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.     

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).     

Asymmetric synthesis of 2-amino-3-hydroxynorbornene-2-carboxylic acid derivatives

The enantioselective synthesis of 2-amino-3-hydroxynorbornene-2-carboxylic acid derivatives (5) was studied using the Diels-Alder reaction between cyclopentadiene and different dienophiles, i.e., alkyl 5-oxo-2-phenyloxazol-4-methylenecarbonates (1) or 2-benzoylamino-3-alkoxycarbonyloxy-acrylates (12), operating with different Lewis acids and both with thermal and with ultrasound conditions. The enantioselective synthesis of the exo/endo compounds 5c,d and 5'c,d was achieved starting from the chiral menthyl acrylates 12b,c using Mg(ClO(4))(2) as the catalyst and ultrasound. The cycloadducts were obtained in very good yield, in mild conditions, in short time, and in good diastereomeric excess (exo, 80%; endo, 87%). Finally, the use of alkylidene-oxazolones or acrylates and EtAlCl(2) or Mg(ClO(4))(2) as the catalyst allowed control of the cycloaddition reaction in favor of the exo or endo products.     

Studies of Diastereoselectivity in Diels-Alder Reactions of (S)S-4a,5,8,8a-Tetrahydro-5,8-methane-2-(p-tolylsulfinyl)-1,4-naphtho- quinones with Cyclopentadiene

The title compounds 6 and 7 have proved to be adequate rigid models to evaluate the ability of the sulfinyl group to control the diastereoselectivity of the [4 + 2] cycloadditions of cyclopentadiene on the ene-dione moiety. The results of thermal and Lewis acid-catalyzed reactions allowed us to establish that both reactivity and endo/exo selectivity were modulated by the presence of the sulfinyl group, the endo-anti-endo or the exo-anti-endo bisadducts being obtained as major products depending on experimental conditions. The role of the association between the SOTol group and several Lewis acids (BF(3).OEt(2), Eu(fod)(3), ZnBr(2)), which shifted the conformational equilibrium around the C-S bond, was used to explain the stereochemical course of the cycloadditions mainly controlled by steric factors. The synthesis of the exo-anti-endo bisadduct 5 was described for the first time.     

Origins of stereoselectivity in the Diels-Alder addition of chiral hydroxyalkyl vinyl ketones to cyclopentadiene: a quantitative computational study

Modest basis set level MP2/6-31G(d,p) calculations on the Diels-Alder addition of S-1-alkyl-1-hydroxy-but-3-en-2-ones (1-hydroxy-1-alkyl methyl vinyl ketones) to cyclopentadiene correctly reproduce the trends in known experimental endo/exo and diastereoface selectivity. B3LYP theoretical results at the same or significantly higher basis set level, on the other hand, do not satisfactorily model observed endo/exo selectivities and are thus unsuitable for quantitative studies. The same is valid also with regard to subtle effects originating from, for example, conformational distributions of reactants. The latter shortcomings are not alleviated by the fact that observed diastereoface selectivities are well-reproduced by DFT calculations. Quantitative computational studies of large cycloaddition systems would require higher basis sets and better account for electron correlation than MP2, such as, for example, CCSD. Presently, however, with 30 or more non-hydrogen atoms, these computations are hardly feasible. We present quantitatively correct stereochemical predictions using a hybrid layered ONIOM computational approach, including the chiral carbon atom and the intramolecular hydrogen bond into a higher level, MP2/6-311G(d,p) or CCSD/6-311G(d,p), layer. Significant computational economy is achieved by taking account of surrounding bulky (alkyl) residues at 6-31G(d) in a low HF theoretical level layer. We conclude that theoretical calculations based on explicit correlated MO treatment of the reaction site are sufficiently reliable for the prediction of both endo/exo and diastereoface selectivity of Diels-Alder addition reactions. This is in line with the understanding of endo/exo selectivity originating from dynamic electron correlation effects of interacting pi fragments and diastereofacial selectivity originating from steric interactions of fragments outside of the Diels-Alder reaction site.     

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.     

Diels-Alder Addition of Dicyclopentadiene with Cyclopentadiene in Polar Solvents

Diels-Alder addition of dicyclopentadiene and cyclopentadiene in polar solvents has been studied to produce tricyclopentadiene（TCPD） that is a potential high-density fuel precursor. GC and MS analysis shows that the adducts contain two isomers, namely exo- and endo-TCPD. Theoretical simulation shows that although the transition state of endo-TCPD has a lower activation energy, exo-TCPD is thermodynamically preferred. Polar solvents can accelerate the reaction rate and improve the exo/endo ratio of TCPD because the transition state of exo-TCPD has a higher polarity than that of endo-TCPD. The solvent effect follows the order of polarity： benzyl methanol〉cyclohexanone〉toluene. The conversion rises when the temperature ranges from 120 to 150 ℃, but the selectivity of TCPD slightly decreases. Increasing the pressure can improve the conversion but the exo/endo ratio of TCPD is unchanged. The apparent kinetics in different solvents was determined via nonlinear regression. The activation energies are 99.47, 101.15, and 107.32 kJ/mol for benzyl methanol, cyclohexanone, and toluene, respectively. The optimal reaction conditions are as follows： benzyl methanol as solvent, temperature 150 ℃, and pressure 900 kPa. After an 11-hour reaction, a conversion of 58.0%, a TCPD selectivity of 95.7%, and an exo/endo ratio of 1/5.3 has been obtained.     

Optically active 1,2-bis(1-arylhydroxymethyl) ferrocene: a new, efficient chiral ligand for scandium-catalyzed asymmetric Diels-Alder reaction

[reaction: see text] The Sc(OTf)3/FERRODIOL (2) complex was prepared at -78 degrees C in CH2Cl2 in the presence of 2,6-lutidine and MS 4A. The chiral scandium Lewis acid-catalyzed asymmetric Diels-Alder reaction of cyclopentadiene (3) with 3-acyloxazolidin-2-ones (4) effectively produced the adduct (5) in a high yield with good selectivity, i.e., endo/exo = 90:10 up to 91% ee (endo).     

A computational study of the Diels-Alder reaction of ethyl-S-lactyl acrylate and cyclopentadiene. Origins of stereoselectivity

The eight diastereoisomeric transition structures of the Diels-Alder addition of ethyl-S-lactyl acrylate and cyclopentadiene have been investigated in the gas phase and in solution by HF, MP2, and density functional theory (B3LYP and B3PW91) methods with the 6-31G(d,p) basis set. At all levels of theory used, the s-cis transition structures are more stable than the s-trans ones. The contribution of the s-trans transition structures increases in solution and, although still small, has to be taken in consideration for correct prediction of stereoselectivity. Diastereofacial selectivity is interpreted in terms of electrostatic (weak hydrogen bonding) C=O...H(C) interactions between the carbonyl group(s) of the dienophile and cyclopentadiene in the energetically favored transition structures. Endo/exo reaction selectivity is attributed to positive orbital interactions between the diene and the acrylate carbonyl oxygen in the endo s-cis transition structures. Ab initio methods reproduce well the experimentally observed trends in both endo/exo and diastereofacial selectivity. Density functional calculations in the gas phase correctly reproduce the observed trends in diastereofacial selectivity but single-point MP2 calculations are necessary to reproduce the experimental trend in endo/exo selectivity.     

Synthesis and Diels-Alder Reactions of a New Kind of Chiral Dienophiles: Cyclic Vinyl-p-tolylsulfilimines

A new kind of chiral dienophiles, cyclic vinyl-p-tolylsulfilimines (2a and 2b), were obtained from the corresponding (Z)-sulfinylacrylonitriles with HBF(4) and methanol. The asymmetric Diels-Alder reaction of optically pure 2a with cyclopentadiene under mild thermal or catalyzed conditions afforded only the endo-4a adduct with complete endo and pi-facial selectivities. The ability of the sulfilimine moiety to enhance the dienophilic reactivity of the double bond is similar to that of the sulfinyl group.     

Asymmetric synthesis of pyrrolo[2,1-a]isoquinoline derivatives by 1,3-dipolar cycloadditions of stabilized isoquinolinium N-ylides with sulfinyl dipolarophiles

Enantiomerically pure pyrrolo[2,1-a]isoquinoline derivatives are obtained by 1,3-dipolar reactions of isoquinolinium azomethine ylides with enantiopure 3-p-tolylsulfinylacrylonitriles, tert-butyl (2E)-4,4-diethoxy-2-p-tolylsulfinylbut-2-enoate, and 5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-ones. Reactions evolve through the anti conformation of the ylide with complete regioselectivity. The facial selectivity is completely controlled by the configuration of the sulfinyl sulfur for acyclic dipolarophiles, whereas it is high (dr 83/17 or 89/11) but controlled by the C-5 configuration for sulfinylfuranones. Complete endo selectivity is observed with cyclic dipolarophiles and substituted acrylonitriles, but it is low with butenoate. The sulfinyl group also exerts a positive influence on the dipolarophilic reactivity toward these ylides.     

Ring closing enyne metathesis: control over mode selectivity and stereoselectivity

Ring closing enyne metathesis to form 10-15-membered rings was achieved by using a tartrate-derived linker to attach ene and yne subunits. The exo/endo selectivity of the ring closure reaction of these substrates was found to be a function of ring size, whereby larger rings (12-15) give endo-products selectively, while smaller rings (5-11) give exo-products. The E/Z selectivity of the resultant macrocyclic 1,3-dienes was not predictable except for 10- and 11-membered rings. However, both the exo/endo-mode selectivity of the ring closure and the E/Z selectivity of the 1,3-dienes were improved by performing these reactions under ethylene atmosphere. The presence of ethylene induces a selective cross metathesis between the alkyne moiety and ethylene to generate an acyclic 1,3-diene which can undergo ring closing diene metathesis between the isolated olefin and the distal monosubstituted double bond of the 1,3-diene to generate exclusively the endo-product with high E-selectivity.     

Donor-Acceptor Complexes in Copolymerization. LXIII. Alternating Diene-Dienophile Copolymers. 15. Copolymerization of Cyclopentadiene and the Isomeric N-Phenyl-5-norbornene-2,3-dlcarboximides with N-Phenylmaleimide

Abstract

The copolymerization of cyclopentadiene (CPD) and N-phenyl-maleimide (NPMI) at 80–195°C, in the presence of a radical catalyst having a short half-life at the reaction temperature and less than 25% solvent, yields a 1:2 CPD-NPMI copolymer (DP 2–3) which is identical (IR, NMR) to the endo 1:1 copolymer (DP 18) obtained under the same conditions from the copolymerization of the endo CPD-NPMI Diels-Alder adduct and NPMI. The exo CPD-NPMI adduct copolymerizes with NPMI under the same conditions to yield an exo 1:1 copolymer (DP 8). Under the same conditions the homopolymerization of the endo and exo CPD-NPMI adducts is effected in the melt at temperatures up to 260°C and in solution at 120–155°C. The homopolymers (DP 3–7) prepared below 210°C retain the configuration of the adducts while the homopolymers prepared at 260°C from either isomer contain both endo and exo configurations due to isomerization. The participation of excited species is suggested by the requirement for high-speed decomposition of radical catalysts to effect homopolymerization and copolymerizations.     

Formal intermolecular 4 + 4 approach to cyclooctanoids: 4 + 3 capture of the Nazarov oxyallyl intermediate with simple 1,3-dienes

[reaction: see text] Simple 1,4-dien-3-ones and 1,3-dienes react in the presence of BF(3).OEt(2) via a domino Nazarov electrocyclization/intermolecular [4 + 3]-cycloaddition sequence to furnish keto-bridged cyclooctenes in good yield. Most cases showed high diastereofacial selectivity and/or endo/exo selectivity, and surprising levels of regioselectivity were observed when isoprene was used as the diene partner.     

exo-selective asymmetric Diels-Alder reaction catalyzed by diamine salts as organocatalysts

[reaction: see text] A novel binaphthyl-based diamine (R)-2 was designed and synthesized. A protonic acid-(R)-2 salt catalyst has the advantage of exhibiting unprecedented high exo selectivity in the asymmetric Diels-Alder reaction of alpha,beta-unsaturated aldehydes. For instance, the reaction between cinnamaldehyde and cyclopentadiene in the presence of 12 mol % of binaphthyl-based diamine (R)-2 and 10 mol % of p-TsOH.H(2)O in alpha,alpha,alpha-trifluorotoluene at -20 degrees C gave the corresponding exo cycloadduct with 92% ee as a major diastereomer (exo/endo = 13/1).     

Selectivity in the electron transfer catalyzed Diels-Alder reaction of (R)-alpha-phellandrene and 4-methoxystyrene

Electron transfer catalysis is an effective method for the acceleration of Diels-Alder reactions between two substrates of similar electron density. The dependence of the selectivity of the Diels-Alder reaction between (R)-alpha-phellandrene and 4-methoxystyrene catalyzed by photoinduced electron transfer with tris(4-methoxyphenyl) pyrylium tetrafluoroborate is studied. Despite the fact that the radical ions involved are highly reactive species, complete regioselectivity favoring attack on the more highly substituted double bond is observed. The endo/exo selectivity and the periselectivity between [4 + 2] and [2 + 2] cycloaddition is found to be solvent-dependent. Stereochemical analysis showed that the periselectivity is correlated with the facial selectivity, with attack trans to the isopropyl group leading to the [4 + 2] product and cis attack leading to the formation of the [2 + 2] product. A good correlation between the dielectric constant of the solvent and the endo/ exo ratio is found, but more polar solvents lead to lower periselectivity. The effect of reactant and catalyst concentrations is found to be smaller. These results are rationalized in the context of the relative stability of the ion-molecule complexes and the singly linked intermediate of the reaction.     

Cu(I)-catalyzed highly exo-selective and enantioselective [3 + 2] cycloaddition of azomethine ylides with acrylates

[reaction: see text] A novel Cu(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with acrylates has been developed. Up to 98/2 exo/endo selectivity and up to 98% enantiomeric excess have been achieved.     

Allylic stereocontrol of the intramolecular Diels-Alder reaction

The stereochemical outcome of the intramolecular Diels-Alder reaction of ester-linked 1,3,8-nonatrienes can be controlled by substituents about a stereogenic center attached to C1. The scope and limitations of this approach have been investigated, with variation in substrate structure about the allylic stereocenter and the dienophile. The stereochemical outcomes of these reactions are explained by reference to B3 LYP/6-31G(d) transition structures. New insights into the conformational preferences of allylic alcohol derivatives are reported, results which allow an explanation of the differing levels of pi-diastereofacial selectivity and cis/trans (i.e. endo/exo) selectivity from the reaction.     

Putative Diels-Alder-Catalyzed Cyclization during the Biosynthesis of Lovastatin

A Diels-Alder cyclization proposed to occur during polyketide synthase assembly of the bicyclic core of lovastatin (1) (mevinolin) by Aspergillus terreus MF 4845 was examined via the synthesis of the N-acetylcysteamine (NAC) thioester of [2,11-(13)C(2)]-(E,E,E)-(R)-6-methyldodecatri-2,8,10-enoate (5a). In vitro Diels-Alder cyclization of the corresponding unlabeled NAC ester 5b, ethyl ester 18b, and acid 20b yielded two analogous diastereomers in each case, under either thermal or Lewis acid-catalyzed conditions. The reaction of thioester 5 proceeds readily at 22 degrees C in aqueous media. For 18b, one product is trans-fused ethyl (1R,2R,4aS, 6R,8aR)-1,2,4a,5,6,7,8,8a-octahydro-2,6-dimethylnaphthalene-1-carboxylate (30) (endo product), and the other is cis-fused ethyl (1R,2S,4aR,6R,8aR)-1,2,4a,5,6,7,8,8a-octahydro-2,6-dimethylnaphthalene-1-carboxylate (31) (exo product). Isomer 21 with stereochemistry analogous to 4a,5-dihydromonacolin L (2), a precursor of 1, was made by transformation of a tricyclic lactone, (1S,2S,4aR,6S,8S,8aS)-1-(ethoxycarbonyl)-1,2,4a,5,6,7,8,8a-octahydro-2-methyl-6,8-naphthalenecarbolactone (22) using reduction and Barton deoxygenation. Comparison of 21 with 30 and 31 confirmed the structural assignments and showed that the nonenzymatic 4 + 2 cyclizations of 5, 18, and 20 proceed via chairlike exo and endo transition states with the methyl substituent pseudoequatorial. The proposed biosynthetic Diels-Alder leading to lovastatin (1) would require an endo conformation with the methyl substituent pseudoaxial. Intact incorporation of the labeled hexaketide triene 5a into 1 was not achieved because of rapid degradation by A. terreus cells.     

Enantioselective Norrish-Yang cyclization reactions of N-(omega-oxo-omega-phenylalkyl)-substituted imidazolidinones in solution and in the solid state

The four N-(omega-oxo-omega-phenyl-alkyl)-substituted imidazolidinones 5-8 were prepared from N-acetylimidazolidinone (4). Upon irradiation, these substrates underwent Norrish-Yang cyclization to the racemic products rac-9-rac-12 (51-75%). The reactions of the N-2-oxoethylimidazolidinones 5 and 6 were conducted in tBuOH, and yielded 1:1 mixtures of exo/endo diastereoisomers rac-9a/rac-9b and rac-10a/rac-10b, accompanied by Norrish type II cleavage products. The reactions of the N-3-oxopropylimidazolidinones 7 and 8 were performed in toluene. The exo diastereoisomers rac-11a and rac-12a were the major diastereoisomers (d.r. approximately equal to 4:1). In the presence of the chiral compounds 1-3, the photocyclization of substrate 8 proceeded with significant enantiomeric excess (5-60% ee). The more sophisticated complexing agents 3 and ent-3 provided better enantiofacial differentiation (up to 60% ee) than the lactams 1 and 2 (up to 26% ee). Low temperatures and an excess of the complexing agent helped to increase the enantioselectivity. The absolute configuration of the major exo product 12a obtained from compound 8 in the presence of complexing agent 3 was unambiguously established by single-crystal X-ray crystallography of its chiral N-methoxyphenylacetyl derivative 15a. In a similar fashion, the absolute configurations of the endo products 12b and ent-12b were established. The N-2-oxoethylimidazolidinone 5, which crystallized in a chiral space group, was irradiated in the solid state. At low levels of conversion, the product 9a/ent-9a was formed with high enantiomeric excess (78% ee). The enantioselectivity deteriorated at higher levels of conversion.