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Abstract:
Enigmazole A
and its congeners, isolated form the sponge
Cinachyrella enigmatica, are
the first known phosphorylated macrolides of marine
origin. Their structure features an 18-membered macrocycle which is decorated with a highly functionalized disubstituted oxazole and a
phosphate ester, rarely found in natural polyketide
s. The macrolactone includes seven stereogenic
centers and an embedded
syn-2,6-disubstituted tetrahydropyran ring with an
exo-methylene
group. Enigmazole A shows cytotoxic activity against numerous cancer cell lines at significant
concentrations. Structural siblings of it interfere
selectively with mutant c-Kit signaling which is an
important target for cancer treatment. The differentiation is found in less than 0.03% of tested
natural products. This exceptional structure and the rare pharmacological activity make
enigmazole A an attractive target for total synthesis.
A concise and convergent synthesis of this natural
product was envisioned featuring a
sequence of a ring closing alkyne metathesis (RCAM)
and a post-metathesis functionalization by a
nobel metal-catalyzed rearrangement with subsequent
hydroalkoxylation.
The required fragment
E
was accessed in 11 steps from a commercial oxazole
precursor by a
palladium-catalyzed C–H activation and a Keck allylation reaction. Enantioselective allylation of
aldehyde
E
and stannane
C
(5 steps) and subsequent Yamaguchi esterification
with acid
D (8 steps)
afforded the metathesis precursor. Smooth RCAM created the 18-membered macrocycle in
excellent yields.
A gold-catalyzed [3,3]-sigmatropic rearrangement of
the propargylic acetate (F) alongside the
alkyne followed by a transannular hydroalkoxylation
(H) of allene G
gave exclusively the desired
syn-tetrahydropyran ring A
in excellent yields. The use of a chiral gold catalyst was mandatory in
this transformation to obtain a diastereomerically
matched system with the substrate
B. Finally,
enigmazole A was obtained after standard manipulations.
Rhizoxin D
was isolated from an endosymbiotic bacterium of the
genus
Burkholderia
which causes the rice seedling blight disease. Its
unprecedented structure exhibits a strained
16-membered macrocycle containing three (E)-olefins, a δ-lactone and a highly unsaturated
sidechain which is terminated with an oxazole heterocycle. The selective cytotoxicity of rhizoxin D
and its derivatives against cancer cell lines led to clinical trials as potential drug candidate. This
high pharmacological potency and the strained structure drew attention to several research
groups to pursue syntheses of this molecule.
The designed synthesis featured two key transformat
ions: a ring-closing diyne metathesis
(RCDM) and a substrate-directed ruthenium-catalyzed
hydrostannation of a 1,3-diyne to create
the embedded 1,3-(
E,E
)-diene.
For this strategy fragment
K
(6 steps) was prepared by an oxidation of thermody
namically resolved
lactols. Fragment
J
(11 steps) was accessible by a challenging alkenylation and an esterification.
The 1,3-diynes in both molecules were installed by
alkynylation reactions with 1,3-pentadiyne.
Horner–Wadsworth–Emmons coupling (HWE) of fragments
J and K gave the metathesis precursor,
which underwent RCDM to obtain macrocycle
I
in moderate yields. Further investigations on the
final steps of the total synthesis of rhizoxin D are ongoing.