Tandem Macrolactone Synthesis: Total Synthesis of (−)‐Exiguolide by a Macrocyclization/Transannular Pyran Cyclization Strategy

Abstract

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.

Total Synthesis of Marine Macrolide Natural Products by the Macrocyclization/Transannular Pyran Cyclization Strategy

“…We termed our designed reaction sequence a 'macrocyclization/transannular pyran cyclization strategy'. 18 However, we were uncertain at the outset of this work whether transannular oxa-Michael addition of macrocyclic ,-unsaturated ketones VI was actually feasible. Although intramolecular oxa-Michael addition has been used commonly in stereoselective synthesis of tetrahydropyran derivatives, 2c,13 its use in a transannular format has been limited to specific cases.…”

Total Synthesis of (+)-Neopeltolide by the Macrocyclization/Transannular Pyran Cyclization Strategy

“…We envisioned that 2 would be accessible from ketone 4 through appropriate functionalization at position C9. In turn, 4 was envisioned to be synthesized from propargylic alcohol 5 through our recently disclosed tandem Meyer–Schuster rearrangement/macrocyclic ring-closing metathesis (RCM)/transannular oxa-Michael addition . It was of concern that our previous attempts at transannular oxa-Michael addition of structurally less complex, 14-membered ring model compounds resulted in an unsatisfactory level of diastereoselectivity.…”

“…The relative configuration of the tetrahydropyran ring of 4 was confirmed by NOE experiments. The preference for 2,6- cis -configured tetrahydropyran 4 over 2,6- trans -configured tetrahydropyran 7- epi - 4 could be reasoned by a late transition state model proposed by Bates et al and was in accordance with our previous study . Noteworthy is the fact that the diastereoselectivity of the transannular oxa-Michael addition, i.e., 91:9 4 :7- epi - 4 , was obviously higher than that previously observed for a relevant model case (i.e., 28 → 29 , 58:42 cis : trans ) .…”

“…The preference for 2,6- cis -configured tetrahydropyran 4 over 2,6- trans -configured tetrahydropyran 7- epi - 4 could be reasoned by a late transition state model proposed by Bates et al and was in accordance with our previous study . Noteworthy is the fact that the diastereoselectivity of the transannular oxa-Michael addition, i.e., 91:9 4 :7- epi - 4 , was obviously higher than that previously observed for a relevant model case (i.e., 28 → 29 , 58:42 cis : trans ) . It appears that the stereochemical course of the transannular oxa-Michael addition depends heavily on the conformational property of the immediate precursor macrocyclic α,β-unsaturated ketones, as anticipated at the outset of this study.…”