Piperidines trans-3,4-disubstituted

Although a number of alkaloids belonging to the simple arylquinolizidine class and the lactonic type had been synthesized, no successful synthesis of cyclophane alkaloids was accomplished until that of lythranidine (94), a unique alkaloid with a 2,6-trans disubstituted piperidine structure, was reported (28, 29). Quinolizidine metacyclophane alkaloids lythrancepines II (95) and III (96) have also been synthesized recently (30, 31). A review on the synthesis of lythranidine (94) is available in Japanese (32). 

The free energy difference between the two rotamers 126a and 126b was estimated to be 0.8 kcal/mol in favor of 126a by temperature-dependent CD curves (40). Free energy differences of derivatives 103,131, and 132 were estimated to be 1.0, 0.7, and 0.2 kcal/mol, respectively. This shows that the important factor in determining the conformational chirality of the biphenyl moiety is the presence of the 2,6-trans disubstituted piperidine ring in the molecule. 

A functionalized piperidine system 204, on deprotection of the BOC group followed by treatment of the resulting amine with Me3Al, afforded a 4 1 mixture of trans- and cis- 4,6-disubstituted quinolizidines 205 and 206 (Scheme 39) <1999T15209>. 

In 2007, Terada et al. extended their previously described chiral phosphoric acid-catalyzed aza-ene-type reaction of M-acyl aldimines with disubstituted enecarbamates (Scheme 28) to a tandem aza-ene-type reaction/cyclization cascade as a one-pot entry to enantioenriched piperidines 121 (Scheme 48). The sequential process was rendered possible by using monosubstituted 122 instead of a disubstituted enecarbamate 76 to produce a reactive aldimine intermediate 123, which is prone to undergo a further aza-ene-type reaction with a second enecarbamate equivalent. Subsequent intramolecular cychzation of intermediate 124 terminates the sequence. The optimal chiral BINOL phosphate (R)-3h (2-5 mol%, R = 4-Ph-C H ) provided the 2,4,6-sub-stituted M-Boc-protected piperidines 121 in good to exceUent yields (68 to > 99%) and accomplished the formation of three stereogenic centers with high diastereo- and exceUent enantiocontrol (7.3 1 to 19 1 transicis, 97 to > 99% ee(trans)) [72]. 

Since almost all natural PDC analogs, 2,6-disubstituted piperidines, are in the trans (LL (SS)) conformation, the selective synthesis of frans-PDC is most valuable. The loading of a small amount of platinum or its oxide, regardless of the... 

Intramolecular amidomercuration of carbamate derivatives to generate 2,6-disubstituted piperidine systems (equation 113 and Table 31) proceeds with low selectivity under conditions of kinetic control (cis.trans = 40 60),246 248 but cyclization under conditions of thermodynamic control highly favors the cis isomer (cis. trans > 98 2).246 Interestingly, only the cis isomer was isolated from cyclization with phe-nylselenenyl chloride in the presence of silica gel.216 ... 

A novel route to optically active piperidines is the imino Diels-Alder reaction between the chiral 2//-azirine 49 and trans-1,3 - p c n t a d i c n c (Scheme 115) <20020L655>. The resulting strained intermediate was a single diastereomer and subsequent halogenation produced the 2,6-disubstituted piperidine. 

A similar type of cascade reaction has been carried out with cyclic alkenes bearing only one olefinic side chain to obtain substituted heterocycles via ruthenium-catalyzed ring closing-ring opening metathesis (RCM-ROM) reactions. The preparation of enantiomerically pure cis- or trans-a,a -disubstituted piperidines has been achieved in the same yield for the two diastereoisomers [35] (Scheme 17). This reaction has also been used as a key step for the synthesis of natural products [36-39]. 

The disubstituted pyrrolidines and piperidines have been demonstrated to be excellent repellents for ants under field conditions. Workers of Monomorium pharaonis effectively repel other species of ants with venom droplets which accumulate on the tip of the sting (37), a strategy that is used with equal success by workers of North American Monomorium species ( 38.) and the European thief ant, Solenopsis fugax (37). The venom of the latter species contains a single alkaloid, trans-2-butyl-5-heptylpyrrolidine (I, m=3, n=6) (1 ), and the... 

The proton magnetic resonance assignments for 241D have been presented (87). The optical rotation, is -1-39° (0.2, CHjOH). The structure of 241D has been confirmed by synthesis (M. W. Edwards, personal communication, 1990). None of the other amphibian piperidines has been isolated for further spectral analysis. However, Bohlmann bands in FTIR spectra will allow assignment of cis or trans configurations to such 2,6-disubstituted piperidines (see Section III,B). 

Disubstituted piperidines (and piperideines) are well known as constituents of myrmicine ant venoms, particularly in fire ants of the genus Solenopsis (125,134,149,161,164). Both cis and trans isomers occur. Cis-and/or rrans-2-methyl-6-nonylpiperidines are prominent ant alkaloids. These ant alkaloids have not been detected in amphibians, but the 4-hydroxy piperidine analog (241D) has. 

The perhydro-isoxazolo[2,3-fl]pyridine system offers a route to 2,6-disubstituted piperidines. For example, the reaction between styrene and the substituted 3,4,5,6-tetrahydropyridine-l-oxide (69) gives the isoxa-zolidine (70) which, on benzylation, gives 71. This was subjected to reductive cleavage of the N—O bond with lithium aluminum hydride, followed by mesylation of the aminodiol produced. Treatment of the mesylate with lithium triethylborohydride gave the trans-2,6-disubstituted piperidine... 

Terada et al. successfully applied the aza ene type reaction to the cascade trans formation by taking advantage ofthe formation of imine products (Scheme 3.30) [69]. They employed monosubstituted enecarbamates [70] instead of the disubstituted versions and as a result, piperidine derivatives with multiple stereogenic centers were obtained in high stereoselectivities. The acid catalyzed aza ene type reaction of the initial aldimines with monosubstituted enecarbamates afforded aza ene type... 

A rapid GC-FT1R method for determination of the cis or trans configuration of 2,6-disubstituted piperidines was developed using, among others, the Solenopsis alkaloids 198a, 198b, 202 and the Monomorium alkaloids 207-209 [480]. A method for determination of the absolute configuration of Solenopsis alkaloids was developed, in which the amines are... 

The metal-free highly enantioselective catalytic hydrogenation of pyridines, especially 2,6-disubstituted pyridines, which are inert to hydrogenation, has been achieved with H2 in toluene by using catalysts generated in situ by hydroboration of alkenes with HB(C6F5)2 a broad range of piperidines has been formed in 44-99% yields with 90 10 0 to 99 1 cis trans ratio. 0... 

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