METATHESIS-BASED SYNTHESIS OF COMPLEX BIOACTIVES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 160

13

14

11

10

19

OH

G-II (20 mol%) N 2 (COOK) 2 , AcO H

CH 2 Cl 2 , reflux, 40 h
60%

O OH OH

9

O

20

OH

O

O O O

O O

CH 2 Cl 2 , reflux, 16 h
62%

O O HO

O

MOMO

MOMO HO

MOMO

OMe OMe O

OMe

27 28 29

( − )-Kendomycin

(dr 3.2:1)
SCHEME 5.11

( E only)

Ring-closing metathesis in the total synthesis of ( )-kendomycin by Mulzer

and coworkers.

with a diimide reduction in 60% yield, and the so obtained macrocycle 29 was further

elaborated to ( )-kendomycin (Scheme 5.11) [25].

To date, the control of E / Z geometry in ring-closing olefin metathesis reactions
is an ongoing challenge and often unpredictable in complex molecular settings. In the
total synthesis of (

)-nakadomarin A reported by Kerr and coworkers, although the
formation of the 8-membered lactam took place uneventfully (

þ

30 31

, 75% yield),
the construction of the 15-membered macrocycle was plagued by the formation of an
inseparable mixture of ( E ) and ( Z ) isomers at a late stage of the synthesis [26]. A close
examination of the metathesis substrate

to

revealed a subtle but crucial difference
with the metathesis precursor 34 reported by Nishida and coworkers, where the amide
functionality was believed to decrease the conformation flexibility of the metathesis
product

32

, thereby enabling the separation of the ( E )- and ( Z )-isomeric metathesis
products [27]. In contrast, Dixon and coworkers examined the ring-closing olefin
metathesis of substrate

35

)-nakadomarin A synthesis [28].
A Z -selective olefin metathesis was achieved in the presence of Grubbs first
generation catalyst and excess of (

36 as the final step of their (

)- or (-)-CSA, whereas the ( E )-isomer pre-
dominated in the absence of CSA. Protonation of amines during ring-closing olefin
metathesis is a well-documented process [29]; however, the reversal of E / Z selectivity
was unprecedented (Scheme 5.12).

þ

5.3. RING-CLOSING ALKYNE METATHESIS

While the application of ring-closing alkene metathesis in the construction of cyclic
molecular frameworks has a cemented position in chemical synthesis, the closely
related ring-closing alkyne metathesis is a relatively newer addition to the synthetic
chemists' toolbox for the preparation of complex bioactive molecules [30]. Most
noteworthy feature of this enabling technology is in the preparation of macrocyclic
structures containing cis -olefin upon partial hydrogenation of the ring-closing alkyne
metathesis product, a strategy that is complementary to the conventional trans -
selective ring-closing alkene metathesis. In 2000, the Furstner group successfully
demonstrated this technology in the stereoselective synthesis of civetone, a valuable
fragrance [31]. Treatment of diyne 37 with either a catalytic amount of the Schrock

alkylidyne complex ( t -BuO) 3 W CCMe 3 or the catalyst generated in situ from

Mo(CO) 6 and p -trifluoromethylphenol led to the smooth and efficient formation of
cycloalkyne 38 . Subsequent Lindlar reduction of cycloalkyne 38 yielded exclusively