METATHESIS-BASED SYNTHESIS OF COMPLEX BIOACTIVES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 159

N N

O O

O O

O O

G-II (20 mol%)

OH OH

CH 2 Cl 2 (5 mM), 23°C, 2 h

HO HO

73%

26 O ( − )-Palmerolide A O

( E / Z > 95/5)

O NH 2 O NH 2

SCHEME 5.10 Ring-closing metathesis in the total synthesis of ( )-palmerolide A
(Nicolaou-Chen et al., 2008).

Palmerolide A is a polyketide secondary metabolite isolated from the circum-
polar tunicate Synoicum adareanum found in shallowwaters around Anvers Island on
the Antarctic Peninsula. It was found to exhibit potent and selective growth inhibitory
properties against melanoma cancer cells UACC-62 (LC 50 = 18 nM), with a
mechanism of action correlating well with other enamide-containing V-ATPase
inhibitors. Total syntheses of natural and antipodal forms of palmerolide A by the
Nicolaou-Chen and De Brabander groups featured a ring-closing olefin metathesis
and an intramolecular Horner-Wadsworth-Emmons olefination for the construction
of the 20-membered macrolactone, respectively [21]. More importantly, theseearly
ventures also enabled the revision of the originally proposed structure. A second-
generation synthesis by the Nicolaou-Chen group demonstrated one of the most
complex examples of ring-closing metathesis to date. In this event, substrate

26
containing multiple sites of unsaturation was subjected to the action of Grubbs second
generation catalyst to afford, upon isolation, 73% yield of palmerolide A.
The application of the ring-closing metathesis reaction as the final step in the
Nicolaou-Chen synthesis is impressive indeed and demonstrates the power of this
process for complex molecule construction (Scheme 5.10) [22].
Retrosynthetically, a cursory analysis often reveals a number of possible
metathesis synthons for the construction of the targeted macrocyclic backbone.
However, despite the versatility of the ring-closing olefin metathesis reaction, its
successful execution frequently requires more in-depth investigations to determine
synthetically viable site(s) for the desired ring closure to take place. Indeed, in
Mulzer's synthesis of kendomycin (( )-TAN2162) [23], a potent endothelin receptor

antagonist with antibacterial and cytostatic properties, the construction of the
16-membered macrocycle using the metathesis protocol presented a significant
challenge. Preliminaries studies revealed that a metathesis-based ring closure at the
C13/C14 junction afforded only low yields of the targeted macrocycle and predom-
inant formation of the undesired C13-C14 Z -olefin [24]. Furthermore, ring closure at
the C9/C10 and C19/C20 positions also proved unsuccessful under a variety of
metathesis conditions. Ultimately, triene substrate

27

lacking the tetrahydropyran
moiety enabled ring-closing olefin metathesis to take place in the presence of the
Grubbs second generation catalyst to furnish exclusively the C10-C11 E -olefin in

62% yield. Introduction of the tetrahydropyran substructure of kendomycin was
postponed to a later stage to avoid impeding the macrocyclization due to atropi-
somerism. Selective saturation of the newly formed double bond in

28

28 was realized