Enantiocontrolled Synthesis of 2,6-Disubstituted Piperidines by Desymmetrization of meso-η-(3,4,5)-Dihydropyridinylmolybdenum Complexes. Application to the Total Synthesis of (−)-Dihydropinidine and (−)-Andrachcinidine

Abstract

A conceptually new approach to the enantiocontrolled synthesis of 2,6-disubstituted piperidines was achieved by desymmetrization of meso-2,6-dimethoxy-eta-(3,4,5)-dihydropyridinylmolybdenum complexes. After protection of the piperidine nitrogen as a urethane derived from (+)- or (-)-trans-2-(alpha-cumyl)cyclohexyl (TCC), a sequential, one-pot methoxide abstraction/nucleophilic addition/methoxide abstraction/nucleophilic addition generated good yields of 2,6-disubstituted-eta-(3,4,5)-dihydropyridinylmolybdenum complexes. This sequence proceeds by way of a highly diastereoselective methoxide abstraction (>40:1). High yielding protodemetalation and N-deprotection provided a simple and enantiocontrolled synthetic entry to a variety of 2,6-disubstituted piperidines. This new method was used for the total synthesis of (-)-dihydropinidine and (-)-andrachcinidine.

Organometallic Enantiomeric Scaffolding: General Access to 2-Substituted Oxa- and Azabicyclo[3.2.1]octenes via a Brønsted Acid Catalyzed [5 + 2] Cycloaddition Reaction

“…The Zstereochemistry depicted for 19b and 19d was confirmed by an X-ray diffraction study on compound 19d (see the Supporting Information for details). In comparison to the electron-rich and reactive alkylidene complexes generated from lactonylmolybdenum scaffold 3, the addition of sp 3 Grignard reagents to the lactamyl scaffold 4 led to stable 2-alkylidene-η-3,4,5-pyridinylmolybdenum complexes 20a,b (Table 1, entries 12,13) in excellent yields. No trace of a Friedel-Crafts-like side-reaction with TFAA was observed.…”

“…An exploration of the reactivity of 6-phenyl-η-2,3,4-pyranylmolybdenum complex 7a with the electron-deficient alkenes methyl vinyl ketone (MVK) and ethyl vinyl ketone (EVK) revealed unanticipated subtleties of the reaction system. Of the various Lewis acids initially studied (EtAlCl 2 , Et 2 AlCl, Sc(OTf) 3 , TiCl 4 , BF 3 •Et 2 O), EtAlCl 2 was able to initiate a rapid and highly efficient [5+2] cycloaddition between 7a and MVK giving the expected cycloadduct 21a in 91% yield within 30 min. Only the exo isomer of compound 21a was formed (Scheme 7).…”

“…1 Short, scalable, and practicable methods of synthesis of high enantiopurity scaffolds TpMo(CO) 2 (3-oxopyranyl) 1 and TpMo(CO) 2 (3-oxopyridinyl) 2 have been developed, 2 and from these simple scaffolds a diverse array of biologically relevant heterocyclic core structures can be obtained in an enantiocontrolled fashion ( Figure 1). [3][4][5][6][7][8][9][10][11][12][13][14][15] The synthetic elaboration of the 3-oxopyranyl and -pyridinyl complexes 1 and 2 often proceeds via the 5-substituted η 3 -pyranyl and -pyridinyl scaffolds 5 and 6 shown in Figure 2.…”

Recent advances of desymmetrization protocol applied in natural product total synthesis

“…Liebeskind group developed a highly diastereoselective methoxide abstraction method which relies on the 'desymmetrization' imparted by the chiral N-protecting group (ÀCO 2 R* in 96. 51 As shown in Scheme 27, the 2,6-disubstituted dihydropyridinylmolybdenum complex (À)-97a was provided by methoxide abstraction of (À)-96 with Ph 3 CPF 6 , subsequent addition of MeMgBr, then ionization of the other methoxide with HBF 4 , and addition of PhMgBr. When reversing the order of nucleophiles added (PhMgBr then MeMgBr), they can obtain the other diastereomeric (+)-97b.…”

The Enantiomeric Scaffold Approach to Highly Functionalized 1-Oxadecalines: Enantio- and Regiocontrolled [4 + 2] Cycloadditions of 5-Alkenyl-η3-Pyranylmolybdenum Complexes

“…In this study, chiral non-racemic stoichiometric molybdenum π-complexes function as enantiomeric scaffolds or organometallic chirons for the rapid enantioselective synthesis of highly functionalized molecules of certain structural complexity. It was demonstrated that pyranyl-and pyridinylmolybdenum scaffolds (1 and 2 , Figure 3), both enantiomeric antipodes of which are readily available, participate in Mo-mediated, regiocontrolled, sequential functionalization at C-2 and C-6 to afford 2,3,6-trisubstituted pyran 31 and piperidine 25,28,32 derivatives. Moreover, they can lead to the rapid assembly of heteroatom-bridged bicyclic ring systems through either [5+2] 23,[33][34][35] or [5+3] 26 cycloaddition processes, or via sequential MukaiyamaMichael and subsequent 1,5-Michael-type reaction.…”