Stereocontrolled conversion of some optically active (4S,5R)-dihydroisoxazoles into acyclic 3-acetamido-1,2-diols

Article abstract of DOI:10.1016/S0040-4020(03)00868-8

Optically active (4S,5R)-dihydroisoxazoles 5a-c (90-91% ee) have been prepared by reaction of the epoxyketones 4a-c with hydroxylamine. Reduction of compounds 5a and 5b using lithium aluminium hydride took place exclusively from the Re face to give (1R,2S,3S)-1,3-disubstituted-3-aminopropane-1,2-diols 6a and 6b. These amino-diols were characterised by N-acetylation and the stereochemical sense of the hydride reduction was confirmed by conversion of amides 7a and 7b into α-amino acid derivatives 10a and 10b.

Full text of DOI:10.1016/S0040-4020(03)00868-8

Tetrahedron 59 (2003) 5731–5736
Stereocontrolled conversion of some optically active
(4S,5R)-dihydroisoxazoles into acyclic 3-acetamido-1,2-diols
*
Jamie F. Bickley, Stanley M. Roberts, Ye Runhui, John Skidmore and Corina B. Smith
Department of Chemistry, Liverpool University, Liverpool L69 7ZD, UK
Received 27 March 2003; revised 8 May 2003; accepted 29 May 2003
Abstract—Optically active (4S,5R)-dihydroisoxazoles 5a–c (90–91% ee) have been prepared by reaction of the epoxyketones 4a–c with
hydroxylamine. Reduction of compounds 5a and 5b using lithium aluminium hydride took place exclusively from the Re face to give
(1R,2S,3S)-1,3-disubstituted-3-aminopropane-1,2-diols 6a and 6b. These amino-diols were characterised by N-acetylation and the
stereochemical sense of the hydride reduction was confirmed by conversion of amides 7a and 7b into a-amino acid derivatives 10a and 10b.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
racemic heterocycles, which could be reduced to yield
amino-diols and/or derivatives of defined stereochemistry
(Scheme 1).
(4S,5R)-Dihydroisoxazoles have been shown to be versatile
intermediates in synthesis through reduction of the hetero-
cycle to form amino-diols of defined stereochemistry. Such
chemistry has been utilised for the preparation of biologi-
cally important poly-hydroxylated amino-acids, amino-
polyols and amino-sugars.1–5
2. Results and discussion
The enones 3a–c were epoxidised using urea–hydrogen
peroxide complex and 1,8-diazabicycloundecene (DBU) in
THF containing poly-L-leucine supported on silica, to yield
enantio-enriched epoxides 4a–c in high yields
(Table 1).14–16 The epoxides 4a–c were reacted with
hydroxylamine to afford the desired (4S,5R)-dihydro-
isoxazoles 5a–c in good yields (Table 2). Chiral HPLC
established that the reaction proceeded without loss of
stereochemical integrity and the identity of compound 5b
was confirmed by X-ray analysis.17
The stereoselectivity of the reduction of (4S,5R)-dihydro-
isoxazoles with reagents such as lithium aluminium hydride
has been attributed to the influence of the substituent at the
4-position.6 anti-Stereochemistry between the newly-
introduced amino moiety and the adjacent alcohol group
may be achieved by direct reduction of the (4S,5R)-
dihydroisoxazole.
(4S,5R)-Dihydroisoxazoles, in turn, may be prepared using
a variety of methods including [3þ2] cycloaddition
chemistry.7 Ito et al. reported the preparation of
4-hydroxy-D2-isoxazolines via intramolecular ring opening
of a,b-epoxy ketone oximes derived from a,b-epoxy
ketones.8 It was also shown that by increasing the
equivalents of hydroxylamine the reaction would proceed
directly to give racemic (4S/R,5R/S)-dihydroisoxazoles.
However, only a narrow range of substrates have been
examined. To date this approach has not been investigated
using non-racemic epoxides. We envisaged that by
The reduction of (4S,5R)-dihydroisoxazoles 5a and 5b was
investigated using the method described by Rosini et al.18
using 4 equiv. of lithium aluminium hydride in diethyl
ether. Upon reduction of 5a, a 7:1 mixture of the desired
amino-diol 6a and styrene glycol was obtained, as observed
1
by H NMR spectroscopy. It is possible that the glycol is
formed by deprotonation of the hydroxyl group and
cleavage of the (4S,5R)-dihydroisoxazole to form benzo-
nitrile and a-hydroxy phenylacetaldehyde. The latter
compound can then be reduced to give styrene glycol
under the reaction conditions (Scheme 2). Benzonitrile (and/
or benzylamine) was not observed in the reaction mixture;
however, it is possible that this material was removed during
the work-up procedure. Similarly the (4S,5R)-dihydro-
isoxazole 5b gave a crude product comprising a mixture
of 6b (85%) and styrene glycol (15%).
employing optically active epoxy-ketones generated by
9–13
Julia-Colonna poly-amino acid catalysed reactions,
´
condensation with hydroxylamine and in situ intramolecular
epoxide opening would generate the corresponding non-
Keywords: dihydroisoxazole; amino-diols.
*
Corresponding author; e-mail: cbsmith76@hotmail.com
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00868-8

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J. F. Bickley et al. / Tetrahedron 59 (2003) 5731–5736
Scheme 1. Reagents and conditions: (i) Ba(OH)2, EtOH, 908C; (ii) Poly-L-leucine-1,3-diaminopropane adsorbed onto silica (PLL–SiO2), DBU, urea–H2O2,
THF; (iii) NH2OH·HCl, pyridine, EtOH, 908C; (iv) LiAlH4, THF, rt; (v) Ac2O, pyridine, rt; (vi) NaIO4 on silica, rt, DCM; (vii) CrO3, H2SO4, acetone, 08C;
(viii) TMSCHN2, hexane, MeOH, rt.
Table 1. The epoxidation of selected enones
Reduction of the diphenyl compound 5c proceeded less
cleanly and this reaction was not investigated further.
Product
R 1
R 2
ee (%)a
Yield (%)b
Time (h)
The diols 7a and 7b were cleaved using sodium periodate on
silica (1.2 mmol/g), then oxidised using Jones’ reagent, to
give the N-acetylated amino acids which were subsequently
converted into the corresponding methyl esters 10a and 10b
(overall yields 64 and 75%, respectively). Authentic
samples of 10a and 10b were also prepared from the
commercially available amino acids. GC analysis of the
compounds 10a and 10b, showed that the configuration of
the amino acids obtained from the oxidative cleavage of the
protected amino-diols corresponded predominantly to the
L-form of the derivatised commercial amino acids 10a (90%
ee), 10b (91% ee). Thus, the reductions of the (4S,5R)-
dihydroisoxazoles 6a (89% ee) and 6b (90% ee) appear to
take place in anti-fashion under complete stereocontrol,
since the optical purities of the starting materials and the
corresponding amino acid derivatives 10a (90% ee) and 10b
(91% ee) match within experimental error.
4a
4b
4c
i-Pr
t-Bu
Ph
Ph
Ph
Ph
90
91
95
78
84
93
24
18
3
a
Determined by chiral HPLC.
Isolated yield after column chromatography (silica gel, hexane/ethyl
acetate).
b
Table 2. Heterocyclisation reaction
Product
R 1
R 2
ee (%)a
Yield (%)b
Time (h)
5a
5b
5c
i-Pr
t-Bu
Ph
Ph
Ph
Ph
89
92
94
73
76
71
14
10
13
a
Determined by chiral HPLC.
Isolated yield after column chromatography (silica gel, hexane/ethyl
acetate).
b
Attempts to purify the crude mixtures containing 6a and 6b
by flash chromatography were unsuccessful, therefore the
amino-diols 6a and 6b were mono-acetylated, using
1.1 equiv. of acetic anhydride in pyridine, to give the
amides 7a and 7b in yields of 73 and 75% (over two steps),
respectively, after column chromatography. The structure of
compound 7a was confirmed by X-ray crystallography.19
In summary, optically active (4S,5R)-dihydroisoxazoles
5a–c are readily formed from the appropriate enones.
Reduction of representative examples of these (4S,5R)-
dihydroisoxazoles takes place with a high degree of
stereocontrol to yield (after acetylation) chiral N-acetyl
amino diols 7a–b both in a state of high diastereomeric
purity.

J. F. Bickley et al. / Tetrahedron 59 (2003) 5731–5736
5733
Scheme 2.
3. Experimental
one (4a) (2.56 g, 78%, 90% ee [chiral HPLC-hexane/
ethanol (9:1)]) as a white solid, mp 468C (from ethanol);
(found: C, 76.2; H, 7.6. C12H14O2 requires C, 75.8; H, 7.4
%); [a]D¼2110 (c 1, CHCl3); nmax (Nujol)/cm21 1710
(CvO) and 1230 (C–O); dH (250 MHz, CDCl3) 1.04 (3H,
d, J¼6.9 Hz, CH3), 1.08 (3H, d, J¼6.9 Hz, CH3), 2.83 (1H,
hept, J¼6.9 Hz, CH(CH3)2), 3.62 (1H, d, J¼1.7 Hz,
COCH), 3.94 (1H, d, J¼1.7 Hz, CHPh), 7.26–7.60 (5H,
m, Ph); dC (100 MHz, CDCl3) 17.3, 18.1 (2£CH3), 37.0
(CH(CH3)2), 58.4 (CHPh), 61.9 (COCH), 125.7, 129.0,
129.1 (ArCH), 135.4 (ArCipso), 208.7 (CvO); m/z (CIþ)
191 (66%) [MþHþ] and 208 (24%) [MþNH4]þ.
3.1. General
Melting points were measured used a Reichert-Jung
Thermovar hot-stage microscope and are uncorrected.
Microanalyses were determined using a Carlo Elba
elemental analyser. Nominal and accurate mass spectra
were recorded on a VG7070E, CIPOS, Kratos Profile HV3
and TRIO1000 using electron ionisation (EIþ) and chemical
ionisation (CIþ). Optical rotations ([a]D) were measured at
ambient temperature (22^38C) from chloroform
solutions using a 0.1 dm path length cell, on a Optical
Activity Ltd AA-1000 polarimeter and are recorded in units
of 1021 deg cm2 g21. Infrared spectra were recorded, with
NaCl discs in Nujol using a Perkin–Elmer 881 infrared
spectrophotometer, over a range of 4000–800 cm21. All 1H
NMR spectra were recorded unless otherwise specified, as
deuteriochloroform solutions using tetramethylsilane as an
internal standard on a Bruker Avance 400 MHz spec-
trometer or a Bruker 250 MHz spectrometer. Chemical
shifts are quoted in parts per million; J-values are given in
Hz. The 13C NMR spectra were recorded on the same
instruments at 100 MHz (using tetramethylsilane as an
internal standard). Chiral high performance liquid chroma-
tography was conducted using a Chiralpak AD column
(Daicel Chemical Industries), 0.4625 cm. Thin layer
chromatography was performed on aluminium backed silica
gel 60 F254 plates in a variety of solvent systems. The plates
were visualised by application of CAM, KMnO4 or
ninhydrin and baked with a heat gun. Flash column
chromatography was conducted with ICN silica 32-63,
3.1.2. 2-Dimethyl-1-[(2R,3S)-3-phenyl-oxiranyl]-propan-
1-one (4b).14 Using the above method and compound (3b)
as starting material 2,2-dimethyl-1-[(2R,3S)-3-phenyl-oxi-
ranyl]-propan-1-one (4b) (2.78 g, 84%, 91% ee [chiral
HPLC-hexane/ethanol (9:1)]) was obtained as a white solid,
mp 598C (from hexane) (lit.,22 68–708C); (found: C, 76.6;
H, 8.0. C13H16O2 requires C, 76.4; H, 7.9%); [a]D¼2194 (c
1, CHCl3); nmax (Nujol)/cm21 1707 (CvO) and 1245
(C–O); dH (400 MHz, CDCl3) 1.26 (9H, s, 3£CH3), 3.85
(1H, d, J¼1.7 Hz, COCH), 3.86 (1H, d, J¼1.7 Hz, CHPh),
7.24–7.58 (5H, m, Ph); dC (100 MHz, CDCl3) 25.7 (3CH3),
43.6 (CMe3) 59.1, 59.3 (COCH, CHPh), 125.7, 128.7, 128.9
(ArCH), 135.7 (ArCipso), 208.1 (CvO); m/z (CIþ) 205
(38%) [MþH]þ (found: [MþH]þ, 205.1226. C13H16O2
requires [MþH]þ, 205.1229).
3.1.3. Phenyl-[(2R,3S)-3-phenyl-oxiranyl]-methanone
(4c).14 Using the above method and compound (3c) as
starting material phenyl-[(2R,3S)-3-phenyl-oxiranyl]-
methanone (4c) (4.32 g, 93%, 95% ee [chiral HPLC-
hexane/ethanol (9:1)]) was obtained as a white solid, mp
908C (from ethanol) (lit.,22 94–968C from ethanol); (found:
C, 80.2; H, 5.4. C15H12O2 requires C, 80.3; H, 5.4%);
[a]D¼2200 (c 1, CHCl3); nmax (Nujol)/cm21 1687 (CvO)
and 1271 (C–O); dH (250 MHz, CDCl3) 4.08 (1H, d,
J¼1.9 Hz, COCH), 4.31 (1H, d, J¼1.9 Hz, CHPh), 7.32–
8.07 (10H, m, 2£Ph); dC (100 MHz, CDCl3) 59.7 (COCH),
61.4 (CHPh), 126.2, 128.8, 129.2, 129.3, 129.4, 134.3
(2ArCH) 134.4, 135.9 (2ArCipso), 193.5 (CvO), m/z (CIþ)
225 (28%) [MþHþ].
˚
60 A. Enones 3a and 3b were prepared according to the
literature.20 Commercially available amino acids (11a–b)
were N-acetylated using literature procedures.21
3.1.1. 2-Methyl-1-[(2R,3S)-3-phenyl-oxiranyl)-propan-1-
one (4a).14 To a solution of (E)-4-methyl-1-phenyl-pent-1-
en-3-one (3a) (3 g, 17.2 mmol) in anhydrous THF (100 mL)
was added successively poly-L-leucine adsorbed onto silica
(6.0 g), urea hydrogen peroxide (1.94 g, 20.7 mmol) and
1,8-diazabicyclo(5,4,0)undec-7-ene (3.85 mL, 25.8 mmol).
The mixture was stirred at room temperature for 24 h. The
mixture was filtered and the polymer washed with ethyl
acetate. Water (150 mL) was added to the filtrate. The
mixture was extracted with ethyl acetate (3£100 mL) and
the combined extracts washed with brine, dried (MgSO4)
and evaporated under reduced pressure to afford a pale
yellow oil (2.78 g). Flash chromatography of the residue
over silica gel with hexane/ethyl acetate (9:1) as the eluent
afforded 2-methyl-1-[(2R,3S)-3-phenyl-oxiranyl)-propan-1-
3.1.4. (4S,5R)-4-Hydroxy-3-isopropyl-5-phenyl-4,5-di-
hydro-isoxazole (5a). To a stirring ethanolic solution
(90 mL)
of
2-methyl-1-[(2R,3S)-3-phenyl-oxiranyl)-
propan-1-one (4a) (8.71 g, 0.046 mol) was added hydroxyl-
amine hydrochloride (9.55 g, 0.137 mol) and pyridine
(14.8 mL, 0.183 mol) and the mixture stirred at reflux
(908C) for 14 h. The reaction mixture was acidified by

5734
J. F. Bickley et al. / Tetrahedron 59 (2003) 5731–5736
addition of 2 M aqueous HCl (80 mL), diluted with water
(400 mL) and extracted with diethyl ether (4£100 mL). The
combined organic extracts were washed with saturated
aqueous copper sulfate solution (2£200 mL), water
(2£100 mL), dried (MgSO4) and evaporated under reduced
pressure to afford a brown oil (8.63 g). Flash chromato-
graphy of the residue over silica gel with hexane/ethyl
acetate (4:1) as the eluent afforded (4S,5R)-4-hydroxy-3-
isopropyl-5-phenyl-4,5-dihydro-isoxazole 5a. (6.82 g, 73%,
89% ee [chiral HPLC-hexane/ethanol (9:1)]) as a white
solid; mp 73–748C (from hexane/diethyl ether); (found: C,
70.3; H, 7.4; N, 6.8. C12H15NO2 requires C, 70.2; H, 7.4; N,
6.8%); [a]D¼þ284 (c 1, CHCl3); nmax (Nujol)/cm21 3276
(OH) and 1623 (CvN); dH (400 MHz, CDCl3) 1.16 (3H, d,
J¼6.8 Hz, CH3), 1.20 (3H, d, J¼6.8 Hz, CH3), 2.41 (1H, br.
s, OH), 2.85 (1H, hept, J¼6.8 Hz, CH(CH3)2), 4.92 (1H, d,
J¼4.1 Hz, CHOH), 5.29 (1H, d, J¼4.1 Hz, CHPh), 7.24–
7.44 (5H, m, Ph); dC (100 MHz, CDCl3) 19.7, 20.5
(2£CH3), 26.4 (CH(CH3)2), 85.4 (CHOH), 88.9 (CHPh),
125.4, 128.2, 128.8 (ArCH), 138.1 (ArCipso), 163.8
(CvN); m/z (CIþ) 206 (100%) [MþH]þ (found:
[MþH]þ, 206.1184. C12H15NO2 requires [MþH]þ,
206.1181).
dropwise to the reaction mixture which was then allowed
to warm to room temperature. After 1.5 h the reaction was
quenched by the careful addition of aqueous solution of
sodium hydroxide (20% aq. soln., 75 mL). The aqueous
layer was extracted with diethyl ether (3£75 mL) and the
combined organic phase was washed with brine (25 mL),
dried (MgSO4) and evaporated under reduced pressure to
afford a mixture of (1R,2S,3S)-3-amino-4-methyl-1-phenyl-
pentane-1,2-diol 6a and styrene glycol (ratio 7:1 by 1H
NMR) as a white solid (1.0 g); nmax (Nujol)/cm21 3394 (18
NH2) and 3309 (2£OH); dH (400 MHz, CDCl3) 0.75 (3H, d,
J¼6.9 Hz, CH3) 0.87 (3H, d, J¼6.9 Hz, CH3), 2.20 (1H,
heptd, J¼6.9, 3.0 Hz, (CH(CH3)2), 2.73 (1H, dd, J¼8.5,
3.0 Hz, CHNH2), 3.22 (1H, app. t, J¼8.5 Hz, CHOH), 3.47
(1H, dd, J¼11.3, 8.3 Hz, styrene glycol), 3.57 (1H, dd,
J¼1.3, 3.5 Hz, styrene glycol), 4.53 (1H, d, J¼8.5 Hz,
CHPh), 4.61 (1H, dd, J¼8.1, 3.5 Hz, styrene glycol), 7.21–
7.45 (10H, m, 2£Ph, diol and styrene glycol); dC (100 MHz,
CDCl3) 13.9 and 18.6 (2£CH3), 28.0 (CH(CH3)2), 61.1
(CHNH2), 68.0 (styrene glycol), 73.8 (CHOH), 74.5
(styrene glycol), 79.8 (CHPh), 124.9, 126.2, 127.1, 127.4,
128.1, 128.3 (2£ArCH, diol and styrene glycol), 141.0,
141.7 (2£ArCipso, diol and styrene glycol); m/z (CIþ) 210
(100%) [MþH]þ (found: [MþH]þ, 210.1498. C13H21NO2
requires [MþH]þ, 210.1494).
3.1.5. (4S,5R)-3-tert-Butyl-4-hydroxy-5-phenyl-4,5-di-
hydro-isoxazole (5b). Using the above method and
compound 4b as starting material (4S,5R)-3-tert-butyl-4-
hydroxy-5-phenyl-4,5-dihydro-isoxazole (5b) (4.32 g, 76%,
92% ee [chiral HPLC-hexane/ethanol (9:1)]) was obtained
as a white solid, mp 758C (from hexane/diethyl ether);
(found: C, 71.1; H, 7.8; N, 6.4. C13H17NO2 requires C, 71.2;
H, 7.8; N, 6.4%); [a]D¼þ191 (c 1, CHCl3); nmax (Nujol)/
cm21 3284 (OH) and 1624 (CvN); dH (400 MHz, CDCl3)
1.26 (9H, s, 3CH3), 2.17 (1H, d, J¼9.0 Hz, OH), 4.92 (1H,
dd, J¼9.0 Hz, 2.9 Hz CHOH), 5.34 (1H, d, J¼2.9 Hz,
CHPh), 7.24–7.38 (5H, m, Ph); dC (100 MHz, CDCl3) 28.8
(3CH3), 33.0 (CMe3) 85.0 (CHOH), 89.3 (CHPh), 125.3,
128.2, 128.8 (ArCH), 137.9 (ArCipso), 165.8 (CvN); m/z
(CIþ) 220 (100%) [MþH]þ (found: [MþH]þ, 220.1345.
C13H17NO2 requires [MþH]þ, 220.1337).
3.1.8. (1R,2S,3S)-3-Amino-4,4-dimethyl-1-phenyl-pen-
tane-1,2-diol (6b). Using the above method with compound
5b as starting material (1R,2S,3S)-3-amino-4,4-dimethyl-1-
phenyl-pentane-1,2-diol 6b and styrene glycol (ratio 6:1 by
1H NMR) was obtained as a white solid (0.98 g), nmax
(Nujol)/cm21 3408 (18 NH2) and 3286 (28 OH); dH
(400 MHz, CDCl3) 0.88 (9H, s, 3£CH3), 2.55 (1H, d,
J¼8.3 Hz, CHNH2), 3.30 (1H, app. t, J¼8.3 Hz, CHOH),
3.42 (1H, dd, J¼11.3, 8.3 Hz, styrene glycol), 3.53 (1H, dd,
J¼11.3, 3.4 Hz, styrene glycol), 4.46 (1H, d, J¼8.3 Hz,
CHPh), 4.57 (1H, dd, J¼8.3, 3.4 Hz, styrene glycol), 7.14–
7.38 (10H, m, 2£Ph, diol and styrene glycol); dC (100 MHz,
CDCl3) 25.8 (3£CH3), 34.1 (CMe3), 63.5 (CHNH2), 67.0
(styrene glycol), 73.5 (styrene glycol), 74.1 (CHOH), 78.5
(CHPh), 124.8, 126.7, 126.8, 126.9, 127.1, 127.3 (2ArCH,
diol and styrene glycol) 140.0, 140.5 (2£ArCipso, diol and
styrene glycol); m/z (CIþ) 224 (100%) [MþH]þ (found:
[MþH]þ, 224.1651. C13H21NO2 requires [MþH]þ,
224.1651).
3.1.6. (4S,5R)-4-Hydroxy-3,5-diphenyl-4,5-dihydro-
isoxazole (5c). Using the above method and compound 4c
as starting material (4S,5R)-4-hydroxy-3,5-diphenyl-4,5-
dihydro-isoxazole (5c) (6.42 g, 71%, 94% ee [chiral
HPLC-hexane/ethanol (9:1)]) was obtained as a white
solid, mp 166–1688C (from ethanol); (found: C, 75.0; H,
5.5; N, 5.8. C15H13NO2 requires C, 75.3; H, 5.5; N, 5.9%);
[a]D¼þ159 (c 1, CHCl3); nmax (Nujol)/cm21 3299 (OH)
and 1634 (CvN); dH (400 MHz, CDCl3) 1.57 (1H, s, OH),
5.38 (1H, d, J¼3.2 Hz, CHOH), 5.56 (1H, d, J¼3.2 Hz,
CHPh), 7.30–7.85 (10H, m, Ph); dC (100 MHz, CDCl3)
85.0 (CHOH), 90.6 (CHPh), 125.7, 127.5, 128.2, 128.8,
129.3, 129.3 (2ArCH), 130.8, 138.1 (2£ArCipso), 157.6
(CvN); m/z (CIþ) 240 (100%) [MþHþ].
3.1.9. N-[(1S,2S,3R)-2,3-Dihydroxy-1-isopropyl-3-
phenyl-propyl]-acetamide (7a). Acetic anhydride (74 mL,
0.78 mmol) was added to a solution of crude (1R,2S,3S)-3-
amino-4,4-dimethyl-1-phenyl-pentane-1,2-diol 6a (151 mg,
0.72 mmol) in pyridine (0.81 mL). The solution was stirred
under nitrogen at room temperature overnight. The reaction
was quenched by addition of 2 M aqueous HCl (3.7 mL) and
water (10 mL). This solution was extracted with ethyl
acetate (3£25 mL) and the combined organic extracts were
washed with saturated copper sulfate solution and water,
dried (Na2SO4) and evaporated under reduced pressure to
afford a yellow oil (150 mg). Flash chromatography of the
residue over silica gel with hexane-ethyl acetate (3:1) as the
eluent afforded N-[(1S,2S,3R)-2,3-dihydroxy-1-isopropyl-
3-phenyl-propyl]-acetamide 7a (132 mg, 73% over two
steps) as a white solid; mp 1358C; (found: C, 66.7; H, 8.4; N,
5.5. C14H21NO3 requires C, 66.9; H, 8.4; N, 5.6%);
3.1.7. (1R,2S,3S)-3-Amino-4-methyl-1-phenyl-pentane-
1,2-diol (6a). A two-necked flask was charged with a
solution of (4S,5R)-4-hydroxy-3-isopropyl-5-phenyl-4,
5-dihydro-isoxazole 5a (1.0 g, 4.88 mmol) in anhydrous
THF (10 mL). The solution was stirred under an atmosphere
of nitrogen and cooled to 08C. A solution of LiAlH4 in
diethyl ether (1 M, 19.5 mL, 19.5 mmol) was added

J. F. Bickley et al. / Tetrahedron 59 (2003) 5731–5736
5735
[a]D¼246 (c 1, CHCl3); nmax (Nujol)/cm21 3390 (28 OH)
and 3260 (CONH), 1670 (CONH); dH (400 MHz, CDCl3)
0.91 (3H, d, J¼6.8 Hz, CH3) 0.95 (3H, d, J¼6.8 Hz, CH3),
1.72 (3H, s, CH3CO), 2.21 (1H, heptd, J¼6.7, 4.9 Hz,
CH(CH3)2), 2.60 (1H, br. s, OH), 3.36 (1H, br. s, OH), 3.92
(1H, ddd, J¼9.4, 7.0, 4.9 Hz, CHNH2), 3.95–4.01 (1H, br.
m, CHOH), 4.79 (1H, d, J¼3.2 Hz, CHPh), 5.21 (1H, d,
J¼9.4 Hz, NH) 7.24–7.42 (5H, m, Ph); dC (100 MHz,
CDCl3) 17.3 and 20.4 (2CH3), 23.0 (CH3), 27.9
(CH(CH3)2), 56.4 (CHNH2), 75.1 (CHOH), 75.8 (CHPh),
126.2, 127.6, 128.6 (ArCH), 141.4 (ArCipso), 171.6
(CvO); m/z (CIþ) 252 (100) [MþH]þ (found: [MþH]þ,
252.1598. C14H21NO3 requires [MþH]þ, 252.1600).
(CONH); dH (400 MHz, CDCl3) 0.92 (3H, d, J¼6.9 Hz,
CH3), 0.95 (3H, d, J¼6.9 Hz, CH3), 2.09 (3H, s, CH3CvO),
2.18 (1H, heptd, J¼6.9, 5.2 Hz, CH(CH3)2), 3.78 (3H, s,
CH3O), 4.63 (1H, dd, J¼8.1, 5.2 Hz, CHNH), 6.24 (1H, d,
J¼8.1 Hz, NH); dC (100 MHz, CDCl3) 18.1 and 19.2
(2£CH3), 23.6 (CH3CvO), 32.0 (CH(CH3)2), 52.2 (CH3O),
57.6 (CHNH), 170.7 and 173.8 (2£CvO); m/z (CIþ) 174
(100%) [MþH]þ (found: [MþH]þ, 174.1133. C8H16NO3
requires [MþH]þ, 174.1130).
3.1.12. (S)-2-Acetylamino-3,3-dimethyl-butyric acid
methyl ester (10b). Using the above method and compound
7b as starting material (S)-2-acetylamino-3,3-dimethyl-
butyric acid methyl ester (10b) (15 mg, 75%, 91% ee
[chiral GC-Lipodex E, 1208C, dichloromethane]) was
obtained as a white solid; (found: C, 57.6; H, 9.1; N, 7.5.
C9H17NO3 requires C, 57.7; H, 9.15; N, 7.5%); [a]D¼236
(c 1, CHCl3); nmax (Nujol)/cm21 3268 (CONH), 1752
(COOMe) 1643 (CONH); dH (400 MHz, CDCl3) 0.98 (9H,
s, 3£CH3), 2.09 (3H, s, CH3CvO), 3.78 (3H, s, CH3O),
4.53 (1H, d, J¼9.6 Hz, CHNH), 6.08 (1H, br. d, NH); dC
(100 MHz, CDCl3) 23.8 (CH3CvO), 26.8 (3CH3), 35.0
(CMe3), 52.2 (CH3O), 60.3 (CHNH), 170.3 and 172.9
(2CvO); m/z (CIþ) 188 (100%) [MþH]þ (found: [MþH]þ,
188.1288. C9H17NO3 requires [MþH]þ, 188.1287).
3.1.10. N-[(1S,2S,3R)-1-tert-Butyl-2,3-dihydroxy-3-
phenyl-propyl]-acetamide (7b). Using the above method
and compound 6b as starting material N-[(1S, 2S, 3R)-1-
tert-butyl-2,3-dihydroxy-3-phenyl-propyl]-acetamide (7b)
(140 mg, 75% over two steps) was obtained as a white
solid; mp 1568C; (found: C, 67.5; H, 8.4; N, 4.8. C15H23NO3
requires C, 67.9; H, 8.7; N, 5.3%); [a]D¼234 (c 1, CHCl3);
nmax (Nujol)/cm21 3392 (28 OH) and 3286 (CONH), 1652
(CONH); dH (400 MHz, CDCl3) 1.00 (9H, s, 3£CH3), 1.73
(3H, s, CH3), 3.87 (1H, dd, J¼10.0, 5.8 Hz, CHNH), 4.07
(1H, app. t, J¼5.8 Hz, CHOH), 4.66 (1H, d, J¼5.8 Hz,
CHPh), 5.60 (1H, d, J¼10.0 Hz, NH), 7.22–7.45 (5H, m,
Ph); dC (100 MHz, CDCl3) 23.1 (CH3), 27.3 (3CH3), 34.4
(CMe3), 60.8 (CHNH), 74.7 (CHOH), 76.5 (CHPh), 126.4,
127.9, 128.7 (ArCH), 141.8 (ArCipso), 171.1 (CvO); m/z
(CIþ) 266 (97%) [MþH]þ (found: [MþH]þ, 266.1750.
C15H23NO3 requires [MþH]þ, 266.1756).
Acknowledgements
We thank Dr G. Zanardi and Mr A. Mehta for some initial
experiments. Also we thank the EPSRC for research funding
(J. S. and C. B. S.) and support from Wenzhou People’s
Government of Zhejiang Province, China for Y. R.
3.1.11. (S)-2-Acetylamino-3-methyl-butyric acid methyl
ester (10a). Sodium periodate on silica (1.2 mmol/g,
300 mg, 0.36 mmol) was added to
a solution of
N-[(2S,3R)-2,3-dihydroxy-1-isopropyl-3-phenyl-propyl]-
acetamide (7a) (30 mg, 0.12 mmol) in dichloromethane
(0.75 mL). The mixture was allowed to stir for 4 h at room
temperature under an atmosphere of nitrogen. The mixture
was filtered and the solid residue washed with dichloro-
methane (2£1 mL). The filtrate was dried (MgSO4) and
evaporated under reduced pressure. The residue was
redissolved in acetone (1 mL). A solution of freshly
prepared Jones’ reagent (1.36 M, 0.11 mL, 0.14 mmol)
was added at 08C, and the mixture was allowed to stir for
70 min at 08C. The mixture was filtered and washed with
(3£1 mL) acetone. The solution was diluted with water
(2.5 mL), extracted with ethyl acetate (5£5 mL) and the
combined organic phase was dried with MgSO4 and
evaporated under reduced pressure. The residue (15 mg,
0.1 mmol) was redissolved in methanol/toluene (1:3, 1 mL)
and a solution of TMSCHN2 in hexane (2 M, 150 mL,
0.3 mmol) was added and allowed to stir for 3 h at room
temperature under an atmosphere of nitrogen. To this
mixture was added acetic acid (0.1 mL) and the solvent was
removed under reduced pressure to afford (S)-2-acetyl-
amino-3-methyl-butyric acid methyl ester (10a) (13 mg,
64%, 90% ee [chiral GC-Lipodex E, 1308C, dichloro-
methane]) as a white solid, mp 61–628C (from ethyl
acetate) (lit.,23 68–698C from ethyl acetate/petroleum
ether); (found: C, 55.4; H, 8.8; N, 8.1. C8H15NO3 requires
C, 55.5; H, 8.7; N, 8.1%); [a]D¼227 (c 1, CHCl3); nmax
(Nujol)/cm21 3273 (CONH), 1739 (COOMe) 1638
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˚
251.32, orthorhombic, spacegroup P212121, a¼9.4964(5) A,
3
˚
˚
˚
b¼9.6786(5) A, c¼15.2331(9) A, U¼1400.10(13) A ,
T¼100 K, Z¼4, m(Mo Ka)¼0.083 mm21, 8743 reflections
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13H17NO2, M¼
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3
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