β-(5-Pyrimidinyl)ethanolamines

2,4-Diphenyl-5-pyrimidinyl methyl ketone ( 8 ) and 2-phenyl-4-methyl-5-pyrimidinyl phenyl ketone ( 12 ) were prepared by condensation of benzamidine with 2-ethoxymethyl-1-phenyl-1,3-butanedione ( 10 ). Their structures were elucidated by the nmr spectra of their derivative alcohols 13 and 14 , respectively. The ketone 8 was converted by way of the bromoketone 15 to 2-[1-methylethylamino]-1-[2,4-diphenyl-5-pyrimidinyl]ethanol hydrochloride ( 17 ) and 2-amino-1-[2,4-diphenyl-5-pyrimidinyl]ethanol hydrochloride ( 20 ). Pharmacologic testing indicated that 17 and 20 did not possess either antihypertensive or beta adrenergic blocking activities.     

A new strategy for the enantioselective synthesis of carba-prostacyclin analogues based on organocopper conjugate addition to a bicyclic azoene and its application to the synthesis of 13,14-dinor-inter-p-phenylene carbacyclin

An enantioselective synthesis of E/Z-13,14-dinor-inter-p-phenylene carbacyclin (E/Z-2d) by a new strategy has been realized that holds the prospect of serving as a general route for carba-prostacyclin analogues. The key intermediate in this synthesis is the bicyclic azoene Ts-9, and the key step is the regio- and stereoselective conjugate addition of the chiral arylcopper compound Cu-8d/P-n-Bu3 to the azoene with formation of hydrazone 7d. Enantioselective synthesis of azoene Ts-9 of 95% ee from ketone 4 was accomplished in four and five steps, respectively. Thus, enantioselective deprotonation of bicyclic ketone 4 with chiral base Li-10 and trapping of lithium enolate 11 with ClSiMe3 gave enol ether 12, which was chlorinated with N-chlorosuccinimide (NCS) to afford chloro ketone 13. Alternatively, chloro ketone 13 was also prepared upon chlorination of 11 with NCS. Chloro ketone 13 was converted to chloro hydrazone 14, which upon treatment with a mild base furnished azoene Ts-9. Arylcopper compound 8d of 98% ee was obtained in two steps from alcohol 16, which was prepared by enantioselective reduction of ketone 17 with (-)-diisopinocampheylchloroborane. Carbacyclin derivative E/Z-2d was found to be essentially inactive as an inhibitor of ADP induced human platelet aggregation, having an IC50 of >10 micromol/L.     

A short synthesis of diastereomeric norambraketals

A short synthesis of diastereomeric norambraketals was accomplished starting from norambreinolide. The reaction of norambreinolide with methyllithium followed by dehydration of the obtained 8α-hydroxy-14,15,16-trinorlabdan-12-one gave 14,15,16-trinorlabd-8(17)-en-12-one. Oxidation of the latter with OsO₄ or peracids with subsequent isomerization of the formed epoxy ketone leads, respectively, to (12R)-8α,12∶12,17- and (12S)-8β,12∶12,17-diepoxy-14,15,16-trinorlabdans. Only the former is fragrant and possesses ambergris odor.     

Synthesis of (±)-4-Demethoxydaunomycinone by Double Diels-Alder Additions to 2, 3, 5, 6-Tetramethylidene-7-oxanorbornane

Sequential Diels-Alder additions of methylvinyl ketone and dehydrobenzene to 2, 3, 5, 6-tetramethylidene-7-oxanorbornane (4) yielded the (5, 12-epoxy-1, 2, 3, 4, 5, 6, 11, 12-octahydro-2-naphtacenyl) methyl ketone (10) which, in few steps was oxidized to a precursos of (±)-4-demethoxydaunomycinone. The preparations of two precursors of anthracyclinones, the (5-acetoxy-) and (12-acetoxy-1, 2, 3, 4-tetrahydro-2-naphtacenyl) methyl ketones (14, 15) are presented. The synthesis of 6, 13-epoxy-6, 13-dihydropentacene (8) is also reported.     

Photodecarbonylation of 2,5,5-Trimethyl-2-(1-propynyl)cyclopentanone. 1,5- vs. 1,4-ring Closure of a Propargyl-Alkyl Biradical

Propargyl-alkyl biradical 12 generated by photodecarbonylation of title ketone 3 undergoes ring closure to cyclobutane 7 and to vinyl carbene 13 , this latter intermediate rearranging to the 5-ethylidenecyclopentenes 8a and 8b .     

Parallel synthesis of novel heteroaromatic acromelic acid analogues from kainic acid

A range of new C-4 heteroaromatic acromelic acid analogues has been synthesized in a parallel fashion from (-)-alpha-kainic acid 1. Protection of the amine and carboxylate groups of 1 followed by ozonolysis gave methyl ketone 8. A silyl enol ether 9, generated regiospecifically from the methyl ketone 8 using "kinetic" conditions, was brominated in situ with phenyltrimethylammonium perbromide to give the key alpha-bromo ketone 10. Parallel cyclization reactions of bromo ketone 10 with thioamides and thioureas were then performed. The aromatic heterocyclic derivatives 11a-d and 19 produced were deprotected to give the new kainoid amino acids 6a-d and 25 in excellent yield. Compounds 6a and 6c show strong binding to the kainate receptor. Reaction of 10 with alternative condensing agents was also briefly investigated.     

Spontaneous hydrolysis reactions of cis- and trans-beta-methyl-4-methoxystyrene oxides (Anethole oxides): buildup of trans-anethole oxide as an intermediate in the spontaneous reaction of cis-anethole oxide

Rates and products of the reactions of trans- and cis-beta-methyl-4-methoxystyrene oxides (1 and 2) (anethole oxides) and beta,beta-dimethyl-4-methoxystyrene oxide (3) in water solutions in the pH range 4-12 have been determined. In the pH range ca. 8-12, each of these epoxides reacts by a spontaneous reaction. The spontaneous reaction of trans-anethole oxide (1) yields ca. 40% of (4-methoxyphenyl)acetone and 60% of 1-(4-methoxyphenyl)-1, 2-propanediols (erythro:threo ratio ca. 3:1). The spontaneous reaction of cis-anethole oxide is more complicated. The yields of diol and ketone products vary with pH in the pH range 8-11, even though there is not a corresponding change in rate. These results are interpreted by a mechanism in which 2 undergoes isomerization in part to the more reactive trans-anethole oxide (1), which subsequently reacts by acid-catalyzed and/or spontaneous reactions, depending on the pH, to yield diol and ketone products. The buildup of the intermediate trans-anethole oxide in the spontaneous reaction of cis-anethole oxide was detected by (1)H NMR analysis of the reaction mixture. Other primary products of the spontaneous reaction of 2 are (4-methoxyphenyl)acetone (73%) and threo-1-(4-methoxyphenyl)-1,2-propanediol (ca. 3%). The rates and products of the spontaneous reaction of 2 and its beta-deuterium-labeled derivative were determined, and the lack of significant kinetic and partitioning deuterium isotope effects indicates that the isomerization of 2 to ketone and to trans-anethole oxide must occur primarily by nonintersecting reaction pathways.     

大环二萜类化合物的研究(Ⅳ)——Isosarcophytol—A前体化合物的合成

Isosarcophytol-A(1)是1982年首次从澳大利亚软珊瑚(Nephthea brassica)中分离鉴定的西松烷型(Cembrane)大环二萜类化合物,其结构为6,10,14-三甲基-3-异丙基-3E,5E,9E,13E-环十四碳四烯-1-醇,是Sarcophytol—A(2)的异构体,但有关1的生物活性试验和全合成研究尚未见报道.我们在前文报道了以低价钛诱导的分子内二羰基偶联为环化方法,完成了天然大环二萜类化合物Cembrene—C的全合成和Sarcophytol—A(2)苄醚衍生物(3)的合成.本文报道以天然法呢醇4为起始原料,经区域选择性氧化、羟醛缩合等六步反应,合成了1的前体化合物11.合成路线如下:     

Excited state (formal) intramolecular proton transfer (ESIPT) in p-hydroxyphenyl ketones mediated by water

Evidence is presented that show p-hydroxyphenyl ketones 6–8 undergo excited state intramolecular proton transfer (ESIPT, via the singlet excited state), mediated by water, which formally transfers the phenol proton to the carbonyl oxygen of the ketone. ESIPT was not observed in neat CH₃CN. The ESIPT process in aqueous media generates the corresponding p-quinone methides 9–11 (and the corresponding conjugate bases (phenolate ions) 12–14), as detected by laser flash photolysis (LFP). It competes effectively with intersystem crossing to the excited triplet state. The respective p-methoxyphenyl ketones 15 and 16 failed to undergo the reaction consistent with the expected lack of proton transfer in these systems. Results for the biphenyl ketone 8 indicate that formal ESIPT can also take place over an extended range, suggesting that the process is likely general for all p-hydroxyaromatic ketones which opens up the possibility for designing photoswitchable processes based on this general phenomenon.     

Studies on α‐Bromination of Ketone in Hydrindane Ring System

The present paper describes the results of various attempts to synthesize 5‐bromo‐6‐ketone ( 11 ). When standard procedures for the α‐bromination were tried, a mixture of 5‐bromo‐6‐ketone ( 11 ) and 7‐bromo‐6‐ketone ( 12 ) was obtained. However, when bromination was carried out under buffered conditions, the desired 5‐bromo‐6‐ketone ( 11 ) could be obtained in a good yield.     

Photochemical Reactions. 153th communication. Photochemistry of acylsilanes: Photolyses and thermolyses of α,β-epoxy silyl ketones

The photolyses and thermolyses of the α,β-epoxy silyl ketones 5 and 6 are described. On n,π*-excitation, the silyl ketones 5 and 6 were transformed to the ketone 7 and the ketene 8 in quantitative yield. The formation of 8 may be explained by initial cleavage of the C(α)? O bond and subsequent C(1)→C(2) migration of the (t-Bu)Me₂Si group. In contrast to the acylsilanes 5 and 6 , the photolyses of the analogous methyl ketones 11 and 12 gave a very complex mixture of products. On thermolysis, 5 and 6 yielded the ketone 7 and the acetylenic compound 9 , which were probably formed via a siloxycarbene intermediate. In addition, the 1,3-dioxle 10 was formed via an initial C(α)? C(β) bond cleavage leading to the ylide g and subsequent intramolecular addition of the carbonyl group. The analogous 1,3-dioxole 13 was obtained on pyrolysis of the methyl ketones 11 and 12 .     

Fully stereocontrolled total syntheses of the prostacyclin analogues 16S-iloprost and 16S-3-oxa-iloprost by a common route, using alkenylcopper-azoalkene conjugate addition, asymmetric olefination, and allylic alkylation

In this article we describe fully stereocontrolled total syntheses of 16S-iloprost (16S-2), the most active component of the drugs Ilomedin and Ventavis, and of 16S-3-oxa-iloprost (16S-3), a close analogue of 16S-2 having the potential for a high oral activity, by a new and common route. The key steps of this route are (1) the establishment of the complete C13-C20 omega side chain of the target molecules through a stereoselective conjugate addition of the alkenylcopper derivative 9 to the bicyclic C6-C12 azoalkene 10 with formation of hydrazone 8, (2) the diastereoselective olefination of ketone 7 with the chiral phosphoryl acetate 39, and (3) the regio- and stereoselective alkylation of the allylic acetate 43 with cuprate 42. These measures allowed the 5E,15S,16S-stereoselective synthesis of 16S-2 and 16S-3, a goal which had previously not been achieved. Azoalkene 10 was obtained from the achiral bicyclic C6-C12 ketone 11 as previously described by using as key step an enantioselective deprotonation. The configuration at C16 of omega-side chain building block 9 has been installed with high stereoselectivity by the oxazolidinone method and that at C15 by a diastereoselective oxazaborolidine-catalyzed reduction of the C13-C20 ketone 23 with catecholborane. Surprisingly, a high diastereoselectivity in the reduction of 23 was only obtained by using 2 equiv of oxazaborolidine 24. Application of substoichiometric amounts of 24 resulted in irreproducible diastereoselectivities ranging from very high to nil.     

Unusual transannular cyclization products of sarcophytoxide, a 14-membered marine cembranoid: anomalous stereochemistry of epoxide-ketone rearrangement

[reaction: see text] Treatment of sarcophytoxide with trimethylsilyl trifluoromethanesulfonate afforded an aromatic ketone as an unusual cyclization product. The modified Mosher's method and X-ray analysis performed on the aromatic ketone revealed that it is a 4:1 mixture of 8(R)- and 8(S)-enantiomers. It also suggested that the precursor ketone has 8(R)-configuration, which is contradictory to that expected from the ordinary epoxide-ketone rearrangement.     

Application of Dimethylaminomethylene Ketone in Heterocycles Synthesis: Synthesis of 2‐(Isoxazolo,Pyrazolo, and Pyrimido) Substituted Analogs of 1,4‐Benzodiazepin‐5‐carboxamides Linked through an Oxyphenyl Bridge

Versatility of dimethylaminomethylene ketone derivative of 2‐(4′‐acetyl)‐phenoxyl‐5‐carboxamido‐1,4‐benzodiazepin‐5‐(4′‐methylpiperazinyl)‐carboxamide ( 6 ) was explored to provide an easy one‐pot access to its 2‐(isoxazolo, pyrazolo, and pyrimido) substituted analogs 8 , 9 , 10 , 11 , 12 , and 13 , respectively.     

Tricyclo[4.2.2.22,5] dodecane and Tricyclo [4.2.2.12,5]undecane. Preliminary communication

A synthesis of tricyclo [4.2.2.2^2,5]dodecane ( 19 ), a novel tricyclic C₁₂H₂₀ compound, is described. The key intermediate ketone 13 was prepared either from the C₁₀-photodimer 1 of cyclopentadienone or the C₁₁-cycloaddition products 11 and 12 . 13 was also transformed to tricyclo [4.2.2.1^2,5]undecane ( 8 ).     

Diarylcuprates for Selective Syntheses of Multifunctionalized Ketones from Thioesters under Mild Conditions

Ketones were selectively synthesized from thioesters by using diarylcuprates(I) generated in situ from copper(I) salts and aryl Grignard reagents in a 1 : 1.3–1.5 ratio under ambient temperature. During the ketone synthesis, various functional groups, such as carbonyl (ketones, esters, and amides), O-protecting groups, halogens, and heteroarenes, were tolerated to afford multifunctionalized ketones in excellent yields. This copper-mediated ketone synthesis could be applied to the synthesis of not only gluconolactone-derived ketone 6 , a synthetic intermediate in the transformation to the SGLT2 inhibitor canagliflozin, but also thiolactol 8 , a valuable synthetic intermediate for (+)-biotin. Control experiments on an isolated diphenylcuprate(I), [CuPh₂]⁻ ( 12 ), and DFT calculations revealed that this ketone synthesis proceeded by oxidative addition of the C−S bond of thioesters to [CuPh₂]⁻, while reductive elimination from the Cu^III intermediate produced the corresponding ketone and an inactive species [(RS)CuPh]⁻, the latter reacted with [CuPh]₄ ( 11 ) to regenerate the reactive diphenylcuprate(I).     

Expedient Protocols for the Installation of 1,5‐Benzoazepino‐Based Privileged Templates on the 2‐Position of 1,4‐Benzodiazepine Through a Phenoxyl Spacer

An efficient novel strategy for the hetero‐annulation of 2‐chloro‐1,4‐benzodiazepine ring, substituted on its 5‐position with a carboxamido group ( 5 ), has been developed to allow the incorporation of 1,5‐benzodiazepine, 1,5‐benzothiazepine, and 1,5‐benzoxazepine ( 8 , 9 , 10 , 11 , 12 , 13 ) rings through their dimethylaminomethylene ketone intermediate ( 7 ).     

Total syntheses of sesterpenic acids: refuted (+/-)-bilosespenes A and B

[reaction: see text] The total syntheses of racemic sesterpenic acids 1 and 2 have been accomplished from creosol (6) in 12 and 13 steps, respectively. Intramolecular Diels-Alder reaction of masked o-benzoquinone 7 generated from 6 and allyl alcohol, stereoselective addition of alkenylcerium(III) chloride 8 to ketone 5, and anionic oxy-Cope rearrangement of dienol 4 are the key steps.     

Enantiospecific total synthesis of (-)-4-thiocyanatoneopupukeanane

Enantiospecific synthesis of the natural enantiomer of the marine sesquiterpene (-)-4-thiocyanatoneopupukeanane (6) is described. The bicyclo[2.2.2]octanecarboxylate 14, obtained from (R)-carvone via Michael-Michael reaction, was transformed into neopupukeananedione 12 by employing rhodium acetate catalyzed intramolecular C-H insertion of the diazo ketones 16 or 19 as the key reaction. Regioselective deoxygenation of the C-2 ketone transformed the dione 12 into neopupukean-4-one 10. Alternately, the keto ester 18 was also transformed into neopupukean-4-one 10 via regioselective deoxygenation of the ketone in 18 followed by intramolecular rhodium carbenoid C-H insertion of the diazo ketone 31. Finally, neopupukean-4-one 10 was transformed into (-)-4-thiocyanatoneopupukeanane 6 via the alcohol 32 and the mesylate 33.     

Total syntheses of epothilones B and d

A convergent, total synthesis of epothilones B (2) and D (4) is described. The key steps are Normant coupling to establish the desired (Z)-stereochemistry at C12-C13, Wadsworth-Emmons olefination of methyl ketone 28 with the phosphonate ester 8, diastereoselective aldol condensation of aldehyde 5 with the enolate of keto acid derivatives to form the C6-C7 bond, selective deprotection of acid 52, and macrolactonization.