The chemistry of zerumbone. Part 5: Structural transformation of the dimethylamine derivatives

Zerumbone (1) and its 6,7-epoxide (2) react with ammonia and dimethylamine regio- and stereospecifically, affording monoamines 3, 4, 7 and 8. All adducts have the same relative configuration at C2 and C3. The conjugate amination is thermodynamically controlled to arrive at a single diastereomer. At 15°C 7 reacts with cyanide to give aminonitrile 10 as the single product, while at 30°C, acyclic aminonitrile 11 is also formed. The reaction with 8 affords at 0°C bicyclic aminonitrile 12 of the asteriscane skeleton, while at 30°C or higher temperature, mixtures of 12 and tricyclic nitriles 13 and 13′ are obtained. Refluxing of 7, 8 and 10 in aqueous acetonitrile promotes scission of the zerumbone ring by retro-Mannich reaction to provide acyclic aldehydes 16-18, respectively. The dimethylamino group of 7, 8 and 10 is eliminated stereospecifically by Cope- and base-catalyzed eliminations to regenerate the zerumbone skeleton in the products 1, 2 and 21. Cope elimination of 12 results in a mixture of 13 and 13′ by deaminative transannular etherification.     

Rearrangement of the carbon skeleton in the intramolecular photoadduct of anthracene and benzene rings

The effectivity of optical switching between anthracene derivatives 3a,b and their intramolecular photocycloadducts 4a,b is impaired by traces of acid. The systematic treatment of 4a,b with an increasing excess of formic acid revealed that—apart from the normal enolether cleavage 4a,b→6a,b→7a,b—a cleavage with rearrangement of the carbon skeleton can occur: 5b→6b′. The driving force is a stability enhancement of the involved carbenium ions 5b→5b′. A further increased excess of formic acid leads finally to a competitive ether cleavage in the tetrahydrofuran ring 5b→8.     

Assessment of heat-sensitive thiophosphate protecting groups in the development of thermolytic DNA oligonucleotide prodrugs

Heat-sensitive thiophosphate protecting groups derived from the alcohol 4 or 10 have provided insights in the design of DNA oligonucleotide prodrugs. Indeed, functional groups stemming from the alcohol 9, 15, 16 or 22 may be applicable to thiophosphate protection of immunostimulatory CpG DNA motifs, whereas those originating from the alcohol 3, 5, 12, 13, 18, 20 or 22 offer adequate protection of terminal phosphodiester functions against ubiquitous exonucleases that may be found in biological environments. Functional groups derived from the alcohol 9, 15, 16, 19 or 23 are suitable for the protection of phosphodiester functions flanking the CpG motifs of immunomodulatory DNA sequences.     

The regioselectivity of the formation of 2-pyrazolylthiazoles and their precursors from the reaction of 2-hydrazinothiazoles with 4,4,4-trifluoro-1-hetaryl-1,3-butanediones

Reaction of 2-hydrazinothiazoles 1 with 1-thienyl- and 1-furyl-1,3-butanediones 2a,b in methanol in the presence of hydrochloric acid mainly leads to a mixture of pyrazoles 3 and pyrazolines 4 or pyrazoles 3 and 5 in strong acidic conditions. Isomeric hydrazones 6 and pyrazolines 4 were formed and isolated in these reactions in the absence of hydrochloric acid. It has been shown that the regioselectivity in the reaction of diketones 2 with hydrazine 1 is governed by both the concentration of acid and the nature of substituents in the 1,3-diketones 2. Cyclization of hydrazones 6 is shown to occur under milder conditions than dehydration for pyrazolines 4. The new heterocyclic compounds were prepared and fully characterized by NMR spectra and by X-ray analysis for 3c.     

Rapid syntheses of (±)-pterocarpans and isoflavones via the gold-catalyzed annulation of aldehydes and alkynes

(±)-Pterocarpan and analogues (4a-c) have been synthesized efficiently via the annulation of salicylaldehydes (1a, 1b and 1c) and o-methoxymethoxylphenylacetylene (2a), followed by a one-pot reduction and acidic cyclization of the ketones (3a-c). In addition, isoflavone derivatives (5a-c) have been synthesized rapidly, in two steps, via the annulation of salicylaldehyde (1a) and arylacetylenes (2b, 2c and 2d), followed by IBX/DMSO oxidation of the isoflavanones (3d, 3e and 3f).     

Seven new alkaloids from the roots of Stemona tuberosa

Seven new alkaloids, named as 1,9-epoxy-9a-hydroxystenine (1), tuberostemoline A (2), tuberostemoline B (3), tuberostemoninol C (4), oxotuberostemonine A (5), the mixture of bisdehydrotuberostemonine D (6), and bisdehydrotuberostemonine E (7), together with four known alkaloids neotuberostemonine (8), sessilifoline B (9), stemoxazolidinone F (10), and tuberostemoninol A (11), were isolated from the roots of Stemona tuberosa. The structures of 1–7 were elucidated through extensive spectroscopic analysis, and the relative configurations of 1–6 and 8 were further confirmed by X-ray crystallographic data. Compounds 8, 9 and the mixture of 6 & 7 exhibited potential acetylcholinesterase (AChE) inhibitory activities.     

New resveratrol oligomers in the stem bark of Vatica pauciflora

Five new resveratrol oligomers; pauciflorols A-C (1-3), isovaticanols B (6) and C (8), and three new oligostilbene glucosides; pauciflorosides A (11), B (13), C (14), were isolated from the stem bark of Vatica pauciflora (Dipterocarpaceae) together with known 17 resveratrol oligomers (4, 5, 7, 9, 10, 12 and 15-25) and bergenin (26). The structures of isolates were established on the basis of detailed spectroscopic analysis. The typical and characteristic spectral properties of some resveratrol oligomers were also discussed.     

Addition of silyloxydienes to 2,6-dibromo-1,4-benzoquinone: an approach to highly oxygenated bromonaphthoquinones for the synthesis of thysanone

The synthesis of tetraoxygenated bromonaphthoquinones 6a, 6b, 6c, 6d, key intermediates for a synthesis of the 3C protease inhibitor, thysanone, were investigated. Addition of 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene 8 to 2,6-dibromo-1,4-benzoquinone 10 in benzene afforded a mixture of naphthoquinone 6a, arising from Diels-Alder addition followed by aromatisation, and Michael adduct 12. The Michael adduct 12 predominated when THF was used as solvent whereas 6a predominated when benzene was used. Naphthoquinone 6a underwent benzylation to naphthoquinone 6c. Addition of 1,1-dimethoxy-3-trimethylsilyloxy-1,3-butadiene 9 to 2,6-dibromo-1,4-benzoquinone 10 followed by benzylation failed to afford the desired bromonaphthoquinone 6d yet methylation did afford naphthoquinone 6b. Bromonaphthoquinone 6d was finally prepared from naphthol 18, obtained from addition of diene 9 to 1,4-benzoquinone 17, followed by ortho-bromination and oxidation. Attempted Sakurai allylation of bromonaphthoquinone 6d afforded naphthodihydrofuran 21. A similar observation was observed for 2-carbomethoxy-1,4-naphthoquinone 22 that also underwent Sakurai allylation to afford naphthodihydrofuran 23. The structure of Michael adduct 12 was confirmed by X-ray crystallography.     

1,2- versus 1,3-Silyl migration in the reaction of acylsilanes with silyl-substituted carbanions

The Peterson olefination of acylsilanes 1 by silylated carbanions 5,14 to give alkenes 13,17 via a 1,3-silyl shift is favored by the stabilization of the carbanion intermediate 16 through two sulfide units versus one as in 12, while a combination of DMPS on 1 and TBS on 14 leads to 1,2-migration product 15.     

Use of epoxidation and epoxide opening reactions for the synthesis of highly functionalized 1-oxaspiro[4.5]decan-2-ones and related compounds

Epoxidation of ethyl 3-(6-hydroxycyclohex-1-en-1-yl)propanoate (11) provided the syn epoxide 12. By invoking chelation controlled epoxide opening the triol derivatives 13 and 14 or the spiro lactone 25 could be obtained. Elimination of HBr from the bromides 26 and 27 produced the spiro cyclohexenones 28 and 29. Epoxidation of the double bond occurred in a diastereoselective manner to give epoxides 30 and 31, respectively. Treatment of the epoxide 31 with LiBr/AcOH gave the bromo hydrin 38. In a ‘merry go round’ fashion 38 was further functionalized on the cyclohexane ring by elimination, epoxidation, and epoxide opening resulting in the bromo hydrin 43. Other cyclohexane derivatives that were produced during these studies include the cyclohexenone 19 and the cyclohexanediol 23. In addition, enolate azidation of the spiro lactone 29 proceeded in a diastereoselective manner providing the α-azido lactone 32.     

Enantiocontrolled synthesis of the epoxycyclohexenone moieties of scyphostatin, a potent and specific inhibitor of neutral sphingomyelinase

The epoxycyclohexenone moieties 2 and 3b of scyphostatin (1), a potent and specific inhibitor of neutral sphingomyelinase, were synthesized in enantiomerically pure forms starting from (−)-quinic acid (11). The synthetic method features (i) the preparation of the olefin masked enones 25 and 29, the precursors for the key aldol-type coupling reaction, (ii) the efficient and stereocontrolled aldol-type coupling reactions between 25 (or 29) and benzaldehyde (8) and Garner's aldehyde analogue 9 to deliver alcohols 23 and 24, respectively, both of which possess the requisite asymmetric quaternary carbon center at the C6 position, and (iii) the stereospecific S_N2-type epoxide ring formation of the mesylates 35 and 47 under mild basic conditions to produce the targeted compounds 2 and 3b, respectively.     

An efficient synthesis of benzofurans and their application in the preparation of natural products of the genus Calea

The intramolecular cyclization of the β-substituted olefins methyl 2-aryloxy-3-dimethylaminopropenoates 3a-3f catalyzed by Lewis acids leads to a short and novel synthesis of benzofurans 2a-2f. When the olefins 4-dimethylamino-3-aryloxy-3-buten-2-ones 4a-4f were used, the cyclization process was faster and provided the corresponding substituted 2-acetylbenzofurans 1a-1f. Among the latter, naturally occurring compounds calebertin (1a), caleprunin A (1b), and caleprunin B (1c) were prepared in good overall yields. These benzofurans were also obtained by direct treatment under MW irradiation of the precursors 1-aryloxypropan-2-ones 7a-7c with DMFDMA, followed by addition of the catalyst, resulting in a route that was one step shorter.     

Photochemical isomerisation studies of rubifolide and bipinnatin J. Unravelling some of the biosynthesis interrelationships between macrocyclic and polycyclic cembranoids found in corals

Irradiation of natural rubifolide (1) and bipinnatin J (2) for short periods of time using a 400 W sunlamp results in photochemical Z- to E-isomerisations to their corresponding E-isomers 10 and 16, respectively, neither of which has yet been discovered in Nature. Prolonged irradiation of rubifolide (1) produces the ring-contracted compound kallolide B (11a), and photooxidation of E-rubifolide (10) leads to epilophodione (12); both 11a and 12 are found in corals. The photoisomerisation studies provide an insight into the most likely origins of more complex cembranoids, for example, 4, 5, 18 and 19 from the archetypal cembranoids 1, 2, and 3 in vivo. The studies also suggest a likely route to the unusually rearranged cembranoid sarcofuranocembrenolide B (23) via a cascade of photo-initiated radical cyclisations and rearrangements from the biradical intermediate 24 produced from cembranoid 22.     

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.     

A facile approach for the synthesis of novel substituted 4H-chromenes and condensation reactions of 4H-chromenes leading to chromenopyrrolones and triazolylchromenopyrrolones

A facile method has been developed for the synthesis of 4H-chromene-3-carboxylates 3a–d by the nucleophilic substitution reaction of 2-hydroxy-2H-chromene-3-carboxylates 2a–d with triethylsilane in the presence of BF₃·O(C₂H₅)₂. Cyclocondensation of 4H-chromene-3-carboxylates 3a–d with benzylamines 4a–d afforded a series of 2,3-dihydrochromenopyrrolones 5a–p and with propargylamine afforded 2-propynyl-2,3-dihydrochromenopyrrolones 6a–d. Click reaction of 6a–d with benzyl azides 7a–d provided a series of 1H-1,2,3-triazolylmethyl-2,3-dihydrochromenopyrrolones 8a–p. Thus synthesized compounds 3a–d, 5a–p, 6a–d, and 8a–p are novel heterocyclic compounds and being reported for the first time.     

A strategy towards the synthesis of plumarellide based on biosynthesis speculation,featuring a transannular 4+2 type cyclisation from a cembranoid furanoxonium ion intermediate

In studies towards a biomimetic synthesis of plumarellide 1, acid-catalysed rearrangement of the furanobutenolide-based acetonide 10b led to the ring system 15b in plumarellide together with the cycloheptene-based ring system 11 found in rameswaralide 4, in a combined yield of 60%. RCM of the ω-dienes 30a and 30b led to the macrocycles 38a and 38b, respectively with the Z-configuration. Treatment of the vinyl bromide/vinyl stannanes 32a and 47 under Stille conditions failed to give the macrocycles 31a and 48, respectively. Reactions of the macrocycles 38a and 38b with TFA containing water produced the 5,6,7-tricyclic compounds 56a and 56b, respectively in >90% yield, instead of the plumarellide-based ring system 52. A summary and perspective on possible pathways from the C-13 acetoxy furanocembranoid 66 and from the C13–C14 unsaturated enol ether/cyclic hemiketal 9/59 to plumarellide 1 in vivo is given.     

Specific features of the reactions of quinazoline and its 4-hydroxy and 4-chloro substituted derivatives with C-nucleophiles

Reactions of quinazoline 1 with indole, pyrogallol and 1-phenyl-3-methylpyrazol-5-one in the presence of acid led to C-4 adducts 2, 3 and 5. Adduct 4 is formed by heating 1 with 1,3-dimethylbarbituric acid without acid catalysis. 1-Phenyl-3-methylpyrazol-5-one reacts with 1 without acid catalysis to form dipyrazolylmethane 6. 4-Chloroquinazoline 8 reacts with 1-phenyl-3-methylpyrazol-5-one to form 4-(1-phenyl-3-methyl-5-oxopyrazol-4-yl) quinazoline 9 and dipyrazolylmethane 6. Heating 8 with 2-methylindole leads to the formation of 4-(2-methylindol-3-yl) quinazoline 10 and tris(2-methylindol-3-yl)methane 11.     

Regioselective reductive opening of substituted phthalans: synthetic applications

The reductive opening of substituted phthalans 6, 11, 12, 20, 21 and 28 with lithium and a catalytic amount of DTBB leads to the formation of corresponding functionalised organolithium intermediates 8, 15, 16, 23, 25 and 29+30 in a regioselective manner. The further reaction of these dianions with different electrophiles, mainly carbonyl compounds, gives the expected functionalised benzylic alcohols 9, 17, 18, 24, 26 and 31+32. The observed stereochemistry can be easily explained taking into account the values of the electron densities deduced by semiempirical PM3 calculations.     

Quencher-free molecular beacon systems with two pyrene units in the stem region

We appended pyrene units covalently onto adenosine and uridine nucleosides (forming A^P and U^P units, respectively) and then incorporated them into oligonucleotides such that they were positioned in complementary locations in opposite strands in the middle positions of hairpin stems. Systems 1 (A^PU^P) and 3 (A^PA^P) individually exhibit aromatic stacking between the opposing pyrene units in the stems of their hairpins and display in their spectra the photophysical properties of strongly red-shifted bands; in contrast, the U^PU^P system 2 exhibits quenching spectra. Systems 1 (A^PU^P) and 3 (A^PA^P) behave as effective molecular beacons (MBs) that change color from green to blue upon duplex formation, whereas 2 (U^PU^P) is an effective MB that changes the intensity of its fluorescence upon forming its perfectly matched duplex.     

Diels-Alder cycloaddition of 2-azadienes to methyl 2-(2,6-dichlorophenyl)-2H-azirine-3-carboxylate in the synthesis of methyl 4-oxo-1,3-diazabicyclo[4.1.0]heptane-6-carboxylates

A number of fused 4-oxo-1,3-diazabicyclo[4.1.0]heptane-6-carboxylates, a new type of compound, have been obtained by Diels-Alder cycloaddition between nucleophilic 2-azadienes and an electrophilic 2H-azirine. The reactions are completely endo- and regioselective, the azirine being added by its less hindered face to the diene. There are two isomers 7 and 8 formed from dienes 1 due either to isomerization of the cycloadducts 7 and 8 or by isomerization of the CN bond of the diene during the reaction. The isomer 10 is formed from diene 2e, and a single diastereoisomer structure 4a-i is formed from dienes 11. Some pyrimidones 8a, 7c/8c, 7e, 10, 11d have been hydrolyzed leading to functionalised aziridines 12, 13 and 15.