FLUOROUS LINKER-FACILITATED SYNTHESIS OF BIOLOGICALLY INTERESTING MOLECULES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 345

R 3

O O

Br

10

R 2

8

N

HN
I

NC

R 1

R 1

R 2

I

OSi( i -Pr) 2 CH 2 CH 2 Rf OSi( i -Pr) 2 CH 2 CH 2 Rf

M -73

M -72

8 sets of 7 compounds

Set of 7 compounds

R 2 R 2

R 3

R 3

O O

N 1. F-HPLC

2. HF

N

N N

R 1 R 1

RfCH 2 CH 2 ( i -Pr) 2 SiO HO

75

M -74

80 sets of 7 compounds 560 Mappicine analogues

Rf

R 1 R 2 R 3

H
p -F
p -OMe
p -CF 3
p -Et

p- Cl
p -OCF 3
o -F
p -Me
p -SMe

C 3 F 7
C 4 F 9
C 6 F 13
C 7 F 15

Me
Pr
Et
s- Bu

H
m -MeOPh
Me
Et

Pr
Bu
C 5 H 11
Ph

C 8 F 17
C 9 F 19
C 10 F 21

i- Pr
c -C 6 H 11
C 2 H 4 - c -C 6 H 11

SCHEME 10.17 Seven-component FMS of a 560-membered mappicine library.

ICl followed by demethylation with BBr 3 to form a quasi-racemic mixture of M- 69 .
N -Propargylation and subsequent radical cyclization with phenyl isonitrile provided
mixture M- 70 . The separation of this mixture by F-HPLC yielded two quasi-
enantiomers. Mappicines ( )- 71b were then obtained in enantiopure

forms after deprotection with TBAF in THF.
In addition to the quasi-racemic FMS mappicine enantiomers shown in
Scheme 10.16, a library containing 560 mappicine analogues was prepared by a
seven-component FMS (Scheme 10.17) [51]. In this case, seven fluorous linkers (Rf)
attached and also encoded the analogous substrates with various substituents (R 1 ).
The seven-component mixture M -72 was split into eight portions and subjected to
N -Propargylations with eight different bromides to give 8 mixtures of M -73 . Each of
the eight mixtures of M -73 was further split into 10 portions for a radical annulation
reactionwith different isonitriles. The resulting 80mixtures ofM -74 were demixed by
F-HPLC and then treated with HF-pyridine to afford a 560-membered mappicine
library 75 .
Cytostatin was isolated from the cultured broth of Streptomyces sp . [52]. This
compound is a potent and selective inhibitor of protein phosphatase 2A. It inhibits
lung metastasis of melanoma cells in mice and has potent cytotoxic activity toward
leukemia cell lines (IC 50 ¼

þ )- 71a and (

42-65 nm). Cytostatin has six chiral centers and its
configuration was previously determined by comparison of spectroscopic, physical,
and biological properties of a synthetic sample and the natural product [53,54].
To confirm the structure of cytostatin, Curran and coworkers employed the FMS
technique to synthesize (

)-cytostatin 76a and its stereoisomers 76b-76d
(Figure 10.2) [55]. These two pairs of enantiomerically pure isomers were believed
to be the most likely candidates of cytostatin.
One of the key steps in this work was the coupling of fluorous quasi-racemic
mixtures M- 80 and M- 83 . Compounds M- 80 contained four chiral centers and the

þ