A stereodivergent approach to syn- and anti-β-hydroxy-γ-amino acids. Enantioselective synthesis of N-Boc-statine and N-Boc-3-epistatine mediated by sulfoxides

Article abstract of DOI:10.1016/S0957-4166(02)00819-4

Asymmetric syntheses of the syn- and anti-stereoisomers of N-Boc statine, based on the stereodivergent reduction of a single sulfoxide 5, derived from N-Boc-L-leucine, are reported.

Full text of DOI:10.1016/S0957-4166(02)00819-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 549–554
A stereodivergent approach to syn- and anti-b-hydroxy-g-amino
acids. Enantioselective synthesis of N-Boc-statine and
N-Boc-3-epistatine mediated by sulfoxides
Francisco Yuste,a,* Angel D´ıaz,a Benjam´ın Ortiz,a Rube´n Sa´nchez-Obrego´n,a Fernando Wallsa and
Jose´ L. Garc´ıa Ruanob,*
aInstituto de Qu´ımica, Universidad Nacional Auto´noma de Me´xico, Circuito Exterior, Cd. Universitaria,
Coyoaca´n 04510, Mexico DF
bDepartamento de Qu´ımica Orga´nica (C-I), Facultad de Ciencias, Universidad Auto´noma de Madrid, Cantoblanco,
28049 Madrid, Spain
Received 21 October 2002; accepted 28 November 2002
Abstract—Asymmetric syntheses of the syn- and anti-stereoisomers of N-Boc statine, based on the stereodivergent reduction of
a single sulfoxide 5, derived from N-Boc-
L
-leucine, are reported. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
A large number of syntheses of statine and its deriva-
tives have been reported.6 Although satisfactory degrees
Recently, b-hydroxy-g-amino acids have received con-
siderable attention, notably those acting as key compo-
nents of peptidomimetic protease inhibitors.1 In
particular statine 1, (3S,4S)-4-amino-3-hydroxy-6-
methylheptanoic acid, a nonproteinogenic amino acid is
an essential component of the naturally occurring pep-
statin, which acts as an inhibitor of aspartic acid
proteases such as renin, pepsin and cathepsin D.2 The
low selectivity of pepstatin provided impetus for the
development of more specific synthetic analogs such as
the widely used cyclohexylstatine 2, in which the
isobutyl moiety of statine has been substituted by a
cyclohexylmethyl group.3 Interestingly, the syn (threo)
relative configuration of the amino and hydroxyl
groups in statine is essential for this bioactivity. How-
ever, several examples of the corresponding
diastereomeric anti (erythro) series are also of natural
occurrence. Thus, for example, isostatine 34 is a compo-
nent of didemnins, a family of cyclodepsipeptides which
exhibits a broad spectrum of biological activities, and
(3R,4S)-3-hydroxy-4-methylamino-5-phenylpentanoic
acid 4 is an amino acid constituent of hapalosin5 (Fig.
1).
of stereocontrol have been achieved, multistep proce-
dures are typically required and the number of general
and unified routes to the four stereoisomers of statine is
small.7 Recently, we have demonstrated that the
DIBAH and DIBAH/ZnBr2 reductions of N-Boc g-
amino-b-keto sulfoxides, derived from readily available
amino acid methyl ester hydrochlorides, produce dia-
stereoisomeric b-hydroxy sulfoxides, this being a gen-
eral stereodivergent procedure to prepare (R1,S2)- and
(S1,S2)-2-amino alcohols, where the desired configura-
tion at the hydroxylic carbon can be obtained by
choosing a suitable reducing system.8 Herein, we report
a unique approach to the syn- and anti-stereoisomers of
N-Boc statine, based on the stereodivergent reduction
of a single b-keto sulfoxide 5, derived from N-Boc-
L-
leucine methyl ester. Since N-Boc- -leucine is also com-
D
mercially available, the synthesis of the four
stereoisomers of statine could be performed using this
methodology.
2. Results and discussion
The overall synthetic sequence is depicted in Scheme 1.
The starting diastereomerically pure (3S,Rs)-N-(tert-
butoxycarbonyl) - 3 - amino - 5 - methyl - 1 - [(4 - methyl-
phenyl)sulfinyl]-2-hexanone 5 was obtained following a
* Corresponding authors. E-mail: yustef@servidor.unam.mx; joseluis.
garcia.ruano@uam.es
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(02)00819-4

550
F. Yuste et al. / Tetrahedron: Asymmetry 14 (2003) 549–554
Figure 1.
previously described synthetic route.9 The reduction of
b-keto sulfoxide 5 with DIBAH at −78°C gave the
b-hydroxy sulfoxide 6a with high stereoselectivity (de
90%).8 An excess of the reducing agent was necessary to
achieve complete transformation of the starting product
in high yields. The b-hydroxy sulfoxide was purified by
column chromatography to produce diastereoisomeri-
cally pure product (de >97%) in 71% yield. The synthe-
sis of the b-hydroxy sulfoxide 6b, with the opposite
configuration at the hydroxylic carbon, was accom-
plished by reduction of the b-keto sulfoxide 5 with
DIBAH/ZnBr2.8 Similarly, the reduction proceeded
with high stereoselectivity (de 85%). Diastereoisomeri-
cally pure 6b (de >97%) was obtained, in 75% yield, by
crystallization of the crude product. Configurational
assignment of the resulting diastereoisomers was
The hydrolysis of the cyano group of hydroxy nitrile 9a
according to several reported procedures yielded either
complex reaction mixtures or the recovery of the start-
ing material. A similar troublesome situation was
observed by Moyano and Perica`s in the hydrolysis of
(3R,4S)-4-(tert-butoxycarbonylamino)-3-hydroxypen-
tanenitrile.6b These authors discovered that this product
could be efficiently protected as a N-Boc oxazolidine
and further transformed into the required carboxylic
acid by the use of non hydrolytic conditions (DIBAH
reduction followed by KMnO4 oxidation at controlled
pH). Following this methodology, the reaction of
hydroxy nitriles 9a and 9b with an excess of 2,2-
dimethoxypropane and a catalytic amount of p-tolue-
nesulfonic acid in refluxing benzene produced, after
column chromatography, cis-N-Boc oxazolidine 10a
(72% yield) and trans-N-Boc oxazolidine 10b (85%
yield), respectively. The reduction of 10a and 10b with
DIBAH at −40°C gave the corresponding aldehydes.
Although the yields of the crude products were high,
these compounds were not very stable and suffered
extensive degradation when purified by silica gel chro-
matography. Therefore, we tried the oxidation step on
crude aldehydes, which involved the use of KMnO4 in
buffered (pH 4) aqueous tert-butyl alcohol.13 Under
these conditions, the protected carboxylic acids 11a and
11b were obtained in 65 and 73% yield, respectively.
1
deduced from the H NMR spectra taking into account
the well-known behavior of diastereoisomeric b-sulfinyl
carbinols,10 which agrees with the predictions made on
the basis of the stereochemical model proposed to
explain the DIBAH reduction of b-keto sulfoxides.11
The synthesis of oxiranes 8 starting from b-sulfinyl
alcohols was performed following a synthetic sequence
involving reduction of the sulfoxides, methylation of
the sulfenyl group and SNi of the sulfonium salt by the
alkoxide generated by treatment with base.12 Thus, the
reduction of the sulfinyl group of 6a and 6b was
accomplished by reaction with TiCl3 in EtOH at room
temperature to furnish the corresponding b-hydroxy
sulfenyl derivatives 7a and 7b, respectively. The reac-
tion of sulfenyl derivatives 7a and 7b with trimethyl
oxonium tetrafluoroborate in anhydrous CH2Cl2 fol-
lowed by aqueous K2CO3 (one-pot procedure) afforded
the optically active oxiranes 8a and 8b. Regioselective
oxirane opening was achieved by treatment of 8a and
8b with Et2AlCN in toluene at −78 to −15°C, affording
hydroxy nitriles 9a and 9b in 88 and 59% yield,
respectively.
Finally, acidic hydrolysis of the oxazolidine protecting
group proceeded in good yields by treatment of 11a and
11b with aqueous AcOH at 70°C producing N-Boc-3-
epistatine 12a7b,14 and N-Boc-statine 12b.7b,14
In summary, we have shown that both (3R,4S)- and
(3S,4S) - 4 - (tert - butoxycarbonylamino) - 3 - hydroxy-
6-methylheptanoic acids 12a and 12b can be easily
synthesized in high diastereomeric purity from the read-
ily available b-keto sulfoxide 5 by a sequence involving
stereodivergent reduction of
5 with DIBAH or
DIBAH/ZnBr2, conversion of the resulting hydroxy
sulfoxides 6a and 6b to oxiranes 8a and 8b, regioselec-

F. Yuste et al. / Tetrahedron: Asymmetry 14 (2003) 549–554
551
Scheme 1. Reagents and conditions: (i) DIBAH, THF, −78°C. (ii) DIBAH/ZnBr2, THF, −78°C. (iii) TiCl3/HCl/EtOH. (iv) 1.
Me3OBF4/CH2Cl2; 2. K2CO3/H2O. (v) Et2AlCN/toluene; −78“−15°C. (vi) DMP/C6H6/D. (vii) 1. DIBAH/Et2O/−40°C; 2.
KMnO4/tBuOH/pH 4. (viii) AcOH/H2O/70°C.
tive opening of the epoxide ring by cyanide ion, simul-
taneous protection of the resulting secondary alcohol
and NH carbamate groups, nitrile to carboxyl transfor-
mation, and final acid hydrolysis of the oxazolidine
protecting group.
troscopy. Mass spectra were measured at 70 eV and
190°C. All described compounds were over 97% pure
by NMR analysis.
3.1.1. (2S,3S,Rs)-N-(tert-Butoxycarbonyl)-3-amino-5-
methyl-1-[(4-methylphenyl)sulfinyl]-2-hexanol, 6a. To a
solution of b-keto sulfoxide 59 (1.14 g, 3.1 mmol, 1
equiv.) in anhydrous THF (20 mL) at −78°C a solution
of DIBAH in toluene (1.5 M, 15.5 mmol, 5 equiv.) was
added dropwise. The reaction mixture was stirred for
10 min at −78°C and the excess of DIBAH was decom-
posed by adding 20 mL of MeOH. The solvents were
removed under vacuum, the residue was treated with 25
mL of 5% HCl and extracted with Et2O (2×50 mL).
The organic layers were combined, washed with brine,
dried (Na2SO4) and evaporated. The crude product (1.2
g, de 90%) was purified by flash chromatography (hex-
ane–ethyl acetate, 20:80), to produce 1.0 g (71%) of 6a
as a white solid, mp 95°C (CH2Cl2–hexane); [h]D +105.0
(c 1.0, CHCl3) de >97%; IR (CHCl3) wmax: 3610, 3439,
2961, 1706, 1596, 1499, 1368, 1163 cm−1; 1H NMR
(CDCl3, 300 MHz): l 0.87 (d, 3H, J 6.6), 0.91 (d, 3H,
J 6.6), 1.32–1.36 (m, 2H), 1.40 (s, 9H), 1.60 (m, 1H),
2.42 (s, 3H), 2.71 (dd, 1H, J 1.8 and 13.5), 3.00 (dd, 1H,
J 10.2 and 13.5), 3.66 (broad m, 1H), 4.06 (broad m,
3. Experimental
3.1. General methods
All moisture sensitive reactions were carried out in
flame dried glassware under an argon atmosphere and
monitored by TLC. Flash chromatography was per-
formed with silica gel 60 (230–400 mesh ASTM). Melt-
ing points were determined in a Culatti melting point
apparatus in open capillary tubes and are uncorrected.
The optical rotations were measured at room tempera-
ture (20–23°C) using a Jasco DIP-360 polarimeter (con-
centration in g/100 mL). The IR spectra were recorded
in a Nicolet-5SX spectrophotometer. The NMR spectra
were determined in CDCl3 solutions at 200 (or 300) and
1
50.3 (or 75.5) MHz for H and 13C NMR, respectively.
J values are given in hertz. The diastereoisomeric
1
excesses were determined by 300 MHz H NMR spec-

552
F. Yuste et al. / Tetrahedron: Asymmetry 14 (2003) 549–554
1H), 4.51 (broad d, 1H, J 8.7), 7.34 and 7.52 (AA‘BB’
system, 4H); 13C NMR (CDCl3, 75 MHz): l 21.4, 23.6,
24.7, 28.3, 39.2, 53.2, 59.6, 69.9, 79.7, 124.0, 130.1,
139.9, 141.5, 156.1; EIMS m/z 369 (5%, M+), 296 (15),
268 (10), 186 (55), 183 (58), 174 (79), 139 (85), 130
(100), 86 (85), 57 (48); HRMS (EI): C19H31NO4S
requires 369.1974. Found: 369.1980.
3.1.4.
(2R,3S)-N-(tert-Butoxycarbonyl)-3-amino-5-
methyl-1-[(4-methylphenyl)sulfenyl]-2-hexanol, 7b. Fol-
lowing the same procedure used for the preparation of
7a, and starting from 0.50 g (1.35 mmol) of 6b, 0.432 g
(90%) of 7b were obtained. The product was purified by
column chromatography. Colorless oil; [h]D −30.2 (c
1.0, CHCl3); IR (CHCl3) wmax: 3443, 2961, 1705, 1498,
1367, 1166 cm−1; H NMR (CDCl3, 300 MHz): l 0.88
1
3.1.2. (2R,3S,Rs)-N-(tert-Butoxycarbonyl)-3-amino-5-
(d, 3H, J 6.6), 0.89 (d, 3H, J 6.6), 1.20–1.35 (m, 2H),
1.43 (s, 9H), 1.50–1.65 (m, 1H), 2.31 (s, 3H), 2.82 (dd,
1H, J 9.9 and 14.0), 3.10 (dd, 1H, J 4.2 and 14.0), 3.50
(broad m, 1H), 3.66 (broad m, 1H), 4.69 (broad d, 1H,
J 9.6), 7.10 and 7.29 (AA‘BB’ system, 4H); 13C NMR
(CDCl3, 75 MHz): l 21.0, 22.1, 23.1, 24.8, 28.4, 40.3,
42.0, 51.5, 70.7, 79.3, 129.9, 130.7, 131.1, 137.2, 156.1;
EIMS m/z 353 (6%, M+), 279 (8), 264 (10), 222 (13),
212 (27), 156 (48), 130 (53), 86 (86), 57 (100).
methyl-1-[(4-methylphenyl)sulfinyl]-2-hexanol, 6b.
A
solution of b-keto sulfoxide 59 (2.8 g, 7.63 mmol, 1
equiv.) in anhydrous THF (5 mL) was added to a
cooled solution of ZnBr2 (0.946 g, 7.63 mmol, 1 equiv.)
in 15 mL of THF at 0°C and the resulting mixture was
stirred at this temperature for 1.5 h. Then the solution
was cooled at −78°C and a 1.5 M solution of DIBAH
in toluene (15 mmol, 1.97 equiv.) was added dropwise.
The reaction mixture was stirred for 1 h at −78°C and
the excess DIBAH was decomposed by adding 20 mL
of MeOH. Once the solution reached room tempera-
ture, the volatiles were removed under vacuum, the
residue was treated with 25 mL of 5% HCl and
extracted with Et2O (2×50 mL). The organic phase was
washed with brine, dried (Na2SO4) and evaporated. The
crude product (2.5 g, de 85%) was purified by crystal-
lization from CH2Cl2/hexane to give 2.11 g (75%) of 6b
as white crystals, mp 115°C; [h]D +111.5 (c 1.0, CHCl3)
de >97%; IR (CHCl3) wmax: 3440, 2961, 1703, 1499,
3.1.5. (S)-1-[(S)-1-(tert-Butoxycarbonylamino)-3-methyl-
butyl]oxirane, 8a. Trimethyloxonium tetrafluoroborate
(2 equiv.) was added to a solution of 7a (0.5 g, 1.42
mmol) in 5 mL of CH2Cl2. The mixture was stirred at
room temperature for 1 h and then a solution of K2CO3
(1.58 mmol) in 3 mL of water was added. The resulting
mixture was vigorously stirred for 24 h. The organic
phase was separated and the aqueous phase was
extracted with CH2Cl2 (3×5 mL). The combined
organic layers were washed with brine, dried and con-
centrated. The residue was purified by column chro-
matography (hexane–ethyl acetate, 8:2) to produce
0.178 g (55%,) of 8a as a white solid, mp 45–47°C; [h]D
−27.6 (c 1.0, CHCl3); IR (CHCl3) wmax: 3443, 2962,
1
1367, 1166 cm−1; H NMR (CDCl3, 300 MHz): l 0.93
(d, 6H, J 6.3), 1.20–1.70 (broad m, 3H), 1.37 (s, 9H),
2.41 (s, 3H), 2.87 (dd, 1H, J 3.6 and 13.5), 2.96 (dd, 1H,
J 8.7 and 13.5), 3.75 (m, 2H, partially interchangeable
with D2O), 4.29 (m, 1H), 4.51 (broad d, 1H, J 9.6), 7.31
and 7.52 (AA‘BB’ system, 4H); 13C NMR (CDCl3, 75
MHz): l 21.4, 22.2, 23.0, 24.7, 28.3, 41.3, 52.7, 60.7,
70.3, 79.2, 123.9, 130.0, 140.4, 141.9, 156.1; EIMS m/z
369 (4%, M+), 296 (10), 268 (9), 186 (40), 174 (100), 139
(53), 130 (84), 86 (90), 57 (82); HRMS (EI):
C19H31NO4S requires 369.1974. Found: 369.1978.
1709, 1500, 1368, 1167 cm−1; H NMR (CDCl3, 300
1
MHz): l 0.91 (d, 3H, J 6.6), 0.94 (d, 3H, J 6.6),
1.35–1.42 (m, 2H), 1.44 (s, 9H), 1.65–1.80 (m, 1H), 2.75
(d, 2H, J 3.8), 2.82–2.86 (m, 1H), 3.50 (broad m, 1H),
4.44 (broad m, 1H); 13C NMR (CDCl3, 75 MHz): l
21.8, 23.3, 24.4, 28.3, 40.8, 46.1, 50.3, 54.5, 79.4, 155.4;
EIMS m/z 229 (not observed, M+), 186 (23), 130 (47),
86 (55), 72 (34), 57 (100).
3.1.3.
(2S,3S)-N-(tert-Butoxycarbonyl)-3-amino-5-
methyl-1-[(4-methylphenyl)sulfenyl]-2-hexanol, 7a. To a
stirred solution of 6a (0.5 g, 1.35 mmol, 1 equiv.) in
EtOH (10 mL) a 15% wt. solution of TiCl3 (2 equiv.) in
20–30% aqueous HCl was added at room temperature.
After 20 min, the solution was cooled in an ice bath,
treated with 10 mL of water and 10 mL of 10%
NaHCO3 and extracted with Et2O (3×15 mL). The
organic phase was washed with brine, dried (Na2SO4)
and evaporated. The residue was crystallized from
CH2Cl2/hexane, to produce 0.41 g (85%) of 7a as a
white solid, mp 97–99°C; [h]D −24.7 (c 1.0, CHCl3); IR
(CHCl3) wma1x: 3442, 3014, 2960, 2930, 1706, 1499, 1368,
1164 cm−1; H NMR (CDCl3, 300 MHz): l 0.90 (d, 3H,
J 6.6), 0.92 (d, 3H, J 6.6), 1.30–1.40 (m, 2H), 1.43 (s,
9H), 1.64 (m, 1H), 2.32 (s, 3H), 2.84 (dd, 1H, J 9.3 and
13.5), 3.08 (dd, 1H, J 3.3 and 13.5), 3.62 (broad m, 1H),
3.72 (broad m, 1H), 4.58 (broad d, 1H, J 7.2), 7.11 and
7.30 (AA‘BB’ system, 4H); 13C NMR (CDCl3, 75
MHz): l 21.0, 21.6, 23.7, 24.7, 28.4, 38.9, 39.4, 52.8,
72.8, 79.9, 129.9, 130.9, 131.0, 136.9, 156.1; EIMS m/z
353 (12%, M+), 222 (25), 212 (45), 156 (70), 130 (92), 86
(100), 57 (93); HRMS (EI): C19H31NO3S requires
353.2025. Found: 353.2034.
3.1.6.
(R)-1-[(S)-1-(tert-Butoxycarbonylamino)-3-
methylbutyl]oxirane, 8b. Following the same procedure
used for the preparation of 8a, and starting from 0.40 g
(1.13 mmol) of 7b, 0.164 g (63%) of 8b were obtained.
The product was purified by column chromatography
(hexane–ethyl acetate, 8:2). Colorless oil; [h]D −43.1 (c
1.0, CHCl3); IR (CHCl3) wmax: 3440, 2961, 1708, 1503,
1368, 1165 cm−1; H NMR (CDCl3, 300 MHz): l 0.95
1
(d, 6H, J 6.6), 1.35–1.55 (m, 2H), 1.43 (s, 9H), 1.65–
1.80 (m, 1H), 2.60 (broad m, 1H), 2.73 (t, 1H, J 4.6),
2.98 (broad m, 1H), 3.97 (broad m, 1H), 4.29 (broad m,
1H); 13C NMR (CDCl3, 75 MHz): l 22.1, 23.0, 24.7,
28.3, 42.3, 44.4, 47.2, 53.9, 79.4, 155.6; EIMS m/z 230
(3%, M++1), 186 (28), 172 (25), 130 (57), 116 (17), 86
(63), 72 (65), 57 (100).
3.1.7. (3R,4S)-4-(tert-Butoxycarbonylamino)-3-hydroxy-
6-methylheptanenitrile, 9a. A solution of 8a (0.285 g,
1.24 mmol, 1 equiv.) in 2 mL of toluene was dropwise
added to a solution of Et2AlCN (2.4 mmol, 1.93 equiv.)
in 5 mL of toluene cooled at −78°C. The resulting
solution was warmed at −15°C and stirred at this

F. Yuste et al. / Tetrahedron: Asymmetry 14 (2003) 549–554
553
temperature for 1 h. Then, 10 mL of a solution of
concentrated HCl and MeOH (8:2) were added and
the resulting mixture was vigorously stirred at −15°C
for 1 h. The mixture was treated with 10 mL of
water and extracted with Et2O (3×15 mL). The
organic phase was washed with brine, dried (Na2SO4)
and concentrated under vacuum. The residue was
crystallized from CH2Cl2/hexane, to produce 0.28 g
(88%) of 9a as a white solid, mp 95–97°C; [h]D −34.1
(c 1.0, CHCl3); IR (CHCl3) wmax: 3591, 3440, 2962,
2252, 1752, 1703, 1690, 1501, 1370, 1161 cm−1; 1H
NMR (CDCl3, 300 MHz): l 0.92 (d, 3H, J 6.6), 0.95
(d, 3H, J 6.6), 1.32–1.42 (m, 2H), 1.45 (s, 9H), 1.68
(m, 1H), 2.53 (m, 2H), 3.75 (broad m, 1H), 3.90
(broad m, 1H), 4.25 (m, 1H, interchangeable with
D2O), 4.66 (broad d, 1H, J 6.3); 13C NMR (CDCl3,
75 MHz): l 21.5, 21.9, 23.3, 24.9, 28.3, 39.3, 53.7,
71.3, 80.6, 118.0, 157.1; EIMS m/z 256 (2%, M+), 186
(28), 130 (82), 86 (95), 57 (100); HRMS (EI):
C13H24N2O3 requires 256.1787. Found: 256.1782.
3.1.10. (4S,5S)-3-(tert-Butoxycarbonyl)-5-cyanomethyl-
4-isobutyl-2,2-dimethyl-1,3-oxazolidine, 10b. Following
the same procedure used for the preparation of 10a,
and starting from 0.09 g (0.35 mmol) of 9b, 0.088 g
(85%) of 10b were obtained. The product was purified
by column chromatography. Colorless oil; [h]D +14.0
(c 1.0, CHCl3); IR (CHCl3) wmax: 2962, 2934, 2873,
1
2254, 1692, 1467, 1391 cm−1; H NMR (CDCl3, 300
MHz): l 0.96 (d, 3H, J 6.3), 0.98 (d, 3H, J 6.3),
1.40–1.80 (broad m, 3H), 1.48 (s, 9H), 1.52 (s, 3H),
1.62 (s, 3H), 2.64 (d, 2H, J 6.6), 3.84 (broad m, 1H),
4.16 (td, 1H, J 2.1 and 6.6); 13C NMR (CDCl3, 75
MHz): l 21.3, 23.9, 24.6, 25.7, 28.5, 42.5*, 60.7,
76.0*, 80.5, 95.0*, 116.6, 151.5 (the signals with an
asterisk are broad and correspond to a rotamer mix-
ture of the N-Boc group); EIMS m/z 296 (1%, M+),
281 (18), 225 (32), 181 (100), 57 (88).
3.1.11.
(4S,5R)-3-(tert-Butoxycarbonyl)-5-carboxy-
methyl-4-isobutyl-2,2-dimethyl-1,3-oxazolidine, 11a. To
a cooled solution (−40°C) of 10a (0.1 g, 0.34 mmol) in
dry Et2O (3 mL) a 1.5 M solution of DIBAH in toluene
(0.4 mL, 0.6 mmol) was added. The mixture was stirred
at −40°C for 1 h, at −20°C for another 1 h period,
treated with EtOAc (3 mL) and then allowed to reach
room temperature. After addition of a saturated
sodium potassium tartrate solution (3 mL), the reaction
mixture was vigorously stirred for 2 h. The mixture was
diluted with EtOAc (5 mL), the organic phase was
separated, washed with brine, dried and concentrated
under vacuum to give 0.077 g (76%) of the correspond-
ing crude aldehyde as a colorless oil. Without further
purification, to this crude product, vigorously stirred
with 2-methyl-2-propanol (2 mL) and 5% NaH2PO4 (2
mL), 1.5 mL (1.5 mmol) of a 1 M solution of KMnO4
was added. After 15 min, the excess of KMnO4 was
decomposed by adding a 10% Na2SO3 solution, the
mixture was cooled at 0°C and acidified with 10% HCl
until pH 4–5. The reaction mixture was extracted with
Et2O (3×10 mL) and the combined extracts were
washed with 10% NaHCO3. The washing liqueurs were
newly acidified (pH 4–5) and extracted with Et2O (3×10
mL). The combined organic extracts were washed with
brine, dried and evaporated. The residue was crystal-
lized from CH2Cl2/hexane to produce 0.07 g (85%) of
11a as a white solid, mp 95–97°C; [h]D −6.8 (c 1.0,
CHCl3); IR (CHCl3) wma1x: 3500–2500, 2960, 2932, 1713,
1686, 1454, 1392 cm−1; H NMR (CDCl3, 300 MHz): l
0.94 (d, 3H, J 6.6), 0.95 (d, 3H, J 6.6), 1.20–1.40 (m,
2H), 1.48 (s, 9H), 1.54 (broad s, 7H), 2.62 (dd, 1H, J
6.6 and 16.5), 2.64–2.73 (broad m, 1H), 4.00 (broad m,
1H), 4.43 (td, 1H, J 4.8 and 6.9); 13C NMR (CDCl3, 75
MHz): l 22.7*, 23.6*, 24.9, 25.1*, 27.2*, 28.5, 34.3,
39.6*, 56.7, 72.6, 80.0, 92.9*, 151.9*, 175.8 (the signals
with an asterisk are broad and correspond to a rotamer
mixture of the N-Boc group); EIMS m/z 316 (1%,
M++1), 300 (12), 244 (40), 200 (43), 158 (18), 57 (100).
3.1.8. (3S,4S)-4-(tert-Butoxycarbonylamino)-3-hydroxy-
6-methylheptanenitrile, 9b. Following the same proce-
dure used for the preparation of 9a, and starting
from 0.15 g (0.65 mmol) of 8b, 0.098 g (59%) of 9b
were obtained. The product was purified by column
chromatography. Colorless oil; [h]D −35.0 (c 1.0,
CHCl3); IR (CHCl3) wmax: 3616, 3441, 2961, 2253,
1704, 1505, 1469, 1392, 1369, 1162 cm−1; 1H NMR
(CDCl3, 300 MHz): l 0.94 (d, 3H, J 6.6), 0.95 (d,
3H, J 6.6), 1.30–1.80 (m, 3H), 1.45 (s, 9H), 2.57 (m,
2H), 3.23 (broad s, 1H, interchangeable with D2O),
3.62 (broad m, 1H), 3.94 (broad m, 1H), 4.67 (broad
m, 1H); 13C NMR (CDCl3, 50 MHz): l 21.9, 23.0,
23.5, 24.7, 28.2, 40.8, 52.3, 69.6, 79.9, 118.2, 156.4;
EIMS m/z 256 (1%, M+), 186 (24), 183 (13), 130 (70),
86 (92), 57 (100).
3.1.9. (4S,5R)-3-(tert-Butoxycarbonyl)-5-cyanomethyl-
4-isobutyl-2,2-dimethyl-1,3-oxazolidine, 10a. A mixture
of 9a (0.2 g, 0.78 mmol,
1
equiv.), 2,2-
dimethoxypropane (7.8 mmol, 10 equiv.), p-toluene-
sulfonic acid monohydrate (0.02 mmol) in dry
benzene (5 mL) was refluxed for 1 h. The mixture
was diluted with Et2O (10 mL), washed with satu-
rated NaHCO3, dried and concentrated under vac-
uum. The residue (0.25 g) was purified by column
chromatography (hexane–ethyl acetate, 8:2) to give
0.166 g (72%) of 10a as a colorless oil; [h]D −2.0 (c
1.0, CHCl3); IR (CHCl3) wmax: 2961, 2929, 2871, 2258,
1
1688, 1467, 1456, 1392 cm−1; H NMR (CDCl3, 300
MHz): l 0.97 (d, 3H, J 6.6), 0.98 (d, 3H, J 6.6),
1.25–1.40 (m, 2H), 1.40–1.55 (m, 1H), 1.48 (s, 9H),
1.53 (s, 3H), 1.55 (s, 3H), 2.57 (dd, 1H, J 7.2 and
16.4), 2.67 (dd, 1H, J 6.9 and 16.4), 4.04 (broad m,
1H), 4.28 (td, 1H, J 4.8 and 6.9); 13C NMR (CDCl3,
75 MHz): l 19.6, 21.3, 21.9*, 22.8, 23.3*, 23.8, 24.7*,
24.9, 25.7*, 28.3*, 28.5, 39.3, 41.9*, 56.7, 72.2, 80.3,
93.8, 116.6, 151.4 (the signals with an asterisk corre-
spond to the minor rotamer of the N-Boc group);
EIMS m/z 296 (1%, M+), 281 (8), 225 (20), 181 (45),
152 (50), 85 (100), 57 (90); HRMS (EI): C16H28N2O3
requires 296.2100. Found: 296.2106.
3.1.12.
(4S,5S)-3-(tert-Butoxycarbonyl)-5-carboxy-
methyl-4-isobutyl-2,2-dimethyl-1,3-oxazolidine, 11b. To
a cooled solution (−40°C) of 10b (0.07 g, 0.23 mmol) in
dry Et2O (3 mL) a 1.5 M solution of DIBAH in toluene
(1 mL, 1.5 mmol) was added. The mixture was stirred
at −40°C for 15 min, treated with EtOAc (3

554
F. Yuste et al. / Tetrahedron: Asymmetry 14 (2003) 549–554
mL) and then allowed to reach room temperature. The
work-up under conditions above described for 11a
afforded 0.06 g (86%) of the corresponding crude alde-
hyde as a colorless oil. Without further purification,
this crude product was submitted to the oxidation
conditions previously used for the preparation of 11a to
produce 0.054 g (85%) of 11b as a white solid, mp
C13H25NO5: C, 56.71; H, 9.15; N, 5.09. Found: C,
56.86; H, 9.35; N, 5.16%.
Acknowledgements
130–132°C; [h]D −2.2 (c 1.0, CHCl3); IR (CHCl3) wmax
:
We thank M. I. Cha´vez, R. Patin˜o, M. A. Pen˜a, J.
Pe´rez, H. R´ıos and L. Velasco for their technical assis-
tance. Financial support from Direccio´n de Investiga-
cio´n Cient´ıfica y Te´cnica CAICYT (BQU2000-0246)
from Spain, is gratefully acknowledged.
3500–2500, 2961, 2931, 1708, 1691, 1393 cm−1; 1H
NMR (CDCl3, 300 MHz): l 0.92 (d, 3H, J 6.0), 0.93 (d,
3H, J 6.0), 1.40–1.65 (broad m, 3H), 1.48 (s, 9H), 1.51
(s, 3H), 1.60 (s, 3H), 2.55–2.75 (m, 2H), 4.00 (broad m,
1H), 4.32 (t, 1H, J 6.4); EIMS m/z 315 (not observed,
M+), 300 (8), 244 (33), 200 (25), 158 (13), 86 (12), 57
(100).
References
3.1.13.
(3R,4S)-4-(tert-Butoxycarbonylamino)-3-
1. Gante, J. Angew. Chem., Int. Ed. 1994, 33, 1699–1720.
2. Umezawa, H.; Aiyagi, T.; Morishima, H.; Matsuzaki,
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B. I.; Lin, T.-Y.; Kawai, M.; Rich, D. H.; Veber, D. F. J.
Med. Chem. 1985, 28, 1779–1790.
hydroxy-6-methylheptanoic acid, 12a. A mixture of 11a
(0.05 g, 0.16 mmol) and 1 mL of 85% AcOH was
heated at 70°C for 40 min. After cooling at room
temperature, the mixture was diluted with EtOAc (5
mL) and washed with 10% NaHCO3 (2×5 mL). The
aqueous phase was acidified to pH 4–5 with 10% HCl
and extracted with Et2O (3×5 mL). The combined
ethereal extracts were washed with brine, dried
(Na2SO4) and evaporated under vacuum. The solid
residue was recrystallized from CH2Cl2/hexane to give
0.032 g (73%) of 12a as a white solid, mp 132–135°C
(lit.7b 132–134°C; lit.14 135–136°C; [h]D −26.5 (c 0.31,
4. Rinehart, K. L.; Kishore, V.; Nagarajan, S.; Lake, R. J.;
Gloh, J. B.; Bozich, F. A.; Li, K.-M.; Maleczka, R. E.,
Jr.; Todsen, W. L.; Munro, M. H. G.; Sullins, D. W.;
Sakai, R. J. Am. Chem. Soc. 1987, 109, 6846–6848.
5. Stratmann, K.; Burgoyne, D. L.; Moore, R. E.; Patter-
son, G. M. L. J. Org. Chem. 1994, 59, 7219–7226.
6. For discussions on synthetic approaches to b-hydroxy-g-
amino acids, see: (a) Pesenti, C.; Bravo, P.; Corradi, E.;
Frigerio, M.; Meille, S. V.; Panzeri, W.; Viani, F.; Zanda,
M. J. Org. Chem. 2001, 66, 5637–5640; (b) Castejo´n, P.;
Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahedron 1996,
52, 7063–7086.
7. For recent stereodivergent syntheses, see: (a) Ref. 6. See
also: (b) Alemany, C.; Bach, J.; Garcia, J.; Lo´pez, M.;
Rodr´ıguez, A. B. Tetrahedron 2000, 56, 9305–9312.
8. Yuste, F.; Ortiz, B.; Carrasco, A.; Peralta, M.; Quintero,
L.; Sa´nchez-Obrego´n, R.; Walls, F.; Garc´ıa Ruano, J. L.
Tetrahedron: Asymmetry 2000, 11, 3079–3090.
9. Ortiz, B.; Herna´ndez, A.; Quintero, L.; Sa´nchez-Obrego´n,
R.; Yuste, F.; Garc´ıa Ruano, J. L. Rev. Soc. Qu´ım. Me´x.
2001, 45, 163–166.
MeOH) (lit.14 −27.6 (c 0.31, MeOH); IR (CHCl3) wmax
:
3725, 3696, 3603, 3439, 2962, 1745, 1707, 1602, 1501,
1369, 1161 cm−1; H NMR (CDCl3, 300 MHz): l 0.91
1
(d, 3H, J 6.6), 0.94 (d, 3H, J 6.6), 1.28–1.35 (m, 2H),
1.45 (s, 9H), 1.60–1.74 (broad m, 1H), 2.49 (broad d,
2H, J 5.9), 3.71 (broad m, 1H), 4.01 (broad m, 1H),
4.67 (broad d, 1H, J 7.7), 4.90 (broad s, 1H); 13C NMR
(CDCl3, 75 MHz): l 21.4, 23.5, 24.6, 28.3, 37.2, 38.8,
53.0, 71.3, 80.0, 156.6, 175.8; EIMS m/z 275 (not
observed, M+), 256 (2), 202 (10), 186 (30), 130 (92), 86
(100), 57 (98). Anal. calcd for C13H25NO5: C, 56.71; H,
9.15; N, 5.09. Found: C, 56.66; H, 9.19; N, 5.01%.
3.1.14.
(3S,4S)-4-(tert-Butoxycarbonylamino)-3-
hydroxy-6-methylheptanoic acid, 12b. Following the
same procedure used for the preparation of 12a, and
starting from 0.05 g (0.16 mmol) of 11a, 0.035 g (80%)
of 12b were obtained. White solid, mp 115–117°C (lit.7b
115–116°C; lit.14 117–118°C; [h]D −38.1 (c 0.31, MeOH)
(lit.14 −39.6 (c 0.31, MeOH); IR (CHCl3) wmax: 3725,
3694, 3604, 3440, 2961, 1745, 1707, 1602, 1501, 1369,
10. Brunet, E.; Garc´ıa Ruano, J. L.; Hoyos, M. A.;
Rodr´ıguez, J. H.; Prados, P.; Alcudia, F. Org. Magn.
Reson. 1983, 21, 643–648.
11. Carren˜o, M. C.; Garc´ıa Ruano, J. L.; Mart´ın, A. M.;
Pedregal, C.; Rodr´ıguez, J. H.; Rubio, A.; Sa´nchez, J.;
Solladie`, G. J. Org. Chem. 1990, 55, 2120–2128.
12. Solladie`, G.; Demailly, G.; Greck, C. Tetrahedron Lett.
1985, 26, 435–438.
1161 cm−1; H NMR (CDCl3, 300 MHz): l 0.92 (d, 3H,
1
J 6.3), 0.93 (d, 3H, J 6.3), 1.25–1.35 (m, 2H), 1.46 (s,
9H), 1.65–1.75 (m, 1H), 2.54 (broad m, 2H), 3.64
(broad m, 1H), 4.01 (broad s, 1H), 4.86 (d, 1H, J 9.0),
5.64 (broad s, 1H); 13C NMR (CDCl3, 75 MHz): l 22.1,
23.1, 24.7, 28.3, 39.8, 41.3, 52.1, 69.7, 79.6, 156.4, 177.7;
EIMS m/z 275 (not observed, M+), 256 (5), 202 (3), 186
(14), 130 (34), 86 (63), 57 (100). Anal. calcd for
13. Abiko, A.; Roberts, J. C.; Takemasa, T.; Masamune, S.
Tetrahedron Lett. 1986, 27, 4537–4540.
14. Rich, D. H.; Sun, E. T.; Boparai, A. S. J. Org. Chem.
1978, 43, 3624–3626.