Denmark s Base Catalyzed Aldol/Allylation
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1 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
2 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.
3 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
4 General eaction verview SiCl 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)
5 ow It All Started X Si t-bu C X Wanted to exploit the concept of strain-release Lewis acidity < o L Si L tetrahedral u - L Si L u trigonal bipyramid
6 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
7 Strain-elease Catalyzed Aldol t-bu Si 1. C, CCl 3, T. F/TF cinnamyl n-pentyl E/Z 0/100 95/5 89/11 89/11 yield 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
8 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
9 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.
10 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
11 Uncatalyzed eactions: E Enolsilanes SiCl 3 1. C, DCM. ac apthylcinnamylα-methylcinnamyl- enylpropargyldihydrocinnamylcyclohexyl- time, hr syn/anti 49/1 16/1 49/1 5.7/1 36/1 5.3/1 1/1 yield Denmark, S. E. JACS, 1999, 11, 498
12 Uncatalyzed eaction: Z Enolsilanes SiCl 3 1. C, DCM. ac Br- 1-aphtylcinnamylα-methylcinnamylcrotyl- enylpropargyl- time, hr syn/anti 1/.3 1/.9 1/1.3 1/1.9 1/. 1/1.9 1/. yield Denmark, S. E. JACS, 1999, 11, 498
13 Catalyzed Aldol: E Enolsilanes C SiCl mol%(s,s)-cat., DCM, -78 o C. ac apthylcinnamylα-methylcinnamyl- enylpropargyl- syn/anti 1/61 <1/99 <1/99 <1/99 1/5.3 anti ee% yield, % Denmark, S. E. JACS, 1999, 11, 498
14 Catalyzed Aldol: Z Enolsilanes C SiCl mol% (S,S)-cat., DCM, -78 o C. ac Br- 1-apthylcinnamylcrotyl- enylpropargyl- syn/anti 18/1 1/1 3/1 9.4/1 7/1 1/3.5 syn ee% yield, % Denmark, S. E. JACS, 1999, 11, 498
15 Current T.S. Model - Too Simplistic SiCl 3 LB* C Si LB* L n
16 chanistic Clues C SiCl 3. ac loading 10% 5% % conc syn/anti 1/14 1/10 1/.4 yield 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
17 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 % ee of syn-adduct % ee of catalyst Denmark, S. E. JACS, 1998, 10, 1990
18 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
19 Double Stereodifferentiating eactions I TIS SiCl 3 10 mol% DCM, 0 mol % TBAI, -78 o C TIS internal relative 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
20 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.
21 Double Stereodifferentiating eactions II TIS SiCl 3 10 mol% DCM, -78 o C TIS internal relative 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
22 thyl Ketones as ucleophiles SiCl mol% DCM, -78 o C n-bui-r- - TBSC - n-bu- n-bu- n-bu- n-bu- n-bu cinnamylα-methylcinnamyl- 1-napthylcyclohexylt-Bu- ee % yield % Denmark, S. E. JACS, 000, 1, 8837
23 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
24 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
25 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
26 Asymmetric Allylation Cl 3 Si DCM stoichiometric, -78 o C o-tol cinnamyl- ee, % yield Denmark, S. E. JC, 1994, 59, 6161
27 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
28 chanistic Studies % ee of product % 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
29 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
30 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 a 3b 3c 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
31 Allylations evisited 1 SiCl 3 1a: 1 =, =; 1b: 1 =, = 1ac: 1 =, =; 1a: 1 =, = DCM, -78 o C (C ) 5 5 mol% 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 % yield % Denmark, S. E. JACS, 001, 13, 9488
32 Crossed-Aldol eactions of Aldehydes (C ) 5 SiCl 3 C 1. CCl 3 /DCM 4:1, -78 o C. 5 mol% 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 % yield Denmark, S. E. ACIEE, 001, 40, 4759
33 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?
34 Acetate Aldols (C ) 5 TBDMS 5 mol% SiCl 4 DCM, -78 o C naphthyl- -naphthyl ee yield ee CF 3 - cinnamyl- -furylcyclohexyldihydrocinnamyl- yield Denmark, S. E. JACS, 00, 14, 13405
35 ropanate Aldols (C ) 5 TBDMS SiCl 4 t-bu DCM, -78 o C 1 mol% naphthyl- -naphnthyl 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 yield Denmark, S. E. JACS, 00, 14, 13405
36 Aldol Additions with thyl Ketones I (C ) 5 TMS 5 mol% SiCl 4 DCM, -7 o C n-busec-but-bui-r- ee % yield Denmark, S. E. L, 003, 5, 303
37 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 cinnamyl- 1-naphthyl- -naphthyl CF 3 - -furyl- -thiophenyldihydrocinnamyl- ee % yield Denmark, S. E. L, 003, 5, 303
38 Vinylogous Aldol (C ) 5 4 TBS 1 mol% SiCl 4, DCM, -78 o C cinnamyl- dihydrocinnamyl- - cinnamyl- cinnamyl- dihydrocinnamyl- - cinnamyl- Et- Et- Et- - - Et- Et- Ett-But-Bu a - a - ee % yield a Diastereoselectivity >99/1 Denmark, S. E. JACS, 003, 15, 7800
39 Allylation evisited, Again (C ) 5 Bu 3 Sn SiCl 4, DCM, -78 o C 5 mol% cinnamylphenylpropargyl- 1-naphthyl- -naphthyl- -furylee % yield % Denmark, S. E. JACS, 001, 13, 6199
40 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
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