A convenient synthesis of substituted γ-pyrones

An efficient and general synthetic method for various 2-mono- and 2,6-disubstituted γ-pyrones has been developed. This utilizes the $\text{C}$-acylation (70–85%) of β-methoxy-α,β-enone lithium enolates $\text{4}$ by acid chlorides $\text{3}$ followed by the acid-catalyzed cyclization (>80%) of the resulting enols $\text{5}$ to γ-pyrones $\text{6}$.     

2-Aryl-6-Polyfluoroalkyl-4-Pyrones as Promising RF-Building-Blocks: Synthesis and Application for Construction of Fluorinated Azaheterocycles

A convenient and general method for the direct synthesis of 2-aryl-6-(trifluoromethyl)-4-pyrones and 2-aryl-5-bromo-6-(trifluoromethyl)-4-pyrones has been developed on the basis of one-pot oxidative cyclization of (E)-6-aryl-1,1,1-trifluorohex-5-ene-2,4-diones via a bromination/dehydrobromination approach. This strategy was also applied for the preparation of 2-phenyl-6-polyfluoroalkyl-4-pyrones and their 5-bromo derivatives. Conditions of chemoselective enediones bromination were found and the key intermediates of the cyclization of bromo-derivatives to 4-pyrones were characterized. Synthetic application of the prepared 4-pyrones has been demonstrated for the construction of biologically important CF₃-bearing azaheterocycles, such as pyrazoles, pyridones, and triazoles.     

A regiospecific synthesis of 8-Methoxy-1,2,3,4,5,6-hexahydro-1,6-methano-3-benzazocines

A regiospecific synthesis of the 6-methoxy-1,2,3,4,5,6-hexahydro-1,6-methano-3-benzazocine system is reported.     

Synthesis of nectriapyrone

A totally synthetic route to the antibacterial fungal metabolite nectriapyrone ( 1 ) has been achieved by condensation of methylmalonyl dichloride with ethyl trans-4-methyl-3-oxo-4-hexenoate followed by hydrolysis, decarboxylation, and methylation of the resulting 3-methyl-4-hydroxy-5-carbethoxy-6-(trans-1-methyl-1-propenyl)-2-pyrone. Exploration of an alternate scheme involving the dehydrogenation of 6-substituted-4-methoxy-5,6-dihydro-2-pyrones, prepared by Reformatsky reaction of ethyl γ-bromo-β-methoxycrotonate with various aldehydes, was abandoned since it did not appear to have general applicability to the preparation of nectriapyrone and its analogs.     

A general strategy for the synthesis of vincamajine-related indole alkaloids: stereocontrolled total synthesis of (+)-dehydrovoachalotine, (-)-vincamajinine, and (-)-11-methoxy-17-epivincamajine as well as the related quebrachidine diol, vincamajine diol, and vincarinol

[structures: see text] The highly convergent stereocontrolled total synthesis of (-)-vincamajinine (7), (-)-11-methoxy-17-epivincamajine (9), and the oxygen-bridged (+)-dehydrovoachalotine (22) are described. Key steps in the synthesis of 7 and 9 involved the stereospecific enolate-driven palladium-catalyzed cross-coupling reaction, a Tollens reaction, an acid-assisted intramolecular cyclization to form the C(7)-C(17) quaternary center, and two stereospecific reductions. The efficiency of this strategy is illustrated by the completion of the synthesis of 7 and 9 in 16 [from d-(+)-tryptophan methyl ester 17] and 17 (from the Sch?llkopf chiral auxiliary 27) reaction vessels, respectively. This constitutes the first total synthesis of these indole alkaloids and provides the first regiospecific route to 11-methoxy-substituted ajmaline/vincamajine-related alkaloids. The synthesis of 22 required a novel DDQ-mediated cyclization to furnish the C(6)-O(17) bond, executed in stereospecific fashion. Completion of these syntheses illustrates a concise and versatile strategy for the synthesis of vincamajine-related alkaloids, which has also been employed to prepare the related compounds quebrachidine diol (53), vincamajine diol (56), and vincarinol (59).     

The synthesis of some 5-methoxypyrimidine nucleosides

The synthesis of 5-methoxyuridine ( 3 ), 5-methoxycytidine ( 6 ), 1-(2-deoxy-β-D-erythropento-furanosyl)-5-methoxyuracil ( 14 ), 5-methoxy-1-β-D-ribofuranosyl-4-thiopyrimidin-2-one ( 5 ), 1-β-D-arabinofuranosyl-5-methoxycytosine ( 12 ), 1-β-D-arabinofuranosyl-5-methoxyuracil ( 8 ) and 1-β-D-arabinofuranosyl-5-methoxy-4-thiopyrimidin-2-one ( 11 ) have been accomplished. Both 3 and 14 were synthesized by alkylation of 2,4-bis(trimethyIsilyI)-5-methoxyuracil ( 1 ) with the appropriately blocked halosugars. Synthesis of the corresponding 5-methoxy-1-β-D-arabinofuranosyl derivatives was accomplished through the intermediate 2,2 -anhydro-1-β-D-arabinofuranosyl-5-methoxyuracil ( 7 ). The cytosine and 4-thiouracil derivatives in both the arabino- and ribo- series were prepared by thiation followed by amination.     

Improved synthesis of several methoxynitronaphthalenes

Summary An improved procedure for the synthesis of several isomeric methoxynitronaphthalenes is described. The key intermediates in the synthesis are the respective nitronaphthylamines and nitronaphthols. The syntheses of 1-methoxy-3-nitronaphthalene (1), 1-methoxy-5-nitronaphthalene (2), and 2-methoxy-5-nitronaphthalene (3) are reported.Part of this work was carried out at the University of Texas at El Paso, El Paso, TX, during the tenure of one of the authors there (C.P.)     

Pyrones: V—The mass spectra and fragmentation mechanisms of some 3(5)-methoxy-4-pyrones

The mass spectra of methyl kojate (2-hydroxymethyl-5-methoxy-4H-pyran-4-one), two deuterated analogues and 14 related 3(5)-methoxy-4-pyrones have been studied. These compounds fragment according to a common mechanism, initiated by primary rearrangement of the molecular ion(s). Guidelines which indicate the presence of 3(5)-methoxy-4-pyrones and allow structural determinations to be made from their mass spectra are presented. For the majority of substituents studied, the nature of the substituent has no major effect upon the fragmentation pattern; the cyano group does. The hydroxy counterparts of the above compounds are readily converted for analysis by simple methylation.     

Synthesis and dehydration reaction of 1-(4-benzyloxyphenyl)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphth-2-ol: possible intermediate of Lasofoxifene

The paper deals with a simple and sufficient synthesis of key precursor of Lasofoxifene. The 1-(4-benzyloxyphenyl)-6-methoxy-2-phenyl-3,4-dihydronaphthalene was prepared by a sequence of five reactions steps: first 1-(4-benzyloxyphenyl)-6-methoxy-3,4-dihydronaphthalene was prepared (70%), and this was quantitatively epoxidized to 7b-[4-(benzyloxy)phenyl]-5-methoxy-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene. Catalytic (ZnI₂) isomerization of the epoxide gave 1-(4-benzyloxyphenyl)-6-methoxy-1,2,3,4-tetrahydronaphthalen-2-one (75%). Its subsequent reaction with phenylmagnesium bromide gave 1-(4-benzyloxyphenyl)-6-methoxy-2-phenyl-1,2,3,4-tetrahydro-2-naphthol (87%). Acid-catalysed dehydration of this alcohol by polyphosphoric acid (25°C) provides 1-(4-benzyloxyphenyl)-6-methoxy-2-phenyl-1,4-dihydronaphthalene (80%). Dehydration in the system of acetic anhydride/polyphosphoric acid gives 1-(4-benzyloxyphenyl)-6-methoxy-2-phenyl-3,4-dihydronaphthalene (66%).     

Stereocontrolled total synthesis of (-)-vincamajinine and (-)-11-methoxy-17-epivincamajine

The first total syntheses of (-)-vincamajinine (5) (from Na-methyl-d-tryptophan methyl ester) and (-)-11-methoxy-17-epivincamajine (6) (from Na-methyl-6-methoxy-d-tryptophan ethyl ester) are described. The syntheses have been completed in a highly stereocontrolled manner (>98% ee). Key steps included the asymmetric Pictet-Spengler reaction, enolate-mediated palladium cross-coupling reaction, and acid-catalyzed formation of the C(7)-C(17) bond. In addition, the triethylsilane/TFA-mediated incorporation of the 2alpha-H (11 to 12) and the borohydride generation of the C(17) hydroxyl function (R) were also stereospecific. The unique highly conjested carbon skeletons of the two alkaloids were completed in a concise manner and in regiospecific fashion.     

A high-yielding enantiospecific synthesis of (−)-7-deoxydaunomycinone

A comparison is made between two regiospecific modes of base-catalysed condensation of 4 (or 7)-methoxy-3-phenylsulfonyl phthalides with chiral bicyclic quinone monoketals, one of which occurs in 95% yield and forms the basis of the first enantiospecific total synthesis of (?)-7-deoxydaunomycinone (3).     

Enantiospecific total synthesis of (-)-(E)16-epiaffinisine, (+)-(E)16-epinormacusine B,and (+)-dehydro-16-epiaffinisine as well as the stereocontrolled total synthesis of alkaloid G

An efficient strategy is described for the total synthesis of the sarpagine-related indole alkaloids (-)-(E)16-epiaffinisine (1), (+)-(E)16-epinormacusine B (2), and (+)-dehydro-16-epiaffinisine (4). A key step employed the chemospecific and regiospecific hydroboration/oxidation at C(16)-C(17); this method has also resulted in the synthesis of (+)-dehydro-16-epinormacusine B (5). The oxy-anion Cope rearrangement followed by protonation of the enolate that resulted under conditions of kinetic control has been employed to generate the key asymmetric centers at C(15), C(16), and C(20) in alkaloid G (7) in a highly stereocontrolled fashion (>43:1). Conditions that favor control of the sarpagine stereochemistry at C(16) vs the epimeric ajmaline configuration at the same stereocenter have been determined. The formation of the required cyclic ether in 4, 5, and 7 was realized with complete control from the top face on treatment of the corresponding alcohols with DDQ/THF or DDQ/aq THF in excellent yields.     

Synthesis,halogenation, and nitration of 6-methyl-3-phenyl-2-pyrone derivatives

Simple methods for the synthesis of 3-aryl-6-methyl-2-pyrones and 3-aryl-5-carbalkoxy-6-methyl-2-pyrones by the reaction of ethyl -formylarylacetates with acetone and acetoacetic acid esters, respectively, are proposed. Some electrophilic substitution reactions of 6-methyl-3-phenyl-2-pyrone and 5-carbethoxy-6-methyl-3-phenyl-2-pyrone were studied.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1477–1480, November, 1985.     

Total synthesis of (+)-kalafungin using a tandem Michael-Dieckmann approach

A stereoselective synthesis of the antibiotic kalafungin 1 is reported. A key step involved the tandem Michael-Dieckmann reaction between methyl 2-methoxy-6-methylbenzoate 11 and the α,β-unsaturated lactone (R)-6-(2-(tert-butyldimethylsilyloxy)ethyl)-4-methoxy-5,6-dihydropyran-2-one 10, which was prepared from (S)-aspartic acid. The C5 alkyl substituent was introduced by the use of methylmagnesium bromide and subsequent stereoselective reduction. A sequence of oxidations followed by acid-catalyzed epimerization delivered (+)-kalafungin 1.     

A one-step synthesis of γ-pyrones

The potassium enolate of 4-methoxy-3-buten-2-one reacts with acid chlorides anhydrides and acylimidazoles by C-acylation and $\text{in situ}$ cyclization to afford 2-substituted γ-pyrones directly.     

Functionalization at C-5 and at the C-6 methyl group of 4-methoxy-6-methyl-2-pyrone

A new entry to C-5 substituted 4-hydroxy-6-methyl-2-pyrones has been achieved. The best conditions to prepare the monobromo and the dibromo derivatives at C-3 and the C-6 methyl group of the title pyrone have been defined. The synthetic applicability of the phosphonium salts at CH₃-C-6 of both 4-methoxy-6-methyl-2-pyrone, 5 , and dehydroacetic acid, 2 , has also been evaluated.     

Synthesis of (±)-4-Demtthoxy-7 11-Dideoxydaungmy-Cinone

Our continued interest in the total synthesis of natural and unnatural antitumor anthracyclines¹ especially the aglycones such as daunomycinone (1)² and 4-demethoxydaunomycinone (2),³ 11-deoxydaunomycinone(3)⁴ and 4-demethoxy-11-deoxydau-nomycinone (4)⁵ led us to investigate various methods for obtaining these products. Recently we have reported the synthesis of 4-demethoxy-7, 11-dideoxydaunomycinone (5) from 5-methoxy-1-tetralone. Now we wish to report the synthesis of 5 starting from 5-methoxy-1-tetralone (9) which was prepared from 1,6-dimethoxy-naphthalene(8). Umezawa⁷ et al. have reported the total synthesis of 4-demethoxy-ll-deoxydaunomycin(6) and 4-demethoxy-11-deoxy-adriamycin (7) from 5-methoxy-2-tetralone.     

A stereodivergent,two-directional synthesis of stereoisomeric C-linked disaccharide mimetics

Dipyranones, such as 1,2-bis[(2R,3S,6S)-3-hydroxy-6-methoxy-3-oxo-6H-pyran-2-yl]ethane, were exploited as templates for the synthesis of some novel C-linked disaccharide analogues. Efficient methods, such as stereoselective reduction and dihydroxylation, were developed for two-directional functionalisation of these templates. Peracetylated derivatives of ten stereoisomeric disaccharide analogues [acetic acid 4,5-diacetoxy-6-methoxy-[(3',4',5'-triacetoxy-6'-methoxytetrahydropyran- 2'-yl)ethyl]tetrahydropyran-3-yl esters] were synthesised from a virtual library of 136 compounds; furthermore, an additional eight stereoisomers could have been synthesised simply by using the enantiomeric ligand in the enantioselective step. The ability of (2S,3S,4R,5R,6R)-6-methoxy-2-[2'-((2'R,3'R,4'S, 5'R,6'S)-3',4',5'-trihydroxy-6'-methoxytetrahydropyran-2'-yl) ethyl]tetrahydropyran-3,4,5-triol to bind to the repressor protein, LacI, was estimated to be similar to that of isopropyl-beta-thiogalactoside. The disaccharide mimetics were concluded to be a new and interesting class of C-linked disaccharide mimetics with promising, though largely unstudied, biological activity.     

Efficient synthesis of 2,9-disubstituted 8-hydroxyadenine derivatives

An efficient and general method for the synthesis of 2,9-disubstituted 8-hydroxyadenines, which are expected to have various biological activities, was realized. 5-Amino-4-cyano-2-hydroxyimidazoles(1) were prepared from aminomalononitrile and isocyanates as key intermediates. The condensation of 1a with amidines, imidates, guanidine, urea and thioureas afforded 8-hydroxyadenines (2-6) possessing various substituents at the 2-position. Furthermore, selective alkylation of 2-amino- and 2-hydroxyadenines (4 and 6) successively proceeded to give the corresponding 2-alkylamino- and 2-alkoxyadenines (5 and 7), respectively. 2-Alkylthioadenines (15) were prepared by an analogous reaction of 1a with benzoyl isothiocyanate and subsequent S-alkylation. The imidazoles 1 are most useful intermediates for the synthesis of 8-hydroxyadenine derivatives.     

Divergent and regioselective synthesis of 1,2,4- and 1,2,5-trisubstituted imidazoles

A divergent and regioselective synthesis of 1,2,4- and 1,2,5-trisubstituted imidazoles from a readily available (two steps) common intermediate has been developed. This methodology is based on the regiocontrolled N-alkylation of 1-(N,N-dimethylsulfamoyl)-5-iodo-2-phenylthio-1H-imidazole (10). When this intermediate is engaged in reaction with methyl triflate, selective formation of the corresponding 1,2,5-trisubsituted 1H-imidazole is observed. NMR studies have revealed that this regioselectivity can be accounted for by in situ rapid isomerization of 10 into its 1,2,4-isomer (13) followed by regiospecific N-alkylation of the latter. Conversely, when key intermediate 10 is slowly added to Meerwein's salt, isomerization can be constrained and regiospecific N-alkylation of 10 leads to 1,2,4-trisubstituted 1H-imidazole with a high selectivity. The general character of this methodology has been illustrated by showing that iodine in position 4 or 5 could be easily substituted by an aryl group by Suzuki coupling, whereas the phenylthio group at position 2 could, after oxidation into sulfone, be displaced by nucleophilic substitution.