Development of Asymmetric Protonation Reactions for the Synthesis of Indoline Alkaloids


Autoria(s): Ni, Jane
Data(s)

2015

Resumo

<p>Nitrogen-containing heterocycles, such as indolines and pyrroloindolines, are prevalent in a variety of diverse natural products, many of which exhibit remarkable biological activities. These frameworks have inspired innovative research aimed at discovering novel methods for their stereoselective preparation.</p> <p>We have developed an enantioselective synthesis of pyrroloindolines based on a formal (3 + 2) cycloaddition of indoles and 2-amidoacrylates. This reaction is promoted by (R)-BINOL•SnCl<sub>4</sub>; this complex is a Lewis acid-assisted Brønsted acid that effects a highly face-selective catalyst-controlled protonation of an enolate. Mechanistic studies also determined that the initial product of this reaction is an indolinium ion, which upon aqueous workup undergoes cyclization to the pyrroloindoline.</p> <p>Based on this result, we investigated alternative nucleophiles to trap the indolinium ion. First, addition of sodium borohydride to the optimized reaction conditions yields indoline-containing amino acid derivatives.</p> <p>Next, carbon nucleophiles were explored. Indole substrates incorporating a tethered alkene were exposed to the conditions for the formal (3 + 2) cycloaddition, resulting in a conjugate addition/asymmetric protonation/Prins cyclization cascade. In this transformation, the indolinium ion is attacked by the olefin, and the resulting carbocation is quenched by a chloride ion. Zirconium tetrachloride was found to be the optimal Lewis acid. Stoichiometric proton and chloride sources were also found to be crucial for reactivity.</p>

Formato

application/pdf

application/pdf

application/pdf

application/pdf

application/pdf

application/pdf

application/pdf

application/pdf

application/pdf

application/pdf

application/pdf

application/pdf

Identificador

http://thesis.library.caltech.edu/8658/72/NiJane2015thesis.pdf

http://thesis.library.caltech.edu/8658/78/NiJane2015_title.pdf

http://thesis.library.caltech.edu/8658/13/NiJane2014_ch1.pdf

http://thesis.library.caltech.edu/8658/14/NiJane2014_ch2.pdf

http://thesis.library.caltech.edu/8658/25/NiJane2014_app1.pdf

http://thesis.library.caltech.edu/8658/30/NiJane2014_app2.pdf

http://thesis.library.caltech.edu/8658/32/NiJane2014_ch3.pdf

http://thesis.library.caltech.edu/8658/43/NiJane2014_app3.pdf

http://thesis.library.caltech.edu/8658/44/NiJane2014_ch4.pdf

http://thesis.library.caltech.edu/8658/45/NiJane2014_app4.pdf

http://thesis.library.caltech.edu/8658/55/NiJane2014_app5.pdf

http://thesis.library.caltech.edu/8658/65/NiJane2014_about%20the%20author.pdf

Ni, Jane (2015) Development of Asymmetric Protonation Reactions for the Synthesis of Indoline Alkaloids. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z95B00C4. http://resolver.caltech.edu/CaltechTHESIS:09152014-112952177 <http://resolver.caltech.edu/CaltechTHESIS:09152014-112952177>

Relação

http://resolver.caltech.edu/CaltechTHESIS:09152014-112952177

http://thesis.library.caltech.edu/8658/

Tipo

Thesis

NonPeerReviewed