CHEM 330

Topics Discussed on Nov 6

The Zimmerman-Traxler mechanistic model (NOT "mechanism") for a kinetically controlled

aldol reaction of an achiral enolate containing an oxophilic metal with an achiral aldehyde:
First interaction between an aldehyde and an enolate containing an oxophilic metal:
complex formation

Selective formation of the trans-type complex for steric reasons; e.g., with an E-enolate:

Mt Mt
O O first O O
(the same holds true
R3 interaction R1 H R3 for a Z enolate)
R1 H
R2 R2
generic E enolate trans - complex

Increased electrophilicity of the aldehyde and increased nucleophilicity of the enolate as

a consequence of complex formation:

Mt The enolate is more

The C=O is more O O
electrophilic, due to nucleophilic due to
the formal (+) on O R1 the formal (–) on Mt
H R3
R2

"Double activation" of the aldehyde-enolate complex toward C–C bond formation due to
increased electrophilicity of the aldehyde and increased nucleophilicity of the enolate

Evolution of the aldehyde-enolate complex toward a chair-like conformer that juxtaposes

nucleophilic and electrophilic carbons for C-C bond formation, and in which as many
groups as possible are pseudoequatorial

Existence of two enantiomeric variants of the conformation (transition state model) that permits
C-C bond formation:

R3 H H R3
R2 Mt R2
R1 O O
R1
Mt Mt
O O R1 H R3 O O
a H R2 H b

a and b are enantiomeric structures. In red: incipient C–C bond. Notice the equatorial
1 2
orientation of R and R in these chair-like constructs

note: the coordination sphere of the metal is completed by an appropriate number of

solvent molecules
lecture of Nov 6 p. 2

Principle: the enolate-aldehyde complex will partition equally between the two enantiomeric
conformers a and b above, because a and b possess identical thermodynamic properties

C–C bond formation from structures a and b though a pericyclic mechanism (one involving
a cyclic movement of electrons):

R3 H H
R3
R2 R2 mild OH O
R1 R1 R1 R3
Mt Mt H3O+
O O O O R2
a H H
a metal alkoxide: initial enantiomeric forms of
product of the aldol rx. the anti diastereomer
H R3 H
R2 R2 R3 mild OH O

R1 R1 R1 R3
Mt Mt H3O+
O O O O R2
b H H

Selective formation of the racemate of the anti diastereomer of the aldol product in the reaction
+
between an aldehyde and an E-enolate containing a strongly oxophilic metal such as Li

Selective formation of the racemate of the syn diastereomer of the aldol product in the reaction
+
between an aldehyde and a Z-enolate containing a strongly oxophilic metal such as Li , e.g.:

R3 H H R3
H Mt H
O O
R1 R2
R1
Mt R1 H R3 Mt
O O O O
a aldehyde - Z-enolate complex b R2
R2
notice that only R1 can be equatorial
H
H in transition state structures a and b H R3
R3
H
metal alkoxides: initial R1
R1 products of the aldol rx. Mt
Mt O O
O O R2
R2 OH O OH O
mild mild
R1 R3 R1 R3
H3O+ R2 H3O+
R2
enantiomeric forms of
the syn diastereomer

Diastereoselectivity of a kinetically controlled aldol reaction between aldehydes and enolates

containing strongly oxophilic metals:

E-enolate à anti aldol product Z-enolate à syn aldol product

lecture of Nov 6 p. 3

Principle: because enolate geometry determines which diastereomer of the aldol product is going
to form, it is essential to be able to create E and Z enolates diastereoselectively from any
carbonyl compound.

Ester enolates: stereoselective preparation of E enolates by deprotonation with LDA in

tetrahydrofuran (THF), e.g.:

O–Li
O LDA, –78°C

THF OEt
OEt

Mechanistic model (NOT "mechanism") for E-enolate formation:

equatorial ...!
S S OEt
Li Li S CH3
O N Solvent H
O N
OEt (THF) Mt
EtO O N
S H

only the "red" H is properly aligned with the π*C=O orbital . . .

OEt
S CH3
H Li
O NH(i-Pr)2
Mt =
O N OEt E-enolate • diisopropylamine
S H coomplex

Stereoselective preparation of Z ester enolates by deprotonation with LDA in THF/HMPA: the

Ireland method. E.g.:

O LDA, –78°C O–Li

OEt THF / HMPA OEt

note: HMPA (hexamethylphosphoramide) is an apolar, aprotic, strongly Lewis basic (=donor)

solvent, which — unfortunately — is rather hazardous: see notes of Oct. 2.

Conformational properties of acyclic carbonyl compounds: preference for a syn (eclipsed)

conformation about the sp2-sp3 C–C bond:
lecture of Nov 6 p. 4

θ=0
O
for the generic carbonyl compound shown on the
R
right, the preferred conformation is the one in which G
the R group eclipses the carbonyl oxygen; i.e., the H H
one in which θ(R–C–C–O) = 0
R = alkyl (e.g., Me)
G = H, alkyl, OR', NRR', etc.

Dunitz-Bürgi angle: the angle of ca. 107° between the axes of the large lobes of a π*C=O orbital
and the axis of the σ C=O bond:

α
π*C=O
R1 Dunitz-Bürgi
C O angle: α ≈ 107°
R2
α