哈佛大学：《高等有机化学》（英文版）Lecture 22 A A Survey of "Soft Enolization" Techniques

Chemistry 206 Advanced Organic Chemistry Handout-22A A Survey of"Soft Enolization"Techniques Mark bilodeau Evans Group seminar, March 10, 1993 Matthew d. shair Friday November 8. 2002

Chemistry 206 Advanced Organic Chemistry Handout–22A A Survey of "Soft Enolization" Techniques Mark Bilodeau Evans Group Seminar, March 10, 1993 Matthew D. Shair Friday November 8, 2002

M. Bilodeau. D.A. Evans A Survey of Soft Enolization Techniques Chem 115 Alkoxides of lanthanum and yttrium A Survey of Soft Enolization Techniques Sasai. Suzuki. Arai. Arai. Shibasaki J. Am. Chem. Soc. 1992. 114. 4418-4420 PhCHO CI THE Lay(ot-Bu)g(3. 3 mol%), -72 C, 30 h, 74% yield Metal alkoxides Zr(ot-Bu)4( 140 mol%), -50 C, 2.5 h, 86% yield Ti(Ot-Bu)4-No coupling product I. Lewis acid/ amine base enolizations A. Horner-Emmons reactions a Catalytic Enantioselective Aldol Reactions of Nitroalkanes B. Glycine Enolates C Methods for General Carbonyl Substrates Laa(0t-Bu)(3.3 mol%) THE MeNO2, 10 equi D Boron Enolates-Enolate Stereochemistry (S)-Binaphthol (15 mol%) LiCL 20 mol% H 'H NMR shows absence of a t-Butoxy group on the catalys R=C-C6H11, 91% yiel ee Mark bilodeau Evans Group Meeting 3/10/93 Tetrahedron Lett. 1993. 34. 851-854 0 -Naphto 50 equiv -50°c,60h Catalyst prepared from: LaCl 7H20(10 mol%) 80% yield (R)(+)bi de(10m%) H20(10 mol%) 22A-01 Ketone Acidity 11/1/01 3: 41 PM

Sasai, Suzuki, Arai, Arai, Shibasaki J. Am. Chem. Soc. 1992, 114, 4418-4420. PhCHO + Catalyst THF Ti(Ot-Bu)4 - No coupling product La3(Ot-Bu)9 (3.3 mol%), -72° C, 30 h, 74% yield Y3(Ot-Bu)8Cl (3.3 mol%), -43° C, 3.5 h, 50% yield Zr(Ot-Bu)4 (140 mol%), -50° C, 2.5 h, 86% yield La3(Ot-Bu)9 (3.3 mol%) (S)-Binaphthol (15 mol%) + THF, rt 2 h 1H NMR shows absence of a t-Butoxy group on the catalyst RCHO, 1 equiv MeNO2, 10 equiv LiCl, 20 mol% H2O, 1 equiv R = c-C6H11, 91% yield, 90% ee R = i-Pr, 80% yield, 85% ee R = PhCH2CH2CHO, 79% yield, 73% ee ■ Catalytic Enantioselective Aldol Reactions of Nitroalkanes Sasai, Itoh, Suzuki, Shibasaki Tetrahedron Lett. 1993, 34, 855-858. Tetrahedron Lett. 1993, 34, 851-854. 1 equiv + MeNO2 50 equiv Catalyst -50° C, 60 h LaCl3•7H2O (10 mol%) (R)-(+)-binaphthoxide (10 mol%) NaOt-Bu (10 mol%) H2O (10 mol%) Catalyst prepared from: 80% yield 92% ee Alkoxides of Lanthanum and Yttrium Mark Bilodeau Evans Group Meeting 3/10/93 A Survey of 'Soft' Enolization Techniques D. Boron Enolates - Enolate Stereochemistry I. Metal Alkoxides II. Lewis Acid/ Amine Base Enolizations A. Horner-Emmons Reactions B. Glycine Enolates C. Methods for General Carbonyl Substrates M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques Chem 115 O Me Cl Me O Ph HO Cl NO2 R HO α−NaphtO NO2 OH α−NaphtO CHO 22A-01 Ketone Acidity 11/1/01 3:41 PM

M. Bilodeau. D.A. Evans A Survey of Soft Enolization techniques Chem 115 Horner-Wadsworth -Emmons reaction Lewis Acid -Tertiary Amine Enolizations i-PrCHO, 1 equiv oEt MecN 1.2 equiv 了 pKa 19.2( DMSO), K,counterion Base= DIPEA, 7 h, 97%, >50: 1E:Z pKa 12.2( Diglyme), Li counterion R'3N-MLn NHCbz NHCbz 85%+ 10% recovered aldehyde a Acidity of a-protons enhanced by coordination of Lewis acid Conventional methods of deprotonation(NaH)resulted in epimerization I This allows the use of mild bases to depronate substrate I A critical issue in the success of procedure of enolization is the Rathke, Nowak J. Org. Chem. 1985, 50, 2624-2626 reversible Lewis acid/amine base association R3N MLn R3NLn a Many reactions surveyed here dont rely on complete enolization of the carbonyl substrate. If the electrophile can withstand the reaction conditions it can access an equilibrium concentration of the enolate R= i-Pr, 40% yield R= n-CaH13, 100% yield 22A-02 Ketone Acidity 11/1/01 3: 41 PM

R3N MLn R3N + MLn ■ Many reactions surveyed here don't rely on complete enolization of the carbonyl substrate. If the electrophile can withstand the reaction conditions it can access an equilibrium concentration of the enolate. pKa 19.2 (DMSO), K+ counterion pKa 12.2 (Diglyme), Li+ counterion LiCl, 1.2 equiv Base, 1.0 equiv i-PrCHO, 1 equiv MeCN 1.2 equiv rt Horner-Wadsworth-Emmons Reaction. Base = DBU, 5 min, 99%, >50:1 E:Z Base = DIPEA, 7 h, 97%, >50:1 E:Z Above conditions using DIPEA 24 h, rt 85% + 10% recovered aldehyde Conventional methods of deprotonation (NaH) resulted in epimerization (Overman JACS 1978, 5179). R= i-Pr, 40% yield R= n-C6H13, 100% yield 1 equiv MgBr2, 1.2 equiv Et3N, 1.1 equiv RCHO, 1 equiv THF rt Rathke, Nowak J. Org. Chem. 1985, 50, 2624-2626. El+ ■ Acidity of a-protons enhanced by coordination of Lewis acid. ■ This allows the use of mild bases to depronate substrate. ■ A critical issue in the success of procedure of enolization is the reversible Lewis acid/amine base association. Lewis Acid - Tertiary Amine Enolizations + MLn R'3N R'3N-MLn R'3N - + M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques Chem 115 R O Me Me O R MLn O MLn-1 R Me O R Me El O OEt (EtO)2P O R OEt O O OEt (EtO)2P O OEt O Me Me NHCbz CHO Me Me NHCbz OEt O 22A-02 Ketone Acidity 11/1/01 3:41 PM

M. Bilodeau. d.A. evans A Survey of Soft Enolization Techniques Chem 115 Formation of Glycine Enolate h、∠N、CO2Me co Me Elan, 1 equiv CO2R Kanemasa, Yoshioka J. Org. Chem. 1988 anemasa,Uchida, Wada. Org. Chem. 1990, CH2Cl, rt Co-Me LiBr, 1.5 equiv 1.2: 1 R=Me/R: Et3N, 1.2 equiv COmE Note: Regiochemistry of addition opposite to that above lequiv THF. rt Glycine Enolate CuCl. 5 mol% cN、CO2Me+RcHo EtN. 5 mol% Et2, Znl2, EtAICl employed in related reactions Ito tet. lett. 1985. 5781 869874) R= Me, 100% yield, 2: 1 trans/cis LiBr, 1.1 equiv R=Et2CH, 75% yield, trans only DBU, 1.0 equ When only EtN is employed -complex mixtures, low yields COmE THF. rt 77% yield, single isomer Ito, Sawamura, Hayashi J. Am. Chem. Soc., 1986, 108, 6405-6406. Grigg et al Tetrahedron198844557570;1989,4546494668 Tetrahedron lett.1989,30,4727-4730,1990,31,65696572 ,西 CO, Me [Au(c-HexNC)2) 'BF4/1(1 mol%) iPrCHO +CN OMe COmE Meo cH2Cl225°c ZnBr2, THF, 90% yield, 1: 2.7 99% yield, 98: 2 trans/cis AgOAc, THF, 90% yield, 1:>9 Related reactions have been conducted with MnBr2, MgBr2OEt, TINO3, CoCh the basis of Cu()'s strong preference for N coordination. Ago has recently been optimised to provide moderate-to-good enantioselectivity Hayashi, Ito et al. Tet Lett. 1991, 32, 2799-2802 22A-03 Ketone Acidity 11/1/01 3: 41 PM

M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques Chem 115 77% yield, single isomer 1 equiv 1 equiv + LiBr, 1.1 equiv DBU, 1.0 equiv THF, rt NaI, MgBr2•OEt2, ZnI2, Et2AlCl employed in related reactions (Bull. Chem. Soc. Jpn. 1989, 62, 869-874). 82% yield AgOAc, THF, 90% yield, 1:>9 ZnBr2, THF, 90% yield, 1:2.7 Formation of Glycine Enolates. Tsuge, Kanemasa, Yoshioka J. Org. Chem. 1988, 53, 1384-1391. Kanemasa, Tatsukawa, Wada, Tsuge Chem. Lett. 1989, 1301-1304. Kanemasa, Uchida, Wada J. Org. Chem. 1990, 55, 4411-4417. LiBr, 1.5 equiv Et3N, 1.2 equiv THF, rt + + Grigg et al Tetrahedron 1988, 44, 557-570; 1989, 45, 4649-4668. Tetrahedron Lett. 1989, 30, 4727-4730; 1990, 31, 6569-6572. 1 equiv 1 equiv 1 equiv 2 equiv Ti(Oi-Pr)3Cl, 1.5 equiv Et3N, 1 equiv CH2Cl2, rt 80% yield 1.2:1 R=Me/R=i-Pr Note: Regiochemistry of addition opposite to that above. + + Lewis Acid Et3N Solvent rt LiBr, MeCN, 89% yield, 1:6 Related reactions have been conducted with MnBr2, MgBr2•OEt2, TlNO3, CoCl2 • Cu(I) catalyzes the reaction but with no enantioselectivity. This has been rationalized on the basis of Cu(I)'s strong preference for N coordination. • Ag(I) has recently been optimised to provide moderate-to-good enantioselectivity . Hayashi, Ito et. al. Tet. Lett. 1991, 32, 2799-2802. CH2Cl2, 25 °C [Au(c-HexNC)2]+BF4- / 1 (1 mol%) i-PrCHO + 1a : R=Et 1b : R=Me Ito, Sawamura, Hayashi J. Am. Chem. Soc., 1986, 108, 6405-6406. (R)-(S) Ito Tet. Lett. 1985, 5781. + RCHO CuCl, 5 mol% Et3N, 5 mol% THF, RT • When only Et3N is employed - complex mixtures, low yields R= Me, 100% yield, 2:1 trans/cis R=Et2CH, 75% yield, trans only 99% yield, 98:2 trans/cis 92% ee Glycine Enolates Ph N CO2Me CO2Me H Ph CO N 2Me MeO2C N O OMe O Li MeO Ph CO2Me N CO2Me Ph N CO2Me CO2Me Ph CO2R H N Ph Me CO2Me MeO2C MeO2C Ph CO2Me H N H Ph CO N 2Me CO2Me MeO2C CO2Me Me Me Me Me Me N Me t-Bu CO2Me CO2Me Me CO2Me t-Bu N CO2Me CN O Fe OMe O PPh2 N PPh2 NCH2CH2NR2 Me H Me i-Pr CO2Me CN CO2Me O N R CO2Me 22A-03 Ketone Acidity 11/1/01 3:41 PM

M. Bilodeau. D.A. Evans A Survey of Soft Enolization Techniques Chem 115 Lithium halide enolizations Magnesium Enolates Kelleher, McKervey, Vibuljan Chem Comm. 1980, 486-488 1986.16.1133-1139 Diethylmalonate acylation C.1 R= n-CBH11, 85% CI MeCN. rt TMSCL, Et3N 85% yield Et20, reflux Reaction can be brought about with less than 1 equiv of Lil. COOH Kaiser. Fohlisch He/. Chim. Acta. 1990. 73. 1504-1514 70% yield 人 MgCh, 2 equiv Et3N, 4 equiv EtOH 75% yield Evans, Bilodeau unpublished results Harmata. Elahmad Tetrahedron lett. 1993. 34. 789-792 MgBr2.0Et2 3M LICIO4 Et2O 16: 1 ratio of isomers Deuterium quench indicates 25% enolization of N-propionyloxazolidinone 22A-04 Ketone Acidity 11/1/01 3: 42 PM

Rathke M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques Chem 115 16:1 ratio of isomers 3M LiClO4 Et3N Et2O Harmata, Elahmad Tetrahedron Lett. 1993, 34, 789-792. 70% yield + LiClO4 Et3N Et2O Kaiser, Fohlisch Helv. Chim. Acta. 1990, 73, 1504-1514. "Reaction can be brought about with less than 1 equiv of LiI." 76%, 60:40 ratio of diastereomers LiI TMSCl, Et3N Et2O, reflux PhCHO R= Ph, 77% R= n-C6H11, 85% slow addn of: RCHO Et2O reflux 4 equiv + LiI 1 equiv Lithium Halide Enolizations Kelleher, McKervey, Vibuljan Chem. Comm. 1980, 486-488. - Evans, Bilodeau unpublished results. 73% yield, 93:7 diastereomer ratio Magnesium Enolates Deuterium quench indicates 25% enolization of N-propionyloxazolidinone MgBr2•OEt2 Et3N CH2Cl2, 0° C 75% yield MVK EtOH MgCl2, 2 equiv Et3N, 4 equiv CO2 MeCN rt 70 % yield MgCl2, 2 equiv NaI, 2 equiv Et3N, 4 equiv CO2 MeCN rt Ketone Carboxylation 85% yield MgCl2, 1 equiv Et3N, 2 equiv MeCN, rt Diethylmalonate acylations J. Org. Chem. 1985, 50, 2622-2624. J. Org. Chem. 1985, 50, 4877-4879. Syn. Comm. 1986, 16, 1133-1139. Me O Me Me O R Me O Me Me O Me Ph OH O O Cl Cl Cl O O O O Cl O O Cl O O O EtO O OEt Me O Cl OEt O EtO O O Me O O COOH O O O O Mg O Me O O N Bn O Me O CO2Me O Me N O Bn O CO2Me 22A-04 Ketone Acidity 11/1/01 3:42 PM

M. Bilodeau, D A. evans A Survey of Soft Enolization Techniques Chem 115 Miscellaneous metals Tin(I)triflate a Bis(2, 4-pentanedionato)nickel() Mukaiyama, Stevens, Iwasawa Chem Lett. 1982, 353 Nelson, Howells, DeLullo, Landen J. Org. Chem. 1980, 45, 1246-1249 R3N Ph(CH2)2CHO Ni(acac(1 mol%) dioxane 85°c,19h Base Et3N, 50% yield (15% self-condensation) . yield (65%) N-Ethylpiperidine, 80%( trace) ■ Zinc chloride Danishefsky, Kiahara J. Am. Chem. Soc. 1974, 96, 7807-7808 Sn(oTi)2 H-ethylpiperidine APrCHO ZnCh, 3 mol TMSO CH2Cl2,-78°C TMSCI R=Et 73% 40°C R=Ph, 80% yield, 91: 9 syn/anti Amine and Sn(oTh are pre-mixed followed by addition of carbonyl substrate Employing TMSCl and Et N alone provide no enol ether This indicates that lewis acid-amine association is reversible Cannot quantitatively enolize simple esters or amides. However, using standard a Dialkylaluminumphenoxide enolization protocol on esters in the presence of PhCHo resulted in a"good"yield of aldol adduct. Employing enolizable aldehydes provides polymerized product Tsuji, Yamada, Kaito, Mandai Tetrahedron Lett. 1979, 2257-2260 Methyl ketones readily self-condense(Chem. Lett. 1982, 1459) Me n-CBHl m n-csH Mukaiyama, Iwasawa Chem Lett. 1982, 1903 i-PrCHO ■ Aluminum trichloride Evans, Bilodeau unpublished results. 人 yield, >97:3 syn/anti Sn(oTf)2 unsuitable for enolization of N-propionylox cH2C2,0°C 22A-05 Ketone Acidity 11/1/01 3: 42 PM

M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques Chem 115 70% enolization (Deuterium Quench) AlCl3 Et3N CH2Cl2, 0° C Miscellaneous Metals Nelson, Howells, DeLullo, Landen J. Org. Chem. 1980, 45, 1246-1249. 90% yield Ni(acac)2 (1 mol%) dioxane 85° C, 19 h + ■ Bis(2,4-pentanedionato)nickel(II) - Employing TMSCl and Et3N alone provide no enol ether. 68% yield ZnCl2, 3 mol % Et3N TMSCl C6H6, 40° C Danishefsky, Kiahara J. Am. Chem. Soc. 1974, 96, 7807-7808. ■ Zinc chloride ■ Dialkylaluminumphenoxide Tsuji, Yamada, Kaito, Mandai Tetrahedron Lett. 1979, 2257-2260. i-Bu2AlOPh Pyridine THF reflux 85% ■ Aluminum trichloride Evans, Bilodeau unpublished results. Mukaiyama, Iwasawa Chem. Lett. 1982, 1903. 95% yield, >97:3 syn/anti i-PrCHO Sn(OTf)2 N-ethylpiperidine CH2Cl2, -78° C ■ Methyl ketones readily self-condense (Chem. Lett. 1982, 1459). ■ Amine and Sn(OTf)2 are pre-mixed followed by addition of carbonyl substrate. This indicates that Lewis acid-amine association is reversible. Tin(II) triflate Mukaiyama, Stevens, Iwasawa Chem. Lett. 1982, 353. Sn(OTf)2 R3N CH2Cl2, -45° C Ph(CH2)2CHO Base = Et3N, 50% yield (15% self-condensation) N-Methylmorpholine, 22% yield (65%) N-Ethylpiperidine, 80% (trace) Pyridine, 0% DBU, 0% Sn(OTf)2 N-ethylpiperidine CH2Cl2, -78° C i-PrCHO R = Et, 73% yield, 93:7 syn/anti R =Ph, 80% yield, 91:9 syn/anti ■ Cannot quantitatively enolize simple esters or amides. However, using standard enolization protocol on esters in the presence of PhCHO resulted in a "good" yield of aldol adduct. Employing enolizable aldehydes provides polymerized product. There is some equilibrium enolization of esters. • Sn(OTf)2 unsuitable for enolization of N-propionyloxazolidinone (Evans, Weber). Me TMSO OMe OMe O O Me n-C6H11 O n-C6H11 Me n-C5H11 Me Me O O Me O O O Me Me Me O O N Bn O Me O Ph O Me O Ph Me OH Ph Me O R R O Me OH Me Me S N S Me O O N S S Me Me Me OH 22A-05 Ketone Acidity 11/1/01 3:42 PM

M. Bilodeau. d.A. evans A Survey of Soft Enolization Techniques Chem 115 Tin enolates Titanium enolates N-ethylpiperidine i-PrCHO The Early Literature Lehnert, W. Tetrahedron Lett. 1970, 4723-4724 Diamines mE DA 65% wield. 9. sy atits TiCl4 Evans. Weber J. Am. Chem. Soc. 1986. 108 6757 THF 75% yie N-ethylpiperidine +PICHO Harrison. C. R. Tetrahedron Lett 1987. 28. 4135-4138 Evans, Clark, Metternich, Novack, Sheppard J. Am. Chem. Soc. 1990, 112, 866 Ketone and aldehyde combined followed by sequential addn of TiCl and then amine 2. i-PrCHO Brocchini. Eberle. Lawton J. Am. Chem. Soc. 1988. 110. 5211-5212 Evans, Sheppard J. Org. Chem. 1990, 55, 5192 人人 0-15:1Z 22A-06 Ketone Acidity 11/1/01 3: 42 PM

The Early Literature 10-15:1 Z/E TiCl4 DIPEA THF -40° C ■ Brocchini, Eberle, Lawton J. Am. Chem. Soc. 1988, 110, 5211-5212. 91% yield 95:5 syn/anti TiCl4 Et3N CH2Cl2, 0° C 30 min + PhCHO Ketone and aldehyde combined followed by sequential addn of TiCl4 and then amine ■ Harrison, C. R. Tetrahedron Lett. 1987, 28, 4135-4138. 75% yield TiCl4 Pyridine THF Titanium Enolates ■ Lehnert, W. Tetrahedron Lett. 1970, 4723-4724. No diamine: 60% yield, 61:39 syn/anti Diamine= TMEDA, 65% yield, 9:91 anti/syn i-PrCHO Sn(OTf)2 N-ethylpiperidine [Diamine] Evans, Clark, Metternich, Novack, Sheppard J. Am. Chem. Soc. 1990, 112, 866. 1. Sn(OTf)2 Et3N 2. i-PrCHO Evans, Weber J. Am. Chem. Soc. 1986, 108, 6757. i-PrCHO Sn(OTf)2 N-ethylpiperidine CH2Cl2, -78° C Tin Enolates M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques Chem 115 79% Diastereoselection >95:5 Sn(OTf)2 Et3N Evans, Sheppard J. Org. Chem. 1990, 55, 5192. O N O O NCS Bn Bn O N O O Me O Me Me O O N O Bn HN O N O O O O H Me Me O Bn Me Me Me OH S N S OBn O O N S S Me BnO Me OH Et Et O EtO OEt O O O EtO OEt O Et Et Ph Me O Ph Ph O Me OH NO2 O S OH CHO N S O NO2 OH O Me OH Me Me H O Me Me Me O CH2 Me XP O O Me CH2 O O O O Me O Me Me Me Me Bn O Me 22A-06 Ketone Acidity 11/1/01 3:42 PM

M. Bilodeau. D.A. Evans A Survey of Soft Enolization Techniques Chem 115 Titanium enolates Reactions of titanium enolates Evans, Clark, Metternich, Novack, Sheppard J. Am. Chem. Soc. 1990, 112, 866. 人人 DIPEA I For Titanium: Enolization process not responsive to tertiary amine structure I DIPEA, Et3N, N-Ethylpiperidine all suitable bases 86%yied,>991 I DBU and tetramethylguanidine do not provide enolate I CH Cl2 is the only suitable solvent for these enolizations Reactions with Representative Electrophiles N-Propionyloxazolidone (1) Ethylisopropylketone Lewis Acid Enolization Lewis Acid Enolization i-PrOTiCl F-PrOTiCl3 99%,>99:1 80 CH2SP TiCI4'2THF 80 A-PrO)2TiCl 70 (A-PrO)3TICI 78%,98:2 PhSCH2Cl 93%,973 I Order of addition of reagents is important for TiCl4 R3N-TiCl4 Irreversible Complexation (CH2)2COEt H2C=CHCOEt CICH2NHCOPh I Order of addition of reagents is not important for i-PrOTiCk or(i-PrO)2TiCl R3N A-ProTiCl3 RaN-TICL(O/Pr) Reversible Complexation: 88%,>99: 1 89%,973 HC(OMe)3 MeOCH2NHCbz ■ Enolizable substrates CH(OMen Substrates Which present problems CH2OH 91%,964 ReAr. R<i-Pr 93%,99:1 J.Am.chem.Soc.190,112,82158216;Jog.Chem.1991,56,57505752 22A-07 Ketone Acidity 11/1/01 3: 42 PM

M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques Chem 115 R=Ar, R99:1 99%, >99:1 BOMCl 93%, 97:3 PhSCH2Cl 89%, 97:3 ClCH2NHCOPh MeOCH2NHCbz 91%, 96:4 93%, 99:1 HC(OMe)3 99%, >99:1 88%, >99:1 78%, 98:2 H2C=CHCOEt H2C=CHCO2Me J. Am. Chem. Soc. 1990, 112, 8215-8216.; J. Org. Chem. 1991, 56, 5750-5752. 1 Reactions with Representative Electrophiles MeO OMe O R O Me PhS O t-Bu Me Me O MeO O Me O R Me O O Me N O Bn O O N Bn O Me O O Me N O Bn O Ti Cl Cl Cl Cl Ti Cln Bn O N O O Me O Me Me O O N O O Bn Me Me OH Me O Me N O Bn O Ti Cln Xp CH2OBn O Me Me O CH2SPh Xp Xp CH2NHCOPh O Me Me O CH2NHCBz Xp Xp CH2OH O Me O O O Me O CH(OMe)2 Xp Xp (CH2)2COEt O Me OMe O Me O Xp 22A-07 Ketone Acidity 11/1/01 3:42 PM

M. Bilodeau. d.A. evans A Survey of Soft Enolization Techniques Chem 115 Aldol reactions of titanium enolate Titanium enolates of thioesters JAm.Chem.Soc.1991,113,1047-1049 Cinquini, Cozzi et al. Tetrahedron 1991, 47, 8767-8774 1991.47,7897-7910 CH2C2,-78°C 2. iPrCHO 1.TiCl4, 1 equiv Et N, 1 equiv 2. i-PrCHO 65% yield, 89: 11 syn/anti CH2C2,-78°c 2. i-PrCHO 4% yield, 84: 16 syn/anti Titanium enolization of esters Cinquini, Cozzi et al. J. Org. Chem. 1992, 57, 4155-4162. 1992,57,63396342 Tanabe, Mukaiyama Chem. Lett. 1984, 1867-1870 Tanabe Bull. Chem. Soc. Jpn. 1989, 62, 1917-1924 TiCl4, 2 equrv i-PrCHO, 1 equiv TiCI(oTf2, 1.5 equiv H2C2,-78°c Et,N. 2.2 CH2C2,0°c Me R=TBS, 98% yield, 10: 90 syn/anti 72% yield Order of addition is crucial, Lewis acid and amine irreversibly associate. Including PhCHO in reaction solution affords no aldol product Xiang, Olivier, Ouimet Tetrahedron Letf. 1992, 33, 457-460 Me EtaN, 2 equiv pMP CH2C278°c PMP TsHN HcHO 80% yield, >96%de CH2C2,40°C When PhCHo is pre-complexed with an equimolar amount of TiCle 22A-08 Ketone Acidity 11/1/01 3: 42 PM

M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques Chem 115 96% yield, 96:4 diastereomer ratio 1. TiCl4 DIPEA CH2Cl2, -78° C 2. i-PrCHO R = Et, 95% yield, 92:8 syn/anti R = i-Pr, 95%, 93:7 syn/anti 1. TiCl4 DIPEA CH2Cl2, -78° C 2. i-PrCHO Aldol Reactions of Titanium Enolates J. Am. Chem. Soc. 1991, 113, 1047-1049. • Order of addition is crucial, Lewis acid and amine irreversibly associate. • Including PhCHO in reaction solution affords no aldol product. 72% yield TiCl2(OTf)2, 1.5 equiv Et3N, 2.2 equiv CH2Cl2, 0° C 4Å M.S. Tanabe, Mukaiyama Chem. Lett. 1984, 1867-1870. Titanium Enolization of Esters Xiang, Olivier, Ouimet Tetrahedron Lett. 1992, 33, 457-460. TiCl4 (1.05 equiv) Et3N (2.1 equiv) PhCHO CH2Cl2, -40° C 70:30 ratio of diastereomers 94% combined yield When PhCHO is pre-complexed with an equimolar amount of TiCl4 a syn diastereomer predominates (90:10). Tanabe Bull. Chem. Soc. Jpn. 1989, 62, 1917-1924. Cinquini, Cozzi et. al. Tetrahedron 1991, 47, 8767-8774. 1991, 47, 7897-7910. 65% yield, 89:11 syn/anti 1. TiCl4, 1 equiv Et3N, 1 equiv CH2Cl2, -78° C 2. i-PrCHO 64% yield, 84:16 syn/anti Titanium Enolates of Thioesters 80% yield, >96% de 2 equiv 1 equiv TiCl4, 2 equiv Et3N, 2 equiv CH2Cl2, -78° C R = Bn, 95% yield, 98:2 syn/anti R = TBS, 98% yield, 10:90 syn/anti i-PrCHO, 1 equiv TiCl4, 2 equiv Et3N, 2 equiv CH2Cl2, -78° C 2 equiv Cinquini, Cozzi et. al. J. Org. Chem. 1992, 57, 4155-4162. 1992, 57, 6339-6342. TsHN O Me O Me Ph O Xc Ph Me OH Me O OEt OEt O Me O Me R O Me O R Me Me Me OH OH Me Me Me O Me O Me Me Me TBSO Me Me HO Me PhS O Me O PhS Me Me Me OH SPh O EtO OH PhS Me Me EtO O PhS O OR PhS O Me RO Me OH Me O PhS Me N Me PMP OBn NPMP O Me OBn Me Me 22A-08 Ketone Acidity 11/1/01 3:42 PM

M. Bilodeau. D.A. Evans A Survey of Soft Enolization Techniques Chem 115 Dialkylboron Triflates Dialkylboron Triflates Evans, Nelson, Vogel, Taber J. Am. Chem. Soc. 1981, 103, 3099-3111 ■ Di-n-butylboron triflate 76.559562. Bull. Chem. Soc. Jpn Lut: ZE= 69: 31 Ether,-78°c Enolizes ketones with 2.6-lutidine or DIPEa in ethereal solvents Diastereoselective Aldol reactions of boron enolates DIPEA R=cC5H11ZE=82:18 J. Am. chem. Soc. 1979. 101 3099-3111 n-Bu2BOTf Bartroli. Shih J. Am. Chem. Soc. 1981. 103 2127. 人 Ether,-78°c Masamune. S. et al. J. Am Chem. Soc. 1981. 103 1566- Borane and lutidine or DIPEA form 1: 1 complex. Complexation reversible as enolization will occur upon addition of ketone Less hindered nitrogen bases- pyridine, Dabco, DBU, and tetramethylguanidine innefective Chiral dialkylboron triflate The more hindered triflate- enolization must be carried out at oc Masamune. Sato. Kim Wollmann J. Am. chem. Soc. 1986. 108. 8279-8281 LaBOTf 、BL2OTf Paterson, l. et. al. Tetrahedron 1990, 46, 4663-4684 lining step rather than complexati (C) All factors being equal anti deprotonation preferred over syn deprotonation. Polniazek, R. Research Report 94:6ZE 22A-09 Ketone Acidity 11/1/01 3: 43 PM

M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques Chem 115 (-)-(Ipc)2BOTf ■ Chiral dialkylboron triflates Masamune, S. et. al. Tetrahedron Lett. 1979, 2225, 2229, 3937. Masamune, S. et. al. J. Am Chem. Soc. 1981, 103, 1566-1568. ■ Diastereoselective Aldol Reactions of Boron Enolates. ■ Di-n-butylboron triflate Evans, Vogel, Nelson J. Am. Chem. Soc. 1979, 101, 6120. Evans, Nelson, Vogel, Taber J. Am. Chem. Soc. 1981, 103, 3099-3111. Evans, Bartroli, Shih J. Am. Chem. Soc. 1981, 103, 2127. Dialkylboron Triflates Enolizes ketones with 2,6-lutidine or DIPEA in ethereal solvents. Mukaiyama, Inoue Chem. Lett. 1976, 559-562. Bull. Chem. Soc. Jpn. 1980, 53, 174-178. Masamune, Sato, Kim, Wollmann J. Am. Chem. Soc. 1986, 108, 8279-8281. Paterson, I. et. al. Tetrahedron 1990, 46, 4663-4684. Tetrahedron Lett. 1989, 30, 997-1000. Tetrahedron Lett. 1986, 27, 4787-4790. ■ Borane and lutidine or DIPEA form 1:1 complex. Complexation reversible as enolization will occur upon addition of ketone. ■ Less hindered nitrogen bases - pyridine, Dabco, DBU, and tetramethylguanidine innefective in the enolization. Attributed to irreversible amine-borane complexation. ■ The more hindered triflate - enolization must be carried out at 0° C. R=Et: Z:E = >97:3 R= i-Pr: Z:E = 45:55 R= t-Bu: Z:E = 25:75 n-Bu2BOTf DIPEA Ether, -78° C R2BOTf DIPEA Ether, -78° C R= n-Bu: Z:E = >97:3 R= c-C5H11: Z:E = 82:18 DIPEA: Z:E = >97:3 Lut: Z:E = 69:31 n-Bu2BOTf Base Ether, -78° C Evans, Nelson, Vogel, Taber J. Am. Chem. Soc. 1981, 103, 3099-3111. Dialkylboron Triflates + L2BOTf + - + - NR'3 NR'3 (A) E and Z enolates derived from deprotonation of syn and anti complexes respectively. (B) Deprotonation is rate determining step rather than complexation. (C) All factors being equal anti deprotonation preferred over syn deprotonation. 1. n-Bu2BOTf Et3N 2. n-BuLi, TMSCl Polniazek, R. Research Report 94:6 Z:E TfOB Me Me BOTf O Me Me Me Me O Me R O O R Me H Me H R O BL2OTf O BL2OTf R H Me H Me R Me OBL2 R OBL2 O Me Et O H H O Et Me TMSO 22A-09 Ketone Acidity 11/1/01 3:43 PM