Asymmetric synthesis of α-mercapto-β-amino acid derivatives: application to the synthesis of polysubstituted thiomorpholines

Article abstract of DOI:10.1016/j.tetasy.2006.04.004

Tandem conjugate addition of homochiral lithium N-benzyl-N-(α-methyl-p-methoxybenzyl)amide to tert-butyl cinnamate and enolate trapping with TsS^tBu proceeds with high diastereoselectivity to give a homochiral anti-α-tert-butylthio-β-amino ester

Full text of DOI:10.1016/j.tetasy.2006.04.004

Tetrahedron: Asymmetry 17 (2006) 1135–1145
Asymmetric synthesis of a-mercapto-b-amino acid
derivatives: application to the synthesis
of polysubstituted thiomorpholines
*
´
Jose I. Candela-Lena, Stephen G. Davies, Paul M. Roberts, Bruno Roux,
´
´
Angela J. Russell, Elena M. Sanchez-Fernandez and Andrew D. Smith
The Department of Organic Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
Received 22 March 2006; accepted 10 April 2006
Available online 6 May 2006
Abstract—Tandem conjugate addition of homochiral lithium N-benzyl-N-(a-methyl-p-methoxybenzyl)amide to tert-butyl cinnamate and
enolate trapping with TsStBu proceeds with high diastereoselectivity to give a homochiral anti-a-tert-butylthio-b-amino ester. Stepwise
deprotection gives the corresponding free a-tert-butylthio-b-amino acid without epimerisation. Tandem conjugate addition of homochi-
ral lithium N-allyl-N-(a-methylbenzyl)amide to tert-butyl cinnamate and enolate trapping with TsStBu followed by conversion of the S-
tert-butyl group to a disulphide, and reduction with Lalancette’s reagent generates polysubstituted thiomorpholine derivatives.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
for the preparation of a-alkylthio-b-amino esters, through
tandem conjugate addition of a homochiral lithium amide
to an a,b-unsaturated ester and trapping of the resultant
b-amino enolate with an electrophilic source of sulphur.
The results of these investigations are delineated herein.
The synthesis of b-amino acids and their derivatives has
been an actively pursued area of research for many years.1
Previous investigations from this laboratory have demon-
strated that the conjugate addition of a homochiral lithium
amide derived from a-methylbenzylamine to an a,b-unsat-
urated carbonyl compound is a highly versatile protocol
for the synthesis of b-amino carbonyl compounds.2 The
preparation of anti-a-alkyl- and anti-a-hydroxy-b-amino
esters is readily achieved upon treatment of the intermedi-
ate b-amino enolate with an alkyl halide3 or (cam-
phorsulphonyl)oxaziridine,4 respectively. Recent studies
by a number of groups have demonstrated that the a-mer-
capto-b-amino carbonyl motif displays potent biological
activity: for instance, pseudotripeptides containing an
a-mercapto-b-amino acid residue have been shown to be
potent inhibitors of aminopeptidase A,5 tetanus neurotoxin6
and botulinum neurotoxin type B,7 whilst azetidinones
derived from a-mercapto-b-amino acids display potent
inhibition of cholesterol absorption.8 As a result of the
biological activity associated with this motif, we proposed
to extend our conjugate addition methodology to allow
2. Results and discussion
2.1. Preparation of a-alkylthio-b-amino esters
Initial studies sought to develop a one-pot synthesis of a-
alkylthio-b-amino esters and various electrophilic sulphur
sources were examined viz. N-phenylthio-e-caprolactam,
t
TsSBn,9 TsS Bu,10 TsSCPh3 and S8. Conjugate addition
of lithium (R)-N-benzyl-N-(a-methylbenzyl)amide to tert-
butyl cinnamate at ꢀ78 ꢁC was followed by treatment with
2 equiv of the electrophilic sulphur source for 1 h at
ꢀ78 ꢁC. Standard aqueous work-up gave the crude reaction
10
1
product, which was analysed by H NMR spectroscopy
(Scheme 1). When N-phenylthio-e-caprolactam was utilised
as the electrophilic sulphur source, two diastereoisomeric
products 2 and 3 were observed in a ratio of 94:6. Lithium
(R)-N-benzyl-N-(a-methylbenzyl)amide has previously been
shown to exhibit high diastereocontrol upon conjugate addi-
tion to tert-butyl cinnamate11 and therefore 2 and 3 were as-
sumed to be epimeric at C(2). The relative configuration of
*
Corresponding author. Tel.: +44 (0)1865 275680; fax: +44 (0)1865
275674; e-mail: steve.davies@chem.ox.ac.uk
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.04.004

1136
J. I. Candela-Lena et al. / Tetrahedron: Asymmetry 17 (2006) 1135–1145
Ph
(i)
t
CO2 Bu
Ph
N
OLi
OtBu
Ph
Ph
1
Ph
Ph
Ph
Ph
N
Ph
N
+
Ph
N
t
t
CO2 Bu
CO2 Bu
t
CO2 Bu
Ph
Ph
Ph
SR
SR
10
R = Ph, anti-2
R = Ph, syn-3
R = Bn, syn-5
R = Bn, anti-4
R = tBu, anti-
6
R = tBu, syn-
7
R = H, syn-
9
R = H, anti-
8
Sulphur
source
anti
:
syn
Yieldb
anti (de) %
76 (>98)
80c (70)
78 (>98)
-
Yieldb
syn (de) %
R
Ph
ratioa
94:6
85:15
98:2
-
-
-
-
-
N
-phenylthio-ε-caprolactam
TsSBn
TsStBu
TsSCPh3
S8
Bn
tBu
CPh3
Hd
85:15
51 (>98)
9 (>98)
Scheme 1. Reagents and conditions: (i) lithium (R)-N-benzyl-N-(a-methylbenzyl)amide, THF, ꢀ78 ꢁC, 2 h, then electrophilic sulphur source, ꢀ78 ꢁC, 1 h,
c
then NH4Cl (satd aq) [acrude; bpurified; anti and syn diastereoisomers inseparable; dafter reduction with NaBH4 in EtOH].
the major product 2 was then assigned as anti based upon
the previously demonstrated preference for protonation or
alkylation of b-amino enolates anti to the amino group.12
Purification allowed isolation of anti-2 in 76% yield and
>98% de (Scheme 1). Analogous procedures with TsSBn
and TsStBu as the electrophilic sulphur sources gave an
inseparable 85:15 mixture of anti-4:syn-5 and a separable
98:2 mixture of anti-6:syn-7, respectively. When TsSCPh3
was used as the electrophilic sulphur source, a complex
mixture was obtained, of which tert-butyl cinnamate and
b-amino ester 10 were the only identifiable components.
Quenching b-amino enolate 1 with S8, meanwhile, produced
an intractable mixture containing several polysulphides.
Reduction of the crude reaction mixture with NaBH4 in
EtOH, however, gave a separable 85:15 mixture of anti-
8:syn-9 (Scheme 1). From these results, reaction of enolate
1 with TsStBu was the most diastereoselective, giving anti-6
in 78% yield and >98% de after purification (Scheme 1).
of the reaction of enolate 1 with TsSBn is a kinetic pheno-
menon and is not due to a post-reaction equilibration
(Scheme 2).
Ph
Ph
Ph
N
Ph
N
+
t
t
CO2 Bu
CO2 Bu
Ph
Ph
SBn
anti-
SBn
syn-
4
5
anti-4:syn-5 81:19 or 63:37
(i)
Ph
Ph
Ph
N
Ph
N
+
t
t
CO2 Bu
CO2 Bu
Ph
Ph
It was postulated that reduced selectivity of the reaction of
enolate 1 with TsSBn when compared to TsStBu could be
due to epimerisation of the products by unreacted 1. A
reverse addition was therefore investigated: a THF solution
of 1 was added dropwise to a solution of TsSBn in THF at
ꢀ78 ꢁC over 20 min, giving an 81:19 mixture of anti-4:
syn-5 (62% de). To discover if the low diastereoselectivity
was due to post-reaction equilibration, the thermodynamic
equilibrium ratio of anti-4:syn-5 was determined. Equili-
bration of the 81:19 mixture of anti-4:syn-5 (62% de) with
KOtBu in CD3OD allowed the incorporation of deuterium
at the a-centre to be followed by 1H NMR. This reached a
plateau at 94% after 25 days, and a ratio of 72:28 for 11:12
was determined (44% de). Identical treatment of a 63:37
mixture of anti-4:syn-5 (26% de)13 gave the same result.
These experiments suggest that the low diastereoselectivity
D
SBn
BnS
D
11
12
11:12 77:23, 94% D incorporation
Scheme 2. Reagents and conditions: (i) KOtBu, CD3OD, rt, 25 days.
The geometry of b-amino enolates such as 1 has been
shown to play an important role in determining the level
of diastereofacial selectivity of enolate alkylation reac-
tions.14 Enolate trapping studies have shown that whilst
the (Z)-b-amino enolate is produced from conjugate
addition of a lithium amide to an a,b-unsaturated ester,
deprotonation of a b-amino ester with LDA proceeds via
an Ireland transition state to generate the diastereoisomeric
(E)-b-amino enolate.14 In order to investigate the effect of

J. I. Candela-Lena et al. / Tetrahedron: Asymmetry 17 (2006) 1135–1145
1137
enolate geometry on the reaction selectivity, a stepwise
protocol was performed. Deprotonation of 1015 with
LDA gave (E)-enolate 13, with subsequent addition of
TsSBn at ꢀ78 ꢁC giving almost a complete reversal in the
diastereofacial selectivity: syn-5 was obtained as the major
diastereoisomer of an inseparable 21:79 mixture of anti-4:
syn-5 (58% de). Disappointingly, when TsStBu was used
as the electrophilic sulphur source, no incorporation of sul-
phur was observed. To investigate this reaction further,
TsStBu was added to enolate 13 and stirred for 1 h at
ꢀ78 ꢁC, followed by addition of TsSBn and stirring for a
An alternative strategy to allow for the synthesis of a-mer-
capto-b-amino acid derivatives was therefore sought by
altering the N-protecting groups of the lithium amide. A
range of homochiral lithium amides have been developed
within this laboratory, which allows for N-deprotection
without recourse to hydrogenolysis. Lithium N-allyl-N-
(a-methylbenzyl)amide enables stepwise deprotection via
deallylation, carbamate formation and acid-promoted
debenzylation,17 whilst lithium N-allyl-N-(a-methyl-p-meth-
oxybenzyl)amide18 and lithium N-benzyl-N-(a-methyl-p-
methoxybenzyl)amide19 allow for oxidative deprotection,
and these were therefore evaluated for their utility in the
synthesis of a-mercapto-b-amino acid derivatives.
1
further hour at ꢀ78 ꢁC. H NMR spectroscopic analysis
of the crude reaction product indicated that a mixture of
S-benzyl products anti-4 and syn-5 was formed exclusively,
with no trace of StBu incorporation detected. Interestingly,
when the temperature of the quench was raised to 0 ꢁC,
addition of TsStBu to enolate 13 gave 35% conversion to
a 98:2 mixture of anti-6:syn-7 (96% de) (Scheme 3).
The conjugate addition of lithium (R)-N-allyl-N-(a-methyl-
benzyl)amide to tert-butyl cinnamate and quenching with
TsStBu gave a 97:3 mixture of anti-14:syn-15, which was
purified to a single diastereoisomer anti-14 in 88% isolated
yield. Removal of the N-allyl group of anti-14 with Wilkin-
son’s catalyst20 gave 16 in 65% yield, whilst deprotection
with Pd(PPh3)4 and N,N-dimethylbarbituric acid (NND-
MBA)21 gave 16 in 95% yield. Subsequent attempts to
reprotect the nitrogen of 16 with a carbamate group were
unsuccessful under a variety of conditions and so the use
of this lithium amide was abandoned (Scheme 4).
Ph
Ph
(i)
Ph
N
Ph
N
OtBu
OLi
t
CO2 Bu
Ph
Ph
10
13
(i)
Ph
N
Ph
Ph
t
CO2 Bu
t
Ph
CO2 Bu
Ph
Ph
N
Ph
N
+
StBu
anti-14
t
t
CO2 Bu
CO2 Bu
Ph
Ph
88%, >98% de
SR
SR
R = Bn, anti-4
R = Bn, syn-5
R = tBu, anti-
6
R = tBu, syn-
7
(ii)
Sulphur
source
TsSBn
TsStBu
TsStBu
anti
:
syn
Yield
syn (de) %
81b (58)
-
O
R
Conditions
ratioa
21:79
-
(iii)
Ph
NH
Bn
tBu
tBu
(i)
(i)
(ii)
Ph
N
OMe
t
X
t
CO2 Bu
CO2 Bu
35c
Ph
98:2
Ph
StBu
16
StBu
Scheme 3. Reagents and conditions: (i) LDA, THF, ꢀ78 ꢁC, 30 min, then
TsSR, ꢀ78 ꢁC, 1 h, then NH4Cl (satd aq); (ii) LDA, THF, ꢀ78 ꢁC, 30 min,
then TsSR, 0 ꢁC, 1 h, then NH4Cl (satd aq) [acrude; banti and syn
95%, >98% de
c
Scheme 4. Reagents and conditions: (i) lithium (R)-N-allyl-N-(a-methyl-
benzyl)amide, THF, ꢀ78 ꢁC, 2 h, then TsStBu, ꢀ78 ꢁC, 1 h, then NH4Cl
(satd aq); (ii) Pd(PPh3)4, NNDMBA; (iii) MeOCOCl, Et3N, DCM, rt,
12 h.
diastereoisomers inseparable; conversion].
2.2. Preparation of 2-(tert-butylthio)-3-amino-3-phenyl-
propanoic acid
For conjugate addition of lithium (R)-N-allyl-N-(a-methyl-
p-methoxybenzyl)amide and lithium (R)-N-benzyl-N-(a-
methyl-p-methoxybenzyl)amide, the reaction protocol was
modified to allow warming to room temperature over
12 h after the addition of TsStBu to effect efficient incorpo-
ration of the electrophile, giving exclusively anti-17 and
anti-19 in excellent yield (Scheme 5). Attempted deallyl-
ation of anti-17 using Wilkinson’s catalyst returned only a
complex mixture after 6 days; addition of magnesium chlo-
ride to the reaction mixture22 did not prove fruitful. Use of
Pd(PPh3)4 and NNDMBA was not effective even after ex-
tended reaction times: only 50% of the starting material
was recovered after 24 h with no deallylation taking place.
Alternative literature N-deallylation strategies mediated
With a reliable protocol for the formation of a-tert-butyl-
thio-b-amino ester anti-6 in hand, attention next turned
to deprotection to the corresponding b-amino acid. N-
Debenzylation of b-amino esters is usually performed via
hydrogenolysis mediated by a palladium catalyst, but it
was predicted that this may be problematic in the case of
anti-6 due to poisoning of the catalyst by sulphur.16 None-
theless, it was of interest to determine whether the bulky
tert-butyl protecting group on the sulphur atom would re-
tard the rate of catalyst poisoning and therefore allow
hydrogenolysis. A range of hydrogenolysis conditions were
investigated for deprotection of anti-6, but no N-debenzy-
lation was observed.

1138
J. I. Candela-Lena et al. / Tetrahedron: Asymmetry 17 (2006) 1135–1145
(p-methoxybenzyl) group and tert-butyl ester functionality
R
could be achieved in one-pot upon treatment with TFA. In
the event, treatment of 21 at room temperature for 24 h
cleaved only the tert-butyl ester but at 55 ꢁC both protect-
ing groups were removed, giving amino acid 22 in 98%
yield and as a single diastereoisomer after ion exchange
chromatography (Scheme 5).
PMP
N
(i) or (ii)
t
CO2 Bu
t
Ph
CO2 Bu
Ph
StBu
(i). R = allyl,
anti-17, 99%, >98% de
(ii). R = benzyl,
anti-19, 99%, >98% de
2.3. Preparation of polysubstituted thiomorpholines
(iii) for anti-17
or (iv) for anti-19
During the course of these studies concerned with the syn-
thesis of a-alkylthio-b-amino esters, it was noted that
whilst the tandem conjugate addition of lithium (R)-N-
allyl-N-(a-methylbenzyl)amide to tert-butyl cinnamate
and quenching with 2 equiv of S8 gave the expected com-
plex mixture of polysulphides 24, subsequent reduction of
crude mixture 24 with NaBH4 gave a 67:33 ratio of thi-
omorpholines 25 and 26. Chromatographic separation
allowed isolation of 25 in 50% yield and 26 in 20% yield
(Scheme 6). The thiomorpholine sub-unit is a commonly
recurring sub-structure in several drugs and drug-like
molecules that exhibit potent biological activity,27 and it
was therefore of interest to probe the formation of 25
and 26 in some detail. The relative configurations of both
NH2
PMP
NH
(v), (vi)
CO2H
t
Ph
CO2 Bu
Ph
StBu
StBu
22
98%, >98% de
21
(iii). 19%, >98% de
(iv). 58%, >98% de
Scheme 5. Reagents and conditions: (i) lithium (R)-N-allyl-N-(a-methyl-p-
methoxybenzyl)amide, THF, ꢀ78 ꢁC, 2 h, then TsStBu, ꢀ78 ꢁC to rt, 12 h,
then NH4Cl (satd aq); (ii) lithium (R)-N-benzyl-N-(a-methyl-p-methoxy-
benzyl)amide, THF, ꢀ78 ꢁC, 2 h, then TsStBu, ꢀ78 ꢁC to rt, 12 h; (iii)
TolSH, AIBN, benzene, reflux; (iv) CAN, MeCN–H2O (v:v 5:1), ꢀ7 ꢁC,
5 min; (v) TFA–DCM (v:v 1:1), 55 ꢁC, 24 h; (vi) Dowex 50WX8-200
[PMP = p-methoxyphenyl].
3
25 and 26 were first established through J coupling con-
stant analysis between C(2)H and C(3)H, and between
1
C(5)H2 and C(6)H, in the H NMR spectra. Additionally,
epimerisation of 25 with KOtBu in MeOH gave the ther-
modynamically more stable isomer 27 whilst identical
treatment of 26 did not produce any epimerisation of
the C(2) centre, thus further serving to confirm the relative
stereochemistry of 25 and 26. The absolute stereochemistry
of (2R,3R,6S,aR)-25 and (2S,3R,6R,aR)-26 was then
assigned on the assumption that the C(3) stereocentre
was formed in a highly diastereoselective manner from
the conjugate addition of the lithium amide (Scheme 6).11
by dibenzylidenediacetone palladium23 or Grubbs’ catalyst24
similarly failed. Radical deallylation was next assayed:25
this gave 21 in only 19% yield and recovered starting
material in 32% yield (Scheme 5). Attempted bis-deprotec-
tion of anti-19 with ceric ammonium nitrate (CAN)19 was
also unsuccessful, giving a complex mixture, while mono-
debenzylation under the reported procedure26 gave only
4% yield of 21. However, extensive reaction optimisation
showed that treatment of anti-19 with CAN at ꢀ7 ꢁC for
5 min allowed isolation of mono-debenzylated 21 in 58%
yield and >98% de (Scheme 5). With 21 available in accept-
able yield, it was anticipated that the removal of the N-
In order to optimise the cyclisation reaction of 24 to
thiomorpholines 25 and 26, some highly purified 24 was
(i)
t
Ph
N
CO2 Bu
Ph
N
OLi
OtBu
Ph
t
CO2 Bu
Ph
Ph
Sx
24
23
(ii)
Me
Me
Me
Ph
N
Ph
N
Ph
N
(iii)
+
S
S
S
Ph
Ph
Ph
t
t
t
CO2 Bu
CO2 Bu
CO2 Bu
27
65%, >98% de
25
50%, >98% de
26
20%, >98% de
[25:26 67:33 separable mixture]
Scheme 6. Reagents and conditions: (i) lithium (R)-N-allyl-N-(a-methylbenzyl)amide, THF, ꢀ78 ꢁC, 2 h, then S8, ꢀ78 ꢁC, 1 h, then NH4Cl (satd aq);
(ii) NaBH4, EtOH, 0 ꢁC to rt, 12 h; (iii) KOtBu, MeOH, rt, 4 days.

J. I. Candela-Lena et al. / Tetrahedron: Asymmetry 17 (2006) 1135–1145
1139
prepared, removing by precipitation and chromatography
any trace amounts of impurities, and especially unreacted
sulphur. The reduction of 24 was then studied with various
reducing agents (Scheme 7). The use of NaBH4 gave only
partial conversion to a 67:33 mixture of thiomorpholines
25 and 26, which were isolated in 45% combined yield. A
mixture of NaBH4 and S8 proved more efficient and no
Ph
N
t
CO2 Bu
Ph
Sx
24
1
starting material could be detected in the H NMR spec-
reduction
trum of the crude reaction mixture. The best result was
achieved with a 1:3 mol ratio of NaBH4–S8; this corre-
sponds to the Lalancette reagent, NaBH2S3, which has
been shown to have reducing properties that are intermedi-
ate between NaBH4 and LiAlH4.28 No difference in reac-
tion efficiency was noted when either a 1:3 mol ratio of
solid NaBH4 and S8 was added to a solution of 24 in
EtOH, or when the Lalancette reagent was preformed in
THF and added to a solution of 24 in EtOH. Thus, thio-
morpholines 25 and 26 were produced as a 67:33 mixture
and isolated in 85% combined yield from 24.
Ph
N
t
CO2 Bu
Ph
S
H
28
S
Me
Ph
N
Ph
N
S
S
Ph
Ph
H
S
t
t
CO2 Bu
CO2 Bu
25+26
29
Me
Me
Ph
N
Ph
N
(i)
Ph
N
Ph
N
+
S
S
t
S
CO2 Bu
Ph
Ph
Ph
Ph
t
t
t
CO2 Bu
CO2 Bu
CO2 Bu
Sx
24
30
25
26
Reagents
S8
Solvent
EtOH
EtOH
EtOH
EtOH
Yield 25+26 (%)c
Figure 1. Postulated mechanism for the cyclisation of 24 to thiomorpho-
lines 25 and 26.
0
NaBH4
45
80
85
85
NaBH4:S8 (1:6)a
NaBH4:S8 (1:3)a
NaBH4:S8 (1:3)a,b
The observation that thiomorpholine 25 is the major prod-
uct suggests that the cyclisation reaction proceeds without
epimerisation of the C(2)-stereocentre, since no trace of the
thermodynamically more stable thiomorpholine 27 was ob-
served. It was therefore hypothesised that the 67:33 mixture
of thiomorpholines 25 and 26 was a result of poor stereo-
control upon reaction of b-amino enolate 23 with S8 giving
24 with an anti:syn ratio of 67:33, rather than stereochem-
ical drift during the cyclisation to thiomorpholines 25 and
26. To investigate the stereoselectivity of the cyclisation
reaction, anti-14 (of known 94% de) was treated with 2-
nitrobenzenesulphenyl chloride to give disulphide 32 in
60% yield and 88% de.31 Reduction of 32 with Lalancette’s
reagent in EtOH gave thiomorpholine 25 in 88% de, consis-
tent with cyclisation of 32 to thiomorpholine 25 being
stereospecific (Scheme 9). Therefore, assuming that both
reactions proceed via the corresponding thiol intermediate,
this result supports the hypothesis that the 67:33 mixture of
thiomorpholines 25 and 26 arises because of low diastereo-
selectivity of the reaction of enolate 23 with S8, giving
polysulphides 24 with an overall anti:syn ratio of 67:33
(Scheme 6).
THF-EtOH
Scheme 7. Reagents and conditions: (i) reagents, solvent, 0 ꢁC to rt, 12 h
[amolar ratio; bpreformed Lalancette reagent; a separable 67:33 mixture
c
of thiomorpholines 25 and 26 was produced; combined yields are
reported].
The cyclisations of d,e- or e,f-unsaturated thiols via radical
chain processes involving homolytic fission of the S–H
bond, 6-exo cyclisation of the resultant S-radical onto the
double bond, and chain propagation by H-atom abstrac-
tion from the chain carrier are well documented29 and have
been shown to proceed readily even at room temperature.30
The mechanism for the cyclisation was therefore postulated
to involve reduction of the mixture of polysulphides 24 to
the corresponding mixture of thiols 28. Generation of a
thiol radical 29 is then immediately followed by cyclisation
onto the allyl group to generate the thiomorpholine skele-
ton 30. Chain propagation results from H-atom abstrac-
tion (Fig. 1). The higher yield of thiomorpholines
obtained with the Lalancette reagent therefore presumably
arises because the reagent is more efficient in effecting the
reduction of polysulphides 24 to thiols 28 than NaBH4
alone. Further corroboration for this mechanism was ob-
tained from labelling studies to determine the origin of
the hydrogen atom that appears at the C(6) methyl group:
these indicated that the hydrogen source is a proton from
the solvent (Scheme 8), presumably as a result of exchange
of the acidic S–H proton of 28 for deuterium in the solvent.
The following transition states for the stereospecific cycli-
sations of the intermediate thiols anti-33 and syn-34 to
the corresponding thiomorpholines 25 and 26, respectively,
are proposed. In the case of anti-33, cyclisation presumably
proceeds via the chair-like transition state 35: this places
only the C(2)-tert-butyl ester substituent in an axial posi-
tion. For syn-34, however, a boat-like transition state 36

1140
J. I. Candela-Lena et al. / Tetrahedron: Asymmetry 17 (2006) 1135–1145
3. Conclusion
Ph
N
D
(i)
Ph
N
The tandem conjugate addition of a range of homochiral
lithium amides to tert-butyl cinnamate and enolate trap-
ping with a variety of electrophilic sulphur sources proceeds
with generally high selectivity to generate the correspond-
ing anti-a-alkylthio-b-amino ester. TsStBu proved to be
the most selective electrophilic sulphur source, giving anti-
a-tert-butylthio-b-amino esters typically in >95% de, which
could be purified chromatographically to single diastereo-
isomers. In the case of conjugate addition of lithium
N-benzyl-N-(a-methyl-p-methoxybenzyl)amide and quench-
ing with TsStBu, the resultant homochiral N-protected
anti-a-tert-butylthio-b-amino ester can be deprotected in
a stepwise manner to give the corresponding a-tert-butyl-
thio-b-amino acid. Meanwhile, conjugate addition of
homochiral lithium N-allyl-N-(a-methylbenzyl)amide to
tert-butyl cinnamate followed by addition of TsStBu, con-
version of the S-tert-butyl group to a disulphide, and
reduction with Lalancette’s reagent offers an efficient entry
to differentially protected, polysubstituted thiomorpholine
derivatives.
S
t
CO2 Bu
Ph
Ph
t
CO2 Bu
Sx
24
31
Solvent
CD3OD
CH3OD
CH3OH
Reducing agent
NaBH4:S8 (1:3)
NaBH4:S8 (1:3)
NaBD4:S8 (1:3)
D incorporation (%)
75
75
0
Scheme 8. Reagents and conditions: (i) reducing agent, solvent, 0 ꢁC to rt,
12 h.
(i)
Ph
N
Ph
N
t
t
CO2 Bu
CO2 Bu
Ph
Ph
StBu
anti-14
S
S
32
60%
NO2
94% de
88% de
4. Experimental
(ii)
4.1. General experimental
All reactions involving organometallic or other moisture-
sensitive reagents were carried out under a nitrogen or
argon atmosphere using standard vacuum line techniques
and glassware that was flame dried and cooled under nitro-
gen before use. The solvents were dried according to the
procedure outlined by Grubbs and co-workers.32 Water
was purified by an Elixꢂ UV-10 system. All other solvents
were used as supplied (analytical or HPLC grade) without
prior purification. Organic layers were dried over MgSO4.
Thin layer chromatography was performed on aluminium
plates coated with 60F254 silica. The plates were visualised
using UV light (254 nm), iodine, 1% aq KMnO4 or 10%
ethanolic phosphomolybdic acid. Flash column chroma-
tography was performed on Kieselgel 60 silica.
Me
Ph
Ph
N
S
t
CO2 Bu
25
quant
88% de
Scheme 9. Reagents and conditions: (i) 2-nitrobenzenesulphenyl chloride,
AcOH, rt, 2 h; (ii) NaBH2S3, EtOH, 0 ꢁC to rt, 12 h.
is preferred because of the large A1,2 strain or A1,3 strain
that would be present in either of the possible chair transi-
tion states (assuming that the N-a-methylbenzyl group
preferentially lies equatorial). Cyclisation gives the ob-
served stereochemical arrangement of thiomorpholines 25
and 26, respectively (Fig. 2).
Elemental analyses were recorded by the microanalysis ser-
vice of the Inorganic Chemistry Laboratory, University of
H
E
Me
N
Ph
N
In
R
Ph
N
Ph
S
S
t
CO2 Bu
Ph
Ph
H
H
t
CO2 Bu
SH
anti-33
35
25
S
Me
N
R
Ph
N
In
Ph
N
Ph
H
S
t
CO2 Bu
Ph
H
Ph
H
E
t
CO2 Bu
SH
syn-34
36
26
Figure 2. Postulated transition states for cyclisation [R = a-methylbenzyl, E = tert-butoxycarbonyl].

J. I. Candela-Lena et al. / Tetrahedron: Asymmetry 17 (2006) 1135–1145
1141
Oxford, UK. Melting points were recorded on a Gallen-
kamp Hot Stage apparatus and are uncorrected. Optical
rotations were recorded on a Perkin–Elmer 241 polarime-
ter with a water-jacketed 10 cm cell. Specific rotations are
reported in 10ꢀ1 deg cm2 gꢀ1 and concentrations in g/100
mL. IR spectra were recorded on Bruker Tensor 27 FT-
IR spectrometer as either a thin film on NaCl plates (film)
or a KBr disc (KBr), as stated. Selected characteristic peaks
are reported in cmꢀ1. NMR spectra were recorded on Bru-
ker Avance spectrometers in the deuterated solvent stated.
The field was locked by external referencing to the relevant
deuteron resonance. Low-resolution mass spectra were re-
corded on either a VG MassLab 20–250 or a Micromass
Platform 1 spectrometer. Accurate mass measurements
were run on either a Bruker MicroTOF and were internally
calibrated with polyanaline in positive and negative modes,
or a Micromass GCT instrument fitted with a Scientific
Glass Instruments BPX5 column (15 m · 0.25 mm) using
amyl acetate as a lock mass.
170.6; m/z (CI+) 524 ([M+H+], 58%), 300 (72), 212
(100), 196 (77), 91 (32).
Data for syn-3: dH (500 MHz, CDCl3) 0.83 (9H, s, CMe3),
1.11 (3H, d, J 6.9, C(a)Me), 3.79 (1H, d, J 13.8, NCHA),
4.10 (1H, d, J 13.8, NCHB), 4.24 (1H, q, J 6.9, C(a)H),
4.31 (1H, d, J 11.7, C(2)H), 4.45 (1H, J 11.7, C(3)H),
7.07–7.65 (20H, m, Ph).
4.4. tert-Butyl (2R,3R,aR)- and (2S,3R,aR)-2-benzylthio-3-
[N-benzyl-N-(a-methylbenzyl)amino]-3-phenylpropanoate
(2R,3R,aR)-anti-4 and (2S,3R,aR)-syn-5
BuLi (2.5 M in hexanes, 0.61 mL, 1.52 mmol), (R)-N-benz-
yl-N-(a-methylbenzyl)amine (331 mg, 1.57 mmol) in THF
(2 mL), tert-butyl cinnamate (200 mg, 0.98 mmol) in THF
(2 mL) and TsSBn (545 mg, 1.96 mmol) were reacted
according to general procedure (a) and gave an 85:15 mix-
ture of anti-4:syn-5. Purification via flash column chroma-
tography (eluent pentane–Et2O 4:1) gave an 85:15 mixture
4.2. General procedures (a) and (b) for lithium amide
conjugate addition/electrophilic sulphur quench
of anti-4:syn-5 as a colourless oil (421 mg, 80%);
C35H39NO2S requires C, 78.2; H, 7.3; N, 2.6; S, 6.0; found
C, 78.2; H, 7.6; N, 2.45; S, 5.7; mmax (film) 1719; m/z (CI+)
538 ([M+H+], 48%), 300 (100), 196 (50), 105 (28), 91 (50).
BuLi (2.5 M in hexanes, 1.55 equiv) was added dropwise
via a syringe to a stirred solution of the requisite amine
(1.6 equiv) in THF at ꢀ78 ꢁC. After stirring for 30 min, a
solution of tert-butyl cinnamate (1 equiv) in THF at
ꢀ78 ꢁC was added dropwise via a cannula. After stirring
for a further 2 h at ꢀ78 ꢁC, the reaction mixture was
quenched with the requisite electrophilic sulphur source
(2 equiv) and either (a) stirred at rt for 1 h; or (b) allowed
to warm to rt over 12 h. Satd aq NH4Cl was added and
the reaction mixture was concentrated in vacuo. The resi-
due was partitioned between DCM and H2O. The organic
phase was separated and the aqueous phase was extracted
twice with DCM. The combined organic extracts were
washed with brine, dried and concentrated in vacuo to give
the crude reaction mixture.
Data for anti-6: dH (500 MHz, CDCl3) 0.94 (3H, d, J 6.8,
C(a)Me), 1.06 (9H, s, CMe3), 3.61 (1H, d, J 13.8, SCHA),
3.66 (2H, AB system, J 13.1, NCH2), 3.80 (1H, d, J 13.8,
SCHB), 3.89 (1H, d, J 11.7, C(2)H), 4.08 (1H, q, J 6.9,
C(a)H), 4.15 (1H, d, J 11.7, C(3)H), 7.18–7.54 (20H, m,
Ph); dC (50 MHz, CDCl3) 14.4, 27.4, 35.4, 50.2, 51.4,
55.8, 60.7, 80.9, 126.7, 126.9, 127.2, 127.4, 127.7, 127.9,
128.0, 128.1, 128.3, 128.8, 129.1, 129.2, 129.8, 137.9,
139.2, 140.0, 143.8, 170.0.
Data for syn-7: dH (500 MHz, CDCl3) 1.17 (3H, d, J 6.9,
C(a)Me), 1.60 (9H, s, CMe3), 3.48 (1H, d, J 13.0, SCHA),
3.59 (1H, d, J 13.0, SCHB), 3.60 (2H, s, NCH2), 3.61
(1H, d, J 12.0, C(2)H), 4.10 (1H, q, J 6.9, C(a)H), 4.45
(1H, d, J 12.0, C(3)H), 6.88–7.52 (20H, m, Ph).
4.3. tert-Butyl (2R,3R,aR)- and (2S,3R,aR)-2-phenylthio-3-
[N-benzyl-N-(a-methylbenzyl)amino]-3-phenylpropanoate
(2R,3R,aR)-anti-2 and (2S,3R,aR)-syn-3
4.5. tert-Butyl (2R,3R,aR)- and (2S,3R,aR)-2-tert-butylthio-
3-[N-benzyl-N-(a-methylbenzyl)amino]-3-phenylpropanoate
(2R,3R,aR)-anti-6 and (2S,3R,aR)-syn-7
BuLi (2.5 M in hexanes, 0.61 mL, 1.52 mmol), (R)-N-benz-
yl-N-(a-methylbenzyl)amine (331 mg, 1.57 mmol) in THF
(2 mL), tert-butyl cinnamate (200 mg, 0.98 mmol) in
THF (2 mL) and N-phenylthio-e-caprolactam (433 mg,
1.96 mmol) were reacted according to general procedure
(a) and gave a 94:6 mixture of anti-2:syn-3. Purification
via flash column chromatography (eluent pentane–Et2O
4:1) gave anti-2 as a colourless oil (388 mg, 76%, >98%
BuLi (2.5 M in hexanes, 0.61 mL, 1.52 mmol), (R)-N-benzyl-
N-(a-methylbenzyl)amine (331 mg, 1.57 mmol) in THF
(2 mL), tert-butyl cinnamate (200 mg, 0.98 mmol) in THF
(2 mL), and TsStBu (479 mg, 1.96 mmol) were reacted
according to general procedure (a) and gave a 98:2 mixture
of anti-6:syn-7. Purification via flash column chromatogra-
phy (eluent pentane–Et2O 4:1) gave anti-6 as a white solid
(384 mg, 78%, >98% de); C32H41NO2S requires C, 76.3; H,
de); C34H37NO2S requires C, 78.0; H, 7.1; N, 2.7; S,
25
6.1; found C, 78.0; H, 7.0; N, 2.3; S, 5.5; ½aꢁD = +31.6
(c 1.0, CHCl3); mmax (film) 1727; dH (500 MHz, CDCl3)
1.19 (3H, d, J 6.9, C(a)Me), 1.44 (9H, s, CMe3), 3.67
(1H, d, J 14.4, NCHA), 3.80 (1H, d, J 14.4, NCHB),
4.18 (1H, q, J 6.9, C(a)H), 4.19 (1H, d, J 11.7, C(2)H),
4.52 (1H, d, J 11.7, C(3)H), 7.07–7.65 (20H, m, Ph); dC
(125 MHz, CDCl3) 17.6, 27.8, 50.8, 54.1, 59.2, 63.5,
81.2, 126.6, 126.7, 127.4, 127.5, 127.7, 127.8, 127.9,
128.1, 128.4, 129.9, 132.8, 133.8, 136.4, 140.5, 144.2,
8.2; N, 2.8; S, 6.4; found C, 76.3; H, 8.5; N, 2.6; S, 6.7; mp
25
69–70 ꢁC; ½aꢁD = ꢀ8.5 (c 1.0, CHCl3); mmax (film) 1718; dH
(500 MHz, CDCl3) 1.12 (3H, d, J 6.8, C(a)Me), 1.13 (9H,
s, CMe3), 1.56 (9H, s, CMe3), 3.77 (2H, app br d, J 12.0,
C(2)H, NCHA), 4.09 (1H, d, J 14.3, NCHB), 4.15 (1H, q, J
6.8, C(a)H), 4.27 (1H, J 11.8, C(3)H), 7.13–7.42 (15H, m,
Ph); dC (50 MHz, CDCl3) 16.8, 28.0, 31.2, 44.1, 49.7, 51.0,
58.7, 63.9, 80.9, 126.6, 127.1, 127.5, 127.7, 127.8, 127.9,

1142
J. I. Candela-Lena et al. / Tetrahedron: Asymmetry 17 (2006) 1135–1145
128.3, 128.9, 130.0, 137.8, 140.6, 143.7, 172.8; m/z (CI+) 504
8.7; N, 3.1; S, 7.1; found C, 74.3; H, 8.7; N, 2.9; S, 6.9;
25
([M+H+], 60%), 300 (100), 196 (60).
½aꢁD = ꢀ10.0 (c 0.9, CHCl3); mmax (film) 1725; dH
(500 MHz, CDCl3) 1.06 (3H, d, J 6.8, C(a)Me), 1.24 (9H,
s, CMe3), 1.56 (9H, s, CMe3), 3.18 (1H, dd, J 14.8, 7.2,
NCHA), 3.37 (1H, dd, J 14.8, 5.8, NCHB), 3.95 (1H, d, J
12.2, C(2)H), 4.08 (1H, q, J 6.8, C(a)H), 4.27 (1H, d, J
12.2, C(3)H), 5.03–5.09 (2H, m, CH@CH2), 5.83–5.91
(1H, m, CH@CH2), 7.19–7.36 (10H, m, Ph); dC (50 MHz,
CDCl3) 17.9, 28.0, 31.3, 44.1, 49.2, 50.3, 58.7, 63.1, 80.8,
116.0, 126.7, 127.4, 127.6, 127.7, 128.0, 128.1, 128.2,
129.8, 137.2, 139.0, 145.2, 173.3; m/z (CI+) 454 ([M+H+],
83%), 250 (100), 146 (38), 105 (16).
Data for syn-5: dH (500 MHz, CDCl3) 1.10 (9H, s, CMe3),
1.11 (3H, d, J 7.0, C(a)Me), 1.64 (9H, s, CMe3), 3.65 (1H,
d, J 14.9, NCHA), 3.72 (1H, d, J 11.7, C(2)H), 3.91 (1H, q,
J 7.0, C(a)H), 4.31 (1H, d, J 11.7, C(3)H), 4.39 (1H, d, J
14.9, NCHB), 7.12–7.45 (15H, m, Ph).
4.6. tert-Butyl (2R,3R,aR)- and (2S,3R,aR)-2-mercapto-3-
[N-benzyl-N-(a-methylbenzyl)amino]-3-phenylpropanoate
(2R,3R,aR)-anti-8 and (2S,3R,aR)-syn-9
BuLi (2.5 M in hexanes, 0.61 mL, 1.52 mmol), (R)-N-benz-
yl-N-(a-methylbenzyl)amine (331 mg, 1.57 mmol) in
THF (2 mL), tert-butyl cinnamate (200 mg, 0.98 mmol) in
THF (2 mL) and S8 (502 mg, 1.96 mmol) were reacted
according to general procedure (a) and gave a complex
mixture of polysulphides. The crude reaction mixture was
suspended twice in Et2O (2 · 5 mL), and the insoluble
sulphur was filtered off. The resultant yellow oil was
redissolved in EtOH (10 mL), cooled to 0 ꢁC and NaBH4
(74 mg, 1.96 mmol) was added portionwise. After 30 min,
the resultant orange suspension was allowed to warm to
rt over 12 h. The solvent was evaporated in vacuo and
the residue diluted with H2O (5 mL) and extracted with
DCM (3 · 10 mL). The combined organic extracts were
dried and concentrated in vacuo. Purification via flash
chromatography (eluent pentane–Et2O 9:1) gave anti-8 as
colourless crystals (first to elute, 225 mg, 51%, >98% de)
and syn-9 as a colourless oil (second to elute, 39 mg, 9%,
>98% de).
4.8. tert-Butyl (2R,3R,aR)-2-tert-butylthio-3-[N-(a-methyl-
benzyl)amino]-3-phenylpropanoate 16
A solution of anti-14 (1.0 g, 2.3 mmol) in DCM (15 mL)
was added to a solution of N,N-dimethyl barbituric acid
(1.3 g, 8.3 mmol) and Pd(PPh3)4 (100 mg, 0.09 mmol) in
DCM (15 mL), and refluxed for 2 h. After cooling to rt,
the solvent was removed in vacuo, Et2O (50 mL) was added
and the precipitate filtered off. The organic extract was
washed twice with a satd aq NaHCO3 and the aqueous lay-
ers were extracted with Et2O. The combined Et2O extracts
were washed with brine, dried, filtered and concentrated in
vacuo. Purification via flash column chromatography (elu-
ent pentane–Et2O 19:1) gave 16 as a colourless oil which
crystallised slowly (900 mg, 95%, >98% de); C25H35NO2S
requires C, 72.6; H, 8.5; N, 3.4; S, 7.75; found C, 72.6;
25
H, 8.8; N, 3.7; S, 7.1; mp 66–67 ꢁC; ½aꢁD = +11.2 (c 1.0,
CHCl3); mmax (film) 1724; dH (500 MHz, CDCl3) 1.12
(9H, s, CMe3), 1.29 (3H, d, J 6.4, C(a)Me), 1.50 (9H, s,
CMe3), 2.1 (1H, br s, NH), 3.32 (1H, d, J 9.3, C(2)H),
3.64 (1H, q, J 6.4, C(a)H), 3.98 (1H, d, J 9.3, C(3)H),
7.18–7.31 (10H, m, Ph); dC (50 MHz, CDCl3) 22.0, 27.9,
30.9, 43.6, 52.8, 55.1, 62.0, 80.8, 126.6, 126.8, 127.2, 127.9,
128.2, 140.6, 146.2, 172.6; m/z (CI+) 414 ([M+H+], 100%).
Data for anti-8: C28H33NO2S requires C, 75.1; H, 7.4; N,
3.1; found C, 75.0; H, 7.3; N, 3.6; mp 193–194 ꢁC,
22
½aꢁD = ꢀ749.2 (c 0.6, CHCl3), mmax (film) 1730; dH
(300 MHz, CDCl3) 0.73 (3H, d, J 6.8, C(a)Me), 1.15 (9H,
s, CMe3), 3.35 (1H, d, J 13.7, NCHA), 3.80 (1H, d, J
13.7, NCHB), 3.92 (1H, q, J 6.8, C(a)H), 4.16 (1H, d, J
11.9 C(2)H), 4.54 (1H, d, J 11.9, C(3)H), 7.08–7.71 (15H,
m, Ph); dC (50 MHz, CDCl3) 12.2, 27.5, 49.8, 54.7, 56.0,
60.7, 81.4, 127.0, 127.2, 127.9, 128.1, 128.2, 128.6, 128.7,
129.5, 129.6, 138.8, 139.6, 142.6, 169.1; m/z (CI+) 448
([M+H+], 12%), 236 (100).
4.9. tert-Butyl (2R,3R,aR)-2-tert-butylthio-3-[N-allyl-N-(a-
methyl-p-methoxybenzyl)amino]-3-phenylpropanoate anti-17
BuLi (2.5 M in hexanes, 1.5 mL, 3.79 mmol), (R)-N-allyl-
N-(a-methyl-p-methoxybenzyl)amine (749 mg, 3.92 mmol)
in THF (5 mL), tert-butyl cinnamate (500 mg, 2.45 mmol)
in THF (5 mL) and TsStBu (718 mg, 2.94 mmol) were
reacted according to general procedure (b) and gave a
99:1 mixture of anti-17:syn-18. Purification via flash column
Data for syn-9: dH (300 MHz, CDCl3) 1.16 (3H, d, J 6.8,
C(a)Me), 1.51 (9H, s, CMe3), 3.50 (1H, d, J 14.4, NCHA),
3.69 (1H, d, J 14.4, NCHB), 3.70 (1H, d, J 11.5, C(2)H),
4.04 (1H, q, J 6.8, C(a)H), 4.42 (1H, d, J 11.5, C(3)H),
7.05–7.49 (15H, m, Ph).
chromatography (eluent pentane–Et2O 25:1) gave anti-17
23
as a yellow oil (1.18 g, 99%, >98% de); ½aꢁD = ꢀ6.4 (c 1.7,
CHCl3); mmax (film) 2975, 1724, 1512, 1367; dH (400 MHz,
CDCl3) 1.49 (3H, d, J 6.7, C(a)Me), 1.70 (9H, s, CMe3),
2.04 (9H, s, CMe3), 3.63 (1H, dd, J 14.7, 7.4, NCHA),
3.85 (1H, dd, J 14.7, 5.6, NCHB), 4.28 (3H, s, OMe), 4.42
(1H, d, J 12.2, C(2)H), 4.50 (1H, q, J 6.7, C(a)H), 4.72
(1H, d, J 12.2, C(3)H), 5.47–5.55 (2H, m, CH@CH2),
6.26–6.37 (1H, m, CH@CH2), 7.28 (2H, d, J 8.8, Ar),
7.66–7.84 (7H, m, Ar, Ph); dC (100 MHz, CDCl3) 17.7,
28.1, 31.2, 44.1, 49.3, 50.2, 55.2, 57.1, 63.0, 80.7, 113.2,
115.6, 127.1, 127.8, 129.0, 129.5, 136.9, 137.2, 138.5,
158.2, 173.0; m/z (ESI+) 484 ([M+H]+, 100%); HRMS
(ESI+) C29H41NNaO3S+ ([M+Na]+) requires 506.2699;
found 506.2711.
4.7. tert-Butyl (2R,3R,aR)-2-tert-butylthio-3-[N-allyl-N-(a-
methylbenzyl)amino]-3-phenylpropanoate anti-14
BuLi (2.5 M in hexanes, 3.0 mL, 7.6 mmol), (R)-N-allyl-N-
(a-methylbenzyl)amine (1.3 g, 7.8 mmol) in THF (10 mL),
tert-butyl cinnamate (1.0 g, 4.9 mmol) in THF (10 mL)
and TsStBu (2.4 g, 9.8 mmol) were reacted according to
general procedure (a) and gave a 97:3 mixture of anti-
14:syn-15. Purification via flash column chromatography
(eluent pentane–Et2O 4:1) gave anti-15 as a colourless oil
(1.95 g, 88%, >98% de); C28H39NO2S requires C, 74.1; H,

J. I. Candela-Lena et al. / Tetrahedron: Asymmetry 17 (2006) 1135–1145
1143
4.10. tert-Butyl (2R,3R,aR)-2-tert-butylthio-3-[N-benzyl-N-
(a-methyl-p-methoxybenzyl)amino]-3-phenylpropanoate
anti-19
vacuo. The residue was partitioned between Et2O (3 mL)
and H2O (3 mL) and the aqueous mixture was purified
via ion exchange chromatography (eluent 1 M aq NH3)
to give 22 as a white solid (97 mg, 98%); mp 142–
23
BuLi (2.5 M in hexanes, 1.5 mL, 3.79 mmol), (R)-N-benzyl-
N-(a-methyl-p-methoxybenzyl)amine (945 mg, 3.92 mmol)
in THF (5 mL), tert-butyl cinnamate (500 mg, 2.45 mmol)
in THF (5 mL) and TsStBu (718 mg, 2.94 mmol) were re-
acted according to general procedure (b) and gave a 99:1
mixture of anti-19:syn-20. Purification via flash column
144 ꢁC; ½aꢁD = +23.7 (c 0.4, MeOH); mmax (film) 3441,
1641, 1364; dH (400 MHz, D2O) 1.20 (9H, s, CMe3), 3.50
(1H, d, J 5.2, C(2)H), 4.52 (1H, d, J 5.2, C(3)H), 7.26–
7.30 (2H, m, Ph), 7.32–7.37 (3H, m, Ph); dC (100 MHz,
D2O) 30.5, 45.3, 50.9, 57.9, 127.0, 129.7, 130.0, 134.8,
177.5; m/z (ESIꢀ) 252 ([MꢀH]ꢀ, 100%); HRMS (ESI+)
C13H19NNaO2S+ ([M+Na]+) requires 276.1029; found
276.1027.
chromatography (eluent pentane–Et2O 25:1) gave anti-19
23
as a yellow oil (1.30 g, 99%, >98% de); ½aꢁD = ꢀ13.5
(c 0.5, CHCl3); mmax (film) 2975, 1717, 1512, 1367; dH
(400 MHz, CDCl3) 1.08 (3H, d, J 6.8, C(a)Me), 1.14 (9H,
s, CMe3), 1.58 (9H, s, CMe3), 3.73 (1H, d, J 14.1, NCHA),
3.78 (1H, d, J 11.8, C(2)H), 3.80 (3H, s, OMe), 4.07 (1H, q,
J 6.8, C(a)H), 4.12 (1H, d, J 14.1, NCHB), 4.26 (1H, d, J
11.8, C(3)H), 6.80 (2H, d, J 8.4, Ar), 7.14–7.38 (12H, m,
Ar, Ph); dC (100 MHz, CDCl3) 16.7, 28.1, 31.3, 44.1,
49.8, 51.0, 55.2, 58.1, 63.8, 81.0, 113.2, 126.6, 127.1,
127.6, 127.9, 128.9, 129.5, 130.0, 135.8, 138.1, 140.8,
158.3, 172.9; m/z (ESI+) 534 ([M+H]+, 100%); HRMS
(ESI+) C33H44NO3S+ ([M+H]+) requires 534.3036; found
534.3032.
4.13. tert-Butyl (2R,3R,6S,aR)- and (2S,3R,6R,aR)-3-
phenyl-4-(a-methylbenzyl)-6-methylthiomorpholine-2-
carboxylate (2R,3R,6S,aR)-25 and (2S,3R,6R,aR)-26
BuLi (2.5 M in hexanes, 18.2 mL, 45.5 mmol), (R)-N-allyl-
N-(a-methylbenzyl)amine (7.58 g, 47.0 mmol) in THF
(60 mL), tert-butyl cinnamate (6.0 g, 29.4 mmol) in THF
(60 mL) and S8 (15.1 g, 58.7 mmol) were reacted according
to general procedure (a) and gave a complex mixture of
polysulphides. The crude reaction mixture was suspended
twice in Et2O (2 · 150 mL) and the insoluble sulphur was fil-
tered off. The resultant yellow oil was redissolved in EtOH
(300 mL), cooled to 0 ꢁC and NaBH4 (2.2 g, 58.7 mmol)
was added portionwise. After 30 min, the resultant orange
suspension was allowed to warm to rt over 12 h. The sol-
vent was evaporated in vacuo and the residue diluted with
H2O (150 mL) and extracted with DCM (3 · 300 mL). The
combined organic extracts were dried and concentrated in
vacuo to give a mixture of 25 and 26 plus other acyclic
adducts. The crude product was dissolved in pentane–
Et2O (v:v 95:5) and the minor diastereoisomer 26 precipi-
tated out. The concentrated mother-liquor was subjected
to flash chromatography (eluent pentane–Et2O 19:1) to give
25 as a viscous oil, which crystallised very slowly into a
waxy solid (5.8 g, 50%, >98% de). Recrystallisation from
ethanol gave 26 as colourless needles (2.3 g, 20%, >98% de).
4.11. tert-Butyl (2R,3R,aR)-2-tert-butylthio-3-[N-(a-methyl-
p-methoxybenzyl)amino]-3-phenylpropanoate 21
CAN (1.24 g, 2.27 mmol) was added portionwise (four
portions of 311 mg, waiting between each addition until
the orange colour of the solution had disappeared) to a
ꢀ7 ꢁC chilled and stirred solution of anti-19 (807 mg,
1.51 mmol) in MeCN–H2O (v:v 5:1, 15 mL). Stirring was
continued at ꢀ7 ꢁC for a further 5 min after the last
CAN addition. The reaction was quenched by the addition
of satd aq NaHCO3 (20 mL) and stirred vigorously for
10 min before extracting with Et2O (3 · 50 mL). The com-
bined organic extracts were dried and concentrated in
vacuo. Purification via flash column chromatography
(eluent pentane–Et2O 15:1) gave 21 as a colourless oil
23
(434 mg, 58%, >98% de); ½aꢁD = +24.0 (c 1.6, CHCl3); mmax
Data for 25: C24H31NO2S requires C, 72.5; H, 7.9; N, 3.5;
(film) 3320, 2973, 1724, 1513, 1367; dH (400 MHz, CDCl3)
1.12 (9H, s, CMe3), 1.27 (3H, d, J 6.3, C(a)Me), 1.49 (9H,
s, CMe3), 1.85–2.05 (1H, br s, NH), 3.32 (1H, d, J 9.2,
C(2)H), 3.59 (1H, q, J 6.3, C(a)H), 3.78 (3H, s, OMe),
3.97 (1H, d, J 9.2, C(3)H), 6.79 (2H, d, J 8.6, Ar), 7.14
(2H, d, J 8.6, Ar), 7.23–7.34 (5H, m, Ph); dC (100 MHz,
CDCl3) 22.0, 28.0, 30.8, 43.7, 52.8, 54.4, 55.2, 62.1, 80.8,
113.6, 127.2, 127.6, 127.9, 128.0, 138.5, 140.7, 158.4,
172.6; m/z (ESI+) 444 ([M+H]+, 100%); HRMS (ESI+)
C26H38NO3S+ ([M+H]+) requires 444.2567; found
444.2559.
S, 8.1; found C, 72.45; H, 8.1; N, 3.5; S, 8.1; mp 70–72 ꢁC;
25
½aꢁD = ꢀ70.3 (c 1.0, CHCl3); mmax (KBr) 1729; dH
(500 MHz, CDCl3) 1.07 (3H, d, J 6.9, C(6)Me), 1.19 (3H,
d, J 6.8, C(a)Me), 1.38 (9H, s, CMe3), 2.32 (1H, dd, J
12.0, 10.6, C(5)HA), 2.90 (1H, dd, J 12.0, 2.7, C(5)HB),
3.39 (1H, d, J 3.9, C(2)H), 3.67 (1H, m, C(6)H), 4.11
(1H, d, J 3.9, C(3)H), 4.16 (1H, q, J 6.8, C(a)H), 7.21–
7.70 (10H, m, Ph); dC (50 MHz, CDCl3) 8.5, 18.6, 27.9,
32.5, 47.5, 54.9, 55.1, 66.6, 80.6, 126.2, 127.2, 127.8,
128.1, 128.4, 128.5, 139.9, 144.1, 169.9; m/z (CI+) 398
([M+H+], 100%), 105 (42).
4.12. (2R,3R)-2-tert-Butylthio-3-amino-3-phenylpropanoic
acid 22
Data for 26: C24H31NO2S requires C, 72.5; H, 7.9; N, 3.5;
S, 8.1; found C, 72.5; H, 7.8; N, 3.35; S, 7.9; mp 171–
25
172 ꢁC; ½aꢁD = +106.4 (c 1.0, CHCl3); mmax (KBr) 1727;
TFA (10 mL) was added dropwise to a solution of 21
(175 mg, 39.4 mmol) in DCM (10 mL) at 0 ꢁC. After
TFA addition was completed, the reaction mixture was
heated at 55 ꢁC for 24 h. The volatiles were removed
in vacuo and the residue was dissolved in methanol
(10 mL) and 6 M aq HCl (5 mL), and re-concentrated in
dH (500 MHz, CDCl3) 1.15 (9H, s, CMe3), 1.22 (3H, d, J
6.8, C(a)Me), 1.46 (3H, d, J 6.9, C(6)Me), 2.68 (1H, dd,
J 11.2, 3.4, C(5)HA), 2.88 (1H, m, C(6)H), 2.99 (1H, dd,
J 11.2, 2.8, C(5)HB), 3.88 (1H, q, J 6.8, C(a)H), 4.05
(1H, d, J 9.5, C(2)H), 4.13 (1H, d, J 9.5, C(3)H), 7.21–
7.68 (10H, m, Ph); dC (125 MHz, CDCl3) 9.0, 19.8, 27.9,

1144
J. I. Candela-Lena et al. / Tetrahedron: Asymmetry 17 (2006) 1135–1145
34.5, 48.2, 52.5, 55.6, 69.3, 81.7, 126.9, 128.0, 128.2, 128.4,
128.9, 129.3, 140.1, 144.2, 169.7; m/z (CI+) 398 ([M+H+],
100%), 105 (53).
(15 mL) and filtering off the insoluble sulphur. The residue
was then purified as previously described to give 25 and 26
(360 mg combined yield, quant).
4.14. tert-Butyl (2S,3R,6S,aR)-3-phenyl-4-(a-methylbenz-
yl)-6-methylthiomorpholine-2-carboxylate 27
Acknowledgements
The authors wish to thank Barbara Odell, for the acquisi-
tion of NMR spectra, and Robin Procter and Joanna Kirk-
patrick, for the acquisition of mass spectra.
KOtBu (0.32 g, 2.8 mmol) was added to a solution of 25
(1.77 g, 4.45 mmol) in EtOH (50 mL). The resultant yellow
mixture was stirred for 3 days at rt. The solvent was
removed in vacuo, and the residue was suspended in H2O
(20 mL) and extracted with DCM (3 · 50 mL). The organic
layer was dried and concentrated in vacuo. The resultant
yellow oil crystallised rapidly and recrystallisation from
ethanol gave 27 as colourless needles (1.15 g, 65%, >98%
de); C24H31NO2S requires C, 72.5; H, 7.9; N, 3.5; S, 8.1;
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2-Nitrobenzenesulphenyl chloride (0.4 g, 2.1 mmol) was
added to a solution of anti-14 (1.0 g, 2.1 mmol) in AcOH
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