Chemistry Reference
In-Depth Information
4.2.3.2. Synthesis of Lactone and Lactam Heterocycles
Intramolecular C - H inser-
tions of diazoacetates and diazoacetamides to form lactone and lactam heterocycles,
respectively, have been developed extensively [3,45,48,53,61,96]. The optimal catalyst
systems for these transformations are Doyle's carboxamidates and Hashimoto's phtha-
loyl catalysts [7,48,58,60,66]. Typically, diazoacetates decompose to form
γ
- lactones;
however,
-lactones can also be formed in selected systems. The formation of the latter
is not particularly favored since the activating effect of the adjacent oxygen is very small
due to its resonance with the carbonyl group. The carboxamidates can achieve excep-
tional enantiocontrol in lactone formation from diazoacetates [46,48,61]. Factors that
control product formation are (i) the reactivity of the C- H bond (3 °
β
1 ° ) and (ii)
favorable fi ve-membered ring formation [66]. Furthermore, regio- and chemoselectivi-
ties can be controlled effectively by the catalyst structure in many cases. Excellent
examples are the reactions of substituted ethyl diazoacetates 30, which in the presence
of chiral dirhodium(II) carboxamidates form the
>
2 °
>>
- butyrolactones 31 preferentially
(Table 4.3) [162-165]. Five-membered ring formation is remarkably favored, since com-
peting benzylic C-H functionalization to form a six-membered ring is not observed
[162,165,166]. In this reaction, the second generation imidazolidinone catalyst Rh
2
(4
S
-
MPPIM)
4
performs very well with yields of 50 to
γ
98% and levels of enantioinduction
in the 87-96% range [162,167]. The
N
- 3 - phenylpropanoyl substituent in this catalyst
is believed to direct the orientation of the carbenoid intermediate and thus enhance
enantiocontrol [168]. In comparison, the fi rst generation catalysts Rh
2
(MEOX)
4
and
Rh
2
(MEPY)
4
afforded only moderate enantiocontrol. An idealized model rationalizes
the observed stereochemistry (Fig. 4.8) [3,49,60]. In the
C
2
- symmetric carboxamidate
complex, quadrants III and IV are blocked by the catalyst and thereby force the carbene
to adopt the shown orientation. The other possible orientation is disfavored presumably
because of more steric interactions with the blocking group in quadrant IV. The intra-
molecular attack can now occur through quadrant I via a half-chair conformation with
the R - group pointing away from the catalyst [155] .
In the desymmetrization reaction of cyclohexyldiazoacetate
32
(Table 4.4), both fi rst
and second generation carboxamidate catalysts give very good enantiocontrol for the
reaction (95-97% ee for the
syn
-diastereomer) [63,169,170]. However, there is a distinct
difference in terms of diastereoselectivity. Whereas the fi rst generation catalysts
Rh
2
(MEOX)
4
and Rh
2
(MEPY)
4
give mixtures of
cis
- fused and
trans
- fused products
33
and
34
, respectively, Rh
2
(4
S
- MACIM)
4
gives a 99:1 ratio of
33
:
34
in 70% yield and with
95% ee of the major product [63,98,169]. This is again attributed to the
N
- substituent in
the second generation catalysts, which gives more control of the carbenoid orientation
[3]. In the desymmetrization of acyclic diazoacetate system
35
(Table 4.5) with alkyl
>
R
R
H
H
O
O
R
H
H
H
H
III
O
O
O
IV
O
II
I
Figure 4.8.
Model for lactone formation with Rh
2
(4
S
- MPPIM)
4
.
