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.     

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.     

Formal Synthesis of (−)‐Cephalotaxine

A formal synthesis of (?)‐cephalotaxine ( 1 ) by means of a highly stereoselective radical carboazidation process is reported. The synthesis begins with the protected (S)‐cyclopent‐2‐en‐1‐ol derivative 10 and uses the concept of self‐reproduction of a stereogenic center (Schemes 5 and 6). For this purpose, the double bond adjacent to the initial chiral center in 10 is converted into an acetonide after stereoselective dihydroxylation. The initial alcohol function is used to build an exocyclic methylene group suitable for the carboazidation process 8 → 7 (Scheme 7). Finally the protected diol moiety is converted back to an alkene ( 14 → 15 → 6 ) and used for the formation of ring B via a Heck reaction ( 6 →(?)‐ 16 ; Scheme 8).     

Natural (−)‐Vasicine as a Novel Source of Optically Pure 1‐Benzylpyrrolidin‐3‐ol

A facile and scalable methodology for the preparation of optically active (3S)‐1‐benzylpyrrolidin‐3‐ol ( 3 ), an important drug precursor, is reported. Starting from the naturally occurring alkaloid (?)‐vasicine ( 1 ), a major alkaloid of the plant Adhatoda vasica, 3 was obtained in 84% overall yield (Scheme 3).     

On the Reactivity of (−)‐(R)‐Carvone and (−)‐4aα,7α,7aβ‐Nepetalactone: Synthesis of New Heterocycles

The 1,3‐dipolar cycloaddition of 4‐chlorobenzonitrile oxide to the unsaturated system of (?)‐(R)‐carvone occurred exclusively at C(8) to give a new isoxazoline derivative. This derivative reacts with NH₂OH to yield a new heterocycle, observed for the first time. On the other hand, the addition of 4‐chlorobenzonitrile oxide to the unsaturated lactone (?)‐4aα,7α,7aβ‐nepetalactone gave, in a good yield, also a new heterocycle, again obtained for the first time. The terpenoid (?)‐(R)‐carvone and iridoid (?)‐4aα,7α,7aβ‐nepetalactone were isolated from Moroccan species Mentha viridis (L.) and Nepeta tuberosa (L.), respectively. The new heterocycles obtained were identified by combination of chromatographic and spectroscopic methods.     

Exaltone® (=Cyclopentadecanone) from Isomuscone® (=Cyclohexadecanone), a One‐C‐Atom Ring‐Contraction Methodology via a Stereospecific Favorskii Rearrangement: Regioselective Application to (−)‐(R)‐Muscone

Treatment of cyclohexadecanone ( 1g ; with I₂ (2.2 mol‐euqiv.) and KOH in MeOH) furnished the unsaturated (Z)‐ester 2g in 83% yield, via a stereospecific Favorskii rearrangement (Scheme 1). Further treatment with 3‐chloroperbenzoic acid (m‐CPBA) afforded the unreported epoxy ester 3g (88% yield), which was cleaved in 33% yield to Exaltone^® (=cyclopentadecanone; 1f ) with NaOH in MeOH/H₂O and then HCl at 65°. This methodology was similarly extended to higher (C₁₇) and lower (C₁₅ to C₁₁) cyclic ketone analogues, as well as regioselectively to (?)‐(R)‐muscone ( 5c ) and homomuscone ( 5f ) (Scheme 2). Olfactive properties of the corresponding macrocyclic 1‐oxaspiro[2,n]alkanes and ‐alkenes 4 and 8 , resulting from a Corey? Chaykovsky oxiranylation, are also presented.     

Alkyne‐Mediated Approach to the Synthesis of (4R,5R)‐5‐Hydroxy‐4‐decanolide and (−)‐Muricatacin

The asymmetric synthesis of two naturally occurring 5‐hydroxy‐γ‐butyrolactones, (4R,5R)‐5‐hydroxy‐4‐decanolide ( 1a ) and (?)‐muricatacin ( 2 ), is described using a general alkyne‐mediated strategy. The key steps involved are Sonogashira coupling for the desired carbon‐chain extension followed by Sharpless asymmetric dihydroxylation to construct the hydroxy‐lactone framework.     

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.     

Stereoselective Synthesis of (−)‐Pinidinone

A simple and efficient stereoselective linear approach to the total synthesis of (?)‐pinidinone has been accomplished starting from propane‐1,3‐diol, and employing Maruoka asymmetric allylation and Grubbs' olefin cross‐metathesis as the key steps.     

Synthesis of (−)‐Pinellic Acid and Its (9R,12S,13S)‐Diastereoisomer

The total synthesis of (?)‐pinellic acid with (9S,12S,13S)‐configuration and its (9R,12S,13S)‐diastereoisomer was achieved in high overall yields from a common intermediate derived from (+)‐L ‐diethyl tartrate.     

Formal Synthesis of (−)‐Cyclaradine Using Ring Closing Metathesis

The stereoselective formal synthesis of (?)‐cyclaradine from the inexpensively available starting material L ‐glutamic acid is described, using Eschenmoser's reagent, and applying Luche reduction, Grignard reaction, and ring closing metathesis (RCM) as the key steps.     

Facile and Efficient Synthesis of (R)‐4‐(Benzyloxy)‐3‐methylbutanenitrile: Toward Developing a Versatile Chiral Building Block

A practical synthesis of (R)‐4‐(benzyloxy)‐3‐methylbutanenitrile, a potential chiral building block, from the corresponding α‐keto ester in high yield and large scale was presented.     

Total Synthesis of (+)‐β‐Himachalene

An enantioselective synthesis of (+)‐β‐himachalene ( 2 ) was accomplished starting from (1S,2R)‐1,2‐epoxy‐p‐menth‐8‐ene ( 3 ) in 15 or 16 steps with an overall yield of ca. 6% (Schemes 3, 5, and 6). Key transformations include an Ireland–Claisen rearrangement, a Corey oxidative cyclization, and a ring expansion.     

Stereocontrolled Total Synthesis of (+)‐trans‐Dihydronarciclasine

A highly stereoselective and efficient total synthesis of trans‐dihydronarciclasine from a readily available chiral starting material was developed. The synthesis defines two of the five stereogenic centers of the natural product by an amino acid ester–enolate Claisen rearrangement. The other three stereogenic centers are created in a highly stereocontrolled fashion via a six‐ring vinylogous ester intermediate, which is generated from the γ,δ‐unsaturated ester functional group of the Claisen rearrangement product in an efficient three‐step sequence. This concise total synthesis exemplifies the use of a highly regioselective Friedel–Crafts‐type cyclization to form the B ring via an isocyanate intermediate derived from an N‐Boc group, which is superior to the conventional method using an imino triflate intermediate. This same N‐Boc group is employed to give high selectivity in the Claisen rearrangement earlier in the sequence.     

Enantioselective determination of R‐(−)‐manidipine and S‐(+)‐manidipine in human plasma by a sensitive and selective chiral LC–MS/MS assay

A sensitive and selective liquid chromatography–tandem mass spectrometric (LC–MS/MS) assay method has been developed and validated for the enantioselective determination of manidipine in human plasma using isotope‐labeled compounds as internal standards. After solid‐phase extraction, R ‐(−)‐manidipine and S ‐(+)‐manidipine were chromatographed on a Chiralpack IC‐3 C₁₈ column using a isocratic mobile phase composed of 2 mm ammonium bicarbonate and acetonitrile (15:85, v /v). The precursor ion to product ion transitions for the enantiomers and internal standards were monitored in the multiple reaction monitoring and positive ionization mode using an API‐4000 mass spectrometer. The method was linear over the concentration range of 0.05–10.2 ng/mL for both enantiomers. The precision and accuracy results over five concentration levels in five different batches were well within the acceptance limits. The mean extraction recovery was >80% for both enantiomers. A variety of stability tests were executed in plasma and in neat samples, which complies with the FDA guidelines. After complete validation, the method was successfully applied to a pharmacokinetic study of a manidipine 20 mg oral dose in 10 healthy South India subjects under fasting conditions. The assay reproducibility is shown through incurred samples reanalysis of 20 subject plasma samples.     

An Efficient Synthesis of a (−)‐Physostigmine's Library for Identifying Potential Anti‐Alzheimer's Agents

An efficient route for the synthesis of (?)‐physostigmine analogs 1a – 1g and 2a – 2k is described. Analogs 1a – 1g were synthesized via copper(I)‐catalyzed cycloaddition between the optically pure azide 10 and a variety of alkynes. Similarly, analogs 2a – 2k were prepared through ‘three‐component Huisgen cycloaddition’ using various amines, propargyl bromine, and 10 in H₂O. Facile preparation of 10 via MacMillan's organocatalysis has made it possible to generate a great diversity of natural product‐like compounds that can be screened for anti‐Alzheimer's effects.     

Studies toward the Synthesis of (R)‐(+)‐Harmicine

The study toward the total synthesis of (R)‐(+)‐harmicine is reported in this paper. The enantioselective synthesis of pyrrolidinone, the main backbone of of (R)‐(+)‐harmicine, has been completed by the methodology based on photo‐induced Wolff rearrangement of α‐diazo‐β‐carbonyl compounds.     

Total Synthesis of (−)‐Norzoanthamine

No bones about it : (?)‐Norzoanthamine, a promising candidate for an anti‐osteoporotic drug, was the target of a total synthesis (see scheme). The final bisaminal formation with AcOH/H₂O gave the DEFG ring, while the cyclization precursor was prepared by installing the remaining bisaminal unit after oxidative cleavage of the cyclopentanol moiety.