Diastereomeric difference of inclusion modes between (-)-epicatechin gallate, (-)-epigallocatechin gallate and (+)-gallocatechin gallate, with beta-cyclodextrin in aqueous solvent

Inclusion complexes of (-)-epicatechin gallate (ECg) as well as (+)-gallocatechin gallate (GCg) and beta-cyclodextrin (beta-CD) in an aqueous solution were investigated using several NMR techniques and a computational method. ECg and EGCg formed a 1:1 complex with beta-CD, in which the A ring and a portion of the C ring were included from the wide secondary hydroxyl group side of the beta-CD cavity, and the B and B' rings were left outside the cavity. GCg formed a 1:2 complex with beta-CD, in which the A and B rings of GCg were included by two molecules of beta-CD. The difference between the two modes of inclusion of the 1:1 complex of ECg, EGCg.beta-CD and the 1:2 complex of GCg.beta-CD might have resulted from the size of the space between the B and B' rings in aqueous solution. As a result of nuclear Overhauser effect (NOE) experiments, GCg was considered to have a large enough space between the B and B' rings to include the B ring in the beta-CD cavity; on the other hand, ECg and EGCg have no such large space.     

Resolution of (+/-)-ibuprofen using (-)-brucine as a chiral selector by thin layer chromatography

The enantiomeric resolution of (+/-)-ibuprofen into its enantiomers was achieved by TLC on silica gel plate using optically pure (-)-brucine as a chiral selector and acetonitrile-methanol (5:1, v/v) as the solvent system. Spots were located in an iodine chamber. The detection limit was 4.9 microg. The effect of concentration of the chiral selector, temperature and pH on resolution has been studied.     

Saturated amine oxides: Part 8. Hydroacridines: Part 27. Effects of N-oxidation and of N-quaternization on the 15N NMR chemical shifts of N-methylpiperidine-derived mono-, bi-, and tricycloaliphatic tertiary amines

The (15)N chemical shifts of 13 N-methylpiperidine-derived mono-, bi- and tricycloaliphatic tertiary amines, their methiodides and their N-epimeric pairs of N-oxides were measured, and the contributions of specific structural parameters to the chemical shifts were determined by multilinear regression analysis. Within the examined compounds, the effects of N-oxidation upon the (15)N chemical shifts of the amines vary from +56 ppm to +90 ppm (deshielding), of which approx. +67.7 ppm is due to the inductive effect of the incoming N(+)--O(-) oxygen atom, whereas the rest is due to the additive shift effects of the various C-alkyl substituents of the piperidine ring. The effects of quaternization vary from -3.1 ppm to +29.3 ppm, of which approx. +8.9 ppm is due to the inductive effect of the incoming N(+)--CH(3) methyl group, and the rest is due to the additive shift effects of the various C-alkyl substituents of the piperidine ring. The shift effects of the C-alkyl substituents in the amines, the N-oxides and the methiodides are discussed.     

Total Synthesis of (−)‐Cleistenolide

An efficient and short total synthesis of (?)‐cleistenolide ( 1 ) from D ‐mannitol with an overall yield of 23.6% is described. The chiron approach for the synthesis of (?)‐cleistenolide involves a one‐C‐atom Wittig olefination, a selective allylic triethylsilyl protection, and a Grubbs‐catalyzed ring‐closure‐metathesis (RCM) reaction as the key steps.     

Asymmetric synthesis of acyclic 1,3-amino alcohols by reduction of N-sulfinyl beta-amino ketones. Formal synthesis of (-)-pinidinol and (+)- epipinidinol

Stereoselective reduction of acyclic N-sulfinyl beta-amino ketones with (LiEt(3)BH) and Li(t-BuO)(3)AlH, respectively, gave anti- and syn-1,3-amino alcohols with excellent selectivity. A formal asymmetric synthesis of the hydroxy piperidine alkaloids (-)-pinidinol and (+)-epipinidinol from a common N-sulfinyl beta-amino ketone ketal precursor was developed. The pinidinol piperidine ring was formed via a novel acid-catalyzed cascade reaction of a N-sulfinylamino silyl protected alcohol ketal.     

Stereodivergent Synthesis of Piperidine Alkaloids by Ring‐Rearrangement Metathesis/Reductive Lactam Alkylation of Nitroso Diels–Alder Cycloadducts

A general methodology for the stereoselective synthesis of 2‐(2‐hydroxyalkyl)piperidine alkaloids by ring‐rearrangement metathesis of nitroso Diels–Alder cycloadducts is reported. The approach is illustrated by the formal synthesis of porantheridine and the total synthesis of andrachcinidine through a diastereodivergent allylation of an N‐alkoxy bicyclic lactam. The asymmetric synthesis of the latter alkaloid provides new insights into the configurational stability of cycloadducts between chloronitroso reagents and cyclopentadiene.     

An approach towards the total synthesis of (+)-epiquinamide and (+)-α-conhydrine from Garner aldehyde

A short and stereoselective route for the synthesis of 1-hydroxyquinolizidine, an advanced synthetic intermediate for the total synthesis of (+)-epiquinamide is presented. The key synthetic steps involve diastereoselective nucleophilic addition on l-serine derived Garner aldehyde and acid mediated (PTSA) ring closing metathesis. The methodology is also elaborated successfully for the total synthesis of (+)-α-conhydrine, an important piperidine alkaloid.     

A new route to trans-2,6-disubstituted piperidine-related alkaloids using a novel C2-symmetric 2,6-diallylpiperidine carboxylic acid methyl ester

A novel C2-symmetric 2,6-diallylpiperidine carboxylic acid methyl ester 1 was prepared by the double asymmetric allylboration of glutaldehyde followed by an aminocyclization and carbamation. On the basis of desymmetrization of 1 using iodocarbamation, one allyl group of 1 was protected and monofunctionalizations of the resulting oxazolidinone 11 were performed. The reaction of the N-methoxycarbonyl piperidine 25 employing decarbamation reagent (n-PrSLi or TMSI) as a key step gave oxazolidinone 26 or 17 including an intramolecular ring formation, which was transformed in a few steps into (-)-porantheridine (2) and (-)-2-epi-porantheridine (3), respectively. In addition, the expedient synthesis of (+)-epi-dihydropinidine (4), (2R,6R)-trans-solenopsin A (5), and precoccinelline (6), starting from 11 is described.     

Development and validation of an ultra high‐performance liquid chromatographic method for the determination of a diastereomeric impurity in (+)‐pinoresinol diglucoside chemical reference substance

(+)‐Pinoresinol 4,4′‐di‐O‐β‐D ‐glucopyranoside ((+)‐PDG) is one of the major lignans with various pharmacological activities which could be isolated from Duzhong and other plant species. In this study, a diastereomeric impurity, (?)‐pinoresinol 4,4′‐di‐O‐β‐D ‐glucopyranoside ((?)‐PDG), the main impurity was identified in (+)‐PDG chemical reference substance (CRS) and a reliable chromatographic method for rapid purity determination of (+)‐PDG CRS was firstly developed. The optimal chromatographic condition was found to be using ACN/1,4‐dioxane–water (2.5:6:91.5, v/v/v) as mobile phase on a Waters Acquity UPLC HSS T3 column (2.1 mm×100 mm, 1.8 μm) with column temperature of 37°C. The method was validated and applied to determine the chromatographic purity of five (+)‐PDG CRS samples. The content of (?)‐PDG in four commercial (+)‐PDG CRS was 8.47–20.30%, whereas no (?)‐PDG was detected in our in‐house prepared (+)‐PDG CRS in which purity was confirmed to be 99.80%. The above results confirmed that this method is fast and highly efficient for purity determination of the (+)‐PDG CRS.     

First Total Synthesis of (−)‐Ligustiphenol

The first asymmetric total synthesis of (?)‐ligustiphenol is reported. The key step was conducted by exploiting a steric hindrance effect to control the formation of the adduct in a nucleophilic α‐Li‐phenolate addition reaction to the intermediate α‐oxo (?)‐menthyl ester. The synthesis is concise and feasible for the construction of analogous compounds and investigation of their biological activity.     

Total synthesis of (-)-dendrobine

Cascading to alkaloids: An 18-step total synthesis of (-)-dendrobine is based on a reaction cascade with a key amine group (see scheme, Bn=benzyl). The amine is the initiator of the cascade and provides an efficient method for installing the stereocenters at C11 and C3. The overall transformation occurs stereoselectively only when the conversion is carried out without the isolation of intermediates.     

Enantioselective Synthesis of (−)‐(R)‐Cordiachromene and (−)‐(R)‐Dictyochromenol Utilizing Intramolecular SNAr Reaction

A simple and efficient enantioselective synthesis of chromene, (?)‐(R)‐cordiachromene ( 1 ), and (?)‐(R)‐dictyochromenol ( 2 ) has been accomplished. This convergent synthesis utilizes intramolecular S_NAr reaction for the formation of chroman ring, and Seebach's method of ‘self‐reproduction of chirality’ should establish the (R)‐configuration of the C(2) side chain as key steps.     

Synthesis of (−)‐3‐Carene‐2,5‐dione via Allylic Oxidation of (+)‐3‐Carene

Activated carbon‐supported CuCl₂ (CuCl₂/AC) is a heterogeneous catalyst for the liquid‐phase selective allylic oxidation of (+)‐3‐carene with tert‐butyl hydroperoxide (TBHP) and O₂ to produce (?)‐3‐carene‐2,5‐dione. The possible reaction mechanism and the effects of different factors on the allylic oxidation were investigated. The optimal conditions are as follows: reaction temperature, 45 °C; molar ratio of CuCl₂ to (+)‐3‐carene, 1%; volume ratio of (+)‐3‐carene to TBHP, 1:3; and reaction time, 12 h. Under the optimal conditions, the conversion of (+)‐3‐carene reached 100%, whereas the selectivity for (?)‐3‐carene‐2,5‐dione reached 78%. The CuCl₂/AC catalyst was characterized via X‐ray diffraction, and the chemical structure of the target compound was identified via infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, mass spectrometry, and optical analysis.     

Total Synthesis of (−)‐Himeradine A

(?)‐Himeradine A is a complex lycopodium alkaloid with seven rings and ten stereogenic centers that shows anticancer activity against lymphoma L1210 cells. A total synthesis has been developed that builds off prior work on (+)‐fastigiatine. A 2,4,6‐trisubstitited piperidine ring forms the core of the quinolizidine segment, and was prepared by diastereoselective reduction of a pyridine and classic resolution of an intermediate. The remaining secondary amine was introduced with a catalyst‐controlled Overman rearrangement. The piperidine segment was coupled in a B‐alkyl Suzuki reaction with a bicyclic bromoenone, which was a key intermediate for the synthesis of (+)‐fastigiatine. The final transformation featured a transannular Mannich reaction and cyclization to complete the quinolizidine. Five bonds and four new rings were generated in this one‐pot procedure. (?)‐Himeradine A was prepared in 17 steps in the longest linear sequence.     

Asymmetric synthesis of (+)-tetrahydropseudodistomin

An efficient asymmetric synthesis of (+)-tetrahydropseudodistomin is described. The important synthetic features include a Maruoka asymmetric allylation and a Sharpless asymmetric dihydroxylation as key steps for the generation of chirality at C-2, -4, and -5 of the trisubstituted piperidine ring.     

Enantioselective synthesis of (+)-l-733,060

An efficient enantioselective synthesis of (+)-l-733,060 from cinnamyl alcohol is described. The key steps include a Sharpless asymmetric epoxidation, a regioselective allyl opening of an epoxide and piperidine ring formation via a one pot Staudinger/aza-Wittig reaction.     

Highly Diastereoselective Total Syntheses of (+)‐7‐Epigoniodiol, (−)‐8‐Epigoniodiol,and (+)‐9‐Deoxygoniopypyrone

An expedient concise total synthesis of (+)‐7‐epigoniodiol, (?)‐8‐epigoniodiol, and (+)‐9‐deoxygoniopypyrone is accomplished. The key transformations include a catalytic hydroxylation and base‐mediated N‐(acetyl)oxazolidinone addition reactions, which could set the consecutive OH motif that is either syn,syn or syn,anti with high diastereoselectivity. Moreover, this approach envisioned to facilitate the synthesis of other representatives of the family with structural and stereochemical variation.     

Unusual Chemoselective RhII‐Catalysed Transformations of α‐Diazocarbonyl Piperidine Cores

The reactivity of various α‐diazocarbonyl piperidine scaffolds, characterised by an increased molecular complexity, was tested with various Rh^II catalysts. The structure of the starting reagent is of relevance to the synthetic results. An unexpected dimerisation took place, starting from the simple piperidine scaffold, to give the hexahydrotetrazine ring system. Products derived from a nitrogen ylide intermediate or aromatic substitution (1,3,4,5‐tetrahydro‐2,5‐methanobenzo[c]azepine and 1,2,3,3a‐tetrahydrocyclopenta[de]isoquinolin‐4(5 H)‐one rings, respectively) were obtained from tetrahydroisoquinoline derivatives. The chemoselectivity of the reaction could be controlled by the choice of starting reagent, Rh^II catalyst and the reaction conditions. Finally, it was found that the azepino heterocycle could coordinate to the catalyst to give new Rh^II complexes.     

Concise asymmetric synthesis of (−)-halosaline and (2R,9aR)-(+)-2-hydroxy-quinolizidine by ruthenium-catalyzed ring-rearrangement metathesis

A ruthenium-catalyzed ring opening-ring closing metathesis reaction serves as the key step in the stereoselective synthesis of a new enantiopure 2-substituted-4,5-dehydropiperidine skeleton, a valuable intermediate for the synthesis of piperidine alkaloids (such as (−)-halosaline) and of hydroxylated quinolizidines (such as (2R,9aR)-(+)-2-hydroxy-quinolizidine).     

Intramolecular carbolithiation of allyl o-lithioaryl ethers: a new enantioselective synthesis of functionalized 2,3-dihydrobenzofurans

A new and easy method for the diastereoselective synthesis of 3-functionalized 2,3-dihydrobenzofuran derivatives from allyl 2-bromoaryl ethers is described. The key step of this transformation involves an intramolecular carbolithiation reaction of allyl 2-lithioaryl ethers. The substituents in both the allyl and the aryl moieties play an important and decisive role in stopping the reaction at the benzofuran thus avoiding a gamma-elimination reaction. Finally, this process is amenable to the synthesis of enantiomerically enriched compounds by using (-)-sparteine as a chiral inductor.