Multicomponent reactions - Zhu.pdf - Index of

Me
N
R1 H
16
Ph
H
MECHANISM A
attack from
bottom side
16 17
(rate-limiting)
MECHANISM B
O
H
N
O H
R1 R2 (S) 20
R 2
O
O
H
O
R3 NC
R attack from
17
bottom side
1 Me Ph
Me Ph
H
H N H
N H
H
H
R1 N
R
O
3
R2 (S)
CO
(S) 18
Me
N
O H
R1 R2 (R) 20
R3 NC
substitution with inversion
(rate-limiting)
MECHANISM C
Scheme 1.9
Me
Ph
H
attack from
top side
(pre-equilibrium)
R1 O Me Ph
H
N
R
N
H
O (S) 19
3
R2 16
17
Ph
H
1.4 Asymmetric Intermolecular Ugi Reactions 7
R 3 NC
substitution
with inversion
attack from
bottom side
(pre-equilibrium)
Me Ph
H
N
H
R
H
1
N
R
O
3
R2CO (R)
(S) 18
tion by the isonitrile proceeds with inversion of configuration [21]. The difference
between B and C is the rate-limiting step. In B, addition of the carboxylate is ratelimiting
and the stereochemical course is kinetically controlled to give intermediate
(R)-20 and hence (R)-19 as major diastereoisomers [21].
Mechanism B may explain why in many cases chiral isocyanides (e.g. 11) give no
asymmetric induction at all [21]. Indeed, the isocyanide is not involved in the transition
state. In mechanism C the substitution by the isocyanide is rate-limiting and
reversible formation of 20 originates a pre-equilibrium. Although (R)-20 should be
kinetically favored, (S)-20 may be more stable because of the destabilizing interac-
Me
Ph
H
N H
H
R1 N
R
O
3
R2 (R)
CO (R) 18
O
H
Me
N
O H
R1 R2 (R) 20
Ph
H
(S) 19
(R) 19