Enantioselective Organic Catalysis: Non-MacMillan Approaches

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1 Enantioselective rganic Catalysis: on-macmillan Approaches Jake Wiener 8 ovember 2000 I. Catalytic Antibodies and Multi-eptide Catalysis II. ase Transfer Catalysis III. Bifunctional rganic Catalysis IV. ophoramide Catalysts V. Catalysis via Enamine Intermediates VI. Catalysts as ucleophilic Triggers VII. Ketone Catalyzed Epoxidations VIII. Amine Catalyzed Epoxidations Catalytic Antibodies and Multi-eptide Catalysis! Antibodies have been used to catalyze a range of specific transformations ecent review, containing pertinent references: ilvert, D., Annu. ev. Biochem., 2000, 69, 751. Slightly older review: sieh-wilson, L. C., iang,., Schultz,. G. Acc. Chem. es., 1996, 29, 164.! Molecules consisiting of multiple linked peptides have been used to catalyze a range of reactions, including azide conjugate additions, asymmetric acylations, the Strecker synthesis, expoxidations, and C additions. These reactions cuurently lack clear mechanistic understandings. elevant ticles: Miller, S. J., et al., Angew. Chem. Int. Ed. Engl., 2000, 39, Miller, S. J., et al., J. Am. Chem. Soc., 1999, 121, Miller, S. J., et al., J. rg. Chem., 1998, 63, Miller, S. J., et al., J. Am. Chem. Soc., 1998, 120, Lipton, M., et al., J. Am. Chem. Soc., 1996, 118, Itsuno, S., et al., J. rg. Chem., 1990, 55, Inoue, S., et al., J. rg. Chem., 1990, 55, 181.

2 ase Transfer Catalysis: Alkylation! Initial report: 'Donnell Br 20 mol% catalyst 17% aq. a C 2 2 = C 2, 4-2 -C 6 4 -C 2, 4--C 6 4 -C 2 2 C, 1-naphthyl-C 2,, Et, 2 C, 3 C 3 CC 2, Et 3 C 60-90% yield 14-56% ee Cinchonine catalyst Lead to the first practical asymmetric synthesis of!-amino acids 'Donnell, M. J., et al., J. Am. Chem. Soc., 1989, 111, 2353.! Slam Dunk: Corey tbu 10 mol% catalyst Cs 2 C 2 2 tbu Br Electrophile 68-91% yield % ee Allylic, benzylic, propargylic bromides Alkyl iodides Cinchonine-derived catalyst Corey, E. J., et al., J. Am. Chem. Soc., 1997, 119, ase Transfer Catalysis: chanism of Alkylation tbu aq. Cs tbu Cs *4 Br rganic ase Aqueous ase *4 tbu tbu rganic ase Catalyst is regenerated and returns to aqueous phase *4 'Donnell, M. J., et al., J. Am. Chem. Soc., 1989, 111, Corey, E. J., et al., J. Am. Chem. Soc., 1997, 119, Corey, E. J., et al., J. Am. Chem. Soc., 1998, 120,

3 ase Transfer Catalysis: Support for Stereochemical Model The intermediacy of a contact ion pair is supported by varying electronics of the enolate aryl substituents tbu 2 *4 tbu! p ee 0 67% % % %! As the value of! becomes more negative, the aryl substiuents become more electron-donating.! As the aryl substituents become more electron donating, electron density on the enolate oxygen increases.! More electron density on the enolate oxygen results in a tighter contact ion pair, bringing the substrate further into the chiral cavity, thereby accentuating the effect of the sterics in the cavity on bond formation higher % ee Corey, E. J., et al., J. Am. Chem. Soc., 1998, 120, ase Transfer Catalysis: Epoxidation of ",#-Unsaturated Ketones Br K toluene, -40 C Cinchonine-derived catalyst % yield % ee % yield % ee C C 3 -C C 6 5 F C C 6 5 Br C 6 4 F C C 3 -C C 6 4 F C 6 5 C n-c 5 11 F C 6 5 2,4-Br 2 -C cyclo-c #-naphthyl cyclo-c 6 11 F Corey, E. J., et al., rg. Lett., 1999, 1, 1287.

4 ase Transfer Catalysis: Stereochemical ationale for Epoxidation of!,"- Unsaturated Ketones F K toluene, -40 C F! uclephilic oxygen of is proximate to " carbon of ketone F! 4-fluorophenyl group wedged between ethyl and quinoline substituents! Carbonyl oxygen is placed close to egative charge on in TS is stabilized by proximate charge acceleration of nucleophilic attack Corey, E. J., et al., rg. Lett., 1999, 1, Cinchonidine-derived catalysts have been used in aldol and nitroaldol reactions: Corey, E. J., et al., Tetrahedron Lett., 1999, 40, Corey, E. J., et al., Angew. Chem. Int. Ed. Engl., 1999, 38, Conjugate additions of thiol have been reported: Wynberg,., J. Am. Chem. Soc., 1981, 103, 417. Analogous michael reactions have been performed: Corey, E. J., et al., rg. Lett., 2000, 2, 1097; Corey, E. J., et al., Tetrahedron Lett., 1998, 39, A Diels-Alder reaction has been reported: Kagan,. Tetraheron Lett., 1989, 30, Bifunctional Enantioselective rganic Catalysts: Ketone eduction 1 2 B 3 S toluene, C osphinamide catalyst Br M apthyl 89% yield 93% ee 83% yield 88% ee 76% yield 77% ee 89% yield 90% ee 82% yield 90% ee 81% yield 82% ee 81% yield 56% ee 87% yield 67% ee 65% yield 86% ee 83% yield >90% ee 71% yield >90% ee = : 83% yield 75% ee = 4-F-: 68% yield 83% ee Bn = : 86% yield 94% ee = C 2 Bn: 84% yield 93% ee Wills, M., et al., J. rg. Chem., 1998, 63, 6068.

5 Bifunctional Enantioselective rganic Catalysts: Stereochemical ationale for Ketone eduction 1 2 B 3 S 2 toluene, C 1 2 osphinamide catalyst Lewis Acid! " 2! B! B "! 2! igh temperatures are required to facilitate catalyst turnover after reduction (to break the numerous B bonds) Lewis base! 11 B and 31 M studies indicate no decomposition of catalyst! Anhydrous conditions not required Wills, M., et al., J. rg. Chem., 1998, 63, Bifunctional Enantioselective rganic Catalysts: Diethyl Zinc Addition 5 mol % catalyst Et 2 Zn TF, 20 C Diazaphopholidine catalyst % yield % ee 2 C >99! Electron withdrawing substituents result in increase in enantioselectivity ossible transition state! "!! ZnEt 2 Zn Et! " Et Buono, G., et al., Tetrahedron Lett., 1998, 39, 2961.

6 Bifunctional Enantioselective rganic Catalysts: Strecker Synthesis C toluene, -40 C 8-72 hours C 3 3!-amino nitrile!-amino acid % yield % ee p-tolyl ,5-xylyl o-tolyl tBu- 4-TBS F naphthyl C 2 -symmetric Guanidine catalyst! o background reaction below 10 C! -methyl derivitive of catalyst is inactive Corey, E.J., et al., rganic Lett., 1999, 1, 157. Bifunctional Enantioselective rganic Catalysts: chanism and Stereochemical ationale for Corey's Strecker Synthesis C toluene, -40 C 8-72 hours C!-amino nitrile C 2 -symmetric Guanidine catalyst! Catalyst Cycle! re-transition state assembly predicts outcome 2 C C C "-stacking 2 C C 2 C C C si face blocked by phenyl ring Corey, E.J., et al., rganic Lett., 1999, 1, 157.

7 Bifunctional Enantioselective rganic Catalysts: Conjugate Addition n n = 1,2, mol % catalyst C 3, 23 C n catalyst C 2 nucleophile % yield % ee 1:1 dr where relevant! n = 2 (cyclohexenone) affords best ee! umerous basic additives tried: basicity and structure have large effect on ee 86% ee 4% ee! This work is an extension of Yamaguchi's work using ubidium prolinate salts: Yamaguchi, M., et al., Tetrahedron, 1997, 53, anessian, S., et al., rganic Lett., 2000, 2, Bifunctional Enantioselective rganic Catalysts: ossible chanism of Conjugate Addition n n = 1,2, mol % catalyst C 3, 23 C n catalyst C 2! ossible iminium ion intermediate C 2 Ionic complex C blocks top face C uc ucleophile approaches bottom face Alternately onlinear effect of catalyst ee on product ee suggests oligomeric TS otential bonding of prolinateiminium ion aggregate to nitroalkane resulting in greater TS organization C anessian, S., et al., rganic Lett., 2000, 2, 2975.

8 Enantioselective Catalysis by osphoramides: Aldehyde Allylation 1 2 Si mol% catalyst TF, -60 C hours 1 2 r r 1 2 % yield syn:anti % ee catalyst C C C :2 77 C : C >99: tBuC :5 82! Unlike Lewis acid catalyzed addition of crotylsilanes and crotylstannanes, this reaction allows access to both syn and anti homoallylic alcohols Iseki, K., et al., Tetrahedron, 1997, 53, For a review of osphorus reagents in enantioselective catalysis, see: Buono, G., et al., Synlett, 1999, 377. Enantioselective Catalysis by osphoramides: chanism of Aldehyde Allylation 2 1 Si mol% catalyst TF, -60 C hours 1 2 r r catalyst! Chair-like transition state accounts for observed diastereo- and enantioselectivity Si M3 Calculation! exacoordinate silicate proposed! Larger (alkyl) 2 of phosphoramide leads to higher ee's Iseki, K., et al., Tetrahedron, 1997, 53, 3513.

9 Enantioselective Catalysis by osphoramides: Acetate Aldol eaction! Variation in the trichlorosilyl enol ether component Si 3 5 mol % catalyst C 2 2, -78 C 93-98% yield 49-87% ee =, nbu, ibu, ir, tbu,, C 2 Si 3 tbu! Variation in the aldehyde component nbu Si C 2 2, -78 C nbu 79-95% yield 84-92% ee = cinnamyl,!-methylcinnamyl, naphthyl, 4-phenyl-phenyl, cyclohexyl, tbu The catalyst! Trichlorosilyl enol ethers are prepared from the corresponding trimethylsilyl enol ethers by treatment with Si 4 and catalytic g(ac) 2 Denmark, S. E., et al., J. rg. Chem., 1998, 63, 918. Enantioselective Catalysis by osphoramides: Syn and Anti Aldol eactions! ropionate aldol with various aldehydes Si 3 15 mol % catalyst C 2 2, -78 C 6-8 hours = cinnamyl, naphthyl, phenyl, tolyl, crotyl 89-97% yield 3:1-18:1 syn:anti 84-96% ee The uncatalyzed reaction at 0 C is slightly anti selective (2:1)! Enforced E-enol silane aldol reaction: anti selective Si 3 C 2 2, -78 C 2hours 94-98% yield 61:1-99:1 anti:syn 94-98% ee = cinnamyl,!-methylcinnamyl, naphthyl, phenyl The uncatalyzed reaction at 0 C is very syn selective (5:1-49:1) The catalyst Denmark, S. E., et al., J. Am. Chem. Soc., 1996, 118, Denmark, S. E., et al., J. Am. Chem. Soc., 1997, 119, 2333.

10 Enantioselective Catalysis by osphoramides: chanism of the Aldol eactions Si 3 catalyst 1 3 C 2 2, -78 C The catalyst! Chair-like transition state accounts for observed diastereo- and enantioselectivities Si exacoordinate silicate proposed Iseki, K., et al., Tetrahedron, 1997, 53, Catalysis Involving Enamine Intermediates: obinson Annulation! Initial report: ajos 3 mol% (S) - proline Ts DMF (anhydrous) 23 C, 20 hours Benzene (Dean-Stark) 92% yield 88% ee ajos, Z. G., J. rg. Chem., 1974, 39, 1615.! Extension to one-pot annulation: Barbas 35 mol% (S) - proline DMS (anhydrous) 35 C, 89 hours 49% yield 76% ee Barbas III, C. F., Tetrahedron Lett., 2000, 41, 6951.

11 Catalysis Involving Enamine Intermediates: chanism of the obinson Annulation C 2 C 2 2 C C 2 C 2! Chair-like transition state accounts for observed stereochemistry Agami, C., et al,, Tetrahedron, 1984, 40, ajos, Z. G., J. rg. Chem., 1974, 39, List, B., et al., J. Am. Chem. Soc., 2000, 122, Catalysis Involving Enamine Intermediates: Acetate Aldol eaction 20 vol. % 30 mol% (S) - proline DMS 23 C, 2-8 hours % yield % ee % yield % ee Br ! Enamine intermediate is proposed, in analogy to the obinson annulation Chair-like TS List, B., et al., J. Am. Chem. Soc., 2000, 122, 2395.

12 Catalysis Involving Enamine Intermediates: Anti Aldol eaction 20 vol. % mol% (S) - proline DMS 23 C, hours % yield anti:syn % ee % yield anti:syn % ee 60 >20:1 >99 62 >20:1 >99 tbu :1 > : :1 >97 51 >20:1 >95 List, B., et al., J. Am. Chem. Soc., 2000, 122, Catalysis Involving Enamine Intermediates: chanistic Aspects of the Anti Aldol eaction 20 vol. % mol% (S) - proline DMS 23 C, hours! E-enamine geometry due to minimization of A(1,3) strain C 2 A(1,3) strain C 2 Minimization of A(1,3) strain Z-enamine E-enamine! Chair-like transition state is proposed! Boat-like transition state explains origin of syn isomer for less hindered and!-oxygenated aldehydes anti syn List, B., et al., J. Am. Chem. Soc., 2000, 122, 7386.

13 Catalysis Involving Enamine Intermediates: Mannich eaction solvent 2 35 mol% (S) - proline 23 C, hours M % yield % ee % yield % ee ! ydroxy acetone can be used in place of acetone solvent 2 35 mol% (S) - proline DMS 23 C, 12 hours M 57% yield 17:1 anti:syn 65% ee List, B. J. Am. Chem. Soc., 2000, 122, Catalysis Involving Enamine Intermediates: chanistic Aspects of the Mannich eaction solvent 2 35 mol% (S) - proline 23 C, hours M! Two potential transition states proposed boat-like TS chair-like TS ' M ' M destabilizing transannular interactions = or Z-enamine when = allowed due to -bonding = or! pposite sense of stereoinduction observed compared to proline-catalyzed aldol reactions Chair-like TS of aldol reaction disfavored ' ' destabilizing A(1,3) interactions in minor resonance contributor M not observed List, B. J. Am. Chem. Soc., 2000, 122, 9336.

14 Catalyst as ucleophilic Trigger: Baylis-illman eaction CF 3 CF 3 DMF, -55 C CF 3 CF 3 time (hours) % yield % ee p cinnamyl Et (C 3 ) 2 CC 2 (C 3 ) 2 C cyclohexyl tbu Quinidine-derived catalyst! ester is less reactive, requiring higher temperatures, resulting in lower ee's 1 atakeyama, S., et al., J. Am. Chem. Soc., 1999, 121, Catalyst as ucleophilic Trigger: chanism of the Baylis-illman eaction 1 reversible addition 1 Y C Minimizes steric interations, and so is favored thermodnamically = Y = atakeyama, S., et al., J. Am. Chem. Soc., 1999, 121,

15 Catalyst as ucleophilic Trigger: [32] Cycloaddition C benzene, 23 C C C 2 1 C 2 4 C = Et, tbu 2 =, C 2 Et 3 =, C 2 4 = Et, ibu,, tbu A % yield = A:B = 94:6-100:0 B =, ir % ee (A) = ophabicyclic catalysts! Best case: C 2 ibu C C 2 Et C 2 Et C 2 ibu 88 % yield 100:0 = A:B 93 % ee! Size of 4 alters enantioselectivity! igid catalyst structure is important for enantioselectivity Zhang,., et al., J. Am. Chem. Soc., 1997, 119, Catalyst as ucleophilic Trigger: chanism of [32] Cycloaddition C 2 ibu 3 C 2 Et C C 2 Et C 2 Et C 2 Et 3 3 C 2 ibu C 2 ibu C 2 ibu 3 C 2 Et 3 C 2 Et! Concerted bond rearrangement ibu 2 C! Concerted mechanism supported by preservation of olefin geometry! Achiral version of this reaction reported by iyan Lu: J. rg. Chem., 1995, 60, Et 2 C Zhang,., et al., J. Am. Chem. Soc., 1997, 119, 3836.

16 Chiral Ketone Catalyzed Alkene Epoxidation: Initial eport from Shi mol % catalyst xone 2 -C 3 C % yield % ee catalyst! eaction tolerates alkyl, aryl, heteroatom-containing substituents! Catalyst works well with trans disubstituted olefins and trisubstituted olefins! epresentative examples: TBS 78 % yield 94 % yield 83 % yield 76 % yield 99 % ee 96 % ee 95 % ee 91 % ee C tbu 89 % yield 97 % yield 35 % yield 94 % yield 97 % ee 87 % ee 91 % ee 98 % ee Chiral Ketone Catalyzed Alkene Epoxidation: chanism of the Shi Epoxidation Shi, Y., et al., J. Am. Chem. Soc., 1997, 119, mol % catalyst xone 2 -C 3 C catalyst! Catalytic Cycle! roposed spiro TS 1 2 S S 4 Shi, Y., et al., J. Am. Chem. Soc., 1997, 119, Catalyst system also works for conjugated dienes: J. rg. Chem., 1998, 63, hydroxy alkenes: J. rg. Chem., 1998, 63, conjugates enynes: J. rg. Chem., 1999, 64, ,2-disubstituted vinylsilanes: J. rg. Chem., 1999, 64, kinetic resolution of racemic cyclic olefins: hydroxy alkenes: J. Am. Chem. Soc., 1999, 121, 7718.

17 Chiral Ketone Catalyzed Alkene Epoxidation: cis lefins with Shi's Catalyst mol % catalyst xone 1 2 -C 3 C % yield Boc % ee catalyst! eaction tolerates cyclic and acyclic alkenes! eaction requires either 1 or 2 have!-electrons or a heteroatom! epresentative examples:! roposed spiro TS 87 % yield 91 % ee 88 % yield 84 % ee Boc (!) 61 % yield 82 % yield 97 % ee 91 % ee Shi, Y., et al., J. Am. Chem. Soc., 2000, ASA. Chiral Ketone Catalyzed Alkene Epoxidation: Initial eport from Yang xone/ac C 3 C % yield % ee! eaction tolerates alkyl, aryl substituents! Catalyst works with trans disubstituted olefins and trisubstituted olefins catalyst! epresentative examples: tbu 99 % yield 47 % ee tbu 95 % yield 76 % ee 83 % yield 33 % ee Yang, D., et al., J. Am. Chem. Soc., 1998, 120, 5943.

18 Chiral Ketone Catalyzed Alkene Epoxidation: Developments by Yang! Modifications to catalyst increase ee of stilbene reactions tbu tbu tbu xone/ac 3 2 -C 3 C tbu % ee! Stereochemical ationale for Yang Epoxidation (Macromodel) Br 95 Yang, D., et al., J. Am. Chem. Soc., 1998, 120, catalyst! More ketone catalyzed epoxidation: Denmark, et al., J. rg. Chem., 1997, 62, mstrong, A., et al., Chem. Commun., 1998, 621. Amine Catalyzed Alkene Epoxidation 5 mol% amine xone (2 eq.) C 3 C: 2 (95:5) ac 3 (10 eq.) pyridine (0.5 eq.) 96% yield ( 1 M) 57% ee Amine Catalyst! The hit parade: 90% yield ( 1 M) 15% ee 20% yield ( 1 M) 25% ee 65% yield ( 1 M) 15% ee 21% yield ( 1 M) 13% ee 93% yield ( 1 M) 9% ee! Stilbenes and disubstiuted aliphatic alkenes do not react Adamo, M. F., et al., J. Am. Chem. Soc., 2000, 122, 8317.

19 adical Cation Intermediates: Amine Catalyzed Alkene Epoxidation roposed catalytic cycle for the alkene epoxidation ationale for bserved Stereochemical utcome KS SET SET face of epoxidation KS 4 KS 5 Adamo, M. F., et al., J. Am. Chem. Soc., 2000, 122, In Conclusion! Many reactions are catalyzed enantioselectively by organic molecules.! These reactions can be grouped by the mode of catalysis, deriving from the fact that numerous, quite different approaches to organic catalysis have been developed.! Despite much success, often the organocatalyzed reactions lack generality (low yields, low ee's, and/or poor substrate scope).! As well, the modes of catalysis often lack generality -- rarely has a catalyst system been applied successfully to several different reactions.! Consequently, vast room for improvemet remains; these examples may act as food for thought.

Asymmetric Catalysis by Lewis Acids and Amines

Asymmetric Catalysis by Lewis Acids and Amines Asymmetric Lewis acid catalysis - Chiral (bisooxazoline) copper (II) complexes - Monodentate Lewis acids: the formyl -bond Amine catalysed reactions Asymmetric