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.
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
Minor Major
R
L
S M
HO Nuc
M
L
S
O^ R
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
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.
L
S
M O
large group^ R
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.
L
S
M
R OH
Nuc
R
O
L
S M
S = small
M = medium
L= large
Nuc
R
L
S M
Nuc OH R
L
S M
HO Nuc
Major Minor
R
L
S M
Nuc OH
S
L
M
M O R
nucleophile
approaches on the
least sterically
hindered face
M = metal
M
R
L
S M
Nuc OH
Nuc
L
M
S
HO
Nuc
R
leads to eclipsed conformation
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:
H
O
Cl Me
Me
OH
Cl Me Tetrahedron 1991 , 47 , 9005.
MeMgCl
dr 88:
H
O
TBSO TBSO
Tetrahedron Lett. 1984 , 25 , 265.
dr 95:
allylSnBu 3
BF 3
MeCeCl 2
H
O
Ph
MeO 2 CCH (^2)
OH
Ph
MeO 2 CCH (^2) Liebigs Ann. Chem. 1989 , 891.
dr 77:
allylBr/Zn
OH
R
L
S M
Nuc OH
Ph^ Major
O
2- t -BuPhO
Me
Felkin-Ahn: Examples
Ph
OH
2- t -BuPhO
Me Tetrahedron Lett. 1986 , 27 , 3091.
dr >99:
Ph
O
MeS Et
Ph
OH
MeS Et Tetrahedron Lett. 1984 , 25 , 4775.
Li( s -Bu) 3 BH
dr >99:
H
O
BocNH
Me
BocNH
Me Liebigs Ann. Chem. 1994 , 121.
dr 89:
NaBH 4
Ph
O
Me 2 N
Me
Ph
OH
Me 2 N
Me Tetrahedron 1993 , 49 , 4293.
dr >99:
OH
HSiMe 2 Ph
TBAF
OMe
Li
OMe
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.
R
L
X
R
R
X = O, CH 2
HOMO
X
R
R
LUMO
E +^ or Nuc –
X
R
R
X = O, CH 2
HOMO
X
R
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 models
with C=X LUMO
σ* C–L S
M
L
R
X L R X
Felkin models
with C=X HOMO
σ* C–L S
M
L
R
X
Major
Chiral Allylic: Examples
Tetrahedron 1984 , 40 , 2257.
dr 71:
R
L
M S
RE
RZ
E+
BzOH 2 C
Me Me
OCH 2 OMe 1. BH 3
2. [Ox] BzOH 2 C
Me Me
OH OCH 2 OMe
( anti -Felkin)
Helv. Chem. Acta 1988 , 71 , 1824.
dr 88:
CBzNH Me
OMe
OLi
CBzNH Me
OMe
O
Me
( anti -Felkin)
MeI
dr 87:
Ph
Me
CO 2 Et
(Felkin)
Me 3 CuLi 2 • BF 3 Ph
Me
CO 2 Et
Me
J. Chem. Soc., Chem. Commun. 1987 , 1572.
dr 79:
Ph
Me ( anti -Felkin)
Me 3 CuLi 2 • BF 3 Ph
Me
CO 2 Et
Me
CO 2 Et
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
H O
PGO R H
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
H O
L M H
M
Nuc
or
J. Am. Chem. Soc.^ Nonchelation (Cram): 1968 , 90 , 4011. J. Am. Chem. Soc.^ Chelation (Cram): 1968 , 90 , 4019. Tetrahedron Lett.^ Nonchelation (Evans): 1994 , 35 , 8537.
1,3-Asymmetric Induction: Examples
Me H
BnO O
allylTMS
BF 3 • OEt 2
Me
BnO OH
dr 85:
Tetrahedron Lett. 1984 , 25 , 729.
H H
H O
BnO R H
BF 3
Me 3 Si
H
TBSO O TBSO OH
dr 76:
Tetrahedron Lett. 1994 , 35 , 8537.
LiO O (^) HH^ H O
TBSO R H
R
OLi
1,3-Asymmetric Induction
The situation is more complicated when both Cα and Cβ are stereogenic.
H
O
R
OPG
M
O
O
R
PG
Nuc
chelation control
H Me H O
PGO R H
M
acyclic control
(Felkin-like)
Nuc
Nuc
OH
R
OPG
1,2- syn
Me 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- anti
Me Me
2,3- syn
Me
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-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.
OML 2
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
O^ M
H
M
H L
X Lig
Lig OH
O
H
M
H L
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.
OML 2
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
O^ M
Lig
Lig
X
R
H
H
M
H L
O
O^ M
Lig
Lig
X
R
H
H
H
L M O
O^ M
R
X
H
H
M
L
Lig
Lig
Felkin T.S. anti- Felkin T.S.
syn , syn syn , syn syn , anti
Me
Zimmerman-Traxler + Felkin: Example
O
O^ B
H
R
Me
H
H
R
Felkin T.S.
Me
O
H
OMe
PMBO
Me
OB( c -Hex) 2
Me
OH
OMe
PMBO
Me O
>95% ds
Me
O
OH
H
R
Me
H
H
R
anti -aldol from
trans-enolate
syn from
Felkin T.S.
Tetrahedron Lett. 1997 , 38 , 8241.
