Enolates: Z(O,R) (O,R)- and E(O,R) (O,R)-enolates

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1 Enolates: Z(,) (,)- and E(,) (,)-enolates egardless of other groups the encircled ' and - determine whether one is Z(,)- or E(,)- enolate. - - ' ' (E)-enolate (Z)-enolate Enolates: deprotonation 90 ' Most stable conformation 30 ' σ C- ' ' π* C= π* C= σ C- ' ax eq -12 ' - ' (E)-enolate (Z)-enolate Corey, E.J.; neen,.a. J. Am. Chem. oc. 1956, 78, 6269.

2 Effect of base on enolisation! Base must be large and hard.! Thus functions only as a base and not as a nucleophile. i i M Ph Ph i i M - K DA TMP MMD (( 2 Ph) 2 i) t-buk M =, a, K pk a elective formation of E/Z- enolates base TMCl TM TM Z(,) E(,) base Z E Et DA ( 3 i) (Et 3 i) ( 2 Phi) 2 >100 <1 cc 6 11 DA ( 3 i) 2 (Et 3 i) 2 ( 2 Phi) Masamune,. Aldrichimica Acta 1982, 15, 47.

3 Enolisation: Ireland-mechanism! According to the Ireland-mechanism an (E)-enolate is formed via a chair form transition state ( = large alkyl group)! If also is large, a (Z)-enolate is formed!! ote the actual proton abstractor and the role of the metal! " ' - 78 C, Br = Et = i-pr = t-bu : : : >20 Ireland,.E. J. Am. Chem. oc. 1976, 98, Collum, D.B. J. Am. Chem. oc. 1991, 113, Collum, D.B. J. Am. Chem. oc. 1997, 119, Dimeric -enolate - DA complex! First X-ray structure for a dimeric complex. i 200 mol-% DA 3 i i 3 TEE TUCTUE: CCD-code FGIC Willard, P.G. J. Am. Chem. oc. 1987, 109, 5539.

4 Application: Taxol K D t-buk D 2 Ketoni Enolaatti tork, G Approach of the electrophile ouk: 106 o (compare: Burgi-Dunitz angle) B! This angle is similar to the Flippin-odge angle! E - E Agami, C. Tetrahedron ett. 1977, Tetrahedron ett. 1979, Tetrahedron 1979, 35, ouk, K.. J. Am. Chem. oc. 1986,108, side view end view equatorial attack i axial attack E E - e

5 Asymmetric Induction in Enolate and Azaenolate Alkylations Intraligand asymmetric induction intraannular extraannular chelate-mediated intraannular M M M 1 M M * * 1 * M 2 * 2 * * 1,3-1,4-1,2-1,3-1,2-1,3- Interligand asymmetric induction M* M n * Evans, D.A. Asymmetric ynthesis 1984, 3, Controlling Face electivity C 2 tbu I = MPA C 2 tbu 1) DA 2) I tbu tbu I = TF hydrolysis C 2 C 2 Tomioka, K.; Koga, K. J. Am. Chem. oc. 1984, 106, Tomioka, K.; Koga, K. Tetrahedron ett. 1984, 5677.

6 AMP-ydrazones in Ketone Alkylation 2 AMP DA AMP Enders, or 3 -X X = I X = 2 67 %ee 99 %ee Enders, D. Asymmetric ynthesis, vol. 3. Chiral Bicyclic actam Enolates KMn 4 2. Cl xidation of pinene: Carlson,.G.; Pierce, J.K. J. rg. Chem. 1971, 36, eduction of oxime: Masui, M.; hioiri, T. Tetrahedron 1995, 51, acetone 1 1 p-ts, toluene Al 4 2 oth, G.P.; eonard,.f.; Tong,. J. rg. Chem. 1996, 61,

7 Chiral Bicyclic actam Enolates 1 s-bu 1 2 X repeat: s-bu; 3 X =,, Ph 2 =, Bn, allyl 3 =,, Bn exo:endo selectivities typically > 98:2 (except:,, 2:1 oth, G.P.; eonard,.f.; Tong,. J. rg. Chem. 1996, 61, Aldol eaction syn anti Chirality can reside in: nuclephile electrophile catalyst ne of the most extensively studied reactions eview: eathcock, C.. cience 1981, 214, 395.

8 Aldol eaction Ph Ph Ph syn anti Enolate syn anti Z E ipr Z E tbu Z 98 2 Bulky - high selectivity Z-enolate -> syn E-enolate -> anti E 8 92 eathcock, C.. J. rg. Chem. 1980, 45, Generation of E/Z-enolates base TMCl TM TM Z(,) E(,) base Z E Et DA ( 3 i) (Et 3 i) ( 2 Phi) 2 >100 <1 cc 6 11 DA ( 3 i) 2 (Et 3 i) 2 ( 2 Phi) Masamune,. Aldrichimica Acta 1982, 15, 47.

9 Aldol eaction * 1 * 3 2 Possible Transition tates: E 1 3 Z M E 3 1 M Z n Cyclic (chelated) T pen T eviews: eathcock, C.. cience 1981, 214, 395. eathcock, C.. Aldrichimica Acta 1990, 23, 99. offmann,.w. Angew. Chem. Int. Ed., Engl. 1987, 26, 488. Mukaiyama, T. rg. eact. 1982, 28, 203.! Type I Classification of aldols follow Zimmermann-Traxler T! Type II open T; syn-selective enol silanes, stannanes, borates, zirconates! Type III open T; anti-selective ketene acetals and thioacetals

10 Aldol - Zimmermann-Traxler T 1 M n 2 1 M anti 2 E(,)-enolate 2 13 M syn Aldol - Zimmermann-Traxler T M n 1 M syn 2 1 Z(,)-enolate 2 13 M anti Diastereoselectivity maximized when 1 and 3 large Diastereoselectivity: B > > a > K - Mg- Zn- Al- B- Ti- Zr Å Å Å 1.92 Å Å Å 2.15 Å

11 Aldol - pen T M M 1 E(,)-enolate anti Z(,)-enolate M E(,)-enolate syn M Z(,)-enolate Boron Enolates X 1 X B 2 Tf 1 X B 2 1 e B X 2 i 1 X B 2 1 Z(,)-enolate typical outcome i X 1 B 2 e X B 2 1 E(,)-enolate can be favored: = cc 6 11 X = tbu Evans, D.A. J. Am. Chem. oc. 1981, 103,

12 Boron Enolate diated Aldol CEt 3 B Tf DIPEA B CEt 3 C - 78 C CEt 3 anti:syn 33: %ee For a similar example, see also: eetz, M.T. Tetrahedron ett. 1986, 27, Masamune,. J. Am. Chem. oc. 1986, 108, Evans Aldol: : on-coordinating tal 2 B α-attack B Bu B Bu 2 B β-attack Explanation: opposing dipoles! Evans, D.A. J. Am. Chem. oc. 1981, 103, 2127.

13 Evans Aldol - Coordinating tal M E i attack E Chelated Z(,)-enolate M M E e attack E on-chelated Z(,)-enolate Evans, D.A. J. Am. Chem. oc. 1982, 104, Evans Aldol DA amd M E, 0 o C E, -78 o C E Ph Ph E E = I, EtI, BnBr, allylbr kinetic ratio > 94 : 6 Evans, D.A. J. Am. Chem. oc. 1982, 104, 1737.

14 ynthesis of BMT,, Amino Acid in Cyclosporine Bn 1) amd 2) I 3) A 4) wern C Bn n(tf) 2 1) 3 BF 4-2) 2 3) K 4) 3 X* C X* n Evans, D.A. J. Am. Chem. oc. 1986, 108, on-evans syn-aldol: Ti Enolates 4 Ti 3 Ti GMUP Thornton, E.. J. rg. Chem. 1991, 56, X-ray: interman, T.; Deebach, D. elv. Chim. Acta 1998, 81, 2093.

15 pen Transition tate: Effect of ewis Acid B A small ewis acids syn B A large ewis acids anti eathcock, C.. J. rg. Chem. 1990, 55, 173. eathcock, C.. J. rg. Chem. 1991, 56, hioiri, T. Tetrahedron ett. 1991, 32, All Four Aldols from a ingle Precursor: eathcock t - Bu TB t - Bu B t - Bu TB TB Mg t - Bu TB Ti t - Bu TB eathcock, C.. J. rg. Chem. 1991, 56, eathcock, C.. Aldrichimica Acta 1990, 23, 99.

16 ummary of Best Aldols B-enolate Ti enolate B-enolate A syn (1) syn (2) anti Evans Thornton eatcock Ph B-enolate i-enol ether syn anti ppolzer ppolzer Chiral Catalysis in Aldol: : Corey 2 *BBr B 2 * tbu -C 2*BBr tbu 2 *B Br Et3 CF 3 CF 3 Ph Ph CF 3 2 B 2 CF 3 Br 2 *BBr Ph Ar Ar 2 B Ph 2 Ph Ester enolates: anti products; thioesters: syn products Corey, E.J. J. Am. Chem. oc. 1990, 112, 4976.

17 Chiral Acyloxyborolidines "Anomeric" i 3 ' "C CAB ' " ' B C C 2 anti-coordination C 2 C 2 B3 ' CAB Yamamoto,. J. Am. Chem. oc. 1991, 113, X-ray AVM: Yamamoto,. J. Am. Chem. oc. 1993, 115, syn-elective Boron Aldol approach from least hindered enolate diastereoface BBu 2 dipoles? Bu B Bu i Pr Bu B Bu

18 Acetate aldol i mol-% cat., -10 o C then TBAF t Bu Ti t Bu Bu t t Bu Aldehyde C C C Ph C Ph C C 6 11 Ph C %ee: Carreira, E. J. Am. Chem. oc. 1994, 116, Acetate aldol mith, A.B. rg. ett. 1999, 1,

19 Acetate aldol 1 2 i 3 t Bu 10 mol-% cat., -10 o C then 1 M Cl 2 1 t Bu Bu t Cu t Bu 2 Tf - 1 Bn t Bu Et 2 Et i Bu i Bu %ee: Evans, D.A. J. Am. Chem. oc. 1997, 119, Cyclic enolates: anti-elective Aldols M n M n yield anti:syn B 57 19:1 nph 3 n :1 24:1 n M Ti( i Pr) :1 ayashi, T. Tetrahedron ett. 1991, 32, 5369.

20 Amphotericin 2 C () 2 P 2 P P Calyculin C 2 C Amphotericin B Alkylation Towards Amphotericin B DA, TMCl -78 o C, TF 64 % TiCl 4, PhC C 2 Cl 2, -78 o C i 3 Major product Karisalmi, K. Tetrahedron 2003, 59,

21 Final steps 6 aney ickel (W-2) Et, o C 50 % 7 Karisalmi, K. Tetrahedron 2003, 59, yn-aldol from Z-enolateZ weakly 17-directing BBu 2 Bn TBDM C 2 Cl 2, -78 to -26 o C, 16 h 69 %, 82 %ds Bn TBDM weakly 17-directing Bafilomycin A Paterson, I. Tetrahedron ett. 1995, 36, 175.

22 Anti-aldols from E-enolates Bu t t Bu aldol 55 %; 19:1 ds Bu t t Bu 1. g(ccf 3 ) 2 2. PdCl 2, C,, CuCl % Ac C 2 C1-C8 sequence of pamamycins Pamamycin Walkup,.D.; Kim, Y.. Tetrahedron ett. 1995, 36, Anti-aldol from E-enolateE Bu t t Bu aldol 64 %; 2:1 ds Bu t t Bu eathcock T 1981, 37, Felkin-Anh Ar Bu t t Bu Pilli,.A.; Murta, M.M. J. rg. Chem. 1993, 58, 338.

23 Anti-aldol for macrolide synthesis aldol 50 % Felkin-Anh Ar Tamm, C. ynthesis 1991, 435.