Selectivity in Organic Synthesis

Reading

Second & Third Year Lecture Courses on Selectivity in Synthesis and references given therein.

W. Carruthers, Some Modern Methods of Organic Synthesis

Stuart Warren, Organic Synthesis - the Disconnection Approach and accompanying workbook.

Sue Thomas, Organic Synthesis, The Roles of Boron and Silicon, Oxford Primer no 1.

Garry Proctor, Stereoselectivity in Organic Synthesis, OCPrimer No 63.

1. Alkene Synthesis

Revise your alkene synthesis, including Wittig / Wadsworth Emmons and Peterson reactions;

alkyne reduction, fragmentation reactions and the Julia reaction. Touch briefly on the Heck

reaction use of Palladium in alkene synthesis.

2. Reactions of Carbonyl Compounds

a. Additions to carbonyls are very important: note Crams rule and variants (Felkin-Ahn etc) and

exceptions to this.

Oxidation and reduction is particularly important for organic synthesis, particularly with

examples where selectivity is important. Note selectivity in the reduction of cyclohexanones, and

of remote stereocontrol via chelation controlled reactions.

b. Reactions of enolates; Cover thermodynamic versus kinetic control in these reactions

(classically in regioselective alkylation of unsymmetrical enolates). Note the preferential

formation of E or Z enolates (what factors can you vary to specifically form the E or Z enolate?)

with acyclic precursors. Look at O versus C alkylation in the reactions of enolates. Cover
regioselectivity in the alkylation of carbonyl compounds, through specific enolate formation (tie

in with the aldol reaction). Note the use of chiral auxiliaries in asymmetric synthesis consider

(usually) as examples of facial enolate selectivity.

Make a note of reactions proceeding via Chair Transition States

One thing worth looking at specifically concerns the preponderance of six membered chair

transition states. These are crucial in determining outcome of reactions such as the Aldol

Reaction (esp boron enolates) and also sigmatropic rearrangments (eg Claisen etc). Using these

two as examples practice drawing out the chair TSs and account for the stereoselectivities of the

reactions - this usually just simply involves putting the less bulky substituents in equatorial

positions. Pay particular attention to the Aldol condensation. For a good in discussion of this see

Carruthers p 48-63 (3rd Edition).

The use of allylic 1,3 strain for stereoselective reactions should also be noted.
1. Illustrate the methods available for the stereoselective formation of substituted alkenes by

answering the following questions (taken from 1998 Paper I Q4)

A. Suggest methods for the following transformations

a.

b.
OH

SiMe3

B. Give mechanisms for the following transformations paying particular attention to

stereochemical features of the reactions.

i.
a.
CHO + Ph 3 P=CHCO2 Et Ph
CO 2 Et

i. EtOH (E) : (Z ) 85 : 15

ii.
CHO + Ph 3 P=CHEt

ii. Toluene, 0C. (E) : (Z ) 4 : 96

b. N i. R
R H R'
+ SO2
Me O S R' Me

(E) : (Z ) 19 : 1

i. LiN(SiMe3 ) 2 , THF, -80C H

N
O
S
O-
c.
Ph +NMe
2
i. Ph H

Me(R) (S) Me Me Me

i. Heat

Pd(OAc)2 , NEt3, PPh3 CO 2tBu

d. I

CO 2 tBu

2. a. Give a rationale behind the selectivities seen in the formation of specific enolates under the

conditions shown below:

O O O
LDA, -78C, DMF, NEt3 ,
Ph THF Ph Ph
RT
b. Discuss the factors which determines the alkylation of enolates either on O or C with

reference to the following.

O OTMS
i LDA, -78C,
Ph THF Ph

ii TMSCl

O X A B
O O K Et
KDA (1eq) Et-X O CO2Et OTs 88% 12%
CO2Et CO2Et CO2Et
Et Cl 60% 40%
I 13% 87%
A B

Why, for a given enolate, is the amount of O alkylation minimised with the formation of the

lithium enolate, but increased with the formation of the potassium enolate?

3. Discuss the selectivities of the following reactions involving nucleophilic addition to carbonyl

compounds:

Cl Cl
EtMgBr
Me H BuMgBr H
Me Me Me
H
H Me Me
HO Et BnO BnO
O
Major HO Bu
O
Major

O HO Me
MeMgBr
Ph Ph
H H
H Me H Me

Major

4. Discuss the use of 1,3 allylic strain in governing the reaction selectivities of the following:
O
Me BH3 then H2 O 2 /NaOH Me O
OH I2 , NaHCO3 O
PhMe2 Si PhMe2 Si
HO I
H Me H Me

replacement of Me with H
renders reaction unselective

O
PhMe2 Si mCPBA PhMe2 Si

Me Me
5. Explain the selectivity of enolate formation, and the stereoselectivity of the aldol reactions in

a. Draw a plausible transition state to explain the stereoselectivity of the E and Z enolate

reactions in b and apply the same reasoning to c.

R %Z %E
a. LDA, THF
O OLi OLi Et 23 77
-78C
+
R R OMe 5 10
R

NEt2 97 3
Z-enolate E-enolate
98 2
tBu
R' R'
b. OH H OH H
OLi O OLi O
R' O R' O
R R
R R
Z-enolate syn
E-enolate anti

c. OH O
OH O OH O LDA, THF OH O
LDA, THF O
O -78C -78C
Ph OEt Ph tBu Ph tBu
Ph OEt tBu
OEt Me Me
then PhCHO Me Me then PrCHO

90 : 10 2 : 98