THE EVOLUTION OF IMMOBILIZED REAGENTS AND THEIR APPLICATION IN FLOW CHEMISTRY FOR THE SYNTHESIS OF NATURAL PRODUCTS AND PHARMACEUTICAL COMPOUNDS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 364

coupling of , with

excess phosphonate being scavenged with an immobilized benzaldehyde resin.
Selective removal of the primary silyl group with camphor sulfonic acid (CSA)
followed by carbonate resin workup afforded the alcohol

74 and 76 proceeded well with very high stereoselectivity to give 77

78 . The latter was then

converted to by treatment with iodine and immobilized triphenylphosphine.

Fragment C was eventually captured onto a phosphine resin to give the phosphonium
salt (

79

) ready for later release from the resin via a further Wittig reaction.
The impressive convergent coupling of the three fragments is shown in
Scheme 11.12. In brief, deprotonation of fragment A

80

58 with LDA and coupling

with fragment B ( . Quenching with acetic acid was

followed by addition of an immobilized diamine to scavenge residual acid and any
unreacted aldehyde. Simple filtration and evaporation then afforded

59 ) gave the aldol product 80

. Following
TBS protection, alkene cleavage by ozonolysis, and workup using immobilized
triphenylphosphine, aldehyde

80

81 could be isolated. The resin-bound phosphonium

salt was next treated with sodium hexamethyldisilylazide (NaHMDS) and washed

with THF to give a salt-free ylide. This was then coupled with the aldehyde

60

to give
exclusively the cis -olefin. Selective deprotection of the primary TBS-protected ether

81

O OTBS

OTBS

TBSO

TBSO OTBS NEt 2 OTBS

1. LDA, THF, -78°C to 40°C
then 59 , -78°C

1. TBSOTf,

CH 2 Cl 2 , 0°C to rt, then MeOH, rt

58

H O

Fragment A

O

2. AcOH, -78°C to rt 2. O 3 , CH 2 Cl 2 , -78°C, 20 min

O

O

NH 2

H OH 3. OTBS

PPh 2 , -78°C to rt

H

81

59

100% (2 steps)

80

99% (3 steps)

Fragment B

S
N

OTBS 1.

2.
3.

NaHMDS, THF, -78°C, then 81

CSA, MeOH, CH 2 Cl 2 , 0°C, 4 h

95%
(3 steps)

60 _

+

PPh 2 I NEt 3 NaCO 3 , CH 2 Cl 2 , rt, 2 h

S
N

S
N

Cl Cl

1. Et 3 N, rt, 50 min

Cl

OH
HO

OTBS

OH
OTBS

O OTBS

O Cl

1. TPAP, NMO, CH 2 Cl 2

0°C to rt, 3 h

2. DMAP, THF/Toluene, 80°C, 2.5 h

NH 2

2.

CO 2 H, rt, 2 h

3. N

H

,

NMe 3 ClO 2
NMe 3 H 2 PO 4

O O

OTBS OTBS

81%

4.
5.

SO 3 H, CH 2 Cl 2 , 1 h

Et 3 N, NH 3 ,MeOH

83 82

t -BuOH/H 2 0, rt, 6 h

3. TBAF, THF, rt, 4 h

S
N

S
N

92% (3 steps)

O O O O

OH OH

DMDO

O

O O

OH OH

56 57 Epothilone C Epothilone A

SCHEME 11.12 Total synthesis of epothilones C 56 and A 57 .