The cannabinoid receptor 1 (CB1) is an inhibitory G protein-coupled receptor abundantly expressed in the central nervous system. It has rich pharmacology and largely accounts for the recreational use of cannabis. We describe efficient asymmetric syntheses of four photoswitchable Δ-tetrahydrocannabinol derivatives (azo-THCs) from a central building block 3-Br-THC. Using electrophysiology and a FRET-based cAMP assay, two compounds are identified as potent CB1 agonists that change their effect upon illumination. As such, azo-THCs enable CB1-mediated optical control of inwardly rectifying potassium channels, as well as adenylyl cyclase.
We describe the convergent synthesis of three prototypical examples of a new class of analogues of the complex, cytotoxic marine macrolide (−)‐zampanolide that incorporate an embedded N‐substituted morpholine moiety in place of the natural tetrahydropyran ring. The final construction of the macrolactone core was based on a high‐yielding intramolecular HWE olefination, while the hemiaminal‐linked side chain was elaborated through a stereoselective, BINAL‐H‐mediated addition of (Z,E)‐sorbamide to a macrocyclic aldehyde precursor. The synthesis of the common functionalized morpholine building block involved two consecutive epoxide openings with tosylamide and the product of the first opening reaction, respectively, as nucleophiles. Of the three morpholino‐zampanolides investigated, the N‐acetyl and the N‐benzoyl derivatives both exhibited nanomolar antiproliferative activity, thus being essentially equipotent with the natural product. In contrast, the activity of the N‐tosyl derivative was significantly reduced.
Studies
are described toward the synthesis of an oxazole-based
analog of (−)-zampanolide (2). Construction of
(−)-dactylolide analog 22 was achieved via alcohol 5 and acid 4 through esterification and Horner–Wadsworth–Emmons
(HWE)-based macrocyclization; however, attempts to attach (Z,E)-sorbamide to 22 proved
unsuccessful. The C(8)–C(9) double bond of the macrocycle was
prone to migration into conjugation with the oxazole ring, which may
generally limit the usefulness of zampanolide analogs with aromatic
moieties as tetrahydropyran replacements.
The identification of the beneficial pharmacokinetic
properties
of aza-spirocycles has led to the routine incorporation of these highly
rigid and three-dimensional structures in pharmaceuticals. Herein,
we report an operationally simple synthesis of spirocyclic dihydropyridines
via an electrophile-induced dearomative semi-pinacol rearrangement
of 4-(1′-hydroxycyclobutyl)pyridines. The various points for
diversification of the spirocyclization precursors, as well as the
synthetic utility of the amine and ketone functionalities in the products,
provide the potential to rapidly assemble medicinally relevant spirocycles.
We describe the total synthesis of the macrodiolide C(13)/C(13')-bis(desmethyl)disorazole Z through double inter-/intramolecular Stille cross-coupling of a monomeric vinyl stannane/vinyl iodide precursor to form the macrocycle. The key step in the synthesis of this precursor was a stereoselective aldol reaction of a formal Evans acetate aldol product with crotonaldehyde. As demonstrated by X-ray crystallography, the binding mode of C(13)/C(13')-bis(desmethyl)disorazole Z to tubulin is virtually identical with that of the natural product disorazole Z. Likewise, C(13)/C(13')bis(desmethyl)disorazole Z inhibits tubulin assembly with at least the same potency as disorazole Z and it appears to be a more potent cell growth inhibitor.
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