Diastereoselective Synthesis of Open‐Chain Secondary Alkyllithium Compounds and Trapping Reactions with Electrophiles

A practical stereoselective iodide–lithium exchange was used in the first general preparation of functionalized stereodefined acyclic secondary nonstabilized lithium reagents from the corresponding secondary alkyl iodides. These lithium reagents react with various electrophiles including carbon electrophiles with high retention of configuration. Kinetic data on the configurational stability of these acyclic alkyllithium reagents are given. This methodology offers a new entry to chiral synthons for the stereoselective synthesis of open‐chain molecules.     

Stereoselective Retentive Domino Transmetalations of Secondary Alkyllithium Compounds to Functionalized Secondary Alkylcopper Reagents

Functionalized secondary alkyllithium reagents obtained by I/Li exchange from the corresponding secondary alkyl iodides undergo two successive transmetalations with Me₃SiCH₂ZnBr?LiBr and CuBr?2 LiCl?Me₂S to provide functionalized secondary alkylcopper compounds with high retention of configuration. These alkylcopper derivatives react further with electrophiles such as alkynyl esters, acid chlorides, allylic chlorides, ketals, ethylene oxide, and 3‐iodocyclopentanone with high retention of configuration. A related sequence of transmetalations with MeMgI and LaCl₃?2 LiCl allows a retentive addition of secondary alkyllithium reagents to acetone. The influence of the solvent on the configurational stability of secondary alkylzinc reagents is described.     

SN1‐Type Substitution Reactions of N‐Protected β‐Hydroxytyrosine Esters: Stereoselective Synthesis of β‐Aryl and β‐Alkyltyrosines

The title compounds were prepared by aldol reaction of anisaldehyde and the respective N,N‐dibenzyl glycinates. Deprotection of the nitrogen atom with Pearlman’s catalyst delivered the unprotected β‐hydroxytyrosine esters, which were further N‐protected as N,N‐phthaloyl (Phth) and N‐fluorenylmethylcarbonyloxy (Fmoc) derivatives. The Friedel–Crafts reaction with various arenes was studied employing these alcohols as electrophiles. It turned out that the facial diastereoselectivitiy depends on the nitrogen protecting group and on the ester group. The unprotected substrates (NH₂) gave preferentially syn‐products but the anti‐selectivity increased when going from NHFmoc over NPhth to NBn₂. If the ester substituent was varied the syn‐preference increased in the order Me <Et <iPr. The reactions were shown to be fully stereoconvergent and proceeded under kinetic product control. A model is suggested to explain the facial diastereoselectivity based on a conformationally locked benzylic cation intermediate. The reactions are preparatively useful for the N‐unprotected isopropyl ester, which gave Friedel–Crafts alkylation products with good syn‐selectivity (anti/syn=21:79 to 7:93), and for the N,N‐dibenzyl‐protected methyl ester, which led preferentially to anti‐products (anti/syn=80:20 to >95:5). Upon acetylation of the latter compound to the respective acetate, Bi(OTf)₃‐catalyzed alkylation reactions became possible, in which silyl enol ethers served as nucleophiles. The respective alkylation products were obtained in high yield and with excellent anti‐selectivitiy (anti/syn≥95:5).     

Preparation of Stereodefined Secondary Alkyllithium Compounds

We have developed a practical stereoretentive iodine/lithium‐exchange process that allows the stereodefined preparation of cis‐ and trans‐cycloalkyllithium compounds from their corresponding stereodefined iodides. Quenching with electrophiles offers stereospecific access to both cis‐ (up to 96 % cis) and trans‐cycloalkyl derivatives (up to 99 % trans). A detailed study of the thermodynamic stabilities, stereochemical behavior, and reactivities of axially and equatorially substituted cyclohexyllithium reagents is reported. Ab initio calculations demonstrate that the formation of oligomeric cyclohexyllithium structures is pivotal for explaining the observed stereochemical preference.     

Diastereo‐ and Regioselective Addition of Thioamide Dianions to Imines and Aziridines: Synthesis of N‐Thioacyl‐1,2‐diamines and N‐Thioacyl‐1,3‐diamines

Addition reactions of thioamide dianions that were derived from N‐arylmethyl thioamides to imines and aziridines were carried out. The reactions of imines gave the addition products of N‐thioacyl‐1,2‐diamines in a highly diastereoselective manner in good‐to‐excellent yields. The diastereomeric purity of these N‐thioacyl‐1,2‐diamines could be enriched by simple recrystallization. The reduction of N‐thioacyl‐1,2‐diamines with LiAlH₄ gave their corresponding 1,2‐diamines in moderate‐to‐good yields with retention of their stereochemistry. The oxidative‐desulfurization/cyclization of an N‐thioacyl‐1,2‐diamine in CuCl₂/O₂ and I₂/pyridine systems gave the cyclized product in moderate yield and the trans isomer was obtained as the sole product. On the other hand, a similar cyclization reaction with antiformin (aq. NaClO) as an oxidant gave the cis isomer as the major product. The reactions of N‐tosylaziridines gave the addition products of N‐thioacyl‐1,3‐diamines with low diastereoselectivity but high regioselectivity and in good‐to‐excellent yields. The use of AlMe₃ as an additive improved the efficiency and regioselectivity of the reaction. The stereochemistry of the obtained products was determined by X‐ray diffraction.     

Diastereoselective Nucleophilic Ring‐Opening Reactions of 2,6‐Diazasemibullvalenes for the Synthesis of Diverse Functionalized Δ1‐Bipyrroline Derivatives

Nucleophilic ring‐opening reactions of 2,6‐diazasemibullvalenes (NSBVs) were investigated. Different types of nucleophile (alcohols, phenols, thiols, carboxylic acids, water, enols, amines, indoles, metal‐halide salts, sodium azide, organozinc compounds, lithium alkynethiolate, and sulfoxonium ylides) were used to afford diverse functionalized Δ¹‐bipyrroline derivatives in good yields with high regio‐ and diastereoselectivity. Most of the reactions featured milder conditions and higher reactivity relative to those for common aziridine derivatives, probably because of the rigid ring system and substitution patterns of NSBVs.     

Homologous SNV Reaction: Synthesis of l‐Methyl‐4‐[4′‐phenylsulfonyl‐1′,3′‐butadienyl]pyridinium Iodide and Its Reactivity with Thiol Groups Giving Rise to the Chromophoric Thioether

Thioether 4‐[(1′E,3′E)‐4′‐phenylsulfanyl‐1,3′‐butadienyl]pyridine 8 and sulfone 4‐(4′‐phenylsulfonyl‐1′,3′‐butadienyl)pyridine 14 were prepared by reaction of the carbanions derived from allylic thioether or allylic sulfone with isonicotinaldehyde. The reaction with the sulfonyl carbanion occurred at the α position and on heating the alcolate gave the dienic sulfone 14 . The corresponding pyridinium iodide 10 and 15 were prepared by reaction with methyl iodide, respectively, on pyridine derivates 8 and 14 . The dienic pyridinium thioether 10 showed a long wavelength absorption band centered at 420 nm. The reaction of dienic pyridinium sulfone 15 with thiophenol gave the dienic pyridinium thioether 10 by a nucleophilic vinylic substitution. The reaction of sulfone 15 with glutathione was of second order and the rate constant was 8.5 M^?1s^?1 at 30°C and pH 7, about 500 times smaller than the rate constant observed with (E)‐1‐methyl‐4‐(2‐methylsulfonyl‐1‐ethenyl)pyridinium iodide 1 . The dienic pyridinium thioether 10 was a negative solvatochrome.     

Regio‐ and Stereoselective Allylic Substitutions of Chiral Secondary Alkylcopper Reagents: Total Synthesis of (+)‐Lasiol, (+)‐13‐Norfaranal,and (+)‐Faranal

Chiral secondary alkylcopper reagents were prepared from chiral secondary alkyl iodides by a retentive I/Li exchange followed by a retentive transmetalation with CuBr?P(OEt)₃. Switching the solvent to THF significantly increased their configurational stability and made these copper reagents suitable for regioselective allylic substitutions. The optically enriched copper species underwent S_N2 substitutions with allylic bromides (up to >99 % S_N2 regioselectivity). The addition of ZnCl₂ and the use of chiral allylic phosphates allowed to switch the regioselectivity towards S_N2′ substitution (up to >99 % S_N2′ regioselectivity) and to perform highly selective anti‐S_N2′ substitutions with absolute control over two adjacent stereocenters. This method was applied in the total synthesis of the three ant pheromones (+)‐lasiol, (+)‐13‐norfaranal, and (+)‐faranal (up to 98:2 dr, 99 % ee).     

Stereodivergent Quaternization of 2‐Alkyl‐2‐p‐tolylsulfinylacetonitriles: NMR Spectroscopic Evidence of Planar and Pyramidal Benzylic Carbanions

Enantiomerically enriched α,α‐disubstituted phenylacetonitriles have been readily prepared by stereoselective quaternization of 2‐alkyl‐2‐[2‐(p‐tolylsulfinyl)phenyl]acetonitriles with different alkylating electrophiles in the presence of bases. The use of potassium hexamethyldisilazane (KHMDS)/[18]crown‐6 ether and NHMDS with alkyl halides afforded S,S_S and R,S_S diastereoisomers, respectively, in high enantiomeric purities, thus providing stereodivergent processes for synthesizing both isomers. The dependence of the stereochemical course of the reactions on the experimental conditions (mainly on the counterion) has been rationalized by assuming a planar or pyramidal structure for the benzylic carbanions. This hypothesis has been supported by NMR spectroscopic studies, which permit one to assign a chelated pyramidal structure to the sodium benzylic carbanions and an almost planar naked carbanionic structure to the potassium benzylic carbanions generated in the presence of [18]crown‐6 ether.     

Nucleophilic Cyclopropanation Reaction with Bis(iodozincio)methane by 1,4‐Addition to α,β‐Unsaturated Carbonyl Compounds

Treatment of α,β‐unsaturated ketones with an electrophilic site at the γ‐position in the presence of trimethylsilyl cyanide with bis(iodozincio)methane afforded the (Z)‐silyl enol ether of the β‐cyclopropyl substituted ketone in good yields. The reaction proceeds by 1,4‐addition to form an enolate, and its sequential intramolecular nucleophilic attack to an adjacent electrophilic site. The reaction of γ‐ethoxycarbonyl‐α,β‐unsaturated ketone and bis(iodozincio)methane in the presence of trimethylsilyl cyanide afforded 1‐ethoxy‐1‐trimethylsiloxycyclopropane derivatives, which can be regarded as the homoenolate equivalent. Additionally, reaction of the obtained homoenolate equivalents with imines give 1‐(E)‐alkenyl‐2‐(1‐aminoalkyl)alkanols diastereoselectively.     

Synthesis and Conformational Analysis of Hybrid α/β‐Dipeptides Incorporating S‐Glycosyl‐β2,2‐Amino Acids

We synthesized and carried out the conformational analysis of several hybrid dipeptides consisting of an α‐amino acid attached to a quaternary glyco‐β‐amino acid. In particular, we combined a S‐glycosylated β^2,2‐amino acid and two different types of α‐amino acid, namely, aliphatic (alanine) and aromatic (phenylalanine and tryptophan) in the sequence of hybrid α/β‐dipeptides. The key step in the synthesis involved the ring‐opening reaction of a chiral cyclic sulfamidate, inserted in the peptidic sequence, with a sulfur‐containing nucleophile by using 1‐thio‐β‐D ‐glucopyranose derivatives. This reaction of glycosylation occurred with inversion of configuration at the quaternary center. The conformational behavior in aqueous solution of the peptide backbone and the glycosidic linkage for all synthesized hybrid glycopeptides was analyzed by using a protocol that combined NMR experiments and molecular dynamics with time‐averaged restraints (MD‐tar). Interestingly, the presence of the sulfur heteroatom at the quaternary center of the β‐amino acid induced θ torsional angles close to 180° (anti). Notably, this value changed to 60° (gauche) when the peptidic sequence displayed aromatic α‐amino acids due to the presence of CH–π interactions between the phenyl or indole ring and the methyl groups of the β‐amino acid unit.     

Lys314 is a Nucleophile in Non‐Classical Reactions of Orotidine‐5′‐Monophosphate Decarboxylase

Molecular versatility : Unusual reactivities such as hydrolysis, nucleophilic aromatic substitution, and addition reactions of human orotidine‐5′‐monophosphate decarboxylase are explained by crystal structures and involve a nucleophilic lysine residue that normally is expected to act solely as a general base (RP=phosphoribosyl, R=CO₂H, CN, acetyl, N₃, I; R′=OH, SH, acetyl, hydroxymethyl).