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A specimen of the ascidian Aplidium uouo from Maui contained two piperidine alkaloids, uoamines A and B, that differed only in the geometry of a 3-thiomethylacrylate ester group. The alkaloids exhibit conformational mobility in the NMR time frame, which complicated the elucidation of their structures by interpretation of spectroscopic data.
The flowers of Cassia spectabilis yielded three new piperidine alkaloids, (-)-3-O-acetylspectaline (1), (-)-7-hydroxyspectaline (2), and iso-6-spectaline (3), together with the known (-)-spectaline (4). The green fruits of this plant were also investigated, resulting in the isolation of 1 and 4. Their structures were elucidated using a combination of multidimensional NMR and MS techniques, and relative stereochemistries were established by NOESY correlations and analysis of coupling constants. The DNA-damaging activity of these compounds was evaluated using a mutant yeast, Saccharomyces cerevisiae, assay.
Bioassay-guided fractionation of the MeOH-CH2Cl2 extract of the Micronesian ascidian Pseudodistoma megalarva yielded three new piperidine alkaloids, pseudodistomins D-F (3-5) and the previously reported pseudodistomins B and C (1 and 2). The structure and stereochemistry of these compounds were established by interpretation of spectral data. Pseudodistomins B-F were found to be active in a cell-based assay for DNA damage induction, but the activity was due to an alternative mechanism.
Calyxamines A (1) and B (2) are 2,2,4,6,6-pentasubstituted piperidine alkaloids possessing novel carbon skeletons isolated from the marine sponge Calyx podatypa collected in Puerto Rico. Their structures, after derivatization with trifluoroacetic acid, have been determined by a combination of X-ray and spectroscopic methods. A plausible biogenetic pathway to the calyxamines is suggested.
A diastereocontrolled synthesis of (+)-febrifugine, a potent antimalarial piperidine alkaloid, has been achieved using a chiral block having a bicyclo[3.2.1]octane framework which exhibits inherent convex-face selectivity.
A method for the diastereoselective synthesis of 2,4-disubstituted piperidines has been developed which enables the complete control of reaction selectivity merely by changing the order of the reaction sequence. These targets provide convenient platforms for drug discovery which contain easily modified points of diversity.
[reaction: see text] Chiral nonracemic bicyclic lactam 3, easily accessible by cyclodehydration of (R)-phenylglycinol and racemic methyl 4-formylhexanoate, was converted to the unsaturated lactams 5, which undergo the stereoselective conjugate addition of lower order cyanocuprates to ultimately lead to enantiopure cis-3,4-disubstituted and 3,4,5-trisubstituted piperidines.
[reaction: see text] The 3-alkoxy-4-arylpiperidine inhibitors of aspartic peptidases are shown to be a new type of non-peptide peptidomimetic inhibitor. These piperidines can be designed from peptide-derived inhibitors by use of a structure-generating program but only after the enzyme active site conformation has been modified in a mechanistically related fashion. New enantioselective syntheses of 3-alkoxy-4-arylpiperidine analogues are described.
[reaction: see text]. Nitrogen-containing tethered diacids, easily prepared by reductive alkylation of diethyl aminomalonate or ethyl cyanoglycinate, undergo double Michael reactions with 3-butyn-2-one to give highly functionalized and substituted piperidines (pipecolic acid derivatives) with surprisingly high stereoselectivity. The heterocyclic double Michael adducts can be induced to undergo further cyclizations to give a variety of azabicyclic and diazabicyclic compounds.
[reaction: see text] The intramolecular Mannich reaction of delta-amino beta-keto esters with aldehydes and ketones is a new methodology for the synthesis of polysubstituted piperidines and is illustrated by the concise asymmetric synthesis of the dendrobate alkaloid (+)-241D and its C-4 epimer.
[reaction: see text] Diels-Alder reactions of enantiomerically enriched 2H-azirine 3-phosphonates and dienes stereoselectively furnish optically pure, bicyclic aziridine adducts that on hydrogenation afford the first examples of enantiopure quaternary piperidine phosphonates.
[reaction: see text] A short and efficient synthesis of 2,5,6-trisubstituted piperidines was achieved by a combination of an aza-Achmatowicz oxidation of a furyl benzenesulfonamide, conjugate addition to the resulting 2H-pyridinone, and subsequent addition of various nucleophiles to a transient N-sulfonyliminium ion. The steric bulk of the tosyl group directs attack of the nucleophile from its opposite side, thereby leading to the formation of cis-substituted products.
C(2)-symmetric 2,6-diallylpiperidine 1-carboxylic acid methyl ester (5) was examined via the double asymmetric allylboration of glutaraldehyde followed by aminocyclization and carbamation as a promising chiral building block for piperidine-related alkaloids, which were synthesized by the desymmetrization of 5 using intramolecular iodocarbamation as a key step. [reaction: see text]
[reaction: see text] Diastereoselective alkylation at the carbonyl alpha-position of chiral nonracemic lactams 2 and 3, the former prepared by cyclocondensation of (R)-phenylglycinol with a racemic gamma-substituted delta-oxoester in a process that involves a dynamic kinetic resolution and the latter by a subsequent equilibration, provides access to enantiopure cis- and trans-3,5-disubstituted piperidines. The usefulness of the approach is illustrated with the synthesis of the alkaloids 20S- and 20R-15,20-dihydrocleavamine.
[reaction: see text] The hydroxy-directed reduction of 1,2-dehydropiperidines with the "ate" complex of DIBAL-H and n-BuLi affords functionalized trans-2,6-disubstituted piperidines. This methodology was employed in the asymmetric synthesis of the quinolizidine alkaloid (-)-lasubine I.
[reaction: see text] A chemo- and stereoselective palladium-catalyzed amination of silylated butenediol dicarbonates has allowed for the introduction of a glycine moiety to obtain a desired functionalized epoxysilane. A stereoselective aldolization then delivered the piperidine ring which may be used as a precursor for the synthesis of a variety of polyhydroxylated azasugars. This efficient approach has been illustrated by the synthesis of 1-deoxymannojirimycin including a stereoselective reduction with LAH and a Tamao-Fleming oxidation of a C-SiMe(2)Ph bond.
A redox-induced six-membered ring chair-chair conformational interconversion in a copper-coordinated trans-piperidine tripodal ligand is demonstrated. Each group of the 1,2,3-substituted ring can potentially ligate the metal; two equatorial groups ligate the metal in the Cu(I) state leaving a disassociated, axial group. However, all three groups (two axial and one equatorial) ligate the metal in the Cu(II) state. Exciton-coupled circular dichroism (ECCD) and 2D NMR were used to characterize the structures.
[reaction: see text] Stereocontrolled synthesis of 2,4,6-trisubstituted piperidine diastereomers has been realized from common intermediates, obtained by a one-pot azaelectrocyclization protocol. Based on the method, the asymmetric synthesis of an indolizidine alkaloid, (-)-dendroprimine, was achieved.