Regio- and stereoselectivity in the reactions of organometallic reagents with an electron-deficient and an electron-rich vinyloxirane: applications for sequential bis-allylic substitution reactions in the generation of vicinal stereogenic centers

Vinyloxiranes provide opportunities for bis-allylic substitution reactions and the generation of new vicinal stereogenic centers if regio- and stereocontrol can be achieved. Ethyl (E)-4,5-epoxy-2-hexenoate affords excellent S(N)2':S(N)2 regioselectivity and anti:syn product diastereoselectivity with dialkyzinc reagents in the presence of CuCN, and conversion of the resultant allylic alcohol to the acetate affords good syn:anti product diastereoselectivity in S(N)2'-selective allylic substitutions with alkylcyanocuprates in THF. (E)-1-(tert-Butyldimethylsilyloxy)-2,3-epoxy-4-hexenonate gives excellent S(N)2':S(N)2 regioselectivity and anti:syn product diastereoselectivity with dialkyzinc reagents in THF or DMF or Grignard reagents in Et(2)O/THF (10/1) in the presence of CuCN. Conversion of the product allylic alcohol into the allylic phosphate affords excellent S(N)2' regioselectivity and syn:anti product diastereoselectivity with lithium alkylcyanocuprates for primary and secondary alkyl transferable ligands, while S(N)2 regioselectivity is observed for the tert-butyl ligand. Reaction conditions have been developed for regio- and stereocontrolled bis-allylic substitution reactions on both electron-rich and electron-deficient alkenyloxiranes, providing a methodology for the generation of vicinal alkane stereogenic centers.     

Organic Stereochemistry. Part 8

This review terminates our general presentation of the principles of stereochemistry with special reference to the biomedicinal sciences. Here, we discuss and illustrate the principles of prostereoisomerism, and apply these to product and substrate? product stereoselectivity in drug metabolism. The review begins with an overview of the concept of prostereoisomerism, discussing such aspects as homotopic, enantiotopic, and diastereotopic groups and faces. The main part of this review is dedicated to drug and xenobiotic metabolism. Here, the concept of prostereoisomerism proves particularly helpful to avoid confusing metabolic reactions in which an existing stereogenic element (e.g., a stereogenic center) influences the course of the reaction (substrate stereoselectivity), with metabolic reactions which create a stereogenic element (almost always a stereogenic center; product stereoselectivity). Specifically, examples of product stereoselectivity will be taken from functionalization reactions (so‐called phase‐I reactions) and conjugation (so‐called phase‐II reactions). Cases where stereoisomeric substrates show distinct product stereoselectivities (substrate? product stereoselectivity) will also be presented.     

Stereoselection in the Betti reaction of valine methyl esters

The multi-component Betti reaction of 2-naphthol, benzaldehyde and (S)-amines, that usually provides highly valuable aminobenzylnaphthol bearing two stereogenic centers, yielded a completely racemic product, when (S)-valine methyl ester was employed as the amine in the usual reaction protocol. The cause of this drawback, that appears to be overlooked in the literature, was investigated. As a result, new reaction conditions were set up, that were able to yield the expected useful product, having two fully resolved stereogenic centers. Furthermore, when the effect of substituents on the phenyl ring was preliminarily studied, we found that 4-fluoro- and 4-chlorobenzaldeyde gave stereoisomerically pure compounds also in the original reaction protocol.     

Palladium-catalyzed asymmetric synthesis of axially chiral allenylsilanes and their application to SE2' chirality transfer reactions

Stepwise application of the Pd-catalyzed S(N)2' reaction and the desilylative S(E)2' reaction to the ambivalent 2-bromo-1-silyl-1,3-dienes provides a novel route to the highly enantioselective construction of tertiary and quaternary propargylic stereogenic centers via axially chiral allenylsilanes.     

Structure/reactivity studies on an alpha-lithiated benzylsilane: chemical interpretation of experimental charge density

Modern organic synthesis (e.g., of natural products) is virtually impossible without employment of enantiomerically enriched compounds. In many cases, alkyllithium compounds are key intermediates for the generation of these stereogenic substances. In recent years, the lithiated carbon atom in silicon-substituted benzyllithium compounds has become a focus of interest because it is possible to maintain its stereogenic information. Starting from a highly enantiomerically enriched benzylsilane, (R,S)-2 x quinuclidine could be obtained, and the absolute configuration at the metalated carbon atom was determined by X-ray diffraction analysis. In solution, a quartet was found in the (13)C NMR spectrum for the metalated carbon atom because of coupling between carbon and lithium, indicating a fixed lithium carbon contact at room temperature. After reaction of (R,S)-2 x quinuclidine with trimethylchlorostannane, the trapped product (S,S)-4 was obtained with a dr > or = 98:2 with inversion of the configuration at the metalated carbon. Multipole refinement against high-resolution diffraction data and subsequent topological analysis of the benchmark system (R,S)-2 x quinuclidine provide insight in the electronic situation and thus the observed stereochemical course of the transformations. Surprisingly, the negative charge generated at the carbanion hardly couples into the phenyl ring. The neighboring silicon atom counterbalances this charge by a pronounced positive charge. Therefore, the alpha-effect of the silicon atom is caused not just by a polarization of the electron density but also by an electrostatic bond reinforcement. Furthermore, the experimentally determined electrostatic potential unequivocally explains the observed back side attack of an electrophile under inversion of the stereogenic center with high diastereomeric ratios.     

Intramolecular Diastereoselective Cascade Cyclization Reaction of N,N′-Bis(Salicylidene)Cyclohexanediimine with Phosphoryltrichloride to a Bis(Chlorophosphorylated) Decahydro-2,4-DI (2-Hydroxyphenyl)Benzo[d][1,3,6]oxadiazepine

Abstract

A new type of cascade cyclization was observed in the phosphorylation reaction of (R,R)- or (S,S)-N,N′-bis(salicylidene)cyclohexanediimine with phosphoryltrichloride, which resulted in the formation of bis(chlorophosphorylated) decahydro-2,4-di(2-hydroxyphenyl)benzo[d][1,3,6]oxadiazepine with two new stereogenic phosphorus atoms and two new stereogenic carbon atoms in the oxadiazepine ring in the β-position to phosphorus. During the synthesis, the N atom attacks the phosphorodichloridate group with the formation of the P–N bond to give an asymmetric phosphorus atom and an iminium ion. This compound with six stereogenic centers crystallizes in the monoclinic centrosymmetric space group P2₁/c and the crystal structure together with solution and solid-state MAS ¹³C and ³¹P NMR studies reveals a preferential formation of stereoisomers.     

Chiral alpha-branched benzylic carbocations: diastereoselective intermolecular reactions with arene nucleophiles and NMR spectroscopic studies

The chiral benzylic alcohols 1-6 were prepared and subjected to S(N)1-type displacement reactions with various arene nucleophiles in acidic medium. Under optimized conditions (HBF(4).OEt(2), CH(2)Cl(2), -78 degrees C --> r.t.) the corresponding 1,1-diarylalkanes 11-18 and 20 were obtained in good chemical yields (48-99%). The facial diastereoselectivity of the reaction is high (d.r. = 91/9-97/3) when the substrate bears a stereogenic carbon center -CHtBuMe in the alpha-position to the electrophilic carbon atom. If the starting material was enantiomerically pure, no significant racemization was observed (94% ee --> 92% ee). The reactions proceed stereoconvergently as demonstrated by the conversion of the separated diastereoisomers syn-1a and anti-1a in separate reactions to the same product syn-11 (d.r. = 97/3). Further evidence for long-lived chiral benzylic carbocations as reaction intermediates was obtained from NMR studies in superacidic medium. The chiral cation 24 was generated in SO(2)ClF as the solvent at -70 degrees C employing SbF(5) as the Lewis acid and characterized by its (1)H and (13)C NMR spectra. NOE measurements suggest a preferred conformation in which the diastereotopic faces of the cation are differentiated by the two carbon substituents R and Me at the stereogenic carbon center in the alpha-position. The hypothesis is further supported by the observation that the diastereoselectivity of the substitution reaction decreases if the bulky tert-butyl (R = tBu) substituent in the substrate 1a is replaced by a smaller ethyl group (2a, R = Et).     

A [4 + 4] 2-pyridone approach to taxol. 3. Stereocontrol during elaboration of the cyclooctane

Intramolecular photocycloaddition of 2-pyridones connected through a four-carbon tether (6-[4-(1,2-dihydro-1-methyl-2-oxo-3-pyridinyl)-4-[[(1,1-dimethylethyl)++ +dimethylsilyl]oxy]butyl]-4-methoxy-1,3-dimethyl-2(1H)-pyridinone) yields a single tetracyclic product with four new stereogenic centers. The diastereoselectivity of this [4 + 4] reaction is fully controlled by a stereogenic carbon of the tether. Treatment of the photoproduct with osmium tetraoxide transforms the alkene to a diol and the enol ether to an alpha-hydroxy ketone, with stereocontrol dictated by nearby lactams that block one face of each alkene. Allylmagnesium bromide addition to the ketone also yields a single diastereomer, but unexpectedly this product results from approach of the nucleophile to the most-hindered face of the ketone. Study of this reaction in a model system has found the allylic nucleophile to be unique, with nonallylic reagents approaching along the expected, least-hindered path. This contrasteric addition likely results from coordination of the allylic nucleophile to the nearby amide. The amide can therefore act either as a steric shield or as a directing group. The three steps of photocycloaddition, cis-hydroxylation, and nucleophilic addition constructs both quaternary carbons of the cyclooctane and four of the five stereogenic centers found in the eight-membered ring of Taxol.     

Total synthesis of (+)-brasilenyne. Application of an intramolecular silicon-assisted cross-coupling reaction

The first enantioselective total synthesis of (+)-brasilenyne (1) has been achieved in 19 linear steps, with 5.1% overall yield from l-(S)-malic acid. The construction of the oxonin core containing a 1,3-cis,cis diene unit was accomplished with a tandem ring-closing metathesis/silicon-assisted intramolecular cross-coupling reaction. In addition, a key propargylic stereogenic center was created through a novel, highly diastereoselective ring opening of a 1,3-dioxolanone promoted by TiCl(4). This reaction proceeded through an oxocarbenium ion intermediate and the asymmetric induction was fully controlled by l-malic acid residue. The C(8) stereogenic center was set by a reagent-controlled asymmetric allylboration.     

Origin of syn/anti diastereoselectivity in aldehyde and ketone crotylation reactions: a combined theoretical and experimental study

We report on experimentally determined and computationally predicted diastereoselectivities of (a) multicomponent crotylation (MCC) reactions of simple aliphatic aldehydes and ketones and (b) of acetal substitution (AS) reactions of aldehyde dimethyl acetals with E- and Z-configurated crotyl trimethylsilane to give homoallylic methyl ethers bearing two newly formed stereogenic centers. We found that corresponding MCC and AS reactions give nearly equal syn/anti ratios. While the crotylations of acetaldehyde and propionaldehyde mainly result in the syn product for E-configurated silane and in the anti product for Z-configurated silane, the syn product is found as main product for the crotylation of pivaldehyde regardless of substrate double bond geometry. Using butanone as substrate, the anti product is found as main product in both cases. By computational investigation employing the B3LYP/6-31+G(d) level of theory in dichloromethane solution (PCM/UAKS), we found that the attack of O-methyl-substituted carboxenium ions by crotyl silane explains the experimentally observed selectivities, indicating that these crotylations in fact proceed in an S(N)1-type reaction via this ionic intermediate. Comparison of relevant open transition-state structures leads to a rationalization of the observed selectivities. For all systems studied, three transition-state conformations are necessary and sufficient to determine the selectivity. This has been confirmed by studying the MCC reactions of isobutyraldehyde. Activation energies for the stereogenic step have been determined by calculation of the transition state and substrate structures in dichloromethane solution at the B3LYP/6-311+G(2d,p)//B3LYP/6-31+G(d) level of theory in dichloromethane solution. The possibility to predict simple diastereoselectivity in general Lewis acid-mediated crotylations of aldehydes and ketones is discussed.     

Rhodium(I)‐Catalyzed Enantioselective Activation of Cyclobutanols: Formation of Cyclohexane Derivatives with Quaternary Stereogenic Centers

The activation of carbon–carbon σ bonds is a complementary method to access uncommon and difficult‐to‐prepare organometallic species. Herein, we describe the activation of tert‐cyclobutanols through an enantioselective insertion of a chiral rhodium(I) complex into the C? C σ bond of the cyclobutane, forming a quaternary stereogenic center and an alkyl‐rhodium functionality that initiates ring‐closure reactions. This technology provides access to a variety of substituted cyclohexane derivatives with quaternary stereogenic centers. The formation of different product families can be controlled by the employed set of reaction conditions and additives. In general, high yields and excellent enantioselectivities of up to 99 % ee are obtained.     

Assignment of the liposidomycin diazepanone stereochemistry

The liposidomycins comprise a family of complex nucleoside antibiotics that inhibit bacterial peptidoglycan synthesis. Their structures (1, 2) feature nucleoside, ribofuranoside, diazepanone, and lipid regions. Several stereogenic centers remain unassigned, including three within the diazepanone region: C-6', C-2'", and C-3'". An intramolecular reductive amination reaction has been used to prepare model diazepanones. Analysis of 40 and two of its diastereomers by NMR spectroscopy, X-ray crystallography, and molecular modeling indicates a close relative configurational and conformational match between 40 and the liposidomycin diazepanone degradation product 43 and allows the assignment of stereochemistry of the natural products as either [C-6'(R), C-2'"(R), C-3'"(R)] or [C-6'(S), C-2'"(S), C-3'"(S)].     

Photooxygenation of the helimers of (-)-isocolchicine: regio- and facial selectivity of the [4 + 2] cycloaddition with singlet oxygen and surprising endoperoxide transformations

Photooxygenation of the helimeric mixture of (-)-(M,7S)/(P,7S)-isocolchicine (6) with the superdienophile singlet oxygen has been studied. Cycloaddition occurred with high regioselectivity at the 7a,11-positions of the alkaloid and predominantly at the diene face anti to the amidic substituent at the stereogenic center C-7, leading to two endoperoxides 7 (syn) and 8 (anti) with an 1:7 ratio. The structure of the minor product 7 was established by X-ray analysis. Investigation of the triethylamine induced transformation of the predominant endoperoxide 8 furnished a mixture of two isomers (M,7S)-10a/(M,7S)-10b in a 2:1 ratio possibly with constitutional interconversion and with (M,7S)-9 as plausible intermediate. Treatment of this mixture with silica gel/ethyl acetate at ambient temperature surprisingly led to an atropenantiomerically pure colchicinoid (M,7S)-12 characterized by an eightmembered oxocine B-ring, the structure and absolute configuration of which could be determined by X-ray analysis. For the unprecedented formation of the novel colchicinoid (M,7S)-12 a plausible reaction pathway is suggested, involving a complete transfer of the (M) helical asymmetry of the intermediate (M)-11 into (S) asymmetry of the newly formed carbon center of (M,7S)-12. Prerequisite for such a scenario is the configurational stability of the intermediate pseudobiaryl (M)-11, under the conditions employed, allowing to transmit the axial chirality onto the chiral center of the product (M,7S)-12.     

Asymmetric synthesis of 2-substituted piperidines using a multi-component coupling reaction: rapid assembly of (S)-coniine from (S)-1-(1-phenylethyl)-2-methyleneaziridine

(S)-Coniine is made using a reaction which assembles the piperidine ring by the sequential formation of four new chemical bonds and installs the C-2 stereogenic centre with high levels of diastereocontrol (90% de).     

Asymmetric synthesis of 2-(2-pyridyl)aziridines from 2-pyridineimines bearing stereogenic N-alkyl substituents and regioselective opening of the aziridine ring

The addition of chloromethyllithium to the imine derived from 2-pyridinecarboxaldehyde and (S)-valinol, protected as its O-trimethylsilyl ether, gave the 1,2-disubstituted aziridine with good yield and diastereoselectivity. The analogous reaction performed on the imine derived from (S)-valine methyl ester gave the product containing the aziridine ring and the alpha-chloro ketone group coming from the attack of chloromethyllithium to the ester function. Other stereogenic alkyl substituents at nitrogen gave less satisfactory results. Moreover, the aziridination protocol did not work on other aromatic imines which were not capable of bidentate chelation, e.g., 3- and 4-pyridineimine and benzaldimine. Preliminary studies showed the possibility to carry out regio- and stereospecific opening reactions of 2-(2-pyridyl)aziridines by attack of internally generated or external nucleophiles.     

A new diastereoselective aza-allyl conjugate addition-Michael addition-ring closure reaction sequence and its application in the construction of six contiguous stereogenic centres

Reaction of the sodium anion of (S)-N-(alpha-methylbenzyl)allylamine with two equivalents of tert-butyl cinnamate results in a remarkable tandem aza-allyl conjugate addition-Michael addition-ring closure reaction, resulting in a chiral aminocyclohexane containing six new vicinal stereogenic centres with excellent levels of stereocontrol.     

Diastereoselective syntheses of deoxydysibetaine, dysibetaine, and its 4-epimer

(+/-)-Deoxydysibetaine 2 and 4-epi-dysibetaine 3 were prepared in a few steps from methyl pyroglutamate through a regioselective Mannich reaction at C-2. Natural (2S,4S)-dysibetaine 1, a sponge metabolite isolated from Dysidea herbacea, and (2S)-2 were synthesized from enantiopure (S)-pyroglutaminol with very high stereoselectivity. The key steps were an original formation of stereogenic quaternary center C-2 and the diastereoselective hydroxylation at C-4.     

Influence of a hydroxy group in the asymmetric reduction of selenides: enantioselective synthesis of naturally occurring monoterpenes

The reductive cleavage of the benzenseleno-group in trans-β-hydroxyselenides, to yield a stereogenic methyne center, has been investigated. When the reaction is carried out with lithium in diethylamine, the equilibrated carbanionic intermediate traps the proton of the neighbouring hydroxy function, blocking the stereogenic center as a product with a predictable chirality. Using this strategy, several natural monoterpenes in enantiomerically pure form have been prepared.     

Catalytic asymmetric diastereodivergent deracemization

Your wish is my command: Deracemization is a powerful strategy wherein a racemate is converted into a 100?% yield of a single enantiopure product. A new concept in catalytic deracemization is presented, in which a racemate with n?stereogenic elements can be selectively converted into each one of 2(m) (m = number of chiral centers of the product) different enantiopure products, by simple tuning of the reaction conditions.     

Stereogenic properties of spiranes combined with four equivalent conventional centres of chirality

Derivatives of the tri-spirane pentaerythritoxy-cyclophosphazene compound, 1, have been used to investigate the stereogenic properties of spiranes combined with four equivalent conventional centres of chirality. In compound 1 the two inner rings are carbocyclic and symmetrical and the two outer rings are cyclotriphosphazenes substituted in different positions to provide the conventional centres of chirality. The case of combining spiranes with four equivalent centres of chirality has been investigated by the reaction of 1 with dimethylamine in a 1 : 8 molar ratio to give four diastereoisomeric products, in which the two cyclophosphazene rings are non-geminally di-substituted in either cis or trans configurations; viz. the cis-cis (2a), cis-trans (2b) and two trans-trans substituted dimethylamine derivatives 2c and 2d. The structure and stereogenic properties of compound 2a (C2 symmetry) have been characterized previously by both X-ray crystallography and 31P NMR spectroscopy on addition of a chiral solvating agent (CSA) and the structures and stereogenic properties of compounds 2b (C1) and 2d (C2) have been similarly characterized in this work. The structure of compound 2c has been characterised by X-ray crystallography and found to be meso with the relatively rare S4 symmetry. The four diastereoisomeric products 2a-2d represent all the possible stereochemical isomers of a spirane combined with four equivalent conventional centres of chirality.