Synthesis of thieno[2′,3′(3′,4′ or 3′,2′):5,6]azepino[2,1-a]isoindolediones from N-Thienyl-2(3)-ylmethylphthalimides

Reduction of N-thienybnethylphthalimides 5a-e followed by the Wittig reaction gave the substituted acetic acids 8a-e . Their corresponding acyl chlorides where cyclized in the presence of aluminium trichloride to furnish the cyclic ketones 9a-e . Treatment of these ketones with bromine followed by triethylamine, or with selenium dioxide led to the thienoazepinoisoindolediones 1a-e .     

Structures de deux β-énaminoesters cycliques: l'α-(tétrahydropyrrolidinylidéne-2) acétate d'éthyle et l'α-(hexahydroazepinylidéne-2) acétate d'éthyle

The structure of ethyl α-(tetrahydro-2-pyrrolidinylidene) and α-(hexahydro-2-azepinylidene) acetates has been determined from the X-ray crystallographic analysis. The results show that, in a solid state, these compounds exist as β-enaminoesters which have a Z configuration. They also show the presence of intra and intermolecular hydrogen bonding.     

Synthesis of 1‐acyl‐2‐oxo‐3‐pyrrolidinecarbonitriles by the reaction of 2‐acylamino‐4,5‐dihydro‐3‐furancarbonitriles with sodium iodide

The reaction of 2‐acylamino‐4,5‐dihydro‐3‐furancarbonitriles 1 with sodium iodide in N,N‐dimethyl‐formamide gave the corresponding 1‐acyl‐2‐oxo‐3‐pyrrolidinecarbonitriles 2 in good yields. Successive treatment of 1 with titanium(IV) chloride and potassium carbonate resulted in the formation of N‐acyl‐1‐cyanocyclopropanecarboxamides 4 . The same compounds 2 were also obtained by treatment of 4 with sodium iodide. The starting compounds 1 were synthesized by the reaction of 2‐amino‐4,5‐dihydro‐3‐furan‐carbonitrile with acyl chlorides in pyridine.     

Alkylation des β-énaminoesters cycliques: Relation entre la taille et la réactivité

Cyclic β-enaminoesters are C-alkylated. Experimental conditions are different according to the ring size, mild with large rings and drastic with small rings where the conjugation is more important. Physical data allow an explanation between the ring size of β-enaminoesters and their reactivity.     

Preparation and Transmetallation of a Triphenylstannyl β-D-Glucopyranoside: A highly stereoselective route to β-D-C-glycosides via glycosyl dianions

The triphenylstannyl β-D -glucopyranoside 4 was synthesized in one step from the 1,2-anhydro-α-D -glucopyranose 3 with (triphenylstannyl)lithium (Scheme 1). Transmetallation of 4 with excess BuLi, followed by quenching the dianion 7 with CD₃OD gave (1S)-1,5-anhydro-3,4,6-tri-O-benzyl-[1-²H]-D - glucitol ( 8 ) in 81% yield (Scheme 2). Trapping of 7 with benzaldehyde, isobutyraldehyde, or acroleine gave the expected β-D -configurated products 11, 12 , and 13 in good yields. Preparation of C-acyl glycosides from acid chlorides, such as acetyl or benzoyl chloride was not practicable, but addition of benzonitrile to 7 yielded 84% of the benzoylated product 14 . Treatment of 7 with MeI led to 15 (30%) along with 40% of 18 , C-alkylation being accompanied by halogen-metal exchange. Prior addition of lithium 2-thienylcyanocuprate increased the yield of 15 to 50% and using dimethyl sulfate instead of MeI led to 77% of 15 . No α-D -anomers could be detected, except with allyl bromide as the electrophile, which yielded in a 1:1 mixture of the anomers 16 and 17 .     

PREFERRED CARBON VS. NITROGEN SULFONYLATION ON β-CARBOLINES

Treatment of 1-methyl-3,4-dihydro-β-carboline with sulfonyl chlorides provided C-acylated products, which preferred vs. indole-N-acylated derivatives.     

Synthesen von 2-Pyronen aus α, β-ungesättigten Säurechloriden und tertiären Aminen

A new synthesis of 2-pyrones has been developed. Two molecules of α, β-unsaturated acid chlorides ( 8 , 12 and 18 ) condense, with loss of two molecules hydrogen chloride, to pairs of substituted 2-pyrones ( 9 and 10 , 13 and 14 , 19 and 20 ) when treated with triethyl amine in chloroform or methylene chloride at room temperature. In the case of 18 , two additional products were obtained, namely the resorcinol derivative 21 and traces of the 1, 3-cyclobutanedione derivative 22 . Under the same conditions the α, β-unsaturated acid chlorides 8 , 15 , 18 and 41 were condensed with trichloroacetyl chloride to give 6-trichloromethyl-2-pyrones ( 42 , 43 , 44 and 46 ). These 2-pyrones are valuable intermediates for the synthesis of 6-carboxy-2-pyrones and 6-methyl-2-pyrones. A methyl group in β-position of the α, β-unsaturated acid chloride appears to be essential for the described condensations, for the acid chlorides 16 and 17 did not yield defined products and the acid chloride 40 reacted with trichloroacetyl chloride in a very low yield. It is considered that the described reactions proceed via the 1, 4-addition of an acid chloride to a vinyl ketene or through the acylation of an intermediate anion by an acyl derivative as outlined in reaction scheme 1. The structures of the 2-pyrones were confirmed by their spectroscopic properties, summarized in table 3, and by some of their chemical transformations.     

Studies on pyrrolidones. Synthesis and N-alkylation of β-enaminoesters derived from pyroglutamic acid

The condensation of iminoether 7 , derived from pyroglutamic acid (4) , with active methylene reagents such as Meldrum's acid or methyl cyanoacetate, lead to β-enaminoesters 2 . Solid-liquid phase transfer N-alkylation of these compounds is described.     

β-substitution of simple pyrroles in metal-assisted reactions with kthyl diazoacetate

The reaction of N-methylpyrrole with ethyl diazoaeelate, assisted by copper bronze or copper powder, as described previously by a number of researchers, produces not only ethyl N-melhylpyrrole-2-acetate ( 3 ), but also heretofore unrecognized ethyl N-melhylpyrrole-3-acetate ( 4 ); the ratio of 3/4 was ca. 84/16. Promotion of this reaction with other transition metal catalysts furnished differing proportions of 3 and 4 , indicating that the metal is intimately involved in the substitution process. Certain agents, notably cupric fluoborate, cupric trifluoromelhylsullonate, palladous acetate, and (π-C₃H₅ PdCI)₂, were particularly active in this reaction and gave β-substi-lulion to the extent of ca. 35-45%. Other pyrrole compounds, namely 1,2-dimethylpyrrole, 1,3-dimethylpyrrole, 3 , and pyrrole, were also found (in preliminary work) to undergo β-substi-tution in their reaction with copper carbenoids.     

Sur la synthèse de chloro-3 indolinones a partir de β-nitrostyrènes diversement substitués

When treated with acetyl chloride and ferric chloride in methylene chloride, at 0°, monosubstituted β-nitrostyrene derivatives such as 2,3 or 4-methyl, -chloro or -fluoro and 3-nitro-β-nitrostyrenes cyclize into the new corresponding 3-chloro-1,3-dihydro-2H-indol-2-one. Reaction with other metal chlorides such as aluminum chloride and titanium tetrachloride does not lead to these heterocyclic derivatives but only produces N-acetyl-N-hydroxy-α-chlorobenzeneacetamides and/or N-(acetyloxy)-α-chlorobenzeneethanimidoyl chlorides.     

SN1‐Type Substitution Reactions of N‐Protected β‐Hydroxytyrosine Esters: Stereoselective Synthesis of β‐Aryl and β‐Alkyltyrosines

The title compounds were prepared by aldol reaction of anisaldehyde and the respective N,N‐dibenzyl glycinates. Deprotection of the nitrogen atom with Pearlman’s catalyst delivered the unprotected β‐hydroxytyrosine esters, which were further N‐protected as N,N‐phthaloyl (Phth) and N‐fluorenylmethylcarbonyloxy (Fmoc) derivatives. The Friedel–Crafts reaction with various arenes was studied employing these alcohols as electrophiles. It turned out that the facial diastereoselectivitiy depends on the nitrogen protecting group and on the ester group. The unprotected substrates (NH₂) gave preferentially syn‐products but the anti‐selectivity increased when going from NHFmoc over NPhth to NBn₂. If the ester substituent was varied the syn‐preference increased in the order Me <Et <iPr. The reactions were shown to be fully stereoconvergent and proceeded under kinetic product control. A model is suggested to explain the facial diastereoselectivity based on a conformationally locked benzylic cation intermediate. The reactions are preparatively useful for the N‐unprotected isopropyl ester, which gave Friedel–Crafts alkylation products with good syn‐selectivity (anti/syn=21:79 to 7:93), and for the N,N‐dibenzyl‐protected methyl ester, which led preferentially to anti‐products (anti/syn=80:20 to >95:5). Upon acetylation of the latter compound to the respective acetate, Bi(OTf)₃‐catalyzed alkylation reactions became possible, in which silyl enol ethers served as nucleophiles. The respective alkylation products were obtained in high yield and with excellent anti‐selectivitiy (anti/syn≥95:5).     

Une nouvelle synthese de β-enaminoindanones

β-Enaminoindanones can abe conveniently prepared in a single stage by treatment of ethyl o-chloromethylbenzoate with various cyclic or acyaclic β-enaminoesters in the presence of sodium hydride in toluene.     

Preparation of β2‐Amino Acid Derivatives (β2hThr, β2hTrp, β2hMet, β2hPro, β2hLys,Pyrrolidine‐3‐carboxylic Acid) by Using DIOZ as Chiral Auxiliary

The title compounds were prepared from valine‐derived N‐acylated oxazolidin‐2‐ones, 1 – 3, 7, 9 , by highly diastereoselective (≥ 90%) Mannich reaction (→ 4 – 6 ; Scheme 1) or aldol addition (→ 8 and 10 ; Scheme 2) of the corresponding Ti‐ or B‐enolates as the key step. The superiority of the ‘5,5‐diphenyl‐4‐isopropyl‐1,3‐oxazolidin‐2‐one’ (DIOZ) was demonstrated, once more, in these reactions and in subsequent transformations leading to various t‐Bu‐, Boc‐, Fmoc‐, and Cbz‐protected β²‐homoamino acid derivatives 11 – 23 (Schemes 3–6). The use of ω‐bromo‐acyl‐oxazolidinones 1 – 3 as starting materials turned out to open access to a variety of enantiomerically pure trifunctional and cyclic carboxylic‐acid derivatives.     

Preparation of 1,5-disubstituted 4-sulfonylpyrazoles, β-cyano-β-sulfonylenamines and 5-substituted 4-sulfonylisoxazoles from β-keto-β-sulfonylenamines

Reaction of β-keto-β-sulfonylenamines 1a,b with N-substituted hydrazines gave 1,5-disubstituted 4-sulfonylpyrazoles 2a-h in moderate yields, which were ring-opened on treatment with n-butyllithium to afford β-cyano-β-sulfonylenamines ( 3a,b,d-f ). 5-Substitued 4-sulfonylisoxazoles 6a-d were also prepared from 1a-d and hydroxylamine.     

Addition de dérivés maloniques sur des β-énaminones cycliques

The addition of activated acctonitriles 6 on cyclic and benzylic β-enaminoketones 5 under basic conditions (sodium ethoxide or trition B) have been investigated. This reaction leads exclusively to the formation of α-pyrones 8 and never to the pyridine ring. The strucutre of the newly synthesized α-pyrone derivatives 8 are supported by nmr and ir spectral data.     

A Mild Isomerization Reaction for β,γ‐Unsaturated Ketone to α,β‐Unsaturated Ketone

A series of β,γ‐unsaturated ketones were isomerized to their corresponding α,β‐unsaturated ketones by the introduction of DABCO in iPrOH at room temperature. The endo‐cyclic double bond (β,γ‐position) on ketone was rearranged to exo‐cyclic double bond (α,β‐position) under the reaction conditions.     

Synthese von diastereo- und enantio-selektiv deuterierten β,ε-, β,β-, β,γ- und γ,γ-Carotinen

Synthesis of Diastereo- and Enantioselectively Deuterated β,ε-, β,β-, β,γ- and γ,γ-Carotenes We describe the synthesis of (1′R, 6′S)-[16′, 16′, 16′-²H₃]-β, εcarotene, (1R, 1′R)-[16, 16, 16, 16′, 16′, 16′-²H₆]-β, β-carotene, (1′R, 6′S)-[16′, 16′, 16′-²H₃]-γ, γ-carotene and (1R, 1′R, 6S, 6′S)-[16, 16, 16, 16′, 16′, 16′-²H₆]-γ, γ-carotene by a multistep degradation of (4R, 5S, 10S)-[18, 18, 18-²H₃]-didehydroabietane to optically active deuterated β-, ε- and γ-C₁₁-endgroups and subsequent building up according to schemes \documentclass{article}\pagestyle{empty}\begin{document}${\rm C}_{11} \to {\rm C}_{14}^{C_{\mathop {26}\limits_ \to }} \to {\rm C}_{40} $\end{document} and C₁₁ → C₁₄; C₁₄+C₁₂+C₁₄→C₄₀. NMR.- and chiroptical data allow the identification of the geminal methyl groups in all these compounds. The optical activity of all-(E)-[²H₆]-β,β-carotene, which is solely due to the isotopically different substituent not directly attached to the chiral centres, is demonstrated by a significant CD.-effect at low temperature. Therefore, if an enzymatic cyclization of [17, 17, 17, 17′, 17′, 17′-²H₆]lycopine can be achieved, the steric course of the cyclization step would be derivable from NMR.- and CD.-spectra with very small samples of the isolated cyclic carotenes. A general scheme for the possible course of the cyclization steps is presented.     

A New General Approach to Enantiomerically Pure Cyclic and Open-Chain (R)- and (S)-α,α-Disubstituted α-Amino Acids

A wide range of cyclic and open-chain α,α-disubstituted α-amino acids 1a-p were prepared. The racemic N-acylated α,α-disubstituted amino acids were resolved by coupling to chiral amines 15-18 derived from (S)-phenylalanine to form diastereoisomers 19/20 or 21/22 that could be separated by crystallization and/or flash chromatography on silica gel (Scheme 3). Selective cleavage via the 1,3-oxazol-5(4H)-ones 10a-p gave the corresponding optically pure α,α-disubstituted amino-acid derivatives 11 or 12 in high yield (Scheme 3). The absolute configurations of the α,α-disubstituted amino acids were determined from X-ray structures of the diastereoisomers 20, 21g′, 22d .     

α-Methylidene- and α-Alkylidene-β-lactams from Nonproteinogenic Amino Acids

Treatment of methyl 2-(1-hydroxyalkyl)prop-2-enoates 1 with conc. HBr solution afforded methyl (Z)-2-(bromomethyl)alk-2-enoates 2 , which were transformed regioselectively into N-substituted methyl (E)-2- (aminomethyl)alk-2-enoates 3 (S_N2 reaction) and into N-substituted methyl 2-(1-aminoalkyl)prop-2-enoates 4 (S_N2′ reaction). Regiocontrol of nucleophilic attack by amine was accomplished simply by choice of solvent, the S_N2 reaction occurring in MeCN and the S_N2′ reaction in petroleum ether. Hydrolysis and lactamization afforded β-lactams 7 and 8 , containing an exocyciic alkylidene and methylidene group at C(3), respectively.     

Enantioselective Synthesis of α-N-Alkylamino Acids via Sultam-Directed ‘Enolate’ Hydroxyamination

Crystalline N-hydroxyamino-acid derivatives 4 , readily available from non-chiral acyl chlorides 2 and sultams 1 , were treated with aldehydes in the presence of NaBH₃CN to give N-alkylhydroxylamines 5 . N,O-Hydrogenolysis of 5 and saponification of 6 furnished (S)-N-alkylamino acids 7 in high optical purity. Similarly, (R)-N-alkylamino acids 12 were obtained from the antipodal acylsultams 8 .