Asymmetric reduction of α-keto aldoxime o -ethers

Article abstract of DOI:10.1055/s-0030-1258355

The catalytic asymmetric reduction of -keto aldoxime O-methyl, O-benzyl, and O-trityl ethers, derived from substituted acetophenones, with borane/oxazaborolidines, by transfer hydrogenation, and with yeast, was studied. The reduction with borane/oxazaborolidines produced the corresponding -hydroxy oxime ethers, -hydroxy hydroxylamine ethers, and -amino alcohols in 39-78% yields and up to 77% ee. The carbonyl group was selectively reduced by transfer hydrogenation with formic acid-triethylamine catalyzed by RhCl[(R,R)-TsDPEN](Ce, and also with yeast, producing -hydroxy oxime ethers, up to 75% ee and 93% ee, respectively. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258355

316
PAPER
Asymmetric Reduction of a-Keto Aldoxime O-Ethers
Mariusz J. Bosiak,* Marcin M. Pakulski
Department of Chemistry, Nicolaus Copernicus University, 7 Gagarin Street, 87-100 Toruń, Poland
Fax +48(56)6542477; E-mail: bosiu@chem.umk.pl
Received 22 September 2010
of a-hydroxy hydroxylamine ethers. Recently, we devel-
oped an asymmetric synthesis of Zileuton®, the 5-lipoxy-
genase inhibitor, containing the N-hydroxyurea
functionality, using asymmetric reduction of an oxime
Abstract: The catalytic asymmetric reduction of a-keto aldoxime
O-methyl, O-benzyl, and O-trityl ethers, derived from substituted
acetophenones, with borane/oxazaborolidines, by transfer hydroge-
nation, and with yeast, was studied. The reduction with borane/ox-
azaborolidines produced the corresponding a-hydroxy oxime ether with borane/oxazaborolidine, as the key transforma-
tion generating the stereogenic centre.23 In this study, we
focused on the asymmetric reduction of a-keto aldoxime
ethers, a-hydroxy hydroxylamine ethers, and b-amino alcohols in
39–78% yields and up to 77% ee. The carbonyl group was selective-
ly reduced by transfer hydrogenation with formic acid–triethyl-
O-ethers with borane/oxazaborolidines, by transfer hy-
amine catalyzed by RhCl[(R,R)-TsDPEN](C5Me5), and also with
yeast, producing a-hydroxy oxime ethers, up to 75% ee and 93% ee,
respectively.
drogenation, and with yeast.
a-Keto aldoximes 1–4 were prepared from acetophenone
and its derivatives in 31–58% yields by the modified Slater
reaction using isoamyl nitrite24 (Table 1). The nitrosation
of 2-methoxyacetophenone did not proceed to the expect-
ed a-keto aldoxime and 2-methoxybenzoic acid was the
only product. Oxime O-methyl, O-benzyl, and O-trityl
ethers were prepared by the Buehler method using silver
oxide and the corresponding halides,25 or by treatment
with sodium hydride followed by the halides. The meth-
ods gave different composition of E/Z isomers for the
oxime benzyl ether 6, and the same composition for the
methyl ether 5. The Buehler method gave better yields and
Key words: a-keto aldoximes, catalytic reduction, oxazaboro-
lidines, transfer hydrogenation, yeast reduction
b-Amino alcohols are important building blocks for phar-
maceuticals and natural products, and are also used as
chiral catalysts and auxiliaries.1,2 Several methods for
synthesis of chiral b-amino alcohols, for example, resolu-
tion of racemates,3–5 enzymatic and microbiological reac-
tions,6–12
catalytic
hydrogenation
or
transfer
hydrogenation of carbonyl compounds,13–17 and asymmet-
ric reduction of substituted ketones with borane/
oxazaborolidines18–20 are known. In contrast to b-amino
alcohols, there are only two methods for a-hydroxy oxime
ethers21,22 and no method is available for the preparation
1
was preferred. The E/Z ratio assignment is based on H
and 13C NMR shifts, according to the methods described
by Hegarty26 and Kreutz.21
Table 1 Synthesis of a-Keto Aldoxime Ethers
method A
O
O
O
R2X, Ag2O, CH2Cl2
N
OH
N
OR2
1. NaOEt, EtOH, r.t.
0 °C→r.t., 24 h
2. i-AmONO, 0 °C, 24 h
3. 3 M HCl (aq)
method B
1. NaH, DMF, 0 °C→r.t., 1 h
R
R
R
2. R2X, r.t., 24 h
5–12
1–4
R
H
Yield (%)
Method
R2X
MeI
Yield (%)
E/Z
1
44
A
B
A
B
A
B
A
5
95
38
98
89
–
100:0
100:0
98:2
30:70
–
MeI
BnBr
BnCl
6
Ph2CHCl, Ph2CHBr –
Ph2CHCl, Ph2CHBr –
–
–
Ph3CCl
7
83
100:0
SYNTHESIS 2011, No. 2, pp 0316–0324
x
x
.
x
x
.2
0
1
0
Advanced online publication: 07.12.2010
DOI: 10.1055/s-0030-1258355; Art ID: P14610SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Asymmetric Reduction of a-Keto Aldoxime O-Ethers
317
Table 1 Synthesis of a-Keto Aldoxime Ethers (continued)
method A
O
O
O
R2X, Ag2O, CH2Cl2
N
OH
N
OR2
1. NaOEt, EtOH, r.t.
0 °C→r.t., 24 h
2. i-AmONO, 0 °C, 24 h
3. 3 M HCl (aq)
method B
1. NaH, DMF, 0 °C→r.t., 1 h
R
R
R
2. R2X, r.t., 24 h
5–12
1–4
R
Yield (%)
Method
R2X
Yield (%)
E/Z
3-OMe
4-OMe
2
3
31
33
A
A
A
A
A
BnBr
MeI
8
94
92
93
81
82
50:50
100:0
100:0
79:21
77:23
9
BnBr
MeI
10
11
12
4-Cl
4
58
BnBr
The oxime ethers 5–12 were reduced with borane in the and small amounts of 23 and 24, which were removed by
presence of oxazaborolidines 13–18 (Table 2) generated refluxing with hydrochloric acid,31 followed by conver-
from (1R,2S)-norephedrine, (S)-1,1-diphenylvalinol, and sion of 19 into oxazolidone 25,32 crystallization, and lib-
terpene b-amino alcohols derived from (1S)-b-pinene, and eration.
(1R)-camphor. The synthesis of 15,27 16, and 1723 has
(E)-2-Oxo-2-phenylacetaldehyde oxime O-methyl ether
been reported from our laboratory, and 18 was generated
(5) was reduced with borane/tetrahydrofuran and 0.1
from
(1R,2S,3R,4S)-3-amino-1,7,7-trimethylbicyc-
equivalent of oxazaborolidine 16, generated in situ from
triisopropyl borate and (1R,2S,3R,4S)-(+)-3-amino-1,7,7-
trimethylbicyclo[2.2.1]heptan-2-ol,23 at room tempera-
lo[2.2.1]heptan-2-ol (19), prepared from (1R)-camphor
(Scheme 1).
Thus, E/Z camphoroquinone monoxime 20, obtained by ture for 30 minutes, producing a mixture of 26–28
nitrosation of (1R)-camphor or by oximation of campho- (Scheme 2). Composition of the mixture indicates a step-
roquinone, was isomerized to E-monoxime (E)-20 by re- wise reduction, first of the carbonyl group, followed by
fluxing the E/Z mixture with water.28 Its reduction with the N=C bond, and finally the reduction of the nitrogen–
zinc in 30% aqueous sodium hydroxide29,30 gave the crude oxygen bond. The mixture was reduced with lithium alu-
amino ketone 21, which was immediately transformed minum hydride to 28 (16% ee). Low enantiomeric excess
into the hydrochloride 22 to prevent self-dimerization. of the final reduction product 28 may indicate the compet-
The hydrochloride was crystallized and the liberated 21 itive reduction with borane not complexed to oxazaboro-
was reduced with lithium aluminum hydride to give 19, lidine.
1. t-BuOK, THF
–30 °C, 10 min
OH
N
2. i-AmONO
Zn
–30 °C, 10 min
3. H2O, reflux, 18 h
NaOH (aq)
1 min
HCl, Et2O
NH2
O
O
O
> 99% ee
(E)-20, 80%
21
1. crystallization
2. NaOH (aq)
3. LiAlH4, Et2O
reflux, 18 h
NH2
OH
OH
+
+
NH2
NH2
NH2•HCl
OH
19, 95%
O
22, 75% (crude)
23, 5%
24, traces
73%
1. 6 M HCl (aq)
reflux, 18 h
2. K2CO3, Et2CO3
130 °C, 2.5 h
3. crystallization
3 M NaOH
EtOH–H2O
reflux, 6 h
NH2
OH
HN
O
O
25, 51%
19, 98%, >99% de
Scheme 1
Synthesis 2011, No. 2, 316–324 © Thieme Stuttgart · New York

318
M. J. Bosiak, M. M. Pakulski
PAPER
Table 2 The Reduction of 5–7 with Borane and 13–18 in Tetrahydrofuran
1. BMS or BH3•THF, 13–18, 0 °C,
2.5 h, r.t., 0.5 h, reflux 18 h
2. 3 M HCl (aq), r.t., 5 h
3. NaOH
O
OH
∗
N
OR
NH2
Ph
Ph
5–7
28
Ph
O
BH
Ph
O
HN
Ph
O
NH
NH
NH
HN
O
O
B
H
B
H
BOi-Pr
BH
HN
O
BH
13
14
15
16
17
18
2-Amino-1-phenylethanol
R
BMS (equiv)
Cat. 13–18
Cat. (equiv)
Yield (%)
72
ee (%)
46
Conf.
R
5
6
Me
1
16
16
16
17
17
17
13
14
15
17
17
17
17
17
18
1
1
2.5
1
71
36
R
Bn
1
70
54
R
1
1
71
55
R
1a
1
63
48
R
1b
1
64
35
R
1 (BH3·THF)
1
59
46
R
1 (BH3·THF)
1
44
27
S
1 (BH3·THF)
1
65
53
R
3
4
4
4a
4
4
1
68
63
R
1
77
66
R
7
6
Tr
1
39
65
R
Bn
1
54
46
R
E/Z Bn 3:7
1
78
72
R
6
Bn
1
81
41
S
a Addition at –78 °C.
b Reversed addition.
The reduction at the molar ratio 5/borane/16 (1:1:1) at the ethers, then the mixture was warmed to room temper-
room temperature for 18 hours, gave two products 27 and ature, and finally refluxed. The results are presented in
28, and the enantiomeric excess increased to 42%. When Table 2.
the reaction mixture, after the slow addition of 5 to bo-
The 54% enantiomeric excess, obtained in the reduction
rane/16 in the same ratio, was refluxed for 18 hours, only
of benzyl ether 6 with BH3/16, was higher as compared to
28 in 72% yield and 46% ee was obtained. Then, O-meth-
methyl ether 5 (46% ee). The results obtained with ox-
yl, O-benzyl, and O-trityl ethers of 2-oxo-2-phenylacetal-
azaborolidine 17 indicate that the maximum product yield
dehyde
oxime
were
reduced
with
borane/
end enantioselectivity is achieved when 4 equivalents of
oxazaborolidines 13–18 at 0 °C by the slow addition of
1. 16 (0.1 equiv)
BH3⋅THF (1 equiv)
THF, 0 °C, 3 h
r.t., 30 min
OH
OH
O
OH
OH
LiAlH4, Et2O
reflux, 18 h
N
OMe
+
HN OMe
+
N
OMe
NH2
NH2
2. MeOH, r.t., 24 h
5
26, 31%
27, 13%
28, 3%
28, 99%, 16% ee
Scheme 2
Synthesis 2011, No. 2, 316–324 © Thieme Stuttgart · New York

PAPER
Scheme 3
Asymmetric Reduction of a-Keto Aldoxime O-Ethers
319
RhCl[(R,R)-TsDPEN](C5Me5)
HCOOH, Et3N, EtOAc, r.t., 18 h
LiAlH4, Et2O
reflux, 18 h
O
OH
OH
N
OMe
N
OMe
NH2
Ph
Ph
Ph
(S)-26
(S)-28
5
45%
73 %
unreacted substrate 55%
75% ee (S)
borane are used and 6 was reduced with BH3/17 producing creased (150 g per 1 mmol of 5), (R)-32 was obtained as
(R)-28 in 77% yield and 66% ee. The R-product was ob- the only reaction product in 77% yield and 93% ee.
tained in the presence of oxazaborolidines 13, 15, 16, and
OH
17, whereas in the presence of 14 and 18 the S-product
N
OMe
was obtained. The E/Z-6 (3:7) was reduced with borane/
17 in the highest yield (78%) and the highest enantioselec-
tivity (72% ee). Enantioselectivities of the reduction of
benzyl and trityl ethers with borane/17 are similar; how-
ever, the trityl ether is less reactive and the product yield
is much lower.
Ph
Saccharomyces cerevisiae
sucrose, (NH4)2HPO4
H2O, r.t., 18 h
(R)-26
50%
O
93% ee (R)
20 g/1 mmol of 5
N
OMe
+
Ph
OH
5
OH
Ph
Ring-substituted a-keto aldoxime O-benzyl ethers were
reduced with borane/17 (Table 3). The best enantioselec-
tivity of 77% ee was obtained for the 3-methoxy deriva-
tive 8 in 49% yield. The reduction of 4-chloro derivative
12 proceeded in 66% yield and 59% ee. O-Benzyl ether 10
was reduced with the lowest enantioselectivity of 31% ee.
(R)-32
3%
93% ee (R)
Scheme 4
Under the same conditions, methyl ether 9 was also re-
duced to the corresponding 1,2-diol, whereas 6 and 11
were not reduced.
Table 3 Reduction of Ring-Substituted a-Keto Aldoxime O-Benzyl
Ethers with Borane/17
In conclusion, six a-keto aldoxime O-methyl, O-benzyl,
and O-trityl ethers, derived from acetophenone and ring
substituted acetophenones were reduced with borane/ox-
azaborolidines 13–18 to chiral a-hydroxy oxime ethers, a-
hydroxy hydroxylamine ethers, or b-amino alcohols. The
best results were obtained with oxazaborolidine 17 (50–
77% ee). The E/Z isomer composition of 6 had a small ef-
fect on the enantioselectivity of the reduction. Selective
reduction of the carbonyl group of 5 was achieved by
the transfer hydrogenation, catalyzed by RhCl[(R,R)-
TsDPEN](C5Me5), leading to (S)-26 in 45% yield and
75% ee. The reduction of 5 with yeast gave (R)-26 in 50%
yield and 93% ee, however, benzyl ether 6 and methyl
ether 11 did not react. When 5 was reduced with an excess
of yeast, diol (R)-28 was the only product (93% ee 77%
yield).
1. BMS, 17
0 °C, 2.5 h
O
OH
0 °C→r.t., 0.5 h→reflux, 18 h
2. 3 M HCl (aq), r.t., 5 h
3. NaOH
N
OBn
NH2
R
R
6, 8, 10, 12
28–31
R
H
Yield (%)
ee (%)
6
28
29
30
31
78
49
74
66
72 (R)
77 (R)
31 (R)
59 (R)
8
3-OMe
4-OMe
4-Cl
10
12
Selective reduction of the keto group was achieved by
transfer hydrogenation of 5 with formic acid–trieth-
ylamine in ethyl acetate, catalyzed by RhCl[(R,R)-
TsDPEN](C5Me5),33–35 at room temperature affording (S)-26
in 45% yield and 75% ee (Scheme 3). Prolongation of the
reduction to 96 hours did not improve the yield. The re-
duction of 5 under the same conditions, catalyzed by
RuCl[(S,S)-TsDPEN](p-cymene), did not proceed.
Experiments with air and moisture sensitive materials were carried
under N2 atmosphere. Glassware were oven dried for several hours,
assembled hot, and cooled in a stream of N2. 1H and 13C NMR spec-
tra were recorded on a Varian Gemini 200 multinuclear instrument,
on a Bruker AMX 300 MHz instrument, Bruker Avance III 400
MHz, or Bruker Avance III 700 MHz instrument at r.t. Chemical
shifts are reported in parts per million (d scale), coupling constants
(J values) are listed in Hertz. IR spectra were recorded on Perkin–
Elmer, Spectrum RX I, FT spectrometer. Optical rotations were
measured on an automatic polarimeter, PolAAr 3000, Optical Ac-
tivity Ltd. GC was performed on a Perkin–Elmer AutoSystem XL
chromatograph using b-Dex 325 capillary column (30 m, 0.25 mm).
Melting points were determined with a Büchi SMP 32 apparatus in
open capillaries and are uncorrected. Elemental analyses were per-
formed using Vario MACRO CHN analyzer (Elementary Analy-
sensysteme GmbH).
O-Methyl ether 5 was also readily reduced with yeast Sac-
charomyces cerevisiae by the modified Kreutz method,21
using water (100 g), sucrose (20 g), and diammonium
phosphate (0.35 g) (Scheme 4). When 20 g of the reducing
mixture per 1 mmol of 5 was used, (R)-26 was obtained in
50% yield and 93% ee. A small amount of (R)-1-phenyl-
ethane-1,2-diol [(R)-32] in 3% yield and 93% ee was also
formed. When the amount of the reducing mixture was in-
Synthesis 2011, No. 2, 316–324 © Thieme Stuttgart · New York

320
M. J. Bosiak, M. M. Pakulski
PAPER
Silica gel 60 (Merck 230–400 mesh) was used for preparative col-
umn flash chromatography. Analytical TLC was performed using
Macherey-Nagel Polygram Sil G/UV254 using 0.2 mm plates. Sol-
vents were purchased from POCh Gliwice, Poland and Sigma-
Aldrich. Toluene was distilled from sodium benzophenone ketyl,
Et2O was distilled from LiAlH4, DMF was dried with MgSO4 and
distilled from BaO, and THF was freshly distilled from sodium
benzophenone ketyl prior to use. Acetophenone, 4¢-methoxyaceto-
phenone, 3¢-methoxyacetophenone, 2¢-methoxyacetophenone, 4¢-
chloroacetophenone, benzyl bromide, triphenylchloromethane, (+)-
(1S,2R)-norephedrine, (1R)-camphor, and diethyl carbonate were
purchased from Sigma-Aldrich. Isopentyl nitrite was purchased
from Alfa Aesar. MeI was purchased from POCh Gliwice, Poland.
(1R,2S,3R,4S)-3-Amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol,23
(E)-(1R)-(+)-3-hydroxyimino-1,7,7-trimethylbicyclo[2.2.1]heptan-
2-one [(E)-20],23 and (S)-diphenylvalinol36 were prepared accord-
ing to literature procedures.
2-(4-Chlorophenyl)-2-oxoacetaldehyde Oxime (4)
Oxime 4 was prepared from 4¢-chloroacetophenone (15.46 g, 100
mmol) according to the procedure described for 1 and crystallized
from MeOH–H2O; yield: 10.68 g (58%); mp 158–158.5 °C (Lit.39
mp 152–153 °C). 1H NMR spectrum showed the presence of a mix-
ture of E/Z-isomers (87:13).
1H NMR (300 MHz, DMSO-d6): d (E-isomer) = 7.59 (d, J = 8.7 Hz,
2 H, CHarom), 7.98 (d, J = 8.7 Hz, 2 H, CHarom), 7.99 (s, 1 H, CH),
12.74 (s, 1 H, OH).
13C NMR (75 MHz, DMSO-d6): d (E-isomer) = 128.50 (2 CHarom),
131.50 (2 CHarom), 134.69 (Carom), 138.16 (Carom), 147.76 (CH),
187.90 (C=O).
1H NMR (300 MHz, DMSO-d6): d (Z-isomer) = 7.54 (d, 2 H,
CHarom), 7.93 (m, 2 H, CHarom), 7.96 (s, 1 H, CH), 13.16 (s, 1 H,
OH).
a-Keto Aldoxime Ethers 5–12; General Procedure
(E)-2-Oxo-2-phenylacetaldehyde Oxime (1); Typical Procedure
Acetophenone (24.03 g, 0.2 mol) was added dropwise to a solution
of Na (4.60 g, 0.2 mol) in anhyd EtOH (200 mL) and the mixture
was stirred for 10 min at r.t. The mixture was cooled to 0 °C and iso-
pentyl nitrite (32.80 g, 0.28 mmol) was added dropwise. The mix-
ture was stirred at this temperature for an additional 1 h and left in
refrigerator for 72 h. Et2O (100 mL) was added, the precipitated sol-
id was collected by filtration, washed with Et2O (2 × 80 mL), and
dissolved in H2O (500 mL). Aq 3 M HCl was added until pH 2, the
precipitated oxime 1 was collected by filtration, dried, and crystal-
lized from H2O; yield: 13.22 g (44%); mp 129–129.5 °C (Lit.37 mp
129 °C).
1H NMR (200 MHz, DMSO-d6): d = 7.47–7.56 (m, 2 H, CHarom),
7.61–7.69 (m, 1 H, CHarom), 7.93–7.99 (m, 2 H, CHarom), 8.03 (s, 1
H, CH), 12.67 (s, 1 H, OH).
13C NMR (50 MHz, DMSO-d6): d = 128.39 (2 CHarom), 129.62 (2
CHarom), 133.18 (CHarom), 136.13 (Carom), 147.75 (CH), 189.04
(C=O).
Method A: The appropriate oxime (60 mmol) was dissolved in
CH2Cl2 (300 mL), alkyl or aryl halide was added in one portion (120
mmol), and the mixture was cooled to 0 °C. Ag2O (66 mmol) was
added in one portion, the mixture was stirred at this temperature for
1.5 h, and at r.t. for 18 h. The precipitated solid was collected by fil-
tration and the solvent was removed. The crude oxime ether was
distilled under reduced pressure.
Method B: A 50% suspension of NaH (0.58 g, 12 mmol) in mineral
oil was washed with n-hexane (2 × 5 mL) under N2 atmosphere. Af-
ter removal of n-hexane, anhyd DMF (15 mL) was added and the
mixture was cooled to 0 °C. A solution of the appropriate oxime (10
mmol) in DMF (15 mL) was added dropwise and the mixture was
stirred at 0 °C for 30 min and at r.t. for another 30 min. Alkyl or aryl
halide (20 mmol) was added in one portion and the mixture was
stirred at r.t. for 18 h. The solvent was removed under reduced pres-
sure and the residue was extracted with CH2Cl2 (3 × 15 mL). The
combined extracts were washed with brine (40 mL) and dried
(MgSO4). The solvent was removed and the product was distilled
under reduced pressure.
(E)-2-(3-Methoxyphenyl)-2-oxoacetaldehyde Oxime (2)
Oxime 2 was prepared from 3¢-methoxyacetophenone (13.51 g, 90
mmol) according to the procedure described for 1, purified by flash
chromatography on silica gel (n-hexane–EtOAc, 70:30) and crystal-
lized from toluene; yield: 4.98 g (31%); mp 108–111 °C.
(E)-2-Oxo-2-phenylacetaldehyde O-Methyl Oxime (5)
Oxime ether 5 was prepared from 1 (8.95 g, 60 mmol) as a light yel-
low liquid, using Method A; yield: 9.29 g (95%); bp 62–63 °C/0.65
mmHg (Lit.40 bp 152–153 °C/60 mmHg).
1H NMR (400 MHz, DMSO-d6): d = 3.82 (s, 3 H, CH3), 7.23 (ddd,
J = 8.0, 2.8, 0.8 Hz, 1 H, CHarom), 7.45 (t, J = 8.0 Hz, 1 H, CHarom),
7.48 (dm, J = 2.8 Hz, 1 H, CHarom), 7.58 (ddd, J = 8.0, 0.8, 0.8 Hz,
1 H, CHarom), 8.06 (s, 1 H, CH), 12.67 (s, 1 H, OH).
13C NMR (100 MHz, DMSO-d6): d = 55.79 (CH3), 114.69 (CHarom),
119.59 (CHarom), 122.60 (CHarom), 130.04 (CHarom), 137.82 (Carom),
148.11 (CH), 159.54 (Carom), 189.02 (C=O).
IR (film): 2940, 2343, 1721, 1656, 1589, 1448, 1327, 1278, 1182,
1095, 1035, 1020, 925, 787, 698, 641 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.10 (s, 3 H, CH3), 7.43–7.51 (m,
2 H, CHarom), 7.55–7.65 (m, 1 H, CHarom), 7.95 (s, 1 H, CH), 8.05–
8.10 (m, 2 H, CHarom).
13C NMR (50 MHz, CDCl3): d = 63.37 (CH3), 128.31 (2 CHarom),
130.03 (2 CHarom), 133.35 (CHarom), 135.87 (Carom), 147.02 (CH),
188.11 (C=O).
Anal. Calcd for C9H9NO3: C, 60.33; H, 5.06; N, 7.82. Found: C,
60.56; H, 5.09; N, 7.87.
(E)-2-Oxo-2-phenylacetaldehyde O-Benzyl Oxime (6)
O-Benzyl oxime 6 was prepared from 1 (2.98, 20 mmol) according
to Method A; yield: 4.66 g (98%); bp 148–150 °C/2.00 mmHg.
(E)-2-(4-Methoxyphenyl)-2-oxoacetaldehyde Oxime (3)
Oxime 3 was prepared from 4¢-methoxyacetophenone (15.02 g, 100
mmol) according to the procedure described for 1 and crystallized
from H2O; yield: 5.87 g (33%); mp 120–120.5 °C (Lit.38 mp
118 °C).
1H NMR (300 MHz, DMSO-d6): d = 3.84 (s, 3 H, CH3), 7.02–7.07
(m, 2 H, CHarom), 7.99–8.04 (m, 2 H, CHarom), 8.01 (s, 1 H, CH),
12.51 (s, 1 H, OH).
IR (film): 3065, 3033, 2949, 2340, 1718, 1655, 1600, 1497, 1451,
1376, 1272, 985, 925, 743, 697 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.31 (s, 2 H, CH2), 7.36–7.47 (m,
7 H, CHarom), 7.54–7.62 (m, 1 H, CHarom), 7.97 (s, 1 H, CH), 7.99–
8.03 (m, 2 H, CHarom).
13C NMR (75 MHz, CDCl3): d = 77.72 (CH2), 128.04 (2 CHarom),
128.29 (CHarom), 128.47 (2 CHarom), 128.66 (2 CHarom), 130.08 (2
CHarom), 133.25 (CHarom), 135.09 (Carom), 136.23 (Carom), 147.36
(CH), 188.16 (C=O).
13C NMR (75 MHz, DMSO-d6): d = 55.53 (CH3), 113.79 (2
CHarom), 128.73 (Carom), 132.06 (2 CHarom), 147.72 (CH), 163.43
(Carom), 186.80 (C=O).
Synthesis 2011, No. 2, 316–324 © Thieme Stuttgart · New York

PAPER
Asymmetric Reduction of a-Keto Aldoxime O-Ethers
321
Anal. Calcd for C15H13NO2: C, 75.30; H, 5.48; N, 5.85. Found: C,
75.49; H, 5.47; N, 5.79.
IR (film): 2941, 2342, 1752, 1655, 1588, 1324, 1276, 1090, 1031,
929, 841, 776, 739 cm–1.
1H NMR (400 MHz, CDCl3): d (E-isomer) = 4.12 (s, 3 H, CH3),
7.46 (dm, J = 8.8 Hz, 2 H, CHarom), 7.88 (s, 1 H, CH), 8.02–8.06
(dm, J = 8.8 Hz, 2 H, CHarom).
13C NMR (100 MHz, CDCl3): d (E-isomer) = 63.44 (CH3), 128.60
(2 CHarom), 131.48 (2 CHarom), 134.05 (Carom), 139.87 (Carom), 147.10
(CH), 186.90 (C=O).
(E)-2-Oxo-2-phenylacetaldehyde O-Trityl Oxime (7)
O-Trityl oxime 7 was prepared from 1 (0.74 g, 5 mmol) and trityl
chloride according to Method A; yield: 1.62 g (83%); oil.
1H NMR (200 MHz, DMSO-d6): d = 7.14–7.51 (m, 18 H, CHarom),
7.55–7.62 (m, 2 H, CHarom), 8.03 (s, 1 H, CH).
13C NMR (50 MHz, DMSO-d6): d = 93.22 (C), 127.46 (3 CHarom),
127.56 (6 CHarom), 127.88 (2 CHarom), 129.11 (6 CHarom), 130.44 (2
CHarom), 133.00 (CHarom), 135.20 (Carom), 143.50 (3 Carom), 147.53
(CH), 188.65 (C=O).
Anal. Calcd for C9H8ClNO2: C, 54.70; H, 4.08; N, 7.09. Found: C,
54.86; H, 4.11; N, 7.15.
2-(4-Chlorophenyl)-2-oxoacetaldehyde O-Benzyl Oxime (12)
Oxime ether 12 was prepared from 4 (0.90 g, 5 mmol) according to
Anal. Calcd for C27H21NO2: C, 82.84; H, 5.41; N, 3.58. Found: C,
83.08; H, 5.36; N, 3.54.
1
Method A; yield: 1.25 g (82%); bp 148–150 °C/0.40 mmHg. H
NMR spectrum showed the presence of a mixture of E/Z-isomers
2-(3-Methoxyphenyl)-2-oxoacetaldehyde O-Benzyl Oxime (8)
Oxime ether 8 was prepared from 2 (1.79 g, 10 mmol) according to
Method A; yield: 2.53 g (94%); bp 165–166 °C/0.43 mmHg. H
NMR spectrum showed the presence of a mixture of E/Z-isomers
(50:50).
(77:23).
IR (film): 3033, 2939, 2876, 2360, 1720, 1655, 1588, 1322, 1271,
1094, 988, 840, 738, 698 cm–1.
1H NMR (400 MHz, CDCl3): d (E-isomer) = 5.32 (s, 2 H, CH2),
7.38–7.45 (m, 7 H, CHarom), 7.94 (s, 1 H, CH), 7.98 (dm, J = 8.4 Hz,
2 H, CHarom).
13C NMR (100 MHz, CDCl3): d (E-isomer) = 77.85 (CH2), 128.49
(2 CHarom), 128.50 (2 CHarom), 128.54 (2 CHarom), 128.64 (CHarom),
128.71 (2 CHarom), 133.95 (Carom), 136.19 (Carom), 139.82 (Carom),
147.45 (CH), 187.06 (C=O).
1
IR (film): 3032, 2940, 2341, 1718, 1654, 1585, 1488, 1455, 1321,
1277, 1226, 1041, 995, 755, 698 cm–1.
1H NMR (300 MHz, CDCl3): d (isomer 1) = 3.81 (s, 3 H, CH3), 5.32
(s, 2 H, CH2), 6.98–7.73 (m, 9 H, CHarom), 7.36 (s, 1 H, CH).
1H NMR (300 MHz, CDCl3): d (isomer 2) = 3.85 (s, 3 H, CH3), 5.39
(s, 2 H, CH2), 6.98–7.73 (m, 9 H, CHarom), 8.01 (s, 1 H, CH).
Anal. Calcd for C15H12ClNO2: C, 65.82; H, 4.42; N, 5.12. Found: C,
65.58; H, 4.39; N, 5.16.
Anal. Calcd for C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C,
71.58; H, 5.60; N, 5.31.
Reduction of a-Keto Aldoxime O-Ethers with Borane/Oxaza-
borolidine; General Procedure
(E)-2-(4-Methoxyphenyl)-2-oxoacetaldehyde O-Methyl Oxime
(9)
To a solution of the appropriate amino alcohol (2 mmol) in THF (10
mL) was added 10 M BMS (borane–methyl sulfide complex) (0.2
mL, 2 mmol) and the mixture was stirred at r.t. for 1 h. THF (5 mL)
and the rest of BMS (0.8 mL, 8 mmol) were added and the mixture
was stirred for another 10 min. The mixture was cooled to 0 °C and
a-keto aldoxime ether (2 mmol) in THF (15 mL) was added in 2.5
h using a syringe pump. The mixture was stirred at 0 °C for 10 min,
at r.t. for 30 min, and refluxed for 18 h. After cooling to r.t., aq 3 M
HCl (12 mL) was added slowly and the mixture was allowed to stir
for 5 h. THF was removed on a rotary evaporator; then EtOAc (30
mL) and NaCl (5 g) were added to the residue, and the mixture was
basified with aq 10% NaOH to pH 12 and stirred for 5 min. The or-
ganic layer was separated and the residue was extracted with EtOAc
(5 × 15 mL). The combined organic extracts were dried (MgSO4).
The solvent was removed and the product was isolated by flash
chromatography on silica gel (CH2Cl2–MeOH, 90:10). The product
was derivatized with trifluoroacetic anhydride in the presence of
Et3N and analyzed by GC on a chiral b-Dex 325 capillary column
(30 m × 0.25 mm). Commercially available chiral 2-amino-1-phe-
nylethanols were also derivatized with trifluoroacetic anhydride and
analyzed by GC as comparative samples.
Oxime ether 9 was prepared from 3 (1.79 g, 10 mmol) according to
Method A; yield: 1.76 g (92%); bp 100–102 °C/0.42 mmHg; mp
44–46 °C.
1H NMR (300 MHz, CDCl3): d = 3.88 (s, 3 H, CH3), 4.08 (s, 3 H,
CH3), 6.94 (dm, J = 9.0 Hz, 2 H, CHarom), 7.92 (s, 1 H, CH), 8.11
(dm, J = 9.0 Hz, 2 H, CHarom).
13C NMR (75 MHz, CDCl3): d = 55.40 (CH3), 63.17 (CH3), 113.64
(2 CHarom), 128.70 (Carom), 132.38 (2 CHarom), 147.08 (CH), 163.90
(Carom), 186.12 (C=O).
Anal. Calcd for C10H11NO3: C, 62.17; H, 5.74; N, 7.25. Found: C,
62.46; H, 5.69; N, 7.21.
(E)-2-(4-Methoxyphenyl)-2-oxoacetaldehyde O-Benzyl Oxime
(10)
Oxime ether 12 was prepared from 3 (0.90 g, 5 mmol) according to
Method A; yield: 1.25 g (93%); bp 184–186 °C/0.66 mmHg.
1H NMR (300 MHz, CDCl3): d = 3.88 (s, 3 H, CH3), 5.30 (s, 2 H,
CH2), 6.92 (dm, J = 9.0 Hz, 2 H, CHarom), 7.31–7.43 (m, 5 H,
CHarom), 7.92 (s, 1 H, CH), 8.05 (dm, J = 9.0 Hz, 2 H, CHarom).
13C NMR (75 MHz, CDCl3): d = 55.36 (CH3), 77.54 (CH2), 113.53
(2 CHarom), 128.31 (CHarom), 128.46 (2 CHarom), 128.60 (2 CHarom),
128.91 (Carom), 132.46 (2 CHarom), 136.40 (Carom), 147.50 (CH),
163.84 (Carom), 186.23 (C=O).
(R)-2-Amino-1-phenylethanol (28)
Reduction with borane/17 gave the product 28; yield: 78%; 72% ee;
mp 58–62 °C (Lit.41 mp 60–62 °C).
GC: tR = 12.56 (R), tR = 13.23 (S), T = 170 °C, f = 35 mL/min.
Anal. Calcd for C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C,
71.58; H, 5.58; N, 5.18.
1H NMR (300 MHz, CDCl3): d = 2.23 (br s, 3 H, OH, NH2), 2.77
(dd, J = 12.9, 7.8 Hz, 1 H, CH2, part of ABX system), 2.96 (dd,
J = 12.9, 3.9 Hz, 1 H, CH2, part of ABX system), 4.62 (dd,
J = 7.8, 3.9 Hz, 1 H, CH, part of ABX system), 7.25–7.49 (m, 5 H,
CHarom).
13C NMR (75 MHz, CDCl3): d = 48.27 (CH2), 72.84 (CH), 125.84
(2 CHarom), 127.65 (CHarom), 128.43 (2 CHarom), 141.86 (Carom).
2-(4-Chlorophenyl)-2-oxoacetaldehyde O-Methyl Oxime (11)
Oxime ether 11 was prepared from 4 (1.79 g, 10 mmol) according
to Method A; yield: 1.60 g (81%), bp 88 °C/0.76 mmHg. 1H NMR
spectrum showed the presence of a mixture of E/Z-isomers (79:21).
Synthesis 2011, No. 2, 316–324 © Thieme Stuttgart · New York

322
M. J. Bosiak, M. M. Pakulski
PAPER
(R)-2-Amino-1-(3-methoxyphenyl)ethanol (29)
Reduction with borane/17 gave the product 29 as a colorless oil;
yield: 49%, 77% ee.
g) was added and the mixture was stirred for 30 min. The precipitate
was collected by filtration, washed with Et2O (2 × 1 mL) and dried
(MgSO4). The Et2O was removed to afford a white crystalline prod-
uct; yield: 0.035 g (86%); mp 59–62 °C (Lit.41 mp 60–62 °C).
GC: tR = 50.49 (R), tR = 53.31 (S), T = 160 °C, f = 35 mL/min.
GC: tR = 12.65 (R), tR = 13.22 (S), T = 170 °C, f = 35 mL/min) re-
vealed 75% ee of S-enantiomer.
1H NMR (300 MHz, CDCl3): d = 2.27 (s, 3 H, OH, NH2), 2.79 (dd,
J = 12.9, 7.8 Hz, 1 H, part of ABX system), 2.94 (dd, J = 12.9, 3.9
Hz, 1 H, part of ABX system), 4.62 (dd, J = 7.8, 3.9 Hz, 1 H, part
of ABX system), 7.25–7.49 (m, 5 H, CHarom).
1H NMR (700 MHz, CDCl3): d = 2.86 (br s, 1 H, CH2, part of ABX
system), 3.01 (br s, 1 H, CH2, part of ABX system), 3.48 (br s, 3 H,
OH, NH2), 3.79 (s, 3 H, CH3), 4.70 (br s, 1 H, CH, part of ABX sys-
tem), 6.80 (dd, J = 8.4, 2.1 Hz 1 H, CHarom), 6.90 (d, J = 7.7 Hz, 1
H, CHarom), 6.92 (d, J = 2.1 Hz, 1 H, CHarom), 7.24 (dd, J = 8.4, 7.7
Hz, 1 H, CHarom).
13C NMR (175 MHz, CDCl3): d = 48.87 (CH2), 55.19 (CH3), 77.20
(CH), 111.35 (CHarom), 113.00 (CHarom), 118.14 (CHarom), 129.42
(CHarom), 144.07 (Carom), 159.71 (Carom).
13C NMR (75 MHz, CDCl3): d = 48.27 (CH2), 72.84 (CH), 125.84
(2 CHarom), 127.65 (CHarom), 128.43 (2 CHarom), 141.86 (Carom).
(R)-2-Hydroxy-2-phenylacetaldehyde O-Methyl Oxime (R)-26
by Reduction with Yeast
Anal. Calcd for C9H13NO2: C, 64.65; H, 7.84; N, 8.38. Found: C,
64.58; H, 7.83; N, 8.30.
To a solution of sucrose (20 g) and diammonium phosphate (0.35 g)
in H2O (100 mL) was added dry yeast Saccharomyces cerevisiae (4
g) at 32 °C, and the mixture stirred for 5 min and left for another 25
min. A solution of 5 (0.98 g, 6 mmol) in EtOH (3 mL) was added,
the mixture stirred for 5 min, and left at 28–30 °C for 18 h. MeOH
(200 mL) was added to the mixture and filtered. After removal of
MeOH under reduced pressure, NaCl (35 g) was added, and the so-
lution was extracted with EtOAc (4 × 30 mL), and the combined or-
ganic solutions were dried (MgSO4). The solvents were removed
under reduced pressure and the product was isolated by flash chro-
matography on silica gel (n-hexane–EtOAc–CH2Cl2, 7:2:1); yield:
(R)-2-Amino-1-(4-methoxyphenyl)ethanol (30)
Reduction with borane/17 gave the product 30; yield: 74%, 50% ee;
mp 70–72 °C (Lit.42 mp 73–75 °C).
GC: tR = 75.65 (R), tR = 77.21 (S), T = 160 °C, f = 35 mL/min.
1H NMR (200 MHz, CDCl3): d = 2.35 (s, 3 H, OH, NH2), 2.84 (dd,
J = 12.8, 7.8 Hz, 1 H, CH2, part of ABX system), 2.90 (dd, J = 12.6,
4.2 Hz, 1 H, CH2, part of ABX system), 3.79 (s, 3 H, CH3), 4.54 (dd,
J = 7.8, 4.2 Hz, 1 H, CH, part of ABX system), 6.91 (dm, J = 8.4
Hz, 2 H, CHarom), 7.30 (dm, J = 8.4 Hz, 2 H, CHarom).
13C NMR (50 MHz, CDCl3): d = 55.48 (CH3), 68.90 (CH2), 73.45
(CH), 114.06 (2 CHarom), 127.34 (2 CHarom), 134.20 (Carom), 161.90
(Carom).
27
0.37 g (37%); colorless oil; [a]D +17.0 (c 4.775, CHCl3) {Lit.21
[a]D20 +3.8 (c 4.5, CHCl3) for 62% ee}. 1H NMR analysis revealed
the presence of a 84:16 mixture of E/Z isomer composition of the
product despite the fact that pure E-oxime ether was used in the re-
duction.
(R)-2-Amino-1-(4-chlorophenyl)ethanol (31)
Reduction with borane/17 gave the product 31; yield: 66%, 59% ee;
mp 94–95 °C (Lit.43 mp 93.5–94.5 °C).
GC: tR = 39.12 (S), tR = 40.00 (R), T = 120 °C, f = 35 mL/min) re-
vealed 93% ee of R-enantiomer.
1H NMR (200 MHz, CDCl3): d (E-isomer) = 2.80 (s, 1 H, OH), 3.89
(s, 3 H, CH3), 5.33 (d, J = 5.0 Hz, 1 H, CH), 7.31–7.41 (m, 5 H,
CHarom), 7.47 (d, J = 5.0 Hz, 1 H, CH).
13C NMR (50 MHz, CDCl3): d (E-isomer) = 61.90 (CH3), 71.69
(CH), 126.35 (2 CHarom), 128.27 (CHarom), 128.74 (2 CHarom),
139.57 (Carom), 150.21 (CH).
GC: tR = 38.94 (R), tR = 41.05 (S), T = 170 °C, f = 30 mL/min.
1H NMR (200 MHz, CDCl3): d = 2.43 (s, 3 H, OH, NH2), 2.75 (dd,
J = 12.6, 8.2 Hz, 1 H, CH2, part of ABX system), 2.96 (dd,
J = 12.6, 3.8 Hz, 1 H, CH2, part of ABX system), 4.62 (dd,
J = 8.2, 3.8 Hz, 1 H, CH, part of ABX system), 7.25–7.38 (m, 4 H,
CHarom).
1H NMR (200 MHz, CDCl3): d (Z-isomer) = 2.80 (s, 1 H, OH), 3.91
(s, 3 H, CH3), 5.82 (d, J = 5.4 Hz, 1 H, CH), 6.92 (d, J = 5.4 Hz, 1
H, CH), 7.31–7.41 (m, 5 H, CHarom).
13C NMR (50 MHz, CDCl3): d = 48.03 (CH2), 71.96 (CH), 127.20
(2 CHarom), 128.64 (2 CHarom), 133.47 (Carom), 140.28 (Carom).
13C NMR (50 MHz, CDCl3): d (Z-isomer) = 62.17 (CH3), 67.75
(CH), 126.24 (2 CHarom), 128.09 (CHarom), 128.62 (2 CHarom),
139.92 (Carom), 151.97 (CH).
(S)-2-Hydroxy-2-phenylacetaldehyde O-Methyl Oxime (S)-26
by Transfer Hydrogenation
To a mixture of 5 (0.163 g, 1 mmol), EtOAc (4 mL), and an azeo-
tropic mixture of formic acid–Et3N (5:2, 0.2 mL) was added
RhCl[(R,R)-TsDPEN](C5Me5) (5 mg) and the mixture stirred at r.t.
for 24 h. The solvents were removed and the product was isolated
by flash chromatography on silica gel (n-hexane–EtOAc–CH2Cl2–
MeOH, 6:0.5:0.5:0.5); yield: 0.074 g (45%); colorless oil.
1H NMR (300 MHz, CDCl3): d = 2.05 (br s, 1 H, OH), 3.89 (s, 3 H,
CH3), 5.33 (d, J = 5.0 Hz, 1 H, CH), 7.31–7.41 (m, 5 H, CHarom),
7.47 (d, J = 5.0 Hz, 1 H, CH).
(R)-1-Phenylethane-1,2-diol [(R)-32] by Reduction with Yeast
To a solution of sucrose (100 g) and diammonium phosphate (1.50
g) in H2O (500 mL) was added dry yeast Saccharomyces cerevisiae
(15 g) at 32 °C, the mixture stirred for 5 min, and left for another 25
min. A solution of 5 (0.65 g, 4 mmol) in EtOH (3 mL) was added,
the mixture stirred for 5 min, and left at 28–30 °C for 18 h. MeOH
(500 mL) was added and filtered. MeOH was removed under re-
duced pressure, NaCl (100 g) was added, and the solution was ex-
tracted with EtOAc (4 × 50 mL), and the combined organic
solutions were dried (MgSO4). The solvents were removed under
reduced pressure and the product was isolated by flash chromatog-
raphy on silica gel (CH2Cl2–MeOH, 95:5); yield: 0.43 g (77%); bp
13C NMR (75 MHz, CDCl3): d = 61.90 (CH3), 71.65 (CH), 126.36
(2 CHarom), 128.25 (CHarom), 128.74 (2 CHarom), 139.65 (Carom),
150.21 (CH).
Anal. Calcd for C9H11NO2: C, 65.44; H, 6.71; N, 8.48. Found: C,
65.50; H, 6.73; N, 8.44.
27
104–106 °C/1.00 mmHg; mp 62–64 °C (Lit.44 mp 64 °C); [a]D
–69 (c 1.46, CHCl3) {Lit.45 [a]D20 –64 (c 1.0, CHCl3)}.
(S)-2-Amino-1-phenylethanol (S)-28 by Reduction of (S)-26
To a solution of LiAlH4 (0.034 g, 0.9 mmol) in Et2O (1 mL) was
added dropwise a solution of (S)-26 (0.049 g, 0.3 mmol) in Et2O (1
mL) and the mixture was stirred at r.t. for 16 h. Aq 10% NaOH (0.05
GC: tR = 36.79 (S), tR = 37.86 (R), T = 130 °C, f = 35 mL/min) re-
vealed 93% ee of R-enantiomer.
Synthesis 2011, No. 2, 316–324 © Thieme Stuttgart · New York

PAPER
Asymmetric Reduction of a-Keto Aldoxime O-Ethers
323
1H NMR (300 MHz, CDCl3): d = 3.68 (dd, J = 11.4, 8.1 Hz, 1 H
part of ABX system), 3.78 (dd, J = 11.4, 3.6 Hz, 1 H, part of ABX
system), 3.75 (s, 2 H, OH, D2O exchangeable), 4.84 (dd, J = 8.1, 3.6
Hz, 1 H, part of ABX system), 7.28–7.40 (m, 5 H, CHarom).
13C NMR (75 MHz, CDCl3): d = 67.93 (CH2), 74.67 (CH), 126.04
(2 CHarom), 127.98 (CHarom), 128.50 (2 CHAr), 140.27 (Carom).
(1R,2R,6S,7S)-(–)-1,10,10-Trimethyl-3-oxa-5-azatricyc-
lo[5.2.1.02,6]decan-4-one (25)
To a mixture of anhyd K2CO3 (0.40 g, 2.9 mmol) in diethyl carbon-
ate (6.50 g, 55 mmol) was added crude 19 (4.22 g, 25 mmol) and the
mixture was stirred at 130 °C for 2.5 h removing the emerging
EtOH. The mixture was cooled to r.t., CH2Cl2 (80 mL) was added
and the remaining K2CO3 was filtered off. The organic layer was
washed with sat. aq NaHCO3 (20 mL) and dried (MgSO4). CH2Cl2
was removed, Et2O (150 mL) was added, the mixture stirred at 0 °C
for 1 h, and left at –20 °C for 48 h. The white precipitate formed was
collected by filtration and crystallized from n-hexane–EtOAc (1:2)
to afford 25 as a crystalline solid; yield: 2.48 g (51%); mp 165–
(1R,3S,4R)-(+)-3-Amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-
one Hydrochloride (22)
(E)-(1R)-(+)-3-Hydroxyimino-1,7,7-trimethylbicyclo[2.2.1]heptan-
2-one [(E)-20;23 5.44 g, 30 mmol] was dispersed in 30% aq NaOH
(25 mL) and Zn powder (10 mm, 5.89 g, 90 mmol) was added. After
completion of the reaction (1 min), Et2O (70 mL) was added and the
mixture was stirred for 1 min. The organic layer was separated and
the residue was extracted with Et2O (2 × 30 mL). The combined
Et2O extracts were washed with H2O (20 mL), brine (20 mL), and
dried (MgSO4) for 2 min. Drying agent was filtered off and a solu-
tion of 2.76 M HCl in Et2O (11 mL) was added. The white precipi-
tate was collected by filtration, washed with Et2O (2 × 30 mL), and
dried under reduced pressure; yield: 4.59 g (75%); mp 241–242 °C
26
166 °C (Lit.32 mp 167.5–168.5 °C); [a]D +86.8 (c 2.19, CHCl3)
{[a]D26 +81.8 (c 2.21, CHCl3)}.
1H NMR (200 MHz, CDCl3): d = 0.91 (s, 3 H, CH3), 0.96 (s, 6 H, 2
CH3), 1.22–1.41 (m, 1 H, CH2), 1.49–1.81 (m, 3 H, 2 CH2), 1.84–
1.92 (m, 1 H, CH), 4.14 (dd, J = 10.0, 4.6 Hz, 1 H, CH), 4.60 (dd,
J = 10.0, 1.6 Hz, 1 H, CH), 5.72 (br s, 1 H, NH).
13C NMR (50 MHz, CDCl3): d = (CH3), 17.95 (CH3), 19.84 (CH2),
20.11 (CH3), 26.48 (CH2), 48.55 (C), 48.57 (CH), 49.17 (C), 54.81
(CH), 85.81 (CH), 160.71 (C=O).
(CH2Cl2–EtOAc) (Lit.46 mp 241–242 °C); [a]D +20.9 (c 1.26,
26
MeOH) {Lit.46 [a]D25 +21 (c 1.28, MeOH)}.
1H NMR (300 MHz, D2O): d = 0.81 (s, 3 H, CH3), 0.84 (s, 3 H,
CH3), 0.93 (s, 3 H, CH3), 1.23–1.36 (m, 2 H, CH2), 1.78–1.92 (m, 2
H, CH2), 2.36 (t, J = 4.5 Hz, 1 H, CH), 3.93 (dd, J = 5.1, 0.9 Hz, 1
H, CH).
13C NMR (75 MHz, CDCl3): d = 8.95 (CH3), 18.34 (CH3), 19.20
(CH2), 19.60 (CH3), 32.08 (CH2), 45.21 (C), 46.77 (CH), 57.57
(CH), 59.79 (C), 217.70 (C=O).
(1R,2R,3S,4S)-(+)-3-Amino-1,7,7-trimethylbicyclo[2.2.1]hep-
tan-2-ol (19) by Hydrolysis of 25
A mixture of 25 (1.95 g, 10 mmol), NaOH (1.60 g, 40 mmol), EtOH
(25 mL), and H2O (12 mL) was refluxed for 6 h. The EtOH was re-
moved, the residue extracted with Et2O (3 × 20 mL), and the com-
bined Et2O layers were dried (MgSO4). The Et2O was removed
affording pure 21 as a white crystalline solid; yield: 1.66 g (98%);
23
mp 158–159 °C (Lit.32 mp 163 °C); [a]D +44.3 (c 1.00, MeOH)
{Lit.32 [a]D25 +36.0 (c 1.04, MeOH)}.
(1R,2R,3S,4S)-(+)-3-Amino-1,7,7-trimethylbicyclo[2.2.1]hep-
tan-2-ol (19)
1H NMR (300 MHz, CDCl3): d = 0.86 (s, 3 H, CH3), 0.89 (s, 6 H, 2
CH3), 1.07–1.17 (m, 1 H, CH2), 1.33–1.52 (m, 2 H, CH2), 1.70 (t,
J = 4.2 Hz, 1 H, CH), 1.71–1.82 (m, 1 H, CH2), 2.18 (br s, 3 H, OH,
NH2), 3.49 (dd, J = 8.7, 4.2 Hz, 1 H, CH), 3.35 (dd, J = 8.7, 1.5 Hz,
1 H, CH).
13C NMR (75 MHz, CDCl3): d = (CH3), 18.29 (CH3), 18.39 (CH2),
19.98 (CH3), 25.47 (CH2), 45.21 (C), 48.48 (CH), 49.42 (C), 50.70
(CH), 72.87 (CH).
To a solution of 22 (4.07 g, 20 mmol) in H2O (20 mL) cooled to 0 °C
was added aq 10% NaOH until pH 10, followed by NaCl (8 g) and
the mixture was stirred for 1 min. The organic layer was separated
and the residue was extracted with Et2O (20 mL). The combined
Et2O extracts were dried (MgSO4) for 3 min, the drying agent was
filtered off, and Et2O was removed to afford 21 as a white crystal-
line solid (3.07 g, 92%), which was immediately dissolved in anhyd
Et2O (50 mL) and added dropwise at 0 °C to a suspension of LiAlH4
(1.90 g, 50 mmol) in anhyd Et2O (100 mL). The mixture was stirred
at r.t. for 18 h, then cooled to 0 °C and aq 10% NaOH (2 mL) was
slowly added. The mixture was stirred at r.t. for another 4 h, the pre-
cipitate was collected by filtration. The precipitate was dissolved in
Et2O by washing with Et2O (2 × 20 mL) and the combined Et2O lay-
ers were dried (MgSO4). Et2O was removed to afford the desired
amino alcohol (2.47 g, 73%) as a mixture of stereoisomers 19 and
23 (95:5) and traces of 24. The crude mixture of isomers (2.00 g,
11.8 mmol) was refluxed in aq 6 M HCl (100 mL) for 18 h. The so-
lution was cooled to 0 °C, and washed with CH2Cl2 (2 × 20 mL) and
Et2O (35 mL). The aqueous layer was basified with aq 10% NaOH
to pH 12 and extracted with Et2O (2 × 30 mL). The combined or-
ganic extracts were washed with brine (20 mL) and dried (MgSO4).
The solvent was removed affording crude 19 as a white crystalline
solid; yield: 1.78 g (89%). The product was purified by sublimation;
Anal. Calcd for C10H19NO: C, 70.96; H, 11.31; N, 8.28. Found: C,
70.92; H, 11.29; N, 8.30.
Acknowledgment
Financial support from the Committee for Scientific Research,
Warsaw, grant PBZ-KBN-126/T09/2004, is acknowledged. The
research was co-financed by the European Social Fund, National
Budget and the Budget of Kujawsko-Pomorskie Voievodship, as a
part of Human Capital Priority VIII Operational Programme, action
8.2 sub 8.2.2 ‘Regional Innovation Strategies’, which is a part of the
System Project of Kujawsko-Pomorskie Voievodship ‘Step in the
future - grants for doctoral students II edition’.
yield: 1.21 g (60%); mp 161.5–163 °C (Lit.32 mp 163 °C); [a]D
25
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1H NMR (300 MHz, CDCl3): d = 0.86 (s, 3 H, CH3), 0.89 (s, 6 H, 2
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Synthesis 2011, No. 2, 316–324 © Thieme Stuttgart · New York

324
M. J. Bosiak, M. M. Pakulski
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