Synthesis and reactions of exo-camphorylsulfonyloxaziridine

Article abstract of DOI:10.1021/jo961991v

The first example of an exo-camphorylsulfonyloxaziridine 4a was prepared by m-CPBA oxidation of camphor imine 9. This surprising result is due to the conformation of the imine which apparently prevents attack of the peracid from the endo direction. Simila

Full text of DOI:10.1021/jo961991v

J . Org. Chem. 1997, 62, 3625-3630
3625
Syn th esis a n d Rea ction s of exo-Ca m p h or ylsu lfon yloxa zir id in e
,
†
‡
†
Franklin A. Davis,* Rajarathnam E. Reddy, Parimala V. N. Kasu,
†
§
Padma S. Portonovo, and Patrick J . Carroll
Departments of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, Drexel University,
Philadelphia, Pennsylvania 19104, and University of Pennsylvania, Pennsylvania 19104
Received October 24, 1996X
The first example of an exo-camphorylsulfonyloxaziridine 4a was prepared by m-CPBA oxidation
of camphor imine 9. This surprising result is due to the conformation of the imine which apparently
prevents attack of the peracid from the endo direction. Similar oxidations of all other camphor-
sulfonylimines result in the endo-oxaziridine exclusively. Asymmetric oxidation of sulfides to
sulfoxides and the R-hydroxylation of enolates by 4 can be interpreted in terms of open transition
states where nonbonded interactions are minimized. These results support earlier conclusions and
predictions of the stereoselectivity and mechanisms of molecular recognition by the N-sulfonylox-
aziridine class of oxidizing reagents.
The enantiopure N-sulfonyloxaziridines 1 and 2, de-
rived from camphor, are important asymmetric oxidants
for the reagent-controlled asymmetric synthesis of sul-
istry is predicted for the product. In this paper we report
our attempts to prepare 3 which ultimately resulted in
the synthesis of the first exo-camphorylsulfonyloxaziri-
dine 4.
1
2
foxides, selenoxides, and the R-hydroxy carbonyl com-
pounds.3 The latter moiety is a key functional group
widely distributed in nature and in pharmacologically
active compounds. Not only do the enantiomeric excesses
often exceed 95%, but the product stereochemistry is
predictable. The mechanism of oxygen transfer from
N-sulfonyloxaziridines to nucleophiles is thought to
,4
N
involve an S 2 type mechanism and is supported by both
theoretical5 and experimental studies. For the oxida-
tion of sulfides to sulfoxides and sulfones, the molecular
recognition is largely steric in origin dictated by the
substituents on the oxaziridine and the substrate.5 For
the hydroxylation of enolates by oxaziridines, the molec-
,6
7
,7
ular recognition was also interpreted in terms of the S
N
2
mechanism where nonbonded interactions are minimized
8
,9
in an “open” or “nonchelated” transition state.
molecular orbital calculations by Bach and co-workers
support the S 2 type mechanism for enolate hydroxyla-
While
N
tions, a “closed” or chelated transition state was pro-
posed.6 It was thought that endo-camphorysulfonyl-
oxaziridine 3 may provide additional details of the
mechanism of oxygen transfer for oxaziridines as well as
being a more effective reagent with enhanced asymmetric
induction. In endo-oxaziridine 3 the sterically demand-
ing elements near the active site oxygen are reversed
compared to 2 and, therefore, the opposite stereochem-
Resu lts a n d Discu ssion
Syn th esis of Oxa zir id in es. The strategy employed
for the synthesis of (+)-4a involves the crucial Michael
reaction of the enolate generated from (+)-camphor (5)
and N,N-bis[(4-methoxyphenyl)methyl]ethenesulfonamide
1
0
(
6) followed by cyclization and oxidation (Scheme 1).
Initial attempts to effect the Michael addition of 6 to 5
using LDA produced only ca. 5% of the desired product
(Table 1, entry 1). The major side product appeared to
be a dimer where 2 equiv of 6 had added to the enolate
as evidenced by NMR and HRMS. Use of LiHMDS or
NaHMDS offered similar or only slightly improved yields
Table 1, entries 2 and 3). However, addition of CuI to
the lithium enolate of camphor, generated using LiH-
MDS, followed by addition of ethenesulfonamide 6 at -78
C and stirring the mixture at -20 °C gave 7 in 82%
isolated yield as a thick gum. Sulfonamide 7 was
obtained as an 80:20 endo/exo mixture of isomers (see
below). Interestingly, the use of KHMDS gave 7 in 44%
yield with the isomeric ratio reversed (Table 1, entry 4).
It has been reported that enolates of camphor react with
alkylating agent to give exo products under kinetic
control and endo products under thermodynamic con-
†
Temple University.
Drexel University.
University of Pennsylvania.
‡
§
X
Abstract published in Advance ACS Abstracts, May 1, 1997.
1) Davis, F. A.; Thimma Reddy, R.; Han, W.; Carroll, P. J . J . Am.
Chem. Soc. 1992, 114, 1428.
(
(
(
(
2) Davis, F. A.; Thimma Reddy, R. J . Org. Chem. 1992, 57, 2599.
3) (a) Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919. (b) Davis,
F. A.; Chen, B.-C. (in Stereoselective Synthesis. Helmchen, G., Hoff-
man, R. W., Mulzer, J ., Schaumann, E., Eds.) Houben-Weyl 1995, E21e,
°
4
497.
4) For reviews on the oxygen transfer reactions of oxaziridines,
(
see: Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703. Davis,
F. A.; Thimma Reddy, R. Comp. Heterocycl. Chem. II. In press.
(
5) Bach, R. D., Wolber, G. J . Am. Chem. Soc. 1984, 106, 1410.
(6) Bach, R. D.; Coddens, B. A.; McDouall, J . J . W.; Schlegel, H. B.;
Davis, F. A. J . Org. Chem. 1990, 55, 3325.
7) Davis, F. A.; Billmers, J . M.; Gosciniak, D. J .; Towson, J . C.;
Bach, R. D. J . Org. Chem. 1986, 51, 4240.
8) Davis, F. A.; Sheppard, A. C.; Chen, B.-C.; Haque, S. M. J . Am.
Chem. Soc. 1990, 112, 6679.
9) Davis, F. A.; Weismiller, M. C.; Murphy, C. K.; Thimma Reddy,
R.; Chen, B.-C. J . Org. Chem. 1992, 57, 7274.
(
(
(
(10) Morris, J .; Wishka, D. G. J . Org. Chem. 1991, 56, 3549.
S0022-3263(96)01991-3 CCC: $14.00 © 1997 American Chemical Society

3
626 J . Org. Chem., Vol. 62, No. 11, 1997
Davis et al.
Sch em e 1
Ta ble 2. Ba se-Ca ta lyzed Isom er iza tion of Su lfon im in e
(
-)-9a
entry
base (1.5 equiv)
temp (°C)/time (h)
endo/exo
1
2
3
4
NaHMDS
LiHMDS
DBU
-78/2.0
-78/2.0
-78/3.0
-78/2.0
93:7
92:8
89:11
90:10
KHMDS
a
Yields are quantitative.
Ta ble 1. Rea ction of th e En ola te of (+)-Ca m p h or (5)
w ith N,N-Bis[(4-m eth oxyp h en yl)m eth yl]-
eth en esu lfon a m id e (6)
F igu r e 1. X-ray structure of exo-camphorylsulfonyloxaziridine
(+)-4a .
temp (°C)/
time (h)
isolated
yield (%)
entry
basea
endo/exo
1
2
3
4
5
LDA
-78 to 0/3.0
-78 to 0/3.5
-78 to 0/3.0
-78 to 0/3.5
mostly dimer
7
15
44
chloride to give oxaziridine 4 in 82% yield as an 80:20
mixture of endo and exo isomers at C(5a). Oxidation of
endo-9 (95:5 endo/exo) gave a nearly identical (82:18)
mixture of oxaziridines indicating that base-catalyzed
epimerization of the imine at C(5a) occurs prior to
oxidation. Crystallization of 4a from EtOAc/n-hexane
afforded the pure endo C(5a) oxaziridine (+)-4a in 60%
yield. All attempts to isolate the minor isomer failed.
The endo configuration at C(5a) of oxaziridine (+)-4a
follows from its X-ray crystal structure (Figure 1), and
LiHMDS
NaHMDS
KHMDS
11:89
80:20
b
LiHMDS-CuI -78 to -20/3.0 82
.0 equiv of (+)-camphor was used. b 3.0 equiv of CuI was used.
a
3
trol.11 Therefore it is unclear why the potassium enolate
of (+)-5, which is presumably formed under thermody-
namically controlled conditions, preferentially affords the
exo product. All attempts to separate the isomers failed.
To the best of our knowledge, this is the first report of
the Michael addition of a ethenesulfonamide to the
lithium cuprate of an enolate.
The removal of p-methoxybenzyl groups in 7 was
readily accomplished using 6.0 equiv of ceric ammonium
nitrate to give sulfonamide 8 in 84% yield. Subsequent
cyclization of 8 was achieved by reflux in toluene with a
catalytic amount of Amberlyst 15 ion exchange resin for
1
this result is confirmed by the H NMR data. The C(5a)
proton appears as a doublet of doublets (J 5a,6 ) 11 Hz,
J
5a,7 ) 3.5 Hz) after decoupling of the C(5) proton which
1
is similar to the H NMR spectra of the endo-(alkylthio)
derivatives of camphor.13
An important advantage of the camphorylsulfonylox-
aziridines is that on oxidation of the corresponding imines
they are obtained as single isomers because the exo face
of the C-N double bond is blocked by the methyl group
of the methylene bridge. In all of the diverse types of
camphorylsulfonyloxaziridines prepared to date, only
3
h, affording camphorsulfonimine 9 in 96% yield.12 That
imine 9 exists as a 80:20 endo/exo mixture was indicated
by the methyl singlets at δ 1.0 and 0.95 for the major
isomer and at δ 0.99 and 0.92 for the minor isomer in
the H NMR spectra. Interestingly, the same 80:20 endo/
exo imine mixture was obtained on cyclization of the
sulfonamide derived from the 11:89 endo/exo mixture of
single isomers are produced which have the endo struc-
ture exclusively, e.g., 1 and 2.1
-4,14
Thus the fact that
the X-ray structure of (+)-4a indicated that it had the
exo structure rather than the endo structure 3 was quite
unexpected (Figure 1). This must mean that fusion of
the 6-membered ring to camphor results in a ring
conformation of 9 such that endo attack by the peracid
oxidizing reagent is much less favorable than exo attack.
1
7
.
Because the isomeric sulfonimines 9 could not be easily
separated by chromatography, an attempt was made to
improve the isomeric ratio by base-catalyzed isomeriza-
tion (Table 2). Indeed, in all cases, treatment of 9 with
base and quenching improved the ratios with NaHMDS,
giving an 93:7 endo/exo mixture (Table 2, entry 1).
Crystallization gave pure endo imine (-)-9.
An approach similar to that shown in Scheme 1, but
starting with (+)-3-chlorocamphor (10),15 was used to
prepare (+)-exo-5a-chlorocamphorylsulfonyloxaziridine
4
b (Scheme 2). Interestingly attempts to added N,N-bis-
[(4-methoxyphenyl)methyl]ethenesulfonamide (6) to the
The mixture of imines 9 was oxidized with 95%
m-CPBA and saturated K CO solution in methylene
2 3
(
13) Goodridge, R. J .; Hambley, T. W.; Haynes, R. K.; Ridley, D. D.
J . Org. Chem. 1988, 53, 2881.
14) For a discussion of formation of endo and exo (fenchonesulfonyl)-
(
(
(
11) Hutchinson, J . H.; Money, T. Can. J . Chem. 1984, 62, 1899.
12) Towson, J . C.; Weismiller, M. C.; Lal, G. S.; Sheppard, A. C.;
oxaziridines, see: Wagner, G.; Verfurth, U. Herrmann, R. Z. Natur-
forsch. 1995, 50b, 283.
Davis, F. A. Org. Synth. 1990, 69, 158.
(15) Kipping, F. A.; Pope, W. J . J . Chem. Soc. 1893, 63, 548.

exo-Camphorylsulfonyloxaziridine
J . Org. Chem., Vol. 62, No. 11, 1997 3627
Sch em e 2
Ta ble 3. Asym m etr ic Oxid a tion of Su lfid es to Su lfoxid es
a
a t r t in CCl4 for 2-4 h
%
ee of sulfoxides (configuration)
entry
oxaziridine
p-tolyl-S(O)-n-Bu
PhCH2S(O)-Me
1
2
3
4
(-)-1b
91 (S)
1 (S)
15 (S)
5 (S)
13 (S)
25 (S)
17 (S)
5 (S)
c
(+)-2a
(+)-4a
(+)-4b
a
Isolated yields 54-70%. b Reference 1. c Reference 9.
F igu r e 2. Transition-state structures for the oxidation of
sulfides.
lithium-copper enolate of 10 resulted in decomposition.
While potassium carbonate/18-crown-6 in toluene gave
a 75:25 endo/exo mixture of 11 (72%), the best conditions
employed the sodium enolate of 10, prepared using NaH,
to give 11 in 88% yield as a 82:18 mixture of isomers
following flash chromatography (Scheme 2). Removal of
the sulfonamide protecting group gave sulfonamide 12
in 70% yield. Cyclization of 12 proved more difficult than
In earlier studies we suggested that complementary
topological dissymmetry near the active site oxygen
in camphorylsulfonyloxaziridines is a fundamental re-
1
,16
quirement for achieving high asymmetric induction.
These studies showed that the molecular recognition
for the asymmetric oxidation of sulfides to sulfoxides
by camphorylsulfonyloxaziridine 1 and 2 was predictable
using a simple active-site model.1 In this model the
,9
8
, and after reflux in toluene with the Amberlyst catalyst
for 24 h, only a 71% yield of 13 could be isolated by flash
chromatography. Importantly, only endo-(+)-13 was
isolated. Apparently, for steric reasons, exo-12 cannot
cyclize to the corresponding imine. Oxidation of (+)-13
gave (+)-4b in 89% isolated yield. The reasonable
assumption made is that C(5a)-chloro oxaziridine (+)-
nonbonded steric interactions between the large (R
L
)
and small (R ) groups of the sulfide (R -S-R ) and the
S
L
S
active-site surface of the oxaziridine were minimized in
a planar transition state arrangement. The related
planar transition-state structures for the oxidation of
sulfides to sulfoxides by 4 are shown in Figure 2. The
low enantiomeric excesses (ee’s) for the asymmetric
oxidation of sulfides to sulfoxides (Table 3) suggests
4
b has the same exo structure as (+)-4a (vide infra).
Asym m etr ic Oxid a tion s. The asymmetric oxidation
L S
that the regions occupied by the R and R group of
of sulfides to sulfoxides by oxaziridines (+)-4a and (+)-
b is summarized in Table 3. Values for camphorylsul-
the sulfide have similar steric environments. The fact
that (S)-sulfoxides are preferentially formed favors
TS-2 and is consistent with the fact that replacement of
X by Cl in 4 lowers the ee (Table 3, compare entries 3
and 4).
The asymmetric hydroxylation of the enolate of 2-meth-
yl-1-tetralone (14) by oxaziridines (+)-4a and (+)-4b is
summarized in Table 4. Hydroxylations were effected,
4
fonyloxaziridines 1 and 2a are included for comparison.
Oxidations were carried out by treating the sulfide with
an equivalent amount of 4 for 2-4 h in CCl
4
at rt (eq 1).
Preparative TLC was used to separate the sulfoxides
from the imines (+)-9 and (+)-13 and the enantiomeric
purity determined by NMR using (R)-(-)-2,2,2-trifluoro-
1
-(9-anthryl)ethanol. The absolute configurations were
established by comparison with those of authentic samples
as previously described.1
(16) Davis, F. A.; Thimma Reddy, R.; McCauley, J . P., J r.; Przeslaw-
ski, R. M.; Harakal, M. E.; Carroll, P. J . J . Org. Chem. 1991, 56, 809.

3
628 J . Org. Chem., Vol. 62, No. 11, 1997
Davis et al.
Ta ble 4. Asym m etr ic Hyd r oxyla tion of th e En ola te of
In summary, studies of the asymmetric oxidation of
sulfides to sulfoxides and enolates to R-hydroxy carbonyl
compounds by the first exo-camphorylsulfonyloxaziridines
2
-Meth yl-1-tetr a lon e (14) by
exo-Ca m p h or ylsu lfon yloxa zir id in es 4 a t r t
2
-methyl-2-hydroxy-1-tetralone (15)
4
can be interpreted in terms of “open” transition states
entry oxaziridine
base
LDA
% isolated yield
% eea (confign)
where nonbonded steric interactions are minimized.
These results provide additional strong support for
similar conclusions and predictions for the stereoselec-
tivity and mechanisms of molecular recognition by the
(+)-2a b
1
2
3
82
90
76
30 (R)
16 (R)
6 (R)
(X ) H) NaHMDS
KHMDS
(+)-2bc
LDA
(X ) Cl) NaHMDS
KHMDS
60
66
61
>95 (R)
>95 (R)
60 (R)
1,3a
4
5
6
N-sulfonyloxaziridine class of oxidizing reagents.
7
8
9
(+)-4a
LDA
(X ) H) NaHMDS
KHMDS
44
57
48
racemic
58 (R)
racemic
Exp er im en ta l Section
Gen er a l P r oced u r e. Column chromatography was per-
formed on silica gel, Merck grade 60 (230-400 mesh). Ana-
lytical and preparative thin layer chromatography were per-
formed on precoated silica gel plates (250 and 1000 µm)
purchased from Analtech Inc. Optical rotations were mea-
sured on Perkin-Elmer Model 341 and 241 polarimeters. THF
was freshly distilled under nitrogen from a purple solution of
sodium and benzophenone. Elemental analyses were per-
formed in the Department of Chemistry, University of Penn-
sylvania, Philadelphia, PA.
1
1
1
0
1
2
(+)-4b
LDA
(X ) Cl) NaHMDS
KHMDS
48
67
53
racemic
6 (R)
racemic
a
Ee’s were determined using Eu(hfc)3. b At 0 °C, see ref 8. c At
-
78 °C, see ref 9.
1
0
N,N-Bis[(4-methoxyphenyl)methyl]ethenesulfonamide (6)
and 3-chloro-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (10)
1
5
were prepared according to literature procedures. m-Chlo-
roperbenzoic acid (m-CPBA) was obtained free of m-chloroben-
zoic acid by being washed with commercial m-CPBA (57-86%)
with buffer at pH 7.4 (NaH
2 3
PO -NaOH) as previously de-
scribed.17
N,N-Bis[(4-m eth oxyp h en yl)m eth yl]-4,7,7-tr im eth yl-3-
oxobicyclo[2.2.1]h ep ta n e-2-eth a n esu lfon a m id e (7) (80:20
En d o/Exo Mixtu r e). In a 50 mL, two-neck, round bottomed
flask equipped with a magnetic stir bar, rubber septum, and
an argon-filled balloon was placed 1.61 g (10.3 mmol) of (+)-
camphor in freshly distilled THF (15 mL). The reaction
mixture was cooled to -78 °C, 10.3 mL (10.3 mmol) of LiHMDS
was added dropwise, and after 15 min the mixture was
warmed to 0 °C and stirred for 20 min. The resulting pale
yellow mixture was cooled to -78 °C, and 1.95 g (10.3 mmol)
of CuI (98%) was quickly added. After the solution was stirred
for 1 h, 1.20 g (3.45 mmol) of N,N-bis[(4-methoxyphenyl)-
methyl]ethenesulfonamide (6) in THF (10 mL) at -78 °C was
added via a double-ended needle to the gray reaction mixture.
The solution was slowly warmed to -20 °C after 30 min,
stirred for 3 h, and quenched at -78 °C by addition of 3 mL of
F igu r e 3. Transition-state structures for the hydroxylation
of the enolates of 14.
as previously described, by addition of 1.0 equiv of the
8
,9
oxaziridine to the preformed enolate at -78 °C.
The
hydroxylations were slow, and it was necessary to warm
the reaction to rt for 12 h prior to quenching at -78 °C
by addition of NH I solution. 2-Hydroxy-2-methyl-1-
4
saturated NH
4
Cl solution. The reaction mixture was warmed
tetralone (15) was isolated by preparative TLC, and the
ee’s and absolute configurations were determined by
comparison with authentic samples.
to rt, diluted with ethyl acetate (40 mL) and water (10 mL),
and filtered through Celite. The aqueous layer was extracted
with ethyl acetate (2 × 15 mL), and the combined organic
portions were washed with water (15 mL) and brine (15 mL),
dried (MgSO ), and concentrated. The product was purified
4
by flash chromatography (15% EtOAc/n-hexane) to afford 1.42
g (82%) of an 80:20 endo/exo mixture of 7 as a thick gum: IR
exo-Camphorylsulfonyloxaziridines 4a and 4b are much
less reactive than endo-oxaziridines 2a and 2b as indi-
cated by the fact that it was necessary to carry out the
hydroxylation of 14 for 12 h at rt (Figure 3). Importantly,
however, even at rt, (+)-4a affords a 2-hydroxy-2-methyl-
(
neat) 2959, 1736, 1611, 1513, 1249, 1142, 1034, 907, 824, 748
-1
1
cm ; H NMR (CDCl ) δ 0.79 (s, 80/100, 3H), 0.84 (s, 20/100,
3H), 0.89 (s, 3H), 0.92 (s, 80/100, 3H), 0.98 (s, 20/100, 3H),
3
1
-tetralone (15) in 58% ee having the (R)-configuration
(
Table 4, entry 8). This result is better than that of
1.25-2.20 (m, 8H), 2.92-3.05 (m, 1H), 3.1-3.2 (m, 1H), 3.8
oxaziridine (+)-2a (0 °C, 30% ee), but poorer than that
of chloro oxaziridine (+)-2b (-78 °C, >95% ee) (Table 4,
entries 1 and 5). As previous studies have shown these
results can be rationalized in terms of transition-state
structures TS-5 and TS-6 where nonbonded steric inter-
actions are minimized in an “open” transition state.3 In
these transition states the reasonable assumption is
made that the sterically most demanding group in the
vicinity of the enolate C-C bond is the enolate-oxygen
metal aggregate.8 This interpretation predicts that
increasing the size of X will result in increased steric
congestion in TS-5, and poorer asymmetric induction is
observed, e.g., 4a (X ) H) 58% ee vs 4b (X ) Cl) 6% ee
(s, 6H), 4.25 (s, 4H), 6.85 (d, 4H, J ) 8.60 Hz), 7.18 (d, 4H, J
+
)
8.46 Hz); mass spectrum (m/z) 499 (M ), 435, 378, 256, 147,
+
1
5
36, 121; exact mass calcd for C28H37NSO 522.2290 (M + Na),
+
found 522.2289 (M + Na).
4
,7,7-Tr im et h yl-3-oxob icyclo[2.2.1]h ep t a n e-2-et h a n e-
su lfon a m id e (8) (80:20 En d o/Exo Mixtu r e). In a 500 mL,
single-neck, round bottom flask fitted with magnetic stir bar
a
was placed 1.42 g (2.84 mmol) of 7, dissolved in CH
mL), and water (80 mL) followed by the addition of 12.45 g
22.72 mmol) of ceric ammonium nitrate (CAN). The reaction
3
CN (200
(
,9
mixture was stirred for 6 h at rt, concentrated, and extracted
with ethyl acetate (2 × 40 mL). The combined organic phases
(17) Bortolini, O.; Campestrini, S.; Di Furia, F.; Modena, G. J . Org.
(
Table 4, entries 8 and 11).
Chem. 1987, 52, 5093.

exo-Camphorylsulfonyloxaziridine
J . Org. Chem., Vol. 62, No. 11, 1997 3629
were washed with brine (15 mL), dried (MgSO
trated, and the crude product was purified by flash chroma-
tography (40% EtOAc/n-hexane) to give 0.62 g (84%) of an 80:
4
), and concen-
rubber septum, and an argon-filled balloon was placed 2.0 g
(10.75 mmol, 2 equiv) of 3-chloro-1,7,7-trimethylbicyclo[2.2.1]-
heptane-2-one (10) in freshly distilled THF (60 mL). The
reaction flask was cooled to 0 °C, 1.04 g (43 mmol) of NaH
was added, and after 15 min the mixture was warmed to rt
and stirred for 20 min. The resulting suspension was cooled
to 0 °C, and 1.72 g (5.38 mmol) of N,N-bis[(4-methoxyphenyl)-
methyl]ethenesulfonamide (6) in THF (20 mL) was added via
syringe. After 1 h the reaction mixture was warmed to rt and
stirring was continued until TLC indicated the absence of
starting material (typically 1.5 h). The reaction mixture was
2
2
0 endo/exo mixture of sulfonamides 8: IR (KBr) 3350, 3265,
960, 1729, 1560, 1324, 1150, 913, 786, 732 cm-1; H NMR
1
3
(CDCl ) δ 0.86 (s, 80/100, 3H), 0.87 (s, 20/100, 3H), 0.91 (s,
3
8
2
H), 0.95 (s, 80/100, 3H), 1.01 (s, 20/100, 3H), 1.3-2.35 (m,
H), 3.15-3.45 (m, 2H), 4.75 (bs, 2H); mass spectrum (m/z)
+
59 (M ), 231, 151, 135, 108, 95, 83, 69. Anal. Calcd for
C
12
H
21NSO
3
: C, 55.5; H, 8.16; N, 5.40. Found: C, 55.10; H,
8
.09; N, 5.55.
[
4aS-(4ar,5r,8r)]-4,4a,5,6,7,8-Hexah ydr o-8,9,9-tr im eth yl-
quenched at rt by addition of 5 mL of NH
4
Cl solution and
5
5
,8-m eth a n o-3H-2,1-ben zoth ia zin e 2,2-Dioxid e (9). In a
0 mL, one-neck round bottom flask fitted with a Dean-Stark
column and a magnetic stir bar were placed 1.23 g (4.7 mmol)
diluted with EtOAc (40 mL) and water (10 mL). The aqueous
phase was extracted with ethyl acetate (2 × 20 mL), and the
combined organic phases were washed with water (15 mL) and
of sulfonamide 8 in toluene (17 mL) and 0.21 g of Amberlyst-
4
brine (15 mL), dried (MgSO ), and concentrated. The crude
1
5 ion exchange resin. The mixture was refluxed for 3 h,
cooled, and filtered, and the filtrate was washed with CH Cl
25 mL). Concentration of the combined organic phases gave
product was purified by flash chromatography (20% EtOAc/
hexanes) to afford 2.32 g (88%) of an 82:18 endo/exo mixture
of 11 as a thick gum: IR (neat) 2960, 1751, 1611, 1585, 1512,
2
2
(
1
-
1 1
.1 g (96%) of an 80:20 endo/exo mixture of isomers. An
3
1303, 1248 cm ; H NMR (CDCl ) δ 0.85 (s, 82/100, 3H), 0.9
analytically pure sample of endo imine 9 was obtained as white
crystals by crystallization (Et
(s, 82/100, 3H), 0.95 (s, 18/100, 3H), 1.0 (s, 18/100, 3H), 1.08
(s, 82/100, 3H), 1.1 (s, 18/100, 3H), 1.57-2.7 (m, 7H), 3.3-3.4
(m, 2H), 3.81 (s, 6H), 4.25 (m, 4H), 6.86-6.89 (d, 4H, J ) 8.58
2
O/n-hexane): mp 90-91 °C;
3
); IR (KBr) 2962, 1737, 1639, 1451,
2
0
[
1
(
R]
D
-37.38° (c 0.67, CHCl
325, 1155, 1141, 1100, 1015, 921, 869, 832 cm ; H NMR
) δ 0.95 (s, 3H), 1.0 (s, 3H), 1.06 (s, 3H), 1.4-1.5 (m,
H), 1.7-1.9 (m, 2H), 2.0-2.2 (m, 4H), 2.6-2.7 (m, 1H), 3.25-
-
1
1
Hz), 7.2-7.23 (d, 4H, J ) 8.63 Hz); mass spectrum (m/z) 533
+
CDCl
3
(M ), 256, 148, 136, 121, 91, 77; mass calcd for C28
534.094, obsd 533.
3
H36NSO Cl
1
3
1
4
1
2
.35 (m, 1H), 3.5-3.6 (m, 1H); 13C NMR (CDCl
) δ 10.376,
9.258, 20.439, 21.103, 22.915, 35.551, 43.753, 47.944, 48.753,
9.982, 59.107, 200.252; mass spectrum (m/z) 241 (M ), 226,
98, 162, 134, 95, 84, 67; exact mass calcd for C12H19NSO
2
3
2-Ch lor o-4,7,7-tr im eth yl-3-oxobicyclo[2.2.1]h ep ta n e-2-
eth a n esu lfon a m id e (12) (82:18 En d o/Exo Mixtu r e). In a
500 mL single-neck, round bottom flask fitted with magnetic
stir bar were placed 1.77 g (3.31 mmol, 1 equiv) of chloro
+
+
+
+
+
42.1214 (M + H ), experimental mass 242.1215 (M + H ).
C, 59.72; H, 7.93; N, 5.80.
Found: C, 59.79; H, 7.90; N, 5.53.
5aS-(5ar,6r,9r,9aS*)]-(+)-Hexah ydr o-9,10,10-tr im eth yl-
,9-m eth a n o-4H-oxa zir in o[3,2-j][2,1]ben zoth ia zin e 3,3-
adduct 11 in CH CN (100 mL) and water (50 mL). To the
3
Anal. Calcd for C12
H
19NSO
2
:
reaction mixture was added 14.7 g (26.83 mmol) of ceric
ammonium nitrate (CAN), and the solution was stirred for 6
h at rt. The solvent was removed, the residue was dissolved
in ethyl acetate (2 × 40 mL), and the combined organic extracts
[
6
Dioxid e (4a ). In a 500 mL, three-neck Morton flask fitted
with a overhead mechanical stirrer were placed 1.1 g (4.4
were washed with brine (15 mL), dried (MgSO ), and concen-
4
trated. The crude product was purified by flash chromatog-
raphy (40% EtOAc/n-hexane) to give 0.673 g (70%) of an 82:
18 endo/exo mixture of 12 as a thick gum: IR (neat) 3350,
mmol) of imine 9 in CH
CO (69 mL), followed by 3.03 g (17.5 mmol) of m-CPBA
95%). The reaction mixture was vigorously stirred for 48 h
at which time a sodium sulfite solution (10 mL) was added.
The reaction mixture was diluted with CHCl (50 mL) and
water (25 mL). The aqueous layer was extracted with CHCl
2 2
Cl (70 mL) and saturated aqueous
K
2
3
(
3265, 2960, 1729, 1560, 1324, 1150, 913, 786, 732 cm-1
; H
1
NMR (CDCl
00, 3H), 1.09 (s, 82/100, 3H), 1.15 (s, 18/100, 3H), 1.65-1.72
m, 2H), 1.9-2.0 (m, 1H), 2.23-2.3 (m, 2H), 2.46-2.53 (m, 1H),
.66-2.69 (m, 1H), 3.5-3.56 (m, 1H), 3.63-3.66 (m, 1H), 4.58
3
) δ 0.94 (s, 3H), 0.98 (s, 82/100, 3H), 1.04 (s, 18/
3
1
3
(
(
2 × 20 mL), and the combined organic phases were washed
2
with a saturated NaHCO
mL), dried (MgSO ), and concentrated. The product was
4
3
solution (2 × 15 mL) and brine (15
+
+
(
8
4
bs, NH); mass spectrum (m/z) 294 (M + H ), 277, 250, 133,
3, 71. Anal. Cacld for C12
.77. Found: C, 49.08; H, 6.65; N, 4.20.
4a R-(4a r,5r,8r)]-(+)-4a -Ch lor o-4,4a ,5,6,7,8-h exa h yd r o-
,9,9-t r im et h yl-5,8-m et h a n o-3H -2,1-b en zot h ia zin e 2,2-
3
H20NSO Cl: C, 49.06, H, 6.86; N,
purified by flash chromatography (20% EtOAc/n-hexane) to
afford 0.96 g (82%) of oxaziridine 4a as an 80:20 endo/exo
mixture. Crystallization (EtOAc/n-hexane) afforded the pure
[
8
2
0
endo-oxaziridine as white crystals: mp 115-116 °C; [R]
88.83° (c 1.54, CHCl ); IR (KBr) 2966, 1356, 1154, 846, 776,
76, 529 cm ; H NMR (CDCl ) δ 0.65 (s, 3H), 0.95 (s, 3H),
.00 (s, 3H), 1.5-2.3 (m, 7H), 2.59-2.7 (m, 1H), 3.2-3.3 (m,
D
Dioxid e (13). In a 50 mL, one-neck, round bottom flask fitted
with a Dean-Stark column and a magnetic stir bar was placed
+
3
-
1
1
6
1
2
2
3
0
.490 g (1.67 mmol) of chloro sulfonamide 12 in toluene (7 mL)
with 0.082 g of Amberlyst-15 ion exchange resin. The reaction
mixture refluxed for 24 h at which time it was cooled and
filtered, and the filtrate was washed with CH Cl (10 mL).
2 2
Concentration gave a solid residue which was purified by flash
chromatography to give 0.322 g (71%) of (+)-13: mp 152-155
1
3
H); C NMR (CDCl
2.016, 30.823, 38.459, 43.944, 47.205, 50.821, 100.631; mass
spectrum (m/z) 257 (M ), 214, 176, 161, 150, 107, 91. Anal.
Calcd for C12 : C, 56.00; H, 7.44; N, 5.44. Found: C,
5.77; H, 7.48; N, 5.11.
3
) δ 8.051, 19.173, 19.231, 19.465, 20.146,
+
H
19NSO
3
5
°
C; [R]20
D
+197.6 (c 0.7, CHCl
3
); IR (KBr) 2962, 1649, 1341,
Typ ica l P r oced u r e for Isom er iza tion of Su lfon im in e
. In a 25 mL, oven dried, two-necked, round bottom flask
-
1 1
1
1
2
326, 1158, 1139, 794 cm ; H NMR (CDCl ) δ 1.01 (m, 3H),
3
9
.059 (m, 3H), 1.15 (s, 3H), 1.76-1.82 (m, 1H), 1.96-2.03 (m,
H), 2.18 (d, 1H, J ) 3.7 Hz), 2.37-2.41 (m, 1H), 2.52-2.56
fitted with an argon balloon, rubber septum, and a magnetic
stir bar was placed 0.030 g (0.12 mmol) of the 80:20 endo/exo
mixture of sulfonimine 9 in freshly distilled THF (2 mL). The
reaction flask was cooled to -78 °C, and 0.18 mL (0.18 mmol)
of 0.1 M solution of the appropriate base was added dropwise.
The reaction mixture was stirred for 2 h and quenched with
(m, 1H), 2.79-2.80 (m, 1H), 3.47-3.52 (m, 1H), 4.06-4.13 (td,
1
2
6
H, J 1,3 ) 13.2 Hz; J 1,2 ) 5.5 Hz); 13C NMR (CDCl
1.26, 22.84, 26.33, 29.06, 35.02, 47.23, 49.08, 53.10, 56.22,
4.26, 188.51; mass calcd for C12 Cl 275, obsd 275.
18NSO Cl: C, 52.26; H, 6.58; N, 5.08.
3
) δ 10.74,
H
18NSO
2
Anal. Calcd for C12
H
2
4
an aqueous NH Cl solution or camphorsulfonic acid [0.12 mmol
Found: C, 52.20; H, 6.52; N, 4.80.
in 1 mL of THF]. After being warmed to rt, the mixture was
diluted with ethyl acetate (10 mL), the aqueous phase was
extracted with ethyl acetate (2 × 5 mL), the combined organic
[5a R-(5a r,6r,9r,9a S*)]-(+)-5a -Ch lor oh exa h yd r o-9,10,-
10-t r im e t h y l-6,9-m e t h a n o -4H -o x a zir in o [3,2-j][2,1]-
ben zoth ia zin e 3,3-Dioxid e (4b). In a 250 mL, three-neck
Morton flask fitted with an overhead mechanical stirrer
were placed 0.241 g (0.88 mmol) of endo chloro imine 13 in
4
phases were washed with brine (10 mL) and dried (MgSO ).
Concentration afforded sulfonimine 9 enriched in the endo
isomer.
2
-Ch lor o-N,N-bis[(4-m eth oxyp h en yl)m eth yl]-4,7,7-tr i-
2 2 2 3
CH Cl (120 mL), saturated aqueous K CO (24 mL), and 0.456
m e t h yl-3-oxob icyclo[2.2.1]h e p t a n e -2-e t h a n e su lfon a -
m id e (11) (82:18 En d o/Exo Mixtu r e). In a 100 mL, two-
neck, round bottom flask equipped with magnetic stir bar,
g (2.63 mmol) of m-CPBA (95%). The reaction mixture was
vigorously stirred for 48 h, at which time a saturated solution
of sodium sulfite (5 mL) was added. The solution was diluted

3
630 J . Org. Chem., Vol. 62, No. 11, 1997
Davis et al.
with CHCl
was extracted with CHCl
phases were washed with a saturated NaHCO
5 mL) and brine (15 mL), dried (MgSO ), and concentrated.
Crystallization (EtOAc/n-hexane) of the residue gave 0.258 g
3
(50 mL) and water (25 mL), and the aqueous phase
(2 × 20 mL). The combined organic
solution (2 ×
with an argon-filled balloon, a rubber septum, and a magnetic
stir bar was placed 0.024 g (0.15 mmol) of 2-methyl 1-tetralone
in freshly distilled THF (2 mL). The reaction flask was cooled
to -78 °C, and 0.18 mL (0.18 mmol, 1.2 equiv) of a 1.0 M
solution of the appropriate base was added via syringe. After
30 min, the reaction mixture was warmed to 0 °C, stirred for
30 min, and cooled to -78 °C and a solution of 0.056 g (0.25
mmol) of the oxaziridine in THF (1 mL) was added via syringe.
The reaction mixture was warmed to rt after 30 min, stirred
for 12 h, and quenched at -78 °C by addition of 3 mL of a
3
3
1
4
2
0
(
89%) of endo-4b: mp 152-153 °C; [R]
D
+63.5° (c 1.76,
); IR (KBr) 2952, 2361, 1734, 1349, 1165, 788, 668 cm-1
) δ 0.79 (s, 3H), 1.10 (s, 3H), 1.2 (s, 3H), 1.74-
CHCl
3
;
1
H NMR (CDCl
3
1
2
3
.81 (m, 1H), 1.89-1.94 (m, 2H), 2.2 (d, 1H, J ) 3.7 Hz), 2.39-
.44 (m, 1H), 2.45-2.49 (m, 1H), 2.88-2.94 (m, 1H), 3.24-
.28 (m, 1H), 3.74-3.8 (td, 1H, J 1,3 ) 14.3 Hz; J 1,2 ) 2.6 Hz);
freshly prepared saturated NH
4
I solution. The solution was
1
3
C NMR (CDCl
3
) δ 9.361, 20.816, 22.966, 26.189, 28.440,
diluted with ethyl acetate (10 mL), the aqueous phase was
3
7.04, 43.97, 47.49, 50.05, 55.59, 73.39, 100.13; mass spectrum
extracted with ethyl acetate (2 × 5 mL), and the combined
+
(
m/z) 291 (M ), 256, 192, 174, 105, 91, 77, 69. Anal. Cacld
for C12 Cl: C, 49.39; H, 6.11; N, 4.8. Found: C, 49.65;
H, 6.64; N, 4.69.
2 2 3
organic phases were washed with a saturated Na S O solution
H
18NSO
3
(2 × 15 mL) and brine (10 mL), dried (MgSO
4
), and concen-
trated. The crude product was purified by preparative TLC
Typ ica l P r oced u r e for Asym m etr ic Oxid a tion of Su l-
fid es to Su lfoxid es. In a 10 mL, oven-dried, two-necked,
round bottom flask fitted with an argon-filled balloon, a rubber
septum, and a magnetic stir bar was placed 0.25 mmol of the
(25% EtOAc/n-hexane) to give 15 as an oil with spectral
2
0
properties identical with an authentic sample: ee 58%; [R]
D
9
20
+9.9° (c 0.66, MeOH) [lit. [R]
D
+17.3° (c 2.0, MeOH)].
appropriate oxaziridine in CCl
4
(10 mL). The sulfide, 1.1
Ack n ow led gm en t. Financial support of the Na-
tional Science Foundation is gratefully acknowledged.
equiv, in CCl (5 mL) was added to the reaction mixture which
4
was stirred at rt for 2-4 h. After the oxidation was complete,
as indicated by TLC, the solvent was removed and the
sulfoxide isolated by preparative TLC (silica gel G). The
enantiomeric purity and absolute configuration were deter-
mined by comparison with authentic samples and literature
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
endo/exo mixtures of compounds 7 and 11 (2 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
1
values.
Typ ica l P r oced u r e for Hyd r oxyla tion of 2-Meth yl-1-
tetr a lon e (14) to 2-Hyd r oxy-2-m eth yl-1-tetr a lon e (15). In
a 25 mL, oven-dried, two-necked, round bottom flask fitted
J O961991V