Asymmetric Organocatalysis Using Chiral Amines

Transcription

1 Asymmetric rganocatalysis Using Chiral Amines Contents: Background Aldol reactions Mannich reactions Amination/xidation reactions Michael reactions Cycloaddition reactions Alkylation reactions C 2 S C 2 2 An Evans Group Friday Seminar Jonathan Lawrence ovember 14 th 2003 event eviews: List, B. "Proline Catalyzed Asymmetric eactions", Tet. 2002, 58, Miller, S. "Amino Acids and Peptides as Asymmetric rganocatalysts", Tet. 2002, 58, List, B. "Asymmetric Aminocatalysis", Synlett 2001, 11, Dalko, P. "Enantioselective rganocatalysis", ACIEE 2001, 40, ther Chiral Amines Cinchona alkaloids: The "nucleophilic" catalysts =, = [(-)-quinine] =, = [(-)-cinchonidine] = [(+)-quinidine] = [(-)-cinchonine] eviews: Pracejus,. Fortschr. Chem. Forsch, 1967, 8, 493. Morrison, J., Mosher,. Asymmetric rganic eactions; Prentice-all: Englewood Cliffs, Wynberg,. Top. Stereochem. 1986, 16, 87. elevant Group Seminars: Karl Scheidt, Asymmetric Catalysis with Chiral Lewis Bases (Part I), March 2001 emaka ajapakse, onmetal-based Asymmertic Catalysis (Part II), March 2001 Essa u, Asymmetric Catalysis with Chiral Lewis Bases (Part III), March 2001 Jake Janey, Asymmetric Catalysis with Chiral Lewis Bases (Part IV), March /20/03 5:26 PM

2 Preliminary Findings Yamada, 1969: C + C 2 preformed enamine /benzene 1:9 Ac, 2 C Yamada, S. TL 1969, 10, % ee The Seminal Experiments 3 mol% L-proline DMF, 20h, rt = = Et 100%, 93% ee 71%, 99% ee 3 mol% L-proline DMF, 72h, rt 52% 74% ee the use of protic solvents severly diminishes enantioselectivity other amino acids as catalysts lead to decreased chemical yield and enantioselectivity Eder, Sauer, and Weichert obtained the corresponding aldol condensation products in similar optical purity using 47 mol% L-proline and 1 Cl 4 ajos, J., Parrish, D. JC 1974, 39, Eder, U., Sauer, G., Weichert,. ACIEE 1971, 10, /20/03 3:24 PM

3 Effect of the Catalyst DMF C 2 "major product" racemic DMF C 2 racemic "major product" C 2 no reaction DMF ajos, J., Parrish, D. JC 1974, 39, Transition States Agami, ouk, C general hydrogen bond energies kcal -C kcal C 2 - favorable (enamine) ---- hydrogen bond - anti to carboxylate electrostatically favored reaction is second-order in proline (non-linear effect observed) second proline acts as a proton shuttle, allowing enamine to be nucleophilic /20/03 3:26 PM Agami, C. TL 1986, 13, ouk, K. JACS 2001, 123, ouk, K., List, B. JACS 2003, 125, hydrogen bond does not lower energy of transition state favorable ---- hydrogen bond additional C---- hydrogen bond further stabilizes system reaction is first order in proline (supported by kinetic data) and no non-linear effect observed for a discussion on 3 +-C----=C bonds, see: ouk, K. JACS, 2002, 124, 7163.

4 The initial reaction: Direct Aldol Addition 1 20 vol% mol% L-proline DMS, 4hr, rt 68% 76% ee 2 Catalyst screen: (selected examples) compound % yield % ee compound % yield % ee (L)-is, (L)-Val < (L)-Tyr, (L)-e C 2 C < List, B., Barbas, C. JACS, 2000, 122, *Barbas, C. JACS, 2001, 123, S C 2 C 2 C 2 S C > * Substrate scope: variation of the aldehyde Direct Aldol Addition 2 C 2 S C product = cat. % yield % ee product = cat. % yield % ee Cl Br List, B. JACS, 2000, 122, Barbas, C. JACS, 2001, 123, DMTC 2 is catalyst of choice for aromatic aldehydes, although chemical yield decreases due to slower rate of reaction α unbranched aldehydes yield no appreciable amount of product with proline catalyst 1 due to enolization and self-aldolization under reaction conditions (DMS/acetone = 4:1) /20/03 3:28 PM

5 Substrate scope: variation of the ketone donor Direct Aldol Addition 3 1 C 2 S C mol % catalyst 2 1 DMS, rt, 24-48hr 2 product = cat. % yield % ee 2 2 Barbas, C. JACS, 2001, 123, < syn anti syn anti Substrate scope: use of α-unbranched aldehydes Direct Aldol Addition 4 20 mol% + 20 mol% L-proline CCl 3, rt, 3-7 d product = % yield 1 % yield 2 % ee * * product = % yield 1 % yield 2 % ee * * reaction performed neat in acetone List, B. L 2001, 3, 573. use of cyclic ketones (cyclopentanone, cyclohexanone) result in moderate yield and diastereoselectivity, and up to 95% ee enone products arise from a Mannich addition-elimination sequence /20/03 3:29 PM

6 Direct Aldol eaction chanism C previously proposed T.S.: metal-free Zimmerman-Traxler model ouk's calculated T.S. 1 2 synclinal approach of aldehyde 1 in pseudo-eqitorial position C- - - distance ~ 2.4 Α DFT calculations in DMS List, B. JACS 2000, 122, List, B., ouk, K. JACS 2003, 125, Synthesis of Anti-1,2-Diols 20 mol% catalyst DMS/acetone 4: hr, rt C 2 S C product = cat. dr % yield % ee 1 >20:1 60 >99 2 >20: product = cat. dr % yield % ee 1 1: (n.d.) 2 1: (50 ) 1 >20:1 62 > < : (33) <5 --- * Cl 2:1 1 >20:1 51 > < :1 38 >97 (84 ) < : (32) 2 3: (78) 1 2:1 40 >97 (97 ) <5 --- List, B. JACS, 2000, 122, Barbas, C. JACS, 2001, 123, more substituted enamine formed due to: increased acidity of proton removed increased stability of enamine due to n.b. --> π* C=C /20/03 3:30 PM

7 Use of Aldehydes as Donors in Direct Aldol 2 equiv mol% L-proline DMF, hr, 4ºC product = dr % yield % ee 4: : : : product = dr % yield % ee Bu Bn 24:1 82 >99 24: : reaction requires lower catalyst loading, shorter times, and only 2 equivalents of aldehyde donor MacMillan, D. JACS, 2002, 124, Trimerization of Acetaldehyde mol% L-proline TF, 0ºC, 5hr 10% 90% ee TF at 0ºC was found to be the optimal conditions for yield and ee rt = 13% y, 57% ee, CCl rt = 2 % y, 68 % ee) chanism: C C 2 C 2 C 2 Mannich condensation C 2 Barbas, C. JC, 2002, 67, /20/03 3:31 PM

8 Propionaldehyde Trimerization A method for carbohydrate assembly 3 10 mol% L-proline DMF, 4ºC, 3d 6% 1:2 α:β, 11% ee 47% reaction analygous to an aldolase enzyme that furnishes the minor product shown above propionaldehyde added slowly dropwise in order to obtain trimer over dimer products enantioselectivity erodes with longer reaction times (after 10 hr product ee = 47%) substituent at C-6 variable by using 1 eq. of corresponding aldehyde and 2 eq. of propionaldehyde Barbas, C. TL, 2002, 43, chanism of Propionaldehyde Trimerization L-proline L-proline 1 2 L-proline L-proline incubating isolated 1 with L-proline led to formation of 2 through epimerization (1:1 ratio of 1:2 after 96 hr) Barbas, C. TL 2002, 43, /20/03 3:34 PM

9 Aldehyde Aldol Addition to Activated Carbonyl Compounds Et 2 C C 2 Et 20 mol% L-proline C 2 Cl 2, 1-3 hr, rt C 2 Et C 2 Et product = % yield % ee Et i-pr Et 2 C C 2 Et n-ex Jorgensen, K. Chem. Comm. 2002, protection of the aldehyde as the dioxolane prevents epimerization of the α center during column chromatography ther Chiral Amine Catalysts for the Direct Aldol Addition Chiral diamines: 1 2 catalyst 30ºC, 2hr 3 4 product = cat. % yield 3 % ee % yield mol% 1 2Tf mol% 1 3 mol% mol% 1 2Tf mol% 1 3 mol% proposed mechanism similar to that of proline catalyzed reactions, with proton transfer from protonated tertiary to Yamamoto, Tet. 2002, 58, /20/03 3:35 PM

10 Mannich eaction: First eport equired Conditions: enamime addition must be faster to the imine than to the corresponding aldehyde formation of the aldimine from a primary amine must be faster than the aldol addition M studies show that Keq(aldehyde imine) = 1 ' 2 ' ' k Aldol K eq =1 k Mannich 3-component reaction verifies hypotheses: C vol% 1 equiv. 1.1 equiv. 35 mol% L-proline acetone/dms 1:4 12 hr 50% 94% ee 2 (+ <20% aldol product) List, B. JACS, 2000, 122, mol% proline and 1.3 eq ketone used without loss of efficiency Mannich eaction: Scope Variation of the ketone donor: C 2 35 mol% L-proline 1.1 eq. p-anisidine acetone/dms 1:4 12 hr, rt PMP 2 = product % yield dr % ee List, B. JACS, 2000, 122, PMP Ar PMP Ar PMP Ar PMP Ar >20: >20: >20: >20:1 > /20/03 3:36 PM

11 Mannich eaction: Transition States Mannich C 2 Aldol non-bonding interactions govern which diastereoface of electrophile is favored Ar List, B. JACS 2002, 124, 827. Mannich eaction: Scope 2 Variation of the aldehyde: aliphatic aldehydes, including α-unbranched are good substrates (60-90% yield, 73-93% ee) aromatic aldehydes are excellent substrates, (79-92% yield, 61-99% ee) Effect of electron donation from the aldehyde: Variation of the catalyst: PMP = % yield dr % ee C 88 15: : : :1 61 proline proves to be the best catalyst, with other catalysts affording reduced yield and optical purity. eaction of acetone with isovaleraldehyde: List, B. JACS 2002, 124, 827. S C 2 60% y., 16% ee 26% y., 0% ee /20/03 3:37 PM

12 Addition of ketones: 1 α-imino Ethyl Glyoxylate as Mannich Acceptor 1 An entry to α-amino acids 2 20 vol% PMP Et 20 mol % L-proline DMS, 2hr, rt product % yield dr % ee 1 2 PMP C 2 Et Barbas, C. JACS 2002, 124, 1842 PMP C 2 Et 2 PMP C 2 Et PMP C 2 Et PMP C 2 Et = 72 >19:1 >99 allyl 79 >19:1 >99 62 >19: >19:1 >99 81 >19:1 >99 Addition of aldehydes: α-imino Ethyl Glyoxylate as Mannich Acceptor 1 An entry to α-amino acids 20 vol% PMP Et 5 mol % L-proline dioxane, 2-24hr, rt = % yield dr % ee :1 99 Et :1 99 i-pr 81 >10:1 93 n-bu 81 3:1 99 n-pent 89 >19:1 >99 71 >19:1 >99 PMP C 2 Et aqueous workup or column chromatography may lead to decreased diastereoselectivities reaction has been performed in aqueous media (Barbas, TL 2003, 44, 1923) Barbas, C. JACS 2002, 124, /20/03 3:38 PM

13 Anti-Selective Mannich eaction Addition of aldehydes: 20 vol% PMP Et 20 mol% DMS, 24-48h, rt PMP C 2 Et = % yield dr % ee Et 44 1:1 75 i-pr 52 10:1 82 n-bu 54 10:1 74 t-bu 57 >10:1 92 n-pent 78 >10:1 76 n-ex 68 >19:1 76 Barbas, C. TL 2002, 43, proposed transition state C 2 Et For a review of SMP use in asymmetric synthesis, see: Enders, D. Synthesis 1996, bettter? C 2 Et Addition of aldehydes: Direct α Amination 1 Cbz Cbz 10 mol% L-proline C 3 C, 0 ºC-rt, 3 hr then ab 4, Et Cbz Cbz 1.5 equiv. 1 equiv. = % yield % ee 97 >95 n-pr 93 >95 n-bu i-pr Bn 95 >95 Bn 2 C C 2 Bn longer reaction time leads to epimerization, so aldehyde is reduced in situ List, B. JACS 2002, 124, /20/03 3:39 PM

14 Direct α Amination 2 Addition of ketones: 1 2 Et 2 C C 2 Et 10 mol% L-proline C 2 Et C 2 Et 1 C 3 C, 1-4d, rt 2 2 C 2 Et C 2 Et 1 2 product 1 ratio 1:2 % yield (1+2) % ee Jorgensen, JACS 2002, 124, Et C 2 Et C 2 Et C 2 Et C 2 Et Bn C 2 Et C 2 Et i-pr C 2 Et C 2 Et 10: (93) 4.5: (94) 3: (99) (93) α xidation of Aldehydes with itrosobenzene 1 The choice of reaction conditions determine or selelctive addition: uncatalyzed =Li, SnBu 3, Si 3 Lewis acid =Si 3 Yamamoto,. L, 2002, 4, Larger basicity of nitrogen allows proline to catalyze -nucleophilic addition: 5 mol% L-proline CCl 3, 4 ºC, 4 h /20/03 3:40 PM a possible transition state MacMillan, D. JACS 2003, 125,

15 Aldehyde scope: α xidation of Aldehydes with itrosobenzene 2 3 equiv. 1 equiv. 5 mol% L-proline CCl 3, 4 ºC, 4 h = % yield % ee n-bu i-pr C 2 C=C = % yield % ee Bn (C 2 ) 3 TIPS C 2 -( 3 ' methyl indole) MacMillan, D. JACS 2003, 125, product most easily isolated as the primary alcohol (ab 4 reduction) Asymmetric rganocatalysis of the Michael eaction Two mechanistic possibilities exist: EWG or :u enamine imminium Examples include: additions to: alkylidene malonates α,β unsaturated nitroalkenes additions of: malonate esters nitroalkanes aromatics (Friedel-Crafts reactions) silyloxy furans Diels-Alder reaction Dipolar cycloaddition /20/03 3:41 PM

16 Michael Additions using Enamine Catalysis: Moderate Success has been Achieved S 100 mol% L-proline S DMF, -15ºC, 7d 81% 28% ee Kozikowski, A. JC, 1989, 54, Bn C 2 Et 100 mol% L-proline DMF, rt, 7d 45% Bn C 2 Et 34% ee Momose, T. J.Chem.Soc., Perkin Trans., 1992, 509. Enamine Catalysis: Examples 2 ecent examples: List: 2 15 mol% L-proline DMS, 24 hr, rt 97% 7% ee 2 Enders: List, B. L 2001, 3, mol% L-proline, 24 hr, rt 74% Et 2 use of as solvent increases ee 73% ee, dr=7.3:1 Enders, Synlett 2002, /20/03 3:42 PM

17 Enamine Catalysis: Examples 3 ecent examples: Barbas: Et Et 20 mol% TF, rt 59% Et 2 C C 2 Et 47% ee Barbas, C. TL, 2001, 42, mol% 2 proposed transition state: TF, rt 85% 2 Et = 56% ee, dr=9:1 = i-pr 72% ee, dr=11:1 2 2 Barbas, C. L 2001, 3, A ighly Enantioselective Michael Addition Using Enamines A ew Chiral Diamine Catalyst 10 equiv. 15 mol% 2 CCl 3, rt, 7 d 2 syn/anti yield dr ee 75 1: : Alexakis, A. L, 2003, 5, with variation of aromatic group on nitroolefin: ee = 96-98% dr = 3.5:1-19:1 selection of aromatic groups used: tolyl, p-methoxyphenyl, p-chlorophenyl, 2-thienyl /20/03 3:43 PM

18 Imminium Catalysis of Conjugate Additions 1 Proline has been used with only mild success: i-pr i-pr 5 mol% CCl 3, rt 91 % C 2 b C 2 i-pr C 2 i-pr 58% ee Proline rubidium salt gives lower ee in the ajos-parrish-weichert reaction 2 5 mol% CCl 3, rt 74 % 68% ee C 2 b 2 Yamaguchi, JC 1996, 61, MacMillan Introduces A ew Catalyst Imminium ion formation lowers the LUM of the system and allows catalysis to occur: LUM versus LUM E M M L.A. Consensation of an aldehyde with the catalyst produces an imminium complex: /20/03 3:44 PM PM3 minimized structure :u

19 Diels-Alder Cycloaddition 1 5 mol% 1-2, rt C hr endo exo C Dienophile scope: = % yield endo:exo % ee(endo) % ee(exo) 75 1: n-pr 92 1: i-pr 81 1: : Cl 1 Furyl 89 1: MacMillan, D. JACS 2000, 122, Diels-Alder Cycloaddition 2 Diene scope: 20 mol% 1-2, rt -24 hr 12 C endo adduct diene product % yield exo:endo % ee C 75 35:1 96 C C C 82 1: Cl 1 C 75 1:5 90 Ac MacMillan, D. JACS 2000, 122, /20/03 3:45 PM Ac C 72 1:11 85

20 Ts C Application to Complex Synthesis SC Ts Cl 40 mol% DMF/ (1:1) 5% 2, 36 h 35 % yield, % de (endo) 70 Ts C exo (92% ee) C endo (93% ee) Ts Kerr, M. JACS 2003, ASAP (+)-apalindole Q itrone Cycloaddition Z 1 20 mol% catalyst ºC Z C endo 1 Z C exo 1 Z 1 endo:exo yield ee (endo) Bn 94: allyl 93: : Bn C 6 4 Cl-4 92 : C 6 4 Cl-4 93 : Bn C : C : Bn 2-napth 95 : Bn c-ex 99 : Bn 81 : Bn 86 : Bn C 6 4 Cl-4 85: Bn C 6 4 Cl-4 80: Bn 2-napth 81: Bn C : Cl 4 catalyst Cl 4 proved to be the best Bronsted acid cocatalyst to promote only enantioselective catalysis high endo selectivity attributed to to favorable placement of group away from geminal dimethyl substituents on catalyst MacMillan, D. JACS 2000, 122, b-39 11/20/03 3:46 PM

21 Friedel-Crafts Alkylation 1: Pyrroles 20 mol% catalyst TF- 2, 3-5 d temp(ºc) yield ee n-pr i-pr PMP C 2 Bn C Substitution on the pyrrole is also possible: TFA catalyst use of -benzyl pyrrole and -allyl pyrrole give similar results Bu 20 mol% catalyst TF- 2, 3-5 d Bu 87% y, 90% ee Pr MacMillan, D. JACS 2001, 123, mol% catalyst TF- 2, 3-5 d Pr 68% y, 97% ee Alkylation of Indoles 1 The need for a new amine catalyst: 20 mol% TFA C 2 Cl 2, - 40 ºC, 2 d 83 % 58% ee Indole is less electron-rich than pyrrole, so is less nucleophilic toward conjugate addition Second generation catalyst: a more reactive variant C 3 - lone pair interaction lone pair exposed Kinetic studies indicate rate of reaction influenced by imminium formation as well as carbon-carbon bond forming event MacMillan, D. JACS 2002, 124, /20/03 3:47 PM

22 Alkylation of Indoles 2 20 mol% catalyst TF- 2, 3-5 d TFA catalyst temp(ºc) yield ee n-pr i-pr C 2 Bz C MacMillan, D. JACS 2002, 124, An increase in rate of reaction and enantioselectivity: :u increased top-face coverage nucleophile-geminal dimethyl interation removed Z Alkylation of Indoles 3 Z 20 mol% catalyst Y 1 C 2 Cl 2 -i-pr, 3-24 hr Y Indole Scope: Y Z 1 temp(ºc) % yield % ee allyl Bn C 2 Bz C 2 Bz Cl -C 2 Bz Application to Simple Synthesis: Br MacMillan, D. JACS 2002, 124, /20/03 3:48 PM mol% catalyst C 2 87% ee, 82% y. 2. Ag 3, a C-2 inhibitor Br

23 Alkylation of Benzenes 2 Z 10 mol% catalyst C 2 Cl 2, 2-4 d 2 Z 2 aniline temp(ºc) % yield % ee Et C 2 Bz C 2 Bz C C p-cl p p MacMillan, D. JACS 2002, 124, Mukaiyama-Michael eaction 1 Cl catalyst other substituted anilines used with similar results catalyst loading can be lowered to 1% without significant loss of yield and enantioselectivity Previous Michael additions with silyloxy furans: TMS Chiral Lewis Acid (bisoxazoline or pyridyl bisoxazoline ligands) Katsuki, Tet. 1997, 53, Desimoni, G. Tet. 2001, 57, note that Lewis acids promote 1,2-addition products when possible, such as α,β unsaturated enals ptimized reaction conditions: TMS /20/03 3:49 PM 20 mol% catalyst C 2 Cl 2, 2 equiv 2 temp (ºC) % yield syn:anti % ee :1 92 n-pr :1 84 i-pr : :6 99 C 2 Bz : 1 90 C : 1 99 DBA catalyst MacMillan, D. JACS 2003, 125, 1192.

24 Mukaiyama-Michael eaction 2 Variation of the silyloxy furan TMS 20 mol% catalyst C 2 Cl 2, 2 equiv 2 % yield syn:anti % ee 87 8: :1 92 Et 83 16:1 90 C : 1 98 C : 7 98 TFA as cocatalyst Tf as cocatalyst : 1 90 MacMillan, D. JACS 2003, 125, Bn 2 C C 2 Bn 1 2 Another Chiral Amine Catalyst Asymmetric Michael Additions 10 mol% Bn neat, rt C 2 Bn 2 C 1 C 2 Bn % yield % ee p p furyl pyridyl n-bu i-pr C Et i-pr 2 94 C 2 :u itroalkane additions to α,β unsaturated ketones has also been performed in good to excellent selectivity (Jorgensen, K. JC 2002, 67, 8331.) Jorgensen, K. ACIEE 2003, 42, /20/03 3:50 PM

25 A Listing of ther Asymmetric rganocatalytic eactions [4+3] cycloadditions: TMS C 20 mol% C TFA C 2 Cl 2, - 78 ºC, 4 d 64 % endo only (89% ee) Michael eactions: armata, M. JACS, 2003, 125, mol% C 2 Cl 2, rt C % ee Tandem Knoevenegel-Diels-Alder eactions: 2 S C 2, rt, 4 d 88% Jorgensen, K. ACIEE 2003, 42, 4955 p- 2 86% ee Barbas, C. ACIEE 2003, 42, /20/03 3:51 PM Summary eactions are direct: Donors can be used without modification -- no need to deprotonate or silylate prior to reaction Electrophiles can be generated in situ (Mannich reaction) most of the time Catalysts are: inexpensive commerially available or easily prepared in both enantiomeric forms non-toxic recoverable Many reactions can be run at room temperature, under an aerobic atmosphere, with wet solvents Many types of reactions can be catalyzed; for some reactions, organocatalysis is the only highly efficient way known (Mannich and Mukaiyama-Michael additions) eaction yield and enantioselectivity is highly dependent on solvent system so require "fine tuning" nly reactions that use ketones or aldehydes as donors (electrophiles for Michael additions) can be catalyzed rganocatalysis using small molecules is a field that has emerged only within the past decade. It is bound to receive increasing attention in the future; as a result, new catalysts will emerge which will allow for the catalysis of reactions previously unutilized in the realm of organocatalysis.