Lewis Base Catalysis: the Aldol Reaction (Scott Denmark) Tom Blaisdell Friday, January 17 th 2014 Topic Talk

Transcription

1 Lewis Base Catalysis: the Aldol eaction (Scott Denmark) Tom Blaisdell Friday, January 17 th 2014 Topic Talk

2 Scott E. Denmark S.B. in Chemistry MIT (ichard. olm and Daniel S. Kemp) D.Sc in Chemistry - ET Zurich (Albert Eschenmoser) Assistant Professor - University of Illinois Associate Professor - University of Illinois Professor - University of Illinois eynold C. Fuson Professor of Chemistry - UIUC Main esearch Interests: Lewis Base Activation of Lewis Acids Palladium- Catalyzed Cross- Coupling of rganosilicon Compounds Tandem Cycloaddition Chemistry of Nitroalkenes Asymmetric ase Transfer Catalysis/Chemoinformatics Aldol Chemistry: Mid- 1990s to mid- 2000s

3 The Aldol eaction ne of the most ubiquitous reactions in organic chemistry Provides numerous selectivity challenges (chemo-, site-, enantio- and diastereoselectivity) continues to serve as a platform for the demonstration of conceptual advances in the ^ield [of organic chemistry]

4 The Aldol eaction TMS Ti 4 C 82% 3:1 syn:anti Mukiyama, T. Chem. Lett. 1973, 9, 1011 B(nBu) 2 N C N >500:1 syn:anti Evans, D. J. Am. Chem. Soc. 1981, 103, 2127

5 Formation of Enoxyborinates and Enoxysilanes B(nBu) Enoxyborinates TMS 1 2 Enoxysilanes Most stable and widely used enolates Allowed for identi^ication of which carbonyl was acting as the nucleophile (site and chemoselectivity) Both have unique reactivity (diastereo- and enantioselectivity)

6 Enoxyborinates Coordination of the aldehyde to the boron is necessary Proceeds through a predictable chair- like transition state B(nBu) 2 Et >97:3 Z/E C C 2 2 Et C Et 77% yield >97:3 syn/anti Et nbu B nbu nex B C C 2 2 Et C 4:96 syn/anti cpent B nex Evans, D. J. Am. Chem. Soc. 1981, 103,

7 Enoxysilanes Unlike boron, the silicon atom is not lewis acidic enough to bind and activate the aldehyde. Cannot form a six- membered transition state equires a secondary Lewis acid for activation and therefore undergo an open transition state Et TMS >99:1 Z/E C BF 3 -Et 2 C C Et 62% yield 60:40 syn/anti TMS C Sn 2 TMS C C 82% yield 70:30 anti/syn eathcock, C. Tetrahedron Le , 25, Mukiyama, T. Chem. Le7., 1987,

8 Enoxysilanes EtS TMS N Ch TMS N Sn(Tf)2 (20 mol %) EtS EtCN 77% 92:8 syn/anti 20 mol % 95:5 e.r. nbu TMS C 2 B 20 mol % Ch EtCN TMS nbu 97% 93:7 syn/anti 97:3 e.r. Mukiyama, T. Chem. Le7., 1990, Yamamoto. J. Am. Chem. Soc. 1991, 113, Nelson, Tetrahedron Asymmetry, 1998, 9,

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10 Denmark s Approach Combining the inherient properties of both enoxyborinates and enoxysilanes Enoxyborinates: Predictable six- membered TS to control diasteroselectivity Enoxysilanes: Able to establish asymmetric control 1. Enoxysilacyclobutanes 2. Lewis base catalysis as a means of activating the metal center tbu LB* ML n

11 Enoxysilacyclobutanes G* 'C ' ' G* '

12 Enoxysilacyclobutanes Strain release Lewis acidity: L L tetrahedral C 2 2 N N rt anti Nu - 90 C anti/syn yield, % 97:3 77 ipr >99:1 72 Et 97:3 58 L L Nu trigonal bipyramid N syn N N Myers, A. J. Am. Chem. Soc. 1990, 112, Myers, A. J. Am. Chem. Soc. 1992, 114,

13 Enoxysilacyclobutanes 1. C C 6 D 6, 100 C 2. F, TF 85:15 syn/anti t 1/2 = 13.3 h tbu 1. 'C CD 3 2. F, TF syn anti 1. C C 6 D 6, 100 C 2. F, TF No eaction E/Z t 1/2 (h) yield (%) syn/ anti 95/ /5 89/11 cinnamyl /7 89/11 n- pentyl /7 89/11 cyclohexyl /1 0/ /58 Denmark, S. J. rg. Chem. 1993, 58,

14 Enoxysilacyclobutanes t-bus 'C CD 3, 20 C t-bus E/Z time (h) syn conv. (%) syn/ anti 4/ /2 4/96 cinnamyl /30 4/96 n- pentyl /10 4/96 cyclohexyl /20 100/ /15 ' t-bus anti ' Denmark, S. J. rg. Chem. 1993, 58,

15 Enoxysilacyclobutanes: chanistic Insight Intramolecular silicon group transfer Intermolecular silicon group transfer C 3 3 C CD 3 D 3 C C (2 eq) 20 C, 1M, benzene 1 h 3 C C 3 CD 3 C 3 D 3 C D 3 C 3 C >99% <1% CD 3 Denmark, S. J. Am. Chem. Soc. 1994, 116,

16 Enoxysilacyclobutanes: Stereochemical Model Twist boat conformation Chair conformation Steric hindrance of t- Bu group makes chair TS unfavorable Denmark, S. J. Am. Chem. Soc. 1994, 116,

17 Enoxysilacyclobutanes: Asymmetric Aldol * 60/40 vs C silyl 80/20 E/Z C M, toluene 2. F, TF - * temp, C syn/anti ee, % (- )- menthol 0 9/1 51 (- )- menthol - 60 >99/1 74 ()- 2,2- diphenylcyclopentanol - 60 >99/1 7 ()- endo- borneol - 60 >99/1 11 ()- trans- 2- phenylcyclohexanol - 60 >99/1 63 (- )- 8- phenylmenthol - 60 >99/1 95 ()- trans- 2- cumylcyclohexanol - 60 >99/1 97 Denmark, S. J. rg. Chem. 1994, 59,

18 Enoxysilacyclobutanes: Asymmetric Aldol S 92/8 Z/E 'C M, toluene -35 C, 2M, 7d 2. F, TF, 2 S ' yield, % ee, % benzaldehyde cinnamaldehyde p- anisaldehyde furual naphthaldehyde a,a,a- tri^luoro- p- tolualdehyde S g(ac) 2 (5 eq) Na 2 P 4 (5 eq), 12 h 94% ee 95% ee Denmark, S. J. rg. Chem. 1994, 59,

19 Denmark s Approach Combining the inherient properties of both enoxyborinates and enoxysilanes Enoxyborinates: Predictable six- membered TS to control diasteroselectivity Enoxysilanes: Able to establish asymmetric control 1. Enoxysilacyclobutanes 2. Lewis base catalysis as a means of activating the metal center tbu LB* ML n

20 Lewis Base Catalysis

21 What are we asking from this system? tal: must expand valence, needs to balance nucleophilicity of the enolate with the needed electrophilicity to coordinate both the aldehyde and Lewis base catalyst Ligands: must be small and strongly electron withdrawing Lewis basic group: Activate metal without cleaving M bond. Must impart asymmetric environment through single- point attachment

22 licon as a rganizational Center L D L L! X X L A D L X L!"!!" X X A X L D L L A X X X q() = q() = q() = q( eq ) = q( ax ) = q() = q() = Gordon, M. J. ys. Chem. 1990, 94,

23 Allylation Inspiration E 3 Z C 5 mol% (,)-1 ipr 2 EtN C 2 2, -78 C E Z E =, z = 82% yield, 1/99 syn/anti, 93:7 e.r. E =, z = 89% yield, 99/1 syn/anti, 97:3 e.r. N N P (C2 ) 5 P N N N N P(N 2 ) 3 - (,)-1 E Z P(N 2 ) 3 Denmark, S. J. rg. Chem. 1994, 59,

24 Trichlorosilyl Enolates: Uncatalyzed TMS g(ac) 2, 4 C 2 2, rt 3 TMS g(ac) 2, 4 C 2 2, rt 3 68% yield 66% yield A sieves, C NaC 3 (aq.) syn anti A sieves, C NaC 3 (aq.) syn anti C time, h syn/anti yield, % C time, h syn/anti yield, % a 6 49:1 92 a 10 1: c 8 16:1 90 b 10 1: d 1 49:1 83 c 16 1: e :1 86 d 10 1: g 2 36:1 91 f 16 1: g 11 1: = : a = Br: b C c C = : d = : e C f C g C Denmark, S. J. Am. Chem. Soc. 1997, 119,

25 Trichlorosilyl Enolates: Lewis Base Catalyzed 3 1. (S,S)-1 (10 mol %) C NaC 3 (aq.) syn C time, h anti syn/anti ee (anti), % yield, % a 2 1: c 2 <1: d 2 <1: e 2 <1: g 2 1: (S,S)-1 (15 mol %) 3 C NaC 3 (aq.) syn anti C time, h syn/anti ee (anti), % yield, % a 6 18: b 6 12: c 8 3: d 6 9.4: f 8 7: g 6 1: Aliphatic aldehydes did not react! Tentative model ' P(N 2 ) 3 = : a = Br: b f C C c C g C = : d = : e C N P N N (S,S)-1 Denmark, S. J. Am. Chem. Soc. 1997, 119,

26 Trichlorosilyl Enolates: chanistic Duality 3 1. phospharamide (10 mol %) C NaC 3 (aq.) syn anti N P N N (S,S)-1 N P N N (S,S)-2 95% yield syn/anti: 1/60 92% ee (anti) 94% yield syn/anti: 97/1 51% ee (syn) N P N N 3a: =; 3b: =i-pr; 3c: =; 3d: =1-naphth phosphoramide time, h syn/anti yield, % a 1.5 1: b 6 27:1 93 c :1 96 d :1 95 Denmark, S. J. Am. Chem. Soc. 1998, 120,

27 Trichlorosilyl Enolates: chanistic Duality 3 1. (S,S)-3c (x mol %) C NaC 3 (aq.) syn anti N P N N 3c 3c N P N N (S,S)-1 N P N N (S,S)-2 Denmark, S. J. Am. Chem. Soc. 1998, 120,

28 Trichlorosilyl Enolates: chanistic Duality N P N N (S,S)-1 3 N P N N (S,S)-2 (P(N 2 ) 3 ) (P(N 2 ) 3 (P(N 2 ) 3 anti syn Denmark, S. J. rg. Chem. 2006, 71,

29 Trichlorosilyl Enolates: Crossed- Aldol TMS n-c :1 Z/E 3 1. Li, Et 2 n-c % yield 99:1 Z/E N P N N (S,S)-1 (5 mol %) Et 3 N, TF, 2 n-c 5 11 n-c % 99:1 syn:anti 89% 99:1 syn:anti TMS n-c :1 E/Z 1. Li, Et n-c % yield 30:1 E/Z N P N N (S,S)-1 (5 mol %) Et 3 N, TF, 2 n-c 5 11 n-c % 1:18 syn:anti 90% 1:49 syn:anti Denmark, S. Angew. Chem. Int. Ed. 2001, 40,

30 Trichlorosilyl Enolates: Crossed- Aldol 1. 2 C (S,S)-4 (5 mol %) 3 1 C 3 /C C, 6 h 2. 1 N P 2 N N (C 2 ) (S,S)-4 enolate 1 2 yield, % syn/anti ee, % Z n- pentyl 92 95:5 90 E n- pentyl 91 3:97 82 Z 95 98:2 81 E 97 1:99 59 Z 2- naphthyl 99 99:1 86 E 2- naphthyl 99 2:98 53 Z c- C :3 44 E c- C : Denmark, S. Angew. Chem. Int. Ed. 2001, 40,

31 Trichlorosilyl Enolates: thyl Ketones 3 C 1. C 2 2, rt 2. NaC 3 n-bu 3 C 1. C 2 2, rt 2. NaC 3 n-bu enolate time, h yield, % enolate time, h yield, % a 7 91 b c 4 92 d 4 91 e 9 93 f n-bu C C a b c C 3 3 TBS C C d e f C Denmark, S. J. Am. Chem. Soc. 2000, 122,

32 Trichlorosilyl Enolates: thyl Ketones 3 1. (S,S)-1 (5 mol %) C 2 2, -78 C 2 h C 2. NaC 3 n-bu 3 1. (S,S)-1 (5 mol %) C 2 2, -78 C C 2. NaC 3 n-bu enolate ee, % yield, % enolate time, h ee, % yield, % a N P N N b c d e (S,S)-1 f C n-bu TBS C C a b c C C d e f C Non- branched aliphatic aldehydes did not react! Denmark, S. J. Am. Chem. Soc. 2000, 122,

33 Trichlorosilyl Enolates: thyl Ketones TMS 1. g(ac) 2, 4 C 2 2, rt 2. 5 mol % 1, C 3. NaC 3 (aq.) N P N N (S,S)-1 catalyst syn/anti yield, % TBS - 1: TBS (S,S) :1 85 TBS (,)- 1 73:1 85 Bn - 1: Bn (S,S)- 1 1: Bn (,)- 1 11:1 77 Denmark, S. J. Am. Chem. Soc. 2000, 122,

34 Trichlorosilyl Enolates: thyl Ketones TMS 1. g(ac) 2, 4 C 2 2, rt mol % (S,S)-1 C 3. NaC 3 (aq.) = : 65%, 75% ee = i-bu: 71%, 57% ee N P N N (S,S)-1 TMS 1. g(ac) 2, 4 C 2 2, rt 2. pump off volatiles n-bu 2. 5 mol % (S,S)-1 C 3. NaC 3 (aq.) n-bu 89%, 92% ee Can the Lewis base catalyzed aldol reacpon be made even more general? tbu 3? Denmark, S. J. Am. Chem. Soc. 2000, 122,

35 4 : An exogenous Lewis acid? TMS 'C 4 Lewis base Selective Aldol Bypasses the formation of trichlorosilyl enolates licon must serve as organizational center for the Lewis base and aldehyde licon complex must facilitate an aldol reaction with the enolate (whether through an open or closed TS)

36 Lewis Base Activation of Lewis Acids TBS 4 (1.1 equiv.) 5 mol % (,)-3 C 2 2, -78 C ee, % yield, % naphthyl naphthyl C C CF 3 C (E)- C=C (E)- C=C() furyl cyclohexyl C 2 C N P N N (S,S)-4 (C 2 ) 5 2 Denmark, S. J. Am. Chem. Soc. 2002, 124,

37 Lewis Base Activation of Lewis Acids TBS t-bu 4 (S,S)-4 (1 mol%) C 2 2, -78 C t-bu TBS 4 (S,S)-4 (1 mol%) C 2 2, -78 C yield, % anti/syn ee, % 93 99:1 >98 1- naphthyl 98 96: naphthyl 95 >99:1 >98 4- C >99: CF 3 C >99:1 92 (E)- C=C 98 >99:1 >98 (E)- C=C(C 3 ) 90 >99:1 92 phenyl propargyl 92 96:4 68 E:Z yield, % anti/syn ee, % 82: :1 72 Et 95: : : :6 88 t- Bu 95: :1 >98 t- Bu 12: :1 >98 N P N N (S,S)-4 (C 2 ) 5 2 Denmark, S. J. Am. Chem. Soc. 2002, 124,

38 Lewis Base Activation of Lewis Acids TBS (S,S)-4 (x mol%) Et 4 Et C 2 2, -78 C (S,S)- 4 (mol %) yield, % anti/syn ee, % C 2 C 2 5% 71 91:9 90 Cyclohexyl 10% 40 89:11 36 N P N N (S,S)-4 (C 2 ) MPA (5 mol %) 3 CD 3 1 : d, 5.76 ppm 13 C: ppm 4 MPA CD 3-60 C P(N 2 ) 3 P(N 2 ) Denmark, S. J. Am. Chem. Soc. 2002, 124, Denmark, S. J. Am. Chem. Soc. 2005, 127, : -110 ppm 2 J -P = 9 z 29 : -206 ppm

39 Lewis Base Activation of Lewis Acids 4 2 N 2 N N 2 P N 2 P N 2 N 2 - Not Lewis acid catalyzed! 2 N P N 2 N 2 P 2 3 TBS - 2 N 2 N N 2 P 2 N P N 2 N 2-2 N 2 N N 2 P 2 N P N 2 N 2 3 TBS ' ' TBS ' Denmark, S. J. Am. Chem. Soc. 2005, 127,

40 Lewis Base Activation of Lewis Acids Denmark, S. J. Am. Chem. Soc. 2005, 127,

41 Glycolate lyl Ketene Acetals 3 ' C (,)-4 4, ipr 2 EtN C 2 2, 70 C ' ' N P N N (C 2 ) 5 (S,S) yield, % syn/anti ee (syn), % ee (anti), % TMS 98 57: t- Bu TMS 93 99: C TMS 98 99: t- Bu TMS 93 4: t- Bu TBS 92 1:99-84 Et 2 C TBS 92 1:99-88 Denmark, S. Angew. Chem. Int. Ed. 2008, 47,

42 Glycolate lyl Ketene Acetals Denmark, S. J. rg. Chem. 2008, 73,

43 Vinylogous Aldol eaction TBS N 4 (S,S)-4 (5 mol%) 10 mol% i-pr 2 NEt C 2 2, -72 C 1-16 h N N P N N (S,S)-4 (C 2 ) 5 2 yield, % γ:α ee, % C 2 C 2 80 >99:1 98 C 3 (C 2 ) 4 79 >99:1 88 (C 3 ) 2 CC 2 84 >99:1 >99 cyclohexyl 63 >99: >99: C >99: CF 3 C >99: furyl 94 >99:1 88 (E)- C=C 94 >99:1 96 (E)- C=C(C 3 ) 91 >99:1 52 Denmark, S. J. Am. Chem. Soc. 2006, 128,

44 Vinylogous Aldol eaction TBS N 4 (S,S)-4 (x mol%) 10 mol% i-pr 2 NEt C 2 2, -72 C (S,S)- 4, mol% time, h γ:α E:Z E- yield, % Z- yield, % Z- ee, % 5 1 >99:1 88: >99:1 48: (E)- C=C 5 1 >99:1 89: (E)- PC=C 0 1 >99:1 20: (E)-isomer N (Z)-isomer N 3 N 4 (S,S)-4 (5 mol%) 10 mol% i-pr 2 NEt C 2 2, -72 C, 1 h (E)-isomer N (Z)-isomer N 3 γ:α E:Z E- yield, % E- ee, % Z- yield, % Z- ee, % TBS >99:1 89: TMS >99:1 82: TIPS >99:1 87: Denmark, S. J. rg. Chem. 2007, 72,

45 Vinylogous Aldol eaction Denmark, S. J. rg. Chem. 2007, 72,