Synthesis and utility of the 3,3-dimethyl-5-substituted-2-pyrrolidinone 'Quat' chiral auxiliary

Article abstract of DOI:10.1016/S0957-4166(02)00166-0

The synthesis and utility of the 3,3-dimethyl-5-substituted-2-pyrrolidinone 'Quat' chiral auxiliary in stereoselective enolate reactions of attached N-acyl side chains combined with the mild and non-racemising conditions required for the ultimate removal of the chiral side chain is described.

Full text of DOI:10.1016/S0957-4166(02)00166-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 647–658
Synthesis and utility of the
3,3-dimethyl-5-substituted-2-pyrrolidinone ‘Quat’ chiral auxiliary
Stephen G. Davies,* Darren J. Dixon, Gilles J.-M. Doisneau, Jeremy C. Prodger and
Hitesh J. Sanganee
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK
Received 21 March 2002; accepted 2 April 2002
Abstract—The synthesis and utility of the 3,3-dimethyl-5-substituted-2-pyrrolidinone ‘Quat’ chiral auxiliary in stereoselective
enolate reactions of attached N-acyl side chains combined with the mild and non-racemising conditions required for the ultimate
removal of the chiral side chain is described. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
based upon
when the group R% is large, steric factors render the
unwanted endocyclic cleavage of the oxazolidinone ring
more favourable. This problem can be overcome by
using lithium hydroperoxide as a nucleophile, since it is
apparently less susceptible to steric hindrance. Unsur-
prisingly, the use of this reagent on a large scale may
prove hazardous and as a result we have devised an
alternative strategy to circumvent this problem.
Chiral
auxiliaries
oxazolidinone
heterocycles1 represent one of the most powerful tools
available to the organic chemist. Treatment of enolates
derived from N-acyloxazolidinones with a variety of
electrophiles can lead to asymmetric alkylation,2
acylation,3 bromination,4 amination,5 hydroxylation6
and most importantly aldol addition.7
However, the utility of a chiral auxiliary in any syn-
thetic strategy is reliant upon the mild and selective
removal of the auxiliary, without racemisation of the
stereogenic centres present in the system. The position
of nucleophilic cleavage in N-acyloxazolidinones is
dependent upon steric and electronic requirements
(Scheme 1).8 The nucleophilic cleavage of unhindered
systems is subject to electronic factors and exocyclic
cleavage occurs to give the required products. However,
2. Results and discussion
We believed that a substantial increase in steric bulk
adjacent to the endocyclic amide bond would impede
nucleophilic attack at this carbonyl and accordingly
encourage an exocyclic cleavage mode of hydrolysis. As
a result we synthesised the ‘Quat’ chiral auxiliaries 1–4
and investigated this hypothesis. The preliminary
results of this study have previously been
communicated9,10 and herein we wish to report our full
investigations into this area.
The ‘Quat’ auxiliaries were prepared according to
Scheme 2. The synthesis began from
L-pyroglutamic
acid 5 which was converted into (S)-(+)-5-hydroxy-
methyl-2-pyrrolidinone 6, via the two-step procedure
of Levy and Silverman in 68% yield.11 In order to
introduce the geminal dimethyl groups adjacent to the
carbonyl functionality, protection of the acidic hydroxy-
methyl and lactam functionality was necessary. This
was effected using an excess of 2,2-dimethoxypropane
and a catalytic quantity of para-toluene sulfonic acid,
in refluxing toluene with azeotropic removal of
Scheme 1.
* Corresponding author.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00166-0

648
S. G. Da6ies et al. / Tetrahedron: Asymmetry 13 (2002) 647–658
which was then converted to bromide 11 using a
Finkelstein-type reaction. Reduction of the car-
bonꢀbromine bond using palladium on charcoal and
triethylamine under an atmosphere of hydrogen lead to
methyl ‘Quat’ 3 as a crystalline solid in near quantita-
tive yield. Alternatively, addition of lithium dimethyl-
cuprate to a THF solution of tosylate 10 at −78°C
afforded ethyl ‘Quat’ 4 in 91% yield.
With the ‘Quat’ auxiliaries 1–4 in hand, an investiga-
tion into their propensity for exo- versus endocyclic
cleavage was undertaken. We envisaged that the bulky
N-pivaloylated auxiliaries would serve as good models
in this respect. The N-pivaloyl derivatives 12–15 were
readily prepared in high yield by reaction of 1–4 with
n-butyllithium in tetrahydrofuran at −78°C followed by
quenching with pivaloyl chloride (Scheme 3).
In most cases cleavage of the N-pivaloyl ‘Quat’ deriva-
tives 12–15 with LiOH in a 3:1 mixture of tetra-
hydrofuran and water at room temperature returned
the auxiliaries in near quantative yield and no endo-
cyclic cleavage products were detected by 1H NMR.
The low yield of 1 was due to partial deprotection of
the hydroxyl group under the hydrolysis conditions.
The N-pivaloyl derivatives of the Evans oxazolidin-2-
ones have previously been shown to give a mixture of
exocyclic and endocyclic cleavage products in various
ratios. Clearly, an increase in steric bulk adjacent to the
endocyclic carbonyl does indeed favour exocyclic cleav-
age, however, the next step in our investigation was to
ascertain the utility of these auxiliaries in asymmetric
transformations, in particular the asymmetric alkyla-
tion and aldol addition.
Scheme 2. Reagents and conditions: (i) EtOH, toluene, H2SO4
(cat.), D, then NaBH4 (1 equiv.) EtOH, rt, 1.5 h; (ii) 2,2-
dimethoxypropane, Tol, PTSA (cat.), D; (iii) LDA (1.1
equiv.), −78°C, MeI, −78°C to rt, LDA (1.1 equiv.), −78°C,
MeI, −78°C to rt; (iv) MeOH, PTSA (cat.), D; (v) TBDMSCl,
DMF, Im; (vi) Ph3CCl, DMAP, NEt3, CH2Cl2, rt; (vii) TsCl,
Et3N/CH2Cl2 (1:2), rt, 4 h; (ix) LiBr (3.0 equiv.), acetone, D,
6 h; (viii) Me2CuLi (3 equiv.), THF, −20°C; (ix) LiBr (3.0
equiv.), acetone, D, 6 h; (x) H2 (1 atm), Pd/C (20%), Et3N,
EtOH/MeOH (1:1), rt, 24 h.
methanol. The oxazolidine product 7 was then quater-
nized adjacent to the carbonyl group using a one-pot
procedure. Thus, a −78°C THF solution of 7 was
treated sequentially with LDA and methyl iodide. After
warming to 0°C the reaction mixture was re-cooled to
−78°C and treated once again with LDA and methyl
iodide before slowly warming to room temperature
overnight. Aqueous work-up and purification through a
single recrystallisation afforded 8 in good yield and on
multigram scale. Quantitative protecting group removal
was effected under standard trans-acetalisation condi-
tions. Thus, subjection of 8 to boiling methanol con-
taining a catalytic quantity of para-toluene sulfonic
acid gave the alcohol product 9 in quantitative yield.
We anticipated that lithium enolates derived from N-
acyl derivatives 16–23 would react with alkyl halides in
a highly stereoselective manner. On the basis of previ-
ous studies we envisaged that the diastereofacial prefer-
ence would be consistent with the operation of a
chelated transition state, with the alkyl halide
approaching from the least sterically hindered face of
the enolate. Formation of the N-acyl derivatives 16–23
according to Evans’ protocol occurred smoothly. Treat-
ment of this series with lithium diisopropylamide in
tetrahydrofuran at 0°C gave the lithium enolate, which
was then quenched with benzyl bromide or
iodomethane to give a series of alkylated products
24–31 (Scheme 4, Table 1).
In order to convert 9 into a useful chiral auxiliary, the
acidic hydroxy methyl group had to be rendered inert,
either by protection or through some other transforma-
tion. Initially, standard hydroxyl protecting groups
were introduced using standard procedures. Thus,
treatment of 9 with TBDMSCl and imidazole in
dimethylformamide gave oxazolidone 1 in good yield.
Similarly, treatment of 9 with trityl chloride and tri-
ethylamine in the presence of a catalytic quantity of
dimethylaminopyridine in dichloromethane gave 2 as a
white solid in 71% yield. Transformation of the hydroxy-
methyl group to either a methyl or an ethyl group was
also possible. In the former case, treatment of the
alcohol with para-toluenesulphonyl chloride and tri-
ethylamine in dichloromethane afforded tosylate 10,
In all cases good to excellent diastereoselectivities were
observed in the alkylation reactions. However, in some
Scheme 3. Reagents and conditions: (i) n-BuLi, pivaloyl chlo-
ride; (iii) LiOH, THF:H2O, 3:1, rt.

S. G. Da6ies et al. / Tetrahedron: Asymmetry 13 (2002) 647–658
649
1
product mixture by 300 MHz H NMR spectroscopy
indicated the presence of only one diastereoisomeric
product 35 (de >97%). The non-crystalline adduct 35
was purified by flash column chromatography on silica
gel. The syn relative stereochemistry of the aldol
product was assigned on the basis of 1H NMR coupling
constants.12 The coupling constant H2–H3 measured for
the product 35 was 3.0 Hz, consistent with the expected
syn relative stereochemistry. The absolute configura-
tions of the new stereogenic centres in 35 were assigned
after removal of the chiral auxiliary. Hydrolysis of 35
using LiOH in a 3:1 mixture of tetrahydrofuran and
water at 0°C generated 3-hydroxy-2-methyl-3-phenyl-
propionic acid 36 as a single diastereoisomer in 94%
yield. Comparison of the specific rotation {[h]2D1 +26.8
(c 0.5, CH2Cl2)} of the crystalline 3-hydroxy-2-methyl-
3-phenylpropionic acid 36 thus obtained, with the liter-
ature value13 for (2S,3S)-36 {[h]2D2=−26.4 (c 1.04,
CH2Cl2)} established its absolute configuration as
(2R,3R) (Scheme 7). The ‘Quat’ chiral auxiliary 3 was
recovered nearly quantitatively in this hydrolysis reac-
tion with no products from endocyclic cleavage being
observed.
Scheme 4. Reagents and conditions: (i) n-BuLi, THF, −78°C;
(ii) R%CH2COCl; (iii) LDA, THF, −78°C; (iv) EX.
cases yields were fairly moderate and methyl ‘Quat’
stood out as auxiliary of choice from this point of view.
With the protected hydroxymethyl-based auxiliaries 16–
19, yields were usually low due to enolate instability
and partial deprotection during the reactions, work-ups
and purifications.
Having established that enolates derived from N-acyl
derivatives 16–23 react with electrophiles in a highly
stereoselective manner, the cleavage of the alkylated
products with LiOH, MeOMgBr, and PhCH2OLi
(Scheme 5, Table 2) was then investigated. Cleavage of
28 gave rise to respectively (S)-2-benzylpropionic acid
32, methyl ester 33, and the benzyl ester 34 and again a
total absence of endocyclic cleavage products. The
absolute configurations were determined by measure-
ment of the specific rotation and comparison with the
literature values, which confirmed that a chelation con-
trol model could account for the sense of stereochemi-
cal induction. The use of chiral shift reagents confirmed
that no racemisation had occurred during the cleavage
reactions.
3. Conclusions
A series of chiral auxiliaries bearing a quaternised
carbon adjacent to the carbonyl group have been syn-
thesised and their effectiveness as chiral auxiliaries
tested. The geminal dimethyl groups were introduced to
act as a steric shield, protecting the auxiliary carbonyl
from nucleophilic attack by lithium hydroxide during
the sidechain hydrolysis step. This was indeed found to
be the case and furthermore the diastereoselectivities in
the alkylation and aldol reactions of attached N-acyl
sidechains were good to excellent making the auxiliaries
attractive from a synthetic point of view. Further chem-
istry of the ‘Quat’ auxiliaries will be reported in the
near future.
Having demonstrated the effectiveness of the ‘Quat’
auxiliaries in asymmetric alkylation, attention was
turned to asymmetric aldol methodology. The N-propi-
onyl derivative 20 was subjected to the dibutylboron
aldol methodology developed by Evans (Scheme 6).
A methylene chloride solution of the N-propionyl
methyl ‘Quat’ 20, at 0°C under an argon atmosphere,
was treated successively with a 1.0 M solution of
dibutylboron triflate in methylene chloride (1.1 equiv.)
and then diisopropylethylamine (1.2 equiv.). To the
resulting solution cooled to −78°C was added benzalde-
hyde (1.2 equiv.) and this mixture was stirred for 1 h at
−78°C and 1.5 h at 0°C. The reaction was then
quenched by the addition of a pH 7 phosphate buffer
solution and methanol, and treated with methanolic
hydrogen peroxide at 0°C for 1 h. Analysis of the crude
Scheme 5. Reagents and conditions: (i) LiOH, THF:H2O, 3:1,
rt; (ii) MeOMgBr, MeOH, 0°C; (iii) BnOLi, THF, 0°C.
Table 1. N-Acylations and C-alkylations of ‘Quat’ chiral auxiliaries
Entry
R
R%
Acylation yield (%)
Product
EX
Alkylation yield (%)
Product
de (%)
t
1
2
3
4
5
6
7
8
CH2OSiMe2 Bu Me
84
66
84
80
90
91
87
85
16
17
18
19
20
21
22
23
PhCH2Br
MeI
PhCH2Br
MeI
PhCH2Br
MeI
PhCH2Br
MeI
33
64
51
44
80
62
78
42
24
25
26
27
28
29
30
31
95
94
96
91
96
89
95
95
t
CH2OSiMe2 Bu CH2Ph
CH2OCPh3
Me
CH2OCPh3
CH2Ph
Me
CH2Ph
Me
Me
Me
Et
Et
CH2Ph

650
S. G. Da6ies et al. / Tetrahedron: Asymmetry 13 (2002) 647–658
Table 2. Cleavage reactions of N-acyl ‘Quats’ 28
Entry
Product
R
Yield (%)
ee (%)
Yield of 3 (%)
1
2
3
32
33
34
H
Me
PhCH2
83
82
94
96
96
96
95
92
97
ether refers to that fraction of petroleum ether boiling
between 40 and 60°C and was redistilled before use. All
other solvents were used as received. Reactions were
performed under an atmosphere of dry nitrogen unless
otherwise stated.
i
Scheme 6. Reagents and conditions: (i) Bu2BOTf; (ii) Pr2NEt;
(iii) PhCHO; (iv) H2O2.
4.1. (5S)-5-Hydroxymethyl-pyrrolidin-2-one 6
To a stirred suspension of pyroglutamic acid 5 (52.0 g,
403 mmol) in dry toluene (260 mL) was added ethanol
(50 g) in one portion and concentrated sulphuric acid (1
mL) via pipette. The reaction vessel was fitted with a
Dean–Stark apparatus and the mixture refluxed with
azeotropic removal of water for 6 h. On cooling, the
reaction mixture was diluted with chloroform (250 mL)
and then treated with anhydrous potassium carbonate
(20 g, 145 mmol). After effervescence ceased, the reac-
tion mixture was filtered through Celite® and concen-
trated in vacuo to afford pyroglutamic acid ethyl ester
as a colourless solid which was used directly in the next
step without further purification or characterisation.
Scheme 7. Reagents and conditions: (i) LiOH, THF:H2O, 3:1,
rt.
4. Experimental
Optical rotations were recorded using a Perkin–Elmer
241 which has a thermally jacketed 10 cm cell and are
given in units of 10−1 deg cm2 g−1. Elemental analyses
were obtained by the Dyson Perrins analytical depart-
ment using a Carla Erba 1106 analyser. Melting points
were recorded using a Gallenkamp hot stage apparatus
and are uncorrected. Infrared spectra were obtained
using a Perkin–Elmer 1750 spectrophotometer; solid
samples as KBr discs and liquid samples as a thin film
between sodium chloride plates. NMR spectra were
recorded using either a Bruker AM500 (1H; 500.13
MHz and 13C; 125.8 MHz), WH 300 (1H; 300.13 MHz),
AM200 (1H; 200 MHz and 13C; 50.3 MHz) or Varian
Gemini 200 (1H; 200 MHz and 13C; 50.32 MHz). All
spectra were recorded using deuteriochloroform as sol-
vent and internally referenced to residual protiochloro-
This material was dissolved in ethanol, cooled to 0°C
with stirring and treated with sodium borohydride
(15.13 g, 400.0 mmol) portionwise over 10 min. The
reaction mixture was slowly warmed to room tempera-
ture (20 min) and stirred for a further 90 min at this
temperature. After cooling to 0°C, concentrated hydro-
chloric acid (ꢀ20 mL) was cautiously added to quench
the reaction. Filtration of the precipitated salts through
Celite® and concentration of the resultant liquor in
vacuo afforded a colourless oil. Purification of this
material by silica gel chromatography [ethyl acetate/
methanol (4:1)] afforded the title compound 6 as
colourless crystals (31.2 g, 68%); mp 84–86°C; (lit.11 mp
66–68°C); [h]D22 +31.8 (c 5.0, EtOH); lit.11 [h]2D0 +29.5 (c
5, EtOH); lH (lit.11) 7.40 (1H br s, NH
OH), 3.84–3.76 (1H, m, CHN), 3.69–3.65 (1H, m,
CH2OH), 3.48–3.42 (1H, m, CH2OH), 2.44–2.26 (2H,
m, CH2CO), 2.22–2.10 (1H, m, CH2CH2CO), 1.84–1.73
(1H, m, CH2CH2CO).
6 ), 4.35 (1H, br s,
1
form (lH 7.27 and lC 77.0) unless otherwise stated. H
6
6
NMR spectra were run on a Bruker WH 300 unless
otherwise stated. 13C NMR were obtained with DEPT
editing or assigned by analogy with spectra so recorded.
All chemical shifts are given in parts per million relative
to tetramethylsilane (lH 0.00) and coupling constants
(J) are given in hertz. Mass spectra were obtained in
the Dyson Perrins analytical department using chemical
ionisation (CI) or electronic ionisation (EI) on a VG
MASSLAB VG 20-250 or on a Open Linx Micromass
Platform 1 using APCI+ or APCI−. High resolution
mass spectra were recorded using chemical ionisation
(CI) on a VG-AutoSpec Instrument. Flash chromatog-
raphy was carried out using silica gel (Kieselgel 60).
Tetrahydrofuran was distilled from sodium benzophe-
none ketyl. Acetonitrile and dichloromethane were
heated at reflux for 1 h over calcium hydride prior to
distillation. Methanol was distilled from glass. Pet.
6
6
6
6
6
4.2. (5S)-1-Aza-2,2-dimethyl-3-oxa-8-oxo-bicyclo[3,3,0]-
octane 7
To a stirred suspension of alcohol 6 (23.12 g, 200.8
mmol) and PTSA (0.180 g, 0.95 mmol) in toluene (500
mL) at room temperature was added 2,2-
dimethoxypropane (70 mL, 569.0 mmol) in one por-
tion. The reaction mixture was heated under reflux for
2 h before the boiling fraction between 65 and 92°C
was removed by distillation. A further portion of 2,2-
dimethoxypropane (70 mL, 569.0 mmol) was added and
the reaction mixture was heated under reflux for an

S. G. Da6ies et al. / Tetrahedron: Asymmetry 13 (2002) 647–658
651
additional 2 h. On cooling, the reaction mixture was
concentrated in vacuo to afford a pale yellow solid.
Dissolution of this crude product in diethyl ether (300
mL) and subsequent decantation of the upper layer
effectively removed the residual PTSA impurity. The
ethereal portion was concentrated in vacuo to afford
the title compound 7 as fine colourless needles (29.60
g, 95%); mp 38°C; wmax (CH2Cl2)/cm−1 1690; [h]D25
+114.7 (c 1.0 in CHCl3); (found: C, 61.55; H, 8.75; N,
8.77. C8H13NO2 requires C, 61.91; H, 8.33; N, 9.03%);
PTSA (0.133 g, 0.70 mmol) in one portion and the
reaction mixture was heated at reflux for 4 h. On
cooling, the volatiles were removed in vacuo to afford
essentially pure title compound 9 as colourless crystals.
A small quantity of this material was recrystallised
from diethyl ether/pentane for analysis (10.11 g, ꢀ
100%); mp 48–49°C; wmax (CH2Cl2)/cm−1 1685 and
3333; [h]2D3 +82.6 (c 1.00, CHCl3); (found: C, 58.89; H,
8.91; N, 9.71. C7H13NO2 requires C, 58.72; H, 9.15; N,
9.70%); lH 7.46 (1H, br s, NH
3.80–3.71 (1H, m, CHN), 3.66 (1H, dd, J 11.5 and 2.9,
CH2O), 3.42 (1H, dd, J 11.5 and 2.9, CH2O), 1.95
(1H, dd, J 11.5 and 2.9, CH2CH), 1.54 (1H, dd, J 11.5
and 2.9, CH2CH), 1.16 (3H, s, CH3), 1.15 (3H, s,
CH3); lC (CDCl3, 50 MHz) 24.89 (CH3), 25.01 (CH3),
6 ), 4.14 (1H, br s, OH6 ),
lH 4.30–4.20 (1H, m, CH
5.6, CH2O), 3.44 (1H, t, J 8.9, CH2
16.6, 12.2 and 8.5, CH2CO), 2.52 (1H, ddd, J 16.5, 9.1
and 0.9, CH2CO), 2.21–2.17 (1H, m, CH2CHN), 1.82–
1.68 (1H, m, CH2CHN), 1.66 (3H, s, CH3), 1.46 (3H,
s, CH3); lC (CDCl3; 50 MHz) 23.51 (CH3), 24.06
6
N), 4.07 (1H, dd, J 8.1 and
6
6
6
O), 2.80 (1H, ddd,
6
6
6
6
6
6
6
6
6
6
6
6
38.20 (CH2), 40.49 (C), 53.46 (CH), 65.11 (CH2), and
(CH2), 26.57 (CH3), 36.96 (CH2), 61.45 (CH), 69.76
(CH2), 91.12 (C), and 171.59 (CO); m/z (CI+, NH3)
156 (M++1).
183.89 (CO); m/z (CI+, NH3) 144 (M++1).
4.5. (5S)-O-p-Toluenesulfynylmethyl-3,3-dimethyl-5-
pyrrolidin-2-one 10
4.3. (5S)-1-Aza-2,2-dimethyl-7,7-dimethyl-3-oxa-8-oxo-
bicyclo[3,3,0]octane 8
To a stirred solution of alcohol 8 (10.06 g, 70.3 mmol)
and p-toluenesulfonyl chloride (21.46 g, 112.6 mmol)
in dichloromethane (120 mL) at room temperature,
was added freshly distilled triethylamine (60 mL) in
one portion. The reaction mixture was stirred at room
temperature for 4 h before the volatiles were removed
in vacuo to afford a brown solid which was subse-
quently dissolved in dichloromethane (200 mL). This
solution was washed with aqueous hydrochloric acid
(1 M, 2×100 mL) and then brine (100 mL), dried
(magnesium sulphate), filtered and concentrated in
vacuo to afford a pale brown solid. A single recrys-
tallisation of this material from dichloromethane/pet.
ether afforded the title compound 10 as off-white crys-
tals (17.72 g, 85%); mp 116–117°C; wmax (CH2Cl2):
1713 cm−1; [h]D23 +21.6 (c 0.50, CHCl3); (found: C,
56.39; H, 6.66; N, 4.56. C14H19SNO4 requires C, 56.55;
H, 6.44; N, 4.71%); lH 7.79 (2H, d, J 8.2, Ar), 7.37
To a stirred solution of acetonide 6 (8.60 g, 55.5
mmol) in THF (200 mL) at −78°C was added a chilled
(ꢀ0°C) solution of LDA (66.5 mmol) in THF (100
mL) via cannula. Stirring was maintained at this tem-
perature for a further 45 min before neat methyl
iodide (4.15 mL, 66.6 mmol) was added slowly via
syringe. On warming to room temperature (30 min)
and rapid cooling to −78°C, a second chilled (ꢀ0°C)
portion of LDA (66.5 mmol) in THF (100 mL) was
added via cannula to the reaction mixture, which was
maintained at this temperature for a further 60 min. A
second quantity of methyl iodide (4.15 mL, 66.6
mmol) was then added and the reaction mixture was
slowly warmed to room temperature overnight.
Removal of volatiles in vacuo afforded a crude yellow
oil which was partitioned between dichloromethane
(200 mL) and water (150 mL) and further extracted
with dichloromethane (2×150 mL). The combined
organic portions were washed with brine (80 mL),
dried (magnesium sulphate), filtered and concentrated
in vacuo to afford a crude yellow solid. Recrystallisa-
tion of this material from diethyl ether/pentane
afforded the title compound 8 as colourless flaky
plates (8.74 g, 86%); mp 82–83°C; wmax (CH2Cl2)/cm−1
1686; [h]2D5 +75.3 (c 1.00, CHCl3); (found: C, 65.47; H,
9.44; N, 7.32. C10H17NO2 requires C, 65.54; H, 9.35;
(2H, d, J 8.1, Ar), 5.90 (1H, br s, NH
J 9.1 and 2.6, CH2O), 3.92–3.79 (2H, m, CH2
CHN), 2.46 (3H, s, ArCH3), 2.04 (1H, dd, J 12.8 and
6.7, CH2CH), 1.54 (1H, dd, J 12.9 and 7.4, CH2CH),
1.15 (3H, s, CH3), 1.15 (3H, s, CH3); lC (CDCl3, 50
MHz): 21.00 (aryl-CH3), 25.05 (C(CH3)2), 38.16 (CH2),
6
), 4.08 (1H, dd,
6
6
O and
6
6
6
6
6
6
6
39.90 (C(CH3)2), 49.44 (CH), 72.30 (CH2), 128.12
(CH), 130.24 (CH), 132.55 (C), 143.56 (C), and 182.83
(CO); m/z (CI+, NH3): 298 (M++1).
N, 7.64%); lH 4.20–4.06 (2H, m, CH
3.37 (1H, t, J 8.3, CH2O), 2.00 (1H, dd, J 12.1 and
5.8, CH2CH), 1.63 (3H, s, CH3), 1.56 (1H, dd, J 12.0
and 8.5, CH2CH), 1.44 (3H, s, CH3), 1.21 (3H, s,
CH3), 1.16 (3H, s, CH3); lC (CDCl3; 50 MHz) 23.64
6 N and CH6 2O),
6
6
6
6
6
4.6. (5S)-5-Bromomethyl-3,3-dimethyl-pyrrolidin-2-one
11
6
6
(CH3), 24.18 (CH3), 25.00 (CH3), 26.54 (CH3), 39.62
(CH2), 47.59 (C), 57.30 (CH), 70.15 (CH2), 91.15 (C),
and 176.43 (CO); m/z (CI+, NH3) 184 (M++1).
A solution of tosylate 10 (17.72 g, 59.6 mmol) and
lithium bromide (15.54 g, 178.9 mmol) in acetone
(120 mL) was heated at reflux for 6 h during which
time the formation of a fine precipitate was observed.
On cooling, the volatiles were removed in vacuo and
the residual material was partitioned between
dichloromethane (80 mL) and distilled water (80 mL)
and further extracted with dichloromethane (2×80
4.4. (5S)-3,3-Dimethyl-5-hydroxymethyl-pyrrolidin-2-
one 9
To a stirred solution of 8 (12.86 g, 70.2 mmol) in
methanol (200 mL) at room temperature was added

652
S. G. Da6ies et al. / Tetrahedron: Asymmetry 13 (2002) 647–658
mL). The combined organic portions were washed with
brine (50 mL), dried (magnesium sulphate), filtered and
concentrated in vacuo to yield a crude yellow solid. A
single recrystallisation of this material from ethyl ace-
tate and pet. ether afforded the title compound 11 as
colourless crystals (11.62 g, 95%); mp 123–124°C; [h]D23
+25.4 (c 1.00, CHCl3); (found: C, 41.02; H, 5.60; N,
6.75. C7H12NOBr requires C, 40.80; H, 5.87; N, 6.80%);
wmax (KBr disk)/cm−1 1700s (CꢁO), 1662s; lH 6.27 (1H,
4.9. (5S)-(+)-3,3-Dimethyl-5-trityloxymethyl-pyrrolidin-
2-one 2
The alcohol 9 (0.818 g, 5.72 mmol) was dissolved in
dichloromethane (15 mL). To this solution were added
4-dimethylamino pyridine (DMAP) (5 mg), triethyl-
amine (1.5 mL, 11.44 mmol), and trityl chloride (1.76 g,
6.29 mmol). The mixture was stirred at room tempera-
ture overnight before being added to a saturated
aqueous sodium bicarbonate solution. The mixture was
repeatedly extracted with dichloromethane and the
combined organic extracts were washed with brine and
dried over MgSO4. After concentration in vacuo, the
residue was purified by column chromatography using
50% ethyl acetate/40–60 pet. ether as eluent giving 2 as
a white solid (1.63 g, 74%), recrystallised in ethyl ace-
tate; mp 187°C; wmax (CH2Cl2)/cm−1 1702; [h]D24 +10.6 (c
0.5 in CHCl3); (found: C, 81.32; H, 7.00; N, 3.59.
C26H22NO2 requires C, 81.01; H, 7.06; N, 3.63%); lH
(CDCl3; 300 MHz) 1.12 (3H, s, gem CH3), 1.18 (3H, s,
br s, NH
6
), 3.94–3.85 (1H, m, CH6 N), 3.43 (1H, dd, J
10.1 and 4.9, CH2
CH2Br), 2.16 (1H, dd, J 12.9 and 7.1, CH2CH), 1.66
(1H, dd, J 13.0 and 7.7, CH2CH), 1.21 (3H, s, CH3),
6
Br), 3.31 (1H, dd, J 10.0 and 7.6,
1.18 (3H, s, CH3); lC 183.1 (C
(CH2Br), 40.8 [(CH3)2C], 36.5 (C
[(CH3)2C], 25.2 [(C6
H3)2C]; m/z 208 (89%, MH+), 206
6
O), 51.9 (C
6 HN), 41.6
6
6
6
H2CH), 25.3
6
(92%, MH+), 167 (100%), 158 (13%), 144 (42%), 126
(74%, MH+−Br).
4.7. (5R)-3,3,5-Trimethyl-pyrrolidin-2-one 3
gem CH3), 1.45 [1H, dd,
(CH3)2CCH2], 1.94 [1H, dd, J 7.0 and 12.7 Hz,
(CH3)2CCH2], 2.9 (1H, t, J 9.0 Hz, OCH2), 3.23 (1H,
dd, J 3.4 and 9.2 Hz, OCH2), 3.79–3.85 (1H, m, NCH),
J 8.3 and 12.7 Hz,
To a stirred solution of bromide 11 (11.626 g, 56.445
mmol) and palladium on charcoal (2.32 g, 20%) in a
degassed mixture of ethanol (50 mL) and methanol (50
mL) under a nitrogen atmosphere was added triethyl-
amine (6.84 g, 67.72 mmol) in one portion. The reac-
tion vessel was fitted with a balloon of hydrogen and
the solution stirred vigorously for 24 h. Filtration of the
reaction mixture through Celite® and subsequent
removal of volatiles in vacuo afforded a white crys-
talline residue. Exhaustive trituration of this material
with pet. ether/diethyl ether (9:1) afforded, after con-
centration in vacuo, a crude white solid. Further purifi-
cation of this material by sublimation (70°C, 0.1
mmHg) afforded the title compound 3 (6.523 g, 91%) as
white needles.
6
6
6
6
6
5.86 (1H, br-s, NH), and 7.12–7.49 (15H, m, aryl); lC
(CDCl3, 50 MHz) 24.98 (CH3), 25.20 (CH3), 38.91
(CH2), 39.98 (C), 50.69 (CH), 67.60 (CH2), 86.85 (C),
127.38 (CH), 128.12 (CH), 128.82 (CH), 143.88 (C),
and 182.79 (CO); m/z (CI+, NH3) 386 (M++1).
4.10. (5R)-(−)-5-Ethyl-3,3-dimethyl-pyrrolidin-2-one 4
A solution of Me2CuLi in THF was prepared at −20°C
by slow addition of a methyl lithium solution (1.4 M in
hexane, 25.4 mL, 35.4 mmol) to copper iodide (3.36 g,
17.7 mmol) in THF (20 mL). To this solution was then
added a solution of 10 (1.75 g, 5.9 mmol) in THF (20
mL). After 45 min at this temperature, the mixture was
stirred at 0°C overnight, and quenched by addition of a
saturated aqueous ammonium chloride solution (50
mL). The product was extracted with diethyl ether
(3×40 mL) and the combined extracts were washed with
brine and dried (MgSO4). Concentration in vacuo left a
brown solid which was filtered on a small column of
silica. Elution with EtOAc furnished 4 as a white solid
(0.756 g, 91%); wmax. (CH2Cl2): 1698 cm−1; [h]D22 −28 (c
2.0, CHCl3); (found: C, 67.97; H, 11.28; N, 9.46.
C8H15NO requires C, 68.04; H, 10.71; N, 9.92%); lH
4.8. (5S)-(+)-5-tert-Butyldimethylsiloxymethyl-3,3-
dimethyl-pyrrolidin-2-one 1
To a solution of the alcohol 9 (3.12 g, 21.78 mmol) in
DMF (22 mL) were added imidazole (1.56 g, 22.9
mmol) and tert-butyldimethylsilylchloride (3.43 g, 22.9
mmol). The reaction mixture was stirred at room tem-
perature overnight, and was then added to water and
extracted with diethyl ether. The combined organic
extracts were washed with brine and dried over MgSO4.
The solvent was removed under reduced pressure and
the residue dried in vacuo. Purification by column
chromatography using 50% ethyl acetate/pet. ether as
eluent gave 1 as a white solid (4.7 g, 84%), recrystallised
in acetonitrile; mp 94°C; wmax (CH2Cl2)/cm−1 1701; [h]D22
+46.8 (c 1.0 in CHCl3); (found: C, 60.57; H, 10.90; N,
5.18. C13H27NO2Si requires C, 60.65; H, 10.57; N,
5.44%); lH (CDCl3; 300 MHz) 0.06 [6H, s, Si(CH3)2],
0.90 [9H, s, SiC(CH3)3], 1.20 [6H, s, C(CH3)2], 1.52 [1H,
(CDCl3, 300 MHz): 0.92 (3H, t, J 7.4, CH2CH3
(3H, s, (CH3)2), 1.18 (3H, s, (CH3)2) 1.53 (3H, m,
CH2CH3+1H, CH2CH), 2.06 (1H, dd, J 6.7 and 12.6,
CH
6 ), 1.16
6
6
6
2CH), 3.50 (1H, m, CH6 CH2CH3), 6.01 (1H, br-s,
NH); m/z (CI+, NH3): 142 (M++1).
4.11. General procedure for formation of N-acylated
pyrrolidinone. 5-(tert-Butyl-dimethyl-siloxymethyl)-1-
(2,2-dimethyl-propionyl)-3,3-dimethyl-pyrrolidin-2-one
12
dd, J 7.8 and 12.5 Hz, (CH3)2CCH2
and 12.5 Hz, (CH3)2CCH2], 3.38 (1H, dd, J 8.6 and 9.8
Hz, OCH2), 3.63–3.75 (2H, m, OCH2 and NCH), and
6 ], 1.98 [1H, dd, J 6.9
6
6
6
6
5.82 (1H, s, NH); lC (CDCl3; 50 MHz) −5.64 (CH3),
18.06 (C) 25.13 (CH3), 25.31 (CH3), 25.70 (CH3), 38.34
(CH2), 52.44 (CH), 67.24 (CH2), and 182.68 (CO); m/z
(CI+, NH3) 258 (M++1).
The auxiliary 1 (0.050 g, 0.195 mmol) was dissolved in
THF (3 cm3) and this solution was cooled to −78°C.
n-BuLi (1.4 M, 0.14 cm3, 0.195 mmol) was then added
dropwise and the mixture left to stir at −78°C for 1 h.

S. G. Da6ies et al. / Tetrahedron: Asymmetry 13 (2002) 647–658
653
Pivaloyl chloride (0.036 cm3, 0.234 mmol) was added
and the solution was allowed to reach room tempera-
ture. The reaction mixture was then poured onto water
and the product was extracted with diethyl ether. The
combined extracts were washed with brine and dried
over MgSO4. After concentration in vacuo the residue
was purified by column chromatography on silica gel.
Elution with EtOAc/pet. ether furnished the desired
compound 12 (0.046 g, 70%) as a colourless oil; [h]D27
−41.0 (c 0.8 in CHCl3); wmax (thin film)/cm−1: 1687
(CCO) and 1739 (OCO); lH (200 MHz, CDCl3) 0.00
[h]2D1 −3.0 (c 0.4, CHCl3); (found: C, 69.29; H, 10.50; N,
6.59. C13H23NO2 requires C, 69.29; H, 10.28; N,
6.21%); lH (CDCl3, 300 MHz): 0.85 (3H, t, J 7.4), 1.15
(3H, s), 1.24 (3H, s), 1.32 (9H, s), 1.38 (1H, m), 1.60
(1H, dd, J 7.8 and 12.9), 1.83 (1H, m), 2.02 (2H, d, J
7.6 and 12.9), 4.10 (1H, m); m/z (CI+, NH3): 228, 226
(M++1), 142.
4.15. General experimental procedure for cleavage
using LiOH
(3H, s, SiCH
Si(CH3)3], 1.16 [3H, s, C(CH3 3
1.31 [9H, s, COC(CH3)3], 1.88 and 1.98 (2H, AB of
ABX, J 7.0, 8.3, and 12.8, CCH2), 3.52 and 3.87 (2H,
AB of ABX, J 2.3, 4.2, and 10.4, OCH2), 4.18–4.28
(1H, m, CH); lC (50 MHz, CDCl3) −5.74 (CH3), 18.13
6
3), 0.02 (3H, s, SiCH3
6
), 0.86 [9H, s,
The appropriate N-acyl substrate was treated at 0°C
with 2.3 equiv. of lithium hydroxide in a 3:1 mixture of
tetrahydrofuran and water. The reaction was monitored
by thin layer chromatography until all the starting
material was consumed. A saturated aqueous sodium
bicarbonate solution was then added and the crystalline
homochiral auxiliary was recovered by extraction with
diethyl ether. Acidification of the aqueous layer to pH
1, and extraction with ethyl acetate furnished the
desired crude acid which was purified by column chro-
matography on silica gel (oil) or by recrystallisation
(solid).
6
6
) ], 1.24 [3H, s, C(CH3 3
6
) ],
6
6
6
6
(C), 25.50 (CH3), 25.72 (CH3), 26.36 (CH3), 26.65
(CH3), 34.75 (CH2), 41.50 (C), 42.16 (C), 55.95 (CH),
62.08 (CH2), 180.28 (CO), 182.76 (CO); m/z (CI+, NH3)
342 (MH+).
4.12. (5S)-1-(2,2-Dimethylpropionyl)-3,3-dimethyl-5-
trityloxymethyl-pyrrolidin-2-one 13
4.16. (5S)-(−)-5-tert-Butyldimethylsiloxymethyl-3,3-
dimethyl-1-(propionyl)-pyrrolidin-2-one 16
Reaction of the auxiliary 2 (0.25 g, 0.65 mmol) as a
solution in THF (3 mL) with n-BuLi (0.46 mL, 0.65
mmol) and pivaloyl chloride (0.12 mL, 0.98 mmol)
furnished the title compound 13 (0.263 g, 86%); (found:
C, 79.09; H, 7.69; 2.78. C31H35NO3 requires C, 79.29;
H, 7.51; N, 2.98%); [h]2D7 −44.0 (c 0.5 in CHCl3); lH
Reaction of the auxiliary 1 (3.00 g, 11.67 mmol) in
solution in THF (50 mL) at 0°C with n-BuLi (1.49 M,
7.83 mL, 12.84 mmol) and propionyl chloride (1.01 mL,
12.84 mmol) with work-up, by addition of water, and
extraction with diethyl ether and column chromatogra-
phy on silica furnished the N-acyl derivative 16 as a
colourless oil (3.07 g, 84%); wmax (CH2Cl2)/cm−1 1694
and 1734; [h]2D4 −78.6 (c 0.5 in CHCl3); (found: C, 61.48;
H, 10.26; N, 4.55. C16H31NO2 requires C, 61.30; H,
9.97; N, 4.47%); lH (CDCl3; 200 MHz) −0.03 (3H, s,
(200 MHz, CDCl3) 1.20 (3H, s, CH3
CH3), 1.35 (9H, s, C(CH3)3), 2.02 and 1.96 (2H, AB of
ABX, J 6.6, 8.7 and 13.0, CCH2), 3.23 and 3.44 (2H,
AB of ABX, J 3.2, 5.1 and 9.4, OCH
m, CH), 7.22–7.47 (15H, m, arylH
6 ), 1.24 (3H, s,
6
6
6
6
2), 4.34–4.44 (1H,
6 ); lC (50 MHz,
6
CDCl3) 25.6, 25.9, 26.4, 26.7, 35.3, 41.7, 42.1, 54.7,
62.8, 86.7, 127.3, 128.0, 128.9, 144.0, 180.2, 182.2.
SiCH
1.10 (3H, t, J 7.3 Hz, CH
(3H, s, CCH3), 1.84–2.04 [2H, m, (CH3)2CCH2
2.92 (2H, m, COCH2), 3.63 (1H, dd, J 2.4 and 10.1 Hz,
OCH2), 3.95 (1H, dd, J 4.8 and 10.1 Hz, OCH2),
4.16–4.27 (1H, m, NCH); lC (CDCl3; 50 MHz) −5.67
6
3), −0.08 (3H, s, SiCH3
3), 1.16 (3H, s, CCH3
], 2.81–
6
), 0.83 [9H, s, SiC(CH3 3
6 ) ],
6
6
), 1.24
4.13. (5R)-(+)-1-(2%,2%-Dimethyl-1%-oxopropyl)-5-methyl-
3,3-dimethyl-pyrrolidin-2-one 14
6
6
6
6
6
Reaction of the auxiliary 3 (0.20 g, 1.57 mmol) in
solution in THF (20 mL) with n-BuLi (1.6 M, 1.08 mL,
1.73 mmol) and pivaloyl chloride (0.24 mL, 1.90 mmol)
furnished the N-acyl derivative 14 as a colourless oil
(0.293 g, 88%); wmax. (CH2Cl2): 1687 and 1731 cm−1;
[h]2D3 +9.0 (c 0.5, CHCl3); (found: C, 68.40; H, 10.61; N,
6.42. C12H21NO2 requires C, 68.21; H, 10.61; N,
6
(CH3), 8.16 (CH3), 18.06 (C), 25.45 (CH3), 25.64 (CH3),
27.31 (CH3), 30.92 (CH2), 34.58 (CH2), 41.54 (C), 54.63
(CH), 62.40 (CH2), 176.14 (CO), 181.80 (CO); m/z (CI+,
NH3) 314 (M++1).
4.17. (5S)-(−)-5-(tert-Butyl-dimethylsiloxymethyl)-3,3-
dimethyl-1-(3-phenyl-propionyl)-pyrrolidin-2-one 17
6.63%); lH (CDCl3, 300 MHz): 1.12 (3H, s, (CH3 2
6
) ),
t
1.22 (3H, s, (CH3 2
6
) ), 1.29 (9H, s, Bu), 1.53 (1H, dd, J
2CH), 2.08 (1H, dd, J 8.0 and 13.0,
8.1 and 13.0, CH
6
Reaction of the auxiliary 1 (0.30 g, 1.17 mmol) in
solution in THF (16 mL) at 0°C with n-BuLi (1.49 M,
0.78 mL, 1.17 mmol) and hydrocinnamoyl chloride
(0.17 mL, 1.17 mmol) with work-up, by addition of
water, and extraction with diethyl ether and column
chromatography on silica furnished the N-acyl deriva-
tive 17 as a colourless oil (0.276 g, 66%); wmax (CH2Cl2)/
cm−1 1693 and 1733; [h]D25 −68.5 (c 0.2 in CHCl3); lH
CH6 2
CH), 4.22 (1H, m, NCH); m/z (CI+, NH3): 212
(M++1), 156, 128.
4.14. (5R)-(−)-1-(2%,2%-Dimethyl-1%-oxopropyl)-5-ethyl-
3,3-dimethyl-pyrrolidin-2-one 15
Reaction of the auxiliary 4 (0.230 g, 1.63 mmol) in
solution in THF (15 mL) with n-BuLi (1.6 M, 1.12 mL,
1.79 mmol) and pivaloyl chloride (0.24 mL, 1.95 mmol)
furnished the N-acyl derivative 15 as a colourless oil
(0.290 g, 79%); wmax. (CH2Cl2): 1729, and 1688 cm−1;
(CDCl3; 200 MHz) 0.01 (3H, s, SiCH3
SiCH3), 0.87 [9H, s, SiC(CH3)3], 1.19 (3H, s, gem CH3
1.28 (3H, s, gem CH3), 1.92–2.00 [2H, m, (CH3)2CCH2
2.96 (2H, t, J 7.81 Hz, COCH2), 3.20–3.29 (2H, m,
6
), 0.03 (3H, s,
),
],
6
6
6
6
6

654
S. G. Da6ies et al. / Tetrahedron: Asymmetry 13 (2002) 647–658
CH2
(1H, dd, J 4.8 and 10.1 Hz, OCH2
NCH), 7.15–7.33 (5H, m, aryl); lC (CDCl3; 50 MHz)
−5.69 (CH3), 18.13 (C), 25.52 (CH3), 25.74 (CH3), 27.39
(CH3), 30.36 (CH2), 34.59 (CH2), 38.95 (CH2), 41.61
(C), 54.71 (CH), 62.46 (CH2), 126.24 (CH), 128.58
(CH), 128.73 (CH), 141.15 (C), 174.49 (CO), 181.88
(CO); m/z (CI+, NH3) 390 (M++1).
6
Ph), 3.66 (1H, dd, J 1.2 and 10.1 Hz, OCH2
6
), 3.97
n-BuLi as a 1.6 M solution in hexane (3.84 mL, 6.15
mmol) was then added dropwise and the mixture left to
stir at −78°C for 1 h. Freshly distilled propionyl chlo-
ride (0.58 mL, 6.7 mmol) was added and the solution
was allowed to reach room temperature. The reaction
mixture was then poured onto water and the product
was extracted with diethyl ether. The combined extracts
were washed with brine and dried over MgSO4. After
concentration in vacuo the residue was purified by
column chromatography on silica gel. Elution with
EtOAc/pet. ether furnished the desired compound 20 as
a colourless oil (0.92 g, 90%); wmax. (CH2Cl2): 1696 and
1731 cm−1; [h]D23 −101 (c 0.5, CHCl3); (found: C, 65.75;
H, 9.04; N, 7.95. C10H17NO2 requires C, 65.54; H, 9.35;
N, 7.64%); lH (CDCl3, 300 MHz): 1.08 (3H, t, J 7.3,
6
), 4.21–4.30 (1H, m,
6
4.18. (5S)-(−)-3,3-Dimethyl-5-triphenylmethoxymethyl-
1-propionyl-pyrrolidin-2-one 18
Reaction of the auxiliary 2 (0.30 g, 0.78 mmol) as a
solution in THF (9 mL) at −78°C with n-BuLi (1.6 M,
0.54 mL, 0.86 mmol) and propionyl chloride (0.101 mL,
1.17 mmol) after work-up, with addition of pH 7
phosphate buffer solution, and extraction with
dichloromethane and column chromatography on alu-
mina furnished the derivative 18 as a crystalline solid
(0.289 g, 84%); mp 110°C; wmax (CDCl3)/cm−1 1697 and
1732; [h]2D5 −77.7 (c 0.09 in CHCl3) (found: C, 79.10; H,
7.34; N, 3.18. C28H23NO3 requires C, 78.88; H, 7.08; N,
3.17%); lH (CDCl3; 200 MHz) 1.12 (3H, t, J 7.3 Hz,
CH2CH3
1.34 (3H, d, J 6.3, CHCH3
13.0, CH2CH), 2.08 (1H, dd, J 9.6 and 13.0, CH2
2.86 (2H, m, CH2CH3), 4.20 (1H, m, CHCH3); m/z
(CI+, NH3): 184 (M++1).
6
), 1.30 (3H, s, (CH3 2
), 1.52 (1H, dd, J 5.4 and
CH),
6 ) ), 1.24 (3H, s, (CH6 3)2)
6
6
6
6
6
4.21. (5R)-(−)-1-(1%-Oxopropyl-3%-phenyl)-5-methyl-3,3-
dimethyl-pyrrolidin-2-one 21
CH2CH3
CH3), 1.95–1.99 [2H, m, (CH3)2CCH2
m, COCH2), 3.29 (1H, J 6.5 and 9.1 Hz, OCH2
(1H, J 3.4 and 9.1 Hz, OCH2), 4.29–4.37 (1H, m,
NCH), and 7.08–7.50 (15H, m, arylH); lC (CDCl3; 50
6
), 1.14 (3H, s, gem CH3
6
), 1.17 (3H, s, gem
], 2.84–2.97 (2H,
), 3.43
6
6
6
6
Reaction of the auxiliary 3 (0.40 g, 3.15 mmol) in
solution in THF (30 mL) with n-BuLi (1.6 M, 2.17 mL,
3.46 mmol) and hydrocinnamoyl chloride (0.56 mL,
3.78 mmol) furnished the N-acyl derivative 21 as a
colourless oil (0.743 g, 91%); wmax. (CH2Cl2): 1693 and
1731 cm−1; [h]D23 −64 (c 0.5, CHCl3); (found: C, 74.41;
H, 8.25; N, 4.95. C16H21NO2 requires C, 74.09; H, 8.16;
N, 5.40%); lH (CDCl3, 300 MHz): 1.18 (3H, s), 1.20
6
6
6
MHz) 8.36 (CH3), 25.75 (CH3), 27.28 (CH3), 30.80
(CH2), 35.24 (CH2), 41.70 (C), 53.27 (CH), 63.26 (CH2),
86.76 (C), 127.10 (CH), 127.83 (CH), 128.68 (CH),
143.89 (C), 175.60 (CO), and 181.30 (CO); m/z (CI+,
NH3) 442 (M++1).
(3H, s), 1.35 (3H, d, J 6.8, CH3
and 13.1, CH2CH), 2.08 (1H, dd, J 7.9 and 13.1), 2.95
(2H, t, J 8.0), 3.24 (2H, t, J 8.0, CH2CH2), 4.24 (1H, m,
NCH), 7.25 (5H, m, arylH
); m/z (CI+, NH3): 260
(M++1), 128.
6 CH), 1.54 (1H, dd, J 5.3
4.19. (5S)-(−)-3,3-Dimethyl-5-triphenylmethoxymethyl-
1-(1%-phenylpropionyl)pyrrolidin-2-one 19
6
6
6
6
Reaction of the auxiliary 2 (0.100 g, 0.26 mmol) as a
solution in THF (3 mL) at −78°C with n-BuLi (1.6 M,
0.18 mL, 0.29 mmol) and hydrocinnamoyl chloride
(0.058 mL, 0.39 mmol), after work-up with addition of
a pH 7 phosphate buffer solution and extraction with
dichloromethane and column chromatography on alu-
mina furnished the derivative 19 as a white solid (0.108
g, 80%); mp 40°C; wmax (CH2Cl2)/cm−1 1695 and 1733;
[h]2D2.5 −43.3 (c 0.15 in CHCl3); (found: C, 81.31; H,
6.50; N, 2.35. C35H35NO3 requires C, 81.21; H, 6.81; N,
4.22. (5R)-(−)-1-(1%-Oxopropyl)-5-ethyl-3,3-dimethyl-
pyrrolidin-2-one 22
Reaction of the auxiliary 4 (0.756 g, 5.36 mmol) in
solution in THF (15 mL) with n-BuLi (1.6 M, 3.69 mL,
5.90 mmol) and propionyl chloride (0.56 mL, 6.43
mmol) furnished the N-acyl derivative 22 as a colour-
less oil (0.924 g, 87%); wmax. (CH2Cl2): 1732, and 1696
cm−1; [h]D21 −121.2 (c 0.8, CHCl3); (found: C, 67.25; H,
9.91; N, 6.67. C11H19NO2 requires C, 66.97; H, 9.71; N,
7.10%); lH (CDCl3, 300 MHz): 0.87 (3H, t, J 7.5), 1.13
(3H, t, J 7.4), 1.17 (3H, s), 1.26 (3H, s), 1.42 (1H, m),
1.65 (1H, dd, J 5.4 and 13.2), 2.01 (2H, d, J 8.7 and
13.2), 2.06 (1H, m), 2.90 (2H, m), 4.05 (1H, m); m/z
(CI+, NH3): 198 (M++1).
2.71%); lH (CDCl3; 200 MHz) 1.21 (3H, s, gem CH3
1.22 (3H, s, gem CH3), 2.01–2.05 [2H, m, (CH3)2CCH2
3.01 (2H, t, J 7.7 Hz, CH2CH2Ph), 3.28–3.55 (4H, m,
OCH2+CH2CH2Ph), 4.37–4.47 (1H, m, NCH), and
7.21–7.52 (20H, m, arylH); lC (CDCl3; 50 MHz) 25.66
6
),
],
6
6
6
6
6
6
6
(CH3), 27.16 (CH3), 30.36 (CH2), 34.98 (CH2), 38.84
(CH2), 41.63 (C), 53.22 (CH), 63.05 (CH2), 86.76 (C),
126.25 (CH), 127.31 (CH), 128.05 (CH), 128.59 (CH),
128.82 (CH), 141.08 (C) 144.00 (C), 174.26 (CO), and
181.70 (CO); m/z (CI+, NH3) 519 (M++1).
4.23. (5R)-(−)-1-(1%-Oxopropyl-3%-phenyl)-5-ethyl-3,3-
dimethyl-pyrrolidin-2-one 23
4.20. (5R)-(−)-1-(1%-Oxopropyl)-5-methyl-3,3-dimethyl-
pyrrolidin-2-one 20
Reaction of the auxiliary 4 (0.40 g, 2.83 mmol) in
solution in THF (15 mL) with n-BuLi (1.5 M, 2.08 mL,
3.12 mmol) and hydrocinnamyl chloride (0.51 mL, 3.40
The auxiliary 3 (0.710 g, 5.6 mmol) was dissolved in
THF (25 mL) and this solution was cooled to −78°C.

S. G. Da6ies et al. / Tetrahedron: Asymmetry 13 (2002) 647–658
655
mmol) furnished the N-acyl derivative 23 as a colour-
4.26. (5S,2%R)-5-tert-Butyldimethylsiloxymethyl-3,3-
less oil (0.659 g, 85%); wmax. (CH2Cl2): 1732, and 1694
cm−1; [h]D21 −71.2 (c 0.53, CHCl3); (found: C, 74.58; H,
8.41. C17H23NO2 requires C, 74.69; H, 8.48%); lH
(CDCl3, 300 MHz): 0.87 (3H, t, J 7.5), 1.17 (3H, s),
1.26 (3H, s), 1.41 (1H, m), 1.65 (1H, dd, J 5.4 and
13.2), 2.00 (2H, d, J 8.6 and 13.1), 2.96 (2H, t, J 7.8),
3.23 (2H, t, J 7.9), 4.06 (1H, m), 7.22 (5H, m); m/z
(CI+, NH3): 274 (M++1), 142.
dimethyl-1-[(2%-methyl-1%-phenyl)propionyl]pyrrolidin-2-
one 25
To a solution of 17 (0.261 g, 0.67 mmol) in THF (4.7
mL) at 0°C was added a solution of LDA (0.5 M as a
solution in THF, 1.67 mL, 0.84 mmol). The resultant
enolate was stirred at 0°C for 1 h before quenching by
addition of methyl iodide (0.125 mL, 2.01 mmol). The
mixture was then stirred at 0°C for a further 45 min.
The reaction mixture was worked up by addition of a
pH 7 phosphate buffer solution and products extracted
repeatedly with diethyl ether. The combined organic
extracts were washed with brine and dried over MgSO4.
Concentration in vacuo and purification by column
chromatography using 10% ethyl acetate/40–60 pet.
ether as eluent furnished the N-acyl derivative 25 as a
clear oil (0.173 g, 64%) with a diastereomeric excess of
94%; wmax (CH2Cl2)/cm−1 1688 and 1732; (found: C,
68.15; H, 9.12; N, 3.16. C23H37NO3Si requires C, 68.44;
H, 9.24; N, 3.47%); lH (CDCl3; 300 MHz) 0.02 (3H, s,
4.24. General procedure for alkylation of the N-acyl
derivatives
To a solution of the N-acyl derivatives in THF cooled
to −78 or 0°C, was added a solution of the base. The
mixture was stirred at this temperature for 1 h and then
quenched by addition of the electrophile (3 equiv.). The
mixture was stirred at this temperature (reaction fol-
lowed by thin layer chromatography until complete).
The reaction mixture was poured into a saturated
aqueous ammonium chloride solution and extracted
repeatedly with diethyl ether. The combined organic
extracts were washed with brine and dried over MgSO4.
After concentration in vacuo, the residue was purified
by column chromatography giving the alkylated N-acyl
derivatives. The diastereomeric excesses were measured
by integration of the signal at lH 2.52–3.36 (PhCH2CH)
from the complementary diastereoisomers by 500 MHz
1H NMR.
SiCH3), 0.04 (3H, s, SiCH3
1.07 (3H, s, gem CH3), 1.16 (3H, d, J 6.8 Hz, CHCH3
1.27 (3H, s, gem CH3), 1.84 [1H, dd, J 9.2 and 13.1 Hz,
6
), 0.87 [9H, s, SiC(CH3 3
6 ) ],
6
6
),
6
(CH3)2CCH2
(CH3)2CCH2
PhCH2
PhCH2
3.98 (1H, dd, J 4.6 and 10.1 Hz, OCH
m, NCH and COCH), and 7.15–7.29 (5H, m, arylH
6
], 1.96 [1H, dd, J 5.4 and 13.2 Hz,
], 2.59 (1H, dd, J 7.8 and 13.3 Hz,
6
6
CH), 3.04 (1H, dd,
J 7.0 and 13.3 Hz,
6
CH), 3.63 (1H, dd, J 2.3 and 10.1 Hz, OCH2
6
),
6
2), 4.09–4.20 (2H,
6
6
6
);
4.25. (5S,2%S)-5-tert-Butyldimethylsiloxymethyl-3,3-
dimethyl-1-[(2%-methyl-1%-phenyl)propionyl]pyrrolidin-2-
one 24
lC (CDCl3; 50 MHz) −5.67 (CH3), 17.08 (CH3), 18.13
(CH3), 25.37 (CH3), 25.74 (CH3), 27.42 (CH3), 34.25
(CH2), 39.43 (CH), 40.63 (CH), 41.77 (C), 54.81 (CH),
62.62 (CH2), 126.26 (CH), 128.42 (CH), 129.33 (CH),
139.99 (C), 178.64 (CO), and 181.56 (CO); m/z (CI+,
NH3) 404 (M++1).
To a solution of 16 (0.30 g, 0.96 mmol) in THF (6 mL)
at 0°C was added a solution of LDA (0.5 M as a
solution in THF, 2.4 mL, 1.2 mmol). The resultant
enolate was stirred at 0°C for 1 h before quenching by
addition of benzyl bromide (0.340 mL, 2.88 mmol). The
mixture was then stirred at 0°C for a further 4–5 h. The
reaction mixture was poured into a saturated aqueous
ammonium chloride solution and extracted repeatedly
with diethyl ether. The combined organic extracts were
washed with brine and dried over MgSO4. Concentra-
tion in vacuo and purification by column chromatogra-
phy using 10% ethyl acetate/40–60 pet. ether as eluent
furnished the N-acyl derivative 24 as a clear oil (0.127
g, 33%) with a diastereomeric excess of 95%; wmax
(CH2Cl2)/cm−1 1692 and 1732; (found: C, 68.44; H,
9.42; N, 3.23. C23H37NO3Si requires C, 68.44; H, 9.24;
4.27. (5S,2%S)-3,3-Dimethyl-5-triphenylmethoxymethyl-
1-[(2%-methyl-1%-phenyl) propionyl]pyrrolidin-2-one 26
To a solution of 18 (0.200 g, 0.45 mmol) in THF (4.0
mL) at 0°C was added a solution of LDA (0.5 M as a
solution in THF, 1.13 mL, 0.57 mmol). The resultant
enolate was stirred at 0°C for 1 h before quenching by
addition of benzyl bromide (0.162 mL, 1.36 mmol). The
mixture was then stirred at 0°C for a further 90 min.
The reaction mixture was worked up by addition of a
pH 7 phosphate buffer solution and products extracted
repeatedly with dichloromethane. The combined
organic extracts were washed with brine and dried over
MgSO4. Concentration in vacuo and purification by
column chromatography using 10% ethyl acetate/40–60
pet. ether as eluent furnished the N-acyl derivative 26
as a white solid (0.122 g, 51%) with a diastereomeric
excess of 96%; mp 122°C; wmax (CH2Cl2)/cm−1 1694 and
1733; (found: C, 81.04; H, 6.76; N, 2.41. C36H37NO3
requires C, 81.32; H, 7.01; N, 2.63%); lH (CDCl3; 500
N, 3.47%); lH (CDCl3; 200 MHz) 0.02 (3H, s, SiCH3
0.04 (3H, s, SiCH3), 0.87 [9H, s, C(CH3)3], 1.07 (3H, d,
J 6.7 Hz, CHCH3), 1.22 (3H, s, gem CH3), 1.27 (3H, s,
gem CH3), 1.94–2.01 [2H, m, (CH3)2CCH2], 2.52 (1H,
dd, J 9.3 and 13.1 Hz, PhCH2CH), 3.12 (1H, dd, J 5.4
and 13.1 Hz, PhCH2CH), 3.64–3.67 (2H, m, OCH2
4.01–4.11 (1H, m, COCH), 4.23–4.28 (1H, m, NCH
7.19–7.29 (5H, m, arylH
6 ),
6
6
6
6
6
6
6
6
6
),
),
6
6
6
); lC (CDCl3; 50 MHz) −5.61
MHz) 1.02 (3H, s, gem CH3
CH3CH), 1.16 (3H, s, gem CH3
and 13.3 Hz, (CH3)2CCH2], 1.95 [1H, dd, J 8.9 and 13.3
Hz, (CH3)2CCH2], 2.51 (1H, dd, J 8.6 and 13.2 Hz,
OCH2), 2.97 (1H, dd, J 7.6 and 8.8 Hz, PhCH2CH),
3.05 (1H, dd, J 6.3 and 13.2 Hz, OCH2), 3.42 (1H, dd,
6
), 1.08 (3H, d, J 6.7 Hz,
(CH3), 15.38 (CH3), 18.13 (C), 25.67 (CH3), 25.77
(CH3), 27.33 (CH3), 34.40 (CH2), 40.16 (CH2), 40.83
(CH), 41.86 (C), 54.76 (CH), 62.69 (CH2), 126.37 (CH),
128.42 (CH), 129.48 (CH), 139.77 (C), 178.64 (CO), and
181.52 (CO); m/z (CI+, NH3) 404 (M++1).
6
6
), 1.83 [1H, dd, J 4.7
6
6
6
6
6

656
S. G. Da6ies et al. / Tetrahedron: Asymmetry 13 (2002) 647–658
J 3.5 and 8.8 Hz, PhCH2
COCH), 4.32–4.37 (1H, m, NCH
m, arylH); lC (CDCl3; 125 MHz) 15.89 (CH3), 25.84
(CH3), 27.04 (CH3), 35.29 (CH2), 40.32 (CH2), 40.77
(CH), 41.86 (C), 53.32 (CH), 63.43 (CH2), 86.79 (C),
126.06 (CH), 127.08 (CH), 127.81 (CH), 128.13 (CH),
128.71 (CH), 129.18 (CH), 139.45 (C), 143.84 (C),
178.11 (CO), and 180.95 (CO); m/z (FAB+) 532 (M++
1).
6
CH), 4.02–4.07 (1H, m,
(CH2Cl2): 1729 and 1693 cm−1; [h]D23 −20 (c 0.6, CHCl3);
(found: C, 74.95; H, 8.26; N, 5.07; C17H23NO2 requires
C, 74.69; H, 8.48; N, 5.12%); lH (CDCl3, 300 MHz):
1.11 (3H, d, J 6.7, CH3), 1.17 (3H, d, J 6.2, CH3), 1.21
6
6
) and 7.11–7.42 (20H,
6
(3H, s, CH3), 1.47 (1H, dd, J 7.8 and 13, CH2
(1H, dd, J 8.5 and 13.0, CH2CH), 2.60 (1H, dd, J 8.0
and 13.2, CH2Ph), 3.05 (1H, dd, J 6.9 and 13.2,
6 CH), 2.05
6
6
CH6 2Ph), 4.1 (1H, m), 4.22 (1H, m), 7.24 (5H, m); m/z
(CI+, NH3): 274 (M++1), 273, 258, 182, 128.
4.28. (5S,2%R)-3,3-Dimethyl-5-triphenylmethoxymethyl-
1-[(2%-methyl-1%-phenyl)propionyl]pyrrolidin-2-one 27
4.30. (2%R,5R)-(−)-1-(1%-Oxopropyl-2%-phenylmethyl)-3,3-
dimethyl-5-methyl-pyrrolidin-2-one 29
To a solution of 19 (0.232 g, 0.45 mmol) in THF (5
mL) at 0°C was added a solution of LDA (0.5 M as a
solution in THF, 1.12 mL, 0.56 mmol). The resultant
enolate was stirred at 0°C for 1 h before quenching by
addition of methyl iodide (0.084 mL, 1.35 mmol). The
mixture was then stirred at 0°C for a further 3.5 h. The
reaction mixture was worked up by addition of a pH 7
phosphate buffer solution and products extracted
repeatedly with dichloromethane. The combined
organic extracts were washed with brine and dried over
MgSO4. Concentration in vacuo and purification by
column chromatography using 10% ethyl acetate/40–60
pet. ether as eluent furnished the N-acyl derivative 27
as a viscous oil (0.105 g, 44%) with a diastereomeric
excess of 91%; wmax (CH2Cl2)/cm−1 1692 and 1734; lH
Reaction of the N-acylated pyrrolidinone 21 (0.317 g,
1.22 mmol) in THF (13 mL), with LDA (0.5 M, 1.46
mmol) and methyl iodide (0.225 mL, 3.67 mmol) fur-
nished the alkylated product 29 as a colourless oil
(0.203 g, 62%) with a diastereomeric excess of 89%.
wmax. (CH2Cl2): 1729 and 1692 cm−1; [h]D23 −76 (c 0.6,
CHCl3); (found: C, 74.54; H, 9.08, C17H23NO2 requires
C, 74.69; H, 8.48%); lH (CDCl3, 300 MHz): 1.08 (1H,
s, gem CH
CH3), 1.36 (3H, d, J 6.3, CH3
13.0, CH2CH), 2.01 (1H, dd, J 8.5 and 13.0, CH2
2.60 (1H, dd, J 8.0 and 13.4, CH2Ph), 3.06 (1H, dd, J
6
3), 1.15 (3H, d, J 6.9, CH3
), 1.42 (1H, dd, J 5.2 and
CH),
6 ), 1.26 (3H, s, gem
6
6
6
6
6
6.8 and 13.4, CH6 2Ph), 4.17 (2H, m, CHN+COCH), 7.26
(5H, m); m/z (CI+, NH3): 274 (M++1), 273, 146, 128.
(CDCl3; 500 MHz) 1.02 (3H, s, gem CH3
gem CH3), 1.16 (3H, d, J 6.8 Hz, CH3CH), 1.81 [1H,
dd, J 9.0 and 13.2 Hz, (CH3)2CCH2], 1.88 [1H, dd, J 5.1
and 13.2 Hz, (CH3)2CCH2], 2.59 (1H, dd, J 7.8 and 13.4
Hz, OCH2), 3.02 (1H, dd, J 7.1 and 13.4 Hz, OCH2),
3.36 (2H, d, J 4.8 Hz, PhCH2CH), 4.10–4.16 (1H, m,
COCH), 4.20–4.25 (1H, m, NCH) and 7.16–7.42 (20H,
m, arylH); lC (CDCl3; 125 MHz) 17.19 (CH3), 25.61
(CH3), 27.29 (CH3), 35.01 (CH2), 39.70 (CH2), 40.63
(CH), 41.12 (C), 53.47 (CH), 63.34 (CH2), 86.77 (C),
126.10 (CH), 126.26 (CH), 127.09 (CH), 127.25 (CH),
127.82 (CH), 127.93 (CH), 127.96 (CH), 128.23 (CH),
128.70 (CH), 129.16 (CH), 139.77 (C), 143.85 (C),
178.07 (CO), and 181.09 (CO); m/z (CI+, NH3) 532
(M++1); m/z found (MH+) 532.2842. C36H38NO3
requires 532.2852.
6 ), 1.12 (3H, s,
4.31. (2%S,5R)-(−)-1-(1%-Oxopropyl-2%-phenylmethyl)-5-
6
6
ethyl-3,3-dimethyl-pyrrolidin-2-one 30
6
6
Reaction of the N-acylated pyrrolidinone 22 (0.194 g,
0.98 mmol) in THF (10 mL), with LDA (0.5 M, 1.17
mmol) and benzyl bromide (0.35 mL, 2.94 mmol) fur-
nished the alkylated product 30 as a colourless oil
(0.220 g, 78%) with a diastereomeric excess of 95%.
wmax. (CH2Cl2): 1730 and 1692 cm−1; [h]D21 −42.3 (c 0.6,
CHCl3); (found: C, 75.16; H, 8.65; C18H25NO2 requires
C, 75.22; H, 8.77%); lH (CDCl3, 300 MHz): 0.80 (1H,
t, J 7.2), 1.20 (3H, d, J 7), 1.19 (3H, s), 1.25 (1H, m),
1.59 (1H, dd, J 5.8 and 13.4), 1.87 (1H, m), 1.99 (1H,
dd, J 8.4 and 13.5), 2.57 (1H, dd, J 8.6 and 13.5), 3.09
(1H, dd, J 6.0 and 13.4), 4.07 (2H, m), 7.23 (5H, m);
m/z (EI+): 287 (M+), 272, 142, 118, 91.
6
6
6
6
6
4.29. (2%S,5R)-(−)-1-(1%-Oxopropyl-2%-phenylmethyl)-3,3-
dimethyl-5-methyl-pyrrolidin-2-one 28
4.32. (2%R,5R)-(−)-1-(1%-Oxopropyl-2%-phenylmethyl)-5-
ethyl-3,3-dimethyl-pyrrolidin-2-one 31
To a solution of the N-acylated pyrrolidinone 20 (0.193
g, 1.05 mmol) in THF (11 mL) cooled to 0°C, was
added a solution of LDA (0.5 M, 1.26 mmol) in THF.
The solution was stirred at 0°C for 1 h and quenched
by addition of benzyl bromide (0.38 mL, 3.15 mmol).
The mixture was left to stir at 0°C for 2 h and allowed
to reach room temperature overnight. The reaction
mixture was then poured onto a saturated aqueous
ammonium chloride solution (20 mL) and extracted
repeatedly with diethyl ether (4×30 mL). The combined
extracts were washed with brine and dried over MgSO4.
After concentration in vacuo, purification of the residue
by flash column chromatography on silica furnished the
desired alkylated product 28 as a colourless oil (0.231 g,
80%), with a diastereomeric excess of 96%. wmax.
Reaction of the N-acylated pyrrolidinone 23 (0.380 g,
1.39 mmol) in THF (14 mL), with LDA (0.5 M, 1.67
mmol) and methyl iodide (0.26 mL, 4.17 mmol) fur-
nished the alkylated product 31 as a colourless oil
(0.110 g, 42%) with a diastereomeric excess of 95%.
wmax. (CH2Cl2): 1729 and 1692 cm−1; [h]D22 −86.4 (c 0.9,
CHCl3); (found: C, 75.13; H, 9.02; N, 5.12. C18H25NO2
requires C, 75.22; H, 8.77; N, 4.87%); lH (CDCl3, 300
MHz): 0.88 (3H, t, J 7.2), 1.08 (3H, s), 1.15 (3H, d, J
7.3), 1.26 (3H, s), 1.46 (1H, m), 1.62 (1H, dd, J 6.0 and
13.3), 1.93 (1H, dd, J 8.7 and 13.3), 2.02 (1H, m), 2.59
(1H, dd, J 7.7 and 13.0), 3.06 (1H, dd, J 6.7 and 13.0),
4.01 (1H, m), 4.12 (1H, m), 7.23 (5H, m); m/z (CI+,
NH3): 290, 288 (M++1), 287, 273, 142.

S. G. Da6ies et al. / Tetrahedron: Asymmetry 13 (2002) 647–658
657
4.33. (S)-(+)-2-Benzylpropanoic acid 32
1 M solution of Bu2BOTf (0.86 mL, 0.86 mmol) in
methylene chloride. After 0.5 h at 0°C the solution
was cooled to −78°C and the freshly distilled benz-
aldehyde (0.095 mL, 0.94 mmol) was added. After
0.5 h at −78°C and 1 h at 0°C, buffer 7 solution (3
mL) and methanol (4 mL) were added. To this mix-
ture, was slowly added a solution of methanol/
aqueous hydrogen peroxide (2:1) (3 mL). After 1 h of
stirring, the solvents were removed in vacuo and the
product extracted with diethyl ether (4×40 mL). The
combined organic extracts were washed with 5%
aqueous bicarbonate solution and brine, and were
dried over MgSO4. The residue left after removal of
the solvent was purified by flash column chromatog-
raphy. Elution with EtOAc/pet. ether (1:4) furnished
the desired compound 35 as an oil (0.189 g, 84%)
which crystallised on cooling. wmax. (CH2Cl2): 3518,
3054, 2986, 1733, 1674, 1422, 1272 and 1259 cm−1;
[h]2D2 −26.9 (c 0.7, CHCl3); (found: C, 70.26; H, 7.92;
N, 5.12; C17H23NO3 requires C, 70.56; H, 8.01; N,
4.84%); lH (CDCl3, 300 MHz): 1.09 (3H, d, J 7.1),
1.17 (3H, s), 1.27 (3H, s), 1.36 (3H, d, J 6.3 CH3),
1.56 (1H, dd, J 5.6 and 13.1), 2.09 (1H, dd, J 8.4 and
13.1), 4.11 (1H, m), 4.26 (1H, m), 5.16 (dd, J 3.05,
1H), 7.36 (5H, m); m/z (CI+, NH3): 272 (M+−18),
184, 128.
Obtained with 83% yield from compounds 28, using
the experimental procedure described above (colour-
less oil); [h]2D1 +28.6 (c 1.0, CHCl3), (lit. [h]2D2 +30.1 (c
3.28, CHCl3); lH (CDCl3, 300 MHz): 1.20 (3H, d, J
6.7), 2.66 (1H, dd, J 8.0 and 13.1), 2.77 (1H, m), 3.10
(1H, dd, J 6.1 and 13.1), 7.26 (5H, m).
4.34. Methyl (R)-(+)-2-benzylpropionate 33
The methylester 33 was prepared in 82% yield as a
clear colourless oil, from pyrrolidinone 28 (0.143 g,
0.52 mmol) in MeOH, and MeOMgBr (0.52 mL, 1.57
mmol) as a 3.0 M solution in methanol. After addi-
tion of the MeOMgBr solution the mixture was
stirred for 1 h at 0°C and 5 h at rt. Usual work-up
and extraction with CH2Cl2 furnished the crude reac-
tion mixture which was purified by flash chromatog-
raphy to yield the methylester 33 (76 mg, 82%) and
the crystalline chiral auxiliary 3 (61 mg, 92%). Methyl
ester: wmax. (CH2Cl2): 3054 and 1730 cm−1; [h]D22 +34.5
(c 0.8, CHCl3), (lit. [h]2D5=+35.9 (c 1.0, CHCl3)); lH
(CDCl3, 300 MHz): 1.16 (3H, d, J 6.7), 2.67 (1H, dd,
J 7.8 and 12.7), 2.74 (1H, m), 3.03 (1H, dd, J 6.2
and 12.7), 3.65 (3H, s), 7.22 (5H, m); m/z (CI+,
NH3): 196 (M++18) and 91.
4.37. (2R,3R)-(+)-3-Hydroxy-2-methyl-3-phenylpropi-
onic acid 36
4.35. Benzyl (S)-(+)-2-benzylpropionate 34
Obtained with 94% yield from compounds 35 using
the experimental procedure described above (white
solid recrystallised in CCl4). wmax. (CH2Cl2): 3410,
3025, 1711, 1456 and 1233 cm−1; [h]D21 +26.8 (c 0.5,
CHCl3), (lit. [h]2D1 −26.4 (c 1.04, CHCl3) for the other
enantiomer; lH (CDCl3, 300 MHz): 1.16 (3H, d, J
7.2), 2.85 (1H, m), 5.19 (1H, d, J 3.9), 7.29 (5H, m).
Pyrrolidinone 28 (0.109 g, 0.4 mmol) in THF (2 mL)
was added at −78°C to a solution of PhCH2OLi, pre-
pared at 0°C by addition of a n-BuLi 1.6 M solution
(0.37 mL, 0.6 mmol) to a solution of benzyl alcohol
(0.083 mL, 0.8 mmol) in THF (0.5 mL). After 1 h of
stirring at 0°C, the reaction was quenched by addi-
tion of 10 mL of pH 7 buffer solution and the prod-
ucts were extracted with ethyl acetate. Flash
chromatography on silica gel furnished the desired
ester 34 (95 mg, 94%) as a clear colourless oil, and
the recovered crystalline auxiliary 3 (49 mg, 97%).
Benzyl ester: wmax. (CH2Cl2): 1731 cm−1; [h]D21 +25.7 (c
1.15, CH2Cl2), (lit. [h]2D1 −26.9 (c 6.12, CH2Cl2) for
the other enantiomer); lH (CDCl3, 300 MHz): 1.19
(3H, t, J 6.8), 2.70 (1H, dd, J 7.5 and 13.0), 2.79
(1H, m), 3.06 (1H, dd, J 6.2 and 13.0), 5.08 (2H, s),
7.28 (10H, m); m/z (CI+, NH3): 273 (M++18), 255
(M+), 237, 108, 91.
Acknowledgements
We thank the EPSRC, CNRS and The Royal Society
for financial support.
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