An enantioselective Brønsted acid-catalyzed N-acyliminium cyclization cascade of tryptamines with enol lactones to form architecturally complex heterocycles in high enantiomeric excess has been developed. The reaction is technically simple to perform as well as atom-efficient and may be coupled to a gold(I)-catalyzed cycloisomerization of alkynoic acids whereby the key enol lactone reaction partner is generated in situ. Employing up to 10 mol % bulky chiral phosphoric acid catalysts in boiling toluene allowed the product materials to be generated in good overall yields (63-99%) and high enantioselectivities (72-99% ee). With doubly substituted enol lactones, high diastereo- and enantioselectivities were obtained, thus providing a new example of a dynamic kinetic asymmetric cyclization reaction.
The first enantioselective synthesis of (-)-himalensine A has been achieved in 22 steps. The synthesis was enabled by a novel catalytic, enantioselective prototropic shift/furan Diels-Alder (IMDAF) cascade to construct the ACD tricyclic core. A reductive radical cyclization cascade was utilized to build the B ring, and end-game manipulations featuring a molecular oxygen mediated γ-CH oxidation, a Stetter cyclization to access the pendant cyclopentenone, and a highly chemoselective lactam reduction delivered the natural product target.
Following notable cases of remarkable potency increases in methylated analogues of lead compounds, this review documents the state-of-the-art in C–H methylation technology.
The bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone-fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure-based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity-building nitro-Mannich/lactamization cascade processes allowed for early structure–activity relationship studies whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine secretion.
Many biologically active macrocycles contain a C–C double bond through which various other derivatives are prepared; the stereochemical identity of the alkene or the resulting moieties can be critical to the beneficial properties of such molecules. Catalytic ring-closing metathesis (RCM) is a widely employed method for the synthesis of large unsaturated rings;1,2 however, cyclizations often proceed without control of alkene stereochemistry.2 Such shortcoming is particularly costly with complex molecules when cyclization is performed after a long sequence of transformations.2 Here, we outline a reliable, practical and general approach for efficient and highly stereoselective synthesis of macrocyclic alkenes by catalytic RCM; transformations deliver up to 97% Z selectivity due to control induced by a tungsten-based alkylidene. Utility is demonstrated by stereoselective preparation of anti-cancer epothilone C [Ref. 3–5] and anti-microbial nakadomarin A [Ref. 6], previously reported syntheses of which have been marred by late-stage non-selective RCM.7–15 The tungsten alkylidene can be manipulated in air, promoting reactions carried out in a fume hood to deliver products in useful yields and high Z selectivity. As a result of efficient RCM and re-incorporation of side products into the catalytic cycle with minimal alkene isomerization, desired cyclizations proceed in preference to alternative pathways even under relatively high concentration (0.1 molar).
A new class of readily accessible chiral amino-phosphine precatalysts derived from 9-amino(9-deoxy) epicinchona alkaloids has been developed. In combination with Ag(I) salts, these amino-phosphines performed as effective cooperative Brønsted base/Lewis acid catalysts in the asymmetric aldol reaction of isocyanoacetate nucleophiles. Under optimal conditions, high diastereoselectivities (up to 98%) and enantioselectivities (up to 98%) were obtained.
A family of 9-amino(9-deoxy) epicinchonine derivatives, possessing a range of mono- and bidentate hydrogen bond donor groups at the 9-position, were synthesised and evaluated for asymmetric organocatalytic activity in the dimethyl malonate Michael addition to beta-nitrostyrene; thiourea derivative was identified as the most effective bifunctional organic catalyst and found to induce high enantioselectivity in the malonate ester Michael addition reaction to a range of nitro olefins.
The construction
and manipulation of amine-containing architectures
is of importance to academic and industrial development and discovery
programs. The photochemical single-electron reduction of imine derivatives
to generate α-amino radical intermediates has emerged as a powerful
umpolung strategy for opening up underexplored routes to such amine
motifs. Furthermore, these radicals have been shown to engage in a
wide variety of chemistry, including radical–radical coupling,
addition to electrophiles, and reductive amination chemistry. The
concept has also begun to see application to iminium ion intermediates
and the extension to enantiocontrolled C–C bond formation.
This Perspective covers recent efforts in this synthetic strategy
to simple and complex amine structures alike.
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