The synthesis of new aromatic prostacyclin analog

The new aromatic prostacyclin analog $\text{3a}$ and $\text{3b}$ were synthesized from the allylic alcohol $\text{5}$ in high regio- and stereoselectivity.     

Synthesis of binzindene prostaglandins: a novel potent class of stable prostacyclin analogs

The phenols $\text{13}$, $\text{16}$, and $\text{21}$, produced with remarkable regioselectivity by the cyclization of compounds $\text{10}$ and $\text{12}$, have been converted to the benzindene prostaglandin analogs $\text{25}$, $\text{20}$, and $\text{24}$, respectively. Compounds $\text{24}$ and $\text{25}$ are potent prostacyclin mimics.     

Synthesis of analogs of prostacyclin containing a thiazone ring

Thiazole analogs of prostacyclin were prepared from the cyclopentene (9), itself, obtained $\text{via}$ novel opening of 3,4-epoxycyclopentene with the lithioallylthioether (4).     

Keto-alkyne cyclisation reactions: heterocyclic prostacyclin analogues

Simple furan, thiophene and pyrrole analogues of prostacyclin have been prepared from readily-available 4-alkvnyl ketones; the cyclohexa[b]-furano-prostacyclin analogue $\text{3}$ has also been synthesised using the keto-alkyne cyclisation procedure.     

Formal total synthesis of β-pipitzol

(±)-$\text{O}$-methylperezone ($\text{1b}$) was obtained by selective oxidative demethylation of (±)-leucoperezone trimethyl ether ($\text{4a}$). Compound ($\text{4a}$) was prepared by condensation of 2,3,5-trimethoxytoluene ($\text{5e}$) with 6-methyl-5-hepten-2-one, followed by reductive removal of the tertiary alcohol. The aromatic precursor $\text{5e}$ was prepared in four steps from 2,3-dimethoxytoluene ($\text{5a}$) and, alternatively, in three steps from 5-bromoveratraldehyde ($\text{6a}$). Racemic $\text{1b}$ and $\text{4a}$ were directly compared with the optically active molecules prepared from natural R(-)-perezone ($\text{1a}$).     

A new synthesis of spirobenzylisoquinolines. Analogues of sibiricine and corydaine

The reduction product of dehydrocordrastine, $\text{6}$, with di-isobutylaluminum hydride spontaneously rearranged to the spirobenzylisoquinolines $\text{7a}$ and $\text{7b}$, analogous to the alkaloids sibiricine ($\text{5a}$), corydaine ($\text{5b}$), and yenhusomidine ($\text{5c}$).     

Synthesis of oxazolidin-2-ones using carbonate ion on a polymeric support

Through the insertion of a carbon dioxide molecule, the oxazolidin-2-ones ($\text{5a}$) and ($\text{5b}$) were prepared by treataent of the salts ($\text{4a}$) and ($\text{4b}$) with carbonate anion on polymeric support. The hydrolysis under basic conditions of ($\text{5a}$) and ($\text{5b}$) afforded the erythro-3-amino-1,2-diols ($\text{6a}$) and ($\text{6b}$) which were fully acetylated: the 2-amino-2-deoxyerythritol derivative ($\text{7b}$) was obtained in 91% yield.     

A short and efficient synthesis of 4-hydroxy-5-(1-hydroxyalkyl)-γ-butyrolactones

The cycloaddition of α,β-epoxyaldehydes or ketones ($\text{2}$) with the ketene acetal MeHC=C(OMe)₂ ($\text{1}$) gives epoxyoxetanes ($\text{3}$) in high yields. Without isolation they can be transformed into 4-hydroxy-5-(1-hydroxyalkyl)-γ-butyrolactones ($\text{6}$) via the epoxy esters $\text{4}$ and trihydroxy esters ($\text{5}$). The lactones $\text{6}$ appear to be valuable precursors for the synthesis of 5-(1-hydroxyalkyl)-3-methyl-2-5H-furanones ($\text{7}$) and 3-methyl-5-ylidene-2-5H-furanones ($\text{8}$)     

Pathways for migration and cleavage of the S-peptide unit of the leukotrienes

Sulfoxides of leukotriene C ($\text{2}$) and various analogs ($\text{5}$, $\text{8}$) undergo a 1,7-migration of sulfur (forming diastereomers $\text{3}$, $\text{6}$, and $\text{9}$, respectively) with noteworthy facility. Generation of the S-halo derivatives of leukotriene C in water results in heterolysis of the CS bond to give (5S, 12R)- and (5S, 12S)-6-$\text{trans}$-leukotriene B in a process which mimics biochemical deactivation.     

Preparation of some highly halogenated derivative of furan

Direct chlorination of 2-(2H-hexafluoropropyl)-tetra- hydrofuran $\text{1}$ gave high yield of 2-(2-chlorohexafluoropropyl)- pentachloro-2,5-dihydrofuran $\text{2}$. Bromination of $\text{1}$ gave very complex mixture of products, from which three compounds, $\text{viz}$. 2-bromo-5-(2H-hexafluoropropyl)-furan $\text{3}$, 3-bromo-5-(2H-hexafluoropropyl)-furan $\text{4}$, and 2,4-dibromo-5-(2H-hexafluoropropyl)furan $\text{5}$ were isolated. Exchange fluorination of $\text{2}$ with dry KF at 240 – 300° led to a stepwise substitution of fluorines for chlorines to give mixtures of chloro-fluoro-2-(2-chlorohexafluoropropyl)-dihydrofurans $\text{7}$,$\text{8}$,$\text{9}$ and $\text{10}$, together with small amounts of 2-(2-chlorohexafluoropropyl)-3,4,5-trichlorofuran $\text{6}$.Exchange fluorination of 3,4-dihalo-2,2,5,5-tetrafluoro- 2,5-dihydrofurans $\text{11a}$ and $\text{11b}$ led to a substitution of fluorine for one vinylic halogen to give 3-halo-2,2,4,5,5-pentafluoro-2,5-dihydrofurans $\text{12a}$ and $\text{12b}$ in good yields.Compounds $\text{2}$ – $\text{12}$ were characterised by n.m.r., m.s., and i.r. spectroscopy and elemental analysis.     

N-Acylated α-aminonitriles and their conversion into 5-aminooxazole, 5(4h)-oxazolone and 4(5h)-imidazolone derivatives

In contrast with the reaction of α-aminonitriles $\text{1}$a, the corresponding $\text{N}$-acylated α-aminonitriles $\text{1}$b-f and oxalyl chloride do not yield pyrazinone derivatives, but 5-aminooxazoles $\text{9}$-$\text{11}$ or 4(5$\text{H}$)-imidazolones $\text{12}$, the latter being converted in some cases into imidazo [2,1-$\text{a}$]isoquinoline-2,5,6(3$\text{H}$)-triones. Reactions of compounds $\text{1}$b-f and ethyl chlorooxoacetate provide evidence for a 5(4$\text{H}$)-iminooxazole intermediate $\text{7}$, which aromatizes to yield 5-aminooxazoles $\text{9}$-$\text{11}$; however, unaromatizable īntermediates of type $\text{7}$ - isolable as 5(4$\text{H}$)y-oxazolones $\text{13}$ after hydrolysis - undergo a catalyzed Dimroth-type rearrangement to give imidazolone derivatives $\text{12}$.     

Biomimetic reactions of germacrenes

The biomimetic reactions of epoxygermacrene-D ($\text{1}$) with basic alumina afforded three new interesting compounds ($\text{4}$, $\text{5}$, and $\text{6}$), two of which ($\text{4}$ and $\text{6}$) have the same carbon skeleton as that of periplanone-A ($\text{3}$), a sexual stimulant for the American cockroach. The remaining one ($\text{5}$) is a bicyclo[3.1.0]hexane derivative, from whch an axisonitrile-3 type compound ($\text{14}$) has been produced. Finally, preisocalamendiol ($\text{2}$) was also converted into $\text{6}$.     

Chemical synthesis of the 5-́half molecule of E.coli tRNA2GLY

A tritriacontanucleotide which has the sequence of the 5$\text{-}\text{?}$half molecule of E.coli glycine tRNA₂, was synthesized by the phosphotriester method involving p-anisidate protection for the 3$\text{-}\text{?}$phosphate ends. Di- and trinucleotide units were prepared from 5$\text{-}\text{?}$dimethoxytrityl-2$\text{-}\text{?}$O-tetrahydrofuranyl-3?-O-(o-chlorophenyl)phosphoryl derivatives of uridine, N-benzoylcytidine, N-benzolyadenosine and N-iso-butyrylguanosine by condensation with 3$\text{,}\text{?}$5$\text{-}\text{?}$unprotected nucleosides followed by phosphorylation to give 3$\text{-}\text{?}$phosphodiester blocks. The 3$\text{-}\text{?}$terminal dimers and trimers were synthesized by using 3$\text{-}\text{?}$(o- chlorophenyl)phosphoro-p-anisidates instead of 3?,5?-unprotected nucleosides. The 3?-phosphodiesters of oligonucleotides with a chain length of larger than 5 were obtained by removal of the 3?-phosphoro-p-anisidate with isoamyl nitrite. The 5$\text{-}\text{?}$dimethoxytrityl group was removed by treatment with zinc bromide under anhydrous conditions. Fragments were designed to use common dimer blocks and to reduce the step for 5$\text{-}\text{?}$deblocking of larger fragments. Finally a 3$\text{-}\text{?}$phosphodiester block with a chain length of 20 was condensed with a 5$\text{-}\text{?}$OH component (tridecanucleotide). The fully protected 33 mer was deblocked and purified by chromatography. The structural integrity of the product was confirmed by mobility shift analysis and complete digestion with RNase T2.     

Synthesis of 3,3,3-trifluoropropionic and 4,4,4-trifluoro-2-ketobutyric acids

Trifluoroethyl cyclohexyl ketone ($\text{4}$) is prepared by acylation of difluoroethylene ($\text{2}$) with cyclohexanecarboxylic acid chloride ($\text{1}$), followed by Cl→F exchange with potassium fluoride in the presence of triethylbenzyl- ammonium chloride. Bayer-Villiger oxidation of ketone ($\text{4}$) with trifluoroperacetic acid gives cyclohexyl trifluoropropionate ($\text{5}$). 3,3,3-trifluoropropionic acid ($\text{6}$) is obtained by treatment of ($\text{5}$) with trimethylsilyl iodide. Condensation of 2,2,2-trifluorodiazoethane ($\text{7}$) with ethyl glyoxylate ($\text{8}$) gives mainly ethyl 4,4,4-trifluoro-2-ketobutyric acid ester ($\text{9}$) which leads after hydrolysis to the corresponding acid ($\text{12}$).     

Cyclic tautomers of tryptamines and tryptophans. V. Formation and reactions of cyclic tautomers of cyclo-L-tryptophanyl-L-proline

Two stereoisomeric cyclic tautomers ($\text{5}$ and $\text{6}$ of cyclo-L-tryptophanyl-L-proline whose stereochemistry was established by x-ray analysis, gave 5- and 6-hydroxytryptophanyl derivatives ($\text{10}$), $\text{11}$, and $\text{19}$) on the hydroxylation with lead tetraacetate in trifluoroacetic acid.     

The Mannich reaction of 9-acetyl- and 9,10-dihydro-9-acetylanthracene. Reduction of the Mannich bases, and stereochemistry of the 9,10-dihydro compound

The Mannich derivatives ($\text{2}$ and $\text{5}$) of 9-acetyl-9,10-dihydroanthracene ($\text{4}$) with amines of different sizes were prepared for study of their biological effects. It was found that formation of the normal Mannich product in acetic acid was accompanied by formation of a secondary Mannich product containing a methylidene group ($\text{3}$ and $\text{6}$). Reduction of compounds $\text{5}$ with NaBH₄ gave aminoalcohols ($\text{10}$), and amino-olefins ($\text{11}$) were prepared from these by elimination. The catalytic reduction of compounds $\text{2}$ on Pd/C, Raney Ni and Adams catalysts was studied under acidic and basic conditions. In acidic media on Pd/C, the 9,10-dihydro compounds ($\text{5}$) were formed; under basic conditions, on all three catalysts the hydrogenation led to deamination. However, for “steric hindrance” reasons the keto group was not reduced in any of the cases. In compounds $\text{5}$, the literature data and the H-NMR spectra indicate that the orientation of the 9-substituent is pseudoaxial     

Cyclopropylidene formation in 7,7-dibromonorcar-3-ene oxides. Synthesis of derivatives of homobenzvalene oxide.

Treatment of $\text{4b}$, $\text{4c}$, and $\text{4d}$ with methyllithium affords $\text{5b}$, $\text{6b}$; $\text{5c}$, $\text{6c}$; and $\text{5d}$ respectively in serviceable yields $\text{via}$ carbenoid cyclization.     

Conformationally selective transannular cyclizations of humulene 9,10-epoxide. Synthesis of the two skeletally different cyclohumulanoids: dl-bicyclohumulenone and dl-africanol

Two cyclohumulanoids, dl-bicyclohumulenone ($\text{4}$) and dl-africanol ($\text{7}$ were synthesized through newly developed conformationally selective transannular cyclization of humulene 9,10-epoxide ($\text{2}$). The epoxide $\text{2}$ was converted to a bicyclohumulenediol diacetate $\text{3a}$ in 70% yield by treatment with BF₃·OEt₂-Ac₂O, while treatment of $\text{2}$ with trimethylsilyl trifluoromethansulfonate gave an africen-10-ol ($\text{5}$a and $\text{5}$b) in 80% yield. The two intermediates $\text{3a}$ and $\text{5a}$ furnished the natural products $\text{4}$ and $\text{7}$ in 30 and 8 % yield from $\text{2}$ respectively.     

Total synthesis of a macrocyclic spermidine alkaloid,codonocarpine

Total synthesis of codonocarpine ($\text{5}$) and its regio-isomer ($\text{1}$$\text{5}$) utilizing a new cyclization procedure is described.     

Synthesis and absolute configuration of +-lineatin,the pheromone of trypodendronlineatum

A new synthesis of (±), (+)- and (-)-lineatin (3,3,7-trimethyl-2, 9-dioxatricyclo [3.3.1.0^4,7] nonane, $\text{1}$) was achieved. The stereochemistry of (+)-lineatin was established as 1$\text{R}$, 4$\text{S}$, 5$\text{R}$, 7$\text{R}$ by an X-ray crystallographic analysis of an intermediate $\text{1}$$\text{5}$.