Biomedical Engineering Reference
In-Depth Information
cleavage. Synthetic transformations afforded bicyclic heterocycles in good to moder-
ate yields, and they were therefore applicable for synthesis of combinatorial libraries
for HTS.
DOS of nitrogen- and sulfur-containing heterocycles enabled the synthesis
of 30 to 50 examples for each heterocyclic scaffold, including thiazolo[4,5-
b
]pyridine, thiazolo[4,5-
d
]pyrimidine-5,7(4
H
,6
H
)-dione, and 1
H
-thiazolo[4,5-
c
][1,
2]thiazin-4(3
H
)one 2,2-dioxide, compounds with a wide range of important biologi-
cal properties [27-30]. The precursor for all those compounds was thiazole-modified
resin
62
(Scheme 7.11).
The synthesis of thiazolo[4,5-
b
]pyridine derivatives
65
involved conversion of
thiazole precursor
62
into the corresponding thiazolo[4,5-
b
]pyridine resin
63
under
Friedlander conditions. Subsequent oxidation of sulfides to sulfones
64
followed by
nucleophilic substitution with various (aliphatic/cyclic/aromatic/heterocyclic) amines
afforded 50 derivatives of thiazolo[4,5-
b
]pyridine
65
[27]. The second route led to
thiazolo[4,5-
d
]pyrimidine-5,7(4
H
,6
H
)-dione
68
via thiazolourea
66
from thiazole
amino ester
62
(R
1
OEt). The ester underwent one-pot cyclization/
N
-alkylation and
afforded derivative
67
after oxidation. Finally, nucleophilic substitution with amines
gave 48 derivatives of the target heterocyclic scaffold
68
[28]. The last skeleton from
the polymer-supported thiazole precursor
62
was prepared by a five-step reaction
sequence. Treatment with benzylsulfonyl chlorides yielded sulfonamide derivative
69
, and subsequent Mitsunobu alkylation with benzyl alcohol followed by cyclization
and oxidation led to sulfone
70
. Final substitution with various amines yielded 34
derivatives of the target 1
H
-thiazolo[4,5-
c
][1,2]thiazin-4(3
H
)one 2,2-dioxide skele-
ton
71
[29].
Stereo- and regioselective tandem acylation/1,3-dipolar cycloaddition of epoxy-
cyclohexenol carboxylic acid with nitrones afforded polymer-supported tetracycle
72
(Scheme 7.12) [31]. Treatment of tetracycle
72
with Yb(OTf)
3
and MeCN or PhCN
afforded derivatives
73
. Lactone
72
was also reacted with primary amine to yield
=
-
hydroxyamides
74
, which underwent aminolysis to form compound
75
. Alternatively,
the liberated hydroxyl- group of
-hydroxyamides
74
was reacted with PhNCO and
afforded tricyclic compounds
76
.
Ring-closing metathesis was used not only for the DOS of complex tricyclic
indoline-based compounds (see Section 7.2.1.1.2), but also for the synthesis of
complex heterocycles containing more heteroatoms [32]. In an analogous manner,
orthogonally protected tetrahydroquinoline
77
was immobilized to alkylsilylated
macrobeads through a three-carbon spacer (Scheme 7.13).
The tetrahydroquinoline precursor
77
underwent three parallel reactions to yield
bridged 10- and 12-membered rings
79
and
81
or trans-fused 12-membered ring-
based polycyclic derivative
83
. The reaction sequences started with
O
-pentenoylation
of the free hydroxyl group,
N
-Fmoc-protecting group removal and
N
-acylation with
trans
-crotonoyl chloride, and 4-pentenoyl chloride or BzCl. Subsequent
N
-Alloc-
protecting group removal followed by
N
-acylation with either BzCl or 4-pentenoyl
chloride afforded intermediates
78
,
80
, and
82
, respectively. These derivatives were
subjected to ring-closing metathesis, and tricyclic heterocycles
79
,
81
, and
83
were
obtained after cleavage from the resin.
