Catalytic Asymmetric Total Synthesis of Exiguolide

Abstract

The catalytic asymmetrict otal synthesis of (À)-exiguolide, ac omplex 20-memberedm acrolide embeddedw ith ab is(tetrahydropyran)m otif, is reported. The convergent synthesis involves the construction of the C1-C11t etrahydropyran segment via catalytic asymmetric allylationa nd Prins cyclization, and the formation of the C12-C21p hosphonates egment via catalytica symmetricc yclocondensation reaction and Johnson-Claisen rearrangement. The synthesiso f15-epi-exiguolide is also described.

Total Synthesis of (−)-Exiguolide, a Potent Anticancer Marine Macrolide

“…It is clear that the Prins cyclization chemistry has made a significant impact on the way of synthesis planning toward polyketide macrolide natural products, as can be seen in total syntheses of exiguolide by Lee, 3 Scheidt, 45 Song, 59,68 and Ishihara. 73 Another important way to improve the synthetic efficiency would be the concept of reaction integration. 83g Integrating multiple transformations into a single step by bypassing the isolation and purification of transient intermediates will help shorten the synthetic path toward complex molecules.…”

“…8. Total synthesis of (−)-exiguolide by Ishihara and co-workers (2020) 73 Ishihara and co-workers accomplished the total synthesis of (−)-exiguolide ((−)-1) according to a retrosynthetic analysis summarized in Scheme 23. The conjugated triene side chain of (−)-1 would be constructed from alkyne 127 through a hydrostannation and a subsequent Liebeskind-Srogl crosscoupling 46 with iodoolefin 78, as previously described by Scheidt et al 45 Alkyne 127 would be accessible from hydroxy ester 128 via a Yamaguchi macrolactonization 22 78 The Fuwa group recently disclosed a concise synthesis of (−)-exiguolide ((−)-1), by exploiting their macrocyclization/transannular pyran cyclization strategy.…”

Synthesis and Applications of Periodate for Fine Chemicals and Important Pharmaceuticals

“…The synthesis of stychnopivotine, malagashanol, stychnosplendine, and isosplendine was reported by Maertens et al 418 The total synthesis of (−)-exiguolide was developed by Ishihara et al using the Lemieux−Johnson oxidation (Scheme 45). 419 The delivered aldehyde formed a pyran substructure, which is a common motif in many macrolides, such as bryostatin 1, rhizoxin D, peloruside A, and leucascandrolide A (Chart 5). Another part of the exiguolide cycle was synthesized using the Malaprade oxidation as described earlier (see Chart 4 in previous section).…”

From Hydrogenation to Transfer Hydrogenation to Hydrogen Auto-Transfer in Enantioselective Metal-Catalyzed Carbonyl Reductive Coupling: Past, Present, and Future

“…Additionally, chiral β-stereogenic alcohols are subject to asymmetric allylation with good levels of catalyst-directed diastereoselectivity, which avoids the handling of configurationally labile chiral α-stereogenic aldehydes (Scheme , middle). , Finally, whereas malondialdehydes are highly intractable, 1,3-diols are abundant chemical feedstocks and are subject to asymmetric double allylation or double crotylation (Scheme , right) . The products of such two-directional chain syntheses are formed as single enantiomers due to the Horeau effect and have been exploited as triketide building blocks in numerous total syntheses of polyketide natural products where they have been shown to significantly enhance step-economy. ,,, …”