A wide range of halogenated bicyclo[1.1.1]pentanes are accessed by functional group tolerant radical ring-opening of tricyclo[1.1.1.01,3]pentane, using triethylborane as initiator.
Photoredox catalysis has transformed the landscape of radical-based synthetic chemistry. Additions of radicals generated through photoredox catalysis to carbon−carbon πbonds are well-established; however, this approach has yet to be applied to the functionalization of carbon−carbon σ-bonds. Here, we report the first such use of photoredox catalysis to promote the addition of organic halides to the carbocycle [1.1.1]propellane; the product bicyclo[1.1.1]pentanes (BCPs) are motifs of high importance in the pharmaceutical industry and in materials chemistry. Showing broad substrate scope and functional group tolerance, this methodology results in the first examples of bicyclopentylation of sp 2 carbon−halogen bonds to access (hetero)arylated BCPs, as well as the functionalization of nonstabilized sp 3 radicals. Substrates containing alkene acceptors allow the single-step construction of polycyclic bicyclopentane products through unprecedented atom transfer radical cyclization cascades, while the potential to accelerate drug discovery is demonstrated through late-stage bicyclopentylations of natural productlike and druglike molecules. Mechanistic investigations demonstrate the importance of the photocatalyst in this chemistry and provide insight into the balance of radical stability and strain relief in the reaction cycle.
A flexible, modular ynamide synthesis is reported that uses trichloroethene as an inexpensive two carbon synthon. A wide range of amides and electrophiles can be converted to the corresponding ynamides, importantly including acyclic carbamates, hindered amides, and aryl amides. This method thus overcomes many of the limitations of other approaches to this useful functionality.
The first synthetic route to yndiamides,anovel class of double aza-substituted alkyne,h as been established by the copper(I)-catalyzed cross-coupling of 1,1-dibromoenamides with nitrogen nucleophiles.T he utility of these compounds is demonstrated in ar ange of transition-metal-catalyzed and acid-catalyzed transformations to affordawide variety of 1,2diamide functionalized products.
Bicyclo[1.1.1]pentanes (BCPs), useful surrogates for para-substituted arenes, alkynes and tert-butyl groups in medicinal chemistry, are challenging to prepare when featuring stereogenic centres adjacent to the BCP. We report the development of an efficient route to α-chiral BCPs, via highly diastereoselective asymmetric enolate functionalization. We also describe the application of this chemistry to the synthesis of BCP analogues of phenylglycine and tarenflurbil, the single enantiomer of the NSAID flurbiprofen.
ASSOCIATED CONTENT Supporting InformationExperimental procedures, copies of 1 H and 13 C NMR spectra (pdf), CIF. This material is available free of charge via the Internet at http://pubs.acs.org.
Yndiamides, underexplored cousins
of ynamides, offer rich synthetic
potential as doubly nitrogenated two carbon building blocks. Here
we report a gold-catalyzed oxidative functionalization of yndiamides
to access unnatural amino acid derivatives, using a wide range of
nucleophiles as a source of the amino acid side chain. The transformation
proceeds under mild conditions, is highly functional group tolerant,
and displays excellent regioselectivity through subtle steric differentiation
of the yndiamide nitrogen atom substituents.
A highly convergent strategy for the synthesis of the natural product (−)‐rubriflordilactone B, and the proposed structure of (−)‐pseudo‐rubriflordilactone B, is described. Late stage coupling of diynes containing the respective natural product FG rings with a common AB ring aldehyde precedes rhodium‐catalyzed [2+2+2] alkyne cyclotrimerization to form the natural product skeleton, with the syntheses completed in just one further operation. This work resolves the uncertainty surrounding the identity of pseudo‐rubriflordilactone B and provides a robust platform for further synthetic and biological investigations.
Ynamides are accessed via copper-catalyzed coupling of Grignard or organozinc nucleophiles with chloroynamides, formed in situ from 1,2-dichloroenamides. The reaction exhibits broad substrate scope, is readily scaled, and overcomes typical limitations in ynamide synthesis such as the use of ureas, carbamates, and bulky or aromatic amide derivatives. This modular approach contrasts with previous routes by installing both the N-and C-substituents of the ynamide as nucleophilic components.
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