An efficient enantiocontrolled synthesis of (+)-4-demethoxydaunomycinone

A chromatography-free, seven-step synthesis of the title compound (3) is described. The tetracyclic carbon skeleton is elaborated by a Diels-Alder strategy in which the 6a,7- and 1O.1Oa-bonds are constructed the epoxy-tetrone (9) and the D-glucose-derived diene (10b) serving as precursors. Interestingly, the cycloaddition reaction leads mainly to the “desired” cycloadduct (11b), revealing a notable diastereofacial reactivity of the diene (10b). Hydrolysis of the cycloadduct (11b) leads to the epoxy-pentone (12b) which is reduced to the dihydroxy-trione (13b). The reaction of the last-cited compound with ethynylmagnesium bromide affords a mixture of the ethynyl-diones (20b) and (21b), the latter compound arising from the precursor (13b) by a prior epimerisation at the 10a-position. The mixture of ethynyldiones (20b) and (21b) is converted into the anthracycline (14b) by the action of lead (IV) acetate. By a hydrolysis-hydration sequence, the anthracycline (14b) is transformed into (+)-4-demethoxydaunomycinone (3).     

Synthesis of an octamethyl-18-crown-6 derivative and the X-ray crystal structure of its 2:1 complex with borane-ammonia

The synthesis of 2,2,3,3,11,11,12,12-octamethyl-1,4,7,10,13,16-hexaoxacyclooctadecane (2) from pinacol (3) by a sequence of reactions (3→4→5→6+5→2) involving alkylation (3→ 4), ozonolysis and reduction (4→5), tosylation (5→6), and cyclisation (5+6→2) is reported. With borane-ammonia, the octamethyl-18-crown-6 derivative 2 forms a crystalline 2:1 complex, (BH₃NH₃)₂ · 2. X-Ray crystallography reveals the two guest BH₃NH₃ molecules are hydrogen bonded in a centrosymmetric manner to the opposite faces of the host 2, which adopts an all-gauche (ag⁺a ag^-a)₃ conformation.     

Stereochemical studies—LVII: Synthesis of optically active compounds by the novel use of meso-compounds—1. Efficient synthesis of two structural types of optically pure prostaglandin intermediates

With an aim to overcome several inefficient aspects of ordinary methods of preparing optically active compounds, we have developed a new method which recommends utilization of symmetrically functionalized meso-compounds in place of racemic compounds.As shown in Scheme 1, when the mesa-compound (I) is monofunctionalized by an optically active functional group (A) and each of the formed diastereomers (II and III) is subjected to further chemical elaborations including protective group transposition, it is theoretically possible to convert the total amount of the starting material (I) into the requisite optically pure product (VI or VII) by selecting synthetic schemes.By employing this novel concept, two structural types of the prostaglandin intermediates ((?)- and ( + )-2a,b) have been prepared from the meso-diols (1a, b) by way of the two diastereomeric monoesters (13a, b and 14a, b) which are produced by the reactions of 1a, b with N-mesyl- and N-phthaloyl-(S)-phenylalanyl chloride (3a, b).     

The synthesis of octavalene (tricyclo[5.1.0.02,8]octa-3,5-diene) and several substituted octavalenes

The first synthesis of octavalene (1a) is reported. The starting material is homobenzvalene (5), to which monobromocarbene is added. The resulting compound 3a takes up bromine across the central bicyclo[1.1.0]butane bond to form the tribromide 7a which undergoes a cyclopropyl bromide-allyl bromide rearrangement on heating. From the product (1Oa) HBr is eliminated to give a 1,3-dibromocyclobutane with a 1,3-butadiene bridge across its 2- and 4-position (11a). Finally, t-butyllithium removes the two Br atoms from 11a and converts it into a 4:1 mixture of 1a and cyclooctatetraene. This reaction sequence represents the first application of protective group strategy in bicyclo[1.1.0]butane chemistry. Octavalene (1a) is shown to rearrange to cyclooctatetraene at 50°. Deuterium-labeled 1a ([1,8-D₂] 1a) is used to prove that a [1,5]-sigmatropic shift does not occur in 1a. Utilizing the above methodology 4-bromooctavalene (1b) and 3-phenyl-5-bromooctavalene (1c) are synthesized from the dibromocarbene adducts 3b and c of homobenzvalene (5) and 5-phenylhomobenzvalene (6), respectively. Surprisingly, 1c was accompanied by a small quantity of 3-bromo-1-phenyloctavalene (1d). Possible mechanisms for the addition of bomine to the bicyclo[1.1.0]butane system of compounds 3 and for the formation of the octavalenes 1 are discussed. In the ¹³C-NMR spectra of 1 and 11 chemical shifts at unexpectedly high field are observed for C-6 of the 1,3-cycloheptadiene moieties.     

A convergent synthesis of (±)daunomycinoni

A convergent AB+CD synthesis of(±)daunomycinone 1 in 14% overall yield from hydroxy phthalan 10 is described. Methyl vinyl ketone reacts with 4,7-dimethoxy isobenzofuran (generated from 10) to provide the adduct 16 which is developed into the AB synthon 30. The cyanophthalide 32 the CD half of the molecule, is attached with good regiocontrol and a subsequent tetracyclic C6-C7 acetonide 40, oxygenated a C-9 to eventually produce a 5:6 mixture 1 and its C-7 epimer 8.     

Resolution of 1-arylalkylamines with 3-O-hydrogen phthalate glucofuranose derivatives: role of steric bulk in a family of resolving agents

The development of three new acidic resolving agents which are hydrogen phthalates of 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose 1, 1,2:5,6-di-O-cyclohexylidene-α-d-glucofuranose 2 and 1,2-O-cyclohexylidene-5,6-O-diphenylmethylidene-α-d-glucofuranose 3 is shown for the resolution of 1-arylalkylamines 7a–k. The salts between 1, 2 and (RS)-1-arylalkylamines 7a–k selectively crystallize 1·(S) 7a–j and 2·(S) 7a–h salts, allowing us to recover the corresponding bases (S) 7a–j and (S) 7a–h, respectively, in good yield and enantiomeric excess (73–95% ee). Whereas, the salts between 3 and (RS)-1-arylalkylamines 7a–c,g–i,k selectively crystallize 3·(S)-7a–c,g–i salts to recover the corresponding bases (S)-7a–c,g–i in poor enantiomeric excess (4–35% ee). The difference between the resolving ability of 1 and 2 for 1-arylalkylamines 7a–h is very slight, but there is considerable difference compared to ortho-substituted 1-arylalkylamines 7i and 7j. The role of substituents on a family of resolving agents 1, 2 and 3 is also discussed to interpret their resolving ability.     

Meso-oxidation of some metalloporphyrins

Treatment of porphyrins with thallium(III) trifluoroacetate in the presence of trifluoroacetic acid results in uncontrolled oxidation at the macrocyclic meso-positions, presumably via radical processes. For example, a mixture of the thallium(III) α γ-dioxoporphodimethene (4a; R = Et), the αβγ-trioxo compound (3), and octaethylxanthoporphyrinogen (6) is obtained when octaethylporphyrin (1; R = Et) is oxidised in the presence of air. More controlled oxidation is achieved when the meso-trifluoroacetoxyporphyrin complexes (8a, b) or metallo-oxophlorins (7a, b) are treated with mild bases in air, the major products being metallo-αγ-dioxoporphodimethenes (4b, c).β-Hydroxy-α-oxophlorins (16) are isolated and characterised for the first time; aspects of the chemistry of this novel oxygenated porphyrin system are reported.     

Synthesis of pyrrolizines by intramolecular capture of 1,4-dipolar intermediates in reactions of enamines with dimethyl acetylenedicarboxylate

Solvent polarity and reaction temperature strongly influence the reactions of dimethyl acetylenedicar-boxylate (DMAD) with 1-pyrrolidinyl enamines of acyclic and cyclic ketones. Whereas DMAD and 1-[1-phenyl-2-(phenylthio)ethenyl]pyrrolidine (3) give only a mixture of the isomeric 1,3-butadienes (5) in apolar solvents, in methanol the main product is the pyrrolizine 7, together with 5. Again in methanol, DMAD reacts at 0-5° with 8, 9 and 10 to give exclusively 1:1 adducts, the pyrrolizines 11,12 and 13, respectively, whereas at ?50° 8 and 9 give 1:2 (enamine : DMAD) adducts, the pyrrolizines 14 and 15, respectively; a single crystal X-ray analysis of 14 gave the structure of the 1:2 adducts. In the same solvent methyl propiolate and 8 give only the linear Michael adduct 17. The enamine-ketone 18 reacts with DMAD in propylene carbonate at 0–5° to give, via (2 + 2)-cycloaddition and ring expansion, 19, and the linear Michael adduct 20. The mechanism of (2 + 2)-cycloaddition and pyrrolizine formation is discussed in terms of a common tied-ion pair intermediate formed in the first, rate-determining step, followed by a second solvent-dependent step.     

The synthesis of shihunine and related compounds from ortho-carboxyphenyl cyclopropyl ketone

Reaction of dicyclopropyl cadmium and phthalic acid monochloride monomethyl ester gives o-carboxyphenyl cyclopropyl ketone (2). Reaction of the methyl ester of 2 with methylamine gives 2 - methyl - 3 - hydroxy-3-cyclopropyl-1-isoindolinone (4b), which is converted by hydrogen halides in chloroform to the rearranged homoallylic halides 5a–c. Thionyl chloride in chloroform converts 2 to 3-(3-chloropropylidene) phthalide (7) which upon reaction with methylamine gives isoshihunine (8). Heating of keto acid 2 with aniline leads to N-phenyl-N-norshihunine (9), while upon heating of 2 with methylamine spiro [(1 - methylpyrrolidine) - 2 - 3′ - (2′ - methyl - 1′ - isoindolinone)] (10) is obtained. 10 is converted to shihunine (1) by 48% HBr solution. The mechanisms of the reactions are discussed.     

Amidoalkylation of mercaptans with glyoxylic acid derivatives

The synthesis of α-alkyl mercaptohippuric acid (3a–d), N-benzyloxycarbonyl-α-methylthioglycine (3e) and their methyl esters (5a–d) by the amido-alkylation of mercaptans with α-hydroxyhippuric acid (2a), α-hydroxy-N-benzyloxycarbonylglycine (2b) and their methoxymethyl ester derivatives 4a and 4b is described. Oxidation with m-chloroperbenzoic acid afforded the corresponding sulfoxides and sulfones and treatment with N-bromosuccinimide in methanol or chlorine in carbon tetrachloride solution exchanged the sulfur containing side chain for a methoxy or a chloro group respectively. (4a, 8).     

A regioselective synthesis of daunomycinone and related anthracyclinones

The phthalic anhydrides 4a and 4b are attacked by the Grignard reagents 15 and 33 in tetrahydrofuran/tetramethylethylene diamine almost exclusively at the carbonyl group, which is situated in the meta position of the methoxy substituent(s). This highly regioselective reaction (minimum: 95:5) is used as the key step in a short synthesis of daunomycinone (2a), 2-methoxy-7-deoxycarminomycinone (22b),γ-rhodomycinone (8), and 10-dexoy-γ-rhodomycinone (9). The products of the addition of 15 to 4a and 4b, the pseudoacids 16 are converted via the olefins 17 and the epoxides 18 into the ketones 19, which lead by application of known reactions to the anthracyclinones 2a, 22a, and 9. The product, formed by addition of 33 to 4a, is converted to γ-rhodomycinone (8) via the quinone 27. The precursors of the Grignard reagents 15 and 33, the bromides 14 and 32, can be prepared easily and in large scale from the carboxylic acid 10, which is readily available from the cheap chemicals hydroquinone and succinic anhydride.     

Polycyclic hydroxyquinones-xix : Regiospecific synthesis of anthracyclinones via the diels-alder reaction with dichloronaphthazarins

A convenient route to the daunomycinone precursor 18via a succession of Diels-Alder reactions from 2,7-dichloronaphthazarin (9) is described. In a similar manner, starting from 2,6-dichloronaphthazarin (19) compound 20, a regioisomer of 18,is synthesized. This methodology constitutes a regiospecific approach to (±)-daunomycinone and related anthracyclinones.     

The orthosomycin family of antibiotics—I : The constitution of flambamycin

The antibiotic, flambamycin, is shown to have the novel oligosaccharide structure (1) associated with two orthoester linkages. It is proposed that flambamycin (1), the everninomicins (28), curamycin, avilamycin, destomycin A (29a), destomycin C (29b), destomycin B (30), hygromycin B (29c), the antibiotics A-396-I (29d) and SS-56C (29e), belong to a new family of antibiotics called the orthosomycins.     

Biosynthesis of tylophorine and tylophorinine

Administration of 3,4-dihydroxyphenyl[2-¹⁴C] alanine to young Tylophora asthmatica plants revealed that ring B and carbon atoms C₉ and C₇ of tylophorine and tylophorinine are derived from dopa. Tracer experiments with 6,7-diphenylhexahydroindolizines (1–7) and (26) demonstrated that compound 1 is efficiently and specifically incorporated into tylophorine (13) and tylophorinine (16). Compounds (3), (4) and (26) were not metabolized by the plants to form (13) and (16) whereas (5) and (6) were utilized to yield (13) and (16). Compound (2) was very poorly converted into (13) and (16) and thus is not on the major biosynthetic pathway of (13) and (16).     

Singlet oxygen photooxygenation of furans : Isolation and reactions of (4+2)-cycloaddition products (unsaturated sec.-ozonides)

Tetraphenylporphin-photosensitized oxygenations of furan (19), 2-methylfuran (26), 2-ethylfuran (39), furfurylalcohol (24), 2-acetylfuran (40), 2-methoxyfuran (42), 2,5-dimethylfuran (30), furfural (25) and 5-methylfurfural (41) in non-polar aprotic solvents yield the corresponding monomeric unsaturated secondary ozonides due to a (4+2)-cycloaddition of singlet oxygen to these furans. With the exception of the ozonide derived from 25, the ozonides were isolated and characterized (¹H- and ¹³C-NMR spectra, etc.). In non-polar aprotic solvents, the ozonides derived from 19, 26 and 39 undergo thermal rearrangements to the corresponding cis-diepoxides and epoxylactones. Ozonide 31, derived from 30, however, dimerizes, only above about 60° is a cis-diepoxide formed from either 31 or its dimer. Rose bengal-photosensitized oxygenations of the furans in alcohols (MeOH, EtOH, i-PrOH) also produce the corresponding ozonides as the primary products of (4+2)-cycloadditions of singlet oxygen to these furans. However, reactions of the alcohols with the ozonides are too fast to allow the ozonides to be isolated. Instead, the same products are obtained as are isolated from reactions carried out by dissolving the ozonides in the alcohols. Depending on the structure of the ozonide, three pathways are available to ozonide/alcohol (ROH) interactions:(1) addition of ROH to yield alkoxy hydroperoxides; one out of several possible isomers is formed in a completely stereoselective and regiospecific reaction; (2) elimination of a bridgehead proton by ROH as a base, as observed with the ozonide derived from 19 to give hydroxy butenolide (78) in yields between 20 and 60%, and (3) ROH-attack on a carbonyl side-chain under elimination of the corresponding alkyl ester, as observed with furfural photooxygenation which yielded hydroxy butenolide (78) in high yields (95%). Interaction of ozonide 31 with tert.-butyl alcohol (t-BuOH) yields quantitatively cis-3-oxo-1-butenylacetate (81) by a Baeyer-Villiger-type rearrangement with vinyl group migration Hydrogenbonding between the alcohol and the peroxy group of the ozonides assist the heterolysis of the C—O bonds in the ozonides; the most stabilized cation develops. Front-attack of ROH on this cation explains the stereoselectivity as well as the regiospecificity of the alkoxy hydroperoxide formation; with a bulky alcohol like t-BuOH, ROH-attack on the cation is sterically hindered thus allowing a rearrangement to occur. 1,3-Dipolar cycloaddition of p-nitrophenyl azide to ozonide 31 proceeds stereoselectively to one of the isomers 87a/87b. Finally, kinetic results of furan photooxygenation in methanol show the following order of furan-reactivity towards singlet oxygen: 30 > 42 > 26 > 19 > 41 > 25, with absolute rate constants ranging from 1.8 × 10⁸ (with 30) to 8.4 × 1O⁴ M^-1P^-1 (with 25).     

Rhodium complexes of PCNHCP: Oxidative addition of dichloromethane and catalytic hydrosilylation of alkynes affording (E)-alkenylsilanes

New rhodium complexes of PC^NHCP have been synthesized by using the silver transfer reagent, [Ag₃(PC^NHCP)₂Cl]Cl₂ (2). In the reaction between 2 and [Rh(COD)Cl]₂ in dichloromethane, the presumably formed nucleophilic Rh^I(PC^NHCP)Cl intermediate (A), undergoes a C–Cl bond activation of CH₂Cl₂ giving cis,mer-Rh^III(PC^NHCP)(CH₂Cl)Cl₂ (3) as the final product. Attempts to isolate A affords the oxidative degradation product of mer-Rh^III(PC^NHCP)Cl₃ complex (4). In contrast, the rhodium(I) center in Rh(PC^NHCP)(CO)Cl (5) is stabilized by the π-back bonding of CO ligand; a robust complex is, therefore, obtained. The solid-state structures of 2 and 3 were determined by X-ray diffraction. Complexes 3–5 are catalyst precursors for efficient, chemoselective hydrosilylation of alkynes. For the reaction between phenylacetylene and dimethylphenylsilane, a rapid hydrosilylation occurs, producing isomers of alkenylsilanes; then a slow isomerization pathway converts (Z)-alkenylsilane to its (E)-isomer. For 3, under catalytic condition, a facile reductive elimination of dichloromethane giving A is anticipated. The similarity in reactivity and selectivity between 3, 4 and 5 suggests the involvement of A as the active species in a common catalytic cycle.     

Medium-sized cyclophanes—XVII : Tetra-, hexa-, octa- and decahydropyrenes from [2.2]metacyclophane. Transannular dehydrogenation,isomerization, and disproportionation reactions by means of benzoyl peroxide,metal salts and sulfuric acids

[2.2]Metacyclophane (1) undergoes a variety of reactions according to the reagents and conditions. These include (1) substitution (path a), (2) transannular dehydrogenation (path b and c), (3) cycloisomerization (path d) and (4) transannular hydrogenation. A brief summary of these reactions is presented.The diversity of the reactions of 1 is further explored using benzoyl peroxide (BPO), cupric chloride, aluminum chloride, other metal salts, H₂SO₄ and FSO₃H. With BPO or cupric chloride, one-electron transfer mechanism is postulated. This involves a tautomeric ion pair formed by the intramolecular arylation with an aryl cation radical. A supporting evidence in favor of the mechanism is presented from experiments using various metal salts in different solvents.On the contrary, the reaction with aluminum chloride gives decahydropyrene (8) and octahydropyrene (11) together with cycloisomerization product 5 and dehydrogenation products 2, 3 and 4. When treated with AlCl₃HCl 1 gives similar products as above but the product ratios are quite different. The major product is 5 but only a trace amount of 8 is formed. The reaction with H₂SO₄ or FSO₃H also produce 2, 4, 5 and 11. Some mechanistic evidence in favor of the disproportionation reaction is presented.     

Total synthesis of arteannuin and deoxyarteannuin

Arteannuin 1 is a new sesquiterpene lactone containing a peroxide linkage and is an antimalarial principle isolated from Artemisia annua L. . R(+)-Citronellal 5 as a starting material for the total synthesis was converted into 11R(-)-methyl dihydroarteannuinate 12 in 14 steps. The key intermediate 4 was obtained from compound 12 in 5 steps. The introduction of hydroperoxide in 4 by photooxidation followed by acid treatment gave 1. Hydroxylation of 4 with osmium tetraoxide afforded deoxyarteannuin 2.     

Reactions of carbethoxyalkylidenetriphenylphosphoranes with aryl azides

The title reaction has been shown to give a complex mixture of products from which triazoles (12 and 17), maleates (13), fumarates (14), triphenylphosphine oxide (15), iminophosphoranes (16) and triazenes (18) have been isolated. Their formation is rationalized by two reaction paths, involving addition of the azide onto the CC and CP bonds of the ylide. Diazoesters 5 and 19, which should result from CP addition, were not isolated, but are believed to give rise to compounds 13,14 and 18.     

The facile conversion of T-2 toxin and neosolaniol into anguidine

T-2 Toxin (5) and neosolaniol (6) are readily converted into anguidine (1) by a procedure where deoxygenation at the C-8 position is achieved, after conversion of the 3-TBDMS ether 7 of neosolaniol (6) to the β-bromide 11 for reduction to the anguidine precursor 12.