Modular peptide-based phosphine ligands in asymmetric catalysis: Efficient and enantioselective cu-catalyzed conjugate additions to five-, six-, and seven-membered cyclic enones [12]

Full text of DOI:10.1021/ja003698p

J. Am. Chem. Soc. 2001, 123, 755-756
755
Scheme 1
Modular Peptide-Based Phosphine Ligands in
Asymmetric Catalysis: Efficient and Enantioselective
Cu-Catalyzed Conjugate Additions to Five-, Six-, and
Seven-Membered Cyclic Enones
Sylvia J. Degrado, Hirotake Mizutani, and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center
Boston College, Chestnut Hill, Massachusetts 02467
ReceiVed October 17, 2000
Table 1. Cu-Catalyzed Enantioselective Addition of Dialkylzinc
Peptide-based catalysts offer attractive and practical options
in the development of asymmetric transformations. Peptides are
easily prepared, consist of readily available chiral building blocks
and are modular. Largely due to these attractive attributes, metal-
peptide complexes have recently been demonstrated to initiate
asymmetric C-C bond forming reactions.1 Research in these
laboratories, involving peptide-based phenolic Schiff bases as
chiral ligands (e.g., 1, Scheme 1), has led to the development of
Ti-catalyzed additions of TMSCN to meso epoxides2 and imines
(Strecker amino acid synthesis),3 and Zr-catalyzed addition of
dialkylzincs to imines.4 The effectiveness of peptidic ligands in
the aforementioned programs led us to investigate their utility in
promoting catalytic enantioselective olefin alkylations with alkyl-
metals.5
Reagents to Cyclopentenonesa
Herein, we report the results of our studies on catalytic
enantioselective conjugate addition of dialkylzinc reagents to
cyclic enones.6,7 These transformations are promoted by (CuOTf)2‚
C6H6 in conjunction with peptide-based chiral phosphine ligands
(2, Scheme 1).8 The method described allows for efficient,
catalytic, and highly enantioselective (>95% ee) functionalization
of not only six- and seven-membered ring enones, but also of
cyclopentenones. It is worth noting that the catalytic asymmetric
conjugate addition of alkylmetals to five-membered ring enones
has previously been shown to be significantly less efficient and
selective than reactions of the larger ring analogues.7
a Conditions: indicated mol % 2 and (CuOTf)2‚C6H6, 3 equiv of
dialkylzinc, toluene, -30 °C (-20 °C for entries 4 and 7). b Conversion
determined by GLC. c Isolated yields after silica gel chromatography.
d Enantioselectivities determined by chiral GLC (R-DEX for entries
1-2; CDGTA for entries 3, 5-8). e GLC yields (volatile products);
representative isolated yields: 52% 4a and 46% 7a. f ee determined
by GLC analysis of the acetal derived from (R,R)-dimethylethylene
diol (CDGTA).
(1) (a) Mori, A.; Nitta, H.; Kudo, M.; Inoue, S. Tetrahedron Lett. 1991,
32, 4333-4336. (b) Abe, H.; Nitta, H.; Mori, A.; Inoue, S. Chem. Lett. 1992,
2443-2446. (c) Nitta, H.; Yu, D.; Kudo, M.; Mori, A.; Inoue, S. J. Am. Chem.
Soc. 1992, 114, 7969-7975. (d) Mori, A.; Abe, H.; Inoue, S. Appl. Organomet.
Chem. 1995, 9, 189-197. For representative reports, where peptides serve as
chiral catalysts (without a metal salt), see: (e) Jarvo, E. R.; Copeland, G. T.;
Papaioannou, N.; Bonitatebus, P. J.; Miller, S. J. J. Am. Chem. Soc. 1999,
121, 11638-11643. (f) Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew.
Chem., Int. Ed., Engl. 2000, 39, 1279-1281.
(2) (a) 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.
(b) Shimizu, K. D.; Cole, B. M.; Krueger, C. A.; Kuntz, K. W.; Snapper, M.
L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1704-1707.
(3) (a) Krueger, C. A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun, W. G.;
Gleason, J. D.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 1999,
121, 4284-4285. (b) Porter, J. R.; Wirschun, W. G.; Kuntz, K. W.; Snapper,
M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 2657-2658.
(4) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am.
Chem. Soc. 2001, 123, in press.
To initiate our studies, we examined the potential utility of
chiral peptidic ligands represented by 1 (Scheme 1). Under a
variety of conditions, however, conjugate additions deliver
racemic products. Treatment of cyclopentenone (3) with 10
mol % 1, a variety of Cu salts,9 and 3 equiv of Et2Zn (toluene,
-30 °C) leads to the formation of the expected ketone product
in >98% conv but in <5% ee. Similar results were obtained with
cyclohexenone and cycloheptenone.
At this point we reasoned that, whereas the phenol Schiff base
may be suitable for association with early transition metals (e.g.,
Ti or Zr), the corresponding P-containing chiral ligand 2 should
provide a “softer” site of binding and may be more appropriate
for late transition metals (e.g., Cu or Zn). Accordingly, we
prepared 2 from commercially available 2-(diphenylphosphino)-
benzaldehyde and performed screening of conditions to establish
the optimum Cu salt and solvent. As illustrated in entry 1 of
Table 1, treatment of cyclopentenone 3 with 1.0 mol % (CuOTf)2‚
C6H6,10 2.4 mol % 211 and 3 equiv of Et2Zn leads to 90% conv12
(5) Hoveyda, A. H.; Heron, N. M. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; p
431-454.
(6) Gomez-Bengoa, E.; Heron, N. M.; Didiuk, M. T.; Luchaco, C. A.;
Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 7649-7650.
(7) (a) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries, A.
H. M. Angew. Chem., Int. Ed. Engl. 1997, 36, 2620-2623. (b) Strangeland,
E. L.; Sammakia, T. Tetrahedron 1997, 53, 16503-16510. (c) Naasz, R.;
Arnold, L. A.; Pineschi, M.; Keller, E.; Feringa, B. L. J. Am. Chem. Soc.
1999, 121, 1104-1105. (d) Alexakis, A.; Benhaim, C.; Fournioux, X.; van
den Heuvel, A.; Leveque, J.-M.; March, S.; Rosset, S. Synlett 1999, 1811-
1813. (e) Hu, X.; Chen, H.; Zhang, X. Angew. Chem., Int. Ed. 1999, 38, 3518-
3521. (f) Yamanoi, Y.; Imamoto, T. J. Am. Chem. Soc. 1999, 64, 2988-
2989. (g) Escher, I. H.; Pfaltz, A. Tetrahedron 2000, 56, 2879-2888. (h)
Chataigner, I.; Gennari, C.; Piarulli, U.; Ceccarelli, S. Angew. Chem., Int.
Ed., Engl. 2000, 39, 916-918.
(9) The following Cu salts were examined: CuCN, CuCl, CuBr‚Me2S, CuI,
CuOAc, Cu(OTf)2, and (CuOTf)2‚C6H6. Solvents screened were THF, Et2O,
toluene, CH2Cl2, and ClCH2CH2Cl. Among various possible combinations,
Cu(OTf)‚C6H6 in toluene proved to be the most efficient combination.
(10) (a) Salomon, R. G.; Kochi, J. K. J. Am. Chem. Soc. 1973, 95, 1889-
1897. (b) Salomon, R. G.; Kochi, J. K. J. Am. Chem. Soc. 1973, 95, 3300-
3310.
(11) Approximately 20% excess ligand (vs CuOTf) is used to avoid
competing background reactions.
(12) Complete conversion and identical enantioselection is observed at
higher catalyst loading. For example, with 2.8 mol % (CuOTf)2‚C6H6 and 7.0
mol % 2, >98% conv is achieved in 6 h.
(8) For a recent report in connection with a peptide-based phosphine ligand
(Pd-catalyzed allylic substitution), see: Gilbertson, S. R.; Collibee, S. E.;
Agarkov, A. J. Am. Chem. Soc. 2000, 122, 6522-6523.
10.1021/ja003698p CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/04/2001

756 J. Am. Chem. Soc., Vol. 123, No. 4, 2001
Communications to the Editor
Scheme 2a
Table 2. Cu-Catalyzed Enantioselective Addition of Dialkylzinc
Reagents to Cyclohexenones and Cycloheptenonesa
a Conditions: 1.0 mol % (CuOTf)2‚C6H6, 2.4 mol % chiral ligand, 3
equiv of (i-Pr)2Zn, -30 °C.
substrate, 4c is obtained in 65% ee when 14 is used (vs 79% ee
with 2). When phosphine 15 (Gly replaced by n-Bu)16 is employed
in the reaction of 3, however, cyclopentanone 4c is isolated in
85% ee (94%). The above observations imply that if complete
ligand screening is carried out specifically for each substrate, a
different optimal chiral phosphine construct may emerge for that
particular enone.2
a Conditions: 1.0 mol % (CuOTf)2‚C6H6, 2.4 mol % 2, 3 equiv of
alkylzinc, toluene, -30 °C (-20 °C for entry 5). All reactions required
12 h, except for entries 2 and 7. b Conversion determined by GLC.
c Isolated yields after silica gel chromatography. d Enantioselectivities
were determined by chiral GLC (CDGTA for entries 1-5, 7, 9; â-DEX
for entries 6, 8). See Supporting Information for details.
The present catalytic asymmetric method delivers Zn-enolate
intermediates that can be functionalized in situ. For example,
sequential catalytic addition/alkylation of 12 provides 16 in
97% ee, 80% yield, and with >15:1 diastereoselectivity (Scheme
3). Pd-mediated regioselective oxidation (f17),17 followed by
Wacker oxidation18 completes a four-step enantioselective syn-
thesis of anti-cancer clavularin B19 (42% overall from com-
mercially available 12).
after 12 h (toluene, -30 °C), where ketone 4a is obtained in 78%
yield and 97% ee (chiral GLC).13 Addition of Bu2Zn (3f4b) and
functionalized alkylzinc 5 (f4d) takes place smoothly with 98%
and >98% ee, respectively (entries 2 and 4, Table 1). With the
sterically more hindered (i-Pr)2Zn as the alkylating agent (entry
3, Table 1), the catalytic addition proceeds to completion (>98%
conv) but is less enantioselective (79% ee; see below for ligand
optimization).
As depicted in entries 5-7 of Table 1, Cu-catalyzed conjugate
additions of dimethyl-cyclopentenone 6 are equally efficient. In
the presence of 1-2.5 mol % (CuOTf)2‚C6H6 and 2.4-6 mol %
2 reactions are complete within 12 h and deliver the desired
products in g98% ee.14 In contrast, the sterically more hindered
alkene of 8 (entry 8) undergoes conjugate addition reluctantly:
higher catalyst loadings are required for appreciable conversion
(7.5 mol % Cu salt and 17.5 mol % 2). The desired product 9 is
however obtained in 97% ee (56%).15
Scheme 3
Chiral phosphine 2 and CuOTf promote enantioselective
conjugate additions to larger ring enones as well. As illustrated
in Table 2, cyclohexenone 10 undergoes Cu-catalyzed conjugate
additions in the presence of 1.0 mol % (CuOTf)2‚C6H6 and 2.4
mol % 2 (>98% conv in all cases). Entries 1-3 and 5 of Table
2 indicate that when n-alkylzinc reagents are used, chiral ketones
11a-11c and 11e are isolated in >70% yield and g95% ee. As
before (entry 3, Table 1), reaction with (i-Pr)2Zn occurs with lower
enantioselectivity (72% ee). A similar trend is observed with
reactions of cycloheptenone 12 (entries 6-9, Table 2); most
n-alkylzincs, except for (i-Pr)2Zn (entry 9), participate in facile
and highly enantioselective transformations.
In brief, we disclose an effective protocol for the enantio-
selective addition of dialkylzincs promoted by catalysts that are
composed of commercially available components and can be
easily modified.20 Future studies are aimed at deciphering various
mechanistic issues and the application of peptidic phosphine
ligands to enantioselective additions involving acyclic substrates.
Development of other asymmetric C-C bond forming transfor-
mations with this class of chiral ligands is in progress as well.21
To address the issue of lower enantiocontrol in additions
involving i-Pr2Zn, we set out to identify an improved chiral ligand
through the positional optimization strategy,2a with cyclohexenone
10 serving as the substrate. As illustrated in Scheme 2, we have
established that reactions promoted by phosphine 14 (t-Leu at
AA1, t-Bu-Tyr at AA2 and Gly at AA3) deliver 11d in 91% ee
(vs 72% ee with 2 as catalyst). Ligand 14 also provides a better
selectivity in reaction of cycloheptenone 12 with i-Pr2Zn (81%
ee vs 62% ee with 2). In contrast, with cyclopentenone 3 as
Supporting Information Available: Experimental procedures and
spectral and analytical data for all recovered starting materials and reaction
products (PDF). This material is available free of charge via the Internet
at http//:www.acs.pubs.org.
JA003698P
(16) In all screenings, two sets of ligands involving Gly and n-Bu as AA3
were examined. Structural modifications thus involved variations at AA1 and
AA2. Further details will be disclosed in the full account of this work.
(17) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011-1013.
(18) Tsuji, J.; Shimizu, I.; Yamamoto, K. Tetrahedron Lett. 1976, 34,
2975-2976.
(19) (a) Tamura, R.; Watabe, K.; Ono, N.; Yamamoto, Y. J. Org. Chem.
1993, 58, 4471-4472. (b) Hiroya, K.; Zhang, H.; Ogasawara, K. Synlett 1999,
592-532.
(20) For an alternative approach to similar products through catalytic
asymmetric hydride addition, see: Moritani, Y.; Apella, D. H.; Jurkauskas,
V.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 6797-6798.
(21) This research was supported by the NIH (General Medical Sciences)
and DuPont. We are grateful to Professor M. L. Snapper and C. A. Luchaco-
Cullis for helpful discussions.
(13) Reactions proceed with equal facility in the absence of 2. This suggests
that a rapidly generated chiral phosphine‚Cu complex promotes the enantio-
selective addition.
(14) Reaction of 6 with dialkylzinc 5 proceeds to ∼80% conv with 2.4
mol % 2 and 1.0 mol % of the Cu salt (48% yield and >98% ee).
(15) Once the identity of the optimum ligand (e.g., 2) and Cu salt
(CuOTf)2‚C6H6 were established, a brief screening of various solvents was
again performed; toluene remained the most effective medium. Representaive
data from this study (8 as substrate and Et2Zn): CH2Cl2 (20% conv, 21%
ee); ClCH2CH2Cl (32% conv, 42% ee), THF (<5% conv), Et2O (31% conv,
92% ee), 50% hexanes in toluene (<5% conv).