Highly effective and recyclable chiral auxiliaries: A study of the synthesis and use of three 4-isopropyl-5,5-diaryloxazolidin-2-ones

Article abstract of DOI:10.1039/b102020j

A series of three 5,5-diaryl substituted oxazolidin-2-ones (diphenyl, dinaphthyl and ditolyl) have been synthesised. Studies on the benzylation of the lithium enolates of N-acyl derivatives reveal that the yields obtained were sensitive to the method of quenching the reaction. This was particularly acute for the 5,5-diphenyl system where effective yields (69%) and high diastereoselectivities (dr 98 : 2) are only observed when the reactions were quenched into aqueous buffer. Methylation studies on the N-acyl derivatives showed that the most advantageous results (58-69%, dr ≥ 91 : 9) were only observed using the sodium enolates. The 5,5-ditolyl-4-isopropyloxazolidin-2-one proved to be more efficacious in terms of efficiency and diastereoselectivity (dr ≥ 97 : 3). Subsequent, simple alkaline hydrolyses of the alkylation products allowed for the high recovery and recyclability of the 5,5-diaryl substituted oxazolidin-2-ones without any deleterious endocyclic cleavage. In addition, the acyl portions were recovered in high yield from the alkaline hydrolyses without any evidence of racemisation.

Full text of DOI:10.1039/b102020j

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Highly effective and recyclable chiral auxiliaries: a study of the
synthesis and use of three 4-isopropyl-5,5-diaryloxazolidin-2-ones
Karen Alexander (née Gillon),a Stuart Cook,b Colin L. Gibson*a and Alan R. Kennedy†a
1
a Department of Pure & Applied Chemistry, University of Strathclyde, 295 Cathedral Street,
Glasgow, UK G1 1XL. E-mail: c.l.gibson@strath.ac.uk
b Hickson &Welch Ltd., Wheldon Road, Castleford, West Yorks., UK WF10 2JJ
Received (in Cambridge, UK) 2nd March 2001, Accepted 16th May 2001
First published as an Advance Article on the web 8th June 2001
A series of three 5,5-diaryl substituted oxazolidin-2-ones (diphenyl, dinaphthyl and ditolyl) have been synthesised.
Studies on the benzylation of the lithium enolates of N-acyl derivatives reveal that the yields obtained were sensitive
to the method of quenching the reaction. This was particularly acute for the 5,5-diphenyl system where effective
yields (69%) and high diastereoselectivities (dr 98 : 2) are only observed when the reactions were quenched into
aqueous buffer. Methylation studies on the N-acyl derivatives showed that the most advantageous results (58–69%,
dr у 91 : 9) were only observed using the sodium enolates. The 5,5-ditolyl-4-isopropyloxazolidin-2-one proved to be
more efficacious in terms of efficiency and diastereoselectivity (dr у 97 : 3). Subsequent, simple alkaline hydrolyses
of the alkylation products allowed for the high recovery and recyclability of the 5,5-diaryl substituted oxazolidin-2-
ones without any deleterious endocyclic cleavage. In addition, the acyl portions were recovered in high yield from the
alkaline hydrolyses without any evidence of racemisation.
Introduction
Chiral auxiliary methodology continues to be an effective
method in asymmetric synthesis.1 Currently, the most useful
chiral auxiliaries are those which function by controlling the
diastereoselectivity of attached acyl fragments. In this context,
perhaps the most widely used auxiliaries are the versatile
oxazolidin-2-one chiral auxiliaries 1 and 2, pioneered by
Evans. The N-acyl derivatives of Evans auxiliaries 1 and 2
have been utilised in numerous highly diastereoselective reac-
tions including alkylation, amination, azidation, bromination,
hydroxylation, aldol additions, Diels–Alder cycloadditions and
conjugate additions.2 The wide ranging usefulness of the Evans
auxiliaries 1 and 2 coupled with the generally high diastereo-
selectivities has led to the development of a broad range of
oxazolidin-2-one auxiliaries. Thus, oxazolidin-2-one auxiliaries
have been prepared from a number of chiral sources including
terpenes (e.g. 3–5),3 carbohydrates (e.g. 6–8),4 anthracenes,5
amino indanols6 and abiogenetic amino acids7 (see Fig. 1).
Recently, solid phase synthesis has been applied to auxiliary
chemistry with the development of a number of polymer sup-
ported oxazolidin-2-ones (e.g. 9 and 10).8 However, problems
have been reported with the polymer attachment of serine
Fig. 1 Some representative examples of oxazolidin-2-one auxiliaries.
based oxazolidinones in the preparation of 9.8e
A crucial factor for the utility of a chiral auxiliary is that it
must be efficiently introduced and it must be easily removed
without disrupting the newly formed stereogenic centres. One
of the drawbacks of the Evans methodology involves the
removal of the auxiliary. If the N-acyl group is sterically
demanding or α-branched then the unwanted endocyclic
hydrolysis can predominate to give a ring opened amide
12 rather than the required exocyclic cleavage to afford
the carboxylic acid derivative 13 and the recovered chiral
auxiliary 1 (Scheme 1).9 The endocyclic cleavage can be circum-
vented by hydrolysis using lithium hydroperoxide, however, the
† Address correspondence regarding the X-ray crystallography to this
author.
Scheme 1
1538
J. Chem. Soc., Perkin Trans. 1, 2001, 1538–1549
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b102020j

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Treatment of the amino alcohols 19a–c with triphosgene
under biphasic conditions in toluene and aqueous potassium
hydroxide provided the 5,5-diaryl-1,3-oxazolidin-2-ones 16a
(73%), 16b (59%) and 16c (54%). Alternatively, the di(4-tolyl)-
1,3-oxazolidin-2-one 16c could be prepared in 62% yield using
triphosgene and triethylamine in THF (Scheme 2).18
Fig. 2
hazardous nature of this reagent detracts from its large scale
applicability.
Scheme 2 Reagents and conditions: i, 6 equiv. ArMgBr, Ϫ10 ЊC; ii,
Cl3COC(O)OCl3, KOH, CH3C6H5 or Et3N, THF.
A solution to the problem of undesired endocyclic hydrolysis
is the use of 5,5-disubstituted oxazolidin-2-ones 14–17. Thus,
Davies et al. introduced the 5,5-dimethyloxazolidin-2-ones 14,10
while Cardillo et al. have used the 5,5-dialkyloxazolidin-2-ones
15 in diastereoselective hydrochlorination reactions.11 However,
the 5,5-dimethyloxazolidin-2-ones 14 suffer low yields when the
enolates derived from the N-acyl derivatives are alkylated with
less reactive alkyl halides. Consequently, we12 and others13,14
have investigated the 5,5-diaryloxazolidin-2-ones 16 and 17
with the aim of generating highly diastereoselective and effi-
cient auxiliaries that do not undergo subsequent undesirable
endocyclic cleavage. Subsequently, Hintermann and Seebach
reported an elegant and comprehensive study of the use of
N-acyl derivatives of 5,5-diphenyloxazolidin-2-one 16a in a
number of diastereoselective reactions.15,16 These studies
included enolate alkylation reactions of N-acyl derivatives of
5,5-diphenyloxazolidin-2-one 16a where decomposition of the
enolate was observed. This decomposition led to acyl cleavage
and formation of 5,5-diphenyloxazolidin-2-one 16a.15 Recently,
Davies and co-workers compared the benzylation of N-acyl
derivatives of 5,5-dialkyloxazolidin-2-ones 15 and the 5,5-
diphenyloxazolidin-2-ones 17 (see Fig. 2) and observed enolate
alkylation problems with the latter.17 We now describe the
preparation of 5,5-diaryl-4-isopropyloxazolidin-2-ones 16a–c
including a comprehensive study on the alkylation (methylation
and benzylation) and azidation of N-acyl enolates. The judi-
cious use of appropriate work up of the benzylation reac-
tions leads to a maximisation of alkylation yields while efficient
enolate methylations were achieved using sodium enolates.
These studies also indicate that the 5,5-ditolyl-1,3-oxazolidin-2-
one 16c is the most effective in terms of diastereoselective
and efficiency. Part of this work has previously been
communicated.12
N-Acylation of the 5,5-diaryl-1,3-oxazolidin-2-ones
The N-acylation of 1,3-oxazolidin-2-ones is usually carried
out by N-deprotonation with butyllithium at Ϫ78 ЊC.19 Using
this methodology the N-acyl-5,5-diaryl-1,3-oxazolidin-2-ones
20a–c and 21a–c were prepared in 46–98% yield. It should be
noted that the 5,5-diphenyl auxiliary 16a gave consistently
lower N-acylation yields using this procedure (entries 1 and 6,
Table 1). This is a consequence of the fact that the 5,5-diphenyl
auxiliary 16a is poorly soluble in THF even at room temper-
ature while the auxiliaries 16b and 16c are fully soluble at
Ϫ78 ЊC.
In an attempt to use conditions that were more amenable to
large scale generation of N-acylated 1,3-oxazolidin-2-ones we
investigated alternative procedures.4e,20 Thus, improved yields
(84%) in the N-acylation of the 5,5-diphenyl-1,3-oxazolidin-2-
one 16a were realised using the appropriate acid chloride with
triethylamine and N,N-dimethylaminopyridine (entry 2, Table
1). Similarly, 20c was obtained in quantitative yield using this
modified procedure (entry 5, Table 1) (Scheme 3).
Results and discussion
Synthesis of 5,5-diaryl auxiliaries
The syntheses of the 5,5-diaryl-1,3-oxazolidin-2-ones 16a–c
were realised by a two step procedure involving addition of
the appropriate Grignard reagents to (S)-valine methyl ester
hydrochloride 18. Thus, addition of 6 equivalents of phenyl-
magnesium bromide to ester hydrochloride 18 furnished the
diphenyl alcohol 19a in 54% yield. We also wished to probe
the effect of the steric space about the C-5 position in 1,3-oxa-
zolidin-2-ones 16, consequently, the di(2-naphthyl)amino alco-
hol 19b was similarly prepared in 60% yield. However, attempts
to prepare the more sterically demanding di(1-naphthyl) or
di(2-tolyl)amino alcohols by a similar approach were unsuc-
cessful. Since the preparation of diphenyl amino alcohol 19a
generates three equivalents of benzene we wished to prepare a
more environmentally friendly 1,3-oxazolidin-2-one that would
be amenable to large scale use. Thus, the di(4-tolyl) amino
alcohol 19c was prepared similarly in 52% yield.
Scheme 3 Reagents and conditions: i, BuLi, Ϫ78 ЊC, PhCH2CH2COCl;
ii, Et3N, 20 mol% DMAP, PhCH2CH2COCl, CH2Cl2; iii, BuLi, Ϫ78 ЊC,
CH3CH2COCl; iv, Et3N, 20 mol% DMAP, CH3CH2COCl; CH2Cl2.
Diastereoselective alkylations
The efficacy of 1,3-oxazolidin-2-one auxiliaries are gener-
ally expressed in terms of the diastereoselectivities and
yields achieved in alkylation reactions of enolates derived
from N-acyl-1,3-oxazolidin-2-ones.2–8,12,13,15–17 Accordingly, we
initially investigated the benzylation of the enolates derived
from the N-propionyl-1,3-oxazolidin-2-ones 21a–c (Scheme 4).
Thus, LDA mediated enolate formation was carried out at 0 ЊC
J. Chem. Soc., Perkin Trans. 1, 2001, 1538–1549
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Table 1 Synthesis of N-acylated 5,5-diaryl-1,3-oxazolidin-2-ones 20a–c and 21a–c
Entry
Reactant
Ar
Methoda,b
N-Acylated 1,3-oxazolidin-2-one yield (%)
1
2
3
4
5
6
7
8
9
16a
16a
16b
16c
16c
16a
16b
16c
16c
Ph
Ph
A
B
A
A
B
A
A
A
B
20a (46)
20a (84)
20b (97)
20c (82)
20c (100)
21a (70)
21b (90)
21c (98)
21c (74)
2-Naphthyl
4-Tolyl
4-Tolyl
Ph
2-Naphthyl
4-Tolyl
4-Tolyl
a Method A BuLi, THF, Ϫ78 ЊC, acid chloride. b Method B Et3N, DMAP, room temperature, acid chloride.
Table 2 Enolate alkylations of N-acylated-1,3-oxazolidin-2-ones 20a–c and 21a–c
Entry
1,3-Oxazolidin-2-one
Base
Electrophile
Alkylated product (%)
dra
1
2
3
4
5
6
7
8
9
10
11
12
13
21a
21a
21a
21b
21b
21c
21c
20a
20a
20b
20b
20c
20c
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
NaHMDS
LDA
NaHMDS
LDA
BnBr
BnBr
BnBr
BnBr
BnBr
BnBr
BnBr
MeI
MeI
MeI
MeI
MeI
22a (46)b
22a (33)c
22a (69)d
22b (55)b
22b (34)c
22c (66)b
22c (31)c
23a (48)c
23a (69)b
23b (42)d
23b (58)b
23c (32)d
23c (64)b
98.5 : 1.5
98.5 : 1.5
98 : 2
95.5 : 4.5
96 : 2
98 : 2
96 : 4
96 : 4
95.5 : 4.5
93 : 7
91 : 9
97.5 : 2.5
97 : 3
NaHMDS
MeI
a Determined by 1H NMR. b Reaction quenched via the addition of aq. NH4Cl. c Reaction quenched via the addition of 0.01 M phosphate buffer pH
7. d Reaction quenched via the addition of 0.16 M phosphate buffer pH 7.
these cases, the alkylated products were obtained in 55% (dr
95.5 : 4.5) and 66% (dr 98 : 2) yields, respectively (Table 2,
entries 4 and 6), after quenching into aqueous ammonium
chloride.
As a further measure of the efficacy of our auxiliaries, the
alkylation of the N-dihydrocinnamoyl-5,5-diaryl-1,3-oxazol-
idin-2-ones 20a–c was investigated using the less reactive methyl
iodide as the electrophile (Scheme 5). Accordingly, generation
Scheme 4 Reagents and conditions: i, LDA, 0 ЊC, 2.5 h; ii, 3 equiv.
BnBr, 0 ЊC, 23 h; iii, aq.NH4Cl; iv, 0.01 M phosphate buffer pH 7;
v, 0.16 M phosphate buffer pH 7.
followed by treatment with excess benzyl bromide. In the
case of N-acyl derivative 21a, although a satisfying 98.5 : 1.5
diastereomeric ratio of 22a was achieved after quenching the
reaction into aqueous ammonium chloride, the efficiency was a
moderate 46% (Table 2 entry 1). Changing the conditions for
quenching the reaction by the use of 0.01 M phosphate buffer
Scheme 5 Reagents and conditions: i, LDA, 0 ЊC, 1 h; ii, 3 equiv. MeI,
led to a diminished yield of 33% (Table 2 entry 2). The use of a
0.16 M phosphate buffer at pH 7 was found to be the most
efficacious method of quenching the benzylation reaction and
led to a greatly improved yield of 69% (Table 2 entry 3). While
the diastereomeric ratio is 98 : 2 in this case, a single recrystal-
lisation from pentane gave diastereomerically pure 22a.
0 ЊC, 20 h; iii, 0.16 M phosphate buffer pH 7; iv, NaHMDS, Ϫ78 ЊC,
1 h; v, 5 equiv. MeI, Ϫ78 ЊC, 20 h; vi, aq. NH4Cl.
of the lithium enolate of N-dihydrocinnamoyl-5,5-diaryl-1,3-
oxazolidin-2-ones 20a followed by methylation at 0 ЊC gave a
poor yield (48%) of the alkylated product 23a (Table 2 entry 8).
The use of our modified reaction quench procedure of 0.16 M
phosphate buffer at pH 7 also gave a poor yield of methylated
products 23b and 23c (Table 2 entries 10 and 12). Evans et al.
have documented that the methylation of sodium enolates of
N-acyl-1,3-oxazolidin-2-ones resulted in superior yields over
the corresponding lithium enolates. Thus, formation of the
sodium enolates of the N-dihydrocinnamoyl-5,5-diaryl-1,3-
oxazolidin-2-ones 20a–c and methylation at Ϫ78 ЊC with excess
methyl iodide provided the alkylated products N-dihydro-
cinnamoyl-5,5-diaryl-1,3-oxazolidin-2-ones 23a–c in improved
yields (58–69%) (Table 2, entries 9, 11 and 13). Although the
yields are significantly better in the methylations using sodium
After the completion of our studies21 Hintermann and
Seebach reported that low yields of benzylation were obtained
from lithium enolates of N-acyl-5,5-diphenyl-1,3-oxazolidin-2-
ones.15 These workers attributed the low yields to the decom-
position of the lithium enolate via a ketene pathway. Further-
more, Davies and co-workers attributed the low yields of 22a
(35%), generated under similar conditions, to the unreactive
nature of the lithium enolate of 21a.17 However, using our con-
ditions followed by the appropriate reaction quench conditions
provides benzylated 22a in 69% yield.
The work up methodology was less critical in the benzylation
of the lithium enolates of 1,3-oxazolidin-2-ones 21b and 21c. In
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J. Chem. Soc., Perkin Trans. 1, 2001, 1538–1549

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away from the C(2) phenyl groups. Their position lies over the
1,3-oxazolidin-2-one ring such that they effectively shield the
Re face of the C(16) amide carbonyl so that the isopropyl group
acts as a pseudo tert-butyl group.10e,15
The X-ray structure indicates that the two C(2) phenyl groups
on the 1,3-oxazolidin-2-one ring in 22a are not directed over the
heterocyclic ring. Indeed, in 22a the pro-S phenyl group is
approximately co-linear with the C(2)–C(3) bond, with C3–C2–
C10–C15 and C3–C2–C10–C11 torsional angles of Ϫ3.2(6)Њ
and Ϫ179.6(3)Њ, respectively. The pro-R phenyl group in
22a is approximately co-linear with the C(2)–O(1) bond with
O1–C2–C4–C9 and O1–C2–C4–C5 torsional angles of
Ϫ1.1(5)Њ and 178.9(3)Њ, respectively. The arrangements of these
phenyl groups ensure that there is no deleterious shielding of
the C(1) Re face. This is in contrast to the molecular modelling
studies of Davies and co-workers on the enolate of a (4S)-N-
acyl-4,5,5-triphenyl-1,3-oxazolidin-2-one.17 In these modelling
studies, a C-5 pro-R phenyl ring was orientated over the 1,3-
oxazolidin-2-one ring, resulting in steric hindrance of both
faces of the heterocyclic ring. The decrease in diastereoselectiv-
ity using the (4S)-N-acyl-4,5,5–triphenyl-1,3-oxazolidin-2-one
over the 5,5-dimethyl analogue was attributed to the facial
steric hindrance of the C-5 pro-R phenyl ring in the former.
Diastereoselective azidation reactions
As a further test of the utility of 5,5-diaryl-1,3-oxazolidin-2-
ones 16a–c as chiral auxiliaries we decided to investigate the use
of these systems in diastereoselective azidation processes. Evans
et al. have reported a comprehensive study on the use of the
Evans’ phenylalaninol 1,3-oxazolidin-2-one auxiliaries 1 in two
complementary approaches to the synthesis of 2-azido-
carboxylic acids (dr 97 : 3 and 91 : 9).23 Accordingly, we investi-
gated these azidation protocols using our most efficacious
5,5-ditolyl auxiliary in the form of the N-dihydrocinnamoyl
derivative 20c. Treatment of N-dihydrocinnamoyl derivative
20c with potassium hexamethyldisilylamide at Ϫ78 ЊC followed
by the addition of a pre-cooled (Ϫ78 ЊC) solution of 2,4,6-
triisopropylsulfonyl azide.24 The reaction was allowed to age for
just two minutes before quenching with glacial acetic acid
which afforded the azide 1,3-oxazolidin-2-one 24 in 65% yield
and a diastereomeric ratio of 96 : 4. Alternatively, preparation
of the boron enolate of N-dihydrocinnamoyl derivative 20c
followed by treatment with N-bromosuccinimide provided the
crude bromo-1,3-oxazolidin-2-one 25. The crude bromo-1,3-
oxazolidin-2-one 25 was reacted with tetramethylguanidinium
azide25 to afford the 1,3-oxazolidin-2-one azide 26 in 55% yield
and a diastereomeric ratio of 95.5 : 4.5.
Fig. 3 Chem3D Pro representation of the X-ray structure of 22a.
enolates relative to the lithium counterparts, there is little
difference in the diastereoselectivities observed (Table 2, entries
8–13).
The 5,5-ditolyl-1,3-oxazolidin-2-one derivatives 20c and 21c
proved to be the most efficacious in these alkylation studies
giving diastereomeric ratios of у97 : 3 and yields у64%. These
results compare well with other 5,5-disubstituted 1,3-oxazol-
idin-2-one auxiliaries.10,13–17 Although enolate alkylations of the
5,5-diphenyl-1,3-oxazolidin-2-one derivatives 20a and 21a were
less diastereoselective (dr у 93 : 7), the advantages are the
highly crystalline nature of all the 5,5-diphenyl-1,3-oxazolidin-
2-one derivatives 16a, 20a–23a. This feature has already been
outlined by Seebach et al.15 and allows easier purification and
separation of the diastereomers. However, the production of
benzene as a by-product in the preparation of amino alcohol
19a may have adverse environmental implications.
The foregoing benzylated products 22a–c and methylated
compounds 23a–c represent complementary diastereomers
which allowed the rapid establishment of the diastereomeric
With the complementary diastereomers 24 and 26, in hand, it
was possible to determine the respective diastereoselectivities by
normal phase HPLC analysis (Scheme 6).
1
ratios. These ratios were determined by H NMR by measure-
ment and comparison of the peak areas on expanded spectra
corresponding to the benzyl protons of each complementary
diastereomer present. Alternatively or additionally, the peak
areas of the three methyl resonances were measured and the
proportions established of the major and minor diastereomers.
Hydrolysis and recovery of the chiral auxiliaries
Following diastereoselective reactions, chiral auxiliaries must
be efficiently cleaved from the acyl portion in order to isolate
the newly formed chiral product and recover the parent
1,3-oxazolidin-2-one. In the light of the reported problems in
X-Ray crystallographic studies
In order to establish the absolute configuration at the newly
formed stereocentre at C-2Ј (C(17) X-ray numbering) in the
alkylation reactions a single crystal X-ray analysis was carried
out on the recrystallised 22a (dr >99.5 : 0.5) (Fig. 3).‡ The
diffraction data, by themselves, give no reliable information
of the absolute structure, this was based on the known (S)
configuration at C(3). This established the configuration at
C(17) as (R) and is consistent with the lk delivery of the electro-
phile to the 2Si face of a carbonyl-metal-carbonyl Z-enolate of
21a, in accord with the results of Evans et al. and Davies and
Sanganee.22,10a
‡ X-Ray crystallographic data: C28H29NO3, M = 427.52, monoclinic,
a = 10.765(4), b = 9.013(4), c = 12.835(5) Å, β = 111.43(3)Њ, U =
1159.3(8) Å3, T = 123 K, space group P21, Z = 2, µ(Mo-Kα) = 0.079
mmϪ1
, 5803 measured reflections, 4556 unique (Rint = 0.0406),
2θmax = 52Њ. Final refinement to convergence using SHELXL97 on F 2
gave R1 = 0.0635 for 2954 observed reflections with I > 2σ(I) and
wR2 = 0.1890 for all reflections. All non-hydrogen atoms were treated
anisotropically and all hydrogen atoms were placed in calculated posi-
tions and in a riding mode. As the diffraction data on their own give no
reliable information on the absolute structure, this was based on the
known stereochemistry at C3. CCDC reference number 159626. See
http://www.rsc.org/suppdata/p1/b1/b102020j/ for crystallographic files
in .cif or other electronic format.
In line with the published crystal structure of 20a,15 the two
methyl groups of the C(3) isopropyl group in 22a are directed
J. Chem. Soc., Perkin Trans. 1, 2001, 1538–1549
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Table 3 Hydrolysis of N-acylated 5,5-diaryl-1,3-oxazolidin-2-ones 22a–c and 23a–c
Entry
1,3-Oxazolidin-2-one (dr)
Recovered oxazolidin-2-one (%)
Acid (%)
%ee Acida
1
2
3
4
5
6
22a (>99 : 1)
22b (95.5 : 4.5)
22c (98 : 2)
23a (96 : 4)
23b (91 : 9)
23c (97 : 3)
16a (94)
16b (91)
16c (98)
16a (95)
16b (100)
16c (100)
27 (60)
27 (71)
27 (55)
28 (94)
28 (72)
28 (62)
98b
92
96
89b
81
92b
a Determined by comparison of the [α]D with the literature values.27 b The [α]D was measured at a significantly lower concentration than the literature
value.
Scheme 8 Reagents and conditions: i, 2 equiv. LiOH, THF–H2O.
mentary diastereomeric complexes. Consequently, the absolute
configuration and the ees of (R)-2-methyl-3-phenylpropionic
acid 27 and (S)-2-methyl-3-phenylpropionic acid 28 were
established by comparison of the measured specific rotation
with the published value.27 Within the constraints of using
specific rotations to determine the ees, there was no evidence
of substantial loss of stereochemical integrity at C-2 in (R)-2-
Scheme 6 Reagents and conditions: i, KHMDS, Ϫ78 ЊC; ii, 2,4,6-
methyl-3-phenylpropionic acid 27 or (S)-2-methyl-3-phenyl-
propionic acid 28, with respect to the original diastereomeric
ratios (Table 3).
triisopropylsulfonyl azide, Ϫ78 ЊC; iii, AcOH Ϫ78–30 ЊC; iv, Bu2BOTf,
iPr2NEt, Ϫ78 ЊC; v, N-bromosuccinimide; vi, tetramethylguanidinium
azide, 0 ЊC.
1,3-oxazolidin-2-one removal (vide supra)9 it was important to
confirm that the presence of aromatic groups at C-5 allowed for
the mild non-destructive cleavage. By suppressing the unwanted
endocyclic cleavage this should lead to efficient recovery of
the auxiliary and acyl portion. The archetypal test of 1,3-
oxazolidin-2-one recyclability has been the hydrolysis of alkyl-
ated acyl auxiliaries.9,10a,15,17 Accordingly, alkaline hydrolysis of
the benzylated products 22a–c with lithium hydroxide in aque-
ous THF afforded the (R)-2-methyl-3-phenylpropionic acid 27
in 55–71% yield together with the recovered auxiliaries 16a
(94%), 16b (91%), and 16c (98%), respectively. No products
resulting from the undesired endocyclic cleavage pathway were
observed and this was further evidenced by the exceptionally
high recovery of the auxiliaries 16a–c (Scheme 7, Table 3 entries
1–3).
Conclusions
Studies of the benzylation of three N-propionyl-5,5-diaryl sub-
stituted 1,3-oxazolidin-2-ones 21a–c revealed that expedient use
of the appropriate reaction quench (pH 7 buffer for 21a, aque-
ous NH4Cl for 21b,c) leads to maximal yields (55–68%) as well
as high stereoinduction (dr 95.5 : 4.5–98 : 2). Similar investi-
gations on the methylation of three N-dihydrocinnamoyl-5,5-
diaryl substituted 1,3-oxazolidin-2-ones 20a–c disclosed that
the use of sodium enolates led to the most efficacious reactions
(58–69%).
The presence of the 5,5-diaryl groups completely suppressed
any unwanted endocyclic cleavage in subsequent simple
alkaline hydrolyses. This allowed for the high recovery and
recyclability of the 5,5-diaryl substituted 1,3-oxazolidin-2-ones
16a–c. In addition, the acyl portion was recovered in high yield
without any evidence of racemisation.
In general, the 5,5-ditolyl-1,3-oxazolidin-2-ones 16c gave the
best levels of stereoinduction (dr у 97 : 3) in the alkylation of
the appropriate N-acyl derivatives. While lower levels of stereo-
induction (dr у 93 : 7) were realised in similar studies with the
5,5-diphenyl-1,3-oxazolidin-2-ones 16a, the highly crystalline
nature of the derivatives provides a rapid method of purifi-
cation and enhancement of diastereomeric purity (100%)
through recrystallisation. However, the synthesis of 5,5-
diphenyl-1,3-oxazolidin-2-ones 16a is deleterious in environ-
mental terms as a result of the production of benzene as a
by-product.
Scheme 7 Reagents and conditions: i, 2 equiv. LiOH, THF–H2O.
Similar lithium hydroxide hydrolysis of the methylated prod-
ucts 23a–c afforded (S)-2-methyl-3-phenylpropionic acid 28 in
62–94% yield as well as the recovered auxiliaries 16a (95%), 16b
(100%), and 16c (100%), respectively (Scheme 8, Table 3 entries
3–6).
Experimental
Initial attempts to determine the ees of (R)-2-methyl-3-
phenylpropionic acid 27 and the (S) enantiomer 28 by 1H
NMR in conjunction with the chiral solvating agent (R,R)-
diphenyldiaminoethane10a,26 were unsuccessful because of
insufficient differences in the chemical shifts of the comple-
Instrumentation
Melting points were determined on a Reichert 7905 hot stage
and are uncorrected. Specific rotations were measured at 20 ЊC
in a 1 cm3 cell with a pathlength of 10 cm using a Perkin-Elmer
1542
J. Chem. Soc., Perkin Trans. 1, 2001, 1538–1549

View Article Online
341 polarimeter. The [α]D values are given in 10Ϫ1 deg cm2 gϪ1
and the concentrations are given in g 100 cm Ϫ3. 1H NMR spec-
tra were recorded on Bruker WM-250, JEOL 270, or Bruker
400 spectrometers in the indicated solvents operating at 250,
270 or 400 MHz, respectively. 13C NMR spectra were obtained
on the same instruments operating at 62.89, 67.80, and 100
MHz, respectively. The following abbreviations were used: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doub-
let of doublets; dq, doublet of quartets; sep, septet. Coupling
constants were recorded in Hz. Infrared (IR) spectra were
recorded on a Nicolet Impact 400D FTIR spectrometer either
as liquid films or as KBr discs. Mass spectra were recorded on
a JEOL JMS AX505 spectrometer at Strathclyde or at the
EPSRC National Mass Spectrometry service, Swansea. Micro-
analyses were performed by the microanalytical service at
Strathclyde. HPLC analysis was performed using an Applied
Chromatography Systems (ACS) Model 351 isocratic pump in
conjunction with a Zorbax 5 µm silica column (250 × 4.6 mm)
with 1% tert-butyl methyl ether in isooctane (1 cm3 minϪ1) as
the eluant. The peaks were detected with an ACS Model 750/12
UV detector set at 254 nm and an ACS Chiramonitor. The data
were collected on a Viglen computer fitted with a SUMMIT
data card and the chromatograms were integrated using
COMUS SUMMIT software.
General procedure for the synthesis of the diaryl amino alcohols
(S)-Valine methyl ester hydrochloride 18 (ca. 60 mmol) was
added portionwise over 20 min to a 2 M solution of the
appropriate Grignard reagent [prepared from aryl bromide
(8 equiv.) in THF (240 cm3) and magnesium turnings (8.8
equiv.)] cooled in an ice–salt bath under a N2 atmosphere. The
reaction mixture was stirred for 4 h at room temperature before
being quenched into a mixture of 2 M aqueous HCl and
crushed ice. The mixture was basified by the addition of aque-
ous ammonia. The organic layer was separated and the aqueous
layer was washed with EtOAc (×3). The organic extracts were
combined, dried over MgSO4 and the solvent removed in vacuo
to yield the crude amino alcohol which was recrystallised.
(S)-2-Amino-1,1-diphenyl-3-methylbutan-1-ol
19a.
The
required amino alcohol was obtained from (S)-valine methyl
ester hydrochloride 18 (10.079 g, 59.99 mmol) as a white solid,
(8.241 g, 32.23 mmol, 54%) (EtOH), mp 93–96 ЊC (lit.30 94–
95 ЊC) (Found: C, 79.77; H, 8.15; N, 5.70: MHϩ 256.1704. Cal-
culated for C17H21NO: C, 79.96; H, 8.29; N, 5.49%: 256.1701);
[α]D Ϫ130.2 (c = 1.10, CHCl3) (lit.30 Ϫ127.7 (c = 0.639,
CHCl3)); νmax (KBr) 3380 (br, O–H), 3338 (m, N–H), 3278 (m,
N–H), 3082, 3057, 3019 (m, aromatic C–H), 1658, 1592 (m,
C᎐C) cmϪ1; δH (CDCl3) 7.63–7.11 (m, 10H, aryl-H), 3.83 (d,
᎐
1H, J 2.2, –CHNH2), 1.76 (m, 1H, –CH(CH3)2), 0.91 (d, 3H,
J 7.0, –CH3), 0.86 (d, 3H, J 7.0, –CH3); δC (CDCl3) 148.16,
145.05, 128.57, 128.20, 127.00, 126.43, 126.07, 125.85 (aryl-C),
79.85 (C-β), 60.33 (C-α), 28.00 (–CH(CH3)), 23.15 (–CH3),
16.28 (–CH3).
General methods
Anhydrous reactions were carried out under an atmosphere of
nitrogen in oven-dried glassware (140 ЊC). Anhydrous sol-
vents were obtained using standard procedures: glacial acetic
acid (Ac2O, CrO3), dichloroethane (NaH), diisopropylamine
(CaH2), diisopropylethylamine (CaH2), methanol (Mg(OMe)2),
THF (K metal), toluene (Na metal) and triethylamine (CaH2).
Benzyl bromide (79–81 ЊC @ 14 mmHg), dihydrocinnamoyl
chloride (111–112 ЊC @ 18 mmHg), methyl iodide (43–44 ЊC),
propionyl chloride (77–79 ЊC) and thionyl chloride (77–79 ЊC)
were all fractionally distilled before use. All other reagents were
used as supplied. The 0.01 phosphate buffer was prepared by
dissolving the appropriate buffer tablet in water (200 cm3) (0.01
M phosphate buffer, 2.7 mM KCl, 0.137 M NaCl). The 0.16 M
phosphate buffer solution (pH 7.0) was prepared using 82 cm3
of 0.2 M Na2HPO4 and 37 cm3 of 0.1 M citric acid. Flash
column chromatography was performed according to the
procedure of Still et al.28 using silica gel (230–400 mesh).
(S)-2-Amino-1,1-di(2Ј-naphthyl)-3-methylbutan-1-ol 19b. The
amino alcohol was obtained from (S)-valine methyl ester
hydrochloride 18 (7.022 g, 41.80 mmol) as a white solid (8.653
g, 24.37 mmol, 60%) (PriOH), mp 196–198 ЊC (Found: C, 84.56;
H, 6.99; N, 3.89: MHϩ 356.2060. C25H25NO requires: C, 84.47;
H, 7.09; N, 3.94%: 356.2014); [α]D Ϫ372.2 (c = 0.70, CHCl3);
νmax (KBr) 3443 (br, O–H), 3411 (m, N–H), 3334 (m, N–H),
3064, 3040 (m, aromatic C–H), 1626, 1597 (m, C᎐C) cmϪ1
;
᎐
δH (CD2Cl2) 8.21–7.43 (m, 14H, aryl-H), 4.19 (d, 1H, J 2.2,
–CHNH2), 1.81 (m, 1H, –CH(CH3)2), 1.00 (d, 3H, J 7.0,
–CH3), 0.96 (d, 3H, J 7.0, –CH3); δC (CD2Cl2) 146.09, 142.98,
133.90, 132.85, 132.71, 128.75, 128.68, 128.07, 127.93, 126.65,
126.51, 126.44, 126.22, 125.97, 124.82, 124.49, 124.22 (aryl-C),
80.48 (C-β), 60.03 (C-α), 28.75 (–CH(CH3)2), 23.17, 16.37
(–CH3).
Measurement of alkylation diastereomeric ratios
The diastereomeric ratios of 22a–c and 23a–c were measured
using 1H NMR analysis. This was achieved by comparison
of the peak areas on expanded sections of the spectra for
the benzyl methylene resonances for each complementary
diastereomer present in the reaction mixture and/or the three
methyl resonances of both diastereomers.
(S)-2-Amino-1,1-di(4Ј-tolyl)-3-methylbutanol
19c.
The
desired amino alcohol was obtained from (S)-valine methyl
ester hydrochloride 18 (6.995 g, 41.64 mmol) as colourless
needles (6.132 g, 21.67 mmol, 52%) (EtOH–H2O), mp 96–98 ЊC
(Found: C, 80.40; H, 8.87; N, 5.00: MHϩ 284.2041. C19H25NO
requires: C, 80.52; H, 8.89; N, 4.94%: 284.2014); [α]D Ϫ108.4
(c = 0.66, CHCl3); νmax (KBr) 3513 (br, O–H), 3390 (m, N–H),
3323 (m, N–H), 3092, 3057, 3022 (m, aromatic C–H), 1603,
(S)-Valine methyl ester hydrochloride 18
1508 (m, C᎐C) cmϪ1; δH (CDCl3) 7.49–7.06 (m, 8H, aryl-H),
᎐
To a suspension of -valine (30 g, 256 mmol) in dry MeOH (250
cm3) at Ϫ10 ЊC under N2 was added thionyl chloride (23.25 cm3,
320 mmol) portionwise over 10 min. The heterogeneous mix-
ture was warmed to room temperature and heated at reflux for
2 h. The reaction mixture was allowed to cool to room temper-
ature to afford a white crystalline solid (33.763 g, 202 mmol,
79%) (MeOH–diethyl ether), mp 168–169 ЊC (lit.29 165–170 ЊC)
(Found: C, 42.68; H, 8.86; N, 8.36. Calculated for C6H14NO2Cl:
C, 42.99; H, 8.42; N, 8.36%); [α]D ϩ24.1 (c = 1.98, MeOH)
3.78 (d, 1H, J 2.4, –NCH), 2.27 (s, 6H, –PhCH3), 1.76 (m, 1H,
–CH(CH3)2), 0.92 (d, 3H, J 7.0, –CH3), 0.88 (d, 3H, J 7.0,
–CH3); δC (CDCl3) 145.32, 142.35, 136.27, 135.87, 129.30,
128.93, 125.92, 125.46 (aryl-C), 79.75 (C-β), 60.38 (C-α), 28.01
(–CH(CH3)2), 23.19 (–CH3), 21.18 (PhCH3), 16.31 (–CH3).
General procedures for the preparation of the 1,3-oxazolidin-2-
ones
(lit.,29 = ϩ23 1 (c = 2, MeOH)); νmax (KBr) 1740 (s, C᎐O str)
Method A. Using aqueous potassium hydroxide. To a vigor-
ously stirred suspension of the amino alcohol (1 equiv.) in
12.5% aqueous potassium hydroxide (6.2–6.4 equiv.) and tolu-
ene (1.4 M) at room temperature under N2 was added a 1.7 M
solution of triphosgene in toluene (3.6 equiv.) dropwise over 20
min. The resultant slurry was aged for 2 h and the white solid
᎐
cmϪ1; δH (CDCl3) 8.76 (s, 3H, –NH3), 3.96 (d, 1H, J 3.1,
–NCH), 3.77 (s, 3H, –OCH3), 2.43 (m, 1H, CH(CH3)2), 1.15
(d, 3H, J 3.0, –CH3), 1.12 (d, 3H, J 3.0, –CH3); δC (CDCl3)
169.02 (CO2H), 58.78 (–OCH3), 52.96 (–NCH), 29.96
(–CH(CH3)2), 18.57, 18.34 (–CH3).
J. Chem. Soc., Perkin Trans. 1, 2001, 1538–1549
1543

View Article Online
formed was filtered off and washed several times with water and
toluene. Recrystallisation gave the appropriate 1,3-oxazolidin-
2-ones 16a–c.
stirred for 2 h at this temperature. Freshly distilled acid chloride
(1.1 equiv.) was added dropwise at Ϫ78 ЊC and the mixture
was stirred for 30 min and at room temperature for a further
24 h. The reaction mixture was poured into phosphate buffer
(0.01 M) and the organic phase was separated. The aqueous
layer was washed with DCM (×2) and the organic extracts were
combined and washed with aqueous saturated NaHCO3 and
brine. The organic phase was dried over MgSO4 and the solvent
removed in vacuo. Flash column chromatography afforded the
appropriate acylated 1,3-oxazolidin-2-ones.
Method B. Using triethylamine. To a suspension of the amino
alcohol (1 equiv.) in THF (0.2 M) cooled in an ice bath under
N2 was added triethylamine (2.2 equiv.) in one portion. A 0.35
M solution of triphosgene in THF (1.16 equiv.) was added
rapidly. The ice bath was removed and the slurry was aged
for 45 min at room temperature. The resultant white solid was
filtered and washed with THF and EtOAc. The filtrate was
dried over MgSO4 and the solvent removed in vacuo to give a
white solid. Column chromatography (EtOAc–hexane, 1 : 1)
and recrystallisation gave the desired compound.
Method D. Using triethylamine. To a solution or suspension
of the 1,3-oxazolidin-2-one (1 equiv.) in DCM (0.1–0.16 M) at
room temperature under N2 was added DMAP (0.2 equiv.) and
triethylamine (1.2 equiv.). Freshly distilled acid chloride (1.3
equiv.) was added dropwise over 5 min and the mixture was
stirred for 5 h at room temperature. The reaction mixture was
quenched into saturated aqueous NH4Cl and the organic phase
was separated. The aqueous layer was washed with DCM (×3)
and the organic extracts were combined, washed with aqueous
saturated NaHCO3 and brine, dried over MgSO4 and the
solvent removed in vacuo. Purification via flash column chrom-
atography afforded the requisite acylated 1,3-oxazolidin-2-ones.
(S)-5,5-Diphenyl-4-isopropyl-3-(1Ј-oxopropyl)-1,3-oxazol-
idin-2-one 21a. Using method C with (S)-5,5-diphenyl-4-
isopropyl-1,3-oxazolidin-2-one 16a (0.563 g, 2.00 mmol) and
propionyl chloride (0.2 cm3, 2.3 mmol) followed by flash
column chromatography eluting with DCM–hexane (6 : 4)
furnished the title compound 21a as a white solid (0.471 g,
1.4 mmol, 70%), mp 110–113 ЊC (lit.15 111–112 ЊC) (Found: C,
74.83; H, 7.06; N, 4.04; MHϩ 338.1749. Calculated for
C21H23NO3: C, 74.75; H, 6.87; N, 4.15%: 338.1756.); [α]D
Ϫ258.3 (c = 1.04, CHCl3) (lit.15 [α]D Ϫ239.7 (c = 0.74, CHCl3));
νmax (KBr) 1772 (s, C᎐O), 1708 (s, C᎐O) cmϪ1; δH (CDCl3) 7.49–
(S)-5,5-Diphenyl-4-isopropyl-1,3-oxazolidin-2-one
16a.
Using method A with (S)-2-amino-1,1-diphenyl-3-methyl-
butan-1-ol 19a (3.945 g, 15.47 mmol) afforded the title com-
pound as white needle-like crystals (3.176 g, 11.3 mmol, 73%)
(EtOH–H2O), mp 247–250 ЊC (lit.13 253.2–253.9 ЊC) (Found: C,
76.73; H, 6.85; N, 4.87: MHϩ 282.1400. Calculated for
C18H19NO2: C, 76.84; H, 6.81; N, 4.98%: 282.1494); [α]D Ϫ263.4
(c = 0.51, CHCl3) (lit.13 [α]D Ϫ253.1 (c = 0.1, CHCl3)); νmax
(KBr) 3292 (m, N–H), 1764, 1745 (s, C᎐O) cmϪ1; δH (d6-DMSO)
᎐
8.13 (s, 1H, ϪNH), 7.68–7.21 (m, 6H, aryl-H), 4.38 (s, 1H,
HN–H), 1.83 (m, 1H, –CH(CH3)2), 0.90 (d, 3H, J 6.8, –CH3),
0.52 (d, 3H, J 6.8, –CH ); δ (d -DMSO) 157.33 (C᎐O), 145.36,
᎐
3
C
6
139.80, 128.37, 128.06, 127.68, 127.19, 125.51, 125.09 (aryl-C),
87.65 (C-β), 64.19 (C-α), 29.06 (CH(CH3)2), 16.60, 14.50
(–CH3).
(S)-5,5-Di(2Ј-naphthyl)-4-isopropyl-1,3-oxazolidin-2-one
16b. Using method A with (S)-2-amino-1,1-di(2Ј-naphthyl)-3-
methylbutan-1-ol 19b (2.483 g, 6.99 mmol) gave the title com-
pound as white needles (1.581 g, 4.15 mmol, 59%) (toluene), mp
240–242 ЊC (Found: C, 81.65; H, 5.78; N, 3.37: MHϩ 382.1818.
C26H23NO2 requires: C, 81.86; H, 6.08; N, 3.67%: 382.1807);
[α]D Ϫ373.6 (c = 0.06, CHCl3); νmax (KBr) 3285 (br, N–H), 1754,
᎐
᎐
7.25 (m, 10H, aryl-H), 5.38 (d, 1H, J 3.5, –NCH), 2.93 (dq, 1H,
J 17.3 and 7.3, –CHAHCH3), 2.73 (dq, 1H, J 17.3 and 7.3,
–CHHBCH3), 1.98 (m, 1H, –CH(CH3)2), 1.09 (t, 3H, J 7.3,
–CHAHBCH3), 0.88 (d, 3H, J 7.0, –CH3), 0.76 (d, 3H, J 6.5,
1706 (s, C᎐O) cmϪ1; δH (CDCl3) 8.09–7.16 (m, 14H, aryl-H),
᎐
6.62 (s, 1H, –CHNH), 4.63 (d, 1H, J 2.9, HNCH), 1.93 (m,
1H, –CH(CH3)2), 0.97 (d, 3H, J 6.8, –CH3), 0.75 (d, 3H, J 6.8,
–CH3); δC (CDCl ) 174.19 (C(᎐O)CH CH ), 153.28 (C᎐O),
᎐
᎐
3
2
3
142.57, 138.43, 129.09, 128.77, 128.57, 128.13, 126.14, 125.83
(aryl-C), 89.56 (C-β), 64.60 (C-α), 30.11 (–CH2CH3), 29.10
(–CH(CH3)2), 22.00, 16.57 (–CH3), 8.85 (–CH2CH3).
–CH3); δC (CDCl ) 158.97 (C᎐O), 136.59, 133.17, 132.98,
᎐
3
132.97, 132.75, 128.80, 128.69, 128.63, 128.02, 127.75, 127.71,
126.86, 126.77, 126.77, 126.73, 126.69, 125.52, 124.80, 124.59,
124.52, 124.40 (aryl-C), 89.99 (C-β), 65.43 (C-α), 29.96
(–CH(CH3)2), 21.25, 15.90 (–CH3).
(S)-5,5-Di(2Ј-naphthyl)-4-isopropyl-3-(1Љ-oxopropyl)-1,3-
oxazolidin-2-one 21b. Using method C with (S)-5,5-di(2Ј-
naphthyl)-4-isopropyl-1,3-oxazolidin-2-one 16b (0.258 g, 0.69
mmol) and propionyl chloride (0.07 cm3, 0.81 mmol) followed
by flash column chromatography using DCM–hexane (9 : 1) as
the eluant furnished the desired product as a white crystalline
solid (0.265 g, 0.62 mmol, 90%), mp 145–147 ЊC (EtOH)
(Found: C, 79.90; H, 6.13; N, 3.19: MHϩ 438.2109. C29H27NO3
requires: C, 79.61; H, 6.22; N, 3.21%: 438.2069); [α]D Ϫ385.2
(S)-5,5-Di(4Ј-tolyl)-4-isopropyl-1,3-oxazolidin-2-one
16c.
Using method A with (S)-2-amino-1,1-di(4Ј-tolyl)-3-methyl-
butanol 19c (2.000 g, 7.07 mmol) gave the title compound as
colourless needles (1.182 g, 3.83 mmol, 54%) (EtOH), mp 186–
188 ЊC (Found: C, 77.45; H, 7.53; N, 4.55: MHϩ 310.1829.
C20H23NO2 requires: C, 77.64; H, 7.48; N, 4.53%: 310.1807);
[α]D Ϫ235.7 (c = 1.03, CHCl3); νmax (KBr) 3264 (br, N–H), 1749,
1717 (s, C᎐O) cmϪ1; δH (CDCl3) 7.44–7.09 (m, 8H, aryl-H), 6.52
(c = 1.02, CHCl3); νmax (KBr) 1770 (s, C᎐O), 1713 (s, C᎐O)
᎐
᎐
᎐
cmϪ1; δH (CD2Cl2) 7.80–6.94 (m, 14H, aryl-H), 5.31 (d, 1H,
J 3.0, –NCH), 2.55 (dq, 1H, J 17.4 and 7.3, –CHAHCH3),
2.32 (dq, 1H, J 17.4 and 7.3, –CHHBCH3), 1.66 (m, 1H,
–CH(CH3)2), 0.68 (t, 3H, J 7.3 –CH2CH3), 0.56 (d, 3H, J 6.8,
–CH3), 0.42 (d, 3H, J 6.8, –CH3); δC (CD2Cl2) 174.33
(s, 1H, –CHNH), 4.32 (d, 1H, J 3.2, –CHNH), 2.32 (s, 6H,
PhCH3), 1.83 (m, 1H, –CH(CH3)2), 0.89 (d, 3H, J 6.8, –CH3),
0.71 (d, 3H, J 6.8, –CH3); δC (CDCl ) 159.00 (C᎐O), 141.40,
᎐
3
138.09, 137.50, 136.67, 129.33, 128.89, 126.47, 125.83 (aryl-C),
89.64 (C-β), 66.06 (C-α), 29.81 (–CH(CH3)2), 21.23, 21.06
(PhCH3), 15.97 (–CH3).
Using method B with (S)-2-amino-1,1-di(4Ј-tolyl)-3-methyl-
butanol 19c (0.255 g, 0.90 mmol) the title compound was
obtained as fine, white needle-like crystals (0.171 g, 0.56 mmol,
62%) (EtOH–H2O) with identical spectroscopic data to those
reported above.
(–(C᎐O)CH CH ), 153.51 (C᎐O), 139.92, 136.05, 133.59,
᎐
᎐
2
3
133.41, 133.18, 129.54, 129.11, 128.89, 128.78, 128.13, 127.99,
127.52, 127.31, 127.25, 125.22, 125.01, 124.55, 124.32 (aryl-C),
90.11 (C-β), 64.37 (C-α), 30.82 (–CH2CH3), 29.16 (CH(CH3)2),
22.31, 16.62 (–CH3), 8.97 (–CH2CH3).
(S)-5,5-Di(4Ј-tolyl)-4-isopropyl-3-(1Љ-oxopropyl)-1,3-
oxazolidin-2-one 21c. Using method C with (S)-5,5-di(4Ј-tolyl)-
4-isopropyl-1,3-oxazolidin-2-one 16c (0.250 g, 0.81 mmol) and
propionyl chloride (0.08 cm3 0.92 mmol) followed by flash
column chromatography using hexane–EtOAc (3 : 1) as the elu-
ant furnished the title compound as a colourless solid (0.288 g,
0.79 mmol, 98%), mp 58.5–60.5 ЊC (Found: C, 75.54; H, 7.63;
N, 3.74: MHϩ 366.2042. C27H27NO3 requires: C, 75.59; H, 7.45;
General procedures for the acylation of the 1,3-oxazolidin-2-ones
Method C. Using n-butyllithium. To a solution or suspension
of the 1,3-oxazolidin-2-one (1 equiv.) in THF (0.07–0.1 M) at
Ϫ78 ЊC under N2 was added n-butyllithium (1.6 M in hexane,
1.04 equiv.) portionwise over 10 min and the mixture was
1544
J. Chem. Soc., Perkin Trans. 1, 2001, 1538–1549

View Article Online
N, 3.83%: 366.2069); [α]D Ϫ218.9 (c = 1.00, CHCl3); νmax (KBr)
1773 (s, C᎐O), 1702 (s, C᎐O) cmϪ1; δH (CDCl3) 7.36–7.10 (m,
8H, aryl-H), 5.33 (d, 1H, J 3.5, –NCH), 2.94 (dq, 1H, J 17.3
and 7.3, –CHAHCH3), 2.73 (dq, 1H, J 17.3 and 7.3,
–CHHBCH3), 2.31 (s, 3H, –PhCH3), 2.29 (s, 3H, –PhCH3), 1.09
(t, 3H, J 7.3 –CH2CH3), 0.87 (d, 3H, J 6.9, –CH3), 0.75 (d, 3H,
δH (CDCl3) 7.33–7.09 (m, 13H, aryl-H), 5.31 (d, 1H, J 3.8,
–NCH), 3.31–2.81 (m, 4H, –CH2CH2–), 2.31 (s, 3H, –PhCH3),
2.29 (s, 3H, –PhCH3), 1.95 (m, 1H, –CH(CH3)2), 0.83 (d, 3H,
J 6.9, –CH3), 0.72 (d, 3H, J 6.9, –CH3); δC (CDCl3) 172.46
᎐
᎐
(–(C᎐O)CH –), 153.36 (C᎐O), 140.56, 139.80, 138.55, 137.84,
᎐
᎐
2
135.61, 129.74, 129.21, 128.59, 126.31, 126.00, 125.67 (aryl-C),
89.74 (C-β), 64.75 (C-α), 36.95 (CH2CH2Ph), 30.65 (CH2-
CH2Ph), 30.03 (–CH(CH3)2), 21.94, 21.26, 21.19, 16.60 (–CH3).
Using method D with (S)-5,5-di(4Ј-tolyl)-4-isopropyl-1,3-
oxazolidin-2-one 16c (0.302 g, 0.98 mmol) and dihydro-
cinnamoyl chloride (0.19 cm3, 1.28 mmol) followed by flash
column chromatography using EtOAc–hexane (1 : 1) as the
eluant gave the desired product as a pale yellow oil (0.426 g,
0.98 mmol, 100%) with identical spectroscopic data to those
reported above.
J 6.9, –CH3); δC (CDCl ) 174.22 (–(C᎐O)CH CH ), 153.40
᎐
3
2
3
(C᎐O), 139.87, 137.81, 135.71, 129.70, 129.19, 126.00, 125.70
᎐
(aryl-C), 89.66 (C-β), 64.60 (C-α), 30.08 (CH2CH3), 29.10
(CH(CH3)2), 22.02 (–CH3), 21.26, 21.18 (–PhCH3), 16.60
(–CH3), 8.83 (–CH2CH3).
Using method D with (S)-5,5-di(4Ј-tolyl)-4-isopropyl-1,3-
oxazolidin-2-one 16c (0.650 g, 2.10 mmol) and propionyl
chloride (0.24 cm3, 2.76 mmol) followed by flash column
chromatography using EtOAc–hexane (1 : 1) as the eluant gave
the title compound as a colourless oil (0.568 g, 1.56 mmol, 74%)
with identical spectroscopic data to those reported above.
(S)-5,5-Diphenyl-4-isopropyl-3-(1Ј-oxo-3Ј-phenylpropyl)-
General procedures for the alkylation of the N-acyl-1,3-
oxazolidin-2-ones
1,3-oxazolidin-2-one 20a. Using method
C with (S)-5,5-
Method E. Using LDA with 0.01 M phosphate buffer. To a
solution of the appropriate N-acyl-1,3-oxazolidin-2-one THF
(0.15 M) at 0 ЊC was added a solution of lithium diisopropyl-
amide [prepared from diisopropylamine (1.01 equiv.) in THF
(0.46 M) at Ϫ78 ЊC and n-butyllithium (1.6 M in hexane, 1.19
equiv.)] and the resulting enolate was stirred at 0 ЊC for 1 h. The
appropriate alkyl halide (2.96 equiv.) was added dropwise over
10 min and the mixture stirred for 24 h at 0 ЊC. The reaction was
quenched into 0.01 M phosphate buffer and the organic phase
separated. The aqueous phase was washed with DCM (×3) and
the organic extracts combined, washed with brine, dried over
MgSO4 and the solvent remove in vacuo to give the crude alkyl-
ated products. Purification via flash column chromatography
afforded the desired products.
diphenyl-4-isopropyl-1,3-oxazolidin-2-one 16a (0.562 g, 2.00
mmol) and dihydrocinnamoyl chloride (0.3 cm3, 2.1 mmol) fol-
lowed by flash column chromatography using DCM–hexane
(17 : 3) furnished the title compound as a white solid (0.379 g,
0.92 mmol, 46%) (EtOAc–hexane), mp 89.0–92.5 ЊC (lit.15
97–98 ЊC) (Found: C, 78.51; H, 6.59; N, 3.31: MHϩ 414.2072.
Calculated for C27H27NO3: C, 78.42; H, 6.58; N, 3.39%:
414.2069); [α]D Ϫ168.3 (c = 0.66, CHCl3) (lit.15 [α]D Ϫ179.0
(c = 1.14, CHCl3)); νmax (KBr) 1776 (s, C᎐O), 1695 (s, C᎐O)
᎐
᎐
cmϪ1; δH (CDCl3) 7.47–7.17 (m, 15H, aryl-H), 5.39 (d, 1H,
J 3.3, –NCH), 3.33–2.81 (m, 4H, –CH2CH2–), 1.96 (m, 1H,
–CH(CH3)2), 0.85 (d, 3H, J 6.8, –CH3), 0.74 (d, 3H, J 6.8,
–CH3); δC (CDCl ) 172.44 (–(C᎐O)CH –), 153.23 (C᎐O),
᎐
᎐
3
2
142.51, 140.50, 138.35, 133.02, 129.14, 128.81, 128.60, 128.17,
126.36, 126.13, 125.81 (aryl-C), 89.64 (C-β), 64.74 (C-α), 33.09
(CH2CH2Ph), 30.66 (CH2CH2Ph), 30.08 (–CH(CH3)2), 21.93,
16.56 (–CH3).
Using method D with (S)-5,5-diphenyl-4-isopropyl-1,3-
oxazolidin-2-one 16a (0.450 g, 1.60 mmol) and dihydro-
cinnamoyl chloride (0.31 cm3, 2.08 mmol) followed by flash
column chromatography using EtOAc–hexane (1 : 1) as the
eluant gave the title compound as a white solid (0.556 g, 1.34
mmol, 84%) with identical spectroscopic data to those reported
above.
(S)-5,5-Di(2Ј-naphthyl)-4-isopropyl-3-(1Ј-oxo-3Ј-phenyl-
propyl)-1,3-oxazolidin-2-one 20b. Using method C with (S)-5,5-
di(2Ј-naphthyl)-4-isopropyl-1,3-oxazolidin-2-one 16b (0.226 g,
0.59 mmol) and dihydrocinnamoyl chloride (0.10 cm3 0.65
mmol) followed by flash column chromatography using
EtOAc–hexane (1 : 1) as the eluant furnished the title com-
pound as a viscous, colourless oil (0.294 g, 0.57 mmol, 97%)
(Found: MHϩ 514.2390. C35H32NO3 requires MHϩ: 514.2382);
Method F. Using LDA with 0.16 M phosphate buffer. As per
method E, except the reaction mixture was quenched into
enough 0.16 M phosphate buffer so that pH 7 was maintained.
Method G. Using LDA with aqueous ammonium chloride. As
per method E, except the reaction mixture was quenched into
saturated aqueous NH4Cl.
Method H. Using NaHMDS. To a solution of the appropri-
ate N-acyl-1,3-oxazolidin-2-one in THF (0.24 M) at Ϫ78 ЊC
was added a solution of sodium hexamethyldisilylamide in
THF (2 M, 1.11 equiv.) and the resulting enolate was stirred at
Ϫ78 ЊC for 1 h. Methyl iodide (5 equiv.) was added and the
mixture stirred for 24 h at Ϫ78 ЊC. The reaction was quenched
into saturated aqueous NH4Cl and the product was extracted
using DCM (×2) and EtOAc. The organic extracts were com-
bined and washed with brine, dried over MgSO4 and the solvent
removed in vacuo to give the crude methylated N-acyl-1,3-
oxazolidin-2-one. The pure methylated material was obtained
via flash column chromatography.
(2ЈR,4S)-5,5-Diphenyl-4-isopropyl-3-(1Ј-oxo-2Ј-benzyl-
propyl)-1,3-oxazolidin-2-one 22a. Using method E with (S)-5,5-
diphenyl-4-isopropyl-3-(1Ј-oxopropyl)-1,3-oxazolidin-2-one
21a (0.150 g, 0.455 mmol) and benzyl bromide (0.16 cm3, 1.35
mmol) gave the crude product as a yellow semi-solid. Purifi-
cation via flash column chromatography using DCM–hexane
(3 : 1) as the eluant furnished the title compound (0.065 g, 0.15
mmol, 33%); δH (CDCl3) 7.47–7.16 (m, 15H, aryl-H), 5.36 (d,
1H, J 3.3, –NCH), 4.10–3.97 (m, 1H, –CHCH3), 3.16 (dd, 1H,
J 13.4 and 7.3, –CHAHPh), 2.60 (dd, 1H, J 13.4 and 7.9,
–CHHBPh), 1.87 (m, 1H, –CH(CH3)2), 0.84 (d, 3H, J 6.9,
–CH3), 0.70 (d, 3H, J 6.9, –CH3), 0.59 (d, 3H, J 6.7, –CH3).
The diastereomeric ratio of 98.5 : 1.5 was obtained by meas-
urement and comparison of peak areas in the 1H NMR for the
benzyl methylene resonances for the major (δ 3.16 and 2.60)
and minor (δ 2.81 and 2.45) isomers.
[α]D Ϫ233.5 (c = 1.02, CHCl3); νmax (liq. film) 1779 (s, C᎐O),
᎐
1712 (s, C᎐O) cmϪ1; δH (CDCl3) 8.15–7.09 (m, 19H, aryl-H),
᎐
5.66 (d, 1H, J 3.2, –NCH), 3.34–2.87 (m, 4H, –CH2CH2–), 2.02
(m, 1H, –CH(CH3)2), 0.92 (d, 3H, J 7.0, –CH3), 0.78 (d, 3H,
J 7.0, –CH ); δ (CDCl ) 172.53 (–(C᎐O)CH –), 153.23 (C᎐O),
᎐
᎐
3
C
3
2
140.44, 139.23, 135.43, 133.25, 132.99, 132.79, 129.38, 128.91,
128.55, 127.84, 127.74, 127.22, 127.00, 126.32, 124.89, 124.74,
124.15, 123.89 (aryl-C), 90.01 (C-β), 64.18 (C-α), 36.94
(CH2CH2Ph), 30.60 (CH2CH2Ph), 30.33 (–CH(CH3)2), 22.16,
16.58 (–CH3).
(S)-5,5-Di(4Ј-tolyl)-4-isopropyl-3-(1Ј-oxo-3Ј-phenylpropyl)-
1,3-oxazolidin-2-one 20c. Using method C with (S)-5,5-di(4Ј-
tolyl)-4-isopropyl-1,3-oxazolidin-2-one 16c (0.342 g, 1.11
mmol) and dihydrocinnamoyl chloride (0.18 cm3, 1.21 mmol)
followed by flash column chromatography using EtOAc–
hexane (1 : 1) as the eluant furnished the title compound as a
colourless oil (0.402 g, 0.91 mmol, 82%) (Found: MHϩ
442.2371. C29H31NO3 requires MHϩ: 442.2382); [α]D Ϫ153.4
(c = 1.05, CHCl3); νmax 1784 (s, C᎐O), 1705 (s, C᎐O) cmϪ1
;
᎐
᎐
J. Chem. Soc., Perkin Trans. 1, 2001, 1538–1549
1545

View Article Online
Using method F with (S)-5,5-diphenyl-4-isopropyl-3-(1Ј-
oxopropyl)-1,3-oxazolidin-2-one 21a (0.154 g, 0.458 mmol) and
benzyl bromide (0.17 cm3, 1.43 mmol) followed by flash column
chromatography using DCM–hexane (4 : 1) as the eluant
furnished the desired compound 22a as a white crystalline
solid (0.134 g, 0.315 mmol, 69%); δH (CDCl3) 7.48–7.10 (m,
15H, aryl-H), 5.35 (d, 1H, J 3.5, –NCH), 4.03 (m, 1H,
–CHCH3), 3.16 (dd, 1H, J 13.6 and 7.3, –CHAHPh), 2.60 (dd,
1H, J 13.6 and 7.7, –CHHBPh), 1.80 (m, 1H, –CH(CH3)2), 0.84
(d, 3H, J 6.5, –CH3), 0.70 (d, 3H, J 7.0, –CH3), 0.59 (d,
21c (0.259 g, 0.71 mmol) and benzyl bromide (0.26 cm3, 2.19
mmol) followed by flash column chromatography using DCM–
hexane (4 : 1) as the eluant furnished the desired compound
as a pale yellow oil (0.213 g, 0.47 mmol, 66%) (Found: MHϩ
456.2559. C30H33NO3 requires: 456.2539); νmax (KBr) 1779 (s,
C᎐O), 1770 (s, C᎐O) cmϪ1; δH (CDCl3) 7.32–7.09 (m, 13H, aryl-
H), 5.30 (d, 1H, J 3.5, –NCH), 4.04 (m, 1H, –CHCH3), 3.17
(dd, 1H, J 13.2 and 7.0, –CHAHPh), 2.59 (dd, 1H, J 13.3 and
8.3, –CHHBPh), 2.31 (s, 3H, –PhCH3), 2.28 (s, 3H, –PhCH3),
1.87 (m, 1H, –CH(CH3)2), 0.86 (d, 3H, J 6.8, –CH3), 0.70 (d,
3H, J 6.8, –CH3), 0.58 (d, 3H, J 6.5, –CH3); δC (CDCl3) 176.48
᎐
᎐
3H, J 7.0, –CH3); δC (CDCl ) 176.41 (–(C᎐O)CH –), 153.04
᎐
3
2
(C᎐O), 142.52, 140.50, 139.46, 138.32, 129.43, 129.03, 128.77,
᎐
(–(C᎐O)CH –), 153.16 (C᎐O), 139.82, 139.51, 138.55, 137.83,
᎐ ᎐
2
128.57, 128.50, 128.15, 126.46, 126.11, 125.87 (aryl-C), 89.47
(C-β), 64.67 (C-α), 39.97 (–CH2–), 39.37 (CHCH3), 30.11
(–CH(CH3)2), 21.70, 16.53, 16.30 (–CH3). The diastereomeric
ratio of 98 : 2 was obtained by measurement and comparison
of peak areas in the H NMR for the benzyl methylene reson-
ances for the major (δ 3.19 and 2.63) and minor (δ 2.85 and
2.48) isomers.
135.65, 129.63, 129.45, 129.45, 129.19, 128.49, 126.46, 126.02,
125.78 (aryl-C), 89.58 (C-β), 64.65 (C-α), 40.04 (–CH2–), 39.38
(–CHCH3), 29.86 (–CH(CH3)2), 21.77 (–CH3), 21.28, 21.20
(PhCH3–), 16.52, 16.33 (–CH3). The diastereomeric ratio of
98 : 2 was obtained by measurement and comparison of peak
1
1
areas in the H NMR for the methyl resonances for the major
(δ 0.86 and 0.58) and minor (δ 1.23 and 0.76) isomers.
Using method G with (S)-5,5-diphenyl-4-isopropyl-3-(1Ј-
oxopropyl)-1,3-oxazolidin-2-one 21a (0.337 g, 1.00 mmol) and
benzyl bromide (0.36 cm3, 3.03 mmol) followed by flash column
chromatography using DCM–hexane (4 : 1) as the eluant
furnished the desired compound as a white solid (0.196 g,
0.46 mmol, 46%). The diastereomeric ratio of 98.5 : 1.5 was
obtained by measurement and comparison of peak areas in the
1H NMR for the benzyl methylene resonances for the major
(δ 3.16 and 2.60) and minor (δ 2.81 and 2.45) isomers.
Using method E with (S)-5,5-di(4Ј-tolyl)-4-isopropyl-3-(1Љ-
oxopropyl)-1,3-oxazolidin-2-one 21c (0.119 g, 0.324 mmol) and
benzyl bromide (0.12 cm3, 0.95 mmol) followed by flash column
chromatography using DCM–hexane (4 : 1) as the eluant
furnished the desired compound as a pale yellow oil (0.0461 g,
0.1 mmol, 31%) The diastereomeric ratio of 98 : 2 was obtained
by measurement and comparison of peak areas in the 1H NMR
for the methyl resonances for the major (δ0.70 and 0.58) and
minor (δ 1.23 and 0.76) isomers.
A portion of 22a was recrystallised from pentane to give
colourless needle-like crystals, mp 134–136 ЊC (Found: C,
78.40; H, 6.72; N, 3.03: MHϩ428.2191. C28H29NO3 requires: C,
78.65; H, 6.85; N, 3.28%: MHϩ428.2226); [α]D Ϫ200.6 (c = 0.53,
CHCl3); νmax (KBr) 1774 (s, C᎐O), 1692 (s, C᎐O). The remain-
ing spectroscopic data were identical to those reported above
for method F. The diastereomeric ratio was found to be >99 : 1.
(2ЉR,4S)-5,5-Di(2Ј-naphthyl)-4-isopropyl-3-(1Ј-oxo-2Ј-
(2ЈS,4S)-5,5-Diphenyl-4-isopropyl-3-(1Ј-oxo-2Ј-benzyl-
propyl)-1,3-oxazolidin-2-one 23a. Using method E with (S)-5,5-
diphenyl-4-isopropyl-3-(1Ј-oxo-3Ј-phenylpropyl)-1,3-oxazol-
idin-2-one 20a (0.110 g, 0.27 mmol) and methyl iodide (0.05
cm3, 0.80 mmol) followed by flash column chromatography
using DCM–hexane (4 : 1) as the eluant furnished the
desired product as a colourless oil (0.056 g, 0.13 mmol, 37%)
(Found: MHϩ 428.2231. C28H30NO3 requires: MHϩ 428.2226);
νmax (KBr) 1780 (s, C᎐O), 1708 (s, C᎐O) cmϪ1; δH (CDCl3) 7.38–
᎐
᎐
benzylpropyl)-1,3-oxazolidin-2-one 22b. Using method G with
(S)-5,5-di(2Ј-naphthyl)-4-isopropyl-3-(1Љ-oxopropyl)-1,3-
oxazolidin-2-one 21b (0.350 g, 0.80 mmol) and benzyl bromide
(0.29 cm3, 2.43 mmol) followed by flash column chromato-
graphy using DCM–hexane (7 : 3) as the eluant furnished the
desired compound as a white semi solid (0.234 g, 0.44 mmol,
55%) (Found: MHϩ 528.2515. C36H33NO3 requires: 528.2539);
νmax (KBr) 1782 (s, C᎐O), 1702 (s, C᎐O) cmϪ1; δH (CDCl3) 8.15–
᎐
᎐
6.97 (m, 15H, aryl-H), 5.37 (d, 1H, J 3.3, –NCH), 4.03–3.92
(m, 1H, –CHCH3), 2.82 (dd, 1H, J 13.8 and 7.1, –CHAHPh),
2.45 (dd, 1H, J 13.8 and 7.4, –CHHBPh), 1.97 (m, 1H,
–CH(CH3)2), 1.23 (d, 3H, J 6.9, –CH3), 0.88 (d, 3H, J 6.8,
–CH3), 0.77 (d, 3H, J 6.8, –CH3); δC (CDCl3) 176.36
(–(C᎐O)CH–), 152.89 (C᎐O), 142.32, 139.29, 138.38, 129.06,
᎐
᎐
129.01, 128.77, 128.57, 128.40, 128.13, 126.26, 126.14, 125.78
(aryl-C), 89.47 (C-β), 64.56 (C-α), 39.42 (–CH2–), 38.81
(CHCH3), 30.13 (–CH(CH3)2), 22.01, 17.77, 16.53 (–CH3). The
diastereomeric ratio of 96 : 4 was obtained by measurement
᎐
᎐
7.14 (m, 19H, aryl-H), 5.65 (d, 1H, J 2.7, –NCH), 4.06 (m, 1H,
–CHCH3), 3.20 (dd, 1H, J 13.3 and 7.3, –CHAHPh), 2.62 (dd,
1H, J 13.3 and 7.8, –CHHBPh), 1.92 (m, 1H, –CH(CH3)2), 0.84
(d, 3H, J 6.4, –CH3), 0.76 (d, 3H, J 6.8, –CH3), 0.64 (d, 3H,
1
and comparison of peak areas in the H NMR for the methyl
J 6.8, –CH ); δ (CDCl ) 176.58 (–(C᎐O)CH –), 152.99 (C᎐O),
resonances for the major (δ 0.88 and 0.77) and minor (δ 0.70
and 0.59) isomers.
᎐
᎐
3
C
3
2
139.43, 135.43, 132.98, 132.79, 129.45, 129.25, 129.01, 128.77,
128.60, 128.52, 127.84, 127.73, 127.20, 126.98, 126.90, 126.49,
124.92, 124.18, 123.99 (aryl-C), 89.85 (C-β), 64.19 (C-α), 40.09
(–CH2–), 39.47 (–CHCH3), 30.15 (–CH(CH3)2), 21.96, 16.57,
16.28 (–CH3). The diastereomeric ratio of 95.5 : 4.5 was
obtained by measurement and comparison of peak areas in the
1H NMR for the benzyl methylene resonances for the major
(δ 3.20 and 2.62) and minor (δ 2.85 and 2.47) isomers.
Using method E with (S)-5,5-di(2Ј-naphthyl)-4-isopropyl-3-
(1Љ-oxopropyl)-1,3-oxazolidin-2-one 21b (0.123 g, 0.281 mmol)
and benzyl bromide (0.1 cm3, 0.84 mmol) followed by flash
column chromatography using DCM–hexane (7 : 3) as the
eluant furnished the desired compound as a white semi-solid
(0.056 g, 0.1 mmol, 34%). The spectroscopic data were identical
to those reported above. The diastereomeric ratio of 96 : 4 was
obtained by measurement and comparison of peak areas in the
1H NMR for the benzyl methylene resonances for the major
(δ 3.19 and 2.62) and minor (δ 2.85 and 2.49) isomers.
Using method H with (S)-5,5-diphenyl-4-isopropyl-3-(1Ј-
oxo-3Ј-phenylpropyl)-1,3-oxazolidin-2-one 20a (0.150 g, 0.36
mmol) and methyl iodide (0.12 cm3, 1.8 mmol) followed by flash
column chromatography using DCM–hexane (4 : 1) as the elu-
ant furnished the title compound as a colourless oil (0.106 g,
0.25 mmol, 69%). Spectroscopic analysis indicated that this
material was identical to that given above. The diastereomeric
ratio of 95.5 : 4.5 was obtained by measurement and com-
parison of peak areas in the 1H NMR for the benzyl methylene
resonances for the major (δ 2.81 and 2.45) and minor (δ 3.16
and 2.60) isomers.
(2ЉS,4S)-5,5-Di(2Ј-naphthyl)-4-isopropyl-3-(1Ј-oxo-2Ј-
benzylpropyl)-1,3-oxazolidin-2-one 23b. Using method F with
(S)-5,5-di(2Ј-naphthyl)-4-isopropyl-3-(1Ј-oxo-3Ј-phenylpropyl)-
1,3-oxazolidin-2-one 20b (0.137 g, 0.27 mmol) and methyl
iodide (0.05 cm3, 0.80 mmol) followed by flash column
chromatography using DCM–hexane (4 : 1) as the eluant fur-
nished the desired product as a viscous colourless oil (0.060 g,
0.11 mmol, 42%) (Found: MHϩ 528.2380. C36H34NO3 requires
(2ЉR,4S)-5,5-Di(4Ј-tolyl)-4-isopropyl-3-(1Ј-oxo-2Ј-benzyl-
propyl)-1,3-oxazolidin-2-one 22c. Using method G with (S)-5,5-
di(4Ј-tolyl)-4-isopropyl-3-(1Љ-oxopropyl)-1,3-oxazolidin-2-one
528.2539); νmax (CHCl ) 1778 (s, C᎐O), 1702 (s, C᎐O) cmϪ1
;
᎐
᎐
3
1546
J. Chem. Soc., Perkin Trans. 1, 2001, 1538–1549

View Article Online
δH (CDCl3) 8.15–7.09 (m, 19H, aryl-H), 5.65 (d, 1H, J 3.0,
–NCH), 4.01 (m, 1H, –CHCH3), 2.85 (dd, 1H, J 13.9 and 7.9,
–CHAHPh), 2.49 (dd, 1H, J 13.9 and 6.9, –CHHBPh),
2.02 (m, 1H, –CH(CH3)2), 1.27 (d, 3H, J 6.8, –CH3), 0.90 (d,
3H, J 6.8, –CH3), 0.82 (d, 3H, J 6.8, –CH3); δC (CDCl3) 176.52
(–(C᎐O)CH–), 152.86 (C᎐O), 139.07, 139.04, 135.48, 133.23,
132.99, 132.76, 129.26, 129.03, 128.71, 128.60, 128.50, 128.15,
127.84, 127.68, 127.14, 126.98, 126.78, 126.05, 124.82, 124.48,
124.15, 123.91 (aryl-C), 89.79 (C-β), 63.97 (C-α), 39.40
(–CH2–), 38.79 (–CHCH3), 30.42 (–CH(CH3)2), 22.26, 18.17,
16.53 (–CH3). The diastereomeric ratio of 93 : 7 was obtained
by measurement and comparison of peak areas in the 1H NMR
for the methyl resonances for the major (δ 0.82) and minor
(δ 0.64) isomers.
nitrogen atmosphere was added a pre-cooled solution of
(S)-5,5-di(4Ј-tolyl)-4-isopropyl-3-(1Ј-oxo-3Ј-phenylpropyl)-1,3-
oxazolidin-2-one 20c (0.503 g, 1.11 mmol) in THF (4 cm3) via
cannula transfer. The resulting pale yellow potassium enolate
was aged for 30 min at Ϫ78 ЊC. A pre-cooled (Ϫ78 ЊC) solution
of trisyl§ azide24 (0.410 g, 1.33 mmol) in THF (4 cm3) was added
via cannula. After the addition was complete, the bright yellow
reaction mixture was stirred for 2 min and then quenched with
glacial acetic acid (0.30 cm3, 5.08 mmol). The reaction mixture
was allowed to warm to ∼30 ЊC in a water bath over 45 min. The
solution was partitioned between DCM (25 cm3) and brine
(35 cm3). The aqueous phase was washed with DCM (3 × 10
cm3). The combined organic extracts were washed with aqueous
NaHCO3 solution, dried over MgSO4 and evaporated. Purifi-
cation of the crude residue twice by column chromatography
using 5 : 1 hexane–EtOAc afforded the desired product as
a colourless oil (0.354 g, 0.73 mmol, 65%) (Found: MHϩ
483.2396. C29H35N5O3 requires: 483.2396); νmax (liq. film) 2114
(s, –N ), 1782 (s, C᎐O), 1710 (s, C᎐O) cmϪ1; δH (CDCl3) 7.32–
᎐
᎐
Using method H with (S)-5,5-di(2Ј-naphthyl)-4-isopropyl-3-
(1Ј-oxo-3Ј-phenylpropyl)-1,3-oxazolidin-2-one 20b (0.694 g,
1.35 mmol) and methyl iodide (0.42 cm3, 6.74 mmol) followed
by flash column chromatography using DCM–hexane (7 : 3) as
the eluant furnished the title compound as a colourless viscous
oil (0.413 g, 0.78 mmol, 58%). Spectroscopic analysis indi-
cated that this material was identical to that given above. The
diastereomeric ratio of 91 : 9 was obtained by measurement
᎐
᎐
3
6.95 (m, 13H, aryl-H), 5.23 (d, 1H, J 3.5, –NCH), 5.14 (dd,
1H, J 8.4 and 5.4, –CHN3), 2.66 (dd, 1H, J 14.3 and 5.4,
–CHAHCHN3), 2.60 (dd, 1H, J 14.3 and 8.4, –CHHBCHN3),
2.24 (s, 3H, –PhCH3), 2.21 (s, 3H, –PhCH3), 1.94 (m, 1H,
–CH(CH3)2), 0.84 (d, 3H, J 7.2 CH(CH3)2), 0.74 (d, 3H, J 7.2,
1
and comparison of peak areas in the H NMR for the methyl
resonances for the major (δ 0.94 and 0.82) and minor (δ 0.77
and 0.64) isomers.
CH(CH3)2); δC (CDCl ) 170.22 (–(C᎐O)CH–), 152.86 (C᎐O),
᎐
᎐
3
(2ЉS,4S)-5,5-Di(4Ј-tolyl)-4-isopropyl-3-(1Ј-oxo-2Ј-benzyl-
propyl)-1,3-oxazolidin-2-one 23c. Using method F with (S)-5,5-
di(4Ј-tolyl)-4-isopropyl-3-(1Ј-oxo-3Ј-phenylpropyl)-1,3-oxazol-
idin-2-one 20c (0.176 g, 0.40 mmol) and methyl iodide (0.08
cm3, 1.28 mmol) followed by flash column chromatography
using DCM–hexane (4 : 1) as the eluant furnished the desired
product as a colourless oil (0.058 g, 0.13 mmol, 32%) (Found:
MHϩ 456.2511. C30H34NO3 requires: 456.2539); νmax (KBr)
1782 (s, C᎐O), 1702 (s, C᎐O) cmϪ1; δH (CDCl3) 7.33–6.97 (m,
139.41, 138.84, 138.13, 135.95, 135.00, 129.84, 129.47, 129.30,
128.87, 128.24, 125.87, 125.46 (aryl-C), 90.49 (C-β), 65.54
(C-α), 61.76 (–CHN3), 37.02 (–CH2–), 29.93 (–CHCH3), 21.90
(–CH3), 21.26, 21.18 (–PhCH3), 16.60 (–CH3). The diastereo-
meric ratio of 96 : 4 was measured by HPLC analysis (Zorbax
column) using tert-butyl methyl ether–isooctane (99 : 1) as the
eluant at 1 cm3 minϪ1 (minor peak 27.46 min, major peak 30.56
min).
᎐
᎐
13H, aryl-H), 5.30 (d, 1H, J 3.2, –NCH), 3.97 (m, 1H,
–CHCH3), 2.84 (dd, 1H, J 13.9 and 7.3, –CHAHPh), 2.47 (dd,
1H, J 13.9 and 7.3, –CHHBPh), 2.31 (s, 3H, –PhCH3), 2.29 (s,
3H, PhCH3), 1.95 (m, 1H, –CH(CH3)2), 1.23 (d, 3H, J 7.0,
–CH3), 0.86 (d, 3H, J 6.8, –CH3), 0.77 (d, 3H, J 6.8, –CH3);
(2ЉS,4S)-5,5-Di(4Ј-tolyl)-3-(2Љ-bromo-3Љ-phenyl-1Љ-
oxopropyl)-4-isopropyl-1,3-oxazolidin-2-one 25
To a solution of (S)-5,5-di(4Ј-tolyl)-4-isopropyl-3-(1Ј-oxo-3Ј-
phenylpropyl)-1,3-oxazolidin-2-one 20c (0.216 g, 0.49 mmol) in
DCM (5 cm3) at Ϫ78 ЊC under N2 was added diisopropylethyl-
amine (0.11 cm3, 0.63 mmol) followed by the dropwise addition
of dibutylboryl triflate ¶ (1 M in DCM, 0.52 cm3 0.52 mmol).
The pale yellow boron enolate was aged for 15 min at Ϫ78 ЊC
and then for 1 h at 0 ЊC. The boron enolate was then added
rapidly to a pre-cooled slurry of N-bromosuccinimide (0.117 g,
0.66 mmol) in DCM (1 cm3) via cannula transfer. The mixture
was aged for 1.5 h at Ϫ78 ЊC before a red slurry was formed
which was stirred at Ϫ78 ЊC for a further 1 h. The reaction
mixture was quenched by pouring into 0.5 M sodium bisulfate–
brine (1 : 1, 10 cm3). The solution was extracted with EtOAc
(3 × 5 cm3) and the combined organic layers were washed with
0.5 M aqueous sodium thiosulfate–brine (10 cm3) and brine
(10 cm3), dried over Na2SO4 and concentrated in vacuo to
give the crude α-bromocarboximide as a yellow oil (0.306 g);
δ (CDCl ) 176.38 (–(C᎐O)CH–), 153.04 (C᎐O), 139.62, 139.51,
᎐
᎐
H
3
138.55, 137.83, 135.65, 129.63, 129.45, 129.45, 129.19, 128.49,
126.46, 126.02, 125.78 (aryl-C), 89.61 (C-β), 64.58 (C-α), 39.37
(–CH2–), 38.83 (–CHCH3), 30.08 (–CH(CH3)2), 22.02 (–CH3),
21.26, 21.19 (PhCH3–), 17.83, 16.58 (–CH3). The diastereo-
meric ratio of 97.5 : 2.5 was obtained by measurement and
comparison of peak areas in the 1H NMR for the methyl
resonances for the major (δ 0.77) and minor (δ 0.58) isomers.
Using method H with (S)-5,5-di(4Ј-tolyl)-4-isopropyl-3-(1Ј-
oxo-3Ј-phenylpropyl)-1,3-oxazolidin-2-one 20c (0.629 g, 1.43
mmol) and methyl iodide (0.44 cm3, 7.13 mmol) followed by
flash column chromatography using DCM–hexane (4 : 1)
furnished the title compound as a colourless oil (0.416 g, 0.91
mmol, 64%). Spectroscopic analysis indicated that this material
was identical to that given above. The diastereomeric ratio of
97 : 3 was obtained by measurement and comparison of peak
νmax (liq. film) 1785 (s, C᎐O), 1708 (s, C᎐O), 700 (s, C–Br) cmϪ1
;
᎐
᎐
δH (CDCl3) 7.45–6.96 (m, 13H, aryl-H), 5.84 (dd, 1H, J 8.8 and
6.5, –CHBr), 5.34 (d, 1H, J 3.1, –NCH), 3.48 (dd, 1H, J 14.1
and 8.8, –CHAHCHN3), 3.21 (dd, 1H, J 14.1 and 6.5,
–CHHBCHN3), 2.32 (s, 3H, –PhCH3), 2.30 (s, 3H, –PhCH3),
2.01 (m, 1H, –CH(CH3)2), 0.96 (d, 3H, J 7.0, –CH(CH3)2), 0.84
(d, 3H, J 7.0, –CH(CH3)2).
1
areas in the H NMR for the methyl resonances for the major
(δ 0.85 and δ 0.76) and minor (δ 0.69 and 0.58) isomers.
X-Ray crystallographic study of (2ЈR,4S)-5,5-diphenyl-4-
isopropyl-3-(1Ј-oxo-2Ј-benzylpropyl)-1,3-oxazolidin-2-one 22a
Colourless crystals of 22a were grown from pentane solution. A
sample with approximate dimensions 0.45 × 0.25 × 0.15 mm
was mounted directly into the cold-stream of a Rigaku AFC7S
diffractometer using an oil drop method.
(2ЈR,4S)-3-(2Ј-Azido-3Ј-phenyl-1Ј-oxopropyl)-5,5-di(4Љ-tolyl)-
4-isopropyl-1,3-oxazolidin-2-one 26
To a solution of the unpurified α-bromocarboximide 25 (0.281
g, 1.47 mmol) in DCM (4 cm3) at 0 ЊC was added tetramethyl-
guanidinium azide25 (0.233 g, 1.47 mmol) in one portion. The
(2ЈS,4S)-3-(2Ј-Azido-3Ј-phenyl-1Ј-oxopropyl)-5,5-di(4Љ-tolyl)-4-
isopropyl-1,3-oxazolidin-2-one 24
To a solution of potassium hexamethyldisilylazide (0.5 M in
§ The IUPAC name for trisyl is 2,4,6-triisopropylsulfonyl.
¶ The IUPAC name for triflate is trifluoromethanesulfonate.
THF, 2.54 cm3, 1.27 mmol) in THF (4 cm3) at Ϫ78 ЊC under a
J. Chem. Soc., Perkin Trans. 1, 2001, 1538–1549
1547

View Article Online
resulting solution was stirred for 4 h at 0 ЊC and then quenched
by the addition of saturated aqueous NaHCO3 (15 cm3) and the
product was extracted using DCM (3 × 15 cm3). The organic
extracts were combined and washed with brine (15 cm3), dried
over Na2SO4 and the solvent removed in vacuo to give a yellow
semi-solid. The α-azidocarboximide was purified by column
chromatography using hexane–EtOAc (5 : 1) then hexane–
EtOAc (7 : 1) as the eluant which furnished the title compound
as a colourless oil (0.189 g), contaminated by the starting
oxazolidin-2-one 20c (68 : 32), corresponding to an overall
yield of 58% (Found: MHϩ 500.2662. C29H35N5O3 requires:
Hydrolysis of (2ЉR,4S)-5,5-di(2Ј-naphthyl)-4-isopropyl-3-
(1Ј-oxo-2Ј-benzylpropyl)-1,3-oxazolidin-2-one
22b.
Using
method I with the title compound (0.138 g, 0.262 mmol, dr
95.5 : 4.5) gave (S)-5,5-di(2Ј-naphthyl)-4-isopropyl-1,3-oxazol-
idin-2-one 16b as a white solid (0.0912 g, 0.239 mmol, 91%).
Also isolated as a colourless oil was (R)-2-methyl-3-phenyl-
propionic acid 27 (0.0304 g, 0.185 mmol, 71%); [α]D Ϫ24.6
(c = 1.14, CHCl3), 92% ee.
Hydrolysis of (2ЉR,4S)-5,5-di(4Ј-tolyl)-4-isopropyl-3-(1Ј-
oxo-2Ј-benzylpropyl)-1,3-oxazolidin-2-one 22c. Using method I
with the title compound (0.143 g, 0.314 mmol, dr 98 : 2) gave
(S)-5,5-di(4Ј-tolyl)-4-isopropyl-1,3-oxazolidin-2-one 16c as a
white solid (0.095 g, 0.307 mmol, 98%), mp 181–188 ЊC (EtOH)
(Found: C, 77.60; H, 7.48; N, 4.28. Calculated for C18H19NO2:
C, 77.644; H, 7.48; N, 4.53%). Also isolated as a colourless oil
was (R)-2-methyl-3-phenylpropionic acid 27 (0.0281 g, 0.171
mmol, 55%); [α]D Ϫ25.7 (c = 0.92, CHCl3), 96% ee.
Hydrolysis of (2ЈS,4S)-5,5-diphenyl-4-isopropyl-3-(1Ј-oxo-
2Ј-benzylpropyl)-1,3-oxazolidin-2-one 23a. Using method I with
the title compound (0.192 g, 0.45 mmol, dr 96.5 : 3.5) gave (S)-
5,5-diphenyl-4-isopropyl-1,3-oxazolidin-2-one 16a as a white
solid (0.0371 g, 0.132 mmol, 95%), mp 247–250 ЊC (EtOH–
H2O) (lit.13 253.2–253.9 ЊC) (Found: C, 76.44; H, 6.90; N, 4.83.
Calculated for C18H19NO2: C, 76.84; H, 6.81; N, 4.98%). Also
isolated as a colourless oil was (S)-2-methyl-3-phenylpropionic
acid 28 (0.069 g, 0.423 mmol, 94%); [α]D ϩ24.1 (c = 0.55,
CHCl3), 89% ee.
500.2662); νmax (liq. film) 2114 (s, –N ), 1782 (s, C᎐O), 1710 (s,
᎐
3
C᎐O) cmϪ1; δH (CDCl3) 7.42–7.13 (m, 13H, aromatic-H), 5.42
᎐
(d, 1H, J 3.3, –NCH), 5.09 (dd, 1H, J 10.1 and 4.3, –CHN3),
3.44 (dd, 1H, J 13.6 and 4.3, –CHAHCHN3), 3.00 (dd, 1H,
J 13.6 and 10.3, –CHHBCHN3), 2.35 (s, 3H, –PhCH3), 2.33
(s, 3H, –PhCH3), 2.00 (m, 1H, –CH(CH3)2), 0.88 (d, 3H, J 6.8,
–CH(CH3)2), 0.73 (d, 3H, J 6.8, CH(CH3)2); δC (CDCl3) 170.48
(–(C᎐O)CH–), 152.85 (C᎐O), 139.17, 138.98, 138.10, 136.23,
᎐
᎐
135.24, 129.91, 128.77, 128.60, 128.58, 127.46, 125.69, 125.62
(aryl-C), 90.68 (C-β), 64.79 (C-α), 62.07 (–CHN3), 38.09
(–CH2–), 30.04 (–CHCH3), 21.95 (–CH3), 21.27, 21.18
(–PhCH3), 16.47 (–CH3). The diastereomeric ratio of 95.5 : 4.5
was measured by HPLC analysis (Zorbax normal phase
column) using tert-butyl methyl ether and isooctane (99 : 1) as
the eluant at 1 cm3 minϪ1 (major peak 32.26 min, minor peak
39.13 min).
Hydrolysis of (2ЉS,4S)-5,5-di(2Ј-naphthyl)-4-isopropyl-3-
(1Ј-oxo-2Ј-benzylpropyl)-1,3-oxazolidin-2-one
23b.
Using
General procedure I. Hydrolysis of the alkylated oxazolidin-2-
ones
method I with the title compound (0.200 g, 0.379 mmol, dr
91 : 9) gave (S)-5,5-di(2Ј-naphthyl)-4-isopropyl-1,3-oxazolidin-
2-one 16b as a white solid (0.1463 g, 0.379 mmol, 100%), mp
240–242 ЊC (Found: C, 81.41; H, 6.26; N, 3.54. Calculated for
C18H19NO2: C, 81.86; H, 6.08; N, 3.67%). Also isolated as a
colourless oil was (S)-2-methyl-3-propionic acid 28 (0.0449 g,
0.273 mmol, 72%); [α]D ϩ21.7 (c = 0.74, CHCl3), 81% ee.
Hydrolysis of (2ЉS,4S)-5,5-di(4Ј-tolyl)-4-isopropyl-3-(1Ј-
oxo-2Ј-benzylpropyl)-1,3-oxazolidin-2-one 23c. Using method I
with the title compound (0.1916 g, 0.421 mmol, dr 97 : 3) gave
(S)-5,5-di(4Ј-tolyl)-4-isopropyl-1,3-oxazolidin-2-one 16c as a
white solid (0.130 g, 0.42 mmol, 100%), mp 181–188 ЊC. Also
isolated as a colourless oil was (S)-2-methyl-3-propionic acid
28 (0.0434 g, 0.265 mmol, 63%); [α]D ϩ24.9 (c = 0.51, CHCl3),
92% ee.
A portion of the alkylated 1,3-oxazolidin-2-one was dissolved
in THF–H2O (3 : 1 mixture, 0.06 M) and cooled in an ice
bath. Lithium hydroxide (2 equiv.) was added in one portion
and the mixture stirred at 0 ЊC for 1 h and at room temper-
ature for 24 h. A saturated solution of NaHCO3 was added
and the organic and aqueous layers were separated. The
aqueous layer was washed with DCM (×3). The organic
extracts were combined, washed with brine, dried over
MgSO4 and the solvent removed in vacuo to give the auxiliary
as a white solid which was either subjected to flash column
chromatography using ethyl acetate–hexane (1 : 1) as the
eluant or recrystallised from the appropriate solvent. The
spectroscopic data of the recovered auxiliaries were identical to
those recorded above.
To the original aqueous extract was added 1 M HCl until pH
2–3 was reached. The mixture was washed with EtOAc (×3) and
the organic extracts were combined, washed with brine, dried
over MgSO4 and the solvent removed in vacuo followed by flash
column chromatography using ethyl acetate–hexane (1 : 1)
as the eluant to give the carboxylic acid, 2-methyl-3-phenyl-
propionic acid 27 or 28 as a colourless liquid (Found: MHϩ
165.0942. C10H14O2 requires: 165.0916); δH (CDCl3) 7.34–7.19
(m, 5H, aryl-H), 3.09 (dd, 1H, J 12.8 and 7.8, –CHAHPh),
2.85–2.64 (m, 2H, –CHHBPh, –CHCH3), 1.20 (d, 3H, J 6.8,
–CH3). The absolute configuration and enantiomeric purity
were assigned by comparison of the measured optical rotation
with literature values (27 98% ee [α]D Ϫ26.2 (c = 1.0, CHCl3), 28
95% ee [α]D ϩ25.6 (c = 1.0, CHCl3)).27
Acknowledgements
We are grateful to Hickson & Welch for a fully funded student-
ship (to KA). We also thank Dr Sheetal Handa (BP Chemicals)
and Dr Terry Lowdon (Hickson & Welch) for valuable discus-
sions and to Professor Kyuji Ohta (Strathclyde University) for
translation of ref. 13. We are indebted to the EPSRC National
Mass Spectrometry Service, Swansea for running some mass
spectra.
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