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
S = smallM = mediumL= large
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
Tetrahedron Lett. 1980, 21, 1035.
BuLi or Bu2CuLi
w/ BuLi 63:37w/ Bu2CuLi 94:6
Ph
OPhO
MePh
OHPhO
Me
Tetrahedron Lett. 1986, 27, 3091.
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
S = smallM = mediumL= large
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
Tetrahedron Lett. 1994, 35, 285.
dr 88:12
H
OCl
Me
Me
OHCl
Me
Tetrahedron 1991, 47, 9005.
MeMgCl
dr 88:12
H
OTBSO TBSO
Tetrahedron Lett. 1984, 25, 265.
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
Tetrahedron Lett. 1986, 27, 3091.
dr >99:1
Ph
OMeS
EtPh
OHMeS
Et
Tetrahedron Lett. 1984, 25, 4775.
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
Tetrahedron 1993, 49, 4293.
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
Tetrahedron 1984, 40, 2257.
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
dr 85:15Tetrahedron Lett. 1984, 25, 729.
H HOH
RHBnO
BF3
Me3Si
H
TBSO O TBSO OH
dr 76:24Tetrahedron Lett. 1994, 35, 8537.
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
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
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
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
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.
Tetrahedron Lett. 1997, 38, 8241.