Catalytic enantioselective synthesis of quaternary all-carbon stereogenic centers. Preparation of α,α′-disubstituted β,γ-unsaturated esters through Cu-catalyzed asymmetric allylic alkylations

Article abstract of DOI:10.1021/ol047331r

(Chemical Equation Presented) Peptide-based chiral ligands, readily prepared from commercially available materials, are used to promote Cu-catalyzed asymmetric allylic alkylations of α,β-unsaturated esters bearing a γ-phosphate with various alkylzinc reagents. These transformations lead to the formation of α,α′-dialkyl-β,γ-unsaturated esters in high yields as well as high regio- (re) and enantloselectivities (ee).

Full text of DOI:10.1021/ol047331r

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1255-1258
Catalytic Enantioselective Synthesis of
Quaternary All-Carbon Stereogenic
Centers. Preparation of
r,r′-Disubstituted â,γ-Unsaturated
Esters through Cu-Catalyzed
Asymmetric Allylic Alkylations
Kerry E. Murphy and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467
amir.hoVeyda@bc.edu
Received December 27, 2004
ABSTRACT
Peptide-based chiral ligands, readily prepared from commercially available materials, are used to promote Cu-catalyzed asymmetric allylic
alkylations of -unsaturated esters bearing a -phosphate with various alkylzinc reagents. These transformations lead to the formation of
r′-dialkyl- -unsaturated esters in high yields as well as high regio- (re) and enantioselectivities (ee).
r
â,γ
,
â
γ
r
,
Development of efficient protocols for catalytic enantio-
selective synthesis of quaternary all-carbon stereogenic
centers is an important and challenging goal in modern
organic synthesis.1 A related class of transformations that
are of particular synthetic utility includes reactions that
generate a quaternary carbon stereogenic site adjacent to a
carbonyl group. A number of studies in the past few years
have aimed to provide solutions to this problem. Among
strategies2 that have resulted from such efforts are those
involving Pd-catalyzed arylations,3 allylations,4 Heck reac-
tions5 and carbonylations,6 metallocene-catalyzed acylations,7
Cr-catalyzed alkylations,8 and Rh-,9 Pd-,10 and La-catalyzed11
conjugate additions.
All of the above approaches involve addition of a metal
enolate to a carbon electrophile,12 and cyclic metal enolates
are employed in nearly all instances. An alternative approach
(4) (a) Sawamura, M.; Nagata, H.; Sakamoto, H.; Ito, K. J. Am. Chem.
Soc. 1992, 114, 2586-2592. (b) Trost, B. M.; Radinov, R.; Grenzer, E. M.
J. Am. Chem. Soc. 1997, 119, 7879-7880. (c) Trost, B. M.; Schroeder, G.
M. J. Am. Chem. Soc. 1999, 121, 6759-6760. (d) Trost, B. M.; Schroeder,
G. M.; Kristensen, J. Angew. Chem., Int. Ed. 2002, 41, 3492-3495. (e)
Hayashi, T.; Kanehira, K.; Hagihara, T.; Kumada, M. J. Org. Chem. 1988,
53, 113-120. (f) You, S.-L.; Hou, X.-L.; Dai, L.-X.; Zhu, X.-Z. Org. Lett.
2001, 3, 149-151. (g) Kuwano, R.; Uchida, K.; Ito, Y. Org. Lett. 2003, 5,
2177-2179. (h) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004,
126, 15044-15045. (i) Trost, B. M.; Frederiksen, M. U. Angew. Chem.,
Int. Ed. 2005, 44, 308-310.
(5) (a) Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am.
Chem. Soc. 1998, 120, 6477-6487. (b) Lee, S.; Hartwig, J. F. J. Org. Chem.
2001, 66, 3402-3415. (c) Dounay, A. B.; Hatanaka, K.; Kodanko, J. J.;
Oesterich, M.; Overman, L. E.; Pfeifer, L. A.; Weiss, M. M. J. Am. Chem.
Soc. 2003, 125, 6261-6271.
(1) For recent reviews, see: (a) Corey, E. J.; Guzman-Perez, A. Angew.
Chem., Int. Ed. 1998, 37, 388-401. (b) Christoffers, J.; Mann, A. Angew.
Chem., Int. Ed. 2001, 40, 4591-4597. (c) Denissova, I.; Barriault, L.
Tetrahedron 2003, 59, 10105-10146. (d) Douglas, C. J.; Overman, L. E.
Proc. Nat. Acad. Sci. U.S.A. 2004, 101, 5363-6367.
(2) For catalytic asymmetric cycloaddition approaches, see: (a) Evans,
D. A.; Murry, J. A.; von Matt, P.; Norcross, R. D.; Miller, S. J. Angew.
Chem., Int. Ed. Engl. 1995, 34, 798-800. (b) Corey, E. J. Angew. Chem.,
Int. Ed. 2002, 41, 1651-1667. (c) Huang, Y.; Iwama, T.; Rawal, V. H. J.
Am. Chem. Soc. 2002, 124, 5950-5951.
(3) (a) Chieffi, A.; Kamikawa, K.; Ahman, J.; Fox, J. M.; Buchwald, S.
L. Org. Lett. 2001, 3, 1897-1900. (b) Hamada, T.; Chieffi, A.; Ahman, J.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1261-1268.
10.1021/ol047331r CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/02/2005

that involves a carbonyl-containing electrophile and would
deliver the alkyl group as a nucleophile is illustrated in eq
1.13 Catalytic asymmetric allylic alkylation14,15 of R,â-
unsaturated esters, bearing a trisubstituted olefin and a
leaving group at the γ position, may afford the desired all-
carbon stereogenic center in the optically enriched or pure
form. Importantly, this strategy provides access to optically
enriched acyclic products that can be easily modified in a
variety of ways as a result of the presence of the carboxylic
ester and the terminal olefin. Herein, we disclose the results
of our studies toward the development of the catalytic
asymmetric protocol summarized in eq 1.
Next, to identify a more efficient and selective catalyst,
we carried out ligand screening studies, taking advantage of
the facile modularity16 of the peptide-based class of chiral
Schiff bases. Approximately 90 ligand candidates were
synthesized on solid support,17 cleaved, and tested for their
ability to promote the Cu-catalyzed enantioselective alkyla-
tion depicted in Scheme 1. These investigations led us to
identify 4a and 4b as the more attractive alternatives to 3.
Thus, as illustrated in entries 1-2 of Table 1, Cu-catalyzed
Table 1. Enantioselective Cu-Catalyzed Allylic Alkylations
We initiated our studies by investigating the feasibility of
the proposed catalytic asymmetric alkylation under the
conditions outlined recently by us for enantioselective
additions of alkylzincs to the derived allylic phosphates
bearing a disubstituted olefin (R2 ) H in eq 1). As illustrated
in Scheme 1, we established that in the presence of 10 mol
yielda reb eec
entry R1
(alkyl)2Zn
ligand prod (%)
(%) (%)
1
2
3
4
5
6
7
8
Me 1a Et2Zn
4a
4b
4a
4a
4b
4a
4a
4b
2
2
5
6
6
7
8
9
52d >98
90
87
88
77
77
46
Me 1a Et2Zn
43d >98
Me 1a [Me2CH(CH2)3]2Zn
Me 1a [AcO(CH2)4]2Zn
Me 1a [AcO(CH2)4]2Zn
Me 1a i-Pr2Zn
t-Bu 1b Et2Zn
t-Bu 1b [AcO(CH2)4]2Zn
80
78
78
90
79
77
>98
60
78
80
Scheme 1. Initial Studies on Cu-Catalyzed Allylic Alkylations
>98 >98
>98
83
a Isolated yields after silica gel chromatography; all reactions proceeded
to >98% conversion. b Determined by analysis of 400 MHz 1H NMR
spectra. c Determined by chiral GLC analysis of the derived carboxylic acid
(â-Dex column for entries 1-3 and 7) or conversion to the derived MPTA
ester followed by 400 MHz 1H NMR analysis. d Low yields due to product
volatility.
asymmetric alkylation of 1 with Et2Zn in the presence of 4a
and 4b leads to the formation of 2 in 90% and 87% ee,
respectively (>98% conversion and re with both chiral
ligands).
Additional data regarding Cu-catalyzed enantioselective
allylic alkylations of methyl ester 1a and tert-butyl ester 1b
are summarized in Table 1. Several features of these data
% of dipeptide Schiff base 3 and 5 mol % of (CuOTf)2‚
C6H6 unsaturated ester 1 undergoes efficient alkylation
(>98% conv) to afford 2, bearing the desired quaternary all-
carbon stereogenic center, in 83% ee and >98% re (regio-
isomeric excess; SN2′/SN2).
(6) Hayashi, T.; Tang, J.; Kato, K. Org. Lett. 1999, 1, 1487-1489.
(7) (a) Mermerian, A. H.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 4050-
4051. (b) Hills, I. D.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 3921-
3924.
(14) For related previous reports from these laboratories regarding
catalytic asymmetric allylic alkylations, see: (a) Luchaco-Cullis, C. A.;
Mizutani, H.; Murphy, K. E.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2001,
40, 1456-1460. (b) Kacprzynski, M. A.; Hoveyda, A. H. J. Am. Chem.
Soc. 2004, 126, 10676-10681. (c) Larsen, A. O.; Leu, W.; Nieto Overhuber,
C.; Campbell, J. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 11130-
11131. (d) Van Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.; Hoveyda,
A. H. J. Am. Chem. Soc. 2005, 127, in press.
(8) Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 62-63.
(9) Sawamura, M.; Hamashima, H.; Ito, Y. J. Am. Chem. Soc. 1992,
114, 8295-8296.
(10) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002,
124, 11240-11241.
(15) For representative catalytic asymmetric allylic alkylations (with hard
alkylmetals) reported by other laboratories, see: (a) Dubner, F.; Knochel,
P. Tetrahedron Lett. 2000, 41, 9233-9237. (b) Malda, H.; van Zijl, A. W.;
Arnold, L. A.; Feringa, B. L. Org. Lett. 2001, 3, 1169-1171. (c) Shi, W.-
J.; Wang, L.-X.; Fu, Y.; Zhu, S.-F.; Zhou, Q.-L. Tetrahedron: Asymmetry
2003, 14, 3867-3872. (d) Karlstrom, A. S. E.; Huerta, F. F.; Meuzelaar,
G. J.; Backvall, J.-E. Synlett 2001, 923-926. (e) Tissot-Croset, K.; Polet,
D.; Alexakis, A. Angew. Chem., Int. Ed. 2004, 43, 2426-2428.
(16) For screening strategies and significant attributes of the amino acid-
based ligands, see: Hoveyda, A. H. In Handbook of Combinatorial
Chemistry; Nicolaou, K. C., Hanko, R., Hartwig, W., Eds.; Wiley-VCH:
Weinheim, 2002; pp 991-1016.
(11) Sasai, H.; Emori, E.; Arai, T.; Shibasaki, M. Tetrahedron Lett. 1996,
37, 5561-5564.
(12) For examples involving organic catalysts, see: (a) Dolling, U.-F.;
Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984, 106, 446-447
(alkylation). (b) Shaw, S. A.; Aleman, P.; Vedejs, E. J. Am. Chem. Soc.
2003, 125, 13368-13369 (acyl transfer). (c) Mase, N.; Tanaka, F.; Barbas,
C. F. Angew. Chem., Int. Ed. 2004, 43, 2420-2423 (aldol additions). (d)
Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876-8877 (Stetter).
(13) For related catalytic asymmetric approaches leading to the formation
of tertiary carbon stereogenic sites R to carbonyls, see: (a) Luchaco-Cullis,
C. A.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 8192-8193. (b)
Murphy, K. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 4690-4691.
(17) See the Supporting Information for details.
1256
Org. Lett., Vol. 7, No. 7, 2005

are noteworthy: (i) Catalytic alkylations are not limited to
reactions of Et2Zn and can be efficiently carried out in the
presence of the more sterically hindered alkylmetals (entries
3-6 and 8) or those that bear heteroatom substituents (entries
4, 5 and 8). However, as the example in entry 6 indicates,
addition with a secondary alkylzinc reagent leads to the
formation of the desired product with lower optical purity.
(ii) Comparison of entries 1 with 7 and 4 with 8 indicates
that catalytic alkylations are more enantioselective with the
sterically bulky tert-butyl ester 1b. (iii) Overall, chiral ligands
4a and 4b should together be considered as optimal. In
certain cases, 4a delivers a more selective transformation
(compare entries 1 and 2), but there are also instances, as
exemplified by the outcome of reactions in entries 4 and 5,
that 4b is the superior chiral ligand (78% vs 60% re with
77% ee in both cases).
The Cu-catalyzed asymmetric reactions described above
allow access to all-carbon quaternary stereogenic centers that
bear alkyl substituents (in addition to the carboxylic ester
and the newly generated vinyl group). Due to the significance
of corresponding aryl-containing compounds in the enantio-
selective synthesis of biologically active molecules (see
Scheme 2 for an example), we set out to investigate the
feasibility of applying the present protocol to the asymmetric
synthesis of this class of molecules. Our attempts to identify
conditions that lead to efficient catalytic asymmetric additions
of Ph2Zn resulted only in low conversions (<30% conversion
after 24 h) and enantioselectivities.
with ligand 3 proved to be more facile (>98% conversion)
but equally nonselective (29% ee and <2% re). However,
since the same transformation in the presence of ligand 10
proceeds to 92% conv after 24 h and affords 13 in 48% ee
and >98% re, we initiated a ligand screening study in search
of an effective ligand for Cu-catalyzed alkylations of 12a.
Screening studies (involving ∼90 candidates) led us to
establish that in the presence of dipeptide 11a, â,γ-unsatur-
ated ester 13 can be obtained efficiently (>98% conversion
in 24 h) and in 79% ee and >98% re. To improve
enantioselectivity, and based on recent observations regarding
the effect of the amide terminus on asymmetric induction,
we examined the catalytic activity of a dozen chiral dipep-
tides17 related to 11a but with altered secondary amide
groups. These studies pointed to benzyl amide 11b as the
most optimal.18 Thus, as illustrated in entry 1 of Table 2, in
the presence of 6 mol % of 11b and 2.5 mol % of the Cu(I)
triflate salt, alkylation of 12a with Et2Zn proceeds to >98%
conversion in 24 h to afford 13 in >98% re and 86% ee. In
a similar fashion, as shown in entry 2 of Table 2, 14 is
obtained in >98% re and 94% ee. Catalytic asymmetric
alkylations of tert-butyl ester 12b is more sluggish but affords
the desired products in >98% re. In contrast to reactions of
methyl-substituted olefin 1b (vs 1a), reactions of the more
sterically hindered 12b are somewhat less enantioselective
than reactions of methyl ester 12a.
An alternative approach to the synthesis of the corre-
sponding aryl-containing compounds would involve catalytic
asymmetric alkylation of aryl-substituted substrates, such as
12a (see Table 2). Initial studies indicated that addition of
Et2Zn in the presence of 10 mol % of chiral ligand 4a (5
mol % of (CuOTf)2‚C6H6 at -15 °C) leads to 52% conver-
sion after 24 h to afford 13 in 23% ee and 60% re. Reaction
It is important to note that ligand 11b is significantly less
effective ligand than 4a,b in Cu-catalyzed enantioselective
additions to 1a; as an example, in the presence of 6 mol %
of 11b methyl ester 2 is formed in only 31% ee (>98% re,
>98% conversion after 24 h at -30 °C). Moreover, catalytic
alkylations of 1a,b with a chiral dipeptide bearing a benzyl
amide terminus that is derived from 4a does not lead to
improved enantioselection; conversion of 1a to 2 in the
presence of such a ligand (under conditions shown in Table
1) leads to isolation of the desired product in 77% ee (vs
90% with 4a and 87% with 4b). Such variations in the
identity of the optimal ligand should not come as a surprise.
Change of substrate structure, in which a smaller Me group
has been exchanged for a larger Ph unit, may well be
expected to require an altered chiral pocket for effective
asymmetric induction. The versatility of the amino acid-based
chiral ligands is partly because the structure of the catalyst
can be adjusted so that high selectivity can be achieved even
Table 2. Enantioselective Cu-Catalyzed Allylic Alkylations of
Olefins Bearing a Phenyl Substituent
yielda
(%)
reb
(%) (%)
eec
entry
R1
(alkyl)2Zn product
1
2
3
4
Me
Me
t-Bu 12b
t-Bu 12b
12a
12a
Et2Zn
Me2Zn
Et2Zn
Me2Zn
13
14
15
16
95
85
80
87d
>98 86
>98 94
>98 79
>98 89
a Isolated yields after silica gel chromatography; all reactions proceeded
to >98% conversion. b Determined by analysis of 400 MHz 1H NMR
spectra. c Determined by chiral GLC (Chiraldex-GTA column for entry 1)
or chiral HPLC (Chiralcel OJ column for entries 2-4). Reaction carried
out with 12 mol % of 11b and 5 mol % of Cu salt at -15 °C.
(18) For other instances, where modification of the amide terminus of
an amino acid-based ligand has resulted in significant improvements in
enantioselectivity of metal-catalyzed reactions, see: (a) Josephsohn, N. S.;
Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 4018-
4019. (b) Mampreian, D. M.; Hoveyda, A. H. Org. Lett. 2004, 6, 2829-
2832.
Org. Lett., Vol. 7, No. 7, 2005
1257

18, followed by a routine olefination affords unsaturated
diester 19, which has been converted to aminoglutethimide
AG,21 a highly efficient aromatase inhibitor that has been
used effectively against breast cancer in post-menopausal
women.22 Conversion of 18 to 20 underlines the utility of
the products obtained through the present protocol to the
synthesis of optically enriched â-amino acids that bear an
all-carbon quaternary center.23
Scheme 2. Representative Applications of the Cu-Catalyzed
Enantioselective Method to the Preparation of Biologically
Active Molecules
In summary, we disclose an efficient Cu-catalyzed protocol
for the preparation of acyclic â,γ-unsaturated esters that bear
an all-carbon quaternary stereogenic center R to the carbonyl
group. We demonstrate that the presence of the ester and
olefin functional groups present a large number of possibili-
ties for functionalization of the optically enriched products
(including conversion to various heterocycles). The present
protocol thus allows access to versatile nonracemic chiral
molecules that should find utility in organic synthesis and
cannot be readily prepared by alternative methods.
Future studies will focus on development of other catalytic
alkylation reactions that generate quaternary carbon stereo-
genic centers as well as those that utilize alternative
alkylmetal reagents.
Acknowledgment. This paper is fondly dedicated to the
memory of the late Professor Murray Goodman, a pioneer
in the field of peptide chemistry. Financial support was
generously provided by the NIH (GM-47480).
with substrates that present different steric challenges.19 Thus,
if high selectivities and yields are to be obtained with
different classes of substrates, a (small) collectionsrather
than a single optimal catalystsmight be required. This
scenario may be viewed as superior to one where a single
chiral catalyst is available but selectivities vary widely and
are at times not at synthetically useful levels.
Supporting Information Available: Experimental and
analytical data for substrates and products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL047331R
(20) (a) Nishide, K.; Katoh, T.; Imazato, H.; Node, M. Heterocycles 1998,
47, 839-845. (b) Katoh, T.; Nishide, K.; Node, M.; Ogura, H. Heterocycles
1999, 50, 833-841. (c) Abe, T.; Suzuki, T.; Sekiguchi, K.; Hosokawa, S.;
Kobayashi, S. Tetrahedron Lett. 2003, 44, 9303-9305.
As was mentioned above, the products of the asymmetric
Cu-catalyzed alkylation can be easily manipulated en route
to the synthesis of a range of biologically active molecules
that bear quaternary carbon stereogenic centers. Several
representative examples are illustrated in Scheme 2. Hy-
droboration of optically enriched 2 leads to the formation
of lactone 17, which has been converted to ethosuximide.20
Alternatively, conversion of 13 to optically enriched aldehyde
(21) Harvey, H. A.; Lipton, A.; Santen, R. J. Cancer Res. (Suppl.) 1982,
42, 3261-3469.
(22) (a) Fogliato, G.; Fronza, G.; Fuganti, C.; Grasselli, P.; Servi, S. J.
Org. Chem. 1995, 60, 5693-5695. (b) Fadel, A.; Garcia-Argote, S.
Tetrahedron: Asymmetry 1996, 7, 1159-1166. (c) Achmatowicz, O.;
Malinowska, I.; Szechner, B. Tetrahedron Lett. 1997, 53, 7917-7928.
(23) For recent reviews regarding enantioselective synthesis of â-amino
acids, see: (a) Kobayashi, S.; Kobayashi, J.; Ishiani, H.; Ueno, M. Chem.,
Eur. J. 2002, 8, 4185-4190. (b) Ma, J.-A, Angew. Chem., Int. Ed. 2003,
42, 4290-4299. (c) Sewald, N. Angew. Chem., Int. Ed. 2003, 42, 5794-
5795.
(19) For a more extended discussion, see: Hoveyda, A. H.; Hird, A.
W.; Kacprzynski, M. A. Chem. Commun. 2004, 1779-1785.
1258
Org. Lett., Vol. 7, No. 7, 2005