Sigmatropic Rearrangements Accompanying the Addition of Dichlorocarbene to Norbornadiene

A new product arising from the reaction of dichlorocarbene with norbornadiene, 6endo-(2,2-dichlorovinyl)-cis-bicyclo[3.1.0]hex-2-ene, is described. It does not arise from the normal exo-l,2-adduct, but possibly originates by sigmatropic rearrangement of an initially formed zwitterionic intermediate.     

Stoffwechselprodukte von Mikroorganismen. 89. Mitteilung [1]. Synthese von zwei diastereomeren 2, 4, 6-Trimethylpimelinsäuren. Ein Beitrag zur Stereochemie des Borrelidins

By conventional methods a mixture of diastereomeric 2,4, 6-trimethylpimelic acids was prepared and separated by counter-current distribution. The two meso-compounds were isolated in crystalline form, one of them (m.p. 130°) giving a dimethyl ester identical with a degradation product of the antibiotic borrelidin. The chirality (2-R,4-r,6-S) of the acid of m.p. 130° was determined by an X-ray structural analysis (see following paper).     

Synthese von Haschisch-Inhaltsstoffen. 4. Mitteilung

(?)-Cannabidiol has been synthesized from (+)-cis- and (+)-trans-p-menthadien-(2, 8)-ol-(1) and olivetol, using N, N-dimethylformamide dineopentyl acetal or weak acids, such as oxalic, picric, or maleic acid, as catalysts. Since the chirality of (+)-trans-p-menthadien-(2, 8)-ol-(1) is known, the above synthesis constitutes an unambiguous prove for the absolute configuration of (?)-cannabidiol and the two isomeric (?)-6a, 10a-trans-tetrahydrocannabinols. If stronger acids, such as p-toluenesulfonic, trifluoroacetic, or hydrochloric acid, are used as mediators for the reaction, (?)-Δ⁸-6a, 10a-trans-tetrahydrocannabinol is obtained as the main product. Transformation of the thermodynamically more stable Δ⁸-tetrahydrocannabinol into the less stable Δ⁹-isomer was achieved in a practically quantitative yield by addition of hydrochloric acid and elimination of the elements of hydrochloric acid by means of potassium t-amylate. If resorcinols I were used instead of olivetol in the condensation reaction with strong acids, the corresponding homologues of Δ⁸-tetrahydrocannabinol were obtained in varying yields.     

One‐Pot Synthesis of Fused Pyrroles through a Key Gold‐Catalysis‐Triggered Cascade

A two‐step, one‐pot synthesis of fused pyrroles is realized by firstly condensing an N‐alkynylhydroxammonium salt with a readily enolizable ketone under mild basic conditions and then subjecting the reaction mixture to a gold catalyst, which triggers a cascade reaction involving a facile initial [3.3]‐sigmatropic rearrangement of the gold‐catalysis product, that is, an N,O‐dialkenylhydroxamine. The reaction provides a facile access to polycyclic pyrroles in moderate to good yields.     

Reaction of 4-(N,N-Dimethylaminophenyl)magnesium Bromide with Palladium Tetrakis(triphenylphosphine)

The influence of reaction conditions on catalyzed by Pd(PPh₃)₄ cross-coupling of 4-N,N-dimethylaminophenylmagnesium bromide with 4-bromobenzonitrile in tetrahydrofuran was investigated. The yield of the product of the catalytic process, 4-N,N-dimethylamino-4'-cyanobiphenyl, and of the main product of noncatalytic process, 4-N,N-dimethylaminophenyl 4'-bromophenyl ketone, is mainly governed by the order of introduction of reagents and catalyst into the reaction zone. Experimental observations and analysis of side products suggested conclusions on the processes resulting in deactivation of the catalyst.     

Supramolecular Photochirogenesis. 3. Enantiodifferentiating Photoisomerization of Cyclooctene Included and Sensitized by 6-O-Mono(o-methoxybenzoyl)–cyclodextrin

Supramolecular enantiodifferentiating photoisomerization of (Z)-cyclooctene (1Z) to chiral (E)-isomer (1E) through inclusion and sensitization by 6-O-mono(o-methoxybenzoyl)--cyclodextrin (2) was investigated in water and in aqueous methanol solutions at various temperatures. A dramatic inversion of the product chirality was observed to occur by simply changing the solvent from water to methanol. Thus, the supramolecular photosensitization in aqueous solution gave (R)-(–)-1E in 15% enantiomeric excess (ee), whereas in methanol the antipodal (S)-(+)-1E was obtained in 5% ee. The temperature and solvent dependencies of the product ee are discussed.     

[2,3]-Wittig Sigmatropic Rearrangement of Steroidal 16β-Propargyl Ethers for the Synthesis of 25-Hydroxyvitamin D Side Chain Analogues

An efficient [2,3]-Wittig sigmatropic rearrangement of the pregnadiene derivative 2b allowed the one-step introduction of a side chain with the natural (20R) chirality and the 25-hydroxy group of the principal metabolites of vitamin D.     

Über den Anteil sigmatroper 1, 5-Wanderung von Kohlenwasserstoffgruppen bei der thermolytischen Skelettisomerisierung 5,5-disubstituierter 1, 3-Cyclohexadiene

On the Extent of Sigmatropic 1, 5-Migration of Hydrocarbon Groups in the Thermolytic Skeletal Rearrangement of 5,5-Disubstituted 1,3-Cyclohexadienes The uncatalyzed skeletal isomerization of 5, 5-disubstituted 1, 3-cyclohexadienes was investigated with the aim to establish the extent to which sigmatropic 1,5-shifts of hydrocarbon groups are participating in these reactions. Gas phase pyrolysis of 5,5-diethyl-1,3-cyclohexadiene ( 7 ) at 460° followed by chloranil aromatization yields only 4% of 1,3-diethylbenzene resulting from 7 through a 1, 5-ethyl migration in the primary reaction step. 2, 3-Dimethylethylbenzene (56%) and 1, 4-diethylbenzene (4%) are obtained as other C₁₀-compounds. This shows that isomerization proceeds mainly through a sequence of electrocyclic and 1, 7-shift reactions. Ethylbenzene (24%) and other aromatic C₈- and C₉-hydrocarbons are formed to a considerable extent, indicating that C, C-bond cleavage is a major competing process and that the 1, 3-diethylbenzene found is the result of a radical recombination reaction and not of a concerted sigmatropic shift of the ethyl group. 5-Methyl-5-phenyl-1, 3-cyclohexadiene ( 12 ) yields 3-methylbiphenyl ( 14 ) and biphenyl upon thermolysis and aromatization. Through ¹³C-substitution of the methyl group in 12 it is shown that in solution at 300° skeletal isomerization proceeds through electrocyclic and 1, 7-H-shift reactions exclusively. In the gas phase at 500° 4% of the isomerization product is formed by a 1, 5-shift of a substitutent, presumably of the methyl group, through a dissociative mechanism. Thermolysis of 5, 5-diphenyl-1, 3-cyclohexadiene ( 22 ) at 560° in the gas phase leads to 1, 1-diphenyl-1, 3, 5-hexatriene ( 23 ) and 1-vinyl-4-phenyl-1, 2-dihydronaphthalene ( 24 ) through electrocyclic reaction steps. In addition a small amount of m-terphenyl is obtained at high conversion of 22 . This indicates that sigmatropic 1,5-phenyl migration can participate in product formation only at high temperature and in the absence of other irreversible pathways to stable products.     

Über die «aus dem Ring»-Claisen-Umlagerung von Naphthalinderivaten

When a mixture of (E)- and (Z)-1-propenylnaphth-2-yl-allylether ((E/Z)- 5 ) is heated to 182° only the (E)-isomer rearranges to give the ‘out-of-ring’ product (E/Z)- 16 , (Z)- 5 remains unchanged. At higher temperature (Z)- 5 yields 2-methyl-naphtho[2,1-b]furane ( 15 ) as the main product. The mixture of β-chloro-allyl derivatives (E/Z)- 6 behaves in a similar way. These findings led us to suspect that the ‘out-of-ring’ products 16 and 18 are formed by direct [1, 5s] allyl migration from the starting ethers (E)- 5 and (E)- 6 . Kinetic' measurements made on (E)- and (Z)- 5 and the independently synthesized (E)- and (Z)-1-allyl-1-propenyl-1 H-naphthalen-2-ones ((E)- and (Z)- 17 ) show however, that the ethers (E)- 5 and (E)- 6 undergo a double [3s, 3s] rearrangement (i.e. Claisen followed by Cope rearrangement) and hydrogen migration to yield the ‘out-of-ring’ products (E/Z)- 16 and (E/Z)- 18 (Scheme 9). In the (Z)-series steric factors prevent the intermediate naphthalenones (Z)- 17 and (Z)-19 from undergoing the Cope rearrangement and instead, at higher temperature, cleavage of the allyl group occurs (Scheme 11). The isopropenyl derivative 7 behaves in a similar way (Scheme 5). Rearrangement of (E/Z)-1-propenylnaphth-2-yl benzyl ether ( 8 ) requires a higher temperature (214°). The nature of the products obtained (Scheme 4) makes the occurrence of a direct sigmatropic [1,5s] shift of the benzyl group very unprobable. In the case of (E/Z)-2-propenylnaphth-1-yl allyl ether ( 10 ) both isomers rearrange to yield the ‘out-of-ring’ product 30 and the para-Claisen product 32 (Scheme 7). This experiment also provides evidence against a sigmatropic [1,5s] shift of the allyl group. The same conclusion can be drawn from the thermal behaviour of (E/Z)-2-propenylphenyl allyl ether (11) and 6-t-butyl-2-propenylphenyl allyl ether ( 12 ) where only 11 yields traces of the ‘out-of-ring’ product 35 (Scheme 8). Up to this date there is no evidence whatsoever for the existence of a sigmatropic [1,5s] migration of an allyl group from oxygen to carbon. Thermal rearrangement of (E/Z)-1-propenylnaphth-2-yl propargyl ether ( 9 ) yields only (E/Z)-1-propenyl-benz[e]indan-2-one ( 27 ) (and its secondary product 28 ). The mechanism for this reaction is given in Scheme 12. Treatment of a mixture of (E/Z)- 18 with base yields the (Z)-cyclisation product 2,4-dimethylnaphth[2,1-b]oxepine ( 43 ) (Scheme 13).     

Synthesis of Substituted 1-Thiocyanatobutadienes and their Application in a Diels-Alder/[3,3] Sigmatropic Rearrangement Tandem Reaction

Summary. The retrosynthetic analysis of Ibogamine, a natural psychotropic alkaloid with exceptional anti-addictive properties found in both enantiomeric forms, requires an efficient access to a racemic cyclohexene. This cyclohexene can be obtained via the sequence Diels-Alder/[3,3] sigmatropic rearrangement reaction starting from substituted 1-thiocyanatobutadienes. An efficient synthesis of the enone, a stable precursor of 1-thiocyanatobutadienes, is reported. Enolisation of this enone was studied to find the optimal conditions to get the desired 1-thiocyanatobutadienes with good Z-selectivity.     

On possible redirection of the course of anionic oxy-cope rearrangements

The β, γ-unsaturated ketones bicyclo[2.2.1]hept-2-en-7-one (10) and 7,7-dimethoxybicyclo[2.2.1]hept-2-en-5-one (15) have been condensed with 1-metalated trans-1-methoxybutadienes (7a or 7b) and 2-isopropenylcyclopentenes (8b or 8c). Oxyanion formation within the resulting alcohols is followed by skeletal rearrangement at room temperature. Careful product analysis has revealed the [3,3] sigmatropic reaction manifold to be followed almost exclusively. Only in the case of 13 is a modest amount (4%) of formal antarafacialretention [1,3] sigmatropic bridgehead carbon migration in evidence. Consequently, the structural features inherent to these alcohols are not conducive to redirecting electronic reorganization to an alternative isomerization process.     

Chirality driven mesomorphic behaviour difference: dichiral compounds containing two lactate groups

ABSTRACT

Four compounds containing two lactate groups and one perfluorocarbon chain are designed and synthesised, whose chirality is tuned by changing the chirality of the lactic acid residues. (R,S)- and (S,R)-2 stereoiosomers exhibit an enantiotropic SmA phase, while (R,R)- and (S,S)-2 stereoisomers exhibit an enantiotropic SmA phase and an enantiotropic SmC_d* one. Therefore, the chirality of the compounds plays an important role in the mesomorphic behaviours of the compounds. The optical activity of these liquid crystals is dominated by the chirality of the lactate group near the core. (R)- and (S)-1 with one lactic acid residue and one perfluorocarbon chain exhibit only an enantiotropic SmA phase.     

Hydrogen‐Bond‐Induced Chiral Axis Construction: Theoretical Study of Cinchonine–Thiourea‐Catalyzed Enantioselective Intramolecular Cycloaddition

Theoretical calculations were performed to investigate the mechanism and enantioselectivity of cinchonine–thiourea‐catalyzed intramolecular hetero‐Diels–Alder cycloaddition of ethynylphenol derivatives to afford axial chirality naphthalenylpyran products via a vinylidene ortho‐quinone methide (VQM) intermediate. The results show that this transformation occurs through a reaction pathway involving the deprotonation of the naphthol moiety by the quinuclidine base, intramolecular proton transfer in ammonium naphthalenolate, and [4+2] cycloaddition. It is found that the axial chirality of the VQM intermediate is generated by the protonation step, which affects the enantioselectivity of the reaction. The enantioselectivity for the generation of the VQM intermediate is controlled by steric repulsion with the cinchonine framework, which provides an R‐axial chirality VQM as the major intermediate. Moreover, the enantioselectivity for the axial chirality of the naphthopyran product is controlled by the cycloaddition step, in which an extra hydrogen bond between the naphthalenol and cinchonine moieties leads to a favorable configuration for the generation of the S‐axial chirality naphthopyran product. The calculated enantioselectivity and enantiomeric excesses coincide with experimental observations.     

The photochemical synthesis of novel heterocyclic compounds from s-triazolo[4,3-b]pyridazine

s-Triazolo[4,3-b]pyridazine (I) photochemically reacted with cyclooctene, cyclododecene, bicyclo[2.2.2]oct-2-ene, bicyclo[2.2.1]hept-2-ene and indene to form tri and tetracyclic triazoles (II-X). Generally, two or more products were formed. For example the reaction with cyclooctene gave 4a,5,7,8,9,10,10a,11-octahydro-11-methylene-6H-cycloocta[4,5]-pyrrole[1,2-b]-s-triazole (II) and the corresponding 11-cyanomethyl product (III). When I was reacted with open chain alkenes, various isomers of the substituted pyrrolo[1,2-b]triazoles (XI-XV) were formed. Since the reaction was not stereospecific, cycloaddition must be a two step process.     

Developments of Asymmetric Synthesis Mediated by Chiral Sulfur Reagents

Abstract

Our work on the thio-Claisen rearrangement mediated by an adjacent sulfinyl group is reviewed. The substrates could easily be prepared on a large scale from diacetone-D-glucose. The rearrangement was effected with a diastereoselectivity of 95:5, in favor of the (S,S) or the (R,R) isomer. An approach to natural bis(lactones) was investigated, using a halolactonization reaction and a second [3,3] sigmatropic shift, again mediated by the sulfinyl group. The second part deals with the catalytic enantioselective benzylidenation of aldehydes, mediated by chiral sulfur ylides. We have introduced simple C ₂ symmetric thiolanes for that purpose. The procedure is very practical and enantiomeric excesses up to 96% have been reported for the model of stilbene oxide. A series of ferrocenyl sulfides with planar chirality has also been investigated, leading to unexpected diastereoselectivities and enantiomeric excesses up to 94%.     

Skeletal Rearrangements of Organoalkali Metal Compounds

Organometallic compounds of the alkali metals undergo concerted [1,n] sigmatropic migration of aryl, vinyl, carbonyl, alkoxycarbonyl, silyl, germyl, and related groups. Sigmatropic migration of alkyl, benzyl, and hydrogen occur only under special circumstances and then may occur by an alternate fragmentation-recombination pathway. Allyl groups may migrate by the latter process or by a concerted [2,3] sigmatropic reaction. These molecular rearrangements are discussed from the viewpoint of simple molecular orbital theory. By suitable choice of the alkali metal, temperature, ligands of the alkali cation and/or the solvent, considerable control may be exercised over the rate of rearrangement, the relative migratory aptitude of groups, and the mechanistic pathway.     

Stereoselectivity in reactions of metal complexes. VI. Kinetic study of the interconversion of cis-N and trans-N (S)-aspartato-N-acetato(amino-acidato)cobalt(III) complexes

The cis-N/trans-N interconversion of the title compound containing glycine and (R)- or (S)-leucine has been studied by polarimetric and spectrophotometric techniques. Equilibrium constants were determined on the basis of kinetic and thermodynamic data. It is shown that the chirality of the bidentate amino-acid has a pronounced influence on the cis-trans equilibrium of these systems. Possible mechanisms of the interconversion reaction are discussed.     

Studies on Chirality Transfer in the [2,3] Sigmatropic Rearrangement of Anions Derived from Trialkylstannylmethyl Allylic Ethers. Stereospecific Synthesis of (2R)-3-Benzyloxy-2-methylpropanol.

Virtually complete chirality transfer is observed in the [2,3] sigmatropic rearrangement of the anion derived from trialkylstanylmethyl ($\text{E}$)- or ($\text{Z}$)-allylic ethers.     

Synthesis and optical rotation of the (-)-cannabidiols

N, N-Dimethylformamide-dineopentylacetal mediates the direct formation of (-)-cannabidiol from (+)-trans- or (+)-cis-p-menthadiene-(2,8)-ol-(1) and olivetol. This reaction provides a simple synthetic entry into the series of optically active constituents of haschisch and defines at the same time the chirality of these compounds.     

Synthesis of Highly Substituted Cyclobutane Fused‐Ring Systems from N‐Vinyl β‐Lactams through a One‐Pot Domino Process

In this contribution, aminocyclobutanes, as well as eight‐membered enamide rings, have been made from N‐vinyl β‐lactams. The eight‐membered products have been formed by a [3,3]‐sigmatropic rearrangement, whereas the aminocyclobutanes have been derived from a domino [3,3]‐rearrangement/6π‐electrocyclisation process. The aminocyclobutanes have been obtained in a highly diastereoselective fashion. The cyclobutane ring system tolerates fusion even if adjacent quaternary centres are present. Systems containing up to four fused rings are readily accessible. The reaction profile has been investigated by using Gaussian 03. This study suggests that two reaction pathways for aminocyclobutane formation are possible. In one pathway the [3,3]‐sigmatropic rearrangement is the rate‐limiting step and in the second pathway the electrocyclisation is rate limiting. Taken together, these reactions should facilitate the construction of fused heterocycles.