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

(±)