Enantioselective synthesis of β-hydroxy amines and aziridines using asymmetric transfer hydrogenation of α-amino ketones

Article abstract of DOI:10.1039/b102895m

Enantioselective transfer hydrogenation of α-amino ketones is an effective method for the asymmetric synthesis of β-hydroxy amines and aziridines.

Full text of DOI:10.1039/b102895m

View Online / Journal Homepage / Table of Contents for this issue
Enantioselective synthesis of ꢀ-hydroxy amines and aziridines using
asymmetric transfer hydrogenation of ꢁ-amino ketones
Aparecida M. Kawamoto† and Martin Wills*
1
Department of Chemistry, University of Warwick, Coventry, UK CV4 7AL
Received (in Cambridge, UK) 29th March 2001, Accepted 22nd June 2001
First published as an Advance Article on the web 26th July 2001
Enantioselective transfer hydrogenation of α-amino ketones is an effective method for the asymmetric synthesis
of β-hydroxy amines and aziridines.
TsDPEN 2 with the same ruthenium complex, a system first
Introduction
reported by Noyori,3 gave superior results (Scheme 1) when
used with the formic acid–triethylamine hydrogen source.5b
Since the enantioselectivies of the reduction were high, we con-
sidered that this might be a suitable method for the synthesis of
aziridines of high enantiomeric excess.
Aziridines are valuable synthetic reagents and intermediates.
In particular they benefit from high reactivity due to the
small, strained, nitrogen-containing rings, thus permitting their
rapid conversion into a range of derivatives. The synthesis of
enantiomerically pure aziridines is a desirable objective since
the physiological properties of both the aziridines themselves
and the products formed from them are likely to be dependent
on the absolute configuration.1
Results and discussion
The racemic reduction of α-amino ketones is generally
routinely carried out through the use of sodium borohydride
or other hydride reagents. Enantioselective reduction of such
substrates by transfer hydrogenation had not been reported
prior to our initial studies, and we feared that it may be
inhibited by chelation of the metal of the catalyst by the reduc-
tion product. Recent work in our group has revealed that the
use of an amide or carbamate derivative to protect the amine
prevents this and renders the reaction high yielding and select-
ive.5 Following conversion of the hydroxy group to a tosylate
and deprotection of the amine it is possible to cyclise the
product through an SN2 mechanism, to give the aziridine in
high ee.5b
Enantiomerically enriched aziridines may be formed by the
enantioselective catalysis of the addition of a nitrene onto one
face of a prochiral alkene.2 However, the most conceptually
simple approach to these targets is probably through the
cyclisation of an appropriate enantiomerically pure β-amino
alcohol precursor.1 Whilst a number of homochiral β-amino
alcohols are available from natural sources such as amino acids,
the range of materials is limited. In this paper we describe a
simple and expedient route for the enantioselective synthesis of
aziridines via α-amido ketone reduction followed by cyclisation.
We have previously described the use of enantioselective
transfer hydrogenation3–5 for the reduction of ketones contain-
ing α-amido groups (Scheme 1).5 In the example shown we first
During the last two decades, the conversion of 2-amino
alcohols to aziridines6,7 has been achieved by one-pot
cyclisations
employing
triphenylphosphine–carbon
tetrachloride–triethylamine8 or triphenylphosphine dibromide–
triethylamine.9 Although the combination of triphenyl-
phosphine–diethyl azodicarboxylate (Mitsunobu reagent) has
been used for intramolecular dehydrations,10 application of this
reagent to the synthesis of aziridines has also been reported.11,12
According to Pfister,13 aziridines are generally obtained success-
fully if there is at least one substituent attached to either of the
two carbon atoms between oxygen and nitrogen.
For the synthesis of N-benzyl-2-phenylaziridine 3 we began
with the preparation of α-(N-benzyl-amino) ketone from
readily available and inexpensive bromoacetophenone and
benzylamine, followed by tBoc-protection of the NH group to
give α-(N-benzyl-N-tBoc)amino ketone 4 in 79% yield. Reduc-
tion of 4 using sodium borohydride gave the racemic alcohol
rac-5 in 98% yield. Enantioselective reduction of 4 was success-
fully achieved using both the (1S,2R)-cis-aminoindanol–
propan-2-ol and (1R,2R)-TsDPEN–formic acid systems. In
both cases the enantiomeric excesses (ee) were determined by
chiral HPLC. The aminoindanol system afforded S-(ϩ)-5
in 60% yield and 88% ee, while the (1R,2R)-TsDPEN–formic
acid system gave S-(ϩ)-5 in 74% yield and 98% ee. The absolute
configuration was confirmed by conversion to the O-tert-
butyldimethylsilyl ether S-(ϩ)-6 (see later discussion) by
treatment of the precursor alcohol 5 with tert-butylchloro-
Scheme 1 Reagents and conditons: i) 0.5 mol% [Ru(cymene)Cl2]2
1 mol% 1, iPrOH, 2.5 mol% KOH, rt. ii) 0.5 mol% [Ru(cymene)Cl2]2
1 mol% 2, HCO2H, Et3N, rt.
employed a catalyst formed by the combination of (1S,2R)-cis-
1-aminoindan-2-ol 1 with [Ru(cymene)Cl2]2 and propan-2-ol–
KOH as the hydrogen source,5a which gave a product of 79% ee.
In subsequent studies we found that the combination of (R,R)-
† On leave from the Brazilian Space Aeronautical Institute—Praca
Mal. Eduardo Gomes 50, Vila das Acacias, SJ Campos, SP, Brazil.
1916
J. Chem. Soc., Perkin Trans. 1, 2001, 1916–1928
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b102895m

View Online
dimethylsilane and imidazole (49% yield). Deprotection of the
nitrogen atom in S-(ϩ)-5 gave the amino alcohol S-(ϩ)-7 which
was the subject of cyclisation studies. Attempts to achieve this
via O-tosylation followed by base treatment failed,14 however
the use of Mitsunobu conditions resulted in formation in
low yield (23%), but high enantiomeric excess, of the aziridine
R-(Ϫ)-3.10 The ee of the aziridine 3 was determined to be 98%
(as might be obtained from the reduction of 8) may inhibit, and
lead to subsequent decomposition of, the aminoalcohol–Ru()
complex.3 In contrast the monotosylated diamine may well
form much stronger complexes with the same metal, and be
resistant to such chelation-initiated decomposition. The con-
figuration of S-(ϩ)-9 was determined by deprotection of the
nitrogen atom with TFA to give the known amino alcohol
S-(ϩ)-1020 in 27% yield. Conversion of the same sample of
S-(ϩ)-9 to S-(ϩ)-6 with tert-butylchlorodimethylsilane and
imidazole, and subsequently with phenyl bromide and sodium
hydride, served to confirm the absolute configuration of the
product of reduction of 4 as described previously (Scheme 2).
Alcohol S-(ϩ)-9 was cyclised to the N-tBoc-aziridine R-(Ϫ)-
15
by 1H NMR analysis using 6 mol% Eu(hfc)3 chiral shift
reagent. The racemic aziridine was also synthesised in an iden-
tical manner (27% yield for the cyclisation step) (Scheme 2).
1
11 in 92% yield and 99% ee (determined by H NMR analysis
using 6 mol% Eu(hfc)3 chiral shift reagent) through treatment
with tosyl chloride and base,14a thus delivering an efficient
synthesis of aziridines in high yield and enantioselectivity.21
Cyclisation of racemic ( )-1-phenyl-2-(tert-butoxycarbonyl-
amino)ethanol was also achieved in 92% yield through treat-
ment with tosyl chloride and base (in order to supply a racemic
standard).
2-Methylaziridine has been prepared using the classic
method of Wenker,21,22 through cyclisation of the sulfate ester
of 1-aminopropan-2-ol. In an attempt to improve the synthetic
method of formation of 2-methylaziridine, cyclisation with
tosyl chloride and KOH was used. Boc-protection of the
NH group of ( )-1-aminopropan-2-ol gave the ( )-1-tBoc-
aminopropan-2-ol 12 in 95% yield, which was then used in two
different reactions. It was i) cyclised to the N-tBoc aziridine 13
through treatment with tosyl chloride and base (57%), and
ii) oxidised with pyridium dichromate to give ( )-1-tBoc-
aminopropan-2-one 14 in 88% yield. Reduction of 14 using the
ruthenium based catalyst, with TsDPEN 2 and formic acid, was
achieved in 87% yield and gave a product of [α]2D0 ϩ27.5 (c = 1,
CH2Cl2). We have assigned, on the basis of the sense of reduc-
tion of 8, S configuration to compound 12. Alcohol 12 was then
cyclised to N-tBoc-2-methylaziridine R-(Ϫ)-13 in 56% yield,
through treatment with tosyl chloride and base (Scheme 4). The
Scheme 2 Reagents and conditions: i) 0.5 mol% [Ru(cymene)Cl2]2
1 mol% 1, iPrOH, 2.5 mol% KOH, rt. ii) 0.5 mol% [Ru(cymene)Cl2]2
1 mol% 2, HCO2H, Et3N, rt. iii) TFA, CH2Cl2. iv) DEAD, PPh3, THF.
In an attempt to identify an improved route, the synthesis
of N-tBoc-2-phenylaziridine was also an objective of our study.
N-Acylaziridine has been prepared according to essentially
three synthetic routes from N-acyl-α-amino alcohols. The first
method involves activation of the hydroxy group by converting
it into a tosylate or mesylate and subsequent ring-closure by
means of a strong base (LiHMDS or NaH).16 The second
method is most frequently used and requires the Mitsunobu
conditions.17,18 Thirdly N-acylaziridines have been prepared
using the expensive and hazardous diethylaminosulfur trifluor-
ide (DAST).19 For this project we employed the straightforward
cyclisation method of N-tBoc-amino alcohols described by
Wessig et al.14a
The synthetic route began with 2-(N-tert-butoxycarbonyl-
amino)acetophenone 8 and is summarised in Scheme 3. Our
Scheme 4 Reagents and conditions: i) 0.5 mol% [Ru(cymene)Cl2]2
1 mol% 2, HCO2H, Et3N, rt. ii) TsCl, KOH, THF.
resulting aziridine exhibits [α]2D0 Ϫ42.2 (c = 1, dichloromethane).
Since the alcohol is not UV active, the exact enantiomeric
excess of the pure compound could not be measured by chiral
HPLC. However Wessig et al.14a have previously referred to the
synthesis of enantiomerically pure (S)-N-tBoc-2-methyl-
aziridine, which has [α]D20 ϩ39.2 (c = 1, CH2Cl2). Since aziridine
13 has [α]2D0 Ϫ42.2 (c = 1, CH2Cl2), we can then conclude that
it is of high ee and R configuration as expected since the
cyclisation process normally occurs with an inversion of
configuration.
Scheme 3 Reagents and conditions: i) 0.5 mol% [Ru(cymene)Cl2]2
1 mol% 2, HCO2H, Et3N, rt. ii) TFA, CH2Cl2. iii) DEAD, PPh3, THF.
studies revealed that the monotosylated diamine system was
highly efficient at the reduction of 8, furnishing alcohol S-(ϩ)-9
in 86% yield, [α]2D0 ϩ0.8 (c = 2 ethanol), and 99% ee as measured
by chiral HPLC. In contrast the (1S,2R)-cis-aminoindanol–
Ru()–propan-2-ol system totally failed in this application. The
reasons for this dramatic difference are not fully clear, however
we have previously speculated that chelating reduction products
In view of the importance of 2-hydroxy-2-propylamine
derivatives, such as bisprolol 15,23 as β-selective adrenoceptor
blocking agents (β-blockers) used in the treatment of hyper-
tension, angina pectoris, cardiac arrhythmias, glaucoma, and
J. Chem. Soc., Perkin Trans. 1, 2001, 1916–1928
1917

View Online
prevention of migraine attacks, we chose to examine the syn-
thetic approach to such targets through the enantioselective
transfer hydrogenation of the corresponding ketone precursor.
butoxycarbonyl-N-benzylamino)-2-oxo-3-phenoxypropane 20
was prepared from the reaction of 2-(chloromethyl)allyl phenyl
ether with benzyl amine, tBoc protection and ozonolysis. Enan-
tioselective reduction of ketone 20 was successfully achieved
using both (1R,2R)-TsDPEN–formic acid and (1S,2R)-(ϩ)-cis-
1-aminoindan-2-ol–propan-2-ol systems. The (1S,2R)-cis-
aminoindanol system afforded (R)-(ϩ)-21 in 99% yield with
61% ee, while the (1R,2R)-TsDPEN–formic acid system gave
(R)-(ϩ)-21 in 99% yield with 60% ee. That the absolute
configurations of R-(ϩ)-21 and R-(ϩ)-16 were both identical
was confirmed by conversion of R-(ϩ)-21 to the O-tert-butyl-
dimethylsilyl ether R-(ϩ)-19 by treatment with tert-butylchloro-
dimethylsilane and imidazole. Deprotection of the nitrogen
atom in R-(ϩ)-21 gave the corresponding amino alcohol (not
illustrated) for which attempts to cyclise using Mitsunobu
conditions failed.
The route to 2-hydroxy-2-propylamine and its corresponding
aziridine derivative is outlined is Scheme 5. The substrate was
Our assignment of the configuration of compound R-(ϩ)-21
was based on analogy with the result from a short synthesis of
R-(Ϫ)-propranolol, a known β-adrenergic blocking agent24
(Scheme 6). Reaction of 1-naphthol with epichlorohydrin
Scheme 5 Reagents and conditions: i) 0.5 mol% [Ru(cymene)Cl2]2
1 mol% 1, iPrOH, 2.5 mol% KOH, rt. ii) 0.5 mol% [Ru(cymene)Cl2]2
1 mol% 2, HCO2H, Et3N, rt. iii) TsCl, KOH, THF.
prepared by tBoc-protection of the NH group of allylamine
(98% yield), oxidation with m-chloroperoxybenzoic acid (88%),
ring opening with phenol (to give racemic 16, 92% yield).
Compound rac-16 was then i) cyclised to rac-N-tBoc-2-
(phenoxymethyl)aziridine 17 in 66% yield, and ii) oxidised with
pyridine dichromate to afford 18 in 31% yield. Reaction of
ketone 18 using the (1R,2R)-TsDPEN–formic acid system gave
the corresponding alcohol R-(Ϫ)-16 in 84% ee (measured by
chiral HPLC) and 86% yield. The configuration is based on
analogy with the synthesis of (R)-propranolol described in
the next section. In contrast the (1S,2R)-cis-aminoindanol–
Ru()–propan-2-ol system totally failed in this application.
Conversion of the same sample of R-(Ϫ)-16 to R-(ϩ)-19 with
tert-butylchlorodimethylsilane and imidazole, followed by
benzyl bromide and sodium hydride, was undertaken to con-
firm the absolute sense of the product of reduction of 20 as
described in the next section.
Scheme 6 Reagents and conditions: i) 0.5 mol% [Ru(cymene)Cl2]2
1 mol% 1, iPrOH, 2.5 mol% KOH, rt. ii) 0.5 mol% [Ru(cymene)Cl2]2
1 mol% 2, HCO2H, Et3N, rt. iii) TFA, DCM.
afforded ( )-3-(1-naphthyloxy)-1,2-epoxypropane in 61% yield,
which was followed by a ring opening reaction with isoprop-
ylamine to give the racemic amino alcohol, ( )-N-isopropyl-
N-[2-hydroxy-3-(1-naphthyloxy)propyl]amine 24 in 93%
yield. tBoc-protection of the amino group of this alcohol gave
the ( )-N-tBoc-N-isopropyl-N-[2-hydroxy-3-(1-naphthyloxy)-
propyl]amine 22 in 99% yield. Oxidation of compound 22 with
pyridinium dichromate afforded the ketone, N-(tBoc)-iso-
propyl-N-[2-oxo-3-(1-naphthyloxy)propyl]amine, 23 in 68.5%
yield. Enantioselective reduction of ketone 23 was successfully
achieved using both (1R,2R)-TsDPEN–formic acid and
(1S,2R)-(ϩ)-cis-1-aminoindan-2-ol–propan-2-ol systems. The
(1S,2R)-cis-aminoindanol system afforded R-(ϩ)-22 in 99%
yield with [α]2D0 Ϫ1.9 (c = 0.89, ethanol), while the (1R,2R)-
TsDPEN–formic acid system gave R-(Ϫ)-22 in 98% yield with
[α]2D0 Ϫ2.92 (c = 0.96, ethanol). Deprotection of the amine
gave the amino acid, (R)-(ϩ)-N-isopropyl-N-[2-hydroxy-3-(1-
naphthyloxy)propyl]amine (propranolol) 24, in 85% yield and
83.0% ee as measured by chiral HPLC, with [α]2D0 ϩ5.19 (c = 1.6,
ethanol) for (1R,2R)-TsDPEN–formic system, and 93% yield,
64% ee, with [α]2D0 ϩ6.26 (c = 0.74 ethanol) for (1S,2R)-cis-
aminoindanol system.
Alcohol R-(Ϫ)-16 was then cyclised to the corresponding
aziridine R-(Ϫ)-17 in 63% yield, through treatment with tosyl
chloride and base. The resulting aziridine has a high [α]2D0 (Ϫ68.9
(c = 1, ethanol)), and enantiopurity (84% ee). We believe that
this represents a competitive, and highly practical approach
for the reduction of this class of ketones, which are normally
regarded as ‘difficult’ substrates due to the lack of steric dif-
According to the literature,24 S-(Ϫ)-propranolol has [α]2D0
Ϫ23.2 (c = 1.08, ethanol). Therefore, comparing the values of
[α]2D0 of both compounds, we can conclude that our route for
the enantioselective reduction of ketone 22 leads to R-(ϩ)-
propranolol 24. By confirming the configuration of R-(ϩ)-
ferentiation between the groups flanking the C᎐O group.
᎐
Considering the importance of 2-hydroxy-3-phenoxypropyl-
amine derivatives, some alternative routes to produce the
corresponding ketone precursors were examined. (R)-(ϩ)-1-(N-
1918
J. Chem. Soc., Perkin Trans. 1, 2001, 1916–1928

View Online
propranolol, and considering the steric and electronic similarity
of the groups OPh with Onaphthyl, and benzyl with isopropyl,
we have assigned the configuration of compound 16 and con-
sequently compound 21, as also R-configured.
([M ϩ H]ϩ, 42%), 270 (46), 227 (67), 226 (100), 169 (22), 120
(56), 106 (40), 91 (34) (Found: [M ϩ H]ϩ, 326.1753. C20H23NO3
requires m/z, 326.1756).
rac-2-(N-tert-Butoxycarbonyl-N-benzylamino)-1-phenylethanol
5
Conclusion
α-(N-tert-Butoxycarbonyl-N-benzylamino)acetophenone
4
In conclusion, we have demonstrated that the use of mono-
tosylated diamine–formic acid–triethylamine and cis-1-amino-
indan-2-ol–propan-2-ol systems are highly effective at the
enantioselective reduction of tBoc-protected α-aminoketones
and this process provides an efficient method for the enantio-
selective syntheses of enantiomerically enriched β-amino
alcohol and aziridines.
(1.60 g, 5.00 mmol) was dissolved in 20 ml of MeOH–H2O
(9 : 1), in an ice bath. Sodium borohydride (0.25 g, 7.00 mmol)
dissolved in 10 mL of MeOH–H2O (9 : 1) was added slowly to
the ketone solution. The reaction mixture was allowed to warm
up to room temperature. When the reaction was completed
(TLC), it was concentrated under reduced pressure. The residue
was dissolved in diethyl ether (30 mL) and worked up with
ammonium chloride saturated solution (30 mL). The phases
were separated and the aqueous layer extracted with diethyl
ether (2 × 20 mL). The organic layers were dried over
anhydrous magnesium sulfate, filtered and the solvent removed
under reduced pressure. The crude compound was purified
using medium pressure flash chromatography eluting with 15%
ethyl acetate–petroleum 40 : 60 to give 2-(N-tert-butoxy-
carbonyl-N-benzylamino)-1-phenylethanol 5 as a white solid
(1.60 g, 98%), mp 66–68 ЊC (Found: C, 73.24; H, 7.66; N, 4.20.
C20H25NO3 requires C, 73.37; H, 7.70; N, 4.28%); νmax(CDCl3)/
Experimental
All reactions, unless otherwise stated, were run under an
atmosphere of nitrogen. Room temperature refers to ambient
temperature (20–22 ЊC), 0 ЊC refers to an ice slush bath and
Ϫ78 ЊC refers to a dry ice–acetone bath. Heated experiments
were conducted using thermostatically controlled oil baths.
Reactions were monitored by TLC using aluminium backed
silica gel 60 (F254) plates, visualised using UV 254 nm and
phosphomolybdic acid, ninhydrin or potassium permanganate
dips as appropriate. Flash column chromatography was carried
out routinely using 60 Å silica gel (Merck). Reagents were used
as received from commercial sources unless otherwise stated.
Acetophenone was purified by short path distillation before
use. Formic acid–triethylamine (5 : 2 molar) is a commercially
available azeotrope (Fluka). NMR spectra were recorded on a
Bruker DPX (300 MHz) spectrometer. The spectra solutions
were in deuterated chloroform (CDCl3) unless otherwise stated.
Chemical shifts are reported in δ units, parts per million down-
field from TMS. Coupling constants (J) are measured in hertz.
IR spectra were recorded on a Perkin–Elmer 1310 FTIR
instrument using sodium chloride plates. Mass spectra were
recorded on a 7070E VG mass spectrometer. Melting points
were recorded on a Stuart Scientific SMP 1 instrument and are
uncorrected. Optical rotations were measured with an AA-1000
polarimeter and are given in 10Ϫ1 deg cm2 gϪ1. Determination
of enantiomeric excesses by HPLC analysis was achieved using
a Waters 501 HPLC pump, Water tuneable absorbance detector,
Waters 746 data module and a Daicel Chiral OD 4.6 × 25 cm
column.
cmϪ1 3509 (OH), 2927, 2365, 2357, 1669 (C᎐O), 1454, 1415,
᎐
1246, 1164, 731, 699; δH(300 MHz, CDCl3) 1.48 (9 H, s, CH3),
3.32 (1 H, br d, J 12.4, CH(OH)CHH), 3.51–3.59 (1 H, m,
CH(OH)CHH), 4.07–4.46 (1 H, m, CHH-Ar), 4.44 (2 H, br d,
J 14.3, CHH-Ar, OH), 4.88 (1 H, m, C(OH)H), 7.18–7.36 (10
H, m, Aryl H); δC (75.5 MHz, CDCl3) 28.80 ((CH3)3C), 52.89
(CH2), 56.04 (CH2), 74.53 (CH(OH)), 81.42 ((CH3)3C), 126.21,
127.36, 127.76, 128.80, 129.01, 129.16, 130.17, 138.34, 142.78
(Ar-ipso), 164.19 (C᎐O); m/z (FAB) 326 ([M ϩ H]ϩ, 14%), 254
᎐
(84%), 226 (10%), 164 (22%), 154 (55%), 91 (100).
2-(N-Benzylamino)-1-phenylethanol 7
Benzylamine (1.29 g, 12.1 mmol) and triethylamine (7.6 g, 75.0
mmol) were stirred in dichloromethane (50 mL) for 30 minutes.
2-Bromoacetophenone (3.0 g, 15.1 mmol) in dichloromethane
(10 mL) was added dropwise and the reaction stirred for 6
hours. Ammonium chloride saturated solution (30 mL) was
added. The phases were separated and the aqueous layer
extracted with dichloromethane (3 × 20 mL). The combined
organic layers were dried over anhydrous magnesium sulfate,
filtered and the solvent removed in vacuo, to give α-(N-benzyl-
amino)acetophenone as a yellow oil, which was then dissolved
in 20 ml of MeOH–H2O (9 : 1), in an ice bath. Sodium boro-
hydride (0.86 g, 22.6 mmol) dissolved in 10 ml of MeOH–H2O
(9 : 1) was added slowly to the ketone solution. The reaction
mixture was allowed to warm up to room temperature. When
the reaction was completed (TLC), it was concentrated under
reduced pressure. The residue was dissolved in diethyl ether
(30 mL) and worked up with ammonium chloride saturated
solution (30 mL). The phases were separated and the aqueous
layer extracted with diethyl ether (2 × 20 mL). The organic
layers were dried over anhydrous magnesium sulfate, filtered
and the solvent removed under reduced pressure. Recrystallis-
ation of crude compound ethyl acetate–petroleum 40 : 60 gave
2-(N-benzylamino)-1-phenylethanol as a white solid (0.98 g,
35.8%), mp 93–96 ЊC; νmax(CDCl3)/cmϪ1 3400, 3000, 2950, 2850,
2254, 1444, 903, 728; δH(300 MHz, CDCl3) 2.40 (2 H, br s, OH,
NH), 2.75 (1 H, dd, J 8.8, 12.0, C(OH)CHH), 2.93 (1 H, dd,
J 3.6, 12.0, C(OH)CHH), 3.83 (2 H, ABsystem, JAB 13.2), 4.73
(1 H, dd, J 3.6, 8.8, C(OH)H), 7.25–7.35 (10 H, m, Aryl H);
δC(75.5 MHz, CDCl3) 53.93 (CH2), 56.94 (CH2), 72.20 (CH),
126.22, 127.56, 127.91, 128.51, 128.78, 128.91 (Ar-ipso); m/z
(CI) 228 ([M ϩ H]ϩ, 100%), 226 (45), 212 (20), 210 (66), 150
(10), 120 (65), 108 (36), 91 (55) (Found: [M ϩ H]ϩ, 228.1380.
C15H17NO requires m/z, 228.1388).
ꢁ-(N-tert-Butoxycarbonyl-N-benzylamino)acetophenone 4
Benzylamine (1.02 g, 9.5 mmol) and triethylamine (5.06 g, 50.0
mmol) were stirred in dichloromethane (20 mL) for 30 minutes.
2-Bromoacetophenone (3) (1.99 g, 10.0 mmol) in dichloro-
methane (10 mL) was added dropwise and the reaction stirred
for 3 hours. Di-tert-butyl dicarbonate (2.18 g, 10.0 mmol) in
dichloromethane (10 mL) was added and the reaction mixture
was stirred overnight. Ammonium chloride saturated solution
(30 mL) was added. The phases were separated and the aqueous
layer extracted with dichloromethane (3 × 20 mL). The com-
bined organic layers were dried over anhydrous magnesium
sulfate, filtered and the solvent removed in vacuo, to give 4 as
a yellow oil. Purification by flash chromatography on silica
eluting with 5–10% ethyl acetate–petroleum ether 40 : 60, gave a
light yellow solid (2.45 g, 79.3%), mp 66–67 ЊC; νmax(CDCl3)/
cmϪ1 2960, 1703 (C᎐O), 1450, 1365, 1245, 1224, 1164; δ (300
᎐
H
MHz, CDCl3) (1 : 1 mixture of NCO rotamers) 1.41 (4.5 H, s,
CH3), 1.50 (4.5 H, s, CH3), 4.47 (1 H, s, CHH-Ph), 4.55 (1 H, s,
CHH-Ph), 4.61 (1 H, s, C(᎐O)-CHH), 4.63 (1 H, s, C(᎐O)-
᎐
᎐
CHH), 7.22–7.90 (10 H, m, Aryl H); δC (75.5 MHz, CDCl3)
28.64 ((CH ) C), 51.45 (C(᎐O)CH ), 52.56 (N(Boc)CH ), 80.72
᎐
3
3
2
2
((CH3)3C), 127.82, 127.94, 128.09, 128.31, 128.53, 129.01,
129.16, 133.89 (Ar-ipso), 196.56 (C᎐O); m/z (CI) 326
᎐
J. Chem. Soc., Perkin Trans. 1, 2001, 1916–1928
1919

View Online
rac-N-Benzyl-2-phenylaziridine 3
product was determined to be of 99% ee by HPLC analysis
(Chiral OD, hexane–ethanol–diethylamine = 97 : 3 : 0.1 (0.5
mL minϪ1), S isomer 31.97 min, R isomer 33.19 min), mp 105–
107 ЊC; [α]2D0 ϩ33.8 (c = 2, ethanol); νmax(CDCl3)/cmϪ1 3414,
2248, 1637, 1452, 1201, 908, 728; δH(300 MHz, CDCl3) 2.35
(2 H, br s, OH, NH), 2.77 (1 H, dd, J 9.0, 12.2, C(OH)CHH),
To a solution of ( )-2-benzylamino-1-phenylethanol 7 (0.9 g,
3.98 mmol) and triphenylphosphine (1.36 g, 5.20 mmol) in
THF (30 mL), stirred under nitrogen in an ice bath, was slowly
added diethyl azodicarboxylate (0.9 g, 5.20 mmol) via syringe.
The ice bath was removed and the mixture stirred at room
temperature for 6 hours. It was then worked up with sodium
bicarbonate saturated solution (20 mL). The phases were separ-
ated and the aqueous layer extracted with ethyl acetate (2 × 20
mL). The organic layers were dried over anhydrous magnesium
sulfate, filtered and the solvent removed under reduced
pressure. The crude compound was purified using medium
pressure flash chromatography eluting with 5% ethyl acetate–
petroleum 40 : 60 to give the aziridine 3 as a pale oil (0.22 g,
26.5%); νmax(neat)/cmϪ1 3028, 2970, 2824, 1597, 1488, 1444,
1349, 1137, 1086, 1027, 823, 735; δH(300 MHz, CDCl3) 1.84
(1 H, d, J 6.6, CHHaz), 1.98 (1 H, d, J 3.2, CHHaz), 2.49 (1 H,
dd, J 3.4, 6.6, CHaz), 3.59 (1 H, d, J 13.8, CHHPh), 3.68 (1 H, d,
J 13.8, CHHPh), 7.21–7.38 (10 H, m, Aryl H); δC(75.5 MHz,
CDCl3) 38.38 (Ph-CH2), 41.93 (CH2az), 65.17 (CHaz), 126.66,
127.29, 127.38, 128.26, 128.71, 128.77, 139.53, 140.54 (Ar-ipso);
m/z (EI) 210 ([M ϩ H]ϩ, 100%), 208 (23), 120 (10), 118 (20),
91 (26) (Found: [M ϩ H]ϩ, 210.1309. C15H15N requires m/z,
210.1304).
2.95 (1 H, dd, J 3.6, 12.2, C(OH)CHH), 3.86 (2 H, ABsystem
,
JAB 13), 4.75 (1 H, dd, J 3.6, 9.0, C(OH)H), 7.20–7.38 (10 H,
m, Aryl H); δC(75.5 MHz, CDCl3) 53.77 (CH2), 56.69 (CH2),
71.20 (CH), 126.19, 127.75, 127.99, 128.62, 128.81, 128.97
(Ar-ipso); m/z (CI) 228 ([M ϩ H]ϩ, 100%), 226 (7), 210 (10),
120 (36), 108 (11), 91 (11) (Found: [M ϩ H]ϩ, 228.1384.
C15H17NO requires m/z, 228.1388).
(R)-(؊)-N-Benzyl-2-phenylaziridine 3
To a solution of (S)-2-benzylamino-1-phenylethanol 5 (0.33 g,
1.45 mmol) and triphenylphosphine (0.58 g, 2.20 mmol) in
THF (15 mL), stirred under nitrogen in an ice bath, was slowly
added diethyl azodicarboxylate (0.38 g, 2.20 mmol) via syringe.
The ice bath was removed and the mixture was stirred at room
temperature for 6 hours. It was then worked up with sodium
bicarbonate saturated solution (10 mL). The phases were separ-
ated and the aqueous layer extracted with ethyl acetate (2 × 10
mL). The organic layers were dried over anhydrous magnesium
sulfate, filtered and the solvent removed under reduced pres-
sure. The crude compound was purified using medium pressure
flash chromatography eluting with 5% ethyl acetate–petroleum
ether 40 : 60 to give the aziridine R-(Ϫ)-3 as a pale oil (0.07 g,
23%). The product was determined to be of 98% ee by chiral
shift reagent ([Eu(hfc)3], 6 mol%); [α]2D0 Ϫ49 (c = 2, ethanol);
νmax(neat)/cmϪ1 3350, 3058, 3021, 2977, 1734, 1604, 1495, 1453,
1259, 1172, 1028, 940, 733, 697; δH(300 MHz, CDCl3) 1.84 (1 H,
d, J 6.6, CHHaz), 1.98 (1 H, d, J 3.2, CHHaz), 2.50 (1 H, dd,
J 3.2, 6.6, CHaz), 3.69 (1 H, d, J 13.8, CHHPh), 3.58 (1 H, d,
J 13.8, CHHPh), 7.21–7.42 (10 H, m, Aryl H); δC(75.5 MHz,
CDCl3) 38.36 (Ph-CH2), 41.92 (CH2az), 65.15 (CHaz), 126.65,
127.28, 127.38, 128.25, 128.70, 139.51, 140.54 (Ar-ipso); m/z
(CI) 210 ([M ϩ H]ϩ, 100%), 209 (45), 120 (7), 108 (17), 91 (24)
(Found: [M ϩ H]ϩ, 210.1279. C15H15N requires m/z, 210.1283).
(S)-(؉)-2-[N-(tert-Butoxycarbonyl)-N-(benzyl)amino]-1-phenyl-
ethanol 5
A mixture of (p-cymene)ruthenium() chloride dimer (0.13 mg,
0.0021 mmol) and (1R,2R)-TsDPEN 2 (0.15 mg, 0.0042 mmol)
in a 5 : 2 formic acid–triethylamine mixture (2.5 mL) was stirred
at 28 ЊC for 15 min. 2-[N-(tert-Butoxycarbonyl)-N-benzyl-
amino]-1-phenylethanone 4 (0.27 g, 0.83 mmol) was added
and the solution was stirred at 28 ЊC for 24 hours. Then the
mixture was filtered through silica and washed with ethyl acetate
(50 mL). The solvent was evaporated under reduced pressure to
give the crude compound, which was purified by flash chrom-
atography (5% v/v ethyl acetate–petroleum ether 40 : 60) to
give the product S-(ϩ)-5 as a white solid (0.20 g, 74.0%). The
product was determined to be of 98% ee by HPLC analysis
(Chiral OD, hexane–ethanol–diethylamine = 95 : 5 : 0.1 (0.5
mL minϪ1), R isomer 13.93 min, S isomer 15.27 min), mp 64–
65 ЊC; [α]2D0 ϩ3.3 (c = 2 ethanol); νmax(CDCl3)/cmϪ1 3435 (OH),
( )-2-(N-tert-Butoxycarbonylamino)-1-phenylethanol 9
To a solution of ( )-2-amino-1-phenylethanol (1.37 g, 10.0
mmol) in dichloromethane (30 mL), triethylamine (1.52 g,
15.0 mmol) followed by di-tert-butyl dicarbonate (2.18 g, 10.0
mmol) were added. The reaction mixture was stirred overnight
then saturated ammonium chloride solution (30 mL) added.
The phases were separated and the aqueous layer extracted with
dichloromethane (2 × 30 mL). The combined organic layers
were dried over magnesium sulfate, filtered, and the solvent
removed in vacuo to give rac-9 as a white solid (2.25 g, 95%),
mp 120–121 ЊC; νmax(Nujol)/cmϪ1 3362, 1675, 1531, 1276, 1166,
962, 957, 903, 750; δH(300 MHz, CDCl3) 1.44 (9 H, s, CH3),
3.18–3.27 (1 H, m, CHH), 3.39 (1 H, br s, OH), 3.42–3.49 (1 H,
m, CHH), 4.78–4.81 (1 H, m, CH), 5.03 (1 H, br s, NH), 7.26–
7.35 (5 H, m, Aryl H); δC(75.5 MHz, CDCl3) 28.75 ((CH3)3C),
48.73 (CH2), 74.3 (CH), 80.23 ((CH3)3C), 126.28, 128.16,
3029, 2975, 2931, 1667 (C᎐O), 1494, 1454, 1414, 1366, 1314,
᎐
1246, 1165, 1123, 1086, 1060, 1028, 878, 746; δH(300 MHz,
CDCl3) 1.48 (9 H, s, CH3), 3.32 (1 H, d, J 12.8, CH(OH)CHH),
3.52–3.50 (1 H, m, CH(OH)CHH), 4.18 (1 H, d, J 15.6,
CHHPh), 4.43–4.46 (2 H, m, CHH-Ar, OH), 4.85–4.96 (1 H, m,
C(OH)H), 7.18–7.35 (10 H, m, Aryl H); δC (75.5 MHz, CDCl3)
28.81 ((CH3)3C), 52.89 (CH2), 56.05 (CH2), 74.55 (CH(OH)),
81.44 ((CH3)3C), 126.21, 127.76, 127.94, 128.81, 129.01, 129.16,
138.32, 142.78 (Ar-ipso); m/z (FAB) 326 ([M ϩ H]ϩ, 43%), 254
(100), 220 (24), 164 (22), 120 (49) (Found: [M ϩ H]ϩ, 328.1915.
C20H25NO3 requires m/z, 328.1913). The reduction using
(1S,2R)-1–propan-2-ol was carried out using identical con-
ditions to those reported.4b The product, S-(ϩ)-5 was formed in
60% yield and 88% ee as determined by chiral HPLC analysis.
128.87, 142.22 (Ar-ipso), 157.36 (C᎐O); m/z (FAB) 238
᎐
([M ϩ H]ϩ, 40%), 182 (63), 164 (100), 154 (29), 137 (26), 120
(29) (Found: [M ϩ H]ϩ, 238.1449. C13H19NO3 requires m/z,
238.1443).
(S)-(؉)-2-(N-Benzylamino)-1-phenylethanol 7
To a solution of 2-(N-tert-butoxycarbonyl-N-benzylamino)-1-
phenylethanol S-(Ϫ)-5 (0.2 g, 0.61 mmol) in dichloromethane
(2 mL), TFA (2 mL) was added slowly. After 2 hours the solvent
was removed and the resulting product was dissolved in ethyl
acetate and NaOH solution 0.2 M was added until the pH = 7.
The product was then extracted with ethyl acetate and the com-
bined organic layers were dried over magnesium sulfate, filtered
and the solvent removed in vacuo. Recrystallisation (ethyl
acetate–petroleum ether 40 : 60) gave (S)-2-(N-benzylamino)-1-
phenylethanol 7 as a white solid (0.11 g, 78.6% yield). The
( )-N-(tert-Butoxycarbonyl)-2-phenylaziridine 11
To a solution of ( )-2-(N-tert-butoxycarbonylamino)-1-phenyl-
ethanol 9 (0.3 g, 1.10 mmol) and tosyl chloride (0.23 g, 1.20
mmol) in dry THF (20 mL) was added KOH (0.30 g, 5.40
mmol) freshly powered (with the help of a ball mill) at room
temperature. The reaction mixture was left stirring overnight.
It was then dissolved in diethyl ether (30 mL) and filtered. The
1920
J. Chem. Soc., Perkin Trans. 1, 2001, 1916–1928

View Online
solvent was removed under reduced pressure to give pure
aziridine R-(Ϫ)-11 as a pale oil (0.22 g, 92.0%). νmax(neat)/cmϪ1
2366, 2336, 2319, 1717, 1655, 1469, 1391, 1317, 1303, 1280,
1253, 1229, 1153, 852, 794; δH(300 MHz, CDCl3) 1.50 (9 H, s,
(CH3)3C), 2.31 (1 H, d, J 3.58, CHHaz), 2.67 (1 H, d, J 6.40,
CHHaz), 3.48 (1 H, dd, J 3.58, 6.41, CHaz), 7.31–7.40 (5 H, m,
Aryl H); δC(75.5 MHz, CDCl3) 28.29 ((CH3)3C), 35.24 (CH2),
39.70 (CH), 81.76 ((CH3)3C), 126.74, 128.15, 128.84, 137.67
temperature. The reaction mixture was left stirring overnight.
Then it was dissolved in diethyl ether (30 mL) and filtered. The
solvent was removed under reduced pressure to give a pale oil
as a pure aziridine R-(Ϫ)-11 (0.22 g, 92.0%). The product was
determined to be 99% ee by chiral shift reagent ([Eu(hfc)3],
6 mol%), [α]2D0 Ϫ137 (c = 2, ethanol); νmax(neat)/cmϪ1 3408, 3058,
2977, 2933, 1719, 1663, 1597, 1473, 1318, 1155, 1020, 962, 852,
765; δH(300 MHz, CDCl3) 1.44 (9 H, s, (CH3)3C), 2.26 (1 H, d,
J 3.5, CHHaz), 2.62 (1 H, d, J 6.2, CHHaz), 3.42 (1 H, dd, J 3.5,
6.2, CHaz), 7.24–7.33 (5 H, m, Aryl H); δC(75.5 MHz, CDCl3)
28.29 ((CH3)3C), 35.24 (CH2), 39.70 (CH), 81.82 ((CH3)3C),
(Ar-ipso), 162.52 (C᎐O); m/z (CI) 220 ([M ϩ H]ϩ, 47%), 181
᎐
(100), 164 (90), 146 (10), 120 (70) (Found: [M ϩ H]ϩ, 220.1334.
C13H17NO2 requires m/z, 220.1338).
126.73, 128.15, 128.84, 137.66 (Ar-ipso), 162.54 (C᎐O); m/z
᎐
(CI) 220 ([M ϩ H]ϩ, 97%), 181 (77), 164 (100), 146 (10), 120
(18) (Found: [M ϩ H]ϩ, 220.1332. C13H17NO2 requires m/z,
220.1338).
2-[N-(tert-Butoxycarbonyl)amino]acetophenone 8
( )-2-(N-tert-Butoxycarbonylamino)-1-phenylethanol 9 (2.55
g, 10.75 mmol) was added to an ice cold solution of pyridinium
dichromate (15.0 g, 39.83 mmol) in anhydrous N,N-
dimethylformamide (50 mL). The reaction mixture was stirred
overnight, then worked up with brine (60 mL). The compound
was extracted with diethyl ether (3 × 60 mL). The combined
organic layers were dried over anhydrous magnesium sulfate,
filtered and concentrated under reduced pressure to give the
crude compound which was purified by flash chromatography
eluting with 10% ethyl acetate–petroleum ether 40 : 60 to give
2-[N-(tert-butoxycarbonyl)amino]acetophenone 8 as a white
solid (2.23 g, 88.1%), mp 55–58 ЊC; νmax(CDCl3)/cmϪ1 3425,
2970, 2342, 2247, 1685, 1582, 1488, 1444, 1363, 1217, 1159,
1049, 984, 903, 867; δH(300 MHz, CDCl3) 1.48 (9 H, s, CH3),
4.66 (2 H, d, J 4.52, CH2), 5.60 (1 H, br s, NH), 7.46–7.97 (5 H,
m, Aryl H); δC(75.5 MHz, CDCl3) 28.74 ((CH3)3C), 47.89
(CH2), 80.19 ((CH3)3C), 128.20, 129.24, 134.30, 134.92 (Ar-
ipso), 156.15 (C᎐O), 193.5 (C᎐O); m/z (FAB) 236 ([M ϩ H]ϩ,
(S)-(؊)-O-(tert-Butyldimethylsilyl)-2-(N-tert-butoxycarbonyl-
amino)-1-phenylethanol
(S)-2-(N-tert-Butoxycarbonylamino)-1-phenylethanol S-(ϩ)-9
(0.3 g, 1.26 mmol) and imidazole (0.21 g, 3.15 mmol) were
dissolved in 10 mL of DMF and treated with tert-butyl-
chlorodimethylsilane (TBDMSCl) (0.23 g, 1.52 mmol). The
mixture was stirred at 35–45 ЊC until the starting materials
were completely consumed (followed by TLC). The reaction
was then treated with sodium bicarbonate saturated solution
(20 mL) and extracted with diethyl ether (3 × 20 mL). The
combined organic layers were dried over anhydrous magnesium
sulfate, filtered and concentrated under reduced pressure to give
the crude compound which was purified by flash chrom-
atography eluting with 5% ethyl acetate–petroleum ether 40 : 60
to give the product as a pale liquid (0.37 g, 84.1%). This was
determined to be of 92% ee by HPLC analysis (Chiral OD
hexane–ethanol–diethylamine = 97 : 3 : 0.1 (0.5 mL minϪ1),
S isomer 7.59 min, R isomer 9.96 min), [α]2D0 ϩ55.7 (c = 2,
ethanol); νmax(neat)/cmϪ1 3460, 3373, 2956, 2885, 1716, 1504,
1435, 1390, 1252, 1171, 1098, 976, 870, 700; δH(300 MHz,
CDCl3) 0.00 (3 H, s, SiCH3(CH3)), 0.14 (3 H, s, SiCH3(CH3)),
1.01 (9H, s, Si-C(CH3)3), 1.54 (9 H, s, CH3), 3.11–3.20 (1 H,
m, CHH), 3.42–3.56 (1 H, m, CHH), 4.86–4.90 (1H, m, CH),
7.35–7.43 (5 H, m, Aryl H); δC(75.5 MHz, CDCl3) Ϫ4.65
(SiCH3(CH3)), Ϫ4.34 (SiCH3(CH3)), 18.61 (Si-C(CH3)3), 26.22
(Si-C(CH3)3), 28.81 ((CH3)3C), 49.50 (CH2), 74.20 (CH), 79.60
((CH3)3C), 126.37, 127.82, 128.60, 142.80 (Ar-ipso), 156.25
᎐
᎐
23%), 180 (87), 154 (27), 136 (100), 105 (30), 97 (47) (Found:
[M ϩ H]ϩ, 236.1284. C13H17NO3 requires m/z, 236.1287).
(S)-2-(N-tert-Butoxycarbonylamino)-1-phenylethanol S-(؉)-9
A mixture of (p-cymene)ruthenium() chloride dimer (0.34 mg,
0.006 mmol) and (1R,2R)-TsDPEN 2 (0.40 mg, 0.011 mmol) in
a 5 : 2 formic acid–triethylamine mixture (3.0 mL) was stirred
at 28 ЊC for 15 min. 2-[N-(tert-Butoxycarbonyl)amino]aceto-
phenone 8 (0.50 g, 2.13 mmol) was added and the solution was
stirred at 28 ЊC for 24 hours. Then the mixture was filtered
through silica and washed with ethyl acetate (60 mL). The
solvent was evaporated under reduced pressure to give the
crude compound, which was purified by flash chromatography
(5% v/v ethyl acetate–petroleum ether 40 : 60) to give the S-(ϩ)-
9 as a white solid (0.44 g, 86.3%). The product was determined
to be of 99% ee by HPLC analysis (Chiral OD, hexane–
ethanol–diethylamine = 95 : 5 : 0.1 (0.5 mL minϪ1), S isomer
17.86 min, R isomer 19.49 min), mp 66–68 ЊC [α]2D0 ϩ3.5 (c = 1,
ethanol); νmax(CDCl3)/cmϪ1 3423, 2978, 2931, 1693, 1514, 1454,
1392, 1367, 1251, 1170, 1094, 1065, 910, 733, 700; δH(300 MHz,
CDCl3) 1.43 (9 H, s, CH3), 3.16–3.25 (1 H, m, CHH), 3.41–3.47
(1 H, m, CHH), 3.56 (1 H, br s, OH), 4.76–4.79 (1 H, m,
CH(OH)), 5.08 (1 H, br s, NH), 7.24–7.34 (5 H, m, Aryl H);
δC(75.5 MHz, CDCl3) 28.75 ((CH3)3C), 48.70 (CH2), 74.19
(CH), 80.19 ((CH3)3C), 126.29, 128.14, 128.85, 142.24
(C᎐O); m/z (CI) 352 ([M ϩ H]ϩ, 96%), 296 (100), 278 (16), 252
᎐
(77), 221 (82), 181 (72).
(S)-O-(tert-Butyldimethylsilyl)-2-[N-(tert-butoxycarbonyl)-N-
benzylamino]-1-phenylethanol S-(؉)-6
To a suspension of sodium hydride (0.05 g, 1.14 mmol) in
dry THF (10 mL), (S)-O-(tert-butyldimethylsilyl)-2-[N-)tert-
butoxycarbonyl)amino]-1-phenylethanol (0.2 g, 0.57 mmol)
was added at room temperature and it was stirred for 1 hour.
Then a solution of benzyl bromide (0.15 g, 0.85 mmol) in dry
THF (5 mL) was added slowly. The reaction was left stirring
until the starting materials had been completely consumed
(followed by TLC). The reaction was then treated with sodium
bicarbonate saturated solution (20 mL) and extracted with ethyl
acetate (3 × 20 mL). The combined organic layers were dried
over anhydrous magnesium sulfate, filtered and concentrated
under reduced pressure to give the crude compound which was
purified by flash chromatography eluting with 5% ethyl acetate–
petroleum ether 40 : 60 to give the protected compound as a
pale liquid (0.25 g, 100%). The product was determined to be
of 92% ee by HPLC analysis (Chiral OD, hexane–ethanol–
diethylamine = 97 : 3: 0.1 (0.5 mL minϪ1), S isomer 8.63 min, R
isomer 9.45 min), [α]D20 ϩ52.3 (c = 2, ethanol); νmax(neat)/cmϪ1
3058, 3028, 2955, 2919, 2846, 1700, 1693, 1458, 1440, 1363,
1247, 1167, 1020, 947, 838, 779; δH(300 MHz, CDCl3) (1 : 1
mixture of NCO rotamers) 0.00 (1.5 H, s, SiCH3(CH3)), 0.004
(Ar-ipso), 157.34 (C᎐O); m/z (FAB) 238 ([M ϩ H]ϩ, 52%), 182
᎐
(72), 164 (100), 154 (40), 137 (35), 120 (30) (Found: [M ϩ H]ϩ,
238.1448. C13H19NO3 requires m/z, 238.1443). The reduction
using (1S,2R)-1–propan-2-ol was carried out using identical
conditions to those reported; however no reduction product
was isolated.4b
(R)-(؊)-N-(tert-Butoxycarbonyl)-2-phenylaziridine 11
To a solution of (S)-2-(N-tert-butoxycarbonylamino)-1-phenyl-
ethanol S-(ϩ)-9 (0.3 g, 1.10 mmol) and tosyl chloride (0.23 g,
1.20 mmol) in dry THF (20 mL) was added KOH (0.30 g, 5.40
mmol) freshly powered (with the help of a ball mill) at room
J. Chem. Soc., Perkin Trans. 1, 2001, 1916–1928
1921

View Online
(1.5 H, s, SiCH3(CH3)), 0.17 (1.5 H, s, SiCH3(CH3)), 0.19 (1.5 H,
s, SiCH3(CH3)), 1.02 (4.5 H, s, Si-C(CH3)3), 1.06 (4.5 H, s,
Si-C(CH3)3), 1.56 (4.5 H, s, C(CH3)3), 1.65 (4.5 H, s, C(CH3)3),
3.13 (0.5 H, dd, J 9.1, 14.2, CH), 3.23 (0.5 H, dd, J 7.9, 14.3,
CH), 3.40 (0.5 H, dd, J 4.7, 14.5, CH), 3.60 (0.5 H, dd, J 3.4,
13.8, CH), 4.46 (0.5 H, d, J 5.8, H), 4.48 (0.5 H, d, J 6.8, CH),
4.58 (0.5 H, d, J 6.8, CH), 4.72 (0.5 H, d, J 5.8, CH), 5.08
(0.5 H, dd, J 5.0, 8.0, CH), 5.24 (0.5 H, dd, J 3.6, 9.0, CH),
7.25–7.49 (10 H, m, Aryl H); δC(75.5 MHz, CDCl3) 26.31
(SiCH3(CH3)), 28.85 (Si-C(CH3)3), 28.96 ((CH3)3C), 51.81,
53.25 (CH2), 55.54, 56.45 (CH2), 68.37 (Si-C(CH3)3), 73.84,
74.52 (CH), 80.12 ((CH3)3C), 126.35, 127.03, 127.35, 127.44,
127.63, 127.99, 128.47, 128.61, 128.78, 128.82, 138.78, 139.12,
formamide (20 mL). The reaction mixture was stirred overnight,
thenworkedupwithbrine(30mL).Thecompoundwasextracted
withdiethylether(3 × 30mL). Thecombinedorganiclayerswere
dried over anhydrous magnesium sulfate, filtered and concen-
trated under reduced pressure to give the crude compound which
was purified by flash chromatography eluting with 40% ethyl
acetate–petroleum ether 40 : 60 to give ( )-1-(N-tert-butoxy-
carbonylamino)propan-2-one 14 as a colourless liquid (0.88 g,
88.0%); νmax(neat)/cmϪ1 3357, 2977, 2926, 1699, 1510, 1356,
1283, 1247, 1159, 1071, 955, 882, 779; δH(300 MHz, CDCl3)
1.45 (9 H, s, C(CH3)3), 2.18 (3 H, s, CH3), 4.03 (2 H, d, J 4.71,
CH2), 5.24 (1 H, br s, NH); δC(75.5 MHz, CDCl3) 27.49 (CH3),
28.69 ((CH ) C), 51.31 (CH ), 80.23 ((CH ) C), 164.05 (C᎐O);
᎐
3
3
2
3 3
143.36 (Ar-ipso), 156.10 (C᎐O); m/z (FAB) 442 ([M ϩ H]ϩ,
m/z (CI) 174 ([M ϩ H]ϩ, 100%), 163 (12), 147 (25) (Found:
[M ϩ H]ϩ, 174.1127. C8H15NO3 requires m/z, 174.1130).
᎐
29%), 342 (44), 328 (45), 254 (88), 221 (74), 164 (29), 120 (59),
91 (100).
A sample of S-(ϩ)-6 with identical data to that cited above
was also prepared by the reaction of S-(ϩ)-5 with TBDMSCl
and imidazole in DMF following the same procedure as that
previously described for S-(ϩ)-9. The product was formed in
49% yield and exhibited [α]2D0 ϩ36.0 (c = 2, ethanol).
S-(؉)-1-(N-tert-Butoxycarbonylamino)propan-2-ol 12
A mixture of (p-cymene)ruthenium() chloride dimer (0.62 mg,
0.010 mmol) and (1R,2R)-TsDPEN 2 (0.74 mg, 0.02 mmol) in
a 5 : 2 formic acid–triethylamine mixture (3.0 mL) was stirred
at 28 ЊC for 15 min. ( )-1-(N-tert-Butoxycarbonylamino)-
propan-2-one 14 (0.70 g, 4.04 mmol) was added and the solution
was stirred at 28 ЊC for 24 hours. Then the mixture was filtered
through silica and washed with ethyl acetate (60 mL). The solv-
ent was evaporated under reduced pressure to give the crude
compound, which was purified by flash chromatography (30%
v/v ethyl acetate–petroleum ether 40 : 60) to give S-(ϩ)-12 as a
colourless liquid (0.62 g, 87.3%). [α]2D0 ϩ27.5 (c = 2, dichloro-
methane); νmax(neat)/cmϪ1 3355, 2974, 2934, 1691, 1528, 1458,
1393, 1368, 1276, 1252, 1173, 1039, 991, 942, 901, 865, 838;
δH(300 MHz, CDCl3) 1.18 (3 H, d, J 6.41, CH3), 1.45 (9 H, s,
C(CH3)), 2.96–3.05 (2 H, m, CHH, OH), 3.23–3.30 (1 H, m,
CHH), 3.85–3.95 (1H, m, CHH), 5.01 (1H, br s, NH); δC(75.5
MHz, CDCl3) 21.03 (CH3), 28.75 ((CH3)3C), 48.35 (CH2),
( )-1-(N-tert-Butoxycarbonylamino)propan-2-ol 12
To a solution of ( )-1-aminopropan-2-ol (2.0 g, 26.62 mmol) in
dichloromethane (50 mL), triethylamine (3.95 g, 15.0 mmol)
followed by di-tert-butyl dicarbonate (2.18 g, 39.0 mmol) were
added. The reaction mixture was stirred overnight, then satur-
ated ammonium chloride solution (30 mL) was added. The
phases were separated and the aqueous layer extracted with
dichloromethane (2 × 30 mL). The combined organic layers
were dried over magnesium sulfate, filtered, and the solvent
removed in vacuo. Purification by flash chromatography on
silica with 20% ethyl acetate–petroleum ether 40 : 60, gave the
compound rac-12 as colourless liquid of high viscosity (4.44 g,
95.3%); νmax(neat)/cmϪ1 2977, 2357, 1685, 1517, 1363, 1276,
1159, 1108, 976, 750; δH(300 MHz, CDCl3) 1.17 (3 H, d, J 6.41,
CH3), 1.45 (9 H, s, C(CH3)3), 2.95–3.04 (2 H, m, CHH, OH),
3.23–3.29 (1 H, m, CH), 3.88–3.90 (1H, m, CHH), 5.12 (1 H, br
s, NH); δC(75.5 MHz, CDCl3) 20.32 (CH3), 28.47 ((CH3)3C),
68.09 (CH), 80.07 ((CH ) C), 155.60 (C᎐O); m/z (FAB) 176
᎐
3
3
([M ϩ H]ϩ, 27%), 155 (100), 154 (100), 136 (80), 120 (50), 107
(31) (Found: [M ϩ H]ϩ, 176.1279. C8H17NO3 requires m/z,
176.1287).
47.91 (CH ), 67.06 (CH), 79.83 ((CH ) C), 164.25 (C᎐O);
᎐
2
3
3
R-(؊)-N-(tert-Butoxycarbonyl)-2-methylaziridine 13
m/z (FAB) 176 ([M ϩ H]ϩ, 74%), 154 (6), 137 (9), 120 (100),
103 (13) (Found: [M ϩ H]ϩ, 176.1286. C8H17NO3 requires m/z,
176.1287).
To a solution of (ϩ)-1-(N-tert-butoxycarbonylamino)propan-
2-ol S-(ϩ)-12 (1.0 g, 5.71 mmol) and tosyl chloride (1.63 g, 8.56
mmol) in dry THF (20 mL) was added KOH (1.60 g, 28.55
mmol) freshly powered (with the help of a ball mill) at room
temperature. The reaction mixture was left stirring overnight.
Then it was dissolved in diethyl ether (40 mL) and filtered. The
solvent was removed under reduced pressure and the crude
compound was purified using flash chromatography eluting
with 20% ethyl acetate–petroleum ether 40 : 60 to give the
R-(Ϫ)-13 as a colourless liquid (0.50 g, 55.7%) [α]2D0 Ϫ42.2
(c = 1, dichloromethane); νmax(neat)/cmϪ1 3064, 2977, 2932,
1718, 1600, 1475, 1458, 1407, 1393, 1368, 1310, 1257, 1224,
1154, 1088, 1063, 1028, 940, 908, 867, 831, 769; δH(300 MHz,
CDCl3) 1.27 (3 H, d, J 5.5, CH3), 1.46 (9 H, s, (CH3)3C), 1.89
(1 H, d, J 3.8, CHHaz), 2.24 (1 H, d, J 5.8, CHHaz), 2.24–2.49
(1 H, m, CHaz); δC(75.5 MHz, CDCl3) 17.77 (CH3), 28.31
((CH3)3C), 32.86 (CH2), 33.95 (CH), 81.29 ((CH3)3C), 162.58
( )-N-(tert-Butoxycarbonyl)-2-methylaziridine 13
To a solution of ( )-1-(N-tert-butoxycarbonylamino)propan-
2-ol 12 (2.0 g, 11.41 mmol) and tosyl chloride (3.05 g, 15.98
mmol) in dry THF (40 mL) was added KOH (3.10 g, 56.11
mmol) freshly powered (with the help of a ball mill) at room
temperature. The reaction mixture was left stirring overnight.
Then it was dissolved in diethyl ether (50 mL) and filtered. The
solvent was removed under reduced pressure and the crude
compound was purified using flash chromatography eluting
with 20% ethyl acetate–petroleum ether 40 : 60 to give the
aziridine rac-13 as a colourless liquid (1.27 g, 56.7%);
νmax(neat)/cmϪ1 3006, 2989, 2357, 1714, 1451, 1275, 1260, 1159,
749; δH(300 MHz, CDCl3) 1.22 (3 H, d, J 5.6, CH3), 1.41 (9 H, s,
(CH3)3C), 1.82 (1 H, d, J 3.8, CHHaz), 2.19 (1 H, d, J 5.8,
CHHaz), 2.14–2.43 (1 H, m, CHaz); δC(75.5 MHz, CDCl3) 17.28
(CH3), 28.12 ((CH3)3C), 32.41 (CH2), 33.69 (CH), 80.92
(C᎐O); m/z (FAB) 158 ([M ϩ H]ϩ, 16%), 156 (10), 128 (6), 119
᎐
(15), 108 (37), 58 (100) (Found: [M ϩ H]ϩ, 158.1181. C8H15NO2
requires m/z, 158.1181).
((CH ) C), 162.58 (C᎐O); m/z (FAB) 158 ([M ϩ H]ϩ, 16%), 156
᎐
3
3
(10), 128 (6), 119 (15), 108 (37), 58 (100) (Found: [M ϩ H]ϩ,
158.1181. C8H15NO2 requires m/z, 158.1181).
N-(tert-Butoxycarbonyl)allylamine
To a solution of allylamine (3.0 g, 52.54 mmol) in dichloro-
methane (80 mL), triethylamine (6.91 g, 68.30 mmol) followed
by di-tert-butyl dicarbonate (11.57 g, 53.0 mmol) were added.
The reaction mixture was stirred overnight, then saturated
ammonium chloride solution (50 mL) added. The phases were
separated and the aqueous layer extracted with dichloro-
( )-1-(N-tert-Butoxycarbonylamino)propan-2-one 14
( )-1-(N-tert-Butoxycarbonylamino)propan-2-ol (1.0 g, 5.71
mmol) was added to an ice cold solution of pyridinium
dichromate (6.44 g, 17.13 mmol) in anhydrous N,N-dimethyl-
1922
J. Chem. Soc., Perkin Trans. 1, 2001, 1916–1928

View Online
methane (2 × 50 mL). The combined organic layers were dried
over magnesium sulfate, filtered, and the solvent removed
in vacuo. Purification by flash chromatography on silica with
10% ethyl acetate–petroleum ether 40 : 60, gave the product as
white solid (8.1 g, 98.1%); νmax(CDCl3)/cmϪ1 3352, 2976, 1693,
1519, 1366, 1250, 1173, 990, 917, 862, 780; δH(300 MHz,
(0.53 g, 2.81 mmol) in dry THF (10 mL) was added KOH
(0.52 g, 9.35 mmol) freshly powered (with the help of a ball
mill) at room temperature. The reaction mixture was left
stirring overnight. Then it was dissolved in diethyl ether (20
mL) and filtered. The solvent was removed under reduced
pressure and the crude compound was purified using flash
chromatography eluting with 10% ethyl acetate–petroleum
ether 40 : 60 to give the aziridine as a pale liquid (0.31 g,
66.4%). νmax(neat)/cmϪ1 2977, 2931, 2874, 1719, 1599, 1587,
1496, 1457, 1426, 1392, 1367, 1307, 1244, 1222, 1157, 1079,
1038, 996, 968, 854, 754, 691; δH(300 MHz, CDCl3) 1.44 (9 H, s,
(CH3)3C), 2.25 (1 H, d, J 4.0, CHHaz), 2.38 (1 H, d, J 6.0,
CHHaz), 2.80–2.86 (1 H, m, CHaz), 4.0 (1 H, dd, J 4.9, 10.6,
C-CHH-O-Ph), 4.16 (1 H, dd, J 4.9, 10.6, C-CHH-O-Ph),
6.89–7.33 (5 H, m, Aryl H); δC(75.5 MHz, CDCl3) 27.65
((CH3)3C), 29.31 (CH2), 35.57 (CH2), 67.24 (CH), 81.25
CDCl ) 1.45 (9 H, s, C(CH ) ), 3.73–3.75 (2 H, m, CH ᎐CH-
᎐
2
3
3
3
CH2), 4.71 (1 H, br s, NH), 5.10 (1 H, dq, J 10.2, 1.5, CHHcis),
5.18 (1 H, dq, J 17.1, 1.5, CHHtrans), 5.84 (1 H, ddt, J 10.2, 17.1,
5.5, ᎐CH-CH ); δ (75.5 MHz, CDCl ) 28.75 ((CH ) C), 43.42
᎐
2
C
3
3 3
(CH ᎐CH-CH ), 79.69 ((CH ) C), 116.01 (CH ᎐CH-CH ),
᎐
᎐
2
2
3
3
2
2
135.30 (CH ᎐CH-CH ), 156.17 (C᎐O).
᎐
᎐
2
2
rac-N-(tert-Butoxycarbonyl)-2,3-epoxypropylamine
A solution of N-(tert-butoxycarbonyl)allylamine (3 g, 19.08
mmol) in anhydrous dichloromethane (60 mL) was added
dropwise to a stirred solution of m-chloroperoxybenzoic acid
(9.87 g, 57.24 mmol) at room temperature. Then it was refluxed
for 6 hours and worked up with sodium bicarbonate saturated
solution (40 mL). The compound was extracted with ethyl
acetate (3 × 40 mL). The combined organic layers were dried
over anhydrous magnesium sulfate, filtered and concentrated
under reduced pressure to give the crude compound which was
purified by flash chromatography eluting with 10% ethyl
acetate–petroleum ether 40 : 60 to give N-(tert-butoxycarb-
onyl)-2,3-epoxypropylamine as a pale liquid (2.75 g, 88.3%) of
high viscosity which crystallised on the bench after one week;
νmax(CDCl3)/cmϪ1 3451, 2980, 2931, 2252, 1704, 1510, 1454,
1391, 1367, 1332, 1251, 1170, 1097, 1041, 1020, 908, 849, 735,
648; δH(300 MHz, CDCl3) 1.45 (9 H, s, C(CH3)3), 2.60 (1 H,
dd, J 2.6, 4.5, OCHHCH-CH2), 2.78 (1 H, dd, J 4.5, 4.3,
OCHHCH-CH2), 3.07–3.12 (1 H, m, CH- CH2-NH), 3.17–3.29
(1 H, m, CHH-NH), 3.51–3.56 (1 H, m, CHH-NH), 4.76 (1 H,
br s, NH); δC(75.5 MHz, CDCl3) 28.73 ((CH3)3C), 42.01
(O-CH2-CH-CH2), 45.41 (O- CH2-CH-CH2), 51.23 (O-CH2-
((CH ) C), 114.36, 120.92, 129.24 (Ar-ipso), 158.06 (C᎐O);
᎐
3
3
m/z (FAB) 250 ([M ϩ H]ϩ, 80%), 249 (70), 194 (100), 176 (15),
154 (80), 136 (34), 107 (29) (Found: [M ϩ H]ϩ, 250.1441.
C14H19NO3 requires m/z, 250.1443).
rac-1-(N-tert-Butoxycarbonylamino)-2-oxo-3-phenoxypropane
18
1-(N-tert-Butoxycarbonylamino)-2-hydroxy-3-phenoxypropane
rac-16 (1.77 g, 6.62 mmol) was added to an ice cold solution of
pyridinium dichromate (8.51 g, 23.17 mmol) in anhydrous N,N-
dimethylformamide (30 mL). The reaction mixture was stirred
overnight, then worked up with brine (40 mL). The compound
was extracted with diethyl ether (3 × 40 mL). The combined
organic layers were dried over anhydrous magnesium sulfate,
filtered and concentrated under reduced pressure to give the
crude compound which was purified by flash chromatography
eluting with 10% ethyl acetate–petroleum ether 40 : 60 to give
1-(N-tert-butoxycarbonylamino)-2-oxo-3-phenoxypropane 18
as a white solid (0.54 g, 31.0%), mp 65 ЊC; νmax(neat)/cmϪ1 3438,
2983, 2254, 1711, 1600, 1496, 1369, 1246, 1170, 1066, 909, 732;
δH(300 MHz, CDCl3) 1.46 (9 H, s, C(CH3)3), 4.34 (2 H, d, J 5.1,
CH-CH ), 80.03 ((CH ) C), 164.29 (C᎐O); m/z (CI) 174
᎐
2
3 3
([M ϩ H]ϩ, 62%), 135(100), 118(84), 74(35), 57(7) (Found:
[M ϩ H]ϩ, 174.1131. C8H15NO3 requires m/z, 174.1130).
CH -NH), 4.64 (2 H, s, O-CH -C(᎐O)), 5.23 (1 H, br s, NH),
᎐
2
2
6.86–7.35 (5 H, m, Aryl-H); δC(75.5 MHz, CDCl3) 28.69
((CH3)3C), 48.81 (CH2), 72.16 (CH2), 80.46 ((CH3)3C),
rac-1-(N-tert-Butoxycarbonylamino)-2-hydroxy-3-phenoxy-
propane 16
114.83, 122.43, 130.18 (Ar-ipso), 157.82 (C᎐O), 164.50 (C᎐O);
᎐
᎐
m/z (CI) 266 ([M ϩ H]ϩ, 87%), 265 (100), 258 (10), 242 (7), 239
(5) (Found: [M ϩ H]ϩ, 266.1392. C14H19NO4 requires m/z,
266.1392).
Potassium hydroxide (0.65 g, 11.6 mmol), in water (15 mL), was
cooled at 0 ЊC, then N-(tert-butoxycarbonyl)-2,3-epoxypropyl-
amine (1 g, 5.77 mmol) and phenol (1.08 g, 11.6 mmol) were
added to the solution. The reaction was warmed up to room
temperature, left stirring overnight, then neutralised with 2 M
hydrochloric acid. The compound was extracted with ethyl
acetate(3 × 30mL).Thecombinedorganiclayersweredriedover
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure to give the crude compound which was purified
by flash chromatography eluting with 20% ethyl acetate–
petroleum ether 40 : 60 to give 1-(N-tert-butoxycarbonylamino)-
2-hydroxy-3-phenoxypropane rac-16 as a pale liquid (2.49 g,
92.2%); νmax(neat)/cmϪ1 3359, 3060, 2977, 2931, 1690, 1599,
1587, 1497, 1456, 1391, 1366, 1245, 1170, 1123, 1070, 1044, 993,
925, 855, 813, 781, 754, 737, 691; δH(300 MHz, CDCl3) 1.46
(9 H, s, C(CH3)3), 3.26–3.35 (2 H, m, CH2), 3.44–3.52 (1 H, m,
C(OH)H), 3.90–4.01 (2 H, m, CH2), 4.08 (1 H, br s, OH), 5.01
(1 H, br s, NH), 6.86–7.32 (5 H, m, Aryl-H); δC(75.5 MHz,
CDCl3) 28.74 ((CH3)3C), 48.89 (CH2), 69.66 (CH2), 70.35
(CH), 80.34 ((CH3)3C), 114.87, 121.62, 129.94 (Ar-ipso), 158.75
R-(؊)-1-(N-tert-Butoxycarbonylamino)-2-hydroxy-3-phenoxy-
propane 16
A mixture of (p-cymene)ruthenium() chloride dimer (0.31 mg,
0.0051 mmol) and (1R,2R)-TsDPEN 2 (0.37 mg, 0.0102 mmol)
in a 5 : 2 formic acid–triethylamine mixture (2.5 mL) was stirred
at 28 ЊC for 15 min. 1-(N-tert-Butoxycarbonylamino)-2-oxo-3-
phenoxypropane 18 (0.54 g, 2.04 mmol) was added and the
solution was stirred at 28 ЊC for 24 hours. Then the mixture was
filtered through silica and washed with ethyl acetate (60 ml).
The solvent was evaporated under reduced pressure to give the
crude compound, which was purified by flash chromatography
(20% v/v ethyl acetate–petroleum ether 40 : 60) to give the R-
(Ϫ)-16 as a white solid (0.47 g, 86.2%). The product was deter-
mined to be of 84% ee by HPLC analysis (Chiral OD, hexane–
ethanol–diethylamine = 95 : 5 : 0.1 (0.5 mL minϪ1), R isomer
22.48 min, S isomer 41.64 min), mp 70–72 ЊC; [α]2D0 Ϫ7.2 (c = 1,
ethanol); νmax(neat)/cmϪ1 3359, 3060, 2977, 2931, 1690, 1599,
1587, 1497, 1456, 1391, 1366, 1245, 1170, 1123, 1070, 1044, 993,
925, 855, 813, 781, 754, 737, 691; δH(300 MHz, CDCl3) 1.46
(9 H, s, C(CH3)3), 3.26–3.35 (2 H, m, CHH, C(OH)H), 3.44–3.52
(1 H, m, CHH), 3.90–4.01 (2 H, m, CH2), 4.11 (1 H, br s, OH),
4.99 (1 H, br s, NH), 6.88–7.33 (5 H, m, Aryl-H); δC(75.5 MHz,
CDCl3) 28.74 ((CH3)3C), 43.89 (CH2), 69.62 (CH2), 70.39 (CH),
80.34 ((CH3)3C), 114.87, 121.64, 129.95 (Ar-ipso), 158.74
(C᎐O); m/z (CI) 268 ([M ϩ H]ϩ, 50%), 212 (100), 209 (15)
᎐
(Found: [M ϩ H]ϩ, 268.1551. C14H21NO4 requires m/z,
268.1549).
rac-N-(tert-Butoxycarbonyl)-2-phenoxymethylaziridine 17
To a solution of 1-(N-tert-butoxycarbonylamino)-2-hydroxy-3-
phenoxypropane rac-16 (0.5 g, 1.87 mmol) and tosyl chloride
J. Chem. Soc., Perkin Trans. 1, 2001, 1916–1928
1923

View Online
(C᎐O); m/z (CI) 268 ([M ϩ H]ϩ, 35%), 212 (63), 192 (11),
was added and the reaction mixture was stirred overnight. The
᎐
168 (35), 154 (100), 136 (70), 107 (26) (Found: [M ϩ H]ϩ,
268.155464. C14H21NO4 requires m/z, 268.154883). The reduc-
tion using (1S,2R)-1–propan-2-ol was attempted using identical
conditions to those reported however no reduction product was
isolated.4b
reaction was then filtered and DMF was removed. Dichloro-
methane (30 mL) was then added followed by di-tert-butyl
dicarbonate (1.27 g, 5.80 mmol) dissolved in 10 mL of dichloro-
methane. The reaction mixture was stirred overnight, then
saturated ammonium chloride solution (30 mL) added. The
phases were separated and the aqueous layer extracted with
dichloromethane (2 × 30 mL). The combined organic layers
were dried over magnesium sulfate, filtered, and the solvent
removed in vacuo. Purification by flash chromatography on
silica with 10% ethyl acetate–hexane 60 : 80, gave the product as
a colourless liquid (0.56 g, 27.3%); νmax(neat)/cmϪ1 3366, 3064,
3030, 2976, 2929, 1950, 1809, 1694, 1599, 1587, 1495, 1454,
1409, 1365, 1339, 1301, 1243, 1169, 1119, 1078, 1053, 1031,
993, 915, 882, 816, 754, 692; δH(300 MHz, CDCl3) 1.45 (9 H, s,
(R)-(؊)-N-(tert-Butoxycarbonyl)-2-phenoxymethylaziridine 17
To a solution of chiral 1-N-(tert-butoxycarbonylamino)-2-
hydroxy-3-phenoxypropane R-(Ϫ)-16 (0.38 g, 1.42 mmol) and
tosyl chloride (0.41 g, 2.13 mmol) in dry THF (10 mL) was
added KOH (0.40 g, 7.10 mmol) freshly powdered (with the
help of a ball mill) at room temperature. The reaction mixture
was left stirring overnight. Then it was dissolved in diethyl ether
(20 mL) and filtered. The solvent was removed under reduced
pressure and the crude compound was purified using flash
chromatography eluting with 20% diethyl ether–hexane to give
the aziridine R-(Ϫ)-17 as a colourless liquid (0.22 g, 62.9%).
The product was determined to be of 83.7% ee by HPLC analy-
sis (Chiral OD, hexane–ethanol–diethylamine = 95 : 5 : 0.1 (0.5
mL minϪ1), R isomer 22.48 min, S isomer 41.64 min); [α]2D0
Ϫ68.9 (c = 1, ethanol); νmax(neat)/cmϪ1 2979, 2932, 2360, 1722,
1600, 1497, 1458, 1393, 1308, 1245, 1222, 1156, 1110, 1080,
1039, 996, 968, 853, 832, 754, 692; δH(300 MHz, CDCl3) 1.44
(9 H, s, (CH3)3C), 2.25 (1 H, d, J 3.6, CHHaz), 2.38 (1 H, d,
J 6.0, CHHaz), 2.80–2.87 (1 H, m, CHaz), 4.0 (1 H, dd, J 4.9,
10.6, C-CHH-O-Ph), 4.16 (1 H, dd, J 4.9, 10.6, C-CHH-O-Ph),
6.89–7.31 (5 H, m, Aryl H); δC(75.5 MHz, CDCl3) 27.65
((CH3)3C), 29.32 (CH2), 35.57 (CH2), 67.25 (CH), 81.26
C(CH ) ), 3.91 (2 H, m, Ph-O-CH ), 4.45 (4 H, br m, ᎐C-CH ,
᎐
3
3
2
2
CH -Ph), 5.04 (1 H, s, ᎐CHH), 5.11 (1 H, br s, ᎐CHH), 6.88–
᎐
᎐
2
7.38 (10 H, m, Ar-H); δC(75.5 MHz, CDCl3) 28.76 ((CH3)3C),
48.63 (CH ), 49.40 (CH ), 50.07 (CH ), 60.15 (C᎐CH ), 71.27
᎐
2
2
2
2
(C(CH ) ), 80.49 (C᎐CH ), 114.53, 115.07, 121.32, 127.65,
᎐
3
3
2
127.87, 128.38, 128.92, 129.83, 138.38, 140.91 (Ar-ipso), 158.89
(C᎐O); m/z (FAB) 354 ([M]ϩ, 70%), 307 (25), 298 (87), 254 (70),
᎐
204 (90), 160 (23), 154 (90), 136 (62), 107 (27) (Found:
[M ϩ H]ϩ, 354.2064. C22H27NO3 requires m/z, 354.2069).
1-(N-Butoxycarbonyl-N-benzylamino)-2-oxo-3-phenoxypropane
20
N-(tert-Butoxycarbonyl)-N-(benzyl)-2-(phenoxymethyl)allyl-
amine (0.17 g, 0.48 mmol) was stirred in dichloromethane (10
mL) at Ϫ78 ЊC. An empty trap followed by a trap containing
a solution of 5% potassium iodide in 50% acetic acid–water
were connected to the outlet. Ozone was passed through the
reaction mixture for 20 minutes after which time the solution
appeared pale blue. Oxygen was bubbled through the solution
for 10 minutes followed by nitrogen for 20 minutes. Triphenyl-
phosphine (0.19 g, 0.72 mmol) was added and the cooling
bath removed. The reaction was stirred overnight, the solvent
removed and purified by column chromatography yielding the
product 20 as a colourless liquid of high viscosity (0.08 g, 47%
yield). νmax(neat)/cmϪ1 3371, 3064, 2977, 2930, 1740, 1694, 1599,
1589, 1495, 1454, 1427, 1393, 1366, 1292, 1245, 1165, 1126,
1080, 1060, 967, 886, 754, 692; δH(300 MHz, CDCl3, 1 : 1 mix-
ture of NCO rotamers) 1.44 (4.5 H, s, C(CH3)3), 1.49 (4.5 H, s,
C(CH3)3), 4.12 (1 H, s, N-CHH-Ph), 4.20 (1 H, s, N-CHH-Ph),
((CH ) C), 114.36, 120.92, 129.24 (Ar-ipso), 158.05 (C᎐O); m/z
᎐
3
3
(FAB) 250, ([M]ϩ, 80%), 249 (70), 194 (100), 176 (15), 154 (80),
136 (34), 107 (29) (Found: [M ϩ H]ϩ, 250.1441. C14H19NO3
requires m/z, 250.1443).
2-(Chloromethyl)allyl phenyl ether
Sodium hydride (0.10 g, 2.5 mmol) was stirred in DMF (7 mL)
at 0 ЊC and to this phenol (0.094 g, 1 mmol) was added slowly.
Once the addition was complete the reaction was stirred for 20
minutes. The cooling bath was removed and the stirring was
continued for a further hour at room temperature. 3-Chloro-2-
chloromethylprop-1-ene (0.125 g, 1 mmol) was added and the
reaction was stirred overnight. Saturated ammonium chloride
solution (10 mL) was added to quench the reaction and then the
aqueous solution was extracted with ethyl acetate. The organic
layers were dried over magnesium sulfate, filtered and concen-
trated under reduced pressure to give the crude compound
which was purified using medium pressure flash chrom-
atography eluting with 1% ether–hexane to give the product as a
pale oil (0.08 g, 43.7%). νmax(neat)/cmϪ1 3062, 3039, 2925, 2867,
1930, 1840, 1775, 1702, 1654, 1597, 1495, 1456, 1443, 1407,
1368, 1334, 1299, 1241, 1172, 1079, 1056, 1033, 993, 919, 883,
814, 753, 691, 665; δH(300 MHz, CDCl3) 4.19 (2 H, br d, J 0.7,
4.48 (1 H, s, C(᎐O)-CHH), 4.51 (2 H, s, Ph-O-CH ), 4.59 (1 H,
᎐
2
s, C(᎐O)-CHH), 6.80–7.35 (10 H, m, Ar-H); δ (75.5 MHz,
᎐
C
CDCl3) 28.64 ((CH3)3C), 51.60 (CH2), 53.70 (CH2), 72.24
(CH ), 81.06 (C(CH ) ), 80.49 (C᎐CH ), 114.78, 122.18, 127.98,
᎐
2
3
3
2
128.59, 129.05, 130.07, 137.88 (Ar-ipso), 156.21 (C᎐O), 157.97
᎐
(C᎐O); m/z (FAB) 356 ([M ϩ H]ϩ, 31%), 307 (20), 300 (100),
᎐
289 (10), 256 (26), 220 (21), 154 (69), 136 (45), 120 (32) (Found:
[M ϩ H]ϩ, 356.1862. C21H25NO4 requires m/z, 356.1862).
CH ), 4.63 (2 H, br s, CH ), 5.37 (1 H, m, ᎐CHH), 5.39 (1 H, m,
᎐
2
2
R-(؉)-1-(N-tert-Butoxycarbonyl-N-benzylamino)-2-hydroxy-3-
phenoxypropane 21
᎐CHH), 6.90–7.00 (3 H, m, Ar-H), 7.25–7.35 (2 H, m, Ar-H);
᎐
δC(75.5 MHz, CDCl3) 45.52 (CH2), 68.26 (CH2), 115.17,
A mixture of (p-cymene)ruthenium() chloride dimer (0.26 mg,
0.0043 mmol) and (1R,2R)-TsDPEN 2 (0.30 mg, 0.0086 mmol)
in a 5 : 2 formic acid–triethylamine mixture (2.5 mL) was stirred
at 28 ЊC for 15 min. 1-(N-tert-Butoxycarbonyl-N-benzylamino)-
2-oxo-3-phenoxypropane (0.61 g, 1.72 mmol) was added and the
solution was stirred at 28 ЊC for 24 hours. Then the mixture was
filtered through silica and washed with ethyl acetate (60 ml).
The solvent was evaporated under reduced pressure to give the
crude compound, which was purified by flash chromatography
(20% v/v ethyl acetate–petroleum ether 40 : 60) to give the
product 21 as a colourless liquid (0.61 g, 99.0%). The product
was determined to be of 59.7% ee by HPLC analysis (Chiral
OD, hexane–ethanol–diethylamine = 95 : 5 : 0.1 (0.5 mL
minϪ1), S isomer 21.09 min, R isomer 22.98 min); [α]2D0 ϩ7.45
117.93, 121.56, 129.91, 141.25 (Ar-ipso), 158.80 (C᎐CH ),
᎐
2
164.35 (C᎐CH ); m/z (EI) 184, 182 ([M ϩ H]ϩ 62, 86%), 148,
᎐
2
147 (57, 100), 133, 131 (50, 26), 119, 118 (15, 7), 94, 93 (36, 6)
(Found: [M ϩ H]ϩ, 184.0472, 182.0501. C14H19NO4 requires
m/z, 184.0469, 182.0498).
N-(tert-Butoxycarbonyl)-N-(benzyl)-2-(phenoxymethyl)allyl-
amine
Sodium hydride (0.62 g, 5.80 mmol) was stirred in DMF
(20 mL) and to this benzylamine (0.62 g, 5.80 mmol) in 5 mL
of DMF was added slowly. Once the addition was completed
the reaction was stirred for a further 1 hour at room temper-
ature. Then 2-(chloromethyl)allyl phenyl ether in 5 mL of DMF
1924
J. Chem. Soc., Perkin Trans. 1, 2001, 1916–1928

View Online
(c = 2, ethanol); νmax(neat)/cmϪ1 3430, 3061, 3028, 2973, 2928,
1947, 1736, 1694, 1598, 1586, 1495, 1453, 1413, 1391, 1365,
1288, 1244, 1168, 1132, 1077, 995, 967, 924, 881, 814, 754, 691;
δH(300 MHz, CDCl3) 1.47 (9 H, s, C(CH3)3), 3.44–3.53 (2 H, m,
C(OH)H, OH), 3.82–3.94 (2 H, m, Boc-N-CH2-Ph), 4.06–4.23
(2 H, m, CH(OH)-CH2-N-Boc), 4.48 (2 H, AB system, JAB 14.7,
Ph-O-CH2), 6.87–7.36 (10 H, m, Aryl-H); δC(75.5 MHz,
CDCl3) 28.15 ((CH3)3C), 50.41 (CH2), 52.40 (CH2), 68.78
(CH2), 69.98 (CH), 81.00 ((CH3)3C), 114.21, 120.86, 127.16,
ABsystem, JAB 13.0, NHCH2-Ph), 3.98 (2 H, d, J 5.3, Ph(O)-CH2),
4.05–4.13 (1 H, m, CH(OH)), 6.89–7.35 (10 H, m, Aryl H);
δC(75.5 MHz, CDCl3) 51.48 (CH2), 54.10 (CH2), 68.66 (CH),
70.64 (CH2), 114.92, 121.48, 127.69, 128.59, 128.95, 129.89
(Ar-ipso); m/z (CI) 258 ([M ϩ H]ϩ, 80%), 240 (5), 148 (7), 120
(18), 108 (8), 91 (10) (Found: [M ϩ H]ϩ, 258.1498. C16H19NO2
requires m/z, 258.1494).
rac-1-(N-Benzylamino)-2-hydroxy-3-phenoxypropane
128.39, 129.31, 137.74 (Ar-ipso), 164.09 (C᎐O); m/z (FAB) 358
᎐
To a solution of 1-(N-tert-butoxycarbonyl-N-benzylamino)-
2-hydroxy-3-phenoxypropane rac-21 (0.76 g, 2.11 mmol) in
dichloromethane (2 mL) TFA (2 mL) was added slowly. After 2
hours the solvent was removed and the resulting product was
dissolved in ethyl acetate and NaOH solution 0.2 M was added
until the pH = 7. The product was then extracted with ethyl
acetate and the combined organic layers were dried over
magnesium sulfate, filtered and the solvent removed in vacuo.
Recrystallisation (ethyl acetate–petroleum ether 40 : 60) gave
1-(N-benzylamino)-2-hydroxy-3-phenoxypropane (racemic) as
a white solid (0.34 g, 47% yield). Mp 74–76 ЊC; νmax(CDCl3)/
cmϪ1 3402, 2925, 1644, 1599, 1587, 1453, 1301, 1245, 1173,
1078, 1041, 909, 752, 691; δH(300 MHz, CDCl3) 2.55 (2 H, br s,
OH, NH), 2.78 (1 H, dd, Jab 12.06, Jbc 7.72, CHbHaCHc(OH)),
2.88 (1 H, dd, Jab 12.25, Jac 3.96, CHbHaCHc(OH)), 3.83 (2 H,
ABsystem, JAB 13.37, NHCH2-Ph), 3.96 (2 H, d, J 5.09, Ph(O)-
CH2), 4.04–4.15 (1 H, m, CH(OH)), 6.84–7.38 (10 H, m, Aryl
H); δC(75.5 MHz, CDCl3) 51.48 (CH2), 54.10 (CH2), 68.66
(CH), 70.64 (CH2), 114.93, 121.44, 127.58, 128.55, 128.92,
129.45, 129.89, 140.24 (Ar-ipso); m/z (CI) 258 ([M ϩ H]ϩ, 90%),
256 (17), 168 (21), 164 (18), 162 (12), 146 (8), 120 (31), 106 (10)
(Found: [M ϩ H]ϩ, 258.1498. C16H19NO2 requires m/z,
258.1494).
([M ϩ H]ϩ, 71%), 302 (90), 282 (15), 258 (91), 208 (35), 194
(10), 154 (86), 164 (16), 136 (60), 120 (44) (Found: [M ϩ H]ϩ,
358.2014. C21H27NO4 requires m/z, 358.2018). The reduction
using (1S,2R)-1–propan-2-ol was carried out using identical
conditions to those reported.4b The product, R-(ϩ)-21 was
formed in 99% yield and 61% ee as determined by chiral HPLC
analysis.
1-(N-tert-Butoxycarbonyl-N-benzylamino)-2-hydroxy-3-phen-
oxypropane rac-21
1-(N-tert-Butoxycarbonyl-N-benzylamino)-2-oxo-3-phenoxy-
propane (0.70 g, 1.97 mmol) was dissolved in 15 mL of MeOH–
H2O (9 : 1), in an ice bath. Sodium borohydride (0.25 g, 7.00
mmol) dissolved in 10 mL of MeOH–H2O (9 : 1) was added
slowly to the ketone solution. The reaction mixture was allowed
to warm up to room temperature. When the reaction was com-
pleted (TLC), it was concentrated under reduced pressure. The
residue was dissolved in diethyl ether (30 mL) and worked up
with saturated ammonium chloride solution (30 mL). The
phases were separated and the aqueous layer extracted with
diethyl ether (2 × 20 mL). The organic layers were dried over
anhydrous magnesium sulfate, filtered and the solvent removed
under reduced pressure. The crude compound was purified
using medium pressure flash chromatography eluting with
20% ethyl acetate–petroleum ether 40 : 60 to give 1-(N-tert-
butoxycarbonyl-N-benzylamino)-2-hydroxy-3-phenoxypropane
21 as a colourless liquid (0.70 g, 99%); νmax(neat)/cmϪ1 3425,
3061, 3028, 2973, 2928, 1948, 1693, 1598, 1586, 1537, 1494,
1453, 1413, 1365, 1288, 1244, 1169, 1133, 1077, 1043, 995, 966,
923, 881, 814, 753, 691; δH(300 MHz, CDCl3) 1.47 (9 H, s,
C(CH3)3), 3.44–3.57 (2H, m, C(OH)H, OH), 3.88–3.94 (2 H, m,
N(Boc)-CH2-Ph), 4.06–4.17 (2 H, m, CH(OH)CH2), 4.48 (2 H,
AB system, JAB 14.7, Ph-O-CH2), 6.87–7.36 (10 H, m, Aryl H);
δC(75.5 MHz, CDCl3) 28.77 ((CH3)3C), 51.02 (CH2), 53.02
(CH2), 69.42 (CH2), 70.61 (CH), 86.50 ((CH3)3C), 114.82,
O-(tert-Butyldimethylsilyl)-1-(N-tert-butoxycarbonylamino)-2-
hydroxy-3-phenoxypropane and subsequently R-(؉)-19 from
R-(؉)-16
1-(N-tert-Butoxycarbonylamino)-2-hydroxy-3-phenoxypropane
R-(Ϫ)-16 (0.3 g, 1.12 mmol) and imidazole (0.19 g, 2.80 mmol)
were dissolved in 10 mL of DMF and treated with tert-
butylchlorodimethylsilane (TBDMSCl) (0.21 g, 1.35 mmol).
The mixture was stirred at 35–45 ЊC until the starting materials
were completely consumed (followed by TLC). The reaction
was then treated with sodium bicarbonate saturated solution
(20 mL) and extracted with diethyl ether (3 × 20 mL). The
combined organic layers were dried over anhydrous magnesium
sulfate, filtered and concentrated under reduced pressure to give
the crude compound which was purified by flash chrom-
atography eluting with 20% ethyl acetate–petroleum ether
40 : 60 to give O-(tert-butyldimethylsilyl)-1-(N-tert-butoxy-
carbonylamino)-2-hydroxy-3-phenoxypropane as a colourless
liquid (0.42 g, 99%); [α]D20 Ϫ12.05 (c = 2, ethanol); νmax(neat)/
cmϪ1 2929, 1703, 1674, 1652, 1600, 1497, 1390, 1366, 1328,
1245, 1172, 1062, 987, 937, 836, 777, 752, 691; δH(300 MHz,
CDCl3) Ϫ0.0001 (3 H, s, SiCH3(CH3)3), 0.0231 (3 H, s,
SiCH3(CH3)3), 0.80 (9 H, s, Si-C(CH3)3), 1.33 (9 H, s, C(CH3)3),
3.08–3.16 (1 H, m, CHH-NH), 3.26–3.34 (1 H, m, CHH-NH),
3.76 (2 H, dd, J 1.32, 5.75, Ph-O-CH2), 3.98–4.04 (1 H, m, CH),
4.70 (1 H, br s, NH), 6.75–7.25 (5 H, m, Aryl H); δC(75.5 MHz,
CDCl3) Ϫ4.46 (SiCH3(CH3)3), Ϫ4.11 (SiCH3(CH3)3), 26.20 (Si-
C(CH3)3), 28.79 ((CH3)3C), 44.65 (CH2), 70.31 (CH2), 70.40
(CH), 114.78, 121.29, 122.29, 129.86, 135.54 (Ar-ipso), 163.97
121.46, 127.78, 129.01, 129.93, 137.50 (Ar-ipso), 164.14 (C᎐O);
᎐
m/z (FAB) 358 ([M ϩ H]ϩ, 31%), 307 (27), 302 (40), 289 (16),
258 (43), 208 (17), 154 (100), 136 (72), 120 (30) (Found:
[M ϩ H]ϩ, 358.2021. C21H27NO4 requires m/z, 358.2018).
R-(؉)-1-(N-Benzylamino)-2-hydroxy-3-phenoxypropane
To a solution of 1-(N-tert-butoxycarbonyl-N-benzylamino)-2-
hydroxy-3-phenoxypropane R-(ϩ)-21 (0.48 g, 1.34 mmol) in
dichloromethane (2 mL) TFA (2 mL) was added slowly. After
2 hours the solvent was removed and the resulting product
was dissolved in ethyl acetate and 0.2 M NaOH solution was
added until the pH = 7. The product was then extracted with
ethyl acetate and the combined organic layers were dried over
magnesium sulfate, filtered and the solvent removed in vacuo.
Recrystallisation (ethyl acetate–petroleum ether 40 : 60) gave
1-(N-benzylamino)-2-hydroxy-3-phenoxypropane as a white
solid (0.34 g, 47.0% yield). The product was determined to be of
45.6% ee by HPLC analysis (Chiral OD, hexane–ethanol–
diethylamine = 95 : 5 : 0.1 (0.5 mL minϪ1), S isomer 21.27 min,
R isomer 60.49 min), mp 64–66 ЊC; [α]2D0 ϩ9.4 (c = 2, ethanol);
νmax(CDCl3)/cmϪ1 3375, 2926, 2252, 1681, 1599, 1495, 1454,
1244, 1043, 908, 732, 649; δH(300 MHz, CDCl3) 2.24 (2 H, br s,
OH, NH), 2.81 (1 H, dd, Jab 12.1, Jbc 7.7, CHbHaCHc(OH)),
2.91 (1 H, dd, Jab 12.2, Jac 3.9, CHbHaCHc(OH)), 3.85 (2 H,
(C᎐O); m/z (FAB) 382 ([M ϩ H]ϩ, 25%), 326 (26), 282 (63), 268
᎐
(100), 232 (6), 174 (8), 154 (20), 136 (16), 107 (10) (Found:
[M ϩ H]ϩ, 382.2413. C20H35NSiO4 requires m/z, 382.2413).
This was converted into R-(ϩ)-19 (100 mg scale) by treatment
with sodium hydride–benzyl bromide using the same procedure
as employed for S-(+)-6 previously described. The product
was formed in 50% yield and exhibited [α]2D0 ϩ0.70 (c = 2,
ethanol).
J. Chem. Soc., Perkin Trans. 1, 2001, 1916–1928
1925

View Online
O-(tert-Butyldimethylsilyl)-1-(N-tert-butoxycarbonyl-N-benzyl-
amino)-2-hydroxy-3-phenoxypropane S-(؉)-19 from R-(؉)-21
The reaction was then treated with water (5 mL) and extracted
with diethyl ether (3 × 10 mL). The combined organic layers
were dried over anhydrous magnesium sulfate, filtered and con-
centrated under reduced pressure to give the crude compound
which was recrystallised with ether to give ( )-N-isopropyl-
N-[2-hydroxy-3-(1-naphthyloxy)propyl]amine 24 as a white
solid (0.24 g, 93%). Mp 88–89 ЊC; νmax(CDCl3)/cmϪ1 3429, 2253,
1655, 1581, 1461, 1396, 1268, 1103, 908, 734, 650; δH(300 MHz,
CDCl3) 1.11 (6 H, d, J 6.4, CH(CH3)2), 1.51 (2 H, br s, OH,
NH), 2.82–2.90 (2 H, m, CH2NH), 2.89–3.03 (1 H, m,
CH(CH3)2), 4.11–4.24 (3 H, m, CH2CH(OH)), 6.84 (1 H, dd,
J 1.2, 7.4, Ar-H), 7.34–7.52 (4 H, m, Ar-H), 7.76–7.83 (1 H, m,
Ar-H), 8.21–8.26 (1 H, m, Ar-H); δC(75.5 MHz, CDCl3) 23.51
(CH3), 23.65 (CH3), 49.31 (CH), 49.85 (CH2), 68.98 (CH),
71.06 (CH2), 105.28, 121.00, 122.21, 125.65, 126.23, 126.83,
127.93 (Ar-ipso); m/z (CI) 260 ([M ϩ H]ϩ, 77%), 242 (7),
145 (34), 128 (6), 116 (74), 100 (100), 98 (28), 84 (13), 72 (31), 58
(30) (Found: [M ϩ H]ϩ, 260.1646. C16H21NO2 requires m/z,
260.1650).
R-(ϩ)-1-(N-tert-Butoxycarbonyl-N-benzylamino)-2-hydroxy-
3-phenoxypropane 21 (0.2 g, 0.56 mmol) and imidazole (0.08 g,
1.12 mmol) were dissolved in 10 mL of DMF and treated
with tert-butylchlorodimethylsilane (TBDMSCl) (0.13 g, 0.84
mmol). The mixture was stirred at 35–45 ЊC until the starting
materials had been completely consumed (followed by TLC).
The reaction was then treated with sodium bicarbonate satur-
ated solution (20 mL) and extracted with diethyl ether (3 × 20
mL). The combined organic layers were dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure to give the crude compound which was purified by
flash chromatography eluting with 20% ethyl acetate–petroleum
ether 40 : 60 to give O-(tert-butyldimethylsilyl-1-(N-tert-butoxy-
carbonyl-N-benzylamino)-2-hydroxy-3-phenoxypropane
R-
(ϩ)-19 as a colourless liquid (0.25 g, 99%); [α]2D0 ϩ0.7 (c = 2,
ethanol); νmax(neat)/cmϪ1 3429, 3064, 3031, 2955, 2929, 2857,
1696, 1600, 1587, 1496, 1462, 1409, 1366, 1245, 1171, 1135,
1078, 1049, 980, 880, 836, 808, 775, 753, 691; δH(300 MHz,
CDCl3) Ϫ0.10 (6 H, s, Si(CH3)2), 0.90 (9 H, s, Si-C(CH3)3), 1.44
(4.5 H, s, C(CH3)3), 1.51 (4.5 H, s, C(CH3)3), 3.13–3.20 (1 H, m,
C(O)Si-CHH-NBoc), 3.44–3.59 (1 H, m, C(O)SiCHH-NBoc),
3.80–3.93 (2 H, m, N-CH2-Ph), 4.40 (2H, d, J 15.45, Ph-O-
CH2), 4.70–4.74 (1 H, m, Ph-O-CH2-CH(OSi)), 6.80–7.30 (10
H, m, Aryl H); δC(75.5 MHz, CDCl3) Ϫ4.33 (SiCH3(CH3)3),
Ϫ4.14 (SiCH3(CH3)3), 18.48 (Si-C(CH3)3), 26.27 ((CH3)3C),
28.81 (Si-C(CH3)3), 50.26, 50.83 (CH2), 51.95, 52.92 (CH2),
69.31 (CH2), 70.26, 70.64 (CH), 77.42, 77.85 (C(CH3)3), 105.42,
114.78, 117.77, 120.77, 121.07, 122.48, 125.57, 126.18, 126.78,
N-tert-Butoxycarbonyl-N-isopropyl-N-[2-hydroxy-3-(1-naphth-
yloxy)propyl]amine rac-22
To a solution of ( )-N-isopropyl-N-[2-hydroxy-3-(1-naphthyl-
oxy)propyl]amine (0.95 g, 3.66 mmol) in dichloromethane (40
mL), triethylamine (1.85 g, 18.30 mmol) followed by di-tert-butyl
dicarbonate (1.60 g, 7.32 mmol) were added. The reaction
mixture was stirred overnight, then saturated ammonium
chloride solution (30 mL) was added. The phases were separ-
ated and the aqueous layer extracted with dichloromethane
(2 × 40 mL). The combined organic layers were dried over
magnesium sulfate, filtered, and the solvent removed in vacuo.
Purification by flash chromatography on silica with 10% ethyl
acetate–hexane, gave the product 22 as a colourless liquid (1.45
g, 98.7%); νmax(neat)/cmϪ1 3416, 3053, 2975, 2931, 2876, 1865,
1658, 1596, 1581, 1509, 1476, 1457, 1403, 1367, 1347, 1269,
1241, 1213, 1164, 1128, 1103, 1069, 1020, 1001, 922, 900, 878,
861, 792, 771, 735, 571; δH(300 MHz, CDCl3) 1.15 (3 H, d, J 6.6,
CH(CH3)CH3), 1.24 (3 H, d, J 6.9, CH(CH3)CH3), 1.51 (9 H, s,
C(CH3)3), 3.52 (2 H, d, J 4.3, CH2-N(tBoc)), 4.05–4.07 (1 H, m,
CH(CH3)2), 4.17–4.25 (3 H, m, CH2CH(OH)), 5.29 (1 H, br s,
OH), 6.85 (1 H, d, J 7.4, Ar-H), 7.35–7.52 (4 H, m, Ar-H), 7.78–
7.85 (1 H, m, Ar-H), 8.19–8.24 (1 H, m, Ar-H); δC(75.5 MHz,
CDCl3) 20.89 (CH(CH3)CH3), 21.40 (C(CH3)CH3), 28.86
(C(CH3)3), 47.46 (CH), 66.24 (CH2), 70.24 (CH2), 72.50 (CH),
81.17 (C(CH3)3), 105.16, 120.99, 122.04, 125.64, 125.82, 126.30,
127.55, 127.84, 128.14, 128.91, 129.82, 133.73, 163.95 (C᎐O);
᎐
m/z (FAB) 472 ([M ϩ H]ϩ, 27%), 372 (100), 358 (95), 322 (7),
154 (14), 136 (12), 120 (17) (Found: [M ϩ H]ϩ, 472.2883.
C27H41NSiO4 requires m/z, 472.2883).
( )-3-(1-Naphthyloxy)-1,2-epoxypropane
To a solution of 1-naphthol (2 g, 13.87 mmol) in 20 mL of dry
DMF was added NaH (1.11 g, 27.74 mmol) and the mixture
was heated to 80 ЊC for 1 hour. To this solution was added
epichlorohydrin (2.57 g, 27.74 mmol) and it was stirred for
4 hours at 80 ЊC. The solution was cooled and poured into 30
mL of water. The product was then extracted with diethyl ether
(3 × 30 mL), dried with MgSO4 and concentrated to give the
crude compound which was purified by flash chromatography
(10% v/v ethyl acetate–hexane) to give the product as a colour-
less liquid (1.69 g, 61%); νmax(neat)/cmϪ1 3053, 3000, 2926, 1628,
1595, 1580, 1576, 1508, 1465, 1440, 1349, 1271, 1241, 1179,
1157, 1109, 1101, 1083, 1069, 1020, 999, 960, 916, 862, 841, 793,
772, 728, 635, 614; δH(300 MHz, CDCl3) 2.83 (1 H, dd, J 2.6,
4.9, CH-O-CHH), 2.94 (1 H, t, J 4.2, CH-O-CHH), 3.45–3.50
(1 H, m, Ar-O-CH2-CH-O-CH2), 4.11 (1 H, dd, J 5.6, 11.1,
Ar-O-CHH-CH-O-CH2), 4.37 (1 H, dd, J 3.2, 11.1, Ar-
O-CHH-CH-O-CH2), 6.77–6.79 (1 H, m, Ar-H), 7.32–7.52
(4 H, m, Ar-H), 7.75–7.82 (1 H, m, Ar-H), 8.27–8.32 (1 H, m,
Ar-H); δC(75.5 MHz, CDCl3) 45.17 (CH2), 50.67 (CH2), 69.34
(CH), 105.36, 121.26, 122.44, 125.75, 125.98, 126.14, 126.94,
127.88, 134.92, 154.63 (Ar-ipso); m/z (CI) 201 ([M ϩ H]ϩ,
100%), 200 (13), 185 (53), 144 (17), 115 (10).
126.80, 127.99, 134.89 (Ar-ipso), 154.53 (C᎐O); m/z (FAB) 360
᎐
([M ϩ H]ϩ, 12%), 304 (20), 260 (42), 160 (100), 154 (25), 136
(20) (Found: [M ϩ H]ϩ, 360.2170. C21H29NO4 requires m/z,
360.2174).
N-tert-Butoxycarbonyl-N-isopropyl-N-[2-oxo-3-(1-naphthyl-
oxy)propyl] amine 23
N-tert-Butoxycarbonyl-N-isopropyl-N-[2-hydroxy-3-(1-naphth-
yloxy)propyl]amine 22 (1.40 g, 3.89 mmol) was added to a
solution of pyridinium dichromate (5.13 g, 13.63 mmol) in
anhydrous N,N-dimethylformamide (30 mL). The reaction
mixture was stirred overnight, then worked up with brine (40
mL). The compound was extracted with diethyl ether (3 × 40
mL). The combined organic layers were dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure to give the crude compound which was purified by
flash chromatography eluting with 10% ethyl acetate–hexane to
give N-tert-butoxycarbonyl-N-isopropyl-N-[2-oxo-3-(1-naphth-
yloxy)propyl]amine 23 (0.95 g, 68.5%); νmax(neat)/cmϪ1 3054,
2976, 2930, 1742, 1699, 1695, 1651, 1597, 1581, 1509, 1464,
1398, 1365, 1270, 1243, 1214, 1165, 1105, 1077, 1021, 902, 875,
792, 771; δH(300 MHz, CDCl3) 1.06, 1.09 (6 H, 2 × dd, ratio
60 : 40, J 6.8, 6.9, CH(CH3)2), 1.41, 1.49 (9 H, 2 × s, ratio
60 : 40, C(CH3)3), 4.21, 4.25 (2 H, 2 × s, ratio 60 : 40, CH2),
( )-N-Isopropyl-N-[2-hydroxy-3-(1-naphthyloxy)propyl]amine
24
A solution of the epoxide (0.2 g, 1.0 mmol) in acetonitrile
(1 mL) was treated with anhydrous metal salt (CaCl2) (0.11 g,
1.0 mmol), then stirred until the salt had completely dissolved.
The resulting solution was treated under stirring, at room tem-
perature, with the required amount of the amine (0.12 g, 2.0
mmol). After the addition of the amine was complete, the reac-
tion mixture was stirred until the reagents had been consumed.
1926
J. Chem. Soc., Perkin Trans. 1, 2001, 1916–1928

View Online
4.44–4.65 (1 H, m, CH(CH3)2), 4.80, 4.88 (2 H, 2 × s, ratio
60 : 40, CH2), 6.71–6.75 (1 H, m, Ar-H), 7.34–7.56 (4 H, m,
Ar-H), 7.79–7.87 (1 H, m, Ar-H), 8.30–8.33 (1 H, m, Ar-H);
δC(75.5 MHz, CDCl3) 20.88, 21.30 (CH(CH3)2), 28.69, 28.84
(C(CH3)3), 46.44 (CH), 49.13 (CH2), 72.67 (CH2), 80.54
(C(CH3)3), 105.25, 121.80, 122.10, 126.16, 127.06, 128.08,
135.03 (Ar-ipso); m/z (FAB) 357 ([M]ϩ, 64%), 339 (16), 313 (18),
302 (98), 289 (14), 258 (61), 158 (59), 154 (100), 136 (95), 116
(58), 107 (65), 95 (79) (Found: [M]ϩ, 357. C21H27NO4 requires
m/z, 357).
m/z (CI) 260 ([M ϩ H]ϩ, 77%), 242 (7), 145 (34), 128 (6), 116
(74), 100 (100), 98 (28), 84 (13), 72 (31), 58 (30) (Found:
[M ϩ H]ϩ, 260.1650. C16H21NO2 requires m/z, 260.1650). The
compound from reduction of 23 using Ru()–aminoindanol 1
was deprotected in an identical manner to give R-(ϩ)-24 in 93%
yield and 64% ee.
Acknowledgements
This paper is dedicated to the memory of Barrie Percival.
We thank the Brazilian CNPq for a Scholarship to A. K. and
Professor D. Games and Dr B. Stein of the EPSRC National
Mass Spectroscopic Service (Swansea) for HRMS analysis of
certain compounds. We wish to acknowledge the use of the
EPSRC’s Chemical Database Service at Daresbury.25
(R)-(؊)-N-tert-Butoxycarbonyl-N-isopropyl-N-[2-hydroxy-3-
(1-naphthyloxy)propyl]amine 22
A mixture of (p-cymene)ruthenium() chloride dimer (0.17 mg,
0.0028 mmol) and (1R,2R)-TsDPEN 2 (0.21 mg, 0.0021 mmol)
in a 5 : 2 formic acid–triethylamine mixture (2.5 mL) was stirred
at 28 ЊC for 15 min. N-Isopropyl-N-[2-oxo-3-(1-naphthyloxy)-
propyl]amine (0.37 g, 1.12 mmol) was added the solution was
stirred at 28 ЊC for 24 hours. Then the mixture was filtered
through silica and washed with ethyl acetate (60 ml). The solv-
ent was evaporated under reduced pressure to give the crude
compound, which was purified by flash chromatography (20%
v/v ethyl acetate–petroleum ether 40 : 60) to give R-(Ϫ)-22 as a
colourless liquid (0.36 g, 98.4%); [α]2D0 Ϫ2.92 (c = 0.96, ethanol);
νmax(neat)/cmϪ1 3418, 3053, 2974, 2931, 1738, 1687, 1596, 1581,
1509, 1403, 1366, 1269, 1164, 1103, 1069, 1020, 1001, 899,
861, 792, 771, 736; δH(300 MHz, CDCl3) 1.15 (3 H, d, J 6.6,
CH(CH3)CH3), 1.24 (3 H, d, J 6.8, CH(CH3)CH3), 1.51 (9 H, s,
C(CH3)3), 3.52 (2 H, d, J 4.5, CH2-N(tBoc)), 4.04–4.11 (1 H, m,
CH(CH3)2), 4.17–4.25 (3 H, m, CH2CH(OH)), 5.17 (1 H, br s,
OH), 6.85 (1 H, d, J 7.4, Ar-H), 7.34–7.52 (4 H, m, Ar-H), 7.77–
7.84 (1 H, m, Ar-H), 8.19–8.25 (1 H, m, Ar-H); δC(75.5 MHz,
CDCl3) 20.88 (CH(CH3)CH3), 21.39 (C(CH3)CH3), 28.86
(C(CH3)3), 49.08 (CH), 66.27 (CH2), 70.21 (CH2), 72.90 (CH),
81.17 (C(CH3)3), 105.15, 120.99, 122.04, 125.64, 125.81, 126.30,
References
1 (a) For a comprehensive survey of methods of aziridine synthesis
from double bonds, including a discussion of cyclisations of
β-amino alcohols see J. E. G. Kemp, in Comprehensive Organic
Synthesis, Volume 7, Academic Press, New York, 1991, ch. 3.5,
pp. 470–483; (b) R. S. Atkinson and B. J. Kelly, J. Chem. Soc.,
Chem. Commun., 1987, 1362.
2 (a) D. A. Evans, M. M. Faul and M. T. Bilodeau, J. Org. Chem.,
1991, 113, 726; (b) Z. Li, K. R. Conser and E. N. Jacobsen,
J. Am. Chem. Soc., 1993, 115, 5326; (c) D. A. Evans, M. M. Faul,
M. T. Bilodeau, B. A. Anderson and D. Barnes, J. Am. Chem. Soc.,
1993, 115, 5328; (d ) M. J. Haddadin, J. P. Freeman, Small Ring
Heterocycles, ed. A. Hassner, N.Y., 1985, part 3, p. 283; (e)
R. Paredes, H. Bastos, R. Montoya, A. L. Charez, W. R. Dolbier Jr.
and C. R. Burkholder, Tetrahedron, 1988, 44, 6821; ( f ) A. Azman,
J. Kroller and B. Plesnicar, J. Am. Chem. Soc., 1970, 101, 1107.
3 Monotosylated diamines with Ru() in iPrOH or HCO2H–TEA (a)
S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya and R. Noyori,
J. Am. Chem. Soc., 1995, 117, 7562; (b) A. Fujii, S. Hashiguchi,
N. Uematsu, T. Ikariya and R. Noyori, J. Am. Chem. Soc., 1996,
118, 2521; (c) K. Püntener, L. Schwink and P. Knochel, Tetrahedron
Lett., 1996, 37, 8165. Monotosylated diamines with Rh() in
iPrOH; (d ) K. Mashima, T. Abe and K. Tani, Chem. Lett., 1998,
1199; (e) K. Mashima, T. Abe and K. Tani, Chem. Lett., 1998, 1201;
( f ) K. Murata, T. Ikariya and R. Noyori, J. Org. Chem., 1999, 64,
2186.
4 (a) M. J. Palmer and M. Wills, Tetrahedron: Asymmetry, 1999, 10,
2045; (b) M. Palmer, T. Walsgrove and M. Wills, J. Org. Chem., 1997,
62, 5226; (c) M. Wills, M. Gamble, M. Palmer, A. R. C. Smith, J. R.
Studley and J. A. Kenny, J. Mol. Catal. A; Chem., 1999, 146, 139; (d )
A. R. C. Smith, J. A. Kenny, A. J. R. Heck, J. J. Kettenes-van der
Bosch and M. Wills, Tetrahedron: Asymmetry, 1999, 10, 3267; (e)
M. Wills, M. J. Palmer, A. R. C. Smith, J. A. Kenny and
T. Walsgrove, Molecules, 2000, 5, 1; ( f ) J. A. Kenny, K. Versluis,
A. J. R. Heck, T. Walsgrove and M. Wills, Chem. Commun., 2000,
99.
126.80, 127.99, 134.89 (Ar-ipso), 154.53 (C᎐O); m/z (CI) 360
᎐
([M ϩ H]ϩ, 13%), 304 (21), 260 (36), 160 (98), 136 (19), 133
(100) (Found: [M ϩ H]ϩ, 360.2177. C21H29NO4 requires m/z,
360.2175). The reduction using (1S,2R)-1–propan-2-ol was
carried out using identical conditions to those reported.4b The
product, R-(Ϫ)-22 was formed in 99% yield and 64% ee as
determined by chiral HPLC analysis.
(R)-(؉)-N-Isopropyl-N-[2-hydroxy-3-(1-naphthyloxy)propyl]-
amine 24
To a solution of (R)-N-tert-butoxycarbonyl-N-isopropyl-N-[2-
hydroxy-3-(1-naphthyloxy)propyl]amine R-(Ϫ)-22 (0.32 g, 0.90
mmol) in dichloromethane (2 mL) TFA (2 mL) was added
slowly. After 2 hours the solvent was removed and the resulting
product was dissolved in ethyl acetate and NaOH solution 0.2
M was added until the pH = 7. The product was then extracted
with ethyl acetate and the combined organic layers were dried
over magnesium sulfate, filtered and the solvent removed
in vacuo. Recrystallisation (ethyl acetate–petroleum ether
40 : 60) gave (R)-N-isopropyl-N-[2-hydroxy-3-(1-naphthyloxy)-
propyl]amine R-(ϩ)-24 as a light yellow solid (0.20 g, 84.5%
yield). The product was determined to be of 83.0% ee by
HPLC analysis (Chiral OD, hexane–ethanol–diethylamine =
95 : 5 : 0.1 (0.5 mL minϪ1), R isomer 32.91 min, S isomer 54.76
min), mp 88–89 ЊC; [α]D20 ϩ5.1 (c = 1.6, ethanol); νmax(CDCl3)/
cmϪ1 3429, 2253, 1655, 1581, 1461, 1396, 1268, 1103, 908, 734,
650; δH(300 MHz, CDCl3) 1.11 (6 H, d, J 6.4, CH(CH3)2), 2.14
(2 H, br s, OH, NH), 2.81–2.91 (2 H, m, CH2NH), 2.98–3.04
(1 H, m, CH(CH3)2), 4.11–4.21 (3 H, m, CH2CH(OH)), 6.83
(1 H, dd, J 0.9, 7.5, Ar-H), 7.34–7.53 (4 H, m, Ar-H), 7.78–
7.83 (1 H, m, Ar-H), 8.21–8.28 (1 H, m, Ar-H); δC(75.5 MHz,
CDCl3) 23.45 (CH(CH3)CH3), 23.59 (C(CH3)CH3), 49.36
(CH), 49.83 (CH2), 69.81 (CH), 71.04 (CH2), 80.05 (C(CH3)3),
105.27, 121.01, 122.21, 125.65, 126.23, 126.84, 127.93 (Ar-ipso);
5 (a) J. A. Kenny, M. J. Palmer, A. R. C. Smith, T. Walsgrove and
M. Wills, Synlett, 1999, 1615; (b) A. Kawamoto and M. Wills,
Tetrahedron: Asymmetry, 2000, 11, 3257.
6 S. Gabriel, Ber. Dtsch. Chem. Ges., 1888, 21, 1049.
7 H. Wenker, J. Am. Chem. Soc., 1935, 57, 2328.
8 R. Appel and R. Kleinstuck, Chem. Ber., 1974, 107, 5.
9 I. Okada, K. Ichimura and R. Sudo, Bull. Chem. Soc. Jpn., 1970, 43,
1185.
10 O. Mitsunobu, Synthesis, 1981, 1.
11 J. T. Carlock and M. P. Mack, Tetrahedron Lett., 1978, 19,
5153.
12 P. G. Sammes and S. Smith, J. Chem. Soc., Chem. Commun., 1983,
682.
13 J. R. Pfister, Synthesis, 1984, 969.
14 (a) P. Wessig and J. Schwarz, Synlett, 1997, 893; (b) F. Effenberger
and U. Stelzer, Tetrahedron: Asymmetry, 1995, 6, 283.
15 H. J. C. Yeh, S. K. Balani, H. Yagi, R. M. E. Greene, N. D. Sharma,
D. R. Boyd and D. M. Jerina, J. Org. Chem., 1986, 51, 5439.
16 (a) J. F. Dellaria and K. J. Sallin, Tetrahedron Lett., 1990, 31, 2661;
(b) D. S. Jones, A. Srinivasan, S. Kasina, A. R. Fritzberg and D. W.
Wilkening, J. Org. Chem., 1989, 54, 1940; (c) L. M. Gustavson, T. N.
Rao, D. S. Jones and A. Fritzgerg, Tetrahedron Lett., 1991, 32,
5485.
17 M. Ho, J. K. K. Chung and N. Tang, Tetrahedron Lett., 1993, 34,
6513.
J. Chem. Soc., Perkin Trans. 1, 2001, 1916–1928
1927

View Online
18 (a) A. K. Bose, D. P. Sahu and M. S. Manhas, J. Org. Chem., 1981,
46, 1229; (b) D. P. Sahu, P. Mashava, M. S. Manhas and A. K. Bose,
J. Org. Chem., 1983, 48, 1142; (c) P. Wipf and C. P. Miller,
Tetrahedron Lett., 1992, 33, 6267.
19 Y. K. Li, K. Luthaman and U. Hacksell, Tetrahedron Lett., 1992, 33,
4487.
literature results ([α]2D0 = Ϫ163.5 (c = 1, DCM)) for the S compound;
ref. 14(a).
21 H. Wenker, J. Am. Chem. Soc., 1935, 57, 2328.
22 P. A. Leighton, W. A. Perkins and M. L. Renquist, J. Am. Chem.
Soc., 1947, 69, 1540.
23 K. Kitaori, Y. Furukawa, H. Yoshimoto and J. Otera, Tetrahedron
Lett., 1998, 39, 3173.
24 H. Takahashi, S. Sakuraba, H. Takeda and K. Achiwa, J. Am.
Chem. Soc., 1990, 112, 5876.
25 D. A. Fletcher, R. F. McMeeking and D. Parkin, J. Chem. Inf.
Comput. Sci., 1996, 36, 746.
20 There appears to be a discrepancy in the signs of optical rotation
for compound 11. Previous work, and the conversion of 9 to
S-(ϩ)-10, suggests that 11 should be
R configuration (i.e.
through inversion). Our optical rotation for 11 ([α]2D0 = Ϫ137 (c = 1,
EtOH)) suggests that it is in fact S when compared with the
1928
J. Chem. Soc., Perkin Trans. 1, 2001, 1916–1928