Malcolm P. Huestis
Genentech
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Featured researches published by Malcolm P. Huestis.
Angewandte Chemie | 2011
Malcolm P. Huestis; Lina Chan; Keith Fagnou
heterocyclic chemistry. However, the general importance of these heterocycles have driven chemists to continue developing novel methods to access differentially substituted indoles and pyrroles. Over 100 years later, Larock s indole synthesis (Scheme 1 b) aptly highlighted the utility of transition-metal catalysis in the formation of aromatic heterocycles. In the subsequent decade, palladium has continued to play a central role in this diverse reaction class. More recently, an increasing number of examples have appeared in the literature featuring a transition metal catalyzed oxidative C H bond functionalization event as a fundamental step in the formation of various heterocycles. This mode of reactivity is particularly desirable since the cost to install activating functionality, such as halides, is obviated. A particular focus has been placed on annulative couplings of nitrogen-substituted aryl or vinyl groups with internal alkynes catalyzed by rhodium(III) complexes. Our group has previously exploited this approach, developing reactions forming indoles 12a] (Scheme 1c), pyrroles, isoquinolines, and isoquinolones. Despite these recent advances, a pharmaceutically relevant target that continues to represent a significant synthetic challenge is the unsymmetrical 2,3-aliphatic-substituted indole (Scheme 1). To the best of our knowledge, all methods for constructing indoles with 2,3-aliphatic substitution other than methyl require multistep procedures, and the opposite C2/C3 regioisomer cannot be accessed by the same method. In the context of rhodium(III)-catalyzed annulations, the difficulties associated with this substrate class derive from poor regioselectivity in the 1,2-migratory insertion across unsymmetrical aliphatic-substituted internal alkynes as well as rate inhibition by dialkyl-substituted internal alkynes. Previous studies on the mechanism of our indole-forming reaction revealed that, while there is little influence from steric effects in the alkyne insertion event, this step is largely controlled by electronic effects. Therefore, in cases we have investigated in which there is one aryl (or sp hybridized) substituent on the alkyne, this group is delivered proximal to the indole nitrogen atom with very high regioselectivity. On the basis of these results a working hypothesis was conceived in which an enyne would function as a coupling partner with a bias for highly regioselective alkyne insertion leading to the production of a C2-vinyl-substituted heterocycle (Scheme 2). Herein, we report the realization of this goal, namely the ability to control which regioisomer is obtained by employing the appropriate enyne, and formation of unsymmetrical 2,3aliphatic-substituted indoles and pyrroles by facile hydrogenation of the resulting alkene at the C2 position of the heterocycle. The nonhygroscopic, bench-weighable complex [Cp*Rh(MeCN)3](SbF6)2 catalyzed the annulation reaction under mild reaction conditions (20–60 8C), required no inert atmosphere, and displayed broad substrate scope with respect to the formation of both indoles and pyrroles. Our studies were initiated by the reaction of an enyne with acetanilide under our first-generation reaction conditions. Despite a low yield of the isolated product (11%), the reaction yielded exclusively the desired 2-alkenyl indole regioisomer (Table 1, entry 1). The incompatibility of enynes with acetanilide under more mild reaction conditions (entry 2) led us to examine a wide variety of anilides, Scheme 1. Challenges in the synthesis of 2,3-aliphatic indoles.
Journal of Organic Chemistry | 2008
Benoit Liegault; Doris Lee; Malcolm P. Huestis; Keith Fagnou
New reaction conditions for intramolecular palladium(II)-catalyzed oxidative carbon-carbon bond formation under air are described. The use of pivalic acid as the reaction solvent, instead of acetic acid, results in greater reproducibility, higher yields, and broader scope. This includes the use of electron-rich diarylamines as illustrated in the synthesis of three naturally occurring carbazole products: Murrayafoline A, Mukonine, and Clausenine. A variety of side products have also been isolated, casting light on competing reaction pathways and revealing new reactivity with palladium(II) catalysis.
Organic Letters | 2009
Malcolm P. Huestis; Keith Fagnou
Subjection of N-methyl 6- and 7-azaindole N-oxides to a Pd(OAc)2/DavePhos catalyst system enables regioselective direct arylation of the azine ring. Following deoxygenation, 7-azaindole substrates undergo an additional regioselective azole direct arylation event in good yield.
Journal of Medicinal Chemistry | 2015
Snahel Patel; Fred E. Cohen; Brian Dean; Kelly De La Torre; Gauri Deshmukh; Anthony A. Estrada; Arundhati Sengupta Ghosh; Paul Gibbons; Amy Gustafson; Malcolm P. Huestis; Claire E. Le Pichon; Han Lin; Wendy Liu; Xingrong Liu; Yichin Liu; Cuong Ly; Joseph P. Lyssikatos; Changyou Ma; Kimberly Scearce-Levie; Young G. Shin; Hilda Solanoy; Kimberly L. Stark; Jian Wang; Bei Wang; Xianrui Zhao; Joseph W. Lewcock; Michael Siu
Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here we describe the generation of potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hinge-binding interactions to infer a binding mode and specific design parameters to optimize for CNS druglike molecules, we came to focus on the di(pyridin-2-yl)amines because of their combination of desirable potency and good brain penetration following oral dosing. Our lead inhibitor GNE-3511 (26) displayed concentration-dependent protection of neurons from degeneration in vitro and demonstrated dose-dependent activity in two different animal models of disease. These results suggest that specific pharmacological inhibition of DLK may have therapeutic potential in multiple indications.
Chemcatchem | 2015
Heng Chen; Malcolm P. Huestis
The development of a benzylic amine directed ortho‐sulfonamidation of aryl CH bonds with sulfonyl azides was investigated. The combination of a commercially available iridium(III) complex with a silver salt gave rise to an active manifold capable of promoting efficient CN bond formation for a variety of substrates.
Journal of Organic Chemistry | 2013
Alexander D. Thompson; Malcolm P. Huestis
Nucleophilic aromatic substitution of 2- or 4-cyanoazines with the anions derived from aliphatic α,α-disubstituted esters and nitriles leads to displacement of the cyanide function. Enabling cyanides to be used as highly active leaving groups in S(N)Ar reactions provides additional flexibility in starting materials for synthesis. We show that, in many cases, the cyanide leaving group is displaced preferentially in the presence of halogens. The resulting heteroaryl iodides, bromides, and chlorides subsequently can be used as handles for further chemical diversification.
Bioorganic & Medicinal Chemistry Letters | 2014
Matthew Volgraf; Lina Chan; Malcolm P. Huestis; Hans E. Purkey; Michael Burkard; Mary Geck Do; Julie Harris; Kevin W. Hunt; Xingrong Liu; Joseph P. Lyssikatos; Sumeet Rana; Allen A. Thomas; Guy Vigers; Michael Siu
The development of 1,3,4,4a,5,10a-hexahydropyrano[3,4-b]chromene analogs as BACE1 inhibitors is described. Introduction of the spirocyclic pyranochromene scaffold yielded several advantages over previous generation cores, including increased potency, reduced efflux, and reduced CYP2D6 inhibition. Compound 13 (BACE1 IC50=110 nM) demonstrated a reduction in CSF Aβ in wild type rats after a single dose.
Tetrahedron Letters | 2013
Malcolm P. Huestis; Wendy Liu; Matthew Volgraf; Hans E. Purkey; Christine Yu; Weiru Wang; Darin Smith; Guy Vigers; Darrin Dutcher; Kevin W. Hunt; Michael Siu
Abstract A series of unique bicyclic aminooxazolines were synthesized and found to exhibit micromolar inhibition of β-secretase-1 (BACE-1). The aminooxazolines were procured by an intramolecular diethylaminosulfur trifluoride (DAST)-mediated ring closure of a benzylic urea onto a secondary alcohol.
Archive | 2011
Adam Cook; Indrani W. Gunawardana; Malcolm P. Huestis; Kevin W. Hunt; Nicholas C. Kallan; Andrew T. Metcalf; Brad Newhouse; Michael Siu; Tony P. Tang; Allen A. Thomas; Matthew Volgraf
Journal of Organic Chemistry | 2016
Malcolm P. Huestis