Enantioselective conjugate silyl additions to cyclic and acyclic unsaturated carbonyls catalyzed by Cu complexes of chiral N-heterocyclic carbenes

Article abstract of DOI:10.1021/ja910989n

(Figure Presented) An efficient Cu-catalyzed protocol for enantioselective addition of a dimethylphenylsilanyl group to a wide range of cyclic and acyclic unsaturated ketones, esters, acrylonitriles, and α,β,γ,σ- dienones is disclosed. Reactions are performed in the presence of 1-2 mol % of commercially available and inexpensive CuCl, a readily accessible monodentate imidazolinium salt, and commercially available (dimethylphenylsilyl) pinacolatoboron. Cu-catalyzed enantioselective conjugate additions proceed to completion within only 2 h to afford the desired silanes in 87-97% yield and 90:10-99:1 enantiomeric ratio (er). Use of a proton source (e.g., MeOH) is not required; accordingly, synthetically versatile α-silyl boron enolates can be obtained. The special utility of the present protocol, in comparison with the related catalytic enantioselective aldol and boronate conjugate additions, is discussed and illustrated through various functionalizations of the enantiomerically enriched Β-silylcarbonyls. Copyright

Full text of DOI:10.1021/ja910989n

Published on Web 02/11/2010
Enantioselective Conjugate Silyl Additions to Cyclic and Acyclic Unsaturated
Carbonyls Catalyzed by Cu Complexes of Chiral N-Heterocyclic Carbenes
Kang-sang Lee and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received January 4, 2010; E-mail: amir.hoveyda@bc.edu
Scheme 1. Catalytic Cycle for Silane Conjugate Additions
Development of practical and efficient methods for catalytic
enantioselective formation of C-Si bonds is an important and
challenging goal of research in chemical synthesis;1 transformations
delivering ꢀ-silylcarbonyls are particularly attractive. A Si-based
substituent, among other functions, serves as a masked hydroxyl group;
it is sufficiently robust to allow for a range of functionalization
processes that involve the carbonyl unit without causing decomposition
or side reactions (e.g., retro-aldol).2 If silyl conjugate addition is
used,3-5 the resulting enol resides adjacent to a sizable silyl group
and an electron-donating C-Si bond (e.g., iii, Scheme 1) and can thus
react efficiently and stereoselectively with electrophiles. A number of
catalytic enantioselective silyl conjugate additions to R,ꢀ-unsaturated
carbonyls have been disclosed.6,7 Such protocols, promoted by Pd-
and Rh-based phosphine complexes, are noteworthy but operate within
a relatively narrow substrate range (e.g., require cis alkenes7b), at times
proceed with low to moderate enantioselectivity6 or moderate ef-
ficiency,7 or demand reagents (e.g., Cl2PhSi-SiMe3), which afford
ꢀ-dihalosilylcarbonyls that must be alkylated (MeLi) prior to efficient
product isolation. Herein, we outline a Cu-catalyzed protocol for
enantioselective addition of a dimethylphenylsilanyl group to unsatur-
ated cyclic and acyclic ketones, lactones, esters, and acrylonitriles as
well as cyclic R,ꢀ,γ,δ-dienones. Reactions proceed in 87-97% yield
and 90:10-99:1 er with 1-2 mol % of an inexpensive commercially
available Cu salt and silylborane reagent, as well as easily accessible
monodentate chiral imidazolinium salts (3-4 steps from diphenyleth-
ylenediamine in ∼50% overall yield).8
Promoted by a NHC-Cu Complexa
a B(pin) ) pinacolatoboron.
Table 1. Initial Examination of Various Chiral NHC Complexesa
Our investigations were initiated partly based on observations by
Sadighi and co-workers,9 who demonstrated that NHC-Cu-alkoxides
(e.g., i, Scheme 1) react with bis(pinacolato)diboron [B2(pin)2] to afford
the derived NHC-Cu-B(pin). Such a process is likely driven by the
formation of the B-O bond in pinacolatoboron alkoxide that is
generated as a byproduct. As outlined in Scheme 1, we sought to
determine whether an NHC-Cu-alkoxide (i) reacts with the sterically
more congested (dimethylphenylsilyl)pinacolatoboron to deliver an
NHC-Cu-silane (ii), which would undergo reaction with an unsatur-
ated carbonyl to effect formation of a C-Si bond (iii). We surmised
that ii would be preferred over NHC-Cu-boronate since formation
of a Si-O is energetically less favored than a B-O bond.10 Reaction
of the resulting copper enolate with dimethylphenylsilylpinacolatoboron
(1, Scheme 1) regenerates ii, affording boron enolate iv. We have
illustrated that NHC-Cu-enolates (e.g., iii) react readily with B2(pin)2
to release the catalytically active NHC-Cu-B(pin).11 If the same
process proceeds with 1, the catalytic process would not require an
alcohol additive (MeOH), which is used to induce turnover in catalytic
Cu-B(pin) additions to alkenes.12 The versatile boron enolate (vs
protonated ketone) would thus be obtained as a result of the projected
conjugate silane addition.
a Under N2 atmosphere. b Determined by analysis of 400 MHz 1H
NMR spectra of unpurified mixtures. c Yields of purified products. d By
HPLC analysis; see the Supporting Information (SI) for details. Mes )
2,4,6-trimethylphenyl.
based carbenes 213 and 314 as well as monodentate variants 415
and 58 with CuCl, promote conjugate addition of the silane unit. It
should be noted that none of the products derived from the
1
formation of a C-B bond are observed (<2% by 400 MHz H
NMR), and the presence of a proton source (MeOH) is not required.
Moreover, enantioselectivity is higher with monodentate complexes
4 and 5, with the C1-symmetric chiral catalyst (5) delivering the
optimal er (96:4, entry 4).
We began by probing the ability of a number of chiral NHC-Cu
complexes in catalyzing the addition of 1 to cyclohexenone to afford
ꢀ-silylketone 6; key results are summarized in Table 1. All Cu-
based carbenes, generated in situ from reaction of bidentate Ag-
Imidazolinium salts are more robust (less light sensitive) than
the derived monodentate NHC-Ag complexes (e.g., 4-5, Table
1). Accordingly, simultaneous with our efforts to identify an optimal
catalyst that can be utilized in lower loading (e.g., 1 mol %), we
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C O M M U N I C A T I O N S
Table 3. NHC-Cu-Catalyzed Enantioselective Conjugate
Scheme 2. Enantioselective Synthesis of ꢀ-Silylketone 6 with
Various Chiral C1-Symmetric NHC Complexesa
Additions of Silanes to Acyclic R,ꢀ-Unsaturated Enonesa
entry
R
yield (%)b
erc
1
2
3
4
5
6
7
Me
n-pent
i-Pr
Ph
p-OMeC6H4
p-CF3C6H4
o-MeC6H4
88
96
87
91
94
97
96
97:3
98:2
97:3
98.5:1.5
97:3
96:4
a Under conditions in Table 1, except with 1.0 mol % CuCl, 1.1 mol %
7-12, 2.2 mol % NaOt-Bu. All conv >98% by analysis of 400 MHz H
NMR spectra of unpurified mixtures. Enantiomeric ratios by HPLC analysis
(see the SI for details).
1
93.5:6.5
Table 2. NHC-Cu-Catalyzed Enantioselective Conjugate Additions
of Silanes to Cyclic R,ꢀ-Unsaturated Carbonylsa
a-cSee Table 2.
Scheme 3a
a See Table 2 for reaction conditions.
Scheme 4. Cu-Catalyzed Enantioselective Additions to Cyclic
Dienones
a Under N2 atm with 1.1 mol % 12, 1 mol % CuCl and 2.2 mol %
NaOt-OBu at -78 °C for 1 h; >98% conv in all cases. b Yields of
purified products. c By HPLC analysis; see the SI for details.
d Imidazolinium salt 11 (2.2 mol % with 2.0 mol % CuCl and 4.4 mol
% NaOtt-Bu) used for 12 h.
turned to variants of the aforementioned C1-symmetric imidazo-
linium salts. As shown in Scheme 2, ligands where the symmetric
NAr unit bears larger substituents deliver lower enantioselectivity
(7-9). Next, we examined candidates containing a 2,4,6-trimethy-
laniline (NMes; cf. 7, not shown in Scheme 2)16 or a 2,6-
diethylphenylamine (cf. 8) along with dissymmetric NAr groups.
Optimal enantioselectivities were obtained with 12 (Scheme 2); as
before (i.e., with 7-8), the catalyst bearing a smaller meta
substituent (Me) furnishes higher selectivity (97.5:2.5 vs 91:9 er
with 10).16 Two additional points merit mention: (1) C1-Symmetric
NHC complexes17 offer a larger degree of diversity versus
C2-symmetric variants (i.e., each NAr unit can be modified
independently) and, thus, are more advantageous in connection with
reaction optimization. (2) The ligands corresponding to 10-12, but
bearing an NMes unit, promote less selective conjugate additions,16,18
indicating cooperativity between the two NAr units of the chiral
ligand. The lower er observed with C2-symmetric 4 versus C1-
symmetric 5 (Table 1) further supports the above notion.
Cyclic unsaturated ketones undergo enantioselective silyl conjugate
addition in the presence of 1.1 mol % 12 and 1.0 mol % CuCl (Table
2). Reactions proceed to >98% conversion after only one hour at
-78 °C, affording the desired ꢀ-silylketones in 87-95% yield and
90:10-99:1 er. Five- (entries 1 and 5), six- (entries 2 and 6), and seven-
(entries 3 and 7) as well as eight-membered (entry 4) ring enones are
effective substrates. Unsaturated ketones that contain sterically con-
gested electrophilic sites readily undergo conjugate silyl addition within
1 h (entries 5-6, Table 2). Conjugate addition to an unsaturated lactone
is efficient (entry 8, Table 2) but proceeds with lower enantioselectivity
(vs the related ketone: 92:8 er vs 97.5:2.5 er in entry 2).
Reactions of trans acyclic R,ꢀ-unsaturated ketones proceed with
equally high efficiency and enantioselectivity (Table 3) as when cis
olefins of cyclic enones are involved. Substrates bearing alkyl (entries
1-3, Table 3) or aryl (entries 4-7) substituents undergo reaction to
afford the desired products in 87-97% yield and up to 98.5:1.5 er.
Neither the efficiency nor the enantioselectivity is affected by the
electronic attributes (entries 4-6) or the presence of an ortho
substituent (entry 7).
The Cu-catalyzed protocol extends beyond reactions of alkyl
ketones, as illustrated by the formation of 13 (Scheme 3) in 92%
yield and 95.5:4.5 er. As the additional cases in Scheme 3 indicate,
acrylonitriles (e.g., 14), a class of substrates that is inert to Rh-
catalyzed silyl conjugate additions,7b and unsaturated esters (15 and
16) are effective substrates.
Our preliminary investigations indicate that the present catalytic
protocol can be readily carried out with R,ꢀ,γ,δ-dienones, affording
the 1,6-addition products exclusively (>98% site selectivity), with
effective control of olefin geometry and in high enantioselectivity;
the examples in Scheme 4 are illustrative. Several points regarding
the observations in Scheme 4 are worthy of note: (1) The optimal
catalyst for this class of transformations is derived from C2-
symmetric imidazolinium salt 19 (Scheme 4), since NHC-Cu
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C O M M U N I C A T I O N S
Scheme 5. ꢀ-Silylketones versus the Corresponding Boronates
Acknowledgment. Financial support was provided by the NSF
(CHE-0715138) and the NIH (GM-57212). K-s. L. is grateful for
a Schering-Plough Graduate Fellowship. We thank Ms. Jamie
O’Brien for helpful suggestions. Mass spectrometry facilities at
Boston College are supported by the NSF (DBI-0619576).
Supporting Information Available: Experimental procedures and
spectral, analytical data for all products. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
complex 12 delivers substantially lower E/Z ratios and levels of
enantiomeric purity (20 in 2:1 Z:E and 94.5:5.5 and 54:46 er,
respectively; 21 in >98% E and 69.5:30.5 er). (2) The high alkene
stereoselectivity and enantioselectivity with which 21 is formed
indicates that reaction likely occurs through an s-cis diene. (3) The
enantiomerically enriched allylsilanes can be used in reactions with
various electrophiles; the diastereoselective oxidation affording 22
is a case in point. Further development of this class of conjugate
additions is ongoing in these laboratories.
(1) For reviews on the use of organosilanes in organic synthesis, see: (a) Chan,
T. H.; Wang, D. Chem. ReV. 1992, 92, 995. (b) Jones, G. R.; Landais, Y.
Tetrahedron 1996, 52, 7599. (c) Fleming, I.; Barbero, A.; Walter, D. Chem.
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(2) For a review on the utility of ꢀ-silylcarbonyls in synthesis, see: Fleming,
I., Science of Synthesis; Thieme: Stuttgart, Germany, 2002; Vol. 4; p 927.
(3) Enantiomerically enriched ꢀ-silylcarbonyls have been prepared by catalytic
conjugate hydride additions to trisubstituted Si-substituted enones. See:
Lipshutz, B. H.; Tanaka, N.; Taft, B. R.; Lee, C.-t. Org. Lett. 2006, 8,
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(4) Enantiomerically enriched ꢀ-silylcarbonyls can be accessed by catalytic
conjugate additions of alkyl or aryl groups to silyl-substituted enones. See:
(a) Shintani, R.; Okamoto, K.; Hayashi, T. Org. Lett. 2005, 7, 4757. (b)
Balskus, E. P.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 6810. (c)
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(5) Catalytic non-enantioselective methods that afford ꢀ-silylcarbonyls have
been disclosed. For example, see: Conjugate silane additions: (a) Lipshutz,
B. H.; Sclafani, J. A.; Takanami, T. J. Am. Chem. Soc. 1998, 120, 4021.
(b) Auer, G.; Weiner, B.; Oestreich, M. Synthesis 2006, 2113. Conjugate
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Chem. 1978, 146, 87. (d) Ito, H.; Ishizuka, T.; Tateiwa, J.-i.; Sonoda, M.;
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(c) Walter, C.; Fro¨hlich, R.; Oestreich, M. Tetrahedron 2009, 65, 5513.
(8) Lee, K.-S.; Hoveyda, A. H. J. Org. Chem. 2009, 74, 4455.
(9) (a) Laitar, D. S.; Mu¨ller, P.; Sadighi, J. P. J. Am. Chem. Soc. 2005, 127,
17196. (b) Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P. Organometallics 2006,
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The Cu-catalyzed enantioselective silane conjugate additions
described herein are of substantial utility and complement the related
processes involving boronates,19 which, upon oxidation, can also
furnish the corresponding ꢀ-hydroxy carbonyls. The present set of
protocols, however, offers distinct advantages; two examples are
illustrated in Scheme 5. First, whereas the boron enolate derived
from catalytic boronate conjugate addition to six-membered ring
enones undergoes facile aldol addition,11,19d the corresponding
enolates from reactions of cyclopentenone or cycloheptenone are
unreactive.20 In contrast, as depicted in Scheme 5, the boron
enolates of all ring sizes (only five- and seven-membered rings
shown) obtained through catalytic silyl additions react readily with
aldehydes to afford the desired ꢀ-silyl,ꢀ-hydroxyketones 23 and
24. The neighboring donor C-Si bonds likely enhance the
nucleophilicity of the boron enolates through hyperconjugative
effects;21 in contrast, the low-lying C-B σ* in the related boronate
addition products can diminish enolate nucleophilicity.
(10) A value of ∼125 kcal/mol-1 is attributed to a B-O bond (vs ∼110 kcal/
mol-1 for a Si-O bond). See: (a) Sanderson, R. T. Chemical Bonds and
Bond Energy; Academic Press: New York, 1976; p 128. (b) Sanderson,
R. T. Polar CoValence; Academic Press: New York, 1983; p 82.
(11) Lee, K.-S.; Zhugralin, A. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009,
131, 7253.
(12) (a) Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3160. (b) Lee,
Y.; Jang, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 18234.
(13) Van Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.; Hoveyda, A. H.
J. Am. Chem. Soc. 2005, 127, 6877.
(14) Brown, M. K.; May, T. L.; Baxter, C. A.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2007, 46, 1097.
(15) For representative applications of the corresponding C2-symmetric imida-
zolinium salt, see: (a) Chaulagain, M. R.; Sormunen, G. J.; Montgomery,
J. J. Am. Chem. Soc. 2007, 129, 9568. (b) Lillo, V.; Prieto, A.; Bonet, A.;
D´ıaz-Requejo, M. M.; Ram´ırez, J.; Pe´rez, P. J.; Ferna´ndez, E. Organome-
tallics 2009, 28, 659. (c) Reference 12a.
Second, pinacolatoboronates are sensitive to common organo-
metallics such as aryl- or alkyllithiums as well as the derived
Grignard reagents. In contrast, ꢀ-silylketones can be easily func-
tionalized, often with high diastereoselectivity, through reaction with
such reagents. The example in Scheme 5 (f26) is representative;
the ꢀ-boronate ketones are converted to unidentifiable products.22
As also presented in Scheme 5, subsequent oxidation23 (f27)
furnishes the enantiomerically enriched syn-1,3-diol. A similar
procedure with a boronate product would require prior oxidation
and protection of the resulting carbinol (to avoid retro-aldol upon
treatment with arylmetal).
(16) See the Supporting Information for details regarding these screening studies.
(17) For design of C1-symmetric monodentate chiral NHC-Cu complexes and
comparison of their utility vs C2-symmetric variants, see ref 8.
(18) For example, the NMes-containing derivative of 12 promotes formation of
ꢀ-silylketone 6 in >98% conversion and 91:9 er (vs 97.5:2.5 er).
(19) (a) Lee, J.-E.; Yun, J. Angew. Chem., Int. Ed. 2008, 47, 145. (b) Reference
15b. (c) Sim, H.-S.; Feng, X.; Yun, J. Chem.sEur. J. 2009, 15, 1939. (d)
Chen, I.-H.; Yin, L.; Itano, W.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2009, 131, 11664.
The Cu-catalyzed additions should prove to be of utility in
complex molecule synthesis. For example, ketoester 28 (eq 1),
accessed through a racemic synthesis followed by HPLC separation
of the enantiomers, was recently utilized in an approach to
biologically active natural product (+)-erysotramidine.24 As shown
in eq 1, the desired intermediate can now be easily synthesized by
a one-pot procedure in 92% yield, as a single diastereomer and in
97.5:2.5 er. The stability of the silyl group toward n-BuLi (see
above) allows for conversion of the boron enolate to its more
nucleophilic Li-based derivative.
(20) Lee, K.-S.; Hoveyda, A. H., unpublished results.
(21) Houk, K. N.; Moses, S. R.; Wu, Y.-D.; Rondan, N. G.; Ja¨ger, V.; Schohe,
R.; Fronczek, F. R. J. Am. Chem. Soc. 1984, 106, 3880.
(22) Ferna´ndez, E.; Maeda, K.; Hooper, M. W.; Brown, J. M. Chem.sEur. J.
2000, 6, 1840.
(23) Fleming, I.; Sanderson, P. E. J. Tetrahedron Lett. 1987, 28, 4229.
(24) Tietze, L. F.; To¨lle, N.; Kratzert, D.; Stalke, D. Org. Lett. 2009, 11, 5230.
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