哈佛大学：《高等有机化学》（英文版）Lecture 33 Introduction to Organosilicon Chemistry

D. A. Evans Introduction to Organosilicon Chemistry Chem 206 http://www.courses.fasharvardedu/-chem206/ Problems to Contemplate Chemistry 206 Advanced Organic Chemistry Lecture number 33 TBSO OH OTBS KHMDS THF,-78℃c Introduction to Organosilicon Chemistry icon Bonding Considerations Calter, M. A Ph. D Thesis, Harvard University, 1993 Silicon-Proton Analogy C=0 Addition of organosilanes Sigmatropic Rearrangements of Organosilanes The C=o addition illustrated in eq 1 proceeds while the carbon analogue (eq 2) does not. Explain I Anionic(Brook) Rearrangement I Peterson olefination reaction OTMS I Survey of Silicon(and related) Protecting Groups RO-P Reading Assignment for this Lecture RO OR Carey& Sundberg, Advanced Organic Chemistry, 4th Ed. Part B Chapter 9, " C-C Bond Forming Rxns of Boron, Silicon& Tin", 595 OMe Fleming, I; Barbero, A Walter, D "Stereochemical control in using silicon-containing compounds. "Chem. Rev. 1997, 97, 20 Moser, W.H. The brook Rearrangement in Tandem Bond Formation e, C. E: Panek, J.S. selective reactions of chiral allyl- and bonds"chem.Rev.195,95,1293-1316 Provide a mechanism for the indicated transformation Ager, D J. "The Peterson olefination reaction "Org. Reactions 1990, 38, 1-224 Colvin, E. "Silicon in Organic Synthesis " Butterworths, 1981 人 Bois, et al. "Silicon Tethered reactions"Chem. Rev 1995 95. 1253-1277. Matthew d shair Wednesda December 11. 2002 Takeda, Org. Let, 2000, 2, 903-1905

D. A. Evans Chem 206 Matthew D. Shair Wednesday, December 11, 2002 http://www.courses.fas.harvard.edu/~chem206/ Reading Assignment for this Lecture: Introduction to Organosilicon Chemistry Chemistry 206 Advanced Organic Chemistry Lecture Number 33 Introduction to Organosilicon Chemistry ■ Silicon Bonding Considerations ■ The Silicon–Proton Analogy ■ C=O Addition of Organosilanes ■ Sigmatropic Rearrangements of Organosilanes ■ Anionic (Brook) Rearrangements ■ Peterson Olefination Reaction ■ Survey of Silicon (and related) Protecting Groups Masse, C. E.; Panek, J. S. "Diastereoselective reactions of chiral allyl- and allenylsilanes with activated C-X pi-bonds." Chem. Rev. 1995, 95, 1293-1316. Ager, D. J. "The Peterson olefination reaction." Org. Reactions 1990, 38, 1-224 Fleming, I.; Barbero, A.; Walter, D. "Stereochemical control in organic synthesis using silicon-containing compounds." Chem. Rev. 1997, 97, 2063-2192. (Web) Moser, W. H. "The Brook Rearrangement in Tandem Bond Formation Strategies," Tetrahedron 2001, 57, 2065-2084 (handout) Colvin, E. "Silicon in Organic Synthesis," Butterworths, 1981 KHMDS THF, -78 °C Calter, M. A. Ph. D. Thesis, Harvard University, 1993. 94% Bu3Sn Bu3Sn OMe TBSO Me OH OMe OH OTBS Explain what drives this rearrangement. TBS = Si Me Me CMe3 O TMS RO P OR R P O O RO OR SiR3 R P OTMS O RO OR The C=O addition illustrated in eq 1 proceeds while the carbon analogue (eq 2) does not. Explain (1) R H O O Me RO P OR R P O O RO OR Me R P OMe O RO OR (2) Me OLi Me3Si O X Me H H O OSiMe3 X Takeda, Org. Lett, 2000, 2, 903-1905 Provide a mechanism for the indicated transformation Problems to Contemplate Bois, et al. "SiliconTethered Reactions" Chem. Rev. 1995, 95, 1253-1277. (Handout) Carey & Sundberg, Advanced Organic Chemistry, 4th Ed. Part B Chapter 9, " C–C Bond Forming Rxns of Boron, Silicon & Tin", 595– 680

D. A. Evans Bonding considerations: Carbon vs Silicon Chem 206 Bonding Considerations: Carbon vs Silicon Hypervalent 5-Coordinate Silicon Compounds Average Bond dissociation energies(Kcal/mol) Akiba, " Chemistry of hypervalent Compounds"Wiley-VCH, Chapters 4-5, 1999 C-c C-Si Si-si C-F Si-F Penta-coordinate silicates are commonly observed MesiA nEta Ph3 SiF2 verage Bond Lengths(A) C-H Si-H C-c C-Si C-o Si-c Nucleophilic substitution at Silicon 1541.871431.66 10 F-SiMe ○→ better thai Me3 SHOCMe3 C-SP Duhamel et al. J. Org. Chem. 1996, 61, 2232 gC-c H3C-CH3 BDE= 83 kca/mol H3C-SiH3 BDE -76 kcal/mol OSiMe3 Bond length=1.534A Bond length =1.87A HF This trend is even more dramatic with pi-bonds Stork et al. JACS. 1968. 90. 4462 4464 TC-C= 65 kcal/mol C-Si= 36 kcal/mol I Si-Si= 23 kcal/mol i Thermal Rearrangements One may readily access divalent intermediates Group /V Electronegativities(Pauling CH2 H,C=Cl Carbon Silicon Germanium Tin Lead Me 255 190 201 196233 +2 Oxidation state becones increasingly more stable

D. A. Evans Bonding Considerations: Carbon vs Silicon Chem 206 Bonding Considerations: Carbon vs Silicon C–C C–Si 83 76 Si–Si 53 C–O Si–O 86 108 C–H Si–H 83 76 C–F Si–F 116 135 Average Bond dissociation eneregies (Kcal/mol) C–C C–Si 1.54 1.87 C–O Si–O 1.43 1.66 Average Bond Lengths (Å) p C–C = 65 kcal/mol p C–Si = 36 kcal/mol p Si–Si = 23 kcal/mol This trend is even more dramatic with pi-bonds: s* C–Si s* C–C s C–Si s C–C Bond length = 1.87 Å Bond length = 1.534 Å H3C–SiH3 BDE ~ 76 kcal/mol H3C–CH3 BDE = 83 kcal/mol better than Group IV Electronegativities (Pauling) Carbon Silicon Germanium Tin Lead 2.55 1.90 2.01 1.96 2.33 +2 Oxidation state becones increasingly more stable C Si d– d+ Hypervalent 5-Coordinate Silicon Compounds Akiba, "Chemistry of hypervalent Compounds" Wiley-VCH, Chapters 4-5, 1999 Penta-coordinate silicates are commonly observed Nucleophilic substitution at Silicon F F–SiMe3 + OSiMe3 KOCMe3 O K Me3Si–OCMe3 Duhamel et al. J. Org. Chem. 1996, 61, 2232 OSiMe3 MeLi O Li Me3Si–Me Stork et al. JACS. 1968, 90, 4462, 4464 THF THF –20 ° 2h Thermal Rearrangements One may readily access divalent intermediates Si Me Me Si CH2 Me Me H2C CH2 thermolysis H Si Me Me thermolysis Si Me Me Si Me Me H Colvin, pp 7-9 C-SP3 Si-SP3 C-SP3 C-SP3 C C C C C Si C Si MeSiF4 NEt4 Ph3SiF2 NR4 RO–SiMe3 RO

K Scheidt D. A. Evans Hypervalent Silicon Ate-Complexes Chem 206 1689A CF Inorg Chem. 1984, 23, 13 J.Am. Chem. Soc.1987,109,476 2.198A 1668A 1604A 2.104A 1597A J Organomet Chem. 1981, 221, 137 Acta Crystallogr. Sect. C 1984, 40,476

K. Scheidt, D. A. Evans Hypervalent Silicon Ate-Complexes Chem 206 1.689 Å 1.647 Å Inorg. Chem. 1984, 23, 1378 J. Am. Chem.Soc. 1987, 109, 476 Si Ph Ph O F3C CF3 F F Si Ph Ph F CF3 F S(NMe2 )3 J. Organomet.Chem. 1981, 221, 137. F Si F Ph F F 1.668 Å 1.604 Å 1.597 Å Acta Crystallogr. Sect. C 1984, 40, 476 Cl Me O 2.104 Å 2.198 Å

D. A. Evans Bonding considerations: Carbon vs Silicon Chem 206 Carbonyl addition Reactions The prospect of catalysis was investigated 1970 DAE Objective: Develop a reagent that will transform aldehydes into protected cyanohydrins in one step Me3Si-CN 1-5 min OSiMe3 reaction was instaneous and quantitative OSiR3 1-5 min i Principle established that normally inaccessible cyanohydrin derivatives G=carbanion-stabilizing FG Carbonyl Anion Equivalent may now be accessed TMSO CN >95% yield R3Si-G Candidates Carbonyl Adducts only 1, 2-addition OSiR3 95%ye R,Si-CN with Truesdale, Carroll, Chem Commun. 1973, 55: J. Org. Chem. 1974, 39, 914 Tetrahedron Lett 1973, 4929(first discussion of Nu catalysis) OSiR R3Si-OSO,Ar R- The Silicon Advantage From the preceding case, it is clear that AHs is more exothermic than AHH R3Si-OPR R-tPOR2 X XcN一 Hsi>AH Thermalc=o addition of mscn is not a clean reaction Nucleophilic Catalysis e3SI-CN OSiMe ato:65:35

D. A. Evans Bonding Considerations: Carbon vs Silicon Chem 206 Carbonyl addition Reactions 1970 DAE Objective: Develop a reagent that will transform aldehydes into protected cyanohydrins in one step R H O SiR3 G + R G OSiR3 H R G OSiR3 Li R3Si G Candidates Carbonyl Adducts R3Si CN R CN OSiR3 H R3Si OSO2Ar R SO2Ar OSiR3 H R3Si OPR2 R POR2 OSiR3 H G = carbanion-stabilizing FG Carbonyl Anion Equivalent Thermal C=O addition of TMSCN is not a clean reaction + Me3Si CN C5H11 H OSiMe3 CN 50 C° Me H O C4H9 H OSiMe3 + ratio: 65:35 2-5 hr The prospect of catalysis was investigated C5H11 H OSiMe3 CN 1-5 min ZnI2 reaction was instaneous and quantiltative 1-5 min CN– Principle established that normally inaccessible cyanohydrin derivatives may now be accessed Me Me Me OTMS CN >95% yield (ZnI2 catalysis) Me Me TMSO Me CN 92% yield only 1,2-addition (ZnI2 catalysis) O TMSO CN >95% yield only 1,2-addition (CN– catalysis) with Truesdale, Carroll, Chem Commun. 1973, 55; J. Org. Chem.. 1974, 39, 914 Tetrahedron Lett 1973, 4929 (first discussion of Nu catalysis) + Me3Si CN Me H O "The Silicon Advantage" R R O + X CN R R O–X CN DHSi > DHH From the preceding case, it is clear that DHSi is more exothermic than DHH R R O Nucleophilic Catalysis C N R R O CN Me3Si CN R R OTMS CN C N + LiNR2

D. A. Evans Carbonyl Addition Reactions-2 Chem 206 Explain the following observations The Proton-Silicon Correlation +○c三N 1-4 addition with their proton counterparts but with an attendant greater exothermicity i Organosilanes undergo a range of thermal rearrangements processes in direct analogy with their proton counterparts TMSCN 1-2 addition k(S=106K(H TMSO CN A J. Ashe Ill. JACS 1970. 92. 1233 OSiMe. heat c Colvin, pp 37-8 th Truesdale Grimm, Nesbitt, JAcs1975,97,3229 JAcS1977.99.5009 OTMS Si transfer is intramolecular etal,JAcS1974.96,4283 Non-catalyzed processes may also occur if a proper geometry for atom transfer can be achieved oc1976.41 Me3Sc式N→-CN-SMe3 MS Organosilicon hydrides undergo transition metal catalyzed hydrosilylation processes in direct analogy with normal hydrogenation reactions H RO-P RO OR H-SIRa Me H-H Me 8/-8~m RhO catalysis Rh(o catalysis Hydrosilylation of C-C Bonds". T. Hayashi In Comprehensive Asymmetric Catalysis, Jacobsen, E.N. Pfaltz, A and Yamamoto, H Editors; Springer Verlag eidelberg, 1999; Vol L, 319-332

D. A. Evans Carbonyl Addition Reactions-2 Chem 206 Explain the following observations O O + C N OH OH CN THF/H2O O TMSO CN TMSCN O O + benzene C N 1-4 addition 1-2 addition R1 R2 OSiMe3 SR RS– ZnI2 R1 R2 SR SR with Truesdale, Grimm, Nesbitt, JACS 1975, 97, 3229 JACS 1977, 99, 5009 Me3Si SR R1 R2 O + Me3Si OEt O N2 R H O CN– or F– OEt O N2 R OTMS 1-5 min with Truesdale, Grimm JOC 1976, 41, 3335 R H O O TMS RO P OR + R P O O RO OR SiR3 R P OTMS O RO OR with Hurst, Takacs JACS 1978, 100, 3467 Non-catalyzed processes may also occur if a proper geometry for atom transfer can be achieved R O P O R OR TMSO RO R OTMS P O RO RO "The Proton–Silicon Correlation" ■ Organosilanes undergo carbonyl addition processes in direct analogy with their proton counterparts but with an attendant greater exothermicity. ■ Organosilanes undergo a range of thermal rearrangements processes in direct analogy with their proton counterparts. X H X H k(Si) =10+6 K(H) A. J. Ashe III, JACS 1970. 92, 1233 O O Me3Si O Me MeMe Me C O O SiMe3 O Me Me Me Me heat Colvin, pp 37-8 ■ Organosilicon hydrides undergo transition metal catalyzed hydrosilylation processes in direct analogy with normal hydrogenation reactions R N O SiR3 SiR3 R N O SiR3 SiR3 Yoder et al., JACS 1974. 96, 4283 DG* 15-22kcal/mol Si transfer is intramolecular Me3Si C N C N SiMe3 rt H–SiR3 H–H R Me R Me H R Me SiR3 Rh(I) catalysis Rh(I) catalysis "Hydrosilylation of C–C Bonds". T. Hayashi In Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; and Yamamoto, H. Editors; Springer Verlag: Heidelberg, 1999; Vol I, 319-332

D. A. Evans Carbonyl[1, 2]&[1, 3] Sigmatropic Rearrangements Chem 206 [1, 3-Sigmatropic Rearrangements The Brook Rearrangement(s) Rsi Rsi A G. Brook Accts. Chem. Research 1974.. 77-84 R Y=C; X=O Ea=8-11 kcal/mol Complete retention of Si OSiR3 Ea= 28 kcal/mol Ph A G. Brook Accts. Chem. Research 1974. 7.77-84 OEt Brook speculates that a hypervalent Si intermediate. Brook has documented that retention at Silicon inversion at Carbon occur might be involved in the rearrangemer Transformations Involving the Brook Rearrangement Y=C: X= C Moser, W.H. The Brook Rearrangement in Tandem Bond Formation Strategies, Tetrahedron 2001, 57, 2065-2084 CH Inversion of si Acylsilanes stereochemistry was noted O R2BH HC H Ea 48 kcal/mol H.Kwartetal,JACS1973.95,8678 Theoretical calculations lead to the conclusion that the concerted [1, 3] E+) sigmatropic rearrangement with retention of Si-configuration should represent the lower energy pathway Yamabe, JACS 1997. 119. 808 12SR3s、 At the present time these rearrangements are not well studied

D. A. Evans Carbonyl [1,2] & [1,3] Sigmatropic Rearrangements Chem 206 "The Brook Rearrangement(s)" [1,3]-Sigmatropic Rearrangements Y C X R3Si R Y C X R R3Si Np Si Ph Me O Ph Y = C; X = O 110 °C Ph O Np Si Me Ph Np Si Ph O Me Ph Complete retention of Si stereochemistry was noted. Ea = 28 kcal/mol A. G. Brook Accts. Chem. Research 1974, 7, 77-84 Brook speculates that a hypervalent Si intermediate might be involved in the rearrangement. Y = C; X = C Np Si CH2 Me Ph H 500 °C H2C H Ph Si Me Np Inversion of Si stereochemistry was noted. Ea = 48 kcal/mol H. Kwart et al., JACS 1973. 95, 8678 Theoretical calculations lead to the conclusion that the concerted [1,3] sigmatropic rearrangement with retention of Si-configuration should represent the lower energy pathway. Yamabe, JACS 1997, 119, 808 At the present time these rearrangements are not well studied, A. G. Brook Accts. Chem. Research 1974, 7, 77-84 C OH R3Si Ph Ph C O H Ph Ph SiR3 Et2NH DMSO Et2NH C O R3Si Ph Ph C O SiR3 Ph Ph Ea ~ 8-11 kcal/mol H N H Et Et H N H Et Et Brook has documented that retention at Silicon & inversion at Carbon occur. Transformations Involving the Brook Rearrangement Moser, W. H. "The Brook Rearrangement in Tandem Bond Formation Strategies," Tetrahedron 2001, 57, 2065-2084 R SiR3 O Acylsilanes Li R El(+) R R3Si O R R O R Li R3Si Li El(+) R O R R3Si El [1,2] Si SiR3 O Cl O Li SiR3 Cu(I) R R R2BH [Ox] R SiR3

D.A. Evans Transformations Involving the Brook Rearrangement Chem 206 Transformations Involving the Brook Rearrangement intramolecular alkylations may be carried out. Moser. W. H "The Brook ment in Tandem Bond formaton OTMS Rso日 [1, 2 Si RaSi R [12]Si Takeda JACS 1993, 115, 9351: Synlett 1994, 178: SynLett 1997, 255 These reagents are useful homoenolate anion equivalents CH2+) OSiMe3 Evans. d.a Andrews. g. c: Buckwalter. B. JACS 1974. 96 5560 Me? si a Si-Variant: still Mac Donald JAcs 1974. 96 5561 Brook Equilibrium Reich JACS 1980, 102, 1423(see footnote 8) 33] Me3Si SiMe OSiMe3 12]Si THF SiMe Tetrahedron 2001. 57. 2065-2084. footnote 16

D. A. Evans Chem 206 Transformations Involving the Brook Rearrangement Moser, W. H. "The Brook Rearrangement in Tandem Bond Formation Strategies," Tetrahedron 2001, 57, 2065-2084 R SiR3 O Li R El(+) R R3Si O R R O R Li R3Si Li El(+) R O R R3Si El [1,2] Si O R R3Si s-BuLi O R R3Si Li O R Li SiR3 O R R3Si El El(+) O R These reagents are useful homoenolate anion equivalents R CH2 (–) O "Metalated Allylic Ethers as Homoenolate Anion Equivalents". Evans, D. A.; Andrews, G. C.; Buckwalter, B. JACS 1974, 96, 5560. Si–Variant: Still & MacDonald JACS 1974, 96, 5561 Brook Equilibrium C OLi Me3Si Ph Ph C O Li Ph Ph SiMe3 THF C OLi Me3Si H Ph C O Li H THF Ph SiMe3 Reich JACS 1980, 102, 1423 (see footnote 8) Reich JACS 1980, 102, 1423 R SiR3 O Li (CH2 )4–I R C OTMS R H3O O + Intramolecular alkylations may be carried out: SiR3 O PhS R OLi OSiMe3 OH R PhS Takeda JACS 1993, 115, 9351; Synlett 1994, 178; SynLett 1997, 255 PhS O LiO SiR3 R [1,2] Si PhS O OSiMe3 R SiR3 O PhS OLi R OSiMe3 OLi R Me3Si PhS LiO SiR3 O R [1,2] Si PhS OSiMe3 O R PhS OSiMe3 OLi R [3,3] Tetrahedron 2001, 57, 2065-2084, footnote 16 Transformations Involving the Brook Rearrangement

D.A. Evans Transformations Involving the Brook Rearrangement Chem 206 The natural product target The key reaction bUli Me3Si-CH-SMe OLi TMEDA carbanion-stabizing groups facilitate elimination Elimination could also be effected with dilute acid SiMe3 Takeda, Org. Lett, 2000, 2, 903-1905 Me3SI OI The B-Effect (lecture 31) 10% H2so4 The peterson olefination reaction Org. Reactions 1990, 38, 1-224 C N analogy provided by whitmore et al. JACS 1947, 69, 1551 The key paper: Peterson, J. Org. chem. 1968, 33, 780-784 It was Petersons intent to find a silicon analog to the Wittig xn. The reaction concept is outlined below. Mechanistic aspects of Beta-OH Elimination Me3Si-CH2M R The B-Efect (lecture 31) Me3Si-O Hudrlik et al JACS 1975. 97. 1464 Colvin chapter 12, pp 141 Me3Si 0-MgCl Me3 Si-CH2MgCI Na& alkoxides: Eliminate R2CuLi He Me3Si OH KH Me3 Si-OK(Na ote site of nu attack. why

D. A. Evans Transformations Involving the Brook Rearrangement Chem 206 Me OLi Me3Si O X Me H H O OSiMe3 X Takeda, Org. Lett, 2000, 2, 903-1905 Me H RO CHO Me Me The natural product target: The key reaction The Peterson Olefination Reaction The key paper: Peterson, J. Org. chem. 1968, 33, 780-784 C N Si P It was Peterson's intent to find a silicon analog to the Wittig rxn. The reaction concept is outlined below: R R O Me3Si CH2M OM R R Me3Si O R R Me3Si M OM R R Me3Si Me3Si CH2MgCl R R O O–MgCl R R Me3Si these adducts are quite stable Magnesium alkoxides: Stable Na & K alkoxides: Eliminate OH R R Me3Si KH R R Me OK (Na) 3Si rt Elimination could also be effected with dilute acid 10% H2SO4 R R Me3Si OH rt analogy provided by Whitmore et al. JACS 1947, 69, 1551 Me3Si CH2 SMe nBuLi TMEDA Me3Si CH SMe Li Me3Si CH SMe Li O Ph Ph C Ph Ph MeS carbanion-stabiizing groups facilitate elimination H OH R R Me3Si Mechanistic aspects of Beta-OH Elimination Me3Si OH Pr H Pr H H + Pr H Pr H Anti Elimination Me3Si OK Pr H Pr H KH H Pr Pr H Syn Elimination Hudrlik et al. JACS 1975, 97, 1464 Colvin chapter 12, pp 141 Ager, D. J. "The Peterson olefination reaction." Org. Reactions 1990, 38, 1-224 R3Si OH Pr H R H Me3Si O Pr H H KH R H Pr H reaction is stereospecific note site of nu attack. Why? The b-Effect (lecture 31) The b-Effect (lecture 31) R2CuLi

D. A. Evans The peterson olefination reaction Chem 206 a Simple Examples: Taken from Organic Rxns review Miyakolide(+1-1 Ripin, Halstead, and Campos Me3 Si-CH2Mge→ cs199121,68166826 Nah orison This reagent is better that H2C=PPh3 for hindered ketones olefin geometry challenge Boeckman, Tet. Lett 1973, 3437 0 OMe TMS LNOM OEt >95% Nozaki JACS 1974. 96. 1620 OPMB OPMB CO, Me B-BuLi ba olvent E: Z >90% LDA THF 73:27 NaHMDS THF 18:82 Chan. Tet. Lett 1978. 2383 LDA PhMe 66: 33 n-Hexyl Chan, Chem. Commun 1982, 969 Hudrlik, JACS 1981, 103, 6251

D. A. Evans The Peterson Olefination Reaction Chem 206 Boeckman, Tet. Lett 1973, 3437 ■ Simple Examples: Taken from Organic Rxns review NaH orTsOH This reagent is better that H2C=PPh3 for hindered ketones >90% O Me3Si CH2MgBr OH SiMe3 CH2 Me O Me H H Me H2C Me Chan, Tet. Lett 1978, 2383 Nozaki, JACS 1974, 96, 1620 >95% >90% O Me3Si OEt O O OEt Me3Si SiMe3 OH O O O O Me Me Me H O Me OH Me OH OH OMe OH Me O O Miyakolide (+)-1 H H O OPMB O OMe Me O Xp 1 9 O OPMB OMe Me O Xp 1 9 CO2Me entry base solvent E : Z 1 2 3 4 LDA NaHMDS 73 : 27 18 : 82 66 : 33 66 : 33 LDA LDA TMS OMe O Conditions –78 °C 19-E with Ripin, Halstead, and Campos JACS 1999, 121, 6816-6826. Miyakolide presents an interesting olefin geometry challenge Chan, Chem. Commun 1982, 969 R OH SiMe3 Me3Si B O O Me Me Me R Me R Hudrlik, JACS 1981, 103, 6251 Me3Si H n-Hexyl O OH CMe3 OLi n-Hexyl Me3Si CMe3 O O CMe3 n-Hexyl OH CMe3 n-Hexyl OH n-Hexyl Me3Si CMe3 OH LiN(TMS)2 t-BuLi MgBr2 SOCl2 THF Et2O THF PhMe H + KH RCHO BF3 •OEt2 KH

D. A. Evans The peterson olefination Reaction Chem 206 Bunnelle-Peterson Allylsilane Synthesis TMSO KN(TMS)2 silica gel TMSO M=L→M=CeCl 93% (E四=1:7 Application to Leucasandrolide: Rychnovsky JACS,2001, 123, 8420 ( t-Bu)Me?si ell et al. Tetrahedron 1994. 50. 6643 OH HO Reaction may be altered significantly with an attendant chenge in stereoselection The seco acid eland Enolate Claisen Coupled to Peterson Olefination 5.5: 1 ratio SiMe The Pivotal Step TMSCI OH O CH2N2 BF3. 0Et2 BF3“OEt2 OTBS ato et al. chem. Lett 1986. 1553 TBSO silica gel TBs

D. A. Evans The Peterson Olefination Reaction Chem 206 O Me N O N O Me OTMS TMSO Me Me OTMS O O O Me OTMS TMSO Me Me OTMS O N O N O Me Me3Si KN(TMS)2 (E):(Z) = 13:1 O O Me OTMS TMSO Me Me OTMS O N O N O Me (t-Bu)Me2Si t-BuLi (E):(Z) = 1:7 Bell et al. Tetrahedron 1994, 50, 6643 Reaction may be altered significantly with an attendant chenge in stereoselection R SiMe3 O O OH LiN(TMS)2 TMSCl CH2N2 R CO2Me SiMe3 OH syn:anti = 96:4 (See Lecture 15) Ireland Enolate Claisen Coupled to Peterson Olefination R CO2Me R CO2Me KH BF3 •OEt2 Sato et al. Chem. Lett 1986, 1553 Application to Leucasandrolide: Rychnovsky JACS, 2001, 123, 8420 O OMe O Me OH Me Me O O O OMe O Me OH Me Me O HO The seco acid OH The Pivotal Step: O O Me OBn H O SiMe3 TBSO O OH O Me OBn OTBS BF3 •OEt2 base, 78% 5.5:1 ratio Bunnelle-Peterson Allylsilane Synthesis R O R O Me3Si CH2M R 2 SiMe3 SiMe3 OH M = Li ® M = CeCl2 silica gel R SiMe3 Me THPO SiMe3 90% Ph SiMe3 Me 93% TMSO SiMe3 TBSO TMSO O OEt TBSO TMSCH2MgCl CeCl3 silica gel 87%