Asymmetric conjugate additions to chiral α,β-unsaturated oxazolines with sulfonyl carbanions

Article abstract of DOI:10.1016/S0040-4020(01)01151-6

Addition of sulfonyl carbanions with or without an electrophilic tether has been shown, under certain conditions, to add to α,β-unsaturated oxazolines in good yields and high de's. When 4-bromobutylsulfonyl carbanions are added to unsaturated oxazolines,

Full text of DOI:10.1016/S0040-4020(01)01151-6

TETRAHEDRON
Pergamon
Tetrahedron 58 62002) 207±213
Asymmetric conjugate additions to chiral a,b-unsaturated
oxazolines with sulfonyl carbanions
Laura F. Basil,a A. I. Meyersa,p and A. Hassnerb
aDepartment of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
bDepartment of Chemistry, Bar Ilan University, Ramat-Gan 52990, Israel
Received 30 August 2001; revised 30 October 2001; accepted 15 November 2001
AbstractÐAddition of sulfonyl carbanions with or without an electrophilic tether has been shown, under certain conditions, to add to
a,b-unsaturated oxazolines in good yields and high de's. When 4-bromobutylsulfonyl carbanions are added to unsaturated oxazolines, three
contiguous stereocenters are formed and good yields of 1,2,3-substituted cyclohexanes are obtained as a 5:1 mixture of only two dia-
stereomers. The sulfonyl substituent may be reductively cleaved to form selectively 1,2-disubstituted cyclohexanes. q 2002 Published by
Elsevier Science Ltd.
Over the years, chiral a,b-unsaturated oxazolines have been
utilized as Michael acceptors with the oxazoline moiety
exerting high stereocontrol over the newly formed stereo-
centers. Examples have been reported using naphthyl,
cinnamyl, and alkyl conjugated systems.1 For instance,
when a variety of organolithiums were added to 1-naphthyl
oxazolines 61 and 1a) followed by addition of an external
electrophile, the resulting tandem addition products were
obtained in good yield with high de's1a,b 6Scheme 1).
Recently, one of us2 has observed interesting conjugate
additions with allylic sulfonyl carbanions to achiral cyclic
and acyclic enones. Products were obtained in good
chemical yields with excellent relative stereoselectivity.
While conjugate additions with highly reactive organo-
lithiums to chiral oxazolines are well precedented,1a,c
addition with more stabilized carbanions 6e.g. sulfonyl
carbanions), have, to date, not been studied. In light of
earlier results, we decided to explore sulfonyl carbanion
additions using chiral a,b-unsaturated oxazolines with the
intention of obtaining control of absolute stereochemistry.
Initial results using the allylic sulfonyl carbanion 22a were
interesting though not synthetically useful. After much
experimental manipulation, the yield of 4 using the styryl
oxazoline 3a1c was never greater than 25%. The best con-
ditions involved forming the sulfonyl carbanion 61.4 equiv.
in THF) with LDA 61.2 equiv.) at 2958C followed by
addition of the oxazoline 61.0 equiv. in THF) then HMPA
64.3 equiv.). The reaction was allowed to proceed at 2958C
for 1 h, then warmed to 2788C and quenched with saturated
Scheme 1.
Scheme 2.
Keywords: Michael additions; pKa of sulfonylmethylenes and unsaturated oxazolines; chiral b-substituted carboxylic acids.
Corresponding author. Tel.: 11-970-491-6897; fax: 11-970-491-2114; e-mail: aimeyers@lamar.colostate.edu
p
0040±4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020601)01151-6

208
L. F. Basil et al. / Tetrahedron 58 *2002) 207±213
added to the oxazoline 3a, a respectable yield of addition
product was observed, and only one diastereomer was
detected, indicating that the addition took place with high
stereoselectivity 6Table 1, entry 1). The synthesis of the
a,b-unsaturated oxazolines 63a±f) were readily achieved
with high trans selectivity by previously described pro-
cedures.1c Interestingly, if the reaction mixture was
quenched at 2788C, only the adduct 9 was seen, yet if the
reaction solution was allowed to warm 62508C) before
quenching, only starting materials were observed, further
supporting the reversibility of the process. Other
a,b-unsaturated oxazolines were examined and the mixed
results obtained are summarized in Table 1. It seems that
electron donating groups 6at the vinylic position of the
a,b-unsaturated oxazolines) on the oxazolines lead to
poor yields of product 6entries 3, 4) whereas electron with-
drawing groups are much more ef®cient 6entries 1, 2, 5),
accompanied by excellent diastereoselectivities 6.20:1).
Scheme 3.
aqueous NH4Cl solution. Interestingly, only two of the
possible eight diastereomers were observed, consistent
with previous results,2 with the major being favored by
6:1 6determined by GC/MS). Noaddition was seen with
the 2-propenyl oxazoline 3b.3 Not surprisingly, due to the
reactivity of the allylic bromide, sulfone self-cyclization to
5 was found to be a competing process 6Scheme 2).
In order to circumvent the formation of 5, the debromo-
allylic sulfone 62a was employed, but no addition to the
oxazoline 3a was observed 6Scheme 3).
This unexpected lack of addition led us to reexamine the
reaction partners. The pKa of a C±H that is both allylic and
adjacent to a sulfone is in the low 20s,4 while the pKa o f a
C±H next to an oxazoline is generally assumed to be in the
mid-30s. From these relative acidities it is reasonable to
assume that addition should not be a favored process.
When intramolecular self-cyclization becomes an option
6cf. 2), the small amount of addition product formed can
be funneled on to oxazoline adduct 4. However, when
self-cyclization is not an option, as with the sulfone 6, the
reversal of the intermediate 7 is highly favored to return to
3a and b and no addition process can occur. In this case
where 2 is employed, most of the sulfonyl anion will be
shunted off to dimerization to give 5 6Scheme 4).
From earlier work,2 the sulfonyl anion additions to electro-
philic ole®ns occur with high anti selectivity 6as drawn in
adduct 9). The structures were determined by nOe NMR
studies on both cyclic and acyclic addition products.
NOESY data on adduct 9a supported anti addition with
the oxazoline systems 6Fig. 1). There was a strong nOe
correlation between the Ha methylene protons 62.7 and
3.5 ppm, benzene-d6, 500 MHz) and the Hb methylene
protons 61.6 and 2.0 ppm, benzene-d6, 500 MHz) which
should not be observable with the syn isomer.
Additions were also carried out with the 4-bromobutyl
sulfone 10 to form the cyclohexyl oxazolines, 11 and 12.
As observed with the previously described cyclopentyl
oxazoline 4, only two of the eight possible diastereomers
were formed with the major one favored by at least 5:1.
Also, in this instance, the chemical yield of the cyclohexyl
derivatives was higher. After many experimental variations
were examined, the optimum conditions appeared to be the
formation of the sulfone anion in THF at 2788C with
To increase the ef®ciency of addition, the less acidic alkyl
sulfone 8 was utilized. Since the pKa o f a C±Ha toa sul-
fone4 is ca. 30 and closer to that of the oxazoline anion, it
should be reasonable to expect to force the equilibrium
toward product. When an excess of the sulfone 8 was
Scheme 4.

L. F. Basil et al. / Tetrahedron 58 *2002) 207±213
Table 1. Addition of alkyl sulfonyl carbanions to chiral a,b-unsaturated oxazolines
209
Entry
R
Product
9a
Conditionsa
Yield 6%)
72c
d.r.b
.96:4
96:4
1
2
Ph 63a)
A
B
9b
78c
3
4
9c
A
A
20d
10d
±
±
9d
5
9e
A
70d
.96:4
a
6A) To a solution of 8 65 equiv.), containing n-BuLi 64.5 equiv.) in THF was added 3. The reaction stirred at 2788C for 30 min, then quenched with 2-
propanol. 6B) To a solution of 8 61.2 equiv.), containing n-BuLi 61.0 equiv.) in THF was added 3. Upon addition of 3, the reaction was quenched immediately
with 2-propanol.
Based on NMR and GC/MS data.
Isolated yield.
GC yield.
b
c
d
5 equiv. of sulfone 10 and 4.5 equiv. LTMP as the base,
the sulfonyl carbon stereocenters were identical in 11 and 12
and that cyclization with bromide displacement had
occurred from different faces. Moreover, comparison of
the 1H NMR 6300 MHz) spectra of the desulfonylated
compounds showed that the phenyl ring and the oxazoline
moiety were cis to each other in the minor adduct 12
6Scheme 5).
followed by addition of the oxazoline 3a. After stirring
the reaction for 16 h at 2788C, the cyclized products 11
and 12 were isolated in 67% combined yield. The separation
of 11 and 12 was readily accomplished, and the structure of
the major adduct 11 was determined by X-ray crystal-
lography. The major diastereomer possessed, as expected,
all its substituents trans to each other and equatorially
disposed. As was observed with 9a, the initial addition
yielded the anti adduct. Desulfonylation5 of 11 and 12
produced distinctly different diastereomers. Along with
the X-ray structures, this further supported the notion that
When adducts 11 and 12 were separately resubjected to
either sulfone anion 10 or to NaOMe, no change in dia-
stereomeric composition of 11 and 12 occurred. This indi-
cated that the observed diastereomeric ratio found is not due
to equilibration during the reaction conditions, and that the
products are kinetically formed.
As the cyclization step was responsible for the loss of
stereoselectivity, it was felt that by slowing the rate of
ring closure, the diastereoselectivity might be increased.
To this end, the less reactive 4-chloro analog of the halo
sulfone 10 was investigated. Unfortunately, not only was the
ring closure not improved, but also the initial addition step
by the sulfonyl anion was no longer selective. It is con-
ceivable that the solution structure of the sulfonyl anion
had dramatically changed in the presence of the chloride,
which may be complexed with Li ion.2d
Figure 1.
Scheme 5.

210
L. F. Basil et al. / Tetrahedron 58 *2002) 207±213
Scheme 6.
Scheme 7.
Reductive desulfonylation of the addition products 9a, 11,
and 12 proceeded well using 5% Na6Hg).5 Once desulfonyl-
ated, the oxazoline moiety of 13 was hydrolyzed to the
known carboxylic acid, 14.6 Comparison of optical rotation
of 14 with the literature value supported the absolute stereo-
chemistry shown 6[a]ˆ21 6c 1, CHCl3); lit.6: [a]ˆ23, neat)
6Scheme 6).
Further studies were initiated in an attempt toenhance the
reactivity of the Michael acceptor. To this end, oxazoline 16
Scheme 8.
Scheme 9.

L. F. Basil et al. / Tetrahedron 58 *2002) 207±213
211
was prepared containing a cyano group adjacent to the
1.1. Synthesis of trans a,b-unsaturated oxazolines
oxazoline. The synthesis of 16 was achieved by ®rst con-
densing 6S)-t-leucinol with the ethyl imidate of malono-
nitrile, and followed with a base-catalyzed condensation
with benzaldehyde. This sequence furnished a single ole®n
isomer 16 in an overall yield of 68% 6Scheme 7).
New compounds 3c±f were synthesized by the procedure
outlined by Shipman and Meyers1c and physical data are
described later.
1.1.1. *4S)-tert-Butyl-2-**E)-2-*4-nitrophenyl)ethenyl)-
oxazoline, 3c. From para-nitrobenzaldehyde, 52% as a
The anion, which should develop a to the cyano-oxazoline
during Michael addition, is now a much weaker base than
the previously mentioned alkyl sulfone 6. When the addition
reaction was undertaken, the starting oxazoline 16 was
consumed very quickly both by the 4-bromobutyl sulfone
anion of 10 and by the allylic sulfone anion 2. Not sur-
prisingly, the reactions leading to 17 and 18 were found to
be non-stereoselective. Due to the poor selectivity observed
for 17 and 18, noexperimental details are included in this
report. Thus, another example has been presented where
comparing the relative pKa's of the nucleophile and the
addition product predicted feasibility of the reaction. There-
fore, adjusting the reversibility to maximize the rate of
product formation 6via pKa values) can lead toa process
which is: `too successful' where the delicate balance of
stereochemistry will suffer 6Scheme 8).
yellow solid mpˆ97±998C; [a]25 ˆ281.6 6c 1.5; CHCl3);
D
1H NMR 6CDCl3, 300 MHz) d 0.93 6s, 9H), 4.01 6dd, Jˆ
10.2, 8.1 Hz, 1H), 4.15 6app t, Jˆ8.4 Hz, 1H), 4.3 6dd, Jˆ
9.9, 8.4 Hz, 1H), 6.79 6d, Jˆ16.2 Hz, 1H), 7.34 6d, Jˆ
16.2 Hz, 1H), 7.6 6d, Jˆ8.7 Hz, 1H), 8.22 6d, Jˆ8.7 Hz,
1H); 13C NMR 6CDCl3, 75 MHz) d 25.8, 33.8, 68.5, 76.3,
119.6, 124.1, 127.8, 136.8, 141.5, 147.8, 162.2; IR 6neat)
1652, 1610, 1530, 1346 cm21; HRMS 6FAB1) fo r
C15H19N2O3 6M1H)1: Calcd 275.1397 Found 275.1394.
1.1.2. *4S)-tert-Butyl-2-**E)-2-*4-methoxyphenyl)ethenyl)-
oxazoline, 3d. From para-anisaldehyde, 51% yield as a
light yellow powder mpˆ82±848C; [a]25 ˆ274.8 6c1,
D
1
CHCl3); H NMR 6CDCl3, 300 MHz) d 0.93 6s, 9H), 3.82
6s, 3H), 3.97 6dd, Jˆ9.9, 7.8 Hz, 1H), 4.12 6app t, Jˆ8.4 Hz,
1H), 4.26 6dd, Jˆ10.2, 8.4 Hz, 1H), 6.54 6d, Jˆ16.2 Hz,
1H), 6.88 6d, Jˆ8.4 Hz, 2H), 7.27 6d, Jˆ16.2 Hz, 1H),
7.42 6d, Jˆ8.4 Hz, 2H); m/z 259 6M)1, 202 6M257
6t-Bu))1.
The high stereoselectivity observed by these successful
conjugate additions 69a, 9b, 9e, 11) are consistent with the
previously described rationale.1c Thus, complexation of the
solvated lithium cation with the p-cloud of the Michael
acceptor 19 may occur on the face anti tothe bulky
t-butyl group, leading to 20 by addition to the b face. In
addition, since more than one stereocenter is being created
in this process the selectivity of the newly formed center
adjacent tothe sulfone appears tobe quite high. This is in
agreement with the model proposed for kinetically-
controlled Michael additions by Seebach and Golinski.7 In
this model, the donor±acceptor p-systems prefer a gauche
relationship to each other, with the H-atom of the donor in
an antiperiplanar orientation to the p-system of the acceptor
6as shown in 21). The former 621) is more stereoelec-
tronically favored than the alternative approach model 22.
The stereochemistry of the products we obtained are in
agreement with the Seebach model, as seen by the NOE
of the a-methylene of the propyl group and the a-methylene
in the 2-position of the oxazoline in 9a. Thus, the proximity
of propyl group to the 2-methylene protons, as seen in 21,
supports the stereochemistry 6Scheme 9).
1.1.3. *4S)-tert-Butyl-2-**E)-*4-methylpentenyl)-oxazo-
line, 3e. From isovaleraldehyde, 62% yield as an opaque
oil [a]25 ˆ216.5 6c 0.56, CHCl3); 1H NMR 6CDCl3,
D
300 MHz) d 0.89 6br s, 12H), 0.92 6s, 3H), 1.72 6sept.,
Jˆ6.6 Hz, 1H), 2.06 6t, Jˆ7.5 Hz, 2H), 3.89 6dd, Jˆ9.9,
8.1 Hz, 1H), 4.04 6dd, Jˆ8.4, 8.4 Hz, 1H), 4.19 6dd, Jˆ
9.9, 8.6 Hz, 1H), 5.99 6d, Jˆ15.9 Hz, 1H), 6.51 6ddd, Jˆ
15.2, 7.2, 7.2 Hz, 1H); HRMS 6FAB1) fo r CH24NO
13
6M1H)1: Calcd 210.1858 Found 218.1863.
1.1.4. *4S)-tert-Butyl-2-**E)-2-*2-furanyl)ethenyl)-oxazo-
line, 3f. From 2-furaldehyde, 44% yield as a yellow solid
which darkens over time mpˆ74±768C; [a]25 ˆ283 6c
D
1
0.44, CHCl3); H NMR 6CDCl3, 300 MHz) d 0.92 6s, 9H),
3.97 6dd, Jˆ10.2, 7.8 Hz, 1H), 4.1 6app t, Jˆ8.1 Hz, 1H),
4.24 6dd, Jˆ9.9, 8.4 Hz, 1H), 4.24 6dd, Jˆ9.9, 8.4 Hz, 1H),
6.41±6.48 6m, 1H), 6.55 6d, Jˆ16.2 Hz, 1H), 7.08 6d, Jˆ
16.2 Hz, 1H), 7.44 6s, 1H); 13C NMR 6CDCl3, 75 MHz) d
25.9, 33.9, 68.2, 76.3, 111.8, 112.3, 113.2, 126.4, 143.8,
151.4, 162.8; IR 6®lm) 1652, 1624, 981, 967 cm21; HRMS
In conclusion the conjugate addition of sulfonyl carbanions
tochiral a,b-unsaturated oxazolines can occur with very
high diastereoselectivity when the appropriate substituents
are present. In the examples where cyclization followed the
addition step, this produced three contiguous stereocenters
formed selectively in one reaction. When the pKa of both
partners are matched appropriately, the addition is not only
very stereochemically ef®cient but also synthetically
practical.
6FAB1) fo r C H18NO2 6M1H)1: Calcd 220.1338 Found
13
220.1328.
1.2. General procedure for addition of sulfone 8 to a,b-
unsaturated oxazolines
Method A: To a solution of 8 62 mmol) in 5 ml dry THF at
2788C was added n-butyllithium 62 M in hexanes,
1.8 mmol). The bright yellow solution was stirred for
15 min at 2788C and the oxazoline 60.4 mmol, dried azeo-
tropically with toluene) was added in 2 ml THF. A dark red
color soon followed and, after stirring for 20 min at 2788C,
the reaction was quenched with 2-propanol. The solution
was allowed to warm to room temperature, and then was
diluted with H2O 615 ml). The mixture was extracted with
1. Experimental
Alkyl sulfones 8 and 10 were synthesized according to
procedures set forth by Crandall and Pradat.8

212
L. F. Basil et al. / Tetrahedron 58 *2002) 207±213
EtOAc 63£30 ml), dried over Na2SO4, and concentrated.
The residue was puri®ed by ¯ash chromatography 65%
EtOAC/hexanes±20% EtOAC/hexanes).
and the solution was stirred for 20 min. Sulfone 10
6242 mg, 0.86 mmol) in 1.5 ml dry THF was added and
the mixture was stirred for 10 min while the reaction turned
yellow in color. The oxazoline 3a 640 mg, 0.17 mmol) in
1 ml THF was added. The reaction was stirred at 2788C and
after 16 h, 1 ml MeOH was added. The solvent was
removed, and the residue was dissolved in EtOAc 630 ml)
and H2O 615 ml). The EtOAc layer was washed with a phos-
phate buffer 6pHˆ4) and brine 615 ml each). The EtOAc
layer was then dried over Na2SO4, ®ltered, and concen-
trated. The residue mixture was puri®ed by ¯ash chroma-
tography 610% EtOAc/hexanes and 25% EtOAc/hexanes)
yielding 40 mg of 11 656%) and 18 mg of 12 611%).
Method B: To a solution of 8 60.48 mmol) in 5 ml dry THF
at 2788C was added n-butyllithium 62 M in hexanes,
0.4 mmol). The bright yellow solution was stirred for
15 min at 2788C and the oxazoline 60.4 mmol, dried azeo-
tropically from toluene) was added in 2 ml THF. A dark red
color soon followed and the reaction was quenched with
2-propanol within 5 min. The remainder of the procedure
was identical tomethod A.
1.2.1. *4S)-tert-Butyl-2-**2R,3S)-2-phenyl-3-phenylsul-
fonylhexyl)-oxazoline, 9a. From oxazoline 3a,1c method
1.3.1.
phenyl-3-phenylsulfonylcyclohexane,
*1R,2R,3S)-1-**4S)-4-tert-Butyl-2-oxazolinyl)-2-
11. Colorless
A, 72% isolated yield as a viscous, colorless oil [a]25
ˆ
D
1
213.8 6c 0.74, CHCl3); H NMR 6CDCl3, 300 MHz) d
0.5±2.0 6m, 16H), 2.88 6dd, Jˆ15, 11 Hz, 1H), 3.16 6dd,
Jˆ15, 4.5 Hz, 1H), 3.25 6ddd, Jˆ4.5, 4.5, 3 Hz, 1H), 3.65
6ddd, Jˆ10.5, 9, 1.5 Hz, 1H), 3.83±3.96 6m, 3H), 7.15±7.25
6m, 5H), 7.6 6dd, Jˆ7.8, 7.8 Hz, 2H), 7.65 6d, Jˆ7.2 Hz,
1H), 7.9 6d, Jˆ7.2 Hz, 2H); 13C NMR 6CDCl3, 75 MHz) d
13.6, 21.4, 25.6, 26.3, 27.1, 33.4, 40.2, 68.9, 75.5, 126.9,
128.4, 128.6, 129.1, 133.5, 139, 140, 164.8; IR 6neat)
needles 6recrystallized from EtOH); mpˆ183±1858C;
[a]25 ˆ2102 6c 0.55, CHCl3); 1H NMR 6CDCl3,
D
300 MHz) d 0.66 6s, 9H), 1.44±1.82 6m, 3H), 1.94±2.16
6m, 2H), 2.46±2.54 6m, 1H), 2.61 6ddd, Jˆ11.4, 11.4,
3.3 Hz, 1H), 3.3 6dd, Jˆ11.4, 11.4 Hz, 1H), 3.38 6ddd, Jˆ
7.5, 7.5, 7.5 Hz, 1H), 3.47 6ddd, Jˆ11.4, 11.4, 3.3 Hz, 1H),
3.76 6dd, Jˆ8.7, 8.7 Hz, 1H), 3.81 6dd, Jˆ7.2, 7.2 Hz, 1H),
6.94 6br s, 5H), 7.17 6dd, Jˆ9, 6 Hz, 2H), 7.32 6d, Jˆ8.1 Hz,
3H); 13C NMR 6CDCl3, 75 MHz) d 25.8, 26.4, 26.5, 31.4,
323.4, 46.7, 47.8, 68, 69.1, 76.1, 128, 128.8, 128.9, 129.5,
130, 133.3, 139.5, 141, 168. This sample was subjected to
single crystal X-ray determination, and the data deposited
with the Cambridge Crystallographic Data Center.
1668 cm21; HRMS 6FAB1) fo r CH34NO3S 6M1H)1:
25
Calcd 428.2259 Found 428.2266.
1.2.2. *4S)-tert-Butyl-2-**2R,3S)-2-*4-nitrophenyl)-3-
phenylsulfonylhexyl)-oxazoline, 9b. From oxazoline 3c,
method B, 78% isolated yield as a colorless oil [a]25
ˆ
D
1
215 6c 0.5, CHCl3); H NMR 6CDCl3, 300 MHz) d 0.6±
0.7 6m, 12H), 1.15±1.28 6m, 2H), 1.85±2.10 6m, 2H), 3.19
6dd, Jˆ13.5, 11.4 Hz, 1H), 3.38±3.49 6m, 3H), 3.7 6app t,
Jˆ8.4 Hz, 1H), 3.82 6app t, Jˆ8.7 Hz, 1H), 4.03 6dd, Jˆ
10.2, 8.7 Hz, 1H), 7.47 6d, Jˆ9 Hz, 2H), 7.59 6app t,
Jˆ7.5 Hz, 2H), 7.66±7.71 6m, 1H), 7.95 6d, Jˆ8 Hz, 2H),
8.10 6d, Jˆ8 Hz, 2H); 13C NMR 6CDCl3, 75 MHz) d 13.9,
21.6, 25.8, 26.9, 32.2, 33.3, 39.8, 65.2, 68.7, 75.8, 123.2,
128.3, 129.3, 130.3, 133.9, 138.9, 146.5, 147.8, 164.6; IR
1.3.2. *1S,2R,3S)-1-**4S)-4-tert-Butyl-2-oxazolinyl)-2-
phenyl-3-phenylsulfonylcyclohexane, 12. Colorless solid;
mpˆ164±1678C; [a]25 ˆ133 6c 0.32, CHCl3); H NMR
1
D
6CDCl3, 300 MHz) d 0.38 6s, 9H), 1.42±1.84 6m, 3H),
1.95±2.0 6m, 1H), 2.07±2.14 6m, 1H), 2.5±2.55 6m, 1H),
2.69 6ddd, Jˆ11.7, 11.7, 3.3 Hz, 1H), 3.3 6dd, Jˆ11.4,
11.4 Hz, 1H), 3.47 6ddd, Jˆ12, 12, 3.6 Hz, 1H), 3.54±
3.64 6m, 2H), 3.92±4.02 6m, 1H), 6.93 6br s, 5H), 7.18
6dd, Jˆ7.8, 7.8 Hz, 2H), 7.3±7.37 6m, 3H); Anal. Calcd
for C25H31NO3S´1/2H2O: C, 69.09; H, 7.42. Found: C,
69.24; H, 7.30.
6neat) 1667, 1520 cm21; HRMS 6FAB1) fo r C H32N2O5S
25
6M1H)1: Calcd 473.2112 Found 473.2095.
1.2.3. *4S)-tert-Butyl-2-**2R,3S)-2-*2-furyl)-3-phenyl-
sulfonylhexyl)-oxazoline, 9e. From oxazoline 3f, method
1.4. Desulfonylation of 11 and 12
A, 70% isolated yield as a light yellow oil [a]25 ˆ216.5 6c
Following the procedure of Trost et al.,5 the sulfonyl oxazo-
line 11 or 12 620 mg), powdered Na2HPO4 6400 mg), and
5% Na6Hg) beads 6,600 mg) were added to2 ml dry
MeOH at 08C. The mixture was allowed to warm to room
temperature and was stirred 12 h. The mercury was removed
by ®ltration, and the solvent was removed in vacuo. The
residue was dissolved in EtOAc and washed with saturated
aqueous NaHCO3. After drying over Na2SO4 and concen-
trating, the residue was puri®ed by ¯ash chromatography
65% EtOAc/hexane).
D
1
0.55, CHCl3); H NMR 6CDCl3, 300 MHz) d 0.67 6t, Jˆ
7.2 Hz, 3H), 0.78 6s, 9H), 1.11±1.25 6m, 2H), 1.62±1.99 6m,
2H), 2.76 6dd, Jˆ15.3, 11.1 Hz, 1H), 3.16 6d, Jˆ14.1 Hz,
1H), 3.47 6ddd, Jˆ10, 3.3, 3.3 Hz, 1H), 3.74 6app t, Jˆ
8.4 Hz, 1H), 3.93±4.07 6m, 3H), 6.15 6d, Jˆ3.3 Hz, 1H),
6.21 6br s, 1H), 7.21 6s, 1H), 7.53±7.67 6m, 3H), 7.93 6d,
Jˆ6.9 Hz, 2H); 13C NMR 6CDCl3, 75 MHz) d 13.8, 21.1,
25.8, 26.6, 26.7, 33.7, 35.0, 65.9, 68.7, 75.7, 107.4, 110.5,
128.9, 129.3, 133.8, 138.8, 141.6, 153.4, 164.9; HRMS
6FAB1) fo r CH31NO4S 6M1H)1: Calcd 418.2052
23
Found 418.2056.
1.4.1. trans-2-Phenylcyclohexyl oxazoline. From oxazo-
line 11, 11 mg as a colorless oil, 85% yield; H NMR
1
1.3. Cyclohexyl oxazolines 11 and 12
6CDCl3, 300 MHz) d 0.65 6s, 9H), 1.4±1.6 6m, 4H), 1.7±
1.9 6m, 3H), 2.1±2.2 6m, 2H), 2.6±2.7 6m, 1H), 2.7±2.9 6m,
1H), 3.5±3.6 6m, 1H), 3.8±3.9 6m, 2H), 7.1±7.2 6m, 5H);
13C NMR 6CDCl3, 75 MHz) d 26.4, 26.8, 27.4, 32.7, 36.3,
44.4, 47.8, 69.5, 127.8, 128.5, 129.2, 146.4, 170; m/z 285
6M)1, 228 6M2t-Bu)1.
The sulfone 10 and the oxazoline 3a were dried azeo-
tropically prior to use. To a solution of tetramethylpiperi-
dine 60.86 mmol, 150 ml) in 2.5 ml dry THF at 2788C was
added n-butyllithium 62 M in hexane, 0.4 ml, 0.77 mmol)

L. F. Basil et al. / Tetrahedron 58 *2002) 207±213
213
1.4.2. cis-2-Phenylcyclohexyl oxazoline. From oxazoline
12, 8 mg as a colorless oil. 62% yield; H NMR 6CDCl3
2. Supporting information
1
300 MHz) d 0.58 6s, 9H), 1.2±1.9 6m, 9H), 2.6±2.7 6m,
2H), 3.5±3.6 6m, 2H), 3.9 6dd, Jˆ6.9, 6 Hz, 1H), 7.0±7.2
6m, 5H); 13C NMR 6CDCl3, 75 MHz) d 26.5, 26.7, 31.9,
33.4, 35.8, 45.3, 48.2, 69.3, 76.4, 127.3, 128.6, 129.3,
145.7, 160.8; m/z 285 6M)1, 228 6M2t-Bu)1.
1H and most 13C NMR spectra for 3c, 3d, 3e, 3f, 9a, 9b, 9e,
11, 12, 16, 17, and 18. X-Ray crystallographic data for
compound 11. NOESY and TOCSY data for adduct 9a.
Acknowledgements
1.4.3. *4S)-4-tert-Butyl-2-**E)-1-cyano-2-phenylethenyl)-
oxazoline, 16. To30 ml Et 2O was added malononitrile
621 mmol) and ethanol 60.8 ml, 21 mmol). While main-
taining vigorous stirring, the solution was aerated with dry
HCl gas for 30 min. The mixture was allowed to stir for 6 h
at room temperature, and then cooled to 08C. The resultant
precipitate 6the desired imidate) was collected, washed with
Et2Om and used without further puri®cation. The imidate
was dissolved in dry CH2Cl2 630 ml), 6S)-t-leucinol was
added, and the mixture was stirred for 12 h at room tempera-
ture. The solution was diluted with saturated aqueous
NaHCO3 650 ml) and extracted with EtOAc 62£50 ml).
The layers were separated and the organic phase was
washed with saturated aqueous NH4Cl 62£50 ml). The
organic layer was dried over Na2SO4, ®ltered, and concen-
trated. The crude residue was puri®ed by ¯ash chroma-
tography 610% EtOAc/hexanes) to yield 1.3 g of oxazo-
line 15 as a dark yellow ®lm 685% yield from the imidate).
To a round-bottomed ¯ask equipped with a Dean±Stark
condenser was combined oxazoline 15 61.4 g, 8.43 mmol),
benzaldehyde 60.78 ml, 7.67 mmol), and 1,8-diaza-
bicyclo[5.4.0]undec-7-ene 60.34 ml, 2.3 mmol) in benzene
640 ml). The solution was heated at re¯ux for 12 h, then
cooled and the solution was washed with brine 630 ml)
and the organic layer drawn off. The organic layer was
dried over Na2SO4, ®ltered, and concentrated. The residue
was puri®ed by ¯ash chromatography 62% EtOAc/hexanes
and 5% EtOAc/hexanes) to give the desired compound 16
61.56 g, 80% yield) as off-white needles. Mpˆ81±838C;
Authors 6L. B., A. I. M.) are grateful to the National Science
Foundation for partial ®nancial support. A. I. M. and A. H.
are alsograteful tothe US±Israel Binatinoal Science
Foundation for ®nancial support. Dr Chris Rithner and
Susie Miller are gratefully acknowledged for obtaining
NOESY, TOCSY NMR and X-ray crystal data, respec-
tively.
References
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[a]25 ˆ289.7 6c 1.8, CHCl3); 1H NMR 6CDCl3,
D
300 MHz) d 0.94 6s, 9H), 4.06 6dd, Jˆ9.9, 7.8 Hz, 1H),
4.23 6dd, Jˆ8.4, 8.3 Hz, 1H), 4.35 6dd, Jˆ10.2, 8.6 Hz,
1H), 7.41±7.51 6m, 3H), 7.88 6s, 1H), 7.9±7.93 6m, 2H);
13C NMR 6CDCl3, 100 MHz) d 159.6, 149.8, 132.2, 132.1,
130.3, 129.1, 115.5, 100.3, 76.4, 69.6, 34.0, 25.7; HRMS
6. Levene, P. A.; Marker, R. F. J. Biol. Chem. 1932, 97, 563.
7. Seebach, D.; Golinski, J. Helv. Chim. Acta 1981, 64, 1413.
8. Crandall, J.; Pradat, C. J. Org. Chem. 1985, 50, 1327.
6FAB1) fo r C H19N2O 6M1H)1: Calcd 255.14974 Found
16
255.14973.