A catalytic asymmetric synthesis of cyclohexylnorstatine

Full text of DOI:10.1021/jo960351p

J . Org. Chem. 1996, 61, 6033-6037
6033
We have previously reported that anti-3-amino 1,2-
diols, readily available in high enantiomeric purity
through the use of a catalytic Sharpless epoxidation5 as
the sole source of chirality, are convenient starting
materials for the enantioselective synthesis of R-amino
acids,6 â-amino acids,7 and model R-hydroxy â-amino
acids.8 We wish to disclose in the present paper the
enantioselective synthesis of cyclohexylnorstatine in a
fully protected form by application of this general meth-
odology.
A Ca ta lytic Asym m etr ic Syn th esis of
Cycloh exyln or sta tin e
Mireia Pasto´, Patr´ıcia Castejo´n, Albert Moyano,
Miquel A. Perica`s,* and Antoni Riera*
Departament de Quı´mica Orga`nica, Universitat de
Barcelona, c/ Mart´ı i Franque`s 1-11,
08028 Barcelona, Spain
Received February 20, 1996
Resu lts a n d Discu ssion
Our synthetic strategy is outlined in Scheme 1.
(E)-4-Cyclohexyl-2-buten-1-ol (4),9 the substrate for
Sharpless epoxidation, was prepared in the present
instance by Swern oxidation of commercial 2-cyclohexyl-
ethanol (3), followed by highly stereoselective Wittig
reaction with ethyl triphenylphosphoranylacetate and
reduction with DIBALH (Scheme 2). This procedure is
amenable to multigram scale and takes place with a 87-
88% overall yield. The allyl alcohol 4 was then submitted
to a Sharpless epoxidation5d in the presence of catalytic
amounts of D-(-)-diisopropyl tartrate (7.5%) and titanium
tetraisopropoxide (5%). Conducting the reaction at -20
°C for 24 h, (2R,3R)-4-cyclohexyl-2,3-epoxy-1-butanol (5)
could be isolated in 87% yield. The enantiomeric excess
of the so prepared 5 is 90% according to 1H NMR analysis
of its diastereomeric Mosher esters.
In tr od u ction
The isopropyl ester of cyclohexylnorstatine (1) is the
C-terminal residue of KRI 1314 (2), a tripeptide with
potent renin inhibitory activity.1 Other bioactive small
peptides also contain this R-hydroxy â-amino acid sub-
structure.2
A regioselective ring opening of 5, performed with a
nitrogen nucleophile, should lead to our key intermediate
(see Scheme 1), already possessing a 3-amino 1,2-diol
functionality array and that can be converted to the
ultimate target by simple stereochemical manipulation
and adjustment of oxidation level.
Several preparations of 1 in homochiral or scalemic
forms have been reported in recent years. However, they
either use chiral natural products as starting materials,
and involve in all cases a large number of steps,3 or
employ stoichiometric amounts of expensive chiral aux-
iliaries and/or chiral promoters.4 A catalytic asymmetric
synthesis of 1, which could be of high interest for the
potential large scale production of the compound, is still
lacking.
According to previous experience in our laboratories,
we initially performed the ring opening process with
benzhydrylamine in the presence of titanium tetraiso-
proxide10 (Scheme 3). The C-3/C-2 selectivity was 88/12
and, after chromatographic separation of the regioiso-
mers, the desired 3-benzhydrylamino derivative 6 was
isolated in 61% yield. The benzhydrylamino group was
subsequently changed to the more convenient Boc-amino
by hydrogenolysis over Pearlman’s catalyst in the pres-
ence of Boc2O. A 85% yield of the N-Boc-3-amino 1,2-
diol 8 was obtained in this way. This intermediate has
also been prepared through the following alternative pro-
cedure: Treatment of 5 with titanium diazidodiisopro-
poxide11 induces a completely regioselective nucleophilic
ring opening, the 3-azido 1,2-diol 7 being isolated in 99%
yield. The hydrogenolysis of 7 over 10% Pd-C in the
presence of Boc2O then affords 8 in 97% yield. Whereas
this last sequence is clearly superior at the laboratory
scale, the ring opening with benzhydrylamine (which
avoids the use of potentially risky azides) can be prefer-
able when work at a larger scale is considered.
(1) Iizuka, K.; Kamijo, T.; Harada, H.; Akahane, K.; Kubota, T.;
Umeyama, H.; Kiso, Y. J . Chem. Soc., Chem. Commun. 1989, 1678-
1680.
(2) (a) Dhanoa, D. S.; Parsons, W. H.; Greenlee, W. J .; Patchett, A.
A. Tetrahedron Lett. 1992, 33, 1725-1728. (b) Yang, L.; Weber, A. E.;
Greenlee, W. J .; Patchett, A. A. Tetrahedron Lett. 1993, 34, 7035-
7038.
(3) (a) Kobayashi, Y.; Takemoto, Y.; Ito, Y.; Terashima, S. Tetrahe-
dron Lett. 1990, 31, 3031-3034. (b) Matsumoto, T.; Kobayashi, Y.;
Takemoto, Y.; Ito, Y.; Kamijo, T.; Harada, H.; Terashima, S. Tetrahe-
dron Lett. 1990, 31, 4175-4178. (c) Inokuchi, T.; Tanigawa, S.;
Kanazaki, M.; Torii, S. Synlett 1991, 707-708. (d) Dugger, R. W.;
Ralbowsky, J . L.; Bryant, D.; Commander, J .; Massett, S. S.; Sage, N.
A.; Selvidio, J . R. Tetrahedron Lett. 1992, 33, 6763-6766. (e) Patel,
D. V.; Rielly-Gauvin, K.; Ryono, D. E.; Free, C. A.; Smith, S. A.; Petrillo,
E. W. J . Med. Chem. 1993, 36, 2431-2447.
(4) (a) Kobayashi, Y.; Takemoto, Y.; Kamijo, T.; Harada, H.; Ito, Y.;
Terashima, S. Tetrahedron 1992, 48, 1853-1868. (b) Ojima, I.; Park,
Y. H.; Sun, C. M.; Brigaud, T.; Zhao, M. Tetrahedron Lett 1992, 33,
5737-5740. (c) Hattori, K.; Yamamoto, H. Tetrahedron 1994, 50, 2785-
2792.
(5) (a) Katsuki, T.; Sharpless, K. B. J . Am. Chem. Soc. 1980, 102,
5974-5976. (b) Rossiter, B. E. In Asymmetric Synthesis; Morrison, J .
D., Ed.; Academic Press: New York, 1985; Vol. 5, pp 193-246. (c) Finn,
M. G.; Sharpless, K. B. In Asymmetric Synthesis; Morrison, J . D., Ed.;
Academic Press: New York, 1985; Vol. 5, pp 247-308. (d) Gao, Y.;
Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune, H.; Sharpless,
K. B. J . Am. Chem. Soc. 1987, 109, 5765-5780. (e) Sharpless, K. B.;
Wooddard, S. S.; Finn, M. G. Pure Appl. Chem. 1983, 55, 1823-1836.
(f) Sharpless, K. B.; Behrens, C. H.; Katsuki, T.; Lee, A. W. M.; Martin,
V. S.; Takatani, M.; Viti, S. M.; Walker, F. J .; Woodard, S. S. Pure
Appl. Chem. 1983, 55, 589-604.
(6) (a) Poch, M.; Alco´n, M.; Moyano, A.; Perica`s, M. A.; Riera, A.
Tetrahedron Lett. 1993, 34, 7781-7784. (b) Castejo´n, P.; Moyano, A.;
Perica`s, M. A.; Riera, A. Synthetic Commun. 1994, 24, 1231-1238.
(7) Alco´n, M.; Canas, M.; Poch, M.; Moyano, A.; Perica`s, M. A.; Riera,
A. Tetrahedron Lett. 1994, 35, 1589-1592.
(8) (a) Pasto´, M.; Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahe-
dron: Asymmetry 1995, 6, 2329-2342. (b) Pasto´, M.; Moyano, A.;
Perica`s, M. A.; Riera, A. Tetrahedron: Asymmetry 1996, 7, 243-262.
(9) Huyser, E.; Munson, L. R. J . Org. Chem. 1965, 30, 1436-1439.
(10) Canas, M.; Poch, M.; Verdaguer, X.; Moyano, A.; Perica`s, M.
A.; Riera, A., Tetrahedron Lett. 1991, 32, 6931-6934.
(11) M. Caron, P. R. Carlier, K. B. Sharpless, J . Org. Chem. 1988,
53, 5185-5187.
S0022-3263(96)00351-9 CCC: $12.00 © 1996 American Chemical Society

6034 J . Org. Chem., Vol. 61, No. 17, 1996
Notes
Sch em e 1
Sch em e 2
submitted to reduction with DIBALH in CH2Cl2 which
led in good yield to the secondary alcohol 11 without any
alteration in stereochemical purity. Treatment of 11 with
a tenfold excess of ethyl vinyl ether and a catalytic
amount of PPTS provided in 83% yield the 1-ethoxyethyl
derivative 12, as a ca. 1:1 mixture of epimers at the acetal
moiety.
To complete the synthesis, the primary hydroxyl group
was selectively deprotected by treatment with tetrabu-
tylammonium fluoride in THF, and the resulting primary
alcohol 13 (89% yield) was oxidized with the RuCl3/NaIO4
system14 to the fully protected cyclohexylnorstatine de-
rivative 14 in 86% yield. To facilitate chiral HPLC
analysis, crude 14 was transformed into the known
hydroxy ester 153e by treatment with ethyl orthoacetate
and subsequent acidic workup. The spectroscopic data
of 15 turned out to be fully coincident with those reported
in the literature. The enantiomeric excess of 15 was 94%,
as determined by chiral HPLC with a Chiralcel OD-R
column.
Sch em e 3
In summary, we have developed an efficient approach
to the bioactive stereoisomer of cyclohexylnorstatine from
(E)-4-cyclohexyl-2-buten-1-ol. The synthesis involves
nine steps and can be accomplished in 28% overall yield.
The source of enantioselectivity in the sequence is a
catalytic Sharpless epoxidation. According to that, both
enantiomeric series of the target R-hydroxy-â-amino acid
are equally available (by simply selecting the enantio-
meric series of the tartrate ester employed in the epoxi-
dation). If required, the anti diastereomers could also
be prepared (with even greater efficiency) by this meth-
odology, by simply supressing the C-2 inversion se-
quence.8 Further applications of this flexible approach
to R-hydroxy â-amino acids are in progress in our
laboratories and will be reported in due course.
The N-Boc amino diol 8 is a highly crystalline solid
which offers good opportunity for enantioenrichment.
Thus, a single crystallization from ether/hexane at this
stage allows improvement of the enantiomeric excess up
to 94%, as indicated by chiral HPLC analysis of the final
product in the sequence (see below). Besides the work
described here, 8 has also shown to be a convenient
precursor of both anti and syn aminoalkyl epoxides,12
which are valuable intermediates for the synthesis of
hydroxyethylene dipeptide isosteres.
Conversion of 8 into our target, protected cyclohexyl-
norstatine, requires only inversion at C-2 and oxidation
of the primary hydroxy group. However, these operations
are not straightforward, and attention must be paid to
the implementation of orthogonal protection schemes for
the different functions along the sequence.
Bearing this idea in mind, the primary hydroxy group
in 8 was selectively protected by reaction with TBDMS-
Cl/imidazole in DMF to afford the secondary alcohol 9
in 83% yield (Scheme 4). Inversion at C-2 under Mit-
sunobu conditions using p-nitrobenzoic acid as the nu-
cleophile13 took place very cleanly to afford the diaste-
reomerically pure syn derivative 10 in 89% yield. At this
point, it seemed desirable to convert the p-nitrobenzoate
to a less labile function. To this end, 10 was first
Exp er im en ta l Section
Gen er a l. Melting points were determined in an open capil-
lary tube and are uncorrected. Optical rotations were measured
on a Perkin-Elmer 241 MC polarimeter. The 1H NMR spectra
were recorded at 200 or 300 MHz in CDCl3 unless specified
otherwise. J values are given in Hz. The 13C NMR spectra were
recorded at 50.3 or 75.4 MHz in CDCl3 unless specified other-
wise. Signal multiplicities were established by DEPT experi-
ments. In all cases, chemical shifts are in ppm downfield of
TMS. Mass spectra were recorded at 70 eV ionizing voltage;
ammonia was used for chemical ionization (CI). Elemental
analyses were performed by the “Servei d’Ana`lisis Elementals
del CSIC de Barcelona”. 2-Cyclohexylethanol (99%) was pur-
chased from Aldrich. THF and diethyl ether were distilled from
sodium benzophenone ketyl; CH2Cl2 was distilled from CaH2,
and triethylamine from KOH. All reactions were performed in
oven-dried glassware under a N2 atmosphere. Reaction progress
was followed by TLC (Merck DC-Alufolien Kieselgel 60 F254).
Chromatographic separations were carried out using Et3N
pretreated (2.5% v/v) SiO2 (70-230 mesh), eluting with hexane/
ethyl acetate mixtures of increasing polarity. HPLC analyses
were performed with Nucleosil 120 C18 or Chiralcel OD-R
columns.
(12) Castejo´n, P.; Pasto´, M.; Moyano, A.; Perica`s, M. A.; Riera, A.
Tetrahedron Lett. 1995, 36, 3019-3022.
(13) Martin, S. F.; Dodge, J . A. Tetrahedron Lett. 1991, 32, 3017-
3020.
(14) Carlsen, P. H. J .; Katsuki, T.; Mart´ın, V. S.; Sharpless, K .B.
J . Org. Chem. 1981, 46, 3936-3938.

Notes
J . Org. Chem., Vol. 61, No. 17, 1996 6035
Sch em e 4
(E)-4-Cycloh exyl-2-bu ten -1-ol (4). (a) To a stirred solution
yield) of 5 as a colorless oil: 1H NMR (200 MHz) δ 0.80-1.80
(m, 13H), 2.15 (bs, 1H), 2.90 (m, 1H), 2.98 (m, 1H), 3.60 (dd, J
of oxalyl chloride (8.16 mL. 93.6 mmol) in CH2Cl2 (170 mL) at
-78 °C was added DMSO (14.63 g, 187 mmol) in CH2Cl2 (42
mL) via cannula. After stirring for 10 min, commercial 2-cy-
clohexylethanol (10.0 g, 78.0 mmol) in CH2Cl2 (70 mL) was added
via cannula. After a further 30 min period, triethylamine (39.46
g, 390 mmol) was slowly added and stirring was continued for
2 h. Following aqueous workup, CH2Cl2 extraction, drying with
Na2SO4, and solvent evaporation, cyclohexylacetaldehyde (9.7
g, 77.0 mmol), pure enough for the continuation of the synthesis,
was obtained. (b) To the crude aldehyde (7.5 g, 59.4 mmol) in
dichloromethane (80 mL), ethyl triphenylphosphoranylacetate
(24.84 g, 71.3 mmol) in dichloromethane (90 mL) was added,
and the mixture was refluxed for 24 h. The solvent was then
evaporated and the residue extracted with petroleum ether.
Evaporation and column chromatography allowed the isolation
of ethyl (E)-4-cyclohexyl-2-butenoate (10.39 g, 52.93 mmol), and
of a small amount (0.29 g) of the corresponding (Z) isomer. (c)
To a stirred solution of the stereochemically pure (E) ester (9.0
g, 45.85 mmol) in diethyl ether (60 mL) at -78 °C, 20% DIBALH
in hexanes (115 mL, 115 mmol) was added via cannula. After
30 min of stirring, methanol (100 mL) was added. Precipitated
aluminum oxide was separated by filtration and washed with
CH2Cl2. This solution was washed with saturated brine, dried
(MgSO4), and evaporated to an oily residue which was purified
by column chromatography to afford 6.77 g (87% overall yield)
of 4 as a colorless liquid: 1H NMR (200 MHz) δ 0.8-1.8 (m, 11H),
1.92 (m, 2H). 2.60 (bs, 1H), 4.06 (m, 2H), 5.62 (m, 2H); 13C NMR
(50 MHz) δ 26.2 (CH2), 26.4 (CH2), 32.9 (CH2), 37.7 (CH), 40.1
(CH2), 63.4 (CH2), 129.9 (CH), 131.5 (CH).
) 10 Hz, J ) 5 Hz, 1H), 3.92 (dd, J ) 10 Hz, J ) 2 Hz, 1H); 13
C
NMR (50 MHz) δ 26.0 (CH2), 26.1 (CH2), 26.2 (CH2), 32.9 (CH2),
33.5 (CH2), 35.6 (CH), 39.2 (CH2), 54.7 (CH), 58.9 (CH), 61.6
(CH2); MS(CI) m/e 188 (M + 18+, 100%), 205 (M + 35+, 12%);
[R]25 +35.65 (c 1.15, CHCl3).
D
P r ep a r a tion of th e Mosh er Ester of 5. The following
procedure was used starting from (a) a racemic sample of 5,
prepared by epoxidation of 4 with m-CPBA, and (b) the enan-
tioenriched sample of (+)-5 whose preparation has been de-
scribed in the preceding experiment: To a solution of 5 (0.030
g, 0.18 mmol) in dry CH2Cl2 (0.6 mL) at room temperature, (N,N-
dimethylamino)pyridine (0.022 g), triethylamine (117 µL), and
(+)-R-methoxy-R-(trifluoromethyl)phenylacetyl chloride (35 µL)
were sequentially added, and the resulting orange solution was
stirred for 60 min, until no starting material could be detected
by TLC. The reaction was quenched by addition of 3-(dimethyl-
amino)propylamine, and the solvent was removed under vacuum.
Filtration of the residue through a short pad of silicagel afforded
0.060 g (86% yield) of the corresponding Mosher ester: 1H NMR
(300 MHz) of the diastereomeric mixture from (()-5 δ 0.80-
1.80 (m, 13H + 13H), 2.81-2.86 (m, 1H + 1H), 2.87-3.10 (m,
1H + 1H), 3.60 (s, 3H + 3H), 4.23 (dd, J ) 12 Hz, J ) 5.4 Hz,
1H), 4.24 (dd, J ) 12, J ) Hz, J ) 6 Hz, 1H), 4.54 (dd, J ) 12
Hz, J ) 3.6 Hz, 1H), 4.57 (dd, J ) 12 Hz, J ) 3.3 Hz, 1H), 7.4-
7.6 (m, 5H + 5H).
The enantiomeric excess of the sample from (+)-5 was
determined by integration and mathematical analysis of the dd
signals at 4.54 and 4.57 ppm, which correspond to one of the
CH2O protons of each diastereomer.
(2R,3R)-4-Cycloh exyl-2,3-ep oxy-1-bu ta n ol (5). To a sus-
pension of powdered, freshly activated 4 Å molecular sieves (0.78
g) in dry CH2Cl2 (37 mL), cooled at -20 °C, were sequentially
added via cannula with stirring D-(-)-diisopropyl tartrate (0.45
g, 1.93 mmol) in dry CH2Cl2 (11.4 mL), titanium tetraisopro-
poxide (390 µL, 1.30 mmol), and a solution of 4 (4.0 g, 25.9 mmol)
in dry CH2Cl2 (11.4 mL). The resulting mixture was stirred for
30 min at -20 °C, and a solution of tert-butyl hydroperoxide
(TBHP) in isooctane (18.7 mL, 2.78 M, 51.9 mmol) was then
added via cannula. The reaction mixture was stirred for 24 h
at -20 °C and quenched with a cold (0 °C) solution of FeSO4‚
7H2O (8.65 g, 31.1 mmol) and tartaric acid (2.33 g, 15.5 mmol)
in H2O (25 mL). After the layers were separated and the
aqueous one extracted with dichloromethane (2 × 25 mL), the
combined organic extracts were cooled to 0 °C and treated with
a cold 30% NaOH solution in saturated brine (2.6 mL) with
vigorous stirrring. After 2 h at 0 °C, water (15 mL) was added,
the layers were separated, and the aqueous one was extracted
with diethyl ether (2 × 25 mL). The combined organic extracts
were dried (Na2SO4) and evaporated to an oily residue, which
was purified by column chromatography to afford 3.84 g (87%
(2S,3S)-3-(Ben zh yd r yla m in o)-4-cycloh exyl-1,2-b u t a n e-
d iol (6). To a solution of 5 (0.66 g, 3.91 mmol) in dry
1,2-dichloroethane (25 mL) at room temperature were sequen-
tially added benzydrylamine (1.39 g, 7.82 mmol) in 1,2-dichlo-
roethane (25 mL) and Ti(OiPr)4 (3.48 mL, 11.7 mmol) via
cannula. The solution was heated under reflux for 24 h and
cooled, and a 10% NaOH in saturated brine (7.5 mL) was added,
the resulting suspension being stirred at room temperature for
an additional period of 12 h. The mixture was filtered through
Celite, the organic layer was separated, and the aqueous one
was extracted with dichloromethane (3 × 20 mL). The combined
organic extracts were dried over MgSO4 and the solvents
evaporated in vacuo. The crude product was dissolved in ether,
and solid CO2 was added to the solution until a white precipitate
appeared. The mixture was filtered through a pad of Celite and
the residue thoroughly washed with diethyl ether. Solvent
evaporation yielded an oil that was purified by flash chroma-
tography to afford 0.11 g (8% yield) of the unwanted regioisomer,
(2S,3S)-2-(benzhydrylamino)-4-cyclohexyl-1,3-butanediol, and
0.84 g (61% yield) of 6 as a colorless oil that slowly crystallizes

6036 J . Org. Chem., Vol. 61, No. 17, 1996
Notes
1
on standing: mp 69-72 °C; H NMR (200 MHz) δ 0.6-1.8 (m,
8.3 (d, 2H); 13C NMR (50 MHz) δ -5.5 (CH3), 19 (C), 25.6 (CH3),
26.1 (CH2), 26.2 (CH2), 26.4 (CH2), 28.2 (CH3), 32.5 (CH2), 33.7
(CH2), 33.9 (CH), 39.7 (CH2), 48.1 (CH), 62.2 (CH2), 77.8 (CH),
13H), 2.9 (m, 1H), 2.8-3.1 (m, 2H), 3.5-3.9 (m, 3H), 5.0 (s, 1H),
7.1-7.5 (m, 10H); 13C NMR (50 MHz) δ 26.0 (CH2), 26.2 (CH2),
26.3 (CH2), 33.2 (CH2), 33.6 (CH2), 34.0 (CH), 38.4 (CH2), 54.5
(CH), 64.0 (CH2), 64.3 (CH), 71.7 (CH), 127.1 (CH), 127.2 (CH),
123.5 (CH), 130.8 (CH), 138 (C), 150 (C), 155 (C), 164 (C); [R]25
D
-11.4 (c ) 2.42, CHCl3). Anal. Calcd for C28H46N2O7Si: C,
61.06; H, 8.42; N, 5.09. Found: C, 61.16; H,8.54; N, 4.95.
(2R,3S)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-3-[(ter t-bu toxy-
ca r bon yl)a m in o]-4-cycloh exyl-2-bu ta n ol (11). To a solution
of 10 (0.3 g, 0.54 mmol) in CH2Cl2 (4.5 mL) at -20 °C was added
DIBALH (2.2 mL, 2.17 mmol, 20% in hexanes) and the mixture
stirred at -20 °C, the progress of the reaction being monitored
by TLC. After 2 h, methanol (3 mL) was added and the solution
treated with water (15 mL); phases were then separated, and
the aqueous one was extracted with CH2Cl2 (2 × 10 mL). The
combined organic extracts were dried over MgSO4 and concen-
trated in vacuo, and the residue was purified by flash chroma-
tography to afford 0.15 g (71% yield) of 11 as a colorless oil: 1H
NMR (200 MHz,) δ 0.07 (s, 6H), 0.90 (s, 9H), 1.1-2 (m, 13H),
127.3 (CH), 128.1 (CH), 128.5 (CH), 143.1 (C), 143.7 (C); [R]25
D
+5.8 (c 1.99, CHCl3). Anal. Calcd for C23H31NO2: C, 78.15; H,
8.84; N, 3.96. Found: C, 77.89; H, 8.95; N, 3.72.
(2S,3S)-3-Azid o-4-cycloh exyl-1,2-bu ta n ed iol (7). To a
suspension of titanium diazidodiisopropoxide (Ti(OiPr)2(N3)2)
(1.76 g, 7.05 mmol) in dry benzene (30 mL) under argon, heated
to 75 °C, a solution of 5 (1 g, 5.87 mmol) in dry benzene (30 mL)
was added via cannula. The mixture was stirred at 75 °C for
5-10 min and cooled to room temperature, and the solvent was
eliminated in vacuo . Diethyl ether (115 mL) and 5% H2SO4
(45 mL) were added to the residue, and the mixture was stirred
for 60 min until both layers were transparent. After phase
separation, the aqueous one was extracted with dichloromethane
(2 × 30 mL), and the combined organic extracts were dried over
MgSO4 and evaporated. A white solid was obtained that was
recrystallized from hexanes to afford 1.24 g (99% yield) of 7 as
1.44 (s, 9H), 2.7 (m, 1H), 3.4-3.8 (m, 4H)., 4.7-4.8 (m, 1H); 13
C
NMR (50 MHz) δ -5.5 (CH3), -5.4 (CH3), 19 (C), 25.8 (CH3),
26.2 (CH2), 26.3 (CH2), 26.5 (CH2), 28.3 (CH3), 32.8 (CH2), 33.7
(CH2), 34.1 (CH), 40.3 (CH2), 48.3 (CH), 64.9 (CH2), 73.4 (CH),
1
white crystals: mp 47-50 °C, H NMR (200 MHz) δ 0.80-1.80
(m, 13H), 2.10 (bs, 1H), 2.68 (bs, 1H), 3.60 (m), 3.71 (m); 13C
NMR (50 MHz) δ 26.0 (CH2), 26.2 (CH2), 26.4 (CH2), 32.3 (CH2),
34.1 (CH2), 34.4 (CH), 38.2 (CH2), 62.0 (CH), 63.0 (CH2), 74.0
156 (C); [R]25 -23.8 (c ) 1.85, CHCl3).
D
(2R,3S)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-3-[(ter t-bu toxy-
ca r b on yl)a m in o]-4-cycloh exyl-2-(1-et h oxyet h oxy)b u t a n e
(12). To a solution of 11 (0.16 g, 0.4 mmol) in CH2Cl2 (2 mL) at
room temperature were added ethyl vinyl ether (0.4 mL, 4 mmol)
and a catalytic amount of pyridinium p-toluenesulfonate, and
the mixture was stirred until no starting product could be
detected by TLC. The solution was then treated with water;
phases were separated and the organic one was extracted with
dichloromethane. The combined organic extracts were dried
over MgSO4 and concentrated, yielding an oil that was purified
by flash chromatography to give 0.16 g (83% yield) of 12 (1:1
mixture of diastereomers at the 1-ethoxyethoxy group), as an
oil: 1H NMR (200 MHz) δ 0.06 (s, 6H), 0.9 (s, 9H), 0.9-2 (m,
13H), 1.2 (t, J ) 7.1 Hz, 3H), 1.3 (m, 3H), 1.43 (s, 9H), 3.3 -4
(m, 6H), 4.6 (m, 1H), 4.7-5 (m, 1H); 13C NMR (50 MHz) δ -5.4,
15.5, 19, 20.9, 26.1, 26.3, 26.6, 26.8, 28.6, 33.2, 33.3, 33.8, 34.1,
34.3, 34.4, 39.5, 40,2, 48.4, 48.6, 61.3, 61.3, 62.9, 63.9, 77.9, 78.1,
100.2, 101.3; MS(CI) m/e 170 (100%), 126 (76%).
(2R,3S)-3-[(ter t-Bu toxyca r bon yl)a m in o]-4-cycloh exyl-2-
(1-eth oxyeth oxy)-1-bu ta n ol (13). To a solution of 12 (0.16 g,
0.33 mmol) in tetrahydrofuran (3 mL) was added tetrabutylam-
monuim fluoride (0.6 mL, 0.66 mmol, 1.1M in THF). The
mixture was stirred at room temperature and the progress of
the reaction monitored by TLC. After 10 min, the solution was
treated with water (10 mL), phases were separated, and the
organic one was extracted with dichloromethane. The combined
organic phases were dried over MgSO4 and concentrated in
vacuo. The residue was purified by chromatography to give 0.11
g (89% yield) of 13 (1:1 mixture of diastereomers) as a colorless
oil: 1H NMR (200 MHz) δ 0.8-2 (m, 13H), 1.1-1.4 (m, 6H), 1.44
(s, 9H), 3.4-4 (m, 7H), 4.5-4.8 (m, 2H); 13C NMR (50 MHz) δ
15.1, 20.2, 20.6, 26.1, 26.3, 26.5,28.3, 32.7, 33.7, 33.8, 34.1, 39.4,
39.7, 47.4, 48.0, 61.0, 61.2, 61.9 , 62.3, 76.3, 81.5, 99.3, 102.0.
(CH); [R]25 -13.6 (c 1.84, CHCl3). Anal. Calcd for C10H19
-
D
N3O2: C, 56.32; H, 8.98; N, 19.70. Found: C, 56.44; H, 9.05; N,
19.74.
(2S,3S)-3-[(ter t-Bu t oxyca r b on yl)a m in o]-4-cycloh exyl-
1,2-bu ta n ed iol (8). (a) From 6: A solution of 6 (1.06 g, 3 mmol)
and Boc2O (0.85 g, 3.9 mmol) in ethyl acetate (5 mL) was added
via cannula to a stirred suspension of 20% Pd(OH)2/C (0.1 g) in
ethyl acetate (2 mL) under H2. The mixture was hydrogenated
at atmospheric pressure until no starting material could be
observed by TLC, filtered through Celite thoroughly washing
with CH2Cl2, and evaporated. The oily residue was purified by
flash chromatography to afford 0.72 g (85% yield) of 8: mp 65-
1
68 °C (from diethyl ether/hexanes); H NMR (200 MHz) δ 0.8-
1.9 (m, 13H), 1.45 (s, 9H), 3.1-3.2 (m, 1H), 3.3-3.4 (m,1H), 3.5-
3.8 (m, 4H), 4.5-4.6 (m, 1H); 13C NMR (50 MHz) δ 26.0 (CH2),
26.3 (CH2), 26.4 (CH2), 28.3 (CH3), 32.1 (CH2), 34.2 (CH), 38.9
(CH2), 49.9 (CH), 62.9 (CH2), 74.9 (CH), 80 (C), 158 (C); [R]25
D
-24.4 (c 1.59, CHCl3). Anal. Calcd for C15H29NO4: C, 62.74;
H, 10.10; N, 4.88. Found: C, 62.86; H,10.19; N, 4.71.
(b) From 7: A solution of 7 (1.07 g, 5.01 mmol) and Boc2O
(1.42 g, 6.52 mmol) in ethyl acetate (11 mL) was added via
cannula to a stirred suspension of 10% Pd/C (0.11 g) in ethyl
acetate (1.9 mL) under H2, and the mixture was hydrogenated
at atmospheric pressure for 18 h. Workup as in (a ) afforded
1.40 g (97% yield) of 8.
(2S,3S)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-3-[(ter t-bu toxy-
ca r bon yl)a m in o]-4-cycloh exyl-2-bu ta n ol (9). To a solution
of 8 (0.33 g, 1.14 mmol) in dimethylformamide (5.5 mL) at room
temperature were added TBDMS-Cl (0.22 g, 1.48 mmol) and
imidazole (0.17 g, 2.5 mmol), and the progress of the reaction
was monitored by TLC. After 48 h, diethyl ether (30 mL) was
added and the mixture washed with saturated NH4Cl solution
(20 mL). The organic layer was separated and dried over
MgSO4, and the solvents were evaporated in vacuo. The crude
product was purified by chromatography yielding 0.38 g (83%
yield) of 9 as a colorless oil: 1H NMR (200 MHz) δ 0.08 (s, 6H),
0.91 (s, 9H), 1.1-2 (m, 13H), 1.44 (s, 9H), 2.8 (m, 1H), 3.5-3.9
(m, 4H), 4.8-4.9 (m, 1H); 13C NMR (50 MHz) δ -5.5 (CH3), 18.0
(C), 25.8 (CH3), 26.1 (CH2), 26.4 (CH2), 26.5 (CH2), 28.3 (CH3),
32.5 (CH2), 34.1 (CH2), 34.2 (CH), 38.7 (CH2), 50.8 (CH), 64.4
(CH2), 73.5 (CH), 80 (C), 156 (C); MS(CI) m/e 170 (100%), 126
Anal. Calcd for
C19H37NO5: C, 63.48; H, 10.37; N, 3.90.
Found: C, 63.32; H,10.39; N, 3.85.
(2R,3S)-3-[(ter t-Bu toxyca r bon yl)a m in o]-4-cycloh exyl-2-
(1-eth oxyeth oxy)bu ta n oic Acid (14). To a solution of 13 (0.07
g, 0.20 mmol) in 1.55 mL of a mixture of CH3CN/CCl4/H2O (1/
1/1.5) were added NaHCO3 (0.12 g, 1.4 mmol), NaIO4 (0.25 g,
1.17 mmol), and RuCl3 (catalytic amount), and the reaction
mixture was stirred at room temperature for 48 h. When no
starting material could be detected by TLC, water (15 mL) and
diethyl ether (15 mL) were added; the organic layer was
separated and the aqueous one washed with ether (15 mL),
acidified with phosphate buffer (pH ) 5.6), and extracted with
ether (3 × 15 mL). The combined organic extracts were dried
over Na2SO4 and concentrated in vacuo to yield 14 (0.07 g, 86%
yield) as an oil: 1H NMR (200 MHz) δ 0.8-2.0 (m, 19H), 1.43
(s, 9H), 3.4-3.7 (m, 2H), 4.0-4.3 (m, 2H), 4.7-5.1 (m, 2H).
Der iva tiza tion of 14 in to th e Kn ow n Hyd r oxy Ester 15.3e
Crude 14 (0.07 g, 0.18 mmol) was treated with ethyl orthoacetate
(0.1 mL, 0.55 mmol) in toluene (0.22 mL), and the mixture was
heated under reflux for 24 h. Following aqueous workup, drying,
and evaporation, the ethyl ester of 14 (0.06 g) was transformed
into the known ethyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-4-
(90%); [R]25 -17.6 (c ) 2.00, CHCl3).
D
(2R,3S)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-3-[(ter t-bu toxy-
ca r bon yl)a m in o]-4-cycloh exyl-2-[(p-n itr oben zoyl)oxy]bu -
ta n e (10). To a solution of 9 (0.27 g, 0.68 mmol) in benzene (13
mL) at room temperature were added PPh3 (0.86 g, 3.3 mmol),
p-nitrobenzoic acid (0.49 g, 2.9 mmol), and diethyl azodicarboxy-
late (0.52 mL, 3.3 mmol), and the mixture was stirred at room
temperature for 12 h. Solvent was removed in vacuo, and the
residue was purified by flash chromatography to afford 0.33 g
(89% yield) of 10 as a colorless oil: 1H NMR (200 MHz) δ 0.00
(s, 3H), 0.03 (s, 3H), 0.8-2 (m, 13H), 0.83 (s, 9H), 1.38 (s, 9H),
3.7-3.9 (m, 2H), 4.1-4.6 (m, 2H), 5.1-5.3 (m,1H), 8.2 (d, 2H),

Notes
J . Org. Chem., Vol. 61, No. 17, 1996 6037
cyclohexyl-2-hydroxybutanoate (15) by treatment with a mixture
of THF (30 mL) and 0.65 M HCl (2.3 mL) for 5 h. To isolate 15,
the mixture was washed with saturated NaHCO3 and extracted
with ether. The combined organic extracts were dried over
MgSO4 and the solvents evaporated in vacuo. The oily residue
was purified by flash chromatography to afford 15 as a colorless
oil. 1H NMR (200 MHz) δ 0.8-2 (m, 15H), 1.4 (s, 9H), 3.1 (m,
1H), 4.0-4.4 (m, 4H), 4.6 (m, 1H); 13C NMR (75.4 MHz) δ 14.1
(CH3), 26.2 (CH2), 26.3 (CH2), 26.5 (CH2), 28.2 (CH3), 32.9 (CH2),
33.5 (CH2), 34.2 (CH), 39.9 (CH2); 50.2 (CH), 62.2 (CH2), 72.4
(CH), 79.3 (C), 155.2 (C), 173.9 (C). Conditions for Chiral HPLC
analysis: Chiralcel OD-R column, 30% MeOH/0.5 M NaClO4,
0.5 mL/min. (2S,3R) Stereoisomer [minor]: 22.6 min; (2R,3S)
stereoisomer [major]: 27.7 min.
Ack n ow led gm en t. Financial support from CIRIT-
CICYT through grant QFN93-4407 is gratefully ac-
knowledged. M. Pasto´ and P. Castejo´n thank CIRIT
(Generalitat de Catalunya) for predoctoral fellowships.
J O960351P