Asymmetric sulfonium ylide mediated cyclopropanation: Stereocontrolled synthesis of (+)-LY354740

Article abstract of DOI:10.1002/chem.200500693

The reaction of ester-stabilized sulfonium ylides with cyclopentenone to give (+)-5 ((1S,5R,6S)-ethyl 2-oxobicyclo[3.1.0]hexane-6-carboxylate), an important precursor to the pharmacologically important compound (+)-LY354740, has been studied using chiral sulfides operating in both catalytic (sulfide, Cu(acac)₂, ethyl diazoacetate. 60°C) and stoichiometric modes (sulfonium salt, base, room temperature). It was found that the reaction conditions employed had a major influence over both diastereo- and enantio-selectivity. Under catalytic conditions, good enantioselectivity with low diastereoselectivity was observed, but under stoichiometric conditions low enantioselectivity with high diastereoselectivity was observed. When the stoichiometric reactions were conducted at high dilution, diastereoselectivity was reduced. This indicated that base-mediated betaine equilibration was occurring (which is slow relative to ring closure at high dilution). Based on this model, conditions for achieving high enantioselectivity were established as follows: use of a preformed ylide, absence of base, hindered ester (to reduce ylide-mediated betaine equilibration), and low concentration. Under these conditions high enantioselectivity (95% ee) was achieved, albeit with low diastereocontrol. Our model for selectivity has been applied to other sulfonium ylide mediated cyclopropanation reactions and successfully accounts for the diastereoselectivity observed in all such reported reactions to date.

Full text of DOI:10.1002/chem.200500693

DOI: 10.1002/chem.200500693
Asymmetric Sulfonium Ylide Mediated Cyclopropanation: Stereocontrolled
Synthesis of (+)-LY354740
Varinder K. Aggarwal* and Emma Grange[a]
Abstract: The reaction of ester-stabi-
lized sulfonium ylides with cyclopente-
none to give (+)-5 ((1S,5R,6S)-ethyl 2-
oxobicyclo[3.1.0]hexane-6-carboxylate),
an important precursor to the pharma-
cologically important compound (+)-
LY354740, has been studied using
chiral sulfides operating in both cata-
lytic (sulfide, Cu(acac)2, ethyl diazoace-
tate, 608C) and stoichiometric modes
(sulfonium salt, base, room tempera-
ture). It was found that the reaction
conditions employed had a major influ-
ence over both diastereo- and enantio-
selectivity. Under catalytic conditions,
good enantioselectivity with low dia-
stereoselectivity was observed, but
under stoichiometric conditions low
enantioselectivity with high diastereo-
selectivity was observed. When the
stoichiometric reactions were conduct-
ed at high dilution, diastereoselectivity
was reduced. This indicated that base-
mediated betaine equilibration was oc-
curring (which is slow relative to ring
closure at high dilution). Based on this
model, conditions for achieving high
enantioselectivity were established as
follows: use of a preformed ylide, ab-
sence of base, hindered ester (to
reduce ylide-mediated betaine equili-
bration), and low concentration. Under
these conditions high enantioselectivity
(95% ee) was achieved, albeit with low
diastereocontrol. Our model for selec-
tivity has been applied to other sulfoni-
um ylide mediated cyclopropanation
reactions and successfully accounts for
the diastereoselectivity observed in all
such reported reactions to date.
Keywords: asymmetric synthesis ·
cyclopropanation · diastereoselec-
tivity · LY354740 · sulfur ylides
Introduction
l-Glutamic acid is an important excitatory amino acid neu-
rotransmitter that acts on many receptors in the mammalian
central nervous system, including a major family called the
metabotropic glutamate receptors (mGlu).[1] Hence, these
are attractive pharmaceutical targets for the treatment of a
wide variety of neuropsychiatric and neurological disor-
ders,[2] including anxiety and panic disorders, depression,
schizophrenia, neuropathic pain, Parkinsonꢀs disease, seizure
disorders, strokes, other neurodegenerative disorders, and
for treating stimulant (e.g., cocaine and nicotine) abuse and
opioid withdrawal.
A range of conformationally constrained analogues (e.g.,
1, 2, and 3) were known to be potent, but unselective ago-
nists for the receptor subtype mGlu2. Studies on the low-
energy conformations of 1 and 2 indicated that l-glutamic
acid adopts a fully extended conformation in the receptor,
and based on this study the bicyclic amino acid (+)-
LY354740 was designed, synthesized, and found to be a
highly selective and potent agonist for the mGlu2 recep-
tor.[3,4]
Indeed, administration of (+)-LY354740 to rodents re-
vealed its anxiolytic qualities,[4–8] and further studies in
humans have shown that it can block fear-potentiated startle
reflexes to shock anticipation with a decrease in anxiety, and
that in patients with a panic disorder, (+)-LY354740 blocked
the anxiogenic effect of a panic-inducing challenge and was
free of sedative action.[9–11]
[a] Prof. V. K. Aggarwal, E. Grange
School of Chemistry, University of Bristol
Cantockꢀs Close, Bristol BS8 1TS (UK)
Fax : (+44)117-954-6315
E-mail: v.aggarwal@bristol.ac.uk
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FULL PAPER
(+)-LY354740 has been shown to be an orally active, se-
lective, and exceptionally potent agonist at mGlu2. This
compound also has the potential for the treatment of de-
pression and schizophrenia,[12] to display positive effects in
an in vitro epilepsy model,[13,14] to have potential anti-Par-
kinsonian properties,[15,16] and to attenuate the behavioral
signs of morphine-withdrawal.[17,18] It has elicited much in-
terest as a potential therapeutic drug, especially since the
use of current clinically available anxiolytics, such as diaze-
pam (valium), is restricted by limited efficacy and adverse
side effects, for example, dependency and sedation.[17,18]
This considerable biological importance has generated a
flurry of synthetic endeavors towards a stereoselective syn-
thesis of this class of compounds.[3,19–32] Many of these syn-
theses have proceeded via cyclopropane 5 (Scheme 1),
in situ. However, this produced our first surprise, as instead
of observing high diastereoselectivity, a 1:1 ratio of diaste-
reomers was formed for both cases, albeit with good levels
of enantioselectivity when using ylide 7 (Table 1). We were
shocked that ylides 7 and 8 gave such diametrically different
results to those reported for ylide 4. Was this due to the
small difference in structure (compare 8 and 4) or due to
the different reaction conditions employed? We suspected
the latter and so chose to study the stoichiometric reaction
with preformed sulfonium salts.
Treatment of sulfonium salts
10 and 11 with DBU gave, as
expected, products with very
high
diastereoselectivity
(Table 2). The tert-butyl ester
12 was also tested and again cy-
clopropanes were obtained, but
with slightly lower diastereose-
Scheme 1. (+)-LY354740 synthesis via cyclopropane 5.[3]
which can be generated, with high diastereoselectivity (de=
diastereomeric excess), from the reaction of ylide 4 (see
later, formed in situ by the treatment of sulfonium salt 10
with DBU (1,8-diazobicyclo[5.4.0]undec-7-ene)) with cyclo-
pentenone.[3,28] Subsequent diastereoselective conversion by
hydantoin formation[29] and optical resolution furnished
(+)-LY354740.[3]
Current routes to enantiomerically enriched cyclopropane
5 are either very long (11 steps from commonly available
starting materials)[29,30] or involve resolution.[27] We consid-
ered the possibility of using an enantioselective sulfonium
ylide mediated cyclopropanation to provide a one step
asymmetric synthesis of the required cyclopropane. Based
on the high enantioselectivity achieved in related epoxida-
tion,[33–39] aziridination,[39–41] and cyclopropanation chemis-
try,[41,42] and the established high diastereoselectivity ob-
served in reactions of 4 with cyclopentenone,[3,28] we expect-
ed very high levels of stereocontrol. Although our studies
did not ultimately deliver such goals, the mechanistic under-
standing that we acquired during these studies now provides
a general framework that can be used to account for the se-
lectivity observed in all of the sulfonium ylide mediated cy-
clopropanations found in the literature to date.
Table 1. Metal-catalyzed cyclopropanation.
Sulfide
Yield [%][a]
5:9
ee [%, 5][b]
ee [%, 9][b]
6
74
81
1:1
1:1
81
–
75
–
THT
[a] Total isolated yield. [b] Determined by chiral GC.
Table 2. Base-mediated cyclopropanation.
Entry Salt Yield [%][a] exo:endo ee [%, exo][b] ee [%, endo][b]
Results and Discussion
1
2
3
4
5
10
11
12
13
14
78
74
86
87
73
29:1
26:1
18:1
9.6:1
4:1
–
–
–
14
38
–
–
–
80
84
We initiated our studies by using our established catalytic
sulfonium ylide methodology,[41,42] which utilizes either
chiral sulfide 6 or tetrahydrothiophene (THT), together
with ethyl diazoacetate and Cu(acac)2, to form ylides 7 or 8
[a] Total isolated yield. [b] Determined by chiral GC.
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569

V. K. Aggarwal and E. Grange
lectivity. Our next big surprise came in the evaluation of
chiral sulfonium salts 13 and 14, which both gave moderate
diastereoselectivity, but very low enantioselectivity for the
required exo isomer.
So, the metal-catalyzed sulfonium ylide reaction (operat-
ing under neutral conditions) delivered low diastereoselec-
tivity but high enantioselectivity, whereas base-mediated cy-
clopropanation delivered high diastereoselectivity but low
enantioselectivity. The different selectivities observed under
these different conditions suggested that a base-mediated
equilibration of the intermediate betaine had occurred in
the latter case.
taine equilibration resulted in a decrease in the enantiose-
lectivity of the reaction, but an improvement in its diaste-
reoselectivity.
The relative rates of ring closure of the two betaines can
be expected to be quite different. The conformation re-
quired for the ring closure of 16 is accompanied by trans-an-
nular steric hindrance, and also by high torsional strain aris-
ing from three eclipsing syn-cyclopropane substituents. Thus,
ring closure of 16 will be much slower than 15.
Based on this model, the lower diastereoselectivity ob-
served with the tert-butyl esters relative to the ethyl esters
(Table 2, entry 3 versus 1 and 2, and entry 5 versus 4) can be
rationalized as follows: for the tert-butyl esters, the proton
alpha to the ester group is more sterically hindered than in
the ethyl esters; therefore, for these compounds the rate of
epimerization is reduced and subsequently lower diastereo-
selectivity is observed.
Thus, our working model was
that, under neutral conditions
and elevated temperatures, be-
taines 15 and 16 were formed
nonreversibly in a 1:1 ratio, and
then underwent ring closure to
give the cyclopropanes with a
degree of enantioselectivity that
reflected the confomer ratio of ylide 7 (Scheme 2, ee=enan-
tiomeric excess).
Supporting experiments: If our model was correct, then con-
ducting the reaction at higher dilution would reduce the rate
of betaine equilibration (a bimolecular process) without re-
ducing the rate of cyclization (a unimolecular process), and
thus result in lower diastereoselectivity. This is exactly what
was observed (Table 3).
Table 3. Dilution experiments.
Entry
Concentration [m]
5:9[a]
1
2
3
0.5
26:1
16:1
11:1
0.05[b]
0.005[b]
Scheme 2. Metal-catalyzed cyclopropanation (neutral conditions).
[a] Ratio determined by GC. [b] 96 h reaction time.
In contrast, under basic conditions we believe that al-
though betaines 15 and 16 were again formed in a 1:1 ratio,
because cyclization of betaine 16 is slow, base-mediated epi-
merization converted it to betaine 17, which subsequently
underwent fast cyclization to give ent-5 (Scheme 3). This be-
We had expected that conducting the reaction in the ab-
sence of base by preforming ylide 8[43] would result in low
diastereocontrol, but it did not. Instead, high dia-
stereocontrol was still observed, and again diastereoselectiv-
ity was found to be concentration dependent (Table 4, en-
Table 4. Preformed ylide-mediated cyclopropanation.
Entry
Salt
Concentration [m]
exo:endo[a]
1
8
8
8
18
18
0.5
22:1
8:1
2:1
2:1
2:1
2[b]
3[b]
4
0.05
0.005
0.5
5[c]
4
[a] Ratio determined by GC. [b] 96 h reaction time. [c] In dichlorome-
thane.
Scheme 3. Base-mediated cyclopropanation.
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Chem. Eur. J. 2006, 12, 568 – 575

Sulfonium Ylide Mediated Cyclopropanations
FULL PAPER
tries 1–3). Clearly, the ylide itself was able to act as a base
and effect betaine equilibration. Interestingly, ylide 18, bear-
ing a tert-butyl ester, effected low diastereocontrol even at a
very high concentration, indicating that this bulky ylide was
less able to deprotonate the sterically hindered betaine in-
termediate.
Our results show that in order to limit betaine equilibra-
tion (and therefore maximize enantioselectivity) the ylide-
mediated reaction has to be conducted under base free con-
ditions with a hindered ester substituent.
Thus, ylide 19, which bears a tert-butyl ester, was pre-
pared, and its subsequent reaction with cyclopentenone fur-
nished the desired cyclopropanes with high enantioselectivi-
ty, but as expected with low diastereoselectivity (Scheme 4).
Scheme 4. Highly enantioselective cyclopropanation.
Attempts to control the diastereoselectivity by using a-sub-
stituted enones were not successful.[44]
Application of the model to literature examples: Many ex-
amples of cyclopropanations utilizing ester-stabilized sulfo-
nium ylides have been reported, but the origin of the dia-
stereoselectivity of these reactions has either not been dis-
cussed or has been reported erroneously. The model we
have put forward in this paper has been extended to all the
literature examples we are aware of and successfully ac-
counts for the diastereoselectivity observed.
Scheme 5. Examples of diastereoselective, base-mediated cyclopropana-
tion. References for reactions (from top to bottom)=[21,27–29,45].
According to our model, reactions in which betaine equili-
bration competes effectively with ring closure will result in
high selectivity for the formation of the exo diastereomer.
In Schemes 1 and 5, base-mediated equilibration is responsi-
ble for high diastereoselectivity.[3,21,27–29,45] Ruano has also
observed good diastereoselectivity in favor of the exo cyclo-
propane (Scheme 6), presumably because betaine equilibra-
tion, mediated by the ylide or base, is also occurring here.[46]
Our model dictates that low diastereoselectivity can be
expected at high reaction temperatures, as the rate of the
unimolecular process (ring closure) will be accelerated rela-
tive to the bimolecular process (betaine equilibration).
Indeed, Payne reported the first ever example of enone cy-
clopropanation by using ylide 4, but only low diastereoselec-
tivity was observed for the cyclopropanation of cyclohexe-
none at an elevated temperature (Scheme 7).[43] The de-
crease in selectivity at elevated temperatures is further illus-
trated in Scheme 8.[3]
Scheme 6. Diastereoselective cyclopropanation of unsaturated chiral sulf-
oxides.[46]
Scheme 7. High-temperature cyclopropanation.[43]
If ring closure is slowed down by other means, then be-
taine equilibration and high diastereoselectivity can still be
achieved even at high temperatures. An additional substitu-
ent at the a-position of the enone will do just that, as shown
in Scheme 9; for this reaction high diastereoselectivity was
observed despite operating at 808C.[47]
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V. K. Aggarwal and E. Grange
the reactive amide enolate) low diastereoselectivity is ob-
served.
Meyers was able to achieve high stereocontrol using the
carboxylate ylide 23 (Scheme 10d).[49] In this example, the
much improved diastereoselectivity may be due to either
the more basic ylide being able to effect betaine equilibra-
tion or from a diastereoselective attack of the ylide on the
chiral substrate.[50]
Scheme 8. Diastereoselectivity dependence on temperature.[3]
Finally, one would expect faster ring closure and so re-
duced diastereoselectivity with even better leaving groups.
Indeed, Ruano observed a very significant difference be-
tween the outcome of the reactions of 4 and 24 with lactone
22 (compare Schemes 6 and 11).[46] Whereas, betaine equili-
Scheme 9. Diastereoselective cyclopropanation of an a-substituted
enone.[47]
Conversely, if ring closure is accelerated, because the
anion of the betaine has been made more reactive, then dia-
stereoselectivity will be reduced. This has been observed in
lactam cyclopropanation, as illustrated in Scheme 10.[48,49]
The low diastereoselectivity observed in Scheme 10a and b
Scheme 11. endo-Selective cyclopropanation.[46]
bration can account for the formation of the thermodynami-
cally more stable exo isomer, as illustrated in Scheme 6, in
Scheme 11 the endo isomer predominates. Presumably in
the latter case, fast ring closure (better leaving group ability)
and slow betaine equilibration (the intermediate betaine is
more hindered) lead to a diastereoselectivity that reflects
the selectivity of the initial addition, which is influenced by
the nature of the ylide and the substituents on the electro-
phile. We believe that this is a more accurate explanation
for the observed selectivities than that reported.[46]
Generally, ylide-mediated cyclopropanation of acyclic
substrates can be expected to proceed with high diastereose-
lectivity because of free-bond rotation in the intermediate
betaine, which allows for ring closure to the more stable
trans diastereomer. The cyclic nature of the substrates dis-
cussed above renders such bond rotation impossible, so that
high diastereoselectivity can only be achieved either through
betaine equilibration or a diastereoselective initial attack of
the ylide upon the electrophile.
Conclusion
Scheme 10. Lactam cyclopropanation reactions: a),b) reference [48] and
c),d) reference [49].
Stabilized sulfonium ylides react with cyclopentenone to
give the corresponding cyclopropane with high diastereose-
lectivity as a result of base or ylide-mediated equilibration
of the intermediate betaine. When using chiral sulfonium
ylides, betaine equilibration compromises enantioselectivity,
because whilst one diastereomer ring closes rapidly, the
other diastereomer undergoes epimerization at the ester
stereocenter ultimately leading to the opposite enantiomer
of the cyclopropane.
had been rationalized from the assumption that the high
diastereocontrol achieved in the initial addition had been
subsequently scrambled by betaine equilibration. In fact, we
believe the opposite is true, as our model provides a much
more satisfactory explanation; that is, initial attack upon the
substrate by the ylide is nonselective, and without the oppor-
tunity for betaine equilibration (due to fast ring closure of
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Sulfonium Ylide Mediated Cyclopropanations
FULL PAPER
General procedure for metal-catalyzed cyclopropane synthesis: 2-Cyclo-
penten-1-one (1 equiv), Cu(acac)2 (5 mol%), and either tetrahydrothio-
phene or sulfide 6 (1 equiv) were stirred in anhydrous 1,2-DCE (0.5m)
and warmed to 608C. Ethyl diazoacetate in 1,2-DCE (1 equiv, 2m) was
then added over 24 h by means of a syringe pump and the reaction mix-
ture was stirred for a further hour. After cooling, water was added and
after shaking, the layers were separated. The aqueous layer was thrice ex-
tracted with dichloromethane, and the organics were combined, dried
over MgSO4, filtered, and concentrated in vacuo. Chromatography of the
residue (PE/EtOAc 4:1) gave the cyclopropanes.
Betaine equilibration can be inhibited by conducting the
reaction under base free conditions, and by employing hin-
dered ester substituents on the stabilized ylide. Under these
conditions, high enantioselectivity was achieved with ylide
19, albeit with low diastereoselectivity. Operating reactions
in high dilution and with elevated temperatures can also
result in a further reduction in the rate of betaine equilibra-
tion and thus enhance enantioselectivity. Conversely, if equi-
libration is desired (to provide high diastereoselectivity),
then the use of base (e.g., DBU) or an unhindered ylide, as
well as conducting the reaction at a high concentration and
a low temperature, is recommended.
Using sulfide 6 (0.38 g, 1.52 mmol)
(1S,5R,6S)-Ethyl-2-oxobicyclo[3.1.0]hexane-6-carboxylate (5): Isolated
yield: 100 mg, 40% (cubes); 81% ee; Rf =0.35 (EtOAc/PE, 33:67); m.p.
56–588C (lit.[27] m.p. 63–658C, À99% ee); [a]2D3 =+47.3 (c=1.0 in metha-
nol) (lit.[29]
=
[a]2D3 =+64.3 (c=1.0 in methanol), 98% ee); 1HNMR
The discovery of betaine equilibration has provided the
basis for an important model that successfully accounts for
the diastereoselectivity observed in all reported sulfonium
ylide mediated cyclopropanations to date.
(400 MHz, CDCl3): d=1.27 (t, J=7.0 Hz, 3H; CH3), 2.00–2.17 (m, 4H),
2.20–2.30 (m, 2H), 2.51 (td, J=5.5, 3.5 Hz, 1H; CH2CH), 4.16 ppm (q,
J=7.0 Hz, 2H; CH2CH3); 13C NMR (101 MHz, CDCl3): d=14.2 (CH3),
22.5 (CH2CH), 26.5 (CHCO2), 29.2 (CH2CH), 31.9 (CH2CO), 35.8
(CHCO), 61.2 (OCH2), 170.4 (CO2), 211.5 ppm (C=O).
We have established a simple test to determine if betaine
equilibration is occurring, as diastereoselectivity would then
depend on concentration. Increased dilution results in lower
diastereoselectivity, because the rates of ring closure (a un-
imolecular process) remain unchanged, but the rates of be-
taine equilibration (a bimolecular process) are reduced.
Clearly the model discussed may be applicable to other
ylides, and so this test could be applied to other ylide reac-
tions, for example, the elegant cyclopropanation reactions
employing ammonium ylides,[51] to determine the origin of
the stereocontrol observed.
(1R,5S,6S)-Ethyl-2-oxobicyclo[3.1.0]hexane-6-carboxylate (9): Isolated
yield: 86 mg, 34% (colorless oil); 75% ee; Rf =0.27 (EtOAc/PE 33:67);
[a]2D3 =+10.4 (c=1.0 in methanol); 1HNMR (400 MHz, CDCl 3): d=1.28
(t, J=7.5 Hz, 3H; CH3), 2.01–2.10 (m, 1H), 2.20–2.48 (m, 6H), 4.16 ppm
(q, J=7.5 Hz, 2H; CH2CH3); 13C NMR (101 MHz, CDCl3): d=14.2
(CH3), 20.1 (CH2CH), 28.7 (CHCH2), 29.9 (CHCO2), 34.2 (CHCO), 37.9
(CH2CO), 61.2 (OCH2), 169.8 (CO2), 213.4 ppm (C=O).
General procedure for base-mediated cyclopropane synthesis from sulfo-
nium salts 10–14: DBU (1 equiv) was added to a suspension of sulfonium
salt (1 equiv) in anhydrous toluene or dichloromethane (50 mm–0.5m) at
room temperature, and after 5 minutes 2-cyclopenten-1-one (1 equiv)
was added. The mixture was then stirred for a minimum of 18 h before
being quenched by the addition of aqueous hydrochloric acid (0.5m). The
phases were separated, the aqueous layer was thrice extracted with di-
chloromethane and the combined organic phases were washed with
brine, dried over MgSO4, filtered, and then concentrated in vacuo. Chro-
matography of the residue (PE/EtOAc 4:1) gave the cyclopropanes.
Experimental Section
General: Reactions requiring anhydrous conditions were performed with
oven-dried glassware, under a nitrogen atmosphere. Reaction mixtures
were stirred magnetically. Anhydrous THF, dichloromethane, and tolu-
ene were obtained from a purification column composed of activated alu-
mina (A-2). Anhydrous 1,2-dichloroethane (1,2-DCE) was obtained from
Fluka. PE refers to the fraction of light petroleum ether boiling between
408C and 608C. Sulfide 6 was synthesized as previously reported.[36] All
chemicals were purchased from Aldrich.
General procedure for cyclopropane synthesis with preformed ylides 8,
18, and 19: 2-Cyclopenten-1-one (1 equiv) was added to the preformed
ylide (1 equiv) in anhydrous toluene or dichloromethane (50 mm–4m), at
room temperature. The mixture was stirred for a minimum of 18 h before
concentration in vacuo. Chromatography of the residue (PE/EtOAc 4:1)
gave the cyclopropanes.
Using ylide 19 in toluene (1.14 g, 0.2m), 18 h
(1S,5R,6S)-tert-Butyl-2-oxobicyclo[3.1.0]hexane-6-carboxylate (20): Iso-
lated yield: 0.29 g, 49% (needles); 95% ee; Rf =0.43 (EtOAc/PE 33:67);
m.p. 68–698C (PE); [a]2D5 =+29.6 (c=1.0 in methanol); 1HNMR
(400 MHz, CDCl3): d=1.45 (s, 9H; CH3), 1.94 (t, J=2.5 Hz, 1H;
CHCO2), 2.02–2.26 (m, 5H), 2.45 ppm (td, J=5.5, 3.5 Hz, 1H; CHCH2);
13C NMR (101 MHz, CDCl3): d=22.4 (CH2CH), 27.5 (CHCO2), 28.0
(CH3), 28.8 (CH2CH), 31.9 (CH2CO), 35.5 (CHCO), 81.4 (quat C), 169.3
(CO2), 211.7 ppm (C=O); IR (neat): n˜ =2977, 1732 (C=O), 1701 (C=O),
1147 cmÀ1; MS (CI): m/z (%): 197 [M+H]+ (25), 141 [MÀC4H7]+ (100);
elemental analysis calcd (%) for C11H16O3: C 67.32, H8.22; found: C
67.26, H8.06.
IR spectra were recorded on a Perkin–Elmer Spectrum One FT-IR spec-
trometer, and only selected absorbencies (n˜) are reported. 1HNMR and
13C NMR spectra were recorded at 400 MHz and 101 MHz, respectively,
on a Jeol Delta GX/400 instrument. Chemical shifts are given relative to
TMS or the appropriate residual solvent peak. LRMS (m/z) were record-
ed on a Micromass Analytical Autospec spectrometer, with only molecu-
lar ions [M+] and major peaks being reported, and with intensities
quoted as percentages of the base peak. HRMS were recorded by using a
Bruker Daltronics ApexIV 7Tesla FT-ICR-MS. Elemental analyses were
carried out using a Perkin–Elmer 2400 CHN elemental analyzer. Chro-
matographic separation was achieved on silica gel (Merck Kieselgel 60,
230–400 mesh), and reactions were monitored by TLC analysis on alumi-
num-backed silica plates (60F254, 0.2 mm), which were visualized using
UV fluorescence (254 nm) and p-anisaldehyde/D. Melting points were de-
termined on a Kofler hot stage. Optical rotations were measured using a
Perkin–Elmer 241 MC polarimeter. [a]D values are given in
10À1 8mLmgÀ1. Diastereomeric ratios and enantiomeric excesses were de-
termined by chiral GC (Supelco 120, gamma dex; 20 m”0.25 mm”
0.25 mm). Cyclopropane stereochemistry has been assigned according to
the observed optical rotations of compound 5 and by analogy with the
stereochemical induction previously observed in ylide-mediated epoxida-
tion,[33–39] aziridination,[39–41] and cyclopropanation[41,42] reactions employ-
ing sulfide 6.
(1R,5S,6S)-tert-Butyl-2-oxobicyclo[3.1.0]hexane-6-carboxylate (21): Iso-
lated yield: 0.17 g, 26% (needles); 82% ee; Rf =0.37 (EtOAc/PE 33:67);
m.p. 55–578C (PE); [a]2D5 =+19.0 (c=1.0 in methanol); 1HNMR
(400 MHz, CDCl3): d=1.46 (s, 9H; CH3), 2.03–2.07 (m, 1H), 2.13–
2.42 ppm (m, 6H); 13C NMR (101 MHz, CDCl3): d=20.0 (CH2CH), 28.1
(CH3), 29.5 (CH2CH), 29.9 (CHCO2), 33.9 (CHCO), 37.8 (CH2CO), 81.7
(quat C), 168.8 (CO2), 213.3 ppm (CO); IR (neat): n˜ =2942, 1714 (C=O),
1399, 1142 cmÀ1; MS (CI): m/z (%): 197 [M+H]+ (15), 141 [MÀC4H7]+
(100); elemental analysis calcd (%) for C11H16O3: C 67.32, H8.22; found:
C 67.22, H8.12.
General procedure for the formation of salts 10, 11, and 12: Dimethyl
sulfide or tetrahydrothiophene (1 equiv), and ethyl bromoacetate or tert-
Chem. Eur. J. 2006, 12, 568 – 575
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www.chemeurj.org
573

V. K. Aggarwal and E. Grange
butyl bromoacetate (0.9 equiv) were stirred in acetone (2.8m) at room
temperature for 18 h. The resultant precipitate was then collected by fil-
tration, washed with acetone, and dried in vacuo to give the sulfonium
salts.[43]
(1R,3R,4S)-2-tert-Butylcarboxymethyl-3-[(1R,4S)-7,7-dimethyl-2-
oxobicyclo[2.2.1]hept-1-yl]-2-thioniabicyclo[2.2.1]heptane tetrafluorobo-
rate (14): A solution of NaBF4 (3.20 g, 280 mmol) in water (5 mL) was
added to a solution of sulfide 6 (1.06 g, 42.4 mmol) and tert-butyl bro-
moacetate (4.07 mL, 280 mmol) in dichloromethane (0.4 mL), and the
mixture was stirred vigorously at room temperature for 120 h. After this
time, water (20 mL) and dichloromethane (20 mL) were added. The re-
sulting layers were then separated, and the aqueous layer extracted with
dichloromethane (2”10 mL). The organic layers were combined, dried
over MgSO4, filtered, and concentrated in vacuo. The residues were re-
dissolved in dichloromethane (5 mL) and added dropwise to rapidly stir-
red PE (400 mL). After 18 h the resultant precipitate was collected by fil-
tration and dried in vacuo to give the sulfonium salt 14 as an amorphous
white powder (1.79 g, 93%); Rf =0.23 (dichloromethane/MeOH95:5);
m.p. 102–1038C (Et2O); [a]2D5 =+53.1 (c=1.0 in CHCl3); 1HNMR
(400 MHz, (D3C)2CO): d=1.17 (s, 3H; C16H3), 1.18 (s, 3H; C16H3), 1.47
(s, 9H; C(CH3)3), 1.63–1.88 (m, 3H), 2.00–2.35 (m, 8H), 2.53 (d, J=
12.5 Hz, 1H; C12HH), 2.67 (ddd, J=19.0, 5.0, 3.0 Hz, 1H; C2HH), 3.29
(brs, 1H; C8H), 4.33 (d, J=17.0 Hz, 1H; SCHH), 4.35 (s, 1H; C7H), 4.50
(d, J=17.0 Hz, 1H; SCHH), 4.61 ppm (d, J=5.0 Hz, 1H; C11H);
13C NMR (101 MHz, (D3C)2CO): d=18.7 (CH3), 21.2 (CH3), 24.1 (CH2),
26.3 (CH2), 26.6 (CH2), 27.2 (C(CH3)3), 33.4 (CH2) 41.0 (CH2), 43.2
(CH), 43.6 (CH2), 45.2 (CH), 46.6 (CH2), 49.8 (quat C), 60.2 (CH), 68.3
(CH), 84.9 (C(CH3)3), 163.4 (CO2), 214.3 ppm (C=O). IR (neat): n˜ =
2967, 1734 (C=O), 1042, 1025 cmÀ1; MS (FAB): m/z (%): 365 [MÀBF4]+
(100), 309 [MÀC4H8BF4]+ (18); elemental analysis calcd (%) for
C21H33BF4O3S: C 55.76, H7.35; found: C 55.74, H7.33.
Ethyl (dimethylsulfonio)acetate bromide (10): Isolated yield: 14.0 g, 75%
(cubes); Rf =0.24 (dichloromethane/MeOH95:5); 1HNMR (400 MHz,
CDCl3): d=1.33 (t, J=7.0 Hz, 3H; CH2CH3), 3.51 (s, 6H; SCH3), 4.29
(q, J=7.0 Hz, 2H; CH2CH3), 5.28 ppm (s, 2H; SCH2CO); 13C NMR
(101 MHz, (D3C)2SO): d=14.4 (CH2CH3), 25.4 (SCH3), 45.0 (SCH2), 63.3
(OCH2), 165.2 ppm (C=O).
Ethyl (tetrahydrothiophenio)acetate bromide (11): Isolated yield: 13.8 g,
64% (needles); Rf =0.25 (dichloromethane/MeOH95:5); m.p. 127–
1288C (decomp, acetone); 1HNMR (400 MHz, CDCl 3): d=1.32 (t, J=
7.0 Hz, 3H; CH2CH3), 2.45–2.57 (m, 4H; 4S(CH2CH2)2), 3.82–3.93 (m,
2H; 2S(CHHCH2)2), 3.98–4.12 (m, 2H; 2S(CHHCH2)2), 4.30 (q, J=
7.0 Hz, 2H; CH2CH3), 5.08 ppm (s, 2H; SCH2CO); 13C NMR (101 MHz,
(D3C)2SO): d=14.4 (CH2CH3), 28.8 (S(CH2CH2)2), 44.6 (S(CH2CH2)2),
54.3 (SCH2CO), 63.2 (OCH2), 166.0 ppm (C=O); IR (neat): n˜ =2900,
1716 (C=O), 1313, 1192 cmÀ1; MS (FAB): m/z (%): 175 [MÀBr]+, (100);
elemental analysis calcd (%) for C8H15BrO2S: C 37.66, H5.93; found: C
37.62, H5.92.
tert-Butyl (tetrahydrothiophenio)acetate bromide (12): Isolated yield:
18.7 g, 85% (cubes); Rf =0.25 (dichloromethane/MeOH95:5); m.p. 130–
1338C (decomp, acetone); 1HNMR (400 MHz, CDCl 3): d=1.48 (s, 9H;
CH3), 2.47–2.55 (m, 4H; 4S(CH2CH2)2), 3.81–3.90 (m, 2H; 2S-
(CHHCH2)2), 3.90–4.12 (m, 2H; 2S(CHHCH2)2), 4.93 ppm (s, 2H;
SCH2CO); 13C NMR (101 MHz, (D3C)2SO): d=28.2 (CH3), 28.9 (S-
(CH2CH2)2), 43.3 (S(CH2CH2)2), 44.9 (SCH2CO), 84.8 (quat C),
General procedure for preforming ylides 8, 18, and 19: A saturated aque-
ous solution of K2CO3 (0.6 mL per mmol of sulfonium salt), followed by
an aqueous NaOHsolution (50% w/w, 40 mL per mmol of sulfonium
salt) was added to a solution of the sulfonium salt in dichloromethane
(0.6m) at 08C. The mixture was stirred for 10 minutes before being
warmed to room temperature and stirred for a further 20 minutes. The
phases were then separated, and the aqueous layer was thrice extracted
with dichloromethane. The combined organic layers were dried over
oven-dried K2CO3, filtered, and concentrated in vacuo to give the
ylide.[43]
164.9 ppm (C=O); IR (neat): n˜ =2902, 1712 (C=O), 1142 cmÀ1
; MS
(FAB): m/z (%): 203 [MÀBr]+ (70), 147 [MÀC4H8Br]+ (100); elemental
analysis calcd (%) for C10H19BrO2S: C 42.41, H6.76; found: C 42.52, H
7.02.
Formation of salts 13 and 14:
(1R,3R,4S)-2-Ethylcarboxymethyl-3-
[(1R,4S)-7,7-dimethyl-2-oxobicyclo-
[2.2.1]hept-1-yl]-2-thioniabicyclo-
[2.2.1]heptane tetrafluoroborate (13):
The two geometric isomers of these ylides (which are best represented by
enolate structures) are in equilibrium, and this causes the 1HNMR spec-
troscopic signals observed at room temperature to be broadened.[52]
A
solution of NaBF4 (1.57 g,
140 mmol) in water (2.5 mL) was
added to a solution of sulfide 6 (0.50 g,
20.0 mmol) and ethyl bromoacetate
Ethyl (tetrahydrothiophenylidene)acetate (8): Isolated yield: 3.40 g, 99%
(white crystalline solid); Rf =0.25 (dichloromethane/MeOH95:5); m.p.
58–598C (dichloromethane); HNMR (400 MHz, CDCl 3): d=1.23 (t, J=
1
(1.60 mL, 140 mmol) in dichloromethane (0.65 mL), and the mixture was
stirred vigorously at room temperature for 48 h. After this time, water
(10 mL) and dichloromethane (10 mL) were added. The resulting layers
were then separated, and the aqueous layer extracted with dichlorome-
thane (2”10 mL). The organic layers were combined, dried over MgSO4,
filtered, and concentrated in vacuo. The residues were redissolved di-
chloromethane (0.2 mL) and Et2O (10 mL) was added. The resultant pre-
cipitate was collected and dried in vacuo to give the sulfonium salt 13 as
fine plates (0.72 g, 85%); Rf =0.22 (dichloromethane/MeOH95:5); m.p.
151–1538C (Et2O); [a]2D5 =+67.8 (c=1.0 in CHCl3); 1HNMR (400 MHz,
(D3C)2CO): d=1.17 (s, 3H; C16H3), 1.19 (s, 3H; C16H3), 1.26 (t, J=
7.0 Hz, 3H; CH2CH3), 1.49 (ddd, J=12.0, 9.5, 4.0 Hz, 1H; CHH), 1.62–
1.70 (m, 1H), 1.74–1.89 (m, 2H), 2.03 (d, J=18.5 Hz, 1H; C2HH) 2.03–
2.12 (m, 1H), 2.17–2.32 (m, 4H), 2.35 (dt, J=13.0, 2.0 Hz, 1H; C12HH),
2.55 (d, J=13.0 Hz, 1H; C12HH), 2.68 (ddd, J=18.5, 4.5, 3.0 Hz, 1H;
C2HH), 3.30 (brs, 1H; C8H), 4.24 + 4.26 (qAB, J=11.0, 7.0 Hz, 2H;
OCH2CH3), 4.38 (brs, 1H; C7H), 4.39 (d, J=17.0 Hz, 1H; SCHH), 4.55
(d, J=17.0 Hz, 1H; SCHH), 4.64 ppm (d, J=5.0 Hz, 1H; C11H);
13C NMR (101 MHz, (D3C)2CO): 9.9 (CH3), 15.2 (CH3), 17.7 (CH3), 20.6
(CH2), 22.8 (CH2), 23.0 (CH2), 29.8 (CH2) 37.4 (CH2), 39.7 (CH), 40.1
(CH2), 41.6(CH), 42.1(CH2), 46.3 (quat C), 56.6 (CH), 59.5 (OCH2), 63.7
(CH), 161.2 (CO2), 211.7 ppm (C=O); IR (neat): n˜ =2906, 1733 (C=O),
1321, 1066, 1015 cmÀ1; MS (ESI): m/z (%): 337 [MÀBF4]+ (30), 217
(100); elemental analysis calcd (%) for C19H29BF4O3S: C 53.78, H6.89;
found: C 53.95, H6.80.
7.0 Hz, 3H; CH2CH3), 1.66–1.79 (m, 2H; 2S(CH2CHH)2), 2.08–2.16 (m,
2H; 2S(CH2CHH)2), 2.76 (m, 2H; 2S(CHHCH2)2), 3.04 (brs, 1H;
SCHCO), 3.68 (brt, 2H, J=11.5 Hz, 2S(CHHCH2)2), 4.04 ppm (q, J=
7.0 Hz, 2H; CH2CH3); 13C NMR (101 MHz, CDCl3): d=15.0 (CH3), 24.5
(S(CH2CH2)2), 32.9 (SCHCO), 42.1 (S(CH2CH2)2), 57.9 (OCH2),
170.4 ppm (C=O); IR (neat): n˜ =2925, 1606 (C=C), 1437, 1108 cmÀ1
HRMS: m/z: calcd for C8H14O2S: 175.0793 [M+H]+; found: 175.0787.
;
tert-Butyl (tetrahydrothiophenylidene)acetate (18): Isolated yield: 5.6 g,
98% (off-white crystalline solid); Rf =0.25 (dichloromethane/MeOH
95:5); m.p. 388C (dichloromethane); 1HNMR (400 MHz, CDCl 3): d=
1.44 (brs, 9H; CH3), 1.84–1.93 (m, 2H; 2S(CH2CHH)2), 2.44–2.47 (m,
2H; 2S(CH2CHH)2), 2.92 (brs, 1H; SCHCO), 3.01–3.06 (m, 2H; 2S-
(CHHCH2)2), 3.14–3.19 ppm (m, 2H; 2S(CHHCH2)2); 13C NMR
(101 MHz, CDCl3): d=27.6 (S(CH2CH2)2), 29.1 (CH3), 35.2 (SCHCO),
45.6 (S(CH2CH2)2), 77.4 (quat C), 170.2 ppm (C=O); IR (neat): n˜ =2973,
1712, 1613 (C=C), 1332, 1120 cmÀ1; HRMS: m/z: calcd for C10H18O2S:
203.1106 [M+H]+; found: 203.1097.
(1R,3R,4S)-2-tert-Butylcarboxymethyl-3-[(1R,4S)-7,7-dimethyl-2-oxobi-
cyclo[2.2.1]hept-1-yl]-2-thiabicyclo[2.2.1]hept-2-ylidene acetate (19): Iso-
lated yield 1.77 g, 99% (amorphous white powder); Rf =0.23 (dichloro-
methane/MeOH95:5); m.p. 113–114 8C (dichloromethane); [a]2D3 =+0.07
(c=1.0 in CHCl3); 1HNMR (400 MHz, CDCl 3): d=1.04 (brs, 3H;
C16H3), 1.13 (brs, 3H; C16H3), 1.43 (brs, 9H; C(CH3)3), 1.79–2.22 (m,
12H), 2.47 (dt, J=18.5, 3.5 Hz, 1H; C2HH), 2.98 (brs, 1H; C8H), 3.08
(brs, 1H; C13 H), 3.16 (d, J=5.0 Hz, 1H; C7H), 3.27 ppm (brs, 1H;
574
www.chemeurj.org
ꢁ 2006 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 568 – 575

Sulfonium Ylide Mediated Cyclopropanations
FULL PAPER
C11H); 13C NMR (101 MHz, CDCl3): d=20.2 (CH3), 21.2 (CH3), 24.2
(CH2), 25.6 (CH2), 37.4 (CH2), 29.0 (CH2), 29.2 (C(CH3)3), 39.9 (CH2),
40.2 (CH), 43.6 (CH), 43.8 (CH2) , 44.9 (CH), 49.5 (quat C), 60.0 (CH),
61.0 (C(CH3)3), 74.6 (CH), 169.7 (CO2), 214.7 ppm (C=O); IR (neat): n˜ =
2967, 1736 (C=O), 1607 (C=C), 1333, 1111 cmÀ1; HRMS: m/z: calcd for
C21H32O3S: 365.2145 [M+H]+; found: 364.2142.
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Received: June 17, 2005
Published online: September 27, 2005
Chem. Eur. J. 2006, 12, 568 – 575
ꢁ 2006 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
www.chemeurj.org
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