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 362

S
N

S
N

S

macrolactonisation

O OTBS

OTBS

O O N

O

OH OH

Wittig

O

Epoxidation Coupling

OTBS

O

O

aldol O

CHO

OH

OH

I

Epothilone A 56 Epothilone C 57 Fragment A 58 Fragment B 59 Fragment C 60

SCHEME 11.8 Retrosynthesis of the epothilone core.

system of ionic liquid and toluene. Double bond isomerization was achieved using an
immobilized iridium catalyst which was specifically developed for this synthesis.

The yield and selectivity of the process were excellent, affording the phenolic styrene
53

52,

with a trans to cis ratio of 11:1. Final conversion of the styrene to 55 was achieved

effectively using an immobilized cobalt salen catalyst in the presence of molecular

oxygen that effected an oxidative dimerization process to give a compound that
underwent spontaneous intramolecular Diels-Alder reaction to generate carpanone
55

54

in excellent overall yield as a crystalline product.
The most challenging target from this period, however, was the synthesis of
the epothilones A [17]. Here, it was envisaged the epothilone core

could be assembled from the coupling of three main fragments, A

56 and C 57

58 59, 60

,B and C

(Scheme 11.8).
The key step in the preparation of fragment A

58

involved a modified
Mukaiyama aldol used to set up the C -3 stereochemistry in compound

66
(Scheme 11.9). This reaction was mediated by formation of a chiral borane complex
with 63, which catalyzed the asymmetric coupling of aldehyde 62 with the

trimethylsilyl enol ether 64 . The reaction proceeded in excellent yield and high

ee ( to

quench the reaction and remove boric acid contaminants. Filtration and concen-
tration provided a suspension of amino acid

92%). The workup required a small amount of water and polyol resin 65

63 and the aldol product 66 . Subsequent

O OH OH

TMSO

OH

Ph OH N

MeO

NHTs OH OH

(Polyol)

63 64 65

1. 63 , BH 3 . THF, CH 2 Cl 2 , 0°C to rt 30 min
2. 62 , -98°C, 15 min

1. DMAP, TBSCl, CH 2 Cl 2

rt, 2 h 30 min (96%)

O O OH

OH OTBS MeO OTBS

3

2. O 3 , CH 2 Cl 2 , -78°C, 20 min then

3. 64 , -98°C to -78°C, 1 h 45 min
4. H 2 O, 65 , -78°C to rt, 6 h

61

PPh 2 , -78°C to rt, 14 h (93%)

62 66

92% (4 steps)

NEt 2

TBSOTf, CH 2 Cl 2
0°C to rt, 2 h 45 min
then MeOH, rt, 1 h

100%

1. LDA, -78°C to -15°C 1. TMSCH 2 Li, Pentane, 0°C, 3 h

O OTBS O OTBS O OTBS

then MeI, -78°C, 2 h then MeOH, 0°C to rt, 5 h

OTBS OTBS MeO OTBS

CO 2 H, rt, 2 h

2. 2. CO 2 H, rt, 1 h 30 min

68 67 Fragment A 58

94% (2 steps) 100% (2 steps)

SCHEME 11.9 Synthesis of fragment A 58 .