http://www.courses.fas.harvard.edu/~chem206/
R
OTMS
H Rβ
O OP
BF3?OEt2
Me
H iPr
O OPMB
Me
iPr
OH OPMB
R
O
Me
H iPr
O OPMB
Me
iPr
OH OPMB
R
O
R
OTMS BF
3?OEt2
Rβ
OH OP
R
O
iPr
OH OPMB
R
O
Me
Chem 206Sarah Siska, C. A. Morales
Matthew D. Shair Monday, November 4, 2002
a73 Reading Assignment for this Week:
Carey & Sundberg: Part A; Chapter 8Reactions of Carbonyl Compounds
Models for Carbonyl Addition
Chemistry 206
Advanced Organic Chemistry
Lecture Number 20
The Evolution of Models for Carbonyl Addition
a73 Useful Reviews
(1)
1,3-Anti
Construct a model for the addition process in eq 1 using the principles learned thus far in the course.
Felkin
96 : 4
4 : 96
R = t-Bu
R = Me
R = Me, t-Bu ≥ 97 : 3
(2)
(3)
a73 A problem
Aldehydes 1 & 2 contain 2 stereocenters, each of which may influence the course of the addition process. For 1, the reaction is Felkin selective for all
enolsilanes; however, for 2, this is not the case. Explain. For the answer see: Evans, JACS 1996, 118, 4322. (pdf)
1
2
Fischer
Cram
Cornforth
Felkin
Anh/Eisenstein
Cieplak
Tomoda
a73 1,2-Asymmetric Induction Models
a73 1,3-Asymmetric Induction Models
a73 Merged 1,2- and 1,3-Asymmetric Induction
a73 Unpredicted, highly selective carbonyl additions
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
Reetz, M. T. Angew. Chem. Int. Ed. Engl. 1984, 23, 556-569
Morrison, J. D.; Mosher, H. S. Asymmetric Organic Reactions; Prentice Hall Inc.: 1971
Wipf, P.; Kim, Y. J. Am. Chem. Soc. 1994, 116, 11678-11688, ref. 1-5, 7
Chem 206Sarah Siska, C. A. Morales Models for Carbonyl Addition Introduction
R
RS RM
RL
O
H RL
RM
O
H RM/L
O
X
R
RS RM
RL
HO Nu
Nu RL
OH
RM
Nu RM/L
OH
X
Nu RL
OH
RM
Nu RM/L
OH
X
R
RS RM
RL
Nu OH
RL/X
RS RM
OR M
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 for
α-heteroatom (non-chelating) cases
Nu:
Felkin-Anh model
Felkin products anti-Felkin products
a73 Examples:
also Cram-chelate product
Nu–M
Nu–M
Nu–M
+
+
+
a73 Definition of Terms
glucose*
CHO
OHH
HHO
HHO
CH2OH
CO2, H2CO
H OH
OHH
HHO
HHO
CH2OH
COOH
OHH
HHO
HHO
CH2OH
HO H
COOH
chlorophyll*
Fischer, E. Ber. 1894, 27, 3189Freudenberg, K. Adv. in Carbohydrate Chem. 1966, 21, 1
chlorophyll*
Fischer, and the Dawn of Asymmetric Induction
Fischer, E. Ber. 1890, 23, 2611Fischer, E. Ber. 1894, 27, 3189
Assimilation in nature: propagation of asymmetry from one chiral molecule to another
"To my knowledge these observations furnish the first definitive evidence that further synthesis with asymmetric
systems proceeds in an asymmetric manner."
L-arabinose
1) HCN
2) hydrolysis
L-mannonic acid L-gluconic acid
+
~3 : 1
not isolated initially, but later found in
mother liquor
-Emil Fischer, 1894
Chem 206Sarah Siska, C. A. Morales Cram's Rule
R O M
R O M
O
R
RS RM
RL
RL
RM
RS
RL
RM
RS
R
RS RM
RL
HO Nu
R
RS RM
RL
Nu OH
RL
RM
RS
R OH
Nu
Don Cram: 1952
Nu:
Nu-M
Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74, 5828
predicted(Felkin product) (anti-Felkin
product)
Cram acyclic model
torsional effects not considered
Nu: activated carbonyl considered to be largest group
steric repulsion between R
L and R not discussed
Features and Liabilities
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."
+
90° trajectoryof nucleophile
Nu-M = RMgX, LAH
RL = Ph
RM = Me, Et
RS = H
R = H, Ph, Me, Et
Basis for Model
selectivities ranging from 2:1 to >4:1, favoring Felkin product
HNH
Me
Ph O MgBr
NH
H
MgBr
Ph O MgBr
O
Ph Me
NH3Cl
Me
MePh
OHp-tolyl
NH3Cl
MePh
p-tolylHO
NH3Cl
Nu:
a73 Bottom Line
Cram's acyclic model is a convenient mnemonic that predicts Felkin
products in α-alkyl or aryl aldehydes or ketones.
p-CH3C6H4MgBr
Nu:
Among the 27 cited reactions whose stereoselection is "predicted" by Cram's acyclic rule:
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
major(anti-Felkin) minor(Felkin)
yield not reported
Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74, 5828
one proposed transition state: in the end, a suggestion of a chelate . . .
Curtin, D. Y.; Pollak, P. I. J. Am. Chem. Soc. 1951, 73, 992
? Low or unreported yields may result in misleading selectivities? Model based on qualitative assessment of steric bulk
+
a73 Possible Pitfalls
Chem 206Sarah Siska, C. A. Morales Cornforth-1
Don Cram: 1959
R O M
XRS
RM/L
R O M
O
Ph Ph
MeX
O
Ph OR
M
Me Ph
CH3MgI
CH3Li
A major
Ph Ph
MeX
OHR'
X
OHOMe
RL
RM
RS
Ph Ph
MeX
R'HO
B minor
Nu:
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.
CH3 > OSO2C6H4CH3-p > OCOCH3 > OH
The acyclic model would predict the opposite product
in the case of an α-heteroatom -- a new model is
needed!
Cram acyclic model
Cram chelate model
Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81, 2748
"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."
Nu:
+
? expects groups OH, OR, OAc, NR2, NHAc to chelate
1) R'-M
2) H3O+
A : BR'-M
Winstein, S.; Holmes, N. J. J. Am. Chem. Soc. 1955, 77, 5562
nucleophile approaches from the back face
Nu:
11.5 : 19 : 1
yield of A (%)
2050
R O M
R O M
X
O
R Cl
RS RL
RL
RS
X
RL
RS
R Cl
RS RL
R'HO
R Cl
RS RL
OHR'
X
RL
RS
R OH
Nu
Cornforth: 1959
Nu:
Cornforth model
Cornforth, J. W.; Cornforth, R. H.; Mathew, K. K. J. Chem. Soc. 1959, 112
1) R'-M
Et2O, -70 °C2) AcOH
? argument based on importance of
polarization in transition state, and evidence
of selectivity in α-chlorocyclohexanone
additions
? ". . . where the dipoles are antiparallel, the
polarization of the carbonyl group would be
easiest," thereby lowering transition state
energy
? a modification of Cram's rule for
electronegative, non-chelating
α-substituents X
+
predicted(Felkin)
as in Cram acyclic model, torsional effects not considered
Nu: activated carbonyl considered to be largest group
Features
90° trajectoryof nucleophile
net dipole of molecule minimized
(anti-Felkin)
Additions to -Chloro Carbonyls
RL
O
Ph O
O RS RM
O
R Cl
RS RL
Cl
O R O M
RL
RS
R(M)
H
Ph
O MH
R(M)
H
O MH Ph
Nu:
Nu:
O
Cl
O
R
Cl
RLRS
O
H Et
Cl
n-Bu Et
O
n-Bu Et
Cl
OH
X
n-Bu Et
Cl
OH
n-Bu
Et
O
Ph
R
O
H
R
Mei-Pr
PhNu
R
OH
A
PhNu
R
OH
PhNu
R
OH
PhNu
R
OH
B
Karabatsos: 1967
Karabatsos, G. J. J. Am. Chem. Soc. 1967, 89, 1367
Nu-M
Karabatsos model
Given Cram's acyclic model, Karabatsos is surprised by the following selectivities:
+
? it appears that i-Pr is effectively
smaller than Me, if Ph = RL
Karabatsos' explanation: Cram transition states are incorrect
? ratios depend not on Nu a163 H and Nu a163 RM,
but instead on RM a163 O vs. RL a163 O
major
minor
H°
Me a163 O – Ph a163 Oi-Pr a163 O – Ph a163 O
Compared Interaction
0.6 kcal/mol0.2 kcal/mol
A : B
2–4 : 11–2 : 1
2nd-best conformerCornforth, J. W.; Cornforth, R. H.;
Mathew, K. K. J. Chem. Soc. 1959, 112
Prelog, V. Bull. Soc. Chim. Fr. 1956, 987Bellamy, L. J.; Thomas, L. C.; Williams, R. L. J. Chem. Soc. 1956, 3704
Bellamy, L. J.; Williams, R. L. ibid. 1957, 4294
Nu:
Cornforth model
Chem 206Sarah Siska, C. A. Morales Cornforth-2
7 (Felkin) 3 (anti-Felkin)
aq. NaOH
1) n-BuMgBr
2) AcOH
+
aq. NaOH
(±)
(±) (±)
:68%
Cornforth: Rationalization and Evidence
Corey, E. J. J. Am. Chem. Soc. 1953, 75, 2301Corey, E. J.; Burke, H. J. ibid. 1955, 77, 5418
Support and Contradiction for Dipole Minimization
Chlorohydrin Synthesis
(note: methylpyruvate does not adopt this conformation)
These were known products.
O MR
RS
RL
O MR
RM
RS
RM
O
H
M
RM
RSRL
RS
RL
OR
N
H
Z
RM
RSRL
≈
O
H RL
RM
RM
RLNu
RM
OH
RLNu
RM
OH
RL O
R RL
Me
RL
RS RM
OR M
LiAlH4
RL
RS RM
OR M
R RL
Me
OH
R RL
Me
OH
A
B
R
MeEt
i-Prt-Bu
RL
RS RMNu
R OH
Felkin: 1968
Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 18, 2199
Felkin model
? "reactant-like" transition state
? assumption of torsional strain in partially formed
or broken bonds: first fully staggered acyclic
model
? substituents minimized around R; leads to
inconsistency in aldehyde substrates
a169 see DAE Chem 206 Lecture Notes (2000),
18-08
? polar effect: maximize separation between
incoming anionic nucleophile and electronegative
α-substituent (RS, RM, or RL)
Nu:
larger RL ≈ better selectivity
substituents minimized around
ketone R
90° trajectory of nucleophile
RL = Cy RL = Ph
A / B
1.62.0
4.11.6
2.83.2
5.049
torsional strain accounted for; leads to
fully staggered product
+
Features
larger nucleophile ≈ better selectivity
Reduction of -Methyl Ketones
Chem 206Sarah Siska, C. A. Morales Felkin-1
Karabatsos model
Nu:
Nu:
Karabatsos, G. J. J. Am. Chem. Soc. 1967, 89, 1367
? energy difference (??H°) between interactions
of RM a163 O and RL a163 O determines product
ratio
? reactant-like transition state
? model based on most stable ground-state
conformation
? energy differences between major and minor
conformations are <1 kcal/mol
Nu-M
+
major(Felkin)
minor(anti-Felkin)
Rationalizations
most stable ground state
conformer
a) ?H°(imine N a163 R) ≈ ?H°(carbonyl O a163 R)
b) imine geometry ≈ complexed C=O geometry
?H°(imine N a163 R) ≈ ?H°(complexed C=O O a163 R)
Z = alkyl, OR, NR2
Nu:
RL
RS RM
ROM
RM
RL RS
ROM
(CH2)4 (CH2)4OMe
H
Nu: Nu:
O
Cyt-Bu
Me
O
Me
LAH
LiAlH4
Me
t-Bu Cy
OH
1.6
Me
OH
t-Bu Cy
Me
OH
1
Me
OH
H
OMe
RL
RS
RM
Me
Me Me
O
Felkin: Accounting for Less Selective Reactions
1) The t-butyl ketone case
? cannot adopt Felkin-type conformation; still considered as a reactant-like transition state
? selectivity based on competition between torsional strain and steric strain
possible when R
M is relatively
small
torsional strain(large Nu:)steric strain(small Nu:)
+
:
Chem 206Sarah Siska, C. A. Morales Felkin-2
major
Nu:
? with α-branching, in any staggered conformation, syn-pentane is
impossible to avoid
2) Transition states for minor products (does not consider conformers
with RL next to R)
3) 2-methylcyclohexanone
possible for small
nucleophiles
+
Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 18, 2199; 2205
RL
RS RM
HOM
RL
RS RM
HOM
RL
RS RM
OH M
Nu:
Nu:
Nu:
X
RS RM/L
OR M
OX
RM/LRS H
M
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, 5065Bürgi, H. B.; Dunitz, J. D.;
Lehn, J. M.; Wipff, G. Tetrahedron 1974, 30, 1563
Weaknesses in Felkin's Argument
Nu:
? main repulsion to minimize between Nu and electronegative group X --
no justification given
1) Polar effect
2) Breakdown for aldehydes
wrong prediction
Anh's Solutions
1) Antiperiplanar effect
? best acceptor σ* orbital
aligned parallel to pi and pi*
orbitals of carbonyl; stabilization of incoming
anion
piC=O a163 σ*C-X
nNu a163 σ*C-X
? without ketone R, important steric interaction removed:
would predict RM to be next to H rather than carbonyl
2) Non-perpendicular attack
? incorporation of the Bürgi-Dunitz trajectory
favored disfavored
Nu
Chem 206Sarah Siska, C. A. Morales Ciekplak Model
Et
H Me
OH Li
H–
Cl
H Me
OH Li
H–
RS
RL
RS
RL
OR RM
O MR RM
θ = 107°
Nu:
X
H Me
OH Li
H–
ORR M
Anh's Calculated Transition State Energies
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
1.5 ?
θ
θ = 90°, 100°, 110°
rotate C–C bond by 30° increments
1.63 ?
2-methylbutanal(Felkin-Anh model) 2-chloropropanal(Felkin-Anh polar model)
The model:
Lowest energy transition states:
STO-3G ab initio method (low level)
(interpolated using a quadratic curve)
Karabatsos model
Nu:
95 – 105°
Non-perpendicular attack
most stable ground state
conformer
a range of angles for optimum overlap
>2.7 kcal/mol
EFelkin model EG1
G1
C Nu
C Nuσ?
H
XD
HRM/L O M
Nu
C XD
C XD
C XA
C XA
XD
RS RM/L
OR M
σ
(Houk disputes the ordering of C–H, C–C)
CieplakFelkin Anh
σ
σ? σ?
σ
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
Cieplak Model for Carbonyl Addition
- DAE
Cieplak model
Nu:
? similar to Anh-Eisenstein modification of the
Felkin model: stabilization of nucleophile via
antiperiplanar C–XD bond
? 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
? importance of torsional effects (Felkin, Anh,
Houk, Paddon-Row) disputed
σC–Xd a163 σ*C---Nu
C–H > C–C > C–N > C–O
better donor
"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."
Chem 206Sarah Siska, C. A. Morales Correlating Theory with Experiment-Peter Wipf-1
Me
OMe
O
O
O
Me
OTMS
O
Me
OBz
O
O
O
O O
O
O
O
O
Me
OH
O
' (58%)
' (39%)
' (42%)
R'
OR
O R'
ORHO
Me R'
ORMe
HO
MeMgBrTHF
-78 °C
+
4,4-Disubstituted Cyclohexadienones: Experimental Data
7.9 : 1 (26%) 4.8 : 1 (81%) 8.6 : 1 (32%)
5.5 : 1 (53%) 17.7 : 1 (93%)
KEY: : (yield)
8.2 : 1 (85%)
32 : 1 (79%) 11 : 1 (29%)
~4 ?
("vinylogous Felkin-Anh")
CF2CF3
OMe
O
R'
OR
O
M
O
Me
OMe
O
Me
OMe
Nuβ
α
β
α Nu
CF2CF3
OMeHO
Me
CF2CF3
OMeMe
HO
Nu-M
solvent +
1
5
:
Wipf Seeking an Explanation
"vinylogous Anh-Eisenstein" model "vinylogous Cieplak" model
? 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
LUMO of enone has phase inversion due to double bond
between carbonyl and donor/acceptor orbital
Stereoelectronic effect?
Chelate shielding of the β face is not likely, since 1,4-addition, when
it does occur, is β-selective.
Electrostatic effect?
Substrate with inverted dipole exhibits good β selectivity!
Neither vinylogous Felkin nor vinylogous Cieplak sufficiently explains or predicts selectivity.
? stabilizing HOMO of nucleophile? predicts β attack -- wrong product!
Wipf, P.; Kim, Y. J. Am. Chem. Soc. 1994, 116, 11678
Wipf, P.; Jung, J-K. Chem. Rev. 1999, 99, 1469
-3
-2
-1
0
1
2
3
4
-3 -2 -1 0 1 2 3 4
calc. dipole moment [Debye]
ln
Chem 206Sarah Siska, C. A. Morales Correlating Theory with Experiment-Peter Wipf-2
O
O
O O
O
Me
OMe
O
CF2CF3
OMe
O
OO Me
OMe O O
[ ' (42%)]
32 : 1 (79%) 8.6 : 1 (32%) 4.8 : 1 (81%)
Quantitative Correlation Between Facial Selectivity and Dipole Moment
Qualitative Assessment
? calculated dipole moments of five representative dienones using SPARTAN
? linear correlation between perpendicular vector of dipole moment and natural log of facial selectivity
? validity of ground-state dipole moment: complexed carbonyl should affect dipoles of all dienone substrates in same manner
? approach of nucleophile toward positive end of dipole favored
Dipole Moment Calculations
CO2Me
O
CO2Me
O
EWG
O
OH
CO2Me
CO2Me
HO Nu
O
O
O R R
CO2Me
CO2Me
Nu OH
anti
δ+
Nu:
δ–
syn anti
δ+
Nu:
δ–
δ–
syn
Nu
δ–
δ+
δ–
δ–
δ+
δ+
δ+
synanti
O
X
NaBH4
Nu-M
NaBH4
MeLi
A
X
HHO
C D
X
OHH
B
p-PhNO2
F
CO2Me
CF3
SiMe3
OH
X
An Electrostatic Take on Some Controversial Cases
synanti
Cheung, et al. J. Am. Chem. Soc. 1986, 108, 1598
A : B
+
66 : 3462 : 38
61 : 3959 : 41
45 : 5543 : 57
favorable electrostatic
interaction
hydroxyl may create too
much lone-pair
repulsion
(Felkin-Anh)
Adcock, W.; Cotton, J.; Trout, N. A. J. Org. Chem. 1994, 59, 1867
(Felkin-Anh)
+
Nu-M
70>90 3010
:
::
favorable electrostatic
interaction
Mehta, G.; Khan, F. A. J. Am. Chem. S, 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
Chem 206Sarah Siska, C. A. Morales Houk & Heathcock
X
O
X
ONu
δ+
δ–
δ–
δ+ Nu
δ+
δ–δ–δ
+
O
X
NaBH4
MeOH
X
X
H
OH
A X
OH
H
B
Houk: Axial Effect
axial attack equatorial attack
Heq OH
eq OAceq Br
eq Clax OH
ax OAcax Cl
ax F
60 : 4061 : 39
71 : 2966 : 34
71 : 2985 : 15
83 : 1788 : 12
87 : 13
A : B
Wu, Y-D.; Tucker, J. A.; Houk, K. N. J. Am. Chem. Soc. 1991, 113, 5018Paddon-Row, M. N.; Wu, Y-D.; Houk, K. N. J. Am. Chem. Soc. 1992, 114, 10638
Rationalization:
repulsive
a remote electrostatic effect
preferred
+
attractive
R
MeO H
OH M
OMe
H R
OH M
Nu:
Nu:
O
H R
OMe
OLi
t-Bu
A
R
OMe
t-Bu
O OH
R
OMe
t-Bu
O OH
B
R
MeEt
i-PrPh
t-Bu
Felkin-Anh polar model
+
Felkin anti-Felkin
THF, -78 °C
A : B
Lodge, E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 3353
58 : 4276 : 24
92 : 0883 : 17
93 : 07
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 above conformer
"Quite simply, we believe our data show that the
Anh-Eisenstein hypothesis is only partly correct."
steric effect on Nu: is underemphasized
steric effect on Nu: is overemphasized
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.
Heathcock: -Alkoxy Lithium Aldol
Chem 206Sarah Siska, C. A. Morales 1,2-Induction
H R
OP
PO H
R
H O M H O M
H
O
P
HR O M
R
PO H
OH
Nu
M
electrostatic modelFelkin-Anh model
? best acceptor σ* orbital aligned parallel to pi and
pi* orbitals of carbonyl: hyperconjugative
stabilization
? leads directly to staggered conformation,
Felkin product
Nu: Nu:
Are Felkin-selective reactions of
α-heteroatom aldehydes going through
the Felkin-Anh transition state?
? assumes a covalent transition state in which FMO
stabilization dominates
? leads directly to staggered conformation,
Felkin product
? dipoles of carbonyl and α-C-O are minimized, with
increasing stabilization as pyramidalization occurs at
the reactive center
? assumes a more ionic transition state in which
coulombic interactions dominate
? larger pi* coefficient on C of oxocarbenium species may
enable a wider range of angles for nucleophilic trajectory
piC=O a163 σ*C-OP
RL
RS RM
OH M
XRS
RM/L
R O MX
RM
RL
RS RM
OR M
X
RS RM/L
OR M
XD
RS RM/L
OR M
RM/L
X RS
OR M
RL
RL
RS
RM
RS
R O MR O M
RS
RL
O MR
Nu:
Nu:Nu: Nu:
Nu: Nu:
Nu: Nu:
Nu:
PDAS
Felkin model (1968)steric, torsional
Cornforth model (1959)electrostatic
Models Proposed for 1,2-Asymmetric Induction
Cram acyclic model (1952)steric Cram rigid model (1959)chelation
Karabatsos model (1967)ground-state, steric Felkin-Anh model (1977)steric, torsional, Bürgi-Dunitz
Felkin-Anh polar model (1977)electronic, torsional, Bürgi-Dunitz Cieplak model (1981)electronic, torsional, Bürgi-Dunitz
electrostatic model (2001)electrostatic, torsional, Bürgi-DunitzTomoda EFOE model (1997)
ground-state, steric, electronic
H
Me
Me
O
H Rβ
OBn
Me
SiMe3
n-Bu2Zn
Me
SiMe3
SiMe3
SiMe3
R'
TiLn
O
O
H
Rβ
BnHH
H
n-Bu
n-Bu
Me
Me
Me
R
A
OH
R' Rβ
OBn
n-Bu
TiLn
O
O
H
Rβ
BnHH
H
B
R'
OBnOH
Rβ
RS
O
R RL
RSRM
RM
O
R X
RMRS
H O
R
M
RM RSX
O
TiLnO
H
Nu
H
Rβ Bn
R RL
RSRMOHH
R X
RMRSNuHO
H H
OR M
RS R
L
RM
R RL
RSRMHO H
R X
RMRSNu OH
Nu:
1,3-Asymmetric Induction: Open-Chain Models
Brienne, M-J.; Ouannès, C.; Jacques, J. Bull. Soc. Chim. Fr. 1968, 3, 1036
RL
Jacques steric model
Nu:
Nu:
+
major minor
LAH
3-D depiction of Jacques model
? rationalization similar to Felkin: minimization of R a163 β-R steric interactions
+
major minor
NuMgX
Cram polar model
? an adaptation of the Cram steric model, with the key feature being dipole minimization of electronegative substituent X and carbonyl
Leitereg, T. J.; Cram, D. J. J. Am. Chem. Soc. 1968, 90, 4011, 4019
RMgX, RLi, and R2CuLi fail to give high chelation
selectivities for β-alkoxy aldehydes.
1,3-anti
Chem 206Sarah Siska, C. A. Morales 1,3-Induction-1
Reetz: Chelation in -Alkoxy Aldehydes
Reetz proposes possible transmetallation event of
nucleophile: internal delivery.
Reagent
TiCl4
CH2Cl2
-78 °C
Reagent
yields ≥90%
R' A : B
+
95 : 05
95 : 05
90 : 10
95 : 5
99 : 01
Nu:
? leads to a chair-like intermediate
Cram-Reetz chelate model
1,3-syn
Reetz, M. T.; Jung, A. J. Am. Chem. Soc. 1983,
105, 4833
(hydrocarbon R groups)
Chem 206Sarah Siska, C. A. Morales 1,3-Induction-2
OSiMe3
i-Pr
O
H R
X BF3?OEt2
-78 °C
H H
OR M
X R
β
H
X
OPMB
OTBS
OPMB
OTBS
OAc
Cl
Me
A 1,3-anti
R
X
i-Pr
O OH
i-Pr
i-Pr
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
C(Me2)CHCH2
R
O
i-Pr R
OH X
B 1,3-syn
1,3-Asymmetric Induction: Open-Chain Models
Nu:
Evans polar model
A : B
Evans: Mukaiyama Aldols
yield (%)
92 : 08
80 : 2081 : 19
73 : 27
43 : 57
83 : 1758 : 42
91
8487
90
79
8488
? staggered to avoid torsional strain
? dipoles of Cβ–X and carbonyl minimized
? non-perpendicular nucleophile trajectory
Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett. 1994, 35, 8537Evans, 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
++ H Rα
OR M
X R
β
H
O
H i-Pr
OP
Me
OSiMe3
R
R
t-Bui-Pr
Me
A
OH
Nu i-Pr
OP
Me
B
OH
Nu i-Pr
OP
Me
Evans Merged Model for 1,2- and 1,3-Asymmetric Induction
Nu:
Evans merged model
? for non-chelating conditions
? 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
? predicts 1,2-Felkin control and 1,3-anti
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
P = PMB P = TBS yield (%)A : B A : B
99 : 0198 : 02
97 : 03
9498
86
99 : 0195 : 05
71 : 29
9388
92
yield (%)
The stereoreinforcing case (Felkin and 1,3-anti induction coincide)
+
Felkin anti-Felkin
BF3?OEt2
CH2Cl2
-78 °C
Chem 206Sarah Siska, C. A. Morales Merged Models
O
H i-Pr
OPMB
Me
OSiMe3
R
H Rα
OR M
X R
β
H
R
t-Bui-Pr
Me
C
OH
Nu i-Pr
OPMB
Me
D
OH
Nu i-Pr
OPMB
Me
Me H
OH M
PMBOi-PrH
The non-stereoreinforcing case: Felkin control opposes 1,3-stereocontrol
+
Felkin anti-Felkin
C : DCH
2Cl2
C : Dtolueneyield (%) yield (%)
96 : 0456 : 44
17 : 83
8998
82
88 : 1232 : 68
06 : 94
7586
92
Nu:
Evans merged model
? with a small nucleophile, β-stereocenter becomes
the dominant control element
? 1,3-induction is enhanced in nonpolar
media
Evans Merged Model for 1,2- and 1,3-Asymmetric Induction
Nu:
non-stereoreinforcingtransition state
BF3?OEt2
solvent
-78 °C
H Rα
OP
H H
HPO R
β
PO H
Rα
H O M H O M
H O M
Nu:Nu:
Nu:
OR
O
H Rβ
OP1
OP2O
H Rβ
OP2
OP1
Nu Rα
OP
OH
Nu
OH
Rβ
OP
Integration of α- and β-Alkoxy Aldehyde Models in Non-chelating Systems
Which is stereoreinforcing, anti or syn?
"Felkin" product predicted
electrostatic modelFelkin-Anh model
Evans model
For β-alkoxy aldehydes:
For α-alkoxy aldehydes:
1,3-anti product predicted
non-chelating Lewis acid
? under non-chelating
conditions, 1,3-anti
selectivity is observed
Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett. 1994, 35, 8537-8540
? no systematic electronic +
steric study has been done
How does the
α-alkoxy substituent
affect the
conformation of the
β-stereocenter?
For α,β-bisalkoxy aldehydes:
non-chelating
Lewis acid
Chem 206Sarah Siska, C. A. Morales Examples
SS
Me
Me
OTBDPS S
S
Me Me O
H
OP
P
MOMTBS
TBDPS
RL
PO H
HO
S
S
Me Me OH
PO
SS
Me
Me
OTBDPS
Me OH
PO
SS
Me
Smith: Rapamycin
t-BuLi, 10% HMPA/THF-78 °C
+
Aanti-Felkin BFelkin
A : B yield (%)
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
2 : 15 : 1
>20 : 1
3275
60
Nu:
suggested as reactive conformer
OTBS
S
OTBS
S
BnO
O
H
OTBS
TBSO
O
O
OBn
O
H
BF3?Et2O
CH2Cl2, -78 °C
20 h
BF3?Et2O
CH2Cl2, -78 °C
O
SBnO
OH
OTBS
TBSO
O
S
OH
O
O
BnO
Kobayashi: Monosaccharide Derivatives on the Solid Phase
ds >98 : 2
anti-Felkin
1,3-syn
Kobayashi, S.; Wakabayashi, T.; Yasuda, M. J. Org. Chem. 1998, 63, 4868
after cleavage from resin, 61% over 4
steps, the third of which is the aldol
ds 95 : 5
after cleavage from resin, 61% over 4
steps, the third of which is the aldol
1,3-anti
Felkin
Chem 206Sarah Siska, C. A. Morales Conclusions
a73 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.
a73 While the Felkin-Anh model has withstood the test of time for hydrocarbon α-substituents, the numerous 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.
a73 Nucleophilic additions to α-heteroatom-substituted carbonyl compounds are highly sensitive to solvent, nature and size of nucleophile, nature and size of protecting group, and
size of other α-substituent.