Asymmetric synthesis of β-haloaryl β-amino acid derivatives

Article abstract of DOI:10.1039/b108573p

Lithium N-benzyl-N-α-methyl-4-methoxybenzylamide may be employed as a homochiral ammonia equivalent for the synthesis of homochiral β-haloaryl β-amino acid derivatives via a strategy involving its conjugate addition to α,β-unsaturated β-haloaryl acceptors and subsequent oxidative deprotection with ceric ammonium nitrate.

Full text of DOI:10.1039/b108573p

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Asymmetric synthesis of ꢀ-haloaryl ꢀ-amino acid derivatives
Steven D. Bull, Stephen G. Davies,* Santiago Delgado-Ballester, Peter M. Kelly,
Luke J. Kotchie, Massimo Gianotti, Mario Laderas and Andrew D. Smith
1
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford,
UK OX1 3QY. E-mail: steve.davies@chemistry.ox.ac.uk
Received (in Cambridge, UK) 20th September 2001, Accepted 15th October 2001
First published as an Advance Article on the web 16th November 2001
Lithium N-benzyl-N-α-methyl-4-methoxybenzylamide may be employed as a homochiral ammonia equivalent
for the synthesis of homochiral β-haloaryl β-amino acid derivatives via a strategy involving its conjugate addition
to α,β-unsaturated β-haloaryl acceptors and subsequent oxidative deprotection with ceric ammonium nitrate.
Introduction
β-Haloaryl β-amino acids are an important sub-class of β-
amino acids which have been widely employed within medicinal
chemistry.1 Previous synthetic strategies employed for the
synthesis of these pharmacologically active compounds include
the enzymatic resolution of β-haloaryl β-amino esters using
the lipase Amano PS,2 diastereoselective cycloaddition between
β-haloaryl imines and ketenes,3 and the Lewis acid catalyzed
addition of a tributylstannane to a chiral oxazolidine.4 While
these reports represent efficient approaches towards the asym-
metric synthesis of specific β-haloaryl β-amino acid targets,
they lack generality and are therefore not applicable to the
synthesis of libraries of homochiral β-haloaryl β-amino acid
derivatives.5 We have previously shown that a wide range of
β-amino acid derivatives can be efficiently prepared via the
conjugate addition of homochiral lithium amides derived
from α-methylbenzylamine to α,β-unsaturated esters and sub-
sequent reductive N-deprotection.6 While these approaches
offer versatile routes to β-amino acid derivatives, β-haloaryl
β-amino acid derivatives are incompatible with this method-
ology as the haloaryl functionality within the substrate is
labile under either the hydrogenolytic or Birch reduction con-
ditions required for deprotection of the N-α-methylbenzyl
group. We have previously described the development of a third
generation homochiral ammonia equivalent, lithium (S)-N-
benzyl-N-α-methyl-4-methoxybenzylamide, for the asymmetric
synthesis of homochiral β-amino acids and β-lactams which
involves deprotection via oxidative debenzylation7 and now
describe herein how this methodology may be employed for the
asymmetric synthesis of a wide range of homochiral β-haloaryl
β-amino acid derivatives. Part of this work has been previously
communicated.8
Fig. 1 General strategy for the asymmetric synthesis of β-haloaryl
β-amino acid derivatives.
Results and discussion
Scheme 1 Reagents and conditions: (i) tert-butyl diethylphosphono-
acetate (1.15 equiv.), n-BuLi (1.10 equiv.), THF, Ϫ78 ЊC then haloaryl
aldehyde, Ϫ78 ЊC to RT.
Synthesis of tert-butyl ꢀ-haloaryl ꢁ,ꢀ-unsaturated esters
Our synthetic strategy for the synthesis of β-haloaryl β-amino
esters relied upon the conjugate addition of homochiral lithium
N-benzyl-α-methyl-4-methoxybenzylamide 1 to suitably func-
tionalised β-haloaryl α,β-unsaturated esters (Fig. 1). The
required fluoro-, chloro-, bromo- and iodo-substituted tert-
butyl (E)-β-haloarylprop-2-enoate conjugate acceptors 2–9
were readily prepared in >95% crude de9 via Wadsworth–
Emmons reaction of the parent benzaldehyde with the lithium
anion of tert-butyl diethylphosphonoacetate. Purification gave
multigram quantities of 2–9 in high yields as single diastereo-
isomers (Scheme 1).
Conjugate addition of N-benzyl-ꢁ-methyl-4-methoxybenzyl-
amide 1 to ꢁ,ꢀ-unsaturated esters 2–9
Conjugate addition of (S)-1 to the fluoro- and iodo- substi-
tuted α,β-unsaturated esters 2–5 and (R)-1 to the bromo- and
chloro-substituted α,β-unsaturated esters 6–9 afforded the
N-benzyl-N-α-methyl-4-methoxybenzyl protected β-amino
esters 10–17 with high levels of crude diastereoselectivity (88–
94% de). While 3-fluoro (3R,αS)-10, 2-iodo (3R,αS)-11 and 2-
bromo (3S,αR)-15 could be purified by fractional recrystallis-
3112
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This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b108573p

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ation (Et2O–hexane) to 97% de, 98% de and 98% de, respect-
ively, repeated chromatography of the oily β-amino esters
12–14 and 16–17 did not enhance the diastereoselectivity of the
products arising from the crude reaction mixtures. β-Amino
esters 12–14 and 16–17 were therefore carried forward as
mixtures of diastereoisomers (Scheme 2).
The absolute configurations of 10–17 were assigned by
analogy to the model previously developed to explain the
stereoselectivity observed during addition of homochiral
lithium amides to α,β-unsaturated acceptors,10 and the known
stereoselectivity of lithium amide 1 upon addition to tert-
butyl cinnamate.7
CAN promoted oxidative debenzylations
3-Fluoro (3R,αS)-10 (97% de), 2-iodo (3R,αS)-11 (98% de),
and 2-bromo (3S,αR)-15 (98% de), were subjected to mono
N-benzylic deprotection via treatment with CAN (2.1 equiv.),
furnishing the N-α-methyl-4-methoxybenzyl protected β-amino
esters 18–20 in 75–86% yield. Further treatment of 3-fluoro
(3R,αS)-18, 2-iodo (3R,αS)-19 and 2-bromo (3S,αR)-20
with CAN (4.0 equiv.) gave the desired tert-butyl 3-amino
β-haloarylpropanoates 21–23 in 51–68% yield. The ee of each
β-amino ester 21–23 was shown to be 97–98%, via derivatis-
ation with Mosher’s acid chloride and comparison of the 19F
1
and H NMR spectra of the resulting amides with authentic
racemic samples (Scheme 3).
Treatment of tertiary β-amino ester 12 (88% de) with CAN
(2.1 equiv.) gave tert-butyl (3R,αS)-3-(α-methyl-4-methoxy-
benzylamino)-3-(iodophenyl)propanoate 24 in 77% yield and
88% de. (3R,αS)-24 could not be purified to homogeneity at
this stage by chromatography, so further treatment of (3R,αS)-
24 (88% de) with CAN (4.0 equiv.) gave tert-butyl (R)-3-amino-
3-iodophenylpropanoate 25 in 49% yield and in 88% ee as
determined by Mosher’s ester analysis (Scheme 4).
An alternative deprotection strategy was next devised to
enable the corresponding (R)-methyl ester 27 to be obtained in
high enantiomeric excess. Thus, treatment of (3R,αS)-24 (88%
de) with methanolic HCl afforded the methyl ester hydro-
chloride salt of (3R,αS)-26 which was recrystallised [ethyl
acetate–hexane (6 : 1)]. Conversion of (3R,αS)-26ؒHCl to its
free amine using saturated aqueous NaHCO3 solution gave
1
(3R,αS)-26 in 75% overall yield and 97% de as shown by H
NMR spectroscopic analysis. Deprotection of 26 via treatment
with CAN afforded (S)-27 in 48% yield. The ee of (S)-27 was
shown to be 97% by Mosher’s amide derivatisation and com-
parison of the 19F NMR spectrum with an authentic racemic
standard (Scheme 5).
This protocol was therefore adopted for the deprotection of
those β-amino esters 13–14, 16–17 which could not be purified
to homogeneity after the conjugate addition of lithium amide 1
to the appropriate α,β-unsaturated acceptor. Thus, CAN
Scheme 2 Reagents and conditions: (i) (S)-1 (1.6 equiv.), THF, Ϫ78 ЊC;
a
(ii) (R)-1 (1.6 equiv.), THF, Ϫ78 ЊC.
As shown by 1H NMR
spectroscopic analysis.
Scheme 3 Reagents and conditions: (i) CAN (2.1 equiv.), MeCN–H2O (5 : 1), RT; (ii) CAN (4.0 equiv.), MeCN–H2O (5 : 1), RT.
J. Chem. Soc., Perkin Trans. 1, 2001, 3112–3121
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mono-debenzylation of 13–14, 16–17 gave mono-deprotected
secondary β-amino tert-butyl esters 28–31 in good yields, which
were subsequently treated with methanolic HCl, recrystallised
and treated with saturated aqueous bicarbonate to give the
mono-deprotected secondary β-amino methyl esters 32–35 in
94–96% de. Deprotection of 32–35 via treatment with CAN
afforded 36–39 in 51–61% yield. The ee’s of β-amino esters
36–39 were shown to be 94–96% by conversion to the Mosher’s
amide and comparison of the 19F NMR spectrum of each with
an authentic racemic standard (Scheme 6).
Having demonstrated the wide applicability of this stepwise
oxidative N-deprotection protocol for the preparation of
β-monohaloaryl β-amino acid derivatives, extension to the
preparation of β-3,4-difluorophenyl-3-aminopropanoic acid
42, an integral part of a variety of biologically active pseudo-
peptides shown to exhibit potent pharmacological activity,1
was undertaken. Thus, tert-butyl 3-(3,4-difluorophenyl)prop-
2-enoate 40 was prepared by Wittig reaction with 3,4-difluoro-
benzaldehyde, giving 40 as a single diastereoisomer after
recrystallisation in 88% yield. Conjugate addition of lithium
amide (R)-1 gave tert-butyl (3S,αR)-3-(3,4-difluorophenyl)-
3-(N-benzyl-α-methyl-4-methoxybenzylamino)propanoate 41
with a crude de of 90%. Recrystallisation allowed purification
of (3S,αR)-41 to 97% de in 86% yield. To demonstrate the
versatility of this oxidative deprotection methodology, N-
debenzylation of both N-protecting groups by treatment of
(3S,αR)-41 with CAN (6 equiv.) and subsequent treatment
with aqueous acid gave (S)-3-(3,4-difluorophenyl)-3-amino-
propanoic acid 42 in 63% yield. The ee of 42 was shown to be
97% by conversion to the methyl ester, derivatisation with
homochiral and racemic Mosher’s acid chloride and
subsequent 19F NMR analysis (Scheme 7).
Scheme 4 Reagents and conditions: (i) CAN (2.1 equiv.), MeCN–H2O
(5 : 1), RT; (ii) CAN (4.0 equiv.), MeCN–H2O (5 : 1), RT.
Scheme 5 Reagents and conditions: (i) HCl, MeOH; (ii) recrystallis-
ation [ethyl acetate–hexane (6 : 1)]; (iii) NaHCO3 (aq); (iv) CAN (4.0
equiv.), MeCN–H2O (5 : 1), RT.
Scheme 7 Reagents and conditions: (i) tert-butyl diethylphosphono-
acetate, n-BuLi, THF, Ϫ78 ЊC; (ii) (R)-1 (1.6 equiv.), THF, Ϫ78 ЊC; (iii)
CAN (6.0 equiv.), MeCN–H2O then HCl (aq); (iv) Dowex 50W–X8.
Scheme 6 Reagents and conditions: (i) CAN (2.1 equiv.), MeCN–H2O (5 : 1), RT; (ii) HCl, MeOH; (iii) recrystallisation [ethyl acetate–hexane (6 : 1)];
then NaHCO3 (aq); (iv) CAN (4.0 equiv.), MeCN–H2O (5 : 1), RT.
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General procedure 2
Conclusions
n-Butyllithium (1.55 equiv.) was added dropwise to a stirred
solution of amine (1.6 equiv.) in anhydrous THF at Ϫ78 ЊC
under N2 and stirred for thirty minutes before addition of the
β-haloaryl-α,β-unsaturated acceptor in anhydrous THF via
cannula at Ϫ78 ЊC and stirred for a further two hours. The
reaction was quenched with saturated aqueous ammonium
chloride (5 ml) and partitioned between brine and 1 : 1 Et2O–
DCM. The organic layer was washed successively with 10%
citric acid solution, saturated aqueous sodium bicarbonate
solution and brine, dried and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel.
In summary, the full potential of lithium N-benzyl-N-α-methyl-
4-methoxybenzylamide 1 as a homochiral ammonia equivalent
for the asymmetric synthesis of a range of β-haloaryl β-amino
acid derivatives has been demonstrated. The two-step deprotec-
tion protocol allows the direct isolation of β-amino esters ready
for further synthetic elaboration of the amine functionality (e.g.
for β-peptide synthesis). Although only one example is given,
the one-step deprotection protocol is general and gives the
parent β-amino acids directly. Work is currently underway
directed towards transferring this versatile methodology to
polymer support for the asymmetric synthesis of libraries of
homochiral β-amino acids.
General procedure 3
Experimental
CAN (2.1 equiv.) was added to a solution of the amine (1.0
equiv.) in 5 : 1 MeCN–H2O and the solution stirred for two
hours at room temperature. The reaction was quenched by
addition of saturated aqueous sodium bicarbonate solution
and partitioned between brine and Et2O, dried and concen-
trated in vacuo. The crude product was purified by column
chromatography.
General experimental
All reactions involving organometallic or other moisture-
sensitive reagents were performed under an atmosphere of
nitrogen via standard vacuum line techniques. All glassware 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. All other solvents
were used as supplied (analytical or HPLC grade), without
prior purification. All organometallic reagents were used as
supplied. All other reagents were used as supplied, without
prior purification. Reactions were dried with MgSO4. Thin
layer chromatography (TLC) was performed on aluminium
sheets coated with 60 F254 silica gel. Sheets were visualised using
iodine, UV light or 1% aqueous KMnO4 solution. Flash
chromatography was performed on Kieselgel 60 silica gel.
Nuclear magnetic resonance (NMR) spectra were recorded
on a Bruker DPX 400 (1H: 400 MHz and 13C: 100.6 MHz)
spectrometer or a Bruker AC 200 (1H: 200 MHz and 13C: 50.3
MHz) spectrometer in the deuteriated solvent stated. All
chemical shifts (δ) are quoted in ppm and coupling constants
(J) in Hz. Coupling constants 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 multiplicities were assigned using a DEPT
sequence. 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 stated. Only
the characteristic peaks are quoted. Low resolution mass
spectra (m/z) were recorded on VG MassLab 20–250 or Micro-
mass Platform 1 spectrometers and high resolution mass
spectra (HRMS) on a Micromass Autospec 500 OAT spec-
trometer. Techniques used were chemical ionisation (CI, NH3),
or atmospheric pressure chemical ionisation (APCI) using
partial purification by HPLC with methanol–acetonitrile–water
(40 : 40 : 20) as the eluent. Optical rotations were recorded on a
Perkin-Elmer 241 polarimeter with a path length of 1 dm and
General procedure 4
CAN (4.0 equiv.) was added to a solution of the amine (1.0
equiv.) in 5 : 1 MeCN–H2O and the solution stirred overnight
at room temperature. The reaction was quenched by addition
of saturated aqueous sodium bicarbonate solution and
partitioned between brine and Et2O, dried and concentrated
in vacuo. The crude product was purified by column
chromatography.
General procedure 5
Hydrogen chloride gas was bubbled through MeOH at RT for
ten minutes before addition of the amine in MeOH. After two
hours the reaction was concentrated in vacuo and the resultant
solid recrystallised. After recrystallisation, the white solid was
partitioned between Et2O and saturated aqueous sodium
bicarbonate solution, dried and concentrated in vacuo.
Preparation of tert-butyl (E )-3-(3-fluorophenyl)prop-2-enoate 2
Following general procedure 1, tert-butyl diethylphosphono-
acetate (2.73 g, 10.83 mmol), n-BuLi (2.5 M, 4.2 ml, 10.3 mmol)
in THF (10 ml) and 3-fluorobenzaldehyde (1.22 g, 9.85 mmol)
in THF (10 ml) gave, after purification by column chrom-
atography on silica gel (hexane–Et2O 40 : 1), 2 (2.01 g, 92%) as a
colourless oil; νmax (film) 2980 (CH), 1712 (C᎐O); δ (400 MHz,
᎐
H
CDCl3) 1.56 [9H, s, OC(Me)3], 6.38 [1H, d, J 16.0, C(2)H], 7.07
[1H, m, Ph(5)H C6H4F], 7.18–7.38 [3H, m, Ph(2)H, Ph(4)H and
Ph(6)H C6H4F], 7.52 [1H, d, J 16.0, C(3)H]; δC (100 MHz,
CDCl3) 28.6, 81.2, 114.6, 117.2, 122.1, 124.3, 130.8, 137.4,
142.5, 163.3, 166.5; m/z (CIϩ) 223 (MHϩ, 50%), 166 (MHϩ
Ϫ
are given in units of 10Ϫ1 deg cm2
g
Ϫ1. Concentrations are
C4H8 100%); HRMS (CIϩ) C13H16FO2 requires 223.1134, found
223.1133.
quoted in g/100 ml. Melting points were recorded on a Leica
VMTG Galen III apparatus and are uncorrected. Elemental
analyses were performed by the microanalysis service of the
Inorganic Chemistry Laboratory, Oxford.
Preparation of tert-butyl (E )-3-(2-iodophenyl)prop-2-enoate 3
Following general procedure 1, tert-butyl diethylphosphono-
acetate (5.0 g, 19.8 mmol), n-BuLi (1.6 M, 11.85 ml, 19.0 mmol)
in THF (20 ml) and 2-iodobenzaldehye (4.0 g, 17.2 mmol) in
THF (10 ml) gave, after purification by column chrom-
atography on silica gel (hexane–Et2O 40 : 1), 3 (5.39 g, 93%) as
General procedure 1
n-Butyllithium (1.05 equiv.) was added dropwise to a stirred
solution of tert-butyl diethylphosphonoacetate (1.1 equiv.) in
anhydrous THF at Ϫ78 ЊC under N2 and the solution left to stir
for thirty minutes. The phosphonate solution was transferred
via cannula to the aldehyde (1.0 equiv.) in anhydrous THF at
Ϫ78 ЊC under Ar and the resulting solution warmed to RT over
two hours. The reaction was quenched with saturated aqueous
ammonium chloride (5 ml), partitioned between EtOAc and
H2O, dried and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel.
a yellow oil; νmax (film) 2977 (CH), 1708 (C᎐O), 1637 (C᎐C);
᎐
᎐
δH (400 MHz, CDCl3) 1.55 [9H, s, OC(Me)3], 6.25 [1H, d,
J 15.7, C(2)H], 7.04 [1H, t, J 7.6, Ph(4)H C6H4I], 7.34 [1H, t,
J 7.6, Ph(5)H C6H4I], 7.56 [1H, d, J 7.6, Ph(6)H C6H4I], 7.83
[1H, d, J 15.7, C(3)H], 7.90 [1H, d, J 7.6, Ph(3)H C6H4I];
δC (100 MHz, CDCl3) 28.6, 81.2, 101.7, 123.4, 127.7, 128.9,
130.7, 135.9, 140.4, 147.1, 166.0; m/z (CIϩ) 331 (MHϩ, 10%),
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348 (MNH4ϩ, 30%); HRMS (CIϩ) C13H16IO2 requires 331.0195,
found 331.0194.
C6H4Br], 7.48 [1H, m, Ph(4)H C6H4Br], 7.50 [1H, d, J 16.0,
C(3)H], 7.65 [1H, s, Ph(2)H C6H4Br]; δC (100 MHz, CDCl3)
28.1, 80.8, 121.7, 122.9, 126.5, 130.3, 130.6, 132.7, 136.7, 141.7,
165.8; m/z (CIϩ) 283 (MHϩ, 30%); HRMS (CIϩ) C13H16BrO2
requires 283.0334, found 283.0329.
Preparation of tert-butyl (E )-3-(3-iodophenyl)prop-2-enoate 4
Following general procedure 1, tert-butyl diethylphosphono-
acetate (4.1 g, 16.3 mmol), n-BuLi (2.5 M, 6.2 ml, 15.5 mmol) in
THF (15 ml) and 3-iodobenzaldehye (3.43 g, 14.8 mmol) in
THF (15 ml) gave, after purification by column chrom-
atography on silica gel (hexane–Et2O 40 : 1), 4 (4.15 g, 85%) as a
yellow oil; νmax (film) 1707 (C᎐O), 1638 (C᎐C); δ (400 MHz,
Preparation of tert-butyl (E )-3-(4-bromophenyl)prop-2-enoate 9
Following general procedure 1, tert-butyl diethylphosphono-
acetate (2.7 g, 10.9 mmol), n-BuLi (2.5 M, 4.2 ml, 10.3 mmol)
in THF (10 ml) and 4-bromobenzaldehyde (1.2 g, 9.9 mmol)
in THF (10 ml) gave, after purification by column chrom-
atography on silica gel (hexane–Et2O 40 : 1), 9 (2.0 g, 92%) as
white needles; mp 66 ЊC (hexane–Et2O); found C, 55.3%, H,
5.1%; C13H15BrO2 requires C, 55.15%, H, 5.3%; νmax (KBr) 1707
᎐
᎐
H
CDCl3) 1.54 [9H, s, OC(Me)3], 6.36 [1H, d, J 16.0, C(2)H], 7.12
[1H, t, J 7.8, Ph(5)H C6H4I], 7.47 [1H, d, J 16.0, C(3)H], 7.48
[1H, d, J 8.0, Ph(6)H C6H4I], 7.69 [1H, d, J 8.3, Ph(4)H C6H4I],
7.87 [1H, s, Ph(2)H C6H4I]; δC (100 MHz, CDCl3) 28.6, 81.2,
95.1, 122.0, 127.6, 130.9, 137.0, 137.3, 139.1, 142.1, 166.2; m/z
(CIϩ) 331 (MHϩ, 40%), 348 (MNH4ϩ, 35%); HRMS (CIϩ)
C13H16IO2 requires 331.0195, found 331.0197.
(C᎐O), 1637 (C᎐C); δ (400 MHz, CDCl3) 1.53 [9H, s,
᎐
᎐
H
CO2C(Me)3], 6.35 [1H, d, J 16.0, C(2)H], 7.35–7.53 [5H, m, Ph
and C(3)H)]; δC (50 MHz, CDCl3) 28.1, 80.7, 120.9, 124.1,
129.3, 132.0, 133.5, 142.1, 166.0; m/z (NH3) 284.2 (MHϩ, 25%),
228.2 (MHϩ Ϫ C4H8, 100%).
Preparation of tert-butyl (E )-3-(4-iodophenyl)prop-2-enoate11
5
Following general procedure 1, tert-butyl diethylphosphono-
acetate (3.9 g, 15.5 mmol), n-BuLi (2.5 M, 9.25 ml, 14.8 mmol)
in THF (20 ml) and 4-iodobenzaldehye (3.1 g, 13.5 mmol) in
THF (20 ml) gave, after purification by column chrom-
atography on silica gel (hexane–Et2O 40 : 1) and recrystallis-
ation (hexane–Et2O), 5 (4.2 g, 94%) as white needles; mp 65–66
ЊC (hexane–Et2O); δH (400 MHz, CDCl3) 1.54 [9H, s, OC(Me)3],
6.38 [1H, d, J 16.0, C(2)H], 7.24 [2H, m, Ph(2)H and Ph(6)H
C6H4I], 7.51 [1H, d, J 16.0, C(3)H], 7.72 [2H, d, J 8.5, Ph(3)H
and Ph(5)H C6H4I].
Preparation of tert-butyl (3R,ꢁS)-3-(3-fluorophenyl)-3-(N-
benzyl-N-ꢁ-methyl-4-methoxybenzylamino)propanoate 10
Following general procedure 2, n-BuLi (2.5 M, 2.8 ml, 7.0
mmol), (S)-α-methyl-4-methoxybenzylamine (1.74 g, 7.2 mmol)
in THF (10 ml) and (E)-2 (1.0 g, 4.5 mmol) in THF (10 ml)
gave, after purification by column chromatography on silica gel
(hexane–Et2O 10 : 1) and recrystallisation (hexane–Et2O), 10
(1.60 g, 77%) as a white solid; found: C, 75.2; H, 7.3; N 3.0%;
C29H34FNO3 requires C, 75.1; H, 7.4; N, 3.0%; mp 87–88 ЊC
(hexane–Et2O); [α]2D0 Ϫ25.0 (c 1.0, CHCl3); νmax (KBr disc) 2971
Preparation of tert-butyl (E )-3-(3-chlorophenyl)prop-2-enoate 6
(CH), 1735 (C᎐O), 1509 (OMe), 1246 (Ph–OMe); δ (400 MHz,
᎐
H
CDCl3) 1.27 [9H, s, OC(Me)3], 1.28 [3H, d, J 6.9, C(α)Me], 2.46
[1H, dd, J2A,2B 14.8, J2A,3 9.9, C(2) HA], 2.52 [1H, dd, J2B,2A 14.8,
J2B,3 5.0, C(2)HB], 3.66 (2H, s, NCH2Ph), 3.81 (3H, s, OMe),
3.93 [1H, q, J 6.9, C(α)H], 4.42 [1H, dd, J3,2A 9.9, J3,2B 5.0,
C(3)H], 6.88 [2H, m, Ph(3)H and Ph(5)H C6H4OMe], 6.95 [1H,
m, Ph(2)H C6H4F], 7.16–7.35 (10H, m, Ph); δC (100 MHz,
CDCl3) 16.8, 27.8, 38.0, 50.7, 55.2, 56.5, 58.9, 80.9, 113.5,
113.9, 115.1, 123.7, 126.6, 127.9, 128.2, 128.8, 129.5, 135.7,
141.4, 145.0, 158.5, 162.8, 171.0; m/z (APCIϩ) 464 (MHϩ, 20%).
Following general procedure 1, tert-butyl diethylphosphono-
acetate (5.9 g, 23.5 mmol), n-BuLi (2.5 M, 9.0 ml, 22.5 mmol) in
THF (15 ml) and 3-chlorobenzaldehyde (3.0 g, 21.4 mmol)
in THF (15 ml) gave, after purification by column chrom-
atography on silica gel (hexane–Et2O 40 : 1), 6 (4.69 g, 92%) as a
colourless oil; νmax (film) 2979 (CH), 1712 (C᎐O); δ (400 MHz,
᎐
H
CDCl3) 1.54 [9H, s, OC(Me)3], 6.38 [1H, d, J 16.0, C(2)H], 7.18
[1H, m, Ph(4)H C6H4Cl], 7.25–7.39 [2H, m, Ph(5)H and Ph(6)H
C6H4Cl], 7.50 [1H, s, Ph(2)H C6H4Cl], 7.52 [1H, d, J 16.0,
C(3)H]; δC (100 MHz, CDCl3) 28.0, 80.8, 121.8, 126.3, 127.8,
130.0, 130.2, 135.0, 136.7, 142.1, 166.1; m/z (CIϩ) 239 (MHϩ,
65%), 182 (MHϩ Ϫ C4H8, 100%); HRMS (CIϩ) C13H16ClO2
requires 239.0839, found 239.0838.
Preparation of tert-butyl (3R,ꢁS)-3-(2-iodophenyl)-3-(N-benzyl-
N-ꢁ-methyl-4-methoxybenzylamino)propanoate 11
Following general procedure 2, n-BuLi (2.5 M, 1.88 ml, 4.7
mmol), (S)-α-methyl-4-methoxybenzylamine (1.17 g, 4.9 mmol)
in THF (10 ml) and (E)-3 (1.0 g, 3.0 mmol) in THF (10 ml)
gave, after purification by column chromatography on silica gel
(hexane–Et2O 15 : 1) and recrystallisation (hexane–Et2O), 11
(1.32 g, 76%) as white crystals; mp 98–99 ЊC (hexane–Et2O);
found: C, 61.1; H, 6.05; N, 2.5%; C29H34INO3 requires C, 60.95;
H, 6.0; N, 2.45%; [α]2D2 Ϫ34.5 (c 1.0, CHCl3); νmax (film) 3020
(CH), 1716 (C᎐O), 1512 (OMe), 1216 (Ph–OMe); δ (400 MHz,
Preparation of tert-butyl (E )-3-(2-bromophenyl)prop-2-enoate 7
Following general procedure 1, tert-butyl diethylphosphono-
acetate (5.8 g, 23.1 mmol), n-BuLi (2.5 M, 9.25 ml, 21.1 mmol)
in THF (20 ml) and 2-bromobenzaldehyde (3.3 g, 17.8 mmol) in
THF (20 ml) gave, after purification by column chromatography
on silica gel (hexane–Et2O 40 : 1), 7 (4.7 g, 93%) as a colourless
oil; νmax (film) 1710 (C᎐O), 1635 (C᎐C); δ (400 MHz, CDCl3)
᎐
H
᎐
᎐
H
CDCl3) 1.19 [9H, s, OC(Me)3], 1.49 [3H, d, J 6.8, C(α)Me], 2.18
[1H, dd, J2A,2B 14.0, J2A,3 9.6, C(2)HA], 2.60 [1H, dd, J2B,2A 14.0,
J2B,3 5.8, C(2)HB], 3.75 (2H, ABq, NCH2Ph), 3.76 (3H, s, OMe),
3.88 [1H, q, J 6.8, C(α)H], 4.74 [1H, dd, J3,2A 9.6, J3,2B 5.8,
C(3)H], 6.81 [2H, m, Ph(3)H and Ph(5)H C6H4OMe], 6.95 [1H,
m, Ph(6)H C6H4I], 7.21 (5H, m, Ph), 7.27 [2H, m, Ph(2)H and
Ph(6)H C6H4OMe], 7.40 [1H, m, Ph(5)H C6H4I], 7.64 [1H, m,
Ph(4)H C6H4I], 7.81 [1H, m, Ph(3)H C6H4I]; δC (100 MHz,
CDCl3) 13.2, 28.3, 43.4, 50.8, 55.7, 56.6, 66.7, 80.8, 102.2,
113.7, 126.8, 128.0, 128.6, 128.8, 129.5, 130.3, 136.3, 140.1,
143.3, 145.9, 158.8, 170.7; m/z (APCIϩ) 572 (MHϩ, 15%), 135
(C9H11Oϩ, 95%).
1.54 [9H, s, CO2C(Me)3], 6.32 [1H, d, J 15.9, C(2)H], 7.19 [1H,
m, Ph(4)H C6H4Br], 7.30 [1H, m, Ph(5)H C6H4Br], 7.58 [2H, m,
Ph(3)H and Ph(6)H C6H4Br], 7.96 [1H, d, J 15.9, C(3)H]; δC
(100 MHz, CDCl3) 28.1, 80.7, 122.9, 125.2, 127.6, 130.9, 133.3,
134.6, 141.9, 165.7; m/z (CIϩ) 283 (MHϩ, 10%); HRMS (CIϩ)
C13H16BrO2 requires 283.0334, found 283.0336.
Preparation of tert-butyl (E )-3-(3-bromophenyl)prop-2-enoate 8
Following general procedure 2, tert-butyl diethylphosphono-
acetate (1.5 g, 5.94 mmol), n-BuLi (2.5 M, 2.27 ml, 5.67 mmol)
in THF (10 ml) and 3-bromobenzaldehyde (1.0 g, 5.40 mmol)
in THF (10 ml) gave, after purification by column chrom-
atography on silica gel (hexane–Et2O 40 : 1), 8 (1.3 g, 85%) as a
Preparation of tert-butyl (3R,ꢁS)-3-(3-iodophenyl)-3-(N-benzyl-
N-ꢁ-methyl-4-methoxybenzylamino)propanoate 12
colourless oil; νmax (film) 1709 (C᎐O), 1639 (C᎐C); δ (400
᎐
᎐
H
MHz, CDCl3) 1.54 [9H, s, OC(Me)3], 6.36 [1H, d, J 16.0,
C(2)H], 7.24 [1H, t, J 7.9, Ph(5)H C6H4Br], 7.42 [1H, m, Ph(6)H
Following general procedure 2, n-BuLi (2.5 M, 3.9 ml, 9.7
3116
J. Chem. Soc., Perkin Trans. 1, 2001, 3112–3121

View Article Online
mmol), (S)-α-methyl-4-methoxybenzylamine (2.26 g, 9.4 mmol)
in THF (20 ml) at Ϫ78 ЊC and (E)-4 (2.0 g, 6.06 mmol) in THF
(20 ml) gave, after purification by column chromatography on
silica gel (hexane–Et2O 15 : 1), 12 (2.56 g, 74%) as a pale green
atography on silica gel (hexane–Et2O 5 : 1) and recrystallisation,
15 as a white solid (3.77 g, 82%); found C, 66.2; H, 7.0, N, 2.6%;
C29H34BrNO3 requires C, 66.4; H, 6.5; N, 2.7%; [α]2D3 ϩ59.4
(c 1.03, CHCl3); νmax (film) 1729 (C᎐O), 1510 (OMe), 1249
᎐
oil; [α]2D0 Ϫ18.0 (c 1.0, CHCl3); νmax (film) 1725 (C᎐O), 1511
(Ph–OMe); δH (400 MHz, CDCl3) 1.17 [9H, s, CO2C(Me)3],
1.43 [3H, d, J 6.8, C(α)Me)], 2.28 [1H, dd, J2A,2B 13.9, J2A,3 10.3,
C(2)HA], 2.63 [1H, dd, J2B,2A 13.9, J2B,3 5.4, C(2)HB], 3.76 (2H,
ABq, J 15.4, NCH2Ph), 3.78 (3H, s, OMe), 3.91 [1H, q, J 6.8,
C(α)H], 4.91 [1H, dd, J3,2A 10.3, J3,2B 5.4, C(3)H], 6.82 [2H, m,
Ph(3)H and Ph(5)H C6H4OMe], 7.11 [1H, m, Ph(4)H C6H4Br],
7.14–7.27 (5H, m, Ph), 7.29 [2H, m, Ph(2)H and Ph(6)H
C6H4OMe], 7.36 [1H, m, Ph(3)H C6H4Br], 7.53 [1H, m, Ph(5)H
C6H4Br], 7.65 [1H, m, Ph(6)H C6H4Br]; δC (100 MHz, CDCl3)
12.9, 27.6, 42.2, 50.4, 55.2, 56.2, 61.0, 80.3, 113.2, 125.3, 126.3,
127.5, 128.0, 128.7, 129.0, 130.0, 132.9, 135.8, 141.9, 142.6,
158.3, 170.2; m/z (APCIϩ) 524 (MHϩ, 20%).
᎐
(OMe), 1247 (Ph–OMe); δH (400 MHz, CDCl3) 1.29 [9H, s,
OC(Me)3], 1.30 [3H, d, J 6.9, C(α)Me], 2.42 [1H, dd, J2A,2B 14.7,
J2A,3 10.0, C(2)HA], 2.48 [1H, dd, J2B,2A 14.7, J2B,3 5.1, C(2)HB],
3.64 (2H, s, NCH2Ph), 3.81 (3H, s, OMe), 3.93 [1H, q, J 6.9,
C(α)H], 4.36 [1H, dd, J3,2A 10.0, J3,2B 5.1, C(3)H], 6.88 [2H, m,
Ph(3)H and Ph(5)H C6H4OMe], 7.08 [1H, m, Ph(5)H C6H4I],
7.20–7.28 (4H, m, Ph), 7.30 [2H, m, Ph(2)H and Ph(6)H
C6H4OMe], 7.41 [1H, m, Ph(6)H C6H4I], 7.58 [1H, m, Ph(4)H
C6H4I], 7.75 [1H, m, Ph(2)H C6H4I]; δC (100 MHz, CDCl3) 16.9,
27.8, 34.6, 50.7 55.2, 56.6, 58.9, 80.5, 94.1, 113.5, 126.6, 127.5,
127.9, 128.1, 128.8, 129.9, 135.6, 136.0, 137.2, 141.4, 144.8,
158.5, 170.8; m/z (APCIϩ) 572 (MHϩ, 5%), 135 (C9H11Oϩ,
100%); HRMS (CIϩ) C29H35INO3 requires 572.1662, found
572.1658.
Preparation of tert-butyl (3S,ꢁR)-3-(3-bromophenyl)-3-(N-
benzyl-N-ꢁ-methyl-4-methoxybenzylamino)propanoate 16
Following general procedure 2, n-BuLi (2.5 M, 5.64 ml, 14.1
mmol), (R)-α-methyl-4-methoxybenzylamine (3.37 g, 14.1
mmol) in THF (20 ml) and (E)-8 (2.5 g, 8.8 mmol) in THF (30
ml) gave, after purification by column chromatography on silica
gel (hexane–Et2O 5 : 1), 16 (3.7 g, 80%) as a colourless oil; [α]2D0
Preparation of tert-butyl (3R,ꢁS)-3-(4-iodophenyl)-3-(N-benzyl-
N-ꢁ-methyl-4-methoxybenzylamino)propanoate 13
Following general procedure 2, n-BuLi (2.5 M, 2.2 ml, 5.4
mmol), (S)-α-methyl-4-methoxybenzylamine (1.27 g, 5.25
mmol) in THF (15 ml) and (E)-5 (1.12 g, 3.4 mmol) in THF
(15 ml) gave, after purification by column chromatography on
silica gel (hexane–Et2O 15 : 1), 13 (1.53 g, 79%) as a white foam;
ϩ18.6 (c 1.03, CHCl3); νmax (film) 1724 (s, C᎐O); δH (400 MHz,
᎐
CDCl3) 1.28 [9H, s, OC(Me)3], 1.29 [3H, d, J 6.8, C(α)Me], 2.44
[1H, dd, J2A,2B 14.7, J2A,3 9.9, C(2)HA], 2.50 [1H, dd, J2B,2A 14.7,
J2B,3 5.6, C(2)HB], 3.65 (2H, m, NCH2PH), 3.81 (3H, s, OMe),
3.93 [1H, q, J6.8, C(α)H], 4.39 [1H, dd, J3,2A 9.8, J3,2B 5.0,
C(3)H], 6.88 [2H, m, Ph(3)H and Ph(5)H C6H4OMe], 7.20–7.29
[6H, m, Ph and Ph(5)H C6H4Br], 7.32 [2H, m, Ph(2)H and
Ph(6)H C6H4OMe], 7.38 [2H, m, Ph(4)H and Ph(6)H C6H4Br],
7.56 [Ph(2)H C6H4Br]; δC (100 MHz, CDCl3) 16.9, 27.8, 38.0,
50.7, 55.2, 56.6, 59.0, 80.4, 113.5, 122.2, 126.6, 126.9, 127.9,
128.2, 128.8, 130.1, 129.6, 130.1, 131.2, 135.6, 141.4, 144.7,
158.5, 170.9; m/z (APCIϩ) 524 (MHϩ, 5%); HRMS (CIϩ)
C29H35BrNO3 requires 524.1800, found 524.1795.
[α]2D0 Ϫ6.9 (c 1.0, CHCl3); νmax (film) 2975 (CH), 1726 (C᎐O),
᎐
1511 (OMe), 1248 (Ph–OMe); δH (400 MHz, CDCl3) 1.25 [9H,
s, OC(Me)3], 1.26 [3H, d, J 6.4, C(α)Me], 2.42 [1H, dd, J2A,2B
14.8, J2A,3 10.1, C(2)HA], 2.48 [1H, dd, J2B,2A 14.8, J2B,3 4.9,
C(2)HB], 3.62 (2H, ABq, NCH2Ph), 3.80 (3H, s, OMe), 3.89
[1H, q, J 6.4, C(α)H], 4.35 [1H, dd, J3,2A 10.1, J3,2B 4.9, C(3)H],
6.86 [2H, m, Ph(3)H and Ph(5)H C6H4OMe], 7.16 [2H, m,
Ph(2)H and Ph(6)H C6H4I], 7.25 (5H, m, Ph), 7.29 [2H, m,
Ph(2)H and Ph(6)H C6H4OMe], 7.65 [2H, m, Ph(3)H and
Ph(5)H C6H4I]; δC (100 MHz, CDCl3) 16.9, 27.8, 37.9, 50.7,
55.2, 56.6, 58.9, 80.5, 92.6, 113.7, 126.8, 128.1, 128.4, 129.0,
130.5, 136.0, 137.4, 141.7, 142.3, 158.8, 171.3; m/z (CIϩ) 572
(MHϩ, 30%); HRMS (CIϩ) C29H35INO3 requires 572.1662,
found 572.1660.
Preparation of tert-butyl (3S,ꢁR)-3-(4-bromophenyl)-3-(N-
benzyl-N-ꢁ-methyl-4-methoxybenzylamino)propanoate 17
Following general procedure 2, n-BuLi (1.6 M, 3.5 ml, 5.47
mmol, 1.55 equiv.), (R)-α-methyl-4-methoxybenzylamine (1.38
g, 5.7 mmol, 1.6 equiv.) and in THF (20 ml) and (E)-9 (1.0 g,
3.53 mmol, 1.0 equiv.) in THF (10 ml) gave, after purification
by column chromatography on silica gel (hexane–Et2O 6 : 1)
17 (1.60 g, 86%) as a colourless oil; [α]2D4 ϩ10.4 (c 1.0, CHCl3);
Preparation of tert-butyl (3S,ꢁR)-3-(3-chlorophenyl)-3-(N-
benzyl-N-ꢁ-methyl-4-methoxybenzylamino)propanoate 14
Following general procedure 2, n-BuLi (2.5 M, 2.6 ml, 6.5
mmol), (R)-α-methyl-4-methoxybenzylamine (1.61 g, 6.7
mmol) in THF (15 ml) and (E)-6 (1.12 g, 3.4 mmol) in THF
(15 ml) gave, after purification by column chromatography on
silica gel (hexane–Et2O 15 : 1), 14 (1.26 g, 78%) as a pale green
oil; [α]2D0 Ϫ19.2 (c 1.0, CHCl3); νmax (film) 2976 (C–H), 1726
νmax (film) 2976, 2933 (C–H), 1725 (C᎐O), 1511 (OMe), 1248
᎐
(Ph–OMe), 1153 (C–O); δH (400 MHz, CDCl3) 1.26 [9H, s,
CO2C(Me)3], 1.27 [3H, d, J 7.4, C(α)Me], 2.45 [1H, dd, J2A,2B
14.8, J2A,3 10.1, C(2)HA], 2.53 [1H, dd, J2B,2A 14.8, J2B,3 4.8,
C(2)HB], 3.64 (2H, ABq, NCH2), 3.81 (3H, s, OMe), 3.92 [1H,
q, J 7.4, C(α)H], 4.38 [1H, dd, J3,2A 10.1, J3,2B 4.8, C(3)H], 6.87
[2H, d, J 8.6, Ph(3)H and Ph(5)H C6H4OMe], 7.17–7.33 (9H,
m, Ph), 7.46 [2H, d, J 8.4, Ph(3)H and Ph(5)H C6H4Br]; δC (100
MHz, CDCl3) 16.9, 27.8, 37.9, 50.7, 55.2, 56.6, 58.7, 80.4, 113.5,
120.8, 126.6, 127.9, 128.1, 128.8, 129.9, 131.1, 135.7, 141.2,
141.4, 158.5, 170.9; m/z (APCIϩ) 524.0 (MHϩ, 10%), 134.8
(C9H11Oϩ, 100%); HRMS (CIϩ) C29H35BrNO3 requires
524.1800; found 524.1798.
(C᎐O), 1512 (OMe), 1249 (Ph–OMe); δ (400 MHz, CDCl3)
᎐
H
1.27 [9H, s, OC(Me)3], 1.28 [3H, d, J 6.9, C(α)Me], 2.45 [1H, dd,
J2A,2B 14.7, J2A,3 9.9, C(2)HA], 2.50 [1H, dd, J2B,2A 14.7, J2B,3 5.1,
C(2)HB], 3.65 (2H, ABq, NCH2Ph), 3.81 (3H, s, OMe), 3.93
[1H, q, J 6.9, C(α)H], 4.40 [1H, dd, J3,2A 9.9, J3,2B 5.1, C(3)H],
6.89 [2H, m, Ph(3)H and Ph(5)H C6H4OMe], 7.19–7.33 (10H,
m, ArH), 7.41 [1H, s, Ph(2)H C6H4Cl]; δC (100 MHz, CDCl3)
16.8, 27.8, 38.0, 50.7, 55.2, 56.6, 59.0, 80.5, 113.4, 126.4, 126.6,
127.2, 127.9, 128.2, 128.3, 128.8, 129.4, 133.9, 135.63, 141.4,
144.4, 158.5, 170.9; m/z (APCIϩ) 480 (MHϩ, 10%); HRMS
(CIϩ) C29H35ClNO3 requires 480.2306, found 480.2307.
Preparation of tert-butyl (3R,ꢁS)-3-(3-fluorophenyl)-3-(N-ꢁ-
methyl-4-methoxybenzylamino)propanoate 18
Preparation of tert-butyl (3S,ꢁR)-3-(2-bromophenyl)-3-(N-
benzyl-N-ꢁ-methyl-4-methoxybenzylamino)propanoate 15
Following general procedure 3, CAN (2.49 g, 4.53 mmol) and
10 (1.0 g, 2.16 mmol) in 5 : 1 MeCN–H2O (12 ml) gave, after
work up and purification by column chromatography on silica
gel (hexane–Et2O 4 : 1–1% NEt3), 18 (706 mg, 86%) as a yellow
oil; [α]2D0 Ϫ20.3 (c 1.0, CHCl3); νmax (film)/cmϪ1 3329 (NH), 1724
Following representative procedure 2, n-BuLi (2.5 M, 5.5 ml,
13.7 mmol), (R)-α-methyl-4-methoxybenzylamine (3.4 g, 14.1
mmol) in THF (20 ml) and (E)-7 (2.5 g, 8.8 mmol) in THF
(30 ml) gave, after successive purification by column chrom-
(C᎐O); δH (400 MHz, CDCl3) 1.36 [3H, d, J 6.5, C(α)Me], 1.40
᎐
J. Chem. Soc., Perkin Trans. 1, 2001, 3112–3121
3117

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[9H, s, OC(Me)3], 2.56 [1H, dd, J2A,2B 14.9, J2A,3 6.6, C(2)HA],
2.64 [1H, dd, J2B,2A 14.9, J2B,3 6.6, C(2)HB], 3.66 [1H, q, J 6.5,
C(α)H], 3.79 (3H, s, OMe), 4.15 [1H, t, J 6.6, C(3)H], 6.83 [2H,
m, Ph(3)H and Ph(5)H C6H4OMe], 6.92 [1H, m, Ph(2)H
C6H4F], 7.04 [2H, m, Ph(4)H and Ph(6)H C6H4F], 7.18 [2H, m,
Ph(2)H and Ph(6)H C6H4OMe], 7.24 [1H, m, Ph(5)H C6H4F];
δC (100 MHz, CDCl3) 22.4, 28.0, 43.5, 54.1, 55.2, 56.7, 80.6,
113.7, 113.9, 114.1, 122.7, 127.6, 129.8, 137.8, 145.7, 158.5,
162.9, 170.7; m/z (APCIϩ) 374 (MHϩ, 55%), 135 (C9H11Oϩ,
100%); HRMS (CIϩ) C22H29FNO3 requires 374.2132, found
374.2138.
Preparation of tert-butyl (R)-3-(2-iodophenyl)-3-amino-
propanoate 22
Following general procedure 4, CAN (4.56 g, 8.31 mmol) and
19 (1.0 g, 2.08 mmol) in 5 : 1 MeCN–H2O (24 ml) gave, after
work up and purification by column chromatography on silica
gel (hexane–Et2O 8 : 1–1% NEt3), 22 (368 mg, 51%) as a pale
green oil; [α]2D2 ϩ36.9 (c 0.95, CHCl3); νmax (film) 3379 (NH),
1725 (C᎐O); δH (400 MHz, CDCl3) 1.44 [9H, s, OC(Me)3], 2.47
᎐
[1H, dd, J2A,2B 15.9, J2A,3 9.5, C(2)HA], 2.67 [1H, dd, J2B,2A 15.9,
J2B,3 4.0, C(2)HB], 4.38 [1H, dd, J3,2A 9.5, J3,2B 4.0, C(3)H], 6.95
[1H, m, Ph(4)H C6H4I], 7.35 [1H, m, Ph(5)H C6H4I], 7.50 [1H,
m, Ph(6)H C6H4I], 7.82 [1H, m, Ph(2)H C6H4I]; δC (100 MHz,
CDCl3) 28.1, 43.4, 56.2, 80.9, 99.3, 127.0, 128.6, 129.0, 139.6,
146.1, 171.0; m/z (APCIϩ) 348 (MHϩ, 30%), 292 (MHϩ Ϫ C4H8,
100%); HRMS (CIϩ) C13H19INO2 requires 348.0461, found
348.0466.
Preparation of tert-butyl (3R,ꢁS)-3-(2-iodophenyl)-3-(N-ꢁ-
methyl-4-methoxybenzylamino)propanoate 19
Following general procedure 3, CAN (7.05 g, 12.8 mmol) and
11 (3.5 g, 6.12 mmol) in 5 : 1 MeCN–H2O (90 ml) gave, after
work up and purification by column chromatography on silica
gel (hexane–Et2O 8 : 1–1% NEt3), 19 (632 mg, 75%) as a pale
Preparation of tert-butyl (S)-3-(2-bromophenyl)-3-amino-
propanoate 23
green oil; νmax (film) 3326 (NH), 1722 (C᎐O), 1512 (OMe), 1247
᎐
(Ph–OMe); [α]1D9 Ϫ33.8 (c 1.0, CHCl3); δH 400 MHz, CDCl3)
1.36 [3H, d, J 6.5, C(α)Me], 1.45 [9H, s, OC(Me)3], 2.38 [1H, dd,
J2A,2B 14.9, J2A,3 9.3, C(2)HA], 2.59 [1H, dd, J2B,2A 14.9, J2B,3 6.4,
C(2)HB], 3.54 [1H, q, J 6.5, C(α)H], 3.79 (3H, s, OMe), 4.54
[1H, dd, J3,2A 9.3, J3,2B 6.4, C(3)H], 6.81 [2H, m, Ph(3)H and
Ph(5)H C6H4OMe], 6.95 [1H, m, Ph(6)H C6H4I], 7.19 [2H, m,
Ph(2)H and Ph(6)H C6H4OMe], 7.31 [1H, m, Ph(4)H C6H4I],
7.37 [1H, m, Ph(5)H C6H4I], 7.80 [1H, m, Ph(3)H C6H4I];
δC (100 MHz, CDCl3) 22.1, 28.1, 43.0, 53.9, 55.2, 60.9, 80.7,
99.9, 113.6, 127.6, 127.8, 128.4, 128.9, 138.1, 139.6, 144.3,
158.4, 170.6; m/z (CIϩ) 482 (MHϩ, 100%), 135 (C9H11Oϩ, 75%);
HRMS (CIϩ) C22H29INO3 requires 482.1192, found 482.1193.
Following general procedure 4, CAN (2.71 g, 4.94 mmol) and
20 (536 mg, 1.24 mmol) in 5 : 1 MeCN–H2O (24 ml) gave, after
work up and purification by column chromatography on silica
gel (hexane–Et2O 1 : 1), 23 (254 mg, 68%) as a yellow oil;
[α]2D0 Ϫ45.0 (c 1.02, CHCl3); νmax (film) 3381 (NH), 2978 (C–H),
1724 (C᎐O), 1150 (C–O); δ (400 MHz, CDCl3) 1.43 [9H, s,
᎐
H
OC(Me)3], 1.82, (2H, br s, NH2), 2.49 [1H, dd, J2A,2B 15.8, J2A,3
9.3, C(2)HA], 2.68 [1H, dd, J2B,2A 15.8, J2B,3 4.0, C(2)HB], 4.75
[1H, dd, J3,2A 9.3, J2,2B 4.0, C(3)H], 7.08–7.13 and 7.29–7.33 [2 ×
1H, m, Ph(4)H and Ph(5)H C6H4Br], 7.52–7.54 [2H, m, Ph(3)H
and Ph(6)H C6H4Br]; δC (100 MHz, CDCl3) 28.0, 43.2, 51.4,
80.8, 123.0, 127.4, 127.7, 128.6, 132.9, 143.3, 171.0; m/z
(APCIϩ) 302.0 (MHϩ, 15%), 246.0 (MHϩ Ϫ C4H8, 100%);
HRMS (CIϩ) C13H19BrNO2 requires 300.0599, found 300.0609.
Preparation of tert-butyl (3S,ꢁR)-3-(2-bromophenyl)-3-(N-ꢁ-
methyl-4-methoxybenzylamino)propanoate 20
Following general procedure 3, CAN (6.59 g, 12.0 mmol) and
15 (3.0 g, 5.73 mmol) in 5 : 1 MeCN–H2O (60 ml) gave, after
work up and purification by column chromatography on silica
gel (hexane–EtOAc 9 : 1–1% NEt3), 19 (2.14 g, 86%) as a
Preparation of tert-butyl (3R,ꢁS)-3-(3-iodophenyl)-3-(N-ꢁ-
methyl-4-methoxybenzylamino)propanoate 24
Following general procedure 3, CAN (2.01 g, 3.7 mmol) and 12
(2.0 g, 3.5 mmol) in 5 : 1 MeCN–H2O (24 ml) gave, after work
up and purification by column chromatography on silica gel
(hexane–Et2O 8 : 1–1% NEt3), 24 (1.30 g, 77%) as a pale green
oil; [α]1D9 Ϫ18.0 (c 1.0, CHCl3); νmax (film) 3328 (NH), 1724
colourless oil; νmax (film) 2979, 2929 (C–H), 1721 (C᎐O), 1513
᎐
(OMe), 1266 (Ph–OMe); [α]2D3 ϩ28.7 (c 1.03, CHCl3); δH (400
MHz, CDCl3) 1.35 [3H, d, J 6.5, C(α)Me], 1.43 [9H, s,
OC(Me)3], 1.95 (1H, br s, NH), 2.47 [1H, dd, J2A,2B 14.8, J2A,3
8.8, C(2)HA], 2.63 [1H, dd, J2B,2A 14.8, J2B,3 5.0, C(2)HB], 3.56
[1H, q, J 6.5, C(α)H], 3.78 (3H, s, OMe), 4.69 [1H, dd, J3,2A 8.8,
J3,2B 5.0, C(3)H], 6.82 [2H, m, Ph(3)H and Ph(5)H C6H4OMe],
7.09 [1H, td, J 7.8, J 1.7, Ph(4)H C6H4Br], 7.19 [2H, d, Ph(2)H
and Ph(6)H C6H4OMe], 7.28 [1H, td, J 8.0, J 1.2, Ph(5)H
C6H4Br], 7.40 [1H, dd, J 7.8, J 1.6, Ph(3)H C6H4Br], 7.52 [1H,
dd, J 8.0, J 1.2, Ph(6)H C6H4Br]; δC (100 MHz, CDCl3) 22.2,
28.0, 42.7, 54.0, 55.2, 56.0, 80.6, 113.6, 123.7, 127.5, 127.6,
128.4, 128.5, 132.9, 138.1, 141.5, 158.4, 170.7; m/z (APCIϩ) 434
(MHϩ, 35%); HRMS (CIϩ) C22H29BrNO3 requires 434.1331,
found 434.1335.
(C᎐O); δH (400 MHz, CDCl3) 1.34 [3H, d, J 6.5, C(α)Me], 1.38
᎐
[9H, s, OC(Me)3], 2.51 [1H, dd, J2A,2B 14.8, J2A,3 6.4, C(2)HA],
2.60 [1H, dd, J2B,2A 14.8, J2B,3 6.4, C(2)HB], 3.63 [1H, q, J 6.5,
C(α)H], 3.79 (3H, s, OMe), 4.05 [1H, t, J 6.4, C(3)H], 6.81 [2H,
d, J 8.7, Ph(3)H and Ph(5)H C6H4OMe], 7.02 [1H, t, J 7.8,
Ph(5)H C6H4I], 7.15 [2H, m, Ph(2)H and Ph(6)H C6H4OMe],
7.23 [1H, m, Ph(6)H C6H4I], 7.55 [1H, m, Ph(4)H C6H4I], 7.60
[1H, m, Ph(2)H C6H4I]; δC (100 MHz, CDCl3) 22.5, 28.0, 43.6,
54.3, 55.2, 56.8, 80.7, 94.4, 113.7, 126.6, 127.6, 130.1, 136.1,
136.3, 137.7, 145.5, 158.5, 170.6; m/z (APCIϩ) 482 (MHϩ, 10%),
135 (C9H11Oϩ, 100%); HRMS (CIϩ) C22H29INO3 requires
482.1192, found 482.1197.
Preparation of tert-butyl (R)-3-(3-fluorophenyl)-3-amino-
propanoate 21
Preparation of tert-butyl (R)-3-(3-iodophenyl)-3-amino-
propanoate 25
Following general procedure 4, CAN (2.19 g, 4.0 mmol) and 18
(373 mg, 1.0 mmol) in 5 : 1 MeCN–H2O (12 ml) gave, after work
up and purification by column chromatography on silica gel
(hexane–Et2O 1 : 1), 21 (126 mg, 53%) as a yellow oil; [α]2D0
ϩ11.6 (c 1.0, CHCl3); νmax (film) 3382 (NH), 1725 (C᎐O); δ
Following general procedure 4, CAN (3.10 g, 5.65 mmol) and
24 (680 mg, 1.41 mmol) in 5 : 1 MeCN–H2O (18 ml) gave, after
work up and purification by column chromatography on silica
gel (hexane–Et2O 1 : 2), 25 (240 mg, 49%) as a yellow oil; [α]2D2
᎐
H
(400 MHz, CDCl3) 1.43 [9H, s, OC(Me)3], 1.82 (2H, br s, NH2),
2.57 [2H, m, C(2)H2], 4.38 [1H, m, C(3)H], 6.95 [1H, m, Ph(5)H
C6H4F], 7.10 [1H, m, Ph(2)H C6H4F], 7.14 [1H, m, Ph(6)H
C6H4F], 7.29 [1H, m, Ph(4)H C6H4F]; δC (100 MHz, CDCl3)
28.0, 45.0, 52.3, 80.9, 113.3, 114.1, 121.9, 130.0, 147.2, 162.9,
171.0; m/z (APCIϩ) 240 (MHϩ, 5%), 184 (MHϩ Ϫ C4H8, 100%);
HRMS (CIϩ) C13H19FNO2 requires 240.1400, found 240.1402.
ϩ11.2 (c 0.99, CHCl3); νmax (film) 3380 (NH), 1732 (C᎐O); δ
᎐
H
(400 MHz, CDCl3) 1.41 [9H, s, OC(Me)3], 1.79 (2H, br s, NH2),
2.55 [2H, d, J 6.8, C(2)H2], 4.31 [1H, t, J 6.8, C(3)H], 7.06 [1H,
t, J 7.8, Ph(5)H C6H4I], 7.32 [1H, d, J 7.8, Ph(6)H C6H4I], 7.58
[1H, m, Ph(4)H C6H4I], 7.72 [1H, m, Ph(2)H C6H4I]; δC (100
MHz, CDCl3) 28.0, 45.1, 52.2, 81.0, 94.5, 125.6, 130.3, 135.3,
136.3, 147.1, 170.9; m/z (APCIϩ) 348 (MHϩ, 5%), 292 (MHϩ Ϫ
3118
J. Chem. Soc., Perkin Trans. 1, 2001, 3112–3121

View Article Online
C4H8, 100%); HRMS (CIϩ) C13H19INO2 requires 348.0461,
found 348.0473.
oil; [α]2D0 ϩ20.0 (c 1.0, CHCl3); νmax (film) 3329 (NH), 1728
(C᎐O); δH (400 MHz, CDCl3) 1.35 [3H, d, J 6.5, C(α)Me], 1.39
᎐
[9H, s, OC(Me)3], 2.54 [1H, dd, J2A,2B 14.8, J2A,3 6.4, C(2)HA],
2.62 [1H, dd, J2B,2A 14.8, J2B,3 7.6, C(2)HB], 3.64 [1H, q, J 6.5,
C(α)H], 3.79 (3H, s, OMe), 4.11 [1H, dd, J3,2A 7.6, J3,2B 6.4,
C(3)H], 6.82 [2H, m, Ph(3)H and Ph(5)H C6H4OMe], 7.16–7.21
[5H, m, Ph(4)H, Ph(5)H, Ph(6)H C6H4Cl and Ph(2)H, Ph(6)H
C6H4OMe], 7.24 [1H, s, Ph(2)H C6H4Cl]; δC (100 MHz, CDCl3)
22.5, 28.0, 43.5, 53.4, 55.2, 56.8, 80.7, 113.7, 125.2, 127.0, 127.2,
127.7, 129.6, 134.1, 137.8, 145.2, 158.5, 170.7; m/z (APCIϩ)
390 (MHϩ, 15%), 135 (C9H11Oϩ, 100%); HRMS (CIϩ)
C22H29ClNO3 requires 390.1836, found 390.1836.
Preparation of methyl (3R,ꢁS)-3-(3-iodophenyl)-3-(N-ꢁ-methyl-
4-methoxybenzylamino)propanoate 26
Following general procedure 5, 24 (1.5 g, 3.12 mmol) was added
to a saturated solution of HCl in MeOH (20 ml). Concentration
in vacuo, recrystallisation (EtOAc–hexane) and treatment with
saturated aqueous NaHCO3 gave 26 (1.03 g, 75%) as a colour-
less oil; mp (HCl salt) 168–169 ЊC (EtOAc–hexane); found: C,
48.0; H, 4.8; N, 3.0%; C19H23IClNO3 requires C, 48.0; H, 4.9; N,
2.9%; [α]1D9 Ϫ17.1 (c 1.0, CHCl3); νmax (film) 3326 (NH), 1734
(C᎐O), 1513 (OMe), 1246 (Ph–OMe); δ (400 MHz, CDCl3)
᎐
H
Preparation of tert-butyl (3S,ꢁR)-3-(3-bromophenyl)-3-(N-ꢁ-
1.35 [3H, d, J 6.5, C(α)Me], 2.61 [1H, dd, J2A,2B 15.4, J2A,3 6.0,
C(2)HA], 2.70 [1H, dd, J2B,2A 15.4, J2B,3 7.8, C(2)HB], 3.61 [1H,
q, J 6.5, C(α)H], 3.64, 3.80 (2 × 3H, s, CO2Me and OMe), 4.10
[1H, dd, J3,2A 6.0, J3,2B 7.8, C(3)H], 6.81 [2H, m, Ph(3)H and
Ph(5)H C6H4OMe], 7.03 [1H, m, Ph(5)H C6H4I], 7.14 [2H, m,
Ph(2)H and Ph(6)H C6H4OMe], 7.23 [1H, d, J 7.7, Ph(6)H
C6H4I], 7.58 [1H, m, Ph(4)H C6H4I], 7.60 [1H, m, Ph(2)H
C6H4I]; δC (100 MHz, CDCl3) 22.4, 42.2, 51.7, 54.3, 55.2, 56.4,
94.5, 115.0, 126.2, 127.6, 130.2, 136.1, 136.3, 137.6, 145.3,
158.5, 171.8; m/z (APCIϩ) 440 (MHϩ, 5%), 135 (C9H11Oϩ,
100%); HRMS (CIϩ) C19H23INO3 requires 440.0723, found
440.0716.
methyl-4-methoxybenzylamino)propanoate 30
Following general procedure 3, CAN (1.96 g, 3.6 mmol) and 16
(937 mg, 1.8 mmol) in 5 : 1 MeCN–H2O (24 ml) gave, after work
up and purification by column chromatography on silica gel
(hexane–Et2O 8 : 1–1% NEt3), 30 (621 mg, 80%) as a clear oil;
[α]2D0 ϩ21.5 (c 0.96, CHCl3); νmax (film) 3328 (NH), 1724 (C᎐O);
᎐
δH (400 MHz, CDCl3) 1.34 [3H, d, J 6.5, C(α)Me], 1.39 [9H, s,
OC(Me)3], 1.84 (1H, br s, NH), 2.53 [1H, dd, J2A,2B 14.8, J2A,3
6.1, C(2)HA], 2.61 [1H, dd, J2B,2A 14.8, J2B,3 7.7, C(2)HB], 3.63
[1H, q, J 6.5, C(α)H], 3.79 (3H, s, OMe), 4.09 [1H, dd, J3,2A 6.1,
J3,2B 7.7, C(3)H], 6.82 [2H, m, Ph(3)H and Ph(5)H C6H4OMe],
7.16 [2H, m, Ph(2)H and Ph(6)H C6H4OMe], 7.17–7.21 [2H, m,
Ph(5)H and Ph(6)H C6H4Br], 7.35 [1H, m, Ph(4)H C6H4Br],
7.42 [1H, m, Ph(2)H C6H4Br]; δC (100 MHz, CDCl3) 22.5, 28.0,
43.6, 54.3, 55.2, 56.8, 80.7, 113.7, 122.4, 125.6, 127.6, 129.9,
130.2, 130.3, 137.8, 145.5, 158.5, 170.6; HRMS (CIϩ)
C22H29BrNO3 requires 434.1331, found 434.1330.
Preparation of methyl (R)-3-(3-iodophenyl)-3-aminopropanoate
27
Following general procedure 4, CAN (1.90 g, 3.46 mmol) and
26 (380 mg, 0.85 mmol) in 5 : 1 MeCN–H2O (12 ml) gave, after
work up and purification by column chromatography on silica
gel (hexane–Et2O 1 : 2–1% NEt3), gave 27 (125 mg, 48%) as a
yellow oil; [α]2D0 ϩ12.8 (c 1.0, CHCl3); νmax (film) 3377 (NH),
Preparation of tert-butyl (3S,ꢁR)-3-(4-bromophenyl)-3-(N-ꢁ-
methyl-4-methoxybenzylamino)propanoate 31
2949 (CH), 1732 (C᎐O); δ (400 MHz, toluene-d ) 2.20 [1H, dd,
᎐
H
8
Following representative procedure 3, CAN (2.20 g, 4.0 mmol)
and 17 (1.0 g, 1.9 mmol) in MeCN–H2O 5 : 1 (9 ml) gave, after
work-up and column chromatography on silica gel (hexane–
Et2O 5 : 1), 31 (595 mg, 72%) as a colourless oil; [α]2D4 ϩ 32.8
J2A,2B 16.1, J2A,3 4.8, C(2)HA], 2.25 [1H, dd, J2B,2A 16.1, J2B,3 8.8,
C(2)HB], 3.31 (3H, s, CO2Me), 4.01 [1H, dd, J3,2B 8.8, J3,2A 4.8,
C(3)H], 6.65 [1H, m, Ph(5)H C6H4I], 6.99 [1H, m, Ph(6)H
C6H4I], 7.36 [1H, m, Ph(4)H C6H4I], 7.60 [1H, m, Ph(2)H
C6H4I]; δC (100 MHz, toluene-d8) 44.2, 51.4, 52.6, 95.2, 126.2,
130.7, 136.2, 136.9, 148.4, 172.1; m/z (APCIϩ) 306 (MHϩ, 50%);
HRMS (CIϩ) C10H13INO2 requires 305.9991, found 305.9984.
(c 1.0, CHCl3); νmax (film) 2974, 2930 (C–H), 1725 (C᎐O), 1512
᎐
(OMe), 1246 (Ph–OMe), 1152 (C–O); δH (400 MHz, CDCl3)
1.33 [3H, d, J 6.4, C(α)Me], 1.38 [9H, s, CO2C(Me)3], 2.50–2.61
[2H, m, C(2)H2], 3.59 [1H, q, J 6.8, C(α)H], 3.79 (3H, s, OMe),
4.09 [1H, app t, J 6.9, C(3)H], 6.81 [2H, m, Ph(3)H and Ph(5)H
C6H4OMe], 7.13–7.17 (4H, m, C6H4Br), 7.41 [2H, d, J 8.5,
Ph(2)H and Ph(6)H C6H4OMe]; δC (50 MHz, CDCl3) 22.4,
28.0, 43.6, 54.1, 55.3, 56.6, 80.7, 113.7, 120.8, 127.5, 128.8,
131.4, 137.8, 142.0, 158.4, 170.7; m/z (APCIϩ) 434.1 (MHϩ,
10%), 134.9 (C9H11Oϩ, 100%); HRMS (CIϩ) C22H29BrNO3
requires 434.1331, found 434.1334.
Preparation of tert-butyl (3R,ꢁS)-3-(4-iodophenyl)-3-(N-ꢁ-
methyl-4-methoxybenzylamino)propanoate 28
Following general procedure 3, CAN (11.6 g, 21.1 mmol) and
13 (5.75 g, 10.1 mmol) in 5 : 1 MeCN–H2O (90 ml) gave, after
work up and purification by column chromatography on silica
gel (hexane–Et2O 8 : 1–1% NEt3), 28 (4.26 g, 88%) as a yellow
oil; [α]1D9 Ϫ23.9 (c 1.0, CHCl3); νmax (film) 3326 (NH), 1723
(C᎐O) 1512 (OMe), 1246 (Ph–OMe); δ (400 MHz, CDCl3)
Preparation of methyl (3R,ꢁS)-3-(4-iodophenyl)-3-(N-ꢁ-methyl-
᎐
H
1.32 [3H, d, J 6.5, C(α)Me], 1.38 [9H, s, OC(Me)3], 2.51 [1H, dd,
J2A,2B 14.9, J2A,3 6.1, C(2)HA], 2.59 [1H, dd, J2B,2A 14.9, J2B,3 7.8,
C(2)HB], 3.59 [1H, q, J 6.5, C(α)H], 3.79 (3H, s, OMe), 4.08
[1H, dd, J3,2A 6.1, J3,2B 7.8, C(3)H], 6.81 [2H, m, Ph(3)H and
Ph(5)H C6H4OMe], 7.03 [2H, m, Ph(2)H and Ph(6)H C6H4I],
7.14 [2H, m, Ph(2)H and Ph(6)H C6H4OMe], 7.61 [2H, m,
Ph(3)H and Ph(5)H C6H4I]; δC (100 MHz, CDCl3) 22.3, 28.0,
43.6, 54.1, 55.3, 56.7, 80.7, 92.4, 113.7, 127.5, 129.2, 137.4,
137.9, 142.8, 158.5, 170.7; m/z (APCIϩ) 482 (MHϩ, 5%), 135
(C9H11Oϩ, 100%); HRMS (CIϩ) C22H29INO3 requires 482.1192,
found 482.1201.
4-methoxybenzylamino)propanoate 32
Following general procedure 5, 28 (3.0 g, 6.24 mmol) was added
to a saturated solution of HCl in MeOH (20 ml). Concentration
in vacuo, recrystallisation (EtOAc–hexane) and treatment with
saturated aqueous NaHCO3 gave 32 (2.12 g, 71%) as a colour-
less oil; mp (HCl salt) 181–182 ЊC (EtOAc–hexane); [α]2D2 Ϫ21.6
(c 1.2, CHCl3); νmax (film) 3326 (NH), 1737 (C᎐O), 1511 (OMe),
᎐
1246 (Ph–OMe); δH (400 MHz, CDCl3) 1.32 [3H, d, J 6.5,
C(α)Me], 2.61 [1H, dd, J2A,2B 15.4, J2A,3 6.3, C(2)HA], 2.71 [1H,
dd, J2B,2A 15.4, J2B,3 7.3, C(2)HB], 3.59 [1H, q, J 6.5, C(α)H],
3.63, 3.79 (2 × 3H, s, CO2Me and OMe), 4.13 [1H, dd, J3,2B 7.3,
J3,2A 6.3, C(3)H], 6.81 [2H, m, Ph(3)H and Ph(5)H C6H4OMe],
7.03 [2H, m, Ph(2)H and Ph(6)H C6H4I], 7.14 [2H, m, Ph(2)H
and Ph(6)H C6H4OMe], 7.62 [2H, m, Ph(3)H and Ph(5)H
C6H4I]; δC (100 MHz, CDCl3) 22.3, 42.1, 51.6, 54.1, 55.3, 56.3,
92.6, 113.6, 127.0, 129.0, 137.5, 137.7, 142.5, 158.5, 171.9; m/z
(APCIϩ) 440 (MHϩ, 5%), 135 (C9H11Oϩ, 100%); HRMS (CIϩ)
C19H23INO3 requires 440.0723, found 440.0721.
Preparation of tert-butyl (3S,ꢁR)-3-(3-chlorophenyl)-3-(N-ꢁ-
methyl-4-methoxybenzylamino)propanoate 29
Following general procedure 3, CAN (2.45 g, 4.56 mmol) and
14 (1.04 g, 2.17 mmol) in 5 : 1 MeCN–H2O (12 ml) gave, after
work up and purification by column chromatography on silica
gel (hexane–Et2O 8 : 1–1% NEt3), 29 (664 mg, 79%) as a clear
J. Chem. Soc., Perkin Trans. 1, 2001, 3112–3121
3119

View Article Online
Preparation of methyl (3S,ꢁR)-3-(3-chlorophenyl)-3-(N-ꢁ-
methyl-4-methoxybenzylamino)propanoate 33
δH (400 MHz, CDCl3) 2.64 [2H, m, C(2)H2], 3.68 (3H, s,
CO2Me), 4.39 [1H, br s, C(3)H], 7.12 [2H, m, Ph(2)H and Ph(6)
C6H4I], 7.66 [2H, m, Ph(3)H and Ph(5) C6H4I]; δC (100 MHz,
CDCl3) 43.6, 51.7, 52.1, 92.7, 128.3, 137.7, 137.8, 172.1; m/z
(APCIϩ) 306 (MHϩ, 25%); HRMS (CIϩ) C10H13INO2 requires
305.9991, found 305.9999.
Following general procedure 5, 29 (1.89 g, 4.87 mmol) was
added to a saturated solution of HCl in MeOH (20 ml). Con-
centration in vacuo, recrystallisation (EtOAc–hexane) and
treatment with saturated aqueous NaHCO3 gave 33 (1.48 g,
79%) as a colourless oil; mp (HCl salt) 169–170 ЊC (EtOAc–
hexane); [α]2D0 ϩ17.2 (c 1.0, CHCl3); found C, 59.4; H, 6.0; N,
3.8%; C19H23Cl2NO3 requires C, 59.4; H, 6.0; N, 3.6%; νmax
Preparation of methyl (S)-3-(3-chlorophenyl)-3-amino-
propanoate 37
(film) 3329 (NH), 1737 (C᎐O); δH (400 MHz, CDCl3) 1.34 [3H,
Following general procedure 4, CAN (2.58 g, 4.70 mmol) and
33 (408 mg, 1.18 mmol) in 5 : 1 MeCN–H2O (12 ml) gave, after
work up and purification by column chromatography on silica
gel (hexane–Et2O 1 : 2), 37 (135 mg, 54%) as a yellow oil; [α]2D0
᎐
d, J 6.5, C(α)Me], 1.86 (1H, br s, NH), 2.63 [1H, dd, J2A,2B 15.4,
J2A,3 6.1, C(2)HA], 2.73 [1H, dd, J2B,2A 15.4, J2B,3 7.8, C(2)HB],
3.63 [1H, q, J 6.5, C(α)H], 3.64, 3.79 (2 × 3H, s, CO2Me and
OMe), 4.16 [1H, dd, J2A,3 6.1, J2B,3 7.8, C(3)H], 6.83 [2H, m,
Ph(3)H, Ph(5)H C6H4OMe], 7.16 [2H, m, Ph(2)H, Ph(6)H
C6H4OMe], 7.16 [1H, m, Ph(6)H C6H4Cl], 7.19–7.23 [3H, m,
Ph(2)H, Ph(4)H, Ph(5)H C6H4Cl]; δC (100 MHz, CDCl3) 22.4,
42.1, 51.6, 54.2, 55.7, 56.5, 113.7, 125.1, 127.2, 127.4, 127.6,
129.8, 134.3, 137.6, 145.0, 158.5, 171.9; m/z (APCIϩ) 348
(MHϩ, 10%).
Ϫ11.5 (c 1.0, CHCl3); νmax (film) 3376 (NH), 1732 (C᎐O); δ
᎐
H
(400 MHz, CDCl3) 1.88 (2H, br s, NH2), 2.17 [2H, m, C(2)H2],
3.69 (3H, s, CO2Me), 4.40 [1H, m, C(3)H], 7.21 [1H, t, J 7.8,
Ph(5)H C6H4Cl], 7.29 [1H, d, J 7.8, Ph(6)H C6H4Cl], 7.39 [1H,
d, J 7.8, Ph(4)H C6H4Cl], 7.53 [1H, s, Ph(2)H C6H4Cl]; δC (100
MHz, CDCl3) 43.7, 51.7, 52.1, 124.9, 129.4, 130.2, 130.6, 134.9,
146.9, 172.1; m/z (APCIϩ) 214 (MHϩ, 35%); HRMS (CIϩ)
C10H13ClNO2 requires 214.0635; found 214.0628.
Preparation of methyl (3S,ꢁR)-3-(3-bromophenyl)-3-(N-ꢁ-
methyl-4-methoxybenzylamino)propanoate 34
Preparation of methyl (S)-3-(3-bromophenyl)-3-amino-
propanoate 38
Following general procedure 5, 30 (750 mg, 173 mmol) was
added to a saturated solution of HCl in MeOH (20 ml). Con-
centration in vacuo, recrystallisation (EtOAc–hexane) and
treatment with saturated aqueous NaHCO3 gave 34 (487 mg,
66%) as a colourless oil; [α]2D0 ϩ13.5 (c 1.0, CHCl3); νmax (film)
Following general procedure 4, CAN (1.90 g, 3.46 mmol) and
34 (338 mg, 0.86 mmol) in 5 : 1 MeCN–H2O (12 ml) gave, after
work up and purification by column chromatography on silica
gel (hexane–Et2O 1 : 2), 38 (114 mg, 51%) as a yellow oil; [α]2D0
3326 (NH), 1736 (C᎐O), 1512 (OMe), 1246 (Ph–OMe); δH (400
Ϫ10.7 (c 1.0, CHCl3); νmax (film) 3375 (NH), 1732 (C᎐O); δ
᎐
H
᎐
MHz, CDCl3) 1.38 [3H, d, J 6.5, C(α)Me], 1.84 (1H, br s, NH),
2.63 [1H, dd, J2A,2B 15.4, J2A,3 6.1, C(2)HA], 2.72 [1H, dd, J2B,2A
15.4, J2B,3 7.7, C(2)HB], 3.62 [1H, q, J 6.5, C(α)H], 3.64, 3.79
(2 × 3H, s, CO2Me and OMe), 4.14 [1H, dd, J3,2B 7.7, J3,2A 6.1,
C(3)H], 6.81 [2H, m, Ph(3)H and Ph(5)H C6H4OMe], 7.14–7.21
[4H, m, Ph(2)H and Ph(6)H C6H4OMe, Ph(5)H and Ph(6)H
C6H4Br], 7.37 [1H, m, Ph(2)H C6H4Br], 7.41 [1H, m, Ph(4)H
C6H4Br]; δC (100 MHz, CDCl3) 22.4, 42.1, 51.6, 54.3, 55.2, 56.5,
113.7, 122.6, 125.6, 127.6, 130.1, 130.1, 130.4, 137.6, 145.3,
158.5, 171.8; m/z (CIϩ) 392 (MHϩ, 15%), 135 (C9H11Oϩ, 100%);
HRMS (CIϩ) C19H23BrNO requires 392.0861, found 392.0858.
(400 MHz, CDCl3) 1.89 (2H, br s, NH2), 2.64 [2H, m, C(2)H2],
3.69 (3H, s, OMe), 4.40 [1H, m, C(3)H], 7.22–7.29 [3H, m,
Ph(4)H, Ph(5)H, and Ph(6)H C6H4Br], 7.37 [1H, s, Ph(2)H
C6H4Br]; δC (100 MHz, CDCl3) 43.7, 51.7, 52.2, 124.4, 125.4,
126.5, 127.6, 129.9, 146.6, 174.3; m/z (APCIϩ) 258 (MHϩ,
20%); HRMS (CIϩ) C10H13BrNO2 requires 258.0130, found
258.0131.
Preparation of methyl (S)-3-(4-bromophenyl)-3-amino-
propanoate 39
Following general procedure 4, CAN (2.79 g, 5.08 mmol) and
35 (500 mg, 1.27 mmol) in 5 : 1 MeCN–H2O (18 ml) gave, after
work up and purification by column chromatography on silica
gel (hexane–Et2O 1 : 1), 39 (172 mg, 52%) as a yellow oil; [α]2D0
Ϫ12.8 (c 0.9, CHCl3); νmax (film) 3373 (NH), 2946 (C–H), 1734
Preparation of methyl (3S,ꢁR)-3-(4-bromophenyl)-3-(N-ꢁ-
methyl-4-methoxybenzylamino)propanoate 35
Following general procedure 5, 31 (2.2 g, 5.08 mmol) was added
to a saturated solution of HCl in MeOH (75 ml). Concentration
in vacuo, recrystallisation (EtOAc–hexane) and treatment with
saturated aqueous NaHCO3 gave 35 (1.45 g, 73%) as a colour-
less oil; [α]2D0 ϩ14.9 (c 0.9, CHCl3); νmax (film) 2959 (C–H), 1736
(C᎐O), 1512 (OMe), 1245 (Ph–OMe); δ (400 MHz, CDCl3)
(C᎐O); δ (400 MHz, CDCl ) 1.79 (2H, br s, NH ), 2.62 [2H, m,
᎐
H
3
2
C(2)H2], 3.69 (3H, s, OMe), 4.40 [1H, app t, J 6.8, C(3)H], 7.23–
7.26 [2H, m, Ph(2)H and Ph(6)H C6H4Br], 7.44–7.47 [2H, m,
Ph(3)H and Ph(5)H C6H4Br]; δC (100 MHz, CDCl3) 43.7, 51.7,
52.0, 121.1, 128.0, 131.7, 143.5, 172.2; m/z (APCIϩ) 260 (MHϩ,
10%); HRMS (ESI) C10H13BrNO2 requires 258.0130, found
258.0134.
᎐
H
1.32 [3H, d, J 6.5, C(α)Me], 1.44 (1H, br s, NH), 2.61 [1H, dd,
J2A,2B 15.4, J2A,3 6.4, C(2)HA], 2.71 [1H, dd, J2B,2A 15.4, J2B,3 7.5,
C(2)HB], 3.62 [1H, q, J 6.5, C(α)H], 3.63, 3.79 (2 × 3H, s,
CO2Me and OMe), 4.14 [1H, app t, J 6.9, C(3)H], 6.80–6.84
[2H, m, Ph(3)H and Ph(5)H C6H4OMe], 7.12–7.17 [4H, m,
Ph(2)H and Ph(6)H C6H4OMe, Ph(2)H and Ph(6)H C6H4Br],
7.41–7.44 [2H, m, Ph(3)H and Ph(5)H C6H4Br]; δC (100 MHz,
CDCl3) 22.3, 42.0, 51.6, 54.2, 55.3, 56.2, 113.7, 121.0, 127.6,
128.8, 129.0, 131.6, 131.7, 137.6, 141.7, 150.0, 158.5, 171.8; m/z
(CIϩ) 392.1 (MHϩ, 10%), 135.1 (C9H11Oϩ, 100%); HRMS (ESI)
C19H23BrNO3 requires 392.0861, found 392.0861.
Preparation of tert-butyl (E )-3-(3,4-difluorophenyl)prop-2-
enoate 40
(tert-Butoxycarbonylmethylene)triphenylphosphorane (5.79 g,
15.4 mmol, 1.1 equiv.) was added to a stirred solution of 3,4-
difluorobenzaldehyde (1.98 g, 14.0 mmol, 1.0 equiv.) in DCM
(20 ml) under nitrogen at RT and stirred for sixteen hours
before being diluted with DCM (30 ml) and concentrated in
vacuo. Purification of the residue by column chromatography
on silica gel (hexane–Et2O 30 : 1) yielded a partially separable
mixture of stereoisomers. The E isomer was purified to homo-
geneity by recrystallisation (hexane–Et2O) to give 40 as white
needles (3.5 g, 88%); mp 61 ЊC (hexane–Et2O); found: C, 64.9;
H, 5.6%; C13H14F2O2 requires C, 65.0; H, 5.9%; νmax (KBr)
Preparation of methyl (R)-3-(4-iodophenyl)-3-aminopropanoate
36
Following general procedure 4, CAN (1.0 g, 1.84 mmol) and 32
(200 mg, 0.46 mmol) in 5 : 1 MeCN–H2O (6 ml) gave, after work
up and purification by column chromatography on silica gel
(hexane–Et2O 1 : 2), 36 (85 mg, 61%) as a yellow oil; [α]2D0 ϩ11.5
2979, 2927 (C–H), 1701 (C᎐O), 1640 (C᎐C), 1150 (C–O);
᎐
᎐
δH (400 MHz, CDCl3) 1.51 [9H, s, CO2C(Me)3], 6.26 (1H, d,
t
(c 1.06, CHCl3); νmax (film) 3375 (NH), 2950 (CH), 1732 (C᎐O);
J 16.0, C᎐CHCO Bu), 7.06–7.34 (3H, m, Ph), 7.46 (1H, d,
᎐
2
᎐
3120
J. Chem. Soc., Perkin Trans. 1, 2001, 3112–3121

View Article Online
t
J 16.0, HC᎐CHCO Bu); δ (50 MHz, CDCl ) 28.1, 80.8, 116.0,
(MHϩ, 80%), 185.0 (MHϩ Ϫ NH3, 100%); HRMS (ESI)
᎐
2
C
3
117.6, 121.3, 124.5, 131.8, 141.1, 148.7, 154.3, 165.7; m/z (CI,
NH3) 284.2 (MHϩ, 25%), 228.2 (MHϩ Ϫ C4H8, 100%).
C9H8NO2F2 requires 200.0523, found 200.0531.
Acknowledgements
Preparation of tert-butyl (3S,ꢁR)-3-(3,4-difluorophenyl)-3-(N-
benzyl-N-ꢁ-methyl-4-methoxybenzylamino)propanoate 41
The authors wish to thank the EPSRC and Rhône Poulenc
Rorer for providing a CASE award (A. D. S.), New College,
Oxford for a Junior Research Fellowship (A. D. S.), the
Fundación Sèneca for providing a studentship (S. D.-B.) and
the University of Bologna for funding (M. G.).
Following representative procedure 2, n-BuLi (8.64 ml, 2.5 M,
21.6 mmol), (R)-1 (5.37 g, 22.3 mmol) in THF (15 ml) and
(E)-40 (3.36 g, 14.0 mmol) gave, after purification by column
chromatography on silica gel (hexane–Et2O 15 : 1) and
recrystallisation (Et2O–hexane), 41 as white crystals (5.8 g,
86%); [α]2D6 ϩ13.9 (c 1.0, CHCl3); found: C, 72.2; H, 6.9; N,
2.9%; C29H33F2NO3 requires C, 72.3; H, 6.9; N, 2.9%; mp 84–
References
1 M. A. Patane, M. G. Bock and H. G. Selnick, PCT Int. Appl. WO
9857641, A119981223, 1998; M. A. Patane, M. G. Bock and H. G.
Selnick, Chem. Abstr., 1998, 130, 81520; S. P. Adams, K. C. Lin, W.
C. Lee, A. C. Castro, C. N. Zimmerman, C. E. Hammond, Y. S.
Liao, J. H. Cuervo and J. Singh, PCT Int. Appl. WO 9622966 A1
960801, 1996.
2 S. J. Faulconbridge, K. E. Holt, L. G. Sevillano, C. J. Lock, P. D.
Tiffin, N. Tremayne and S. Winter, Tetrahedron Lett., 2000, 41, 2679.
3 J. D. Bourzat and A. Commercon, Tetrahedron Lett., 1993, 34, 6049.
4 M. K. Mokhallalati, M.-J. Wu and L. N. Pridgen, Tetrahedron Lett.,
1993, 34, 47.
5 For an approach toward the asymmetric synthesis of β-haloaryl-
β-amino esters on solid phase see Y. Lee and R. B. Silverman, Org.
Lett., 2000, 303.
6 S. G. Davies and O. Ichihara, Tetrahedron: Asymmetry, 1991, 183;
M. E. Bunnage, A. J. Burke, S. G. Davies and C. J. Goodwin,
Tetrahedron: Asymmetry, 1995, 165; S. G. Davies and D. J. Dixon,
J. Chem. Soc., Perkin Trans. 1, 1998, 2629; S. G. Davies and
O. Ichihara, Tetrahedron: Asymmetry, 1996, 1919; S. G. Davies and
O. Ichihara, Tetrahedron Lett., 1999, 40, 9313.
86 ЊC; νmax (film) 2973, 2933 (C–H), 1735 (C᎐O), 1512 (OMe
᎐
bend), 1243 (Ph–O), 1151 (C–O); δH (400 MHz, CDCl3) 1.25
[9H, s, OC(Me)3], 1.29 [3H, d, J 6.8, C(α)Me], 2.46 [2H, m,
C(2)H2], 3.65 (2H, app s, NCH2Ph), 3.82 (3H, s, OMe), 3.92
[1H, q, J 6.8, C(α)H], 4.39 [1H, dd, J3,2A 10.4, J3,2B 4.3, C(3)H],
6.88 (2H, m, Ph), 7.07–7.31 (10H, m, Ph); δC (125 MHz, CDCl3)
17.4, 27.8, 37.6, 50.7, 55.2, 56.8, 58.3, 80.5, 113.6, 116.8, 117.1,
123.9, 126.7, 127.9, 128.2, 128.7, 135.6, 139.6, 141.2, 148.7,
150.7, 158.6, 170.8; m/z (NH3) 482.1 (MHϩ, 10%), 348.1 (MHϩ
Ϫ C9H11O, 100%).
Preparation of (S)-3-(3,4-difluorophenyl)-3-aminopropionic acid
42
CAN (15.0 g, 27.42 mmol) was added portionwise to a stirred
solution of 41 (2.20 g, 4.57 mmol) in MeCN–H2O (150 ml, 5 : 1)
at RT. After 16 h sat. aq. NaHCO3 (100 ml) was added. The
reaction mixture was partitioned between Et2O (3 × 50 ml) and
H2O (100 ml) and the solvent removed in vacuo. 1 M HCl
(15 ml) was added to the crude reaction mixture and the result-
ant solution was stirred at RT for 16 hours before concentration
in vacuo. Purification via ion exchange chromatography gave 42
(575 mg, 63%) as a white solid; mp 226–230 ЊC; [α]2D3 Ϫ3.2 (c 1.0,
7 S. D. Bull, S. G. Davies, P. M. Kelly, M. Gianotti and A. D. Smith,
J. Chem. Soc., Perkin Trans. 1, 2001, 3106; (S)-α-methyl-4-
methoxybenzylamine is commercially available from Lancaster
Synthesis Ltd., Morecambe, UK.
8 S. D. Bull, S. Delgado-Ballester, S. G. Davies, G. Fenton, P. M. Kelly
and A. D. Smith, Synlett, 2000, 9, 1257.
9 All reaction diastereoselectivities were calculated by 1H 400 MHz
NMR spectroscopic analysis of the crude reaction mixture.
10 J. F. Costello, S. G. Davies and O. Ichihara, Tetrahedron:
Asymmetry, 1994, 5, 1999.
H2O); νmax (KBr disc) 2955 (C–H), 1617 (C᎐O); δ (500 MHz,
᎐
H
D2O), 2.78 [1H, dd, J2A,2B 16.2, J2A,3 6.7, C(2)HA], 2.87 [1H, dd,
J2B,2A 16.2, J2B,3 7.9, C(2)HB], 4.63 [1H, app t, J 7.3, C(3)H],
7.22–7.39 (3H, m, Ph); δC (125 MHz, D2O) 40.6, 52.2, 116.7,
118.5, 124.2, 133.4, 150.4, 150.7, 177.2; m/z (APCIϩ) 202.1
11 G. Cristalli, E. Camaioni, S. Vittori, R. Volpini, P. A. Borea,
A. Conti, S. Dionisotti, E. Ongini and A. Monopoli, J. Med. Chem.,
1995, 38, 1462.
J. Chem. Soc., Perkin Trans. 1, 2001, 3112–3121
3121