Cu-catalyzed asymmetric conjugate additions of dialkyl- and diarylzinc reagents to acyclic β-silyl-α,β-unsaturated ketones. Synthesis of allylsilanes in high diastereo- and enantiomeric purity

Article abstract of DOI:10.1021/ol071331k

A readily available and simple (MW = 444.5 g/mol) valine-based chiral phosphine is used to promote highly efficient catalytic asymmetric conjugate additions of dialkyl- and diarylzinc reagents to acyclic β-silyl-α, β-unsaturated ketones. The catalytic asy

Full text of DOI:10.1021/ol071331k

ORGANIC
LETTERS
2007
Vol. 9, No. 16
3187-3190
Cu-Catalyzed Asymmetric Conjugate
Additions of Dialkyl- and Diarylzinc
Reagents to Acyclic
â
-Silyl-r,â-unsaturated Ketones.
Synthesis of Allylsilanes in High
Diastereo- and Enantiomeric Purity
Monica A. Kacprzynski, Stephanie A. Kazane, Tricia L. May, and
Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467
amir.hoVeyda@bc.edu
Received June 5, 2007
ABSTRACT
A readily available and simple (MW
conjugate additions of dialkyl- and diarylzinc reagents to acyclic
access to versatile allylsilanes that bear a trisubstituted olefin in high diastereo- and enantiomeric purity.
)
444.5 g/mol) valine-based chiral phosphine is used to promote highly efficient catalytic asymmetric
â
-silyl- -unsaturated ketones. The catalytic asymmetric protocol allows
r,â
â-Silylcarbonyls are versatile molecules that have significant
potential in stereoselective synthesis.1 The sterically demand-
ing silyl group and the electron-donating (hyperconjugative)
attributes of the C-Si bond can induce stereodifferentiation
in reactions of neighboring prostereogenic sites (e.g., alkenes
or enolates); the C-Si may be converted to a hydroxyl group
(oxidation) or an alkane unit (protiodesilylation). The
aforementioned attributes of organosilanes have been ex-
ploited in the design and development of myriad protocols
in stereoselective synthesis.2 Herein, we report a Cu-catalyzed
method for asymmetric conjugate additions (ACA)3 of
dialkyl- and diarylzinc reagents to â-silyl-substituted R,â-
unsaturated ketones; these catalytic transformations afford
â-silylketones efficiently (59-95% isolated yield) and in
high enantiomeric purity (87-96% ee). This study includes,
to the best of our knowledge, the first examples of efficient
catalytic ACA of diarylzinc reagents to acyclic enones. The
chiral ligand is an easily accessible small-molecule phosphine
that contains the inexpensive (both antipodes) amino acid
valine.
A number of catalytic enantioselective strategies have been
reported that deliver â-silylcarbonyls. Among such methods
are the Pd-catalyzed 1,4-silylation of R,â-unsaturated ketones
(1) Fleming, I. Science of Synthesis; Thieme: Stuttgart, Germany, 2002;
Vol. 4; pp 927-946.
(2) (a) Fleming, I.; Barbaro, A.; Walter, D. Chem. ReV. 1997, 97, 2063-
2192. For related Si-based stereoselective strategies developed in these
laboratories, see: (b) Hale, M. R.; Hoveyda, A. H. J. Org. Chem. 1992,
57, 1643-1645. (c) Hale, M. R.; Hoveyda, A. H. J. Org. Chem. 1994, 59,
4370-4364. (d) Young, D. G. J.; Gomez-Bengoa, E.; Hoveyda, A. H. J.
Org. Chem. 1999, 64, 692-693.
(3) For recent reviews on catalytic asymmetric conjugate addition (ACA)
reactions, see: (a) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171-
196. (b) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221-3236.
(c) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. in Modern
Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim,
Germany, 2002; pp 224-258.
10.1021/ol071331k CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/30/2007

with PhCl2Si-SiMe3,4 Rh-catalyzed ACA of vinyl- and
arylboronic acids to â-silylketones and esters5 as well as the
related processes involving silylboronic acids and cyclic
enones.6 Other protocols of note consist of Al-catalyzed ACA
of stabilized carbanions to unsaturated â-silyl imides7 and
Cu-catalyzed hydride additions to trisubstituted olefins of
â-silylesters (polymethylhydrosiloxane as hydride source).8
We judged that an effective method for Cu-catalyzed ACA
of readily available dialkyl and diarylzinc reagents to
â-silylketones would be of value. Such a protocol delivers
the same class of products as the Pd-catalyzed disilylation
and Rh-catalyzed ACA but would benefit from several
advantages. The Pd-catalyzed approach requires a less atom-
economical disilane that deposits a PhCl2Si at the â carbon,
requiring treatment with MeLi (conversion to a PhMe2Si
group) to access the desired â-silylketone. Moreover, the Rh-
catalyzed ACA5 has not been extended to reactions of
alkylboronic acids.
reaction to >98% conversion to afford â-silylketone 2 at
ambient temperature in the presence of 4 mol % (CuOTf)2‚
C6H6. The simpler chiral phosphine 4, however, delivers 2
in markedly higher enantioselectivity (96% vs 76% ee). It
should be noted that enantioselectivities do not change
significantly at lower temperatures. Preliminary examination
of chiral N-heterocyclic carbenes,11 also developed in these
laboratories for Cu-catalyzed ACA, indicates that these chiral
complexes are less effective for this class of reactions
(formation of 2 in <80% ee).
As illustrated in entry 1 of Table 1, with 2.5 mol % of
Table 1. Cu-Catalyzed ACA of Dialkylzinc Reagents to
Acyclic â-Silyl-R,â-Unsaturated Enonesa
To initiate our investigations, we prepared â-silylenone
19 (Scheme 1) and examined the ability of a select number
Scheme 1. Initial Examination of Chiral Amino Acid-Based
Phosphines
of amino acid-based chiral phosphines, previously developed
in these laboratories,10 to catalyze the corresponding ACA
with Et2Zn. As illustrated in Scheme 1, chiral ligands 310a,h
and 410c,h (10 mol % used in preliminary screening) promote
a All reactions carried out under N2 atm with 3 equiv (alkyl)2Zn.
Reactions times: 1 h with Et2Zn (3 h for entry 5) and 6 h with Me2Zn.
b Isolated yields after purification; >98% conversion in all cases. c Deter-
mined by chiral GLC or HPLC analysis; see the Supporting Information
for details. d Lower isolated yield is due to product volatility.
(4) (a) Hayashi, T.; Matsumoto, Y.; Ito, Y. J. Am. Chem. Soc. 1998,
110, 5579-5581. (b) Matsumoto, Y.; Hayashi, T. Tetrahedron 1994, 50,
335-346.
(5) Shintani, Y.; Okamoto, K.; Hayashi, T. Org. Lett. 2005, 7, 4757-
4759.
(6) Walter, C.; Auer, G.; Oestreich, M. Angew. Chem., Int. Ed. 2006,
45, 5675-5677.
chiral phosphine 4, 1.0 mol % of (CuOTf)2‚C6H6 and 3 equiv
of Et2Zn (22 °C), â-silylketone 2 is obtained in 77% yield
and 96% ee. Cu-catalyzed ACA of Et2Zn with the substrate
bearing a dimethylphenylsilyl unit proceeds efficiently to
afford 5 in 95% yield and 96% ee (entry 2). Similar
efficiency and enantiopurity levels are observed with the less
reactive Me2Zn (entries 3-4, Table 1).
(7) Balskus, E. P.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 6810-
6812.
(8) Lipshutz, B. H.; Tanaka, N.; Taft, B. R.; Lee, C.-T. Org. Lett. 2006,
8, 1963-1966.
(9) See the Supporting Information for experimental details.
(10) (a) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc.
2001, 123, 755-756. (b) Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J.
Am. Chem. Soc. 2002, 124, 779-781. (c) Degrado, S. J.; Mizutani, H.;
Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 13362-13363. (d) Luchaco-
Cullis, C. A.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 8192-8193.
(e) Hird, A. W.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 1276-
1279. (f) Mampreian, D. M.; Hoveyda, A. H. Org. Lett. 2004, 6, 2829-
2832. (g) Wu, J.; Mampreian, D. M.; Hoveyda, A. H. J. Am. Chem. Soc.
2005, 127, 4584-4585. (h) Brown, M. K.; Degrado, S. J.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2005, 44, 5306-5310. (i) Hird, A. W.; Hoveyda,
A. H. J. Am. Chem. Soc. 2005, 127, 14988-14989.
Enantioselective synthesis of iso-propylketone 8 (entry 5)
and phenyl- substituted ketones 9 and 10, generated in 75-
(11) (a) Lee, K.-s.; Brown, M. K.; Hird, A. W.; Hoveyda, A. H. J. Am.
Chem. Soc. 2006, 128, 7182-7184. (b) Brown, M. K.; May, T. L.; Baxter,
C. A.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46, 1097-1100.
3188
Org. Lett., Vol. 9, No. 16, 2007

91% isolated yields and 89-95% ee, indicate that the Cu-
catalyzed ACA can be performed with substrates that bear
a sterically hindered carbonyl substituent. Two additional
points merit mention: (1) All reactions were carried out with
commercial grade dialkylzinc reagents. (2) All efforts to
establish conditions for efficient Cu-catalyzed ACA of longer
chain (e.g., (n-Bu)2Zn, (i-Pr)2Zn) or functionalized (e.g.,
[AcO(CH2)4]2Zn) dialkylzinc reagents proved unsuccessful;
<5% conversion was observed in such cases.12
Next, we considered the possibility of using diarylzinc
reagents. We judged this critical to our investigations, not
only because of the aforementioned limitation vis-a`-vis
dialkylzinc reagents but also since examples of catalytic ACA
involving arylmetals are scarce.13 To the best of our
knowledge, there are no reports of diarylzinc reagents used
in catalytic ACA of acyclic R,â-unsaturated carbonyls.14
As illustrated in entry 1 of Table 2, under the conditions
surmised that, under such conditions, carbonyl activation by
the Lewis acidic Zn salts that give rise to uncatalyzed
conjugate addition would be avoided. With THF as the
solvent, catalytic ACA proceeds (>98% conversion, 1 h)
with significant improvement in enantioselectivity: 11 is
obtained in 83% ee. Further screening (see Table 2) led to
identification of DME as the optimal medium (entry 5, >98%
conversion, 88% ee).
The Cu-catalyzed ACA of commercially available Ph2Zn
(1.5 equiv) to â-silylenone 1, shown in entry 1 of Table 3,
Table 3. Cu-Catalyzed ACA with Diarylzinc Reagents and
Acyclic â-Silyl-R,â-unsaturated Enonesa
Table 2. Screening of Solvents in Cu-Catalyzed ACA of
Ph2Zn to Enone 1a
entry
solvent
toluene
THF
1,4-dioxane
Et2O
conversion (%)b
ee (%)c
1
2
3
4
5
>98
>98
>98
>98
>98
17
83
59
68
88
DME
a All reactions carried out under N2 atm. b Determined by analysis of
400 MHz 1H NMR spectra. c Determined by chiral HPLC analysis; see the
Supporting Information for details.
a All reactions carried out under N2 atm. b Isolated yields after purifica-
tion; >98% conversion in all cases. c Determined by chiral GLC or HPLC
analysis; see the Supporting Information for details. d Reaction run with
2.0 equiv Ar2Zn. e Reaction run in the presence of 10 mol % catalyst.
shown in Scheme 1, â-silyl-R,â-unsaturated ketone 1 un-
dergoes ACA to afford â-phenyl ketone 11 but in only 17%
ee. Control experiments indicated that low selectivity is likely
due to competitive uncatalyzed addition: treatment of Ph2-
Zn with enone 1 in toluene results in >98% conversion to
rac-11 in 1 h (22 °C). To minimize direct addition, we
investigated Cu-catalyzed ACA in coordinating solvents; we
proceeds to >98% conversion within 6 h when performed
in DME at 0 °C in the presence of 2.5 mol % 4 and 1 mol
% Cu salt; â-silylketone 11 is isolated in 81% yield and 92%
ee. As depicted in entry 2, under identical conditions, 12 is
obtained in 79% yield and 94% ee. Catalytic transformation
with (p-MeOC6H4)2Zn is more sluggish (>98% conv in 16
h, entry 3), delivering 13 in 82% isolated yield and 87% ee.
As noted in entry 4 of Table 3, when (p-CF3C6H4)2Zn is
used, ACA is significantly less efficient: 10 mol % 4 and 5
mol % (CuOTf)2‚C6H6 is required for >98% conversion in
48 h; â-silylketone 14 is obtained in 66% yield and 87% ee.
In addition to the widely appreciated oxidations that yield
â-hydroxyketones,15 enantiomerically enriched â-silylenones
can be utilized to access a number of useful organic
(12) Attempts to promote reactions of longer chain alkylzinc reagents
with the more active chiral bidentate N-heterocyclic carbenes (cf. ref 11)
results in >98% conversion and only a complex mixture of products. Studies
to address this shortcoming are in progress.
(13) One example of Cu-catalyzed ACA of PhMgBr to an R,â-
unsaturated methyl ketone has been reported. See: (a) Lo´pez, F.; Haru-
tyunyan, A.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2004, 126,
12784-12785. For an example involving a cyclic enone, see: (b) Martin,
D.; Kehrli, S.; d’Augustin, M.; Clavier, H.; Mauduit, M.; Alexakis, A. J.
Am. Chem. Soc. 2006, 128, 8416-8417.
(14) For Cu-catalyzed ACA of diarylzinc reagents to cyclic enones,
see: (a) Reference 11a. (b) Schinneri, M.; Seitz, M.; Kaiser, A.; Reiser, O.
Org. Lett. 2001, 3, 4259-4262. (c) Pena, D.; Lopez, F.; Harutyunyan, S.
R.; Minnaard, A. J.; Feringa, B. L. Chem. Commun. 2004, 1836-1837. (d)
Shi, M.; Wang, C.-J.; Zhang, W. Chem.sEur. J. 2004, 10, 5507-5516.
For asymmetric allylic alkylations processes, see: (e) Kacprzynski, M. A.;
May, T. L.; Kazane, S. A.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2007,
46, 4554-4558.
(15) For example, subjection of â-silylketone 6 (entry 3, Table 1) to
HBF4‚Et2O, followed by KF, KHCO3, and H2O2 affords the corresponding
â-hydroxyketone in 76% overall yield (95% ee).
Org. Lett., Vol. 9, No. 16, 2007
3189

Scheme 2. Synthesis of Enantiomerically Enriched
Trisubstituted Allylsilanes and Tertiary Alcohols from Catalytic
ACA Products
Scheme 3. Stereoselective Functionalizations of
Enantiomerically Enriched and Diastereomerically Pure
Allylsilane 19
isocyanate.23 The two-step sequence gives rise to lactam 20,
bearing an all-carbon quaternary stereogenic center,20 in 70%
overall yield and >98% de (95% ee). Reaction of 19 with
benzaldehyde furnishes secondary alcohol 21, containing an
allylic quaternary stereogenic center, in 76% yield and 80%
de (95% ee). Thus, the ability to control the stereochemistry
of the trisubstituted alkene of the enantiomerically enriched
enol triflates (e.g., 16) and higher reactivity of the major E
isomer is translated to application of the catalytic ACA
method to stereoselective syntheses of quaternary carbons
(cf. 18, 20, and 21).
We thus introduce an efficient method for Cu-catalyzed
ACA of dialkyl- and diarylzinc reagents to â-silylenones.
Reactions require a simple (MW ) 444.5 g/mol) chiral
phosphine, prepared from commercially available o-diphen-
ylphosphine benzaldehyde (Aldrich) and an inexpensive
amino acid. We have previously shown10c that chiral ligand
4 can be prepared by and used directly without purification.
As the example in eq 1 indicates, commercially available
(CuOTf)2‚toluene can be used in a practical manner (weighed
out on a bench top) to promote catalytic ACA.
molecules. As illustrated in Scheme 2, when the product from
catalytic ACA of Et2Zn and â-silylenone 15 is subjected to
4.5 equiv of Tf2O (at 22 °C, 12 h), enol triflate 16 is obtained
in 98% isolated yield as a 6.6:1 mixture of E:Z isomers.
Treatment of the mixture with Pd-catalyzed cross coupling
reactions,16 as illustrated in Scheme 2, leads to the formation
of allylsilane 17 in 61% yield as a single olefin isomer
(>20:1 E:Z).17 Thus, only the E enol triflate undergoes
catalytic cross coupling (81% yield based E isomer).18
Enantiomerically enriched allylsilane 17 can be used in
stereoselective processes.19 The two-step sequence in Scheme
2 is representative: diastereoselective epoxidation and
fluoride-mediated desilylation/epoxide cleavage generates
tertiary allylic alcohol 1820 in 97% overall yield and 96%
ee.
Enantiomerically enriched enol triflate 16 (96% ee) can
be stereoselectively alkylated with a cuprate reagent;21
synthesis of allylsilane 19 (Scheme 3), generated in 80%
isolated yield in >20:1 E:Z selectivity,22 is a case in point.
Enantiomerically enriched allylsilane 19 participates in a
highly diastereoselective cycloaddition with chlorosulfonyl
(16) For a review on the utility of enol triflates in synthesis, see: Ritter,
K. Synthesis 1993, 735-762.
(17) Willis, M. C.; Claverie, C. K. Tetrahedron Lett. 2001, 42, 5105-
5107.
1
(18) Unreacted enol triflate Z isomer was detected in the 400 MHz H
NMR of the unpurified mixture.
(19) For utility of allylsilanes in organic synthesis, see: (a) Masse, C.
E.; Panek, J. S. Chem. ReV. 1995, 95, 1293-1316. (b) Fleming, I.; Barbero,
A.; Walter, D. Chem. ReV. 1997, 97, 2063-2192. (c) Barbero, A.; Pulido,
F. J. Acc. Chem. Res. 2004, 37, 817-825. For a recent catalytic asymmetric
method for synthesis of allylsilanes, see ref 14e. For a diastereoselective
method used for synthesis of enantiomerically enriched allylsilanes, see:
(d) S. Schmidtmann, E.; Oestrich, M. Chem. Commun. 2006, 3643-3645.
(20) Quaternary Stereocenters: Challenges and Solutions for Organic
Synthesis; Christophers, J., Baro, A., Eds.; Wiley-VCH: Weinheim,
Germany, 2006.
Development of new catalysts and methods that initiate
C-C bond forming reactions of â-silyl enones with a wider
range of alkylmetal reagents is in progress.
Acknowledgment. Financial support was provided by the
NIH (Grant GM-47480). M.A.K. and S.A.K. were Novartis
Graduate and Undergraduate Fellows, respectively.
(21) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1980, 21, 4313-
4316.
(22) On the basis of previous studies (McMurry, J. E.; Scott, W. J.
Tetrahedron Lett. 1980, 21, 4313-4316) it is likely that, at least to some
extent, the cuprate derived from the minor Z enol triflate isomerizes to the
more reactive E vinylcopper reagent, which undergoes cross coupling.
(23) Woerpel, K. A.; Romero, A. Org. Lett. 2006, 8, 2127-2130 and
references cited therein.
Supporting Information Available: Experimental pro-
cedures and spectral data for products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL071331K
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Org. Lett., Vol. 9, No. 16, 2007