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 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 by the Macrocyclization/Transannular Pyran Cyclization Strategy

“…The preference for 2,6-cis-configured tetrahydropyran 4 over 2,6trans-configured tetrahydropyran 7-epi-4 could be reasoned by a late transition state model proposed by Bates et al 23 and was in accordance with our previous study. 9 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). 9 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.…”

“…9 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). 9 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. Not only the proximal C3 and C5 stereogenic centers but also the spatially segregated C11 and C13 stereogenic centers have a significant impact on the conformation of 27, indicating the presence of long-range stereochemical communications between remote stereogenic centers along the macrocyclic framework.…”

“…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. 9 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. Nonetheless, we anticipated that the formation of the 2,6cis-configured tetrahydropyran ring would be favored in this case, by considering the conformational constraint induced by multiple substituents along the macrocyclic backbone.…”

Exploring a Non-Comfort Zone: Central Chirality-Generating Macrocyclizations

“…Several approaches for the construction of the 14-membered ring during the total synthesis of marine natural product biselide A (18) were investigated by Britton et al 14 The macrocyclic Reformatsky reaction of a linear precursor 13 bearing an adjacent C-15 tert-butyldiphenylsilyl (TBDPS) ether protection failed under the rhodium-catalyzed conditions reported by Honda 15 (Scheme 4). However, the macrocycle was formed as a 3.5:1 mixture of diastereomers when less stereochemically hindered tert-butyldimethylsilyl (TBS)-protected analogue 14 was screened.…”