Diastereoselective sulfur ylide promoted aldol/epoxidation

Article abstract of DOI:10.1016/j.tetlet.2006.07.141

A mixture of cyclohexanone or 4-methylcyclohexanone and an aromatic aldehyde is treated with dimethylsulfoxonium methylide to effect a tandem aldol/epoxidation reaction. The resulting product contains three or four new stereocenters but only one of the po

Full text of DOI:10.1016/j.tetlet.2006.07.141

Tetrahedron Letters 47 (2006) 7209–7212
Diastereoselective sulfur ylide promoted aldol/epoxidation
a,
a
a,
b
*
Jeffrey A. Hansen, Colin R. Smith, Ryan J. Linder and John C. Huffman
a
Department of Chemistry, DePauw University, Greencastle, IN 46135, USA
Department of Chemistry, Indiana University, Bloomington, IN 47405, USA
b
Received 26 August 2005; revised 20 July 2006; accepted 27 July 2006
Abstract—A mixture of cyclohexanone or 4-methylcyclohexanone and an aromatic aldehyde is treated with dimethylsulfoxonium
methylide to effect a tandem aldol/epoxidation reaction. The resulting product contains three or four new stereocenters but only
one of the possible four or eight diastereomers is formed.
ꢀ
2006 Elsevier Ltd. All rights reserved.
The epoxide has long been a useful functional group in
organic synthesis allowing for the formation of new
reaction. While a b-hydroxyl directing effect in the sulfur
1
12
ylide epoxidation is rare, there are several examples of
1
3
carbon–carbon bonds and providing a pathway to a
variety of other functional groups. This, together with
the pharmaceutical industry’s ever-growing need for
methods to produce single enantiomers of chiral com-
an a-alkoxy or hydroxy directing effect.
We have developed an interesting and highly selective
epoxidation reaction between b-hydroxy ketones and
2
14
15
pounds, has spurred much activity in the development
sulfoxonium ylides. The b-hydroxy ketones 1 and 2
of new stereoselective epoxidation reactions.3–7 Most
of the work has involved oxidation of alkenes and is
highlighted by the excellent methods of Sharpless/Kat-
were prepared via generation of the lithium enolate of
cyclohexanone with LDA followed by addition of benz-
aldehyde. They were isolated as a mixture of two diaste-
reomers (Scheme 1). When this mixture was reacted with
dimethylsulfoxonium methylide a single diastereomer of
the resulting epoxide was isolated. The structure of this
product was assigned as 3 based on proton and carbon
NMR spectra.
3
4
5
6
suki, Jacobsen, Shi, and Julia Although less work
has been done in the area of methylene transfer to the
carbonyl group, impressive selectivities have been
achieved by Aggarwal and co-workers using chiral
7
,8
sulfonium ylides.
Hydroxyl group directing effects have been observed in
several different reactions including peracid epoxidation
Upon separation of the hydroxy-ketone diastereomers
by column chromatography we were surprised to find
9
of allylic alcohols and Simmons-Smith cyclopropana-
1
0
tion of allylic alcohols. An interesting example of a
carbon–carbon double bond exhibiting a directing effect
O
OH
O
OH O
1
2
. LDA
.
7
6
7
6
1
1
on sulfur ylide epoxidation has also been reported.
+
O
However, none of the stereoselective epoxidation meth-
ods mentioned above take advantage of the hydroxyl
directing effect save perhaps the Sharpless method.
Indeed, all achieve their remarkable selectivity through
careful control of the steric environment during the
H
1:syn
2: anti
O
(
H C) S CH2
3
2
OH
O
Keywords: Stereoselective; Epoxidation; Sulfur ylide.
*
Corresponding author. Tel.: +1 765 658 4613; fax: +1 765 658
084; e-mail: jhansen@depauw.edu
Present address: Lilly Corporate Center, Indianapolis, IN 46285-
813, USA.
6
3: syn,syn
4
Scheme 1.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.141

7210
J. A. Hansen et al. / Tetrahedron Letters 47 (2006) 7209–7212
that performing the epoxidation reaction on each of
these isomers separately provided the same single diaste-
reomer in approximately 50% yield (Scheme 1). Moni-
toring the reaction by TLC immediately after
combining the reagents clearly indicated that the hydro-
xy ketones equilibrate under the reaction conditions.
This equilibration could occur either by deprotona-
tion/reprotonation a to the ketone or retro-aldol/
aldol. Isolation of styrene oxide (formed from
epoxidation of benzaldehyde) argued for the retro-
aldol/aldol. Clearly, only one of the isomers reacts to
form the epoxide.
O
O
O
OH
O
(
H C) S CH2
3 2
H
+
1 and 2
OH
O
3
X-ray crystallographic analysis of the higher R hydroxy-
Scheme 2.
f
1
6
ketone diastereomer confirmed its structure as 1 (syn).
The crystal structure of 3 revealed it to have a syn,
Table 1. Tandem aldol/epoxidation of cyclohexanones and aromatic
aldehydes
1
7
syn configuration (Fig. 1).
a
b
Entry Ketone Aldehyde
Product
Yield
(%)
Our recognition that the two diastereomers of the b-
hydroxy ketone equilibrated under the reaction condi-
tions led us to investigate a one-pot aldol/epoxidation
sequence. Accordingly, when a 1:1 mixture of cyclohex-
anone and benzaldehyde in DMF is treated with
OH
O
O
O
1
H
71
60
40
25
41
Cl
Cl
4
1
.75 equiv of dimethylsulfoxonium methylide, the
sulfoxonium ylide catalyzes the aldol reaction and then
adds to the carbonyl to form the epoxide (Scheme 2).
OH
O
O
O
O
O
2
3
4
5
O
O
H
No diastereomeric product could be detected by NMR
for any of the examples we studied. Isolated yields are
typically in the range of 40–70% using cyclohexanone
and a variety of aromatic aldehydes (Table 1). In all
cases, small amounts of aldol product and styrene oxide
5
MeO
OH
O
MeO
O
O
H
(
or the equivalent) are present before purification. We
6
found that using 1.75 equiv of ylide was optimal and
using a larger excess of ylide did not improve the yield.
Surprisingly, replacing cyclohexanone with 4-methyl-
cyclohexanone also produced a single diastereomer—
this time with four new stereocenters. However,
cyclopentanone provided only aldol product with no
epoxidation. Aliphatic aldehydes provided complex
mixtures.
OH
O
O
O
O
O
O
H
7
OH
O
O
H
We believe the stereoselectivity results from attraction of
the positively charged sulfur of the ylide to the oxygen of
the hydroxyl group and possibly from hydrogen bond-
ing between the hydroxyl hydrogen and the ylide oxy-
8
OH
O
O
O
6
H
41
Cl
Cl
9
a
1
13
19
All products were characterized by H and C NMR.
Isolated yield after column chromatography.
b
gen. The resulting complex formed between the ylide
1
8
and 1 positions the ylide for equatorial attack on the
carbonyl which leads to epoxide 3. However, hydroxy
ketone 2 either does not easily form such a complex with
the ylide or the resulting complex does not result in
epoxidation. The fact that 8 and 9 are also produced
as single diastereomers strongly suggests that the reac-
tion is under thermodynamic control.
Use of sulfonium ylides in this reaction provided only
Figure 1.
small quantities of the epoxide product 3 with styrene

J. A. Hansen et al. / Tetrahedron Letters 47 (2006) 7209–7212
7211
oxide as the predominant product. Interestingly, the ste-
reochemistry of the sulfonium ylide reaction appears to
be the same as for the sulfoxonium ylide even though
8. For recent reviews of sulfur ylide chemistry, see: (a)
Aggarwal, V. K.; Richardson, J. Chem. Commun. 2003,
2
644–2651; (b) Aggarwal, V. K.; Winn, C. L. Acc. Chem.
1
8
Res. 2004, 37, 611–620.
sulfonium ylides typically add axially.
9
. Chamberlain, P.; Roberts, M. L.; Whitham, G. H. J.
Chem. Soc. B 1970, 1374–1381.
In summary, a novel tandem aldol/epoxidation reaction
promoted by dimethylsulfoxonium methylide has been
developed. This reaction constructs three new stereocen-
ters with complete diastereoselectivity. A variety of aro-
matic aldehydes can be combined with cyclohexanone or
1
0. See: Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A.
B. Chem. Rev. 2003, 103, 977–1050, for a review of
stereoselective cyclopropanation.
11. Bly, R. S.; DuBose, C. M., Jr.; Konizer, G. B. J. Org.
Chem. 1968, 33, 2188–2193.
4
-methylcyclohexanone. Acyclic ketones and nonaro-
12. Mazitschek, R.; Huwe, A.; Giannis, A. Org. Biomol.
Chem. 2005, 3, 2150–2154.
matic aldehydes did not participate in this reaction.
1
3. For example, see: (a) Smith, A. B., III; Fukui, M.;
Vaccaro, H. A.; Empfield, J. R. J. Am. Chem. Soc. 1991,
1
13, 2071–2092; (b) Marschner, C.; Baumgartner, J.;
Acknowledgements
Griengl, H. Liebigs Ann. Chem. 1994, 999–1004; (c) Gala,
D.; DiBenedetto, D. J.; Clark, J. E.; Murphy, B. L.;
Schumacher, D. P.; Steinman, M. Tetrahedron Lett. 1996,
We thank the Camille and Henry Dreyfus Foundation
and DePauw University for financial support of this
work.
3
7, 611–614; (d) Brown, B.; Hegedus, L. S. J. Org. Chem.
2000, 65, 1865–1872; (e) Sarabia, F.; Mart ´ı n-Ortiz, L.;
L o` pez-Herrara, F. J. Org. Lett. 2003, 5, 3927–3930.
1
4. For a review of the chemistry of dimethylsulfoxonium
methylide, see: Gololobov, Y. G.; Nesmeyanov, A. N.;
Lysenko, V. P.; Boldeskul, I. E. Tetrahedron 1987, 43,
References and notes
2
609–2651.
1
. For recent reviews of epoxidation chemistry, see: (a)
Jacobsen, E. N.; Wu, M. H. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer-Verlag: Berlin, 1999; Vol. II, pp 649–677;
1
5. Spectral data for 1 and 2 are consistent with those
found in: Kitamura, M.; Nakano, K.; Miki, T.; Okada,
M.; Noyori, R. J. Am. Chem. Soc. 2001, 123, 8939–
8
950.
(
b) Katsuki, T. In Comprehensive Asymmetric Catalysis;
1
1
6. The crystal structures of 1 (and 2) have been previously
reported. See Ref. 15.
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer-Verlag: Berlin, 1999; Vol. II, pp 621–648; (c)
Aggarwal, V. K. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer-Verlag: Berlin, 1999; Vol. II, pp 679–693.
7. Crystallographic data (excluding structure factors) for
compound 3 have been deposited with the Cambridge
Crystallographic Data Centre as Supplementary Publica-
tion Number CCDC 276175. Copies of the data can be
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: +44 (0)1223
2
3
. Rouhi, A. M. Chem. Eng. News 2004, 82, 47–62.
. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH: New York, 1993; pp 103–
3
36033 or e-mail: deposit@ccdc.cam.ac.uk).
1
58.
1
8. Sulfoxonium ylides typically add equatorially to cyclo-
hexanones while sulfonium ylides add axially. See: Corey,
E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353–
4
5
. Jacobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima,
I., Ed.; VCH: New York, 1993; pp 159–202.
. (a) Shi, Y. Acc. Chem. Res. 2004, 37, 488–496; (b) Yang,
D. Acc. Chem. Res. 2004, 37, 497–505; (c) Wang, Z. X.;
Tu, Y.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806–9807;
1
364.
1
9. Representative procedure for aldol/epoxidation: A solu-
tion of sulfoxonium ylide was prepared by adding tri-
methylsulfoxonium iodide to a suspension of NaH (42 mg
of 50% in mineral oil, 0.875 mmol, washed 3· with
hexanes) in DMF (7.5 mL). This solution was added
dropwise to a stirred mixture of benzaldehyde (53 mg,
(
1
d) Wang, Z. X.; Tu, Y.; Frohn, M.; Shi, Y. J. Org. Chem.
997, 62, 2328–2329; (e) Wang, Z. X.; Tu, Y.; Frohn, M.;
Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224–
1235.
1
6
. (a) Julia, S.; Masana, J.; Vega, J. C. Angew. Chem., Int.
Ed. Engl. 1980, 92, 968–969; (b) Bentley, P. A.; Bergeron,
S.; Cappi, M. C.; Hibbs, D. E.; Hursthouse, M. B.;
Nugent, T. C.; Pulido, R.; Roberts, S. M.; Wu, L. E. J.
Chem. Soc., Chem. Commun. 1997, 739–740; (c) Porter, M.
J.; Skidmore, J. J. Chem. Soc., Chem. Commun. 2000,
0
4
.5 mmol), cyclohexanone (49 mg, 0.5 mmol) and ground
˚
A molecular sieves in DMF (5 mL) at À50 ꢁC. The
resulting mixture was allowed to stir for 8 min, then was
placed in an ice-water bath and stirred for 20 min. The
reaction mixture was poured into 100 mL ice-cold ether
and washed with water (3 · 10 mL) and satd Na S O
1
215–1225.
2
2
3
(
4
10 mL). The organic layer was dried (MgSO ), concen-
7
. (a) Bellenie, B. R.; Goodman, J. M. J. Chem. Soc., Chem.
Commun. 2004, 1076–1077; (b) Aggarwal, V. K.; Coogan,
M. P.; Stenson, R. A.; Jones, R. V. H.; Fieldhouse, R.;
Blacker, J. Eur. J. Org. Chem. 2002, 319–326; (c) Aggar-
wal, V. K.; Ford, J. G.; Thompson, A.; Jones, R. V. H.;
Standen, M. C. H. J. Am. Chem. Soc. 1996, 118, 7004–
trated, and purified by column chromatography.
Compound 3: White crystalline solid (71%). Mp 73–75 ꢁC;
R = 0.33 (5:1 hexanes/EtOAc); H NMR (CDCl ): d
7
3
2
1
1
f
3
.15–7.5 (m, 5H), 4.95 (d, J = 1.7 Hz, 1H), 3.73 (s, 1H),
.45 (d, J = 3.2 Hz, 1H), 2.71 (d, J = 3.2 Hz, 1H) and 1.1–
.1 (m, 9H); C NMR (CDCl ): d 142.2, 128.0, 126.8,
25.8, 72.2, 63.2, 51.9, 44.2, 35.2, 25.2, 23.9, and 21.8.
1
3
7
005; (d) Breau, L.; Ogilvie, W. W.; Durst, T. Tetrahedron
3
Lett. 1990, 31, 35–38; (e) Solladi e´ -Cavallo, A.; Diep-
Vohuule, A.; Sunjic, V.; Vinkovic, V. Tetrahedron: Asym-
metry 1996, 7, 1783–1788; (f) Li, A.-H.; Dai, L.-X.; Hou,
X.-L.; Huang, Y.-Z.; Li, F.-W. J. Org. Chem. 1996, 61,
1
Compound 4: White crystalline solid (71%). H NMR
(
2
2
CDCl
3
): d 7.31 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz,
H), 5.02 (s, 1H), 3.85 (s, 1H), 3.55 (d, J = 3.2 Hz, 1H),
.75 (d, J = 3.2 Hz, 1H) and 1.1–2.1 (m, 9H).
4
89–493; (g) Zanardi, J.; Leriverend, C.; Aubert, D.;
Julienne, K.; Metzner, P. J. Org. Chem. 2001, 66, 5620–
623.
Compound 5: White crystalline solid (60%). IR 3446,
935, 2861, 1503, 1490, 1445, 1239, 1039; 1H NMR
2
5

7212
J. A. Hansen et al. / Tetrahedron Letters 47 (2006) 7209–7212
(
CDCl
3
): d 6.82 (s, 1H), 6.75 (s, 2H), 5.93 (s, 2H), 4.88 (d,
J = 3.2 Hz, 1H), 4.94 (d, J = 1.7 Hz, 1H), 3.50 (br s, 1H),
3.31 (d, J = 3.2 Hz, 1H), 2.67 (d, J = 3.2 Hz, 1H) and 1.2–
1.9 (m, 9H).
J = 1.7 Hz, 1H), 3.73 (s, 1H), 3.44 (d, J = 3.2 Hz, 1H),
1
3
2
(
7
.71 (d, J = 3.2 Hz, 1H) and 1.1–2.0 (m, 9H); C NMR
CDCl ): d 147.4, 146.3, 136.3, 118.8, 107.9, 106.7, 100.9,
2.1, 63.1, 52.0, 44.5, 35.2, 25.2, 23.9, and 22.0.
3
Compound 8: White crystalline solid (41%). IR 3453,
1
2926, 2868, 1494, 1451, 902, 753, 734, 702; H NMR
Compound 6: White crystalline solid (40%). IR 3460,
3
(CDCl ): d 7.1–7.5 (m, 5H), 4.93 (d, J = 1.7 Hz, 1H), 3.80
3
1
J
005, 2938, 2859, 1601, 1588, 1491, 1464, 1438, 1235, 1083,
(s, 1H), 3.52 (d, J = 3.2 Hz, 1H), 2.75 (d, J = 3.2 Hz, 1H),
1.1–2.2 (m, 8H) and .86 (d, J = 5.4 Hz, 3H); C NMR
1
13
050, 1028, 759;
H
NMR (CDCl
3
):
d
7.49 (dd,
= 7.7 Hz,
1
= 7.4 Hz, J = 1.7 Hz, 1H), 7.21 (td, J
2
1
(CDCl
35.1, 32.2, 32.0, 29.9, and 22.4.
Compound 9: White crystalline solid (41%). H NMR
(CDCl ): d 7.31 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 8.7 Hz,
3
): d 142.0, 128.0, 126.8, 125.8, 72.1, 62.9, 51.7, 43.7,
J2 = 1.7 Hz, 1H), 6.95 (t, J = 7.7 Hz, 1H), 6.82 (d,
J = 8.1 Hz, 1H), 5.18 (s, 1H), 3.78 (s, 3H), 3.70 (s, 1H),
1
3
1
1
4
.48 (d, J = 3.5 Hz, 1H), 2.69 (d, J = 3.5 Hz, 1H), 2.15 (m,
3
1
3
H) and 1.1–2.0 (m, 8H); C NMR (CDCl
30.2, 127.8, 127.7, 120.3, 109.9, 67.4, 63.2, 55.3, 52.1,
1.0, 35.3, 25.3, 24.0, and 22.5.
3
): d 155.5,
2H), 4.91 (s, 1H), 3.82 (s, 2H), 3.50 (d, J = 3.2 Hz, 1H),
2.78 (d, J = 3.2 Hz, 1H), 1.9–2.1 (m, 2H), 1.67 (m, 1H),
1
3
1.2–1.5 (m, 5H), and 0.88 (d, J = 5.4 Hz, 3H); C NMR
(CDCl ) 140.7, 132.3, 128.3, 127.0, 71.8, 62.9, 51.8, 43.6,
35.0, 32.1, 32.0, 29.9, and 22.6.
1
Compound 7: White crystalline solid (25%). H NMR
3
(
3
CDCl ): d 7.34 (s, 1H), 6.34 (d, J = 1.2 Hz, 1H), 6.26 (d,