Biomedical Engineering Reference
In-Depth Information
MgBr
1.
SO
3
H
1.
CuI, THF, -10°C to 0°C, 2 h
O
Br
OH
I
OTHP
OTHP
2.
NaI, 2-Butanone
2.
CO
2
H
Trisamine
69
75°C, 1 h
70
rt, 24 h
71
94% (2 steps)
97% (2 steps)
1.
SO
3
H
MeOH, rt, 7 h
78%
2.
Al
2
O
3
.
HCrO
3
Cl
CH
2
Cl
2
, rt, 30 min
O
H
F
ragment B
59
SCHEME 11.10
Synthesis of fragment B
59
.
filtration allowed the chiral amino acid catalyst
to be recovered and recycled,
while concentration of the filtrate afforded the pure adduct
63
66
. Following TBS
66
67
protection of
, homologation was achieved in two steps. First, treatment
with (trimethylsilylmethyl)lithium followed by an immobilized acid quench pro-
vided
to give
. After monomethylation and again quenching with an immobilized acid,
fragment A (
68
) was obtained in excellent yield without requiring any chro-
matographic purification.
Fragment B,
58
(Scheme 11.10).
Following acid-catalyzed tetrahydropyranyl protection and conversion to iodide
59
, was prepared in five steps from the bromide
69
70
,
displacement with the cuprate derived from 3-butenylmagnesium bromide gave
.
Addition of a carboxylic acid and a trisamine resin, together, quenched the reaction
and simultaneously scavenged the dissolved copper salts. Following filtration and
evaporation, compound
71
was deprotected and the resulting alcohol was oxidized
to its corresponding aldehyde, fragment B
71
59
, using chlorochromate absorbed onto
basic alumina.
The final fragment C (
60)
was generated as its immobilized phosphonium salt
(
80
) using a convergent process (Scheme 11.11). The Horner-Wadsworth-Emmons
1.
TBSCl
DMAP
OH
OTBS
OTBS
CH
2
Cl
2
, rt, 1 h 30 min
TBSCl, CH
2
Cl
2
, rt
DMAP
O
O
2.
MeLi, THF, -78°C, 40 min
O
1.
2.
BuLi, THF, -78°C to rt
O
OH
OTBS
O
3.
98%
rt, 30 min
72
CO
2
H, rt, 45 min
73
74
S
N
H
95% (3 steps)
OTBS
1.
NEt
3
NaCO
3
77
S
H
S
N
MeOH, rt, 45 min
O
OTBS
Cl
P(OEt)
2
2.
P(OEt)
3
, 160°C, 3 h
Cl
75
82% (2 steps)
76
S
N
S
N
S
N
1.
PPh
2
, I
2
1.
CSA, MeOH, CH
2
Cl
2
0°C, 2 h
OTBS
PPh
2
MeCN, Et
2
O
OTBS
OTBS
Toluene, 90°C, 18 h
2.
2.
NEt
2
, rt
NEt
3
NaCO
3
, 2 h
79
78
PPh
2
I
73% (2 steps)
100% (4 steps)
I
OH
80
Fragment C
SCHEME 11.11
Synthesis of fragment C
60
.
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