Biomedical Engineering Reference
In-Depth Information
yielded derivative
234
. The final product
235
[dr
=
6:1 (
P
:
M
)] was released from
the resin by treatment with HF
pyridine. Alternatively, the precursor
234
was heated
prior to cleavage from the support to reverse the atropdiastereomeric ratio, leading
to product
236
[dr
ยท
1:7 (
P
:
M
)]. The number of library compounds was 1412. The
products were submitted for numerous phenotypic and protein-binding assays.
N
-Acyl iminium ion cyclizations/nucleophilic addition allowed formation of stere-
ochemically diverse skeletons based on tetrahydro-2
H
-oxazolo[3,2-
a
]pyrazin-5(3
H
)-
ones and tetrahydro-2
H
-thiazolo[3,2-
a
]pyrazin-5(3
H
)-ones (Scheme 7.33) [64]. The
conversion was based on unmasking of the aldehyde that underwent intramolecular
condensation with an amide to yield iminium ions. The cyclization proceeded toward
the peptide carboxy terminus (called
eastbound cyclization
). The iminium ions were
attacked immediately by internal nucleophiles (oxygen or sulfur) to afford final
bicyclic heterocycles
238
to
241
. Depending on the stereochemistry of the
=
-amino
acid used (introducing an R
2
substituent), diastereoisomers
238
or
240
were created
OMe
PG
R
1
Y
MeO
O
N
N
O
2
S
H
*
R
2
O
O
2
N
237
Y = O, S
i or ii, iii, i
R
2
R
2
R
3
O
R
3
O
N
O
N
O
N
N
NH
2
NH
2
+
Y
Y
R
1
R
1
Major
238
239
Minor
or
R
2
R
2
R
3
O
R
3
O
N
O
N
O
N
N
+
NH
2
NH
2
Y
Y
R
1
R
1
Major
240
241
Minor
SCHEME 7.33
Stereoselective synthesis of eight diastereoisomers based on two types of
heterocycles. Reagents and conditions: (i) 50% TFA/DCM, rt, 2 to 3 h; (ii) 2-mercaptoethanol,
DBU, DMF, rt, 10 min; (iii) R
3
SO
2
Cl, 2,6-lutidine, DCM, rt, on.
