A Strategy for the Convergent and Stereoselective Assembly of Polycyclic Molecules

Abstract

The stereoselective oxidative coupling of cyclic ketones via silyl bis-enol ethers followed by ring-closing metathesis is shown to be a general and powerful reaction sequence for the preparation of diverse polycyclic scaffolds from simple precursors. The modular strategy successfully constructs substructures prevalent in numerous bioactive natural product families, varying in substitution and carbocyclic composition. Several of the prepared compounds were shown to possess potent cytotoxic activity against a panel of tumor cell lines. The utility of this strategy was further demonstrated by a concise and highly convergent 17-step formal synthesis of the complex antimalarial marine diterpene, (+)-7,20-diisocyanoadociane.

Direct Enantio‐ and Diastereoselective Oxidative Homocoupling of Aldehydes

“…This elegant approach has been pursued by Baran and co‐workers in the coupling of, for example, oxazolidinones and oxindoles with ketones applying lithium diisopropylamide (LDA) with copper(II) or iron(III) . Furthermore, Robinson and Thomson disclosed a related oxidative coupling of cyclic ketones by silyl‐bis‐enol ethers . These reactions generated racemic products with low diastereoselectivitities and moderate yields.…”

“…[2] Furthermore,R obinson and Thomson disclosed ar elatedo xidative coupling of cyclick etonesb ys ilyl-bis-enol ethers. [3] These reactions generated racemic products with lowd iastereoselectivitities and moderate yields.T of urther investigate these reactions, Casey and Flowersa pplied 7 Li NMR to elucidate the mechanism for the oxidative coupling of lithium enolates. [4] Finally, Hirao and co-workersd emonstrated that oxo-vanadium(V) induces coupling between boron and silyl enolates.…”

Synthesis of a Novel 1,4-Dicarbonyl Scaffold – Ethyl 3-Formyl-4,5-dihydrofuran-2-carboxylate – and Its Application to the Synthesis of Pyridazines

“…1 Among the most notable are the 1,4-dicarbonyl compounds, leading to the development of many convenient and efficient methods for their synthesis. Some of the most typical methods for preparing 1,4-dicarbonyl compounds are as follows: (a) stereodivergent synthesis by traceless chargeaccelerated sulfonium rearrangement; 2 (b) Stetter reaction between an aldehyde and a Michael acceptor catalyzed by carbenes derived from thiazolium salts; 3 (c) zinc-mediated chain extension reaction of 1,3-dicarbonyl compounds 4 or cyclopropanols; 5 (d) coupling reaction of either silyl enol ethers with -halo carbonyl compounds by visible light induced radicals 6 or of -carbonyl alkyl halides with metal enolates; 7 (e) oxidative organocatalytic enolation of aldehyde and reaction with enolsilanes 8 or oxidative carboncarbon bond formation via silyl bis-enol ethers to form diketones; 9,10 and (f) oxidative redox cross coupling via [3,3]-diaza Cope rearrangement. 11 Many typical methods for preparing 1,4-dicarbonyl scaffolds were found in this literature survey, although most of them report the synthesis of 1,4-diketones.…”

Concise Synthesis of the Antiplasmodial Isocyanoterpene 7,20‐Diisocyanoadociane

“…[8] An intermolecular conjugate addition/ enolate trapping strategy was devised with the goal of maximizing convergency and overall efficiency;this approach appeared to offer the flexibility to be generalizable to many ICTs. [10] Double equatorial nucleophilic methylation, activation by trifluoroacetylation and treatment with TMSCN and TiCl 4 led to stereochemically uncontrolled formation of 1 and its three stereoisomers.Several subsequent formal syntheses were based on the formation of the Corey dione,a nd thus inherited its troublesome endgame.T hese achievements include aD iels-Alder approach strategically similar to Coreysf rom the Miyaoka group, [11] an oxidative enolate coupling/ring-closing metathesis approach from Robinson and Thomson [12] and our own conjugate addition/ enolate trapping strategy. [6a] In 1987, Corey and Magriotis described the first synthesis of DICAt hrough al ogical, Diels-Alder based strategy that generated tetracyclic diketone (Corey dione) 7 in about two dozen steps (Scheme 1).…”