Medium-Sized Carbocycles and Ethers from 4-Pyrones: A Photocyclization− Fragmentation Approach¹

Medium-Sized Carbocycles and Ethers from 4-Pyrones:  A Photocyclization− Fragmentation Approach1</sup

Synthesis of Bridged Bicyclic Ethers and Fused Oxetanes from Pyran-4-ones via Tandem Solvent Trapping and Norrish Type II Cyclization¹

Polyalkyl pyran-4-ones 1a−c were irradiated in methanol or ethanol. Although the expected solvent trapping products 3 could be observed, extended irradiation times allowed exclusive formation of secondary photoproducts 4 and 5 in combined yields of 37−64%. These bicyclic compounds are believed to arise from γ-hydrogen abstraction by the excited enone chromophore of 3, followed by closure of the resulting biradical through one of two possible pathways. Moderate stereoselectivity was observed in the radical coupling to produce 4, whereas the analogous closure to 5 was completely diastereoselective. Tautomerization of the enol precursors to 5 also occurred with complete selectivity for protonation from the exo face. Overall, this process converts simple, planar heterocycles and alkanols into complex products in a single transformation

Cyclopentene Synthesis from 1,3-Dienes via Base-Induced Ring Contraction of 3,6-Dihydro-2<i>H</i>-thiopyrans: Studies on Diastereoselection and Mechanism

An investigation of the scope and mechanism of a new synthesis of cyclopentenes from 3,6-dihydro-2H-thiopyrans is described. Alkyl halides substituted with an electron-withdrawing group in the α-position were reacted with sodium thiosulfate, yielding the corresponding Bunte salts, which could be transformed to reactive thiocarbonyl compounds by elimination of the elements of bisulfite with mild base treatment. In situ trapping by 1,3-dienes afforded in good yields a variety of 3,6-dihydro-2H-thiopyrans substituted with electron-withdrawing groups at the 2-position. Exposure of these cycloadducts to strong base at low temperature effected a novel ring contraction, affording 2-(methylthio)-3-cyclopentenes after quenching with methyl iodide. The level of diastereoselectivity exhibited during the generation of these cyclopentenes was found to be dependent on the nature of the electron-withdrawing group at the 2-position of the dihydrothiopyran as well as the substitution pattern originally present in the diene component. In some cases, reducing the temperature during the ring contraction resulted in the isolation of good yields of vinyl cyclopropanes of high isomeric purity. With one substrate, highly diastereoselective rearrangement of a vinyl cyclopropane to a cyclopentene was unambiguously demonstrated, suggesting that this might be a key feature of the overall ring contraction mechanism

Synthesis and Biological Activity of Aminoguanidine and Diaminoguanidine Analogues of the Antidiabetic/Antiobesity Agent 3-Guanidinopropionic Acid

3-Guanidinopropionic acid (1) has been demonstrated both to improve insulin sensitivity and to promote weight loss selectively from adipose tissue in animal models of non-insulin-dependent diabetes mellitus (NIDDM). However, 1 has also been shown to be a substrate for both the creatine transporter and creatine kinase, leading to marked accumulation in muscle tissue as the corresponding N-phosphate. The corresponding aminoguanidine analogue 2 was recently discovered to retain the antidiabetic activity of 1 while being markedly less susceptible to creatine-like metabolism, suggesting that it should have less potential to accumulate in muscle. Further structural modification of 2 was undertaken to investigate whether the antidiabetic potency could be augmented while maintaining resistance to creatine-like metabolism. Modifications such as α-alkylation, homologation, and bioisosteric replacement of the aminoguanidine all were detrimental to antidiabetic activity. However, the simple regioisomeric aminoguanidinoacetic acid 9 and diaminoguanidinoacetic acid analogue 7 were found to be equipotent to 2, leading eventually to the discovery of the significantly more potent diaminoguanidinoacetic acid regioisomers 52 and 53. Further attempts to modify the more active template represented by 52 led only to reductions in antidiabetic activity. Each of the new active analogues displayed the same resistance to creatine-like metabolism as 2. Further testing of 7, 9, and 53 in obese diabetic ob/ob mice confirmed that weight loss is induced selectively from adipose tissue, similar to the lead 1. Administration of 53 to insulin-resistant rhesus monkeys led to reductions in both fasting and post-prandial plasma glucose levels with concomitant reductions in plasma insulin levels, suggesting that the compound improved the action of endogenous insulin. Compounds 7 and 53 were selected for further preclinical development