Lewis base activation of Lewis acids. Vinylogous aldol reactions

Article abstract of DOI:10.1021/ja035448p

A highly regioselective vinylogous aldol reaction catalyzed by SiCl₄ and a chiral phosphoramide (R,R)-5, providing δ-hydroxy enones for a variety of aldehyde and dienol ether structures, has been developed. Low catalyst loadings (1 mol %) can b

Full text of DOI:10.1021/ja035448p

Published on Web 06/07/2003
Lewis Base Activation of Lewis Acids. Vinylogous Aldol Reactions
Scott E. Denmark* and Gregory L. Beutner
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois, Urbana, Illinois 61801
Received April 3, 2003; E-mail: denmark@scs.uiuc.edu
In 1935, R. C. Fuson formulated the principle of vinylogy to
highly enantio- and diastereoselective addition of silyl ketene acetals
to aldehydes.9 In view of the exquisite sensitivity of this catalyst
system to the steric demand of the substrates, we envisioned that
reaction of a dienol ether would be favored at the less-substituted,
γ-position. Initial investigations with the ethyl crotonate-derived
dienol ether 3a10 and benzaldehyde 1a reveal that the γ-addition
product 4aa can be obtained exclusively in the presence of 2 and
only 1 mol % of (R,R)-5 (Table 1, entry 1). The reaction of 3a
with cinnamaldehyde 1b under similar conditions provided com-
parable yield and selectivity. The aliphatic aldehyde 1c, often a
problematic case in other SiCl4-promoted aldol processes,9 also
reacted to provide the product with high regio- and enantioselec-
tivity. However, the use of 5 mol % of (R,R)-5 and 5 mol % of
diisopropylethylamine was required for consistently high yields.
In all cases, the resulting enoate was exclusively of E configuration.
Extension of this method to other dienol ethers demonstrated
the substrate scope of the 2/phosphoramide catalyst system. The
methyl tiglate-derived dienol ether 3b10 yielded the γ-addition
products 4ba and 4bb as single constitutional isomers with high
enantioselectivity in the additions to 1a and 1b (entries 4 and 5).
However, despite several attempts, 3b did not react with 1c. The
ethyl senecioate-derived dienol ether 3c10 exclusively formed the
γ-addition products with high enantioselectivity using all three
aldehydes employed in the initial survey (entries 7-9).11
The use of a dienol ether bearing a substituent at the γ-position
introduced the challenge of diastereoselectivity for the 2/phos-
phoramide catalyst system. Initial studies with an ethyl 2-pen-
tenoate-derived dienol ether showed poor regioselectivities. How-
ever, increasing the size of the ester group led to a dramatic
improvement. Thus, the tert-butyl 2-pentenoate-derived dienol ether
3d10 provided exclusively the γ-addition product 4da (entry 10).
This high regioselectivity is complemented by high anti diastereo-
selectivity and good enantioselectivity. Although high yields and
good selectivities can be obtained in the additions of 3d to 1a and
1b, this dienol ether is unreactive with 1c (entry 12).
Reactions of the dioxanone-derived dienol ether 610 formed only
the γ-addition products 7a-c in high yields and good enantiose-
lectivities (Table 2). Interestingly, the observed trend in enantio-
selectivity for the additions of 6 is 1c > 1b > 1a. This trend with
respect to aldehyde is opposite to that observed in all other cases
(Table 1, entries 1-3). The nucleophile consistently approaches
the Re face of the aldehyde, generally forming the 5R product.5a,6b,12
The extremely high selectivity of the catalyst for reaction at the
γ-position of the dienol ether could be understood by examination
of its reactivity patterns with simple silyl ketene acetals. ReactIR
studies on the rates of addition of the methyl acetate-, methyl
propanoate-, and methyl isobutyrate-derived silyl ketene acetals to
1a revealed a striking kinetic dependence on the degree of
R-substitution: the acetate-derived silyl ketene acetal required <30
s to go to completion, and the propanoate-derived ketene acetal
required 3 min.9 Furthermore, the reaction of the isobutyrate-derived
silyl ketene acetal required more than 12 h to reach completion!
provide a better understanding of the “anomalous” reactivity of
some unsaturated compounds.1 He recognized that when a func-
tional group is attached to an unsaturated moiety, “the influence
of (that) functional group might sometimes be propagated along
the chain and make itself apparent at some remote point in the
molecule.” Since then, this simple concept has been applied in
countless reactions, extending the electrophilic or nucleophilic
character of a functional group.
However, the possibility of reaction at a remote position does
not guarantee that it will be favored or even observed. Reactions
involving vinylogous systems must address regioselectivity, along
with diastereo- and enantioselectivity. The problem is illustrated
in the chemistry of dienolates, wherein reaction at the remote
position is disfavored. Because of the high electron density at C(2)
of a metallo-dienolate, reaction at the R-position is favored
kinetically over reaction at the γ-position (eq 1).2
The advantages of a vinylogous addition process involving
dienolates, especially when an aldehyde is used as the electrophile,
are considerable because the γ-addition product is a common motif
that has found application in synthesis.3 A strategy that has proven
successful for overcoming the inherent R-selectivity of metallo-
dienolates involves steric differentiation of the reactive centers
through the use of bulky modifiers that discriminate the enolate
reactive sites.4
A different strategy that allows for high γ-selectivity is the use
of Lewis acid catalysis in the addition of silyl dienol ethers. Unlike
the reactions of metallo-dienolates, which are under electrostatic
control, the reactions of silyl dienol ethers are under FMO control,
therefore favoring reaction at C(4).2 The application of Lewis acids
in γ-selective aldol processes provides an attractive target for
asymmetric catalysis. Indeed, Carreira,5 Campagne,6 and Scettri7
have reported the use of Ti(IV) and Cu(II) complexes for the highly
regio- and enantioselective additions of dioxanone- and simple ester-
derived dienol ethers to a wide variety of aldehydes. Furthermore,
Evans has employed a Cu(II) bisoxazoline catalyst in the addition
of dienol ethers to R-alkoxy aldehydes.8 Although selectivities are
generally high for these catalysts in the case of dioxanone-derived
dienol ethers, simple ester-derived dienol ethers typically display
lower yields and selectivities. We report herein a new method for
catalytic enantioselective vinylogous aldol reactions that exhibits
high regio-, diastereo-, and enantioselectivity for a number of dienol
ether and aldehyde structures.
A previous disclosure from these laboratories demonstrated that
the combination of a catalytic amount of the chiral bis-phosphor-
amide (R,R)-514 and silicon tetrachloride (2) is able to promote a
9
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J. AM. CHEM. SOC. 2003, 125, 7800-7801
10.1021/ja035448p CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Vinylogous Aldol Reactions of Simple, Ester-Derived Dienolates 3a-d with Aldehydes 1a-c
1
2
3
4
5
a
entry
dienolate
R
R
R
R
R
product
yield, %
γ/Rb
drb
erc
1
2
3
4
5
6
7
8
9
3ad
3ad
3af
3bd
3bd
3bf
3cd
3cd
3cf
Ph (1a)
Et
Et
Et
Me
Me
Me
Et
Et
Et
t-Bu
t-Bu
t-Bu
H
H
H
Me
Me
Me
H
H
H
H
H
H
H
4aa
4ab
4ac
4ba
4bb
4bc
4ca
4cb
4cc
4da
4db
4dc
89e
84e
68g
93e
88
>99:1
>99:1
>99:1
>99:1
>99:1
ND
>99:1
>99:1
>99:1
99:1
99:1
98:2
95:5
99.5:0.5
99.5:0.5
ND
96:4
94:6
97.5:2.5
94.5:5.5
91:9
PhCHdCH (1b)
PhCH2CH2 (1c)
Ph (1a)
PhCHdCH (1b)
PhCH2CH2 (1c)
Ph (1a)
PhCHdCH (1b)
PhCH2CH2 (1c)
Ph (1a)
PhCHdCH (1b)
PhCH2CH2 (1c)
H
H
H
H
H
Me
Me
Me
H
H
H
H
H
H
H
H
H
91e
97h
73
10
11
12
3dd
3dd
3df
Me
Me
Me
92i
71
>99:1
>99:1
ND
H
H
99:1
ND
H
ND
a Yields of analytically pure material. b Determined by 1H NMR analysis. c Determined by CSP-SFC. d Reactions employed 1.1 equiv of SiCl4, 1.2 equiv
of dienolate, 0.01 equiv of (R,R)-5 at 0.2 M in CH2Cl2 at -78 °C for 3 h. e R absolute configuration. f Conditions as above with 0.05 equiv of (R,R)-5, 0.05
equiv of i-Pr2EtN at 0.2 M in CH2Cl2 at -78 °C for 24 h. g S absolute configuration. h E/Z, 97:3. i 4R,5R absolute configuration.
Table 2. Vinylogous Aldol Reactions of Dioxanone-Derived
Dienolate 6 with Aldehydes 1a-c
Acknowledgment. We are grateful to the National Science
Foundation (CHE 0105205) for generous financial support. G.L.B.
thanks Boehringer-Ingelheim Pharmaceuticals, Inc. for a graduate
fellowship.
Supporting Information Available: Full characterization of all
dienol ethers and aldol products along with representative procedures
for the addition reactions (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
a
entry
R
product
yield, %
γ/Rb
erc
1
2
3
Ph (1a)d
7a
7b
7c
92e
88e
83g
>99:1
>99:1
>99:1
87:13
89:11
94.5:5.5
References
PhCHdCH (1b)d
PhCH2CH2 (1c)f
(1) Fuson, R. C. Chem. ReV. 1935, 16, 1.
(2) (a) Fleming, I. Frontier Orbitals and Organic Chemical Reactions; Wiley-
Interscience: New York, 1996; p 45. (b) Herrmann, J. L.; Kieczykowski,
G. R.; Schlessinger, R. H. Tetrahedron Lett. 1973, 26, 2433.
(3) (a) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. ReV. 2000,
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Chem. Soc. 2002, 124, 5654. (c) Kim, Y.; Singer, R. A.; Carreira, E. M.
Angew. Chem., Int. Ed. 1998, 37, 1261.
a Yields after chromatography. b Determined by 1H NMR analysis.
c Determined by CSP-SFC. d Reactions employed 1.1 equiv of 2, 1.2 equiv
of dienolate, 0.01 equiv of (R,R)-5 at 0.2 M in CH2Cl2 at -78 °C for 3 h.
e R absolute configuration. f Reactions employed 1.1 equiv of 2, 1.2 equiv
of dienolate, 0.05 equiv of (R,R)-5, 0.05 equiv of i-Pr2EtN at 0.2 M in
CH2Cl2 at -78 °C for 24 h. g S absolute configuration.
(4) Saito, S.; Shiozawa, M.; Ito, M.; Yamamoto, H. J. Am. Chem. Soc. 1998,
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(5) (a) Singer, R. A.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 12360.
(b) Krueger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120, 837.
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(10) The silyl dienol ethers were by modification of the procedure of
Schlessinger et al., ref 2b.
(11) Product 4cb was a 97:3 mixture of E/Z enoates.
(12) (a) Masamune, S.; Sato, T.; Kim, B.; Wollmann, T. A. J. Am. Chem. Soc.
1986, 108, 8279. (b) Nun˜ez, M. T.; Martin, V. S. J. Org. Chem. 1990,
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2049.
This reactivity trend is opposite to the scale of π-nucleophilicity
determined by Mayr and co-workers.13 It is possible that this trend
is dictated by steric factors at the reaction center. In the case of the
ethyl crotonate-derived dienol ether 3a, the observed R-/γ-selectivity
represents favorable reaction at the less sterically demanding
γ-position. In the 2-pentenoate derived-dienol ether 3d, both re-
active centers are monosubstituted. Introduction of a tert-butyl ester
was required for high regioselectivity in the C-C bond forming
reaction.
In conclusion, we have developed a highly regioselective, chiral-
Lewis-base-catalyzed, vinylogous aldol reaction that provides
γ-hydroxy enones in high enantio- and diastereoselectivities for a
number of aldehyde and dienol ether structures. Low catalyst
loadings (1 mol %) can be employed without compromising yields
or selectivities. Further studies are underway to extend this method
to ketone- and aldehyde-derived dienol ethers.
(13) Burfeindt, J.; Patz, M.; Mueller, M.; Mayr, H. J. Am. Chem. Soc. 1998,
120, 3629.
(14) Catalyst (R,R)-5 is commercially available from Obiter Research, LLC.
Contact waboulanger@obiterresearch.com.
JA035448P
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J. AM. CHEM. SOC. VOL. 125, NO. 26, 2003 7801