Influence of a 2-fluoro substituent on diastereoselectivity in the 1,3-dipolar cycloadditions of nitrones

Article abstract of DOI:10.1039/a702810e

It is clear that the role of 1,2-asymmetric induction on the 1,3-dipolar cycloaddition of nitrones is influenced by the presence of a fluorine atom at the C-2 position. 2-Fluoro nitrones, synthesized by three different methods, have been subjected to the intermolecular 1,3-dipolar cycloaddition with ethyl vinyl ether. The stereostructures of isoxazolidines formed were determined by their conversion into 2,7-dioxa-6-azabicyclo[3.2.1]octanes. The diastereoselectivity of 2-fluoro nitrones was the reverse of that of the corresponding 2-hydro nitrones. This fact supports that the conformation with relief from the dipole repulsion between the fluorine atom and the oxygen atom of the nitrone is a preferred one for 2-fluoro nitrones, while the corresponding 2-hydro nitrones adopt the conformation with the least 1,3-allylic strain.

Full text of DOI:10.1039/a702810e

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Influence of a 2-fluoro substituent on diastereoselectivity in the
1,3-dipolar cycloadditions of nitrones
Masataka Ihara,* Yuko Tanaka, Nobuyuki Takahashi, Yuji Tokunaga and
Keiichiro Fukumoto
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-77, Japan
It is clear that the role of 1,2-asymmetric induction on the 1,3-dipolar cycloaddition of nitrones is
influenced by the presence of a fluorine atom at the C-2 position. 2-Fluoro nitrones, synthesized by three
different methods, have been subjected to the intermolecular 1,3-dipolar cycloaddition with ethyl vinyl
ether. The stereostructures of isoxazolidines formed were determined by their conversion into 2,7-dioxa-
6-azabicyclo[3.2.1]octanes. The diastereoselectivity of 2-fluoro nitrones was the reverse of that of the
corresponding 2-hydro nitrones. This fact supports that the conformation with relief from the dipole
repulsion between the fluorine atom and the oxygen atom of the nitrone is a preferred one for 2-fluoro
nitrones, while the corresponding 2-hydro nitrones adopt the conformation with the least 1,3-allylic strain.
CH2Ph
Introduction
O
O
N
H
Me
H
O–
Because of their important physical and biological properties,
the regio- and stereo-controlled synthesis of organofluorine
compounds is of importance.1 We observed earlier that the
intramolecular 1,3-dipolar cycloaddition of the nitrone 1 pro-
duced, in a highly stereoselective manner, the bicyclic isoxazol-
idine 2, convertible into 1β-methylcarbapenem 3,2 while the
corresponding fluorinated nitrone 4 gave a 1:2.8 mixture of two
stereoisomers 5 and 63 (Scheme 1). The results could be
explained as follows: the desired stereoisomer 2 was diastereo-
selectively formed via conformation 8, this having the least 1,3-
allylic strain. However, conformation 8 was not favourable for
the fluorinated compound mainly because of the dipole repul-
sion between the fluorine atom and the oxygen atom of
the nitrone; therefore, the alternative conformation 7 became
the preferred one. In view of this, we were interested in study-
ing the intermolecular 1,3-dipolar cycloaddition of nitrones
possessing a fluorine atom at the C-2 position in order to con-
firm the above explanation. It was further considered that the
cycloadducts would be useful as precursors of pharmacologic-
ally interesting compounds, such as fluoroamino acids.
H
O
110 °C
N+
Me
H
O
Me
CH2Ph
O
1
2
HO
Me
H
H
N
SR
O
F
Me
O–
CO2H
O
N+
3
CH2Ph
O
4
180 °C
CH2Ph
CH2Ph
O
O
N
O
N
On the basis of the above considerations, the reaction of
3-oxygenated fluoro nitrones 9 with ethyl vinyl ether has been
investigated, because the stereochemistry of the stereogenic
centre, newly introduced by the cycloaddition, could be deter-
mined by the conversion of the cycloadduct 10 into 2,7-dioxa-
6-azabicyclo[3.2.1]octanes 11 and 12 (Scheme 2). We herein
describe our results which support our earlier assumption.
H
H
F
F
Me
Me
H
O
H
O
+
Me
Me
O
5
6
Results and discussion
H
O
X
H
H
X = F
X = H
Preparation of nitrones
H
O
O
CH2Ph
N
O–
O
2-Fluoropropan-1-ol derivatives having a protected oxygen
functionality at the C-3 position were synthesized by three dif-
ferent methods. The 2-methyl and 2-ethyl derivatives 17 and 19
were prepared as optically active compounds from the phenyl-
menthyl esters 13 and 15, which were diastereoselectively syn-
thesized starting with diethyl fluoromalonate.4 The hydroxy
group of 13 (an epimeric mixture in a ca. 5:1 ratio), was
protected with a tert-butyldimethylsilyl (TBDMS) group. The
reduction of the phenylmenthyl ester group of 14 was per-
formed using lithium borohydride to give 17 (85%), [α]D24 ϩ0.90
(MeOH). Other hydride reagents were ineffective for the reduc-
tion. The optical purity was established as 83% ee by conversion
of 17 into 18 reaction with (S)-α-methoxy-α-(trifluoromethyl)-
Me
CH2Ph
Me
Me
N
X
Me
H
O–
H
8
7
Scheme 1
phenylacetic acid (MTPA)5 in the presence of DCC and
DMAP6 in ClCH2CH2Cl.7 The corresponding ethyl compound
19, [α]D24 ϩ 1.39 (CHCl3), was similarly prepared, and its optical
purity was determined as 90% ee (Scheme 3).
The 2-phenyl derivative 25 was synthesized through the
J. Chem. Soc., Perkin Trans. 1, 1997
3043

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Ph
Me
O–
N+
O
N
R1
F
MCPBA
OCH2Ph
O
H
OCH2Ph
R2O
R3
Ph
F
EtO
O
R1
R3
R4
10
R4
27
26
OR2
SiF4
Pri2NEt
H2O
9
1) DMPI
2) MeLi
F
Me
F
Me
HO
OCH2Ph
RO
OCH2Ph
Ph
F
R4
O
Me
28
O
N
R4
+
R3
O
29 R = H
R1
F
O
PhCOCl
pyridine
N
Ph
R3
30 R = COPh
R1
for 30
1) H2, 10% Pd-C
AcOH
12
11
Scheme 2
2) separation
F
Me
OH
R1
F
PhCO2
for 14 and 16
LiBH4
OR2
R1
F
O
H
Me
R2O
OTBDMS
Ph
O
31
13 R1 = Me, R2 = H
17 R1 = Me, R2 = H
18 R1 = Me, R2 = MTPA
19 R1 = Et, R2 = H
Scheme 5
MTPA
TBDMSCl
imidazole
DCC
14 R1 = Me, R2 = TBDMS
15 R1 = Et, R2 = H
DMAP
of the major isomer 31, separated by the HPLC technique, was
determined by further transformation (vide infra).
The preceeding alcohol 28 was further transformed into the
MTPA
DCC
DMAP
TBDMSCl
imidazole
ester 32 in 93% overall yield in three steps (Scheme 6). Treat-
16 R1 = Et, R2 = TBDMS
20 R1 = Et, R2 = MTPA
Scheme 3
F
Me
HO
OCH2Ph
fluorination of ( )-methyl mandelate 21. Thus, the treatment of
21 with diethylaminosulfur trifluoride (DAST)8 in CH2Cl2 pro-
vided 22 (92%). The aldol reaction of 22 with formaldehyde in
the presence of LDA afforded 23 (58%) which was converted
into 25 by the protection of the hydroxy group, followed by
reduction with lithium borohydride (Scheme 4).
28
1) DMPI
2) NaClO2
MeCH=CMe2
3) CH2N2
LDA;
CH2O
F
OH
F
Ph
F
Me
DAST
F
Me
RO
MeLi
HO
Me
OCH2Ph
CO2Me
Ph
CO2Me
OCH2Ph
Ph
CO2Me
MeO2C
Me
21
22
23 R = H
TBDMSCl
imidazole
33
32
24 R = TBDMS
TBDMSOTf
2,6-demethylpyridine
H
2 , 10% Pd-C
AcOH
for 24
LiBH4
F
Ph
F
Me
F
Me
TBDMSO
OH
HO
Me
OH
TBDMSO
Me
OR
Me
Me
25
34
Scheme 4
35 R = CH2Ph
36 R = H
H2, 10% Pd-C
AcOH
It was assumed that a large difference between the bulkiness
of two groups neighbouring the fluorine atom would be
required to obtain an interpretable result. For this purpose, the
introduction of alkyl groups at the C-3 position was tried as
shown in Scheme 5. Regioselective ring opening of the epoxide
27, which was prepared from 26, was carried out using
tetrafluorosilane in the presence of diisopropylethylamine and
water.9 Oxidation of the resulting alcohol 28, obtained in 69%
yield, with the Dess–Martin periodinane (DMPI),10 followed by
reaction with methyllithium, provided the secondary alcohols
29 as a 1.7:1 mixture of two diastereoisomers in 75% overall
yield. After benzoylation of 29, the benzyl group of the result-
ing compound 30 was removed by hydrogenolysis utilizing 10%
Pd–C in the presence of acetic acid. The relative configuration
Scheme 6
ment of 32 with methyllithium provided the tertiary alcohol 33
(87%). Deblocking of the benzyl group of 33 gave the diol 34,
whilst protection of the hydroxy group of 33 with a TBDMS
group, followed by the removal of the benzyl group of the
resulting compound 35, produced the alcohol 36.
In order to compare the degree of stereoselectivity, the
corresponding alcohols 38, 42 and 43 carrying a hydrogen atom
instead of the fluorine atom were newly prepared starting with
37 and 39 as shown in Scheme 7.
Oxidation of the alcohol 17 with DMPI10 in the presence of
pyridine, followed by reaction with N-benzylhydroxylamine at
3044
J. Chem. Soc., Perkin Trans. 1, 1997

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Table 1 1,3-Dipolar cycloaddition of nitrones having a fluorine atom at the C-2 position with ethyl vinyl ether
Entry
Nitrone
R1
R2
R3
R4
Isoxazolidines
Yield
Ratio of A to B
1
2
3
4
5
6
44
45
46
47
48
49
Me
Et
Ph
Me
Me
Me
TBDMS
TBDMS
TBDMS
PhCO
H
H
H
H
Me
Me
H
H
H
Me
Me
Me
57
58
59
60
61
62
86
85
97
100
83
84
1.1:1
1.1:1
1:1.1
2.5:1
2.0:1
4.1:1
H
TBDMS
O–
N+
1) LiAlH4
2) TBDMSCl, Et3N
DMAP
F
R
1) DMPI
F
R
pyridine
Ph
Ph
TBDMSO
Ph
TBDMSO
OH
C
TBDMSO
OH
H2
2) PhCH2NHOH
MeO2C
CO2Me
H
NOE
38
37
17 R = Me
19 R = Et
44 R = Me
45 R = Et
TBDMSOTf
2,6-dimethylpyridine
Me
O–
N+
Me
Ph
F
F
Ph
TBDMSO
Me
OCH2Ph
HO
Me
OCH2Ph
TBDMSO
Ph
TBDMSO
OH
Me
Me
25
40
41
46
H2
10% Pd-C
H2, 10% Pd-C
O–
F
Me
F
Me
PhCO2
OH
MeLi
PhCO2
H
N+
Ph
Me
H
Me
Me
RO
Me
OH
47
31
Me
Me
OCH2Ph
MeO2C
O–
42 R = TBDMS
43 R = H
F
Me
F
Me
RO
Me
OH
RO
Me
N+
Ph
39
Me
Me
Scheme 7
room temperature, gave the nitrone 44, [α]D24 Ϫ41.4 (CHCl3), in
53% overall yield. The ethyl compound 45, [α]D24 Ϫ46.9 (CHCl3),
was similarly prepared in 63% overall yield from 19. The geom-
etry of the nitrones was assigned as Z-form on the basis of the
observation of NOE (2.3%) between the olefinic hydrogen at
6.70 ppm and the benzylic hydrogens at 4.88 ppm of 45. 2-
Fluoro nitrones 46–49 and the 2-hydro nitrones 52–56 were
synthesized by the same procedure as already described
(Scheme 8). The olefinic hydrogens of all the nitrones resonate
in the range 6.59–6.98 ppm.
48 R = H
49 R = TBDMS
34 R = H
36 R = TBDMS
R
R
O–
N+
TBDMSO
OH
TBDMSO
Ph
50 R = Me
51 R = Et
38 R = Ph
52 R = Me
53 R = Et
54 R = Ph
O–
N+
1,3-Dipolar cycloaddition of nitrones
R
Me
Me
The cycloaddition of nitrones with ethyl vinyl ether was exam-
ined under various conditions. It has been found that the reac-
tion rate of 2-fluoro nitrones is a little faster than that of the
corresponding 2-hydro nitrones. In order to complete the reac-
tion within a reasonable reaction time, a temperature above
80 ЊC was required. The cycloaddition of the hindered nitrones
48, 49, 55 and 56 was carried out for 16 h at 105 ЊC. Results of
cycloaddition performed at 80 ЊC or 105 ЊC are shown in Tables
1 and 2 (Schemes 9 and 10). Four stereoisomers were obtained
by each reaction, but no formation of regioisomers was
observed.11
No appropriate catalyst for the cyclization was found.
Although cycloadducts were produced by the treatment of
nitrones with ethyl vinyl ether at 10 000 atm and room temper-
ature, no improvement of yield and diastereoselectivity was
observed.
RO
Me
OH
RO
Me
Ph
Me
55 R = H
56 R = TBDMS
43 R = H
42 R = TBDMS
Scheme 8
68A was determined by the NOE (1.8%) between the methyl
group (1.16 ppm, d, J 21.4 Hz) at the C-4 position and the axial
hydrogen (2.62 ppm, dd, J 11.9, 2.8 Hz) at the C-8 position. On
the other hand, the corresponding hydro-isoxazolidines 63A
and 63B (Table 2, entry 1) gave a separable 1:1.6 mixture of
73A and 73B (81%). The NOE (3.4%) was observed between the
methyl group (1.05 ppm, d, J 7.3 Hz) and the axial hydrogen
(2.30 ppm, br d, J 11.6 Hz) of the minor product 73A.
Isoxazolidines produced were converted into 2,7-dioxa-6-
azabicyclo[3.2.1]octanes in order to establish their stereo-
chemistry. Treatment of a mixture of 57A and 57B (Table 1,
entry 1) with toluene-p-sulfonic acid in hot benzene provided
68A (40%) and 68B (37%). The structure of the major isomer
A 1.1:1 mixture of 69A and 69B was obtained from a mix-
ture of the isoxazolidines 58A and 58B (Table 1, entry 2) carry-
ing a fluorine atom and ethyl group, while a 1.2:1 mixture of
74A and 74B resulted from the corresponding non-fluorinated
compounds 64A and 64B (Table 2, entry 2). Furthermore, a
J. Chem. Soc., Perkin Trans. 1, 1997
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Table 2 1,3-Dipolar cycloaddition of nitrones having a hydrogen atom at the C-2 position with ethyl vinyl ether
Entry
Nitrone
R1
R2
R3
R4
Isoxazolidines
Yield
Ratio of A to B
1
2
3
4
5
52
53
54
55
56
Me
Et
Ph
Me
Me
TBDMS
TBDMS
TBDMS
H
H
H
H
Me
Me
H
H
H
Me
Me
63
64
65
66
67
84
88
95
1:1.6
1.2:1
1:4.6
1:1.1
1:2.5
66
TBDMS
11 (53)a
a Yield based on the recovered starting material.
ucts were determined by NOE experiments and comparison
with spectral data.
The compounds which belong to a series of A are produced
by the approach of the ethyl vinyl ether from the less hindered
side of the conformation 77 of nitrones or from the hindered
side of conformation 78 (Scheme 11). On the other hand, the
Ph
Ph
O–
R1
O
F
O
N
O
N
R2O
R3
N+
Ph
H
H
R1
+
R1
F
heat
EtO
R4
H
F
EtO
R3
R4
R3
R4
OR2
OR2
Ph
44 ~ 49
57B ~ 62B
57A ~ 62A
O
N
L
H
S
EtO
X
B
Ph
R4
O
H
EtO
–O
N
EtO
Ph
F
3
H
R3
H
O
O
S
L
H
H
H
R4
F
8
4
H
X = F
R1
Ph
H
O
N+
R1
H
H
Ph
N+
N
R3
–O
X
X
X = H
NOE
S
L
78
68A R1 = Me, R3 = R4 = H
69A R1 = Et, R3 = R4 = H
70A R1 = Ph, R3 = R4 = H
71A R1 = R4 = Me, R3 = H
72A R1 = R3 = R4 = Me
68B R1 = Me, R3 = R4 = H
69B R1 = Et, R3 = R4 = H
70B R1 = Ph, R3 = R4 = H
71B R1 = R4 = Me, R3 = H
72B R1 = R3 = R4 = Me
77
EtO
EtO
Ph
O
N
H
Scheme 9
S
EtO
X
L
Ph
H
Ph
H
O–
A
R1
H
O
O
N
O
N
R2O
R3
N+
Ph
+
R1
H
R1
H
S = small group
L = large group
EtO
heat
EtO
R4
R3
R4
R3
R4
H
OR2
OR2
Scheme 11
52 ~ 56
63A ~ 67A
63B ~ 67B
attacks of the dipolarophile from the other sides of the two
conformations lead to a series of B. Although the observed
results support that conformation 77 with the relief from the
dipole repulsion is the preferred form for the fluoro nitrones,
while the non-fluorinated ones take the conformation 78 with
the least 1,3-allylic strain, the differences of the ratios of the
two stereoisomers are rather small.
The isoxazolidines 60 (Table 1, entry 4), obtained in 100%
yield from 47 possessing a tertiary carbon at the C-3 position,
was transformed, in two steps, into 71A and 71B in the ratio
of 2.5:1. The stereostructure of the major product 71A was
established by the NOE experiments; 2.3% NOE between the
equatorial hydrogen (4.29 ppm, dq, J 19.8, 6.8 Hz) at the C-3
and the methyl group (1.29 ppm, d, J 22.3 Hz) at the C-4 pos-
ition and 2.1% NOE between the axial hydrogen (2.04 ppm, dd,
J 12.3, 1.7 Hz) at the C-8 and the methyl group at the C-4
position.
Ph
R4
O
H
N
H
H
R3
H
8
O
O
H
H
H
R4
H
4
H
R1
R3
O
R1
H
Ph
N
NOE
73A R1 = Me, R3 = R4 = H
74A R1 = Et, R3 = R4 = H
75A R1 = Ph, R3 = R4 = H
76A R1 = R3 = R4 = Me
73B R1 = Me, R3 = R4 = H
74B R1 = Et, R3 = R4 = H
75B R1 = Ph, R3 = R4 = H
76B R1 = R3 = R4 = Me
The 1,3-dipolar cycloaddition of the tertiary alcohol 48 gave
a 2.0:1 mixture of isoxazolidines 61A and 61B, both of which
were separated by column chromatography (Table 1, entry 5).
The structure of 72A, derived from 61A, was determined by the
NOE (1.4%) between the hydrogen (2.02 ppm, dd, J 11.9, 2.1
Scheme 10
1:1.1 mixture of 70A and 70B and a 1:4.6 mixture of 75A and
75B were produced in the case of the phenyl compounds (Table
1, entry 3 and Table 2, entry 3). Structures of the bridged prod-
3046
J. Chem. Soc., Perkin Trans. 1, 1997

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Hz) at the C-8 and the methyl group (1.37 ppm, d, J 23.1 Hz) at
the C-4 position. The corresponding hydro compounds 66A
and 66B were obtained in the ratio of 1:1.1 (Table 2, entry 4).
The stereostructure of 76B, derived from the major product
66B, was established by the NOE (1.2%) between the axial
hydrogen (1.89 ppm, d, J 11.3 Hz) at the C-8 and the axial
hydrogen (1.75 ppm, dq, J 7.1, 1.9 Hz) at the C-4 position.
A comparably good degree of diastereoselectivity was
observed on the cycloaddition of the TBDMS ether 49 (Table 1,
entry 6), a 4.1:1 mixture of 62A and 62B being obtained in 84%
yield. The corresponding hydroisoxazolidines 67A and 67B
were produced in a ratio of 1:2.5 (Table 2, entry 5). The stereo-
structures of the products were determined by correlation with
the previously described compounds. These findings support
the above assumption. Conformations 77 and 78 were favour-
able ones for fluoro- and hydro-nitrones, respectively, although
the fluorine and the hydrogen atoms would not be entirely on
the plane of the nitrones.
in dry THF (3.0 cm3), and the mixture was stirred for 18 h at
45 ЊC. After the addition of saturated aq. NaHCO3, the mixture
was extracted with AcOEt. The extract was washed with brine,
dried and evaporated to give a residue, which was purified by
column chromatography on silica gel. Elution with AcOEt–
hexane (1:20, v/v) yielded 17 (83.2 mg, 85%) as an oil, [α]D24
ϩ0.90 (c 10.1, MeOH); νmax(neat)/cmϪ1 3400 and 1260; δH(300
MHz, CDCl3) 0.08 (6H, s, SiMe2), 0.90 (9H, s, But), 1.31
(3H, d, J 21.9, CFMe), 2.07 (1H, br t, J 6.6, OH) and 3.60–3.83
(4H, m); m/z (EI) 1625.0720 (Mϩ Ϫ But. C6H14FO2Si requires
165.0747).
(؉)-(2R)-2-(tert-Butyldimethylsiloxymethyl)-2-fluorobutan-1-ol
19
An oil (66%), [α]D24 ϩ1.39 (c 0.59, CHCl3); νmax(neat)/cmϪ1 3420
and 1260; δH(300 MHz, CDCl3) 0.06 (6H, s, SiMe2), 0.85–0.96
(12H, m), 1.56–1.78 (2H, m), 2.09 (1H, br t, J 6.4, OH) and
3.61–3.82 (4H, m); m/z (EI) 237.1687 (Mϩ ϩ H. C11H26FO2Si
requires 237.1686).
Experimental
3-(tert-Butyldimethylsiloxy)-2-fluoro-2-phenylpropan-1-ol 25
An oil (90%), νmax(neat)/cmϪ1 3420 and 1260; δH(300 MHz,
CDCl3) 0.02 (3H, s, SiMe), 0.05 (3H, s, SiMe), 0.88 (9H, s, But),
2.28 (1H, br t, J 7.0, OH), 3.88–4.25 (4H, m) and 7.28–7.46
(5H, m, Ph); m/z (EI) 207.0872 (Mϩ Ϫ H Ϫ F Ϫ But. C11H15O2Si
requires 207.0841).
All reactions were carried out under a positive atmosphere of
dry N2, unless otherwise indicated. Solvents were distilled prior
to use: THF, Et2O, hexane and benzene were freshly distilled
from Na and benzophenone; CH2Cl2, ClCH2CH2Cl and DMF
were distilled from CaH2 and stored over 4 Å molecular sieves;
pyridine and triethylamine were distilled from KOH and stored
over KOH. All extracts were dried over MgSO4, and the solvent
was removed by rotary evaporation under reduced pressure. All
new compounds are homogenous on HPLC and TLC, and their
(2R)-3-(tert-Butyldimethylsiloxy)-2-fluoro-2-methylpropyl (S)-
(3,3,3-trifluoro-2-methoxy-2-phenyl)propionate 18
To a stirred solution of 17 (6.9 mg, 31 µmol), (S)-(Ϫ)-α-
methoxy-α-(trifluoromethyl)phenylacetic acid (8.7 mg, 37 µmol)
and DMAP (3.8 mg, 31 µmol) in dry ClCH2CH2Cl (0.5 cm3) at
0 ЊC was added DCC (9.6 mg, 46 µmol). After being stirred for
14 h at room temperature, the reaction mixture was diluted with
Et2O and then filtered through Celite. Evaporation of the sol-
vent gave 18 as an oil, νmax(neat)/cmϪ1 1760 and 1250; δH(300
MHz, CDCl3) 0.04 (6H, s, SiMe2), 0.88 (9H, s, But), 1.32 (3H,
d, J 21.6, CFMe), 3.42–3.76 (5H, m), 4.30–4.54 (2H, m,
CH2OCO) and 7.35–7.60 (5H, m, Ph); m/z (EI) 381.1170
(Mϩ Ϫ But. C16H21F4O4Si requires 381.1145).
1
purities were further verified by 300 or 500 MHz H NMR
spectra. J Values are recorded in Hz.
(؊)-(1R,3R,4S)-8-Phenyl-p-menthan-3-yl (2ЈS)-3Ј-(tert-butyl-
dimethylsiloxy)-2Ј-fluoro-2Ј-methylpropionate 14
A mixture of 134 (134 mg, 0.397 mmol), TBDMSCl (89.9 mg,
0.596 mmol) and imidazole (54.1 mg, 0.795 mmol) in dry DMF
(2.7 cm3) was stirred for 12 h at room temperature. After add-
ition of water, the mixture was extracted with AcOEt. The
extract was washed with water and brine, dried and evapor-
ated. The residue was subjected to column chromatography on
silica gel with AcOEt–hexane (1:20, v/v) as the eluent to give 14
(165 mg, 92%) as an oil, [α]D23 Ϫ15.3 (c 2.93, CHCl3); νmax(neat)/
cmϪ1 1730 and 1250; δH(300 MHz, CDCl3) 0.06 (6H, s, SiMe2),
0.85 (3H, d, J 6.2, 1-Me), 0.88 (9H, s, But), 0.94–1.08 (3H, m),
1.25 (3H, s, 8-Me), 1.26 (3H, d, J 21.2, CFMe), 1.36 (3H, s, 8-
Me), 1.40–1.60 (3H, m), 1.94–2.10 (2H, m), 3.60–3.93 (2H, m),
4.83–5.20 (1H, m, 3-H) and 7.10–7.36 (5H, m, Ph); m/z (EI)
331.2070 (Mϩ Ϫ CMe2Ph. C17H32FO3Si requires 331.2105).
(2R)-2-(tert-Butyldimethylsiloxymethyl)-2-fluorobutyl (S)-
(3,3,3-trifluoro-2-methoxy-2-phenyl)propionate 20
An oil, νmax(neat)/cmϪ1 1760 and 1250; δH(300 MHz, CDCl3)
0.00 (3H, s, SiMe), 0.03 (3H, s, SiMe), 0.86 (9H, s, But), 0.94
(3H, t, J 7.7, CH2Me), 1.45–1.84 (2H, m, CFCH2Me), 3.50–
3.75 (5H, m), 4.26–4.59 (2H, m, CH2OCO) and 7.34–7.61 (5H,
m, Ph); m/z (EI) 395.1265 (Mϩ Ϫ But. C17H23F4O4Si requires
395.1302).
(؊)-(1R,3R,4S)-8-Phenyl-p-menthan-3-yl (2ЈS)-2Ј-(tert-butyl-
dimethylsiloxymethyl)-2Ј-fluorobutyrate 16
Methyl 2-fluorophenylacetate 22
To a stirred solution of methyl mandelate (810 mg, 4.87 mmol)
in dry CH2Cl2 (15 cm3) at Ϫ78 ЊC was slowly added DAST (1.57
g, 9.74 mmol), and the mixture was stirred for 19 h at room
temperature. After dilution with AcOEt, the mixture was
washed with saturated aq. NaHCO3, water and brine, dried and
evaporated to give a residue. This was chromatographed on
silica gel with Et2O–hexane (1:5, v/v) as the eluent to afford 22
(752 mg, 92%) as an oil (Found: C, 64.15; H, 5.4. C9H9FO2
requires C, 64.3; H, 5.4%); νmax(neat)/cmϪ1 1760 and 1220;
δH(300 MHz, CDCl3) 3.77 (3H, s, OMe), 5.79 (1H, d, J 47.6,
CFH) and 7.34–7.51 (5H, m, Ph); m/z (EI) 168 (Mϩ).
An oil (95%), [α]2D3 Ϫ15.3 (c 11.0, CHCl3); νmax(neat)/cmϪ1 1760,
1730 and 1260; δH(300 MHz, CDCl3) Ϫ0.05–0.13 (6H, m,
SiMe2), 0.65–1.12 (15H, m), 1.16–1.80 (12H, m), 1.95–2.12 (4H,
m), 3.28–3.96 (2H, m, CFCH2), 4.79–5.00 (1H, m, 3-H) and
7.06–7.34 (5H, m, Ph); m/z (EI) 325.2240 (Mϩ Ϫ CMe2Ph.
C18H34FO4Si requires 345.2261).
Methyl 3-(tert-butyldimethlysiloxy)-2-fluoro-2-phenyl-
propionate 24
An oil (99%), νmax(neat)/cmϪ1 1745 and 1260; δH(300 MHz,
CDCl3) 0.065 (3H, s, SiMe), 0.073 (3H, s, SiMe), 0.88 (9H, s,
But), 3.81 (3H, s, OMe), 3.94 (1H, dd, J 16.1 and 11.4, 3-H),
4.34 (1H, dd, J 31.5 and 11.4, 3H) and 7.31–7.61 (5H, m, Ph);
m/z (EI) 313.1587 (Mϩ ϩ H. C16H26FO3Si requires 313.1635).
Methyl 2-fluoro-3-hydroxy-2-phenylpropionate 23
To a stirred LDA solution, prepared from diisopropylamine
(309 mg, 3.05 mmol) and 1.56  BuLi in hexane (1.82 cm3, 2.84
mmol) in dry THF (15 cm3) at Ϫ78 ЊC, was added 22 (352 mg,
2.03 mmol) in dry THF (15 cm3). After thr mixture had been
stirred for 30 min at Ϫ78 ЊC, an excess of gaseous formaldehyde
was introduced at Ϫ78 ЊC. The mixture was then further stirred
(؉)-(2R)-3-(tert-Butyldimethylsiloxy)-2-fluoro-2-methylpropan-
1-ol 17
To a suspension of LiBH4 (191 mg, 8.77 mmol) in dry THF (1.0
cm3) at 0 ЊC was added a solution of 14 (197.3 mg, 0.437 mol)
J. Chem. Soc., Perkin Trans. 1, 1997
3047

View Article Online
for 70 min at the same temperature after which it was par-
titioned between 10% aq. HCl and Et2O. The organic layer was
separated, washed with saturated aq. NaHCO3 and brine,
dried and evaporated. The residue was subjected to column
chromatography on silica gel with AcOEt–hexane (3:7, v/v) as
the eluent to give 23 (239 mg, 58%) as a solid. Recrystallization
of this from Et2O–hexane afforded needles, mp 66.0–66.5 ЊC
(Found: C, 60.35; H, 5.3. C10H11FO3 requires C, 60.6; H, 5.6%);
νmax(neat)/cmϪ1 3620, 3500, 1750 and 1265; δH(300 MHz,
CDCl3) 2.32 (1H, br s, OH), 3.83 (3H, s, OMe), 3.94–4.12 (1H,
m, 3-H), 4.22–4.46 (1H, m, 3-H) and 7.36–7.59 (5H, m, Ph); m/z
(EI) 198 (Mϩ).
3-Benzyloxy-2-fluoro-1,2-dimethylpropyl benzoate 30
A mixture of 29 (185 mg, 0.872 mmol) and benzoyl chloride
(0.163 cm3, 1.40 mmol) in dry pyridine (0.377 cm3, 4.67 mmol)
was stirred for 2.5 h at room temperature. After dilution with
Et2O, the mixture was washed with water, 10% aq. KHSO4 and
brine, dried and evaporated. The residue was chromatographed
on silica gel with AcOEt–hexane (1:9, v/v) as the eluent to
give 30 (277 mg, 98%) as a pale yellowish oil (Found: C, 71.8;
H, 6.55. C19H21FO3 requires C, 72.15; H, 6.7%); νmax(neat)/
cmϪ1 1720; δH(300 MHz, CDCl3) 1.34–1.40 (3H, m, 1-Me),
1.42–1.52 (3H, m, 2-Me), 3.56–3.66 (2H, m, 3-H2), 4.54–4.58
(2H, m, OCH2Ph), 5.34–5.48 (1H, m, 1-H), 7.22–7.72 (8H, m,
8 × ArH) and 7.98–8.18 (2H, m, 2 × ArH); m/z (EI) 316
(Mϩ).
3-Benzyloxy-1,2-epoxy-2-methylpropane 27
A mixture of 2612 (13.3 g, 88.5 mmol), NaHCO3 (22.3 g, 266
mmol) and m-CPBA (22.9 g, 106 mmol) in CH2Cl2 (200 cm3)
was stirred for 2 h at room temperature. The reaction mixture
was partitioned between 10% aq. Na2S2O3 and Et2O. The
organic layer was separated, washed with saturated aq.
NaHCO3 and brine, dried and evaporated. The product was
purified by column chromatography on silica gel with AcOEt–
hexane (1:39 v/v) as the eluent to give 27 (10.7 g, 73%) as an
oil; νmax(neat)/cmϪ1 1110; δH(300 MHz, CDCl3) 1.40 (3H, s,
2-Me), 2.63 (1H, d, J 4.8, 1-H), 2.75 (1H, d, J 4.8, 1-H), 3.46
(1H, d, J 11.0, 3-H), 3.58 (1H, d, J 11.0, 3-H), 4.54 (1H, d,
J 12.1, OCHHPh), 4.60 (1H, d, J 12.1, OCHHPh) and 7.34
(5H, s, Ph); m/z (EI) 177.0916 (Mϩ Ϫ H. C11H13O2 requires
177.0899).
2-Fluoro-3-hydroxy-1,2-dimethylpropyl benzoate 31
A mixture of 30 (975 mg, 3.08 mmol), 10% Pd–C (25 mg) and
AcOH (6 × 10Ϫ3 cm3) in MeOH (12 cm3) was stirred for 12 h at
room temperature under a H2 atmosphere. The mixture was
filtered through Celite after which it was evaporated to afford a
residue. This was purified by column chromatography on silica
gel. Elution with AcOEt–hexane (1:4, v/v) afforded a 1.7:1
mixture of alcohols (565 mg, 81%). The major isomer 31 was
separated by HPLC using Dynamax Microsorb silica (5 µm,
4 × 250 mm) with CH2Cl2–hexane–AcOEt (2:8:1, v/v/v, 1.0
cm3 minϪ1) as the eluent (Found: C, 63.9; H, 6.75. C12H15FO3
requires C, 63.7; H, 6.7%); νmax(neat)/cmϪ1 3500 and 1720;
δH(300 MHz, CDCl3) 1.42 (3H, d, J 22.0, 2-Me), 1.44 (3H, dd,
J 6.6 and 1.5, 1-Me), 2.26–2.32 (1H, br s, OH), 3.66–3.80 (2H,
m, 3-H2), 5.45 (1H, dq, J 14.7 and 6.6, 1-H), 7.62–7.43 (3H,
m, 3 × ArH) and 8.01–8.04 (2H, m, 2 × ArH); m/z (EI) 209
(Mϩ Ϫ OH).
3-Benzyloxy-2-fluoro-2-methylpropanol 28
To a stirred solution of diisopropylethylamine (9.73 cm3, 55.8
mmol) and water (4.02 cm3, 223 mmol) in Et2O (100 cm3) with
ice cooling was slowly added a solution of 27 (9.28 g, 55.8
mmol) in dry Et2O (50 cm3). During the addition, an excess of
tetrafluorosilane was simultaneously introduced to the reaction
mixture. After being stirred for 2 h at 0 ЊC followed by treat-
ment with potassium fluoride (30 g), the mixture was extracted
with AcOEt. The extract was washed with brine, dried and
evaporated to give a residue, which was subjected to chrom-
atography on silica gel. Elution with AcOEt–hexane (1:17, v/v)
gave 28 (7.10 g, 69%) as an oil (Found: C, 66.75; H, 7.7.
C11H15FO2 requires C, 66.65; H, 7.65%); νmax(neat)/cmϪ1
3400; δH(300 MHz, CDCl3) 1.36 (3H, d, J 22.3, 2-Me), 1.95–
2.00 (1H, br s, OH), 3.38–3.79 (4H, m, 1- and 3-H2), 4.59 (2H,
d, J 3.3, OCH2Ph) and 7.22–7.38 (5H, m, Ph); m/z (EI) 198
(Mϩ).
Methyl 3-benzyloxy-2-fluoro-2-methylpropionate 32
After the oxidation of 28 (1.66 g, 8.38 mmol) using Dess–
Martin periodinane (11.5 g, 27.1 mmol), to a stirred mixture of
the resulting aldehyde, tert-butyl alcohol (45 cm3), pH 3.5
phosphate buffer (30 cm3) and 2-methylbut-2-ene (2.88 cm3,
27.1 mmol) at room temperature was added NaClO2 (2.03 g,
18.0 mmol). The mixture was stirred for 2 h at room temper-
ature and then diluted with Et2O. After acidification by add-
ition of 10% aq. KHSO4 with ice cooling, the mixture was
extracted with AcOEt. The extract was washed with brine,
dried and evaporated to give the corresponding acid, which
was used in the following reaction without purification.
A mixture of the crude acid and an excess of diazomethane
in THF (35 cm3) was kept for 3 h at room temperature. Concen-
tration of the mixture under reduced pressure afforded a resi-
due, which was chromatographed on silica gel. Elution with
Et2O–hexane (2:9, v/v) provided 32 (1.76 g, 93%) as an oil,
νmax(neat)/cmϪ1 1760; δH(300 MHz, CDCl3) 1.54 (3H, d, J 21.2,
2-Me), 3.59–3.86 (2H, m, 3-H2), 3.81 (3H, s, OMe), 4.51–4.68
(2H, m, OCH2Ph) and 7.21–7.36 (5H, m, Ph); m/z (EI) 226.1043
(Mϩ. C12H15FO3 requires 226.1005).
4-Benzyloxy-3-fluoro-3-methylbutan-2-ol 29
To a stirred mixture of Dess–Martin periodinane (2.51 g, 5.92
mmol) in dry CH2Cl2 (3.5 cm3) at room temperature was added
a solution of 28 (3.63 mg, 1.83 mmol) in dry CH2Cl2 (4.5 cm3).
After being stirred for 2 h, the mixture was partitioned between
saturated aq. NaHCO3–2% aq. Na2S2O3 (1:7, v/v) and Et2O.
The organic layer was separated, washed with water and brine,
dried and evaporated to afford the crude aldehyde, which was
used in the following reaction without purification.
4-Benzyloxy-3-fluoro-2,3-dimethylbutan-2-ol 33
To a stirred solution of the above product in dry THF (15
cm3) at 0 ЊC was added 1.04  MeLi in Et2O (2.28 cm3, 2.37
mmol). The mixture was stirred for 12 h at the same temper-
ature and then poured into saturated aq. NH4Cl with ice cool-
ing. The mixture was extracted with Et2O and the extract was
washed with brine, dried and evaporated. Column chrom-
atography of the product on silica gel with AcOEt–hexane (1:9,
v/v) as the eluent provided 29 (293 mg, 75%) as an oil (Found:
C, 67.8; H, 8.0. C12H17FO2 requires C, 67.9; H, 8.05%);
νmax(neat)/cmϪ1 3450; δH(300 MHz, CDCl3) 1.15–1.23 (3H, m,
1-H3), 1.31 and 1.33 [3H, (1:1.7), each d, each J 22.3, 3-Me],
2.23–2.34 (1H, m, OH), 2.47–2.73 (2H, m, 4-H2), 3.94–4.08
(1H, br s, 2-H), 4.55–4.62 (2H, m, OCH2Ph) and 7.24–7.44 (5H,
m, Ph); m/z (EI) 212 (Mϩ).
To a solution of 1.04  MeLi in Et2O (0.605 cm3, 0.629 mmol)
in dry THF (1.5 cm3) at 0 ЊC was added a solution of 32 (65 mg,
0.29 mmol) in dry THF (2.0 cm3), and the mixture was stirred
for 15 min at 0 ЊC. After being poured onto saturated aq.
NH4Cl, the mixture was extracted with Et2O. The extract was
washed with brine, dried and evaporated to give a residue,
which was subjected to silica gel column chromatography.
Elution with AcOEt–hexane (1:17, v/v) afforded 33 (56 mg,
87%) as an oil (Found: C, 69.0; H, 8.45. C13H19FO2 requires
C, 68.85; H, 8.27%); νmax(neat)/cmϪ1 3450; δH(300 MHz,
CDCl3) 1.23 (3H, s, Me), 1.26 (3H, s, Me), 1.40 (3H, d, J 22.7,
2-Me), 2.82 (1H, d, J 1.8, OH), 3.69 (2H, d, J 18.3, 4-H2),
4.59 (2H, s, OCH2Ph) and 7.28–7.39 (5H, m, Ph); m/z (EI)
226 (Mϩ).
3048
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
2-Fluoro-2,3-dimethylbutane-1,3-diol 34
4-Benzyloxy-2,3-dimethylbutan-2-ol 40
A mixture of 33 (980 mg, 4.33 mmol), 10% Pd–C (20 mg) and
AcOH (6 × 10Ϫ3 cm3) in MeOH (20 cm3) was stirred for 12 h at
room temperature under an H2 atmosphere. The mixture was
filtered through Celite, after which evaporation of the filtrate
gave a residue, which was chromatographed on silica gel. Elu-
tion with AcOEt–hexane (2:3, v/v) provided 34 (464 mg, 79%)
as an oil, νmax(neat)/cmϪ1 3400; δH(300 MHz, CDCl3) 1.27
(3H, s, Me), 1.30 (3H, s, Me), 1.34 (3H, d, J 22.0, 2-Me),
2.56–2.62 (1H, br s, OH), 2.63–2.78 (1H, br s, OH), 3.65–3.76
(1H, m, 1-H) and 3.92–4.03 (1H, m, 1-H); m/z (EI) 121.0665
(Mϩ Ϫ Me. C5H10FO2 requires 121.0677).
To a stirred solution of 1.04  MeLi in Et2O (14.4 cm3, 15.3
mmol) in dry hexane (15 cm3) at 0 ЊC was added a solution of
3913 (1.26 g, 6.11 mmol) in dry THF (25 cm3). After being
stirred for 10 min at 0 ЊC, the mixture was poured into saturated
aq. NH4Cl and extracted with Et2O. The extract was washed
with brine, dried and evaporated to give a residue, which was
subjected to column chromatography on silica gel. Elution with
AcOEt–hexane (1:5 v/v) provided 40 (1.40 g, 90%) as a pale
yellowish oil; νmax(neat)/cmϪ1 3450; δH(300 MHz, CDCl3)
0.89 (3H, d, J 7.0, 3-Me), 1.13 (3H, s, Me), 1.20 (3H, s, Me),
1.86–1.96 (1H, m, 3-H), 3.48–3.60 (2H, m, 4-H2), 4.52 (2H,
s, OCH2Ph) and 7.27–7.38 (5H, m, Ph); m/z (EI) 193.1227
(Mϩ Ϫ Me. C12H17O2 requires 193.1228).
3-(tert-Butyldimethylsiloxy)-2-fluoro-2,3-dimethylbutan-1-ol 36
An oil (85%), νmax(neat)/cmϪ1 3350; δH(300 MHz, CDCl3) 0.10
(3H, s, SiMe), 0.11 (3H, s, SiMe), 0.84 (9H, s, But), 1.27 (3H, s,
Me), 1.28 (3H, s, Me), 1.36 (3H, d, J 22.3, 2-Me), 2.40–2.79
(1H, br s, OH), 3.58–3.76 (1H, m, 1-H) and 3.80–3.92 (1H, m,
1-H); m/z (EI) 235.1509 (Mϩ Ϫ Me. C11H24FO2Si requires
235.1530).
3-(tert-Butyldimethylsiloxy)-2,3-dimethylbutan-1-ol 42
A mixture of 41 (1.09 g, 3.40 mmol) and 10% Pd–C (20 mg)
in MeOH (15 cm3) was stirred for 12 h at room temperature
under an H2 atmosphere. Filtration through Celite, followed by
evaporation of the filtrate, gave a residue, which was chromato-
graphed on silica gel. Elution with AcOEt–hexane (3:17, v/v)
provided 42 (729 mg, 93%) as an oil (Found: C, 61.8; H, 12.25.
C12H28O2Si requires C, 62.0; H, 12.1%); νmax(neat)/cmϪ1 3375;
δH(300 MHz, CDCl3) 0.11 (6H, s, SiMe2), 0.85 (9H, s, But), 0.91
(3H, d, J 7.1, 2-Me), 1.20 (3H, s, Me), 1.30 (3H, s, Me), 1.57–
1.71 (1H, m, 2-H), 3.34 (1H, br t, J 4.7, OH) and 3.66 (2H, m,
1-H2); m/z (EI) 175 (Mϩ Ϫ But).
1-Benzyloxy-3-(tert-butyldimethylsiloxy)-2-fluoro-2,3-dimethyl-
butane 35
To a stirred mixture of 33 (12.0 mg, 53 µmol) and 2,6-
dimethylpyridine (0.015 cm3, 0.133 mmol) in dry CH2Cl2
(0.5 cm3) at 0 ЊC was added tert-butyldimethylsilyl trifluoro-
methanesulfonate (0.016 cm3, 69 µmol), and the mixture was
stirred for 2 h at the same temperature. After dilution with
Et2O, the mixture was washed with water, 10% aq. KHSO4 and
brine, dried and evaporated to give a residue. This was purified
by silica gel column chromatography. Elution with AcOEt–
hexane (1:19 v/v) afforded 35 (16.0 mg, 90%) as a pale yel-
lowish oil (Found: C, 67.05; H, 9.75; C19H33FO2Si requires C,
67.0; H, 9.75%); νmax(neat)/cmϪ1 1260; δH(300 MHz, CDCl3)
0.05 (3H, s, SiMe), 0.07 (3H, s, SiMe), 0.80 (9H, s, But),
1.24 (6H, s, 2 × Me), 1.39 (3H, d, J 22.3, 2-Me), 3.54–3.76
(2H, s, 1-H2), 4.49 (1H, d, J 12.1, OCHHPh), 4.66 (1H, d,
J 12.1, OCHHPh) and 7.26–7.35 (5H, m, Ph); m/z (EI) 283
(Mϩ Ϫ But).
2,3-Dimethylbutane-2,4-diol 43
A pale yellowish oil (96%), νmax(neat)/cmϪ1 3550; δH(300 MHz,
CDCl3) 0.86 (3H, d, J 7.3, 2-Me), 1.19 (3H, s, Me), 1.27 (3H, s,
Me), 1.75–1.87 (1H, m, 2-H), 3.14–3.48 (2H, br s, 2 × OH)
and 3.64–3.74 (2H, m, 1-H2); m/z (EI) 103.0776 (Mϩ Ϫ Me.
C5H11O2 requires 103.0758).
(؊)-N-[(2R)-3-(tert-Butyldimethylsiloxy)-2-fluoro-2-methyl-
propylidene]benzylamine N-oxide 44
To a stirred mixture of Dess–Martin periodinane (151 mg,
0.357 mmol) and pyridine (55.0 mg, 0.357 mmol) in dry CH2Cl2
(0.8 cm3) at room temperature was added a solution of 17 (26.5
mg, 0.119 mmol) in dry CH2Cl2 (0.2 cm3), and the mixture was
stirred for 1 h at the same temperature. After addition of Et2O,
saturated aq. NaHCO3 and 10% aq. Na2S2O3, the resulting mix-
ture was further stirred for 30 min at the same temperature. The
aqueous layer was separated and extracted with Et2O and the
combined organic layer and extracts were washed with satur-
ated aq. NaHCO3 and brine, dried and evaporated to give the
aldehyde as an oil; νmax(neat)/cmϪ1 1745 and 1260; δH(300 MHz,
CDCl3) 0.05 (6H, s, SiMe2), 0.07 (9H, s, But), 0.89 (3H, d, J
10.3, 2-Me), 3.71–3.99 (2H, m, 3-H2) and 9.78 (d, J 5.1, CHO),
which was used in the next reaction without purification.
A mixture of the above product and N-benzylhydroxylamine
(22.0 mg, 0.179 mmol) in dry CH2Cl2 (0.65 cm3) was stirred
for 12 h at room temperature. After dilution with CH2Cl2, the
mixture was washed with 10% KHSO4 and brine, dried and
evaporated to give a residue, which was purified by column
chromatography on silica gel. Elution with AcOEt–hexane
(3:7, v/v) provided 44 (20.6 mg, 53%) as an oil, [α]2D4 Ϫ41.4 (c
1.44, CHCl3); νmax(neat)/cmϪ1 1600 and 1250; δH(300 MHz,
CDCl3) 0.01 (6H, s, SiMe2), 0.85 (9H, s, But), 1.60 (3H, d, J
22.7, 2-Me), 3.78 (1H, dd, J 18.9 and 11.2, 3-H), 4.24 (1H, dd,
J 30.9 and 11.2, 3-H), 4.85 (1H, d, J 13.7, NCHHPh), 4.90
(1H, d, J 13.7, NCHHPh), 6.74 (1H, d, J 12.1, 1-H) and 7.38
(5H, br s, Ph); δC(125 MHz, CDCl3) Ϫ5.5, Ϫ5.4, 17.5, 18.3,
25.9, 65.2, 70.5, 96.7, 129.1, 129.2, 129.4, 132.5 and 138.3; m/z
(EI) 325.1899 (Mϩ. C17H28FNO2Si requires 325.1873).
1-Benzyloxy-3-(tert-butyldimethylsiloxy)-2,3-dimethylbutane 41
An oil (91%) (Found: C, 70.55; H, 10.6. C19H34O2Si requires C,
70.75; H, 10.65%); νmax(neat)/cmϪ1 1260; δH(300 MHz, CDCl3)
0.03 (6H, s, SiMe2), 0.81 (9H, s, But), 0.97 (3H, d, J 6.9, 2-Me),
1.18 (3H, s, Me), 1.24 (3H, s, Me), 1.69–1.81 (1H, m, 3-H), 3.21
(1H, t, J 9.1, 1-H), 3.69 (1H, dd, J 9.1 and 3.8, 1-H), 4.44 (1H,
d, J 11.9, OCHHPh), 4.49 (1H, d, J 11.9, OCHHPh) and 7.22–
7.34 (5H, m, Ph); m/z (EI) 265 (Mϩ Ϫ But)
3-(tert-Butyldimethylsiloxy)-2-phenylpropan-1-ol 38
To a suspension of LiAlH4 (2.85 g, 75.1 mmol) in dry Et2O (200
cm3) at 0 ЊC was added a solution of dimethyl phenylmalonate
(12.1 g, 51.0 mmol) in dry Et2O (50 cm3), and the mixture was
stirred for 22 h at room temperature. After addition of Et2O
and water (10.0 cm3), the mixture was further stirred and then
filtered through Celite. Evaporation of the filtrate gave the
crude diol (8.85 g) as a colourless oil.
To a mixture of the above product, tert-butyldimethylsilyl
chloride (4.12 g, 26.5 mmol) and DMAP (162 mg, 1.33 mmol)
in dry CH2Cl2 (26 cm3) at 0 ЊC was added triethylamine (4.06
cm3, 29.2 mmol), and the mixture was stirred for 12 h at room
temperature. The mixture was partitioned between water and
Et2O. The organic layer was separated, washed with 10% aq.
KHSO4 and brine, dried and evaporated. Column chrom-
atography of the residue on silica gel with AcOEt–hexane
(1:19, v/v) afforded 38 (2.99 g, 44%) as an oil (Found: C, 67.7;
H, 9.8. C15H26O2Si requires C, 67.6; H, 9.85%); νmax(neat)/cmϪ1
3400; δH(300 MHz, CDCl3) 0.00 (6H, s, SiMe2), 0.85 (9H, s,
But), 2.30–3.30 (2H, m), 3.50–4.30 (4H, m) and 7.00–7.50 (5H,
m, Ph); m/z (EI) 209 (Mϩ Ϫ But).
(؊)-N-[(2R)-2-(tert-Butyldimethylsiloxymethyl)-2-fluorobutyl-
idene]benzylamine N-oxide 45
An oil (63%): [α]D24 Ϫ46.9 (c 1.29, CHCl3); νmax(neat)/cmϪ1 1600
J. Chem. Soc., Perkin Trans. 1, 1997
3049

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and 1255; δH(300 MHz, CDCl3) 0.01 (6H, s, SiMe2), 0.82–0.92
(12H, m), 1.66–1.87 (1H, m, 3-H), 2.21–2.48 (1H, m, 3-H), 3.78
(1H, dd, J 18.3 and 11.3, OCHHCF), 4.29 (1H, dd, J 31.7 and
11.3, OCHHCF), 4.88 (2H, s, NCH2Ph), 6.70 (1H, d, J 12.1,
1-H) and 7.39 (5H, br s, Ph); δC(125 MHz, CDCl3) Ϫ5.4, 7.6,
18.3, 24.1, 25.9, 64.5, 70.4, 99.7, 129.0, 129.1, 129.3, 132.5 and
137.8; m/z (EI) 339.2017 (Mϩ. C18H30FNO2Si requires
339.2030).
N-[3-(tert-Butyldimethylsiloxy)-2-phenylpropylidene]benzyl-
amine N-oxide 54
Needles (58%), mp 113.7–114.2 ЊC (Found: C, 71.6; H, 8.5; N,
3.8. C22H31NO2Si requires C, 71.5; H, 8.45; N, 3.8%); νmax(neat)/
cmϪ1 1590 and 1260; δH(300 MHz, CDCl3) Ϫ0.08 (6H, s,
SiMe2), 0.81 (9H, s, But), 3.85 (1H, dd, J 9.8 and 5.9, 3-H), 3.98
(1H, dd, J 9.8 and 4.9, 3-H), 4.31–4.40 (1H, m, 2-H), 4.91 (2H,
s, NCH2Ph), 6.98 (1H, d, J 7.3, 1-H), 7.22–7.32 (5H, m, Ph) and
7.37–7.41 (5H, m, Ph); δC(75 MHz, CDCl3) Ϫ5.6, 18.1, 25.8,
45.5, 64.4, 69.5, 127.0, 128.3, 128.4, 128.8, 129.0, 129.2, 132.8,
138.6 and 139.2; m/z (EI) 369 (Mϩ).
N-[3-(tert-Butyldimethylsiloxy)-2-fluoro-2-phenylpropylidene]-
benzylamine N-oxide 46
Needles (82%), mp 79.0–79.5 ЊC; νmax(neat)/cmϪ1 1610, 1590
and 1260; δH(300 MHz, CDCl3) Ϫ0.02 (3H, s, SiMe), 0.00 (3H, s,
SiMe), 0.84 (9H, s, But), 4.02 (1H, dd, J 17.6 and 11.4, 3-H),
4.59 (1H, dd, J 31.5 and 11.4, 3-H), 4.89 (2H, s, NCH2Ph), 6.95
(1H, d, J 11.7, 1-H) and 7.20–7.52 (10H, m, 2 × Ph); δC(75 MHz,
CDCl3) Ϫ5.5, 18.3, 25.8, 66.5, 70.8, 125.2, 128.2, 128.6, 128.95,
129.04, 129.3, 132.5 and 137.3; m/z (EI) 387.2030 (Mϩ.
C22H30FNO2Si requires 387.2030).
N-(3-Hydroxy-2,3-dimethylbutylidene)benzylamine N-oxide 55
An oil (27%), νmax(neat)/cmϪ1 3450 and 1600; δH(300 MHz,
CDCl3) 1.08 (3H, d, J 7.1, 2-Me), 1.14 (3H, s, Me), 1.24 (3H, s,
Me), 3.16–3.27 (1H, m, 2-H), 4.93 (2H, s, NCH2Ph), 6.70 (1H,
d, J 7.4, 1-H) and 7.31–7.43 (5H, m, Ph); m/z (EI) 221.1407
(Mϩ. C13H19NO2 requires 221.1415).
N-[3-(tert-Butyldimethylsiloxy)-2,3-dimethylbutylidene]benzyl-
amine N-oxide 56
N-(3-Benzoyloxy-2-fluoro-2-methylbutylidene)benzylamine
N-oxide 47
An oil (90%), νmax(neat)/cmϪ1 1595; δH(300 MHz, CDCl3) Ϫ0.05
(3H, s, SiMe), 0.02 (3H, s, SiMe), 0.73 (9H, s, But), 1.03 (3H, d,
J 6.9, 2-Me), 1.11 (3H, s, Me), 1.18 (3H, s, Me), 2.98–3.07 (1H,
m, 2-H), 4.86 (2H, s, NCH2Ph), 6.59 (1H, d, J 8.0, 1-H) and
7.36 (5H, s, Ph); m/z (EI) 278.1575 (Mϩ Ϫ But. C15H24NO2Si
requires 278.1575).
Needles (75%), mp 103–104 ЊC; νmax(neat)/cmϪ1 1720 and 1600;
δH(300 MHz, CDCl3) 1.30 (3H, d, J 6.6, 3-Me), 1.76 (3H, d, J
23.4, 2-Me), 4.92 (2H, s, NCH2Ph), 5.87 (1H, dq, J 19.8 and 6.6,
3-H), 6.77 (1H, d, J 12.8, 1-H), 7.35–7.58 (8H, m, 8 × ArH)
and 8.01–8.04 (2H, m, 2 × ArH); m/z (EI) 329.1440 (Mϩ.
C19H20FNO3 requires 329.1427).
2-Benzyl-3-[2Ј-(tert-butyldimethylsiloxy)-1Ј-fluoro-1Ј-methyl-
ethyl]-5-ethoxyisoxazolidines 57
N-(2-Fluoro-3-hydroxy-2,3-dimethylbutylidene)benzylamine
N-oxide 48
An oil (86%), νmax(neat)/cmϪ1 1260; δH(300 MHz, CDCl3)
Ϫ0.02–0.10 (6H, m, SiMe2), 0.82–0.95 (9H, m, But), 1.10–1.60
(6H, m), 1.87–2.67 (2H, m), 3.23–4.45 (7H, m), 5.02–5.25 (1H,
m, 5-H) and 7.17–7.45 (5H, m, Ph); m/z (EI) 397.2321 (Mϩ.
C21H36FNO3Si requires 397.2341).
A pale yellowish oil (44%) (Found: C, 65.25; H, 7.6; N, 5.85.
C13H18FNO2 requires C, 65.15; H, 7.45; N, 5.9%); νmax(neat)/
cmϪ1 3200 and 1260; δH(300 MHz, CDCl3) 1.18 (3H, s, Me),
1.22 (3H, d, J 3.3, Me), 1.67 (3H, d, J 23.1, 2-Me), 4.94 (1H, s,
NCH2Ph), 6.42 (1H, br s, OH), 6.91 (1H, d, J 14.6, 1-H) and
7.40–7.46 (5H, m, Ph); m/z (EI) 224 (Mϩ Ϫ Me).
2-Benzyl-3-[1Ј-(tert-butyldimethylsiloxymethyl)-1Ј-fluoro-
propyl]-5-ethoxyisoxazolidines 58
An oil (85%), νmax(neat)/cmϪ1 1260 and 1255; δH(300 MHz,
CDCl3) 0.01–0.11 (6H, m, SiMe2), 0.63–1.03 (9H, m, But), 1.10–
1.28 (6H, m), 1.52–2.68 (6H, m), 3.22–4.44 (7H, m), 5.01–5.22
(1H, m, 5-H) and 7.19–7.47 (5H, m, Ph); m/z (EI) 411.2581
(Mϩ. C22H38FNO3Si requires 411.2605).
N-[3-(tert-Butyldimethylsiloxy)-2-fluoro-2,3-dimethylbutyl-
idene]benzylamine N-oxide 49
An oil (86%) (Found: C, 64.25; H, 9.15; N, 4.2. C19H32FNO2Si
requires C, 64.35; H, 9.4; N, 3.95%); νmax(neat)/cmϪ1 1580;
δH(300 MHz, CDCl3) Ϫ0.04 (3H, s, SiMe), 0.03 (3H, s, SiMe),
0.75 (9H, s, But), 1.19 (3H, d, J 1.6, Me), 1.20 (3H, s, Me), 1.70
(3H, d, J 22.5, 2-Me), 4.83–4.95 (2H, m, NCH2Ph), 6.69 (1H, d,
J 12.1, 1-H) and 7.37 (5H, s); m/z (EI) 296 (Mϩ Ϫ But).
2-Benzyl-3-[2Ј-(tert-butyldimethylsiloxy)-1Ј-fluoro-1Ј-phenyl-
ethyl]-5-ethoxyisoxazolidines 59
An oil (97%), νmax(neat)/cmϪ1 1260; δH(300 MHz, CDCl3)
Ϫ0.25–0.20 (6H, m, SiMe2), 0.60–1.30 (12H, m), 2.10–2.59 (2H,
m), 3.13–4.50 (7H, m), 4.67–5.30 (1H, m, 5-H), 7.11–7.63 (10H,
m, 2 × Ph); m/z (EI) 459.2642 (Mϩ. C26H38FNO3Si requires
459.2605).
N-[3-(tert-Butyldimethylsiloxy)-2-methylpropylidene]benzyl-
amine N-oxide 52
An oil (81%), νmax(neat)/cmϪ1 1595 and 1250; δH(300 MHz,
CDCl3) Ϫ0.02 (3H, s, SiMe), 0.00 (3H, s, SiMe), 0.84 (9H, s,
But), 1.10 (3H, d, J 7.0, 2-Me), 3.13–3.27 (1H, m, 2-H), 3.55
(1H, dd, J 9.8 and 5.1, 3-H), 3.69 (1H, dd, J 9.8 and 4.6, 3-H),
4.87 (2H, s, NCH2Ph), 6.60 (1H, d, J 7.0, 1-H) and 7.37 (5H, s,
Ph); δC(75 MHz, CDCl3) Ϫ5.7, 13.0, 18.0, 25.7, 34.1, 64.2, 69.1,
128.6, 128.7, 129.0, 132.7 and 142.2; m/z (EI) 307.1985 (Mϩ.
C17H29NO2Si requires 307.1968).
2-Benzyl-3-(2Ј-benzoyloxy-1Ј-fluoro-1Ј-methylpropyl)-5-ethoxy-
isoxazolidines 60
A pale yellowish oil (100%), νmax(neat)/cmϪ1 1720 and 1180;
δH(300 MHz, CDCl3) 0.98–1.58 (9H, m), 2.33–2.77 (2H, m),
3.25–4.44 (6H, m), 5.12–5.66 (2H, m), 7.23–7.59 (8H, m) and
7.94–8.04 (2H, m); m/z (EI) 401.2011 (Mϩ. C23H28FNO4
requires 401.2003).
N-[2-(tert-Butyldimethylsiloxymethyl)butylidene]benzylamine
N-oxide 53
2-Benzyl-3-(1Ј-fluoro-2Ј-hydroxy-1Ј,2Ј-dimethylpropyl)-5-
ethoxyisoxazolidines 61
An oil (47%), νmax(neat)/cmϪ1 1597, 1590 and 1260; δH(300
MHz, CDCl3) Ϫ0.03, (3H, s, SiMe), 0.00 (3H, s, SiMe), 0.84
(9H, s, But), 0.90 (3H, t, J 7.5, 3-Me), 1.44–1.65 (2H, m, 3-H2),
2.99–3.11 (1H, m, 2-H), 3.65 (1H, dd, J 9.9 and 4.6, CHHO),
3.74 (1H, dd, J 9.9 and 4.2, CHHO), 4.88 (2H, s, NCH2Ph),
6.59 (1H, d, J 7.3, 1-H) and 7.38 (5H, br s, Ph); δC(75 MHz,
CDCl3) Ϫ5.9, 11.2, 17.7, 21.0, 25.4, 61.6, 69.0, 128.3, 128.6,
132.7, 140.90 and 140.94; m/z (EI) 321.2130 (Mϩ. C18H31NO2Si
requires 321.2124).
Compound 61A: a pale yellowish oil (55%), νmax(neat)/cmϪ1
3350; δH(300 MHz, CDCl3) 1.12–1.51 (12H, m), 2.38–2.86
(2H, m), 3.36–4.69 (6H, m), 5.26–5.32 (1H, m) and 7.26–7.36
(5H, m, Ph); m/z (EI) 311.1897 (Mϩ. C17H26FNO3 requires
311.1874).
Compound 61B: a pale yellowish oil (28%), νmax(neat)/cmϪ1
3400; δH(300 MHz, CDCl3) 0.89 (3H, s), 1.12–1.28 (9H, m),
3.30–4.44 (5H, m), 5.07–5.38 (1H, m), 6.00–6.20 (1H, m) and
3050
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
7.27–7.43 (5H, m, Ph); m/z (EI) 311.1914 (Mϩ. C17H26FNO3
requires 311.1874).
and 2.8, 8-H), 3.41 (1H, br d, J 4.9, 5-H), 3.65 (1H, br dd, J
15.6, 12.2, 3-H), 3.76 (1H, br d, J 12.8, NCHHPh), 3.82 (1H, br
dd, J 39.1, 12.2, 3-H), 4.21 (1H, d, J 12.8, NCHHPh), 5.62 (1H,
br d, J 3.7, 1-H) and 7.16–7.57 (5H, m, Ph); m/z (EI) 237.1141
(Mϩ. C13H16FNO2 requires 237.1165).
Further elution with AcOEt–hexane afforded 68B (11.2 mg,
37%) as an oil, νmax(neat)/cmϪ1 1440 and 1420; δH(300 MHz,
CDCl3) 1.47 (3H, d, J 22.6, 4-Me), 2.08 (1H, br dd, J 12.5
and 1.5, 8-H), 2.13–2.21 (1H, m, 8-H), 3.50 (1H, br dd, J 8.5,
6.1, 5-H), 3.56 (1H, br d, J 10.4, 3-H), 3.88 (1H, d, J 13.4,
NCHHPh), 4.08 (1H, dd, J 11.0 and 10.4, 3-H), 4.23 (1H, d,
J 13.4, NHHPh), 5.56 (1H, br dd, J 5.5 and 3.1, 1-H) and 7.22–
7.46 (5H, m, Ph); m/z (EI) 237.1141.
2-Benzyl-3-[2Ј-(tert-butyldimethylsiloxy)-1Ј-fluoro-1Ј,2Ј-dimethyl-
propyl]-5-ethoxyisoxazolidines 62
Compound 62A: an oil (80%), νmax(neat)/cmϪ1 1170; δH(300
MHz, CDCl3) 0.08–0.15 (6H, m), 0.84–0.90 (9H, m), 1.13–1.56
(12H, m), 2.42–2.86 (2H, m), 3.28–4.46 (5H, m), 5.16–5.34 (1H,
m, 5-H) and 7.22–7.42 (5H, m, Ph); m/z (EI) 425.2768 (Mϩ.
C23H40FNO3Si requires 425.2759).
Compound 62B: a pale yellowish oil (84%), νmax(neat)/cmϪ1
1180; δH(300 MHz, CDCl3) 0.90–0.16 (6H, m, SiMe2), 0.86–
0.90 (9H, m, But), 1.09–1.58 (12H, m), 2.11–2.48 (2H, m), 3.24–
4.52 (5H, m), 4.98–5.08 (1H, m, 5-H) and 7.21–7.44 (5H, m,
Ph); m/z (EI) 425.2769 (Mϩ. C23H40FNO3Si requires 425.2759).
6-Benzyl-4-ethyl-4-fluoro-2,7-dioxa-6-azabicyclo[3.2.1]octanes
69A, B
Compound 69A: an oil (41%), [α]D24 ϩ54.5 (c 0.47, CHCl3);
νmax(neat)/cmϪ1 1440, 1455 and 1450; δH(300 MHz, CDCl3)
0.56 (3H, t, J 7.3, 4-CH2CH3), 1.48 (1H, dq, J 29.9 and 7.3,
4-CHH), 1.55 (1H, dq, J 30.5 and 7.3, 4-CHH), 2.06–2.14 (1H,
m, 8-H), 2.58 (1H, dd, 1H, J 11.9 and 2.7, 8-H), 3.51 (1H, br d,
J 5.5, 5-H), 3.64 (1H, dd, J 15.9 and 12.8, 3-H), 3.72 (1H, d, J
12.2, NCHHPh), 3.81 (1H, dd, J 39.1 and 12.8, 3-H), 4.23 (1H,
d, J 12.2, NCHHPh), 5.63 (1H, br d, J 3.1, 1-H) and 7.28–7.38
(5H, m, Ph); δC(125 MHz, CDCl3) 5.4, 26.3, 32.0, 60.7, 62.0,
67.5, 98.6, 128.0, 128.7, 129.4 and 136.5; m/z (EI) 251.1304
(Mϩ. C14H18FNO2 requires 251.1322).
2-Benzyl-3-[2Ј-(tert-butyldimethylsiloxy)-1Ј-methylethyl]-5-
ethoxyisoxazolidines 63
An oil (84%), νmax(neat)/cmϪ1 1260; δH(300 MHz, CDCl3)
Ϫ0.01–0.30 (6H, m, SiMe2), 0.91–1.27 (15H, m), 1.30–2.55 (3H,
m), 2.87–3.03 (1H, m), 3.31–4.28 (6H, m), 5.09–5.18 (1H, m,
5-H) and 7.23–7.43 (5H, m, Ph); m/z (EI) 379.2546 (Mϩ.
C21H37NO3Si requires 379.2543).
2-Benzyl-3-[1Ј-(tert-butyldimethylsiloxymethyl)propyl]-5-
ethoxyisoxazolidines 64
An oil (88%), νmax(neat)/cmϪ1 1260; δH(300 MHz, CDCl3)
Ϫ0.10–0.04 (6H, m, SiMe2), 0.93–1.72 (17H, m), 2.20–2.26 (1H,
m), 2.32–2.49 (1H, m), 2.95–3.14 (1H, m), 3.30–3.89 (6H, m),
4.05–4.28 (1H, m), 5.05–5.19 (1H, m, 5-H) and 7.20–7.46 (5H,
m); m/z (EI) 393.2694 (Mϩ. C22H39NO3Si requires 393.2699).
Compound 69B: an oil (36%), [α]D24 Ϫ51.2 (c 0.55, CHCl3);
νmax(neat)/cmϪ1 1460 and 1455; δH(300 MHz, CDCl3) 0.96 (3H,
t, J 7.3, 4-CH2CH3), 1.83 (2H, br dq, J 25.0, 7.3, 4-CH2), 2.05
(1H, br dd, J 12.2 and 1.8, 8-H), 2.16 (1H, br ddd, J 12.2, 6.1
and 3.1, 8-H), 3.56 (1H, br dd, J 8.5 and 6.1, 1-H), 3.60 (1H, br
d, J 11.0, 3-H), 3.90 (1H, d, J 13.4, NCHHPh), 4.02 (1H, br t, J
11.0, 3-H), 4.22 (1H, d, J 13.4, NCHHPh), 5.55 (1H, dd, J 5.5
and 3.1, 1-H) and 7.28–7.44 (5H, m, Ph); δC(125 MHz, CDCl3)
7.0, 28.0, 34.5, 61.8, 63.4, 66.2, 97.4, 127.6, 128.5, 128.8 and
136.9; m/z (EI) 251.1300 (Mϩ).
2-Benzyl-3-[2Ј-(tert-butyldimethylsiloxy)-1Ј-phenylethyl]-5-
ethoxyisoxazolidines 65
An oil (95%), νmax(neat)/cmϪ1 1260 and 1255; δH(300 MHz,
CDCl3) Ϫ0.10–0.06 (6H, m, SiMe2), 1.16–1.40 (9H, m, But),
1.52 –1.55 (3H, m), 2.15–2.40 (1H, m), 3.17–4.46 (9H, m), 5.19–
5.30 (1H, m, 5-H) and 7.19–7.60 (10H, m); m/z (EI) 441.2686
(Mϩ. C26H39NO3Si requires 441.2699).
6-Benzyl-4-fluoro-4-phenyl-2,7-dioxa-6-azabicyclo[3.2.1]octanes
70A, B
Compound 70A: an oil (34%), νmax(neat)/cmϪ1 1490 and 1450;
δH(300 MHz, CDCl3) 2.10–2.24 (1H, m, 8-H), 2.84 (1H, br dd,
J 12.1 and 3.3, 8-H), 3.73–3.91 (3H, m), 4.13 (1H, d, J 13.2,
NCHHPh), 4.35 (1H, dd, J 40.1 and 13.0, 3-H), 5.72 (1H, br d,
J 3.3, 1-H) and 7.18–7.63 (10H, m, Ph); m/z (EI) 299.1342 (Mϩ.
C18H18FNO2 requires 299.1322).
2-Benzyl-3-(2Ј-hydroxy-1Ј,2Ј-dimethylpropyl)-5-ethoxyisoxazol-
idines 66
Compound 66A: an oil (32%), νmax(neat)/cmϪ1 1260; δH(300
MHz, CDCl3) 0.84–1.74 (12H, m), 1.89–2.72 (2H, m), 3.12–
4.23 (5H, m), 5.08–5.17 (1H, m) and 7.22–7.43 (5H, m, Ph); m/z
(EI) 247.1594 (Mϩ Ϫ HOEt. C15H21NO2 requires 247.1571).
Compound 66B: an oil (34%), νmax(neat)/cmϪ1 3350 and 1280;
δH(300 MHz, CDCl3) 0.78–1.32 (12H, m), 2.06–2.67 (2H, m),
3.14–4.39 (5H, m), 5.31–5.34 (1H, m, 5-H) and 7.25–7.40 (5H,
m); m/z (EI) 247.1553.
Compound 70B: an oil (38%), νmax(neat)/cmϪ1 1490 and 1450;
δH(300 MHz, CDCl3) 1.94 (1H, br d, J 12.8, 8-H), 1.98–2.11
(1H, m, 8-H), 3.70 (1H, br dd, J 9.3 and 6.0, 5-H), 3.95 (1H, d,
J 13.2, NCHHPh), 4.17–4.43 (3H, m), 5.65 (1H, br dd, J 5.5
and 2.6, 1-H) and 7.23–7.55 (10H, m, 2 × Ph); m/z (EI)
299.1333 (Mϩ).
2-Benzyl-3-[2Ј-(tert-butyldimethylsiloxy)-1Ј,2Ј-dimethylpropyl]-
5-ethoxyisoxazolidines 67B
6-Benzyl-4-fluoro-3,4-dimethyl-2,7-dioxa-6-azabicyclo[3.2.1]-
octanes 71A, B
An oil (60%) (Found: C, 68.1; H, 10.0; N, 3.55. C23H41NO3Si
requires C, 67.95; H, 9.9; N, 3.45%); νmax(neat)/cmϪ1 1160;
δH(300 MHz, CDCl3) 0.04–0.09 (6H, m, SiMe2), 0.82–1.24 (9H,
m, But), 1.62–1.71 (1H, m), 2.04–2.39 (2H, m), 3.02–4.22 (5H,
m), 5.02–5.05 (1H, m, 5-H) and 7.18–7.43 (5H, m, Ph); m/z (EI)
407 (Mϩ ϩ H).
A mixture of 60A, B (61.0 mg, 0.151 mmol) and KOH (13 mg,
0.28 mmol) in MeOH (4.5 cm3) was stirred for 19 h at room
temperature. After concentration under reduced pressure, the
residue was taken up into Et2O. The organic layer was washed
with brine, dried and evaporated. Column chromatography of
the residue on silica gel with AcOEt–hexane (1:17, v/v) as elu-
ent gave the corresponding alcohols (40.0 mg, 98%) as a pale
yellowish oil, νmax(neat)/cmϪ1 3500; δH(300 MHz, CDCl3) 1.25–
1.52 (9H, m), 2.37–2.81 (2H, m), 3.15–4.52 (8H, m), 5.02–5.32
(2H, m) and 7.23–7.41 (5H, m, Ph); m/z (EI) 297.1717 (Mϩ.
C16H24FNO3 requires 297.1740).
A mixture of the above alcohols (26.0 mg, 87 µmol) and
toluene-p-sulfonic acid (9.2 mg, 48 µmol) in benzene (3 cm3) was
heated for 6 h at 50 ЊC. After dilution with Et2O, the mixture
was washed with saturated aq. NaHCO3 and brine, dried and
evaporated to afford a residue, which was subjected to column
6-Benzyl-4-fluoro-4-methyl-2,7-dioxa-6-azabicyclo[3.2.1]-
octanes 68A, B
A mixture of 57A, B (51.9 mg, 0.136 mmol) and toluene-p-
sulfonic acid (13.0 mg, 0.068 mmol) in benzene (2.0 cm3) was
heated under reflux for 7 h. After dilution with AcOEt, the
mixture was washed with saturated aq. NaHCO3 and brine,
dried and evaporated to give a residue, which was subjected to
column chromatography on silica gel. Elution with AcOEt–
hexane (1:10, v/v) provided 68A (12.0 mg, 40%) as an oil,
νmax(neat)/cmϪ1 1460 and 1450; δH(300 MHz, CDCl3) 1.16 (3H,
d, J 21.4, 4-Me), 2.02–2.11 (1H, m, 8-H), 2.62 (1H, dd, J 11.9
J. Chem. Soc., Perkin Trans. 1, 1997
3051

View Article Online
chromatography on silica gel. Elution with Et2O–hexane (1:7,
v/v) provided 71A (13.6 mg, 56%) as a solid, mp 88–90 ЊC
(Found: C, 66.75; H, 7.25; N, 5.75. C14H18FNO2 requires C,
66.9; H, 7.2; N, 5.55%); νmax(neat)/cmϪ1 1180; δH(300 MHz,
CDCl3) 1.15 (3H, d, J 6.8, 3-Me), 1.29 (3H, d, J 22.3, 4-Me),
2.04 (1H, dd, J 12.3 and 1.7, 8-H), 2.12–2.20 (1H, m, 8-H), 3.51
(1H, dd, J 9.3 and 5.7, 5-H), 3.87 (1H, d, J 13.6, NCHHPh),
4.20 (1H, d, J 13.6, NCHHPh), 4.29 (1H, dq, J 19.8 and 6.8,
3-H), 5.51 (1H, dd, J 5.1 and 2.9, 1-H) and 7.23–7.44 (5H, m,
Ph); m/z (EI) 251 (Mϩ).
Further elution gave 71B (5.6 mg, 22%) as an oil (Found: C,
66.65; H, 7.35; N, 5.25); νmax(neat)/cmϪ1 1200; δH(300 MHz,
CDCl3) 1.24 (3H, d, J 23.1, 4-Me), 1.39 (3H, d, J 7.3, 3-Me),
2.00–2.11 (1H, m, 8-H), 2.58 (1H, dd, J 11.9 and 2.4, 8-H), 3.37
(1H, t, J 4.4, 5-H), 3.74 (1H, d, J 12.5, NCHHPh), 3.98 (1H, dq,
J 24.2 and 7.3, 3-H), 4.16 (1H, d, J 12.5, NCHHPh), 5.63 (1H,
d, J 3.3, 1-H) and 7.26–7.39 (5H, m, Ph); m/z (EI) 251 (Mϩ).
6-Benzyl-4-phenyl-2,7-dioxa-6-azabicyclo[3.2.1]octanes 75A, B
Compound 75A: an oil (11%), νmax(neat)/cmϪ1 1500 and 1460;
δH(500 MHz, CDCl3) 1.84–1.91 (1H, m, 8-H), 2.24 (1H, br d,
J 12.2, 8-H), 3.03–3.09 (1H, m, 4-H), 3.56–3.64 (1H, m,
5-H), 3.86 (1H, br d, J 11.6, 3-H), 4.02 (1H, d, J 13.4,
NCHHPh), 4.20 (1H, d, J 13.4, NCHHPh), 4.47 (1H, dd, J
11.6 and 4.9, 3-H), 5.66 (1H, br d, J 3.1, 1-H) and 7.28–7.46
(10H, m, Ph); m/z (EI) 281.1409 (Mϩ. C18H19NO2 requires
281.1416).
Compound 75B: an oil (50%), νmax(neat)/cmϪ1 1500 and 1455;
δH(500 MHz, CDCl3) 2.16 (1H, br d, J 11.6, 8-H), 2.31 (1H, br
ddd, J 11.6, 5.9 and 3.5, 8-H), 2.96 (1H, br dd, J 11.6 and 6.1,
4-H), 3.68 (1H, br d, J 5.9, 5-H), 3.83 (1H, br d, J 12.8,
NCHHPh), 3.86 (1H, br dd, J 11.0 and 6.1, 3-H), 4.13 (1H, d,
J 12.8, NCHHPh), 4.20 (1H, br dd, J 11.6 and 11.0, 3-H), 5.68
(1H, br d, J 3.5, 1-H) and 7.18–7.40 (10H, m, 2 × Ph); m/z (EI)
281.1402.
6-Benzyl-4-fluoro-3,3,4-trimethyl-2,7-dioxa-6-azabicyclo[3.2.1]-
octanes 72A, B
6-Benzyl-3,3,4-trimethyl-2,7-dioxa-6-azabicyclo[3.2.1]octane
76B
Compound 72A: a pale yellowish oil (64%) (Found: C, 67.75;
H, 7.6; N, 5.3. C15H20FNO2 requires C, 67.9; H, 7.6; N, 5.3%);
νmax(neat)/cmϪ1 1150; δH(300 MHz, CDCl3) 1.18 (3H, s, 3-Me),
1.37 (3H, d, J 23.1, 4-Me), 1.85 (3H, d, J 6.6, 3-Me), 2.02 (1H,
dd, J 11.9 and 2.1, 8-H), 2.15–2.23 (1H, m, 8-H), 3.48 (1H, dd,
J 7.8 and 6.2, 5-H), 3.85 (1H, d, J 13.5, NCHHPh), 4.15 (1H,
d, J 13.5, NCHHPh), 5.52–5.54 (1H, m, 1-H) and 7.26–7.45
(5H, m, Ph); m/z (EI) 265 (Mϩ).
A pale yellowish oil (74%), νmax(neat)/cmϪ1 1180; δH(300 MHz,
CDCl3) 0.84 (3H, d, J 7.1, 4-Me), 1.15 (3H, s, Me), 1.39 (3H, s,
Me), 1.75 (1H, dq, J 7.1 and 1.9, 4-H), 1.89 (1H, d, J 11.3, 8-H),
2.15–2.22 (1H, m, 8-H), 3.15 (1H, dd, J 5.8 and 1.9, 5-H), 3.68
(1H, d, J 12.9, NCHHPh), 4.12 (1H, d, J 12.9, NCHHPh),
5.59 (1H, d, J 3.6, 1-H) and 7.21–7.40 (5H, m, Ph); m/z (EI)
247.1557 (Mϩ. C15H21NO2 requires 247.1571).
Compound 72B: a pale yellowish oil (53%) (Found: C, 68.0;
H, 7.6; N, 5.45); νmax(neat)/cmϪ1 1150; δH(300 MHz, CDCl3)
1.19 (3H, s, 3-Me), 1.22 (3H, d, J 23.4, 4-Me), 1.50 (3H, s,
3-Me), 2.00–2.08 (1H, m, 8-H), 2.51 (1H, dd, J 11.7 and 3.4,
8-H), 3.40 (1H, dd, J 5.2 and 1.1, 5-H), 3.74 (1H, d, J 12.6,
NCHHPh), 4.16 (1H, d, J 12.6, NCHHPh), 5.61 (1H, d, J 3.3,
1-H) and 7.26–7.40 (5H, m, Ph); m/z (EI) 265 (Mϩ).
Acknowledgements
We thank Mr K. Kawamura, Ms K. Mushiake, Ms M. Suzuki,
Ms A. Satoh and Ms Y. Maehashi of this Institute for micro-
analyses, spectral measurements and the preparation of the
paper.
6-Benzyl-4-methyl-2,7-dioxa-6-azabicyclo[3.2.1]octanes 73A, B
Compound 73A: an oil (31%), νmax(neat)/cmϪ1 1460 and 1450;
δH(500 MHz, CDCl3) 1.05 (3H, d, J 7.3, 4-Me), 1.84–1.93 (1H,
m, 4-H), 1.94–1.98 (1H, m, 8-H), 2.30 (1H, br d, J 11.6, 8-H),
3.31 (1H, br d, J 11.0, 5-H), 3.36 (1H, dd, J 11.0 and 4.9, 3-H),
3.79 (1H, br d, J 12.8, NCHHPh), 4.18 (1H, br d, J 12.8,
NCHHPh), 4.20 (1H, br dd, J 11.0 and 5.5, 3-H), 5.56 (1H, br
d, J 3.1, 1-H) and 7.27–7.42 (5H, m, Ph); m/z (EI) 219.1259
(Mϩ).
References
1 (a) J. T. Welch and S. Eswarakrishnan, Fluorine in Bioorganic
Chemistry, Wiley, New York, 1991; (b) R. Feller and Y. Kobayashi,
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Asymmetry, 1994, 5, 1041.
Compound 73B: an oil (50%), νmax(neat)/cmϪ1 1470 and 1460;
δH(500 MHz, CDCl3) 0.71 (3H, d, J 6.7, 4-Me), 1.78–1.86 (1H,
m, 4-H), 1.98 (1H, br d, J 11.6, 8-H), 2.18–2.25 (1H, m, 8-H),
3.21 (1H, br d, J 5.5, 5-H), 3.59 (1H, br t, J 11.0, 3-H), 3.65 (1H,
dd, J 11.0 and 6.7, 3-H), 3.73 (1H, d, J 12.8, NCHHPh), 4.21
(1H, d, J 12.8, NCHHPh), 5.59 (1H, br d, J 3.7, 1-H) and 7.25–
7.42 (5H, m, Ph); m/z (EI) 219.1246 (Mϩ. C13H17NO2 requires
219.1259).
5 J. A. Dale, D. L. Dull and H. S. Mosher, J. Org. Chem., 1969, 34,
2543.
6 B. Neises and W. Steglich, Angew. Chem., Int. Ed. Engl., 1978, 17,
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7 M. Ihara, M. Suzuki, A. Hirabayashi, Y. Tokunaga and
K. Fukumoto, Tetrahedron: Asymmetry, 1995, 6, 2053.
8 M. Hudlicky, Org. React., 1988, 35, 513.
9 M. Simizu and H. Yoshioka, Tetrahedron Lett., 1988, 29, 4101.
10 D. B. Dess and J. C. Martin, J. Am. Chem. Soc., 1991, 113, 7277.
11 The results are consistent with the frontier orbital theory:
I. Fleming, Frontier Orbitals and Organic Reactions, Wiley,
Chichester, 1976, p. 148.
12 R. H. Baker, K. H. Cornell and M. J. Cron, J. Am. Chem. Soc., 1948,
70, 1490.
13 N. Cohen, W. F. Eichel, R. J. Lopresti, C. Neukom and G. Saucy,
J. Org. Chem., 1976, 41, 3505.
6-Benzyl-4-ethyl-2,7-dioxa-6-azabicyclo[3.2.1]octanes 74A, B
Compound 74A: an oil (40%), νmax(neat)/cmϪ1 1465 and 1455;
δH(500 MHz, CDCl3) 0.88 (3H, t, J 7.3, 4-CH2CH3), 1.34–1.44
(1H, m, 4-CHH), 1.45–1.55 (1H, m, 4-CHH), 1.55–1.63 (1H, m,
4-H), 1.93–2.02 (1H, m, 8-H), 2.23 (1H, br d, J 11.6, 8-H), 3.39–
3.42 (m, 2H), 3.80 (1H, br d, J 12.8, NCHHPh), 4.14 (1H, dd, J
11.0 and 4.6, 3-H), 4.17 (1H, br d, J 12.8, NCHHPh), 5.55 (1H,
br d, J 3.1, 1-H) and 7.25–7.42 (5H, m, Ph); m/z (EI) 233.1398
(Mϩ).
Compound 74B: an oil (33%), νmax(neat)/cmϪ1 1470 and 1460;
δH(500 MHz, CDCl3) 0.53 (3H, t, J 7.3, 4-CH2CH3), 1.07–1.19
(2H, m), 1.49–1.53 (1H, m, 4-H), 1.95 (1H, br d, J 11.6, 8-H),
2.20–2.28 (1H, m, 8-H), 3.37 (1H, br d, J 5.5, 5-H), 3.59 (1H, br
t, J 10.9, 3-H), 3.66 (1H, t, J 10.9, 3-H), 3.71 (1H, br d, J 12.8,
NCHHPh), 4.23 (1H, br d, J 12.8, NCHHPh), 5.60 (1H, br d, J
3.1, 1-H) and 7.25–7.41 (5H, m, Ph); m/z (EI) 233.1432 (Mϩ.
C14H19NO2 requires 233.1416).
14 P. Grisenti, P. Ferraboschi, A. Manzocchi and E. Santaniello,
Tetrahedron, 1992, 48, 3827.
15 M. Ihara, F. Setsu, M. Shohda (née Hosoda), N. Taniguchi,
Y. Tokunaga and K. Fukumoto, J. Org. Chem., 1994, 59, 5317.
Paper 7/02810E
Received 24th April 1997
Accepted 14th July 1997
3052
J. Chem. Soc., Perkin Trans. 1, 1997