Enantioselective synthesis of α-hydroxy-β-amino acids from α-amino acids mediated by sulfoxides

Article abstract of DOI:10.1016/j.tet.2007.07.072

The synthesis of the optically pure (2S,3S)- and (2R,3S)-3-amino-2-hydroxybutanoic acids from commercially available (S)-alanine derivatives is reported. The key step of the synthetic sequence is the conversion of γ-amino sulfoxides into γ-amino alcohols

Full text of DOI:10.1016/j.tet.2007.07.072

Tetrahedron 63 (2007) 10521–10527
Enantioselective synthesis of a-hydroxy-b-amino acids
from a-amino acids mediated by sulfoxides
a
Ruben Sanchez-Obregon, Fernando Salgado, Benjamın Ortiz, Eduardo Dıaz,
a
a
a
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Francisco Yuste,a, Fernando Walls and Jose L. Garcıa Ruano
a
b,
*
*
ꢀ
ꢀ
a
´
Instituto de Quꢀımica, Universidad Nacional Autoꢀnoma de Mexico, Circuito Exterior, Cd. Universitaria,
´
Coyoacaꢀn 04510, Mexico D. F., Mexico
bDepartamento de Quꢀımica Orgaꢀnica (C-I), Facultad de Ciencias, Universidad Autoꢀnoma de Madrid,
Cantoblanco, 28049-Madrid, Spain
Received 20 December 2006; revised 13 July 2007; accepted 23 July 2007
Available online 29 July 2007
Abstract—The synthesis of the optically pure (2S,3S)- and (2R,3S)-3-amino-2-hydroxybutanoic acids from commercially available (S)-
alanine derivatives is reported. The key step of the synthetic sequence is the conversion of g-amino sulfoxides into g-amino alcohols by treat-
ment with TFAA and sym-collidine. The efficiency of this non-oxidative Pummerer reaction (NOPR) is dependent on the stereochemistry of
the starting sulfoxide.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
The non-oxidative Pummerer reaction is an interesting pro-
cess allowing the stereoselective conversion of b-amino sulf-
oxides into the corresponding b-amino alcohols by reaction
with TFAA and sym-collidine (Scheme 1). These reactions,
which occur with inversion of configuration at the carbon
bearing the sulfinyl group, were discovered and extensively
used by Zanda’s group.15 To the best of our knowledge, how-
ever, the conversion of g-amino sulfoxides into the corre-
sponding g-amino alcohols under analogous conditions
has received little attention.16 Given that these compounds
are obvious precursors of b-amino acids, and that we have
recently reported the synthesis of b-hydroxy-g-amino sulf-
oxides (both epimeric hydroxyl compounds) starting from
the readily available amino acid methyl ester hydrochlo-
rides,17 we chose to examine the behavior of such g-amino
sulfoxides under the conditions of the non-oxidative
Pummerer reaction. The objectives of this study were to syn-
thesize 3-amino-1,2-propanediols, precursors of a-hydroxy-
b-amino acids (Scheme 1), to compare the behavior of the
g-amino sulfoxides with that of the b-amino derivatives,
and to examine the influence of the stereochemistry of the
starting materials on the reaction course. In this paper we
report the results obtained in this study.
a-Hydroxy-b-amino acids constitute an important class of
substances that has received considerable attention because
of the occurrence thereof in biologically active molecules.1
For example, this entity is present in antitumor agents
(paclitaxel2), aminopeptidase inhibitors (bestatin3 and
amastatin4), rennin inhibitors (KRI-13145), angiotensin
converting enzymes (microginin6), and antibacterial agents
(dideoxy-kanamycin A7). In recent years, much effort has
been devoted to the asymmetric synthesis of a-hydroxy-b-
amino acid structural units and a large number of synthetic
approaches thereto have been developed including, among
others: (i) homologation of chiral amino acids,8 (ii) Ojima’s
b-lactam ring opening methodologies,9 (iii) asymmetric
aminohydroxylation10 or enantioselective epoxidation of
olefins followed by nucleophilic ring opening of the result-
ing chiral epoxides,11 (iv) electrophilic hydroxylation of
chiral enolates,12 and (v) addition of nucleophiles to chiral
a-amino aldehydes13 and imines.14 Although satisfactory
degrees of stereocontrol have been achieved for these
processes, most of them involve multi-step reaction
sequences, and therefore the search for new routes to synthe-
size both diastereoisomers of a given a-hydroxy-b-amino
acid starting with a common precursor continues to be of
considerable interest.
2. Results and discussion
The overall synthetic sequence is depicted in Scheme 2. The
starting optically pure (3S,Rs)-N-(tert-butoxycarbonyl)-3-
amino-1-[(4-methylphenyl)sulfinyl]-2-butanone (1a) and
* Corresponding authors. E-mail addresses: yustef@servidor.unam.mx;
joseluis.garcia.ruano@uam.es
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.072

10522
R. Saꢀnchez-Obregoꢀn et al. / Tetrahedron 63 (2007) 10521–10527
SOTol
RO2C NH
RO2C NH
R3
R4
Non-oxidative
Pummerer reaction
(NOPR)
1. TFAA, sym-collidine
2. NaBH4
R2
R1
R4
R2
R1
R3
OH
RO2C NH
RO2C NH
RO2C NH
RO2C NH
CO2H
SOTol
OH
OP
Ref.17
NOPR
CO2R
OP
OP
H
R2
R1
R2
R1
R2
R1
R2
R1
H
H
syn or anti
syn or anti
syn or anti
Scheme 1.
(3S,Rs)-N-(tert-butoxycarbonyl)-3-amino-5-methyl-1-[(4-
methylphenyl)sulfinyl]-2-hexanone (1b) were obtained
following a previously described synthetic route.17a,c The
reduction of b-keto sulfoxide 1a (or 1b) with DIBAH or DI-
BAH/ZnBr2 gave the g-amino-b-hydroxy sulfoxides 2a and
3a17a (or 2b and 3b17c), respectively, as diastereoisomeri-
cally pure products. These compounds were converted into
the corresponding tert-butyldimethylsilyl ethers 4a and 4b
(5a and 5b) and then reacted with TFAA (5–10.5 equiv)
and sym-collidine in acetonitrile at room temperature. The
reaction mixtures were then diluted with a large excess of
18
saturated aqueous NaHCO3 and left at ambient tempera-
ture. In this way the sulfenamides 6a and 6b were obtained
in excellent yields (86 and 81% yields) after 48 and 22 h, re-
spectively. In stark contrast, after 7 days, compound 7a was
produced in only 25% yield (substantial recovered 5a) and
NHBoc
p-Tol
R
S
(i)
(ii)
O
NHBoc
O
NHBoc
OR'
p-Tol
p-Tol
1a R=Me
1b R=i-Bu
R
S
R
S
OR'
O
O
3a, b R'=H
2a, b R'=H
(iii)
(iii)
4a, b R'=TBDMS
5a, b R'=TBDMS
(iv)
(iv)
Tol S
Boc
Tol S
Boc
N
N
N
R
OH
R
6a,b
OH
7a
OTBDMS
OTBDMS
(v)
(v)
Tol
S
Boc
Tol S
Boc
O
Tol S
Boc
N
O
N
O
(viii)
R
H
R
H
R
OMe
OTBDMS
OTBDMS
OTBDMS
8a,b
12b
9a
(vi)
(vi)
O
.
.
HCl H2N
HC l H2N
O
R
OH
R
OH
OH
(vii)
OH
(vii)
10a
11a
NH2
NH2
O
O
R
OH
R
OH
OH
13a
OH
14a
Scheme 2. Reagents and conditions: (i) DIBAH, THF, ꢀ78 ꢁC; (ii) DIBAH–ZnBr2, THF, ꢀ78 ꢁC; (iii) TBDMSCl, imidazole; (iv) (1) TFAA, sym-collidine,
0/25 ꢁC, (2) NaHCO3–H2O, 25 ꢁC; (v) PCC, CH2Cl2, 25 ꢁC; (vi) (1) KMnO4–t-BuOH, pH 4, (2) HCl(g)–Et2O, 25 ꢁC; (vii) ion-exchange chromatography;
(viii) (1) Na2Cr2O7, H2SO4, ꢀ15/25 ꢁC, (2) CH2N2, Et2O.

R. Saꢀnchez-Obregoꢀn et al. / Tetrahedron 63 (2007) 10521–10527
10523
the conversion of 5b to 7b did not take place at all (5b is
quantitatively recovered).19
intermediates would be opened by the trifluoroacetate anion
affording compounds 6 and 7. On the assumption that the
five membered intermediates II or III might be sufficiently
stable to be observable, we chose to follow the reaction
by NMR spectroscopy. When 4a was dissolved in CD3CN
containing 5 equiv of TFAA, substantial deshielding of the
methylene hydrogens a- to sulfur was observed, as expected
for the formation of the acyloxysulfonium salt I, but no sig-
nals attributable to II or III were ever seen.25 Upon addition
of sym-collidine to this solution, the only new absorptions,
which appeared were those corresponding to the trifluoro-
acetate of 6a, thus precluding to obtain any proof supporting
the formation of the intermediates II or III.
The reaction of 6a, 6b, and 7a with PCC at room temperature
gave the aldehydes 8a, 8b, and 9a, respectively. The oxida-
tion of 8a and 9a using KMnO4 in buffered (pH 4) aqueous
tert-butyl alcohol produced the corresponding carboxylic
acids. Although the yields of the crude products were high,
these compounds are not very stable and suffer extensive
degradation on attempted purification by silica gel chroma-
tography. Therefore the crude carboxylic acids were dis-
solved in ether saturated with hydrogen chloride, which
effected removal of both the protecting groups and sulfon-
amide cleavage, and generated the hydrochloride salts of
10a and 11a in 42 and 76% yields. The known free
amino acids, (2S,3S)-alloisothreonine20,21 (13a) and
(2R,3S)-isothreonine20–23 (14a) were generated from the
hydrochloride salts by ion exchange using a SCX column.
Unexpectedly, oxidation of aldehyde 8b with KMnO4 and
subsequent hydrogen chloride treatment of the crude oxida-
tion product, under conditions identical to those used for 8a
and 9a, produced the corresponding hydrochloride as a mix-
ture of C-2 epimers. In contrast, oxidation of 8b with sodium
dichromate in sulfuric acid at ꢀ15 ꢁC and esterification of
the crude product with diazomethane, gave the diasterio-
merically pure methyl ester 12b (74%).
It is remarkable that the conditions under which 4a and 4b
are converted into 6a and 6b are either inefficient or ineffec-
tive for the generation of the corresponding products from 5a
or 5b, respectively. The cause of this phenomenon must be
associated with the sulfoxide stereochemistry, but the pre-
cise role, which it plays is not clear. It may be a consequence
of the different easiness of the acyloxysulfonium salts to
evolve into their corresponding sulfuranes or azasulfonium
salt intermediates, that would be determined by the steric
interactions of the nearly eclipsed conformation [for the
C(1)–C(2) bond] that I and I0 must adopt to be transformed
into II and II0 (much higher for I0) and/or by the higher
stability of the trans intermediates (II and III) with respect
to the cis ones (II0 and III0).
If the conversion of g-amino sulfoxides into the correspond-
ing amino diols by the non-oxidative Pummerer reaction
proceeds by a mechanism analogous to that proposed by
Zanda15d for the b-amino sulfoxide series, then the reaction
sequence depicted in Scheme 3 would be expected. After the
formation of the acyloxysulfonium salts (I and I0) by reac-
tion of the sulfinyl oxygen with TFAA, the intramolecular
attack of the amide anion (generated after adding sym-
collidine) to the sulfur at these salts would yield the thia-
azacyclopentane rings (III and III0), probably through the
sulfurane intermediates (II and II0).24 Finally, these
Although the mechanism depicted in Scheme 3 seems to be
appropriated to explain the most of the experimental results,
some doubts subsist from the fact that intermediates II or III
cannot be detected in our NMR experiments, despite of their
presumable stability, which seriously put in question their
existence. In such a case other mechanistic possibilities
must be considered for these reactions. One of them assumes
an almost concerted process, like that depicted in the
Scheme 4, where the nitrogen attack produces the cleavage
4a or 4b
5a or 5b
TFAA
TFAA
Tol
Tol
OCOCF3
OCOCF3
Boc NH
S+
Boc NH
+
S
-OCOCF3
-OCOCF3
R
R
OTBDMS
OTBDMS
I
I'
sym-collidine
OBut
sym-collidine
OBut
N
OBut
N
OBut
Tol
Tol
Tol
Tol
O
O
O
O
N
+
+
S
S
S
OCOCF3
S
OCOCF3
N
-OCOCF3
-OCOCF3
R
R
R
R
OTBDMS
III
OTBDMS
II'
OTBDMS
III'
OTBDMS
II
Then hydrolysis
Then hydrolysis
6a or 6b
7a or 7b
Scheme 3.

10524
R. Saꢀnchez-Obregoꢀn et al. / Tetrahedron 63 (2007) 10521–10527
Tol
S
O
Tol
Tol
Boc
R
OCOCF3
Boc
R
O
Boc
R
NH
N
N
S+
S+
CF3
CF3
sym-collidine
-OCOCF3
CH2
CH2
OTBDMS
O
O
OTBDMS
OTBDMS
I
Scheme 4.
of the S–OCOCF3 bond and the simultaneous intramolecular
attack of the leaving trifluoroacetate to the properly arranged
carbon, resulting in the formation of trifluoroacetate deriva-
tive of 6 from I. The evolution of I0 (derived from 5) accord-
ing to a similar route would involve a much more unstable
TS due to the almost eclipsed (R/OTBDMS) interaction.
This proposal would involve an intramolecular attack of
the nucleophilic trifluoroacetate, thus contrasting with the
intermolecular attack proposed in Scheme 3. Some informa-
tion about these two possibilities could be obtained by study-
ing the reaction in the presence of external nucleophiles,
which would compete with CF3COꢀ2 only for the intermolec-
ular processes. Thus, we have performed the reaction of 4a
with TFAA and sym-collidine in the presence of tetrabutyl-
ammonium acetate (different concentrations were used). In
all the cases, compound 6a and their corresponding trifluoro-
acetate were exclusively formed, whereas the acetate of the
alcohol 6a was not detected in any experience. Taking into
account that CH3COꢀ2 has higher nucleophilic character
than CF3COꢀ2 , the absence of the acetate in the reaction
mixtures is not compatible with the intermolecular attack
proposed in Scheme 3.
were measured at 70 eV and 190 ꢁC. All described com-
pounds were over 97% pure by NMR analysis.
3.1.1. (2S,3S,Rs) tert-Butyl-3-(tert-butyldimethylsilyl-
oxy)-4-[(4-methylphenyl)sulfinyl]butan-2-ylcarbamate
(4a). A mixture of hydroxy sulfoxide 2a17a (0.96 g,
2.93 mmol, 1 equiv) tert-butyldimethylsilyl chloride
(3 equiv), imidazole (6 equiv), and 1 mL of anhydrous
DMF was stirred at room temperature for 48 h. Then, cold
water (60 mL) was added and the aqueous phase was ex-
tracted with CH2Cl2 (3ꢂ60 mL). The organic layers were
combined, washed with brine, dried (Na2SO4), and evapo-
rated. The crude product was purified by flash chromato-
graphy (hexane–ethyl acetate 80:20), to produce 1.15 g
(89%,) of 4a as a white sticky solid; [a]D +118.0 (c 1.0,
CHCl3); IR (CHCl3) nmax: 3455, 1709, 1599, 1497, 1368,
1
1165 cmꢀ1; H NMR (CDCl3, 300 MHz): d 0.13 (s, 3H),
0.20 (s, 3H), 0.94 (s, 9H), 1.08 (d, 3H, J 6.9), 1.43 (s, 9H),
2.41 (s, 3H), 2.64 (dd, 1H, J 9.0 and 12.9), 2.86 (dd, 1H, J
3.3 and 12.9), 3.74 (br m, 1H), 4.21 (br m, 1H), 4.52 (br d,
1H, J 6.9), 7.32 and 7.54 (AA0BB0 system, 4H); 13C NMR
(CDCl3, 75 MHz): d ꢀ4.5, ꢀ4.4, 15.1, 18.2, 21.4, 25.9,
28.4, 50.7, 63.8, 69.3, 79.5, 123.9, 130.0, 141.4, 141.5,
155.0; EIMS m/z 442 (1%, M++1), 384 (8), 368 (10), 328
(100), 310 (32), 246 (16), 206 (20), 144 (45), 139 (42),
123 (28), 88 (26), 57 (77). Anal. Calcd for C22H39NO4SSi:
C, 59.82; H, 8.90; N, 3.17. Found: C, 59.89; H, 8.87; N, 3.10.
In summary, we have shown that both (2S,3S)- and (2R,3S)-
3-amino-2-hydroxybutanoic acid (13a) and (14a) can be
synthesized in high optical purity from the readily available
b-keto sulfoxide 1a, by a sequence involving five steps: ste-
reodivergent reduction of 1a with DIBAH or DIBAH/ZnBr2,
protection of the resulting hydroxy sulfoxides, non-oxida-
tive Pummerer reactions, oxidation of the resulting primary
alcohols into acids and final deprotection. The efficiency of
the key step of the sequence, the non-oxidative Pummerer
reaction, is strongly dependent on the stereochemistry of
the starting g-amino sulfoxides.
3.1.2. (2S,3S,Rs) tert-Butyl-2-(tert-butyldimethylsilyl-
oxy)-5-methyl-1-[(4-methylphenyl)sulfinyl]hexan-3-yl-
carbamate (4b). Following the same procedure used for the
preparation of 4a, and starting from 0.369 g (1 mmol) of
2b,17c 0.417 g (92%) of 4b was obtained. The product was
purified by column chromatography (hexane–ethyl acetate
8:2), oil; [a]D +92.2 (c 1.0, CHCl3); IR (CHCl3) nmax: 3450,
1709, 1500, 1367, 1166 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
d 0.15 (s, 3H), 0.21 (s, 3H), 0.89 (d, 3H, J 6.6), 0.91 (d, 3H, J
6.9), 0.94 (s, 9H), 1.15–1.35 (m, 2H), 1.43 (s, 9H), 1.55–1.75
(m, 1H), 2.42 (s, 3H), 2.66 (dd, 1H, J 9.0 and 12.9), 2.83 (dd,
1H, J 2.1 and 13.2), 3.74 (br m, 1H), 4.17 (m, 1H), 4.31 (br d,
1H, J 9.3), 7.32 and 7.55 (AA0BB0 system, 4H); 13C NMR
(CDCl3, 75 MHz): d ꢀ4.5, ꢀ4.3, 18.2, 21.4, 21.6, 23.6,
24.6, 25.9, 28.3, 39.1, 53.1, 63.6, 69.6, 79.3, 123.9, 130.0,
141.3, 141.4, 155.3.
3. Experimental section
3.1. General methods
All moisture sensitive reactions were carried out in flame
dried glassware under argon atmosphere and monitored by
TLC. Flash chromatography was performed with silica gel
60 (230–400 mesh ASTM). Melting points were determined
in a Culatti melting point apparatus in open capillary tubes
and are uncorrected. The optical rotations were measured
at room temperature (20–23 ꢁC) using a Perkin–Elmer 343
polarimeter (concentration in g/100 mL). The IR spectra
were recorded in a FTIR Bruker Tensor 27 spectrophotome-
ter. The NMR spectra were determined in CDCl3 solutions
unless otherwise indicated at 200 (or 300) and 50.3 (or
3.1.3. (2S,3R,Rs) tert-Butyl-3-(tert-butyldimethylsilyl-
oxy)-1-[(4-methylphenyl)sulfinyl]butan-2-ylcarbamate
(5a). Following the same procedure used for the preparation
of 4a, and starting from 0.96 g (2.93 mmol) of 3a,17a 1.2 g
(93%) of 5a was obtained. The product was purified by
column chromatography (hexane–ethyl acetate 75:25), mp
152–154 ꢁC (CH2Cl2–hexane); [a]D +117.0 (c 1.0, CHCl3);
1
75.5) MHz for H and 13C NMR, respectively. J values are
1
given in hertz. The diastereoisomeric excesses were deter-
mined by 300 MHz H NMR spectroscopy. Mass spectra
IR (CHCl3) nmax: 3447, 1702, 1498, 1367, 1165 cmꢀ1; H
1
NMR (CDCl3, 300 MHz) (major rotamer): d 0.10 (s, 6H),

R. Saꢀnchez-Obregoꢀn et al. / Tetrahedron 63 (2007) 10521–10527
10525
0.88 (s, 9H), 1.21 (d, 3H, J 6.9), 1.46 (s, 9H), 2.40 (s, 3H),
2.69–2.98 (m, 2H), 4.06–4.26 (br m, 2H), 4.69 (br d, 1H),
7.30 and 7.56 (AA0BB0 system, 4H); (minor rotamer):
d 0.17 (s, 3H), 0.26 (s, 3H), 0.95 (s, 9H), 1.13 (d, 3H, J 6.9),
1.41 (s, 9H), 2.41 (s, 3H), 2.69–2.98 (m, 2H), 4.06–4.26 (br
m, 2H), 4.69 (br d, 1H), 7.32 and 7.51 (AA0BB0 system, 4H);
13C NMR (CDCl3, 75 MHz) (major rotamer): d ꢀ4.8, ꢀ4.3,
17.9, 18.5, 21.4, 25.8, 28.4, 48.3, 63.6, 70.3, 79.4, 123.9,
129.9, 140.9, 141.4, 155.6; (minor rotamer): d ꢀ4.8, ꢀ4.2,
17.9, 18.2, 21.4, 26.0, 28.4, 50.5, 63.8, 69.1, 79.4, 123.9,
130.0, 140.9, 141.4, 155.3. Anal. Calcd for C22H39NO4SSi:
C, 59.82; H, 8.90; N, 3.17. Found: C, 59.69; H, 8.98; N, 3.03.
anhydride (3.5 mL, 25.2 mmol, 10.5 equiv) were added.
The solution was allowed to reach room temperature and
stirred for 22 h. Then 60 mL of 10% NaHCO3 was added
and the resulting mixture was vigorously stirred for 20 h.
The mixture was extracted with Et2O (4ꢂ50 mL). The or-
ganic phase was separated, washed with 5% HCl (50 mL),
saturated NaHCO3 (2ꢂ50 mL), brine (50 mL), dried, and
concentrated. The product was purified by column chroma-
tography (hexane–ethyl acetate 85:15) to produce 0.946 g
(81%) of 6b as a colorless oil; [a]D ꢀ45.3 (c 1.0, CHCl3);
IR (CHCl3) nmax: 3500, 2956, 2860, 1704, 1675, 1468,
1367, 1296, 1163, 1118 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
d 0.06 (s, 3H), 0.09 (s, 3H), 0.83 (d, 6H, J 6.3), 0.90 (s, 9H),
1.30–1.80 (m, 3H), 1.53 (s, 9H), 2.33 (s, 3H), 3.35 (br s, 2H),
3.54–3.80 (m, 2H), 4.43 (br t, 1H. J 9.6), 7.12 and 7.38
(AA0BB0 system, 4H); 13C NMR (CDCl3, 75 MHz):
d ꢀ4.6, ꢀ4.2, 18.1, 21.1, 21.3, 23.5, 24.7, 25.9, 28.1, 38.2,
58.8, 63.3, 73.6, 82.3, 129.3, 129.6, 135.5, 138.2, 158.1.
3.1.4. (2R,3S,Rs) tert-Butyl-2-(tert-butyldimethylsilyl-
oxy)-5-methyl-1-[(4-methylphenyl)sulfinyl]hexan-3-yl-
carbamate (5b). Following the same procedure used for the
preparation of 4a, and starting from 1.011 g (2.74 mmol) of
3b,17c 1.225 g (93%) of 5b was obtained. The product was
purified by column chromatography (hexane–ethyl acetate
85:15), mp 81–82 ꢁC (CH2Cl2–hexane); [a]D +98.4 (c 1.0,
CHCl3); IR (CHCl3) nmax: 3446, 1701, 1499, 1367,
3.1.7. (2S,3R) tert-Butyl-3-(tert-butyldimethylsilyloxy)-4-
hydroxybutan-2-yl-[(4-methylphenyl)sulfenyl]carba-
mate (7a). To a cooled solution of 5a (0.93 g, 2.1 mmol,
1 equiv) in 30 mL of dry acetonitrile, sym-collidine
(0.83 mL, 6.3 mmol, 3 equiv) and trifluoroacetic anhydride
(1.48 mL, 10.5 mmol, 5 equiv) were added. The solution
was allowed to reach room temperature and stirred for 7
days. Then 50 mL of 10% NaHCO3 was added and the
resulting mixture was vigorously stirred for 48 h. After the
addition of water (50 mL), the mixture was extracted with
Et2O (4ꢂ50 mL). The organic phase was separated, washed
with 5% HCl (50 mL), saturated NaHCO3 (50 mL), brine
(50 mL), dried, and evaporated. The product was purified
by column chromatography (hexane–ethyl acetate 8:2) to
produce 0.232 g (25%) of 7a as colorless oil; [a]D ꢀ77.6
(c 1.0, CHCl3); IR (CHCl3) nmax: 3478, 2930, 2858, 1702,
1
1166 cmꢀ1; H NMR (CDCl3, 300 MHz): d 0.10 (s, 6H),
0.87 (s, 9H), 0.95 (d, 6H, J 6.3), 1.20–1.75 (m, 3H), 1.45
(s, 9H), 2.39 (s, 3H), 2.74 (dd, 1H, J 3.0 and 12.9), 2.91 (dd,
1H, J 10.2 and 12.9), 4.05–4.20 (m, 2H), 4.62 (br d, 1H, J
9.6), 7.28 and 7.57 (AA0BB0 system, 4H); 13C NMR (CDCl3,
75 MHz): d ꢀ4.7, ꢀ4.2, 17.9, 21.3, 22.1, 23.2, 24.9, 25.8,
28.4, 41.9, 50.8, 63.9, 69.8, 79.3, 123.9, 129.8, 141.1,
141.2, 156.0.
3.1.5. (2S,3S) tert-Butyl-3-(tert-butyldimethylsilyloxy)-4-
hydroxybutan-2-yl-[(4-methylphenyl)sulfenyl]carba-
mate (6a). To a cooled solution of 4a (0.93 g, 2.1 mmol,
1 equiv) in 30 mL of dry acetonitrile, sym-collidine
(0.83 mL, 6.3 mmol, 3 equiv) and trifluoroacetic anhydride
(1.48 mL, 10.5 mmol, 5 equiv) were added. The solution
was allowed to reach room temperature and stirred for
48 h. Then 50 mL of 10% NaHCO3 was added and the re-
sulting mixture was vigorously stirred for 48 h. After the ad-
dition of water (50 mL), the mixture was extracted with Et2O
(4ꢂ50 mL). The organic phase was separated, washed with
5% HCl (50 mL), saturated NaHCO3 (2ꢂ50 mL), brine
(50 mL), dried, and concentrated. The residue was purified
by column chromatography eluting with hexane–ethyl ace-
tate 9:1 to produce 0.80 g (86%) of 6a as a colorless oil;
[a]D ꢀ51.6 (c 1.0, CHCl3); IR (CHCl3) nmax: 3485, 2929,
2857, 1700, 1679, 1460, 1368, 1299, 1163 cmꢀ1; 1H NMR
(CDCl3, 300 MHz): d 0.08 (s, 3H), 0.09 (s, 3H), 0.90 (s,
9H), 1.21 (d, 3H, J 6.8), 1.48 (s, 9H), 2.32 (s, 3H), 3.43
(br d, 2H, J 2.3), 3.69 (td, 1H, J 2.7 and 8.7), 4.49 (qd, 1H,
J 6.8 and 8.7), 7.11 and 7.19 (AA0BB0 system, 4H); 13C
NMR (CDCl3, 75 MHz): d ꢀ4.6, ꢀ4.3, 15.9, 18.1, 21.0,
25.9, 28.1, 56.5, 63.3, 74.4, 82.3, 126.1, 129.5, 136.2,
136.8, 157.6; EIMS m/z 442 (3%, M++1), 441 (2), 386 (6),
368 (6), 328 (54), 284 (43), 166 (100), 123 (34), 57 (33).
Anal. Calcd for C22H39NO4SSi: C, 59.82; H, 8.90; N,
3.17. Found: C, 59.99; H, 8.97; N, 3.22.
1671, 1469, 1368, 1311, 1162 cmꢀ1 1H NMR (CDCl3,
;
300 MHz): d 0.08 (s, 3H), 0.11 (s, 3H), 0.93 (s, 9H), 1.24
(d, 3H, J 6.9), 1.42 (s, 9H), 2.31 (s, 3H), 3.36 (dd, 1H, J
7.5 and 11.9), 3.49 (dd, 1H, J 4.2 and 11.9) 3.74 (dt, 1H, J
4.1 and 7.6), 4.69 (dq, 1H, J 4.1 and 6.9), 7.08 (A2B2 system,
4H); 13C NMR (CDCl3, 75 MHz): d ꢀ4.8, ꢀ4.4, 15.8, 18.0,
21.0, 25.8, 28.0, 54.8, 63.1, 75.5, 82.2, 124.0, 129.3, 135.6,
137.4, 158.4. Anal. Calcd for C22H39NO4SSi: C, 59.82; H,
8.90; N, 3.17. Found: C, 59.72; H, 8.65; N, 3.28.
3.1.8. (2S,3S) tert-Butyl-3-(tert-butyldimethylsilyloxy)-4-
oxobutan-2-yl-[(4-methylphenyl)sulfenyl]carbamate
(8a). To a solution of 6a (0.441 g, 1 mmol, 1 equiv) in 15 mL
of CH2Cl2, freshly prepared pyridinium chlorochromate
(0.323 g, 1.5 mmol, 1.5 equiv) was added. The mixture
was stirred at room temperature for 30 h. After filtration
the solvent was removed under vacuum. The product was
purified by column chromatography (hexane–ethyl acetate
95:5) to produce 0.337 g (77%) of 8a as colorless oil; [a]D
ꢀ43.4 (c 0.5, CHCl3); IR (film) nmax: 2932, 2859, 1733,
1701, 1468, 1368, 1298, 1163 cmꢀ1 1H NMR (CDCl3,
;
300 MHz): d 0.05 (s, 3H), 0.08 (s, 3H), 0.92 (s, 9H), 1.21
(d, 3H, J 6.7), 1.45 (s, 9H), 2.31 (s, 3H), 4.00 (dd, 1H, J
2.3 and 6.7), 4.66 (qd, 1H, J 6.7 and 6.7), 7.13 (A2B2 system,
4H), 9.55 (d, 1H, J 2.3); 13C NMR (CDCl3, 75 MHz):
d ꢀ5.0, ꢀ4.7, 14.7, 18.1, 21.0, 25.7, 28.0, 57.8, 79.2, 82.2,
125.2, 129.5, 136.4 (2C), 156.7, 202.1; EIMS m/z 439
(1%, M+), 384 (5), 326 (15), 298 (14), 166 (100), 123
3.1.6. (2S,3S) tert-Butyl-2-(tert-butyldimethylsilyloxy)-1-
hydroxy-5-methylhexan-3-yl-[(4-methylphenyl)sulfenyl]-
carbamate (6b). To a cooled solution of 4b (1.164 g,
2.4 mmol, 1 equiv) in 120 mL of dry acetonitrile, sym-
collidine (3 mL, 22.7 mmol, 9.5 equiv) and trifluoroacetic

10526
R. Saꢀnchez-Obregoꢀn et al. / Tetrahedron 63 (2007) 10521–10527
(34), 57 (33). Anal. Calcd for C22H37NO4SSi: C, 60.10; H,
8.48; N, 3.19. Found: C, 59.97; H, 8.77; N, 3.11.
3.1.12. (2R,3S)-3-Amino-2-hydroxybutanoic acid hydro-
chloride (11a). Following the same procedure used for
the preparation of 10a, and starting from 0.107 g
(0.24 mmol) of 9a, 0.029 g (76%,) of 11a was obtained as
a white gummy solid. 1H NMR (D2O positioned at
4.78 ppm, 300 MHz): d 1.37 (d, 3H, J 6.6), 3.65–3.76 (m,
1H), 4.31 (d, 1H, J 5.1).
3.1.9. (2S,3S) tert-Butyl-2-(tert-butyldimethylsilyloxy)-5-
methyl-1-oxohexan-3-yl-[(4-methylphenyl)sulfenyl]car-
bamate (8b). Following the same procedure used for the
preparation of 8a, and starting from 0.460 g (0.95 mmol)
of 6b, 0.340 g (74%) of 8b was obtained. The product was
purified by column chromatography (hexane–ethyl acetate
85:15). Colorless oil; [a]D ꢀ52.0 (c 1.0, CHCl3); IR
(CHCl3) nmax: 2932, 2861, 1730 (sh), 1704, 1468, 1368,
3.1.13. (2S,3S)-Methyl 3-[tert-butoxycarbonyl-[(4-methyl-
phenyl)sulfenyl]amino]-5-methylhexanoate (12b). A stirred
solution of the aldehyde 8b (0.336 g, 0.70 mmol) in 3 mL of
acetone at ꢀ15 ꢁC was treated with 1.5 mL of Jones reagent.
After being stirred at this temperature for 1 h and at room tem-
perature for 24 h, the mixture was diluted with water and ex-
tracted with ether (4ꢂ10 mL). The organic layer was washed
with brine (3ꢂ10 mL), dried, and concentrated. The residue
was treated with an excess of ethereal solution of diazome-
thane. The crude product was purified by preparative thin layer
chromatography (hexane–ethyl acetate 95:5) to produce
0.265 g (74%) of 12b. [a]D ꢀ46.0 (c 0.4, CHCl3); IR (film)
nmax: 2955, 2931, 2860, 1738, 1705, 1469, 1367, 1294,
1
1297, 1163 cmꢀ1; H NMR (CDCl3, 300 MHz): d 0.04 (s,
3H), 0.07 (s, 3H), 0.83 (d, 3H, J 6.0), 0.90 (d, 3H, J 6.0),
0.91 (s, 9H), 1.22–1.75 (m, 3H), 1.47 (s, 9H), 2.31 (s, 3H),
3.89 (dd, 1H, J 2.4 and 7.5), 4.63 (br t, 1H. J 7.8), 7.09
and 7.29 (AA0BB0 system, 4H), 9.55 (br s, 1H); 13C NMR
(CDCl3, 75 MHz): d ꢀ5.0, ꢀ4.7, 18.1, 21.1, 21.7, 23.0, 24.6,
25.7, 28.1, 37.7, 61.7, 78.3, 82.1, 127.5, 129.5, 135.5, 137.4,
157.3, 202.0; EIMS m/z 481 (1%, M+), 368 (26), 308 (11),
200 (100), 185 (17), 123 (19), 117 (13), 73 (20), 57 (48).
1
3.1.10. (2S,3R) tert-Butyl-3-(tert-butyldimethylsilyloxy)-
4-oxobutan-2-yl-[(4-methylphenyl)sulfenyl]carbamate
(9a). Following the same procedure used for the preparation
of 8a, and starting from 0.236 g (0.53 mmol) of 7a, 0.083 g
(35%) of 9a was obtained. The product was purified by
column chromatography (hexane–ethyl acetate 9:1). White
crystals, mp 80–81 ꢁC (CH2Cl2–hexane); [a]D ꢀ14.3 (c 1,
CHCl3); IR (film) nmax: 2931, 2858, 1736, 1703, 1470,
1162 cmꢀ1; H NMR (CDCl3, 500 MHz): d 0.04 (s, 3H),
0.06 (s, 3H), 0.52 (br d, 3H), 0.80 (d, 3H, J 6.5), 0.91 (s,
9H), 1.20–1.40 (m, 2H), 1.50 (s, 9H), 1.72 (m, 1H), 2.32 (s,
3H), 3.63 (s, 3H), 4.29 (d, 1H, J 8.0), 4.51 (m, 1H), 7.10
and 7.30 (AA0BB0 system, 4H); 13C NMR (CDCl3,
75 MHz): d ꢀ5.3, ꢀ5.1, 18.2, 21.1, 21.5, 23.1, 24.6, 25.7,
28.1, 37.7, 51.7, 61.8, 73.6, 81.9, 128.0, 129.3, 136.1, 137.2,
157.2, 172.6. Anal. Calcd for C26H45NO5SSi: C, 61.02; H,
8.90; N, 2.74. Found: C, 60.76; H, 8.95; N, 2.70.
1368, 1295, 1164 cmꢀ1 1H NMR (CDCl3, 300 MHz):
;
d 0.07 (s, 3H), 0.12 (s, 3H), 0.93 (s, 9H), 1.15 (d, 3H, J
6.9), 1.45 (s, 9H), 2.31 (s, 3H), 4.01 (dd, 1H, J 2.7 and
6.9), 4.68 (qd, 1H, J 6.9 and 6.9), 7.11 (s, 4H), 9.58 (d,
1H, J 2.7); 13C NMR (CDCl3, 75 MHz): d ꢀ4.9, ꢀ4.4,
15.2, 18.1, 21.0, 25.7, 28.1, 56.3, 79.9, 82.0, 124.7, 129.5,
136.1, 136.8, 156.8, 201.8. Anal. Calcd for C22H37NO4SSi:
C, 60.10; H, 8.48; N, 3.19. Found: C, 60.24; H, 8.53; N, 3.17.
3.1.14. (2S,3S)-3-Amino-2-hydroxybutanoic acid (13a).
Prepared from 10a (0.040 g, 0.26 mmol), using a Varian
Bond Elut SCX column and a 2 M solution of NH3 in meth-
anol as eluant. Further purification was performed by silica
gel chromatography using methanol–isopropanol–ammoni-
um hydroxide 1:1:0.5, to produce 0.030 g (96%) of 13a.
Amorphous white solid, mp 239–241 ꢁC (lit.20 242–
243 ꢁC; lit.21 240–241 ꢁC); [a]D ꢀ25.2 (c 1, H2O) [(lit.20
3.1.11. (2S,3S)-3-Amino-2-hydroxybutanoic acid hydro-
chloride (10a). To a stirred mixture of the aldehyde 8a
(0.337 g, 0.77 mmol, 1 equiv), 2-methyl-2-propanol
(5 mL) and a 5% aqueous solution of NaH2PO4 (3 mL)
a 1 M aqueous solution of KMnO4 (4.5 mL, 4.5 mmol,
5.8 equiv) was added at room temperature. After 10 min,
the excess of KMnO4 was decomposed by adding 10%
Na2SO3 solution, the mixture was cooled at 0 ꢁC and acidi-
fied with 10% HCl until pH 4–5. The reaction mixture was
extracted with Et2O (4ꢂ15 mL). The combined organic ex-
tracts were washed with brine, dried, and concentrated under
vacuum, to give 0.327 g of the corresponding crude acid.
Without further purification, to this crude product a saturated
ethereal hydrogen chloride solution (20 mL) was added. The
starting deep yellow solution was becoming pale as small
white crystalline product was settling down in the ethereal
layer. After 6 h, the crystals were filtered, washed with anhy-
drous ether, and dried at vacuum to produce 0.050 g (42%)
of hygroscopic white crystals; [a]D ꢀ16.0 (c 0.5, H2O); IR
1
ꢀ26.15 (c 1.1, H2O); lit.21 ꢀ25.7 (c 1.1, H2O)]; H NMR
(D2O, DSS, 300 MHz): d 1.20 (d, 3H, J 6.6), 3.71 (m, 1H),
4.20 (d, 1H, J 3.3); 13C NMR (D2O, DSS, 75 MHz):
d 14.7, 52.4, 74.3, 179.5.
3.1.15. (2R,3S)-3-Amino-2-hydroxybutanoic acid (14a).
Prepared from 11a (0.029 g, 0.18 mmol), using a Varian
Bond Elut SCX column and a 2 M solution of NH3 in meth-
anol as eluant. Further purification was performed by silica
gel chromatography using methanol–isopropanol–ammoni-
um hydroxide 1:1:0.5, to produce 0.021 g (97%) of 14a.
Amorphous white solid; [a]D +22.0 (c 0.5, H2O) [(lit.20
+22.2 (c 0.46, H2O); lit.21 +21.6 (c 1.1, H2O); lit.22 +22.6
1
(c 0.5, H2O); lit.23 +23.5 (c 2, H2O)]; H NMR (D2O posi-
tioned at 4.68 ppm, 300 MHz): d 1.16 (d, 3H, J 6.6), 3.39
(dq, 1H, J 4.8 and 6.6), 3.85 (d, 1H, J 4.8); 13C NMR
(D2O, dioxane as external reference at 67.4 ppm,
75 MHz): d 15.3, 50.6, 73.5, 177.9.
1
(KBr) nmax: 3700–2300, 1735, 1585, 1481, 1202 cmꢀ1; H
NMR (D2O positioned at 4.67 ppm, 300 MHz): d 1.14 (d,
3H, J 6.6), 3.73 (dq, 1H, J 3.3 and 6.6), 4.40 (d, 1H, J
3.6); 13C NMR (D2O, dioxane as external reference at
67.4 ppm, 75 MHz): d 12.6, 49.8, 70.8, 174.9; HRMS
(FAB+) C4H10NO3 requires: 120.0660. Found: 120.0658.
Acknowledgements
ꢀ
ꢀ
ꢀ
We thank M. I. Chavez, E. Garcıa-Rıos, E. Huerta, R. Patin˜o,
ꢀ
ꢀ
M. A. Pen˜a, F. J. Perez, B. Quiroz, H. Rıos, L. Velasco, and

R. Saꢀnchez-Obregoꢀn et al. / Tetrahedron 63 (2007) 10521–10527
10527
Tetrahedron 1999, 55, 3025; (d) Crucianelli, M.; Bravo, P.;
Armone, A.; Corradi, E.; Meille, S. V.; Zanda, M. J. Org.
Chem. 2000, 65, 2965; (e) Pesenti, C.; Bravo, P.; Corradi, E.;
Frigerio, M.; Meille, S. V.; Panzeri, W.; Viani, F.; Zanda, M.
J. Org. Chem. 2001, 66, 5637; (f) Volonterio, A.; Bravo, P.;
Pesenti, C.; Zanda, M. Tetrahedron Lett. 2001, 42, 3985; (g)
Pesenti, C.; Armone, A.; Arosio, P.; Frigerio, M.; Meille,
S. V.; Panzeri, W.; Viani, F.; Zanda, M. Tetrahedron Lett.
2004, 45, 5125.
M. N. Zavala for their technical assistance. We also thank,
Dr. J. M. Muchowski for reviewing the manuscript. Finan-
cial support from Consejo Nacional de Ciencia
ꢀ
y
Tecnologıa, Conacyt-Mexico (41662-Q) and Ministerio de
ꢀ
Educacion y Ciencia of Spain (Grant CTQ-2006-06741/
ꢀ
BQU) is gratefully acknowledged.
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Taking into account that Zanda et al. have also isolated the
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butane intermediate resulting in the nitrogen attack seem to
be the most probable intermediate also for b-amino sulfoxides.
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