Studies toward the synthesis of pinolidoxin, a phytotoxic nonenolide from the fungus Ascochyta pinodes. Determination of the configuration at the C-7, C-8, and C-9 chiral centers and stereoselective synthesis of the C(6)-C(18) fragment

The absolute stereochemistry at the C-7, C-8, and C-9 chiral centers of pinolidoxin (1) has been determined by chemical and spectral methods. First, the synthesis of four stereoisomeric fully benzoylated 2,3-erythro-1,2,3,4-heptanetetrols, corresponding to the C(6)-C(18) portion of the natural substance, has been accomplished starting from meso-tartaric acid. As next step, the selection of the synthetic tetrabenzoate possessing "natural" stereochemistry (10a'), suitable for absolute configuration determination, has been carried out by correlation with its "natural" homologue derived from degradation of pinolidoxin. Determination of the stereochemistry at the title chiral centers has been carried out by application of the Mosher's method both to 7a', a compound stereochemically related to 10a', and to pinolidoxin itself. The stereoselective synthesis of a protected form of the C(6)-C(18) portion of pinolidoxin, to be used in its total synthesis, has also been accomplished starting from commercially available D-erythronolactone.     

Total synthesis of xanthanolides

The total synthesis and determination of the absolute configuration of (+)- and (−)-sundiversifolide have been achieved via intramolecular acylation and Wittig-lactonization as the key steps. The xanthanolide sesquiterpene lactones, 8-epi-xanthatin (1), dihydroxanthatin (2), and xanthatin (3) were also prepared, starting from a common intermediate derived from the synthesis of sundiversifolide.     

Total synthesis of TT-1 (rasfonin), an α-pyrone-containing natural product from a fungus Trichurus terrophilus

Total synthesis of TT-1 (1=rasfonin), an α-pyrone-containing natural product from a Fungi Imperfecti Trichurus terrophilus culture was achieved by a stereoselective method in optically active form, which further provided evidence for the whole structure of TT-1 (1) including the absolute stereochemistry.     

Aurilide, a cytotoxic depsipeptide from the sea hare Dolabella auricularia: isolation, structure determination, synthesis, and biological activity

The bioassay-guided fractionation of the cytotoxic constituents of the Japanese sea hare Dollabella auricularia led to the isolation of aurilide (1), a 26-membered cyclodepsipeptide. The gross structure of 1 was established by spectroscopic analysis including 2D NMR techniques. The absolute stereostructure was determined by chiral HPLC analysis of acid hydrolysates of 1 and by the enantioselective synthesis of a degradation product arising from a dihydroxylated fatty acid portion. The enantioselective synthesis of 1 was achieved in 12% overall yield (16 steps) and confirmed the absolute stereostructure of 1. The cytotoxicity of 1 was evaluated using a synthetic sample, which was found to exhibit potent cytotoxicity against HeLa S₃ cells with an IC₅₀ of 0.011 μg/mL. Further biological and pharmacological studies of 1 have been carried out by using synthetic 1.     

First synthesis and absolute configuration of decaturin D

The first synthesis of (+)-decaturin D (1), an antiinsectant diterpenoid isolated from Penicillium thiersii, was accomplished by employing our original spiro-cyclization reaction as the key step. The absolute configuration of the naturally occurring 1 was determined.     

Total synthesis of peumusolide A, NES non-antagonistic inhibitor for nuclear export of MEK

The first total synthesis of peumusolide A (1) has been achieved by combination of regio- and stereo-selective aluminum-mediated hydroiodination to 2-yn-1-ol and enantioselective reduction of 4-en-1-yn-3-one with the chiral oxazaborolidine as the key reactions. This total synthesis has unequivocally established our proposed absolute structure of 1.     

Total synthesis and structural revision of (+)-amphidinolide W

An enantioselective first total syntheis of amphidinolide W (2) and a revision of its C6 absolute stereochemistry (1) are described. Amphidinolide W (1), a 12-membered macrolide isolated from Amphidinium sp., has shown potent antitumor properties against a variety of NCI tumor cell lines. The synthesis is convergent, and four of the five chiral centers were derived through asymmetric synthesis. The synthesis features Sharpless asymmetric dihydroxylation, diastereoselective alkylation, efficient cross metathesis of functionalized substrates, and novel functional group transformations using selective lipase-catalyzed hydrolysis of the primary acetate group. Of particular note, the C6 absolute stereochemistry of amphidinolide W (1) has now been revised through our current synthesis.     

The first synthesis and absolute configuration of glaucescenolide

The first synthesis of glaucescenolide (1), a cytotoxic sesquiterpene isolated from the liverwort, Schistochila glaucescens, was achieved by starting from 2,2,6-trimethylcyclohexanone (2). The absolute configuration of the naturally occurring 1 was confirmed as 5S,7S,10R.     

Asymmetric synthesis of aerothionin, a marine dimeric spiroisoxazoline natural product, employing optically active spiroisoxazoline derivative

Successful first synthesis of optically pure (+)- and (−)-aerothionins (1) from the racemic spiroisoxazoline derivative 8 has been accomplished. The absolute configuration of natural (+)-1 was determined by comparison of (+)- and (−)-8 with related derivatives.     

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     

Determination of the absolute stereochemistry and asymmetric total synthesis of madindolines A and B: a practical improvement to a second-generation approach from the first-generation

In this report, we describe an efficient, highly convergent, stereocontrolled first total synthesis and a second-generation synthesis of madindolines A 1 and B 2, potent selective inhibitors of interleukin 6. The key steps include (1) asymmetric oxidative ring-closure reaction of tryptophol 3 to construct a chiral 3a-hydroxyfuroindoline 4 using the modified Sharpless asymmetric epoxidation condition, (2) highly diastereoselective acylation to build up the quaternary carbon center, and (3) intramolecular acylation of ester 32 with allylsilanes to produce the full substituted cyclopentenedione units. Our first synthetic route defines for the first time both their relative and absolute configurations. Moreover, a more efficient second-generation synthesis was designed, which is suitable for gram-scale preparation of these compounds.     

Synthesis of (±) Combretastatin

Combretastatin (1) is a new plant product isolated recently by Pettit et al ¹. from the South African tree, Combretum caffrum that possesses central nervous system antineoplastic activity and is being evaluated against several of National Cancer Institute's key evaluation systems. The structure of 1 was established on the basis of its spectral properties and confirmed by X-ray analysis. However, the absolute configuration and the synthesis of 1 have not been reported so far. As combretastatin is present in the plant in only 0.0008% and the isolation technique is much tedious, there is an urgent need for the synthesis of 1 for further evaluation of its activity. This prompted us t o report the first synthesis of (±)1.     

Synthesis of the (+)-Enantiomer of Taonianone,a Furanoid Diterpene from Brown Algae

The constitution and absolute configuration of the furanoditerpene taonianone ( 1 ) has been established by synthesis starting from (–)-carveol ( 2 ).     

Chiral synthesis of maconelliol: a novel cyclobutanoid terpene alcohol from pink hibiscus mealybug, Maconellicoccus hirsutus

The chiral synthesis of maconelliol, [2,2-dimethyl-3-(1-methylethylidene)cyclobutyl] methanol, the alcohol moiety of the major sex pheromone component isolated from the pink hibiscus mealybug, Maconellicoccus hirsutus, is described. The compound was synthesized in six steps from alpha-pinene and the key step is dehydration of 5 to 7 through the intermediate 6. The absolute configuration of the naturally occurring maconelliol was determined as R.     

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.     

Synthesis of the anti-Helicobacter pylori agent (+)-spirolaxine methyl ether and the unnatural (2"S)-diastereomer

The first enantioselective synthesis of the anti-Heliocbacter pylori agent (+)-spirolaxine methyl ether 2b has been carried out in a convergent fashion establishing that the absolute stereochemistry of the natural product is in fact (3R, 2"R, 5"R, 7"R) after initial synthesis of the unnatural (2"S)-diastereomer 2a. The key step in the synthesis of (+)-spirolaxine methyl ether 2b involved a heterocycle-activated Julia-Kocienski olefination between benzothiazole-based spiroacetal sulfone 4b and phthalide aldehyde 3a. (2"R, 5"S, 7"S)-Spiroacetal sulfone 4b was prepared via cyclisation of protected dihydroxyketone 6b, which in turn was derived from the coupling of the acetylide derived from (R)-acetylene 24b with aldehyde 3a. Phthalide aldehyde 3a was prepared via intramolecular acylation of bromocarbamate 15, which was available via titanium tetrafluoride-(+)-BINOL-mediated allylation of 3,5-dimethoxybenzaldehyde 13. Union of the sulfone 4b and aldehyde 3a fragments successfully completed the enantioselective synthesis of (+)-spirolaxine methyl ether 2b. The synthesis of the unnatural (3R, 2"S, 5"R, 7"R)-diastereomer of spirolaxine methyl ether 2a was also undertaken in a similar manner by union of phthalide aldehyde 3a with (2"S, 5"S, 7"S)-spiroacetal sulfone 4a derived from (S)-acetylene 24a.     

An enantioselective total synthesis of (S)-(−)-licochalcone E: determination of the absolute configuration

The absolute configuration of (−)-licochalcone E (1) was determined to be (S) via the first enantioselective total synthesis of the compound. The chirality in (S)-(−)-licochalcone E (1) was installed by asymmetric methylation of the Evans' oxazolidinone derivatives.     

Total synthesis and absolute stereochemistry of plakortone E

The absolute stereochemistry of plakortone E, a cytotoxic metabolite of the Caribbean sponge, was established to be 1, by the synthesis of the racemic C-8 epimer (±)-2 and then of (−)-1 itself, which was identical with the natural compound.     

Diastereoselective synthesis of 1-α-phenylethyl-3,3-dimethyldiaziridine. Conformation and configuration of three-membered ring nitrogen heterocycles containing an asymmetric substituent on the nitrogen atom

The synthesis of 1-(S)--phenylethyl-3,3-dimethyldiaziridine from N-(S)--phenylacetonimine and hydroxylamine-O-sulfonic acid has been carried out with high diastereoselectivity. The absolute configuration of the diastereomers was established by comparison with oxaaziridine analogs based on their NMR and CD spectra, and atom-atomic potential calculations. A test has been proposed to establish the absolute configuration of N--phenylethyl-substituted three-membered ring heterocycles using NMR, and the mechanism of epimination of imines is discussed, which is similar to their oxidation mechanism.Communication 60 in the series Asymmetric Nitrogen; for Communication 59, see [1].Translated from Geterotsiklicheskikh Soedinenii, No. 11, pp. 1461–1465, November, 1988.     

Total synthesis of (+)-benzastatin E via diastereoselective Grignard addition to 2-acylindoline

[reaction: see text] A stereoselective total synthesis of (+)-benzastatin E (1) is described. The synthesis involves a diastereoselective Grignard addition to 2-acylindoline 2, which is derived from commercially available (S)-2-indolinecarboxylic acid (3). The unknown absolute configuration of (+)-1 is determined as (9S,10R).