O-(1-phenylbutyl)benzyloxyacetaldoxime, a versatile reagent for the asymmetric synthesis of protected 1,2-aminoalcohols and 2-hydroxymethyl nitrogen heterocycles

Article abstract of DOI:10.1055/s-2002-34235

Addition of organometallic reagents to O-(1-phenylbutyl)benzyloxyacetaldoxime in the presence of boron trifluoride diethyl etherate is highly diastereoselective; the resulting hydroxylamines are readily converted into protected 1,2-aminoalcohols and 2-hydroxymethyl nitrogen heterocycles, including the iminosugar 1,4-dideoxy-1,4-imino-D-ribitol, in high enantiomeric excess.

Full text of DOI:10.1055/s-2002-34235

1730
LETTER
O-(1-Phenylbutyl)benzyloxyacetaldoxime, a Versatile Reagent for the
Asymmetric Synthesis of Protected 1,2-Aminoalcohols and 2-Hydroxymethyl
Nitrogen Heterocycles
O
-(1-Phenylbut
r
y
a
loxyacetald
c
oximejhjhj
e
k
y S. Cooper,a Alexander S. Larigo,a1 Pierre Laurent,a Christopher J. Moody,*a Andrew K. Takleb
a
School of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, UK
b
GlaxoSmithKline, New Frontiers Science Park North, Third Avenue, Harlow CM19 5AW, UK
Received 21 August 2002
Dedicated to the memory of Alex Larigo.
Table 1 Addition of Organometallic Reagents to O-(1-Phenyl-
butyl)benzyloxyacetaldoxime 1
Abstract: Addition of organometallic reagents to O-(1-phenylbu-
tyl)benzyloxyacetaldoxime in the presence of boron trifluoride di-
ethyl etherate is highly diastereoselective; the resulting
hydroxylamines are readily converted into protected 1,2-aminoal-
cohols and 2-hydroxymethyl nitrogen heterocycles, including the
iminosugar 1,4-dideoxy-1,4-imino-D-ribitol, in high enantiomeric
excess.
Key words: asymmetric synthesis, organometallic reagents,
oximes, amino alcohols, piperidines
Oxime Organometallic
configu- Reagent
ration
Hydroxylamine Yield/% dea/%
(configuration at
new centre)
R
S
MeLi
2a (R)
2b (S)
2c (R)
2d (R)
75
61
82
79
44b
72
56
83
45
81
84
75
87
Compounds with a chiral centre adjacent to nitrogen occur
commonly in nature and are also widely used as synthetic
intermediates, ligands and chiral auxiliaries. Although
many routes to this structural unit already exist,2 new ste-
reoselective methods remain of interest. One powerful
method for the construction of such asymmetric centres is
the stereoselective addition to C=N bonds of imines, hy-
drazones, oximes, and nitrones,3–5 and we have described
the addition reactions of O-(1-phenylbutyl)oxime ethers
in the asymmetric synthesis of amines,6 -amino acids,7
and their -homologues.6 We now report that O-(1-phe-
nylbutyl)benzyloxyacetaldoxime 1 is a particularly versa-
tile intermediate for the asymmetric synthesis of a range
of nitrogen-containing compounds.
H2C=CHLi
n-PrMgCl
i-PrMgCl
R
R
S
90
90
H2C=CHCH2MgBr 2e (S)
42
R
R
S
n-BuLi
2f (R)
2g (R)
2h (S)
90
PhLi
>95
90
PhCH2MgBr
S
4-BrC6H4CH2MgBr 2i (S)
90
R
R
2-lithiothiophene
2-lithiothiazole
2j (S)
2k (S)
80
The (E)-oxime ether 1 was prepared in either enantio-
meric form by reaction of the commercially available al-
dehyde with either (R)- or (S)-O-(1-phenylbutyl)hydrox-
ylamine,8 followed by chromatographic separation from
the corresponding Z-isomer.9 Addition of organolithium
or Grignard reagents in the presence of boron trifluoride
diethyl etherate in toluene at low temperature proceeded
smoothly and gave the corresponding hydroxylamines 2
in reasonable yield and in good diastereomeric excess
(Table 1).10 The only exception to this was the reaction in-
volving the addition of allylmagnesium bromide which
showed poor diastereoselectivity (42% de), although the
major diastereomer was readily isolated. The stereochem-
istry at the new asymmetric centre was assigned on the ba-
sis of previous work, and on the subsequent
transformations of the hydroxylamines 2.
>95
a Determined from the 1H NMR spectrum of 2 by integration of the
CHNH signals.
b Yield of the major diastereomer after separation.
The N–O bond in the hydroxylamines 2 was readily
cleaved using either zinc in acetic acid with sonication or
using molybdenum hexacarbonyl. The resulting amines
were not isolated but immediately protected as their
t-butyl or benzyl carbamates. The protected 1,2-aminoal-
cohols 3 were formed in good yield and high enantiomeric
excess as evidenced by HPLC on a chiral stationary phase
(Table 2).
The O-benzyl-N-tert-butoxycarbonyl-1,2-aminoalcohols
3a and 3e were deprotected by hydrogenolysis to give the
known N-Boc-1,2-aminoalcohols 4a and 4b (Scheme 1)
thereby confirming the stereochemistry of the original
addition to the chiral oxime ether 1.11–13
Synlett 2002, No. 10, Print: 01 10 2002.
Art Id.1437-2096,E;2002,0,10,1730,1732,ftx,en;D15802ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
O-(1-Phenylbutyl)benzyloxyacetaldoxime
1731
Table 2 N–O Bond Cleavage in Hydroxylamines 2 and Protection of Resulting Amines as Carbamates 3
Hydroxyl-
amine
Methoda
R
R
Protected 1,2-aminoalcohol 3
Yield/%
eeb/%
configuration
2a
2b
2ed
2f
A
B
B
A
A
Me
t-Bu
Bn
3a
3b
3c
3d
3e
3f
R
S
S
R
S
S
67
76
70
67
84
77
97
ndc
91
93
83
98
H2C=CH
H2C=CHCH2
n-Bu
Bn
t-Bu
t-Bu
t-Bu
2h
Bn
2k
A
2-thiazolyl
a Method A: Mo(CO)6, aq MeCN; Method B: Zn, HOAc, ultrasound.
b Determined by HPLC on ChiralCel OD using hexane–isopropanol (85:15 to 95:5) as eluent.
c nd = not determined.
d The major diastereomer was used in this reaction.
Scheme 1
The versatility of the 1,2-aminoalcohol derivatives ob-
tained by stereoselective addition to O-(1-phenylbu-
tyl)benzyloxyacetaldoxime 1 was further illustrated by
the synthesis of the nitrogen heterocycles 6 (Scheme 2).
Thus N-allylation of the benzyl carbamates 3b and 3c
gave the corresponding N-allyl derivatives 5 in good
yield. Treatment with benzylidene bis(tricyclohexylphos-
phine)dichlororuthenium (Grubbs’ catalyst) resulted in
ring-closing metathesis (RCM) reaction to give the 2,5-di-
hydropyrrole 6a (90%) and the 1,2,3,6-tetrahydropyridine
6b (84%),14 useful precursors to 5- and 6-membered ring
iminosugars, as illustrated by the synthesis of 1,4-
dideoxy-1,4-imino-D-ribitol, a naturally occurring gly-
cosidase inhibitor isolated from the mulberry tree Morus
alba.15,16 Thus reaction of dihydropyrrole 6a with a cata-
lytic amount of osmium tetroxide in the presence of N-
Scheme 2
methylmorpholine-N-oxide (NMO) resulted in dihydrox-
ylation from the least hindered face to give, after acetyla-
tion, the protected iminosugar 7 (84% over two steps).
Hydrogenolysis of 7 in methanolic hydrochloric acid gave
1,4-dideoxy-1,4-imino-D-ribitol as its hydrochloride salt
8 in quantitative yield (Scheme 2).16,17
In summary, we have shown that the oxime ether 1 is a
versatile reagent for the asymmetric synthesis of protected
1,2-aminoalcohols and nitrogen heterocycles.
Acknowledgement
We thank the EPSRC for support of this work, GlaxoSmithKline
for a CASE award (to T.S.C.), and the EPSRC Mass Spectrometry
Centre at Swansea for mass spectra.
Synlett 2002, No. 10, 1730–1732 ISSN 0936-5214 © Thieme Stuttgart · New York

1732
T. S. Cooper et al.
LETTER
dropwise over 30 min at this temperature, and the mixture
stirred until all starting material was consumed. The reaction
mixture was quenched at this temperature with aq sat.
ammonium chloride solution (10 mL), and allowed to warm
to r.t. The mixture was extracted with ether (3 15 mL),
combined, dried (K2CO3), filtered and evaporated. The
residue was purified by column chromatography on silica
gel.
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19
Boc-alaninol)(4a); mp 49–50 °C (lit.,12 mp 52–53 °C); [ ]D
+8.6 (c 0.8, CHCl3) {lit.,12 [ ]D26 +10.0 (c 1.0, MeOH)}; (S)-
N-tert-butoxycarbonyl-1-hydroxy-3-phenyl-2-propylamine
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(9) (E)-(S)-(–)-O-(1-Phenylbutyl)benzyloxyacetaldoxime [(S)-
1]; colourless oil; [ ]D24 –6.7 (c 0.90, CHCl3); H (300 MHz;
CDCl3) 7.54 (1 H, t, J = 6.8 Hz, N=CH), 7.31 (10 H, m,
ArH), 5.09 (1 H, t, J = 7.0 Hz, OCH), 4.44 (2 H, AB, J = 12.5
Hz, CH2Ph), 4.07 (2 H, m, CH2CHN), 1.95 (1 H, m, CHH),
1.73 (1 H, m, CHH), 1.51–1.26 (2 H, m, CH2Me), 0.95 (3 H,
t, J = 7.3 Hz, Me); C (75 MHz; CDCl3) 147.5 (N=CH),
142.8 (C), 137.9 (C), 128.8 (CH), 128.7 (CH), 128.4 (CH),
128.2 (CH), 127.8 (CH), 127.1 (CH), 85.6 (OCH), 72.7
(CH2), 67.1 (CH2), 38.7 (CH2), 19.3 (CH2), 14.4 (Me).
(10) General procedure. The oxime ether 1 (3.9 mmol, 1 equiv)
was dissolved in toluene (10 mL) under nitrogen and cooled
to –78 °C or –90 °C. Boron trifluoride etherate (11.8 mmol,
3 equiv) was added and the mixture stirred for 15 min. The
organometallic reagent (11.8 mmol, 3 equiv) was added
(12) Hamada, Y.; Shibata, M.; Sugiura, T.; Kato, S.; Shioiri, T. J.
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(17) 1,4-Dideoxy-1,4-imino-D-ribitol hydrochloride salt 8; mp
124–125 °C (lit.,15 mp 130–132 °C); [ ]D25 +53.3 (c 0.75,
H2O) {lit.,15 [ ]D20+53.9 (c 1.0, H2O)}.
Synlett 2002, No. 10, 1730–1732 ISSN 0936-5214 © Thieme Stuttgart · New York