N-Hydroxymethyl derivatives of α-amino aldehydes used for the stereoselective syntheses of β-amino-α-hydroxy acids

Article abstract of DOI:10.1016/j.tetasy.2014.03.012

The N-hydroxymethyl derivatives of α-amino aldehydes 1 were utilized for the effective synthesis of several β-amino-α-hydroxy acid derivatives in a one-pot process starting from the corresponding α-amino aldehydes. Properly protected methyl esters 3 were

Full text of DOI:10.1016/j.tetasy.2014.03.012

Tetrahedron: Asymmetry 25 (2014) 625–631
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
N-Hydroxymethyl derivatives of
a-amino aldehydes used
for the stereoselective syntheses of b-amino-
a-hydroxy acids
⇑
Youngran Seo, Hyeonjeong Kim, Da Won Chae, Young Gyu Kim
Department of Chemical and Biological Engineering, Seoul National University, Seoul 151-744, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 January 2014
Accepted 13 March 2014
The N-hydroxymethyl derivatives of
a
-amino aldehydes 1 were utilized for the effective synthesis of sev-
-amino
-amino aldehyde
derivatives 1 with more than 20:1 stereoselectivity. The application of suitably protected b-amino-
eral b-amino-
a-hydroxy acid derivatives in a one-pot process starting from the corresponding a
aldehydes. Properly protected methyl esters 3 were prepared in 65–79% yields from
a
a-
hydroxy esters was shown by an efficient synthesis of the bioactive peptide, bestatin, and its more potent
analogue, AHPBA-Val, in high yields from ent-3a.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
We have reported that an N-hydroxymethyl group bonded to an
amino group of
nucleophile for the stereoselective syntheses of several
b-hydroxy acids and their analogues7 as well as a stabilizer of labile
-amino aldehydes.8 Due to the simplicity and diverse utility of the
N-hydroxymethyl derivatives of -amino aldehydes, we have at-
tempted to extend their application for the efficient and stereose-
lective syntheses of b-amino- -hydroxy acids, which have been
synthesized mostly via reagent-controlled synthetic methods such
as the asymmetric aminohydroxylations,9 the selective opening of
a chiral epoxide,10 and asymmetric Mannich reactions.11
a
-amino aldehydes can be useful as an internal
The development of efficient synthetic methods for preparing
b-amino-a-hydroxy acids has been an attractive subject since
c
-amino-
non-proteinogenic amino acids have been frequently found in
a
biologically active natural products.1 For example, typical b-ami-
a
no-a-hydroxy acid units are embedded in the anticancer and anti-
bacterial agent bestatin,2 the aminopeptidase inhibitor amastatin,3
the glutamate transporter blocker threo-b-benzyloxyaspartic acid
(TBOA),4 and the anticancer paclitaxel5 (Fig. 1). Some b-amino-
a
a
-hydroxy acids have also been used as chiral synthons or
auxiliaries.6
O
2. Results and discussion
OH
AcO
O
Ph
NH
O
NH2
O
In our previous reports, natural c-amino-b-hydroxy acids and
their derivatives have been synthesized via stereoselective intra-
molecular conjugate additions of the N-hydroxymethyl group in
Ph
O
Bn
N
H
CO2H
O
OH
O
H
OH
OAc
HO
paclitaxel
A toward
c-amino-a,b-unsaturated esters, which were prepared
OBz
from
a-amino aldehyde 1 by Wittig-type olefination reactions
bestatin
NH2
CO2H
(Scheme 1a).7
CO2H
For efficient syntheses of b-amino-a-hydroxy acids using a sim-
NH2
O
H
N
HO2C
ilar method, we needed a one less carbon Michael acceptor for the
N-hydroxymethyl group than the ,b-unsaturated ester group of A
(Scheme 1a and b). We envisioned that either a -amino-
b-unsaturated nitro group of B1 or a -amino- ,b-unsaturated
i-Bu
N
H
N
H
CO2H
a
OBn
L-TBOA
Figure 1. b-Amino-
OH
O
c
a,
c
a
amastatin
-hydroxy acid units in natural products.
arylsulfoxide group of C1 would undergo facile conjugate additions
with the N-hydroxymethyl group to give the desired key interme-
diate B2 or C2, respectively. Next, the nitromethyl group of B2 or
the arylsulfinylmethyl group of C2, obtained via intramolecular
conjugate addition, could be easily transformed into a carboxylic
a
⇑
Corresponding author. Tel.: +82 2 880 8347; fax: +82 2 885 6989.
E-mail address: ygkim@snu.ac.kr (Y.G. Kim).
http://dx.doi.org/10.1016/j.tetasy.2014.03.012
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

626
Y. Seo et al. / Tetrahedron: Asymmetry 25 (2014) 625–631
P
R
conjugate
addition
Nef
NH2
P
R
NH2
N
reaction
N
OH
O
CO2H
R
CO2H
R
NO2
OH
OH
NO2
B1
γ-amino-α,β-unsaturated nitro group
B2
γ-amino-β-hydroxy acids
β-amino-α-hydroxy acids
Henry reaction
Pummerer
rearrangement
and dehydration
P
R
conjugate
addition
P
P
R
P
P
R
N
N
OH
olefination
CO2Me
N
OH
H
olefination
N
OH
N
O
O
R
S(O)Ph
O
R
S
OH
A
O
C1
γ-amino-α,β-unsaturated sulfoxide
γ
α β
-amino- , -unsaturated ester
C2
Ph
1
(a) previous syntheses of γ-amino-β-hydroxy acids
(b) retrosynthetic analysis of β-amino-α-hydroxy acids
Scheme 1. Synthetic strategy.
acid or an aldehyde moiety via the Nef reaction12 or the Pummerer
rearrangement,13 respectively, (Scheme 1b).
Our initial efforts to prepare key intermediate B1 or C1 were not
successful. For the installation of the a,b-unsaturated arylsulfoxide
group in C1, an olefination reaction of 1a (P = Boc, R = CH2Ph) was
attempted with (diethylphosphoryl)methylphenylsulfoxide14 or
with trimethylsilylmethylphenylsulfoxide (not shown).15 How-
ever, neither of the desired intermediates with a phenylsulfinyl
group of C1 or C2 (Scheme 1b) was produced.
Boc
Bn
Boc
Bn
Boc
Bn
N
N
N
O
PhSO2CH2NO2
DMAP, 57%
O
BNAH, MW
62%
O
NO2
OH
NO2
PhO2S
2a
O3, DBU
1a
4a
MeOH, -78 °C
85%
KMnO4
The introduction of another potent Michael acceptor, a nitroole-
fin group, was attempted to obtain B1 (Scheme 1b). The Henry (ni-
tro-aldol) reaction16 of 1a with nitromethane (CH3NO2) under
conventional reaction conditions produced a nitro-aldol adduct
without the required N-hydroxymethyl group.17 We have previ-
ously observed that an N-hydroxymethyl group bonded to an ami-
no group could be readily removed under basic or acidic
conditions.8a In order to overcome the elimination issue of the N-
hydroxymethyl group, probably caused by the basic conditions of
the nitro-aldol reaction, we thought that a more reactive derivative
of CH3NO2 was needed in order to produce the desired nitroolefin
group in situ from facile dehydration of the initial nitro-aldol
intermediate.
Boc
Boc
Bn
HCl NH2
Bn
N
N
3M HCl, 80 °C
92%
MeI, K2CO3
70% from 4a
O
O
CO2H
Bn
OH
(2R,3S)-AHPBA
Scheme 2. b-Amino-
CO2Me
CO2H
3a
5a
a
-hydroxy acids by a stepwise process.
to ꢀ78 °C),19 where 3a was obtained from 2a in 85% yield
(Scheme 2). No peaks from the minor isomer were seen in either
the GC or 1H NMR charts of 3a. The stereochemistry of 3a was as-
sumed to be trans based on our previous reports on the conjugate
addition of the N-hydroxymethyl group to the a,b-unsaturated es-
ter group, in which the trans-oxazolidines were obtained from a fa-
vored H-eclipsed allylic conformation in the transition state.7,20
The NMR coupling constants of the oxazolidine ring of 3a were
not useful for determining its relative stereochemistry because of
the flexible conformation of 3a. Finally, the stereochemistry of 3a
Among the activated nitromethane derivatives known in the lit-
erature,18 phenylsulfonylnitromethane (PhSO2CH2NO2) was well
suited for our purpose with some modification of the reported
reaction conditions. Initially, none of the desired nitro-aldol prod-
ucts were produced with a dianion of phenylsulfonylnitromethane,
prepared by treatment of phenylsulfonylnitromethane with LDA
(3 equiv) at low temperature.18b Other bases such as BuLi, KHMDS,
K2CO3, or Cs2CO3 did not help, nor did the use of a monoanion of
phenylsulfonylnitromethane, with only the starting materials
being recovered after the reactions.
When the base was changed to TEA, some of the adduct with a
phenylsulfonylnitromethane group was produced in low yield as a
diastereomeric mixture (approximately a 2:1 ratio by its 1H NMR
spectrum). Among the amine bases tested, such as TEA, DMAP, pyr-
idine, N-methylmorpholine, and DBU, the highest yield (57%) of the
diastereomeric adduct was obtained with DMAP. In the 1H NMR
spectrum of the adduct, no double bond seemed to be present. A
downfield shift of the methine proton at approximately 5.5 ppm
was typical for protons at the carbon of phenylsulfonylnitrome-
thane and its coupling pattern of doublets seemed to indicate the
presence of a cyclized product 2a (Scheme 2).
was confirmed after conversion into a known b-amino-a-hydroxy
acid, (2R,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid (AHPBA)
as its HCl salt after global deprotection of the protecting groups
of 3a under acidic conditions (Scheme 3). Its spectroscopic and
physical data, as well as the enantiomeric purity matched well
with those reported in the literature.21
Boc
Boc
NH2
HCl
i-Bu
PhSO2CH2NO2;
N
N
3 M HCl
88%
O
O
CO2H
O3, MeOH, -78 °C
R
R
OH
(2R,3S)-AHMHA
CO2Me
OH
1
3
3a R = Bn (72%); 3b R = i-Bu (69%);
3c R = i-Pr (65%); 3d R = Me (67%);
3e R = CH2OTBS (79%).
Scheme 3. b-Amino-a-hydroxy acids by a one-pot process.
Both the structure and stereochemistry of adduct 2a were
established after oxidation of the phenylsulfonylnitromethyl group
of 2a into the carboxylic ester group of 3a at low temperature (ꢀ98
Additional evidence about the stereochemistry and the stere-
oselectivity of 2a was obtained after reduction of the phen-

Y. Seo et al. / Tetrahedron: Asymmetry 25 (2014) 625–631
OH
627
ylsulfonylnitromethyl group of 2a into the nitromethyl group of 4a
OH
Boc
with N-benzylnicotinamide (BNAH) under microwave (MW) irra-
diation (Scheme 2).22 Again, the minor isomer was not detected
in either the GC or 1H NMR charts of 4a. The following two-step
transformation23 of 4a into 3a via 5a supported the stereoselective
formation of 2a.
- H2O
Boc
Bn
N
SO2Ph
NO2
N
SO2Ph
NO2
Bn
OH
6a
7a
The efficiency of the transformation of 1a into 3a could be fur-
ther improved upon by an in situ oxidation of the diastereomeric
adduct 2a without its isolation. Thus, methyl ester 3a was pro-
duced in 72% yield from a-amino aldehyde 1a in a one-pot process
(Scheme 3), which gave a much higher yield than that of the step-
Boc
Bn
Boc
Bn
N
N
O
PhSO2CH2NO2
DMAP
O
wise process in Scheme 2 (overall 48% yield).
NO2
OH
PhO2S
2a
The one-pot process was also successfully applied to other
1a
a
-amino aldehydes, which were derived from commercially avail-
able -amino acids (Scheme 3). The methyl ester derivatives of
b-amino- -hydroxy acid 3b–3e were obtained in 65% to 79% yields
a
Scheme 4. Proposed sequential reaction mechanism for 2a from 1a and
a
PhSO2CH2NO2.
with more than 20:1 stereoselectivity by following a one-pot pro-
cedure. Most of the reaction conditions were the same as those for
the phenylalaninal derivative 1a, as described above, except for the
valinal derivative 3c, with which a higher reaction temperature of
50 °C instead of room temperature was required at the aldol con-
densation stage. Both the structure and stereochemistry of 3b–3e
were assigned by analogy to that of 3a.
nearly one isomer. The selectivity for the trans-oxazolidine ring
could be explained as proposed in the previous reports regarding
the intramolecular conjugate addition of the N-hydroxymethyl
group to an
a
,b-unsaturated ester group.7a The much improved
selectivity herein can be attributed to the considerably favored
H-eclipsed conformation in the transition state because of the in-
creased allylic (A1,3) strain from the bulkier cis-substitutent on
the olefin (either SO2Ph or NO2) in the (R)-eclipsed conformation.20
A similar enhanced selectivity has previously been observed in the
Further proof for the structural assignment of 3b was also pro-
vided by the transformation of 3b into a known b-amino-a-hydro-
xy acid unit in amastatin as a HCl salt of its enantiomer (Scheme 3),
and (2R,3S)-3-amino-2-hydroxy-5-methylhexanoic acid, (2R,3S)-
AHMHA, was produced in 88% yield via hydrolysis of 3b by follow-
ing the same global deprotection protocol as described for 3a,
whose spectroscopic and specific rotation data were nearly identi-
cal with those reported in the literature.24
Based on our structural investigation of 2a, we propose that the
desired oxazolidine 2a is probably produced from an intramolecu-
lar conjugate addition of the N-hydroxymethyl group to the acti-
vated nitroolefin of 7a, which was generated in turn by the facile
dehydration of the resulting nitro-aldol intermediate 6a
(Scheme 4). The possibility of the direct cyclization of 6a into 2a
was excluded based on the basic reaction conditions, under which
an SN2 reaction between the N-hydroxymethyl group and the b-hy-
droxy group of 6a seems difficult.
stereoselective synthesis of threo-b-hydroxy-L-glutamic acid, when
the stereochemistry of the conjugated ester group was changed
from an E- to a Z-olefin.7d
In order to demonstrate the utility of the properly protected
form of b-amino-
tiomer of 3a, ent-3a, from commercially available N-Boc-
a
-hydroxy acids 3, we also synthesized an enan-
-phenyl-
D
alanine according to the same protocol as shown in Scheme 3 (66%
yield from ent-1a, not shown). A simple peptide coupling of free
carboxylic acid ent-5a, produced via basic hydrolysis of ent-3a,
with L-leucine methyl ester (L-Leu-OMe), and then the following
hydrolysis gave bestatin as its TFA salt (Scheme 5). Thus, a known
dipeptide bestatin was obtained in high yield (92%) without sepa-
rate protection and/or deprotection steps. Its spectroscopic and
physical data were identical with those in the literature.2a Further-
more, a bestatin analogue, AHPBA-Val, was also synthesized by fol-
lowing the same synthetic process (Scheme 5); this has been
reported to be a more potent aminopeptidase inhibitor compared
to bestatin.25
Therefore, the three sequential reactions, that is, the nitro-aldol,
the dehydration, and the intramolecular conjugate addition reac-
tions, must occur in just one step from 1a to 2a (Scheme 4). Other
points to note here are that the dehydration reaction from 6a to 7a
did not require any additives, acids or good leaving groups, and
that a separate conjugate addition step from 7a to 2a was not re-
3. Conclusion
quired, as was necessary with the
a,b-unsaturated ester group
for the syntheses of
c
-amino-b-hydroxy acids.7
In conclusion, we have developed a novel and efficient synthetic
High stereoselectivity seemed to be achieved in the intramolec-
ular conjugate addition of 7a into 2a because only two out of the
four possible isomers were notable in the 1H NMR spectrum of
2a. The absence of the minor cis-isomer in both the GC and 1H
NMR charts of 3a suggested that an excellent selectivity (more
than 20:1) was attained in the intramolecular conjugate addition
of the N-hydroxymethyl group of 7a to give the trans-isomer as
method for preparing b-amino-
tives from the corresponding
N-hydroxymethyl group. The desired b-amino-
derivatives 3 were produced with high stereoselectivity in a one-
pot process from the reactions of -amino aldehydes with the
a
a
-hydroxy acids and their deriva-
-amino aldehydes by utilizing an
-hydroxy acid
a
a
N-hydroxymethyl group and phenylsulfonylnitromethane in the
presence of an amine base, followed by in situ oxidation. Thus,
Boc
Bn
N
Boc
Bn
Boc
Bn
TFA
Bn
O
NH2
O
R
N
N
L-Leu-OMe, or
L-Val O-Me
2M NaOH
92%
2M NaOH;
TFA
O
O
N
H
CO2H
NH
O
CO2Me
CO2H
OH
CO2Me
R
Bestatin·TFA R = i-Bu, (quant.)
ent-3a
66% from ent-
ent-5a
8 R = i-Bu (92%)
AHPBA-Val·TFA R = i-Pr, (93%)
1a
9 R = i-Pr (72%)
Scheme 5. Syntheses of bestatin and its potent derivative, AHPBA-Val.

628
Y. Seo et al. / Tetrahedron: Asymmetry 25 (2014) 625–631
the protected b-amino-
from the corresponding
yields with more than 20:1 stereoselectivity in one reaction flask.
Both the absolute and relative configurations of 3a and 3b were
established beyond doubt after a one-step acidic hydrolysis into
a
-hydroxy esters 3a–3e were prepared
-amino aldehydes 1a–1e in 65–79%
5.03 (br s, 1H), 5.40 (d, 1H, J = 9.3, HC(NO2)SO2Ph), 7.05–7.93
a
(m, 10H); 13C NMR d 28.3, 37.9, 59.1, 78.3, 78.8, 81.7, 101.2
(HC(NO2)SO2Ph), 127.2–136.3 (the peaks of the aryl carbons),
152.1; IR (film): 1345, 1399, 1566, 1703 cmꢀ1; HRMS (CI) calcd
for C22H27N2O7S 463.1539 ([M+H]+), found 463.1541.
the known b-amino-a-hydroxy acids, (2R,3S)-AHPBA and (2R,3S)-
AHMHA produced as their HCl salts, respectively. A probable reac-
tion mechanism for the three sequential reactions, that is, the ni-
tro-aldol, the dehydration, and the intramolecular conjugate
addition reactions, was proposed in order to rationalize the reac-
tion results. We have also shown that the appropriately protected
b-amino-a-hydroxy acid derivatives 3 could be useful building
blocks for the synthesis of biologically active peptides such as best-
atin and amastatin.
4.2.2. tert-Butyl (4S,5R)-4-isobutyl-5-((phenylsulfonyl)nitrom-
ethyl)oxazolidine-3-carboxylate 2b
67% (607 mg); colorless oil; The major isomer of 2b:27 1H NMR
(600 MHz, 40 °C)28 d 1.02 (d, 3H, J = 6.6), 1.05 (d, 3H, J = 6.6), 1.47–
1.58 (m, 2H), 1.51 (s, 9H), 1.72–1.79 (m, 1H), 4.67 (d, 1H, J = 9.6),
4.71 (d, 1H, J = 4.2), 4.75 (t, 1H, J = 7.2), 5.13 (br s, 1H), 5.36 (d,
1H, J = 9.6, HC(NO2)SO2Ph), 7.61–8.00 (m, 5H); 13C NMR d 22.7,
25.0, 28.4, 41.7, 56.4, 77.9, 78.3, 81.7, 101.3 (HC(NO2)SO2Ph),
129.6–136.1 (the peaks of the aryl carbons), 152.9; IR (film):
1345, 1399, 1566, 1706 cmꢀ1; HRMS (CI) calcd for C19H29N2O7S
429.1695 ([M+H]+), found 429.1696.
4. Experimental
4.1. General
4.3. Oxidation procedure of 2a to methyl ester 3a
Materials were obtained from commercial suppliers and were
used without further purification. Methylene chloride was distilled
from calcium hydride immediately prior to use. Air or moisture
sensitive reactions were conducted under a nitrogen atmosphere
using oven-dried glassware and standard syringe/septa techniques.
The reactions were monitored with a SiO2 TLC plate under UV light
(254 nm) and by visualization with a ninhydrin staining solution. A
CEM Discover SP microwave unit was used for microwave reac-
tions. In the microwave reactions, the reaction temperature and
pressure were monitored by the provided monitoring software.
Column chromatography was performed on silica gel 60 (70–230
mesh). Optical rotations were determined at ambient temperature
with a digital polarimeter and are the average of ten measure-
ments. 1H and 13C NMR spectra were measured at 400 MHz and
100 MHz, respectively in CDCl3 unless stated otherwise. The 1H
NMR spectroscopic data were reported as follows in ppm (d) from
the internal standard (TMS, 0.0 ppm): chemical shift (multiplicity,
integration, coupling constant in Hz). The 13C NMR spectra were
referenced with the 77.16 resonance of CDCl3, 39.51 resonance of
DMSO-d6, or 49.00 resonance of MeOH-d4. Gas chromatographic
To a diastereomeric mixture 2a (220 mg, 0.48 mmol) in THF
(3 mL) were added methanol (3 mL) and DBU (0.22 mL, 1.43 mmol)
at room temperature. The reaction mixture was cooled to ꢀ78 °C
and ozone was bubbled over 30 min. After the starting material
had disappeared, the reaction mixture was quenched with acetic
acid. The organic solvents were removed under reduced pressure
after the reaction mixture was warmed up to room temperature.
The resulting residue was then partitioned between EtOAc
(20 mL) and an aqueous saturated solution of NH4Cl (20 mL). The
aqueous layer was extracted with EtOAc (20 mL ꢁ 2), and the com-
bined organic layers were dried over MgSO4, filtered, and concen-
trated under reduced pressure. The organic residue was purified by
silica gel chromatography (hexane/EtOAc = 8:1) to afford the de-
sired ester 3a.
4.3.1. 3-tert-Butyl 5-methyl (4S,5R)-4-benzyloxazolidine-3,5-
dicarboxylate 3a
85% (130 mg); ½a 1D3
ꢂ
¼ ꢀ25:6 (c 0.76, CHCl3); 1H NMR (50 °C)28
d
1.44 (s, 9H), 2.88 (dd, 1H, J = 8.0, 13.4), 3.07 (br d, 1H, J = 13.4), 3.68
(s, 3H), 4.37 (br s, 1H), 4.40 (s, 1H), 4.73 (s, 1H), 5.19 (br s, 1H),
7.19–7.30 (m, 5H); 13C NMR d 28.4, 38.5, 52.4, 60.1, 78.5, 79.5,
80.9, 126.9, 128.7, 129.6, 136.9, 152.5, 171.0; IR (film): 1165,
analyses were carried out with
a
capillary column
(30 m ꢁ 0.25 mm). Infrared spectra were obtained as a film on a
SiO2 wafer. Low and high resolution mass spectra were measured
by the CI ionization method and analyzed by magnetic sector mass
analyzer.
1700, 1752 cmꢀ1
; HRMS (CI) calcd for C17H24NO5 322.1654
([M+H]+), found 322.1654.
4.4. General one-pot procedure for methyl ester 3
4.2. General procedure for adduct 2a or 2b from 1a or 1b
To
a-amino aldehyde 1a (R = Bn, 82 mg, 0.29 mmol) in THF
To
a-amino aldehyde 1a (R = Bn, 230 mg, 0.82 mmol) in THF
(1 mL) were added phenylsulfonylnitromethane26 (199 mg,
0.90 mmol) and DMAP (151 mg, 1.24 mmol). The mixture was stir-
red at room temperature for 2 days until the starting material 1a
had disappeared. The reaction mixture was diluted with EtOAc
(5 mL), to which was added an aqueous saturated solution of NH4Cl
(20 mL). The resulting mixture was separated and the aqueous
layer was extracted with EtOAc (20 mL ꢁ 3). The combined organic
layers were dried over MgSO4, filtered, and concentrated under re-
duced pressure. The organic residue was purified by silica gel chro-
matography (hexane/EtOAc = 4:1) to afford the desired adduct 2a
as a diastereomeric mixture (ca. 2:1).
(0.2 mL) were added phenylsulfonylnitromethane (65 mg,
0.32 mmol) and DMAP (54 mg, 0.44 mmol). The reaction mixture
was stirred at room temperature for 2 days with vigorous stirring
until the starting material 1a had disappeared. The mixture was di-
luted with THF (3 mL) and methanol (3 mL), to which was added
DBU (0.13 mL, 0.88 mmol) at room temperature. The reaction mix-
ture was then cooled to ꢀ78 °C, and ozone was bubbled through
over 30 min. After quenching the reaction with acetic acid (less
than 1 mL), the resulting mixture was warmed up to room temper-
ature. After removing the solvent under reduced pressure, the res-
idue was partitioned between EtOAc (10 mL) and an aqueous
saturated solution of NH4Cl (20 mL). The aqueous layer was ex-
tracted with EtOAc (20 mL ꢁ 3), and the combined organic layers
were dried over MgSO4, filtered, and concentrated under reduced
pressure. The organic residue was purified by silica gel chromatog-
raphy (hexane/EtOAc = 8:1) to afford the desired ester 3a (61 mg,
0.21 mmol, 72%) as a colorless oil.
4.2.1. tert-Butyl (4S,5R)-4-benzyl-5-((phenylsulfonyl)nitromethyl)
oxazolidine-3-carboxylate 2a
57% (281 mg); colorless oil; The major isomer of 2a:27 1H NMR
(600 MHz, 40 °C)28 d 1.44 (s, 9H), 2.89 (dd, 1H, J = 7.2, 13.5), 3.07
(br s, 1H), 4.66 (d, 1H, J = 9.3), 4.70 (br s, 1H), 4.82 (t, 1H, J = 7.2),

Y. Seo et al. / Tetrahedron: Asymmetry 25 (2014) 625–631
629
4.4.1. 3-tert-Butyl 5-methyl (4S,5R)-4-isobutyloxazoline-3,5-
4.5.1.2. tert-Butyl (4S,5R)-4-isobutyl-5-(nitromethyl)oxazoli-
dicarboxylate 3b
dine-3-carboxylate 4b. 72% (50 mg); colorless oil; ½a D14
¼ ꢀ8:2
ꢂ
69% (54 mg); colorless oil; ½a D16
ꢂ
¼ ꢀ6:7 (c 0.34, CHCl3); 1H NMR
(c 0.26, CHCl3); 1H NMR (50 °C)28 d 0.98 (d, 3H, J = 6.4), 1.02
(d, 3H, J = 6.4), 1.43–1.51 (m, 1H), 1.51 (s, 9H), 1.61–1.71 (m,
2H), 3.98 (t, 1H, J = 6.4), 4.39–4.51 (m, 3H), 4.74 (d, 1H, J = 4.8),
5.20 (d, 1H, J = 4.8); 13C NMR d 22.5, 23.0, 25.2, 28.5, 42.2, 56.9,
(50 °C)28 d 0.99 (d, 3H, J = 6.8), 1.01 (d, 3H, J = 6.4), 1.43–1.48 (m,
1H), 1.48 (s, 9H), 1.58–1.65 (m, 1H), 1.68–1.73 (m, 1H), 3.77 (s,
3H), 4.24 (t, 1H, J = 6.6), 4.34 (s, 1H), 4.82 (d, 1H, J = 3.6), 5.28 (d,
1H, J = 3.6); 13C NMR d 22.2, 23.0, 25.3, 28.4, 42.3, 52.4, 57.9,
76.8, 78.2, 79.1, 81.3, 153.2; IR (film): 1372, 1559, 1704 cmꢀ1
HRMS (CI) calcd for
289.1760.
;
79.1, 79.1, 80.8, 152.9, 171.5; IR (film): 1169, 1702, 1755 cmꢀ1
;
C
13H25N2O5 289.1763 ([M+H]+), found
HRMS (CI) calcd for
288.1808.
C
14H26NO5 288.1811 ([M+H]+), found
4.5.2. Two-step procedure for 3a from 4a
Nitromethyloxazolidine 4a (R = Bn, 73 mg, 0.23 mmol) in t-
BuOH (2 mL) was stirred in an aqueous solution of 0.5 M KOH buf-
fered with 1.25 M of K2HPO4 (1.5 mL) at room temperature for
5 min. To the reaction mixture an aqueous solution of 0.5 M
KMnO4 (0.90 mL) was slowly added at 0 °C and then stirred at
room temperature for 1 h. The reaction was quenched with an
aqueous saturated solution of Na2SO3 (5 mL) at 0 °C, and the reac-
tion mixture was acidified with an aqueous solution of 1 M HCl
(6 mL). The resulting mixture was separated, and the aqueous layer
was extracted with EtOAc (10 mL ꢁ 3). The combined organic lay-
ers were dried over MgSO4, filtered, and concentrated under re-
duced pressure to afford the corresponding acid intermediate 5a.
To crude acid 5a in DMF (2 mL) was added K2CO3 (94 mg,
0.68 mmol) and MeI (0.03 mL, 0.45 mmol). After 1 h at room tem-
perature, the mixture was poured into cold water (10 mL). The
resulting mixture was extracted with diethyl ether (10 mL ꢁ 3).
The combined organic layers were dried over MgSO4, filtered,
and concentrated under reduced pressure. The organic residue
was purified by silica gel chromatography (hexane/EtOAc = 8:1)
to afford the desired ester 3a (51 mg, 70%) as a colorless oil.
4.4.2. 3-tert-Butyl 5-methyl (4S,5R)-4-isopropyloxazolidine-3,5-
dicarboxylate 3c
65% (109 mg), colorless oil; ½a D17
ꢂ
¼ ꢀ10:7 (c 1.17, CHCl3); 1H
NMR (50 °C)28 d 0.89 (d, 3H, J = 6.4), 0.90 (d, 3H, J = 6.4), 1.39 (s,
9H), 1.89–1.98 (m, 1H), 3.67 (s, 3H), 3.89 (d, 1H, J = 5.2), 4.36 (s,
1H), 4.72 (d, 1H, J = 3.2), 5.19 (br s, 1H); 13C NMR d 18.0, 18.8,
28.3, 31.0, 52.3, 64.6, 76.8, 80.0, 80.6, 153.3, 171.8; IR (film):
1173, 1711, 1757 cmꢀ1; HRMS (CI) calcd for C13H24NO5 274.1654
([M+H]+), found 274.1658.
4.4.3. 3-tert-Butyl 5-methyl (4S,5R)-4-methyloxazolidine-3,5-
dicarboxylate 3d
67% (81 mg), colorless oil; ½a D15
ꢂ
¼ ꢀ5:9 (c 0.44, CHCl3); 1H NMR
(50 °C)28 d 1.37 (d, 3H, J = 6.4), 1.46 (s, 9H), 3.77 (s, 3H), 4.14 (br s,
1H), 4.24 (d, 1H, J = 3.2), 4.84 (d, 1H, J = 3.8), 5.20 (d, 1H, J = 3.8); 13
C
NMR d 19.3, 28.5, 52.6, 55.0, 79.2, 80.8, 81.9, 152.6, 170.9; IR (film):
1175, 1707, 1756 cmꢀ1; HRMS (CI) calcd for C11H20NO5 246.1341
([M+H]+), found 246.1345.
4.4.4. 3-tert-Butyl 5-methyl (4S,5R)-4-((tert-butyldimethylsilyl-
oxy)methyl)oxazolidine-3,5-dicarboxylate 3e
79% (93 mg), colorless oil; ½a D15
ꢂ
¼ ꢀ10:5 (c 0.71, CHCl3); 1H NMR
4.6. General procedure for b-amino-
or AHMHAꢃHCl, from 3a and 3b
a
-hydroxy acids, AHPBAꢃHCl
(50 °C)28 d 0.06 (s, 3H), 0.07 (s, 3H), 0.90 (s, 9H), 1.46 (s, 9H), 3.72–
3.81 (m, 2H), 3.77 (s, 3H), 4.07 (br s, 1H), 4.71 (d, 1H, J = 3.6), 4.79
(d, 1H, J = 3.2), 5.19 (br s, 1H); 13C NMR d ꢀ5.3, 18.2, 25.9, 28.5,
52.5, 60.2, 61.7, 77.9, 80.1, 80.9, 152.5, 171.3; IR (film): 839,
Methyl ester 3a (R = Bn, 152 mg, 0.47 mmol) in an aqueous
solution of 3 M HCl (8 mL) was heated at 80 °C for 8 h. After cooling
back to room temperature, the resulting mixture was washed with
CH2Cl2 (20 mL ꢁ 2) and EtOAc (20 mL ꢁ 2). The aqueous layer was
concentrated under reduced pressure to give the AHPBAꢃHCl salt.
1175, 1709, 1752 cmꢀ1
; HRMS (CI) calcd for C17H34NO6Si
376.2155 ([M+H]+), found 376.2159.
4.5. Stepwise procedure for methyl ester 3
4.6.1. (2R,3S)-3-Amino-2-hydroxy-4-phenylbutanoic acid hydro-
chloride AHPBAꢃHCl (R = Bn)
4.5.1. General procedure for nitromethyloxazolidine 4a or 4b
To conjugate adduct 2a (R = Bn, 67 mg, 0.15 mmol) in toluene
(2 mL) were added N-benzylnicotinamide (BNAH, 93 mg,
0.44 mmol) and AIBN (5 mg, 0.03 mmol). The reaction mixture
was reacted at 60 °C for 1 h in a microwave (MW) reactor
(15 W). Next, the mixture was diluted with EtOAc (2 mL), to which
was added H2O (5 mL). The organic layer was separated and the
aqueous layer was extracted with EtOAc (10 mL ꢁ 3). The com-
bined organic layers were dried over MgSO4, filtered, and concen-
trated under reduced pressure. The organic residue was purified by
silica gel chromatography (hexane/EtOAc = 8:1) to afford nitrom-
ethyloxazolidine 4a.
92% (85 mg); white solid; mp 206–208 °C (lit21a; 209–210 °C);
½
a 2D6
ꢂ
¼ ꢀ28:8 (c 1.68, 1 M HCl); (lit.21b
[a]D = +29.3 (c 0.43, 1 M
HCl); 1H NMR (DMSO-d6) d 2.88 (dd, 1H, J = 9.6, 13.4), 3.03 (dd,
1H, J = 5.2, 13.4), 3.58–3.60 (m, 1H), 3.89 (d, 1H, J = 2.4), 7.27–
7.36 (m, 5H), 8.18 (br s, 1H); 13C NMR d 35.1, 53.9, 67.4, 126.9,
128.6, 129.3, 136.2, 172.7; IR (film); 1072, 1730, 2931,
3040 cmꢀ1; HRMS (CI) calcd for C10H14NO3 196.0974 ([M+H]+),
found 196.0971.
4.6.2. (2R,3S)-3-Amino-2-hydroxy-5-methylhexanoic acid hydro-
chloride AHMHAꢃHCl (R = i-Bu)
88% (93 mg); white solid; mp 208–210 °C (lit.24a 188–189 °C,
lit.24b 228–229 °C) 1H NMR (MeOH-d4) d 0.98 (d, 3H, J = 6.4), 1.00
(d, 3H, J = 6.4), 1.47–1.54 (m, 1H), 1.64–1.79 (m, 2H), 3.56 (dt,
1H, J = 3.2, 7.0), 4.23 (d, 1H, J = 3.2); 13C NMR d 22.5, 22.7, 25.4,
4.5.1.1. tert-Butyl (4S,5R)-4-benzyl-5-(nitromethyl)oxazolidine-
3-carboxylate 4a. 62% (29 mg); colorless oil; ½a D15
¼ ꢀ5:7 (c 2.53,
ꢂ
CHCl3); 1H NMR (50 °C)28 d 1.51 (s, 9H), 2.82 (dd, 1H, J = 9.2, 12.0),
3.26 (br d, 1H, J = 12.0), 3.95–4.01 (m, 2H), 4.32 (dd, 1H, J = 8.4,
12.8), 4.58–4.63 (m, 1H), 4.69 (d, 1H, J = 4.0), 5.17 (br s, 1H),
7.23–7.37 (m, 5H); 13C NMR d 28.4, 38.7, 59.2, 76.5, 78.6, 78.8,
81.4, 127.4, 129.1, 129.4, 136.4, 152.8; IR (film): 1370, 1557,
1679 cmꢀ1; HRMS (CI) calcd for C16H23N2O5 323.1607 ([M+H]+),
found 323.1611.
39.8, 52.8, 70.4, 174.4; IR (film): 1101, 1657, 2960, 3367 cmꢀ1
;
HRMS (CI) calcd for C7H16NO3 162.1130 ([M+H]+), found
162.1131. The free amino acid form of (2R,3S)-AHMHA was ob-
tained in quantitative yield by treating (2R,3S)-AHMHAꢃHCl with
a Dowex resin (50WX8); ½a D28
ꢂ
¼ þ25:0 (c 1.28, AcOH), (lit.24b
½
a 2D5
ꢂ
¼ þ25:2 (c 0.6, AcOH)).

630
Y. Seo et al. / Tetrahedron: Asymmetry 25 (2014) 625–631
4.7. Peptide synthesis from methyl ester ent-3a
References
1. (a) Bergmeier, S. C. Tetrahedron 2000, 56, 2561–2576; (b) Bauvois, B.;
Dauzonne, D. Med. Res. Rev. 2006, 26, 88–130; (c) Luan, Y.; Mu, J.; Xu, W.
Mini-Rev. Org. Chem. 2008, 5, 134–140.
2. (a) Bergmeier, S. C.; Stanchina, D. M. J. Org. Chem. 1999, 64, 2852–2859; (b)
Nemoto, H.; Ma, R.; Suzuki, I.; Shibuya, M. Org. Lett. 2000, 2, 4245–4247; (c)
Lee, B. W.; Lee, J. H.; Jang, K. C.; Kang, J. E.; Kim, J. H.; Park, K.-M.; Park, K. H.
Tetrahedron Lett. 2003, 44, 5905–5907; (d) Kudyba, I.; Raczko, J.; Jurczak, J. J.
Org. Chem. 2004, 69, 2844–2850; (e) Feske, B. D. Curr. Org. Chem. 2007, 11, 483–
496.
3. Tobe, H.; Morishima, H.; Aoyagi, T.; Umezawa, H.; Ishiki, K.; Nakamura, K.;
Yoshioka, T.; Shimauchi, Y.; Inui, T. Agric. Biol. Chem. 1982, 46, 1865–1872.
4. Shimamoto, K. Chem. Rec. 2008, 8, 182–199.
5. (a) Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem., Int. Ed. 1994, 33, 15–44;
(b) Borah, J. C.; Gogoi, S.; Boruwa, J.; Kalita, B.; Barua, N. C. Tetrahedron Lett.
2004, 45, 3689–3691.
4.7.1. Preparation of ent-5a
To methyl ester ent-3a (R = Bn, 283 mg, 0.88 mmol) in THF
(2 mL) was added an aqueous solution of 2 M NaOH (6 mL), and
the reaction mixture was stirred at room temperature over 2 h.
After the reaction mixture was diluted with EtOAc (10 mL), the
pH was adjusted to ca. 1 with an aqueous solution of 1 M HCl.
The aqueous phase was extracted with EtOAc (20 mL ꢁ 2). The
combined organic layers were dried over MgSO4, filtered, and con-
centrated under reduced pressure to afford the corresponding acid
ent-5a.
4.7.1.1. 3-(tert-Butoxycarbonyl)-(4R,5S)-4-benzyloxazolidine-5-
6. (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835–875; (b) Ager,
D. J.; Prakash, I.; Schaad, D. R. Aldrichim. Acta 1997, 30, 3–12.
carboxylic acid ent-5a. 92% (249 mg); ½a D14
¼ þ17:0 (c 0.92,
ꢂ
CHCl3); 1H NMR d 1.43 (s, 9H), 2.90 (dd, 1H, J = 8.2, 13.4), 3.07
(br s, 1H), 4.43 (br s, 1H), 4.43 (s, 1H), 4.74 (br s, 1H), 5.18 (br s,
1H), 7.19–7.33 (m, 5H), 9.82 (s, 1H); 13C NMR d 28.4, 38.5, 60.1,
78.2, 79.5, 81.4, 127.0, 128.8, 129.6, 136.6, 152.7, 175.1; IR (film):
1704, 1750, 2978 cmꢀ1; HRMS (CI) calcd for C16H22NO5 308.1498
([M+H]+), found 308.1495.
7. (a) Yoo, D.; Oh, J. S.; Kim, Y. G. Org. Lett. 2002, 4, 1213–1215; (b) Yoo, D.; Kwon,
S.; Kim, Y. G. Tetrahedron: Asymmetry 2005, 16, 3762–3766; (c) Yoo, D.; Kim, H.;
Kim, Y. G. Synlett 2005, 1707–1710; (d) Kim, H.; Yoo, D.; Kwon, S.; Kim, Y. G.
Tetrahedron: Asymmetry 2009, 20, 2715–2719; (e) Yoo, D.; Song, J.; Kang, M. S.;
Kang, E.; Kim, Y. G. Terahedron: Asymmetry 2011, 22, 1700–1704.
8. (a) Hyun, S. I.; Kim, Y. G. Tetrahedron Lett. 1998, 39, 4299–4302; (b) Yoo, D.; Oh,
J. S.; Lee, D. W.; Kim, Y. G. J. Org. Chem. 2003, 68, 2979–2982.
9. (a) Rubin, A. E.; Sharpless, K. B. Angew. Chem., Int. Ed. 1997, 36, 2637–2640; (b)
O’Brien, P. Angew. Chem., Int. Ed. 1999, 38, 326–329; (c) Donohoe, T. J.; Johnson,
P. D.; Pye, R. J. Org. Biomol. Chem. 2003, 1, 2025–2028; (d) Abraham, E.; Davis, S.
G.; Millican, N. L.; Nicholson, R. L.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem.
2008, 6, 1655–1664.
4.7.2. General procedure for dipeptides 8 and 9
To crude ent-5a (76 mg, 0.23 mmol) in THF (25 mL) at 0 °C were
10. (a) Dou, D.-M.; Liu, Y.-C.; Chen, C.-S. J. Org. Chem. 1993, 58, 1287–1289; (b)
Pastó, M.; Castejón, P.; Moyano, A.; Pericàs, M. A.; Riera, A. J. Org. Chem. 1996,
61, 6033–6037; (c) Tosaki, S.-Y.; Tsuji, R.; Ohshima, T.; Shibasaki, M. J. Am.
Chem. Soc. 2005, 127, 2147–2155.
11. (a) Matsunaga, S.; Yoshida, T.; Morimoto, H.; Kumagai, N.; Shibasaki, M. J. Am.
Chem. Soc. 2004, 126, 8777–8785; (b) Dziedzic, P.; Schyman, P.; Kullberg, M.;
Córdova, A. Chem. Eur. J. 2009, 15, 4044–4048; (c) Gassa, F.; Contini, A.;
Fontana, G.; Pellegrino, S.; Gelmi, M. L. J. Org. Chem. 2010, 75, 7099–7106.
12. Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017–1047. and references therein..
13. Suzuki, T.; Honda, Y.; Izawa, K.; Williams, R. M. J. Org. Chem. 2005, 70, 7317–
7323. and references therein.
14. The Horner–Wadsworth–Emmons olefination reaction: Rein, T.; Reiser, O. Acta
Chem. Scand. 1996, 50, 369–379. and references therein.
15. The Peterson olefination reaction: Standen, L. F.; Gravestock, D.; Ager, D. J.
Chem. Soc. Rev. 2002, 31, 195–200. and references therein.
16. Luzzio, F. A. Tetrahedron 2001, 57, 915–945. and references therein.
17. Under the basic reaction conditions of 1a with nitromethane (CH3NO2), nitro-
aldol adduct I was obtained in 85% yield, which did not have the crucial
N-hydroxymethyl group for the intramolecular conjugate addition. Neither the
desired nitro-aldol product II nor nitroolefin III containing the N-
added N-methylmorpholine (27
l
L, 0.25 mmol) and isobutyl chlo-
roformate (32 L, 0.25 mmol). After 5 min,
l
L-leucine methyl ester
(47 mg, 0.26 mmol) was added to the reaction mixture, and the
mixture was stirred at room temperature for 5 h. After the removal
of the solvents, the residue was partitioned between H2O (20 mL)
and EtOAc (20 mL). The aqueous phase was extracted with EtOAc
(20 mL ꢁ 2), and the combined organic layers were dried over
MgSO4, filtered, and concentrated under reduced pressure. The or-
ganic residue was purified by silica gel chromatography (hexane/
EtOAc = 8:1) to afford the desired ester of dipeptide 8.
4.7.2.1. [3-(tert-Butoxycarbonyl-(4R,5S)-4-benzyloxazolidine-5-
carboxylic acid]-L-leucine methyl ester 8. 92% (94 mg); color-
less oil; ½a 1D5
ꢂ
¼ ꢀ10:7 (c 0.96, CHCl3); 1H NMR (50 °C)28 d 0.94 (d,
6H, J = 6.0), 1.40 (s, 9H), 1.52–1.63 (m, 2H), 1.64–1.70 (m, 1H),
2.99 (dd, 1H, J = 5.8, 13.4), 3.08 (dd, 1H, J = 5.8, 13.4), 3.74 (s, 3H),
4.34 (d, 1H, J = 3.2), 4.49–4.53 (m, 1H), 4.65–4.60 (m, 1H), 6.78
(d, 1H, J = 8.0), 7.22–7.33 (m, 5H); 13C NMR d 21.8, 22.8, 24.9,
28.1, 38.8, 41.4, 50.2, 52.3, 60.0, 78.7, 80.5, 80.7, 126.7, 128.5,
129.8, 136.8, 152.4, 169.9, 172.7; IR (film): 1156, 1698, 1742,
3335 cmꢀ1; HRMS (CI) calcd for C23H35N2O6 435.2495 ([M+H]+),
found 435.2491.
hydroxymethyl group were observed.
OH
OH
Boc
Boc
NH
Boc
Bn
N
Boc
Bn
N
O
N
+
MeNO2
or
Bn
NO2
Bn
NO2
OH
NO2
OH
OH
I
II
III
1a
18. (a) Ambroise, L.; Jackson, R. F. W. Tetrahedron Lett. 1996, 37, 2311–2314; (b)
Wade, P. A.; Murray, J. K., Jr.; Shah-Patel, S.; Palfey, B. A.; Caroll, P. J. J. Org. Chem.
2000, 65, 7723–7730; (c) Concellón, J. M.; Rodríguez-Solla, H.; Concellón, C. J.
Org. Chem. 2006, 71, 7919–7922.
19. Other reagents examined for the oxidation of the phenylsulfonylnitromethyl
group included TiCl3, AcOH/NaNO2, and SnCl2. (a) Trost, B. M.; Madsen, R.; Guile,
S. D.; Brown, B. J. Am. Chem. Soc. 2000, 122, 5947–5956. A possible mechanism
for the mild oxidative Nef reaction of the phenylsulfonylnitromethyl group
from 2a to 3a is shown below based on the literature; that is, the nitronate
4.7.2.2. [3-(tert-Butoxycarbonyl-(4R,5S)-4-benzyloxazolidine-5-
carboxylic acid]-L-valine methyl ester 9. 70% (198 mg); color-
less oil; ½a 1D5
ꢂ
¼ ꢀ0:8 (c 0.54, CHCl3); 1H NMR (50 °C)28 d 0.89 (d,
3H, J = 6.0), 0.93 (d, 3H, J = 6.8), 1.38 (s, 9H), 2.14–2.22 (m, 1H),
3.00 (dd, 1H, J = 6.2, 13.8), 3.08 (dd, 1H, J = 6.2, 13.8), 3.76 (s, 3H),
4.35 (d, 1H, J = 3.2), 4.53–4.58 (br s, 1H), 5.28 (br s, 1H), 6.9 (d,
1H, J = 8.0), 7.23–7.33 (m, 5H); 13C NMR d 21.8, 22.8, 24.9, 28.1,
38.8, 41.4, 50.2, 52.3, 60.0, 78.7, 80.5, 80.7, 126.7, 128.5, 129.8,
136.8, 152.4, 169.9, 172.7; IR (film): 1162, 1696, 1741,
3354 cmꢀ1; HRMS (CI) calcd for C22H33N2O6 421.2339 ([M+H]+),
found 421.2337.
produced under the basic conditions is oxidized with O3 to give an
a-keto
phenylsulfonyl group and the following solvolysis of the -keto phenylsulfonyl
a
group by methanol afforded the corresponding methyl ester.; (b) Barton, D. H.
R.; Motherwell, W. B.; Zard, S. I. Tetrahedron Lett. 1983, 24, 5227; (c) Trost, B. M.;
Stenkamp, D.; Pulley, S. R. Chem. Eur. J. 1995, 1, 568
Boc
Boc
N
N
Boc
Bn
Boc
Bn
O
O
N
N
Acknowledgements
O
O
O3
MeOH
base
Bn
Bn
SO2Ph
SO2Ph
O
N
O
N
SO2Ph
OMe
O
O
We would like to thank the BK-21 Program, the Fundamental
R&D Program for Core Technology of Materials funded by the Min-
istry of Knowledge Economy. Y.S. thanks the Global Ph.D. Fellow-
ship that the National Research Foundation of Korea has
conducted from 2011.
O
O
2a
phenylsulfonylnitronate
α-keto phenylsulfone
3a
20. (a) Hirama, M.; Hioki, H.; Ito, S. Tetrahedron Lett. 1988, 29, 3125–3128; (b)
Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1860.

Y. Seo et al. / Tetrahedron: Asymmetry 25 (2014) 625–631
631
21. (a) Andrés, J. M.; Martínez, M. A.; Pedrosa, R.; Pérez-Encabo, A. Tetrahedron:
25. Chung, M.-C.; Lee, H.-J.; Chun, H.-K.; Lee, C.-H.; Kim, S.-I.; Kho, Y.-H. Biosci.,
Biotechnol., Biochem. 1996, 60, 898–900.
26. Phenylsulfonylnitromethane was prepared according to the reported
procedure. Weigl, U.; Heimberger, M.; Pierik, A. J.; Rétey, J. Chem. Eur. J.
2003, 9, 652–660.
´
´
ˇ ´
Asymmetry 2001, 12, 347–353; (b) Tasic, G.; Matovic, R.; Saicic, R. N. J. Serb.
Chem. Soc. 2004, 69, 981–990.
22. Ono, N.; Tamura, R.; Tanikaga, R.; Kaji, A. J. Chem. Soc., Chem. Commun. 1981,
71–72.
23. Foresti, E.; Palmieri, G.; Petrini, M.; Profeta, R. Org. Biomol. Chem. 2003, 1, 4275–
4281.
27. The spectroscopic data were assigned for the major isomer only, except for the
peaks on the aryl ring.
24. (a) Tobe, H.; Morishima, H.; Naganawa, H.; Takita, T.; Aoyagi, T.; Umezawa, H.
Agric. Biol. Chem. 1979, 43, 591–596; (b) Martín-Zamora, E.; Ferrete, A.; Llera, J.
M.; Muñoz, J. M.; Pappalardo, R. R.; Fernández, R.; Lassaletta, J. M. Chem. Eur. J.
2004, 10, 6111–6129.
28. A better resolution on the NMR spectra was obtained at higher temperature
due to the fast conformational equilibrium of the oxazolidine ring.