Organic Chemistry

772 CHAPTER 18 Carbonyl Compounds II

CANCER CHEMOTHERAPY

Two compounds—vernolepin and helinalin—owe

their effectiveness as anticancer drugs to conju-

gate addition reactions.

Cancer cells are cells that have lost their ability to control

their growth; therefore, they proliferate rapidly. DNA poly-

merase is an enzyme that a cell needs to make a copy of its

DNA for a new cell. DNA polymerse has an SH group and

each of these drugs has two -unsaturated carbonyl groups.

Irreversible conjugate addition of the enzyme to an -unsat-

urated carbonyl group inactivates the enzyme.

a,b

a,b

vernolepin helenalin

H 2 C

CH 2

H

H

OH

HC

O

O

O

O

O

H

CH 2

O

CH 2

H

OH

CH 3

O

H

CH 3

H

enzyme

O

O

CH 2

O

O

CH 2

S

enzyme

HS

conjugate addition

active inactive

18.14 Nucleophilic Addition to -Unsaturated

Carboxylic Acid Derivatives

carboxylic acid derivatives, like aldehydes and ke-

tones, have two electrophilic sites for nucleophilic attack: They can undergo conjugate

additionor nucleophilic acyl substitution. Notice that they undergo nucleophilic acyl

substitutionrather than direct additionbecause the carbonyl com-

pound had a group that can be replaced by a nucleophile. In other words, as with non-

conjugated carbonyl compounds, nucleophilic acyl addition becomes nucleophilic

acyl substitution if the carbonyl group is attached to a group that can be replaced by

another group (Section 18.3).

Nucleophiles react with carboxylic acid derivatives with reactive

carbonyl groups, such as acyl chlorides, to form nucleophilic acyl substitution prod-

ucts. Conjugate addition products are formed from the reaction of nucleophiles with

less reactive carbonyl groups, such as ester and amides.

O

C

Cl

O

C

NHCH 3

O

C

OCH 3

O

C

NHCH 3

OCH (^3) product of
conjugate
addition
product of
nucleophilic
acyl substitution

• CH 3 OH


• CH 3 OH
  a,b-unsaturated
  a,b-unsaturated
  a,b-Unsaturated a,b-unsaturated
  A,B
  O
  C
  OCH 3
  O
  C
  OCH 3
  Br


• HBr