Piperidine derivatives total synthesis

Perhydro derivatives of pyrido[l,2-7)][l,2]oxazines are frequently applied in the total synthesis of various alkaloids to control the stereochemistry, and pyrido[l,2-c][l,3]oxazines and [l,3]oxazino[3,4-u]quinolines were also used in the stereoselective syntheses of different alkaloids. Perhydropyrido[l,2-c][l,3]oxazines and their benzologs are formed form 2-(2-hydroxyethyl) piperidines and from their benzologs to justify the stereochemistry of 2-(2-hydroxyethyl) derivatives. Different optically active pipecolic acids can be prepared via 4-phenylperhydropyrido[2,l-c][l,4]oxazin-l-ones. 

An excellent example of a RCM/ROM domino process is shown in the total synthesis of the piperidine alkaloid (-)-halosaline (6/3-19) by Blechert and coworkers (Scheme 6/3.3) [231]. The key step is the reaction of the enantiopure cyclopentene derivative 6/3-17 to give 6/3-18 with 5 mol% of the catalyst 6/3-13. Further transformations of 6/3-18 led to the natural product 6/3-19. 

Ring-closing reactions promoted by mercuric salts are valuable transformations which find an increasing use in the total synthesis of various natural products.130-140 Several examples of solvomercurations demonstrating the applicability of these transformations to the synthesis of natural product precursors are presented in Table 2. Piperidines (entry a), 141 pyrans (entries b-d), 142-144 and furans (entries e, f)14S>146 have been obtained in good yields and diastereoselectivity. These derivatives serve as starting materials for various natural products and can be demercu-rated under reducing conditions.147... 

Chiral Lewis acids have been employed by Yamamoto et al. [197 -199] in order to carry out enantioselective aza Diels-Alder reactions starting from achiral substrates however, these transformations required stoichiometric amounts of the chiral mediator 3-16 which was generated in situ from (fl)-binaphthol and triphenylborate. The best results were obtained with the pyridine derivative 3-14 which afforded the desired cycloadduct 3-15 in high optical purity (Fig. 3-5). Using chiral imines, the authors found a high level of double asymmetric induction, and this methodology could be applied to the enantioselective total synthesis of two piperidine alkaloids. 

Moderate asymmetric induction and low yields are observed when the compound 5, prepared from (A, )-hexadienal and (15,25)-pseudoephedrine, undergoes cycloaddition with the nitroso derivative 6. The major cycloadduct 7 is obtained together with minor amounts of diastereomers (d.r. 62 24 11 3) and after chromatography is isolated in 32% yield. Its configuration is first assigned by H NMR, and then by conversion into the known (+ )-(S)-2-methyl-l-(4-toluenesulfonyl)piperidine. Compound 7 is the key intermediate for the total synthesis of an amino allose derivative135. 

Verazine (37) has been the subject of a formal total synthesis (Scheme 1) based on the earlier reported versatile syntheses of solanidine and tomatidenol. As in the earlier work, Michael addition of the anion of the configurationally pure nitro-ester (30) to (29) gave the C-22 epimeric mixture (31), from which the individual diastereomers were isolated after acetylation. The (22S)-acetate (32) was converted via thioketal (34) and lactam (35) into the piperidine derivative (36). Base treatment of the N-chloro-derivative of (36) then gave verazine (37). 

Intramolecular enamine formation between an aldehyde or ketone and the nitrogen atom of a piperidine ring can serve as the key step in the preparation of quinolizidine derivatives. For example, the ketal (184), prepared by double addition of the lithio derivative (183) to 6-methoxy-2,3,4,5-tetrahydropyridine, can be easily cyclized to the quinolizidine derivative (185) by double acid-catalyzed deprotection, cyclization, and dehydration (Scheme 31). These reactions constitute the first steps of a stereocontrolled total synthesis of the alkaloid ( )-porantherine <87JA4940>. 

Similar cyclizations using piperidines with leaving groups at C-2 are probably mediated by iminium ions. For example, a total synthesis of epilupinine <83H(20)40i > relies on the anodic oxidation of the lactam (223) to the methoxy derivative (224), which was subsequently converted into the quinolizidine (225) through a titanium tetrachloride-mediated cyclization, a reaction that has been... 

The total synthesis of (+)-azimic and (+)-carpamic acids, based on intermediates derived from D-glucose, has been reported. The important sequence of events in the synthesis of the latter is the transformation of the protected azido-aldehyde (51) into the piperidine (52), manipulation of which leads to (-t-)-carpamic acid (53) (Scheme 85). 

Hydroformylation of substrates incorporating O- or N-nudeophilic moieties leads to cyclic hemiacetals, acetals, 0,N-acetals, or enamines depending on the reaction conditions and the functional groups of the substrates. In the total synthesis of the anticancer agent, natural product leucascandroUde A (24), three different carbonyla-tion steps were incorporated (Scheme 12.1). Alkene 20 underwent a cyclohydrocar-bonylation reaction under hydroformylation conditions, resulting in the formation of hemiacetal 21. The other two carbonylation steps involved formylation of 18 and intramolecular alkoxycarbonylation of alkene 22 [28]. Various tryptamine derivatives [29] and the framework of piperidine alkaloids [30] were also synthesized via cyclohydrocarbonylation starting from functionalized homoallylic amines or aniline derivatives, respectively. 

The method of Bella is a supreme example of how the organocatalytic asymmetric Mannich reaction can facilitate the synthesis of simple pyrrolidine or piperidine alkaloids starting from achiral starting materials. Therefore, in the snbsequent paragraphs, we wish to review recent efforts made by various research groups to implement an organocatalytic asymmetric Mannich reaction as key step in the total synthesis of alkaloids, predominately derived from L-Om and n-Lys. 

BINOL-derived phosphoric acid catalyst affording the P-amino ketone (231) in 96% yieldand92% ee (Scheme 11.51) [156]. The total synthesis of (-)-anabasine (232) was completed in three more steps in 55% overall yield (i) reduction of the conjugated double bond, (ii) lednction of the ester moiety with an excess DIBAL-H resulting in the formation of the piperidine ring, and (iii) removal of the PMP-protective group. 

An efficient enantioselective total synthesis of (—) -cis-clavidpitic acid was reported by Park and coworkers (Scheme 12.3) [103]. The asymmetric phase-transfer catalytic alkylation of 65a with 68 was employed as the key step, producing the urmatural oi-amino acid derivative 69 for the introduction of the 5S chirality. Starting from a glycine derivative 65a, Maruoka and coworkers successfully developed a strategy for the asymmetric synthesis of cyclic amino acids having a piperidine or azepane core structure by the combination of a phase-transfer catalytic asymmetric alkylation and a subsequent diastereoselective reductive amination. This approach allows the... 

Pyridine and its partially or totally unsaturated derivatives such as tetrahydropy-ridines, DHPs, and piperidines are ubiquitous cores found in numerous natural product skeletons and in synthetic compounds of primary interest for synthetic chemistry, agrochemistry, or pharmacology. Among the various methodologies available for the synthesis of these compounds, multicomponent approaches have attracted much attention in the last few years. Most of these sequences are initiated by a Michael addition. 

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