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1.
J Am Chem Soc ; 139(30): 10569-10577, 2017 08 02.
Article in English | MEDLINE | ID: mdl-28683552

ABSTRACT

A mechanistic study of a new heterocycloisomerization reaction that forms annulated aminopyrroles is presented. Density functional theory calculations and kinetic studies suggest the reaction is catalyzed by trace copper salts and that a Z- to E-hydrazone isomerization occurs through an enehydrazine intermediate before the rate-determining cyclization of the hydrazone onto the alkyne group. The aminopyrrole products are obtained in 36-93% isolated yield depending on the nature of the alkynyl substituent. A new automated sampling technique was developed to obtain robust mechanistic data.

2.
J Am Chem Soc ; 137(41): 13414-24, 2015 Oct 21.
Article in English | MEDLINE | ID: mdl-26397716

ABSTRACT

A catalytic enantioselective approach to the synthesis of indolines bearing two asymmetric centers, one of which is all-carbon and quaternary, is described. This reaction proceeds with high levels of diastereoselectivity (>20:1) and high levels of enantioselectivity (up to 99.5:0.5 er) in the presence of CsOH·H2O and a quinine-derived ammonium salt. The reaction most likely proceeds via a delocalized 2-aza-pentadienyl anion that cyclizes either by a suprafacial electrocyclic mechanism, or through a kinetically controlled 5-endo-trig Mannich process. Density functional theory calculations are used to probe these two mechanistic pathways and lead to the conclusion that a nonpericyclic mechanism is most probable. The base-catalyzed interconversion of diastereoisomeric indolines in the presence of certain quaternary ammonium catalysts is observed; this may be rationalized as a cycloreversion-cyclization process. Mechanistic investigations have demonstrated that the reaction is initiated via a Makosza-like interfacial process, and kinetic analysis has shown that the reaction possesses a significant induction period consistent with autoinduction. A zwitterionic quinine-derived entity generated by deprotonation of an ammonium salt with the anionic reaction product is identified as a key catalytic species and the role that protonation plays in the enantioselective process outlined. We also propose that the reaction subsequently occurs entirely within the organic phase. Consequently, the reaction may be better described as a phase-transfer-initiated rather than a phase-transfer-catalyzed process; this observation may have implications for mechanistic pathways followed by other phase-transfer-mediated reactions.

3.
J Org Chem ; 80(23): 11699-705, 2015 Dec 04.
Article in English | MEDLINE | ID: mdl-26168077

ABSTRACT

Herein we describe our exploration, using density functional theory calculations, of a conjugate addition-rearrangement sequence that leads to medium-ring cyclic amines. On the basis of the results of our calculations, we conclude that the rearrangement step is rate determining. In addition, we analyze the role of a carbanion lone pair in the rearrangement step, concluding that it functions as a substituent on a [3,3] sigmatropic shift, rather than a nucleophile; thus, the Woodward-Hoffmann rules are not circumvented in this reaction via involvement of orthogonal orbitals on an atom involved in the rearrangement.

4.
Org Lett ; 16(18): 4818-21, 2014 Sep 19.
Article in English | MEDLINE | ID: mdl-25188876

ABSTRACT

The theoretical investigation of concerted and stepwise Cope rearrangements of natural products led to the prediction that some concerted Cope rearrangements can be promoted by noncovalent association of their transition state structures with ammonium cations.


Subject(s)
Benzoquinones/chemical synthesis , Biological Products/chemical synthesis , Terpenes/chemical synthesis , Ammonium Compounds/chemistry , Benzoquinones/chemistry , Benzoquinones/pharmacology , Biological Products/chemistry , Cordia/chemistry , Molecular Structure , Plant Roots/chemistry , Terpenes/chemistry , Terpenes/pharmacology
5.
J Org Chem ; 79(1): 432-5, 2014 Jan 03.
Article in English | MEDLINE | ID: mdl-24236542

ABSTRACT

Although evidence has mounted in recent years for the biosynthetic relevance of [4 + 2] cycloaddition reactions, other cycloadditions have received much less attention. Herein we used density functional theory (DFT) calculations to assess the viability of nitrone-alkene (3 + 2) cycloaddition reactions proposed to occur during the biosynthesis of several alkaloid natural products (flueggines and virosaines). The results of our calculations indicate that these reactions have low enough intrinsic barriers and diastereoselectivity that they can proceed without enzymatic intervention.


Subject(s)
Alkaloids/biosynthesis , Alkaloids/chemistry , Alkenes/chemistry , Biological Products/chemical synthesis , Nitrogen Oxides/chemistry , Biological Products/chemistry , Cycloaddition Reaction , Molecular Structure , Quantum Theory , Stereoisomerism
6.
Org Lett ; 15(11): 2700-3, 2013 Jun 07.
Article in English | MEDLINE | ID: mdl-23721122

ABSTRACT

Mimics of the T7-loop of the bacterial cell division protein FtsZ have been designed and synthesized. The design is based on the X-ray cocrystal structure of P. aeruginosa FtsZ:SulA. Fast Rigid Exhaustive Docking (FRED) was employed to select compounds that can mimic the key interacting residues. Bicyclic oxazolidinones 1a-d were selected for further study and synthesized from a key bicyclic aziridine intermediate, which is synthesized from a readily available unsaturated aldehyde and amides derived from α-amino acids.


Subject(s)
Aziridines/chemistry , Aziridines/chemical synthesis , Bacterial Proteins/chemistry , Cytoskeletal Proteins/chemistry , Escherichia coli/chemistry , Oxazolidinones/chemical synthesis , Amino Acid Sequence , Bacterial Proteins/metabolism , Cell Division/physiology , Crystallography, X-Ray , Cytoskeletal Proteins/metabolism , Escherichia coli/cytology , Models, Molecular , Oxazolidinones/chemistry , Protein Binding , Pseudomonas aeruginosa
7.
J Org Chem ; 78(1): 104-15, 2013 Jan 04.
Article in English | MEDLINE | ID: mdl-23121542

ABSTRACT

The Prins cyclization of syn-ß-hydroxy allylsilanes and aldehydes gives cis-2,6-disubstituted 4-alkylidenetetrahydropyrans as sole products in excellent yields regardless of the aldehyde (R″) or syn-ß-hydroxy allylsilane substituent (R') used. By reversing the R″ and R' groups, complementary exocyclic stereocontrol can be achieved. When the anti-ß-hydroxy allylsilanes are used, the Prins cyclization gives predominantly cis-2,6-disubstituted 4-alkylidenetetrahydropyrans, now with the opposite olefin geometry in excellent yield. The proposed reaction mechanism and the observed stereoselectivity for these processes are supported by DFT calculations.


Subject(s)
Alkenes/chemical synthesis , Bryostatins/chemical synthesis , Pyrans/chemical synthesis , Alkenes/chemistry , Bryostatins/chemistry , Cyclization , Molecular Structure , Pyrans/chemistry , Stereoisomerism
8.
J Org Chem ; 76(14): 5803-12, 2011 Jul 15.
Article in English | MEDLINE | ID: mdl-21650164

ABSTRACT

Routes to structurally unique spiro-fused pyrazolidoylisoxazolines are reported. These methods start with monosubstituted hydrazines or hydrazides and utilize the nitrile oxide 1,3-dipolar cycloaddition reaction to generate the targeted spiro-fused bis-heterocycles. Molecular shape space diversity analyses were performed on these pyrazolidoylisoxazolines showing that manipulation of the appended R groups significantly changes the molecular shape.


Subject(s)
Isoxazoles/chemical synthesis , Spiro Compounds/chemistry , Cyclization , Isoxazoles/chemistry , Molecular Structure , Stereoisomerism
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