Cytochalasan synthesis: total synthesis of the naturally occurring [13]cytochalasan proxiphomin

Abstract

Proxiphomin (I ), a naturally occurring [I 3]cytochalasan, has been synthesized by a route which uses an intramolecular Diels-Alder reaction of the long chain 3 -( I -oxotrienyl)pyrrol-2(5H) -one (1 8) to form the 13-membered ring. This cyclization gave a mixture of endo and exo isomers (19) and (21), the endo isomer (1 9) being carried through t o proxiphomin. Although the endo-exo selectivity was small, (1 9) : (21 ) = 52: 48, the Diels-Alder cyclization was useful in that n o epimerization had occurred at C-5. Cyclization of a mixture of Diels-Alder precursors (1 8) and (33) prepared from racemic pyrrolidinone (32) gave all four cyclized products (19), ( 21), (34), and (36) which were 1-debenzoylated, separated, and characterized.

An enantioselective, modular, and general route to the cytochalasins: Synthesis of L-696,474 and cytochalasin B

“…The transfer of the nitrogen-containing appendage to the ␣-face in structures 4 and 9 was deliberate, providing a strategic device for stereochemical control of a key intramolecular Diels-Alder reaction. Although the Diels-Alder disconnection has been widely used in syntheses of the isoindolone core of the cytochalasins (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12), its implementation has almost universally followed the ''natural'' cycloreversion of a cyclohexene such as 6, whereas our synthetic plan invoked a different Diels-Alder disconnection by prior migration of the cyclohexene double bond (Fig. 3).…”

“…Previous efforts directed toward the synthesis of the cytochalasins fall into two general categories: those that form the sixmembered ring of the isoindolone core and the larger, macrocyclic ring simultaneously in a late-stage intramolecular DielsAlder cyclization (2)(3)(4)(5)(6)(7) and those that form the isoindolone core first by using an intermolecular Diels-Alder reaction and then append the macrocycle in a stepwise fashion (8,9). We planned to pursue a somewhat different implementation of the latter strategy by targeting a different bond pair for Diels-Alder disconnection and by developing much of the stereochemistry of the macrocyclic portion of the molecule before its introduction in a fragment coupling process.…”

“…he cytochalasins are fungal metabolites with complex and diverse molecular structures and a range of biological effects and thus have been of interest to synthetic chemists (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Many cytochalasins inhibit cell division and are known to induce an apoptotic response, activities that are thought to arise from the ability of these molecules to inhibit the polymerization of actin (13,14).…”

Approach Towards the Total Synthesis of Rhizoxin: Enantioselective Preparation of the Lactone Core

“…), -78°C, Me 2 S] 20 did not lead to the expected aldehyde 17 but to the corresponding dimethyl acetal derivative. However, addition of pyridine 21 to the reaction mixture [(O 3 , CH 2 Cl 2 /MeOH 1:1, pyridine (6 equiv), -78°C, Me 2 S] gave aldehyde 17 in 94% yield (Scheme 6).…”

Synthesis of Bicyclo[4.3.0]Non-3-ene-7,9-diones via Solventless Diels–Alder Methodology

“…For example, the Diels-Alder reaction has been applied to the synthesis of the 8-azabicyclo [4.3.0]nonanone core of cytochalasans. [3][4][5][6][7][8][9][10][11][12] Strained bicyclic Diels-Alder adducts are also of interest as, inter alia, monomers in ring-opening methathesis polymerization (ROMP) reactions. [13][14][15][16] Recently, the synthesis of compound 1 by a tandem Diels-Alder cycloaddition= intramolecular lactonization (Scheme 1) under solventless conditions was reported.…”