A chiral Ag-based catalyst for practical, efficient, and highly enantioselective additions of enolsilanes to α-ketoesters

Article abstract of DOI:10.1021/ja061166o

A Ag-based chiral catalyst promotes efficient and highly enantioselective aldol additions of ketone-derived enolsilanes to α-ketoesters in the presence of a readily available amino acid-based ligand and commercially available AgF₂. α-Ketoester

Full text of DOI:10.1021/ja061166o

Published on Web 04/29/2006
A Chiral Ag-Based Catalyst for Practical, Efficient, and Highly
Enantioselective Additions of Enolsilanes to r-Ketoesters
Laura C. Akullian, Marc L. Snapper,* and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received February 17, 2006; E-mail: amir.hoveyda@bc.edu
Table 1. Initial Screening of Chiral Ligands. Selected Dataa
Research in these laboratories has led to the discovery of chiral
amino acid-based metal complexes that catalyze C-C bond
formation by addition of carbon nucleophiles to imines,1 ketones,2
and olefins.3 An objective of these programs is the development
of efficient and practical methods for enantioselective formation
of sterically hindered carbon centers, such as all-carbon quaternary
stereogenic centers4 and tertiary alcohols.2 Accordingly, we have
initiated a program toward development of effective catalysts for
asymmetric aldol reactions of ketones.
Through enantioselective Mukaiyama aldol reactions,5 R-ke-
toesters can be converted to synthetically versatile optically enriched
tertiary alcohols. A limited number of related catalytic protocols
have been disclosed. Evans has outlined the use of chiral C2-
temp
C)
conv
(%)b
ee
symmetric bis(oxazolinyl)Cu(II) complexes in catalytic enantiose-
lective additions of tert-butyl thioketene acetals to alkyl-substituted
R-ketoesters (36% ee with i-Pr-substituted ketone).6 Pagenkopf has
used modified bis(oxazoline) ligands in Cu(II)-catalyzed reactions
of dienolsilanes to aryl- and alkyl-substituted R-ketoesters.7 Bolm
has shown that C1-symmetric chiral sulfoximines are effective in
Cu(II)-catalyzed aldol reactions of acetophenone-derived trimeth-
ylsilylenol ether and n-alkyl-substituted R-ketoesters.8 Nonetheless,
noteworthy shortcomings persist. Substrate generality, particularly
in reactions of enolsilanes with R-ketoesters that bear sterically
demanding substituents, remains a challenge. There are pressing
issues of practicality: Cu(II)-catalyzed processes require rigorous
exclusion of air and moisture (drybox techniques).
entry
ligand
Ag salt
(
°
(%)c
1
2
4a
4a
4b
4c
4c
5a
5b
5c
5d
5d
5d
AgOAc
0
55
40
<2
<2
AgF
0
0
0
0
0
0
0
0
3
AgOAc or AgF
AgOAc
AgF
<2
4
54
13
23
56
29
18
63
84
84
5
73
6
AgF
>98
>98
>98
>98
60
7
AgF
8
AgF
9
AgF
10
11
AgF
-30
-30
AgF2
>98
a Reactions in CH2Cl2 (entries 1-9) or THF (entries 10-11), under N2
atm, 24 h. b Determined by 400 MHz H NMR analysis. c Determined by
1
chiral HPLC analysis (see Supporting Information for details).
Herein we report a new Ag-based chiral catalyst that promotes
enantioselective additions of ketone-derived enolsilanes to R-keto-
esters that contain alkyl, alkenyl, and aromatic substituents.9
Reactions proceed to >98% conversion with 1-10 mol % of AgF2
and an amino acid-based ligand that bears a pyridyl Schiff basesa
metal/ligand combination identified as optimal for the first time.
Desired products are typically isolated in >90% yield and in up to
96% ee. Highest enantioselectivities are observed with sterically
demanding alkyl-substituted R-ketoesters. The method is operation-
ally simple: reactions can be easily carried out with commercially
aVailable Ag salts (without purification), in air and with undistilled
solVent.
reactivity and enantioselectivity (Table 1). Phosphines, such as 4a,
optimal for Mannich-type reactions,1c,11 promote nonselective
additions (entries 1-2, Table 1). Salicyl-based systems, such as
4b, are ineffective (entry 3). However, pyridyl-based 4c in
combination with AgF delivers 3 in 73% conversion and 23% ee
(24 h, 0 °C). Further screening indicated that higher asymmetric
induction can be attained with L-t-Leu as AA1 and L-Phe as AA2:
3 is isolated in 56% ee with 5a and AgF (entry 6). Examination of
modified pyridyl termini, represented by 5b-d (entries 7-9),
pointed to Me-substituted 5d as the preferred ligand (63% ee, >98%
conv). Lowering of temperature12 leads to enhancement of enan-
tioselectivity (84% ee) but reduced reactivity (60% conv). To
improve catalyst activity, we turned to AgF2, an oxidant that can
serve as a source of AgF.13 Under optimized conditions (entry 11,
Table 1), the reaction proceeds to >98% conversion to afford 3 in
84% ee (86% ee and 92% yield at -40 °C; entry 1, Table 2).
As the findings summarized in Table 2 illustrate, the combination
of AgF2 and 5d can be used to catalyze enantioselective aldol
reactions of enolsilanes and a variety of R-ketoesters in high yield
and in up to 96% ee.
Catalyst optimization strategies developed in these laboratories10
were utilized to probe the efficiency of an assortment of amino
acid-based ligands in combination with a range of transition metal
salts (e.g., Cu(I), Cu(II), Ag(I), Al(III), Zn(II), Sc(III), and Yb(III)
salts) to promote enantioselective Mukaiyama aldol addition of
R-ketoester 1 and enolsilane 2. With L- or D-Val and Phe serving
as the initial representative amino acid moieties (AA1 and AA2;
see Table 1), small peptides including those bearing a phosphine
(e.g., 4a), a phenol (e.g., 4b), or a pyridyl (e.g., 4c) N-terminus
moiety were investigated; ligands bearing a single amino acid, as
well as those with amine and amide linkages at their N-termini (vs
Schiff bases, such as 4a-c) were scrutinized.
Several points regarding data in Table 2 are noteworthy. (1)
Reactions of n-alkyl-substituted substrates deliver products in 86-
92% ee (entries 1-3). Addition to methyl pyruvate affords the
desired product in 60% ee and 62% yield (>98% conv, -30 °C,
24 h). However, Ag-catalyzed processes are particularly effective
Preliminary studies led us to determine that AgOAc or AgF, in
combination with certain dipeptide ligands, generate appreciable
9
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J. AM. CHEM. SOC. 2006, 128, 6532-6533
10.1021/ja061166o CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Ag-Catalyzed Enantioselective Aldol Additions to
R-Ketoesters
We have thus identified a chiral amino acid-based ligand that in
combination with AgF2 promotes efficient and enantioselective
Mukaiyama aldol additions to R-ketoesters. The catalytic process
is effective with a range of substrates, particularly, those that bear
sterically hindered alkyl substituents; the method is complementary,
in terms of substrate range, to related catalytic enantioselective
procedures.6-8 Investigations directed toward outlining the mecha-
nistic details13 of the catalytic protocol are in progress.
Acknowledgment. This paper is dedicated to Professor K. C.
Nicolaou on the occasion of his 60th birthday. Financial support
was provided by the NIH (GM-57212).
Supporting Information Available: Experimental procedures and
spectral and analytical data for all compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
temp
C)
time
(h)
yield
(%)a
ee
entry
G
R
(
°
(%)b
1
2c
3
4
5
6
7
8
9
(CH2)2Ph
(CH2)2CO2Me
CH2 i-Pr
i-Pr
Ph
Ph
Ph
-40
-30
-30
-30
-15
-40
-30
-30
-40
-40
-30
-30
48
24
24
24
48
48
24
24
48
48
24
48
92
95
95
93
61
>98
98
97
90
86
92
87
95
92
88
95
90
96
90
60
72
Ph
i-Pr
i-Pr
Cy
Cy
t-Bu
Me
Ph
Me
Ph
Ph
Ph
Ph
cyclopropyl
H2CdCH(Me)
Ph
10
11
12
98
93
95
2-thienyl
a With 1.2 equiv of enolsilane; >98% conversion; isolated yields.
b Determined by chiral GLC or HPLC analysis (see the Supporting
Information for details). c The corresponding R-ketomethylester was used.
References
(1) (a) Kruger, C. A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun, W. G.;
Gleason, J. D.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 1999,
121, 4284-4285. (b) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.;
Snapper, M. L. J. Am. Chem. Soc. 2001, 123, 984-985. (c) Josephsohn,
N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126,
3734-3735.
(2) (a) Deng, H.; Isler, M. P.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2002, 1009-1012. (b) Wieland, L. C.; Deng, H.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 15453-15456.
(3) (a) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001,
123, 755-756. (b) Luchaco-Cullis, C. A.; Hoveyda, A. H. J. Am. Chem.
Soc. 2002, 124, 8192-8193. (c) Murphy, K. E.; Hoveyda, A. H. J. Am.
Chem. Soc. 2003, 125, 4690-4691. For an overview, see: (d) Hird, A.
W.; Kacprzynski, M. A.; Hoveyda, A. H. Chem. Commun. 2004, 1779-
1785.
(4) (a) Kacprzynski, M. A.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126,
10676-10681. (b) Wu, J.; Mampreian, D. A.; Hoveyda, A. H. J. Am.
Chem. Soc. 2005, 127, 4584-4585. (c) Hird, A. W.; Hoveyda, A. H. J.
Am. Chem. Soc. 2005, 127, 14988-14989.
(5) For reviews on catalytic enantioselective aldol reactions, see: Modern
Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, Germany,
2004.
(6) (a) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W. J. Am.
Chem. Soc. 1999, 121, 686-699 and references therein. See also: (b)
van Lingen, H. L.; van de Mortel, J. K. W.; Hekking, K. F. W.; van Delft,
F. L.; Sonke, T.; Rutjes, F. P. J. T. Eur. J. Org. Chem. 2003, 317-324.
(7) Le, J. C.-D.; Pagenkopf, B. L. Org. Lett. 2004, 6, 4097-4099.
(8) (a) Langner, M.; Bolm, C. Angew. Chem., Int. Ed. 2004, 43, 5984-5987.
(b) Langner, M.; Remy, P.; Bolm, C. Chem.sEur. J. 2005, 11, 6254-
6256.
(9) For Ag-catalyzed enantioselective aldol reactions of aldehydes, see: (a)
Yanagisawa, A.; Matsumoto, Y.; Nakashima, K.; Asakawa, K.; Yamamoto,
H. J. Am. Chem. Soc. 1997, 119, 9319-9320. For addition to aldimines,
see ref 1c.
(10) Cole, B. M.; Shimizu, K. D.; Kruger, C. A.; Harrity, J. P.; Snapper, M.
L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1668-1671.
(11) For Ag(I)-catalyzed enantioselective additions to aldimines (AgOAc and
amino acid-based phosphines), see: Josephsohn, N. S.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 4018-4019.
(12) At lower temperatures, increased reactivity is observed with THF as solvent
(e.g., 42% conv in CH2Cl2 for entry 10).
with sterically hindered substrates (entries 4-10; 88-96% ee with
those bearing R-branched alkyl and alkenyl groups). Reactions of
aryl-substituted R-ketoesters proceed efficiently but with lower
selectivity (entries 11-12); however, these are the best selectivities
reported to date. (2) Enolsilanes derived from 3,3-dimethyl-2-
butanone (entry 5) and acetone (entries 6 and 8) can be used;
sterically hindered enolsilanes require elevated temperature (-15
°C) to proceed to >98% conversion. (3) Higher enantioselectivities
can be obtained at -40 °C (vs -30 °C), although longer reaction
times are needed (48 vs 24 h). For example, the process in entry
10 (Table 2) affords the desired tertiary alcohol in 91% ee (85%
yield) at -30 °C (24 h). (4) There is <2% conjugate addition
product formed with the R,â-unsaturated substrate in entry 10.14
(5) Optically enriched products bearing a suitably positioned
carboxylic ester (cf. entry 2, Table 2) can be converted to the
derived lactone simply by the use of acidic workup conditions; the
example in eq 1 is illustrative. (6) Ag-catalyzed reactions were set
up in air on a benchtop; the solution was purged with N2 and the
vessel sealed. Reactions can be carried out exposed to air and in
commercial grade undistilled THF (eq 2). (7) Although transforma-
tions in Table 2 were run with 10 mol % catalyst, enantioselective
additions proceed to >98% conversion, in high yield and enantio-
selectivity with 1 mol % catalyst loading (even when the solution
is exposed to air); the example in eq 2 is illustrative.15
(13) Preliminary studies indicate that AgF2 is reduced by enolsilanes. For a
similar reduction of Ag(I) to Ag(0) by an enolsilane, see: Ito, Y.; Konoike,
T.; Saegusa, T. J. Am. Chem. Soc. 1975, 97, 649-651.
(14) For examples of Cu(II)-catalyzed asymmetric conjugate additions of
enolsilanes to unsaturated carbonyls, see: Johnson, J. S.; Evans, D. A.
Acc. Chem. Res. 2000, 33, 325-335 and references therein.
(15) When reactions are performed at >50 mg scale, addition of 1 equiv of
MeOH is required for complete conversion. For example, the reaction in
eq 2, with 250 mg of R-ketoester, proceeds to 33% conversion (10 mol
% of 5d, -30 °C, 24 h) but to >98% conversion in the presence of 1
equiv of MeOH. Presumably, on small scale, there is sufficient moisture
present to ensure high conversion. Mechanistic details regarding the
importance of a proton source are under investigation and will be reported
in due course.
The catalytic process can be carried out with Danishefsky’s diene
(eq 3).11 Reactions proceed with R-ketoesters that bear sterically
hindered alkyl substituents with significantly higher enantioselec-
tivity than that previously reported.16 In contrast to Cu(II)-catalyzed
methods,17 the Ag-catalyzed reactions are run under operationally
simple conditions.
(16) Yao, S.; Johannsen, M.; Audrain, H.; Hazell, R. G.; Jorgensen, K. A. J.
Am. Chem. Soc. 1998, 120, 8599-8605.
(17) For an overview of related catalytic enantioselective cycloadditions to
ketones, see: Jorgensen, K. A. Eur. J. Org. Chem. 2004, 2093-2102.
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