Selectivity models

Stereoselectivity Models: α-Chiral Carbonyl Compounds

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

R

OL

S M

S = smallM = mediumL= large

NucR

L

S M

Nuc OH

RL

S M

HO Nuc

Cram chelate oranti-Felkin-Ahn

Cram orFelkin-Ahn

when R = H

NucL

S MNuc

L

S M

OH OHReliable models that can be used forpredictions and rationaluzations ofstereoselective additions of a widevariety of nucleophiles into α-chiral

carbonyl compounds.

Carreira: Chapter 2.1 – 2.5

controlling theconformation ofthis 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.

OR

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.

LS

MR Nuc

OH

R

OL

S M


NucR

L

S M

Nuc OH

RL

S M

HO Nuc

MajorMinor

RL

S M

HO Nuc

M

LS

RO

nucleophile approaches on the

least sterically hindered face

M = metal

M

L

S R

HO

Nuc

RL

S M

HO Nuc

L = OR, NHR, etc.

L

S

MM

M

Nuc

Nuc

RL

S M

HO Nuc

MajorH

OBnO SnMe3

LiClO4

Cram-Chelate Rule: Examples

OHBnO

Tetrahedron Lett. 1992, 33, 1817.

dr 96:4

H

OBnOCH2O

MeBu

OHBnOCH2O

Me


BuLi or Bu2CuLi

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

Ph

OPhO

MePh

OHPhO

Me


LiAlH4

dr 72:28

Et

OTBSO

MeEt

TBSO

Me

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

dr 85:15

HO MeMeLiTiCl4

Nuc

1,2-Asymmetric Induction: Cram 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.

LS

M ORlarge group

oriented anti to the carbonyl group

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.

LS

MR OH

Nuc

R

OL

S M


NucR

L

S M

Nuc OH

RL

S M

HO Nuc

MinorMajor

RL

S M

Nuc OH

S

LM

O RMnucleophile

approaches on the least sterically hindered face

M = metal

M

RL

S M

Nuc OH

Nuc

L

M

S

HO

Nuc

R

leads to eclipsed conformation

RL

S M

Nuc OH

MajorH

OPh

Me

Cram-Chelate Rule: Examples

Me

OHPh

Me


dr 88:12

H

OCl

Me

Me

OHCl

Me

Tetrahedron 1991, 47, 9005.

MeMgCl

dr 88:12

H

OTBSO TBSO


dr 95:5

allylSnBu3BF3

MeCeCl2

H

OPh

MeO2CCH2

OHPh

MeO2CCH2Liebigs 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 thecarbonyl

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

OL

S M

S = smallM = mediumL= large or EWG

NucR

L

S M

Nuc OH

RL

S M

HO Nuc

MinorMajor

RL

S M

Nuc OH

OR

RL

S M

Nuc OHM R OH

NucL

S M

L

S M

nucleophile approaches on

the least sterically hindered face

L

M SRO

Nuc

L

M SNuc

RHO

M = metal

Cram &Felkin-Ahnpredict the

same product

leads to staggered conformation

RL

S M

Nuc OH

MajorPh

O2-t-BuPhO

Me

Felkin-Ahn: Examples

Ph

OH2-t-BuPhO

Me


dr >99:1

Ph

OMeS

EtPh

OHMeS

Et


Li(s-Bu)3BH

dr >99:1

H

OBocNH

Me

BocNH

Me

Liebigs Ann. Chem. 1994, 121.

dr 89:11

NaBH4

Ph

OMe2N

MePh

OHMe2N

Me


dr >99:1

OH

HSiMe2PhTBAF

OMe

Li

OMe

~90º ~105º

How the Reaction Partner Approaches: Orbital Control

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.

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.

RL

XR

R

X = O, CH2

HOMO

XR

R

LUMO

E+ or Nuc–

XR

R

X = O, CH2

HOMO

XR

R

LUMO

E+

Nuc

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.

X

Felkin modelswith C=X LUMO

σ*C–L S

M

L

R

X RL X

Felkin modelswith C=X HOMO

σ*C–L S

M

L

R

X

Addition to α-Chiral C–C Double Bonds

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

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.

L

S M

S = smallM = mediumL= large or EDG

EXL

S M

E R

MinorMajor(anti-Felkin)

R

RRE

RZ

RE

RZX

L

S M

R ERE

RZX

L

M S

RE

RZ

E+

R

L

M S

E

RERZ

X

L

S M

E RRE

RZX

R RE

RZ

E+

Houk modelS group isoriented on

the same sideas the electrophile

(anti-Felkin)

1,3-allylic strainmodel

SL

M

Major

Chiral Allylic: Examples


dr 71:29

R

L

M S

RE

RZ

E+

BzOH2C

Me Me

OCH2OMe 1. BH32. [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

CO2EtMe

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

dr 79:21

Ph

Me(anti-Felkin)

Me3CuLi2•BF3 Ph

Me

CO2EtMe

CO2Et

1,3-Asymmetric InductionStereogenic 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

MOO

R

PG

Nuc

chelation control

H HOH

RHPGO

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 HOH

MHL

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 allylTMSTiCl4

Me

BnO OH

dr 95:5J. Am. Chem. Soc. 1983, 105, 4833.

TiOO

Me

Bn

Cl

Cl

ClCl

SiMe3

HO O NaBH4Et2BOMe

dr 98:2Tetrahedron Lett. 1987, 28, 155.

OR

O HO OH

OEt

OO B

Oi-Pr

HRO2CEt

Et

BH4

Me4NBH(OAc)3

HOAcdr 92:8

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

HO OH

O(CH2)3Ph

O

H B

Oi-Pr

ORO2C

OAc

OAcH

1,3-Asymmetric Induction: Examples

Me H

BnO OallylTMSBF3•OEt2

Me

BnO OH


H HOH

RHBnO

BF3

Me3Si

H

TBSO O TBSO OH


LiO

O H HOH

RHTBSO

R

OLi

1,3-Asymmetric InductionThe situation is more complicated when both Cα and Cβ are stereogenic.

H

O

R

OPG

MOO

R

PG

Nuc

chelation control

H MeOH

RHPGO

M

acyclic control(Felkin-like)

Nuc

Nuc

OH

R

OPG

1,2-synMe Me

2,3-anti

2,3-anti: stereocenters are reinforcing under nonchelating conditions; chelating conditions lead to opposing influences and are less predictable

H

O

R

OPG

Nuc

OH

R

OPG

1,2-antiMe Me

2,3-synMe

2,3-syn: stereocenters are reinforcing under chelating conditions; nonchelating conditions lead to opposing influences and are less predictable

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

Closed Transition States: Zimmerman-TraxlerClosed 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

XR1

X = OR, SR, alkylM = 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-antiR1

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

MO

Lig

LigH

X

H

R1R2

favored T.S.

O

MO

Lig

LigH

X

R1

HR2

Closed Transition States: Zimmerman-Traxler + FelkinWhen 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

unsubstitutedenolate

favored T.S.

H

O

X

OH O

3,4-syn(Felkin product)

Major

L

M

L

MX

OH OL

M3,4-anti

(anti-Felkin product)Minor

O

MO

H

M

LH

X Lig

LigOH

O

H

M

LH

X

X

OH O

2,3-syn(Felkin product)

L

M

H



OML2

X

cis-enolate

H

O

X

OH O

syn, synMinor

L

M

L

MX

OH OL

M2,3-syn-3,4-anti

Major

R

R R

Felkin anti-Felkin

O

MO

Lig

Lig

X

R

H

H

M

LHO

MO

Lig

Lig

X

R

H

H

H

ML O

MO

R

X

H

H

ML

Lig

Lig

Felkin T.S. anti-Felkin T.S.

syn, syn syn, syn syn, anti

L



OML2

X

trans-enolate

H

O

X

OH O

2,3-anti-3,4-synMajor

L

M

L

MX

OH OL

Manti, antiMajor

R R

Felkin anti-Felkin

O

MO

Lig

Lig

X

H

R

H

M

LH O

MO

H

X

R

H

HM

Lig

Lig

Felkin T.S. anti-Felkin T.S.

anti, syn anti, anti

R

Me

Zimmerman-Traxler + Felkin: Example

O

BO

H

R

Me

H

HR

Felkin T.S.

Me

O

H

OMe

PMBO

MeOB(c-Hex)2

Me

OH

OMe

PMBO

MeO

>95% ds

MeO

OH

H

R

Me

H

HR

anti-aldol fromtrans-enolate

syn fromFelkin T.S.


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Selectivity models