Diastereoselective Approach to cis-4-Methyl/thiol-Pipecolic Esters Based on RCM Reaction and Conjugate Michael Addition

Abstract A synthetic route for the access to enantiopure cis-4-methyl/thiol-pipecolic esters is presented. It is based on the ring-closing metathesis reaction to build the α,β-unsaturated piperidin-2-one derived from (S)-(–)-phenylethylamine, followed by either diastereoselective conjugate addition of methylorganocuprate allowing access to cis-4-methyl pipecolic ester or by tandem diastereoselective hydrosulforization–thionization reaction providing access to cis-4-thiol pipecolic ethyl esters. GRAPHICAL ABSTRACT


INTRODUCTION
Cyclic a-amino acids are present in many biologically important compounds. [1] Specifically, 4-substituted pipecolic acids (4-substituted piperidine-2-carboxylic acid) and their derivatives are key fragments of compounds of pharmacological interest.
In this sense, approaches toward the synthesis of racemic or cis-trans-4-substituted mixture are known, [4] and several methodologies to the synthesis of trans-4-substituted pipecolic acids [5] and processes for the synthesis of cis-4-substituted pipecolic acid have been also disclosed. [6] In this article, we describe a diastereoselective synthetic route to cis-4-methyl= thiol pipecolic ethyl esters based on the ring-closing methathesis reaction followed by either diastereoespecific conjugate addition of methylorganocuprate or by tandem diastereospecific hydrosulforization=thionization reaction. Interestingly, the presence of the ester function located at C-6 on the piperidine ring directs the nucleophilic attack on the Michael addition reaction.

cis-4-METHYL/THIOL-PIPECOLIC ESTERS
With the a,b-unsaturated piperidin-2-one in our hands, we started to explore the conjugate addition of methylcuprate to the a,b-unsaturated lactam 7a. In this sense, Hanessian [10] reported that the conjugate addition of organocuprates to N-Boc unsaturated lactams delivers a mixture of cis and trans diastereoisomers. After testing various reaction conditions, the best result was obtained by the use of chlorotrimethylsilane (TMSCl), which accelerates copper-mediated conjugate addition reaction in THF. [11] This procedure afforded the desired 4-methyl piperidin-2-one 8a as a mayor diastereoisomer (determined direct from the 1 H NMR spectra of the crude reaction mixture), in 80% yield. The analysis of twodimensional nuclear Overhauser spectroscopy (2D-NOESY) experiments of lactam 8a indicates that both substituents are cis-oriented for the lactam ring (Scheme 3). It is worth noting that Antoni et al. [12] reported a highly diastereoselective conjugate addition of methylorganocuprate to enantiopure N-Boc pipecolic a,b-unsaturated esters; however, in this case only the trans-4-methyl pipecolic ester was obtained.
in the presence of di-tert-butyl dicarbonate to give the N-Boc-protected piperidines 10a and 10b. The comparison of its optical rotation confirmed that 10a and 10b are enantiomers and as a correlation compound 8a have the (R) configuration at C-4 (Scheme 4). We then oriented our attention to the reactivity of 7a (major diastereoisomer) toward Lawesson's reagent (LR), taking into account our previous report. [14] When compound 7a was treated with 0.5 equivalents of LR in boiling toluene, the expected unsaturated thioamide 11a was obtained in 70% yield. Interestingly, the treatment of 7a with an equimolar amount of LR gave a mixture of compound 11a and the unexpected 4-mercapto-substituted thioamide 12a as a single diastereoisomer. The use of 2 equivalents of LR resulted in exclusive formation of compound 12a in 73% yield. Finally, compound 7b showed the same behavior toward LR (Scheme 5).  Compounds 12a and 12b were crystallized and the absolute configuration at C-4 was determined by x-ray analysis diffraction as (R) for 12a and (S) for 12b, and the presence of the thiol function was also confirmed (Fig. 3). [15] To obtain the corresponding pipecolic ethyl ester, compound 12b was treated with BH 3 SMe 2 , affording the desired reduced compound 13b in 95% yield. Debenzylation of 13b was performed under Birch conditions to give the desired piperidine 14b in 43% yield (Scheme 6).
In conclusion, an efficient method for the diastereoselective synthesis of cis-4-methyl=thiol-pipecolic ethyl esters from (S)-phenylethylamine has been developed.
The stereochemical outcome showed that the conjugate addition occurs from the same side of the ester function located at C-6 on the piperidine ring. Expansion of the protocol scope and application of this methodology to the total synthesis are currently under way in our group.

General Procedure for Conjugate Michael Addition of Organocuprate
Methyl lithium (0.5 M in Et 2 O, 5 eq) was added to a suspension of CuBr SMe 2 (5 eq) in Et 2 O at À15 C. The resulting yellow suspension was stirred for 45 min at À15 C, and then 7a (0.100 g, 0.183 mmol, 1 eq) in 6 mL of Et 2 O and TMSCl (0.148 mL, 0.585 mmol, 3.2 equiv) were successively added. The mixture was warmed to 0 C and stirred for 18 h. After quenching at 0 C with saturated NH 4 Cl, a few drops of saturated NH 4 OH were added until the aqueous layer remained colorless. The organic layer was separated, dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo. The crude residue was purified by column chromatography to afford the expected product 8a as a white solid in 80% yield.
General Procedure for Thionation of a,b-Unsaturated Lactams 7a and 7b Lawesson's reagent (1.024 mmol, 2.0 eq) was added to a solution of 7a (0.140 g, 0.512 mmol, 1.0 eq) in 10 mL of dry toluene. The resulting mixture was stirred for 4 h at reflux temperature and then concentrated under reduced pressure. The residue was purified by column chromatography using 80:20 petroleum ether=AcOEt as the eluent to give the compound 12a as a white solid in 60% yield.

FUNDING
We are grateful to CONACyT (Project 154104) for financial support, and A. Z. thanks CONACyT for the postdoctoral scholarship (165517).

SUPPORTING INFORMATION
Full experimental details and 1 H and 13 C NMR spectra for this article can be accessed on the publisher's website.