Versatile and stereoselective synthesis of diamino diol dipeptide isosteres, core units of pseudopeptide HIV protease inhibitors

Full text of DOI:10.1021/jo971202p

9348
J . Org. Chem. 1997, 62, 9348-9353
particularly effective against HIV-PR with IC50 values
Ver sa tile a n d Ster eoselective Syn th esis of
between 0.2 and 0.4 nM.5b,6
Dia m in o Diol Dip ep tid e Isoster es, Cor e
Un its of P seu d op ep tid e HIV P r otea se
In h ibitor s
Fabio Benedetti,*,† Stanislav Miertus,‡
Stefano Norbedo,† Alessandro Tossi,§ and
Pavel Zlatoidzky†
Department of Chemical Sciences and Department of
Biochemistry, Biophysics and Macromolecular Sciences,
University of Trieste, via Giorgieri 1, I-34127 Trieste, Italy,
and Polytech, Area di Ricerca, Padriciano 99,
34012 Trieste, Italy
Identically substituted dihydroxyethylene isosteres 1
(R ) R′) can be obtained from C2-symmetrical building
blocks7 or from the pinacol coupling of R-amino alde-
hydes.8 Incorporation of different residues R and R′ in
the diamino diol structure 1 by a convergent synthesis
has been recently reported;9 however, this methodology
has only been described for benzyl substituents and is
characterized by poor stereoselectivity in the crucial diol-
forming step. In connection with a project on the
synthesis of pseudopeptide inhibitors of HIV-1 protease,10
we required homochiral all-S 1,4-diamino 2,3-diols. In
this paper, we describe a practical and stereoselective
synthesis that gives access to (S,S,S,S)-1 with either
identical or nonidentical R and R′ groups. In our
synthetic strategy (Scheme 1), the four-carbon-atom
framework is assembled first, starting from a Boc-
protected L-amino acid that provides the first asymmetric
center; the stereochemistry of the remaining centers is
then controlled by chiral induction.
Received J uly 1, 1997
The human immunodeficiency virus type 1 (HIV-1),
which is responsible for AIDS, encodes for three en-
zymes: a reverse transcriptase, a proteinase (HIV-PR),
and an integrase. Each enzyme plays an essential role
in the replication cycle and can thus be the target of
antiretroviral therapy aimed at the selective inhibition
of the virus’s proliferation.1 In the search for new drugs
for the treatment of AIDS, an intense effort has been
devoted to developing efficient inhibitors of the viral
enzymes, in particular of the transcriptase and, more
recently, of the proteinase.2
The HIV-1 protease is a homodimeric aspartic pro-
tease3 responsible for the proteolytic cleavage of the
Pr55gag and Pr165gag-pol polyproteins from which struc-
tural proteins and the three viral enzymes originate.4 The
presence of a C2 axis of symmetry in the homodimer has
inspired the development of a new class of protease
inhibitors based on pseudopeptides of the type Pn--P2-
P1-P1′-P2′--Pn′ containing a C2-symmetric 1,4-diamino 2,3-
diol 1 as the P1-P1′ nonscissile core unit of a short peptide
chain.2b,5 Pseudopeptides containing dibenzyl-substitut-
ed derivatives of 1, such as, for example, the Abbott
inhibitors A-75925, A-76256, and A-76214, have proved
The first step consists of the synthesis of the trans-
enones 6. Our initial attempts to prepare 6a by the
Wittig reaction of the â-keto phosphonium salt 5 failed
at an early stage as we could not obtain 5 from the
known11 bromide 4. However, â-keto phosphonates 3 are
readily prepared from amino esters 2;12 thus, trans-
enones 6 were obtained in excellent yield by the Horner-
Wadsworth-Emmons reaction of 3 with the appropriate
aldehyde, in dry ethanol, in the presence of 1 equiv of
potassium carbonate13 (Scheme 1). Replacement of etha-
nol by acetonitrile and of potassium carbonate by diiso-
propylethylamine14 resulted in lower yields and, in the
case of 6a , in the R,â to â,γ migration of the double bond.
* To whom correspondence should be addressed.
† Department of Chemical Sciences.
‡ Polytech.
§ Department of Biochemistry, Biophysics and Macromolecular
Sciences.
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Phys. 1996, 204, 173.
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2901. (b) Chakravarty, P. K.; Combs, P.; Roth, A.; Greenlee, W. J .
Tetrahedron Lett. 1987, 28, 611. A 1:6 ratio of amino ester to dimethyl
methylphosphonate was sufficient to obtain phosphonates 3 in excellent
yields and without racemization.
(13) Mikolajczyk, M.; Balczewski, P. Synthesis 1987, 659.
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S0022-3263(97)01202-4 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 26, 1997 9349
Sch em e 1a
Sch em e 2a
a
Reagents and conditions: (a) Ph(CF3)(OMe)COCl, Py, 25 °C.
lecularly hydrogen bonded to the protected amino group,
as in the cyclic-Cram model 12. This would lead in any
case to the same preference for hydride attack at the si
face of the carbonyl and would explain the observation
that the selectivity is not markedly affected by the nature
of the reducing agent or by the medium.
a
Reagents and conditions: (a) 6 equiv of LiCH2PO(OMe)2, THF,
-78 °C, 84-92%; (b) R′CHO, Na2CO3, EtOH, 25 °C, 48-90%; (c)
NaBH4, MeOH, 0 °C, 50-90%; (d) m-CPBA, CH2Cl2, 25 °C, 65-
73%; (e) NaN3 (5 equiv), NH4Cl (3 equiv), MeOH/H2O, 80 °C; (f)
The absolute stereochemistry of the new stereocenter
was confirmed by the preparation of the oxazolidine 13
by treatment of 7e with dimethoxypropane in the pres-
ence of catalytic p-toluensulfonic acid. The NMR spec-
trum of the oxazolidine shows the presence of two
rotamers, in a 1:1 ratio, with a coalescence temperature
above 70 °C;17 irradiation of either H4 or H5 of each
rotamer induces a transfer of saturation to the corre-
sponding proton of the other rotamer. NOE analysis,
extended to both rotamers, gave a 20% enhancement
between H4 and H5 that is consistent with a cis relation-
ship between the two protons, also confirmed by the 5.5
Hz coupling constant.18 The enantiomeric purity of the
amino alcohols 7 was a major concern since amino
ketones 3 and 6 are prone to racemize via enolization.
Thus, the optical purity of the amino alcohols was
determined by converting (S,R)-7a into the corresponding
Mosher ester 14 (Scheme 2). Racemic 7a was also
synthesized by applying the same sequence to the methyl
ester of D,L-phenylalanine and converted into a 1:1
H
2 (1 atm), 10% Pd/C, 60-95% for two steps (e + f); (g) NH3, EtOH,
80 °C, 36-90%; (h) 6 N HCl, 90 °C.
Ta ble 1. Na BH4 Red u ction of En on es 6
ratio % yield of
enone
R
R′
7 (S,R):8 (S,S) alcohol 7a
6a
6b
6c
6d
6e
6f
CH2Ph CH2Ph
CH2Ph CH2(cyclohexyl)
CH2Ph CH3
3:1
3:1
2:1
16:1
15:1
16:1
4:1
73
70
48
90
74
75
75
s-Bu
i-Pr
i-Pr
Me
CH2(cyclohexyl)
CH2Ph
i-Bu
6g
i-Bu
a
Isolated yield, after purification by column chromatography
and/or crystallization.
Sodium borohydride reduction of enones 6 in methanol
gave mixtures of amino alcohols 7 and 8 with a diaste-
reoselectivity level that depends on the bulkiness of the
R group (Table 1). The ratio of (S,R)-7 to the undesired
1
S,S isomer 8 was determined by H NMR and ranges
1
from around 15:1 for 6d -f, with a bulky isopropyl or sec-
butyl side chain, to 2:1 for 6c. Pure S,R diastereoisomers
7 could be easily obtained by chromatographic separation
of the mixture or by crystallization. Similar results were
obtained with lithium borohydride in methanol and with
lithium tri-tert-butoxyaluminum hydride in THF, while
1,4 reduction leading to the corresponding saturated
ketone is predominant when the reaction is carried out
with NaBH4 in isopropyl alcohol. The observed stereo-
selectivity and its dependence on the size of the side chain
R are in agreement with previous results on the reduction
of R-amino ketones15 and can be explained with the Cram
or Felkin-Anh models16 for the addition of hydride to
the free carbonyl group, NH-Boc and R being the
medium and large group, respectively.15a Alternatively,
the addition could take place with the carbonyl intramo-
mixture of diastereoisomeric esters 14 and 15. The H
NMR spectrum of the mixture shows well-resolved
(15) (a) Albeck, A.; Persky, R. Tetrahedron 1994, 21, 6333. (b)
Maugras, I.; Poncet, J .; J ouin, P. Tetrahedron 1990, 46, 2807. (c)
Dufour, M.-N.; J ouin, P.; Poncet, J .; Pantaloni, A.; Castro, B. J . Chem.
Soc., Perkin Trans. 1 1986, 1895. (d) Tramontini, M. Synthesis 1982,
605.
(16) (a) Cram, D. J .; Elhafez, F. A. A. J . Am. Chem. Soc. 1952, 74,
3210. (b) Anh, N. T.; Eisenstein, O. Nouv. J . Chem. 1977, 1, 61. (c)
Fleischer, J . M.; Gushurst, A. J .; J orgensen, W. L. J . Org. Chem. 1995,
60, 490.
(17) See, for example: Garner, P.; Park, J . M. J . Org. Chem. 1987,
52, 2361.
(18) A molecular mechanics conformational analysis of cis- and
trans-13 gave eight minima for the cis isomer and 11 minima for the
trans isomer; H4-H5 coupling constants were calculated for each
conformer by the Haasnot-Altona equation and are 4.6-6.0 Hz for
cis-13 and 1.1-4.9 Hz for trans-13. Haasnot, C. A. G.; De Leeuw, F.
A. A. M.; Altona, C. Tetrahedron 1980, 36, 2783.

9350 J . Org. Chem., Vol. 62, No. 26, 1997
Notes
1a .8a The NMR spectra of 1a clearly indicate the pres-
ence of a symmetric structure. Since we start from
L-phenylalanine (and no racemization occurs, as we have
shown), the configuration of the first asymmetric center
must necessarily be S and only three configurations are
possible for a symmetric species, namely S,S,R,R, S,R,R,S,
and S,S,S,S. The first configuration can be excluded
because it corresponds to a meso structure, while 1a is
optically active ([R]25 ) -41), and the second configu-
D
ration is not consistent with the trans geometry of
epoxides 9. Therefore, the configuration of 1a must be
necessarily S,S,S,S, thus confirming all the previous
stereochemical assignments.
F igu r e 1. Transition states for the epoxidation of alkenes 7.
A leads to S,S-epoxide; B leads to R,R-epoxide 9.
signals for a vinyl proton and for the methoxy group
(Scheme 2); from the integration of these signals in the
spectrum of the ester 14 obtained from optically active
7a it was thus possible to establish an enantiomeric
excess g(95 ( 3)% for the alcohol, corresponding to the
optical purity of the starting amino ester. Epimerization
at the R-carbon is thus negligible.
The synthesis of nonsymmetrical diol 11d , which is
obtained in overall 40% yield from isoleucine methyl
ester, illustrates the versatility of our sequential ap-
proach to dipeptide isosteres with nonidentical R and R′
groups. An additional advantage of the method is that
it leads directly to differentially protected diamino diols
11. This allows the two amino groups to be coupled with
different peptide chains, thus giving easy access to
nonsymmetrical pseudopeptides of general structure Pn-
-P2-P1-P1′-P2′--Pn′.24 Pseudopeptides with different Pn-
-P2 and P2′--Pn′ are particularly interesting as HIV-
protease inhibitors because the C2 symmetry of the
central P1-P1′ fragment matches the symmetry of the
enzyme’s active site, while the inhibitor’s important
properties, such as binding, transport, and bioavailabil-
ity, can be tuned by the amino acid sequence in the Pn-
-P2 and P2′--Pn′ fragments.10a Finally, via the key epoxide
intermediate 9, this route can also be extended to the
synthesis of “normal” (H2N-P1-P1′-COOH) rather than
C2-symmetrical (H2N-P1-P1′-NH2) dihydroxyethylene
isosteres. Further work in this direction is currently in
progress.
The next step in the synthesis is the stereoselective
epoxidation of alcohols 7. Peracid epoxidation of acyclic
allylic alcohols leads preferentially to threo epoxy alco-
hols19 and was thus expected to provide the epoxides with
the required R,R stereochemistry at the new stereo-
centers. Indeed m-chloroperoxybenzoic acid epoxidation
of 7 proceeds in good yields, and only one diastereoisomer
(9) was detected in all cases by NMR and reversed-phase
HPLC analysis.20 While the preferential formation of 9
was predicted, the very high degree of stereocontrol is
noteworthy, as selectivity is often poor in the epoxidation
of trans-substituted allylic alcohols.19 The highly ordered
transition states for epoxidation at the diastereotopic
faces of the double bond are shown in Figure 1. We
suggest that the branched X ) CH(NHR)Boc residue is
sufficiently bulky to destabilize transition state A through
allylic 1,3-strain.21 Rotation around bond a relieves this
interaction and directs the epoxidation on the opposite
face, as in B, leading to epoxides 9. High levels of
stereoselectivity have also been observed in the amide-
and urethane-directed allylic epoxidation of R-branched
trans-substituted or terminal acyclic olefins.22
Exp er im en ta l Section
Moisture-sensitive reactions were carried out in oven-dried
vessels under a positive argon pressure. THF was dried over
CaH2, fractionated, and redistilled from sodium benzophenone
before use. Reversed-phase HPLC chromatography was carried
out on
a Supelcosil C18 analytical column. Flash column
The potential of our approach was demonstrated with
the synthesis of monoprotected diamino diols 11a and
11d (Scheme 1). Direct introduction of the second amino
group can be obtained by refluxing for 1 week the
corresponding epoxide 9 in ethanol saturated with am-
monia; alternatively, regioselective ring opening of the
epoxide by sodium azide in the presence of ammonium
chloride23 gives the azido diol 10, which is then hydro-
genated over 10% Pd on carbon. The direct ring opening
with ammonia is more convenient for a large-scale
synthesis, while the stepwise method provides higher
yields with the rather unreactive epoxide 9a (60% vs
30%). Amino diol 11d can be obtained in over 90% yield
by either method. For the assessment of the absolute
stereochemistry of the four asymmetric centers, the
N-Boc diol 11a was deprotected to give the diamino diol
chromatography was performed on silica gel 60 (230-400 mesh);
silica gel 60F254 coated plastic sheets were used for TLC and
developed with I2. Melting points were determined in an open
capillary apparatus and are uncorrected. Optical rotations were
measured at 581 nm in methanol. IR spectra were recorded as
Nujol mulls, unless otherwise noted. 1H NMR spectra (400 MHz)
and 13C NMR spectra (100.4 MHz) were recorded for CDCl3
solutions containing Me4Si as an internal standard, unless
otherwise specified. Mass spectra were obtained by electrospray
ionization (es). Elemental analyses were obtained at the in-
house facility of the Department of Chemical Sciences. Phos-
phonates 3a ([R]25 ) -52 (c 0.4)), 3e ([R]25 ) -22 (c 0.2)) and
D
D
3g ([R]25 ) -38 (c 0.63)) were obtained as described;12 phos-
D
phonate 3d was also obtained with the same method.
Dim et h yl [(3S)-3-[N-(ter t-b u t yloxyca r b on yl)a m in o]-4-
m eth yl-2-oxoh exyl]p h osp h on a te (3d ): 92%; colorless oil;
1
[R]25 ) -43° (c 0.2); IR (film) 3430, 3300, 1710, 1250 cm-1; H
D
NMR δ 0.90 (t, 3H), 0.98 (d, 3H), 1.10 (m, 1H), 1.33 (m, 1H),
1.45 (s, 9H), 2.00 (m, 1H), 3.11 (dd, 1H, J ) 14.2, 21.7 Hz), 3.30
(dd, 1H, J ) 4.2, 22.5 Hz), 3.80 (d, 6H, J ) 11.2 Hz), 4.33 (dd,
1H, J ) 4.4, 9.0 Hz), 5.34 (d, NH); 13C NMR δ 11.5, 15.9, 23.9,
28.2, 35.8, 38.6 (d, J ) 132 Hz), 53.0 (d, J ) 7.4 Hz), 64.8, 79.8,
155.7, 201.3; MS m/z 338 [MH]+, 282 [MH - C4H8]+, 238 [MH
- C5H10O2]+.
(19) (a) Rossiter, B. A.; Verhoeven, T. R.; Sharpless, K. B. Tetrahe-
dron Lett. 1979, 20, 4733. (b) Narula, A. S. Tetrahedron Lett. 1981,
22, 2017. (c) Rao, A. S.; Paknikar, S. K.; Kirtane, J . G. Tetrahedron
1983, 39, 2323.
(20) C18 Supelcosil column; MeCN/H2O (2:8 to 7:3 gradient) + 0.05%
trifluoroacetic acid.
(21) Hoffmann, R. W. Chem. Rev. (Washington, D.C.) 1989, 89, 1841.
(22) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. (Washington,
D.C.) 1993, 93, 1307.
En on es 6. Oven dried K2CO3 (553 mg, 4.0 mmol) was added
in small portions, over 15 min, to a stirred solution of phospho-
(23) (a) Caron, M.; Sharpless, K. B. J . Org. Chem. 1985, 50, 1557.
(b) Guthrie, R. D.; Murphy, D. J . Chem. Soc. 1968, 5288.
(24) Benedetti, F.; Norbedo, S.; Antcheva, N.; Tossi, A.; Miertus, S.;
Romeo, D. Unpublished results.

Notes
J . Org. Chem., Vol. 62, No. 26, 1997 9351
nate 3 (4.0 mmol) and the appropriate aldehyde (4.0 mmol) in
absolute ethanol (40 mL). After 4 h (25 min for 6a and 6e), the
reaction mixture was filtered and the solution was neutralized
with glacial acetic acid. The solvent was removed under reduced
pressure, 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 product was
purified by flash chromatography with diethyl ether and petro-
leum ether (1:1) as eluant.
1.79 (m, 1H), 2.14 (m, 2H), 4.58 (m, 1H), 5.44 (d, NH), 6.17 (d,
1H, J ) 15.6 Hz), 6.98 (dt, 1H, J ) 15.6, 8 Hz); 13C NMR δ 18.8,
22.3, 27.8, 28.3, 41.8, 53.1, 79.5, 127.4, 148.7, 155.1, 198.2; MS
m/z 256 [MH]+, 200 [MH - C4H8]+, 156 [MH - C5H8O2]+.
Red u ction of th e En on es. NaBH4 (378 mg, 10 mmol) was
added in small portions over 10 min, at 0 °C, to a stirred solution
of 6 (10 mmol) in methanol. After 1 h at 0 °C the solution was
neutralized with glacial acetic acid, the solvent was removed
under reduced pressure, and the residue was partitioned be-
tween ethyl acetate and saturated aqueous NaHCO3. The
aqueous phase was extracted with ethyl acetate, and the
combined organic phases were washed with brine, dried over
sodium sulfate and rotary evaporated to give the crude allyl
alcohol 7.
(5S)-5-[N-(ter t-Bu tyloxyca r bon yl)a m in o)]-1,6-d ip h en yl-
2-h exen -4-on e (6a ): 50% from 3a and phenylacetaldehyde;
white crystals: mp 79-80 °C, from diisopropyl ether/petroleum
ether; [R]25D ) -6.2 (c 1.0); IR (Nujol) 3360, 1690, 1623 cm-1
;
(4R,5S)-5-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-4-h yd r oxy-
1,6-d ip h en yl-2-h exen e (7a ): 78%; white crystals; mp 118 °C,
1H NMR δ 1.40 (s, 9H), 2.97 (dd, 1H, J ) 5.9, 13.7 Hz), 3.06 (dd,
1H, J ) 6.8, 13.7 Hz), 3.48 (d, 2H, J ) 6.6 Hz), 4.79 (m, 1H),
5.26 (d, NH), 6.08 (d, 1H, J ) 15.6 Hz), 7.03 (dt, 1H, J ) 6.6,
15.6 Hz), 7.10-7.32 (m, 10H); 13C NMR δ 28.3, 38.5, 38.8, 58.4,
79.7, 126.79, 126.85, 128.0, 128.4, 128.7, 128.8, 129.5, 136.1,
137.2, 147.7, 155.1, 197.4; MS m/z 366 [MH]+, 310 [MH -
C4H8]+, 266 [MH - C5H8O2]+. Anal. Calcd for C23H27NO3: C,
75.6; H, 7.44; N, 3.83. Found: C, 75.8; H, 7.54; N, 3.86.
(5S)-5-[N-(ter t-Bu t yloxyca r b on yl)a m in o]-1-cycloh exyl-
6-p h en yl-2-h exen -4-on e (6b): 80% from 3a and cyclohexylac-
etaldehyde; white crystals, mp 63 °C, from hexane; [R]25D ) -6.5
from diisopropyl ether; [R]25D ) -26.2 (c 1.0); IR 3380, 1668 cm-1
;
1H NMR δ 1.36 (s, 9H), 2.74 (m, 1H), 2.84 (dd, 1H, J ) 5.5, 14.3
Hz), 3.39 (dd, 1H, J ) 6.8, 21.4 Hz), 3.45 (dd, 1H, J ) 6.8, 21.4
Hz), 3.95 (m, 1H), 4.20 (m, 1H), 4.56 (m, NH), 5.60 (dd, 1H, J )
6.2, 15.4 Hz), 5.91 (dt, 1H, J ) 6.8, 15.4 Hz), 7.14-7.35 (m, 10H);
13C NMR δ 28.3, 35.5, 37.6, 56.1, 73.1, 79.7, 126.1, 126.4, 127.3,
128.46, 128.54, 129.4, 133.3, 137.1, 138.0, 156.1; MS m/z 368
[MH]+, 350 [MH - H2O]+. Anal. Calcd for C23H29NO3: C, 75.2;
H, 7.95; N, 3.81. Found: C, 74.9; H, 7.95; N, 3.70.
1
(c 0.23); IR 3450, 3350, 1715, 1690, 1630 cm-1; H NMR δ 0.90
(4R,5S)-5-[N-(ter t-Bu tyloxycar bon yl)am in o]-1-cycloh exyl-
4-h yd r oxy-6-p h en yl-2-h exen e (7b): 75%; white crystals; mp
(m, 2H), 1.20 (m, 2H), 1.4 (m, 1H), 1.41 (s, 9H), 1.65 (m, 6H),
2.07 (dd, 2H, J ) 6.8, 7.3 Hz), 2.98 (dd, 1H, J ) 13.7, 5.9 Hz),
3.10 (dd, 1H, J ) 13.7, 6.3 Hz), 4.82 (m, 1H), 5.30 (d, NH), 6.09
(d, 1H, J ) 16.1 Hz), 6.90 (dt, 1H, J ) 7.3, 16.1 Hz), 7.11-7.27
(m, 5H); 13C NMR δ 26.2, 26.3, 28.3, 33.2, 37.3, 38.6, 40.6, 58.1,
79.6, 126.8, 128.4 (two signals), 129.5, 136.2, 149.0, 155.1, 197.3;
MS m/z 372 [MH]+, 316 [MH - C4H8]+, 272 [MH - C5H8O2]+.
Anal. Calcd for C23H33NO3: C, 74.3; H, 8.95; N, 3.79. Found:
C, 74.0; H, 9.05; N, 3.77.
143-145 °C, from ethyl acetate; [R]25 ) -36 (c 0.21); IR 3350,
D
1690, 1670 cm-1; 1H NMR δ 0.89 (m, 2H), 1.19 (m, 2H), 1.36 (m,
10H), 1.70 (m, 6H), 1.94 (m, 2H), 2.73 (m, 1H+OH), 2.85 (dd,
1H, J ) 5.4, 14.2 Hz), 3.94 (m, 1H), 4.16 (m, 1H), 4.60 (d, NH),
5.49 (dd, 1H, J ) 6.3, 15.4 Hz), 5.71 (dt, 1H, J ) 7.8, 15.4 Hz),
7.18-7.30 (m, 5H); 13C NMR δ 26.3, 26.5, 28.3, 33.1, 36.2, 37.8,
40.5, 56.6, 74.5, 79.7, 126.4, 128.4, 129.3, 129.4, 132.9, 138.1,
156.4; MS m/z 374 [MH]+, 318 [MH - C4H8]+. Anal. Calcd for
C
23H35NO3: C, 73.9; H, 9.44; N, 3.77. Found: C, 73.4; H, 9.52;
N, 3.82.
(4R,5S)-5-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-4-h yd r oxy-
(5S)-5-[N-(ter t-Bu tyloxycar bon yl)am in o]-6-ph en yl-2-h ex-
en -4-on e (6c): 83% from 3a and acetaldehyde; white solid, mp
52 °C; [R]25 ) +3.3 (c 0.24); IR (CCl4) 3430, 3352, 1714, 1696,
D
1633 cm-1
;
1H NMR δ 1.41 (s, 9H), 1.88 (dd, 3H, J ) 1.0, 6.8
6-p h en yl-2-h exen e (7c): 48%; white crystals; mp 105 °C, from
diisopropyl ether; [R]25 ) -40 (c 0.21); IR (CCl4) 3442, 3352,
Hz), 2.96 (dd, 1H, J ) 5.6, 13.7 Hz), 3.11 (dd, 1H, J ) 6.3, 13.7
Hz), 4.79 (m, 1H,), 5.28 (d, NH), 6.18 (dd, 1H, J ) 15.6, 1.0 Hz),
6.94 (dq, 1H, J ) 15.6, 6.8 Hz), 7.11-7.28 (m, 5H); 13C NMR δ
18.5, 28.3, 38.3, 58.2, 79.6, 126.8, 128.4, 128.8, 129.5, 136.2,
145.1, 155.1, 197.2; MS m/z 290 [MH]+, 234 [MH - C4H8]+, 190
[MH - C5H8O2]+.
D
1686 cm-1 1H NMR δ 1.36 (s, 9H), 1.74 (d, 3H, J ) 6.6 Hz),
;
2.73 (m, 1H), 2.84 (dd, 1H, J ) 5.6, 14 Hz), 3.00 (m, OH), 3.94
(m, 1H), 4.13 (m, 1H), 4.60 (d, NH), 5.54 (dd, 1H, J ) 6.6, 15.4
Hz), 5.76 (dq, 1H, J ) 6.6, 15.4 Hz), 7.19-7.30 (m, 5H); 13C NMR
δ 17.9, 28.3, 36.2, 56.6, 74.6, 79.7, 126.4, 128.4, 129.0, 129.3,
129.7, 138.0, 156.4; MS m/z 292 [MH]+, 236 [MH - C4H8]+. Anal.
Calcd for C17H25NO3: C, 70.1; H, 8.69; N, 4.83. Found: C, 69.5;
H, 8.69; N, 4.85.
(5S,6S)-5-[N-(ter t-Bu tyloxycar bon yl)am in o]-1-cycloh exyl-
6-m eth yl-2-octen -4-on e (6d ): 80% from 3d and cyclohexylac-
etaldehyde; colorless oil; [R]25 ) +3.5 (c 0.87); IR (film) 3427,
D
1
3330, 1716, 1693, 1626 cm-1; H NMR δ 0.87 (m, 4H), 0.96 (d,
(4R,5S,6S)-5-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-1-cyclo-
h exyl-4-h yd r oxy-6-m eth yl-2-octen e (7d ): 90%; white solid;
mp 69-70 °C, from hexane; [R]25D ) -30.5 (c 0.2); IR 3365, 3300,
3H), 1.03-1.36 (m, 4H), 1.44 (m, 10H), 1.59-1.71 (m, 3H), 1.85
(m, 1H), 2.13 (m, 2H), 4.51 (dd, 1H, J ) 5, 8.8 Hz), 5.27 (d, NH),
6.18 (d, 1H, J ) 15.6 Hz), 6.96 (dt, 1H, J ) 7.6, 15.6 Hz); 13C
NMR δ 11.6, 16.0, 24.1, 26.1, 26.2, 28.3, 33.1, 37.2, 37.8, 40.5,
61.7, 79.4, 128.8, 148.2, 155.7, 198.4; MS m/z 338 [MH]+, 282
[MH - C4H8]+, 238 [MH - C5H8O2]+.
1683 cm-1 1H NMR δ 0.87-0.96 (m, 8H), 1.06-1.35 (m, 4H),
;
1.44 (m, 10H), 1.57 (m, 1H), 1.69 (m, 4H), 1.95 (m, 2H), 2.77 (m,
OH), 3.58 (m, 1H), 4.23 (m, 1H), 4.43 (d, NH), 5.42 (dd, 1H, J )
7, 15 Hz), 5.73 (dt, 1H, J ) 6, 15 Hz); 13C NMR δ 11.1, 16.0,
24.9, 26.3, 26.5, 28.3, 32.9, 33.1, 35.8, 37.8, 40.4, 59.7, 73.3, 79.5,
128.9, 132.9, 157.2; MS m/z 340 [MH]+, 322 [MH - H2O]+. Anal.
Calcd for C20H37NO3: C, 70.7; H, 11.0; N, 4.13. Found: C, 70.2;
H, 11.1; N, 4.17.
(5S)-5-[N-(ter t-bu tyloxycar bon yl)am in o]-6-m eth yl-1-ph en -
yl-2-h ep ten -4-on e (6e): 48% from 3e and phenylacetaldehyde;
colorless oil; [R]25D ) -7.0 (c 0.2); IR 3400, 1720, 1700, 1630 cm-1
;
1H NMR δ 0.76 (d, 3H), 0.98 (d, 3H), 1.43 (s, 9H), 2.10 (m, 1H),
3.55 (d, 2H, J ) 6.4 Hz), 4.49 (dd, 1H, J ) 4.4, 8.8 Hz), 5.26 (d,
NH), 6.18 (d, 1H, J ) 15.6 Hz), 7.09-7.33 (m, 6H); 13C NMR δ
15.7, 18.8, 27.3, 29.8, 37.8, 61.1, 78.5, 125.8, 127.3, 127.7, 127.8,
136.3, 146.2, 154.9, 197.3; MS m/z 318 [MH]+, 262 [MH -
C4H8]+, 218 [MH - C5H8O2]+.
(4R,5S)-5-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-4-h yd r oxy-
6-m eth yl-1-p h en yl-2-h ep ten e (7e): 63% after chromatography
(1:1 diethyl ether and petroleum ether); white solid; mp 58-61
°C; [R]25 ) -34 (c 0.5); IR 3367, 1685 cm-1; 1H NMR δ 0.91 (d,
D
3H), 0.96 (d, 3H), 1.43 (s, 9H), 1.77 (m, 1H), 2.84 (m, OH), 3.39
(d, 2H), 3.54 (m, 1H), 4.20 (m, 1H), 4.47 (d, NH), 5.55 (dd, 1H,
J ) 6.83, 15.1 Hz), 5.89 (dt, 1H, J ) 6.84, 15.1 Hz), 7.15-7.35
(m, 5H); 13C NMR δ 17.3, 19.2, 27.3, 28.0, 37.8, 59.5, 72.4, 78.5,
125.1, 127.4, 127.5, 129.0, 131.4, 139.0, 156.1; MS m/z 320
[MH]+, 246 [MH - C4H8-H2O]+.
(7S)-7-[N-(ter t-bu tyloxyca r bon yl)a m in o]-2,8-d im eth yl-4-
n on en -6-on e (6f): 87% from 3e and isovaleraldehyde; colorless
oil; [R]25D ) -3.7 (c 0.51); IR (film) 3435, 3350, 1714, 1700, 1630
cm-1 1H NMR δ 0.8 (d, 3H), 0.9 (d, 6H), 0.98 (d, 3H), 1.43 (s,
;
9H), 1.79 (m, 1H), 2.12 (m, 3H), 4.52 (dd, 1H, J ) 4.1, 8.7 Hz),
5.30 (d, NH), 6.20 (d, 1H, J ) 15.5 Hz), 6.96 (dt, 1H, J ) 7.6,
15.5 Hz); 13C NMR δ 16.7, 19.8, 22.38, 22.42, 27.9, 28.3, 31.0,
41.9, 61.9, 79.4, 128.7, 148.3, 155.9, 198.3; MS m/z 284 [MH]+,
228 [MH - C4H8]+, 184 [MH - C5H8O2]+.
(6R,7S)-7-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-6-h yd r oxy-
2,8-d im eth yl-4-n on en e (7f): 71% after chromatography (1:1
diethyl ether and petroleum ether); white solid; mp 53 °C; [R]25
D
) -13 (c 0.34); IR 3450, 3365, 1685 cm-1; 1H NMR δ 0.87-0.98
(m, 12H), 1.19 (m, 1H), 1.44 (s, 9H), 1.64 (m, 1H), 1.93 (m, 2H),
2.7 (m, OH), 3.55 (m, 1H), 4.19 (m, 1H), 4.45 (d, NH), 5.45 (dd,
1H J ) 6.8, 15.6 Hz), 5.72 (dt, 1H, J ) 7.3, 15 Hz); 13C NMR δ
(2S )-2-[N -(t er t -b u t yloxyca r b on yl)a m in o]-7-m e t h yl-4-
octen -3-on e (6g): 90% from 3g and isovaleraldehyde; colorless
oil; [R]25D ) -1.6 (c 0.74); IR (film) 3425, 3348, 1700, 1628 cm-1
;
1H NMR δ 0.93 (d, 6H), 1.34 (d, 3H, J ) 6.8 Hz), 1.44 (s, 9H),

9352 J . Org. Chem., Vol. 62, No. 26, 1997
Notes
18.4, 20.1, 22.2, 22.3, 28.2, 28.3, 29.0, 41.7, 60.4, 73.5, 79.4, 129.4,
133.0, 157.0; MS m/z 332 [MH]+, 276 [MH - C4H8]+, 232 [MH
- C5H8O2]+.
3430, 3390, 2105, 1685, 1252 cm-1; 1H NMR δ 2.85 (m, 2H), 3.22
(m, 2H), 3.35 (m, 1H), 3.5 (m, 1H), 3.79 (m, 1H), 3.88 (m, 1H),
4.48 (d, NH), 7.18-7.31 (m, 10H); 13C NMR δ 28.2, 36.8, 37.2,
52.8, 63.6, 70.3, 71.8, 80.7, 126.6, 126.7, 128.3, 128.4, 128.6,
128.7, 129.2, 129.3, 137.0, 137.4, 157.4; MS m/z 427 [MH]+, 384
[MH - HN3]+, 371 [MH - C4H8]+.
(2S,3R)-2-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-3-h yd r oxy-
7-m eth yl-4-octen e (7g): 84% after chromatography (1:1 diethyl
ether and petroleum ether); colorless oil; IR (CCl4) 3442, 1693
cm-1; 1H NMR δ 0.89 (m, 6H), 1.08 (d, 3H, J ) 7.0 Hz), 1.44 (s,
9H), 1.63 (m, 1H), 1.94 (m, 2H), 2.88 (m, OH), 3.78 (m, 1H,),
4.13 (m, 1H), 4.75 (m, NH), 5.43 (dd, 1H, J ) 6.2, 15.4 Hz), 5.69
(dt, 1H, J ) 7, 15.4 Hz); 13C NMR δ 15.4, 22.2, 22.3, 28.2, 28.3,
41.7, 51.0, 75.6, 79.4, 129.6, 132.4, 156.2; MS m/z 258 [MH]+.
Ep oxid es 9. 60% m-Chloroperoxybenzoic acid (3.05 g, 10.6
mmol) was added in small portions to a stirred solution of 7 (8.8
mmol) in dichloromethane. After 24 h at room temperature, the
solution was washed with 10% aqueous sodium metabisulfite
and saturated aqueous NaHCO3 and dried over sodium sulfate.
The solvent was rotary evaporated, and the crude product was
purified by flash chromatography eluting with 2:1 diethyl ether
and petroleum ether.
(2S,3S,4S,5S,6S)-2-Azid o-5-[N-(ter t-b u t yloxyca r b on yl)-
a m in o]-1-cycloh exyl-3,4-d ih yd r oxy-6-m eth ylocta n e (10d )
was obtained with the same method (95%) from epoxide 9d :
gummy syrup; [R]25D ) -13 (c 0.58); IR (CCl4) 3446, 3384, 2105,
1
1690, 1255 cm-1; H NMR δ 0.90-1.02 (m, 9H), 1.14-1.25 (m,
3H), 1.38-1.44 (m, 11H), 1.59-1.71 (m, 6H), 1.85 (m, 1H), 2.03
(m, 1H), 2.56 (m, OH), 3.32 (d, 1H, J ) 8.8 Hz), 3.45 (m, 1H),
3.60 (m, 2H), 4.24 (m, OH), 4.58 (d, NH); 13C NMR δ 12.0, 16.6,
22.6, 26.0, 26.3, 26.4, 28.2, 32.3, 33.5, 34.3, 34.4, 39.0, 57.2, 60.5,
70.1, 71.9, 80.5, 158.0; MS m/z 399 [MH]+, 343 [MH - C4H8]+,
299 [MH - C5H8O2]+.
(2S,3S,4S,5S)-5-Am in o-2-[N-(ter t-bu tyloxyca r bon yl)a m i-
n o]-3,4-d ih yd r oxy-1,6-d ip h en ylh exa n e (11a ). Method A.
The crude azide 10a (205 mg) in 5 mL of methanol was stirred
under 1 atm hydrogen for 12 h in the presence of catalytic 10%
Pd/C. The solid was filtered off, and the solvent was rotary
evaporated. The crude product was purified by flash chroma-
tography with 90:10:1 CH2Cl2-MeOH-NEt3 mixture as eluant
(60% from the epoxide 9a ). Method B. 9a (510 mg, 1.33 mmol)
in 25 mL of ethanol saturated with NH3 was heated at 80 °C in
a sealed tube for 7 days. Solvent evaporation and flash chro-
(2R,3R,4S,5S)-5-[N-(ter t-Bu t yloxyca r b on yl)a m in o]-2,3-
ep oxy-4-h yd r oxy-1,6-d ip h en ylh exa n e (9a ): 70%; white solid;
1
mp 135-136 °C; [R]25 ) -16 (c 0.24); IR 3348, 1683 cm-1; H
D
NMR δ 1.36 (s, 9H), 2.54 (m, OH), 2.81 (m, 1H), 2.87 (d, 2H),
2.92 (dd, 1H), 2.97 (dd, 1H, J ) 2.2, 4.0 Hz), 3.20 (dt, 1H, J )
2.2, 5.5 Hz), 3.63 (m, 1H,), 3.99 (m, 1H,), 4.66 (d, NH), 7.16-
7.34 (m, 10H); 13C NMR δ 28.3, 36.2, 37.9, 55.2, 56.1, 58.6, 71.4,
79.7, 126.6, 126.8, 128.5, 128.7, 129.0, 129.3, 136.8, 137.5, 155.8;
MS m/z 384 [MH]+, 328 [MH - C4H8]+, 284 [MH - C5H8O2]+.
Anal. Calcd for C23H29NO4: C, 71.6; H, 7.51; N, 3.48. Found:
C, 71.5; H, 7.60; N, 3.54.
matography gave the product (36%): white solid; mp 162-164
1
°C; [R]25 ) -41 (c 0.23); IR 3430, 3358, 1688 cm-1; H NMR δ
D
1.34 (s, 9H), 2.58 (dd, 1H, J ) 9.5, 13 Hz), 2.84 (m, 1H), 2.89
(dd, 1H, J ) 4, 13 Hz), 3.19 (dd, 1H, J ) 3, 14 Hz), 3.43 (m, 1H),
3.53 (m, 1H), 3.62 (d, 1H, J ) 9.2 Hz), 3.95 (m, 1H), 4.53 (d,
NH), 7.17-7.31 (m, 10H); 13C NMR δ 28.2, 36.4, 39.3, 52.3, 55.8,
70.5, 73.3, 80.2, 126.4, 126.6, 128.5, 128.6, 128.9, 129.1, 129.30,
129.34, 129.4, 129.6, 138.4, 157.3; MS m/z 401 [MH]+, 345 [MH
- C4H8]+, 301 [MH - C5H8O2]+.
(2R,3R,4S,5S)-5-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-1-cy-
cloh exyl-2,3-ep oxy-4-h yd r oxy-6-p h en ylh exa n e (9b): 68%;
white solid; mp 153 °C; [R]25D ) -16 (c 0.18); IR 3351, 1684 cm-1
;
1H NMR δ 0.96 (m, 2H), 1.13-1.27 (m, 3H), 1.36 (s, 9H), 1.41
(m, 3H), 1.70 (m, 5H), 2.64 (m, OH), 2.88 (m, 2H), 2.98 (m, 2H),
3.65 (m, 1H), 4.02 (m, 1H), 4.78 (d, NH), 7.21-7.31 (m, 5H); 13
C
NMR δ 26.09, 26.12, 26.3, 28.3, 33.1, 33.5, 35.7, 36.1, 39.2, 54.8,
55.1, 59.0, 71.3, 79.5, 126.4, 128.4, 129.3, 137.6, 155.6; MS m/z
390 [MH]+, 334 [MH - C4H8]+, 290 [MH - C5H8O2]+.
(2S,3S,4R,5R)-2-[N-(ter t-Bu t yloxyca r b on yl)a m in o]-4,5-
ep oxy-3-h yd r oxy-1-p h en ylh exa n e (9c): 67%, white solid: mp
(2S,3S,4S,5S,6S)-2-Am in o-5-[N-(ter t-bu tyloxyca r bon yl)-
a m i n o ]-1-c y c lo h e x y l-3,4-d i h y d r o x y -6-m e t h y lo c t a n e
(11d ): 100% from 10d (Method A); 90% from 9d (Method B);
1
oil, [R]25 ) -9.5° (c 0.56); IR (CCl4) 3360, 1700 cm-1; H NMR
D
δ 0.96 (m, 9H), 1.14-1.40 (m, 6H), 1.44 (s, 9H), 1.65 (m, 6H),
2.04 (m, OH), 3.28 (d, 1H, J ) 3.9 Hz), 3.48 (m, 1H), 3.61-3.72
(m, 2H), 4.51 (d, NH); 13C NMR δ 12.1, 16.6, 22.2, 26.1, 26.3,
26.5, 28.3, 32.6, 32.7, 34.2, 34.5, 40.5, 52.0, 56.5, 70.7, 71.5, 80.1,
157.9; MS m/z 373 [MH]+, 317 [MH - C4H8]+, 273 [MH -
C5H8O2]+.
108 °C; [R]25 ) -9.3 (c 0.36); IR (CCl4) 3440, 3365, 1685 cm-1
;
D
1H NMR δ 1.27 (d, 3H, J ) 5.4 Hz), 1.37 (s, 9H), 2.87 (m, 2H +
OH), 3.00 (m, 2H), 3.54 (m, 1H), 4.03 (m, 1H), 4.79 (d, NH), 7.20-
7.31 (m, 5H); 13C NMR δ 17.0, 28.2, 36.1, 52.1, 54.7, 60.1, 71.8,
79.5, 126.4, 128.4, 129.3, 137.5, 155.6; MS m/z 308 [MH]+, 252
[MH - C4H8]+, 208 [MH - C5H8O2]+.
(2S,5S,3S,4S)-2,5-Dia m in o-3,4-d ih yd r oxy-1,6-d ip h en yl-
h exa n e (1a ). A suspension of 11a (60 mg, 0.15 mmol) in 6 N
HCl was stirred at 90 °C for 30 min. The resulting solution was
concentrated in vacuo, neutralized with 3 N aqueous NaOH, and
extracted with chloroform (3 × 20 mL). The organic phases were
dried over Na2SO4, and the solvent was removed under reduced
(2R,3R,4S,5S,6S)-5-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-1-
cycloh exyl-2,3-ep oxy-4-h yd r oxy-6-m eth ylocta n e (9d ): 65%;
white crystals; mp 81-83 °C, from diisopropyl ether; [R]25
)
D
+11 (c 0.37); IR 3465, 3382, 3325, 1686 cm-1; 1H NMR δ 0.90-
0.97 (m, 8H), 1.16 (m, 1H), 1.24 (m, 3H), 1.35 (m, 1H), 1.44 (m,
11H), 1.6 (m, 1H), 1.71 (m, 4H), 2.75 (d, OH), 2.84 (m, 1H), 3.03
(m, 1H), 3.66 (m, 2H), 4.69 (d, NH); 13C NMR δ 11.5, 16.1, 24.0,
26.0, 26.1, 26.3, 28.3, 33.0, 33.5, 35.4, 35.7, 39.3, 54.8, 58.3, 59.2,
69.9, 79.3, 156.3; MS m/z 356 [MH]+, 300 [MH - C4H8]+, 256
[MH - C5H8O2]+. Anal. Calcd for C20H37NO4: C, 67.56; H,
10.49; N, 3.96. Found: C, 67.7; H, 10.6; N, 3.99.
pressure to give a white solid (45 mg, 0.15 mmol, 100%): mp
1
150 °C dec; [R]25 ) -33° (c 0.18); H NMR δ 2.63 (dd, 2H, J )
D
11, 13 Hz); 2.85 (dd, 2H, J ) 3, 13 Hz); 3.58 (d, 2H, J ) 11 Hz);
3.91 (m, 2H); 7.22-7.33 (m, 10H); 13C NMR δ 38.6, 56.8, 72.8,
126.7, 128.8, 129.0, 138.5; MS m/z 301 [MH]+, 284 [MH - NH3]+.
(4S,5R)-3-(ter t-Bu t yloxyca r b on yl)-2,2-d im et h yl-5-[1-(3-
p h en ylp r op en yl)]-4-(2-p r op yl)-1,3-oxa zolid in e (13). 2 mg
(0.01 mmol) of TsOH‚H2O were added to 7e (123 mg, 0.39 mmol)
in 2,2-dimethoxypropane (2 mL); the solution was refluxed for
75 min and then partitioned between diethyl ether and saturated
aqueous NaHCO3. The organic phase was washed with brine
and dried over sodium sulfate; the solvent was evaporated in
vacuo, and the crude product was purified by flash chromatog-
raphy with diethyl ether and petroleum ether (7:3) as eluant to
give 83 mg (60%) of oily product: 1H NMR (C6D6, 70 °C) δ 0.98
(d, 3H), 1.02 (d, 3H), 1.44 (s, 9H), 1.59 (s, 3H), 1.68 (s, 3H), 1.95
(m, 1H), 3.20 (d, 2H, J ) 6.6 Hz), 3.57 (m, 1H), 4.39 (dd, 1H, J
) 5.5, 6 Hz), 5.48 (m, 1H, J ) 1.5, 6.6, 15.4 Hz), 5.86 (m, 1H, J
) 1.1, 6.6, 15.4 Hz), 7.15-7.35 (m, 5H); 13C NMR (two sets of
signals) δ 18.9 and 19.4, 21.5 and 21.9, 23.7 and 25.2, 26.5 and
27.1, 28.4, 28.7, 38.9, 64.98 and 65.05, 65.8 and 67.1, 77.7 and
78.1, 79.5 and 79.8, 126.1, 126.2, 128.5, 128.7, 134.3 and 134.4,
152.6; MS m/z 374 [MH]+, 318 [MH - C4H8]+, 274 [MH -
C5H8O2]+.
(2R,3R,4S,5S)-5-[N-(ter t-Bu t yloxyca r b on yl)a m in o]-2,3-
epoxy-4-h ydr oxy-6-m eth yl-1-ph en ylh eptan e (9e): 73%; white
solid; mp 80 °C; [R]25 ) +11 (c 0.2); IR 3367, 1685 cm-1 1H
;
D
NMR δ 0.89 (d, 3H), 0.95 (d, 3H), 1.45 (s, 9H), 2.00 (m, 1H),
2.57 (d, OH), 2.79 (dd, 1H, J ) 7, 15 Hz), 2.95 (m, 2H), 3.55 (m,
1H), 3.62 (m, 1H), 4.61 (d, NH), 7.16-7.39 (m, 5H); 13C NMR δ
17.3, 20.1, 28.4, 28.5, 37.9, 56.4, 58.5, 59.0, 70.5, 79.5, 126.7,
128.6, 129.0, 137.0, 156.4; MS m/z 336 [MH]+, 280 [MH -
C4H8]+, 236 [MH - C5H8O2]+.
(2S,3S,4S,5S)-2-Azid o-5-[N-(ter t-Bu tyloxyca r bon yl)a m i-
n o]-3,4-d ih yd r oxy-1,6-d ip h en ylh exa n e (10a ). NaN3 (170
mg, 2.61 mmol), NH4Cl (90 mg, 1.68 mmol), and epoxide 9a (200
mg, 0.52 mmol) in 6 mL of 8:1 MeOH-H2O were heated at 80
°C in a sealed tube for 48 h. The reaction mixture was cooled
to room temperature and partitioned between diethyl ether and
10% aqueous NaHCO3. The aqueous phase was extracted with
diethyl ether, and the combined organic phases were washed
with brine and dried over sodium sulfate. The solvent was
rotary evaporated, and the resulting crude azide was used
Mosh er Ester s 14 a n d 15. (R)-(-)-R-Methoxy-R-(trifluo-
romethyl)phenylacetyl chloride (7.2 mg, 0.028 mmol) was added
without further purification: [R]25 ) -21 (c 0.36); IR (CCl4)
D

Notes
J . Org. Chem., Vol. 62, No. 26, 1997 9353
to a solution of (-)-7a or (()-7a (8.0 mg, 0.022 mmol) in pyridine
(0.2 mL). The solution was stirred at room temperature for 18
h, diluted with 2 mL of dichloromethane, and washed with 10%
aqueous citric acid. The water phase was extracted with
dichloromethane (1 mL). The combined organic phases were
passed through a short pad of silica gel, which was then eluted
with 5 mL of dichloromethane. The solvent was rotary evapo-
rated, obtaining 4 mg (0.007 mmol, 32%) of a white solid. 14:
1H NMR δ 1.4 (s, 9H), 2.4 (dd, 1H), 2.82 (dd, 1H), 3.4 (d, 2H),
3.56 (s, 3H), 4.1 (m, 1H), 4.2 (d, 1H), 5.55 (dd, 1H), 5.65 (m, NH),
6.08 (dt, 1H), 7-7.5 (m, 15H). 15: 1H NMR δ 1.4 (s, 9H), 2.6
(m, 1H), 2.8 (m, 1H), 3.4 (m, 2H), 3.54 (s, 3H), 4.2 (m, 1H), 4.4
(m, 1H), 5.45 (m, 1H), 5.6 (m, NH), 5.97 (dt, 1H), 7-7.5 (m, 15H).
Ack n ow led gm en t. We wish to thank the Istituto
Superiore di Sanita` (ISS) for financial support and the
University of Trieste for a postdoctoral grant to P.Z.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 6-15 (51 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 O971202P