Total synthesis of Amaryllidaceae alkaloids, (+)-vittatine and (+)-haemanthamine, starting from d-glucose

The stereoselective total synthesis of (+)-vittatine 1 and (+)-haemanthamine 2 starting from d-glucose is described. The cyclohexene ring in 1 was prepared in an optically active form from d-glucose using Ferrier's carbocyclization reaction, and the critical quaternary carbon was stereoselectively generated via chirality transfer by the Claisen rearrangement of cyclohexenol 6. The hexahydroindole skeleton was effectively constructed by the intramolecular aminomercuration-demercuration of 14, followed by Chugaev reaction to provide 16. Finally, Pictet-Spengler reaction completed the first chiral synthesis of (+)-vittatine 1. On the other hand, the α-hydroxylation of the ester 5 stereoselectively proceeded to give α-hydroxy ester 19, to which was introduced an amino function to provide 4. A similar transformation of 4, as employed in the synthesis of vittatine, furnished (+)-haemanthamine 2.     

Total synthesis of (+)-ambruticin S

A convergent total synthesis of the novel antifungal agent ambruticin S (1) has been completed from the assembly of intermediates 18, 33 and 52 that served as the respective A-, B-, and C-ring precursors. The first generation approach to a potential A-ring intermediate eventuated in the synthesis of 9a via a route that featured oxidation of the dihydroxy furan 2 and elaboration of the dihydropyranone 3 derived therefrom. Although 9a served as a precursor of 31E to complete a formal synthesis of 1, there were several inefficiencies associated with the preparation of 9a. A more expedient and efficient route to an A-ring subunit was devised that commenced with the carbohydrate-derived bisacetonide aldehyde 10 and produced 18 in five steps and 46% overall yield. The synthesis of the cyclopropyl sulfone 33 was initiated with the enantioselective cyclopropanation of 19 catalyzed by Rh₂[5(S)-MEPY]₄. Ring opening of the resultant lactone 20 followed by a series of refunctionalizations gave 33 in a total of seven steps and 46% yield from 19. Coupling of the A- and B-ring precursors 18 and 33 was then achieved via a modified Julia coupling followed by deprotection and oxidation to furnish the key intermediate 35. The dihydropyran core of the C-ring subunit precursor 49 was formed from the ring closing metathesis of the diene 48, which was prepared in three steps from the known epoxide 45, followed by oxidation. A chelation-controlled addition to the methyl ketone 49 set the stage for a stereoselective [2,3]-Wittig rearrangement that delivered the alcohol 51 that was then transformed in two steps to the sulfone 52. A traditional Julia coupling of 52 and 35 proceeded with excellent stereoselectivity, and subsequent removal of the various protecting groups gave ambruticin S (1). The longest linear sequence was 13 steps and proceeded in 4.3% overall yield.     

Chemoselective asymmetric synthesis of C-3a-(3-hydroxypropyl)tetrahydropyrrolo[2,3-b]indole and C-4a-(2-aminoethyl)-tetrahydropyrano[2,3-b]indole derivatives

The asymmetric synthesis of new tetrahydropyrrolo[2,3-b]indole 19 and tetrahydropyrano[2,3-b]indole 20 rings, substituted in position C-3a and C-4a with a hydroxy- and an amino functionalized chain, respectively, was performed starting from the racemic spiro[cyclohexane-1,3′-indoline]-2′,4-diones 7. The enantiopure spiro oxo-azepinoindolinone (+)-10, obtained from (±)-7 by the way of an asymmetric ring enlargement, and the amino acid (+)-14, obtained by the hydrolysis of 10, were prepared as key intermediates for the synthesis of enantiopure compounds (−)-19 and (−)-20. Since the amino acid 14 is the common intermediate for the chemoselective preparation of derivatives 19 and 20, experimental and computational studies were performed in order to selectively obtain these compounds and to provide a mechanistic rationalization for their formation.     

Synthesis of (+)-perillyl alcohol from (+)-limonene

(+)-Perillyl alcohol (1) has been synthesised in four steps and 39% overall yield from commercially available limonene oxide (4). The sequence features, as its key step, a palladium(0)-mediated transformation of a secondary allylic acetate (6) into its primary isomer (7). An application of (+)-perillyl alcohol (1) in a formal synthesis of naturally occurring (−)-mesembrine (2) and (−)-mesembranol was demonstrated.     

Convergent and enantioselective total synthesis of (−)-nalanthalide, a potential Kv1.3 blocking immunosuppressant

The first total synthesis of (−)-nalanthalide (1), a novel blocker of the voltage-gated potassium channel Kv1.3 from a microorganism, was accomplished in a convergent manner by utilizing coupling reaction of the trans-decalin 5 with 3-lithio-γ-pyrone 4. The key intermediate 5 was efficiently prepared from the known trans-decalone 7 through a [2,3]-Wittig rearrangement of the stannylmethyl ether 6 to install the stereogenic center at C9 and the exo-methylene function at C8.     

Total synthesis of (+)-galanthamine starting from d-glucose

The stereoselective total synthesis of (+)-galanthamine (+)-1 starting from d-glucose is described. The cyclohexene ring in (+)-1 was prepared in an optically active form from d-glucose using Ferrier’s carbocyclization reaction, and the critical quaternary carbon was stereoselectively generated via chirality transfer based on the Claisen rearrangement of a cyclohexenol. The dibenzofuran skeleton was effectively constructed by the bromonium ion-mediated intramolecular cyclization of a cyclohexene possessing a phenolic ether function. After the introduction of a carbon-carbon double bond, the Pictet-Spengler type cyclization, followed by the reduction of the amide function completed the chiral synthesis of (+)-1.     

Novel annulated products from aminonaphthyridinones

2-(4-Methoxyphenyl)-1-oxo-1,2-dihydro-1,6-naphthyridine-4-carboxamide (4c) underwent Hofmann rearrangement with iodobenzene diacetate in methanol to give the corresponding 4-amino compound (6c). This, when reacted with 2,4-pentanedione and then hot phosphoryl chloride (attempted Combes synthesis) gave a new heterocyclic system, 6-(4-methoxyphenyl)-2-methylpyrido[3,2-c]pyrrolo[2,3-e]azocin-7(6H)-one (9c). This showed typical pyrrole-type reactivity at the 3-position. Alternatively, an attempt to convert the 4-NH₂ in 6c to 4-OH by diazotization gave, instead, a [1,2,3]triazolo[1,5-a]pyridine-3-carboxaldehyde (16c). The same series of reactions on a benzo analog, 2-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxamide (4a), gave the same results.     

Wagner-Meerwein rearrangement in the course of the ozonolysis of a bornene derivative

The ozonolysis of the bicyclo[2.2.1]heptene derivative 1 or 2 gave the octaline derivative 6 (the structure was confirmed by X-ray crystallographic analysis) or 7. The exo-addition of ozone to the double bond of 1 or 2 was followed by the fragmentation in carbonyl oxide and aldehyde. Then, the strong electrophilic character of the carbonyl oxide induces an unexpected Wagner-Meerwein rearrangement to give zwitterion 4. Finally, a fragmentation reaction with elimination of dioxygen gave the tetrasubstituted C-C double bonds of 6 or 7.     

Aromatics to bis-triquinane: a tandem oxidative dearomatization of bis-phenol,cycloaddition, photorearrangement and a rapid entry into carbocyclic framework of Xeromphalinone E

A novel approach for the synthesis of a bird-shaped bis-triquinane 3, a fascinating carbocyclic framework closely related to the skeleton of Xeromphalinone E 1 from readily available 2,6-dimethyl phenol 8 has been reported. The synthesis of bis-cyclohexadienones 6, 22a–e by oxidative acetylation of tetramethyl bisphenols 7, 20a–e has been investigated using two different reagents under varying reaction conditions. The cycloaddition of bis-cyclohexadienone 6 gives two carbocycles, bis-adduct 4b and mono-adduct 5d in a stereocontrolled manner. The photochemical sigmatropic 1,2-acyl shift in 4b furnished 3 and monotriquinane 9 linked with a 9-acetoxy-9-methyl-endo-tricyclo[5,2,2,0^2,6]undeca-4,10-diene-8-one system. Two different pentasubstituted phenols 13 and 14 were also isolated during an attempted oxa-di-π-methane (ODPM) rearrangement of mono-adduct 5d via aromatisation of the cyclohexadienone ring. The photochemical behaviour of bis-cyclohexadienones 6, 22a–e has also been investigated under UV irradiation and two different aromatized products were isolated for each bis-cyclohexadienone by migration and elimination of acetate groups.     

Synthesis of 5-alkyl(or aryl)pyrrolo[1,2-a]quinoxalin-4(5H)-ones by denitrocyclisation of N-alkyl(or aryl)-1-(2-nitrophenyl)-1H-pyrrole-2-carboxamides. Evidence of a Smiles rearrangement

An efficient method for the synthesis of hitherto unknown alkyl(or aryl)pyrrolo[1,2-a]quinoxalin-4(5H)-ones 8a-g, 16 and 17 has been established. The method is based on the synthesis of the corresponding N-alkyl(or aryl)-1-(2-nitrophenyl)-1H-pyrrole-2-carboxamides 3a-c and 7a-c,e which undergo denitrocyclisation with NaH in DMF in 4.5 or 2 h. When 3a was treated with NaH in DMF for 30 min the product of a Smiles rearrangement, 9, was isolated. Under similar conditions but for 4.5 h 9 was converted into 8a. This confirms the involvement of a Smiles rearrangement during the denitrocyclisation process. Conversion of 3b into isomeric pyrroloquinoxalinones 12 and 13 confirms a process involving two pathways, direct denitrocylisation of 3b and Smiles rearrangement of 3b followed by denitrocylisation, respectively. Furthermore, denitrocylisation of 7d into pyrroloquinoxalinones 16 and 17 suggests that similar cyclisation pathways are followed by N-arylcarboxamides.     

Total synthesis of (+)-epiepoformin, (+)-epiepoxydon and (+)-bromoxone employing a useful chiral building block, ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclohexanecarboxylate

Enantioselective total synthesis of (+)-epiepoformin 1, (+)-epiepoxydon 2 and (+)-bromoxone 3 using a chiral building block, ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclo- hexanecarboxylate 6, is described. Since the synthesis afforded intermediates 18, 2 and 25, it accomplished a formal synthesis of (−)-theobroxide 19, (−)-phyllostine 22, (+)-herveynone 27 and (−)-asperpentyn 28. The usefulness of 6 for the synthesis of natural epoxycyclohexene derivatives was demonstrated.     

First enantiospecific synthesis of marine nor-sesquiterpene (+)-austrodoral from (−)-sclareol

A short and efficient synthesis of the rearranged nor-sesquiterpenes (+)-austrodoral (1) and (+)-austrodoric acid (2), recently isolated from the Antarctic marine mollusk Austrodoris kerguelenensis, from diterpene (−)-sclareol (4) is reported. The key step of the sequence is the pinacol rearrangement of the drimanetriol 11.     

Synthesis of the marine furanoditerpene (−)-marginatone

A synthesis of the marine labdane furanoditerpene (−)-marginatone 1 has been accomplished by a short sequence of reactions starting from (+)-coronarin E 5. The key step is the stereocontrolled-intramolecular electrophilic cyclisation of the (+)-dihydrocoronarin E 6, to the tetracyclic marginatane skeleton 7, which is subsequently functionalized by allylic oxidation to give 1. As (+)-coronarin E 5 was previously synthesized from (−)-sclareol 10, the herein reported preparation constitutes the first formal total synthesis of (−)-marginatone 1, by which its absolute configuration has been confirmed.     

Asymmetric synthesis of the 6-cyanoindole derivatives as non-steroidal glucocorticoid receptor modulators using (+)- and (−)-tert-butyl 6-cyano-3-[3-ethoxy-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl]-1H-indole-1-carboxylate

We have successfully synthesized enantiomerically pure (+)- and (−)-tert-butyl 6-cyano-3-[3-ethoxy-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl]-1H-indole-1-carboxylate (+)-1 and (−)-1, which are key intermediates of non-steroidal glucocorticoid receptor modulators, by employing a cinchona alkaloid catalyzed addition of 6-cyanoindole to ethyl trifluoropyruvate. The optimized method can be applied to large-scale synthesis. Furthermore, using the key intermediates (+)-1 and (−)-1, enantiomerically pure glucocorticoid receptor modulators (+)-3 and (−)-3 can be synthesized (>99% ee for both compounds). The glucocorticoid receptor binding affinity was influenced by the stereogenic center at the trifluoromethyl alcohol moiety; compound (−)-3 showed a higher binding affinity compared to (+)-3.     

Claisen rearrangements based on vinyl fluorides

2-Fluoroalk-1-en-3-ols (4), available from terminal alkenes (1) by bromofluorination, subsequent dehydrobromination of the 1-bromo-2-fluoroalkanes (2) to form 2-fluoroalkenes (3) and selenium dioxide mediated allylic oxidation with tert-butylhydroperoxide, undergo Johnson-Claisen rearrangement on treatment with trimethyl orthoacetate to give methyl 4-fluoroalk-4-enoates (7) in high yields. In contrast Ireland-Claisen rearrangement of 3-acetoxy-2-fluorodec-1-ene (9b) with triethylamine and TMSOTf in ether failed. Instead of the expected formation of a carboxylic acid, selective C-silylation of the α-position to the carboxyl group to form 14 occurred. However, Ireland-Claisen rearrangement was successful with corresponding chloroacetates 10 and propionates 11 of four 2-fluoroalk-1-en-3-ols (4) to give 2-chloro-4-fluoroalk-4-enecarboxylic acids (15) or its 2-methyl derivatives 16, respectively, in moderate yields. These [3,3]-sigmatropic rearrangements are diastereoselective giving trans-configured double bonds, exclusively. Corresponding esters derived from (Z)-2-fluorocyclododec-2-enol (22), did rearrange to yield mixtures of diastereomers much less selectively. Also 2-fluorodec-2-enol (6), which was prepared by rearrangement of 2-fluoro-2-octyloxirane (5) with TMSOTf and triethylamine, was successfully applied as a starting material for [3,3]-sigmatropic rearrangements. The corresponding 3-(1-fluoroethenyl)alkanoic acid derivatives 17 and 18 were formed in moderate yield.     

Formation of 3,4-dimethyl-2-pyrones from allene carboxylates and 2-silyloxydienes via 3-carboethoxyethylidene cyclobutanols

The 3-carboethoxyethylidene cyclobutanols 4 are prepared in two steps via [2+2] cycloaddition of the 2-silyloxydienes 1 and the allene carboxylate 2 followed by acidic hydrolysis. Treatment of these cyclobutanols 4 with various bases affords good yields of the substituted 3,4-dimethyl-2-pyrones 6. The proposed mechanism involves ring opening of the metal alkoxide 7 to give the carbanion 8, which undergoes proton transfer to give the more stable carbanion 9 and double bond isomerization to give the enolate 10, which then forms the pyrone ring 6 via attack on the ester via 11.     

Transformations of lignans. Part 10: Acid-catalysed rearrangements of arboreol and wodeshiol and conversion of gmelanone oxime into a dihydropyranone derivative

The synthesis of gmelanone 2 by a pinacol-type rearrangement of arboreol 1 supports its biogenesis and confirms its relative and absolute configuration. The further transformation of gmelanone oxime 12 into the dihydropyranone oxime 13 supports the intermediacy of gmelanone like intermediates in the rearrangements of furofuran lignans to pyran derivatives. In contrast, acid-catalysed rearrangement of wodeshiol 7 affords the dihydropyranone 8.     

The first synthesis and characterisation of elusive cone 1,2-diformyl tetralkoxycalix[4]arenes and their derivatives

The synthesis and isolation of elusive tetralkoxycalix[4]arenes 2 in the cone conformation and bearing two formyl groups in proximal (1,2) positions at the upper rim are described for the first time. They were obtained as a mixture with the distal (1,3) regioisomers 3 by optimizing the Gross formylation reaction on the tetralkoxycalix[4]arenes 1. After reduction to the corresponding alcohols, compounds 4 could be isolated and oxidized to 1,2-diformyl (2) and 1,2-diacid (6) tetralkoxycalix[4]arenes. These 1,2-difunctionalized derivatives are useful intermediates for the synthesis of calixarene-based molecular receptors having proximal binding groups.     

Experimental and theoretical approaches into the C- and D-ring problems of sterol biosynthesis. Hydride shift versus C-C bond migration due to cation conformational changes controlled by the counteranion

The C- and D-ring problems of sterol biosynthesis, how an enzyme overcomes the Markovnikov wall, were investigated by using a model compound from an experimental as well as theoretical standpoint. When model diol 20 was treated with BF₃·Et₂O, SnCl₄, TiF₄, Sc(OTf)₃, FeCl₃, or TfOH, spirocyclic ether 21 was formed as the sole product via a tert-cationic intermediate 16 through 1,2-hydride shift. However, the treatment with TiCl₄ afforded six-membered ring products 22, 23, 24, 25, 26, and 27 via the ring expansion into the unstable six-membered ring secondary cation 17. Occurrence of both α and β chloride 23 and 24 is distinctive evidence of the existence of secondary cation 17, ruling out the idea of the concerted mechanism. Molecular mechanics calculations of the naked cation 15 elucidated two possible conformers, parallel 15-I (five membered ring and cationic plane) that is favorable for the hydride shift generating 16 and perpendicular 15-II leading to C-C bond migration to 17. The first ab initio calculation of the cation conformation in the presence of counteranions such as [TiCl₄OH]⁻, [TiF₄OH]⁻, [BF₃OH]⁻, and [OTf]⁻ entirely supported our experimental results. Although the counteranion [TiCl₄OH]⁻ stabilizes perpendicular cation 15-II, it destabilizes the parallel conformer 15-I significantly, and thus, the C-C bond migration to 17 becomes the only possible pass. On the other hand, [TiF₄OH]⁻, [BF₃OH]⁻, and [OTf]⁻ stabilize parallel conformer 15-I and the hydride shift to 16 becomes the only possible pass. The relative location or distance of the counteranion from the cation should be the biggest factor to control the stability and, thus, the conformation of the cation. Our results indicate that the carboxylate anions in the enzyme cavity enable to control the conformation of pre-C-ring cationic intermediate 3 to be perpendicular leading to six-membered C-ring secondary cation 4. The parallel conformation of the cation 5 could lead to hydride shift to give tirucallanoids or lanostanoids. Therefore, this result is the first example that overcame the big Markovnikov wall experimentally and theoretically at least to our knowledge.     

Unexpected formation of a chiral δ-lactone by reduction of the 1,3-dicarbonylic cyclopentanoid derivatives

We have described the synthesis of highly functionalized chiral cyclopentanoids, which are important building units for synthesis of biological active compounds. The (−)- or (+)-7,7-dimethoxy-1,4,5,6-tetrachlorobicyclo[2.2.1]hept-5-en-2-endo-yl acetate, obtained from the enzyme catalyzed transesterification of the racemate, was converted to α-diketone chiral. The α-diketone was treated with H₂O₂/NaOH and esterified with CH₂N₂ to furnish a mixture of the compounds (+)- or (−)-10 and (+)- or (−)-11. The reduction of the (+)- or (−)-10 and/or (+)- or (−)-11 with BH₃·THF furnished the lactone (+)- or (−)-13 with excellent yield. The α-diketone was reduced with indium metal in the presence of NH₄Cl furnishing the acyloin (+)-14 in 67% of yield. The treatment of acyloin (+)-14 with Pb(OAc)₄ furnished the aldehyde (+)-15 with 80% of yield. The reduction of the aldehyde (+)-15 with NaBH₄ has again produced the lactone (+)-13.