Post on 27-May-2018
Chapter 34 — Diastereoselectivity
- The Felkin-Ahn model for carbonyl conformations and diastereoselective nucleophilic attack - The effect of electronegative atoms on carbonyl conformation - Carbonyl chelation and stereoselectivity --------------------------------------------------------------------- - The aldol reaction’s chair-like transition state and stereoselective formation of syn and anti isomers - Selective production of cis and trans enolates of ketones
- Stereospecificity vs. stereoselectivity (and a pre-midterm review of reactions)
The conformations of acyclic carbonyls
The Felkin-Ahn model for carbonyl conformations
Ph•••O eclipsed
H•••O eclipsed
nothing eclipsed, largest substituent perpendicular
Alpha-substituted carbonyls assume conformations that:
1) avoid all eclipsed interactions
2) have the largest substituent perpendicular to the plane of the carbonyl
PhH
O
Me
O
H
Ph
Me H
H
HH
O
Ph Me
O
H
H
Ph Me
O
HPh
Me
H
H
O
PhMe
H
O
HPh
H
Me
H
O
PhH
Me
O
RL
M
S
LR
O
M S
O
RL
S
M
Nucleophilic attack on a Felkin-Ahn conformation 1.
The most stable conformation will be attacked by the nucleophile from the least hindered trajectory. What trajectory…?
…remember Bürgi and Dunitz!
O
HPh
H
Me
O
HPh
Me
HHindered
by Ph Hindered
by Ph Hindered
by Me Hindered
by H
This is the easiest approach for the nucleophile
? PhH
O
Me
EtMgCl
Nucleophilic attack on a Felkin-Ahn conformation 2.
O
HPh
Me
HEt–
HPh
Me
HEt
OH
PhEt
Me
OHPh
H
O
Me
EtMgClPh
EtMe
OHMajor (Minor)
Another example
Unstable conformer
Stable conformers
Product
Redrawing the product Newman projection into a Newman projection with the main substituents (Me, tBu in this case) opposite to each other often makes it easier to translate back into a normal zig-zag structure
Me
O
Et NaBH4
O
Me H
tBu
Et
O
MetBu
Et
H
O
MetBu
H
EtH–
MetBu
Et
H
OHH
OHtBu
EtHH
Me
MeEt
OH
Electronegative α-substituents occupy the perpendicular position because of σ*–π* alignment
O
XO
Xπ*
σ* O
X
O
Xσ*
π*
X = halogen, NR2, OR
EWG have low-energy σ* orbitals that can conjugate to the neighbouring carbonyl π* orbital ONLY when the alignment is right (i.e. only when the EWG is perpendicular to the carbonyl plane)
Electronegative α-substituents occupy the perpendicular position: example
Homework: Check which product would have formed if you put “R” in the perpendicular position instead of NBn2
O
HNBn2
O
HNBn2
R
H
O
H NBn2
R
H
R
O
HBn2N
H
R
OMe
OLi
Nu
OH
HNBn2
R
H
NuOH
HR
H
Bn2N
Nu
O
OMeOH
NBn2Nu
ROH
NBn2Nu =
Chelation-controlled carbonyl conformations
Alpha substituents with lone pairs can coordinate divalent (or higher valency) metal ions together with the carbonyl lone pairs.
The chelation ring becomes the dominant factor in determining the conformation, and gives VERY high selectivity for nucleophilic attack.
Common chelating metals:
Zn2+, Cu2+, Ti4+, Ce3+, Mg2+ (MgCl+ is not as good)
Non-chelating metals:
Li+, Na+, K+.
O
R'OR
O
R'NR2
O
R'SR
O
R'L
M2+
O
R' Et
L
H
M2+
M2+or or
Chelation control can reverse selectivity
O
R'OR
O
R'RO
M2+O
R'RO
Et
H
M2+O
R' Et
RO
H
M2+
R'RO
Et
H
–ONu O–
R' Et
RO
H
M2+
Nu
Nu Nu
R'OR
HO Nu
R'OR
Nu OH
Reaction in presence of a chelating metal
Reaction in absence of a chelating metal
Chelation control can reverse selectivity: example
Ph
OOMe
PhOMe
H OH
PhOMe
HO HNaBH4
73% 27%
Ph
OOMe
PhOMe
Me OH
PhOMe
HO MeMe2Mg
1% 99%
Work these problems to make sure you can predict the right products
Attack on α-substituted carbonyls: summary
Your choices for predicting the reactive conformation:
1. Normal Felkin-Ahn model (No α-heteroatoms)
2. Electronegative heteroatom perpendicular
3. Electonegative heteroatom chelated and in the plane of the carbonyl
(p. 895, CGWW)
Aldol reactions are stereoselective!!! (so no more wiggly bonds)
trans enolate
cis enolate
anti aldol
syn aldol
O OLi OO
HOHLDA, –78 °C
(±)
O OH
(±)
Ph
O
Ph
OLi
Ph
OO
H OHLDA, –78 °C
(±)
Ph
O OH
(±)
syn aldol
anti aldol
Explaining cis-enolate—syn-aldol product selectivity using a cyclic chair-like T.S.
O
R
Me
HLi
O
H
PhOO
H
Ph
R
Me
HLi
R
OLi
MeO
PhH R
O
MePh
OH
R
OLi
O
PhH
(±)
Explaining trans-enolate—anti-aldol product selectivity using a chair-like T.S.
O
R
MeLi
O
H
PhH
OO
H
Ph
R
H
MeLi
R
OLi
Me
O
PhH R
O
MePh
OH
(±)
Selective production of cis and trans ketone enolates
1. Cyclic ketones must make trans enolates
2. Bulky R groups can drive cis enolate formation
3. Treatment with bulky boron reagents that attach to the enolate oxygen atom drives formation of a trans boron enolate
O OLiOLiLDA, –78 °C
2 % 98 %
H Ph
OO
Ph
OH
(±)
Ph
O
Ph
O
O
H
Et3N,
Ph
O OH
(±)
BCl
B
OLDA, –78 °C
OLiH
O O OH
(±)