N-Alkyl salts derived from ephedrine do not promote enantioselective Corey-Chaykovsky reactions involving sulfonium methylides under phase-transfer conditions

Article abstract of DOI:10.1016/j.tetasy.2008.05.029

N-Alkyl salts derived from ephedrine have twice been reported to act as chiral phase-transfer catalysts in Corey-Chaykovsky reactions between sulfonium ylides and benzaldehyde; reportedly furnishing the terminal epoxide product in moderate-excellent enantiomeric excess. This study unequivocally demonstrates that these reactions proceed without measurable stereoinduction and explains how previous studies mistakenly attributed product optical activity to asymmetric catalysis.

Full text of DOI:10.1016/j.tetasy.2008.05.029

Tetrahedron: Asymmetry 19 (2008) 1414–1417
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Tetrahedron: Asymmetry
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N-Alkyl salts derived from ephedrine do not promote enantioselective
Corey–Chaykovsky reactions involving sulfonium methylides under
phase-transfer conditions
Sarah A. Kavanagh, Stephen J. Connon *
Centre for Synthesis and Chemical Biology, School of Chemistry, University of Dublin, Trinity College, Dublin 2, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Alkyl salts derived from ephedrine have twice been reported to act as chiral phase-transfer catalysts in
Corey–Chaykovsky reactions between sulfonium ylides and benzaldehyde; reportedly furnishing the ter-
minal epoxide product in moderate–excellent enantiomeric excess. This study unequivocally demon-
strates that these reactions proceed without measurable stereoinduction and explains how previous
studies mistakenly attributed product optical activity to asymmetric catalysis.
Received 9 May 2008
Accepted 28 May 2008
Available online 24 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1
. Introduction
tween benzaldehyde 5 and trimethylsulfonium iodide 6 in a bipha-
2 2
sic CH Cl /NaOH(aq) solvent mixture in the presence of the
ephedrine-derived salt 7 furnished styrene oxide 8 in moderate
yield and excellent selectivity (Scheme 2).
Over the past five decades, the Corey–Chaykovsky reaction1
Scheme 1) has been proven to be a robust and practical method
(
for the synthesis of synthetically valuable epoxide derivatives from
aldehydes. Whilst considerable progress towards a general, enan-
tioselective variant of this alkylidene transfer reaction using chiral
Interestingly, although no background reaction in the absence
of the catalyst was reported, the enantioselectivity of the process
appeared to increase with increased catalyst loading (35% ee at
1 mol % loading, 97% ee at 20% loading). Over 20 years later, Zhang
2,3
sulfides/sulfonium ylides has been made,
analogous catalytic
3
7
processes using sulfonium methylides (i.e., 1, R = H, Scheme 1)
which furnish terminal epoxides with high (>80% ee) enantioselec-
tivity have thus far proven elusive.4
et al. reported a similar study detailing the use of the lipophilic
catalysts 9 and 10 designed to facilitate the formation of chiral
micelles. Again significant enantioselectivity was reported to be
achievable, in this instance a curious dependence of enantioselec-
tivity on both temperature and reaction time was observed (in
general product ee increased with temperature, up to 40 °C, and
reaction time, up to 60 h). In both reports the product’s specific
rotation was used to both assign absolute configuration and deter-
mine ee.
2
. Results and discussion
Over the course of a research programme aimed at the design of
5
novel organocatalysts for methylene transfer to aldehydes, we
were intrigued to discover two reports detailing the moderate-
highly enantioselective synthesis of terminal epoxides using the
Corey–Chaykovsky reaction under the influence of phase-transfer
catalysis. In 1975, Hiyama et al.6 disclosed that the reaction be-
Encouraged by what we saw as a significant opportunity to de-
velop this hitherto underexploited methodology (particularly con-
sidering the general difficulties associated with the catalytic
O
O
R1
S
R2
R1
S
R2
R4
O
1
2
2
-SR R
R4
R4
R3
R3
slow
R3
fast
*
*
1
3
4
Scheme 1. Mechanism of the Corey–Chaykovsky reaction.
*
Corresponding author.
E-mail address: connons@tcd.ie (S. J. Connon).
0
957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.05.029

S. A. Kavanagh, S. J. Connon / Tetrahedron: Asymmetry 19 (2008) 1414–1417
1415
Hiyama et al.
Me3S I (6, 1.12 equiv.)
CH Cl /NaOH
Br
HO
O
2
2
(aq.)
O
N
R
3
8 °C, 48 h
Ph
7
(20 mol%)
7
9
1
R = C H
2
5
R = n-C12H25
5
8 45%, 97% ee
0 R = n-C16H33
NaOH(aq.) = (50% w/v, 15 equiv.)
Zhang et al.
Me3S I (6, 1.12 equiv.)
CH2Cl2/NaOH(aq.)
O
O
3
8 °C, 48 h
9
or 10 (18 mol%)
5
8 (cat. 9) 61%, 42% ee
(
cat. 10) 59%, 57% ee
NaOH(aq.) = (50% w/v, 83.33 equiv.)
Scheme 2. Conditions employed and results obtained by Hiyama et al. and Zhang et al.
O
Me S
I
3
Hiyama conditions
00%, 0% ee
O
1
CH2Cl2/NaOH(aq. )
2
0
[
α] = +9.3 (c1.00)
D
3
8 °C, 48 h
, 9 or 10 (cat.)
7
5
8
Zhang conditions
cat. 9, 77%, 0% ee
O
2
D
0
[
α] = + 12.0 (c 0.38)
cat. 10, 78%, 0% ee
[α]2 = + 17.4 (c 0.32)
0
D
11
Scheme 3. Outcome of representative asymmetric Corey–Chaykovsky reactions carried out in our laboratory.
asymmetric synthesis of terminal epoxides from achiral starting
materials ) through the design of new phase-transfer catalysts
impurity (which is inseparable from
8
by either column
8
chromatography or rudimentary vacuum distillation) is present
both before and after chromatography in the reaction catalysed
for these and related reactions—we repeated the key experiments
detailed in both papers precisely. Whist we did observe some
catalysis of the reaction by the ephedrinium salts9 and product
optical activity, in both cases CSP-HPLC analysis (Chiralcel OD-H
column 4.6 Â 250 mm, 99.9:0.1 hexane/i-PrOH solvent) of the
product after chromatography indicated that 8 had been formed
as a racemic mixture (Scheme 3). Several repetitions of the exper-
iment gave reproducible results.
1
1
by 10. Very similar spectra were obtained from the other reac-
tions outlined in Scheme 3.
To verify that 11 forms under these basic phase-transfer condi-
tions and that it is responsible for the optical activity of the chro-
matographed product mixture—catalysts 7 and 9–10 were exposed
to the reaction conditions outlined in Scheme 3 in the absence of
either benzaldehyde or sulfonium salt (Scheme 4). Each of the
three catalysts completely decomposed to form 11 in quantitative
yield (Scheme 4 and Fig. 3). This would explain the strong depen-
dence of the enantioselectivity on the reaction conditions (temper-
The CSP-HPLC chromatograms from these reactions along with
those of rac-8 are shown in Figure 1. It is noteworthy that a peak
not derived from 8 at 15.6–16 min retention time is present in
the catalysed reactions despite chromatographic purification of
6
,7
ature, time, loading) in the earlier studies: factors likely to afford
greater decomposition of the catalyst to enantiopure/enantio-
enriched 11 would yield a ‘product’ of higher specific rotation.
10
the product prior to HPLC analysis. The presence and identity
of the impurity was confirmed by 1H NMR analysis to be epoxide
12
1
1, presumably formed in high enantiomeric excess from the
Isolated 11 possessed a large specific rotation {[
D
a] = +64.6
base-mediated ring closure of 7 and 9–10. Figure 2 shows that this
(c 0.71)} and an identical retention time (15.7 min) to the previously

1
416
S. A. Kavanagh, S. J. Connon / Tetrahedron: Asymmetry 19 (2008) 1414–1417
A
8
11
8
11
8
11
3
.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4
B
3
.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4
ppm)
(
Figure 2. 1H NMR spectroscopic analysis (400 MHz, CDCl
, highfield expansion) of
3
the reaction outlined in Scheme 3 catalysed by 10 under Zhang’s conditions. (A)
Spectrum of the crude material after 48 h. (B) Spectrum after chromatography.
A
3
3
3
.6
.6
.6
3.2
3.2
3.2
2.8
2.8
2.8
2.4
2.4
2.4
2.0
2.0
2.0
1.6
1.6
1.6
1.2
1.2
1.2
0.8
0.8
0.8
0.4
0.4
0.4
0.0
0.0
0.0
B
C
Figure 1. CSP-HPLC analysis of the reactions outlined in Scheme 3. (A) Racemic 8.
B) Reaction catalysed by 7 under Hiyama’s conditions. (C) Reaction catalysed by 9
under Zhang’s conditions.
(
(
ppm)
Figure 3. 1H NMR spectroscopic analysis (400 MHz, CDCl
3
, highfield expansion) of
the reaction outlined in Scheme 4 catalysed by 10 under Zhang’s conditions. (A)
Spectrum of the reaction (organic phase) at t = 0 h. (B) Spectrum of the reaction
unidentified component in the chromatograms shown in Figure 1
(Fig. 4). To be certain that epoxide racemisation occurs neither dur-
ing chromatography nor under the reaction conditions, a sample of
commercially available enantiopure (R)-8 was purified by the same
column chromatography methodology used throughout this study,
and in a second experiment, pure (R)-8 (1.0 equiv) was added at
t = 0 h to a Corey–Chaykovsky reaction and upon completion the
products were isolated and analysed by CSP-HPLC. In both cases
no evidence for racemisation was found.13
(
organic phase) at t = 32.5 h. (C) Isolated 11 from the same reaction after
chromatography.
reaction. The authors were unfortunate that the catalyst decompo-
sition product, which is responsible for the optical activity that
they observed, is an epoxide difficult to separate from the desired
epoxide product. This impurity may well also have been difficult to
identify at low levels (max. 20%) with lowfield NMR instrumenta-
tion. With the benefit of CSP-HPLC analysis and highfield NMR
(400–600 MHz), it can be unequivocally shown that these ammo-
nium salt-catalysed methylene transfer reactions furnish racemic
products exclusively.
3
. Conclusion
Thus, it is certain that the reliance of both earlier studies6,7 on
the specific rotation data led to the error in reporting 7 and 9-10
as being capable of asymmetric catalysis of the Corey–Chaykovsky
Hiyama conditions
CH2Cl2/NaOH(aq.)
Zhang conditions
CH Cl /NaOH
(aq. )
2
2
7
11
00%
9 or 10
11
3
8 °C, 48 h
38 °C, 48 h
1
100% from 9
1
00% from 10
Scheme 4. Decomposition of catalysts 7 and 9–10 under the reaction conditions in the absence of 5 or 6.

S. A. Kavanagh, S. J. Connon / Tetrahedron: Asymmetry 19 (2008) 1414–1417
1417
4.
For examples, see: (a) Trost, B. M.; Hammen, R. F. J. Am. Chem. Soc. 1973, 95,
62; (b) Breau, L.; Durst, T. Tetrahedron: Asymmetry 1991, 2, 367; (c) Aggarwal,
9
V. K.; Coogan, M. P.; Stenson, R. A.; Jones, R. V. H.; Fieldhouse, R.; Blacker, J. Eur.
J. Org. Chem. 2002, 319; (d) Bellenie, B. R.; Goodman, J. M. Chem. Commun. 2004,
1
076.
Kavanagh, S. A.; Piccinini, A.; Fleming, E. M.; Connon, S. J. Org. Biomol. Chem.
008, 6, 1339.
5.
2
6.
7.
8.
9.
Hiyama, T.; Mishima, T.; Sawada, H.; Nozaki, H. J. Am. Chem. Soc. 1975, 97, 1626.
Zhang, Y.; Du, W. Tetrahedron: Asymmetry 1997, 8, 2723.
For example, see: Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421.
The control reaction without any catalyst afforded 8 in 16% yield under
otherwise identical conditions.
1
0. Chromatography was carried out under conditions recommended in Ref. 7:
silica gel, hexane/ether 10:1, R 0.5. The product was isolated as a single spot.
f
f
Variation of the solvent composition and R always resulted in the observation
of a single non-baseline spot.
Figure 4. CSP-HPLC analysis of the reaction outlined in Scheme 4. The decompo-
sition of catalyst 10 under Zhang’s reaction conditions.
1
1. Such base-mediated transformations are precedented. For recent examples
see: (a) Couty, F.; David, O.; Durrat, F.; Evano, G.; Lakhdar, S.; Marrot, J.; Vargas-
Sanchez, M. Eur. J. Org. Chem. 2006, 3479; (b) Rozwadowska, M. D. Tetrahedron:
Asymmetry 2006, 17, 1749; (c) Robiette, R.; Conza, M.; Aggarwal, V. K. Org.
Biomol. Chem. 2006, 4, 621.
References
1
2. During the preparation of this manuscript, we were pleased to find that in
1
980, Rosenberger had questioned Hiyama’s results and suggested that 11 may
1
.
(a) Johnson, A. W.; LaCount, R. B. J. Am. Chem. Soc. 1961, 83, 417; (b) Corey, E. J.;
Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 867; (c) Franzen, V.; Driesen, H.-E.
Chem. Ber. 1963, 96, 1881; (d) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc.
be the cause of the observed specific rotation. Their proof was not unequivocal
however and their work pre-dated that of Zhang et al. Rosenberger’s work does
not appear in a Scifinder Scholar search for papers which cite Hiyama’s work
1
965, 87, 1353.
For recent reviews see: (a) Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997,
7, 2341; (b) Aggarwal, V. K.; Richardson, J. Chem. Commun. 2003, 2644; (c)
(
although it does in a Web of Science search)—which has no doubt contributed
to a general misconception that the results outlined in Ref. 6 are still valid, see:
a) Rosenberger, M.; Jackson, W.; Saucy, G. Helv. Chim. Acta 1980, 63, 1665; for
2
.
9
(
Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res. 2004, 37, 611; (d) McGarrigle, E. M.;
Myers, E. L.; Illa, O.; Shaw, M. A.; Riches, S. L.; Aggarwal, V. K. Chem. Rev. 2007,
examples, of relatively recent papers which cite Refs. 6 and 7 as examples of
enantioselective phase-transfer catalysis see: (b) Llewellyn, D. B.; Adamson, D.;
Arndtsen, B. A. Org. Lett. 2000, 2, 4165; (c) Tohma, H.; Takizawa, S.; Watanabe,
H.; Fukuoka, Y.; Maegawa, T.; Kita, Y. J. Org. Chem. 1999, 64, 3519; (d) Ramón,
D. J.; Yus, M. Curr. Org. Chem. 2004, 8, 149; (e) Yadav, A. K.; Singh, A. Bull. Chem.
Soc. Jpn. 2002, 75, 587.
107, 5841.
3
.
Representative recent examples: (a) Aggarwal, V. K.; Alonso, E.; Bae, I.; Hynd,
G.; Lydon, K. M.; Palmer, M. J.; Patel, M.; Porcelloni, M.; Richardson, J.; Stenson,
R. A.; Studley, J. R.; Vasse, J.-L.; Winn, C. L. J. Am. Chem. Soc. 2003, 125, 10926;
(
4
b) Davoust, M.; Brière, J.-F.; Jaffrès, P.-A.; Metzner, P. J. Org. Chem. 2005, 70,
166; (c) Deng, X.-M.; Cai, P.; Ye, S.; Sun, X.-L.; Liao, W.-W.; Li, K.; Tang, Y.; Wu,
Y.-D.; Dai, L.-X. J. Am. Chem. Soc. 2006, 128, 9730.
1
3. In these experiments, epoxide
8 was detected in >99% ee and 53% ee,
respectively.