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Selectivity Guidelines and a Reductive Elimination-Based Model for Predicting the Stereochemical Course of Conjugate Addition Reactions of Organocuprates to γ-Alkoxy-α,β-Enoates
Abstract
Current models used to predict the stereochemical outcome of organocopper conjugate addition processes focus on the nucleophilic addition step as stereochemistry-determining. Recent kinetic, NMR, kinetic isotope effect, and theoretical density functional studies strongly support the proposal that stereochemical preferences in these processes are dictated by the reductive elimination step, transforming Cu(III) to Cu(I) intermediates. A new model that considers various steric and stereoelectronic factors involved in the transition state of the reductive elimination step is proposed and then used to interpret the results of systematic studies of arylcuprate conjugate addition reactions with cis and trans gamma-alkoxy-alpha,beta-enoates. The results give rise to the following selectivity guidelines for this process. To achieve high anti-addition diastereoselectivities the use of trans esters with a bulky nonalkoxy substituent at the gamma-position is recommended. While stereoelectronics disfavor syn-addition, a judicious choice of properly sized gamma-substituents may lead to the predominant formation of syn-products, especially with cis enoates. However, high syn-selectivities may be achieved by using gamma-amino-alpha,beta-enoates.
... R f ¼ 0.50 (hexane-EtOAc, 4 : 1); [a] 24 D ¼ À33.5 (c 0.38, CHCl 3 ); IR (KBr): 3448, 2931, 2858, 1726, 1465, 1374, 1253, 1082, 838 cm À1 ; 1 H NMR (500 MHz, CDCl 3 ): d 9.77 (s, 1H), 5.89 (ddd, 17.4, 9.9, 7.8 Hz, 1H), 5.33 (d, J ¼ 17.2 Hz, 1H), 5.26 (d, J ¼ 10.2 Hz, 1H), 4.54 (t, J ¼ 6.7 Hz, 1H), 4.10 (t, J ¼ 7.2 Hz, 1H), 3.75 (dd, J ¼ 7.2, 1.8 Hz, 1H), 2.80-2.72 (m, 1H), 2.45-2.40 (m, 1H), 2.38 (dd, J ¼ 8.1, 1.5 Hz, 1H), 1.45 (s, 3H), 1.34 (s, 3H), 1.04 (d, J ¼ 6.6 Hz, 3H), 0.89 (s, 9H), 0.10 (s, 3H), 0.06 (s, 3H) ppm; 13 C NMR (75 MHz, CDCl 3 ): d 202.6, 134.7, 118.6, 108.3, 79.2, 79.1, 73.0, 47.2, 32.3, 28.0, 26.0, 25.4, 18.2, 15.3, À3.7, À4.2 ppm; MS m/z 365, [M + Na] + ; HRMS calcd for C 18 H 34 O 4 NaSi [M + Na] + 365.2119, found 365.2117.(2R,3R)-1-((6S,7aS)-8,8-Dimethyl-2,2-dioxidohexahydro-1H-3a,6-methanobenzo[c]isothiazol-1-yl)-3-hydroxy-2methylbutan-1-one(13) ...
An efficient stereoselective total synthesis of (+)-mupirocin H is described. The chiron and asymmetric strategies were appropriately utilized for the rapid construction of the novel five-membered lactone with six stereogenic centres. The C3–C5 triol segment was derived directly from readily-available D-ribose, and the chirality at the C6 position was introduced by means of substrate-controlled conjugate addition. The remaining chiral centers (C10 and C11) were obtained by Oppolzer's protocol, and the olefin was generated through a Julia–Kocienski olefination.
... Proposed anti configuration based on the modified Felkin-Anh model.In a previous attempt to perform the conjugate addition, Paulsen and Stubbe37,38 employed lithiated cuprates in an effort to achieve the synthesis of sufficient L-alloproduct 63 (Scheme 28), unfortunately, with only modest success. After a comprehensive literature survey30,67,[69][70][71] was carried out, an adaption to the methodology was initiated with stereoselectivity in mind. This will be presented in detail in Section 3.3.1. ...
A convergent synthesis of one isomer of the C14-C29 fragment of mirabalin is disclosed. The key steps include a Marshall allenylation, a Mukaiyama aldol reaction and a Crimmins aldolization, which allow the control of 10 out of 25 stereogenic centers present in the molecule.
A new approach to secoiridoids, based on the synthesis of the key functionalized intermediates 4 and 5, is presented. These compounds were tested in formal [3+3] cycloadditions. Acyl-chloride 15 was transformed into enol α,β-unsaturated ester 16, which was involved in a N-heterocyclic carbene rearrangement to give an advanced precursor 17 in the total synthesis of secoiridoids
Palladium(II) catalysis has been used in the substrate-controlled 1,2-chiral induction of the conjugate addition of boronic acids to enantiopure α,β-unsaturated ketones and esters without competition from the Mirozoki–Heck reaction. Bedford's palladacycle was found to control the stereoselectivity without the need for additional chiral ligands. We report that the PdII-catalyzed conjugate addition reaction between boronic acids and acyclic ketones or esters that bear a hydroxyl substituent at their γ-position (glyceraldehyde derivatives) can afford high levels of anti stereoselection, comparable to those reported previously using more expensive RhI catalysts. On the other hand, high levels of syn stereoselectivity were observed with acyclic esters that bear an amino substituent at their γ-position (serine derivatives). In this case, the levels of stereoselection could be enhanced by using cyclic derivatives derived from Garner's aldehyde.
HBTU is a standard coupling agent commonly used for the activation of free carboxylic acids during the solution and solid phase peptide synthesis. 1-Hydroxybezotriazole (HOBt) plays a significant role in reducing the racemization during peptide synthesis, hence it is regularly used as a coupling additive. Here, we are reporting the mild and facile conjugate addition of HOBt to E-vinylogous gamma-amino acids mediated by the HBTU. The reaction is moderately diastereoselective and novel beta-OBt substituted gamma-amino acids were isolated in moderate to good yields. The single crystal analysis of methyl esters of major (anti) and minor (syn) conjugate addition products infer that the formation of exclusively N-alkylated benzotriazole N-oxides instead of O-alkylation of HOBt. In addition, we showed the utilization of beta-OBt substituted gamma-amino acids in peptides synthesis and studied their conformations in single crystals.
α-d-xylo-7,3-Unsaturated lactone, a versatile chiral building block, undergoes Cu-catalyzed conjugated addition with high yield and stereoselectivity. When the conjugated reaction is quenched with a suitable alkyl halide, a tandem stereoselective conjugated/α-alkylation reaction is achieved. Further, selective hydrolysis of the 1,2-O-isopropylidene moiety followed by oxidative cleavage and reduction reaction, afforded the title compounds.
Epoxy alcohol anti-10, derived from a desymmetrizing Sharpless epoxidation (up to 97 % ee) of divinylcarbinol 9, provided the unsaturated 1,3-diol syn-11 upon treatment with RedAl®; syn-11 was converted into the α,β-unsaturated esters (E)- or (Z)-7b in three steps. Cu-promoted 1,4-addition of vinylmagnesium halides to the (E)-ester proceeded with diastereoselectivities of up to 91 % and Cu-catalyzed 1,4-additions with diastereoselectivities of up to 82 %. The potassium enolate of the major vinylation product syn-22b was hydroxylated by the Davis oxaziridine with perfect but unprecedented diastereoselectivity. The resulting hydroxy ester, α,βsyn,β,γsyn-32, furnished the “eastern moiety” building block 6 of the title compounds in three steps.
β,γ-Disubstituted butyrolactones were produced effectively and steroeselectively from arsonium ylides generated in situ and substituted olefins. The transformation could be realized in one-pot or in two steps, which depended on the electronic properties of the olefins. With the adjustment of the solvent and in the presence of EtOH, α,β,γ-trisubstituted butyrolactones were also obtained in high yield from arsonium ylides and substituted olefins.
Treatment of a range of O-protected glycolate derivatives of the chiral auxiliary N-1-(1′-naphthyl)ethyl-O-tert-butylhydroxylamine with KHMDS in the presence of 18-crown-6 followed by addition of an alkyl halide generates α-substituted derivatives with very high levels of diastereoselectivity. Alternatively, reaction of the potassium enolate of a propanoate or O-protected glycolate derivative of N-1-(1′-naphthyl)ethyl-O-tert-butylhydroxylamine with a range of aldehydes gives syn-aldol products with high levels of diastereoselectivity. These adducts may be reductively cleaved with LiAlH4 to give enantiopure α-alkoxy-, α-substituted-β-alkoxy- and α,β-dialkoxyaldehydes in good yield.
Two new synthetic approaches, involving substrate directed aza-Claisen rearrangements and aza-Claisen rearrangements mediated by chiral Pd(II) catalysts, have been developed for the stereoselective synthesis of (2R,3S)-2-amino-3,4-dihydroxybutyric acid, a dihydroxylated α-amino acid from the edible mushroom, Lyophyllum ulmarium and its (2S,3S)-unnatural diastereomer.
We have developed a highly diastereoselective route to construct rel-(7S,8S,7'R,8'S)-7,7'-epoxylignan skeleton, wherein stereocontrolled Michael addition to γ-oxyenone intermediate and subsequent (α-alkylation to the resulting ketone are keys to the synthesis.
Chiral nonracemic aminated nitroso acetals were synthesized via diastereoselective multicomponent [4 + 2]/[3 + 2] cycloadditions employing new (S,E)-γ-nitrogenated nitroalkenes 5a-c as heterodienes, ethyl vinyl ether (EVE) as a dienophile, and selected electron-deficient alkenes as 1,3-dipolarophiles. The employment of different organic solutions of LiClO4 or LiCl as promoter systems provided the respective nitroso acetals with yields from 34-72% and good levels of diastereoselectivity. In addition, the nitroso acetal 9c was transformed to the pyrrolizidin-3-one derivative 14c, proving the usefulness of the route in the synthesis of an interesting chiral compound. The elucidation of the stereostructures was based on 2D COSY, NOESY and HSQC NMR experiments as well as an X-ray diffraction experiment.
The high diastereoselectivity in the Michael addition of nitromethane to α,β-unsaturated γ-amino esters, crystal conformations of β-nitromethane substituted γ-amino acids and peptides are studied. Results suggest that the N-Boc protected amide NH, conformations of α,β-unsaturated γ-amino esters and alkyl side chains play a crucial role in dictating the high diastereoselectivity of nitromethane addition to E-vinylogous amino esters. Investigation of the crystal conformations of both α,β-unsaturated γ-amino esters and the Michael addition products suggests that an H-C(γ)-C(β)[double bond, length as m-dash]C(α) eclipsed conformer of the unsaturated amino ester leads to the major (anti) product compared to that of an N-C(γ)-C(β)[double bond, length as m-dash]C(α) eclipsed conformer. The major diastereomers were separated and subjected to the peptide synthesis. The single crystal analysis of the dipeptide containing β-nitromethane substituted γ-amino acids reveals a helical type of folded conformation with an isolated H-bond involving a nine-atom pseudocycle.
Conjugate additions of Gilman cyanocuprates to (S)-N-amino-2-(methoxymethyl)pyrrolidine (SAMP)-hydrazones 4, 5 derived from cyclic and acyclic α,β-unsaturated ketones were investigated. A protocol utilizing copper(II) sulfate/ammonium chloride was evolved, which allowed cleavage of SAMP (S)-1 under the hydrolysis and work-up conditions, followed by recovery of the auxiliary with ethylenediaminetetraacetic acid (EDTA). The enantioselectivity of cuprate additions was dominated for cyclic SAMP-hydrazones 4 by the cuprate alkyl substituent and the ring size, in the case of acyclic arylidene SAMP-hydrazones 5, however, by the nature of the aryl substituent. Electron-donating substituents gave poor enantiomeric excesses, whereas electron-withdrawing groups provided excellent ee values of 98–99%. The configuration of the new stereocenter was determined to be (R). Moreover, a reaction sequence was developed which integrates a tandem 1,4-addition/methylation and traceless hydrolytic cleavage of the auxiliary (S)-1 in a one-pot reaction, resulting in enantiomerically pure methyl ketones 11–13, each of them with>99% ee.
Various substituted arylcuprates undergo stereocontrolled additions to L-serine-derived γamino- and γ-carbamato-α,β-enoates with high syn-selectivities. The stereochemical outcome of these reactions is fully consistent with the reductive elimination-based model proposed previously. This method is well suited for the preparation of a broad range of biologically active amaryllidaceae constituents and their aromatic analogues.
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.
A new stereoselective tandem reaction consisting of the metal-free conjugate addition of boronic acids followed by an intramolecular ring opening of a cyclic acetal has been disclosed. Optically pure polysubstituted tetrahydropyrans have been synthesized diastereoselectively by this new reaction. Two new C-C bonds and up to three stereocenters are formed in a single step, allowing the generation of quaternary stereocenters.
Conjugate addition of a 50:50 pseudoenantiomeric mixture of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide and lithium (S)-N-3,4-dimethoxybenzyl-N-(α-methylbenzyl)amide to a range of racemic acyclic γ-amino-α,β-unsaturated esters (derived from the corresponding α-amino acids) effects their efficient parallel kinetic resolution, allowing the preparation of enantiopure β,γ-diamino esters. The β,γ-diamino ester products of these reactions are readily converted into the corresponding substituted 4-aminopyrrolidin-2-ones via N-debenzylation and cyclization.
Pancratistatin is a phenanthridone-type natural product isolated from several plants of the Amaryllidaceae family. Its potent antiproliferative, antivascular, antiviral, and antiparasitic properties have attracted the attention of synthetic, biological, and medicinal chemists. Pancratistatin's low natural availability and complex structure have steered many of these research projects toward the preparation of its simplified synthetic analogues with useful levels of activity. In this work we have developed synthetic chemistry aimed at the preparation of pancratistatin analogues with a truncated cyclitol portion of the molecule. The described synthetic pathways are based on a highly anti-diastereoselective arylcuprate conjugate addition to gamma-alkoxy-alpha,beta-enoates and syn-selective azidation at the alpha-position of ester enolates. Analogues with the formally cleaved C3-C4 bond, and thus containing an open ring C, as well as a compound containing a truncated lactol moiety in lieu of the cyclitol, were prepared. Several of the analogues exhibited weak antiproliferative activity, with the highest potency observed in the case of the lactol analogue. From these results implications for the design of future pancratistatin analogues are discussed. Furthermore, the synthetic pathways can be used to construct pancratistatin-mimetic libraries, in which the cyclitol moiety is replaced by other cyclic motifs.
The asymmetric conjugate addition and allylic alkylation using Grignard reagents have been reviewed. Reportedly, major advancements are realized in enantioselective conjugate addition and allylic substitution using Grignard reagents in the presence of chiral copper complexes. Noteworthy of these breakthroughs are the addition of simple alkyl Grignard reagents to acyclic enones and thioesters with excellent levels of stereocontrol and the generation of quaternary centers via conjugate addition of Grignard reagents. In addition to this is the potential use of MeMgBr as a hard carbon nucleophile to generate chiral allylic products that are considered as highly versatile chiral synthons. Lastly, the development of iterative catalytic protocols to generate acyclic structures with arrays of multiple stereocenters offers opportunities in complex natural product synthesis as demonstrated in emerging field of lipidomics.
Pancratistatin is a potent anticancer natural product, whose clinical evaluation is hampered by the limited natural abundance and the stereochemically complex structure undermining practical chemical preparation. Fifteen aromatic analogues of conduritol F, l-chiro-inositol, and dihydroconduritol F that possess four of the six pancratistatin stereocenters have been synthesized and evaluated for anticancer activity. These compounds serve as truncated pancratistatin analogues lacking the lactam ring B, but retaining the crucial C10a-C10b bond with the correct stereochemistry. The lack of activity of these compounds provides further insight into pancratistatin's minimum structural requirements for cytotoxicity, particularly the criticality of the intact phenanthridone skeleton. Significantly, these series provide rare examples of simple aromatic conduritol and inositol analogues and, therefore, this study expands the chemistry and biology of these important classes of compounds.
Conjugate addition of lithium dimethylcuprate to acyclic alpha,beta-unsaturated esters of varying lengths bearing terminal alkyl or phenyl groups leads to a preponderance of syn 1,3-adducts when one methyl is already present. Conversion to enoates, and iteration of cuprate additions also favors syn adducts to give contiguous deoxypropionate units in a growing chain. The effect of end-group variation (Me, i-Pr, phenyl, tert-butyl) in conjunction with the nature of the ester group (Me, tert-butyl, etc.) on the diastereoselectivity of syn and anti products was studied. The results are rationalized in terms of inductor effects related to the minimization of the 1,5-pentane interactions in energetically favored folded conformations and corroborated by homodecoupling NMR studies.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.
The substrate-controlled RhI-catalyzed conjugate addition of aryl- and alkenylboronic acids to alpha,beta-unsaturated esters which bear gamma- and delta-oxygen substituents takes place in a highly anti diastereoselective fashion either when using gamma-hydroxyl unprotected starting materials or when the gamma-oxygen substituent is protected with a nonbulky group. The delta-oxygen substituent plays a role in the stereoselectivity of the reaction, and better results are obtained when this OH-group is protected.
The C-9 diastereomer of amphidinoketide I has been synthesized. An asymmetric CuH-catalyzed hydrosilylation based on the Solvias nonracemic Josiphos-related ligand (R,S)-PPF-P(t-Bu)2 was successfully used to introduce each of three stereocenters found in the target compound.
Chiral alpha,beta-unsaturated esters, containing a single, gamma-stereogenic centre, show modest levels of substrate control upon conjugate addition of lithium dibenzylamide. Double diastereoselective conjugate additions of homochiral lithium N-benzyl-N-(alpha-methylbenzyl)amide to the homochiral alpha,beta-unsaturated esters display "matching" and "mismatching" effects. In each case, however, these additions proceed under the dominant stereocontrol of the lithium amide to give the corresponding beta-amino esters in high de. A remarkable reversal in stereoselectivity is noted by changing the ester functionality to an oxazolidinone. Subsequent O-deprotection and cyclisation of the resultant beta-amino adducts gives access to the corresponding beta-amino-gamma-substituted-gamma-butyrolactones in good yield and high de.
tert-Butyl (RS)-3-methoxy- and (RS)-3-tert-butyldiphenylsilyloxy-cyclopent-1-ene-carboxylates display excellent levels of enantiorecognition in mutual kinetic resolutions with both lithium (RS)-N-benzyl-N-(alpha-methylbenzyl)amide and lithium (RS)-N-3,4-dimethoxybenzyl-N-(alpha-methylbenzyl)amide. A 50 : 50 pseudoenantiomeric mixture of lithium (S)-N-benzyl-N-(alpha-methylbenzyl)amide and lithium (R)-N-3,4-dimethoxybenzyl-N-(alpha-methylbenzyl)amide allows for the efficient parallel kinetic resolution of the tert-butyl (RS)-3-oxy-substituted cyclopent-1-ene-carboxylates, affording differentially protected 3-oxy-substituted cispentacin derivatives in high yield and >98% de. Subsequent N-deprotection and hydrolysis provides access to 3-oxy-substituted cispentacin derivatives in good yield, and in >98% de and >98% ee, while stereoselective epimerisation and subsequent deprotection affords the corresponding transpentacin analogues in good yield, and in >98% de and >98% ee.
For Abstract see ChemInform Abstract in Full Text.
The first total synthesis of (+)-olivin (1), the naturally occurring enantiomer of the aglycon of olivomycin A, is described. The synthesis is highly stereoselective, featuring the reaction of (γ-methoxyallyl)boronate 21 with chiral aldehyde 17 and the addition of lithiodivinylcuprate to unsaturated aldehyde 40 as the key diastereoselective transformations. The anthracenone nucleus of 1 was constructed beginning with the coupling of unsaturated ester 42 and phthalide 46. The vinyl unit of naphthoate 48 was oxidized to the acetic ester appendage in 53, and then the final C-C bond of anthracenone 54 was established by a Dieckmann cyclization. The C(2′) hydroxyl group of 57 was oxidized to the necessary side-chain carbonyl function, and then the C(2) hydroxyl group was introduced stereoselectively by the mCPBA epoxidation of the mono TBDMS enol ether prepared from 58. All five acid-labile protecting groups were removed in a single operation to complete the synthesis.
With a direct kinetic study, activation parameters for the 1,4-cuprate addition to enones (see the Arrhenius plot,▴) and the 1,6-addition to acceptor-substituted enynes (█) were determined for the first time. Both reactions might involve σ copper(III) species which are formed by oxidative addition of the respective substrate to the cuprate.
The role of Me3SiCl to accelerate the conjugate addition of organocopper reagents has been examined by comparison of the stereochemical results of reactions with 6- and 2,6-disubstituted cyclohexenones, and mechanism involving an initial coordination of the chlorosilane to enones has been proposed.
Various alkylcuprates were added to the Z and E vinylogous esters of N,O-diprotected (D) or (L) serinal 1. Good to excellent yields and asymmetric inductions were observed.
Dynamics 13C NMR studies of 7-substituted 2-methoxy-methylenecyclohexanes indicate that the proportion of axial orientation decreases as the 7-substituent becomes less electron donating, the equatorial conformer being largely predominant in the 7-cyano derivative.
Vinylic cuprate reagents add with excellent diastereoselectivity (>10:1) to carbohydrate derived enones and α,β-unsaturated esters. The stereochemical outcome of these transformations is consistent with a Felkin-type addition pathway.
The conjugate addition of organocopper reagents, mainly the higher order cuprates R3CuLi2, to (E)-γ-hydroxy-α,β-unsaturated phenyl sulfones takes place with excellent yields and high anti-selectivity.
The intramolecular nitrile oxide cycloaddition reaction on chiral (E) and (Z) olefins featuring a sulphur atom along the carbon chain connecting dipole and dipolarophile occurs with poor to excellent stereoselectivity, which is mainly affected by the substitutents at the allylic stereocenter. The possibility of converting the cycloadducts into stereoisomerically pure β-ketols has been established in one case.
The catalytic osmylation of electron-poor allylic ethers and alcohols was studied. In the case of γ-alkoxy E-enoates reaction selectivity was found to range from 2:1 to 8:1 in favor of the (2,3-syn - 3,4-anti) product, regardless of the double bond substitution. Lower (if any) selectivity was found for the Z-isomers. On the contrary, 2-Mthylene-3-hydroxy esters were osmylated with virtually complete 2,3-syn selectivity.The factors affecting the stereochemical outcome of the reactions are discussed
Cuprate reagents in the presence of trimethylchlorosilane add with excellent Tr-face selectivity and yield to α,β-unsafcurated ketone and aldehyde bearing In γ-position a masked aldehyde represented by the C-2 of a norephedrine-derlved oxazolidine. The title compounds are obtained in high enantlomeric excess after removal of the chiral auxiliary and of the protective group.
A concise and efficient synthesis of C37∼C54 tricyclic JKL-ring unit (2) of halichondrin B (1) utilizing C2-symmetric spiroketal derivative (5) as a synthetic key intermediate, easily provided from dimethyl L-(+)-tartrate, is reported.
Mycalamide B, a potent antitumour agent, was synthesised from cheap, readily available starting materials: ethyl lactate, ethyl isobutyrate, 4-chlorobutanal, and 4-chlorobutanoyl chloride. The trioxabicyclo[4.4.0]decane ring system was created by reaction of a methoxymethyl ether with a silyloxyoxirane induced by phosphorus pentoxide.
The macrolide bafilomycin A(1) was synthesized starting from D-valine and D-mannitol as chiral progenitors of propionate units. Acyclic subunits corresponding to different parts of the molecule were constructed based on an iterative 1,2-asymmetric induction protocol as a distinctive feature of the synthesis. The assembly of two segments encompassing the entire carbon framework of the macrolide was achieved by using a Stille coupling. The resulting seco-ester was further manipulated to provide crystalline bafilomycin A(1) via a conventional carbodiimide-mediated Keck-type macrolactonization.
The synthesis of non-peptidic acyclic and conformationally constrained compounds is described with the intention of designing models and chemical intermediates, for an inhibitor of the enzyme renin.
The conjugate addition of methylcuprates and methyllithium to ethyl 5-phenyl-1,3-dioxolan-4-yl-2-propenoate was investigated. It was found that the stereoselectivity is highly dependent on the reagent used. In reactions with stabilized methylcuprates, the anti-1,4-addition product is mainly formed, whereas syn-diastereoselectivity is observed in the reaction with methyllithium. Additions of methyllithium were optimized with respect to solvent and additives.
The stereoselectivity of the addition of cuprates to a polyfunctional γ-alkoxy enone depended on the γ-hydroxyl protective group. Protection as a blocking silyl ether gave the best results (de=93–95%). An unexpected and original cleavage-oxidation reaction at ambient temperature transformed the addition products into well known lactones well characterized in the literature. Comparison of the spectral data of these lactones with those in the literature allowed the configuration of the new asymmetric centers to be assigned.
Tricyclic tetrahydronaphthalenes comprising cis- and trans-fused lactones, and aryl substituted functionalized indanes were synthesized in enantiopure form.
A straightforward method is developed for the synthesis of enantiopure (3S,4R)-3-amino-4-alkyl-2-piperidinone derivatives, six-membered lactam-bridged dipeptides, via highly diastereofacial selective 1,4-addition of organocuprate to the chiral oxazolidine α,β-unsaturated ester 1 as the key step.
The reaction of γ-amino-α,β-unsaturated esters prepared from l-serine with diversely substituted arylcuprates affords the corresponding syn-adducts. Transformation of the amino group to an isocyanate, followed by Friedel–Crafts intramolecular condensation, leads to enantiopure 3,4-disubstituted tetrahydroisoquinolin-1-ones, which can be reduced to the corresponding tetrahydroisoquinolines.
Stereocontrolled addition of organocuprate reagents to γ-alkoxy-α,β-unsaturated esters can be done in one- and two-directional modes with excellent 1,2-induction. Enolate hydroxylations proceed with high diastereoselectivity affording acyclic chains with three to five contiguous stereogenic centers of the propionate and phenylpropionate triad types.
Following an homologation sequence the readily available enantiomerically pure gamma-hydroxy vinyl sulfone 2 has been transformed, with complete control of the stereochemistry, into gamma-hydroxy vinyl sulfones of polypropionate structure. The four stereotriads have been prepared by stereoselective additions of organometallics to the vinyl sulfone moiety and by stereoselective reduction of beta-hydroxyketones. In a similar way, these triads are the substrates for the stereoselective introduction of the fourth consecutive asymmetric center.
A four‐membered ring of two lithium and two nitrogen atoms is in the central unit of the dimer in the title ( 1 ), a complex between an alkali metal and a neutral phosphorus ylide. Surprisingly, this is the first time that such a model complex for the generation of ylides from phosphonium salts and alkali metal bases has been characterized in the solid state. The structure in solution was also determined, and the complexation energies for this and other model complexes were estimated by ab initio calculations. equation image
When the copper center is stabilized by donor ligands such as H 2 O and NH 3 , trialkylcopper compounds correspond to energy minima at all levels of theory used in the calculations (MP2, SCRF, BLYP). These results support proposals that such species are intermediates in cuprate addition and substitution reactions and at the same time suggest that descriptions of trialkylcopper systems as Cu II rather than Cu III complexes may be more appropriate.
An efficient, highly stereoselective synthesis of the C10–C31 (BCDEF ring) portion of pinnatoxin A has been achieved utilizing tandem double hemiketal formation/intramolecular hetero-Michael addition to construct the 6,5,6-dispiroketal (BCD ring) system and subsequent intramolecular ketalization to form the 5,6-bicycloketal (EF ring) system as key steps.
Copper-catalyzed conjugate addition reactions of Grignard reagents to γ-alkoxy-α,β-unsaturated ketones, derived from mandelic acid, have been studied. Diastereoselectivity is strongly dependent on the nature of the γ-alkoxy protection group. Bulky silyl protection gives poor stereoselectivities, whereas the ketone bearing benzyloxymethylene (BOM) protection reacts with excellent yields and stereoselectivities.
Treatment of acyclic γ-ureido α,β-unsaturated esters with lithium dialkyl or diaryl cuprates leads to the corresponding β,γ-substituted esters with high syn-stereoselectivity. The potassium enolates of these compounds react with trisyl azide or the Davis oxaziridine reagent to give all syn-orientated α-azido esters, or α-hydroxy esters. Mitsunobu inversion with azide ion produces diastereomeric compounds. The products are excellent examples of functionalized diamines and amino alcohols which can also be made in an iterative manner.
The synthesis of cyclopropane derivatives via a MIRC reaction of azidirinyl-methylene-malonates is described. In this way it is possible to introduce a hydrogen, a phenylthio, a tributylstannyl and an olefinic function at the cyclopropane ring, that further contains an alkylamino substituent. Addition of CuCN catalyzed Grignard reagents gave the most promising results. The diastereoselectivity was dependent on the aziridine nitrogen substituent and the bulkiness of the reagent. Copyright (C) 1996 Elsevier Science Ltd
Activation of O2 by cytochrome P-450 monooxygenase is generally thought to proceed by way of a peroxoiron(III) porphyrinate species that is then transformed into an oxoiron(IV) porphyrinate radical cation. Such a radical cation, the “picket fence” model compound 1, has now been isolated for the first time from the peroxoiron(III) species by treatment with HBF4 · Et2O.
The Lewis acid mediated addition of organocopper reagents to the trans-ester (7a) produced the anti-isomer (8a) predominantly, while addition to the cis-derivative (7b) gave the syn-isomer (9a) preferentially, and addition of organometallic compounds to the diester (7c) also afforded the syn-isomer (9b) predominantly; this change in diastereoselectivity indicates the importance of the double bond geometry in controlling the 1,2-asymmetric induction of γ-alkoxy-α,β-unsaturated carbonyl compounds.
N,N-Dibenzlamino aldehydes, readily accessible from amino acids, can be converted into λ-N,N-dibenzylamino α,β-didehydro amino acid esters without racemization; these undergo stereoselective Diels-Alder reactions and 1,3-dipolar cycloaddition with diazomethane, the sense of diastereoselectivity being opposite to that predicted by the conventional principle of 1,3-allylic strain.
Various substituted arylcuprates undergo stereocontrolled additions to a d-mannitol-derived γ-alkoxy-α,β-enoate with exclusive anti-selectivity. The method is well suited for the preparation of a broad range of biologically active Amaryllidaceae alkaloids and their aromatic analogues. A model accounting for the stereochemical outcome of this process is presented.Graphical abstract
The chemo- and stereoselectivity in reactions with E and Z isomers of ethyl 3-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]acrylate, 1 and 2, are strongly dependent on the composition of the organocopper reagent. Synthetically useful yields and stereoselectivities are obtained with reagents of good nucleophilicity, e. g. RCu-TMSI-LiI. A transition state model based on copper-alkene π-complex formation with intramolecular chelation of the γ-oxygen to lithium of a copper-lithium cluster can be used to rationalize the observed anti selectivity.
d-Xylose serves as a starting material for approaches to the synthesis of the glucosidase inhibitors, (+)-cyclophellitol (1) and (+)-epi-cyclophellitol (2). An investigation of the cyclization of diastereomeric oxiranyl radicals to achieve this goal was moderately successful with the diastereomer that would have led to epi-cyclophellitol undergoing cyclization. An alternative route to cyclophellitol from d-xylose employed Grubbs' ring closure metathesis and radical transformations to complete the synthesis.
Systematic studies of organocuprate conjugate additions to three pairs of γ-epimeric and geometrically isomeric γ-chiral acyclic enones (1a, 2a; 1b, 2b; and 3, 4) and two pairs of γ-chiral acyclic enoates (5, 6 and 7, 8) allowed us to generalize diastereofacial selectivity of these reactions. The diastereoselectivity depended on the double-bond geometry, the configuration at the γ-position, and the reaction conditions. In reactions without activating additives, cuprate added to the si-face of the geometrically isomeric pair of E- and Z-enones (1a and 2a) with high diastereoselectivity (98%), while their epimers at the γ-position (3 and 4) yielded re-facial adduct preferentially (86−97%). Addition of TMSCl and HMPA together not only accelerated the addition reaction but also completely changed the pattern of π-facial selectivity. In reactions containing those additives, cuprates added to isomeric E- and Z-enones with reverse facial selectivity: E-enone 1a gave the si-facial adduct exclusively, whereas isomeric Z-enone 2a yielded the re-facial adduct with high selectivity (97%). Their γ-epimers gave opposite results; namely, the E-isomer 3 reacted with re-facial selectivity (97%), while the Z-isomer 4 reacted with si-facial selectivity (75%). Under conditions where both TMSCl and HMPA were present, even the enoates (5−8) reacted efficiently with similarly reverse and high facial selectivity. On the basis of these results, we postulate a general and clear-cut rule to predict diastereofacial selectivity of cuprate conjugate additions in which a possibility of Z−E isomerization of starting enones is taken into account as a crucial determinant.
Cuprate reagents add to ester 2 with excellent π-face selectivity (≥95:5) and furnish the title compounds in high enantiomeric excess after removal of the chiral auxiliary.
We have observed that α,β-unsaturated oxazolines 9, bearing a β-glucose unit, when treated with allylic lithium reagents, give stereoselectivity that is opposite that predicted by Meyers' arguments. Alkyllithium reagents add in the predicted manner. Unsaturated ester 10, when treated with lithium diallylcuprates, gives the same relative stereochemistries as are afforded by the alkyllithium reagents with oxazoline 9. Lithium dialkylcuprates, when added to 10, provide the stereochemistry obtained by treating oxazolines 9 with allyllithiums. Both allyllithiums and alkyllithiums add to oxazoline 15 in the manner predicted by Meyers.
A study on the stereochemistry of the acid-catalyzed cyclization between N-protected norephedrine and α,β-unsaturated dimethyl acetals to give the title compounds is reported. Such heterocycles, on the basis of their different formation and reactivity behavior, are best classified as type I and type II oxazolidines, bearing electron-rich or -poor olefinic appendages respectively. The kind of catalyst as well as the reaction time dramatically affects the sense and the degree of the asymmetric cyclizations. Thermodynamic control is observed in the case of the type I cyclization products by using pyridinium tosylate (Py·Ts) as catalyst. In the type II series, on the contrary, Py·Ts-catalyzed cyclizations are shown to be kinetically controlled, whereas thermodynamic control is obtained when BF3·Et2O is used as catalyst. The mechanism and the factors determining the kinetic preference for the cis C2/C6 isomer are discussed. The addition of cuprate reagents to type II oxazolidine 3Ac takes place with excellent π-face discrimination, affording, after nondestructive removal of the chiral auxiliary, 3-alkylsuccinaldehydic acid methyl esters in high enantiomeric purity. Experimental evidence, together with theoretical considerations, provides a reasonable rationalization for the observed selectivity of the conjugate addition.
Addition of cuprates to chiral methyl beta-formyl carboxylates 1a-1d provided gamma-lactones 2-7 in excellent trans-selectivity. The high diastereofacial selectivity was only obtained employing diethyl ether as solvent while tetrahydrofuran gave inferior results. Similar solvent effects were observed in the additions of various Grignard reagents to 1a, which afforded gamma-lactones 2,3,12, and 13 in moderate trans-selectivity. The best solvent for these reactions was dichloromethane. The 1,3-induction of cuprate additions was studied by using aldehydes 8a-8c. The results obtained were interpreted in terms of chelate-controlled additions with formation of seven-membered ring chelates which involve both carbonyl functions of aldehyde 1 or 8. The function of ester groups as effective ligands of lithium or MgX cations may also be of importance for other stereoselective reactions employing organometallic reagents.
The S(N)2'-selective reaction of organocopper or organozinc reagents with allylic chlorides having a chiral center at the delta-position proceeds with up to 100% diastereoselectivity. The observed 1,2-asymmetric induction conforms to pure steric control (Cram-Felkin-Anh model) even in cases where conventional chelation control may seem to operate, and the level of the selectivity was found to be much higher than those found for the additions of organometallics to structurally comparable alpha-substituted carbonyl compounds.
Kinetic isotope effects were determined for the chlorotrimethylsilane-mediated reactions of cyclohexenone with lithium dibutylcuprate in tetrahydrofuran and with lithium butyl(tert-butylethynyl)cuprate in ether. For the reaction in tetrahydrofuran, the observation of a significant carbonyl oxygen isotope effect (16k/17k = 1.018−1.019) and small olefinic carbon isotope effects (12k/13k = 1.003−1.008) is consistent with rate-limiting silylation of an intermediate π-complex. Theoretically predicted isotope effects for model reactions support this conclusion. Rate-limiting silylation is also supported by relative reactivity studies of chlorotrimethylsilane versus chlorodimethylphenylsilane. The absence of a significant butyl-group carbon isotope effect on product formation indicates that the cuprate butyl groups are nonequivalent in the intermediate leading to the product-determining step. In diethyl ether the isotope effects revert to values similar to those found previously in reactions of cyclohexenone with lithium dibutylcuprate in the absence of chlorotrimethylsilane, consistent with no change in the overall mechanism in this solvent. A mechanistic hypothesis for the differing effects of TMSCl with changes in solvent and substrate is presented.
An operationally simple method has been developed for the stereocontrolled construction of polypropionate stereotriads in high enantio- and diastereomeric purities. The method consists of the stereocontrolled addition of lithium dimethylcuprate to an enantiopure γ-alkoxy-α,β-unsaturated ester, followed by hydroxylation of the corresponding enolate. This leads to an anti/syn orientation of the γ-alkoxy-β-methyl-α-hydroxy ester unit. Chain extension and reiteration of the process, after appropriate functionalization, lead ultimately to an 11-carbon acyclic chain harboring three contiguous polypropionate triads with the correct anticipated absolute configuration. The method relies on two basic bond-forming reactions that involve consecutive 1,2-induction. It is admirably stereocontrolled through four iterative cycles of cuprate additions and hydroxylations. Inversion of the α-alkoxy group after each α-hydroxylation allows passage to stereotriads of different configurations. Thus three of the four possible stereotriad combinations are accessible directly using this simple and general method. The C19−C28 acyclic chain of rifamycin S, harboring eight stereogenic carbon atoms (three triads), was constructed starting with an enantiopure precursor that contains a single stereogenic center. A common precursor serves as the starting chiron for a variety of other propionate derived macrolides and ionophores.
The reaction pathway of transfer of a methyl group of a cuprate cluster (Me2CuLi)2 to acrolein (conjugate addition of the methyl group) has been studied with the hybrid density functional B3LYP method. All intermediates and transition structures (TSs) on the potential surface of the reaction as well as the structures on the intrinsic reaction coordinate near the C−C bond forming stage of the reaction have been determined. In addition to two previously proposed species, a lithium/carbonyl coordination complex (CPli) and a copper/olefin complex retaining a closed cuprate structure (CPcl), a new copper/olefin complex with an open cuprate structure (CPop) was characterized and proven to be an intermediate directly leading to the conjugate addition product (PD) via a TS of C−C bond formation (TS). The overall pathway of the reaction can be viewed, in one way, as C−C bond formation via reductive elimination of a Cu(III) species and, in another, as a 1,4-addition of MeLi assisted by copper. The present studies revealed that the large cluster framework of (Me2CuLi)2 allows intricate cooperation of two lithium atoms and a copper atom. A small cluster such as Me2CuLi cannot achieve such cooperative action of different metal atoms as smoothly as larger clusters such as (Me2CuLi)2 and Me2CuLi·LiCl. Mechanistic relationships between conjugate addition, carbocupration, and alkylation reactions of cuprate are discussed. A close similarity has been found between the conjugate addition and the carbocupration of acetylene for the cooperative action of metal and the involvement of a Cu(III) species.