We have already reported that acyclic glycols 1 generally react with oxalyl chloride in tetrahydrofuran (THF) in the presence of triethylamine at 0°C or room temperature to form the unstable cyclic oxalate 4 together with the cyclic carbonates 2: unsubstituted, monosubstituted, and erythro-1,2-disubstituted ethylene glycols produced 4 and/or the polymeric oxalates as the major products, while threo-1,2-disubstituted ethylene glycols and pinacol afforded 2 as the major products. 1)According to our proposed mechanism 1) illustrated in Chart 1, the formation of the carbonate 2a from pinacol (1a) in the presence of triethylamine is interpreted in terms of stereochemically controlled formation of the tetrahedral intermediate 6 from the initially formed s-trans intermediate 5, followed successively by deprotonation and stereoelectronically controlled cleavage (the nonbonding electron pairs contributing to bond cleavage are shown as shaded lobes) of the C-C bond through 7 and 3. The cyclic oxalate 4a can be formed only after the conformer 7 changes into 8. The almost exclusive formation of 2a from pinacol (1a) is attributable to the large rotational barrier from 7 to 8 compared with the activation energy for the decay of 7 leading to 3. If this is the case, the corresponding tetrahedral intermediate 11 from trans-1,2-cyclohexanediol (9d) should produce the carbonate 12d exclusively, because it cannot undergo ring-inversion and must go through the boat form 13 for the formation of the oxalate 14d. However, 'normal' cyclization of the s-trans intermediate 10 leading to 11 (course A) suffers from severe steric congestion as depicted as 10A. In the case of the acyclic series, this steric interaction (5A) would be avoided by bringing the conformation close to the eclipsed form 5B. If the cyclization of 10 takes place from the other side of the carbonyl plane as shown in 10B (course B), the tetrahedral intermediate 15 with a boat or twist-boat conformation is formed as a result of 'abnormal' cyclization. Once 15 is formed, the exclusive formation of the cyclic oxalate 14d is expected through 16. Thus it is of considerable interest to study the reactions of 1,2-cycloalkanediols with oxalyl chloride in the presence of triethylamine. Table 1 summarizes the results of the reactions of some selected 1,2-cycloalkanediols with 1.1-1.3 mol eq of oxalyl chloride in THF in the presence of triethylamine at 0°C for 40 min. The formation of the cyclic oxalate 14b is suggestive of the absence of the 'normal' cyclization for trans-1,2-cyclopentanediol (9b). Unfortunately, the absence of the cyclic carbonate 12b cannot be a proof against the 'normal' cy- The relationship between the product patterns and the configurations of 1,2-cycloheptane-and 1,2-cyclooctanediols 9 in the cyclocondensations with oxalyl chloride in the presence of triethylamine at 0°C has been shown analogous to that obtained for 1,2-disubstituted acyclic ethylene glycols 1: cis-1,2-cyclooctanediol (9f) produced the cyclic oxalate 14f as the major product, while trans-1,2...

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Based on the mechanism postulated for the formation of the cyclic carbonates 3 in the reactions of glycols 1 with oxalyl chloride in the presence of triethylamine, we present here three efficient syntheses of the cyclic oxalates 2 of various glycols 1 by controlling the formation of 3: replacement of the base by pyridine markedly diminishes yields of 3 in all reactions, realizing dramatic reversals of the product ratios in the reactions with the (R*,R*)-compounds 1g-i, q, r and pinacol (1k); although considerable amounts of the oxalate polymers are formed in the reactions with some (R*,S*)-glycols, this drawback can be removed by the use of 2,4,6-collidine instead of pyridine; 1,1-oxalyldiimidazole is useful for the synthesis of two selected cyclic oxalates 2e, f. The cyclic oxalates 2 other than trisubstituted and tetrasubstituted ones were found to be very reactive: kinetic studies on the hydrolysis of 1,4-dioxane-2,3-dione (2a) as well as its mono-and some selected 5,6-disubstituted derivatives 2 have revealed that they undergo hydrolysis 260-1500 times more rapidly than diethyl oxalate (12) in acetate buffer-acetonitrile (pH 5.69) at 25°C. Although the cyclic oxalate 2l from cis-1,2-cyclopentanediol (1l) was 1.5 times more reactive than 2a, it has been shown with other substrates that increasing number of the alkyl substituents decreases the rate of hydrolysis. On the contrary, the phenyl group was found to have somewhat accelerative effect.

Drug design using boron‐containing heterocycles has attracted a great deal of attention because these compounds are believed to possess high biological activity. However, information on the synthetic methodology and pharmacokinetic profiling of boron‐containing compounds is limited. In this study, we provide a new synthetic route for preparation of spiro‐fused benzoxaborin derivatives and investigate their in vitro pharmacokinetic properties. Our efforts led to the successful construction of a chemical library of spiro‐fused benzoxaborin derivatives with appropriate physicochemical and in vitro pharmacokinetic properties for oral drugs. These results indicate that the synthesized boron‐containing compounds are therefore eligible for classification in a novel chemical library.

As pupil size is affected by psychotropic drugs in all mammals, it has been used as a well-established clinical indicator for the preclinical and clinical development of novel drugs. It has been reported that activation of the serotonin (5-HT)1A receptor differently affects pupil response in rodents (mydriasis) and humans (miosis). Thus, it is important to establish a quantitative system for measuring pupil size using other species, such as nonhuman primates. Common marmosets have recently attracted a great deal of attention as suitable experimental animals in the psychoneurological field because of handling ease compared with other nonhuman primates and the requirement for small amounts of test drugs. In this study, we constructed a system for measuring changes in pupil size using an infrared eye-tracking camera and evaluated the effects on pupil size of the 5-HT1A receptor agonists buspirone, 8-OH-DPAT and buspirone active metabolite 1-(2-pyrimidinyl) piperazine. Our results show that both buspirone and 8-OH-DPAT significantly decrease pupil size in a dose-dependent manner. The 5-HT1A receptor antagonist WAY 100635 completely blocked both buspirone and 8-OH-DPAT-induced miosis, whereas 1-(2-pyrimidinyl) piperazine had no effect on pupil size. These results suggest that measurement of pupil size may be a useful biomarker for predicting the pharmacodynamics of new 5-HT1A receptor agonists.

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