THE NEGISHI CROSS-COUPLING IN THE SYNTHESIS OF NATURAL PRODUCTS AND BIOACTIVE MOLECULES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 37

I

O O OTBS

O O OH OH

25

PMP

X Me

NH 2

OTBS PMBO N

OMe

(+)-Discodermolide 24 HO TBSO CHO

OH O

HO TBSO

28

OPMB

O O

26a (X = Br)
26b (X = I)

27

O O

SCHEME 2.7 Retrosynthetic analysis of ( þ )-discodermolide 24 .

fragments 25 , 26 , and 27 which would all be synthesized from a common precursor

28 (Scheme 2.7).

Only four steps were needed to synthesize precursor starting from

commercially available ( S )-methyl 3-hydroxy-2-methylpropionate. Six additional
steps led to iodide

28

25 or vinyl bromide 26a , while the analogous vinyl iodide 26b was

obtained from via a Ni-catalyzed bromine-iodine exchange. Unfortunately, as

this approach was not completely satisfactory from a step economy point of view of
step economy, a second strategywas envisioned for the preparation of

26a

26b , which was

ultimately obtained in only two steps starting from .

With all the necessary intermediates in hands, the key coupling reactions could
then be investigated (Scheme 2.8). The first approach was to exploit organocuprate
chemistry by performing a lithium-halogen exchange of the vinylic bromide,
followed by a transmetalation with a copper salt and the coupling with iodide

25

.
Unfortunately, despite the use of various catalysts, no product could be observed.
Therefore, a palladium-catalyzed cross-coupling was considered as an alternative.
Interestingly, the coupling of

25

catalyzed
by PdCl 2 (dppf) provided the desired product, albeit with a low yield (14%). Since a
large amount of unreacted

26a with the Grignard reagent derived from 25

26a was recovered at the end of the reaction, the use of

1. t- BuLi (2 equiv) THF, -78°C
2. Copper salt
3. 25 , -78°C to rt

Br

OTBS

OPMB

26a

1. t- BuLi (3 equiv)
Et 2 O, -78°C to rt

I

O O OTBS OTBS

2. Pd(PPh 3 ) 4 (0.05 equiv)

Et 2 O, rt

O O OTBS

25

29

PMP

I

PMP

OPMB

OPMB

26a

+ ZnCl 2

1. t- BuLi (2 equiv) Et 2 O, -78°C
2. MgBr 2
3. 26a , PdCl 2 (dppf)

I

OPMB

O O OTBS 66%

14%

25 PMP

SCHEME 2.8 Coupling reaction of two key intermediates in the synthesis of

( þ )-discodermolide 24 .