RESUMO
A highly convergent, enantioselective total synthesis of brevetoxin A is reported. The development of a [X+2+X] Horner-Wadsworth-Emmons/cyclodehydration/reductive etherification convergent coupling strategy allowed a unified approach to the synthesis of two advanced tetracyclic fragments from four cyclic ether subunits. The Horner-Wittig coupling of the two tetracyclic fragments provided substrates that were explored for reductive etherification, the success of which delivered a late-stage tetraol intermediate. The tetraol was converted to the natural product through an expeditious selective oxidative process followed by methylenation.
Assuntos
Éteres Cíclicos/síntese química , Toxinas Marinhas/síntese química , Oxocinas/síntese química , Catálise , Ciclização , Éteres Cíclicos/química , Toxinas Marinhas/química , Estrutura Molecular , Oxocinas/química , EstereoisomerismoRESUMO
Brevetoxin A is a decacyclic ladder toxin that possesses 5-, 6-, 7-, 8-, and 9-membered oxacycles, as well as 22 tetrahedral stereocenters. Herein, we describe a unified approach to the B, E, G, and J rings based upon a ring-closing metathesis strategy from the corresponding dienes. The enolate technologies developed in our laboratory allowed access to the precursor acyclic dienes for the B, E, and G medium-ring ethers. The strategies developed for the syntheses of these four monocycles ultimately provided multigram quantities of each of the rings, supporting our efforts toward the completion of a convergent synthesis of brevetoxin A.
Assuntos
Éteres/síntese química , Toxinas Marinhas/síntese química , Oxocinas/síntese química , Alquilação , Ciclização , Éteres/química , Toxinas Marinhas/química , Estrutura Molecular , Oxocinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A concise approach to the core skeleton of the welwitindolinone alkaloids was developed on the basis of sequential cycloaddition reactions. First, a palladium catalyzed enantioselective [6 + 3] trimethylenemethane cycloaddition onto a tropone nucleus was used to generate the requisite bicyclo[4.3.1]decadiene. Subsequent modifications to the cycloadduct allowed for an intramolecular [4 + 2] cycloaddition to generate the oxindole and complete the core of the natural product family.
Assuntos
Alcaloides/síntese química , Indóis/síntese química , Nitrilas/síntese química , Alcaloides/química , Ciclização , Alcaloides Indólicos , Indóis/química , Estrutura Molecular , Nitrilas/química , Oxindóis , Paládio/química , Tropolona/análogos & derivados , Tropolona/síntese química , Tropolona/químicaRESUMO
A total synthesis of brevetoxin A is reported. Two tetracyclic coupling partners, prepared from previously reported advanced fragments, were effectively united via a Horner-Wittig olefination. The resulting octacycle was progressed to substrates that were explored for reductive etherification, the success of which led to a penultimate tetraol intermediate. The tetraol was converted to the natural product through an expeditious selective oxidative process followed by methylenation.
Assuntos
Toxinas Marinhas/síntese química , Oxocinas/síntese química , Aldeídos/química , Alcenos/química , Toxinas Marinhas/química , Oxirredução , Oxocinas/química , Especificidade por SubstratoRESUMO
The cyanosubstituted trimethylenemethane donor undergoes palladium-catalyzed [6 + 3] cycloaddition with a variety of tropones to yield bicyclo[4.3.1]decadienes in excellent regio-, diastereo-, and enantioselectivity. Products of the Pd-TMM [6 + 3] cycloaddition participate in a thermal [3,3] sigmatropic rearrangement to yield bicyclo[3.3.2]decadienes in good yield.
Assuntos
Compostos Bicíclicos com Pontes/síntese química , Lipídeos/síntese química , Metano/análogos & derivados , Polienos/síntese química , Tropolona/análogos & derivados , Compostos Bicíclicos com Pontes/química , Catálise , Ciclização , Cetonas/síntese química , Cetonas/química , Lipídeos/química , Metano/química , Paládio/química , Polienos/química , Tropolona/químicaRESUMO
A second-generation synthesis of the BCDE fragment of brevetoxin A is described. Novel reactions were developed that extend the utility of the asymmetric glycolate alkylation reaction and improve scale-up to provide gram quantities of the B and E subunits. Significant improvements to the convergent assembly of the tetracycle were also realized. In addition, formation of the A ring lactone was accomplished to complete the ABCDE pentacycle.
Assuntos
Toxinas Marinhas/síntese química , Oxocinas/síntese química , Estrutura MolecularRESUMO
A stereoselective synthesis of the BCDE fragment of brevetoxin A has been completed. anti-Glycolate aldol, glycolate alkylation, and ring-closing metathesis reactions were employed as key bond-forming events. A convergent assembly strategy was employed that relied on a Horner-Wadsworth-Emmons union of two complex fragments. Subsequent cyclization and dehydration led to efficient generation of an intermediate endocyclic enol ether, which was advanced to a tetracyclic fragment. [reaction: see text]
Assuntos
Éteres Cíclicos/síntese química , Toxinas Marinhas/síntese química , Oxocinas/síntese química , Hidrocarbonetos Policíclicos Aromáticos/síntese química , Alquilação , Catálise , Ciclização , Éteres Cíclicos/química , Toxinas Marinhas/química , Estrutura Molecular , Oxocinas/química , Hidrocarbonetos Policíclicos Aromáticos/química , EstereoisomerismoRESUMO
[reaction: see text] A highly diastereoselective anti aldol addition utilizing a variety of N-glycolyloxazolidinethiones has been developed. Enolization of an N-glycolyloxazolidinethione with titanium (IV) chloride and (-)-sparteine followed by addition of an aldehyde activated with additional TiCl(4) resulted in highly anti-selective aldol additions, typically with no observable syn isomers. Allyl-protected glycolates demonstrated the highest levels of selection and yields, although O-benzyl and O-methyl glycolyloxazolidinethiones also performed well.