Total Synthesis of (+)-Pleuromutilin Fazakerley, Neal J.; Helm, Matthew D.; Procter, David J.
Chemistry : a European journal,
May 17, 2013, Letnik:
19, Številka:
21
Journal Article
Recenzirano
The first enantiospecific total synthesis of the antibacterial natural product (+)‐pleuromutilin has been achieved. The approach includes the synthesis of a non‐racemic cyclisation substrate from ...(+)‐trans‐dihydrocarvone, a highly selective SmI2‐mediated cyclisation cascade, an electron transfer reduction of a hindered ester, and the first efficient conversion of (+)‐mutilin to the target.
Two‐electron cyclisation cascade: The first enantiospecific total synthesis of the antibacterial (+)‐pleuromutilin has been achieved. The approach includes the synthesis of a non‐racemic cyclisation substrate from (+)‐trans‐dihydrocarvone, a highly selective SmI2‐mediated cyclisation cascade, an electron transfer reduction of a hindered ester, and the first efficient conversion of (+)‐mutilin to the target (see scheme; Piv=pivaloyl).
Chemoselective Suzuki–Miyaura cross‐coupling generally requires a designed deactivation of one nucleophile towards transmetallation. Here we show that boronic acids can be chemoselectively reacted in ...the presence of ostensibly equivalently reactive boronic acid pinacol (BPin) esters by kinetic discrimination during transmetallation. Simultaneous electrophile control allows sequential chemoselective cross‐couplings in a single operation in the absence of protecting groups.
Set phases to stun: Chemoselective Suzuki–Miyaura cross‐coupling can be achieved by kinetic discrimination of boronic acids and BPin esters during transmetallation. Simultaneous electrophile control allows sequential chemoselective cross‐couplings in a single operation in the absence of protecting groups.
Ligand metathesis of Pd(II) complexes is mechanistically essential for cross-coupling. We present a study of halide→OH anion metathesis of (Ar)PdII complexes using vinylBPin as a bifunctional ...chemical probe with Pd(II)-dependent cross-coupling pathways. We identify the variables that profoundly impact this event and allow control to be leveraged. This then allows control of cross-coupling pathways via promotion or inhibition of organoboron transmetalation, leading to either Suzuki–Miyaura or Mizoroki–Heck products. We show how this transmetalation switch can be used to synthetic gain in a cascade cross-coupling/Diels–Alder reaction, delivering borylated or non-borylated carbocycles, including steroid-like scaffolds.
Display omitted Despite renewed pleas by the World Health Organisation for action to be taken against antimicrobial resistance, the development of new antibiotics has not kept pace with demand. The ...pleuromutilin class is vastly under explored and could hold a key weapon in the battle against antimicrobial resistance. This report explores the synthesis and synthetic chemistry of this structurally intriguing, densely functionalised and biologically important natural product.
The Cu-catalyzed azide–alkyne cycloaddition (CuAAC) reaction is used as a ligation tool throughout chemical and biological sciences. Despite the pervasiveness of CuAAC, there is a need to develop ...more efficient methods to form 1,4-triazole ligated products with low loadings of Cu. In this paper, we disclose a mechanistic model for the ynamine-azide (3 + 2) cycloadditions catalyzed by copper(II) acetate. Using multinuclear nuclear magnetic resonance spectroscopy, electron paramagnetic resonance spectroscopy, and high-performance liquid chromatography analyses, a dual catalytic cycle is identified. First, the formation of a diyne species via Glaser–Hay coupling of a terminal ynamine forms a Cu(I) species competent to catalyze an ynamine-azide (3 + 2) cycloaddition. Second, the benzimidazole unit of the ynamine structure has multiple roles: assisting C–H activation, Cu coordination, and the formation of a postreaction resting state Cu complex after completion of the (3 + 2) cycloaddition. Finally, reactivation of the Cu resting state complex is shown by the addition of isotopically labeled ynamine and azide substrates to form a labeled 1,4-triazole product. This work provides a mechanistic basis for the use of mixed valency binuclear catalytic Cu species in conjunction with Cu-coordinating alkynes to afford superior reactivity in CuAAC reactions. Additionally, these data show how the CuAAC reaction kinetics can be modulated by changes to the alkyne substrate, which then has a predictable effect on the reaction mechanism.
An electrochemical method for the green and practical synthesis of a broad range of substituted isoxazoline cores is presented. Both aryl and more challenging alkyl aldoximes are converted to the ...desired isoxazoline in an electrochemically enabled regio‐ and diastereoselective reaction with electron‐deficient alkenes. Additionally, in‐situ reaction monitoring methods compatible with electrochemistry equipment have been developed in order to probe the reaction pathway. Supporting analyses from kinetic (time‐course) modelling and density functional theory support a stepwise, radical‐mediated mechanism, and discounts hypothesised involvement of closed shell 3+2 cycloaddition pathways.
Isoxazolines without the 3+2: An electrochemical method for the synthesis of isoxazoline cores is presented. Both aryl and more challenging alkyl aldoximes are converted to the desired isoxazoline through an electrochemically enabled regio‐ and diastereoselective reaction with electron‐deficient alkenes. Supporting analyses from kinetic (time‐course) modelling and density functional theory support a stepwise, radical‐mediated mechanism, and discount hypothesised involvement of closed‐shell 3+2 cycloaddition pathways.
The Janus family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) play an essential role in the receptor signaling of cytokines that have been implicated in the pathogenesis of severe asthma, and ...there is emerging interest in the development of small-molecule-inhaled JAK inhibitors as treatments. Here, we describe the optimization of a quinazoline series of JAK inhibitors and the results of mouse lung pharmacokinetic (PK) studies where only low concentrations of parent compound were observed. Subsequent investigations revealed that the low exposure was due to metabolism by aldehyde oxidase (AO), so we sought to identify quinazolines that were not metabolized by AO. We found that specific substituents at the quinazoline 2-position prevented AO metabolism and this was rationalized through computational docking studies in the AO binding site, but they compromised kinome selectivity. Results presented here highlight that AO metabolism is a potential issue in the lung.
A general synthetic sequence involving simply prepared starting materials provides rapid access to diverse, novel tricyclic architectures inspired by pleuromutilin. SmII‐mediated radical cyclization ...cascades of dialdehydes, prepared using a new, one‐pot, copper‐catalyzed double organomagnesium addition to β‐chlorocyclohexenone, proceed with complete sequence selectivity and typically with high diastereocontrol to give analogues of the target core. Our expedient approach (ca. 7 steps) allows non‐traditional, de novo synthetic access to analogues of the important antibacterial that can′t be prepared from the natural product by semisynthesis.
Cascade processes: A general synthetic sequence involving simply prepared starting materials provides rapid access to diverse, novel tricyclic architectures inspired by pleuromutilin. SmII‐mediated radical cyclization cascades of dialdehydes, prepared using a new, one‐pot, copper‐catalyzed double organomagnesium addition to β‐chlorocyclohexenone, provide rapid access to novel analogues of the core of the important antibacterial (see scheme).
Herein we describe a strategy for the selective, electron transfer reduction of lactones of all ring sizes and topologies using SmI(2)-H(2)O and a Lewis base to tune the redox properties of the ...complex. The current protocol permits instantaneous reduction of lactones to the corresponding diols in excellent yields, under mild reaction conditions and with useful chemoselectivity. We demonstrate the broad utility of this transformation through the reduction of complex lactones and sensitive drug-like molecules. Sequential electron transfer reactions and syntheses of deuterated diols are also described.
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