Denmark s Base Catalyzed Aldol/Allylation Evans Group Seminar ovember 1th, 003 Jimmy Wu Lead eferences: Denmark, S. E. Acc. Chem. es., 000, 33, 43 Denmark, S. E. Chem. Comm. 003, 167 Denmark, S. E. Chem. ev. 003, 103, 763 Denmark, S. E. JC, 1998, 63, 9517
Background X c M X c equires stoichiometric amounts of covalently bound auxiliaries 1 TMS MLn* 1 Ligand is often deactivating Diastereoselectivity can be high but are often variable S S MLn* S Base S umber of literature examples is still limited.
Lewis Base Activated Aldol M G* (Activating Group) M G* M G* Must be more reactive than non-bound substrate Must react via a closed T.S. to obtain good selectivities
General eaction verview SiCl 3 1 1 E enolsilane ---> anti product ighly diastereoselective (up to 99:1 anti/syn) ighly enantioselective (up to 98% ee) Z enolsilane ---> syn product ighly diasteroselective (up to 18:1 syn/anti) ighly enantioselective (up to 98% ee)
ow It All Started X Si t-bu C X Wanted to exploit the concept of strain-release Lewis acidity < 109.5 o L Si L tetrahedral u - L Si L u trigonal bipyramid
Literature Examples F 3 C CF 3 F 3 C CF 3 M u Et 4 M u F 3 C CF 3 F 3 C CF 3 M = Si and Ge Ligand C-(Ge).6 o Germanium compound is able to catalyze the ene reaction while silicon is not. Martin, J. C. JC, 1981, 46, 1049 Denmark, S. E. rganometallics, 1990, 9, 3015
Strain-elease Catalyzed Aldol t-bu Si 1. C, CCl 3, T. F/TF 1 3 4 cinnamyl n-pentyl E/Z 0/100 95/5 89/11 89/11 yield 80 94 95 91 syn/anti 4/58 95/5 93/7 93/7 5 cyclohexyl 89/11 85 >99/1 Also worked for thiosilylketene acetals but both E and Z gave syn selectivity. Amide derived enolsilanes were unselective. Denmark, S. E. JACS, 1994, 116, 706
chanistic Studies 3 C Si 3 C C 3 C Si C 3 3 C Si CD 3 D 3 C Si Si CD 3 Si C 3 D 3 C D 3 C D 3 C Must go through a trigonal bipyramidal T.S. with internal transfer of silicon Analagous studies with Kt-Bu as a catalyst revealed complete deuterium scrambling. Cannot go through an octahedreal T.S. Denmark, S. E. JACS, 1994, 116, 706
T.S. Models t-bu Si syn diastereomer Closed boat-like T.S. entacoordinate silicon Evans proposes similar T.S. in Zr based aldol (Evans, D. A. TL, 1980, 1, 3975.
nd Generation of LB Catalyzed Aldol SiCl 3 chiral LB C Trichlorosilane required for sufficient Lewis acidity Silicon can expand valency by Simultaneous activation of u - and El via closed T.S. Facial selectivity comes from chiral base
Uncatalyzed eactions: E Enolsilanes SiCl 3 1. C, DCM. ac 3 1 3 4 5 6 7-1-apthylcinnamylα-methylcinnamyl- enylpropargyldihydrocinnamylcyclohexyl- time, hr 6 8 1 11 1 36 syn/anti 49/1 16/1 49/1 5.7/1 36/1 5.3/1 1/1 yield 9 90 83 86 91 8 9 Denmark, S. E. JACS, 1999, 11, 498
Uncatalyzed eaction: Z Enolsilanes SiCl 3 1. C, DCM. ac 3 1 3 4 5 6 7-4-Br- 1-aphtylcinnamylα-methylcinnamylcrotyl- enylpropargyl- time, hr 10 10 16 10 1 16 11 syn/anti 1/.3 1/.9 1/1.3 1/1.9 1/. 1/1.9 1/. yield 97 93 95 95 64 89 89 Denmark, S. E. JACS, 1999, 11, 498
Catalyzed Aldol: E Enolsilanes C SiCl 3 1. 10 mol%(s,s)-cat., DCM, -78 o C. ac 3 1 3 4 5-1-apthylcinnamylα-methylcinnamyl- enylpropargyl- syn/anti 1/61 <1/99 <1/99 <1/99 1/5.3 anti ee% 93 97 88 9 8 yield, % 95 94 94 98 90 Denmark, S. E. JACS, 1999, 11, 498
Catalyzed Aldol: Z Enolsilanes C SiCl 3 1. 15 mol% (S,S)-cat., DCM, -78 o C. ac 3 1 3 4 5 6-4-Br- 1-apthylcinnamylcrotyl- enylpropargyl- syn/anti 18/1 1/1 3/1 9.4/1 7/1 1/3.5 syn ee% 95 96 84 9 91 58 yield, % 95 89 96 97 94 9 Denmark, S. E. JACS, 1999, 11, 498
Current T.S. Model - Too Simplistic SiCl 3 LB* C Si LB* L n
chanistic Clues C SiCl 3. ac 3 1 3 loading 10% 5% % conc. 0.5 0.5 0.5 syn/anti 1/14 1/10 1/.4 yield 94 90 84 Syn/anti ratio is highly dependent on catalyst loading Simple change in silicon valency cannot account for rate acceleration Bulkier catalysts lowers and even switches diastereoselectivities Denmark, S. E. JACS, 1998, 10, 1990 Denmark, S. E. JACS, 1999, 11, 498
chanistic roposal Two competetive pathways, one for the formation of each diastereomer Anti diastereomer dominates with less bulky ligands and higher conc. Syn diasteromer dominates with more bulky ligands and lower conc. % ee of anti-adduct 100 90 80 70 60 50 40 30 0 % ee of syn-adduct 10 0 0 0 40 60 80 100 % ee of catalyst Denmark, S. E. JACS, 1998, 10, 1990
Unified T.S. Model Cl Si Cl Cl anti Cl Cl Si Cl syn cationic octahedral cationic trigonal bipyramidal Ligand binding causes Cl - to dissociate: Bu 4 Cl inhibits reaction because of the common ion effect Bu 4 Tf and TBAI accelerate reaction rates by increasing ionic strength
Double Stereodifferentiating eactions I TIS SiCl 3 10 mol% DCM, 0 mol % TBAI, -78 o C TIS internal relative 1 3 4 5 6 7 8 9 10 11 - - 1-apthyl- 1-apthyl- cinnamyl- cinnamyl- crotyl- crotyl- tiglyl- tiglyl- catalyst (,) (S,S) (,) (S,S) (,) (S,S) (,) (S,S) (,) (S,S) achiral relative dr (syn/anti) 53/1 3/1 14/1 14/1 9/1 15/1 >50/1 >50/1 13/1 19/1 7/1 internal dr (syn/anti) 4/1 1/8 89/1 1/17 14/1 1/6 15/1 1/5 13/1 1/5 5/1 Denmark, S. E. L, 00, 4, 3473
T.S. Models TIS Cl - TIS Cl - TIS Cl - SiL n SiL n Si L n Minimizes steric interactions between substituents on enolate and bulky ligands on silicon Anti diastereomer may be formed via a boat-like T.S. A 1,3 strain is minimized but severe non-bonding interactions exist between subtrate and ligands on silicon. on-bonding interactions arising from chair T.S. can give rise to boat-like T.S.
Double Stereodifferentiating eactions II TIS SiCl 3 10 mol% DCM, -78 o C TIS internal relative 1 3 4 5 6 7 8 9 10 11 - - 1-apthyl- 1-apthylcinnamyl- cinnamyl- crotyl- crotyl- tiglyl- tiglyl- catalyst (,) (S,S) (,) (S,S) (,) (S,S) (,) (S,S) (,) (S,S) achiral relative dr (syn/anti) 30/1 6/1 17/1 18/1 >50/1 >50/1 8/1 37/1 >50/1 >50/1 9/1 internal dr (syn/anti) 16/1 1/10 30/1 1/10 10/1 1/8 7/1 1/6 3/1 1/3 1.4/1 Denmark, S. E. L, 00, 4, 3477
thyl Ketones as ucleophiles SiCl 3 1 5 mol% DCM, -78 o C 1 1 3 4 5 6 7 8 9 10 n-bui-r- - TBSC - n-bu- n-bu- n-bu- n-bu- n-bu- 1 - - - - cinnamylα-methylcinnamyl- 1-napthylcyclohexylt-Bu- ee % 87 85 81 49 86 84 91 86 89 9 yield % 98 98 97 93 94 94 95 9 79 81 Denmark, S. E. JACS, 000, 1, 8837
Double Stereodifferentiating eactions n-bu SiCl 3 TBS 10 mol% cat. n-bu TBS (,) - 1/15.6 syn/anti, 56% yield (S,S) -.7/1 syn/anti, 47% yield achiral - 1/1.3 syn/anti, 41% yield TBS SiCl 3 10 mol% cat. TBS (,) - 73/1 syn/anti, 85% yield (S,S) - 1.5/1 syn/anti, 85% yield achiral - 1./1 syn/anti, 81% yield Denmark, S. E. JACS, 000, 1, 8837
T.S. Models n-bu SiCl 3 TBS ( *) 3 Cl Si Cl ( TBS *) 3 Felkin T.S. n-bu Cl - n-bu TBS SiCl 3 TBS ( *) 3 Cl Cl - TBS Si Cl ( *) 3 TBS dipoles minimized Denmark, S. E. JACS, 000, 1, 8837
Silyl Ketene Acetals SiCl 3 1 t-bu Bu Bu DCM, -0 o C t-bu 1 yields >84% 83% ee (S) F 3 C Et M e 80% ee 86% ee (S) 80% ee 35% ee 76% ee 68% ee 11% ee 35% ee 0% ee 3% ee 43% ee t-bu Et 56% ee 49% ee 8% ee 3% ee Denmark, S. E. JACS, 00, 14, 433
Asymmetric Allylation Cl 3 Si DCM stoichiometric, -78 o C 1 3 4 5 6 - o-tol- 4- - 4-- 4- cinnamyl- ee, % 60 65 1 50 33 38 yield 81 81 76 80 69 67 Denmark, S. E. JC, 1994, 59, 6161
Diastereoselective Allylations Cl 3 Si >99/1 stoich. cat. DCM, -78 o C 56% ee, /98 syn/anti Cl 3 Si >99/1 stoich. cat. DCM, -78 o C 60% ee, 98/ syn/anti Denmark, S. E. JC, 1994, 59, 6161
chanistic Studies 70 60 % ee of product 50 40 30 0 10 0 0 0 40 60 80 100 % ee of catalyst 1st order in aldehyde 1st order in allylsilane 1.77th order in catalyst due to competing pathways involving 1 or phosporamides bound to silicon. Denmark, S. E. JACS, 000, 1, 101
T.S. Models Cl Si Cl (* ) 3 Cl - Cl Si Cl Cl - C C (* ) 3 (* ) 3 cationic octahedral cationic trigonal bipyramidal Facial selectivity is lower because the cationic octahedral T.S. gives the opposite facial selectivity as the cationic trigonal bipyramidal T.S. Denmark, S. E. JACS, 000, 1, 101
Bisphosphoramides Cl 3 Si 5 mol% cat. DCM, -78 o C 1 cat. 1a ee % 0 config. 6 cat. ee% 56 config. S 3 4 1b 1c 1d 35 17 65 7 8 9 3a 3b 3c 18 87 67 S S S 5 1e 46 1a: n= 1b: n=3 1c: n=4 (C ) n 1d: n=5 1e: n=6 3a: n=4 3b: n=5 (C ) n 3c: n=6 Denmark, S. E. JACS, 000, 1, 101 Denmark, S. E. JACS, 001, 13, 9488
Allylations evisited 1 SiCl 3 1a: 1 =, =; 1b: 1 =, = 1ac: 1 =, =; 1a: 1 =, = DCM, -78 o C (C ) 5 5 mol% 1 1 3 4 5 6 7 8 9 silanes 1a 1a 1a 1b 1b 1c 1c 1d 1d - -naphthyl cinnamyl- - cinnamyl- - cinnamyl- cinnamyl- syn/anti 1/99 1/99 99/1 99/1 ee % 87 87 81 86 80 94 88 96 88 yield % 85 9 86 8 57 89 78 89 70 Denmark, S. E. JACS, 001, 13, 9488
Crossed-Aldol eactions of Aldehydes (C ) 5 SiCl 3 C 1. CCl 3 /DCM 4:1, -78 o C. 5 mol% 1 3 4 5 6 7 8 9 10 enolate Z E Z E Z E Z E Z E - cinnamylcinnamylcrotylcrotylphenylpropargylphenylpropargyldihydrocinnamyldihydrocinnamyl- syn/anti 98/ 1/99 99/1 1/99 99/1 /98 98/ /98 95/5 1/99 ee % 81 59 4 6 5 5 7 76 8 66 yield 95 97 86 88 85 91 98 99 47 79 Denmark, S. E. ACIEE, 001, 40, 4759
3rd Generation of LB Catalyzed Aldol Limitation of current methodology is the ability to prepare the required trichlorosilanes. SiCl 4 Si Cl Cl Cl Cl - Lewis Acidic?
Acetate Aldols (C ) 5 TBDMS 5 mol% SiCl 4 DCM, -78 o C 1 3 4 5-1-naphthyl- -naphthyl- 4-- 4-ee 93 80 94 94 97 yield 97 98 98 97 97 6 7 8 9 10 ee 91 94 87 88 81 4-CF 3 - cinnamyl- -furylcyclohexyldihydrocinnamyl- yield 97 95 94 86 7 Denmark, S. E. JACS, 00, 14, 13405
ropanate Aldols (C ) 5 TBDMS SiCl 4 t-bu DCM, -78 o C 1 mol% 1 3 4 5 6 7 8-1-naphthyl- -naphnthyl- 4-- 4-CF 3 cinnamylphenylpropargyldihydrocinnamyl a - dr 99/1 96/4 >99/1 >99/1 >99/1 >99/1 96/4 93/7 a eaction run with 0.1 equiv of TBAI ee 98 94 98 98 9 98 68 89 yield 93 98 95 88 93 98 9 55 Denmark, S. E. JACS, 00, 14, 13405
Aldol Additions with thyl Ketones I (C ) 5 TMS 5 mol% SiCl 4 DCM, -7 o C 1 3 4 5 n-busec-but-bui-r- ee % 98 98 99 94 yield 81 70 7 76 Denmark, S. E. L, 003, 5, 303
Aldol Additions with thyl Ketones II (C ) 5 n-bu TMS 5 mol% SiCl 4 n-bu DCM, -7 o C, 10 mol% i-r Et 1 3 4 5 6 7 8 9 - cinnamyl- 1-naphthyl- -naphthyl- 4-- 4-CF 3 - -furyl- -thiophenyldihydrocinnamyl- ee % 99 99 9 99 99 99 90 89 yield 99 98 95 9 98 96 88 79 Denmark, S. E. L, 003, 5, 303
Vinylogous Aldol (C ) 5 4 TBS 1 mol% 4 1 5 3 SiCl 4, DCM, -78 o C 1 5 3 1 3 4 5 6 7 8 9 10 1 cinnamyl- dihydrocinnamyl- - cinnamyl- cinnamyl- dihydrocinnamyl- - cinnamyl- Et- Et- Et- - - Et- Et- Ett-But-Bu- 3 - - - - - - - - - - 4 - - - - - - - - - - 5 - - - - - - - - a - a - ee % 98 96 90 99 99 9 88 95 89 8 yield 89 84 68 93 88 91 97 73 9 71 a Diastereoselectivity >99/1 Denmark, S. E. JACS, 003, 15, 7800
Allylation evisited, Again (C ) 5 Bu 3 Sn SiCl 4, DCM, -78 o C 5 mol% 1 3 4 5 6 7-4- cinnamylphenylpropargyl- 1-naphthyl- -naphthyl- -furylee % 94 83 65 94 93 6 yield % 91 90 91 9 94 9 65 Denmark, S. E. JACS, 001, 13, 6199
ropargylation (C ) 5 SnBu 3 SiCl 4, DCM, -78 o C 5 mol% = = cinnamyl = -naphthyl 81% (97% ee ()) 90% (87% ee ()) 95% (93% ee ()) Denmark, S. E. JACS, 001, 13, 6199