Browsing by Subject "Metathesis (Chemistry)"

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    Applications of ring-closing metathesis in construction of alkaloid natural products : synthetic studies on the immunosuppressant FR901483 and lundurines A-C
    (2008-05) Simila, Suvi Tuula, 1978-; Martin, Stephen F.
    Ring-closing metathesis (RCM) has proven to be a valuable tool for constructing alkaloid-like, poly-cyclic compounds. The syntheses of alkaloid structures we were interested in developing, could utilize RCM to construct a spirocyclic structure for the immunosuppressant FR901483 and the tetracyclic framework of lundurines A-C asymmetrically. The azaspirane core of FR901483 was obtained via an addition of an allylsilane to an N-acyl iminium ion, and a RCM. Other key functional group manipulations were a stereoselective hydroboration and a subsequent lactonization that provided a precursor for a lactone-lactam rearrangement. This rearrangement provided the azatricyclic core of FR901483. In the enantioselective approach to FR901483 a new mildly cleavable protecting group was developed. Addition of a zinc nucleophile to a chiral N-acyl iminium ion, and a RCM provided the desired precursor for the hydroboration/lactone-lactam rearrangement sequence but without a sufficient stereoselection. A novel approach toward the total synthesis of lundurines A-C has been developed. The key features of the approach involve an intramolecular cyclopropanation of the indole C(2)-C(3) double bond, an enantioselective tandem RCM to construct the tetracyclic core and a concise synthesis to access the RCM precursor. An Ugi reaction was utilized with both cyclic and acyclic ketones, 2-vinyltryptamine derivative, a carboxylic acid and an isocyanide to access diverse compounds, including RCM precursors. An alternative reductive amination route to construct the RCM precursor for the lundurines was found to be more efficient and high yielding than the Ugi approach. An RCM was utilized to affect the closure of the five-and eight-membered rings of the tetracyclic core. This constitutes as the first example of RCM of a 2-vinylindole derivative to give an indole-fused eight-membered ring.
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    Applications of ring-closing metathesis reactions tot he total syntheses of (+)-anatoxin-a and 8-epi-xanthatin and progress toward the total synthesis of (+)-pinnamine
    (2005) Brenneman, Jehrod Burnett; Martin, Stephen F.
    The application of ring-closing enyne metathesis (RCEYM) reactions to the preparation of biologically active natural products has been described. During the course of the studies toward the assembly of the potent nicotinic acetylcholine receptor agonists (+)-anatoxin-a and (+)-pinnamine, several new methods were developed to obtain suitable metathesis precursors. A method to prepare α-branched enones bearing a high degree of functional group diversity was accomplished from carboxylic acid precursors using a new titanium-mediated Peterson olefination sequence, and a new catalytic diastereoselective method for the preparation of cis-2,5-disubstituted pyrrolidines bearing unsaturated moieties was discovered. The application of these methods to the total synthesis of (+)-anatoxin-a constituting the first application of a RCM approach to the azabicyclo[4.2.1]nonane skeleton is described. Studies directed toward the total synthesis of the related alkaloid (+)-pinnamine are also discussed. In a related effort, the first total synthesis of the cytotoxic farnesyltransferase inhibitor 8-epi-xanthatin was achieved. The total synthesis featured a palladiumcatalyzed carbonylation-lactonization sequence to prepare an α-methylene lactone bearing enyne moieties. A subsequent domino RCEYM-cross metathesis between this enyne and methyl vinyl ketone produced the fully functionalized pseudoguaianolide skeleton and completed the total synthesis. Additionally, a new chiral Nenoyloxazolidininone bearing a dinaphthylmethyl group was prepared and utilized as a substrate to explore the addition reactions of aluminum acetylides to imides.
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    I. The synthesis of homoallylic amines via a 1,2-metalate rearrangement; II. The synthesis of bridged azabicyclic structures via ring-closing olefin metathesis
    (2003-05) Neipp, Christopher Ernest; Martin, Stephen F.
    A convergent, stereoselective route to homoallylic sulfonamides has been described. Homoallylic sulfonamides with di- and trisubstituted double bonds were prepared in good yields and with excellent control of alkene geometry via a cuprateinduced 1,2-metalate rearrangement of α-lithiated N-trisyl 2-pyrroline. Removal of the N-trisyl group was achieved by sonication of the sulfonamides in the presence of Li(0) wire and catalytic di-tert-butylbiphenyl. The utility of this method was illustrated by its application toward the synthesis of a squalene synthetase inhibitor. In other efforts, a versatile approach to bridged azabicyclic structures was developed. This process involved the ring-closing metathesis (RCM) of cis-2,6- dialkenyl N-acyl piperidines, which were prepared in six steps from glutarimide or in three steps from 4-methoxypyridine. The N-acyl protecting group of these piperidines played a crucial role in this sequence by stabilization of the C2,C6 bisaxial conformers necessary for their RCM. In this manner, a diverse array of bridged azabicyclic structures were obtained in excellent yields. Application of this RCM strategy toward the synthesis of (±)-cocaine and compounds structurally related to vellosimine has been reported.
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