Chiral oxime ethers in asymmetric synthesis. Part 4. Asymmetric synthesis of N-protected amines and β-amino acids by the addition of organometallic reagents to ROPHy/SOPHy-derived aldoximes

Article abstract of DOI:10.1039/a907186e

Addition of organolithium or Grignard reagents to (R)- or (S)-O-(1-phenylbutyl)aldehyde oximes 1 in the presence of boron trifluoride-diethyl ether results in the formation of hydroxylamines 2 in good to excellent diastereoselectivity. Subsequent cleavage of the N-O bond with zinc-acetic acid-ultrasound, and carbamate formation, gives N-protected amines 3 in good enantiomeric purity (77-100% ee). When allylmagnesium bromide was used as the organometallic reagent, the resulting hydroxylamines were converted into β-amino acid derivatives 4 and γ-aminb alcohols 5. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a907186e

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Chiral oxime ethers in asymmetric synthesis. Part 4.1 Asymmetric
synthesis of N-protected amines and ꢀ-amino acids by the addition
of organometallic reagents to ROPHy/SOPHy-derived aldoximes
James C. A. Hunt,a Cephas Lloyd,a Christopher J. Moody,*a Alexandra M. Z. Slawin†b and
Andrew K. Taklec
a School of Chemistry, University of Exeter, Stocker Road, Exeter, UK EX4 4QD
b Department of Chemistry, Loughborough University, Loughborough, Leicestershire,
UK LE11 3TU
c SmithKline Beecham Pharmaceuticals, New Frontiers Science Park (North),
Coldharbour Road, The Pinnacles, Harlow, Essex, UK CM19 5AW
Received (in Cambridge, UK) 6th September 1999, Accepted 17th September 1999
Addition of organolithium or Grignard reagents to (R)- or (S)-O-(1-phenylbutyl)aldehyde oximes 1 in the presence of
boron trifluoride–diethyl ether results in the formation of hydroxylamines 2 in good to excellent diastereoselectivity.
Subsequent cleavage of the N–O bond with zinc–acetic acid–ultrasound, and carbamate formation, gives N-protected
amines 3 in good enantiomeric purity (77–100% ee). When allylmagnesium bromide was used as the organometallic
reagent, the resulting hydroxylamines were converted into β-amino acid derivatives 4 and γ-amino alcohols 5.
compromise, we have demonstrated the use of such auxiliaries
Introduction
in the asymmetric synthesis of the piperidine alkaloid (R)-(Ϫ)-
Optically active nitrogen-containing compounds play a fund-
amental role in life processes. Even relatively simple chiral
compounds such as amines, amino alcohols, and amino acids
occupy vital roles such as hormones, neurotransmitters, build-
ing blocks, etc. In addition, amines and their substituted deriv-
atives find increasing use as key intermediates in asymmetric
coniine,5 and α-amino acids.1 We now describe the details of
a new method for the asymmetric synthesis of N-protected
amines, and, in the case of homoallylamines, their subsequent
conversion into β-amino acid derivatives.6
Results and discussion
synthesis as chiral ligands and chiral auxiliaries. Therefore the
development of new methods for the diastereo- and enantio-
selective synthesis of amines has been a major objective for
organic chemists.2 Many of these methods are based on the
A range of aldoxime ethers 1 was readily prepared by reaction
of the corresponding aldehyde with either ROPHy or SOPHy,
prepared as previously described,4 or more conveniently from
the N-phthaloyl derivative of ROPHy or SOPHy by hydrazine
hydrate-mediated deprotection followed by in situ reaction with
the aldehyde. Alkyl, cycloalkyl, aromatic and heteroaromatic
aldehydes all reacted satisfactorily. The (E)-oxime ethers 1 were
separated from the (Z)-isomers, the amount of which varied
from 0 to 33% according to the nature of the aldehyde substitu-
ent, by column chromatography and were isolated as colourless
oils in moderate to excellent yield (Table 1). The naphthalde-
hyde-derived oxime 1j and the thiazole derivative 1m were solids,
and on recrystallisation formed crystals suitable for X-ray
analysis. In the case of the naphthaldehyde oxime 1j the racemic
derivative gave better crystals, and hence the analysis was
carried out on the racemate. The X-ray crystal structures are
shown in in Figs. 1 and 2,7 and not only confirm the E-geometry
nucleophilic addition of organometallic reagents to the C᎐N
᎐
bond (Scheme 1), the stereochemistry of the addition being
Scheme 1 (X = alkyl, aryl, POR2, SOR, SO2R, NR2, OR, SiR3, etc.;
Met = Li, Mg, Z, Ce, Sn, etc.).
controlled by the presence of a chiral auxiliary attached to the
C or N atoms of the C᎐N bond, or by a chiral reagent–catalyst–
᎐
ligand system.3
We have recently shown that the addition of organolithium
or Grignard reagents to the C᎐N bond of oxime ethers derived
᎐
about the C᎐N bond, but also the preferred trans-arrangement
from (R)- and (S)-O-(1-phenylbutyl)hydroxylamine (ROPHy/
SOPHy) proceeds in a highly diastereoselective manner
(Scheme 1, X = OCHPrPh).4 The choice of the 1-phenylbutyl
group as the chiral auxiliary on the oxime oxygen represents a
significant improvement over the corresponding 1-phenethyl
derivatives, and although the 2-methyl-1-phenylpropyl group
gave better results,4 the starting material for the preparation of
the required hydroxylamine is not commercially available in
both enantiomeric forms. Hence, although the use of oxime
ethers derived from ROPHy/SOPHy represents something of a
᎐
about the N–O bond. In both structures (and also in the
ROPHy oxime of cinnamaldehyde1), the phenyl ring of the
auxiliary adopts a conformation in which it is almost per-
pendicular to the planar CH᎐N–O oxime unit. Calculations at
᎐
the semi-empirical level (Mopac Version 6.0, AM1 Hamil-
tonian8) support the fact that (in the gas phase) the trans-
orientation about the N–O bond is the more stable, and that
there is a high barrier to rotation about the N–O bond — ≈32 kJ
molϪ1 for the oxime ether MeCH᎐NOCH Ph. Interestingly,
᎐
2
they also show that the conformation adopted by the phenyl
ring (as shown in the X-ray crystal structures) is the minimum-
energy conformation in the gas phase, and hence, in view of the
low solvating power of toluene, probably also in solution.
† Present address: Department of Chemistry, University of St
Andrews, St Andrews, UK KY16 9ST. Correspondence concerning
X-ray crystallography should be addressed to this author.
J. Chem. Soc., Perkin Trans. 1, 1999, 3443–3454
This journal is © The Royal Society of Chemistry 1999
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Table 1 Preparation of O-(1-phenylbutyl)aldehyde oximes 1
R
Oxime
Yield (%)
n-Pr
(R)-1a
(R)-1b
(R)-1c
(S)-1d
(R)-1e
(R)-1f
(S)-1f
(R)-1g
(S)-1g
(R)-1h
(S)-1h
(S)-1i
(S)-1j
(S)-1k
(S)-1l
(S)-1m
58
54
78
62
84
77
76
56
50
98a
88a
75b
78
78
59
47
Pri
CHEt2
H2C᎐CHCH2CH2
PhCH2O(CH2)4
c-C6H11
c-C6H11
PhCH2
PhCH2
Ph
Ph
4-MeOC6H4
2-naphthyl
2-pyridyl
2-thienyl
thiazol-2-yl
᎐
Fig.
1
X-Ray molecular structure of ( )-O-(1-phenylbutyl)-2-
naphthaldehyde oxime ( )-1j, with crystallographic numbering scheme.
a Racemate described in ref. 4. b Ref. 4.
The addition of organolithium and Grignard reagents to the
oxime ethers 1 was carried out in toluene at Ϫ78 ЊC in the pres-
ence of boron trifluoride–diethyl ether and gave the corre-
sponding hydroxylamines 2 in good yield (Table 2), although
Grignard reagents appear to add efficiently to oximes of ali-
phatic aldehydes only. The use of toluene as solvent is essential
for the success of the reaction, and although diethyl ether can
be used as a co-solvent, for example when the Grignard reagent
is supplied in diethyl ether, the use of THF is particularly dele-
terious both in terms of yield and stereoselectivity. We assume
this is because it competes with the weakly Lewis basic oxime
ether for the boron trifluoride (see below). The oxime ethers
derived from heteroaromatic aldehydes gave poor results: no
product was isolated from the addition of allylmagnesium
bromide to the thiophene oxime 1l, and the thiazole
oxime 1m gave only a poor yield of the hydroxylamine 2u, and
the diastereoisomeric excess (de) was only 20%. In the case of
the phenylacetaldehyde oxime ethers 1g the addition reactions
were carried out at ≈Ϫ90 ЊC. In all except four cases (2c, 2g, 2m
and 2u), the diastereoselectivity of the addition was excellent
(>90%); the de was determined from the 1H NMR of the mix-
ture, although in some cases it was impossible to obtain an
accurate estimate of the de. These reactions are described as
>90% de, etc., reflecting the limits of accuracy of NMR inte-
gration in certain cases. The stereochemistry of the new chiral
centre was assigned on the basis of our previous work,9 using
the mnemonic that if the incoming group R1 has a lower
priority in the Sequence Rules than the existing group R, the
new stereocentre has the same configuration as the auxiliary
(Scheme 2), i.e. the nucleophile approaches from the side of
Fig. 2 X-Ray molecular structure of (S)-O-(1-phenylbutyl)thiazol-2-
ylcarbaldehyde oxime (S)-1m with crystallographic numbering scheme.
oxime ether species in solution is not known; calculations (vide
supra) suggest that there is a marginal preference for complex-
ation of the boron trifluoride to oxygen rather than nitrogen,
although the complex is much weaker than that formed
between boron trifluoride and THF, which has a calculated
equilibrium constant at least two orders of magnitude greater.
The calculations also suggest that complexation significantly
lowers the barrier to rotation about the N–O bond. Hence the
involvement of non-planar non-trans-conformations of the
oxime ether as the reacting species cannot be ruled out.
The N–O bond in hydroxylamines 2 was readily cleaved using
the zinc–acetic acid–ultrasound protocol,10 and the resulting
amine was protected without purification as either its tert-butyl
or benzyl carbamates 3. The carbamates 3 were generally solids,
and could be purified further by recrystallisation. The enantio-
meric purity of the N-protected amines 3 was determined by
HPLC analysis using a chiral stationary phase by comparison
with the racemic product which was synthesised separately. As
expected the observed enantiomeric excess (ee) of the carba-
mates 3 (Table 3) closely followed the de of the hydroxylamines
2. In the case of the carbamates 3l and 3m, the protecting
groups were removed by hydrogenolysis and acid treatment,
respectively, to give the corresponding amines; comparison with
literature data confirmed that the stereochemical assignments
for 3l and 3m (Table 3) were correct.11
Scheme 2
the C᎐N bond opposite to the phenyl group of the auxiliary.
᎐
However, this does not explain why the 1-phenylbutyl chiral
auxiliary is more effective than the corresponding 1-phenethyl
derivative. Unfortunately, the exact nature of the reacting
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Table 2 Addition of organometallic reagents to O-(1-phenylbutyl)aldehyde oximes 1
Oxime
R
R1Met
Hydroxylamine
Yield (%)
de (%)
>90
>90
86
(R)-1a
(R)-1a
(R)-1b
(R)-1c
(S)-1d
(R)-1e
(R)-1e
(R)-1f
(S)-1f
(R)-1f
(R)-1f
(S)-1f
(R)-1g
(R)-1g
(S)-1g
(S)-1g
(S)-1h
(R)-1h
(S)-1i
(S)-1j
(S)-1m
n-Pr
n-Pr
Pri
CHEt2
H2C᎐CH(CH2)2
PhCH2O(CH2)4
PhCH2O(CH2)4
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
PhCH2
PhCH2
PhCH2
PhCH2
Ph
Ph
PriMgCl
PhCH2MgCl
2a
2b
2c
2d
2e
2f
2g
2h
2i
70
21
78
100
91
98
61
95
68
77
80
85
62
92
72
67
72
100
80
50
7
H2C᎐CHCH2MgBr
᎐
H2C᎐CHCH2MgBr
96
᎐
PhLi
>90
>95
83
>90
>90
>90
96
96
79
91
>96
>96
>95
92
96
>90
20
᎐
n-PrMgCl
PhLi
n-BuLi
t-BuLi
PhLi
2j
2k
2l
H2C᎐CHCH2MgBr
᎐
H2C᎐CHCH2MgBr
᎐
EtMgBr
PriMgCl
n-BuLi
BuiLi
2m
2n
2o
2p
2q
2r
2s
2t
n-BuLi
H2C᎐CHCH2MgBr
᎐
4-MeOC6H4
2-naphthyl
thiazol-2-yl
H2C᎐CHCH2MgBr
᎐
n-BuLi
H2C᎐CHCH2MgBr
2u
᎐
Table 3 Cleavage of hydroxylamines 2 and protection of resulting amines
Hydroxylamine
R
R1
Carbamate
R2
Yield (%)
ee (%)a
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2n
2o
2p
2q
2r
2s
2t
n-Pr
n-Pr
Pri
Pri
PhCH2
H2C᎐CHCH2
H2C᎐CHCH2
Ph
n-Pr
Ph
n-Bu
t-Bu
Ph
(S)-3a
(S)-3b
(R)-3c
(R)-3d
(R)-3e
(R)-3f
(S)-3g
(R)-3h
(R)-3i
(S)-3j
(R)-3k
(S)-3k
(S)-3l
(S)-3m
(S)-3n
(S)-3o
(R)-3p
(S)-3q
(S)-3r
Bn
Bn
Bn
Bn
58
85
47
75
82
85
31
79
25
62
67
51
37
78
67
87
66
62
83
91
97b
78
᎐
᎐
CHEt2
H2C᎐CHCH2CH2
PhCH2O(CH2)4
PhCH2O(CH2)4
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
PhCH2
PhCH2
PhCH2
Ph
91
Bn
91b
88
᎐
t-Bu
t-Bu
Bn
Bn
Bn
Bn
Bn
Bn
t-Bu
t-Bu
Bn
Bn
Bn
77
96b
96
100b
92
H2C᎐CHCH2
᎐
᎐
H2C᎐CHCH2
89
Pri
98b
>96b
>96b
92b
95
n-Bu
Bui
n-Bu
H2C᎐CHCH2
H2C᎐CHCH2
n-Bu
Ph
᎐
᎐
4-MeOC6H4
2-naphthyl
98
91
Bn
a Enantiomeric excess (ee) obtained from HPLC analysis on a chiral stationary phase (Chiracel OD or ChiralPak AD) using hexane–propan-2-ol as
eluent (from 99.5:0.5 to 92:8). b After recrystallisation.
With a range of homoallylamines in hand,12 we next investi-
gated their conversion into β-amino acid derivatives. The wide-
spread occurrence of β-amino acids as constituents of a range
of biologically active natural products, together with their role
as precursors to β-lactams, and their incorporation into β-
peptides with defined secondary structure,13 has focused atten-
tion on these homologues of α-amino acids. The development
of new methods for the asymmetric synthesis of β-amino acids
is therefore of current interest, and several methods have been
reported.14 The most commonly used methods are summarised
in Scheme 3: the homologation of α-amino acids using the
Arndt–Eistert procedure,15 the asymmetric conjugate addition
of amines and amides to α,β-unsaturated carboxylic acid
derivatives,16 and the diastereoselective addition of ester enolate
equivalents or allyl organometallic reagents to the C᎐N double
᎐
bond of imines or hydrazones.17 Other routes include the ring
opening of aziridines,18 biotransformations,19 and a range of
methods based on chiral auxiliaries, catalysts, and functional
group interconversions.20
Initial attempts to cleave the alkene bond in the N-protected
homoallylamines using ruthenium oxidants were unsatisfac-
tory, but the double bond was readily cleaved by ozonolysis in
methanolic sodium hydroxide21 to give the N-Cbz amino esters
4 in moderate yield (Table 4). The configuration of the β-
phenyl-β-alanine derivative 4d was confirmed as (R) by com-
parison of its optical rotation with a literature value.22
J. Chem. Soc., Perkin Trans. 1, 1999, 3443–3454
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Table 4 Oxidative cleavage of N-benzyloxycarbonyl homoallylamines
range of substituents, and further exemplify the synthetic utility
of ROPHy/SOPHy-derived oximes.
Experimental
For general experimental details, see refs. 4 and 9. The hydroxyl-
amines 2 were characterised as diastereoisomeric mixtures; the
NMR data refer to the major diastereomer.
Homoallylamine
R
Carbamate
Yield (%)
3c
3d
(R)-3k
3p
3q
Pri
CHEt2
c-C6H11
Ph
(R)-4a
(R)-4b
(R)-4c
(R)-4d
(S)-4e
36
52
39
41
33
Preparation of oxime ethers: general method
A suspension of (R)- or (S)-N-(1-phenylbutoxy)phthalimide
(6.00 mmol) in ethanol (20 mL) was heated until the phthalim-
ide dissolved. Hydrazine hydrate (0.30 mL, 6.10 mmol) was
added at this elevated temperature and a colourless precipitate
was observed to form as the solution was slowly allowed to cool
to room temperature. The aldehyde (7 mmol) was added at
room temperature and the suspension was stirred until the reac-
tion was adjudged complete by TLC (typically 2–16 h). The
solvent was evaporated off, and tetrachloromethane (30 mL)
and magnesium sulfate were added to the residue. The resulting
suspension was filtered, the filtrate evaporated, and the residue
purified by column chromatography (dichloromethane–light
petroleum).
4-MeOC6H4
(R)-O-(1-Phenylbutyl)butyraldehyde oxime 1a. Obtained
from the cleavage of (R)-N-(1-phenylbutoxy)phthalimide and
subsequent condensation of the hydroxylamine with n-butyr-
aldehyde, as an oil (58%), [α]D25 ϩ7.7 (c 0.72, CH2Cl2); spectro-
scopic data identical to those previously reported for the
(S)-isomer.5
Scheme 3
The method was also extended to the synthesis of γ-amino
alcohols 5 by modification of the ozonolysis work-up condi-
tions. Thus, the N-Cbz amines 3d and 3k were subjected to
ozonolysis in dichloromethane, followed by reductive work-up
to give the amino alcohols 5a and 5b in 56 and 50% yield,
respectively (Scheme 4).
(R)-O-(1-Phenylbutyl)isobutyraldehyde oxime 1b. Obtained
from the cleavage of (R)-N-(1-phenylbutoxy)phthalimide and
subsequent condensation of the hydroxylamine with iso-
butyraldehyde, as a colourless oil (54%) (Found: Mϩ, 219.1625.
C14H21NO requires M, 219.1623); [α]D22 ϩ9.9 (c 0.95, CH2Cl2);
νmax (CH2Cl2)/cmϪ1 2967, 1514, 1467, 1027, 923; δH (300 MHz;
CDCl3) 7.31 (6H, m, ArH, CHN), 5.02 (1H, t, J 7.2, OCH),
2.44 (1H, m, CHMe2), 1.93 (1H, m, CHH), 1.71 (1H, m, CHH),
1.34 (2H, m, CH2), 1.05 (3H, d, J 6.8, MeCMe), 1.03 (3H, d,
J 6.8, MeCMe), 0.92 (3H, t, J 7.3, Me); δC (75 MHz; CDCl3)
156.0, 142.6, 128.2, 127.2, 126.8, 84.5, 38.4, 29.3, 20.3, 20.2,
18.9, 14.1; m/z (EI) 219 (Mϩ, 1%), 133 (82), 117 (13), 107 (27),
91 (100), 77 (44), 51 (20).
Scheme 4
Finally, since asymmetric induction in radical reactions is a
topic of current interest, and oxime ethers are known to be
good radical acceptors,23 we briefly examined the addition of
alkyl radicals to the SOPHy oxime of benzaldehyde, (S)-1h
(Scheme 5). Using the conditions developed by Naito and co-
(R)-2-Ethyl-O-(1-phenylbutyl)butyraldehyde
oxime
1c.
Obtained from the cleavage of (R)-N-(1-phenylbutoxy)phthal-
imide and subsequent condensation of the hydroxylamine with
2-ethylbutyraldehyde, as a colourless oil (78%) (Found: Mϩ,
247.1941. C16H25NO requires M, 247.1936); [α]D20 ϩ8.4 (c 1,
CH2Cl2); νmax (CH2Cl2)/cmϪ1 2935, 1452, 1027, 924; δH (300
MHz; CDCl3) 7.27 (6H, m, ArH, CHN), 5.06 (1H, t, J 6.8,
OCH), 1.99 (1H, m, CH), 1.95 (1H, m, CHH), 1.75 (1H, m,
CHH), 1.39 [6H, m, CH2, (MeCH2)2C], 0.93 (3H, t, J 7.4,
MeCH2), 0.87 (3H, t, J 7.5, Me), 0.73 (3H, t, J 7.4, MeCH2);
δC (75 MHz; CDCl3) 154.9, 142.6, 128.1, 127.1, 126.7, 84.3,
43.0, 38.3, 25.64, 25.58 18.8, 14.0, 11.5, 11.3; m/z (EI) 248
(MHϩ, 1%), 204 (2), 176 (1), 150 (1), 133 (96), 117 (18), 105
(37), 91 (100), 84 (73), 77 (52), 71 (40), 65 (15), 51 (82).
Scheme 5
workers,23d we found that the addition of isopropyl and ethyl
radicals (from the corresponding iodoalkanes) to oxime ether
1h did give the desired hydroxylamines 6. However, in both
cases the yield was poor, and the diastereoselectivity was worse
(85% de for 6a, 51% de for 6b) than in the addition of organo-
metallic reagents described above.
Hence we have established a new method for the asymmetric
synthesis of N-protected amines including homoallylamines,
N-protected β-amino esters and γ-amino alcohols based on the
highly diastereoselective addition of organometallic reagents to
oxime ethers. The routes are simple and versatile, tolerate a
(S)-O-(1-Phenylbutyl)pent-4-enaldehyde oxime 1d. Obtained
from the cleavage of (S)-N-(1-phenylbutoxy)phthalimide and
subsequent condensation of the hydroxylamine with pent-4-
enal, as a colourless oil (62%); [α]D23 Ϫ13.9 (c 1.0, CH2Cl2)
(Found: Mϩ, 231.1627. C15H21NO requires M, 231.1623); νmax
(film)/cmϪ1 3062, 3027, 2957, 2930, 2868, 1642, 1452; δH (300
MHz; CDCl3) 7.45 (1H, t, J 5.8, CHN), 7.31 (5H, m, ArH), 5.76
(1H, m, H C᎐CH), 5.02 (3H, m, H C᎐CH, OCH), 2.22 (4H, m,
᎐
᎐
2
2
2 × CH2), 1.90 (1H, m, CHH), 1.70 (1H, m, CHH), 1.37 (2H,
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m, CH2), 0.91 (3H, t, J 7.3, Me); δC (75 MHz; CDCl3) 150.4,
142.6, 136.9, 128.2, 127.3, 126.7, 115.6, 84.6, 38.4, 30.8, 28.9,
18.9, 14.0; m/z (EI) 231 (Mϩ, 0.1%), 185 (2), 133 (61), 105 (13),
91 (100), 77 (18).
1.48 (2H, m, CH2), 0.99 (3H, t, J 7.3, Me); δC (75 MHz; CDCl3)
148.5, 142.5, 132.5, 129.6, 128.6, 128.3, 127.4, 127.0, 126.8,
85.5, 38.3, 18.9, 14.1; m/z (EI) 253 (Mϩ, 7%), 212 (5), 133 (92),
117 (7), 104 (22), 91 (100), 77 (35).
(R)-5-Benzyloxy-O-(1-phenylbutyl)pentaldehyde oxime 1e.
The oxime was obtained from the cleavage of (R)-N-(1-
phenylbutoxy)phthalimide and subsequent condensation of the
hydroxylamine with 5-benzyloxypentanal,24 as a colourless oil
(84%); [α]D23 Ϫ132.2 (c 0.9, CHCl3) (Found: Mϩ, 339.2196.
C22H29NO2 requires M, 339.2198); νmax (neat)/cmϪ1 3436, 2092,
1635, 1103; δH (300 MHz; CDCl3) 7.44 (1H, t, J 6.2, CHN),
7.38–7.23 (10H, m, ArH), 5.03 (1H, t, J 6.8, OCH), 4.48 (2H, s,
PhCH2), 3.45 (2H, t, J 6.1, CH2O), 2.17 (2H, q, J 6.8, CH2),
1.92 (1H, m, CHH), 1.71–1.32 (7H, m, CHH, 3 × CH2), 0.94
(3H, t, J 7.3, Me); δC (75 MHz; CDCl3) 150.9, 142.7, 138.5,
128.4, 128.2, 127.6, 127.5, 127.2, 126.7, 84.9, 72.9, 69.8, 38.4,
29.3, 29.1, 13.5, 18.9, 14.1; m/z (EI) 339 (Mϩ, 0.2%), 248 (1), 207
(7), 149 (2), 133 (76), 105 (16), 91 (100), 77 (20).
(S)-O-(1-Phenylbutyl)benzaldehyde oxime (S)-1h. Obtained
from the cleavage of (S)-N-(1-phenylbutoxy)phthalimide and
subsequent condensation of the hydroxylamine with benzalde-
hyde, as a colourless oil (88%); [α]D20 Ϫ68.0 (c 1.1, CH2Cl2);
spectroscopic data identical with those of the (R)-enantiomer.
(S)-O-(1-Phenylbutyl)-p-anisaldehyde oxime 1i. Obtained
from the cleavage of (S)-N-(1-phenylbutoxy)phthalimide and
subsequent condensation of the hydroxylamine with p-anis-
aldehyde as previously described.4
(S)-O-(1-Phenylbutyl)-2-naphthaldehyde oxime 1j. Obtained
from the cleavage of (S)-N-(1-phenylbutoxy)phthalimide and
subsequent condensation of the hydroxylamine with 2-naphth-
aldehyde, as a colourless solid (78%); mp 78.5–81 ЊC (from light
petroleum); [α]D20 Ϫ37.9 (c 5.6, CH2Cl2) (Found: C, 82.8; H, 6.9;
N, 4.6. C21H21NO requires C, 83.1; H, 7.0; N, 4.6%); νmax (KBr)/
cmϪ1 3439, 3062, 3025, 2962, 2931, 2873, 1637, 1605, 1453;
δH (300 MHz; CDCl3) 8.34 (1H, s, CHN), 7.83 (5H, m, ArH),
7.44 (7H, m, ArH), 5.32 (1H, t, J 7.0, OCH), 2.12 (1H, m,
CHH), 1.90 (1H, m, CHH), 1.50 (2H, m, CH2), 1.04 (3H, t,
J 7.4, Me); δC (75 MHz; CDCl3) 148.8, 142.5, 134.1, 133.2,
130.3, 128.4, 128.3, 128.2, 127.9, 127.5, 126.9, 126.8, 126.5,
123.2, 85.7, 38.4, 19.0, 14.1; m/z (EI) 304 (MHϩ, 11%), 303 (Mϩ,
0.1), 171 (5), 153 (16), 133 (68), 127 (31), 115 (14), 105 (14), 91
(100), 77 (23).
(R)-O-(1-Phenylbutyl)cyclohexanecarbaldehyde oxime (R)-1f.
Obtained from the cleavage of (R)-N-(1-phenylbutoxy)phthal-
imide and subsequent condensation of the hydroxylamine with
cyclohexanecarbaldehyde, as a colourless oil (77%); [α]D22 ϩ17.0
(c 0.98, CH2Cl2) (Found: Mϩ, 259.1936. C17H25NO requires M,
259.1936); νmax (CH2Cl2)/cmϪ1 2935, 1449, 1027, 930, 686;
δH (300 MHz; CDCl3) 7.32 (6H, m, ArH, CHN), 5.04 (1H, t,
J 6.3, OCH), 2.18 (1H, m, CH), 1.95 (1H, m, CHH), 1.74 (7H,
m, CHH, 3 × CH2), 1.29 (6H, m, 3 × CH2), 0.92 (3H, t, J 7.3,
Me); δC (75 MHz; CDCl3) 155.0, 142.7, 128.1, 127.2, 126.8,
84.5, 38.5, 38.4, 30.5, 25.9, 25.4, 18.9, 14.1; m/z (EI) 259 (Mϩ,
1%), 149 (1), 133 (98), 127 (10), 117 (13), 107 (14), 91 (100), 83
(87), 77 (28).
(S)-O-(1-Phenylbutyl)pyridine-2-carbaldehyde oxime 1k.
Obtained from the cleavage of (S)-N-(1-phenylbutoxy)phthal-
imide and subsequent condensation of the hydroxylamine with
pyridine-2-carbaldehyde, as a colourless oil (78%); [α]D22 ϩ64.0
(c 1.1, CHCl3) (Found: Mϩ, 254.1419. C16H18N2O requires M,
254.1419); δH (300 MHz; CDCl3) 8.58 (1H, s, CHN), 8.23 (1H,
s, ArH), 7.72 (1H, s, ArH), 7.62 (1H, s, ArH), 7.34 (6H, m,
ArH), 5.24 (1H, t, J 7.2, OCH), 2.03 (1H, m, CHH), 1.84 (1H,
m, CHH), 1.37 (2H, m, CH2), 0.92 (3H, t, J 6.8, Me); δC (75
MHz; CDCl3) 151.9, 149.5, 149.3, 142.2, 136.3, 128.3, 127.5,
126.8, 123.8, 120.9, 86.1, 38.3, 18.9, 14.0; m/z (EI) 254 (Mϩ,
0.7%), 133 (24), 122 (15), 91 (100), 78 (21), 77 (10), 66 (3), 65
(11), 55 (5), 53 (4), 52 (11), 51 (21), 50 (9).
(S)-O-(1-Phenylbutyl)cyclohexanecarbaldehyde oxime (S)-1f.
Obtained from the cleavage of (S)-N-(1-phenylbutoxy)phthal-
imide and subsequent condensation of the hydroxylamine with
cyclohexanecarbaldehyde, as a colourless oil (76%); [α]D22 Ϫ17.9
(c 1.1, CH2Cl2); spectroscopic data identical with those of the
(R)-enantiomer.
(R)-O-(1-Phenylbutyl)phenylacetaldehyde oxime (R)-1g.
Obtained from the cleavage of (R)-N-(1-phenylbutoxy)phthal-
imide and subsequent condensation of the hydroxylamine with
phenylacetaldehyde, as a colourless oil (56%); [α]D20 Ϫ20.7 (c 1,
CH2Cl2) (Found: Mϩ, 267.1635. C18H21NO requires M,
267.1623); νmax (film)/cmϪ1 3437, 2958, 1652, 1635, 1496, 1454;
δH (300 MHz; CDCl3) 7.58 (1H, t, J 6.5, CHN), 7.33 (8H, m,
ArH), 7.18 (2H, m, ArH), 5.16 (1H, t, J 7.0, OCH), 3.51 (2H, d,
J 6.5, CH2Ph), 1.99 (1H, m, CHH), 1.79 (1H, m, CHH), 1.51–
1.38 (2H, m, CH2), 0.99 (3H, t, J 7.3, Me); δC (75 MHz; CDCl3)
149.5, 128.9, 128.7, 128.3, 127.4, 126.9, 126.8, 84.8, 38.5, 36.0,
19.0, 14.2; m/z (EI) 268 (MHϩ, 4%), 267 (Mϩ, 1), 226 (8), 176
(3), 152 (1), 133 (75), 105 (24), 91 (100), 77 (26), 65 (26), 51 (14).
(S)-O-(1-Phenylbutyl)thiophene-2-carbaldehyde oxime 1l.
Obtained from the cleavage of (S)-N-(1-phenylbutoxy)phthal-
imide and subsequent condensation of the hydroxylamine with
thiophene-2-carbaldehyde, as a colourless oil (59%); [α]D22 Ϫ116.5
(c 0.9 in CH2Cl2) (Found: Mϩ, 259.1031. C15H17NOS requires
M, 259.1047); νmax (CH2Cl2)/cmϪ1 2963, 1210, 1023, 951;
δH (300 MHz; CDCl3) 8.29 (1H, s, CHN), 7.34 (4H, m, ArH),
7.26 (2H, m, ArH), 7.15 (1H, m, ArH), 7.00 (1H, m, ArH), 5.17
(1H, t, J 6.7, OCH), 2.03 (1H, m, CH2), 1.79 (1H, m, CH2), 1.39
(2H, m, CH2), 0.95 (3H, t, J 7.3, Me); δC (75 MHz; CDCl3)
143.3, 142.2, 136.0, 129.0, 128.2, 127.4, 127.1, 127.1, 126.8,
85.6, 38.1, 18.9, 14.0; m/z (EI) 259 (Mϩ, 5%), 133 (70), 91 (100),
77 (18).
(S)-O-(1-Phenylbutyl)phenylacetaldehyde
oxime
(S)-1g.
Obtained from the cleavage of (S)-N-(1-phenylbutoxy)phthal-
imide and subsequent condensation of the hydroxylamine with
phenylacetaldehyde, as a colourless oil (50%); [α]D22 ϩ22.5 (c 1,
CH2Cl2); spectroscopic data identical with those of the
(R)-enantiomer.
(S)-O-(1-Phenylbutyl)thiazol-2-ylcarbaldehyde oxime 1m.
Obtained from the cleavage of (S)-N-(1-phenylbutoxy)phthal-
imide and subsequent condensation of the hydroxylamine with
thiazole-2-carbaldehyde, as a colourless solid (47%); mp 73–
74 ЊC (from aq. ethanol); [α]D22 Ϫ136.1 (c 1.0 in CHCl3) (Found:
C, 64.4; H, 6.2; N, 10.7. C14H16N2OS requires C, 64.6; H, 6.2;
N, 10.8%); νmax (KBr)/cmϪ1 2958, 2932, 2872, 1485, 1454, 983;
δH (300 MHz; CDCl3) 8.36 (1H, d, J 0.9, CHN), 7.83 (1H, d,
J 10.9, ArH), 7.39–7.26 (6H, m, ArH), 5.22 (1H, dd, J 6.7, 7.3
OCH), 2.02 (1H, m, CHH), 1.80 (1H, m, CHH), 1.48–1.34 (2H,
(R)-O-(1-Phenylbutyl)benzaldehyde oxime (R)-1h. Obtained
from the cleavage of (R)-N-(1-phenylbutoxy)phthalimide and
subsequent condensation of the hydroxylamine with benzalde-
hyde, as a colourless oil (98%); [α]D20 ϩ72.0 (c 0.85, CH2Cl2)
(Found: Mϩ, 253.1470. C17H19NO requires M, 253.1467);
νmax (film)/cmϪ1 2959, 2933, 1493, 1448; δH (300 MHz; CDCl3)
8.17 (1H, s, CHN), 7.56 (2H, m, ArH), 7.36 (8H, m, ArH), 5.23
(1H, t, J 6.8, OCH), 2.03 (1H, m, CHH), 1.82 (1H, m, CHH),
J. Chem. Soc., Perkin Trans. 1, 1999, 3443–3454
3447

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m, CH2), 0.96 (3H, t, J 7.4, Me); δC (75 MHz; CDCl3) 161.7 (C),
143.9 (CH), 143.5 (CH), 141.6 (CH), 128.3 (CH), 127.7 (CH),
126.8 (CH), 119.9 (CH), 86.6 (CH), 38.0 (CH2), 18.9 (CH2),
14.0 (CH3); m/z (EI) 260 (Mϩ, 7%), 133 (52), 111 (4), 105 (8), 91
(100), 77 (7), 58 (3).
NCH), 2.18 (2H, CH CH᎐), 1.78 (1H, m, CHH), 1.71 (1H, m,
᎐
2
Me2CH), 1.55 (2H, m, CHH), 1.36 (1H, m, CH2), 0.92 (3H, t,
J 7.3, Me), 0.89 (3H, d, J 6.8, Me2C), 0.83 (3H, d, J 6.8, Me2C);
δC (75 MHz; CDCl3) 143.1, 136.3, 128.2, 127.2, 126.8, 116.8,
84.9, 65.2, 38.5, 32.9, 28.6, 19.2, 19.1, 18.5, 14.1; m/z (EI) 261
(Mϩ, 6%), 239 (3), 220 (39), 218 (6), 184 (1), 178 (12), 162 (19),
141 (2), 133 (85), 117 (46), 112 (29), 104 (50), 100 (3), 91 (100),
77 (52).
Organometallic addition reactions
General method. An oxime ether 1 (3.9 mmol) was dissolved
in toluene (10 mL) and the solution was cooled to Ϫ78 ЊC.
Boron trifluoride–diethyl ether (11.8 mmol) was added and the
solution was stirred for 15 min. The organometallic reagent
(11.8 mmol in its supplied solvent) was added dropwise over 15
min, and the mixture was stirred at Ϫ78 ЊC until all the starting
material was consumed (typically 2–12 h). The reaction mixture
was quenched at Ϫ78 ЊC with saturated aq. ammonium chlor-
ide, and allowed to warm up to room temperature. The solvent
was removed under reduced pressure and the residue par-
titioned between dichloromethane (20 mL) and water (20 mL).
The layers were separated and the aqueous layer was washed
with further portions of dichloromethane (2 × 20 mL). The
combined organic extracts were washed with brine and then
dried (MgSO4), filtered and evaporated. Column chrom-
atography of the residue on silica gel (dichloromethane–light
petroleum 1:2) gave the hydroxylamine 2.
(R)-5-Ethyl-N-[(R)-1-phenylbutoxy]hept-1-en-4-ylamine
2d.—Obtained from the addition of allylmagnesium bromide
to oxime ether (R)-1c, as a colourless oil (100%, 96% de)
(Found: Mϩ, 289.2403. C19H31NO requires M, 289.2406); νmax
(CH2Cl2)/cmϪ1 2962, 1638, 1453, 914, 686; δH (400 MHz;
CDCl ) 7.29 (5H, m, ArH), 5.79 (1H, m, CH᎐), 5.29 (1H, br s,
᎐
3
NH), 5.07 (2H, m, CH ᎐), 4.54 (1H, t, J 6.5, OCH), 2.89 (1H,
᎐
2
m, NCH), 2.21 (2H, t, J 6.2, CH2CH), 1.84 (1H, m, CHH), 1.59
(1H, m, CHH), 1.43 (1H, m, CHHMe), 1.38 (3H, m, CHEt2,
CHHMe, CHHMe), 1.27 (2H, m, CHHMe), 1.16 (1H, m,
CHHMe), 0.93 (3H, t, J 7.3, Me), 0.86 (3H, t, J 7.3, MeCH2),
0.81 (3H, t, J 7.3, MeCH2); δC (75 MHz; CDCl3) 143.2, 136.6,
128.2, 127.2, 126.8, 116.6, 84.9, 61.3, 41.8, 38.3, 32.2, 22.0, 21.8,
19.1, 14.1, 11.9, 11.6; m/z (EI) 289 (Mϩ, 0.1%), 248 (32), 218 (5),
203 (1), 166 (2), 157 (12), 133 (75), 116 (79), 105 (45), 91 (76), 86
(100), 77 (45), 70 (26), 55 (50), 51 (58).
(R)-1-Phenyl-N-[(S)-1-phenylbutoxy]pent-4-enylamine
2e.—Obtained from the addition of phenyllithium to oxime
ether (S)-1d, as a colourless oil (91%, >90% de) (Found: Mϩ,
309.2188. C21H27NO requires M, 309.2093); νmax (film)/cmϪ1
3058, 3026, 2955, 2930, 2869, 1641, 1495, 1456; δH (300 MHz;
General method for allylmagnesium bromide addition to oxime
ethers. An oxime ether 1 (3.9 mmol) was dissolved in toluene
(10 mL) under nitrogen and cooled to Ϫ78 ЊC. Boron
trifluoride–diethyl ether (11.8 mmol) was added, and the mix-
ture stirred for 15 min. Allylmagnesium bromide (11.8 mmol) in
diethyl ether was added dropwise over 15 min, and the mixture
was stirred until all starting material was consumed (typically
2–12 h). The reaction mixture was quenched at Ϫ78 ЊC with
water, allowed to warm to room temperature, and extracted
with diethyl ether (3 × 15 mL). The combined extracts
were dried (K2CO3), filtered and evaporated. The residue was
purified by flash chromatography on silica gel using
dichloromethane–light petroleum (1:2) as eluent to give the
hydroxylamine 2.
CDCl ) 7.30 (10H, m, ArH), 5.71 (1H, m, H C᎐CH), 5.44 (1H,
᎐
2
3
br s, NH), 4.95 (2H, m, H C᎐CH), 4.35 (1H, dd, J 5.5, 8.3,
᎐
2
OCH), 4.00 (1H, dd, J 5.9, 8.2, NCH), 1.91 (2H, m, CH2), 1.62
(2H, m, CH2), 1.36 (1H, m, CHH), 1.15 (1H, m, CHH), 0.91
(2H, m, CH2), 0.70 (3H, t, J 7.3, Me); δC (75 MHz; CDCl3)
143.4, 142.5, 138.0, 128.3, 128.2, 127.9, 127.3, 127.2, 126.6,
114.9, 85.3, 65.2, 38.6, 32.9, 30.3, 18.9, 13.9; m/z (EI) 309 (Mϩ,
0.9%), 281 (1), 230 (7), 198 (6), 165 (13), 133 (26), 91 (100).
(R)-8-Benzyloxy-N-[(R)-1-phenylbutoxy]octan-4-ylamine
2f.—Obtained from the addition of n-propylmagnesium chlor-
ide to oxime ether (R)-1e, as a colourless oil (98%, >95% de)
(Found: Mϩ, 383.2837. C25H37NO2 requires M, 383.2824); νmax
(neat)/cmϪ1 3430, 2954, 2924, 2865, 1146, 1103; δH (300 MHz;
CDCl3) 7.33 (10H, m, ArH), 5.00 (1H, br s, NH), 4.54 (1H, dd,
J 7.6, 5.7, OCH), 4.51 (2H, s, PhCH2), 3.46 (2H, t, J 6.5,
CH2O), 2.89 (1H, m, NCH), 1.81 (1H, m, CHH), 1.62–1.28
(13H, m, CHH, 6 × CH2), 0.94 (3H, t, J 7.3, Me), 0.93 (3H, t,
J 7.0, Me); δC (75 MHz; CDCl3) 143.4, 138.7, 128.4, 128.3,
127.6, 127.5, 127.3, 126.6, 85.2, 72.9, 70.3, 60.2, 38.8, 34.4, 31.6,
30.0, 22.6, 19.3, 19.0, 14.4, 14.1; m/z (EI) 383 (Mϩ, 1%), 343 (3),
277 (6), 251 (48), 208 (48), 178 (57), 160 (24), 133 (74), 91 (100),
77 (49).
(S)-2-Methyl-N-[(R)-1-phenylbutoxy]hexan-3-ylamine
2a.—Obtained from the addition of isopropylmagnesium
chloride to oxime ether (R)-1a, as a colourless oil (70%, >90%
de) (Found: Mϩ, 263.2255. C17H29NO requires M, 263.2249);
νmax (film)/cmϪ1 2955, 2930, 2868, 1455, 1378; δH (300 MHz;
CDCl3) 7.30 (5H, m, ArH), 5.25 (1H, br s, NH), 4.55 (1H, dd,
J 5.9, 7.9, OCH), 2.61 (1H, m, NCH), 2.00 (1H, m, CHH), 1.79
(1H, m, CHH), 1.33 (7H, m, CH, 3 × CH2), 0.91 (12H, m,
4 × Me); δC (75 MHz; CDCl3) 143.6, 128.3, 127.2, 126.6, 85.1,
65.6, 38.9, 29.8, 28.9, 20.2, 19.2, 19.0, 17.7, 14.3, 14.1; m/z (EI)
263 (Mϩ, 0.2%), 220 (0.3), 133 (38), 91 (100), 88 (33).
(S)-1-Phenyl-N-[(R)-1-phenylbutoxy]pentan-2-ylamine
2b.—Obtained from the addition of benzylmagnesium chloride
to oxime ether (R)-1a, as a colourless oil (21%, >90% de)
(Found: Mϩ, 311.2260. C21H29NO requires M, 311.2249); νmax
(film)/cmϪ1 3025, 2954, 2926, 2869, 1451; δH (300 MHz; CDCl3)
7.30 (10H, m, ArH), 4.61 (1H, dd, J 5.5, 7.6, OCH), 2.99 (2H,
m, PhCH2), 2.72 (1H, m, NCH), 1.87 (1H, m, CHH), 1.45 (7H,
m, CHH, 3 × CH2), 0.99 (3H, t, J 7.1, Me), 0.90 (3H, t, J 6.7,
Me); NH not observed; δC (75 MHz; CDCl3) 143.4, 139.6,
129.6, 128.4, 128.3, 127.3, 126.6, 126.1, 85.4, 62.0, 38.9, 38.7,
33.9, 19.6, 19.3, 14.2, 14.2; m/z (EI) 311 (Mϩ, 0.2%), 220 (20),
179 (14), 149 (20), 133 (67), 105 (15), 91 (100), 77 (16).
(R)-2-Methyl-N-[(R)-1-phenylbutoxy]hex-5-en-3-ylamine
2c.—Obtained from the addition of allylmagnesium bromide to
oxime ether (R)-1b, as a colourless oil (78%, 86% de) (Found:
Mϩ, 261.2094. C17H27NO requires M, 261.2093); νmax (CH2Cl2)/
cmϪ1 3054, 2963, 2935, 2874, 1465, 916; δH (300 MHz; CDCl3)
(S)-5-Benzyloxy-1-phenyl-N-[(R)-1-phenylbutoxy]pentyl-
amine 2g.—Obtained from the addition of phenyllithium to
oxime ether (R)-1e, as a colourless oil (61%, 83% de) (Found:
Mϩ, 417.2674. C28H35NO2 requires M, 417.2668); νmax (neat)/
cmϪ1 3417, 2932, 2865, 1454, 1105; δH (300 MHz; CDCl3) 7.83–
7.26 (15H, m, ArH), 5.47 (1H, br s, NH), 4.47 (2H, s, PhCH2),
4.39 (1H, dd, J 5.5, 9.8, OCH), 4.00 (1H, dd, J 6.0, 14.0, NCH),
3.40 (2H, t, J 6.5, CH2O), 1.67–1.52 (5H, m, 2 × CH2, CHH),
1.40–1.18 (3H, m, CHH, CH2), 0.96 (2H, m, CH2), 0.73 (3H, t,
J 7.3, Me); δC (75 MHz; CDCl3) 143.5, 142.7, 138.6, 134.8,
128.4, 128.34, 128.16, 127.92, 127.89, 127.7, 127.5, 127.4, 127.3,
127.2, 126.7, 126.6, 85.3, 72.9, 70.0, 65.9, 38.7, 33.7, 29.7, 22.8,
18.9, 13.9; m/z (EI) 417 (Mϩ, 0.5%), 312 (4), 285 (14), 212 (23),
133 (32), 106 (27), 91 (100), 77 (16).
(R)-1-Cyclohexyl-N-[(R)-1-phenylbutoxy]pentylamine
2h.—Obtained from the addition of n-butyllithium to oxime
ether (R)-1f, as a colourless oil (95%, >90% de) (Found: Mϩ,
317.2729. C21H35NO requires M, 317.2719); νmax (film)/cmϪ1
3030, 2957, 2923, 2850, 1490, 1452; δH (300 MHz; CDCl3) 7.33
7.28 (5H, m, ArH), 5.74 (1H, m, CH᎐), 5.28 (1H, br s, NH),
᎐
5.03 (2H, m, ᎐CH ), 4.51 (1H, t, J 7.2, OCH), 2.56 (1H, m,
᎐
2
3448
J. Chem. Soc., Perkin Trans. 1, 1999, 3443–3454

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(5H, m, ArH), 5.29 (1H, br s, NH), 4.54 (1H, dd, J 6.1, 7.7,
OCH), 2.58 (1H, dd, J 7.0, 5.3, NCH), 1.9–0.9 (27H, m, CH,
10 × CH2, 2 × Me); δC (75 MHz; CDCl3) 143.4, 128.3, 127.2,
126.7, 84.8, 65.1, 39.1, 38.7, 29.6, 28.9, 28.8, 28.4, 26.8, 26.7,
26.6, 23.0, 19.2, 14.2, 14.1; m/z (EI) 317 (Mϩ, 1%), 134 (24), 133
(85), 132 (27), 128 (45), 117 (29), 115 (10), 102 (100), 91 (100),
77 (29).
(R)-1-Cyclohexyl-2,2-dimethyl-N-[(S)-1-phenylbutoxy]-
propylamine 2i.—Obtained from the addition of tert-butyl-
lithium to oxime ether (S)-1f, as a colourless oil (68%, >90% de)
(Found: MHϩ, 318.2791. C21H36NO requires m/z, 318.2797);
νmax (film)/cmϪ1 3027, 2955, 2930, 2848, 1450, 1350; δH (300
MHz; CDCl3) 7.31 (5H, m, ArH), 5.45 (1H, br s, NH), 4.55
(1H, dd, J 5.8, 7.5, OCH), 2.40 (1H, s, NCH), 1.80–1.10 (15H,
m, CH, 7 × CH2), 0.92 (3H, t, J 7.3, Me), 0.91 (9H, s, CMe3);
δC (75 MHz; CDCl3) 143.9, 128.1, 127.0, 126.7, 83.9, 73.1, 38.8,
38.6, 35.5, 35.0, 28.5, 28.0, 27.5, 26.9, 26.5, 19.2, 14.1; m/z (EI)
318 (MHϩ, 3%), 260 (100), 234 (3.0), 170 (1.7), 133 (19), 128
(69), 91 (30).
(S)-1-Cyclohexyl-N-[(R)-1-phenylbutoxy]benzylamine
2j.—Obtained from the addition of phenyllithium to oxime
ether (R)-1f, as a colourless oil (77%, >90% de) (Found: Mϩ,
337.2407. C23H31NO requires M, 337.2405); νmax (film)/cmϪ1
3257, 3027, 2925, 2848, 1486, 1445, 1353; δH (300 MHz; CDCl3)
7.30 (10H, m, ArH), 5.61 (1H, br s, NH), 4.31 (1H, dd, J 5.3,
8.3, OCH), 3.75 (1H, d, J 7.7, NCH), 1.50 (7H, m, CH,
3 × CH2), 1.35–0.70 (8H, m, 4 × CH2), 0.65 (3H, t, J 7.2, Me);
δC (75 MHz; CDCl3) 138.6, 136.9, 123.4, 123.2, 122.6, 122.1,
121.7, 121.4, 80.0, 66.1, 35.6, 33.7, 25.4, 24.4, 21.2, 21.0, 13.1,
8.7; m/z (EI) 337 (Mϩ, 1%), 254 (35), 205 (68), 173 (38), 133
(79), 122 (94), 104 (26), 91 (100), 77 (27).
(R)-1-Cyclohexyl-N-[(R)-1-phenylbutoxy]but-3-enylamine
2k.—Obtained from the addition of allylmagnesium bromide
to oxime ether (R)-1f, as a colourless oil (80%, 96% de) (Found:
Mϩ, 301.2407. C20H31NO requires M, 301.2406); νmax (CH2Cl2)/
cmϪ1 2930, 1446, 1250, 916; δH (300 MHz; CDCl3) 7.31 (5H,
1.55–1.32 (3H, m, CH2, CMe2), 1.01 (3H, t, J 6.8, CMeMe),
0.98 (3H, t, J 6.8, CMeMe), (3H, t, J 7.1, Me); δC (75 MHz;
CDCl3) 143.2, 139.7, 129.1, 128.4, 128.2, 127.2, 126.5, 126.1,
85.0, 67.1, 38.7, 33.7, 19.2, 19.0, 18.0, 14.1; m/z (EI) 311 (Mϩ,
1%), 220 (10), 133 (20), 91 (100), 88 (36).
(S)-1-Phenyl-N-[(S)-1-phenylbutoxy]hexan-2-ylamine
2o.—Obtained from the addition of n-butyllithium to oxime
ether (S)-1g, as a colourless oil (72%, >96% de) (Found: Mϩ,
325.2399. C22H31NO requires M, 325.2405); νmax (film)/cmϪ1
3427, 2956, 2931, 1652, 1451; δH (300 MHz; CDCl3) 7.25 (10H,
m, ArH), 5.22 (1H, br s, NH), 4.56 (1H, dd, J 5.8, 9.8, OCH),
3.09 (1H, m, NCH), 2.73 (2H, dd, J 6.2, 3.2, CH2Ph), 1.82 (1H,
m, CHH), 1.60–1.29 (9H, m, 4 × CH2, CHH), 0.95 (3H, t,
J 7.3, Me), 0.89 (3H, t, J 7.1, Me); δC (75 MHz; CDCl3) 143.3,
139.2, 129.4, 128.3, 128.3, 127.3, 126.7, 126.1, 85.1, 61.8, 38.7,
38.3, 31.5, 28.3, 22.9, 19.3, 14.2, 14.1; m/z (EI) 326 (MHϩ, 11%),
268 (1), 234 (28), 210 (2), 193 (22), 176 (7), 163 (16), 149 (16),
133 (67), 117 (29), 91 (100), 77 (19), 65 (18).
(S)-4-Methyl-1-phenyl-N-[(S)-1-phenylbutoxy]pentan-2-
ylamine 2p.—Obtained from the addition of isobutyllithium to
oxime ether (S)-1g, as a colourless oil (67%, >96% de) (Found:
Mϩ, 325.2405. C22H31NO requires M, 325.2405); νmax (film)/
cmϪ1 3425, 3029, 2956, 2871, 1635, 1496, 1454; δH (300 MHz;
CDCl3) 7.26 (10H, m, ArH), 5.17 (1H, br s, NH), 5.47 (1H, t,
J 7.1, OCH), 3.16 (1H, q, J 6.5, NCH), 2.76 (2H, m, CH2Ph),
1.71 (1H, m, CHH), 1.69–1.31 (5H, m, CH, 2 × CH2), 1.18 (1H,
m, CHMe2), 0.95 (3H, t, J 7.3, Me), 0.87 (3H, t, J 6.5, CMeMe),
0.86 (3H, t, J 6.5, CMeMe); δC (75 MHz; CDCl3) 143.3, 139.1,
129.4, 128.3, 128.2, 127.2, 126.6, 126.0, 85.6, 41.1, 28.6, 24.9,
23.0, 22.6, 19.2, 14.1; m/z (EI) 325 (Mϩ, 0.1%), 268 (1), 234 (21),
193 (6), 148 (2), 133 (53), 117 (26), 102 (63), 91 (100), 65 (14), 65
(14), 51 (78).
(S)-1-Phenyl-N-[(S)-1-phenylbutoxy]pentylamine
2q.—
Obtained from the addition of n-butyllithium to oxime ether
(S)-1h, as a colourless oil (72%, >95% de) (Found: Mϩ,
311.2258. C21H29NO requires M, 311.2249); νmax (film)/cmϪ1
3252, 3032, 2955, 2930, 2873, 1449; δH (300 MHz; CDCl3) 7.32
(10H, m, ArH), 5.39 (1H, br s, NH), 4.63 (1H, t, J 7.3, OCH),
4.00 (1H, dd, J 5.2, 8.8, NCH), 2.00 (1H, m, CHH), 1.87 (1H,
m, CHH), 1.65 (2H, m, CH2), 1.31 (6H, m, 3 × CH2), 0.97 (3H,
t, J 7.3, Me), 0.92 (3H, t, J 7.3, Me); δC (75 MHz; CDCl3) 143.1,
141.7, 128.2, 128.1, 127.8, 127.31, 127.26, 126.8, 85.3, 65.8,
38.5, 33.5, 28.3, 22.8, 19.2, 14.1, 14.0; m/z (EI) 311 (Mϩ, 0.5%),
179 (67), 147 (56), 133 (77), 122 (75), 105 (21), 91 (100).
m, ArH), 5.80 (1H, m, CH᎐), 5.34 (1H, br s, NH), 5.06 (2H,
᎐
m, ᎐CH ), 4.53 (1H, t, J 6.7, OCH), 2.60 (1H, m, NCH), 2.24
᎐
2
(2H, m, CH CH᎐), 1.79–1.07 (15H, m, cyclohexyl, CH CH ),
᎐
2
2
2
0.92 (3H, t, J 7.3, Me); δC (75 MHz; CDCl3) 143.3, 136.4, 128.2,
127.2, 126.7, 116.9, 84.9, 64.6, 38.7, 33.2, 29.7, 29.1, 26.6,
26.5, 19.2, 14.1; m/z (EI) 301 (Mϩ, 1%), 260 (46), 169 (26),
133 (78), 128 (86), 117 (52), 105 (54), 91 (100), 77 (65), 67 (59),
55 (76).
(S)-1-Cyclohexyl-N-[(S)-1-phenylbutoxy]but-3-enylamine
2l.—Obtained from the addition of allylmagnesium bromide to
oxime ether (S)-1f, as a colourless oil (85%, 96% de), with iden-
tical spectroscopic properties to those of the enantiomer.
(R)-1-Phenyl-N-[(R)-1-phenylbutoxy)]butan-2-ylamine
2m.—Obtained from the addition of ethylmagnesium bromide
to oxime ether (R)-1g, as a colourless oil (62%, 79% de) (Found:
Mϩ, 297.2100. C20H27NO requires M, 297.2093); νmax (film)/
cmϪ1 3440, 3027, 2958, 2873, 1494, 1454, 1029; δH (300 MHz;
CDCl3) 7.36–7.16 (10H, m, ArH), 5.25 (1H, br s, NH), 4.58
(1H, dd, J 7.4, 6.1, OCH), 3.03 (1H, quintet, J 6.3, NCH), 2.74
(2H, d, J 6.6, PhCH2), 1.84 (1H, m, CHH), 1.63–1.29 (5H, m,
2 × CH2, CHH), 0.95 (3H, t, J 7.4, Me), 0.91 (3H, t, J 7.1, Me);
δC (75 MHz; CDCl3) 143.2, 139.1, 129.3, 128.34, 128.27, 127.2,
126.6, 126.1, 85.1, 63.1, 38.7, 37.7, 24.4, 19.3, 14.1, 10.3; m/z
(EI) 297 (Mϩ, 1%), 268 (2), 239 (2), 218 (5), 194 (5), 165 (6), 133
(46), 91 (100).
(S)-3-Methyl-1-phenyl-N-[(R)-1-phenylbutoxy]butan-2-
ylamine 2n.—Obtained from the addition of isopropylmag-
nesium chloride to oxime ether (R)-1g, as a colourless oil
(92%, 91% de) (Found: Mϩ, 311.2242. C21H29NO requires M,
311.2249); νmax (film)/cmϪ1 3440, 3027, 2958, 2871, 1494, 1463,
1029; δH (300 MHz; CDCl3) 7.37–7.14 (10H, m, ArH), 5.24
(1H, br s, NH), 4.54 (1H, dd, J 7.3, 6.0, OCH), 2.92 (1H, m,
NCH), 2.73 (1H, dd, J 4.1, 14.0, PhCHH), 2.46 (1H, dd, J 9.3,
14.0, PhCHH), 2.03 (1H, m, CHH), 1.76 (1H, m, CHH),
(R)-1-Phenyl-N-[(R)-1-phenylbutoxy]but-3-enylamine 2r.—
Obtained from the addition of allylmagnesium bromide to
oxime ether (R)-1h, as a colourless oil (100%, 92% de) (Found:
Mϩ, 295.1938. C20H25NO requires M, 295.1936); νmax (CH2Cl2)/
cmϪ1 2962, 1640 1492, 1451, 1248, 918; δH (300 MHz; CDCl3)
7.26 (10H, m, 2 × ArH), 5.72 (1H, m, ᎐CH), 5.43 (1H, br s,
᎐
NH), 5.03 (2H, m, ᎐CH ), 4.55 (1H, t, J 7.2, OCH), 4.07 (1H,
᎐
2
dd, J 6.1, 7.6, NCH), 2.71 (1H, m, NCH), 2.42 (1H, m,
CH CH᎐), 1.83 (1H, m, CHH), 1.60 (1H, m, CHH), 1.34 (2H,
᎐
2
m, CH2), 0.93 (3H, t, J 7.3, Me); δC (75 MHz; CDCl3) 142.8,
140.9, 134.7, 128.3, 128.1, 127.8, 127.7, 127.4, 127.3, 126.7,
117.2, 85.2, 65.1, 38.3, 19.1, 14.1; m/z (EI) 295 (Mϩ, 0.2%), 164
(8), 163 (16), 146 (7), 134 (20), 132 (40), 91 (100), 77 (55).
(S)-1-(4-Methoxyphenyl)-N-[(S)-1-phenylbutoxy]but-3-
enylamine 2s.—Obtained from the addition of allylmagnesium
bromide to oxime ether (S)-1i, as a colourless oil (80%, >96%
de) (Found: Mϩ, 325.2042. C21H27NO2 requires M, 325.2042);
νmax (CH2Cl2)/cmϪ1 2961, 1611, 1512, 1453, 1329, 1176, 1032,
916; δH (300 MHz; CDCl3) 7.23 (5H, m, ArH), 7.15 (2H, d,
ArH), 6.91 (2H, d, ArH), 5.65 (1H, m, CH᎐), 5.36 (1H, br s,
᎐
NH), 5.02 (2H, m, CH ᎐), 4.55 (1H, t, J 6.7, OCH), 3.79 (3H, s,
᎐
2
OMe), 2.71 (1H, m, NCH), 2.45 (2H, m, CH CH᎐), 1.80 (1H,
᎐
2
m, CHH), 1.56 (1H, m, CHH), 1.35 (2H, m, CH2), 0.91 (3H, t,
J 7.3, Me); δC (75 MHz; CDCl3) 158.9, 142.9, 135.2, 132.8,
128.9, 128.2, 127.2, 126.7, 117.0, 113.6, 85.3, 64.5, 55.3, 38.4,
38.3, 19.2, 14.1; m/z (EI) 325 (Mϩ, 0.1%), 284 (35), 176 (13), 161
J. Chem. Soc., Perkin Trans. 1, 1999, 3443–3454
3449

View Article Online
(57), 149 (3), 133 (69), 117 (24), 106 (8), 91 (100), 77 (53), 65
(28), 51 (29).
portions of diethyl ether. The combined organic extracts were
dried (MgSO4), filtered and evaporated. Column chroma-
tography of the residue on silica gel (dichloromethane–light
petroleum gradient elution) gave the Cbz-protected amine.
(S)-1-(2-Naphthyl)-N-[(S)-1-phenylbutoxy]pentylamine
2t.—Obtained from the addition of n-butyllithium to oxime
ether (S)-1j, as a colourless solid (50%, >90% de); mp 76–77 ЊC
(from ethanol) (Found: C, 83.1; H, 8.9; N, 3.8. C25H31NO
requires C, 83.1; H, 8.6; N, 3.9%); νmax (KBr)/cmϪ1 3437, 3058,
3027, 2954, 2929, 2867, 1638, 1455; δH (300 MHz; CDCl3) 7.82
(3H, m, ArH), 7.66 (1H, s, ArH), 7.45 (2H, m, ArH), 7.37 (1H,
dd, J 6.9, 8.5, ArH), 7.21 (5H, m, ArH), 5.47 (1H, br s, NH),
4.57 (1H, dd, J 6.2, 7.4, OCH), 4.11 (1H, dd, J 5.2, 9.0, NCH),
2.01 (1H, m, CHH), 1.76 (2H, m, CH2), 1.57 (1H, m, CHH),
1.30 (6H, m, 3 × CH2), 0.90 (3H, t, J 7.3, Me), 0.85 (3H, t, J 7.3,
Me); δC (75 MHz; CDCl3) 142.9, 139.1, 133.3, 132.9, 128.2,
127.9, 127.8, 127.6, 127.2, 126.8, 126.7, 125.9, 125.8, 125.6,
85.2, 65.9, 38.5, 33.4, 31.8, 28.3, 22.8, 19.2, 14.1, 14.0; m/z (EI)
361 (Mϩ, 0.4%), 229 (12), 197 (31), 172 (19), 154 (10), 141 (43),
133 (31), 115 (5), 91 (100), 77 (6).
(S)-(؉)-N-Benzyloxycarbonyl-2-methylhexan-3-ylamine 3a.
Obtained from the cleavage of hydroxylamine 2a and protec-
tion, as a colourless solid (58%, 91% ee); mp 50–51 ЊC (from
light petroleum); [α]D25 ϩ4.8 (c 1.0, CH2Cl2) (Found: C, 72.6; H,
8.9; N, 5.6. C15H23NO2 requires C, 72.3; H, 9.3; N, 5.6%); νmax
(KBr)/cmϪ1 3324, 2966, 2808, 1690, 1532, 1450, 1245; δH (300
MHz; CDCl3) 7.33 (5H, m, ArH), 5.10 (2H, s, PhCH2), 4.56
(1H, br d, J 9.0, NH), 3.53 (1H, m, NCH), 1.74 (1H, m, CH),
1.35 (4H, m, 2 × CH2), 0.90 (9H, m, 3 × Me); δC (75 MHz;
CDCl3) 156.5, 136.8, 128.5, 128.0, 66.5, 56.1, 34.7, 32.1, 19.4,
19.2, 17.5, 14.1; m/z (EI) 249 (Mϩ, 1%), 206 (18), 162 (26), 107
(11), 91 (100).
(S)-1-(Thiazol-2-yl)-N-[(S)-1-phenylbutoxy]but-3-enyl-
amine 2u.—Obtained from the addition of allylmagnesium
bromide to the oxime ether (S)-1m, as a yellow oil (7%, 20% de)
(Found: MHϩ, 303.1529. C17H23N2OS requires m/z, 303.1548);
νmax (film)/cmϪ1 3079, 3029, 2958, 2931, 2871, 1494, 1454, 1027;
δH (400 MHz; CDCl3) 7.74 (1H, d, J 3.2, ArH), 7.35–7.24 (6H,
(S)-(؊)-N-Benzyloxycarbonyl-1-phenylpentan-2-ylamine 3b.
Obtained from the cleavage of hydroxylamine 2b and protec-
tion, as a colourless solid [85%, 92% ee, 97% ee (recrystallised)];
mp 81–83 ЊC (from light petroleum); [α]D24 Ϫ6.6 (c 0.64, CH2Cl2)
(Found: C, 76.8; H, 7.7; N, 4.7. C19H23NO2 requires C, 76.7;
H, 7.8; N, 4.7%); νmax (KBr)/cmϪ1 3426, 3329, 3027, 2955, 2925,
2868, 1701, 1537; δH (300 MHz; CDCl3) 7.30 (10H, m, ArH),
5.12 (1H, d, J 12.3, PhCHHO), 5.07 (1H, d, J 12.6, PhCHHO),
4.63 (1H, br d, J 8.1, NH), 3.94 (1H, br m, NCH), 2.08 (2H, d,
J 6.2, PhCH2), 1.43 (4H, m, 2 × CH2), 0.91 (3H, t, J 6.3, Me);
δC (75 MHz; CDCl3) 156.0, 138.1, 136.8, 129.5, 128.5, 128.4,
128.0 (2C), 126.4, 66.5, 52.0, 41.3, 30.4, 19.2, 13.0; m/z (EI) 297
(Mϩ, 0.9%), 206 (23), 189 (15), 162 (24), 108 (32), 98 (25), 91
(100), 77 (13).
m, ArH), 5.73 (1H, m, CH᎐), 5.65 (1H, br s, NH), 5.10 (2H, m,
᎐
H C᎐), 4.63 (1H, t, J 6.1, OCH), 4.45 (1H, dd, J 6.1, 7.6, NCH),
᎐
2
2.57 (1H, m, CHHC᎐), 2.45 (1H, m, CHHC᎐), 1.68–1.21 (4H,
᎐
᎐
2 × CH2), 0.80 (3H, t, J 7.4, Me); δC (100 MHz; CDCl3) 173.2,
142.7, 142.1, 133.5, 128.4, 127.4, 126.5, 118.7, 118.5, 85.7, 62.6,
38.5, 37.8, 18.9, 13.9; m/z (EI) 303 (MHϩ, 14%), 183 (5), 166
(100), 150 (100), 140 (40), 113 (19), 100 (26), 86 (55), 72 (20).
General method for the preparation of Boc-protected amines
(R)-(؊)-N-Benzyloxycarbonyl-2-methylhex-5-en-3-ylamine
3c. Obtained from the cleavage of hydroxylamine 2c and pro-
tection, as a colourless oil (47%, 78% ee) (Found: Mϩ, 247.1572.
C15H21NO2 requires M, 247.1572); [α]D22 Ϫ30.0 (c 2.0, CH2Cl2);
νmax (CH2Cl2)/cmϪ1 3055, 2989, 2306, 1721, 1421, 1269; δH (300
Zinc dust (40 mmol) was added to a mixture of a hydroxyl-
amine 2 (1 mmol) in acetic acid–water (6.5 mL; 1:1). The
mixture was placed in a sonic bath at 40 ЊC and the reaction
was followed by TLC until completion. The zinc was filtered off
and washed with diethyl ether. The filtrate was basified with
saturated aq. sodium bicarbonate solution and the aqueous
layer exhaustively extracted with dichloromethane (8 × 15 mL).
The extracts were combined, dried (Na2SO4), filtered and evap-
orated. The residue was dissolved in dichloromethane (7 mL),
and di-tert-butyl dicarbonate (4 mmol) and DMAP (cat.) were
added. The mixture was stirred at room temperature for 12 h.
Saturated aq. sodium bicarbonate (10 mL) was added and the
mixture stirred for 10 min before being extracted with dichloro-
methane (4 × 10 mL), and the organic extracts were com-
bined, dried (Na2SO4), filtered and evaporated. The residue was
purified by flash chromatography on silica gel, eluting with
dichloromethane–light petroleum (1:1).
MHz; CDCl ) 7.33 (5H, m, ArH), 5.79 (1H, m, CH᎐), 5.10
᎐
3
(2H, s, CH O), 5.04 (2H, m, CH ᎐), 4.64 (1H, d, J 7.7, NH),
᎐
2
2
3.59 (1H, m, NCH), 2.24 (1H, m, CHHCH᎐), 2.16 (1H, m,
᎐
CHHCH᎐), 1.75 (1H, m, CHMe ), 0.93 (3H, d, J 7.6, Me), 0.90
᎐
2
(3H, d, J 7.6, Me); δC (75 MHz; CDCl3) 156.4, 136.8, 134.8,
128.5, 128.4, 127.98, 127.97, 117.4, 66.5, 55.8, 36.9. 31.5, 19.2,
19.0, 17.7; m/z (EI) 247 (Mϩ, 1%), 234 (1), 190 (2), 162 (44), 149
(1), 118 (4), 107 (16), 91 (100), 83 (82), 77 (12), 65 (23), 51 (65).
(R)-(؊)-N-Benzyloxycarbonyl-5-ethylhept-1-en-4-ylamine 3d.
Obtained from the cleavage of hydroxylamine 2d and protec-
tion, as a colourless oil (75%, 91% ee) (Found: Mϩ, 275.1885.
C17H25NO2 requires M, 275.1885); [α]D22 Ϫ29.7 (c 0.97, CH2Cl2);
νmax (CH2Cl2)/cmϪ1 3055, 2987, 2305, 1716, 1420, 1259; δH (300
General method for the preparation of Cbz-protected amines
MHz; CDCl ) 7.33 (5H, m, ArH), 5.79 (1H, m, CH᎐), 5.09 (2H,
᎐
3
Zinc powder (40 mmol) was added to a solution of the hydroxyl-
amine 2 (1 mmol) in acetic acid (1 mL), water (1 mL) and THF
(2 mL), and the mixture was place in a sonic bath at 50 ЊC until
all the hydroxylamine had been consumed. The resulting mix-
ture was filtered into a separating funnel, and the solid residue
was washed successively with NaOH (2 M; 10 mL) and diethyl
ether (10 mL). The washing was repeated once more and the
ether layer was separated. The aqueous layer was washed with
diethyl ether (2 × 20 mL). The combined washings were dried
over (Na2SO4), filtered and the solvent removed under reduced
pressure. The residue was dissolved in a mixture of THF (2 mL)
and water (2 mL), potassium carbonate (1.1 mmol) was added
and the mixture was stirred at room temperature. After 10 min,
benzyl chloroformate (1.1 mL) was added carefully, and the
heterogeneous solution was stirred vigourously for 1 h. Water
(10 mL) and diethyl ether (10 mL) were added, the layers sep-
arated, and the aqueous layer was washed with two further
s, CH O), 5.06 (2H, m, CH ᎐), 4.63 (1H, d, J 8.5, NH), 3.83
᎐
2 2
(1H, m, NCH), 2.20 (2H, m, CH CH᎐), 1.43–1.16 [5H, m,
᎐
2
(MeCH2)2CH], 0.92 [6H, t, J 7.0, (MeCH2)2C]; δC (75 MHz;
CDCl3) 156.2, 136.8, 135.0, 128.5, 128.00, 127.96, 117.3, 66.5,
52.2, 44.4, 37.0, 22.3, 21.7, 11.8, 11.5; m/z (EI) 275 (Mϩ, 0.2%),
234 (57), 204 (26), 190 (71), 160 (54), 146 (2), 118 (3), 107 (13),
91 (100), 83 (72), 65 (29), 51 (32).
(R)-(؉)-N-Benzyloxycarbonyl-1-phenylpent-4-enylamine 3e.
Obtained from the cleavage of hydroxylamine 2e and protec-
tion, as a colourless solid [82%, 89% ee, 91% ee (recrystallised)];
mp 69–71 ЊC (from light petroleum); [α]D24 ϩ27.6 (c 1.0, CH2Cl2)
(Found: C, 77.3; H, 7.1; N, 4.7. C19H21NO2 requires C, 77.3; H,
7.2; N, 4.7%); νmax (KBr)/cmϪ1 3329, 3058, 3027, 2935, 2909,
2843, 1685, 1537, 1255; δH (300 MHz; CDCl3) 7.25 (10H, m,
ArH), 5.80 (1H, m, H C᎐CH), 5.06 (5H, m, PhCH , NH,
᎐
2
2
H C᎐CH), 4.72 (1H, dd, J 7.8, 15.1, NCH), 2.06 (2H, m, CH ),
᎐
2
2
3450
J. Chem. Soc., Perkin Trans. 1, 1999, 3443–3454

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1.88 (2H, m, CH2); δC (75 MHz; CDCl3) 155.7, 142.3, 137.5,
136.4, 128.7, 128.5, 128.2, 127.4, 126.4, 115.4, 66.8, 55.0,
35.8, 30.4; m/z (EI) 296 (MHϩ, 4%), 295 (Mϩ, 1), 240 (43), 196
(41), 160 (27), 145 (35), 132 (50), 117 (37), 104 (67), 91 (100),
77 (70).
66.8, 60.6, 43.4, 30.1, 29.3, 26.3; m/z (EI) 323 (Mϩ, 0.1%),
240 (77), 240 (65), 196 (62), 155 (5), 132 (26), 104 (25), 91 (100),
77 (31).
(R)-(؊)-N-Benzyloxycarbonyl-1-cyclohexylbut-3-enylamine
(R)-3k. Obtained from the cleavage of hydroxylamine 2k and
protection, as a colourless solid (67%, 92% ee); mp 69–71 ЊC
(from light petroleum) (Found: C, 74.8; H, 8.7; N, 4.8.
C18H25NO2ؒ0.1H2O requires C, 74.7; H, 8.8; N, 4.8%) (Found:
Mϩ, 287.1885. C18H25NO2 requires M, 287.1885); [α]D22 Ϫ16 (c
0.5, CH2Cl2); νmax (CH2Cl2)/cmϪ1 3435, 2931, 2854, 1721, 1507,
1448, 1340, 1213; δH (300 MHz; CDCl3) 7.33 (5H, m, ArH),
(R)-(؉)-8-Benzyloxy-N-(tert-butoxycarbonyl)octan-4-
ylamine 3f. Obtained from the cleavage of 2f and protection, as
a colourless oil (85%, 88% ee); [α]D24 ϩ7.8 (c 0.54, CHCl3) (Found:
MHϩ, 336.2549. C20H34NO3 requires m/z, 336.2539); νmax (neat)/
cmϪ1 3344, 2933, 2863, 1699, 1521, 1365; δH (300 MHz; CDCl3)
7.34 (5H, m, ArH), 4.49 (2H, s, PhCH2), 4.32 (1H, br d, J 6.2,
NH), 3.55 (1H, br s, NCH), 3.46 (2H, t, J 6.4, CH2O), 1.67–1.54
(2H, m, CH2), 1.43 (9H, s, CMe3), 1.43–1.28 (8H, m, 4 × CH2),
0.90 (3H, m, Me); δC (75 MHz; CDCl3) 155.7, 138.6, 128.3,
127.6, 127.5, 78.8, 72.9, 70.2, 50.4, 37.8, 35.4, 29.7, 28.4, 22.6,
19.1, 14.0; m/z (EI) 336 (MHϩ, 3%), 292 (47), 278 (46), 262 (24),
234 (62), 212 (29), 206 (15), 192 (87), 172 (74), 130 (46), 116
(86), 107 (63), 91 (100), 77 (60).
5.75 (1H, m, CH᎐), 5.09 (2H, m, CH ᎐), 5.02 (2H, s, CH O),
᎐
᎐
2
2
4.55 (1H, br d, J 9.0, NH), 3.58 (1H, m, NCH), 2.28 (1H, m,
CH CH᎐), 2.14 (1H, m, CH CH᎐), 1.73 (5H, m, cyclohexyl),
᎐
᎐
2
2
1.09 (6H, m, cyclohexyl); δC (100 MHz; CDCl3) 156.3, 136.7,
134.7, 128.5, 128.1, 117.5, 66.5, 55.2, 41.4, 39.7, 36.7, 28.3, 26.4,
26.2, 26.1; m/z (EI) 287 (Mϩ, 1%), 246 (51), 202 (61), 180 (3),
160 (44), 138 (10), 120 (3), 107 (34), 91 (100), 79 (39), 65 (51),
55 (50), 51 (31).
(S)-(؊)-5-Benzyloxy-N-(tert-butoxycarbonyl)-1-phenylpentyl-
amine 3g. Obtained from the cleavage of 2g and protection, as a
colourless oil (31%, 77% ee); [α]D22 Ϫ18.0 (c 2.0, CHCl3) (Found:
Mϩ, 369.2301. C23H31NO3 requires M, 369.2304); νmax (neat)/
cmϪ1 3338, 2975, 2935, 2861, 1699, 1496, 1170; δH (300 MHz;
CDCl3) 7.37–7.24 (10H, m, ArH), 4.83 (1H, br s, NH), 4.60
(1H, br s, NCH), 4.48 (2H, s, PhCH2), 3.44 (2H, t, J 6.4, CH2O),
1.76–1.59 (4H, m, 2 × CH2), 1.51–1.27 (2H, m, CH2), 1.42 (9H,
br s, CMe3); δC (75 MHz; CDCl3) 144.1, 138.5, 128.5, 128.4,
127.7, 127.5, 127.1, 126.3, 72.9, 70.0, 54.1, 36.8, 29.4, 28.4, 23.0;
m/z (EI) 369 (Mϩ, 1%), 268 (11), 206 (25), 161 (26), 150 (82),
106 (100), 91 (80).
(S)-(؉)-N-Benzyloxycarbonyl-1-cyclohexylbut-3-enylamine
(S)-3k. Obtained from the cleavage of hydroxylamine 2l and
protection, as a colourless solid (51%, 89% ee); mp 67–68 ЊC
(from light petroleum); [α]D22 ϩ19.2 (c 1.2, CHCl3); identical
spectroscopic properties with those of the enantiomer.
(S)-(؊)-N-Benzyloxycarbonyl-3-methyl-1-phenylbutan-2-
ylamine 3l. Obtained from the cleavage of 2n and protection, as
a colourless solid (37%, 98% ee); mp 103–104 ЊC (from light
petroleum); [α]D26 Ϫ2.0 (c 0.8, CHCl3) (Found: C, 76.6; H, 8.1;
N, 4.6. C19H23NO2 requires C, 76.7; H, 7.8; N, 4.7%); νmax
(KBr)/cmϪ1 3345, 2950, 2873, 1687, 1535, 1234, 1024; δH (300
MHz; CDCl3) 7.35–7.17 (10H, m, ArH), 5.05 (1H, d, J 12.1,
CHHO), 5.01 (1H, d, J 12.1, CHHO), 4.60 (1H, br d, J 9.5,
NH), 3.83 (1H, m, NCH), 2.82 (1H, dd, J 6.0, 13.8, PhCHH),
2.69 (1H, dd, J 8.0, 13.8, PhCHH), 1.77 (1H, m, CHMe2), 0.98
(3H, d, J 6.8, Me), 0.93 (3H, d, J 6.8, Me); δC (75 MHz; CDCl3)
196.1, 156.6, 138.4, 136.7, 129.2, 128.5, 128.4, 127.9, 126.3,
66.5, 57.3, 38.6, 30.8, 19.6, 17.2; m/z (EI) 297 (Mϩ, 1%), 254
(100), 206 (79), 162 (81), 107 (13), 91 (100), 77 (14).
(R)-(؉)-N-Benzyloxycarbonyl-1-cyclohexylpentylamine 3h.
Obtained from the cleavage of hydroxylamine 2h and protec-
tion, as a colourless solid [79%, 96% ee (recrystallised)]; mp 98–
99 ЊC (from light petroleum); [α]D23 ϩ13.0 (c 1.0, CH2Cl2) (Found:
C, 75.2; H, 9.1; N, 4.5. C19H29NO2 requires C, 75.2; H, 9.6; N,
4.6%); νmax (KBr)/cmϪ1 3437, 2925, 2850, 1690, 1639, 1537; δH
(300 MHz; CDCl3) 7.35 (5H, m, ArH), 5.12 (1H, d, J 12.1,
PhCHH), 5.07 (1H, d, J 12.2, PhCHH), 4.54 (1H, br d, J 9.8,
NH), 3.49 (1H, m, NCH), 1.8–0.9 (17H, m, CH, 8 × CH2), 0.89
(3H, t, J 5.8, Me); δC (75 MHz; CDCl3) 156.4, 136.8, 128.5,
128.1, 66.5, 55.8, 42.2, 32.1, 29.7, 28.3, 28.1, 26.5, 26.3, 26.3,
22.7, 14.1; m/z (CI) 304 (MHϩ, 10%), 170 (100), 86 (60).
(S)-(؊)-N-(tert-Butoxycarbonyl)-1-phenylhexan-2-ylamine
3m. Obtained from the cleavage of 2o and protection, as a
colourless solid (78%, >96% ee); mp 74–75 ЊC (from 50% aq.
ethanol); [α]D20 Ϫ9.5 (c 1.05, CH2Cl2) (Found: C, 73.9; H, 10.1;
N, 4.9. C17H27NO2 requires C, 73.6; H, 9.8; N, 5.0%); νmax
(KBr)/cmϪ1 3367, 2977, 2921, 2857, 1683, 1527, 1365; δH (300
MHz; CDCl3) 7.24 (5H, m, ArH), 4.28 (1H, br s, NH), 3.80
(1H, br s, NCH), 2.75 (2H, d, J 6.1, CH2Ph), 1.41 (9H, s,
CMe3), 1.31 (6H, m, 3 × CH2), 0.87 (3H, t, J 6.9, Me); δC (75
MHz; CDCl3) 155.5, 138.4, 129.5, 128.2, 126.2, 33.9, 28.3,
28.15, 22.5, 14.0; m/z (CI) 278 (MHϩ, 22%), 240 (2), 239 (14),
222 (4), 127 (5), 126 (15), 112 (11), 111 (36), 110 (13), 97 (16), 96
(22), 87 (11), 86 (68), 71 (19), 70 (100).
(R)-(؊)-N-Benzyloxycarbonyl-1-cyclohexyl-2,2-dimethyl-
propylamine 3i. Obtained from the cleavage of hydroxylamine
2i and protection, as a colourless oil (25%, 96% ee); [α]D23 Ϫ1.0
(c 0.38, CH2Cl2) (Found: MHϩ, 304.2282. C19H30NO2 requires
m/z, 304.2277); νmax (KBr)/cmϪ1 3577, 3345, 2925, 2848, 1696,
1532; δH (300 MHz; CDCl3) 7.35 (5H, m, ArH), 5.15 (1H, d,
J 12.2, PhCHH), 5.08 (1H, d, J 12.2, PhCHH), 4.75 (1H, br d,
J 9.8, NH), 3.32 (1H, dd, J 11.0, 1.7, NCH), 1.69 (5H, m, CH,
2 × CH2), 1.15 (6H, m, 3 × CH2), 0.93 (9H, s, CMe3); δC (75
MHz; CDCl3) 156.9, 136.8, 128.5, 128.1, 66.7, 63.7, 38.5, 35.6,
33.9, 28.4, 27.3, 26.8, 26.4, 26.2; m/z (EI) 304 (MHϩ, 2%), 246
(100), 220 (17), 176 (15), 91 (58).
(S)-(؊)-N-(tert-Butoxycarbonyl)-4-methyl-1-phenylpentan-2-
ylamine 3n. Obtained from the cleavage of 2p and protection, as
a colourless solid (67%, >96% ee); mp 116–117 ЊC (from 50% aq.
ethanol); [α]D20 Ϫ23.6 (c 1.1, CH2Cl2) (Found: C, 74.0; H, 10.0; N,
5.0. C17H27NO2 requires C, 73.6; H, 9.8; N, 5.0%); νmax (KBr)/
cmϪ1 3407, 2098, 1683, 1652, 1365, 1172; δH (300 MHz; CDCl3)
7.22 (5H, m, ArH), 4.27 (1H, br s, NH), 3.90 (1H, br s, NCH),
2.75 (2H, d, J 4.6, CH2Ph), 1.75–1.61 (1H, m, CHMe2), 1.40
(9H, s, CMe3), 1.22 (2H, t, J 7.2, CH2CMe2), 0.88 (6H, t, J 6.4,
CMe2); δC (75 MHz; CDCl3) 155.4, 138.3, 129.6, 128.2, 126.2,
78.9, 49.6, 43.6, 41.9, 28.4, 24.8, 23.2, 22.0; m/z (CI) 278 (MHϩ,
87%), 239 (100), 222 (19), 186 (25), 179 (5), 178 (51), 159 (14),
134 (3), 133 (10), 117 (3), 116 (14), 112 (11), 88 (12), 87 (8),
86 (67).
(S)-(؊)-N-Benzyloxycarbonyl-ꢁ-cyclohexylbenzylamine
3j.
Obtained from the cleavage of hydroxylamine 2j and protec-
tion, as a colourless solid [62%, 100% ee (recrystallised)]; mp
119–121 ЊC (from light petroleum–dichloromethane); [α]D22
Ϫ23.4 (c 1.0, CH2Cl2) (Found: C, 78.0; H, 8.2; N, 4.2.
C21H25NO2 requires C, 78.0; H, 7.8; N, 4.3%); νmax (KBr)/cmϪ1
3437, 3360, 2919, 2853, 1690, 1521; δH (300 MHz; CDCl3) 7.25
(10H, m, ArH), 5.25 (1H, br d, J 8.7, NH), 5.12 (1H, d, J 12.3,
PhCHH), 5.04 (1H, d, J 12.3, PhCHH), 4.51 (1H, t, J 8.2,
NCH), 1.90–0.90 (11H, m, CH, 5 × CH2); δC (75 MHz; CDCl3)
156.0, 141.7, 136.5, 128.5, 128.4, 128.20, 128.15, 127.1, 126.9,
J. Chem. Soc., Perkin Trans. 1, 1999, 3443–3454
3451

View Article Online
(S)-(؊)-N-Benzyloxycarbonyl-1-phenylpentylamine 3o. Ob-
tained from the cleavage of hydroxylamine 2q and protection,
as a colourless solid [87%, 92% ee (recrystallised)]; mp 80–81 ЊC
(from light petroleum); [α]D21 Ϫ24.0 (c 1.0, CH2Cl2) (Found: C,
76.8; H, 7.9; N, 4.7. C19H23NO2 requires C, 76.7; H, 7.8; N,
4.7%); νmax (KBr)/cmϪ1 3419, 3334, 3031, 2950, 2930, 2855,
1680, 1534, 1257, 1045; δH (300 MHz; CDCl3) 7.28 (10H,
m, ArH), 5.12 (1H, d, J 12.2, PhCHH), 5.09 (1H, br s, NH),
5.04 (1H, d, J 12.2, PhCHH), 4.68 (1H, dd, J 7.3, 14.7, NCH),
1.76 (2H, m, CH2), 1.27 (4H, m, 2 × CH2), 0.88 (3H, t, J 6.9,
Me); δC (75 MHz; CDCl3) 155.7, 142.7, 136.5, 128.6, 128.5,
128.2, 127.3, 126.4, 66.8, 55.5, 36.5, 28.3, 22.5, 14.0; m/z (EI)
297 (Mϩ, 0.4%), 240 (77), 196 (70), 132 (20), 104 (27), 91 (100),
77 (21).
The mixture was acidified to pH 1 with hydrochloric acid (1 M)
and extracted with diethyl ether (2 × 5 mL). The aqueous layer
was basified to pH 14 with aq. sodium hydroxide (3 M) and
extracted with dichloromethane (4 × 5 mL). The extracts were
combined, dried (Na2SO4), filtered and evaporated to give the
title compound as a colourless oil (41%); [α]D20 Ϫ38.7 (c 0.15,
CH2Cl2) {lit.,11a [α]D Ϫ37.3 (c 0.12, CH2Cl2)}; δH (300 MHz;
CDCl3) 7.28–7.21 (5H, m, ArH), 2.90–2.80 (1H, m, PhCHH),
2.46–2.37 (1H, m, PhCHH), 1.75–1.64 (1H, m, CHMe2), 1.19
(2H, br s, NH2), 1.01 (3H, d, J 5.5, Me), 0.99 (3H, d, J 5.5, Me).
(S)-(؉)-1-Phenylhexan-2-ylamine hydrochloride. The N-Boc-
amine 3m (140 mg, 0.5 mmol) was dissolved in 1,4-dioxane
(4 mL). Conc. hydrochloric acid was added dropwise to the
mixture until all of the amine was consumed (45 min). The
1,4-dioxane was removed in vacuo and the residue triturated
with diethyl ether to give the title compound as a colourless
solid (67%); mp 157–158 ЊC (lit.,11b 161–162 ЊC); [α]D20 ϩ20.0
(c 0.2, H2O) {lit.,11b [α]D20 ϩ14.95 (H2O)}; δH (400 MHz; CDCl3)
(R)-(؉)-N-Benzyloxycarbonyl-1-phenylbut-3-enylamine 3p.
Obtained from the cleavage of hydroxylamine 2r and protec-
tion, as a colourless solid (66%, 95% ee); mp 68–69 ЊC (from
light petroleum) (Found: C, 76.7; H, 6.6; N, 4.9. C18H19NO2
requires C, 76.8; H, 6.8; N, 5.0%) (Found: Mϩ, 281.1416.
C18H19NO2 requires M, 281.1416); [α]D22 ϩ43.6 (c 0.5, CH2Cl2);
νmax (CH2Cl2)/cmϪ1 3437, 3061, 2929, 1721, 1503, 1419, 1251,
893; δH (300 MHz; CDCl3) 7.28 (10H, m, ArH), 5.67 (1H,
m, CH᎐), 5.13 (2H, m, ᎐CH ), 5.09 (2H, s, CH O), 5.08 (1H, br
ϩ
8.46 (3H, br s, NH3 ), 7.31–7.25 (5H, m, ArH), 3.47 (1H, br s,
NCH), 3.24 (1H, PhCHH), 2.94 (1H, br s, PhCHH), 1.70–1.30
(6H, m, 3 × CH2), 0.85 (3H, br s, Me).
General method for the preparation of Cbz-protected ꢀ-amino
methyl esters
᎐
᎐
2
2
s, NH), 4.82 (1H, m, CHN), 2.54 (2H, m, CH CH᎐); δ (75
᎐
2
C
MHz; CDCl3) 155.7, 142.0, 136.5, 133.8, 128.6, 128.5, 128.1,
127.3, 126.3, 126.2, 118.4, 66.8, 54.5, 41.0; m/z (EI) 281 (Mϩ,
0.1%), 240 (65), 196 (60), 132 (21), 107 (11), 91 (100), 77 (47),
65 (46).
Ozone was passed through a solution of an N-Cbz-protected
homoallylamine 3 (1.64 mmol) in CH2Cl2 (13 mL) and meth-
anolic sodium hydroxide (3.3 mL; 2.5 M) at Ϫ78 ЊC. After 2 h
(complete consumption of starting material) a yellow precipi-
tate had formed. Diethyl ether (5 mL) and water (5 mL) were
added and allowed to warm to room temperature. The mixture
was exhaustively extracted with diethyl ether (5 × 5 mL). The
extracts were combined, dried (Na2SO4), filtered and evapor-
ated. Column chromatography on silica gel eluting with diethyl
ether–light petroleum (1:1) gave the ester.
(S)-(؊)-N-Benzyloxycarbonyl-1-(4-methoxyphenyl)but-3-
enylamine 3q. Obtained from the cleavage of hydroxylamine 2s
and protection, as a colourless solid (62%, 98% ee); mp 67–68 ЊC
(from light petroleum) (Found: C, 73.3; H, 6.8; N, 4.5.
C19H21NO3 requires C, 73.0; H, 6.7; N, 4.4%) (Found: MHϩ,
312.2249. C19H22NO3 requires m/z, 312.1521); [α]D22 Ϫ36.6 (c 0.7,
CH2Cl2); νmax (CH2Cl2)/cmϪ1 3433, 3054, 2986, 2305, 1718,
1511, 1260; δH (300 MHz; CDCl3) 7.32 (5H, m, ArH), 7.21 (2H,
Methyl (R)-(؊)-3-benzyloxycarbonylamino-4-methylpentan-
oate 4a. Obtained from the oxidative cleavage of the Cbz-
protected homoallylamine 3c, as a colourless oil (36%) (Found:
Mϩ, 279.1471. C15H21NO4 requires M, 279.1471); [α]D24 Ϫ24.6
(c 1.4, CHCl3); νmax (film)/cmϪ1 3346, 2955, 1692, 1661, 1549,
1474, 1250; δH (300 MHz; CDCl3) 7.35 (5H, m, ArH), 5.15 (1H,
br s, NH), 5.10 (2H, s, CH2O), 3.84 (1H, m, NCH), 3.65 (3H, s,
OMe), 2.53 (2H, d, J 3.21, CH2CO), 1.84 (1H, m, CHMe2), 0.92
(6H, d, J 6.8, Me2C); δC (100 MHz; CDCl3) 172.1, 156.0, 136.6,
128.5, 128.0 (2 C), 66.6, 53.6, 51.7, 36.9, 31.7, 19.3, 18.5; m/z
(EI) 279 (Mϩ, 2%), 236 (14), 206 (1), 192 (20), 162 (1), 144 (2),
128 (1), 108 (7), 91 (100), 79 (3), 65 (5), 55 (2).
d, J 8.5, ArH), 7.18 (2H, d, J 8.5, ArH), 5.66 (1H, m, CH᎐),
᎐
5.13 (2H, m, CH ᎐), 5.09 (2H, s, CH O), 5.08 (1H, br s, NH),
᎐
2
2
4.76 (1H, d, J 6.1 NCH), 3.81 (3H, s, MeO), 2.43 (2H, m,
CH CH᎐); δ (100 MHz; CDCl3) 158.8, 155.6, 136.5, 134.1,
᎐
2
C
133.9, 128.5, 128.2, 127.5, 118.3, 114.0, 66.7, 55.3, 54.1, 41.0;
one aromatic C not observed; m/z (EI) 312 (MHϩ, 16%), 288
(1), 271 (70), 251 (45), 226 (58), 204 (29), 176 (19), 161 (100),
146 (8), 136 (67), 121 (42), 105 (12), 92 (39), 70 (36), 52 (3).
(S)-(؊)-N-Benzyloxycarbonyl-1-(2-naphthyl)pentylamine 3r.
Obtained from the cleavage of hydroxylamine 2t and protec-
tion, as a colourless oil (83%, 91% ee); [α]D22 Ϫ22.2 (c 1.0, CH2Cl2)
(Found: Mϩ, 347.1878. C23H25NO2 requires M, 347.1885); νmax
(KBr)/cmϪ1 3406, 3324, 3052, 2955, 2930, 2858, 1696, 1527,
1239; δH (300 MHz; CDCl3) 7.80 (4H, m, ArH), 7.45 (8H, m,
ArH), 5.27 (1H, d, J 8.4, NH), 5.15 (1H, d, J 12.2, PhCHH),
5.07 (1H, d, J 12.2, PhCHH), 4.88 (1H, dd, J 7.1, 13.8, NCH),
1.86 (2H, m, CH2), 1.32 (4H, m, 2 × CH2), 0.90 (3H, t, J 6.9,
Me); δC (75 MHz; CDCl3) 155.8, 140.2, 136.5, 133.4, 132.8,
128.6, 128.5, 128.22, 128.18, 128.0, 127.7, 126.2, 125.8, 125.2,
124.6, 66.8, 55.6, 36.4, 28.4, 22.5, 14.0; m/z (EI) 347 (Mϩ, 6%),
290 (28), 256 (38), 246 (47), 212 (13), 182 (14), 154 (17), 141
(10), 127 (15), 91 (100).
Methyl (R)-(؊)-3-benzyloxycarbonylamino-4-ethylhexanoate
4b. Obtained from the oxidative cleavage of the Cbz-protected
homoallylamine 3d, as a colourless oil (52%) (Found: Mϩ,
307.1783. C17H25NO4 requires M, 307.1783); [α]D25 Ϫ18 (c 0.4,
CHCl3); νmax (film)/cmϪ1 3352, 2964, 2877, 1699, 1662, 1236; δH
(300 MHz; CDCl3) 7.34 (5H, m, ArH), 5.11 (1H, br s, NH),
5.09 (2H, s, CH2O), 4.11 (1H, m, NCH), 3.63 (3H, s, OMe),
2.51 (2H, m, CH2CO), 1.38–1.28 [5H, m, (CH2Me)2C, CH],
0.89 [6H, t, J 7.1, (MeCH2)C]; δC (75 MHz; CDCl3) 172.2,
156.0, 136.7, 128.4, 128.0 (2 C), 66.6, 51.6, 50.0, 44.2, 37.0, 22.0,
21.6, 11.4, 10.9; m/z (EI) 307 (Mϩ, 1%), 236 (22), 206 (4), 192
(34), 172 (1), 163 (6), 127 (2), 107 (6), 91 (100), 65 (11), 55 (7).
Deprotection reactions
Methyl (R)-(؊)-3-benzyloxycarbonylamino-3-cyclohexylprop-
anoate 4c. Obtained from the oxidative cleavage of the Cbz-
protected homoallylamine (R)-3k, as a colourless solid (39%);
mp 71–72 ЊC (Found: C 68.0; H, 8.0; N, 4.4%; Mϩ, 319.1783.
C18H25NO4 requires C, 67.7; H, 7.9; N, 4.4%) M, 319.1783); [α]D22
Ϫ14 (c 0.7, CHCl3); νmax (CH2Cl2)/cmϪ1 3313, 2923, 2852, 2093,
1729, 1691, 1646, 1544; δH (300 MHz; CDCl3) 7.35 (5H, m,
(S)-(؊)-3-Methyl-1-phenylbutan-2-ylamine. The N-Cbz-
amine 3l (64 mg, 0.21 mmol) was dissolved in methanol (5 mL)
and Pd/C (5%; cat.) was added. The reaction mixture was
stirred under a hydrogen atmosphere for 2.5 h. The catalyst was
filtered off and washed with methanol. The methanol was
evaporated and the residue was taken up in diethyl ether (5 mL).
3452
J. Chem. Soc., Perkin Trans. 1, 1999, 3443–3454

View Article Online
ArH), 5.10 (1H, br s, NH), 5.09 (2H, s, CH2O), 3.80 (1H,
m, NCH), 3.65 (3H, s, OMe), 2.54 (2H, d, J 5.3, CH2CO),
1.66–1.80 (5H, m, cyclohexyl), 1.47 (1H, m, CH), 1.26–0.87
(5H, m, cyclohexyl); δC (75 MHz; CDCl3) 172.3, 156.0, 136.7,
128.4, 128.0 (2 C), 66.6, 52.9, 51.6, 41.3, 36.6, 29.7, 29.0, 26.2,
16.0, 25.9; m/z (EI) 319 (Mϩ, 3%), 246 (1), 236 (17), 202 (2), 162
(2), 136 (1), 108 (11), 91 (100), 79 (6), 65 (7), 55 (12).
(S)-(؉)-3-Benzyloxycarbonylamino-3-cyclohexylpropan-1-ol
5b. Obtained from the oxidative cleavage (with reductive work-
up) of the protected homoallylamine (S)-3k, as a colourless
solid (50%); mp 90–91 ЊC (Found: C, 69.8; H, 8.63; N, 4.6.
C17H25NO3 requires C, 70.1; H, 8.6; N, 4.8%. Found: MHϩ,
292.1915. C17H26NO3 requires m/z, 292.1912); [α]D17 ϩ8 (c 0.5,
CH2Cl2); νmax (film)/cmϪ1 3382, 3326, 2909, 2852, 1687, 1664,
1535, 1621, 1049; δH (300 MHz; CDCl3) 7.34 (5H, m, ArH),
5.13 (1H, d, J 12.1, CHHO), 5.06 (1H, d, J 12.1, CHHO), 4.66
(1H, br d, J 9, NH), 3.64 (3H, m, CH2OH, NCH), 2.97 (1H, br
s, OH), 1.87–1.66 (6H, m, 3 × CH2), 1.40–0.94 (7H, m,
3 × CH2, CH); δC (75 MHz; CDCl3) 157.5, 136.4, 128.6, 128.2,
128.1, 67.0, 59.1, 52.4, 52.3, 35.5, 29.7, 28.7, 26.3, 26.2; m/z (CI)
292 (MHϩ, 3%), 208 (1), 170 (8), 124 (10), 112 (28), 97 (67), 91
(13), 84 (34), 70 (100), 58 (7), 52 (81).
Methyl (R)-(؉)-3-benzyloxycarbonylamino-3-phenylpropan-
oate 4d. Obtained from the oxidative cleavage of the Cbz-
protected homoallylamine 3p, as a colourless solid (41%); mp
65–66 ЊC (from n-hexane) (lit.,22 65 ЊC) (Found: C, 68.9; H, 6.2;
N, 4.4%; Mϩ, 313.1314. Calc. for C18H19NO4: C, 69.0; H, 6.1; N,
4.5%; Mϩ, 313.1314); [α]D22 ϩ17.1 (c 1, CHCl3) {lit.,22 for (S)-
enantiomer [α]D21 Ϫ15.8 (c 0.55, CHCl3)}; νmax (film)/cmϪ1 3332,
3033, 2952, 1733, 1701, 1533, 1242; δH (300 MHz; CDCl3) 7.30
(10H, m, ArH), 5.79 (1H, br s, NH), 5.18 (1H, m, NCH), 5.10
(2H, s, CH2O), 3.60 (3H, s OMe), 2.86 (2H, m, CH2CO); δC (75
MHz; CDCl3) 171.2, 155.6, 140.8, 136.4, 128.7, 128.5, 128.1,
127.7, 126.2, 77.2, 66.9, 57.9, 40.5; m/z (EI) 313 (Mϩ, 2%), 240
(3), 222 (4), 196 (8), 178 (29), 164 (16), 146 (4), 121 (6), 107 (18),
104 (32), 91 (100), 77 (9), 65 (8), 51 (5).
Radical additions
General method for the alkyl radical addition to the benzalde-
hyde oxime ethers. An oxime ether (0.50 g, 1.98 mmol), ethanol
(0.29 mL, 4.94 mmol) and alkyl iodide (4.94 mmol) were dis-
solved in dichloromethane (5 mL). The mixture was cooled to
Ϫ78 ЊC under nitrogen. Boron trifluoride–diethyl ether (1.25
mL, 9.88 mmol) was added and the mixture stirred for 15 min.
Triethylborane (4.9 mL, 4.94 mmol) was added dropwise over a
period of 30 min. The mixture was stirred at Ϫ78 ЊC for 5 h,
and allowed to warm to room temperature overnight. Saturated
aq. ammonium chloride (10 mL) was added, the layers separ-
ated and the aqueous layer extracted with diethyl ether (2 × 10
mL). The combined extracts were dried (MgSO4), filtered and
evaporated. The residue was purified by column chrom-
atography on silica gel eluting with diethyl ether–light petrol-
eum (1:20) to give the following compounds.
Methyl
(S)-(؊)-3-benzyloxycarbonylamino-3-(4-methoxy-
phenyl)propanoate 4e. Obtained from the oxidative cleavage of
the Cbz-protected homoallylamine 3q, as a colourless solid
(33%); mp 76–77 ЊC (from n-hexane) (Found: C, 66.5; H, 6.0; N,
4.1%; Mϩ, 343.1420. C19H21NO5 requires C, 66.5; H, 6.2; N,
4.1%; M, 343.1420); [α]D22 Ϫ26 (c 0.5, CHCl3); νmax (film)/cmϪ1
3340, 1740, 1726, 1517, 1255; δH (300 MHz; CDCl3) 7.33 (5H,
m, ArH), 7.22 (2H, d, J 8.6, ArH), 6.85 (2H, d, J 8.6, ArH), 5.73
(1H, br s, NH), 5.10 (2H, s, CH2O), 5.09 (1H, m, NCH), 3.78
(3H, s, OMe), 3.60 (3H, s, OMe), 2.83 (2H, m, CH2CO); δC (100
MHz; CDCl3) 171.3, 159.0, 155.5, 136.4, 132.9, 128.5, 128.1,
128.0, 127.6, 114.1, 66.8, 55.2, 51.8, 51.2, 40.6; m/z (EI) 343
(Mϩ, 11%), 298 (1), 283 (11), 252 (10), 226 (37), 208 (91), 193
(42), 176 (32), 162 (63), 151 (33), 134 (76), 119 (32), 107 (44), 91
(100), 77 (46), 65 (42), 51 (31).
(S)-2-Methyl-1-phenyl-N-[(S)-1-phenylbutoxy]propyl-
amine 6a.—Obtained from the addition of 2-iodopropane to
the benzaldehyde oxime ether (S)-1h, as a colourless oil (11%,
85% de) (Found: MHϩ, 298.2168. C20H28NO requires m/z,
298.2171); νmax (neat)/cmϪ1 3430, 2958, 2933, 2851, 1454; δH
(400 MHz; CDCl3) 7.38–7.23 (10H, m, ArH), 5.51 (1H, br s,
NH), 4.59 (1H, dd, J 6.9, 6.9, OCH), 3.79 (1H, d, J 6.8, NCH),
2.16 (1H, m, CHMe2), 1.82 (1H, m, CHH), 1.57 (1H, m, CHH),
1.40–1.29 (2H, m, CH2), 0.98 (3H, t, J 6.7, Me), 0.95 (3H, t,
J 8.6, Me), 0.80 (3H, d, J 6.8, Me); δC (75 MHz; CDCl3) 143.0,
140.5, 128.3, 128.1, 127.9, 127.3, 127.1, 126.8, 84.9, 71.1, 38.4,
30.5, 20.2, 19.2, 18.5, 14.1; m/z (CI) 298 (MHϩ, 12%), 166 (10),
150 (100), 148 (29), 134 (11), 106 (30).
General method for the preparation of Cbz-protected 1,3-amino
alcohols
An N-Cbz-protected homoallylamine 3 (0.87 mmol) was
dissolved in dichloromethane (5 mL) and cooled to Ϫ78 ЊC.
Ozone was passed for 3 h and flushed with nitrogen. The reac-
tion mixture was warmed to 0 ЊC and ethanol was added to
homogenise the mixture. Sodium borohydride (1.91 mmol) in
aq. ethanol (50%; 8 mL) was added dropwise to the reaction
mixture, which was stirred for 12 h. The reaction mixture was
poured into ice–water containing a few drops of HCl and
extracted with diethyl ether (4 × 5 mL). The organic extracts
were combined, dried (Na2SO4), filtered and evaporated. The
residue was purified by flash chromatography on silica gel,
eluting with ethyl acetate–light petroleum (1:1).
(S)-1-Phenyl-N-[(S)-1-phenylbutoxy]propylamine
6b.—
Obtained from the addition of iodoethane to the benzaldehyde
oxime ether (S)-1h, as a colourless oil (11%, de 51%) (Found:
MHϩ, 284.2019. C19H26NO requires m/z, 284.2014); νmax (neat)/
cmϪ1 3423, 2960, 2933, 2873, 1492, 1454; δH (400 MHz; CDCl3)
7.9 (10H, m, ArH), 5.35 (1H, br s, NH), 4.65 (1H, dd, J 7.3, 7.3,
OCH), 3.95 (1H, dd, J 5.0, 8.8, NCH), 2.05 (1H, m, CHH), 1.90
(1H, m, CHH), 1.76–1.00 (4H, m, 2 × CH2), 0.98 (3H, t, J 7.3,
Me), 0.88 (3H, t, J 7.4, Me); δC (75 MHz; CDCl3) 143.1, 141.3,
128.30, 128.29, 127.9, 127.4, 127.3, 126.7, 85.4, 67.4, 38.6, 30.5,
26.7, 18.9, 14.2, 10.6; m/z (CI) 284 (MHϩ, 32%), 166 (7), 150
(44), 136 (100), 134 (54), 106 (30), 91 (7).
(R)-(؊)-3-Benzyloxycarbonylamino-4-ethylhexan-1-ol
5a.
Obtained from the oxidative cleavage (with reductive work-up)
of the protected homoallylamine 3d, as a colourless solid (56%);
mp 39–40 ЊC (Found: C, 68.8; H, 9.3; N, 4.9%; Mϩ, 279.1836.
C16H25NO3 requires C, 68.8; H, 9.0; N, 5.0%); M, 279.1834); [α]D17
Ϫ10 (c 0.2, CH2Cl2); νmax (film)/cmϪ1 3415, 3333, 2962, 2933,
2976, 1702, 1537, 1248, 1058; δH (300 MHz; CDCl3) 7.34 (5H,
m, ArH), 5.11 (1H, d, J 12.1, CHHO), 5.05 (1H, d, J 12.1,
CHHO), 4.79 (1H, d, J 9.3, NH), 3.96 (1H, m, NCH), 3.65 (2H,
m, CH2OH), 3.10 (1H, br s, OH), 1.76 (1H, m, CH), 1.45–1.17
(6H, m, 3 × CH2), 0.91 (6H, t, J 8.7, 2 × CH3); δC (75 MHz;
CDCl3) 157.5, 136.4, 128.5, 128.2, 128.0, 66.9, 59.1, 49.1, 45.5,
35.6, 22.6, 22.1, 14.2, 11.9, 11.6; m/z (EI) 279 (0.3%), 262 (10),
236 (20), 222 (1), 208 (70), 190 (22), 164 (80), 146 (10), 108 (23),
91 (100), 77 (24), 65 (41), 55 (35).
Crystal data
Common to both determinations: Rigaku AFC7S diffract-
ometer with Cu radiation. T = 296 K, all non-H atoms refined
anisotropically. CCDC reference number 207/360. See http://
www.rsc.org/suppdata/p1/1999/3443 for crystallographic files in
.cif format.
( )-O-(1-Phenylbutyl)-2-naphthaldehyde oxime ( )-1j. C21-
H21NO, M = 303.4, monoclinic, P21/c, a = 18.514(3), b =
7.606(2), c = 12.166(1) Å, β = 105.58(1)Њ, V = 1650 Å3, ρcalc
=
1.22 g cmϪ3, Z = 4, µ(Cu-Kα) = 0.58 mmϪ1; 2767 reflections
J. Chem. Soc., Perkin Trans. 1, 1999, 3443–3454 3453

View Article Online
15 For recent examples of the Arndt–Eistert homologation of α-amino
measured, 2676 independent (Rint 0.06), 1942 observed with
I > 2σ(I), to yield R = 0.047.
acids, see: J. Podlech and D. Seebach, Angew. Chem., Int. Ed. Engl.,
1995, 34, 471; Liebigs Ann., 1995, 1217; R. Caputo, E. Cassano, L.
Longobardo and G. Palumbo, Tetrahedron, 1995, 51, 12337; D.
Seebach, M. Overhand, F. N. M. Kuhnle, B. Martinoni, L. Oberer,
U. Hommel and H. Widmer, Helv. Chim. Acta, 1996, 79, 913; C.
Guibourdenche, D. Seebach and F. Natt, Helv. Chim. Acta, 1997,
80, 1; A. Leggio, A. Liguori, A. Procopio and G. Sindona, J. Chem.
Soc., Perkin Trans. 1, 1997, 1969; R. E. Marti, K. H. Bleicher and
K. W. Bair, Tetrahedron Lett., 1997, 38, 6145.
(S)-O-(1-Phenylbutyl)thiazol-2-ylcarbaldehyde oxime (S)-1m.
C14H16N2OS, M = 260.4, monoclinic, P21, a = 9.087(3), b =
7.841(4), c = 10.648(3) Å, β = 111.95(2)Њ, V = 704 Å3, ρcalc = 1.23
g cmϪ3, Z = 2, µ(Cu-Kα) = 1.96 mmϪ1; 1226 reflections meas-
ured, 1148 independent (Rint 0.15), 839 observed with I > 2σ(I),
to yield R = 0.039; the Flack parameter, 0.05(7), did not allow
an unambiguous determination of absolute stereochemistry to
be made. The assignment of the (S)-configuration is based on
the chemistry involved.
16 S. G. Davies and D. R. Fenwick, J. Chem. Soc., Chem. Commun.,
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Fenwick and O. Ichihara, Tetrahedron: Asymmetry, 1997, 8, 3387;
T. Ishikawa, K. Nagai, T. Kudoh and S. Saito, Synlett, 1998, 1291;
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Acknowledgements
We thank the EPSRC for support of this work, the EPSRC and
SmithKline Beecham for a CASE Award (to C. L.), Dr Andrew
Lightfoot for preliminary experiments and helpful discussions,
and the EPSRC Mass Spectrometry Centre at Swansea for mass
spectra. We are grateful to Drs Jonathan Goodman and John
Sandall for the calculations of oxime geometries.
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Paper 9/07186E
3454
J. Chem. Soc., Perkin Trans. 1, 1999, 3443–3454