An efficient synthesis of N-protected threo (2R,3S)-3-amino-1,2-epoxy phenylbutane

Article abstract of DOI:10.1016/j.tetlet.2005.06.134

A precise and versatile method was developed for the synthesis of threo amino epoxide derivatives, which are useful intermediates for protease inhibitors. It involves the diastereoselective reduction of the carbonyl group of γ-N,N-dibenzyl amino α-hydroxy β-keto sulfide prepared from an amino acid, and its subsequent stereospecific conversion to an amino epoxide via acetoxy halogenation in high yield.

Full text of DOI:10.1016/j.tetlet.2005.06.134

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5811–5814
An efficient synthesis of N-protected threo
(2R,3S)-3-amino-1,2-epoxy phenylbutane
Takayuki Suzuki, Yutaka Honda and Kunisuke Izawa*
AminoScience Laboratories, Ajinomoto Co., Inc., Suzuki-cho, Kawasaki-ku, Kawasaki-shi 210-8681, Japan
Received 9 June 2005; revised 24 June 2005; accepted 27 June 2005
Available online 15 July 2005
Abstract—A precise and versatile method was developed for the synthesis of threo amino epoxide derivatives, which are useful inter-
mediates for protease inhibitors. It involves the diastereoselective reduction of the carbonyl group of c-N,N-dibenzyl amino
a-hydroxy b-keto sulfide prepared from an amino acid, and its subsequent stereospecific conversion to an amino epoxide via acetoxy
halogenation in high yield.
Ó 2005 Elsevier Ltd. All rights reserved.
Optically active a-amino epoxides have been widely used
as key building blocks for pharmaceuticals, particularly
for HIV protease inhibitors. For instance, erythro (S,S)-
amino epoxide can be used as the key intermediate for
saquinavir,1 nelfinavir,2 and fosamprenavir,3 whereas
threo (R,S) can be used for atazanavir.4 Several methods
have been reported for the synthesis of threo amino
epoxides, for example, the halomethylation of optically
active amino aldehydes5 and the asymmetric epoxida-
tion of olefins.6 However, there are various difficulties
associated with the industrial application of these meth-
ods, such as the multi-step transformation required to
produce the amino aldehyde as the raw material, the
requirement for a cryogenic reaction, the use of expen-
sive reagents, etc. In the pursuit of synthetic approaches
to the intermediates for HIV protease inhibitors,7 we
recently reported a practical synthesis of a b-amino a-
hydroxy acid involving a Pummerer rearrangement of
a b-keto sulfoxide followed by a stereoselective acyl
migration.8 The a-hydroxy b-keto sulfide that is the
Pummerer product of this reaction can be reduced to
an amino diol which in turn forms the precursor for
an amino epoxide—the N-Cbz derivative thereof being
reduced by sodium borohydride to an erythro diol pref-
erentially in the ratio of erythro/threo = 2/1.9,10 In this
present paper, we report a new approach to the synthesis
of the threo diol involving selective reduction followed
by efficient epoxidation.10
b-Keto sulfoxide 2 was prepared by the reaction
between N,N-dibenzyl L-phenylalanine benzyl ester 1 and
dimsyl anion, followed by a Pummerer rearrangement
under HCl acidic conditions affording the a-hydroxy
sulfide 3.8 Crude 3 was easily reduced with sodium boro-
hydride in an alcoholic solvent to give the amino diol
derivative 4a, in which the threo (R,S)-isomer was pre-
dominantly formed in a ratio of about 10/111 (Scheme
1). Each diastereomer could be isolated by means of sil-
ica gel column chromatography. As the tert-butoxycar-
bonyl (Boc) group is more commonly utilized in the
synthesis of HIV protease inhibitor intermediates,4 the
N-Boc derivative (R,S)-4b was also prepared by hydro-
genolysis of the dibenzyl group of (R,S)-4a followed
by treatment with di-tert-butoxy dicarbonate (Scheme
1). Amongst the known procedures for the epoxidation
of 1,2-diols, methods involving Mitsunobu conditions12
appear the most efficient, but the use of expensive
reagents as well as safety concerns prohibit their appli-
cation on an industrial scale. Cyclization under basic
conditions after activation of either of the hydroxy
groups has been generally used,13 although the complete
regioselective introduction of the leaving group to the
specified hydroxy group is difficult to achieve and leads
to a reduction in diastereomeric purity during epoxida-
tion. Furthermore, threo (R,S)-amino epoxide is espe-
cially difficult to isolate as pure crystals having a
higher solubility than the corresponding erythro isomer.
The stereospecific conversion of (R,S)-amino diols to
Keywords:
Amino
acid;
Aminoalkyl
epoxide;
Pummerer
rearrangement.
*
Corresponding author. Tel.: +81 44 245 5066; fax: +81 44 211
7610; e-mail: kunisuke_izawa@ajinomoto.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.134

5812
T. Suzuki et al. / Tetrahedron Letters 46 (2005) 5811–5814
O
O
S
O
Bn2N
Ph
CO2Bn
i
iii
Bn2N
Ph
Bn2N
Ph
S
ii
OH
3
1
2
OH
OH
OH
iv
vi
Bn2N
Ph
OH
Bn2N
Ph
OH
BocHN
OH
+
v
vii
Ph
(2R,3S)-4b
(2R,3S)-4a
(2S,3S)-4a
8 % from 3
61 % from (2R,3S)-4a
67 % from 3
Scheme 1. Preparation of the N-protected threo (2R,3S)-amino diols 4a and b. Reagents and conditions: (i) DMSO, NaNH2, THF, 0 °C; (ii) 10%
citric acid aq; (iii) 2 M HCl, DMSO, ambient temp; (iv) NaBH4, EtOH, H2O, 0 °C; (v) 1 M HCl; (vi) H2, 5% Pd–C, MeOH, ambient temp; (vii)
(Boc)2O, Et3N, MeOH, ambient temp.
(R,S)-amino epoxides is thus a target of significant inter-
est. Acetoxy halogenation reactions of vicinal hydroxy
groups are occasionally used for the derivatization of
nucleosides and sugars14—the most common methodol-
ogy being transformation with a-acetoxyisobutyryl
halide. Ghosh et al. reported the application of this
method to the synthesis of amino epoxides in moderate
yields.15 We had previously developed an efficient acet-
oxy bromination method that proceeds via the methoxy
ethylidene derivative for the synthesis of 20,30-dideoxy-
nucleosides.16 This selective reaction has advantages in
terms of the fact that the milder reaction conditions pro-
duce fewer by-products and thus presented itself as a
potentially promising means of producing (R,S)-amino
epoxides from (R,S)-amino diols (Scheme 2 and Table
1). The reaction of N,N-dibenzyl (R,S)-amino epoxide
4a with trimethyl orthoacetate in the presence of trifluo-
roacetic acid afforded the methoxy ethylidene derivative
5a. Acetyl bromide was then added to the reaction mix-
ture containing 5a. Regioselective bromination took
place at the less sterically hindered carbon and 2-acetoxy
1-bromide 6a was successfully obtained in 80% from 4a
in two steps. Compound 6a was treated with potassium
carbonate in alcohol to give the desired (R,S)-amino
epoxide 8a in 98%.17 No other diastereomeric/enantio-
meric isomers of 8a were detected by HPLC. Compound
(R,S)-8a proved readily convertible to the diastereo-
meric isomer (S,S)-8b by Beaulieu and WernicÕs meth-
od.5c The same sequence of reactions using
chlorotrimethyl silane instead of acetyl bromide also
gave (R,S)-8a via the acetoxy chloride 7a. N-Boc
(R,S)-amino epoxide 8b was also synthesized from
(R,S)-4b, by using pyridinium p-toluenesulfonate for
methoxy ethylidene formation (Scheme 3). The lower
yield in the case of acetoxy bromination is likely to be
due to the partial degradation of the Boc group under
acidic conditions. The remarkable difference in the acet-
oxy chlorination reaction was the significant formation
of regio isomer (S,S)-7c, which was confirmed18 by sepa-
ration of each isomer by silica gel column (Scheme 4).
In conclusion, a practical synthesis of N-protected threo
(2R,3S)-3-amino-1,2-epoxy phenylbutane has been deve-
loped. It involves the diastereoselective reduction of c-
N,N-dibenzyl amino a-hydroxy b-keto sulfide followed
by stereospecific conversion to the amino epoxide via
OH
OAc
O
O
O
i
ii
iii
Bn2N
Ph
Bn2N
Ph
OH
Bn2N
Ph
X
O
Bn2N
Ph
(2R,3S)-6a (X = Br)
(2R,3S)-7a (X = Cl)
(2R,3S)-4a
(2R,3S)-5a
(2R,3S)-8a
Scheme 2. Preparation of the N,N-dibenzyl threo (2R,3S)-amino epoxide 8a. Reagents and conditions: (i) CH(OMe)3, CF3CO2H, CH2Cl2, ambient
temp; (ii) AcBr (X = Br) or Me3SiCl (X = Cl), CH2Cl2, ambient temp; (iii) K2CO3, MeOH, ambient temp.
Table 1. Preparation of the threo amino epoxide from the threo amino diol
Entry
Amino diol
Acetoxy halide
X
Amino epoxide
Yielda (%)
Yield (%)
1
2
3
4
(R,S)-4a
(R,S)-4a
(R,S)-4b
(R,S)-4b
(R,S)-6ab
Br
Cl
Br
Cl
80
71
57
76
(R,S)-8a
(R,S)-8a
(R,S)-8b
(R,S)-8b
98
80
99
89
(R,S)-7ab
(R,S)-6bb
(R,S)-7b + (S,S)-7c
a The optical purity (ee) and the diastereomeric excess (de) of each compound were higher than 98%, as determined by chiral HPLC.
b Detailed analysis of the formation of regio isomers was not undertaken. No impurity larger than 5% (peak area vs. product) was detected in HPLC.

T. Suzuki et al. / Tetrahedron Letters 46 (2005) 5811–5814
OAc
5813
OH
O
O
O
i
ii
iii
BocHN
Ph
BocHN
Ph
OH
BocHN
X
O
BocHN
Ph
Ph
(2R,3S)-6b (X = Br)
(2R,3S)-7b (+ 7c a) (X = Cl)
(2R,3S)-4b
(2R,3S)-5b
(2R,3S)-8b
Scheme 3. Preparation of the N-Boc threo (2R,3S)-amino epoxide 8b. Reagents and conditions: (i) CH(OMe)3, p-TsOH–pyridine, CH2Cl2, ambient
temp; (ii) AcBr (X = Br) or Me3SiCl (X = Cl), CH2Cl2, ambient temp; (iii) K2CO3, MeOH, ambient temp. (aSee Scheme 4.)
OH
OAc
Cl
BocHN
Ph
OH
BocHN
Ph
Cl
BocHN
Ph
OAc
+
(2R,3S)-4b
(2R,3S)-7b
(2S,3S)-7c
56 % from (2R,3S)-4b
15 % from (2R,3S)-4b
Scheme 4. Formation of the regio isomers 7b and c. Reagents and conditions shown in Scheme 3.
Suzuki, T.; Izawa, K. Org. Lett. 2002, 4, 447–449; (c)
acetoxy halogenation. This method also represents a
potential industrial manufacturing process for threo
amino epoxides, providing a versatile synthesis using
safe and inexpensive reagents without the need for a
cryogenic reaction.
Honda, Y.; Katayama, S.; Kojima, M.; Suzuki, T.;
Kishibata, N.; Izawa, K. Org. Biomol. Chem. 2004, 2,
2061–2070.
8. (a) Suzuki, T.; Honda, Y.; Izawa, K.; Williams, R. M. J.
Org. Chem. 2005, 70, in press; (b) Suzuki, T.; Honda, Y.;
Izawa, K.; Ajinomoto Co., Inc.; U.S. Patent 6 169 200,
2001.; (c) Suzuki, T.; Honda, Y.; Izawa, K.; Ajinomoto
Co., Inc.; Eur. Pat. Appl., EP767168, 1997.
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11. Typical procedure: to
a solution of 2 (94.3 mg,
0.233 mmol) in dimethyl sulfoxide (1.6 mL) was added
2 M HCl (0.4 mL). After the mixture had been stirred for
15 h at ambient temperature, it was cooled in an ice bath
and saturated NaHCO3 aqueous solution (1.5 mL) was
added. Water (4 mL) and ethyl acetate (8 mL) were added
to the mixture and extracted. After the organic layer had
been separated, the resulting aqueous layer was extracted
twice with ethyl acetate (3 mL). The combined organic
layers were washed with water (5 mL) and saturated NaCl
aqueous solution (5 mL), then dried over anhydrous
Na2SO4, and concentrated under reduced pressure to give
crude 3a. To a solution of crude 3a in a mixed solvent of
ethanol (2 mL) and water (0.2 mL) was added sodium
borohydride (18.4 mg, 0.48 mmol) at 0 °C. After the
mixture had been stirred for 50 min at 0–5 °C, 1 M HCl
was added to adjust pH to 4.8, and the mixture was
concentrated under reduced pressure. Water (5 mL) and
ethyl acetate (20 mL) were added to the concentrate and
extracted, and the organic layer was washed with satu-
rated NaCl aqueous solution (5 mL), then dried over
anhydrous Na2SO4, and concentrated under reduced
pressure. HPLC analysis revealed a diastereomeric ratio
of about 10/1. The resulting residue was purified through
preparative silica gel thin-layer chromatography to obtain
(2R,3S)-4a (56.2 mg, 0.155 mmol, 67% from 2) and
(2S,3S)-4a (7.0 mg, 0.019 mmol, 8% from 2). 1H NMR
for (2R,3S)-4a (300 MHz, CDCl3) d = 2.7 (m, 1H), 3.06–
3.23 (m, 3H), 3.42 (d, 2H), 3.52–3.60 (m, 2H), 3.99 (d, 2H),
7.21–7.36 (m, 15H). Mass (ESI) m/z 362 (MH+).
2. Kaldor, S. W.; Kalish, V. J.; Davies, J. F.; Shetty, B. V.;
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temperature, saturated NaHCO3 aqueous solution
(16 mL) and dichloromethane (10 mL) were added to the
mixture and extracted. The organic layer was washed with
saturated NaCl aqueous solution (15 mL) and dried over
anhydrous Na2SO4, and concentrated under reduced
pressure. The resulting residue was purified through silica
gel column chromatography to obtain (2R,3S)-6a
1
(588.4 mg, 1.262 mmol, 80% from (2R,3S)-4a). H NMR
(300 MHz, CDCl3) d = 2.16 (s, 3H), 2.66 (dd, 1H), 3.10
(dd, 1H), 3.17–3.25 (m, 2H), 3.49 (d, 2H), 3.59 (dd, 1H),
4.04 (d, 2H), 5.05 (m, 1H), 7.14 (m, 2H), 7.19–7.35 (m,
13H). Mass (ESI) m/z 466 (MH+). To a solution of
(2R,3S)-6a (75.1 mg, 0.161 mmol) in methanol (1.6 mL)
was added potassium carbonate (45 mg). After the mixture
had been stirred for 2 h at ambient temperature, sus-
pended matter was removed by filtration, and the filtrate
was concentrated under reduced pressure. Water (5 mL)
and ethyl acetate (10 mL) were added to the residue and
extracted. The organic layer was washed with saturated
NaCl aqueous solution (5 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure to
obtain (2R,3S)-8a (54.1 mg, 0.158 mmol, 98% from
(2R,3S)-6a). 1H NMR (300 MHz, CDCl3) d = 2.20 (dd,
1H), 2.59 (dd, 1H), 2.69–2.80 (m, 1H), 2.98 (m, 1H), 3.15
(m, 1H), 3.82 (d, 2H), 3.88 (d, 2H), 7.00–7.04 (m, 2H),
7.17–7.33 (m, 13H). Mass (ESI) m/z 344 (MH+).
15. Ghosh, A. K.; Hussain, K. A.; Fidanze, S. J. Org. Chem.
1997, 62, 6080–6082.
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Ajinomoto, Co., Inc.; Japan Kokai Tokkyo Koho,
JP01224390, 1989; (b) Shiragami, H.; Ineyama, T.; Uch-
ida, Y.; Izawa, K. Nucleosides Nucleotides 1996, 15, 47–58.
17. Typical procedure: to a solution of (2R,3S)-4a (569.4 mg,
1.575 mmol) in dichloromethane (16 mL) were added
trimethyl orthoacetate (0.5 mL) and trifluoroacetic acid
(0.13 mL). After the mixture had been stirred for 4 h at
ambient temperature, it was concentrated under reduced
pressure. To a solution of the resulting residue in
dichloromethane (14 mL) acetyl bromide (1.29 mL) in
dichloromethane (2 mL) was added dropwise for 4 min.
After the mixture had been stirred for 5 h at ambient
18. The structure of 7c, which only consists of a single
diastereomer was determined by NMR. Absolute config-
uration is based on the original configuration in L-Phe.