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Enolates: Z(O,R)- and E(O,R)-Enolates Enolates: Z(O,R)- and E(O,R)-enolates Regardless of other groups the encircled R' and O- determine whether one is Z(O,R)- or E(O,R)- enolate. R R O- O- R' H H R' (E)-enolate (Z)-enolate Enolates: deprotonation 90° R R H O H O 30° R O R' H H R' H O H Heq π π R' R *C=O R *C=O H H σ O σ O Hax Most stable C-H C-H conformation R' H H R' -12 ° H O H 104 ° R R - O O- R' H H R' (E)-enolate (Z)-enolate Corey, E.J.; Sneen, R.A. J. Am. Chem. Soc. 1956, 78, 6269. Effect of base on enolisation ! Base must be large and hard. ! Thus functions only as a base and not as a nucleophile. Ph Ph Si Si Si Si - + N N N N O K Li Li M M LDA LiTMP MHMDS ((Me2Ph)2Si)NLi t-BuOK M = Li, Na, K pKa 36 37 26 25 18-20 Selective formation of E/Z- enolates O base TMSCl OTMS OTMS R R R Z(O,R) E(O,R) RbaseZE Et LDA 30 70 (Me3Si)2NLi 70 30 (Et3Si)2NLi 99 1 (Me2PhSi)2NLi >100 <1 cC6H11 LDA 61 39 (Me3Si)2NLi 85 15 (Et3Si)2NLi 94 6 (Me2PhSi)2NLi 99 1 Masamune, S. Aldrichimica Acta 1982, 15, 47. Enolisation: Ireland-mechanism ! According to the Ireland-mechanism an (E)-enolate is formed via a chair form transition state (R = large alkyl group) ! If also R’ is large, a (Z)-enolate is formed! ! Note the actual proton abstractor and the role of the metal! R , LiBr N N Li R H R R R + Li - 78 °C - - O O O H R' O R = Et 50 : 1 "R R = i-Pr 21 : 1 R= t-Bu 1 : >20 Ireland, R.E. J. Am. Chem. Soc. 1976, 98, 2868. Collum, D.B. J. Am. Chem. Soc. 1991, 113, 9571. Collum, D.B. J. Am. Chem. Soc. 1997, 119, 4765. Dimeric Li-enolate - LDA complex ! First X-ray structure for a dimeric complex. R Si O O 3 200 mol-% LDA Li O Li N O Si Li Li N O O SiR3 STEREO STRUCTURE: CCSD-code FOGRIC Willard, P.G. J. Am. Chem. Soc. 1987, 109, 5539. Application: Taxol D O O K O t-BuOK D2O O O O O O O Ketoni Enolaatti Stork, G. 1995. Approach of the electrophile o Houk: 106 (compare: NB! This angle is similar to Burgi-Dunitz angle) the Flippin-Lodge angle! E E Agami, C. Tetrahedron Lett. 1977, 2801-2804. O R Tetrahedron Lett. 1979, 1855-1858. - RR Tetrahedron 1979, 35, 961-967. R OH Houk, K.N. J. Am. Chem. Soc. 1986,108, 2659-2662. side view end view Si O equatorial axial E attack attack O- O E Re Asymmetric Induction in Enolate and Azaenolate Alkylations Intraligand asymmetric induction intraannular extraannular chelate-mediated intraannular OM OM OM O M * R1 R M * R1 OO * O R OM R2 R2 * * * R R 1,3- 1,4- 1,2-1,3- 1,2- 1,3- Interligand asymmetric induction M* ML * O O n Evans, D.A. Asymmetric Synthesis 1984, 3, 1-110. Controlling Face Selectivity CO2tBu MeI L = HMPA tBuO N H 1) LDA O 2) MeI CO Me L 2 Li NO OtBu N Li O OMe O tBuO L MeI L = THF hydrolysis O O CO2Me CO2Me Tomioka, K.; Koga, K. J. Am. Chem. Soc. 1984, 106, 2718. Tomioka, K.; Koga, K. Tetrahedron Lett. 1984, 5677. SAMP-Hydrazones in Ketone Alkylation O N Li N OMe SAMP N LDA N N NH2 OMe OMe SAMP Enders, 1976 Me Me O O O + H3O Me-X Me N Li N N N or O 3 Me X = I 67 %ee 99 %ee X = OSO2Me Enders, D. Asymmetric Synthesis, vol. 3. Chiral Bicyclic Lactam Enolates OH O . KMnO4 NH2OH HCl N acetone Oxidation of pinene: OH OH Carlson, R.G.; Pierce, J.K. J. Org. Chem. 1971, 36, 2319-2324. LiAlH4 Reduction of oxime: O Masui, M.; Shioiri, T. Tetrahedron 1995, 51, R1 OH O R1 8363-8370. NH2 O N H O OH p-TsOH, toluene Me O N H O Roth, G.P.; Leonard, S.F.; Tong, L. J. Org. Chem. 1996, 61, 5710-5711. Chiral Bicyclic Lactam Enolates R1 R1 R1 O O R X O s-BuLi 2 R2 N N repeat: N R3 H O H OLi s-BuLi; R3X H O R1 = H, Me, Ph exo:endo selectivities typically > 98:2 R2 = Me, Bn, allyl (except: H, Me, H 2:1 R3 = H, Me, Bn Roth, G.P.; Leonard, S.F.; Tong, L. J. Org. Chem. 1996, 61, 5710-5711. Aldol Reaction O OH O OH O O + + R R HR syn anti Chirality can reside in: •nuclephile •electrophile •catalyst One of the most extensively studied reactions Review: Heathcock, C.H. Science 1981, 214, 395. Aldol Reaction O OH O OH O O + + RPh RPh R HPh syn anti R Enolate syn anti HZ 50 50 E6535 iPr Z 90 10 Bulky R - high selectivity E4555 Z-enolate -> syn tBu Z 98 2 E-enolate -> anti E892 Heathcock, C.H. J. Org. Chem. 1980, 45, 1066. Generation of E/Z-enolates O base TMSCl OTMS OTMS R R R Z(O,R) E(O,R) R base ZE Et LDA 30 70 (Me3Si)2NLi 70 30 (Et3Si)2NLi 99 1 (Me2PhSi)2NLi >100 <1 cC6H11 LDA 61 39 (Me3Si)2NLi 85 15 (Et3Si)2NLi 94 6 (Me2PhSi)2NLi 99 1 Masamune, S. Aldrichimica Acta 1982, 15, 47. Aldol Reaction OOH O- O + * R2 R1 * R3 R1 R3 H R2 R1 L R1 H H M RE O L O RE O R3 O Possible Transition States: ML R3 RZ n RZ Cyclic (chelated) TS Open TS Reviews: Heathcock, C.H. Science 1981, 214, 395. Heathcock, C.H. Aldrichimica Acta 1990, 23, 99. Hoffmann, R.W. Angew. Chem. Int. Ed., Engl. 1987, 26, 488. Mukaiyama, T. Org. React. 1982, 28, 203. Classification of aldols ! Type I – follow Zimmermann-Traxler TS ! Type II – open TS; syn-selective – enol silanes, stannanes, borates, zirconates ! Type III – open TS; anti-selective – ketene acetals and thioacetals Aldol - Zimmermann-Traxler TS R1 L OOH H OLM R2 O R1 R3 R H 3 R2 anti ML O n H R1 R2 E(O,R)-enolate R1 L OOH R3 OLM R2 O R1 R3 H H R2 syn Aldol - Zimmermann-Traxler TS R1 L OOH H OLM H O R1 R3 R3 R R2 2 syn ML O n R2 R1 H Z(O,R)-enolate R1 L OOH R3 OLM H O R1 R3 H R R2 2 anti Li-O 1.92-2.00 Å Mg-O 2.01-2.03 Å Zn-O 1.92-2.16 Å Diastereoselectivity maximized when R1 and R3 large Al-O 1.92 Å Diastereoselectivity: B > Li > Na > K B-O 1.36-1.47 Å Ti-O 1.62-1.73 Å Zr-O 2.15 Å Aldol - Open TS O OOH O R2 H HR2 R3 H R1 R3 H R3 R OM R1 OM R2 1 E(O,R)-enolate anti Z(O,R)-enolate O OOH O R2 H HR2 R1 R3 H R3 R3 H R2 R1 OM R1 OM E(O,R)-enolate syn Z(O,R)-enolate Boron Enolates BR OTf O 2 OBR O 2 R1 R1 X R1 X X H Re OBR BR 2 X O 2 R Z(O,R)-enolate typical outcome X 1 HSi R1 OBR HSi 2 E(O,R)-enolate can be favored: X O X R = cC H R H BR2 6 11 1 Re R1 X = tBuS Evans, D.A. J. Am. Chem. Soc. 1981, 103, 3099-3111. Boron Enolate Mediated Aldol B RCHO OH O O OTf B O - 78 C DIPEA R SCEt3 SCEt3 SCEt3 anti:syn 33:1 98-99.9 %ee For a similar example, see also: Reetz, M.T. Tetrahedron Lett. 1986, 27, 4721. Masamune, S. J. Am. Chem. Soc. 1986, 108, 8279. Evans Aldol: Non-Coordinating Metal L2 B O O OH O O OR ORN O N α-attack L L O O B O O O N O N L2 B OOH O OR N R Bu N Me β-attack O O O R B O O O H Bu H N O O Explanation: opposing dipoles! Evans, D.A. J. Am. Chem. Soc. 1981, 103, 2127. Evans Aldol - Coordinating Metal M O O O O E+ O N O N E Si attack Chelated Z(O,R)-enolate O OM O OM O E+ O N N O N O Re attack E O Non-chelated Z(O,R)-enolate Evans, D.A. J. Am. Chem. Soc. 1982, 104, 1737. Evans Aldol M O O O O O O + o LDA E , 0 C O N O N O N NaHMDS E+, -78 oC E O O O O O N O N E Ph Ph E = MeI, EtI, BnBr, allylBr kinetic ratio > 94 : 6 Evans, D.A. J. Am. Chem. Soc. 1982, 104, 1737. Synthesis of MeBMT, Amino Acid in Cyclosporine O O 1) NaHMDS 2) MeI O O N 3) LAH H O NCS 4) Swern Bn O N O Bn Sn(OTf)2 + - 1) Me3O BF4 S NHMe NCS 2) H2O HN HO X*N X*N O 3) KOH O OH + O OSnL 4) H3O O Evans, D.A.
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