Carbon-Carbon Bond Forming Reactions with Silacycles: Aldol and Asymmetric Aldol Reactions, Study notes of Organic Chemistry

Download Carbon-Carbon Bond Forming Reactions with Silacycles: Aldol and Asymmetric Aldol Reactions and more Study notes Organic Chemistry in PDF only on Docsity! Strain Release Lewis Acidity: Recent Advances In Asymmetric Synthesis Aparajita Banerjee Organic Seminar December 13, 2006 M Nu . . D C A B M A B Nu C D Outline  Introduction - Basic Principle  Application In Carbon—Carbon bond forming Reactions - 4 Membered Silacycle - Aldol and Asymmetric Aldol Reaction - Addition To α,β-Unsaturated Carbonyl - Allylation Reaction - 5 Membered Silacycle - Asymmetric Allylation/Crotylation Reaction - Enantioselective Friedel-Crafts Alkylation Reaction - Enantioselective [3 + 2] Cycloaddition Reaction - Asymmetric Diels Alder Reaction - Tandem Reaction  Application In Natural Product Synthesis  Strain Release Chemistry With Al  Conclusion Example of Strain Release Lewis Acidity  Aldol Reaction Denmark, S. E.; Griedel, B. D.; Coe, D. M. J. Org. Chem. 1993, 58, 988 Matsumoto. K.; Oshima, K.; Utimoto, K. J. Org. Chem. 1994, 59, 7152 Acyclic Analogue Cyclic Analogue  Allylation of Aldehyde Dual Activation of the silane and aldehyde Acyclic Analogue Cyclic Analogue O Si H Ph Ph H3CO O Si t-Bu H3C CH3 + H O Ph C6D6 / 1M 20 oC 120 h No Reaction CH3 + H O Ph CDCl3 / 1M 20 oC 2.2 h 94% H3CO O Si t-Bu CH3 E:Z (95:5) H3C O Ph OH CH3 H3C O Ph CH3 OH + 95:5 Ph Si H3C CH3 + H O Ph 160 oC 24 h No Reaction Ph Si + H O Ph 130 oC 12 h Ph O Si Ph aq. HCl MeOH Ph OH 85% SiMe O O MeO CH3 CH3 H Ph Historical Background Perozzi, E. F.; Michalak, R. S.; Figuly, G. D.; Stevenson, W. H. III, Bess, D. B.; Ross, M. R.; Martin, J. C. J. Org. Chem. 1981, 46, 1049 Stevenson III, W. H.; Wilson, S.; Martin, J.C.; Farnham, W. B. J. Am. Chem. Soc. 1985, 107, 6340 Si O O Si 4 coordinated Distorted Tetrahedral Si 5 coordinated Trigonal Bipyramidal Si O O Endocyclic C-Si-O  ~ 94.4o Endocyclic C-Si-O  ~ 85.3o Si O O CF3 CF3 CF3 CF3 O Si O F3C CF3 F3C CF3 Li PhLi A B Hypervalency of Silicon ∆E > 200 kCal/mol 10 electrons 4 orbitals ? Hypervalent Bonding Concept of 3c-4e bond Alekseev, N. V.; Heller, G.; Niedenzu, K.; Tandura, S. N.; Trofimenko, S.; Vorkonkov, M. G. Top. Curr. Chem. 1986, 131, 99 Involved in the formation of 5 bonds Si Possibility 1 3S 3p 3d sp2 dp hybridize sp3d Energy p d sp2 sp2p Possibility 2 ‘Strain Release Lewis Acidity’ Denmark, S. E.; Jacobs, R. T.; Dai-Ho, G.; Wilson, S. Organometallics 1990, 9, 3015 If ∠A-X-B less than 94.40 Further distortion in tetrahedral geometry  more strained  greater Lewis acidity A X B C D X = Si, ∠A-X-B = 94.40 ? by Germanium Bond Length: Ge–O  1.989 Å Ge–C  1.951 Å Bond Angle: Endocyclic C-Si-O  ~ 83.5o (Ideal  90o) Ge O O F3C CF3 F3C CF3 Bond Length: Ge–O  1.786 Å Ge–C  1.898 Å Bond Angle: Endocyclic C-Ge-O  ~ 91.5o (Ideal  109.5o) Expected More strained than Si analogue Longer than expected Release of strain Expected: Ge analogue much more Lewis acidic than Si analogue Ge O O CF3F3C CF3 F3C Et4N     Ge Ge O O O O Distorted Tetrahedral Trigonal Bipyramidal Average increase in Bond Length: Gei–O  0.203 Å Ge–C  0.053 Å Enhanced Lewis Acidity by Germanium Analogue Denmark, S. E.; Jacobs, R. T.; Dai-Ho, G.; Wilson, S. Organometallics 1990, 9, 3015 Ge analogue much more Lewis acidic than Si analogue : Proof  Intramolecular Ene Reaction:  Intramolecular [4+2] Cycloaddition Reaction: No Reaction with Si Analogue No Reaction with Si Analogue Ge O O F3C CF3 F3C CF3 1 CHO CH3H3C H3C CH3 1 CH2Cl2/ 20 oC OH H3C CH3 H3C + H3C CH3 H3C OH trans cis CH3 H O SCH3 1 CH2Cl2 / 20 oC 63% O H H CH3 SCH3 E-isomer trans-isomer Si  More explored because of its practical applicability Different Silacycles  4-Membered silacycle  Ring spans along axial-equatorial  Ring spans along axial-equatorial X, Y  O, O X, Y  O, N X, Y  N, N Si Si Nu 4-coordinated 5-coordinated Nu Si X Y Si X Y Nu 4-coordinated 5-coordinated Nu Denmark, S. E.; Griedel, B. D.; Coe, D. M. J. Org. Chem. 1993, 58, 988 Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L. J. Am. Chem. Soc. 2002, 124, 7920  5-Membered silacycle Si Directed Aldol Reaction Myers, A. G.; Widdowson, K. L. J. Am. Chem. Soc. 1990, 112, 9672 Asymmetric Version:  Without apparent Catalyst  Pericyclic transition state OSi(CH2CH3)2 N H3C CH3 CH3 H O H OSi(CH2CH3)2O CH3 H3C CH3 OSi(CH2CH3)2O CH3 H3C CH3 + + CH2Cl2 -30 oC 1 anti syn 1.8:1 N O SiO CH3 CH3 H CH3 H + H O hexane 23 oC, 10 h N O O O Si H3C CH3 CH3 H N O O O Si H3C CH3 CH3 H + anti-isomer syn-isomer39:1 yield: 77% (for anti-isomer) 2 Mechanism: Myers, A. G.; Kephart, S. E.; Chen, H. J. Am. Chem. Soc. 1992, 114, 7922 Path A Path B Si Directed Aldol Reaction Si R O O N H CH3 R Si R O O H R = CH3 pseudo rotation SiO N O R O H H CH3 R Si O N O O H CH3 H R R N H H3C O R Si R O O N H CH3 R Si R H CH3 R O N O O H R = CH3 pseudo rotation SiO N O R O H H CH3 R Si O N O O H CH3 H R R Si Directed Aldol Reaction Mechanism: Path A Path B  10 fold rate acceleration for silacyclopentane  2X106 fold rate acceleration for silacyclobutane Path A: Operative Si R O O N H CH3 R Si R H CH3 O N O O H R = (CH2)3 R= (CH2)4 pseudo rotation SiO N O R O H H CH3 R Si O N O O H CH3 H R R R Si R O O N H CH3 R Si R O O H R = (CH2)3 R = (CH2)4 pseudo rotation SiO N O R O H H CH3 R Si O N O O H CH3 H R R N H H3C O R Expected Angle: 90o Expected Angle: 90o Aldol Reaction of Silyl-enol derivative of Ester Denmark, S. E.; Griedel, B. D.; Coe, D. M. J. Org. Chem. 1993, 58, 988 Denmark, S. E.; Griedel, B. D.; Coe, D. M. Schnute, M. E. J. Am. Chem. Soc. 1994, 116, 7026 Cyclic Analogue Acyclic Analogue t1/2 entry R1 R2 R3 R4 (min) 1 2 3 4 t-butyl t-butoxy t-butyl t-butyl 5 33 2100 - CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 O MeO Si t-Bu CH3H3C CH3 + Ph H O 1M C6D6 120 h No Reaction Si O R2 R3 R4R1O PhCHO C6D6, 1M 20 oC O O R1O R3 R 4 Ph Si R2 O Me Me Si MeO Me + O H SiMe O O MeO CH3 CH3 H Ph O MeO Si OCHPh H3C CH3 CH3 O Ph H O O MeO H3C CH3 Si Me Path A Intramolecular silicon group transfer O O MeO H3C CH3 Si H3C PhCHO Path B Intermolecular silicon group transfer Open TS Closed TS Crossover Experiment  Path A Aldol Reaction: Asymmetric Version Proposed Asymmetric Variant of Aldol Reaction Denmark, S. E.; Griedel, B. D. J. Org. Chem. 1994, 59, 5136 O Me Si X R*O RCHO Si O O X Me H R1 OR* O O Si Me X R1 O OH OR* X Me R*OH + HF, THF Si Cl Cl R1 With Chiral Enoxysilacyclobutane derived from ester Denmark, S. E.; Griedel, B. D. J. Org. Chem. 1994, 59, 5136 Important Observations: - Unaaceptably low yield due to large component C-silyl esters and (Z)-ketene acetal isomers X O CH3 Si Y Si CH3X O Y a b 1a, b: X = OCH3, Y = (-)-8-phenylmenthol 2a, b: X = OCH3, Y = (-)-trans-2-cumylcyclohexanol oxygen silylated carbon-silylated Aldol Reaction: Asymmetric Version entry ketene temp, °C syni/anti ee (%) acetal 1 1 -60 >99/1 95 2 2 -60 >99/1 97 CH3O O Si R*O CH3 + PhCHO 1) 0.5M, toluene 2) 1 h, HF/THF/H2O R*OH 60/40 Oxygen vs Carbon-silyl 80/20 E/Z O PhH3CO OH CH3 syn-isomer 1,2 vs 1,4-addition: Why the observed regiochemistry? Denmark, S. E.; Griedel, B. D.; Coe, D. M. Schnute, M. E. J. Am. Chem. Soc. 1994, 116, 7026 O Si CH3O H CH3 t-Bu + O H 20 °C O CH3O H CH3 Si t-Bu H + O H O H3CO Si R 1,2-addition 1,4-addition C6D6 t1/2 = 8 min 84% 100:0 SiR1 O O MeO CH3 CH3 R2 SiR1 O MeO CH3 CH3 6 Membered TS Eneregetically Accessible 8 Membered TS O R2 Addition To α,β-Unsaturated Carbonyl Outline  Introduction - Basic Principle  Application In Carbon—Carbon bond forming Reactions - 4 Membered Silacycle - Aldol and Asymmetric Aldol Reaction - Addition To α,β-Unsaturated Carbonyl - Allylation Reaction - 5 Membered Silacycle - Asymmetric Allylation/Crotylation Reaction - Enantioselective Friedel-Crafts Alkylation Reaction - Enantioselective [3 + 2] Cycloaddition Reaction - Asymmetric Diels Alder Reaction - Tandem Reaction  Application In Natural Product Synthesis  Strain Release Chemistry With Al  Conclusion Allylation Reaction: With Four Membered Silacycle Acyclic Analogue Cyclic Analogue  Allyl-alkoxy silacyclobutane more reactive than Allyl-phenyl silacyclobutane Matsumoto. K.; Oshima, K.; Utimoto, K. J. Org. Chem. 1994, 59, 7152 Ph Si H3C CH3 + H O Ph 160 oC 24 h No Reaction Ph Si + H O Ph 130 oC 12 h Ph O Si Ph aq. HCl MeOH Ph OH 85% + H O Ph 1. 100 oC 12 h Ph OHSi O 2. aq. HCl 83%  Introduction of the Asymmetry: Choice of Chiral auxiliary : Si O O Cl H3C H3C H3C H3C  Ring induces: - reactivity - chirality Chiral 1,2-amino alcohols OH NH Me Me Ph Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L. J. Am. Chem. Soc. 2002, 124, 7920 Chiral 1,2-diamines NHBn NHBn Inactive Catalyst Asymmetric Allylation Reaction With Five Membered Silacycle O Si O Cl Me Me Me Me O Si O Me Me Me Me Cl N Si N Cl Me Me acyclic six-membered A B CO Si O Me Me Me Me Cl + O HPh Toluene 23 °C 52% OH Ph 1 Asymmetric Allylation Reaction With Five Membered Silacycle Synthesis of Chiral Silane Reagent: From Chiral 1,2-amino alcohols From Chiral 1,2-diamines Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L. J. Am. Chem. Soc. 2002, 124, 7920 Kubota, K.; Leighton, J. L. Angew. Chem. Int. Ed. 2003, 42 , 946 NH NH p-BrC6H4 p-BrC6H4 (R,R) CH2Cl2 88% Cl3Si+ DBU N Si N Cl p-BrC6H4 p-BrC6H4 (R,R) 2 (S,S) OH NH Me Me Ph N Si O Cl CH3 H3C Ph CH2Cl2 88% Cl3Si + Et3N 2:1 dr 1 Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L. J. Am. Chem. Soc. 2002, 124, 7920 Kubota, K.; Leighton, J. L. Angew. Chem. Int. Ed. 2003, 42 , 946 Asymmetric Allylation Reaction With Five Membered Silacycle With aldehyde: 2 N Si O Cl CH3 H3C Ph O Ht-Bu Toluene OH t-Bu+ 96% ee - 10 oC, 2 h (S) (S,S) 80% 1 N Si N Cl p-BrC6H4 p-BrC6H4 + O HPh - 10 °C, 20 h OH Ph CH2Cl2 (R,R) S-isomer 98% ee 69% Proposed mechanism: Berger, R.; Duff, K.; Leighton, J. L. J. Am. Chem. Soc. 2004, 126, 5686  Ketone derived Benzoylhydrazone Asymmetric Allylation Reaction With Five Membered Silacycle N Si N O Ph H3C H Ph N O Cl Me N Si N O Ph H3C Ph N O HCl Me N Si N O Ph H3C Ph HCl NO Me N HPh NHBz N Si O Cl CH3 H3C Ph (S,S) + (1.5 equiv) N CH3Ph NHBz R1 + CHCl3 40 oC, 24 hN Si O Cl CH3 H3C Ph NHNHBzR2 86%, 90% ee Berger, R.; Duff, K.; Leighton, J. L. J. Am. Chem. Soc. 2004, 126, 5686  Ketone derived Benzoylhydrazone Asymmetric Allylation Reaction With Five Membered Silacycle OSi N N Ph O N HPh CH3 CH3 Cl + - Ph H Ph N Si O OMe CH3 H3C Ph (S,S) + N Me N Me Ph PhO N Me N H Ph PhO NR N Si O Cl CH3 H3C Ph + N Si O Cl Ph CH3 H3C Ph + N H N H Ph PhO White Powder 1 Rabbat, P. M. A.; Valdez, S. C.; Leighton, J. L. Org. Lett. 2006, ASAP ? No reaction  With Aldimine H3CO H2N CH3 N Si O Cl CH3 H3C Ph (S,S)-1 Asymmetric Allylation Reaction With Five Membered Silacycle R1 OSi N O N HPh CH3 CH3 Cl + - R H HN O R3 R2 NH HO N HR (S,S)-1 N H HO CH3 HN HO CH3 Et2O, 23 oC 20 h 85% (S,S)-1 92% ee (S,S)-1 N Si O Cl CH3 H3C Ph N R2R1 R1 + NH O R3 OSi N N R3 O N HPh CH3 CH3 Cl + - R2 R1 HN O R3 R2 NH Outline  Introduction - Basic Principle  Application In Carbon—Carbon bond forming Reactions - 4 Membered Silacycle - Aldol and Asymmetric Aldol Reaction - Addition To α,β-Unsaturated Carbonyl - Allylation Reaction - 5 Membered Silacycle - Asymmetric Allylation/Crotylation Reaction - Enantioselective Friedel-Crafts Alkylation Reaction - Enantioselective [3 + 2] Cycloaddition Reaction - Asymmetric Diels Alder Reaction - Tandem Reaction  Application In Natural Product Synthesis  Strain Release Chemistry With Al  Conclusion Different Approach in Carbon-Carbon Bond Forming Reaction N Si O Me Ph Me Cl Nucleophile present in the silane moiety N Si O Me Ph Me Cl Ph + External Nucleophile ? Yes Enantioselective Friedel-Crafts Alkylation Enantioselective [3 + 2] Acylhydrazone- Enol Ether Cycloaddition N Si O Cl Ph CH3 H3C Ph + N R2R2 NHCOR ArH ? R 1 Ar R2 NHNHCOR N Si O Cl Ph CH3 H3C Ph + N HR2 NHCOR ? EDG HN N R1 EDG O R Enantioselective Friedel-Crafts Alkylation Shirakawa, S.; Berger, R.; Leighton, J. L. J. Am. Chem. Soc. 2005, 127, 2858 OSi N N Ph O N HPh CH3 CH3 Cl + - Ph H Ph ArH ArH Bulky Phenyl Group X Plausible Mechanism : + N Hi-PrO2C NHBz ArH (1.5 equiv) (S,S)-1 Toluene, -20 oC, 20 h Ari-PrO2C NHNHBz OSi N Ph O N HPh CH3 CH3 ClH + - Ph H Ph N Si O Cl CH3 H3C Ph N HPh + NH O Ph (S,S)-1 (~2:1) dr Entry ArH Yield(%) ee(%) 1 65 95 NMe2 N H NO2 N S Bn OMe 2 3 4 74 76 91 88 88 89 Outline  Introduction - Basic Principle  Application In Carbon—Carbon bond forming Reactions - 4 Membered Silacycle - Aldol and Asymmetric Aldol Reaction - Addition To α,β-Unsaturated Carbonyl - Allylation Reaction - 5 Membered Silacycle - Asymmetric Allylation/Crotylation Reaction - Enantioselective Friedel-Crafts Alkylation Reaction - Enantioselective [3 + 2] Cycloaddition Reaction - Asymmetric Diels Alder Reaction - Tandem Reaction  Application In Natural Product Synthesis  Strain Release Chemistry With Al  Conclusion Tandem Aldol-Allylation Reaction  Potential Problem in Polyketide Synthesis: Oligomerization  Possible Solution: Termination by allylation Wang, X.; Meng, Q.; Nation A. J.; Leighton, J. L. J. Am. Chem. Soc. 2002, 124, 10672 O Si O Me Me Me Me O 1  Reaction: + OH OH Ph O HPh 1 Toluene 40 °C, 24h OH Ph 60%; 11:1 dr 29% O HR + H3C O MLn n OH OH O CH3 CH3 HR n-1 OH OH OH CH3 CH3 R n-1 CH3 O HR + H3C O Ln M CH3 n Tandem Aldol-Allylation Reaction: Extension O Si O O H3C H3C H3C H3C O Si O O H3C H3C H3C H3C Three Stereogenic Centres Four Stereogenic Centres Wang, X.; Meng, Q.; Nation A. J.; Leighton, J. L. J. Am. Chem. Soc. 2002, 124, 10672 Wang, X.; Meng, Q.; Nicholas, R. P.; Xu, Y.; Leighton, J. L. J. Am. Chem. Soc. 2005, 127, 12806 O Si O O H3C H3C H3C H3C Tertiary Carbinol O HCy Toluene 40 °C, 60 hO Si OMe Me Me Me O OH OH Cy CH3 30%; 2:15 dr Toluene 40 °C, 60 h O Si OMe Me Me Me O H3C OH OH Cy CH3 71%; 10:1 dr Cy H O O HCy Toluene 40 °C, 80 h O Si OMe Me Me Me O OH OH Cy CH3 81%; 66:5:24:7:4 dr CH3 H3C CH3 Toluene O Si OMe Me Me Me O O HCy + CH3 CH3 Cy 58%; 14:1 dr CH3 CH3 reflux, 50 h HO HO Schmidt, D. R.; O’Malley, S. J.; Leighton, J. L. J. Am. Chem. Soc. 2003, 125, 1190  With Alkyne Substrate: Access to Both syn and anti 1,5-diol BDPP: (2,4)-bis(diphenylphosphino)pentane Entry R1 R2 Ligand ds Yield 1 2 3 4 75 89 83 8212:88 90:10 20:80 80:20(R,R)-BDPP (S,S)-BDPP (R,R)-BDPP (S,S)-BDPP n-Pr n-Pr Ph Ph CH2CCH CH2CCH CH2CCH CH2CCH Tandem Silylformylation—Allylsilylation OH R2R1 O R1 R2 Si H O R1 R2 Si H H Si H t-Bu t-Bu t-Bu + + 10 mol % CuCl 10 mol % NaO-t-Bu 10 mol % Ligand Toluene, 12-24 h BA OH OH R i. 10 mol % ((PhO)3P)2Rh(CH3COOH)2.BF4, CO, Benzene, 60 oC ii. O R Si H t-Bu R = n-Pr, 55%, 78:22 dr R = Ph, 38%, 90:10 dr R = n-Pr, 80:20 dr R = Ph, 90:10 dr OH OH R i. 10 mol % ((PhO)3P)2Rh(CH3COOH)2.BF4, CO, Benzene, 60 oC ii. O R Si H t-Bu R = n-Pr, 44%, 79:21 dr R = Ph, 43%, 88:12 dr R = n-Pr, 80:20 dr R = Ph, 88:12 dr n-Bu4NF, THF, heat n-Bu4NF, THF, heat A B Outline  Introduction - Basic Principle  Application In Carbon—Carbon bond forming Reactions - 4 Membered Silacycle - Aldol and Asymmetric Aldol Reaction - Addition To α,β-Unsaturated Carbonyl - Allylation Reaction - 5 Membered Silacycle - Asymmetric Allylation/Crotylation Reaction - Enantioselective Friedel-Crafts Alkylation Reaction - Enantioselective [3 + 2] Cycloaddition Reaction - Asymmetric Diels Alder Reaction - Tandem Reaction  Application In Natural Product Synthesis  Strain Release Chemistry With Al  Conclusion Synthesis of (+)-SCH 351448 Bolshakov, S.; Leighton, J. L. Org. Lett. 2005, 7, 3809 - Isolated in 2000 - Low-density Lipoprotein receptor Retrosynthesis O OH O CH3 O HO O OHO O O H3C O NaO2C H3C CH3 CO2H H3C CH3 O OBn OH CH3 O NaO2C H3C CH3 O O O OBnOR O H3C CO2H H3C CH3 OO OH O CH3 CH3 OH3C H3C R = TBS A B C RCM 3 4 1 2 5 Steps B C A BnO2C O OBn OH OH H3C CH3 CH35 Synthesis of Dolabelide D: Retrosynthesis Park, P. K.; O’Malley, S. J.; Schmidt, D. R.; Leighton, J. L. J. Am. Chem. Soc. 2006, 128, 2796 - Isolated in 1997 - Important cytotoxic agent Dolabelide D Total Synthesis of Dolabelide D OAc O CH3 OH OH CH3 HO CH3 OH H3C OH O CH3 OAc n-Pr O RCM Esterification 2 3 OAc O H3C O OH CH3 CH3 OAc n-Pr OH OH CH3 OH HO 1 CH3 Dolabelide D A A B B CH3 CH3 PMBO O 4 O PMBO O OH CH3 CH3 5 + Park, P. K.; O’Malley, S. J.; Schmidt, D. R.; Leighton, J. L. J. Am. Chem. Soc. 2006, 128, 2796 Synthesis of Fragment 2 11% overall yield from 6 Total Synthesis of Dolabelide D i. 2 mol % [Rh(acetone)2(P(OPh)3)2]BF4 CO, Benzene, 60 oC ii. MeLi, Et2O, -78 to 23 oC 56% 4:1 dr HO Si HO n-Pr CH3 8 H Si H t-Bu OH n-Pr + 4 mol % CuCl, 4 mol % NaO-t-Bu, 4 mol % (R,R)-BDPP, Benzene 95% 4:1 dr H Si O t-Bu H3C n-Pr 6 7 Silylformylation Crotylsilylation O O OH CH3 OAc n-Pr CH3 2 8 steps t-Bu CH3H3C Synthesis of Dolabelide D  First Total Synthesis of Dolabelide D 14 linear steps from 6  2% Overall yield Park, P. K.; O’Malley, S. J.; Schmidt, D. R.; Leighton, J. L. J. Am. Chem. Soc. 2006, 128, 2796 Synthesis of Fragment 3 2 3+ 4 steps 1 Dolabelide D O H CH3 CH3 OPMB CH3 O PMBO O OH CH3 CH3 ent-13, CH2Cl2; NaH, PMBBr, THF, reflux 53% 6 Steps 12 14 5 Asymmetric Crotylation of aldehyde 4 5+ RO O CH3 OH CH3CH3 5 steps 3 OTESBMPOOAc N Si N p-BrC6H4 p-BrC6H4 Cl R 10 R = H 13 R = CH3 CH3 H O 10, CH2Cl2, - 20 oC 80 % 98 % ee CH3 OH CH3 CH3 PMBO 2 Steps O 9 11 4 Asymmetric Allylation of aldehyde Strain Release Lewis Acidity: Al(III) Complexes Catalyzed Asymmetric Acyl Halide - Aldehyde Cyclocondensation (AAC) Reactions  With Unsubstituted Acylhalide Nelson, S. G.; Spencer, K. L. Angew. Chem. Int. Ed. 2000, 39, 1323 O CH3Br O CH2CH2PhH + 10 mol% 1 i-Pr2NEt, CH2Cl2 - 50 oC 96% O O CH2CH2Ph 97% ee O CH3X O R1H + O O R1 X = Br, Cl O . [R1CHO.Al(III)] Al(III)-Catalyst R3N R3N R3(H)N.X N Al N N Bn CH3 i-Pri-Pr SO2CF3F3CO2S 1 Nelson, S. G.; Kim, B-K.; Peelen, T. J. J. Am. Chem. Soc. 2000, 122, 9318 Strain Release Lewis Acidity: Al(III) Complexes 1.DMF Complex Me N1 N3 Al N2 114.0° Plane angles (sum) = 358.6° Me N1 N3 Al N2 97.5° O H NMe2 99.8° N Al N N Bn CH3 i-Pri-Pr SO2CF3F3CO2S 1 Active Catalyst Inactive Catalyst Lacking a lewis basic residue in the ligand backbone Nelson, S. G.; Kim, B-K.; Peelen, T. J. J. Am. Chem. Soc. 2000, 122, 9318 Ligand defined distorted 4-coordinate geometryKey to reactivity  Strain Release Lewis Acidity: Al(III) Complexes N Al N CH3 TfTf 4 N Al N N Bn CH3 i-Pri-Pr TfTf 1 N Al N N CH3 CH3 TfTf 2 N Al O N CH3 TfTf 3 Total Synthesis of (-)-Malyngolide: (−)-Malyngolide - 4 Steps - 54% Overall Yield Nelson, S. G.; Zhonghui, W. J. Am. Chem. Soc. 2000, 122, 10470 N Al N N Bn CH3 i-Pri-Pr SO2CF3F3CO2S 1 OO H3C nC9H19 OH OHC OBn 10 mol % 1, EtCOBr, i-Pr2NEt, CH2Cl2, -50 oC O O H3C OBn OO H3C nC9H19 OH 85% 94% ee, 91:9 cis:trans 3 Steps 2 3 - An Antibiotic Outline  Introduction - Basic Principle  Application In Carbon—Carbon bond forming Reactions - 4 Membered Silacycle - Aldol and Asymmetric Aldol Reaction - Addition To α,β-Unsaturated Carbonyl - Allylation Reaction - 5 Membered Silacycle - Asymmetric Allylation/Crotylation Reaction - Enantioselective Friedel-Crafts Alkylation Reaction - Enantioselective [3 + 2] Cycloaddition Reaction - Asymmetric Diels Alder Reaction - Tandem Reaction  Application In Natural Product Synthesis  Strain Release Chemistry With Al  Conclusion Conclusion  Release of strain of four or five membered silacycles in going from four coordinated distorted tetrahedral geometry to five coordinated trigonal bipyramidal geometry  Constraining silicon in a small ring (four or five) causes Lewis acidity  Enhanced lewis acidity of five membered silacycles containing heteroatom than four membered silacycles  Application of the Lewis acidity of these silacycles in various type of carbon-carbon bond forming reactions  Lewis acidity of some neutral electron-rich Al (III) complex due to distorted ground state coordination geometry imposed by the ligand backbone