Stereoselective synthesis of (S)-dapoxetine: a chiral auxiliary mediated approach

Enantiopure 4‐oxazolin‐2‐ones and 4‐methylene‐2‐oxazolidinones as chiral building blocks in a divergent asymmetric synthesis of heterocycles

“…The solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (30 g/g of crude, hexane/EtOAc, 9:1) to afford a mixture of 1a (0.135 g, 55%) as an amber oil and 2a (16) [M + 1] + , 114 (22), 106 (100), 105 (38), 80 (32), 78 (18 2.2.3 | (4R,5R)-4-Hydroxy-4,5-dimethyl-3-((S)-1-phenylethyl)oxazolidin-2-one (12) and (4R,5S)-4-hydroxy-4,5-dimethyl-3-((S)-1phenylethyl)oxazolidinone (13) A mixture of 3a (0.880 g, 0.01 mol) and 4b (1.470 g, 0.01 mol) was placed in a threaded ACE glass pressure tube with a sealed Teflon screw cap under N 2 atmosphere. It was stirred and irradiated with MW (200 W) at 120°C for 90 minutes.…”

“…Therefore, it may be attractive to integrate the tetrasubstituted heterocyclic double bond of the 4-oxazolin-2-one heterocycle within a sixmembered ring and explore its reactivity with Michael acceptors (eg, 8a). Accordingly, enantiopure tetrahydrobenzo[d]oxazol-2(3H)-ones 39a-b were prepared by reacting adipoin (38) with chiral isocyanates 4a-b under solvent free conditions in quantitative yields (Scheme 9).…”

“…The stereoselectivity estimated from the theoretical calculations matches the experimental dr very closely. It has been reported that the chiral α-phenylethyl auxiliary is readily removed by hydrogenolysis after acting as a valuable inductor for asymmetric synthesis [36][37][38][39][40][41][42][43]71 Hence, it is expected that such auxiliary can be removed in a like manner for most of the products obtained in the current study without affecting their functionalities. Experimental studies are being carried out to test this idea, and the results will be reported in due course.…”

“…34,35 Among the chiral auxiliaries used in asymmetric synthesis, those based on the 1-phenylethylamino group-containing scaffolds proved to be very efficient in many diastereoselective processes. [36][37][38][39][40][41][42][43] On the basis of the previously developed regioselective synthesis of N-substituted 4-oxazolin-2-ones 1 and 4-methylene-2-oxazolidinones 2, resulting from the condensation of α-ketol 3a and isocyanates 4 (Scheme 1), 44,45 in a preliminary report, we presented the one-pot synthesis of the optically pure version of heterocycles 1-2 by introducing the N-(S)-methylbenzyl moiety as the chiral auxiliary. 46 Although this methodology was also efficient for the preparation of the corresponding 3-substituted 4-oxazolin-2-thiones 6 and 4methylene-1,3-oxazolidin-2-thiones 7, 47 these heterocycles were not able to undergo further reactions when utilizing the thioenamide functionality as a nucleophile.…”

A novel and practical asymmetric synthesis of dapoxetine hydrochloride

“…However, only a few methods have been reported for the synthesis of enantiopure dapoxetine hydrochloride. The earlier methods included chiral/enzymatic resolution [ 5 ], whereas the newer approaches encompass asymmetric dihydroxylation of trans -methyl cinnamate or cinnamyl alcohol [ 6 ], chiral azetidin-2,3-dione [ 7 ], asymmetric C–H amination reactions of a prochiral sulfamate [ 8 ], oxazaborolidine reduction of 3-chloropropiophenone or ketone [ 9 ], and an imidazolidin-2-one chiral auxiliary mediated acetate aldol reaction [ 10 ]. However, these methods are undermined by poor yield, low enantioselectivity, and complex synthetic procedure.…”