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O
O
HO
O-THP
HO
13
O
a, b
Me
Me
H
71%
c63%
12
CO
2
Bn
11
CO
2
Bn
Me
14
O
O
H
O
H
9
e, f
8a
d
g
O
9a
O
O
66%
75%
Me
H
H
H
H
Me
CO
2
Bn
Me
CO
2
Bn
CO
2
Bn
16
15
17
O
OEt
OEt
O
P
H
H
O
H
H
O
H
H
O
N
h
8a
O
O
Me
H
H
i
Me
88%
20
H
H
Me
H
H
Me
COOH
2
10a
19
CHO
75%
18
N
Me
PAR-1 IC
50
=150nM
M
2
inactive
Scheme 2.1
A representative synthesis of himbacine-derived thrombin receptor
antagonists.
59
The key exo-selective intramolecular Diels-Alder reaction
proceeds with high diastereoselectivity. Reagents and conditions: (a)
Bu
n
Li/THF, BnOCOCl, -78 1C; (b) DOWEX/MeOH; (c) 13, 4-pyrro-
lidinylpyridine, DCC/CH
2
Cl
2
; (d) H
2
, Lindlar/THF; (e) o-xylene,
185 1C, (f) DBU; (g) H
2
, PtO
2
/MeOH; (h) SOCl
2
/toluene, 80 1C, then
Bu
3
SnH, (Ph
3
P)
4
Pd; (i) 20,Bu
n
Li, hexane/THF, 0 1C.
presence of palladium(0). Horner-Wadsworth-Emmons reaction of aldehyde 19
with the appropriate phosphonate 20 gave the vinylpyridine derivative 10a in
excellent yield.
The diastereoselectivity of the IMDA reaction can be rationalized as shown in
Figure 2.6. Within the ordered transition state of the thermal cyclization, con-
formation A is disfavored due to allylic A
1,3
strain. The favored conformation B
facilitates the facial selectivity of C
3a
-C
9a
bond formation, engendering a cis
relationship between the C
3
methyl group and C
3a
hydrogen in 16.Therelative
stereochemistry between C
3a
and C
9a
is a function of the exo-selective nature of
the IMDA reaction, and the relative stereochemistry between C
3a
and C
4
is
controlled by the choice of cis-dienophile. The C
9a
stereogenic center was readily
epimerized by treatment with DBU. Catalytic reduction of the internal double
bond incorporated the stereogenic center at C
8a
in the required relative stereo-
chemistry. In short, the intramolecular Diels-Alder reaction lends itself to the
construction the tricyclic motif by incorporating five new stereogenic centers with
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