458-88-8Relevant academic research and scientific papers
Lewis Acid-Mediated S(N)2 type displacement by grignard reagents on chiral perhydropyrido[2,1-b]pyrrolo[1,2-d][1,3,4]oxadiazine. Chirality induction in asymmetric synthesis of 2-Substituted piperidines
Yamazaki, Naoki,Kibayashi, Chihiro
, p. 4623 - 4626 (1997)
Et2AlCl-mediated nucleophilic alkylation with Grignard reagents on chiral perhydropyrido[2,1-b]pyrrolo[l,2-d][1,3,4]oxadiazine has proved to proceed via an S(N)2 mechanism at low temperatures (below -80°C) with high to excellent inversive stereoselection, while, at an elevated temperature, hydrazonium ions are formed preferentially leading to retentive stereoselection. This methodology provides useful access to enantioselective preparation of 2-substituted piperidines and is used for asymmetric synthesis of (+)-coniine.
Polymer-supported (-)-8-phenylmenthyl auxiliary as an effective solidphase chiral inductor in the addition of nucleophiles to N-acyliminium Ions
Forero-Doria, Oscar,Santos, Leonardo S.,Nachtigall, Fabiane M.,Shankaraiah, Nagula
, p. 696 - 702 (2018/02/27)
Aim and Objective: According to our interest in developing new methods for the construction of intricate molecules, a reliable polymer-supported (-)-8-phenylmenthyl chiral auxiliary for the addition of different nucleophiles to chiral-supported N-acyliminium precursors were developed. Material- and Method-: Merrifield resin was employed to anchor (-)-8-phenylmenthol, which was prepared by nitration of (-)-8-phenylmenthyl chloroacetate followed by reduction of nitro group and subsequent Merrifield resin coupling. Treatment of a suspension of polymer-supported chloroformate and piperidinone in the presence of Et3N resulted in attachment of the substrate onto the solid-support. Treatment of the resulting resin with LiEt3BH/MeOH afforded methoxypiperidine in 87% yield. Then, the addition of allyltrimethylsilane, TMSCN, 2-(trimethylsiloxy)propene and triisopropylsilyloxyfuran and others to the N-acyliminium ion derived from chiral 2-methoxypiperidine carbamate was studied. Results: The stereochemical outcome of the addition of nucleophiles to the supported N-acyliminium ion derived from 2-methoxypiperidine carbamate was proposed through the Si-face, affording after resin cleavage 2-substituted piperidines in 70%-84% yields and selectivities ranging from 4:1-11.1. Moreover, the key intermediates of chiral piperidines have been employed for the synthesis of simple chiral alkaloids such as (R)-pipecolic acid, (R)-pelletierine, (S)-coniine and (R,R)-myrtine. Conclusion: The proposed supported-chiral auxiliary for asymmetric approach may be expected to result not only in efficient solid-phase syntheses of a wide range of alkaloids but also in the development of useful new solid-phase methodologies, particularly for the asymmetric additions to iminium precursors. This work describes the first example of solid-phase synthesis by using supported (-)-8-phenylmenthyl as an effective chiral inductor and would be useful for the synthesis of chiral building block libraries.
Structure, activity and stereoselectivity of NADPH-dependent oxidoreductases catalysing the S-selective reduction of the imine substrate 2-methylpyrroline
Man, Henry,Wells, Elizabeth,Hussain, Shahed,Leipold, Friedemann,Hart, Sam,Turkenburg, Johan P.,Turner, Nicholas J.,Grogan, Gideon
, p. 1052 - 1059 (2015/05/05)
Oxidoreductases from Streptomyces sp. GF3546 [3546-IRED], Bacillus cereus BAG3X2 (BcIRED) and Nocardiopsis halophila (NhIRED) each reduce prochiral 2-methylpyrroline (2MPN) to (S)-2-methylpyrrolidine with >95 % ee and also a number of other imine substrates with good selectivity. Structures of BcIRED and NhIRED have helped to identify conserved active site residues within this subgroup of imine reductases that have S selectivity towards 2MPN, including a tyrosine residue that has a possible role in catalysis and superimposes with an aspartate in related enzymes that display R selectivity towards the same substrate. Mutation of this tyrosine residue - Tyr169 - in 3546-IRED to Phe resulted in a mutant of negligible activity. The data together provide structural evidence for the location and significance of the Tyr residue in this group of imine reductases, and permit a comparison of the active sites of enzymes that reduce 2MPN with either R or S selectivity.
Bisnucleophilic substitution as a synthetic tool for ready access to the piperidine alkaloids (+)-Connine, (+)-β-conhydrine, (+)-8-ethylnorlobelol, and (-)-halosaline
Raju, Galla,Anitha, Kadimi,Krishna, Palakodety Radha
, p. 937 - 941 (2015/04/27)
Herein we report the stereoselective total synthesis of (+)-connine, (+)-β-conhydrine, (+)-8-ethylnorlobelol, and (-)-halosaline via bisnucleophilic substitution with benzylamine as the key step.
Characterization of three novel enzymes with imine reductase activity
Gand,Müller,Wardenga,H?hne
, p. 126 - 132 (2015/02/19)
Imine reductases (IRED) are promising catalysts for the synthesis of optically pure secondary cyclic amines. Three novel IREDs from Paenibacillus elgii B69, Streptomyces ipomoeae 91-03 and Pseudomonas putida KT2440 were identified by amino acid or structural similarity search, cloned and recombinantly expressed in E. coli and their substrate scope was investigated. Besides the acceptance of cyclic amines, also acyclic amines could be identified as substrates for all IREDs. For the IRED from P. putida, a crystal structure (PDB-code 3L6D) is available in the database, but the function of the protein was not investigated so far. This enzyme showed the highest apparent E-value of approximately Eapp = 52 for (R)-methylpyrrolidine of the IREDs investigated in this study. Thus, an excellent enantiomeric purity of >99% and 97% conversion was reached in a biocatalytic reaction using resting cells after 24 h. Interestingly, a histidine residue could be confirmed as a catalytic residue by mutagenesis, but the residue is placed one turn aside compared to the formally known position of the catalytic Asp187 of Streptomyces kanamyceticus IRED.
A [3+3] cyclization strategy for asymmetric synthesis of alkyl substituted piperidine-2-ones using 1,2-cyclic sulfamidates: A formal synthesis of (S)-coniine from l-norvaline
Karanfil, Abdullah,Balta, Berrin,Eskici, Mustafa
, p. 10218 - 10229,12 (2020/09/02)
Regioselective ring-opening reactions of a set of representative 1,2-cyclic sulfamidates with lithium triethylorthopropiolate proceeded efficiently to deliver the corresponding δ-amino-α,β-unsaturated esters after acidic hydrolysis. Hydrogenation of the unsaturated esters and subsequent thermal cyclization afforded the related alkyl substituted piperidine-2-ones. This approach represents a novel [3+3] cyclization strategy for the asymmetric synthesis of alkyl substituted piperidin-2-ones. Efficiency of the cyclization process is illustrated by a formal asymmetric synthesis of (S)-coniine from l-norvaline.
Cyclohydrocarbonylation-based strategy toward poly-substituted piperidines
Arena, Giada,Zill, Nicolas,Salvadori, Jessica,Girard, Nicolas,Mann, Andre,Taddei, Maurizio
scheme or table, p. 2294 - 2297 (2011/06/26)
Chemical equations presented. Convenient accesses to enantiomerically pure 2-, 2,3-, 2,6-, 2,3,6-substituted piperidines and 1,4-substituted indolizine are described. At first, indium-mediated aminoallylation and -crotylation of aldehydes with (R)-phenylglycinol or (1R,2S)-1-amino-2-indanol gave homoallylamines with high stereocontrol. Then, these products, submitted to a Rh(I)-catalyzed hydroformylative cyclohydrocarbonylation, afforded perhydrooxazolo[3,2-a]piridines whose oxazolidines are opened with nucleophiles. Finally, the removal of the chiral auxiliaries delivered the enantiomerically pure piperidines.
Regioselective and stereoselective copper(I)-Promoted allylation and conjugate addition of N -Boc-2-lithiopyrrolidine and N -Boc-2-lithiopiperidine
Coldham, Iain,Leonori, Daniele
experimental part, p. 4069 - 4077 (2010/08/20)
Copper salts have been screened for transmetalation and electrophilic quench of N-tert-butoxycarbonyl-2-lithiopyrrolidine (N-Boc-2-lithiopyrrolidine) and N-Boc-2-lithiopiperidine, formed by deprotonation of N-Boc-pyrrolidine and N-Boc-piperidine, respectively. Transmetalation with zinc chloride then (lithium chloride solubilized) copper cyanide followed by allylation typically gives mixtures of regioisomers (SN2 and SN2′ products), whereas transmetalation with copper iodideTMEDA then allylation occurs regioselectively (SN2 mechanism). Addition to an enone or α,β-unsaturated ester occurs by 1,4-addition. Asymmetric deprotonation of N-Boc-pyrrolidine or dynamic resolution in the presence of a chiral ligand of N-Boc-2-lithiopiperidine followed by the zinc/copper chemistry was successful and gave the allylated pyrrolidine and piperidine products with good enantioselectivity, although use of the copper iodide chemistry resulted in some loss of enantiopurity. The chemistry provides formal syntheses of (+)-allosedridine, (+)-lasubine II, and (+)-pseudohygroline and has been used for the synthesis of (+)-coniine, (-)-pelletierine, (+)-coniceine, (-)-norhygrine, and the ant extract alkaloids cis- and trans-2-butyl-5- propylpyrrolidine.
Asymmetrie synthesis of unsaturated monocyclic and bicyclic nitrogen heterocycles
Nomura, Hiroshi,Richards, Christopher J.
supporting information; experimental part, p. 2892 - 2895 (2009/12/06)
Hydrolysis of scalemic trichloroacetamides Cl3CCONHCH(R) CHCH2 and allylatlon, or acylatlon with but-3-enoic acid, followed by ring-closing metathesis resulted In the formation of unsaturated pyrrolidine and piperidine building blocks. These were employed in the synthesis of (S)-coniine (R = Pr) and a formal synthesis of (+)-anlsomycln (R = p-MeOC 6H4). Extension of this methodology with R = CH 2CHCH2 employing two ring-closing metatheses resulted In the synthesis of unsaturated quinolizidinone and indolizidinone frameworks.
A general and enantiodivergent method for the asymmetric synthesis of piperidine alkaloids: concise synthesis of (R)-pipecoline, (S)-coniine and other 2-alkylpiperidines
Etxebarria, Juan,Vicario, Jose L.,Badía, Dolores,Carrillo, Luisa
, p. 11421 - 11428 (2008/03/13)
A simple and very efficient protocol for the preparation of highly enantioenriched 2-alkylpiperidines has been set up, which allows the preparation of the final heterocycles with any wanted configuration at the stereogenic center starting from the same starting material. The key step of the synthesis relies on a diastereodivergent aza-Michael reaction protocol using the readily available and cheap reagent (+)-(S,S)-pseudoephedrine as chiral auxiliary.
