We report here a mechanistically distinct tactic to carry E2-type eliminations on alkyl halides. This strategy exploits the interplay of α-aminoalkyl radical-mediated halogen-atom transfer (XAT) with desaturative cobalt catalysis. The methodology is highyielding, tolerates many functionalities, and was used to access industrially relevant materials. In contrast to thermal E2 eliminations where unsymmetrical substrates give regioisomeric mixtures, this approach enables, by fine-tuning of the electronic and steric properties of the cobalt catalyst, to obtain high olefin positional selectivity. This unprecedented mechanistic feature has allowed access to contra-thermodynamic olefins, elusive by E2 eliminations.
The aryloxy triester phosphoramidate prodrug approach has been used with success in drug discovery. Herein, we describe the first application of this prodrug technology to the monophosphate derivative of the phosphoantigen HMBPP and one of its analogues. Some of these prodrugs exhibited specific and potent activation of Vγ9/Vδ2 T-cells, which were then able to lyse bladder cancer cells in vitro. This work highlights the promise of this prodrug technology in the discovery of novel immunotherapeutics.
Diamine-mediated
α-deprotonation of O-alkyl
carbamates or benzoates with alkyllithium reagents, trapping of the
carbanion with organoboron compounds, and 1,2-metalate rearrangement
of the resulting boronate complex are the primary steps by which organoboron
compounds can be stereoselectively homologated. Although the final
step can be easily monitored by 11B NMR spectroscopy, the
first two steps, which are typically carried out at cryogenic temperatures,
are less well understood owing to the requirement for specialized
analytical techniques. Investigation of these steps by in situ IR
spectroscopy has provided invaluable data for optimizing the homologation
reactions of organoboron compounds. Although the deprotonation of
benzoates in noncoordinating solvents is faster than that in ethereal
solvents, the deprotonation of carbamates shows the opposite trend,
a difference that has its origin in the propensity of carbamates to
form inactive parasitic complexes with the diamine-ligated alkyllithium
reagent. Borylation of bulky diamine-ligated lithiated species in
toluene is extremely slow, owing to the requirement for initial complexation
of the oxygen atoms of the diol ligand on boron with the lithium ion
prior to boron–lithium exchange. However, ethereal solvent,
or very small amounts of THF, facilitate precomplexation through initial
displacement of the bulky diamines coordinated to the lithium ion.
Comparison of the carbonyl stretching frequencies of boronates derived
from pinacol boronic esters with those derived from trialkylboranes
suggests that the displaced lithium ion is residing on the pinacol
oxygen atoms and the benzoate/carbamate carbonyl group, respectively,
explaining, at least in part, the faster 1,2-metalate rearrangements
of boronates derived from the trialkylboranes.
Robust synthetic methods which show broad substrate scope are of great utility in the synthesis of complex organic molecules. Within this arena, synthetic methods employing boronic esters are especially useful since they undergo a wide variety of transformations with very high levels of stereoselectivity. In particular, boronic esters can undergo single or multiple homologations using enantioenriched metal carbenoids. The addition of a suitable enantioenriched lithium or magnesium carbenoid to a boronic ester, with subsequent 1,2-migration, gives a homologated boronic ester with high stereocontrol. The process, termed lithiation-borylation, can be iterated allowing a carbon chain to be "grown" one atom at time with remarkable precision. The iterative homologation has been likened to a molecular assembly line and resembles the way nature assembles natural products, e.g. in polyketide synthase machinery. The application of lithiation-borylation chemistry to the synthesis of a broad variety of natural products is discussed in this Review.
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