The aldol reaction with metal enolates proceeds by a chair-like, pericyclic process: favored. disfavored. favored. disfavored

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1 The aldol reaction with metal enolates proceeds by a chair-like, pericyclic process: Z-enolates: M 2 M 2 syn 2 C 2 favored 2 M 2 anti disfavored E-enolates: M 2 2 C 3 C 3 C 2 favored 2 M M disfavored In practice, the stereochemistry can be highly metal dependent; only boron reliably follows the indicated pathways Z and E enolates form syn and anti aldol adducts by minimizing the 1,3-diaxial interactions between and 2 in each chair-like transition state. 2 2 anti syn JACS, 1957, 1920 T, 1975, 1225 JC, 1980, 1066.

2 Preparation of (Z) and (E)- oron enolates Et Et (n-u) 2 Tf i-pr 2 Et, Et 2 (c-ex) 2 Cl Et 3, Et 2, -78 C Et Et (nu) 2 >97% (Z) (nu) 2 C -78 C C -78 C Et Et racemic syn >99% racemic anti >97% JACS, 1979, 6120 JACS, 1989, 3441 >99% (E) Z-selective preparation of boron enolates from Evans' Acyl oxazolidinones (Imides) C 3 nu 2 Tf C 2 Cl 2 u u Tf - i-pr 2 Et C 3 u u >100:1 Z:E Pure. Appl. Chem., 1981, 1109.

3 Syn-Selective Aldol eactions of Imide-Derived oron (Z)-Enolates u u Unreactive open coordination site required for pericyclic aldol reaction! (n-u) 2 C 3 C Favored Chiral Auxiliary allows one to distinguish the prochiral faces of the aldehyde, resulting in a highly diastereoselective process nly si face of aldehyde is attacked Disfavored Pure. Appl. Chem. 1981, Diastereomeric transition states are of unequal energy, leading to the formation of one diastereomer of a pair preferentially

4 Application of the Technology nu 2 Tf, i-pr 2 Et C 2 Cl 2, 0 C C, -78 C=> 23 C =( ) 2 C, >497:1 dr = nu, 141:1 dr =C 6 4, > 500:1 dr nu 2 Tf, i-pr 2 Et C 2 Cl 2, 0 C C, -78 C=> 23 C =( ) 2 C, >500:1 dr = nu, >500:1 dr =C 6 4, > 500:1 dr Amino Acid Synthesis: r nu 2 Tf, i-pr 2 Et C 2 Cl 2, 0 C C, -78 C=> 23 C r a i 2. 2 /Pd-C 2 T, 1987, 39. Aldol Additions of Chiral Crotonate Imides nu 2 Tf, Et 3 C 2 Cl 2, 0 C (nu) 2 C 2 C >96% de T, 1986, = =( ) 2 C =C 6 5

5 Methods for Cleavage of Imide Auxiliaries Transamidation: Al( ) 3 Cl C 2 Cl 2, 0 C 3 C Weinreb Amide a free!-hydroxyl group is required T, 1981, Mei DIA 3 C ydrolysis: 3 i TF, 2 3 T, 1987, 6141 i displays greatest regioselectivity for attack on the exocyclic carbonyl eductive Cleavage: r ial 4, TF r 90% Esterification: i r

6 Anti-Selective Aldol eactions in elated Systems TS 1. (c-ex) 2 Cl Et 3, Et 2, 0 C TS 2. i-prc Ch 3 88%de TS 1. (c-ex) 2 Cl Et 3, Et 2, 0 C TS 2. i-prc Ch 3 92%de The C.2 stereocenter is the dominant control element for both substrates: TS Ch 3 (c-ex) 2 3 C C(iPr)TS TS Ch 3 Minimization of A(1,3) interactions in the enolate biases the approach of the aldehyde to the methyl-bearing pi-face of the enolate, while the E-geometry afford anti-aldol products Tetrahedron, 1992, 2127.

7 Paterson Aldol, Part 1 Tf 2 =(-)-Ipc 2 Tf derived from pinene 3 C (-)-IpcTf ipret 2 3 C (Ipc) 2 2 C 2 Tetrahedron, 1990, enolization on less hindered side of ketone with Z selectivity highest ee's with unhindered aldehydes aldol additions of methyl ketones not selective E-enolate does not lead to a selective anti aldol reaction =Et, 2 = ipr 66% ee, 96:4 syn:anti =ipr, 2 = C 2 C( ), 88% ee, 95:5 syn:anti =Et, 2 = C 2 C( ), 91% ee, 98:2 syn:anti C 3 C 2 3 C minimizes steric interactions between the Ipc ligand on boron and the substituent on the ketone. Disfavored Favored 2 2

8 Paterson Aldol, Part 2 Anti Aldol eactions of actate-derived Ketones z 1. (c-ex) 2 Cl Et 3 Et 2 z (c-ex) 2 diastereofacial selectivity is very high; alpha-chiral aldehydes afford anti-aldol adducts with high diastereoselectivity regardless of the stereochemistry. C 14h, -78 C 2 2, p7 z anti trans =ipr, 94%de =Et, 99%de =, 99%de =C 2 CC, 90%de Synthesis, 1998, 639. z (c-ex) 2 Matched z >94% de z (c-ex) 2 Mismatched z A 84% de z (c-ex) 2 Cl Et 3 i-prc z i-pr 95%, 86%de

9 Stereochemical ationale: formyl hydrogen bond: z (c-ex) 2 C 3 C z favored disfavored z z For the utility of these approaches, see Paterson's synthesis of leandolide: JACS, 1994,

10 Chiral alpha-sulfinyl ester: Solutions for the Acetate Aldol Problem Ar S C 2 tu i-pr 2 Mgr Ar S tu tumgr C SAr tu Al/g tu 80-91% ee J. Chem. Soc., Chem Commun. 1977, 162. Ar S Mg tu Approach of the aldehyde from the side of the non-bonded pair of electrons on sulfur; group of aldehyde is anti to ulfinyl substitutent Chiral Acetate Enolate addition to Aldehydes C 2 Me -mandelic acid Mgr AcCl 3 C DA ACIEE, 1987, 24. M M 2 C C -135 Evans: use a temporary substituent to afford acetate aldol products selectively: S 1. u 2 Tf i-pr 2 Et 2. C simple -acetyl imides do not react selectively! 3 CS 1. ai, 60 C 2. 2 K 86-99% ee 84-96% ee JACS, 1981, 2127.

11 Enantioselective Mukaiyama Aldol eactions u n-u Ts 3 n-u Ts Si face of aldehyde blocked by indole ring T, 1992, 6907 SiMe 3 2 3, 20 mol% C 2 5 C, -78 C; 1 Cl/TF 2 Tetrahedron, 1993, 1761 =, 2 =, 89%ee =c-ex, 2 =, 93%ee =c-ex, 2 =u, 86%ee

12 Catalytic, Enantioselective Acetate Aldol Additions with Silyl Ketene Acetals t-u Carreira, JACS, 1994, 8837 T, 1997, 927 Tetrahedron, 1998, 7025 An Example of Axial Chirality Ti t-u t-u r (-)-1 nly re face of aldehyde attacked when(-)-1 is used nly si face of aldehyde attacked when ()-1 is used TMS 2 1. (-)-1, 0.5-5mol% Et 2, 4h, TAF, TF 2 2 = 97%ee 2 = 97%ee 2 = 94%ee 2 = Alkenyl and Alkynyl aldehydes are particularly good substrates for this process 94%ee

13 Acetone Enolate Equivalent: 2-Methoxypropene Aldol Additions t-u Carreira, JACS, 1995, 3649 Ti r ipr ipr (-)-2 nly re face of aldehyde attacked when (-)-2 is used nly si face of aldehyde is attacked when ()-2 is used 1. (-)-2, mol% 0->23 C C Cl ( 2 C) 3 TS 2 C 2-methoxypropene as solvent unhindered aldehydes give highest ee's 98%ee 97%ee 90%ee 91%ee s 4

14 Corey Enantioselective Acetate Aldol S S r 3 3 C S 3 C 2 Cl 2 Et 3 2 C X 2 S C -90 C, 2h =, 91%ee =ipr, 83%ee S JACS, 1989, 5493 S vs. S favored disfavored pi-facial selectivity dictated by the catalyst 3

15 Catalytic Enantioselective Aldol Additions Cu 1 2 2SbF 6 - Cu 2 2 2Tf - pen T.S. Cu u si-face TMS S (10mol%) C 2 Cl 2, -78 C 2. 1 Cl, TF JACS, 1999, 669. S 2 Z or E geometry of enol Irrelevant in open T.S. Z E =, 2 =tu =, 2 =Et =, 2 =Et 99%ee 97%ee 97:3 syn:anti 85% ee 86:14 syn:anti Me TMS (10mol%) C 2 Cl 2, -78 C 2. 1 Cl, TF Me 3 C 2 identate Coordination of the pyruvate is proposed =, 2 =SEt =, 2 =Stu =, 2 =SEt 97%ee 96%ee, 94:6 syn:anti 98% ee, 98:2 syn:anti JACS, 1997, 7893.

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