In the synthesis of (2R,2¢R)-threo-(+)-methylphenidate, a ring-closing metathesis approach was adopted to construct the piperidine ring, while Sharpless asymmetric epoxidation was used for the efficient generation of two contiguous stereocenters.Key words: (2R,2¢R)-threo-(+)-methylphenidate, ritalin, attention deficit hyperactivity disorder (ADHD), cis-allylic alcohol, Sharpless asymmetric epoxidation, bisolefin, ring-closing metathesis (RCM) (±)-threo-Methylphenidate hydrochloride, commonly called ritalin on the market, is used mainly for the treatment of attention deficit hyperactivity disorder (ADHD) in children in the USA. 2 This medication is also used to treat patients with Narcolepsy (or disorder of sleep regulation). Methylphenidate is a mild stimulant that works by affecting the levels of neurotransmitters in the nervous system. It has been marketed as racemate although the (2R,2¢R)-threo-(+)-methylphenidate hydrochloride (1) is ca. 13 times more active than the corresponding (2S,2¢S)-threo-(-)-methylphenidate hydrochloride. 3 Various synthetic approaches for the preparation of the active isomer have been reported including resolution, 4 catalyst-mediated synthesis 5 and few stereoselective syntheses. 6 Amongst the reported syntheses, the enantioselective synthesis by Winkler et al. 5a using Doyle's rhodium-catalyzed C-H insertion reaction is the shortest. A recent review encompassing all the previous syntheses is worth noting. 5b Recently we have introduced chiral 2,3-epoxy aldehydes as electrophiles in the diastereoselective Baylis-Hillman reaction 7 and in the Passerini reaction. 8 In continuation of our interest in the use of chiral epoxides, herein we have invoked Sharpless asymmetric epoxidation for generating two contiguous stereocenters and Grubbs' ring-closing metathesis protocol as the key steps towards the total synthesis of methylphenidate 1 (Scheme 1).Accordingly, chiral piperidine present in 1 was built through the ring-closing metathesis of bisolefin 2. The amino functional group was introduced by S N 2 mode of the diol which in turn was obtained by the regioselective ring-opening reaction of epoxide 3 by Ph 2 CuLi. The appropriate stereoselective epoxide 3 was efficiently prepared from Sharpless asymmetric epoxidation of allylic alcohol obtained by the selective reduction of allylated propargyl alcohol, which in turn could be prepared from the commercially available propargyl alcohol (4).Scheme 2 Reagents and conditions: (a) allyl bromide, CuI, TBAI, K 2 CO 3 , DMF, r.t., 85%; (b) Ni(OAc) 2 ·4H 2 O, ethylenediamine, NaBH 4 , H 2 atmosphere, EtOH, r.t., 90%; (c) (-)-DIPT, Ti(Oi-Pr) 4 , cumene hydroperoxide, CH 2 Cl 2 , -20 °C, 83%; (d) (i) PhLi, CuI, Et 2 O, -40 °C to 0 °C; (ii) NaIO 4 , MeOH, 73% over two steps.Thus, propargylic alcohol (4; Scheme 2), upon coupling with allyl bromide in the presence of CuI-K 2 CO 3 -tetrabutylammonium iodide (TBAI) in DMF at room temperature, gave 5 in 85% yield. 9 The triple bond present in 5 was partially reduced in the presence of nickel acetate and ...