Timothy R. Newhouse
Yale University
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Featured researches published by Timothy R. Newhouse.
Angewandte Chemie | 2011
Timothy R. Newhouse; Phil S. Baran
C-H oxidation has a long history and an ongoing presence in research at the forefront of chemistry and interrelated fields. As such, numerous highly useful articles and reviews have been written on this subject. Logically, these are generally written from the perspective of the scope and limitations of the reagents employed. This Minireview instead attempts to emphasize chemoselectivity imposed by the nature of the substrate. Consequently, many landmark discoveries in the field of C-H oxidation are not discussed, but hopefully the perspective taken herein will allow C-H oxidation reactions to be more readily incorporated into synthetic planning.
Chemical Society Reviews | 2009
Timothy R. Newhouse; Phil S. Baran; Reinhard W. Hoffmann
In this tutorial review the economies of synthesis are analysed from both detailed and macroscopic perspectives, using case-studies from complex molecule synthesis. Atom, step, and redox economy are more than philosophical constructs, but rather guidelines, which enable the synthetic chemist to design and execute an efficient synthesis. Students entering the field of synthesis might find this tutorial helpful for understanding the subtle differences between these economic principles and also see real-world situations where such principles are put into practice.
Journal of the American Chemical Society | 2010
Timothy R. Newhouse; Chad A. Lewis; Kyle J. Eastman; Phil S. Baran
This report details the invention of a method to enable syntheses of psychotrimine (1) and the kapakahines F and B (2, 3) on a gram scale and in a minimum number of steps. Mechanistic inquiries are presented for the key enabling quaternization of indole at the C3 position by electrophilic attack of an activated aniline species. Excellent chemo-, regio-, and diastereoselectivities are observed for reactions with o-iodoaniline, an indole cation equivalent. Additionally, the scope of this reaction is broad with respect to the tryptamine and aniline components. The anti-cancer profiles of 1-3 have also been evaluated.
Journal of the American Chemical Society | 2008
Timothy R. Newhouse; Phil S. Baran
new process for the union of anilines with tryptamine derivatives has been developed, furnishing C-3 quaternized pyrroloindoline architectures. This chemoselective coupling of a tryptamine with 1.2 equiv of 2-iodoaniline proceeds efficiently on a gram-scale using only the simple reagents N-iodosuccinimide and triethylamine. Using this new reaction, the complex natural product psychotrimine has been fashioned with a rare level of efficiency and practicality. From a readily available bromotryptamine, only four steps (41-45% overall isolated yield) are necessary to procure gram quantities of the natural product. Functional group manipulations, protecting group chemistry, and unnecessary redox fluctuations have been minimized.
Angewandte Chemie | 2011
Klement Foo; Timothy R. Newhouse; Ikue Mori; Hiromitsu Takayama; Phil S. Baran
Polymeric tryptamine-based alkaloids belong to a structurally and biologically fascinating class of natural products.[1] Whereas the vast majority of such molecules are linked through C–C bonds, a small subset are linked from the C3 of one indole nucleus to the N1 of another. Psychotetramine (1, Figure 1A) represents the curious case of a tryptamine tetramer containing both types of connectivity: a C3–C3 linked dimer bonded to a C3–N1 dimer through an unusual C7–N1 linkage. This interesting alkaloid was isolated in 2004,[2] but due to the limited quantity from Nature and its complicated NMR spectra, a final chemical structure including stereochemistry was not determined. In this communication, a joint venture between our groups (H. T. and P. S. B.) is described, leading to the total synthesis and final structure elucidation of 1. The pursuit of this complex natural product also led to an efficient enantioselective synthesis of the related alkaloid (+)-psychotrimine, an improved procedure for direct-indole aniline coupling, and one of the most complex and demanding contexts for a Buchwald-Hartwig amination.
Journal of the American Chemical Society | 2009
Timothy R. Newhouse; Chad A. Lewis; Phil S. Baran
Gram-scale, enantiospecific total syntheses of the anti-leukemia marine natural products kapakahines B and F have been completed. Two powerfully simplifying transformations have enabled the gram-scale synthesis of this natural product family: (1) an oxidative N-C bond-forming reaction that sets a key quaternary center with complete stereocontrol and (2) a unique strategy for the construction of twisted macrocycles via dynamic equilibration of complex late-stage intermediates.
Journal of Organic Chemistry | 2013
Lufeng Zou; Robert S. Paton; Albert Eschenmoser; Timothy R. Newhouse; Phil S. Baran; K. N. Houk
The site selectivities and stereoselectivities of C-H oxidations of substituted cyclohexanes and trans-decalins by dimethyldioxirane (DMDO) were investigated computationally with quantum mechanical density functional theory (DFT). The multiconfiguration CASPT2 method was employed on model systems to establish the preferred mechanism and transition state geometry. The reaction pathway involving a rebound step is established to account for the retention of stereochemistry. The oxidation of sclareolide with dioxirane reagents is reported, including the oxidation by the in situ generated tBu-TFDO, a new dioxirane that better discriminates between C-H bonds on the basis of steric effects. The release of 1,3-diaxial strain in the transition state contributes to the site selectivity and enhanced equatorial C-H bond reactivity for tertiary C-H bonds, a result of the lowering of distortion energy. In addition to this strain release factor, steric and inductive effects contribute to the rates of C-H oxidation by dioxiranes.
Journal of the American Chemical Society | 2015
Yifeng Chen; Justin P. Romaire; Timothy R. Newhouse
A highly practical and general palladium-catalyzed methodology for the α,β-dehydrogenation of esters and nitriles is reported. Generation of a zinc enolate or (cyanoalkyl)zinc species followed by the addition of an allyl oxidant and a palladium catalyst results in synthetically useful yields of α,β-unsaturated esters, lactones, and nitriles. Preliminary mechanistic investigations are consistent with reversible β-hydride elimination and turnover-limiting, propene-forming reductive elimination.
Chemical Reviews | 2017
Joshua E. Zweig; Daria E. Kim; Timothy R. Newhouse
First-row transition-metal-mediated reactions constitute an important and growing area of research due to the low cost, low toxicity, and exceptional synthetic versatility of these metals. Currently, there is considerable effort to replace existing precious-metal-catalyzed reactions with first-row analogs. More importantly, there are a plethora of unique transformations mediated by first-row metals, which have no classical second- or third-row counterpart. Herein, the application of first-row metal-mediated methods to the total synthesis of natural products is discussed. This Review is intended to highlight strategic uses of these metals to realize efficient syntheses and highlight the future potential of these reagents and catalysts in organic synthesis.
Journal of the American Chemical Society | 2016
Yifeng Chen; Aneta Turlik; Timothy R. Newhouse
A practical and direct method for the α,β-dehydrogenation of amides is reported using allyl-palladium catalysis. Critical to the success of this process was the synthesis and application of a novel lithium N-cyclohexyl anilide (LiCyan). The reaction conditions tolerate a wide variety of substrates, including those with acidic heteroatom nucleophiles.