The Evolution of Models for Carbonyl Addition
Evans Group Afternoon Seminar
Sarah Siska
February 9, 2001
Fischer
Cram
Cornforth
Felkin
Anh/Eisenstein
Cieplak
Tomoda
The Evolution of Models for C=O Addition
Reviews
SJS Commentary
Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191-1223
Gung, B. W. Tetrahedron 1996, 52, 5263-5301
Ager, D. J.; East, M. B. Tetrahedron 1992, 48, 2803-2894
great overview
thorough comparison of more recent models
1,2 and 1,3 difunctionality
Reetz, M. T. Angew. Chem. Int. Ed. Engl. 1984, 23, 556-569
chelation vs. non-chelation control
Morrison, J. D.; Mosher, H. S. Asymmetric Organic Reactions;
Prentice Hall Inc.: 1971
Wipf, P.; Kim, Y. J. Am. Chem. Soc. 1994, 116, 11678-16888, ref. 1-5, 7
older models; historical perspective
excellent collection of references
Outline
I. 1,2-Asymmetric Induction Models
A. Historical Perspective
B. Evolution: from empirical to computational
1. Steric models
2. Electronic models
3. Polar models; recent support for electrostatics
II. 1,3-Asymmetric Induction Models
A. Chelation model
B. Non-chelation models
1. Steric model
2. Polar model
III. Merged 1,2- and 1,3-Asymmetric Induction
IV. Unpredicted, highly selective carbonyl additions
A. Rapamycin (Smith)
B. Carbohydrate derivatives (Kobayashi)
00-handout 2/12/01 2:31 PM
Definition of Terms
Nu:
Felkin product = commonly accepted term for the
major carbonyl addition product predicted by the
Felkin-Anh model; also predicted by Cram and
Karabatsos for steric cases, Cornforth and Evans for
α-heteroatom (non-chelating) cases
R
Felkin-Anh model
O
HO
R
Nu
Nu–M
RL
Nu
RL
R
+
RL
OH
Nu–M
RL
H
RL
Nu
+
RL
Nu
RM
RM
O
RM
OH
RM/L
OH
Nu–M
RM/L
Nu
X
RM
RS
OH
O
OH
R
RM
RS
RM
H
O M
RL/X
Examples:
RS
RM
RS
+
RM/L
Nu
X
also Cram-chelate
product
X
Felkin products
anti-Felkin products
Fischer, and the Dawn of Asymmetric Induction
COOH
CHO
H
OH
HO
H
HO
H
1) HCN
2) hydrolysis
L-arabinose
OH
HO
H
OH
H
HO
H
HO
H
CH2OH
COOH
H
+
H
not isolated initially,
but later found in
mother liquor
H
CH2OH
acid
~3
HO
HO
CH2OH
L-mannonic
H
OH
L-gluconic
:
acid
1
"To my knowledge these observations furnish the first definitive
evidence that further synthesis with asymmetric systems
proceeds in an asymmetric manner."
-Emil Fischer, 1894
Fischer, E. Ber. 1890, 23, 2611
Fischer, E. Ber. 1894, 27, 3189
Assimilation in nature: propagation of asymmetry from one chiral molecule to another
CO2, H2CO
glucose*
chlorophyll*
chlorophyll*
Fischer, E. Ber. 1894, 27, 3189
Freudenberg, K. Adv. in Carbohydrate Chem. 1966, 21, 1
01-handout 2/12/01 2:33 PM
McKenzie: Detection of Asymmetric Induction
The problematic mandelic acid synthesis
O
Ph
H
[H]
OR*
OH
HO
OR* +
Ph
Ph
Me
H
KOH/H2O
OR*
O
O
H
OH
Ph
probable
racemization
O
O
(±)-mandelic acid
Me
R* =
OH
H
Kipping, F. S. Proc. Chem. Soc. 1900, 16, 226
McKenzie, A. J. Chem. Soc. 1904, 1249
Me
Reduction of (–)-menthylpyruvate:
Cohen, J. B.; Whiteley, C. E. Proc. Chem. Soc. 1900, 16, 212;
J. Chem. Soc. 1901, 79, 1305
bornyl
(Kipping)
Grignard addition: a solution
O
O
R*OH
OH
Ph
Ph
-H2O
O
R'
1) R'MgX
OR*
2) H2O
3) KOH/H2O
H
R'
OH
Ph
O
When R' ≠ Ph, product
mixture is optically active!
racemization
not possible
i-Pr
HO
+
O
R' = Me, Et, Ph
H
HO
OH
Ph
O
R*OH = Me
OH
(yield not reported)
H
(–)-menthol
McKenzie, A. J. Chem. Soc. 1904, 1249
Prelog's Generalization for α-Keto Esters
• First suggested in 1951 at the XIIth International Congress of
Pure and Applied Chemistry
RM
O
RS
R
RL
O
O
• An empirical model: orientations of alkyl substituents and
carbonyls were largely intuitive
M
• Rules established for assessing stereoselectivity:
- ee's <5% disregarded
- saponification yields <80% unreliable
- optical rotations uniformly performed
- RS, RM, and RL hydrocarbon residues
- when RM ≈ RL, selectivity often poor
Nu:
Prelog model
Basis for Rule
O
R'
1) R'MgX
O
Ph
O
RL
RS RM
OH
Ph
2) H+/H2O
3) KOH/H2O
HO
OH
O
+
R'
OH
Ph
RL
RS RM
O
predicted
HO
+
selectivities ranged from 8% to 69% ee,
determined by polarimetry
Features
RM
smallest groups on
chiral moiety staggered
around ester carbonyl
nucleophile attacks on the
same face as RS (usually H);
90° trajectory
02-handout 2/12/01 2:34 PM
O
RS
R
RL oriented anti to principal chain
RL
O
O
M
trans-coplanar carbonyls: greatest
charge separation in transition state
Nu:
Prelog, V. Helv. Chim. Acta 1953, 36, 308
Prelog, V. Bull. Soc. Chim. Fr. 1956, 987
Atrolactic Acid Synthesis
O
Ph
1) PhMgBr
O
Me
RL
Chiral Alcohol
HO
OH
Me
2) H+/H2O
3) KOH/H2O
RS RM
O
OH
+
Ph
HO
OH
Me
O
RS RM
O
predicted
% "asymmetric synthesis"
Original Prelog model
(determined by optical rotation)
H
Me
HO
RL
25% (–)
i-Pr
O
RM
R
OH
Me
RL
+
RS
O
O
M
12% (+)
i-Pr
Nu:
H
Me
R
Revised Prelog model
Me
69% (+)
RM
OH
H
O
RS
R
Me
R
Me
RL
O
O
M
Nu:
13% (–)
H
Prelog, V. Helv. Chim. Acta 1953, 36, 308
Prelog, V. Bull. Soc. Chim. Fr. 1956, 987
OH
Cram: 1952
Nu:
Cram's Rule: "In reactions of the following type, that
diastereomer will predominate which would be formed by
the approach of the entering group from the least
hindered side of the double bond when the rotational
conformation of the C–C bond is such that the double
bond is flanked by the two least bulky groups attached to
the adjacent asymmetric center."
RS
RL
O M
R
RM
Cram acyclic model
Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74, 5828
Basis for Model
O
RL
R
RS
HO
Nu-M
Nu
RL
R
RM
RS
RM
Nu
predicted
(Felkin product)
Features and Liabilities
03-handout 2/12/01 2:35 PM
RS
RM
(anti-Felkin product)
RS
RL
steric repulsion
between RL and
R not discussed
RL
R
activated carbonyl considered
to be largest group
Nu:
90° trajectory
of nucleophile
+
R
Nu-M = RMgX, LAH
RL = Ph
RM = Me, Et
RS = H
R = H, Ph, Me, Et
selectivities ranging
from 2:1 to >4:1,
favoring Felkin product
OH
O M
RM
Nu R
S
RL
R
torsional effects not considered
OH
RM
Cram: 1952
Among the 27 cited reactions whose stereoselection is "predicted" by Cram's acyclic rule:
O
Ph
p-tolyl
p-CH3C6H4MgBr
Me
OH
HO
Me
Ph
+
p-tolyl
Me
Ph
NH3Cl
NH3Cl
yield not reported
NH3Cl
minor
(Felkin)
major
(anti-Felkin)
Curtin, D. Y.; Pollak, P. I. J. Am. Chem. Soc. 1951, 73, 992
Ranking of steric bulk of α-substituents is somewhat arbitrary:
Me > NH3Cl due to the amino group's formation of a non-rigid "more adaptable" ion pair
in the end, a suggestion of a chelate . . .
one proposed transition state:
Nu:
Nu:
H
Me
Ph
H
H
N
O
Ph
O MgBr
MgBr
Me
NH
MgBr
Possible Pitfalls
• Low or unreported yields may result in misleading selectivities
• Model based on qualitative assessment of steric bulk
Bottom Line
Cram's acyclic model is a convenient mnemonic that predicts Felkin products in α-alkyl or aryl aldehydes or ketones.
Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74, 5828
Cram: 1959
Methyl has greater effective bulk than OH; Cram cites "A-values" of
Winstein, who compares the relative tendency of groups to occupy the
equatorial position on a cyclohexane ring.
Nu:
RS
CH3 > OSO2C6H4CH3-p > OCOCH3 > OH
RL
O M
R
The acyclic model would predict the opposite product in the case of an
α-heteroatom -- a new model is needed!
RM
Winstein, S.; Holmes, N. J. J. Am. Chem. Soc. 1955, 77, 5562
Nu:
O
Ph
RS
R
X
O
X
R'
1) R'-M
Ph
Me
2) H3O
+
Cram acyclic model
HO
OH
Ph
Ph
X
M
+
Ph
Ph
Me
X
A
major
RM/L
R'
Me
B
minor
R'-M
X
A:B
yield of A (%)
CH3MgI
CH3Li
OH
OMe
11.5 : 1
9:1
20
50
Cram chelate model
Nu:
nucleophile approaches
from the back face
• expects groups OH, OR, OAc, NR2, NHAc to chelate
O M
OR
Ph
Me
Ph
"The open-chain model applies to systems which contain only
groups attached to asymmetric carbon of the starting material which
are incapable of complexing with organometallic reagents."
Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81, 2748
04-handout 2/12/01 2:36 PM
Bartlett: Early Chlorohydrin Work
O
Me
1) MeMgBr
Cl
OH
HO Me
Cl
Cl
+
2) H3O+
82%
major
Bartlett, P. D.; Rosenwald, R. H. J. Am. Chem. Soc. 1934, 56, 1990
O
OH
OH
1) t-BuMgCl
Cl
2) H3O
Cl
Cl
+
ratio based on relative rates of
reaction with hydroxide; acid
titration showed k1 > 300 k2
+
72%
:
73
Cornforth proposes axial Cl as
reactive conformer:
27
NaOH
k2: slow
NaOH
k1: fast
Nu:
O
OH
O
O
Cl
NaOH
H
HOCl
fast
Cl
Bartlett, P. D. J. Am. Chem. Soc. 1935, 57, 224
In contrast:
O
Me
OH
MeMgX
Me
HO Me
Me
Me
+
:
~1
1
Chiurdoglu, G. Bull. Soc. Chim. Belges 1938, 47, 241
Cornforth: 1959
• argument based on importance of polarization in transition state,
and evidence of selectivity in α-chlorocyclohexanone additions
Nu:
RS
X
• ". . . where the dipoles are antiparallel, the polarization of the
carbonyl group would be easiest," thereby lowering transition state
energy
O M
R
RL
• a modification of Cram's rule for electronegative, non-chelating
α-substituents X
Cornforth model
Additions to α-Chloro Carbonyls
O
Cl
R
RS
RL
HO
1) R'-M
R'
R'
Cl
R
Et2O, -70 °C
2) AcOH
RS
RL
predicted
(Felkin)
+
OH
Cl
R
RS
RL
(anti-Felkin)
Features
net dipole of
molecule minimized;
analogous to Prelog
activated carbonyl considered
to be largest group
Nu:
90° trajectory
of nucleophile
RS
X
R
O M
RL
Nu R
S
X
R
as in Cram acyclic model,
torsional effects not considered
OH
RL
Cornforth, J. W.; Cornforth, R. H.; Mathew, K. K. J. Chem. Soc. 1959, 112
05-handout 2/12/01 2:37 PM
Cornforth: Rationalization and Evidence
Support and Contradiction for Dipole Minimization
O
Cl
R
Cl
O
O
O
RS
RL
O
Cl
R
Cl
O
RS RL
Bellamy, L. J.; Thomas, L. C.; Williams, R. L.
J. Chem. Soc. 1956, 3704
Bellamy, L. J.; Williams, R. L. ibid. 1957, 4294
Corey, E. J. J. Am. Chem. Soc. 1953, 75, 2301
Corey, E. J.; Burke, H. J. ibid. 1955, 77, 5418
O
Ph
RL
RS RM
Prelog, V. Bull. Soc. Chim. Fr. 1956, 987
(note: methylpyruvate does not
adopt this conformation)
Chlorohydrin Synthesis
O
OH
H
2) AcOH
Cl
Et
n-Bu
+
Cl
:
aq. NaOH
CO3H
X
O
n-Bu
O M
R
3
RL
Cornforth model
aq. NaOH
1) Na0, NH3
2)
RS
(anti-Felkin)
7
Et
n-Bu
(Felkin)
(±)
n-Bu
Et
Cl
68%
Nu:
OH
1) n-BuMgBr
Et
O
Et
1) H2, Lindlar
n-Bu
n-Bu
Et
(±)
(±)
CO2H
Et
CO3H
2)
CO2H
Cornforth, J. W.; Cornforth, R. H.; Mathew, K. K. J. Chem. Soc. 1959, 112
Karabatsos: 1967
Given Cram's acyclic model, Karabatsos is surprised by the following selectivities:
O
OH
OH
Ph
H
Nu-M
Ph
Nu
R
+
Ph
Nu
R
A:B
Me
i-Pr
2–4 : 1
1–2 : 1
R
R
A
B
• it appears that i-Pr is effectively
smaller than Me, if Ph = RL
Karabatsos' explanation: Cram transition states are incorrect
Nu:
R(M)
H
OH
OH
H
R
O (M)
M
Ph
Ph
Nu
R
R
major
minor
H
Nu:
Karabatsos model
• ratios depend not on Nu ↔ H and Nu ↔ RM,
but instead on RM ↔ O vs. RL ↔ O
Ph
O M
H
Ph
Nu
2nd-best conformer
Compared Interaction
∆∆H°
Me ↔ O – Ph ↔ O
i-Pr ↔ O – Ph ↔ O
0.6 kcal/mol
0.2 kcal/mol
Karabatsos, G. J. J. Am. Chem. Soc. 1967, 89, 1367
06-handout 2/12/01 2:38 PM
Karabatsos: 1967
Nu:
• energy difference (∆∆H°) between interactions of RM ↔ O and
RL ↔ O determines product ratio
RS
R
O MM
R
• reactant-like transition state
• model based on most stable ground-state conformation
RL
• energy differences between major and minor conformations are
<1 kcal/mol
Karabatsos model
O
Nu-M
RL
H
RM
OH
OH
RL
Nu
+
RL
Nu
RM
RM
RM
major
(Felkin)
R
O LM
R
RS
minor
(anti-Felkin)
Nu:
Rationalizations
RS
M
R
O M
R
≈
RM
H
RL
RL
Z
O
Z = alkyl, OR, NR2
N
RM
H
RS
RL
RS
a) ∆H°(imine N ↔ R) ≈ ∆H°(carbonyl O ↔ R)
b) imine geometry ≈ complexed C=O geometry
∴ ∆H°(imine N ↔ R) ≈ ∆H°(complexed C=O O ↔ R)
most stable
ground state
conformer
Karabatsos, G. J. J. Am. Chem. Soc. 1967, 89, 1367
Felkin: 1968
• "reactant-like" transition state
Nu:
• assumption of torsional strain in partially formed or broken bonds:
first fully staggered acyclic model
RM
RS
R
• substituents minimized around R; leads to inconsistency in
aldehyde substrates
➞ see DAE Chem 206 Lecture Notes (2000), 18-08
O M
RL
• polar effect: maximize separation between incoming anionic
nucleophile and electronegative α-substituent (RS, RM, or RL)
Felkin model
Reduction of α-Methyl Ketones
A/B
O
OH
R
RL
R
Me
+
RL
R
Me
Me
A
Features
larger nucleophile ≈
better selectivity
Nu:
90° trajectory
of nucleophile
RM
RS
R
substituents
minimized around
ketone R
OH
LiAlH4
RL
B
R
RL = Cy
RL = Ph
Me
Et
i-Pr
t-Bu
1.6
2.0
4.1
1.6
2.8
3.2
5.0
49
Nu
RM
RS
O M
R
OH
torsional strain
accounted for; leads to
fully staggered product
RL
RL
larger RL ≈ better selectivity
Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 18, 2199
07-handout 2/12/01 2:39 PM
Felkin: Accounting for Less Selective Reactions
1) The t-butyl ketone case
• with α-branching, in any staggered conformation, syn-pentane is impossible to avoid
O
OH
t-Bu
Cy
t-Bu
Me
Me RL
OH
LiAlH4
Cy
Cy
+ t-Bu
Me
RM
Me RS
Me
O
Me
1.6
1
:
Nu:
2) Transition states for minor products (does not consider conformers with RL next to R)
Nu:
Nu:
RM
RS
M O
R
possible when RM
is relatively small
RS
RL
M O
possible for small
nucleophiles
R
RM
RL
3) 2-methylcyclohexanone
• cannot adopt Felkin-type conformation; still considered as a reactant-like transition state
• selectivity based on competition between torsional strain and steric strain
O
OH
LiAlH4
Me
OH
Me
+
(CH2)4
Me
O
(CH2)4
Me
H
H
steric strain
(small Nu:)
major
Me
O
torsional strain
(large Nu:)
Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 18, 2199; 2205
Weaknesses in Felkin's Argument
1) Polar effect
Anh's Solutions
1) Antiperiplanar effect
• best acceptor σ* orbital aligned parallel to π and π*
orbitals of carbonyl; stabilization of incoming anion
Nu:
Nu
RS
RM/L
R
O M
• main repulsion to minimize
between Nu and
electronegative group X -no justification given
RS
RM/L
H
O
X
M
X
2) Breakdown for aldehydes
Nu:
M O
2) Non-perpendicular attack
Nu:
Nu:
RM
RS
πC=O ↔ σ*C-X
nNu ↔ σ*C-X
H
• without ketone R, important
steric interaction removed:
would predict RM to be next
to H rather than carbonyl
RL
wrong prediction
RM
RS
H
O M
RL
favored
RM
RS
M O
H
RL
disfavored
• incorporation of the Bürgi-Dunitz trajectory
Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 18, 2199
08-handout 2/12/01 2:41 PM
Anh, N. T.; Eisenstein, O. Nouv. J. Chim. 1977, 1, 61
Bürgi, H. B.; Dunitz, J. D.; Shefter, E. J. Am. Chem. Soc. 1973, 95, 5065
Bürgi, H. B.; Dunitz, J. D.; Lehn, J. M.; Wipff, G. Tetrahedron 1974, 30, 1563
Anh: Orbital Factors
Hypothesis: The conformer with greatest dissymmetry will give greatest relative ratio of diastereomers.
π
Me
H
O
H
• suggests that both steric and orbital factors
control asymmetric induction
diastereotopic faces of π bond
top face has greater electron density
H
• "at longer distances , orbital factors might be
more effective than steric factors"
nucleophile will
preferentially attack
more positive side
Conformers with large π orbital dissymmetry
O
O
H
H
Me
H
Me
H
Felkin conformers
not considered
H
Cl
propanal
Cram
2-chloropropanal
Cornforth
Anh, N. T.; Eisenstein, O.; Lefour, J-M.; Dâu, M-E. J. Am. Chem. Soc. 1973, 95, 6146
Anh's Calculated Transition State Energies
The model:
Lowest energy transition states:
1.5 Å
H–
θ = 90°, 100°, 110°
(interpolated using
a quadratic curve)
θ
Me
H
H
O
H–
Li
1.63 Å
H–
H
Me
H
O
Li
θ = 107°
H
Me
H
O
Li
X
Et
rotate C–C bond by
30° increments
2-methylbutanal
(Felkin-Anh model)
STO-3G ab initio method (low level)
RS
R
O M
R
RL
>2.7 kcal/mol
R
Nu:
R
O MM
RL
G1
most stable
ground state
conformer
09-handout 2/12/01 3:25 PM
2-chloropropanal
(Felkin-Anh polar model)
Non-perpendicular attack
Nu:
RS
Cl
Karabatsos model
EFelkin model ≈ EG1
95 – 105°
R
R
O
M
a range of angles for optimum overlap
Anh, N. T.; Eisenstein, O. Tetrahedron Lett. 1976, 155
Anh, N. T.; Eisenstein, O. Nouv. J. Chim. 1977, 1, 61
Anh, N. T. Top. Curr. Chem. 1980, 88, 146
Cieplak Model for Carbonyl Addition
• similar to Anh-Eisenstein modification of the Felkin model: stabilization of nucleophile via
antiperiplanar C–XD bond
Nu:
RS
RM/L
R
O M
• assumes an electron-poor transition state: aligns best donor C–XD anti to incoming
nucleophile to stabilize σ* of forming bond
• a model generated to explain unexpected selectivities
XD
• importance of torsional effects (Felkin, Anh, Houk, Paddon-Row) disputed
Cieplak model
Nu
σ∗ C
H
σ∗ C
XA
σ∗ C
Nu
σC
Nu
RM/L
O
XD
M
H
XD
Felkin Anh
σC–Xd ↔ σ*C---Nu
Cieplak
better donor
σC
σC
XA
XD
C–H > C–C > C–N > C–O
(Houk disputes the ordering of C–H, C–C)
"Structures are stabilized by stabilizing their highest energy filled
states. This is one of the fundamendal assumptions in frontier
molecular orbital theory. The Cieplak hypothesis is nonsense."
"Just because a hypothesis correlates a set of observations doesn't
make that hypothesis correct."
DAE, Chem 206 2000, Lecture 18
Cieplak, A. S. J. Am. Chem. Soc. 1981,103, 4540; Cieplak, A. S.; Tait, B. D.; Johnson, C. R. J. Am. Chem. Soc. 1989, 111, 8447
Preliminary Results
Wipf: 4,4-Disubstituted Cyclohexadienones
An interesting selectivity en route to a total synthesis
O
BnO
OH
BnOCH2Li
O
O
Cbz2N
HO
mCPBA, CCl4
70 °C, 2 h
+
O
-78 °C
>50%
O
O
Cbz2N
OH
O
O
O
radical inhibitor
O
Cbz2N
1α
BnO
OBn
O
Cbz2N
1β
:
5
1
O
Verification - better yield, different nucleophile
O
Me
OH
HO
O
Me
MeMgBr, THF
Boc2N
O
-78 °C
84%
O
OH
Me
Aranorosin
2β
:
N
H
Me
O
Boc2N
2α
6
C6H13
O
O
Boc2N
O
O
+
O
O
1
• little steric bias as determined by molecular mechanics minimization of geometry
• likely to be an electrostatic or stereoelectronic (hyperconjugation, orbital distortion, etc) explanation
Wipf, P.; Kim, Y. J. Am. Chem. Soc. 1994, 116, 11678
Wipf, P.; Jung, J-K. Chem. Rev. 1999, 99, 1469
10-handout 2/12/01 2:44 PM
4,4-Disubstituted Cyclohexadienones: Experimental Data
~4 Å
OR
HO
MeMgBr, THF
OR
Me
OR
+
O
R'
-78 °C
Me
R'
HO
R'
α
β
KEY: α : β (yield)
β
("vinylogous Felkin-Anh")
β'
β
(58%)
β
OH
O
OMe
7.9 : 1 (26%)
α
α
4.8 : 1 (81%)
β
8.6 : 1 (32%)
β
5.5 : 1 (53%)
β
OTMS
β
OBz
O
O
O
O
O
Me
O
O
Me
α
17.7 : 1 (93%)
O
Me
α
α
α
(39%)
O
O
Me
β'
β
(42%)
O
O
O
β'
α
8.2 : 1 (85%)
α
32 : 1 (79%)
11 : 1 (29%)
Wipf, P.; Kim, Y. J. Am. Chem. Soc. 1994, 116, 11678
Wipf, P.; Jung, J-K. Chem. Rev. 1999, 99, 1469
Effect of Changing Nucleophile
OMe
Nu-M, solvent
HO
OMe
Me
OMe
HO
Me
+
O
Me
Me
Me
α
β
Nu-M
yield (%)
α:β
solvent
MeMgBr
NaBH4 or LAH
HC≡CMgBr
H9C4C≡CLi
PhMgBr
MeLi
MeLi
BnOCH2Li
81
100
70
26
83
87
77
84
4.8 : 1
1:1
1:1
1.1 : 1
3.6 : 1
2.1 : 1
3.3 : 1
3:1
THF
MeOH or THF
THF
THF
THF
THF
Et2O
THF
• C-sp2 and C-sp3 nucleophiles exhibit facial selectivity, while C-sp and hydride donors are non-selective
• stereoselectivity highly sensitive to nature of nucleophile (electronic structure, aggregation state)
• any selectivity observed is in favor of α attack, anti to the 4-oxygen substituent
Wipf, P.; Kim, Y. J. Am. Chem. Soc. 1994, 116, 11678
Wipf, P.; Jung, J-K. Chem. Rev. 1999, 99, 1469
11-handout 2/12/01 2:45 PM
Wipf Seeking an Explanation
Stereoelectronic effect?
Neither vinylogous Felkin nor vinylogous Cieplak sufficiently explains or predicts selectivity.
Nu
β
β
OMe
O
OMe
LUMO of enone has phase
inversion due to double bond
between carbonyl and
donor/acceptor orbital
O
α
Me
Me
α Nu
"vinylogous Anh-Eisenstein" model
"vinylogous Cieplak" model
• stabilizing HOMO of nucleophile
• predicts β attack -- wrong product!
• stabilizing σ* of the incipient bond
• predicts α attack, but no qualitative correlation between
ratio of isomers and σ energy of donor C–C bonds
M
Chelate shielding of the β face is
not likely, since 1,4-addition, when
it does occur, is β-selective.
OR
O
R'
Electrostatic effect?
Substrate with inverted dipole exhibits good β selectivity!
OMe
HO
Nu-M, solvent
OMe
Me
OMe
+
O
CF2CF3
Me
CF2CF3
HO
α
CF2CF3
β
:
1
5
Wipf, P.; Kim, Y. J. Am. Chem. Soc. 1994, 116, 11678
Wipf, P.; Jung, J-K. Chem. Rev. 1999, 99, 1469
Quantitative Correlation Between Facial Selectivity and Dipole Moment
Qualitative Assessment
µ
µ
µ
O
O
OMe
O
O
O
O
Me
α
α
α
8.6 : 1 (32%)
[β' (42%)]
32 : 1 (79%)
4.8 : 1 (81%)
Dipole Moment Calculations
4
µ⊥
3
ln (α/β)
2
Me
O
α
1
O
OMe
O
• calculated dipole moments of five
representative dienones using SPARTAN
O
• linear correlation between perpendicular
vector of dipole moment and natural log of
facial selectivity
O
0
• validity of ground-state dipole moment:
complexed carbonyl should affect dipoles of all
dienone substrates in same manner
-1
OMe
• approach of nucleophile toward positive end
of dipole favored
-2
CF2CF3
-3
-3
-2
-1
0
1
2
3
4
calc. dipole moment [Debye]
µ⊥
12-handout 2/12/01 2:46 PM
Wipf, P.; Kim, Y. J. Am. Chem. Soc. 1994, 116, 11678
Wipf, P.; Jung, J-K. Chem. Rev. 1999, 99, 1469
An Electrostatic Take on Some Controversial Cases
O
anti
X
A:B
p-C6H4NO2
F
CO2Me
CF3
SiMe3
OH
66 : 34
62 : 38
61 : 39
59 : 41
45 : 55
43 : 57
(Felkin-Anh)
syn
HO
H
H
NaBH4
OH
+
X
X
X
A
B
Cheung, C. K.; Tseng, L. T.; Lin, M-H.; Srivastava, S.; le Noble, W. J. J. Am. Chem. Soc. 1986, 108, 1598
O
anti
syn
Nu:
δ–
δ+
O
anti
syn
Nu:
δ–
favorable
electrostatic
interaction
hydroxyl may create too
much lone-pair repulsion
δ+
EWG
OH
δ–
Adcock, W.; Cotton, J.; Trout, N. A. J. Org. Chem. 1994, 59, 1867
(Felkin-Anh)
O
anti
syn
HO
Nu
Nu
Nu-M
OH
O
δ–
Nu
+
+
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Nu-M
C
:
D
NaBH4
MeLi
70
>90
:
:
30
10
δ+
δ
favorable
electrostatic
interaction
δ+
δ– O δ+
R
δ– O
R
Mehta, G.; Khan, F. A. J. Am. Chem. Soc. 1990, 112, 6140
Paddon-Row, M. N.; Wu, Y-D.; Houk, K. N. J. Am. Chem. Soc. 1992, 114, 10638
Ganguly, B.; Chandrasekhar, J.; Khan, F. A.; Mehta, G. J. Org. Chem. 1993, 58, 1734
Houk: Axial Effect
O
H
NaBH4
OH
+
OH
X
MeOH
X
A:B
H
eq OH
eq OAc
eq Br
eq Cl
ax OH
ax OAc
ax Cl
ax F
60 : 40
61 : 39
71 : 29
66 : 34
71 : 29
85 : 15
83 : 17
88 : 12
87 : 13
X
H
X
A
B
axial attack
equatorial attack
Rationalization:
a remote electrostatic effect
attractive
δ– Nu
δ+
O
+
δ
+
δ
δ– X
preferred
O
+
δ
δ– X
δ– Nu
repulsive
Wu, Y-D.; Tucker, J. A.; Houk, K. N. J. Am. Chem. Soc. 1991, 113, 5018
Paddon-Row, M. N.; Wu, Y-D.; Houk, K. N. J. Am. Chem. Soc. 1992, 114, 10638
13-handout 2/12/01 2:47 PM
Tomoda: The Exterior Frontier Orbital Extension (EFOE) Model
The EFOE model is a quantitative, ground-state model for carbonyl addition based on the Salem-Klopman
equation, which has an exchange repulsion (steric) term, an electrostatic term, and a donor-acceptor orbital
interaction term. The EFOE model combines the steric term with the orbital term, leaving out coulombic
interactions.
Klopman, G. J. Am. Chem. Soc.1968, 90, 223
Salem, L. J. Am. Chem. Soc. 1968, 90, 543
Assumption: the volume of the outer (exterior) space nearest to a reaction center should contain steric
information of the substrate, since it is the space which a nucleophile must occupy.
Calculates PDAS, a steric factor, and EFOE density, an electronic factor, for ground states:
π-plane-divided accessible space (PDAS) = the space outside the van der Waals radii of the atoms nearest the
reaction center; calculated by integrating the space within 2.65 Å of the molecular surface
exterior frontier orbital electron (EFOE) density = the π-plane-divided electron density of a frontier orbital
(LUMO of carbonyl) summed over points that satisfy the following condition: the absolute total value of the wave
functions belonging to the carbonyl carbon makes a maximum contribution to the total value of FMO wave
function at the point.
λ = EFOE (a)2 – EFOE (b)2
Relates activation enthalpy (or product ratio) to EFOE density: ∆∆H‡ = mλ + n (m > 0; n = a constant)
• claims linear correlations between ln (ax/eq) and λ for 4-substituted-trans-decalone
reductions, but data are somewhat scattered
• claims to predict kinetics from ground-state effects
The "axial effect" of 4-substituted cyclohexanones "could be reasonably explained by ground-state factors - the
extension of LUMO and the molecular conformation - without invoking other influences."
(generated to explain selectivities often explained by the Cieplak model)
Tomoda, S.; Senju, T. Tetrahedron 1997, 53, 9057
Tomoda, S.; Senju, T. Tetrahedron 1999, 55, 3871
Tomoda, S.; Senju, T. J. Chem. Soc. Chem. Commun. 1999, 621
➞ Tomoda, S. Chem. Rev. 1999, 99, 1243
Heathcock: α-Alkoxy Lithium Aldol
OLi
O
H
O
OH
t-Bu
R
t-Bu
THF, -78 °C
OMe
O
R
+
OH
R
t-Bu
OMe
OMe
A
B
Felkin
anti-Felkin
R
A:B
Me
Et
i-Pr
Ph
t-Bu
58 : 42
76 : 24
92 : 08
83 : 17
93 : 07
"Quite simply, we believe our data show that the Anh-Eisenstein hypothesis is only partly correct."
Lodge, E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 3353
steric effect on Nu:
is underemphasized
Nu:
Nu:
H
R
H
O M
steric effect on Nu:
is overemphasized
H
MeO
H
O M
OMe
R
Felkin-Anh polar model
Evans electrostatic model
• Would expect some
erosion of selectivity as size
of R increases -- observe
just the opposite!
• As R is anti to incoming
nucleophile, increasing size of R
should not erode selectivity
• As R gets larger, conformation
may be more "locked" in the Evans
conformer
In both models, the stereoelectronic or electrostatic control element is not consistently dominant!
Both the size and the electronic properties of the α-substituents must be considered.
14-handout 2/12/01 2:48 PM
Are Felkin-selective reactions of α-heteroatom aldehydes
going through the Felkin-Anh transition state?
Felkin-Anh model
Evans electrostatic model
Nu:
Nu:
H
Rα
H
O M
PO
H
H
O M
Rα
OP
• leads directly to staggered
conformation, Felkin product
• leads directly to staggered
conformation, Felkin product
• best acceptor σ* orbital aligned parallel to π
and π* orbitals of carbonyl: hyperconjugative
stabilization
• dipoles of carbonyl and α-C-O are
minimized, with increasing stabilization as
pyramidalization occurs at the reactive center
Rα
H
Nu
O
M
PO
H
H
H
O
O
πC=O ↔ σ*C-OP
P
• assumes a covalent transition state in
which FMO stabilization dominates
M
Rα
• assumes a more ionic transition state in
which coulombic interactions dominate
• larger π* coefficient on C of oxocarbenium
species may enable a wider range of angles for
nucleophilic trajectory
How does the Cornforth model compare to the Evans
electrostatic model?
Cornforth model
Nu:
Evans electrostatic model
Nu:
H
PO
H
PO
O M
H
H
O M
Rα
Rα
• leads to torsionally strained
conformation, Felkin-Anh product
• leads directly to staggered
conformation, Felkin-Anh product
• dipoles of carbonyl and α-C-O are
minimized for the ground state:
reactant-like transition state
• dipoles of carbonyl and α-C-O are
minimized, with increasing stabilization as
pyramidalization occurs at the reactive center
H
Nu
PO
PO
H
H
O
H
Rα
O
M
Rα
• assumes a more ionic transition state in
which coulombic interactions dominate
• assumes a more ionic transition state in
which coulombic interactions dominate
• perpendicular trajectory of nucleophile
• larger π* coefficient on C of oxocarbenium
species may enable a wider range of angles for
nucleophilic trajectory
15-handout 2/12/01 2:49 PM
Models Proposed for 1,2-Asymmetric Induction
Nu:
Nu:
RS
Nu:
Nu:
RS
RS
RS
RL
X
O M
R
O M
R
Cram acyclic model (1952)
steric
RM
H
RL
RL
Nu:
O M
RS
RM/L
RS
RM/L
R
O M
R
O M
RL
Felkin model (1968)
steric, torsional
Karabatsos model (1967)
ground-state, steric
Nu:
RS
O M
RM
O M
R
Cram rigid model (1959)
chelation
Nu:
RM
R
M
RM/L
Cornforth model (1959)
electrostatic
Nu:
RS
R
RL
RM
X
O
XD
X
Felkin-Anh model (1977)
Felkin-Anh polar model (1977)
steric, torsional, Bürgi-Dunitz
electronic, torsional,
Bürgi-Dunitz
000000
00000000
00000
00000000
00000
000000
PDAS
00000000
00000
000000
00000000
00000
000000
00000000
00000
000000
00000000
00000
000000
00000000
00000
Cieplak model (1981)
electronic, torsional,
Bürgi-Dunitz
Nu:
X
RS
R
O M
RM/L
Tomoda EFOE model (1997)
ground-state, steric, electronic
Evans electrostatic model (2001)
electrostatic, torsional, Bürgi-Dunitz
Reetz: Chelation in β-Alkoxy Aldehydes
O
H
OBn
OH
Reagent, TiCl4
Rβ
R'
CH2Cl2, -78 °C
SiMe3
Me
SiMe3
Rβ
OH
OBn
+
yields ≥90%
Reagent
OBn
R'
Rβ
R'
Rβ
A
B
1,3-anti
1,3-syn
A:B
Me
95 : 05
Nu:
Me
Me
H
95 : 05
H Rβ
n-Bu2Zn
SiMe3
Me
SiMe3
Me
n-Bu
n-Bu
95 : 5
Me
n-Bu
O
H
H
90 : 10
O
TiLn
Bn
Cram-Reetz chelate model
99 : 01
H
RMgX, RLi, and R2CuLi fail to give high chelation selectivities for β-alkoxy aldehydes.
Leitereg, T. J.; Cram, D. J. J. Am. Chem. Soc. 1968, 90, 4011, 4019
Still, W. C.; Schneider, J. A. Tetrahedron Lett. 1980, 21, 1035
Nu
Rβ
H
H
Reetz proposes possible
transmetallation event of
nucleophile: internal delivery.
HRβ
H
H
R'
TiLn
O Bn
O
Bn
O
TiLn
O
• leads to a chair-like
intermediate
Reetz, M. T.; Jung, A. J. Am. Chem. Soc. 1983, 105, 4833
16-handout 2/12/01 2:50 PM
1,3-Asymmetric Induction: Open-Chain Models
O RM
Nu:
RS
R
H
H
R
O M
H OH RM RS
LAH
RL
R
+
H RM RS
HO
R
RL
RL
major
Nu:
00
000
000
00
00
000
R
000
00
000
000
000
000
000
000
0000
0000
000000
00
0000
0000
R
R
00
000
0000
0000000
0000
0000
minor
(hydrocarbon R groups)
L
RS
RM
RL
Jacques steric model
S
• rationalization similar to Felkin:
minimization of R ↔ β-R steric interactions
M
3-D depiction of Jacques model
Brienne, M-J.; Ouannès, C.; Jacques, J. Bull. Soc. Chim. Fr. 1968, 3, 1036
M
O
H
O RS
H
Nu:
R
NuMgX
RM
HO Nu RS RM
X
R
X
Nu OH RS RM
R
major
R
RM
+
X
RS
X
minor
• an adaptation of the Cram steric model, with the key feature being dipole
minimization of electronegative substituent X and carbonyl
Cram polar model
Leitereg, T. J.; Cram, D. J. J. Am. Chem. Soc. 1968, 90, 4011, 4019
1,3-Asymmetric Induction: Open-Chain Models
Evans: Mukaiyama Aldols
O
OSiMe3
i-Pr
X
H
O
BF3•OEt2
R
OH
X
O
OH
X
+
i-Pr
-78 °C
R
i-Pr
R
A
B
1,3-anti
1,3-syn
X
R
A:B
yield (%)
OPMB
OTBS
OPMB
OTBS
OAc
Cl
Me
i-Pr
i-Pr
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
C(Me2)CHCH2
92 : 08
80 : 20
81 : 19
73 : 27
43 : 57
83 : 17
58 : 42
91
84
87
90
79
84
88
Nu:
H
H
R
O M
• staggered to avoid torsional strain
• dipoles of Cβ–X and carbonyl minimized
X
Rβ
H
Evans polar model
• non-perpendicular nucleophile trajectory
Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett. 1994, 35, 8537
Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc. 1996, 116, 4322
See also: Bonini, C.; Esposito, V.; D'Auria, M.; Righi, G. Tetrahedron 1997, 53, 13419
17-handout 2/12/01 2:51 PM
Evans Merged Model for 1,2- and 1,3-Asymmetric Induction
Nu:
• for non-chelating conditions
H
Rα
R
O M
X
Rβ
• a merger of the Felkin-Anh (1,2) model and the Evans polar (1,3) model
• minimized dipole moment
• non-perpendicular trajectory
• RL anti to incoming nucleophile
H
• predicts 1,2-Felkin control and 1,3-anti
Evans merged model
The stereoreinforcing case (Felkin and 1,3-anti induction coincide)
Felkin
OSiMe3
O
OP
OH
anti-Felkin
OP
OH
R
H
i-Pr
Me
Nu
BF3•OEt2
CH2Cl2, -78 °C
i-Pr
+
Nu
i-Pr
Me
Me
B
A
R
P = PMB
A:B
t-Bu
i-Pr
Me
99 : 01
98 : 02
97 : 03
OP
yield (%)
P = TBS
A:B
yield (%)
94
98
86
99 : 01
95 : 05
71 : 29
93
88
92
Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G.; Livingston, A. B. J. Am. Chem. Soc. 1995, 117, 6619
Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc. 1996, 118, 4322
Evans Merged Model for 1,2- and 1,3-Asymmetric Induction
The non-stereoreinforcing case: Felkin control opposes 1,3-stereocontrol
Felkin
OSiMe3
O
OPMB
H
OH
R
i-Pr
OPMB
Nu
BF3•OEt2
solvent, -78 °C
Me
anti-Felkin
i-Pr
OH
+
OPMB
Nu
i-Pr
Me
Me
C
D
R
C:D
CH2Cl2
yield (%)
C:D
toluene
yield (%)
t-Bu
i-Pr
Me
96 : 04
56 : 44
17 : 83
89
98
82
88 : 12
32 : 68
06 : 94
75
86
92
Nu:
Me
H
H
O M
PMBO
H
i-Pr
non-stereoreinforcing
transition state
Nu:
H
Rα
R
O M
• with a small nucleophile, β-stereocenter becomes the dominant control
element
• 1,3-induction is enhanced in nonpolar media
X
Rβ
H
Evans merged model
18-handout 2/12/01 2:52 PM
Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G.; Livingston, A. B. J. Am. Chem. Soc. 1995, 117, 6619
Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc. 1996, 118, 4322
Integration of α- and β-Alkoxy Aldehyde Models in Non-chelating Systems
For α-alkoxy aldehydes:
Felkin-Anh model
For β-alkoxy aldehydes:
Evans electrostatic model
Evans model
Nu:
Nu:
Nu:
H
H
H
H
H
O M
PO
H
Rα
O M
Rα
OP
PO
Rβ
non-chelating Lewis acid
• no systematic
electronic +
steric study has
been done
Lewis acid
OH
OP
Nu
Rβ
H
1,3-anti product predicted
• under non-chelating conditions,
1,3-anti selectivity is observed
OH
Rα
Nu
non-chelating
H
O M
Evans, D. A.; Duffy, J. L.; Dart, M. J.
Tetrahedron Lett. 1994, 35, 8537-8540
OP
"Felkin" product predicted
For α,β-bisalkoxy aldehydes:
Nu:
PO
H
H
O M
+
Nu:
Nu:
H
H
P1O
H
Which is stereoreinforcing, anti or syn?
OP2
O
??
H
O M
H
O M
H
Rβ
H
Rβ
1
Rα
PO
Rβ
P2O
H
1
OP
Rβ
OP2
O
OP
H
How does the α-alkoxy substituent affect the conformation of the β-stereocenter?
Smith: Rapamycin
S
Me
t-BuLi, 10% HMPA/THF
-78 °C
S
Me
Me
Me
OTBDPS
OH
S
+
PO
PO
Me
Me
Me
OP
OTBDPS
A
anti-Felkin
solid state conformation of TBS-protected
aldehyde (X-ray structure) resembles Evans
electrostatic model conformation:
OH
S
S
H
S
Me
S
S
O
S
Me
Me
S
B
Felkin
P
A:B
yield (%)
MOM
TBS
TBDPS
2:1
5:1
>20 : 1
32
75
60
Nu:
TBSO
H
H
O
PO
H
O
H
RL
RL
suggested as reactive conformer
Smith, A. B., III; Condon, S. M.; McCauley, J. A.; Leazer, J. L., Jr.; Leahy, J. W.; Maleczka, R. E., Jr. J. Am. Chem. Soc. 1997, 119, 947
19-handout 2/12/01 2:54 PM
Kobayashi: Monosaccharide Derivatives on the Solid Phase
TBSO
OTBS
1,3-syn
O
BnO
TBSO
H
OTBS
S
OH
O
BnO
S
OTBS
BF3•Et2O
CH2Cl2, -78 °C
20 h
anti-Felkin
ds >98 : 2
after cleavage from resin, 61% over 4
steps, the third of which is the aldol
OTBS
O
OBn
O
H
O
OH
BnO
O
S
1,3-anti
O
S
O
BF3•Et2O
CH2Cl2, -78 °C
Felkin
ds 95 : 5
after cleavage from resin, 61% over 4
steps, the third of which is the aldol
Kobayashi, S.; Wakabayashi, T.; Yasuda, M. J. Org. Chem. 1998, 63, 4868
Final Thoughts
Factors affecting preferred conformation
1) Solvent effects
Nu:
P1O
H
P2O
• more polar solvent (higher dielectric constant): increase in induced dipole moment of solute
• also can reduce the value of dipole-dipole or dipole-point charge interactions
• in β-alkoxy non-chelation cases, less polar solvent correlates with better diastereoselectivity
• results may be unpredictable
2) Anionic character of reagent
Electrostatically-controlled processes: "increasing the more favorable electrostatic
interaction should accelerate the reaction rate and the selectivity." -P. Wipf
Processes not governed by electrostatics: usually run at low
temperatures to slow down the reaction to improve the selectivity
3) Size of nucleophile, size of protecting group, size of other α-substituent
While the Felkin-Anh model has withstood the test of time for hydrocarbon α-substituents, the number of
exceptions to the electronic model have sparked a flurry of new explanations, beginning with Cieplak in
1981. The debate continues, between steric, torsional, electronic, and electrostatic effects.
Judging by the Smith and Kobayashi results, as well as many others, it remains a challenge to predict the
stereochemical outcome of addition to α- and β-heteroatom-substituted carbonyl compounds. It may be
that more than one model is operational in a single system.
20-handout 2/12/01 2:56 PM
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