Introduction of cis-vicinal amino alcohol functionality into the cyclohexane ring employing (1S,2S)-2-amino-1,2-diphenylethanol: Synthesis of enantiopure aminocyclohexitols

Article abstract of DOI:10.1016/S0957-4166(01)00484-0

Pd(0)-catalyzed allylic amination of 3-bromocyclohexene with (1S,2S)-2-amino-1,2-diphenylethanol and subsequent intramolecular oxyselenenylation of the resulting allylic amine 6 followed by oxidation-elimination afforded the valuable cis-fused bicyclic olefin 10. Oxyselenenylation of cyclohexene with (1S,2S)-N-(benzyloxycarbonyl)-2-amino-1,2-diphenylethanol and subsequent oxidation-elimination gave the allylic ether 18. Intramolecular aminoselenenylation of 18 followed by oxidation-elimination provided the cis-fused bicyclic olefin 21, which is the regioisomer of 10. Further stereoselective transformation of 10 afforded enantiopure aminocyclohexitols.

Full text of DOI:10.1016/S0957-4166(01)00484-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2649–2655
Introduction of cis-vicinal amino alcohol functionality into the
cyclohexane ring employing (1S,2S)-2-amino-1,2-diphenylethanol:
synthesis of enantiopure aminocyclohexitols
Kwan Soo Kim,* Sung Ook Choi, Jong Myun Park, Yong Joo Lee and Jin Hwan Kim
Department of Chemistry, Yonsei University, Seoul 120-749, South Korea
Received 23 August 2001; accepted 29 October 2001
Abstract—Pd(0)-catalyzed allylic amination of 3-bromocyclohexene with (1S,2S)-2-amino-1,2-diphenylethanol and subsequent
intramolecular oxyselenenylation of the resulting allylic amine 6 followed by oxidation–elimination afforded the valuable cis-fused
bicyclic olefin 10. Oxyselenenylation of cyclohexene with (1S,2S)-N-(benzyloxycarbonyl)-2-amino-1,2-diphenylethanol and subse-
quent oxidation–elimination gave the allylic ether 18. Intramolecular aminoselenenylation of 18 followed by oxidation–elimination
provided the cis-fused bicyclic olefin 21, which is the regioisomer of 10. Further stereoselective transformation of 10 afforded
enantiopure aminocyclohexitols. © 2001 Published by Elsevier Science Ltd.
1. Introduction
In fact, valienamine 1, validamine 2, and valiolamine 3
all have the cis vicinal amino alcohol functionality and
many aminoglycoside antibiotics6 also contain the
aminocyclo-hexitol having the cis-vicinal amino alcohol
functionality. Although several methods are available
for the synthesis of aminocyclohexitols,7 there still
remains a need for a new methodology starting from
simple starting materials because the aminocyclitols are
structurally very diverse and the new methodology
could be applied for the synthesis of other highly
functionalized cyclic compounds. Herein, we report
new methods for the synthesis of aminocyclohexitols by
introducing the cis-amino alcohol functionality into the
cyclohexane ring employing (1S,2S)-2-amino-1,2-
diphenyl-ethanol not only as the nitrogen and oxygen
atom source but also as the source of chirality.8
Various aminocyclohexitols are found to be potent
glycosidase inhibitors and also occur as the integral
part of important antibiotics, glycosidase inhibitors,
and other natural products. For example, the aminocy-
clohexitol valienamine 1, which itself is an a-glucosi-
dase inhibitor,1 is also a structural component of both
the antibiotic validmycins2 and the glycosidase inhibitor
arcabose.3 Aminocyclohexitols validamine 2 and valio-
lamine 3 were isolated from the same microorganism as
that for valienamine and were also found to be glycosi-
dase inhibitors.4 A characteristic functionality identified
in these aminocyclohexitols is the vicinal amino alcohol
moiety. Introduction of the trans-vicinal amino alcohol
functionality is relatively straightforward while intro-
ducing the cis functionality is considered to be more
complicated.5
2. Results and discussion
HO
OH
OH
HO
HO
HO
HO
HO
HO
Enantiomerically pure (1S,2S)-2-amino-1,2-diphenyl-
ethanol 49 was readily prepared by a two-step sequence:
(i) Sharpless asymmetric aminohydroxylation of trans-
stilbene using sodium benzyl N-chlorocarbamate,
K2OsO2(OH)4, and (DHQ)2PHAL to afford (1S,2S)-N-
(benzyloxycarbonyl)-2-amino-1,2-diphenylethanol 5;10
(ii) selective cleavage of the Cbz group of 5 by catalytic
hydrogenolysis in the presence of 2,2%-dipyridyl11 to give
the desired compound 4 in 93% yield. Displacement of
NH2
HO
NH2
NH2
OH
OH
OH
3
1
2
* Corresponding author. Tel.: +82-2-2123-2640; fax: +82-2-364-7050;
e-mail: kwan@yonsei.ac.kr
0957-4166/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0957-4166(01)00484-0

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K. S. Kim et al. / Tetrahedron: Asymmetry 12 (2001) 2649–2655
H2N
Ph
OH
Ph
Pd(PPh3)4, PPh3, Et3N
NH OH
Ph Ph
NH OH
Ph Ph
+
+
:
THF, 45~50 oC
(95%)
Br
4
6
7
1
1
PhSeOTf
THF/CH2Cl2, -78 oC
SePh
SePh
O
Ph
Ph
O
Ph
Ph
O
Ph
Ph
CbzCl, NaH
NaIO4, NaHCO3
+
7
THF
(98%)
MeOH/H2O
65~70 oC
(91%)
N
H
N
Cbz
N
Cbz
10
8 (70%)
9
Scheme 1.
the bromide in 3-bromohexene by the amino group of 4
was accomplished by Pd(0)-catalyzed allylic substitu-
tion as shown in Scheme 1. Thus, to a THF solution of
3-bromocyclohexene, Pd(PPh3)4 (0.05 equiv.), PPh3 (0.2
equiv.), and triethylamine (3 equiv.), a THF solution of
the compound 4 was slowly added at 45–50°C. The
reaction mixture was stirred for a further 5 h at the
same temperature to afford an inseparable 1:1 mixture
of the diastereomeric allylic amines 6 and 7 in 95%
yield. A mixture of compounds 6 and 7 was treated
with PhSeOTf at −78°C to give only the cis-fused
bicyclic phenylselenenyl oxazine 8 in 70% yield along
with the unreacted 7. After protection of the secondary
amine 8 with Cbz group, the resultant selenide 9 was
treated with NaIO4 in the presence of NaHCO3 to give
a valuable intermediate, the bicyclic olefin 10 in high
yield.
To achieve the trans-1,2-diaxial opening of the epi-
selenonium ion, the hydroxyl group should attack the
C(3) position in the conformation A. It is, however,
supposed that such a cyclization leading to the seven-
membered ring would be unfavorable. When commer-
cially available (1S,2R)-2-amino-1,2-diphenylethanol
was used instead of (1S,2S)-2-amino-1,2-diphenyl-
ethanol, the Pd(0)-catalyzed allylic amination
of 3-bromocyclohexene proceeded without problems
but the subsequent intramolecular oxyselenenylation
did not occur at all. The chair conformation of the
bicyclic compound 8 would have both phenyl groups
equatorial, whereas in the corresponding bicyclic com-
pounds obtained employing (1S,2R)-2-amino-1,2-
diphenylethanol, one of the phenyl groups in the chair
form would be in the axial position. Therefore, the
energy of the transition state of the intramolecular
oxyselenenylation might be high enough to prevent the
cyclization. The absolute configuration of the com-
pound 10 was assigned by its conversion into N-
(p - toluenesulfonyl) - (1R,2S) - 2 - aminocyclohexanol, of
which enantiomer is known,13 by a three-step sequence:
(i) hydrogenation of the double bond and cleavage of
the Cbz group in the compound 10 with H2 and
Pd(OH)2, (ii) N-tosylation of the resulting amine with
p-TsCl and triethylamine, and (iii) cleavage of the
oxazine ring by hydrogenolysis using Pd/C in the pres-
ence of a small amount of c-HCl.
Attempted direct conversion of the Cbz-protected
derivative of the amine 6 into the bicyclic compound 10
by the Pd(II)-mediated oxidative cyclization was not
successful.12 To understand the unreactivity of 7 to
cyclization under oxyselenenylation conditions, we con-
sidered the transition state model for the intramolecular
cyclization. The episelenonium ion, which would be the
first intermediate for the cyclization of 7, could possess
either the conformation A or B as shown in Fig. 1. The
conformation A would be more favorable over the
conformation B in which an unfavorable non-bonding
interaction would exist between one of the phenyl
groups and the pseudoaxial hydrogen at the C(6)
position.
The olefin 10 is an ideal intermediate for further
stereoselective transformation because the bicyclic ring
is cis-fused and two bulky phenyl groups are located at
the equatorial position. In order to demonstrate the
usefulness of the present method for the synthesis of
aminocyclitols, we have conducted several more com-
pletely stereoselective conversions with 10 as shown in
Scheme 2. Indeed, the reaction of 10 with dimethyl-
dioxirane (DMD) afforded exclusively the epoxide 11,
in which the epoxide ring is trans to the oxazine ring, in
88% yield. Diaxial ring opening of the epoxide 11 with
PhSeNa, obtained from diphenyldiselenide (DPDS)
with NaBH4, gave exclusively the hydroxyselenide 12,
whereupon oxidation with NaIO4 followed by elimina-
Ph
Ph
Se
+
Se
+
1
2
1
3
3
NH2
HN
6
H
Ph
Ph
H
H
OH
OH
Ph
Ph
H
H
B
A
Figure 1. Two half-chair conformation of the episelenonium
ion generated from olefin 7.

K. S. Kim et al. / Tetrahedron: Asymmetry 12 (2001) 2649–2655
2651
OH
OH
O
O
Ph
Ph
O
Ph
Ph
PhSe
O
Ph
Ph
DPDS, NaBH4
NaIO4, NaHCO3
DMD
10
acetone
0 oC
EtOH/THF
(95%)
MeOH/H2O
65~70 oC
(83%)
N
Cbz
11
N
Cbz
N
Cbz
12
13
(88%)
NaH
MeNCS
MeI, THF
SCH3
O
H3CN
O
O
H3CN
O
Ph
Ph
O
Ph
Ph
I(sym-collidine)2ClO4
CHCl3
(66% in two steps)
N
Cbz
I
N
Cbz
15
14
Scheme 2.
subsequent elimination of the selenoxide gave the
bicyclic olefin 21, which is the regioisomer of 10.
Attempted direct conversion of 18 to 21 mediated by
the intramolecular catalytic or stoichiometric aminopal-
ladation of 18 was not successful. The unreactivity of
19 in the intramolecular aminoselenenylation reaction
could be explained in the same way as for compound 7.
tion provided the allylic alcohol 13 in high yield. To
generate another vicinal cis-aminohydroxyl group, the
compound 13 was treated with methyl isothiocyanate
and methyl iodide in the presence of sodium hydride to
yield 14. Without purification, the compound 14 was
cyclized upon treatment with I(sym-collidine)2ClO4 to
afford the compound 15, which contains two vicinal
cis-amino alcohol functionalities, in 66% yield in two
steps.
3. Conclusion
We could also prepare the regioisomer of the bicyclic
olefin 10 starting from cyclohexene and (1S,2S)-N-
(benzyloxycarbonyl)-2-amino-1,2-diphenylethanol 5. To
a solution of the compound 5, N-phenyselenophthal-
imide (N-PSP), and cyclohexene in methylene chloride
was added slowly BF3·OEt2 (0.1 equiv.) at 0°C. The
reaction mixture was stirred for a further 2 h at room
temperature to afford the oxyselenide 16 and its
diastereomer 17 in about 1:1 ratio in 97% yield as
shown in Scheme 3. Oxidation and elimination of the
mixture of 16 and 17 followed by the intramolecular
aminoselenenylation of the resulting mixture of olefins
18 and 19 provided the bicyclic selenide 20 along with
the unreacted 19. Oxidation of the selenide 20 and the
We have developed two new methods for the construc-
tion of the cis-amino alcohol functionality on the cyclo-
hexane ring. Our first method consists of the
Pd(0)-catalyzed allylic amination of 3-bromocyclohex-
ene with (1S,2S)-2-amino-1,2-diphenylethanol and the
subsequent intramolecular oxyselenenylation of the
resulting allylic amine. We have also shown as the
second method that the oxyselenenylation of cyclohex-
ene with (1S,2S)-N-Cbz-2-amino-1,2-diphenylethanol
and the subsequent intramolecular aminoselenenylation
provided the cis-amino alcohol functionality. The
present methods could be used not only for the synthe-
sis of enantiopure aminocyclohexitols but may also be
SePh
SePh
HO
Ph
NHCbz
Ph
BF OEt2
NPSP,
3
O
NHCbz
Ph
+
O
NHCbz
Ph
+
:
CH2Cl2
(97%)
Ph
16
Ph
17
5
1
1
NaIO4, NaHCO3
MeOH/H2O, 75~80 oC
(93%)
SePh
Cbz
N
Cbz
N
Ph
Ph
Ph
Ph
BF OEt2
NPSP,
3
NaIO4, NaHCO3
O
NHCbz
Ph
O
NHCbz
Ph
+
CH2Cl2
MeOH/H2O
75~80 oC
(91%)
O
O
Ph
18
Ph
20 (91%) + 19
21
1
: 1
19
Scheme 3.

2652
K. S. Kim et al. / Tetrahedron: Asymmetry 12 (2001) 2649–2655
applied in the preparation of other important natural
products.
solution of the mixture of compounds 6 and 7 (5.29
g, 18.04 mmol) in CH2Cl2 (10 mL) at −78°C. After
stirring for 3 h at −78°C, the reaction mixture was
diluted with CH2Cl2 and neutralized with saturated
aqueous sodium bicarbonate solution. The organic
phase was washed with brine, dried, and evaporated.
The residue was purified by flash chromatography
(hexane/EtOAc, 6:1) to give the title compound 8 as
a yellow oil (2.83 g, 70%): Rf=0.29 (hexane/EtOAc,
4. Experimental
4.1. General
All reactions were conducted under a positive pres-
sure of dry argon with dry, freshly distilled solvents
unless otherwise noted. All reagents were purchased
from commercial suppliers and used without further
purification unless otherwise noted. Flash column
chromatography was performed employing 230–400
mesh silica gel. Thin-layer chromatography was per-
formed using silica gel 60 F254 precoated plates (0.25
mm thickness) with a fluorescent indicator. Melting
points are uncorrected. IR spectra were recorded on a
Nicolet Impact 400 FT-IR spectrometer. NMR spec-
tra were recorded on a Bruker 250, Varian 300, or
Bruker 500 NMR spectrometer. Chemical shifts are
reported in parts per million (ppm) downfield from
tetramethylsilane (TMS) unless otherwise noted. Opti-
cal rotations were measured with a Rudolph Autopol
III automatic polarimeter.
1
6:1); [h]D=−32.6 (c=0.54, CHCl3); H NMR (CDCl3,
250 MHz): l 1.52–1.57 (m, 1H), 1.68–1.90 (m, 4H),
2.17–2.27 (m, 1H), 2.47 (ddd, J=24.4, 12.2, 4.6 Hz,
1H), 3.46–3.50 (m, 1H), 3.77 (brs, 1H), 4.08 and 4.37
(ABq, J=9.2 Hz, 2H), 4.24 (brs, 1H), 6.97–7.56 (m,
15H); 13C NMR (CDCl3, 63 MHz): l 21.7, 26.4, 26.6,
46.3, 50.0, 60.5, 77.7, 86.1, 127.4, 127.7, 127.8, 127.9,
128.1, 128.5, 129.3, 130.1, 133.6, 139.4, 140.2; IR
(CHCl3 film) 3311 cm−1. Anal. calcd for C26H27NOSe:
C, 69.64; H, 6.07; N, 3.12. Found: C, 69.64; H, 6.04;
N, 3.18%.
4.4. (2S,3S,8S,9S,10S)-4-Benzyloxycarbonyl-2,3-di-
phenyl-8-phenylselenenyloctahydrobenzo-1,4-oxazine 9
A mixture of compound 8 (2.59 g, 5.79 mmol) and
NaH (463 mg, 11.57 mmol) in THF (35 mL) was
stirred at 0°C for 30 min. Benzyl chloroformate (1.30
mL, 8.68 mmol) was slowly added to this solution at
room temperature. The reaction mixture stirred for a
further 1 h and diluted with CH2Cl2. The organic
layer was washed with brine, dried, and evaporated.
The residue was purified by flash chromatography
(hexane/EtOAc, 8:1) to give the title compound 9 as
a yellow oil (3.30 g, 98%): Rf=0.38 (hexane/EtOAc,
4.2. (1S,2S,1%S)- and (1S,2S,1%R)-2-(Cyclohex-2%-enyl-
amino)-1,2-diphenylethanol 6 and 7
To a solution of 3-bromocyclohexene (1.46 mL, 11.43
mmol), Pd(PPh3)4 (661 mg, 0.57 mmol), PPh3 (600
mg, 2.29 mmol) and triethylamine (4.78 mL, 34.30
mmol) in THF (30 mL) was added slowly a solution
of (1S,2S)-2-amino-1,2-diphenylethanol
4 (2.93 g,
1
13.72 mmol) in THF (10 mL) at 45–50°C. After stir-
ring for 5 h at the same temperature, the reaction
mixture was diluted with ethyl acetate and neutralized
with saturated aqueous sodium bicarbonate solution.
The organic phase was washed with brine, dried, and
evaporated. The residue was purified by flash chro-
matography (hexane/EtOAc, 2:1) to give a mixture of
6 and 7 as a yellow oil (3.19 g, 95%): Rf=0.30 (hex-
ane/EtOAc, 2:2); 1H NMR (CDCl3, 250 MHz): l
1.35–1.44 (m, 2H), 1.45–1.58 (m, 1H), 1.69–1.90 (m,
3H), 3.05–3.11 (m, 1H), 3.05 (brs, 1H), 3.69 (dd, J=
8.5, 4.9 Hz, 1H), 4.49 (dd, J=8.5, 4.9 Hz, 1H), 5.40–
5.80 (m, 2H), 6.99–7.25 (m, 10H); 13C NMR (CDCl3,
125 MHz): l 19.5, 20.2, 25.3, 29.1, 31.0, 50.3, 51.7,
68.2, 68.4, 77.7, 77.9, 126.9, 127.4, 127.8, 127.9,
128.4, 129.2, 129.3, 129.7, 129.9, 140.7, 141.2, 141.4,
141.5; IR (CHCl3 film) 3378 cm−1. Anal. calcd for
C20H23NO: C, 81.87; H, 7.90; N, 4.77. Found: C,
81.86; H, 7.94; N, 4.84%.
6:1); [h]D=−39.6 (c=0.56, CHCl3); H NMR (CDCl3,
500 MHz): l 1.71–1.75 (m, 3H), 1.86–1.89 (m, 1H),
1.99–2.07 (m, 1H), 2.17–2.24 (m, 1H), 3.77–3.78 (m,
1H), 4.19 (t, J=2.5 Hz, 1H), 4.34 and 4.35 (ABq,
J=9.8 Hz, 2H), 4.60–4.63 (m, 1H), 4.88 and 4.92
(ABq, J=12.0 Hz, 2H), 6.84–7.57 (m, 15H); 13C
NMR (CDCl3, 125 MHz): l 21.4, 25.0, 26.5, 45.7,
51.5, 61.5, 67.3, 77.3, 85.8, 126.9, 127.3, 127.7, 127.9,
128.2, 128.4, 129.4, 129.9, 133.8, 136.2, 138.7, 140.9,
157.3; IR (CHCl3 film) 1698 cm−1. Anal. calcd for
C34H33NO3Se: C, 70.09; H, 5.71; N, 2.40. Found: C,
70.08; H, 5.85; N, 2.44%.
4.5. (2S,3S,9R,10S)-4-Benzyloxycarbonyl-2,3-diphenyl-
2,3;5,6;9,10-hexahydrobenzo-1,4-oxazine 10
A solution of compound 9 (2.27 g, 3.89 mmol) and
NaIO4 (1.98 g, 9.34 mmol) in methanol (50 mL) and
water (8 mL) in the presence of NaHCO3 (392 mg.
4.67 mmol) was stirred for 10 min at room tempera-
ture and for 48 h at 65–70°C. After removal of some
methanol by evaporation, the concentrated solution
was diluted with CH2Cl2. The organic layer was
washed with brine, dried, and evaporated. The residue
was purified by flash chromatography (hexane/
EtOAc, 6:1) to give the title compound 10 as a white
solid (1.51 g, 91%): mp 121–123°C; Rf=0.31 (hexane/
4.3. (2S,3S,8S,9S,10S)-2,3-Diphenyl-8-phenylselenenyl-
octahydrobenzo-1,4-oxazine 8
To a stirred solution of PhSeBr (5.53 g, 23.45 mmol)
,
in CH2Cl2 (20 mL) in the presence of 4 A molecular
sieves was added a THF (15 mL) solution of AgOTf
(7.412 g, 28.86 mmol) at −78°C and the reaction mix-
ture stirred for further 20 min at the same tempera-
ture. To this reaction mixture was slowly added a
1
EtOAc, 6:1); [h]D=−16.9 (c=0.52, CHCl3); H NMR
(500 MHz, CDCl3): l 1.76 (brs, 1H), 2.20–2.30 (m,

K. S. Kim et al. / Tetrahedron: Asymmetry 12 (2001) 2649–2655
2653
3H), 4.21 (m, 1H), 4.30 (m, 1H), 4.40 and 4.43 (ABq,
J=9.7 Hz, 2H), 4.88 (m, 2H), 5.82–5.85 (m, 1H),
6.01–6.03 (m, 1H), 6.87–7.25 (m, 15H); 13C NMR (125
MHz, CDCl3): l 22.19, 26.10, 53.10, 61.82, 67.34,
71.09, 85.86, 124.70, 126.82, 127.11, 128.05, 128.21,
128.39, 133.31, 136.16, 138.72, 141.20, 157.20; IR
(CHCl3 film) 1698 cm−1. Anal. calcd for C28H27NO3: C,
79.03; H, 6.40; N, 3.29. Found: C, 79.04; H, 6.45; N,
3.31%.
4.8. (2S,3S,8S,9S,10S)-4-Benzyloxycarbonyl-8-hydroxy-
2,3-diphenyl-2,3;5,10;8,9-hexahydrobenzo-1,4-oxazine 13
Compound 12 (970 mg, 1.62 mmol) was subjected to
the same reaction conditions as that for the preparation
of 10 from 9. The reaction mixture was purified by flash
chromatography (hexane/EtOAc, 5:2) to afford the title
compound 13 as an oil (594 mg, 83%): Rf=0.15 (hex-
ane/EtOAc, 3:1); [h]D=−3.9 (c=0.54, CHCl3); 1H
NMR (CDCl3, 500 MHz): l 1.67 (brs, 1H), 2.33–2.37
(m, 1H), 2.53–2.58 (m, 1H), 4.17 (brs, 1H), 4.24 (brs,
1H), 4.39 and 4.46 (ABq, J=9.7 Hz, 2H), 4.47–4.51 (m,
1H) 4.87 and 4.93 (ABq, J=12.2 Hz, 2H), 5.82–5.84
(m, 1H), 5.94–5.96 (m, 1H), 6.87–7.26 (m, 15H); 13C
NMR (CDCl3, 125 MHz): l 24.5, 48.0, 61.6, 67.5, 68.1,
77.1, 86.3, 125.4, 127.0, 127.4, 128.0, 128.1, 128.4,
129.3, 135.9, 138.4, 140.6, 157.3; IR (CHCl3 film) 1694,
3420 cm−1. Anal. calcd for C28H27NO4: C, 76.17; H,
6.16; N, 3.17. Found: C, 76.19; H, 6.16; N, 3.14%.
4.6. (5S,6S,8R,9S,10S,11S)-4-Benzyloxycarbonyl-5,6-di-
phenyloctahydro-1,7-dioxa-4-azacyclopropa[a]naphthal-
ene 11
A solution of compound 10 (232 mg, 0.55 mmol) and
dimethyldioxirane (2 equiv., ca. 0.05 M) in acetone (22
mL) was stirred at 0°C for 5 h. The reaction mixture
was evaporated to a quarter volume, diluted with meth-
ylene chloride, washed with brine. The organic phase
was dried and evaporated. The residue was purified by
flash chromatography (hexane/EtOAc, 5:1) to give the
title compound 11 as an oil (212 mg, 88%): Rf=0.17
4.9. (4R,7S,8S,10S,11R,12S,13S)-6-Benzyloxycarbonyl-
4-iodo-3-methyl-2-oxo-7,8-diphenyldecahydro-1,9-dioxa-
3,6-diazacyclopenta[a]naphthalene 15
1
(hexane/EtOAc, 6:1); [h]D=−14.4 (c=0.50, CHCl3); H
NMR (CDCl3, 500 MHz): l 1.39 (brs, 1H), 1.97–2.0
(m, 1H), 2.07–2.17 (m, 2H), 3.25 (brs, 1H), 3.34 (brs,
1H), 4.19–4.22 (m, 1H), 4.39 and 4.42 (ABq, J=9.78
Hz, 2H), 4.51 (m, 1H), 4.82–4.93 (m, 2H), 6.87–7.24 (m,
15H); 13C NMR (CDCl3, 125 MHz): l 20.4, 23.0, 41.3,
50.1, 52.2, 54.7, 61.4, 72.8, 86.3, 127.0, 127.1, 128.0,
128.1, 128.3, 128.4, 136.1, 138.3, 140.8, 157.1; IR
(CHCl3 film) 1694 cm−1. Anal. calcd for C28H27NO4: C,
76.17; H, 6.16; N, 3.17. Found: C, 76.23; H, 6.10; N,
3.14%.
A mixture of compound 13 (234 mg, 0.52 mmol) and
NaH (42 mg, 1.05 mmol) in THF (3 mL) was stirred at
0°C for 30 min and warmed to room temperature. A
THF (1 mL) solution of methyl isothiocyanate (57 mg,
0.79 mmol) was added to this solution and the reaction
mixture was stirred for
a
further
1
h. Then
iodomethane (98 mL, 1.57 mmol) was added and the
reaction mixture was stirred for further 30 min and
evaporated to give crude 14. A solution of the crude 14
and iodonium di-sym-collidine perchlorate (490 mg,
1.05 mmol) in CHCl3 (5 mL) was stirred at room
temperature for 20 h. The reaction mixture was diluted
with CHCl3 and washed with brine. The organic layer
was dried and evaporated. The residue was purified by
flash chromatography (hexane/EtOAc, 5:2) to afford
the title compound 15 as an oil (215 mg, 66%): Rf=0.21
4.7. (2S,3S,7R,8R,9S,10S)-4-Benzyloxycarbonyl-8-
hydroxy-2,3-diphenyl-7-phenylselenenyloctahydrobenzo-
1,4-oxazine 12
A solution of diphenyldiselenide (922 mg, 2.95 mmol)
and NaBH4 (223 mg, 5.91 mmol) in ethanol (20 mL)
was stirred at room temperature for 20 min. To this
solution was slowly added a THF (10 mL) solution of
compound 11 (652 mg, 1.48 mmol). The reaction mix-
ture was stirred for 30 min, diluted with water, evapo-
rated to a half volume, and diluted again with CH2Cl2.
The organic layer was washed with brine, dried, and
evaporated. The residue was purified by flash chro-
matography (hexane/EtOAc, 5:2) to give the title com-
pound 12 as an oil (840 mg, 95%): Rf=0.23
1
(hexane/EtOAc, 3:1); [h]D=−3.3 (c=0.51, CHCl3); H
NMR (CDCl3, 500 MHz): l 2.25 (d, J=12.2 Hz, 1H),
2.70–2.78 (m, 1H), 3.22 (s, 3H), 3.98–4.07 (m, 2H),
4.34–4.42 (m, 4H), 4.49 (brs, 1H), 4.83 and 4.97 (ABq,
J=12.0 Hz, 2H), 6.8–7.26 (m, 15H); 13C NMR (CDCl3,
125 MHz): l 21.7, 32.3, 35.0, 51.8, 61.5, 63.9, 67.9,
72.2, 77.5, 86.4, 127.1, 127.3, 127.9, 128.2, 128.2, 128.5,
128.6, 128.8, 135.5, 137.5, 139.9, 156.8; IR (CHCl3 film)
1689, 1766 cm−1. Anal. calcd for C30H29IN2O5: C,
57.70; H, 4.68; N, 4.49. Found: C, 57.74; H, 4.75; N,
4.45%.
1
(hexane/EtOAc, 3:1); [h]D=−40.9 (c=0.55, CHCl3); H
NMR (CDCl3, 500 MHz): l 1.61–1.63 (m, 1H), 1.90–
1.93 (m, 1H), 2.12 (brs, 1H), 2.31–2.36 (m, 1H), 2.62
(ddd, J=24.75, 12.27, 2.28 Hz, 1H), 3.37 (brs, 1H),
4.11 (brs, 1H), 4.34 and 4.37 (ABq, J=9.8 Hz, 2H),
4.44–4.46 (m, 1H), 4.52 (brs, 1H), 4.83–4.88 (m, 2H),
6.86–7.57 (m, 20H); 13C NMR (CDCl3, 125 MHz): l
20.7, 25.6, 45.1, 51.0, 62.0, 67.4, 72.5, 77.2, 86.4, 126.9,
127.4, 127.9, 127.9, 128.0, 128.2, 128.3, 128.4, 129.2,
132.3, 133.8, 136.0, 138.3, 140.6, 157.3; IR (CHCl3 film)
1690, 3436 cm−1. Anal. calcd for C34H33NO4Se: C,
68.22; H, 5.56; N, 2.34. Found: C, 68.27; H, 5.54; N,
2.34%.
4.10. (1S,2S,1%S,2%S)-2-Amino-N-benzyloxycarbonyl-O-
(2%-phenylselenenylcyclohexyl)-1,2-diphenylethanol 16
and 17
To a solution of compound 5 (4 g, 11.6 mmol), cyclo-
hexene (2.8 mL, 27.9 mmol), and NPSP (3.88 g, 12.8
mmol) in CH2Cl2 (50 mL) was added slowly BF3·OEt2
(144 mL, 1.1 mmol) at 0°C. The reaction mixture was
stirred at room temperature for 2 h, diluted with
CH2Cl2, neutralized with saturated aqueous sodium
bicarbonate solution. The organic layer was washed

2654
K. S. Kim et al. / Tetrahedron: Asymmetry 12 (2001) 2649–2655
with brine, dried, and evaporated. The residue was
purified by flash chromatography (hexane/EtOAc, 4:1)
to afford a mixture of compounds 16 and 17 (6.6 g,
4.13. (2S,3S,9S,10R)-4-Benzyloxycarbonyl-2,3-di-
phenyl-2,3;7,8;9,10-hexahydrobenzo-1,4-oxazine 21
1
97%): Rf=0.37 (hexane/EtOAc, 7:1); H NMR (CDCl3,
A solution of 20 (1.5 g, 2.6 mmol), NaIO4 (1.32 g, 6.2
mmol), and NaHCO3 (433 mg. 5.1 mmol) in methanol
(60 mL) and water (10 mL) was heated at 75–80°C for
48 h. After removal of some methanol by evaporation,
the reaction mixture was diluted with methylene chlo-
ride. The organic layer was washed brine, dried, and
evaporated. The residue was purified by flash chro-
matography (hexane/EtOAc, 7:1) to afford the title
compound 21 as a colorless oil (1.0 g, 91%): Rf=0.35
500 MHz): l 1.02–2.02 (m, 8H), 3.15–3.28 (m, 2H),
4.55–4.66 (m, 2H), 4.82 (brs, 1H), 4.94–5.00 (m, 2H),
7.01–7.57 (m, 20H); 13C NMR (CDCl3, 125 MHz): l
22.5, 23.0, 24.8, 25.1, 28.4, 31.5, 31.8, 47.4, 48.1, 60.9,
61.8, 66.6, 77.1, 79.3, 80.8, 84.5, 127.0, 127.1, 127.2,
127.5, 127.6, 128.2, 128.3, 128.5, 128.1, 129.4, 133.6,
134.5, 136.8, 138.7, 139.7, 140.3, 140.8, 156.0, 156.1; IR
(CHCl3 film) 1713, 1729, 3339, 3434 cm−1. Anal. calcd
for C34H35NO3Se: C, 69.85; H, 6.03; N, 2.40. Found: C,
69.89; H, 6.08; N, 2.33%.
1
(hexane/EtOAc, 7:1); [h]D=−141.0 (c=0.5, CHCl3); H
NMR (CDCl3, 500 MHz): l 1.65–1.78 (m, 1H), 1.91–
2.04 (m, 2H), 2.17–2.29 (m, 1H), 4.17 (brs, 1H), 4.72
(brs, 1H), 5.15 (s, 2H), 5.30–5.41 (m, 3H), 5.68 (brs,
1H), 7.19–7.38 (m, 15H); 13C NMR (CDCl3, 125 MHz):
l 19.5, 28.3, 49.1, 66.0, 67.5, 76.0, 127.1, 127.6, 127.76,
127.79, 127.9, 128.0, 128.3, 128.4, 128.5, 128.54, 128.9,
139.1, 140.8, 156.1; IR (CHCl3 film) 1654, 1692, cm−1.
Anal. calcd for C28H27NO3: C, 79.03; H, 6.40; N, 3.29.
Found: C, 79.08; H, 6.26; N, 3.27%.
4.11. (1S,2S,1%S)- and (1S,2S,1%R)-2-Amino-N-benzyl-
oxy-carbonyl-O-(cyclohex-2%-enyl)-1,2-diphenylethanol
18 and 19
A solution of the mixture of 16 and 17 (6.0 g, 10.3
mmol), NaIO4 (5.3 g, 24.7 mmol), and NaHCO3 (1.73
g. 20.6 mmol) in methanol (120 mL) and water (20 mL)
was heated at 75–80°C for 48 h. After removal of some
methanol by evaporation, the reaction mixture was
diluted with methylene chloride. The organic layer was
washed brine, dried, and evaporated. The residue was
purified by flash chromatography (hexane/EtOAc, 3:1)
to afford a mixture of 18 and 19 (4.10 g, 93%): Rf=0.37
Acknowledgements
This work was supported by Korea Research Founda-
tion Grant (KRF-2000-DP0266).
1
(hexane/EtOAc, 3:1); H NMR (CDCl3, 250 MHz): l
1.26–1.65 (m, 4H), 1.83–2.17 (m, 2H), 3.60 (brs, 1H),
4.62–4.64 (m, 1H), 4.82 (brs, 1H), 4.95 (brs, 2H),
5.47–5.85 (m, 3H), 7.13–7.58 (m, 15H); 13C NMR
(CDCl3, 63 MHz): l 18.7, 19.2, 25.2, 27.4, 29.6, 61.3,
66.8, 71.1, 72.4, 82.2, 82.4, 126.7, 127.0, 127.2, 127.4,
127.9, 128.3, 128.4, 129.1, 132.2, 136.7, 140.2, 141.2,
156.1; IR (CHCl3 film) 1693, 1729, 3359, 3442 cm−1.
Anal. calcd for C28H29NO3: C, 78.66; H, 6.84; N, 3.28.
Found: C, 78.66; H, 6.83; N, 3.06%.
References
1. Kameda, Y.; Asano, N.; Yoshikawa, M.; Matsui, K. J.
Antibiot. 1980, 33, 1575.
2. (a) Kameda, Y.; Horii, S. J. C. S. Chem. Comm. 1972,
746; (b) Suami, T.; Ogawa, S.; Chida, N. J. Antibiot.
1980, 33, 98.
3. Schmidt, D.; Frommer, W.; Junge, B.; Mu¨ller, L.; Win-
gender, W.; Truscheit, E.; Schafer, D. Naturwis-
senschaften 1977, 64, 535.
4. Kameda, Y.; Asano, N.; Yoshikawa, M.; Takeuchi, M.;
Yamaguchi, T.; Matsui, K.; Horii, S.; Fukase, H. J.
Antibiot. 1984, 37, 1301.
4.12. (2S,3S,5S,9S,10S)-4-Benzyloxycarbonyl-2,3-di-
phenyl-5-phenylselenenyloctahydrobenzo-1,4-oxazine 20
To a solution of the mixture of 18 and 19 (4.5 g, 10.5
mmol) and NPSP (3.5 g, 11.6 mmol) in methylene
chloride (60 mL) was slowly added BF3·OEt2 (130 mL,
1.0 mmol) at 0°C. The reaction mixture was stirred at
room temperature for 7 h, diluted with methylene chlo-
ride, neutralized with saturated aqueous sodium bicar-
bonate solution. The organic phase was washed with
brine, dried, and evaporated. The residue was purified
by flash chromatography (hexane/EtOAc, 12:1) to
afford the title compound 20 as a colorless solid (2.8 g,
91%): Rf=0.37 (hexane/EtOAc, 7:1); mp 62–64 °C;
[h]D=−49.6 (c=1.2, CHCl3); 1H NMR (CDCl3, 250
MHz): l 1.27–1.53 (m, 4H), 1.76–1.88 (m, 2H), 3.31–
3.42 (m, 1H), 3.88–4.26 (m, 2H), 5.01–6.17 (m, 4H),
6.87–7.97 (m, 20H); 13C NMR (CDCl3, 63 MHz): l
21.4, 31.3, 34.3, 44.5, 56.3, 68.1, 74.8, 125.5, 127.3,
127.5, 127.6, 127.8, 128.3, 128.6, 128.62, 128.8, 129.1,
129.5, 135.0, 136.5, 139.0, 141.7, 156.6; IR (CHCl3 film)
1693 cm−1. Anal. calcd for C34H33NO3Se: C, 70.09; H,
5.71; N, 2.40. Found: C, 70.04; H, 5.79; N, 2.49%.
5. For the discussion of introducing the cis and trans
aminoalcohol functionality, see: Knapp, S. Chem. Soc.
Rev. 1999, 28, 61.
6. Hooper, I. R. In Aminoglycoside Antibiotics; Umezawa,
H.; Hooper, I. R., Eds.; Springer: Berlin, 1982; Chapter 1
7. For selected references for the synthesis of aminocyclo-
hexitols, see; (a) Trost, B. M.; Dudash, Jr, J.; Hembre, E.
J. Chem. Eur. J. 2001, 7, 1619; (b) Sellier, O.; van de
Weghe, P.; Nouen, D. L.; Strehler, C.; Eustache, J.
Tetrahedron Lett. 1999, 40, 853; (c) Trost, B. M.; Chu-
pak, L. S.; Lu¨bbers, T. J. Am. Chem. Soc. 1998, 120,
1732; (d) Angelaud, R.; Landais, Y. Tetrahedron Lett.
1997, 38, 1407; (e) Shing, T. K. M.; Wan, L. H. Angew
Chem., Int. Ed. Engl. 1995, 34, 1643; (f) Knapp, S.; Patel,
D. V. J. Am. Chem. Soc. 1983, 105, 6985; (g) Paulsen, H.;
Heiker, F. R. Angew Chem., Int. Ed. Engl. 1980, 19, 904.
8. (R,R)-Hydrobenzoin has been used for the synthesis of
aminocyclopentitols by one of us, see: Kim, K. S.; Park,
J. I.; Ding, P. Tetrahedron Lett. 1998, 39, 6471.

K. S. Kim et al. / Tetrahedron: Asymmetry 12 (2001) 2649–2655
2655
9. Lyle, G. G.; Lacroix, W. J. Org. Chem. 1963, 28, 900.
10. Li, G.; Angert, H. H.; Sharpless, K. B. Angew Chem., Int.
Ed. Engl. 1996, 35, 2813.
11. In the absence of 2,2%-dipyridyl, the desired amino alco-
hol 4 was obtained in lower yield because of the partial
cleavage of other benzylic CꢀN and CꢀO bonds. For
effect of 2,2%-dipyridyl in the catalytic hydrogenolysis, see:
Sajiki, H.; Kuno, H.; Hirota, K. Tetrahedron Lett. 1998,
39, 7127.
12. Intramolecular oxypalladation of the Cbz-protected 6 or
the amine 6 itself did not give the desired compound but
instead the benzylic hydroxyl group in the compound 6
or the Cbz-protected 6 was rapidly oxidized to the ketone
when molecular oxygen was used with a copper salt. For
a review for oxypalladation of alkenes, see: Hosokawa,
T.; Murahashi, S. Heterocycles 1992, 33, 1079.
13. Li, G.; Chang, H.-T.; Sharpless, K. B. Angew Chem., Int.
Ed. Engl. 1996, 35, 451.