Aldol Condensation

The aldol reaction was discovered by Aleksandr Porfir'evich Borodin in 1872 where he
first observed the formation of "aldol", 3-hydroxybutanal, from acetaldehyde under the
influence of catalysts such as hydrochloric acid or zinc chloride.

Acid and Base catalyzed reaction

Find examples of aldol condensation (including modified)???

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Diastereofacial Selectivity in the Aldol Addition Reaction-
Zimmerman-Traxler Chair-Like Transition States

The enantiomeric transition states (not shown) should have equal energies.

Diastereomeric transition states should have different energies.

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Zimmerman and Traxler proposed that the aldol reaction with metal enolates proceeds via a
chair-like, pericyclic process. In practice, the stereochemistry can be highly metal dependent.

(Z)- and (E)-enolates afford syn- and anti-aldol adducts, respectively, by minimizing
1,3-diaxial interactions between R1 and R2 in each chair-like TS‡.

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 Aldol and Related Reactions
Aldol reactions refer to the condensation of a nucleophilic enolate species
with an electrophilic carbonyl moiety along with its analogs. Several approaches are
available for imposing asymmetric control in aldol reactions:

Substrate control: This refers to the addition of an achiral enolate (or allyl
metal reagent) to a chiral aldehyde (generally bearing a chiral center at
the α-position). In this case, diastereoselectivity is determined by transition
state preference according to Cram-Felkin-Ahn considerations.
Open TS (diastereomers)
Closed TS (Stereospecific)

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In general, the aldol
reaction of an
aldehyde with metal
enolate creates two
new chiral centers in
the product molecule,
and this may lead to
four possible
stereoisomers 2a, 2b,
2c, and 2d

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Reagent control:
Two types of aldol reagents that can lead to opposite stereochemistry in aldol condensation reactions. In the
following structures, compound 4 can be used for obtaining anti-aldol products, and compound 5 can be
employed for synthesizing syn-aldol products. When aldol reagent 5 is treated with aldehyde in the presence
of n-Bu2BOTf and Et3N, syn-aldol product 6 can be produced with high diastereoselectivity

Find anti-aldol product?

syn-aldol product
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Double stereodifferentiation: This refers to the addition of a chiral enolate
or allyl metal reagent to a chiral aldehyde.

Three stereo centers

Reference: J. Am. Chem. SOC. 1995,117, 9073-9074

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Reference: J. Am. Chem. SOC. 1995,117, 9073-9074

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Reference: J. Am. Chem. SOC. 1995,117, 9073-9074

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The following parameters are critically important for stereochemical control:
1. The size of the substituent moiety in the enolate
2. The proper choice of reagents
3. The conditions chosen for enolization

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