Catalytic enantioselective alkylations of tetrasubstituted olefins. Synthesis of all-carbon quaternary stereogenic centers through Cu-catalyzed asymmetric conjugate additions of alkylzinc reagents to enones

Article abstract of DOI:10.1021/ja0553811

A method for Cu-catalyzed asymmetric conjugate addition (ACA) of dialkylzinc reagents to tetrasubstituted five- and six-membered cyclic enones that afford quaternary all-carbon stereogenic centers in up to 95% ee is reported. Catalytic ACAs are practical

Full text of DOI:10.1021/ja0553811

Published on Web 10/07/2005
Catalytic Enantioselective Alkylations of Tetrasubstituted Olefins. Synthesis
of All-Carbon Quaternary Stereogenic Centers through Cu-Catalyzed
Asymmetric Conjugate Additions of Alkylzinc Reagents to Enones
Alexander W. Hird and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received August 12, 2005; E-mail: amir.hoveyda@bc.edu
Scheme 1
Conjugate additions of carbon nucleophiles to unsaturated
carbonyls constitute an important class of C-C bond forming
reactions in organic chemistry. A significant amount of effort has
been directed toward the development of Cu-1 and Rh-catalyzed2
asymmetric conjugate addition (ACA) of alkylmetal and aryl- and
vinylboronic acid reagents to cyclic and acyclic unsaturated
carbonyls. Nearly all such studies have focused on transformations
that deliver tertiary carbon stereogenic centers. The exception is
the recent report by Alexakis and co-workers regarding an efficient
Cu-catalyzed procedure3 for ACA to â-substituted cyclohexenones.
Reactions afford all-carbon quaternary stereogenic centers4 in up
to 96% ee. Because of the low substrate reactivity, the more Lewis
acidic3 but less atom-economical trialkylaluminum reagents (versus
dialkylzinc reagents) were required in the above study; thus, the
investigation involved additions of the more readily available Et3-
Al and (mostly) Me3Al.
Scheme 2. Catalyst Optimization through Positional Scanning
Studiesa
Herein, we disclose a practical method for catalytic ACA of
dialkylzinc reagents to cyclic enones that afford quaternary all-
carbon stereogenic centers4 in up to 95% ee. Reactions proceed to
>98% conversion with 2 mol % of air-stable CuCN and a new
chiral ligand that bears an anthranilic acid-based N-terminus5 (versus
(CuOTf)2‚C6H6 and Schiff base phosphines identified previously).6
Transformations are carried out in undistilled commercial grade
toluene. To the best of our knowledge, the present protocol
represents the first cases of catalytic enantioselective alkylmetal
addition to tetrasubstituted olefins.7
We initiated our studies by examining the ability of a range of
amino acid-based ligands and Cu salts to promote the ACA of Et2-
Zn to cyclic enone 1 (Scheme 1).8 These screening studies led us
to establish that the combination of CuCN and chiral ligand 2a,
bearing a dipeptide moiety with the N-terminus capped as an o-
phenoxy amide, delivers the desired product 3 efficiently (>98%
conversion, 24 h at 0 °C) and with appreciable enantioselectivity
(42% ee; R enantiomer major). Use of alternative Cu salts (e.g.,
(CuOTf)2‚C6H6, CuBr) and/or solvents (THF, CH2Cl2) results in
significantly less selective ACA (<20% ee).8 Reactions in the pres-
ence of the derived phosphine- (e.g., 4) and pyridyl-based ligands
(e.g., 5) leads to >98% conversion, but 3 is formed in <2% ee.8 It
must be noted that the combination of (CuOTf)2‚C6H6 and chiral
amino acid-based phosphine ligands, reported previously6 for ACA
of cyclic di- and trisubstituted enones, is ineffective (∼50%
conversion, <15% ee) in reactions of the present class of substrates.
To identify a more effective chiral catalyst, we carried out further
optimization studies; the modular nature of the peptidic ligand was
exploited in the systematic alteration of each structural unit of the
chiral ligand (positional scanning).9 The results of these investiga-
tions are summarized in Scheme 2.
a The reaction and conditions used are shown in Scheme 1 (10 mol %
loading).
Thus, undaunted by the ineffectiveness of 4 and 5 (Scheme 1), we
set out to explore more extensively the effect of steric and electronic
modifications of the ligand’s N-terminus. The resulting screening
studies8 revealed that the combination of CuCN and dipeptide 2b,
where anthranilic acid is used to cap the N-terminus, gives rise to
efficient formation of the opposite product enantiomer (S)-3 in 47%
ee ((R)-3 formed with 2a). Examination of various derivatives of
2b indicated that in the presence of 2c the Cu-catalyzed ACA
affords (S)-3 in 63% ee. Subsequent examination of the ligand
C-terminus (2d) and the two amino acid moieties allowed us to
identify 2f as a chiral ligand that promotes the enantioselective
synthesis of (S)-3 in 85% ee (>98% conversion).11 Further
optimization studies led us to determine that treatment of 1 with 2
mol % of 2f, 2 mol % of CuCN, and 1.5 equiv of Et2Zn delivers
(S)-3 in 82% ee and 89% isolated yield (see entry 1, Table 1; 85%
ee with 10 mol % catalyst loading).
With an effective chiral catalyst in hand, identified through
screening of ∼90 ligand candidates, we examined the scope of the
catalytic protocol. The results of these studies are summarized in
Table 1; several points regarding these data are noteworthy. (1)
Transformations can be performed effectively with five- and six-
Previous investigations indicate10 that the present class of chiral
amino acid-based ligands complex with the transition metal
(including Cu(I)-based systems)6f within the N-terminus moiety.
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10.1021/ja0553811 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Cu-Catalyzed ACA of Dialkylzincs to Tetrasubstituted
Scheme 3. Representative Functionalizations of ACA Products
Enonesa
a Conditions: 2 mol % of 2f, 2 mol % of CuCN, 1.5 equiv of (alkyl)2Zn
in toluene, undistilled toluene, N2 atm; except entry 4, 5 mol % of 2f and
CuCN, and entry 11, 5 mol % of 2f, CuCN, and 3 equiv of Me2Zn. b Isolated
yields after silica gel chromatography. c Determined by chiral GLC; see
the Supporting Information for details.
process gives rise to the corresponding cyclic trisubstituted olefin
(e.g., 22; Scheme 3).
In brief, we have identified a chiral ligand (2f) that, in the
presence of air-stable CuCN, can be used to promote ACA of
alkylzincs to tetrasubstituted cyclic enones to afford all-carbon
quaternary stereogenic centers. The above attributes should render
the present catalytic asymmetric method of notable utility. Study
of the full scope of this method and development of catalytic
asymmetric additions to â-substituted enones7 and the related acyclic
substrates will be disclosed in due course.
membered ring substrates and a range of dialkylzinc reagents
(commercially available Me2Zn, Et2Zn, n-Bu2Zn, and i-Pr2Zn used).
Reactions are effective with alkyl as well as t-Bu esters (see below
for decarboxylations). (2) All transformations were performed in
undistilled toluene. When purified solvent (passed through Cu and
alumina column) is used, significantly lower enantioselectivities
are observed.12 As the requisite Cu salt and ligand are air stable,
catalytic ACA can be carried out on the benchtop. Rigorous air
exclusion techniques are not required during setup until the addition
of dialkylzinc reagent. Such protocols do not lead to significant
loss of alkylzinc reagent, as ACA processes proceed to >98% con-
version with 1.5 equiv of alkylmetal. (3) Reactions of five-mem-
bered ring enones are less selective than six-membered ring sub-
strates (66-86% ee versus 82-95% ee). The examples shown, how-
ever, to the best of our knowledge, are the first instances of catalytic
ACA to â-disubstituted cyclopentenones. (4) As shown in Table
1, the optimal reaction temperature can be case dependent. For in-
stance, the ACA in entry 9, when performed at 0 and -30 °C, af-
fords 15 in 79 and 57% ee, respectively. (5) In the absence of a
chiral ligand, under otherwise identical conditions, conjugate addi-
tions proceed readily (>98% conversion). This fact, together with
the enantioselectivities in Table 1, suggests that either formation
of the Cu-ligand complex is irreversible or that the chiral complex
is more effective in promoting addition than CuCN. A potentially
relevant experimental observation is that premixing 2f and CuCN
for at least 3 h (22 °C) is required for high enantioselectivity to be
obtained. As an example, (S)-3 is formed in only 51% ee (versus
82% ee) when 2f and CuCN are premixed for 1 h. (6) Initial studies
indicate that the present enantioselective protocol can be run on
reasonable scale; the reaction in entry 4, when carried out at 0.5 g
scale, affords 9 in 87% ee and 76% isolated yield.
Acknowledgment. Financial support was generously provided
by the NIH (GM-47480).
Supporting Information Available: Experimental procedures and
spectral, analytical data for all reaction products (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171-196. (b) Feringa,
B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. Modern Organocopper
Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim, Germany, 2002; pp
224-258.
(2) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 8033-8061.
(3) d’Augustin, M.; Palais, L.; Alexakis, A. Angew. Chem., Int. Ed. 2005,
44, 1376-1378.
(4) (a) Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105-10146. (b)
Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5363-5367.
(5) For enantioselective Cu-catalyzed allylic alkylations promoted by amino
acid-based ligands bearing N,N-Cu binding sites (pyridyl Schiff base
N-terminus), see: Luchaco-Cullis, C. A.; Mizutani, H.; Murphy, K. E.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2001, 40, 1456-1460.
(6) For example, see: (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) Wu, J.; Mampreian, D. M.; Hoveyda, A. H.
J. Am. Chem. Soc. 2005, 127, 4584-4585. (f) Brown, M. K.; Degrado,
S. J.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2005, 44, 5306-5310 and
references therein. For reactions with a phosphine ligand bearing an amide
N-terminus linkage, see: (g) Hird, A. W.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2003, 42, 1276-1279.
(7) The protocol described herein is ineffective with the less activated but
also less sterically hindered â-substituted cyclic enones (see ref 3).
(8) See the Supporting Information for details.
(9) Cole, B. M.; Shimizu, K. D.; Krueger, C. A.; Harrity, J. P.; Snapper, M.
L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1668-1671.
(10) (a) Ref 6f. (b) Josephsohn, N. S.; Kuntz, K. W.; Snapper, M. L.; Hoveyda,
A. H. J. Am. Chem. Soc. 2001, 123, 11594-11599.
Optically enriched ACA products can be functionalized to afford
a variety of synthetically useful chiral building blocks (Scheme 3).
Decarboxylation of products affords the desired cyclic â,â-dialkyl
ketones in high yield under a variety of conditions (3f19 and 11
and 12f20a,b, Scheme 3); optically enriched products 20a,b cannot
be easily accessed by catalytic ACA of alkylaluminums.3 The
presence of â-ketoester allows access to optically enriched cy-
cloalkenes. For the synthesis of 21, formation of the derived enol
phosphate and treatment with a cuprate reagent delivers the optically
enriched unsaturated ester with a tetrasubstituted olefin and an
allylic quaternary carbon stereogenic center. A reduction/elimination
(11) The origin of selectivity variations shown in Scheme 2 is unclear at the
present time and is the subject of ongoing mechanistic investigations.
(12) For example, the reaction in entry 4, when carried out with purified toluene,
affords (R)-9 in 57% ee (versus 90% ee with undistilled toluene). Initial
studies suggest that adventitious moisture may be responsible for this
unexpected difference; addition of undistilled solvent to purified solvent
restores high selectivity. Further studies are in progress.
JA0553811
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