Progress in the Chemistry of Cytochalasans
103
5.2.1 Total Synthesis of Cytochalasin B
The synthesis of cytochalasin B (110) (Schemes 7 and 8) commenced from the
intermolecular HWE condensation of diethyl 3-oxo-2-butylphosphonate [270] with
N,N-dibenzyl phenylalanal F1 [271] followed by selective mono-N-debenzylation,
enolization and silylation to provide the expected diene F2 [272] Of particular
mention, it is crucial to choose the N,N-dibenzyl protecting system to avoid epimerization in the HWE reaction [273]. The Diels–Alder substrate F4 was obtained by
an addition-elimination sequence by mixing of the silyl enol ether F2 [274] (1.0 eq)
with the known exo-methylene lactone F3 (racemic, 1.1 eq) in methanol at 23°C.
Under high temperature, intramolecular Diels–Alder smoothly proceeded to generate
two diastereomeric products with the desired endo diastereomer F5 in 77% yield.
After the deprotection of the N-benzyl protecting group, the tricyclic compound
F5 was protected with a Boc group to afford F6 in one pot. After cleavage of
NBn 2
O
1) diethyl 3-oxo-2-butylphosphonate,
Ba(OH) 2 , 87%
2) 2,3-dichloro-5,6-dicyanobenzoquinone, 86%
3) TBSOTf, 2,6-lutidine, 99%
NHBn
OTBS
O
O
AcO
N
OTBS
O
O
Bn
N
OTBS
O
O
Bn
N
TBSO
O
O
Ot-Bu
O
N
O
O
Ot-Bu
O
m-xylene,
150°C, 77%.
1) H 2 , 10% Pd/C,
BOC 2 O, Et 3 N,
96%
1) TBAF, AcOH
2) KHMDS, THF, B7,
93% (two steps)
3) (CH 3 ) 2 CuLi, 95%
N
Cl
B7
Tf 2 N
N
O
O
O
F9
N
H
OH
O
F10
O
1) dimethyldioxirane, 100%.
2) trifuoroacetic acid
3) PhI(OAc) 2 , 4 Å MS, 92% (two steps)
ethylenediamine, tert-amyl
alcohol, 96%
O
N
OTBS
F1
F2
CH 3 OH, 98%
B3
F4
F5
F6
F8
Scheme 7 Synthesis of intermediate F10