An
11-step synthesis of (+)-neopeltolide was developed. The C1–C7
carboxylic acid and the C8–C16 alcohol were prepared, each
in six steps, from (R)- and (S)-epichlorohydrin,
respectively. After esterification, our tandem macrocyclization/transannular
pyran cyclization strategy was applied to a stereocontrolled construction
of the neopeltolide macrolactone. The side chain was synthesized in
six steps from ethyl 4-oxazolecarboxylate through palladium-catalyzed
cross-couplings. A Mitsunobu reaction of the neopeltolide macrolactone
and the side chain completed the synthesis.
Tetrahydropyran‐containing macrolactones were synthesized by integrating Meyer–Schuster rearrangement, macrocyclic ring‐closing metathesis, and transannular oxa‐Michael addition under gold and ruthenium catalysis. Single‐step access to a variety of 14‐ to 20‐membered macrolactones containing a tetrahydropyran ring was possible from readily available linear precursors in good yields and with moderate to excellent diastereoselectivity. A 13‐step synthesis of (−)‐exiguolide, an anticancer marine macrolide, showcased the feasibility of our tandem reaction sequence for macrolactone synthesis and also demonstrated the power of transannular reactions for rapid assembly of the tetrahydropyran rings of the target natural product.
Tetrahydropyran-containing macrolactones were synthesized by integrating Meyer-Schuster rearrangement, macrocyclic ring-closing metathesis, and transannular oxa-Michael addition under gold and ruthenium catalysis. Single-step access to a variety of 14to 20-membered macrolactones containing a tetrahydropyran ring was possible from readily available linear precursors in good yields and with moderate to excellent diastereoselectivity. A 13-step synthesis of (À )-exiguolide, an anticancer marine macrolide, showcased the feasibility of our tandem reaction sequence for macrolactone synthesis and also demonstrated the power of transannular reactions for rapid assembly of the tetrahydropyran rings of the target natural product.
Total synthesis of (+)-neopeltolide, a potent antiproliferative marine macrolide natural product, was accomplished in 11 steps from a commercially available inexpensive material. The 14-membered macrolactone skeleton embedded with a 2,6-cis-substituted tetrahydropyran ring was synthesized in an expedient fashion by our newly developed macrocyclization/transannular pyran cyclization strategy. A concise synthetic entry to the oxazole-containing side chain was developed by exploiting palladium-catalyzed cross-coupling reactions. Total synthesis of (+)-9-epi-neopeltolide was also achieved in 12 steps by late-stage stereochemical diversification at the C9 position.
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