Asymmetric Deprotonation Research Articles

PH-Responsive Properties of Asymmetric Nanopapers of Nanofibrillated Cellulose.

Inspired by plant movements driven by the arrangement of cellulose, we have fabricated nanopapers of nanofibrillated cellulose (NFC) showing actuation under pH changes. Bending was achieved by a concentration gradient of charged groups along the film thickness. Hence, the resulting nanopapers contained higher concentration of charged groups on one side of the film than on the opposite side, so that pH changes resulted in charge-dependent asymmetric deprotonation of the two layers. Electrostatic repulsions separate the nanofibers in the nanopaper, thus facilitating an asymmetric swelling and the subsequent expanding that results in bending. Nanofibrillated cellulose was modified by 2,2,6,6-tetramethylpiperidin-1-yloxyl radical (TEMPO) oxidation at two reaction times to get different surface concentrations of carboxylic acid groups. TEMPO-oxidized NFC was further chemically transformed into amine-modified NFC by amidation. The formation of graded nanopapers was accomplished by successive filtration of NFC dispersions with varying charge nature and/or concentration. The extent of bending was controlled by the charge concentration and the nanopaper thickness. The direction of bending was tuned by the layer composition (carboxylic acid or amine groups). In all cases, a steady-state was achieved within less than 25 s. This work opens new routes for the use of cellulosic materials as actuators.

Diastereoselective Lithiation of N-Benzyl Pyrroloimidazolones Derived from l-Proline Hydantoin

An N-benzyl pyrroloimidazolone derived from l-proline hydantoin undergoes asymmetric lithiation with n-BuLi/TMEDA in toluene to give products of electrophile quench (E+) that range from 87:13 to 91:9 diastereomeric ratio (dr). All products appear to have the same relative stereochemistry as determined by transmetalation of benzylic stannanes, which gave identical major diastereomers for several products as to what was observed by direct lithiation–substitution of the starting material. X-Ray crystallography of the major diastereomer of the benzophenone adduct established (R)-configuration at the benzylic center, i.e., anti stereochemistry with respect to the imidazolone. Lithiation of a selectively deuterated analogue of the starting material according to the optimized conditions, followed by benzophenone quench, gave diastereomeric products with far lower selectivity (53:47 dr) than lithiation of the non-deuterated analogue (91:9 dr) owing to a large primary kinetic isotope effect. These preliminary results imply that metalation of the N-benzyl pyrroloimidazolone may follow an asymmetric deprotonation pathway to give a benzylic carbanion that retains its configuration during electrophile quench.

ChemInform Abstract: Development of Chiral Heteroleptic Magnesium Amides; Asymmetric Deprotonations Mediated by Six‐Membered Metallocyclic Amidomagnesium Naphtholates.

AbstractA series of chiral six‐membered metallocyclic amidomagnesium naphthalates is prepared and used in the asymmetric deprotonation of prochiral ketones.

Asymmetric total synthesis of (-)-lundurine B and determination of its absolute stereochemistry.

A total synthesis of the Kopsia tenuis alkaloid (-)-lundurine B has been achieved. A quaternary chiral carbon has been created by an asymmetric deprotonation using a symmetric spiro cyclohexanone intermediate with a chiral lithium amide. The hexacyclic skeleton was sequentially constructed through metal-mediated reactions. The absolute stereochemistry of intermediate 5 has been unambiguously established by X-ray crystallographic analysis. This is the first description of the absolute stereochemistry of Kopsia tenuis alkaloids based on chemical synthesis.

ChemInform Abstract: Solvent‐Free Synthesis of a Secondary N‐Benzhydrylamine as a Chiral Reagent for Asymmetric Deprotonation of Bicyclic N‐Benzylamino Ketones.

Abstract(R)‐N‐benzhydryl‐1‐phenylethylamine is utilized as chiral auxiliary in asymmetric deprotonations of N‐benzyl analogues of tropinone and granatanone.

Development of chiral heteroleptic magnesium amides; asymmetric deprotonations mediated by six-membered metallocyclic amidomagnesium naphtholates

A series of enantioenriched six-membered metallocyclic amidomagnesium naphtholates were prepared and used to probe the structure–reactivity/selectivity relationships of heteroleptic magnesium base complexes within asymmetric deprotonation reactions. An effective complex was identified and applied within enantioselective enolisation processes, delivering good levels of enantioselectivity and also revealing key structural requirements for achieving such selectivity.

ChemInform Abstract: Asymmetric Transformations by Deprotonation Using Chiral Lithium Amides

AbstractReview: 392 refs.

Solvent-Free Synthesis of a Secondary N-Benzhydrylamine as a Chiral Reagent for Asymmetric Deprotonation of Bicyclic N-Benzylamino Ketones

Several chiral secondary N -benzhydrylamines were synthesized in good yields (68–92%) without racemization by the direct alkylation of amines with benzhydryl chloride under solvent-free conditions. Using the solvent-free conditions ( R )- N -benzhydryl-1-phenylethylamine was obtained with the highest yield (92%), purified on ion-exchange resin, and converted to its hydrochloride salt. The resulting chiral amine hydrochloride was transformed into lithium amide/lithium chloride mixture used in asymmetric deprotonations of N -benzyl analogues of tropinone and granatanone followed by aldol reactions giving products in high ­diastereomeric purities (up to 96%) and enantiomeric excesses of 77 to 96%.

Enantioselective desymmetrization of prochiral ketones via an organocatalytic deprotonation process

The first desymmetrization of 4-substituted cyclohexanones by organocatalytic asymmetric deprotonation at low catalyst loading is reported. The combination of N,O-bis(trimethylsilyl)acetamide (BSA) and chiral quaternary ammonium aryloxide salts has been used as an efficient organocatalytic system to provide silyl enolates in high yields and with modest ee.

Preparation and Reactions of Enantiomerically Pure α-Functionalized Grignard Reagents

A strategy for the generation of enantiomerically pure α-functionalized chiral Grignard reagents is presented. The approach involves the synthesis of α-alkoxy and α-amino sulfoxides in ≥99:1 dr and ≥99:1 er via asymmetric deprotonation (s-BuLi/chiral diamine) and trapping with Andersen's sulfinate (menthol derived). Subsequent sulfoxide → Mg exchange (room temperature, 1 min) and electrophilic trapping delivers a range of enantiomerically pure α-alkoxy and α-amino substituted products. Using this approach, either enantiomer of products can be accessed in 99:1 er from asymmetric deprotonation protocols without the use of (-)-sparteine as the chiral ligand. Two additional discoveries are noteworthy: (i) for the deprotonation and trapping with Andersen's sulfinate, there is a lack of stereospecificity at sulfur due to attack of a lithiated intermediate onto the α-alkoxy and α-amino sulfoxides as they form, and (ii) the α-alkoxy-substituted Grignard reagent is configurationally stable at room temperature for 30 min.

Asymmetric Synthesis of 2-Arylpyrrolidines by Cationic Cyclization

Homoallylic amines were prepared by asymmetric deprotonation of benzylamines using n-BuLi and (–)-sparteine to give chiral organolithiums to which were added prenyl bromide. Removal of the Boc protecting group gave anilines that were found to undergo Bronsted acid catalyzed or iodine-mediated cyclization to give aryl-substituted pyrrolidine heterocyclic products with high enantioselectivity.

Approaches to the enantioselective synthesis of ferrugine and its analogues

A four-step synthetic route, to ferrugine (2α-benzoyltropane), its methyl analogue (2-acetyltropane) and their N-benzyl analogues is reported. The reaction sequence uses tropinone or N-benzylnortropinone aldols as key intermediates. Reduction of aldol derived N-tosylhydrazones and oxidation of the side chain hydroxyl group followed by spontaneous diastereomer equilibration provides the final products. Relative configuration of the exo,anti N-methyl and N-benzyl aldols was retained during N-tosylhydrazone formation. The relative stereochemistry of N-tosylhydrazones was assigned by single crystal diffraction. The final products, ferrugine and its methyl analogue, were synthesized in enantiomerically pure form via asymmetric deprotonation of tropinone using chiral lithium amide/lithium chloride aggregate prepared in situ from (S,S)-N,N-bis(1-phenylethyl)amine hydrochloride.

Evaluation of the Chiral DIANANE Backbone as Ligand for Organolithium Reagents

Novel endo,endo-2,5-diaminonorbonane-derived tertiary C2-symmetrical diamines were synthesized via the one-pot reductive amination of enantiomerically pure norbornane-2,5-dione. These ligands were applied to various catalytic reactions such as asymmetric deprotonation, asymmetric bromine-lithium exchange, and enantioselective addition of aryl- and allkylithium reagents to aromatic aldimines.

N-Butyllithium

n-Butyllithium (n-BuLi) is one of the most prominent organolithium reagents in the whole of synthetic chemistry,[1] [2] [3] and available as solutions in alkanes such as pentane, hexane, or heptane, which is usually encountered as a pale yellow solution. It is unstable towards air or moisture but stable in an atmosphere of nitrogen. It has been widely used in organic reactions, such as regioselective lithiation reaction,[ 4 ] reversible metathesis reaction,[ 5 ] Claisen rearrangement,[ 6 ] phospho-Fries rearrangement,[ 7 ] coupling reaction,[ 8 ] asymmetric deprotonation–electrophilic trapping reaction,[ 9 ] enantioselective hydroxyalkylation,[ 10 ] etc. In general, n-butyllithium is commercially available and can also be prepared readily by the reaction of 1-bromobutane or 1-chlorobutane with Li metal (Scheme [1]).[ 11 ] An overview of the usage of n-BuLi in ­organic synthesis is presented below.

Asymmetric Synthesis and Metal Complexes of aC3-Symmetric P-Stereogenic Triphosphine, (R)-MeSi(CH2PMe(t-Bu))3(MT-Siliphos)

Asymmetric deprotonation of PMe2(t-Bu)(BH3) with s-BuLi/(−)-sparteine, followed by treatment with MeSiCl3, gave a 2.6:1 mixture of the C3- and C1-symmetric triphosphine–boranes MeSi(CH2PMe(t-Bu)(BH3))3 (3). Recrystallization gave highly diastereomerically and enantiomerically enriched C3-3. After deprotection with morpholine, the triphosphine (R)-MeSi(CH2PMe(t-Bu))3 (4; (Me, t-Bu)-Siliphos or MT-Siliphos) was used to prepare the metal complexes [Rh(MT-Siliphos)(norbornadiene)][OTf] (5), Ru(MT-Siliphos)(DMSO)Cl2 (6), [Ru(MT-Siliphos)(NCMe)3][OTf]2 (7), M(MT-Siliphos)(PPh3) (M = Pd (8), Pt (9)), Cu(MT-Siliphos)(Cl) (10), and polymeric [Cu2Cl2(μ-(κ2,κ1)-MT-Siliphos)]∞ (11). The crystal structures of C3-3 and of complexes 5, 7, and 11 were determined, and dynamic processes in 6 and 8 were characterized by variable-temperature NMR spectroscopy.

Stereocontrolled asymmetric synthesis of syn-E-1,4-diol-2-enes using allyl boronates and its application in the total synthesis of solandelactone F

The solandelactones A-H comprise a novel class of oxygenated fatty acids bearing an eight-membered lactone, trans cyclopropane, and a 2-ene-1,4-diol subunit. The relative stereochemistry of the 1,4-diol subunit is anti in solandelactones A, C, E & G, and syn in solandelactones B, D, F & H. Having prepared one member of the solandelactones bearing anti stereochemistry (solandelactone E), we have targeted the syn series and developed methodology for the synthesis of enantioenriched syn-2-ene-1,4-diols. The methodology comprises asymmetric deprotonation of an alkyl 2,4,6-triisopropylbenzoate using sBuLi/sparteine, followed by addition of the α-lithiobenzoate to β-silyl vinyl boronic acid ethylene glycol ester. The boron-ate complex generated undergoes a 1,2-metallate rearrangement furnishing an intermediate allyl boronic ester which is trapped by an aldehyde in the presence of MgBr(2) to furnish anti-β-hydroxy E-allylsilanes in good yields, high diastereoselectivity and high enantioselectivity. These sensitive products were oxidized using mCPBA to the corresponding epoxides and subsequently treated with acid to furnish syn-E-2-ene-1,4-diols (~4:1 d.r.). Application of the methodology to appropriately functionalized aldehyde and ω-alkenyl 2,4,6-triisopropylbenzoate coupling partners, led to a short, highly selective route to solandelactone F (bearing a syn-E-2-ene-1,4-diol).

ChemInform Abstract: Towards Energetically Viable Asymmetric Deprotonations: Selectivity at more Elevated Temperatures with C2‐Symmetric Magnesium Bisamides.

AbstractThe novel C2‐symmetric magnesium bisamide MBSA shows an unique ability to function efficiently in asymmetric deprotonation reactions.

Synthesis of NS9544 Acetate

NS9544 acetate is a monoamine reuptake inhibitor that is a candidate for the treatment of neuropathic pain. After all attempts at a classical resolution of intermediate E failed, an asymmetric synthesis was undertaken in which the chirality was introduced by asymmetric deprotonation of tropinone A using the chiral lithium amide base B.

One-ligand Catalytic Asymmetric Deprotonation of a Phosphine Borane: Synthesis of P-Stereogenic Bisphosphine Ligands

A new protocol for the catalytic asymmetric deprotonation of a phosphine borane using s-BuLi and substoichiometric quantities of chiral diamines is reported. The method involves three sequential additions of s-BuLi, and use of (-)-sparteine or the (+)-sparteine surrogate facilitates access to P-stereogenic phosphines with opposite configuration. The method is exemplified by the catalytic asymmetric synthesis of each enantiomer of precursors to QuinoxP*, trichickenfootphos, and Mini-PHOS.

Investigation of bispidines as the stoichiometric ligand in the two-ligand catalytic asymmetric deprotonation of N-boc pyrrolidine

A range of achiral bispidines have been synthesized and evaluated as the stoichiometric ligand in the two-ligand catalytic asymmetric deprotonation of N-Boc pyrrolidine.