CHEM 330
Topics Discussed on Oct 21
Conformationally mobile (flexible) cyclohexanones: those carrying substituents characterized by
a small A-value; for instance, small alkyls like Me, Et, ..., e.g.:
Me
O
Principle: the 6-membered ring in the enolate of a conformationally mobile cyclohexanone may
readily access either half-chair conformer, because the energy difference between the two is
small. For instance:
ΔE ≈ 0.9 kcal/mol: the
CH3 axial CH3 experiences
LiO
Me
LiO
H
H
H
only ONE 1,3--diaxial
(gauche -butane)
interaction
H
CH3
H
H
LiO
Consequence: the inherent preference for the axial mode of alkylation may manifest itself from
either conformer, complicating the prediction of the stereochemical outcome of alkylation
reactions.
The 6-membered ring will generally tend to evolve from a half-chair to a chair-like
conformer during the alkylation reaction. However, a multitude of interactions
(steric, conformational, etc.) will determine which half-chair conformer of the enolate
is more likely to participate in the alkylation event
Alkylation of enolates of simple 3-substituted cyclohexanones leading selectively to trans
products, e.g.:
Li, NH3 (liq)
R
O
tBuOH
PhCH2Br
Me
LiO
(small alkyl,
e.g., Me)
O
Me
CH2Ph
because:
H
H
H
CH3
LiO
axial Me
conformer of
the enolate
H
axial alkylation
from axial Me
conformer of
the enolate
CH3
H
H
insignificant
H steric
R interaction
LiO
H
Br
favored
O
Me
CH2Ph
observed
product
lecture of Oct 21
p. 2
whereas:
equatorial Me
conformer of
the enolate
LiO
H
CH3
Br
axial alkylation
from equatorial
Me conformer
of the enolate
H
H
H
significant
steric
H interaction
R
LiO
CH3
O
H
H
H
H
disfavored
Me
CH2Ph
Conclusion: refining what was stated earlier regarding conformationally fixed cyclohexanone
enolates, the stereochemical outcome of the C-alkylation of a generic cyclohexanone enolate is
controlled by:
(i) the innate preference for axial alkylation through a chair-like transition state;
(ii) the steric interactions between the incoming electrophile and various molecular subunits;
(iii) conformational factors.
All such factors contribute to determining the overall energy of the transition states leading to
the various possible products. The major product of the reaction (at least initially) will always
be the one obtained through the least energetic transition state — so long as the reaction is
strictly kinetically controlled.
The interplay of the above factors in the stereochemical course of the alkylation of enolates of
more complex cyclohexanones: the case of decalones
Decalone: a ketone based on the decalin framework, e.g.:
21
O
O
decalin
(cis or trans)
1-decalone
2-decalone
Similarity between trans-2-decalone and the A-B ring system of most steroids
Me R
Z = H, Me
Z
could be
–OH or =O
Me
H
O
H
(O)
H
H
H
Alkylation of enolates of trans-2-decalones as an issue of special relevance in the synthesis of
steroids and other bioactive substances of current interest
lecture of Oct 21
p. 3
Trans-decalones as conformationally fixed cyclohexanones
H
H
O
conformationally rigid:
ring flips generate very
energetic conformers...
O
H
H
Analogy between 2-decalones and 3-alkylcyclohexanones and potential difficulties encountered
during their attempted conversion into regiochemically defined enolates by direct deprotonation
Dissolving metal reduction of conjugated 2-decalones as a means to access regiochemically
defined enolates; e.g.:
Li, NH3 (liq)
tert-BuOH
O
LiO
Selective formation of a trans-decalin framework during protonation of the (presumed) dianion
intermediate in the dissolving metal reduction of unsaturated decalones:
R
R
R
e—
Li, NH3 (l)
O
tBuOH
O
R = H or Me
O
radical anion
the (presumed) dianion forms
selectively as the more stable
trans-decaline isomer
R
R
tBuOH
LiO
LiO
H
H
Axial alkylation preference in the reaction of enolates of trans-decalones in which the substituent
Z at the ring junction is an H atom; e.g.:
R
tert-BuOH
O
H
H
Li, NH3 (l)
Me
MeI
O
(e.g.)
O
H
[R=H]
H
O
H
Me
likewise:
H
E (e.g, MeI)
O
H
E
H
H
E
H
H
O
H
O
H
H
H
H
lecture of Oct 21
p. 4
Problems with the axial alkylation of enolates of trans-decalones in which group Z at the ring
junction is alkyl: a developing syn-pentane interaction (notes of Oct. 14) between the incoming
electrophile and the alkyl substituent promotes equatorial alkylation:
R
Me
Li, NH3 (l)
tert-BuOH
O
O
Me
O
H
E
O
H
E
normally
favored
Me
mode of
alkylation
H
O
H
H
H
[ R = Me ]
Me
E
developing
syn-pentane
interaction
full synpentane
interaction
Me
E
chair -like
trans. state
H
O
H
H
the energy required to overcome the developing syn-pentane interaction is greater
than the energy required to cause alkylation through a twist-boat conformation !!
Therefore, the alkylation occurs via:
normally
disfavored
Me
O
H
twist-boat -like
trans. state
Me
O
mode of
alkylation
H
Me
O
H
H
E
twist-boat conformation
H
H
E
E
Me
O
E
H
H
O
H
E
Me
ring
flip
H
Me
E
H
Me
E (e.g, MeI)
Likewise:
O
O
H
H
Enolates of decalones in which an alkyl (e.g., a methyl) group is present at the ring junction:
preferential alkylation of via an energetic twist-boat transition state to avoid an even more
energetic syn-pentane interaction.
Kinases (phosphokinases): enzymes that are involved in cell signaling, and that act by
transferring a phosphoryl unit from ATP to the OH group (or other nucleophilic heteroatoms) of
particular aminoacid residues in certain proteins
Kinase inhibitors: drugs that block the activity of kinases (treatment of cancer & other diseases)