Enantioselective Synthesis with Lithium/(−)-Sparteine Carbanion Pairs

“Chiral carbanions”—that is, enentiomerically enriched lithium–carbanion pairs in which the carbanionic center carries the chiral information—were regarded until recently as “exotic species.” In the past ten years it has become clear that they can, in fact, play a meaningful role in enantioselective synthesis, since substitution for lithium occurs here stereospecifically, usually with retention of configuration. They are also more readily and commonly accessible than was originally assumed. The trick lies in the use of lithium cations with chiral ligands, whether in the form of alkyllithium species used as bases in kinetically controlled, enantiotopically discriminating deprotonation, or in thermodynamically controlled equilibration in configurationally labile epimeric ion pairs. The lupine alkaloid (?)-sparteine has shown itself admirably suited as a chiral bidentate ligand, and its efficiency and breadth of application are so far unsurpassed. This contribution constitutes an overview of the preparation of chiral reagents, convering primarily “umpoled” synthons such as homoenolates. 1-oxyalkanides with a broad pattern of substitution, and α-aminobenzyl anions.     

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).     

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.     

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.     

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).     

Crystallographic report: A two‐dimensional homochiral coordination polymer: [cadmium(II) bis(S‐(−)‐lactate)]n

In the two‐dimensional (2D) homochiral structure of [cadmium(II) bis(S‐(?)‐lactate)]_n, the lactate ligand adopts a µ₃‐bridging mode to connect two cadmium atoms, leading to the formation of a 2D network. Copyright © 2004 John Wiley & Sons, Ltd.     

Validation of a high‐performance liquid chromatography method for the determination of (−)‐α‐bisabolol from particulate systems

A reversed‐phase high performance liquid chromatography method has been developed and validated for determination and quantitation of the natural sesquiterpene (−)‐α‐bisabolol. Furthermore the application of the method was done by characterization of chitosan milispheres and liposomes entrapping Zanthoxylum tingoassuiba essential oil, which contains appreciable amount of (−)‐α‐bisabolol. A reversed‐phase C₁₈ column and gradient elution was used with the mobile phase composed of (A) acetonitrile–water–phosphoric acid (19:80:1) and (B) acetonitrile. The eluent was pumped at a flow rate of 0.8 mL/min with UV detection at 200 nm. In the range 0.02–0.64 mg/mL the assay showed good linearity (R² = 0.9999) and specificity for successful identification and quantitation of (−)‐α‐bisabolol in the essential oil without interfering peaks. The method also showed good reproducibility, demonstrating inter‐day and intra‐day precision based on relative standard deviation values (up to 3.03%), accuracy (mean recovery of 100.69% ± 1.05%) and low values of detection and quantitation limits (0.0005 and 0.0016 mg/mL, respectively). The method was also robust for showing a recovery of 98.81% under a change of solvent in standard solutions. The suitability of the method was demonstrated by the successful determination of association efficiency of the (−)‐α‐bisabolol in chitosan milispheres and liposomes. Copyright © 2009 John Wiley & Sons, Ltd.     

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.     

Synthetic Strategies for (−)‐Cannabidiol and Its Structural Analogs

(?)‐Cannabidiol ((?)‐CBD), a non‐psychoactive phytocannabinoid from Cannabis, and its structural analogs have received growing attention in recent years because of their potential therapeutic benefits, including neuroprotective, anti‐epileptic, anti‐inflammatory, anxiolytic, and anti‐cancer properties. (?)‐CBD and its analogs have been obtained mainly based on extraction from the natural source; however, the conventional extraction‐based methods have some drawbacks, such as poor quality control along with purification difficulty. Chemical‐synthetic strategies for (?)‐CBD could tackle these issues, and, additionally, generate novel (?)‐CBD analogs that exhibit advanced biological activities. This review concisely summarizes the historic and recent milestones in the synthetic strategies for (?)‐CBD and its analogs.     

Highly Efficient Asymmetric Synthesis of Vinylic Amino Alcohols by Zn‐Promoted Benzoyloxyallylation of Chiral N‐tert‐Butanesulfinyl Imines: Facile and Rapid Access to (−)‐Cytoxazone

An efficient and convenient α‐hydroxyallylation approach for the asymmetric synthesis of a variety of β‐amino‐α‐vinyl alcohols has been successfully developed. A wide range of vinylic amino alcohol derivatives could be obtained in very good yields and with excellent diastereomeric ratios of up to 99:1 in favor of anti isomers by highly diastereoselective Zn‐promoted benzoyloxyallylation of chiral N‐tert‐butanesulfinyl imines with 3‐bromopropenyl benzoate at room temperature. In particular, excellent enantioinduction of the two new stereogenic centers was observed, with up to 98 % ee. The method provides a new route for the direct α‐hydroxyallylation of imines in a highly stereoselective manner. Moreover, the synthetic value of the method has also been demonstrated by the most concise and straightforward synthesis of (?)‐cytoxazone yet reported.     

Method development for determination of (+)‐catechin and (−)‐epicatechin by micellar electrokinetic chromatography: Annual characterization of field grown blackberries

Berries are a rich source of antioxidants compounds, among which is the catechin group. Determination of the monomers (catechin and epicatechin) in fruits is a first step in the way to establish a relationship between polyphenols and their effects on human health. The purpose of this work is to develop a method to determine free catechins in blackberry by MEKC and to characterize levels of catechins in fresh fruits of Rubus fruticosus var. Lochness throughout the annual production period. A methanolic extract was prepared from fresh fruit. Then, it was evaporated and the residue was extracted with diethyl ether. MEKC conditions: phosphoric acid, 30 mmol/L; SDS, 40 mmol/L and triethylamine, 0.1% v/v at pH 2.3; ?15 kV of voltage; 10‐s hydrodynamic injection; 25°C temperature; and detection at 200 nm. Instrumental and interday precision were lower than 4.7 and 10% RSD, respectively. Only (?)‐epicatechin was quantified in blackberries and ranged from 120 to 620 mg/kg fresh weight, which were the lowest values in December and the highest in June. A solid–liquid extraction and an MEKC method were successfully applied to determine (?)‐epicatechins in blackberry for the first time. A strong dependence of (?)‐epicatechin on the annual average temperature was observed.     

Anion⋅⋅⋅Si Interactions in an Inverse Sandwich Complex: A Computational Study

Combination of an electron‐rich molecule (e.g. chloride anion or nitrile group) with a chlorinated cyclohexasilane ring produces a supramolecular inverse sandwich complex formed by two guests (Cl^? or R?C≡N) strongly bonded to both faces of a planar host (Si₆ ring). In‐depth theoretical studies were carried out to investigate the nature of the bonding interactions that generate such a stable complex. Second‐order Møller–Plesset perturbation theory (MP2) calculations confirmed that the presence of the Cl substituents is fundamental to the stability of the supramolecular assemblies. The density functional theory (DFT) functional wB97XD gave an estimation of the contribution of dispersion interactions to the binding energy. These interactions become more important as the Cl atoms of the rings are systematically replaced by methyl groups or hydrogen atoms. Analysis of the topology of the electron density and the reduced density gradient gave insight into the binding of the studied supramolecular assemblies.     

The Use of (−)‐Sparteine/Organolithium Reagents for the Enantioselective Lithiation of 7,8‐Dipropyltetrathia[7]helicene: Single and Double Kinetic Resolution Procedures

The effect of organolithium reagent (RLi: R=nBu, iPr, sBu, tBu), solvent (diethyl ether, diethyl ether/THF and MTBE), and stoichiometry on the (?)‐sparteine‐mediated silylation of 7,8‐dipropyltetrathia[7]helicene shows that, unusually, substantially more than 0.5 equivalent of RLi (R=iPr, sBu, tBu) and a large excess of (?)‐sparteine (R=nBu, sBu) is often needed to achieve substantial conversions and good ee values. With nBuLi, however, just one equivalent of the organolithium reagent is sufficient to obtain high conversions. Our best results were obtained using the convenient tBuLi/(?)‐sparteine adduct with which the need for a high (?)‐sparteine/RLi ratio can be avoided. Single‐ and double‐kinetic resolution (KR) procedures give enantiopure samples of 2‐trimethylsilyl‐ and 2,13‐di(trimethylsilyl)‐7,8‐dipropyltetrathia[7]helicene and two‐step double‐KR combining (?)‐sparteine/sBuLi and chiral formamides affords the synthetically valuable 2‐formyl‐7,8‐dipropyltetrathia[7]helicene. This is the first use of (?)‐sparteine for the enantioselective lithiation of helicenes and the first report of tBuLi outperforming sBuLi in a (?)‐sparteine‐mediated procedure.     

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.