Biomedical Engineering Reference
In-Depth Information
(a)
Macrocycle synthesis
via
Pd(II)-catalyzed Allylic C-H Oxidation
"Chelate" (operative)
"Non-chelate" (not operative)
cat. Pd(II)
cat. sulfoxide
benzoquinone
H
O
Pd
Pd
HO
via
Pd
Pd
O
O
O
O
O
O
O
O
14-19 membered
ring systems
allylic C-H bond
83
84
85
86
O
O
(b)
Total synthesis 6-deoxyerythronolide B
89
PMP
PMP
PMP
HO
Ph
O
O
O
O
O
O
Ph
S
⋅
S
Ph
Me
Pd(OAc)
2
N
Me
17 steps
19%
4 steps
76%
(30 mol%)
O
O
OH
O
O
BQ (2 equiv)
CH
2
Cl
2
45°C, 72 h
H
O
O
O
O
O
OH
OH
H
Pd
O
O
O
O
O
O
34%
(56%, 2 recycles)
88
O
Pseudo-ephedrine
derived Myers' auxiliary
HO
O
90
("chelate")
91
(dr > 40:1)
6-Deoxyerythronolide B
87
SCHEME 1.22
Synthesis of 6-deoxyerythronolide B by Stang and White.
elimination). Interestingly, benzoquinone plays an active and crucial role in the latter
event as reductive elimination does not occur in its absence. Stang and White later
applied this macrolactonization strategy to the total synthesis of 6-deoxyerythrono-
lide B (
), the aglycone of the antibiotic erythromycin (Scheme 1.22b) [74]. The key
C-H oxidation precursor
87
was prepared using traditional synthetic methods for
polyketide synthesis, that is, a linear and iterative combination of stereoselective aldol
and alkylation reactions. Treatment of
88
88
with 10mol% of Pd(OAc)
2
/bis-sulfoxide
catalyst
(generated
in situ
) unfortunately led to only trace amounts of product even
over prolonged reaction times. However, by increasing the catalyst loading to 30mol
% and the concentration of the reaction medium to 0.02M,
89
could be obtained in
34% yield. Recycling (twice) the unreacted starting material afforded 56% isolated
yield of macrocycle
91
40:1).
Based on previous mechanistic findings [72b], deuterium-labeling experiments, and
molecular modeling studies, the reaction is believed to proceed through rapidly
interconverting
p
-allyl Pd-carboxylate intermediates
91
with excellent levels of diastereoselectivity (dr
H
83
and
84
(Scheme 1.22a,
intermediate
in Scheme 1.22b). The high level of diastereoselectivity arises from
the product-like transannular character of the transition state for C-O bond
formation (reductive elimination), favoring a pseudoequatorial positioning of the
exocyclic alkene.
90
1.9. IRIDIUM-CATALYZED BORYLATION OF sp
2
C-H BONDS
Arylboronate esters and acids hold a privileged place as important synthetic
intermediates in the areas of fine chemical production and material sciences, as
well as in natural product synthesis [75]. Notably, these versatile synthons participate
in metal-catalyzed cross-coupling reactions as well as in 1,2- and 1,4-additions to
carbonyls [76]. Typically, they are prepared from the corresponding aryl halides,
which are derived from simple arenes, therefore limiting their scope and availability
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