Highly enantioselective ylide-mediated synthesis of terminal epoxides

Article abstract of DOI:10.1039/c2cc32101g

The highly efficient asymmetric epoxidation of aldehydes by methylene transfer is now possible using new sulfonium salts. This journal is

Full text of DOI:10.1039/c2cc32101g

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Highly enantioselective ylide-mediated synthesis of terminal epoxidesw
Alessandro Piccinini, Sarah A. Kavanagh and Stephen J. Connon*
Received 22nd March 2012, Accepted 25th May 2012
DOI: 10.1039/c2cc32101g
The highly efficient asymmetric epoxidation of aldehydes by
methylene transfer is now possible using new sulfonium salts.
The importance of chiral epoxides as synthetic building blocks
in asymmetric synthesis is extremely difficult to overstate.
While the highly enantioselective Sharpless,1,2 and Jacobsen-
Katsuki,3–5 protocols for the epoxidation of internal alkenes are
now mature technologies of inestimable value, the conversion of
terminal alkenes to enantioenriched 1-oxiranes has proven a
considerably more difficult process to control.5,6 Arguably the
current method of choice (in terms of product ee) for the
catalytic synthesis of these molecules is the Co-salen complex-
catalysed kinetic resolution of racemic epoxides.6a,7,8 While
Scheme 1 Benchmark methodologies for the asymmetric synthesis of
progress towards the efficient asymmetric oxidation of terminal
alkenes has been made – e.g. Fe/Mn-porphyrin complexes,9
chiral Ti10 and Pt-complexes11 and chiral dioxiranes (styrene
styrene oxide (2) from benzaldehyde (1) by methylene transfer.
a chiral sulfide and a Simmons–Smith type Zn-carbenoid, and
substrates only),12 the difficulties in preparing terminal epoxides
in 490% ee via alkene oxidation has fostered interest in
alternative protocols.13 One methodology which holds
promise is catalytic methylene transfer to aldehydes mediated
by sulfonium ylides.14 Since it is often from the aldehyde that
the alkene substrate for oxidation processes is prepared, a
methylene transfer reaction would represent a more direct
synthesis of the product, which could potentially be performed
in an operationally simple manner, in a transition metal-ion
free environment. The stabilised- and semi-stabilised sulfonium
ylide-mediated asymmetric epoxidation of aldehydes catalysed
by chiral sulfides has proven a highly useful process for the
formation of 1,2-disubstituted epoxides with excellent product
diastereo- and enantioselectivity.15,16 In an unfortunate parallel to
the alkene oxidation methodologies, the corresponding sulfonium
ylide-mediated aldehyde oxidation to form terminal epoxides
(nearly 40 years after the first disclosed asymmetric attempt)17
is characterised by moderate yields and low-moderate levels of
product enantiomeric excess.18–22 For instance, both bench-
mark methodologies (A and B, developed by Goodman19 and
Aggarwal20 respectively, Scheme 1) for the conversion of the
archetypal substrate benzaldehyde (1) to styrene oxide (2)
involve the employment of (super)stoichiometric loadings of
furnish the product in o60% yield and ee. In an attempt to
develop a more atom-economic process, we have shown that
the ylide can be generated via an alkylation and subsequent
deprotonation route (C, Scheme 1).23,24b Sulfide 6 could be
utilised at 20 mol% loading if the alkylating agent and base
were added portion-wise, however no progress was made
towards improving upon the mediocre enantioselectivity
which bedevils this (otherwise) potentially very useful reaction.
With the goal of solving this problem, we reflected upon the
likely causes of the low enantioselectivity. The first major
difficulty - as Aggarwal14b has pointed out - associated with
epoxidation using unstabilised ylides is irreversible betaine
formation. Thus the enantioselectivity is derived from the
face-selective addition of the ylide to the aldehyde alone.
Our thinking behind the identification of the second problem,
i.e. the root-cause of the poor facial selectivity which results
from the use of the C2-symmetric catalyst 6, is outlined in Fig. 1.
It is assumed that the aldehyde is likely to approach the ylide in
such a way that: (a) it avoids the large catalyst substituent in the
b-orientation (as drawn, Fig. 1A and B), (b) charge separation/
gauche interactions are minimised in the transition state, and c)
that the large aryl aldehydic substituent is directed into the
solvent. In this scenario one can see that attack at the aldehyde
si-face (leading to the observed (R)-product enantiomer,
Fig. 1B) appears favourable to attack at the re-face (Fig. 1A)
due to an unavoidable steric clash between the carbonyl group
(which increases as the tetrahedral betaine geometry is
approached) and the large a-catalyst substituent. This may explain
why enantioselectivity is unsatisfactory: one is attempting to act
upon a relatively small steric discrepancy between the aldehydic
School of Chemistry, Centre for Synthesis and Chemical Biology,
Trinity Biomedical Sciences Institute, University of Dublin,
Trinity College, Dublin 2, Ireland. E-mail: connons@tcd.ie;
Fax: +35316712826
w Electronic supplementary information (ESI) available: Experimental
procedures and characterisation data. See DOI: 10.1039/c2cc32101g
c
7814 Chem. Commun., 2012, 48, 7814–7816
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and 50% ee (entry 1). The 2-naphthyl analogue 7b proved only
marginally superior to 7a (entry 2), with a further increase
in product ee possible through the modification of 7a via
the introduction of m-methyl substituents (i.e. 7c, entry 3).
Interestingly, we also noted the mild influence of reaction
concentration on enantioselectivity (entry 4). Replacement of
the methyl substituents with larger phenyl moieties resulted in
a significant improvement in performance (i.e. 7d, 79–83% ee,
entries 4–5), however further aggrandisement of the aryl
substituents led to decreased product yields and optical purity
(i.e. 7e, entries 7–8).
Our attention now turned to the alkoxide substituent. We
had posited that in lower energy conformations the alkoxy
substituent would be likely to be orientated towards the ylide
carbon (and thus be capable of influencing enantioselectivity)
in order to allow the larger aryl moieties to be directed
into the solvent. It was found that 7f – an ethoxy analogue
of 7d – could promote the epoxidation of 1 with good
enantioselectivity in CH2Cl2 (entry 9), however, in THF
solvent the product ee increased to 95% (entry 10). The
corresponding benzyloxy salt 7g mediated the formation of
(S)-2 in 490% ee in either the halogenated or ethereal solvent
(entries 11–13), albeit with slightly lower product ee than was
possible using 7f. While it is possible to utilise the salt in catalytic
amounts if the base and alkylating agent are added portion-wise,
the SN2 alkylation of 7f is too slow under the relatively dilute
conditions conducive to enantioselective epoxidation for this to
be practicable. However, after methylene transfer the sulfide can
be efficiently recovered by chromatography and re-alkylated to
give 7f. Our study now concentrated on the question of substrate
scope (Table 2).
Fig. 1 Proposed stereochemical rationale and catalyst design.
CQO (Fig. 1A) and C–H bonds. The catalyst’s t-butyl group is
seemingly not of sufficient steric bulk to allow efficient discrimina-
tion between the two possible Burgi-Dunitz trajectories. If our
hypothesis is correct, the circumvention of the problem would
involve the relatively straightforward matter of designing a catalyst
with considerably larger substituents at C–2 and C–5, so that the
steric interaction with the aldehyde carbonyl group is of sufficient
magnitude to preclude attack at the re-face (Fig. 1C). We
envisaged that sulfonium salts derived from sulfides of augmented
steric bulk (e.g. 6a - the size of the aryl and alkoxide substituents of
which is tunable, Fig. 1) could represent a solution to the problem.
Accordingly, novel sulfonium salts were prepared and evaluated in
the epoxidation of 1 (Table 1). Even the salt equipped with the
smallest of aryl and alkoxide substituents (i.e. 7a) represented a
step forwards – leading to the formation of (S)-2 in excellent yield
Table 1 Preliminary catalyst evaluation
We were pleased to find that benzaldehyde (1), along with
both activated and hindered analogues (8 and 9 respectively)
underwent methylene transfer in excellent isolated yield and
enantioselectivity (entries 1–3). The relatively electron-rich
p-anisaldehyde (10), enal 11 and the aliphatic aldehyde 12
were produced in good yields but with lower optical purity
(72, 82 and 81% ee respectively, entries 4–6). It is noteworthy,
that these general levels of product ee remain considerably
higher than those hitherto obtainable using ylide-based
procedures. The high potential utility of this metal-free epoxidation
(and its complementarity to existing methods) is illustrated by
formation of epoxides 21–23 in 490% yield and Z90% ee
(entries 7–9). These products bear readily oxidisable sulfide, olefin
and N-heterocyclic functionality likely to be incompatible with
epoxidation methodologies involving the use of strong oxidants.
In summary, new chiral sulfonium salts have been designed.
The optimal material (7f) is capable of mediating highly
enantioselective aldehyde epoxidation reactions involving
methylene transfer – a process hitherto characterised by
prohibitively low enantioselectivity. While the current process
still requires 100 mol% of the salt, the sulfide generated after
methylene transfer can be readily recycled in 70–75% yield
after chromatography. The protocol generates terminal epoxides
in good-excellent yield inside one hour via an operationally
simple protocol. This aldehyde-based methodology has the
potential to serve as a complementary technology for the
enantioselective synthesis of epoxides bearing readily oxidisable
sulfide-, N-heterocycle- and olefin-based functionality likely to be
Entry
Salt
Solvent
Conc. (M)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
7a
7b
7c
7c
7d
7d
7e
7e
7f
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
0.066
0.066
0.066
0.02
0.066
0.02
0.066
0.02
0.066
0.02
89
83
93
82
92
89
70
60
93
95
94
92
92
50
56
57
61
79
83
62
64
78
95
92
92
92
9
10
11
12
13
7f
7g
7g
7g
CH2Cl2
CH2Cl2
THF
0.066
0.02
0.02
a
Determined by 1H NMR spectroscopy using styrene as an internal
b
standard. Determined by CSP-HPLC.
c
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Chem. Commun., 2012, 48, 7814–7816 7815

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Table 2 Evaluation of the substrate scope
in Comprehensive Asymmetric Catalysis, ed. E. N. Jacobsen, A. Pfaltz
and H. Yamamoto, Springer, New York, 1999, p. 649;
(d) E. N. Jacobsen, Acc. Chem. Res., 2000, 33, 421.
7 (a) M. Tokunaga, J. F. Larrow, F. Kakiuchi and E. N. Jacobsen,
Science, 1997, 277, 936; (b) S. E. Schaus, B. D. Brandes, J. F. Larrow,
M. Tokunaga, K. B. Hansen, A. E. Gould, M. E. Furrow and
E. N. Jacobsen, J. Am. Chem. Soc., 2002, 124, 1307.
8 For related methodologies see: W. Hirahata, R. M. Thomas,
E. B. Lobkovsky and G. W. Coates, J. Am. Chem. Soc., 2008,
130, 17658.
9 (a) J. P. Collman, Z. Wang, A. Straumanis, M. Quelquejeu and
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B. Andrioletti, S. Zrig and M. Quelquejeu-Etheve, Chem. Soc.
Rev., 2005, 34, 573.
Entry
1c
Substrate
Product
Yielda (%)
eeb (%)
95
95
2c
3d
4d
5d
92
89
80
88
95
93
72
10 (a) K. Matsumoto, Y. Sawada, B. Saito, K. Sakai and T. Katsuki,
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M. A. Shaw, S. L. Riches and V. K. Aggarwal, Chem. Rev.,
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82
81
90
15 Representative examples: (a) N. Furukawa, Y. Sugihara and
H. Fujihara, J. Org. Chem., 1989, 54, 4222; (b) V. K. Aggarwal,
H. Abdel-Rahman, R. V. H. Jones, H. Y. Lee and B. D. Reid,
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16 Shibasaki et al. found that chiral La-complexes can catalyse the
enantioselective epoxidation of ketones with superstoichiometric
sulfoxonium methylide: T. Sone, A. Yamaguchi, S. Matsunaga and
M. Shibasaki, J. Am. Chem. Soc., 2008, 130, 10078.
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Jones, R. Fieldhouse and J. Blacker, Eur. J. Org. Chem., 2002, 319.
21 Early claims involving the use of chiral phase-transfer catalysts
(ref. 21a,b) were later shown (ref. 21c) to be in error:
(a) T. Hiyama, T. Mishima, H. Sawada and H. Nozaki, J. Am.
Chem. Soc., 1975, 97, 1626; (b) Y. Zhang and W. Wu, Tetrahedron:
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6c
7d
8d
75
94
91
92
90
9d,e
92
a
b
Isolated yields. Determined by CSP-HPLC. Using (R,R)–7f.
e
Using (S,S)–7f. 0.015 M reaction concentration.
c
d
problematic in reactions which rely on olefin oxidation
chemistry.
Financial support from Science Foundation Ireland is grate-
fully acknowledged. We thank Dr J. Goodman for helpful
discussions.
Notes and references
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24 Related work: (a) S. A. Kavanagh, A. Piccinini, E. M. Fleming and
S. J. Connon, Org. Biomol. Chem., 2008, 6, 1339; (b) S. A. Kavanagh,
A. Piccinini and S. J. Connon, Adv. Synth. Catal., 2010, 352, 2089.
c
7816 Chem. Commun., 2012, 48, 7814–7816
This journal is The Royal Society of Chemistry 2012