Cis 2,6 disubstituted piperidines

Likewise, a cis-2,6-disubstituted piperidine natural product, (-)-lobeline (98, Scheme 8.4.30) was synthesized from the chiral Af-alkyl pyridinium salt ent-80 via a sequence that included addition of a Reformatsky reagent to an intermediate oxazolidine. °... 

Having completed the intramolecular nitroso-Diels-Alder reaction, the shape of the bicyclic oxazinolactam 188 allowed for a diastereoselective successive addition of two nucleophiles (Scheme 41.40). The addition of methylmag-nesium bromide into 188 at 0°C because the carbonyl is activated by the N O bond, followed by sodium boro-hydride in acetic acid, delivers the cis-2,6 disubstituted piperidine precursor 190. The diastereoselectivity could be explained by the fact that the presence of the oxazino ring would force the C4a substituent of the N-alkoxypiperidi-nium unit 189 into a pseudoequatorial position, and the stereoelectronically axial attack of the hydride led diaster-eoselectively to the desired compound 190, which was eventually transformed into (-)-lepadin B 191. 

Tetrahydropyridines 103 undergo a Michael reaction to afford [ran.s-(2,3)-cis-(2,6)-trisubstituted piperidines 104 (97T9553). The reaction is stereoselective (a single stereoisomer was obtained) and provides a convenient route to the 5,8-disubstituted indolizidine 105 and 1,4-disubstituted quinolizidine system 106 (found in Dendrobates alkaloids) by introduction of various alkyl, alkenyl, or... 

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 ... 

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. 

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... 

Methyl 7-oxoocten-2-oate (X, CH3-CO-CH2-CH2-CH2-CH=CH-COOCH3) can be transformed to the corresponding 2,6-disubstituted piperidine derivative (A) by reductive amina-tion with ammonium acetate/Na[H3BCN] and subsequent intramolecular Michael addition. Interestingly, ( )-X gives cis- and (Z)-X gives ra .y-2,6-disubstituted A as exclusive reaction product. 

Although it is outside the scope of this review, it is important to note that dias-tereoselective lithiation-substitutions of enantioenriched substrates which have a permanent chiral center can be very useful. A representative example which indicates the flexibility of the approach is the conversion of (S)-66 to the cis- and tra s-2,6-disubstituted piperidine natural products, 67 and 68 (Scheme 18) [47, 48]. The key to the synthesis of both diastereomers is initial formation of transproducts which, in case of formylation, can be equilibrated to a more stable cis-isomer. The ready availabiUty of either (S) or ( )-66 makes this procedure of general value for stereocontroUed synthesis of highly enantioenriched cis- and... 

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... 

Remuson and coworkers reported that highly diastereoselective synthesis of 2,6-cis-disubstituted-4-methylenepiperidines based on a Mannich type intramolecular cyclization of allylsilane [37]. Reaction of p-aminohydroxysilane 116 with carbonyl derivative in the presence of TFA in a mixture of H2O-THF (1 1) led to 4-methylenepiperidine 117. Oxidation with osmium tetraox-ide in the presence of Na3H3lOe in AcOH led to piperidin-4-one followed by the stereoselective reduction with NaBH4 afforded (- -)-241D (13) and its C-4 epimer 118 in a ratio of 83 17 (Scheme 20). 

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