METATHESIS-BASED SYNTHESIS OF COMPLEX BIOACTIVES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 167

OTHP

O

OTHP

O

OH

G-II (15 mol%)
CH 2 Cl 2 , reflux, 24 h

OTBS

O

B

+

O

O

B OTBS

O

O 58%

TBDPSO

O

OTBDPS

76 77 78 ( − )-Amphidinolide K

( E / Z = 7.5:1)

SCHEME 5.22 Enyne cross-metathesis in the total synthesis of ( )-amphidinolide K by Lee

and coworkers.

78

in 58% yield with an E / Z ratio of 7.5:1. The vinyl boronate

afford diene boronate

78

functionality within served as a useful handle for the subsequent palladium-

mediated cross-coupling reaction, and its further elaboration enabled the completion
of the total synthesis of ( )-amphidinolide K (Scheme 5.22).

5.6. TETHERED METATHESIS

While the cross-metathesis reaction has demonstrated its utility as a powerful carbon-
carbon bond forming process, its intramolecular variant in the context of ring-closing
metathesis is more favorable based on entropy. Furthermore, ring-closing metathesis
reactions generally offer greater control over the geometry of the newly formed
carbon-carbon double bond, where a Z configuration olefin is preferred in the case of
small- to medium-sized rings. As such, one strategy to capitalize on the advantages of
the ring-closingmetathesis reaction is through a tethered approach, where the suitably
selected tether is cleaved after the metathesis process, liberating an intermediate that
is synthetically equivalent to the result of the corresponding cross-metathesis
reaction. This principle was elegantly demonstrated by Movassaghi et al. in their
concise synthesis of anticancer agents (-)-acylfulvene and (-)-irofulven [45]. Hence,
treatment of bis-silyloxy-tethered substrate with Grubbs second generation

catalyst smoothly delivered dihydrodioxasilepine

79

83

, which was desilylated to

84

furnish triol in 74-79% yield over two steps. This silicon-tethered cascade process

was presumably initiated through reaction at the most accessible terminal olefin with
the generation of ruthenium carbenoid

, followed by ring-closing enyne metathesis
and formation of a second metal carbenoid species

80

, which underwent ring-closing
metathesis to afford bicyclic system 83 . Application of the tethered strategy greatly
improved the overall efficiency of the carbon-carbon bond forming processes and
circumvented the isolation of sensitive intermediates. Triol

82

was subjected to
further elaboration that involved an additional late-stage ring-closing metathesis
event to complete the enantioselective total synthesis of (-)-acylfulvene and
(-)-irofulven (Scheme 5.23).
In the formal total synthesis of (-)-cochleamycin A reported by Lee and
Mukherjee, a related silaketal-tethered cascade metathesis process was developed
for the synthesis of stereochemically defined 1,4-substituted ( E , Z )-1,3-dienes [46].
Upon treatment of bis-silyloxy-tethered dienyne

84

with Grubbs second gener-
ation catalyst, followed by desilylation (TBAF) to remove the silicon tether, diol
86

85

was isolated in 61% yield over two steps. Further functionalization of diol 86