Asymmetric synthesis of N-protected amino acids by the addition of organolithium carboxyl synthons to ROPHy/SOPHy-derived aldoximes and ketoximes.

Article abstract of DOI:10.1039/b310624a

A new asymmetric synthesis of alpha-amino acids is described in which the key step is the highly diastereoselective addition of organolithium carboxyl synthons (2-furyllithium, phenyllithium, vinyllithium) to (R)- and (S)-O-(1-phenylbutyl) oximes to give hydroxylamines, with vinyllithium being the most satisfactory nucleophilic reagent. Subsequent reductive cleavage of the N-O bond in hydroxylamines, followed by N-protection, and oxidative cleavage of the carboxyl precursor gave a range of N-protected amino acids and esters. The method was exemplified by the synthesis of a range of derivatives of non-proteinogenic amino acids such as 4-bromophenylalanine, tert-leucine, norvaline, cyclohexyl- and aryl-glycines, 2-amino-8-oxodecanoic acid (Aoda) and alpha-methylvaline.

Full text of DOI:10.1039/b310624a

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-
Asymmetric synthesis of N-protected amino acids by the addition
of organolithium carboxyl synthons to ROPHy/SOPHy-derived
aldoximes and ketoximes†
Tracey S. Cooper,a Pierre Laurent,a Christopher J. Moody*a and Andrew K. Takleb
a Department of Chemistry, University of Exeter, Stocker Road, Exeter, UK EX4 4QD
b Department of Medicinal Chemistry, Neurology and GI Centre of Excellence for
Drug Discovery, GlaxoSmithKline Research & Development Ltd., New Frontiers Science Park,
Third Avenue, Harlow, Essex, UK CM19 5AW
Received 3rd September 2003, Accepted 7th November 2003
First published as an Advance Article on the web 1st December 2003
A new asymmetric synthesis of α-amino acids is described in which the key step is the highly diastereoselective
addition of organolithium carboxyl synthons (2-furyllithium, phenyllithium, vinyllithium) to (R)- and (S)-O-
(1-phenylbutyl) oximes 2 to give hydroxylamines 3, with vinyllithium being the most satisfactory nucleophilic reagent.
Subsequent reductive cleavage of the N–O bond in hydroxylamines 3, followed by N-protection, and oxidative
cleavage of the carboxyl precursor gave a range of N-protected amino acids and esters. The method was exemplified
by the synthesis of a range of derivatives of non-proteinogenic amino acids such as 4-bromophenylalanine,
tert-leucine, norvaline, cyclohexyl- and aryl-glycines, 2-amino-8-oxodecanoic acid (Aoda) and α-methylvaline.
details of a new route to α-amino acids based on the highly
diastereoselective addition of organolithium carboxyl synthons
to a range of O-(1-phenylbutyl) oximes.
Introduction
The development of new methodology for the asymmetric syn-
thesis of α-amino acids, both natural and unnatural, continues
to attract the attention of chemists worldwide.2–9 Many of these
methods involve stereoselective additions to C᎐N bonds,10–16
Results and discussion
᎐
and in this context we have recently reported the highly
diastereoselective addition of organometallic reagents to the
C᎐N bond of chiral oxime ethers to give non-racemic hydroxyl-
᎐
In order to adapt our asymmetric synthesis of protected amines
(Scheme 1) into a route to N-protected amino acids, two strat-
egies were considered (Scheme 2). The first involved the use of
an oxime ether 1 which incorporates the carboxylic acid pre-
cursor, RA; addition of organometallic reagents, followed by
cleavage of the N–O bond, and conversion of RA into a carb-
oxyl group would then give the required amino acid. Altern-
atively the carboxyl synthon can be added as an organometallic
reagent, RAMet (Scheme 2b), to the oxime ether 2, the two
routes being stereocomplementary, since one enantiomer of
the 1-phenylbutyl auxiliary can give both enantiomers of the
α-amino acid. The former strategy (Scheme 2a) has been the
subject of a previous article,24 and therefore we now report
details of the second approach.
In order to investigate the viability of such an approach, a
wide range of O-(1-phenylbutyl) oxime ethers was required.
These were prepared by condensation of the relevant aldehyde
or ketone with (R)- or (S)-O-(1-phenylbutyl)hydroxylamine,
obtained by hydrazine hydrate cleavage of the corresponding
N-phthaloyl derivatives, as previously described.18 A range of
oxime ethers 2 derived from aliphatic aldehydes (oximes 2a–2h),
a dialkyl ketone (oxime 2i), aromatic aldehydes (oximes 2j–2m),
and two aromatic ketones (oximes 2n, 2o) was thus prepared
(Table 1). The starting carbonyl compounds were chosen to
provide a variety of substituents in the final α-amino acids,
including α-methyl quaternary amino acids from the methyl
ketoximes 2i, 2n, and 2o, and naturally occurring non-proteino-
genic α-amino acids such as 2-amino-8-oxodecanoic acid
(Aoda) and 4-bromophenylalanine from the aldoxime ethers 2g
and 2h respectively. The aldehyde starting material for oxime
ether 2g was prepared as shown in Scheme 3.
amines.17,18 This subsequently resulted in the development of
oxime ethers derived from (R) and (S) O-(1-phenylbutyl)-
hydroxylamines, which we term ROPHy and SOPHy by
analogy with Enders’ RAMP and SAMP hydrazones, as useful
reagents for asymmetric synthesis, and their application in the
asymmetric synthesis of chiral amines (Scheme 1).1,17,18 The
methodology has been applied to the asymmetric synthesis of
various nitrogen containing compounds including the hemlock
piperidine alkaloids (Ϫ)-coniine and (ϩ)-pseudoconhydrine,19
β-amino acids,20 1-(2-thiazolyl)ethylamines,21 including the
cytotoxic thiazole-containing peptide virenamide B,22 and, in
combination with ring-closing metathesis, a range of nitrogen
heterocycles, including iminosugars.1,23 We now report the
Several nucleophilic carboxyl synthons RA were considered
as suitable reagents to add to oxime ethers 2. However, pre-
liminary experiments quickly established that oxime ethers did
not undergo addition of cyanide (in the form of Et2AlCN)
Scheme 1
† Chiral oxime ethers in asymmetric synthesis. Part 6.1
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 6 5 – 2 7 6
265

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Table 1 Preparation of (R)- and (S)-O-(1-phenylbutyl) oximes 2
Oxime
R1
R2
Configuration
Yield/%
2a
n-Pr
i-Pr
H2C᎐CH(CH2)2
t-Bu
CMe2Et
c-Hex
EtC(᎐CH2)(CH2)5
4-BrC6H4CH2
i-Pr
i-Pr
Ph
H
H
H
H
H
H
H
H
Me
Me
H
H
H
H
Me
Me
S
S
S
S
S
S
R
R
S
R
S
R
S
S
S
S
73a
2b
57b
2c
56c
᎐
2d
93d
2e
33
2f
90c
2g
47 (ϩ36% Z-isomer)
40
61
᎐
2h
2i(S)
2i(R)
2j
68
93c
87d
93
2k
2l
2m
2n
2o
4-MeOC6H4
2,5-Me2C6H3
3-F,2-MeC6H3
Ph
94
48d
30
4-BrC6H4
a Ref. 19. b (R)-enantiomer described in ref. 20. c Ref. 20. d Ref. 18.
Scheme 3
of the furan ring with a range of reagents has been reported to
give the carboxylic acid.25,26 The strategy has been used in the
synthesis of carbohydrates,27,28 and, more relevantly, in other
routes to amino acids.29,30 Thus 2-furyllithium was generated
using a literature method,30 and added to the oxime ether in
toluene at Ϫ78 ЊC in the presence of boron trifluoride etherate
according to our normal protocol.1 The results were generally
disappointing (Table 2, Entries 1–3); the aldoxime ether 2h
underwent addition of 2-furyllithium to give the hydroxylamine
3a in modest yield (40%) and reasonable diastereomeric excess
(de) (83%). However, the additions to the ketoxime ethers 2i(S )
and 2o proceeded poorly, although the latter gave the hydroxyl-
amine 3c with excellent diastereocontrol. Additions to the
aromatic aldoxime ethers 2j–2l proved unsatisfactory.
The second organometallic carboxyl synthon investigated
was phenyllithium. The benzene ring can be cleaved oxidatively
to give a carboxylic acid, and this strategy has already found
use in the synthesis of α-amino acids from chiral α-alkyl-
benzylamine derivatives.14,31–34 Therefore phenyllithium was
added to the aldoxime ethers 2b, 2d and 2e under the usual
conditions. The additions proceeded with excellent dia-
stereoselectivity to give the hydroxylamines 3d–3f, although the
yields were poor (Table 2, Entries 4–6).
Scheme 2 [RA = carboxylic acid precursor].
᎐
or acetylide (in the form of TMSC᎐CLi) nucleophiles. For
᎐
example, Et2AlCN did not add to the pivaldehyde derived
oxime ether 2d under conditions reported to be successful for
other C᎐N electrophiles.13 Presumably this illustrates the poor
᎐
reactivity of such oxime ethers to all but the most reactive
nucleophiles, although in the case of 2d there is additional steric
hindrance. Therefore attention turned to other nucleophilic
carboxyl synthons.
The group RA that was chosen for initial study was the furan
group, since 2-furyllithium is readily generated, and oxidation
Finally the use of vinyl organometallic reagents as carboxyl
synthons was investigated. Vinylmagnesium bromide (as sup-
plied commercially in THF) did not add to the oxime ethers 2,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 6 5 – 2 7 6
266

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Table 2 Addition of organolithium carboxyl synthons to oxime ethers 2 to give hydroxylamines 3
Entry
Oxime ether
R1
R2
RA
Hydroxylamine
Configurationa
Yield/%
de/%b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
2h
4-BrC6H4CH2
i-Pr
4-BrC6H4
i-Pr
t-Bu
CMe2Et
n-Pr
H
2-furyl
2-furyl
2-furyl
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
S,R
R,S
R,S
R,S
R,S
R,S
R,S
R,S
S,S
S,R
S,R
S,S
R,R
S,S
S,S
S,S
40
31
14
38
31
32
87
77
74
76
54
46
50
16
10
10
83
52
>95
95
>98
>98
84
94
92
>95
>95
98
2i(S)
2o
Me
Me
H
H
H
H
H
H
H
Me
H
H
H
H
2b
2d
2e
2a
H2C᎐CH
᎐
2c
H2C᎐CH(CH2)2
H2C᎐CH
᎐
᎐
2f
c-Hex
H2C᎐CH
᎐
2g
EtC(᎐CH2)(CH2)5
H2C᎐CH
᎐
᎐
2i(R)
2j
i-Pr
H2C᎐CH
᎐
Ph
H2C᎐CH
᎐
2k
2l
2m
2n
4-MeOC6H4
2,5-Me2C6H3
3-F,2-MeC6H3
Ph
H2C᎐CH
91
95
95
64
᎐
H2C᎐CH
᎐
H2C᎐CH
᎐
Me
H2C᎐CH
᎐
a The configurations refer to the new chiral center, assigned on the basis of our previous work, and the starting chiral auxiliary respectively.
b Determined from the 1H-NMR spectrum of the crude hydroxylamine 3 before chromatography.
Table 3 Conversion of hydroxylamines 3 into N-protected amines 4
Entry
Hydroxylamine
R1
R2
RA
Amine
Pg
Configuration
Yield/%
ee/%a
1
2
3
4
5
6
7
8
9
3a
3d
3e
3f
4-BrC6H4CH2
i-Pr
t-Bu
CMe2Et
n-Pr
H
H
H
H
H
H
H
H
Me
H
H
2-furyl
Ph
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
Boc
Ac
Ac
S
72
38
28
6
89
53
52
70
80
9
83
98
>98
>98
nd
nd
nd
97
nd
90
nd
R
R
R
R
R
S
S
S
S
R
Ph
Ac
3g
3h
3i
H2C᎐CH
Cbz
Cbz
Cbz
Cbz
Cbz
Ac
᎐
H2C᎐CH(CH2)2
H2C᎐CH
᎐
᎐
c-Hex
H2C᎐CH
᎐
3j
EtC(᎐CH2)(CH2)5
H2C᎐CH
᎐
᎐
3k
3l
i-Pr
H2C᎐CH
᎐
10
11
Ph
H2C᎐CH
4j
4k
᎐
3m
4-MeOC6H4
H2C᎐CH
CBz
85
᎐
a Determined by HPLC on a chiral stationary phase by comparison with the racemate; nd = not determined at this stage—measured at amino ester
stage in the case of 4e and 4f.
THF being known to be generally deleterious to such reactions.
However vinyllithium, generated from tetravinyltin by the liter-
ature protocol,35 added smoothly to a range of oxime ethers 2
to give the corresponding hydroxylamines 3g–3p. With the
exception of the aromatic oxime ethers 2l–2n, the yields are
acceptable, and for the most part, the diastereoselectivity of
the addition reaction is good (Table 2, Entries 7–16). Hence
vinyllithium proved the most satisfactory of the various
organometallic carboxyl synthons investigated.
In all the addition reactions of organolithium reagents
described in Table 2, the stereochemistry of the new chiral
centre was assigned on the basis of our previous work, and, in
some cases, by the subsequent conversion of the hydroxyl-
amines 3 into α-amino acids of known configuration (see
below). The diastereoselectivity of the addition was determined
from the 1H-NMR spectrum of the crude hydroxylamine prod-
uct before chromatography. No attempt was made to investigate
other auxiliaries (cf. ref. 18) even in cases where the addition
reaction failed.
With a range of chiral hydroxylamines 3 containing a
carboxylic acid precursor, RA, in hand, their conversion into
α-amino acid derivatives was undertaken. This was achieved by
initial cleavage of the N–O bond using our previously described
zinc/acetic acid/ultrasound method, and was exemplified for the
furan derivative 3a, the phenyl derivatives 3d–3f, and the vinyl
derivatives 3g–3m. The resulting amines were not isolated but
were immediately converted into their tert-butyl or benzyl carb-
amates or N-acetyl derivatives by reaction with di-tert-butyl
dicarbonate, benzyl chloroformate or acetic anhydride respect-
ively. The N-protected amines 4 were isolated in varying yield
(Table 3), and their enantiomeric purity established by com-
parison with the independently synthesized racemate by HPLC
on a chiral stationary phase.
The conversion of the RA substituent in the N-protected
amines 4 into a carboxylic acid (or ester) was carried out under
standard oxidative conditions. Thus the furan ring in 4a was
oxidatively cleaved using Ru(),25,30 to give N-Boc 4-bromo-
phenylalanine 5a in modest yield. Likewise the phenyl ring in 4c
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 6 5 – 2 7 6
267

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Table 4 Oxidative cleavage of the RA group in amines 4 to give amino acids 5
Entry
Amine
RA
Methoda
Amino acid
R1
R2
Pg
R
Configuration
Yield/%
1
2
3
4
5
6
7
8
9
4a
4c
4e
4f
4g
4h
4i
2-furyl
Ph
A
B
C
C
C
B
B
A
C
5a
5b
5c
5d
5e
5f
5g
5h
5i
4-BrC6H4CH2
t-Bu
n-Pr
MeO2CCH2CH2
c-Hex
EtCO(CH2)5
i-Pr
H
H
H
H
H
H
Me
H
H
Boc
Ac
H
H
Me
Me
Me
H
H
H
Me
S
33
R
R
R
R
S
S
R
S
63b
59c
40d
70
H2C᎐CH
Cbz
Cbz
Cbz
Cbz
Cbz
Ac
᎐
H2C᎐CH
᎐
H2C᎐CH
᎐
H2C᎐CH
39
38
24
58
᎐
H2C᎐CH
᎐
4j
4k
H2C᎐CH
Ph
᎐
H2C᎐CH
4-MeOC6H4
Cbz
᎐
a Method A: RuCl3, NaIO4, CCl4–MeCN–H2O; Method B: RuCl3, H5IO6, CCl4–MeCN–H2O; Method C: O3, NaOH, MeOH, CH2Cl2, Ϫ78 ЊC.
b This conversion is reported for the (S)-enantiomer in ref. 14. c 86% ee as determined by HPLC. d 93% ee as determined by HPLC.
was cleaved with Ru() to give N-acetyl tert-leucine 5b in 63%
yield; this transformation has previously been reported for the
(S)-enantiomer.14 The vinyl groups in amines 4e–4k were
cleaved to the carboxylic acid using Ru() or using Marshalls’
ozonolysis procedure which leads directly to the methyl ester.36
Hence the vinyl compounds 4e, 4g and 4k were ozonized in a
mixture of methanolic sodium hydroxide and dichloromethane
to give the corresponding N-Cbz methyl esters of the amino
acids norvaline 5c, cyclohexylglycine 5e and 4-methoxy-
phenylglycine 5i in reasonable yield (Table 3, Entries 3, 5, 9).
Similar treatment of amine 4f resulted in cleavage of both
double bonds and the formation of dimethyl N-Cbz glutamate
5d (Table 3, Entry 4). The double bonds in amines 4h–4j were
cleaved using Ru() to give the carboxylic acids 5f–5h (Table
3, Entries 6–8). Oxidation of 4h gave N-Cbz 2-amino-8-oxo-
decanoic acid (Aoda) 5f, a component of the cyclic peptide
apicidin,37 in modest yield, whereas similar oxidation of 4i gave
the N-protected quaternary amino acid, α-methylvaline 5g.
Finally Ru() oxidation of 4j gave N-acetylphenylglycine 5h
in poor yield, possible due to competing oxidation of the
phenyl ring. The oxidative cleavage reactions are summarized in
Table 4, and the amino acid derivatives thus obtained are shown
in Fig. 1.
Thus we have extended the use of chiral ROPHy and SOPHy
derived oximes in the asymmetric synthesis of α-amino
acids, and exemplified their use by the synthesis of a range
of derivatives of non-proteinogenic amino acids such as
4-bromophenylalanine, tert-leucine, norvaline, cyclohexyl-
and aryl-glycines, 2-amino-8-oxodecanoic acid (Aoda) and
α-methylvaline. The method complements other approaches to
the asymmetric synthesis of α-amino acids by addition of
Fig. 1
under reduced pressure and the residue purified by column
chromatography on silica gel (eluting with ether–light petrol-
eum (1 : 20) unless otherwise stated).
nucleophiles to C᎐N bonds.
᎐
(E )-(S )-(؊)-O-(1-Phenylbutyl)butyraldehyde oxime 2a.
Prepared as described previously.19
Experimental
For general experimental details, see ref. 1. Hydroxylamines 3
were characterized as diastereomeric mixtures; the NMR data
refer to the major diastereomer.
(E )-(S )-(؉)-O-(1-Phenylbutyl)isobutyraldehyde oxime 2b.
Prepared as described previously for the (R)-enantiomer.20
(E )-(S )-(؊)-O-(1-Phenylbutyl)pent-4-enaldehyde oxime 2c.
Prepared as described previously.20
General procedure for the preparation of oxime ethers 2
A suspension of (R)- or (S)-N-(1-phenylbutoxy)phthalimide18
(3.0 g, 10.17 mmol) in ethanol (50 mL) was heated until the
phthalimide dissolved. Hydrazine hydrate (0.6 mL, 12.4 mmol)
was added at this elevated temperature and the reaction mixture
was heated under reflux for a further 1 h. The solution was then
allowed to cool to room temperature. The aldehyde or ketone
(12 to 30 mmol) was added at room temperature and the reac-
tion mixture stirred overnight. The solvent was evaporated
(E )-(S )-(؊)-O-(1-Phenylbutyl)pivaldedehyde oxime 2d.
Prepared as described previously.18
(E )-(S )-(؉)-O-(1-Phenylbutyl)-2,2-dimethylbutyraldehyde
oxime 2e. Obtained from the condensation of (S)-O-(1-
phenylbutyl)hydroxylamine with 2,2-dimethylbutyraldehyde as
a colourless oil (33%); [α]2D4 ϩ16.0 (c 1.24, CHCl3); (Found:
MHϩ, 248.2015. C16H25NO ϩ H requires 248.2014); νmax(film)/
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 6 5 – 2 7 6
268

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cmϪ1 2955, 2868, 1444, 1024, 927, 697; δH (300 MHz; CDCl3)
fluoroacetic acid (50%, 30 mL) was added at 0 ЊC and then the
7.35–7.27 (6 H, m, ArH, HC᎐N), 5.07 (1 H, t, J 6.9, OCH), 1.95
reaction was allowed to warm to rt. After 5 h, the solution was
diluted in dichloromethane (130 mL) and carefully washed
successively with a saturated solution of sodium hydrogen
carbonate (40 mL), brine (50 mL), water (50 mL) and dried
(K2CO3), filtered and evaporated to give 7-ethyloct-7-enal
(quantitative yield) as an oil which was not further purified for
the next step; νmax(film)/cmϪ1 3078, 2966, 2935, 2853, 2715,
1716, 1639, 1460, 1368, 1214, 1158, 1117, 881; δH (300 MHz;
᎐
(1 H, m, CHH), 1.73 (1 H, m, CHH ), 1.40 (4 H, m, CH2), 1.03
(3 H, s, Me), 1.01 (3 H, s, Me), 0.95 (3 H, t, J 7.4, Me), 0.76
(3 H, t, J 7.5, Me); δC (75 MHz; CDCl3) 157.9 (CH), 142.5 (C),
128.0 (CH), 127.1 (CH), 126.8 (CH), 84.3 (CH), 38.1 (CH2),
36.7 (C), 33.5 (CH2), 25.0 (Me), 24.6 (Me), 18.8 (CH2), 14.0
(Me), 8.5 (Me); m/z (CI) 248 (MHϩ, 100%), 166 (8), 150 (36),
132 (3), 115 (25), 108 (7), 100 (53).
CDCl ) 9.77 (1 H, t, J 1.7, CHO), 4.70 (1 H, br s, ᎐CHH), 4.69
᎐
3
(E )-(S )-(؊)-O-(1-Phenylbutyl)cyclohexanecarboxaldehyde
oxime 2f. Prepared as described previously.20
(1 H, br s, ᎐CHH ), 2.44 (2 H, dt, J 7.3, 1.7, CH CHO), 2.01
᎐
2
(4 H, m, CH C(᎐CH )CH ), 1.64 (2 H, m, CH ), 1.51–1.27 (4 H,
᎐
2
2
2
2
m, 2 × CH2), 1.02 (3 H, t, J 7.5, Me).
(E )-(R)-(؊)-O-(1-Phenylbutyl)-7-ethyloct-7-enaldehyde
oxime 2g. (a) 7,7-Dimethoxyheptanal38 (5.5 g, 31.6 mmol) was
dissolved in THF (150 mL) under nitrogen and cooled to 0 ЊC.
Ethylmagnesium bromide (3 M in ether; 21 mL, 63.2 mmol)
was added dropwise at this temperature, and the mixture stirred
until all starting material was consumed. The reaction mixture
was quenched at this temperature with aqueous saturated
ammonium chloride solution (50 mL), and allowed to warm to
room temperature. The mixture was extracted with ether (3 × 50
mL), combined, dried (K2CO3), filtered and evaporated. The
residue was purified by column chromatography on silica gel
eluting with ethyl acetate–light petroleum (1 : 5) to give 9,9-di-
methoxynonan-3-ol (3.355 g, 52%) as a colourless oil; δH (300
MHz; CDCl3) 4.35 (1 H, t, J 5.7, CH(OMe)2), 3.51 (1 H, m,
CHOH), 3.31 (6 H, s, CH(OMe)2), 1.59–1.30 (12 H, m,
6 × CH2), 0.93 (3 H, t, J7.4, CH2Me).
Solid TPAP (289 mg, 5 mol%, 0.82 mmol) was added in one
portion to a stirred mixture of the above alcohol (3.355 g, 16.42
mmol), NMO (2.885 g, 24.63 mmol) and powdered 4 Å molecu-
lar sieves (8 g) in dry dichloromethane (33 mL) at room temper-
ature under nitrogen. On completion (2 h monitored by TLC)
the reaction mixture was filtered through a short pad of silica,
eluting with ethyl acetate. The filtrate was evaporated to give
crude 9,9-dimethoxynonan-3-one as a colourless oil (3.243 g,
98%) which was used without further purification; νmax(film)/
cmϪ1 2981, 2940, 2858, 2827, 1711, 1455, 1414, 1373, 1194,
1132, 1050, 958, 738; δH (300 MHz; CDCl3) 4.34 (1 H, t, J 5.7,
CH(OMe)2), 3.30 (6 H, s, CH(OMe)2), 2.41 (4 H, m,
CH2(CO)CH2), 1.57 (4 H, m, 2 × CH2), 1.32 (4 H, m, 2 × CH2),
1.04 (3 H, t, J 7.4, CH2Me); δC (75 MHz; CDCl3) 211.9 (C),
104.6 (CH), 52.8 (Me), 42.4 (CH2), 36.1 (CH2), 32.5 (CH2), 29.3
(CH2), 24.6 (CH2), 24.0 (CH2), 8.0 (Me).
(b) Methyltriphenylphosphonium bromide (14.565 g, 40.77
mmol) was dissolved in toluene (90 mL) under nitrogen and
cooled to 0 ЊC. n-Butyllithium (1.6 M in hexane; 25.5 mL, 40.77
mmol) was added dropwise at this temperature and allowed to
warm to room temperature for 30 min and then cooled to 0 ЊC.
This solution was slowly added to a solution of 9,9-di-
methoxynonan-3-one (2.750 g, 13.59 mmol) in toluene (55 mL)
under nitrogen at 0 ЊC. The reaction was the allowed to warm
to room temperature and stirred for 5 h and acetone (50 mL)
was added to quench the reaction. The solution was filtered
through a short pad of silica, eluting with ethyl acetate. The
residue was purified by column chromatography on silica gel
eluting with ethyl acetate–light petroleum (1 : 9) to give 8,8-di-
The crude aldehyde was condensed with (R)-O-(1-phenyl-
butyl)hydroxylamine (7.12 mmol) according to the general
method to give the title compound (1.005 g, 47%) as a colourless
oil; [α]2D3 Ϫ29.2 (c 1.30, CHCl3); (Found: Mϩ, 301.2408.
C20H31NO requires 301.2405); νmax(film)/cmϪ1 3088, 3063, 3032,
2960, 2930, 2873, 2855, 1644, 1496, 1450, 1363, 1107, 1061,
1025, 974, 917, 887, 758, 697; δH (300 MHz; CDCl3) 7.42 (1 H,
J 6.3, N᎐CH), 7.29 (5 H, m, ArH), 5.01 (1 H, t, J 6.9, OCH),
᎐
4.68 (1 H, d, J 1.0, CHH᎐), 4.66 (1 H, d, J 1.0, CHH᎐), 2.13
᎐
᎐
(2 H, q, J 7.1, CH2), 2.06–1.83 (5 H, m, 2 × CH2, CHH), 1.69
(1 H, m, CHH ), 1.50–1.19 (8 H, m, 4 × CH2), 1.01 (3 H, t, J 7.4,
Me), 0.92 (3 H, t, J 7.4, Me); δC (75 MHz; CDCl3) 151.4 (C),
151.2 (CH), 142.7 (C), 128.2 (CH), 127.2 (CH), 126.7 (CH),
107.5 (CH2), 84.5 (CH), 38.4 (CH2), 36.2 (CH2), 29.4 (CH2),
28.73 (CH2), 28.68 (CH2), 27.4 (CH2), 26.6 (CH2), 18.9 (CH2),
14.0 (Me), 12.4 (Me); m/z (EI) 301 (Mϩ, 3%), 284 (54), 272 (48),
258 (26), 134 (98), 107 (42), 92 (100), 77 (44), 55 (50).
Also obtained was (Z)-(R)-(Ϫ)-7-O-(1-phenylbutyl)-7-
ethyloct-7-enaldehyde oxime as a colourless oil (0.770 g, 36%);
νmax(film)/cmϪ1 3088, 3063, 3032, 2960, 2930, 2873, 2855, 1644,
1496, 1450, 1363, 1107, 1061, 1025, 974, 917, 887, 758, 697;
δH (300 MHz; CDCl3) 7.29 (5 H, m, ArH), 6.61 (1 H, J 5.5,
CHN), 5.04 (1 H, t, J 6.8, OCH), 4.70 (2 H, m, CH2), 2.40 (2 H,
m, CH2), 2.07–1.84 (5 H, m, 2 × CH2, CHH), 1.71 (1 H, m,
CHH ), 1.54–1.23 (8 H, m, 4 × CH2), 1.03 (3 H, t, J 7.4, Me),
0.93 (3 H, t, J 7.4, Me); δC (75 MHz; CDCl3) 152.0 (CH), 151.4
(C), 143.1 (C), 128.2 (CH), 127.2 (CH), 126.4 (CH), 107.6
(CH2), 84.8 (CH), 38.6 (CH2), 36.1 (CH2), 29.1 (CH2), 28.71
(CH2), 27.5 (CH2), 26.1 (CH2), 25.8 (CH2), 18.9 (CH2), 14.0
(Me), 12.4 (Me).
(E )-(R)-(؊)-O-(1-Phenylbutyl)-4-bromophenylacetaldehyde
oxime 2h. Obtained from the condensation of (R)-O-(1-
phenylbutyl)hydroxylamine with 4-bromophenylacetaldehyde
as a colourless oil (40%); [α]2D4 Ϫ32.6 (c 1.4, CH2Cl2); (Found:
MHϩ, 346.0811. C18H2079BrNO ϩ H requires 346.0807);
νmax(film)/cmϪ1 3028, 1488, 1452, 1358, 1307, 1200; δH (300
MHz; CDCl ) 7.50 (1 H, t, J 6.6, HC᎐N), 7.40 (2 H, d, J 8.5,
᎐
3
ArH), 7.38–7.26 (5 H, m, ArH), 6.98 (2 H, d, J 8.5, ArH),
5.10 (1 H, t, J 6.9, OCH), 3.40 (2 H, d, J 6.6, CH2PhBr), 1.93
(1 H, m, CHH), 1.74 (1 H, m, CHH ), 1.41 (2 H, m, CH2), 0.97
(3 H, t, J 7.3, Me); δC (75 MHz; CDCl3) 148.7 (CH), 142.7 (C),
137.3 (C), 135.5 (C), 131.7 (CH), 130.5 (CH), 128.3 (CH), 127.4
(CH), 126.7 (CH), 84.9 (CH), 38.3 (CH2), 35.3 (CH2), 18.9
(CH2), 14.0 (Me); m/z (CI) 346/344 (MHϩ, 28%), 268 (8), 217
(6), 200 (28), 168 (18), 150 (100), 137 (3), 120 (18), 108 (6),
91 (1).
methoxy-2-ethyloct-1-ene (2.196 g, 81%) as
a colourless
oil; νmax(film)/cmϪ1 3068, 2935, 2853, 2827, 1644, 1455, 1383,
1358, 1194, 1122, 1076, 1046, 963, 886; δH (300 MHz; CDCl3)
4.68 (2 H, br, ᎐CH ), 4.36 (1 H, t, J 5.7, CH(OMe) ), 3.31
(E )-(S )-(؉)-O-(1-Phenylbutyl)-3-methylbutan-2-one oxime
2i(S). Obtained from the condensation of (S)-O-(1-phenyl-
butyl)hydroxylamine with 3-methylbutan-2-one as a pale yellow
oil (61%); [α]2D3 ϩ38.7 (c 1.06, CHCl3); (Found: MHϩ, 234.1861.
C15H23NO ϩ H requires 234.1858); νmax(film)/cmϪ1 3032, 2960,
1449, 1372, 1234, 1034, 922, 758, 702; δH (300 MHz; CDCl3)
7.36–7.22 (5 H, m, ArH), 5.04 (1 H, t, J 6.7, OCH), 2.45 (1 H,
heptet, J 6.8, CH(Me)2), 1.89 (1 H, m, CHH), 1.84 (3 H, s, Me),
1.72 (1 H, m, CHH ), 1.37 (2 H, m, CH2), 1.03 (3 H, d, J 6.8,
᎐
2
2
(6 H, s, CH(OMe)2), 2.00 (4 H, m, 2 × CH2), 1.64–1.21
(8 H, m, 4 × CH2), 1.02 (3 H, t, J7.5, CH2Me); δC (75 MHz;
CDCl3) 151.8 (C), 107.7 (CH2), 104.7 (CH), 52.8 (Me), 36.4
(CH2), 32.7 (CH2), 29.5 (CH2), 28.9 (CH2), 28.0 (CH2), 24.7
(CH2), 12.6 (Me); a satisfactory mass spectrum could not be
obtained.
(c) 8,8-Dimethoxy-2-ethyloct-1-ene (2.180 g, 10.88 mmol)
was dissolved in chloroform (60 mL) and aqueous tri-
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 6 5 – 2 7 6
269

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Me), 1.00 (3 H, d, J 6.8, Me), 0.92 (3 H, t, J 7.4, Me); δC (75
MHz; CDCl3) 161.2 (C), 143.3 (C), 128.0 (CH), 126.9 (CH),
126.4 (CH), 84.1 (CH), 38.7 (CH2), 34.1 (CH), 19.9 (Me), 19.8
(Me), 18.8 (CH2), 14.1 (Me), 11.1 (Me); m/z (CI) 234 (MHϩ,
100%), 150 (2), 125 (1), 108 (3), 86 (8).
General procedure for the addition of organometallic reagents
The oxime ether 2 (3.9 mmol, 1 eq.) was dissolved in toluene
(10 mL) under nitrogen and cooled to Ϫ78 ЊC or Ϫ90 ЊC. Boron
trifluoride etherate (11.8 mmol, 3 eq.) was added and the mix-
ture stirred for 15 min. The organometallic reagent (11.8 mmol,
3 eq.) was added dropwise over 30 min at this temperature, and
the mixture stirred until all starting material was consumed.
The reaction mixture was quenched at this temperature with
aqueous saturated ammonium chloride solution (10 mL), and
allowed to warm to room temperature. The mixture was
extracted with ether (3 × 15 mL), combined, dried (K2CO3),
filtered and evaporated. The residue was purified by column
chromatography on silica gel (eluting with ether–light petrol-
eum (1 : 20) unless otherwise stated).
(E )-(R)-(؊)-O-(1-Phenylbutyl)-3-methylbutan-2-one oxime
2i(R). Obtained from the condensation of (R)-O-(1-phenyl-
butyl)hydroxylamine with 3-methylbutan-2-one as a colourless
oil (68%); [α]2D5 Ϫ30.8 (c 1.04, CHCl3); remaining data as for
above enantiomer.
(E )-(S )-(؊)-O-(1-Phenylbutyl)benzaldehyde oxime 2j.
Prepared as described previously.20
(E )-(R)-(؉)-O-(1-Phenylbutyl)-4-methoxybenzaldehyde
oxime 2k. Prepared as described previously.18
Addition of 2-furyllithium
2-Furyllithium was prepared in diethyl ether following a liter-
ature protocol.30
(E )-(S )-(؊)-O-(1-Phenylbutyl)-2,5-dimethylbenzaldehyde
oxime 2l. Obtained from the condensation of (S)-O-(1-phenyl-
butyl)hydroxylamine with 2,5-dimethylbenzaldehyde as a col-
ourless oil (93%); [α]2D2 Ϫ63.0 (c 1.19, CHCl3); (Found: MHϩ,
282.1863. C19H23NO ϩ H requires 282.1858); νmax(film)/cmϪ1
3027, 2950, 2924, 2873, 1495, 1449, 1029, 947, 809, 702; δH (300
MHz; CDCl ) 8.36 (1 H, s, N᎐CH), 7.42 (1 H, s, ArH), 7.30
(1S,1ЈR)-(؊)-N-(1-Phenylbutoxy)-2-(4-bromophenyl)-1-
(2-furyl)ethylamine 3a. Obtained from the addition of 2-furyl-
lithium to (R)-O-(1-phenylbutyl)-4-bromophenylacetaldehyde
oxime 2h as a yellow oil (40%, 83% de); [α]2D4 Ϫ42.5 (c 1.13,
CHCl3); (Found: MHϩ, 414.1068. C22H2479BrNO2 ϩ H requires
414.1069); νmax(film)/cmϪ1 3021, 2954, 2925, 2872, 1490, 1447,
1071, 734, 701; δH (300 MHz; CDCl3) 7.40–7.22 (8 H, m, ArH,
fur-H5), 6.92 (2 H, d, J 8.3, ArH), 6.16 (1 H, m, fur-H4), 6.13 (1
H, m, fur-H3), 5.45 (1 H, br s, NH), 4.46 (1 H, dd, J 6.2, 7.5,
OCH), 4.22 (1 H, t, J 7.1, HCNH), 3.02 (1 H, dd, J 7.1, 13.7,
ArCHH), 2.97 (1 H, dd, J 7.1, 13.7, ArCHH ), 1.72 (1 H, m,
CH2), 1.51 (1 H, m, CH2), 1.30 (2 H, m, CH2), 0.86 (3 H, t, J 7.1,
Me); δC (75 MHz; CDCl3) 153.8 (C), 142.8 (C), 141.5 (CH),
136.9 (C), 131.3 (CH), 130.8 (CH), 128.2 (CH), 127.3 (C), 126.6
(CH), 120.3 (C), 110.2 (CH), 107.7 (CH), 85.5 (CH), 60.2 (CH),
38.4 (CH2), 36.8 (CH2), 19.0 (CH2), 14.0 (Me); m/z (CI) 416/414
(MHϩ, 23%), 336 (5), 268 (26), 266 (40), 264 (12), 188 (12), 168
(16), 150 (100), 133 (2), 108 (6), 96 (56), 91 (2).
᎐
3
(5 H, m, ArH), 7.02 (2 H, br s, ArH), 5.20 (1 H, t, J 6.9, OCH),
2.32 (3 H, s, Me), 2.27 (3 H, s, Me), 2.02 (1 H, m, CHH), 1.80
(1 H, m, CHH ), 1.44 (2 H, m, CH2), 0.95 (3 H, t, J 7.4, Me);
δC (75 MHz; CDCl3) 147.7 (CH), 142.4 (C), 135.5 (C), 133.6
(C), 131.8 (C), 130.6 (CH), 130.3 (CH), 128.2 (CH), 127.3 (CH),
127.2 (CH), 126.8 (CH), 85.4 (CH), 38.3 (CH2), 20.9 (Me), 19.4
(Me), 18.9 (CH2), 14.0 (Me); m/z (FAB) 282 (MHϩ, 19%), 281
(100), 280 (32), 150 (54), 148 (11), 133 (100), 132 (19), 115 (7),
105 (15).
(E )-(S )-(؊)-O-(1-Phenylbutyl)-3-fluoro-2-methylbenzalde-
hyde oxime 2m. Obtained from the condensation of (S)-O-(1-
phenylbutyl)hydroxylamine with 3-fluoro-2-methylbenzalde-
hyde as a colourless oil (94%); [α]2D3 Ϫ49.5 (c 1.07, CHCl3);
(Found: C, 75.7; H, 7.2; N, 4.8. C18H20FNO requires C, 75.8; H,
7.1; N, 4.9%); νmax(film)/cmϪ1 3057, 2950, 2929, 2873, 1567,
(2R,1ЈS )-(؊)-N-(1-Phenylbutoxy)-2-(2-furyl)-3-methyl-2-
butylamine 3b. Obtained from the addition of furyllithium to
(S)-O-(1-phenylbutyl)-3-methylbutan-2-one oxime 2i(S) as a
colourless oil (31%, 52% de); [α]2D4 Ϫ31.9 (c 1.22, CHCl3);
1449, 1239, 1019, 947; δH (300 MHz; CDCl ) 8.35 (1 H, s, N᎐
᎐
3
CH), 7.32 (6 H, s, ArH), 7.08 (1 H, m, ArH), 6.98 (1 H, m,
ArH), 5.19 (1 H, t, J 6.9, OCH), 2.26 (3 H, d, J 2.0, Me), 2.02
(1 H, m, CHH), 1.80 (1 H, m, CHH ), 1.56–1.32 (2 H, m, CH2),
0.95 (3 H, t, J 7.4, Me); δC (75 MHz; CDCl3) 161.3 (CF, d, JCF
241.6), 146.7 (CH, d, JCF 4.0), 142.2 (C), 132.8 (C, d, JCF 4.7),
128.3 (CH), 127.5 (CH), 126.9 (CH), 126.7 (CH, d, JCF 8.9),
123.8 (C, d, JCF 17.4), 122.6 (CH, d, JCF 3.3), 115.8 (CH, d, JCF
23.3), 85.7 (CH), 38.1 (CH2), 18.9 (CH2), 14.0 (Me), 10.7 (Me,
d, JCF 4.0); m/z (CI) 286 (MHϩ, 14%), 266 (6), 182 (21), 155 (8),
154 (100), 133 (88), 91 (32).
(Found: Mϩ, 285.2096. C19H27NO requires 285.2093); νmax
-
(film)/cmϪ1 3032, 2960, 2934, 2868, 1454, 1362, 1152, 1014, 912,
702; δH (300 MHz; CDCl3) 7.37–7.25 (6 H, m, ArH, fur-H5),
6.33 (1 H, dd, J 1.7, 3.3, fur-H4), 6.19 (1 H, m, fur-H3), 5.38
(1 H, br s, NH), 4.43 (1 H, dd, J 5.6, 7.8, OCH), 2.24 (1 H,
heptet, J 6.9, CH(Me)2), 1.69 (1 H, m, CHH), 1.47 (1 H, m,
CHH ), 1.33 (3 H, s, Me), 1.30 (1 H, m, CHH), 1.20 (1 H, m,
CHH ), 0.89 (3 H, d, J 8.8, Me), 0.85 (3 H, m, Me), 0.77 (3 H, d,
J 8.8, Me); δC (75 MHz; CDCl3) 158.2 (C), 143.5 (C), 140.6
(CH), 128.1 (CH), 127.0 (CH), 126.5 (CH), 109.8 (CH), 106.8
(CH), 85.0 (CH), 63.1 (C), 38.9 (CH2), 33.0 (CH), 18.9 (CH2),
17.9 (Me), 17.1 (Me), 16.9 (Me), 14.1 (Me); m/z (EI) 285 (Mϩ,
4%), 279 (7), 263 (18), 256 (26), 234 (100), 230 (22), 219 (32),
218 (69), 213 (18), 204 (94).
(E )-(S )-(؊)-O-(1-Phenylbutyl)acetophenone oxime 2n.
Prepared as described previously.18
(E )-(S )-(؊)-O-(1-Phenylbutyl)-4-bromoacetophenone oxime
2o. Obtained from the condensation of (S)-O-(1-phenylbutyl)-
hydroxylamine with 4-bromoacetophenone as a pale yellow oil
(30%); [α]2D4 Ϫ74.7 (c 1.62, CDCl3); (Found: MHϩ, 346.0811.
C18H2079BrNO ϩ H requires 346.0807); νmax(film)/cmϪ1 3037,
2955, 2934, 2868, 1608, 1480, 1454, 1316, 1004, 922, 814, 691;
δH (300 MHz; CDCl3) 7.45–7.22 (9 H, m, ArH), 5.22 (1 H, dd,
J 6.3, 7.1 OCH), 2.27 (3 H, s, Me), 2.01 (1 H, m, CHH), 1.81 (1
H, s, CHH ), 1.42 (2 H, m, CH2), 0.96 (3 H, t, J 7.4, Me); δC (75
MHz; CDCl3) 153.2 (C), 142.8 (C), 135.7 (C), 131.3 (CH), 128.2
(CH), 127.6 (CH), 127.2 (CH), 126.6 (CH), 123.1 (C), 85.5
(CH), 38.5 (CH2), 18.9 (CH2), 14.1 (Me), 12.6 (Me); m/z (CI)
346/344 (MHϩ, 100%), 269 (10), 268 (51), 200 (42), 168 (6), 166
(11), 150 (49), 120 (32), 108 (12), 91 (4), 52 (18).
(1R,1ЈS )-(؉)-N-(1-Phenylbutoxy)-1-(4-bromophenyl)-1-
(2-furyl)ethylamine 3c. Obtained from the addition of furyl-
lithium to (S)-O-(1-phenylbutyl)-4-bromoacetophenone oxime
2o as a colourless oil (14%, ∼95% de); [α]2D0 ϩ20.5 (c 1.22,
CHCl3); (Found: MHϩ, 414.1068. C22H2479BrNO2 ϩ H requires
414.1069); νmax(film)/cmϪ1 2960, 2924, 2868, 1495, 1449, 1070,
1014, 819, 697; δH (300 MHz; CDCl3) 7.40–7.19 (10 H, m, ArH,
fur-H5), 6.36 (1 H, dd, J 2.1, 3.3, fur-H4), 6.30 (1 H, d, J 3.3,
fur-H3), 5.65 (1 H, br s, NH), 4.49 (1 H, dd, J 5.9, 7.8, OCH),
1.71 (3 H, s, Me), 1.68 (1 H, m, CHH), 1.48 (1 H, m, CHH ),
1.28 (1 H, m, CHH), 1.12 (1 H, m, CHH ), 0.81 (3 H, t, J 7.3,
Me); δC (75 MHz; CDCl3) 157.3 (C), 148.2 (C), 142.8 (CH),
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 6 5 – 2 7 6
270

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141.5 (C), 131.0 (CH), 128.6 (CH), 128.2 (CH), 127.2 (CH),
126.7 (CH), 121.1 (C), 110.1 (CH), 107.8 (CH), 85.4 (CH), 63.1
(C), 38.4 (CH2), 24.5 (Me), 18.9 (CH2), 14.0 (Me); m/z (CI) 414/
412 (MHϩ, 0.1%), 245 (4), 244 (7), 242 (19), 215 (94), 213 (100),
197 (72), 196 (34), 183 (24), 133 (65), 120 (5), 107(15), 91 (15).
[α]2D6 Ϫ90.5 (c 0.74, CHCl3); (Found: MHϩ, 248.2017. C16H25NO
ϩ H requires 248.2014); νmax(film)/cmϪ1 3257, 3083, 3063, 3022,
2955, 2930, 2868, 1455, 1373, 1358, 1107, 1061, 1030, 994, 912,
758, 697; δH (300 MHz; CDCl3) 7.30 (5 H, m, ArH), 5.76 (1 H,
ddd, J 17.5, 10.3, 8.1, ᎐CH), 5.21 (3 H, m, NH, ᎐CH ), 4.55
᎐
᎐
2
(1 H, dd, J 7.7, 6.0, OCH), 3.35 (1 H, br q, J 6.7, NCH), 1.78
(1 H, m, CHH), 1.58–1.15 (7 H, m, CHH, 3 × CH2), 0.89 (3 H,
t, J 8.6, Me), 0.85 (3 H, t, J 7.1, Me); δC (75 MHz; CDCl3) 143.3
(C), 139.8 (CH), 128.3 (CH), 127.2 (CH), 126.6 (CH), 116.4
(CH2), 85.5 (CH), 64.2 (CH), 38.7 (CH2), 33.9 (CH2), 19.1
(CH2), 19.0 (CH2), 14.1 (Me), 14.0 (Me); m/z (CI) 248 (MHϩ,
53%), 236 (13), 149 (36), 133 (100), 116 (16), 107 (23), 98 (9), 91
(12).
Additions of phenyllithium
Phenyllithium was used as commercially supplied in cyclo-
hexane–ether.
(1R,1ЈS )-(؊)-N-(1-Phenylbutoxy)-2-methyl-1-phenylpropyl-
amine 3d. Obtained from the addition of phenyllithium to
(S)-O-(1-phenylbutyl)isobutyraldehyde oxime 2b as a colour-
less oil (38%, 95% de); [α]2D2 Ϫ64.9 (c 1.17, CHCl3); (Found:
MHϩ, 298.2171. C20H27NO ϩ H requires 298.2171); νmax(film)/
cmϪ1 3027, 2960, 1495, 1454, 1362, 1024, 753; δH (300 MHz;
CDCl3) 7.40–7.24 (10 H, m, ArH), 5.59 (1 H, d, J 7.7, NH), 4.34
(1 H, dd, J 5.3, 8.3, OCH), 3.72 (1 H, d, J 7.7, CH), 1.85 (1 H,
heptet, J 6.8, CH(Me)2), 1.56 (1 H, m, CHH), 1.33 (1 H, m,
CHH ), 1.09 (1 H, m, CHH), 0.90 (3 H, d, J 6.7, Me), 0.85 (1 H,
m, CHH ), 0.67 (3 H, d, J 6.7, Me), 0.67 (3 H, t, J 7.3, Me);
δC (100 MHz; CDCl3) 143.6 (C), 141.7 (C), 128.4 (CH), 128.2
(CH), 127.7 (CH), 127.1 (CH), 126.8 (CH), 126.5 (CH), 85.1
(CH), 71.9 (CH), 38.7 (CH2), 31.0 (CH), 20.0 (Me), 19.3 (Me),
18.7 (CH2), 13.8 (Me); m/z (CI) 298 (MHϩ, 34%), 166 (5), 150
(100), 133 (4), 106 (10), 72 (1).
(3R,1ЈS )-(؊)-N-(1-Phenylbutoxy)-3-hepta-1,6-dienylamine
3h. Obtained from the addition of vinyllithium to (S)-O-(1-
phenylbutyl)pent-4-enaldehyde oxime 2c as a colourless oil
(77%, 94% de); [α]2D6 Ϫ83.5 (c 0.85, CHCl3); (Found: MHϩ,
260.2012. C17H25NO ϩ H requires 260.2014); νmax(film)/cmϪ1
3257, 3078, 3027, 2955, 2925, 2863, 1690, 1644, 1598, 1501,
1450, 1358, 1301, 1199, 1107, 1061, 1030, 994, 907, 758, 697;
δH (300 MHz; CDCl3) 7.29 (5 H, m, ArH), 5.75 (2 H, m, 2 ×
᎐CH), 5.17 (2 H, m, ᎐CH ), 4.95 (2 H, m, ᎐CH ), 4.54 (1 H, dd,
᎐
᎐
᎐
2
2
J 7.5, 5.9, OCH), 3.36 (1 H, q, J 7.2, NCH), 2.02 (2 H, m, CH2),
1.77 (1 H, m, CHH), 1.60–1.19 (5 H, m, CHH, 2 × CH2), 0.89
(3 H, t, J 7.2, Me), NH signal not observed; δC (75 MHz;
CDCl3) 143.2 (C), 139.4 (CH), 138.2 (CH), 128.3 (CH), 127.3
(CH), 126.6 (CH), 116.8 (CH2), 114.7 (CH2), 85.5 (CH), 63.8
(CH), 38.7 (CH2), 30.9 (CH2), 30.0 (CH2), 19.2 (CH2), 14.1
(Me); m/z (CI) 260 (MHϩ, 95%), 215 (50), 169 (18), 128 (100).
(1R,1ЈS )-(؊)-N-(1-Phenylbutoxy)-2,2-dimethyl-1-phenyl-
propylamine 3e. Obtained from the addition of phenyllithium to
(S)-O-(1-phenylbutyl)pivaldehyde oxime 2d as a colourless
solid (31%, >98% de); mp 39–40 ЊC; [α]2D4 Ϫ67.1 (c 1.46, CHCl3);
(Found: MHϩ, 312.2322. C21H29NO ϩ H requires 312.2327);
νmax(Nujol)/cmϪ1 3027, 2955, 2863, 1449, 1362, 1050, 1004, 697;
δH (300 MHz; CDCl3) 7.45–7.28 (10 H, m, ArH), 5.74 (1 H, s,
NH), 4.41 (1 H, dd, J 5.0, 8.9, OCH), 3.82 (1 H, s, CH), 1.49
(1 H, m, CHH), 1.31 (1 H, m, CHH ), 0.86 (2 H, m, CH2), 0.86
(9 H, s, 3 × Me), 0.61 (3 H, t, J 7.4, Me); δC (100 MHz; CDCl3)
143.8 (C), 141.1 (C), 129.2 (CH), 128.2 (CH), 127.2 (CH), 127.1
(CH), 126.7 (CH), 126.5 (CH), 85.2 (CH), 74.5 (CH), 38.7
(CH2), 33.6 (C), 27.2 (Me), 18.6 (CH2), 13.7 (Me); m/z (CI) 312
(MHϩ, 1%), 254 (37), 133 (41), 121 (99), 90 (98), 76 (44).
(1S,1ЈS )-(؊)-N-(1-Phenylbutoxy)-1-cyclohexylprop-2-enyl-
amine 3i. Obtained from the addition of vinyllithium to (S)-O-
(1-phenylbutyl)cyclohexanecarboxaldehyde oxime 2f as
a
colourless oil (74%, 92% de); [α]2D7 Ϫ72.3 (c 0.83, CHCl3);
(Found: Mϩ, 287.2248. C19H29NO requires 287.2249);
νmax(film)/cmϪ1 3263, 3064, 3030, 2958, 2926, 2853, 1494, 1451,
1106, 1061, 1028, 996, 916, 760, 700; δH (300 MHz; CDCl3) 7.29
(5 H, m, ArH), 5.76 (1 H, ddd, J 17.0, 10.7, 8.7, ᎐CH), 5.28
᎐
(1 H, br s, NH) 5.13 (2 H, m, ᎐CH ), 4.53 (1 H, dd, J 7.7, 5.8,
᎐
2
OCH), 3.12 (1 H, dd, J 8.7, 6.6, NCH), 1.84–0.89 (15 H, m, CH,
7 × CH2), 0.88 (3 H, t, J 7.2, Me); δC (75 MHz; CDCl3) 143.4
(C), 138.2 (CH), 128.2 (CH), 127.2 (CH), 126.7 (CH), 117.2
(CH2), 85.3 (CH), 69.6 (CH), 39.0 (CH), 38.7 (CH2), 30.0
(CH2), 28.9 (CH2), 26.5 (CH2), 26.23 (CH2), 26.20 (CH2), 19.2
(CH2), 14.1 (Me); m/z (FI) 287 (Mϩ, 100%), 202 (21), 133 (8).
(1R,1ЈS )-(؊)-N-(1-Phenylbutoxy)-2,2-dimethyl-1-phenyl-
butylamine 3f. Obtained from the addition of phenyllithium to
(S)-O-(1-phenylbutyl)-2,2-dimethylbutyraldehyde oxime 2e as
a colourless oil (32%, >98% de); [α]2D1 Ϫ55.2 (c 1.05, CHCl3);
(Found: MHϩ, 326.2491. C22H31NO ϩ H requires 326.2484);
νmax(film)/cmϪ1 3021, 2960, 2868, 1598, 1490, 1449, 1362, 1301,
1198, 1024, 906, 697; δH (300 MHz; CDCl3) 7.39–7.26 (10 H, m,
ArH), 5.73 (1 H, s, NH), 4.40 (1 H, dd, J 4.9, 8.8, OCH), 3.89
(1 H, s, HCNH), 1.47 (1 H, m, CHH), 1.24 (1 H, m, CHH ),
1.21 (2 H, m, CH2), 0.95 (2 H, m, CH2) 0.84 (3 H, t, J 7.4, Me),
0.82 (3 H, s, Me), 0.76 (3 H, s, Me), 0.63 (3 H, t, J 7.2, Me);
δC (75 MHz; CDCl3) 143.8 (C), 140.9 (C), 129.3 (CH), 128.2
(CH), 127.1 (CH), 127.1 (CH), 126.6 (CH), 126.4 (CH), 85.1
(CH), 72.7 (CH), 38.7 (CH2), 36.2 (C), 31.9 (CH2), 23.7 (Me),
23.6 (Me), 18.6 (CH2), 13.7 (Me), 8.0 (Me); m/z (CI) 326 (MHϩ,
30%), 254 (100), 194 (15), 176 (36), 161 (65), 133 (93), 122 (75),
105 (52), 91 (25).
(3S,1ЈR)-(؉)-N-(1-Phenylbutoxy)-9-ethyl-3-deca-1,9-dienyl-
amine 3j. Obtained from the addition of vinyllithium to
(E)-(R)-O-(1-phenylbutyl)-7-ethyloct-7-enaldehyde oxime 2g as
a colourless oil (76%, >95% de); [α]2D5 ϩ72.3 (c 1.01, CHCl3);
(Found: MHϩ, 330.2792. C22H35NO ϩ H requires 330.2797);
νmax(film)/cmϪ1 3258, 3078, 3022, 2960, 2925, 2873, 2848, 1639,
1491, 1455, 1358, 1102, 1061, 1030, 989, 912, 886, 758, 697;
δH (300 MHz; CDCl3) 7.30 (5 H, m, ArH), 5.76 (1 H, ddd,
J 17.3, 10.2, 7.9, ᎐CH), 5.15 (3 H, m, NH, ᎐CH ), 4.67 (2 H, m,
᎐
᎐
2
᎐CH2), 4.54 (1 H, dd, J 7.5, 5.8, OCH), 3.33 (1 H, q, J 6.9,
᎐
NCH), 1.97 (4 H, m, 2 × CH2), 1.78 (1 H, m, CHH), 1.59–1.14
(11 H, m, CHH, 5 × CH2), 1.01 (3 H, t, J 7.4, Me), 0.89 (3 H, t,
J 7.3, Me); δC (75 MHz; CDCl3) 151.7 (C), 143.3 (C), 139.8
(CH), 128.3 (CH), 127.3 (CH), 126.6 (CH), 116.5 (CH2), 107.4
(CH2), 85.5 (CH), 64.4 (CH), 38.7 (CH2), 36.2 (CH2), 31.7
(CH2), 29.3 (CH2), 28.7 (CH2), 27.6 (CH2), 25.7 (CH2), 19.2
(CH2), 14.1 (Me), 12.4 (Me); m/z (CI) 330 (MHϩ, 100%), 198
(11), 180 (8), 133 (9).
Addition of vinyllithium
Vinyllithium was prepared in ether by transmetallation of
tetravinyltin using methyllithium according to the literature
procedure.35 The additions of vinyllithium were carried out at
Ϫ90 ЊC.
(3S,1ЈR)-(؉)-N-(1-Phenylbutoxy)-3,4-dimethyl-3-pent-1-
enylamine 3k. Obtained from the addition of vinyllithium to
(R)-3-O-(1-phenylbutyl)-3-methylbutan-2-one oxime 2i(R) as a
colourless oil (54%, >95% de); [α]2D6 ϩ117.3 (c 0.81, CHCl3);
(3R,1ЈS )-(؊)-N-(1-Phenylbutoxy)-3-hex-1-enylamine 3g.
Obtained from the addition of vinyllithium to (S)-O-(1-phenyl-
butyl)butyraldehyde oxime 2a as a colourless oil (87%, 84% de);
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 6 5 – 2 7 6
271

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(Found: C, 78.5; H, 10.9; N, 5.3. C17H27NO requires C, 78.1; H,
10.4; N, 5.3%); νmax(film)/cmϪ1 2960, 2924, 2873, 1449, 1362,
922, 702; δH (300 MHz; CDCl3) 7.30 (5 H, m, ArH), 5.93 (1 H,
aldehyde oxime 2m as a yellow oil, (10%, 95% de); [α]2D6 ϩ30.3
(c 0.89, CDCl3); (Found: MHϩ, 314.1891. C20H24FNO ϩ H
requires 314.1920); νmax(film)/cmϪ1 3032, 2955, 2924, 2873,
1582, 1465, 1239, 917, 789, 697; δH (400 MHz; CHCl3) 7.31–
7.24 (5 H, m, ArH), 7.03 (2 H, m, ArH), 7.02 (1 H, m, ArH),
dd, J 17.7, 11.1, ᎐CH), 5.11 (1 H, dd, J 11.1, 1.3, ᎐CHH), 5.05
᎐
᎐
(1 H, dd, J 17.7, 1.3, ᎐CHH ), 5.04 (1 H, br, NH), 4.55 (1 H, dd,
᎐
J 7.9, 5.5, OCH), 1.93 (1 H, heptet, J 6.9, CHMe2), 1.76 (1 H,
m, CHH), 1.62–1.21 (3 H, m, CHH, CH2), 1.06 (3 H, s, CMe),
0.89 (6 H, m, CHMe2), 0.80 (3 H, d, J 6.9, Me); δC (75 MHz;
CDCl3) 143.6 (C), 142.0 (CH), 128.2 (CH), 127.1 (CH), 126.5
(CH), 113.9 (CH2), 85.2 (CH), 63.7 (C), 39.0 (CH2), 32.4 (CH),
19.2 (CH2), 17.5 (Me), 17.4 (Me), 17.1 (Me), 14.1 (Me); m/z (FI)
262 (MHϩ, 24%), 261 (100), 202 (8), 97 (8).
6.00 (1 H, ddd, J 6.8, 13.5, 17.1, CH᎐CH ), 5.35 (1 H, br s, NH),
᎐
2
5.23 (2 H, m, CH᎐CH ), 4.78 (1 H, d, J 6.8, NHCH ), 4.58 (1 H,
᎐
2
dd, J 6.2, 7.6, OCH), 2.16 (3 H, d, J 2.1, Me), 1.78 (1 H, m,
CHH), 1.55 (1 H, m, CHH ), 1.37 (1 H, m, CHH), 1.26 (1 H, m,
CHH ), 0.92 (3 H, t, J 7.3, Me); δC (100 MHz; CDCl3) 161.3
(CF, d, JCF 241.8), 142.9 (C), 140.1 (C), 137.6 (CH), 128.2 (CH),
127.3 (CH), 126.6 (CH, d, JCF 4.7), 126.5 (CH, d, JCF 2.8), 123.3
(C), 122.7 (CH, d, JCF 3.1), 117.1 (CH2), 113.9 (C, d, JCF 23.2),
85.5 (CH), 63.8 (CH, d, JCF 2.6), 38.4 (CH2), 18.8 (CH2), 14.0
(Me), 10.0 (Me, d, JCF 6.1); m/z (CI) 312 (M ϩ NH4ϩ, 4%), 223
(3), 222 (12), 210 (4), 182 (23), 164 (19), 149 (100), 133 (100),
132 (24), 91 (20).
(1S,1ЈS )-(؊)-N-(1-Phenylbutoxy)-3-phenyl-3-prop-1-enyl-
amine 3l. Obtained from the addition of vinyllithium to (S)-O-
(1-phenylbutyl)benzaldehyde oxime 2j as a colourless oil (46%,
98% de); [α]2D6 Ϫ56.8 (c 0.54, CHCl3); (Found: C, 81.4; H, 8.6; N,
4.7. C19H23NO requires C, 81.1; H, 8.2; N, 5.0%); νmax(film)/
cmϪ1 3027, 2950, 2934, 2868, 1490, 1460, 917, 753, 697; δH (300
MHz; CDCl3) 7.42–7.25 (10 H, m, ArH), 6.11 (1 H, ddd, J 7.1,
(2S,1ЈS )-(؊)-N-(1-Phenylbutoxy)-2-phenyl-2-but-3-enyl-
amine 3p. Obtained from the addition of vinyllithium to (S)-O-
(1-phenylbutyl)acetophenone oxime2n as a colourless oil (10%,
64% de); [α]2D6 Ϫ5.3 (c 4.73, CHCl3); (Found: MHϩ, 296.2016.
C20H25NO ϩ H requires 296.2014); νmax(film)/cmϪ1 3411, 2960,
2924, 2852, 1603, 1454, 1372, 1029; δH (300 MHz; CDCl3) 7.33–
J 10.1, J 17.3, HC᎐CH ), 5.40 (1 H, s, NH), 5.25 (2 H, m,
᎐
2
CH᎐CH ), 4.62 (2 H, m, OCH, NCH), 1.81 (1 H, m, CHH),
᎐
2
1.57 (1 H, m, CHH ), 1.37 (2 H, m, CH2), 0.91 (3 H, t, J 7.2,
Me); δC (75 MHz; CDCl3) 143.0 (C), 139.8 (C), 138.6 (CH),
128.4 (CH), 128.0 (CH), 127.9 (CH), 127.6 (CH), 127.3 (CH),
126.7 (CH), 116.8 (CH2), 85.4 (CH), 68.2 (CH), 38.5 (CH2),
19.1 (CH2), 14.0 (Me); m/z (FI) 281 (Mϩ, 100%), 191 (13), 148
(93), 133 (18).
7.25 (10 H, m, ArH), 6.33 (1 H, dd, J 10.8, 17.6, CH᎐CH ), 5.25
᎐
2
(1 H, br s, NH), 5.20 (2 H, ddd, J 1.1, 10.8, 23.3, CH᎐CH ), 4.54
᎐
2
(1 H, dd, J 5.7, 8.0, OCH), 1.47 (3 H, s, Me), 1.44 (1 H, m,
CHH), 1.25 (1 H, m, CHH ), 0.93 (2 H, m, CH2), 0.88 (3 H, t,
J 7.2, Me); δC (75 MHz; CDCl3) 149.4 (C), 143.0 (CH), 135.5
(C), 128.2 (CH), 127.8 (CH), 127.1 (CH), 126.7 (CH), 126.7
(CH), 126.4 (CH), 114.0 (CH2), 85.3 (CH), 64.3 (C), 38.7 (CH2),
28.2 (Me), 18.8 (CH2), 14.1 (Me); m/z (CI) 296 (MHϩ, 33%),
268 (15), 226 (7), 164 (10), 163 (19), 133 (73), 131 (100), 91 (54).
(1R,1ЈR)-(؉)-N-(1-Phenylbutoxy)-1-(4-methoxyphenyl)-1-
prop-2-enylamine 3m. Obtained from the addition of vinyl-
lithium to (R)-O-(1-phenylbutyl)-4-methoxybenzaldehyde
oxime 2k as a colourless oil (50%, 91% de); [α]2D7 ϩ36.1 (c 0.83,
CHCl3); (Found: C, 77.5; H, 8.5; N, 4.4. C20H25NO2 requires C,
77.1; H, 8.1; N, 4.5%); (Found: MHϩ, 312.1971. C20H25NO2 ϩ
H requires 312.1963); νmax(film)/cmϪ1 3257, 3063, 3030, 2958,
2933, 2872, 2836, 1610, 1512, 1454, 1303, 1247, 1176, 1036, 918,
828, 760, 700; δH (300 MHz; CDCl3) 7.26 (5 H, m, ArH), 7.15
(2 H, m, ArH), 6.79 (2 H, m, ArH), 6.07 (1 H, ddd, J 17.3, 10.2,
General method for the cleavage of the N–O bond and
preparation of N-protected amines
Zinc dust (2.61 g, 40 mmol) was added to a mixture of the
hydroxylamine (1 mmol) in acetic acid : water (1 : 1; 6.5 mL).
The mixture was placed in a sonic bath at 40 ЊC and the reaction
followed by TLC until completion (typically 2–6 h). The zinc
was filtered and washed with ether. The filtrate was basified
with sodium hydrogen carbonate solution (sat.) and the aque-
ous layer was extracted with dichloromethane (8 × 15 mL). The
extracts were combined, dried (MgSO4), filtered and evapor-
ated. The residue was dissolved in dichloromethane (7 mL) and
treated with:
(i) di-tert-butyl dicarbonate (0.87 g, 4 mmol) and DMAP
(cat.) and stirred for 12 h,
or (ii) sodium carbonate (0.21 g, 2 mmol) was added to the
residue dissolved in THF : water (1 : 1; 10 mL), cooled to 0 ЊC
and treated with benzyl chloroformate. The mixture was
warmed to room temperature and stirred for 12 h,
7.0, ᎐CH), 5.35–5.15 (3 H, m, NH, ᎐CH ), 4.58 (1 H, dd, J 7.7,
᎐
᎐
2
6.0, OCH), 4.49 (1 H, d, J 7.0, NCH), 3.75 (3 H, s, OMe), 1.79
(1 H, m, CHH), 1.60–1.16 (3 H, m, CHH, CH2), 0.88 (3 H, t,
J 7.3, CH2Me); δC (75 MHz; CDCl3) 159.3 (C), 143.3 (C), 139.1
(CH), 132.2 (C), 129.3 (CH), 128.5 (CH), 127.5 (CH), 126.9
(CH), 116.7 (CH2), 114.0 (CH), 85.7 (CH), 67.8 (CH), 55.5
(Me), 38.8 (CH2), 19.4 (CH2), 14.3 (Me); m/z (CI) 312 (MHϩ,
6%), 204 (4), 180 (12), 162 (17), 147 (100), 133 (15), 91 (8).
(1S,1ЈS )-(؊)-N-(1-Phenylbutoxy)-3-(2,5-dimethylphenyl)-3-
prop-1-enylamine 3n. Obtained from the addition of vinyl-
lithium to (S)-O-(1-phenylbutyl)-2,5-dimethylbenzaldehyde
oxime 2l as a yellow oil (16%, 95% de); [α]2D6 Ϫ43.1 (c 1.16,
CHCl3); (Found: MHϩ, 310.2163. C21H27NO ϩ H requires
310.2171); νmax(film)/cmϪ1 3431, 3027, 2955, 2919, 1613, 1454,
968; δH (400 MHz; CDCl3) 7.35–7.03 (8 H, m, ArH), 6.79 (1 H,
or (iii) the residue was dissolved in anhydrous pyridine
(10 mL) and treated with excess acetic anhydride and stirred for
12 h.
br s, NH), 6.56 (1 H, dd, J 10.6, 17.5, CH᎐CH ), 5.34 (1 H, dd,
᎐
2
The mixture was extracted with dichloromethane (4 ×
10 mL), combined, dried (MgSO4), filtered and evaporated. The
residue was purified by flash chromatography to give the
Boc-, Cbz and acetyl-protected amines. The enantiomeric
purity of the protected amines was determined by HPLC on a
chiral stationary phase, typically ChiralPak AD with hexane–
isopropanol (99 : 1) as eluant, by comparison with the
independently synthesized racemate.
J 0.9, 10.6, CH᎐CHH), 5.19 (1 H, m, NHCH ), 5.08 (1 H, t,
᎐
J 6.8, OCH), 4.94 (1 H, dd, J 0.9, 17.5, CH᎐CHH ), 2.33 (3 H, s,
᎐
Me), 1.78 (1 H, m, CHH), 1.58 (1 H, m, CHH ), 1.42 (3 H, s,
Me), 0.94 (2 H, m, CH2), 0.84 (3 H, t, J 7.3, Me); δC (100 MHz;
CDCl3) 134.5 (C), 134.2 (CH), 132.0 (C), 130.7 (C), 129.4 (CH),
128.8 (CH), 128.2 (CH), 128.0 (CH), 127.0 (CH), 126.6 (C),
126.4 (CH), 122.9 (CH2), 85.4 (CH), 30.9 (CH), 26.9 (CH2),
20.9 (Me), 18.88 (Me), 18.83 (CH2), 13.9 (Me); m/z (CI) 310
(MHϩ, 0.1%), 290 (6), 204 (12), 177 (13), 176 (100), 158 (23),
133 (90), 132 (11), 107 (4), 96 (26).
(S )-(؊)-N-(tert-Butoxycarbonyl)-1-(4-bromophenyl)-1-
(2-furyl)ethylamine 4a. Obtained by the zinc mediated N–O
bond cleavage and subsequent N-protection of hydroxylamine
3a as a colourless oil (72% over two steps, 83% ee); [α]2D4 Ϫ5.9
(c 1.07, CHCl3); (Found: MHϩ, 366.0712. C17H2079BrNO3 ϩ H
(1S,1ЈS )-(؉)-N-(1-Phenylbutoxy)-3-(3-fluoro-2-methyl-
phenyl)-3-prop-1-enylamine 3o. Obtained from the addition of
vinyllithium to (S)-O-(1-phenylbutyl) 3-fluoro-2-methylbenz-
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 6 5 – 2 7 6
272

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requires 366.0706); νmax(film)/cmϪ1 3359, 2979, 1678, 1519,
1365, 1250, 1167, 1009, 810, 735; δH (300 MHz; CDCl3) 7.36
(1 H, d, J 1.4, fur-H5), 7.34 (2 H, d, J 8.2, ArH), 6.89 (2 H, d,
J 8.2, ArH), 6.26 (1 H, dd, J 1.4, 3.2, fur-H4), 6.01 (1 H, d,
J 3.2, fur-H3), 4.98 (1 H, br s, NH), 4.80 (1 H, m, NHCH ), 3.06
(2 H, d, J 6.8, ArCH2), 1.41 (9 H, s, 3 × Me); δC (75 MHz;
CDCl3) 154.8 (C), 153.4 (C), 141.7 (CH), 136.1 (C), 131.3 (CH),
131.0 (CH), 120.4 (C), 110.2 (CH), 106.6 (CH), 53.3 (CH), 49.8
(C), 40.1 (CH2), 28.3 (Me); m/z (ES) 356/354 (MHϩ, 40%), 282
(30), 281 (100), 267 (32), 265 (18), 225 (6), 222 (11), 221 (67), 73
(68), 55(42).
Me); δC (75 MHz; CDCl3) 155.9 (C), 138.9 (CH), 136.7 (C),
128.4 (CH), 127.94 (CH), 127.89 (CH), 114.3 (CH2), 66.4
(CH2), 53.1 (CH), 37.0 (CH2), 18.9 (CH2), 13.8 (Me); m/z (CI)
234 (MHϩ, 10%), 190 (12), 173 (6), 152 (19), 146 (7), 119 (7), 91
(100).
(R)-(؊)-N-Benzyloxycarbonyl-3-hepta-1,6-dienylamine
4f.
Obtained from cleavage of the N–O bond of hydroxylamine 3h
and subsequent protection. The crude product was purified by
column chromatography on silica gel, eluting with ether–light
petroleum (1 : 4) to give the pure product as a colourless solid
(53% over two steps); mp 36–38 ЊC; [α]2D6 Ϫ8.4 (c 0.83, CHCl3);
(Found:Mϩ,245.1431.C15H19NO2 requires245.1416);νmax(KBr)/
cmϪ1 3319, 3078, 3032, 2981, 2930, 2848, 1685, 1639, 1532,
1450, 1296, 1255, 1071, 989, 912, 753, 697; δH (300 MHz;
(R)-(؉)-N-Acetyl-2-methyl-1-phenylpropylamine 4b.
Obtained by the zinc mediated N–O bond cleavage and sub-
sequent N-protection of hydroxylamine 3d as a colourless solid
(38% over two steps, 98% ee); mp 135–136 ЊC (lit.,39 mp 120 ЊC;
lit.,40 mp 119–120 ЊC); [α]2D4 ϩ105.5 (c 1.1, CHCl3) (lit.,39
[α]2D0 ϩ135 (c 3.8, MeOH); lit.,40 [α]D ϩ72.3 (c 3.8, MeOH));
(Found: MHϩ, 192.1388. C12H17NO ϩ H requires 192.1388);
νmax(Nujol)/cmϪ1 3426, 3272, 3078, 2960, 2924, 1649, 1557,
1454, 702; δH (300 MHz; CDCl3) 7.36–7.20 (5 H, m, ArH), 5.85
(1 H, m, NH), 4.76 (1 H, t, J 8.5, CH), 2.00 (4 H, m, MeCO,
CH(Me)2), 0.97 (3 H, d, J 6.6, Me), 0.83 (3 H, d, J 6.6, Me);
δC (75 MHz; CDCl3) 169.3 (C), 141.6 (C), 128.5 (CH), 127.1
(CH), 126.9 (CH), 59.1 (CH), 33.4 (Me), 23.5 (CH), 19.7 (Me),
18.8 (Me); m/z (CI) 192 (MHϩ, 100%), 148 (6), 141 (18), 108 (2),
106 (7), 94 (2), 77 (13), 72 (3).
CDCl ) 7.35 (5 H, m, ArH), 5.89–5.68 (2 H, m, 2 × ᎐CH), 5.22–
᎐
3
4.94 (6 H, m, CH Ph, 2 × ᎐CH ), 4.70 (1 H, br d, J 5.7, NH),
᎐
2
2
4.20 (1 H, br m, NCH), 2.11 (2 H, q, J 7.4, CH2), 1.60 (2 H, m,
CH2); δC (75 MHz; CDCl3) 156.0 (C), 138.6 (C), 137.8 (CH),
136.7 (CH), 128.7 (CH), 128.3 (CH), 115.4 (CH2), 115.1 (CH2),
66.8 (CH2), 53.1 (CH), 34.3 (CH2), 30.1 (CH2), one ArCH not
observed; m/z (EI) 245 (Mϩ, 16%), 216 (27), 204 (54), 201 (19),
172 (22), 154 (32), 147 (25), 110 (21), 100 (12), 91 (100).
(S )-(؊)-N-Benzyloxycarbonyl-1-cyclohexylprop-2-enylamine
4g. Obtained from cleavage of the N–O bond of hydroxylamine
3i and subsequent protection. The crude product was purified
by column chromatography on silica gel, eluting with ether–
light petroleum (7 : 13) to give the pure product as a colourless
solid (52% over two steps); mp 74–76 ЊC; [α]2D7 Ϫ32.2 (c 0.87,
CHCl3); (Found: C, 75.0; H, 8.5; N, 5.0. C17H23NO2 requires C,
74.7; H, 8.5; N, 5.1%); (Found: Mϩ, 273.1736. C17H23NO2
requires 273.1729); νmax(KBr)/cmϪ1 3331, 3078, 2917, 2851,
1683, 1653, 1539, 1450, 1296, 1250, 1020, 912, 656; δH (300
MHz; CDCl3) 7.34 (5 H, m, ArH), 5.74 (1 H, ddd, J 16.7, 10.4,
(R)-(؉)-N-Acetyl-2,2-dimethyl-1-phenylpropylamine 4c.
Obtained by the zinc mediated N–O bond cleavage and
subsequent N-protection of hydroxylamine 3e as a colourless
solid (28% over two steps, >98% ee); mp 175–176 ЊC (lit.,14
S-enantiomer mp 177–177.5 ЊC); [α]2D4 ϩ42.7 (c 1.03, CHCl3)
(lit.,41 [α]2D6 ϩ77; lit.,14 S-enantiomer [α]2D8 Ϫ92.0 (c 2.05,
EtOH)); (Found: Mϩ, 205.1463. C13H19NO requires 205.1467);
νmax(Nujol)/cmϪ1 3313, 2960, 2914, 1644, 1547, 1367, 1101, 727;
δH (300 MHz; CDCl3) 7.35–7.20 (5 H, m, ArH), 6.18 (1 H, d,
J 9.6, NH), 4.85 (1 H, d, J 9.6, CH), 2.03 (3 H, s, Me), 0.94 (9 H,
s, 3 × Me); δC (75 MHz; CDCl3) 169.3 (C), 140.1 (C), 128.1
(CH), 127.7 (CH), 127.0 (CH), 61.5 (CH), 34.8 (C), 26.6 (Me),
23.5 (Me); m/z (FI) 205 (Mϩ, 100%), 149 (15), 148 (11), 57 (7).
6.0, ᎐CH), 5.15 (4 H, m, CH Ph, ᎐CH ), 4.75 (1 H, br d, J 8.5,
᎐
᎐
2
2
NH), 4.04 (1 H, br m, NCH), 1.81–1.56 (5 H, m, CH, 2 ×
CH2), 1.42 (1 H, br, CHH), 1.29–0.86 (5 H, m, CHH, 2 × CH2);
δC (75 MHz; CDCl3) 156.0 (C), 137.2 (C), 136.6 (CH), 128.5
(CH), 128.1 (CH), 115.4 (CH2), 66.7 (CH2), 58.2 (CH), 42.2
(CH), 29.3 (CH2), 28.6 (CH2), 26.3 (CH2), 26.10 (CH2), 26.08
(CH2); one ArCH not observed; m/z (FI) 273 (Mϩ, 100%), 190
(10), 91 (4), 83 (11).
(R)-(؉)-N-Acetyl-2,2-dimethyl-1-phenylbutylamine 4d.
Obtained by the zinc mediated N–O bond cleavage and sub-
sequent N-protection of hydroxylamine 3f as a colourless solid
(6% over two steps, >98% ee); mp 125–126 ЊC; [α]2D4 ϩ35.1
(c 0.37, CHCl3); (Found: MHϩ, 220.1703. C14H21NO ϩ H
requires 220.1701); νmax(Nujol)/cmϪ1 3308, 2965, 2924, 1644,
1536, 1378, 1101, 732; δH (300 MHz; CDCl3) 7.36–7.22 (5 H, m,
ArH), 6.15 (1 H, m, NH), 4.90 (1 H, d, J 9.6, CH), 2.01 (3 H, s,
MeCO), 1.29 (2 H, m, CH2), 0.90 (3 H, s, Me), 0.89 (3 H, t,
J 7.4, Me), 0.83 (3 H, s, Me); δC (100 MHz; CDCl3) 169.0 (C),
140.0 (C), 128.2 (CH), 127.7 (CH), 126.9 (CH), 60.2 (CH), 37.3
(C), 31.8 (CH2), 23.6 (Me), 23.1 (Me), 22.9 (Me), 8.2 (Me); m/z
(CI) 220 (MHϩ, 100%), 162 (6), 161 (45), 149 (32), 148 (44), 106
(32), 105 (77), 88 (8), 60 (17).
(S )-(؉)-N-Benzyloxycarbonyl-9-ethyl-3-deca-1,9-dienyl-
amine 4h. Obtained from cleavage of the N–O bond of hydroxy-
lamine 3j and subsequent protection. The crude product was
purified by column chromatography on silica gel, eluting with
ether–light petroleum (1 : 10) to give the pure product as a
colourless oil (70% over two steps, 97% ee); [α]2D1 ϩ12.9 (c 1.16,
CHCl3); (Found: MHϩ, 316.2279. C20H29NO2 ϩ H requires
316.2276); νmax(film)/cmϪ1 3329, 3068, 3034, 2965, 2933, 2858,
1701, 1645, 1527, 1456, 1338, 1240, 1070, 992, 919, 888, 736,
697; δH (300 MHz; CDCl3) 7.34 (5 H, m, ArH), 5.74 (1 H, ddd,
J 17.0, 10.4, 5.8, ᎐CH), 5.13 (4 H, m, CH Ph, ᎐CH ), 4.71
᎐
᎐
2
2
(3 H, m, ᎐CH , NH), 4.16 (1 H, br, NCH), 1.99 (4 H, m,
᎐
2
2 × CH2), 1.59–1.21 (8 H, m, 4 × CH2), 1.01 (3 H, t, J 7.5, Me);
δC (75 MHz; CDCl3) 155.8 (C), 151.5 (C), 138.7 (CH), 136.6
(C), 128.5 (CH), 128.1 (CH), 114.6 (CH2), 107.5 (CH2), 66.7
(CH2), 53.4 (CH), 36.1 (CH2), 35.1 (CH2), 29.0 (CH2), 28.7
(CH2), 27.7 (CH2), 25.5 (CH2), 12.4 (Me), one ArCH not
observed; m/z (CI) 316 (MHϩ, 95%), 272 (60), 255 (25), 224
(27), 163 (28), 152 (33), 146 (23), 91 (100).
(R)-(؊)-N-Benzyloxycarbonyl-3-hex-1-enylamine 4e.
Obtained from cleavage of the N–O bond of hydroxylamine 3g
and subsequent protection. The crude product was purified by
column chromatography on silica gel, eluting with ether–light
petroleum (3 : 7) to give the pure product as a colourless solid
(89% over two steps); mp 55–56 ЊC; [α]2D6 Ϫ10.1 (c 0.79, CHCl3);
(Found: C, 72.2; H, 8.3; N, 5.9. C14H19NO2 requires C, 72.1; H,
8.2; N, 6.0%); (Found: MHϩ, 234.1514. C14H19NO2 ϩ H
requires 234.1494); νmax(KBr)/cmϪ1 3323, 3063, 2959, 2925,
2863, 1683, 1537, 1460, 1306, 1262, 1075, 917; δH (300 MHz;
(S )-(؉)-N-Benzyloxycarbonyl-3,4-dimethyl-3-pent-1-enyl-
amine 4i. Obtained from cleavage of the N–O bond of hydroxy-
lamine 3k and subsequent protection. The crude product was
purified by column chromatography on silica gel, eluting with
ether–light petroleum (3 : 7) to give the pure product as a col-
ourless oil (80% over two steps); [α]2D5 ϩ24.6 (c 1.22, CHCl3);
(Found: C, 73.5; H, 9.0; N, 5.7. C15H21NO2 requires C, 72.8; H,
CDCl ) 7.37–7.11 (5 H, m, ArH), 5.67 (1 H, m, ᎐CH), 5.29
᎐
3
(1 H, br d, J 7.9, NH), 5.20–4.91 (4 H, m, CH Ph, ᎐CH ), 4.15
᎐
2
2
(1 H, br, NCH), 1.53–1.20 (4 H, m, 2 × CH2), 0.88 (3 H, t, J 6.9,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 6 5 – 2 7 6
273

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8.6; N, 5.7%); (Found: MHϩ, 248.1646. C15H21NO2 ϩ H
requires 248.1650); νmax(film)/cmϪ1 3350, 3088, 3063, 3032,
2967, 2870, 1729, 1500, 1455, 1248, 1214, 1069, 1009, 917;
δH (300 MHz; CDCl3) 7.33 (5 H, m, ArH), 5.91 (1 H, dd, J 17.5,
(0.37 mmol, 1 eq.) sodium hydroxide (1.85 mmol, 5 eq.) in
dichloromethane (12 mL) and methanol (5 mL) at Ϫ78 ЊC.
After 2 h diethyl ether (5 mL) and water (5 mL) were added and
the reaction mixture allowed to warm to room temperature.
The mixture was exhaustively extracted with diethyl ether (5 ×
5 mL). The extracts were combined, dried (MgSO4), filtered and
evaporated under reduced pressure to give the crude ester.
10.5, ᎐CH), 5.19–4.97 (4 H, m, CH Ph, ᎐CH ), 4.83 (1 H, s,
᎐
᎐
2
2
NH), 2.07 (1 H, br, CHMe2), 1.37 (3 H, s, CMe), 0.87 (6 H, dd,
J 6.8, 4.9, CHMe2); δC (75 MHz; CDCl3) 154.9 (C), 141.5 (CH),
136.9 (C), 128.7 (CH), 128.3 (CH), 128.2 (CH), 113.7 (CH2),
66.3 (CH2), 59.6 (C), 35.5 (CH), 20.5 (Me), 17.4 (Me), 17.2
(Me); m/z (CI) 248 (MHϩ, 56%), 204 (33), 187 (11), 152 (13),
119 (11), 97 (21), 91 (100).
(R)-(؊)-Methyl 2-benzyloxycarbonylaminopentanoate 5c
(N-Cbz-norvaline methyl ester). Obtained from ozonolysis of
olefin 4e. The crude product was purified by column chromato-
graphy on silica gel, eluting with ether–light petroleum (1 : 2)
to give the pure product as a colourless oil (59%, 86% ee);
(lit.,44 racemate, oil); [α]2D6 Ϫ2.3 (c 0.86, CHCl3); (Found: C,
63.6; H, 7.5; N, 5.2. C14H19NO4 requires C, 63.4; H, 7.2; N,
5.3%); (Found: Mϩ, 265.1311. C14H19NO4 requires 265.1314);
νmax(film)/cmϪ1 3345, 3068, 3032, 2960, 2868, 1718, 1523, 1456,
1347, 1260, 1214, 1107, 1061, 1025; δH (300 MHz; CDCl3) 7.44–
7.20 (5 H, m, ArH), 5.34 (1 H, br d, J 7.0, NH), 5.10 (2 H, s,
CH2Ph), 4.38 (1 H, q, J 7.0, NCH), 3.73 (3 H, s, OMe), 1.88–
1.52 (2 H, m, CH2), 1.47–1.21 (2 H, m, CH2), 0.92 (3 H, t, J 7.2,
Me); δC (75 MHz; CDCl3) 173.4 (C), 156.1 (C), 136.5 (C), 128.7
(CH), 128.4 (CH), 128.3 (CH), 67.2 (CH2), 53.9 (CH), 52.5
(Me), 34.9 (CH2), 18.7 (CH2), 13.8 (Me); m/z (FI) 265 (Mϩ,
100%), 221 (3), 179 (5).
(S )-(؊)-N-Acetyl-1-phenylprop-2-enylamine 4j. Obtained by
the zinc mediated N–O bond cleavage and subsequent
N-protection of hydroxylamine 3l as a colourless solid (9% over
two steps, 90% ee); mp 72–73 ЊC (lit.,42 racemate mp 66 ЊC); [α]2D4
Ϫ72.2 (c 1.69, CDCl3); (Found: MHϩ, 176.1076. C11H13NO ϩ
H requires 176.1075); νmax(Nujol)/cmϪ1 3431, 3247, 3057, 2919,
2847, 1649, 1536, 1367, 1137, 702; δH (300 MHz; CHCl3)
7.32–7.23 (5 H, m, ArH), 6.05 (1 H, br s, NH), 5.95 (2 H, m,
CH᎐CH ), 5.19 (2 H, m, CH᎐CH ), 1.96 (3 H, s, Me); δ (100
᎐
᎐
2
2
C
MHz; CDCl3) 169.1 (C), 140.5 (C), 137.2 (CH), 128.7 (CH),
127.7 (CH), 127.2 (CH), 115.7 (CH2), 55.1 (CH), 30.9 (Me); m/z
(CI) 192 (MHϩ, 100%), 148 (6), 141 (18), 108 (2), 106 (7), 94 (2),
77 (13), 72 (3).
(R)-(؉)-N-Benzyloxycarbonyl-1-(4-methoxyphenyl)prop-2-
enylamine 4k. Obtained from cleavage of the N–O bond of
hydroxylamine 3m and subsequent protection. The crude
product was purified by column chromatography on silica gel,
eluting with ether–light petroleum (3 : 7) to give the pure prod-
uct as a colourless solid (85% over two steps); mp 74–76 ЊC; [α]2D8
ϩ61.8 (c 0.73, CHCl3); (Found: C, 72.8; H, 6.3; N, 4.6.
C18H19NO3 requires C, 72.7; H, 6.4; N, 4.7%); (Found: MHϩ,
298.1456. C18H19NO3 ϩ H requires 298.1443); νmax(KBr)/cmϪ1
3307, 3027, 2996, 2935, 2832, 1685, 1532, 1512, 1301, 1247,
1173, 1025; δH (300 MHz; CDCl3) 7.39–7.05 (7 H, m, ArH),
(R)-(؉)-Dimethyl N-benzyloxycarbonylglutamate 5d.
Obtained from ozonolysis of diene 4f. The crude product was
purified by column chromatography on silica gel, eluting with
light petroleum–ether (2 : 3) to give the pure product as a
colourless oil (40%, 93% ee); [α]2D6 ϩ23.2 (c 0.99, MeOH) (lit.,45
S-enantiomer [α]2D0 Ϫ22.2 (c 1, MeOH)); δH (300 MHz; CDCl3)
7.44–7.18 (5 H, m, ArH), 5.49 (1 H, d, J 7.5, NH), 5.10 (2 H, s,
CH2Ph), 4.41 (1 H, q, J 7.5, NCH), 3.74 (3 H, s, OMe), 3.65 (3
H, s, OMe), 2.52–2.31 (2 H, m, CH2), 2.29–2.09 (1 H, m, CHH),
2.07–1.87 (1 H, m, CHH ); δC (75 MHz; CDCl3) 173.4 (C), 172.6
(C), 156.2 (C), 136.4 (C), 128.8 (CH), 128.5 (CH), 128.4 (CH),
67.4 (CH2), 53.6 (CH), 52.9 (Me), 52.1 (Me), 30.2 (CH2), 27.9
(CH2).
6.82 (2 H, d, J 9.2, ArH), 5.94 (1 H, m, ᎐CH), 5.44 (6 H, m,
᎐
CH Ph, ᎐CH , NH, NCH), 3.73 (3 H, s, OMe); δ (75 MHz;
᎐
2
2
C
CDCl3) 159.2 (C), 155.9 (C), 138.0 (CH), 136.6 (C), 133.0 (C),
128.6 (CH), 128.4 (CH), 128.3 (CH), 115.6 (CH2), 114.2 (CH),
67.0 (CH2), 56.7 (CH), 55.4 (Me); one ArCH not observed; m/z
(CI) 298 (MHϩ, 3%), 254 (6), 237 (17), 206 (30), 190 (14), 147
(100), 100 (12), 91 (29).
(R)-(؊)-Methyl
2-benzyloxycarbonylamino-2-cyclohexyl-
ethanoate 5e. Obtained from ozonolysis of olefin 4g. The crude
product was purified by column chromatography on silica gel,
eluting with ether–light petroleum (1 : 4) to give the pure prod-
uct as a colourless oil (70%); [α]2D8 Ϫ18.7 (c 1.07, CHCl3) (lit.,45
S-enantiomer [α]2D8 ϩ17.38 (c 1.07, CHCl3)); (Found: C, 66.6; H,
7.4; N, 4.3. C17H23NO4 requires C, 66.9; H, 7.6; N, 4.6%);
(Found: MHϩ, 306.1721. C17H23NO4 ϩ H requires 306.1705);
νmax(film)/cmϪ1 3350, 3032, 2929, 2854, 1724, 1522, 1451, 1341,
1213, 1061, 1025; δH (300 MHz; CDCl3) 7.48–7.19 (5 H, m,
ArH), 5.39 (1 H, d, J 8.8, NH), 5.10 (2 H, s, CH2Ph), 4.29 (1 H,
dd, J 8.8, 5.3, NCH), 3.72 (3 H, s, OMe), 1.87–1.46 (6 H, m,
3 × CH2), 1.36–0.90 (5 H, m, CH, 2 × CH2); δC (75 MHz;
CDCl3) 172.8 (C), 156.4 (C), 136.5 (C), 128.8 (CH), 128.4 (CH),
67.2 (CH2), 59.0 (CH), 52.3 (Me), 41.2 (CH), 29.6 (CH2), 28.2
(CH2), 26.2 (CH2); one ArCH not observed; m/z (CI) 306
(MHϩ, 7%), 262 (65), 246 (11), 202 (11), 170 (88), 138 (6), 119
(8), 91 (100).
Oxidations
(S )-(؉)-N-tert-Butoxycarbonyl-3-(4-bromophenyl)alanine 5a.
Sodium metaperiodate (163 mg, 0.762 mmol) in CCl4 : CH3CN
: H2O (2 : 3 : 3, v/v) and RuCl3ؒ3H2O (1.3 mg, 0.00635 mmol)
were stirred vigorously for 20 min, and furan 4a (45 mg, 0.127
mmol) was then added and the mixture turned black. Sodium
metaperiodate was then added until the yellow colouration was
restored. The mixture was then stirred for a further 20 min. An
acid–base extraction, drying over MgSO4, evaporation and tri-
turation with ether gave the title compound as a colourless solid
(14.4 mg, 33%); mp 116–117 ЊC (lit.,43 racemate mp 117–118
ЊC); [α]2D4 ϩ20.0 (c 0.25, MeOH) (lit.,43 [α]2D0 ϩ9.6 (c 2, EtOAc));
νmax(KBr)/cmϪ1 3424, 2361, 1693, 1489, 1396, 1366, 1251, 1163,
1071, 1011; δH (300 MHz; CDCl3) 7.42 (2 H, d, J 8.2, ArH),
7.06 (2 H, d, J 8.2, ArH), 4.96 (1 H, d, J 7.0, NH), 4.59 (1 H, m,
NHCH ), 3.15 (1 H, m, CHHAr), 3.02 (1 H, m, CHHAr), 1.42
(9 H, s, 3 × Me); CO2H not observed.
(S )-(؉)-2-Benzyloxycarbonylamino-8-oxodecanoic acid 5f
(N-Cbz-Aoda). The diene 4h (100 mg, 0.320 mmol) was stirred
at room temperature in carbon tetrachloride (1.5 mL), aceto-
nitrile (1.5 mL) and water (2 mL) with periodic acid (456 mg,
2.000 mmol) for 10 min. RuCl3ؒ3H2O (1 mg, 0.006 mmol,
2 mol%) was added and the reaction mixture stirred at room
temperature for 3 h. Water (5 mL) and dichloromethane (5 mL)
were added and the aqueous layer was basified to pH 9 with
saturated aqueous sodium hydrogen carbonate solution. The
solution was extracted with dichloromethane (3 × 5 mL) and
the aqueous layer was acidified (pH 1) with hydrochloride
(R)-N-Acetyl-tert-leucine 5b. Prepared in 63% yield by
oxidative cleavage of (R)-(ϩ)-N-acetyl-2,2-dimethyl-1-phenyl-
propylamine 4c exactly as described for the (S)-enantiomer.14
General procedure for the preparation of N-Cbz-protected
amino esters by ozonolysis of vinyl compounds. Ozone was
passed through a solution of the vinyl compound (4e–4g, 4k)
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 6 5 – 2 7 6
274

View Article Online
acid (2 M). The solution was further extracted with dichloro-
methane (3 × 5 mL). The last dichloromethane organic layers
were combined, dried (MgSO4), filtered and evaporated in
vacuo. The crude product was purified by column chromato-
graphy on silica gel, eluting with acetic acid–dichloromethane–
light petroleum (1 : 1 : 8) to give the pure product as a colourless
oil (42 mg, 39%); [α]2D5 ϩ6.9 (c 1.30, CHCl3) (lit.,37 not given);
(Found: MHϩ, 336.1808. C18H25NO5 ϩ H requires 336.1811);
νmax(film)/cmϪ1 3329, 3063, 3027, 2939, 2858, 2576, 1712, 1522,
1456, 1404, 1342, 1217, 1050; δH (300 MHz; CDCl3) 7.43–7.22
(5 H, m, ArH), 7.08 (1 H, br s, OH), 6.22 (1 H, br, NH, minor
rotamer), 5.42 (1 H, d, J 7.9, NH, major rotamer), 5.10 (2 H,
AB, J 11.5, CH2Ph), 4.35 (1 H, m, NCH, major rotamer), 4.25
(1 H, br, NCH, minor rotamer), 2.39 (4 H, m, 2 × CH2), 1.86
(1 H, m, CHH), 1.75–1.45 (3 H, m, CHH, CH2), 1.44–1.18 (4 H,
m, 2 × CH2), 1.03 (3 H, t, J 7.3, Me); δC (75 MHz; CDCl3) major
rotamer 212.7 (C), 176.8 (C), 156.5 (C), 136.3 (C), 128.7 (CH),
128.3 (CH), 128.2 (CH), 67.2 (CH2), 54.0 (CH), 42.3 (CH2),
36.1 (CH2), 32.3 (CH2), 28.8 (CH2), 25.2 (CH2), 23.7 (CH2), 8.0
(Me); m/z (ES) 693 (2 M ϩ Na, 25%), 688 (2 M ϩ NH4, 25), 358
(M ϩ Na, 45), 353 (M ϩ NH4, 75), 336 (MHϩ, 100), 292 (35).
ate, not given); [α]2D8 ϩ106.9 (c 0.58, CHCl3); (Found: C, 65.1; H,
5.8; N, 4.1. C18H19NO5 requires C, 65.6; H, 5.8; N, 4.3%);
(Found: Mϩ, 329.1252. C18H19NO5 requires 329.1263);
νmax(KBr)/cmϪ1 3383, 3012, 2971, 2945, 2889, 2843, 1739, 1700,
1516, 1434, 1314, 1256, 1208, 1179, 1050; δH (300 MHz; CDCl3)
7.43–7.11 (7 H, m, ArH), 6.87 (2 H, d, J 8.7, ArH), 5.83 (1 H, d,
J 6.4, NH), 5.31 (1 H, d, J 7.1, NCH), 5.08 (2 H, AB, J 12.1,
CH2Ph), 3.78 (3 H, s, OMe), 3.71 (3 H, s, OMe); δC (75 MHz;
CDCl3) 171.8 (C), 160.0 (C), 155.6 (C), 136.4 (C), 128.9 (C),
128.8 (CH), 128.7 (CH), 128.4 (CH), 114.6 (CH), 67.3 (CH2),
57.6 (CH), 55.5 (Me), 53.0 (Me); m/z (FI) 329 (Mϩ, 100%).
Acknowledgements
We thank the EPSRC and GlaxoSmithKline for support, the
EPSRC Mass Spectrometry Centre at Swansea, and the EPSRC
Chemical Database Service at Daresbury.48
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10153.
(S )-(؉)-2-Benzyloxycarbonylamino-2,3-dimethylbutanoic
acid 5g (N-Cbz-ꢀ-methylvaline). The olefin 4i (100 mg, 0.400
mmol) was stirred at room temperature in carbon tetrachloride
(1.5 mL), acetonitrile (1.5 mL) and water (2 mL) with periodic
acid (456 mg, 2.00 mmol) for 10 min. RuCl3ؒ3H2O (2 mg, 0.008
mmol, 2 mol%) was added and the solution heated at 50 ЊC
for 5 h. Water (5 mL) and dichloromethane (5 mL) were added
and the aqueous layer was basified to pH 9 with saturated
aqueous sodium hydrogen carbonate solution. The solution
was extracted with dichloromethane (3 × 5 mL) and the aque-
ous layer was acidified (pH 1) with hydrochloride acid (2 M).
The solution was further extracted with dichloromethane (3 ×
5 mL). The last dichloromethane organic layers were combined,
dried (MgSO4), filtered and evaporated in vacuo. The crude
product was purified by column chromatography on silica gel,
eluting with acetic acid–dichloromethane–light petroleum (1 : 1
: 8) to give the pure product as a colourless oil (40 mg, 38%);
[α]2D3 ϩ16.3 (c 0.80, CHCl3); (Found: MHϩ, 266.1391. C14H19-
NO4 ϩ H requires 266.1392); νmax(film)/cmϪ1 3409, 3327, 3062,
3031, 2971, 2639, 2547, 1715, 1507, 1456, 1410, 1343, 1258,
1069; δH (300 MHz; CDCl3) 9.72 (1 H, br, OH), 7.33 (5 H, m,
ArH), 5.39 (1 H, br s, NH), 5.09 (2 H, s, CH2Ph), 2.21 (1 H, br
m, CHMe2), 1.56 (3 H, s, CMe), 0.96 (6 H, dd, J 9.2, 7.0,
CHMe2); δC (75 MHz; CDCl3) 178.9 (C), 155.7 (C), 136.4 (C),
128.8 (CH), 128.44 (CH), 128.38 (CH), 67.1 (CH2), 63.2 (C),
35.0 (CH), 19.1 (Me), 17.5 (Me), 17.4 (Me); m/z (FI) 265 (Mϩ,
100%), 220 (7), 114 (18), 108 (31).
15 G. Borg, M. Chino and J. A. Ellman, Tetrahedron Lett., 2001, 42,
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(R)-(؊)-N-Acetylphenylglycine 5h. (S)-(Ϫ)-N-Acetyl-1-
phenylprop-2-enylamine 4j (30 mg, 0.17 mmol) was dissolved in
CCl4 : CH3CN : H2O (2 : 2 : 3; v/v; 3 mL), sodium metaperio-
date (147.6 mg, 0.69 mmol) and RuCl3ؒ3H2O (cat.) was added
and the mixture was stirred for 2 h. The product was extracted
with ethyl acetate (3 × 5 mL), dried (MgSO4), filtered, concen-
trated and purified by flash chromatography to give the title
compound as a colourless solid (8 mg, 24%); mp 188–189 ЊC
(lit.,46 190–191 ЊC); [α]2D0 Ϫ100.0 (c 0.80, MeOH) (lit.,46 [α]2D2
Ϫ215.5 (c 1.30, 95% EtOH)); (400 MHz; CD3OD) 7.45–7.35 (5
H, m, ArH), 5.41 (1 H, s, NHCH ), 2.00 (3 H, s, Me); NH and
CO2H not observed; δC (100 MHz; CDCl3) 171.4 (C), 169.3 (C),
136.9 (C), 128.3 (CH), 127.8 (CH), 127.3 (CH), 57.1 (CH), 20.8
(Me).
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(S )-(؉)-Methyl
2-benzyloxycarbonylamino-2-(4-methoxy-
phenyl)ethanoate 5i. Obtained from ozonolysis of olefin 4k. The
crude product was purified by column chromatography on silica
gel, eluting with ether–light petroleum (1 : 2) to give the pure
product as a colourless solid (58%); mp 54–56 ЊC (lit.,47 racem-
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