Acetogenin synthesis

Synthesis of Annonaceae acetogenins with long aliphatic chain including tetra-hydrofuran fragments 97YGK877. 

The acetogenin (+)-solamin and analogs were prepared via a ruthenium-catalyzed Alder-ene reaction/butenolide formation (Scheme 37).96 Of particular note is the ability of the ruthenium to catalyze the reaction in the presence of free hydroxyls, sulfides, and sulfones. Yields ranged from 65% for the sulfide to 88% for the sulfone. Trost has also applied this reaction to the total synthesis of (+)-ancepsenolide, which features a bis-Alder-ene reaction (Scheme 38).97... 

Stereoselective intramolecular oxymercuration of carbohydrate derivatives was proposed as the key reaction for efficient preparation of mono- and dihydroxylated unsymmetrical bis-tetrahydrofuran skeletons present in naturally occurring biologically active acetogenins. The trans- and. mz-selective intramolecular oxymercurations were explored in an enantioselective synthesis of the bis-tetrahydrofuran skeleton of mucoxin (Fig. 57).73... 

A double intramolecular Sn> O-cyclization for the stereoselective synthesis of the bistetra-hydrofuran core of Acetogenins has been achieved <99JOC2259>. 

Laurencia nipponica (790), and the structure and absolute configuration were confirmed by total synthesis (791). This new compound is a stereoisomer of the known (3Z)-isoprelaurefucin. A Malaysian Laurencia pannosa has yielded (3Z)-chlorofucin (698) (578), and (3Z)-bromofucin (699), which is also a new C15-acetogenin, is found in a South African sea hare, Aplysia parvula (792). The (3 )-neoisoprelaurefucin (700) was found in Laurencia obtusa collected in Turkish waters (557). 

A synthesis of the Annonaceous acetogenin asimicin and a side-chain analogue has been achieved by a highly convergent route in which Grubbs cross-metathesis played a key role.98... 

The use of iodoetherification has been exploited in the synthesis of precursors to mono- and bis-THF acetogenins,234 potent antitumor and pesticides. Also, has been used in the synthesis of tetrahydrofuran analogs of precursors to pseudomonic acid.235 As well, N1S has been used as the iodine source, for example in the synthesis of other acetogenins.236 Other compounds synthesized via iodocyclization include ( )-(a)-multistriatin,237 ( )-velbanamine, and ( )-isovalbanamine,238 and (+)-citreoviral.239... 

Tanaka has shown that in his synthesis of a variety of diastereomeric annonac-eous acetogenins (9, Scheme 3) the carbinol stereocenter can be generated with predictable selectivity by reagent control of either enantiomer of the chiral ligand [24], He applied this method in the total synthesis of murisolin (9, n= 1), a member of family of over 350 natural polyketides isolated from various annon-aceaes plants (Scheme 4). 

These are called acetogenins (or sometimes polyketides). Many of these compounds are aromatic, and their pathway of formation is the principal means of synthesis of the benzene ring in nature. Not all are lipids, because partial reduction often leaves oxygen-containing groups, which render the product soluble in water. 

A stereocontrolled synthesis of the /ra j-tetrahydrofuran units in Annonaceae acetogenins that relies on the Sharpless asymmetric dihydroxylation protocol is outlined in Scheme 60 <1999TA2551>. In the first step, the disubstituted double bond of the starting material is dihydroxylated followed by monoprotection as a methoxymethyl ether. Einally, a cobalt-catalyzed oxidation using molecular oxygen as oxidant furnishes the /ra j-tetrahydrofuran. 

Cerium(IV) ammonium nitrate in aqueous acetonitrile will also cleave a p-methoxyp/zeny/ ether (presumably to benzoquinone).335 The reaction was used in a synthesis of Stigmastellin A [Scheme 4.183] to release a primary alcohol in the presence of a benzyl ether.339 In an extension of the method, a bidirectional strategy for the synthesis of 2,3 5-trisubstitute d tetrahydrofuran components of annonaceous acetogenins benefited from the simultaneous protection of two primary hydroxyls as their Cj-symmetric hydroquinone ether [Scheme 4.184].340... 

RECENT PROGRESS ON THE CHEMICAL SYNTHESIS OF ANNONACEOUS ACETOGENINS AND THEIR STRUCTURALLY MODIFIED MIMICS... 

On basis of this work, we recently completed the total synthesis of five mono-THF acetogenins (Scheme 10-4), 4-deoxyannomonatacin, tonkinecin, ° (10/ )-... 

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