Felkin anh 4 - Lecture notes 1-9 PDF

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Stereoselectivity Models: α-Chiral Carbonyl Compounds controlling the conformation of this C–C bond is key

O

Nuc

Nuc L

L M

S = small M = medium L= large

Nuc

L R

R S

HO

OH

S

R

M

S

Cram or Felkin-Ahn

M

Cram chelate or anti-Felkin-Ahn

when R = H Reliable models that can be used for predictions and rationaluzations of stereoselective additions of a wide variety of nucleophiles into α-chiral carbonyl compounds.

OH

OH

L

L Nuc

S

Carreira: Chapter 2.1 – 2.5

Review: Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191–1223.

M

Nuc S

M

1,2-Asymmetric Induction: Cram-Chelate Rule 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. O

Nuc

Nuc

S = small L M = medium L= large

HO

OH

L

L

R

S

Nuc

R

M

S

R

M

S

Minor

L = OR, NHR, etc.

M

Major

Nuc R M

R O

S

M = metal

L M

nucleophile approaches on the least sterically hindered face

OH

L

M

Nuc

HO L

R S

S

Nuc

M

Nuc S M

L O

M R

M

Nuc L

HO S

R

HO

Nuc

L R S

M

Cram, D. J. J. Am. Chem. Soc. 1952, 74, 5828.; J. Am. Chem. Soc. 1953, 75, 6005.; J. Am. Chem. Soc. 1963, 85, 1245.

Cram-Chelate Rule: Examples

Nuc

HO L

R OH

O SnMe3

BnO

S

BnO

M

Major

H

LiClO4 dr 96:4 Tetrahedron Lett. 1992, 33, 1817.

BuLi or Bu2CuLi

O BnOCH2O

H

LiAlH4

Me

PhO

Ph Me

Bu

Tetrahedron Lett. 1980, 21, 1035.

OH

PhO

BnOCH2O

w/ BuLi 63:37 w/ Bu2CuLi 94:6

Me O

OH

Ph

dr 72:28

Me

Tetrahedron Lett. 1986, 27, 3091.

MeLi TiCl4

O TBSO

HO TBSO

Et

Et Me

Me

dr 85:15

Me

J. Chem. Soc., Chem. Commun. 1986, 1600.

1,2-Asymmetric Induction: Cram Rule Cram thought that in the absence of a chelating group sterics played the biggest role in limiting the conformation of the α-C–carbonyl bond. O

Nuc

Nuc

S = small L M = medium L= large

HO

OH

L

L

R

S

R

M

S

R

M

S

Major

large group oriented anti to the carbonyl group

R M

Nuc

M

R M

O

Minor OH Nuc

L

L

Nuc

OH

L R S

S

Nuc S

M

M

M = metal M

nucleophile approaches on the M least sterically hindered face

M L R

O S

HO

R L S Nuc

Nuc

OH

L R S

M

Nuc leads to eclipsed conformation Cram, D. J. J. Am. Chem. Soc. 1952, 74, 5828.; J. Am. Chem. Soc. 1953, 75, 6005.; J. Am. Chem. Soc. 1963, 85, 1245.

Cram-Chelate Rule: Examples

Nuc

OH

L O Ph

MeCeCl2 H

Me

S

OH

M

Major

Ph

Me Me

dr 88:12

R

Tetrahedron Lett. 1994, 35, 285.

O Ph

allylBr/Zn H

dr 77:23

MeO2CCH2

OH Ph MeO2CCH2

Liebigs Ann. Chem. 1989, 891.

allylSnBu3 BF3

O TBSO

H

OH TBSO

dr 95:5

O

Tetrahedron Lett. 1984, 25, 265.

Cl

MeMgCl H

Me

OH Cl

dr 88:12 Tetrahedron 1991, 47, 9005.

Me Me

1,2-Asymmetric Induction: Felkin-Ahn Model 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. O

S = small L M = medium L= large or S EWG

Nuc R

M

Nuc L

L

R

S

M

R S

M

Major large group is placed orthogonal to the carbonyl, M group on the same side as the carbonyl

M

R

R

O

L

Minor OH

Nuc

L

L

Nuc S

M

S

Nuc

HO

OH

M

OH R

S

M

Cram & Felkin-Ahn predict the same product

Nuc M = metal L

L HO

nucleophile approaches on the least sterically hindered face

O M

R S

Nuc

Nuc

R L

M

S Nuc

S

OH R

M

leads to staggered conformation 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.

Felkin-Ahn: Examples

Nuc

OH

L O 2-t-BuPhO

NaBH4 Ph

Me

OH 2-t-BuPhO

R S

M

Major

Ph Me

dr >99:1 Tetrahedron Lett. 1986, 27, 3091.

HSiMe2Ph TBAF

O Me2N

Ph Me

OH Me2N

Ph Me

dr >99:1 Tetrahedron 1993, 49, 4293.

OMe OH

O Li

BocNH

H Me

BocNH

dr 89:11

Me

OMe

Liebigs Ann. Chem. 1994, 121.

O MeS

Li(s-Bu)3BH Ph

Et

OH MeS

dr >99:1 Tetrahedron Lett. 1984, 25, 4775.

Ph Et

How the Reaction Partner Approaches: Orbital Control The trajectory of the approach of both nucleophiles and electrophiles to a π-system can be rationalized by considering the orientation of the HOMO or LUMO of the π-system. E+ Nuc ~105º

~90º R

E+ or Nuc–

R X

R

R

X

R

X

R

X = O, CH2 HOMO

X

R

R

X = O, CH2 HOMO

LUMO

LUMO

The Felkin-Ahn model also has an orbital component that helps to explain the observed selectivity. Delocalization of electron density by hyperconjugation between the σ*C–L and the π-system.

R L

X

R

M X

L

X

M X

L

σ*C–L

S R

Felkin models with C=X LUMO

L

σ*C–L

S R

Felkin models with C=X HOMO

Bürgi, H. B.; Dunitz, J. D. J. Am. Chem. Soc. 1973, 95, 5065; Bürgi, H. B.; Dunitz, J. D. Tetrahedron 1974, 30, 1563; 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.

Addition to α -Chiral C–C Double Bonds Two models can be used to explain the selectivity observed when electrophiles are added to α-chiral (allylic) C–C double bonds. Both give the same product. R

S = small M = medium L= large or EDG

E

EX

RE

L S

M

R

R RE

L S

RZ

M

RE

L

X

S

RZ

Major (anti-Felkin)

E+

M

M

X RZ

Minor

E+ RE

R

E

RZ

M

S

RZ

M

1,3-allylic strain model

L

L

E RE RZ

S

S L

E

R

RE

R

X

Houk model S group is oriented on the same side as the electrophile (anti-Felkin)

Houk, K. N. J. Am. Chem. Soc. 1982, 104, 7162; Houk, K. N. J. Am. Chem. Soc. 1984, 106, 3880.

R RE

L S

M

X RZ

Chiral Allylic: Examples OCH2OMe BzOH2C Me

Me

M

BzOH2C

dr 71:29

Me

RE

R

OCH2OMe

OH

1. BH3 2. [Ox]

E+

Major

L

Me

RZ

S

(anti-Felkin)

Tetrahedron 1984, 40, 2257.

Me CBzNH

MeI

OMe Me

CBzNH

dr 88:12

OLi

Helv. Chem. Acta 1988, 71, 1824.

OMe Me

O

(anti-Felkin)

Me Ph

CO2Et Me

Me3CuLi2•BF3

Ph

dr 87:13

CO2Et Me

(Felkin) Me

Me3CuLi2•BF3

Ph Me

CO2Et

dr 79:21

Ph

CO2Et Me

J. Chem. Soc., Chem. Commun. 1987, 1572.

(anti-Felkin)

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. Nuc O

OPG

OH

OPG

R H

O

R

M Nuc

O

R

1,3-anti

PG

chelation control Nuc

Nuc

H H

H O

PGO

H

H M or H

H O

L

R

H M

acyclic control (Felkin-like)

M 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.

Chelation control requires two adjacent vacant coordination sites at the metal center and a protecting group that enables complexation with the Lewis acid.

1,3-Asymmetric Induction: Examples SiMe3 BnO

allylTMS TiCl4

O

Me

H

BnO

OH

Cl

Me

Me

dr 95:5

O

J. Am. Chem. Soc. 1983, 105, 4833.

HO

O

NaBH4 Et2BOMe

O OR

HO

OH

J. Am. Chem. Soc. 1988, 110, 3560.

O O

RO2C

B

Et

H Et

Tetrahedron Lett. 1987, 28, 155.

HOAc dr 92:8

Cl

i-Pr

O

dr 98:2

Me4NBH(OAc)3

Cl

Bn

OEt

HO

Cl

Ti

O

BH4

OH

i-Pr

O

O O(CH2)3Ph

H RO2C

B

H O

OAc

OAc

1,3-Asymmetric Induction: Examples Me3Si BnO

allylTMS BF3•OEt2

O

Me

H

dr 85:15

BnO

OH

H H

H O

BF3

Me BnO

Tetrahedron Lett. 1984, 25, 729.

R

H

OLi R

LiO TBSO

O

TBSO H

OH

O

H H

H O

dr 76:24 TBSO

Tetrahedron Lett. 1994, 35, 8537.

R

H

1,3-Asymmetric Induction The situation is more complicated when both Cα and Cβ are stereogenic. 2,3-anti: stereocenters are reinforcing under nonchelating conditions; chelating conditions lead to opposing influences and are less predictable Nuc O

OPG

H

H H

Me

OH M

O

R Me

OPG

Nuc PGO

2,3-anti

R

R Me

H

1,2-syn

acyclic control (Felkin-like) 2,3-syn: stereocenters are reinforcing under chelating conditions; nonchelating conditions lead to opposing influences and are less predictable Nuc O

OPG

OH

OPG

R H

O

R Me

Me

2,3-syn

M

O PG

chelation control Notice that in both cases a 1,3-anti "diol" is produced

R

Nuc Me

1,2-anti

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. O OML2 R1

X H

R2

H

Lig O

H

X

M

OH Lig R2

O

X R1

R2 R1

cis-enolate

O

2,3-syn

favored T.S.

X = OR, SR, alkyl M = Li, B, Ti, Sn, etc. O OML2 X

H

X H

R2

M

O

R1

OH R2

X R1

R2 H

O

Lig

O

R1

trans-enolate

Lig

favored T.S.

2,3-anti

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

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. O L

OH

OML2

O

L

H

X

X

M

OH L

X

M

unsubstituted enolate

X

H M

O L M

3,4-anti (anti-Felkin product) Minor

X

H

H

M

3,4-syn (Felkin product) Major

Lig

O

Lig

O

favored T.S.

OH O

H

L M

L

O X

OH M

2,3-syn (Felkin product)

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. Felkin

O L

OML2

M

Lig

X

H

L

M

Lig

O

R

M

O

H L

M

O

Felkin T.S.

syn, syn

X M

R

2,3-syn-3,4-anti Major

Lig

R M

R

H

H O

O

L

syn, syn Minor

cis-enolate

H

OH X

X

M

X

O

L

R

H

H

anti-Felkin OH

L Lig

M

Lig X M

O

H

Lig

O H R

H

anti-Felkin T.S.

syn, syn

syn, anti

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. Felkin

O L

anti-Felkin OH

OML2

O

L

H

M

R

X

R

M

Lig M

R H

L

M Lig

O

H M

H

Lig X M

O

R

R

anti, anti Major

H

H O

X

2,3-anti-3,4-syn Major

trans-enolate

O L H

Felkin T.S.

anti, syn

O

L

X

X

M

OH

anti-Felkin T.S.

anti, anti

Lig

Zimmerman-Traxler + Felkin: Example Me H PMBO

Me

OB(c-Hex)2

>95% ds

O

anti-aldol from trans-enolate

OMe Me

Me O

PMBO

OH OMe

syn from Felkin T.S. H R H

H R

R B

O

Me

O Me

H

R OH

Me

O Me

H

H

Felkin T.S. Tetrahedron Lett. 1997, 38, 8241....