Orthogonal N,N-deprotection strategies of β-amino esters

Article abstract of DOI:10.1039/b106389h

β-Amino esters derived from the stereoselective conjugate addition of homochiral lithium N-benzyl-N-α-methyl-4-methoxybenzylamide to α,β-unsaturated esters may be orthogonally mono-N-deprotected under either oxidative or acid-promoted reaction conditions. Further oxidative deprotection affordsβ-amino acids or β-lactams.

Full text of DOI:10.1039/b106389h

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Orthogonal N,N-deprotection strategies of ꢀ-amino esters
Steven D. Bull, Stephen G. Davies,* Peter M. Kelly, Massimo Gianotti and Andrew D. Smith
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford,
UK OX1 3QY. E-mail: steve.davies@chemistry.ox.ac.uk
1
Received (in Cambridge, UK) 18th July 2001, Accepted 9th October 2001
First published as an Advance Article on the web 12th November 2001
β-Amino esters derived from the stereoselective conjugate addition of homochiral lithium N-benzyl-N-α-methyl-4-
methoxybenzylamide to α,β-unsaturated esters may be orthogonally mono-N-deprotected under either oxidative
or acid-promoted reaction conditions. Further oxidative deprotection affords β-amino acids or β-lactams.
Introduction
β-Amino acids are an important class of natural product
which are widespread among nature.1 We have previously
reported that a wide range of homochiral (enantiomerically
pure) 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 subsequent N-deprotection.2 For example, addition of
lithium (S)-N-benzyl-N-α-methylbenzylamide 1 to tert-butyl
cinnamate
2 affords tert-butyl (3R,αS)-3-(N-benzyl-N-α-
methylbenzylamino)-3-phenylpropanoate 3 in >95% de, which
on hydrogenolytic deprotection affords homochiral tert-butyl
(R)-3-amino-3-phenylpropanoate 4 (Scheme 1).3
Scheme 2 Reagents and conditions: (i) (S)-5, Ϫ78 ЊC, THF then
NH4Cl(aq); (ii) RhCl(PPh3)3, MeCN–H2O (9 : 1), ∆; (iii) MeOH, HCl,
RT; (iv) MeMgBr (1.1 equiv.), Et2O, 0 ЊC; (v) Na–NH3; (vi) Pd(OH)2–C,
5 atm H2, MeOH then Hϩ and ion exchange.
there are certain limitations regarding the functionality
that may be incorporated into the target molecule due to
the hydrogenolytic or Birch reduction conditions which are
required for the direct removal of either the N-benzyl or the
N-α-methylbenzyl protecting groups. We have previously
reported that ceric ammonium nitrate (CAN) may be employed
for the oxidative mono-debenzylation of N-benzyl tertiary
amines,6 and now report herein that this methodology may be
employed as part of an orthogonal deprotection strategy for
conjugate addition products derived from the stereoselective
conjugate addition of a third generation lithium amide to α,β-
unsaturated esters. Part of this work has been communicated
previously.7
Scheme 1 Reagents and conditions: (i) (S)-1 (1.6 equiv.), THF, Ϫ78 ЊC;
(ii) Pd(OH)2–C, MeOH, 5 atm H2.
We have also described the extension of this methodology
to the asymmetric synthesis of β-lactams, a distinct class of
natural product displaying antimicrobial activity.4 Thus, con-
jugate addition of lithium (S)-N-allyl-N-α-methylbenzylamide
5 to tert-butyl crotonate proceeds to give tert-butyl (3S,αS)-3-
(N-allyl-N-α-methylbenzylamino)butanoate
6 in >95% de.
Subsequent mono-deprotection of the tertiary amino function-
ality of β-amino ester 6 via treatment with Wilkinson’s catalyst
or via palladium-mediated deallylation affords tert-butyl
(3S,αS)-3-(N-α-methylbenzylamino)butanoate 7. Subsequent
cyclisation to the β-lactam 8 and reductive deprotection of the
N-α-methylbenzyl protecting group under Birch conditions
affords β-lactam 9. Alternatively, hydrogenation and ester
hydrolysis of β-amino ester 7 yields the parent β-amino acid 10
(Scheme 2).5
Results and discussion
Orthogonal deprotection strategies
The susceptibility of N-4-methoxybenzylamine protecting
groups to undergo either oxidative8 or acid promoted9 benzylic
cleavage under mild conditions prompted us to consider the use
of commercially available (S)-N-α-methyl-4-methoxybenzyl-
While these approaches offer versatile routes to β-amino acid
derivatives and homochiral templates for further manipulation,
3106
J. Chem. Soc., Perkin Trans. 1, 2001, 3106–3111
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b106389h

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amine10 11 as the stereodirecting fragment of a homochiral
ammonia equivalent. Thus, (S)-N-benzyl-N-α-methyl-4-
methoxybenzylamine 12 was prepared via reductive amination
of (S)-11 with benzaldehyde. The capacity of homochiral
lithium amide (S)-13 to undergo stereoselective conjugate
additions to α,β-unsaturated acceptors was initially investigated
for the asymmetric synthesis of the known β-amino ester tert-
butyl (R)-3-amino-3-phenylpropanoate 16. Thus, deproton-
ation of (S)-12 with n-BuLi in THF at Ϫ78 ЊC afforded lithium
amide (S)-13 which added to tert-butyl cinnamate to give
tert-butyl (3R,αS)-3-(N-benzyl-N-α-methyl-4-methoxybenzyl-
1
amino)-3-phenylpropanoate 14 in 92% crude de by H NMR
spectroscopy. Purification via chromatography on silica gel,
followed by fractional recrystallisation (Et2O–hexane 3 : 1) gave
homochiral (3R,αS)-14 in 77% yield as a single diastereoisomer
(>99% de) by 1H NMR spectroscopy (Scheme 3).
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; (iii) CAN
(6.0 equiv.), MeCN–H2O (5 : 1), RT; (iv) 1 M HCl(aq), Et2O (1 : 1), RT
then ion exchange chromatography.
Scheme 5 Reagents and conditions: (i) TFA–DCM (1 : 1), RT.
PPh3–(PyS)2 in refluxing acetonitrile15 gave (4R,αS)-N-(α-
methyl-4-methoxybenzyl)-4-phenylazetidin-2-one 20 in 83%
yield. Oxidative removal of the N-α-methyl-4-methoxybenzyl
protecting group from β-lactam 20 with aqueous CAN (3.0
equiv.) furnished (R)-4-phenylazetidin-2-one 21 in 68% yield
(Scheme 6).16 The stereochemical integrity of 21 was assumed to
Scheme 3 Reagents and conditions: (i) benzaldehyde (1.05 equiv.),
EtOH, ∆ then NaBH4, 0 ЊC to RT; (ii) n-BuLi, THF, Ϫ78 ЊC; (iii) tert-
butyl cinnamate, THF, Ϫ78 ЊC; (iv) chromatography then
recrystallisation [ether–hexane (3 : 1)].
Treatment of β-amino ester 14 with aqueous CAN (2.1
equiv.) resulted in mono-deprotection of the N-benzyl protect-
inggrouptoaffordtert-butyl(3R,αS)-3-(N-α-methyl-4-methoxy-
benzylamino)-3-phenylpropanoate 15 in 89% yield. Further
treatment of (3R,αS)-15 with aqueous CAN (4.0 equiv.)
resulted in removal of the N-α-methyl-4-methoxybenzyl pro-
tecting group to afford tert-butyl (R)-3-amino-3-phenyl-
propanoate 16 in 64% yield {[α]2D3 ϩ19.7 (c 0.96, CHCl3); lit.11
[α]2D3 ent-16 Ϫ21.0 (c 1.0, CHCl3)}. The susceptibility of both
the N-benzyl and N-α-methyl-4-methoxybenzyl protecting
groups to oxidative removal upon treatment with aqueous
CAN suggested that the oxidative deprotection of these
N-protecting groups could be achieved in a single step.12 There-
fore, treatment of (3R,αS)-14 with CAN (6.0 equiv.) gave a
crude reaction product13 which, after acidic hydrolysis and
purification by ion exchange chromatography, furnished (R)-3-
amino-3-phenylpropionic acid 17 {[α]2D3 ϩ6.8 (c 1.0, H2O); lit.14
[α]2D3 ϩ6.5 (c 1.0, H2O)} in 62% yield (Scheme 4).
Complementary methodology for the mono-deprotection
of N-benzyl-N-α-methyl-4-methoxybenzyl protected β-amino
ester 14 was also developed which relied upon the acid lability
of the N-α-methyl-4-methoxybenzyl group. Thus, tertiary
β-amino ester (3R,αS)-14 in dichloromethane (DCM) was
treated with TFA at RT, which resulted in deprotection of both
the tert-butyl ester and N-α-methyl-4-methoxybenzyl protect-
ing groups, to afford (R)-3-N-benzylamino-3-phenylpropionic
acid 18 in 78% yield (Scheme 5).
Scheme 6 Reagents and conditions: (i) TFA–DCM (1 : 2), RT; (ii)
(PyS)2 (1.2 equiv.), PPh3 (1.2 equiv.), MeCN, ∆; (iii) CAN (3.0 equiv.),
MeCN–H2O (5 : 1), RT.
remain intact during this debenzylation on the basis of its
specific rotation {[α]2D3 ϩ136.9 (c 0.69, MeOH); lit.17 [α]2D3 ϩ132.0
(c 1.0, MeOH)}.
Alternatively, treatment of (R)-18 with PPh3–(PyS)2 in reflux-
ing acetonitrile gave (R)-N-benzyl-4-phenylazetidin-2-one 2218
in 82% yield. While N-benzyl β-lactams have been shown to be
prone to debenzylation under Birch reduction conditions,19
attempted CAN-promoted debenzylation to give the parent
azetidin-2-one 23 returned only starting material. While we had
anticipated that the β-lactam functionality might facilitate
N-benzyl deprotection with CAN, this observation is consistent
with previous reports by ourselves6 and others20 that cyclic
tertiary N-benzylamines and N-benzylamides are inert to this
oxidative protocol (Scheme 7).
With selective complementary routes toward the N-α-methyl-
4-methoxybenzyl protected β-amino ester 15 and N-benzyl
protected β-amino ester 18 in hand, we investigated their con-
version to their corresponding N-protected β-lactams. Thus,
treatment of secondary amine (3R,αS)-15 with TFA afforded
(3R,αS)-3-(N-α-methyl-4-methoxybenzylamino)-3-phenylprop-
ionic acid 19 in 96% yield. Subsequent ring closure with
Asymmetric synthesis of (R)-4-vinylazetidin-2-one
Unsaturated β-amino acid derivatives21 have been shown
to exhibit a range of biological activity and are sensitive to
J. Chem. Soc., Perkin Trans. 1, 2001, 3106–3111
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Scheme 7 Reagents and conditions: (i) (PyS)2 (1.2 equiv.), PPh3 (1.2
equiv.), MeCN, ∆; (ii) CAN (3 equiv.), MeCN–H2O (5 : 1), RT.
hydrogenation. Since the use of (S)-N-benzyl-N-α-methyl-
benzylamide 1 requires removal of the N-α-methylbenzyl
protecting group from its conjugate addition products via
hydrogenation, this amide cannot be readily used for the
synthesis of such unsaturated β-amino acid derivatives.22 The
N-deprotection strategies developed herein for conjugate add-
ition products of lithium amide (S)-13 provides a route to this
class of compound. This methodology was therefore applied
toward the asymmetric synthesis of vinyl β-lactam 28, an
analogue of which has previously been used in the asymmetric
synthesis of thienamycin precursors.23 Thus, conjugate addition
of lithium amide (S)-13 to tert-butyl penta-2,4-dienoate gave
tert-butyl (3R,αS)-3-(N-benzyl-N-α-methyl-4-methoxybenzyl-
Scheme 8 Reagents and conditions: (i) (S)-13 (1.6 equiv.), THF, Ϫ78
ЊC; (ii) CAN (2.1 equiv.), MeCN–H2O (5 : 1), RT; (iii) TFA–DCM
(1 : 2), RT; (iv) (PyS)2 (1.2 equiv.), PPh3 (1.2 equiv.), MeCN, ∆; (v)
CAN (3.0 equiv.), MeCN–H2O (5 : 1), RT.
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) or where stated on a Bruker AMX 500 (1H: 500 MHz
and 13C: 125.3 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. In all cases, the reaction diastereoselectivity was
1
amino)pent-4-enoate 24 in 98% crude de by H NMR, and
in 81% yield and in 98% de after purification. Subsequent
N-debenzylation with CAN gave tert-butyl (3R,αS)-3-(N-α-
methyl-4-methoxybenzylamino)pent-4-enoate 25 in 73% yield
and 98% de. Transformation of secondary amine 25 to its
N-protected β-lactam derivative 27 via ester hydrolysis to afford
the N-protected β-amino acid 26 (98% de) and cyclisation with
PPh3–(PyS)2 gave (4R,αS)-27 (98% de) in good yield. Treatment
of 27 with CAN successfully cleaved the N-α-methyl-4-
methoxybenzyl protecting group to afford the target β-lactam
28 in 69% yield with the vinylic functionality intact (Scheme 8).
1
assessed by peak integration of the H NMR spectrum of the
crude reaction mixture. Infrared spectra were recorded on a
Perkin–Elmer 1750 IR Fourier Transform spectrophotometer
using either thin films on NaCl plates (film) or KBr discs (KBr)
as stated. Only the characteristic peaks are quoted. Low
resolution mass spectra (m/z) were recorded on a VG MassLab
20-250 or Micromass Platform 1 spectrometer and high reso-
lution mass spectra (HRMS) on a Micromass Autospec 500
OAT spectrometer or on a Waters 2790 Micromass LCT Exact
Mass Electrospray Ionisation Mass Spectrometer. Techniques
used were chemical ionisation (CI, NH3), atmospheric pressure
chemical ionisation (APCI) or electrospray ionisation (ESI)
using partial purification by HPLC with methanol–
acetonitrile–water (40 : 40 : 20) as the eluent. Specific optical
rotations were recorded on a Perkin-Elmer 241 polarimeter
with a water-jacketed 10 cm cell and are given in units of 10Ϫ1
deg cm2 gϪ1. Concentrations are quoted in g/100 ml. Melting
points were recorded on a Leica VMTG Galen III apparatus
and are uncorrected. Elemental analysis of crystalline 14 was
performed by the microanalysis service of the Inorganic Chem-
istry Laboratory, Oxford; all other products were not amenable
to analysis and so were characterised by high resolution mass
spectrometry.
Conclusions
Tertiary β-amino esters derived from conjugate addition of
homochiral lithium N-benzyl-N-α-methyl-4-methoxybenzyl-
amide 13 to α,β-unsaturated acceptors may be selectively
mono-deprotected via treatment with CAN to afford N-4-
methoxy-α-methylbenzyl β-amino esters. Subsequent cyclis-
ation and oxidative deprotection of these adducts enables
β-lactams to be obtained in good yield. Further applications of
these deprotection strategies will be reported in due course.
Experimental
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. n-Butyllithium was
used as a solution in hexanes at the molarity stated. Ceric
ammonium nitrate (ACS grade) was used as supplied. All other
solvents and reagents were used as supplied (Analytical or
HPLC grade), 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
Representative procedure 1
n-Butyllithium (1.55 equiv.) was added dropwise to a stirred
solution of N-benzyl-N-α-methyl-4-methoxybenzylamine 12
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J. Chem. Soc., Perkin Trans. 1, 2001, 3106–3111

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(1.6 equiv.) in anhydrous THF at Ϫ78 ЊC under nitrogen. After
thirty minutes, a solution of the α,β-unsaturated ester (1.0
equiv.) in anhydrous THF was added dropwise via cannula and
the reaction was stirred at Ϫ78 ЊC for two hours before the
addition of saturated aqueous ammonium chloride, and
warmed to RT. The resultant solution was partitioned between
brine and 1 : 1 DCM–Et2O and the combined organic extracts
dried (MgSO4), filtered and concentrated in vacuo before
purification by column chromatography.
THF (20 ml) gave, after successive purification by chrom-
atography (hexane–Et2O 10 : 1) and recrystallisation (Et2O–
hexane 3 : 1), 14 (2.37 g, 77%) as white needles; mp 83–84 ЊC
(Et2O–hexane); Found: C, 77.75; H, 7.65; N, 3.1%; C29H35NO3
requires C, 78.2; H, 7.9; N, 3.1%; [α]2D0 Ϫ14.2 (c 1.0, CHCl3);
νmax/cmϪ1 1727 (C᎐O), 1511 (OMe), 1248 (Ph–OMe); δ (400
᎐
H
MHz, CDCl3) 1.28 [9H, s, OC(Me)3], 1.31 [3H, d, J 6.9,
C(α)Me], 2.53 [1H, dd, J2A,2B 14.5, J2A,3 10.0, C(2)HA], 2.60 [1H,
dd, J2B,2A 14.5, J2B,3 5.1, C(2)HB], 3.68 (2H, ABq, NCH2Ph),
3.83 (3H, s, OMe), 4.00 [1H, q, J 6.9, C(α)H], 4.45 [1H, dd, J3,2A
10.0, J3,2B 5.1, C(3)H], 6.91 [2H, m, Ph(3)H, Ph(5)H C6H4OMe],
7.20–7.40 (10H, m, Ph), 7.47 [2H, m, Ph(2)H, Ph(6)H
C6H4OMe]; δC (100 MHz, CDCl3) 16.3, 27.8, 38.8, 50.8, 55.2,
56.3, 59.7, 80.1, 113.4, 126.4, 127.1, 127.9, 128.1, 128.2, 128.9,
136.1, 141.9, 142.0, 158.4, 171.2; m/z (CIϩ) 446.5 (MHϩ, 20%),
135 (C9H11Oϩ, 80%); HRMS (CIϩ) C19H23INO3 requires
446.2695, found 446.2689.
Representative procedure 2
CAN was added portionwise to a stirred solution of the
substrate (1.0 equiv.) in MeCN–H2O (5 : 1) and stirred at RT.
After sixteen hours, the reaction was quenched by the addition
of saturated aqueous sodium bicarbonate solution and stirred
vigorously for ten minutes before extraction with Et2O.
The combined organic extracts were dried (MgSO4), filtered
and concentrated in vacuo before purification by column
chromatography.
Preparation of tert-butyl (3R,ꢁS)-3-(N-ꢁ-methyl-4-methoxy-
benzylamino)-3-phenylpropanoate 15
Following representative procedure 2, CAN (3.88 g, 7.08 mmol)
was added to 14 (1.50 g, 3.37 mmol) in MeCN–H2O (5 : 1)
(24 ml) at RT. After work-up, purification by column chrom-
atography on silica gel [hexane–Et2O (8 : 1)–1% NEt3], gave 15
(1.06 g, 89%) as a colourless oil; [α]2D0 Ϫ21.7 (c 0.97, CHCl3);
Representative procedure 3
TFA was added dropwise to a stirred solution of the substrate
in DCM and stirred at RT overnight. After concentration in
vacuo, the residue was partitioned between saturated aqueous
sodium bicarbonate solution (10 ml) and EtOAc (50 ml). The
separated aqueous phase was extracted with EtOAc (5 × 50 ml),
and the combined organic extracts dried (MgSO4), filtered
and concentrated in vacuo before purification by column
chromatography.
νmax/cmϪ1 (film) 3338 (br, NH), 2975, 2931 (C–H), 1725 (C᎐O),
᎐
1512 (OMe), 1246 (Ph–OMe), 1151 (C–O); δH(400 MHz,
CDCl3) 1.34 [3H, d, J 6.4, C(α)Me], 1.38 [9H, s, OC(Me)3], 2.53
[1H, dd, J2A,2B 15.3, J2A,3 6.2, C(2)HA], 2.61 [1H, dd, J2A,2B 15.3,
J2B,3 7.9, C(2)HB], 3.62 [1H, q, J 6.4, C(α)H], 3.79 (3H, s, OMe),
4.15 [1H, dd, J2A,3 6.2, J2B,3 7.9, C(3)H], 6.84 [2H, m, Ph(3),
Ph(5) C6H4OMe], 7.19 [2H, d, J 8.2, Ph(2), Ph(6) C6H4OMe],
7.23–7.38 (5H, m, Ph); δC 22.2, 28.0, 43.9, 53.8, 55.2, 57.0, 80.4,
113.7, 127.1, 127.2, 127.6, 128.4, 138.2, 142.9, 158.4, 171.0; m/z
APCIϩ 356.2 (MHϩ, 10%), 134.9 (C9H11Oϩ, 100%); HRMS
(CIϩ) C22H29NO5 requires 356.2232; found 356.2226.
Representative procedure 4
(PyS)2 (1.2 equiv.) was added to a stirred solution of the
substrate (1.0 equiv.) and PPh3 (1.2 equiv.) in MeCN and heated
at reflux overnight. After cooling, the reaction was con-
centrated in vacuo and the residue purified by column
chromatography.
Preparation of tert-butyl (R)-3-phenyl-3-aminopropanoate11 16
Preparation of (S)-N-benzyl-N-ꢁ-methyl-4-methoxybenzyl-
amine 12
Following representative procedure 2, CAN (5.55 g, 10.1 mmol)
was added to 15 (899 mg, 2.53 mmol) in 5 : 1 MeCN–H2O (24
ml). After work-up, purification by column chromatography on
silica gel (hexane–Et2O 1 : 2) gave 16 (358 mg, 64%) as a yellow
oil; [α]2D3 ϩ19.7 (c 0.96, CHCl3); lit.11 [α]2D3 for ent-16 Ϫ21.0 (c 1.0,
CHCl3); δH(400 MHz, CDCl3) 1.42 [9H, s, OC(Me)3], 1.79 (2H,
br s, NH2), 2.59 [2H, m, C(2)H2], 4.38 [1H, app t, J 6.5, C(3)H],
7.24–7.37 (5H, m, Ph).
Benzaldehyde (7.0 ml, 69.3 mmol) was added dropwise to a
stirred solution of (S)-N-α-methyl-4-methoxybenzylamine 11
(10.0 g, 66 mmol) in EtOH (150 ml) and heated at reflux. After
two hours, the reaction was cooled to 0 ЊC before the portion-
wise addition of NaBH4 (4.0 g, 105.6 mmol), and left to stir
overnight. After concentration in vacuo, the residue was
partitioned between H2O (50 ml) and DCM (3 × 100 ml), dried
and concentrated in vacuo to give 12 (15.8 g, 99%) as a colour-
less oil which was subsequently used without further purific-
ation; νmax/cmϪ1 (film) 3320 (NH), 2959, 2832 (C–H), 1510,
1451 (OMe), 1243 (Ph–OMe); [α]1D9 Ϫ64.0 (c 1.0, CHCl3); δH(400
MHz, CDCl3) 1.36 [3H, d, J 6.6, C(α)Me], 3.70 (2H, ABq,
NCH2Ph), 3.78 [1H, q, J 6.6, C(α)H], 3.82 (3H, s, OMe), 6.90
[2H, m, Ph(3)H and Ph(5)H C6H4OMe], 7.24–7.37 [7H, m,
Ph(2)H and Ph(6)H C6H4OMe; Ph]; δC (50 MHz, CDCl3) 24.5,
51.6, 55.3, 56.9, 113.9, 126.9, 127.3, 127.8, 128.2, 128.4, 137.6,
140.7, 158.7; m/z APCIϩ 242.1 (MHϩ, 10%), 264.2 (MNaϩ, 5%),
134.9 (C9H11Oϩ, 100%); HRMS (CIϩ) C16H20NO requires
242.1545; found 242.1548. The ee of this material was shown
Preparation of (R)-3-phenyl-3-aminopropionic acid14 17
CAN (5.91 g, 10.8 mmol) was added to a stirred solution of 14
(800 mg, 1.79 mmol) in MeCN–H2O (5 : 1) (36 ml) at RT. After
sixteen hours, saturated aqueous sodium bicarbonate solution
(10 ml) was added and the resultant solution extracted with
Et2O (3 × 100 ml), dried and concentrated in vacuo to yield a
yellow oil which was dissolved in Et2O (5 ml) before the
dropwise addition of 1 M HCl(aq) (5 ml), and stirred at RT.
After a further sixteen hours, the aqueous and organic layers
were separated. The aqueous layer was concentrated in vacuo to
yield a pale yellow solid which was purified by ion exchange
chromatography using Dowex 50X8–200 to give 17 as a white
solid (189 mg, 64%); [α]2D3 ϩ6.8 (c 1.0, H2O); lit.14 [α]2D3 ϩ6.5
(c 1.0, H2O); δH(400 MHz, D2O) 2.59 [2H, m, C(2)H2], 4.38
[1H, app t, J 6.5, C(3)H], 7.24–7.37 (5H, m, Ph).
1
to be >99% by H NMR chiral shift experiments with (S)-O-
acetylmandelic acid and in comparison with a racemic
sample.24
Preparation of tert-butyl (3R,ꢁS)-3-(N-benzyl-N-ꢁ-methyl-4-
Preparation of (R)-3-N-benzylamino-3-phenylpropionic acid 18
methoxybenzylamino)-3-phenylpropanoate 14
Following representative procedure 3, TFA (4 ml) and 14 (1.0 g,
2.24 mmol) in DCM (4 ml) gave, after work-up and purification
by column chromatography on silica gel (CHCl3–MeOH 10 : 1),
18 (446 mg, 78%) as an off-white solid; [α]2D4 ϩ56.3 (c 1.0,
Following representative procedure 1, n-butyllithium (1.6 M,
6.7 ml, 10.8 mmol), (S)-12 (2.68 g, 11.1 mmol) in THF (20 ml)
at Ϫ78 ЊC and tert-butyl (E)-cinnamate (1.42 g, 6.94 mmol) in
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MeOH); νmax/cmϪ1 (film) 3030 (C–H), 1560 (C᎐O); δ (400
Preparation of tert-butyl (3R,ꢁS)-3-(N-benzyl-N-ꢁ-methyl-4-
᎐
H
MHz, CDCl3) 2.62 [1H, dd, J2A,2B 17.1, J2A,3 1.9, C(2)HA], 3.00
[1H, dd, J2B,2A17.1, J2B,3 11.7, C(2)HB], 3.57 (1H, d, J 13.6,
NCHA), 4.16 [1H, dd, J3,2B 11.7, J3,2A 1.9, C(3)H], 4.31 (1H, d,
J 13.6, NCHA), 7.29–7.47 (10H, m, Ph); δC (100 MHz, CDCl3)
40.4, 47.4, 57.9, 128.0, 128.7, 128.8, 128.9, 129.3, 129.4, 130.6,
132.5, 135.8, 176.2; m/z APCIϩ 256.2 (MHϩ, 100%); HRMS
(CIϩ) C16H18NO2 requires 256.1338; found 256.1343.
methoxybenzylamino)pent-4-enoate 24
Following representative procedure 1, n-butyllithium (2.5 M,
6 ml, 15.1 mmol), (S)-12 (3.75 g, 15.6 mmol) in THF (20 ml)
at Ϫ78 ЊC and tert-butyl (E)-penta-2,4-dienoate (1.5 g, 9.73
mmol) in THF (30 ml) gave, after purification by chrom-
atography (hexane–Et2O 16 : 1), 24 (3.1 g, 81%) as a colourless
oil; [α]2D4 ϩ8.7 (c 1.0, CHCl3); νmax/cmϪ1 (film) 2975 (C–H), 1726
(C᎐O), 1609 (C᎐C), 1509 (OMe), 1247 (Ph–OMe); δ (400
᎐
᎐
H
Preparation of (3R,ꢁS)-3-(N-ꢁ-methyl-4-methoxybenzylamino)-
3-phenylpropionic acid 19
MHz, CDCl3) 1.36 [3H, d, J 6.8, C(α)Me], 1.39 [9H, s,
OC(Me)3], 2.27 [1H, dd, J2A,2B 14.4, J2A,3 8.9, C(2)HA], 2.34 [1H,
dd, J2B,2A 14.4, J2B,3 5.3, C(2)HB], 3.65 (2H, ABq, NCH2Ph), 3.0
(3H, s, OMe), 3.81–3.88 [1H, m, C(3)H], 3.96 [1H, q, J 6.8,
C(α)H], 5.10–5.27 [2H, m, C(5)H2], 5.89–5.98 [1H, m, C(4)H],
6.84 [2H, m, Ph(3)H, Ph(5)H C6H4OMe], 7.19–7.35 (7H, m,
Ph); δC(100 MHz, CDCl3) 12.2, 18.1, 38.5, 50.3, 55.2, 56.9, 57.2,
80.1, 113.3, 115.8, 126.5, 128.1, 128.2, 128.8, 136.2, 138.7,
141.6, 158.3, 171.2; m/z (CIϩ) 396.4 (MHϩ, 20%), 135.1
(C9H11Oϩ, 100%); HRMS (CIϩ) C25H34NO3 requires 396.2539,
found 396.2531.
Following representative procedure 3, 15 (800 mg, 2.25 mmol)
and TFA (5 ml) in DCM (6 ml) gave, after work-up and purifi-
cation by column chromatography on silica gel (CHCl3–MeOH
10 : 1), 19 (645 mg, 96%) as a white foam; [α]2D4 ϩ12.3 (c 1.0,
MeOH); νmax/cmϪ1 (film) 1642 (C᎐O), 1513 (OMe), 1203 (Ph–
᎐
OMe); δH (400 MHz, CDCl3) 1.67 [3H, d, J 6.5, C(α)Me], 2.67–
2.80 [2H, m, C(2)H2], 3.80 (3H, s, OMe), 4.12 [1H, q, J 6.4,
C(α)H], 4.54–4.59 [1H, m, C(3)H], 6.94–6.98 [2H, m, Ph(3),
Ph(5) C6H4OMe], 7.25–7.29 [2H, m, Ph(2), Ph(6) C6H4OMe],
7.43–7.52 (5H, m, Ph); δC(100 MHz, CDCl3) 19.5, 40.3, 56.3,
56.7, 59.7, 1136.1, 129.3, 130.0, 130.9, 131.2, 137.2, 162.3,
177.8; m/z APCIϩ 300.2 (MHϩ, 15%), 134.9 (C9H11Oϩ, 100%);
HRMS (CIϩ) C18H22NO5 requires 356.1599; found 356.1601.
Preparation of tert-butyl (3R,ꢁS)-3-(N-ꢁ-methyl-4-methoxy-
benzylamino)pent-4-enoate 25
Following representative procedure 2, CAN (3.9 g, 7.1 mmol)
was added to 24 (1.0 g, 2.54 mmol) in MeCN–H2O (5 : 1) (30
ml) at RT. After work-up, purification by column chrom-
atography on silica gel [hexane–Et2O (5 : 1)–1% NEt3] gave 25
(562 mg, 73%) as a colourless oil; [α]2D4 Ϫ58.6 (c 1.05, CHCl3);
νmax/cmϪ1 (film) 2973, 2835 (C–H), 1726 (C᎐O), 1609 (C᎐C),
Preparation of (4R,ꢁS)-N-(ꢁ-methyl-4-methoxybenzyl)-4-
phenylazetidin-2-one 20
Following representative procedure 4, (PyS)2 (440 mg, 2.0
mmol), PPh3 (524 mg, 2.0 mmol) and 19 (500 mg, 1.67 mmol)
were heated in refluxing MeCN (50 ml). After work-up, the
residue was purified by column chromatography on silica gel
(hexane–Et2O 1 : 1) to give 20 (391 mg, 83%) as a colourless oil;
[α]2D4 ϩ45.1 (c 1.0, CDCl3); νmax/cmϪ1 (film) 3031, 2976 (C–H),
᎐
᎐
1511 (OMe), 1243 (Ph–OMe), 1161 (C–O); δH(400 MHz,
CDCl3) 1.31 [3H, d, J 6.5, C(α)Me], 1.45 [9H, s, OC(Me)3],
2.39–2.41 [2H, m, C(2)H2], 3.49 [1H, m, C(3)H], 3.80 (3H, s,
OMe), 3.81 [1H, q, J 6.4, C(α)H], 5.07–5.17 [2H, m, C(5)H2],
5.62–5.70 [1H, m, C(4)H], 6.83–6.87 [2H, m, Ph(3)H, Ph(5)H
1746 (C᎐O), 1509 (OMe), 1245 (Ph–OMe); δ (400 MHz,
᎐
H
C6H4OMe], 7.23–7.27 [2H, d,
J 8.2, Ph(2)H, Ph(6)H
CDCl3) 1.26 [3H, d, J 7.5, C(α)Me], 2.81 [1H, dd, J3A,3B 14.5,
J3A,4 2.2, C(3)HA], 3.22 [1H, dd, J3B,3A 14.5, J3A,4 5.3, C(3)HB],
3.81 (3H, s, OMe), 5.00 [1H, q, J 7.5, C(α)H], 4.25 (1H, dd, J4,3B
5.3, J4,3A 2.2), 6.83–6.87 [2H, m, Ph(3), Ph(5) C6H4OMe], 7.11–
7.15 [2H, m, Ph(2), Ph(6) C6H4OMe], 7.27–7.37 (5H, m, Ph);
δC (100 MHz, CDCl3) 18.9, 446.2, 0.3, 51.5, 53.1, 59.7, 113.1,
129.3, 130.0, 130.9, 131.2, 137.2, 162.3, 177.8; m/z APCIϩ 282.2
(MHϩ, 100%); HRMS (CIϩ) C18H20NO2 requires 282.1494;
found 282.1489.
C6H4OMe]; δC(100 MHz, CDCl3) 23.0, 28.1, 41.3, 53.9, 55.2,
57.8, 80.5, 113.7, 115.6, 128.2, 138.1, 139.7, 158.5, 171.0; m/z
APCIϩ 306.3 (MHϩ, 15%), 135.1 (C9H11Oϩ, 100%); HRMS
(ESI) C18H28NO5 requires 306.2069; found 306.2068.
Preparation of (3R,ꢁS)-3-(N-ꢁ-methyl-4-methoxybenzylamino)-
pent-4-enoic acid 26
Following representative procedure 3, TFA (4 ml) and 25 (800
mg, 2.63 mmol) in DCM (10 ml) gave, after work-up and purifi-
cation by column chromatography on silica gel (CHCl3–MeOH
10 : 1), 26 (562 mg, 86%) as a white solid; [α]2D3 ϩ14.7 (c 1,
Preparation of (R)-4-phenylazetidin-2-one17 21
MeOH); νmax (film/cmϪ1) 1612 (C᎐O), 1516 (OMe), 1252 (Ph–
Following representative procedure 2, CAN (592 mg, 1.08
mmol) and 20 (100 mg, 0.36 mmol) in MeCN–H2O (5 : 1) gave,
after work-up and purification by column chromatography on
silica gel (hexane–Et2O 1 : 1), 21 (36 mg, 68%) as a colourless
oil; [α]2D3 ϩ136.9 (c 0.69, MeOH), [α]2D3 lit.17 ϩ132.0 (c 1, MeOH);
δH (400 MHz, CDCl3) 2.88 [1H, ddd, J3A,3B 14.0, J3A,4 2.5, J3A,NH
1.0, C(3)HA], 3.45 [1H, ddd, J3B,3A 14.0, J3B,4 5.3, J3B,NH 2.4,
C(3)HB], 4.73 [1H, dd, J4,3B 5.3, J4,3A 2.5, C(4)H], 6.30 (1H, br s,
NH), 7.31–7.42 (5H, m, Ph).
᎐
OMe); δH (500 MHz, d4-MeOH) 1.86 [3H, d, J 6.9, C(α)Me],
2.68 [1H, dd, J2A,2B 16.7, J2A,3 8.5, C(2)HA], 2.79 [1H, dd, J2B,2A
16.7, J2B,3 4.5, C(2)HB], 4.04 (3H, s, OMe), 4.21–4.25 [1H, br m,
C(3)H], 4.55 [1H, q, J 6.9, C(α)H], 5.66–5.74 [2H, m, C(5)H2],
6.00–6.07 [1H, m, C(4)H], 7.22–7.25 [2H, m, Ph(3)H and
Ph(5)H C6H4OMe], 7.60–7.63 [2H, m, Ph(2)H and Ph(6)H
C6H4OMe]; δC (125 MHz, d4-MeOH) 19.2, 36.7, 56.2, 56.3,
58.5, 116.2, 123.4, 130.0, 131.3, 133.8, 162.4, 177.6; m/z APCIϩ
250.2 (MHϩ, 30%), 135.1 (C9H11Oϩ, 100%); HRMS (ESI)
C14H19NO3Na requires 272.1263; found 272.1272.
Preparation of (R)-N-benzyl-4-phenylazetidin-2-one18 22
Following representative procedure 4, (PyS)2 (311 mg, 1.2
mmol), PPh3 (370 mg, 1.41 mmol) and 18 (300 mg, 1.18 mmol)
were heated in refluxing MeCN (50 ml). After work-up, the
residue was purified by column chromatography on silica gel
(hexane–Et2O 2 : 1) to give 22 (228 mg, 82%) as a colourless oil;
[α]2D3 ϩ94.5 (c 1.0, MeOH), [α]2D3 lit. (ent-22)18 Ϫ54.4 (c 0.59,
MeOH); δH (400 MHz, CDCl3) 2.87 [1H, dd, J3A,3B 14.7, J3A,4
1.7, C(3)HA], 3.35 [1H, dd, J3B,3A 14.7, J3A,4 5.5, C(3)HB], 3.76
(1H, d, J 15.1, NCHA), 4.40 [1H, dd, J4,3B 5.5, J4,3A 1.7, C(4)H],
4.81 (1H, d, J 15.1, NCHB), 7.13–7.16 (2H, m, Ph), 7.25–7.39
(8H, m, Ph).
Preparation of (4R,ꢁS)-N-(ꢁ-methyl-4-methoxybenzyl)-4-
vinylazetidin-2-one 27
Following representative procedure 4, (PyS)2 (425 mg, 1.93
mmol), PPh3 (505 mg, 1.93 mmol) and 26 (400 mg, 1.61 mmol)
were heated in refluxing MeCN (80 ml). After cooling and con-
centration of the reaction in vacuo, column chromatography of
the residue on silica gel (Et2O–hexane 1 : 1) gave 27 (325 mg,
87%) as a colourless oil; [α]2D4 Ϫ97.0 (c 1.05, CHCl3); νmax/cmϪ1
(film) 2976 (C–H), 1746 (C᎐O), 1513 (OMe), 1244 (Ph–OMe);
᎐
δH(400 MHz, CDCl3) 1.54 [3H, d, J 7.2, C(α)Me], 2.62 [1H, dd,
3110
J. Chem. Soc., Perkin Trans. 1, 2001, 3106–3111

View Online
1995, 1109; S. G. Davies and O. Ichihara, Tetrahedron. Lett., 1998,
39, 6045.
6 S. D. Bull, S. G. Davies, A. W. Mulvaney, R. S. Prasad and A. D.
Smith, J. Chem. Soc., Perkin Trans. 1, 2000, 3765.
7 S. D. Bull, S. D. Ballester, S. G. Davies, P. M. Kelly and A. D. Smith,
Synlett, 2000, 1257.
J3A,3B 14.6, J3A,4 1.7, C(3)HA], 3.03 [1H, dd, J3B,3A 14.6, J3B,4 5.1,
C(3)HB], 3.79–3.83 [1H, m, C(4)H], 3.81 (3H, s, OMe), 4.92
[1H, q, J 7.2, C(α)H], 5.14–5.24 [2H, m, C(2Ј)H2], 5.82 [1H, m,
C(1Ј)H], 6.86–6.90 [2H, m, Ph(3)H, Ph(5)H C6H4OMe], 7.21–
7.25 [2H, m, Ph(2)H, Ph(6)H C6H4OMe]; δC (100 MHz, CDCl3)
19.3, 42.9, 51.2, 53.1, 55.2, 113.8, 118.3, 128.4, 132.3, 138.4,
158.9, 166.2; m/z APCIϩ 232.2 (MHϩ, 100%), 135.1 (C9H11Oϩ,
60%); HRMS (ESI) C14H18NO2 requires 231.1338; found
231.1332.
8 I. Badea, P. Cotelle and J.-P. Catteau, Synth. Commun., 1994, 24,
2011.
9 G. M. Brooke, S. Mohammed and M. C. Whiting, J. Chem. Soc.,
Chem. Commun., 1997, 1511; G. M. Brooke, S. Mohammed and
M. C. Whiting, J. Chem. Soc., Perkin Trans. 1, 1997, 3371.
10 Commercially available from Lancaster Synthesis.
11 S. G. Davies, N. M. Garrido, O. Ichihara and I. A. S. Walters,
J. Chem. Soc., Chem. Commun., 1993, 1153.
Preparation of (R)-4-vinylazetidin-2-one25 28
Following representative procedure 2, CAN (1.06 g, 1.95 mmol)
and 27 (150 mg, 0.65 mmol) in MeCN–H2O (5 : 1) (12 ml) gave,
after work-up and purification by column chromatography on
silica gel (hexane–Et2O 1 : 1), 28 (44 mg, 69%) as a colourless
oil; [α]2D4 ϩ47.0 (c 0.6, CHCl3); δH (400 MHz, CDCl3) 2.62 [1H,
dd, J3A,3B 14.6, J3A,4 1.7, C(3)HA], 3.03 [1H, dd, J3B,3A 14.6, J3B,4
5.1, C(3)HB], 3.79–3.83 [1H, m, C(4)H], 5.14–5.24 [2H, m,
C(2Ј)H2], 5.82 [1H, m, C(1Ј)H], 6.00 (1H, br s, NH); δC (100
MHz, CDCl3) 19.3, 42.9, 51.2, 53.1, 55.2, 113.8, 118.3, 128.4,
132.3, 138.4, 158.9, 166.2; m/z (CIϩ) 98.1 (MHϩ, 100%).
12 A similar double debenzylation and methanolysis procedure has
recently been reported by Podlech for the synthesis of β-amino
methyl esters see J. Podlech, Synth. Commun., 2000, 1779.
13 The crude reaction mixture is consistent with the imine of 16 and
benzaldehyde by 1H NMR spectroscopic analysis. Presumably
successive deprotection of the N-benzyl and the N-α-methyl-
4-methoxybenzyl protecting groups (giving benzaldehyde and
4-methoxyacetophenone) and subsequent in situ reaction of
benzaldehyde with the primary amine gives rise to the imine which
is hydrolysed upon treatment with aqueous acid.
14 V. A. Soloshonok, N. A. Fokina, A. V. Rybakova, I. P. Shishinka,
S. V. Galushko, A. E. Sorochinsky and V. P. Kukhar, Tetrahedron:
Asymmetry, 1995, 6, 1601.
15 S. Kobayashi, T. Iimori, T. Izawa and M. Ohno, J. Am. Chem. Soc.,
1981, 103, 2406.
16 The N-α-methyl-4-methoxybenzyl protecting group has previously
been oxidatively cleaved from a β-lactam; see J. Podlech and
S. Steurer, Synthesis, 1999, 650.
Acknowledgements
The authors wish to acknowledge the financial support of New
College, Oxford for a Junior Research Fellowship (A. D. S.)
17 H. Nagai, T. Shiozawa, K. Achiwa and Y. Terao, Chem. Pharm.
Bull., 1993, 41, 1933.
18 M. Shimizu, S. Maruyama, Y. Suzuki and T. Fujisawa, Heterocycles,
1997, 45, 1883.
19 For instance see J. E. T. Corrie, J. R. Hlubucek and G. Lowe,
J. Chem. Soc., Perkin Trans. 1, 1977, 1421; G. D. Annis, E. M.
Hebblethwaite, S. T. Hodgson, D. M. Hollinshead and S. V. Ley,
J. Chem. Soc., Perkin Trans. 1, 1983, 2851.
20 B. Hungerhoff, S. S. Samanta, J. Roels and P. Metz, Synlett, 2000,
77.
21 As a representative example see K. L. Reinhart, K. Harada,
M. Namikoshi, C. Chen, C. A. Harvis, M. H. G. Murray, J. W.
Blunt, P. E. Mulligan, V. R. Beasley and W. W. Carmichael, J. Am.
Chem. Soc., 1988, 110, 8557.
22 For an alternative approach to the asymmetric synthesis of
unsaturated β-amino esters via lithium amide methodology see S. G.
Davies, D. R. Fenwick and O. Ichihara, Tetrahedron: Asymmetry,
1997, 8, 3387.
23 S. G. Davies and D. R. Fenwick, J. Chem. Soc., Chem. Commun.,
1997, 565; N. Asao, N. Tsukada and Y. Yamamoto, J. Chem. Soc.,
Chem. Commun., 1993, 1660.
24 D. Parker, Chem. Rev., 1991, 91, 1441.
25 H. Rehling and H. Jensen, Tetrahedron Lett., 1972, 13, 2793;
H. Pietsch, Tetrahedron Lett., 1976, 17, 4053.
References
1 For examples of bioactive natural products containing β-amino
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E. Dilip de Silva, P. Lassota, T. M. Allen, R. Van Soest, R. J.
Andersen and M. R. Boyd, J. Am. Chem. Soc., 1999, 121, 5899; (b)
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59, 4849; (d ) P. A. Grieco, Y. S. Hon and A. Perez-Madrano, J. Am.
Chem. Soc., 1988, 110, 1630.
2 For instance see S. G. Davies, O. Ichihara and I. A. S. Walters,
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Perkin Trans. 1, 1994, 1129; S. G. Davies and O. Ichihara, J. Synth.
Org. Chem. Jpn., 1997, 55, 42.
3 S. G. Davies and O. Ichihara, Tetrahedron: Asymmetry, 1991, 2,
183.
4 G. Albers-Schönberg, B. H. Arison, O. D. Hensens, J. Hirshfield,
K. Hoogsteen, E. A. Kaczka, R. E. Rhodes, J. S. Kahan, F. M.
Kahan, R. W. Ratcliffe, E. Walton, L. J. Ruswinkle, R. B. Morin and
B. G. Christensen, J. Am. Chem. Soc., 1978, 100, 6491.
5 S. G. Davies and D. R. Fenwick, J. Chem. Soc., Chem. Commun.,
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