Homochiral lithium amides for the asymmetric synthesis of β-amino acids

Article abstract of DOI:10.1016/j.tetasy.2006.05.008

Secondary homochiral lithium amides derived from α-methylbenzylamine undergo highly diastereoselective conjugate additions to a range of α,β-unsaturated esters. The corresponding β-amino acids are readily liberated by successive N-debenzylation and ester hydrolysis, furnishing (R)-β-amino butyric acid, (R)-β-amino pentanoic acid, (S)-β-leucine, (R)-β-amino octanoic acid, (S)-β-phenylalanine, (S)-β-tyrosine methyl ether, (S)-β-tyrosine hydrochloride and (S)-β-(2-methoxyphenyl)-β-amino propanoic acid in high yields and high ee. The application of this procedure to the synthesis of the natural products (R)-β-DOPA and (R)-β-lysine is demonstrated. The development of a simplified one-pot reaction protocol applicable to the multi-gram scale synthesis of homochiral β-amino esters is also delineated.

Full text of DOI:10.1016/j.tetasy.2006.05.008

Tetrahedron: Asymmetry 17 (2006) 1793–1811
Homochiral lithium amides for the asymmetric synthesis
of b-amino acids
Stephen G. Davies,* Narciso M. Garrido, Dennis Kruchinin, Osamu Ichihara,
Luke J. Kotchie, Paul D. Price, Anne J. Price Mortimer, Angela J. Russell
and Andrew D. Smith
The Department of Organic Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
Received 10 April 2006; accepted 15 May 2006
Available online 18 July 2006
Abstract—Secondary homochiral lithium amides derived from a-methylbenzylamine undergo highly diastereoselective conjugate addi-
tions to a range of a,b-unsaturated esters. The corresponding b-amino acids are readily liberated by successive N-debenzylation and ester
hydrolysis, furnishing (R)-b-amino butyric acid, (R)-b-amino pentanoic acid, (S)-b-leucine, (R)-b-amino octanoic acid, (S)-b-phenyl-
alanine, (S)-b-tyrosine methyl ether, (S)-b-tyrosine hydrochloride and (S)-b-(2-methoxyphenyl)-b-amino propanoic acid in high yields
and high ee. The application of this procedure to the synthesis of the natural products (R)-b-DOPA and (R)-b-lysine is demonstrated.
The development of a simplified one-pot reaction protocol applicable to the multi-gram scale synthesis of homochiral b-amino esters is
also delineated.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
asymmetric synthesis.10 While Arndt–Eistert homologation
of a-amino acids11 and enzymatic resolution12 are popular
routes to specific b-amino target molecules, the develop-
ment of general and reliable methodology for their asym-
metric synthesis is of widespread synthetic interest. Many
asymmetric routes to b-amino acids have been developed,
including the stereoselective addition of homochiral eno-
lates to imines,13 the conjugate addition of amines to
homochiral a,b-unsaturated esters,14 the diastereo- and
enantioselective addition of N-benzylhydroxylamines to
imides,15 the catalytic reduction of b-amino crotonates16
or (E)-b-(acylamino)acrylic acids17 and the dipolar cyclo-
addition of homochiral nitrones18 among others.19 Chiral
auxiliary approaches involving the use of sulfinimines,20
hydropyrimidines21 and pyrimidinones22 have also been
developed specifically for the synthesis of b-amino acids.
b-Amino acids are components of a variety of naturally
occurring products of biological significance, including
alkaloids and peptides. For example, the b-phenylalanine
unit is found in celacinnine, a member of the spermidine
alkaloids,1 while Taxolꢁ, a potent anti-cancer agent, con-
tains a-hydroxy-b-phenylalanine as an essential component
of its anti-tumour activity.2 (R)-b-Tyrosine is the b-amino
acid component of the cyclodepsipeptide, jasplakinolide,3
while its enantiomer has been identified as a component
of the antibiotic edeine A.4 b-Lysine residues have been
identified as key components of a range of antibiotics such
as streptothrycin F,5 the racemomycins6 and viomycin,7
while b-arginine is a component of blasticidin S.8 While
the pharmacological activity of these compounds has often
been the focus of these studies, the importance of b-amino
acid derivatives as tools to probe the secondary and tertiary
structures of proteins and b-peptides has been receiving
increasing recognition.9 The favourable biological and
conformational activities of b-amino acids and peptides
has stimulated the development of methodology for their
Despite these advances, the simplest and most elegant
approach to the preparation of b-amino acids undoubtedly
involves the conjugate addition of a homochiral ammonia
source to an a,b-unsaturated ester.23 Although the use of
lithium amides as strong bases has been extensively studied
and is universally recognised, their ability to act as nucleo-
philes in Michael additions has received relatively little
attention. Within this field, Schlessinger et al. first observed
that LDA adds in a conjugate manner to ethyl crotonate in
*
Corresponding author. Tel.: +44 1865 275680; fax: +44 1865 275674;
e-mail: steve.davies@chem.ox.ac.uk
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.05.008

1794
S. G. Davies et al. / Tetrahedron: Asymmetry 17 (2006) 1793–1811
near quantitative yield over 30 years ago.24 Yamamoto
et al. demonstrated the potential utility of this transforma-
tion by showing that lithium benzyltrimethylsilyl amide
(LSA) 1 adds in a conjugate fashion to methyl crotonate25
and extended this methodology to the conjugate addition
of amido cuprates to homochiral a,b-unsaturated accep-
tors.26 Hawkins et al. reported the first diastereoselective
conjugate addition of a homochiral lithium amide, showing
that lithium amide 2 undergoes highly diastereoselective
conjugate addition to a range of a,b-unsaturated accep-
tors.27 However, deprotection of the N-naphthyl protecting
groups of the resultant b-amino esters requires forcing
conditions, using 500% (w/w) of palladium hydroxide
catalyst for removal by hydrogenolysis.28 We subsequently
communicated that chiral lithium amides such as 3 derived
from readily available a-methylbenzylamine undergo
highly diastereoselective conjugate additions to a,b-unsatu-
rated esters, with deprotection of the resultant b-amino
esters readily achieved by hydrogenolysis under mild condi-
tions.29 A variety of uses of this methodology have since
been reported.30 Both Bovy31 and Sewald32 subsequently
showed that lithium N-trimethylsilyl-N-a-methylbenzyl-
amide 4 can undergo stereoselective conjugate addition
reactions, while Enders et al. have introduced lithiated
TMS-SAMP 5 as a chiral ammonia equivalent.33 Recent
advances within this area include the catalytic use of homo-
chiral diethers to confer stereocontrol in the conjugate
addition of lithium amide 1 to a,b-unsaturated esters
(Fig. 1).34
level of diastereoselectivity upon conjugate addition of a
primary amine to an a,b-unsaturated acceptor. Treatment
of (R)-a-methylbenzylamine with methyl crotonate in
refluxing ethanol gave the secondary b-amino ester 6 in a
moderate 35% yield and with 4% de, in slight favour of
the (3S,aR)-diastereoisomer, consistent with the results
previously reported by Furukawa et al.14 Similarly, conju-
gate addition of lithium (R)-a-methylbenzylamide to
methyl crotonate at ꢀ78 ꢂC in THF gave secondary b-amino
ester 6 in 28% yield as a 1:1 mixture of (3S,aR)- and
(3R,aR)-diastereoisomers, along with N-a-methylbenzyl
crotonamide 7, the product of 1,2-addition, in 35% yield
(Scheme 1).
Ph
NH2
CO2Me
Ph
NH
(i)
CO2Me
Me
Me
6, 35%, 4% d.e.
(ii)
O
Ph
Ph
NH
+
CO2Me
Me
N
H
Me
6, 28%, 0% d.e.
7, 35%
Scheme 1. Reagents and conditions: (i) EtOH, D; (ii) n-BuLi (0.95 equiv),
THF, ꢀ78 ꢂC then methyl crotonate (0.65 equiv), THF, ꢀ78 ꢂC.
Ph
SiMe3
Ph
N
Li
Ph
N
The conjugate addition reactions of chiral secondary lith-
ium amides were subsequently investigated as previous
chiral recognition studies from this laboratory imply
that lithium (RS)-N-3,4-dimethoxybenzyl-N-a-methylbenzyl-
amide exerts a powerful stereodirecting influence upon
the b-centre of an a,b-unsaturated acceptor upon conjugate
addition.35 Lithium (R)-N-3,4-dimethoxybenzyl-N-a-meth-
ylbenzylamide was therefore added to methyl, benzyl and
tert-butyl crotonate at ꢀ78 ꢂC, resulting in exclusive 1,4-
addition and furnishing the b-amino esters (3R,aR)-8–10
in good yield and with high levels of diastereoselectivity
(>95% de). However, addition of lithium (R)-N-3,4-
dimethoxybenzyl-N-a-methylbenzylamide to benzyl or
tert-butyl crotonate at 15 ꢂC resulted in a substantial
decrease in the observed levels of diastereoselectivity
(70% and 66% de, respectively), indicating that low temper-
ature is essential for high diastereoselectivity in this reac-
tion (Scheme 2).
Li
N
LI
1
2
3
OMe
TMS
SiMe3
N
Ph
N
Li
N
Li
4
5
Figure 1. Lithium amides for conjugate addition.
Herein, we wish to delineate the full details of the general-
ity of our lithium amide methodology and its application to
the synthesis of a variety of simple b-amino acids and
selected natural product targets. Moreover, we also
demonstrate a simplified one-pot reaction protocol that is
applicable to the multi-gram scale synthesis of homochiral
b-amino esters.
A notable reduction in stereoselectivity and reactivity for
this conjugate addition process was observed upon reaction
of either lithium (R)-N-(2-methoxybenzyl)-N-a-methyl-
benzylamide or lithium (R)-N-(2,4-dimethoxybenzyl)-N-a-
methylbenzylamide with tert-butyl cinnamate. Under
standard reaction conditions at ꢀ78 ꢂC, these additions
proceeded to only 36% and 42% conversion, respectively,
furnishing a 50:50 mixture of b-amino ester diastereoiso-
mers 11 and 12 in each case. Presumably, the reduced
2. Results and discussion
2.1. Conjugate addition of chiral lithium amides
The thermal 1,4 conjugate addition of (R)-a-methylbenzyl-
amine to methyl crotonate was first examined to assay the

S. G. Davies et al. / Tetrahedron: Asymmetry 17 (2006) 1793–1811
1795
OMe
synthetic route to b-amino acids. Addition of methyl, benz-
yl and tert-butyl crotonate to lithium amide (R)-3 at
ꢀ78 ꢂC gave b-amino esters (3R,aR)-14–16 in good iso-
lated yield (>80%) and in consistently high de. Addition
of methyl, benzyl and tert-butyl crotonate to lithium amide
(R,R)-17 at ꢀ78 ꢂC was also evaluated, giving b-amino
esters (3R,aR,a0R)-18–20, respectively. Although high lev-
els of stereoselectivity (>97% de) using lithium amide
(R,R)-17 were observed, both the rate of reaction and yield
of the isolated b-amino ester products were noticeably
attenuated in comparison to the corresponding products
derived from lithium amide (R)-3 (Scheme 4).
OMe
OMe
OMe
Ph
N
Li
Ph
N
CO2R
Me
CO2R
)-8-10
(i)
Me
(3
R
,α
R
β-amino ester
R
T (ºC)
-78
-78
-78
15
Yield(%) d.e.*
8
9
10
9
10
Me
Bn
tBu
Bn
tBu
68
74
75
56
94
>95
>95
>95
70
Ph
Ph
15
66
Ph
N
Li
Ph
N
* As shown by 1H NMR spectroscopic analysis of the crude reaction mixture
CO2R
3
Me
(3 ,α
Scheme 2. Reagents and conditions: (i) lithium (R)-N-3,4-dimethoxy-
benzyl-N-a-methylbenzylamide, THF, ꢀ78 ꢂC or 15 ꢂC.
CO2R
Me
R
R)-14-16
(i)
R
β-amino ester Yield (%) d.e. (%)
reactivity and low stereoselectivity observed in these reac-
tions arises from the formation of a chelated lithium amide
species such as 13, resulting in disruption of the normal
chelation controlled lithium amide transition state and a
corresponding decrease in stereoselectivity (Scheme 3).
Me
Bn
tBu
14
15
16
85
88
82
95
95
>98
Ph
N
Ph
Ph
N
Li
Ph
CO2R
Me
,αR,
17
CO2R
(3
R
α'R)-17-20
Me
(ii)
OMe
R
β-amino ester Yield (%) d.e. (%)
Ph
N
(i)
Me
Bn
Bu
18
19
20
57
23
60
>99
>97
>98
t
t
CO2 Bu
CO2 Bu
Ph
Ph
0% d.e.
36% conversion
11
Scheme 4. Reagents and conditions: (i) lithium (R)-N-benzyl-N-a-meth-
ylbenzylamide 3 or lithium (R,R)-N,N-bis(a-methylbenzyl)amide 17, THF,
ꢀ78 ꢂC.
0% d.e.
(ii)
42% conversion
OMe
As a result of the lower isolated yields of the b-amino esters
derived from reaction with lithium amide (R,R)-17, the
synthetic generality of this protocol was evaluated using
lithium (R)-N-benzyl-N-a-methylbenzylamide 3.
Ph
N
Li
O
X
OMe
Me
13, X = H or OMe
Ph
N
t
2.2. Addition of lithium N-benzyl-N-a-methylbenzylamide to
a range of b-substituted a,b-unsaturated esters
CO2 Bu
Ph
12
To investigate the scope of this methodology, a range of
b-aryl and b-alkyl substituted a,b-unsaturated acceptors
were added to homochiral lithium amide (R)-3. In each
case, the reaction proceeded to give the desired b-amino
ester 21–35 in high de (91%–>95%). In each case, the con-
figuration of the major diastereoisomer was assigned by
analogy with the model previously developed to explain
the stereoselectivity observed during addition of lithium
Scheme 3. Reagents and conditions: (i) lithium N-(2-methoxybenzyl)-N-a-
methylbenzylamide, THF, ꢀ78 ꢂC; (ii) lithium N-(2,4-dimethoxybenzyl)-
N-a-methylbenzylamide, THF, ꢀ78 ꢂC.
As methoxy-substituted N-benzyl groups are highly suscep-
tible to oxidative cleavage36 while being relatively inert
towards hydrogenolysis compared to an N-benzyl
group,37,38 this conjugate addition methodology was
extended to the use of homochiral lithium (R)-N-benzyl-
N-a-methylbenzylamide 3 and C2 symmetric lithium
(R,R)-N,N-bis(a-methylbenzyl)amide 17. Tertiary b-amino
esters derived from conjugate addition of these lithium
amides were predicted to prove amenable to global
N-deprotection by hydrogenolysis and realise an efficient
N-benzyl-N-a-methylbenzylamide
to
a,b-unsaturated
acceptors (Scheme 5).39
Within this series, it is noticeable that the yield of the iso-
lated b-amino ester is considerably enhanced with the use
of tert-butyl esters when compared to other ester protecting
groups. With sterically unencumbered ester protecting

1796
S. G. Davies et al. / Tetrahedron: Asymmetry 17 (2006) 1793–1811
Ph
forming the lithium amide by deprotonation of the corres-
ponding amine in THF with n-BuLi at ꢀ78 ꢂC, followed by
addition of a solution of the a,b-unsaturated ester in THF
at ꢀ78 ꢂC. This protocol ensures that alternative reaction
manifolds such as conjugate addition, 1,2-addition or c-
deprotonation of the a,b-unsaturated ester by n-BuLi does
not compete with lithium amide addition. In order to sim-
plify this reaction procedure, the viability of a one-pot
reaction protocol was investigated to enable competition
between deprotonation of the amine by n-BuLi followed
by lithium amide conjugate addition with any of the many
alternative reactions to be evaluated.40 Using the conjugate
addition to tert-butyl cinnamate as a model, a solution of
n-BuLi (1.55 equiv) in hexanes at ꢀ78 ꢂC was added
to a solution of (S)-N-benzyl-N-a-methylbenzylamine (1.6
equiv) and tert-butyl cinnamate (1.0 equiv) in THF at
ꢀ78 ꢂC, giving, after addition of saturated aqueous NH4Cl
and standard workup, the desired b-amino ester (3R,aS)-27
in >98% de and in 82% isolated yield. This reaction proto-
col is readily reproduceable on a multi-gram scale and has
been used for the preparation of over 15 g of b-amino ester
27. This one-pot reaction protocol was next tested with
tert-butyl crotonate and methyl (E)-4-methyl-pent-2-eno-
ate as representative a,b-unsaturated esters containing
c-acidic protons, giving exclusively the corresponding
b-amino esters (3S,aS)-16 and (3R,aS)-39 in >98% de
and in 93% and 89% yield, respectively (Scheme 7). Fur-
ther optimisation of this reaction protocol indicated that
similar levels of reaction efficiency could be achieved using
n-BuLi (1.05 equiv), (S)-N-benzyl-N-a-methylbenzylamine
(1.1 equiv) and the a,b-unsaturated ester (1.0 equiv). In
each case, the conjugate addition reaction proceeded to
complete conversion, giving the corresponding b-amino
esters in >98% de.
Ph
Ph
N
Li
Ph
N
3
CO2R2
CO2R2
R1
R1
(i)
21-35
R2
Yield (%)
67
d.e. (%)
95
R1
Et
Et
β-amino ester
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
Bn
tBu
Bn
92
75
81
68
39
96
31
95
72
96
63
64
73
79
>95
>95
>95
94
91
>95
92
>95
90
>95
>95
91
n
n
-pent
-pent
Ph
tBu
Me
Bn
Ph
Ph
tBu
Bn
2-MeOC6H4
2-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-BnOC6H4
4-BnOC6H4
tBu
Bn
tBu
Me
Bn
tBu
tBu
#
>95
>95
3,4-(OCH2O)C6H3
3,4-(MeO)2C6H3
#
#
Performed in the enantiomeric series
Scheme 5. Reagents and conditions: (i) lithium (R)-N-benzyl-N-a-meth-
ylbenzylamide 3, THF, ꢀ78 ꢂC.
groups (Bn, Et, Me), conjugate addition and 1,2 addition
to the ester carbonyl can compete, resulting in a mixture
of products. For example, addition of lithium (R)-N-
benzyl-N-a-methylbenzylamide 3 to ethyl or benzyl (E)-4-
methyl-pent-2-enoate gave 56% and 38% of the required
b-amino esters 36 (95% de) and 38 (95% de), respectively,
together with 25% and 29%, respectively, of amide 37,
resulting from sequential 1,2- and then 1,4-lithium amide
addition. Addition to tert-butyl (E)-4-methyl-pent-2-eno-
ate resulted in exclusive formation of tert-butyl b-amino
ester 39, which was isolated in 91% yield and 95% de
(Scheme 6).
Ph
Ph
N
(i)
t
t
CO2 Bu
CO2 Bu
27, 16, 39
Yield (%)
R
R
Ph
Ph
Ph
d.e. (%)
>98
>98
R
Ph
Ph
N
O
Ph
Ph
(i)
Ph
N
Li
+
Ph
N
27
16
39
82
93
89
Me
CH(Me)2
CO2R
N
>98
CO2R
Scheme 7. Reagents and conditions: (i) n-BuLi (1.55 equiv), (S)-N-benzyl-
N-a-methylbenzylamine (1.6 equiv), a,b-unsaturated ester (1.0 equiv),
THF, ꢀ78 ꢂC.
R = Et, (3
R = Bn, (3
R = t
S
S
,α
,α
,α
R
R
R
)-36
)-38
)-39
37
Bu, (3
S
R
Et
Bn
tBu
β-amino ester Yield (%) β-amino amide Yield(%)
Having demonstrated the generality of this conjugate addi-
tion approach and the viability of a one-pot reaction pro-
tocol, deprotection of the N-benzyl and ester protecting
groups to the parent b-amino acids was investigated.
36
38
39
37
37
--
56
38
91
25
29
0
Scheme 6. Reagents and conditions: (i) lithium (R)-N-benzyl-N-a-meth-
ylbenzylamide 3, THF, ꢀ78 ꢂC.
2.4. Deprotection of b-amino esters
Initial investigations for deprotection of the N-benzyl and
N-a-methylbenzyl protecting groups of tertiary b-amino
esters concentrated upon the susceptibility of N-benzylic
bonds to hydrogenolysis. Treatment of b-amino ester
(3S,aR)-32 (>95% de) with Pd(OH)2 on C in MeOH/
2.3. The development of a one-pot lithium amide conjugate
addition protocol
The standard experimental protocol for this highly dia-
stereoselective conjugate addition reaction involves pre-

S. G. Davies et al. / Tetrahedron: Asymmetry 17 (2006) 1793–1811
1797
H2O/AcOH under 1 atm of H2 furnished, after treatment
with aqueous HCl, (S)-b-tyrosine methyl ester hydrochlo-
ride 41 in quantitative yield. In this debenzylation reaction,
there are four possible benzylic bonds that could be
cleaved; however, only the N-benzyl, N-a-methylbenzyl
and the O-benzyl ether are susceptible to hydrogenolysis.
This remarkable chemoselective debenzylation is proposed
to arise from the intermediacy of a hydrogen bonded inter-
mediate 40 that holds the C(3)-b-aryl group in a conforma-
tion that disfavours hydrogenolysis and cleavage of the
benzylic C(3)–N bond. The enantiomeric purity (>95%
ee) of (S)-41 was confirmed by 1H NMR spectroscopic
analysis in the presence of (S)-2,2,2-trifluoro-1-(9-
anthryl)ethanol and comparison with an authentic racemic
sample, with acidic hydrolysis yielding (S)-b-tyrosine
hydrochloride 42. Similarly, treatment of benzyl (3S,aR)-
3-(N-benzyl-N-a-methylbenzylamino)-3-(4-benzyloxyphe-
nyl)propanoate 33 (91% de) with Pd(OH)2 on C in EtOH
under 5 atm H2 gave (S)-b-tyrosine hydrochloride 42 after
treatment of the crude reaction mixture with aqueous HCl
(Scheme 8).
tert-butyl diethylphosphonoacetate) gave b-amino ester
44 in >98% de and in 90% isolated yield. N-Benzyl depro-
tection was readily achieved by hydrogenolysis, giving
b-amino ester 45 in 98% yield, with subsequent treatment
of 45 with HCl (g) for 5 min in cold Et2O affording
(R)-b-DOPAÆHCl 46 in 93% yield (Scheme 9).
Ph
Ph
N
t
t
BnO
BnO
CO2 Bu
(i)
BnO
BnO
CO2 Bu
44, 90%, >98% d.e.
43
(ii)
NH2.HCl
CO2H
NH2
t
(iii)
HO
HO
HO
HO
CO2 Bu
Ph
46, 93%
45, 98%
Ph
H
Scheme 9. Reagents and conditions: (i) lithium (S)-N-benzyl-N-a-meth-
ylbenzylamide 3, THF, ꢀ78 ꢂC; (ii) Pd(OH)2/C, H2 (1 atm), MeOH/H2O/
AcOH; (iii) HCl (g), Et2O.
Ph
N
Ph
N
O
(i)
CO2Me
OMe
BnO
BnO
Having shown that tertiary N-benzyl-N-a-methylbenzyl-
protected b-amino esters are susceptible to hydrogenolysis,
tert-butyl b-amino esters 22, 24, 27, 29, 31 and 39 were
treated with Pd/C under 6 atm of H2, either in AcOH or
MeOH, furnishing the corresponding primary b-amino
esters 47–52 in uniformly good yields. Deprotection of
the resulting b-amino tert-butyl esters by consecutive treat-
ment with TFA and 2 N HCl, followed by purification via
ion-exchange chromatography, gave the corresponding b-
amino acids 53–58 in excellent yields. Comparison of the
sign and magnitude of the specific rotations of the known
b-amino acids prepared using this protocol with the litera-
ture values allowed unambiguous assignment of their
absolute configurations. The ees of (S)-b-phenylalanine
55 (>95% ee), (S)-b-tyrosine methyl ether 56 (97% ee)
and (S)-b-(2-methoxyphenyl)-b-phenylpropionic acid 57
(>95% ee) were determined by derivatisation to the corre-
40
32
NH3Cl
CO2Me
HO
41
(ii)
Ph
Ph
N
NH3Cl
(iii)
1
sponding methyl esters and H NMR chiral shift experi-
CO2Bn
CO2H
ments with O-acetylmandelic acid and comparison with
authentic racemic samples. As the ees of b-amino acids
55–57 are equivalent to the des of the corresponding b-ami-
no esters 27, 29 and 31, this indicates that racemisation
does not occur during the deprotection procedure.
Although the ee of b-amino acids 53, 54 and 58 were not
determined, similar high levels of enantiomeric excess are
assured (Scheme 10).
BnO
HO
33
42
Scheme 8. Reagents and conditions: (i) Pd(OH)2/C, H2 (1 atm), MeOH/
H2O/AcOH then HCl (aq); (ii) HCl (aq), D; (iii) Pd(OH)2/C, H2 (5 atm),
EtOH then HCl (aq).
This methodology was next applied to the synthesis of the
hydrochloride salt of (R)-3,4-dihydroxy-b-phenylalanine
{(R)-b-DOPA} 46, a naturally occurring b-amino acid
recently isolated from Cortinarius vioalaceus.41 Conjugate
addition of lithium amide (S)-3 to tert-butyl (E)-3-(3,4-dib-
enzyloxyphenyl)prop-2-enoate 43 (prepared in 81% yield
and >98% de by Horner Wadsworth Emmons reaction of
the corresponding aldehyde and the lithium anion of
As an alternative deprotection procedure, direct global
deprotection of the benzyl b-amino esters 15, 21, 23, 28, 30
and 38 facilitated direct conversion to the corresponding b-
amino acid hydrochloride salts by hydrogenolysis followed
by treatment with aqueous HCl. Purification via ion-
exchange chromatography gave the corresponding b-amino
acids 53–54 and 56–59 with comparable spectroscopic

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S. G. Davies et al. / Tetrahedron: Asymmetry 17 (2006) 1793–1811
Ph
NH2
Ph
N
NH2
(i) or (ii)
(iii)
t
t
CO2H
CO2 Bu
CO2 Bu
R
R
R
22, 24, 27, 29, 31, 39
47-52
53-58
β-amino ester
β-amino acid
R
Et
n-pent
(i) or (ii)
(i)
(i)
(ii)
(ii)
(ii)
(ii)
Yield (%)
Yield (%)
89%
95%
96%
85%
22
24
27
29
31
39
47
48
49
50
51
52
53
54
55
56
57
58
95%
83%
84%
91%
91%
88%
Ph
2-MeOC6H4
4-MeOC6H4
iPr
96%
97%
Scheme 10. Reagents and conditions: (i) Pd/C, H2 (5 atm), MeOH; (ii) Pd/C, H2 (5 atm), AcOH; (iii) TFA, DCM (1:1) then 2 N HCl, then Dowex 50WX-
200.
properties and specific rotations to the literature. The ee of
(R)-b-amino butyric acid 59 (97% ee) was determined by
derivatisation to the methyl ester and 1H NMR chiral shift
experiments with O-acetylmandelic acid and comparison
with an authentic racemic sample (Scheme 11).
this manner, reduction of commercially available N-Boc
pyrolidinone 60 with DIBAL-H,53 subsequent Wittig
olefination54 and further N-Boc protection gave (E)-61 in
56% overall yield over three steps. Addition of 61 to lith-
ium amide (R)-3 gave a 77:23 mixture of b-amino ester
63 in >95% de55 and by-product 62, which could be sepa-
rated by exhaustive chromatography, although in practice
this crude material was immediately deprotected by trans-
fer hydrogenolysis, affording b-amino ester 64 in 51%
yield over two steps and in 96% ee.56 Subsequent treatment
of b-amino ester 64 with TFA in dichloromethane,
2.5. Application: asymmetric synthesis of (R)-b-lysine
Having demonstrated the generality of this lithium amide
methodology for the synthesis of a range of simple b-
substituted-b-amino acids, the application of this strategy
to the synthesis of (R)-b-lysine 65 was investigated. b-
Lysine is one of the most important naturally occurring
b-amino acids, the (S)-enantiomer being produced in the
anaerobic catabolism of (S)-a-lysine in Clostridia42 by the
lysine 2,3-aminomutase enzyme,43 which has been used
for the in vitro preparation of multi-gram quantities of this
enantiomer.44 Furthermore, (S)-b-lysine is a building block
in a number of natural products, including the streptothri-
cin (or racemomycin) family of antibiotics,45 lysinomicin,46
tuberactinomycins B and O,47 capreomycins 1A and 1B,48
and 3-epi-deoxynegamycin.49 Although less common, (R)-
b-lysine is a constituent of the anti-HIV agent bellen-
amine,50 with the (S)-enantiomer showing little bioactivity.
Previous synthetic strategies towards the preparation of b-
lysine include the use of Arndt–Eistert homologation from
ornithine51 and a nitrone cycloaddition.52 Our strategy cen-
tred around the incorporation of the C-6 amino group into
the a,b-unsaturated ester prior to conjugate addition. In
followed by purification by ion-exchange chromatography,
21
afforded (R)-b-lysine 65 in quantitative yield ½aꢁD ¼ ꢀ19:3
(c 0.63, 1 M HCl), lit.50 [a]D = ꢀ19.5 (c 1.0, 1 M HCl)
(Scheme 12). The asymmetric synthesis of (R)-b-lysine 65
has therefore been achieved in six steps, 29% overall yield
and in 96% ee.
In conclusion, homochiral lithium amides derived from
a-methylbenzylamine undergo diastereoselective conjugate
addition to a range of b-alkyl and b-aryl a,b-unsaturated
esters with high and predictable levels of stereoinduction.
The resulting tertiary b-amino esters are readily deprotec-
ted by N-debenzylation via hydrogenolysis and subsequent
ester hydrolysis to afford the corresponding b-amino acids
in high yields and in high ee. Furthermore, the develop-
ment of a new, simplified one-pot reaction protocol appli-
cable to the multi-gram scale synthesis of homochiral
b-amino esters has been achieved. The further application
Ph
NH3Cl
NH2
(i) or (ii)
(iii)
Ph
N
CO2H
CO2H
CO2Bn
R
R
R
15, 21, 23, 28, 30, 38
53-54, 56-59
β-amino ester
β-amino acid
R
Me
Et
Conditions
Yield (%)
68%
90%
88%
87%
15
21
23
28
30
38
59
53
54
56
57
58
(i)
(ii)
(ii)
(ii)
(ii)
(ii)
n-pent
2-MeOC6H4
4-MeOC6H4
iPr
58%
86%
Scheme 11. Reagents and conditions: (i) Pd(OH)2/C, H2 (5 atm), EtOH; (ii) Pd/C, H2 (5 atm), AcOH then 2 N HCl; (iii) Dowex 50WX-200.

S. G. Davies et al. / Tetrahedron: Asymmetry 17 (2006) 1793–1811
1799
O
plicities were assigned using a DEPT sequence. In all cases,
the reaction’s diastereoselectivity was assessed by peak
integration of the 1H NMR spectrum of the crude reaction
mixture. Infrared spectra were recorded on a Perkin–Elmer
1750 IR Fourier transform spectrophotometer using either
thin films on NaCl plates (film) or KBr discs (KBr) as sta-
ted. Only the characteristic peaks are quoted. Low resolu-
tion mass spectra (m/z) were recorded on B.G. micromass
ZAB 2F instrument, VG MassLab 20–250 or Micromass
Platform 1 spectrometers and high resolution mass spectra
(HRMS) on a Micromass Autospec 500 OAT spectrometer
or on a Waters 2790 Micromass LCT Exact Mass Electro-
spray Ionisation Mass Spectrometer. The techniques used
were chemical ionisation (CI, NH3), atmospheric pressure
chemical ionisation (APCI) or electrospray ionisation
(ESI) using partial purification by HPLC with methanol–
acetonitrile–water (40:40:20) as eluent. Specific optical
rotations were recorded on a Perkin–Elmer 241 polari-
meter with a water-jacketed 10 cm cell and are given in
units of 10ꢀ1 deg cm2 gꢀ1. Concentrations are quoted in
g/100 mL. Melting points were recorded on a Leica VMTG
Galen III apparatus and are uncorrected. Elemental analy-
ses were performed by the microanalysis services of the
Dyson Perrins Laboratory or the Inorganic Chemistry
Laboratory, Oxford.
t
(i, ii, iii)
CO2 Bu
NBoc
56%
3 steps
N(Boc)2
61
60
88%
62 : 63
77 : 23
(iv)
t
CO2 Bu
62
+
NBoc2
NH2
(v)
t
CO2 Bu
Ph
51%
2 steps
NBoc2
Ph
N
t
64, 96% ee
CO2 Bu
63
NBoc2
quant.
(vi)
NH2
CO2H
NH2
65
Scheme 12. Reagents and conditions: (i) DIBAL-H, THF ꢀ78 ꢂC; (ii)
t
Ph3P@CHCO2 Bu, toluene, 110 ꢂC; (iii) Boc2O, DMAP, MeCN; (iv)
lithium (R)-N-benzyl-N-a-methylbenzylamide 3, THF, ꢀ78 ꢂC; (v)
NH4HCO2, Pd/C, MeOH, 65 ꢂC; (vi) TFA, DCM, then Dowex 50WX-
200.
3.2. Representative procedure 1
n-Butyllithium (1.6 M, 1.55 equiv) was added dropwise to a
stirred solution of the amine (1.6 equiv) in anhydrous THF
at ꢀ78 ꢂC under nitrogen. After 30 min, a solution of the
a,b-unsaturated ester (1.0 equiv) in anhydrous THF was
added dropwise via a cannula and stirred at ꢀ78 ꢂC for
the specified time prior to the addition of saturated aque-
ous ammonium chloride and warmed to rt. The resultant
solution was partitioned between brine and 1:1 DCM/
Et2O, and the combined organic extracts were dried,
filtered and concentrated in vacuo before purification by
column chromatography.
of this methodology for complex natural product synthesis
is currently ongoing within our laboratory.
3. Experimental
3.1. General experimental
All reactions involving organometallic or other moisture
sensitive reagents were performed under an atmosphere
of nitrogen via standard vacuum line techniques. All glass-
ware was flame-dried and allowed to cool under vacuum.
THF was distilled under an atmosphere of dry nitrogen
from sodium benzophenone ketyl. Water was distilled. n-
Butyllithium was used as a solution in hexanes at the
molarity stated. All other solvents and reagents were used
as supplied (Analytical or HPLC grade), without prior
purification. The reactions were dried with MgSO4. Thin
layer chromatography (TLC) was performed on aluminium
sheets coated with 60 F254 silica. The sheets were visualised
using iodine, UV light or 1% aqueous KMnO4 solution.
Flash chromatography was performed on Kieselgel 60
silica. Nuclear magnetic resonance (NMR) spectra were
recorded on Bruker DPX 400 (1H: 400 MHz and 13C:
100.6 MHz), AMX 500 (1H: 500 MHz and 13C:
125.3 MHz), Bruker W-H 300 (1H: 300 MHz) or Varian
200 (1H: 200 MHz) spectrometers in the deuterated solvent
stated. All chemical shifts (d) are quoted in parts per mil-
lion and coupling constants (J) in Hertz. Coupling con-
stants are quoted twice, each being recorded as observed
in the spectrum without averaging. Residual signals from
the solvents were used as an internal reference. 13C multi-
3.3. Representative procedure 2
Pd/C was added to a stirred solution of conjugate addition
product in AcOH or MeOH and stirred under hydrogen
(6 atm) at rt in a Fischer–Porter bottle. After filtration
through Celiteꢁ, the residue was concentrated in vacuo, dis-
solved in DCM (200 mL), washed with 10% aqueous NaH-
CO3, dried and concentrated in vacuo before purification.
3.4. Representative procedure 3
TFA (2 mL) was added to a stirred solution of the tert-
butyl b-amino stirred for 2 h at rt. After concentration in
vacuo, treatment with 1 M HCl (5 mL) and concentration
in vacuo gave the b-amino acid hydrochloride, which was
purified by ion-exchange chromatography on Dowex
50WX200 to give the free amino acid.
3.5. Representative procedure 4
Pd/C was added to a stirred solution of the conjugate
addition product in AcOH or EtOH and stirred under

1800
S. G. Davies et al. / Tetrahedron: Asymmetry 17 (2006) 1793–1811
hydrogen (6 atm) at rt in a Fischer–Porter bottle. After fil-
tration through Celiteꢁ, the residue was concentrated in va-
cuo, dissolved in 2 M HCl, washed (Et2O) and concentrated
in vacuo before purification via ion-exchange chromatogra-
phy on Dowex 50WX200 to give the free amino acid.
3.9. Preparation of benzyl (3R,aR)-3-(N-3,4-dimethoxyben-
zyl-N-a-methylbenzylamino)butanoate 9
Following representative procedure 1, n-BuLi (1.6 M,
1.1 mL, 1.8 mmol), (R)-N-3,4-dimethoxybenzyl-N-a-methyl-
benzylamine (487 mg, 1.8 mmol) in THF (10 mL) and
benzyl crotonate (200 mg, 1.1 mmol) in THF (5 mL)
gave, after column chromatography on silica gel (petrol
40–60/Et2O 2:1), 9 (378 mg, 74%) as a colourless oil:
3.6. Preparation of methyl (3R,aR)- and methyl (3S,aR)-3-
(N-a-methylbenzylamino)butanoate 6
A solution of (R)-a-methylbenzylamine (2.42 g, 20 mmol)
and methyl crotonate (2.0 g, 20 mmol) in EtOH (100 mL)
was heated at reflux for 18 h before concentration in vacuo.
Purification via column chromatography on silica gel
(Et2O) gave 6 (1.56 g, 35%) as a 48:52 mixture of diastereo-
isomers: dH (200 MHz, CDCl3) 1.06 and 1.08 (2 · 3H, d, J
6.4, C(4)H3), 1.34 (2 · 3H, d, J 5.9, C(a)Me), 2.25–2.53
(2 · 2H, m, C(2)H2), 2.90 and 3.00 (2 · 1H, m, C(3)H),
3.65, 3.68 (2 · 3H, s, CO2Me), 3.88 and 3.93 (2 · 1H, q, J
5.9, C(a)H), 7.20–7.28 (2 · 5H, m, Ph).26
C28H33NO4 requires C, 75.1; H, 7.4; N, 3.1%, found: C,
75.4; H, 7.7; N, 3.0%; ½aꢁD ¼ þ13:3 (c 1.3, CH2Cl2); dH
20
(300 MHz, CDCl3) 1.15 (3H, d, J 6.7, C(4)H3), 1.37 (3H,
d, J 6.9, C(a)Me), 2.19 (1H, dd, J2A,2B 14.2, J2A,3 7.7,
C(2)HAHB), 2.42 (1H, dd, J2B,2A 14.2, J2B,3 6.3,
C(2)HAHB), 3.52 (1H, m, C(3)H), 3.66 (2H, app s,
NCH2), 3.87 and 3.89 (2 · 3H, s, OMe), 3.89 (1H, q,
J 6.9, C(a)H), 4.83 (1H, ABq, J 12.4, OCHAHB), 5.02
(1H, ABq, J 12.4, OCHAHB), 6.76–7.01 (3H, m, Ph),
7.19–7.37 (5H, m, Ph); dC (50 MHz, CDCl3) 17.1, 18.4,
40.1, 49.1, 49.9, 57.3, 65.9, 110.7, 111.6, 120.3, 126.8,
127.9, 128.1, 128.2, 128.4, 128.6, 134.3, 144.5, 147.9,
149.1, 172.3; m/z (CI+) 448 (MH+, 60%); mmax/cmꢀ1 (film)
2985, 2830 (C–H), 1725 (C@O).
3.7. Preparation of methyl (3R,aR)- and methyl (3S,aR)-3-
(N-a-methylbenzylamino)butanoate 6 and (R)-N-(a-methyl-
benzyl)crotonamide 7
Following representative procedure 1, n-BuLi (1.6 M,
19.4 mL, 31 mmol), (R)-a-methylbenzylamine (3.78 g,
32 mmol) in THF (100 mL) and methyl crotonate (2.0 g,
20 mmol) in THF (30 mL) gave, after 30 min, and subse-
3.10. Preparation of tert-butyl (3R,aR)-3-(N-3,4-dimeth-
oxybenzyl-N-a-methylbenzylamino)butanoate 10
Following representative procedure 1, n-BuLi (1.4 M,
1.5 mL, 2.15 mmol), (R)-N-3,4-dimethoxybenzyl-N-a-meth-
ylbenzylamine (602 mg, 2.23 mmol) in THF (10 mL) and
tert-butyl crotonate (200 mg, 1.39 mmol) in THF (5 mL)
gave, after column chromatography on silica gel (petrol
40–60/Et2O 1:1), 10 (478 mg, 83%) as a colourless oil:
quent recrystallisation (hexane/Et2O 3:1), 7 (1.32 g, 35%)
25
as white needles: ½aꢁD ¼ þ155:0 (c 1.7, CHCl3), lit.57 (ent)
[a]D = ꢀ121.4 (c 1.8, CHCl3); dH (200 MHz, CDCl3) 1.52
(3H, d, J 7.0, C(a)Me), 1.84 (3H, dd, J4,3 6.9, J4,2 1.6,
C(4)H3), 5.21 (1H, app quin, J 7.3, C(a)H), 5.66 (1H, br
s, NH), 5.80 (1H, dd, J2,3 15.1, J2,4 1.6, C(2)H), 6.87 (1H,
dq, J3,2 15.1, J3,4 6.9, C(3)H), 7.21–7.39 (5H, m, Ph). The
mother liquor was concentrated and purified by chromato-
graphy on silica gel (Et2O) to give an inseparable 1:1 mix-
ture of (3R,aR)- and (3S,aR)-6 as a colourless oil (1.23 g,
28%) with identical spectroscopic properties to those previ-
ously reported.
C25H35NO4 requires C, 72.6; H, 8.5; N, 3.9%, found C,
20
72.8; H, 8.8; N, 3.7%; ½aꢁD ¼ þ2:3 (c 1.7, CH2Cl2); dH
(300 MHz, CDCl3) 1.13 (3H, d, J 6.8, C(a)Me), 1.37 (3H,
d, J 7.1, C(4)H3), 1.39 (9H, s, OtBu), 2.04 (1H, dd, J2A,2B
14.1, J2A,3 9.1, C(2)HAHB), 2.42 (1H, dd, J2B,2A 14.1,
J2B,3 4.7, C(2)HAHB), 3.42–3.51 (1H, m, C(3)H), 3.57
(1H, ABq, J 14.8, NCHAHB), 3.70 (1H, ABq, J 14.8,
NCHAHB), 3.89 and 3.90 (2 · 3H, s, OMe), 3.92 (1H, q,
J 6.8, C(a)H), 6.79–6.96 (3H, m, Ph), 7.22–7.39 (5H, m,
Ph); dC (50 MHz, CDCl3) 18.2, 18.6, 27.9, 40.7, 49.3,
50.1, 55.7, 55.8, 58.1, 80.1, 110.8, 111.1, 120.3, 126.8,
127.8, 128.2, 134.8, 144.6, 147.9, 149.0, 172.2; m/z (CI+)
414 (MH+, 57%); mmax/cmꢀ1 (film) 2970, 2930 (C–H),
1725 (C@O).
3.8. Preparation of methyl (3R,aR)-3-(N-3,4-dimethoxy-
benzyl-N-a-methylbenzylamino)butanoate 8
Following representative procedure 1, n-BuLi (1.6 M, 10.7
mL, 17.0 mmol), (R)-N-3,4-dimethoxybenzyl-N-a-methyl-
benzylamine (4.7 g, 17.6 mmol) in THF (20 mL) and methyl
crotonate (1.1 g, 11.0 mmol) in THF (20 mL) gave, after
column chromatography on silica gel (petrol 40–60/Et2O
2:1), 8 (2.8 g, 68%) as a colourless oil: C22H29NO4 requires
3.11. Preparation of tert-butyl (aR,3S)- and tert-butyl
(aR,3R)-3-[N-(2-methoxybenzyl)-N-(a-methylbenzyl)-
amino]-3-phenyl-propionate 11
C, 71.1; H, 7.9; N, 3.8%, found C, 71.4; H, 8.15; N, 3.7%;
20
½aꢁD ¼ ꢀ5:2 (c 1.1, CH2Cl2); dH (500 MHz, CDCl3) 1.16
(3H, d, J 6.6, C(4)H3), 1.38 (3H, d, J 6.8, C(a)Me), 2.14
(1H, dd, J2A,2B 14.4, J2A,3 7.2, C(2)HAHB), 2.40 (1H, dd,
J2B,2A 14.4, J2B,3 7.2, C(2)HAHB), 3.42–3.52 (1H, m,
C(3)H), 3.44 (3H, s, CO2Me), 3.49 (2H, ABq, NCH2),
3.88 and 3.91 (2 · 3H, s, OMe), 3.83–3.96 (1H, m,
C(a)H), 6.78–7.03 (3H, m, Ph), 7.20–7.31 (5H, m, Ph); dC
(50 MHz, CDCl3) 16.4, 18.2, 40.3, 49.0, 49.6, 51.3, 56.9,
110.6, 111.7, 120.4, 126.7, 128.0, 134.2, 144.5, 147.9,
149.1, 172.9; m/z (CI+) 372 (MH+, 35%); mmax/cmꢀ1 (film)
2970, 2830 (C–H), 1735 (C@O).
Following representative procedure 1, n-BuLi (0.31 mL,
0.76 mmol),
(R)-N-2-methoxybenzyl-N-a-methylbenzyl-
amine (189 mg, 0.79 mmol) in THF (10 mL) and tert-butyl
cinnamate (100 mg, 0.49 mmol) in THF (5 mL) gave, after
column chromatography on silica gel (pentane/Et2O
100:1), an inseparable 50:50 mixture of tert-butyl
(aR,3S)- and tert-butyl (aR,3R)-3-N-(2-methoxybenzyl)-
N-a-methylbenzylamino-3-phenylpropanoate 11 (13 mg,
6%); dH (400 MHz, CDCl3) 1.20 (9H, s, OtBu), 1.22 (9H,
s, OtBu), 1.27 (3H, d, J 6.9, C(a)Me), 1.28 (3H, d, J 6.8,

S. G. Davies et al. / Tetrahedron: Asymmetry 17 (2006) 1793–1811
1801
C(a)Me), 2.49–2.60 (2H, m, C(2)H2), 2.68 (1H, dd, J 14.6,
J 10.5, C(2)HAHB), 2.87 (1H, dd, J 14.4, J 5.0, C(2)HAHB),
3.57 (1H, ABq, J 16.2, NCHAHB), 3.73 (2H, app s, NCH2),
3.78 (3H, s, OMe), 3.80 (3H, s, OMe), 3.91 (1H, q, J 6.8,
C(a)H), 3.95–3.99 (1H, obsc q, C(a)H), 4.02 (1H, ABq, J
16.1, NCHAHB), 4.32–4.37 (2H, m, 2 · C(3)H), 6.78 (1H,
dd, J 8.3, J 1.0, Ar), 6.81 (1H, dd, J 8.4, J 1.0, Ar), 6.89
(1H, app td, J 7.6, J 1.1, Ar), 6.97 (1H, app td, J 7.7, J
1.0, Ar), 7.12–7.36 (19H, m, Ph, Ar), 7.43–7.48 (4H, m,
Ph, Ar), 7.65 (1H, app dd, J 7.6, J 1.8, Ar); dC
(100 MHz, CDCl3) 15.9, 19.6, 22.8, 38.4, 39.4, 43.2, 43.7,
55.1, 57.6, 58.6, 60.1, 60.6, 80.0, 80.1, 109.7, 120.3, 126.6,
126.7, 126.9, 127.0, 127.1, 127.8, 127.9, 128.0, 128.4,
128.6, 129.5, 129.6, 129.9, 130.5, 144.4, 144.7, 156.6,
171.1, 171.3; m/z (ESI+) 446 (100%, MH+); HRMS
C29H36NO3 (MH+) requires 446.2695, found 446.2696;
C(a)H), 2.19 (1H, dd, J2A,2B 14.2, J2A,3 7.8, C(2)HAHB),
2.46 (1H, dd, J2B,2A 14.2, J2B,3 6.3, C(2)HAHB), 3.47–3.59
(1H, m, C(3)H), 3.57 (3H, s, CO2Me), 3.78 (2H, ABq,
NCH2), 3.97 (1H, q, J 6.9, C(a)H), 7.25–7.50 (10H, m,
Ph); dC (50 MHz, CDCl3) 17.5, 18.6, 39.7, 49.6, 49.9,
51.4, 57.6, 126.7, 127.1, 127.8, 128.1, 128.4, 128.8, 141.7,
144.3, 172.7; m/z (CI+) 312 (MH+, 100%); mmax/cmꢀ1 (film)
2970 (C–H), 1735 (C@O).
3.14. Preparation of benzyl (3R,aR)-3-(N-benzyl-N-a-
methylbenzylamino)butanoate 15
Following representative procedure 1, n-BuLi (1.6 M,
4.4 mL, 7.0 mmol), (R)-N-benzyl-N-a-methylbenzylamine
(1.53 g, 7.2 mmol) in THF (10 mL) and benzyl crotonate
(792 mg, 4.5 mmol) in THF (5 mL) gave, after column
chromatography on silica gel (petrol 40–60/Et2O 7:3), 15
(1.55g, 88%) as a colourless oil: C26H29NO2 requires C,
m
max/cmꢀ1 (film) 160 (C@C), 1726 (C@O).
3.12. Preparation of tert-butyl (aR,3S)- and tert-butyl
(aR,3R)-3-N-(2,4-dimethoxybenzyl)-N-a-methylbenzyl-
amino-3-phenylpropanoate 12
80.6; H, 7.5; N, 3.6%, found C, 80.8; H, 7.9; N, 3.7%;
20
½aꢁD ¼ þ12:0 (c 1.2 in CH2Cl2); dH (300 MHz) 1.16 (3H,
d, J 6.7, C(4)H3), 1.36 (3H, d, J 6.8, C(a)Me), 2.19 (1H,
dd, J2A,2B 14.2, J2A,3 8.0, C(2)HAHB), 2.42 (1H, dd,
J2B,2A 14.2, J2B,3 5.8, C(2)HAHB), 3.47–3.52 (1H, m,
C(3)H), 3.68 (1H, ABq, J 14.8, NCHAHB), 3.84 (1H,
ABq, J 14.8, NCHAHB), 3.91 (1H, q, J 6.8, C(a)H), 4.93
(1H, ABq, J 12.4, OCHAHB), 5.05 (1H, ABq, J 12.4,
OCHAHB), 7.16–7.47 (15H, m, Ph); dC (50 MHz, CDCl3)
17.8, 18.5, 39.6, 49.6, 50.0, 57.8, 66.0, 126.8, 127.1,
127.9, 128.2, 128.3, 128.5, 128.6, 136.2, 141.9, 144.4,
172.5; m/z (CI+) 388 (MH+, 37%); mmax/cmꢀ1 (film) 3015,
2970 (C–H), 1735 (C@O).
Following representative procedure 1, n-BuLi (0.31 mL,
0.76 mmol), (R)-N-2,4-dimethoxybenzyl-N-a-methylbenz-
ylamine (213 mg, 0.79 mmol) in THF (10 mL) and tert-
butyl cinnamate (100 mg, 0.49 mmol) in THF (5 mL) gave,
after column chromatography on silica gel (pentane/Et2O
100:1), an inseparable 50:50 mixture of tert-butyl
(aR,3S)- and tert-butyl (aR,3R)-3-N-(2,4-dimethoxy-
benzyl)-N-a-methylbenzylamino-3-phenylpropanoate 12
(38 mg, 16%): dH (400 MHz, CDCl3) 1.21 (3H, s, OtBu),
1.24 (3H, s, OtBu), 1.26 (3H, d, J 6.9, C(a)Me), 1.31 (3H,
d, J 6.8, C(a)Me), 2.48–2.59 (2H, m, C(2)H2), 2.71 (1H,
dd, J 14.3, J 10.3, C(2)HAHB), 2.89 (1H, dd, J 14.5, J
4.7, C(2)HAHB), 3.49 (1H, ABq, J 15.7, NCHAHB), 3.66
(2H, app d, J 2.6, NCH2), 3.75 (3H, s, OMe), 3.78 (3H,
s, OMe), 3.79 (3H, s, OMe), 3.82 (3H, s, OMe), 3.89–4.00
(3H, m, CHAHBNC(a)H, NC(a)H), 4.31–4.37 (2H, m,
2 · C(3)H), 6.39 (2H, app dd, J 9.8, J 2.7, Ar), 6.44 (1H,
app dd, J 8.3, J 2.4, Ar), 6.51 (1H, app dd, J 8.4, J 2.7,
Ar), 7.20–7.48 (22H, m, Ph, Ar); dC (100 MHz, CDCl3)
15.9, 19.0, 27.8, 38.4, 39.0, 42.8, 43.3, 55.1, 55.2, 55.3,
55.3, 57.3, 58.0, 59.8, 60.3, 79.9, 80.0, 97.8, 104.0, 122.1,
122.6, 126.5, 126.6, 126.8, 126.9, 127.8, 127.9, 127.9,
128.0, 128.3, 128.6, 130.1, 130.3, 141.0, 142.2, 144.6,
144.8, 157.5, 157.7, 159.2, 159.3, 171.2, 171.3; m/z (ESI+)
476 [100%, MH+]; HRMS C30H38NO4 (MH+) requires
476.2801, found 476.2802; mmax/cmꢀ1 (film) 1588 (C@C),
1613 (C@C), 1726 (C@O).
3.15. Preparation of tert-butyl (3R,aR)-3-(N-benzyl-N-a-
methylbenzylamino)butanoate 16
Following representative procedure 1, n-BuLi (1.6 M,
1.35 mL, 2.15 mmol), (R)-N-benzyl-N-a-methylbenzyl-
amine (472 mg, 2.2 mmol) in THF (10 mL) and tert-butyl
crotonate (200 mg, 1.39 mmol) in THF (5 mL) gave, after
column chromatography on silica gel (petrol 40–60/Et2O
7:3), 16 (403 mg, 82%) as a colourless oil: C23H31NO2
requires C, 78.15; H, 8.8; N, 4.0%, found C, 78.3; H, 8.9;
20
N, 3.8%; ½aꢁD ¼ ꢀ3:7 (c 1.1, CH2Cl2); dH (500 MHz,
CDCl3) 1.12 (3H, d, J 6.3, C(4)H3), 1.36 (3H, d, J 6.8,
C(a)Me), 1.40 (9H, s, OtBu), 2.02 (1H, dd, J2A,2B 14.3,
J2A,3 8.2, C(2)HAHB), 2.42 (1H, dd, J2B,2A 14.3, J2B,3 5.1,
C(2)HAHB), 3.33–3.53 (1H, m, C(3)H), 3.62 (1H, ABq, J
16.0, NCHAHB), 3.78 (1H, ABq, J 16.0, NCHAHB), 3.91
(1H, q, J 6.8, C(a)H), 7.16–7.48 (10H, m, Ph); dC
(50 MHz, CDCl3) 18.3, 19.0, 27.9, 40.4, 49.7, 50.3, 58.5,
79.9, 126.6, 126.8, 127.1, 127.9, 128.3, 142.3, 144.5, 172.2;
m/z (CI+) 354 (MH+, 100%); mmax/cmꢀ1 (film) 2970 (C–
H), 1720 (C@O).
3.13. Preparation of methyl (3R,aR)-3-(N-benzyl-N-a-
methylbenzylamino)butanoate 14
Following representative procedure 1, n-BuLi (1.4 M,
2.2 mL, 3.1 mmol), (R)-N-benzyl-N-a-methylbenzylamine
(678 mg, 3.2 mmol) in THF (10 mL) and methyl crotonate
(200 mg, 2.0 mmol) in THF (5 mL) gave, after column
chromatography on silica gel (petrol 40–60/Et2O 4:1), 14
(527 mg, 85%) as a colourless oil: C20H26NClO2 (14ÆHCl)
3.16. One-pot reaction protocol for the preparation of tert-
butyl (3S,aS)-3-(N-benzyl-N-a-methylbenzylamino)butano-
ate 16
n-BuLi (2.5 M, 31.5 mL, 78.7 mmol) at ꢀ78 ꢂC was added
dropwise to a stirred solution of (S)-N-benzyl-N-a-methyl-
benzylamine (17.14 g, 17.0 mL, 81.2 mmol) and tert-butyl
crotonate (7.21 g, 50.8 mmol) in anhydrous THF
requires C, 69.05; H, 7.5; N, 4.0%, found C, 69.1; H, 7.9;
20
N, 4.2%; ½aꢁD ¼ ꢀ3:4 (c 1.2, CH2Cl2); dH (300 MHz,
CDCl3) 1.21 (3H, d, J 6.7, C(4)H3), 1.36 (3H, d, J 6.9,

1802
S. G. Davies et al. / Tetrahedron: Asymmetry 17 (2006) 1793–1811
(100 mL) at ꢀ78 ꢂC under nitrogen and stirred for 2 h prior
to the addition of saturated aqueous ammonium chloride
(10 mL) and warmed to rt. The resultant solution was
partitioned between brine and DCM (3 · 100 mL), and
the combined organic extracts were concentrated in vacuo.
The residue was re-dissolved in DCM (200 mL), washed
successively with 10% aqueous citric acid solution
(2 · 100 mL), saturated aqueous NaHCO3 (100 mL) and
brine (100 mL), dried and concentrated in vacuo before
purification by column chromatography on silica gel
found C, 78.35; H, 9.3; N, 3.8%; dH (300 MHz, CDCl3)
1.27 (3H, d, J 6.8, C(4)H3), 1.35 (9H, s, OtBu), 1.53 (6H,
d, J 6.4, C(a)Me), 1.97–2.21 (2H, m, C(2)H2), 3.40–3.58
(1H, m, C(3)H), 4.17 (2H, q, J 6.8, C(a)H), 7.14–7.28
(10H, m, Ph); dC (50 MHz, CDCl3) 19.1, 20.4, 27.9, 43.9,
48.1, 53.9, 79.7, 126.4, 127.9, 128.0, 128.2, 128.4, 145.6,
171.9; m/z (CI+) 368 (MH+, 78%); mmax/cmꢀ1 (film) 2970
(C–H), 1725 (C@O).
3.20. Preparation of benzyl (3R,aR)-3-(N-benzyl-N-a-
methylbenzylamino)pentanoate 21
(Et2O/pentane 1:20) to give 16 (16.7 g, 93%) as a colourless
24
oil ½aꢁD ¼ þ3:6 (c 0.8, CHCl3) with spectroscopic proper-
ties consistent with those reported above.
Following representative procedure 1, n-BuLi (1.6 M,
9.1 mL, 14.6 mmol), (R)-N-benzyl-N-a-methylbenzylamine
(3.2 g, 15.0 mmol) in THF (25 mL) and benzyl (E)-2-pent-
enoate (1.8 g, 9.4 mmol) in THF (25 mL) gave, after col-
umn chromatography on silica gel (petrol 40–60/Et2O
1:1), 21 (2.53 g, 67%) as a colourless oil: C27H31NO2
3.17. Preparation of methyl (3R,aR,a0R)-3-(N,N-bis-
(a-methylbenzyl)amino)butanoate 18
Following representative procedure 1, n-BuLi (1.6 M,
2.6 mL, 4.1 mmol), (R,R)-N,N-bis-(a-methylbenzyl)amine
(954 mg, 4.2 mmol) in THF (5 mL) and methyl crotonate
(265 mg, 2.7 mmol) in THF (5 mL) gave, after column chro-
requires C, 80.8; H, 7.8; N, 3.5%, found C, 80.5; H, 7.8;
20
N, 3.3%; ½aꢁD ¼ þ23:6 (c 1.1, CHCl3); dH (500 MHz,
CDCl3) 1.01 (3H, t, J 7.3, C(5)H3), 1.37 (3H, d, J 7.0,
C(a)Me), 1.34–1.40 (1H, m, C(4)HAHB), 1.51–1.58 (1H,
m, C(4)HAHB), 2.08–2.10 (2H, m, C(2)H2), 3.28–3.33
(1H, m, C(3)H), 3.57 (1H, ABq, J 14.8, NCHAHB), 3.81
(1H, ABq, J 14.8, NCHAHB), 3.87 (1H, q, J 7.0, C(a)H),
4.91 (1H, ABq, J 12.3, OCHAHB), 5.08 (1H, ABq, J 12.3,
OCHAHB), 7.20–7.46 (15H, m, Ph); dC (50 MHz, CDCl3)
11.8, 19.6, 26.3, 36.6, 50.0, 55.7, 57.7, 66.1, 126.9, 127.2,
128.1, 128.4, 128.5, 128.7, 141.9, 143.2, 173.1; m/z (CI+)
402 (MH+, 100%); mmax/cmꢀ1 (film) 3062, 3029 (C–H),
1733 (C@O).
matography on silica gel (petrol 40–60/Et2O 4:1), 18
20
(492 mg, 57%) as a pale yellow oil: ½aꢁD ¼ ꢀ7:6 (c 1.1,
CH2Cl2); C21H27NO2 requires C, 77.5; H, 8.4; N, 4.3%,
found C, 77.3; H, 8.5; N, 4.2%; dH (500 MHz, CDCl3)
1.28 (3H, d, J 6.8, C(4)H3), 1.54 (6H, d, J 7.0, C(a)Me),
2.10–2.26 (2H, m, C(2)H2), 3.40 (3H, s, CO2Me), 3.42–
3.50 (1H, m, C(3)H), 4.19 (2H, q, J 7.0, C(a)H), 7.14–7.30
(10H, m, Ph); dC (50 MHz, CDCl3) 18.8, 20.9, 42.3, 48.3,
51.1, 53.6, 126.5, 127.0, 128.0, 145.5, 172.8; m/z (CI+) 326
(MH+, 100%); mmax/cmꢀ1 (film) 2970 (C–H), 1735 (C@O).
3.18. Preparation of benzyl (3R,aR,a0R)-3-(N,N-bis-
(a-methylbenzyl)amino)butanoate 19
3.21. Preparation of tert-butyl (3R,aR)-3-(N-benzyl-N-a-
methylbenzylamino)pentanoate 22
Following representative procedure 1, n-BuLi (1.6 M,
1.9 mL, 3.1 mmol), (R,R)-N,N-bis-(a-methylbenzyl)amine
(709 mg, 3.2 mmol) in THF (5 mL) and benzyl crotonate
(347 mg, 2.0 mmol) in THF (5 mL) gave, after column
Following representative procedure 1, n-BuLi (1.6 M,
1.3 mL, 2.1 mmol), (R)-N-benzyl-N-a-methylbenzylamine
(500 mg, 2.4 mmol) in THF (25 mL) and tert-butyl (E)-
pent-2-enoate (210 mg, 1.34 mmol) in THF (25 mL) gave,
after column chromatography on silica gel (petrol 40–60/
chromatography on silica gel (petrol 40–60/Et2O 4:1), 19
20
(180 mg, 23%) as a pale yellow oil; ½aꢁD ¼ þ9:6 (c 1.1,
Et2O 9:1), 22 (456 mg, 92%) as a colourless oil:
CH2Cl2); C27H31NO2 requires C, 80.8; H 7.8; N, 3.5%,
found C, 80.6; H, 7.7; N, 3.6%; dH (500 MHz, CDCl3)
1.28 (3H, d, J 6.8, C(4)H3), 1.54 (6H, d, J 7.0, C(a)Me),
2.18–2.27 (2H, m, C(2)H2), 3.47–3.52 (1H, m, C(3)H),
4.19 (2H, q, J 7.0, C(a)H), 4.86 (1H, ABq, J 11.5,
OCHAHBPh), 4.90 (1H, ABq, J 11.5, OCHAHBPh), 7.14–
7.42 (15H, m, Ph); dC (50 MHz, CDCl3) 18.9, 20.9, 42.6,
48.3, 53.9, 65.8, 126.5, 128.0, 128.2, 128.4, 128.6, 136.3,
145.5, 172.2; m/z (CI+) 402 (MH+, 100%); mmax/cmꢀ1 (film)
1730 (C@O).
C24H33NO2 requires C, 78.4; H, 9.05; N, 3.8%, found C,
20
78.3; H, 9.3; N, 3.55%; ½aꢁD ¼ þ22:4 (c 1.1, CHCl3); dH
(500 MHz, CDCl3) 1.04 (3H, t, J 7.3, C(5)H3), 1.38 (3H,
d, J 7.0, C(a)Me), 1.43 (9H, s, OtBu), 1.36–1.53 (2H, m,
C(4)H2), 1.88–1.96 (2H, m, C(2)H2), 3.28 (1H, m,
C(3)H), 3.53 (1H, ABq, J 14.9, NCHAHB), 3.81 (1H,
ABq, J 14.9, NCHAHB), 3.86 (1H, q, J 7.0, C(a)H),
7.24–7.47 (10H, m, Ph); dC (50 MHz, CDCl3) 11.9, 20.2,
26.3, 28.0, 37.7, 50.1, 55.5, 58.0, 79.9, 126.8, 127.1, 128.2,
128.3, 128.4, 142.1, 143.2, 172.6; m/z (CI+) 367 (MH+,
100%); mmax/cmꢀ1 (film) 3062, 3027 (C–H), 1728 (C@O).
3.19. Preparation of tert-butyl (3R,aR,a0R)-3-(N,N-bis-
(a-methylbenzyl)amino)butanoate 20
3.22. Preparation of benzyl (3R,aR)-3-(N-benzyl-N-a-
methylbenzylamino)octanoate 23
Following representative procedure 1, n-BuLi (1.6 M,
1.0 mL, 1.64 mmol), (R,R)-N,N-bis-(a-methylbenzyl)amine
(382 mg, 1.70 mmol) in THF (5 mL) and tert-butyl croto-
nate (150 mg, 1.1 mmol) in THF (5 mL) gave, after column
Following representative procedure 1, n-BuLi (1.6 M,
6.49 mL, 10.4 mmol), (R)-N-benzyl-N-a-methylbenzyl-
amine (2.27 g, 10.7 mmol) in THF (15 mL) and benzyl
(E)-oct-2-enoate (1.56 g, 6.7 mmol) in THF (20 mL) gave,
after column chromatography on silica gel (petrol 40–60/
chromatography on silica gel (petrol 40–60/Et2O 4:1), 20
20
(234 mg, 60%) as a colourless oil: ½aꢁD ¼ þ2:6 (c 1.2,
CH2Cl2); C24H33NO2 requires C, 78.4; H, 9.05; N, 3.8%,
Et2O 4:1), 23 (2.22 g, 75%) as a colourless oil:

S. G. Davies et al. / Tetrahedron: Asymmetry 17 (2006) 1793–1811
1803
20
½aꢁD ¼ þ11:9 (c 1.6, CHCl3); C30H37NO2 requires C, 81.2;
3.25. Preparation of benzyl (3S,aR)-3-(N-benzyl-N-a-meth-
ylbenzylamino)-3-phenylpropanoate 26
H, 8.4; N, 3.2%, found C, 81.1; H, 8.4, N, 3.0%; dH
(500 MHz, CDCl3) 0.90 (3H, t, J 7.3, C(8)H3), 1.16–1.38
(6H, m, CH3C(7)H2C(6)H2C(5)H2), 1.35 (3H, d, J 7.0,
C(a)Me), 1.49–1.59 (2H, m, C(4)H2), 2.08 (1H, dd, J2A,2B
14.5, J2A,3 8.5, C(2)HAHB), 1.98 (1H, dd, J2B,2A 14.5,
J2B,3 4.3, C(2)HAHB), 3.33–3.39 (1H, m, C(3)H), 3.56
(1H, ABq, J 14.9, NCHAHB), 3.82 (1H, ABq, J 14.9,
NCHAHB), 3.86 (1H, q, J 7.0, C(a)H), 4.98 (1H, ABq, J
12.3, OCHAHB), 5.07 (1H, ABq, J 12.3, OCHAHB), 7.20–
7.45 (15H, m, Ph); dC (50 MHz) 14.0, 19.7, 22.6, 26.6,
31.7, 33.5, 36.8, 50.0, 54.1, 58.0, 66.1, 126.9, 127.1, 128.2,
128.4, 128.5, 128.7, 136.4, 142.1, 143,4, 173.1; m/z (CI+)
444 (MH+, 90%); mmax/cmꢀ1 (film) 3063, 3030 (C–H),
1733 (C@O), 1146 (C–O).
Following representative procedure 1, n-BuLi (1.6 M,
1.2 mL, 1.95 mmol), (R)-N-benzyl-N-a-methylbenzylamine
(427 mg, 2.0 mmol) in THF (10 mL) and benzyl cinnamate
(300 mg, 1.26 mmol) in THF (5 mL) gave, after column
chromatography on silica gel (petrol 40–60/Et2O 4:1), 26
20
(221 mg, 39%) as a colourless oil: ½aꢁD ¼ þ3:8 (c 1.0,
CH2Cl2); C31H32NClO2 (26ÆHCl) requires C, 76.6; H, 6.6;
N, 2.9%, found C, 76.3; H, 6.9; N, 2.8%; dH (300 MHz,
CDCl3) 1.23 (3H, d, J 6.8, C(a)Me), 2.62 (1H, dd, J2A,2B
14.9, J2A,3 9.1, C(2)HAHB), 2.68 (1H, dd, J2B,2A 14.9,
J2B,3 5.8, C(2)HAHB), 3.68 (2H, ABq, NCH2), 3.99 (1H,
q, J 6.8, C(a)H), 4.48 (1H, dd, J3,2A 9.1, J3,2B 5.8,
C(3)H), 4.90 (2H, s, OCH2), 7.08–7.42 (20H, m, Ph); dC
(50 MHz, CDCl3) 15.9, 37.4, 50.7, 56.8, 59.4, 66.1, 126.8,
127.0, 127.4, 128.0, 128.2, 128.5, 128.6, 128.8, 136.0,
141.6, 141.8, 144.2, 171.9; m/z (CI+) 450 (MH+, 71%);
3.23. Preparation of tert-butyl (3R,aR)-3-(N-benzyl-N-a-
methylbenzylamino)octanoate 24
Following representative procedure 1, n-BuLi (1.6 M,
1.5 mL, 2.3 mmol), (R)-N-benzyl-N-a-methylbenzylamine
(509 mg, 2.4 mmol) in THF (25 mL) and tert-butyl (E)-
oct-2-enoate (300 mg, 1.51 mmol) in THF (25 mL) gave,
after column chromatography on silica gel (petrol 40–60/
m
max/cmꢀ1 (film) 3030, 2920 (C–H), 1710 (C@O).
3.26. Preparation of tert-butyl (3S,aR)-3-(N-benzyl-N-a-
methylbenzylamino)-3-phenylpropanoate 27
Et2O 9:1), 24 (501 mg, 81%) as
a colourless oil:
Following representative procedure 1, n-BuLi (1.6 M,
5.7 mL, 9.1 mmol), (R)-N-benzyl-N-a-methylbenzylamine
(2.0 g, 9.5 mmol) in THF (10 mL) and tert-butyl cinnamate
(1.21 g, 5.9 mmol) in THF (10 mL) gave, after column
20
½aꢁD ¼ þ7:6 (c 1.4, CHCl3); C27H39NO2 requires C, 79.2;
H, 9.6; N, 3.4%, found: C, 79.1; H, 9.9; N, 3.3%; dH
(500 MHz, CDCl3) 0.90 (3H, t, J 7.2, C(8)H3), 1.15–1.60
(8H, m, CH3C(7)H2C(6)H2C(5)H2C(4)H2), 1.34 (3H, d, J
7.0, C(a)Me), 1.41 (9H, s, OtBu), 1.99 (1H, dd, J2A,2B
14.5, J2A,3 9.4, C(2)HAHB), 1.98 (1H, dd, J2B,2A 14.5,
J2B,3 3.5, C(2)HAHB), 3.28–3.33 (1H, m, C(3)H), 3.50
(1H, ABq, J 15.0, NCHAHB), 3.81 (1H, ABq, J 15.0,
NCHAHB), 3.83 (1H, q, J 7.0, C(a)H), 7.22–7.42 (10H,
m, Ph); dC (50 MHz, CDCl3) 13.9, 20.3, 22.5, 26.4, 27.9,
31.7, 33.3, 37.7, 50.0, 53.8, 58.3, 79.9, 126.6, 127.0, 127.1,
128.0, 128.3, 142.3, 143.3, 172.5; m/z (CI+) 409 (MH+,
100%); mmax/cmꢀ1 (film) 3062, 3027 (C–H), 1728 (C@O),
1147 (C–O).
chromatography on silica gel (petrol 40–60/Et2O 4:1), 27
20
(2.37 g, 96%) as a colourless oil: ½aꢁD ¼ þ3:9 (c 0.7,
CHCl3); C28H33NO2 requires C, 80.9; H, 8.0; N, 3.4%,
found: C, 80.6; H, 7.8; N, 3.2%; dH (500 MHz, CDCl3)
1.24 (9H, s, OtBu), 1.29 (3H, d, J 6.8, C(a)Me), 2.45–2.60
(2H, m, C(2)H2), 3.71 (2H, ABq, NCH2), 4.03 (1H, q, J
6.8, C(a)H), 4.43 (1H, dd, J3,2A 9.9, J3,2B 5.2, C(3)H),
7.18–7.47 (15H, m, Ph); dC (50 MHz, CDCl3) 16.1, 27.7,
38.5, 50.8, 57.0, 59.9, 126.7, 127.0, 127.2, 127.5, 128.0,
128.3, 141.9, 142.0, 144.4, 171.4; m/z (MH+) 416 (MH+,
100%); mmax/cmꢀ1 (film) 2970, 2930 (C–H), 1710 (C@O).
3.24. Preparation of methyl (3S,aR)-3-(N-benzyl-N-a-
methylbenzylamino)-3-phenylpropanoate 25
3.27. One-pot reaction protocol for the preparation of tert-
butyl (3R,aS)-3-(N-benzyl-N-a-methylbenzylamino)-3-phe-
nylpropanoate 27
Following representative procedure 1, n-BuLi (1.6 M,
1.5 mL, 2.3 mmol), (R)-N-benzyl-N-a-methylbenzylamine
(509 mg, 2.4 mmol) in THF (25 mL) and methyl cinnamate
(300 mg, 1.85 mmol) in THF (25 mL) gave, after column
n-BuLi (2.5 M, 23.5 mL, 58.8 mmol) at ꢀ78 ꢂC was added
dropwise to a stirred solution of (S)-N-benzyl-N-a-methyl-
benzylamine (13.5 g, 13.3 mL, 64.0 mmol) and tert-butyl
cinnamate (10.0 g, 49.0 mmol) in anhydrous THF
(100 mL) at ꢀ78 ꢂC under nitrogen and stirred for 2 h prior
to the addition of saturated aqueous ammonium chloride
(10 mL) and warmed to rt. The resultant solution was
partitioned between brine and DCM (3 · 100 mL) and
the combined organic extracts were concentrated in vacuo.
The residue was re-dissolved in DCM (200 mL), washed
successively with 10% aqueous citric acid solution
(2 · 100 mL), saturated aqueous NaHCO3 (100 mL) and
brine (100 mL), dried and concentrated in vacuo before
purification by chromatography on silica gel (Et2O/pen-
chromatography on silica gel (petrol 40–60/Et2O 9:1), 25
20
(467 mg, 68%) as a colourless oil: ½aꢁD ¼ ꢀ4:2 (c 1.1,
CH2Cl2); C25H28NClO2 (25ÆHCl) requires C, 73.25; H,
6.9; N, 3.4%, found: C, 73.5; H, 7.1; N, 3.5%; dH
(300 MHz, CDCl3) 1.21 (3H, d, J 6.9, C(a)Me), 2.55 (1H,
dd, J2A,2B 14.9, J2A,3 9.2, C(2)HAHB), 2.68 (1H, dd,
J2B,2A 14.9, J2B,3 5.7, C(2)HAHB), 3.46 (3H, s, CO2Me),
3.65 (1H, ABq, J 14.6, NCHAHB), 3.74 (1H, ABq, J
14.6, NCHAHB), 4.00 (1H, q, J 6.8, C(a)H), 4.43 (1H,
dd, J3,2A 9.3, J3,2B 5.7, C(3)H), 7.16–7.42 (15H, m, Ph);
dC (50 MHz, CDCl3) 15.6, 37.4, 50.6, 51.4, 56.6, 59.2,
126.7, 126.8, 127.0, 127.1, 127.4, 127.7, 128.0, 128.2,
128.3, 141.5, 141.9, 144.2, 172.5; m/z (CI+) 374 (MH+,
85%); mmax/cmꢀ1 (film) 3060, 3020, 2845 (C–H), 1740
(C@O), 1490, 1450.
tane 1:20) to give 27 (16.7 g, 82%) as a colourless oil;
24
½aꢁD ¼ ꢀ3:4 (c 1.1, CHCl3) with spectroscopic properties
consistent with those reported above.

1804
S. G. Davies et al. / Tetrahedron: Asymmetry 17 (2006) 1793–1811
3.28. Preparation of benzyl (3S,aR)-3-(N-benzyl-N-a-meth-
ylbenzylamino)-3-(2-methoxyphenyl) propanoate 28
(10H, m, Ph), 7.43 (2H, m, Ar); dC (50 MHz, CDCl3)
16.0, 37.8, 50.7, 55.2, 56.8, 59.0, 66.1, 113.8, 126.8, 127.1,
127.8, 128.1, 128.2, 128.4, 133.8, 136.1, 141.9, 144.4,
159.1, 172.1; m/z (CI+) 479 (MH+, 30%); mmax/cmꢀ1 (film)
3062, 3030 (C–H), 1734 (C@O).
Following representative procedure 1, n-BuLi (1.6 M,
0.5 mL, 0.84 mmol), (R)-N-benzyl-N-a-methylbenzylamine
(183 mg, 0.86 mmol) in THF (15 mL) and benzyl (E)-3-(2-
methoxyphenyl)prop-2-enoate (145 mg, 0.54 mmol) in
THF (10 mL) gave, after column chromatography on silica
3.31. Preparation of tert-butyl (3S,aR)-3-(N-benzyl-N-a-
methylbenzylamino)-3-(4-methoxyphenyl)propanoate 31
gel (petrol 40–60/Et2O 4:1), 28 (80 mg, 31%) as a colourless
20
oil: ½aꢁD ¼ þ8:6 (c 0.6, CHCl3); C32H33NO3 requires C,
Following representative procedure 1, n-BuLi (1.6 M,
1.0 mL, 1.6 mmol), (R)-N-benzyl-N-a-methylbenzylamine
(360 mg, 1.7 mmol) in THF (15 mL) and tert-butyl (E)-3-
(4-methoxyphenyl)prop-2-enoate (249 mg, 1.1 mmol) in
THF (10 mL) gave, after column chromatography on silica
80.1; H, 6.9; N, 2.9%, found C, 79.9; H, 7.1; N, 2.7%; dH
(500 MHz, CDCl3) 1.26 (3H, d, J 6.7, C(a)Me), 2.76 (1H,
dd, J2A,2B 14.6, J2A,3 9.1, C(2)HAHB), 2.68 (1H, dd,
J2B,2A 14.6, J2B,3 6.5, C(2)HAHB), 3.76 (2H, ABq,
NCH2), 3.81 (3H, s, OMe), 4.11 (1H, q, J 6.7, C(a)H),
4.84 (1H, ABq, J 12.5, OCHAHB), 4.93 (1H, ABq, J 12.5,
OCHAHB), 4.96 (1H, dd, J3,2A 9.1, J3,2B 6.5, C(3)H),
6.89–6.96 (2H, m, Ar), 7.09–7.46 (17H, m, Ar, Ph); dC
(50 MHz, CDCl3) 14.3, 38.9, 50.7, 53.5, 55.2, 56.4, 65.9,
111.1, 120.6, 126.7, 126.8, 128.1, 128.2, 128.4, 128.6,
128.9, 129.1, 129.9, 136.3, 142.2, 144.8, 158.1, 172.0; m/z
(CI+) 480 (MH+, 60%); mmax/cmꢀ1 (film) 3062, 3028 (C–
H), 1735 (C@O).
gel (petrol 40–60/Et2O 4:1), 31 (453 mg, 96%) as a colour-
20
less oil: ½aꢁD ¼ þ2:2 (c 1.0, CHCl3); C29H35NO3 requires C,
78.2; H, 7.9; N, 3.1%, found: C, 78.4; H, 7.9; N, 2.9%; dH
(500 MHz, CDCl3) 1.24 (9H, s, OtBu), 1.26 (3H, d, J 6.8,
C(a)Me), 2.46 (1H, dd, J2A,2B 14.4, J2A,3 10.2, C(2)HAHB),
2.68 (1H, dd, J2B,2A 14.4, J2B,3 5.0, C(2)HAHB), 3.67 (2H,
app s, NCH2), 3.81 (3H, s, OMe), 3.99 (1H, q, J 6.8,
C(a)H), 4.35 (1H, dd, J3,2A 10.3, J3,2B 5.0, C(3)H), 6.85–
6.89 (2H, m, Ar(3)H, Ar(5)H), 7.16–7.42 (12H, m, Ph);
dC (50 MHz, CDCl3) 16.4, 27.8, 38.6, 50.8, 55.2, 57.1,
59.2, 80.2, 113.6, 126.7, 127.0, 128.1, 128.2, 128.4, 129.6,
134.1, 142.2, 144.6, 159.0, 171.6; m/z (CI+) 445 (MH+,
50%); mmax/cmꢀ1 (film) 3061 (C–H), 1726 (C@O).
3.29. Preparation of tert-butyl (3S,aR)-3-(N-benzyl-N-a-
methylbenzylamino)-3-(2-methoxyphenyl)propanoate 29
Following representative procedure 1, n-BuLi (1.6 M,
1.3 mL, 2.05 mmol), (R)-N-benzyl-N-a-methylbenzylamine
(448 mg, 2.11 mmol) in THF (15 mL) and tert-butyl (E)-3-
(2-methoxyphenyl)prop-2-enoate (310 mg, 1.32 mmol) in
THF (10 mL) gave, after column chromatography on silica
3.32. Preparation of methyl (3S,aR)-3-(N-benzyl-N-a-
methylbenzylamino)-3-(4-benzyloxyphenyl)propanoate 32
Following representative procedure 1, n-BuLi (1.6 M,
1.3 mL, 2.1 mmol), (R)-N-benzyl-N-a-methylbenzylamine
(1.6 g, 7.4 mmol) in THF (15 mL) and methyl (E)-3-(4-
benzyloxyphenyl)prop-2-enoate (1.2 g, 4.6 mmol) in THF
(10 mL) gave, after column chromatography on silica gel
gel (petrol 40–60/Et2O 9:1), 29 (558 mg, 95%) as a colour-
20
less oil: ½aꢁD ¼ þ15:0 (c 0.9, CHCl3); C29H35NO3 requires
C, 78.2; H, 7.9; N, 3.1%, found: C, 78.35; H, 7.6; N,
3.3%; dH (500 MHz, CDCl3) 1.18 (9H, s, OtBu), 1.25
(3H, d, J 6.8, C(a)Me), 2.62 (2H, app d, C(2)H2), 3.73
(2H, ABq, NCH2), 3.84 (3H, s, OMe), 4.08 (1H, q, J 6.8,
C(a)H), 4.86 (1H, t, J 8.0, C(3)H), 6.89–6.94 (2H, m, Ar),
7.14–7.43 (12H, m, Ar, Ph); dC (50 MHz, CDCl3) 14.2,
27.6, 40.1, 45.8, 53.9, 55.1, 56.5, 79.8, 110.8, 120.4, 126.5,
126.7, 128.0, 128.2, 128.4, 129.3, 130.0, 142.5, 144.9,
158.2, 171.4; m/z (CI+) 445 (MH+, 100%); mmax/cmꢀ1 (film)
3061, 3027 (C–H), 1728 (C@O).
(petrol 40–60/Et2O 4:1), 32 (1.38 g, 63%) as a pale yellow
20
oil: ½aꢁD ¼ ꢀ0:8 (c 2.0, CH2Cl2); C32H33NO3 requires C,
80.1; H, 6.9; N, 2.9%, found C, 80.2; H, 7.2; N, 3.1%; dH
(500 MHz, CDCl3) 1.24 (3H, d, J 6.8, C(a)Me), 2.55 (1H,
dd, J2A,2B 14.9, J2A,3 9.4, C(2)HAHB), 2.68 (1H, dd,
J2B,2A 14.9, J2B,3 6.3, C(2)HAHB), 3.49 (3H, s, CO2Me),
3.70 (2H, ABq, NCH2), 4.02 (1H, q, J 6.8, C(a)H), 4.40
(1H, dd, J3,2A 9.4, J3,2B 6.0, C(3)H), 5.07 (2H, s, OCH2),
7.20–7.49 (19H, m, Ph); dC (50 MHz, CDCl3) 15.7, 37.6,
50.6, 51.4, 56.6, 58.7, 70.0, 114.7, 126.8, 127.0, 127.7,
128.0, 128.1, 128.3, 128.7, 129.3, 134.2, 137.4, 141.7,
3.30. Preparation of benzyl (3S,aR)-3-(N-benzyl-N-a-meth-
ylbenzylamino)-3-(4-methoxyphenyl)propanoate 30
144.4, 158.2, 172.6; m/z (CI+) 480 (MH+, 46%); mmax
cmꢀ1 (film) 1730 (C@O).
/
Following representative procedure 1, n-BuLi (1.6 M,
3.0 mL, 4.8 mmol), (R)-N-benzyl-N-a-methylbenzylamine
(1.0 g, 4.9 mmol) in THF (15 mL) and benzyl (E)-3-(4-
methoxyphenyl)prop-2-enoate (825 mg, 3.1 mmol) in
THF (10 mL) gave, after column chromatography on silica
3.33. Preparation of benzyl (3S,aR)-3-(N-benzyl-N-a-meth-
ylbenzylamino)-3-(4-benzyloxyphenyl)propanoate 33
gel (petrol 40–60/Et2O 4:1), 30 (1.06 g, 72%) as a colourless
Following representative procedure 1, n-BuLi (1.6 M,
5.6 mL, 9.0 mmol), (R)-N-benzyl-N-a-methylbenzylamine
(2.0 g, 9.3 mmol) in THF (15 mL) and benzyl (E)-3-(4-
benzyloxyphenyl)prop-2-enoate (2.0 g, 5.8 mmol) in THF
(10 mL) gave, after column chromatography on silica gel
20
oil: ½aꢁD ¼ þ7:1 (c 1.0, CHCl3); C32H33NO3 requires C,
80.1; H, 6.9; N, 2.9%, found: C, 80.2; H, 6.6; N, 2.6%;
dH (500 MHz, CDCl3) 1.27 (3H, d, J 6.8, C(a)Me), 2.62
(1H, dd, J2A,2B 14.7, J2A,3 9.9, C(2)HAHB), 2.68 (1H, dd,
J2B,2A 14.7, J2B,3 5.3, C(2)HAHB), 3.71 (2H, ABq,
NCH2), 3.82 (3H, s, OMe), 4.03 (1H, q, J 6.8, C(a)H),
4.46 (1H, dd, J3,2A 9.9, J3,2B 5.3, C(3)H), 4.93 (2H, ABq,
OCH2), 6.86–6.91 (2H, m, Ar(3)H, Ar(5)H), 7.12–7.33
(petrol 40–60/Et2O 4:1), 33 (2.1 g, 64%) as a pale yellow
20
oil: ½aꢁD ¼ ꢀ3:5 (c 1.7, CH2Cl2); C38H37NO3 requires C,
82.1; H, 6.7; N, 2.5%, found: C, 82.25; H, 7.0; N, 2.5%;
dH (300 MHz, CDCl3) 1.26 (3H, d, J 6.9, C(a)Me), 2.60

S. G. Davies et al. / Tetrahedron: Asymmetry 17 (2006) 1793–1811
1805
(1H, dd, J2A,2B 14.7, J2A,3 9.7, C(2)HAHB), 2.72 (1H, dd,
J2B,2A 14.7, J2B,3 5.5, C(2)HAHB), 3.73 (2H, ABq,
NCH2), 4.01 (1H, q, J 6.8, C(a)H), 4.45 (1H, dd, J3,2A
9.7, J3,2B 5.5, C(3)H), 4.92 (2H, s, OCH2Ph), 5.06 (2H, s,
OCH2Ph), 7.10–7.48 (24H, m, Ph); dC (50 MHz, CDCl3)
15.9, 37.6, 50.7, 56.8, 58.9, 66.0, 70.0, 114.5, 114.7, 123.5,
127.0, 127.4, 127.7, 128.0, 128.8, 128.3, 128.6, 128.8,
129.1, 129.4, 134.1, 136.0, 137.2, 141.8, 144.3, 158.2,
172.2; m/z (CI+) 556 (MH+, 13%); mmax/cmꢀ1 (film) 3030,
2930 (C–H), 1730 (C@O).
(2.34 g, 11.0 mmol) in THF (25 mL) and ethyl (E)-4-
methyl-pent-2-enoate (980 mg, 6.9 mmol) in THF
(25 mL) gave, after column chromatography on silica gel
(petrol 40–60/Et2O 9:1), 36 (1.37 g, 56%) as a colourless
20
oil: ½aꢁD ¼ ꢀ2:5 (c 1.0, CHCl3); C23H31NO2 requires C,
78.15; H, 8.8; N, 4.0%, found C, 78.0; H, 8.9; N, 4.0%;
dH (500 MHz, CDCl3) 0.87 (3H, d, J 6.7, C(4)Me), 1.10
(3H, d, J 6.7, C(4)Me), 1.22 (3H, t, J 7.0, OCH2CH3),
1.40 (3H, d, J 7.0, C(a)Me), 1.73 (1H, m, C(4)H), 1.92
(1H, dd, J2A,2B 15.9, J2A,3 2.5, C(2)HAHB), 2.13 (1H,
dd, J2B,2A 15.9, J2B,3 9.0, C(2)HAHB), 3.25 (1H, m,
C(3)H), 3.52 (1H, ABq, J 14.9, NCHAHB), 3.80 (1H,
ABq, J 14.9, NCHAHB), 3.81 (1H, q, J 7.0, C(a)H),
4.06 (2H, q, J 7.0, OCH2CH3), 7.22–7.48 (10H, m, Ph);
dC (50 MHz, CDCl3) 14.0, 19.5, 20.1, 20.9, 32.7, 34.8,
51.2, 57.9, 58.4, 60.1, 126.8, 127.2, 128.2, 128.4, 128.5,
3.34. Preparation of tert-butyl (3R,aS)-3-(3,4-methylenedi-
oxyphenyl)-3-(N-benzyl-N-a-methylbenzylamino)propanoate
34
Following representative procedure 1, n-BuLi (2.5 M,
1.8 mL, 4.7 mmol), (S)-N-benzyl-N-a-methylbenzylamine
(2.6 g, 12.1 mmol) in THF (15 mL) and tert-butyl (E)-3-
(3,4-methylenedioxyphenyl)prop-2-enoate (1.5 g, 6.0 mmol)
in THF (15 mL) gave, after column chromatography on sil-
141.7, 142.4, 173.7; m/z (CI+) 354 (MH+, 100%); mmax
cmꢀ1 (film) 1733 (C@O). Further elution afforded 37
(894 mg, 25%) as white solid: mp 97–100 ꢂC;
/
a
21
½aꢁD ¼ þ89:3 (c 1.8, CHCl3); C36H42N2O requires C,
83.4; H, 8.2; N, 5.4%, found: C, 83.5; H, 8.2; N, 5.3%;
dH (300 MHz, DMSO-d6, 353 K) two rotamers 0.78 and
0.93 (2 · 3H, m, C(4)Me), 1.32 (6H, d, J 6.7, C(a)Me),
1.65 (1H, m, C(4)H), 1.83–1.96 (1H, m, C(2)HAHB),
2.00–2.32 (1H, m, C(2)HAHB), 3.41–3.48 (1H, br s,
C(a)H), 3.51 (1H, app t, J 6.1, C(3)H), 3.73–3.86 and
4.18–4.26 (2 · 2H, br s, NCH2), 7.15–7.49 (20H, m, Ph);
dC (125 MHz, DMSO-d6) two rotamers 17.0, 18.8, 20.0,
20.1, 20.2, 20.4, 20.5, 32.1, 33.0, 33.7, 45.6, 46.8, 51.1,
51.2, 51.6, 54.5, 56.7, 56.9, 57.5, 57.7, 126.1, 126.3,
126.5, 126.7, 126.8, 127.1, 127.2, 127.3, 127.9, 128.9,
128.5, 138.8, 139.9, 141.3, 141.5, 141.6, 141.7, 142.1,
ica gel (hexane/Et2O 1:9), 34 (2.0 g, 73%) as a colourless
23
oil: ½aꢁD ¼ ꢀ0:3 (c 1.5, CHCl3); dH (400 MHz, CDCl3) 1.26
(9H, s, OtBu), 1.28 (3H, d, J 6.8, C(a)Me), 2.37–2.53 (2H,
m, C(2)H2), 3.67 (2H, app s, NCH2), 3.99 (1H, q, J 6.8,
C(a)H), 4.29–4.33 (1H, m, C(3)H), 5.96 (2H, s, OCH2O),
6.74–7.43 (13H, m, Ph); dC (100 MHz, CDCl3) 16.2, 27.8,
38.6, 50.8, 57.0, 59.6, 80.2, 100.9, 107.6, 108.7, 121.2,
126.5, 126.8, 127.8, 127.9, 128.1, 128.4, 135.9, 141.7, 144.1,
146.5, 147.5, 171.1; m/z (APCI+) 460 (MH+, 10%); HRMS
þ
C29H34NO4 requires 460.2498, found 460.2488; mmax
/
cmꢀ1 (film) 3027, 2975 (C–H), 1728 (C@O).
3.35. Preparation of tert-butyl (3R,aS)-3-(3,4-dimethoxy-
phenyl)-3-(N-benzyl-N-a-methylbenzylamino)propanoate 35
142.2, 171.8, 172.1; m/z (CI+) 519 (MH+, 100%); mmax
cmꢀ1 (KBr) 3051, 3045 (C–H), 1646 (C@O).
/
Following representative procedure 1, n-BuLi (2.5 M,
8.9 mL, 22.2 mmol), (S)-N-benzyl-N-a-methylbenzylamine
(4.5 g, 23.6 mmol) in THF (15 mL) and tert-butyl (E)-3-
(3,4-methoxyphenyl)prop-2-enoate (3.0 g, 6.0 mmol) in
THF (15 mL) gave, after column chromatography on silica
3.37. Preparation of benzyl (3S,aR)-3-(N-benzyl-N-a-meth-
ylbenzylamino)-4-methyl-pentanoate 38
Following representative procedure 1, n-BuLi (1.6 M,
1.7 mL, 2.8 mmol), (R)-N-benzyl-N-a-methylbenzylamine
(611 mg, 2.9 mmol) in THF (10 mL) and benzyl (E)-4-
methyl-pent-2-enoate (370 mg, 1.8 mmol) in THF (5 mL)
gave, after column chromatography on silica gel (petrol
gel (hexane/Et2O 2:1), 35 (4.2 g, 79%) as a colourless oil:
22
½aꢁD ¼ ꢀ0:07 (c 0.95, CHCl3); dH (400 MHz, CDCl3) 1.26
(9H, s, OtBu), 1.27 (3H, d, J 6.8, C(a)Me), 2.47 (1H, dd,
J2A,2B 14.6, J2A,3 10.1, C(2)HAHB), 2.55 (1H, dd, J2B,2A
14.6, J2B,3 4.9, C(2)HAHB), 3.67 (2H, ABq, J 14.9,
NCH2), 3.87, 3.90 (2 · 3H, s, OMe), 4.01 (1H, q, J 6.8,
C(a)H), 4.35 (1H, dd, J3,2A 10.1, J3,2B 4.9, C(3)H), 6.80–
6.96 (3H, m, Ar), 7.17–7.43 (10H, m, Ph); dC (100 MHz,
CDCl3) 17.1, 27.9, 38.2, 50.7, 55.7, 55.8, 57.4, 59.3, 80.2,
110.4, 111.7, 119.9, 126.5, 126.8, 127.8, 128.0, 128.1,
128.1, 134.5, 141.3, 144.3, 147.9, 148.5, 171.3; m/z (APCI+)
40–60/Et2O 9:1), 38 (283 mg, 38%) as a colourless oil:
20
½aꢁD ¼ ꢀ4:8 (c 1.3, CHCl3); C28H33NO2 requires C, 80.9;
H, 8.0; N, 3.4%, found C, 80.9; H, 8.3; N, 3.35%; dH
(500 MHz, CDCl3) 0.84 (3H, d, J 6.8, C(4)Me), 1.09
(3H, d, J 6.6, C(4)Me), 1.38 (3H, d, J 6.8, C(a)Me),
1.71 (1H, m, C(4)H), 1.95 (1H, dd, J2A,2B 16.0, J2A,3
2.5, C(2)HAHB), 2.13 (1H, dd, J2B,2A 16.0, J2B,3 9.1,
C(2)HAHB), 3.27 (1H, m, C(3)H), 3.51 (1H, ABq, J
15.0, NCHAHB), 3.78 (1H, ABq, J 15.0, NCHAHB),
3.77 (1H, q, J 6.8, C(a)H), 5.01 (1H, ABq, J 12.3,
OCHAHB), 5.05 (1H, ABq, J 12.3, OCHAHB), 7.18–7.46
(15H, m, Ph); dC (50 MHz, CDCl3) 19.5, 20.1, 20.9,
32.6, 34.7, 51.2, 57.8, 58.3, 66.1, 126.8, 127.2, 128.2,
128.4, 128.5, 128.7, 136.3, 141.7, 142.2, 173.4; m/z (CI+)
416 (MH+, 100%); mmax/cmꢀ1 (film) 3063, 3029 (C–H),
1734 (C@O), 1146 (C–O). Further elution afforded 37
(271 mg, 29%) as a white solid with spectroscopic proper-
ties consistent with those reported above.
476 (MH+, 5%), 265 (MH+ꢀC15H16N, 100%); HRMS
þ
C30H38NO4 requires 476.2801, found 476.2807; mmax
/
cmꢀ1 (film) 2975 (C–H), 1724 (C@O).
3.36. Preparation of ethyl (3S,aR)-3-(N-benzyl-N-a-meth-
ylbenzylamino)-4-methyl-pentanoate 36 and (3S,aR,a0R)-N-
benzyl-N-a-methylbenzyl 3-(N-benzyl-N-a-methylbenzyl-
amino)-4-methyl pentamide 37
Following representative procedure 1, n-BuLi (1.6 M,
6.7 mL, 10.7 mmol), (R)-N-benzyl-N-a-methylbenzylamine

1806
S. G. Davies et al. / Tetrahedron: Asymmetry 17 (2006) 1793–1811
3.38. Preparation of tert-butyl (3S,aR)-3-(N-benzyl-N-a-
methylbenzylamino)-4-methyl-pentanoate 39
52.4, 116.0, 126.7, 128.8, 156.7, 172.3; m/z (CI+) 196
(MH+ꢀHCl, 15%); mmax/cmꢀ1 (film) 1720 (C@O).
Following representative procedure 1, n-BuLi (1.6 M,
1.25 mL, 2.0 mmol), (R)-N-benzyl-N-a-methylbenzylamine
(450 mg, 2.1 mmol) in THF (25 mL) and tert-butyl (E)-4-
methyl-pent-2-enoate (220 mg, 1.3 mmol) in THF (25 mL)
gave, after column chromatography on silica gel (petrol
3.41. Preparation of (S)-b-tyrosine hydrochloride 42
Compound 41 (245 mg, 1.06 mmol) was dissolved in 5 M
aqueous HCl (5 mL) and heated to reflux overnight. Con-
centration in vacuo gave 42 (227 mg, 99%) as a white solid:
25
24
40–60/Et2O 4:1), 39 (450 mg, 91%) as a colourless oil:
½aꢁD ¼ þ3:6 (c 1.4, H2O); lit.58 (ent) ½aꢁD ¼ ꢀ3:1 (c 1.65,
H2O); dH (200 MHz, D2O) 2.88 (2H, m, C(2)H2), 4.44–
4.53 (1H, m, C(3)H), 7.11–7.25 (4H, m, Ph); dC (63 MHz,
D2O) 37.6, 115.8, 126.8, 128.6, 156.3, 173.5.
24
½aꢁD ¼ ꢀ1:9 (c 1.4, CHCl3); C25H35NO2 requires C, 78.7;
H, 9.25; N, 3.7%, found: C, 78.8; H, 9.2; N, 3.8%; dH
(500 MHz, CDCl3) 0.90 (3H, d, J 6.8, C(4)Me), 1.12 (3H,
d, J 6.8, C(4)Me), 1.41 (3H, d, J 7.1, C(a)Me), 1.42 (9H,
s, OtBu), 1.67–1.72 (1H, m, C(4)H), 1.82 (1H, dd, J2A,2B
16.1, J2A,3 2.1, C(2)HAHB), 1.98 (1H, dd, J2B,2A 16.1,
J2B,3 9.5, C(2)HAHB), 3.24–3.28 (1H, m, C(3)H), 3.49
(1H, ABq, J 14.2, NCHAHB), 3.77 (1H, ABq, J 14.2,
NCHAHB), 3.77 (1H, q, J 7.1, C(a)H), 7.23–7.48 (10H,
m, Ph); dC (50 MHz, CDCl3) 19.5, 20.1, 21.0, 28.0, 32.8,
36.2, 51.2, 57.7, 57.9, 79.9, 126.8, 127.2, 128.5, 141.8,
142.1, 172.8; m/z (CI+) 381 (MH+, 100%); mmax/cmꢀ1 (film)
3062, 3027 (C–H), 1729 (C@O).
3.42. Alternative preparation of (S)-b-tyrosine hydrochloride
42
Following representative procedure 4, 33 (1.56 g,
2.9 mmol) in MeOH (5 mL) and Pd(OH)2/C (1.4 g) at rt
gave 42 (441 mg, 76%) as a white powder, which displayed
identical spectroscopic properties as those reported above
25
½aꢁD ¼ þ3:2 (c 0.6, H2O).
3.43. Preparation of tert-butyl (E)-3-(3,4-dibenzyloxy-
phenyl)prop-2-enoate 43
3.39. One-pot reaction protocol for the preparation of tert-
butyl (3R,aS)-3-(N-benzyl-N-a-methylbenzylamino)-4-
methyl-pentanoate 39
n-BuLi (2.5 M, 12.0 mL, 30.0 mmol) was added to a stirred
solution of tert-butyl diethylphosphonoacetate (7.93 g,
31.4 mmol) in THF (20 mL) and stirred for 30 min before
the addition of 3,4-dibenzyloxybenzaldehyde (8.00 g,
25.1 mmol) and allowed to warm to rt overnight. Saturated
aqueous ammonium chloride (10 mL) was added and the
resultant solution partitioned between brine and DCM
(3 · 100 mL) and the combined organic extracts were dried,
filtered and concentrated in vacuo. Recrystallisation from
Et2O/hexanes afforded (E)-43 (8.50 g, 81%) as white crys-
tals: mp 59–61 ꢂC; dH (400 MHz, CDCl3) 1.27 (9H, s,
OtBu), 4.85 (2 · 2H, s, OCH2Ph), 5.94 (1H, d, J 15.9,
C(2)H), 6.60–7.18 (13H, m, Ar, Ph), 7.22 (1H, d, J 15.9,
C(3)H); dC (100 MHz, CDCl3) 27.9, 70.5, 70.9, 81.6,
113.2, 113.9, 117.8, 122.4, 126.9, 127.0, 127.6, 127.8,
128.2, 136.5, 136.6, 143.0, 148.6, 150.5, 166.2; m/z (CI+)
417.5 (MH+, 25%), 361.1 (MH+ꢀC4H8, 100); HRMS
n-BuLi (2.5 M, 21.9 mL, 54.7 mmol) was added dropwise
to a stirred solution of (S)-N-benzyl-N-a-methylbenzyl-
amine (11.9 g, 11.8 mL, 56.5 mmol) and tert-butyl (E)-4-
methyl-pent-2-enoate (6.0 g, 35.3 mmol) in anhydrous
THF (100 mL) at ꢀ78 ꢂC under nitrogen and stirred for
2 h prior to the addition of saturated aqueous ammonium
chloride (10 mL) and warmed to rt. The resultant solution
was partitioned between brine and DCM (3 · 100 mL), and
the combined organic extracts were concentrated in vacuo.
The residue was re-dissolved in DCM (200 mL), washed
successively with 10% aqueous citric acid solution
(2 · 100 mL), saturated aqueous NaHCO3 (100 mL) and
brine (100 mL), dried and concentrated in vacuo before
purification by column chromatography on silica gel
(Et2O/pentane 1:10) to give 39 (12.0 g, 89%) as a colourless
C27H28O requires 416.1987, found 416.1993; mmax/cmꢀ1
þ
24
4
oil ½aꢁD ¼ þ1:9 (c 1.1, CHCl3) with spectroscopic proper-
(film) 1694 (C@O), 1640 (C@C).
ties consistent with those reported above.
3.44. Preparation of tert-butyl (3R,aS)-3-(3,4-dibenzyloxy-
phenyl)-3-(N-benzyl-N-a-methylbenzylamino)propanoate 44
3.40. Preparation of (S)-b-tyrosine methyl ester hydro-
chloride 41
Following representative procedure 1, n-BuLi (2.5 M,
14.2 mL, 35.4 mmol), (S)-N-benzyl-N-a-methylbenzyl-
amine (7.61 g, 36.0 mmol) in THF (15 mL) and (E)-43
(5.0 g, 12.0 mmol) in THF (15 mL) gave, after column
Pd(OH)2 on carbon (150 mg) was added to a stirred solu-
tion of 32 (375 mg, 0.81 mmol) in MeOH/H2O/AcOH
(40:4:1, 11.2 mL) and stirred under a hydrogen atmosphere
(1 atm) at rt overnight. After filtration through Celiteꢁ
(eluent MeOH) and concentration in vacuo, the residue
was treated with 1 M aqueous HCl and concentrated in
chromatography on silica gel (hexane/Et2O, 9:1), 44
22
(7.11 g, 90%) as a colourless oil: ½aꢁD ¼ ꢀ2:0 (c 1.4,
CHCl3); dH (400 MHz, CDCl3) 1.19 (3H, d, J 6.8,
C(a)Me), 1.25 (9H, s, OtBu), 2.40–2.55 (2H, m, C(2)H2),
3.60 (2H, app s, NCH2), 3.85 (1H, q, J 6.8, C(a)H),
4.28–4.31 (1H, m, C(3)H), 5.20 (2 · 2H, s, OCH2Ph),
6.89–7.52 (23H, m, Ph); dC (100 MHz, CDCl3) 16.6, 27.8,
38.4, 50.7, 57.1, 59.2, 71.2, 71.3, 80.1, 114.3, 115.5, 120.8,
126.4, 126.7, 127.2, 127.3, 127.7, 128.0, 128.1, 128.4,
128.5, 135.1, 137.3, 137.5, 144.2, 147.9, 148.5, 172.0; m/z
vacuo to give 41 (72 mg, quant) as a white solid;
20
½aꢁD ¼ þ10:6 (c 1.9, H2O); C10H14NClO3 requires C,
51.8; H, 6.0; N, 6.05%, found C, 52.0; H, 6.2; N, 5.75%;
dH (200 MHz, D2O) 2.88 (1H, dd, J2A,2B 16.0, J2A,3 8.1,
C(2)HAHB), 2.96 (1H, dd, J2B,2A 16.0, J2B,3 6.9,
C(2)HAHB), 3.45 (3H, s, CO2Me), 4.53 (1H, m, C(3)H),
7.27–6.69 (4H, m, Ph); dC (50 MHz, D2O) 37.4, 50.8,

S. G. Davies et al. / Tetrahedron: Asymmetry 17 (2006) 1793–1811
1807
(CI+) 628.2 (MH+, 25%); HRMS C42H45NO requires
CH3C(7)H2C(6)H2C(5)H2C(4)H2), 2.15 (1H, dd, J2A,2B
15.5, J2A,3 8.8, C(2)HAHB), 2.35 (1H, dd, J2B,2A 15.5,
J2B,3 4.0, C(2)HAHB), 3.11 (1H, m, C(3)H); dC (50 MHz,
CDCl3) 13.8, 22.4, 25.6, 28.0, 31.7, 37.3, 43.7, 48.3, 80.5,
172.4; m/z (CI+) 215 (MH+, 50%); mmax/cmꢀ1 (film) 3383
(N–H), 1728 (C@O).
þ
4
628.3427, found 628.3422; mmax/cmꢀ1 (film) 1724 (C@O),
1505 (OCH2Ph).
3.45. Preparation of tert-butyl (R)-3-(3,4-dihydroxyphenyl)-
3-aminopropanoate 45
Pd(OH)2 on carbon (0.25 g, 0.18 mmol) was added to a
stirred solution of 44 (1.0 g, 4.0 mmol) in degassed metha-
nol (10 mL) with AcOH (0.5 mL) under 1 atm H2 and stir-
red for 16 h. The crude reaction mixture was filtered
through Celiteꢁ (eluent MeOH) to yield 45 as a yellow
oil. Purification via column chromatography on silica gel
3.49. Preparation of tert-butyl (S)-3-phenyl-3-aminoprop-
anoate 49
Following representative procedure 2, 27 (1.6 g, 3.8 mmol)
in AcOH (8 mL) and Pd/C (510 mg) at rt gave, after puri-
fication by column chromatography on silica gel (petrol/
(CHCl3/MeOH 3:1) afforded 45 (0.37 g, 98%) as yellow
Et2O 1:1), 49 (705 mg, 84%) as
a colourless oil:
23
20
oil; ½aꢁD ¼ þ1:0 (c 0.70, CHCl3); dH (400 MHz, CDCl3)
½aꢁD ¼ ꢀ21:0 (c 1.0, CHCl3); C13H19NO2 requires C,
70.6; H, 8.65; N, 6.3%, found C, 70.55; H, 8.3; N, 6.4%;
dH (300 MHz, CDCl3) 1.42 (9H, s, OtBu), 1.75 (2H, s,
NH2), 2.59 (2H, app d, C(2)H2), 4.38 (1H, t, J 6.8,
C(3)H), 7.25–7.38 (5H, m, Ph); dC (50 MHz, CDCl3)
27.9, 45.2, 52.7, 80.7, 126.5, 127.4, 128.7, 144.9, 171.6;
m/z (CI+) 222 (MH+, 50%); mmax/cmꢀ1 (film) 1724 (C@O).
1.04 (9H, s, OtBu), 2.58–2.87 (2H, m, C(2)H2), 4.33–4.37
(C(3)H), 6.62–6.72 (3H, m, Ar), dC (100 MHz, CDCl3)
27.2, 39.5, 51.6, 83.8, 115.3, 116.3, 120.1, 127.4, 144.6,
145.3, 170.þ6; m/z (ESI+) 254 (MH+, 100%); HRMS
C13H19NO4 requires 254.1392, found 254.1396; mmax
/
cmꢀ1 (film) 3018 (C–H), 1716 (C@O).
3.46. Preparation of (R)-b-DOPA hydrochloride 46ÆHCl
3.50. Preparation of tert-butyl (S)-3-(2-methoxyphenyl)-3-
aminopropanoate 50
Ester 45 (0.25 g, 0.99 mmol) was added portionwise to a
solution of HCl (g) in Et2O (10 mL) at 0 ꢂC and stirred
for 5 min. The organic solvents were removed in vacuo to
Following representative procedure 2, 29 (525 mg,
1.2 mmol) in AcOH (5 mL) and Pd/C (155 mg) at rt gave,
after purification by column chromatography on silica gel
afford 46ÆHCl (0.22 g, 93%) as an off white solid:
23
½aꢁD ¼ ꢀ5:0 (c 0.50, 6 M HCl); dH (400 MHz, CD3OD)
(DCM/MeOH 9:1), 50 (268 mg, 91%) as a colourless oil;
2.93 (1H, dd, J2A,2B 17.7, J2A,3 6.1, C(2)HAHB), 2.95 (1H,
dd, J2B,2A 17.7, J2B,3 8.3, C(2)HAHB), 4.54 (1H, dd, J3,2B
8.3, J3,2A 6.1, C(3)H), 6.78–6.90 (3H, m, Ar); dC
(100 MHz, CD3OD) 39.5, 53.3, 115.8, 117.1, 120.1, 129.0,
147.5, 148.þ0, 173.6; m/z (ESI+) 198.1 (MH+, 100); HRMS
C9H12NO4 requires 198.0766, found 198.0760; mmax/cmꢀ1
(KBr) 3042 (C–H), 1716 (C@O).
20
½aꢁD ¼ ꢀ20:0 (c 0.7, CHCl3); C14H21NO3 requires C,
66.9; H, 8.4; N, 5.6%, found C, 67.0; H, 8.7; N, 5.8%; dH
(300 MHz, CDCl3) 1.40 (9H, s, OtBu), 1.93 (2H, br s,
NH2), 2.59 (1H, dd, J2A,2B 15.4, J2A,3 8.8, C(2)HAHB),
2.70 (1H, dd, J2B,2A 15.4, J2B,3 5.0, C(2)HAHB), 3.84 (3H,
s, OMe), 4.56 (1H, dd, J3,2A 8.8, J3,2B 5.0, C(3)H), 6.83–
6.94 (2H, m, Ar(3)H, Ar(5)H), 7.18–7.32 (2H, m, Ar(4)H,
Ar(6)H); dC (50 MHz, CDCl3) 27.9, 43.0, 48.4, 55.2, 80.5,
110.6, 120.8, 127.2, 128.3, 132.7, 157.0, 172.1; m/z (CI+)
251(MH+, 100%); mmax/cmꢀ1 (film) 1724 (C@O).
3.47. Preparation of tert-butyl (R)-3-aminopentanoate 47
Following representative procedure 2, 22 (550 mg,
1.5 mmol) in MeOH (5 mL) and Pd/C (305 mg) at 50 ꢂC
3.51. Preparation of tert-butyl (S)-3-(4-methoxyphenyl)-3-
aminopropanoate 51
gave, after Kugelrohr distillation, 47 (245 mg, 95%) as a
20
colourless oil: ½aꢁD ¼ ꢀ22:3 (c 1.5, CHCl3); C9H19NO2
requires C, 62.4; H, 11.05; N, 8.1%, found C, 62.3; H,
11.1; N 7.9%; dH (300 MHz, CDCl3) 0.92 (3H, t, J 7.4,
C(5)H3), 1.45 (9H, s, OtBu), 1.34–1.46 (2H, m, C(4)H2),
2.14 (1H, dd, J2A,2B 15.5, J2A,3 8.9, C(2)HAHB), 2.37 (1H,
dd, J2B,2A 15.5, J2B,3 4.0, C(2)HAHB), 3.06 (1H, m,
C(3)H); dC (50 MHz, CDCl3) 10.2, 27.9, 30.1, 43.3, 49.7,
80.3, 172.3; m/z (CI+) 174 (MH+, 36%); mmax/cmꢀ1 (film)
3400 (N–H), 1728 (C@O).
Following representative procedure 2, 31 (120 mg,
0.27 mmol) in AcOH (5 mL) and Pd/C (55 mg) at rt gave,
after purification by column chromatography on silica gel
(DCM/MeOH 95:5), 51 (62 mg, 91%) as a colourless oil:
20
½aꢁD ¼ ꢀ14:1 (c 0.8, CHCl3); C14H21NO3 requires C,
66.9; H, 8.4; N, 5.6%, found: C, 66.7; H, 8.7; N, 5.3%;
dH (300 MHz, CDCl3) 1.40 (9H, s, OtBu), 1.84 (2H, s,
NH2), 2.55 (2H, m, C(2)H2), 3.77 (3H, s, OMe), 4.32
(1H, t, J 7.4, C(3)H), 6.84 (2H, m, Ar(3)H, ArPh(5)H),
7.26 (2H, m, Ar(2)H, Ar(4)H); dC (50 MHz, CDCl3) 27.9,
45.3, 50.0, 55.2, 80.7, 114.0, 127.6, 159.1, 171.7; m/z
(CI+) 251 (MH+, 35%); mmax/cmꢀ1 (film) 1724 (C@O).
3.48. Preparation of tert-butyl (R)-3-aminoctanoate 4859
Following representative procedure 2, 24 (328 mg,
0.8 mmol) in MeOH (5 mL) and Pd/C (150 mg) at rt gave,
after purification by column chromatography on silica gel
(Et2O/MeOH 4:1), 48 (142 mg, 83%) as a colourless oil:
3.52. Preparation of tert-butyl (S)-4-methyl-3-amino-
pentanoate 52
20
½aꢁD ¼ ꢀ14:3 (c 0.7, CHCl3); C12H25NO2 requires C,
66.9; H, 11.7; N, 6.5%, found C, 66.6; H, 11.7; N, 6.8%;
dH (500 MHz, CDCl3) 0.87 (3H, t, J 6.9, C(8)H3), 1.43
(9H, s, OtBu), 1.52 (2H, br s, NH2), 1.23–1.56 (8H, m,
Following representative procedure 2, 39 (1.3 g,
3.48 mmol) in AcOH (5 mL) and Pd/C (530 mg) at rt gave,

1808
S. G. Davies et al. / Tetrahedron: Asymmetry 17 (2006) 1793–1811
after Kugelrohr distillation, 52 (510 mg, 88%) as a colour-
3.58. Preparation of (S)-b-leucine 58
20
less oil: ½aꢁD ¼ ꢀ25:8 (c 3.4, CHCl3); C10H21NO2 requires
C, 64.1; H, 11.3; N, 7.5%, found C, 64.1; H, 11.2; N,
7.5%; dH (300 MHz, CDCl3) 0.88 and 0.89 (2 · 3H, d, J
6.8, C(4)Me2), 1.44 (9H, s, OtBu), 1.58 (1H, m, C(4)H),
2.13 (1H, dd, J2A,2B 15.4, J2A,3 9.7, C(2)HAHB), 2.36 (1H,
dd, J2B,2A 15.4, J2B,3 3.4, C(2)HAHB), 2.96 (1H, m,
C(3)H); dC (50 MHz, CDCl3) 17.6, 18.6, 27.9, 33.1, 40.8,
53.5, 80.4, 172.7; m/z (CI+) 188 (MH+, 50%); mmax/cmꢀ1
(film) 3385 (N–H), 1728 (C@O).
Following representative procedure 3, 52 (380 mg,
2.1 mmol) and TFA (3 mL) gave, after purification by
ion-exchange chromatography, 58 (258 mg, 97%) as a
white solid with spectroscopic properties consistent
24
with those of the literature: ½aꢁD ¼ ꢀ48:2 (c 1.1, H2O),
22
lit.33 (ent) ½aꢁD ¼ þ40:3 (c 1.02, H2O).
3.59. Preparation of (R)-b-aminobutanoic acid 59
Following representative procedure 4, 15 (2.11 g,
5.44 mmol) in EtOH (5 mL) and Pd(OH)2 on C (1.0 g) at
rt gave, after recrystallisation (MeOH), 59 (379 mg, 68%)
3.53. Preparation of (R)-b-aminopentanoic acid 53
Following representative procedure 3, 47 (120 mg,
0.7 mmol) and TFA (1 mL) gave, after purification by
ion-exchange chromatography, 53 (73 mg, 89%) as a white
solid with spectroscopic properties consistent with those of
as white needles with spectroscopic properties consistent
19
with those of the literature: ½aꢁD ¼ ꢀ39:8 (c 0.5, H2O),
18
lit.63 (ent) ½aꢁD ¼ þ38:8 (c 0.48, H2O).
20
23
the literature: ½aꢁD ¼ ꢀ40:8 (c 0.8, H2O), lit.60 ½aꢁD ¼ ꢀ37:0
3.60. Preparation 2 of (R)-3-aminopentanoic acid 53
(c 0.7, H2O).
Following representative procedure 4, 15 (370 mg,
0.96 mmol) in EtOH (5 mL) and Pd/C (190 mg) at rt gave
3.54. Preparation of (R)-b-aminooctanoic acid 54
(R)-3-aminopentanoic acid hydrochloride 53ÆHCl (142 mg,
Following representative procedure 3, 48 (62 mg,
0.3 mmol) and TFA (1 mL) gave, after purification by
ion-exchange chromatography, 54 (45 mg, 95%) as a white
solid with spectroscopic properties consistent with those of
20
98%) as a white powder: mp 137–139 ꢂC; ½aꢁD ¼ ꢀ22:9 (c
0.8, H2O); C5H12NO2Cl requires C, 39.1; H, 7.9; N,
9.1%, found: C, 39.2; H, 8.1; N, 8.7%; dH (300 MHz,
D2O) 0.72 (3H, t, J .4, C(5)H3), 1.46 (2H, app q, J 7.0,
C(4)H), 2.43 (1H, dd, J2A,2B 17.7, J2A,3 8.1, C(2)HAHB),
2.58 (1H, dd, J2B,2A 17.7, J2B,3 4.4, C(2)HAHB), 3.31 (1H,
m, C(3)H); dC (50 MHz, D2O) 8.5, 24.9, 35.3, 49.3, 174.5;
m/z (CI+) 117 (MH+, 100%); mmax/cmꢀ1 (film) 3400 (N–
H), 1703 (C@O), 1613. Purification by ion-exchange chro-
matography gave (R)-3-aminopentanoic acid 53 (90 mg,
24
20
the literature: ½aꢁD ¼ ꢀ28:3 (c 0.5, H2O), lit.61 ½aꢁD ¼ ꢀ31:1
(c 0.51, H2O).
3.55. Preparation of (S)-b-phenylalanine 55
Following representative procedure 3, 49 (505 mg,
2.3 mmol) and TFA (3 mL) gave, after purification by
ion-exchange chromatography, 55 (364 mg, 96%) as a
90%) as a white solid with spectroscopic properties consis-
20
tent with those of the literature: ½aꢁD ¼ ꢀ40:0 (c 1.5, H2O);
23
lit.60 ½aꢁD ¼ ꢀ37:0 (c 0.7, H2O).
white solid with spectroscopic properties consistent with
20
those of the literature: mp 227–229 ꢂC; ½aꢁD ¼ ꢀ7:0 (c 1.0,
22
H2O), lit.62 ½aꢁD ¼ ꢀ6:3 (c 0.8, H2O).
3.61. Preparation 2 of (R)-b-aminoctanoic acid 54
3.56. Preparation of (S)-b-(2-methoxyphenyl)-b-amino
propionic acid 56
Following representative procedure 4, 23 (432 mg,
1.08 mmol) in AcOH (5 mL) and Pd/C (228 mg) at rt gave
(R)-b-aminoctanoic acid hydrochloride 54ÆHCl (190 mg,
Following representative procedure 3, 50 (175 mg,
0.7 mmol) and TFA (1 mL) gave, after purification by
quantitative) as
a
white powder: mp 103–104 ꢂC;
20
½aꢁD ¼ ꢀ16:6 (c 1.1, H2O); C8H18NO2Cl requires C, 49.1;
H, 9.3; N, 7.2%, found C, 49.0; H, 9.45; N, 6.95%; dH
(200 MHz, D2O) 0.62 (3H, t, J 6.3, C(8)H3), 0.99–1.21
(6H, m, CH3C(7)H2C(6)H2C(5)H2), 1.44 (2H, m,
C(4)H2), 2.43 (1H, dd, J2A,2B 17.5, J2A,3 7.9, C(2)HAHB),
2.60 (1H, dd, J2B,2A 17.5, J2B,3 4.6, C(2)HAHB), 3.37 (1H,
m, C(3)H); dC (50 MHz, D2O) 13.0, 21.4, 23.7, 30.3, 31.5,
35.6, 48.1, 174.4; m/z 159 (MH+, 100%); mmax/cmꢀ1
(KBr) 1710 (C@O), 1605. Purification by ion-exchange
chromatography gave (R)-b-aminoctanoic acid 54
ion-exchange chromatography, 56 (116 mg, 85%) as a
20
white solid: mp 208–210 ꢂC; ½aꢁD ¼ þ15:5 (c 1.0, H2O);
dH (300 MHz, D2O) 2.50–2.70 (2H, m, C(2)H2), 3.67 (3H,
s, OMe), 4.41–4.52 (1H, m, C(3)H), 6.7–7.3 (4H, m, Ph);
dC (50 MHz, D2O) 38.1, 40.5, 55.1, 111.6, 120.0, 123.1,
128.3, 130.0, 157.0, 178.0; m/z (ESIꢀ) 194 (MꢀHꢀ,
ꢀ
100%); HRMS C10H12NO3 requires 194.0817, found
194.0816; mmax/cmꢀ1 (KBr) 2966 (N–H, O–H), 1612
(C@O).
(111 mg, 88%) as a white solid with spectroscopic proper-
20
ties consistent with those of the literature: ½aꢁD ¼ ꢀ28:6
20
3.57. Preparation of (S)-b-tyrosine methyl ether 57
(c 0.4, H2O); lit.61 ½aꢁD ¼ ꢀ31:1 (c 0.51, H2O).
Following representative procedure 3, 51 (280 mg,
1.1 mmol) and TFA (5 mL) gave, after purification by
ion-exchange chromatography, 57 (206 mg, 96%) as a
3.62. Preparation 2 of (S)-b-(2-methoxyphenyl)-b-amino-
propionic acid 56
white solid with spectroscopic properties consistent with
20
those of the literature: ½aꢁD ¼ ꢀ1:4 (c 0.2, H2O), lit.18
Following representative procedure 4, 28 (35 mg,
0.07 mmol) in AcOH (5 mL) and Pd/C (45 mg) at rt gave
20
½aꢁD ¼ ꢀ7:2 (c 1.0, H2O).

S. G. Davies et al. / Tetrahedron: Asymmetry 17 (2006) 1793–1811
1809
(S)-b-(2-methoxyphenyl)-b-aminopropionic acid hydro-
chloride 56ÆHCl (20 mg, 92%) as white powder:
was filtered through Celiteꢁ, the phases were separated,
and the aqueous phase was extracted with further Et2O
(2 · 100 mL). The combined organic extracts were washed
with saturated aqueous NH4Cl (2 · 100 mL), dried
(K2CO3), filtered and the solvent was removed in vacuo.
Purification via column chromatography (EtOAc/40–60
petrol 1:4) afforded N-tert-butoxycarbonyl-2-hydroxypyr-
rolidine (1.70 g, 84%) as a colourless oil with spectroscopic
properties consistent with those of the literature:52 dH
(400 MHz, CDCl3) rotamers 1.39 and 1.42 (2 · 9H, s,
OtBu), 1.72–204 (4H, m, C(2)H2C(3)H2), 3.14–3.26 (1H,
m, C(4)HAHB), 3.35–3.47 (1H, m, C(4)HAHB), 5.27–5.41
(1H, m, C(1)H); m/z (CI+) 170 ((MꢀOH)+, 40%), 114
((MꢀOtBu)+, 12), 70 (100); mmax/cmꢀ1 (film) 3431 (O–H),
2977 (C–H), 1684 (C@O). To a stirred solution of N-tert-
butoxycarbonyl-2-hydroxypyrrolidine (1.00 g, 5.35 mmol)
in toluene (50 mL) under Ar was added (tert-butoxycar-
bonylmethyl)triphenylphosphorane (2.01 g, 5.35 mmol),
and the mixture heated to reflux for 18 h. After concentra-
tion in vacuo, purification via column chromatography
(Et2O/pentane 15:85) afforded tert-butyl (E)-6-(N-tert-but-
oxycarbonylamino)hex-2-enoate (1.16 g, 76%, >99:1 E:Z)
as a colourless oil that solidified on standing: mp 59–
60 ꢂC; dH (400 MHz, CDCl3) 1.40 and 1.44 (2 · 9H, s,
OtBu), 1.57–1.64 (2H, m, C(5)H2), 2.14–2.20 (2H, m,
C(4)H2), 3.42–3.47 (2H, m, C(6)H2), 4.65 (1H, br s, NH),
5.72 (1H, dt, J 15.7, 1.5, C(2)H), 6.79 (1H, dt, J 15.7,
7.0, C(3)H); dC (100 MHz, CDCl3) 28.1, 28.3, 28.5, 29.2,
40.0, 79.1, 80.1, 123.5, 146.6, 155.9, 165.8; m/z (EI+) 349
((MNaMeCN)+, 100%), 308 (MNa+, 55), 286 (MH+, 10);
HRMS C14H27NO4Na+ requires 308.1838, found
308.1832; mmax/cmꢀ1 (film) 3365 (N–H), 2978 (C–H), 1715
(C@O), 1695 (C@O), 1652 (C@C), 1520 (C@O). To a stir-
red solution of tert-butyl (E)-6-(N-tert-butoxycarbonyl-
amino)hex-2-enoate (800 mg, 2.81 mmol) in MeCN
(7 mL) under Ar were added Boc2O (1.22 g, 5.61 mmol)
and DMAP (84 mg, 0.70 mmol). The mixture was stirred
at rt for 18 h, after which time the volatile material was
removed in vacuo. Purification via column chromatogra-
phy on silica gel (Et2O/pentane 1:10) afforded 61
(953 mg, 88%) as a colourless oil; dH (400 MHz, CDCl3)
1.47 (9H, s, OtBu), 1.50 (18H, s, 2 · OtBu), 1.72 (2H, quin-
tet, J 7.4, C(5)H2), 2.15–2.20 (2H, m, C(4)H2), 3.58 (2H, t,
J 7.3, C(6)H2), 5.74 (1H, dt, J 15.6, 1.4, C(2)H), 6.83 (1H,
dt, J 16.0, 6.8, C(3)H); dC (100 MHz, CDCl3) 27.4, 28.0,
28.1, 29.2, 45.8, 80.1, 82.2, 123.4, 146.6, 152.5, 165.8; m/z
(EI+) 793 (M2Na+, 100%), 408 (MNa+, 35), 403
(MNH4þ, 20); HRMS C18H35NO6Na+ requires 408.2362,
found 408.2358; mmax/cmꢀ1 (film) 2980 (C–H), 1793, 1751,
1718, 1701 (C@O), 1654 (C@C).
a
20
½aꢁD ¼ þ20:0 (c 0.5, H2O); C10H14NO3Cl requires C,
51.8; H, 6.1; N, 6.05%, found: C, 51.9; H, 6.0; N, 6.0%;
dH (300 MHz, D2O) 2.87 (1H, dd, J2A,2B 17.1, J2A,3 6.5,
C(2)HAHB), 3.00 (1H, dd, J2B,2A 17.1, J2B,3 6.1,
C(2)HAHB), 3.69 (3H, s, OMe), 4.65 (1H, m, C(3)H),
6.83–7.22 (4H, m, Ph); dC (50 MHz, D2O) 35.8, 48.9,
55.5, 111.7, 121.0, 122.2, 128.9, 131.3, 157.1, 173.9; m/z
(CI+) 196 (MH+, 100%); mmax/cmꢀ1 (KBr) 1715 (C@O),
1605. Purification by ion-exchange chromatography gave
(S)-3-(2-methoxyphenyl)-b-phenylpropionic acid 56 (95%)
with spectroscopic properties consistent with those
20
reported above: ½aꢁD ¼ þ14:1 (c 1.0, H2O).
3.63. Preparation of (S)-b-tyrosine methyl ether 57
Following representative procedure 4, 30 (431 mg,
0.9 mmol) in AcOH (5 mL) and Pd/C (80 mg) at rt gave
(S)-b-(4-methoxyphenyl)-b-aminopropionic acid hydro-
chloride 57ÆHCl64 (153 mg, 87%) as a white powder: mp
20
166–168 ꢂC (decomp); ½aꢁD ¼ þ2:7 (c 0.5, H2O);
C10H14NO3Cl requires C, 51.8; H, 6.1; N, 6.05%, found
C, 51.6; H, 6.2; N, 6.25%; dH (500 MHz, D2O) 2.96 (1H,
dd, J2A,2B 17.1, J2A,3 6.8, C(2)HAHB), 3.08 (1H, dd,
J2B,2A 17.1, J2B,3 7.8, C(2)HAHB), 3.72 (3H, s, OMe),
4.56 (1H, m, C(3)H), 6.95 (2H, d, J 8.8, Ar(3)H and
Ar(5)H), 7.32 (2H, d, J 8.8, Ar(2)H and Ar(6)H); dC
(50 MHz, D2O) 37.4, 50.7, 55.1, 114.6, 125.5, 128.7,
159.6, 173.7; m/z 195 (MH+, 55%), mmax/cmꢀ1 (KBr) 1723
(C@O), 1616. Purification by ion-exchange chromatogra-
phy gave (S)-b-tyrosine methyl ether 57 (63%) with spec-
troscopic properties consistent with those reported above:
20
½aꢁD ¼ ꢀ1:0 (c 0.3, H2O).
3.64. Preparation 2 of (S)-b-Leucine 58
Following representative procedure 4, 38 (225 mg,
0.61 mmol) in AcOH (5 mL) and Pd/C (80 mg) at rt gave
(S)-b-leucine hydrochloride 58ÆHCl (90 mg, 87%) as a white
powder: C6H14NO2Cl requires C, 43.0; H, 8.4; N, 8.4%,
found C, 43.0; H, 8.65; N, 8.0%; dH (200 MHz, D2O)
0.77, 0.78 (2 · 3H, d, J 6.8, C(4)(CH3)2), 1.79 (1H, m,
C(4)H), 2.47 (1H, dd, J2A,2B 17.7, J2A,3 8.9, C(2)HAHB),
2.63 (1H, dd, J2B,2A 17.7, J2B,3 8.9, C(2)HAHB) 3.27 (1H,
m, C(3)H); dC (50 MHz, D2O) 16.6, 17.0, 29.6, 33.1, 53.2,
174.8; m/z (CI+) 131 (MH+, 100); mmax/cmꢀ1 (KBr) 1710
(C@O), 1603. Purification by ion-exchange chromatogra-
phy gave (S)-b-leucine 58 (97%) with spectroscopic proper-
20
ties consistent with those reported above: ½aꢁD ¼ ꢀ48:6 (c
1.0, H2O).
3.66. Preparation of tert-butyl (3R,aR)-3-(N-benzyl-N-
[a-methylbenzyl]amino)-6-(N0,N0-di-tert-butoxycarbonyl-
amino)hexanoate 63 and tert-butyl (E)-6-(N,N-di-tert-
butoxycarbonylamino)hex-3-enoate 62
3.65. Preparation of tert-butyl (E)-6-(N,N-di-tert-butoxy-
carbonylamino)hex-2-enoate 61
To a stirred solution of pyrrolidinone 2 (2.00 g, 10.8 mmol)
in THF (40 mL) under N2 at ꢀ78 ꢂC was added DIBAL-H
(1.0 M in hexanes, 16.2 mL, 16.2 mmol) dropwise. The
resulting solution was stirred at ꢀ78 ꢂC for 2 h and then
saturated aqueous KOAc (20 mL) was added. The mixture
was poured into Et2O/saturated aqueous NH4Cl (3:1,
200 mL) and stirred at rt for 18 h. The resulting slurry
Following representative procedure 1, n-BuLi (1.6 M,
0.45 mL, 0.72 mmol), (R)-N-benzyl-N-a-methylbenzyl-
amine (164 mg, 0.78 mmol) in THF (10 mL) and 61
(100 mg, 0.26 mmol) in THF (10 mL) gave, after column
chromatography on silica gel (30–40 petrol/Et2O 19:1), 62
(6 mg, 6%) as a colourless oil: dH (400 MHz; CDCl3)

1810
S. G. Davies et al. / Tetrahedron: Asymmetry 17 (2006) 1793–1811
1.45, (9H, s, OtBu), 1.52 (18H, s, 2 · OtBu), 2.31–2.36 (2H,
m, J 7.4, C(5)H2), 3.03 (2H, dd, J 7.0, 1.1, C(2)H2), 3.58–
3.62 (2H, m, C(6)H2), 5.54 (1H, m, C(4)H), 5.64 (1 H, m,
C(3)H); dC (100 MHz; CDCl3) 27.2, 28.1, 34.1, 45.5, 80.5,
82.2, 124.2, 128.4, 152.5; m/z (ESI+) 793 (M2Na+, 68%),
408 (MNa+, 100); HRMS C18H35NO6Na+ requires
408.2362, found 408.2360; mmax/cmꢀ1 (film) 2979 (C–H),
1790, 1732, 1695 (C@O), 1602 (C@C). Further elution
afforded a mixed fraction of b-amino ester 63 and alkene
rt for 1 h, after which time the volatile material was re-
moved in vacuo. The residue was dissolved in water
(1 mL), the pH adjusted to 8 with aqueous NaOH (1 M),
and this material was purified by ion-exchange chromato-
graphy to afford the title compound 65 as a pale yellow
21
viscous oil (23 mg, quant): ½aꢁD ¼ ꢀ19:3 (c 0.63, 1 M
HCl), lit.50 [a]D = ꢀ19.5 (c 1.0, 1 M HCl); dH (400 MHz;
D2O) 1.46–1.67 (4H, m, C(5)H2C(4)H2), 2.26 and 2.36
(2H, ABX system, AB part, JAB 15.6, JAX 7.5, JBX 6.6,
C(2)H2), 2.88 (2H, t, J 7.4, C(6)H2), 3.25 (1H, m, C(3)H);
dC (100 MHz; D2O) 24.2, 31.4, 39.7, 42.1, 48.8, 179.9;
m/z (CI+) 147 (MH+, 30%), 129 ((MꢀOH)+, 80), 112
(44), 70 (100); mmax/cmꢀ1 (film) 3352 (N–H), 2160
ðNH3þÞ, 1637 (N–H bending), 1562 ðCO2ꢀÞ, 1401 ðCO2ꢀÞ.
62 (4 mg, 74:26). Further elution then afforded 63 (67 mg,
22
44%, >95% de) as a colourless oil: ½aꢁD ¼ þ6:4 (c 0.75,
CHCl3); dH (400 MHz; CDCl3) 1.25–1.63 (3H, m obscured,
C(5)HAHB and C(4)H2), 1.35 (3H, d, J 7.0, C(a)Me), 1.40
(9H, s, OtBu), 1.51 (18H, s, 2 · OtBu), 1.83–1.88 (2H, m,
C(2)H2), 1.96 (1H, m, C(5)HAHB), 3.33 (1H, m, C(3)H),
3.48 (1H, d, J 14.9, PhCHAHB), 3.53–3.63 (2H, m,
C(6)H2), 3.77 (1H, d, J 14.5, PhCHAHB), 3.81 (1H, q, J
6.9, C(a)H), 7.21–7.43 (10H, m, Ph); dC (100 MHz; CDCl3)
20.1, 27.2, 28.0, 28.1, 30.9, 37.9, 46.6, 50.1, 53.8, 57.8, 79.9,
81.9, 126.6, 126.9, 127.9, 128.1, 128.2, 141.5, 142.6, 152.6,
171.9; m/z (ESI+) 619 (MNa+, 45%), 597 (MH+, 100);
Acknowledgements
We thank the Ministerio de Educacion y Ciencias and the
British Council for a Fleming Fellowship (N.M.G.) and
New College, Oxford, for a Junior Research Fellowship
(A.D.S.).
þ
HRMS C35H53N2O6 requires 597.3904, found 597.3898;
m
max/cmꢀ1 (film) 2977 (C–H), 1950, 1876, 1789, 1747,
1723, 1694 (C@O).
References
3.67. Preparation of tert-butyl (R)-3-amino-6-(N,N-di-tert-
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23
½aꢁD ¼ ꢀ5:7 (c 1.08, CHCl3); dH (400 MHz; CDCl3) 1.32–
1.43 (2H, m, C(5)H2), 1.44 (9H, s, OtBu), 1.49 (18H, s,
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3.52–3.70 (2H, m, C(6)H2); dC (100 MHz; CDCl3) 25.5,
28.1, 34.2, 43.4, 46.2, 48.1, 80.7, 82.2, 152.6, 171.8; m/z
(EI+) 827 (M2Na+, 20%), 805 (M2H+, 100), 403 (MH+,
95), 303 ((MHꢀBoc)+, 25); HRMS C20H39N2O requires
þ
6
403.2808, found 403.2810; mmax/cmꢀ1 (film) 3380 (N–H),
2978 (C–H), 1784, 1728, 1697 (C@O).
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1
55. Extensive signal broadening in the H NMR spectrum of the
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