Efficient Cu-catalyzed asymmetric conjugate additions of alkylzincs to trisubstituted cyclic enones

Article abstract of DOI:10.1021/ja021081x

The first examples of efficient catalytic asymmetric conjugate addition (ACA) of alkylzincs to trisubstituted cyclic enones is disclosed. These Cu-catalyzed reactions proceed efficiently with five- and seven-membered ring substrates to afford the desired products in ≥95% ee. Intermediate enolates can be trapped with alkyl halides to generate a quaternary stereogenic center. The requisite chiral ligand is prepared from commercially available materials and can be used in situ without further purification in the presence of commercial grade (CuOTf)2·PhMe. Copyright

Full text of DOI:10.1021/ja021081x

Published on Web 10/17/2002
Efficient Cu-Catalyzed Asymmetric Conjugate Additions of Alkylzincs to
Trisubstituted Cyclic Enones
Sylvia J. Degrado, Hirotake Mizutani, and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received August 14, 2002
Table 1. Cooperative Interplay between AA1 and AA2 Moieties of
the Chiral Peptide Ligands on Reactivity and Selectivity
A considerable amount of research has focused on the develop-
ment of catalytic asymmetric conjugate additions (ACA) of
alkylmetals to R,â-unsaturated carbonyls.1 Previous reports from
these laboratories have outlined effective methods for Cu-catalyzed
reactions of alkylzincs with disubstituted enones,2 providing solu-
tions to problems regarding efficient asymmetric additions to
cyclopentenones2a and acyclic enones.2b A number of synthetically
important challenges, however, remain unsolved. One relates to the
availability of catalytic ACA involving sterically hindered trisub-
stituted enones. To the best of our knowledge, there are no existing
reports that address this task.3 Herein we report efficient and highly
selective Cu-catalyzed ACA of alkylzincs to trisubstituted unsatur-
ated cyclic ketones. In contrast to previous ACA reactions promoted
by amino acid-based chiral ligands,2 the present transformations
are catalyzed by a Schiff base derivative of a single amino acid
that is commercially available and inexpensive (L- or D-valine).
The ligand can be prepared and used directly without isolation and
purification to afford high enantioselectivities. The resulting metal
enolates can be reacted diastereoselectively to deliver cyclic ketones
of high optical purity that bear a quaternary stereogenic center.4
entry
AA1
AA2
conv (%)a
ee (%)b
1
2
3
4
5
6
L-t-Leu
L-Val
L-t-Leu
L-Val
L-t-Leu
L-Val
L-Phe
L-Phe
Gly
Gly
-
3
4
5
6
7
8
93
32
87
92
>98
97
85
76
93
91
83
96
-
a Determined by GLC. b Determined by chiral GLC.
t-Leu), renders the present method cost-effective. (3) The data in
Table 1 indicate cooperativity between the AA1 and AA2 residues
of the dipeptidic chiral ligands.
The results summarized in Table 2 illustrate that Cu-catalyzed
ACA of alkylzincs to a range of cyclic trisubstituted enones are
readily promoted by 8. Although, as expected, reactions proceed
more slowly than disubstituted enones,2a conversions are high with
enantioselectivities g95% ee. In many cases isolated yields are
lower than percent conversions due to volatility of the products.
Several additional points are noteworthy: (1) Transformations
in entries 1-8 and 11-12 (Table 2) afford 1.5-4:1 ratio of anti:
syn diastereomers. In contrast, 16a and 16b (entries 9 and 10) are
formed as 3:1 mixtures of syn:anti isomers. In the case of all
cyclopentenyl products, treatment with DBU or Et3N (MeOH, 22
°C) allows equilibration to the anti isomer (see Table 2).6 With
medium-ring products 18a-b, similar conditions do not lead to
improved diastereomeric purity.
(2) All processes in Table 2 are effected in the presence of ligand
8. Two exceptions are additions to enone 15 (entries 9-10) where
192b is significantly more efficient (data in entries 9-10, Table 2
relate to reactions catalyzed by 19). As an example, when 8 is used
as the catalyst, 16b is formed in 95% ee but along with ∼40% of
an unidentifiable impurity.7
We began our investigation with screening of various amino acid-
based ligand candidates.5 These studies indicated that peptide-based
phosphine 3 (Table 1, entry 1) promotes the ACA of Et2Zn to
trisubstituted enone 1 to afford 2 in 85% ee (93% conv after 24 h).
The identity of ligand 3 was consistent with previous findings.2
Also expected was that, as shown in entry 2 of Table 1, substitution
of AA1 from L-t-Leu to L-Val leads to lowering of selectivity (76
vs 85% ee) and substantial reduction in reactivity (32 vs 93% conv).
However, the results shown in entries 3-4 of Table 1 were
unanticipated for two reasons: First, insertion of achiral Gly as
AA2 in place of L-Phe leads to notable improvement of enanti-
oselectivity (compare entries 3 and 4 to 1 and 2). Second, in contrast
to when AA2 is L-Phe (entries 1 and 2), with Gly as the AA2, the
ligands bearing L-t-Leu (entry 3) and L-Val (entry 4) as AA1 provide
comparable reactivity and selectivity. With the positive influence
of an achiral AA2, we examined the utility of the derived
monoamino acid ligands 7 and 8, leading us to establish that Schiff
base 8 (entry 6) promotes ACA of Et2Zn to 1 in 96% ee (97%
conv). These findings are noteworthy for several reasons: (1) The
identity of the optimal ligand varies considerably from the two
different dipeptide ligands required for ACA of disubstituted cyclic2a
or acyclic enones.2b (2) The requirement for a single amino acid
residue (vs a dipeptide), and that being the inexpensive Val (vs
(3) Six-membered ring trisubstituted enones are inert to catalytic
ACA conditions (<5% conv after 12 h). As formerly disclosed,2b
products expected from cyclohexenyl substrates can be obtained
through catalytic additions/intramolecular enolate alkylations of
* To whom correspondence should be addressed. E-mail: amir.hoveyda@bc.edu.
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J. AM. CHEM. SOC. 2002, 124, 13362-13363
10.1021/ja021081x CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Cu-Catalyzed ACA of Alkylzinc Reagents to Cyclic Trisubstituted Enonesa
a Conditions: indicated mol % 8 (except entries 9-10) and (CuOTf)2‚C6H6, 3 equiv of alkylzinc in toluene, 0 °C, indicated duration, N2 atm. b Ligand
8 used in all cases, except entries 9-10, where 19 was employed. c Determined by GLC analysis of unpurified reaction mixtures. d Isolated yields after
purification of conjugate addition products. e By GLC and 400 MHz 1H NMR analysis. Performed by treatment with 1 equiv of DBU in MeOH at 22 °C for
12-24 h (3 equiv of Et3N used for entries 9-10). f By chiral GLC analysis measured for both diastereomers (see the Supporting Information for details).
Scheme 1. Cu-Catalyzed ACA with Commercially Available and
Unpurified Materials
suitably functionalized acyclic enones such as 20 (to give 21). The
present protocol, however, delivers the corresponding seven-
membered ring adducts (see entries 11-12, Table 2). Such products
cannot be obtained by the aforementioned tandem approach;
reactions of the acyclic enone tosylates (homologue of 20) only
afford acyclic conjugate addition adducts such as 22.2b
(4) The purported Zn-enolate intermediates react with various
alkyl halides. Addition of MeI or PhCH2Br and DMPU8 to the
reaction of 11 with Et2Zn (Table 2, entry 5) affords 23 and 24 in
4:1 (65% yield) and >20:1 (70% yield) diastereoselectivity,
respectively.
Supporting Information Available: Experimental procedures and
spectral and analytical data for reaction products (PDF). This material
is available free of charge via the Internet at http://www.pubs.acs.org.
References
(1) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171-196.
(2) (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) Luchaco-Cullis, C. A.; Hoveyda, A.
H. J. Am. Chem. Soc. 2002, 124, 8192-8193.
(3) For catalytic asymmetric conjugate additions to trisubstituted R,â-
unsaturated malonates (<60% ee), see: Alexakis, A.; Rosset, S.; Allamand,
J.; March, S.; Guillen, F.; Benhaim, C. Synlett 2001, 1375-1378.
(4) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 110, 388-
401.
(5) Cole, B. M.; Shimizu, K. D.; Krueger, C. A.; Harrity, J. P. A.; Snapper,
M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1668-
1671.
(6) Equilibration reactions proceed to afford the less volatile products in 70
to >98% isolated yields.
(7) See the Supporting Information for complete data regarding reactions in
Table 2 when performed in the presence of 19 (except entries 9 and 10).
(8) See the Supporting Information for experimental details.
(9) Choi, H. Y.; Choi, J. Y.; Yang, H. Y.; Kim, Y. H. Tetrahedron:
Asymmetry 2002, 13, 801-804.
(5) Treatment of a sample of commercially available phosphine
25 (not further purified) with amine 26 (no purification after removal
of Boc group) in the presence of MgSO4 leads to a solution of
ligand 8 after 12 h (Scheme 1). An appropriate aliquot of this
solution was then used to effect the formation of 12b with
commercially available materials 11, (CuOTf)2‚PhMe9 and Et2Zn
(none were purified). The desired product was obtained in 94% ee
and 62% yield (compare to entry 5, Table 2; 2:1 prior to
equilibration).
Acknowledgment. This work was supported by the NIH (GM-
47480).
JA021081X
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