Diastereoselective [2,3]-sigmatropic rearrangements of lithium N-benzyl-O-allylhydroxylamides bearing a stereogenic centre adjacent to the migration terminus

Article abstract of DOI:10.1039/b207069n

The diastereoselective [2,3]-sigmatropic rearrangements of lithium N-benzyl-O-allylhydroxylamides bearing a stereogenic centre adjacent to the migration terminus are examined. (E)-N-Benzyl-O(4-phenylpent-2-enyl)hydroxylamine rearranges in 30% de to afford

Full text of DOI:10.1039/b207069n

View Article Online / Journal Homepage / Table of Contents for this issue
Diastereoselective [2,3]-sigmatropic rearrangements of lithium
N-benzyl-O-allylhydroxylamides bearing a stereogenic centre
adjacent to the migration terminus
1
Steven D. Bull, Stephen G. Davies,* Sara Hernández Domíngez, Simon Jones, Anne J. Price,
Thomas G. R. Sellers and Andrew D. Smith
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford,
UK OX1 3QY. E-mail: steve.davies@chemistry.ox.ac.uk
Received (in Cambridge, UK) 18th July 2002, Accepted 1st August 2002
First published as an Advance Article on the web 2nd September 2002
The diastereoselective [2,3]-sigmatropic rearrangements of lithium N-benzyl-O-allylhydroxylamides bearing a
stereogenic centre adjacent to the migration terminus are examined. (E)-N-Benzyl-O-(4-phenylpent-2-enyl)-
hydroxylamine rearranges in 30% de to afford syn-(3RS,4RS )-3-(N-benzyl-N-hydroxy)-4-phenylpent-1-ene as the
major diastereoisomer, consistent with the rearrangement proceeding under moderate steric control. Rearrange-
ments of both lithium (E)- and (Z)-N-benzyl-O-(4-methoxy-4-phenylbut-2-enyl)hydroxylamides furnish syn-
(1RS,2RS )-1-phenyl-1-methoxy-3-(N-benzylamino)but-3-ene in ≥90% and 88% de respectively, consistent with
these rearrangements proceeding under chelation control.
Introduction
Reactions that are capable of producing multiple functionalities
both regio- and stereoselectively are essential for synthesis.
Sigmatropic rearrangements,1 in particular stereoselective [2,3]-
sigmatropic shifts,2 are one such class of transformations that
have found extensive synthetic application.3 Within this field,
previous investigations from our laboratory have shown that,
upon treatment with n-BuLi in THF, a range of N-benzyl-O-
allylhydroxylamines 1 undergo an intramolecular [2,3]-sigma-
tropic rearrangement to afford N-benzyl-N-hydroxyallylamines
2, which after subsequent reduction afford the corresponding
N-benzyl-N-allylamines 3 in good yield.4 The allylic amine
functionality produced in this rearrangement protocol has been
recognised both for its presence in molecules of biological
interest,5 and as a synthon for the introduction of a variety of
Fig. 1
other functional groups (Scheme 1).6
We present herein our investigations concerning the effect of
allylic C(4)-stereocentres bearing alkyl and alkoxy substituents
on the diastereoselectivity of the N,O-rearrangement. Part of
this work has been previously communicated.8
Results
Probing steric effects in the diastereoselective [2,3]-sigmatropic
N,O-rearrangement
Initial attention was directed towards elucidating the level of
diastereoselectivity imposed in the N,O-rearrangement on the
basis of steric control through rearrangement of (E)-N-benzyl-
O-(4-phenylpent-2-enyl)hydroxylamine 8, which was prepared
from racemic 2-phenylpropanal 4 in five steps. Wittig reaction
of aldehyde 4 with ethyl (triphenylphosphoranylidene)acetate
gave the (E)-α,β-unsaturated ester 5 in quantitative yield and in
>95% de.9 Subsequent DIBAL–H reduction gave the allylic
alcohol 6 in 75% yield, followed by bromination with PBr3 and
bromide displacement with the potassium anion of benzalde-
hyde oxime to afford oxime 7 in 64% yield over two steps.
Scheme 1 Reagents and conditions: (i) n-BuLi, THF, Ϫ78 ЊC to rt;
(ii) Zn, HCl(aq), 80 ЊC.
Due to the expanding interest in the stereoselective synthesis
of such compounds,7 investigations concerning the rearrange-
ment of chiral N-benzyl-O-allylhydroxylamines are described
herein. It was envisaged that a stereogenic centre adjacent to the
migration terminus could control the diastereoselectivity of the
reaction, allowing the stereoselective synthesis of allylic amines
(Fig. 1).
Reduction of the C᎐N bond with pyridine–borane–HCl gave
᎐
the desired substrate (E)-N-benzyl-O-(4-phenylpent-2-enyl)-
hydroxylamine 8 in 78% yield (Scheme 2).
Deprotonation of (E)-N-benzyl-O-(4-phenylpent-2-enyl)-
hydroxylamine 8 according to our established protocol4 pro-
DOI: 10.1039/b207069n
J. Chem. Soc., Perkin Trans. 1, 2002, 2141–2150
This journal is © The Royal Society of Chemistry 2002
2141

View Article Online
acid hydrochloride (commercially available10 as a 2 : 1 mixture
of (2SR,3RS )-13 to (2RS,3RS )-14 diastereoisomers)11 was
transformed into a mixture of the primary amines 17 and 18.
Thus, treatment of the mixture of 13 and 14 with thionyl
chloride in methanol and subsequent N-Boc protection, fol-
lowed by DIBAL–H reduction to the aldehyde and Wittig
extension12 gave a 2 : 1 ratio of syn-(3RS,4RS )-15 to anti-
(3SR,4RS )-16 diastereoisomers of 3-(N-tert-butoxycarbonyl)-
4-phenylpent-1-ene. Hydrogenation and N-Boc deprotection
gave an authentic sample of a 2 : 1 mixture of syn-(2RS,3RS )-
to anti-(2RS,3SR)-2-phenyl-3-aminopentane 17 and 18 respec-
tively (Scheme 4).
Scheme 2 Reagents and conditions: (i) Ph3P᎐CHCO2Et (1.0 eq.), THF;
᎐
Ϫ78 ЊC to rt; (ii) DIBAL–H (2.5 eq.), CH2Cl2; Ϫ78 ЊC to rt; (iii) PBr3,
Et2O, rt; (iv) PhCH᎐NOK, THF, rt; (v) BH3–pyr, EtOH, HCl, rt.
᎐
moted the [2,3]-sigmatropic N,O-rearrangement, affording a
mixture of allylic amines 9 and 10 in >90% conversion, but
with only a moderate 30% diastereomeric excess.9 In order to
facilitate identification of the relative configuration within
hydroxylamines 9 and 10, separation by chromatography was
attempted. However, 9 and 10 proved somewhat unstable to
purification on silica, which furnished 9 and 10 as an insepar-
able mixture of diastereoisomers in 43% yield, much lower than
that expected from the high levels of conversion apparent in the
crude reaction mixture. Subsequent reduction of the mixture
of hydroxylamines 9 and 10 (65 : 35, 30% de) to amines 11
and 12 was effected using Zn–HCl (aq), which also facilitated
their separation by flash chromatography, affording the amines
11 and 12 in 53% (82% of theoretical) and 30% (86% of
theoretical) yields respectively (Scheme 3).
Scheme 4 Reagents and conditions: (i) MeOH, SOCl2, 0 ЊC to rt; (ii)
Boc2O, NaHCO3, MeOH, 0 ЊC to rt; (iii) DIBAL–H (1.1 eq.), toluene
Ϫ78 ЊC; (iv) Ph3PCH3Br (1.05 eq.), n-BuLi, THF, Ϫ78 ЊC to rt; (v)
Pd(OH)2 on C, H2 (1 atm), MeOH, rt; (vi) TFA, CH2Cl2, rt then
NaOH(aq)
.
The relative configurations within 11 and 12 were established
via chemical correlation in which 2-amino-3-phenylbutanoic
Concomitant hydrogenation and hydrogenolysis of the
minor diastereoisomer (3SR,4RS )-12 from the N,O-rearrange-
ment of O-allylhydroxylamine 8 afforded anti-(2RS,3SR)-2-
phenyl-3-aminopentane 18 (Scheme 5), which was shown by 1H
NMR spectroscopy to be identical to the minor component
prepared from 2-amino-3-phenylbutanoic acid hydrochloride
(Scheme 4). This protocol establishes unambiguously that the
major diastereoisomer from the rearrangement of 8 is syn-
(3RS,4RS )-3-(N-benzyl-N-hydroxy)-4-phenylpent-1-ene 9, and
that of the minor diastereoisomer is anti-(3SR,4RS )-3-(N-
benzyl-N-hydroxy)-4-phenylpent-1-ene 10.
Scheme 5 Reagents and conditions: (i) Pd(OH)2 on C, H2 (1 atm),
MeOH, rt.
Probing stereoelectronic and chelation effects in the
diastereoselective [2,3]-sigmatropic N,O-rearrangement
In order to probe whether an alkoxy substituent would allow
stereocontrol in the [2,3]-N,O-rearrangement, (E)-N-benzyl-
O-(4-methoxy-4-phenylbut-2-enyl)hydroxylamine 24 was pre-
pared as a model substrate. Thus, methyl O-methylmandelate
19 was reduced with DIBAL–H in toluene at Ϫ78 ЊC and the
Scheme 3 Reagents and conditions: (i) n-BuLi, THF, Ϫ78 ЊC then rt;
(ii) H2O; (iii) Zn, HCl (aq), 80 ЊC.
2142
J. Chem. Soc., Perkin Trans. 1, 2002, 2141–2150

View Article Online
resulting aldehyde treated in situ with ethyl (triphenylphos-
phoranylidene)acetate to afford the (E)-α,β-unsaturated ester
20 in an unoptimised 53% yield and >95% de. Reduction of
ester 20 with DIBAL–H in toluene gave allylic alcohol 21 in
80% yield, which was subsequently treated with N-bromo-
succinimide in the presence of triphenylphosphine to afford the
unstable allylic bromide 22. Treatment of the crude reaction
product of the bromination reaction with the potassium anion
derived from benzaldehyde oxime afforded oxime 23 in an
overall 45% yield from allylic alcohol 21. Reduction of oxime
23 with pyridine–borane–HCl gave the desired rearrange-
ment substrate (E)-N-benzyl-O-(4-methoxy-4-phenylbut-2-
enyl)hydroxylamine 24 in 57% yield (Scheme 6).
The relative syn-(1RS,2RS ) configuration within 1-phenyl-1-
methoxy-3-(N-benzylamino)but-3-ene 26 was established by
X-ray crystallographic analysis of its crystalline HCl salt, which
unambiguously identified syn-(1RS,2RS )-26 as the major dia-
stereoisomer from the N,O-rearrangement of hydroxylamine 24
(Fig. 2).8
Fig. 2 X-Ray crystal structure of hydrated syn-(1RS,2RS )-26ؒHCl.
The high diastereoselectivity (≥90%) observed upon re-
arrangement of (E)-hydroxylamine 24 was confirmed by the
synthesis of an authentic sample of the minor anti-(1RS,2SR)-
diastereoisomer 28 arising from the rearrangement and reduc-
tion protocol. Thus, methyl O-methylmandelate 19 was reduced
to the corresponding aldehyde and, after in situ formation of
the benzyl imine 27, vinylmagnesium bromide addition
Scheme 6 Reagents and conditions: (i) DIBAL–H (1.1 eq.), toluene,
afforded
anti-(1RS,2SR)-1-phenyl-1-methoxy-3-(N-benzyl-
Ϫ78 ЊC, then Ph3P᎐CHCO2Et (1.1 eq.), Ϫ78 ЊC to rt; (ii) DIBAL–H
᎐
amino)but-3-ene 28 in >95% de.13 Comparison of the 1H
NMR spectra from the crude reaction mixture of the Zn–HCl
reduction of the crude rearrangement products allowed con-
firmation of the rearrangement diastereoselectivity as ≥90%
de (Scheme 8).
(2.5 eq.), toluene, Ϫ78 ЊC; (iii) NBS (1.05 eq.), Ph3P (1.1 eq.), CH2Cl2,
rt; (iv) PhCH᎐NOK, THF, rt; (v) BH3–pyr, EtOH, HCl, 50 ЊC.
᎐
Treatment of hydroxylamine 24 with 1.1 equivalents of n-
BuLi in THF at Ϫ78 ЊC, followed by warming to rt resulted
in [2,3]-rearrangement, giving the required allyl amine 25 in
>90% conversion and ≥90% de.9 Zn–HCl reduction of the
crude reaction mixture afforded syn-(1RS,2RS )-1-phenyl-1-
methoxy-3-(N-benzylamino)but-3-ene 26 in 90% de, which was
purified by chromatography furnishing syn-(1RS,2RS )-amine
26 in 63% yield and 97% de (Scheme 7).
Scheme 8 Reagents and conditions: (i) DIBAL–H (1.1 eq.), CH2Cl2,
Ϫ78 ЊC then benzylamine (1.0 eq.), MeOH, Ϫ78 ЊC to rt; (ii) BF3ؒEt2O
(3 eq.), CH2Cl2, Ϫ78 ЊC then vinylmagnesium bromide, Ϫ78 ЊC to rt.
To probe the influence of the double bond geometry in the
N,O-rearrangement, the preparation and rearrangement of
(Z)-N-benzyl-O-(4-methoxy-4-phenylbut-2-enyl)hydroxylamine
34 was investigated. O-Alkylation of benzaldehyde oxime with
propargyl bromide 29 gave the oxime 30 in 87% yield, with
Scheme 7 Reagents and conditions: (i) n-BuLi, THF, Ϫ78 ЊC; (ii) Zn,
HCl (aq), 80 ЊC.
J. Chem. Soc., Perkin Trans. 1, 2002, 2141–2150
2143

View Article Online
subsequent deprotonation and reaction with benzaldehyde
affording the di-substituted alkyne 31 in 77% yield. O-
Methylation afforded alkyne 32, with hydrogenation with
Lindlar’s catalyst to the (Z)-alkene 33 and reduction of the
imine with pyridine–borane–HCl furnishing the desired (Z)-
amine 34 (Scheme 9).
Discussion
Models for the diastereoselective N,O-rearrangement
The diastereoselectivity observed upon reaction of an acyclic
C᎐C bond with an adjacent stereocentre have been widely
᎐
investigated. Probably the most studied reaction in this field
concerns 1,2-asymmetric induction for the conjugate addition
of alkoxides,14 amines,15 carbon nucleophiles,16 and metal
amides17 to α,β-unsaturated acceptors, with the levels of dia-
stereoselectivity in these transformations generally being
rationalised by a modified Felkin–Anh model as developed by
Houk et al.18 In the preferred transition state of such reactions,
an allylic σ-bond is oriented antiperiplanar to the trajectory of
the approaching reagent, with the conformational preference of
the allylic stereocentre considered a combination of steric
effects (approach anti to the largest allylic substituent) and
stereoelectronic effects (approach anti to the best electron with-
drawing group). Application of a modification of this model
has been applied to [2,3]-sigmatropic Wittig rearrangements by
Brückner,19 and utilisation of this model for the rearrangement
of (E)-N-benzyl-O-(4-phenylpent-2-enyl)hydroxylamine 8 pre-
dicts the predominant formation of syn-(3RS,4RS )-3-(N-
benzyl-N-hydroxy)-4-phenylpent-1ene 11 (Fig. 3). To minimise
Scheme 9 Reagents and conditions (i) PhCH᎐NOK (1.1 eq.), THF,
᎐
0 ЊC to rt; (ii) LHMDS (1.1 eq.), THF, Ϫ78 ЊC, 30 min then PhCHO;
(iii) NaH (1.1 eq.), THF, 0 ЊC then MeI (3 eq.), 0 ЊC to rt; (iv) Lindlar’s
catalyst, H2 (4 atm), MeOH, rt; (v) BH3–pyr, EtOH, 0 ЊC then EtOH–
HCl, rt.
Treatment of (Z)-hydroxylamine 34 with n-BuLi under
the standard rearrangement conditions gave a crude reaction
mixture which indicated that the rearrangement had proceeded
in >90% conversion and in 88% de to furnish syn-hydroxyl-
amine 25. Purification gave syn-25 (identical to that formed
from rearrangement of (E)-hydroxylamine 24) in 98% de and in
51% yield. Further reduction of 25 with Zn–HCl furnished syn-
(1RS,2RS )-1-phenyl-1-methoxy-3-(N-benzylamino)but-3-ene
26 in 98% de and 63% yield (Scheme 10).
Fig. 3 Steric control of diastereoselectivity.
steric interactions in the transition state, the allylic stereocentre
will preferentially adopt a conformation whereby the nitrogen
atom will attack anti- to the large C(4) phenyl substituent,
with the C(4) hydrogen atom oriented onto the inside of the
transition state model to minimise allylic strain. Rearrangement
with the nitrogen anti-to the C(4) methyl group furnishes the
minor anti-(3SR,4RS )-diastereoisomer 12.
Further application of this model to the rearrangements
of (E)- and (Z)-N-benzyl-O-(4-methoxy-4-phenylbut-2-enyl)-
hydroxylamines 24 and 34 respectively predicts that these
rearrangement processes would occur under stereoelectronic
control. In this scenario, rearrangement of the lithium anion of
(E)-N-benzyl-O-(4-methoxy-4-phenylbut-2-enyl)hydroxylamine
24 would proceed via attack of the nitrogen atom anti- to the
electron withdrawing methoxy substituent, giving rise to the
anti-(1SR,2RS ) diastereoisomer 28 (Fig. 4).
As the major diastereoisomer from rearrangement of 24 is
actually the syn-(1RS,2RS ) diastereoisomer 25, it is clear that
this form of stereoelectronic control is not the dominat factor in
Scheme 10 Reagents and conditions: (i) n-BuLi, THF, Ϫ78 to rt; (ii)
Zn, HCl(aq), 80 ЊC.
2144
J. Chem. Soc., Perkin Trans. 1, 2002, 2141–2150

View Article Online
amines
furnish
syn-(1RS,2RS )-1-phenyl-1-methoxy-3-N-
benzylaminobut-3-ene with ≥90% and 88% de respectively,
consistent with the rearrangement proceeding under chelation
control. Current investigations within our laboratory are
directed toward probing enantioselective [2,3]-sigmatropic
N,O-rearrangements, and the application of this methodology
to natural product synthesis.
Experimental
General experimental
Melting points were determined using a Gallenkamp hot
stage apparatus, and are uncorrected. Infrared spectra were
recorded using a Perkin-Elmer Paragon 1000 Fourier transform
spectrometer. NMR spectra were recorded using Bruker DPX
400 (1H 400 MHz, 13C 100 MHz), or Varian Gemini 200 (1H 200
MHz, 13C 50 MHz) spectrometers. Chemical shifts (δ) were
recorded in ppm, coupling constants (J) were recorded in
Hertz. Chemical shifts were referenced to residual protonated
solvent. Spectra were recorded at rt unless otherwise stated.
Assignment of carbon spectra was aided by DEPT editing. Low
resolution mass spectra were recorded using a VG MASSLAB
20–250 spectrometer. High resolution mass spectra were
obtained by Mr R. Procter using a VG Autospec spectrometer.
Elemental analyses were obtained by Mrs Anne Douglas of
the Inorganic Chemistry Laboratory, University of Oxford.
Column chromatography was performed using silica (Merck,
70–320 mesh). TLC was performed on aluminium backed
Kieselgel 60 F254 plates (Merck). Plates were developed using
either a UV lamp (254 nm), 10% phosphomolybdic acid in
ethanol, or KMnO4 (1% solution in 2% aqueous acetic acid,
containing 7% potassium carbonate). Benzaldehyde was dis-
tilled immediately prior to use from calcium hydride. THF was
distilled from sodium benzophenone ketyl; CH2Cl2 was distilled
from calcium hydride. All other solvents were used as supplied,
without further purification. All yields quoted represent
isolated yields. LHMDS was used as a commercially available
1.0 M solution in THF
Fig. 4 Stereoelectronic model predicts anti-(1SR,2RS )-28 as the
major diastereoisomer.
this rearrangement. As an alternative model, the possibility of
the rearrangement pathway proceeding via a chelated transition
state was evaluated.20 Thus, allowing for lithium chelation
between nitrogen and the C(4) oxygen substituent, a prediction
for preferential attack onto the alkene functionality syn to the
C(4)-OMe substituent, furnishing the observed syn-(1RS,2RS )
diastereoisomer 25 can be made. Application of this model to
the rearrangement of (Z)-N-benzyl-O-(4-methoxy-4-phenyl-
but-2-enyl)hydroxylamine 34 also predicts the predominant
formation of the syn-(1RS,2RS ) diastereoisomer 25 (Fig. 5).21
(E )-Ethyl 4-phenylpent-2-enoate 5. 2-Phenylpropanal
4
(4.0 g, 3.96 mL, 29.9 mmol) was added dropwise to a stirred
solution of Ph P᎐CHCOOEt (10.4 g, 29.9 mmol) in THF
᎐
3
(100 mL) at Ϫ78 ЊC and stirred for 1 h before warming to rt.
After 72 h, aq sat NH4Cl (50 mL) was added, and the resultant
solution extracted with EtOAc (3 × 50 mL), washed with sat
brine (50 mL), dried (MgSO4), filtered and concentrated in
vacuo. The resulting white solid was taken up in ice-cold petrol
and filtered to remove Ph3PO. Concentration in vacuo gave 5
{5.96 g, quantitative yield, >95% (E)} as a yellow oil which was
utilised for further reactions without further purification
although a small portion was purified for characterisation by
column chromatography {10% EtOAc–petrol (40 : 60)} giving a
pale yellow oil. νmax/cmϪ1 (film) 2976 (m, C–H), 1718 (s, C᎐O),
᎐
1650 (m, C᎐C), 1452 (m, C᎐C aromatic); δ (400 MHz, CDCl )
᎐
᎐
H
3
1.28 (3H, t, J 7.1, CH2CH3), 1.44 (3H, d, J 7.1, CHCH3), 3.63
(1H, m, CHCH3), 4.19 (2H, q, J 7.1, OCH2CH3), 5.81 (1H,
d, J 15.7, CH᎐CHCOOEt), 7.12 (1H, dd, J 15.7, 6.7, CH᎐
CHCOOEt), 7.19–7.35 (5H, m, aromatic CH); δC (50 MHz,
CDCl3) 14.1, 20.1 (PhCHCH3 and OCH2CH3), 42.0 (PhCH),
᎐
᎐
Fig. 5 Chelation model predicts syn-(1RS,2RS )-25 as the major
diastereoisomer.
60.3 (OCH CH ), 120.2 (CH᎐CHCOOEt), 127.0, 127.6, 128.9
In conclusion, we have demonstrated that the diastereoselec-
tive [2,3]-sigmatropic rearrangements of lithium N-benzyl-O-
allylhydroxylamides bearing a stereogenic centre adjacent to the
migration terminus can proceed with high levels of diastereo-
᎐
2
3
(aromatic CH), 143.6 (ipso-C), 152.9 (CH CHCH᎐CH), 167.0
᎐
3
(COOEt); m/z (APCI) 205 (MHϩ, 100%), 177 (17%), 159 (MHϩ
Ϫ EtOH, 45%), 131 (12%), 122 (15%), 105 (27%).
selectivity.
(E)-N-Benzyl-O-(4-phenylpent-2-enyl)hydroxyl-
amine rearranges to afford syn-(3RS,4RS )-3-(N-benzyl-N-
hydroxy)-4-phenylpent-1-ene as the major diastereoisomer
in 30% de, consistent with the rearrangement proceeding
under moderate steric control. Rearrangements of both (E)-
and (Z)-N-benzyl-O-(4-methoxy-4-phenylbut-2-enyl)hydroxyl-
(E )-4-Phenylpent-2-en-1-ol 6. DIBAL–H (1.0 M solution in
CH2Cl2, 36.8 mL, 36.8 mmol) was added dropwise to a stirred
solution of 5 (3.0 g, 14.7 mmol) in CH2Cl2 (50 mL) at Ϫ78 ЊC
and stirred for 1 h before being allowed to warm to rt over-
night. Na2SO4ؒ10H2O (50 g) was added slowly and the resulting
J. Chem. Soc., Perkin Trans. 1, 2002, 2141–2150
2145

View Article Online
slurry stirred for a further hour and filtered through Celite®.
The filtrate was diluted with further CH2Cl2 (50 mL) and
washed with aq HCl (2 × 75 mL, 1 M), aq sat NaHCO3 (2 ×
75 mL) and sat brine (2 × 75 mL), dried (MgSO4), filtered and
concentrated in vacuo. Purification by column chromatography
{25% EtOAc–petrol (40 : 60)} gave 6 (1.78 g, 75%) as a colour-
less oil. νmax/cmϪ1 (film) 3340 (br, s, O–H), 2966 (m C–H), 1602
(MHϩ, 100%), 145 (53), 106 (11), 91 (20); HRMS Calculated for
C19H22NOϩ: 268.1701. Found: 268.1696.
syn-(3RS,4RS )-3-(N-Benzyl-N-hydroxyamino)-4-phenylpent-
1-ene 9 and anti-(3SR,4RS )-3-(N-benzyl-N-hydroxyamino)-4-
phenylpent-1-ene 10. n-BuLi (1.1 M, 1.5 mL, 1.65 mmol) was
added to a stirred solution of 8 (400 mg, 1.50 mmol) in THF
(28 mL) at Ϫ78 ЊC and stirred for 30 min before warming to rt
over 1 h. Water (10 mL) was added slowly and the solution
extracted into Et2O (3 × 30 mL), dried (MgSO4), filtered and
then concentrated in vacuo. Purification by column chroma-
tography {10% Et2O–petrol(40 : 60)–1% Et3N} afforded
an inseparable mixture of unstable diastereoisomers 9 and 10
(340 mg, 43%) as a colourless oil.
(w, C᎐C), 1452 (m, C᎐C aromatic): δ (400 MHz, CDCl ) 1.40
᎐
᎐
H
3
(3H, d, J 7.0, CH3), 1.58 (1H, br s, OH), 3.49 (1H, m, CHCH3),
4.13 (2H, d, J 5.8, CH OH), 5.67 (1H, dt, J 15.4, 5.8, CH᎐
᎐
2
CHCH ), 5.89 (1H, dd, J 15.4, 6.7, CH᎐CHCH), 7.20–7.39
᎐
2
(5H, m, aromatic CH); δC (50 MHz, CDCl3) 21.0 (CH3), 41.9
(CHCH ), 63.6 (CH OH), 126.4 (CH᎐CH), 127.4, 128.0, 128.7
᎐
3
2
(aromatic CH), 137.6 (CH᎐CH), 145.8 (ipso-C); m/z (APCI)
᎐
146 (10%), 145 (MHϩ Ϫ H2O, 100%).
syn-(3RS,4RS )-9: δH (400 MHz, CDCl3) 1.22 (3H, d, J 6.7,
CH CH), 3.14–3.25 (2H, m, CH CH and NCHCH᎐CH ),
᎐
3
3
2
3.68 (1H, d, J 13.4, NCHHPh), 3.93 (1H, d, J 13.4, NCHHPh),
4.50 (1H, br s, OH), 5.12–5.19 (1H, m, CH᎐CHH), 5.44 (1H, d,
Benzaldehyde (E )-O-(4-phenylpent-2-enyl)oxime 7. PBr3
(0.624 g, 0.22 mL, 2.80 mmol) was added dropwise to a stirred
solution of 6 (1.0 g, 6.17 mmol) in Et2O (30 mL) at rt and was
stirred for 18 h. Water (10 mL) was added slowly and the
solution extracted into Et2O (3 × 30 mL), washed with aq
sat NaHCO3 (50 mL) and then sat brine (2 × 50 mL), dried
(MgSO4), filtered and concentrated in vacuo to give the crude
bromide (1.23 g, 88%) as a yellow oil, which was used immedi-
ately in the next step. δH (200 MHz, CDCl3) 1.39 (3H, d, CH3),
3.52 (1H, m, CHCH3), 3.98 (2H, d, CH2Br), 5.65–6.02 (2H,
᎐
J 10.3, CH᎐CHH), 6.01–6.08 (1H, m, CH᎐CH ), 7.09–7.47
᎐
᎐
2
(10H, m, aromatic CH).
anti-(3SR,4RS )-10: δH (400 MHz, CDCl3) 1.43 (3H, d, J 6.5,
CH CH), 3.14–3.25 (2H, m, CH CH and NCHCH᎐CH ), 3.74
᎐
3
3
2
(1H, d, J 13.5, NCHHPh), 3.99 (1H, d, J 13.5, NCHHPh),
4.61 (1H, br s, OH), 4.90 (1H, d, J 17.4, CH᎐CHH), 5.12–5.19
᎐
(1H, m, CH᎐CHH), 5.72–5.98 (1H, m, CH᎐CH ), 7.09–7.47
᎐
᎐
2
(10H, m, aromatic CH).
m, CH᎐CH), 7.18–7.38 (5H, m, aromatic CH). KOtBu (1.22 g,
᎐
syn-(3RS,4RS )-3-(N-Benzylamino)-4-phenylpent-1-ene
11
10.9 mmol) was added to a stirred solution of benzaldehyde
oxime (1.32 g, 10.9 mmol) in THF (150 mL), and the mixture
stirred for 30 min, after which time a solution of bromide
(1.23 g, 5.45 mmol) in Et2O (10 mL) was added via cannula. The
solution was stirred for 72 h at rt after which time aq phosphate
pH 7 buffer (50 mL) was added and the resultant solution
extracted into Et2O (3 × 50 mL), washed with sat brine (2 ×
75 mL), dried (MgSO4), filtered, and concentrated in vacuo
to give an orange oil. Purification by column chromatography
{3% Et2O–petrol (40 : 60)} afforded 7 (1.05 g, 73%) as a pale
and anti-(3SR,4RS )-3-(N-benzylamino)-4-phenylpent-1-ene 12.
Zinc powder (413 mg, 6.35 mmol) was added to a stirred solu-
tion of 9 and 10 (340 mg, 1.37 mmol) in aq HCl (30 mL, 1 M),
and heated to 80 ЊC for 1 h. After cooling, the reaction mixture
was made alkaline (pH 10) by the addition of aq NaOH
(35 mL, 1 M) and extracted into Et2O (3 × 50 mL), dried (Mg-
SO4), filtered and concentrated in vacuo. Purification by column
chromatography {20% Et2O–petrol(40 : 60)} gave 12 (96 mg,
30%) and 11 (168 mg, 53%) as pale yellow oils.
anti-(3SR,4RS )-12: νmax/cmϪ1 (film) 3328 (w, N–H), 3027 (m,
yellow oil. νmax/cmϪ1 (film) 2966 (m, C–H), 1601 (w, C᎐C), 1492
᎐
C–H), 1603 (w, C᎐C), 1494 (m, C᎐C aromatic), 1453 (m, C᎐C
᎐
᎐
᎐
(m, C᎐C aromatic); δ (400 MHz, CDCl3) 1.40 (3H, d, J 7.0,
᎐
H
aromatic); δH (400 MHz, CDCl3) 1.33 (3H, d, J 7.1, CH3), 2.94
(1H, m, CH3CH), 3.14 (1H, dd, J 8.3, 5.8, CHCHNH), 3.60
(1H, d, J 13.6, NHCHHPh), 3.82 (1H, d, J 13.6, NHCHHPh),
CH3), 3.53 (1H, m, CHCH3), 4.68 (2H, d, J 6.3, CH2O), 5.75
(1H, dt, J 15.5, 6.3, CH᎐CHCH O), 6.00 (1H, dd, J 15.5, 6.6,
᎐
2
CH CHCH᎐CH), 7.19–7.61 (10H, m, aromatic CH), 8.11 (1H,
᎐
3
5.03 (1H, d, J 17.2, CH᎐CHH), 5.13 (1H, d, J 10.2, CH᎐CHH),
᎐
᎐
s, CH᎐N); δ (50 MHz, CDCl ) 21.0 (CH ), 42.0 (PhCHCH ),
᎐
C
3
3
3
5.48–5.56 (1H, m, CH᎐CH ), 7.19–7.31 (10H, m, aromatic
᎐
2
75.1 (CH O), 124.5 (CH᎐CH), 126.5, 127.3, 127.6, 128.7,
᎐
2
CH); δC (50 MHz, CDCl3) 17.0 (CH3), 44.2 (CH3CH),
129.0, 130.0 (aromatic CH), 132.6 (ipso-C), 140.2 (CH᎐CH),
᎐
51.0 (NHCH ), 66.0 (NHCH), 117.1 (CH᎐CH ), 126.5, 126.9,
᎐
2
2
145.7 (ipso-C), 149.0 (CH᎐N); m/z (APCI) 266 (MHϩ, 16%),
᎐
128.2, 128.3, 128.5 (aromatic CH), 139.0 (CH᎐CH ), 140.9
᎐
2
(ipso-C), 143.9 (ipso-C); m/z (APCI) 253 (15%), 252 (MHϩ,
100%), 145 (96%). Calculated for C18H21N: C 86.0, H 8.4, N 5.6.
Found C 85.95, H 8.4, N 5.35%.
145 (100%), 123 (14%), 122 (62%), 106 (56%); HRMS calcu-
lated for C18H20NOϩ: 266.1544. Found: 266.1544.
syn-(3RS,4RS )-11: νmax/cmϪ1 (film) 3326 (w, N–H), 3027 (m,
(E )-N-Benzyl-O-(4-phenylpent-2-enyl)hydroxylamine
8.
Pyridine–borane complex (8 M in excess pyridine, 1.31 mL,
9.65 mmol) in EtOH (5 mL) was added to a stirred solution of
7 (1.05 g, 3.97 mmol) in EtOH (40 mL) at rt before cooling to
0 ЊC and the dropwise addition of 10% HCl in EtOH (15 mL)
over 5 min. After stirring for a further 2 h the solution was
neutralised with excess aq sat NaHCO3, extracted into CH2Cl2
(3 × 50 mL), washed with aq CuSO4 (2 × 50 mL, 1 M) and
water (50 mL), dried (MgSO4), filtered and concentrated
in vacuo. Purification by column chromatography {20% Et2O–
C–H), 1603 (w, C᎐C), 1494 (m, C᎐C aromatic), 1453 (m, C᎐C
᎐
᎐
᎐
aromatic); δH (400 MHz, CDCl3) 1.18 (3H, d, J 7.0, CH3), 2.71
(1H, m, CH CH), 3.03 (1H, app t, J 8.8, CHCHCH᎐CH ), 3.52
᎐
3
2
(1H, d, J 13.8, NHCHH), 3.76 (1H, d, J 13.8, NHCHH), 5.18
(1H, d, J 17.1, CH᎐CHH), 5.28 (1H, d, J 10.1, CH᎐CHH),
᎐
᎐
5.62–5.71 (1H, m, CH᎐CH ), 7.00–7.32 (10H, m, aromatic
᎐
2
CH); δC (50 MHz, CDCl3) 19.4 (CH3), 44.3 (CH3CH), 50.8
(NHCH Ph), 66.4 (NHCHCH᎐CH ), 118.2 (CH᎐CH ), 126.8,
᎐
᎐
2
2
2
128.0, 128.2, 128.4, 128.8 (aromatic CH), 140.0 (CH᎐CH ),
᎐
2
petrol (40 : 60)} gave 8 (0.83 g, 78%) as a colourless oil. νmax
/
140.6 (ipso-C), 144.5 (ipso-C); m/z (APCI) 253 (20%), 252
(MHϩ, 100%), 145 (91%); HRMS Calculated for C18H22Nϩ:
252.1752. Found 252.1756.
cmϪ1 (film) 3260 (br, N–H), 2965 (m, C–H), 1602 (w, C᎐C),
᎐
1494 (m, C᎐C aromatic), 1453 (m, C᎐C aromatic); δ (400
᎐
᎐
H
MHz, CDCl3) 1.38 (3H, d, J 7.0, CH3), 3.48 (1H, m, CHCH3),
4.06 (2H, s, NHCH2), 4.16 (2H, d, J 6.4, CH2O), 5.58 (1H, dt,
syn-(3RS,4RS )-3-[N-(tert-Butoxycarbonyl)amino]-4-phenyl-
pent-1-ene 15 and anti-(3SR,4RS )-3-N-(tert-butoxycarbonyl)-4-
phenylpent-1-ene 16. Thionyl chloride (2.41 g, 0.90 mL,
11.6 mmol) was added dropwise to a stirred solution of β-
methylphenylalanine hydrochloride (1 g, 4.64 mmol, 2 : 1 syn-
(2SR,3RS )-13: anti-(2RS,3RS )-14) in MeOH (20 mL) at 0 ЊC
and allowed to warm to rt over 18 h. Concentration in vacuo
J 15.5, 6.4, CH᎐CHCH O), 5.68 (1H, br s, NH), 5.88 (1H, dd,
᎐
2
J 15.5, 6.6, CH CHCH᎐CH), 7.19–7.36 (10H, m, aromatic
᎐
3
CH); δC (50 MHz, CDCl3) 21.0 (CH3), 42.0 (PhCHCH3), 56.6
(PhCH NH), 74.8 (CH O), 124.8 (CH᎐CH), 126.4, 127.5,
᎐
2
2
127.7, 128.7, 129.2 (aromatic CH), 137.7 (ipso-C), 139.8 (CH᎐
᎐
CH), 145.8 (ipso-C); m/z (Probe CI (NH3)) 269 (19%), 268
2146
J. Chem. Soc., Perkin Trans. 1, 2002, 2141–2150

View Article Online
ϩ
afforded β-methylphenylalanine methyl ester hydrochloride
as a white solid which was used without further purification.
Di-tert-butyl dicarbonate (1.06 g, 4.88 mmol), followed by
NaHCO3 (1.49 g, 17.8 mmol) was added to a solution of the
crude ester in MeOH (20 mL) cooled to 0 ЊC and allowed to
warm to rt over 48 h. The reaction mixture was filtered through
Celite® and the filtrate concentrated in vacuo. The resulting
solid was redissolved in Et2O, filtered and concentrated in vacuo
to give the crude product as a white solid. Purification via
column chromatography {25% Et2O : petrol (40 : 60)} afforded
a 2 : 1 syn-(2SR,3RS )- to anti-(2RS,3RS )-mixture of N-(tert-
butoxycarbonyl)-3-methylphenylalanine methyl esters as a
colourless viscous oil (0.411 g, 32% over 2 steps). νmax (thin film)/
cmϪ1 3365 (N–H, br), 2977 (C–H), 1714 (C᎐O, s br), 1454 (C᎐C
CH), 155.3 (NHCOOtBu); m/z (APCIϩ) 162 (44%, MH2
Ϫ
COOtBu), 146 (20), 145 (100, PhCH(Me)CHCH᎐CH );
ϩ
᎐
2
ϩ
HRMS Calculated for C16H24NO2 : 262.1807. Found 262.1819.
syn-(2RS,3RS )-2-Phenyl-3-aminopentane 17 and anti-
(2RS,3SR)-2-phenyl-3-aminopentane 18. Pd(OH)2 on carbon
(20%, 10 mg, cat) was added to a stirred solution of 15 and 16
(62 mg, 0.238 mmol) in MeOH (5 mL) and stirred under H2
(1 atm) for 18 h at rt. The crude reaction mixture was filtered
through Celite® and concentrated in vacuo. Purification via
column chromatography {15% Et2O : petrol (40 : 60)} afforded
a 2 : 1 mixture of syn-(2RS,3RS )-3-N-(tert-butoxycarbonyl)-1-
ethyl-2-phenylpentane and anti-(2RS,3SR)-3-N-(tert-butoxy-
carbonyl)-1-ethyl-2-phenylpentane as a colourless oil (55 mg,
88%). νmax (film)/cmϪ1 3351 (N–H, br), 2968 (C–H, s), 1703
᎐
᎐
aromatic, m); δH major diastereomer (400 MHz, CDCl3) 1.37
(3H, m, CHCH3), 1.41 (9H, s, C(CH3)3), 3.35 (1H, m, MeCH ),
3.70 (3H, s, OMe), 4.47–4.54 (1H, m, CHNH), 4.80 (1H, br d,
J 8.8, NH), 7.15–7.34 (5H, m, aromatic CH); δH minor dia-
stereomer (400 MHz, CDCl3) 1.37 (3H, m, CHCH3), 1.41 (9, s,
C(CH3)3), 3.19 (1H, m, MeCH), 3.57 (3H, s, OCH3), 4.47–4.54
(1H, m, CHNH), 5.05 (1H, br, NH), 7.15–7.34 (5H, m, aro-
matic CH); δC major diastereomer (100 MHz, CDCl3) 17.6
(CHCH3), 28.2 (CCH3), 42.1 (MeCH), 52.0 (CH3O), 58.7
(NHCH), 79.9 (CMe3), 127.2, 127.6, 128.5 (aromatic CH),
140.9 (ipso-C), 155.7 (CO2Me), 172.3 (NHCOOtBu); δC minor
diastereomer (100 MHz, CDCl3) 16.5 (CHCH3), 28.2 (CCH3),
42.9 (MeCH), 51.9 (CH3O), 59.0 (NHCH), 79.9 (CMe3),
127.0, 127.6, 128.4 (aromatic CH), 141.3 (ipso-C), 155.1
(CO2Me), 172.3 (NHCOOtBu); m/z (APCIϩ) 249 (13%) 195
(C᎐O, s), 1454 (C᎐C aromatic); δ major diastereomer (400
᎐
᎐
H
MHz, CDCl3) 0.91 (3H, t, J 7.4, CH2CH3), 0.98–1.11 (1H,
m, MeCH2), 1.30–1.57 (13H, m, CH3CHPh, C(CH3)3 and
MeCH2), 2.91–2.95 (1H, m, MeCHPh), 3.63–3.72 (1H, m,
CHNH), 4.16 (1H, br d, J 9.3, NH), 7.18–7.33 (5H, m, aromatic
CH); δH minor diastereomer (400 MHz, CDCl3) 0.85 (3H, t,
J 7.4, CH2CH3), 1.30–1.57 (14H, m, CH3CHPh, C(CH3)3 and
MeCH2), 2.91–2.95 (1H, m, MeCHPh), 3.63–3.72 (1H, m, CH-
NH), 4.98 (1H, br d, J 9.7, NH), 7.18–7.33 (5H, m, aromatic
CH); δC major diastereomer (100 MHz, CDCl3) 10.6 (CH2CH3),
17.4 (CH3CH2), 26.0 (CH2), 28.4 (C(CH3)3), 44.9 (MeCH),
56.7 (CHNH), 78.8 (C(CH3)3), 126.3, 128.2, 128.3 (aromatic
CH), 142.9 (ipso-C), 156.0 (NHC᎐O); δ minor diastereomer
(100 MHz, CDCl3) 10.4 (CH2CH3), 19.1 (CH3CH2), 25.3
(CH2), 28.4 (C(CH3)3), 43.3 (MeCH), 57.2 (CHNH), 78.9
᎐
C
ϩ
(13%), 194 (PhCH(Me)CH(NH4 )CO2Me, 100%), 134 (94%),
121 (18%).
(C(CH3)3), 126.4, 127.8, 128.2 (aromatic CH), 144.2 (ipso-C),
ϩ
DIBAL–H (1.5 M in toluene, 1.05 mL, 1.57 mmol) was
added dropwise to a stirred solution of 2 : 1 syn-(2SR,3RS )-
to anti-(2RS,3RS )-N-(tert-butoxycarbonyl)-3-methylphenyl-
alanine methyl esters (420 mg, 1.43 mmol) in toluene (20 mL)
under Ar at Ϫ78 ЊC and stirred for 12 h at Ϫ78 ЊC before the
dropwise addition of MeOH (5 mL). After warming to rt aq
NaK[CH(OH)CO2]2 (20 mL, 1 M) was added and the solution
was stirred for a further 1.5 h before being extracted into Et2O
(3 × 30 mL) and the combined organic extracts dried (MgSO4),
filtered and concentrated in vacuo to give crude aldehyde which
was used without further purification. A stirred suspension of
Ph3PCH3Br (1.07 g, 3.00 mmol) in THF (15mL) under N2 was
cooled to Ϫ78 ЊC and BuLi (1.69 M in hexanes, 1.69 mL, 2.86
mmol) was added dropwise. The solution was stirred at rt for
30 min, cooled to Ϫ78 ЊC and a solution of crude aldehyde in
THF (10 mL) was added via cannula. The reaction mixture was
warmed to rt and stirred for a further 4 h before the addition
of water (20 mL). The organic material was extracted into Et2O
(3 × 30 mL), washed with sat brine (50 mL), dried (MgSO4),
filtered and then concentrated in vacuo to give the crude product
as a yellow oil. Purification via column chromatography {15%
Et2O–petrol(40 : 60)} gave a 2 : 1 mixture of 15 and 16 as viscous,
pale yellow oil (84 mg, 23%). νmax (film)/cmϪ1 3349 (N–H,
156.0 (NHC᎐O); m/z (APCIϩ) 236 (18%), 208 (MH
Ϫ
᎐
2
ϩ
C(CH3)3, 32%), 164 (MH2 Ϫ COOtBu, 60%), 147 (PhCH-
(Me)CHϩCH2CH3, 98%), 105 (100%); HRMS Calculated for
C16H26NO2 : 264.1964. Found MHϩ 264.1969.
ϩ
TFA (1 mL) was added to a stirred solution of a 2 : 1 mixture
of syn-(2RS,3RS )-N-(tert-butoxycarbonyl)-1-ethyl-2-phenyl-
pentane and anti-(2RS,3SR)-N-(tert-butoxycarbonyl)-1-ethyl-
2-phenylpentane (37 mg, 0.14 mmol) in CH2Cl2 (2 mL) under
Ar and the solution stirred for 1 h at rt before concentration in
vacuo. The residue was dissolved in aq NaOH (10 mL, 1 M) and
the organic material extracted into Et2O (3 × 10 mL), dried
(MgSO4), filtered and concentrated in vacuo to afford 17 and
18 as a pale yellow oil (20 mg, 85%). νmax (thin film)/cmϪ1 3371
(N–H, br), 2961 (C–H, s), 1453 (C᎐C aromatic, m); δ major
᎐
H
diastereomer (400 MHz, CDCl3) 0.98 (3H, t, J 7.4, CH2CH3),
1.13–1.73 (7H, m, CH2Me, NH2 and CH3CH2), 2.60–2.68 (1H,
m, MeCH), 2.72–2.81 (1H, m, CHNH2), 7.19–7.34 (5H, m,
aromatic CH); δH minor diastereomer (400 MHz, CDCl3) 0.93
(3H, t, J 7.4, CH2CH3), 1.13–1.73 (7H, m, CH2Me, NH2 and
CH3CH2), 2.72–2.81 (2H, m, CHNH2 and MeCH), 7.19–7.34
(5H, m, aromatic CH); δC major diastereomer (100 MHz,
CDCl3) 10.4 (CH3CH2), 18.5 (CH3CH), 27.4 (CH2), 46.0 (Ph-
CHMe), 57.9 (CHNH2), 127.1, 128.1, 128.4 (aromatic CH),
144.9 (ipso-C); δC minor diastereomer (100 MHz, CDCl3) 10.9
(CH3CH2), 15.6 (CH3CH), 27.9 (CH2), 45.1 (PhCHMe), 58.4
(CHNH2), 126.3, 128.0, 128.3 (aromatic CH), 145.4 (ipso-C);
m/z (APCIϩ) 219 (14%), 164 (MHϩ, 30%), 147 (M Ϫ NH2,
55%), 105 (100%).
br), 2976 (C–H, m), 1703 (C᎐O, s), 1496 (C᎐C aromatic, m);
᎐
᎐
δH major diastereomer 15 (400 MHz, CDCl3) 1.29–1.33 (3H, m,
CH3CH), 1.40 (9H, s, C(CH3)3), 2.95 (1H, m, MeCH), 4.32–
4.47 (2H, br m, NH and NHCH), 5.07–5.12 (2H, m, CH᎐CH ),
᎐
2
5.70–5.79 (1H, m, CH᎐CH ), 7.18–7.33 (5H, m, aromatic CH);
᎐
2
δH minor diastereomer 16 (400 MHz, CDCl3) 1.29–1.33 (3H, m,
CH3CH), 1.44 (9H, s, C(CH3)3), 2.95 (1H, m, MeCH), 4.32–4.47
anti-(2RS,3SR)-2-Phenyl-3-aminopentane 18. Pd(OH)2 on
carbon (20%, 10 mg, cat) was added to a solution of 12 (41 mg,
0.163 mmol) in MeOH (5 mL), and the solution stirred under
H2 (1 atm) for 18 h. The crude reaction mixture was filtered
through Celite and concentrated in vacuo to give 18 (11 mg,
42%) as a colourless oil. νmax/cmϪ1 (film) 3340 (br, N–H), 2963
(s, C–H), 1455 (m, C᎐C aromatic); δ (400 MHz, CDCl3)
0.93 (3H, t, J 7.4, CH2CH3), 1.15–1.29 (1H, m, CH2CH3), 1.30
(3H, d, J 6.9, CH3CHPh), 1.41–1.52 (1H, m, CH2CH3), 1.98
(2H, br s, NH2), 2.72–2.79 (1H, m, CH3CH), 2.80–2.83 (1H, m,
(2H, br m, NH and NHCH), 5.07–5.12 (2H, m, CH᎐CH ),
᎐
2
5.59–5.67(1H, m, CH᎐CH ), 7.18–7.33(5H, m, aromaticCH);δ
᎐
2
C
major diastereomer 15 (100 MHz, CDCl3) 17.2 (CH3CH), 28.3
((CH3)3C), 43.8 (MeCH), 57.8 (CHN), 79.0 (C(CH3)3), 115.4
(CH᎐CH ), 126.6, 128.0, 128.2 (5 × ArCH), 137.1 (CH᎐CH ),
᎐
᎐
2
2
142.4 (ipso-CH), 155.3 (NHCOOtBu); δC minor diastereomer
16 (100 MHz, CDCl3) 17.2 (CH3CH), 28.3 ((CH3)3C), 44.2
᎐
H
(MeCH), 57.9 (CHN), 79.0 (C(CH ) ), 115.5 (CH᎐CH ),
᎐
3
3
2
126.6, 128.0, 128.3 (5 × ArCH), 137.1 (CH᎐CH ), 142.6 (ipso-
᎐
2
J. Chem. Soc., Perkin Trans. 1, 2002, 2141–2150
2147

View Article Online
CHNH2), 7.19–7.33 (5H, m, aromatic CH); δC (100 MHz,
CDCl3) 10.8 (CH2CH3), 15.9 (CH3CHPh), 27.7 (CH2CH3),
45.0 (PhCHCH3), 58.4 (CHNH2), 126.1, 127.9, 128.3 (aromatic
CH), 145.2 (ipso-C); m/z (APCI) 219 (14%), 164 (MHϩ, 21%),
147 (MHϩ Ϫ NH3, 67%), 105 (100%); HRMS Calculated for
C11H18Nϩ: 164.1439. Found 164.1437.
petrol (40 : 60)} gave 23 (1.36 g, 45% over two steps) as a yellow
oil. νmax/cmϪ1 (film) 2928 (m, C–H), 1602 (w, C᎐C), 1492 (m,
᎐
C᎐C aromatic), 1448 (m, C᎐C aromatic); δ (400 MHz, CDCl )
᎐
᎐
H
3
3.36 (3H, s, OCH3), 4.70–4.72 (3H, m, CH3OCH and CH2O),
5.89–6.03 (2H, m, CH᎐CH), 7.29–7.60 (10H, m, aromatic CH),
᎐
8.12 (1H, s, PhCH᎐N); δ (50 MHz, CDCl ), 56.5 (CH O), 74.2
᎐
C
3
3
(CH2O), 83.7 (CH3OCH), 127.1, 127.3, 128.0, 128.2, 128.8,
128.9 (aromatic CH), 130.1 (CH᎐CH), 132.4 (ipso-C), 134.7
(E )-Ethyl 4-phenyl-4-methoxybut-2-enoate 20. DIBAL–H
(1.5 M solution in toluene, 12.2 mL, 18.4 mmol) was added
dropwise to a stirred solution of methyl O-methylmandelate 19
(3.0 g, 16.7 mmol) in toluene (80 mL) at Ϫ78 ЊC over 45 min
whilst maintaining the temperature below Ϫ70 ЊC. After 2
᎐
(CH᎐CH), 141.1 (ipso-C), 149.1 (CH᎐N); m/z (APCI) 250
᎐
᎐
(MHϩ Ϫ MeOH, 21%), 129 (22%), 122 (28%), 105 (17%), 104
(100%); Calculated for C18H19NO2: C 76.8, H 6.8, N, 5.0. Found
C 77.1, H 6.7, N 5.0%.
hours, Ph P᎐CHCOOEt (6.39 g, 18.4 mmol) was added and the
᎐
3
mixture warmed to rt over 18 h before the addition of
Na2SO4ؒ10H2O (25 g) and the resulting slurry stirred for a
further 1 h. The mixture was filtered through Celite®, diluted
with toluene (100 mL) and washed successively with aq HCl
(2 × 100 mL), aq sat NaHCO3 (2 × 100 mL) and sat brine (2 ×
100 mL), dried (MgSO4), filtered and concentrated in vacuo.
Purification by column chromatography {10% Et2O–petrol-
(40 : 60)} gave 20 (1.96 g, 53%) as a colourless oil. νmax/cmϪ1
(E )-N-Benzyl-O-(4-phenyl-4-methoxybut-2-enyl)hydroxyl-
amine 24. A solution of pyridine–borane complex (8 M in
excess pyridine, 3.13 mL, 21.4 mmol) in EtOH (5 mL) was
added to a stirred solution of 23 (0.80 g, 2.85 mmol) in EtOH
(15 mL) at rt and the solution cooled to 0 ЊC before the addition
of 10% HCl in EtOH (30 mL). The stirred reaction mixture was
heated to 50 ЊC for 18 h, and cooled to rt before the solution
was made alkaline to pH 10 by the addition of aq NaOH
(50 mL, 1 M). The organic material was extracted into CH2Cl2
(3 × 60 mL) and the combined organic extracts washed with aq
CuSO4 (3 × 100 mL, 1 M) and water (100 mL), dried (MgSO4),
filtered and concentrated in vacuo. Purification by column
chromatography {8% Et2O–petrol (40 : 60)} afforded 24 (0.462
g, 57%) as a colourless oil. νmax/cmϪ1 (film) 3250 (m, N–H), 2926
(film) 2983 (m, C–H), 1720 (s, C᎐O), 1658 (m, C᎐C aromatic);
᎐
᎐
δH (400 MHz, CDCl3) 1.28 (3H, t, J 7.1, CH2CH3), 3.34 (3H, s,
OCH3), 4.18 (2H, q, J 7.1, OCH2CH3), 4.78 (1H, d, J 5.5,
CH OCHCH᎐CH), 6.08 (1H, d, J 15.7, CH᎐CHCOOEt), 6.96
᎐
᎐
3
(1H, dd, J 15.7, 5.5, CHCH᎐CH), 7.30–7.40 (5H, m, aromatic
᎐
CH); δC (50 MHz, CDCl3) 14.1 (CH2CH3), 56.8 (OCH3), 60.5
(OCH CH ), 82.6 (PhCHOCH ), 121.1 (CH᎐CHCOOEt),
(m, C–H), 1602 (w, C᎐C), 1495 (m, C᎐C aromatic), 1453 (m,
᎐
᎐ ᎐
2
3
3
127.3, 128.5, 128.9 (aromatic CH), 139.1 (ipso-C), 147.5
C᎐C aromatic); δ (400 MHz, CDCl ) 3.32 (3H, s, OCH ), 4.04
᎐
H 3 3
(2H, s, NHCH ), 4.17 (2H, d, J 4.3, CH᎐CHCH ), 4.63 (1H, d,
᎐
2 2
(CHCH᎐CH), 166.6 (COOEt); m/z (APCI) 189 (MHϩ
Ϫ
᎐
MeOH, 65%), 161 (94%), 133 (82%), 117 (28%), 115 (100%);
Calculated for C13H16O3: C 70.9, H 7.3. Found: C 70.9, H 7.5%.
J 4.4, CH OCHCH᎐CH), 5.68 (1H, br s, NH), 5.79–5.81 (2H,
᎐
3
m, CH᎐CH), 7.28–7.38 (10H, m, aromatic CH); δ (50 MHz,
᎐
C
CDCl3) 56.4 (CH2O), 56.6 (OCH3), 74.1 (NHCH2), 83.8
(CH3OCH), 127.0, 127.7, 127.9, 128.6, 128.7 (aromatic CH),
(E )-1-Phenyl-1-methoxybut-2-en-4-ol 21. DIBAL–H (1.5 M
in toluene, 15.2 mL, 22.7 mmol) was added dropwise to a
stirred solution of 20 (2.0 g, 9.09 mmol) in toluene (50 mL) at
Ϫ78 ЊC and stirred for 1 h followed by the dropwise addition of
MeOH (10 mL). The solution was allowed to warm to rt and
aq NaK[CH(OH)CO2]2 (75 mL, 1 M) was added. After 18 h,
the organic material was extracted into toluene (3 × 50 mL),
washed with sat brine (2 × 75 mL), dried (MgSO4), filtered and
concentrated in vacuo. Purification by column chromatography
{50% EtOAc–petrol (40 : 60)} gave 21 (1.30 g, 80%) as a colour-
less oil. νmax/cmϪ1 (film) 3380 (br s, O–H), 2933 (m, C–H), 1602
129.2 (CH᎐CH), 134.3 (CH᎐CH), 137.7, 141.1 (ipso-C); m/z
᎐
᎐
(Probe CI {NH3}) 284 (MHϩ, 19%), 253 (20%), 252 (MHϩ
Ϫ
ϩ
MeOH, 100%); HRMS Calculated for C18H22NO2 : 284.1650.
Found: 284.1655.
syn-(1RS,2RS )-1-Phenyl-1-methoxy-3-(N-benzyl-N-hydroxy-
amino)but-3-ene 25. a. Preparation from rearrangement of
(E)-24; n-BuLi (1.75 M solution in hexanes, 0.61 mL, 1.1
mmol) was added dropwise to a stirred solution of 24 (300 mg,
1.06 mmol) in THF (21 mL) at Ϫ78 ЊC and stirred for 1 h before
warming to rt over 1 h. Water (10 mL) was added and the
organic material was extracted into Et2O (3 × 30 mL), dried
(MgSO4), filtered and concentrated in vacuo to yield the crude
product 25 (281 mg, 94%) as a colourless oil with identical
spectroscopic properties to that prepared from rearrangement
of (Z)-34.
b. Preparation from rearrangement of (Z)-34; n-BuLi (2.5 M
solution in hexanes, 0.17 mL, 0.38 mmol) was added dropwise
to a stirred solution of 34 (103 mg, 0.30 mmol) in THF (10 mL)
at Ϫ78 ЊC and stirred for 1 h before warming to rt over 1 h.
Water (25 mL) was added and the organic material was
extracted into Et2O (3 × 25 mL), dried (MgSO4), filtered and
concentrated in vacuo. Purification by column chromatography
{5% Et2O–petrol (40 : 60)} gave 25 (53 mg, 51%) as a colourless
oil. νmax/cmϪ1 (KBr disc) 3338 (s, O–H), 2923 (m, C–H), 1494
(m), 1455 (s); δH (400 MHz, CDCl3) 3.27 (3H, s, CH3O), 3.50
(1H, m, CHCHNOH), 3.75 (1H, d, J 13.4, NCHHPh), 4.03
(1H, d, J 13.4, NCHHPh), 4.51 (1H, d, J 7.2, CH3OCHCH),
(w, C᎐C), 1453 (m, C᎐C aromatic); δ (400 MHz, CDCl ) 1.38
᎐
᎐
H
3
(1H, t, J 6.1, OH), 3.33 (3H, s, OCH3), 4.17 (2H, m, CH2OH),
4.66 (1H, d, J 5.9, OCHCH᎐CH), 5.81–5.93 (2H, m, CH᎐CH),
᎐
᎐
7.27–7.39 (5H, m, aromatic CH); δC (50 MHz, CDCl3) 56.3
(OCH3), 56.6 (CH2OH), 83.9 (CH3OCH), 127.0, 128.0, 128.7
(aromatic CH), 131.8 (CH᎐CH), 141.0 (ipso-C); m/z (APCI)
᎐
161 (MHϩ Ϫ H2O, 12%), 155 (17%), 147 (MHϩ Ϫ MeOH,
57%), 129 (100%), 122 (58%), 121 (29%).
Benzaldehyde (E )-O-(4-phenyl-4-methoxybut-2-enyl)oxime
23. PPh3 (3.23 g, 11.7 mmol) was added to a stirred solution
of 21 (1.9 g, 10.7 mmol) in CH2Cl2 (40 mL), followed by the
addition of N-bromosuccinimide (2.09 g, 11.2 mmol) over
5 min and stirred at rt for 3 h before the addition of water
(15 mL). The organic material was extracted into CH2Cl2 (3 ×
30 mL), washed with brine (50 mL), dried (MgSO4), filtered
and concentrated in vacuo to afford the crude bromide 22 as a
pink solid, which was used immediately in the next step. KOtBu
(2.18 g, 21.3 mmol) was added to a stirred solution of benzal-
dehyde oxime (2.39 g, 21.3 mmol) in THF (200 mL), and the
mixture stirred for 30 min before the addition of a solution of
bromide 22 (10.7 mmol) in THF (20 mL) via cannula. After 18
h, the reaction was quenched with aq phosphate pH 7 buffer
(100 mL), extracted into Et2O (3 × 100 mL), washed with sat
brine (2 × 100 mL), dried (MgSO4), filtered and concentrated
in vacuo. Purification by column chromatography {5% Et2O–
4.95 (1H, d, J 17.3, CH᎐CHH), 5.18 (1H, d, J 10.5, CH᎐CHH),
᎐
᎐
5.43 (1H, br s, OH), 5.77–5.88 (1H, m, CH᎐CH ), 7.22–7.39
᎐
2
(10H, m, aromatic CH); δC (100 MHz, CDCl3) 56.8 (OCH3),
61.3 (PhCH ), 69.7, 84.8 (2 × CH), 120.7 (CH᎐CH ), 127.1,
᎐
2
2
127.8, 127.9, 128.1, 128.2, 129.3 (aromatic CH), 132.1 (CH᎐
᎐
CH2), 137.8, 139.1 (ipso-C); m/z (APCI) 284 (MHϩ, 40%), 252
(MHϩ Ϫ MeOH, 100%), 129 (60%), 106 (30%). Calculated for
C18H19NO2: C 76.3, H 7.5, N 4.9. Found: C 76.2, H 7.4, N 4.9%.
2148
J. Chem. Soc., Perkin Trans. 1, 2002, 2141–2150

View Article Online
syn-(1RS,2RS )-1-Phenyl-1-methoxy-3-(N-benzylamino)but-
3-ene 26. Zinc powder (650 mg, 9.93 mmol) was added to a
stirred solution of crude 25 (281 mg, 0.993 mmol) in aq HCl
(1 M, 25 mL) and heated to 80 ЊC for 2 h. After cooling, aq
NaOH (1 M, 30 mL) was added until pH 10, and the organic
material extracted into Et2O (3 × 30 mL), dried (MgSO4),
filtered and concentrated in vacuo. Purification by column
chromatography {50% Et2O–petrol (40 : 60)} gave 26 (168 mg,
63%) as a pale yellow oil which solidified on standing to a waxy
cream solid. (Mp 41–43 ЊC); νmax/cmϪ1 (film) 3330 (w, N–H),
2822 (m, C–H), 1603 (w, C᎐C), 1494 (m, C᎐C aromatic), 1453
(1H, dd, J 8.4, 5.3, CHNH), 3.24 (3H, s, OCH3), 3.59 (1H, d,
J 13.6, PhCHH), 3.83 (1H, d, J 13.6, PhCHH), 4.26 (1H, d,
J 5.3, CHOCH ), 5.04 (1H, d, J 17.1, CH᎐CHH), 5.22 (1H, dd,
᎐
3
J 10.2, 1.7, CH᎐CHH), 5.72 (1H, ddd, J 17.1, 10.2, 8.4, CH᎐
᎐
᎐
CH2), 7.19–7.37 (10H, m, aromatic CH); δC (50 MHz, CDCl3)
50.7 (PhCH2), 57.2 (OCH3), 65.7 (NHCH), 86.5 (CHOCH3),
118.3 (CH᎐CH ), 126.8, 127.7, 127.8, 128.1, 128.2, 128.3
᎐
2
(aromatic CH), 136.8 (CH᎐CH ), 139.1, 140.4 (ipso-C); m/z
᎐
2
(APCI) 268 (MHϩ, 40%), 236 (MHϩ Ϫ MeOH, 70%), 161
(10%), 150 (15%), 129 (100%), 106 (15%); HRMS Calculated
for C18H22NOϩ: 268.1701. Found: 268.1699.
᎐
᎐
(m, C᎐C aromatic); δ (400 MHz, CDCl ) 3.21 (3H, s, OCH ),
᎐
H
3
3
3.31 (1H, t, J 8.2, CHCH᎐CH ), 3.62 (1H, d, J 13.2, NHCHH),
Benzaldehyde O-prop-2-ynyloxime 30. KOtBu (1.0 g, 9.1
mmol, 1.0 eq.) was added to a solution of benzaldehyde oxime
(1.0 g, 8.25 mmol, 1.1 eq.) in THF (10 mL) at 0 ЊC. After 15 min
propargyl bromide 29 (1.4 mL, 12.4 mmol) was added dropwise
and stirred overnight before the addition of NH4Cl(aq) (40 mL).
The resultant mixture was extracted with Et2O, dried, and
concentrated in vacuo. Purification by column chromatography
{20% Et2O–petrol (40 : 60)} gave 30 (1.14 g, 87%) as a clear
yellow oil. νmax/cmϪ1 (film) 3293 (s, alkyne C–H), 2925 (m,
᎐
2
3.87 (1H, d, J 13.2, NHCHH), 4.07 (1H, d, J 8.2, CH3OCH),
4.93 (1H, d, J 17.2, CH᎐CHH), 5.03 (1H, d, J 10.4, CH᎐CHH),
᎐
᎐
5.48–5.56 (1H, m, CH᎐CH ), 7.23–7.35 (10H, m, aromatic
᎐
2
CH); δC (100 MHz, CDCl3) 51.2 (NHCH2Ph), 56.8 (OCH3),
66.9 (NHCHCH᎐CH ), 86.6 (PhCHOCH ), 118.6 (CH᎐CH ),
᎐
᎐
2
3
2
126.7, 127.8, 127.9, 128.0, 128.1, 128.3 (aromatic CH), 136.7
(CH᎐CH ), 138.9 (ipso-C), 140.5 (ipso-C); m/z (APCI) 323
᎐
2
(13%), 269 (12%), 268 (MHϩ, 100%), 237 (13%), 236 (MHϩ
Ϫ
MeOH, 82%); HRMS Calculated for C18H22NOϩ: 268.1701.
Found 268.1706.
C–H); δH (400 MHz, CDCl ) 2.54 (1H, t, J 2.4, C᎐CH), 4.80
᎐
᎐
3
᎐
(2H, d, J 2.4, CH C᎐CH), 7.38–7.46 (3H, m, aromatic CH),
᎐
2
7.60–7.64 (2H, m, aromatic CH), 8.15 (1H, s, CH᎐N); δ (50
᎐
C
syn-(1RS,2RS )-1-Phenyl-1-methoxy-3-(N-benzylamino)but-
3-ene hydrochloride 26ؒHCl. HCl (g) was bubbled through a
solution of 26 (106 mg, 0.397 mmol) in Et2O (15 mL) for 2 min
and the solvent removed in vacuo to afford the crude product
26ؒHCl (108 mg, 85%) as a cream coloured solid. A small por-
tion was purified for characterisation and X-ray crystallography
by recrystallisation (1 : 3 petrol : CH2Cl2, white needles). Mp
167–169 ЊC; νmax/cmϪ1 (KBr disc) 3361 (br, N–H), 2696 (br,
MHz, CDCl3) 61.7 (CH2), 74.8, 79.5 (2 × alkyne C), 127.3,
128.7, 130.2 (aromatic CH), 131.7 (ipso-C), 150.0 (CH᎐N);
᎐
m/z (APCI) 160 (MHϩ, 100%), 144 (25%), 129 (95%), 122
(30%), 106 (90%); HRMS Calculated for C10H10NOϩ: 160.0762.
Found: 160.0760.
Benzaldehyde O-(4-hydroxy-4-phenylbut-2-ynyl)oxime 31.
LHMDS (1.0 M in THF, 6.29 mL, 6.29 mmol) was added to
30 (909 mg, 5.72 mmol) in THF (10 mL) at Ϫ78 ЊC. After
30 min, benzaldehyde (0.87 mL, 8.58 mmol) was added and the
mixture stirred for a further hour at Ϫ78 ЊC and warmed to rt
for 1 hour before the addition of H2O (30 mL) and the mixture
extracted with EtOAc (3 × 30 mL), dried and concentrated
in vacuo. Purification by column chromatography {30% Et2O–
petrol (40 : 60)} gave 31 (1.17 g, 77%) as a colourless oil.
νmax/cmϪ1 (film) 3400 (br, s, O–H), 3062 (m, C–H), 3029 (m,
C–H), 2919 (m, C–H), 1957 (w), 1888 (w), 1811 (w); δH (400
MHz, CDCl3) 2.99 (1H, br s, OH), 4.88 (2H, d, J 1.1, CH2), 5.53
(1H, s PhCHOH), 7.31–7.42 (6H, m, aromatic CH), 7.57–7.64
C–H), 1602 (m, C᎐C), 1471 (C᎐C aromatic), 1454 (C᎐C aro-
᎐
᎐
᎐
matic); δH (400 MHz, CD3OD) 3.28 (3H, s, CH3O), 3.87 (1H, t,
J 9.7, NH CHCH᎐CH ), 4.20 (1H, d, J 13.3, NH CHHPh),
᎐
2
2
2
4.35 (1H, d, J 13.3, NH2CHHPh), 4.45 (1H, d, J 9.7, CH3-
OCH), 5.11 (1H, d, J 17.0, CH᎐CHH), 5.41 (1H, d, J 10.4, CH᎐
᎐
᎐
CHH), 5.76–5.83 (1H, m, CH᎐CH ), 7.31–7.55 (10H, m,
᎐
2
aromatic CH); δC (100 MHz, CD3OD) 48.5 (CH3O), 56.9
(PhCH NH ), 67.1 (CHCH᎐CH ), 83.5 (PhCHOCH ), 127.4
᎐
2
2
2
3
(CH᎐CH ), 129.1 (CH᎐CH ), 129.3, 129.8, 130.3, 130.6, 131.0
᎐
᎐
2
2
(aromatic CH), 132.4 (ipso-C), 137.4 (ipso-C); m/z (APCI) 323
(12%), 269 (15%), 268 (Mϩ, 100%), 237 (14%), 236 (83%).
(4H, m, aromatic CH), 8.13 (1H, s, CH᎐N); δ (100 MHz,
᎐
C
᎐
anti-(3RS,4SR)-3-(N-Benzylamino)-1-phenyl-1-methoxybut-
3-ene 28. DIBAL–H (5.98 ml, 1.0 M in hexanes, 5.98 mmol)
was added dropwise to a stirred solution of methyl O-methyl-
mandelate (979 mg, 5.4 mmol) in CH2Cl2 (10 ml) at Ϫ78 ЊC.
After two hours, benzylamine (0.59 ml, 5.44 mmol) was added,
and the mixture allowed to reach rt over a period of 16 h.
MeOH (5 ml) was then added, followed after 5 minutes by
aqueous sodium potassium tartrate (20 ml, 1.0 M). After
stirring for four hours, water (50 ml) was added and the
resultant mixture extracted with CH2Cl2 (3 × 50 ml), dried
(MgSO4), and concentrated in vacuo to yield the crude imine 27
(1.0 g, 78% crude yield), which was used without purification in
the next step. δH (200 MHz, CDCl3) 3.41 (3H, s, OCH3), 4.61
CDCl ) 62.1 (CH ), 64.5 (CHOH), 82.5, 86.6 (C᎐C), 126.8,
᎐
3
2
127.3, 128.4, 128.6, 128.8, 130.2 (aromatic CH), 131.7, 140.3
(ipso-C), 150.1 (C᎐N); m/z (APCI) 249 (MHϩ Ϫ H2O, 10%),
᎐
117 (15%), 104 (100%). Calculated for C17H15NO2: C 77.0, H
5.7, N 5.3. Found: C 76.9, H 5.7, N 5.3%.
Benzaldehyde O-(4-methoxy-4-phenylbut-2-ynyl)oxime 32. A
solution of 31 (1.17 g, 4.40mmol) in THF (10 mL) was added
by cannula to a stirred suspension of NaH (60% dispersion in
mineral oil, 194 mg, 4.84 mmol, prewashed with pentane) in
THF (10 mL) at 0 ЊC. After 30 min, methyl iodide (0.8 mL, 13.2
mmol) was added, and the mixture stirred for 18 h and allowed
to reach rt. Methanol (10 mL), water (20 mL), and brine
(10 mL) were then added, and the mixture extracted with
EtOAc (3 × 30 mL), dried (MgSO4) and concentrated in vacuo.
Purification by column chromatography {50% Et2O–petrol (40 :
60)} gave 32 (1.03 g, 84%) as a pale yellow oil. νmax/cmϪ1 (film)
2929 (m, C–H), 1957 (w), 1895 (w), 1745 (m), 1668 (m), 1607
(m); δH (200 MHz, CDCl3) 3.48 (3H, s, OCH3), 4.92 (2H, d,
J 1.7, CH2), 5.20 (1H, t, J 1.7, PhCHOCH3), 7.35–7.68 (10H,
(2H, br s, CH Ph), 4.83 (1H, d, J 5.7, CH᎐N), 7.21–7.42 (10H,
᎐
2
m, aromatic CH), 7.74 (1H, dt, J 5.7, 1.5).
BF3ؒEt2O (0.57 mL, 4.66 mmol) was added to a stirred solu-
tion of the imine (371 mg, 1.55 mmol) in THF (10 ml) at
Ϫ78 ЊC and stirried for 30 min before the addition of vinyl-
magnesium bromide (1.0 M in THF, 10 mL) over 5 minutes.
After stirring at Ϫ78 ЊC for 30 min, the reaction mixture was
allowed to warm to rt. After a further two hours, water (100 ml)
was added, and the mixture extracted with CH2Cl2 (3 × 50 ml),
dried (MgSO4), and concentrated in vacuo. Purification by
column chromatography {20% Et2O–petrol (40 : 60)} gave 28
(112 mg, 27%) as a pale yellow oil. νmax/cmϪ1 (film) 3328 (w)
(N–H), 2929 (m), 1495 (m), 1453 (s); δH (400 MHz, CDCl3) 3.23
m, aromatic CH), 8.17 (1H, s, PhCH᎐N); δ (50 MHz, CDCl )
᎐
C
3
᎐
55.9 (OCH ), 62.1 (OCH C᎐C), 73.1 (CH(OCH )Ph), 83.8,
᎐
3
2
3
᎐
84.2 (C᎐C), 127.5, 127.7, 128.7, 128.9, 130.3 (aromatic CH),
᎐
132.1, 138.4 (ipso-C), 150.1 (CH᎐N); m/z (APCI) 280 (MHϩ,
᎐
20%), 117 (15%), 104 (100%); HRMS Calculated for C17H14-
NOϩ (MHϩ Ϫ MeOH): 248.1075. Found: 248.1082.
J. Chem. Soc., Perkin Trans. 1, 2002, 2141–2150
2149

View Article Online
6 (a) K. Burgess and M. J. Ohlmeyer, J. Org. Chem., 1991, 56, 1027;
(b) J. C. A. Hunt, P. Laurent and C. J. Moody, Chem. Commun.,
2000, 18, 1771; (c) J. A. Marshall and A. W. Garafalo, J. Org. Chem.,
1993, 58, 3675; (d ) R. Jumnah, J. M. J. Williams and A. C. Williams,
Tetrahedron Lett., 1993, 34, 6619.
7 (a) B. M. Trost and R. C. Bunt, J. Am. Chem. Soc., 1994, 116, 4089;
(b) F. Effenberger, B. Gutterer and J. Syed, Tetrahedron: Asymmetry,
1995, 6, 2933; (c) P. Merino, S. Anoro, E. Castillo, F. Merchan and
T. Tejero, Tetrahedron: Asymmetry, 1996, 7, 1887; (d ) T. Hayashi
and M. Ishigedani, Tetrahedron, 2001, 57, 2589; (e) R. B. Grossman,
W. M. Davis and S. L. Buchwald, J. Am. Chem. Soc., 1991, 113,
2321.
(Z )-Benzaldehyde O-(4-methoxy-4-phenylbut-2-enyl)oxime
33. Lindlar’s catalyst (200 mg) was added to 32 (912 mg, mmol)
in methanol (10 mL), and stirred under 4 atm H2 for 4 days. The
mixture was then filtered through Celite, and concentrated
in vacuo before purification by column chromatography {10%
Et2O–petrol (40 : 60)} to give 33 (803 mg, 66%) as a colourless
oil. νmax/cmϪ1 (film) 2932 (s, C–H), 1955 (w), 1882 (w), 1812 (w),
1723 (m), 1602 (m); δH (400 MHz, CDCl3) 3.38 (3H, s, OCH3),
4.84 (1H, ddd, J 13.0, 6.1, 1.4, OCHH), 4.94 (1H, ddd, J 13.0,
6.8, 1.5, OCHH), 5.09 (1H, d, J 9.0, CHOCH3), 5.78 (1H, app
ddt, J 11.3, 9.0, 1.3, CH CH᎐CH), 5.87–5.93 (1H, m, CH -
᎐
2
2
8 S. D. Bull, S. G. Davies, S. Jones, J. V. A. Ouzman, A. J. Price and
D. J. Watkin, Chem. Commun., 1999, 2079.
CH᎐CH), 7.28–7.41 (8H, m, aromatic CH), 7.56–7.60 (2H, m,
᎐
9 As shown by 1H NMR spectroscopic analysis of the crude reaction
mixture.
aromatic CH), 8.11 (1H, s, CH᎐N); δ (50 MHz, CDCl ) 56.8
᎐
C
3
(OCH3), 70.4 (CH2), 79.5 (PhCHOCH3), 127.1, 127.6, 128.2,
128.2, 129.0, 129.2, 130.4 (aromatic CH and C᎐C), 132.6 (ipso-
10 As supplied by the Aldrich Chemical Company Ltd.
11 The assignment of relative configuration to the commercially
available (2SR,3RS )-13 and (2RS,3RS )-14 diastereoisomers
᎐
C), 134.5 (C᎐C), 141.6 (ipso-C), 149.5 (PhC᎐N); m/z (APCI)
᎐
᎐
250 (MHϩ Ϫ MeOH, 10%), 147 (PhCHCH᎐CHCH OHϩ, 5%),
1
᎐
2
was taken with consideration of the H NMR data available from
129 (15%), 122 (PhCH᎐NHOHϩ, 15%), 104 (100%). Calculated
the literature; see Y. Kataoka, Y. Seto, M. Yamamoto, T. Yamada,
S. Kuwata and H. Watanabe, Bull. Chem. Soc. Jpn., 1976, 49, 1081.
12 Using the protocol developed previously for aldehyde substrates
which are sensitive to racemisation/epimerisation; see J. R. Luly,
J. F. Dellaria, J. J. Plattner, J. L. Soderquist and N. Yi, J. Org. Chem.,
1987, 52, 1487.
᎐
for C18H19NO2: C 76.8, H 6.8, N 5.0. Found: C 76.5, H 6.5,
N 4.8%.
(Z )-N-Benzyl-O-(4-methoxy-4-phenylbut-2-enyl)hydroxyl-
amine 34. Borane–pyridine complex (0.76 mL) was added to 33
(304 mg, 1.08 mmol) in EtOH (20 mL) at 0 ЊC, followed by the
dropwise addition of 10% EtOH–HCl (30 mL) over 5 minutes
before being allowed to warm to rt and stirred for a further
18 h. The reaction mixture was then basified with saturated
aqueous Na2CO3, extracted with CH2Cl2 (3 × 40 mL), dried (Mg-
SO4), and concentrated in vacuo before purification by column
chromatography {10% Et2O–petrol (40 : 60)} to give 34 (221
mg, 72%) as pale yellow oil. νmax/cmϪ1 (film) 3260 (m), 2928 (s),
1953 (w), 1861 (w), 1811 (w), 1602 (m); δH (400 MHz, CDCl3)
3.29 (3H, s, OCH3), 4.08 (2H, s, PhCH2), 4.29 (1H, dd, J 12.7,
4.6, OCHH), 4.39 (1H, dd, J 12.7, 6.0, OCHH), 4.93 (1H,
13 (a) The diastereoselectivity observed upon addition of organo-
metallic reagents to imines has found wide application in synthesis;
for
a review see D. Enders and U. Reinhold, Tetrahedron:
Asymmetry, 1997, 8, 1895; (b) For related cases of additions of
organometallic reagents to (a) a chiral α-aldoxime acetal see
H. Fujioka, M. Masahiro, Y. Okaichi, T. Yoshida, H. Annoura,
Y. Kita and Y. Tamura, Chem. Pharm. Bull., 1989, 37, 602; (c) an
alkoxymethyl oxime ether see Y. Ukaji, K. Kume, T. Watai and
T. Fujisawa, Chem. Lett., 1991, 173; (d ) N-alkylketimines and 1,3-
oxazolidines see A. G. Steinig and D. M. Spero, J. Org. Chem., 1999,
64, 2406; (e) chiral 1,2-bisimines see S. Roland and P. Mangeney,
Eur. J. Org. Chem., 2000, 1373.
14 J. Mulzer, M. Kappert, G. Huttner and I. Jibril, Angew. Chem., Int.
Ed. Engl., 1984, 23, 704.
d, J 7.8, CHOCH ), 5.67–5.77 (2H, m, CH᎐CH), 7.25–7.38
᎐
3
15 (a) H. Matsunaga, T. Sakamaki, H. Nagaoka and Y. Yamada,
Tetrahedron Lett., 1983, 24, 3009; (b) N. Asao, T. Shimada,
N. Tsukada and Y. Yamamoto, Tetrahedron Lett., 1994, 35, 8425;
(c) U. A. Hausermann, A. Linden, J. Song and M. Hesse, Helv.
Chim. Acta, 1996, 23, 704; (d ) For a recent addition of a
hydroxylamine see A. G. Moglioni, E. Muray, J. A. Castillo,
Á. Álvarez-Larena, G. Y. Moltrasio, V. Branchadell and R. M.
Otuño, J. Org. Chem., 2002, 67, 2402.
16 (a) Y. Chounan, Y. Ono, S. Nishii, H. Kitahara, S. Ito and Y.
Yamamoto, Tetrahedron, 2000, 56, 2821; (b) Y. Yamamoto, S. Nishii
and T. Ibuka, Chem. Commun., 1987, 1572; (c) Y. Yamamoto,
Y. Chounan, S. Nishii, T. Ibuka and H. Kitahara, J. Am. Chem. Soc.,
1992, 114, 7652; (d ) A. Stoncius, C. A. Mast and N. Sewald,
Tetrahedron: Asymmetry, 2000, 11, 3849.
17 (a) N. Asao, T. Shimada, T. Sudo, N. Tsukada, K. Yazawa,
Y. S. Gyoung, T. Uyehara and Y. Yamamoto, J. Org. Chem., 1997,
62, 6274; (b) N. Sewald, K. D. Hiller, M. Koerner and M. Findeisen,
J. Org. Chem., 1998, 63, 7263.
18 K. N. Houk, M. N. Paddon-Row, N. G. Rondan, Y.-D. Wu,
F. K. Brown, D. C. Spellmeyer, J. T. Metz, Y. Li and
R. J. Loncharich, Science, 1986, 231, 1108.
(10H, m, aromatic CH); δC (50 MHz, CDCl3) 56.2 (OCH3),
56.6 (PhCH2), 69.8 (OCH2), 78.9 (PhCH), 126.6, 127.5,
127.6, 128.0, 128.5, 128.6, 129.0 (aromatic CH and C᎐C), 133.9
᎐
(C᎐C), 137.6, 141.3 (ipso-C); m/z (CI) 284 (MHϩ, 15%), 252
᎐
(MHϩ Ϫ MeOH, 100%), 222 (10%), 161 (15%), 147 (25%), 130
(20%), 105 (25%), 92 (20%). Calculated for C18H21NO2: C 76.3,
H 7.5, N 4.9. Found: C 76.4, H 7.2, N 4.9%.
Acknowledgements
The authors wish to acknowledge the EPSRC for a studentship
and the SCI for a Messel Scholarship (T. G. R. S) and New
College, Oxford for a Junior Research Fellowship (A. D. S).
References and notes
1 I. Coldham in Comprehensive Functional Group Transformations,
A. R. Katritzky, O. Meth-Cohn and C. W. Rees, Pergamon Press,
Oxford, 1995, Vol. 1, p. 404.
2 (a) R. W. Hoffmann, Angew. Chem., 1979, 18, 563; (b) D. Enders and
H. Kempen, Synlett, 1994, 969; (c) M. T. Reetz, N. Griebenow and
R. Goddard, Chem. Commun., 1995, 1605; (d ) J. C. Anderson and
A. Flaherty, J. Chem. Soc., Perkin Trans. 1, 2001, 267; (e) J. Mulzer
and D. Riether, Org. Lett., 2000, 2, 3139; ( f ) D. Enders, M. Bartsch
and J. Runsink, Synthesis, 1999, 243.
3 (a) For examples of the synthetic utility of the [2,3]-Wittig
rearrangement see: T. Nakai and K. Mikami, Chem. Rev., 1986,
86, 885; (b) T. Nakai and K. Mikami, Org. React., 1994, 46, 105;
(c) J. A. Marshall in C–C σ Bond Formation, ed. G. Pattenden,
vol. 3 of Comprehensive Organic Synthesis, eds. B. M. Trost and
I. Fleming, Pergamon Press, 1990, 975.
4 (a) S. G. Davies, S. Jones, M. A. Sanz, F. C. Teixeira and J. F. Fox,
Chem. Commun., 1998, 2235; (b) S. G. Davies, J. F. Fox, S. Jones, A.
J. Price, M. A. Sanz, T. G. R. Sellers, A. D. Smith and F. C. Teixeira,
J. Chem. Soc., Perkin Trans. 1, 2002, 1757.
19 (a) For other examples where the diastereoselectivity of the [2,3]-
Wittig rearrangement has been rationalised in a similar manner see
R. Brückner, Chem. Ber., 1989, 122, 193; (b) R. Brückner and
H. Priepke, Angew. Chem., Int. Ed. Engl., 1988, 27, 278; (c) E. Nakai
and T. Nakai, Tetrahedron Lett., 1988, 29, 4587; (d ) K. Mikami and
T. Nakai, Synthesis, 1991, 594; (e) H. Priepke and R. Brückner,
Chem. Ber., 1990, 123, 153.
20 (a) The need for a metal counter-ion in the [2,3]-Wittig
rearrangement has been the cause of much debate. Theoretical
calculations have shown that the preferred transition structure of
the Wittig rearrangement required the lithium cation; see : Y.-D. Wu,
K. N. Houk and J. A. Marshall, J. Org. Chem., 1990, 1421;
(b) However, in some cases E/Z and anti/syn ratios of products in the
Wittig rearrangement have been shown to be independent of
the metal counterion; see B. Kruse and R. Brückner, Tetrahedron
Lett., 1990, 31, 4425.
21 For an example where the diastereoselectivity observed for a [2,3]-
Wittig rearrangement has been rationalised via a chelated transition
state see S. W. Scheuplein, A. Kusche, R. Brückner and K. Harms,
Chem. Ber., 1990, 123, 917.
5 (a) Z. Zhang and R. Scheffold, Helv. Chim. Acta, 1993, 76, 2602;
(b) R. B. Cheikh, R. Chaabouni, A. Laurent, P. Mijon and A. Nafti,
Synthesis, 1983, 685.
2150
J. Chem. Soc., Perkin Trans. 1, 2002, 2141–2150