Highly enantioselective carbonyl-ene reactions catalyzed by a hindered silyl-salen-cobalt complex

Article abstract of DOI:10.1021/ol071342d

We report here the enantioselective carbonyl-ene reactions of various 1,1-disubstituted and trisubstituted alkenes with ethyl glyoxylate. The reactions are catalyzed by a new Co-salen complex, in which bulky triisobutylsilyl (TIBS) substituents occupy the

Full text of DOI:10.1021/ol071342d

ORGANIC
LETTERS
2007
Vol. 9, No. 20
3869-3872
Highly Enantioselective Carbonyl-ene
Reactions Catalyzed by a Hindered
Silyl−Salen−Cobalt Complex
Gerri E. Hutson, Apurva H. Dave, and Viresh H. Rawal*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue,
Chicago, Illinois 60637
Vrawal@uchicago.edu
Received June 6, 2007
ABSTRACT
We report here the enantioselective carbonyl-ene reactions of various 1,1-disubstituted and trisubstituted alkenes with ethyl glyoxylate. The
reactions are catalyzed by a new Co salen complex, in which bulky triisobutylsilyl (TIBS) substituents occupy the positions ortho to the
phenolic oxygens. This complex catalyzes the reactions under nearly ideal conditions at room temperature and using catalyst loadings as
low as 0.1 mol % and provides the chiral, homoallylic alcohol products in excellent yields, enantioselectivities, and diastereoselectivities.
−
s
s
The enantioselective carbonyl-ene reaction, an atom-
economic analogue of the asymmetric metal-allylation reac-
tion, provides direct access to chiral homoallylic alcohols
under mild conditions.1 Since the first report on the topic
by Yamamoto and co-workers,2 the catalytic enantioselective
carbonyl-ene reaction has been the subject of investigation
in several laboratories. The electronic requirements of the
reaction generally necessitate that the carbonyl component
be strongly electron-deficient, most often a glyoxylate.
Among the notable contributions to the development of
enantioselective carbonyl-ene reactions is the use of Ti-
BINOL complexes by Nakai/Mikami,3 Cu-Box catalysts by
Evans4a,b and Vederas,5 Sc-PyBox catalysts by Evans,4c and
tridentate-Cr(III)-Schiff base complexes by Jacobsen.6,7
Our recent work on the use of C2-symmetric metal-salen
(3) (a) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1989, 111,
1940-1941. (b) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1990,
112, 3949-3954. (c) Mikami, K.; Matsukawa, S. J. Am. Chem. Soc. 1993,
115, 7039-7040 and references herein. For further extensions of this
chemistry, see: Yuan, Y.; Zhang, X.; Ding, K. Angew. Chem., Int. Ed.
2003, 42, 5478-5480.
(4) (a) Evans, D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.; Tregay,
S. W. J. Am. Chem. Soc. 1998, 120, 5824-5825. (b) Evans, D. A.; Tregay,
S. W.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T. J. Am. Chem. Soc. 2000,
122, 7936-7943. (c) Evans, D. A.; Wu, J. J. Am. Chem. Soc. 2005, 127,
8006-8007.
(1) For reviews, see: (a) Mikami, K.; Shimizu, M. Chem. ReV. 1992,
92, 1021-1050. (b) Mikami, K.; Terada, M.; Narisawa, S.; Nakai, T. Synlett
1992, 255-265. (c) Berrisford, D. J.; Bolm, C. Angew. Chem., Int. Ed.
1995, 34, 1717-1719. (d) Dias, L. C. Curr. Org. Chem. 2000, 4, 305-
342. (e) Mikami, K.; Terada, M. ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Heidel-
berg, 1999; Vol. III, Chapter 32.
(5) Gao, Y.; Lane-Bell, P.; Vederas, J. C. J. Org. Chem. 1998, 63, 2133-
2143.
(6) (a) Ruck, R. T.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 2882-
2883. (b) Ruck, R. T.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2003, 42,
4771-4774.
(2) Maruoka, K.; Hoshino, Y.; Shirasaka, T.; Yamamoto, H. Tetrahedron
Lett. 1988, 29, 3967-3970.
10.1021/ol071342d CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/01/2007

complexes as effective Lewis acid catalysts for Diels-Alder
reactions motivated us to examine such complexes for the
carbonyl-ene reaction.8
%.8c The enhanced effectiveness of the silyl salens was
rationalized to be a result of sterics-based distortion of the
otherwise flat salen framework. Through similar reasoning,
we have developed a triisobutylsilyl(TIBS)-substituted C2-
symmetric Co-salen complex for promoting the carbonyl-
ene reaction of various 1,1-disubstituted and trisubstituted
alkenes with ethyl glyoxylate. These reactions proceed at
room temperature using catalyst loadings as low as 0.1 mol
% and produce γ,δ-unsaturated-R-hydroxy carboxylic esters
in excellent yields, enantioselectivities, and diastereoselec-
tivities.17
For the initial studies, we examined the carbonyl-ene
reaction of ethyl glyoxylate (2a) and R-methyl styrene (3a),
promoted by the cobalt complex of the commercially
available t-butylsalen ligand (Table 1).18 The reaction was
Over the years, C2-symmetric metal-salen complexes have
proven to be useful in a wide range of reaction types.9 First
developed in the context of epoxidation and epoxide opening
chemistry, these complexes have also been utilized more
recently as chiral Lewis acid catalysts for many other
reactions, including Diels-Alder,8,10 hetero-Diels-Alder,11
hydrocyanation,12 silylcyanation,13 aldol,14 alkylation,15 and
conjugate addition16 reactions. These complexes are easy to
prepare and have good benchtop stability. Importantly, the
steric and electronic environment of the salens can be varied
with ease. In connection with our enantioselective Diels-
Alder work, we sought to accentuate the subtle asymmetric
topology of the commonly used C2-symmetric salen frame-
work (1a) and found the corresponding silyl-substituted salen
cobalt complexes (e.g., 1b) to be superb catalysts for Diels-
Alder reactions, functioning at loadings as low as 0.05 mol
Table 1. Variation of the Cobalt(III) Salen Scaffold at the R1
and R2 Position
entry catalyst
R1
R2
time (h) yielda (%) eeb (%)
(7) For other reports on the enantioselective carbonyl-ene reaction, see:
(a) Kezuka, S.; Ikeno, T.; Yamada, T. Org. Lett. 2001, 3, 1937-1939.
Hetero-ene reaction: (b) Carreira, E. M.; Lee, W.; Singer, R. A. J. Am.
Chem. Soc. 1995, 117, 3649-3650. Additions to imines: (c) Drury, W. J.;
Ferraris, D.; Cox, C.; Young, B.; Lectka, T. J. Am. Chem. Soc. 1998, 120,
11006-11007. Enamines as nucleophiles: (d) Matsubara, R.; Nakamura,
Y.; Kobayashi, S. Angew. Chem., Int. Ed. 2004, 43, 1679-1681. (e)
Matsubara, R.; Nakamura, Y.; Kobayashi, S. Angew. Chem., Int. Ed. 2004,
43, 3258-3260. (f) Terada, M.; Machioka, K.; Sorimachi, K. Angew. Chem.,
Int. Ed. 2006, 45, 2254-2257.
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
-(CH2)4- t-Bu
-(CH2)4- TMS
24
2
84
77
93
97
98
95
97
34
51
46
54
62
90
98
Ph
Ph
Ph
Ph
Ph
t-Bu
TMS
TES
TIPS
TIBSc
15
2
2
2
2
1g
(8) (a) Huang, Y.; Iwama, T.; Rawal, V. H. J. Am. Chem. Soc. 2000,
122, 7843-7844. (b) Huang, Y.; Iwama, T.; Rawal, V. H. Org. Lett. 2002,
4, 1163-1166. (c) Huang, Y.; Iwama, T.; Rawal, V. H. J. Am. Chem. Soc.
2002, 124, 5950-5951. (d) Takenaka, N.; Huang, Y.; Rawal, V. H.
Tetrahedron 2002, 58, 8299-8305. (e) McGilvra, J. D.; Rawal, V. H. Synlett
2004, 2440-2442.
a
b
Isolated yield. Determined by chiral HPLC analysis using a Daicel
Chiralcel AD column (98.5% hexanes, 1.5% iPrOH). c TIBS ) triisobutyl
silyl.
(9) (a) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691-1693.
For salen reviews, see: (b) Cozzi, P. G. Chem. Soc. ReV. 2004, 33, 410-
421. (c) Katsuki, T. AdV. Synth. Catal. 2002, 344, 131-147. (d) McGarrigle,
E. M.; Gilheany, D. G. Chem. ReV. 2005, 105, 1563-1602. (e) Katsuki, T.
Synlett 2003, 281-297. (f) Canali, L.; Sherrington, D. C. Chem. Soc. ReV.
1999, 28, 85-93. (g) Achard, T. R. J.; Clutterbuck, L. A.; North, M. Synlett
2005, 1828-1847. (h) Atwood, D. A.; Harvey, M. J. Chem. ReV. 2001,
101, 37-52. (i) Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A. Chem.
Commun. 2002, 919-927.
carried out in methylene chloride at room temperature in the
presence of 5 mol % of catalyst 1a and produced chiral
alcohol 4a in >95% conversion and 28% ee, with the (R)-
enantiomer predominating. Solvent optimization studies
revealed that in toluene the product was formed in compa-
rable conversion and with higher selectivity (34% ee, entry
1). On the other hand, the product was formed in only trace
amounts in coordinating solvents such as diethyl ether and
(10) Yamashita, Y.; Katsuki, T. Synlett 1995, 829-830.
(11) Schaus, S. E.; Branalt, J.; Jacobsen, E. N. J. Org. Chem. 1998, 63,
403-405.
(12) For example, see: Sigman, M. S.; Jacobsen, E. N. J. Am. Chem.
Soc. 1998, 120, 5315-5316.
(17) Hutson, G.; Rawal, V. H. Abstracts of Papers, 233rd ACS National
Meeting, Chicago, IL, United States, March 25-29, 2007; American
Chemical Society: Washington DC, 2007; ORGN-557 (Chemical Ab-
stracts: 2007:296584). While this manuscript was being readied for
publication, a report appeared on the use of C2-symmetric salen complexes
for carbonyl-ene reactions (4-92% ee). See: Chaladaj, W.; Kwiatkowski,
P.; Maker, J.; Jurczak, J. Tetrahedron Lett. 2007, 48, 2405-2408.
(18) Other metal-salen complexes of the general structure 1a were
examined for this carbonyl-ene reaction, but none gave satisfactory results.
Under similar conditions (5 mol % of catalyst, toluene, 24 h), the following
results were obtained: Cr-salen, 28% ee, >95% conversion; Mn-salen,
7% ee, 33% conversion; Al-salen, 16% ee, 85% conversion.
(13) Chen, F.; Feng, X.; Qin, B.; Zhang, G.; Jiang, Y. Org. Lett. 2003,
5, 949-952.
(14) Evans, D. A.; Janey, J. M.; Magomedov, N.; Tedrow, J. S. Angew.
Chem., Int. Ed. 2001, 40, 1884-1888.
(15) (a) Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127,
62-63. (b) Kwiatkowski, P.; Chaladaj, W.; Jurczak, J. Tetrahedron Lett.
2004, 45, 5343-5346.
(16) (a) Bandini, M.; Fagioli, M.; Melchiorre, P.; Melloni, A.; Umani-
Ronchi, A. Tetrahedron Lett. 2003, 44, 5843-5846. (b) Taylor, M. S.;
Zalatan, D. N.; Lerchner, A. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2005,
127, 1313-1317.
3870
Org. Lett., Vol. 9, No. 20, 2007

ethyl acetate. As anticipated, the corresponding silyl-salen
complex was more effective at promoting the reaction, albeit
only marginally.
Table 2. Salen Complex Catalyzed Enantioselective
Carbonyl-ene Reactions
To improve the enantioselectivities to useful levels, we
next examined salen complexes derived from the acyclic
diamine, 1,2-diphenylethane-1,2-diamine. The parent, t-butyl-
substituted salen complex (1c) gave the product in higher
ee and promoted the reaction at a good rate (entry 2). As
before, the corresponding TMS-substituted salen complex
(1d) was even more effective. The reaction was complete in
less than 2 h, giving the product in 97% yield and 54% ee.
A steady increase in enantioselectivity was observed as the
steric bulk of the silyl substituent was increased from TMS
to TES to TIPS. When the TIBS-substituted salen complex
was employed, the product was obtained in 98% ee (Table
1, entry 6).19
The TIBS-salen-catalyzed carbonyl-ene reaction protocol
proved to be broadly effective. A variety of 1,1-disubstituted
and trisubstituted alkenes were reacted with ethyl glyoxylate
and gave the expected homoallylic alcohol products in good
to excellent yields and uniformly excellent enantioselectivi-
ties (Table 2). For the reaction with R-methyl styrene, the
reaction proceeded nearly as well when the catalyst loading
was lowered from 5 mol % to 1 mol %. The lower loading
decreased the rate of the reaction slightly, with no change
in ee (Table 2, entry 1). The catalyst loading could be
decreased to 0.1 mol % and still provide a synthetically useful
reaction. As in the case of R-methyl styrene (3a), methylene
cyclopentane (3b) also underwent the asymmetric carbonyl-
ene reaction with 2a in excellent yields and enantioselec-
tivities with catalyst loadings as low as 0.1 mol % (entry 2).
It is noteworthy that at 1 mol % loading this reaction went
to completion in just 10 min.
Symmetric alkenes 3c-f were effective partners in the
carbonyl-ene reaction and provided the expected alcohol
products in high enantioselectivities (entries 3-6). The
reaction of alkene 3f was both highly enantioselective and
diastereoselective, producing the E-alkene isomers in 33:1
ratio (entry 6). Bulky alkenes such as 2,3,3-trimethylbutene
(3g) and 2,4,4-trimethylpent-1-ene (3h) also reacted well but
required longer time to complete the reaction (entries 7 and
8). Hydrogen abstraction in the latter took place exclusively
from the less-substituted carbon. Trisubstituted alkene 3-ethyl-
2-pentene (3i) gave the ene product in good diastereoselec-
tivity, with the major diastereomer having been formed in
96% ee (entry 9).
a
b
Isolated yields. Determined by chiral HPLC or chiral GC. Please
see the Supporting Information for details on the assignment of absolute
and relative stereochemistry of the reaction products. With 5 mol % of
c
d
catalyst loading, reaction reached 80% conversion within 10 min.
Isobutylene was added at -80 °C, then a -20 °C bath was used. e Reaction
f
g
performed at 0 °C. (S,S)-catalyst used for ee determination. Regiose-
lectivity was >99:1. E/Z ratios determined by 1H NMR spectroscopic
h
analysis; (E)-configuration established by NOESY.
and gave enol ether product 4j in good yield, high diaste-
reoselectivity, and excellent enantioselectivity (80% yield,
18:1 dr, 98% ee). The relative stereochemistry of the major
diastereomer was assigned by converting it to the benzoyl-
protected â-hydroxy ketone and comparing its NMR spec-
trum with that reported in the literature.20
The use of silyl enol ethers in the carbonyl-ene reaction
presents the possibility of forming either fuctionalized silyl
enol ethers or, upon hydrolysis, the attainment of useful aldol
products of ketones and glyoxylate.3c,6 To assess the capabil-
ity of TIBS-salen complex 1g to promote such reactions,
we carried out the reaction of enol-TBS ether of cyclohex-
anone (3j) and ethyl glyoxylate in the presence of complex
1g (eq 1). The reaction went to completion in under 30 min
(19) The different silyl salen ligands were readily prepared using the
procedure described in the accompanying publication: Thadani, A. N.;
Huang, Y.; Rawal, V. H. Org. Lett. 2007, 9, 3873-3876. See also the
Supporting Information.
Examination of other aldehydes resulted in the discovery
of Co(III)TIBS-SbF6 salen promotion of unactivated olefin
Org. Lett., Vol. 9, No. 20, 2007
3871

additions to pyridine-2-carboxaldehyde (eq 2). This interest-
ing result represents, to our knowledge, the first example of
a catalyzed, asymmetric carbonyl-ene reaction between a
monocarbonyl and an unactivated alkene.21,22 The reaction
is very efficient, producing product 4k in 84% yield and
>99% enantioselectivity. It is noteworthy that neither
pyridine-3-carboxaldehyde nor pyridine-4-carboxaldehyde
are reactive under the same conditions. Similarly, other
electron-deficient aromatic aldehydes (2-nitrobenzaldehyde,
4-nitrobenzaldehyde, pentafluorobenzaldehyde) were also
unreactive under identical conditions. On the basis of the
observation that only glyoxylate and pyridine-2-carboxal-
dehyde are effective partners in the present carbonyl-ene
reaction, we postulate that the reaction involves activation
of the aldehyde via bidentate coordination to the cobalt(III)
metal center.23
Figure 1. ORTEP representations (edge and top views) of TIBS-
salen complex 1g.
that one of the quadrants on the hydroxyl-coordinated face
is much larger than the other (O1-Co-O3 angle ) 108.5°).
Naturally, because the structure is not that of the catalyst
complexed to a reactive carbonyl compound,8c it does not
provide direct information on the factors responsible for the
observed high enantioselectivities. What is clear is that the
large TIBS groups accentuate the otherwise subtle asym-
metric environment of the salen scaffold.
The results above demonstrate the high effectiveness of
Co(III)TIBS-SbF6 salen complex 1g to function as a catalyst
for the carbonyl-ene reaction of ethyl glyoxylate with a wide
range of alkenes. The catalyst is easily prepared and does
not require a drybox for its preparation or handling. This
methodology provides chiral â-hydroxy esters in high yields
and excellent enantioselectivities (up to 98% ee) and dias-
tereoselectivities. The reactions are carried out under nearly
ideal conditionssat room temperature and using catalyst
loadings as low as 0.1 mol %. The catalyst has also been
found to promote the carbonyl-ene reaction of a silyl enol
ether and ethyl glyoxylate as well as that of an alkene and
2-pyridinecarboxaldehyde.
To develop an understanding of the chiral environment in
the hindered TIBS-salen complex, we sought to obtain a
crystal structure of this compound. A crystalline solid suitable
for X-ray diffraction was obtained from an ether-hexane
solution of 1g.24 The X-ray structure (Figure 1)20 appears to
be that of either the Co(IV) oxo complex or the Co(III)
hydroxide. On the basis of the large Co-O(3) bond length
(2.109 Å) as well as the presence of residual electron density
near the oxygen, corresponding to a hydrogen atom, the
structure is determined to be that of the cobalt hydroxide.
The edge view of the square pyramidal complex shows that
the bulky TIBS groups induce a significant twist to the plane
of the salen ligand. Furthermore, coordination of the hydroxyl
group to the salen backbone is highly asymmetrical, such
Acknowledgment. This work was supported by the
National Institutes of Health. Additional support through The
GlaxoSmithKline Dr. Lendon N. Pridgen Fellowship Award
and the ARCS (Achievement Rewards for College Students)
Foundation Scholarship to G.E.H. is also acknowledged.
(20) See Supporting Information for further details.
(21) Asymmetric carbonyl-ene reactions of simple unactivated aldehydes
and electron-rich alkenes, such as silyl enol ethers, have been reported.
See, inter alia, refs 6, 7b, and 3c.
(22) For recent examples of racemic carbonyl-ene reactions of unactivated
alkenes and aromatic/aliphatic aldehydes, see: Ho, C.; Ng, S.; Jamison, T.
F. J. Am. Chem. Soc. 2006, 128, 11513-11528.
Supporting Information Available: Experimental details
and characterizations for all new compounds and crystal
structure data. This material is available free of charge via
the Internet at http://pubs.acs.org.
(23) For examples of bidentate-coordinated cobalt-salen complexes,
see: (a) Kushi, Y.; Tada, T.; Fujii, Y.; Yoneda, H. Bull. Chem. Soc. Jpn.
1982, 55, 1834-1839. (b) Bailey, N. A.; Higson, B. M.; McKenzie, E. D.
J. Chem. Soc., Dalton Trans. 1972, 503-508.
(24) To date, our attempts to obtain a crystalline complex of 1g and
glyoxylate have proven unsuccessful.
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