An efficient formal synthesis of (S)-dapoxetine from enantiopure 3-hydroxy azetidin-2-one

An efficient formal synthesis of S-(+) dapoxetine starting from 3-hydroxy azetidin-2-one is described. The intermediate (S)-3-(dimethyl amino)-3-phenylpropan-1-ol was synthesized in enantiopure form starting with 3-hydroxy azetidin-2-one in seven steps.     

Synthesis of (r)- and (s)-1-formyl-6,7,8,9-tetrahydro- N,N-(dipropyl)-3H-benz[e]indol-8-amines: Potent and orally active 5-ht1a receptor agonists

An efficient synthesis of the potent and orally active 5-HT_1A agonists, (R)-(+)- and (S)-(-)-1-formyl-6,7,8,9-tetrahydro-N,N-dipropyl-3H-benz[e]indol-8-amines 1a and 1b , is described. This synthesis was accomplished in twelve steps from commercially available 1,5,6,7-tetrahydro-4H-indol-4-one ( 5 ). The key step involved a regio-controlled Friedel-Crafts acylation of 1-(p-toluenesulfonyl)indol-4-acetyl chloride with ethylene to yield a versatile synthon, 3-(p-toluenesulfonyl)-6,7,8,9-tetrahydro-3H-benz[e]indol-8-one ( 10 ). Subsequent coupling of this ketone with chiral α-methylbenzylamine under reductive amination conditions yielded a mixture of diastereomers. These diastereomers were efficiently separated by either chromatography or fractional recrystallization of the derived hydrochloride salts. Debenzylation of the pure diastereomers was followed by alkylation and formylation to yield (R)-(+)- and (S)-(-)-enantiomers 1a and 1b with >99% purity.     

Reactions of 1,3,5-triazinylnitroformaldoximes 3*. Interaction of 1,3,5-triazinylnitroformaldoximes with malonic acid esters

The reaction of 6-R-4-methoxy-1,3,5-triazin-2-ylnitroformaldoximes with dimethyl malonate gives the zwitterionic 4-methoxycarbonyl-3-(4-R-6-methoxy-1,3,5-triazin-2-yl)-4,5-dihydroisoxazol-5-ones. X-ray structural analysis has been carried out on the zwitterionic 4-methoxycarbonyl-3-(4-methoxy-6-piperidino-1,3,5-triazin-2-yl)-4,5-dihydroisoxazol-5-one.     

Optically active imidazole-containing polymers

In order to investigate the stereospecificity of enzyme-catalyzed reactions, an optically active copolymer of 4(5)-vinylimidazole and 2,5(S)-dimethyl-1-hepten-3-one was synthesized, and its effects on the solvolytic rates, in ethanol-water, of the p-nitrophenyl and 4-carboxy-2-nitrophenyl esters of 3(R)- and 3(S)-methylpentanoic acid and of the commercially available N-carbobenzoxy-(R)- and (S)-phenylalanine p-nitrophenyl esters were investigated. The optically active comonomer was prepared by thermal decomposition of solid (+)-1-piperidino-2,5(S)-dimethylheptan-3-one hydrochloride, which was obtained from the reaction of 2(S)-methylbutyllithium with 3-piperidino-2-methylpropionitrile. The 3(R)-methylpentanoic acid was prepared in 92% optical purity from L -alloisoleucine via diazotization in concentrated hydrobromic acid and subsequent reductive debromination with zinc amalgam in dilute hydrochloric acid. In the optically active copolymer-catalyzed solvolyses of the optically active esters performed at pH values of 6–8 no significant differences between the solvolytic rates of (R) and (S) isomers of substrates were observed. Poly-L -histidine was also employed as a catalyst for the solvolyses of these substrates. At pH 6.0 in ethanol–water the latter catalyst also failed to exhibit specificity towards (R) and (S) substrates.     

Synthesis of (+)-1,3:2,5-dianhydroviburnitol ((+)-(1R,2R,3S,5R,6S)-4,7-dioxatricyclo[3.2.1.03,6]octan-2-ol)

Epoxidation of (?)-(1R,2R,4R)-2-endo-cyano-7-oxabicyclo[2.2.1]hept-5-en-2-exo-yl acetate ((?)-5) followed by saponification afforded (+)-(1R,4R,5R,6R)-5,6-exo-epoxy-7-oxabicyclo[2.2.1]heptan-2-one ((+)-7). Reduction of (+)-7 with diisobutylaluminium hydride (DIBAH) gave (+)-1,3:2,5-dianhydroviburnitol ( = (+)-(1R,2R,3S,4R,6S)-4,7-dioxatricyclo[3.2.1.0^3,6]octan-2-ol; (+)-3). Hydride reductions of (±)-7 were less exo-face selective than reductions of bicyclo[2.2.1]heptan-2-one and its derivatives with NaBH₄, AlH₃, and LiAlH₄ probably because of smaller steric hindrance to endo-face hydride attack when C(5) and C(6) of the bicyclo-[2.2.1]heptan-2-one are part of an exo oxirane ring.     

2-Polyfluoroalkylchromones. 8. 2-Trifluoromethyl- and 6-nitro-2-trifluoromethylchromones in reactions with amines

The reactions of 6-nitro-2-trifluoromethylchromone with benzylamine, ethanolamine, and aniline afforded 3-benzyl(2-hydroxyethyl,phenyl)amino-4,4,4-trifluoro-1-(2-hydroxy-5-nitrophenyl)but-2-en-1-ones, respectively, whereas the reactions with ethylenediamine and diethylenetriamine gave rise to 5-(2-hydroxy-5-nitrophenyl)-7-trifluoromethyl-2,3-dihydro-1H-1,4-diazepine and 5-(2-hydroxy-5-nitrophenyl)-7-trifluoromethyl-1,4,8-triazabicyclo[5.3.0]dec-4-ene, respectively. Morpholine added at the double bond of 2-trifluoromethyl- and 6-nitro-2-trifluoromethylchromones to form 2-morpholino-2-trifluoromethylchroman-4-one and its 6-nitro-substituted analog, respectively, whereas piperidine reacted only with 2-trifluoromethylchromone to yield 2-piperidino-2-trifluoromethylchroman-4-one.     

Carbonylation of (+)-2-carene induced by iron-pentacarbonyl.

(+)-2-carene heated neat with iron pentacarbonyl leads to α-phellandrene-Fe(CO)₃ complex ( ～15 % ), p. cymene ( ～15 % ), (-)-(1S)-3,8,8-trimethylbicyclo (4.1.1) oct-3-ene-7-one ( ～50 % ) and (+)-(1S,7S)-3,8,8-trimethylbicyclo (4.1.1.) oct-3-ene-7-ol ( ～20 % ).     

2-Amino-4-dimethylamino-1-thia-3-azabutadienes as Precursors of Thiazoles

The reaction of 2-amino-4-dimethylamino-1-thia-3-azabutadienes 1 with f -bromoketones gave rise to 2-aminothiazoles 2 together with 2-( N , N -dimethylaminomethylenamino)thiazoles 3 . Competitive mechanisms are described. Furthermore, reaction of diene 1a with methyl f -bromoacetate or hydroxylamine- O -sulfonic acid yielded respectively 2-( N , N -dimethylaminomethylenamino)thiazolin-4-one 4 and 5-amino-1,2,4-thiadiazole 5 .     

Enantioselective synthesis of the bisabolane sesquiterpene (+)-1-hydroxy-1,3,5-bisabolatrien-10-one and revision of its absolute configuration

The enantioselective synthesis of (S)-1-hydroxy-1,3,5-bisabolatrien-10-one 1 is here described. This sesquiterpene was prepared using (S)-3-(2-methoxy-4-methyl-phenyl)butan-1-ol as a chiral building block. Two different pathways were employed and both turned out to be high yielding, affording 1 in good chemical purity and without any racemization of the existing stereocenter. The spectroscopic data of the synthetic (S)-1 were in very good agreement with those reported for the natural compound, which was extracted from Juniperus formosana heartwood and from the leaves of J. chinensis. The positive sign of the measured optical rotation value of synthetic (S)-1 allows the unambiguous assignment of the absolute configuration of (+)-1 as the (S)-enantiomer. This finding corrects the previous configuration determination which indicated the opposite result. At last, since even (R)-3-(2-methoxy-4-methyl-phenyl)butan-1-ol is preparable in high enantiomer purity by mean of a different biocatalytic process, the formal synthesis of natural (R)-1 was also accomplished.     

Total synthesis and structural elucidation of ent-micropyrone and (+)-ascosalipyrone

The total synthesis of 6-[(1S,3S)-1,3-dimethyl-2-oxopentyl]-4-hydroxy-3,5-dimethyl-2H-pyran-2-one (22), the enantiomer of the natural product micropyrone (1), was achieved in 9 linear steps (10% overall yield), from Evans auxiliary (R)-12 with key coupling of the dianion of dione 17 and aldehyde 11. Formation of the pyrone ring and subsequent oxidation at C7 was achieved without epimerization of the sensitive position α to both the pyrone ring and the carbonyl. The same sequence using the alternate dione 24 achieved the total synthesis of 6-[(1S,3S)-1,3-dimethyl-2-oxopentyl]-4-hydroxy-3-methyl-2H-pyran-2-one (28), the (+)-enantiomer of the natural product, ascosalipyrone (2). In both cases diastereomeric aldehydes 11 and 16 were taken through the synthetic sequence to give two possible diastereomers of the natural products. Comparison of the (1)H and (13)C NMR data for the synthetic isomers with that reported for the natural products determined their relative stereochemistry. Comparison of the optical rotation obtained for 22 established it to be the enantiomer of micropyrone.     

Synthesis of optically active forms of seudenol,the pheromone of douglas fir beetle

(R)-(+)-Seudenol (3-methylcyclohex-2-en-1-ol) and its antipode were synthesized from optically active forms of 3-iodocyclohex-2-en-1-ol by treatment with Me₂CuLi. Their absolute configurations were determined by converting (+)-3-iodocyclohex-2-en-1-ol to the known (R)-(+)-cyclohex-2-en-1-ol.     

On the First Marine Stigmastane Sterols and Sterones Having a 24,25-Double Bond. Isolation from the Sponge Stelletta sp. of Deep Coral Sea

The sponge Stelletta sp. (Astrophorida, Stellettidae), collected at ?700 m in the Coral Sea, is shown to contain sterones and sterols of the stigmastane type with a C(24)?C(25) bond for which there is no precedent in the sea. Structure elucidation of the second abundant of these steroids, stigmasta-4,24(25)-dien-3-one ((+)- 1 ), is based on 1D and 2D NMR spectra and chemical transformation to acetate (?)- 5 . Stigmasta-4,24(25)-diene-3,6-dione ((?)- 3 ), present in trace amounts in the sponge, was obtained in sufficient quantity for NMR study by oxidation of the also present, inseparable, and abundant 4:1 mixture of stigmasta-5,24(25)-dien-3β-ol ( 6 ) and its 5,6-dihydro derivative 7 (Scheme 1). This oxidation also afforded the ketone analogues (+)- 8 and (+)- 9 , which could be separated, thus making structure elucidation possible. The 6β-hydroxystigmasta-4,24(25)-dien-3-one ((+)- 4 ), also present in trace amounts in the sponge, was obtained in sufficient amount for NMR study, together with its C(6) epimer (+)- 11 , by hydroperoxidation of (+)- 8 followed by deoxygenation (Scheme 2). The last trace steroid of the sponge, stigmasta-4,6,24(25)-trien-3-one ((?)- 2 ), was structurally elucidated using limited NMR data and comparison with the other stigmastanes. These stigmastanes, as the only steroids of this sponge, are likely to function as stabilizers of its cell walls; their phytosteroid structure, for a sponge which lives in the dark of deep waters, suggest origin through a complex food chain, possibly followed by bioelaboration in the sponge.     

Stereoselective synthesis of new (+)-1-{(1R,3R,6S)-4,7,7-trimethylbicyclo[4.1.0]hept-4-en-3-yl}ethan-1-one derivatives

A procedure was developed for the stereoselective synthesis of aminated derivatives of (+)-1-{(1R,3R,6S)-4,7,7-trimethylbicyclo[4.1.0]hept-4-en-3-yl}ethan-1-one. The configuration of the side-chain chiral center in (+)-1-{(1R,3R,6S)-4,7,7-trimethylbicyclo[4.1.0]hept-4-en-3-yl}ethan-1-ol was determined by X-ray analysis. Diketene and Meldrum’s acid were proposed as initial compounds for the synthesis of, respectively, 3-oxobutanoic and malonic acid esters having a 1-ethyl-4,7,7-trimethylbicyclo[4.1.0]hept-4-ene fragment.     

Efficient synthesis of NK(1) receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation

An efficient stereoselective synthesis of the orally active NK(1) receptor antagonist Aprepitant is described. A direct condensation of N-benzyl ethanolamine with glyoxylic acid yielded a 2-hydroxy-1,4-oxazin-3-one which was activated as the corresponding trifluoroacetate. A Lewis acid mediated coupling with enantiopure (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol afforded a 1:1 mixture of acetal diastereomers which was converted into a single isomer via a novel crystallization-induced asymmetric transformation. The resulting 1,4-oxazin-3-one was converted via a unique and highly stereoselective one-pot process to the desired alpha-(fluorophenyl)morpholine derivative. Interesting and unexpected [1,2]-Wittig and [1,3]-sigmatropic rearrangements were identified during the optimization of these key steps. In the final step, a triazolinone side chain was appended to the morpholine core. The targeted clinical candidate was thus obtained in 55% overall yield over the longest linear sequence.     

Captodative Formyl- and Acyl(amino)alkenes Containing a Terminal Double Bond or a Weakly Basic Tertiary Amino Group

Piperidine reacts with 3-bromo-3-buten-2-one to give a mixture of 3,4-dipiperidinobutan-2-one and 3-piperidino-3-buten-2-one. The latter is also formed by the action of a strong base (Et₃N in THF or MeONa in MeOH) on the dipiperidino derivative. Analogous reaction of 2-bromo-3-phenylpropenal with N-methylaniline affords 2-[methyl(phenyl)amino]-3-phenylpropenal which is the first captodative formyl(amino)alkene having a weakly basic tertiary amino group.     

A one-pot reaction of (chlorocarbonyl) phenyl ketene with β-ketoamides and thiochromen-2-one

Readily available (chlorocarbonyl)phenyl ketene and a varied set of β-ketoamides were reacted in a one-step procedure to produce 2-pyrone derivatives. β-Ketoamide derivatives are versatile intermediates for the synthesis of heterocyclic compounds. For instance, 1-morpholino-3-phenyl-1,3-propanedione, 1-phenyl-3-piperidino-1,3-propanedione, 1-phenyl-3-pyrrolidino-1,3-propanedione, 1-piperidino-1,3-butanedione, 1-morpholino-2-phenyl ethanone were used in these reactions to produce 2-pyrone derivatives. In addition, the preparation of 4-hydroxy-3-phenylthiochromeno[4,3-b]pyran-2,5-dione derivatives and 4-hydroxy-7-methyl-3-phenyl pyrano[3,2-c]chromeno-2,5-dione were described. For the synthesis of these compounds 4-hydroxy-2H-thiochromen-2-ones and 4-hydroxy-8-methyl-2H-chromen-2-one were reacted with (chlorocarbonyl)phenyl ketene and the final products were isolated in good yields.     

Formation of pyrimidin-2-ylcyanamide and 2-aminopyrimidine in the reaction of aniline derivatives with cyanamide and dimethylamino-1-pyridyl-2-propenone

Substituted o- and p-nitroanilines and m-benzylaminoanilines in the reaction with cyanamide failed to yield the corresponding arylguanidines, and in the presence of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one formed 4-pyridyl-substituted pyrimidin-2-ylcyanamides and 2-amino-pyrimidines.     

The absolute configuration of (+)- and (−)-1-phenylundec-4-yn-3-ols. Synthesis of (R)-4-dodecanolide,a component of the defensive secretion of rove beetle Bledius mandibullaris

Hydrogenation of the triple bond of (+)-1-phenylundec-4-yn-3-ol (obtained from (+)-[η⁶-(3-hydroxyundec-4-yn-1-yl)benzene]chromium tricarbonyl) with the NaBH₄-NiCl₂·6H₂O reagent system in MeOH leads to (?)-1-phenylundecan-3-ol. Ozonolysis of the phenyl ring in the corresponding acetate gives (R)-(?)-acetoxydodecanoic acid, lactonization of which leads to the known (R)-(+)-4-dodecanolide. The starting (+)-1-phenylundec-4-yn-3-ol was thus shown to have the S-configuration.     

Derivatives of imidazo-<Emphasis Type="Italic">sym</Emphasis>-triazine

2-Dimethylamino-4,6,7,8-tetrahydroimidazo[1,2-a]-sym-triazin-4-one synthesized by us previously is converted by the action of aryl isocyanates and arenesulfonyl chlorides into the corresponding derivatives of urea and N-arenesulfonyl-substituted imidazo-sym-triazinones. It was shown that 6-(2-chloroethoxy)-2-dimethylamino-4-(methoxycarbonylmethylamino)-sym-triazine is converted by thermolysis into 2-dimethylamino-8-methoxycarbonylmethyl-4,6,7,8-tetrahydroimidazo[1,2-a]-1,3,5-triazin-4-one, which is also obtained by the action of methyl bromoacetate on the imidazo-sym-triazinone. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1230–1235, August, 2008.     

Microbiological transformations—XII: Microbiological reduction of racemic 1-(2',2',3'-trimethyl-cyclopent-3'-en-1'-yl)propan-2-one and 1-(2',2',3'-trimethyl-cyclopent-3'-en-1'-yl)butan-2-one by rhodotorula mucilaginosa

The microbiological reduction of (±)-l-(2',2',3'-trimethylcyclopent-3'-en-l'-yl)-propan-2-one (4) and (±)-1-(2',2',3'-trimethylcyclopent-3'-en-l'-yl)-butan-2-one (5) by Rhodotorula mucilaginosa was investigated. Both enantiomers of 4 are reduced stereospecifically to corresponding alcohols; (+)-(2S, l'R)-(2',2',3'-trimethylcyclopent-3'-en-l'-yl)-propan-2-ol (6) and (-)-(2S,l'S)-(2',2',3'-trimethylcyclopent-3'-en-l'-yl)-propan-2-ol (7). p ]The substrate selectivity in the reduction of 5 was observed: R enantiomer of 5 yields stereospecifically (+)-(2S,1'R)-(2',2',3'-trimethylcyclopent-3'-en-l'-yl)-butan-2-ol (8) while S(-)5 remains unchanged.