Selective methodologies for the synthesis of biologically active piperidinic compounds

Abstract

The synthesis of optically active substituted piperidines has been achieved by using four different methodologies. The first one is an intramolecular nucleophilic displacement of activated alcohol moieties that was used to build up the piperidine ring of (-)-prosophylline and (-)-slaframine, and the second one is a ring-closing metathesis of unsaturated amines which was employed in the synthesis of (+)-sedamine and 4a,5-dihydrostreptazoline. The third methodology is the alpha-functionalization of N-Boc piperidines which was particularly useful in the synthesis of argatroban, and the fourth one is a ring expansion of prolinols to 3-chloropiperidines or 3-hydroxypiperidines which was utilized to synthesize (-)-paroxetine, (-)-pseudoconhydrine, the piperidine ring of (-)-velbanamine and (+)-zamifenacin.

Imino Glycals via Ruthenium-Catalyzed RCM and Isomerization

“…Methods for the synthesis of imino glycals include the reduction of lactams and subsequent elimination, 12 electrochemical oxidation of piperidines, followed by elimination, 13 addition of nucleophiles to pyridinium salts and subsequent partial reduction, 6 nucleophilic ring opening of aziridines followed by cyclization (formal [3+3]-annulation), 14 and hydroformylation of homoallyl amides. 15 Ring-closing olefin metathesis (RCM), although a well-established and commonly used method for the synthesis of piperidine and pyrrolidine derivatives via RCM of allyl amines or amides, 10,16,17 has scarcely been applied to enamines or enamides. Notable examples have been published by Rutjes and co-workers, 18 who reported the synthesis of five-and six-membered cyclic enamides and by Arisawa et al, 19,20 who described the synthesis of indoles.…”

“…These imino glycals are fully protected aza analogues of L-rhodinal, 46 the glycal of the 2,3,6-tridesoxy sugar 47 L-rhodinose, and are potentially useful building blocks for the synthesis of azasugars or piperidine alkaloids, as outlined in the introduction. The synthesis starts from L-alanine (10), which was converted into the N-Boc-protected 11a and N-Cbz-protected L-alanine methyl esters 11b, respectively. 48 Their reduction with diisobutylaluminum hydride at low temperature furnished the respective aldehydes 12a and 12b, 48 which were then treated with vinylmagnesium chloride to give the allyl alcohols 13a and 13b.…”

Stereoselective asymmetric synthesis of (+)‐sedamine and (+)‐allosedamine

“…3 Consequently these bifunctional compounds have been the subject of considerable synthetic efforts, prompting an exceptional development of methodologies for the asymmetric approaches. 4 Sedamine, allosedamine, and their stereoisomers, 1a,b and 2a,b respectively, (see Fig. 1) fall into this category.…”

Rhodium(I)-Complexes Catalyzed 1,4-Conjugate Addition of Arylzinc Chlorides to N-Boc-4-pyridone

“…Due to their importance in medicinal chemistry, considerable efforts have been devoted to develop efficient synthetic strategies for the synthesis of piperidine derivatives. Most of these strategies involve using chiral auxiliaries/chiral starting materials and have been developed into effective methods for the synthesis of a wide variety of N -heterocycles [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. The synthesis of 2,3-dihydro-4-pyridones via conjugate addition reactions have also been reported [ 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ].…”