204.
hexane; [R]25 +10.4 (c 0.4); IR (Nujol) 3363, 1691 cm-1 1H
;
D
ter t-Bu tyl (1S,2R,4S)-2,4-Dih yd r oxy-1-p h en yl-p en tyl-
ca r ba m a te (6e). With the same procedure, 5e (800 mg, 2.73
NMR δ 0.83-0.94 (m, 13H), 1.36 (s, 9H), 1.45-1.52 (m, 2H),
1.73 (m, 1H), 2.51 (m, 1H), 2.71 (m, 1H), 2.84 (bs, OH), 3.51
(m, 1H), 3.65 (m, 1H), 4.54 (d, NH, J ) 9.7 Hz); 13C NMR δ
11.8, 16.4, 18.5, 19.1, 24.0, 28.5, 30.2, 35.6, 58.4, 58.9, 62.1,
70.9, 79.6, 156.5; ES-MS m/z 302 [MH]+, 246, 202. Anal. Calcd
for C16H31NO4: C 63.74, H 10.36, N 4.67. Found: C 63.6, H
10.4, N 4.80.
mmol) gave 6e (483 mg, 1.64 mmol, 60%): white solid; mp 116
1
°C; [R]25 +38 (c 0.1); IR (Nujol) 3363, 1683 cm-1; H NMR δ
D
1.13 (d, 3H, J ) 6.2 Hz), 1.26 (m, 1H), 1.40 (s, 9H), 1.53 (m,
1H), 2.71 (bs, 2H, OH), 4.01 (m, 1H), 4.15 (m, 1H), 4.62 (m,
1H), 5.41 (d, NH, J ) 5.5 Hz), 7.25-7.35 (m, 5H, Ph); 13C NMR
δ 24.3, 28.4, 40.7, 59.7, 68.8, 75.0, 80.0, 127.76, 127.81, 128.6,
138.6, 155.9; ES-MS m/z 296 [MH]+. Anal. Calcd for C16H25
-
ter t-Bu tyl (1S,2S,3R,4R)-3,4-Ep oxy-2-h yd r oxy-1-p h en -
ylp en tylca r ba m a te (5e). With the same procedure, 4e (1.75
g, 6.32 mmol) gave 1.30 g (4.42 mmol, 70%) of a white solid:
NO4: C 65.1, H 8.53, N 4.74. Found: C 65.3, H 8.44, N 4.75.
Gen er al P r ocedu r e for th e Cyclization of N-Boc Am in o
Alcoh ols. (4S,5R)-4-Ben zyl-5-[(2R)-2-h yd r oxy-3-p h en yl-
p r op yl]-1,3-oxa zolid in -2-on e (7a ). NaH (519 mg of a 60%
dispersion in mineral oil, 13.0 mmol) was added portionwise
to a solution of aminodiol 6a (2.50 g, 6.49 mmol) in 50 mL of
dry THF, at room temperature, under an argon atmosphere.
The mixture was stirred overnight, quenched with 50 mL of a
saturated NH4Cl solution, and stirred for a further 30 min.
The aqueous layer was extracted twice with ethyl acetate. The
combined organic layers were washed with brine and dried
over anhydrous Na2SO4. The solvent was rotary evaporated,
and the crude oil was purified by flash chromatography (ethyl
acetate/petroleum ether, 1:1) to obtain 1.72 g (5.52 mmol, 85%)
mp 135 °C, from isopropyl ether; [R]25 +53 (c 0.2); IR (Nujol)
D
3370, 1682 cm-1; H NMR δ 1.22 (d, 3H, J ) 5.1 Hz), 1.41 (s,
1
9H), 2.42 (m, 1H), 2.62 (m, 1H), 2.96 (m, 1H), 3.87 (m, 1H),
4.91 (bs, OH), 5.56 (d, NH, J ) 7.3 Hz), 7.27-7.37 (m, 5H,
Ph); 13C NMR δ 17.0, 28.4, 51.6, 58.5, 59.3, 72.2, 80.0, 127.1,
127.9, 128.7, 138.5, 155.6; ES-MS m/z 294 [MH]+. Anal. Calcd
for C16H23NO4: C 65.5, H 7.90, N 4.77. Found: C 65.3, H 8.28,
N 4.71.
Gen er a l P r oced u r e for th e Red u ctive Rin g Op en in g
of Ep oxid es 5. ter t-Bu tyl (1S,2R,4R)-1-Ben zyl-2,4-d ih y-
d r oxy-5-p h en ylp en tylca r ba m a te (6a ). A 70% solution of
Red-Al in toluene (10 mL, 35 mmol) was added dropwise, at 0
°C, under an argon atmosphere to a solution of epoxide 5a 20
(4.50 g, 11.7 mmol) in 60 mL of dry THF. The mixture was
stirred at room temperature for 48 h and then cooled in an ice
bath and quenched by dropwise addition of water (4.4 mL, 245
mmol) and NaF (10.3 g, 245 mmol). The mixture was stirred
for 30 min, and the solid was filtered off and washed several
times with ethyl acetate. The solution was dried over anhy-
drous Na2SO4, and the solvent was removed to obtain the crude
product, which was purified by flash chromatography (ethyl
acetate/petroleum ether, 3:7), giving a white solid (2.71 g, 7.02
of colorless oil 7a : [R]25D -42 (c 0.2); IR (neat) 3400, 1730 cm-1
;
1H NMR δ 1.92 (m, 1H), 2.06 (m, 1H), 2.37 (bs, OH), 2.62 (dd,
1H, J ) 11.0, 13.4 Hz), 2.82 (dd, 1H, J ) 3.8, 13.4 Hz), 2.85
(d, 2H, J ) 6.6 Hz), 3.96 (m, 1H), 4.08 (m, 1H), 4.88 (ddd, 1H,
J ) 4.4, 7.3, 11.5 Hz), 5.11 (bs, NH), 7.12-7.34 (m, 10H); 13C
NMR δ 35.5, 36.4, 43.5, 56.8, 70.6, 78.0, 126.7, 127.2, 128.7,
128.9, 129.0, 129.1, 129.37, 129.43, 136.3, 137.7, 158.1; ES-
MS m/z 312 [MH]+.
(4S,5R)-4-Isop r op yl-5-[(2S)-2-h yd r oxy-3-m eth ylbu tyl]-
1,3-oxa zolid in -2-on e (7b). With the same procedure, 6b (1.00
g, 3.46 mmol) gave 7b (610 mg, 2.83 mmol, 82%): mp 119-
mmol, 60%): mp 121-122 °C; [R]25 -18 (c 0.2); IR (Nujol)
D
3353, 1685 cm-1; H NMR δ 1.35 (s, 9H), 1.60 (m, 1H), 1.70
1
120 °C from pentane/diisopropyl ether; [R]25 -4.4 (c 0.3); IR
D
(Nujol) 3200, 1730 cm-1; 1H NMR δ 0.92-1.00 (m, 12H), 1.75-
1.96 (m, 4H), 2.42 (bs, OH), 3.62 (m, 2H), 4.77 (ddd, 1H, J )
3.8, 7.4, 10.2 Hz); 13C NMR δ 16.9, 18.0, 18.6, 20.0, 27.9, 32.6,
33.0, 61.6, 74.6, 79.8, 160.0; MS (EI) m/z 215 (M+•, 0), 197 (2),
172 (81), 154 (33), 98 (100), 85 (43), 73 (35). Anal. Calcd for
(m, 1H), 2.76 (m, 4H), 3.78 (m, 1H), 3.83 (m, 1H), 4.04 (m,
1H), 4.68 (d, NH, J ) 8.4 Hz), 7.14-7.33 (m, 10H); 13C NMR
δ 28.2, 35.6, 38.2, 44.6, 56.5, 73.7, 74.5, 79.8, 126.4, 126.6,
128.3, 128.4, 128.6, 129.1, 129.2, 129.4, 137.8, 156.3; ES-MS
m/z 386 [MH]+, 330, 286. Anal. Calcd for C23H31NO4: C 71.66,
H 8.10, N 3.63. Found: C 71.6, H 8.14, N 3.68.
C
11H21NO3: C 61.35, H 9.83, N 6.53. Found: C 61.4, H 9.99,
N 6.31.
(4S,5R)-4-Isopr opyl-5-[(2R)-2-h ydr oxy-3-ph en ylpr opyl]-
ter t-Bu t yl
(1S,2R,4S)-2,4-Dih yd r oxy-1-isop r op yl-5-
m eth ylh exylca r ba m a te (6b). With the same procedure, 5b
(1.50 g, 5.22 mmol) gave 6b (1.06 g, 3.65 mmol, 70%): white
1,3-oxa zolid in -2-on e (7c). With the same procedure, 6c (1.40
g, 4.15 mmol) gave 7c (918 mg, 3.48 mmol, 84%): mp 131-
crystals, mp 126-128 °C; [R]25 -11 (c 0.3); IR (Nujol) 3400,
D
1690 cm-1; 1H NMR δ 0.83-0.89 (m, 12H), 1.38 (m, 10H), 1.55
(m, 1H), 1.58 (m, 1H), 1.89 (m, 1H), 3.39 (m, 1H), 3.56 (m,
1H), 3.76 (m, 1H), 4.49 (d, NH, J ) 9.2 Hz); 13C NMR δ 17.5,
18.3, 20.3, 27.9, 28.3, 34.2, 34.8, 60.3, 74.2, 77.7, 79.6, 157.0;
MS (EI) m/z 289 (M+•, 0.05), 246 (0.2), 232 (0.2), 216 (1), 189
132 °C from pentane/diisopropyl ether; [R]25 -3.2 (c 0.2); IR
D
(Nujol) 3300, 1730 cm-1; H NMR δ 0.86 (d, 3H, J ) 6.8 Hz),
1
0.95 (d, 3H, J ) 6.6 Hz), 1.81 (m, 2H), 2.01 (ddd, 1H, J ) 6.8,
10.4, 14.5 Hz), 2.37 (bs, OH), 2.82 (dd, 1H, J ) 7.5, 13.6 Hz),
2.87 (dd, 1H, J ) 5.7, 13.6 Hz), 3.55 (pseudo t, 1H, J ) 6.7
Hz), 4.09 (m, 1H), 4.75 (ddd, 1H, J ) 3.3, 7.3, 10.4 Hz), 6.67
(bs, NH), 7.22-7.33 (m, 5H); 13C NMR δ 18.0, 19.9, 27.8, 34.8,
43.2, 61.6, 70.7, 78.7, 126.6, 128.6, 129.4, 137.8, 159.9; ES-
MS m/z 264 [MH]+. Anal. Calcd for C15H21NO3: C 68.40, H
8.04, N 5.34. Found: C 68.9, H 8.21, N 5.40.
(2), 172 (12), 116 (44), 72 (100), 57 (79). Anal. Calcd for C15H31
NO4: C 62.24, H 10.79, N 4.86. Found: C 61.8, H 10.7, N 4.88.
ter t-Bu t yl (1S,2R,4R)-2,4-Dih yd r oxy-1-isop r op yl-5-
-
p h en ylp en t ylca r b a m a t e (6c). With the same procedure,
5c20 (2.00 g, 5.96 mmol) gave 6c (1.53 g, 4.53 mmol, 76%): oil;
[R]25D -6.9 (c 0.3); IR (Nujol) 3363, 1691 cm-1; 1H NMR δ 0.87
(m, 6H), 1.43 (s, 9H), 1.54 (m, 1H), 1.68 (pseudo d, 1H, J )
14.2 Hz), 1.92 (m, 1H), 2.74 (dd, 1H, J ) 5.9, 13.2 Hz), 2.80
(dd, 1H, J ) 6.8, 13.2 Hz), 3.42 (m, 1H), 3.55 (bs, OH), 3.78
(m, 1H), 4.07 (m, 2H), 4.54 (d, NH, J ) 9.8 Hz), 7.18-7.31 (m,
5H); 13C NMR δ 17.2, 20.2, 27.7, 28.3, 37.9, 44.6, 60.0, 73.58,
73.62, 79.5, 126.4, 128.4, 129.3, 138.0, 156.9; ES-MS m/z 338
[MH]+, 302.
(4S,5R)-4-[(1S)-1-Met h ylp r op yl]-5-[(2S)-2-h yd r oxy-3-
m eth ylbu tyl]oxa zolid in -2-on e (7d ). With the same proce-
dure, 6d (1.20 g, 3.95 mmol) gave 7d (707 mg, 3.08 mmol,
78%): mp 66-69 °C from pentane/diisopropyl ether; [R]25
D
-10.5 (c 0.2); IR (neat) 3420, 1740 cm-1; 1H NMR δ 0.86-0.97
(m, 12H), 1.15 (m, 1H), 1.59 (m, 2H), 1.75-1.90 (m, 3H), 2.52
(bs, OH), 3.63 (m, 2H), 6.87 (s, NH); 13C NMR δ 10.7, 16.0,
16.9, 18.6, 24.7, 32.6, 33.0, 34.3, 61.1, 74.5, 79.8, 160.0; ES-
MS m/z 230 [MH]+. Anal. Calcd for C12H23NO3: C 62.84, H
10.11, N 6.13. Found: C 62.7, H 10.0, N 5.70.
ter t-Bu tyl (1S,2R,4S)-2,4-Dih yd r oxy-5-m eth yl-1-[(1S)-
1-m eth ylp r op yl]h exylca r ba m a te (6d ). With the same pro-
cedure, 5d (2.00 g, 6.64 mmol) gave 6d (1.29 g, 4.25 mmol,
(4S,5R)-4-P h en yl-5-[(2S)-2-h yd r oxyp r op yl]oxa zolid in -
2-on e (7e). With the same procedure, 6e (352 mg, 1.19 mmol)
gave 7e (244 mg, 1.10 mmol, 93%): mp 103 °C from pentane/
64%): oil; [R]25 -7.7 (c 0.2); IR (neat) 3460, 1690 cm-1 1H
;
D
NMR δ 0.91 (m, 12H), 1.05 (m, 1H), 1.44 (m, 11H), 1.57-1.71
(m, 3H), 3.50 (m, 1H), 3.61 (m, 1H), 3.71 (bs, OH), 3.89 (m,
1H), 4.16 (bs, OH), 4.56 (d, NH, J ) 9.3 Hz); 13C NMR δ 11.3,
diisopropyl ether; [R]25D +45 (c 0.2); IR (Nujol) 3405, 1723 cm-1
;
1H NMR δ 1.07 (d, 3H, J ) 6.2 Hz), 1.21 (pseudo t, 1H, J )
J . Org. Chem, Vol. 67, No. 24, 2002 8641

Benedetti et al.
4.2, 14.6 Hz), 1.40 (ddd, 1H, J ) 7.3, 9.7, 14.6 Hz), 2.21 (bs,
OH), 3.83 (m, 1H), 4.88 (d, 1H, J ) 8.0 Hz), 4.99 (ddd, 1H, J
) 4.2, 8.0, 9.7 Hz), 6.03 (bs, NH), 7.22 (m, 2H), 7.37 (m, 3H);
13C NMR δ 23.2, 39.9, 59.8, 65.7, 79.5, 127.2, 129.0, 136.6,
159.4; ES-MS m/z 222 [MH]+. Anal. Calcd for C12H15NO3: C
65.1, H 6.83, N 6.33. Found: C 65.2, H 7.18, N 6.17.
38.2, 54.6, 59.3, 77.6, 126.9, 129.0, 129.1, 136.5, 159.3; ES-
MS m/z 247 [MH]+. Anal. Calcd for C12H14N4O2: C 58.5, H
5.73, N 22.8. Found: C 59.0, H 5.30, N 22.4.
Gen er a l Syn th esis of Azid o Alcoh ols 10. ter t-Bu tyl
(1S,2R,4S)-4-Azid o-1-b en zyl-2-h yd r oxy-5-p h en ylp en t yl-
ca r ba m a te (10a ). NaH (157 mg of a 60% dispersion in
mineral oil, 3.92 mmol) was added to 8a (1.20 g, 3.57 mmol)
in 20 mL of dry THF, under an argon atmosphere, and the
mixture was stirred at room temperature for 1 h. Boc anhy-
dride (935 mg, 4.28 mmol) was then added in small portions,
and stirring was continued for 2 h. 20% aqueous citric acid
(20 mL) was then added, and the aqueous layer was separated
and extracted twice with ethyl acetate. The combined organic
phases were washed with a saturated NaHCO3 solution, the
solvent was rotary evaporated, and the residue was taken up
in 50 mL of a 4:1 mixture of methanol and water. K2CO3 (987
mg, 7.14 mmol) was added, and the mixture was stirred
overnight, neutralized with glacial acetic acid, concentrated
to one-fifth of its original volume, and extracted twice with
ethyl acetate. The combined organic layers were washed with
saturated NaHCO3 and brine and dried over anhydrous Na2-
SO4. The solvent was rotary evaporated, and the crude product
was purified by flash chromatography (ethyl acetate/petroleum
ether mixtures), giving pure 10a (1.03 g, 2.50 mmol, 70%):
white solid, mp 121-123 °C; [R]25D -5.0 (c 0.2); IR (Nujol) 3376,
Gen er a l Syn th esis of Azid es 8. (4S,5R)-4-Ben zyl-5-
[(2S)-2-a zid o-3-p h en ylp r op yl]-1,3-oxa zolid in -2-on e (8a ).
Et3N (2.14 mL, 15.4 mmol) and methane sulfonyl chloride (0.60
mL, 7.71 mmol) were added dropwise to alcohol 7a (1.60 g,
5.14 mmol) in 25 mL of dry dichloromethane, at 0 °C, under
an argon atmosphere. After 2 h the solution was diluted with
25 mL of dichloromethane and washed with ice cold water,
ice cold 10% aqueous HCl, saturated aqueous NaHCO3, and
brine. After drying over anhydrous Na2SO4 the solvent was
removed under reduced pressure to give the mesylate. NaN3
(501 mg, 7.71 mmol) and 18-crown-6 (1.36 g, 5.14 mmol) were
added to a DMSO solution (3 mL) of the crude mesylate, and
the mixture was stirred for 24 h at 50 °C. Water (20 mL) was
added, and the mixture was extracted several times with ethyl
acetate. The combined organic layers were washed with water
and brine and then dried over anhydrous Na2SO4. The solvent
was rotary evaporated, and flash chromatography (1:1 ethyl
acetate/petroleum ether) of the residue gave pure 8a (1.30 g,
3.86 mmol, 75%): white solid, mp 74-76 °C; [R]25D +25 (c 0.2);
IR (neat) 3300, 2105, 1750 cm-1; 1H NMR δ 1.62 (m, 1H), 1.99
(m, 1H), 2.58 (dd, 1H, J ) 11.5, 13.4 Hz), 2.82 (dd, 1H, J )
3.7, 13.4 Hz), 2.94 (d, 2H), J ) 6.6 Hz), 4.00 (m, 2H), 4.93 (m,
2H), 7.12-7.37 (m, 10H); 13C NMR δ 34.4, 36.5, 41.7, 56.5,
60.4, 76.3, 127.1, 127.3, 128.7, 128.8, 129.1, 129.3, 136.2, 136.5,
157.9; ES-MS m/z 337 [MH]+, 294, 216. Anal. Calcd for
1
3310, 2103, 1686 cm-1; H NMR δ 1.35 (s, 9H), 1.50 (m, 1H),
1.65 (ddd, 1H, J ) 2.8, 10.1, 13.2 Hz), 2.71 (m, 1H), 2.87 (m,
3H), 3.49 (bs, OH), 3.82 (m, 1H), 3.88 (m, 1H), 3.95 (m, 1H),
4.54 (m, NH), 7.17-7.33 (m, 10H); 13C NMR δ 28.2, 36.3, 37.3,
41.6, 57.1, 60.8, 70.8, 80.0, 126.6, 126.8, 128.3, 128.6, 129.1,
129.3, 137.4, 137.6, 156.6; ES-MS m/z 411 [MH]+, 355, 311.
Anal. Calcd for C23H30N4O3: C 67.29, H 7.37, N 13.65. Found:
C 67.5, H 7.45, N 13.7.
C
19H20N4O2: C 67.84, H 5.99, N 16.66. Found: C 68.0, H 6.11,
N 16.5.
(4S,5R)-4-Isop r op yl-5-[(2R)-2-a zid o-3-m eth ylbu tyl]-1,3-
ter t-Bu t yl (1S,2R,4R)-4-Azid o-1-isop r op yl-2-h yd r oxy-
5-m eth ylh exylca r ba m a te (10b). Oxazolidinone 8b (450 mg,
1.87 mmol) gave, with the same procedure, the protected amino
oxa zolid in -2-on e (8b). Alcohol 7b (550 mg, 2.55 mmol) gave
azide 8b (491 mg, 2.04 mmol, 80%), coeluting with a small
amount (8%) of elimination product 9b. 8b was purified by
crystallization: mp 48-50 °C; [δ]25D +93 (c 0.3); IR (CCl4) 3250,
2100, 1760 cm-1; 1H NMR δ 0.92 (d, 3H, J ) 6.4 Hz), 0.98 (m,
9H), 1.53 (pseudo t, 1H, J ) 12.1 Hz), 1.76-1.92 (m, 3H), 3.53
(m, 1H), 3.63 (m, 1H), 4.80 (m, 1H), 6.79 (bs, NH); 13C NMR δ
17.9, 19.0, 19.1, 19.7, 27.8, 30.8, 33.3, 61.9, 65.0, 77.1, 160.0;
ES-MS m/z 241 [MH]+, 213, 198.
(4S,5R)-4-Isop r op yl-5-[(2S)-2-a zid o-3-p h en ylp r op yl]-
1,3-oxa zolid in -2-on e (8c). Alcohol 7c (850 mg, 3.23 mmol)
gave 8c (772 mg, 2.68 mmol, 83%): white solid, mp 84 °C;
[R]25D +111 (c 0.25); IR (Nujol) 3236, 2104, 1747 cm-1; 1H NMR
δ 0.89 (d, 3H, J ) 6.8 Hz), 0.96 (d, 3H, J ) 6.6 Hz), 1.55 (ddd,
1H, J ) 1.2, 2.0, 14.3 Hz), 1.75 (m, 1H), 1.91 (ddd, 1H, J )
2.4, 11.4, 14.3 Hz), 2.88 (dd, 1H, J ) 7.8, 13.8 Hz), 2.91 (dd,
1H, J ) 5.9, 13.8 Hz), 3.59 (pseudo t, 1H, J ) 7.8 Hz), 3.92
(m, 1H), 4.81 (ddd, 1H, J ) 2.0, 7.5, 11.4 Hz), 6.68 (bs, NH),
7.22-7.35 (m, 5H); 13C NMR δ 19.1, 19.6, 27.8, 33.6, 41.8, 60.4,
61.8, 76.7, 127.0, 128.7, 129.3, 136.7, 159.9; ES-MS m/z 289
[MH]+. Anal. Calcd for C15H20N4O2: C 62.43, H 6.99, N 19.5.
Found: C 62.8, H 7.10, N 19.5.
alcohol 10b (471 mg, 1.50 mmol, 80%): oil; [R]25 +14 (c 0.2);
D
IR (neat) 3330, 3440, 2100, 1690 cm-1; H NMR δ 0.89-0.99
1
(m, 12H), 1.45 (m, 10H), 1.84 (m, 3H), 2.88 (d, OH, J ) 6.6
Hz), 3.52 (m, 1H), 3.56 (m, 1H), 3.82 (m, 1H), 4.42 (d, NH, J )
8.8 Hz); 13C NMR δ 18.0, 18.1, 19.1, 20.0, 28.3, 28.7, 33.2, 34.2,
60.8, 65.4, 69.6, 79.8, 157.1; ES-MS m/z 315 [MH]+, 259, 215.
ter t-Bu tyl (1S,2R,4S)-4-Azid o-1-isop r op yl-2-h yd r oxy-5-
p h en ylp en tylca r ba m a te (10c). Oxazolidinone 8c (700 mg,
2.43 mmol) gave, with the same procedure, the protected amino
alcohol 10c (669 mg, 1.84 mmol, 76%): white solid, mp 67 °C;
1
[R]25 +21 (c 0.4); IR (Nujol) 3392, 3378, 2103, 1689 cm-1; H
D
NMR δ 0.92 (d, 3H, J ) 6.8 Hz), 0.96 (d, 3H, J ) 6.8 Hz), 1.43
(s, 9H), 1.43-1.57 (m, 2H), 1.82 (m, 1H), 2.88 (m, 3H), 3.49
(m, 1H), 3.85 (m, 1H), 3.98 (m, 1H), 4.38 (d, NH, J ) 8.8 Hz),
7.22-7.31 (m, 5H); 13C NMR δ 18.1, 20.0, 28.3, 28.7, 37.0, 41.7,
60.7, 60.8, 69.4, 79.8, 126.8, 128.6, 129.3, 137.4, 157.1; ES-
MS m/z 363 [MH]+, 307. Anal. Calcd for C19H30N4O3: C 62.92,
H 8.34, N 15.5. Found: C 63.3, H 8.49, N 15.2.
ter t-Bu t yl (1S,2R,4R)-4-Azid o-2-h yd r oxy-5-m et h yl-1-
[(1S)-1-m eth ylp r op yl]h exylca r ba m a te (10d ). Oxazolidi-
none 8d (500 mg, 1.97 mmol) gave, with the same procedure,
the protected amino alcohol 10d (549 mg, 1.67 mmol, 85%):
(4S,5R)-4-[(1S)-1-Meth ylp r op yl]-5-[(2R)-2-a zid o-3-m eth -
ylbu tyl]-1,3-oxa zolid in -2-on e (8d ). Alcohol 7d (650 mg, 2.83
mmol), with the same procedure, gave 8d (577 mg, 2.27 mmol,
oil; [R]25 +18 (c 0.2); IR (neat) 3450, 3353, 2105, 1691 cm-1
;
D
80%): oil; [R]25D +102 (c 0.2); IR (neat) 3450, 2105, 1740 cm-1
;
1H NMR δ 0.90-0.99 (m, 12H), 1.12 (m, 1H), 1.44 (m, 11H),
1.56 (m, 2H), 1.84 (m, 1H), 3.12 (d, OH, J ) 6.6 Hz), 3.57 (m,
2H), 3.87 (m, 1H), 4.45 (d, NH, J ) 9.0 Hz); 13C NMR δ 11.2,
16.0, 18.0, 19.1, 24.7, 28.3, 33.2, 34.0, 35.4, 60.1, 65.4, 69.2,
79.8, 157.2; ES-MS m/z 329 [MH]+, 286, 273, 239, 216.
1H NMR δ 0.88-1.02 (m, 12H), 1.17 (m, 1H), 1.54 (m, 3H),
1.85 (m, 2H), 3.54 (ddd, 1H, J ) 2.1, 5.0, 11.4 Hz), 3.70 (dd,
1H, J ) 7.5, 8.3 Hz), 4.80 (ddd, 1H, J ) 2.0, 7.5, 11.4 Hz),
6.70 (s, NH); 13C NMR δ 10.4, 15.6, 17.9, 19.0, 25.7, 30.8, 33.3,
33.8, 60.9, 65.0, 77.0, 160.1; ES-MS m/z 255 [MH]+, 227, 212.
ter t-Bu tyl (1S,2R,4R)-4-Azido-2-h ydr oxy-1-ph en ylpen tyl-
ca r ba m a te (10e). Oxazolidinone 8e (160 mg, 0.65 mmol) gave,
with the same procedure, the protected amino alcohol 10e (177
(4S,5R)-4-P h en yl-5-[(2R)-2-azido-pr opyl]-1,3-oxazolidin -
2-on e (8e). Alcohol 7e (224 mg, 1.01 mmol), with the same
procedure, gave 8e (180 mg, 0.73 mmol, 72%): mp 106 °C;
mg, 0.55 mmol, 85%): mp 89 °C; [R]25 +63 (c 0.2); IR (Nujol)
D
1
1
[R]25 +97 (c 0.2); IR (Nujol) 3269, 2106, 1747 cm-1; H NMR
3384, 2103, 1685 cm-1; H NMR δ 1.25 (d, 3H, J ) 6.6 Hz),
D
δ 1.02 (ddd, 1H, J ) 2.0, 10.8, 14.5 Hz), 1.18 (d, 3H, J 6.6 Hz),
1.22 (m, 1H), 3.67 (m, 1H), 4.93 (d, 1H, J ) 8.0 Hz), 5.03 (m,
1H), 5.96 (bs, NH), 7.22 (m, 2H), 7.38 (m, 3H); 13C NMR δ 20.0,
1.28 (m, 1H), 1.40 (s, 9H), 1.53 (m, 1H), 2.13 (bs, OH), 3.73
(m, 1H), 4.07 (ddd, 1H, J ) 2.2, 4.8, 10.6 Hz), 4.59 (m, 1H),
5.30 (bs, NH), 7.30 (m, 5H); 13C NMR δ 20.0, 28.4, 40.2, 54.7,
8642 J . Org. Chem., Vol. 67, No. 24, 2002

Ritonavir and Its C-2 Epimer
59.6, 71.0, 80.1, 127.7, 127.9, 128.8, 138.6, 155.7; ES-MS m/z
321 [MH]+. Anal. Calcd for C16H24N4O3: C 60.0, H 7.55, N 17.5.
Found: C 59.8, H 7.99, N 17.2.
cm-1; 1H NMR δ 0.80 (d, 3H, J ) 6.8 Hz), 0.85 (d, 3H, J ) 6.8
Hz), 0.91 (m, 6H), 1.21 (m, 1H), 1.37 (s, 6H), 1.44 (s, 9H), 1.54
(m, 1H), 1.61 (m, 1H), 2.16 (m, 1H), 3.42 (m, 1H), 3.50 (m,
1H), 3.63 (m, 1H), 4.40 (d, NH, J ) 10.3 Hz); 13C NMR δ 15.6,
17.6, 18.5, 19.5, 20.2, 26.6, 28.4, 30.1, 30.9, 33.0, 58.4, 70.0,
74.3, 79.0, 98.3, 156.1; MS (EI) m/z 329 (M+•, 0.01%), 314 (0.01),
172 (11), 157 (33), 116 (29), 99 (100), 57 (92). Anal. Calcd for
Gen er a l P r oced u r e for th e Red u ction of Azid es. ter t-
Bu tyl (1S,2R,4S)-4-Am in o-1-ben zyl-2-h yd r oxy-5-p h en yl-
p en tylca r ba m a te (11a ). Azide 10a (800 mg, 1.95 mmol) in
30 mL of methanol was stirred overnight under a H2 atmo-
sphere in the presence of 10% Pd/C. The mixture was filtered
through a short pad of Celite, and the solvent was removed
under reduced pressure to obtain pure 11a (750 mg, 1.95
C
18H35NO4: C 65.61, H 10.71, N 4.27. Found: C 65.8, H 11.0,
N 4.28.
(4S,5S)-4-Ben zyl-5-[(2S)-2-a zid o-3-p h en ylp r op yl]-1,3-
mmol, 100%): white solid, mp 130-132 °C; [R]25 +1.0 (c 2);
D
oxa zolid in -2-on e (16). Meth od A. Diisopropyl ethylamine
(2.2 mL, 12.5 mmol) and methanesulfonyl chloride (0.48 mL,
6.24 mmol) were added, in order, to a solution of diol 6a (800
mg, 2.08 mmol) in 20 mL of 1,2-dichloroethane, under an argon
atmosphere. The mixture was refluxed for 5 h, cooled to room
temperature, diluted with 20 mL of dichloromethane, and
washed with ice cold water, ice cold 10% aqueous HCl,
saturated aqueous NaHCO3, and brine. The organic layer was
dried over anhydrous Na2SO4, and the solvent was evaporated
to give the crude mesylate 15. To a solution of crude 15 in 2
mL of DMSO were then added NaN3 (203 mg, 3.12 mmol) and
18-crown-6 (550 mg, 2.08 mmol), and the reaction was carried
out as previously described for the synthesis of 8a , affording
IR (Nujol) 3380, 3340, 3280, 1687 cm-1
;
1H NMR δ 1.34 (s,
9H), 1.59 (m, 1H), 1.75 (ddd, 1H, J ) 2.9, 7.3, 14.2 Hz), 2.53
(m, 1H), 2.80 (m, 2H), 3.08 (dd, 1H, J ) 3.9, 13.7 Hz), 3.52 (m,
1H), 3.82 (m, 1H), 3.88 (m, 1H), 4.46 (d, NH, J ) 8.8 Hz), 7.16-
7.32 (m, 10H); 13C NMR δ 28.3, 36.5, 37.4, 44.5, 50.5, 55.2,
71.6, 79.1, 126.1, 126.4, 128.2, 128.6, 129.2, 129.6, 138.3, 138.7,
155.6; ES-MS m/z 385 [MH]+. Anal. Calcd for C23H32N2O3: C
71.84, H 8.39, N 7.29. Found: C 71.7, H 8.32, N 7.33.
ter t-Bu tyl (1S,2R,4R)-4-Am in o-1-isop r op yl-2-h yd r oxy-
5-m eth ylh exylca r ba m a te (11b). Hydrogenation of 10b (300
mg, 0.95 mmol), under the same conditions, gave 11b (261 mg,
0.91 mmol, 95%): oil; [R]25 +15 (c 0.2); IR (neat) 3310, 1690
D
cm-1; 1H NMR δ 0.84 (d, 3H, J ) 6.8 Hz), 0.88 (d, 6H, J ) 6.8
Hz), 0.94 (d, 6H, J ) 6.8 Hz), 1.43 (s, 9H), 1.45-1.57 (m, 2H),
1.63 (m, 1H), 2.29 (dd, 1H, J ) 3.4, 6.8 Hz), 2.96 (bs, OH, NH2),
3.01 (m, 1H), 3.60 (pseudo dt, 1H, J ) 3.4, 10.2 Hz), 3.69 (m,
1H), 4.34 (d, NH, J ) 10.2 Hz); 13C NMR δ 15.3, 17.8, 18.6,
20.3, 27.2, 28.4, 33.8, 34.3, 54.0, 57.8, 70.6, 79.0, 156.1; ES-
MS m/z 289 [MH]+, 233, 189.
350 mg (1.04 mmol, 50%) of azide 16 as an oil: [R]25 -35 (c
D
0.2); IR (neat) 3285, 2106, 1755 cm-1; 1H NMR δ 1.62 (m, 1H),
1.86 (m, 1H), 2.74-2.91 (m, 4H), 3.54 (m, 1H), 3.66 (m, 1H),
4.42 (m, 1H), 6.02 (bs, NH), 7.13-7.36 (m, 10H); 13C NMR δ
38.2, 40.2, 41.4, 59.2, 59.5, 78.5, 127.0, 127.4, 128.6, 129.00,
129.04, 129.3, 135.5, 136.6, 158.4; ES-MS m/z 337 [MH]+.
Meth od B. Thionyl chloride (145 mg, 1.22 mmol) was added
to a solution of azide 10a (100 mg, 0.24 mmol) in 2 mL of dry
THF under an argon atmosphere, and the reaction mixture
was kept at room temperature for 18 h. Evaporation of the
solvent under reduced pressure gave the crude azide 16, which
was purified by flash chromatography (1:1 ethyl acetate/
petroleum ether) (65 mg, 0.19 mmol, 80%).
ter t-Bu tyl (1S,2R,4S)-4-Am in o-1-isop r op yl-2-h yd r oxy-
5-p h en ylp en tylca r ba m a te (11c). Hydrogenation of 10c (500
mg, 1.38 mmol) gave 11c (441 mg, 1.31 mmol, 95%): white
solid, mp 158-162 °C; [R]25D +1.7 (c 0.2); IR (Nujol) 3350, 1695
cm-1; 1H NMR δ 0.85 (d, 3H, J ) 7.0 Hz), 0.94 (d, 3H, J ) 7.0
Hz), 1.45 (s, 9H), 1.63 (m, 1H), 1.73 (m, 1H), 2.25 (m, 1H),
2.57 (dd, 1H, J ) 9.3, 13.4 Hz), 2.84 (dd, 1H, J ) 4.0, 13.4
Hz), 3.1 (bs, OH, NH2), 3.57 (m, 2H), 3.78 (m, 1H), 4.37 (d,
NH, J ) 10.2 Hz), 7.19-7.32 (m, 5H); 13C NMR δ 15.5, 20.3,
26.9, 28.4, 37.4, 44.8, 50.3, 58.4, 70.4, 79.0, 126.4, 128.5, 129.2,
138.6, 156.2; ES-MS m/z 337 [MH]+, 281. Anal. Calcd for
ter t-Bu t yl (1S,2S,4S)-4-Azid o-1-b en zyl-2-h yd r oxy-5-
p h en ylp en tylca r ba m a te (17). With the same procedure
described for the synthesis of 10a , oxazolidinone 16 (300 mg,
0.89 mmol) gave the N-Boc amino alcohol 17 (271 mg, 0.66
mmol, 74%): oil; [R]25D -19 (c 0.2); IR (neat) 3350, 2105, 1690
C
19H32N2O3: C 67.80, H 9.58, N 8.36. Found: C 68.1, H 9.72,
N 8.21.
ter t-Bu t yl (1S,2R,4R)-4-Azid o-2-h yd r oxy-5-m et h yl-1-
1
cm-1; H NMR δ 1.24-1.52 (m, 10H), 1.62 (m, 1H), 2.85 (m,
4H), 3.72 (m, 2H), 3.85 (m, 1H), 4.89 (d, NH, J ) 8 Hz), 7.15-
7.28 (m, 10H); 13C NMR δ 28.3, 38.4, 41.2, 55.5, 62.0, 69.8,
79.4, 126.3, 126.7, 126.8, 128.3, 128.4, 128.6, 129.2, 129.3,
136.9, 138.2, 156.0; ES-MS m/z 412 [MH]+, 384, 355, 311.
ter t-Bu t yl (1S,2S,4S)-4-Am in o-1-b en zyl-2-h yd r oxy-5-
p h en ylp en tylca r ba m a te (18). Hydrogenation of 17 (200 mg,
0.49 mmol), as described for the synthesis of 11a , gave 18 (178
mg, 0.46 mmol, 95%): white solid, mp 58-60 °C; [R]25D -19 (c
[(1S)-1-m eth ylp r op yl]h exylca r ba m a te (11d ). Hydrogena-
tion of 10d (400 mg, 1.22 mmol) gave 11d (354 mg, 1.17 mmol,
96%): mp 158-162 °C; [R]25 +6.2 (c 0.2); IR (Nujol) 3452,
D
3332, 1695 cm-1; 1H NMR δ 0.87-0.95 (m, 12H), 1.42 (s, 9H),
1.40-1.64 (m, 5H), 1.97 (m, 1H), 2.99 (m, 1H), 3.62 (m, 1H),
3.76 (m, 1H), 4.33 (d, NH, J ) 10.1 Hz); 13C NMR δ 11.9, 16.4,
17.7, 18.7, 22.5, 28.3, 34.0, 34.3, 34.5, 53.8, 58.3, 70.3, 78.9,
156.1; ES-MS m/z 303 [MH]+.
1
0.2); IR (neat) 3438, 3365, 1700 cm-1; H NMR δ 1.24-1.52
(m, 2H), 1.42 (s, 9H), 2.48 (dd, 1H, J ) 8.2, 13.6 Hz), 2.80 (dd,
1H, J ) 4.9, 13.6 Hz), 2.86 (d, 2H, J ) 7.5 Hz), 3.06 (m, 1H),
3.4 (bs, NH2, OH), 3.66 (m, 1H), 3.78 (m, 1H), 5.10 (d, NH, J
) 9.7 Hz), 7.08-7.30 (m, 10H); 13C NMR δ 28.4, 38.8, 38.9,
46.8, 53.9, 56.3, 71.4, 78.9, 126.0, 126.6, 128.3, 128.6, 129.0,
129.3, 129.5, 129.6, 137.7, 138.8, 155.9; ES-MS m/z 385 [MH]+,
329. Anal. Calcd for C23H32N2O3: C 71.84, H 8.39, N 7.29.
Found: C 72.0, H 8.48, N 7.12.
ter t-Bu tyl (1S,2R,4R)-4-Azido-2-h ydr oxy-1-ph en ylpen tyl-
ca r ba m a te (11e). Hydrogenation of 10e (80 mg, 0.25 mmol)
gave 11e (74 mg, 0.25 mmol, 100%): oil; [R]25 +38 (c 0.2); IR
D
(neat) 3450, 1690 cm-1; 1H NMR δ (50 °C) 1.16 (d, 3H, J ) 6.6
Hz), 1.22 (m, 1H), 1.36 (s, 9H), 1.48 (m, 1H), 3.31 (m, 4H),
4.23 (m, 1H), 4.50 (m, 1H), 5.63 (bs, NH), 7.29 (m, 5H); 13C
NMR (50 °C) δ 22.1, 28.2, 39.3, 44.8, 59.6, 70.5, 79.6, 127.4,
128.1, 128.2, 139.8, 155.6; ES-MS m/z 295 [MH]+.
ter t-Bu tyl (1S)-1-[(4R,6S)-6-Isop r op yl-2,2-d im eth yl-1,3-
d ioxa n -4-yl]-2-m eth ylp r op ylca r ba m a te (13). Aminodiol
diol 6b (240 mg, 0.83 mmol) and p-toluensulfonic acid (15 mg,
0.079 mmol) were refluxed in 5 mL of dimethoxypropane. The
solvent was rotary evaporated and the residue partitioned
between diethyl ether and a saturated NaHCO3 solution. The
aqueous layer was extracted again with ether. The combined
organic layers were washed with brine and dried over anhy-
drous Na2SO4. The solvent was rotary evaporated and the
crude product purified by flash chromatography (15% ethyl
acetate in petroleum ether) to give white crystals (210 mg,
Ack n ow led gm en t. This work was supported by
Istituto Superiore di Sanita` (National Research Pro-
gram on AIDS) and the CNR. We thank Dr. Fabio
Hollan for the mass spectra.
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H
NMR and 13C NMR of compounds 2e, 3, 4, 5, 6, 7, 8, 10, 11,
13, 16, 17, and 18. This material is available free of charge
via the Internet at http://pubs.acs.org.
77%): mp 75-80 °C; [δ]25 -15 (c 0.4); IR (Nujol) 3300, 1690
J O025616G
D
J . Org. Chem, Vol. 67, No. 24, 2002 8643