Synthesis of the Tricarbonyl Subunit (C₈−C₁₉) of Rapamycin via Tandem Chan Rearrangement−Oxidation

Abstract

The base-induced rearrangement of R-(acyloxy)acetates 1 to R-hydroxy-β-keto esters 4 (Chan rearrangement 1 ) is a convenient means for assembling an array of three contiguous oxygenated carbons. This transformation played a pivotal role in our routes to aplasmomycin 2 and boromycin, 3 but otherwise it has been rarely featured in natural product synthesis. 4 The rearrangement is believed to proceed via epoxide 2 which subsequently undergoes fragmentation to 3. Further deprotonation of this species yields an enediolate 5 which can be trapped as the bis-silyl ether 6. In principle, oxidation of Chan products 4 or 6 could afford a 1,2,3-tricarbonyl system, a subunit present in masked form in the important immunosuppressant rapamycin (7); 5 we now report an effective means for realizing this construction. 6 Specifically, we describe a synthesis of the C 8 -C 19 subunit of 7 via a tandem process involving rearrangement of an R-(acyloxy)acetate to an enediolate followed by oxidation of the derived bis-silyl ether with peracid.D-(+)-Xylose (8) was converted via its bis acetonide 7 to 9, which was selectively protected as pivalate 10. 8 The residual hydroxyl substituent was removed by Scheme 1 Scheme 2 2600

Enantiodivergent Transannular Rearrangement of 3‐Isopropyl‐1,4‐benzodiazepine‐2,5‐dione by Memory of Chirality

“…This can be related to the Chan reaction, [20] a base-induced rearrangement of an acyloxyacetate to a 2-hydroxy-3-oxo ester, and the N Ǟ C acyl migration of an acyclic imide, [21] two rare tools used in the total syntheses of aplasmomycin, [22] boromycin, [23] rapamycin, [24] diazonamide A [25] and taxol. [26] In order to explore this original reactivity, bis-Boc BZD 2 was subjected to other bases (Table 1).…”

Synthesis of the northern sector (C8–C19) of rapamycin via Chan rearrangement and oxidation of an α-acyloxyacetate

“…Our new approach was based upon reorganization of an α-acyloxyacetate 52 to an α-hydroxy β-keto ester 53 (Scheme 9). 23 This rearrangement, initially discovered by Chan,24 is nominally an O→C acyl migration which takes place by internal attack of enolate 54 to give transient epoxide 55 . The latter then collapses to 56 .…”

Transannular rearrangement of activated 2,5-diketopiperazines: a key route to original scaffolds

“…However, a better match could be made with the Chan reaction, 2 a rearrangement of an acyloxyacetate to a 2-hydroxy-3-keto-ester in the presence of a strong base (Scheme 5). Its aza-version has been developed on acyclic imides by Hamada et al 3 and extended to biological hits by Wipf and Methot, 11 and White et al, 12,13 as illustrated by the Holton Taxol total synthesis. 14 Scheme 5 The Chan rearrangement.…”