An efficient asymmetric desymmetrization of prochiral glutaric anhydrides with SuperQuat chiral oxazolidin-2-ones

Article abstract of DOI:10.1016/j.tetasy.2008.12.010

The asymmetric desymmetrization of 3-substituted glutaric anhydrides 1 bearing silyl, aryl and alkyl groups with the lithium salt of chiral oxazolidin-2-ones has been studied. The effects of the substituents at the 4- and 5-positions of the oxazolidin-2-ones on the diastereoselectivity of the anhydride opening were studied in detail. A SuperQuat chiral oxazolidin-2-one 2e with 5,5-diaryl substituents showed optimum selectivity.

Full text of DOI:10.1016/j.tetasy.2008.12.010

Tetrahedron: Asymmetry 19 (2008) 2721–2730
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
An efficient asymmetric desymmetrization of prochiral glutaric anhydrides
with SuperQuat chiral oxazolidin-2-ones
*
Narendra Chaubey, Sonali M. Date, Sunil K. Ghosh
Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric desymmetrization of 3-substituted glutaric anhydrides 1 bearing silyl, aryl and alkyl
groups with the lithium salt of chiral oxazolidin-2-ones has been studied. The effects of the substituents
at the 4- and 5-positions of the oxazolidin-2-ones on the diastereoselectivity of the anhydride opening
were studied in detail. A SuperQuat chiral oxazolidin-2-one 2e with 5,5-diaryl substituents showed opti-
mum selectivity.
Received 13 November 2008
Accepted 5 December 2008
Available online 10 January 2009
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
(Fig. 1) because it can easily lead to the asymmetric synthesis of
various classes of small molecules, especially alkaloids possessing
The asymmetric desymmetrization (ADS) of symmetric mole-
cules by enzymatic1 and non-enzymatic methods2 represents a
powerful approach because it allows the generation of stereogenic
centre(s) as well as permits simultaneous two-directional synthe-
sis.3,4 This makes ADS a powerful strategy,5 and a large number of
enantioselective total syntheses have been achieved based on this
idea. The desymmetrization of anhydrides has been a particular
focus of interest. Most investigations of this family of substrates
have employed an achiral alcohol/thiol in combination with a chi-
ral catalyst/enzymes6–10 or chiral reagents such as alcohols11 and
amines.12–17 Recently, carbon-based nucleophiles have also been
used in the presence of chiral catalysts.18–21 The enantioselectivity
and the diastereoselectivity obtained in most of the cases using
these reagents are moderate to good, while in many cases the
selectivity is directly correlated to the substrate structure. The
enantiomerically impure products often obtained with achiral
reagents are not easily convertible to enantiopure forms. The puri-
fication is possible as diastereoisomers by attaching them to a chi-
ral molecule22,23 or an achiral bifunctional molecule.24 Chiral
reagents usually display high diastereoselectivities when reacted
with bi- and tricyclic 2,3-disubstituted meso-carboxylic anhy-
drides. Although a few reagents11–17 have been tested for the
desymmetrization of 3-substituted glutaric anhydrides, the selec-
tivity observed is not very high, and is also variable. The disadvan-
tage of these methods is that the diastereomeric acids and their
derivatives are generally inseparable. Moreover, in most cases,
the chiral reagents are prepared in multistep reactions and so are
not recoverable due to destruction during their removal.
3-hydroxypyrrolidine or piperidine moieties as the core struc-
tures.25–27 These subgroups of alkaloids are frequently found in
Nature,28,29 many of which show a wide range of biological activi-
ties30–32 for potential applications in medicine, and in the design of
new drugs.33–35 We have already shown the utility of 1a for the
syntheses of a pyrrolidine alkaloid, (+)-preussin,36–38 and a piperi-
dine alkaloid, (+)-carpamic acid.39,40 Initially, we attempted the
desymmetrization of anhydride 1a with several chiral reagents
including Heathcock’s 1-(10-naphthyl)ethanol.11 The selectivities
were moderate to poor while the diastereomeric half-acids or their
esters were not separable by chromatography or crystallization. To
overcome this problem, we introduced41 a method for the desym-
metrization of 3-substituted glutaric anhydrides 1 using the lith-
ium salt of Evans’ oxazolidin-2-one 2a.42 Thus, the reaction of 1a
with the lithium salt of 2a provided a mixture of diastereoisomeric
methyl esters 3a and 4a (Table 1) after esterification with diazo-
methane. Although the reaction was clean and quantitative, the
O
R
HN
R1
O
R2
O
O
O
R2
2a; R1= PhCH2-; R2= H
2b; R1= Me2CH-; R2= H
2c; R1= Ph2CH-; R2= H
1a; R = SiMe2Ph
1b
1c
; R = Ph
; R = 4-F-C6H5-
1d; R = Me2CH-
1e; R = Me-
1
2
We were in need of a suitable method for the desymmetrization
of the prochiral 3-[dimethyl(phenyl)silyl]glutaric anhydride 1a
2d
; R = Me2CH-; R = Ph
1
2e
; R = Me2CH-;
R2= 2-MeO-5-Me-C6H3-
* Corresponding author. Tel.: +91 22 25595012; fax: +91 22 25505151.
E-mail address: ghsunil@barc.gov.in (S.K. Ghosh).
Figure 1. Structures of anhydrides and oxazolidin-2-ones.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.12.010

2722
N. Chaubey et al. / Tetrahedron: Asymmetry 19 (2008) 2721–2730
diastereoselectivity was poor (3a:4a = 2/1). Since then we were in
search of a suitable chiral reagent for the desymmetrization of the
1a with very high selectivity. Herein, we describe the development
of a new SuperQuat43 oxazolidin-2-one that can desymmetrize 3-
substituted glutaric anhydrides with very high selectivity.
therefore, began our task by modifying the oxazolidin-2-one with
various substituents. Sibi44 had carried out modifications on Evans’
original oxazolidin-2-one 2a and had shown that the diphenyl-
substituted oxazolidin-2-one 2c (Fig. 1) was superior to 2a in con-
trolling the diastereoselectivity in radical and other reactions.
Therefore, the oxazolidin-2-one 2c was prepared following a
reported procedure.45 The lithium salt of this oxazolidin-2-one 2c
when reacted with anhydride 1a in THF–DMPU [DMPU = 1,3-
dimethyl-3,4,5,6-tetrahydropyrimidin-2(1H)-one] (4/1) at ꢁ78 °C
gave the diastereoisomeric acids with poor selectivity, as judged
by converting them into their corresponding methyl esters 3c
and 4c (3c:4c = 3/1) (Table 1, entry 3). This study indicated that
the steric bulk of the substituent at the 4-position on the oxazoli-
din-2-one had virtually no effect on the diastereoselectivity of the
anhydride opening.
Our next move was to examine the effect of the substituent(s) b
to the nitrogen on the oxazolidin-2-one. There have been a number
of research groups46–48 which have independently introduced
5,5-disubstituted oxazolidin-2-ones called SuperQuats as chiral
auxiliaries mainly to obviate the problems via purification of the
products by crystallization, and limit the endocyclic cleavage dur-
ing removal, which is known to be problematic with Evans’ oxaz-
olidin-2-ones.49 It is also important to note the importance of
these auxiliary types for the general chemist, with regard to their
superior exo-cleavage,43 conformational bias50 and versatility.51,52
More recently, other research groups have used these auxiliaries
and have also shown them to be excellent and versatile. We pre-
pared 4-isopropyl-5,5-diphenyloxazolidin-2-one 2d from (S)-va-
line following the reported procedure.53 The lithium salt of the
oxazolidin-2-one 2d in THF was made using n-BuLi at 0 °C and
was reacted with anhydride 1a at ꢁ78 °C in THF–DMPU (4/1)
(Table 2, entry 1). We were able to see that a clean reaction took
place, and the diastereoselectivity of the anhydride opening was
significantly higher when compared to the earlier results with
oxazolidin-2-ones 2a–c. After diazomethane esterification, the dia-
stereoisomeric methyl esters 3d and 4d were formed in a ratio of
ca. 90:10, as determined by 1H NMR spectroscopy. For further
improvement of the diastereoselectivity, we prepared an oxazolidin-
2-one 2e with bulkier aryl groups at the 5,5-positions (Scheme 1)
following a protocol similar to that used for the preparation of
2d. The reaction of its lithium salt, as described above, with anhy-
dride 1a led to a mixture of diastereoisomeric acids which were
esterified with diazomethane to give the methyl esters 3e and 4e
2. Results and discussion
As reported earlier,41 desymmetrization of anhydride 1a with
Evans’ oxazolidin-2-ones 2a or 2b (Table 1) showed poor selectiv-
ity providing esters 3a or 3b and 4a or 4b, respectively (3:4 ꢀ 2/1).
The parent acids of 3a and 4a were separable by fractional crystal-
lization, while the methyl, benzyl and tert-butyl esters could be
easily separated by conventional column chromatography on a
preparative scale. Presently, we restricted ourselves with the oxaz-
olidin-2-one class of chiral reagents because this fragment is
widely used as a powerful auxiliary for controlling diastereoselec-
tive reactions42 when attached to a carboxylic acid group. We,
Table 1
Desymmetrization of anhydride 1a with chiral oxazolidin-2-ones
SiMe2Ph
O
O
O
O
O
MeO
N
O
1. n-BuLi
THF-DMPU
-78 oC
O
R1
3a-c
HN
R1
O
+
SiMe2Ph
O
2. 1a
3. CH2N2
2a-c
MeO
N
O
R1
4a-c
Entry
R1
2
3
4
Ratioa (3:4)
Yield (%)
1
2
3
PhCH2–
Me2CH–
Ph2CH–
2a
2b
2c
3a
3b
3c
4a
4b
4c
65:35
62:38b
77:23b
96c
95c
89
a
Ratio determined by 1H NMR of the crude product.
Stereochemistry of methyl esters 3b,c and 4b,c was tentatively assigned in
b
analogy with 3a and 4a.
c
Results are from Ref. 41.
Table 2
Desymmetrization of anhydrides 1 with SuperQuat oxazolidin-2-one 2e
O
O
O
O
R
O
1. n-BuLi, THF-
O
R
O
DMPU, -78oC
HN
O
+
MeO
N
O
MeO
N
O
R
R1
R1
R1
R1
2.
R1
R1
4e-i
2d-e
3e-i
O
O
O
1a-e
3. CH2N2
Entry
R
R1
1
3
4
Ratioa (3:4)
Yield (%)
1
2
3
4
5
6
SiMe2Ph
SiMe2Ph
Ph
4-F–C6H4–
Me2CH–
Me–
Ph
1a
1a
1b
1c
1d
1e
3d
3e
3f
3g
3h
3i
4d
4e
4f
4g
4h
4i
90:10
95:5
80
84
80
70
73
74
2-MeO–5-Me–C6H3–
2-MeO–5-Me–C6H3–
2-MeO–5-Me–C6H3–
2-MeO–5-Me–C6H3–
2-MeO–5-Me–C6H3–
95:5b
95:5
90:10b
81:19b
a
Ratio determined by 1H NMR of the crude product.
Stereochemistry of methyl esters 3d,f,h,i and 4d,f,h,i was tentatively assigned in analogy with 3e/3g and 4e/4g.
b

N. Chaubey et al. / Tetrahedron: Asymmetry 19 (2008) 2721–2730
2723
acids were formed in a ratio of 90:10. Although the methyl-substi-
tuted anhydride 1e showed moderate diastereoselectivity (81:19),
the diastereoisomeric ratio enrichment (dr = 94/6) could be easily
improved to 3i:4i = 94:6 by a single crystallization.
MgBr
Me
O
1. (S)-Boc-Val-OMe
2. KOBu-t
OMe
HN
O
R1
R1
66%
To determine the diastereoselectivity of the opening of anhy-
drides with oxazolidin-2-ones 2c–2e, model mixtures of 3c–i and
4c–i were prepared. For this, anhydrides 1a–e were opened up
with methanol to give the racemic monomethyl esters (Scheme 2),
which were then reacted with oxalyl chloride in the presence of
catalytic amount of DMF to give the intermediate acid chlorides.
The lithium salt of oxazolidin-2-ones 2c–2e was prepared using
butyl lithium and was reacted with the acid chlorides to give the
corresponding diastereoisomeric mixtures of 3c–i and 4c–i in al-
most equal proportions and good yields. The ester methyl and/or
silyl methyl protons of diastereomers 3c–e and 4c–e, while the iso-
propyl methyls and/or the ester methyls of the diastereoisomeric
products 3f–i and 4f–i were discernable by 1H NMR (Table 3),
and thus used for diastereoisomer ratio determination.
2e
R1 = 2-OMe-5-Me-C6H3-
Scheme 1. Synthesis of SuperQuat oxazolidin-2-one 2e.
in a 95:5 ratio (Table 2, entry 2). The high diastereoselectivity of
the anhydride opening with 2e is synthetically acceptable.
To examine the generality of this desymmetrization protocol,
various prostereogenic 3-substituted glutaric anhydrides 1b–e
were treated with the Li-salt of 2e under the standardized condi-
tions (Table 2). The choices of the anhydrides were made based
on their utility as key intermediates in the synthesis of various nat-
ural products. The diastereoselectivity of the anhydride opening of
3-aryl-substituted glutaric anhydrides 1b,c was very high (95:5).
For the isopropyl-substituted anhydride 1d, the diastereoisomeric
To assess the sense of chiral induction in the anhydride opening
reactions, it was essential to establish the absolute stereochemistry
of the products. The mixture of acids obtained from the desymmet-
rization reaction of 1a with 2e was converted to a mixture of the
R
1. MeOH, DMAP
R
2.(COCl)2, DMF, CH2Cl2
O
O
O
O
O
MeO
Cl
1a-e
1a; R = SiMe2Ph
1b; R = Ph
O
1c; R = 4-F-C6H4-
1d; R = i-Pr
1e
; R = Me
HN
O
n-BuLi
THF, 0 o
THF,
R2
R1
C
DMPU
-78 oC-r.t.
R2
R1
2c-e
67-74%
2c; R1 = Ph, R2 = H
2d; R1 = Me, R2 = Ph
; R1 = Me,
2e
R2 =2-MeO-5-Me-C6H3
R
R
O
O
O
O
O
O
MeO
N
O
+
MeO
N
O
R2
R1
R2
R2
R1
R2
R1
R1
3c-i
4c-i
1
2
3c; R=SiMe2Ph, R1= Ph, R2= H
; R=SiMe2Ph, R = Ph, R = H
4c
4d
1
2
1
2
3d
; R=SiM e2Ph, R =Me, R =Ph
; R=SiMe2Ph, R =Me, R =Ph
1
2
1
2
4e
; R=SiMe2Ph, R =Me, R =
3e
; R=SiMe2Ph, R =Me, R =
2-MeO-5-Me-C6H3
4f; R=Ph, R1=Me, R2=
2-MeO-5-Me-C6H3
3f; R=Ph, R1=Me, R2=
2-MeO-5-Me-C6H3
2-MeO-5-Me-C6H3
1
2
1
2
4g
3g
; R=4-F-C6H4-, R =Me, R =
; R=4-F-C6H4-, R =Me, R =
2-MeO-5-Me-C6H3
2-MeO-5-Me-C6H3
3h; R =i-Pr, R1=Me, R2=
2-MeO-5-Me-C6H3
3i; R=Me, R1 =Me, R2=
MeO-5-Me-C6H3
4h; R =i-Pr, R1=Me, R2=
2-MeO-5-Me-C6H3
; R=Me, R1 =Me, R2=
4i
2-MeO-5-Me-C6H3
Scheme 2. Preparation of model mixture of diastereomeric methyl esters 3c–i and 4c–i.

2724
N. Chaubey et al. / Tetrahedron: Asymmetry 19 (2008) 2721–2730
Table 3
Chemical shift values (d) in ppm for selected group of protons of diastereoisomeric methyl esters 3c–i and 4c–i
Entry
3/4
CO2Me of 3c–i
CO2Me of 4c–i
CHMe2 of 3d–i
CHMe2 of 4d–i
SiMe of 3c–e
SiMe of 4c–e
1
2
3
4
5
6
7
3c/4c
3d/4d
3e/4e
3f/4f
3g/4g
3h/4h
3i/4i
3.58a
3.47a
3.47
3.55a
—
—
0.32
0.32 and 0.33
3.36a
0.72 and 0.86
0.70 and 0.96
0.70 and 0.88a
0.69 and 0.88a
0.71 and 0.82
0.71 and 0.92
0.71 and 0.84
0.70 and 0.94
0.50 and 0.63a
0.51 and 0.66a
—
—
0.18
0.27 and 0.30
b
—
0.26 and 0.27a
0.31 and 0.34a
3.56
3.52
—
—
—
—
—
—
—
—
b
3.56
—
3.62a
3.64a
3.56a
3.58a
b
b
a
Peaks at these positions were used for estimation of diastereoisomer ratio.
Chemical shifts values could not be obtained with certainty due to overlap of peaks.
b
corresponding t-Bu esters (Scheme 3) which upon simple crystal-
lization gave the pure diastereoisomeric ester 5. The oxazolidin-
2-one moiety from 5 was removed by transesterification using
the benzyl alcohol and Ti(OBn)4 catalyst to give the known
diester 6.36 The (R)-configuration of the silicon-bearing asym-
metric centre in 5 was confirmed from the specific rotation data
tion reaction of 1c with 2e was converted to the tert-butyl ester
8. Removal of the oxazolidin-2-one group was achieved by simple
NaOH hydrolysis providing the acid which was esterified with
diazomethane to give diester 9. In this process also, the oxazoli-
din-2-one 2e was recovered in 93% yield. The tert-butyl ester group
in diester 9 was selectively hydrolyzed with TFA in dichlorometh-
ane to give the diacid monomethyl ester 7 in good yield (Scheme 4).
The absolute stereochemistry of the aryl-bearing centre in 8 was
ascertained to be (R) by comparing the specific rotation data of 7
of 6 {½a 2D2
ꢂ
¼ þ1:15 (c 2.08, MeOH); lit.:36
½
a 2D4
ꢂ
¼ þ1:2 (c 4.46,
MeOH)}.
We also checked the facial selectivity for 3-fluorophenyl-substi-
tuted anhydride 1c by converting it to the known derivative 7. For
this, the diastereoisomeric acid mixture from the desymmetriza-
{½a 2D2
ꢂ
¼ ꢁ3:4 (c 1.54, CHCl3)} with the reported value10
¼ ꢁ4:3 (c 1, CHCl3)}.
{½a 2D0
ꢂ
SiMe2Ph
O
SiMe2Ph
O
O
O
O
O
1. (COCl)2, DMF,
CH2Cl2
t-BuO
N
O
HO
N
O
2. t-BuOH
3.Crystallization
R1
R1
R1
R1
70%
R1 = 2-MeO-5-Me-C6H3-
R1 = 2-MeO-5-Me-C6H3-
5
Ti(OBn)4, BnOH
100 oC, 24 h
78%
SiMe2Ph
O
O
t-BuO
OBn
6
Scheme 3. Determination of the sense of chiral induction for the desymmetrization of 1a with 2e.
C6H4-F-p
O
C6H4-F-p
O
O
O
O
O
1. (COCl)2, DMF,
CH2Cl2
HO
N
O
t-BuO
N
O
2. t-BuOH
R1
R1
R1
R1
86%
R1 = 2-MeO-5-Me-C6H3-
R1 = 2-MeO-5-Me-C6H3-
8
1. NaOH,
THF-MeOH-H2O
80%
2. CH2N2, Et2O
C6H4-F-p
C6H4-F-p
O
O
O
O
TFA, CH2Cl2 (1/1)
87%
HO
OMe
t-BuO
OMe
7
9
Scheme 4. Determination of the sense of chiral induction for 1c desymmetrization with 2e.

N. Chaubey et al. / Tetrahedron: Asymmetry 19 (2008) 2721–2730
2725
The origin of the increase in diastereoselectivity of the anhy-
dride opening with SuperQuat oxazolidin-2-ones 2d and 2e com-
pared to that with Evans’ type oxazolidin-2-ones 2a–c can be
explained on the basis of the conformational preferences of the
oxazolidin-2-ones as shown in Figure 2. In the former type,
the conformation A-2 is favoured over conformation B-2 due to
the steric interaction between the 5-position aryl and isopropyl
methyls, while in the latter type, both conformations A-1 and
B-1 have similar steric interactions. The presence of geminal diaryl
groups at the 5-position of 2d,e would serve to direct the confor-
mation of the stereocontrolling isopropyl group at the 4-position
close to the point of the 3-position nitrogen as shown in B-2. The
stereoinduction step is the kinetically controlled addition of the
oxazolidin-2-one anion to the carbonyl of the prostereogenic anhy-
dride. Of the two carbonyls in the anhydride, the one that has min-
imal steric hindrance provided by the oxazolidin-2-one anion and
the substituent at the anhydride in the transition state underwent
addition to give the observed product diastereoisomer.
chromatography was performed on silica gel (230–400 mesh).
The 1H NMR and 13C NMR spectra were recorded with a Bruker
200 MHz spectrometer. The spectra were referenced to residual
chloroform (d 7.25 ppm, 1H; d 77.00 ppm, 13C). The mass spectra
were recorded on a Shimadzu GC–MS 2010 mass spectrometer
(EI 70 eV). High resolution mass spectra were recorded at 60–
70 eV with a Waters Micromass Q-TOF spectrometer (ESI, Ar).
The IR spectra were recorded with a JASCO FT IR spectrophotome-
ter in NaCl cells or in KBr discs. Peaks are reported in cmꢁ1. Melting
points (mp) were determined on a Fischer John’s melting point
apparatus and are uncorrected. Optical rotations were measured
with a JASCO DIP-360 polarimeter. As the 5,5-aryl groups in oxazo-
lidinones 2d and 2e are diastereotopic and magnetically non-
equivalent, some of the aromatic protons and carbons for these
aryls are discernable by NMR. Similar NMR differences of the aryl
groups are also observed in case of acylated oxazolidinones 3d–i
and 4d–i (vide infra).
4.1. (4S)-5,5-Di(2-methoxy-5-methylphenyl)-4-isopropylox-
azolidin-2-one 2e
O
O
H
H
H
H
H
O
H
O
A solution of 2-methoxy-4-methylphenylmagnesium bromide
was prepared in the usual way by using 2-bromo-4-methylanisole
(30.4 g, 151 mmol), Mg turnings (3.7 g, 154 mmol) and THF
(100 mL) under an argon atmosphere. A solution of N-(tert-butox-
ycarbonyl)-S-valine methyl ester (10 g, 43.2 mmol) in dry THF
(50 mL) was added dropwise to the Grignard solution at 0 °C. After
the addition was over, the reaction mixture was allowed to warm
to room temperature and stirring was continued for 18 h. The reac-
tion mixture was slowly poured into an ice-cold saturated NH4Cl
solution and extracted with ethyl acetate (2 ꢃ 150 mL). The com-
bined organic phase was washed with brine (150 mL), dried over
anhydrous MgSO4 and concentrated under reduced pressure. The
residue was chromatographed followed by crystallization from
petroleum ether to give (2S)-2-tert-butyloxycarbonylamino-1,1-
di(2-methoxy-5-methylphenyl)-3-methylbutanol (14.8 g, 77%).
N
N
OMe
OMe
Me
Me
H
Me
H
H
Me
H
B-1
A-1
Me
O
Me
O
H
H
H
H
N
N
O
O
OMe
OMe
OMe
Me
Me
H
Me
Me
OMe
H
Me
Me
Mp 112–113 °C; ½a D22
ꢂ
¼ ꢁ143:6 (c 1, EtOH); Rf = 0.55 (hexane/ethyl
B-2
A-2
acetate, 90/10); IR (CHCl3 film): 3502, 3454, 1700, 1497 cmꢁ1
;
1H
Figure 2. Conformational preferences of oxazolidin-2-ones.
NMR (200 MHz, CDCl3) d 0.84 (d, J = 6.8 Hz, 6H, CH3CHCH3), 1.40
(s, 9H, t-BuO), 1.51–1.67 (m, 1H, CH3CHCH3), 2.28 (s, 3H, ArCH3),
2.32 (s, 3H, ArCH3), 3.47 (s, 3H, ArOCH3), 3.48 (s, 3H, ArOCH3),
5.05 (d, J = 10 Hz, 1H, NCH), 5.05 (d, J = 10.2 Hz, 1H, NH), 5.29 (s,
br, 1H, OH), 6.60 (d, J = 7.8 Hz, 1H, Ar), 6.64 (d, J = 7.8 Hz, 1H, Ar),
6.90–6.98 (m, 2H, Ar), 7.52 (s, 1H, Ar), 7.58 (d, J = 2 Hz, 1H, Ar);
13C NMR (50 MHz, CDCl3) d 17.1 (CHCH3), 20.6 (ArCH3), 20.8
(ArCH3), 22.6 (CHCH3), 28.3 (3 ꢃ CH3-t-Bu), 29.5 (CHMe2), 55.2
(NCH), 55.3 (OCH3), 55.9 (OCH3), 78.2 (Me3CO), 81.6 (Ar2COH),
111.7 (HC–Ar), 112.3 (HC–Ar), 127.4 (HC–Ar), 127.9 (HC–Ar), 128.1
(HC–Ar), 128.8 (MeC–Ar), 129.6 (MeC–Ar), 129.7 (HC–Ar), 132.5
(HOCC–Ar), 133.0 (HOCC–Ar), 153.8 (MeOC–Ar), 154.8 (MeOC–Ar),
156.2 (C@O). Anal. Calcd for C26H37NO5: C, 70.40; H, 8.41; N,
3.16. Found: C, 70.45; H, 8.42; N, 3.02.
3. Conclusion
In conclusion, the results of this investigation show that spe-
cially substituted diaryl SuperQuat oxazolidin-2-ones in stoichi-
ometric amounts could be efficiently employed for the
desymmetrization of prostereogenic anhydrides on a preparative
scale with very high diastereoselectivity. Therefore, this could form
a convenient method for both the enantioconvergent and enantio-
divergent syntheses of differentially substituted glutaric acid
derivatives. The diastereoselectivity depended significantly on
the substituents b to the amino group, but not on the steric bulk
of the
a-substituents. The SuperQuat oxazolidin-2-ones could be
Potassium tert-butoxide (4.2 g, 37.8 mmol) was added to a stir-
red solution of the alcohol (2S)-2-tert-butyloxyamino-3-methyl-
1,1-di(2-methoxy-5-methylphenyl)butanol (14.0 g, 31.5 mmol) in
dry THF (205 mL) at 0 °C. After 2.5 h, the resulting suspension
was poured into a 10% aqueous solution of NH4Cl (350 mL) and ex-
tracted with CHCl3 (2 ꢃ 200 mL). The extract was washed with
water (2 ꢃ 100 mL), dried over MgSO4 and evaporated under re-
duced pressure. The residue was crystallized from ethyl acetate
to give oxazolidin-2-one 2e (10.0 g, 86%). Mp 266–268 °C;
easily prepared and can be detached from the products easily by
NaOH hydrolysis or Ti(IV)-catalyzed transesterification with high
recovery (>90%) without any loss of purity.
4. Experimental
All reactions were performed in oven-dried (120 °C) or flame-
dried glass apparatus under a dry N2 or argon atmosphere. Tetra-
hydrofuran (THF) was dried from sodium/benzophenone, while
t-BuOH was dried from CaH2 followed by storage over 4 Å molec-
ular sieves. n-BuLi (1.5 M in hexane) was purchased from Aldrich.
Anhydrides 1a,41 1b–e11 and oxazolidin-2-ones 2a–b,54 2c,45 2d53
were prepared following the literature procedures. The column
½
a 2D4
ꢂ
¼ ꢁ346:6 (c 0.5, CHCl3); Rf = 0.4 (CHCl3); IR (KBr): 3359,
1764, 1503 cmꢁ1 1H NMR (200 MHz, CDCl3) d 0.66 (d, J = 6.6 Hz,
;
3H, CH3CHCH3), 0.92 (d, J = 7.2 Hz, 3H, CH3CHCH3), 1.51–1.67 (m,
1H, CH3CHCH3), 2.27 (s, 3H, ArCH3), 2.32 (s, 3H, ArCH3), 3.43 (s,
3H, OCH3), 3.51 (s, 3H, OCH3), 4.76 (d, J = 1.6 Hz, 1H, NCH), 6.22

2726
N. Chaubey et al. / Tetrahedron: Asymmetry 19 (2008) 2721–2730
(br, 1H, NH), 6.62 (d, J = 8.2 Hz, 1H, Ar), 6.69 (d, J = 8.2 Hz, 1H, Ar),
6.97–7.05 (m, 2H, Ar), 7.24 (s, d, J = 1 Hz, 1H, Ar), 7.67(d, J = 2 Hz,
1H, Ar); 13C NMR (50 MHz, CDCl3) d 15.0 (CHCH3), 20.6 (ArCH3),
20.8 (ArCH3), 21.4 (CHCH3), 29.2 (CHMe2), 55.5 (ArOCH3), 56.2 (Ar-
OCH3), 61.6 (NCH), 88.8 (Ar2COCO), 111.3 (HC–Ar), 114.0 (HC–Ar),
127.9 (MeC–Ar), 128.0 (HC–Ar), 128.7 (HC–Ar), 128.7 (MeC–Ar),
129.0 (HC–Ar), 129.1(O@COCC–Ar), 129.5 (HC–Ar), 129.6 (O@COCC–
Ar), 152.9 (MeOC–Ar), 156.3 (MeOC–Ar), 159.8 (C@O). Anal. Calcd
for C22H27NO4: C, 71.52; H, 7.37; N, 3.79. Found: C, 71.37; H,
7.17; N, 3.66.
crude acid chloride. In another flask, n-butyl lithium (0.35 mL,
1.5 M in hexane, 0.52 mmol) was slowly added to a suspension
of oxazolidin-2-one 2e (185 mg, 0.5 mmol) in dry THF (2 mL) at
0 °C under an argon atmosphere until a clear solution resulted
(30 min). The reaction mixture was cooled to ꢁ78 °C, and dry
DMPU (1 mL) was added followed by a solution of the crude acid
chloride in dry THF (5 mL) which was prepared previously. The
mixture was allowed to return to room temperature and was stir-
red for 2 h. The reaction mixture was diluted with water and ex-
tracted with ethyl acetate. The extract was washed with water
and brine, dried and evaporated under reduced pressure. The resi-
due was purified by column chromatography to give an insepara-
ble 1:1 mixture of diastereoisomeric methyl esters 3e and 4e
(212 mg, 67%) as a colourless oil. Data for 4e (obtained from mix-
ture): Rf = 0.56 (hexane/ethyl acetate, 85/15); 1H NMR (CDCl3,
200 MHz) d 0.31 (s, 3H, SiMe), 0.34 (s, 3H, SiMe), 0.70 (d,
J = 6.6 Hz, 3H, CH3CHCH3), 0.94 (d, J = 7.2 Hz, 3H, CH3CHCH3),
1.58–1.75 (m, 1H, CH3CHCH3), 1.85–2.06 (m, 1H, SiCH), 2.23 (s,
3H, ArCH3), 2.36 (s, 3H, ArCH3), 2.23–2.39 (m, 2H, CH2CO2Me),
2.76 (dd, J = 9.6, 17.2 Hz, 1H, NCOCHAHB), 3.04 (dd, J = 4.2,
17.2 Hz, 1H, NCOCHAHB), 3.38 (s, 3H, ArOCH3), 3.48 (s, 6H, ArOCH3,
COOCH3), 5.78 (s, br, 1H, NCH), 6.62 (d, J = 8.4Hz, 1H, Ar), 6.68 (d,
J = 8.2 Hz, 1H, Ar), 6.95–7.06 (m, 2H, Ar), 7.20 (d, J = 2Hz, 1H, Ar),
7.28–7.33 (m, 3H, Ar), 7.42–7.52 (m, 2H, Ar), 7.69 (s, br, 1H, Ar);
13C NMR (CDCl3, 50 MHz) d ꢁ4.6 (SiCH3), ꢁ4.2 (SiCH3), 15.9
(CHCH3), 17.9 (SiCH), 20.5 (2 ꢃ ArCH3), 22.4 (CHCH3), 29.8
(CHMe2), 34.3 (CH2CON), 35.3 (CH2CO2), 51.1 (CO2CH3), 55.3 (Ar-
OCH3), 55.9 (ArOCH3), 62.1 (NCH), 88.9 (Ar2COCO), 110.9 (HC–Ar),
113.8 (HC–Ar), 126.4 (C–Ar), 127.2 (HC–Ar), 127.6 (2 ꢃ HC–Ar), 127.9
(C–Ar), 128.7 (HC–Ar), 128.8 (2 ꢃ C–Ar), 129.0 (2 ꢃ HC–Ar), 130.0
(HC–Ar), 133.9 (2 ꢃ HC–Ar), 136.9 (C–Ar), 152.6 (MeOC–Ar), 153.4
(MeOC–Ar), 156.2 (NCO2), 172.5 (CO2CH3), 173.3 (CON).
4.2. (30R,4S)-5,5-Di(2-methoxy-5-methylphenyl)-3-{3-[dimethyl-
(phenyl)silyl]-4-methoxycarbonyl-1-oxobutyl}-4-isopropyl-
oxazolidin-2-one 3e and its (30S)-diastereoisomer 4e
n-Butyl lithium (1.8 mL, 1.5 M in hexane, 2.7 mmol) was slowly
added to a suspension of oxazolidin-2-one 2e (922 mg, 2.5 mmol)
in dry THF (12.5 mL) at 0 °C under argon atmosphere until a clear
solution resulted (30 min). The reaction mixture was cooled to
ꢁ78 °C after which dry DMPU (6 mL) was added followed by a
solution of the anhydride 1a (670 mg, 2.7 mmol) in dry THF
(12.5 mL). After 4 h at ꢁ78 °C, the reaction mixture was acidified
with 5% citric acid solution and was extracted with ethyl acetate.
The extract was concentrated under reduced pressure and the res-
idue was dissolved in benzene. The benzene solution was washed
several times with water, dried over MgSO4 and concentrated un-
der reduced pressure. The residue was treated with an ether solu-
tion of diazomethane and was concentrated under reduced
pressure. The crude product was purified by column chromatogra-
phy to give 3e (1.32 g, 84%) as an inseparable mixture containing
5% of its diastereoisomer 4e as a colourless oil. Data for 3e:
½
a 2D3
ꢂ
¼ ꢁ165:7 (c 1.68, MeOH); Rf = 0.56 (hexane/ethyl acetate,
85/15); IR (CHCl3 film): 1778, 1735, 1698, 1613, 1503, 1256,
1113 cmꢁ1 1H NMR (CDCl3, 200 MHz) d 0.26 (s, 3H, SiMe), 0.27
;
4.3. (30R,4S)-5,5-Di(2-methoxy-5-methylphenyl)-4-isopropyl-3-
(4-methoxycarbonyl-1-oxobutyl-3-phenyl)oxazolidin-2-one 3f
and its (30S)-diastereoisomer 4f
(s, 3H, SiMe), 0.70 (d, J = 6.6 Hz, 3H, CH3CHCH3), 0.96 (d,
J = 7.2 Hz, 3H, CH3CHCH3), 1.58–1.75 (m, 1H, CH3CHCH3), 1.85–
2.02 (m, 1H, SiCH), 2.22 (s, 3H, ArCH3), 2.24 (dd, J = 8, 15.8 Hz,
1H, CHAHBCO2Me), 2.33 (s, 3H, ArCH3), 2.38 (dd, J = 6.4, 15.8 Hz,
1H, CHAHBCO2Me), 2.95 (d, J = 6.4 Hz, 2H, NCOCH2), 3.45 (s, 3H, Ar-
OCH3), 3.46 (s, 3H, ArOCH3), 3.47 (s, 3H,COOCH3), 5.77 (d, J = 1.8 Hz,
1H, NCH), 6.62 (d, J = 8.4Hz, 1H, Ar), 6.68 (d, J = 8.2 Hz, 1H, Ar),
Following the general procedure described for the desymmetri-
zation of 1a with 2e, anhydride 1b (102 mg, 0.54 mmol) and oxaz-
olidin-2-one 2e (186 mg, 0.5 mmol) gave methyl esters 3f (230 mg,
80%) as an inseparable mixture containing 5% of its diastereoiso-
6.95–7.06 (m, 2H, Ar), 7.20 (d, J = 2Hz, 1H, Ar), 7.28–7.33 (m, 3H,
mer 4f as a colourless oil. Data for 3f: ½a D23
¼ ꢁ172:8 (c 1, MeOH);
ꢂ
13
Ar), 7.42–7.49 (m, 2H, Ar), 7.68 (d, J = 1.8 Hz, 1H, Ar);
C NMR
Rf = 0.6 (hexane/ethyl acetate, 85/15); IR (CHCl3 film): 1777, 1737,
(CDCl3, 50 MHz) d ꢁ4.8 (SiCH3), ꢁ4.2 (SiCH3), 15.7 (CHCH3), 17.1
(SiCH), 20.4 (2 ꢃ ArCH3), 22.3 (CHCH3), 29.6 (CHMe2), 34.1
(CH2CON), 35.1 (CH2CO2), 51.0 (CO2CH3), 55.0 (ArOCH3), 55.6 (Ar-
OCH3), 61.9 (NCH), 88.7 (Ar2COCO), 110.8 (HC–Ar), 113.5 (HC–Ar),
126.2 (C–Ar), 127.1 (HC–Ar), 127.5 (2 ꢃ HC–Ar), 127.7 (C–Ar), 128.5
(HC–Ar), 128.6 (2 ꢃ C–Ar), 128.9 (2 ꢃ HC–Ar), 129.8 (HC–Ar), 133.7
(2 ꢃ HC–Ar), 136.7 (C–Ar), 152.4 (MeOC–Ar), 153.1 (MeOC–Ar), 156.0
(NCO2), 172.3 (CO2CH3), 173.2 (CON); ESI MS: m/z (%) = 632 (3)
(M++H), 555 (13), 554 (100), 510 (16); HRMS: Calcd for C36H46NO7-
Si (M++H) 632.3044. Found: 632.3029.
A model diastereomeric mixture of methyl esters 3e and 4e was
made by using the following procedure. A solution of the anhy-
dride 1a (124 mg, 0.5 mmol) and DMAP (12 mg, 0.1 mmol) in
methanol (5 mL) was stirred at room temperature for 1 h. The sol-
vent was evaporated and the residue was diluted with ethyl ace-
tate. The ethyl acetate solution was washed with dil HCl, water
and brine, dried over MgSO4 and evaporated to give the half ester
(140 mg, 0.5 mmol, 100%). The half ester was dissolved in dry
1702, 1612, 1503 cmꢁ1 1H NMR (200 MHz, CDCl3) d 0.70 (d,
;
J = 6.6 Hz, 3H, CH3CHCH3), 0.88 (d, J = 7 Hz, 3H, CH3CHCH3), 1.58–
1.72 (m, 1H, CH3CHCH3), 2.03 (s, 3H, ArCH3), 2.34 (s, 3H, ArCH3),
2.58 (dd, J = 8, 15.4 Hz, 1H, CHAHBCO2Me), 2.68 (dd, J = 7.2,
15.4 Hz, 1H, CHAHBCO2Me), 3.19–3.31 (m, 2H, NCOCH2), 3.37 (s,
3H, ArOCH3), 3.41 (s, 3H, ArOCH3), 3.56 (s, 3H, COOCH3), 3.65–
3.83 (m, 1H, PhCH), 5.72 (d, J = 1.8 Hz, 1H, NCH), 6.59 (d,
J = 8.2 Hz, 1H, Ar), 6.62 (d, J = 8.2 Hz, 1H, Ar), 6.90–7.05 (m, 3H,
Ar), 7.12–7.21 (m, 5H, Ar), 7.66 (d, J = 2 Hz, 1H, Ar); 13C NMR
(50 MHz, CDCl3) d 15.9 (CHCH3), 20.5 (2 ꢃ ArCH3), 22.3 (CHCH3),
29.7 (CHMe2), 37.3 (PhCH), 40.5 (CH2CO2), 40.9 (CH2CON), 51.3
(CO2CH3), 55.2 (ArOCH3), 55.7 (ArOCH3), 62.0 (NCH), 89.1 (Ar2CO-
CO), 110.9 (HC–Ar), 113.5 (HC–Ar), 126.5 (C–Ar, HC–Ar), 127.2
(2 ꢃ HC–Ar), 127.4 (HC–Ar), 127.7 (C–Ar), 128.3 (2 ꢃ HC–Ar), 128.4
(HC–Ar), 128.8 (C–Ar), 128.9 (C–Ar), 129.0 (HC–Ar), 129.9 (HC–Ar),
142.7 (ipso-C–Ph), 152.5 (MeOC–Ar), 153.5 (MeOC–Ar), 155.9
(NCO2), 170.7 (CO2Me), 171.9 (CON). Anal. Calcd for C34H39NO7:
C, 71.18; H, 6.85; N, 2.44. Found: C, 71.08; H, 6.91; N, 2.29.
Following the general procedure described for the model syn-
thesis of a mixture of 3e and 4e from 1a and 2e, anhydride 1b
(95 mg, 0.5 mmol) and oxazolidin-2-one 2e (186 mg, 0.5 mmol)
gave a 1:1 mixture of diastereoisomeric methyl esters 3f and
4f (203 mg, 71%) as a colourless oil. Data for 4f (obtained
dichloromethane (2 mL), after which dry DMF (6
lL, 0.08 mmol)
was added followed by the addition of oxalyl chloride (107
lL,
1.23 mmol) at 0 °C under an argon atmosphere. After 2 h at room
temperature, the reaction mixture was concentrated under re-
duced pressure followed by high vacuum (0.1 Torr) to give the

N. Chaubey et al. / Tetrahedron: Asymmetry 19 (2008) 2721–2730
2727
from mixture): Rf = 0.6 (hexane/ethyl acetate, 85/15); 1H NMR
(200 MHz, CDCl3) d 0.50 (d, J = 6.6 Hz, 3H, CH3CHCH3), 0.63 (d,
J = 7 Hz, 3H, CH3CHCH3), 1.58–1.72 (m, 1H, CH3CHCH3), 2.24 (s,
3H, ArCH3), 2.33 (s, 3H, ArCH3), 2.54 (dd, J = 8.4, 15.6 Hz, 1H,
CHAHBCO2Me), 2.62 (dd, J = 6, 15.6 Hz, 1H, CHAHBCO2Me), 3.00
(dd, J = 7, 16.6 Hz, 1H, CHAHBCON), 3.41 (dd, J = 10, 16.6 Hz, 1H,
CHAHBCON), 3.44 (s, 3H, ArOCH3), 3.47 (s, 3H, ArOCH3), 3.52 (s,
3H, COOCH3), 3.63–3.83 (m, 1H, PhCH), 5.72 (d, J = 1.8 Hz, 1H,
NCH), 6.59 (d, J = 8.2 Hz, 1H, Ar), 6.68 (d, J = 8.2 Hz, 1H, Ar),
6.98–7.27 (m, 8H, Ar), 7.64 (d, J = 2 Hz, 1H, Ar); 13C NMR
(50 MHz, CDCl3) d 15.6 (CHCH3), 20.56 (2 ꢃ ArCH3), 22.0 (CHCH3),
29.6 (CHMe2), 38.0 (PhCH), 40.2 (CH2CO2), 40.3 (CH2CON), 51.3
(CO2CH3), 55.2 (ArOCH3), 55.9 (ArOCH3), 61.9 (NCH), 88.9 (Ar2CO-
CO), 110.9 (HC–Ar), 113.9 (HC–Ar), 126.3 (C–Ar), 126.6 HC–Ar), 127.2
(2 ꢃ HC–Ar), 127.4 (HC–Ar), 127.8 (C–Ar), 128.3 (2 ꢃ HC–Ar), 128.6
(HC–Ar), 128.8 (C–Ar), 128.9 (C–Ar), 129.0 (HC–Ar), 130.1 (HC–Ar),
142.5 (ipso-C–Ph), 152.6 (MeOC–Ar), 153.3 (MeOC–Ar), 156.2
(NCO2), 171.0 (CO2Me), 171.9 (CON).
(HC–Ar), 113.5 (HC–Ar), 114.8 (d, J = 21.1 Hz, 2 ꢃ HC–Ar), 126.0 (C–
Ar), 127.0 (HC–Ar), 127.3 (C–Ar), 128.5 (HC–Ar), 128.7 (HC–Ar), 128.6
(2 ꢃ C–Ar), 128.9 (2 ꢃ HC–Ar), 129.9 (HC–Ar), 138.1 (ipso-C–Ar),
152.4 (MeOC–Ar), 153.1 (MeOC–Ar), 156.0 (NCO2), 161.3 (d,
J = 243 Hz, FC–Ar), 170.6 (CO2Me), 171.4 (CON).
4.5. (30R,4S)-5,5-Di(2-methoxy-5-methylphenyl)-3-(3-isopropyl-
4-methoxycarbonyl-1-oxobutyl)-4-isopropyloxazolidin-2-one
3h and its (30S)-diastereoisomer 4h
Following the general procedure described for the desymmetri-
zation of 1a with 2e, anhydride 1d (125 mg, 0.8 mmol) and oxaz-
olidin-2-one 2e (275 mg, 0.75 mmol) gave methyl ester 3h
(295 mg, 73%) as an inseparable mixture containing 10% of its dia-
stereoisomer 4h. Data for 3h: ½a D24
¼ ꢁ188:3 (c 0.44, EtOH);
ꢂ
Rf = 0.45 (hexane/ethyl acetate 85/15); IR (CHCl3 film): 1777,
1735, 1700, 1502 cmꢁ1 1H NMR (200 MHz, CDCl3) d 0.67 (d,
;
J = 7 Hz, 3H, CH3CHCH3), 0.71 (d, J = 6.6 Hz, 3H, CH3CHCH3), 0.82
(d, J = 6.8 Hz, 3H, CH3CHCH3), 0.96 (d, J = 7 Hz, 3H, CH3CHCH3),
1.56–1.80 (m, 2H, 2 ꢃ CH3CHCH3), 2.19–2.25 (m, 1H, Me2CHCH),
2.22 (s, 3H, ArCH3), 2.31–2.49 (m, 2H, CH2CO2Me), 2.34 (s, 3H,
ArCH3), 2.80 (dd, J = 6.2 Hz, J = 17.2 Hz, 1H, CHAHBCON), 2.92 (dd,
J = 6.8 Hz, J = 17.2 Hz, 1H, CHAHBCON), 3.46 (s, 3H, ArOCH3), 3.47
(s, 3H, ArOCH3), 3.62 (s, 3H, CO2CH3), 5.76 (d, J = 2 Hz, 1H, NCH),
6.61 (d, J = 8.2 Hz, 1H, Ar), 6.67 (d, J = 8.4 Hz, 1H, Ar), 6.96–7.06
(m, 2H, Ar), 7.18 (d, J = 2.2 Hz, 1H, Ar), 7.68 (d, J = 1.8 Hz, 1H, Ar);
13C NMR (50 MHz, CDCl3) d 16.0 (CHCH3), 18.2 (CHCH3), 19.4
(CHCH3), 20.6 (2 ꢃ ArCH3), 22.5 (CHCH3), 29.8 (CHMe2), 29.9
(CHMe2), 35.3 (CH2CO2), 36.4 (CH2CON), 36.7 (CHCHMe2), 51.5
(CO2CH3), 55.4 (ArOCH3), 56.0 (ArOCH3), 62.3 (NCH), 89.2 (Ar2CO-
CO), 111.0 (HC–Ar), 114.0 (HC–Ar), 126.4 (C–Ar), 127.2 (HC–Ar),
128.0 (C–Ar), 128.8 (HC–Ar), 129.0 (2 ꢃ C–Ar), 129.1 (HC–Ar), 130.1
(HC–Ar), 152.7 (MeOC–Ar), 153.6 (MeOC–Ar), 156.3 (NCO2), 172.3
(CO2Me), 173.5 (CON). ESI MS: m/z (%) = 540 (43) (M++H), 496
(100). HRMS: Calcd for C31H42NO7 (M++H) 540.2961. Found:
540.2946.
Following the general procedure described for the model syn-
thesis of a mixture of 3e and 4e from 1a and 2e, anhydride 1d
(156 mg, 1 mmol) and oxazolidin-2-one 2e (369 mg, 1 mmol) gave
an inseparable 1:1 mixture of diastereoisomeric methyl esters 3h
and 4h (399 mg, 74%) as a colourless oil. Data for 4h (obtained
from mixture): Rf = 0.45 (hexane/ethyl acetate 85/15); 1H NMR
(200 MHz, CDCl3) d 0.71 (d, J = 6.8 Hz, 3H, CH3CHCH3), 0.80 (d,
J = 6.8 Hz, 3H, CH3CHCH3), 0.89 (d, J = 7.2 Hz, 3H, CH3CHCH3),
0.95 (d, J = 7.2 Hz, 3H, CH3CHCH3), 1.56–1.80 (m, 2H,
2 ꢃ CH3CHCH3), 2.19–2.25 (m, 1H, Me2CHCH), 2.22 (s, 3H, ArCH3),
2.31–2.49 (m, 2H, CH2CO2Me), 2.34 (s, 3H, ArCH3), 2.65–2.98 (m,
2H, CH2CON), 3.46 (s, 3H, ArOCH3), 3.47 (s, 3H, ArOCH3), 3.56 (s,
3H, CO2CH3), 5.77 (d, J = 2 Hz, 1H, NCH), 6.61 (d, J = 8.2 Hz, 1H,
Ar), 6.67 (d, J = 8.4 Hz, 1H, Ar), 6.96–7.06 (m, 2H, Ar), 7.18
(d, J = 2.2 Hz, 1H, Ar), 7.68 (d, J = 1.8 Hz, 1H, Ar); 13C NMR
(50 MHz, CDCl3) d 15.8 (CHCH3), 18.6 (CHCH3), 19.2 (CHCH3),
20.4 (2 ꢃ ArCH3), 22.3 (CHCH3), 29.6 (CHMe2), 29.8 (CHMe2),
35.2 (CH2CO2), 35.8 (CH2CON), 37.0 (CHCHMe2), 51.1 (CO2CH3),
55.1 (ArOCH3), 55.7 (ArOCH3), 62.0 (NCH), 88.9 (Ar2COCO), 110.8
(HC–Ar), 113.6 (HC–Ar), 126.2 (C–Ar), 127.1 (HC–Ar), 127.7 (C–Ar),
128.5 (HC–Ar), 128.7 (2 ꢃ C–Ar), 129.0 (HC–Ar), 129.9 (HC–Ar), 152.5
(MeOC–Ar), 153.3 (MeOC–Ar), 156.1 (NCO2), 172.2 (CO2Me), 173.0
(CON).
4.4. (30R,4S)-5,5-Di(2-methoxy-5-methylphenyl)-3-[3-(4-fluoro-
phenyl)-4-methoxycarbonyl-1-oxobutyl]-4-isopropyloxazolidin-
2-one 3g and its (30S)-diastereoisomer 4g
Following the general procedure described for the desymmetri-
zation of 1a with 2e, anhydride 1c (167 mg, 0.8 mmol) and oxazoli-
din-2-one 2e (275 mg, 0.75 mmol) gave a product which was
crystallized from hexane–ethyl acetate to give methyl ester 3g
(308 mg, 70%) contaminated with 5% of its diastereoisomer 4g.
Data for 3g: mp 95–98 °C;
Rf = 0.46 (hexane/ethyl acetate 85/15); IR (KBr): 1765, 1736,
1706, 1504 cmꢁ1 1H NMR (CDCl3, 200 MHz) d 0.69 (d, J = 6.6 Hz,
½
a 2D3
ꢂ
¼ ꢁ173:1 (c 0.84, MeOH);
;
3H, CH3CHCH3), 0.88 (d, J = 6.6 Hz, 3H, CH3CHCH3), 1.55–1.70 (m,
1H, CH3CHCH3), 2.02 (s, 3H, ArCH3), 2.34 (s, 3H, ArCH3), 2.53 (dd,
J = 8.2, 15.6 Hz,1H, CHAHBCO2Me), 2.65 (dd, J = 6.8, 15.4 Hz, 1H,
CHAHBCO2Me), 3.16 (dd, J = 5.6, 17.2 Hz, 1H, NCOCHAHB), 3.36
(dd, J = 9.2, 17.2 Hz, 1H, NCOCHAHB), 3.39 (s, 3H, ArOCH3), 3.42 (s,
3H, ArOCH3), 3.56 (s, 3H, COOCH3), 3.66–3.84 (m, 1H, ArCH), 5.70
(d, J = 1.8 Hz, 1H, NCH), 6.59 (d, J = 8.2 Hz, 1H, Ar), 6.62 (d,
J = 8.4 Hz, 1H, Ar), 6.79–7.04 (m, 5H, Ar), 7.09–7.16 (m, 2H, Ar),
7.65 (d, J = 2Hz, 1H, Ar); 13C NMR (50 MHz, CDCl3) d 15.9 (CHCH3),
20.4 (ArCH3), 20.6 (ArCH3), 22.4 (CHCH3), 29.8 (CHMe2), 36.8
(ArCH), 40.4 (CH2CO2), 41.0 (CH2CON), 51.4 (CO2CH3), 55.3 (Ar-
OCH3), 55.8 (ArOCH3), 62.0 (NCH), 89.2 (Ar2COCO), 111.0 (HC–Ar),
113.6 (HC–Ar), 115.1 (d, J = 21.1 Hz, 2 ꢃ HC–Ar), 126.4 (C–Ar), 127.3
(HC–Ar), 127.6 (C–Ar), 128.5 (HC–Ar), 128.7 (HC–Ar), 128.8 (C–Ar),
128.9 (C–Ar), 129.1 (2 ꢃ HC–Ar), 130.0 (HC–Ar), 138.3 (ipso-C–Ar),
152.6 (MeOC–Ar), 153.5 (MeOC–Ar), 156.0 (NCO2), 161.4 (d,
J = 243 Hz, FC–Ar), 170.6 (CO2Me), 171.8 (CON); ESI MS: m/z
(%) = 592 (10) (M++H), 548 (100); HRMS: Calcd for C34H39NO7F
(M++H) 592.2711. Found: 592.2715.
Following the general procedure described for the model syn-
thesis of a mixture of 3e and 4e from 1a and 2e, anhydride 1c
(208 mg, 1 mmol) and oxazolidin-2-one 2e (369 mg, 1 mmol) gave
an inseparable 1:1 mixture of diastereoisomeric methyl esters 3g
and 4g (437 mg, 74%) as a colourless oil. Data for 4g (obtained from
the mixture): Rf = 0.46 (hexane/ethyl acetate 85/15); 1H NMR
(CDCl3, 200 MHz) d 0.51 (d, J = 6.8 Hz, 3H, CH3CHCH3), 0.66 (d,
J = 6.8 Hz, 3H, CH3CHCH3), 1.48–1.70 (m, 1H, CH3CHCH3), 2.34 (s,
6H, 2 ꢃ ArCH3), 2.47–2.68 (m, 2H, CH2CO2Me), 2.97 (dd, J = 6.8,
16.6 Hz, 1H, NCOCHAHB), 3.39–3.49 (dd, overlapped, 1H, NCO-
CHAHB), 3.45 (s, 3H, ArOCH3), 3.48 (s, 3H, ArOCH3), 3.52 (s, 3H,
COOCH3), 3.66–3.84 (m, 1H, ArCH), 5.73 (d, J = 1.8 Hz, 1H, NCH),
6.57–7.26 (m, 9H, Ar), 7.65 (d, J = 2Hz, 1H, Ar); 13C NMR
(50 MHz, CDCl3) d 15.3 (CHCH3), 20.3 (2 ꢃ ArCH3), 21.8 (CHCH3),
29.3 (CHMe2), 37.2 (ArCH), 40.1 (CH2CO2, CH2CON), 51.1 (CO2CH3),
54.9 (ArOCH3), 55.5 (ArOCH3), 61.7 (NCH), 88.9 (Ar2COCO), 110.7
4.6. (30R,4S)-5,5-Di(2-methoxy-5-methylphenyl)-3-(4-methoxy-
carbonyl-3-methyl-1-oxobutyl)-4-isopropyloxazolidin-2-one 3i
and its (30S)-diastereoisomer 4i
Following the general procedure described for the desymmet-
rization of 1a with 2e, anhydride 1e (70 mg, 0.55 mmol) and

2728
N. Chaubey et al. / Tetrahedron: Asymmetry 19 (2008) 2721–2730
oxazolidin-2-one 2e (185 mg, 0.5 mmol) gave methyl ester 3i
(188 mg, 74%) as an inseparable mixture containing 19% of its dia-
stereoisomer 4i. Recrystallization from hexane–ethyl acetate gave
the methyl ester 3i (124 mg, 49%) as an inseparable mixture con-
taining 6% of its diastereoisomer 4i. Data for 3i: mp 82–84 °C;
128.3 (2 ꢃ HC–Ar), 128.5 (HC–Ar), 128.8 (2 ꢃ HC–Ar), 129.2
(HC–Ar), 133.9 (2 ꢃ HC–Ar), 136.7 (SiC–Ar), 138.1 (ipso-C–Ar), 142.4
(ipso-C–Ar), 153.0 (NCO2), 172.4 (CO2Me), 173.5 (CON). Anal. Calcd
for C32H37NO5Si: C, 70.69; H, 6.86; N, 2.54. Found: C, 70.84; H,
6.94; N, 2.33.
½
a 2D3
ꢂ
¼ ꢁ198:55 (c 0.69, EtOH); Rf = 0.53 (hexane/ethyl acetate
Following the general procedure described for the model syn-
thesis of a mixture of 3e and 4e from 1a and 2e, anhydride 1a
(124 mg, 0.5 mmol) and oxazolidin-2-one 2d (141 mg, 0.5 mmol)
gave an inseparable 1:1 mixture of diastereoisomeric methyl esters
3d and 4d (193 mg, 71%) as colourless oil. Data for 4i (obtained
from mixture): Rf = 0.56 (hexane/ethyl acetate, 85/15); 1H NMR
(200 MHz, CDCl3) d 0.27 (s, 3H, MeSi), 0.30 (s, 3H, MeSi), 0.71 (d,
J = 6.6 Hz, 3H, CH3CHCH3), 0.84 (d, J = 6.8 Hz, 3H, CH3CHCH3),
1.80–2.00 (m, 2H, CH3CHCH3 and SiCH), 2.18–2.40 (m, 2H,
CH2CO2Me), 2.72 (dd, J = 9.2, 17.2 Hz, 1H, CHAHBCON), 3.0 (dd,
J = 4, 17.2 Hz, 1H, CHAHBCON), 3.36 (s, 3H, COOCH3), 5.35 (d,
J = 3.2 Hz, 1H, NCH), 7.22–7.49 (m, 15H, Ar); 13C NMR (50 MHz,
CDCl3) d ꢁ4.7 (SiCH3), ꢁ4.3 (SiCH3), 16.2 (SiCH), 17.9 (CHCH3),
21.6 (CHCH3), 29.8 (CHMe2), 34.1 (CH2CO2), 35.1 (CH2CON), 51.1
(CO2CH3), 64.5 (NCH), 89.2 (Ar2COCO), 125.4 (2 ꢃ HC–Ar), 125.8
(2 ꢃ HC–Ar), 127.7 (2 ꢃ HC–Ar), 127.9 (HC–Ar), 128.3 (2 ꢃ HC–Ar),
128.5 (HC–Ar), 128.8 (2 ꢃ HC–Ar), 129.2 (HC–Ar), 133.9 (2 ꢃ HC–Ar),
136.7 (SiC–Ar), 138.1 (ipso-C–Ar), 142.2 (ipso-C–Ar), 153.0 (NCO2),
172.5 (CO2Me), 173.3 (CON).
85/15); IR (CHCl3 film): 1779, 1736, 1698, 1503 cmꢁ1 1H NMR
;
(200 MHz, CDCl3) d 0.71 (d, J = 6.8 Hz, 3H, CH3CHCH3), 0.92 (d,
J = 6.8 Hz, 3H, CH3CHCH3), 0.95 (d, J = 7.2 Hz, 3H, CHCH3) 1.63–
1.77 (m, 1H, CH3CHCH3), 2.18–2.60 (m, 3H, CH2CO2Me, MeCH),
2.23 (s, 3H, ArCH3), 2.34 (s, 3H, ArCH3), 2.75 (dd, J = 7.4, 16.6 Hz,
1H, NCOCHAHB), 2.90 (dd, J = 6, 16.6 Hz, 1H, NCOCHAHB), 3.47 (s,
3H, ArOCH3), 3.48 (s, 3H, ArOCH3), 3.64 (s, 3H, COOCH3), 5.77 (d,
J = 1.2 Hz, 1H, NCH), 6.62 (d, J = 8.2 Hz, 1H, Ar), 6.68 (d,
J = 8.4 Hz, 1H, Ar), 6.97–7.07 (m, 2H, Ar), 7.18 (d, J = 2Hz, 1H,
Ar), 7.68 (d, J = 2 Hz, 1H, Ar); 13C NMR (50 MHz, CDCl3) d 16.1
(CHCH3), 19.5 (CHCH3), 20.7 (2 ꢃ ArCH3), 22.6 (CHCH3), 26.9
(CHMe), 29.8 (CHMe2), 40.7 (CH2CO2), 41.2 (CH2CON), 51.4
(CO2CH3), 55.4 (ArOCH3), 56.0 (ArOCH3), 62.1 (NCH), 89.2 (Ar2CO-
CO), 111.1 (HC–Ar), 114.0 (HC–Ar), 126.5 (C–Ar), 127.3 (HC–Ar), 128.0
(HC–Ar), 128.8 (C–Ar), 129.0 (C–Ar, HC–Ar), 129.2 (C–Ar), 130.1 (HC–Ar),
152.7 (MeOC–Ar), 153.5 (MeOC–Ar), 156.3 (NCO2), 171.8 (CO2Me),
172.8 (CON). Anal. Calcd for C29H37NO7: C, 68.08; H, 7.29; N,
2.74. Found: C, 67.81; H, 7.23; N, 2.68.
Following the general procedure described for the model syn-
thesis of a mixture of 3e and 4e from 1a and 2e, anhydride 1e
(128 mg, 1 mmol) and oxazolidin-2-one 2e (369 mg, 1 mmol) gave
an inseparable 1:1 mixture of diastereoisomeric methyl esters 3i
and 4i (368 mg, 72%) as a colourless oil. Data for 4i (obtained from
mixture): Rf = 0.53 (hexane/ethyl acetate 85/15); 1H NMR
(200 MHz, CDCl3) d 0.71 (d, J = 6.8 Hz, 3H, CH3CHCH3), 0.95 (d,
J = 6.8 Hz, 3H, CH3CHCH3), 0.97 (d, J = 7.2 Hz, 3H, CHCH3) 1.63–
1.77 (m, 1H, CH3CHCH3), 2.18–2.60 (m, 3H, CH2CO2Me, MeCH),
2.23 (s, 3H, ArCH3), 2.34 (s, 3H, ArCH3), 2.75 (dd, J = 7.4, 16.6 Hz,
1H, NCOCHAHB), 2.90 (dd, J = 6, 16.6 Hz, 1H, NCOCHAHB), 3.47 (s,
6H, 2 ꢃ ArOCH3), 3.58 (s, 3H, COOCH3), 5.78 (d, J = 1.2 Hz, 1H,
NCH), 6.62 (d, J = 8.2 Hz, 1H, Ar), 6.68 (d, J = 8.4 Hz, 1H, Ar),
6.97–7.07 (m, 2H, Ar), 7.18 (d, J = 2Hz, 1H, Ar), 7.68 (d, J = 2 Hz,
1H, Ar); 13C NMR (50 MHz, CDCl3) d 15.9 (CHCH3), 19.5 (CHCH3),
20.5 (2 ꢃ ArCH3), 22.4 (CHCH3), 26.9 (CHMe), 29.7 (CHMe2), 40.2
(CH2CO2), 40.9 (CH2CON), 51.2 (CO2CH3), 55.3 (ArOCH3), 55.9 (Ar-
OCH3), 62.0 (NCH), 89.0 (Ar2COCO), 110.9 (HC–Ar), 113.8 (HC–Ar),
127.2, 128.15 (2C), 128.6, 128.9 (2C), 129.0, 130.0, 152.6
(MeOC–Ar), 153.4 (MeOC–Ar), 156.2 (NCO2), 171.7 (CO2Me), 172.6
(CON).
4.8. (30R,4S)-3-{3-[Dimethyl(phenyl)silyl]-4-methoxycarbonyl-
1-oxobutyl}-4-(diphenylmethyl) oxazolidin-2-one 3c and its
(30S)-diastereoisomer 4c
Following the general procedure described for the desymmetri-
zation of 1a with 2e, anhydride 1a (160 mg, 0.64 mmol) and oxaz-
olidin-2-one 2c (165 mg, 0.65 mmol) gave methyl esters 3c
(294 mg, 89%) as an inseparable mixture containing 23% of its dia-
stereoisomer 4c. The major and minor diastereoisomers were sep-
arated by chromatography to give pure major diastereoisomer 3c
(218 mg, 66%) and minor isomer 4c (71 mg, 22%). Data for major
diastereoisomer 3c: mp 113–114 °C; ½a D23
¼ ꢁ91:8 (c 1, EtOH);
ꢂ
Rf = 0.25 (hexane/ethyl acetate 90/10); IR (CHCl3 film): 1782,
1732, 1698, 1251, 1112 cmꢁ1 1H NMR (200 MHz, CDCl3) d 0.32
;
(s, 6H, Me2Si), 1.88–2.02 (m, 1H, SiCH), 2.20 (dd, J = 8.6, 16.2 Hz,
1H, CHAHBCO2Me), 2.36 (dd, J = 5.2, 16.2 Hz, 1H, CHAHBCO2Me),
2.50 (dd, J = 9.4, 16.4 Hz, 1H, NCOCHAHB), 3.24 (dd, J = 4.6,
16.4 Hz, 1H, NCOCHAHB), 3.58 (s, 3H, COOCH3), 4.31 (dd, J = 2.8,
9 Hz, 1H, OCHAHBCH), 4.39 (dd, J = 9, 9 Hz, 1H, OCHAHBCH), 4.61
(d, J = 5.6 Hz, 1H, PhCHPh), 5.06–5.14 (m, 1H, CONCH), 7.06–7.11
(m, 4H, Ar), 7.25–7.37 (m, 9H, Ar), 7.46–7.52 (m, 2H, Ar); 13C
4.7. (30R,4S)-3-{3-[Dimethyl(phenyl)silyl]-4-methoxycarbonyl-
1-oxobutyl}-5,5-diphenyl-4-isopropyloxazolidin-2-one 3d and
its (30S)-diastereoisomer 4d
NMR (50 MHz, CDCl3)
d
ꢁ4.8 (2 ꢃ SiCH3), 17.5 (SiCH), 33.9
(CH2CO2), 35.8 (CH2CON), 50.8 (Ph2CH), 51.4 (CO2CH3), 56.3
(OCH2), 64.9 (NCH), 126.8 (HC–Ar), 127.6 (HC–Ar), 127.7 (2 ꢃ HC–
Ar), 128.2 (2 ꢃ HC–Ar), 128.5 (2 ꢃ HC–Ar), 128.7 (2 ꢃ HC–Ar), 129.1
(3 ꢃ HC–Ar), 134.0 (2 ꢃ HC–Ar), 136.5 (SiC–Ar), 138.2 (ipso-C–Ar),
139.7 (ipso-C–Ar), 153.3 (NCO2), 172.4 (CO2Me), 173.8 (CON).
HRMS: Calcd for C30H33NO5NaSi (M++Na) 538.2026. Found:
Following the general procedure described for the desymmetri-
zation of 1a with 2e, anhydride 1a (1.36 g, 5.5 mmol) and oxazoli-
din-2-one 2d (1.405 g, 5 mmol) gave methyl esters 3d (2.17 g, 80%)
as an inseparable mixture containing 10% of its diastereoisomer 4d
538.2031. Data for minor diastereoisomer 4c: ½a D26
¼ ꢁ118 (c
ꢂ
as colourless oil. Data for 3d: ½a D25
ꢂ
¼ ꢁ92:85 (c 0.28, EtOH);
1.56, EtOH), Rf = 0.19 (hexane/ethyl acetate 90/10); IR (CHCl3 film):
Rf = 0.56 (hexane/ethyl acetate, 85/15); IR (CHCl3 film): 1780,
1782, 1732, 1699, 1251, 1112 cmꢁ1 1H NMR (200 MHz, CDCl3) d
;
1733, 1714, 1253, 1111 cmꢁ1
;
1H NMR (200 MHz, CDCl3) d 0.18
0.32 (s, 3H, MeSi), 0.33 (s, 3H, MeSi), 1.88–2.04 (m, 1H, SiCH),
2.21 (dd, J = 8, 15.4 Hz, 1H, CHAHBCO2Me), 2.39 (dd, J = 6, 15.4 Hz,
1H, CHAHBCO2Me), 2.76 (dd, J = 3.8, 17.6 Hz, 1H, NCOCHAHB), 3.05
(dd, J = 9.2, 17.6 Hz, 1H, NCOCHAHB), 3.55 (s, 3H, COOCH3), 4.29–
4.42 (m, 2H, CH2OCO), 4.62 (d, J = 5.6 Hz, 1H, Ph2CH), 5.16–5.24
(m, 1H, CHN), 7.03–7.08 (m, 4H, Ar), 7.22–7.28 (m, 6H, Ar), 7.35–
7.40 (m, 3H, Ar), 7.48–7.52 (m, 2H, Ar); 13C NMR (50 MHz, CDCl3)
d ꢁ4.6 (SiCH3), ꢁ4.4 (SiCH3), 17.6 (SiCH), 34.6 (CH2CO2), 35.4
(CH2CON), 50.7 (Ph2CH), 51.5 (CO2CH3), 56.3 (OCH2), 65.0 (NCH),
127.0 (HC–Ar), 127.7 (HC–Ar), 127.8 (2 ꢃ HC–Ar), 128.3 (2 ꢃ HC–Ar),
(s, 6H, Me2Si), 0.72 (d, J = 6.6 Hz, 3H, CH3CHCH3), 0.86 (d,
J = 6.8 Hz, 3H, CH3CHCH3), 1.80–2.00 (m, 2H, CH3CHCH3 and SiCH),
2.15 (dd, J = 8, 15.8 Hz, 1H, CHAHBCO2Me), 2.32 (dd, J = 6.2, 15.8 Hz,
1H, CHAHBCO2Me), 2.82–3.00 (m, 2H, NCOCH2), 3.47 (s, 3H,
COOCH3), 5.34 (d, J = 3.4 Hz, 1H, NCH), 7.22–7.49 (m, 15H, Ar);
13C NMR (50 MHz, CDCl3) d ꢁ4.8 (SiCH3), ꢁ4.2 (SiCH3), 16.3 (SiCH),
17.3 (CHCH3), 21.6 (CHCH3), 29.8 (CHMe2), 34.3 (CH2CO2), 35.3
(CH2CON), 51.3 (CO2CH3), 64.8 (NCH), 89.3 (Ar2COCO), 125.5
(2 ꢃ HC–Ar), 125.9 (2 ꢃ HC–Ar), 127.7 (2 ꢃ HC–Ar), 127.9 (HC–Ar),

N. Chaubey et al. / Tetrahedron: Asymmetry 19 (2008) 2721–2730
2729
128.6 (2 ꢃ HC–Ar), 128.8 (2 ꢃ HC–Ar), 129.2 (2 ꢃ HC–Ar), 129.3
(HC–Ar), 134.1 (2 ꢃ HC–Ar), 136.8 (SiC–Ar), 138.1 (ipso-C–Ar), 139.6
(ipso-C–Ar), 153.4 (NCO2), 172.6 (CO2Me), 173.9 (CON). Calcd for
C30H33NO5NaSi (M++Na) 538.2026. Found: 538.2021.
134.0 (2 ꢃ HC–Ar), 136.0 (C–Ar), 136.9 (C–Ar), 172.5 (CO2Bu-t),
173.1 (CO2Bn).
4.11. (30R,4S)-3-{4-tert-Butoxyoxycarbonyl-3-(4-fluorophenyl)-
1-oxobutyl}-5,5-di(2-methoxy-5-methylphenyl)-4-isopropylox-
azolidin-2-one 8
4.9. (30R,4S)-3-{4-tert-Butoxyoxycarbonyl-3-[dimethyl(phenyl)-
silyl]-1-oxobutyl}-5,5-di(2-methoxy-5-methylphenyl)-4-
isopropyloxazolidin-2-one 5
Following the procedure described for the preparation of tert-
butyl ester 5, a mixture of acids corresponding to methyl esters
3g and 4g (415 mg, 0.71 mmol, 3g:4g = 95:5) gave the tert-butyl
ester 8 (0.39 g, 86%) after crystallization from hexane. Mp 71–
Dry DMF (0.01 mL, 0.13 mmol) was added to a solution of the
mixture of acids corresponding to methyl esters 3e and 4e (3e/
4e = 95/5) (0.62 g, 1 mmol) in dry dichloromethane (10 mL) fol-
lowed by the addition of oxalyl chloride (0.26 mL, 3 mmol) at
0 °C under an argon atmosphere. After 2 h at room temperature,
the reaction mixture was concentrated under reduced pressure fol-
lowed by high vacuum (0.1 Torr) to remove any excess of reagents
and solvents. The residue was dissolved in dry tert-butanol (5 mL),
73 °C; ½a 2D3
ꢂ
¼ ꢁ157 (c 1, EtOH); Rf = 0.63 (hexane/ethyl acetate,
85/15); IR (CHCl3 film): 1775, 1724, 1704, 1606, 1510 cmꢁ1
;
1H
NMR (200 MHz, CDCl3) d 0.68 (d, J = 6.6 Hz, 3H, CH3CHCH3), 0.89
(d, J = 7 Hz, 3H, CH3CHCH3), 1.27 (s, 9H, t-Bu), 1.52–1.74 (m, 1H,
CH3CHCH3), 2.02 (s, 3H, ArCH3), 2.33 (s, 3H, ArCH3), 2.43 (dd,
J = 8.8, 15 Hz, 1H, CHAHBCO2Bu-t), 2.57 (dd, J = 6.6, 15 Hz, 1H,
CHAHBCO2Bu-t), 3.12 (dd, J = 5.4, 17 Hz, 1H, NCOCHAHB), 3.34 (dd,
J = 9 Hz,17 Hz, 1H, NCOCHAHB), 3.37 (s, 3H, ArOCH3), 3.40 (s, 3H,
ArOCH3), 3.56–3.76 (m, 1H, 4-F-PhCH), 5.70 (s, 1H, NCH), 6.58 (d,
J = 8.2 Hz, 1H, Ar), 6.61 (d, J = 8.6 Hz, 1H, Ar), 6.78–7.03 (m, 5H,
Ar), 7.09–7.16 (m, 2H, Ar), 7.64 (d, J = 1.8 Hz, 1H, Ar); 13C NMR
(50 MHz, CDCl3) d 16.0 (CHCH3), 20.4 (ArCH3), 20.6 (ArCH3), 22.4
(CHCH3), 27.8 (3 ꢃ CH3-t-Bu), 29.8 (CHMe2), 37.1 (ArCH), 40.7
(CH2CO2), 42.4 (CH2CON), 55.3 (ArOCH3), 55.8 (ArOCH3), 62.0
(NCH), 80.5 (Me3CO), 89.2 (Ar2COCO), 111.0 (HC–Ar), 113.7 (HC–
Ar), 114.9 (d, J = 21 Hz, 2 ꢃ HC–ArF), 126.5 (C–Ar), 126.9 (C–Ar),
127.3 (HC–Ar), 127.7 (C–Ar), 128.6 (HC–Ar), 129.00 (C–Ar, HC–Ar),
129.1 (2 ꢃ HC–Ar), 130.0 (HC–Ar), 138.4 (d, J = 2.6 Hz, C–Ar), 152.6
(MeOC–Ar), 153.5 (MeOC–Ar), 156.0 (NCO2), 161.4 (d, J = 242 Hz,
FC–ArF), 170.7 (CON, CO2Bu-t). HRMS: Calcd for C37H45NO7F
(M++H) 634.3180. Found: 634.3200.
cooled on ice-water bath and
a solution of DMAP (0.18 g,
1.5 mmol) in dry tert-butanol (5 mL) was cannulated into it. The
mixture was stirred overnight at room temperature and was
evaporated under reduced pressure. The residue was purified by
column chromatography followed by crystallization from hex-
ane–ethyl acetate to give the ester 5 (0.47 g, 70%) as colourless
crystals (de = >95% from NMR). Mp 125–128 °C; ½a D21
¼ ꢁ165:9 (c
ꢂ
0.64, CHCl3); Rf = 0.65 (hexane/ethyl acetate 85/15); IR (CHCl3
film): 1774, 1724, 1705, 1503, 1255, 1114 cmꢁ1
;
1H NMR
(200 MHz, CDCl3) d 0.24 (s, 3H, SiMe), 0.25 (s, 3H, SiMe), 0.68 (d,
J = 6.8 Hz, 3H, CH3CHCH3), 0.96 (d, J = 7 Hz, 3H, CH3CHCH3), 1.35
(s, 9H, t-Bu), 1.62–1.80 (m, 1H, CH3CHCH3), 1.90–2.07 (m, 1H,
SiCH), 2.14 (dd, J = 8.4, 15.8 Hz, 1H, CHAHBCO2Bu-t), 2.22 (s, 3H,
ArCH3), 2.31 (dd, J = 5.4, 15.8 Hz, 1H, CHAHBCO2Bu-t), 2.34 (s, 3H,
ArCH3), 2.91 (dd, J = 6, 18.6 Hz, 1H, NCOCHAHB), 3.02 (dd, J = 6,
18.6 Hz, 1H, NCOCHAHB), 3.46 (s, 6H, ArOCH3), 5.77 (d, J = 2 Hz,
1H, NCH), 6.62 (d, J = 8 Hz, 1H, Ar), 6.68 (d, J = 8 Hz, 1H, Ar), 7.01
(dt, J = 1.8, 8 Hz, 2H, Ar), 7.21 (d, J = 1.8 Hz, 1H, Ar), 7.27–7.31 (m,
3H, Ar), 7.43–7.49 (m, 2H, Ar), 7.68 (d, J = 1.8 Hz, 1H, Ar); 13C
NMR (50 MHz, CDCl3) d ꢁ4.4 (SiCH3), ꢁ3.8 (SiCH3), 15.9 (SiCH),
16.7 (CHCH3), 20.6 (ArCH3), 20.7 (ArCH3), 22.5 (CHCH3), 27.9
(3 ꢃ CH3-t-Bu), 29.9 (CHMe2), 35.3 (CH2CO2), 35.7 (CH2CON), 55.3
(ArOCH3), 55.9 (ArOCH3), 62.1 (NCH), 80.0 (Me3CO), 88.8 (Ar2CO-
CO), 111.0 (HC–Ar), 113.9 (HC–Ar), 126.5 (C–Ar), 127.3 (HC–Ar),
4.12. (3R)-tert-Butyl methyl 3-(4-fluorophenyl)pentane-1,5-
dioate 9
Aqueous sodium hydroxide solution (1 mL, 1 M, 1 mmol) was
added to a stirred solution of ester 8 (0.37 g, 0.58 mmol) in
MeOH–THF (1/1) (2.4 mL) at room temperature. After 2.5 h, the
reaction mixture was concentrated and the residue was diluted
with water (2 mL), acidified with dilute HCl and extracted with
chloroform. The extract was washed with brine, dried over MgSO4
and evaporated under reduced pressure. The residue was diluted
with ether and the precipitate was filtered to give the oxazoli-
din-2-one 2e (0.2 g, 93%). The filtrate was concentrated, esterified
with an ether solution of diazomethane and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy followed by crystallization to give the diester 9 (0.14 g, 80%).
127.7 (HC–Ar, C–Ar), 128.0 (HC–Ar), 128.8 (HC–Ar), 128.9 (C–Ar
,
2 ꢃ HC–Ar), 129.0 (C–Ar), 130.0 (HC–Ar), 133.9 (2 ꢃ HC–Ar), 137.4
(SiC–Ar), 152.6 (MeOC–Ar), 153.3 (MeOC–Ar), 156.2 (NCO2), 172.5
(CO2Bu-t), 172.6 (CON). Anal. Calcd for C39H51NO7Si: C, 69.51; H,
7.63; N, 2.08. Found: C, 69.66; H, 7.66; N, 2.04.
4.10. (3R)-Benzyl tert-butyl 3-[dimethyl(phenyl)silyl]pentane-
1,5-dioate 6
Mp 67–69 °C; ½a 2D4
ꢂ
¼ ꢁ1:2 (c 1.17, MeOH); Rf = 0.53 (hexane/ethyl
1H NMR
(200 MHz, CDCl3) d 1.30 (s, 9H, t-Bu), 2.42–2.73 (m, 4H,
acetate, 90/10); IR (CHCl3 film): 1733, 1606, 1511 cmꢁ1
;
Titanium tetrakis benzyl alkoxide (0.375 M in benzyl alcohol,
2 mL, 0.75 mmol) was added to the tert-butyl ester 5 (336 mg,
0.5 mmol) and the mixture was heated at 100 °C for 28 h. The mix-
ture was cooled to room temperature and water was added under
stirring. The resulting mixture was filtered through a pad of Celite
and the filtrate was evaporated. The benzyl alcohol was removed
under reduced pressure and the residue was chromatographed to
give ester 636 (160 mg, 78%); Rf = 0.64 (hexane/ethyl acetate, 95/
2 ꢃ CH2COO), 3.57 (s, 3H, OCH3), 3.52–3.66 (m, 1H, ArCH), 6.91–
7.01 (m, 2H, Ar), 7.14–7.26 (m, 2H, Ar); 13C NMR (50 MHz, CDCl3)
d 27.7 (3 ꢃ CH3-t-Bu), 37.8 (ArCH), 40.6 (CH2CO2), 41.7 (CH2CO2),
51.4 (CO2CH3), 80.5 (Me3CO), 115.1 (d, J = 21.1 Hz, 2 ꢃ HC–ArF),
128.8 (d, J = 7.9 Hz, 2 ꢃ HC–ArF), 138.1 (ipso-C–ArF), 161.5 (d,
J = 243.2 Hz, FC–ArF), 170.5 (CO2CH3), 171.8 (CO2Bu-t). HRMS: Calcd
for C16H21O4FNa (M++Na) 319.1322. Found: 319.1323.
5); ½a 2D2
ꢂ
¼ þ1:15 (c 2.08, MeOH); IR (CHCl3 film): 1733, 1251,
1112 cmꢁ1
;
1H NMR (200 MHz, CDCl3) d 0.32 (s, 6H, SiMe2), 1.42
4.13. (3R)-Methyl hydrogen 3-(4-fluorophenyl)pentane-1,5-
(s, 9H, t-Bu), 1.85–1.99 (m, 1H, SiCH), 2.16–2.53 (m, 4H,
2 ꢃ CH2COO), 5.03 (s, 2H, ArCH2), 7.34–7.37 (m, 8H, Ar), 7.49–
7.54 (m, 2H, Ar); 13C NMR (50 MHz, CDCl3) d ꢁ4.5 (SiCH3), ꢁ4.3
(SiCH3), 18.5 (SiCH), 28.1 (3 ꢃ CH3-t-Bu), 34.6 (CH2CO2), 35.6
(CH2CO2), 66.2 (PhCH2O), 80.3 (Me3CO), 127.9 (2 ꢃ HC–Ar),
128.1 (HC–Ar), 128.3 (2 ꢃ HC–Ar), 128.5 (2 ꢃ HC–Ar), 129.3 (HC–Ar),
dioate 7
Trifluoroacetic acid (3.25 mL, 42.4 mmol) was added to a stirred
solution of t-butyl ester 9 (95 mg, 0.32 mmol) in dry dichlorometh-
ane (3.25 mL) at 0 °C. After 2 h at 0 °C, the reaction mixture was
concentrated under reduced pressure and the residue was purified

2730
N. Chaubey et al. / Tetrahedron: Asymmetry 19 (2008) 2721–2730
by column chromatography to give monomethyl ester 710 (67 mg,
24. Fleming, I.; Ghosh, S. K. J. Chem. Soc., Chem. Commun. 1994, 99–100. and
references cited therein.
25. Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693–3712.
26. Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003,
59, 2953–2989.
27. Buffat, M. G. P. Tetrahedron 2004, 60, 1701–1729.
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87%). ½a 2D2
¼ ꢁ3:4 (c 1.54, CHCl3); IR (CHCl3 film): 3460–3010 (br),
ꢂ
1734, 1605, 1511 cmꢁ1; 1H NMR (200 MHz, CDCl3) d 2.52–2.80 (m,
4H, 2 ꢃ CH2COO), 3.51–3.69 (m, 1H, ArCH), 3.56 (s, 3H, OCH3),
6.91–7.00 (m, 2H, Ar), 7.13–7.22 (m, 2H, Ar); 13C NMR (50 MHz,
CDCl3) d 37.2 (ArCH), 40.2 (CH2CO2), 40.4 (CH2CO2), 51.7 (CO2CH3),
115.5 (d, J = 21.2 Hz, 2 ꢃ HC–ArF), 128.7 (d, J = 7.9 Hz, 2 ꢃ HC–ArF),
137.8 (d, J = 2.7 Hz, ipso-C–ArF), 161.7 (d, J = 243.8 Hz, FC–ArF),
171.9 (CO2CH3), 177.36 (CO2H).
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