A Concise Stereoselective Total Synthesis of (2R,2′R)-threo-(+)-Methyl­phenidate via a Ring-Closing Metathesis Protocol

Abstract

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 ...

Enantioselective Total Synthesis of (+)‐Ophiobolin A

“…Preparation of compounds 4 a and 4 b : Compounds 4 a and 4 b were thought to be obtained by oxidation of the corresponding bromohydrins ( 24 a and 24 b ), which would be prepared from alkene 23 in a regioselective manner (Scheme ). Alkene 23 was obtained from known compound 20 17 through a regioselective epoxide‐opening reaction with vinylmagnesium bromide and subsequent RCM.…”

Asymmetric Domino Reactions Based on the Use of Chiral Substrates

“…141 Later, the same authors investigated the use of chiral 2,3-epoxy aldehydes as chiral auxiliaries in the Passerini reaction with TosMIC and carboxylic acids as the two other components. 184 As shown in Scheme 1.110, the corresponding densely substituted products were achieved in moderate to good yields and lower diastereoselectivities (40-86% de) than those obtained by using carbohydrate-derived aldehydes. The best results were obtained through double asymmetric induction using a chiral epoxide in combination with chiral …”

Synthetic Applications of Chiral Unsaturated Epoxy Alcohols Prepared by Sharpless Asymmetric Epoxidation

“…As mentioned above, the most useful reactivity of the terminal alkenes of the epoxy alcohol’s side chain is in olefinic metatheses. Krishna et al [ 45 ], in their synthesis of threo -(+)-methylphenidate hydrochloride, treated the epoxy alcohol (2 R ,3 S )-11 (from Z -hexa-2,5-dien-1-ol) with lithium diphenylcuprate to give a 9:1 mixture of C2/C3 regioisomers ( Scheme 16 ). Once they obtained the desired diol 100 , they protected the primary alcohol and substituted the secondary alcohol with azide to prepare the vinylic azide 101 .…”

“… Enantioselective synthesis of threo -(+)-methylphenidate hydrochloride ( 104 ) (Krishna et al [ 45 ]). …”