Total Synthesis of Ascospiroketal A Through a Ag^I‐Promoted Cyclization Cascade

Abstract

The total synthesis of four candidate stereostructures for the marine octaketide ascospiroketal A have been achieved. These concise and highly stereocontrolled syntheses feature a unique Ag(I) -promoted cyclization cascade involving an oxetanyl ketochlorohydrin to access the entire tricyclic core of the natural product in one step. These syntheses also establish the full stereochemistry for the ascospiroketal natural products.

Catalytic Carbonylative Spirolactonization of Hydroxycyclopropanols

“…Moreover, oxaspirolactones can be readily converted to spiroketals (cf. 13 ), 23 which are an important and challenging structural motif prevalent in many bioactive natural products. 24 …”

Total Synthesis and Configurational Assignment of Ascospiroketal A

“…We recently reported ac onvenient strategy fort he synthesis of spiroacetals that involves the Ag I -promoted cyclization of ketochlorohydrins (e.g., 12!14,S cheme 1). [8] This process was also demonstrated in as hort synthesis of cephalosporolidesE (6) and F ( 7), which simply involvedo xidative cleavageo ft he alkene function in 14 and further oxidationo ft he resulting lactol. [8] Considering that the tricycliccoreofthe cephalosporolides contains a5 ,5-spiroacetal similar to that embedded in the ascospiroketals (Figure 1), these studies also provided at emplate fort he synthesis of ascospiroketals Aa nd B.…”

“…[5d] As part of our continued efforts to explore the utility of chlorohydrins as buildingb locks for natural product synthesis, we recently communicated the total synthesis of ascospiroketal A( 1), including the assignment of both relative and absolute stereochemistry for this natural product. [7] Here we pro-vide af ull accounto ft hese efforts including the optimization of the key silver(I)-promoted cyclization cascade.…”

Recent Developments in Total Syntheses of Cephalosporolides, Penisporolides, and Ascospiroketals

“…Gratifyingly, the designed, unprecedented rearrangement of the tricyclic SAFL 112 a to the tricyclic spiroacetal‐ cis ‐fused‐tetrahydrofuran 114 (SAFT) proceeded cleanly with nearly quantitative yield in only two steps ( 112 a → 113 → 114 ). Subsequent functionalization of the side chain of the SAFT 114 including Takai olefination and Stille coupling with vinylstannane 116 a furnished the enantiomer of ascospiroketal A( ent ‐ 14 ), which further confirmed the relative configuration established by Britton . The total synthesis of ent ‐ascospiroketal B was accomplished for the first time in straightforward 6 steps from 112 b .…”