Scheme 33.10. Screening studies for optimization of ligand and Cu salt in catalytic allylic substitution of 51 with Et2Zn (all conversions > 98%).



Scheme 33.10. Screening studies for optimization of ligand and Cu salt in catalytic allylic substitution of 51 with Et2Zn (all conversions > 98%).

order: (1) identify optimal Schiff base type; (2) ascertain the identity of the most desirable Cu salt; (3) determine the optimal peptidic construct (e.g. di- or tripep-tide); (4) further enhance enantioselectivity through identification of optimal Schiff base and the amino acid moieties.

As shown in Scheme 33.10 (first-phase screening), treatment of phosphate 51 (Scheme 33.10) with Et2Zn in the presence of 10 mol% CuCN and chiral ligands 53-56 in tetrahydrofuran (THF) at —30 °C leads to >98% conversion within 6 h. Pyridine dipeptide 56 delivers the highest level of enantioselectivity (34% ee), followed by phosphine 55 (26% ee). To ascertain the identity of the most efficient and selective ligand/Cu salt combination, formation of 52 was examined in two sets of experiments involving ligands 55 and 56 and a collection of Cu salts (see Scheme 33.10, second-phase screening). This study established that 56 and CuCN, overall, provide the most efficient regio- and enantioselective process. Next, we secured the following additional ligand attributes (third-phase screening, Scheme 33.10): (1) an amide terminus is critical to the enantioselectivity - replacement of the NnBu in 56 with an OMe group (57, Scheme 33.10) leads to significant reduction of ee; (ii) incorporation of a third amino acid (58, Scheme 33.10) or removal of one (59) is detrimental to enantioselectivity [25]. The stereochemical outcome from the reaction with 59 (14% ee) once again underlines the importance of the AA2 moiety and indicates that simple attachment of a chiral group to the pyridyl ligation site is not alone sufficient for high asymmetric induction.

We then prepared chiral ligands 60-67 (Scheme 33.10) and examined their ability to initiate the enantioselective alkylation of 51 under the same conditions mentioned above. Thus, the catalytic ability of the derived amine (60), amide (61), and various a-substituted pyridyl systems (62-65) were investigated; in addition, the related indole-based 66 and C2-symmetric 67 were probed. All reactions proceed to >98% conversion and exhibit high degrees of SN2 '/SN2 selectivity, but it is the o-substituted ligand 64 that generates the highest ee. We thus selected o-OiPr pyridyl as the Schiff base moiety, and continued with the optimization of the AA1 and AA2 segments according to methods reported previously in the context of our work on the enantioselective addition of cyanide to meso epoxides and imines [3]. These studies uniformly suggest that L-Phe is the AA2 of choice, and that ligands which bear L-Val (56), L-t Leu (68, Scheme 33.11) and L-Chg (69, Scheme 33.11) at the AA1 position offer similarly superior enantioselection. When D-Val is used as AA1, the sense of enantioselection is reversed, indicating that the stereochemical identity of AA1 is critical to the sense of induction and that the D,L-ligand may deliver lower levels of enantioselectivity than the L,L isomer. The above chiral ligands were subsequently used in catalytic alkylation of a range of aryl olefins in the presence of Et2Zn and 10 mol% CuCN in THF.

The results shown in Scheme 33.11 are representative and point out which ligand provides the highest selectivity for a particular substrate (< 2% SN2 product in all cases). The selectivity and reactivity levels for the disubstituted alkenes are competitive with the recently reported catalytic alkylations of allylic chlorides [26], in which sterically demanding dialkyl zinc reagents (e.g. dineopentyl zinc) are required for high enantioselectivity (< 50% ee with n-alkyl zinc reagents). The cata-




10 mol % 68,10 mol % CuCN 3 equiv Et2Zn, THF, -78 °C

10 mol % 68,10 mol % CuCN 3 equiv Et2Zn, THF, -78 °C TsO


10 mol % 69,10 mol % CuCN 3 equiv Et2Zn, THF, -78 °C F Q

Scheme 33.11. Parallel screening of ligand libraries indicates that pyridyl dipeptides can serve as effective ligands for Cu-catalyzed allylic substitution reactions that afford quaternary carbon centers enantioselectively.

10 mol % 68,10 mol % CuCN 3 equiv Et2Zn, THF, -78 °C

10 mol % 68,10 mol % CuCN 3 equiv Et2Zn, THF, -78 °C TsO

81% ee, lytic enantioselective synthesis of quaternary carbons (e.g. formation of 73 and 75 in Scheme 33.9), however, represents a new and effective method for the regio- and enantioselective preparation of this important class of homochiral compounds.

The significance of the new technology was demonstrated in the context of a brief enantioselective total synthesis offish deterrent sporochnol (Scheme 33.12) [27, 28].

Cu-Catalyzed Enantioselective Conjugate Addition of Dialkyl Zincs to Unsaturated Ketones: Peptidic Phosphines as Chiral Ligands

Another important class of transformations is the catalytic asymmetric conjugate additions of unsaturated carbonyls [29]. We have examined the possibility of using the modular Schiff base polypeptides as ligands that promote this important class

THF, -78 °C, 48 h 2. KOH.aq EtOH, 80 °C

Scheme 33.12. Cu-catalyzed asymmetric allylic substitution with longer chain alkyl zinc reagents and total synthesis of sporochnol.

of transformations [30]. Screening of ligand, Cu salt, and solvent libraries, carried out in a similar manner as described above, indicated that phoshine-based dipep-tides, such as 55 shown in Scheme 33.13, promote various conjugate addition reactions with excellent reactivity and efficiency in the presence of CuOTf. Use of a hydroxyl-containing ligand such as 53 (see Scheme 33.10) or even a pyridyl ligand such as 56 leads to the formation of racemic products. Thus, once again, the modular character of this class of chiral ligands allows facile examination of a different subset of potential ligand structures that provides access to high levels of efficiency and asymmetric induction. The Cu-catalyzed C-C bond-forming reactions require only 2 mol% (CuOTf)2-C6H6 and 2.4 mol% of the peptidic phosphine and can be effected with a wide range of dialkyl zinc reagents. Most importantly, as depicted in Scheme 33.13 and in contrast to the previously reported protocols, the present method provides - for the first time - an efficient and highly enantioselective conjugate addition protocol for cyclopentenones.

Unlike the alkyl zinc reagents shown in Scheme 33.13, use of iPr2Zn leads to moderate levels of asymmetric induction (e.g. 62% ee with cycloheptenone 84 as the substrate). To address this selectivity problem, we set out to identify an improved chiral ligand through the positional optimization strategy, with cyclohexenone 82 serving as the substrate. As illustrated in Scheme 33.14, we established that reactions promoted by 86 (t-Leu at AA1, tBu-Tyr at AA2, and Gly at AA3) deliver 88 in 91% ee (vs. 72% ee with 55). Chiral phosphine ligand 86 also provides a better selectivity in reaction of cycloheptenone 84 with iPr2Zn (81% ee vs. 62% ee with 55). In contrast, with cyclopentenone 78 as the substrate, 90 is obtained in 65% ee when 86 is used (vs. 79% ee with 55). When phosphine 87 (Gly replaced by nBu) is employed in the reaction of 78, however, cyclopentanone 90 is isolated in 85% ee (94%) [31]. The above observations once again demonstrate the utility of facile modularity and its attendant parallel screening. These data imply that if complete ligand screening is carried out specifically for each substrate, a different optimal chiral phosphine construct may emerge for each particular enone.

3equiv Bu2Zn, -30°C

3equiv Bu2Zn, -30°C



Scheme 33.13. Cu-catalyzed asymmetric conjugate additions of cyclic enones with peptidic phosphines as the chiral ligand.

Scheme 33.13. Cu-catalyzed asymmetric conjugate additions of cyclic enones with peptidic phosphines as the chiral ligand.

Scheme 33.14. Cu-catalyzed asymmetric conjugate additions of cyclic enones with peptidic phosphines as the chiral ligand. Conditions: 1.0 mol% (CuOTf)2-C6H6, 2.4 mol% chiral ligand, 3 equiv. (iPr)2Zn, -30 °C.

This last enantioselective transformation catalyzed by peptide-based ligands is also of notable potential synthetic utility. The sequential catalytic addition/alkylation of 84 provides 91 in 97% ee, 80% yield, and with >15:1 diastereoselectivity (Scheme 33.15). Pd-mediated regioselective oxidation (! 92), followed by Wacker oxidation, completes a four-step enantioselective synthesis of the anticancer agent clavularin B (42% overall from commercially available 84) [32].

1.0 mol % (CuOTf)2«C6Hg 2.4 mol % 55, 3equiv Me2Zn, -30°C;

1.0 mol % (CuOTf)2«C6Hg 2.4 mol % 55, 3equiv Me2Zn, -30°C;

c/a itularin B

Scheme 33.15. Application of Cu-catalyzed asymmetric conjugate additions to the enantioselective total synthesis of anticancer agent clavularin B.


Conclusions and Outlook

The studies summarized in this article represent our research group's attempts in the past 5 years to establish a reasonably general protocol for the identification and discovery of chiral catalysts that effect a range of important bond formations enantioselectively and efficiently. By selecting an appropriate class of chiral ligands that satisfies the important criteria of modularity, lack of high symmetry, and availability of multiple but differentiated binding sites, we have been able to develop catalytic asymmetric C-C bond-forming reactions that involve both early (Ti and Zr) and late (Cu and Zn) transition metals. Although optimal ligands, metal centers, protecting groups, and solvents have been typically determined through systematic screening of parallel libraries, mechanistic knowledge along with basic chemical intuition are also critical ingredients along the way. These research activities are the result of the appreciation of the principle that a priori "rational" design of a catalyst may be near impossible since highly detailed mechanistic principles are often not general; such principles can vary with subtle changes in reaction conditions or substrate structure so that, even within a single class of substrates, the identity of the ''optimum catalyst'' may change. These studies are based on the premise that although the design of a specific catalyst may be impossible, general mechanistic principles can be utilized to outline a systematic screening protocol for catalyst identification.

The research described above bears testimony to the fact that this line of research does not advocate that we abandon rational or rigorous investigations of detailed mechanisms of important processes. Elements of design and a priori decisions are still required in determining what collections of catalysts need to be prepared; the framework is simply broader and thus initial bias that may be based on a few initial observations has less of a chance to point us in the wrong direction.

A diversity-based strategy allows us to base our mechanistic hypotheses on a much wider pool of data points - it discourages us from making naive generalities, which are more than often revised soon after a few additional experiments. As demonstrated in the above studies, mechanistic studies based on data that are collected from parallel libraries can provide additional logic and impetus for future efforts in reaction development.


First and foremost, I thank my friend, colleague, and collaborator Professor Marc Snapper. I am grateful to Dr Joseph Harrity, Dr Ken Shimizu, Dr Bridget Cole, Dr Clinton Krueger, Mr Kevin Kuntz, Dr Carolyn Dzierba, Mr James Porter, Mr John Traverse, Ms Courtney Luchaco-Cullis, Dr Hirotake Mizutani, Ms Sylvia Degrado, Dr Wolfgang Wirschun, Ms Kerry Murphy, Mr Nathan Josephsohn, and Mr John Gleason for making numerous invaluable intellectual and experimental contributions to the projects discussed in this article. Research in our laboratories is generously supported by the National Institutes of Health (GM-47480, GM-57212, and postdoctoral fellowships F32-GM-17821 and F32-GM-18209). Additional support has been provided by the National Science Foundation (CHE-9632278), Johnson and Johnson, Pfizer, DuPont, AstraZeneca, Albemarle, ArQule, Dreyfus Foundation, Sloan Foundation, and Deutsche Forschungsgemeinschaft (postdoctoral fellowship to W.W.).

Endnotes and References

1 Jacobsen, E. N., Pfaltz, A., YamamoTo, H. (eds), Comprehensive Asymmetric Catalysis. Springer, Berlin 1999.

2 The word "design" is described in the Unabridged Webster English Dictionary in the following manner: ''To conceive and plan out in mind.'' Based on such a definition, it is unlikely that a chemist can, in general, consider mechanistic data and directly design a catalyst that proves to be optimal in selectivity and reactivity. If by design it is implied (as is often the case) that numerous catalysts are prepared, and then after a period of trial and error a catalyst is determined to be optimal, such an excercise should be referred to as a ''linear screening.'' In such a case, the plan for the direction of screening - and not the catalyst itself - is conceived based on the existing mechanistic data.

3 a) K. D. Shimizu, M. L. Snapper, A. H. Hoveyda, Chem., Eur. J. 1998, 4, 1885-1889; b) M. B. Francis, T. F.

Jamison, E. N. Jacobsen, Curr. Opin. Chem. Biol. 1998, 2, 422-428; c) H. B. Kagan, J. Organomet. Chem. 1998, 567, 3-6; d) K. W. Kuntz, M. L. Snapper, A. H. Hoveyda, Curr. Opin. Chem. Biol. 1999, 3, 313-319; e) B. Jandeleit, D. J. Schaefer, T. S. Powers, H. W. Turner, W. H. Weinberg, Angew. Chem. 1999, 111, 2648-2689; Angew. Chem. Int. Ed. Engl. 1999, 38, 2494-2532; f) M. L. Snapper, A. H. Hoveyda in: Combinatorial Chemistry. Fenniri, H. (ed.), Oxford University Press, Oxford 2000, pp. 433-455.

4 For a recent review regarding the use of some non-C2-symmetric chiral ligands in metal-catalyzed enantioselective reactions, see: a) A. Pfaltz in: Stimulating Topics in Organic Chemistry. Shibasaki, M., Stoddard, J. F., Vogtle, F. (eds), VCH-Wiley, Weinheim 2000, pp. 89-103; b) G. Helmchen, A. Pfaltz, Acc. Chem. Res. 2000, 33, 336-345.

5 For example, see: K. B. Hansen, J. L. Leighton, E. N. Jacobsen, J. Am. Chem. Soc. 1996, 118, 1092410925.

6 a) H. Steinhagen, G. Helmchen, Angew. Chem., Int. Ed. Engl. 1996, 35, 2339-2342; b) M. Shibasaki, H. Sasai, T. Arai, Angew. Chem., Int. Ed. Engl. 1997, 36, 1236-1256.

7 For an example, see: M. Sawamura, H. Nagata, H. Sakamoto, Y. Ito, J. Am. Chem. Soc. 1992, 114, 25862592.

8 a) H. Nitta, D. Yu, M. Kudo, A. Mori, S. Inoue, J. Am. Chem. Soc. 1992, 114, 7969-7975; b) A. Mori, H. Abe, S. Inoue, App. Organomet. Chem. 1995, 9, 189-197.

9 B. M. Cole, K. D. Shimizu, C. A. Krueger, J. P. A. Harrity, M. L. Snapper, A. H. Hoveyda, Angew. Chem. 1996, 108, 1776-1779; Angew. Chem., Int. Ed. Engl. 1996, 35, 16681671.

10 K. D. Shimizu, B. M. Cole, C. A. Krueger, K. W. Kuntz, M. L. Snapper, A. H. Hoveyda, Angew. Chem. 1997, 109, 1781-1785; Angew.

11 a) C. A. Krueger, K. W. Kuntz, C. D. Dzierba, W. G. Wirschun, J. D. Gleason, M. L. Snapper, A. H. Hoveyda, J. Am. Chem. Soc. 1999, 121, 4284-4285; b) J. R. Porter, W. G. Wirschun, K. W. Kuntz, M. L. Snapper, A. H. HoveyDa, J. Am. Chem. Soc. 2000, 122, 2657-2658.

12 For a review on catalytic asymmetric additions to imines, see: S. Kobayashi, H. Ishitani, Chem. Rev.

1999, 99, 1069-1094.

13 For related studies on catalytic asymmetric cyanide addition to imines, see: a) M. S. Iyer, K. M. Gigstad, N. D. Namdev, M. Lipton, J. Am. Chem. Soc. 1996, 118, 49104911; b) M. S. Sigman, E. N. Jacobsen, J. Am. Chem. Soc. 1998, 120, 4901-4902; c) M. S. Sigman,

E. N. Jacobsen, J. Am. Chem. Soc. 1998, 120, 5315-5316; d) H. Ishitani, S. Komiyama, S. Kobayashi, Angew. Chem, Int. Ed. Engl. 1998, 37, 31863188; e) E. J. Corey, M. J. Grogan, Org. Lett. 1999, 1, 157-160; f) H. Ishitani, S. Komiyama, Y. Hasegawa, S. Kobayashi, J. Am. Chem. Soc.

2000, 122, 762-766; g) M. Takamura, Y. Hamashima, H. Usuda, M. Kanai, M. Shibasaki, Angew. Chem., Int. Ed. Engl. 2000, 39, 1650-1652.

14 a) See reference 12; b) M. C. Hansen, S. L. Buchwald, Org. Lett. 2000, 2, 713-715, and references cited therein.

15 N. S. Josephsohn, K. W. Kuntz, M. L. Snapper, A. H. Hoveyda, J. Am. Chem. Soc. 2001, 123, 11594-11599.

16 J. R. Porter, J. F. Traverse, A. H. Hoveyda, M. L. Snapper, J. Am. Chem. Soc. 2001, 123, 984-985.

17 For other catalytic asymmetric alkylations ofimines, see: a) S. E. Denmark, C. M. Stiff, J. Org. Chem. 2000, 65, 5875-5878; b) S. E. Denmark, N. Nakajima, O. J.-C. Nicaise, J. Am. Chem. Soc. 1994, 116, 8797-8798; c) H. Fujihara, K. Nagai, K. Tomioka, J. Am. Chem. Soc. 2000, 122, 12055-12056; for a related review, see: d) S. E. Denmark, O. J.-C. Nicaise, Chem. Commun. 1996, 9991004.

18 J. R. Porter, J. F. Traverse, A. H. Hoveyda, M. L. Snapper, J. Am. Chem. Soc. 2001, 123, 10409-10410.

19 For previous work from these laboratories in connection to catalytic asymmetric allylic substitutions with hard alkylmetals and other related studies, see: a) A. H. Hoveyda, N. M. Heron in: Comprehensive Asymmetric Catalysis. Jacobsen, E. N., Pfaltz, A., Yamamoto, H. (eds), Springer, Berlin 1999, pp. 431-454; for a review concerning catalytic asymmetric addition of soft nucleophiles to olefins, see: b) B. M. Trost, V. L. van Vranken, Chem. Rev. 1996, 96, 395-422.

20 For a review of catalytic enantioselective methods for the synthesis of quaternary carbon stereogenic centers, see: E. J. Corey, A. Guzman-Perez, Angew. Chem. 1998, 110, 402-405; Angew. Chem. Int. Ed. Engl. 1998, 37, 388-401.

21 C. A. Luchaco-Cullis, H. Mizutani, K. E. Murphy, A. H. Hoveyda, Angew. Chem., Int. Ed. Engl. 2001, 40, 14561460.

22 a) C. C. Tseng, S. D. Paisley, H. L. Goering, J. Org. Chem. 1986, 51, 2884-2891; b) J.-E. Backvall, M. Sellen, B. Grant, J. Am. Chem. Soc. 1990, 112, 6615-6621.

23 For Cu-catalyzed (nonasymmetric) addition of organotitanium and organozirconium reagents to allylic phosphates, see: a) A. Masayuki, E. Nakamura, B. H. Lipschutz, J. Org. Chem. 1991, 56, 5489-5491; b) L. M. Venanzi, R. Lehmann, R. Keil, B. H. Lipschutz, Tetrahedron Lett. 1992, 33, 5857-5860.

24 For Cu-catalyzed asymmetric alkylation of allylic phosphates with Grignard reagents, see: a) M. van KiAveren, E. S. M. Persson, A. del ViliAr, D. M. Grove, J-E. Backvaii, G. van Koten, Tetrahedron Lett. 1995, 36, 3059-3062; for W-catalyzed asymmetric alkylation of allylic phosphates with soft nucleophiles, see: b) G. C. Lioyd-Jones, A. Pfaitz, Angew. Chem. 1995, 107, 534; Angew. Chem. Int. Ed. Engl. 1995, 34, 462464.

25 Tripeptide 57 and its derived Me ester afford similar results.

26 a) F. Dubner, P. Knochei, Angew. Chem. 1999, 111, 391-393; Angew. Chem. Int. Ed. Engl. 1999, 38, 379381; b) F. Dubner, P. Knochei, Tetrahedron Lett. 2000, 41, 9233-9237; moreover, in referene 24b, a catalytic alkylation of 1a with nBuMgCl to afford 2a is reported to proceed in 10% ee (92% SN2').

27 For previous enantioselective total syntheses of sporochnol, see: a) M. Takahashi, Y. Shioura, T. Murakami, K. Ogasawara, Tetrahedron: Asymmetry 1997, 8, 12351242; b) T. Kambikubo, M. Shimizu, K. Ogasawara, Enantiomer, 1997, 2, 297-301; c) A. Fadei, L. Vandromme, Tetrahedron: Asymmetry 1999, 10, 1153-1162.

28 For a review on asymmetric catalysis in target-oriented synthesis, see: A. H. Hoveyda in: Stimulating Topics in Organic Chemistry. Vogtie, F., Stoddart, J. F., Shibasaki, M. (eds), VCH-Wiley, Weinheim 2000, pp. 145162.

29 For previous studies on the catalytic asymmetric conjugate additions, see: a) B. L. Feringa, M. Pineschi, L. A. Arnoid, R. Imbos, A. H. M. de Vries, Angew. Chem., Int. Ed. Engl. 1997, 36, 2620-2623; b) E. L. Strangeiand, T. Sammakia, Tetrahedron 1997, 53, 16503-16510; c) R. Naasz, L. A. Arnoid, M. Pineschi, E. Keiier,

B. L. Feringa, J. Am. Chem. Soc. 1999, 121, 1104-1105; d) A. Aiexakis, C. Benhaim, X. Fournioux, A. van den Heuvei, J.-M. LeveQue, S. March, S. Rosset, Synlett 1999, 1811-1813; e) X. Hu, H. Chen, X. Zhang, Angew. Chem., Int. Ed. Engl. 1999, 38, 35183521; f) Y. Yamanoi, T. Imamoto, J. Am. Chem. Soc. 1999, 64, 2988-2989; g) I. H. Escher, A. Pfaitz, Tetrahedron 2000, 56, 2879-2888; h) I.

Chataigner, c. Gennari, u. Piarulli, s. Ceccarelli, Angew. Chem., Int. Ed. Engl. 2000, 39, 916-918.

30 s. j. Degrado, h. Mizutani, a. h. Hoveyda, J. Am. Chem. Soc. 2001, 123, 755-756.

31 In all screenings, two sets of ligands involving Gly and nBu 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. 32 For previous total syntheses of clavularin B, see: a) r. Tamura, k. Watabe, n. Ono, y. Yamamoto, J. Org. Chem. 1993, 58, 4471-4472; b) k. Hiroya, h. Zhang, k. Ogasawara, Synlett 1999, 592-532.

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