Chemistry Reference
In-Depth Information
OMe
O
MeO
OMe
PIFA
H
2
O
O
OMe
OMe
MeOH-CH
2
Cl
2
0°C, 10 min
0°C, 5 min
N
N
OMe
H
H
H
N
N
O
O
N
H
CO
2
Me
CO
2
Me
CO
2
Me
418
(not isolated)
419
(87%)
417
O
O
Me
Me
1. H
2
, Pd/C
6 steps
4 steps
N
N
N
N
2. DPPA
O
N
OBn
O
O
O
Cbz
O
N
421
(57%)
O
Me
420
(37%)
(-)-TAN1251A (
411
) (36%)
SCHEME 10.67.
indications.
160
Central to the success of this synthesis was the generation of the
target's 1-azaspiro[4.5]decane substructure via cyclization of
L
-tyrosine derivative
417
419
421
, through a series of reductions, protection and
N-
alkylation, simultaneous hydrogenolysis of the Cbz and benzyl protecting groups
and coupling of the resulting amino acid established the 1,4-diazabicyclo[3.2.1]
octanone core of
411
. Introduction of the aryl side chain, through aldol condensation,
1,2-reduction of the
. After conversion of
to
a
,
b
-unsaturated amide and finally, deacetalization, furnished
(
)-TAN1251A in 17 steps from
L
-tyrosine.
Wardrop and Zhang have also utilized nitrenium azaspirocyclization to generate
the tricyclic skeleton of FR901483 (
),
161
a potent immunosuppressant isolated
from
Cladobotryium
sp.
162
In this case, exposure of
409
to PIFA in the CH
2
Cl
2
at
0
C for 15 min (Scheme 10.68) led to the rapid consumption of starting material but
provided the desired azaspirane in low yield (34%). While lowering the reaction
temperature to -10
C did not significantly change this outcome, when the reaction
time was abridged to 15 s,
422
could be obtained in high yield on scales of up to 10 g.
This product was now employed as a platform to access the 2-azabicyclo[3.3.1]nonane
core of
423
409
, which was assembled through 6-(
p
-
exo
)-
exo
-
trig
cyclization of the vinyl
.
163
In this case, the cyclohexyl radical generated upon ring
closure, underwent H-atom transfer from the more accessible
exo
-face to generate
radical generated from
424
425
as a single diastereomer. Compound
425
was subsequently converted to
426
,an
advanced intermediate in Snider's synthesis of (
)-desmethylamino FR901483
),
164
in six steps and with an overall yield of 38%.
(
427
