Direct asymmetric epoxidation of aldehydes using catalytic amounts of enantiomerically pure sulfides

Full text of DOI:10.1021/ja961144+

7004
J. Am. Chem. Soc. 1996, 118, 7004-7005
Scheme 1
Direct Asymmetric Epoxidation of Aldehydes Using
Catalytic Amounts of Enantiomerically Pure
Sulfides
Varinder K. Aggarwal,*,† J. Gair Ford,† Alison Thompson,†
Ray V. H. Jones,‡ and Mike C. H. Standen‡
Department of Chemistry, UniVersity of Sheffield
Sheffield S3 7HF, England
Process Technology Department
Zeneca Manufacturing Partnership, Earls Road
Grangemouth, Stirlingshire FK3 8XG, U.K.
Scheme 2
ReceiVed April 8, 1996
The development of catalytic methods for the synthesis of
nonracemic epoxides has been a long standing goal in asym-
metric synthesis.1 Most attention has focused on the asymmetric
oxidation of alkenes, and good enantioselectivities are now
beginning to emerge for an increasing range of substrates.2
Direct epoxidation of carbonyl compounds using sulfur ylides3
has also been studied, but the process usually requires stoichio-
metric amounts of sulfides/sulfur ylides4 and often only gives
moderate enantioselectivities.5 We recently described a catalytic
process for epoxidation involving sulfur ylides which overcomes
the former limitation (Scheme 1) and also described the use of
sulfide 1 for the preparation of nonracemic epoxides.5g,6 The
levels of enantioselectivity were poor, and in this communication
we now describe significant improvements in asymmetric
induction using easily accessible chiral sulfides.
In our first attempts at improving enantioselectivity, we
studied a more substituted analogue of 1, as it had been
previously shown by Durst that the benzyl sulfur ylide derived
from sulfide 2 reacted with aldehydes to give epoxides with
very high enantioselectivity.5k,7 Sulfide 2 was prepared and
tested in the catalytic cycle, but no epoxide was obtained, only
9
stilbene.8 However, using Cu(acac)2 in place of Rh2(OAc)4
and employing a stoichiometric amount of the Durst sulfide 2,
we were delighted to find that epoxidation was the dominant
process again (Scheme 2). The significant difference in epoxide
yield using Cu(acac)2 and Rh2(OAc)4 is a reflection of the
difference in rate of reaction of the metal carbenoid with either
the sulfide (to give ylide) or diazocompound (to give stilbene).
Evidently, the copper carbenoid is less sterically hindered than
the rhodium carbenoid and can therefore react with relatively
hindered sulfides.10 However, the enantiomeric excess was still
only moderate,11 so new chiral sulfides were sought. A positive
feature of the Durst sulfide is that only one of the two
diastereomeric lone pairs reacts with the metallocarbene, result-
ing in the formation of a single sulfur ylide. In the design of
alternative sulfides, it was deemed important to incorporate this
feature to avoid formation of diastereomeric sulfur ylides which
could react with opposite enantioselectivity.5f A disadvantage
of the Durst sulfide is that because of its lengthy synthesis it is
difficult to tune the steric and/or electronic environment of the
sulfur to maximize enantioselectivity. Sulfide 3 was therefore
designed, as it possesses only one reactive sulfur lone pair, and,
being a thioacetal, the R group is readily amenable to “tuning”.
† University of Sheffield.
‡ Zeneca Manufacturing Partnership.
(1) Besse, P.; Veschambre, H. Tetrahedron 1994, 50, 8885-8927.
(2) (a) Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L.
J. Am. Chem. Soc. 1991, 113, 7063-7064. (b) Brandes, B. D.; Jacobsen,
E. N. J. Org. Chem. 1994, 59, 4378-4380. (c) Chang, S.; Heid, R. M.;
Jacobsen, E. N. Tetrahedron. Lett. 1994, 35, 669-672. (d) Chang, S. B.;
Galvin, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 1994, 116, 6937-6938.
(e) Palucki, M.; Pospisil, P. J.; Zhang, W.; Jacobsen, E. N. J. Am. Chem.
Soc. 1994, 116, 9333-9334. (f) Irie, R.; Noda, K.; Ito, Y.; Matsumoto, N.;
Katsuki, T. Tetrahedron: Asymmetry 1991, 2, 481-494. (g) Hamada, T.;
Irie, R.; Katsuki, T. Synlett 1994, 479-481. (h) Katsuki, T. Coord. Chem.
ReV. 1995, 140, 189-214.
(3) (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353-
1364. (b) Trost, B. M.; Melvin, L. S. Sulfur Ylides; Academic Press: New
York, 1975. (c) Robertson, G. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, pp 563-
611.
(4) In one exceptional case Furukawa has carried out epoxidation using
0.5 equiv of sulfide in the presence of an alkyl halide, base, and aldehyde
to give epoxide. However, the yields of the epoxides obtained were very
low (<23% based on aldehyde), and he acknowledged that this was a poor
method for the preparation of epoxides.5b We have also tried this method
and concur with Furukawa. However, Dai and Huang have recently
described essentially the same process for epoxidation and obtained
surprisingly high yields of epoxides (>90%).5j This method is only
applicable to non-enolizable aldehydes and indeed has only been carried
out using PhCHO, p-Me-C6H4CHO, and p-Cl-C6H4CHO. Our catalytic
method can be used for both aliphatic and aromatic aldehydes and can also
be applied to base sensitive aldehydes due to the neutral reaction conditions
employed.5h
(7) (a) Durst, T.; Breau, L.; Ben, R. N. Phosphorus, Sulfur Silicon Relat.
Elem. 1993, 74, 215-232. (b) Ben, R. N.; Breau, L.; Bensimon, C.; Durst,
T. Tetrahedron 1994, 50, 6061-6076.
(8) Diazocompounds readily dimerize in the presence of metal catalysts.
Shankar, B. K. R.; Shechter, H. Tetrahedron. Lett. 1982, 23, 2277-2280.
(9) Salomon, R. G.; Kochi, J. K. J. Am. Chem. Soc. 1973, 95, 3300-
3310.
(10) (a) Aggarwal V. K.; Abdel-Rahman H.; Li Fan; Jones R. V. H.;
Standen, M. C. H. Chem. Eur. J., in press. (b) For a review on ylide
formation by this method, see: Padwa, A.; Hornbuckle, S. F. Chem. ReV.
1991, 91, 263-309.
(11) Durst reported that the benzylide of 2 reacted with benzaldehyde
to give stilbene oxide with >96% ee. The enantioselectivity we obtained
in our catalytic cycle was significantly lower (72% ee), and so we repeated
Durst’s original work but obtained only 71% ee. We have measured our
ee’s by chiral HPLC using a diode array detector to take a UV trace of the
enantiomers as they elute. The UV traces of the two peaks were
superimposable. Durst’s ee’s were determined by NMR using Eu shift
reagents.
(5) (a) Trost, B. M.; Hammen, R. F. J. Am. Chem. Soc. 1973, 95, 962-
964. (b) Furukawa, N.; Sugihara, Y.; Fujihara, H. J. Org. Chem. 1989, 54,
4222-4224. (c) Breau, L.; Ogilvie, W. W.; Durst, T. Tetrahedron. Lett.
1990, 31, 35-38. (d) Solladie-Cavallo, A.; Adib, A. Tetrahedron 1992,
48, 2453-2464. (e) Solladie-Cavallo, A.; Adib, A.; Schmitt, M.; Fischer,
J.; Decian, A. Tetrahedron: Asymmetry 1992, 3, 1597-1602. (f) Aggarwal,
V. K.; Kalomiri, M.; Thomas, A. P. Tetrahedron: Asymmetry 1994, 5, 723-
730. (g) Aggarwal, V. K.; Abdel-Rahman, H.; Jones, R. V. H.; Lee, H. Y.;
Reid, B. D. J. Am. Chem. Soc. 1994, 116, 5973-5974. (h) Aggarwal, V.
K.; Abdel-Rahman, H.; Jones, R. V. H.; Standen, M. C. H. Tetrahedron.
Lett. 1995, 36, 1731-1732. (i) Aggarwal, V. K.; Thompson, A.; Jones, R.
V. H.; Standen, M. Tetrahedron: Asymmetry 1995, 6, 2557-2564. (j) Li,
A. H.; Dai, L. X.; Hou, X. L.; Huang, Y. Z.; Li, F. W. J. Org. Chem. 1996,
61, 489-493. In several cases >90% ee has been obtained: (k) Breau, L.;
Durst, T. Tetrahedron: Asymmetry 1991, 2, 367-370. (l) Solladie-Cavallo,
A.; Diep-Vohuule, A. J. Org. Chem. 1995, 60, 3494-3498.
(6) PCT Int. Appl. WO 95 11, 230, 1995.
S0002-7863(96)01144-4 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 29, 1996 7005
Table 2. Yields, Enantioselectivities, and Ratios of Epoxides
Formed from Aldehydes Using 0.2 eq of Sulfide 3b
Scheme 3
entry
aldehyde
benzaldehyde
p-chlorobenzaldehyde
p-tolualdehyde
cinnamaldehyde
valeraldehyde
yield %
ee %a
trans:cis
1
2
3
4
5
6
73
72
64
73
35
32
93 (R,R)b
92(R,R)b
92(R,R)b
89c
>98:2
>98:2
>98:2
>98:2
92:8
68c
cyclohexanecarboxaldehyde
90c
70:30
a Enantiomeric excess determined by chiral HPLC using a Chiralcel
OD column. b Absolute configuration determined by comparison of [R]D
values with literature values.5b c Absolute configuration (R,R) assumed
by analogy with entries 1-3.
Scheme 4
Table 1. Yields, Enantioselectivities, and Ratios of Stilbene Oxide
Formed from Benzaldehyde Using 0.2 eq of Sulfides 3a-g
entry
sulfide
yield %
ee %a
trans: cis
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
83
73
45
0
56
43
70
41 (R,R)b
93 (R,R)b
93 (R,R)b
>98:2
>98:2
>98:2
88 (R,R)b
83 (R,R)b
92 (R,R)b
>98:2
>98:2
>98:2
3g
a Enantiomeric excess determined by chiral HPLC using a Chiralcel
OD column. b Absolute configuration determined by comparison of [R]D
values with literature values.5b
aldehydes and gave a mixture of trans and cis epoxides, whereas
aromatic aldehydes only gaVe trans epoxides. This contrasts
with sulfides 1 and 2 in which mixtures of trans:cis epoxides
were obtained with benzaldehyde.5k
Sulfides 3a-g were prepared as shown in Scheme 312 (3b
shown; see supporting information for 3a, 3c-g) and incorpo-
rated in the catalytic cycle with benzaldehyde (Table 1). It was
found that high enantioselectivity could be obtained provided
that the thioacetal was substituted at the 2 position (entries 2-7).
Sterically hindered (entries 2, 3, 4, and 5) or electron-
withdrawing groups (entries 6 and 7) resulted in lower yields
in the epoxidation process. The optimum sulfide in terms of
yield (73%) and enantioselectivity (93%) was 3b (entry 2).13,14
This is the highest enantioselectiVity yet reported for trans-
stilbene oxide formation by any method and uses an easily
accessible sulfide, employed in only catalytic quantities. Sulfide
3b was tested with a range of aldehydes, and the results are
summarized in Table 2. It was found that high enantioselectivity
was maintained with both aromatic and aliphatic aldehydes.
Aliphatic aldehydes gave lower yields compared to aromatic
Our mechanistic rationale for the high asymmetric induction
observed is depicted in Scheme 4. The ylide can adopt two
conformations 4a or 4b, but 4a suffers from 1,3 diaxial
interactions of the phenyl group with the axial H’s. 4b may
also suffer from 1,3 interactions between the phenyl and methyl
groups, but as the carbon-bearing ylide is likely to be between
sp2 and sp3 hybridized, this interaction may be smaller than that
encountered in 4a. The aldehyde can attack either face of ylide
4b, but the equatorial methyl group hinders Si face attack and
hence Re face attack is preferred. [In the absence of this group,
both faces of the ylide can be attacked, resulting in much
reduced enantioselectivity (Table 1, entry 1)]. Since the trans
epoxide is obtained, this dictates the orientation of the aldehyde
as it approaches the Re face of the ylide (assuming an end-on
approach rather than a [2 + 2] addition,15 Scheme 4) and gives
the (R,R)-epoxide.
In summary, we have discovered new conditions under which
hindered sulfides can participate in our catalytic cycle for direct
epoxidation of aldehydes and found simple, tuneable, chiral
sulfides which give very high levels of asymmetric induction.
(12) (a) Eliel, E. L.; Frazee, W. J. J. Org. Chem. 1979, 44, 3598-3599.
(b) de Lucchi, O.; Lucchini, V.; Marchioro, C.; Valle, G.; Modena, G. J.
Org. Chem. 1986, 51, 1457.
(13) (a) Using stoichiometric amounts of sulfide 3b, high yield (90%)
and high enantioselectivity (93% ee) were obtained with benzaldehyde, but
with 0.2 equiv of sulfide a slightly lower yield (73%) but the same
enantioselectivity was obtained. To obtain reasonable yields when using
substoichiometric amounts of sulfide, it was found necessary to conduct
reactions at the same effective concentration of sulfide. This presumably
resulted in similar rates of ylide formation and reaction with the aldehyde
and therefore allowed the sulfide to be returned and recycled at the same
rate as that of the stoichiometric process.
(14) While commercial Cu(acac)2 worked well with sulfide 2, no epoxide
was obtained with sulfide 3b. However, using Cu(acac)2 prepared by adding
saturated sodium carbonate to a suspension of copper oxide and acetylac-
etone in H2O (see: Bryant B. E.; Fernelius W. C. Inorg. Synth. 1957, 5,
115), the yields reported in Tables 1 and 2 were obtained. The following
general procedure was used in all of the reactions: To a stirred solution of
sulfide 3b (0.2 mmol), Cu(acac)2 (0.05 mmol), and the aldehyde (1 mmol)
in dichloromethane (0.5 mL) under nitrogen was added a solution of
phenyldiazomethane (1.5 mmol in 0.5 mL of dichloromethane) at room
temperature over a period of 3 h using a syringe pump. After the solution
was stirred for an additional 1 h, the solvent was removed in Vacuo and the
residue was chromatographed on silica gel.
Acknowledgment. We thank Zeneca Manufacturing Partnership,
EPSRC, and Sheffield University for financial support.
Supporting Information Available: Method for the preparation
and analytical data of thioacetals 3a-g, method for the asymmetric
epoxidation process, and assay methods for the product epoxides (7
pages). See any current masthead page for ordering and Internet access
instructions.
JA961144+
(15) It has not been established whether sulfur ylide additions to carbonyl
compounds occur via a [2 + 2] cycloaddition analogous to the phosphorus
ylide reaction or a head to tail addition. However, most literature examples
use the head to tail addition mode to account for the stereoselectivity
observed.5c