Models for Nucleophilic Additions to α-Chiral Carbonyls: Cram-Chelate, Felkin-Ahn, Study notes of Organic Chemistry

Download Models for Nucleophilic Additions to α-Chiral Carbonyls: Cram-Chelate, Felkin-Ahn and more Study notes Organic Chemistry in PDF only on Docsity! Stereoselectivity Models: α-Chiral Carbonyl Compounds Review: Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191–1223. R O L S M S = small M = medium L= large Nuc R L S M Nuc OH R L S M HO Nuc Cram chelate or anti-Felkin-Ahn Cram or Felkin-Ahn when R = H Nuc L S M Nuc L S M OH OH Reliable models that can be used for predictions and rationaluzations of stereoselective additions of a wide variety of nucleophiles into α-chiral carbonyl compounds. Carreira: Chapter 2.1 – 2.5 controlling the conformation of this C–C bond is key 1,2-Asymmetric Induction: Cram-Chelate Rule Cram, D. J. J. Am. Chem. Soc. 1952, 74, 5828.; J. Am. Chem. Soc. 1953, 75, 6005.; J. Am. Chem. Soc. 1963, 85, 1245. O R If the α-carbon has a group that can chelate metals the conformation will be locked. A very reliable model and no amendments have been made to the original proposal. L S M R Nuc OH R O L S M S = small M = medium L= large Nuc R L S M Nuc OH R L S M HO Nuc MajorMinor R L S M HO Nuc M L S RO nucleophile approaches on the least sterically hindered face M = metal M L S R HO Nuc R L S M HO Nuc L = OR, NHR, etc. L S M M M Nuc Nuc R L S M Nuc OH Major H O Ph Me Cram-Chelate Rule: Examples Me OH Ph Me Tetrahedron Lett. 1994, 35, 285. dr 88:12 H O Cl Me Me OH Cl Me Tetrahedron 1991, 47, 9005. MeMgCl dr 88:12 H O TBSO TBSO Tetrahedron Lett. 1984, 25, 265. dr 95:5 allylSnBu3 BF3 MeCeCl2 H O Ph MeO2CCH2 OH Ph MeO2CCH2 Liebigs Ann. Chem. 1989, 891. dr 77:23 allylBr/Zn OH Nuc 1,2-Asymmetric Induction: Felkin-Ahn Model Cornforth, J. W. J. Chem. Soc. 1959, 112.; Felkin, H. Tetrahedron Lett. 1968, 2199.; Ahn, N. T.; Eisenstein, O. Tetrahedron Lett. 1976, 155.; Ahn, N. T.; Eisenstein, O. Nouv. J. Chim. 1977, 1, 61.; Ahn, N. T. Top. Curr. Chem. 1980, 88, 145. large group is placed orthogonal to the carbonyl, M group on the same side as the carbonyl The Cram rule is reliable when there are nonpolar groups. If the α-carbon has polar (EWG) groups that are not able to chelate well (e.g., Cl, OTMS) the model breaks down. After contributions by Cornforth, Felkin, Ahn, and Eisenstein a new model emerged. R O L S M S = small M = medium L= large or EWG Nuc R L S M Nuc OH R L S M HO Nuc MinorMajor R L S M Nuc OH O R R L S M Nuc OHM R OH Nuc L S M L S M nucleophile approaches on the least sterically hindered face L M S RO Nuc L M S Nuc RHO M = metal Cram & Felkin-Ahn predict the same product leads to staggered conformation R L S M Nuc OH MajorPh O 2-t-BuPhO Me Felkin-Ahn: Examples Ph OH 2-t-BuPhO Me Tetrahedron Lett. 1986, 27, 3091. dr >99:1 Ph O MeS Et Ph OH MeS Et Tetrahedron Lett. 1984, 25, 4775. Li(s-Bu)3BH dr >99:1 H O BocNH Me BocNH Me Liebigs Ann. Chem. 1994, 121. dr 89:11 NaBH4 Ph O Me2N Me Ph OH Me2N Me Tetrahedron 1993, 49, 4293. dr >99:1 OH HSiMe2Ph TBAF OMe Li OMe Major Chiral Allylic: Examples Tetrahedron 1984, 40, 2257. dr 71:29 R L M S RE RZ E+ BzOH2C Me Me OCH2OMe 1. BH3 2. [Ox] BzOH2C Me Me OCH2OMeOH (anti-Felkin) Helv. Chem. Acta 1988, 71, 1824. dr 88:12 CBzNH Me OMe OLi CBzNH Me OMe O Me (anti-Felkin) MeI dr 87:13 Ph Me CO2Et (Felkin) Me3CuLi2•BF3 Ph Me CO2Et Me J. Chem. Soc., Chem. Commun. 1987, 1572. dr 79:21 Ph Me (anti-Felkin) Me3CuLi2•BF3 Ph Me CO2Et Me CO2Et 1,3-Asymmetric Induction Stereogenic β-carbons can also exert an influence during nucleophilic additions to carbonyls. High selectivities are typically only observed with electronegative atoms on the β-carbon. Two models have been proposed. One involves chelation. The other involves dipole minimization. Both lead to the same outcome. This is in contrast to the Cram chelation and Felkin-Ahn models. H O R OPG M O O R PG Nuc chelation control H H OH R HPGO M acyclic control (Felkin-like) Nuc Nuc OH R OPG 1,3-anti Chelation control requires two adjacent vacant coordination sites at the metal center and a protecting group that enables complexation with the Lewis acid. H H OH M HL M Nuc or Nonchelation (Cram): J. Am. Chem. Soc. 1968, 90, 4011. Chelation (Cram): J. Am. Chem. Soc. 1968, 90, 4019. Nonchelation (Evans): Tetrahedron Lett. 1994, 35, 8537. 1,3-Asymmetric Induction: Examples Me H BnO O allylTMS TiCl4 Me BnO OH dr 95:5 J. Am. Chem. Soc. 1983, 105, 4833. Ti O O Me Bn Cl Cl Cl Cl SiMe3 HO O NaBH4 Et2BOMe dr 98:2 Tetrahedron Lett. 1987, 28, 155. OR O HO OH OEt O O B O i-Pr HRO2C Et Et BH4 Me4NBH(OAc)3 HOAc dr 92:8 J. Am. Chem. Soc. 1988, 110, 3560. HO OH O(CH2)3Ph O H B O i-Pr O RO2C OAc OAc H Closed Transition States: Zimmerman-Traxler Closed transition state: both nucleophile and electrophile are joined by a metal or Lewis acid promoter. Commonly used in aldol reactions. Useful in many other reactions as well. OML2 X R1 X = OR, SR, alkyl M = Li, B, Ti, Sn, etc. cis-enolate favored T.S. H R2 O R2 X OH R1 O 2,3-syn OML2 X trans-enolate H R2 O R2 X OH R1 O 2,3-anti R1 The diastereoselectivity at the 2- and 3-position is controlled by the configuration of the starting enolate. Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920. Carreira: Ch. 4.1 – 4.3 O M O Lig Lig H X H R1 R2 favored T.S. O M O Lig Lig H X R1 H R2 Closed Transition States: Zimmerman-Traxler + Felkin When α-chiral aldehydes are used, the Zimmerman-Traxler transition state must be used in concert with the Felkin model. The Felkin model only contributes to the facial selectivity of the electrophile. The selectivity is often not great, but the identity of the major diastereomer can be predicted. OML2 X unsubstituted enolate favored T.S. H O X OH O 3,4-syn (Felkin product) Major L M L M X OH O L M 3,4-anti (anti-Felkin product) Minor O M O H M LH X Lig Lig OH O H M LH X X OH O 2,3-syn (Felkin product) L M H Closed Transition States: Zimmerman-Traxler + Felkin When α-chiral aldehydes are used, the Zimmerman-Traxler transition state must be used in concert with the Felkin model. The Felkin model only contributes to the facial selectivity of the electrophile. The selectivity is often not great, but the identity of the major diastereomer can be predicted. OML2 X cis-enolate H O X OH O syn, syn Minor L M L M X OH O L M 2,3-syn-3,4-anti Major R R R Felkin anti-Felkin O M O Lig Lig X R H H M LH O M O Lig Lig X R H H H ML O M O R X H H M L Lig Lig Felkin T.S. anti-Felkin T.S. syn, syn syn, syn syn, anti