METATHESIS-BASED SYNTHESIS OF COMPLEX BIOACTIVES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 162

O

ODMB

HO NH

O t - B u

TBSO

TBSO ODMB HO

t -BuO W

O t -Bu

H

OMe O

O

OMe OH H 2 , Lindlar

quinoline, 1 h

O
O

O
O

N OH

O
O

OH

42

O

PhMe, 85°C 95%

MeO MeO HO

91% MeO MeO

TIPSO

HO

TIPSO HO

41 43 44 ( − )-Cruentaren A

SCHEME 5.14 Ring-closing alkyne metathesis in the total synthesis of ( )-cruentaren by
Maier and coworkers.

tungsten carbene initiator 42 smoothly delivered cycloalkyne 43 in an impressive 91%
yield. The alkyne functionality within macrolactone 44 was strategically retained
throughout the synthesis so as to provide conformational restriction to circumvent
the undesired translactonization upon removal of the TIPS ether. As the final step,
hydrogenation of

under Lindlar conditions concomitantly installed the two cis -
olefins in the macrolactone and the amide containing side chain in 95% yield, thereby
completing the total synthesis of cruentaren A (Scheme 5.14) [32].
As part of the structural elucidation and chemical biology investigations of the
amphidinolide family of cytotoxic macrolides, the F

44

urstner group demonstrated the
application of a sequential ring-closing alkyne metathesis/enyne cross-metathesis
strategy to assemble the macrocyclic s - trans diene unit of (

€

þ )-amphidinolide V [33].

The ring-closing alkyne metathesis precursor was prepared together with its

diastereomeric congeners. Under the influence of the metathesis catalyst generated
in situ from molybdenum complex

45

46 , diyne 45 underwent smooth ring closure to

deliver alkynyl macrolactone in 84% yield. The efficiency of the transformation

was noteworthy, particularly in the presence of the sensitive allylic epoxide and the
olefinic moieties and in view of the strained 14-membered macrocyclic alkyne.
Installation of the s - trans diene functionality also proceeded uneventfully upon
treating alkyne

47

with the Grubbs second generation catalyst under an ethylene
atmosphere to furnish macrocyclic tetraene in 70% yield. The diastereomeric
congeners of macrocycle

47

were also prepared through analogous ring-closing
alkyne metathesis/enyne cross-metathesis sequences. Upon advancing the diastereo-
meric macrolactones to the targeted final compounds with the introduction of the
unsaturated side chain, the structure of amphidinolide V was unambiguously con-
firmed through NMR analysis (Scheme 5.15).

50

5.4. ALKENE CROSS-METATHESIS

The unification of two independent molecular systems through the metathesis
reaction engaging their respective unfunctionalized and unactivated alkene termini
is an efficient and powerful transformation, particularly in the synthesis of complex
bioactive compounds [34]. In the total synthesis of apoptolidin A, a potent and
selective mediator of apoptosis with potential in cancer chemotherapy, Crimmins
et al. demonstrated an impressive late-stage alkene cross-metathesis reaction. In the
presence of Grubbs second generation catalyst, allylic alcohol 51 and diene 52