Biomedical Engineering Reference
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Me-I
NaNH
2
, MeI
Benzene, 45°C
KH, 18-crown-6
THF, 0°C
Me
4
OH
O
O
59%
1. KMnO
4
, Al
2
O
3
, H
2
O, CH
2
Cl
2
2. HCl(g), AcOH
3. AcOH, NaOAc
Me
Me
4a
O
82%
O
(+)-Nootkatone
SCHEME 8.12
Synthesis of (
þ
)-nootkatone.
(a) a highly diastereoselective anionic oxy-Cope rearrangement to secure the C1 and
C13 stereogenic centers, (b) a Petasis-Ferrier reorganization to elaborate the 2,6-
cis
-
tertrahydropyranone ring, and (c) a ring-closing metathesis (RCM) to build the
13-membered macrocyclic ring (Scheme 8.13). The potassium hydride-mediated
anionic oxy-Cope rearrangement of the enantiomerically pure alcohol followed by
treatment with methyl sulfate gave the corresponding methyl enol ether which, after
reaction with
m-
CPBA in the presence of methanol, was converted to the key acetal
intermediate bearing a tertiary alcohol. The latter was subsequently protected as a
2-naphthylmethyl ether and subjected to a hydrozirconation. Treatment with NBS
OH
OMe
O
CPBA
MeOH, 0°C
m-
Me
2
SO
4
, 0°C
KH, 18-crown-6
THF, rt
91%
96%
OBn
OBn
OBn
1. Cp
2
Zr(H)Cl, CH
2
Cl
2
2. NBS
3. PhSeH, Cs
2
CO
3
, MeCN
91%
OMe
OMe
OMe
MeO
NaH, 2-NaphtBr
Bu
4
NI,DMF
96%
MeO
MeO
OH
ONapht
ONapht
PhSe
OBn
OBn
OBn
1.
O
CO
2
H
O
OH
O
TMSOTf,
i
-PrOTMS, CH
2
Cl
2
, 0°C
O
O
ONapht
2. Cp
2
TiMe
2
, THF
3. Me
2
AlCl,CH
2
Cl
2
, rt, 5 min
O
PhSe
42-46%
MeO
2
C
OBn
SePh
O
O
O
O
O
O
1
O
O
13
Cl
HO
2
C
(-)-Okilactomycin
SCHEME 8.13
Synthesis of (
)-okilactomycin.
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