RESUMO
Catalytic asymmetric deprotonation-aldehyde trapping-ring expansion from a 5- to a 6-ring delivers a concise route to each stereoisomer of beta-hydroxy piperidines starting from N-Boc pyrrolidine. The methodology is utilized in a 5-step catalytic asymmetric synthesis of the neorokinin-1 receptor antagonist, (+)-L-733,060.
Assuntos
Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/síntese química , Pirrolidinas/química , Estrutura Molecular , Piperidinas/química , EstereoisomerismoRESUMO
A detailed study on the lithiation-electrophilic trapping of N-sulfonyl ethylene aziridines is described. The optimum results required use of a N-2,4,6-tri-iso-propylbenzenesulfonyl activating group and lithiation using 3 equiv. of s-BuLi-PMDETA for 1 minute before addition of the electrophile. In situ trapping with Me3SiCl was also successful. Electrophilic trapping with aldehydes provided a stereoselective route to syn-hydroxy aziridines. Alternatively, keto aziridines could be stereoselectively reduced to syn-hydroxy aziridines using NaBH4-CeCl3. The relative stereochemistry in two of the hydroxy aziridines was established unequivocally by X-ray crystallography.
Assuntos
Aziridinas/química , Etilenos/química , Lítio/química , Catálise , Cristalografia por Raios X , EstereoisomerismoRESUMO
In 18 out of 20 examples of the organolithium-mediated conversion of beta-alkoxy aziridines into substituted allylic sulfonamides, use of a Bus (Bus = t-BuSO2) substituent on the nitrogen gave higher yields compared to the analogous N-Ts compounds. The success with the N-Bus aziridines facilitated the development of a new route to the spirocyclic core of the histrionicotoxins and completion of a formal synthesis of (+/-)-perhydrohistrionicotoxin.
Assuntos
Venenos de Anfíbios/síntese química , Aziridinas/química , Lítio , Sulfonamidas/síntese química , Compostos OrganometálicosRESUMO
The kinetic profile of the Newman-Kwart rearrangement has been evaluated using microwave heating. After first demonstrating equivalence between conventional convective heating and microwave heating, data was gathered and analyzed to determine the effects of substituent, solvent, and concentration on the reaction order. Reaction rate constants, Arrhenius constants, and activation energies have been determined. The reaction rate shows strong sensitivity to the substituent and modest sensitivity to the solvent. At high concentrations, the reaction order increases from the previously reported first-order to a mixed first/second-order reaction. Overall, this re-evaluation of the Newman-Kwart rearrangement has shown the reaction rate order to be more complex than previously thought. In addition, microwave heating has proven ideal for the rapid collection of data to facilitate this type of kinetic study.
Assuntos
Micro-Ondas , Modelos Químicos , Cinética , Estrutura Molecular , Solventes , TemperaturaRESUMO
A convenient method for the stereoselective synthesis of cyclic beta-amino esters from an iodo alphabeta-unsaturated ester and alpha-methylbenzylamine is described. Subsequent enolate generation and alkylation proceeds with complete stereocontrol, with the two stereogenic centres working together. In this way, a functionalised piperidine suitable for alkaloid natural product synthesis was prepared. The usefulness of the methodology is exemplified with the concise synthesis of a (-)-sparteine surrogate.
Assuntos
Ésteres/química , Ésteres/síntese química , Esparteína/química , Esparteína/síntese química , Alquilação , Cristalografia por Raios X , Ciclização , Modelos Químicos , EstereoisomerismoRESUMO
A new three-step route to azaspirocycles involving the organolithium-mediated conversion of beta-alkoxy aziridines into substituted cyclopentenyl amines, hydroboration, and cyclization has been developed. The methodology is utilized in the construction of the pentacyclic ring system of cephalotaxine. [reaction: see text]
RESUMO
A six-step asymmetric synthesis of natural (-)-sparteine from ethyl 7-iodohept-2-enoate is reported, involving a connective Michael addition of an amino ester-derived enolate to an alpha,beta-unsaturated amino ester.
Assuntos
Aminoácidos/química , Antiarrítmicos/síntese química , Ésteres/química , Esparteína/síntese química , Heptanos/química , Modelos Químicos , EstereoisomerismoRESUMO
Three chiral diamines were synthesised and evaluated as sparteine surrogates in the lithiation-substitution of N-(tert-butoxycarbonyl)pyrrolidine. The synthesis and attempted resolution of sparteine-like diamines [(1S*,2R*,8R*)-10-methyl-6,10-diazatricyclo[6.3.1.0(2,6)]dodecane and (1S*,2R*,9R*)-11-methyl-7,11-diazatricyclo[7.3.1.0(2,7)]tridecane] (via inclusion complex formation) are reported. Unfortunately, it was only possible to resolve the diazatricyclo[7.3.1.0(2,7)]tridecane compound. An alternative route to (1R,2S,9S)-11-methyl-7,11-diazatricyclo[7.3.1.0(2,7)]tridecane starting from the natural product, (-)-cytisine, is described. This simple three-step route furnished gram-quantities of a (+)-sparteine surrogate. X-Ray crystallography of an intermediate in the route, (1R,5S,12S)-3-methoxycarbonyldecahydro-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one, enabled the stereochemistry of all of the tricyclic diamines described in this paper to be unequivocally established. Two other diamines, starting from (S)-proline and resolved 2-piperidine ethanol, were prepared using standard methods. These diamines lacked the bispidine framework of (-)-sparteine and were found to impart vastly inferior enantioselectivity. It was concluded that, for the asymmetric lithiation substitution of N-Boc pyrrolidine, a rigid bispidine framework and only three of the four rings of (-)-sparteine are needed for high enantioselectivity. Furthermore, it is shown that diamine (1R,2S,9S)-11-methyl-7,11-diazatricyclo[7.3.1.0(2,7)]tridecane is the first successful (+)-sparteine surrogate.