`Inverse‐Electron‐Demand' Diels‐Alder Reactions of (E)‐3‐Diazenylbut‐2‐enes in Water

The cycloadditions of (E)‐3‐diazenylbut‐2‐enes 1 with a variety of alkenes 2 – 6 were carried out in water as well as in organic solvents. The reactions were always faster in heterogeneous aqueous medium than in the organic solvents. These conjugated diazenyl‐alkenes behave mainly as heterodienes, and the Diels‐Alder adducts are the sole or at least main reaction products. Pyrroles derived from zwitterionic [3+2] cycloaddition reactions were observed in some cases. The cycloaddition of 1a with (+)‐2‐(ethenyloxy)‐3,7,7‐trimethylbicyclo[4.1.0]heptane ( 5 ) is the first example of an asymmetric `inverse electron‐demand' Diels‐Alder reaction carried out in pure water.     

Application of D‐chiro‐Inositol as a Chiral Template for the Diels?Alder Reaction

The Diels? Alder reaction can reliably provide the expected endo‐product in the presence of secondary orbital overlap. It can be considerably more difficult to access a single enantiomer of the exo‐product. In this paper, a D ‐chiro‐inositol derivative is used as a chiral tether to facilitate the regio‐, diastereo‐, and enatioselective cycloaddition between cinnamic acid and hexa‐3,5‐dienoic acid. The Diels? Alder reaction between these two substrates, or their respective esters, does not occur under thermal conditions. Because of the ease of removal of the chiral tether from the resulting cyclohexene, this approach could provide a viable technique to access otherwise unavailable systems.     

Total Synthesis of (+)‐β‐Himachalene

An enantioselective synthesis of (+)‐β‐himachalene ( 2 ) was accomplished starting from (1S,2R)‐1,2‐epoxy‐p‐menth‐8‐ene ( 3 ) in 15 or 16 steps with an overall yield of ca. 6% (Schemes 3, 5, and 6). Key transformations include an Ireland–Claisen rearrangement, a Corey oxidative cyclization, and a ring expansion.     

Steric and Electronic Effects on an Antibody‐Catalyzed Diels–Alder Reaction

A series of substituted thiophene dioxides was tested as diene substrates for the antibody 1E9, which was elicited with a hexachloronorbornene derivative and normally catalyzes the inverse electron‐demand Diels–Alder reaction between 2,3,4,5‐tetrachlorothiophene dioxide (TCTD) and N‐ethylmaleimide (NEM). Previous structural and computational studies had suggested that the catalytic efficiency of this system derives in part from a very snug fit between the apolar active site and the transition state of this reaction. Nevertheless, replacing all the Cl‐atoms in the hapten with Br‐atoms leads to no loss in affinity (K_d=0.1 nM ), indicating substantial conformational flexibility in the residues that line the binding pocket. Consistent with this observation, the 2,3,4,5‐tetrabromothiophene dioxide is a good substrate for the antibody (k_cat=1.8 min^?1, K_NEM=14 μM ), despite being considerably larger than TCTD. In contrast, normal electron‐demand Diels–Alder reactions between NEM and unsubstituted thiophene dioxide or 2,3,4,5‐tetramethylthiophene dioxide, which are much smaller or nearly isosteric with TCTD, respectively, are not detectably accelerated. These results show that the electronic properties of the 1E9 active site are optimized to a remarkable degree for the inverse electron‐demand Diels–Alder reaction for which it was designed. Indeed, they appear to play a more important role in catalysis than simple proximity effects.     

Novel Synthesis of 2‐Alkylquinolizinium‐1‐olates and Their 1,3‐Dipolar Cycloaddition Reactions with Acetylenes

Several 2‐alkylquinolizinium‐1‐olates 9 , i.e., heterobetaines, were prepared from ketone 11 , the latter being readily available either from pyridine‐2‐carbaldehyde via a Grignard reaction, followed by oxidation with MnO₂, or from 2‐picolinic acid (=pyridine‐2‐carboxylic acid) via the corresponding Weinreb amide and subsequent Grignard reaction. Mesoionic heterobetaines such as quinolizinium derivatives have the potential to undergo cycloaddition reactions with double and triple bonds, e.g., 1,3‐dipolar cycloadditions or Diels? Alder reactions. We here report on the scope and limitations of cycloaddition reactions of 2‐alkylquinolizinium‐1‐olates 9 with electron‐poor acetylene derivatives. As main products of the reaction, 5‐oxopyrrolo[2,1,5‐de]quinolizines (=‘[2.3.3]cyclazin‐5‐ones’) 19 were formed via a regioselective [2+3] cycloaddition, and cyclohexadienone derivatives, formed via a Diels? Alder reaction, were obtained as side products. The structures of 2‐benzylquinolizinium‐1‐olate ( 9a ) and two ‘[2.3.3]cyclazin‐5‐ones’ 19i and 19l were established by X‐ray crystallography.     

δ‐Peptide Analogues of Pyranosyl‐RNA,Part 1 , Nucleo‐δ‐peptides Derived from Conformationally Constrained Nucleo‐δ‐amino Acids: Preparation of Monomers

Cyclic nucleo‐δ‐amino acids that constitute monomers of a conformationally constrained nucleo‐δ‐peptide base‐pairing system have been prepared. Their synthesis starts with an enantioselectively catalyzed chirogenic Diels‐Alder reaction, proceeds via a regioselective ε‐iodolactamization process, and ends with a regio‐ as well as diastereoselective introduction of nucleobases through S_N2‐type opening of a transiently formed N‐acylaziridine ring. Extensive use of X‐ray crystal‐structure analysis has been made to support structure assignments.     

Synthesis of Pyrano[3,2‐b]indole Derivatives Based on Intramolecular Hetero‐Diels?Alder of 2‐Benzylidene‐2,3‐dihydro‐1H‐indol‐3‐ones

Pyrano[3,2‐b]indole derivatives 2 – 6 were synthesized in good yields from 1‐acetyl‐2‐benzylidene‐2,3‐dihydro‐1H‐indol‐3‐ones 8 and 13 – 15 by an intramolecular hetero‐Diels? Alder reaction. The structures of compounds 2a, 3a, 4, 5 , and 6 were unambiguously established by X‐ray analysis. Compounds 4 and 5 were further aromatized to the corresponding derivatives 16 and 17 , respectively.     

Synthesis of 1,2,3,4‐Tetrahydro‐1,2‐dimethylidenenaphthalene: A Reactive s‐cis‐Butadiene Undergoing Highly Chemo‐ and Regioselective Cyclodimerization

1,2,3,4‐Tetrahydro‐1,2‐dimethylidenenaphthalene 11 has been derived in three steps from tetralone. In the condensed state and at −80°, it undergoes a highly chemo‐ and regioselective cyclodimerization to give 3,3′,4,4′‐tetrahydro‐2‐methylidenespiro[naphthalene‐1(2H),2′(1′H)‐phenanthrene] ( 14 ), the structure of which has been established by single‐crystal X‐ray‐diffraction analysis. Dimer 14 undergoes cycloreversion to diene 11 under flash‐pyrolysis conditions. The reaction of diene 11 with SO₂ occurs without acid promoter at −80° and gives a mixture of (±)‐1,4,5,6‐tetrahydronaphth[1,2‐d][1,2]oxathiin 2‐oxide ( 23 ; a single sultine), 1,3,4,5‐tetrahydronaphtho[1,2‐c]thiophene 2,2‐dioxide ( 25 ), and dimer 14 . The high reactivity of diene 1 in its Diels‐Alder cyclodimerization and its highly regioselective hetero‐Diels‐Alder addition with SO₂ can be interpreted in terms of the formation of relatively stable diradical intermediates or by concerted processes with transition states that can be represented as diradicaloids.     

Synthesis of Novel Polycyclic Indole‐Annulated Thiopyranocoumarin Derivatives via Domino Knoevenagel–Hetero‐Diels–Alder Reaction in Aqueous Media

An efficient synthesis of polycyclic indole derivatives is achieved via domino Knoevenagel–hetero‐Diels–Alder reaction of O‐acrylated salicylaldehyde derivatives with dihydroindole‐2‐thiones in H₂O as solvent. The products are formed in good‐to‐excellent yields with high regio‐ and stereoselectivity.     

Substituent Effect on the Competition between Hetero‐Diels‐Alder and Cheletropic Additions of Sulfur Dioxide to 1‐Substituted Buta‐1,3‐dienes

The reactivity of sulfur dioxide toward variously substituted butadienes was explored in an effort to define the factors affecting the competition between the hetero‐Diels‐Alder and cheletropic additions. At low temperature (<−70°), 1‐alkyl‐substituted 1,3‐dienes 1 that can adopt s‐cis‐conformations add to SO₂ in the hetero‐Diels‐Alder mode in the presence of CF₃COOH as promoter. In the case of (E)‐1‐ethylidene‐2‐methylidenecyclohexane ((E)‐ 4a ), the [4+2] cycloaddition of SO₂ is fast at −90° without acid catalyst. (E)‐1‐(Acyloxy)buta‐1,3‐dienes (E)‐ 1c , (E)‐ 1y , and (E)‐ 1z with AcO, BzO, and naphthalene‐2‐(carbonyloxy) substituents, respectively also undergo the hetero‐Diels‐Alder addition with SO₂+CF₃COOH at low temperatures, giving a 1 : 10 mixture of the corresponding cis‐ and trans‐6‐(acyloxy)sultines c‐ 2c,y,z and t‐ 2c,y,z , respectively). Above −50°, the sultines undergo complete cycloreversion to the corresponding dienes and SO₂, which that add in the cheletropic mode at higher temperature to give the corresponding 2‐substituted sulfolenes (=2,5‐dihydrothiophene 1,1‐dioxides) 3 . The hetero‐Diels‐Alder additions of SO₂ follow the Alder endo rule, giving first the 6‐substituted cis‐sultines that equilibrate then with the more stable trans‐isomers. This statement is based on the assumption that the S=O group in the sultine prefers a pseudo‐axial rather than a pseudo‐equatorial position, as predicted by quantum calculations. The most striking observation is that electron‐rich dienes such as 1‐cyclopropyl‐, 1‐phenyl‐, 1‐(4‐methoxyphenyl)‐, 1‐(trimethylsilyl)‐, 1‐phenoxy‐, 1‐(4‐chlorophenoxy)‐, 1‐(4‐methoxyphenoxy)‐, 1‐(4‐nitrophenoxy)‐, 1‐(naphthalen‐2‐yloxy)‐, 1‐(methylthio)‐, 1‐(phenylthio)‐, 1‐[(4‐chlorophenyl)thio]‐, 1‐[(4‐methoxyphenyl)thio]‐, 1‐[(4‐nitrophenyl)thio]‐, and 1‐(phenylseleno)buta‐1,3‐diene, as well as 1‐(methoxymethylidene)‐2‐methylidenecyclohexane ( 4f ) do not equilibrate with the corresponding sultines between −100 and −10°, in the presence of a large excess of SO₂, with or without acidic promoter. The hetero‐Diels‐Alder additions of SO₂ to 1‐substituted (E)‐buta‐1,3‐dienes are highly regioselective, giving exclusively the corresponding 6‐substituted sultines. The 1‐substituted (Z)‐buta‐1,3‐dienes do not undergo the hetero‐Diels‐Alder additions with sulfur dioxide.     

Synthesis of Benzo[g]isochromenes through Photo‐Dehydro‐Diels–Alder Reaction

The Photo‐Dehydro‐Diels–Alder (PDDA) reaction is shown to be a versatile method for the preparation of highly functionalized naphthalenes. Thus, ketones 1 could be cyclized to the 1H‐benzo[g]isochromen‐4‐(3H)‐ones 11 and 12 , mostly in good yields. The influence of various substituents on the regioselectivity of the reaction was investigated, and the mechanism is discussed based on theoretical calculations.     

Intramolecular Hetero‐Diels–Alder Reactions Catalyzed by BiCl3: Stereoselective Synthesis of Benzo‐Annelated Decahydrofuro[3,2‐h][1,6]naphthyridine Derivatives

A novel, efficient synthesis of a series of functionalized, benzo‐annelated decahydrofuro[3,2‐h][1,6]naphthyridine derivatives 3 has been achieved. The protocol is based on the intramolecular hetero‐Diels–Alder (IMHDA) reaction of in situ formed imines derived from an N‐prenylated sugar aldehyde 1 and different aromatic amines 2 in the presence of bismuth(III) chloride as catalyst. The reactions could be run under very mild conditions at room temperature, and were complete within 30 min, affording exclusively and stereoselectively the corresponding trans‐fused products 3 in good‐to‐excellent yields (Table).     

1‐Thiacyclooct‐4‐yne (=5,6‐Didehydro‐3,4,7,8‐tetrahydro‐2H‐thiocin), and Its Sulfoxide and Its Sulfone

1‐Thiacyclooct‐4‐yne (=5,6‐didehydro‐3,4,7,8‐tetrahydro‐2H‐thiocin; 9 ) can be prepared from thiocan‐5‐one ( 6 ) in three steps by applying the so‐called selenadiazole method. The heterocyclic alkyne can be oxidized to the corresponding sulfoxide 16 and sulfone 17 . Due to their geometrical strain, all three cyclic alkynes show high reactivities in Diels? Alder and 1,3‐dipolar cycloadditions. Moreover, tetrathiafulvalenes can be prepared from 9 and 16 by the reaction with CS₂.     

Total Synthesis of (+)‐Machaeriols B and C and of Their Enantiomers with a Cannabinoid Structure

An efficient and concise synthesis of the biologically interesting (+)‐machaeriol B ( 2 ) and its enantiomer 5 was accomplished from O‐phenylhydroxylamine ( 7 ) in four steps (Scheme 2). In addition, the first total synthesis of natural (+)‐machaeriol C ( 3 ) and its enantiomer 6 was achieved from the readily available ester 15 in eight steps (Scheme 4). The key strategies in the syntheses of 2 and 5 involved benzofuran formation through a [3,3]‐sigmatropic rearrangement and trans‐hexahydrodibenzopyran formation by a domino aldol‐type/hetero‐Diels–Alder reaction. In the case of 3 and 6 , the key steps were stilbene formation by a Horner–Wadsworth–Emmons reaction and trans‐hexahydrodibenzopyran formation by domino reactions.     

Synthesis of Spiropyrimidodiazepines and Spirodiazepinopurines by Tandem Nitroso‐ene/Diels–Alder Reactions

New spirocyclic heterocycles 8, 16, 19/20, 25, 27 , and 30 derived from pyrimido[4,5‐b][1,4]diazepin]‐8′(9′H)‐one were synthesised by a tandem nitroso‐ene/Diels–Alder reaction of 4‐(alkenoylamino)‐5‐nitrosopyrimides. The crystal structure of 16 was established by X‐ray analysis. It is characterised by four pairs of intermolecular H‐bonds linking every two molecules in the unit cell. Sequential imine reduction and intramolecular condensation of the C(4′)‐(acylamino)‐pyrimido[4,5‐b][1,4]diazepines 27 and 30 led to the [1,4]diazepino[1,2,3‐gh]purines 28 / 29 and 31 , respectively.     

Competition between Hetero‐Diels‐Alder and Cheletropic Additions of Sulfur Dioxide to 2‐Substituted Buta‐1,3‐dienes. Synthesis of 2‐(1‐Naphthyl)‐ and 2‐(2‐Naphthyl)buta‐1,3‐diene

Chloroprene (=2‐chlorobuta‐1,3‐diene; 4b ) and electron‐rich dienes such as 2‐methoxy‐( 4c ), 2‐acetoxy‐( 4d ), and 2‐(phenylseleno)buta‐1,3‐diene ( 4e ) refused to equilibrate with the corresponding sultines 5 or 6 between −80 and −10° in the presence of excess SO₂ and an acidic promoter. Isoprene ( 4a ) and 2‐(triethylsilyl)‐( 4f ), 2‐phenyl‐( 4g ), and 2‐(2‐naphthyl)buta‐1,3‐diene ( 4i ) underwent the hetero‐Diels‐Alder additions with SO₂ at low temperature. In contrast, 2‐(1‐naphthyl)buta‐1,2‐diene ( 4h ) did not. With dienes 4a, 4g , and 4i , the hetero‐Diels‐Alder additions with SO₂ gave the corresponding 4‐substituted sultine 5 with high regioselectivity. In the case of 4g +SO₂⇄ 5g , the energy barrier for isomerization of 5g to 5‐phenylsultine ( 6g ) was similar to that of the cheletropic addition of 4g to give 3‐phenylsulfolene ( 7g ). The hetero‐Diels‐Alder addition of 4f gave a 1 : 4 mixture of the 4‐(triethylsilyl)sultine ( 5f ) and 5‐(triethylsilyl)sultine ( 6f ). The preparation of the two new dienes 4h and 4i is reported.     

Gold‐Catalyzed 1,2‐/1,2‐Bis‐acetoxy Migration of 1,4‐Bis‐propargyl Acetates: A Mechanistic Study

The late transition metal catalyzed rearrangement of propargyl acetates offers an interesting platform for the development of synthetically useful transformations. We have recently shown that gold complexes can catalyze a highly selective tandem 1,2‐/1,2‐bis‐acetoxy migration in 1,4‐bis‐propargyl acetates to form 2,3‐bis‐acetoxy‐1,3‐dienes. In this way, (1Z,3Z)‐ or (1Z,3E)‐ and (1E,3Z)‐1,3‐dienes could be obtained in a stereocontrolled manner depending on the electronic and steric features of the ancillary ligand bound to gold and the substituents at the propargylic positions. In this work, we report an experimental study on the scope of this transformation, plus a detailed theoretical examination of the reaction mechanism, which has revealed the key features responsible for the reaction stereoselectivity. Synthetic applications towards the one‐pot synthesis of quinoxaline heterocycles and tandem Diels–Alder processes have also been devised.     

7‐Oxanorbornane and Norbornane Mimics of a Distorted β‐D‐Mannopyranoside: Synthesis and Evaluation as β‐Mannosidase Inhibitors

The racemic 7‐oxanorbornanyl and norbornanyl aminoalcohols 3, 4, 42, 45 , and 46 were synthesized and tested as snail β‐mannosidase inhibitors. The amino tetraol 3 was obtained from the known sulfonyl acrylate 9 and furan 10 . Esterification provided 11 that underwent an intramolecular Diels–Alder reaction to the 7‐oxanorbornene 12 . Reduction of 12 to 13 , desulfonylation, isopropylidenation, and cis‐dihydroxylation gave 16 . A second isopropylidenation to 17 , followed by debenzylation and a Mitsunobu–Gabriel reaction provided 19 that was deprotected via 20 to 3 . Diels–Alder cycloaddition of furfuryl acetate and maleic anhydride to 21 , followed by alcoholysis of the anhydride, cis‐dihydroxylation, isopropylidenation, and Barton decarboxylation gave the ester 25 . Deacetylation to 26 and a Mitsunobu–Gabriel reaction led to 27 that was transformed into the N‐Boc analogue 29 , reduced to the alcohol 30 , and deprotected to 4 . The 1‐aminonorbornane 5 was obtained from Thiele's Acid 31 . Diels–Alder cycloaddition of the cyclopentadiene obtained by thermolysis of the diester 32 , methanolysis of the resulting anhydride 33 , dihydroxylation, isopropylidenation, Barton decarboxylation, and Curtius degradation led to the benzyl carbamate 39 that was reduced to the alcohol 40 , transformed into the N‐Boc carbamate 41 , and deprotected to 5 . The alcohol 40 was also transformed into the benzylamine 42 , aniline 45 , and hydroxylamine 46 . Snail β‐mannosidase was hardly inhibited by 3, 4, 42, 45 , and 46 . Only the amino triol 5 proved a stronger inhibitor. The inhibition by 5 depends on the pH value (at pH 3.5: K_i = 1900 μM ; at pH 4.5: K_i = 340 μm; at pH 5.5: K_i = 110 μm). The results illustrate the strong dependence of the inhibition by bicyclic mimics upon the precise geometry and orientation of the amino group as determined by the scaffold. It is in keeping with the hypothesis that the reactive conformation imposed by snail β‐mannosidase is close to a ^1,4B/¹S₃.     

Mono-Gold(I)-Catalyzed Enantioselective Intermolecular Reaction of Ynones with Styrenes: Tandem Diels–Alder and Ene Sequence

Gold-catalyzed intermolecular reaction leading to dihydronaphthalene derivatives in one pot from two equivalents of ynones with respect to styrene is uncovered. The [4+2] Diels–Alder cycloaddition of ynones and styrenes is catalyzed by a mono-gold(I) complex and the conjugated acid to provide an unstable 3,8a-dihydronaphthalene to subsequently undergo an intermolecular ene-type reaction with the π-activated ynone to afford multi-component coupling dihydronaphthalene products. Linear relationships between chiral ligand-gold complexes and chiral dihydronaphthalene products proves mono-gold catalysis that triggers an asymmetric tandem Diels–Alder and ene reaction sequence.     

Synthesis and Characterization of Diastereoisomerically Pure Tetracyclo[6.2.1.13,6.02,7]dodec‐9‐ene‐4‐carboxylic Acid Derivatives

The synthesis and detailed NMR analysis of diastereoisomerically pure samples of 4‐methyltetracyclo[6.2.1.1^3,6.0^2,7]dodec‐9‐ene‐4‐carboxylic acid ( 2 ), tetracyclo[6.2.1.1^3,6.0^2,7]dodec‐9‐ene‐4‐carboxylic acid ( 6 ) and their tert‐butyl esters are reported. Mixtures containing two isomers of the methyl esters of these compounds were obtained by a twofold, sequential Diels‐Alder reaction between cyclopentadiene, and methyl methacrylate or methyl acrylate, respectively. Pure diastereoisomers of the acids were prepared by selective hydrolysis of their methyl esters.