Studies of the Enantiocontrolled Synthesis of the C(10)-C(25) Subunit of Amphidinolide C.

A stereocontrolled synthesis of 28, the C(10)-C(25) component of amphidinolide C (1), has been efficiently achieved. Reaction of the dithiane component 21 with nonracemic bis(epoxide) 19 directly affords functionalized 2,5-trans-disubstituted tetrahydrofuran 22. Propargylation is highly diastereoselective for the formation of the desired C(12)-C(13) anti stereochemistry, and the resulting terminal alkyne 25 is utilized for a regioselective syn-silylstannylation. A general strategy is illustrated for sequential replacement of stannyl and silyl substituents of the trisubstituted alkene to yield (E)-alkenyl iodide 28.

Structure-activity relationship studies of novel 3-oxazolidinedione-6-naphthyl-2-pyridinones as potent and orally bioavailable EP3 receptor antagonists.

Multiple regions of the 3-oxazolidinedione-6-naphthyl-pyridinone series identified via high throughput screening were explored. SAR studies of these regions including the left-hand side oxazolidinedione moiety, α-substituent on the oxazolidinedione ring, central pyridinone core, and substituents on the central pyridinone core led to the discovery of potent EP(3) receptor antagonists such as compound 29 which possesses outstanding rat pharmacokinetic properties. Synthesis and SAR of these novel compounds and DMPK properties of representative compounds are discussed.

Novel 3-Oxazolidinedione-6-aryl-pyridinones as Potent, Selective, and Orally Active EP3 Receptor Antagonists.

High-throughput screening and subsequent optimization led to the discovery of novel 3-oxazolidinedione-6-aryl-pyridinones exemplified by compound 2 as potent and selective EP3 antagonists with excellent pharmacokinetic properties. Compound 2 was orally active and showed robust in vivo activities in overactive bladder models. To address potential bioactivation liabilities of compound 2, further optimization resulted in compounds 9 and 10, which maintained excellent potency, selectivity, and pharmacokinetic properties and showed no bioactivation liability in glutathione trapping studies. These highly potent, selective, and orally active EP3 antagonists are excellent tool compounds for investigating and validating potential therapeutic benefits from selectively inhibiting the EP3 receptor.

Tetrahydro-4-quinolinamines identified as novel P2Y(1) receptor antagonists.

High-throughput screening of the GSK compound collection against the P2Y(1) receptor identified a novel series of tetrahydro-4-quinolinamine antagonists. Optimal substitution around the piperidine group was pivotal for ensuring activity. An exemplar analog from this series was shown to inhibit platelet aggregation.

Reactivity studies of 3,3-bis(trimethylsilyl)-2-methyl-1-propene in Lewis acid-catalyzed allylation reactions.

Allylation reagents, which possess geminal bis-trimethylsilyl substitution, are readily prepared from E- or Z-alkenyl bromides. The reactivity of 3,3-bis(trimethylsilyl)-2-methyl-1-propene (1) is described and predominantly provides ene reactions with aldehydes to give alcohol 2 in the presence of BF3.OEt2. Alternatively, Sakurai allylation reactions of 1 are observed by using stronger Lewis acids in methylene chloride to exclusively yield E-trisubstituted alkenylsilanes 3.

Solid-phase synthesis and configurational reassigment of callipeltin E. Implications for the structures of callipeltins A and B.

Two possible isomers of the natural product callipeltin E (1, 5) were synthesized by using an Fmoc-based solid-phase strategy in 7 steps, in 20% and 26% overall yields, respectively. The (1)H NMR spectrum of synthetic 5 correlated closely with that of the natural product, whereas that of 1 did not, providing confirmation of the configurational reassignment of the N-terminal residue of callipeltin E as D-allothreonine. This result strongly implies that the corresponding residue in the closely related cyclic depsipeptides callipeltins A and B should also be considered a D-allothreonine residue.

Solid-phase synthesis of callipeltin D. Stereochemical confirmation of the unnatural amino acid AGDHE.

[structure: see text] The lipopeptide callipeltin D (1) was synthesized using an Fmoc-based solid-phase strategy in seven steps and 35% overall yield. The 1H NMR of synthetic 1 correlated closely with that of the natural product, confirming the configurational assignment of the novel amino acid constituent (2R,3R,4S)-4-amino-7-guanidino-2,3-dihydroxyheptanoic acid.

Synthesis of the unnatural amino acid AGDHE, a constituent of the cyclic depsipeptides callipeltins A and D.

[reaction: see text] The novel amino acid residue (2R,3R,4S)-4-amido-7-guanidino-2,3-dihydroxyheptanoic acid (AGDHE, 3), a constituent of the cyclic depsipeptides callipeltins A and D, and its (2S,3S,4S) diastereomer were synthesized from a protected L-ornithine derivative in 13 steps (15% overall yield), and its configurational assignment was reexamined by (1)H NMR.