Asymmetric synthesis of syn- and anti-α-deuterio-β3- phenylalanine derivatives

Article abstract of DOI:10.1016/j.tetasy.2011.06.008

The conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl) amide to a range of aryl substituted tert-butyl cinnamate esters followed by reaction of the resultant lithium β-amino enolates with D₂O provides access to anti configured α-deut

Full text of DOI:10.1016/j.tetasy.2011.06.008

Tetrahedron: Asymmetry 22 (2011) 1035–1050
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of syn- and anti-a
-deuterio-b3-phenylalanine derivatives
⇑
Stephen G. Davies , Emma M. Foster, Catherine R. McIntosh, Paul M. Roberts, Timothy E. Rosser,
Andrew D. Smith, James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 April 2011
Accepted 17 May 2011
The conjugate addition of lithium (S)-N-benzyl-N-(a-methylbenzyl)amide to a range of aryl substituted
tert-butyl cinnamate esters followed by reaction of the resultant lithium b-amino enolates with D2O pro-
vides access to anti configured -deuterio-b-aminocinnamate esters in high dr. The corresponding syn
configured diastereoisomers were also obtained with high diastereoselectivity via the conjugate addition
of lithium (S)-N-benzyl-N-( -methylbenzyl)amide to a range of tert-butyl -deuteriocinnamate esters
a
a
a
followed by reaction of the resultant lithium b-amino enolates with 2-pyridone. After deprotection both
the syn- and anti-diastereoisomers of the corresponding
a
-deuterio-b3-amino acids can be isolated in
high dr.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
presented in which BuLi is added to the preformed amine–enolate
complex. This ‘double deprotonation’ strategy13 removes the resid-
ual proton from the amine by reforming the lithium amide base
(e.g., LDA) with subsequent deuteration of the enolate giving
significantly improved levels of deuterium incorporation.14
Previous investigations from our laboratory have demonstrated
that the conjugate addition of enantiopure secondary lithium
The synthesis of enantiopure b-amino acids has become an
important area within organic synthesis. The pharmacological
activities of a variety of b-amino acids and their derivatives have
been well documented.1 For example, the
a-hydroxy-b-phenylala-
nine component of TaxolÒ was found to be essential to its anti-
tumour activity,2 (S)-b-tyrosine was found to be a key component
of the antibiotic edeine A,3 and its antipode (R)-b-tyrosine is the
b-amino acid component of the cyclodepsipeptide jasplakinolide.4
b-Amino acids are also precursors for b-lactam antibiotics5 and
various other compounds of biological interest.6 In addition, the
pharmacological and conformational properties of synthetic pep-
tides derived from b-amino acids have been receiving increasing
attention7 and b-amino acids have become important building
blocks for peptidomimetic studies.8 Within this field, amino acids
specifically labelled with stable isotopes are valuable tools for
the investigation of proteins at the atomic level.9 Methods for the
synthesis of deuterium labelled amino acids include isotopic
amides (derived from
a-methylbenzylamine) to a,b-unsaturated
esters represents a general and efficient synthetic protocol for
the synthesis of b-amino esters and their derivatives.15 This meth-
odology has found numerous applications, including the total syn-
theses of natural products,16 molecular recognition phenomena17
and resolution protocols,18 and has been reviewed.19 While lithium
b-amino enolates have been shown by us to undergo diastereose-
lective alkylation20 and oxidation,21 their diastereoselective
deuteration has yet to be reported. It was envisaged that both
syn- and anti-a-deuterio-b-amino esters 3 could be obtained via
either a tandem conjugate addition/deuteration approach [i.e.,
conjugate addition of (S)-4 to 1 followed by in situ deuteration of
the resultant lithium (Z)-b-amino enolate] or a stepwise protocol
[i.e., deprotonation of b-amino ester 2 followed by deuteration of
the resultant lithium (E)-b-amino enolate] and we report herein
our findings within this area (Scheme 1).
exchange10 or deuteriogenation of
a suitable precursor that
incorporates a double bond.11 One other common method for the
incorporation of deuterium is through deuteration of enolates,
typically generated by deprotonation with lithium amide bases.
For example, Seebach et al. have reported the deuteration of eno-
lates generated by deprotonation with LDA, although only partial
deuterium incorporation was observed; a hydrogen bonded com-
plex between the amine and the lithium enolate was proposed to
account for this effect.12 An alternative protocol was therefore
2. Results and discussion
2.1. Tandem conjugate addition/deuteration of
esters
a,b-unsaturated
tert-Butyl cinnamate 5 was selected as a model system with
which to screen various ‘D+’ sources for high levels of diastereose-
lectivity upon deuteration of the intermediate lithium b-amino
⇑
Corresponding author. Tel.: +44 (0) 1865 275695; fax: +44 (0) 1865 275633.
E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.06.008

1036
S. G. Davies et al. / Tetrahedron: Asymmetry 22 (2011) 1035–1050
1H NMR spectroscopic analysis of the product mixture and com-
Ph
Ph
parison of specific integrals due to the C(2)H resonances. The rela-
tive intensities of the molecular ion peaks in the mass spectra
provided by low resolution mass spectrometric analysis were
found to be consistent with the degree of deuterium incorporation
as judged by 1H NMR spectroscopic analysis. In each case the
maximum deuterium incorporation was expected to be less than
100% due to the suppliers’ disclaimers that the deuterated solvents
employed in this protocol were not 100% isotopically pure
(Scheme 2).26
Ph
N
Ph
N
OtBu
OLi
(i)
(ii)
CO2tBu
CO2tBu
Ar
Ar
Ar
(E)-enolate
1
2
(iii)
Tandem
Stepwise
Approach
Approach
Ph
Ph
Ph
Ph
N
OLi
OtBu
Ph
N
Ph
N
Li
CO2tBu
Ar
Ar
(S)-4
(Z)-enolate
3
D
Scheme 1. Reagents and conditions: (i) (S)-4, THF, ꢀ78 °C then NH4Cl (satd, aq); (ii)
LHMDS, THF, ꢀ78 °C then ‘D+’; (iii) (S)-4, THF, ꢀ78 °C then ‘D+’.
enolate formed from the conjugate addition of lithium (S)-N-ben-
zyl-N-(a-methylbenzyl)amide 4. Prior to the deuteration studies
we sought to confirm that this conjugate addition reaction was
highly diastereoselective such that any diastereoisomeric mixtures
observed following deuteration would be a result of an unselective
enolate deuteration [i.e., be C(2)-epimers] rather than mixtures
arising from an unselective conjugate addition step giving rise to
products with different configurations at C(3). Thus, a solution of
tert-butyl cinnamate 522 at ꢀ78 °C was added to a solution of lith-
ium amide (S)-4 in THF at ꢀ78 °C following our standard procedure
for lithium amide conjugate addition; the resultant solution was
stirred at ꢀ78 °C then quenched by the addition of satd aq NH4Cl
to give, as previously reported,20b 6 in >99:1 dr, and 89% isolated
yield and >99:1 dr after chromatographic purification. The relative
configuration within 6 had previously been assigned by analogy to
the transition state mnemonic23 developed by us to rationalise the
diastereoselectivity exhibited by this class of lithium amide
Figure 1. Chem3D representation of the single crystal X-ray structure of (RS,SR)-6
(some H atoms are omitted for clarity).
The configuration at C(2) within anti-7 (and therefore also that
within syn-8) was established by conversion of anti-7 (93:7 dr) into
the corresponding b-lactam 14 as the 1H NMR 3J coupling constants
between the C(3)H and C(4)H protons within 3,4-disubstituted
b-lactams are known to be diagnostic of the stereochemical
configuration.27 The transformations were first performed on
reagents upon conjugate addition to
a,b-unsaturated esters; this
assignment has now been unambiguously confirmed by single
a,a-diprotio-b-amino ester 6 to confirm that epimerisation of the
crystal X-ray diffraction analysis of the racemic analogue (RS,SR)-
b-stereogenic centre was not occurring. The route involved the
chemoselective debenzylation28 of b-amino ester 6 with CAN29 to
give 9 in 86% yield and >99:1 dr, subsequent transesterification
of 9 to give the corresponding methyl ester 10 in 83% yield and
>99:1 dr, and finally cyclisation30 of 10 to give b-lactam 11 in
89% yield and >99:1 dr upon treatment with MeMgBr, confirming
that all reactions proceeded without compromising the stereo-
chemical integrity at the b-stereocentre within this substrate. An
analogous series of transformations were therefore applied to
6, with the absolute configuration within (3R,
relative to the known (S)-configuration of the
a
S)-6 being assigned
-methylbenzyl
a
group (Fig. 1). This result establishes that any diastereoisomeric
mixtures observed following deuteration of the intermediate lith-
ium b-amino enolate are epimeric at C(2) and not at C(3).24 The
corresponding a-deuteration reactions (employing a range of com-
mercially available deuteron sources, viz. D2O, MeOH-d4 and
AcOH-d4) were next evaluated. The product distributions were
analysed by both 1H NMR spectroscopic and mass spectrometric
analyses. As expected, the 1H NMR spectra of the products were
in accord with formation of the b-amino ester as a mixture of the
two mono-deuterated diastereoisomers anti-7 and syn-8, as well
a-deuterio-b-amino ester anti-7 (93:7 dr) giving b-lactam 14 in
60% overall yield (three steps) with a negligible decrease in deute-
rium incorporation or diastereoisomeric purity (Scheme 3). The
value of the 1H NMR 3J coupling constant observed between the
C(3)H and C(4)H protons within 14 (2.4 Hz) was indicative of an
anti relationship between these protons. The anti relative configu-
rations within b-amino esters 7, 12 and 13 (and the syn configura-
tion within 8) could therefore be confidently assigned.
as a trace amount of
a,a-diprotio-b-amino ester 6. In each case,
the reaction diastereoselectivity was judged by integration of the
distinct resonances arising from the individual diastereoisomers
anti-7 and syn-8.25 The degree of deuteration was determined by
Ph
Ph
Ph
Ph
N
Ph
N
Ph
N
(i)
(ii)
+
CO2tBu
CO2tBu
CO2tBu
CO2tBu
Ph
Ph
Ph
Ph
D
D
6, 89%, >99:1 dr
5
anti-7
syn-8
"D+" Source D Incorporation (%) dra (anti:syn) Yieldc (%)
D2O
92a (91)b
96a (96)b
53a (52)b
93:7
88:12
68:32
91
90
55
CD3OD
CD3CO2D
b
Scheme 2. Reagents and conditions: (i) (S)-4, THF, ꢀ78 °C, 2 h then NH4Cl (satd, aq); (ii) (S)-4, THF, ꢀ78 °C, 2 h then ‘D+’ [a 1H NMR spectroscopic analysis; mass
c
spectrometric analysis; combined isolated yield].

S. G. Davies et al. / Tetrahedron: Asymmetry 22 (2011) 1035–1050
1037
Ph
D
Ph
D
Ph
Ph
Ph
NH
Ph
N
Ph
N
Ph
N
(ii)
+
(i)
CO2tBu
CO2tBu
CO2tBu
CO2tBu
CO2tBu
Ph
Ph
Ar
Ar
Ar
6, >99:1 dr
9, 86%,>99:1 dr
15-20
anti-27-32
syn-33-38
dra,c
(ii)
Products
(anti:syn)
Acceptor
Ar
D Incorporation (%) (anti:syn) Yield (%)
15
16
4-MeOC6H4
4-BrC6H4
27:33
28:34
29:35
30:36
31:37
32:38
78a (77)b
81a (86)b
74a (70)b
80a (75)b
81a (90)b
89a (92)b
>99:1
96:4
60
65
72
67
68
70
O
Ph
NH
(iii)
N
>99:1
>99:1
>99:1
95:5
17
3-BrC6H4
CO2Me
18
19
20
3-FC6H4
Ph
10, 83%, >99:1 dr
Ph
2-BrC6H4
2-IC6H4
11, 89%, >99:1 dr
Scheme 5. Reagents and conditions: (i) (S)-4, THF, ꢀ78 °C, 2 h then D2O [a 1H NMR
b
c
Ph
spectroscopic analysis; mass spectrometric analysis; crude and isolated].
Ph
NH
Ph
N
27–32 with very high levels of diastereoselectivity (P95:5 dr) and
deuterium incorporation (P74%). In each case the configuration of
the major product was assigned as 2,3-anti by analogy to that
unambiguously proven for anti-7 (Scheme 5).
(i)
CO2tBu
CO2tBu
Ph
Ph
D
D
7, 93:7 dra
12, 76%,c 92:8 dra
92% D,a 91% Db
92% D,a 91% Db
(ii)
2.2. Stepwise conjugate addition/deuteration of
esters
a,b-unsaturated
O
Ph
Ph
NH
N
(iii)
Following the alternative ‘stepwise’ conjugate addition/deuter-
ation strategy, deprotonation of -diprotio-b-amino ester 6 fol-
CO2Me
H
D
4
3
a,a
Ph
Ph
H
lowed by diastereoselective deuteration upon the addition of a
‘D+’ source was next investigated. We have previously established
in a range of systems that deprotonation of a b-amino ester gives
rise to (E)-enolates, whereas (Z)-enolates are formed as a result
D
14, 94%,c 92:8 dra
13, 84%,c 93:7 dra
85% Da
92% Da
Scheme 3. Reagents and conditions: (i) CAN, MeCN/H2O (v/v 5:1), rt, 18 h; (ii)
MeOH, SOCl2, reflux, 2 h; (iii) MeMgBr, Et2O, 0 °C, 30 min [a 1H NMR spectroscopic
analysis; mass spectrometric analysis; combined isolated yield].
of a lithium amide conjugate addition reaction to an
a,b-unsatu-
b
c
rated ester.33 In order to confirm that this trend was also observed
in our model system the lithium b-amino enolates derived from
both (i) deprotonation of b-amino ester 6, or (ii) conjugate addition
In order to validate the ‘tandem’ conjugate addition/deuteration
reaction as a synthetically useful process the procedure was
of lithium (S)-N-benzyl-N-(a-methylbenzyl)amide 4 to a,b-unsatu-
applied to a range of
tive C(3)-aryl substitution. The lithium amide conjugate addition
reactions to
,b-unsaturated esters 15–2031 were first quenched
a,b-unsaturated esters incorporating alterna-
rated ester 5, were captured with TESCl to confirm their enolate
geometries by 1H NMR NOE analyses. Thus, in accordance with
a
our previous results, a,a-diprotio-b-amino ester 6 was sequentially
with satd aq NH4Cl to give authentic samples of b-amino esters
21–26 in good yield. In each case very high levels of diastereoselec-
tivity (P98:2 dr) were observed, confirming that any possible dia-
stereoisomeric mixtures obtained from the corresponding tandem
conjugate addition/deuteration reactions would be epimeric at
C(2) rather than C(3) (Scheme 4).32
treated with LDA and TESCl to give triethylsilyl ketene acetal (E)-40
in 98% conversion and >99:1 dr. Conversely, triethylsilyl ketene
acetal (Z)-42 was accessed in 95% conversion and >99:1 dr upon
conjugate addition of (S)-4 to 5 followed by treatment with TESCl
(Scheme 6). 1H NMR NOE analysis of (Z)-42 revealed that when
the C(2)H proton was irradiated, enhancements to the correspond-
ing C(3)H, C(a)Me and CMe3 protons were observed. Additionally,
when the CMe3 protons were irradiated, there was clearly a strong
enhancement to the C(2)H proton. For (E)-40, however, irradiation
of the C(2)H proton showed no enhancement to the tert-butyl
group, but a large enhancement to the Si(CH2CH3)3 protons was
observed. In addition, when the Si(CH2CH3)3 protons were irradi-
ated the only enhancement that was observed was to the C(2)H
Ph
Ph
N
(i)
CO2tBu
CO2tBu
Ar
Ar
15-20
21-26
Acceptor
Product
21
Yield (%)
Ar
dra,b
98:2
Ph
Ph
Ph
15
16
17
18
19
20
96
92
86
83
89
96
4-MeOC6H4
4-BrC6H4
3-BrC6H4
3-FC6H4
22
98:2
Ph
N
Ph
N
OtBu
Ph
N
OtBu
OTES
23
>99:1
98:2
(i)
24
CO2tBu
25
2-BrC6H4
2-IC6H4
>99:1
>99:1
Ph
Ph
OLi
Ph
26
39
(E)-40, 98% conv
6
(E)-enolate
>99:1 (E):(Z)
Scheme 4. Reagents and conditions: (i) (S)-4, THF, ꢀ78 °C, 2 h then NH4Cl (satd, aq)
a
b
Ph
Ph
[
1H NMR spectroscopic analysis; crude and isolated].
Ph
N
OLi
Ph
N
OTES
OtBu
(ii)
Under the optimised conditions, conjugate addition of (S)-4 to
15–20, followed by deuteration of the resultant lithium b-amino
CO2tBu
Ph
Ph
OtBu
Ph
41
(Z)-enolate
(Z)-42, 95% conv
enolates with D2O at ꢀ78 °C, gave the corresponding anti-
a
-deute-
5
>99:1 (Z):(E)
rio-b-amino esters 27–32 as the major products. In most cases 1H
NMR spectroscopic analysis of the crude reaction mixtures indi-
cated that the reactions had all proceeded to full conversion giving
Scheme 6. Reagents and conditions: (i) LDA, THF, TESCl, ꢀ78 °C, 1 h; (ii) (S)-4, THF,
TESCl, ꢀ78 °C, 1 h [TES = SiEt3].

1038
S. G. Davies et al. / Tetrahedron: Asymmetry 22 (2011) 1035–1050
Ph
Ph
D
Ph
D
proton. This stereochemical outcome is consistent with other
b-amino enolate trapping studies34 and also that predicted by the
Ireland chelation-controlled deprotonation transition state mod-
el35 for deprotonation of 6 with LDA.
Ph
N
Ph
N
Ph
N
(i)-(iii)
(i)-(iii)
CO2tBu
CO2tBu
CO2tBu
Ph
Ph
Ph
Lithium b-amino enolate (E)-39, generated by deprotonation of
D
From anti-7: 88%, 66:34 dr,
syn-8, 82:18 dra
anti-7, 88:12 dra
a
,
a
-diprotio-b-amino ester 6 with LDA, was next treated with D2O
-deuterated
90% Da, 84% Db
99% D,a 93% Db
96% D,a 96% Db
at ꢀ78 °C under a range of conditions to give
a
From syn-8: 84%, 50:50 dr,
86% Da, 79% Db
products anti-7 and syn-8 with varying levels of deuterium incor-
poration and diastereoselectivity. Under optimised conditions
a,a-diprotio-b-amino ester 6 was added to 1.0 equiv of LDA at
Scheme 8. Reagents and conditions: (i) LDA, THF, ꢀ78 to 0 °C; (ii) BuLi, ꢀ78 °C; (iii)
H2O, ꢀ78 °C to rt, 30 min.
ꢀ78 °C and the resultant mixture was allowed to warm to 0 °C over
1 h before being cooled to ꢀ78 °C prior to the addition of D2O. This
ꢀ78 °C. Treatment of anti-7 under these conditions gave silyl
ketene acetal 44 in 79% conversion with 69% deuterium incorpora-
tion. The (E)-configuration within 44 was assigned by analogy to
the previous results for capture of enolate (E)-39 with TESCl.
Treatment of syn-8 under identical conditions also gave 44 (in
90% conversion with 67% D incorporation). An estimate of the
kinetic isotope effect may be given by dividing the percentage of
hydrogen removed by the percentage of deuterium removed: for
deprotonation of anti-7, a kinetic isotope effect of 2.6 was calcu-
lated, whereas a kinetic isotope effect of 3.0 was calculated for
deprotonation of syn-8. As deprotonation of both diastereoisomers
gave silyl ketene acetal 44 with good conversion this confirms that
LDA was effecting complete deprotonation. Silyl ketene acetal 44
(69% D incorporation; formed from anti-7) was next treated with
BuLi at ꢀ78 °C (to remove the silyl moiety) followed by the
addition of D2O which gave a product mixture containing anti-7,
produced a 7:93 mixture of
a-deuterio-b-amino esters anti-7 and
syn-8, respectively, which was isolated in relatively poor yield
(55%) with incomplete deuterium incorporation (64%), as
determined by 1H NMR spectroscopic analysis. The corresponding
a,a
-dideuterio-b-amino ester 4336 was not detected (Scheme 7).
Employing
a
‘double deprotonation’ strategy37 [i.e., whereby
(E)-39 was formed upon deprotonation of 6 with LDA, BuLi was
then added, the reaction mixture was allowed to warm to 0 °C then
cooled to ꢀ78 °C before the addition of D2O] gave a 30:70 mixture
of anti-7 and syn-8, respectively, with 91% deuterium
incorporation.
Ph
Ph
Ph
N
Ph
N
OtBu
OLi
(i)
CO2tBu
Ph
Ph
syn-8 and
there was no evidence of the corresponding
ester 6 (Scheme 9). The formation of 80% a,a
a
,
a
-dideuterio 43 in the ratio of 8:12:80 respectively;
-diprotio-b-amino
-dideuterated product
(E)-39
6, >99:1 dr
a,a
55%,c 64% D,a 64% D,b
(ii)
7:93 dr (anti:syn)a
43 reflects the observed 79% deuterium incorporation of interme-
diate 44, and confirms that the proton is selectively removed from
either b-amino ester anti-7 or syn-8 via a kinetic isotope effect.
These data demonstrate that the reaction conditions are not,
therefore, interfering with deuterium incorporation.
Ph
N
Ph
Ph
Ph
Ph
N
Ph
N
+
CO2tBu
CO2tBu
CO2tBu
Ph
Ph
Ph
D
D
D
anti-7
D
syn-8
43
Ph
Ph
Ph
Scheme 7. Reagents and conditions: (i) LDA, THF, ꢀ78 to 0 °C, 1 h; (ii) D2O, ꢀ78 °C
OtBu
OTMS
Ph
N
b
to rt, 30 min [a 1H NMR spectroscopic analysis; mass spectrometric analysis;
Ph
N
Ph
N
(i)-(iii)
(i)-(iii)
c
combined isolated yield].
CO2tBu
CO2tBu
Ph
Ph
Ph
D
D
D
Having studied the diastereoselectivity of deuteration of lith-
44, >99:1 dra
syn-8, 82:18 dra
anti-7, 88:12 dr,a
ium (E)-
deprotonation of
a
-protio-b-amino enolates, the diastereoselectivity of
From anti-7: 79% conv, 69% Da
99% D,a 93% Db
96% D,a 96% Db
a
-deuterio-b-amino esters anti-7 and syn-838
From syn-8: 90% conv, 67% Da
8:12:80
(iv), (v)
was next investigated. Thus, anti-7 and syn-8 were treated with
LDA under ‘double deprotonation’ conditions at ꢀ78 °C followed
by the addition of H2O. When anti-7 (88:12 dr, 96% D incorpora-
tion) was subjected to these conditions a 66:34 mixture of anti-7
and syn-8, respectively, was formed with minimal loss of deute-
rium (90% D incorporation), indicating preferential removal of
(7:8:43)
Ph
D
Ph
Ph
Ph
N
+
Ph
N
+
Ph
N
CO2tBu
CO2tBu
CO2tBu
Ph
Ph
Ph
D
D
the syn-a-proton. If deprotonation was indeed syn diastereoselec-
D
syn-8
anti-7
43
tive, treatment of
a
-deuterio-b-amino ester syn-8 would be pre-
dicted to afford a product with low deuterium incorporation.
However, treatment of syn-8 (82:18 dr, 93% D incorporation) with
LDA under ‘double deprotonation’ conditions followed by the addi-
tion of H2O gave a 50:50 mixture of anti-7 and syn-8, again with
minimal loss of deuterium (86% D incorporation). There are two
possible explanations for this result: either full deprotonation is
not occurring upon treatment with LDA, or a kinetic isotope effect
is overriding any diastereoselective process, with a proton being
more readily removed than a deuteron (Scheme 8).
Scheme 9. Reagents and conditions: (i) LDA, THF, ꢀ78 to 0 °C; (ii) BuLi, ꢀ78 °C; (iii)
TMSCl, ꢀ78 °C; (iv) BuLi, THF, ꢀ78 °C; (v) D2O, ꢀ78 °C [a 1H NMR spectroscopic
b
analysis; mass spectrometric analysis].
Given the limited success of this approach for the preparation of
syn-
protocol could be used to access these substrates. The conjugate
addition of lithium amide (S)-4 to an -deuterio- ,b-unsaturated
a-deuterio-b-amino esters it was envisaged that an alternative
a
a
To monitor whether full deprotonation was indeed occuring,
and to investigate further the diastereoselectivity of deprotonation,
it was envisaged that anti-7 and syn-8 could be treated with LDA
under the ‘double deprotonation’ conditions, then the intermediate
lithium b-amino enolates could be trapped by addition of TMSCl at
ester followed by diastereoselective protonation of the intermedi-
ate lithium b-amino enolate was therefore investigated as it was
anticipated that superior levels of deuterium incorporation
would be observed relative to the ‘stepwise’ conjugate addition/
deuteration protocol.

S. G. Davies et al. / Tetrahedron: Asymmetry 22 (2011) 1035–1050
1039
Ph
D
Ph
D
2.3. Tandem conjugate addition/protonation of
unsaturated esters
a-deuterio-a,b-
(i)
Ph
N
Ph
N
CO2tBu
+
CO2tBu
CO2tBu
Ph
With a Wadsworth-Emmons protocol in mind (i.e., reaction of
an aldehyde with a deuterated phosphonate), the synthesis of
C(2) isotopically labelled tert-butyl cinnamate 47 commenced with
Ph
Ph
D
47, >99:1 dr
99% Da
syn-8
anti-7
the preparation of a,a-dideuterio phosphonate 46 from unlabelled
"H+" Source D Incorporation (%) dra,c (syn:anti) Yield (%)
phosphonate 45. Initially, the base employed for deprotonation of
phosphonate 45 was KOtBu in MeOH-d4, although in this case a
maximum of 89% deuterium incorporation was observed. The level
of deuterium incorporation was increased to 95% by use of KOtBu
94a (94)b
99a (93)b
95a (92)b
96a (97)b
90:10
82:18
73:27
>99:1
85
90
26
75
H2O
MeOH
AcOH
2-pyridone
t
in BuOD.39 However, full conversion of phosphonate 45 to phos-
Scheme 11. Reagents and conditions: (i) (S)-4, THF, ꢀ78 °C, 2 h then ‘H+’, ꢀ78 °C to
rt, 30 min [a 1H NMR spectroscopic analysis; b mass spectrometric analysis; c crude
and isolated].
phonate-d2 46 was obtained upon treatment of 45 with K2CO3 in
D2O.40 Reaction optimisation indicated that 3.0 equiv of K2CO3 as
a solution in D2O provided phosphonate-d2 46 in quantitative yield
with 99% deuterium incorporation. With phosphonate-d2 46 in
hand, attention turned to developing the Wadsworth–Emmons
the results. AcOH (pKa 12.6 in DMSO41) may be preferentially pro-
tonating on oxygen, with subsequent loss of diastereoselectivity
upon tautomerisation, and the greater diastereoselectivity of pro-
tonation by H2O (pKa 31.4 in DMSO42) may be rationalised via a
mechanism in which protonation occurs directly at the C(2) carbon
atom. We have previously demonstrated that high diastereoselec-
tivity can be obtained during the protonation of lithium b-amino
enolates by 2-pyridone via a ‘proton relay’ mechanism where the
proton is delivered directly to the C(2) carbon atom of the enolate;43
this rationale may also, therefore, account for the extremely high
diastereoselectivity observed upon protonation of the intermediate
lithium b-amino enolate with 2-pyridone in this case.
olefination with benzaldehyde to give tert-butyl
a-deuteriocinna-
mate 47 with high diastereoselectivity and deuterium incorpora-
tion. A range of conditions were screened and the combination of
K2CO3 in D2O was found to give 47 with the highest level of deute-
rium incorporation. Thus, under optimised conditions, reaction of
2.0 equiv of 46 with benzaldehyde at 50 °C gave 47 in 95% yield
and >99:1 dr with 99% deuterium incorporation (Scheme 10).
O
O
(i)
(EtO)2P
CO2tBu
(EtO)2P
CO2tBu
D
D
46, quant, 99% Da
This approach represents a significant improvement upon the
45
‘stepwise’ protocol and was therefore applied to a range of
unsaturated esters incorporating alternative C(3)-substitution.
The requisite -deuterio- ,b-unsaturated esters 48–52 were
a,b-
(ii)
a
a
CO2tBu
prepared in good yield from the corresponding aldehydes by
Ph
treatment with phosphonate-d2 46 and K2CO3 in D2O at 50 °C; in
D
47, 95%, >99:1 dr, 99% Da
each case
a-deuterio-a,b-unsaturated esters 48–52 were isolated
in >99:1 dr with P96% deuterium incorporation. Following the
optimised conditions, conjugate addition of (S)-4 to 48–52 gave
the corresponding syn-a-deuterio-b-amino esters 34–38 as the
Scheme 10. Reagents and conditions: (i) K2CO3, D2O, rt, 24 h; (ii) PhCHO, D2O,
50 °C, 30 h [a 1H NMR spectroscopic analysis].
sole products after protonation of the resultant lithium b-amino
enolates with 2-pyridone at ꢀ78 °C.44 In most cases 1H NMR
spectroscopic analysis of the crude reaction mixtures indicated
that very high levels of diastereoselectivity (>99:1 dr) and deute-
rium incorporation (P89%) were observed (Scheme 12).
The conjugate addition of lithium (S)-N-benzyl-N-(
zyl)amide 4 to tert-buyl -deuteriocinnamate 47 was performed at
-deuterio-b-amino
enolate with a range of proton sources, viz. H2O, MeOH, AcOH and
2-pyridone. In each case a diastereoisomeric mixture of the two
mono-deuterated-b-amino esters anti-7 and syn-8, along with a
a-methylben-
a
ꢀ78 °C, followed by protonation of the lithium
a
trace amount of the
a,a-diprotio-b-amino ester 6, was observed.
Ph
The highest level of diastereoselectivity was observed upon proton-
ation of the intermediate lithium b-amino enolate with 2-pyridone,
giving syn-8 in >99:1 dr and 96% deuterium incorporation
(Scheme 11). In each case, the level of deuterium incorporation of
the product mixture of b-amino esters from each reaction was
consistently high (P92%) although slightly lower than that of the
starting material. When compared with the results obtained for
Ph
N
(i)
CO2tBu
CO2tBu
Ar
Ar
D
D
48-52
syn-34-38
Acceptord D Incorporation (%)
Ar
Product D Incorporation (%) dra,c Yield (%)
48
49
50
51
52
99a (99)b
99a (98)b
99a (98)b
99a (98)b
99a (96)b
4-BrC6H4
3-BrC6H4
3-FC6H4
2-BrC6H4
2-IC6H4
34
35
36
37
38
92a (96)b
92a (96)b
90a (91)b
92a (96)b
89a (95)b
>99:1
>99:1
>99:1
>99:1
>99:1
53
59
73
65
53
the deuteration of lithium
a-protio-b-amino enolates, the major
difference between the two sets of data is the high degree of
deuterium incorporation in the products arising from protonation
with AcOH (95%), which is substantially greater than that for
deuteration with AcOH-d4 (53%). While each reaction demonstrated
anti-diastereoselectivity to produce syn-8 as the major product, the
diastereoselectivity ranged from 73:27 to >99:1 dr. The levels of
Scheme 12. Reagents and conditions: (i) (S)-4, THF, ꢀ78 °C, 2 h then 2-pyridone,
a
b
ꢀ78 °C to rt, 30 min
[
1H NMR spectroscopic analysis;
mass spectrometric
c
d
analysis; crude and isolated; compounds 48-52 were isolated in >99:1 dr with
P96% D incorporation].
diastereoselectivity obtained upon protonation of the
a-deuterio
substituted enolate by H2O, MeOH and AcOH were found to be
comparable with those arising from deuteration of the correspond-
2.4. Deprotection to give a-deuterio-b-amino acids
ing
a-protioenolate with D2O, MeOH-d4 and AcOH-d4. While it is
difficult to predict the mechanism that is operating upon addition
of each of the proton/deuteron sources, consideration of the pKa
and structure of the proton/deuteron source is helpful for analysing
The deprotection of anti-7 and syn-8 (as representative exam-
ples) to give the corresponding -deuterio-b-amino acids was next
undertaken. N-Benzyl deprotection of anti-7 (93:7 dr) was
a

1040
S. G. Davies et al. / Tetrahedron: Asymmetry 22 (2011) 1035–1050
achieved by hydrogenolysis in the presence of Pearlman’s catalyst
[Pd(OH)2/C] under 1 atmosphere of hydrogen giving 53 in 47%
yield and 91:9 dr, without compromising the extent of deuterium
incorporation.45 Subsequent treatment of 53 with TFA followed by
purification via ion exchange chromatography on Dowex 50WX8-
and titrated against diphenylacetic acid before use. All other re-
agents 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 60 F254 silica. Plates were visualised using UV light (254 nm),
iodine, 1% aq KMnO4, or 10% ethanolic phosphomolybdic acid.
Flash column chromatography was performed on Kieselgel 60
silica.
Melting points were recorded on a Gallenkamp Hot Stage appa-
ratus and are uncorrected. Optical rotations were recorded on a
Perkin-Elmer 241 polarimeter with a water-jacketed 10 cm cell.
Specific rotations are reported in 10ꢀ1 deg cm2 gꢀ1 and concentra-
tions in g/100 mL. IR spectra were recorded on a 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 Bruker Avance spectrom-
eters in the deuterated solvent stated. Spectra were recorded at rt
unless otherwise stated. The field was locked by external referenc-
ing to the relevant deuteron resonance. Low-resolution mass spec-
tra were recorded on either a VG MassLab 20-250 or a Micromass
Platform 1 spectrometer. Accurate mass measurements were run
on either a Bruker MicroTOF internally calibrated with polyalanine,
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.
200 resin gave
and 91:9 dr, confirming that the stereochemical integrity of the
-centre was maintained during the deprotection sequence.
Deprotection of syn-845 (>99:1 dr) was achieved by an analogous
sequence of reactions to give -deuterio-b-amino acid (R,R)-56 in
a-deuterio-b-amino acid (2S,3R)-54 in 90% yield
a
a
51% yield (in two steps from syn-8) and >99:1 dr, following purifi-
cation via ion exchange chromatography (Scheme 13).
Ph
Ph
Ph
N
NH2
NH2
CO2tBu
CO2tBu
CO2tBu
(i)
(i)
(ii)
(ii)
Ph
Ph
Ph
D
D
D
7, 93:7 dra
53, 47%, 91:9 dra,c
54, 90%, 91:9 dra,c
92% D, a 91% Db
Ph
92% D, a 90% Db
90% D, a 93% Db
N
NH2
NH2
CO2tBu
CO2H
Ph
CO2tBu
Ph
Ph
D
D
D
8, >99:1 dra
55, 82%, >99:1 dra,c
96% D, a 80% Db
56, 62%, >99:1 dra,c
81% D, a 78% Db
4.2. General procedure 1 for lithium amide conjugate addition
96% D, a 97% Db
BuLi (1.55 equiv) was added dropwise to a solution of (S)-N-
Scheme 13. Reagents and conditions: (i) H2 (1 atm), Pd(OH)2/C, MeOH/H2O/AcOH
(v/v/v 40:4:1), rt, 24 h; (ii) TFA/CH2Cl2 (v/v 1:1), rt, 24 h then HCl, Dowex 50WX8-
benzyl-N-(
mL) at ꢀ78 °C. The resultant pink solution was stirred at ꢀ78 °C
for 30 min before the addition of the requisite ,b-unsaturated ester
a-methylbenzyl)amine (1.6 equiv) in THF (0.5 mmol/
b
c
200 [a 1H NMR spectroscopic analysis; mass spectrometric analysis; crude and
isolated].
a
(1.0 equiv) in THF (0.3 mmol/mL) at ꢀ78 °C. The reaction mixture
was then stirred at ꢀ78 °C for 2 h before the addition of either satd
aq NH4Cl, D2O, MeOH-d4, AcOH-d4, H2O, MeOH, AcOH or 2-pyridone,
as specified. The reaction mixture was then allowed to warm to rt
and concentrated in vacuo. The residue was partitioned between
H2O and Et2O and the aqueous layer was extracted with Et2O. The
combined organic extracts were then sequentially washed with
brine, 10% aq citric acid, satd aq NaHCO3 and brine, then dried and
concentrated in vacuo.
3. Conclusion
In conclusion, the conjugate addition of lithium (S)-N-benzyl-N-
(a
-methylbenzyl)amide to a range of
lowed by reaction of the resultant lithium (Z)-b-amino enolates
with D2O provides access to anti configured -deuterio-b-amino
esters in high dr. Attempted preparation of syn configured
a,b-unsaturated esters fol-
a
a
-deuterio-b-amino esters via deprotonation of the corresponding
-diprotio-b-amino esters followed by reaction of the resultant
a,
a
4.3. General procedure 2 for Wadswoth–Emmons olefination
lithium (E)-b-amino enolates with D2O also proceeded with high
diastereoselectivity, although in this case the extent of deuterium
incorporation was poor. An alternative procedure for the prepara-
The requisite aldehyde (0.5 equiv) was added to a solution of
phosphonate-d2 46 (1.0 equiv) and K2CO3 (3.0 equiv) in D2O
(6.0 mmol/mL). The resultant solution was stirred for 30 h at
50 °C, then allowed to cool to rt and extracted with three portions
of Et2O. The combined organic extracts were washed with 10% aq
Na2S2O3, then dried and concentrated in vacuo.
tion of syn configured
therefore developed via the conjugate addition of lithium (S)-N-
benzyl-N-( -methylbenzyl)amide to a range of -deuterio- ,b-
a-deuterio-b-amino esters in high dr was
a
a
a
unsaturated esters followed by reaction of the resultant lithium
(Z)-b-amino enolates with 2-pyridone. After deprotection of two
diastereoisomeric
anti-diastereoisomers of the corresponding
acids were isolated in high dr.
a-deuterio-b-amino esters, both the syn- and
a
-deuterio-b3-amino
4.3.1. tert-Butyl (3R,
3-phenylpropanoate 6
aS)-3-[N-benzyl-N-(a-methylbenzyl)amino]-
Ph
4. Experimental
Ph
N
4.1. General experimental
CO2tBu
Ph
All reactions involving organometallic or other moisture-sensi-
tive reagents were carried out under a nitrogen or argon atmo-
sphere using standard vacuum line techniques and glassware
that was flame dried and cooled under nitrogen before use. Sol-
vents were dried according to the procedure outlined by Grubbs
and co-workers.46 Water was purified by an ElixÒ UV-10 system.
BuLi was purchased from Sigma–Aldrich (as a solution in hexanes)
Following general procedure 1, reaction of (S)-N-benzyl-N-(a-
methylbenzyl)amine (8.19 g, 39.2 mmol) in THF (75 mL), BuLi
(15.2 mL, 37.9 mmol) and 522 (5.00 g, 24.5 mmol) in THF (75 mL),
followed by satd aq NH4Cl (25 mL), gave 6 in >99:1 dr. Purification
via flash column chromatography (eluent 30–40 °C petrol/Et2O,
100:1) gave 6 as a colourless oil (9.07 g, 89%, >99:1 dr); ½a D23
ꢂ

S. G. Davies et al. / Tetrahedron: Asymmetry 22 (2011) 1035–1050
1041
ꢀ2.2 (c 1.4 in CH2Cl2); {lit.15b for enantiomer ½a 2D4
ꢂ
+3.9 (c 1.4 in
)Me), 1.24
THF (1.5 mL), followed by AcOH-d4 (0.5 mL), gave a 68:32 mixture
of 7 and 8 in addition to returned starting material 5. Purification
via flash column chromatography (eluent 40–60 °C petrol/Et2O,
100:1) gave 5 as a colourless oil (37 mg, 41%). Further elution gave
a 68:32 mixture of 7 and 8 as a colourless oil (106 mg, 55%, D incor-
poration 53% [1H NMR], 52% [MS]).
CH2Cl2)}; dH (400 MHz, MeOH-d4) 1.20 (3H, d, J 6.8, C(
a
(9H, s, CMe3), 2.53 (1H, dd, J 14.4, 9.8, C(2)HA), 260 (1H, dd, J
14.4, 5.4, C(2)HB), 3.69 (2H, app s, NCH2Ph), 4.01 (1H, q, J 6.8,
C(a)H), 4.37 (1H, dd, J 9.8, 5.4, C(3)H), 7.13–7.44 (15H, m, Ph).
4.3.1.1. X-ray crystal structure determination for (RS,SR)-6.
Data were collected using an Enraf-Nonius -CCD diffractometer
with graphite monochromated Mo-K radiation using standard
j
4.3.3. tert-Butyl (3R,
propanoate 9
aS)-3-[N-(a-methylbenzyl)amino]-3-phenyl-
a
procedures at 190 K. The structure was solved by direct methods
(SIR92); all non-hydrogen atoms were refined with anisotropic
thermal parameters. Hydrogen atoms were added at idealised
positions. The structure was refined using CRYSTALS.47
Ph
Ph
NH
CO2tBu
X-ray crystal structure data for (RS,SR)-6 [C28H33NO2]: M =
ꢀ
415.58, triclinic, space group P, a = 10.2498(2) Å, b = 10.2921(2) Å,
CAN (1.38 g, 2.52 mmol) was added to a solution of 6 (500 mg,
1.20 mmol) in a mixture of MeCN/H2O (v/v 5:1, 13.8 mL). The
resultant solution was stirred at rt for 18 h then satd aq NaHCO3
(15 mL) was added and the product mixture was extracted with
Et2O (3 ꢁ 20 mL). The combined organic extracts were then
washed with brine, dried and concentrated in vacuo. Purification
via flash column chromatography (eluent 30–40 °C petrol/Et2O,
c = 12.7424(3) Å,
a
= 101.6433(7)°, b = 109.9610(9)°,
c
= 95.8929(7)°,
V = 1215.79(4) Å3, Z = 2,
l
= 0.070 mmꢀ1, colourless block, crystal
dimensions = 0.21 ꢁ 0.23 ꢁ 0.23 mm3.
A total of 5480 unique
reflections were measured for 5 < h < 27 and 4642 reflections were
used in the refinement. The final parameters were wR2 = 0.119 and
R1 = 0.055 [I > ꢀ3.0
r(I)].
Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre as sup-
plementary publication number CCDC 810336. Copies of the data
can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: +44(0) 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].
5:1) gave 9 as a yellow oil (226 mg, 86%, >99:1 dr);29
(c 1.0 in CHCl3); {lit.30
ꢀ16.3 (c 1.5 in CHCl3)}; dH (400 MHz,
CDCl3) 1.39 (3H, d, J 6.5, C( )Me), 1.42 (9H, s, CMe3), 1.91 (1H, br
s, NH), 2.59 (1H, dd, J 14.7, 6.2, C(2)HA), 2.86 (1H, dd, J 14.7, 7.9,
½
a 2D2
ꢂ
ꢀ15.8
½ ꢂ
a 2D3
a
C(2)HB), 3.70 (1H, q, J 6.5, C(a)H), 4.21 (1H, dd, J 7.9, 6.2, C(3)H),
7.21–7.32 (10H, m, Ph).
4.3.2. tert-Butyl (2S,3R,aS)-2-deuterio-3-[N-benzyl-N-(a-methyl-
benzyl)amino]-3-phenylpropanoate 7
4.3.4. Methyl (3R,
propanoate 10
a
S)-3-[N-(
a
-methylbenzyl)amino]-3-phenyl-
Ph
Ph
NH
Ph
N
CO2tBu
CO2Me
Ph
Ph
D
SOCl2 (0.50 mL, 6.86 mmol) was added dropwise to a stirred
solution of 9 (199 mg, 0.61 mmol) in MeOH (6 mL) at 0 °C. The
resultant mixture was heated at reflux for 2 h then allowed to cool
to rt and concentrated in vacuo. The residue was dissolved in
CH2Cl2 (20 mL) and the resultant mixture was washed with satd
aq NaHCO3 (20 mL), then dried and concentrated in vacuo to give
Method A: Following general procedure 1, reaction of (S)-N-ben-
zyl-N-( -methylbenzyl)amine (3.04 g, 7.83 mmol) in THF (15 mL),
a
BuLi (3.04 mL, 7.59 mmol) and 5 (1.00 g, 4.90 mmol) in THF
(15 mL), followed by D2O (5 mL), gave a 93:7 mixture of 7 and 8.
Purification via flash column chromatography (eluent 30–40 °C
petrol/Et2O, 30:1) gave a 93:7 mixture of 7 and 8 as a colourless
oil (1.87 mg, 91%, D incorporation 92% [1H NMR], 91% [MS]).
Data for anti-7: dH (400 MHz, MeOH-d4) 1.26 (9H, s, CMe3), 1.30
10 as a yellow oil (144 mg, 83%, >99:1 dr);30
CHCl3); {lit.30
ꢀ16.3 (c 1.5 in CHCl3)}; dH (400 MHz, CDCl3)
1.35 (3H, d, J 6.5, C( )Me), 1.76 (1H, br s, NH), 2.67 (1H, dd, J
15.3, 6.2, C(2)HA), 2.75 (1H, dd, J 15.3, 7.8, C(2)HB), 3.63 (3H, s,
½
a 2D2
ꢂ
ꢀ20.0 (c 0.1 in
½ ꢂ
a 2D1
a
(3H, d, J 6.8, C(
NCH2Ph), 4.04 (1H, q, J 6.8, C(
7.47 (15H, m, Ph); dC (100 MHz, MeOH-d4) 16.3 (C(
(CMe3), 38.3 (C(2)), 50.9 (NCH2Ph), 57.1 (C( )), 59.7 (C(3)), 80.1
a
)Me), 2.57 (1H, d, J 4.6, C(2)H), 3.72 (2H, app s,
)H), 4.44 (1H, d, J 4.6, C(3)H), 7.19–
)Me), 27.8
OMe), 3.67 (1H, q, J 6.5, C(a)H), 4.22 (1H, dd, J 7.8, 6.2, C(3)H),
a
7.19–7.34 (10H, m, Ph).
a
a
4.3.5. (4R,
a
S)-N(1)-(a-Methylbenzyl)-4-phenylazetidin-2-one 11
(CMe3), 126.5, 126.8, 126.9 (p-Ph), 127.1, 127.8, 128.1, 128.2,
128.3, 128.9, (o,m-Ph), 141.7, 141.8, 144.2, (i-Ph), 171.1 (C(1)).
Data for mixture: ½a D22
ꢀ8.8 (c 1.0 in CHCl3); mmax (film) 1725
ꢂ
O
Ph
(C@O), 1453 (C–N), 1160 (C–O); m/z (ESI+) 417 ([M+H]+, 100%);
N
+
HRMS (ESI+) C28H33DNO2 ([M+H]+) requires 417.2647; found
417.2667.
Ph
Method B: Following general procedure 1, reaction of (S)-N-ben-
MeMgBr (2.13 M in Et2O, 0.28 mL, 0.59 mmol) was added drop-
wise via syringe to a solution of 10 (140 mg, 0.49 mmol) in Et2O
(2.5 mL) at 0 °C. The resultant mixture was stirred for 30 min at
0 °C and then satd aq NH4Cl (5 mL) was added. The reaction mix-
ture was then extracted with Et2O (2 ꢁ 10 mL) and the combined
organic extracts were dried and concentrated in vacuo to give 11
zyl-N-(a-methylbenzyl)amine (248 mg, 1.18 mmol) in THF (2 mL),
BuLi (3.04 mL, 7.59 mmol) and 5 (150 mg, 0.734 mmol) in THF
(2 mL), followed by MeOH-d4 (1 mL), gave an 88:12 mixture of 7
and 8. Purification via flash column chromatography (eluent 40–
60 °C petrol/Et2O, 30:1) gave an 88:12 mixture of 7 and 8 as a col-
ourless oil (275 mg, 90%, D incorporation 96% [1H NMR], 96% [MS]).
Method C: Following general procedure 1, reaction of (S)-N-ben-
as a yellow oil (111 mg, 89%, >99:1 dr);30
CHCl3); {lit.30
+57.9 (c 1.1 in CHCl3)}; dH (400 MHz, CDCl3)
1.30 (3H, d, J 7.2, C( )Me), 2.84 (1H, dd, J 14.8, 2.5, C(3)HA), 3.25
½
a 2D2
ꢂ
+40.0 (c 0.6 in
½ ꢂ
a 2D1
zyl-N-(
a-methylbenzyl)amine (157 mg, 0.744 mmol) in THF
a
(1.5 mL), BuLi (0.45 mL, 0.72 mmol) and 5 (95 mg, 0.47 mmol) in

1042
S. G. Davies et al. / Tetrahedron: Asymmetry 22 (2011) 1035–1050
(1H, dd, J 14.8, 5.4, C(3)HB), 4.30 (1H, dd, J 5.4, 2.5, C(4)H), 5.05 (1H,
q, J 7.2, C( )H), 7.19–7.42 (10H, m, Ph).
Et2O (3 ꢁ 5 mL) and the combined organic extracts were dried
and concentrated in vacuo. Purification via flash column chroma-
tography (eluent 30–40 °C petrol/Et2O, 10:1) gave 14 as a colour-
less oil (73 mg, 94%, 92:8 dr, D incorporation 85% [1H NMR]);
a
4.3.6. tert-Butyl (2S,3R,aS)-2-deuterio-3-[N-(a-methylbenzyl)-
amino]-3-phenylpropanoate 12
½
a 2D2
ꢂ
+27.9 (c 0.8 in CHCl3); {lit.27 for enantiomer ½a 2D0
ꢂ
ꢀ15.8 (c
1.4 in CHCl3)}; dH (400 MHz, CDCl3) 1.32 (3H, d, J 7.2, C(
a
)Me),
2.85 (1H, d, J 2.4, C(3)H), 4.32 (1H, d, J 2.4, C(4)H), 5.07 (1H, q, J
7.2, C( )H), 7.24–7.38 (10H, m, Ph).
a
Ph
NH
CO2tBu
Ph
4.3.9. tert-Butyl (3R,aS)-3-[N-benzyl-N-(a-methylbenzyl)-
amino]-3-(40-methoxyphenyl)propanoate 21
D
CAN (1.38 g, 2.52 mmol) was added to a solution of 7 (500 mg,
1.20 mmol, 93:7 dr, D incorporation 92% [1H NMR], 91% [MS]) in a
mixture of MeCN/H2O (v/v 5:1, 11.8 mL). The resultant solution
was stirred at rt for 18 h then satd aq NaHCO3 (15 mL) was added
and the product mixture was extracted with Et2O (3 ꢁ 20 mL). The
combined organic extracts were then washed with brine, dried and
concentrated in vacuo. Purification via flash column chromatogra-
phy (eluent 30–40 °C petrol/Et2O, 1:5) gave 12 as a yellow oil
(282 mg, 76%, 92:8 dr, D incorporation 92% [1H NMR], 91% [MS]);
Ph
Ph
N
t
CO2Bu
MeO
Following general procedure 1, reaction of (S)-N-benzyl-N-(a-
methylbenzyl)amine (360 mg, 1.70 mmol) in THF (15 mL), BuLi
(1.00 mL, 1.60 mmol) and 1531a (249 mg, 1.14 mmol) in THF
(15 mL), followed by satd aq NH4Cl (5 mL), gave 21 in 98:2 dr. Puri-
fication via flash column chromatography (eluent 40–60 °C petrol/
½
a 2D1
ꢂ
ꢀ18.3 (c 0.3 in CHCl3); mmax (film) 3333 (N–H), 1725 (C@O),
1452 (C–N), 1158 (C–O); dH (400 MHz, CDCl3) 1.37 (3H, d, J 6.5,
C( )Me), 1.39 (9H, s, CMe3), 1.88 (1H, br s, NH), 2.64 (1H, d, J 8.0,
C(2)H), 3.68 (1H, q, J 6.5, C( )H), 4.18 (1H, d, J 8.0, C(3)H), 7.20–
7.35 (10H, m, Ph); dC (100 MHz, CDCl3) 22.3 (C( )Me), 28.0
(CMe3), 43.7 (C(2)), 54.5 (C( )), 57.0 (C(3)), 80.5 (CMe3), 126.6,
a
Et2O, 4:1) gave 21 as a colourless oil (453 mg, 96%, 98:2 dr); ½a D25
ꢂ
a
+1.9 (c 1.0 in CHCl3); {lit.31a
½
a 2D0
ꢂ
ꢀ1.8 (c 3.2 in CHCl3)}; dH
a
(400 MHz, CDCl3) 1.24 (9H, s, CMe3), 1.26 (3H, d, J 6.8, C(a)Me),
a
2.46 (1H, dd, J 14.4, 10.2, C(2)HA), 2.68 (1H, dd, J 14.4, 5.0,
C(2)HB), 3.67 (2H, app s, NCH2Ph), 3.81 (3H, s, OMe), 3.99 (1H, q,
126.8, 127.1, 127.2, 128.2, 128.4 (o,m,p-Ph), 142.8, 146.1 (i-Ph),
171.0 (C(1)); m/z (ESI+) 327 ([M+H]+, 100%); HRMS (ESI+)
21H27DNO2 ([M+H]+) requires 327.2177; found 327.2172.
+
J 6.8, C(
a)H), 4.35 (1H, dd, J 10.2, 5.0, C(3)H), 6.85–6.89 (2H, m,
C
Ar), 7.16–7.42 (12H, m, Ar, Ph).
4.3.7. Methyl (2S,3R,
amino]-3-phenylpropanoate 13
aS)-2-deuterio-3-[N-(a-methylbenzyl)-
4.3.10. tert-Butyl (3R,aS)-3-[N-benzyl-N-(a-methylbenzyl)-
amino]-3-(40-bromophenyl)propanoate 22
Ph
Ph
NH
CO2Me
Ph
N
Ph
t
CO2Bu
D
SOCl2 (0.50 mL, 6.85 mmol) was added dropwise to a stirred
solution of 12 (217 mg, 0.67 mmol, 92:8 dr, D incorporation 92%
[1H NMR], 91% [MS]) in MeOH (4 mL) at 0 °C. The resultant mixture
was heated at reflux for 2 h then allowed to cool to rt and concen-
trated in vacuo. The residue was dissolved in CH2Cl2 (20 mL) and
the resultant mixture was washed with satd aq NaHCO3 (20 mL),
then dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30–40 °C petrol/Et2O, 5:1) gave 13 as a
colourless oil (127 mg, 84%, 93:7 dr, D incorporation 92% [1H
Br
Following general procedure 1, reaction of (S)-N-benzyl-N-(a-
methylbenzyl)amine (240 mg, 1.13 mmol) in THF (2.5 mL), BuLi
(0.44 mL, 1.09 mmol) and 1631b (200 mg, 0.70 mmol) in THF
(2.5 mL), followed by satd aq NH4Cl (5 mL), gave 22 in 98:2 dr.
Purification via flash column chromatography (eluent 40–60 °C
petrol/Et2O, 50:1) gave 22 as a colourless oil (321 mg, 92%, 98:2
dr);48
½
a 2D1
ꢂ
+2.8 (c 0.5 in CHCl3); {lit.49
½
a 2D3
ꢂ
+3.6 (c 1.8 in CHCl3)};
dH (400 MHz, CDCl3) 1.25 (9H, s, CMe3), 1.28 (3H, d, J 6.8,
C( )Me), 2.42–2.54 (2H, m, C(2)H2), 3.66 (2H, app s, NCH2Ph),
3.95 (1H, q, J 6.8, C( )H), 4.37 (1H, dd, J 10.1, 5.1, C(3)H), 7.17–
NMR]); ½a 2D1
ꢂ
ꢀ15.5 (c 0.4 in CHCl3); {lit.27 for enantiomer ½a 2D0
ꢂ
a
+19.7 (c 1.0 in CHCl3)}; dH (400 MHz, MeOH-d4) 1.35 (3H, d, J 6.8,
a
C(a)Me), 2.86 (1H, br d, J 6.6, C(2)H), 3.55 (3H, s, OMe), 3.68 (1H,
7.48 (14H, m, Ar, Ph).
q, J 6.8, C(a)H), 4.12 (1H, d, J 6.6, C(3)H), 7.20–7.36 (10H, m, Ph).
4.3.11. tert-Butyl (3R,
a
S)-3-[N-benzyl-N-(a-methylbenzyl)-
4.3.8. (3S,4R,
azetidin-2-one 14
a
S)-N(1)-(
a
-Methylbenzyl)-3-deuterio-4-phenyl-
amino]-3-(30-bromophenyl)propanoate 23
Ph
O
Ph
N
Ph
N
CO2tBu
Ph
D
MeMgBr (2.13 M in Et2O, 0.17 mL, 0.37 mmol) was added drop-
wise via syringe to a solution of 13 (88 mg, 0.31 mmol, 93:7 dr, D
incorporation 92% [1H NMR]) in Et2O (2 mL) at 0 °C. The resultant
mixture was stirred for 30 min at 0 °C and then satd aq NH4Cl
(2 mL) was added. The reaction mixture was then extracted with
Br
Following general procedure 1, reaction of (S)-N-benzyl-N-(
methylbenzyl)amine (307 mg, 1.45 mmol) in THF (4 mL), BuLi
a-

S. G. Davies et al. / Tetrahedron: Asymmetry 22 (2011) 1035–1050
1043
(0.56 mL, 1.41 mmol) and 1731b (257 mg, 0.91 mmol) in THF
(4 mL), followed by satd aq NH4Cl (1.0 mL), gave 23 in >99:1 dr.
Purification via flash column chromatography (eluent 40–60 °C
petrol/Et2O, 50:1) gave 23 as a colourless oil (384 mg, 86%, >99:1
5.3, C(2)HB), 3.78 (1H, d, J 15.4, NCHAHBPh), 3.87 (1H, d, J 15.4,
NCHAHBPh), 4.01 (1H, q, J 6.8, C( )H), 4.98 (1H, dd, J 10.4, 5.3,
C(3)H), 7.11–7.46 (12H, m, Ar, Ph), 7.57 (1H, dd, J 8.0, 1.1, Ar),
7.71 (1H, dd, J 8.0, 1.6, Ar); dC (100 MHz, CDCl3) 12.9 (C( )Me),
)), 61.1 (C(3)),
a
a
dr); ½a 2D5
ꢂ
ꢀ6.6 (c 1.0 in CHCl3); mmax (film) 3062, 3027, 2975,
27.8 (CMe3), 42.2 (C(2)), 50.7 (NCH2Ph), 56.9 (C(a
2932, 1723 (C@O); dH (400 MHz, CDCl3) 1.34 (9H, s, CMe3), 1.36
80.4 (CMe3), 125.4 (C(20)), 126.4, 126.8, 127.5, 127.6, 128.0,
128.1, 128.8, 130.1, 133.0 (Ar, o,m,p-Ph), 141.9, 142.5, 143.8
(3H, d, J 6.8, C(
dd, J 14.7, 5.3, C(2)HB), 3.73 (2H, app br s, NCH2Ph), 4.04 (1H, q, J
6.8, C( )H), 4.47 (1H, dd, J 9.6, 5.3, C(3)H), 7.20–7.51 (13H, m, Ar,
Ph), 7.62–7.65 (1H, m, Ar); dC (100 MHz, CDCl3) 17.1 (C( )Me),
)), 59.2 (C(3)),
a)Me), 2.53 (1H, dd, J 14.7, 9.6, C(2)HA), 2.58 (1H,
(C(10), i-Ph), 170.3 (C(1)); m/z (ESI+) 497 ([M(81Br)+H]+, 97%), 495
([M(79Br)+H]+,
100%);
HRMS
(ESI+)
C28H32BrNNaO2
þ
a
a
([M(79Br)+Na]+) requires 516.1509; found 516.1509.
28.0 (CMe3), 38.0 (C(2)), 51.0 (NCH2Ph), 57.5 (C(
a
80.6 (CMe3), 122.4 (C(30)), 126.8, 127.0, 127.1 (Ar, p-Ph), 127.9,
128.0, 128.3, 128.3, 129.8, 130.2, 131.3 (Ar, o,m-Ph), 141.3, 143.7,
144.7 (i-Ph, C(10)), 170.9 (C(1)); m/z (ESI+) 496 ([M(81Br)+H]+,
4.3.14. tert-Butyl (3R,aS)-3-[N-benzyl-N-(a-methylbenzyl)-
amino]-3-(20-iodophenyl)propanoate 26
97%), 494 ([M(79Br)+H]+, 100%); HRMS (ESI+) C28H3279BrNNaO2
Ph
þ
([M(79Br)+Na]+) requires 516.1509; found 516.1493.
Ph
N
t
CO2Bu
4.3.12. tert-Butyl (3R,aS)-3-[N-benzyl-N-(a-methylbenzyl)-
amino]-3-(30-fluorophenyl)propanoate 24
I
Ph
Following general procedure 1, reaction of (S)-N-benzyl-N-(a-
methylbenzyl)amine (1.54 g, 7.27 mmol) in THF (20 mL), BuLi
(2.82 mL, 7.04 mmol) and 2031b (1.50 g, 4.54 mmol) in THF
(20 mL), followed by satd aq NH4Cl (10 mL), gave 26 in >99:1 dr.
Purification via flash column chromatography (eluent 30–40 °C
petrol/Et2O, 50:1) gave 26 as a white solid (2.45 g, 96%, >99:1
Ph
N
t
CO2Bu
dr);15 mp 86–87 °C (CHCl3); {lit.50 mp 88 °C}; ½a 2D0
ꢀ20.0 (c 0.8 in
ꢂ
F
CHCl3); {lit.50
½
a 2D4
ꢂ
ꢀ24.5 (c 1.0 in CHCl3)}; dH (400 MHz, CDCl3)
Following general procedure 1, reaction of (S)-N-benzyl-N-(a-
1.18 (9H, s, CMe3), 1.51 (3H, d, J 6.7, C(a)Me), 2.17 (1H, dd, J 13.7,
methylbenzyl)amine (1.11 g, 4.32 mmol) in THF (10 mL), BuLi
(1.80 mL, 4.18 mmol) and 1831b (600 mg, 2.70 mmol) in THF
(10 mL), followed by satd aq NH4Cl (1 mL), gave 24 in 98:2 dr. Puri-
fication via flash column chromatography (eluent 30–40 °C petrol/
9.7, C(2)HA), 2.60 (1H, dd, J 13.7, 5.6, C(2)HB), 3.72 (1H, d, J 15.5,
NCHAHBPh), 3.82 (1H, d, J 15.5, NCHAHBPh), 3.92 (1H, q, J 6.7,
C(a
)H), 4.75 (1H, dd, J 9.7, 5.6, C(3)H), 6.93–6.97 (1H, m, C(40)H),
7.11–7.44 (11H, m, C(60)H, Ph), 7.67 (1H, dd, J 7.9, 1.1, C(50)H),
7.82 (1H, dd, J 7.9, 1.1, C(30)H).
Et2O, 30:1) gave 24 as a colourless oil (970 mg, 83%, 98:2 dr); ½a D21
ꢂ
ꢀ0.5 (c 1.0 in CHCl3); mmax (film) 2976, 1727 (C@O); dH (400 MHz,
CDCl3) 1.27 (9H, s, CMe3), 1.31 (3H, d, J 7.0, C(
m, C(2)H2), 3.69 (2H, app s, NCH2Ph), 4.00 (1H, q, J 7.0, C(
(1H, app dd, J 9.6, 5.6, C(3)H), 6.93–7.45 (14H, m, Ar, Ph); dC
(100 MHz, CDCl3) 16.9 (C( )Me), 27.8 (CMe3), 37.9 (C(2)), 50.9
(NCH2Ph), 57.3 (C( )), 59.0 (C(3)), 80.4 (CMe3), 114.4 (d, J 120),
a
)Me), 2.45–2.54 (2H,
4.3.15. tert-Butyl (2S,3R,aS)-2-deuterio-3-[N-benzyl-N-(a-
a
)H), 4.43
methylbenzyl)amino]-3-(40-methoxyphenyl)propanoate 27
a
Ph
a
114.6 (d, J 120), 123.7, 126.6, 127.0, 127.9, 128.2, 129.5 (Ar,
o,m,p-Ph), 141.3, 143.7, (i-Ph), 144.9 (C(10)), 161.4 (d, J 246.1,
C(30)), 171.2 (C(1)); dF (377 MHz, CDCl3) ꢀ113.6 (C(30)F); m/z
Ph
N
CO2tBu
(ESI+) 456 ([M+Na]+, 100%), 434 ([M+H]+, 100%); HRMS (ESI+)
D
28H33FNO2 ([M+H]+) requires 434.2490; found 434.2490.
þ
MeO
C
Following general procedure 1, reaction of (S)-N-benzyl-N-(a-
4.3.13. tert-Butyl (3R,aS)-3-[N-benzyl-N-(a-methylbenzyl)-
methylbenzyl)amine (289 mg, 1.37 mmol) in THF (3 mL), BuLi
(0.63 mL, 1.32 mmol) and 1531a (200 mg, 0.85 mmol) in THF
(3 mL), followed by D2O (1 mL), gave 27 in >99:1 dr. Purification
via flash column chromatography (eluent 30–40 °C petrol/Et2O,
20:1) gave 27 as a colourless oil (230 mg, 60%, >99:1 dr, D incorpo-
amino]-3-(20-bromophenyl)propanoate 25
Ph
Ph
N
ration 78% [1H NMR], 77% [MS]); ½a 2D5
ꢀ2.3 (c 1.0 in CHCl3); mmax
ꢂ
CO2tBu
(film) 3061, 3028, 3001, 2974, 2933, 2835 (C–H), 1724 (C@O); dH
(400 MHz, CDCl3) 1.26 (9H, s, CMe3), 1.29 (3H, d, J 6.9, C(a)Me),
2.55 (1H, d, J 4.6, C(2)H), 3.68 (1H, d, J 14.8, NCHAHBPh), 3.72
Br
(1H, d, J 14.8, NCHAHBPh), 3.82 (3H, s, OMe), 4.02 (1H, q, J 6.9,
Following general procedure 1, reaction of (S)-N-benzyl-N-(a-
C(
7.18–7.38 (10H, m, Ph), 7.45 (2H, d, J 8.6, C(20)H, C(60)H); dC
(100 MHz, CDCl3) 16.5 (C( )Me), 27.9 (CMe3), 38.5 (C(2)), 50.8
(NCH2Ph), 55.3 (OMe), 57.1 (C(
a
)H), 4.38 (1H, d, J 4.6, C(3)H), 6.90 (2H, d, J 8.6, C(30)H, C(50)H),
methylbenzyl)amine (119 mg, 0.57 mmol) in THF (4 mL), BuLi
(0.22 mL, 0.55 mmol) and 1931b (100 mg, 0.35 mmol) in THF
(4 mL), followed by satd aq NH4Cl (1 mL), gave 25 in >99:1 dr. Puri-
fication via flash column chromatography (eluent 30–40 °C petrol/
Et2O, 20:1) gave 25 as a pale yellow oil (155 mg, 89%, >99:1 dr);
a
a
)), 59.1 (C(3)), 80.1 (CMe3), 113.5
(C(30), C(50)), 126.5, 126.8 (p-Ph), 127.9, 128.0, 128.1 (o,m-Ph),
129.4 (C(20), C(60)), 133.9 (C(10)), 141.9, 144.4 (i-Ph), 158.7 (C(40)),
½
a 2D5
ꢂ
ꢀ26.6 (c 1.0 in CHCl3); mmax (film) 3061, 3028, 2975, 2931,
1723 (C@O); dH (400 MHz, CDCl3); 1.21 (9H, s, CMe3), 1.49 (3H, d,
J 6.8, C( )Me), 2.35 (1H, dd, J 13.9, 10.4, C(2)HA), (1H, dd, J 13.9,
171.2 (C(1)); m/z (ESI+) 447 ([M+H]+, 100%); HRMS (ESI+)
C
29H35DNO3 ([M+H]+) requires 447.2752; found 447.2745.
þ
a

1044
S. G. Davies et al. / Tetrahedron: Asymmetry 22 (2011) 1035–1050
4.3.16. tert-Butyl (2S,3R,
a
S)-2-deuterio-3-[N-benzyl-N-(
a
-
Following general procedure 1, reaction of (S)-N-benzyl-N-(a-
methylbenzyl]amino)-3-(40-bromophenyl)propanoate 28
methylbenzyl)amine (304 mg, 1.44 mmol) in THF (3 mL), BuLi
(0.66 mL, 1.39 mmol) and 1831b (200 mg, 0.9 mmol) in THF
(3 mL), followed by D2O (1 mL), gave 30 in >99:1 dr. Purification
via flash column chromatography (eluent 30–40 °C petrol/Et2O,
20:1) gave 30 as a colourless oil (263 mg, 67%, >99:1 dr, D incorpo-
Ph
Ph
N
t
CO2 Bu
ration 80% [1H NMR], 75% [MS]); ½a 2D5
ꢀ2.3 (c 1.0 in CHCl3); mmax
ꢂ
D
(film) 3028, 2974, 2931 (C–H), 1725 (C@O); dH (400 MHz, CDCl3)
Br
1.32 (9H, s, CMe3), 1.36 (3H, d, J 6.8, C(
C(2)H), 3.72 (1H, d, J 15.0, NCHAHBPh), 3.76 (1H, d, J 15.0,
NCHAHBPh), 4.05 (1H, q, J 6.8, C( )H), 4.49 (1H, d, J 4.3, C(3)H),
6.97–7.04 (1H, m, Ar), 7.22–7.43 (11H, m, Ar, Ph), 7.46–7.50 (2H,
m, Ar, Ph); dC (100 MHz, CDCl3) 17.0 (C( )Me), 27.9 (CMe3), 37.7
)), 59.0 (C(3)), 80.5 (CMe3), 114.6
a)Me), 2.57 (1H, d, J 4.3,
Following general procedure 1, reaction of (S)-N-benzyl-N-(a-
methylbenzyl)amine (297 mg, 1.41 mmol) in THF (3 mL), BuLi
(0.55 mL, 1.36 mmol) and 1631b (250 mg, 0.880 mmol) in THF
(3 mL), followed by D2O (2 mL), gave 28 in 96:4 dr. Purification via
flash column chromatography (eluent 40–60 °C petrol/Et2O, 25:1)
gave 28 as a colourless oil (282 mg, 65%, 96:4 dr, D incorporation
a
a
(C(2)), 51.0 (NCH2Ph), 57.5 (C(
a
(d, J 97.5, C(40), 114.6 (d, J 140.6, C(20)), 123.5 (C(60)), 126.7, 127.1
(p-Ph), 127.9, 128.0, 128.3 (o,m-Ph), 129.6 (C(50)), 141.4, 143.8 (i-
81% [1H NMR], 86% [MS]); ½a 2D4
ꢂ
+2.5 (c 1.0 in CHCl3); mmax (film)
1735 (C@O), 1594 (C@C), 1488 (C–N), 1157 (C–O), 699 (C–Br); dH
Ph), 145.1 (C(10)), 162.9 (d,
J
244.5, C(30)), 171.0 (C(1)); dF
(400 MHz, CDCl3) 1.26 (9H, s, CMe3), 1.29 (3H, d, J 6.8, C(
2.49–2.50 (1H, m, C(2)H), 3.67 (2H, app s, NCH2Ph), 3.97 (1H, q, J
6.8, C( )H), 4.38 (1H, m, C(3)H), 7.20–7.48 (14H, m, Ar, Ph); dC
(100 MHz, CDCl3) 17.0 (C( )Me), 27.8 (CMe3), 37.5 (C(2)), 50.8
(NCH2Ph), 57.3 (C(
)), 58.8 (C(3)), 80.4 (CMe3), 120.9 (C(40)), 127.0,
a)Me),
(377 MHz, CDCl3) ꢀ113.6 (C(30)F); m/z (ESI+) 435 ([M+H]+, 100%);
HRMS (ESI+) C28H32DFNO2 ([M+H]+) requires 435.2553; found
þ
a
435.2545.
a
a
4.3.19. tert-Butyl (2S,3R,aS)-2-deuterio-3-[N-benzyl-N-(a-
126.6 (p-Ph), 127.8, 127.9, 128.2, 128.2, 129.9, 131.2 (Ar, o,m-Ph),
141.1, 141.3, 143.8 (C(10), i-Ph), 170.9 (C(1)); m/z (ESI+) 497
([M(81Br)+H]+, 95%), 495 ([M(79Br)+H]+, 100%); HRMS (ESI+) C28H32
methylbenzyl)amino]-3-(20-bromophenyl)propanoate 31
Ph
D79BrNO2 ([M(79Br)+H]+) requires 495.1752; found 495.1758.
þ
Ph
N
4.3.17. tert-Butyl (2S,3R,aS)-2-deuterio-3-[N-benzyl-N-(a-
CO2tBu
methylbenzyl)amino]-3-(30-bromophenyl)propanoate 29
D
Ph
Br
Following general procedure 1, reaction of (S)-N-benzyl-N-(a-
Ph
N
methylbenzyl)amine (239 mg, 1.13 mmol) in THF (3 mL), BuLi
(0.52 mL, 1.09 mmol) and 1931b (200 mg, 0.71 mmol) in THF
(3 mL), followed by D2O (1 mL), gave 31 in >99:1 dr. Purification
via flash column chromatography (eluent 30–40 °C petrol/Et2O,
20:1) gave 31 as a colourless oil (238 mg, 68%, >99:1 dr, D incorpo-
CO2tBu
D
Br
ration 81% [1H NMR], 90% [MS]); ½a 2D5
ꢂ
ꢀ34.7 (c 1.0 in CHCl3); mmax
Following general procedure 1, reaction of (S)-N-benzyl-N-(a-
methylbenzyl)amine (283 mg, 1.34 mmol) in THF (3 mL), BuLi
(0.52 mL, 1.30 mmol) and 1731b (237 mg, 0.84 mmol) in THF
(3 mL), followed by D2O (1 mL), gave 29 in >99:1 dr. Purification
via flash column chromatography (eluent 30–40 °C petrol/Et2O,
20:1) gave 29 as a colourless oil (300 mg, 72%, >99:1 dr, D incorpora-
(film) 3061, 3028, 2976, 2933 (C–H), 1725 (C@O); dH (400 MHz,
CDCl3) 1.22 (9H, s, CMe3), 1.51 (3H, d, J 6.8, C(a)Me), 2.69 (1H, d,
J 5.3, C(2)H), 3.79 (1H, d, J 15.9, NCHAHBPh), 3.89 (1H, d, J 15.9,
NCHAHBPh), 4.03 (1H, q, J 6.8, C(a)H), 4.99 (1H, d, J 5.3, C(3)H),
7.13–7.17 (1H, m, C(40)H), 7.18–7.47 (11H, m, C(60)H, Ph), 7.59
(1H, dd, J 8.1, 1.3, C(50)H), 7.72 (1H, dd, J 7.8, 1.8, C(30)H); dC
tion, 74% [1H NMR], 70% [MS]); ½a 2D5
ꢂ
ꢀ5.9 (c 1.0 in CHCl3);
mmax (film)
3085, 3062, 3028, 2976, 2932, 2877, 2839, 1725 (C@O); dH
(100 MHz, CDCl3) 12.9 (C(
a
)Me), 27.7 (CMe3), 41.9 (C(2)), 50.8
(400 MHz, CDCl3) 1.28 (9H, s, CMe3), 1.32 (3H, d, J 6.8, C(
2.49 (1H, d, J 4.3, C(2)H), 3.66 (1H, d, J 14.9, NCHAHBPh), 3.70 (1H,
d, J 14.9, NCHAHBPh), 3.99 (1H, q, J 6.8, C( )H), 4.40 (1H, d, J 4.3,
C(3)H), 7.18–7.45 (13H, m, C(40)H, C(50)H, C(60)H, Ph), 7.56–7.58
(1H, m, C(20)H); dC (100 MHz, CDCl3) 17.0 (C(
)Me), 27.9 (CMe3),
37.7 (C(2)), 51.0 (NCH2Ph), 57.4 (C( )), 59.1 (C(3)), 80.5 (CMe3),
a)Me),
(NCH2Ph), 56.9 (C(
a
)), 61.1 (C(3)), 80.4 (CMe3), 125.4 (C(20)),
126.4, 126.8, 127.6, 128.0, 128.1, 128.8, 130.2, 133.0 (C(30), C(40),
C(50), C(60), o,m,p-Ph), 141.9, 142.5, 143.8 (C(10), i-Ph), 170.3
(C(1)); m/z (ESI+) 497 ([M(81Br)+H]+, 96%), 495 ([M(79Br)+H]+,
a
100%); HRMS (ESI+) C28H32D79BrNO2 ([M(79Br)+H]+) requires
a
þ
a
495.1752; found 495.1739.
122.3 (C(30)), 126.7, 127.0 (C(60), p-Ph), 127.8, 128.0, 128.3 (o,m-
Ph), 129.8, 130.2 (C(40), C(50)), 131.3 (C(20)), 141.3, 143.7, 144.6
(C(10), i-Ph), 170.9 (C(1)); m/z (ESI+) 519 ([M(81Br)+Na]+, 95%), 517
4.3.20. tert-Butyl (2S,3R,aS)-2-deuterio-3-[N-benzyl-N-(a-
methylbenzyl)amino]-3-(20-iodophenyl)propanoate 32
([M(79Br)+Na]+, 100%); HRMS (ESI+) C28H32D79BrNO2 ([M(79Br)+
þ
H]+) requires 495.1752; found 495.1752.
Ph
4.3.18. tert-Butyl (2S,3R,aS)-2-deuterio-3-[N-benzyl-N-(a-
Ph
N
methylbenzyl)amino]-3-(30-fluorophenyl)propanoate 30
CO2tBu
Ph
D
I
Ph
F
N
Following general procedure 1, reaction of (S)-N-benzyl-N-(a-
CO2tBu
methylbenzyl)amine (150 mg, 0.72 mmol) in THF (2 mL), BuLi
(0.28 mL, 0.70 mmol) and 20 (150 mg, 0.454 mmol) in THF
(2 mL), followed by D2O (1 mL), gave 32 in 95:5 dr. Purification
via flash column chromatography (eluent 30–40 °C petrol/Et2O,
D

S. G. Davies et al. / Tetrahedron: Asymmetry 22 (2011) 1035–1050
1045
40:1) gave 32 as a white solid (160 mg, 70%, 95:5 dr, D incorpora-
4.3.23. tert-Butyl (3R,aS)-2,2-dideuterio-3-[N-benzyl-N-(a-
methylbenzyl)amino]-3-phenylpropanoate 43
tion 89% [1H NMR], 92% [MS]); C28H31DINO2 requires C, 62.0; H/D,
5.95; N, 2.6. Found: C, 62.2; H/D, 5.9; N, 2.5; mp 84–85 °C (CHCl3);
½
a 2D5
ꢂ
ꢀ24.8 (c 1.0 in CHCl3); mmax (film) 1724 (C@O), 1454 (C–N),
1159 (C–O); dH (400 MHz, CDCl3) 1.21 (9H, s, CMe3), 1.54 (3H, d, J
6.8, C( )Me), 2.62 (1H, d, J 5.8, C(2)H), 3.75 (1H, d, J 15.4,
NCHAHBPh), 3.85 (1H, d, J 15.4, NCHAHBPh), 3.96 (1H, q, J 6.8,
C(
)H), 4.77 (1H, d, J 5.8, C(3)H), 6.94–6.98 (1H, m, C(40)H), 7.13–
7.44 (11H, m, Ph, C(60)H), 7.67–7.69 (1H, dd, J 8.0, 1.6, C(50)H),
7.84 (1H, d, J 8.0, C(30)H); dC (100 MHz, CDCl3) 12.6 (C(
)Me),
)), 66.2 (C(3)),
Ph
Ph
N
a
t
CO2Bu
Ph
a
D
D
Following general procedure 1, reaction of (S)-N-benzyl-N-(a-
a
methylbenzyl)amine (824 mg, 4.00 mmol) in THF (8 mL), BuLi
(1.51 mL, 3.78 mmol) and 47 (500 mg, 2.44 mmol, D incorporation
99% [1H NMR]) in THF (8 mL), followed by D2O (7 mL), gave 43.
Purification via flash column chromatography (eluent 30–40 °C
petrol/Et2O, 50:1) gave 43 as a colourless oil (1.01 g, 99%, >99:1
dr, D incorporation 92% [1H NMR], 97% [MS]); C28H31D2NO2 re-
quires C, 80.5; H/D, 7.97; N, 3.35. Found C, 80.15; H/D, 8.13; N,
27.8 (CMe3), 42.5 (C(2)), 50.6 (NCH2Ph), 56.7 (C(
a
80.3 (CMe3), 101.7 (C(20)), 126.3, 126.7 (p-Ph), 127.5, 127.9,
128.0, 128.1, 128.3 (C(50), o,m-Ph), 129.1 (C(40)), 129.9 (C(60)),
139.6 (C(30)), 142.6, 143.8, 145.3 (i-Ph, C(10)), 170.2 (C(1)); m/z
(ESI+) 543 ([M+H]+, 100%); HRMS (ESI+) C28H32DINO2 ([M+H] ) re-
+
þ
quires 543.1613; found 543.1613.
3.32%; ½a 2D5
ꢂ
ꢀ9.1 (c 0.6 in CHCl3); mmax (film) 1725 (C@O), 1453
4.3.21. (3R,aS,E)-1-tert-Butoxy-1-triethylsiloxy-3-[N-benzyl-N-
(C–N), 1167 (C–O); dH (400 MHz, MeOH-d4) 1.17 (3H, d, C(
a)Me),
(a-methylbenzyl)amino]-3-phenylpropene 40
1.19 (9H, s, CMe3), 3.65 (2H, app s, NCH2Ph), 3.96 (1H, q, J 6.8,
C( )H), 4.34 (1H, s, C(3)H), 7.13–7.43 (15H, m, Ph); dC (100 MHz,
MeOH-d4) 16.4 (C( )Me), 27.2 (CMe3), 37.4 (C(2)), 50.8 (NCH2Ph),
57.6 (C( )), 59.9 (C(3)), 80.5 (CMe3), 126.7, 127.0, 127.3 (p-Ph),
a
Ph
a
Ph
N
OtBu
OTES
a
128.0, 128.1, 128.2, 128.2, 128.3, 128.6 (o,m-Ph), 142.0, 142.1,
144.7 (i-Ph), 172.0 (C(1)); m/z (ESI+) 418 ([M+H]+, 100%); HRMS
Ph
(ESI+) C28H32D2NO2 ([M+H]+) requires 418.2710; found 418.2722.
þ
BuLi (0.48 mL, 1.20 mmol) was added to a solution of diisopro-
pylamine (0.17 mL, 1.25 mmol) in THF (2 mL) at ꢀ78 °C. The resul-
tant solution was stirred at rt for 10 min, then cooled to –78 °C
and stirred for another 5 min. A solution of 6 (100 mg, 0.24 mmol,
>99:1 dr) in THF (2 mL) at ꢀ78 °C was then added dropwise via can-
nula. Thereaction mixturewas allowedto warm to0 °C over 1 h then
was cooled to ꢀ78 °C before a further portion of BuLi (0.19 mL,
0.48 mmol) was added. Stirring was continued at ꢀ78 °C for 1 h fol-
lowed by the rapid injection of TESCl (0.06 mL, 0.38 mmol) via syr-
inge. The reaction mixture was allowed to warm to rt over 30 min,
then the solvent was removed under high vacuum to give the crude
reaction mixture containing silyl ketene acetal 40.
4.3.24. (3R,
[N-benzyl-N-(
aS,E)-1-tert-Butoxy-1-trimethylsiloxy-2-deuterio-3-
a-methylbenzyl)amino]-3-phenylpropene 44
Ph
Ph
N
OtBu
OTMS
Ph
D
From 8: BuLi (0.26 mL, 0.66 mmol) was added to a solution of
diisopropylamine (0.09 mL, 0.66 mmol) in THF (2 mL) at ꢀ78 °C.
The resultant solution was stirred at rt for 10 min, then cooled to
ꢀ78 °C and stirred for another 5 min. A solution of 8 (55 mg,
0.13 mmol, 82:18 dr, D incorporation 99% [1H NMR], 93% [MS])
in THF (2 mL) at ꢀ78 °C was then added dropwise via cannula.
The reaction mixture was allowed to warm to 0 °C over 1 h then
Data for 40: dH (400 MHz, CDCl3) [selected peaks] 0.57–0.67
(6H, m, Si(CH2CH3)3), 1.03 (9H, m, Si(CH2CH3)3), 1.04 (3H, d, J 6.8,
C(
(1H, q, J 6.8, C(
C(3)H), 7.11–7.57 (15H, m, Ph).
a)Me), 1.09 (9H, s, CMe3), 3.49 (1H, d, J 14.8, NCHAHBPh), 3.92
a)H), 4.13 (1H, d, J 9.4, C(2)H), 4.60 (1H, d, J 9.4,
was cooled to ꢀ78 °C before
a further portion of (0.11 mL,
4.3.22. (3R,
aS,Z)-1-tert-Butoxy-1-triethylsiloxy-3-[N-benzyl-N-
0.26 mmol) was added. Stirring was continued at ꢀ78 °C for 1 h
followed by the rapid injection of TMSCl (0.02 mL, 0.16 mmol)
via syringe. The reaction mixture was allowed to warm to rt over
30 min, then the solvent was removed under high vacuum to give
the crude reaction mixture containing 44.
(a-methylbenzyl)amino]-3-phenylpropene 42
Ph
Ph
N
OTES
OtBu
Data for 44: dH (400 MHz, CDCl3) 0.25 (9H, s, SiMe3), 1.03 (3H, d,
J 6.8, C(a)Me), 1.09 (9H, s, CMe3), 3.50 (1H, d, J 14.8, NCHAHBPh),
Ph
3.78 (1H, d, J 14.8, NCHAHBPh), 3.91 (1H, q, J 6.8, C(
(1H, s, C(3)H), 7.10–7.57 (15H, m, Ph).
a)H), 4.60
BuLi (0.20 mL, 0.49 mmol) was added dropwise to a solution of
(S)-N-benzyl-N-( -methylbenzyl)amine (103 mg, 0.490 mmol) in
a
THF (2 mL) at ꢀ78 °C. The resultant pink solution was stirred at
ꢀ78 °C for 30 min before the addition of a solution of 5 (100 mg,
0.49 mmol) in THF (2 mL) at ꢀ78 °C. The reaction mixture was then
stirred at ꢀ78 °C for 2 h before the addition of TESCl (0.13 mL,
0.78 mmol). The reaction mixture was then allowed to warm to
rt over 30 min and the solvent was removed under high vacuum
to give the crude reaction mixture containing an 18:82 mixture
of 6 and 42.
Data for 42: dH (400 MHz, CDCl3) [selected peaks] 0.58–0.65
(6H, m, Si(CH2CH3)3), 0.93 (9H, t, J 7.6, Si(CH2CH)3), 1.47 (9H, s,
CMe3), 1.51 (3H, d, J 6.8, C(a)Me), 3.95 (1H, q, J 6.8, C(a)H), 4.04
(1H, d, J 14.8, NCHAHBPh), 4.18 (1H, d, J 9.8, C(2)H), 4.67 (1H, d, J
9.8, C(3)H), 7.26–7.73 (15H, m, Ph).
4.3.25. tert-Butyl 2,2-dideuterio-2-(diethoxyphosporyl)-
ethanoate 46
O
(EtO)2P
CO2tBu
D
D
tert-Butyl 2-(diethoxyphosporyl)ethanoate 4522 (6.00 g,
23.8 mmol) was added to a solution of K2CO3 (9.86 g, 71.4 mmol)
in D2O (15 mL) and the resultant mixture was stirred at rt for
24 h. The reaction mixture was then extracted with Et2O
(3 ꢁ 10 mL) and the combined organic extracts were dried and

1046
S. G. Davies et al. / Tetrahedron: Asymmetry 22 (2011) 1035–1050
concentrated in vacuo to give 46 as a colourless oil (6.04 g, quant, D
incorporation 99% [1H NMR]);39 dH (400 MHz, CDCl3) 1.34 (6H, t, J
7.0, 2 ꢁ CH2CH3), 1.47 (9H, s, CMe3), 4.20–4.12 (4H, m,
2 ꢁ CH2CH3).
mmax (film) 1725 (C@O); dH (400 MHz, MeOH-d4) 1.17 (3H, d, J 6.8,
C( )Me), 1.19 (9H, s, CMe3), 2.49 (1H, d, J 10.6, C(2)H), 3.65 (2H, app
s, NCH2Ph), 3.96 (1H, q, J 6.8, C( )H), 4.36 (1H, d, J 10.6, C(3)H),
7.13–7.43 (15H, m, Ph); dC (100 MHz, MeOH-d4) 16.4 (C( )Me),
27.2 (CMe3), 37.6 (C(2)), 50.8 (NCH2Ph), 57.6 (C( )), 59.9 (C(3)),
a
a
a
a
4.3.26. tert-Butyl (E)-2-deuterio-3-phenylpropenoate 47
80.5 (CMe3), 126.7, 126.8, 127.0 (p-Ph), 127.3, 128.0, 128.1, 128.2,
128.3, 128.6 (o,m-Ph), 142.0, 142.1, 144.7 (i-Ph), 172.0 (C(1)); m/z
(ESI+) 417 ([M+H]+, 100%); HRMS (ESI+) C28H33DNO2 ([M+H]+) re-
þ
CO2tBu
Ph
quires 417.2647; found 417.2651.
D
4.3.28. tert-Butyl (E)-2-deuterio-3-(40-bromophenyl)propenoate
48
Following general procedure 2, 46 (2.63 mL, 11.1 mmol, D incor-
poration 99% [1H NMR]) was reacted with K2CO3 (4.61 g,
33.3 mmol) and benzaldehyde (0.56 mL, 5.55 mmol) in D2O
(5.90 mL). Purification via flash column chromatography (eluent
30–40 °C petrol/Et2O, 40:1) gave 47 as a colourless oil (1.08 g,
95%, >99:1 dr, D incorporation 99% [1H NMR]);51 mmax (film) 1708
(C@O), 1164 (C–O); dH (400 MHz, CDCl3) 1.55 (9H, s, CMe3), 7.36–
7.39 (3H, m, Ph), 7.50–7.53 (2H, m, Ph), 7.59 (1H, br s, C(3)H); dC
(100 MHz, CDCl3) 28.2 (CMe3), 80.5 (CMe3), 119.5 (C(2)), 127.9,
128.8 (o,m-Ph), 130.0 (p-Ph), 134.6 (i-Ph), 143.4 (C(3)), 166.3
CO2tBu
D
Br
Following general procedure 2, 46 (600 mg, 2.36 mmol, D incor-
poration 99% [1H NMR]), K2CO3 (978 mg, 7.08 mmol), D2O (3 mL)
and 4-bromobenzaldehyde (218 mg, 1.18 mmol) were reacted at
50 °C. Purification via flash column chromatography (eluent
30–40 °C petrol/Et2O, 20:1) gave 48 as a white solid (289 mg,
86%, >99:1 dr, D incorporation 99% [1H NMR], 99% [MS]); mp
45–51 °C; mmax (film) 3004, 2978, 2931, 1707 (C@O), 1624 (C@C);
dH (400 MHz, CDCl3) 1.52 (9H, s, CMe3), 7.34 (2H, d, J 8.6, C(30)H,
C(50)H), 7.48 (2H, d, J 8.6, C(20)H, C(60)H), 7.49 (1H, s, C(3)H); dC
(100 MHz, CDCl3) 28.2 (CMe3), 80.7 (CMe3), 124.1 (C(2), C(40)),
129.3 (C(30), C(50)), 132.0 (C(20), C(60)), 133.6 (C(10)), 142.0 (C(3)),
166.0 (C(1)); m/z (ESI+) 308 ([M(81Br)+Na]+, 95%), 306 ([M(79Br)+
(C(1)); m/z (CI+) 206 ([M+H]+, 100%); HRMS (GC ToF CI+)
þ
C
13H16DO2 ([M+H]+) requires 206.1286; found 206.1290.
4.3.27. tert-Butyl (2R,3R,aS)-2-deuterio-3-[N-benzyl-N-(a-
methylbenzyl)amino]-3-phenylpropanoate 8
Ph
Ph
N
Na]+, 100%); HRMS (ESI+) C13H14D79BrNaO2 ([M(79Br)+Na]+)
þ
t
CO2Bu
Ph
requires 306.0210; found 306.0209.
D
4.3.29. tert-Butyl (E)-2-deuterio-3-(30-bromophenyl)propenoate
49
Method A: Following general procedure 1, reaction of (S)-N-ben-
zyl-N-( -methylbenzyl)amine (492 mg, 2.24 mmol) in THF (4 mL),
a
BuLi (0.91 mL, 2.27 mmol) and 47 (300 mg, 1.46 mmol, >99:1 dr, D
incorporation 99% [1H NMR]) in THF (4 mL), followed by H2O
(2 mL), gave a 90:10 mixture of 8 and 7. Purification via flash col-
umn chromatography (eluent 30–40 °C petrol/Et2O, 50:1) gave a
90:10 mixture of 8 and 7 as a colourless oil (610 mg, 85%, D incor-
poration 94% [1H NMR], 94% [MS]).
CO2tBu
D
Br
Following general procedure 2, 46 (600 mg, 2.36 mmol, D incor-
poration 99% [1H NMR]), K2CO3 (978 mg, 7.08 mmol), D2O (3 mL)
and 3-bromobenzaldehyde (0.14 mL, 1.18 mmol) were reacted at
50 °C. Purification via flash column chromatography (eluent 30–
40 °C petrol/Et2O, 20:1) gave 49 as a colourless oil (400 mg, quant,
>99:1 dr, D incorporation 99% [1H NMR], 98% [MS]); mmax (film)
3061, 2978, 2932, 1708 (C@O), 1624 (C@C); dH (400 MHz, CDCl3)
1.51 (9H, s, CMe3), 7.18 (1H, app t, J 7.8, C(50)H), 7.36 (1H, d, J
7.8, C(60)H), 7.42 (1H, app ddd, J 7.8, 2.8, 1.8, C(40)H), 7.45 (1H, s,
C(3)H), 7.60 (1H, s, C(20)H); dC (100 MHz, CDCl3) 28.2 (CMe3),
80.7 (CMe3), 121.4 (C(2)), 122.9 (C(30)), 126.6 (C(60)), 130.3, 130.6
(C(20), C(50)), 132.7 (C(40)), 136.7 (C(10)), 141.7 (C(3)), 165.7
(C(1)); m/z (ESI+) 308 ([M(81Br)+Na]+, 95%), 306 ([M(79Br)+Na]+,
Method B: Following general procedure 1, reaction of (S)-N-ben-
zyl-N-(a-methylbenzyl)amine (165 mg, 0.780 mmol) in THF
(1.5 mL), BuLi (0.30 mL, 0.76 mmol) and 47 (100 mg, 0.49 mmol,
>99:1 dr, D incorporation 99% [1H NMR]) in THF (1.5 mL), followed
by MeOH (1 mL), gave an 82:18 mixture of 8 and 7. Purification via
flash column chromatography (eluent 30–40 °C petrol/Et2O, 30:1)
gave an 88:12 mixture of 8 and 7 as a colourless oil (183 mg,
90%, D incorporation 99% [1H NMR], 93% [MS]).
Method C: Following general procedure 1, reaction of (S)-N-ben-
zyl-N-(a-methylbenzyl)amine (0.16 mL, 0.78 mmol) in THF
(1.5 mL), BuLi (0.30 mL, 0.76 mmol) and 47 (100 mg, 0.49 mmol,
>99:1 dr, D incorporation 99% [1H NMR]) in THF (1.5 mL), followed
by AcOH (2 mL), gave a 73:27 mixture of 8 and 7 in addition to re-
turned starting material 47. Purification via flash column chroma-
tography (eluent 30–40 °C petrol/Et2O, 50:1) gave returned
starting material 47 (18 mg, 18%). Further elution gave a 74:26
mixture of 8 and 7 as a colourless oil (53 mg, 26%, D incorporation
95% [1H NMR], 92% [MS]).
100%); HRMS (ESI+) C13H14D79BrNaO2 ([M(79Br)+Na]+) requires
þ
306.0210; found 306.0209.
4.3.30. tert-Butyl (E)-2-deuterio-3-(30-fluorophenyl)propenoate
50
Method D: Following general procedure 1, reaction of (S)-N-ben-
zyl-N-(a-methylbenzyl)amine (0.16 mL, 0.78 mmol) in THF
CO2tBu
(1.5 mL), BuLi (0.30 mL, 0.76 mmol) and 47 (100 mg, 0.49 mmol,
>99:1 dr, D incorporation 99% [1H NMR]) in THF (1.5 mL), followed
by 2-pyridone (139 mg, 1.46 mmol), gave 8 in >99:1 dr. Purifica-
tion via flash column chromatography (eluent 30–40 °C petrol/
Et2O, 50:1) gave 8 as a colourless oil (153 mg, 75%, >99:1 dr, D
D
F
Following general procedure 2, 46 (600 mg, 2.36 mmol, D incor-
incorporation 96% [1H NMR], 97% [MS]); ½a 2D1
ꢀ7.0 (c 0.7 in CHCl3);
ꢂ
poration 99% [1H NMR]), K2CO3 (978 mg, 7.08 mmol), D2O (3 mL)

S. G. Davies et al. / Tetrahedron: Asymmetry 22 (2011) 1035–1050
1047
and 3-fluorobenzaldehyde (0.13 mL, 1.18 mmol) were reacted at
Following general procedure 1, reaction of (S)-N-benzyl-N-(a-
50 °C. Purification via flash column chromatography (eluent 30–
40 °C petrol/Et2O, 20:1) gave 50 as a colourless oil (322 mg, quant,
>99:1 dr, D incorporation 99% [1H NMR], 98% [MS]); mmax (film)
2979, 2933, 1708 (C@O), 1626 (C@C); dH (400 MHz, CDCl3) 1.52
(9H, s, CMe3), 7.00–7.06 (1H, m, Ar), 7.15–7.20 (1H, m, Ar), 7.22–
7.34 (2H, m, Ar), 7.51 (1H, s, C(3)H); dC (100 MHz, CDCl3) 28.1
(CMe3), 80.7 (CMe3), 115.5 (d, J 241.3, Ar), 115.5 (d, J 284.4, Ar),
121.3 (C(2)), 123.9, 130.3 (Ar), 136.9 (C(10)), 142.0 (C(3)), 163.0
(d, J 246.1, C(30)), 165.8 (C(1)); dF (377 MHz, CDCl3) ꢀ112.7
(C(30)F); m/z (ESI+) 246 ([M+Na]+, 100%); HRMS (ESI+) C13H14
methylbenzyl)amine (318 mg, 1.50 mmol) in THF (10 mL), BuLi
(0.58 mL, 1.46 mmol) and 48 (267 mg, 0.94 mmol, >99:1 dr, D
incorporation 99% [1H NMR], 99% [MS]) in THF (10 mL), followed
by 2-pyridone (268 mg, 2.82 mmol), gave 34 in >99:1 dr. Purifica-
tion via flash column chromatography (eluent 30–40 °C petrol/
Et2O, 30:1) gave 34 as a colourless oil (248 mg, 53%, >99:1 dr, D
incorporation, 92% [1H NMR], 96% [MS]); ½a 2D5
ꢂ
+1.8 (c 1.0 in CHCl3);
mmax (film) 3062, 3027, 2975, 2932, 1724 (C@O); dH (400 MHz,
CDCl3) 1.30 (9H, s, CMe3), 1.33 (3H, d, J 6.9, C(a)Me), 2.48 (1H, d,
J 10.5, C(2)H), 3.68 (1H, d, J 14.9, NCHAHBPh), 3.72 (1H, d, J 14.9,
DFNaO2 ([M+Na]+) requires 246.1011; found 246.1011.
þ
NCHAHBPh), 4.00 (1H, q, J 6.9, C(a)H), 4.42 (1H, d, J 10.5, C(3)H),
7.27–7.47 (10H, m, Ph) overlapping 7.34 (2H, d, J 8.3, C(20)H,
C(60)H), 7.51 (2H, d, J 8.3, C(30)H, C(50)H); dC (100 MHz, CDCl3)
4.3.31. tert-Butyl (E)-2-deuterio-3-(20-bromophenyl)propenoate
51
17.0 (C(a)Me), 27.9 (CMe3), 37.7 (C(2)), 50.9 (CH2Ph), 57.4 (C(a)),
58.9 (C(3)), 80.5 (CMe3), 121.0 (C(40)), 126.7, 127.6 (p-Ph), 127.8,
128.0, 128.3 (o,m-Ph), 130.0 (C(20), C(60)), 131.2 (C(30), C(50)),
141.2, 141.4, 143.8 (C(10), i-Ph), 171.0 (C(1)); m/z (ESI+) 497
CO2tBu
([M(81Br)+H]+, 97%), 495 ([M(79Br)+H]+, 100%); HRMS (ESI+)
D
Br
þ
C
28H32D79BrNO2
495.1735.
([M(79Br)+H]+) requires 495.1752; found
Following general procedure 2, 46 (600 mg, 2.36 mmol, D incorpo-
ration 99% [1H NMR]), K2CO3 (978 g, 7.08 mmol), D2O (3 mL) and 2-
bromobenzaldehyde (0.14 mL, 1.18 mmol) were reacted at 50 °C.
Purification via flash column chromatography (eluent 30–40 °C pet-
rol/Et2O, 20:1) gave 51 as a colourless oil (456 mg, quant, >99:1 dr, D
incorporation 99% [1H NMR], 98% [MS]); mmax (film) 3064, 3003,
2978, 2932, 1709 (C@O), 1620 (C@C); dH (400 MHz, CDCl3) 1.53
(9H, s, CMe3), 7.17 (1H, app dt, J 7.6, 1.5, C(40)H), 7.24–7.30 (1H, m,
C(50)H), 7.54–7.58 (2H, m, C(30)H, C(60)H), 7.94 (1H, s, C(3)H); dC
(100 MHz, CDCl3) 28.2 (CMe3), 80.7 (CMe3), 122.6 (C(2)), 125.2
(C(20)), 127.7 (C(50), C(60)), 130.9 (C(40)), 133.4 (C(30)), 134.6 (C(10)),
141.8 (C(3)), 165.7 (C(1)); m/z (ESI+) 308 ([M(81Br)+Na]+, 95%),
4.3.34. tert-Butyl (2R,3R,aS)-2-deuterio-3-[N-benzyl-N-(a-
methylbenzyl)amino]-3-(30-bromophenyl)propanoate 35
Ph
Ph
N
CO2tBu
D
Br
306 ([M(79Br)+Na]+, 100%); HRMS (ESI+) C13H14D79BrNaO2
þ
Following general procedure 1, reaction of (S)-N-benzyl-N-(a-
([M(79Br)+Na]+) requires 306.0210; found 306.0214.
methylbenzyl)amine (468 mg, 2.21 mmol) in THF (10 mL), BuLi
(0.86 mL, 2.14 mmol) and 49 (393 mg, 1.38 mmol, >99:1 dr, D incor-
poration 99% [1H NMR], 98% [MS]) in THF (10 mL), followed by 2-
pyridone (395 mg, 4.15 mmol), gave 35 in >99:1 dr. Purification
via flash column chromatography (eluent 30–40 °C petrol/Et2O,
50:1) gave 35 as a colourless oil (402 mg, 59%, >99:1 dr, D incorpo-
4.3.32. tert-Butyl (E)-2-deuterio-3-(20-iodophenyl)propenoate 52
CO2tBu
D
I
ration, 92% [1H NMR], 96% [MS]); ½a 2D5
ꢀ5.1 (c 1.0 in CHCl3); mmax
ꢂ
(film) 3062, 3028, 2975, 2931 (C–H), 1725 (C@O); dH (400 MHz,
Following general procedure 2, 46 (600 mg, 2.36 mmol, D incor-
poration 99% [1H NMR]), K2CO3 (978 mg, 7.08 mmol), D2O (3 mL)
and 2-iodobenzaldehyde (274 mg, 1.18 mmol) were reacted at
50 °C. Purification via flash column chromatography (eluent 30–
40 °C petrol/Et2O, 20:1) gave 52 as a colourless oil (370 mg, 95%,
>99:1 dr, D incorporation 99% [1H NMR], 96% [MS]); mmax (film)
3060, 3003, 2977, 2931, 2871, 1708 (C@O), 1618 (C@C); ddH
(400 MHz, CDCl3) 1.54 (9H, s, CMe3), 7.00 (1H, app dt, J 7.7, 1.6,
C(40)H), 7.31 (1H, app t, J 7.7, C(50)H), 7.52 (1H, dd, J 7.7, 1.6,
C(60)H), 7.80 (1H, s, C(3)H), 7.85 (1H, dd, J 8.1, 1.0, C(30)H); dC
(100 MHz, CDCl3) 28.3 (CMe3), 80.8 (CMe3), 101.3 (C(20)), 122.7
(C(2)), 127.3 (C(60)), 128.5 (C(50)), 131.0 (C(40)), 137.8 (C(10)),
140.0 (C(30)), 146.6 (C(3)), 165.5 (C(1)); m/z (ESI+) 354 ([M+Na]+,
CDCl3) 1.33 (9H, s, CMe3), 1.36 (3H, d, J 6.7, C(
10.5, C(2)H), 3.70 (1H, d, J 15.2, NCHAHBPh), 3.74 (1H, d, J 15.2,
NCHAHBPh), 4.03 (1H, q, J 6.7, C( )H), 4.45 (1H, d, J 10.5, C(3)H),
7.23–7.49 (13H, m, C(40)H, C(50)H, C(60)H, Ph), 7.62 (1H, br s,
C(20)H); dC (100 MHz, CDCl3) 17.0 (C(
)Me), 27.9 (CMe3), 37.7
(C(2)), 51.0 (NCH2Ph), 57.5 (C( )), 59.1 (C(3)), 80.6 (CMe3), 122.3
a)Me), 2.50 (1H, d, J
a
a
a
(C(30)), 126.8, 127.0, 127.1 (C(60), p-Ph), 127.9, 128.0, 128.3
(o,m-Ph), 129.8, 130.2 (C(40), C(50)), 131.3 (C(20)), 141.3, 143.7,
144.7 (C(10), i-Ph), 170.9 (C(1)); m/z (ESI+) 497 ([M(81Br)+H]+, 97%),
495 ([M(79Br)+H]+, 100%); HRMS (ESI+) C28H32D79BrNO2
þ
([M(79Br)+H]+) requires 495.1752; found 495.1740.
100%); HRMS (ESI+) C13H14DINaO2 ([M+Na]+) requires 354.0072;
þ
4.3.35. tert-Butyl (2R,3R,aS)-2-deuterio-3-[N-benzyl-N-(a-
methylbenzyl)amino]-3-(30-fluorophenyl)propanoate 36
found 354.0068.
Ph
4.3.33. tert-Butyl (2R,3R,aS)-2-deuterio-3-[N-benzyl-N-(a-
methylbenzyl)amino]-3-(40-bromophenyl)propanoate 34
Ph
N
CO2tBu
Ph
D
Ph
N
CO2tBu
F
Following general procedure 1, reaction of (S)-N-benzyl-N-(
methylbenzyl)amine (486 mg, 2.30 mmol) in THF (10 mL), BuLi
a-
D
Br

1048
S. G. Davies et al. / Tetrahedron: Asymmetry 22 (2011) 1035–1050
(0.89 mL, 2.23 mmol) and 50 (321 mg, 1.44 mmol, >99:1 dr, D
incorporation 99% [1H NMR], 98% [MS]) in THF (10 mL), followed
by 2-pyridone (410 mg, 4.31 mmol), gave 36 in >99:1 dr. Purifica-
tion via flash column chromatography (eluent 30–40 °C petrol/
Et2O, 40:1) gave 36 as a colourless oil (456 mg, 73%, >99:1 dr, D
tion via flash column chromatography (eluent 30–40 °C petrol/
Et2O, 40:1) gave 38 as a white solid (318 mg, 53%, >99:1 dr, D
incorporation 89% [1H NMR], 95% [MS]); ½a 2D5
ꢀ17.7 (c 1.0 in
ꢂ
CHCl3); mp 65–75 °C; mmax (film) 3085, 3061, 3028, 2976, 2932
(C–H), 1724 (C@O); dH (400 MHz, CDCl3) 1.24 (9H, s, CMe3), 1.57
incorporation 90% [1H NMR], 91% [MS]); ½a 2D5
ꢂ
ꢀ1.9 (c 1.0 in CHCl3);
(3H, d, J 6.7, C(
NCHAHBPh), 3.89 (1H, d, J 15.7, NCHAHBPh), 3.99 (1H, q, J 6.7,
C(
)H), 4.81 (1H, d, J 9.7, C(3)H), 6.95–7.02 (1H, m, C(40)H), 7.15–
7.49 (11H, m, C(60)H, Ph), 7.72 (1H, dd, J 7.8, 1.8, C(50)H), 7.86
(1H, dd, J 8.0, 1.1, C(30)H); dC (100 MHz, CDCl3) 12.6 (C(
)Me),
)), 66.4 (C(3)),
a)Me), 2.23 (1H, d, J 9.7, C(2)H), 3.78 (1H, d, J 15.7,
mmax (film) 3085, 3063, 3028, 2976, 2933, 2877, 2841 (C–H), 1726
(C@O); dH (400 MHz, CDCl3) 1.36 (9H, s, CMe3), 1.38 (1H, d, J 6.8,
a
C(a)Me), 2.56 (1H, d, J 10.4, C(2)H), 3.75 (1H, d, J 14.8, NCHAHBPh),
3.79 (1H, d J 14.8, NCHAHBPh), 4.07 (1H, q, J 6.8, C(
a
)H), 4.52 (1H, d,
a
J 10.4, C(3)H), 6.99–7.06 (1H, m, C(20)H), 7.25–7.46 (11H, m, C(40)H,
27.9 (CMe3), 42.7 (C(2)), 50.6 (NCH2Ph), 56.8 (C(a
C(60)H, Ph), 7.49–7.53 (2H, m, C(50)H, Ph); dC (100 MHz, CDCl3) 17.0
80.4 (CMe3), 101.8 (C(20)), 126.4, 126.8 (p-Ph), 127.6, 128.0,
128.1, 128.4 (C(50), o,m-Ph), 129.2 (C(40)), 129.9 (C(60)), 139.7
(C(30)), 142.7, 143.8, 145.3 (C(10), i-Ph), 170.2 (C(1)); m/z (ESI+)
(C(a)Me), 27.9 (CMe3), 37.7 (C(2)), 51.1 (NCH2Ph), 57.5 (C(a)), 59.1
(C(3)), 80.5 (CMe3), 114.7 (d, J 99.1, C(40)) 114.7 (d, J 140.6, C(20)),
123.9 (C(60)), 126.8, 127.1 (p-Ph), 127.9, 128.1, 128.3 (o,m-Ph),
129.7 (C(50)), 141.4, 143.9 (i-Ph), 145.1 (C(10)), 162.9 (d, J 244.5,
C(30)), 171.0 (C(1)); dF (377 MHz, CDCl3) ꢀ113.6 (C(30)F); m/z
(ESI+) 435 ([M+H]+, 100%); HRMS (ESI+) C28H32DFNO2þ ([M+H]+) re-
quires 435.2553; found 435.2543.
543 ([M+H]+, 100%); HRMS (ESI+) C28H32DINO2 ([M+H]+) requires
þ
543.1613; found 543.1600.
4.3.38. tert-Butyl (2S,3R)-2-deuterio-3-amino-3-phenylpropan-
oate 53
4.3.36. tert-Butyl (2R,3R,
a
S)-2-deuterio-3-[N-benzyl-N-(
a-
NH2
methylbenzyl)amino]-3-(20-bromophenyl)propanoate 37
CO2tBu
Ph
D
Ph
Pd(OH)2/C (50% w/w of substrate, 105 mg) was added to a solu-
tion of 7 (210 mg, 0.48 mmol, 93:7 dr, D incorporation 92% [1H
NMR], 91% [MS]) in MeOH/H2O/AcOH (v/v/v 40:4:1, 12 mL) and
the resultant suspension was stirred at rt for 24 h under H2
(1 atm). The reaction mixture was then filtered through a pad of
CeliteÒ (eluent MeOH) and the filtrate was concentrated in vacuo.
The residue was dissolved in CH2Cl2 and the resultant solution was
washed with satd aq NaHCO3, then dried and concentrated in va-
cuo. Purification via flash column chromatography (eluent Et2O)
gave tert-butyl (S)-2-deuterio-3-phenylpropanoate as a pale yel-
Ph
N
CO2tBu
D
Br
Following general procedure 1, reaction of (S)-N-benzyl-N-(a-
methylbenzyl)amine (521 mg, 2.47 mmol) in THF (10 mL), BuLi
(0.96 mL, 2.39 mmol) and 51 (438 mg, 1.54 mmol, >99:1 dr, D incor-
poration 99% [1H NMR], 98% [MS]) in THF (10 mL), followed by 2-
pyridone (440 mg, 4.62 mmol), gave 37 in >99:1 dr. Purification
via flash column chromatography (eluent 30–40 °C petrol/Et2O,
40:1) gave 37 as a white solid (500 mg, 65%, >99:1 dr, D incorpora-
low oil (4 mg, 3%, D incorporation 99% [1H NMR], 94% [MS]); ½a 2D1
ꢂ
ꢀ12.0 (c 0.5 in CHCl3); mmax (film) 1730 (C@O), 1154 (C–O); dH
(400 MHz, CDCl3) 1.45 (9H, s, CMe3), 2.59–2.53 (1H, m, C(2)H),
2.93 (2H, d, J 7.6, C(3)H2), 7.40–7.21 (5H, m, Ph); dC (125 MHz,
CDCl3) 28.1 (CMe3), 31.1 (C(3)), 36.9 (C(2)), 80.4 (CMe3), 128.9,
128.4, 128.4 (o,m,p-Ph), 140.8 (i-Ph), 172.4 (C(1)); m/z (ESI+) 208
tion 92% [1H NMR], 96% [MS]); ½a 2D5
ꢀ30.1 (c 1.0 in CHCl3); mp
ꢂ
55–65 °C; mmax (film) 3085, 2062, 3028, 2976, 2932, 2880 (C–H),
1725 (C@O); dH (400 MHz, CDCl3) 1.22 (9H, s, CMe3), 1.50 (3H, d, J
6.8, C(
NCHAHBPh), 3.88 (1H, d, J 15.4, NCHAHBPh), 4.02 (1H, q, J 6.8,
C(
)H), 4.98 (1H, d, J 10.4, C(3)H), 7.12–7.17 (1H, m, C(40)H),
7.18–7.46 (11H, m, C(60)H, Ph), 7.58 (1H, dd, J 8.0, 1.1, C(50)H), 7.72
(1H, dd, J 7.8, 1.5, C(30)H); dC (100 MHz, CDCl3) 12.9 (C(
)Me), 27.7
)), 61.1 (C(3)), 80.4
a)Me), 2.34 (1H, d, J 10.4, C(2)H), 3.78 (1H, d, J 15.4,
([M+H]+, 100%); HRMS (FI+) C13H17DO2 ([M]+) requires 207.1364;
+
found 207.1371. Further elution gave 53 as a yellow oil (53 mg,
a
47%, 91:9 dr, D incorporation 92% [1H NMR], 90% [MS]); ½a 2D1
ꢂ
+24.5 (c 1.0 in CHCl3); mmax (film) 3382 (N–H), 3063, 3029, 3004,
2978, 2930 (C–H), 1723 (C@O); dH (400 MHz, CDCl3) 1.40 (9H, s,
CMe3), 1.83 (2H, br s, NH2), 2.53–2.56 (1H, m, C(2)H), 4.35 (1H, d,
J 4.0, C(3)H), 7.20–7.37 (5H, m, Ph); dC (100 MHz, CDCl3) 28.1
(CMe3), 45.0 (C(2)), 52.7 (C(3)), 80.7 (CMe3), 126.3 (p-Ph), 127.3,
128.5 (o,m-Ph), 144.8 (i-Ph), 171.3 (C(1)); m/z (ESI+) 223 ([M+H]+,
a
(CMe3), 42.0 (C(2)), 50.7 (NCH2Ph), 56.9 (C(
a
(CMe3), 125.4 (C(20)), 126.4, 126.8 (p-Ph), 127.6, 128.0, 128.1 (C(60),
o,m-Ph), 128.8 (C(40)), 130.2 (C(50)), 133.0 (C(30)), 141.9, 142.5,
143.8 (C(10), i-Ph), 170.3 (C(1)); m/z (ESI+) 497 ([M(81Br)+H]+, 97%),
495 ([M(79Br)+H]+, 100%); HRMS (ESI+) C28H32D79BrNO2
þ
100%); HRMS (ESI+) C13H19DNO2 ([M+H]+) requires 223.1551;
þ
([M(79Br)+H]+) requires 495.1752; found 495.1738.
found 223.1551.
4.3.37. tert-Butyl (2R,3R,aS)-2-deuterio-3-[N-benzyl-N-(a-
methylbenzyl)amino]-3-(20-iodophenyl)propanoate 38
4.3.39. (2S,2R)-2-Deuterio-3-amino-3-phenylpropionic acid 54
NH2
Ph
CO2H
Ph
Ph
N
CO2tBu
D
D
A solution of 53 (100 mg, 0.45 mmol, 91:9 dr, D incorporation
92% [1H NMR], 90% [MS]) in TFA/CH2Cl2 (v/v 1:1, 3 mL) was stirred
at rt for 24 h. The reaction mixture was then concentrated in vacuo,
HCl (2.0 M in Et2O, 4 mL) was added to the residue, and the resul-
tant mixture was stirred at rt for 5 min then concentrated in vacuo.
This co-evaporation process was repeated once more then the
residue was dissolved in H2O and purified via ion exchange
I
Following general procedure 1, reaction of (S)-N-benzyl-N-(a-
methylbenzyl)amine (376 mg, 1.78 mmol) in THF (10 mL), BuLi
(0.69 mL, 1.72 mmol) and 52 (368 mg, 1.11 mmol, >99:1 dr, D
incorporation 99% [1H NMR], 96% [MS]) in THF (10 mL), followed
by 2-pyridone (317 mg, 3.33 mmol), gave 38 in >99:1 dr. Purifica-

S. G. Davies et al. / Tetrahedron: Asymmetry 22 (2011) 1035–1050
1049
chromatography (DOWEX 50WX8-200, eluent 1.0 M aq NH4OH) to
give 54 as a white foam (67 mg, 90%, 91:9 dr, D incorporation 90%
for a Bright Future Top Achiever Doctoral Scholarship (C.R.M.), and
the New Zealand Federation of Graduate Women for a Research
Fellowship (C.R.M.).
[1H NMR], 93% [MS]); ½a 2D2
ꢂ
+0.7 (c 0.2 in H2O); mmax (film) 3372 br
(N–H), 1711 (C@O); dH (400 MHz, D2O) 2.79 (1H, br d, J 7.8 C(2)H),
4.55 (1H, d, J 7.8, C(3)H), 7.41–7.34 (5H, m, Ph); dC (125 MHz, D2O)
40.1 (C(2)) 52.6 (C(3)), 126.8 (p-Ph), 129.3, 129.2 (o,m-Ph), 135.9 (i-
Ph), 177.2 (C(1)); m/z (ESIꢀ) 165 ([MꢀH]ꢀ, 100%); HRMS (ESIꢀ)
References
1. Tamariz, J. In Enantioselective Synthesis of b-Amino Acids; Juaristi, E., Ed.; Wiley:
New York, 1996; p 45.
2. Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A. T. J. Am. Chem. Soc.
1971, 93, 2325.
C9H9DNO2 ([MꢀH]ꢀ) requires 165.0780; found 165.0781.
ꢀ
3. (a) Roncari, G.; Kurylo-Borowska, Z.; Craig, L. C. Biochemistry 1966, 5, 2153; (b)
Hettinger, T. P.; Craig, C. C. Biochemistry 1968, 7, 4147; (c) Parry, R. J.; Kurylo-
Borowska, Z. J. Am. Chem. Soc. 1980, 102, 836; (d) Gould, S. J.; Thiruvengadam, T.
K. J. Am. Chem. Soc. 1981, 103, 6752.
4.3.40. tert-Butyl (R,R)-2-deuterio-3-amino-3-phenylpropan-
oate 55
NH2
4. (a) Crews, P.; Manes, L. V.; Boehler, M. Tetrahedron Lett. 1986, 27, 2797; (b)
Molinski, T. F.; Faulkner, D. J.; Xu, C.; Clardy, J. C. J. Am. Chem. Soc. 1986, 108,
3123; (c) Greico, P. A.; Hon, Y. S.; Perez-Mendrano, A. J. Am. Chem. Soc. 1998,
110, 1630.
CO2tBu
Ph
D
5. Baldwin, J. E.; Adlington, R. M.; O0Neil, I. A.; Schofield, C.; Spivey, A. C.; Sweeney,
J. B. J. Chem. Soc., Chem. Commun. 1989, 1852.
Pd(OH)2/C (50% w/w of substrate, 272 mg) was added to a solu-
tion of 8 (545 mg, 1.31 mmol, >99:1 dr, D incorporation 96% [1H
NMR], 97% [MS]) in MeOH/H2O/AcOH (v/v/v 40:4:1, 12 mL) and
the resultant suspension was stirred at rt for 24 h under H2
(1 atm). The reaction mixture was then filtered through a pad of
CeliteÒ (eluent MeOH) and the filtrate was concentrated in vacuo.
The residue was dissolved in CH2Cl2 and the resultant solution was
washed with satd aq NaHCO3, then dried and concentrated in va-
cuo. Purification via flash column chromatography (eluent 30–
40 °C petrol/Et2O, 2:1) gave tert-butyl (R)-2-deuterio-3-phenylpro-
panoate as a pale yellow oil (58 mg, 21%, D incorporation 96% [1H
6. (a) Barrett, G. C. In Chemistry and Biochemistry of the Amino Acids; Barrett, G. C.,
Ed.; Chapman & Hall: London, New York, 1985; (b) Rico, J. G.; Lindmark, R. J.;
Rogers, T. E.; Bovy, P. R. J. Org. Chem. 1993, 58, 7948; (c) Nicolaou, K. C.; Dai, W.-
M.; Guy, R. K. Angew. Chem. 1994, 106, 38; (d) Nicolaou, K. C.; Dai, W.-M.; Guy,
R. K. Angew. Chem., Int. Ed. Engl. 1994, 33, 15.
7. For reviews, see: (a) Seebach, D.; Matthews, J. L. Chem. Commun. 1997, 2015; (b)
Gellman, S. H. Acc. Chem. Res. 1998, 31, 173; For selected other papers, see: (c)
Dado, G. P.; Gellman, S. H. J. Am. Chem. Soc. 1994, 116, 1054; (d) Appella, D. H.;
Christianson, L. A.; Karle, I. L.; Powell, D. R.; Gellman, S. H. J. Am. Chem. Soc.
1996, 118, 13071; (e) Appella, D. H.; Christianson, L. A.; Klein, D. A.; Powell, D.
R.; Huang, X.; Barchi, J. J.; Gellman, S. H. Nature 1997, 387, 381; (f) Seebach, D.;
Abele, S.; Gademann, K.; Guichard, G.; Hintermann, T.; Jaun, B.; Matthews, J. L.;
Schrieber, J.; Oberer, L.; Hommel, U.; Widmer, H. Helv. Chim. Acta 1998, 81, 932;
(g) Beke, T.; Somlai, C.; Perczel, A. J. Comput. Chem. 2005, 27, 20; (h) Murray, J.
K.; Farooqi, B.; Sadowsky, J. D.; Scalf, M.; Freund, W. A.; Smith, L. M.; Chen, J.;
Gellman, S. H. J. Am. Chem. Soc. 2005, 127, 13271.
8. (a) Xie, J.; Soleilhac, J.; Schmidt, C.; Peyroux, J.; Roques, B. P.; Fournie-Zaluski,
M. J. Med. Chem. 1989, 32, 1497; (b) Porter, E. A.; Weisblum, B.; Gellman, S. H. J.
Am. Chem. Soc. 2002, 124, 7324.
9. (a) Gani, D.; Young, D. W. J. Chem. Soc., Chem. Commun. 1982, 867; (b)
Ramalingam, K.; Woodard, R. W. J. Org. Chem. 1988, 53, 1900; (c) Wang, M.;
Gould, S. J. J. Org. Chem. 1993, 58, 5176; (d) Felpin, F.-X.; Doris, E.; Wagner, A.;
Valleix, A.; Rousseau, B.; Mioskowski, C. J. Org. Chem. 2001, 66, 305; (e) Caputo,
R.; Longobardo, L. Amino Acids 2007, 32, 401.
NMR], 80% [MS]); ½a D25
ꢂ
+3.5 (c 1.0 in CHCl3). Further elution gave 55
as a yellow oil (227 mg, 82%, >99:1 dr, D incorporation 96% [1H
NMR], 80% [MS]); ½a D25
ꢂ
+3.5 (c 1.0 in CHCl3); mmax (film) 3382 (N–
H), 3063, 3029, 3004, 2978, 2930, 1723 (C@O); dH (400 MHz,
CDCl3) 1.40 (9H, s, CMe3), 1.83 (2H, br s, NH2), 2.53–2.56 (1H, m,
C(2)H), 4.35 (1H, d, J 4.0, C(3)H), 7.20–7.37 (5H, m, Ph); dC
(100 MHz, CDCl3) 28.1 (CMe3), 45.0 (C(2)), 52.7 (C(3)), 80.7
(CMe3), 126.3 (p-Ph), 127.3, 128.5 (o,m-Ph), 144.8 (i-Ph), 171.3
(C(1)); m/z (ESI+) 223 ([M+H]+, 100%); HRMS (ESI+) C13H19DNO2
10. (a) Fujihara, H.; Schowen, R. L. J. Org. Chem. 1984, 49, 2819; (b) Faleev, N. G.;
Ruvinov, S. B.; Saporovskaya, M. B.; Belikov, V. M.; Zakomyrdina, L. N.;
Sakharova, I. S.; Torchinsky, Y. M. Tetrahedron Lett. 1990, 31, 7051; (c) Rose, J.
E.; Leeson, P. D.; Gani, D. J. Chem. Soc., Perkin Trans. 1 1995, 157; (d) Ross, F. C.;
Botting, N. P.; Leeson, P. D. Tetrahedron 1997, 53, 15761.
þ
([M+H]+) requires 223.1551; found 223.1551.
4.3.41. (R,R)-2-Deuterio-3-amino-3-phenylpropanoic acid 56
11. Oba, M.; Ueno, R.; Fukuoka, M.; Kainosho, M.; Nishiyama, K. J. Chem. Soc., Perkin
Trans. 1 1995, 1603.
12. (a) Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J. Am. Chem. Soc. 1983, 105,
5390; (b) Laube, T.; Dunitz, J. D.; Seebach, D. Helv. Chim. Acta 1985, 68, 1373.
13. This strategy has also been used for the deuteration of tetralones, see: Eames,
J.; Weerasooriya, N.; Coumbarides, G. S. Eur. J. Org. Chem. 2002, 181.
14. The consecutive addition of LDA, TMSCl then MeLi has also been shown to
generate base-free enolates which undergo efficient deuteration, see: Stork, G.;
Hudrlik, P. F. J. Am. Chem. Soc. 1968, 90, 4462.
NH2
CO2H
Ph
D
A solution of 55 (100 mg, 0.45 mmol, >99:1 dr, D incorporation
96% [1H NMR], 80% [MS]) in TFA/CH2Cl2 (v/v 1:1, 4 mL) was stirred
at rt for 24 h. The reaction mixture was then concentrated in vacuo,
HCl (2.0 M in Et2O, 4 mL) was added to the residue, and the resul-
tant mixture was stirred at rt for 5 min then concentrated in vacuo.
This co-evaporation process was repeated once more then the res-
idue was dissolved in H2O and purified via ion exchange chroma-
tography (DOWEX 50WX8-200, eluent 1.0 M aq NH4OH) to give
56 as a white solid (46 mg, 62%, >99:1 dr, D incorporation 81%
15. (a) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2, 183; (b) Davies, S.
G.; Garrido, N. M.; Kruchinin, D.; Ichihara, O.; Kotchie, L. J.; Price, P. D.; Price
Mortimer, A. J.; Russell, A. J.; Smith, A. D. Tetrahedron: Asymmetry 2006, 17,
1793; (c) Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Russell, A. J.;
Savory, E. D.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2009, 20, 758;
(d) Davies, S. G.; Garner, A. C.; Nicholson, R. L.; Osborne, J.; Roberts, P. M.;
Savory, E. D.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2009, 7, 2604; (e)
Davies, S. G.; Mujtaba, N.; Roberts, P. M.; Smith, A. D.; Thomson, J. E. Org. Lett.
2009, 11, 1959; (f) Bentley, S. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell,
A. J.; Thomson, J. E.; Toms, S. M. Tetrahedron 2010, 66, 4604; (g) Abraham, E.;
Bailey, C. W.; Claridge, T. D. W.; Davies, S. G.; Ling, K. B.; Odell, B.; Rees, T. L.;
Roberts, P. M.; Russell, A. J.; Smith, A. D.; Smith, L. J.; Storr, H. R.; Sweet, M. J.;
Thompson, A. L.; Thomson, J. E.; Tranter, G. E.; Watkin, D. J. Tetrahedron:
Asymmetry 2010, 21, 1797; (h) Davies, S. G.; Ichihara, O.; Roberts, P. M.;
Thomson, J. E. Tetrahedron 2011, 67, 216; (i) Abraham, E.; Claridge, T. D. W.;
Davies, S. G.; Odell, B.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Smith, L. J.;
Storr, H. R.; Sweet, M. J.; Thompson, A. L.; Thomson, J. E.; Tranter, G. E.; Watkin,
D. J. Tetrahedron: Asymmetry 2011, 22, 69; (j) Brock, E. A.; Davies, S. G.; Lee, J. A.;
Roberts, P. M.; Thomson, J. E. Org. Lett. 2011, 13, 1594; (k) Bagal, S. K.; Davies, S.
G.; Fletcher, A. M.; Lee, J. A.; Roberts, P. M.; Scott, P. M.; Thomson, J. E.
Tetrahedron Lett. 2011, 52, 2216.
[1H NMR], 78% [MS]); mp 208–215 °C; ½a 2D5
ꢂ
+6.0 (c 1.0 in H2O); mmax
(KBr) 2961, 2920, 2839, 2659 (O–H), 1627 (C@O); dH (400 MHz,
D2O) 2.72 (1H, d, J 6.4, C(2)H), 4.55 (1H, d, J 6.4, C(3)H), 7.33–
7.43 (5H, m, Ph); dC (100 MHz, D2O) 40.2 (C(2)), 52.7 (C(3)), 126.9
(p-Ph), 129.2, 129.3 (o,m-Ph), 136.0 (i-Ph), 177.3 (C(1)); m/z (ESI+)
189 ([M+Na]+, 100%); HRMS (ESI+) C9H10DNNaO2 ([M+Na]+)
þ
requires 189.0745; found 189.0745.
16. For selected examples from this laboratory, see: (a) Davies, S. G.; Kelly, R. J.;
Price Mortimer, A. J. Chem. Commun. 2003, 2132; (b) Davies, S. G.; Burke, A. J.;
Garner, A. C.; McCarthy, T. D.; Roberts, P. M.; Smith, A. D.; Rodriguez-Solla, H.;
Vickers, R. J. Org. Biomol. Chem. 2004, 2, 1387; (c) Davies, S. G.; Haggitt, J. R.;
Ichihara, O.; Kelly, R. J.; Leech, M. A.; Price Mortimer, A. J.; Roberts, P. M.; Smith,
Acknowledgements
The authors would like to thank New College, Oxford, for a
Junior Research Fellowship (A.D.S.), the New Zealand Government

1050
S. G. Davies et al. / Tetrahedron: Asymmetry 22 (2011) 1035–1050
A. D. Org. Biomol. Chem. 2004, 2, 2630; (d) Abraham, E.; Candela-Lena, J. I.;
Davies, S. G.; Georgiou, M.; Nicholson, R. L.; Roberts, P. M.; Russell, A. J.;
28. Davies, S. G.; Bull, S. D.; Mulvaney, A. W.; Prasad, R. S.; Smith, A. D.; Fenton, G.
Chem. Commun. 2000, 5, 337.
Sánchez-Fernández, E. M.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry
2007, 18, 2510; (e) Abraham, E.; Davies, S. G.; Millican, N. L.; Nicholson, R. L.;
Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2008, 6, 1655; (f) Abraham, E.;
Brock, E. A.; Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.; Nicholson, R. L.;
Perkins, J. H.; Roberts, P. M.; Russell, A. J.; Sánchez-Fernández, E. M.; Scott, P.
M.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 1665; (g) Davies, S.
G.; Fletcher, A. M.; Roberts, P. M.; Smith, A. D. Tetrahedron 2009, 65, 10192; (h)
Davies, S. G.; Hughes, D. G.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Smith, A.
D.; Thomson, J. E.; Williams, O. M. H. Synlett 2010, 567.
29. Bull, S. D.; Davies, S. G.; Fenton, G.; Mulvaney, A. W.; Prasad, R. S.; Smith, A. D. J.
Chem. Soc., Perkin Trans. 1 2000, 3765.
30. Davies, S. G.; Fenwick, D. R. J. Chem. Soc., Chem. Commun. 1995, 11, 1109.
31. (a) Davies, S. G.; Mulvaney, A. W.; Russell, A. J.; Smith, A. D. Tetrahedron:
Asymmetry 2007, 18, 1554; (b) Bull, S. D.; Davies, S. G.; Delgado-Ballester, S.;
Kelly, P. M.; Kotchie, L. J.; Gianotti, M.; Laderas, M.; Smith, A. D. J. Chem. Soc.,
Perkin Trans. 1 2001, 3112.
32. The relative configurations within 27–32 were assigned by analogy to that
within 7.
17. For selected examples from this laboratory, see: (a) Cailleau, T.; Cooke, J. W. B.;
Davies, S. G.; Ling, K. B.; Naylor, A.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.;
Russell, A. J.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2007, 5, 3922; (b)
Davies, S. G.; Durbin, M. J.; Goddard, E. C.; Kelly, P. M.; Kurosawa, W.; Lee, J. A.;
Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Scott, P. M.; Smith, A.
D. Org. Biomol. Chem. 2009, 7, 761.
18. For selected examples from this laboratory, see: (a) Davies, S. G.; Garner, A. C.;
Long, M. J. C.; Morrison, R. M.; Roberts, P. M.; Smith, A. D.; Sweet, M. J.; Withey,
J. M. Org. Biomol. Chem. 2005, 3, 2762; (b) Aye, Y.; Davies, S. G.; Garner, A. C.;
Roberts, P. M.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 2195; (c)
Abraham, E.; Davies, S. G.; Docherty, A. J.; Ling, K. B.; Roberts, P. M.; Russell, A.
J.; Thomson, J. E.; Toms, S. M. Tetrahedron: Asymmetry 2008, 19, 1356; (d)
Davies, S. G.; Durbin, M. J.; Hartman, S. J. S.; Matsuno, A.; Roberts, P. M.; Russell,
A. J.; Smith, A. D.; Thomson, J. E.; Toms, S. M. Tetrahedron: Asymmetry 2008, 19,
2870.
33. Davies, S. G.; Fletcher, A. M.; Hermann, G. J.; Poce, G.; Roberts, P. M.; Smith, A.
D.; Sweet, M. J.; Thomson, J. E. Tetrahedron: Asymmetry 2010, 21, 6135. See also
Ref. 20c.
34. (a) Uyehara, T.; Asao, N.; Yamamoto, Y. J. Chem. Soc., Chem. Commun. 1989, 753;
(b) Asao, N.; Uyehara, T.; Yamamoto, Y. Tetrahedron 1990, 46, 4563; (c) Jahn, U.;
Müller, M.; Aussieker, S. J. Am. Chem. Soc. 2000, 122, 5212.
35. Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868.
36. An authentic sample of 43 was prepared in 99% yield and >99:1 dr via the
conjugate addition of (S)-4 to a-deuterio-a,b-unsaturated ester 47, followed by
treatment with D2O.
37. Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624.
38. This sample of syn-8 (88:12 dr, D incorporation 99% [1H NMR], 93% [MS]) was
obtained by treatment of
a-deuterio-a,b-unsaturated ester 47 with (S)-4
followed by MeOH, see Section 2.3.
39. Nahmnay, M.; Melman, A. Org. Lett. 2001, 3, 3733.
19. Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833.
20. (a) Davies, S. G.; Walker, J. C. Chem. Commun. 1985, 209; (b) Davies, S. G.;
Garrido, N. M.; Ichihara, O.; Walters, I. A. S. J. Chem. Soc., Chem. Commun. 1993,
1153; (c) Davies, S. G.; Walters, I. A. S. J. Chem. Soc., Perkin Trans. 1 1994, 9,
1129; (d) Davies, S. G.; Ichihara, O.; Walters, I. A. S. J. Chem. Soc., Perkin Trans. 1
1994, 9, 1141.
40. Villieras, J.; Seguineau, P. Tetrahedron Lett. 1988, 29, 477.
41. Bordwell, F. G.; Algrim, D. J. Org. Chem. 1976, 41, 2507.
42. Olmstead, W. N.; Margolin, Z.; Bordwell, F. G. J. Org. Chem. 1980, 45, 3295.
43. (a) Davies, S. G.; Beddow, J. E.; Smith, A. D.; Russell, A. J. Chem. Commun. 2004,
2778; (b) Beddow, J. E.; Davies, S. G.; Ling, K. B.; Roberts, P. M.; Russell, A. J.;
Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2007, 5, 2812.
21. For selected examples, see: Bunnage, M. E.; Burke, A. J.; Davies, S. G.; Millican,
N. L.; Nicholson, R. L.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2003, 1,
3708. See also Refs. 15c,16d–f.
22. Claridge, T. D. W.; Davies, S. G.; Lee, J. A.; Nicholson, R. L.; Roberts, P. M.;
Russell, A. J.; Smith, A. D.; Toms, S. M. Org. Lett. 2008, 10, 5437.
23. Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1994, 5, 1999.
24. anti-Diastereoselectivity has previously been observed upon methylation of
the lithium b-amino enolate formed from the conjugate addition of lithium (R)-
44. Attempted conjugate addition of lithium amide (S)-4 to the C(3)-p-
methoxyphenyl substituted analogue gave 72% conversion to the
corresponding syn-
[1H NMR]), although this compound could not be separated from the
deuterio- ,b-unsaturated ester starting material.
45. Following hydrogenolysis of 7 (S)-2-deuterio-3-phenylpropanoic acid (D
a-deuterio-b-amino ester (>99:1 dr, D incorporation 93%
a-
a
incorporation 99% [1H NMR], 94% [MS]) was isolated in 3% yield. Following
hydrogenolysis of 8 (R)-2-deuterio-3-phenylpropanoic acid (D incorporation
96% [1H NMR], 80% [MS]) was isolated in 21% yield.
N-benzyl-N-(a-methylbenzyl)amide (R)-4 to tert-butyl cinnamate 5 (58:42 dr),
see: Ref. 20c.
46. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518.
47. Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, C. K.; Watkin, D. J. J. Appl.
Crystallogr. 2003, 36, 1487.
48. Yamamoto, Y.; Maeda, K.; Tomimoto, K.; Mase, T. Synlett 2002, 561.
49. Bull, S. D.; Davies, S. G.; Roberts, P. M.; Savory, E. D.; Smith, A. D. Tetrahedron
2002, 58, 4629.
25. 2H NMR spectroscopic analysis, without the contribution of the non-
deuterated product, was also expected to provide a comparison. However,
the line width was not narrow enough to distinguish between resonances for
the two diastereoisomers in the 2H NMR spectrum.
26. All ‘D+’ sources were supplied by Apollo Scientific Ltd [D2O >99.9% D; MeOH-d4
>99.8% D; AcOH-d4 >99.5% D].
27. Sewald, N.; Hiller, K. D.; Korner, M.; Findeisen, M. J. Org. Chem. 1998, 63,
7263.
50. Bull, S. D.; Davies, S. G.; Smith, A. D. J. Chem. Soc., Perkin Trans. 1 2001, 2931.
51. Chackalamannil, S.; Doller, D.; Eagen, K. Tetrahedron Lett. 2002, 43, 5101.