A chiral ligand mediated aza-conjugate addition strategy for the enantioselective synthesis of β-amino esters that contain hydrogenolytically sensitive functionality

Article abstract of DOI:10.1016/j.tet.2015.08.018

Aza-conjugate addition of the lithium anion of N-trimethylsilyl-p-methoxybenzylamine to tert-butyl enoate acceptors, in the presence of a stoichiometric amount of enantiopure 1,2-dimethoxy-1,2-diphenylethane and excess trimethylsilyl chloride, affords ter

Full text of DOI:10.1016/j.tet.2015.08.018

Tetrahedron 71 (2015) 8838e8847
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A chiral ligand mediated aza-conjugate addition strategy for the
enantioselective synthesis of
b-amino esters that contain
hydrogenolytically sensitive functionality
a
a
b
c
a,
*
Robert M. Archer , Marc Hutchby , Caroline L. Winn , John S. Fossey , Steven D. Bull
a
Department of Chemistry, University of Bath, Bath, BA2 7AY, UK
Syngenta, Jealott’s Hill International Research Centre, Bracknell, RG42 6EY, UK
School of Chemistry, University of Birmingham, Birmingham, West Midlands, B15 2TT, UK
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 May 2015
Received in revised form 3 August 2015
Accepted 10 August 2015
Available online 14 August 2015
Aza-conjugate addition of the lithium anion of N-trimethylsilyl-p-methoxybenzylamine to tert-butyl
enoate acceptors, in the presence of a stoichiometric amount of enantiopure 1,2-dimethoxy-1,2-
diphenylethane and excess trimethylsilyl chloride, affords tert-butyl-N-p-methoxybenzyl-
ters with excellent levels of enantiocontrol. These N-p-methoxybenzyl- -amino-esters may be de-
protected under oxidative conditions via treatment with ceric ammonium nitrate, followed by acid
b-amino es-
b
hydrolysis of the resultant imine intermediates, to afford enantiopure
drogenolytically sensitive functionality.
b-amino-esters containing hy-
Keywords:
b-Amino esters
Ó 2015 Elsevier Ltd. All rights reserved.
Enantioselective synthesis
Aza-conjugate addition
Oxidative deprotection
External chiral ligand
1. Introduction
One of the more popular strategies employed for the synthesis
of enantiopure
b-amino acid derivatives involves the stereo-
Enantiomerically pure
b
-amino acids and their derivatives are
selective conjugate addition of aza-nucleophile equivalents to a-b-
17
important chiral building blocks for the synthesis of drug molecules
unsaturated acid equivalents. Within this area, a range of highly
effective protocols have been developed based on the stereo-
selective addition of lithium amides to enoate acceptors. For ex-
ample, Yamamoto and co-workers have reported that achiral
lithium N-trialkylsilylamides such as 1a add to chiral enoate ac-
1
and natural products. They are also useful as monomers for the
2
preparation of biologically active
b
-peptides and ab-peptides that
are more resistant to proteolytic cleavage than peptides derived
3
from
a-amino acids. For example, b-peptides have been reported
4
5
6
7
that display antibiotic, antifungal, antiviral, anticancer, and
ceptors that contain
g
-stereocentres with good levels of diaster-
eocontrol. Alternatively, Davies and co-workers have employed
chiral lithium amides derived from -methylbenzylamine for the
diastereoselective synthesis of an impressive number of -amino
8
18
cholesterol uptake inhibitory activities. Relatively short
sequences are also known to display defined secondary structures,
which enables foldameric -peptides to be used to investigate me-
dicinally relevant protein-protein interactions. However, the range
of naturally occurring -amino acid derivatives available from the
chiral pool is limited, and as a consequence synthetic methodology
b-peptide
9
a
b
b
10
19
esters. Tomioka and co-workers have developed an elegant ex-
ternal chiral ligand approach that enables achiral lithium silyla-
mides to be used as aza-nucleophiles for the enantioselective
b
11
is required for their preparation in enantiopure form. Effective
strategies that currently exist, include those based on kinetic reso-
synthesis of
lithium N-benzyl-N-(trimethylsilyl)amide 1a to
esters 3 in the presence of a stoichiometric amount of the chelating
-symmetric ligand (R,R)-1,2-dimethoxy-1,2-diphenylethane 2,
gave protodesilylated N-benzyl- -amino esters 4 with excellent
levels of enantiocontrol (e.g., 93% ee for 4a). These N-aryl-
amino esters could then be N-deprotected under hydrogenolytic
conditions (Pd(OH) /C, 7 atm. H ) to afford their parent -amino
b
-amino esters. They first reported that addition of
a,b
-unsaturated
12
13
lution, stereoselective addition of enolate equivalents to imines,
14
Curtius rearrangement of chiral succinate derivatives,
ArndteEistert homologation of chiral
genation/reduction of enamine and N-acyl-enamide derivatives.
C
2
15
a
-amino acids, and hydro-
b
16
20
b
-
2
2
b
2
0
esters 5a in good yield (Scheme 1a). This external chiral ligand
*
Corresponding author. E-mail address: s.d.bull@bath.ac.uk (S.D. Bull).
controlled methodology has proven to be useful for the synthesis of
http://dx.doi.org/10.1016/j.tet.2015.08.018
040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
0

R.M. Archer et al. / Tetrahedron 71 (2015) 8838e8847
8839
we now disclose that lithium N-p-methoxybenzyl-N-(trime-
thylsilyl)amide 1e can also be used as an achiral aza-nucleophile in
these type of chiral ligand mediated aza-conjugate addition re-
actions to afford chiral N-p-methoxybenzyl
excellent levels of enantiocontrol. The p-methoxybenzyl (PMB)
fragments of these N-PMB- -amino esters 6 may then be oxida-
tively deprotected using ceric ammonium nitrate (CAN) to afford
chiral NH- -amino esters 5 that may contain hydrogenolytically
sensitive functionality (Scheme 1e).
b-amino-esters 6 with
b
b
2. Results and discussion
As part of a research program directed towards the asymmetric
2
8
synthesis of b-amino acids as chiral precursors for the synthesis
of novel heterocyclic scaffolds, we required access to a range of b-
amino esters containing hydrogenolytically sensitive functionality.
Davies and co-workers had previously reported the use of lithium
N-benzyl-N-a-methyl-p-methoxybenzylamide 7 as a chiral aza-
nucleophile for the diastereoselective synthesis of chiral haloaryl-
2
9
b
-amino esters such as 8, whose N-benzyl and N-PMB protecting
groups could be removed under oxidative conditions via stepwise
3
0
treatment with excess CAN (Scheme 2). This enabled lithium
amide 7 (or its enantiomer) to be used for the asymmetric syn-
theses of a range of hydrogenolytically sensitive haloaryl and pyr-
idinyl containing
good levels of stereocontrol.
b
-amino-acids,
b
-lactams and heterocycles with
2
9,31
Given this precedent, we reasoned
that lithium N-4-methoxybenzyl-1,1,1-trimethyl-silanamide 1e
might be useful as an aza-nucleophile for Tomioka’s chiral ligand
conjugate addition methodology, since it would enable the N-PMB
groups of its corresponding b-amino-ester adducts 6 to be removed
using CAN under oxidative conditions (Scheme 1e).
Scheme 1. Tomioka’s external chiral ligand 2 methodology for the enantioselective
synthesis of -amino esters 5.
b
a range of cyclic
for the synthesis of the drugs otamixaban, premafloxacin, and
b
-amino acid derivatives;21 and intermediates
2
2
2
3
the
and (ꢀ)-kopsinine.
used to deprotect N-benzyl-
namate acceptors were reported to be problematic, sometimes
resulting in competing cleavage of their -nitrogen bonds to afford
alkaloid
natural
products
However, the hydrogenolysis conditions
-amino esters 4a derived from cin-
(ꢀ)-aspidospermidine,
2
4,25
b
b
2
6
unwanted 3-arylpropanoates. In order to address this problem,
Tomioka and co-workers introduced a range of lithium N-(tri-
alkylsilyl)-amides 1bed as second generation aza-nucleophiles for
Scheme 2. Davies’ 2nd generation oxidative deprotection methodology for the dia-
the enantioselective synthesis of N-protected-
with good levels of enantiocontrol (ꢁ86% ee) (Scheme 1bed).
range of different N-deprotection strategies were employed to
deprotect these N-protected- -amino esters 4 to afford their parent
chiral NH- -amino esters 5a in good yield. Chiral N-anthraceny-9-
yl- -amino-esters 4b could be deprotected under milder hydro-
genolytic conditions using H (1 atm) and 10% Pd/C over a period of
4 h (Scheme 1b).26 Chiral N-mesitylamine-
-amino-esters 4c was
deprotected through a three step N-chlorination/regioselective
b-amino esters 4bed
stereoselective synthesis of
functional groups.
b-amino esters containing hydrogenolytically sensitive
2
6,27
2
9
A
b
b
b
N-Trimethylsilyl-p-methoxybenzylamine 9 was first prepared by
ꢂ
2
treating p-methoxybenzylamine with n-butyllithium in THF at 0 C,
2
b
followed by addition of TMSCl and heating at reflux for 12 h. Its
corresponding lithium amide 1e was then generated via treatment
27a
ꢂ
dehydrochlorination/trans-oximation protocol (Scheme 1c);
conditions that could also be used to deprotect N-benzyl- -amino
ester 4a.22 Alternatively, chiral N-allyl-
-amino esters 4d was
deprotected using a tandem rhodium catalysed isomerisation/im-
of 1.5 equiv of amine 9 with n-butyllithium in toluene at ꢀ78 C. A
b
solution of 1.8 equiv of chiral ligand 2 in toluene was then added to
ꢂ
b
this solution of lithium amide 1e in toluene at ꢀ78 C, followed by
further addition of a solution of tert-butyl-cinnamate 3a in toluene
2
7b
ꢂ
ine hydrolysis approach (Scheme 1d).
Further to these reports,
at ꢀ78 C. The reaction was then stirred for 5 h before work-up at

8840
R.M. Archer et al. / Tetrahedron 71 (2015) 8838e8847
ꢂ
ꢀ
78 C using NH
4
Cl(aq). Promisingly, this reaction produced some
-amino ester 6a, albeit in
Table 1
Substrate scope of chiral ligand mediated aza-conjugate addition reactions of lith-
ium amide 1e to a,b-unsaturated ester derivatives 3aeh
of the desired protodesilylated N-PMB-
b
low 35% yield and poor enantioselectivity (25% ee) (Scheme 3a). We
noticed that Tomioka and co-workers had previously reported that
addition of an excess of trimethylsilyl chloride (TMSCl) had the
potential to improve the yield and stereoselectivity of these type of
aza-conjugate addition reactions. Consequently, we repeated this
aza-conjugate reaction under identical conditions, except that we
employed a solution of tert-butyl-cinnamate and 5.0 equiv of TMSCl
in the final addition step. To our delight, the presence of excess
2
0
TMSCl resulted in formation of the desired (R)-N-PMB-b-amino
ester 6a in a much improved 77% yield and 95% ee (Scheme 3b).
Entry
Enoate 3aeha
R
N-PMB-
Amino ester
aeh
b
-
Yield (%)b
ee (%)c,d
6
1
2
3a
3b
6a
6b
77
79
95
95
3
4
5
6
3c
3d
3e
3f
6c
6d
6e
6f
76
62
40e
86
95
95
95
95
7
8
3g
3h
6g
6h
73
68
95
95
Scheme 3. Chiral ligand 2 mediated aza-conjugate addition reaction of lithium amide
1e to tert-butyl enoate 3a in the presence of excess TMSCl affords
b-amino ester 6a in
good yield and high ee.
The scope and limitation of this aza-conjugate addition re-
action was then investigated by reacting lithium amide 1e with
a
See experimental section for syntheses of tert-butyl enoates 3.
Isolated yields of N-PMB-b-amino esters 6aeh after purification by
b
a range of
a
,
b
-unsaturated tert-butyl enoates 3beh in the presence
chromatography.
c
Ee’s of N-PMB-
b
-amino-esters 6aeh inferred from ee values subsequently de-
-amino esters 5aeh (vide infra).
of excess TMSCl, including some substrates that contained
hydrogenolytically sensitive functionality (Table 1). Therefore, tert-
butyl cinnamate ester substrates containing halo-aryl 3bec and
cyano-aryl substituents 3d afforded their corresponding
esters 6bed in good yields (62e79%) and with 95% ee (Table 1,
Entries 2e4). However, (E)-tert-butyl 3-(4-nitrophenyl)acrylate 3e
termined for their parent N-deprotected
b
d
1
Error limit of ꢃ3% ee arising from detection limit of the H NMR chiral deriva-
tisation protocol used to determine the ee’s of -amino esters 5aeh.
-amino ester 6e due to poor conversion, with significant
b
e
b
-amino
Low yield of N-PMB-b
1
amounts of unreacted tert-butyl enoate 3e present in the H NMR spectrum of the
crude reaction product.
proved less reactive, affording N-PMB-b-amino ester 6e in only
4
0% yield and 95% ee (Table 1, Entry 5), with the poor yield being
due to the presence of unreacted tert-butyl enoate 3e. Aza-
conjugate addition reactions of heteroatom containing tert-butyl
enoates were also successful, with (E)-tert-butyl 3-(thiophen-2-yl)
acrylate 3f and (E)-tert-butyl 3-(furan-2-yl)acrylate 3g affording
3 results in dissociation of these heterodimeric complexes to afford
a new monomeric complex 11 containing 1 equiv of lithium amide,
1 equiv of chiral ligand and 1 equiv of enoate. Intramolecular
transfer of the amide fragment of complex 11 to its enoate fragment
then occurs in a highly enantiofacial manner to afford a (Z)-enolate
their corresponding
6% and 73% yield, respectively (Table 1, Entries 6e7). Finally, it
was shown that the simple acyclic (E)-tert-butyl hept-2-enoate 3h
b-amino esters 6f (95% ee) and 6g (95% ee) in
8
4
12 that is then protonated on work-up with NH Cl(aq) to afford
the desired N-PMB- -amino ester 6 (Fig. 1). The role of TMSCl
b
afforded its corresponding N-PMB-
and 95% ee.
b
-amino ester 6h in 68% yield
in improving the yield and enantioselectivity of these type of
aza-conjugate addition reactions is unclear, however its presence
may result in some form of deaggregation occurring to afford
a more reactive lithium amide species that reacts with better levels
of enantiocontrol. Alternatively, it is possible that TMSCl may also
act as an electrophilic O-silylating agent to trap out (Z)-enolate 12
as its corresponding (Z)-silyl-ketene acetal 13 in situ, that is then
Tomioka and co-workers have recently employed 6Li NMR
spectroscopy to demonstrate that addition of chiral ligand 2 to
lithium amide 1e initially results in formation of a mixture of cis-
and trans-cyclic heterodimeric complexes (only trans-dimer 10
shown in Fig. 1).32 They proposed that addition of tert-butyl enoate
2
0

R.M. Archer et al. / Tetrahedron 71 (2015) 8838e8847
8841
proton of 16 is then deprotonated by water to afford a stabilized
benzylic radical resonance form 17. A second equivalent of CAN
then oxidises radical 17 to afford benzylic cation 18 which is res-
onance stabilized as its iminium species 19 that is subsequently
isolated as imine 15a after basic workup. After a short optimisation
screen of solvents, acids and reaction time, it was found that stir-
ring a solution of N-PMB-imine 15a in MeCN/H
presence of 15 equiv of acetic acid at room temperature for 48 h
followed by neutralisation with NaHCO (aq) and purification by
chromatography, furnished (R)- -amino-tert-butyl ester 5a in 83%
yield and 95% ee. The (R)- configuration and 95% ee of (R)-
amino-tert-butyl ester 5a was confirmed by comparison of the sign
2
O (5:1) in the
3
b
b
-
2
3
and magnitude of its specific rotation of [
a
]
D
þ20.0 (c 1.2, CHCl
3
),
2
3
29
with the literature value of [
a
]
D
þ19.7 (c 0.96, CHCl
3
).
Fig. 1. Potential role of TMSCl in improving yields and enantioselectivities of chiral
ligand 2 mediated aza-conjugate addition reactions of lithium amide 1e with tert-butyl
enoates 3.
protonated on work-up with NH
4
Cl(aq) to afford the desired N-
27a
PMB-b-amino ester 6 (Fig. 1).
This would perturb the equilibria
of the potentially reversible intramolecular aza-conjugate addition
step (11%12), by preventing the reverse E1cB-elimination reaction
of (Z)-enolate 12 from occurring. Furthermore, it has been shown
that enolates such as 12 can react with lithium amide complexes of
ligand 2 to afford competing dimeric lithium complexes such as
Scheme 4. CAN mediated oxidative N-deprotection of N-PMB-
afford an intermediate imine 15a that is then hydrolysed under aqueous acidic con-
ditions to afford -amino ester 5a.
b-amino ester 6a to
b
3
3
1
4, which could potentially be responsible for competing non-
stereoselective aza-conjugate addition pathways that afford N-
PMB- -amino ester 6 with poorer levels of control in the absence of
This oxidative N-deprotection methodology was then applied to
unmask the remaining N-PMB- -amino esters 6beh to afford their
corresponding deprotected NH- -amino esters 5beh in moderate
to good yields (36e73%) over two steps (Table 2). It was found that
the <60% yields obtained for formation of NH- -amino esters 5b, 5e
b
b
b
TMSCl. Therefore, it is possible that the presence of excess TMSCl
not only results in (Z)-enolate 12 being rapidly trapped as its O-silyl
ketene acetal 13,34 but also ensures that the concentration of free
enolate 12 remains sufficiently low to ensure that the enantiose-
lective pathway to N-PMB-b-amino ester 6 predominates (Fig. 1).
Having successfully identified conditions that enabled lithium
amide 1e to be used as an effective aza-nucleophile for the enan-
b
and 5f (Entries 2, 4 and 6) were due to competing acid catalysed
cleavage of their tert-butyl ester fragments that gave their corre-
sponding acids during the imine hydrolysis step. Evidence for this
1
competing tert-butyl cleavage pathway was obtained from H NMR
spectroscopic and mass spectrometric analysis of the aqueous
washings of the crude reaction products of their imine hydrolysis
reactions, which clearly revealed the presence of their corre-
tioselective synthesis of N-PMB-
investigated their N-deprotection under oxidative conditions.
Treatment of N-PMB- -amino ester 6a with 4.0 equiv of CAN in
MeCN/H O (5:1) solution, followed by basic work up using NaH-
b-amino esters 6aeh, we next
3
5
b
sponding
The enantiomeric excesses of
firmed as 95% ee using a simple three-component chiral derivati-
b-amino acids.
2
b
-amino esters 5aeh were con-
CO
3
(aq),2 afforded N-PMB-imine 15a in essentially quantitative
9
3
6
yield (Scheme 4). A plausible mechanism for this CAN mediated
oxidative N-deprotection step is presented in Scheme 4, whereby
CAN first acts as an electron acceptor from the p-methoxyphenyl
sation protocol previously developed in our research group. In
this approach, a chiral amine of unknown enantiomeric excess is
derivatised with 2-formylphenyl boronic acid and enantiopure
BINOL to afford a mixture of diastereomeric imino-boronate esters
(
PMP) group to afford a stabilised radical cation 16. A benzylic

8842
R.M. Archer et al. / Tetrahedron 71 (2015) 8838e8847
Table 2
CAN deprotection reactions of N-PMB-b-amino esters 6aeh
Entry N-PMB-
Amino ester
aeh
b
-
R
b
-Amino ester Yield (%)a ee (%)c,d
5aeh
6
1
2
6a
6b
5a
5b
68
95
95
Scheme 5. Chiral derivatisation protocol used to determine the enantiopurity of
amino ester 5a as 95% ee.
b-
56b
3
4
5
6c
6d
6e
5c
5d
5e
68
95
95
95
51b
65
6
7
8
6f
5f
36b
73
95
95
95
6g
6h
5g
5h
60
Fig. 2. a) 1H NMR spectrum of 50:50 mixture of diastereomeric iminoboronate ester
1
a
complexes (RBIN,R)-21 and (SBIN,R)-22. b) H NMR spectrum of a 97.5:2.5 mixture of
Isolated yields of
b
-amino esters 5aeh after purification by chromatography.
b
diastereomeric iminoboronate ester complexes (RBIN,R)-21 and (RBIN,S)-22.
Lower yields of
b-amino esters 5d and 5f due to competing cleavage of their tert-
butyl ester fragments in the imine hydrolysis step to give their corresponding b-
amino acids.
(
Scheme 5b). This ratio was accurately determined by comparison
c
Ee’s determined by derivatisation of
formylphenylboronic acid and (R)-BINOL followed by H NMR spectroscopic anal-
b-amino esters 5aeh with 2-
1
of the integral ratios of the well resolved tert-butyl proton singlet
resonances of (RBIN,R)-21 (O(CH
d
B
D
36
3 3
)) and (RBIN,S)-22 (O(CH )) at
ysis of the ratio of the resultant mixture of diastereomeric imino-boronate esters;.
d
1
Error limit of ꢃ3% in ee arising from the detection limit of the H NMR chiral
0.85 and 1.15 ppm, respectively (Fig. 2b). Therefore, since no ki-
d
derivatisation protocol.
netic resolution occur in the derivatisation process, it follows that
this 97.5:2.5 diasteromeric ratio corresponds to the enantiomeric
ratio of chiral amine 5a, thus allowing us to conclude that it had
been formed in 95% ee.
1
whose ratio can be determined by H NMR spectroscopic analysis.
Since no kinetic resolution occurs in this derivatisation process, this
diasteromeric ratio corresponds to the enantiomeric ratio of the
parent chiral amine. For example,
derivatised via treatment with 2-formylphenylboronic acid 20,
rac)-BINOL, and K CO in CDCl for 10 min to afford a 50:50 mix-
ture of the diastereomeric iminoboronate esters (RBIN,R)-21 and
(SBIN,R)-22 (Scheme 5a). Analysis of the H NMR spectrum of this
mixture revealed well resolved resonances corresponding to the
b-amino ester (R)-5a was first
3
. Conclusions
(
2
3
3
Aza-conjugate addition of lithium amide 1e to tert-butyl
1
enoates, in the presence of a stoichiometric amount of an external
chiral ligand 2 and excess trimethylsilyl chloride, affords tert-butyl
N-PMB-
trol. The resultant tert-butyl N-PMB-
deprotected via treatment with CAN, followed by acid hydrolysis of
b
-amino esters 6aeh with excellent levels of enantiocon-
diastereotopic methylene and tert-butyl ester protons of the
0
0
C
A
A
B
C
b
-amino esters 6aeh may be
(
CH
R
BIN,R)-21 (CH , CH and CH
3
) and (SBIN,R)-22 (CH , CH and
) diastereomers, respectively (Dd
¼0.1e0.4 ppm), whose in-
tegrals could be used to accurately determine their diastereomeric
ratio (Fig. 2a). A sample of -amino ester (R)-5a generated using our
D
3
H
their resultant imine intermediates, to afford their parent chiral
amino-esters 5aeh (95% ee). The ability to deprotect N-PMB-
b
-
-
b
b
amino esters 6 under oxidative conditions enables this second
generation variant of Tomioka’s external chiral ligand mediated
lithium amide methodology to be used for the enantioselective
enantioselective aza-conjugate addition protocol, was then deri-
vatised with 2-formylphenylboronic acid 20 and enantiopure (R)-
1
BINOL, with H NMR spectroscopic analysis revealing that (RBIN,R)-
synthesis of
b-amino esters 6 that contain functionalities that are
21 and (RBIN,S)-22 were present in a diastereomeric ratio of 97.5:2.5
susceptible to hydrogenolysis.

R.M. Archer et al. / Tetrahedron 71 (2015) 8838e8847
8843
4
4
. Experimental
tert-butyl acrylate (2.12 mL, 14.5 mmol), tri(o-tolyl)phosphine
0.40 g, 13.2 mmol) and palladium(II) acetate (0.15 g, 0.66 mmol) in
(
.1. General methods
MeCN (80 mL) was heated at reflux for 17 h. The suspension was
then cooled to room temperature, diluted with water (60 mL) and
extracted with EtOAc (3ꢄ50 mL). The combined organic extracts
Reactions that required the use of dry solvents were conducted in
oven dried glassware under an atmosphere of nitrogen using inert
atmosphere techniques. Dry solvents were obtained by passing
them through anhydrous alumina columns using an Innovative
Technology Inc. PS-400-7 solvent purification system. Petrol refers
to the fraction of petroleum ether boiling at 40e60 C. Hexanes
refers to the hexane fraction of petroleum. Solvents were evaporated
were washed with brine and water, dried over anhydrous MgSO
4
and concentrated in vacuo. The residue was purified by flash
chromatography (EtOAc-petrol, 1:30) to afford the title compound
1
as a yellow oil (1.94 g, 72% yield). H NMR (300 MHz, CDCl
3
)
H
d ¼7.51
ꢂ
(1H, d, J¼16.0 Hz, CH]CHCO
2
), 7.47e7.25 (5H, m, Ph), 6.30 (1H, d,
), 1.46 (9H, s, C(CH ) ); C NMR (75 MHz,
13
J¼16.0 Hz, CH]CHCO
2
3 3
on a B u€ chi Rotorvapor. All commercially available compounds were
CDCl
)
d
C
¼166.3, 143.6, 134.7, 123.0, 128.8, 128.0, 120.2, 80.5, 28.2;
3
1
13
ꢀ1
used as obtained from chemical suppliers. H and C NMR spectra
were run in CDCl using Bruker Avance 250/300/400/500 MHz
spectrometers. Chemical shifts ( ) are quoted in parts per million
and are referenced to the residual solvent peak. Coupling constants
J) are quoted to the nearest 0.1 Hz. Infra-red spectra were recorded
IR (thin film)
16NaO
y
max (cm ): 1703 (s, C]O); HRMS (ESI): m/z 227.1025,
þ
3
C
13
H
2
[MþNa] requires 227.1043.
d
4.2. General procedure 1: synthesis of tert-butyl enoates 3beg
(
on a Perkin Elmer Spectrum 100 FT-IR spectrometer, using a Uni-
versal ATR accessory for sampling, with only selected absorbances
Methylmagnesium bromide (1 equiv) was added to a solution of
tert-butyl 2-(diethoxyphosphoryl)acetate (1 equiv) in dry THF
(0.1 M) at room temperature under an inert atmosphere and the
mixture stirred for 15 min. A dry solution of the appropriate aryl
aldehyde (1 equiv) in THF (0.2M) was then added dropwise (5 min)
and the reaction mixture heated at reflux for 18 h. After cooling to
ꢀ1
quoted as
n in cm . Mass spectra were recorded on a micrOTOF
electrospray time-of-flight (ESI-TOF) mass spectrometer (Bruker
Daltonik GmbH, Bremen, Germany), using acetonitrile or water to
dissolve the sample. TLC was carried out using commercially avail-
able polyethylene backed plates coated with Merck Kieselgel 60
GF254. Plates were visualised under UV light (at 254 nm) or by
staining with potassium permanganate, ninhydrin or phosphomo-
lybdic acid followed by gentle heating. Flash chromatography was
performed under manually generated medium pressure using
room temperature, saturated NH
extracted with Et
O (3ꢄ30 mL). The combined organic extracts
were washed with brine and water, dried over anhydrous MgSO
4
Cl(aq) was added and the mixture
2
4
,
filtered and concentrated in vacuo. The residue was then purified
by silica gel chromatography (EtOAc-petrol, 1:30) to afford the
desired tert-butyl enoate 3.
Merck 60H silica gel (35e75 mm) unless otherwise stated.
4
(
.1.1. (R,R)-1,2-Dimethoxy-1,2-diphenylethane 2. (R,R)-Hydrobenzoin
1.00 g, 4.67 mmol) was added dropwise (5 min) to a stirred
refluxing suspension of sodium hydride (60% dispersion, 0.467 g,
4.2.1. (E)-tert-Butyl
benzaldehyde (0.36 g, 2 mmol) was used to prepare the title
compound as a white solid (0.404 g, 72% yield) using general pro-
3-(4-bromophenyl)acrylate
3b. 4-Bromo-
ꢂ
1
11.7 mmol) in dry THF (10 mL). This mixture was heated at reflux for
cedure 1. Mp 53e55 C; H NMR (300 MHz, CDCl
J¼15.8 Hz, CH]CHCO ), 7.42 (2H, d, J¼6.8 Hz, BrCCHCH), 7.29 (2H,
), 1.46
3
)
d
H
¼7.47 (1H, d,
ꢂ
a further 30 min and then cooled to 0 C prior to the addition of
methyl iodide (15.0 mL, 100 mmol). The reaction was then stirred at
room temperature overnight, whereupon TLC analysis showed
2
d, J¼6.8 Hz, BrCCHCH), 6.31 (1H, d, J¼15.8 Hz, CH]CHCO
2
13
(9H, s, C(CH
3
)
3
); C NMR (75 MHz, CDCl
3
)
C
d ¼166.1, 142.2, 133.6,
ꢂ
ꢀ1
consumption of the starting material. The mixture was cooled to 0 C
132.1, 129.36, 124.2, 120.9, 80.8, 28.2; IR (thin film)
1704 (s, C]O); HRMS (ESI): m/z 305.0129, C13
requires 305.0153.
y
max (cm ):
and quenched with water (10 mL), extracted with EtOAc (3ꢄ50 mL),
H15BrNaO
2
[MþNa]þ
washed with brine, dried over anhydrous MgSO
4
, filtered and con-
centrated in vacuo. The residue was recrystallised from hexane/Et
to afford the title compound as a white crystalline solid (0.68 g, 60%).
2
O
4.2.2. (E)-tert-Butyl
Dichlorobenzaldehyde (0.52 g, 3 mmol) was used to prepare the
3-(2,4-dichlorophenyl)acrylate
3c. 2,4-
2
5
37
23
1
[
(
4
d
a
]
D
ꢀ15.1 (c 1.8, CHCl
3
) Lit.
[
a
]
D
ꢀ15.2 (c 2.1, CHCl
3
); H NMR
300 MHz, CDCl
.34 (2H, s, CHOCH
3
)
d
H
¼7.23e7.15 (6H, m, Ph), 7.08e6.98 (4H, m, Ph),
title compound as a colourless oil (0.59 g, 78% yield) using general
13
1
3
), 3.30 (6H, s, OCH
3
); C NMR (75 MHz, CDCl
3
)
procedure 1. H NMR (300 MHz, CDCl
3
)
H
d ¼7.92 (1H, d, J¼16.0 Hz,
ꢀ
1
C
¼138.2, 127.9, 127.8, 127.6, 87.7, 57.2; IR (thin film)
y
max (cm ):
CH]CHCO
2
), 7.54 (1H, d, J¼8.5 Hz, CHCCl), 7.43 (1H, d, J¼2.0 Hz,
1
C
492 (w, C]C), 1455 (w, C]C); HRMS (ESI): m/z 265.1188,
CClCHCCl), 7.25 (1H, dd, J¼8.6 and 2.0 Hz, CCHCH), 6.35 (1H, d,
þ
13
16
H18NaO
2
[MþNa] requires 265.1199.
J¼16.1 Hz, CH]CHCO
CDCl
¼165.6, 138.1, 136.0, 135.4, 131.5, 129.9, 128.3, 127.5, 123.2,
81.0, 28.2; IR (thin film)
z 295.0244, C13 NaO
2 3 3
), 1.54 (9H, s, C(CH ) ); C NMR (75 MHz,
3 C
) d
ꢀ1
4.1.2. N-(4-Methoxybenzyl)-1,1,1-trimethylsilanamine
9. n-Butyl-
ymax (cm ): 1706 (s, C]O); HRMS (ESI): m/
lithium solution (2.3 M in hexanes, 6.6 mL, 38.2 mmol) was added to
H14Cl
2
2
[MþNa]þ requires 295.0269.
a stirred solution of para-methoxybenzylamine (5.00 g, 36.4 mmol)
ꢂ
in THF (140 mL) at 0 C. The reaction was stirred at room tempera-
4.2.3. (E)-tert-Butyl
Formylbenzonitrile (0.39 g, 3 mmol) was used to prepare the title
compound as a white solid (0.59 g, 82% yield) using general pro-
3-(4-cyanophenyl)acrylate
3d. 4-
ꢂ
ture for 8 h before being cooled to 0 C and a solution of TMSCl
(
4.67 mL, 36.8 mmol) in THF (40 mL) added dropwise. The reaction
was heated at reflux for 12 h, concentrated, triturated with pentane
2ꢄ100 mL) and solvent removed in vacuo to afford the title com-
ꢂ
1
cedure 1. Mp 140e142 C; H NMR (300 MHz, CDCl
d, J¼7.6 Hz, NCCCH), 7.58 (2H, d, J¼7.6 Hz, NCCCHCH), 7.55 (1H, d,
J¼16.1 Hz, CH]CHCO ), 6.45 (1H, d, J¼16.1 Hz, CH]CHCO ), 1.54
); C NMR (75 MHz, CDCl
¼165.4, 141.1, 139.0,
ꢀ
132.6, 128.3, 123.8, 118.4, 113.1, 81.2, 28.1; IR (thin film) ymax (cm ):
3
)
d
H
¼7.67 (2H,
(
1
pound as a yellow oil (5.59 g, 73% yield). H NMR (300 MHz, CDCl
¼7.16 (2H, d, J¼8.6 Hz, CH OCCHCH), 6.82 (2H, d, J¼8.6 Hz,
CH N), 3.7 (3H, s, OCH ),1.90 (1H, br
OCCH), 3.77 (2H, d, J¼7.8 Hz, CH
s, NH), 0.00 (9H, s, Si(CH ); C NMR (75 MHz, CDCl
¼158.2,
36.5, 129.1, 113.85, 55.2, 45.3, 0.0; IR (thin film) max (cm ): 3305
w, NH), 1505, 1499 (m, m, C]C).
3
)
2
2
13
d
H
3
(9H, s, C(CH
3
)
3
3 C
) d
1
3
2
3
13
)
3 3
3
)
d
C
2226 (m, CN), 1702 (s, C]O); HRMS (ESI): m/z 252.0990,
ꢀ
1
[MþNa]þ requires 252.1000.
1
(
y
14 2
C H15NNaO
4.2.4. (E)-tert-Butyl
3-(4-nitrophenyl)acrylate
3e. 4-Nitrobenz
4
.1.3. (E)-tert-Butyl 3-phenylacrylate 3a. A solution of iodobenzene
aldehyde (0.30 g, 2 mmol) was used to prepare the title compound
as a colourless oil (0.35 g, 70% yield) using general procedure 1. H
1
(
2.69 g, 13.2 mmol) diisopropylethylamine (6.90 mL, 39.6 mmol),

8844
R.M. Archer et al. / Tetrahedron 71 (2015) 8838e8847
NMR (300MHz, CDCl
J¼8.7 Hz, O NCCHCH), 7.53 (1H, d, J¼16.0 Hz, CH]CHCO
d, J¼16.0 Hz, CH]CHCO
CDCl
thin film)
15NNaO
3
)
d
H
¼8.14 (2H, d, J¼8.7 Hz, O
2
NCCH), 7.57(2H, d,
), 6.42 (1H,
); C NMR (75 MHz,
5.8 mmol) was used to prepare the title compound as a yellow oil
2
6
2
2
(1.52 g, 77% yield) using general procedure 2. [
a
]
D
þ25.9 (c 3.2,
¼7.43e7.26 (5H, m, Ph), 7.22
), 6.87 (2H, d, J¼8.6 Hz, CHCHCOCH ),
4.09 (1H, dd, J¼8.6 and 5.5 Hz, CHNH), 3.82 (3H, s, OCH ), 3.61 (1H,
1
3
1
2
), 1.46 (9H, s, C(CH
)
3 3
2 2 3 H
CH Cl ); H NMR (300 MHz, CDCl ) d
3
)
d
C
¼165.3, 148.3, 140.9, 140.6, 128.5, 124.5, 124.1, 81.5, 28.1; IR
(2H, d, J¼8.6 Hz, CHCHCOCH
3
3
ꢀ
1
(
C
y
max (cm ): 1708 (s, C]O); HRMS (ESI): m/z 272.0878,
3
þ
A
B
A B
13
H
4
[MþNa] requires 272.0899.
d, J¼12.9 Hz, NHCH H ), 3.51 (1H, d, J¼12.9 Hz, NHCH H ), 2.68
A B
(
1H, dd, J¼15.3 and 8.7 Hz, CH CH CO
2
), 2.56 (1H, dd, J¼15.3 and
A
B
13
4.2.5. (E)-tert-Butyl 3-(thiophen-2-yl)acrylate 3f. Thiophene-2-
5.6 Hz, CH CH CO
2
), 2.20 (1H, br s, NH), 1.40 (9H, s, C(CH
3
)
3
);
C
carboxaldehyde (0.44 g, 4 mmol) was used to prepare the title
compound as a colourless oil (0.60 g, 71% yield) using general
NMR (75 MHz, CDCl
3
)
d
C
¼171.1, 158.6, 142.8, 132.6, 129.3, 128.5,
127.4, 113.8, 80.6, 59.1, 55.3, 50.8, 44.3, 28.0; IR (thin film)
y
max
1
ꢀ1
procedure 1. H NMR (300 MHz, CDCl
3
)
d
H
¼7.67 (1H, d, J¼15.7 Hz,
(cm ): 1721 (s, C]O); HRMS (ESI): m/z 364.1911, C21
H27NNaO
3
CH]CHCO
2
), 7.32 (1H, d, J¼5.1 Hz, CHS), 7.20 (1H, d, J¼3.5 Hz,
[MþNa]þ requires 364.1889.
CHCS), 7.02 (1H, dd, J¼5.1 and 3.6 Hz, CHCHCHS), 6.16 (1H, d,
1
3
J¼15.7 Hz, CH]CHCO
2
), 1.51 (9H, s, C(CH
3
)
3
); C NMR (75 MHz,
4.3.2. (R)-tert-Butyl 3-(4-bromophenyl)-3-((4-methoxybenzyl)amino)-
propanoate 6b. (E)-tert-Butyl 3-(4-bromophenyl)acrylate 1b
(0.55 g, 1.95 mmol) was used to prepare the title compound as
a white solid (0.64 g, 79% yield) using general procedure 2.
3 C
CDCl ) d
film)
¼166.2, 139.8, 136.1, 130.5, 128.0, 119.0, 80.5, 28.2; IR (thin
ꢀ
1
ymax (cm ): 1699 (s, C]O); HRMS (ESI): m/z 233.0591,
C
11
H14NaO
2
S [MþNa]þ requires 233.0612.
2
6
1
[a
]
D
þ38.6 (c 1.71, EtOAc); H NMR (300 MHz, CDCl
3
)
d
H
¼7.40 (2H,
4.2.6. (E)-tert-Butyl
3-(furan-2-yl)acrylate
3g. Furan-2-carbo
d, J¼8.3 Hz, CHCHCBr), 7.18 (2H, d, J¼8.3 Hz, CHCHCBr), 7.09 (2H, d,
xaldehyde (0.48 g, 5 mmol) was used to prepare the title com-
pound as a yellow oil (0.52 g, 65% yield) using general procedure 1.
J¼8.5 Hz, CHCHCOCH
(1H, dd, J¼8.4 and 5.4 Hz, CHNH), 3.72 (3H, s, OCH
A B
3
), 6.77 (2H, d, J¼8.5 Hz, CHCHCOCH
3
), 3.95
3
), 3.48 (1H, d,
1
A
B
H NMR (300 MHz, CDCl
3
)
d
H
¼7.38 (1H, d, J¼1.6 Hz, CHO), 7.26 (1H,
J¼12.5 Hz, NHCH H ), 3.38 (1H, d, J¼12.5 Hz, NHCH H ), 2.52 (1H,
A B
d, J¼15.9 Hz, CH]CHCO
2
), 6.50 (1H, d, J¼3.4 Hz, CHCO), 6.38 (1H,
dd, J¼15.4 and 8.4 Hz, CH CH CO ), 2.40 (1H, dd, J¼15.4 and 5.4 Hz,
13
2
A
B
dd, J¼3.4 and 1.8 Hz, CHCHCHO), 6.18 (1H, d, J¼15.9 Hz, CH]
CH CH CO
2 3 3
), 1.94 (1H, br s, NH), 1.30 (9H, s, C(CH ) ); C NMR
13
CHCO
1
2
), 1.44 (9H, s, C(CH
3
)
3
); C NMR (75 MHz, CDCl
3
)
d
C
¼166.4,
(75 MHz, CDCl
3
)
d
C
¼170.8, 158.6, 141.8, 132.2, 131.6, 129.3, 129.1,
51.2, 144.4, 130.1, 118.0, 114.0, 112.1, 80.4, 28.2; IR (thin film)
y
max
121.1, 113.8, 80.9, 58.5, 55.3, 50.8, 44.1, 28.0; IR (thin film)
y
max
ꢀ
1
ꢀ1
(
[
cm ): 1701 (s, C]O); HRMS (ESI): m/z 217.0875, C11
MþNa] requires 217.0841.
H14NaO
3
(cm ): 1739 (s, C]O); HRMS (ESI): m/z 442.1006, C21
H26BrNNaO
3
þ
[MþNa]þ requires 442.0994.
4
4
.2.7. (E)-tert-Butyl hept-2-enoate 3h. tert-Butyl acrylate (5.92 mL,
0.8 mmol) and Grubbs second generation catalyst (0.10 g) were
4.3.3. (R)-tert-Butyl 3-(2,4-dichlorophenyl)-3-((4-methoxybenzyl)-
amino)propanoate 6c. (E)-tert-Butyl 3-(2,4-dichlorophenyl)acrylate
1c (0.45 g, 1.67 mmol) was used to prepare the title compound as
added to a solution of hex-1-ene (2.89 mL, 13.6 mmol) in CH
2 2
Cl
27
(
29 mL) under an inert atmosphere. The reaction mixture was
a yellow oil (0.52 g, 76% yield) using general procedure 2. [
(c 1.58, CH Cl ); H NMR (300 MHz, CDCl ) d
2 2 3 H
a
]
D
þ24.1
¼7.48 (1H, d, J¼8.5 Hz,
CHCHCCl), 7.29 (1H, d, J¼2.1 Hz, CClCHCCl), 7.19 (1H, dd, J¼8.4 and
2.1 Hz, CHCHCCl), 7.09 (2H, d, J¼8.6 Hz, CHCHCOCH ), 6.75 (2H, d,
J¼8.6 Hz, CHCHCOCH ), 4.44 (1H, dd, J¼8.6 and 4.5 Hz, CHNH), 3.70
(3H, s, OCH
), 3.46 (1H, d, J¼12.5 Hz, NHCH H ), 3.41 (1H, d,
J¼12.8 Hz, NHCH H ), 2.51 (1H, dd, J¼15.6 and 4.7 Hz, CH CH CO
1
stirred at room temperature for 24 h and then filtered through
Celite and concentrated in vacuo. Distillation of the residue affor-
ded the title compound as a colourless oil (1.42 g, 55% yield). Bp
3
ꢂ
1
9
0 C @ 0.8 Torr; H NMR (250 MHz, CDCl
and 6.9 Hz, CH
CH]CH), 5.66 (1H, dt, J¼15.7 and 1.5 Hz, CH
eCH eCH), 1.49 (9H, s,
), 0.93 (3H, t, J¼7.1 Hz,
3
)
d
H
¼6.78 (1H, dt, J¼15.7
3
A
B
2
2
CH]
3
A
B
A
B
CH), 2.10 (2H, qd, J¼7.1 and 1.5 Hz, CH
2
2
2
),
);
A
B
C(CH
CH CH
3
)
3
), 1.37e1.18 (4H, m, CH
3
CH
2
CH
2
2.40 (1H, dd, J¼15.5 and 8.8 Hz, CH CH CO
2 3 3
), 1.31 (9H, s, C(CH )
13
13
3
2
); C NMR (75 MHz, CDCl
3
)
d
C
¼166.6, 148.5, 123.3, 80.3,
C NMR (75 MHz, CDCl
3
)
d
C
¼170.6, 158.7, 138.5, 134.2, 133.3, 129.4,
ꢀ
1
3
2.2, 30.6, 28.5, 22.6,14.2; IR (thin film)
y
max (cm ): 1706 (s, C]O);
129.3, 127.5, 113.8, 81.0, 55.3, 55.1, 51.0, 42.2, 28.1; IR (thin film)
y
max
þ
ꢀ1
HRMS (ESI): m/z 207.1343, C11 20NaO
H
2
[MþNa] requires 207.1361.
(cm ): 1723 (s, C]O); HRMS (ESI): m/z 432.1128, C21
H25Cl
2
NNaO
3
[
MþNa]þ requires 432.1110.
4
.3. General procedure 2: enantioselective synthesis of N-p-
methoxybenyl-
b
-amino esters 6aeh
4.3.4. (R)-tert-Butyl 3-(4-cyanophenyl)-3-((4-methoxybenzyl)amino)-
propanoate 6d. (E)-tert-Butyl 3-(4-cyanophenyl)acrylate 1d
(0.23 g,1 mmol) was used to prepare the title compound as a yellow
n-Butyllithium (2.5 M in hexanes, 1.5 equiv) was added drop-
wise (5 min) to a solution of N-(4-methoxybenzyl)-1,1,1-trimethyl-
2
6
oil (0.23 g, 62% yield) using general procedure 2. [
EtOAc); H NMR (300 MHz, CDCl ) d
3 H
a
]
D
þ42.7 (c 3.35,
¼7.56 (2H, d, J¼8.4 Hz,
CHCHCCN), 7.42 (2H, d, J¼8.4 Hz, CHCHCCN), 7.07 (2H, d, J¼8.6 Hz,
CHCHCOCH ), 4.03 (1H, dd,
), 6.76 (2H, d, J¼8.6 Hz, CHCHCOCH
J¼8.4 and 5.3 Hz, CHNH), 3.71 (3H, s, OCH ), 3.46 (1H, d, J¼12.9 Hz,
ꢂ
1
silanamine 9 (1.5 equiv) in dry toluene (0.33 M) at ꢀ78 C. After
ꢂ
stirring the mixture at ꢀ78 C for 30 min, a solution of chiral ligand
2
(1.8 equiv) in dry toluene (1 M) was added dropwise (5 min). After
3
3
ꢂ
stirring the mixture for a further 30 min at ꢀ78 C, a solution of the
appropriate tert-butyl ester 1 (1 equiv) and TMSCl (5 equiv) in dry
toluene (2 M) was then added dropwise (5 min). The reaction
3
A
B
A B
NHCH H ), 3.38 (1H, d, J¼12.9 Hz, NHCH H ), 2.53 (1H, dd, J¼15.4
A
B
and 8.3 Hz, CH CH CO
2
), 2.41 (1H, dd, J¼15.4 and 5.4 Hz,
ꢂ
A
B
13
mixture was stirred for 5 h at ꢀ78 C and then quenched via the
CH CH CO
(75 MHz, CDCl
118.9,113.8,111.2, 81.2, 58.8, 55.3, 50.9, 43.8, 28.0; IR (thin film) y
max
2
), 2.09 (1H, br s, NH), 1.29 (9H, s, C(CH
3 3
) ); C NMR
careful addition of saturated NH
4
Cl(aq). After allowing the sus-
3 C
) d
¼170.4, 158.7, 148.5, 132.4, 131.8, 129.3, 128.2,
pension to stir and warm to room temperature, saturated NaH-
CO
(aq) was added carefully and extracted with EtOAc (3ꢄ100 mL).
The combined organic extracts were washed with brine and water,
dried over anhydrous MgSO , filtered and concentrated in vacuo
and then purified by silica gel chromatography to afford the desired
N-PMB- -amino ester 6aeh.
ꢀ
1
3
(cm ): 2226 (m, CN), 1703 (s, C]O); HRMS (ESI): m/z 389.1855,
C
22
H
26
N
2
NaO
3
[MþNa]þ requires 389.1841.
4
4.3.5. (R)-tert-Butyl 3-((4-methoxybenzyl)amino)-3-(4-
nitrophenyl)-propanoate 6e. (E)-tert-Butyl 3-(4-nitrophenyl)acry-
late 1e (0.49 g, 2 mmol) was used to prepare the title compound as
a yellow oil (0.33 g, 40% yield) using general procedure 2.
b
4
. 3.1. (R)-tert-Butyl 3-((4-methoxybenzyl)amino)-3-
2
6
1
phenylpropanoate 6a. (E)-tert-Butyl 3-phenylacrylate 1a (1.18 g,
[a
]
D
þ35.7 (c 2.6, EtOAc); H NMR (300 MHz, CDCl
3
)
d
H
¼8.12 (2H, d,

R.M. Archer et al. / Tetrahedron 71 (2015) 8838e8847
8845
J¼8.7 Hz, CHCHCNO
d, J¼8.5 Hz, CHCHCOCH
1H, dd, J¼8.4 and 5.3 Hz, CHNH), 3.70 (3H, s, OCH
A B
2
), 7.47 (2H, d, J¼8.7 Hz, CHCHCNO
), 6.75 (2H, d, J¼8.5 Hz, CHCHCOCH
), 3.46 (1H, d,
2
), 7.06 (2H,
dissolved in MeCNeH
added and the reaction mixture stirred at room temperature for
48 h. The reaction mixture was then diluted with water (5 mL) and
2
O (5:1, 0.2 M), acetic acid (15 equiv) was then
3
3
), 4.08
(
3
A
B
J¼12.9 Hz, NHCH H ), 3.38 (1H, d, J¼12.9 Hz, NHCH H ), 2.53 (1H,
washed with Et
saturated NaHCO
combined organic extracts dried (MgSO
trated in vacuo to afford a crude product that was purified by
2
O (3ꢄ10 mL). The aqueous layer was basified with
(aq), extracted with Et
O (3ꢄ20 mL), and the
), filtered and concen-
A
B
dd, J¼15.4 and 8.4 Hz, CH CH CO
2
), 2.42 (1H, dd, J¼15.4 and 5.3 Hz,
3
2
A
B
13
CH CH CO
75 MHz, CDCl
23.8, 113.9, 81.3, 58.5, 55.3, 50.9, 43.7, 28.0; IR (thin film)
2
), 2.09 (1H, br s, NH), 1.28 (9H, s, C(CH
3
)
3
); C NMR
4
(
3 C
) d
¼170.4, 158.8, 150.7, 147.3, 131.8, 129.3, 128.3,
1
(
[
y
max
chromatography to afford the desired tert-butyl
5aeh.
b-amino ester
ꢀ1
cm ): 1722 (s, C]O); HRMS (ESI): m/z 409.1777, C21
H
26
N
2
NaO
5
þ
MþNa] requires 409.1739.
4.4.1. (R)-tert-Butyl 3-amino-3-phenylpropanoate 5a. N-PMB-b-
4
.3.6. (R)-tert-Butyl 3-((4-methoxybenzyl)amino)-3-(thiophen-2-
yl)-propanoate 6f. (E)-tert-Butyl 3-(thiophen-2-yl)acrylate 1f
0.55 g, 2.61 mmol) was used to prepare the title compound as
a colourless oil (0.78 g, 86% yield) using general procedure 2.
amino ester 6a (0.1 g, 0.3 mmol) was used to prepare the title
compound as a yellow oil (0.044 g, 68% yield) using general pro-
2
7
29
20
(
cedure 3. [
a
]
D
þ20.0 (c 1.2, CHCl
H NMR (300 MHz, CDCl
¼7.15e7.33 (5H, m, Ph), 4.31 (1H, t,
J¼7.0 Hz, CHNH), 2.52 (2H, app d, J=7.0 Hz, CH CO ), 2.41 (2H, br s,
); C NMR (75 MHz, CDCl
¼171.4,
145.4, 128.5, 127.3, 126.3, 80.7, 52.8, 45.4, 28.1; IR (thin film)
3
) Lit.
[
a
]
D
þ19.7 (c 0.96, CHCl
3
);
1
3 H
) d
2
6
1
[
d
a
]
D
þ23.5 (c 3.4, EtOAc);
¼7.19e7.12 (3H, m, CHCHCOCH
CHCHCS), 6.77 (2H, d, J¼8.6 Hz, CHCHCOCH
and 5.5 Hz, CHNH), 3.72 (3H, s, OCH
), 3.63 (1H, d, J¼12.8 Hz,
H
NMR (300 MHz, CDCl
, CHS), 6.89e6.86 (2H, m,
), 4.30 (1H, dd, J¼8.0
3
)
2
2
1
3
H
3
NH
2
), 1.35 (9H, s, C(CH
3
)
3
3 C
) d
3
y
max
ꢀ
1
3
(cm ): 3312 (w, NeH), 1725 (s, C]O); HRMS (ESI): m/z 222.1500,
A
B
A
B
[MþH]þ requires 222.1489.
NHCH H ), 3.50 (1H, d, J¼12.9 Hz, NHCH H ), 2.64 (1H, dd,
13 2
C H20NO
A
B
J¼15.5 Hz, 8.3, CH CH CO ), 2.56 (1H, dd, J¼15.4 and 5.5 Hz,
2
A
B
13
CH CH CO
75 MHz, CDCl
24.4, 113.8, 80.1, 55.3, 54.6, 50.6, 44.6, 28.1; IR (thin film)
2
), 2.07 (1H, br s, NH), 1.32 (9H, s, C(CH
3
)
3
); C NMR
4.4.2. (R)-tert-Butyl
amino)-propanoate 5b. N-PMB-
0.46 mmol) was used to prepare the title compound as a colourless
3-(4-bromophenyl)-3-((4-methoxybenzyl)
(
1
3
)
d
C
¼170.7, 158.6, 147.8, 132.2, 129.5, 126.5, 124.5,
b
-amino ester 6b (0.19 g,
y
max
ꢀ1
23
(
[
cm ): 1722 (s, C]O); HRMS (ESI): m/z 370.1450, C19
MþNa] requires 370.1453.
3
H25NNaO S
oil (0.077 g, 56% yield) using general procedure 3. [
0.92, CDCl ); H NMR (300 MHz, CDCl ) d
3 3 H
a
]
D
þ21.7 (c
¼7.37 (2H, d, J¼8.5 Hz,
CHCHCBr), 7.17 (2H, d, J¼8.5 Hz, CHCHCBr), 4.29 (1H, br s, CHNH ),
2.47 (2H, app d, J=6.7 Hz, CH CO ), 1.76 (2H, br s, NH ), 1.34 (9H, s,
); C NMR (75 MHz, CDCl
¼171.0, 143.7, 131.6, 128.2,
121.0, 81.0, 52.2, 45.1, 28.1; IR (thin film) ymax (cm ): 3662 (m,
þ
1
2
4
.3.7. (R)-tert-Butyl
prop-anoate 6g. (E)-tert-Butyl 3-(furan-2-yl)acrylate 1g (0. 49 g,
.57 mmol) was used to prepare the title compound as a yellow oil
3-(furan-2-yl)-3-((4-methoxybenzyl)amino)
2
2
2
13
C(CH
3
)
3
3 C
) d
ꢀ
1
2
2
6
(
0.62 g, 73% yield) using general procedure 2. [
a
]
D
þ57.3 (c 3.3,
¼7.37 (1H, d, J¼1.9 Hz, CHO),
), 6.84 (2H, d, J¼8.7 Hz,
), 6.32 (1H, dd, J¼3.1 and 1.9 Hz, CHCHO), 6.20 (1H, d,
NeH), 3376 (w, NeH), 1722 (s, C]O); HRMS (ESI): m/z 300.0620,
1
[MþH]þ requires 300.0599.
EtOAc); H NMR (300 MHz, CDCl
3
)
d
H
13 2
C H19BrNO
7
.21 (2H, d, J¼8.7 Hz, CHCHCOCH
3
CHCHCOCH
3
4.4.3. (R)-tert-Butyl
5c. N-PMB- -amino ester 6c (0.14 g, 0.33 mmol) was used to pre-
pare the title compound as a yellow oil (0.066 g, 68% yield) using
3-amino-3-(2,4-dichlorophenyl)propanoate
J¼3.1 Hz, CHCHCHCO), 4.14 (1H, dd, J¼7.7 and 6.4 Hz, CHNH), 3.79
b
A
B
(
3H, s, OCH
3
), 3.68 (1H, d, J¼12.6 Hz, NHCH H ), 3.54 (1H, d,
A B
24
1
J¼12.6 Hz, NHCH H ), 2.18e2.01 (2H, m, CH
2
CO
); C NMR (75 MHz, CDCl
55.3, 141.7, 132.2, 129.4, 113.7, 110.0, 106.8, 80.7, 55.3, 52.3, 50.5,
2
), 1.96 (1H, br s,
general procedure 3. [
CDCl
¼7.44 (1H, d, J¼8.4 Hz, CHCHCCl), 7.20 (1H, d, J¼1.8 Hz,
CClCHCCl), 7.8 (1H, dd, J¼8.4 and 1.9 Hz, CClCHCH), 4.70 (1H, br s,
a
]
D
þ37.6 (c 0.85, CDCl
3
); H NMR (300 MHz,
1
3
NH), 1.40 (9H, s, C(CH
3
)
3
3
)
d
C
¼170.7, 158.6,
3 H
) d
1
ꢀ
1
A B
41.1, 28.0; IR (thin film)
y
max (cm ): 1725 (s, C]O); HRMS (ESI): m/
CHNH
2
), 2.60 (1H, dd, J¼16.0 and 4.0 Hz, NHCH H ), 2.44 (1H, dd,
A B
z 354.1691, C19
H
25NNaO
4
[MþNa]þ requires 354.1681.
J¼16.0 and 9.0 Hz, NHCH H ), 2.29 (2H, br s, NH
2
), 1.36 (9H, s,
¼170.8, 136.4, 133.4, 133.3,
13
C(CH
ꢀ
129.4, 128.4, 127.5, 81.2, 48.7, 42.8, 28.1; IR (thin film) ymax (cm ):
3 3 3 C
) ); C NMR (75 MHz, CDCl ) d
1
4
.3.8. (R)-tert-Butyl 3-((4-methoxybenzyl)amino)heptanoate 6h. (E)-
tert-Butyl hept-2-enoate 1h (1.01 g, 5.5 mmol) was used to prepare
the title compound as a yellow oil (1.2 g, 68% yield) using general
3383 (w, NeH), 1725 (s, C]O); HRMS (ESI): m/z 312.0525,
C
13
H17Cl
2
NNaO
2
[MþNa]þ requires 312.0534.
2
6
1
procedure 2. [
¼7.20 (2H, d, J¼8.6 Hz, CHCHCOCH
CHCHCOCH ), 3.72 (3H, s, OCH ), 3.65 (2H, s, NHCH
quintet, J¼6.1 Hz, CHNH), 2.29 (2H, d, J¼6.1 Hz, CH CO ),1.65 (1H, br s,
NH),1.37 (9H, s, C(CH ),1.30e1.14 (6H, m, CH CH CH CH ), 0.82 (3H,
¼172.4,158.9,133.1,
29.7, 114.1, 80.8, 55.7, 54.8, 50.8, 40.8, 34.4, 28.5, 28.3, 23.2, 14.4; IR
a
]
D
ꢀ3.5 (c 2.02, CH
2
Cl
2
); H NMR (300 MHz, CDCl
), 6.80 (2H, d, J¼8.6 Hz,
), 2.90 (1H,
3
)
d
H
3
4.4.4. (R)-tert-Butyl 3-amino-3-(4-cyanophenyl)propanoate 5d. N-
PMB- -amino ester 6d (0.16 g, 0.45 mmol) was used to prepare the
title compound as a yellow oil (0.057 g, 51% yield) using general
3
3
2
b
2
2
2
1
1
3
)
3
3
2
2
2
procedure 3. [
¼7.68 (2H, d, J¼8.0 Hz, CHCHCCN), 7.55 (2H, d, J¼8.0 Hz,
CHCHCCN), 4.50 (1H, br s, CHNH ), 2.63 (2H, app d, J=6.6 Hz,
CH CO ), 2.14 (2H, br s, NH ), 1.46 (9H, s, C(CH
(75 MHz, CDCl
¼171.6, 145.2, 132.4, 127.3, 118.8, 111.3, 81.3, 52.5,
4.8, 28.1; IR (thin film)
HRMS (ESI): m/z 247.1448, C14
a
]
D
þ16.0 (c 0.5, CDCl
3 3
); H NMR (300 MHz, CDCl )
1
3
t, J¼7.2 Hz, CH
3
CH
2
); C NMR (75 MHz, CDCl
3
)
d
C
d
H
1
2
ꢀ1
13
(
thin film)
y
max (cm ): 1722 (s, C]O); HRMS (ESI): m/z 322.2377,
[MþH] requires 322.2381.
2
2
2
3 3
) ); C NMR
þ
C
19
H
32NO
3
3 C
) d
ꢀ
1
4
ymax (cm ): 2228 (m, CN), 1723 (s, C]O);
4
.4. General procedure 3: oxidative deprotection of tert-butyl
-amino esters 6aeh
H
19
N
2
O
2
[MþH]þ requires 247.1447.
N-PMB-
b
4.4.5. (R)-tert-Butyl 3-amino-3-(4-nitrophenyl)propanoate 5e. N-
Cerium ammonium nitrate (4 equiv) was added to a solution of
the appropriate N-PMB- -amino ester 6 (1 equiv) in MeCNeH
5:1, 0.2 M) and the bright orange solution stirred at room tem-
perature for 2 h before saturated NaHCO (aq) (50 mL) was added.
The mixture was partitioned between brine and Et O and the
aqueous layer further extracted with Et
O (2ꢄ20 mL). The com-
bined organic extracts were dried over anhydrous MgSO , filtered
and concentrated in vacuo. The resultant crude product was
PMB-b-amino ester 6e (0.13 g, 0.33 mmol) was used to prepare the
title compound as a yellow oil (0.057 g, 65% yield) using general
b
2
O
2
5
1
(
procedure 3. [
a
]
D
þ9.1 (c 0.55, CDCl
3
); H NMR (300 MHz, CDCl
), 7.49 (2H, d, J¼8.6 Hz,
), 2.51 ((2H, app d, J=6.7 Hz,
3
)
3
d
H
¼8.11 (2H, d, J¼8.9 Hz, CHCHCNO
2
2
CHCHCNO
CH CO ), 1.78 (2H, br s, NH
(75 MHz, CDCl
28.1; IR (thin film)
2
), 4.42 (1H, br s, CHNH
2
13
2
2
2
2
3 3
), 1.34 (9H, s, C(CH ) ); C NMR
4
3
)
d
C
¼170.6, 152.2, 147.2, 127.4, 123.8, 81.3, 52.3, 45.0,
ꢀ
max (cm ): 3382 (w, NeH), 1720 (s, C]O);
1
y

8846
R.M. Archer et al. / Tetrahedron 71 (2015) 8838e8847
HRMS (ESI): m/z 289.1156,
C
13
H
18
N
2
NaO
4
[MþNa]þ requires
molecular sieves, and CDCl
3
were then added in order to produce
2
89.1164.
a 0.1 M solution of the -amino ester. The solution was stirred for
b
1
0 min before being filtered through a small pad of Celite and the
1
4.4.6. (R)-tert-Butyl 3-amino-3-(thien-2-yl)propanoate 5f. N-PMB-
solution analyzed by H NMR spectroscopy.
b-amino ester 6f (0.2 g, 0.59 mmol) was used to prepare the title
compound as a yellow oil (0.048 g, 36% yield) using general pro-
Acknowledgements
25
1
cedure 3. [
¼7.27 (1H, dd, J¼1.7 and 0.7 Hz, CHS), 6.23 (1H, dd, J¼3.1 and
.8 Hz, CHCHCS), 6.09 (1H, d, J¼3.2 Hz, CHCCS), 4.31 (1H, dd, J¼8.3
a
]
D
3 3
þ18.2 (c 0.44, CDCl ); H NMR (300 MHz, CDCl )
d
H
We would like to thank the Engineering and Physical Sciences
Research Council (EPSRC) and Syngenta for CASE funding (RMA).
1
A
B
and 4.9 Hz, CHNH), 2.68 (1H, dd, J¼15.8 and 5.0 Hz, CH H CO
2
), 2.55
A
B
(
1H, dd, J¼15.4 and 8.4 Hz, CH CH CO
2
)
), 2.34 (1H, br s, NH ),1.3 (9H,
2
13
References and notes
s, C(CH
3
)
3
); C NMR (75 MHz, CDCl
3
d
C
y
¼170.8, 136.9, 128.6, 128.1,
ꢀ
1
127.1, 81.0, 46.8, 42.1, 28.1; IR (thin film)
max (cm ): 1727 (s, C]O);
1. (a) Kuhl, A.; Hahn, M. G.; Dumic, M.; Mittendorf, J. Amino Acids 2005, 29, 89; (b)
þ
HRMS (ESI): m/z 228.1078, C11
H
18NO
2
S [MþH] requires 228.1058.
Kiss, L.; Fulop, F. Chem. Rev. 2014, 114, 1116; (c) Kudo, F.; Miyanaga, A.; Eguchi, T.
Nat. Prod. Rep. 2014, 31, 1056; (d) Lelais, G.; Seebach, D. Biopolymers 2004, 76,
206.
4
.4.7. (R)-tert-Butyl 3-amino-3-(furan-2-yl)propanoate 5g.38 N-
2
. (a) Seebach, D.; Gardiner, J. Acc. Chem. Res. 2008, 41, 1366; (b) Aguilar, M. I.;
Purcell, A. W.; Devi, R.; Lew, R.; Rossjohn, J.; Smith, A. I.; Perlmutter, P. Org.
Biomol. Chem. 2007, 5, 2884; (c) Tew, G. N.; Scott, R. W.; Klein, M. L.; DeGrado,
W. F. Acc. Chem. Res. 2010, 43, 30.
PMB-b-amino ester 6g (0.1 g, 0.31 mmol) was used to prepare the
title compound as a pale green oil (0.048 g, 73% yield) using general
2
5
1
procedure 3. [
¼7.12 (1H, dd, J¼4.5 and 1.9 Hz, CHCHO), 6.89e6.84 (2H, m,
CHOCCH), 4.58 (1H, dd, J¼8.4 and 4.9 Hz, CHNH ), 2.65 (1H, dd,
), 2.57 (1H, dd, J¼15.9 and 8.4 Hz,
a
]
D
þ12.4 (c 1.05, CDCl
3 3
); H NMR (300 MHz, CDCl )
3. Frackenpohl, J.; Arvidsson, P. I.; Schreiber, J. V.; Seebach, D. ChemBioChem 2001,
d
H
2
, 445.
4. Godballe, T.; Nilsson, L. L.; Petersen, P. D.; Jenssen, H. Chem. Biol. Drug Des. 2011,
7, 107.
2
A
B
7
J¼15.9 and 4.9 Hz, CH H CO
2
A
B
13
5. Karlsson, A. J.; Pomerantz, W. C.; Weisblum, B.; Gellman, S. H.; Palecek, S. P. J.
Am. Chem. Soc. 2006, 128, 12630.
6. English, E. P.; Chumanov, R. S.; Gellman, S. H.; Compton, T. J. Biol. Chem. 2006,
281, 2661.
CH H CO
2
), 2.22 (2H, br s, NH
2 3 3
), 1.36 (9H, s, C(CH ) ); C NMR
(
2
75 MHz, CDCl
3
)
d
C
¼170.8, 144.0, 142.6, 124.0, 110.2, 81.0, 48.7, 45.6,
ꢀ1
8.1; IR (thin film) ymax (cm ): 3385 (w, NeH), 1723 (s, C]O);
[MþH]þ requires 212.1287.
7. Kritzer, J. A.; Lear, J. D.; Hodsdon, M. E.; Schepartz, A. J. Am. Chem. Soc. 2004, 126,
HRMS (ESI): m/z 212.1286, C11H18NO
3
9
468.
. Werder, M.; Hauser, H.; Abele, S.; Seebach, D. Helv. Chim. Acta 1999, 82, 1774.
9. Seebach, D.; Matthews, J. L. Chem. Commun. 1997, 2015.
8
4.4.8. (R)-tert-Butyl 3-aminoheptanoate 5h. N-PMB-b-amino ester
1
0. (a) Azzarito, V.; Long, K.; Murphy, N. S.; Wilson, A. J. Nat. Chem. 2013, 5, 161; (b)
Kritzer, J. A.; Stephens, O. M.; Guarracino, D. A.; Reznik, S. K.; Schepartz, A.
Bioorg. Med. Chem. 2005, 13, 11.
6
h (0.21 g, 0.66 mmol) was used to prepare the title compound as
a colourless oil (0.089 g, 60% yield) using general procedure 3.
2
3
1
[
(
(
a
]
D
þ33.3 (c 1.2, CDCl
1H, m, CHNH
), 2.31 (1H, dd, J¼15.6 and 4.0 Hz, CH H CO
1H, dd, J¼15.6 and 8.8 Hz, CH H CO
), 1.36e1.19 (6H, m, CH CH
); C NMR (75 MHz, CDCl
8.2, 28.1, 22.7, 14.0; IR (thin film)
s, C]O); HRMS (ESI): m/z 202.1801, C11
3
); H NMR (300 MHz, CDCl
3
)
d
H
¼3.13e3.00
11. (a) Weiner, B.; Szymanski, W.; Janssen, D. B.; Minnaard, A. J.; Feringa, B. L. Chem.
A
B
Soc. Rev. 2010, 39, 1656; (b) Juaristi, E.; Soloshonok, V. A. Enantioselective Syn-
thesis of b-Amino Acids, 2nd ed.; Wiley-VCH: New York, 2005; (c) Liu, M.; Sibi,
M. P. Tetrahedron 2002, 58, 7991.
2
2
), 2.10
), 1.39 (9H,
), 0.83 (3H, t, J¼6.3 Hz,
¼172.1, 80.5, 48.4, 43.8, 37.2,
A
B
2
), 1.61 (2H, br s, NH
CH CH
2
s, C(CH
CH CH
3
)
3
2
2
2
3
12. (a) Liljeblad, A.; Kanerva, L. T. Tetrahedron 2006, 62, 5831; (b) Goodman, C. G.;
Do, D. T.; Johnson, J. S. Org. Lett. 2013, 15, 2446.
13. (a) Hart, D. J.; Ha, D. C. Chem. Rev. 1989, 89, 1447; (b) Tang, T. P.; Ellman, J. A. J.
Org. Chem. 2002, 67, 7819.
13
2
3
3 C
) d
ꢀ1
2
(
2
ymax (cm ): 3385 (w, NeH), 1723
H24NO
2
[MþH]þ requires
14. Evans, D. A.; Wu, L. D.; Wiener, J. J. M.; Johnson, J. S.; Ripin, D. H. B.; Tedrow, J. S.
J. Org. Chem. 1999, 64, 6411.
02.1807.
15. (a) Guichard, G.; Abele, S.; Seebach, D. Helv. Chim. Acta 1998, 81, 187; (b) Caputo,
R.; Longobardo, L. Amino Acids 2007, 32, 401.
4
.4.9. (R,E)-tert-Butyl 3-((4-methoxybenzylidene)amino)-3-phenyl-
16. (a) Ikemoto, N.; Tellers, D. M.; Dreher, S. D.; Liu, J. C.; Huang, A.; Rivera, N. R.;
Njolita, E.; Hsiao, Y.; McWilliams, J. C.; Williams, J. M.; Armstrong, J. D., III; Sun,
Y.; Mathre, D. J.; Grabowski, E. J. J.; Tillyer, R. D. J. Am. Chem. Soc. 2004, 126,
propanoate 15a. Cerium ammonium nitrate (1.72 g, 2.94 mmol)
was added to a solution of (R)-tert-Butyl 3-((4-methoxybenzyl)
amino)-3-phenylpropanoate 6a (0.251 g, 0.736 mmol) in
3048; (b) Pena, D.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc.
2002, 124, 14552.
MeCNeH
room temperature for 2 h, before saturated NaHCO
was added. The mixture was partitioned between brine and Et
and the aqueous layer further extracted with Et
O (2ꢄ20 mL). The
combined organic extracts were dried over anhydrous MgSO , fil-
tered and concentrated in vacuo to afford the title compound as
2
O (5:1, 9.4 mL) and the bright orange solution stirred at
17. (a) Krishna, P. R.; Sreeshailam, A.; Srinivas, R. Tetrahedron 2009, 65, 9657; (b)
Enders, D.; Wang, C.; Liebich, J. X. Chem.dEur. J. 2009, 15, 11058; (c) Vicario, J. L.;
Badia, D.; Carrillo, L.; Etxebarria, J.; Reyes, E.; Ruiz, N. Org. Prep. Proced. Int. 2005,
3
(aq) (50 mL)
2
O
37, 513; (d) Sibi, M. P.; Itoh, K. J. Am. Chem. Soc. 2007, 129, 8064.
18. Asao, N.; Shimada, T.; Sudo, T.; Tsukada, N.; Yazawa, K.; Gyoung, Y. S.; Uyehara,
2
T.; Yamamoto, Y. J. Org. Chem. 1997, 62, 6274.
4
19. (a) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833;
(b) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E. Tetrahedron
2
2
1
a yellow oil (0.204 g, 82% yield). [
300 MHz, CDCl
¼8.36 (1H, s, CH]N), 7.76 (2H, d, J¼8.5 Hz,
CHCHCOCH
), 7.50 (2H, d, J¼7.7 Hz, Ph), 7.41e7.36 (2H, m, Ph),
.32e7.27 (1H, m, Ph), 6.96 (2H, d, J¼8.5 Hz, CHCHCOCH ), 4.82 (1H,
dd, J¼9.5 and 4.9 Hz, CHN]CH), 3.89 (3H, s, OCH ), 2.97 (1H, dd,
a
]
D
ꢀ30.0 (c 2.9, CH
2
Cl
2
); H NMR
Asymmetry 2012, 23, 1111.
20. Doi, H.; Sakai, T.; Iguchi, M.; Yamada, K.; Tomioka, K. J. Am. Chem. Soc. 2003, 125,
(
3 H
) d
2886.
3
21. Harada, S.; Sakai, T.; Takasu, K.; Yamada, K.; Yamamoto, Y.; Tomioka, K. J. Org.
7
3
Chem. 2012, 77, 7212.
22. Sakai, T.; Kawamoto, Y.; Tomioka, K. J. Org. Chem. 2006, 71, 4706.
3
A
B
A
B
23. Suzuki, M.; Kawamoto, Y.; Sakai, T.; Yamamoto, Y.; Tomioka, K. Org. Lett. 2009,
J¼15.0 and 1.5 Hz, CH H ), 2.86 (1H, dd, J¼14.9 and 4.8 Hz, CH H ),
11, 653.
1
3
1
1
4
.39 (9H, s, C(CH
3
)
3
); C NMR (75 MHz, CDCl
3
)
d
C
¼170.7, 161.7,
24. (a) Harada, S.; Sakai, T.; Takasu, K.; Yamada, K.; Yamamoto, Y.; Tomioka, K.
Chem. Asian J. 2012, 7, 2196; (b) Harada, S.; Sakai, T.; Takasu, K.; Yamada, K.;
Yamamoto, Y.; Tomioka, K. Tetrahedron 2013, 69, 3264.
60.5, 143.1, 130.1, 129.2, 128.5, 127.2, 127.0, 113.9, 80.6, 71.4, 55.4,
ꢀ
ymax (cm ): 1723 (s, C]O); HRMS (ESI): m/
1
4.8, 28.1; IR (thin film)
25NNaO
2
2
2
2
5. Harada, S.; Sakai, T.; Takasu, K.; Yamada, K.; Yamamoto, Y.; Tomioka, K. Tetra-
hedron 2013, 69, 3264.
6. Sakai, T.; Doi, H.; Kawamoto, Y.; Yamada, K.; Tomioka, K. Tetrahedron Lett. 2004,
z 362.1754, C21
H
3
[MþNa]þ requires 362.1732.
45, 9261.
4
.5. General procedure 4: determination of the enantiomeric
7. (a) Sakai, T.; Doi, H.; Tomioka, K. Tetrahedron 2006, 62, 8351; (b) Doi, H.; Sakai,
T.; Yamada, K.; Tomioka, K. Chem. Commun. 2004, 1850.
3
6b
excess of (R)-tert-butyl
b-Amino esters
8. (a) Bull, S. D.; Davies, S. G.; Kelly, P. M.; Gianotti, M.; Smith, A. D. J. Chem. Soc.
Perkin Trans. 1 2001, 3106; (b) Bull, S. D.; Davies, S. G.; Smith, A. D. J. Chem. Soc.
Perkin Trans. 1 2001, 2931; (c) Bull, S. D.; Davies, S. G.; Smith, A. D. Tetrahedron:
Asymmetry 2001, 12, 2941; (d) Bull, S. D.; Davies, S. G.; Roberts, P. M.; Savory, E.
D.; Smith, A. D. Tetrahedron 2002, 58, 4629; (e) Koutsaplis, M.; Andrews, P. C.;
Each (R)-tert-butyl
1.1 equiv) were suspended in a minimum amount of CDCl
Formyl-phenylboronic acid (1.1 equiv), (R)-(BINOL) (1.1 equiv), 4 A
b
-amino ester 5 (1 equiv) and K
2
CO
. 2-
3
(
3
ꢀ

R.M. Archer et al. / Tetrahedron 71 (2015) 8838e8847
8847
Bull, S. D.; Duggan, P. J.; Fraser, B. H.; Jensen, P. Chem. Commun. 2007, 3580; (f)
Evans, C. D.; Mahon, M. F.; Andrews, P. C.; Muir, J.; Bull, S. D. Org. Lett. 2011, 13,
PMB-b-amino ester 5a. This suggests that excess TMSCl is not simply acting to
generate LiCl in situ, which has been shown to affect the aggregation state and
reactivity of lithium amide species in more polar solvents. See: (a) Clegg, W.;
Greer, J. C.; Mair, F. S.; Nolan, P. M.; O’Neill, P. A. Inorg. Chim. Acta. 1997, 258, 1;
(b) Ma, Y.; Hoepker, A. C.; Gupta, L.; Faggin, M. F.; Collum, D. B. J. Am. Chem. Soc.
2010, 132, 15610.
6276.
2
3
9. Bull, S. D.; Davies, S. G.; Delgado-Ballester, S.; Fenton, G.; Kelly, P. M.; Smith, A.
D. Synlett 2000, 1257.
0. (a) Bull, S. D.; Davies, S. G.; Fenton, G.; Mulvaney, A. W.; Prasad, R. S.; Smith, A.
D. J. Chem. Soc. Perkin Trans. 1 2000, 3765; (b) Bull, S. D.; Davies, S. G.; Fenton, G.;
Mulvaney, A. W.; Prasad, R. S.; Smith, A. D. Chem. Commun. 2000, 337.
35. Tert-butyl enoate esters 3 were used as acceptors in these studies to ensure that
competing 1,2-addition of silyl-lithium amide 1e to their carbonyl groups did
not occur. For a previous report where addition of lithium silyl-amide 1a to
3
1. (a) Bull, S. D.; Davies, S. G.; Delgado-Ballester, S.; Kelly, P. M.; Kotchie, L. J.;
Gianotti, M.; Laderas, M.; Smith, A. D. J. Chem. Soc. Perkin Trans. 1 2001, 3112; (b)
Bull, S. D.; Davies, S. G.; Fox, D. J.; Gianotti, M.; Kelly, P. M.; Pierres, C.; Savory, E.
D.; Smith, A. D. J. Chem. Soc. Perkin Trans. 1 2002, 1858; (c) Davies, S. G.; Fletcher,
A. M.; Lv, L.; Roberts, P. M.; Thomson, J. E. Tetrahedron: Asymmetry 2012, 23, 910;
a methyl dienoate acceptor resulted in a mixture of b-amino ester and amide
products. See: Yamamoto, Y.; Asao, N.; Uyehara, T. J. Am. Chem. Soc. 1992, 114,
5427.
36. (a) Perez-Fuertes, Y.; Kelly, A. M.; Johnson, A. L.; Arimori, S.; Bull, S. D.; James, T.
D. Org. Lett. 2006, 8, 609; (b) Perez-Fuertes, Y.; Kelly, A. M.; Fossey, J. S.; Powell,
M. E.; Bull, S. D.; James, T. D. Nat. Protoc. 2008, 3, 210; (c) Powell, M. E.; Kelly, A.
M.; Bull, S. D.; James, T. D. Tetrahedron Lett. 2009, 50, 876; (d) Perez-Fuertes, Y.;
Taylor, J. E.; Tickell, D. A.; Mahon, M. F.; Bull, S. D.; James, T. D. J. Org. Chem. 2011,
15, 6038.
(
d) Davies, S. G.; Fletcher, A. M.; Lv, L.; Roberts, P. M.; Thomson, J. E. Tetrahedron
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West, C. J. Tetrahedron 2012, 68, 4302.
2. Yamamoto, Y.; Nasu, H.; Tomioka, K. Tetrahedron 2013, 69, 3836.
3
3
3. Yamamoto, Y.; Yasuda, Y.; Oulyadi, H.; Maddaluno, J.; Tomioka, K. Tetrahedron
2
010, 66, 2470.
37. Shindo, M.; Koga, K.; Tomioka, K. J. Org. Chem. 1998, 63, 9351.
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Duran, J. E.; Farid, P. N. J. Org. Chem. 2005, 70, 5387.
3
4. The use of 5 equivalents of TMSCl in these aza-conjugate addition reactions
proved optimal, with the use of fewer equivalents leading to lower yields of N-