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Background and purpose The metabolic activity of cytochrome P450 (CYP) 2D6 is highly variable and CYP2D6 genotypes insufficiently explain the extensive and intermediate metabolic phenotypes, limiting the prediction of drug response plus adverse drug reactions. Since CYP2D6 prototypic substrates are positively charged, the aim of this study was to evaluate the organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) as potential contributors to the variability of CYP2D6 hydroxylation of debrisoquine, dextromethorphan, diphenhydramine, perhexiline and sparteine. Experimental approach OCT1/SLC22A1-, OCT2/SLC22A2-, OCT3/SLC22A3-, MATE1/SLC47A1-, and MATE2K/SLC47A2-overexpressing cell lines were used to investigate the transport of the selected drugs. Individuals from a study cohort, well defined with respect to CYP2D6 genotype and sparteine pharmacokinetics, were genotyped for the common OCT1 variants rs12208357 (OCT1-R61C), rs34130495 (OCT1-G401S), rs202220802 (OCT1-Met420del), rs34059508 (OCT1-G465R), OCT2 variant rs316019 (OCT2-A270S) and MATE1 variant rs2289669. Sparteine pharmacokinetics was stratified according to CYP2D6 and OCT1, OCT2 or MATE1 genotype. Key results OCTs and MATE1 transport sparteine and debrisoquine with high affinity in vitro, but OCT- and MATE1-dependent transport of dextromethorphan, diphenhydramine and perhexiline was not detected. Sparteine and debrisoquine transport depends on OCT1 genotype; however, sparteine pharmacokinetics is independent from OCT1 genotype. Conclusions and implications Some drugs that are substrates of CYP2D6 are also substrates of OCTs and MATE1, suggesting overlapping specificities. Variability in sparteine hydroxylation in extensive and intermediate metabolizers cannot be explained by OCT1 genetic variants indicating presence of other factors. Dose-dependent toxicities of dextromethorphan, diphenhydramine and perhexiline appear to be independent from OCTs and MATEs.

Kinetic resolution of 2‐arylindolines (2,3‐dihydroindoles) was achieved by treatment of their N‐tert‐butoxycarbonyl (Boc) derivatives with n‐butyllithium and sparteine in toluene at −78 °C followed by electrophilic quench. The unreacted starting materials together with the 2,2‐disubstituted products could be isolated with high enantiomer ratios. Variable temperature NMR spectroscopy showed that the rate of Boc rotation was fast (ΔG ≠≈57 kJ/mol at 195 K). This was corroborated by DFT studies and by in situ ReactIR spectroscopy. The enantioenriched N‐Boc‐2‐arylindolines were converted to 2,2‐disubstituted products without significant loss in enantiopurity. Hence, either enantiomer of the 2,2‐disubstituted products could be obtained with high selectivity from the same enantiomer of the chiral ligand sparteine (one from the kinetic resolution and the other from subsequent lithiation‐trapping of the recovered starting material). Secondary amine products were prepared by removing the Boc group with acid to provide a way to access highly enantioenriched 2‐aryl and 2,2‐disubstituted indolines., Asymmetric synthesis of 2‐arylindolines was achieved by kinetic resolution with n‐butyllithium and the chiral ligand sparteine followed by electrophilic quench. The recovered starting materials and the 2,2‐disubstituted products were isolated with high enantiomer ratios. Variable temperature NMR spectroscopy and DFT studies were used to determine the rate of Boc rotation.

The lupin alkaloid sparteine is a well-known chiral diamine with a range of applications in asymmetric synthesis, as well as a blocker of voltage-gated sodium channels (VGSCs). However, there is only scarce information on the VGSC-blocking activity of sparteine derivatives where the structure of the parent alkaloid is retained. Building on the recent renewed availability of sparteine and derivatives we report herein how modification of sparteine at position 2 produces irreversible blockers of VGSCs. These compounds could be clinically envisaged as long-lasting local anesthetics.

Three chiral derivatives of the alkaloid sparteine (bispidines), characterized by the 3,7-diazabicyclo[3.3.1]nonane moiety, were designed as efficient ligands in a number of enantioselective reactions due to their metal coordination properties. A full evaluation of the 3D properties of the compounds was carried out, as the geometrical features of the bicyclic framework are strictly related to the efficiency of the ligands in the asymmetric catalysis. The selected molecules have different molecular complexity for investigating the effects of different chiral groups on the bicycle conformation. We report here a thorough analysis of their molecular arrangement, by NMR spectroscopy, single crystal X-ray crystallography, and computational techniques, which put in evidence their conformational preferences and the parameters needed for the design of more efficient ligands in asymmetric synthetic routes. The results confirmed the high molecular flexibility of the compounds, and indicated how to achieve a control of the chair-chair/boat-chair conformational ratio, by adjusting the relative size of the substituents on the piperidine nitrogens.

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.

A novel methodology for the asymmetric synthesis of trans-3,4-diaryl-substituted tetrahydroquinolines via sparteine-assisted stereoselective lithiation of o-substituted N-pivaloylanilines (I), kinetic resolution of epoxides in substitution and a stereospecific Mitsunobu cyclization is developed.

The (+)-sparteine-mediated lithiation–substitution of o-benzyl-N-pivaloylaniline with various ketones was investigated. The obtained highly enantioenriched tertiary alcohols were used for the synthesis of alkenyl-substituted products 12 and 13 as well as 3,3,4-trisubstituted tetrahydroquinoline derivatives 22–24. The reaction with α,β-unsaturated ketones afforded highly enantioenriched 1,4-addition products 28–33 and provided a protocol for the asymmetric synthesis of highly substituted tetralin derivative 34.

5-Mono- and 5,5-disubstituted tricyclic bispidines, derivatives of the known (+)-sparteine surrogate, have been synthesized in four-to-six steps from the natural alkaloid (–)-cytisine and evaluated as chiral ligands in the enantioselective lithiation/stannylation of an O-alkyl carbamate. Structure–selectivity studies revealed that a small 5-endo substituent is tolerated, whereas larger 5-endo substituents and even small 5-exo substituents lead to significantly reduced levels of chirality transfer.

D 7 Li, 15 N heteronuclear shift correlation through scalar cou- pling has successfully been applied to several lithium organyls consisting of polydentate N ligands such as N,N,N',N'-tetramethylethylenediamine (tmeda), N,N,N',N',N''-pentamethyldi- A (pmdta) and (� )-spar- teine. Structural insights on the confor- mation of benzyllithium·pmdta (5 )i n a toluene solution and the strength of ion pairing in combination with PGSE NMR measurements, 1 H, 1 H- NOESY and 1 H, 7 Li-HOESY experi- ments are presented. By studying in detail the formation of 5 in solution, a transient species has been observed for the first time and assigned to a pre- complex of nBuLi and pmdta. In addi- tion, the solution behaviour of the complex formed between benzyllithium and (� )-sparteine (8) has been studied by PGSE and multinuclear NMR spec- troscopy. The straightforward synthesis and first applications in asymmetric lithiations are also reported, which show that the new system benzyllithi- um·(� )-sparteine (8) provide poorer enantioselective induction than the classical nBuLi·(� )-sparteine (6). The results were supported by deprotona- tion experiments confirming that the formation of 8 relies on two relevant factors, namely temperature and lithi- A reagent. The existence of 8 may thus interfere with the asymmetric in- duction when the system nBuLi· (� )-sparteine is used in the enantiose- lective deprotonations of N-Boc-N-(p- methoxyphenyl)-benzylamine conduct- ed in toluene.

This article addresses the mechanistic features of asymmetric car- bolithiation of b-methylstyrenes. While often the presence of functional groups is required to obtain high enantioselec- tivities in carbolithiation reactions, simple b-methylstyrene also gives high selectivities in ()-sparteine-mediated addition of alkyl lithium compounds. Computational studies on the carboli- thiation of b-methylstyrene with ()- sparteine show that the observed selec- tivities are the result of repulsion ef- fects in the diastereomeric transition states between the ()-sparteine·alkyl lithium adduct and the b-methylstyr- ene, upon approximation of the two re- actants. In contrast, for the ortho- amino b-methylstyrene (E)-benzyl(2- propenylphenyl)amine (4) X-ray struc- ture analyses of intermediate lithium amides indicate a carbolithiation mech- anism in which one side of the double bond is shielded by the amide moiety, leaving only one side free for approach of the chiral alkyl lithium adduct.

The aim of this study was to remove the alkaloids from bitter lupin (Lupinus albus L.) seeds by different debittering methods and to produce a lupin bean snack. During production of the snack, the total alkaloid content of seeds decreased significantly (P ≤ 0.01) from 14.4 g/kg to a level that was undetectable. A major alkaloid in lupin seeds was identified as lupanine. It was present at a concentration of 12.513 g/kg, which constituted 87% of the total alkaloid content. The other alkaloids that were identified were sparteine, albine, α-isolupanine and multiflorine. The concentrations of the alkaloids decreased gradually during the debittering process. The values for dry matter, protein, lipid, starch and ash content of seeds changed in a statistically significant manner (P ≤ 0.05, P ≤ 0.01) during production of the snack. Aqueous debittering at room temperature was found to be a more favorable process because it resulted in more acceptable sensorial properties than alkaline and thermal debittering methods. PRACTICAL APPLICATIONS Bitter lupin seeds (Lupinus albus L.) cannot be consumed directly because they naturally contain high amounts of toxic alkaloids, which cause bitterness, despite their high protein content. The aim of this study is to remove bitterness from lupin seeds with different debittering methods and to produce a lupin bean snack.

Tertiary aminoferrocenes complexed to boron trifluoride (BF 3 ) are shown to undergo asymmetric lithiation with alkyllithiums in the presence of bulky chiral 1,2-diaminocyclohexane ligands. This reaction represents the first BF 3 -activated asymmetric lithiation of a prochiral aromatic amine and the first such transformation to be mediated by a chiral diamine other than (-)-sparteine. The process provides rapid access to a broad range of enantiomerically enriched 2-substituted-1-aminoferrocenes, including derivatives with uncommon substitution patterns that are of interest in catalysis. The enantioselectivity of the process is high enough (87:13 to 91:9 er) to allow for isolation of single enantiomers of several products after simple recrystallization as either the free aminoferrocenes or their ammonium fluoroborate salts. Both antipodes of the planar chiral 2-substituted-l-aminoferrocene products are accessible, as confirmed by single crystal X-ray diffraction analysis of two compounds with opposite relative stereochemistry. Single-point calculation of thirty-two different transition states of the reaction at the M06-2X/6-311+g(2d,2p) level produced a computational model that correctly predicted both the sense and extent of chiral induction. Three factors appeared to play important roles in determining enantioinduction during lithiation of BF 3 -complexed tertiary aminoferrocenes: (i) the maintenance of a highly organized eight-membered ring transition state; (ii) the existence of a strong Li···F contact which placed the chiral diamine ligand in close proximity to the ferrocene substrate; (iii) the orientation of the sterically demanding N-alkyl groups of the chiral diamine additives, either away or towards, the aminoferrocene and the alkyllithium. The model may serve as a predictive tool for the rational design of new ligands for this and related asymmetric lithiations.

This study evaluated the effectiveness of extraovular .1% ethacridine lactate alone and edacridine lactate plus spartein sulfate in midtrimester pregnancy termination. In the 60 cases where ethacridine lactate alone was administered, 50 cases aborted within 48 hours of instillation (83.3% success rate). Of these 50, 25 aborted within 24 hours (41.7%). Abortion was complete in 45 cases. The time of onset of uterine contractions ranged from 1 hour to 16.5 hours, with a mean 21-1/4 hours. The mean time of membrane rupture in the series was 23 hours and the induction-abortion interval averaged 27-1/4 hours. Side effects included vomiting (18.3%), shivering (16.6%), fever (3.3%), cervical injuries (6.6%), and excessive blood loss (1.7%). Blood loss until expulsion of the fetus averaged 54.1 ml, and blood loss up to 4 hours after abortion averaged 115.1 ml in cases of complete abortion and 219 ml in cases of incomplete abortion. In the 90 cases where both ethacridine lactate and spartein sulfate were used, 76 aborted within 48 hours (success rate 84.6%) and 40 aborted within 24 hours (44.4%). Abortion was complete in 75% of cases. The abortion-induction interval ranged from 4 hours to 47-3/4 hours, with a mean of 28-1/2 hours. These results, which are comparable to those obtained in other studies, indicate that extraovular ethacridine lactate alone appears to be a safe, efficient, and relatively inexpensive method of midtrimester abortion. Although there were fewer reports of side effects in the group that received spartein sulfate, use of this compound does not reduce the induction-abortion interval. The relatively low incidence of side effects such as vomiting and diarrhea, the antiseptic properties of ethacridine lactate, and the absence of serious complications such as rupture of the uterus and cervicovaginal fistula are advantages of the ethacridine lactate method that nullify the disadvantage of its slightly prolonged induction-abortion interval.

Inspired by pioneering contributions on chiral Bronsted acid mediated reactions and our own studies in aminocatalysis, we are currently exploring asymmetric counteranion-directed catalysis (ACDC) as a general strategy for asymmetric synthesis. According to this concept, catalytic reactions that proceed via cationic intermediates can be performed highly enantioselectively by the incorporation of a chiral counteranion into the catalyst. After our initial proof of concept with organocatalytic transfer hydrogenations and epoxidations, ACDC has recently been extended to transition-metal catalysis with Toste s gold-catalyzed allene cyclizations, and our palladium-catalyzed Tsuji–Trost-type a-allylation of aldehydes. The further exploration of the potential of ACDC in transition-metal catalysis, especially applied to redox reactions, is of great interest and significance. Here we report a highly enantioselective epoxidation of olefins that is catalyzed by a chiral ion pair consisting of an achiral Mn–salen cation and a chiral phosphate counteranion. Stimulated by an important contribution from Kochi et al. , Jacobsen and Katsuki have significantly advanced the catalytic asymmetric epoxidation of unfunctionalized alkenes by introducing chiral Mn–salen catalysts. These complexes display a broad substrate scope although certain olefin classes still fail to be converted with high enantioselectivity. Interestingly, cationic Mn–salen complexes are C2-symmetrical and inherently chiral—even when the salen ligand itself is achiral. In case of the Jacobsen–Kastuki epoxidation, the chiral backbone of the salen ligand fixes the complex in one of the two enantiomorphic confirmations. The neutral donor ligands typically added increase reactivity and enantioselectivity by displacing the apically coordinated anion of the Mn complex. Chiral neutral donor ligands such as sparteine and chiral N-oxides have been used in combination with an achiral Mn–salen complex and shown to shift the equilibrium of enantiomeric conformational isomers of the cationic metal complex to one side. Reasonably good enantioselectivities have been achieved in the corresponding epoxidations. We hypothesized that a chiral counteranion should also be able to induce a preference for one of the two enantiomorphic conformations. Specifically, chiral binol-derived phosphate anions are ideally suited for our purposes, because in addition to possibly inducing one enantiomorphic conformation of the cationic complex, these ions may also amplify the chiral microenvironment around the metal center with suitable substituents at the 3,3’-positions (Figure 1). Overall, this may lead to a new type of chiral Mn–salen catalyst with unique properties.

A series of (–)-sparteine-coordinated lithiosilanes was synthesised and studied by X-ray structural analysis. All lithiosilanes are monomers in the solid state; yet, increasing sizes of substituents at silicon significantly influences their molecular structures. Due to the given stereochemistry of the dinitrogen (–)-sparteine ligand, all systems possess stereoinformation. NMR spectroscopic studies were used to obtain deeper insight into the structures of these compounds in solution. Observed coupling between the silicon and lithium atoms as well as the presence of only one signal for each atom in the NMR spectra are indicative of monomeric structures of the lithiosilanes in solution. Additional quantum chemical calculations on one of the examined (–)-sparteine-coordinated systems provided very small energy differences between the diastereomers.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Regio- and stereoselective 1,3-dipolar cycloaddition of nitrile oxides to internal 2-pentenols and α,β-unsaturated esters catalyzed by (−) sparteine-lanthanide complexes affords corresponding 3-aryl-2-isoxazolines with enantioselectivities up to 68% ee.

Using the chiral ligand (-)- sparteine as additive, the asymmetric allylation of ortho-methoxydiphenylmethane (I) is carried out with e.e.

A novel methodology for the asymmetric synthesis of trans-3,4-diaryl-substituted tetrahydroquinolines via sparteine-assisted stereoselective lithiation of o-substituted N-pivaloylanilines (I), kinetic resolution of epoxides in substitution and a stereospecific Mitsunobu cyclization is developed.

The preparation and synthetic application of novel copper(II)/(+)-sparteine surrogates are described.

The (+)-sparteine-mediated lithiation–substitution of o-benzyl-N-pivaloylaniline with various ketones was investigated. The obtained highly enantioenriched tertiary alcohols were used for the synthesis of alkenyl-substituted products 12 and 13 as well as 3,3,4-trisubstituted tetrahydroquinoline derivatives 22–24. The reaction with α,β-unsaturated ketones afforded highly enantioenriched 1,4-addition products 28–33 and provided a protocol for the asymmetric synthesis of highly substituted tetralin derivative 34.

The deprotonation of β-stereogenic alkyl carbamates 8 with sec-butyllithium/TMEDA proceeds kinetically controlled with differentiation between the diastereotopic protons at the α-methylene group. The lithium intermediates 9A and 9B are trapped by electrophiles to give carboxylic acid esters 10A/B and stannanes 11A/B, 13A/B. The diastereomeric ratio of A to B is independent of the electrophile. The highest efficiency is achieved with β-aryl-β-alkyl-substituted starting compounds 8d–f. The trends in the experimentally observed diastereoselectivities are reflected by the results of semiempirical PM3 calculations on the transition states of the deprotonation reaction. — As a result of double stereodifferentiation, application of the chiral base sec-butyllithium/(-)-sparteine gives rise to efficient kinetic resolution of racemic alkyl carbamates.

(Z)-1,3-Diphenyl-1-propenyl N,N-diisopropylcarbamate (6d) is deprotonated by n-butyllithium/(–)-sparteine (5) with a high degree of enantiotopic differentiation in the γ-position to form the enantiomerically enriched allyllithium derivative 7d. Despite of its high mesomeric stabilization it shows a high degree of configurational stability. Trapping with carbonyl electrophiles proceeds exclusively in a syn-SE' substitution as shown by direct assignments and stereochemical correlations. Thus, the involvement of a η3 complex is suggested. After transfer to the analogous allyltitanates 16 enantiomerically and diastereomerically pure homoaldol products 17 are furnished. Evidence for a competing retro-homoaldol reaction is reported. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

We report a new synthesis of kainoids via allyllithium compounds using an intramolecular cycloalkylation as the key step. Preparation of different substituted pyrrolidines was carried out by using carbamates, that react with the chiral base n-BuLi/(–)-sparteine with strong selection between the diastereotopic protons adjacent to the carbamate group in favour for the pro-S proton. (–)-α-Kainic acid was synthetized from D-serine methyl ester hydrochloride, based on a (–)-sparteine-mediated asymmetric deprotonation of an intermediate carbamate that, by stereospecific anti-SN′SE′ intramolecular cycloalkylation, leads to the pyrrolidine ring precursor of (–)-α-kainic acid, in high yield and diastereoselectivity. Related approaches, starting from L-glutamic acid failed. The intermediate pyrrolidine was further transformed to (–)-α-kainic in three steps. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

The mass spectral fragmentations of 2-cyano-2-methylsparteine (1), 2-cyano-2-phenylsparteine (2), 2-cyano-2-(p-tolyl)sparteine (3), 17-cyanosparteine (4) and 17-cyanolupanine (5) were investigated. Fragmentation pathways, whose identification was assisted by accurate mass measurements and a correlation between the abundances of the M(+*) and the selected fragment ions of the investigated compounds, are discussed. The data obtained create the basis for distinguishing the structural metamers.

Air is enough to mediate the highly enantioselective oxidation of secondary alcohols at room temperature with palladium(II) and sparteine in nonflammable solvents. Examination of the role of solvents capable of hydrogen bonding and their ability to solvate halide anions led to a novel set of conditions for the highly enantioselective oxidative kinetic resolution of secondary alcohols.

N-Cumyl-N-ethylferrocenecarboxamide 5 provides planar chiral carboxamides 6 in high yield and % ee via (−)-sparteine-mediated directed ortho-metalation. Mild decumylation affords secondary amides 7, which serve as intermediates for a convenient and general route to the venerable Ugi planar chiral ferrocenylamines 13 and as versatile precursors for the preparation of novel chiral ferrocenes 15 and 20. The chiral TMS-ferrocenyl derivative 7c is used to prepare the enantiomeric (S)-7f, circumventing the lack of availability of (+)-sparteine.

Benzaldehyde dimethylacetal (1) and 2-aryl-1,3-dioxolanes 5 react with organolithium reagents 2 in the presence of chiral ligands such as sparteine (3), 1-alkoxy-2-aminoethanes, or 1,2-dialkoxyethanes and BF3 to afford monosubstitution products in high yields and in up to 81% enantiomeric excess. The enantioselectivity is strongly influenced by steric effects in the acetal and in the reagent. The highest ee was achieved with 2-(2-isopropyl)-1,3-dioxolane (5c) on treatment with 2-ethylphenyllithium (2i) in the presence of sparteine. The approach was applied to the synthesis of enantioenriched (S)-(−)-neobenodine (17) with 49% ee.

Five novel ortho-, meta-, and para-methyl-substituted triphenylmethyl methacrylate monomers, such as o-tolyldiphenylmethyl methacrylate (o-MeTrMA), di-o-tolylphenylmethyl methacrylate (o-Me2TrMA), tris-o-tolylmethyl methacrylate (o-Me3TrMA), tris-m-tolylmethyl methacrylate (m-Me3TrMA), and tris-p-tolylmethyl methacrylate (p-Me3TrMA) have been synthesized. The methanolysis rates of these monomers were measured in CDCl3-CD3OD (1:1, v/v) by 1H NMR spectroscopy at 30 °C. It was found that the order of the methanolysis rates would be TrMA o-Me2TrMA>o-Me3TrMA and m-Me3TrMA> p-Me3TrMA>o-Me3TrMA. These differences would be attributed to the different sizes and “propeller” steric structures of the bulky side groups. © 2001 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 430–436, 2001

Two generally applicable routes for the synthesis of chiral amino alcohols embodying the bispidine framework have been developed. In linear route A the bispidine framework is built up successively from chiral primary amines via intermediate formation of a piperidinone and a bispidinone. In convergent route B an achiral bispidine is formed first and then the N-substituents are introduced by reaction of the nitrogen bases with chiral electrophiles. In order to determine if the bispidine core and its N-substituents can influence the steric course of enantioselective transformations, bispidine amino alcohols built up by these two routes were investigated as chiral ligands in the enantioselectively catalyzed addition of diethylzinc to aldehydes and chalcone. In general, tridentate ligands containing one chiral amino alcohol fragment and a second amino substituent without a stereogenic center were more efficient than tetradentate ligands with two amino alcohol structural units. With the best ligands the enantioselective addition of diethylzinc to aromatic and aliphatic aldehydes proceeded with 83-98% ee and the nickel-catalyzed addition of diethylzinc to chalcone was achieved with up to 85% ee.

The external chiral ligand-induced enantioselective [2,3]-Wittig rearrangements of crotyl benzyl ethers and crotyl propargylic ethers are described. The most notable is that treatment of (E)-crotyl propargylic ethers with a t-butyllithium/(S;S)-bis(oxazoline) complex provides a relatively high enantioselectivity (up to 89% ee), together with a high threo-diastereoselectivity. Furthermore, examples of the “asymmetric catalytic version” of the rearrangement of crotyl benzyl ethers are presented. Chirality 12:505–509, 2000. © 2000 Wiley-Liss, Inc.

A novel domino-type reaction sequence consisting of an enantioselective intramolecular carbolithiation of 6-phenylhex-5-enyl carbamates and a highly stereospecific retro-[1,4]-Brook rearrangement is reported. The carbocycles are formed with high enantiomeric (er >98 : 2) and diastereoisomer ratios (dr >99 : 1) in good yields (47 – 60%). On the basis of the absolute configuration of the cyclization products, a stereoretentive mechanism is proposed for the retro-[1,4]-Brook rearrangement.

The energies of the diastereomorphic transition stateslk-F and ul-F (see scheme) of the deprotonation reaction were calculated and compared with the experimentally observed results.

An asymmetric intramolecular carbolithiation reaction was developed by combining the (−)-sparteine-mediated enantiotopos-differentiating deprotonation and the anionic 5-exo-trig cyclization. Achiral 6-phenylhex-5-enyl carbamates were efficiently cyclized furnishing regio-, diastereo- (dr >99 : 1), and enantioselectively (er >98 : 2) 1,2-trans-substituted cyclopentanes. The intermediate primary benzylic lithium-carbanion pairs were – in spite of their configurative lability – diastereoselectively substituted by versatile electrophiles creating a third consecutive stereogenic center. Additionally, some 4-functionalized 6-phenylhex-5-enyl carbamates were also cyclized in high yield to provide enantiomerically pure cyclopentanes incorporating three adjacent stereogenic centers.

Enantioselectiveadditionofan alkyllithiumcompound acrossa doublebond is achieved by the complexation of various primary or secondary organolithium compounds with (−)-sparteine [Eq. (a)]. This synthetic route is effective, simple, and may be useful for the synthesis of chiral disubstituted cyclopropanes.

Apowerfulnonenzymaticdesymmetrizationof ameso-diol, coupled with an efficient diastereoselective C–C bond formation at one of the enantiotopic sites is reported. The key step consists of the selection by sec-butyllithium/(−)-sparteine between enantiotopic and diastereotopic groups in the deprotonation step [Eq. (a)]. Kinetic resolutions of desymmetrized racemates (El = [D1] or Me3Sn) also were achieved.

The mass spectral fragmentations of 2-phenylsparteine, 2-(p-tolyl)sparteine, 15-phenylsparteine, 2-phenyl-2-dehydrosparteine, 2-(p-tolyl)-2-dehydrosparteine and 15-phenyl-14-dehydrosparteine were investigated. Fragmentation pathways, elucidation of which was assisted by accurate mass measurements and correlation between the abundances of the M+• and the selected fragment ions of investigated compounds, are discussed. The data obtained create the basis for distinguishing structural isomers. © 1998 John Wiley & Sons, Ltd.

Optically active poly[triphenylmethyl methacrylate-co-phenyl[bis(2-pyridyl)]methyl methacrylate] (poly[TrMA-co-PB2PyMA], poly[diphenyl(2-pyridyl)methyl methacrylate-co-phenyl[bis(2-pyridyl)]methyl methacrylate] (poly[D2PyMA-co-PB2PyMA]), and poly[triphenylmethyl methacrylate-co-diphenyl(2-pyridyl)-methyl methacrylate] (poly[TrMA-co-D2PyMA]) were prepared by helix-sense-selective copolymerization with complexes of organolithium with (−)-sparteine [(−)Sp],(S, S)-(+)- and (R, R)-(−)-2,3-dimethoxy-1,4-bis(dimethylamino)butane [(+)- and (−)DDB], and (S)-(+)-2-(1-pyrrolidinylmethyl)pyridine [(+)PMP] as anionic initiators in toluene at low temperature. The copolymers obtained with (−)Sp and (+)DDB or (−)DDB complexes of organolithium showed low optical activity, but to [(+)PMP] complex with N,N′-diphenyleneamine monolithium amide [(+)PMP–DPEDA–Li)] was effective in synthesizing copolymers of high optical rotation ([α] about +320 to + 370°) which were comparable to those of corresponding homopolymers with one-handed helical structure. The optical rotations of poly[TrMA-co-PB2PyMA] and poly[TrMA-co-D2PyMA] were much more stable than that of poly(D2PyMA) or poly(PB2PyMA) in a solution of CHCl3–2,2,2-trifluoroethanol (10 : 1, v/v) at 25°C, but optical rotation of poly[D2PyMA-co-PB2PyMA] slowly decreased with time in the same conditions. © 1998 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 36: 2127–2133, 1998

“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.

The steady-state pharmacokinetics in serum and urine of the enantiomers of citalopram and its metabolites, demethylcitalopram (DCT) and didemethylcitalopram (DDCT), were investigated after multiple doses of rac-citalopram for 21 consecutive days (40 mg per day) to healthy human subjects who were extensive metabolisers of sparteine and mephenytoin. Comparable pharmacokinetic variability was noted for (+)-(S)-, (-)-(R)- and rac-citalopram. Enantiomeric (S/R) serum concentration ratios for citalopram were always less than unity and were constant during the steady-state dosing interval. A modest, but statistically significant, stereoselectivity in the disposition of citalopram and its two main metabolites was observed. Serum levels of the (+)-(S)-enantiomers of citalopram, DCT, and DDCT throughout the steady-state dosing interval investigated were 37 +/- 6%, 42 +/- 3% and 32 +/- 3%, respectively, of their total racemic serum concentrations. The (+)-(S)-enantiomers of citalopram, DCT, and DDCT were eliminated faster than their antipodes. For (-)-(R)- and (+)-(S)-citalopram, respectively, the serum t1/2 averaged 47 +/- 11 and 35 +/- 4 h and AUCss averaged 4,193 +/- 1,118 h.nmol/l and 2,562 +/- 1,190 h.nmol/l. The observed enantiospecificities were apparently more related to clearance, rather than to distributional mechanisms.