Asymmetric alkylations using SuperQuat auxiliaries - An investigation into the synthesis and stability of enolates derived from 5,5-disubstituted oxazolidin-2-ones

Article abstract of DOI:10.1039/a809715a

Studies on the alkylation of enolates derived from a range of N-acyl-5,5-dimethyloxazolidin-2-ones and N-acyl-5,5-diphenyloxazolidin-2-ones reveal that high yields and high diastereoselectivities are best obtained when homochiral 4-isopropyl-5,5-dimethyloxazolidin-2-one is employed as a chiral auxiliary.

Full text of DOI:10.1039/a809715a

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Asymmetric alkylations using SuperQuat auxiliaries—an
investigation into the synthesis and stability of enolates derived
from 5,5-disubstituted oxazolidin-2-ones
Steven D. Bull, Stephen G. Davies,* Simon Jones and Hitesh J. Sanganee
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford,
UK OX1 3QY
Received (in Cambridge) 14th December 1998, Accepted 4th January 1999
Studies on the alkylation of enolates derived from a range of N-acyl-5,5-dimethyloxazolidin-2-ones and N-acyl-5,5-
diphenyloxazolidin-2-ones reveal that high yields and high diastereoselectivities are best obtained when homochiral
4-isopropyl-5,5-dimethyloxazolidin-2-one is employed as a chiral auxiliary.
ing, there are practical problems associated with its use in
Introduction
synthesis, particularly on a large scale. The yields obtained for
alkylation of enolates derived from N-acyl fragments 2 are not
quantitative, affording α-substituted products 3 in 70–92%
yield for activated electrophiles.6 More importantly these enolate
alkylations often occur with incomplete stereochemical control,
affording oily mixtures of diastereoisomers which must be sep-
arated by chromatography affording diminished yields of the
desired diastereoisomer 3. Major isolation problems may also
occur during nucleophilic cleavage of 3 to the parent auxiliary 1
and homochiral fragment 4, since sterically hindered α-substi-
tuted acyl fragments are cleaved via a competing endocyclic
cleavage to afford N-acyl-amino alcohols 5 (Scheme 2).7 This
The role of chiral auxiliaries in asymmetric synthesis for the
preparation of homochiral molecules is now firmly established
in organic synthesis.1 Perhaps the most versatile and widely
used of these chiral auxiliaries is that devised by Evans et al.
which is based on the use of chiral oxazolidin-2-ones 1 to con-
trol facial selectivity during enolate alkylation of enolates
of N-acyl fragments.2 This methodology has had enormous
impact within the synthetic community since homochiral
α-substituted carboxylic acids arising from this methodology
are easily transformed into a large number of synthetically use-
ful homochiral fragments.3 The general strategy employed when
using Evans’ auxiliary for asymmetric synthesis involves deriv-
atisation of the chiral auxiliary 1 with an acid chloride to afford
an acyl fragment 2, followed by enolate formation and alkyl-
ation with an electrophile to afford a major diastereoisomeric
product 3 containing a new stereogenic centre in high de. Purifi-
cation of the major diastereoisomer 3 to homogeneity, followed
by nucleophilic cleavage, affords the desired homochiral prod-
uct 4 whilst regenerating the chiral auxiliary 1 for further use
(Scheme 1).4 Other developments within this area have seen the
O
O
O
O
R2
R2
exocyclic
O
NH
R
O
N
HO
R1
R1
H
R
H
1
4
3
endocyclic
O
O
O
O
O
R1
(i)
O
NH
R
R2
O
N
R
O
NH
R
HO HN
5
4
R1
R1
R1
R
2
1
5
6
(ii)
Scheme 2
O
O
O
competing endocyclic pathway is particularly troublesome since
it results in a decreased yield of the desired homochiral acid 4,
and a complex mixture of compounds which must be separated.
While this endocyclic cleavage problem may be overcome by
deploying the more nucleophilic species LiOOH for hydrolysis,7
the use of this reagent on a large scale is clearly undesirable.
As part of a continuing program into the development of
robust chiral auxiliaries for use on a large scale, and in order to
address fully these troublesome cleavage problems, we have
recently reported on the development of a new class of chiral
auxiliary, the 5,5-substituted SuperQuats as exemplified by the
5,5-dimethyl derivative 6 (R1 = Me). These auxiliaries provide
superior performance to many of the N-acyl chiral auxiliaries
currently in common usage. Since our initial communication
in this area, a number of publications have appeared which
O
(iii)
R1
R1
O
NH
R
O
N
+
HO
E
E
R
1
4
3
Scheme 1 Reagents and conditions: (i) n-BuLi, R1CH2COCl; (ii) LDA,
electrophile; (iii) LiOH.
extension of this methodology to the stereoselective control
of a wide range of chemistry including aldol reactions, 1,4-
conjugate additions, hydroxylation, halogenation, Diels–Alder
reactions, ene reactions, cyclopropanations, α-amino acid syn-
thesis and iterative propionate homologation.5
Whilst the impact of Evans’ auxiliary 1 has been far reach-
J. Chem. Soc., Perkin Trans. 1, 1999, 387–398
387

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E+
O
Nu
Nu
CH3
H3C
O
Nu
Li
Li
R
O
O
H
H
R
O
O
H
H
H3C
O
H3C
O
N
N
Ph
H
H
H
N
Nu
H
H
H
H
O
H
H
H
R2
8
H
7
R1
Fig. 2 Steric interactions between the geminal 5-C dimethyl groups
and the incoming nucleophile block attack at the carbonyl of the
oxazolidin-2-one.
E
O
O
H
H3C
O
N
R
H
ing a versatile synthesis of a range of SuperQuat auxiliaries 6
derived from glycine, alanine, phenylglycine and valine, each
containing either methyl or phenyl groups at their 5-C position.
H
H
H3C
Synthesis of SuperQuat auxiliaries
Fig. 1 Steric interaction between the benzyl group and the syn 5-C
methyl group results in rotation around the 4-C-benzyl bond directing
the benzyl group beneath the plane of the enolate. This conformation
effectively blocks the bottom face of the enolate from electrophilic
attack.
Three routes were developed for the synthesis of SuperQuat
auxiliaries 6a–h starting from the corresponding parent
α-amino acid methyl ester 9. The first two approaches were used
in the initial phases of these studies and involved the addition
of excess Grignard reagent to the parent α-amino acid methyl
ester 9 to afford the corresponding tertiary alcohol 10, which
was then transformed directly to the corresponding SuperQuat
auxiliary 6 via treatment with 1,1Ј-carbonyldiimidazole (CDI).
Alternatively 10 could be treated with trichloroacetyl chloride
to afford trichloroacetamide 11 which readily underwent base
promoted cyclisation to afford the desired chiral auxiliary 6
(Scheme 3).10
propose the use of 5,5-diphenyloxazolidin-2-ones 6 (R1 = Ph)
for asymmetric synthesis.8,9 At the inception of our work into
the design of SuperQuat auxiliaries, we also considered using
this class of oxazolidin-2-one as a chiral auxiliary, however our
results in this area clearly indicated that alkylation of enolates
derived from 5,5-dimethyloxazolidin-2-ones were more effect-
ive than alkylation of enolates derived from the corresponding
5,5-diphenyloxazolidin-2-ones. We now describe herein the
direct comparison of the performance of enolates derived from
different classes of 5,5-substituted oxazolidin-2-one, which
clearly reveal that 4-isopropyl-5,5-dimethyl SuperQuat is the
auxiliary of choice for asymmetric enolate alkylations. Part of
this work has been previously communicated.10,11
R
R
O
R
(i)
(ii)
O
OH
R1
OH
R1
H2N
H2N
Cl3C
(iii)
N
H
OMe
R1
R1
11
9
10
Results and discussion
Synthetic rationale behind the design of SuperQuat auxiliaries
(v)
R
(iv)
O
O
O
R
In order to address the problems associated with Evans’ aux-
iliary 1, we proposed a range of new oxazolidin-2-ones, the
SuperQuats 6, containing geminal substituents at the 5-C
position. There were two fundamental reasons behind this
structural design. Firstly, it was proposed that the diastereo-
selectivity obtained during alkylation of enolate fragments of
N-acyl SuperQuats 7 would be improved relative to the des
obtained using enolates derived from Evans’ auxiliary, because
the presence of geminal dialkyl groups at 5-C would serve to
direct the conformation of the stereocontrolling group at 4-C
close to the point of enolate alkylation at 2Ј-C. It was reasoned
that this conformation would provide more steric hindrance in
the transition state of the enolate reactions and would result
in increased stereofacial bias towards any incoming electro-
phile.12 We reasoned that this structural design would result in
improved alkylation diastereoselectivities as illustrated for the
enolate 7 of the phenylalanine derived SuperQuat as shown in
Fig. 1. Our second design criterion was based on the geminal
5-C substituents of the SuperQuat auxiliary conferring superior
cleavage properties to the corresponding α-substituted N-acyl
fragment 8, since the presence of 5-C-dialkyl groups would
serve to protect the oxazolidin-2-one carbonyl from nucleo-
philic attack by sterically blocking the Burgi–Dunitz angle of
trajectory at 2-C. As a result, any competing endocyclic cleav-
age pathway should be completely suppressed, and only the
products of the desired exocyclic cleavage pathway would be
produced (Fig. 2).
(vi)
(i)
O
NH
R
OH
R1
O
tBuO
N
H
tBuO
N
H
R1
OMe
R1
R1
6a-h
12
13a-h
Scheme 3 Reagents and conditions: (i) 4 equiv. R1MgBr, THF; (ii)
CCl3COCl, pyridine; (iii) CDI, CH2Cl2; (iv) K2CO3, EtOH; (v) Boc2O,
K2CO3; (vi) t-BuOK, THF.
Scale up of these synthetic routes proved capricious how-
ever since the absolute yields of SuperQuat auxiliary 6
obtained were sensitive to the nature of the functionality of
both the starting α-amino acid methyl ester 9, and the Grignard
reagent deployed. As a result, these routes were superseded by a
versatile protocol which enabled syntheses of all of the Super-
Quats 6a–h used in this study to be carried out on a multigram
scale in good yield (Table 1). Treatment of the methyl esters of
N-Boc α-amino acids 12 with excess Grignard reagent afforded
N-Boc-protected amino alcohols 13a–h, which were then sub-
jected to base catalysed cyclisation with KOtBu to afford
SuperQuat auxiliaries 6a–h. It is interesting to note that the
N-Boc protecting group of 12 serves three functions during this
synthetic protocol. Firstly it acts as a suitable N-protecting
group decreasing the polarity of the parent amino alcohol 10,
thus facilitating its isolation from magnesium salts contained
within the crude reaction mixture. Secondly the presence of the
acidic carbamate proton results in an anion α to the stereogenic
centre of 12 disfavouring racemisation by excess Grignard
Our initial attention was therefore directed towards develop-
388
J. Chem. Soc., Perkin Trans. 1, 1999, 387–398

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Table 1 Preparation of SuperQuats 6 from N-protected α-amino acid
esters 12
Examination of the trend in chemoselectivities described in
Table 2 revealed that introduction of substituents at 5-C of the
oxazolidin-2-one ring had clearly decreased enolate stability/
reactivity towards enolate alkylation. Under these conditions
the enolate fragment derived from the completely unfunctional-
ised oxazolidin-2-one 6i cleanly afforded the desired α-benzyl-
ated fragment 15i in 93% yield with only 7% decomposition to
N-benzyl-SuperQuat 16i. The enolate of SuperQuat 6a, where
the two 5-C hydrogens of the parent oxazolidin-2-one had been
replaced with two methyl groups, resulted in an N-acyl com-
pound 14a whose enolate afforded alkylated material 15a in
79% yield with only small amounts of the decomposition prod-
ucts SuperQuat 6a (6%) and N-benzyl-SuperQuat 16a (11%)
being observed. In contrast, the enolate derived from the
corresponding 5,5-diphenyloxazolidin-2-one 6b was not only
unstable (31% yield of the parent SuperQuat 6b and 29%
yield of N-benzyl-SuperQuat 16b) but relatively unreactive to
electrophilic substitution (11% yield of starting material 14b),
affording the desired α-benzylated product 15b in a derisory
29% yield. These results indicated that useful yields of alkylated
products were only likely to be obtained using lithium enolates
derived from the 5,5-dimethyl-SuperQuat auxiliary, rather
than the corresponding 5,5-diphenyl-SuperQuat analogue.
Overall
SuperQuat
6
yield (%)
R
R1
from 12a
Mp (ЊC)
[α]D23 (CHCl3)
a
b
c
d
e
f
H
H
Me
Ph
Me
Ph
Me
Ph
Me
Ph
40
46
57
47
63
66
63
55
78–82
196–197
64
—
—
Me
Me
Ph
Ph
iPr
iPr
Ϫ2.85 (c 4)
ϩ288.4 (c 0.5)
Ϫ77.6 (c 0.5)
ϩ218.1 (c 1)
Ϫ24.2 (c 1)
ϩ315.6 (c 0.5)
>220
149
>230
87
g
h
>220
a Overall yields based on the two step transformation of 12→13 and
13→6, where alcohol 13 was isolated for characterisation before sub-
1
sequent use. In each case the crude H NMR spectrum indicated that
both transformations were essentially quantitative and clean.
reagent. Finally the N-Boc protecting group of 13 is deployed
as a sacrificial carbonyl equivalent during formation of the
oxazolidin-2-one ring system of 6.11
Initial alkylation studies using achiral N-acyl oxazolidin-2-ones
Probing diastereoselectivities using enolates of 5,5-dimethyl and
5,5-diphenyl SuperQuats
Preliminary alkylation studies carried out on N-acyl com-
pounds derived from Evans’ auxiliary 1 revealed that the
primary decomposition pathway of enolates derived from
oxazolidin-2-one chiral auxiliaries involved fragmentation of
the enolate to afford the parent oxazolidin-2-one, presumably
via a ketene decomposition pathway or via a Claisen conden-
sation type process. We were concerned that introduction of
functional groups at the 5-C position of the oxazolidin-2-one
would have an adverse effect on the reactivity of the corre-
sponding N-acyl enolates and as a result we carried out model
studies on the stability of enolates of N-acyl fragments derived
from the three achiral oxazolidin-2-ones 6a,b and 6i (R,
R1 = H). N-Propionyl oxazolidin-2-ones 14a,b,i were prepared
via treatment of the parent oxazolidin-2-ones 6a,b,i with
n-BuLi at Ϫ78 ЊC in THF, followed by addition of propionyl
chloride. Compounds 14a,b,i were subjected to alkylation
conditions known to cause small amounts of enolate decom-
position for the simplest unsubstituted N-propionyl SuperQuat
14i. Therefore, N-acyl fragments 14a,b,i were deprotonated with
1.1 equiv. of LHMDS in THF at Ϫ78 ЊC for 30 minutes,
followed by addition of 3 equiv. of benzyl bromide at Ϫ78 ЊC
and the reaction mixture stirred for 2 hours. The reaction
mixture was warmed to room temperature, stirred for 24 hours
and after aqueous work-up afforded varying mixtures of start-
ing material 14a,b,i, the desired α-benzylated product 15a,b,i,
and products resulting from enolate decomposition; the Super-
Quats 6a,b,i and N-benzyl SuperQuats 16a,b,i (Scheme 4).
Our attention then turned to probing what effect changing the
stereocontrolling substituent at 4-C of the oxazolidin-2-one
would have on both the diastereoselectivity and yield of alkyl-
ation of N-acyl SuperQuat enolates. N-Acylated SuperQuats
14c–h,j were prepared as described (n-BuLi, propionyl chloride,
THF, Ϫ78 ЊC), and deprotonated and benzylated under the
standard control conditions described (Scheme 5, Table 3).
O
O
O
O
O
O
O
N
O
N
O
N
(i)
+
R1
R1
R1
Ph
R1
R1
R1
R
R
R
14c-h,j
14c-h,j
15c-h,j
+
O
O
O
N
R
Ph
O
NH
+
R1
R1
R1
R1
6c-h,j
R
16c-h,j
Scheme 5 Reagents and conditions: (i) LHMDS, THF, Ϫ78 ЊC, 30 min;
3 equiv. BnBr, 2 h, Ϫ78 ЊC; rt, 24 h.
Once again examination of the trend in selectivities observed in
Table 3 clearly reveals that alkylation of the enolates of 5,5-
diphenyl-N-acyl SuperQuats 14d,f,h resulted in much lower
yields of the desired α-benzylated products than enolates of
the corresponding N-acyl-5,5-dimethyl-SuperQuats 14c,e,g.
The best yielding alanine derived (4R)-N-acyl-5,5-diphenyl-4-
methyl-SuperQuat 14d afforded the desired benzylated product
15d in only 40% yield and 65% de.
O
O
O
O
O
O
O
N
O
N
O
N
(i)
+
R1
R1
R1
Ph
R1
R1
R1
R
R
R
14a,b,i
14a,b,i
15a,b,i
+
These results are consistent with the enolate alkylation
studies recently detailed by Gibson et al. who described the use
of 5,5-diphenyl-SuperQuat and related 5,5-diaryl-SuperQuats
as chiral auxiliaries for asymmetric synthesis.8 They reported
that the enolate of N-propionyl-SuperQuat 14h was benzylated
to afford 15h in >95% de and isolated in a low 46% yield
(LDA, THF, 0 ЊC, BnBr), but with no mention of any products
arising from enolate decomposition. In our hands, the results
obtained for this auxiliary are comparable, however in practice
separation of the alkylated product 15h from acyl starting
O
O
O
N
Ph
O
NH
+
R1
R1
R
R
R1
R1
6a,b,i
16a,b,i
Scheme 4 Reagents and conditions: (i) LHMDS, THF, Ϫ78 ЊC, 30 min;
3 equiv. BnBr, 2 h, Ϫ78 ЊC; rt, 24 h.
J. Chem. Soc., Perkin Trans. 1, 1999, 387–398
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Table 2
Yield (%)
starting
material
Yield (%)
benzylated
material
Yield (%)
N-benzyl
Oxazolidin-
2-one
Yield (%)
SuperQuat
R
R1
SuperQuata
6ib
6a
6b
H
H
H
H
Me
Ph
14i (0)
14a (4)
14b (11)
15i (93)
15a (79)
15b (29)
6i (0)
6a (6)
6b (31)
16i (7)
16a (11)
16b (29)
a Authentic samples of N-benzyl-SuperQuats 16a,b,i were prepared in all cases via deprotonation of the parent SuperQuat 6a,b,i with n-BuLi, and
treatment with benzyl bromide in THF at Ϫ78 ЊC. b Oxazolidin-2-one 6i was purchased from the Aldrich Chemical Company.
Table 3 Diastereoselectivities and yields obtained for benzylation of the enolates of N-acylated SuperQuats 14c–h,j
Yield (%)
starting
Alkylated product
Yield (%)
Yield (%)
N-benzyl
SuperQuat
Yield (%)
SuperQuat
Reactant
R
R1
materiala
de (%)b
14c
14d
14e
14f
14g
14h
14j
Me
Me
Ph
Ph
iPr
iPr
iPr
Me
Ph
Me
Ph
Me
Ph
H
14c (10)
14d (19)
14e (8)
14f (49)
14g (20)
14h (52)
14j (14)
15c (69)
15d (40)
15e (70)
15f (0)
15g (71)
15h (35)
15j (55)
81
65
70
—
>95
>95
>95
6c (11)
6d (16)
6e (5)
6f (8)
6g (0)
6h (4)
6j (18)
16c (10)
16d (25)
16e (17)
16f (43)
16g (9)
16h (9)
16j (13)
a All product ratios were determined by integration of the relevant signals in the 500 MHz 1H NMR spectra. b All diastereomeric ratios were
determined by integration of the relevant signals in the 500 MHz 1H NMR spectra corresponding to the benzylic protons of the major and minor
diastereoisomers. c N-Propionyl SuperQuat 14j was prepared via acylation of Evans’ auxiliary [(4R)-(ϩ)-4-isopropyl-oxazolidin-2-one] purchased
from the Aldrich Chemical Company.
material 14h by silica gel chromatography was not possible.
Seebach et al. subsequently reported that the lithium enolate
of 14h was very unreactive towards alkylation, affording the
N-benzyloxazolidin-2-one 16h as the major product when
benzyl bromide was employed as an electrophile for alkylation.9
Examination of the diastereoselectivities observed when
changing the stereocontrolling group at 4-C of the 5,5-dimethyl-
SuperQuats clearly revealed that increasing the effective
steric bulk at this position leads to a dramatic increase in the
diastereoselectivity of enolate benzylation (14c, R = Me, de =
81%; 14e, R = Ph, de = 70%; 14g, R = iPr, de = >95%), whilst
the overall yield of isolated benzylated product remained
relatively constant (Scheme 5, Table 3).
edge-on conformation orthogonal to the pro-(S)-5-C-phenyl
group with one of the ortho-aromatic ring protons being
directed over the plane of the oxazolidin-2-one ring. This
conformation results in both faces of enolate 18 being steric-
ally hindered and accounts for the observed decreases in both
diastereoselectivity and enolate reactivity observed for the
enolates of these 5,5-diphenyl-SuperQuat systems. These con-
formational analyses are supported by the recently reported
X-ray crystallographic structures of N-acyl-oxazolidin-2-ones
derived from 5,5-diphenyl-SuperQuat.9
Optimisation of alkylation conditions for N-acyl-SuperQuat 14g
Having determined that alkylation of the lithium enolate of
valine derived N-acyl-SuperQuat 14g afforded the best
diastereoselectivities (>95% de), we developed a new set of
alkylation conditions which optimised the yield of benzylated
product 15g. After much investigation13 we found that the
lithium enolate of 14g could be benzylated in THF at Ϫ78 ЊC
with 5 equivalents of BnBr to afford 15g in 93% isolated yield
with less than 3% decomposition product. Furthermore, benzyl-
ation using these conditions at 0 ЊC afforded 15g in an isolated
92% yield, with less than 5% decomposition product. These
conditions contrast favourably with those recently reported by
Seebach et al. who reported that the lithium enolate of N-acyl-
5,5-diphenyl-SuperQuat 14h was completely unreactive towards
alkylation, and could only be benzylated in 81% yield, 96% de,
when the corresponding zinc enolate was deployed.
Molecular modelling on SuperQuat enolates
We were intrigued as to why the introduction of steric bulk at
the 5-C position of the oxazolidin-2-one ring had such an
adverse effect on enolate reactivity. We therefore carried out
molecular modelling studies in order to determine whether
subtle conformational differences between the enolates 17 and
18, of N-propionyl-5,5-dimethyl-4-isopropyl-SuperQuat 14g
and N-propionyl-4,5,5-triphenyl-SuperQuat 14f respectively
could be responsible for the observed differences in enolate
reactivities. Examination of the conformation of enolate 17
clearly revealed a transition state in accordance with the ori-
ginal mechanism proposed for Evans’ auxiliary, involving
formation of a (Z)-enolate; coordination of the exocyclic and
endocyclic carbonyl to the lithium counterion; and approach of
the electrophile from the opposing face to the 4-C stereodirect-
ing group. Furthermore the relative orientation of the stereo-
directing isopropyl group to the 5-C geminal methyl groups was
consistent with our original model for this system, where steric
interactions direct the pro-(R)-isopropyl methyl away from the
gem-dimethyl group, effectively shielding the pro-(R) face of
the enolate.
Cleavage of á-benzylated-N-acyl-SuperQuat 15g
In order to confirm the efficacy of the 5-C-dimethyl substitu-
ents of the SuperQuat auxiliary for completely suppressing any
endocyclic cleavage pathway, we needed to demonstrate that
homochiral α-benzylated-N-propionyl SuperQuat 15g could be
cleaved via alkaline hydrolysis to afford homochiral α-substi-
tuted acid 19, and homochiral SuperQuat 6g (Scheme 6). Grati-
fyingly, treatment of 15g with LiOH (2 equiv.) in THF–H2O
In contrast to 17 the enolate 18 reveals a propeller like con-
formation where steric interactions between the stereodirecting
4-C-phenyl group and the syn-5-C phenyl group result in both
phenyl groups adopting a parallel orientation (Fig. 3). This con-
formation results in the pro-(R)-5-C-phenyl group adopting an
(3:1) afforded the desired carboxylic acid fragment 19 {[α]D23
=
ϩ26.5 (c 1.0 in CHCl3) {lit.,14 [α]D23 = ϩ25.5 (c 1.0 in CHCl3)},
and homochiral SuperQuat 6g {[α]D23 Ϫ23.9 (c 1 in CHCl3)} in
quantitative yield. No products from the endocyclic cleavage
390
J. Chem. Soc., Perkin Trans. 1, 1999, 387–398

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Fig. 3
were determined by peak integration of the crude reaction
O
O
O
O
products’ 1H NMR spectrum. Low resolution mass spectra
(m/z) were recorded on a VG Masslab 20-250, a VG Autospec, a
Trio 1 GCMS, a VG BIO Q or an APCI Platform spectrometer.
Microanalyses were performed by Mr R. Prior of the Dyson
Perrins Analytical Service and at the analytical service of
the Inorganic Chemistry Laboratories, University of Oxford.
Column chromatography was performed on silica gel (Kieselgel
60). Anhydrous THF and diethyl ether were obtained by
distillation from sodium–benzophenone ketyl under nitrogen.
Benzyl bromide was fractionally distilled under vacuum before
use from Na2CO3. n-Butyllithium was used as a solution in
hexanes (approx. 1.4 M) and titrated before use. Lithium bis-
(trimethylsilyl)amide was used as supplied (Aldrich) as a solu-
tion in THF (1 M). Unless otherwise stated all other reagents
were used as supplied. Petrol refers to petroleum ether boiling
in the range indicated. Ether refers to diethyl ether.
(i)
O
N
O
NH
HO
+
Ph
Ph
15g
19
6g
Scheme 6 Reagents and conditions: (i) LiOH, THF, H2O.
1
pathway were observed in the H NMR spectra of the crude
1
reaction product, whilst H NMR experiments with the chiral
shift reagent tris{3-[heptafluoropropyl(hydroxy)methylene]-
(ϩ)-camphorato}europium() indicated no loss of stereo-
chemical integrity at the stereogenic centre of 19 (≥95% ee).
The positive sign of rotation for homochiral acid 19 served to
confirm the absolute stereochemistry of the α-centre formed
during alkylation of the enolate of 14g (vide infra).
General method for the synthesis of á-amino acid methyl ester
hydrochlorides
Conclusions
Thionyl chloride (1.5 equiv.) was carefully added dropwise to a
stirred suspension of the α-amino acid (1 equiv.) in methanol
(2 cm3 mmolϪ1) at 0 ЊC. The reaction was allowed to warm to
room temperature and stirred for 24 hours, after which the sol-
vent was removed in vacuo to give the α-amino acid methyl ester
hydrochloride in quantitative yield. The products had essen-
tially identical 1H NMR spectra and specific rotations to those
in the literature.
Studies on a range of enolates derived from unsubstituted, 5,5-
dimethyl and 5,5-diphenyl oxazolidin-2-ones reveal that very
high diastereoselectivities and yields are only obtained
when homochiral 5,5-dimethyl-4-isopropyloxazolidin-2-one 6g
is employed as a chiral auxiliary. The geminal dimethyl groups
at 5-C of the oxazolidin-2-one ring completely suppress any
endocyclic cleavage pathway enabling simple alkaline cleavage
of 15g with LiOH to afford homochiral α-substituted carb-
oxylic acid 19 in excellent yield.
General method for the synthesis of N-Boc-á-amino acid methyl
esters
Experimental
Solid sodium hydrogen carbonate (3.0 equiv.) was added in one
portion to a stirred solution of the α-amino acid methyl ester
hydrochloride (1 equiv.) in ethanol (sufficient to dissolve the
amino acid methyl ester) at 0 ЊC, immediately followed by addi-
tion of solid Boc2O (1.05 equiv.) in one portion. The reaction
was allowed to warm to room temperature and stirred for 48 h,
after which the reaction was filtered through Celite, washed with
diethyl ether and evaporated. The crude material was redis-
solved in diethyl ether, filtered through Celite with the ether
washings and evaporated to afford the desired N-Boc-α-amino
acid methyl ester. The products had essentially identical spec-
troscopic data to those in the literature.
Melting points (mp) were obtained using a Griffin Gallenkamp
melting point apparatus and are uncorrected. Optical rotations
([α]D25) values are given in 10Ϫ1 deg cm2 gϪ1 and were measured
with a Perkin-Elmer 241 polarimeter with a thermally jack-
eted 1 dm cell at approximately 20 ЊC. Concentrations (c) are
given in g 100 mlϪ1. Infrared (IR) spectra were recorded on a
Perkin-Elmer 1750 Fourier Transform spectrometer and only
characteristic absorptions are reported in wavenumbers (cmϪ1).
Proton magnetic resonance spectra (1H NMR) were recorded in
CDCl3 (unless otherwise stated) at 200 MHz on a Varian
Gemini 200 spectrometer, at 400 MHz on a Bruker AC400 and
at 500 MHz on a Bruker AM500 spectrometer and are refer-
enced to the residual solvent peak. The following abbreviations
were used: s, singlet; d, doublet; t, triplet; q, quartet; sept, sep-
tet; m, multiplet and br, broad. Coupling constants (J) were
recorded in hertz to the nearest 0.5 Hz. Carbon magnetic
resonance spectra (13C NMR) were recorded at 50.3 MHz on a
Varian Gemini 200 spectrometer, at 100.6 MHz on a Bruker
AC400 spectrometer and at 125.7 MHz on a Bruker AMX500
spectrometer using DEPT editing. Diastereomeric excesses
General procedure for the preparation of the dimethyl substituted
N-Boc amino alcohols
Method A. The N-Boc-α-amino acid methyl ester (1 equiv.)
was dissolved in freshly distilled THF (20 cm3 mmolϪ1) and
cooled to 0 ЊC. Methylmagnesium bromide (3.0 M solution in
ether, 4 equiv.) was added dropwise under nitrogen (CARE!
Initial addition results in evolution of methane) over 30 min
J. Chem. Soc., Perkin Trans. 1, 1999, 387–398
391

View Article Online
and the reaction left to stir at room temperature for 30 h. The
reaction was cooled to 0 ЊC, cautiously quenched with saturated
NH4Cl (aq.) and extracted with ethyl acetate (×3). The com-
bined organic extracts were washed with brine, dried (MgSO4)
and evaporated to give the N-Boc amino alcohol.
(1 H, dd, J 2.6 and 10.1, 3-H1), 4.85 (1 H, br, J 10.1, NH);
δC(100 MHz) 16.8 (CH3), 22.3 (CH3), 27.0 (CH3), 28.1 (CH3),
28.4 [(CH3)3C], 29.0 (4-C), 61.7 (3-C), 73.7 (2-C), 79.1
[(CH ) C], 156.9 (C᎐O); m/z (APCI) 232 (4%, MHϩ), 187 (3),
᎐
3
3
176 (20, Mϩ Ϫ C4H7), 158 (100, Mϩ Ϫ C4H9O), 132 (64), 114
(63).
Method B. Magnesium turnings (4 equiv.) were stirred in dry
ether (5 cm3 20 mmolϪ1 Mg) under dry conditions and a small
volume of methyl iodide (4 equiv.) added dropwise with gentle
heating to initiate the formation of the Grignard reagent. Once
an exothermic reaction had commenced, ether (10 cm3 20
mmolϪ1 Mg) was added to the residual methyl iodide and this
addition was continued at a rate as to sustain the reaction at
gentle reflux. Once addition was complete, the reaction was left
to cool to room temperature, and the N-Boc-α-amino acid
methyl ester (1 equiv.) in ether (5 cm3 20 mmolϪ1 Mg) added
dropwise over 15 min. The reaction was left to stir for 48 h, then
quenched with NH4Cl (aq.) and extracted with ether (×3). The
combined organic extracts were washed with brine, dried
(MgSO4) and evaporated to give the desired dimethyl substi-
tuted alcohol.
General procedure for the preparation of the diphenyl substituted
N-Boc amino alcohols
Magnesium turnings (4 equiv.) were stirred in dry THF (5 cm3
20 mmolϪ1 Mg) under dry conditions and a small volume of
bromobenzene (4 equiv.) added dropwise with gentle heating to
initiate the formation of the Grignard reagent. Once an exo-
thermic reaction had commenced, THF (10 cm3 20 mmolϪ1
Mg) was added to the residual bromobenzene and this added
dropwise at a rate as to sustain the reaction at gentle reflux.
Once addition was complete, the reaction was left to cool to
room temperature, and the N-Boc-α-amino acid methyl ester
(1 equiv.) in THF (5 cm3 20 mmolϪ1 Mg) added dropwise over
15 min. The reaction was left to stir for 48 h, then quenched
with NH4Cl(aq) and extracted with ether (×3). The combined
organic extracts were washed with brine, dried (MgSO4) and
evaporated to give the desired diphenyl substituted alcohol.
N-Boc-3-amino-2-methylpropan-2-ol15 13a. The desired
amino alcohol 13a was obtained from N-Boc-glycine methyl
ester 9 (R = H) (15.0 g, 0.087 mol) by Method B as a clear oil
(9.45 g, 57%) after high vacuum distillation, bp 100 ЊC/1 mm
Hg; νmax (Nujol)/cmϪ1 3366, 1694; δH(200 MHz) 1.21 (6 H, s,
2-Me and 1-H3), 1.45 [9 H, s, (CH3)3], 2.51 (1 H, br, OH), 3.12
(1 H, d, J 6.3, 3-H2), 5.04 (1 H, br, NH); δC(50 MHz) 26.7 (2-Me
and 1-C), 28.2 [(CH3)3], 51.1 (3-C), 70.8 [(CH3)3CO], 79.3
N-Boc-2-amino-1,1-diphenylethanol 13b. The desired amino
alcohol 13b was obtained from N-Boc-glycine methyl ester
12 (R = H) (2.50 g, 14.4 mmol) using the above method, fol-
lowed by recrystallisation from hexane–dichloromethane as a
white powder (2.90 g, 64%), mp 100–102 ЊC (Found: C, 72.9;
H, 7.7; N, 4.1. C19H23NO3 requires C, 72.8; H, 7.40; N, 4.5%);
νmax(KBr)/cmϪ1 3370, 1678; δH(400 MHz) 1.39 [9 H, s,
(CH3)3C], 3.48 (1 H, br, OH), 3.95 (2 H, d, J 6.5, 2-H2), 7.28–
7.48 (10 H, m, ArCH); δC(50 MHz) 28.2 [(CH3)3C], 50.3 (2-C),
78.4 [(CH3)3C], 80.0 (1-C), 126.4 (ArCH), 127.4 (ArCH), 128.5
(2-C), 157.2 (C᎐O); m/z (APCI) 245 (6%), 190 (5, MHϩ), 189
᎐
(5), 134 (82), 116 (100).
(3R)-N-Boc-3-amino-2-methylbutan-2-ol 13c. The desired
amino alcohol 13c was obtained from N-Boc--alanine methyl
ester 12 (R = Me) (3.00 g, 0.015 mol) by Method B as a waxy
solid (2.66 g, 87%), mp 32 ЊC; [α]D25 = ϩ1.75 [c 1.6 in CHCl3; lit.,16
ϩ1.6 (c 1.6 in CHCl3)]; νmax (KBr)/cmϪ1 3435, 1694; δH(400
MHz) 1.05 (3 H, d, J 6.8, 4-H3), 1.10 (3 H, s, CH3), 1.15 (3 H, s,
CH3), 1.37 [9 H, s, (CH3)3C], 2.37 (1 H, br, OH), 3.51 (1 H, m,
3-H1), 4.69 (1 H, m, NH); δC(50 MHz) 16.7 (4-C), 26.1 (CH3),
27.9 (CH3), 28.9 [(CH3)3C], 55.1 (3-C), 73.5 (2-C), 79.9
(ArCH), 135.3 (ArCipso), 145.0 (C᎐O); m/z (APCI) 269 (4%),
᎐
251 (2), 240 (20, Mϩ Ϫ C4H9O), 214 (32, Mϩ Ϫ C5H7O2), 196
(100).
(2R)-N-Boc-2-amino-1,1-diphenylpropanol 13d. The desired
amino alcohol 13d was obtained from N-Boc--alanine methyl
ester 9 (R = Me) (1.00 g, 4.92 mmol) using the above method,
followed by recrystallisation from petrol (bp 40–60 ЊC)–ether as
a white powder (1.03 g, 64%), mp 151–152 ЊC; [α]D25 = ϩ46.5
(c 0.2 in CHCl3) (Found: C, 73.3; H, 7.7; N, 4.2. C20H25NO3
requires C, 73.4; H, 7.70; N, 4.3%); νmax(KBr)/cmϪ1 3406, 1673;
δH(400 MHz) 1.09 (3 H, d, J 6.6, 3-H3), 1.35 [9 H, s, (CH3)3C],
2.85 (1 H, br, OH), 4.75 (1 H, m, 2-H1), 4.82 (1 H, m, NH),
7.17–7.23 (2H, m, ArCH), 7.27–7.33 (4H, m, ArCH), 7.44 (2 H,
d, J 7.3, ArCH), 7.50 (2 H, d, J 7.3, ArCH); δC(50 MHz) 16.3
(3-C), 28.2 [(CH3)3C], 51.9 (2-C), 79.4 [(CH3)3C], 80.9 (1-C),
125.8 (ArCH), 126.2 (ArCH), 127.1 (ArCH), 128.4 (ArCH),
[(CH ) C], 156.9 (C᎐O); m/z (APCI) 226 (4%, Mϩ ϩ Na), 159
᎐
3
3
(5), 148 (12, Mϩ Ϫ C4H7), 130 (75, Mϩ Ϫ C4H9O), 104 (100,
Mϩ Ϫ C5H7O2).
(1R)-N-Boc-1-amino-2-methyl-1-phenylpropan-2-ol 13e. The
desired amino alcohol 13e was obtained from N-Boc--
phenylglycine methyl ester 12 (R = Ph) (2.00 g, 7.55 mmol) by
Method A as a fluffy white solid after recrystallisation from
petrol (bp 40–60 ЊC)–ether (1.43 g, 75%), mp 123 ЊC; [α]D25
=
Ϫ29.5 (c 1 in CHCl3) (Found: C, 67.9; H, 8.9; N, 5.2. C15H23-
NO3 requires C, 67.90; H, 8.7; N, 5.3%); νmax (Nujol)/cmϪ1 3473,
3396, 1667; δH(200 MHz) 1.06 (3 H, s, CH3), 1.34 (3 H, s, CH3),
1.40 [9 H, s, (CH3)3], 4.53 (1 H, br d, J 9.5, 1-H1), 5.57 (1 H, br
d, J 9.5, NH), 7.24–7.39 (5 H, m, ArCH); δC(50 MHz) 27.4
(CH3), 27.5 (CH3), 28.2 [(CH3)3C], 62.8 (1-C), 72.7 (2-C), 79.5
[(CH3)3C], 127.6 (ArCH), 128.0 (ArCH), 128.3 (ArCH), 140.1
128.5 (ArCH), 145.3 (ArCipso), 145.4 (ArCipso), 155.9 (C᎐O);
᎐
m/z (APCI) 283 (6%), 265 (3), 255 (5), 254 (32, Mϩ Ϫ C4H9O),
228 (15, Mϩ Ϫ C5H7O2), 211 (22), 210 (100).
(2R)-N-Boc-2-amino-1,1,2-triphenylethanol 13f. The desired
amino alcohol 13f was obtained from N-Boc--phenylglycine
methyl ester 9 (R = Ph) (1.00 g, 3.77 mmol) using the above
method, followed by recrystallisation from petrol (bp 40–
60 ЊC)–ether as a white powder (1.20 g, 82%), mp 197 ЊC;
[α]D25 = ϩ215.2 (c 0.5 in CHCl3) (Found: C, 77.15; H, 7.3; N, 3.40.
C25H27NO3 requires C, 77.1; H, 7.0; N, 3.60%); νmax(KBr)/cmϪ1
3455, 3415, 1670; δH(400 MHz) 1.34 [9 H, s, (CH3)3C], 2.67
(1 H, br, OH), 5.61 (1 H, m, 2-H1), 5.75 (1 H, m, NH), 7.00–
7.03 (2 H, m, ArCH), 7.08–7.18 (8 H, m, ArCH), 7.25–7.29 (1
H, m, ArCH), 7.36 (2 H, t, J 7.6, ArCH), 7.60 (2 H, d, J 7.6,
ArCH); δC(100 MHz) 28.2 [(CH3)3], 60.2 (2-C), 79.6 (1-C), 81.1
[(CH3)3C], 125.5 (ArCH), 126.3 (ArCH), 126.8 (ArCH), 127.2
(ArCH), 127.3 (ArCH), 127.8 (ArCH), 127.9 (ArCH), 128.3
(ArCipso), 156.2 (C᎐O); m/z (APCI) 288 (8%), 266 (8, MHϩ), 221
᎐
(10), 210 (15), 166 (100), 149 (27), 148 (32), 106 (11).
(3R)-N-Boc-3-amino-2,4-dimethylpentan-2-ol 13g. N-Boc--
valine methyl ester 12 (R = i-Pr) (4.00 g, 0.017 mol) was treated
with methylmagnesium bromide (Method B) to yield the
desired amino alcohol 13g (3.45 g, 88%) as a white waxy solid,
mp 45–47 ЊC; [α]D25 ϩ8.7 (c 1 in CHCl3) (Found: C, 62.4; H,
10.9; N, 5.9. C12H25NO3 requires C, 62.30; H, 10.9; N, 6.1%);
νmax(film)/cmϪ1 3445, 1694; δH(400 MHz) 0.90 (3 H, d, J 6.8,
CH3CH), 0.94 (3 H, d, J 6.8, CH3CH), 1.22 (3 H, s, CH3), 1.25
(3 H, s, CH3), 1.44 [9 H, s, (CH3)3C], 2.09 (1 H, m, 4-H1), 3.38
392
J. Chem. Soc., Perkin Trans. 1, 1999, 387–398

View Article Online
(ArCH), 128.5 (ArCH), 138.3 (ArCipso), 144.2 (ArCipso), 144.5
crystalline solid after recrystallisation from petrol (bp 60–
(ArCipso), 155.2 (C᎐O); m/z (APCI) 500 (4%), 448 (15), 412 (3,
80 ЊC)–ethyl acetate (0.283 g, 73%), mp >220 ЊC; [α]D25 = ϩ288.4
(c 0.5 in CHCl3) (Found: C, 75.8; H, 5.95; N, 5.5. C16H15NO2
requires C, 75.9; H, 6.0; N, 5.5%); νmax(KBr)/cmϪ1 3264, 1744,
1723; δH(400 MHz) 1.01 (3 H, d, J 6.5, 4-Me), 4.68 (1 H, q,
J 6.5, 4-H1), 5.32 (1 H, br, NH), 7.26–7.42 (8 H, m, ArCH),
7.51 (2 H, m, ArCH); δC(100 MHz) 19.3 (4-Me), 56.2 (4-C),
89.4 (5-C), 126.0 (ArCH), 126.2 (ArCH), 127.8 (ArCH), 128.1
(ArCH), 128.3 (ArCH), 128.5 (ArCH), 139.2 (ArCipso), 142.4
(ArCipso), 157.9 (2-C); m/z (APCIϩ) 254 (42%, MHϩ), 210 (100),
104 (32).
᎐
Mϩ ϩ Na), 345 (56), 316 (13), 272 (100, Mϩ Ϫ C5H11NO2).
(2R)-N-Boc-2-amino-1,1-diphenyl-3-methylbutanol 13h. The
desired amino alcohol 13h was obtained from N-Boc--valine
methyl ester 9 (R = i-Pr) (4.00 g, 0.017 mol) using the above
method, followed by recrystallisation from petrol (bp 40–
60 ЊC)–ethyl acetate as a crystalline solid (4.48 g, 74%), mp 188–
190 ЊC; [α]D25 = ϩ68.8 (c 1 in CHCl3) (Found: C, 74.3; H, 8.1; N,
3.8. C22H29NO3 requires C, 74.3; H, 8.2; N, 3.9%); νmax(film)/
cmϪ1 3428, 1680; δH(400 MHz) 0.89 (3 H, d, J 6.9, CH3), 0.91
(3 H, d, J 6.9, CH3), 1.34 [9 H, s, (CH3)3C], 1.81 (1 H, dsept,
J 2.0 and 6.9, 3-H1), 2.67 (1 H, br, OH), 4.61 (1 H, dd, J 10.2
and 2.0, 2-H1), 5.04 (1 H, d, J 10.2, NH), 7.15–7.35 (6 H, m,
ArCH), 7.46 (2 H, d, J 7.4, ArCH), 7.51 (2 H, d, J 7.7, ArCH);
δC(100 MHz) 17.4 (CH3), 22.7 (CH3), 28.7 [(CH3)3C], 28.8
(3-C), 59.0 (2-C), 79.0 [(CH3)3C], 82.4 (1-C), 125.3 (ArCH),
125.7 (ArCH), 126.7 (ArCH), 128.2 (ArCH), 128.3 (ArCH),
(4R)-5,5-Dimethyl-4-phenyloxazolidin-2-one 6e. The desired
SuperQuat 6e was obtained from the phenylglycine amino
alcohol 13e (93.8 g, 0.345 mol) by the above method as a
crystalline solid after recrystallisation from ethyl acetate–petrol
(bp 40–60 ЊC) (55.16 g, 84%), mp 149 ЊC; [α]D25 = Ϫ77.6 (c 0.5 in
CHCl3) (Found: C, 69.3; H, 7.05; N, 7.4. C11H13NO2 requires C,
69.1; H, 6.85; N, 7.3%); νmax(CHCl3)/cmϪ1 1753; δH(200 MHz)
0.93 (3 H, s, 5-Me), 1.61 (3 H, s, 5-Me), 4.66 (1 H, s, 4-H1),
6.25 (1 H, s, NH), 7.44–7.25 (5H, m, ArCH); δC(125 MHz)
23.5 (5-Me), 28.0 (5-Me), 65.9 (4-C), 84.6 (5-C), 126.7
(ArCH), 128.72 (ArCH), 128.9 (ArCH), 137.2 (ArCipso),
159.8 (2-C); m/z (CIϩ) 210 (5%), 209 (48), 193 (12), 192 (100,
MHϩ), 148 (10).
145.6 (ArCipso), 146.3 (ArCipso), 156.3 (C᎐O); m/z (APCI) 311
᎐
(5%), 282 (12, Mϩ Ϫ C4H9O), 256 (15, Mϩ Ϫ C5H7O2), 239 (22),
238 (100, Mϩ Ϫ C5H9O3), 221 (18), 196 (6), 150 (42).
General procedure for the preparation of the oxazolidinones
Potassium tert-butoxide (1.1 equiv.) was added in one portion
to a stirred solution of the N-Boc amino alcohol (1 equiv.) in
freshly distilled THF (5 cm3 mmolϪ1) at 0 ЊC. After 30 min,
the solvent was evaporated, and the residue taken up in ethyl
acetate and washed with brine. The organic layer was dried
(MgSO4) and evaporated to give crude product which was
recrystallised to yield the desired oxazolidin-2-one.
(4R)-4,5,5-Triphenyloxazolidin-2-one 6f. The desired Super-
Quat 6f was obtained from the phenylglycine derived amino
alcohol 13f (0.250 g, 0.642 mmol) by the above method as a
white solid after recrystallisation from petrol (bp 60–80 ЊC)–
ethyl acetate (0.164 g, 81%), mp >230 ЊC (lit.,19 246.5–247.2 ЊC);
[α]D25 = ϩ218.1 (c 1 in CHCl3) [lit.,19 ϩ218.15 (c 1 in CHCl3)];
νmax(KBr)/cmϪ1 3274, 1755, 1727; δH(400 MHz) 5.51 (1 H, br,
NH), 5.67 (1 H, s, 4-H1), 7.08 (5 H, s, ArCH), 7.12–7.14 (2 H,
m, ArCH), 7.18–7.21 (3 H, ArCH), 7.42 (1 H, t, J 7.5, ArCH),
7.49 (2 H, t, J 7.5, ArCH), 7.73 (2 H, d, J 7.5, ArCH); δC(100
MHz) 65.8 (4-C), 90.7 (5-C), 126.2 (ArCH), 126.5 (ArCH),
127.3 (ArCH), 127.5 (ArCH), 127.8 (ArCH), 128.3 (ArCH),
128.5 (ArCH), 128.6 (ArCH), 137.1 (ArCipso), 138.8 (ArCipso),
142.8 (ArCipso), 157.9 (2-C); m/z (APCIϩ) 374 (11%), 327 (4),
316 (4, MHϩ), 273 (18), 272 (100, MHϩ Ϫ CO2), 270 (28).
5,5-Dimethyloxazolidin-2-one 6a. The glycine derived amino
alcohol 13a (5.00 g, 26.4 mmol) was cyclised by the described
procedure and recrystallised from ethyl acetate–petrol (bp 60–
80 ЊC) to give the dimethylglycine SuperQuat 6a (2.15 g, 71%)
as off white crystals, mp 78–82 ЊC (lit.,17 79–82 ЊC); νmax(film)/
cmϪ1 3265, 1763; δH(200 MHz) 1.49 (6 H, s, 2 × 5-Me), 3.38
(2 H, s, 4-H2), 5.90 (1 H, br, NH); δC(50 MHz) 27.1 (2 × 5-Me),
52.7 (4-C), 81.1 (5-C), 160.4 (2-C); m/z (APCI) 231 (5%, M2Hϩ),
138 (6, Mϩ ϩ Na), 122 (5, Mϩ ϩ Li), 117 (8), 116 (100, MHϩ).
(4R)-5,5-Dimethyl-4-isopropyloxazolidin-2-one
6g.
The
5,5-Diphenyloxazolidin-2-one 6b. The glycine derived amino
alcohol 13b (2.00 g, 6.38 mol) was cyclised by the described
procedure and recrystallised from hot ethyl acetate to give the
diphenylglycine SuperQuat 6b (1.10 g, 72%), mp 196–197 ЊC
(Found: C, 75.30; H, 5.3; N, 5.8. C15H13NO2 requires C, 75.30;
H, 5.5; N, 5.9%); νmax(KBr)/cmϪ1 3260, 1740; δH(400 MHz) 4.21
(2 H, s, 4-H2), 5.96 (1 H, br, NH), 7.29–7.43 (10 H, m, ArCH);
δC(50 MHz) 53.4 (4-C), 86.5 (5-C), 125.5 (ArCH), 128.2
(ArCH), 128.6 (ArCH), 142.4 (ArCipso), 158.8 (2-C); m/z
(APCI) 251 (5%), 241 (6), 240 (MHϩ, 52), 197 (25), 196 (100,
MHϩ Ϫ CO2).
desired SuperQuat 6g was obtained from the valine derived
amino alcohol 13g (3.04 g, 0.013 mol) by the above method as
white needles after recrystallisation from petrol (bp 40–60 ЊC)–
ethyl acetate (1.46 g, 72%), mp 87 ЊC; [α]D25 = Ϫ24.2 (c 1 in
CHCl3) (Found: C, 61.3; H, 9.6; N, 8.80. C8H15NO2 requires
C, 61.1; H, 9.6; N, 8.9%); νmax(KBr)/cmϪ1 3247, 1739; δH(400
MHz) 0.92 [3 H, d, J 6.6, (CH3)2CH], 0.99 [3 H, d, J 6.6,
(CH3)2CH], 1.39 (3 H, s, 5-Me), 1.49 (3 H, s, 5-Me), 1.82 [1 H,
dsept, J 8.6 and 6.6, CH(CH3)2], 3.19 (1 H, d, J 8.6, 4-H1), 6.31
(1 H, br, NH); δC(50 MHz) 19.8 (CH3), 21.1 (CH3), 21.1 (CH3),
28.3 (CH3), 28.5 [(CH3)2CH], 68.5 (4-C), 83.9 (5-C), 159.9
(2-C); m/z (APCIϩ) 315 (4%, M2Hϩ), 180 (4), 159 (11), 158 (100,
MHϩ).
(4R)-4,5,5-Trimethyloxazolidin-2-one 6c. The desired Super-
Quat 6c was obtained from the alanine derived amino alcohol
13c (2.431 g, 12.0 mmol) by the above method as a white
crystalline solid after recrystallisation from petrol (bp 60–
(4R)-5,5-Diphenyl-4-isopropyloxazolidin-2-one
6h.
The
80 ЊC)–ether (1.015 g, 66%), mp 64 ЊC (lit.,18 61 ЊC); [α]D25
=
desired SuperQuat 6h was obtained from the valine derived
amino alcohol 13h (3.043 g, 8.56 mmol) by the above method as
white needles after recrystallisation from ethyl acetate (1.785 g,
74%), mp >220 ЊC (lit.,19 252.9–253.5 ЊC); [α]D25 = ϩ315.6 (c 0.5
in CHCl3) [lit.,19 ϩ270.78 (c 1 in CHCl3)]; νmax(KBr)/cmϪ1 3293,
1766, 1745; δH(200 MHz) 0.69 (3 H, d, J 6.8, CH3CH), 0.90
(3 H, d, J 6.8, CH3CH), 1.85 [1 H, dsept, J 3.5 and 6.8,
(CH3)2CH], 4.36 (1 H, d, J 3.5, 4-H1), 6.32 (1 H, br, NH),
7.25–7.43 (8 H, m, ArCH), 7.55 (2 H, dd, J 6.6 and 1.0, ArCH);
δC(100 MHz) 18.3 (CH3), 23.5 (CH3), 32.3 [(CH3)2CH], 68.5
(4-C), 92.1 (5-C), 128.4 (ArCH), 129.00 (ArCH), 130.4
(ArCH), 130.8 (ArCH), 131.3 (ArCH), 141.8 (ArCipso), 146.6
Ϫ2.85 (c 4 in CHCl3) [lit.,18 Ϫ2.6 (c 4 in CHCl3)]; νmax(KBr)/
cmϪ1 3274, 1733; δH(400 MHz) 1.15 (3 H, d, J 6.5, 4-Me), 1.30
(3 H, s, 5-Me), 1.42 (3 H, s, 5-Me), 3.62 (1 H, q, J 6.5, 4-H1),
6.45 (1 H, br, NH); δC(100 MHz) 16.1 (CH3), 21.4 (CH3), 27.1
(CH3), 57.1 (4-C), 83.5 (5-C), 159.2 (2-C); m/z (APCI) 281 (5%,
M2ϩ ϩ Na), 259 (8, M2ϩ ϩ H), 210 (6), 152 (33, Mϩ ϩ Na), 130
(100, MHϩ).
(4R)-5,5-Diphenyl-4-methyloxazolidin-2-one 6d. The desired
SuperQuat 6d was obtained from the alanine derived amino
alcohol 13d (0.500 g, 1.53 mmol) by the above method as a
J. Chem. Soc., Perkin Trans. 1, 1999, 387–398
393

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(ArCipso), 161.3 (2-C); m/z (APCIϩ) 282 (27%, MHϩ), 239 (18),
238 (100, MHϩ Ϫ CO2), 236 (21), 196 (20).
(ArCipso), 142.3 (ArCipso), 156.9 (2-C); m/z (APCI) 366 (5%,
Mϩ ϩ Na), 345 (28), 344 (100, MHϩ), 300 (10, MHϩ Ϫ CO2),
122 (6).
General procedure for the N-benzylation of the oxazolidinones
(4R)-N-Benzyl-5,5-dimethyl-4-phenyloxazolidin-2-one
16e.
n-Butyllithium (1.1 equiv.) was added dropwise via syringe to a
stirred solution of the oxazolidin-2-one (1 equiv.) in THF (10
cm3 mmolϪ1) at Ϫ78 ЊC under a nitrogen atmosphere and the
mixture allowed to stir for 15 min. Benzyl bromide (3 equiv.)
was added at Ϫ78 ЊC and the reaction stirred at this temper-
ature for 30 min, then allowed to warm to room temperature
over 24 h. Saturated NH4Cl (aq.) was added and the reaction
extracted with ethyl acetate (×3). The combined organic
extracts were washed with brine, dried (MgSO4) and evaporated
to yield the desired N-benzyl oxazolidinone.
Reaction of the oxazolidinone 6e (0.500 g, 1.97 mmol) as
described above, followed by crystallisation from hot petrol (bp
40–60 ЊC)–ether gave the title compound 16e (0.497 g, 90%) as
needles, mp 117–118 ЊC; [α]D25 = Ϫ108.0 (c 1 in CHCl3) (Found:
C, 76.75; H, 6.7; N, 4.95. C18H19NO2 requires C, 76.8; H, 6.8; N,
5.0%); νmax(KBr)/cmϪ1 1728; δH(400 MHz) 0.94 (3 H, s, 5-Me),
1.44 (3 H, s, 5-Me), 3.68 (1 H, d, J 14.8, PhCH2), 4.13 (1 H, s,
4-H1), 5.00 (1 H, d, J 14.8, PhCH2), 7.11–7.14 (4 H, m, ArCH),
7.29–7.32 (3 H, m, ArCH), 7.39–7.44 (3 H, m, ArCH); δC(50
MHz) 23.8 (5-Me), 28.5 (5-Me), 46.2 (CH2), 68.1 (4-C), 81.3
(5-C), 127.8 (ArCH), 128.1 (ArCH), 128.7 (ArCH), 128.9
(ArCH), 129.1 (ArCH), 135.2 (ArCipso), 135.9 (ArCipso), 158.1
(2-C); m/z (APCI) 304 (5%, Mϩ ϩ Na), 283 (23), 282 (100,
MHϩ), 238 (4, MHϩ Ϫ CO2).
N-Benzyl-5,5-dimethyloxazolidin-2-one 16a. Reaction of the
oxazolidinone 6a (0.200 g, 1.17 mmol) as described above,
followed by silica gel chromatography [ethyl acetate–petrol
(bp 40–60 ЊC), 1:4] gave the title compound 16a (0.239 g,
100%) as a clear oil (Found: MHϩ, 206.1177. C12H16NO2
requires m/z 206.1181); νmax(film)/cmϪ1 1732; δH(400 MHz)
1.42 (6 H, s, 2 × 5-Me), 3.14 (2 H, s, 4-H2), 4.44 (2 H, s, CH2Ph),
7.28–7.35 (5 H, m, ArCH); δC(100 MHz) 27.2 (2 × 5-Me),
48.0 (4-C), 55.9 (CH2Ph), 77.5 (5-C), 128.1 (ArCH), 128.2
(ArCH), 129.0 (ArCH), 136.2 (ArCipso), 157.9 (2-C); m/z
(APCI) 228 (4%, Mϩ ϩ Na), 207 (42), 206 (100, MHϩ), 162 (2),
122 (9).
(4R)-N-Benzyl-4,5,5-triphenyloxazolidin-2-one 16f. The title
compound 16f was obtained after attempted alkylation of the
propionyl SuperQuat 14f (0.100 g, 0.269 mmol) using the pro-
cedure described subsequently, and isolated by column chrom-
atography as a white solid (0.044 g, 40%), mp 161 ЊC; [α]D25
=
ϩ102.0 (c 0.5 in CHCl3) (Found: C, 82.9; H, 5.6; N, 3.3.
C28H23NO2 requires C, 82.9; H, 5.7; N, 3.45%); νmax(KBr)/cmϪ1
1740; δH(200 MHz) 3.61 (1 H, d, J 15.8, CH2Ph), 4.98 (1 H, d,
J 15.8, CH2Ph), 5.18 (1 H, s, 4-H1), 6.89–7.50 (20 H, m, ArCH);
δC(50 MHz) 46.3 (CH2Ph), 68.0 (4-C), 88.1 (5-C), 126.2
(ArCH), 126.7 (ArCH), 127.4 (ArCH), 127.7 (ArCH), 127.9
(ArCH), 128.1 (ArCH), 128.5 (ArCH), 128.7 (ArCH), 128.8
(ArCH), 134.9 (ArCipso), 135.5 (ArCipso), 139.2 (ArCipso), 143.3
(ArCipso), 157.4 (2-C); m/z (APCI) 812 (20%, (MH)2ϩ), 810 (12),
407 (25), 406 (100, MHϩ), 362 (30, MHϩ Ϫ CO2), 343 (30),
238 (50).
N-Benzyl-5,5-diphenyloxazolidin-2-one 16b. Reaction of the
oxazolidinone 6b (0.250 g, 1.04 mmol) as described above, fol-
lowed by crystallisation from ethyl acetate–petrol (bp 40–60 ЊC)
gave the title compound 16b (0.339 g, 99%) as a white powder,
mp 156 ЊC (Found: C, 80.1; H, 6.1; N, 4.2. C22H19NO2 requires
C, 80.2; H, 5.8; N, 4.25%); νmax(KBr)/cmϪ1 1747, 1437; δH(400
MHz) 3.98 (2 H, s, PhCH2), 4.49 (2 H, s, 4-H2), 7.18–7.20 (2 H,
m, ArCH), 7.26–7.38 (13 H, m, ArCH); δC(100 MHz) 48.2
(4-C), 56.5 (PhCH2), 83.3 (5-C), 125.4 (ArCH), 127.9 (ArCH),
128.1 (ArCH), 128.6 (ArCH), 128.8 (ArCH), 135.4 (ArCipso),
142.4 (2 × ArCipso), 157.1 (2-C); m/z (APCI) 330 (100%, MHϩ),
286 (31, MHϩ Ϫ CO2).
(4R)-N-Benzyl-5,5-dimethyl-4-isopropyloxazolidin-2-one
16g. Reaction of the oxazolidinone 6g (0.300 g, 1.908 mmol)
as described above, followed by crystallisation from dichloro-
methane–petrol (bp 60–80 ЊC) gave the title compound 16g
(0.384 g, 81%) as a highly crystalline solid, mp 113 ЊC; [α]D25
=
ϩ74.3 (c 1 in CHCl3) (Found: MHϩ, 248.1659. C15H22NO2
requires m/z 248.1651); νmax(KBr)/cmϪ1 1737; δH(500 MHz) 1.03
[3 H, d, J 7.1, (CH3)2CH], 1.10 [3 H, d, J 7.1, (CH3)2CH], 1.24 (3
H, s, 5-Me), 1.42 (3 H, s, 5-Me), 2.02 [1 H, dsept, J 2.2 and 7.1,
(CH3)2CH], 3.30 (1 H, d, J 2.2, 4-H1), 4.02 (1 H, d, J 15.2,
PhCH2), 5.10 (1 H, d, J 15.2, PhCH2), 7.28–7.39 (5 H, m,
ArCH); δC(50 MHz) 16.8 [(CH3)2CH], 21.3 (5-Me), 22.0
[(CH3)2CH], 28.8 [(CH3)2CH], 29.3 (5-Me), 47.5 (PhCH2), 66.6
(4-C), 81.3 (5-C), 128.1 (ArCH), 128.6 (ArCH), 128.9 (ArCH),
136.3 (ArCipso), 158.3 (2-C); m/z (APCI) 495 (12%, M2Hϩ), 249
(bp 40), 248 (100, MHϩ), 122 (13).
(4R)-N-Benzyl-4,5,5-trimethyloxazolidin-2-one 16c. Reac-
tion of the oxazolidinone 6c (0.150 g, 1.16 mmol) as described
above, followed by purification by silica gel chromatography
[ethyl acetate–petrol (bp 40–60 ЊC), 1:5] gave the title com-
pound 16c (0.227 g, 89%) as a clear oil; [α]D25 = ϩ36.8 (c 1 in
CHCl3) (Found: MHϩ, 220.1332. C13H18NO2 requires m/z
220.1338); νmax(film)/cmϪ1 1743; δH(400 MHz) 1.09 (3 H, d,
J 6.6, 4-Me), 1.30 (3 H, s, 5-Me), 1.35 (3 H, s, 5-Me), 3.29 (1 H,
q, J 6.6, 4-H1), 4.04 (1 H, d, J 15.3, CH2Ph), 4.80 (1 H, d, J 15.3,
CH2Ph), 7.29–7.39 (5 H, m, ArCH); δC(50 MHz) 13.2 (4-Me),
21.5 (5-Me), 26.8 (5-Me), 45.5 (CH2Ph), 58.9 (4-C), 80.7 (5-C),
127.9 (ArCH), 128.1 (ArCH), 128.9 (ArCH), 136.5 (ArCipso),
157.8 (2-C); m/z (APCI) 242 (12%, Mϩ ϩ Na), 221 (18), 220
(100, MHϩ).
(4R)-N-Benzyl-5,5-diphenyl-4-isopropyloxazolidin-2-one
16h. Reaction of the oxazolidinone 6h (0.300 g, 1.07 mmol) as
described above, followed by crystallisation from dichloro-
methane–petrol (bp 60–80 ЊC) gave the title compound 16h
(0.247 g, 62%) as white needles, mp 135 ЊC; [α]D25 = ϩ200.0 (c 1 in
CHCl3) (Found: C, 81.0; H, 6.7; N, 3.7. C25H25NO2 requires C,
80.8; H, 6.8; N, 3.8%); νmax(KBr)/cmϪ1 1737; δH(400 MHz) 0.79
[3 H, d, J 6.7, (CH3)2CH], 1.05 [3 H, d, J 7.4, (CH3)2CH], 1.90
(1 H, m, (CH3)2CH], 4.07 (1 H, d, J 15.2, CH2Ph), 4.10 (1 H,
d, J 1.6, 4-H1), 5.09 (1 H, d, J 15.2, CH2Ph), 6.80 (2 H, d, J 7.5,
ArCH), 7.13 (2 H, t, J 7.5, ArCH), 7.20–7.31 (7 H, m, ArCH),
7.37–7.44 (4 H, m, ArCH); δC(50 MHz) 16.4 (CH3), 22.6 (CH3),
29.8 [(CH3)2CH], 48.3 (CH2Ph), 66.4 (4-C), 88.1 (5-C), 125.4
(ArCH), 126.1 (ArCH), 127.7 (ArCH), 127.9 (ArCH), 128.1
(ArCH), 128.4 (ArCH), 128.7 (ArCH), 135.4 (ArCipso), 139.2
(ArCipso), 144.4 (ArCipso), 157.6 (2-C); m/z (APCI) 743 (18%,
(4R)-N-Benzyl-5,5-diphenyl-4-methyloxazolidin-2-one
16d.
Reaction of the oxazolidinone 6d (0.300 g, 1.18 mmol) as
described above, followed by crystallisation from ethyl acetate–
petrol (bp 40–60 ЊC) gave the title compound 16d (0.324 g, 80%)
as white needles, mp 157–158 ЊC; [α]D25 = ϩ211.8 (c 1 in CHCl3)
(Found: C, 80.2; H, 6.00; N, 4.0. C23H21NO2 requires C, 80.4; H,
6.2; N, 4.1%); νmax(KBr)/cmϪ1 1745; δH(400 MHz) 0.92 (3 H, d,
J 6.5, 4-Me), 4.05 (1 H, d, J 15.3, PhCH2), 4.33 (1 H, q, J 6.5,
4-H1), 4.90 (1 H, d, J 15.3, PhCH2), 7.14 (2 H, m, ArCH), 7.23–
7.39 (13 H, m, ArCH); δC(100 MHz) 15.6 (4-Me), 45.9 (4-C),
57.9 (PhCH2), 87.0 (5-C), 126.0 (ArCH), 126.3 (ArCH), 127.8
(ArCH), 127.9 (ArCH), 128.0 (ArCH), 128.1 (ArCH), 128.3
(ArCH), 128.4 (ArCH), 128.7 (ArCH), 135.6 (ArCipso), 139.4
394
J. Chem. Soc., Perkin Trans. 1, 1999, 387–398

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M2Hϩ), 394 (4, Mϩ ϩ Na), 373 (21), 372 (100, MHϩ), 328 (4,
MHϩ Ϫ CO2).
(25), 252 (100, MHϩ Ϫ CO2), 196 (6), 183 (30), 165 (6), 124 (4),
105 (11).
(4R)-N-Propionyl-4,5,5-trimethyloxazolidin-2-one
14c.
N-Benzyloxazolidin-2-one 16i. Reaction of the oxazolidin-
one 6i (0.500 g, 5.74 mmol) as described above, followed by
chromatography on silica gel eluting with petrol (bp 40–60 ЊC)–
ethyl acetate (7:3 respectively) gave the title compound 16i
(0.233 g, 23%) as a crystalline solid, mp 76–77 ЊC (Found: C,
67.6; H, 6.1; N, 7.85. C10H11NO2 requires C, 67.8; H, 6.3; N,
7.9%); νmax(KBr)/cmϪ1 1740; δH(400 MHz) 3.43 (2 H, t, J 8.0,
4-H2), 4.31 (2 H, t, J 8.0, 5-H2), 4.44 (2 H, s, CH2Ph), 7.29–7.39
(5 H, m, ArCH); δC(50 MHz) 43.9 (4-C), 48.3 (CH2Ph), 61.8
(5-C), 128.2 (ArCH), 128.3 (ArCH), 129.0 (ArCH), 136.0
(ArCipso), 158.8 (2-C); m/z (APCI) 179 (20%), 178 (100, MHϩ),
122 (4), 100 (11).
Reaction of the oxazolidin-2-one 6c (0.350 g, 2.71 mmol) under
the reaction conditions described above, followed by crystallis-
ation from hot petrol (bp 60–80 ЊC) gave the title compound
14c (0.272 g, 54%) as a white solid, mp 84 ЊC (lit.,18 82 ЊC);
[α]D25 = Ϫ57.8 (c 0.9 in CHCl3) [lit.,18 Ϫ51 (c 0.9 in CHCl3)];
νmax(film)/cmϪ1 1760, 1698; δH(400 MHz) 1.16 (3 H, t, J 7.3,
CH2CH3), 1.27 (3 H, d, J 6.6, 4-Me), 1.40 (3 H, s, 5-Me), 1.42
(3 H, s, 5-Me), 2.92 (2 H, m, CH2CH3), 4.17 (1 H, q, J 6.6,
4-H1); δC(100 MHz) 8.3 (CH3CH2), 14.7 (4-Me), 21.5 (5-Me),
27.8 (5-Me), 29.3 (CH2), 58.8 (4-C), 81.4 (5-C), 152.8 (2-C),
174.4 (C᎐Oacyl); m/z (APCI) 279 (4%), 208 (6, Mϩ ϩ Na),
᎐
186 (6, MHϩ), 142 (6, MHϩ Ϫ CO2), 131 (9), 130 (100, Mϩ Ϫ
C3H4O).
(4R)-N-Benzyl-4-isopropyloxazolidin-2-one 16j. Reaction
of the oxazolidinone 6j (0.200 g, 1.55 mmol) as described above,
followed by silica gel chromatography [ethyl acetate–petrol (bp
40–60 ЊC), 1:4] gave the title compound 16j (0.292 g, 86%) as
an oil; [α]D25 = ϩ24.6 (c 1 in CHCl3) (Found: MHϩ, 220.1331.
C13H18NO2 requires m/z 220.1338); νmax(film)/cmϪ1 1732; δH(400
MHz) 0.82 [3 H, d, J 6.9, (CH3)2CH], 0.86 [3 H, d, J 6.9,
(CH3)2CH], 2.07 [1 H, m, (CH3)2CH], 3.55 (1 H, ddd, J 9.0,
5.8 and 3.5, 4-H1), 3.97 (1 H, d, J 15.2, CH2Ph), 4.07 (1 H, dd,
J 9.0 and 5.8, 5-H1), 4.18 (1 H, t, J 9.0, 5-H1), 4.88 (1 H, d,
J 15.2, CH2Ph); δC(100 MHz) 14.1 (CH3), 17.6 (CH3), 27.1
[(CH3)2CH], 45.9 (CH2Ph), 58.1 (4-C), 62.7 (5-C), 127.9
(ArCH), 128.1 (ArCH), 128.8 (ArCH), 135.8 (ArCipso), 158.7
(2-C); m/z (APCI) 242 (3%, Mϩ ϩ Na), 221 (30), 220 (100,
MHϩ), 142 (4), 122 (4).
(4R)-N-Propionyl-5,5-diphenyl-4-methyloxazolidin-2-one 14d.
Reaction of the oxazolidin-2-one 6d (0.300 g, 1.18 mmol) under
the reaction conditions described above, followed by crystallis-
ation from petrol (bp 60–80 ЊC) gave the title compound
14d (0.269 g, 74%) as
a crystalline solid, mp 101 ЊC;
[α]D25 = ϩ299.1 (c 1 in CHCl3) (Found: C, 73.8; H, 6.2; N, 4.5.
C19H19NO3 requires C, 73.8; H, 6.2; N, 4.5%); νmax(film)/cmϪ1
1790, 1705; δH(400 MHz) 1.04 (3 H, d, J 6.5, 4-Me), 1.12 (3 H, t,
J 7.4, CH3CH2), 2.79 (1 H, dq, J 17.9 and 7.4, CH3CH2), 2.94
(1 H, dq, J 17.9 and 7.4, CH3CH2), 5.38 (1 H, q, J 6.5, (4-H1),
7.28–7.41 (8 H, m, ArCH), 7.50 (2 H, d, J 7.0, ArCH); δC(100
MHz) 8.2 (CH3CH2), 16.4 (4-Me), 29.1 (CH3CH2), 57.1 (4-C),
88.0 (5-C), 125.7 (ArCH), 126.0 (ArCH), 128.0 (ArCH), 128.4
(ArCH), 128.7 (ArCH), 128.8 (ArCH), 138.4 (ArCipso), 141.3
(ArCipso), 152.1 (2-C), 173.7 (C᎐Oacyl); m/z (APCI) 332 (6%,
᎐
General procedure for the acylation of the oxazolidin-2-ones
Mϩ ϩ Na), 310 (5, MHϩ), 266 (28, MHϩ Ϫ CO2), 210 (100).
n-Butyllithium (1.1 equiv.) was added dropwise via syringe to a
stirred solution of the oxazolidin-2-one (1 equiv.) in THF (10
cm3 mmolϪ1) at Ϫ78 ЊC under a nitrogen atmosphere and the
mixture allowed to stir for 15 min. Propionyl chloride (1.3
equiv.) was added at Ϫ78 ЊC and the reaction stirred at this
temperature for 30 min, then allowed to warm to room tem-
perature over 2 h. Saturated NH4Cl (aq.) was added and the
reaction extracted with ethyl acetate (×3). The combined
organic extracts were washed with NaHCO3 (aq.), brine, dried
(MgSO4) and evaporated to give the N-acylated oxazolidinone.
(4R)-N-Propionyl-5,5-dimethyl-4-phenyloxazolidin-2-one 14e.
Reaction of the oxazolidin-2-one 6e (0.250 g, 1.31 mmol) under
the reaction conditions described above, followed by crystallis-
ation from cold petrol (bp 40–60 ЊC) gave the title compound
14e (0.302 g, 93%) as a white solid, mp 60 ЊC; [α]D25 = Ϫ47.8 (c 1
in CHCl3) (Found: MHϩ, 248.1290. C14H18NO3 requires m/z
248.1287); νmax(film)/cmϪ1 1777, 1702; δH(200 MHz) 1.01 (3 H,
s, 5-Me), 1.12 (3 H, t, J 8.8, CH3CH2), 1.61 (3 H, s, 5-Me), 3.00
(2 H, q, J 8.8, CH3CH2), 5.08 (1 H, s, 4-H1), 7.10–7.16 (2 H, m,
ArCH), 7.32–7.42 (3 H, m, ArCH); δC(50 MHz) 8.1 (CH3CH2),
23.6 (5-Me), 28.9 (5-Me), 29.3 (CH3CH2), 67.0 (4-C), 82.5 (5-
C), 126.5 (ArCH), 128.8 (ArCH), 129.1 (ArCH), 136.7
N-Propionyl-5,5-dimethyloxazolidin-2-one 14a. Reaction of
the oxazolidin-2-one 6a (0.500 g, 4.34 mmol) under the reaction
conditions described above, followed by crystallisation from
ether–petrol (bp 40–60 ЊC) gave the title compound 14a (0.499
g, 67%) as colourless needles, mp 48 ЊC (Found: C, 55.9; H, 7.8;
N, 8.0. C8H13NO3 requires C, 56.1; H, 7.65; N, 8.2%); νmax(film)/
cmϪ1 1765, 1695; δH(200 MHz) 1.14 (3 H, t, J 7.4, CH3CH2),
1.48 (6 H, s, 2 × 5-Me), 2.91 (2 H, q, J 7.4, CH3CH2), 3.72 (2
H, s, 4-H2); δC(50 MHz) 8.1 (CH3CH2), 27.2 (2 × 5-Me), 28.9
(ArCipso), 153.9 (2-C), 174.1 (C᎐Oacyl); m/z (CI) 265 (20%,
᎐
MHϩ ϩ NH3), 248 (100, MHϩ), 209 (8), 203 (16), 192 (20).
(4R)-N-Propionyl-4,5,5-triphenyloxazolidin-2-one 14f. Reac-
tion of the oxazolidin-2-one 6f (0.200 g, 0.634 mmol) under the
reaction conditions described above, followed by purification by
silica gel chromatography [ethyl acetate–petrol (bp 40–60 ЊC),
1:5] and crystallisation from ether–petrol (bp 60–80 ЊC) gave
the title compound 14f (0.179 g, 76%) as a white solid, mp
48 ЊC; [α]D25 = ϩ257.2 (c 1 in CHCl3) (Found: C, 77.3; H, 5.8; N,
3.65. C24H21NO3 requires C, 77.6; H, 5.70; N, 3.8%); νmax(film)/
cmϪ1 1790, 1694; δH(400 MHz) 1.08 (3 H, t, J 7.5, CH3CH2),
2.94 (2 H, m, CH3CH2), 6.22 (1 H, s, 4-H1), 7.00–7.16 (10 H, m,
ArCH), 7.37–7.47 (3 H, m, ArCH), 7.65 (2 H, d, J 7.2, ArCH);
δC(50 MHz) 7.9 (CH3CH2), 29.2 (CH2), 66.0 (4-C), 89.1 (5-C),
126.2 (ArCH), 126.4 (ArCH), 127.7 (ArCH), 127.9 (ArCH),
128.5 (ArCH), 129.2 (ArCH), 136.1 (ArCipso), 138.3 (ArCipso),
(CH CH ), 54.3 (4-C), 78.6 (5-C), 152.9 (2-C), 174.9 (C᎐Oacyl);
᎐
3
2
m/z (CI) 189 (100%, MHϩ ϩ NH3), 172 (60, MHϩ), 133 (12),
116 (5), 72 (9).
N-Propionyl-5,5-diphenyloxazolidin-2-one 14b. Reaction of
oxazolidin-2-one 6b (0.300 g, 1.25 mmol) under the reaction
conditions described above, followed by column chrom-
atography on silica gel eluting with petrol [bp 40–60 ЊC]–ethyl
acetate (4:1 respectively) gave the title compound 14b (0.267 g,
72%) as a white solid, mp 82–83 ЊC (Found: MHϩ, 296.1292.
C18H18NO3 requires m/z 296.1287); νmax(film)/cmϪ1 1786, 1707;
δH(400 MHz) 1.16 (3 H, t, J 7.4, CH3CH2), 2.94 (2 H, q, J 7.4,
CH3CH2), 4.62 (2 H, s, 4-H2), 7.32–7.43 (10 H, m, ArCH);
δC(100 MHz) 8.1 (CH3), 28.9 (CH3CH2), 54.9 (4-C), 83.8 (5-C),
125.3 (ArCH), 128.5 (ArCH), 128.8 (ArCH), 141.4 (ArCipso),
142.1 (ArCipso), 153.1 (2-C), 173.6 (C᎐Oacyl); m/z (APCI) 394
᎐
(5%, Mϩ ϩ Na), 372 (6, MHϩ), 328 (22, MHϩ Ϫ CO2), 316
(18), 272 (100).
(4R)-N-Propionyl-5,5-dimethyl-4-isopropyloxazolidin-2-one
14g. Reaction of the oxazolidin-2-one 6g (0.300 g, 1.91 mmol)
152.2 (2-C), 174.1 (C᎐Oacyl); m/z (CI) 296 (24%, MHϩ), 253
᎐
J. Chem. Soc., Perkin Trans. 1, 1999, 387–398
395

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under the reaction conditions described above, followed by
crystallisation from hot petrol (bp 60–80 ЊC) gave the title
compound 14g (0.299 g, 73%) as a crystalline solid, mp 62 ЊC;
[α]D25 = Ϫ37.0 (c 1 in CHCl3) (Found: C, 62.1; H, 8.80; N, 6.3.
C11H19NO3 requires C, 61.9; H, 8.9; N, 6.6%); νmax(film)/cmϪ1
1773, 1702; δH(400 MHz) 0.94 [3 H, d, J 6.9, (CH3)2CH], 1.03 [3
H, d, J 6.9, (CH3)2C], 1.18 (3 H, t, J 7.4, CH3CH2), 1.37 (3 H, s,
5-Me), 1.50 (3 H, s, 5-Me), 2.14 [1 H, dsept, J 3.4 and 6.9,
(CH3)2CH], 2.89 (1 H, dq, J 17.5 and 7.4, CH2CH3), 3.00 (1 H,
dq, J 17.5 and 7.4, CH2CH3), 4.14 (1 H, d, J 3.4, 4-H1); δC(100
MHz) 8.7 (CH3CH2), 17.0 (CH3), 21.4 (CH3), 21.5 (5-Me), 28.8
(CH2CH3), 29.1 [CH(CH3)2], 29.5 (5-Me), 66.2 (4-C), 82.8
oxazolidin-2-one (1 equiv.) in THF (15 cm3 mmolϪ1) at Ϫ78 ЊC
under a nitrogen atmosphere and the mixture allowed to stir for
30 min. Benzyl bromide (3 equiv.) was added at Ϫ78 ЊC and the
reaction stirred at this temperature for 2 h, then allowed to
warm to room temperature over a further 22 h. Saturated
NH4Cl (aq.) was added and the reaction extracted with ethyl
acetate (×3). The combined organic extracts were washed with
brine, dried (MgSO4) and evaporated.
N-(2-Methyl-1-oxo-3-phenylpropyl)-5,5-dimethyloxazolidin-
2-one 15a. Benzylation of the corresponding N-propionyl
auxiliary 14a (0.100 g, 0.584 mmol) according to the above
procedure provided the crude reaction product, the com-
(5-C), 153.6 (2-C), 174.6 (C᎐Oacyl); m/z (APCI) 428 [12%,
᎐
(MH)2ϩ], 384 [5, (MH)2ϩ Ϫ CO2], 270 (13), 214 (33, MHϩ), 158
1
position of which was determined by H NMR spectroscopy.
(100).
The benzylated product 15a was isolated by silica gel chrom-
atography [ethyl acetate–petrol (bp 40–60 ЊC); 1:9 respectively]
as an oil (0.120 g, 79%) (Found: MHϩ, 262.1448. C15H20NO3
requires m/z 262.1443); νmax(CHCl3)/cmϪ1 1703, 1783; δH(200
MHz) 1.16 (3 H, d, J 6.7, CH3CH), 1.28 (3 H, s, 5-Me), 1.41
(3 H, s, 5-Me), 2.64 (1 H, dd, J 5.6 and 13.3, PhCH2), 3.03 (1 H,
dd, J 7.2 and 13.3, PhCH2), 3.56 (1 H, d, J 11.0, 4-H1), 3.65
(1 H, d, J 11.0, 4-H1), 4.12 (1 H, m, COCH), 7.12–7.28 (5 H, m,
ArCH); δC(50 MHz) 16.7 (CH3CH), 26.9 (5-Me), 27.0 (5-Me),
39.3 (COCH), 40.0 (PhCH2), 54.4 (4-C), 78.3 (5-C), 126.3
(ArCH), 128.1 (ArCH), 128.3 (ArCH), 139.2 (ArC), 152.3
(4R)-N-Propionyl-5,5-diphenyl-4-isopropyloxazolidin-2-one
14h. Reaction of the oxazolidin-2-one 6h (0.300 g, 1.07 mmol)
under the reaction conditions described above, followed by
crystallisation from hot petrol (bp 60–80 ЊC)–ethyl acetate
gave the title compound 14h (0.242 g, 64%) as a white solid,
mp 106 ЊC; [α]D25 = ϩ199.3 (c 1 in CHCl3) (Found: C, 74.70; H,
6.7; N, 4.0. C21H23NO3 requires C, 74.75; H, 6.9; N, 4.15%);
νmax(film)/cmϪ1 1774, 1710; δH(400 MHz) 0.77 [3 H, d, J 6.8,
(CH3)2CH], 0.88 [3 H, d, J 6.8, (CH3)2CH], 1.10 (3 H, t, J 7.4,
CH3CH2), 1.97 [1 H, dsept, J 3.4 and 6.8 (CH3)2CH], 2.74 (1
H, dq, J 17.3 and 7.4, CH2CH3), 2.94 (1 H, dq, J 17.3 and 7.4,
CH2CH3), 5.38 (1 H, d, J 3.4, 4-H1), 7.26–7.42 (8 H, m, ArCH),
7.48 (2 H, d, J 7.2, ArCH); δC(50 MHz) 8.5 (CH3CH2), 16.2
(CH3CH), 21.7 (CH3CH), 28.1 (CH3CH2), 29.8 [(CH3)2CH],
64.4 (4-C), 89.4 (5-C), 125.8 (ArCH), 125.9 (ArCH), 126.1
(ArCH), 128.1 (ArCH), 128.6 (ArCH), 128.8 (ArCH), 129.1
(ArCH), 138.4 (ArCipso), 142.6 (ArCipso), 153.3 (2-C), 174.3
(2-C), 176.8 (C᎐Oacyl); m/z (CI) 279 (43%, MHϩ ϩ NH3), 262
᎐
(100, MHϩ), 218 (6), 133 (5), 118 (13).
N-(2-Methyl-1-oxo-3-phenylpropyl)-5,5-diphenyloxazolidin-2-
one 15b. Benzylation of the corresponding N-propionyl
auxiliary 14b (0.100 g, 0.339 mmol) according to the above
procedure provided the crude reaction product, the com-
1
position of which was determined by H NMR spectroscopy.
(C᎐Oacyl); m/z (APCI) 472 [4%, (MH)2ϩ], 416 (6), 394 (4), 360
᎐
The benzylated product 15b was isolated by column chrom-
atography [ethyl acetate–petrol (bp 40–60 ЊC); 1:9 respectively]
on silica gel as an oil (0.039 g, 30%) (Found: MHϩ, 386.1767.
C25H24NO3 requires m/z 386.1756); νmax(film)/cmϪ1 1782, 1699;
δH(400 MHz) 1.15 (3 H, J 6.8, CH3CH), 2.64 (1 H, dd, J 13.4
and 6.7, PhCH2), 3.04 (1 H, dd, J 13.4 and 7.9, PhCH2), 4.10
(1 H, m, COCH), 4.55 (2 H, m, 4-H2), 7.13–7.23 (5 H, m,
ArCH), 7.30–7.41 (10 H, m, ArCH); δC(50 MHz) 16.4
(CH3CH), 39.4 (COCH), 39.6 (CH2Ph), 55.1 (4-C), 83.7 (5-C),
125.5 (ArCH), 125.6 (ArCH), 128.5 (ArCH), 128.8 (ArCH),
129.0 (ArCH), 129.3 (ArCH), 135.3 (ArCipso), 139.2 (ArCipso),
(20, Mϩ ϩ Na), 350 (12), 338 (23, MHϩ), 294 (85, MHϩ Ϫ
CO2), 238 (100).
N-Propionyloxazolidin-2-one 14i. Reaction of oxazolidin-2-
one 6i (2.0 g, 0.023 mol) under the reaction conditions
described above, followed by crystallisation from hot petrol
(bp 40–60 ЊC)–ethyl acetate gave the title compound 14i (1.92
g, 58%) as needles, mp 81–82 ЊC (Found: C, 50.3; H, 6.40; N,
9.7. C6H9NO3 requires C, 50.35; H, 6.3; N, 9.8%); νmax(KBr)/
cmϪ1 1768, 1698; δH(400 MHz) 1.22 (3 H, t, J 7.4, CH3CH2),
2.98 (2 H, q, J 7.4, CH3CH2), 4.07 (2 H, t, J 8.1, 4-H2), 4.46
(2 H, t, J 8.1, 5-H2); δC(50 MHz) 8.1 (CH3), 28.6 (CH3CH2),
141.6 (ArCipso), 152.2 (2-C), 176.9 (C᎐Oacyl); m/z (APCI) 386
᎐
(14%, MHϩ), 343 (26), 342 (100, MHϩ Ϫ CO2), 252 (20), 221
42.4 (4-C), 62.1 (5-C), 153.9 (2-C), 174.5 (C᎐Oacyl); m/z
᎐
(6), 195 (8), 180 (19), 91 (15).
(APCI) 166 (52%, Mϩ ϩ Na), 153 (54), 144 (26, MHϩ), 118
(100), 100 (56).
(4R)-N-[(2S)-2-Methyl-1-oxo-3-phenylpropyl]-4,5,5-tri-
methyloxazolidin-2-one 15c. Benzylation of the corresponding
N-propionyl auxiliary 14c (0.100 g, 0.540 mmol) according to
the above procedure provided the crude reaction product, the
composition of which was determined by 1H NMR spec-
troscopy. The benzylated product 15c was obtained in a
diastereomeric excess of 81%, and isolated by column chrom-
atography [ethyl acetate–petrol (bp 60–80 ЊC); 1:9 respectively]
on silica gel as an oil (0.066 g, 44%) in >95% de (1H NMR);
[α]D25 = ϩ4.3 (c 1 in CHCl3) (Found: C, 69.5; H, 8.0; N, 5.1.
C16H21NO3 requires C, 69.8; H, 7.7; N, 5.1%); νmax(film)/cmϪ1
1770, 1698; δH(400 MHz) 1.09 (3 H, d, J 6.5, CH3CH), 1.16
(3 H, d, J 6.8, 4-Me), 1.34 (3 H, s, 5-Me), 1.42 (3 H, s,
5-Me), 2.65 (1 H, dd, J 13.3 and 7.9, PhCH2), 3.07 (1 H, dd,
J 13.3 and 7.1, PhCH2), 4.10–4.18 (2 H, m, 4-H1 and CO-
CH), 7.17–7.29 (5 H, m, ArCH); δC(50 MHz) 14.2 (CH3CH),
16.4 (4-Me), 21.4 (5-Me), 27.6 (5-Me), 39.4 (COCH), 39.9
(PhCH2), 58.9 (4-C), 81.2 (5-C), 126.5 (ArCH), 129.5
N-Propionyl-4-isopropyloxazolidin-2-one 14j. Reaction of
the oxazolidin-2-one 6j (0.300 g, 2.32 mmol) under the reaction
conditions described above, followed by silica gel chrom-
atography (ethyl acetate–petrol, 1:9) gave the title compound
14j (0.402 g, 94%) as an oil; [α]D25 = Ϫ92.8 (c 1 in CHCl3);
νmax(film)/cmϪ1 1781, 1704; δH(400 MHz) 0.86 [3 H, d, J 7.0,
(CH3)2CH], 0.90 [3 H, d, J 7.0, (CH3)2CH], 1.15 (3 H, t, J 7.3,
CH3CH2), 2.36 [1 H, dsept, J 3.5 and 7.0, (CH3)2CH], 2.83–
3.00 (2 H, m, CH3CH2), 4.20 (1 H, dd, J 3.5 and 8.7, 5-H1), 4.26
(1 H, t, J 8.7, 5-H1), 4.42 (1 H, dt, J 8.7 and 3.5, 4-H1); δC(50
MHz) 8.0 (CH3CH2), 14.2 [(CH3)2CH], 17.5 [(CH3)2CH], 28.1
[(CH3)2CH], 28.8 (CH3CH2), 58.1 (4-C), 63.2 (5-C), 154.3
(2-C), 174.0 (C᎐Oacyl); m/z (CI) 203 (100%, MHϩ ϩ NH3), 186
᎐
(52, MHϩ), 147 (10).
General procedure for the benzylation of the N-propionyloxazol-
idin-2-ones
(ArCH), 139.4 (ArCipso), 152.7 (2-C), 177.3 (C᎐Oacyl); m/z
᎐
Lithium bis(trimethylsilyl)amide (1.1 equiv.) was added drop-
wise via syringe to a stirred solution of the N-propionyl-
(APCI) 298 (5%, Mϩ ϩ Na), 277 (9), 276 (72, MHϩ), 232 (15,
MHϩ Ϫ CO2), 130 (100).
396
J. Chem. Soc., Perkin Trans. 1, 1999, 387–398

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(4R)-N-[(2S)-2-Methyl-1-oxo-3-phenylpropyl]-5,5-diphenyl-
4-methyloxazolidin-2-one 15d. Benzylation of the correspond-
ing N-propionyl auxiliary 14d (0.100 g, 0.323 mmol) according
to the above procedure provided the crude reaction product,
the composition of which was determined by 1H NMR
spectroscopy. The benzylated product 15d was obtained in a
diastereomeric excess of 65%, and isolated by column chrom-
atography [ethyl acetate–petrol (bp 60–80 ЊC); 1:4 respectively]
sponding N-propionyl auxiliary 14g (0.100 g, 0.469 mmol)
according to the above procedure provided the crude reaction
product, the composition of which was determined by 1H
NMR spectroscopy. The benzylated product 15g was obtained
in a diastereomeric excess of >95%, and isolated by silica gel
chromatography [ethyl acetate–petrol (bp 40–60 ЊC); 1:9
respectively] as an oil (0.049 g, 34%) in >95% de (by 1H NMR);
[α]D25 = ϩ8.0 (c 1 in CHCl3) (Found: C, 71.3; H, 8.5; N, 4.6.
C18H25NO3 requires C, 71.3; H, 8.3; N, 4.6%); νmax(film)/cmϪ1
1772, 1700; δH(400 MHz) 0.75 [3 H, d, J 6.9, (CH3)2CH], 0.84
[3 H, d, J 6.9, (CH3)2CH], 1.15 (3 H, d, J 6.7, CH3CH), 1.38
(3 H, s, 5-Me), 1.49 (3 H, s, 5-Me), 2.03 [1 H, dsept, J 3.1 and
6.9, (CH3)2CH], 2.64 (1 H, dd, J 13.3 and 3.1, PhCH2), 3.19
(1 H, dd, J 13.3 and 7.2, PhCH2), 4.15 (1 H, d, J 3.1, 4-H1), 4.22
(1 H, m, COCH), 7.26–7.32 (5 H, m, ArCH); δC(50 MHz) 16.5
[(CH3)2CH and 5-Me], 21.2 [(CH3)2CH and 5-Me], 28.7
(CH3CH), 29.4 [(CH3)2CH], 39.3 (COCH), 40.0 (PhCH2), 66.1
(4-C), 82.6 (5-C), 126.5 (ArCH), 128.5 (ArCH), 129.5 (ArCH),
1
on silica gel as an oil (0.051 g, 40%) in 68% de (by H NMR);
[α]D25 = ϩ249.6 (c 0.5 in CHCl3) (Found: MHϩ, 400.1924.
C26H26NO3 requires m/z 400.1913); νmax(film)/cmϪ1 1783, 1699;
δH(400 MHz) major diastereomer: 0.93 [3 H, d, J 6.5,
CH3CH(CO)], 1.06 (3 H, d, J 6.5, 4-Me), 2.67 (1 H, dd, J 13.4
and 8.2, PhCH2), 3.15 (1 H, dd, J 13.4 and 6.7, PhCH2), 4.07
(1 H, m, COCH), 5.41 (1 H, q, J 6.5, 4-H1), 7.28–7.44 (13 H, m,
ArCH), 7.53 (2 H, d, J 7.4, ArCH); minor diastereomer:
0.93 [3 H, d, J 6.5, CH3CH(CO)], 1.22 (3 H, d, J 6.8,
4-Me), 2.59 (1 H, m, CHCH2), 2.94 (1 H, m, CHCH2), 4.02
(1 H, m, CHCH2), 5.38 (1 H, m, 4-H1), 7.28–7.44 (13 H, m,
ArCH), 7.53 (2 H, d, J 7.4, ArCH); δC(100 MHz) mixture of
diastereomers: 16.3 (CH3), 16.4 (CH3), 29.7 (CH3), 39.2
(COCHmajor), 39.5 (CH2), 39.3 (COCHminor), 57.2 (4-Cminor),
57.1 (4-Cmajor), 87.8 (5-C), 125.8 (ArCH), 126.0 (ArCH), 126.3
(ArCH), 128.0 (ArCH), 128.2 (ArCH), 128.4 (ArCH), 128.8
(ArCH), 129.2 (ArCH), 138.3 (ArCH), 139.1 (ArCipso), 141.2
139.5 (ArCipso), 153.6 (2-C), 177.3 (C᎐Oacyl); m/z (APCI) 304
᎐
(100%, MHϩ), 260 (9, MHϩ Ϫ CO2), 158 (63), 122 (15).
(4R)-N-[(2S)-2-Methyl-1-oxo-3-phenylpropyl]-5,5-diphenyl-
4-isopropyloxazolidin-2-one 15h. Benzylation of the corres-
ponding N-propionyl auxiliary 14h (0.100 g, 0.295 mmol)
according to the above procedure provided the crude reaction
product, the composition of which was determined by 1H
NMR spectroscopy. The benzylated product 15h was obtained
in a diastereomeric excess of >95%, and obtained as an
inseparable mixture (0.052 g) of acyl compound 14h and the
desired product 15h (58:42 respectively) after silica gel chrom-
atography [ethyl acetate–petrol (bp 60–80 ЊC); 1:9 respectively].
The compound was thus characterised as fully as possible from
data obtained from the reaction mixture (Found: MHϩ,
428.2230. C28H30NO3 requires m/z 428.2226); νmax(film)/cmϪ1
1784, 1705; δH(400 MHz) 0.60 (3 H, d, J 6.7, CH3CH), 0.72
[3 H, d, J 7.0, (CH3)2CH], 0.85 [3 H, d, J 6.7, (CH3)2CH], 1.90
[1 H, m, (CH3)2CH], 2.61 (1 H, dd, J 13.3 and 7.9, PhCH2), 3.17
(1 H, dd, J 13.3 and 7.2, PhCH2), 4.04 (1 H, m, COCH), 5.40
(1 H, d, J 3.3, 4-H1), 7.14–7.50 (15 H, m, ArCH); δC(100 MHz)
16.1 [(CH3)2CH], 21.5 [(CH3)2CH], 29.6 (CH3CH), 29.9
[(CH3)2CH], 39.1 (COCH), 39.8 (PhCH2), 64.4 (4-C), 89.2
(5-C), 125.6–129.2 (ArCH), 138.1 (ArCipso), 139.2 (ArCipso),
(ArCipso), 151.7 (2-C), 176.2 (C᎐Oacyl); m/z (APCI) 438
᎐
(Mϩ ϩ K, 2%), 422 (8, Mϩ ϩ Na), 400 (8, MHϩ), 356 (100,
MHϩ Ϫ CO2), 210 (67).
(4R)-N-[(2S)-2-Methyl-1-oxo-3-phenylpropyl]-5,5-dimethyl-
4-phenyloxazolidin-2-one 15e. Benzylation of the corresponding
N-propionyl auxiliary 14e (0.100 g, 0.404 mmol) according to
the above procedure provided the crude reaction product, the
composition of which was determined by 1H NMR spec-
troscopy. The benzylated product 15e was obtained in a
diastereomeric excess of 70%, and isolated by chromatography
on silica gel [ethyl acetate–petrol (bp 60–80 ЊC); 3:7 respect-
ively] as an oil (0.075 g, 55%) in 87% de (by 1H NMR);
[α]D25 = Ϫ12.6 (c 1 in CHCl3) (Found: MHϩ, 338.1753. C21H24-
NO3 requires m/z 338.1756); νmax(CHCl3)/cmϪ1 1704, 1773;
δH(200 MHz) major diastereomer: 0.97 (3 H, s, 5-Me), 1.16 (3 H,
d, J 6.7, CH3CH), 1.61 (3 H, s, 5-Me), 2.51 (1 H, dd, J 8.1 and
13.3, PhCH2), 3.14 (1 H, dd, J 6.7 and 13.3, PhCH2), 4.23 (1 H,
m, COCH), 5.09 (1 H, s, 4-H1), 6.96–7.35 (10 H, m, ArCH);
minor diastereomer: 0.95 (3 H, s, 5-Me), 1.19 (3 H, d, J 6.8,
CH3CH), 1.35 (3 H, s, 5-Me), 2.69 (1 H, dd, J 7.1 and 13.5,
PhCH2), 3.02 (1 H, dd, J 8.2 and 13.5, PhCH2), 4.27 (1 H, m,
COCH), 4.94 (1 H, s, 4-H1), 7.10–7.41 (10H, m, ArCH); δC(125
MHz) major diastereomer: 16.5 (CH3CH), 23.8 (5-Me), 29.0
(5-Me), 39.6 (PhCH2 and CH3CH), 67.1 (4-C), 82.1 (5-C),
126.2 (ArCH), 128.3 (ArCH), 128.8 (ArCH), 129.2 (ArCH),
142.3 (ArCipso), 152.8 (2-C), 176.2 (C᎐Oacyl); m/z (CI) 428 (90%,
᎐
MHϩ), 384 (40, MHϩ Ϫ CO2).
N-(2-Methyl-1-oxo-3-phenylpropyl)oxazolidin-2-one
15i.
Benzylation of the corresponding N-propionyl auxiliary 14i
(0.250 g, 1.75 mmol) according to the above procedure provided
the crude reaction product, the composition of which was
determined by 1H NMR spectroscopy. The benzylated product
15i was isolated as an oil by column chromatography [ethyl
acetate–petrol (bp 60–80 ЊC); 1:4 respectively] on silica gel
(0.311 g, 76%) (Found: MHϩ, 234.1125. C13H16NO3 requires
m/z 234.1130); νmax(film)/cmϪ1 1771, 1704; δH(400 MHz) 1.18
(3 H, d, J 6.7, CH3CH), 2.65 (1 H, dd, J 13.3 and 7.9, PhCH2),
3.07 (1 H, dd, J 13.3 and 7.0, PhCH2), 3.89–4.03 (2 H, m, 4-H2),
4.09 (1 H, m, CH3CH), 4.29 (1 H, td, J 9.0 and 7.2, 5-H1), 4.37
(1 H, td, J 9.0 and 6.6, 5-H1), 7.19–7.30 (5 H, m, ArCH); δC(100
MHz) 16.5 (CH3), 39.2 (COCH), 39.6 (PhCH2), 42.7 (4-C), 61.9
(5-C), 126.5 (ArCH), 128.5 (ArCH), 129.4 (ArCH), 139.1
136.1 (ArCipso), 139.1 (ArCipso), 156.0 (2-C), 177.0 (C᎐Oacyl);
᎐
minor diastereomer: 17.0 (CH3CH), 23.5 (5-Me), 28.5 (5-Me),
39.5 (PhCH2), 39.7 (COCH), 67.0 (4-C), 82.3 (5-C), 126.4
(ArCH), 126.5 (ArCH), 128.6 (ArCH), 128.8 (ArCH), 129.1
(ArCH), 129.4 (ArCH), 136.7 (ArCipso), 139.6 (ArCipso), 153.2
(2-C), 176.5 (C᎐Oacyl); m/z (APCI) 360 (4%, Mϩ ϩ Na), 339
᎐
(14), 338 (100, MHϩ), 294 (5), 282 (10), 192 (41), 148 (4),
122 (6).
Attempted alkylation of (4R)-N-propionyl-4,5,5-triphenyl-
oxazolidin-2-one 14f. Benzylation of the corresponding
N-propionyl auxiliary 14f (0.100 g, 0.269 mmol) according to
the above procedure provided the crude reaction product, the
composition of which was determined by H NMR spectro-
scopy. Only the acyl SuperQuat 14f and N-benzyl-SuperQuat
(ArCipso), 153.5 (2-C), 178.9 (C᎐Oacyl); m/z (APCI) 256 (18%,
᎐
Mϩ ϩ Na), 234 (25, MHϩ), 208 (30), 190 (42), 147 (64), 119
(100).
1
(4R)-N-[(2S)-2-Methyl-1-oxo-3-phenylpropyl]-4-isopropyl-
oxazolidin-2-one 15j. Benzylation of the corresponding N-
propionyl auxiliary 14j (0.100 g, 0.540 mmol) according to the
above procedure provided the crude reaction product, the com-
16f were obtained in a 54:46 ratio respectively.
1
(4R)-N-[(2S)-2-Methyl-1-oxo-3-phenylpropyl]-5,5-dimethyl-
4-isopropyloxazolidin-2-one 15g. Benzylation of the corre-
position of which was determined by H NMR spectroscopy.
The benzylated product 15j was obtained in a diastereomeric
J. Chem. Soc., Perkin Trans. 1, 1999, 387–398
397

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excess of >95%, and isolated by column chromatography [ethyl
acetate–petrol (bp 60–80 ЊC), 1.5:9 respectively] on silica gel as
an oil (0.083 g, 56%); [α]D25 = Ϫ9.9 (c 1 in CHCl3) (Found: MHϩ,
276.1605. C16H22NO3 requires m/z 276.1600); νmax(film)/cmϪ1
1779, 1699; δH(400 MHz) 0.60 [3 H, d, J 7.0, (CH3)2CH], 0.84 [3
H, d, J 7.0, (CH3)2CH], 1.16 (3 H, d, J 6.7, CH3CH), 2.16 [1 H,
dsept, J 3.6 and 7.0, (CH3)2CH], 2.63 (1 H, dd, J 13.2 and 7.6,
PhCH2), 3.13 (1 H, dd, J 13.2 and 7.4, PhCH2), 4.12–4.20 (2 H,
m, 5-H1 and COCH), 4.25 (1 H, t, J 8.6, 5-H1), 4.44 (1 H, dt,
J 8.6 and 3.6, 4-H1), 7.16–7.29 (5 H, m, ArCH); δC(50 MHz)
14.1 [(CH3)2CH], 16.4 (CH3CH), 17.8 [(CH3)2CH], 28.1
[(CH3)2CH], 39.4 (COCH), 40.0 (PhCH2), 58.4 (4-C), 63.0
(5-C), 126.5 (ArCH), 128.5 (ArCH), 129.4 (ArCH), 139.4
References
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(ArCipso), 154.0 (2-C), 176.8 (C᎐Oacyl); m/z (APCI) 366 (4%),
᎐
276 (55, MHϩ), 263 (14), 223 (3), 147 (22), 130 (100), 119 (13).
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(2S)-2-Methyl-3-phenylpropanoic acid 19
8 C. L. Gibson, K. Gillon and S. Cook, Tetrahedron Lett., 1998, 39,
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12 Similar arguments have been proposed to explain the high de’s
obtained using 2,2-dimethyloxazolidinone as a chiral auxiliary, see
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Chem. Soc., 1998, 120, 4091, and references contained therein.
13 Use of Na or K enolates at Ϫ78 ЊC led to similar or worse results,
while addition of benzyl bromide before addition of LHMDS at
Ϫ78 ЊC did not improve the alkylation yield.
14 W. Oppolzer and P. Lienard, Helv. Chim. Acta, 1992, 75, 2572.
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Chem. Pharm. Bull., 1997, 45, 185.
Lithium hydroxide monohydrate (0.021 g, 0.51 mmol) was
added to a vigorously stirred solution of (4R)-N-[(2S)-2-
methyl-1-oxo-3-phenylpropyl]-5,5-dimethyl-4-isopropyloxazol-
idin-2-one 15g (0.071 g, 0.234 mmol) in a THF–water mixture
(3:1; 4 cm3) and left to stir for 24 h at room temperature.
The mixture was evaporated, sodium hydrogen carbonate
(10 cm3) added and extracted with ether (3 × 10 cm3). The
combined organic extracts were dried (MgSO4) and evap-
orated to afford recovered SuperQuat 6g [0.036 g, 98%; [α]D25
=
Ϫ23.9 (c 1 in CHCl3)]. The aqueous extracts were acidified (1 M
HCl), extracted with CH2Cl2 (3 × 15 cm3), dried (MgSO4),
and evaporated to give the crude product which was distilled on
a Kugelrohr apparatus to provide the desired acid 19 as
an oil (0.037 g, 96%); [α]D25 = ϩ26.5 (c 1 in CHCl3) [lit.,14 ϩ25.5
(c 1 in CHCl3)]; δH(200 MHz) 1.20 (3 H, d, J 6.5, 2-Me), 2.62–
2.85 (2 H, m, 2-H1 and 3-H1), 3.09 (1 H, dd, J 12.6 and 5.8,
3-H1).
17 W. J. Close, J. Am. Chem. Soc., 1951, 73, 95.
18 R. Le Gendre, P. Thominot, C. Bruneau and P. H. Dixneuf, J. Org.
Chem., 1998, 63, 1806.
19 T. Isobe and K. Fukuda, Jap. Pat. JP09143173 (Chem. Abstr., 1997,
127, 50635x).
Acknowledgements
We thank Oxford Asymmetry International plc (S. D. B.) for
financial support.
Paper 8/09715A
398
J. Chem. Soc., Perkin Trans. 1, 1999, 387–398