Full text of DOI:10.1016/S0040-4020(01)00550-6

TETRAHEDRON
Pergamon
Tetrahedron 57 62001) 6589±6605
Synthesis of a-amino esters by dynamic kinetic resolution of
a-haloacyl imidazolidinones
Stephen Caddick,a,p Carlos A. M. Afonso,b Sara X. Candeias,b Peter B. Hitchcock,a
Kerry Jenkins,a L. Murtagh,d D. Pardoe,c A. Gil Santos,b Nigel R. Treweekea and Robert Weavinga
aCBDD, The Chemistry Laboratory, School of Chemistry, Physics and Environmental Sciences, CPES, University of Sussex, Falmer,
Brighton BN1 9QJ, UK
b
Â
Ã
Departamento de Quõmica, Faculdade de Ciencias e Tecnologia, Universidade Nova de Lisboa, 2825-114 Caparica, Portugal
cCACT, Glaxo SmithKline, New Frontiers Science Park 3North), Third Avenue, Harlow, Essex CM19 5AW, UK
dRhone Poulenc Rorer, Rainham Road South, Dagenham, Essex RM10 3RX, UK
Received 24 January 2001; revised 28 February 2001; accepted 27 March 2001
AbstractÐDynamic kinetic resolution of a-haloacyl imidazolidinones with a variety of nitrogen and carbon nucleophiles has been achieved
with selectivities up to 100% 6d.e.). An unusual dichotomy of diastereoselection has been observed whereby metalated nucleophiles
preferentially react via the 5S,20R diastereomer whilst amine nucleophiles react via the 5S,20S diastereomer. Mild procedures are described
for the couplingand removal of the ephedrine based chiral auxiliary. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results
Dynamic resolution strategies are being increasingly
employed in the synthesis of chiral organic molecules.1±4
The use of a-haloacyl compounds in dynamic kinetic reso-
lution 6DKR) reactions has been an active area of inter-
est.5±18 a-Haloacyl compounds are versatile precursors in
DKR reactions because they are easily obtained in racemic
form. Con®gurational lability can be readily induced and the
a-haloacyl functionality allows access to a wide range of
synthetically useful products via nucleophilic substitution.
We herein present a study on the DKR of a-haloacyl
compounds usinga chiral auxiliary approach which we
have generally developed with a view to amino-acid synth-
esis. We chose to use ephedrine derived imidazolidinones to
provide a chiral environment for ef®cient stereo-differentia-
tion.19 The chiral auxiliary 1 is readily synthesised by the
thermal fusion of ephedrinium chloride and urea.20 This
auxiliary appealed to us because of the availability of both
enantiomers of ephedrine. The saturated cyclohexyl adduct,
2, was furnished ef®ciently accordingto the procedure of
Roos and Drewes.21
2.1. Acylation of imidazolidinone auxiliaries with
racemic 2-bromoacyl bromides
In order to prepare the desired precursors we required an
Scheme 1.
Table 1. Acylation of imidazolidinone auxiliaries 1 and 2 with racemic 2-
bromoacyl bromides
Entry Auxiliary Acid bromide Temp. 68C) Product Yield 6%)
R0
Equiv.
1
2
3
4
1
1
1
2
Me
Et
n-Bu
Et
61.1)
61.1)
61.5)
61.1)
220
220
210
220
3a
3b
3c
4b
96
95
81
61a
Keywords: resolution; diastereoselection; acylation; cleavage reactions.
Correspondingauthor. Tel.: 144-1273-606755; fax: 144-1273-678734;
e-mail: s.caddick@sussex.ac.uk
p
a
79% Yield with respect to recovered 2.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020601)00550-6

6590
S. Caddick et al. / Tetrahedron 57 32001) 6589±6605
Scheme 2.
Table 2. DKR's on substrates 3a±c, 4b and 5a with amine nucleophiles
Entry
Startingmaterial
Nucleophile 6equiv.) a
n-Bu4NX 6eq.)b
Solvent
Temp.c
Time
Productd
Yield 6%)
d.e. 6%)e
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3a
3a
5a
5a
5a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
3b
3b
3c
3c
3c
3c
4b
3a
3a
3a
3b
3c
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Pyrrolidine
Pyrrolidine
Piperidine
Br
Br 62.0)
I
I 62.0)
Br
I
Br
I
I
I
I
I
I
I
I
I
I
I
I
I
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
MeCN
DMF
MeOH
THF
THF
THF
THF
THF
THF
THF
BTF
BMIBF4
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
28
D
rt
rt
rt
rt
D
rt
D
rt
D
D
83
83
rt
D
D
D
D
rt
rt
rt
D
D
77 h
42 h
48 h
44 h
62 h
46 h
91 h
91 h
51 h
69 h
50 h
7 days
24 h
43 h
49 h
4 days
48 h
48 h
63 h
48 h
72 h
43 h
4 days
48 h
48 h
47 h
72 h
6 days
48 h
48 h
75 h
44 h
24 h
47 h
23 h
6a
6a
6a
6a
7a
7a
8a
8a
6a
7a
8a
6a
6a
6a
6a
6a
6b
6b
7b
7b
8b
8b
9b
6b
6b
6c
6c
7c
8c
10b
6a
s-7a
s-7a
s-7b
s-7c
87
80
quant.
85
62
quant.
88
93
58
37
74
62
24
42
57
72
79
68
81
59f
71
6
Piperidine
9
Benzylamine
Pyrrolidine
Piperidine
96
79
91
70
90
84
73
36
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31k
32l
33
34
35
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Pyrrolidine
Pyrrolidine
Piperidine
8
0g
77
97
63
59
76
73
89
88
94
81
62
2
87
I
I
I
I
I
I
I
I
79h
97
Piperidine
Cyclohexylamine
Benzylamine
Benzylamine
Benzylamine
Benzylamine
Pyrrolidine
Piperidine
Benzylamine
Benzylamine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
88
98
45
55
71
99
94
97
79
64
64
94
i
58j
82
100
100
86
65
228
222
215
213
I
I
I
Br 65.0)
I, NO3
I, NO3
I, NO3
80
Amine DKR's carried out at 0.1 M with respect to startingmaterial 6unless otherwise stated).
1.5 equiv. nucleophile used.
a
b
0.2 equiv. n-Bu4NI/n-Bu4NBr used unless otherwise stated in parentheses; 16.0 equiv. n-Bu4NNO3 used in entries 33±35.
rtˆambient temperature); Dˆre¯ux temperature; other values relate to oil bath temperature.
c
d
e
f
Products have the 20R stereochemistry 6as depicted in Scheme 2) unless otherwise stated.
1
d.e. values determined by H NMR signal integrations. Minus 62) pre®x denotes opposite sense of stereoselectivity to that depicted in Scheme 2.
26% recovered 3a 662% d.e. in 20R), 3% recovered 5a 650% d.e. in 20R).
0.08M in 3a. 44% auxiliary, 1; 25% ester, 17a.
16% recovered 3b.
g
h
i
BMIBF4ˆ1-n-butyl-3-methylimidazolium tetra¯uoroborate.
0.083 M in startingmaterial, 27% recovered 3a.
Reaction doped with Et3N´HBr 1.0 equiv.
0.05 M in 3a.
j
k
l

S. Caddick et al. / Tetrahedron 57 32001) 6589±6605
6591
under non-epimerisingconditions simple nucleophilic
substitution reactions of diasteroisomerically pure bromides
proceed with inversion of con®guration. Under epimerising
conditions a number of DKR reactions proceeded in
excellent yield and with high selectivities. Higher levels
of selectivity were generally observed when n-Bu4NI was
used in place of n-Bu4NBr as the epimerisingagent 6entries
1 vs 3; 2 vs 4; 5 vs 6; 7 vs 8). The 20-iodo substrate 5a
gave higher selectivity than the corresponding 20-bromo
Scheme 3.
Table 3. DKR's on substrates 3a±c with ionic nucleophiles
Entry
Startingmaterial
Nucleophile
n-Bu4NX 6equiv.)a
Solventb
Temp.c
rt
rt
rt
D
D
83
83
D
Time
Productd
Yield
d.e. %e
1f
2g
3g
4
5
6
7
8
9
10
11
3a
3a
3a
3b
3b
3b
3b
3c
3c
3b
3b
SDM
SDM
SDM
SDM
SDM
SDM 62.7)
SDM 62.7)
SDM 62.7)
SDM 62.7)
NaN3 61.5)
NaN3 61.5)
Br 62)
Br 62)
I 61)
Br
I
Br
I
Br
I
THF
THF
THF
THF
THF
BTF
BTF
THF
THF
BTF
BTF
6 days
66 h
66 h
48 h
48 h
48 h
48 h
27 h
27 h
30 h
30 h
11a
11a
11a
11b
11b
11b
11b
11c
11c
12b
12b
62
78
74
90
94
93
92
83
54±60
40±60
20±25
35
14
33
28
52
31
31
D
83
83
99
quant.
95
Br
I
23
Sodium dimethyl malonate 6SDM) DKR's carried out by addition of SDM 60.70 M in THF unless otherwise stated) to a solution of startingmaterial 60.1 M in
THF).
0.2 equiv. n-Bu4NI/n-Bu4NBr used unless otherwise stated in parentheses.
a
b
BTFˆBenzotri¯uoride 6a,a,a-Tri¯uorotoluene).
c
rtˆambient temperature; Dˆre¯ux temperature; other values relate to oil bath temperature.
d
Products have the stereochemistry depicted in Scheme 3.
e
d.e. values determined by 1H NMR signal integrations except entries 8 and 9 which were isolated.
SDM 60.034 M in THF) added over 28 h to 3a 60.1 M in THF).
SDM 60.2 M in THF) added over 27 h to 3a 60.2 M in THF).
f
g
²
ef®cient acylation of the imidazolidinone chiral auxiliary.
We developed a convenient and reliable method using
2,6-lutidine and an appropriate racemic 2-bromoacyl bro-
mide 6Scheme 1, Table 1). The products were isolated as
analogue under n-Bu4NI catalysis 6entries 9 vs 3; 10 vs 6;
11 vs 8). Selectivity tended to increase with chain length
6e.g. entries 13 vs 18 vs 27). Also, when the chiral directing
group was changed from phenyl to cyclohexyl an increase in
selectivity was seen 6entry 30 vs 18). The level of stereo-
selectivity was compromised at lower reaction temperatures
6entries 18 vs 17; 20 vs 19; 22 vs 21; 27 vs 26 and 12 vs 3)
although once the optimum d.e. has been reached, raising
the temperature further appeared to have little in¯uence on
the selectivity 6entries 13 vs 3). Of the solvents explored,
THF consistently gave the best results. Polar solvents
resulted in considerable loss of selectivity 6entries 14±16).
We were surprised to observe appreciable methanolysis
when methanol was employed as the solvent 6entry 16). In
the one example in which the per¯uoro solvent BTF was
used a modest drop in selectivity resulted 6entry 24 vs 18).
Duringthe process of optimisation we noticed that increas-
ingthe amount of n-Bu4NX or usingthe ionic liquid 1- n-
butyl-3-methylimidazolium tetra¯uoroborate27 6BMIBF4)
tended to erode the selectivity 6entries 2 vs 1, 4 vs 3 and
25 vs 18). In the case of the DKR of 3a with pyrrolidine this
resulted in actual reversal of the sense of stereoselectivity
6entry 32 vs 5). These counter-intuitive results led us to
probe the effect of ionic strength on the DKR selectivities.
The use of an excess of n-Bu4NNO3 was shown to reverse
the sense of selectivity in the pyrrolidine DKR's of 3a, 3b
and 3c, albeit with low selectivity 6entries 33±35). A mild
drop in selectivity was seen when we doped the reaction of
3a and benzylamine with triethylamine hydrobromide
6entry 31 vs 3).
³
diastereomeric mixtures. Acyl chlorides are effective
reagents in this coupling protocol,§ but the potential for
bromine/chlorine transposition led us to use the correspond-
ingacyl bromides.
2.2. Dynamic kinetic resolution with amine nucleophiles
We examined DKR reactions usingamine nucleophiles as a
potential synthetic approach to enantiomerically enriched
a-amino acid derivatives 6Scheme 2, Table 2). Substrate
epimerisation was effected usingtetra- n-butylammonium
bromide/iodide 6n-Bu4NBr/I).k
Extensive control experiments con®rmed that, as expected,
²
³
21±26
A number of couplingmethods were investigated
but these gave
capricious results and frequently poor yields 6less then 50%).
The diastereomer composition sometimes varied in these reactions but the
subsequent DKR reactions were performed on substrates with 1:1 d.r. or
on mixtures that were at equilibrium under epimerisingconditions 63±
17% d.e.).
For example acylation of 1 with phenylacetyl chloride proceeded with
66% yield and acylation of 1 with propionyl chloride proceeded with 91%
yield usingthe 2,6-lutidine method.
§
k
We observed epimerisation of individual diastereomers in THF and
CDCl3 in the presence of Bu4NBr/I.

6592
S. Caddick et al. / Tetrahedron 57 32001) 6589±6605
2.4. Dynamic kinetic resolutions with sulfur nucleophiles
The results of DKR reactions using 3a and sulfur nucleo-
philes are presented below 6Scheme 4, Table 4).
The high reactivity of the sulfur nucleophiles resulted in
rapid nucleophilic displacement reactions relative to the
epimerisation process and this may explain the lack of selec-
tivity. To overcome this problem these reactions were
performed at higher dilutions than the corresponding
amine DKR's whilst the concentration of n-Bu4NBr was
kept constant. High levels of selectivity were not achieved
which is disappointingfrom a synthetic point of view. From
a mechanistic standpoint it is interestingto note that both
methyl thioglycolate and benzylmercaptan gave the 20R
products 6Table 4, entries 3±5) as the major diastereomer
Scheme 4.
Table 4. DKR's on substrate 3a with sulfur nucleophiles
Entry
Nucleophile
n-Bu4NBr 6equiv.)
[3a] 6M)
Time
Producta
Yield 6%)
d.e. 6%)b
1
2
3
4
5
PhSH
PhSH
MeOCOCH2SH
MeOCOCH2SH
PhCH2SH
2.0
20.0
2.0
20.0
2.0
0.01
0.001
0.01
0.001
0.01
4 days
7 days
48 h
7 days
7 days
S-13a
S-13a
R-14a
R-14a
R-15a
78
96
79
80
56
19
34
9
10
11
Thiol DKR's carried out in THF at rt.
The stereochemistry of the major isomer is indicated by the pre®x in the table and is as depicted in Scheme 4.
a
b
1
d.e. values determined by H NMR signal integration.
2.3. Dynamic kinetic resolution with metalated
nucleophiles
6analogous to the amines), whilst thiophenol gave predomi-
nantly the 20S product 6analogous to the diastereoselection
seen with ionic nucleophiles).
The substrates 3a±c were treated with either sodium
dimethyl malonate 6SDM) or sodium azide under substrate
epimerisingconditions 6Scheme 3). The results of some of
the DKR reactions are summarised in Table 3.
2.5. Methanolysis
The result obtained in the amine DKR carried out in metha-
nol 6see Table 2, entry 16) led us to investigate the cleavage
of the chiral auxiliary usingmild conditions 6Scheme 5,
Table 5). We ascertained that the substrates used were stable
in methanol solutions. However, we discovered that the
auxiliary could be removed under remarkably mild cleavage
conditions employinga simple amine base in methanol;
cleavage of this auxiliary under such mild basic conditions
is surprisingas conventionally, much harsher conditions are
more commonly employed.
In general, good yields were achieved although selectivity
ranged from poor to moderate. Perhaps the most striking
facet in these DKR's was the general observation that the
sense of stereoselection observed with these ionic nucleo-
philes was opposite to that seen in the DKR reactions with
amine nucleophiles. We also observed that DKR reactions
carried out under bromide epimerisation gave higher levels
of selectivity than the correspondingiodide catalysed
DKR's. Substrate 3a reacted relatively quickly with SDM
and good stereoselectivity was only achieved after opti-
misingthe reaction conditions. This was accomplished by
employingslow addition of SDM under dilute conditions
and by havingan excess of epimerisingagent 6entries 1±3).
It is interestingto note that the per¯uoro solvent, BTF,
g ave an improved d.e., over THF, in the DKR of3b with
SDM 6entry 5 vs 7). Duringthe course of our investi-
gation we have attempted to carry out DKR reactions
usingazide nucleophiles to enable us to access synthetic-
ally important a-amino acids. Typically these DKR's
have proceeded with no appreciable selectivity, as one
might expect from such a small nucleophile. However,
encouraged by the malonate DKR's carried out in BTF,
we used this solvent in the DKR's with NaN3 6entries 10
and 11). We were grati®ed to observe some selectivity
albeit modest.
The 2-aminopropionyl substrates generally cleaved readily
using1.2 equiv. of Et 3N whilst the 2-aminobutyryl and
2-aminohexanoyl substrates typically required a higher
concentration of Et3N and longer reaction times. The enan-
tiomeric excess of some of the products was shown to be
78±90% implyinga degree of racemisation. The relation-
ship between the strength of the base and the ef®ciency of
the methanolysis was implied by the methanolysis of
substrate 16 with Et3N and HuÈnig's base 6Table 5, entries
9 and 10, respectively).
3. Discussion
In this study we have not sought to optimise every DKR but
to ascertain the salient features that are important in DKR

S. Caddick et al. / Tetrahedron 57 32001) 6589±6605
6593
Scheme 5.
Table 5. Methanolysis of N-acylimidazolidinones
Entry
Substrate
[substrate]
R3N
Time
Products
Yield
6M)
Estera
1 6Yield)
1
2
3
4
5
6
7
8
9
10
S-6a
R-6a
R-6b
R-6c
R-7a
R-7c
R-8a
R-8c
16
0.11
0.11
0.11
0.12
0.10
0.50
0.10
0.50
0.10
0.10
Et3N 61.2)
Et3N 61.2)
Et3N 66.0)b
Et3N 66.0)b
Et3N 61.2)
Et3N 66.1)
Et3N 61.2)
Et3N 66.1)
Et3N 61.0)
i-Pr2NEt 61.0)
24 h
23 h
6 days
7 days
26 h
16 days
26 h
16 days
76 h
76 h
S-17a
R-17a
R-17b
R-17c
R-18a
R-18c
R-19a
R-19c
20
72
75
84
62
39
68
71
65
39
78
73
77
85c
79
37
49
19
63d
34e
47f
16
20
Reactions carried out in dry methanol at re¯ux.
a
The product e.e. was determined by chiral HPLC 6Chiralcelw OD) for entries 1±4. Entries 1, 2 and 4 gave 90% e.e; entry 3 gave 78% e.e..
b
c
d
e
f
1.2 equiv. Et3N followed by 4.8 equiv. after 48 hours.
5% recovered R-6b.
20% recovered R-8c.
29% recovered 16.
3% recovered 16.
systems of this type. From our results we can make a
alteringthe conformation and hence reversingthe stereo-
number of generalisations. Perhaps the most intriguing
aspect of this study is the dichotomy of stereoselectivity
observed between the metalated and the neutral nucleo-
philes. The former can be rationalised utilisinga model
originally proposed in other related systems.10,15 To account
for the anomalous stereoselectivity observed with amine
nucleophiles, we have previously proposed a model based
on a hydrogen bonded amine-substrate complex. In this
model we postulated that a bifurcated hydrogen bond
bridges the imidazolidinone and acyl carbonyl groups thus
selectivity of the DKR reaction 6Fig. 1).1,5 We have used
this model as a simple device from which we can predict the
stereochemical outcome of our reactions and it can be used
to rationalise all DKR results presented thus far. However,
as will be discussed in the followingpaper, we have carried
out extensive molecular modellingexperiments and feel that
the assembly shown in Fig. 2 is probably more accurate. It
too relies on a H-bond model in which the amine forms a
more conventional H-bond with the strongly basic ring car-
bonyl group. The stereochemical outcome is governed by
Figure 1.
Figure 2.

6594
S. Caddick et al. / Tetrahedron 57 32001) 6589±6605
the steric and/or electrostatic interactions between the
bromine leavingrgoup and the phenyl rgoup on the
auxiliary. As the amine undergoes substitution a twisting
of the C1±C2 bond is required which potentiates these inter-
actions in the 20R isomer but not in the 20S isomer, hence its
greater reactivity with H-bonding nucleophiles.
The acylation utilises the amine base 2,6-lutidine thus
obviatingthe need for organometallic bases and the asso-
ciated low temperatures that they necessitate. The mild
methanolysis reactions have synthetic potential although
the usefulness of this protocol may be limited by the accom-
panyingreduction of optical purity. Work is continuingto
further extend the scope of dynamic resolutions toward
asymmetric synthesis and to probe the reactive properties
observed with N-acyl imidazolidinones.
The sense of diastereocontrol in the DKR reactions with
methyl thioglycolate and benzylmercaptan were analogous
to those of the amine DKR's. The poor selectivity may, in
part, be a re¯ection of the relatively poor hydrogen bond
donor properties of thiols. The result of the DKR with thio-
phenol, which reacted preferentially with the 20R diastereo-
mer, is easily understood in that in the presence of Et3N,
thiophenol exists as a salt complex 6pKa PhSHˆ6.5; pKa
Et3NH1ˆ10.7). Hence under the reaction conditions thio-
phenol will react principally as the thiophenolate anion and
the model previously presented for metalated nucleophiles
applies in this case.
5. Experimental
All glasswares were oven dried and cooled in a desiccator
6P2O5 desiccant) prior to use. Reaction solvents were pre-
dried and distilled immediately prior to use. Tetrahydro-
furan 6THF) was pre-dried over sodium wire and distilled
from sodium/benzophenone under a nitrogen atmosphere.
Methanol was distilled from iodine/magnesium turnings
under a nitrogen atmosphere. N,N-Dimethyl formamide
6DMF), acetonitrile and dichloromethane 6DCM) were
distilled from calcium hydride powder under a nitrogen
atmosphere.
The diminished selectivity seen with amine DKR's in polar
solvents might be attributed to the disruption of hydrogen
bondinginteractions. Similarly the presence of high concen-
trations of organic salts lead to selectivity erosions and
reversals in some cases. In addition to disruptinghydrogen
bonding, the ionic strength media would also provide
stabilisation of localised partial charges in the transition
state. Hence a formal SN2 mechanism would become
increasingly favourable. This would tend to result in prefer-
Commercially supplied reagents were used as supplied
except for acyl halides which were distilled prior to use.
1-n-Butyl-3-methylimidazolium tetra¯uoroborate 6BMIBF4)
28
was prepared followingreported procedure.
ential reaction of the 20R diastereomer. This also holds true
Flash column chromatography was carried out using Merck
60 silica gel 670±240 mm) or basic alumina 6activated,
Brockmann grade II). The non polar liquid phase was either
distilled hexanes or petroleum ether 40±608C boiling
fraction unless otherwise stated. Pet30±40 refers to petroleum
ether 30±408C boilingfractions which were distilled prior to
use. Other eluents were used as supplied. Thin layer
chromatography was carried out using Merck Kieselgel 60
F254 pre-coated, glass backed plates. The plates were
visualised usingultraviolet light 6254 nm), KMnO 4 solution,
ninhydrin or iodine as appropriate. HPLC was carried out
usinga Chiralcel OD-H 60.46 cm B£25 cm) stationary
phase.
2
for the reaction carried out in the ionic solvent BMIBF4
.
The use of n-Bu4NI as the epimerisingagent presumably
generates the 20-iodo analogues in-situ. This may account
for the enhanced stereoselectivity with amines. Indeed, the
use of the stoichiometric 20-iodo substrate led to higher dia-
stereoselectivities. This behaviour can also be explained
usingthe revised H-bond model which will be presented
in detail in the adjoiningpaper.
4. Conclusion
We have shown that dynamic kinetic resolution of a-halo-
acyl imidazolidinones can be successfully applied towards
the synthesis of a range of enantiomerically enriched
products. The use of amine nucleophiles in particular allows
access to a-amino acid derivatives, often with excellent
yield and stereoselectivity 6up to 100%). We have achieved
DKR reactions with sodium dimethylmalonate as a carbon
nucleophile. The potential for asymmetric carbon±carbon
bond homologation is very appealing although further
optimisation may be needed if this approach is to be syn-
thetically useful. The poor selectivities observed with sulfur
nucleophiles are disappointing. Our use of the ephedrine
derived chiral auxiliaries was justi®ed from a practical
and economic standpoint. The diastereomeric nature of the
products of these DKR reactions greatly assists in the
separation and puri®cation of the desired stereoisomer
whereas in an enantioselective process one must generate
the product with initially high e.e. unless the product can be
enriched by crystallisation. The development of facile
couplingand cleavaeg protocols alleviates some of the
inherent disadvantages associated with chiral auxiliaries.
1H NMR spectra were recorded on BruÈker AMX 500, ARX
400, WM 360 or DPX 300 spectrometers. Chemical shifts
are reported down®eld in parts per million 6ppm) from a
tetramethyl silane reference. 13C NMR spectra were
recorded on BruÈker AMX 500, ARX 400 or DPX 300
spectrometers at 125, 100 or 75 MHz, respectively. Infra
red spectra were recorded on a Perkin±Elmer FT-IR 1720
spectrometer as thinly dispersed ®lms 6from DCM) between
sodium chloride plates unless otherwise stated. Low resolu-
tion 6EI/FAB) mass spectra were recorded usinga Fisons
Autospec or Kratos mass spectrometer. High resolution
accurate mass determinations were carried out by the
EPSRC National Mass Spectrometry Service, University
of Wales-Swansea, Singleton Park, Swansea, Wales.
Optical rotations were carried out usinga Perkin±Elmer
241 or Optical Activity Mod. AA-1000 digital polarimeters
with a cell path length of 10 or 5 cm, respectively. The mean
value for 10 a readings was taken. Melting points were
carried out on a Gallenkamp meltingpoint apparatus and
are uncorrected. X-Ray crystal structure data was collected

S. Caddick et al. / Tetrahedron 57 32001) 6589±6605
6595
usingEnraf±Nonius CAD software. Structure solutions and
re®nements were carried out using shelxs-86 and shelxl-
93 programs, respectively.
20R-3b: mp 85±878C; nmax 3042, 2985, 2946, 2889, 1736,
1690, 1389 cm21; dH 6CDCl3) 7.28±7.14 65H, m, ArH),
5.74 61H, t, Jˆ7.3 Hz, COCH6Br)CH2), 5.26 61H, d, Jˆ
8.8 Hz, NCH6Ph)CH), 3.85 61H, dq, Jˆ6.6, 8.8 Hz,
NCH6CH3)CH), 2.78 63H, s, NCH3), 2.03 61H, ddq,
Jˆ7.3, 7.3, 13.8 Hz, CH6Br)CHAHBCH3), 1.92 61H, ddq,
Jˆ7.3, 7.3, 13.8 Hz, CH6Br)CHAHBCH3), 0.94 63H, t, Jˆ
7.3 Hz, CH2CH3), 0.73 63H, d, Jˆ6.6 Hz, CHCH3); dC
6CDCl3): 168.1, 154.7, 135.4, 128.4, 128.2, 126.9, 59.2,
53.8, 46.8, 28.3, 27.1, 15.1, 12.0; m/z 6EI) 338 6M1), 259,
189, 132, 58; Found M1, 338.0629. C15H19BrN2O2 requires
5.1. Auxiliary coupling reactions
General procedure. To a stirred solution of imidazolidinone
in DCM or THF, under an inert atmosphere 6argon or N2),
was added 2,6-lutidine. The solution was cooled and 2RS-
bromoacyl halide was added in a drop wise fashion. The
reaction was monitored by TLC and quenched with satu-
rated 6aq.) NH4Cl. The mixture was diluted with DCM and
extracted with saturated 6aq.) NH4Cl 64±5 portions). The
combined aqueous phase was back extracted with DCM
and the combined organic phase was washed once with
brine and dried with MgSO4. The crude product was puri®ed
by column chromatography.
M, 338.0630; Rfˆ0.46 Hex./EtOAc 66:4); [a]25 ˆ279.88
D
6cˆ1.0, CHCl3).
20S-3b: mp 75±778C; nmax 3031, 2978, 2934, 2877, 1736,
1690, 1389 cm21; dH 6CDCl3) 7.28±7.20 63H, m, ArH),
7.06 62H, m, ArH), 5.80 61H, t, Jˆ7.2 Hz, COCH6Br)CH2),
5.24 61H, d, Jˆ8.5 Hz, NCH6Ph)CH), 3.91 61H, dq, Jˆ6.5,
8.5 Hz, NCH6CH3)CH), 2.79 63H, s, NCH3), 2.00 61H, ddq,
Jˆ7.2, 7.3, 14.3 Hz, CH6Br)CHAHBCH3), 1.89 61H, ddq,
Jˆ7.2, 7.3, 14.3 Hz, CH6Br)CHAHBCH3), 0.84 63H, t, Jˆ
7.3 Hz, CH2CH3), 0.75 63H, d, Jˆ6.6 Hz, CHCH3); dC
6CDCl3): 168.6, 154.9, 136.3, 128.6, 128.2, 126.8, 59.9,
53.8, 46.9, 28.2, 28.0, 14.8, 11.8; m/z 6EI) 338 6M1), 259,
149, 132, 57, 41; Found M1, 338.0638. C15H19BrN2O2
requires M, 338.0630; Rfˆ0.58 Hex./EtOAc 66:4);
5.1.1. Preparation of /20RS,4S,5R)-1-N-/20-bromopropa-
noyl)-3,4-dimethyl-5-phenylimidazo-lidin-2-one, 20RS-
3a /Table 1, entry 1). 1 6100.3 mg, 5.3 mmol), 2,6-lutidine
60.07 mL, 0.60 mmol), 2RS-bromopropanoyl bromide
60.06 mL, 0.57 mmol), DCM 63.0 mL). Reaction performed
at 2208C. Reaction time 2 h. Puri®cation 6SiO2, Hex/EtOAc
8:2, 7:3 and 6:4) gave the diastereomers 20RS-3a as a white
crystalline solid 6164.3 mg, 96%).
[a]25 ˆ2105.38 6cˆ1.1, CHCl3).
D
20R-3a: mp 144.9±147.58C; nmax 3031, 2977, 2917, 2352,
1729, 1693, 1651, 1634, 1556, 1515, 1471, 1429, 1387,
1308, 1289, 1239, 1192, 1059, 991, 946, 776, 759, 700,
676 cm21; dH 6CDCl3) 7.37±7.22 65H, m, Ph), 5.98 61H,
q, Jˆ6.8 Hz, COCH6Br)CH3), 5.34 61H, d, Jˆ8.8 Hz,
NCH6Ph)CH), 3.92 61H, m, NCH6CH3)CH), 2.86 63H, s,
NCH3), 1.78 63H, d, Jˆ6.8 Hz, CH6Br)CH3), 0.82 63H, d,
Jˆ6.6 Hz, CHCH3); dC 6CDCl3) 170.5, 156.6, 137.3, 130.4,
130.1, 128.9, 60.1, 55.7, 41.6, 30.3, 22.2, 17.1; m/z 6EI) 326
6M1), 245 6M12Br), 189 6M12COCH6Br)CH3), 175, 132,
91, 77, 58, 42; Found M1, 324.0473. C14H17BrN2O2
5.1.3. Preparation of /20RS,4S,5R)-1-N-/20-bromohexa-
noyl)-3,4-dimethyl-5-phenylimidazolidin-2-one, 20RS-3c
/Table 1, entry 3). 1 6426 mg, 2.43 mmol), 2,6-lutidine
60.31 mL, 2.66 mmol), 2RS-bromohexanoyl bromide
60.58 mL, 3.65 mmol), DCM 69 mL). Reaction performed
at 2108C. Reaction time 25 min. Puri®cation 6SiO2, Pet/
EtOAc 4:1±3:1) gave 20RS-3c 6720 mg, 81%).
20R-3c; mp 86.5±88.58C; nmax 2927, 2857, 1732, 1688,
1457, 1423, 1390, 1313, 1261, 1201, 1071, 757,
701 cm21; dH 6CDCl3) 7.30±7.13 65H, m, Ph), 5.81 61H,
t, Jˆ7.4 Hz, COCH6Br)CH2), 5.27 61H, d, Jˆ8.8 Hz,
NCH6Ph)CH), 3.86 61H, m, NCH6CH3)CH), 2.79 63H, s,
NCH3), 2.06±1.84 62H, m, CH6Br)CH2CH2), 1.39±1.17
64H, m, CH2CH2CH2CH3), 0.82 63H, t, Jˆ7.0 Hz,
±CH2CH3), 0.74 63H, d, Jˆ6.6 Hz, CHCH3); dC 6CDCl3)
167.2, 153.7, 134.3, 127.4, 127.2, 125.9, 58.2, 52.7, 44.0,
32.4, 28.4, 27.3, 21.2, 14.1, 12.8; m/z 6EI) 366 6M1), 325
6M12C3H7), 287 6M12Br), 245, 232, 189 6Aux), 175, 132,
58; Found M1, 366.0943. C17H23BrN2O2 requires M,
requires M, 324.0473; Rfˆ0.22 Pet/EtOAc 62:1); [a]32
ˆ
D
282.48 6cˆ6.3, CHCl3).
20S-3a: mp 132.5±133.58C; nmax 3076, 3035, 2989, 2879,
1729, 1688, 1495, 1445, 1422, 1377, 1307, 1289, 1259,
1237, 1188, 1137, 1107, 1082, 1060, 1029, 991, 948, 864,
811, 781, 757, 742, 698, 672 cm21; dH 6CDCl3) 7.34±7.27
63H, m, 3ArH), 7.13 62H, m, 2ArH), 6.00 61H, q, Jˆ6.7 Hz,
COCH6Br)CH3), 5.29 61H, d, Jˆ8.3 Hz, NCH6Ph)CH), 4.00
61H, m, NCH6CH3)CH), 2.88 63H, s, NCH3), 1.75 63H, d,
Jˆ6.7 Hz, CH6Br)CH3), 0.82 63H, d, Jˆ6.5 Hz, CHCH3);
dC 6CDCl3): 169.4, 155.3, 136.6, 129.0, 128.7, 127.2, 60.4,
54.2, 40.5, 28.6, 21.4, 15.2; m/z 6EI) 324 6M1), 245,
189, 175, 132, 91, 77, 58, 42; Found M1, 324.0473.
C14H17BrN2O2 requires M, 324.0473; Rfˆ0.53 Pet/EtOAc
366.0943; Rfˆ0.72 Pet/EtOAc 61:1); [a]25 ˆ244.48
D
6cˆ0.6, CHCl3).
20S-3c; mp 71.2±73.58C; nmax 3033, 2957, 2872, 1732,
1688, 1457, 1422, 1390, 1313, 1289, 1261, 1201, 1071,
983, 757, 701, 672 cm21; dH 6CDCl3) 7.29±7.20 63H, m,
3ArH), 7.05 62H, m, 2ArH), 5.89 61H, t, Jˆ7.3 Hz,
COCH6Br)CH2), 5.25 61H, d, Jˆ8.5 Hz, NCH6Ph)CH),
3.91 61H, m, NCH6CH3)CH), d 2.79 63H, s, NCH3), 2.10±
1.80 62H, m, CH6Br)CH2CH2), 1.30±1.06 64H, m,
CH2CH2CH2CH3), 0.76 63H, t, Jˆ8.3 Hz, CH2CH3; 3H, d,
Jˆ6.7 Hz, CHCH3); dC 6CDCl3) 167.0, 153.2, 134.5, 126.8,
126.5, 125.1, 58.1, 52.0, 43.3, 32.6, 27.6, 26.4, 20.3, 13.1,
12.1; m/z 6EI) 366 6M1), 325 6M12C3H7), 287 6M12Br),
245, 205, 191, 175, 132, 84, 49; Found M1, 366.0943.
62:1); [a]32 ˆ289.28 6cˆ8.9, CHCl3).
D
5.1.2. Preparation of /20RS,4S,5R)-1-N-/20-bromobuta-
noyl)-3,4-dimethyl-5-phenylimidazo-lidin-2-one, 20RS-
3b /Table 1, entry 2). 1 61.00 g, 5.26 mmol), 2,6-lutidine
60.68 mL, 0.58 mmol), 2RS-bromobutanoyl bromide
60.68 mL, 5.81 mmol), DCM 630 mL). Reaction performed
at 2208C. Reaction time 90 min. Puri®cation 6SiO2, Pet/
EtOAc 8:2±6:4) gave 20RS-3b 61.70 g, 95%).

6596
S. Caddick et al. / Tetrahedron 57 32001) 6589±6605
C17H23BrN2O2 requires M, 366.0943; Rfˆ0.81 Pet/EtOAc
5.1.6. Preparation of /20RS,4S,5R)-1-N-/20-iodopropa-
noyl)-3,4-dimethyl-5-phenylimidazolidin-2-one, 20RS-
5a. To a stirred solution of 3a 6750 mg, 2.31 mmol, 29%
d.e. in 20S-3a) in acetone 65 mL) was added a solution of
sodium iodide 61.23 M, 3.75 mL, 4.62 mmol) in acetone.
After 22 h the reaction mixture was ®ltered through a sinter
and the ®ltrate was reduced in vacuo. The crude residue was
dissolved in DCM 620 mL) and was washed with distilled
water 64£10 mL) and brine 610 mL). The organic phase was
dried with MgSO4 and the crude product was puri®ed by
column chromatography 6SiO2, Hex:EtOAc 8:1±2:1) to
give the product diastereomers of 5a as white crystalline
solids 6796 mg, 92.7%, 50.0% d.e. in favour of 20R-5a).
61:1); [a]25 ˆ280.08 6cˆ1.7, CHCl3).
D
5.1.4. Preparation of /20RS,4S,5R)-1-N-/20-bromobuta-
noyl)-3,4-dimethyl-5-cyclohexylimidazo-lidin-2-one,
20RS-4b /Table 1, entry 4). 2 60.50 g, 2.56 mmol), 2,6-
lutidine 60.33 mL, 2.83 mmol), 2RS-bromobutanoyl bro-
mide 60.33 mL, 2.82 mmol), DCM 615 mL). Reaction
performed at 2208C. Reaction time 70 min. Puri®cation
6SiO2, Hex/EtOAc 9:1±6:4 then EtOAc) gave 20RS-4b
60.54 g, 61%) and recovered 2 60.09 g, 18%).
20R-4b: mp 120.5±1228C; nmax 2970, 2930, 2848, 1721,
1679, 1392 cm21; dH 6CDCl3) 5.75 61H, t, Jˆ7.3 Hz,
COCH6Br)CH2), 4.35 61H, dd, Jˆ2.4, 7.3 Hz, NCH-
6C6H11)CH), 3.63 61H, dq, Jˆ6.9, 7.3 Hz, NCH6CH3)CH),
2.71 63H, s, NCH3), 2.04 61H, ddq, Jˆ7.3, 7.4, 14.2 Hz,
CH6Br)CHAHBCH3), 1.97 61H, ddq, Jˆ7.3, 7.4, 14.2 Hz,
CH6Br)CHAHBCH3), 1.73±1.56 66H, m, ±6CH2)3±), 1.27
63H, d, Jˆ6.9 Hz, CHCH3), 1.25±1.04 65H, m, CH-
6CH2)2±), 0.94 63H, t, Jˆ7.4 Hz, CH2CH3); dC 6CDCl3):
169.3, 155.4, 60.0, 58.7, 54.4, 47.0, 40.0, 32.2, 27.7, 27.3,
27.1, 26.1, 12.9, 12.0; m/z 6EI) 344 6M1), 265, 223, 183,
113, 41; Found M1, 344.1110. C15H25BrN2O2 requires M,
344.1099; Rfˆ0.44 Hex./EtOAc 66:4); [a]Dˆ26.98 6cˆ1.0,
CHCl3).
20R-5a; mp 138.0±140.48C; nmax 3031, 2974, 2913, 1728,
1681, 1428, 1398, 1373, 1305, 1288, 1265, 1234, 1209,
1175, 1155, 1087, 1058, 1039, 986, 946, 860, 804, 755,
758, 737, 699, 674 cm21; dH 6CDCl3) 7.31±7.17 65H, m,
Ph), 6.03 61H, q, Jˆ6.9 Hz, COCH6I)CH3), 5.25 61H, d,
Jˆ8.8 Hz, NCH6Ph)CH), 3.85 61H, m, NCH6CH3)CH),
2.78 63H, s, NCH3), 1.85 63H, d, Jˆ6.9 Hz, CH6I)CH3),
0.73 63H, d, Jˆ6.6 Hz, CHCH3); dC 6CDCl3) 171.7, 156.1,
136.7, 129.8, 129.6, 128.5, 60.5, 55.1, 29.7, 23.6, 17.0, 16.6;
m/z 6EI) 372 6M1), 245 6M12I), 191 6M12COCH6I)CH3),
175, 132, 91, 77, 58, 42; Found M1, 372.0335. C14H17IN2O2
requires M, 372.0335; Rfˆ0.30 Pet/EtOAc 62:1); [a]36
ˆ
D
286.08 6cˆ1.2, CHCl3).
20S-4b: mp 86.5±90.58C; nmax 6KBr) 2947, 2925, 2852,
1727, 1683, 1389 cm21
;
dH 6CDCl3) 5.75 61H, t,
20S-5a; mp 125.6±126.78C; nmax 3033, 2983, 2919, 2352,
1728, 1681, 1556, 1539, 1495, 1455, 1422, 1373, 1309,
1289, 1259, 1233, 1202, 1172, 1129, 1081, 1060, 1030,
987, 946, 862, 810, 781, 757, 737, 699, 672 cm21; dH
6CDCl3) 7.29±7.20 63H, m, 3ArH), 7.07±7.04 62H, d,
2ArH), 6.06 61H, q, Jˆ6.9 Hz, COCH6I)CH3), 5.19 61H,
d, Jˆ8.4 Hz, NCH6Ph)CH), 3.94 61H, m, NCH6CH3)CH),
2.81 63H, s, NCH3), 1.81 63H, d, Jˆ6.8 Hz, CH6I)CH3), 0.74
63H, d, Jˆ6.6 Hz, CHCH3); dC 6CDCl3) 171.4, 155.4, 136.8,
129.0, 128.7, 127.2, 60.5, 54.1, 28.6, 23.1, 15.8, 15.2; m/z
6EI) 372 6M1), 245 6M12I), 191 6M12COCH6I)CH3), 175,
132, 91, 77, 58, 42; Found M1, 372.0335. C14H17IN2O2
requires M, 372.0335; Rfˆ0.58 Pet/EtOAc 62:1);
Jˆ7.1 Hz, COCH6Br)CH2), 4.28 61H, dd, Jˆ2.7, 8.1 Hz,
NCH6C6H11)CH), 3.71 61H, dq, Jˆ6.9, 7.1 Hz, NCH-
6CH3)CH), 2.74 63H, s, NCH3), 2.14 61H, ddq, Jˆ7.1, 7.3,
14.3 Hz, CH6Br)CHAHBCH3), 2.00 61H, ddq, Jˆ7.1,
7.3, 14.3 Hz, CH6Br)CHAHBCH3), 1.69±1.51 66H, m,
±6CH2)3±), 1.26 63H, d, Jˆ6.8 Hz, CHCH3), 1.19±0.95
65H, m, CH6CH2)2±), 1.01 63H, t, Jˆ7.3 Hz, CH2CH3); dC
6CDCl3): 169.3, 155.6, 60.5, 54.4, 47.8, 39.0, 32.5, 28.4,
27.7, 27.6, 26.8, 26.1, 26.0, 12.8, 12.1; m/z 6EI) 344
6M1), 265, 223, 183, 113, 41; Found M1, 344.1131.
C15H25BrN2O2 requires M, 344.1099; Rfˆ0.60 Hex./
EtOAc 66:4); [a]Dˆ215.18 6cˆ1.2, CHCl3).
[a]39 ˆ254.08 6cˆ1.2, CHCl3).
D
5.1.5. Preparation of /4S,5R)-1-N-/phenylacetyl)-3,4-
dimethyl-5-phenyl-imidazolidin-2-one, 16. 1 6500 mg,
2.64 mmol), 2,6-lutidine 60.31 mL, 2.66 mmol), phenyl-
acetyl chloride 60.52 mL, 3.93 mmol), THF 610 mL). Reac-
tion performed at 08C. Reaction time 4 h. Puri®cation 6SiO2,
Pet/Et2O 3:1±1:2) gave 16 as a white crystalline solid
6534 mg, 65.6%).
5.2. Dynamic kinetic resolutions /DKR) with amine
nucleophiles
5.2.1. General procedure. To a stirred solution of 20-halo-
acylimidazolidinone, tetra-n-butylammonium halide and
triethylamine in an appropriate solvent was added the
amine nucleophile. Reactions were monitored by TLC and
were worked up by dilution in diethyl ether and washed with
distilled water. The organic phase was dried with MgSO4
and the crude product was puri®ed by column chroma-
tography unless otherwise stated.
16; mp 123.5 2124.18C; nmax 3064, 3030, 2980, 2892,
1953, 1726, 1668, 1602, 1495, 1455, 1422, 1361, 1263,
1176, 1093, 1077, 1031, 999, 951, 934, 873, 844, 819,
793, 704, 640, 600 cm21; dH 6CDCl3) 7.24±7.11 68H, m,
ArH), 7.00±7.97 62H, m, ArH), 5.21 61H, d, Jˆ8.6 Hz,
NCH6Ph)CH), 4.27 62H, s, COCH2Ph), 3.80 61H, m,
NCH6CH3)CH), 2.75 63H, s, NCH3), 0.70 63H, d, Jˆ
6.6 Hz, CHCH3); dC 6CDCl3) 170.8, 156.1, 136.9, 135.0,
130.2, 128.9, 128.7, 128.5, 127.4, 127.1, 59.9, 54.2, 42.2,
28.7, 15.4; m/z 6EI) 308 6M1), 217 6M12PhCH2), 191
6M12COCH2Ph), 175, 135, 118, 91, 58; Found M1,
308.1525. C19H20N2O2 requires M, 308.1525; Rfˆ0.53
5.2.2. Typical procedure for DKR of 20RS-3a with
benzylamine /1.5 equiv.), Bu4NBr /0.2 equiv.), THF
[0.10 M] /Table 2, entry 1, for speci®c conditions of
related experiments see Table 2). 20RS-3a 665.0 mg,
0.20 mmol), Bu4NBr 612.9 mg, 0.040 mmol), Et3N
60.034 mL, 0.240 mmol), benzylamine 60.033 mL,
0.302 mmol) in THF 62.0 mL). Reaction time 77 h.
Pet/EtOAc 61:1); [a]31 ˆ260.38 6cˆ1.4, CHCl3).
D

S. Caddick et al. / Tetrahedron 57 32001) 6589±6605
6597
Puri®cation 6SiO2, Pet/EtOAc 2:1±1:2) gave 20R-6a
661.4 mg, 87.5%, 57.8% d.e.).
N6CHBHACH2)2), 1.65 64H, s, N6CH2CH2)2), 1.34 63H, d,
Jˆ6.8 Hz, CH6NR2)CH3), 0.79 63H, d, Jˆ6.6 Hz, CHCH3);
dC 6CDCl3) 174.0, 156.0, 137.1, 128.8, 128.4, 127.5, 59.7,
59.0, 54.3, 50.5, 28.7, 23.8, 16.6, 15.4; m/z 6EI) 315 6M1),
149, 132, 117, 98, 84, 56, 42; Found M1, 315.1947.
C18H25N3O2 requires M, 315.1947; Pet/EtOAc 61:2);
5.2.3. DKR of 20RS-5a with benzylamine /Table 2, entry
9). 20RS-5a 674.3 mg, 0.200 mmol), Bu4NI 614.7 mg,
0.040 mmol), Et3N 60.033 mL, 0.237 mmol), benzylamine
60.033 mL, 0.302 mmol) in THF 62.0 mL). Reaction time
51 h. Puri®cation 6SiO2, Hex/EtOAc 1:1) gave 20R-6a
667.5 mg, 96.1%, 78.8% d.e.).
[a]25 ˆ247.18 6cˆ1.2, CHCl3).
D
20S-7a; nmax 2971, 1729, 1689, 1456, 1422, 1391, 1310,
1260, 1230, 1202, 1172, 1070, 945, 860, 758, 701 cm21
;
20R-6a; nmax 3335, 3063, 3031, 2979, 2935, 2869, 1954,
1729, 1681, 1606, 1587, 1495, 1455, 1423, 1387, 1310,
1288, 1234, 1205, 1155, 1125, 1066, 1029, 966, 948, 910,
858, 810, 735, 701, 628 cm21; dH 6CDCl3) 7.38±7.13 610H,
m, 2Ph), 5.33 61H, d, Jˆ8.6 Hz, NCH6Ph)CH), 4.80
61H, q, Jˆ6.8 Hz, COCH6NHR)CH3), 3.94 61H, m,
NCH6CH3)CH), 3.48 61H, d, Jgemˆ12.5 Hz, HNCHAHBPh),
3.43 61H, d, Jgemˆ12.5 Hz, HNCHBHAPh), 2.84 63H, s,
NCH3), 2.27 61H, br s, NH), 1.34 63H, d, Jˆ6.8 Hz,
CH6NH)CH3), 0.83 63H, d, Jˆ6.5 Hz, CHCH3); dC
6CDCl3) 176.3, 157.3, 140.0, 136.6, 128.4, 128.1, 128.04,
127.99, 126.8, 126.7, 59.4, 55.3, 53.9, 51.4, 28.1, 19.4, 14.8;
m/z 6EI) 351 6M1), 260 6M12PhCH2), 246 6M12NCH2Ph),
191 6Aux H1), 175, 134, 91, 58, 42; Found M1, 351.1947.
C21H25N3O2 requires M, 351.1947; Rfˆ0.18 Pet/EtOAc
dH 6CDCl3) 7.28±7.08 65H, m, Ph), 5.30 61H, d,
Jˆ8.6 Hz, NCH6Ph)CH), 4.70 61H, q, Jˆ6.9 Hz, COCH-
6NR2)CH3), 3.87 61H, m, NCH6CH3)CH), 2.78 63H, s,
NCH3), 2.70 62H, d, Jgemˆ6.2 Hz, N6CHAHBCH2)2), 2.62
62H, d, Jgemˆ6.4 Hz, N6CHBHACH2)2), 1.70 64H, s,
N6CH2CH2)2), 1.28 63H, d, Jˆ6.9 Hz, CH6NR2)CH3), 0.75
63H, d, Jˆ6.6 Hz, CHCH3); dC 6CDCl3) 173.5, 155.3, 136.5,
128.2, 127.7, 126.7, 58.9, 58.3, 53.3, 49.9, 28.0, 23.4, 15.0,
14.8; m/z 6EI) 315 6M1), 245, 217, 191, 175, 132, 117, 99,
56, 42; Found M1, 315.1947. C18H25N3O2 requires M,
315.1947; [a]25 ˆ293.78 6cˆ0.6, CHCl3).
D
5.2.5. Typical procedure for DKR of 20RS-3a with piperi-
dine /1.5 equiv.), n-Bu4NBr /0.2 equiv.), THF [1.0 M]
/Table 2, entry 7, for speci®c conditions of related
experiments see Table 2). 20RS-3a 665.1 mg, 0.20 mmol),
Bu4NBr 612.9 mg, 0.04 mmol), Et3N 60.034 mL,
0.24 mmol), piperidine 60.03 mL, 0.30 mmol), in THF
62.0 mL). Reaction time 91 h. Reaction mixture diluted
with EtOAc 610 mL), washed with distilled water
64£10 mL) and dried with MgSO4. Repeated triteration in
61:1); [a]37 ˆ219.88 6cˆ2.7, CHCl3).
D
20S-6a; nmax 3326, 3062, 3031, 2979, 2934, 1729, 1681,
1605, 1495, 1455, 1423, 1387, 1353, 1310, 1289, 1260,
1235, 1205, 1158, 1126, 1065, 1029, 966, 948, 808, 740,
702 cm21; dH 6CDCl3) 7.34±7.13 610H, m, 2Ph), 5.29 61H,
d, Jˆ8.7 Hz, NCH6Ph)CH), 4.76 61H, q, Jˆ6.7 Hz,
COCH6NHR)CH3), 3.92 61H, m, NCH6CH3)CH), 3.74
0
Et2O and dryingin vacuo gave 2 R-8a as a clear viscous oil
657.7 mg, 88%, 57% d.e.).
61H, d, Jgemˆ12.3 Hz, HNCHAHBPh), 3.64 61H, d, Jgem
ˆ
12.3 Hz, HNCHBHAPh), 2.85 63H, s, NCH3), 2.18 61H, br
s, NH), 1.30 63H, d, Jˆ6.8 Hz, CH6NH)CH3), 0.82 63H, d,
Jˆ6.4 Hz, CHCH3); dC 6CDCl3) 178.5, 157.7, 142.6, 138.9,
131.0, 130.8, 130.7, 129.3, 129.2, 60.5, 58.1, 56.1, 55.0,
30.6, 22.3, 17.5; m/z 6EI) 351 6M1), 260 6M12PhCH2),
246 6M12NCH2Ph), 191 6AuxH1), 134, 91, 77, 58, 42;
Found M1, 351.1947. C21H25N3O2 requires M, 351.1947;
20R-8a; nmax 3548, 3033, 2934, 2853, 2804, 1729, 1687,
1606, 1495, 1455, 1422, 1392, 1309, 1288, 1261, 1173,
1119, 1101, 1073, 1037, 970, 933, 908, 861, 809, 785,
758, 736, 703, 678, 632 cm21; dH 6CDCl3) 7.27±7.12 65H,
m, Ph), 5.26 61H, d, Jˆ8.8 Hz, NCH6Ph)CH), 4.82 61H, q,
Jˆ6.8 Hz, COCH6NR2)CH3), 3.78 61H, m, NCH6CH3)CH),
2.74 63H, s, NCH3), 2.38 64H, m, N6CH2)2), 1.40 64H,
m, Jˆ5.2 Hz, 6CH2)2CH2), 1.24 62H, m, Jˆ5.2 Hz,
6CH2CH2)2CH2), 1.10 63H, d, Jˆ6.9 Hz, CH6NR2)CH3),
0.72 63H, d, Jˆ6.6 Hz, CHCH3); dC 6CDCl3) 173.6, 155.9,
137.3, 128.6, 128.3, 127.6, 59.9, 59.4, 54.1, 50.4, 28.8, 26.9,
25.0, 15.6, 12.0; m/z 6EI) 329 6M1), 245, 132, 112, 84, 55,
41; Found M1, 329.2103. C19H27N3O2 requires M,
Rfˆ0.30 Pet./EtOAc 61:1); [a]37 ˆ2106.48 6cˆ2.6,
D
CHCl3).
5.2.4. Typical procedure for DKR of 20RS-3a with pyrro-
lidine /1.5 equiv.), n-Bu4NI /0.2 equiv.), THF [0.10 M]
/Table 2, entry 6, for speci®c conditions of related
experiments see Table 2). 20RS-3a 665.1 mg,
0.200 mmol), Bu4NI 614.9 mg, 0.040 mmol), Et3N
329.2103; [a]25 ˆ248.58 6cˆ2.2, CHCl3).20S-8a; nmax
D
3429, 3067, 3035, 2980, 2937, 2856, 2754, 2697, 1723,
1682, 1607, 1497, 1423, 1396, 1311, 1287, 1262, 1237,
1207, 1163, 1116, 1101, 1073, 1037, 1010, 971, 932, 906,
861, 810, 796, 780, 746, 703, 676, 634, 569 cm21; dH
6CDCl3) 7.27±7.04 65H, m, Ph), 5.24 61H, d, Jˆ8.5 Hz,
NCH6Ph)CH), 4.82 61H, q, Jˆ7.0 Hz, COCH6NR2)CH3),
3.84 61H, m, NCH6CH3)CH), 2.75 63H, s, NCH3), 2.62
62H, m, N6CHAHBCH2)2), 2.50 62H, m, N6CHBHAH2)2),
1.46 64H, m, 6CH2CH2)2CH2), 1.34 62H, m, 6CH2)2CH2),
1.15 63H, d, Jˆ7.0 Hz, CH6NR2)CH3), 0.71 63H, d,
Jˆ6.6 Hz, CHCH3); dC 6CDCl3) 174.1, 155.9, 137.1,
128.9, 128.4, 127.2, 60.3, 59.6, 54.2, 50.9, 28.5, 26.9, 25.1,
15.4, 14.0; m/z 6EI) 329 6M1), 245, 132, 112, 91, 56, 41;
Found M1, 329.2103. C19H27N3O2 requires M, 329.2103;
60.033 mL,
0.237 mmol),
pyrrolidine
60.025 mL,
0.299 mmol) in THF 62.0 mL). Reaction time 46 h.
Reaction mixture diluted with DCM 65 mL), washed with
distilled water 64£5 mL) and dried with MgSO4. Repeated
triteration in Et2O and dryingin vacuo gave 2 0R-7a as a
viscous straw oil 664.2 mg, 100%, 42% d.e.).
20R-7a; nmax 3033, 2971, 1729, 1457, 1421, 1391, 1310,
1230, 1173, 1077, 1031, 944, 860, 808, 757, 681 cm21
;
dH 6CDCl3) 7.32±7.24 63H, m, ArH), 7.15 62H,
d, Jˆ7.0 Hz, ArH), 5.31 61H, d, Jˆ8.6 Hz, NCH-
6Ph)CH), 4.77 61H, q, Jˆ6.7 Hz, COCH6NR2)CH3), 3.88
61H, m, NCH6CH3)CH), 2.82 63H, s, NCH3), 2.60 62H, d,
Jgemˆ5.8 Hz, N6CHAHBCH2)2), 2.47 62H, d, Jgemˆ5.6 Hz,
Rfˆ0.19 Pet/EtOAc 61:1); [a]35 ˆ248.08 6cˆ2.3, CHCl3).
D

6598
S. Caddick et al. / Tetrahedron 57 32001) 6589±6605
5.2.6. Typical procedure for DKR of 20RS-3b with
benzylamine /Table 2, entry 17, for speci®c conditions
of related experiments see Table 2). 20RS-3b 667.8 mg,
0.20 mmol), Bu4NI 614.8 mg, 0.04 mmol), Et3N
m/z 6EI) 329 6M1), 300, 231, 205, 175, 132, 112, 70, 55, 42;
Found M1, 329.2103. C19H27N3O2 requires M, 329.2103;
Rfˆ0.375 EtOAc/MeOH 61:1); [a]25 ˆ273.98 6cˆ1.0,
D
CHCl3).
60.034 mL,
0.24 mmol),
benzylamine
60.033 mL,
0.30 mmol), in THF 62.0 mL). Reaction time 48 h. Puri®-
cation 6SiO2, Hex/EtOAc 6:4) gave 20R-6b 656.0 mg, 77%,
59% d.e.).20R-6b: mp 76.5±77.58C; nmax 6KBr) 3432, 3084,
3063, 3029, 2977, 2937, 2916, 1718, 1678, 1399 cm21; dH
6CDCl3) 7.29±7.10 610H, m, ArH), 5.23 61H, t, Jˆ8.5 Hz,
NCH6Ph)CH), 4.57 61H, dd, Jˆ5.1, 7.2 Hz, COCH-
6NHBn)CH2), 3.83 61H, dq, Jˆ6.6, 8.5 Hz, NCH6CH3)CH),
3.43 61H, d, Jgemˆ12.8 Hz, NHCHAHBPh), 3.33 61H, d,
Jgemˆ12.8 Hz, NHCHAHBPh), 2.74 63H, s, NCH3), 2.14
61H, brs, NH), 1.70 61H, ddq, Jˆ5.1, 7.4, 14.4 Hz,
CH6NHBn)CHAHBCH3), 1.48 61H, ddq, Jˆ7.2, 7.4,
14.4 Hz, CH6NHBn)CHAHBCH3), 0.93 63H, t, Jˆ7.4 Hz,
CH2CH3), 0.73 63H, d, Jˆ6.6 Hz, CHCH3); dC 6CDCl3):
175.9, 155.5, 140.3, 136.8, 128.4, 128.11, 128.07, 128.3,
126.9, 126.7, 60.9, 59.5, 54.0, 51.6, 28.1, 26.7, 14.8, 10.4;
m/z 6EI) 365 6M1), 336, 274, 191, 148, 91; Found M1,
365.2103. C22H27N3O2 requires M, 365.2103; Rfˆ0.20
20S-7b: mp 108±109.58C; nmax 6KBr) 3095, 3063, 3033,
2971, 2878, 2812, 1718, 1686, 1393 cm21; dH 6CDCl3)
7.26±7.19 63H, m, ArH), 7.08 62H, d, Jˆ6.6 Hz, ArH),
5.28 61H, d, Jˆ8.5 Hz, NCH6Ph)CH), 4.81 61H, dd,
Jˆ6.0, 7.4 Hz, COCH6NR2)CH2), 3.83 61H, dq, Jˆ6.6,
8.5 Hz, NCH6CH3)CH), 2.76 63H, s, NCH3), 2.71 62H, m,
N6CHACHBCH2)2), 2.58 62H, m, N6CHACHBCH2)2), 1.77
61H, ddq, Jˆ7.4, 7.5, 13.9 Hz, CH6NR2)CHAHBCH3),
1.67±1.55 65H, m, CH6NR2)CHAHBCH3, N6CH2CH2)2),
0.74 63H, d, Jˆ6.6 Hz, CHCH3), 0.73 63H, t, Jˆ7.5 Hz,
CH2CH3); dC 6CDCl3): 173.1, 155.7, 136.8, 128.4, 128.0,
127.1, 62.8, 59.2, 53.8, 49.5, 28.2, 23.55, 23.53, 15.9, 10.3;
m/z 6EI) 329 6M1), 300, 260, 245, 231, 205, 175, 132, 112,
70, 55, 42; Found M1, 329.2103. C19H27N3O2 requires M,
329.2103; Rfˆ0.27 EtOAc/MeOH 61:1); [a]25 ˆ292.68
D
6cˆ1.0, CHCl3).
Hex./EtOAc 66:4); [a]25 ˆ29.78 6cˆ1.0, CHCl3).
5.2.8. Typical procedure for DKR of 20RS-3b with
piperidine /Table 2, entry 21, for speci®c conditions of
related experiments see Table 2). 20RS-3b 668.2 mg,
0.20 mmol), Bu4NI 615.0 mg, 0.04 mmol), Et3N 60.034
mL, 0.24 mmol), piperidine 60.030 mL, 0.30 mmol), in
THF 62.0 mL). Reaction time 72 h. Puri®cation6SiO2,
Hex/Et2O 7:3, 6:4 then Et2O) gave 20R-8b 654.0 mg, 78%,
88% d.e.) and recovered 20RS-3b 610.8 mg, 16%).20R-8b:
mp 89±918C; nmax 6KBr) 3063, 3021, 2979, 2963, 2929,
2854, 2798, 1731, 1686, 1387 cm21; dH 6CDCl3) 7.26±
7.19 63H, m, ArH), 7.15 62H, d, Jˆ6.5 Hz, ArH), 5.28
61H, d, Jˆ8.8 Hz, NCH6Ph)CH), 4.69 61H, dd, Jˆ5.6,
8.9 Hz, COCH6NR2)CH2), 3.79 61H, dq, Jˆ6.6, 8.8 Hz,
NCH6CH3)CH), 2.76 63H, s, NCH3), 2.45±2.34 64H, m,
N6CH2CH2)2CH2), 1.68 61H, ddq, Jˆ7.4, 8.9, 13.5 Hz,
CH6NR2)CHACHBCH3), 1.51 61H, ddq, Jˆ5.6, 7.3,
13.5 Hz, CH6NR2)CHACHBCH3), 1.41±1.35 64H, m,
N6CH2CH2)2CH2), 1.26±1.21 62H, m, 6CH2CH2)2CH2),
0.80 63H, d, Jˆ7.4 Hz, CH2CH3), 0.74 63H, d, Jˆ6.6 Hz,
CHCH3); dC 6CDCl3): 172.5, 155.7, 137.0, 128.2, 127.9,
127.3, 65.7, 59.2, 53.8, 50.2, 28.4, 26.7, 24.8, 19.6, 15.2,
11.1; m/z 6EI) 343 6M1), 314, 233, 191, 126, 110, 56, 41;
Found M1, 343.2260. C20H29N3O2 requires M, 343.2260;
D
20S-6b: mp 40±428C; nmax 3453, 3063, 3032, 2972, 2935,
1731, 1671, 1382 cm21; dH 6CDCl3) 7.26±7.13 68H, m,
ArH), 7.06 62H, d, Jˆ6.7 Hz, ArH), 5.18 61H, t, Jˆ
8.7 Hz, NCH6Ph)CH), 4.54 61H, dd, Jˆ4.5, 7.2 Hz,
COCH6NHBn)CH2), 3.80 61H, dq, Jˆ6.6, 8.7 Hz,
NCH6CH3)CH), 3.66 61H, d, Jgemˆ12.8 Hz, NHCHAHBPh),
3.56 61H, d, Jgemˆ12.8 Hz, NHCHAHBPh), 2.75 63H, s,
NCH3), 2.01 61H, brs, NH), 1.72 61H, ddq, Jˆ4.5, 7.3,
13.5 Hz, CH6NHBn)CHAHBCH3), 1.41 61H, ddq, Jˆ7.2,
7.3, 13.5 Hz, CH6NHBn)CHAHBCH3), 0.82 63H, t, Jˆ
7.3 Hz, CH2CH3), 0.73 63H, d, Jˆ6.6 Hz, CHCH3); dC
6CDCl3): 175.5, 155.3, 140.5, 136.6, 128.5, 128.4,
128.1, 126.9, 126.7, 60.9, 59.1, 54.0, 52.7, 28.1, 27.2,
15.0, 10.8; m/z 6EI) 365 6M1), 336, 274, 260, 191, 148,
91; Found M1, 365.2103. C22H27N3O2 requires M,
365.2103; Rfˆ0.26 Hex./EtOAc 66:4); [a]25 ˆ288.38
D
6cˆ0.8, CHCl3).
5.2.7. Typical procedure for DKR of 20RS-3b with pyrro-
lidine /Table 2, entry 19, for speci®c conditions of related
experiments see Table 2). 20RS-3b 668.4 mg, 0.20 mmol),
Bu4NI 614.9 mg, 0.04 mmol), Et3N 60.034 mL, 0.24 mmol),
pyrrolidine 60.025 mL, 0.30 mmol), in THF 62.0 mL).
Reaction time 72 h. Puri®cation 6SiO2, Hex/EtOAc 6:4
then EtOAc) gave 20R-7b 642.0 mg, 63%, 73% d.e.) and
recovered 20RS-3b 68.3 mg, 12%).
Rfˆ0.40 EtOAc/MeOH 61:1); [a]25 ˆ272.28 6cˆ1.0,
D
CHCl3).
20S-8b: mp 128.5±1308C; nmax 6KBr) 3084, 3063, 3029,
2989, 2938, 2878, 2857, 2796, 1719, 1682, 1393 cm21; dH
6CDCl3) 7.25±7.19 63H, m, ArH), 7.07 62H, d, Jˆ6.6 Hz,
ArH), 5.26 61H, d, Jˆ8.4 Hz, NCH6Ph)CH), 4.82 61H, dd,
Jˆ6.3, 8.3 Hz, COCH6NR2)CH2), 3.84 61H, dq, Jˆ6.6,
8.4 Hz, NCH6CH3)CH), 2.76 63H, s, NCH3), 2.60±2.49
64H, m, N6CH2CH2)2CH2), 1.77 61H, ddq, Jˆ7.6, 8.3,
13.5 Hz, CH6NR2)CHACHBCH3), 1.53±1.32 67H, m,
CH6NR2)CHACHBCH3, N6CH2CH2)2CH2), 0.74 63H, t,
Jˆ7.6 Hz, CH2CH3), 0.73 63H, d, Jˆ6.6 Hz, CHCH3); dC
6CDCl3): 172.8, 155.8, 136.8, 128.4, 128.0, 127.0, 65.3,
59.4, 53.7, 50.4, 28.1, 26.7, 24.9, 21.7, 14.9, 10.7; m/z
6EI) 343 6M1), 314, 233, 191, 126, 110, 69, 56, 42; Found
M1, 343.2260. C20H29N3O2 requires M, 343.2260; Rfˆ0.35
20R-7b: mp 79±828C; nmax 6KBr) 3089, 3068, 3028, 2978,
2935, 2895, 2848, 2799, 1716, 1684, 1393 cm21; dH
6CDCl3) 7.25±7.19 63H, m, ArH), 7.11 62H, d, Jˆ6.3 Hz,
ArH), 5.26 61H, d, Jˆ8.5 Hz, NCH6Ph)CH), 4.79 61H, dd,
Jˆ5.8, 8.0 Hz, COCH6NR2)CH2), 3.81 61H, dq, Jˆ6.7,
8.5 Hz, NCH6CH3)CH), 2.76 63H, s, NCH3), 2.58 62H, m,
N6CHACHBCH2)2), 2.44 62H, m, N6CHACHBCH2)2), 1.76
61H, ddq, Jˆ7.4, 8.0, 14.0 Hz, CH6NR2)CHAHBCH3),
1.68±1.54 65H, m, CH6NR2)CHAHBCH3, N6CH2CH2)2),
0.86 63H, t, Jˆ7.4 Hz, CH2CH3), 0.74 63H, d, Jˆ6.7 Hz,
CHCH3); dC 6CDCl3): 173.2, 155.7, 136.9, 128.3, 127.9,
127.2, 62.9, 59.4, 53.8, 49.3, 28.3, 23.4, 23.1, 15.0, 10.6;
Hex./EtOAc 66:4); [a]25 ˆ275.48 6cˆ1.0, CHCl3).
D

S. Caddick et al. / Tetrahedron 57 32001) 6589±6605
6599
5.2.9. DKR of 20RS-3b with cyclohexylamine, re¯ux
/Table 2, entry 23). 20RS-3b 668.8 mg, 0.20 mmol),
Bu4NI 615.0 mg, 0.04 mmol), Et3N 60.035 mL, 0.25
mmol), cyclohexylamine 60.035 mL, 0.31 mmol), in THF
62.0 mL) at re¯ux. Reaction time 4 days. Puri®cation
6SiO2, Hex/EtOAc 7:3, 1:4 then Et2O) gave 20R-9b
663.6 mg, 88%, 81% d.e.).
27.8, 27.4, 26.8, 26.4, 26.1, 26.0, 12.8, 10.1; m/z 6EI) 371
6M1), 342, 280, 197, 148, 91; Found M1, 371.2580.
C22H33N3O2 requires M, 371.2573; Rfˆ0.22 Hex./EtOAc
66:4); [a]25 ˆ22.28 6cˆ1.0, CHCl3).
D
20S-10b: nmax 3440, 3085, 3062, 3028, 2928, 2853, 1732,
1682, 1386 cm21; dH 6CDCl3) 7.26 62H, d, Jˆ6.9 Hz,
2o-ArH), 7.19 62H, t, Jˆ6.9, 7.3 Hz, 2m-ArH), 7.14 61H,
t, Jˆ7.3 Hz, p-ArH), 4.47 61H, dd, Jˆ4.5, 7.3 Hz,
COCH6NHBn)CH2), 4.22 61H, dd, Jˆ2.2, 7.3 Hz, CH-
6C6H11)CH), 3.64 61H, d, Jgemˆ12.8 Hz, NHCHAHBPh),
3.58 61H, d, Jgemˆ12.8 Hz, NHCHAHBPh), 3.55 61H, dq,
Jˆ6.9, 7.3 Hz, NCH6CH3)CH), 2.68 63H, s, NCH3), 2.44
61H, brs, NH), 1.84 61H, m, CHCH6cCH2)5), 1.67±1.51
67H, m, CH6NHBn)CH2CH3, 56cyclohexyl)CH), 1.15±
0.93 65H, m, 56cyclohexyl)CH), 1.01 63H, t, Jˆ7.3 Hz,
CHCH3); dC 6CDCl3): 175.8, 155.8, 140.0, 128.5, 128.2,
126.8, 60.9, 58.8, 54.7, 52.7, 39.3, 32.5, 27.8, 27.7, 27.6,
26.9, 26.2, 26.0, 13.0, 10.3; m/z 6EI) 371 6M1), 342, 280,
197, 148, 86; Found M1, 371.2572 C22H33N3O2 requires M,
20R-9b: mp 114±1168C; nmax 6KBr) 3409, 3068, 3035,
2974, 2924, 2851, 1706, 1686, 1395 cm21; dH 6CDCl3)
7.26±7.19 63H, m, ArH), 7.08 62H, d, Jˆ6.7 Hz, ArH),
5.23 61H, d, Jˆ8.5 Hz, NCH6Ph)CH), 4.76 61H, t, Jˆ
6.1 Hz, COCH6NHR)CH2), 3.84 61H, dq, Jˆ6.5, 8.5 Hz,
NCH6CH3)CH), 2.77 63H, s, NCH3), 2.11 61H, brs, NH),
2.00±1.93 61H, m, NHCH6CH2)5), 1.90±1.83 61H, m,
c-C6H11CH), 1.67±1.57 62H, m, CH6NR2)CHACHBCH3,
cC6H11, CH), 1.51±1.38 64H, m, CH6NR2)CHACHBCH3,
c-C6H11, 3CH), 1.09±0.83 65H, m, c-C6H11,), 0.90 63H, t,
Jˆ7.3 Hz, CH2CH3), 0.75 63H, d, Jˆ6.5 Hz, CHCH3); dC
6CDCl3): 176.8, 155.5, 136.6, 128.3, 128.0, 126.9, 59.5,
57.4, 55.0, 53.8, 34.2, 32.6, 28.1, 27.6, 26.0, 24.9, 24.8,
14.8, 10.2; m/z 6EI) 357 6M1), 328, 274, 191, 140, 41;
Found M1, 357.2417 C21H31N3O2 requires M, 357.2416;
371.2573; Rfˆ0.28 Hex./EtOAc 66:4); [a]25 ˆ221.38
D
6cˆ1.3, CHCl3).
Rfˆ0.26 EtOAc; [a]25 ˆ239.58 6cˆ1.1, CHCl3).
5.2.11. DKR of 20RS-3c with benzylamine, re¯ux /Table
2, entry 27). 20RS-3c 6167.8 mg, 0.457 mmol), Bu4NI
633.8 mg, 0.092 mmol), Et3N 60.076 mL, 0.545 mmol),
benzylamine 60.075 mL, 0.686 mmol) in THF 64.6 mL) at
re¯ux. Reaction time 72 h. Puri®cation 6SiO2, Pet/EtOAc
4:1±2:1) gave 20R-6c as a white semi-solid 6127.8 mg,
71.2%, 82% d.e.).
D
20S-9b: mp 91±958C; nmax 6KBr) 3448, 3068, 3032, 2964,
2941, 2926, 2851, 1732, 1681, 1391 cm21; dH 6CDCl3)
7.26±7.18 63H, m, ArH), 7.08 62H, d, Jˆ6.7 Hz, ArH),
5.28 61H, d, Jˆ8.8 Hz, NCH6Ph)CH), 4.59 61H, dd,
Jˆ4.1, 6.6 Hz, COCH6NHR)CH2), 3.88 61H, dq, Jˆ6.7,
8.8 Hz, NCH6CH3)CH), 2.77 63H, s, NCH3), 2.33 61H,
brs, NH), 2.19±2.14 61H, m, NHCH6CH2)5), 1.84±1.49
66H, CH6NR2)CHACHBCH3, c-C6H11, 5CH), 1.42±1.31
61H, m, CH6NR2)CHACHBCH3), 1.20±0.92 65H, m,
c-C6H11), 0.78 63H, t, Jˆ7.4 Hz, CH2CH3), 0.75 63H, d,
Jˆ6.7 Hz, CHCH3); dC 6CDCl3): 176.0, 155.4, 136.6,
128.4, 128.1, 126.9, 59.2, 58.0, 55.3, 54.0, 34.1, 32.9,
28.1, 27.2, 26.0, 25.1, 24.7, 15.0, 9.9; m/z 6EI) 357 6M1),
328, 274, 191, 140, 58, 41; Found M1, 357.2418
C21H31N3O2 requires M, 357.2416; Rfˆ0.36 EtOAc;
20R-6c; nmax 6KBr) 3335, 3061, 3030, 2954, 2865, 1729,
1679, 1604, 1456, 1423, 1386, 1311, 1231, 1172, 1127,
1074, 1030, 968, 914, 832, 746, 701, 626 cm21; dH
6CDCl3) 7.29±7.09 610H, m, 2Ph), 5.23 61H, d, Jˆ8.5 Hz,
NCH6Ph)CH), 4.62 61H, t, Jˆ5.6 Hz, COCH6NHR)CH2),
3.83 61H, m, NCH6CH3)CH), 3.42 61H, d, Jgemˆ12.8 Hz,
NHCHAHBPh), 3.32 61H, d, Jgemˆ12.8 Hz, NHCHBHAPh),
2.74 63H, s, NCH3), 2.05 61H, br s, NH), 1.65 61H,
m, CH6NHR)CHAHBCH2), 1.45±1.19 65H, m, CH6NHR)-
CHBHACH2, CH2CH2CH2CH3), 0.81 63H, t, Jˆ7.1 Hz,
CH2CH3), 0.73 63H, d, Jˆ6.6 Hz, CHCH3); dC 6CDCl3)
174.7, 154.3, 139.4, 135.6, 127.5, 127.4, 127.1, 126.0,
125.8, 58.8, 58.1, 53.0, 51.8, 32.3, 27.2, 26.5, 21.7, 14.0,
13.0; m/z 6EI) 393 6M1), 336 6M12C4H9), 302
6M12CH2Ph), 288, 211, 191 6AuxH1), 176, 132, 91;
Found M1, 393.2416. C24H31N3O2 requires M, 393.2416;
[a]25 ˆ296.38 6cˆ1.0, CHCl3).
D
5.2.10. DKR of 20RS-4b with benzylamine, re¯ux /Table
2, entry 30). 20RS-4b 670.0 mg, 0.20 mmol), Bu4NI
615.0 mg, 0.04 mmol), Et3N 60.036 mL, 0.26 mmol),
benzylamine 60.034 mL, 0.31 mmol), in THF 62.0 mL) at
re¯ux. Reaction time 48 h. Puri®cation 6SiO2, Hex/EtOAc
6:4) gave 20R-10b 672.9 mg, 97%, 86% d.e.).
Rfˆ0.31 Pet/Et2O 61:1); [a]25 ˆ219.38 6cˆ3.4, CHCl3).
D
20R-10b: mp 88±908C; nmax 6KBr) 3438, 3063, 3032, 2968,
2928, 2854, 1724, 1683, 1389 cm21; dH 6CDCl3) 7.29 62H,
d, Jˆ7.3 Hz, 2o-ArH), 7.23 62H, t, Jˆ7.2, 7.3 Hz, 2m-ArH),
7.15 61H, t, Jˆ7.2 Hz, p-ArH), 4.58 61H, dd, Jˆ5.3,
7.3 Hz, COCH6NHBn)CH2), 4.28 61H, dd, Jˆ2.8, 7.2 Hz,
20S-6c; nmax 3333, 3031, 2955, 1732, 1679, 1495, 1455,
1422, 1393, 1311, 1232, 1204, 1173, 1072, 1029, 971,
833, 742, 701 cm21; dH 6CDCl3) 7.27±7.05 610H, m,
2Ph), 5.18 61H, d, Jˆ8.7 Hz, NCH6Ph)CH), 4.62 61H, t,
Jˆ7.2 Hz, COCH6NHR)CH2), 3.80 61H, m, NCH-
6CH3)CH), 3.65 61H, d, Jgemˆ12.7 Hz, NHCHAHBPh),
3.55 61H, d, Jgemˆ12.7 Hz, NHCHBHAPh), 2.76 63H, s,
NCH3), 2.04 61H, br s, NH), 1.64 61H, m, CH6NHR)-
CHAHBCH2), 1.39 61H, m, CH6NHR)CHBHACH2), 1.21
64H, m, CH2CH2CH2CH3), 0.75 63H, t, Jˆ6.9 Hz,
CH2CH3), 0.73 63H, d, Jˆ6.6 Hz, CHCH3); dC 6CDCl3)
174.7, 154.3, 139.4, 135.6, 127.5, 127.4, 127.1, 126.0,
125.8, 58.8, 58.1, 53.0, 51.8, 32.3, 27.2, 26.5, 21.7, 14.0,
13.0; m/z 6EI) 393 6M1), 336 6M12C4H9), 302
CHCH6C6H11)CH),
3.74
61H,
d,
Jgemˆ12.8 Hz,
NHCHAHBPh), 3.64±3.37 62H, m, NHCHAHBPh, NCH-
6CH3)CH), 2.68 63H, s, NCH3), 2.30 61H, brs, NH), 1.73±
1.54 67H, m, CH6NHBn)CHAHBCH3, CHCH6cCH2)5),
56cyclohexyl)CH), 1.44 61H, ddq, Jˆ7.3, 7.3, 13.7 Hz,
CH6NHBn)CHAHBCH3), 1.25 63H, d, Jˆ7.0 Hz, CHCH3),
1.20±1.00 65H, m, 56cyclohexyl)CH), 0.89 63H, t,
Jˆ7.3 Hz, CH2CH3); dC 6CDCl3): 175.6, 155.9, 139.6,
128.22, 128.18, 126.9, 60.3, 59.6, 54.5, 51.8, 38.7, 32.5,

6600
S. Caddick et al. / Tetrahedron 57 32001) 6589±6605
6M12CH2Ph), 191 6AuxH1), 176, 132, 91, 57; Found M1,
393.2416. C24H31N3O2 requires M, 393.2416; Rfˆ0.15 Pet/
CH6NR2)CHAHBCH2), 1.47 61H, m, CH6NR2)CHBHACH2),
1.37 64H, m, N6CH2CH2)2CH2), 1.25±1.10 66H, m,
CH2CH2CH2CH3, 6CH2)2CH2), 0.80 63H, t, Jˆ7.0 Hz,
CH2CH3), 0.73 63H, d, Jˆ6.6 Hz, CHCH3); dC 6CDCl3)
172.4, 155.5, 136.9, 128.1, 127.8, 127.2, 63.9, 59.1, 53.6,
50.1, 28.7, 28.3, 26.6, 26.0, 24.6, 22.7, 15.1, 14.0; m/z 6EI)
371 6M1), 314 6M12C4H9), 245, 191 6AuxH1), 154, 132,
124, 84, 69, 41; Found M1, 371.2573. C22H33N3O2 requires
Et2O 61:1); [a]25 ˆ273.18 6cˆ1.1, CHCl3).
D
5.2.12. Typical procedure for DKR of 20RS-3c with
pyrrolidine /1.5 equiv.), Bu4NI /0.2 equiv.), THF
[0.10 M], re¯ux /Table 2, entry 28, for speci®c conditions
of related experiments see Table 2). 20RS-3c 673.2 mg,
0.20 mmol), Bu4NI 615.0 mg, 0.041 mmol), Et3N
60.034 mL, 0.244 mmol), pyrrolidine 60.025 mL, 0.299
mmol) in THF 62.0 mL) at re¯ux. Reaction time 143 h.
Puri®cation 6SiO2, Pet/Et2O 2:1±1:1, Et2O) gave 20R-7c as
a clear colourless oil 671.1 mg, 99.4%, .98% d.e.).
M, 371.2573; Rfˆ0.54 Pet/Et2O 61:1); [a]32 ˆ262.78
D
6cˆ4.7, CHCl3).
20S-8c; nmax 3033, 2932, 2857, 1729, 1682, 1495, 1456,
1421, 1392, 1310, 1288, 1260, 1228, 1202, 1172, 1123,
1092, 1071, 1033, 967, 942, 863, 756, 739, 702 cm21; dH
6CDCl3) 7.26±7.13 65H, m, Ph), 5.27 61H, d, Jˆ8.8 Hz,
NCH6Ph)CH), 4.77 61H, t, Jˆ8.7 Hz, COCH6NR2)CH2),
3.79 61H, m, NCH6CH3)CH), 2.75 63H, s, NCH3), 2.38
64H, m, N6CH2-)2), 1.65 61H, m, CH6NR2)CHAHBCH2),
1.43 61H, m, CH6NR2)CHBHACH2), 1.45 64H, m,
N6CH2CH2)2CH2), 1.37 62H, t, Jˆ5.0 Hz, 6CH2)2CH2),
1.13 64H, m, CH2CH2CH2CH3), 0.80 63H, t, Jˆ7.0 Hz,
CH2CH3), 0.73 63H, d, Jˆ6.9 Hz, CHCH3); dc6CDCl3)
173.0, 155.3, 136.4, 128.0, 127.6, 126.6, 63.2, 59.0, 53.3,
50.1, 29.3, 27.9, 27.7, 26.2, 24.4, 22.3, 14.4, 13.6; m/z 6EI)
371 6M1), 314 6M12C4H9), 245, 191 6AuxH1), 154, 140,
124, 84, 57, 42; Found M1, 371.2573. C22H33N3O2 requires
20R-7c; nmax 3033, 2958, 2872, 1729, 1683, 1606, 1456,
1421, 1391, 1310, 1229, 1201, 1172, 1089, 1071, 1031,
972, 942, 904, 865, 829, 755, 683, 633 cm21; dH 6CDCl3)
7.25±7.16 63H, m, ArH), 7.11 62H, m, ArH), 5.26 61H, d,
Jˆ8.6 Hz, NCH6Ph)CH), 4.89 61H, t, Jˆ6.9 Hz, COCH-
6NR2)CH2), 3.82 61H, m, NCH6CH3)CH), 2.76 63H, s,
NCH3), 2.57 62H, d, Jgemˆ5.5 Hz, N6CHAHBCH2)2), 2.45
62H, d, Jgemˆ5.4 Hz, N6CHBHACH2)2), 1.77±1.47 62H, m,
CH6NR2)CH2CH2), 1.54 64H, m, N6CH2CH2)2), 1.23 64H,
m, CH2CH2CH2CH3), 0.81 63H, t, Jˆ6.6 Hz, CH2CH3),
0.74 63H, d, Jˆ6.6 Hz, CHCH3); dC 6CDCl3) 173.6,
156.1, 137.3, 128.7, 128.4, 127.6, 61.7, 59.9, 54.2, 49.7,
30.1, 28.8, 28.7, 23.8, 23.3, 15.4, 14.4; m/z 6EI) 357 6M1),
300 6M12C4H9), 245, 191 6AuxH1), 141, 110, 42; Found
M1, 357.2416. C21H31N3O2 requires M, 357.2416; Rfˆ0.15
M, 371.2573; Rfˆ0.13 Pet/Et2O 61:1); [a]35
ˆ
D
240.786cˆ1.1, CHCl3).
Pet/Et2O 61:1); [a]32 ˆ275.48 6cˆ3.9, CHCl3).
5.3. Dynamic kinetic resolutions with metalated
nucleophiles
D
20S-7c; nmax 3034, 2957, 2872, 1729, 1683, 1456, 1422,
1392, 1311, 1288, 1260, 1229, 1202, 1171, 1089, 1071,
1031, 972, 942, 864, 828, 737, 702 cm21; dH 6CDCl3)
7.23±7.15 63H, m, ArH), 7.06 62H, d, Jˆ7.0 Hz, ArH),
5.27 61H, d, Jˆ8.6 Hz, NCH6Ph)CH), 4.87 61H, t,
Jˆ6.6 Hz, COCH6NR2)CH3), 3.81 61H, m, NCH6CH3)CH),
2.74 63H, s, NCH3), 2.68 62H, d, Jgemˆ5.4 Hz,
5.3.1. General procedure using sodium dimethyl malo-
nate. To a stirred solution of 20-haloacylimidazolidinone
and tetra-n-butylammonium halide in THF 6unless stated
otherwise), under N2, was added a solution of sodium
dimethylmalonate 6NaDMM) in THF. Reactions were
monitored by TLC and were worked up by quenching
with saturated, aqueous NH4Cl and extraction into DCM.
The combined organic fractions were then washed with
distilled water and dried with MgSO4 and the crude product
was puri®ed by column chromatography.
N6CHAHBCH2)2),
2.57
62H,
d,
Jgemˆ5.6 Hz,
N6CHBHACH2)2), 1.77±1.47 62H, m, CH6NR2)CH2CH2),
1.63 64H, s, N6CH2CH2)2), 1.23 64H, m, CH2CH2CH2CH3),
0.72 66H, d, Jˆ6.3 Hz, CHCH3, CH2CH3); dC 6CDCl3)
173.0, 155.5, 136.6, 128.3, 128.0, 127.1, 61.3, 59.1, 53.7,
49.4, 30.2, 28.1, 27.8, 23.4, 22.7, 14.9, 13.9; m/z 6EI) 357
6M1), 300 6M12C4H9), 220, 205, 140, 57; Found M1,
357.2416. C21H31N3O2 requires M, 357.2416; Rfˆ0.06
5.3.2. Typical procedure for DKR of 20RS-3a with
sodium dimethylmalonate /1.2 equiv.) over 28 h,
Bu4NBr /2.0 equiv.), THF /Table 3, entry 1, for speci®c
conditions of related experiments see Table 3). 20RS-3a
6200.0 mg, 0.615 mmol), Bu4NBr 6396.9 mg, 1.231 mmol),
THF 66.0 mL), NaDMM 60.034 M, 20 mL, 1.231 mmol)
added slowly over 28 h. TLC revealed some remaining
startingmaterial after 116 h so additional NaDMM
60.034 M, 2.0 mL, 0.069 mmol) was added over 8 h.
Reaction quenched after 141 h 6in total). Puri®cation
6SiO2, Pet/Et2O 1:3) gave 20R-11a 6144.0 mg, 62.3%, 54±
60% d.e.).
Pet/Et2O 61:1); [a]33 ˆ247.38 6cˆ2.4, CDCl3).
D
5.2.13. DKR of 20RS-3c with piperidine, re¯ux /Table 2,
entry 29). 20RS-3c 60.10M, 2.0 mL, 0.200 mmol), Bu4NI
614.9 mg, 0.040 mmol), Et3N 60.034 mL, 0.244 mmol),
piperidine 60.030 mL, 0.293 mmol) in THF 62.0 mL) at
re¯ux. Reaction time 48 h. Puri®cation 6SiO2, Pet/Et2O
1:1) gave 20R-8c as a clear colourless oil 669.9 g, 94.1%,
.98% d.e.).
20R-8c; nmax 3033, 2932, 2856, 2805, 1729, 1682, 1607,
1495, 1421, 1392, 1311, 1288, 1260, 1235, 1204, 1173,
1121, 1072, 1036, 1000, 969, 942, 910, 863, 829, 739,
703, 671, 632 cm21; dH 6CDCl3) 7.32±7.07 65H, m, Ph),
5.27 61H, d, Jˆ8.8 Hz, NCH6Ph)CH), 4.79 61H, br t,
COCH6NR2)CH2), 3.79 61H, m, NCH6CH3)CH), 2.75
63H, s, NCH3), 2.44 64H, m, N6CH2)2), 1.68 61H, m,
20R-11a; mp 90.7±95.68C; nmax 2955, 2360, 1734, 1682,
1424, 1392, 1330, 1197, 1071, 1003, 974, 948, 911, 863,
810, 787, 739, 702, 677 cm21; dH 6CDCl3) 7.26±7.10 63H,
m, ArH), 7.05 62H, m, Jˆ6.4 Hz, ArH), 5.22 61H, d,
Jˆ8.7 Hz, NCH6Ph)CH), 4.49 61H, dt, JAˆ12.5 Hz, JBˆ
7.0 Hz, COCH6CHR2)CH3), 3.89 61H, m, NCH6CH3)-
CHR2), 3.74 61H, d, Jˆ11.2 Hz, CHCH6CO2R)2), 3.66

S. Caddick et al. / Tetrahedron 57 32001) 6589±6605
6601
63H, s, CO2CH3), 3.61 63H, s, CO2CH3), 2.77 63H, s, NCH3),
1.10 63H, d, Jˆ7.0 Hz, CH6CHR2)CH3), 0.72 63H, d,
Jˆ6.5 Hz, CHCH3); dC 6CDCl3) 174.2, 169.4, 169.1,
155.5, 137.1, 129.0, 128.7, 128.5, 59.6, 54.7, 54.2, 53.1,
53.0, 38.6, 28.6, 15.9, 15.4; m/z 6EI) 376 6M1), 345, 312,
280, 245, 205, 189, 132, 84; Found M1, 376.1634.
C19H24N2O6 requires M, 376.1634; Rfˆ0.49 Pet/EtOAc
28.0, 22.9, 14.8, 9.8; m/z 6EI) 390 6M1), 359, 326, 299,
259, 189, 173, 141; Found M1, 390.1791. C20H26N2O6
requires M, 390.1791; Rfˆ0.274 Hex./EtOAc 66:4);
[a]25 ˆ2104.48 6cˆ1.4, CHCl3).
D
5.3.4. Typical procedure for DKR of 20RS-3c with
sodium
dimethylmalonate
/2.7 equiv.),
Bu4NBr
61:1); [a]25 ˆ231.68 6cˆ0.8, CHCl3).
/0.2 equiv.), THF /Table 3, entry 8, for speci®c con-
ditions of related experiments see Table 3). 20RS-3c
60.250 mmol), Bu4NBr 616.2 mg, 0.050 mmol), THF
62.5 mL), NaDMM 60.692 M, 1.0 mL, 0.692 mmol), heated
at re¯ux under N2. Reaction quenched after 27 hours.
Puri®cation 6SiO2, Pet/Et2O 2:1±1:2) gave 20R-11c
686.9 mg, 83.2%, 52.1% d.e.).
D
20S-11a; mp 59.0±63.08C; nmax 2955, 1733, 1683, 1423,
1393, 1197, 1072, 1025, 975, 948, 912, 863, 791, 757,
735, 702, 632 cm21; dH 6CDCl3) 7.28±7.11 65H, m, Ph),
5.18 61H, d, Jˆ8.6 Hz, NCH6Ph)CH), 4.63 61H, dt,
JAˆ12.2 Hz, JBˆ6.8 Hz, COCH6CHR2)CH3), 3.84 61H, m,
NCH6CH3)CH), 3.71 61H, d, Jˆ12.8 Hz, CHCH6CO2R)2),
3.63 63H, s, CO2CH3), 3.39 63H, s, CO2CH3), 2.78 63H, s,
NCH3), 1.15 63H, d, Jˆ7.0 Hz, CH6CHR2)CH3), 0.73 63H,
d, Jˆ6.6 Hz, CHCH3); dC 6CDCl3) 174.3, 169.1, 168.7,
155.6, 136.4, 128.7, 128.3, 127.6, 60.0, 54.9, 54.2, 53.0,
52.9, 38.7, 28.6, 16.3, 15.4; m/z 6EI) 376 6M1), 345, 312,
285, 245, 189, 159, 127, 58; Found M1, 376.1634.
C19H24N2O6 requires M, 376.1634; Rfˆ0.37 Pet/EtOAc
20R-11c; nmax 3456, 2956, 2873, 1735, 1678, 1423, 1393,
1317, 1265, 1195, 1073, 1034, 988, 944, 898, 865, 801, 738,
702, 632 cm21; dH 6CDCl3) 7.26±7.12 65H, m, Ph), 5.18
61H, d, Jˆ8.5 Hz, NCH6Ph)CH), 4.76 61H, dt, Jˆ6.5,
7.5 Hz, COCH6CHR2)CH2), 3.82 61H, m, NCH6CH3)CH),
3.79 61H, d, Jˆ10.4 Hz, CHCH6CO2R)2), 3.58 63H, s,
CO2CH3), 3.41 63H, s, CO2CH3), 2.78 63H, s, NCH3),
1.53 62H, m, CH6CHR2)CH2CH2), 1.18 64H, m,
CH2CH2CH2CH3), 0.78 63H, t, Jˆ6.6 Hz, CH2CH3), 0.73
63H, d, Jˆ6.6 Hz, CHCH3); dC 6CDCl3) 173.5, 169.0,
168.7, 155.7, 136.5, 128.6, 128.2, 127.6, 60.2, 54.2, 53.7,
52.8, 42.8, 30.2, 28.6, 28.2, 23.2, 15.3, 14.2; m/z 6EI) 418
6M1), 387, 354, 330, 303, 287, 201, 189, 169, 132, 113, 58;
Found M1, 418.2104. C22H30N2O6 requires M, 418.2104;
61:1); [a]25 ˆ272.88 6cˆ1.5, CHCl3).
D
5.3.3. Typical procedure for DKR of 20RS-3b with
sodium
dimethylmalonate
/2.7 equiv.),
Bu4NBr
/0.2 equiv.), THF /Table 3, entry 4, for speci®c con-
ditions of related experiments see Table 3). 20RS-3b
668.3 mg, 0.20 mmol), Bu4NBr 613.1 mg, 0.04 mmol),
THF 62.0 mL), NaDMM 60.7 M, 0.80 mL, 0.55 mmol)
added at re¯ux. Reaction time 48 h. Puri®cation 6SiO2,
Pet/EtOAc 9:1, 7:3 then 6:4) gave 20R-11b 670.8 mg,
90%, 35% d.e.).
Rfˆ0.42 Pet/Et2O 61:2); [a]34 294.48 6cˆ1.9, CHCl3).
D
20S-11c; nmax 3457, 3063, 3034, 2956, 2872, 1734, 1681,
1606, 1495, 1456, 1423, 1392, 1319, 1193, 1089, 1074,
1034, 987, 945, 899, 854, 829, 737, 703, 472 cm21; dH
6CDCl3) 7.26±7.15 63H, m, ArH), 7.08 62H, m, ArH),
5.26 61H, d, Jˆ8.7 Hz, NCH6Ph)CH), 4.66 61H, m,
COCH6CHR2)CH2), 3.90 61H, m, NCH6CH3)CH),
3.81 61H, d, Jˆ11.1 Hz, CHCH6CO2R)2), 3.66 63H, s,
CO2CH3), 3.60 63H, s, CO2CH3), 2.79 63H, s, NCH3), 1.59
61H, m, CH6CHR2)CHAHBCH2), 1.43 61H, m, CH-
6CHR2)CHBHACH2), 1.10 64H, m, CH2CH2CH2CH3), 0.74
63H, d, Jˆ6.6 Hz, CHCH3), 0.68 63H, t, Jˆ7.0 Hz,
CH2CH3); dC 6CDCl3) 173.6, 169.6, 169.2, 155.7, 137.2,
128.8, 128.5, 128.6, 59.7, 54.1, 53.4, 53.0, 42.6, 30.3,
28.7, 27.5, 23.3, 15.4, 14.2; m/z 6EI) 418 6M1), 387, 354,
330, 303, 287, 220, 205, 189, 169, 132, 57; Found M1,
418.2104. C22H30N2O6 requires M, 418.2104; Rfˆ0.17
20R-11b; mp 98±99.58C; nmax 3037, 3005, 2984, 2963,
2879, 1736, 1721, 1676, 1394, 1326 cm21; dH 6CDCl3)
7.25±7.20 63H, m, ArH), 7.08 62H, d, Jˆ6.5 Hz, ArH),
5.26 61H, d, Jˆ8.7 Hz, NCH6Ph)CH), 4.62 61H, ddd,
Jˆ4.6, 7.5, 11.1 Hz, COCH6CHR2)CH2), 3.90 61H, dq,
Jˆ6.5, 8.7 Hz, NCH6CH3)CH), 3.82 61H, d, Jˆ11.1 Hz,
CHCH6CO2R)2), 3.66 63H, s, CO2CH3), 3.61 63H, s,
CO2CH3), 2.78 63H, s, NCH3), 1.75 61H, ddq, Jˆ4.6, 7.6,
14.3 Hz, CH6CHR2)CHACHBCH3), 1.51 61H, ddq, Jˆ6.5,
7.6, 14.3 Hz, CH6CHR2)CHACHBCH3), 0.74 63H, d,
Jˆ6.5 Hz, CHCH3), 0.62 63H, t, Jˆ7.6 Hz, CH2CH3); dC
6CDCl3) 172.9, 169.1, 168.6, 155.2, 136.7, 128.3, 128.3,
128.0, 127.0, 59.3, 53.6, 52.5, 42.9, 28.1, 22.9, 14.9, 9.3;
m/z 6EI) 390 6M1), 359, 326, 299, 259, 189, 173, 141; Found
M1, 390.1791. C20H26N2O6 requires M, 390.1791; Rfˆ0.26
Pet/Et2O 61:2); [a]35 ˆ210.38 6cˆ2.3, CHCl3).
D
Hex./EtOAc 66:4); [a]25 ˆ231.68 6cˆ1.3, CHCl3).
5.3.5. General procedure using sodium azide. 20-Halo-
acylimidazolidinone was stirred in benzotri¯uoride
6a,a,a-Tri¯uorotoluene, BTF) with tetra-n-butylammo-
nium halide and sodium azide at 838C. Reactions were
monitored by TLC and were worked up by dilution with
DCM and extraction with distilled water and brine. The
organic phase was dried with MgSO4 and the crude product
was puri®ed by column chromatography.
D
20S-11b; nmax 3068, 3037, 2975, 2958, 2881, 1755, 1735,
1677, 1394, 1317 cm21; dH 6CDCl3) 7.26±7.12 65H, m,
ArH), 5.19 61H, d, Jˆ8.4 Hz, NCH6Ph)CH), 4.73 61H,
ddd, Jˆ4.5, 7.3, 10.6 Hz, COCH6CHR2)CH2), 3.84 61H,
dq, Jˆ6.5, 8.4 Hz, NCH6CH3)CH), 3.80 61H, d, Jˆ
10.6 Hz, CHCH6CO2R)2), 3.60 63H, s, CO2CH3), 3.40
63H, s, CO2CH3), 2.77 63H, s, NCH3), 1.68 61H, ddq,
Jˆ4.5, 7.5, 14.1 Hz, CH6CHR2)CHACHBCH3), 1.55 61H,
ddq, Jˆ7.4, 7.5, 14.1 Hz, CH6CHR2)CHACHBCH3), 0.82
63H, t, Jˆ7.5 Hz, CH2CH3), 0.73 63H, d, Jˆ6.5 Hz,
CHCH3); dC 6CDCl3) 172.7, 168.5, 168.2, 155.2, 136.0,
128.0, 127.7, 127.1, 59.6, 53.6, 52.8, 52.34, 52.29, 43.1,
5.3.6. Typical procedure for DKR of 20RS-3b with
sodium azide /1.5 equiv.), Bu4NBr /0.2 equiv.), BTF,
838C /Table 3, entry 10, for speci®c conditions of related
experiments see Table 3). 20RS-3b 668.1 mg, 0.20 mmol),
Bu4NBr 613.0 mg, 0.040 mmol), NaN3 619.8 mg,

6602
S. Caddick et al. / Tetrahedron 57 32001) 6589±6605
0.30 mmol), BTF 62.0 mL) heated at 838C. Reaction
quenched after 30 h. Puri®cation 6SiO2, Hex/EtOAc 8:2,
6:4) gave 20R-12b 660.5 mg, 100%, 31.0% d.e.).
354.1358. C20H22N2O2S requires M, 354.1402; [a]25
2638 6cˆ1.0 Hz, CHCl3).
ˆ
D
20S-13a; nmax 2976, 1728, 1686, 1429, 1380, 1241, 1201,
755, 700 cm21; dH 6CDCl3) 7.45±7.00 610H, m, 10ArH),
5.45±5.35 61H, q, Jˆ6.5 Hz, NCH6CH3)CH), 5.1 61H, d,
20R-12b; mp 113±1148C; nmax 3068, 3053, 3032, 2970,
2928, 2879, 2105, 1727, 1685, 1394, 1231 cm21; dH
6CDCl3) 7.30±7.21 63H, m, ArH), 7.09±7.07 62H, m,
ArH), 5.21 61H, d, Jˆ8.5 Hz, NCH6Ph)CH), 4.99 61H, dd,
Jˆ4.7, 9.0 Hz, COCH6N3)CH2), 3.87 61H, dq, Jˆ6.6,
8.5 Hz, NCH6CH3)CH), 2.77 63H, s, NCH3), 1.87 61H,
ddq, Jˆ4.7, 7.3, 14.2 Hz, CH6N3)CHACHBCH3), 1.72 61H,
ddq, Jˆ7.3, 9.0, 14.2 Hz, CH6N3)CHACHBCH3), 1.02 63H,
t, Jˆ7.3 Hz, CH2CH3), 0.75 63H, d, Jˆ6.6 Hz, CHCH3); dC
6CDCl3) 170.1, 155.1, 135.9, 128.7, 128.3, 126.8, 62.0, 59.6,
54.1, 28.2, 24.7, 14.9, 10.8; m/z 6EI) 302 6MH1), 274, 259,
217, 190, 132, 58; Found MH1, 302.1613. C15H20N5O2
requires MH, 302.1617; Rfˆ0.31 Hex./EtOAc 66:4);
Jˆ6.8 Hz,
NCH6Ph)CH),
3.74±3.65
61H,
m,
COCH6SPh)CH3), 2.65 63H, s, NCH3), 1.25 63H, d, Jˆ
6.8 Hz, NCHCH3), 0.65 63H, d, Jˆ6.6 Hz, CH6SPh)CH3);
dC 6CDCl3) 172.0, 155.7, 136.9, 134.6, 133.1, 129.3, 129.1,
129.0, 128.9, 128.6, 128.5, 128.4, 127.2, 126.3, 126.2, 60.2,
54.2, 43.5, 28.5, 17.4, 15.2; m/z 6EI) 354 6M1), 245; Found
M1, 354.1405. C20H22N2O2S requires M, 354.1402;
[a]25 ˆ21568 6cˆ1.0, CHCl3).
D
5.4.3. Typical procedure for DKR of 20RS-3a with meth-
yl thioglycolate /1.5 equiv.), n-Bu4NBr /2.0 equiv.), THF
[0.01 M] /Table 4, entry 3, for speci®c conditions of
related experiments see Table 4). 20RS-3a 665.0 mg,
0.20 mmol), Bu4NBr 6130 mg, 0.40 mmol), Et3N 60.033
mL, 0.24 mmol), methyl thioglycolate 60.027 mL,
0.30 mmol) in THF 620 mL). Reaction time 48 h. Puri®-
cation 6SiO2, Pet/EtOAc 5:1) gave 20R-14a 655 mg, 79%,
9% de).
[a]25 ˆ2180.88 6cˆ0.8, CHCl3).
D
20S-12b; mp 109±1108C; nmax 3089, 3036, 2989, 2938,
2881, 2102, 1709, 1681, 1384, 1211 cm21; dH 6CDCl3)
7.28±7.20 63H, m, 3ArH), 7.07±7.05 62H, m, 2ArH), 5.27
61H, d, Jˆ8.6 Hz, NCH6Ph)CH), 4.97 61H, dd, Jˆ4.4,
8.9 Hz, COCH6N3)CH2), 3.89 61H, dq, Jˆ6.7, 8.6 Hz,
NCH6CH3)CH), 2.76 63H, s, NCH3), 1.89 61H, ddq,
Jˆ4.4, 7.3, 14.1 Hz, CH6N3)CHACHBCH3), 1.64 61H, ddq,
Jˆ7.3, 8.9, 14.1 Hz, CH6N3)CHACHBCH3), 0.95 63H, t,
Jˆ7.3 Hz, CH2CH3), 0.73 63H, d, Jˆ6.7 Hz, CHCH3); dC
6CDCl3) 170.3, 155.0, 136.0, 128.5, 128.2, 126.8, 61.6, 59.2,
54.0, 28.1, 24.9, 14.8, 10.5; m/z 6EI) 302 6MH1), 259, 217,
190, 132, 28; Found MH1, 302.1615. C15H20N5O2 requires
20R-14a; nmax 3431, 2102, 1728, 1646, 1424, 1374,
1291 cm21; dH 6CDCl3) 7.25±7.05 65H, m, ArH), 5.20±
5.05 62H, m, NCH6CH3)CH6Ph)N), 4.0±3.90 61H, m,
COCH6SR)CH3), 3.60 63H, s, OCH3), 3.30 62H, s,
SCH2CO), 2.75 63H, s, NCH3), 1.35 63H, d, Jˆ6.8 Hz,
CHCH3), 0.70 63H, d, Jˆ6.6 Hz, CHCH3); dC 6CDCl3)
171.6, 171.3, 155.9, 137.0, 129.0, 128.5, 127.2, 60.2, 54.2,
52.9, 39.7, 31.6, 28.6, 17.2, 15.3; m/z 6EI) 350 6M1), 277,
246; Found M1, 350.1292. C17H22N2O4S requires M,
MH, 302.1617; Rfˆ0.39 Hex./EtOAc 66:4); [a]25 ˆ252.98
D
6cˆ1.0, CHCl3).
350.1300; [a]25 ˆ2588 6cˆ1.0, CHCl3).
D
5.4. Dynamic kinetic resolutions with sulfur nucleophiles
20S-14a; nmax 2976, 1729, 1682, 1424, 1291, 1200 cm21; dH
6CDCl3) 7.25±7.15 65H, m, ArH), 5.31 61H, d, Jˆ8.5 Hz,
NCH6Ph)CH), 5.10 61H, q, Jˆ6.7 Hz, NCH6CH3)CH), 4.0±
3.9 61H, m, COCH6SR)CH3), 3.55 63H, s, OCH3), 3.05±
2.85 62H, m, SCH2CO), 2.75 63H, s, NCH3), 1.35 63H, d,
Jˆ6.8 Hz, CHCH3), 0.70 63H, d, Jˆ6.6 Hz, CHCH3); dC
6CDCl3) 171.1, 155.6, 136.6, 128.8, 128.5, 127.4, 59.6,
54.2, 52.7, 39.4, 30.9, 28.8, 16.6, 15.6; m/z 6EI) 350 6M1),
277, 246; Found M1, 350.1292. C17H22N2O4S requires M,
5.4.1. General procedure. To a stirred solution of 20-halo-
acylimidazolidinone, tetra-n-butylammonium bromide and
triethylamine in THF was added thiol. Reactions were
monitored by TLC and were worked up by removal of
THF in vacuo. The crude mixture was taken up in DCM
and washed with distilled water. The organic phase was
dried with MgSO4 and the crude product was puri®ed by
column chromatography.
350.1300; [a]25 ˆ2708 6cˆ1.0, CHCl3).
D
5.4.2. Typical procedure for DKR of 20RS-3a with thio-
phenol /1.5 equiv.), Bu4NBr /2.0 equiv.), THF [0.010 M]
/Table 4, entry 1, for speci®c conditions of related
experiments see Table 4). 20RS-3a 665 mg, 0.20 mmol),
Bu4NBr 6129 mg, 0.40 mmol), Et3N 60.033 mL,
0.24 mmol), thiophenol 60.031 mL, 0.30 mmol) in THF
620 mL). Reaction time 4 days. Puri®cation 6SiO2, Pet/
EtOAc 5:1) gave 20S-13a 65 6 mg, 78%, 19% d.e.).
5.4.4. DKR of 20RS-3a with benzyl mercaptan
/1.5 equiv.), Bu4NBr /2.0 equiv.), THF [0.010 M]
/Table 4, entry 5, for speci®c conditions of related
experiments see Table 4). 20RS-3a 665.0 mg, 0.20 mmol),
Bu4NBr 6129 mg, 0.40 mmol), Et3N 60.033 mL, 0.24
mmol), benzyl mercaptan 60.027 mL, 0.30 mmol) in THF
620 mL). Reaction time 7 days. Puri®cation 6SiO2, Pet/
EtOAc 5:1) gave 20R-15a 641 mg, 56%, 11% d.e.).
20R-13a; nmax 2974, 1726, 1683, 1422, 1372, 1235, 1201,
753, 701 cm21; dH 6CDCl3) 7.25±6.92 610H, m, ArH),
5.31±5.22 62H, m, NCH6CH3)CH6Ph)N), 3.91±3.81 61H,
m, COCH6SPh)CH3), 2.80 63H, s, NCH3), 1.20±1.15 63H,
d, Jˆ6.8 Hz, NCHCH3), 0.75 63H, d, Jˆ6.6 Hz,
CH6SPh)CH3); dC 6CDCl3) 172.4, 157.0, 137.6, 136.4,
132.5, 129.9, 129.8, 129.5, 129.5, 129.0, 60.7, 55.3, 43.3,
29.8, 17.6, 16.5; m/z 6EI) 354 6M1), 245; Found M1,
20R-15a; nmax 3447, 2974, 2933, 1725, 1680, 1422, 1372,
1235, 1201, 1060, 757, 701 cm21; dH 6CDCl3) 7.25±7.00
610H, m, ArH), 5.30±5.25 61H, d, Jˆ8.4 Hz, NCH6Ph)CH),
5.10±5.00 61H, m, NCH6CH3)CH), 3.85±3.75 61H, m,
COCH6SR)CH3), 3.5±3.2 62H, m, SCH2Ph), 2.70 63H, s,
NCH3), 1.35 63H, d, Jˆ6.8 Hz, NCHCH3), 0.70 63H, d,
Jˆ6.6 Hz, CH6SR)CH3); dC 6CDCl3) 171.1, 155.8, 137.8,

S. Caddick et al. / Tetrahedron 57 32001) 6589±6605
6603
136.9, 129.6, 128.9, 128.7, 128.5, 127.5, 127.3, 59.6, 54.2,
39.7, 32.9, 28.8, 16.6, 15.6; m/z 6EI) 368 6M1), 277, 246;
Found M1, 368.1576. C21H24N2O2S requires M, 368.1558;
[a]25 ˆ139.58 6cˆ1.15, CHCl3); Lit.30 [a]29 ˆ145.08
254 nm; temp. 258C; ¯ow rate 0.50 mL 21
D
D
6cˆ1.0, MeOH); HPLC: 6Chiralcel OD-H); detection l
; eluent
hexanes/isopropanol, Et2NH 695:5, 1%); RT 11.23 mins;
[a]25 ˆ27.78 6cˆ1.0, CHCl3).
D
89.8% e.e.
20S-15a; nmax 1728, 1682, 1455, 1423, 1375, 1236,
1200 cm21; dH 6CDCl3) 7.25±7.00 65H, m, ArH), 5.10±
4.95 62H, m, NCH6Ph)CH6Ph)N), 3.86±3.75 62H, d,
Jˆ8.5, SCH2Ph), 3.75±3.65 61H, m, COCH6SR)CH3),
2.70 63H, s, NCH3), 1.30 63H, d, Jˆ6.8 Hz, NCHCH3),
0.65 63H, d, Jˆ6.6 Hz, CH6SR)CH3); dC 6CDCl3) 171.3,
154.9, 137.8, 136.2, 128.7, 128.1, 127.8, 127.6, 126.4,
126.3, 59.2, 53.1, 39.3, 33.9, 27.7, 16.9, 14.4; m/z 6EI)
368 6M1), 277, 246; Found M1, 368.1551. C21H24N2O2S
5.5.5. Methanolysis of 20R-6b with triethylamine
/1.2 equiv.), MeOH [0.11 M] /Table 5, entry 3). 20R-6b
6196.7 mg, 0.54 mmol), Et3N 60.090 mL, 0.65 mmol),
MeOH 64.7 mL) at re¯ux. Reaction time 6 days. Puri®cation
6SiO2, Pet30±40/Et2O 9:1 then Pet/EtOAc 6:4) gave 2R-17b
as a clear, colourless oil 694.2 mg, 84%) and 1 686.7 mg,
85%).
requires M, 368.1558; [a]25 ˆ21408 6cˆ1.0, CHCl3).
5.5.6. /R)-Methyl 2-/benzylamino)-butanoate, 2R-17b.
nmax 3337, 3086, 3028, 2966, 2878, 1735, 1454,
1197 cm21; dH 6CDCl3) 7.22±7.08 65H, m, Ph), 3.68 61H,
d, Jgemˆ13.0 Hz, NCHAHBPh), 3.57 63H, s, OCH3), 3.51
61H, d, Jgemˆ13.0 Hz, NCHBHAPh), 3.10 61H, t, Jˆ
6.5 Hz, COCH6NHBn)CH2), 1.81 61H, s, NH), 1.58 61H,
ddq, Jˆ6.5, 7.5, 13.0 Hz, CH6NHBn)CHAHBCH3), 1.54
61H, ddq, Jˆ6.5, 7.5, 13.0 Hz, CH6NHBn)CHAHBCH3),
0.82 63H, t, Jˆ7.5 Hz, CH2CH3); dC 6CDCl3) 175.5,
139.7, 128.0, 127.9, 126.7, 61.7, 51.8, 51.2, 26.3, 9.9; m/z
D
5.5. N-Acylimidazolidinone methanolysis reactions
General procedure. N-acylimidazolidinone was stirred in
methanol. Triethylamine was added to the solution and the
reaction and the progress of the reaction was monitored by
TLC. Work-up was effected by removal of the methanol in
vacuo. The crude product was taken up in DCM and the
organic phase was washed with distilled water and brine.
The organic phase was dried with MgSO4 and the product
6FAB) 208 6MH1), 148, 91, 51; Found MH1, 208.1338.
C12H18NO2 requires MH1, 208.1338; Rfˆ0.52 Pet30±40
/
12
1
puri®ed by column chromatography 6SiO2) usingPet
Et2O in view of the volatility of many of the products.
/
30±40
Et2O 66:4); [a]25 ˆ134.78 6cˆ4.95, CHCl3), Lit.
D
[a]Dˆ142.48 6cˆ1.0, MeOH); HPLC: 6Chiralcel ODH);
detection l 254 nm; temp. 258C; ¯ow rate 0.50 mL 21
eluent hexane/isopropanol 697:3); RT 12.92 mins; 78% e.e.
;
5.5.1. Methanolysis of 20S-6a with triethylamine
/1.2 equiv.), MeOH [0.11 M] /Table 5, entry 1). 20S-6a
6103.8 mg, 0.296 mmol), Et3N 60.050 mL, 0.355 mmol),
MeOH 62.6 mL) at re¯ux. Reaction time 24 h. Puri®cation
6SiO2, Pet30±40/Et2O 4:1 then Pet/EtOAc 1:1±2:1) gave
2S-17a as a colourless liquid 640.5 mg, 71.7%). Chiral
auxiliary 1 was recovered 641.2 mg, 73.3%).
5.5.7. Methanolysis of 20R-6c with triethylamine /1.2±
6.0 equiv.), MeOH [0.12 M] /Table 5, entry 4). 20R-6c
691.8 mg, 0.233 mmol), Et3N 60.039 mL, 0.280 mmol)
then additional Et3N 60.156 mL, 1.12 mmol) added after
48 h, MeOH 62.0 mL) at re¯ux. Reaction time 7 days in
total. Puri®cation 6SiO2, Pet30±40/Et2O 14:1 then Pet/
EtOAc 1:1) gave 2R-17c as a colourless liquid 633.8 mg,
61.7%). Chiral auxiliary 1 was recovered 634.9 mg, 78.8%).
5.5.2. /S)-Methyl 2-/benzylamino)-propionate, 2S-17a.
nmax 3419, 3054, 2927, 2854, 1729, 1455, 1266, 1148,
1029, 896, 737, 703 cm21; dH 6CDCl3) 7.34±7.25 65H, m,
Ph), 3.81 61H, d, Jgemˆ12.8 Hz, NCHAHBPh), 3.74 63H, s,
OCH3), 3.68 61H, d, Jgemˆ12.8 Hz, NCHBCHAPh), 3.41
61H, q, Jˆ17.0 Hz, COCH6NHBn)CH3), 1.87 61H, br s,
NH), 1.34 63H, d, Jˆ7.0 Hz, CHCH3); dC 6CDCl3) 176.6,
140.1, 128.9, 128.7, 127.5, 56.3, 52.4, 52.2, 19.6; m/z 6FAB)
194 6MH1), 134, 91, 55, 43; Found MH1, 194.1181.
C11H16NO2 requires M, 194.1181; Rfˆ0.78 Pet/EtOAc
5.5.8. /R)-Methyl 2-/benzylamino)-hexanoate, 2R-17c.
nmax 3328, 3029, 2955, 2860, 1737, 1496, 1455, 1378,
1196, 1028, 991, 736, 699 cm21; dH 6CDCl3) 7.26±7.17
65H, m, Ph), 3.65 63H, s, OCH3), 3.73 61H, d, Jgemˆ12.9 Hz,
NCHAHBPh), 3.55 61H, d, Jgemˆ12.9 Hz, NCHBHAPh), 3.19
61H, t, Jˆ6.7 Hz, COCH6NHBn)CH2), 1.73 61H, br s, NH),
1.56 62H, m, CHCH2CH2), 1.24 64H, m, CH2CH2CH2CH3),
1.34 63H, t, Jˆ6.9 Hz, CH2CH3); dC 6CDCl3) 176.6, 140.3,
128.8, 128.7, 127.5, 61.1, 52.6, 52.1, 33.8, 28.3, 22.9, 14.4;
m/z 6EI) 235 6M1), 176, 106, 91, 65, 28; Found M1,
235.1572. C14H21NO2 requires M, 235.1572; Rfˆ0.63 Pet/
61:7); [a]25 ˆ237.28 6cˆ0.7, MeOH); Lit.29 [a]21
ˆ
D
D
241.08; HPLC: 6Chiralcel OD-H); detection l 254 nm;
temp. 258C; ¯ow rate 0.50 mL 21; eluent-hexane/isopropa-
nol, Et2NH 695:5, 1%); R.T.-10.10 mins; 89.8% e.e.
Et2O 65:1); [a]37 ˆ126.58 6cˆ1.02, CHCl3); HPLC: 6Chir-
5.5.3. Methanolysis of 20R-6a with triethylamine
/1.2 equiv.), MeOH [0.11 M] /Table 5, entry 2). 20R-6a
6110.7 mg, 0.315 mmol), Et3N 60.053 mL, 0.380 mmol),
MeOH 62.75 mL) at re¯ux. Reaction time 23 h. Puri®cation
6SiO2, Pet30±40/Et2O 4:1 then Pet/EtOAc 1:1) gave 2R-17a
as a clear, colourless oil 644.6 mg, 74.5%) and 1 646.5 mg,
77.3%).
D
alcel ODH); detection l 254 nm; temp. 238C; ¯ow rate
;
0.50 mL 21
15.50 mins; 90.8% e.e.
eluent hexanes/isopropanol 698:2); RT
5.5.9. Methanolysis of 20R-7a with triethylamine
/1.2 equiv.), MeOH [0.10 M] /Table 5, entry 5). 20R-7a
6216.4 mg, 0.687 mmol), Et3N 60.115 mL, 0.825 mmol),
MeOH 66.9 mL) at re¯ux. Reaction time 26 h. Puri®cation
6SiO2, Pet30±40/Et2O 5:1±3:1 then Pet/EtOAc 1:1±0:1) gave
2R-18a as a colourless liquid 642.9 mg, 39.2%). Chiral
auxiliary 1 was recovered 647.6 mg, 36.5%).
5.5.4. /R)-Methyl 2-/benzylamino)-propionate, 2R-17a.
Spectral data 6IR, 1H- and 13C NMR) identical to the enan-
tiomer 2S-17a; m/z 6FAB) 194 6MH1), 134, 91, 55, 43;
Found MH1, 194.1181. C11H16NO2 requires M, 194.1181;

6604
S. Caddick et al. / Tetrahedron 57 32001) 6589±6605
5.5.10. /R)-Methyl 2-/pyrrolidinyl)-propionate, 2R-18a.
nmax 3391, 2926, 2361, 1739, 1683, 1456, 1379, 1265,
737 cm21; dH 6CDCl3) 3.66 63H, s, OCH3), 3.90 61H, q,
Jˆ6.9 Hz, CO6NR2)CHCH3), 2.24 64H, m, N6CH2CH2)2),
1.74 64H, s, N6CH2CH2)2), 1.30 63H, d, Jˆ7.0 Hz,
CHCH3); dC 6CDCl3) 174.7, 62.6, 52.0, 51.4, 23.8, 17.7;
m/z 6EI) 157 6M1), 142, 98, 56, 28; Found M1, 157.1103.
C8H15NO2 requires M, 157.1103; Rfˆ0.29 Pet/EtOAc 61:7);
CHCH2CH2; N6CH2CH2)2CH2; CH2CH2CH2CH3), 0.82
63H, t, Jˆ6.9 Hz, CH3); dC 6CDCl3) 173.5, 68.9, 51.3,
51.2, 29.7, 28.9, 26.8, 25.0, 23.0, 14.4; m/z 6EI) 213 6M1),
154, 124, 110, 98, 84, 69, 55, 41, 29; Found M1, 213.1729.
C12H23NO2 requires M, 213.1729; Rfˆ0.90 Pet/EtOAc
61:1); [a]25 ˆ129.58 6cˆ1.9, CHCl3).
D
5.5.17. Methanolysis of 16 with triethylamine
/1.0 equiv.), MeOH [0.10 M] /Table 5, entry 9). 16
6101.7 mg, 0.330 mmol), Et3N 60.045 mL, 0.323 mmol),
MeOH 63.2 mL) at re¯ux. Reaction time 76 h. Puri®cation
6SiO2, Pet30±40/Et2O 5:1±1:1 then EtOAc) gave 20 as a
colourless liquid 619.3 mg, 38.9%). Chiral auxiliary 1 was
recovered 621.0 mg, 33.5%) and 16 was recovered
629.2 mg, 28.7%).
[a]31 ˆ130.38 6cˆ0.03, CHCl3).
D
5.5.11. Methanolysis of 20R-7c with triethylamine
/6.1 equiv.), MeOH [0.50 M], /Table 5, entry 6). 20R-7c
6334.4 mg, 0.935 mmol), Et3N 60.790 mL, 5.668 mmol),
MeOH 61.9 mL) at re¯ux. Reaction time 16 days. Puri®-
cation 6SiO2, Pet30±40/Et2O 5:1±3:1 then Pet/EtOAc 1:1±
0:1) gave 2R-18c as a colourless liquid 6127.4 mg,
68.4%). Chiral auxiliary 1 was recovered 687.6 mg, 49.3%).
5.5.18. Methyl phenylacetate 20. nmax 6liquid ®lm) 3065,
3031, 2952, 2843, 1740, 1603, 1497, 1455, 1436, 1256,
1161, 1076, 1013, 843, 762, 697 cm21; dH 6CDCl3) 7.37±
7.27 65H, m, Ph), 3.71 63H, s, OCH3), 3.65 62H, s,
COCH2Ph); dC 6CDCl3) 171.9, 133.9, 129.2, 128.5, 127.0,
51.9, 41.1; m/z 6EI) 150 6M1), 91, 65, 28; Found M1,
160.0681. C9H10O2 requires M, 160.0681; Rfˆ0.97 Pet/
EtOAc 61:1).
5.5.12. /R)-Methyl 2-/pyrrolidinyl)-hexanoate, 2R-18c.
nmax 2956, 2873, 1735, 1460, 1378, 1192, 1149,
736 cm21; dH 6CDCl3) 3.58 63H, s, OCH3), 3.02 61H, q,
Jˆ7.1 Hz, CO6NR2)CHCH2), 2.49 64H, m, N6CH2CH2)2,
1.62 66H, m, N6CH2CH2)2); CHCH2CH2), 1.22 64H, m,
CH2CH2CH2CH3), 0.81 63H, t, Jˆ6.9 Hz, CH3); dC
6CD2Cl2) 173.8, 66.5, 51.2, 50.5, 31.5, 28.5, 23.8, 23.0,
14.0; m/z 6EI) 199 6M1), 140, 110, 96, 84, 69, 55, 41, 28;
Found M1, 199.1572. C11H21NO2 requires M, 199.1572;
5.5.19. Methanolysis of 16 with ethyl diisopropylamine
/1.0 equiv.), MeOH [0.10 M] /Table 5, entry 10). 16
Rfˆ0.69 Pet/EtOAc 61:1); [a]25 ˆ10.818 6cˆ3.2, CHCl3).
6100.4 mg,
0.325 mmol),
ethyl
diisopropylamine
D
60.057 mL, 0.327 mmol), MeOH 63.2 mL) at re¯ux. Reac-
tion time 76 h. Puri®cation 6SiO2, Pet30±40/Et2O 5:1±1:1
then EtOAc) gave 20 638.2 mg, 78.3%). Chiral auxiliary 1
was recovered 628.8 mg, 46.6%) and 16 was recovered
62.5 mg, 2.5%).
5.5.13. Methanolysis of 20R-8a with triethylamine
/1.2 equiv.), MeOH [0.10 M] /Table 5, entry 7). 20R-8
6213.7 mg, 0.649 mmol), Et3N 60.109 mL, 0.782 mmol),
MeOH 66.5 mL) at re¯ux. Reaction time 26 h. Puri®cation
6SiO2, Pet30±40/Et2O 10:1 then Pet/EtOAc 1:1±1:2) gave
2R-19a as a colourless oil 678.9 mg, 71.0%). Chiral auxili-
ary 1 was recovered 623.4 mg, 19.0%).
5.6. Structure elucidation
The absolute stereochemistry of the diastereomers 20S-3a,
20R-3a, 20R-3c, 20S-3b, 20R-4b, 20S-5a, 20S-12b were
con®rmed by X-ray crystallography. Details of these struc-
tures have been lodged at the Cambridge Crystallographic
Database 6CIF 155713, 155714, 155715, 155716, 155717,
155718, 155719).
5.5.14. /R)-Methyl 2-/piperidyl)-propionate, 2R-19a. nmax
3451, 2936, 2854, 2809, 2758, 1736, 1451, 1380, 1343,
1309, 1229, 1163, 1133, 1098, 1055, 1029, 981, 944, 908,
862, 838, 789, 751 cm21; dH 6CDCl3) 3.67 63H, s, OCH3),
3.24 61H, q, Jˆ7.0 Hz, CO6NR2)CHCH3), 2.50 64H, m,
N6CH2CH2)2CH2), 1.55 64H, m, 6CH2CH2)2CH2), 1.44
62H, m, 6CH2)2CH2), 1.24 63H, d, Jˆ6.9 Hz, CHCH3); dC
6CDCl3) 173.4, 63.4, 51.2, 50.9, 26.8, 24.9, 14.7; m/z 6EI)
171 6M1), 156, 112, 96, 84, 69, 56, 41, 28; Found M1,
171.1259. C9H17NO2 requires M, 171.1259; Rfˆ0.66 Pet/
Acknowledgements
We gratefully acknowledge EPSRC, BBSRC, SmithKline
Beecham Pharmaceuticals, Novartis, AstraZeneca and the
Association for International Cancer Research 6St Andrews,
Scotland) for support. We gratefully acknowledge ESPRC
Mass Spectrometry Service at Swansea. We gratefully
Ã
acknowledge the FundacËaÄo para a Ciencia e Tecnologia
6FCT, project PRAXIS XXI PCEX/C/QUI/53/96 and a
PhD grant for S. X. C., Ref. PRAXIS XXI/BD/4024/94).
EtOAc 61:1); [a]31 ˆ120.58 6cˆ4.2, CHCl3).
D
5.5.15. Methanolysis of 20R-8c with triethylamine
/6.1 equiv.), MeOH [0.50 M] /Table 5, entry 8). 20R-8c
6481.2 mg, 1.295 mmol), Et3N 61.10 mL, 7.892 mmol),
MeOH 62.6 mL) at re¯ux. Reaction time 16 days. Puri®-
cation 6SiO2, Pet30±40/Et2O 10:1 then Pet/EtOAc 10:1±0:1)
gave 2R-19c as a colourless liquid 6178.1 mg, 64.5%).
Chiral auxiliary 1 was recovered 6155.8 mg, 63.3%) and
20R-8c was recovered 696.0 mg, 20.0%).
References
5.5.16. /R)-Methyl 2-/piperidyl)-hexanoate, 2R-19c. nmax
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