Asymmetric synthesis of (4S,5S)-2-oxo-4-phenyloxazolidine-5-carboxylic acid using a 1,2-addition of PhMgBr to an N-sulfinimine derived from (R)-glyceraldehyde acetonide and (S)-t-BSA

Article abstract of DOI:10.1016/j.tetasy.2010.10.012

We report an asymmetric synthesis of (4S,5S)-2-oxo-4-phenyloxazolidine-5- carboxylic acid via stereoselective addition of phenylmagnesium bromide (PhMgBr) to an N-sulfinimine derived from (R)-glyceraldehyde acetonide. (S)- and (R)-Glyceraldehyde acetonides, important chiral synthons in synthetic organic chemistry, are prepared from the corresponding epichlorohydrin using an identical synthetic methodology.

Full text of DOI:10.1016/j.tetasy.2010.10.012

Tetrahedron: Asymmetry 21 (2010) 2619–2624
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of (4S,5S)-2-oxo-4-phenyloxazolidine-5-carboxylic
acid using a 1,2-addition of PhMgBr to an N-sulfinimine derived from
(R)-glyceraldehyde acetonide and (S)-t-BSA
K. Chandra Babu a,b, Raman Vysabhattar a, K. S. V. Srinivas a, Satish Nigam a, G. Madhusudhan a,
,
⇑
K. Mukkanti b
a Inogent Laboratories Private Limited, A GVK BIO Company, Nacharam, Hyderabad 500 076, India
b Centre for Pharmaceutical Sciences, J.N.T. University, Kukatpally, Hyderabad 500 072, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We report an asymmetric synthesis of (4S,5S)-2-oxo-4-phenyloxazolidine-5-carboxylic acid via stereose-
lective addition of phenylmagnesium bromide (PhMgBr) to an N-sulfinimine derived from (R)-glyceralde-
hyde acetonide. (S)- and (R)-Glyceraldehyde acetonides, important chiral synthons in synthetic organic
chemistry, are prepared from the corresponding epichlorohydrin using an identical synthetic
methodology.
Received 4 August 2010
Accepted 6 October 2010
Available online 20 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
O
NH2
3-Amino-3-phenylpropane-1,2-diol is a key chiral structural
component in a variety of therapeutically active molecules, such
as the side chain of Taxol1 and its 2-oxazolidinone derivatives, such
as cytoxazone and epi-cytoxazone.2,7 The syn-b-aminoalcohols,
such as 1,2-aminoindanols, serve as biologically active molecules
as well as chiral ligands.3 Only a few methods are available in
the literature for the synthesis of chiral 3-amino-3-phenylpro-
pane-1,2-diol, such as asymmetric epoxidations1,4 or asymmetric
dihydroxylations5,6 of the corresponding cinnamyl alcohol or its
ester followed by functional group transformations. Most of these
reported methods are primarily applicable for the synthesis of
anti-b-aminoalcohol1 but are limited for directly obtaining syn-b-
aminoalcohol (Fig. 1).
O
Ph
NH
OH
OH
OH
Taxol C-13 side chain
cis-1-amino-2-indanol
O
O
HN
O
HN
O
OH
OH
MeO
MeO
However, inversion at either stereogenic center of anti-b-amino
alcohol can produce the corresponding syn-isomer, although there
is the possibility of racemisation resulting in reduced yields.1 Of
course, syn-b-aminoalcohol itself can be synthesized using Sharp-
less asymmetric oxyamination7a (aminohydroxylation), conjugate
addition of a chiral amine to a cinnamyl ester followed by diaste-
reoselective enolate oxidation,7b and other methods7 but some-
times achieving regioselectivity is a tedious task. There is thus
felt a need by organic chemists to define a new methodology to
synthesize syn-3-amino-3-phenylpropane-1,2-diol in high regiose-
lectivity. Moreover, the ethyl ester of syn-(4S,5S)-2-oxo-4-phenyl-
oxazolidine-5-carboxylic acid 1 can be epimerized to ethyl ester
of anti-isomer 2 but not vice versa.8 In this context we took upon
(-)-cytoxazone
(+)-epi-cytoxazone
Figure 1. Structures of Taxol side chain, cis-1-amino-2-indanol, cytoxazone and
epi-cytoxazone.
the asymmetric synthesis of syn-(4S,5S)-3-amino-3-phenylpro-
pane-1,2-diol 11 followed by its oxidation to carboxylic acid 1 as
the target.
Herein, we report an asymmetric synthesis of 1 via the stereo-
selective 1,2-addition of phenylmagnesium bromide (PhMgBr) to
an N-sulfinimine9 derived from (R)-glyceraldehyde acetonide fol-
lowed by non-racemising oxidation of the primary alcohol to the
corresponding carboxylic acid. These chiral glyceraldehyde aceto-
nides are prepared from the commercially available corresponding
epichlorohydrin (Scheme 1).
⇑
Corresponding author. Tel.: +91 40 6628 1215; fax: +91 40 2715 1270.
E-mail address: madhusudhan.gutta@inogent.com (G. Madhusudhan).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.10.012

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K. C. Babu et al. / Tetrahedron: Asymmetry 21 (2010) 2619–2624
Among the various methods considered, nucleophilic 1,2-addi-
O
O
tion of an aryl or alkyl carbanion to an imine double bond is a ver-
satile and popular method for the preparation of functionalizsed
amines.21 However, in this strategy both the yield and stereoselec-
tivity were predominantly influenced by the electrostatic and ste-
ric factors of both substrates, that is, the imine and the
nucleophile.22a Incorporation of a stereo-directing motif, such as
chiral sulfinimines is evident for its potential to synthesize chiral
amines in a stereoselective fashion.22b The aldehyde (R)-8, on
reaction with (S)-t-butylsulfinamide [(S)-t-BSA] using CuSO4 in
dichloromethane at room temperature yielded (S,E)-N-(((S)-2,2-di-
methyl-1,3-dioxolan-4-yl)methylene)-2-methylpropane-2-sulfin-
amide 9 with 98.94% de (Scheme 3). No epimerisation at the
HN
O
O
N
S
O
OH
O
9
syn-(4S,5S)
1
O
O
Cl
O
O
a-center was detected by high performance liquid chromatogra-
phy (HPLC) analysis of chiral sulfinimine 9, which provides access
to a diverse range of substituted imines. The de of 9 indirectly
establishes the enantiomeric excess (ee) of (R)-8.
(R)-8
(R)-epichlorohydrin
Scheme 1. Retrosynthesis of (4S,5S)-2-oxo-4-phenyloxazolidine-5-carboxylic acid, 1.
The 1,2-addition of phenylmagnesium bromide to benzyl imine
derivative of (S)-8 is reported in the literature but with low diaste-
reoselectivity.23 Alternatively, chiral N-sulfinimine was chosen as
an auxiliary to achieve good de during the 1,2-addition to imine
9. Chiral sulfinimine 9 upon treatment with PhMgBr in ether at
ꢀ70 °C gave the (S)-N-((S)-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-
(phenyl)methyl)-2-methylpropane-2-sulfinamide 10 with high
diastereoselectivity (95.24% de by HPLC). Herein, the impact of
temperature on stereoselectivity was studied (between 0 and
ꢀ70 °C) and we obtained a maximum de of the targeted compound
10 at ꢀ70 °C. This reaction was scaled up to 50.0 g.
2. Results and discussion
Both (S)- and (R)-glyceraldehyde acetonides are very important
chiral synthons for the total synthesis of biologically active mole-
cules and pharmaceutically important moieties.10–12,21 The prepa-
ration of (R)-glyceraldehyde acetonide is well documented in the
literature using
tonide is synthesized from
D
-mannitol,13–16 whereas (S)-glyceraldehyde ace-
L
-ascorbic acid.17 To the best of our
knowledge, no methods have so far been reported for the prepara-
tion of both (S)- and (R)-glyceraldehyde acetonide using an identi-
cal synthetic methodology. In this context, we decided to develop
an efficient, simple, and identical synthetic strategy to prepare
(S)- and (R)-glyceraldehyde acetonide and showed its application
in the synthesis of the targeted compound 1.
Accordingly, (R)-epichlorohydrin on reaction with acetone cata-
lyzed by boron trifluoride etherate at 40 °C gave corresponding
chloro compound, (R)-5 which was further treated with sodium
benzoate in dimethylsulfoxide (DMSO) at 160 °C to give benzoate
ester (R)-6 in good yield.18,19 Hydrolysis of the O-benzoyl group
in (R)-6 using sodium hydroxide in ethanol gave protected glycerol
(S)-7 that was further oxidized to the desired (R)-glyceraldehyde
acetonide (R)-8 using Swern oxidation20 (Scheme 2). The same
synthetic approach was successfully applied to (S)-epichlorohydrin
as well, yielding the (S)-glyceraldehyde acetonide (S)-8.
It is apparent that the 1,2-addition of PhMgBr to chiral sulfini-
mine 9 proceeds via transition state 9a (Scheme 4). The stereose-
lectivity resulting from the addition of organometallic reagents to
the C–N double bond of sulfinimines can generally be predicted
by assuming chelated, chair-like transition states resulting from
coordination of the metal ion with the sulfinyl oxygen.21b
Deprotection of the t-butylsulfonyl group and 1,3-dimethyl ace-
tal in 10 was performed in acidic media (methanolic HCl) to give
syn-b-aminoalcohol 11. The amine functionality in 11 was pro-
tected as N-Boc derivative 12. The next step in the sequence is
the formation of 2-oxazolidinone. The N-Boc protective group
was advantageously utilizsed for the formation of an oxazolidinone
ring, thereby avoiding the protection and deprotection of the pri-
mary hydroxyl group. Thus, compound 12, on exposure to NaH in
THF cyclizsed regioselectively to 13. Alcohol 13 has been con-
firmed to exist in a threo configuration (syn product) by the charac-
teristic H4 and H5 signals that appear in the 1H NMR spectra and is
in agreement with the reported values of similar compounds.2b,8
Since the absolute stereochemistry of (R)-8 and t-BSA were known,
the identity of the stereocenters of 13 was elucidated and con-
firmed to be (4S,5S).
Acetone
BF3·OEt2
O
O
Cl
O
40 ºC, 5 h
80 %
Cl
(R)-epichlorohydrin
(R)-5
To oxidize the primary alcohol of compound 13, into the respec-
tive acid 1 in a non-racemising way, various methods were at-
tempted, such as ruthenium catalyzed NaIO4, PCC, PDC, KMnO4,
and others. After numerous efforts, we finally developed a simple
and feasible method using cost effective reagent CrO3 (Jones’ meth-
od) to oxidize compound 13 into corresponding carboxylic acid 1
in moderate yields ꢁ55% (Scheme 5) and these are summarized
in Table 1. Racemic, syn- and anti-carboxylic acids 1 were prepared
as reference standards by following the literature procedure on
similar compounds.24 Chiral and chemical HPLC methods were
developed to characterize and determine the % of ee or de in the
final compound 1. The possibility of racemization during oxidation
was ruled out as HPLC showed the enantiomeric purity of the
respective carboxylic acid 1 to be 99% ee. Compound 1 has been
utilized to synthesize cis-1-amino-2-indanol.3c
O
NaOH
NaOBz
O
BzO
ethanol, reflux
1h, 90 %
DMSO, 160 ºC
5 h, 87 %
(R)-6
O
(COCl)2, TEA
O
O
O
HO
O
DMSO, -78 ºC
2 h, 50 %
(S)-7
(R)-8
The ester of 1 (syn) can be epimerized to the respective anti-iso-
mer but not vice versa. Earlier, the ethyl ester of 1 (syn racemic)
Scheme 2. Synthesis of (R)-glyceraldehyde acetonide from (R)-epichlorohydrin.

K. C. Babu et al. / Tetrahedron: Asymmetry 21 (2010) 2619–2624
2621
O
S
NH2
O
S NH
(COCl)2, TEA
O
PhMgBr
O
O
O
O
N
O
O
O
S
O
O
HO
Et2O, -70 ºC
5 h, 82 %
DCM, rt
12 h, 95 %
DMSO, -78 ºC
2 h, 50 %
(S)-7
(R)-8
9
10
98.94% de
95.24% de
O
ClH.H2N
OH
BocHN
OH
OH
O
HN
(Boc)2O
HCl
NaH
OH
OH
TEA, DCM
0 ºC, 8 h
78 %
MeOH, rt
THF, rt
2 h, 92 %
12 h, 85 %
11
12
13
syn-(4S,5S)
Scheme 3. Synthesis of syn-(4S,5S)-5-(hydroxymethyl)-4-phenyloxazolidin-2-one 13.
O
H
S
NH
O
O
O
O
O
S
N
N
O
S
Mg
O
Ph
O
Br
10
95.24 % de
9
9a
98.94 % de
Scheme 4. Mechanistic pathway for the addition of PhMgBr to convert sulfinimine 9 into sulfinamine 10.
3. Conclusion
O
O
In conclusion, three objectives of the present research work
have been addressed. (i) Synthetically important intermediates
(S) and (R)-glyceraldehyde acetonides have been prepared from
the corresponding chiral epichlorohydrin using identical synthetic
methodology. (ii) We have established the diastereoselectivity (de)
during the Grignard reaction onto (S,E)-N-(((S)-2,2-dimethyl-1,3-
dioxolan-4-yl)methylene)-2-methylpropane-2-sulfinamide 9. (iii)
A simpler, non-racemising method has been developed to oxidize
alcohol 13 into the respective carboxylic acid 1.
O
HN
HN
Oxidation
O
OH
OH
O
syn-(4S,5S)
syn-(4S,5S)
13
1
O
O
HN
4. Experimental
4.1. General
Epimerization
OH
O
Melting points were determined on Buchi 540 melting point
apparatus and are uncorrected. FT-IR spectra were recorded as
KBr pellet on Nicolet 380 FT-IR Instrument (Model Thermo Elec-
tron Corporation-Spectrum One), 1H and 13C NMR (proton decou-
pled) spectra were recorded on a Varian 400 MHz spectrometer
using DMSO-d6 or CDCl3 as solvent and tetramethylsilane (TMS)
as the internal standard. Mass spectra were recorded on Agilent tri-
ple quadrupole mass spectrometer equipped with turboion spray
interface at 375 °C. All the organic extracts were dried over sodium
sulfate after work-up.
anti-(4S,5R)
2
Scheme 5. Oxidation of 13 into corresponding carboxylic acid 1.
had been epimeried to its ethyl ester of the anti-isomer 2 (racemic).8
Thus, this strategy is diverse enough to produce both syn- and anti-
isomers as per the requirements. Moreover, the stereocenters in 2
are similar to the Taxol side chain.25
The dry reactions were carried out under a nitrogen atmosphere
with magnetic/mechanical stirring. Unless otherwise mentioned,

2622
K. C. Babu et al. / Tetrahedron: Asymmetry 21 (2010) 2619–2624
Table 1
Attempted conditions to oxidize alcohol 13 into acid 1
Solvent number
Oxidising agent
Solvent
Yield (%)
Remarks
1
2
3
4
5
6
PCC
PDC
KMnO4
NaIO4, RuCl2
NaIO4, TEMPO and RuCl2
CrO3, H2SO4 (Jones oxidation)
DMF
DMF
Acetone
CCl4, CH3CN
Acetone
Acetone, H2O
—
18
—
10
13
55
No reaction
Incompletion
Decomposed
Low yield
Incompletion
Completed
all solvents and reagents used were of LR grade. TLC was per-
formed on precoated silica-gel plates, which were visualized using
UV light and sulfuric acid/ethanol (5:95) charring. Flash column-
chromatography was carried out on silica gel (230–400 mesh)
unless otherwise stated.
4.5. Preparation of (R)-2,2-dimethyl-1,3-dioxolane-4-
carbaldehyde (R)-8
Freshly distilled DMSO (37.5 g 0.48 mol), diluted in 50 mL of
anhydrous DCM, was added drop wise to a well stirred solution of
oxalyl chloride (27.9 g, 0.22 mol) in anhydrous DCM (50 mL) main-
tained at ꢀ78 °C. The mixture became yellow and (S)-glycerol aceto-
nide (S)-7 (26.4 g, 0.20 mol) diluted with 100 mL of anhydrous DCM
was introduced drop wise to the solution which was then stirred for
15 min. Next, TEA (101 g, 1.0 mol) was added dropwise and the mix-
ture was heated to rt. Water (500 mL) and DCM (500 mL) were
added to the reaction mass. The organic layer was washed with
water (250 mL) and the combined aqueous layer was extracted with
dichloromethane (3 ꢄ 500 mL). The combined organic layer was
dried over (Na2SO4) filtered and the solvent was evaporated under
reduced pressure to give 16.0 g of crude material which was rapidly
purified by fractional distillation (bath temperature 60–90 °C, 3 mm
Hg) to give compound (R)-8 as colorless oil (13 g, yield: 50%). IR
4.2. Preparation of (R)-4-(chloromethyl)-2,2-dimethyl-1,3-
dioxolane (R)-5
To a solution of (R)-epichlorohydrin (50.0 g, 0.540 mol) and ace-
tone (500 mL), BF3ꢂOEt2 (0.5 mL) was added at 0 °C (ice bath). After
stirring for 1 h, the reaction mixture was heated to 40 °C and again
stirred for 5 h. After concentration under reduced pressure com-
pound (R)-5 was obtained as a colorless oil (65.12 g, yield: 80%).
Bp 63 °C/37 Torr. IR (Neat) m
max: 2988, 1066, 845 cmꢀ1. dH (CDCl3,
300 MHz): 1.37 (s, 3H), 1.45 (s, 3H), 3.50 (m, 1H), 3.56–3.61 (m,
1H), 3.87–3.91 (m, 1H), 4.10–4.15 (m, 1H), 4.3–4.34 (m,1H). dC
(CDCl3, 125 MHz) d: 25.1, 26.6, 44.3, 67.2, 75.2, 109.8.
½
a 2D5
ꢃ
¼ þ35:9 (c 5.3, C6H6). ESI MS for (M) = 150.0 and 151.0 (M+).
(CHCl3) mmax: 3390, 2969, 2929, 1736, 1460, 1379, 1254, 1200,
1157, 1042, 829.2 cmꢀ1. dH (CDCl3, 300 MHz): 1.44 (s, 3H), 1.49 (s,
3H), 3.91 (d, 1H), 4.2 (d, 1H), 4.4 (m, 1H), 9.55 (d, J = 1.8 Hz, 1H). dC
4.3. Preparation of ((R)-2,2-dimethyl-1,3-dioxolan-4-yl) methyl
benzoate (R)-6
(CDCl3, 125 MHz): 24.7, 25.8, 65.1, 79.5, 110.8, 201.4. ½a D25
¼ þ53:8
ꢃ
(c 2.0, CHCl3). ESI MS for (M+) = 131.02.
A
mixture of (R)-5 (60.0 g, 0.398 mol), sodium benzoate
(114.6 g, 0.796 mol), and anhydrous DMSO (900 mL) was stirred
at rt for 10 min. Then, the reaction mixture was heated to 160 °C
and again stirred for 5 h. The reaction was allowed to cool rt, di-
luted with 10% aqueous Na2CO3 solution (900 mL), and extracted
with CH2C12 (3 ꢄ 200 mL). The dried (Na2SO4) organic extracts
were concentrated in vacuo and the oily residue was distilled at re-
duced pressure to afford compound (R)-6 as a colorless oil (81.0 g,
4.6. Preparation of (S,E)-N-(((S)-2,2-dimethyl-1,3-dioxolan-4-
yl)methylene)-2-methylpropane-2-sulfinamide 9
To a solution of aldehyde (R)-8 (30.0 g, 0230 mol) in DCM
(300 mL), (S)-t-butylsulfinamide (33.4 g, 0.276 mol), and anhy-
drous CuSO4 (110.1 g, 0.69 mol) was added and stirred at rt for
10 min. Then, the reaction mixture was heated to 40 °C and again
stirred for 12 h, the reaction mass was allowed to cool rt and fil-
tered. The organic solution was dried with (Na2SO4) distilled under
vacuo to give compound 9 as oil (51.0 g, yield: 95%). Ee (98.9%) was
determined by Chemical HPLC (X-BRIDGERP-18), 0.02 M ammo-
nium bicarbonate pH 7 with ACOH and ACN, gradient program,
1 mL/min, major enantiomer (R) tr = 9.338 min, minor enantiomer
yield: 87%). Bp 120–130 °C/0.5 Torr. IR (CHCl3) mmax: 1066, 1722,
844 cmꢀ1. dH (CDCl3, 300 MHz): 1.36 (s, 3H), 1.46 (s, 3H), 3.88
(dd, 1H, J = 5.9, 8.4 Hz), 4.15 (dd, 1H, J = 6.6, 8.4 Hz), 4.36 (dd, 1H,
J = 5.5, 11.4 Hz), 4.41 (dd, 1H, J = 4.8, 11.4 Hz), 4.43–4.57 (m, 1H),
7.43–7.46 (m, 1H), 8.05–8.07 (m, 2H). dC (CDCl3, 125 MHz): 25.4,
26.7, 65.0, 66.4, 73.6, 109.8, 128.3, 129.6, 129.6, 133.0, 166.2.
½
a 2D5
ꢃ
¼ þ7:35 (c 1.0, CHCl3). ESI MS for (M+) = 237.08.
(S) tr = 8.90 min. IR (CHCl3) m .
max: 3280, 1376.1, 1153, 1063 cmꢀ1
dH (DMSO, 300 MHz): 1.19 (s, 9H), 1.44 (s, 3H), 1.50 (s, 3H),
3.99–4.04 (m, 1H), 4.18–4.23 (m, 1H), 4.89–4.93 (m, 1H), 7.87 (d,
1H). dC (DMSO, 125 MHz): 25.2, 26.3, 56.5, 66.5, 76.2, 109.8,
4.4. Preparation of ((S)-2,2-dimethyl-1,3-dioxolan-4-
yl)methanol (S)-7
168.0. ½a 2D5
ꢃ
¼ þ63:7 (c 1.0, EtOH). ESI MS for (M+) = 234.05.
A mixture of (R)-6 (60.0 g, 0.3253 mol), EtOH (300.0 mL), and
NaOH (12.1 g, 0.304 mol) with water (120.0 mL), was stirred at rt
for 10 min. Then, the reaction mixture was heated to 90 °C and stir-
red again for 1 h. The reaction mass was allowed to cool rt and ex-
tracted with CH2C12 (3 ꢄ 200 mL). The dried (Na2SO4) organic
extracts were distilled in vacuo to give compound (S)-7 as a color-
4.7. Preparation of (S)-N-((S)-((S)-2,2-dimethyl-1,3-dioxolan-4-
yl)(phenyl)methyl)-2-methyl propane-2-sulfinamide 10
A solution of chiral imine 9 (50.0 g, 0.214 mol) in diethyl ether
(200 mL) was added dropwise over a period of 30 min to a stirred
solution of phenylmagnesium bromide 3.0 M solution in diethyl
ether (186.2 mL, 0.257 mol) at ꢀ78 °C under argon. After being stir-
red for 15 h at room temperature, the reaction mixture was poured
into saturated aqueous NH4C1 (300 mL). The organic layer separated
and the aqueous layer extracted with ether (2 ꢄ 300 mL). The com-
bined organic layer was dried over anhydrous (MgSO4), filtered, and
concentrated in vacuo. Purification of the residue by flash chroma-
less oil (30.1 g, yield: 90%). Bp 80–90 °C/20 Torr. IR (Neat) mmax
:
3450, 1390, 1380, 1050, 840 cmꢀ1; dH (CDCl3, 300 MHz): 1.36 (s,
3H), 1.46 (s, 3H), 3.58 (dd, 1H, J = 3.6, 11.6 Hz), 3.68 (dd, 1H,
J = 4.0, 11.6 Hz), 3.78 (ddd, 1H, J = 1.0, 3.8, 7.81 Hz), 4.03 (ddd,
1H, J = 1.0, 4.1, 7.8 Hz), 4.27–4.19 (m, 1H). dC (CDCl3, 125 MHz):
25.3, 26.7, 63.0, 65.8, 76.2, 109.8. ½a D25
¼ þ14:4 (neat) ESI MS for
ꢃ
(M+) = 132.9.

K. C. Babu et al. / Tetrahedron: Asymmetry 21 (2010) 2619–2624
2623
tography (ethyl acetate/hexane 1:3) afforded compound 10 as a
white solid (54.74 g, yield: 82%). De (96.5%) was determined by
Chemical HPLC (Chiralpack AD-H), hexane/EtOH 40:60, 1 mL/min,
major syn-isomer (S,S) tr = 4.00 min, minor anti-isomer (R,S)
tr = 3.83 min. Mp: 127–130 °C. IR (KBr) mmax: 3292, 1464,
1066 cmꢀ1. dH (DMSO, 300 MHz): 1.07 (s, 9H), 1.22 (s, 3H), 1.32 (s,
3H), 3.94–4.04 (m, 2H), 4.23 (dd, 1H), 4.30–4.36 (m, 1H), 5.33 (d,
1H, ex.D2O), 7.26–7.35 (m, 5H). dC (DMSO, 75 MHz): ꢁ25.3, 26.5,
55.2, 61.5, 66.0, 78.0, 109.2, 127.1, 127.6, 128.6, 140.5.
(VI) trioxide (9.3 g, 0.093 mol), concd H2SO4 (10.0 mL), H2O
(20.0 mL)] in acetone (100.0 mL) at 0 °C. The mixture was stirred
for 3 h and isopropanol (50.0 mL) was added to the reaction mix-
ture and stirred for 0.5 h. The organic layer was evaporated, and
then diluted with water (250.0 mL), after which were added
100 mL of 2 M NaHCO3. The organic layer was separated and dried
over Na2SO4, and evaporated to give 1 as a white solid (5.8 g, yield:
55%). The diastereoselectivity dr (99.14%) was determined by Chi-
ral HPLC (Chiralpack AD-H), hexane/EtOH/IPA/0.2 mL TFA
(840:120:40:0.2 mL TFA) 1 mL/min, major diastereomer (S,S)
tr = 14.0 min, minor diastereomer (S,R) tr = 10.3 min. Mp = 245–
½
a 2D5
ꢃ
¼ þ77:2 (c 1.0, EtOH). ESI MS for (M+ +Na) = 334.13.
4.8. Preparation of (2S,3S)-3-amino-3-phenylpropane-1,2-diol
248 °C. IR (KBr) mmax: . dH (DMSO,
3279, 1748, 1715 cmꢀ1
hydrochloride 11
300 MHz): 12.93 (br, 1H), 8.32 (s, 1H), 7.25 (m, 5H), 5.17–5.31
(dd, 2H). dC (DMSO, 125 MHz): 38.8, 57.3, 77.0, 128.0, 128.4,
To a solution of protected chiral amine 10 (50.0 g, 0.160 mol) in
methanol (100 mL) was added dropwise a solution of MeOH/HCl
(10%) (88.0 mL, 0.240 mol) over a period of 30 min. The solution
was stirred for 12 h at room temperature and then concentrated
in vacuo. The amine hydrochloride was obtained as a white solid
after precipitation from ether and was used without further purifi-
cation. Compound 11 was obtained as a white solid (27.7 g, yield:
128.9, 137.2, 158.0, 168.2. ½a D25
¼ þ63:3 (c 1.20, DMF). ESI MS for
ꢃ
(M++Na) = 230.0.
Acknowledgment
G.M. thanks Inogent Laboratories Private Limited, a GVK BIO
Company financial support.
85%). Mp 255 °C. IR (KBr) mmax: 3352, 3089, 1577, 1488, 1386.9,
1058.7, 702.2 cmꢀ1. dH (DMSO, 300 MHz): 2.99–3.05 (1H, dd,
J = 6.9, 11.6 Hz), 3.14–3.20 (1H, dd, J = 6.0, 11.1), 3.89–3.95 (1H,
ddd, J = 4.3, 5.4, 6.4), 4.28 (1H, d, J = 6.0), 7.36–7.42 (m, 5H). dC
(D2O, 100 MHz): 134.8, 131.8, 131.4, 130.3, 73.3, 64.7, 58.8.
References
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½
a 2D5
ꢃ
¼ þ3:7 (c 1.05, MeOH). ESI MS for (M+) = 168.02.
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To a solution of chiral amino alcohol 11 (25.0 g, 0.122 mol) in
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0.134 mol) added slowly under an argon atmosphere at 0 °C. After
the reaction mixture was stirred at rt for 8 h, The organic layer was
dried over (Na2SO4) and concentrated in vacuo to give compound
12 as a white solid (25.6 g, yield: 78%), which was recrystallized
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3.64–3.68 (m, IH), 4.53–4.61 (dd, 2H, J = 8.4, 14.1), 4.67 (d, J = 5.1,
1H), 7.13–7.28 (m, 5H). dC (DMSO, 75 MHz): 28.2, 56.3, 62.7,
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4.10. Preparation of (4S,5S)-5-(hydroxyl methyl)-4-phenyl-
oxazolidin-2-one 13
To a solution of compound 12 (25.0 g, 0.0935 mol) in anhydrous
THF (100 mL) was added sodium hydride (5.81 g, 1.0 mol (60% w/w
in mineral) at room temperature and the mixture was stirred un-
der a nitrogen atmosphere for 2 h. The reaction mixture was con-
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1745 cmꢀ1. dH (DMSO, 300 MHz): 2.94–3.03 (ddd, 2H), 4.71–4.75
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ꢃ
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