With the rapid development and complex challenges of chemical substances, new drug synthesis pathways are usually the most effective.185815-59-2,4-Isobutyldihydro-2H-pyran-2,6(3H)-dione,as a common compound, the synthetic route is as follows.
Preliminary experiments related to the acylative KR of the racemic sec-thiol 1 with glutaric anhydride (2a) in the presence of bifunctional (thio)urea-derived organocatalysts 10-12 and sulphonamide 13 (Table 1 ). Initial results were far from encouraging – acylation proceeded smoothly at low catalyst loading (5 mol%), but resulted in products of low enantiomeric excess (entries 1 -4). Of the four catalysts tested sulphonamide 13 proved superior to the (thio)urea- derivatives and could promote the KR with a very modest selectivity (kfast/kS|0W) of 1.5 (13% ee at 50% conv., entry 4). Further experimentation identified methyl ie f-butylether (MTBE) as the optimal solvent overall, although the KR of 1 was slower but more selective in THF (entries 4-7).[0061] These results represented the first examples of direct catalytic asymmetric KR of a thiol. Subsequently, KR reactions using 3-substituted achiral anhydride electrophiles 3a-5 were tried. This complicated matters considerably, as now control over the formation of 4 possible thioester diastereomers is required. In addition, it allowed for the possibility of a conceptually novel type of catalytic process where both kinetic resolution and anhydride desymmetrisation occur simultaneously. Gratifyingly, this proved to be the case – use of anhydrides 3a-5 resulted in more enantioselective acylations (entries 8-1 1 ), with methyl glutaric anhydride (3a) proving optimal. Using this electrophile the resolved thiol could be isolated in 33% ee at 50% conversion (using either 1 or 5 mol% of catalyst 13), corresponding to S = 2.7.[0062] Product esters 7a and 7b were both formed with excellent enantioselectivity (>90% ee) and with encouraging diastereocontrol (67:33 dr, entry 8). With respect to the anhydride, the desymmetrisation aspect of the reaction was highly selective – the parameter eedesymm (Table 1 ) represents the percentage excess of products derived from attack of the thiol 1 at one prochiral anhydride carbonyl moiety over the other (i.e. the enantiomeric excess of the desymmetrised product if the combined thioester diastereomers were substituted by an achiral (non-hydroxide) nucleophile without racemisation). It is also noteworthy that in the presence of triethylamine as an achiral catalyst the diastereoselectivity is reversed, with 19 as the major diastereomer.[0063] Next the steric and electronic characteristics of the catalyst were systematically varied through the synthesis and evaluation of sulfonamides 14-17. While the electron deficient pentafluorophenyl-substituted catalyst fared a little better than 13, less acidic analogues 15-17 respectively possessed enhanced selectivity profiles (entries 12-15). Given the superiority of the hindered promoter 16, it was decided to accentuate the steric bulk of the sulfonamide further via the synthesis of the novel catalyst 18, which proved almost as active as 13 yet promoted the acylation with a synthetically useful KR selectivity of 8.5 (entry 16). Further optimisation of the reaction conditions (entries 17-19) resulted in the KR of thiol 1 with outstanding selectivity (S = 25.5) – allowing the isolation of resolved (f?)-1 in 90% ee at 54% conversion, along with ester 7a (formed as the major diastereomer, 89:11 dr) in 98% ee, with an excellent attendant eedesymm of 96% (entry 19).; [0064] Thus, under optimum conditions 18 is capable of mediating the highly efficient and selective KR of a substrate class previously outside the orbit of direct enantioselective catalytic acylation, with the simultaneous desymmetrisation of a synthetically useful class of inexpensive achiral anhydride acylating agent – also with excellent enantioselectivity. To demonstrate that the desymmetrisation and kinetic resolution processes are synergistic, we next carried out the process under optimum conditions using the non-prochiral anhydrides 2a, 2b and 3b (entries 20-22). Kinetic resolution was either too slow or proceeded with lower enantioselectivity using these electrophiles.[0065] Attention now turned to the question of substrate scope (Table 2). It was found that variation of the steric bulk of both the aromatic and aliphatic substituent is well tolerated by the catalyst – for example, a-Me, -Et, -‘Pr and -fBu derivatives of benzyl mercaptan (i.e. 1 and 20- 22, entries 1 -4) could be resolved with excellent selectivity (up to S > 50), resulting in the isolation of the unreacted thiol with >90% ee at ca. 50% conversion. A strong correlation between increasing aliphatic substituent bulk and selectivity was observed; however it is noteworthy that even the challenging substrate 20 (where the steric discrepancy between the two carbon-based substituents is smallest) could be resolved with synthetically useful selectivity. Variation of the characteristics of the aromatic substituent produced interesting results – substitution in the para-position either slightly reduces or has no impact onenantioselectivity (23-25, entries 5-7), while steri…
185815-59-2, 185815-59-2 4-Isobutyldihydro-2H-pyran-2,6(3H)-dione 11480690, aTetrahydropyrans compound, is more and more widely used in various.
Reference£º
Patent; THE PROVOST, FELLOWS AND SCHOLARS OF THE COLLEGE OF THE HOLY AND UNDIVIDED TRINITY OF QUEEN ELIZABETH, NEAR DUBLIN; CONNON, Stephen Joseph; PESCHIULLI, Aldo; PROCURANTI, Barbara; WO2011/70028; (2011); A1;,
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