Synthesis of BCD tricyclic analogues of the novel cardiac glycoside rhodexin A

A concise synthesis of novel cardiac glycoside analogues of rhodexin A, 14 and 24, having the BCD tricyclic system is described. The key constructive step is an inverse-electron demand Diels-Alder reaction of the silyl enol ether 4 and the 2-acetyldiene, 7 and 15.     

Intramolecular Diels-Alder reaction of 2-diphenylphosphinyl-5-(propargyloxymethyl)furans followed by nucleophilic 1,2-rearrangement of the phosphinyl group

The base-catalyzed intramolecular Diels-Alder reactions of 2-diphenylphosphinyl-5-(propargyloxymethyl)furans 2a-e gave the tetrahydrofuran ring annulated o-diphenylphosphinophenols 3a-e in 70-80% yields, a novel reaction involving an intramolecular Diels-Alder reaction of furan diene with allenyl ether dienophile followed by a nucleophilic 1,2-rearrangement of the diphenylphosphinyl group.     

Facile synthesis of 7-10 membered rings by intramolecular condensation using dialkylcarbonate as solvent

A convenient large-scalable synthesis of 1-benzazepines 19 as an important intermediate of CCR5 antagonist, oral HIV-1 therapy, was established. The anilination of o-halogenobenzaldehyde 9 with alkylamino-acid 16 gave o-formylaniline-acid 17. Compound 17 was esterified followed by the improved reaction using the combination of alcoholate and dialkyl carbonate in one-pot, to easily produce 19. Namely, these new processes afforded the desired product 19 in only two steps from the starting materials, as compared with the previous 10 steps. Moreover, these convenient methodologies were applied to other heterocycles to give 8-10 membered rings, such as 1-benzazocine, 1-benzazonine, and 1-benzazecine.     

Synthetic approach to potential precursors of sclerophytin A

A direct approach to simple bicyclic analogues of the antitumor natural diterpene, sclerophytin A, is described. The readily available bicyclic ketone 8 (prepared from furan and trichloroacetone) was enantioselectively methylated to give the optically active ketone 11. Regioselective allylation using Negishi's method afforded the α,α-dialkyl ketone 12, which was converted to the chloroacetate 15 by hydroboration-oxidation and protection. Regioselective Baeyer-Villiger oxidation afforded the lactone 7a which could be transformed into the silyl ether 7b. Tebbe olefination furnished a mixture of two enol ethers in which the desired product 17 was the minor isomer. Several attempts to use the major endocyclic enol ether 18 to give the tricyclic analogues of sclerophytin proved unsuccessful. Opening of the lactone of 18 and selective protection of the diol afforded the primary alcohol 24 which was oxidized to the keto aldehyde 25. Unfortunately pinacol coupling of 25 did not give any cyclic product. The diene 27 was also prepared from 25 but all attempts at ring-closing metathesis of 27 met with the same fate. The failure of these various cyclization methods underscores the difficulty in forming medium-sized ring systems, especially those cis-fused at the 2- and 5-positions of a tetrahydrofuran ring.     

Synthesis of new tropinone derivatives by palladium-catalyzed couplings of 8-azabicyclo[3.2.1]oct-2-enyl nonaflates

Whereas tropinone derived nonaflate 3 was no suitable precursor for Heck-reactions, the related carbamate 7 was an excellent substrate for palladium-catalyzed processes. Nonaflate 7 was either isolated in excellent yield by LDA treatment of ketone 5 followed by trapping with NfF (nonafluorobutanesulfonyl fluoride) or generated in situ by fluoride-catalyzed reaction of silyl enol ether 6 with NfF. The desired 1,3-diene 8 was prepared by conventional Heck-reaction of nonaflate 7 with methyl acrylate in almost quantitative yield. Alternatively, the one-pot nonaflation-Heck protocol starting from silyl enol ether 6 provided 8 in good yield. The couplings of acrylonitrile or phenyl vinyl sulfone were also performed with in situ generated 7 and they afforded the expected 1,3-dienes 9 and 10 in good yields. The Sonogashira-reaction with phenylacetylene also started from silyl enol ether 6 and provided enyne 11 via 7 in good yield. A Diels-Alder reaction of 1,3-diene 8 with N-phenyl maleimide at 100 °C furnished tetracyclic adduct 12 in good yield, with excellent diastereofacial selectivity, but with low endo-exo-selectivity. Nonaflate 14 was easily obtained from the corresponding unsaturated bicyclic ketone 13. It behaved differently in an attempted Heck-reaction and mainly led to fragmentation products 15 and 16, whereas the expected 1,3-diene 17 was formed only as minor component. However, 14 could successfully be used in a Sonogashira-reaction with phenylacetylene to afford compound 18. These transformations demonstrate the great potential of tropinone derived alkenyl nonaflates for diversity oriented syntheses of interesting compounds containing an 8-azabicyclo[3.2.1]octane scaffold.     

Synthesis of the spiroketal fragment of bistramide A via an exocyclic enol ether

An efficient synthesis of the spirocyclic fragment 1 of bistramides is reported. An olefination reaction of lactone 4 with sulfone 5 gave the enol ether 3, which upon cyclization in acidic media provided the spiroketal ring system. This compound was then converted into the C19-C36 fragment of the bistramides via successive Julia-Kocienski and Horner-Emmons olefinations.     

Synthesis of bis-(3,5)pyrazolophanes via double cycloadditive macrocyclisation

Double cycloadditive macrocyclisation of bis-hydrazonoyl chlorides 5 were performed with bis-allyl ethers 9 and 10, bis-vinyl ether 14 and bis-propargyl ether 18. The title compounds having a 18-, 19-, 22- or 24- membered ring annulated to the pyrazole units were obtained with good overall yield.     

Total synthesis of lycogarubin C utilizing the Kornfeld-Boger ring contraction

An efficient synthesis of lycogarubin C (3) was completed in seven steps from the known 1-(phenylsulfonyl)indole-3-carbaldehyde in 30% overall yield, via a Diels-Alder reaction between (Z)-1,2-di(1H-indol-3-yl)ethene 9b and dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (7), followed by a Kornfeld-Boger ring contraction to form the pyrrole ring.     

Formation and sigmatropic rearrangement of PhCOC(NO2)CH2 cycloadducts of 1,3-cyclohexadiene: a theoretical study

Competing cycloaddition pathways for the reaction of 2-nitro-1-phenyl-2-propen-1-one with 1,3-cyclohexadiene were investigated employing computational methods. A bifurcating pathway was found for formation of nitroketone 3 and nitronic ester 5. A second bifurcating pathway was found for the formation of nitroketone 4 and enol ether 6. Sigmatropic rearrangements of two cycloadducts, nitronic ester 5 and enol ether 6, were also studied computationally. The reaction pathways were mapped using the B3-LYP/6-311G(d) method and relative energies for species 3-6 were calculated at the same level. Solution-phase corrections were performed by the PCM method. The calculations for both bifurcating cycloaddition pathways indicate kinetic control with similar rate-determining activation energies. The nitroketone 3 is more stable than nitronic ester 5 by 5.3 kcal/mol and nitroketone 4 is more stable than enol ether 6 by 3.9 kcal/mol, consistent with the observed direction of sigmatropic rearrangement.     

Preparation, crystal structure, and spectroscopic, chemical, and electrochemical properties of (2E,4E)-4-[4-(dimethylamino)phenyl]-1-(3-guaiazulenyl)-1,3-butadiene compared with those of (E)-2-[4-(dimethylamino)phenyl]-1-(3-guaiazulenyl)ethylene

Wittig reaction of 3-[4-(dimethylamino)phenyl]propanal (5) with (3-guaiazulenylmethyl)triphenylphosphonium bromide (4) in ethanol containing NaOEt at 25 °C for 24 h under argon gives the title (2E,4E)-1,3-butadiene derivative 6E in 19% isolated yield. Spectroscopic properties, crystal structure, and electrochemical behavior of the obtained new extended π-electron system 6E, compared with those of the previously reported (E)-2-[4-(dimethylamino)phenyl]-1-(3-guaiazulenyl)ethylene (12), are documented. Furthermore, reaction of 6E with 1,1,2,2-tetracyanoethylene (TCNE) in benzene at 25 °C for 24 h under argon affords a new Diels-Alder adduct 8 in 59% isolated yield. Along with spectroscopic properties of the [π4+π2] cycloaddition product 8, the crystal structure, possessing a cis-3,6-substituted 1,1,2,2-tetracyano-4-cyclohexene unit, is shown. Moreover, reaction of 6E with (E)-1,2-dicyanoethylene (DCNE) under the same reaction conditions as the above gives no product; however, this reaction in p-xylene at reflux temperature (138 °C) for four days under argon affords a new Diels-Alder adduct 9 in 54% isolated yield. Although reaction of 6E with DCNE in toluene at reflux temperature (110 °C) for four days under argon provides 9 very slightly, reaction of 6E with dimethyl acetylenedicarboxylate (DMAD) in toluene at reflux temperature for two days under argon yields a new Diels-Alder adduct 10, in 58% isolated yield, which upon oxidation with MnO₂ in CH₂Cl₂ at 25 °C for 1 h gives 11, converting a (CH₃)₂N-4″ into CH₃NH-4″ group, in 37% isolated yield. The crystal structure of 11 supports the molecular structure 10 possessing a partial structure cis-3,6-substituted 1,2-dimethoxycarbonyl-1,4-cyclohexadiene. The title basic studies on the above are reported in detail.     

The total synthesis of (−)-connatusin A, a hirsutane-type sesquiterpene isolated from the fungus Lentinus connatus BCC8996

The title sesquiterpenoid natural product 1 has been prepared for the first time using the enantiomerically pure cis-1,2-dihydrocatechol 3 as starting material. Key steps associated with the synthesis include a Diels-Alder cycloaddition reaction of the acetonide 5 with cyclopentenone (4) and an oxa-di-π-methane rearrangement of bicylco[2.2.2]octenone 6 derived from the initial adduct. The product of this sequence, the cyclopropannulated triquinane 7, was elaborated, over a further eight steps including those involving Upjohn dihydroxylation and Swern oxidation protocols, to the target 1. A single-crystal X-ray analysis served to confirm the structure of this synthetically derived material.     

Exploration of a proposed biomimetic synthetic route to plumarellide. Development of a facile transannular Diels-Alder reaction from a macrocyclic enedione leading to a new 5,6,7-tricyclic ring system

A concise synthesis of the macrocyclic vinylbutenolide 19 is described, based on a facile RCM reaction of the substrates 16/18. Treatment of 19 with TFA containing water led to the 5,6,7-tricyclic compound 27, in a single step, in >90% yield, rather than to the alternative ring system 23 found in plumarellide (1). A rationale for the formation of 27 is presented, involving initial acid-catalysed hydrolysis of the furanmethanol intermediate 20 to the furanoxonium ion 21, which is next hydrolysed to the enol ether cyclic hemiketal 22. The intermediate 22 undergoes rapid tautomerisation and isomerisation producing enedione 24, which then takes part in a transannular Diels-Alder cyclisation to 26. Dehydration of 26 finally produces the tricyclic compound 27.     

Approaches to the synthesis of arisugacin A

Approaches to the synthesis of the important acetylcholinesterase inhibitor, arisugacin A, are described. Two different routes to the key AB ring system are described: the first utilizes an intramolecular Diels-Alder reaction on a furan substrate and the second a 6π-electrocyclization of a substituted triene followed by cycloaddition with singlet oxygen. The successful synthesis of a fully functionalized AB ring system of arisugacin A, the tetraol 52 from hydroxy-β-ionone 22 in 16 steps and 9.3% overall yield is described. Several useful synthetic transformations to this molecule and its analogues are reported, e.g., the formation of the furan Diels-Alder cycloadduct 14 and its conversion into the oxa-bridged structures 17 and 21, the preparation of the dienes 25 and 26 and the conversion of the later into the endoperoxide 30 and its diol 36, the preparation of the endoperoxide 40 and the oxa-bridged system 42, and finally the use of the enelactone 43 and its ultimately successful conversion into 52. In addition, several novel rearrangements are described, producing the unusual compounds 62, 65, and 67. Finally, the successful coupling of the pyrone unit to the AB ring system is described to give compounds 70 and 71. The novel reduction of these compounds to the cyclic ether 74 is described.     

Sequential homo-coupling Diels-Alder/retro Diels-Alder reaction of 5,5′-bi-1,2,4-triazine-containing thiamacrocycles as a new route to thiacrown ethers incorporating a 2,2′-bipyridine subunit

A new route to thiacrown ethers 5a-d and 6a-d incorporating a 2,2′-bipyridine subunit is elaborated using, (1) homo-coupling of 1,2,4-triazine sulfides 3a-d tethered to poly(ethylene glycol) chains with potassium cyanide and (2) Diels-Alder/retro Diels-Alder reaction with norbornadiene or 1-pyrrolidino-1-cyclopentene as the key steps.     

A chemoenzymatic total synthesis of the hirsutene-type sesquiterpene (+)-connatusin B from toluene

The first total synthesis of the hirsutene-type sesquiterpenoid natural product (+)-connatusin B (2) is reported. The cis-1,2-dihydrocatechol 3, which is obtained in enantiomerically pure form via the enzymatic dihydroxylation of toluene, served as the starting material. Diels-Alder cycloaddition and oxa-di-π-methane rearrangement reactions represent key chemical steps in the reaction sequence leading to the cyclopropane ring-fused linear triquinane 14. Reductive cleavage of the three-membered ring within this framework and various functional group interconversions then provide the title compound 2.     

A novel and practical synthetic route for the total synthesis of lycopene

A novel route for the total synthesis of lycopene 1 is described. The synthesis is based on: (i) a condensation between 4,4-dimethoxy-3-methylbutanal 4 and methylenebisphosphonic acid tetraethyl ester 5, leading to the C6-phosphonate 6, followed by (ii) a modified Wittig-Horner reaction between 6 and 6-methyl-5-hepten-2-one 7 producing dimethoxy-3,5,9-triene 8, and (iii) another modified Wittig-Horner reaction between C15-phosphonate 2 and C10-triene dialdehyde 3 producing all-E-lycopene. The synthetic steps are easily operated and practical for the large-scale production.     

Diastereoselective synthesis of antiquorin and related polyoxygenated atisene-type diterpenes

A diastereoselective approach to polyoxygenated atisene-type diterpenes starting from (S)-(+)-carvone is described. The key steps used in the preparation of the atisene framework are an intramolecular Diels-Alder reaction, an intramolecular diazoketone cyclopropanation, an endocyclic cyclopropane ring cleavage and the regioselective reduction of an allylic bromide by a low-valent chromium species. The synthesis of natural atisanes antiquorin (1), atis-16-ene-3,14-dione (3), atis-16-ene-2,3,14-trione (8) and 3β-hydroxy-atis-16-ene-2,14-dione (9) following this approach is presented. Also described is the synthesis of 18-hydroxy-atis-16-ene-3,14-dione (5), the structure erroneously assigned to an atisene isolated from the Fijian plant Euphorbia fidjiana. This work shows that the natural atisene isolated from this plant is, in fact, the epimer at C-4 of this compound.     

An efficient synthesis of the CD rings model for merrilactone A

A synthetic route to the CD rings of merrilactone A was explored by using the model system 9a, which was easily converted from 7,7-dibromohepta-2,6-dienoic acid ethyl ester (8) by the successive Stille-Mizoroki-Heck reaction. The D ring 14 was constructed by applying the intramolecular Tsuji-Trost reaction to the formation of a γ-lactone, whereas the formation of the C ring 18 was effectively accomplished in one step by methylation and conjugate addition toward 1,1-dibromo-1-alkene 17 using Miyashita’s protocol.     

Design and synthesis of (E)-4-((3-ethyl-2,4,4-trimethylcyclohex-2-enylidene)methyl)benzoic acid

(E)-4-((3-Ethyl-2,4,4-trimethylcyclohex-2-enylidene)methyl)benzoic acid, 6, was synthesized in 87% starting from β-cyclocitral. The target compound 6 was synthesized starting from 1 via a Grignard reaction to form alcohol 2. Compound 2 was converted to Wittig salt 3 by treatment with aldehyde 4 in butyllithium and hexane at −78 °C to form ester 5. Ester 5 was saponified and, following acidification, acid 6 was isolated as white solid yield 87%.     

Functionalization of C60 via organometallic reagents

The reaction of [60]fullerene with organolithium and Grignard reagents carrying orthoester, acetal or other end groups yielded adducts 3-5 at the 6-6 bond of C60 after quenching with trifluoroacetic acid. The adducts could be easily methylated or benzylated with methyl iodide or benzyl bromide in the presence of potassium tert-butoxide to yield exclusively the 1,4-disubstituted C60 6 and 7a,b. Cleavage of the orthoester, acetal and silylether groups gave the corresponding carboxylic acid 9, aldehydes 10a,b and 11 and alcohols 12 and 13a,b. The carboxylic acid 9 readily reacted with alanine ethyl ester under standard peptide coupling conditions to give 14 in 55% yield. Attempts to generate a silyl enol ether from the reaction of aldehyde 10b with TIPSOTf and triethylamine failed. Instead the reaction led to a cyclized ether 16a (or alcohol 16b in the absence of silylating agent) resulting from the addition of an initially formed fulleride anion to the aldehyde group. The corresponding acetal 4b reacted similarly. The reaction of aldehyde 10b with aniline also gave a cyclized product 19. Surprisingly, aldehyde 11, which no longer carried an acidic fullerene proton reacted with aniline to give a product 20 resulting from an intramolecular Diels-Alder reaction followed by aromatization of a primarily formed N-phenylimine. Alcohol 13b could be readily converted to the corresponding bromide using tetramethyl-α-bromoenamine. The bromide was reacted with the carbanion derived from the protected glycine derivative to yield the diastereomeric fullerene amino acid derivatives 1-benzyl-4-[α-propyl-tert-butylglycinate benzophenone imine] 1,4-dihydro[60]fullerenes 24a and 24b.