Stereoselective Total Synthesis of Sesquiterpenoids: (+)-Sativene and (+)-Cyclosativene

Abstract

The well-known tricyclic sesquiterpenoid (?)-sativene, isolated in 1965 from Helminthosporium sativum and shown to possess structure and absolute configuration as indicated by structure 1 ³, has been implicated^3,4 as an intermediate in the biogenesis of the fungal toxin (?)-helminthosporal (2)⁵. Two total syntheses of the racemic modification of sativene have been reported^6,7. A closely related sesquiterpenoid, (+)-cyclosativene, was isolated from Abies magnifica A. Murr. and was shown to possess structure 3 ^8,9. The absolute configuration of this material, although not established unambiguously, has been proposed¹⁰ as indicated by formula 3. The total synthesis of cyclosativene has not as yet been achieved directly, although it has been obtained indirectly via acid-promoted rearrangement of sativene^8,9,11,12. We report herein a total synthesis of (+)-sativene (4) and (+)-cyclosativene (3) via a stereoselective route which unambiguously establishes the absolute configuration of both natural products.     

Synthesis of Coleon U

The recent publication by Matsumoto¹ of a synthesis of Coleon U²(1) prompts us to present our own preparation of this poly-hydroxy diterpene as the tri-O-methyl (12a) and tetra-O-methyl ethers (12b). In a previous communication³ we outlined our approach which is aimed at several similar natural products such as Coleon C⁴ (1b), Lycoxanthol⁵ (2), etc. and differs considerably from that of the Japanese group. Formally at least, the two syntheses start with the same material, (+) ferruginol methyl ether 5a. In our case the latter was prepared by recorded methods from methyl O-methyl podocarpate after introducing the iso-propyl sidechain⁶ (→4), transforming the C.4 methoxycarbonyl residue to a methyl⁷ (→5a, ferruginol methyl ether) which was oxidised at the benzylic position of the B ring to give sugiol methyl ether 5b.     

A Convenient Synthesis of 3-Methoxyphthalic Anhydride

Many antibiotics of the anthracycline family¹ possess structures for which 3-methoxyphthalic anhydride (1) would be a suitable synthon² in a total synthesis. A classic synthesis of (1) has employed 3-nitrophthalic acid³ but, in our hands, proceeded in low overall yield. Recent syntheses have utilized the Diels Alder reaction of dimethyl acetylenedicarboxylate (2) with 1-methoxy-1,3-cyclohexadiene,⁴ 1,4-diacetoxybutadiene,⁵ 2-acetoxyfuran,⁶ 2-methoxyfuran⁷ or furan⁸ to obtain 3-hydroxyphthalic acid or a derivative. We now wish to report a convenient Diels-Alder synthesis of (1) from 3-methoxy-2-pyrone (3).     

Phospha-alkynes - Useful Building Blocks in Organic Chemistry1

Abstract

The syntheses of phospholes (7, [3+2]-cycloaddition), bicyclophosphaalkenes (17, [4+2]-cycloaddition), and phosphabenzenes (15, [4+2]-cycloaddition followed by an extrusion process) starting from the phosphaalkynes (4) are described. The 2–Dewar phosphabenzene 18, obtained from the cyclobutadiene 21 and 4 (R =^tBu), is the starting material for the synthesis of the valency isomers 19, 20, 22, and 23.     

An Improved Total Synthesis of (±) - Podocarpic Acid by a Cyclialkylation Route

A number of total syntheses of (±) - podocarpic acid (i) have been described¹ King, King and Topliss² first identified one of the products from nonstereo-selective cyclization of (4) with polyphosphoric acid as (±)- ethyl-O-methylpodocarpate (2) and correlated that with the corresponding acid (3), prepared in an extremly poor yield (ca 0.4%)³ by Bhattacharyya³, and Haworth and Moore⁴ by cyclization of (5) with a mixture of sulfuric acid and acetic acid. More recently Mancini, Fringuelli and Taticchi⁵ prepared (3) (in 4.8% yield) by repeating Howorth¹ s cyclization of (4). In continuation of our studies on cyclialky-     

Enantioconvergent Synthesis of (-)-α-Cuparenone Involving Chiral Inversion of a Ketone Intermediate

The acid (-)-2 was converted to the ketone (-)-6. Unsaturated ketone (+)-14 was synthesised from (-)-6. The ketone (+)-7 prepared from the acid (+)-3 on 1,2-ketone transposition, furnished the optical antipode (-)-6.     

Syntisis of 4-Demethoxy-7, 11-dideoxydaunomycinone

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-deoxydaunomycinone (4)⁵ led us to probe methods of obtaining these products of absolute enantitomeric purity. Earlier it was demonstrated that the AB ring synthon 5 having a chiral centre on fusion with phthalic anhydride gave 4-demethoxy-7-deoxy-daunomycinone (6) with no loss of optical purity⁶ and the same was further transformed to 2 [7-(S)-9(S)].     

Asymmetric Synthesis of (S)-Homoproline and (S)-Homopipecolic Acid1

As for (S)—homoproline (3) there is a marked discrepancy between the directions of the optical rotation reported by two groups of chemists3,4. Here we wish to communicate novel asymmetric syntheses of (S)—homoproline (3) and (S)—homopipecolic acid (4) carried out in connection with our asymmetric cyclization studies². We also examined catalytic potentialities of these unnatural β-amino acids in asymmetric aldol cyclization.     

Synthesis of 2′,3′-Dideoxy-2′-Fluorokanamycin A

2′,3′-Dideoxy-2′-fluorokanamycin A (23) was prepared by condensation of 6-azido-4-0-benzoyl-2,3,6-trideoxy-2-fluoro-α-D-ribo-hexopyranosyl bromide (13) and a protected disaccharide (19). Methyl 4,6-0-benzylidene-3-deoxy-β-D-arabino-hexopyranoside (5) prepared from methyl 4,6-0-benzylidene-3-chloro-3-deoxy-β-D-allo-hexopyranoside (1) by oxidation with pyridinium chlorochromate followed by reduction with Na₂ S₂O₄ was fluorinated with the DAST reagent to give methyl 4,6-O-benzylidene-2,3-dideoxy-2-fluoro-β-D-ribo-hexopyranoside (7). Successive treatment of 7 with NBS, NaN₃ and SOBr₂ gave 13. The structure of the final product (23) was determined by the ¹H and ¹⁹F and shift-correlated 2D NMR spectra.     

Synthesis of Potential Antimicrobial Agents from Maltose. III. Introduction of an Amino Group Into the 3′-Position of 1,6-Anhydro-Disaccharides

Abstract

Regioselective cleavage of 1,6-anhydro-maltose (1) with periodate and the subsequent recyclization with nitromethane gave 1,6-anhydro-3′-deoxy-3′-nitro-disaccharides (3). Three diastereomers, prepared by benzylidenation of 3, were separated by column chromatography. Each of 4′,6′-O-benzylidene derivatives successively underwent debenzylidenation, reduction of the nitro group, and peracetylation to give 3′-acetamido-3′-deoxy-disaccharide derivatives (7, 8, and 9). The configurations of the 3-amino sugar moietres in 7 (D-gluco), 8 (D-manno) and 9 (D-galacto) were determined on the basis of the ¹H NMR data. The main product (7) was further modified to the 6-deoxy-6-nitro derivative.     

A Convenient Synthesis of (Z)-7-Nonadecen-Ll-One and (Z)-7-Eicosen-Ll-Cne -the Pheromones of Peach Fruit Moth

In 1977 Tamaki¹ et al have isolated and synthesized² (Z)-7-nonadecen-ll-one (la) and (Z)-7-eicosen-l1-one (1b) which are active components of the female sex pheromones of the peach fruit moth Carposina niponensis Walsingham, a major economic pest of apple, peach and other fruits of Japan. We report in this communication a practical, convenient and stereospecific route to 1a and 1b.     

The Reaction of N-Phenyliminoketenylidenetriphenyl-phosphorane with α,β-Unsaturated Carbonyl Compounds. Synthesis of New Pyran Derivatives

Abstract

The reaction of N-phenyliminoketenylidenetriphenylphosphorane [a] (1), with 2-benzylidene-1, 3-indandione (2), 1,2-diphenyl-3,4-pyrazolidenedione (3)and/or 5-benzylidene barbituric acid (4) has been investigated. When ylide 1 was allowed to react with compounds 2, 3 or 4 in THF at ambient temp. the corresponding new pyrano-phosphoranylidenes 5, 6 or 7 were obtained. The elemental microanalyses, IR, ¹H NMR, ³¹P NMR and MS data agree with the structure of the cyclic iminophosphoranes by [4+2]-cycloaddition and exclude 4-membered ring structure by [2+2]-cycloaddition. When the Wittig reaction was carried on the pyrano-phosphoranes 5, 6 or 7 using p-nitrobenzaldehyde, the exocyclic olefins together with triphenylphosphine oxide were isolated.     

A Total Synthesis of (±)-Trichodiene

Trichodiene (1), a sesquiterpene hydrocarbon, was isolated from the extract of mycelium of Trichothecium roseum. The structure of trichodiene (1) was elucidated by Nozoe and Machida in 1970 via degradation and spectroscopy.¹ Trichodiene (1) has been shown to be the biogenetic precursor of the trichothecane family of sesquiterpenoids as characterized by the cytotoxic fungal metabolite (-)-trichodermin (2).^2,3 The structure and absolute stereochemistry of (-)-trichodermin (2) were determined by X-ray diffraction and, therefore, the structure and absolute stereochemistry of trichodiene (1) are now firmly established.⁴ We wish to report a total synthesis of (±)-trichodiene (1) via previously reported lactone 3.^5,6     

Synthesis of the Four Configurational Isomers of N-Benzoyl-2, 3, 6-Trtdeoxy-3-C-Methyl-3-Amino-L-Hexose from the (2S, 3R)-Diol Obtained from α-Methylcinnamaldehyde by Fermentation with Baker'S Yeast

Abstract

The erythro and threo chiral C₅ methyl ketones (4) and (5), prepared from the (2S, 3R)-methyl diel (1b), were converted into the phenylsulfenimines (6) and (7), which, in turn, on reaction with allyl-magnesiutn bromide, yielded after acid hydrolysis and benzoylation, the diastereoisomeric C₈-N-aminodiol derivatives (9) and (11), with threo stereochemistry relative to positions 4 and 5. Ozonolysis of (9) and (11) yielded the l-arabino and l-xylo 3-O-methyl branched aminodeoxysugar derivatives (13) and (15), respectively. Using diallylzinc as the reagent, the diastereoisomeric erythro products (8) and (10) were obtained. The latter materials gave the l-ribo-and l-lyxo-(lL-vancosamine) derivatives (12) and (14) upon oxonolysis. The ¹H and ¹³C NMR spectra of the four isomeric aminodeoxysugar derivatives (12)—(15) were discussed.     

A Stereoselective and Regioselective Total Synthesis of (π)-Trichodiene

Trichodiene (1), a sesquiterpene hydrocarbon, was isolated and characterized by Nozoe and Machida in 1970.¹ Trichodiene (1) has been shown to be the biogenetic precursor of the trichothecane family of sesquiterpenoids characterized by the cytotoxic fungal metabolite (–)-trichodermin (2).^2,3 We recently reported a total synthesis of (±)-trichodiene (1) via lactone 3.⁴ Now, we wish to report another stereoselective total synthesis of (±)-trichodiene (1) via lactone 3 which is highly regioselective.     

Synthesis of Retro-γ-Ionols and the Corresponding-Ionones1

Both the direct² and the sensitized^3,4 photolyses of (E)-β-ionol (2) have been studied in some detail. In a preliminary publication⁵ we have indicated that direct photolyses of (E)-β-ionol (2) with λ = 254 nm yields (Z)-retro-γ-ionol (3) as the primary product; upon further irradiation 3 is converted into the corresponding (E)-isomer (4) which rapidly yields the bicyclic alcohol 5. A quantitative study revealed that the photoconversion of (E)-β-ionol with λ = 254 nm to 3 is about 10 times faster than the conversion of 3 into (E)-retro-γ-ionol.⁶ This rate difference thus allows the photosynthesis of 3.     

The Reaction of Diethanolamine with 2-Chloronitrobenzene-A Reinvestigation

In a report on the reaction of 2-chloronitrobenzene (1) with diethanolamine (2), Meltsner et al ¹ claim that the expected S_NAr product, N-(2-nitrophenyl)diethanolamine (3), is not formed; rather that the products are 2,2′-dichloroazobenzene (4), 2-nitrophenol (5), 2-chloroaniline (6) and 4-(2-aminophenyl)morpholine (7). Similar products in which the nitro function is reduced are also reported² for the corresponding reaction with ethanolamine. In this laboratory, in an attempted preparation of 2,2′-dichloroazobenzene (4) for reference purposes in photochemical studies on the antineoplastic agent 5-(3-azido-4-chlorophenyl)-6-ethyl-pyrimidin-2,4-diamine³, the expected S_NAr product (3) was obtained along with other products.     

First Stereqselective Synthesis of Nitrophenyl 2-Deoxy- β-D-glycosides

α-Dithiophosphates of peracetylated 2-deoxyhexc-pyranoses, 1a, 1b and 2, uhich are easily prepared by addition of organic phosphorodithioic acids to glycais react smoothly with resin-bound 2- and 4-nitrophenoxides to give stereoselectively the respective nitrophenyl 2-deoxy-β-D-hexopyranosides (3, 4, 5 and 6) in high yields. Glycosylation of the 2, 4-dinitro'phenoxide, however, leads with comparable stereoselectivity to 2,4-dinitrophenyl 2-deoxy- α-D-hexopyranosides (7 and 8).

Glycosides 3 - 6 are quantitatively deacetylatec by Amberlyst A-26 (OH^-), whereas glycosides 7 and 8, under the same reaction conditions undergo splitting of the O-glycosidic bond.     

Reactions of Cyclic Anhydrides XIV. Facile Syntheses of Fused Heterocycles via Anilic Acids Pyridobenzoxazinones,Isoquinolinobenzoxazinones and Isocoumarinoquinolines

o-Carboxyhomomaleanilic acids (5) and o-carboxyhomophthalanilic acids (6) on treatment with sodium acetate-acetic anhydride furnished pyridobenzoxazinones (8) and isoquinolinobenzoxazinones (9) respectively in quantitative yields. Conversion of o-formylhomophthalanilic acid (7) to isocoumarinoquinoline (11) via 2-axo-3(o-carboxyphenyl)quinoline (10) is also described.     

Oxidation of Cyclic Hemiacetals into Diketones: Final Steps in the Conversion of a Triterpenoid Ring a into a Steroidal Enone by a New Short Route

As a part of our studies in the conversion of triterpenoids into steroids we have reported¹ that the Jones oxidation of some triterpenoid hemiacetals (1) gives acyloxy acids (2) instead of the desired 1,5-diketones (3). We now report² the shortest route yet for the reconstruction of a triterpenoid ring A ketone (4) into a steroidal enone (7) involving as key steps the exhaustive Baeyer-Villiger oxidation³ of triterpenoid ketones (4) into δ-lactones (5) and mild chromium(VI) oxidation of cyclic hemiacetals (1) into diketones (3).