The role of steric and electronic interactions in the stereocontrol of the asymmetric 1,3-dipolar reactions of 5-ethoxy-3-p-(S)-tolylsulfinylfuran-2(5H)-ones with diazoalkanes: theoretical calculations and experimental evidences

The addition of diazomethane and diazoethane to (5S,SS)- and (5R,SS)-5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-ones (1a and 1b) and their 4-methylderivatives (2a and 2b) proceeded in almost quantitative yields and complete regioselectivity. The observed pi-facial selectivity is determined by the configurations at both C-5 and the sulfinyl group, the later being the most important. The syn adducts were almost exclusively obtained from 1a and 2a in apolar solvents but the pi-facial selectivity was strongly decreased in more polar solvents. On the other hand, the major adducts from 1b and 2b were the anti ones and such predominance was slightly increased with solvent polarity. The exo-selectivity was complete in all the cases except for the anti approach to compounds 2a (in polar solvents) and 2b. The role of the sulfinyl group in this behavior was inferred by comparison of these results with those obtained in reactions of diazoalkanes with 5-methoxyfuran-2(5H)-one (3). Steric interactions seem to be the main ones responsible for the observed exo selectivity of reactions with diazoethane, but electronic factors, which can be modulated by the solvent, are also significant in the pi-facial selectivity control. DFT computational methods are able to correctly predict the reactivity, regioselectivity, and pi-facial selectivity exhibited by 5-alkoxyfuranones as well as their changes with the solvent polarity. A C-H.O hydrogen bond, involving the oxygen atom of the 5-alkoxy group at dipolarophiles and the endo-hydrogen atom at dipoles, seems to play a key role in the electronic interactions influencing the stereochemical course of these reactions.     

First asymmetric cycloaddition of carbonyl ylides to vinyl sulfoxides and furan-2(5H)-ones

The Rh2(OAc)4-catalyzed reactions of o-(methoxycarbonyl)-alpha-diazoacetophenone with enantiomerically pure 5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-ones 1a and 1b afford 4,10-epoxybenzo[4,5]cyclohepta[1,2-c]furan-3,9-diones 6a and 6b, in good or moderate yields and in a completely regioselective way. The pi-facial selectivity is complete for 1a, which only yields anti-6a adducts, and very high for 1b. The endo stereoisomers are favored with respect to the exo ones in both reactions. The sulfinyl group significantly increases the reactivity of the dipolarophile as it has been demonstrated by studying the behavior of 5-methoxyfuran-2(5H)-one (3).     

The role of the sulfinyl group on the course of the reactions of 3-p-tolylsulfinylfuran-2(5H)-ones with nitrones. synthetic uses of cycloreversion processes

[reaction: see text] The reaction of enantiopure 3-p-tolylsulfinylfuran-2(5H)-ones (2a and 2b) with cyclic (4) and acyclic (6) nitrones afforded furoisoxazolidines (5 and 7) in high yields under mild conditions. The reactivity of the dipolarophile was dramatically enhanced by the sulfinyl group, which modulated the pi-facial selectivity (it was complete for reactions from 2b, yielding only the anti adducts) and was the main controller of the endo/exo selectivity. Cycloreversion processes from the resulting sulfinyl furoisoxazolidines proceeded readily and were to be considered to account for an improvement in the selectivity (facial and endo/exo) and even for an inversion of it when the composition of the reaction mixtures obtained under kinetic and thermodynamic conditions were quite different.     

Influence of the Sulfinyl Group on the Chemoselectivity and pi-Facial Selectivity of Diels-Alder Reactions of (S)-2-(p-Tolylsulfinyl)-1,4-benzoquinone

Diels-Alder reactions of (S)-2-(p-tolylsulfinyl)-1,4-benzoquinone (1a) with cyclic (cyclopentadiene and cyclohexadiene) and acyclic dienes (1-[(trimethylsilyl)oxy]-1,3-butadiene and trans-piperylene) under different thermal and Lewis acid conditions are reported. Chemoselectivity (reactions on C(2)-C(3) versus C(5)-C(6) double bonds) is mainly related to the cyclic (on C(5)-C(6)) or acyclic (on C(2)-C(3)) structure of the diene. The high pi-facial selectivity observed could be controlled by choosing adequate experimental conditions.     

Synthesis and dienophilic behavior of (S)-2-cyano-3-(p-tolylsulfinyl)-1,4- benzoquinone

Hydrocyanation of 2-(p-tolylsulfinyl)-1,4-benzoquinone (2) followed by oxidation with PhI(OAc)(2) gives 2-cyano-3-(p-tolylsulfinyl)-1,4-benzoquinone (1). The generation of 1 in the presence of cyclic and acyclic dienes affords the Diels-Alder adducts with a complete chemo- (only reaction with the sulfinyl-substituted double bond takes place), regio- (controlled by the cyano group), and endo selectivity (with respect to the quinone moiety), whereas the pi-facial selectivity is dependent on the structure of the diene.     

1,3-dipolar cycloadditions of diazoalkanes to activated sulfoxides: influence of Lewis acids

[reaction: see text] The reactions of diazomethane and diazoethane with (S)-3-p-tolylsulfinylfuran-2(5H)-one (3) and its 4-methyl derivative (4) have been studied. The sulfinyl group was able to completely control the pi-facial selectivity of all these reactions, which decreased when the polarity of the solvent increased and could be inverted in the presence of Lewis acids, Yb(OTf)(3) being the most efficient catalyst. This behavior made possible the stereodivergent synthesis of diastereoisomeric pyrazolines in almost quantitative yields and de's higher than 98%. The endo/exo selectivity was also complete in reactions of 3 with diazoethane, whereas 4 afforded an easily separable 1:1 mixture of diastereoisomers. Steric factors accounts for the endo/exo selectivity, whereas electrostatic interactions must also be considered to explain the facial selectivity.     

1,5-Asymmetric induction in boron-mediated aldol reactions of beta-oxygenated methyl ketones

This tutorial review describes that high levels of substrate-controlled, 1,5-stereoinduction are obtained in the boron-mediated aldol reactions of beta-oxygenated methyl ketones with achiral and chiral aldehydes. Remote induction from the boron enolates gives the 1,5-anti adducts, with the enolate pi-facial selectivity critically dependent upon the nature of the beta-alkoxy protecting group. This 1,5-anti aldol methodology has been strategically employed in the total synthesis of several natural products with remarkable pharmacological activities. At present, the origin of the high level of 1,5-anti induction obtained with the boron enolates is unclear, although a model based on hydrogen bonding between the beta-alkoxy oxygen and the formyl aldehyde hydrogen has recently been proposed.     

(Z)-3-p-tolylsulfinylacrylonitrile as a chiral dienophile: diels-alder reactions with furan and acyclic dienes

The behavior of (Z)-3-p-tolylsulfinylacrylonitrile (1) as a chiral dienophile has been evaluated from its reactions with furan and acyclic dienes. Electrostatic interactions of the cyano group with the sulfinyl one restrict the conformational mobility around the C-S bond, thus controlling the pi-facial selectivity, which is almost complete in all cases, the approach of the diene from the less-hindered face of the dienophile (that bearing the lone electron pair) in the predominant rotamer being the favored one. The regioselectivity is also completely controlled by the cyano group. Additionally, the reactivity of compound 1 as well as its endo-selectivity are both higher than those observed for the corresponding (Z)-3-sulfinylacrylates, thus proving the potential of sulfinylnitriles as chiral dienophiles.     

Cyclic vinyl p-tolyl sulfilimines as chiral dienophiles: Diels-Alder reactions with furan and acyclic dienes

The dienophilic behavior of the sulfilimine 2, synthesized from (Z)-3-p-tolylsulfinylacrylonitrile 1, in its Diels-Alder reactions with furan and acyclic dienes has been investigated. A complete pi-facial selectivity for 2, opposite to that observed from its precursor 1, is the main feature of all these cycloadditions. Moreover, the high exo selectivity observed in reactions of 2 with furan (not observed for 1) contrasts with the almost complete endo selectivity with other cyclic and acyclic dienes. Additionally, the opposite regioselectivities obtained for 2 with Dane's diene and 1-substituted butadienes (not observed for 1) are also noteworthy. This behavior allows dienophiles 1 and 2 to be considered as complementary precursors from a synthetic point of view.     

Totally regio- and stereoselective behavior of mono- and diactivated cyclic alkenes in the Lu reaction: synthesis of enantiopure functionalized cyclopentanes

5-Alkoxyfuran-2(5H)-ones and their optically pure 3-p-tolylsulfinyl derivatives, synthetic equivalents of the acyclic esters, react with dipoles generated from allenoates and PPh(3) (Lu reaction), in a completely regioselective, pi-facial selective and endo-selective manner, yielding bicyclic adducts, which are easily converted into optically pure highly substituted cyclopentane derivatives.     

Reverse turn induced pi-facial selectivity during polyaniline-supported cobalt(II) salen catalyzed aerobic epoxidation of N-cinnamoyl L-proline derived peptides

A novel chemo- and diastereoselective aerobic epoxidation of the N-cinnamoyl peptides catalyzed by polyaniline-supported cobalt(II) salen (PASCOS) is described. The N-cinnamoyl proline derived peptides 1 show a high pi-facial selectivity during these epoxidations. The origin of this diastereoselectivity in 1 has been attributed to (i) the propensity of the N-cinnamoyl proline amide to exist predominantly as trans rotamer in CDCl3, DMSO-d6, and CH3CN medium and (ii) existence of these peptides as organized structures (gamma- and beta-turns) due to the presence of intramolecular hydrogen bonds. An extensive solution NMR and MD simulation study on 1d and 1f indicates that the origin of the high pi-facial selectivity is due to the well-defined gamma- and beta-turns which result in the hindrance of one face of the cinnamoyl double bond in the transition state of the epoxidation reaction.     

Diels-Alder reactions of nitro-2(1H)-pyridones with 2,3-dimethyl-1,3-butadiene

Diels-Alder (DA) reactions of 3- or 5-nitro-2(1H)-pyridones and nitro-2(1H)-pyridones containing a methoxycarbonyl group with 2,3-dimethyl-1,3-butadiene were examined. The DA reactions of 3-nitro-2(1H)-pyridones in this paper represent, to the best of our knowledge, the first report of DA reactions of 3-substituted 2(1H)-pyridones and consequent production of isoquinolones. Performing the same reactions with 5-nitro-2(1H)-pyridones yielded quinolones. DA reactions of 2(1H)-pyridones with nitro and methoxycarbonyl groups produced isoquinolones, quinolones and phenanthridones (the double DA adducts), aromatized or hydrogenated. The substituent effect was evaluated by calculating the activation energy, using the ab initio MO method.     

First asymmetric hetero Diels-Alder reaction of 1-sulfinyl dienes with nitroso derivatives. A new entry to the synthesis of optically pure 1,4-imino-L-ribitol derivatives

Hetero Diels-Alder (HDA) cycloaddition of chiral 1-p-tolylsulfinyl-1,3-pentadiene with benzyl nitrosoformate, under mild conditions, yields 2H-1,2-oxazine 3 with complete regioselectivity and pi-facial diastereoselectivity. Sequential osmylation and protection of the resulting glycol gives the oxazine 5 which is directly transformed into enantiomerically pure 1,4,5-trideoxy-1,4-imino-L-ribitol 8 by reduction under Pd/C.     

Methylene substitution reactions in a quadrupole ion trap selectivity of ethylene,ethylene oxide,and dimethyl ether reactive ions

To elucidate the selectivity of methylene substitution reactions of monosubstituted and disubstituted oxyaromatic compounds in a low pressure quadrupole ion trap environment, the relative abundances of covalently bound and loosely bound adducts formed by ion/molecule reactions with ethylene (ET), ethylene oxide (ETOX), and dimethyl ether (DME) were compared. Adduct ions of all three reagent gases were formed in both a conventional ion source and a quadrupole ion trap and characterized by collisionally activated dissociation. For DME and ET, the covalently bound adducts formed at (M + 45)⁺ and (M + 41)⁺, respectively, are direct precursors to the methylene substitution product ions at (M + 13)⁺. ETOX and ET do not demonstrate the same functional group selectivity for methylene substitution as previously observed for DME. This is attributed to differences in reaction exothermicities and competing reactions.     

Reaction between N-alkylhydroxylamines and chiral enoate esters: more experimental evidence for a cycloaddition-like process, a rationale based on DFT theoretical calculations, and stereoselective synthesis of new enantiopure beta-amino acids

The reactions between N-benzyl- and N-methylhydroxylamine and chiral enoate esters, derived from D-glyceraldehyde and (-)-verbenone, respectively, have been investigated. Theoretical calculations show that the most favorable mechanism involves the concerted cycloaddition of the hydroxylamine to the substrate. This result is in good agreement with the stereospecificity observed when the trisubstituted olefins are used. The open-chain adducts have been isolated when the processes are carried out at low temperatures and for short reaction times. These compounds evolve to the corresponding isoxazolidinones on standing at room temperature or under acid catalysis. The high pi-facial diastereoselection has been rationalized on the basis of steric effects induced by the dioxolane ring for D-glyceraldehyde derivatives or by the cyclobutane gem-dimethyl substitution for esters prepared from (-)-verbenone. As an application of these reactions, new beta-amino acids have been synthesized in a highly efficient and stereocontrolled manner.     

PHOTOCHEMICAL AND FREE RADICAL INITIATED REACTIONS OF1,3-DIMETHYLTHYMINE WITH ISOPROPANOL

Abstract— A photochemically induced reaction of 1 ,3-dimethylthymine (DMT) with isopropanol leads to the formation of four alcohol adducts. The products have been identified as the cis and trans isomers of 5 ,6-dihydro-1,3-dimethyll-6-(2-hydroxy-2-propyl) thymine (I and II), 2.4-diaza-8-hydroxy-2.4,6.8-tetramethylbicyclo[4.2.0]octan-1,3-dione (III), and 5 ,6-dihydro-1,3-dimethyl-6-(2-oxo-l-propyl)-thymine (IV). An acetone photosensitized reaction of DMT with isopropanol gives the same products in a similar relative yield distribution. In both of these reactions, cyclobutane dimers of DMT are produced as well. Free radical reactions of 2-hydroxyisopropyl radicals with DMT, initiated by decomposition of di- t -butyl peroxide, leads to formation of only one of the cis and trans isomers described above. along with 1 ,3-dimethyl-5-(2-hydroxy-2-methyl-1-propyl)uracil (V).     

Heterocyclen-synthesen mit 4,4-bis(trifluormethyl)-1,3-diazabuta-1,3-dienen, II [1] spektroskopische untersuchung der isonitril- und dimethoxy-carben-addukte

[4+1] Cycloaddition reactions of 4,4-bis(trifluoromethyl)-1,3-diazabuta-1,3-dienes 3, accessible by reaction of amidines with hexafluoroacetone in the presence of dehydrating reagents, with isonitriles and dimethoxycarbene are described. Configuration of the isonitrile adducts 5 – 9 can be determined on basis of the ¹⁹F NMR data.     

Influence of the beta-alkoxy group on the diastereoselectivity of Aldol reactions of tetrahydro-4H-thiopyran-4-one with 4-Alkoxytetrahydro-2H-thiopyran-3-carboxaldehydes

The diastereoselectivity of the aldol reaction of tetrahydro-4H-thiopyran-4-one (3) with 1,4-dioxa-8-thiaspiro[4.5]decane-6-carboxaldehyde (9a) under a variety of conditions is examined. Under optimized conditions, three of the four possible diastereomers from this aldol reaction can be obtained selectively (3-16:1). Reactions of 9a with the Li, B, Mg(II), and Ti(IV) enolates of 3 and with the corresponding trimethylsilyl enol ether 4b in the presence of BF(3) x OEt(2), SnCl(4), or TiCl(4) as promoters gave the Felkin adducts exclusively (>95%) as mixtures of syn (11a) and anti (12a) diastereomers. Use of the "amine-free" Li enolate of 3 gave 12a with a much higher diastereoselectivity (9:1) and yield (70%) than that obtained using the lithium diisopropylamide-generated Li enolate of 3 (2-3:1; 15-40%). The TiCl(4)-promoted reaction of 4b with 9a gave 11a with excellent selectivity (16:1). In contrast, the MgBr(2) x OEt(2)-promoted reaction of 4b with 9a gave the anti-Felkin adducts exclusively as a 3:1 mixture of syn (13a)/anti (14a) diastereomers. Similar aldol reactions of 3 with the cis and trans isomers of 4-(methoxy)methoxytetrahydro-2H-thiopyran-3-carboxaldehyde (9b and 9c) were examined to probe the influence of the ketal protecting group in 9a on the observed aldol diastereoselectivity. The results are rationalized by applying Evans' stereochemical model for merged 1,2- and 1,3-asymmetric induction (non-chelation), with the exception of the MgBr(2) x OEt(2)-promoted reactions of 4b with 9a, 9b, and 9c, which are accommodated by assuming chelation control. Comparison of the reactions of 9a, 9b, and 9c suggests that the ketal group in 9a uniquely allows high levels of either Felkin or anti-Felkin selectivity to be achieved.     

Ethyl 5-chloro-2-oxopent-3-ynoate,a new acetylenic dienophile in the Diels-Alder reactions

The lithium derivative of propargyl chloride reacts with diethyl oxalate to give ethyl 5-chloro-2-oxopent-3-ynoate. Under mild conditions, this ester undergoes Diels-Alder reactions with conjugated dienes of various structure. The adducts formed from five-membered cyclic dienes exist as stable enols and the adducts from cyclohexadiene and 2,3-dimethylbuta-1,3-diene exist in the keto form.     

Synthesis and properties of the first stable silylene-isocyanide complexes

The first stable silylene-isocyanide complexes, [Tbt(Mes)SiCNAr] (5 c: Ar=Tip, 5 d: Ar=Tbt, 5 e: Ar=Mes*; Tbt=2,4,6-tris[bis(trimethylsilyl)methyl]phenyl, Mes=mesityl, Tip=2,4,6-triisopropylphenyl, Mes*=2,4,6-tri-tert-butylphenyl) were successfully synthesized by the reaction of a kinetically stabilized disilene, [Tbt(Mes)Si=Si(Mes)Tbt] (1), with bulky isocyanides, ArNC (3c-e). The spectroscopic data of 5 c-e and theoretical calculations for a model molecule indicated that 5 c-e are not classical cumulative compounds but the first stable silylene-Lewis base complexes. The reactions of 5 c-e with triethylsilane and 1,3-dienes gave the corresponding silylene adducts, and they underwent isocyanide-exchange reactions in the presence of another isocyanide at room temperature. These results indicate dissociation of complexes 5 c-e to the corresponding silylene 2 and isocyanides 3 c-e under very mild conditions. The reaction of 5 c with methanol gave the MeOH adduct 16, [Tbt(Mes)SiHC(OMe)NTip], which has a hydrogen atom on the silicon atom. This regioselectivity can be explained in terms of the contribution of zwitterionic resonance structures D and E, which have an anion on the silicon atom. This result indicates that 5 c is not a classical cumulene having Si=C double bonds that should react with methanol to give adducts bearing a methoxyl group on the silicon atom. Although the reactions of 5 c-e with electrophilic reagents such as methanol, hydrogen chloride, and methyl iodide gave the formal silylene adducts, the studies on the reaction mechanism by trapping experiments and the observation of the intermediate suggested that the reaction mainly or partially proceeds by initial nucleophilic attack of the silicon atom, as is the case in the formation of 16 in the reaction of 5 c with methanol. It was revealed that 5 c-e show the nucleophilicity of the silicon atom, most likely resulting from the contribution of the zwitterionic resonance structures D and E.