Synthesis of highly functionalized bicyclo[m.n.1]alkanones via a cationic reaction cascade

[reaction: see text] The acid-mediated Prins/pinacol and the triple domino reactions Diels-Alder/Prins/pinacol were used to construct highly functionalized bicyclo[m.n.1]alkanones 19-29 and 33a-c possessing various ring sizes from ketals 8-18 and 31a-c in 44-96% yields. This approach proves to be highly efficient and reliable to generate high molecular complexity in a single step.     

A one-pot sequence of Stille and Heck couplings: synthesis of various 1,3,5-hexatrienes and their subsequent 6pi-electrocyclizations

Palladium-catalyzed cross-coupling reactions of 2-bromocyclohex-1-enyl triflates 7 and 11 with a variety of alkenylstannanes occurred chemoselectively at the site of the triflate leaving group to give bromobutadienes which readily underwent Heck reactions with acrylates and styrene. Both steps could be performed in the same flask to give differentially functionalized hexatrienes in up to 88% overall yield. With simple stannanes, the same catalyst precursor could be used for both coupling steps making it possible to perform the whole sequence with only one portion of catalyst. For some of the functionally substituted stannanes, specifically adjusted catalyst systems had to be used. The 1,3,5-hexatrienes obtained were further transformed, in particular the methoxy-substituted compounds 14a-c were converted to bicyclo[4.4.0]decenones 30 (71-97%), bicyclo[4.3.0]nonenones 35 (74-93%), cyclodecynone 37a (47%), and cyclononynone 39a (15%). Thermal electrocyclizations of the other hexatrienes gave tetrahydronaphthalines 31 (60-61%), the tricyclic lactone 32 (72-75%) and decahydrophenanthrene 33 (75 %) in good yields.     

Intramolecular Pauson-Khand reactions of methylenecyclopropane and bicyclopropylidene derivatives as an approach to spiro(cyclopropanebicyclo[n.3.0]alkenones)

The trimethylsilyl-protected enynes 9a-c and 14a,b with alkynyl substituents on the three-membered ring or on the double bond of a methylenecyclopropane or a bicyclopropylidene moiety were prepared in two steps from the alcohols 6a-c and 12a,b, respectively, by conversion to the iodides and their coupling with lithium (trimethylsilyl)acetylide (8) in 38-73% overall yields. The bicyclopropylidene derivative 9d was synthesized in 49% yield directly from bicyclopropylidene (3) by lithiation followed by coupling with (5-iodopent-1-ynyl)trimethylsilane (11). Enynes 9b-d were protiodesilylated by treatment with K2CO3 in methanol to give the corresponding unprotected enynes 10b-d in 53, 74 and 94% yield, respectively. Enynes 17a-c with a carbonyl group adjacent to the acetylenic moiety were synthesized from oxo derivatives 15a-c by Wittig olefination followed by coupling with 8 in 47, 18 and 12% overall yield, respectively. Pauson-Khand reactions of the methylenecyclopropane derivatives with a substituent on the ring (9a,b and 10a) as well as on the double bond (14a,b and their in situ prepared protiodesilylated analogues) proceeded smoothly by stirring of the corresponding enyne with [Co2(CO)8] in dichloromethane at ambient temperature followed by treatment of the formed complexes with trimethylamine N-oxide under an oxygen atmosphere at -78 degrees C to give tricyclic or spirocyclopropanated bicyclic enones 18a,b, 19a, 20a,b, 21a,b in good yields. Alkynylbicyclopropylidene derivatives 9c,d and 10c,d formed the corresponding cobalt complexes at -78 to -20 degrees C. Treatment of the latter with N-methylmorpholine N-oxide under an argon atmosphere at -20 degrees C gave the spirocyclopropanated tricyclic enones 18c, 19c and 18d in 31-45% yields. The structure of 19c was proved by X-ray crystal structure analysis. The cyclization of enynones 17a-c in MeCN at 80 degrees C gave the spirocyclopropanated bicyclic diketones 22a-c in 38-65% yields. Intramolecular PKRs of the enynes 25a,d with a chiral auxiliary adjacent to the triple bond gave the corresponding products 26a,d in 70 and 79% yield, respectively, as 5:1 and 8:1 mixtures of diastereomers, respectively. Addition of lithium dimethylcuprate or higher order cuprates to the double bond of the former furnished bridgehead-substituted bicyclo[3.3.0]octanones 27a-c in 57-86% yields. Protiodesilylation of 27a followed by acetal cleavage gave the enantiomerically pure spirocyclopropanated bicyclo[3.3.0]octanedione (1R,5R)- 29a with [alpha]D(20)=-148 (c=1.0 in CHCl3) in 55% overall yield.     

Stereoselective preparation of ceramide and its skeleton backbone modified analogues via cyclic thionocarbonate intermediates derived by catalytic asymmetric dihydroxylation of alpha,beta-unsaturated ester precursors

A novel and efficient synthetic route to ceramide 1a and skeleton backbone modified ceramide analogues 1b,c is reported. The syntheses utilize osmium-catalyzed asymmetric dihydroxylation of (E)-alpha, beta-unsaturated ester 5a-c as the chiral induction step, with the desired configurations in the products 1a-c, 2a, and 13 being generated by regioselective azide substitution at the alpha position of alpha,beta-dihydroxyesters 6a-c via a cyclic thionocarbonate intermediate. Azido esters 10a-c are converted to the corresponding ceramides 1a-c by a sequence of azide reduction, N-acylation, ester reduction (NaBH(4)/LiBr), and Birch reduction of the triple bond (Li, EtNH(2)). These seven- to eight-step syntheses afford the target compounds 1a-c with excellent stereocontrol and in 30-42% overall yields. Furthermore, propargylic alpha-azido-beta-hydroxyester 10a is converted to D-erythro-sphingosine 2a via simultaneous reduction of the triple bond, azido, and ester functional groups with LiAlH(4), providing a highly concise and practical four-step synthesis of this key naturally occurring sphingolipid. The L-erythro stereoisomers are also available in high enantiomeric purity by the method described herein.     

Efficient synthesis of substituted vinyl ethers using the Julia olefination

Julia olefination between alpha-alkoxy sulfones 2a-c and a wide variety of ketones or aldehydes afforded substituted vinyl ethers in 46-90% yields. Sulfones 2a-c were readily prepared in two steps from commercially available reagents in 68-80% yields. Optimization revealed that the nature of the base, the solvent, and the temperature were crucial to obtaining the desired vinyl ethers. [reaction: see text]     

Ionic liquid phase organic synthesis (IoLiPOS) methodology applied to the preparation of new 3,4-dihydropyrimidine-2(1H)-ones bearing bioisostere group in N-3 position

The ionic liquid phase organic synthesis (IoLiPOS) methodology has been used for the preparation of new 3,4-dihydropyrimidine-2(1H)-ones (DHPMs) bearing bioisostere group in N-3 position. For the 3,4-DHPMs substituted with various thiazole rings, the strategy involved a three-component Biginelli condensation in the second step with good yields (93-96%) from ILP bound acetoacetate, aromatic aldehyde (93-97% yield), and N-methyl urea followed by N-3 alkylation with chloroacetonitrile on the ILP bound 3,4-DHPM. Quantitative thionation of the nitrile group grafted on the ILP bound 3,4-DHPM was realized in MeOH with a 40-48% solution of ammonium sulfide and subsequent addition of α-bromoketone produced the thiazole ring appended on the 3,4-DHPM core. After cleavage by transesterification, the target compounds were obtained in good overall yields (47-50%). The efficiency of the IoLiPOS methodology was also demonstrated by the preparation of new 3,4-DHPMs with a tetrazole ring in N-3 position in 5 steps (53-61% overall yield) via the ILP bound 3-cyanomethyl 3,4-DHPM as key intermediate.     

Cyclopentanone ring expansion leading to functionalized delta-lactams: short synthesis of simple sedum alkaloids

Monosubstituted epoxides react with (cyclopentenyloxy)trimethylsilane to afford, after subsequent oxidative fragmentation, a pair of diastereomeric 8-membered iodolactones. When these lactones are separately treated with sodium azide, followed by reduction over Lindlar's catalyst, lactone ring contraction yields 6-membered monosubstituted lactams. When (R)-1,2-epoxypentane is used in this 5 + 3 - 2 overall ring expansion sequence, one final step involving delta-lactam to piperidine reduction yields natural (-)-halosaline and (-)-epihalosaline in five steps and 12% and 23% overall yields, respectively.     

Free-radical-mediated conjugate additions. Enantioselective synthesis of butyrolactone natural products: (-)-enterolactone, (-)-arctigenin, (-)-isoarctigenin, (-)-nephrosteranic acid, and (-)-roccellaric acid

Lewis acid-mediated conjugate addition of alkyl radicals to a differentially protected fumarate 10 produced the monoalkylated succinates with high chemical efficiency and excellent stereoselectivity. A subsequent alkylation or an aldol reaction furnished the disubstituted succinates with syn configuration. The chiral auxiliary, 4-diphenylmethyl-2-oxazolidinone, controlled the stereoselectivity in both steps. Manipulation of the disubstituted succinates obtained by alkylation furnished the natural products (-)-enterolactone, (-)-arctigenin, and (-)-isoarctigenin. The overall yields for the target natural products were 20-26% over six steps. Selective functionalization of the disubstituted succinates obtained by aldol condensation gave the paraconic acid natural products (-)-nephrosteranic acid (8) and (-)-roccellaric acid (9). The overall yield of the natural products 8 and 9 over four steps was 53% and 42%, respectively.     

Synthesis of hexacyclic parnafungin A and C models

A convergent, practical route to unstable hexacyclic parnafungin A and C models has been developed. Two iodoxanthones were prepared in four or five steps (33-50% overall yield). Suzuki-Miyaura coupling of the iodoxanthones with excess readily available 3-carbomethoxy-2-nitrophenyl pinacol boronate afforded the hindered highly functionalized 2-arylxanthones (53-58%) in the first key step. In the second key step, zinc reduction gave benzisoxazolinones that were treated with MsCl and then base to generate the unstable hexacyclic parnafungin A (13% overall yield for 8 steps) and C (8% overall yield for 9 steps) models. Analogously to the parnafungins, hexacyclic parnafungin C model decomposes to a phenanthridine with a half-life of 2 d in CDCl(3).     

Syntheses of the first N-mono- and N,N'-dipolyfluoroalkyl-4,4'-bipyridinium compounds

Reactions of 4,4'-bipyridine (1) with excess of polyfluoroalkyl iodides (2a-d) at 100-110 degrees C, under neat conditions, led to the formation of monoquaternary salts (3a-d) in > 90% yields. Salts 3a-d were metathesized with LiN(SO2CF3)2 either in water or water/acetone mixtures to form ionic liquids (4a-d), respectively, in > 88% yields. When 1 was reacted with 2.5 equivalent of 2a-c in DMF at 110 degrees C, the diquaternary salts 5a-c were formed in > 85% yields. Alternatively, 5a-c were also synthesized by heating a mixture of 3a-c and 2a-c (1.25 equivalent) in DMF. The metathesis reaction of 5a-c with LiN(SO2CF3)2 produced dicationic ionic liquids (6a-c) in > 86% yield.     

Intermolecular Diels-Alder reactions of brominated masked o-benzoquinones with electron-deficient dienophiles. A detour method to synthesize bicyclo[2.2.2]octenones from 2-methoxyphenols

Intermolecular Diels-Alder reactions of masked o-benzoquinones, i.e., 6,6-dimethoxy-2,4-cyclohexadienones 5-7 and 21-24 generated from 2-methoxyphenols 1-3 and 17-20, respectively, with electron-deficient dienophiles leading to highly functionalized bicyclo[2.2.2]octenones are described. The masked o-benzoquinones (MOBs) 5-7 underwent Diels-Alder cycloadditions with methyl acrylate, methyl methacrylate, and methyl vinyl ketone to provide bicyclo[2.2.2]octenones 13a-c to 15a-c (direct method) in low to moderate yields with the concomitant formation of considerable amounts of dimers 9-11. To retard dimerization and to improve the yields of the requisite bicyclo[2.2.2]octenones, a detour method comprised of sequential bromination of 2-methoxyphenols 1-4, oxidation and Diels-Alder reaction, and debromination has been developed. The oxidation of bromophenols 17-20 produced MOBs 21-24 which are stable enough to be isolated. The MOBs 21-24 underwent cycloaddition with electron-deficient dienophiles in a very efficient manner to afford the corresponding cycloadducts 25a-c to 28a-c in good to high yields without self-dimerization. When the cycloadducts 25a-c to 28a-c were treated with either Bu(3)SnH/AIBN or tributylammonium formate-palladium reagent, the corresponding debrominated products 13a-cto 16a-c were obtained in high to excellent yields. In general, the cycloadducts 13a-c to 15a-c were obtained in 20-40% higher yields via the detour method than those via the direct method. In both routes, the Diels-Alder reactions proceeded in a highly regio- and stereoselective manner to furnish a single cycloadduct in each case.     

Mechanism of autoxidation of 5,7-dihydroxytryptamine: effect of fluorine substitution at positions 4 and/or 6

Analogs of 5,7-dihydroxytryptamine (5,7-DHT), namely, 4-fluoro-, 6-fluoro-, and 4,6-difluoro-5,7-DHT's (30a-c) were synthesized starting from 4-fluorophenol (7a), 4-fluorobenzyl alcohol (12) and 2,4-difluorophenol (7b), respectively. Regiospecific hydroxylation and formylation ortho to fluoro groups, both via aryllithium intermediates, were made possible by the blocking effect of tert-butyldimethylsilyloxy functions and allowed the conversion of the starting materials to the key intermediates, namely, 3,5-bis(tert-butyldimethylsilyloxy)-2-fluoro-, 4-fluoro- and 2,4-difluorobenzaldehydes (11a, b and 19, respectively). The latter were converted in one step to the corresponding benzyloxybenzaldehydes, from which indole-2-carboxylates 22a-c were synthesized via azidostyrenes 21a-c, respectively. Decarbonylation of the indole-2-carboxaldehydes (24a-c) produced from 22a-c in two steps gave 2,3-unsubstituted indoles 25a-c, respectively. Introduction of the aminoethyl side chains on C-3 of 25a-c via the corresponding indole-3-acetonitriles, and subsequent debenzylation generated the hydroxytryptamines, which were isolated as their creatinine sulfate salts 30a-c, respectively. Cyclic voltammetric studies indicated that like 5,7-DHT, 30a-c undergo electrochemical oxidation in 1 M H2SO4 via the corresponding p-quinoneimine derivatives 31a-c by an electrochemical-chemical-electrochemical (ECE) process. The voltammetrically detectable products of the ECE process appear to be the corresponding 5-hydroxytryptamine-4,7-dione (6) derivatives 33a-c. The nature of the interaction of dissolved O2 with 30a-c at pH 7.4 appears to be strikingly different from that of 5,7-DHT, which undergoes autoxidation at pH 7.4 via the 4-hydroperoxy derivative 4 to the quinone 6.(ABSTRACT TRUNCATED AT 250 WORDS)     

Asymmetric catalytic aziridination of dihydronaphthalenes for the preparation of substituted 2-aminotetralins

An enantioselective synthesis of substituted 2-aminotetralins from dihydronaphthalenes in four steps is described. The key step is the Jacobsen’s (diimine)copper-catalyzed asymmetric aziridination of dihydronaphthalenes to the respective aziridines in 33-82% yields and 60-87% enantiomeric excess. The enantioselectivity and the yield were dependent on the properties of the nitrene precursor. pTsNIPh appeared in general to give better results than pNsNIPh. Aziridines were ring-opened in the benzylic position by catalytic hydrogenolysis in quantitative yields, and deprotected in two steps to the respective 2-aminotetralins in 66-85% yields. The synthesis of (S)-2-aminotetralin (>98% ee) and (S)-2-amino-7-methoxytetralin (56% ee) were accomplished in 30 and 52% overall yields, respectively.     

Synthesis of large macrocyclic tetraaza compounds with a methylene backbone: Cyclo[-NH- (CH2)n-]4, (n = 6, 7, 8, 9 and 10). The formation of 28-, 32-, 36-, 40- and 44-membered rings

A series of macrocyclic tetraamines with 28-, 32-, 36-, 40- and 44-membered rings have been efficiently prepared from the corresponding ditosylamide and monobromoalcohol derivatives in 6 steps via a double condensation reaction. Overall yields were: 41, 41, 46, 29, and 33%, respectively, for 1,8,15,22-tetraazacyclooctacontane ( 11a ), 1,9,17,25-tetraazacyclodotriacontane ( 11b ), 1,10,19,28-tetraazacyclohexatriacontane ( 11c ), 1,11,21,31-tetraazacyclotetracontane ( 11d ) and 1,12,23,34-tetraazacyclotetratetracontane ( 11e ).     

Bridged tetraquaternary salts from N,N'-polyfluoroalkyl-4,4'-bipyridine

4,4'-Bipyridine (1) with excess of polyfluoroalkyl bromide or iodides 2a-d at 100-110 degrees C without solvent gave the monoquaternary salts 3a-d in >90% yields. However, 1 with 2.5 equiv of 2a-c in DMF at 110 degrees C resulted in the diquaternary salts 5a-c in >85% yields. In DMF, 5a-c were obtained in comparable yields when a molar excess of 2a-c reacted with 3a-c. 1,4-Dibromobutane with 3a,b in DMF at 100 degrees C led to the tetraquaternary salts 7a,b in approximately 85% yields. In water or acetone/water as a solvent, salts 3a-d and 5a-c were metathesized with LiN(SO(2)CF(3))(2) and KSO(3)CF(3) to produce monoquaternary ionic liquids 4a-h in >88% yields and diquaternary ionic liquids 6a-f in >86% yields, respectively. Tetraquaternary ionic liquids 8a,b were obtained when LiN(SO(2)CF(3))(2) was reacted with salts 7a,b. These compounds were stable to 340 degrees C as determined by DSC. They are the first N-mono-, N,N'-di-, and N,N,N',N'-tetra-4,4'-polyfluoroalkylbipyridinium quaternary salts and ionic liquids.     

Preparation of benzene, furan, and thiophene analogs of duocarmycin SA employing a newly-devised phenol-forming reaction

Five A-ring analogs of duocarmycin SA 9a-e were synthesized in racemic form modifying our second synthetic route toward duocarmycin SA. The problem encountered at the crucial phenol forming step to secure 17a, b from 16a, b under the conventionally used Kuwajima conditions was overcome by devising a more convenient method: simple heating of 16a-c in benzene in the presence of bis(triphenylphosphine)palladium(II) chloride (10 mol%), cesium carbonate (3 eq), and triphenylphosphine (0.3 eq) gave 17a-c in high yields of 86-91%. The intermediates 17a-e were readily led to the A-ring analogs (+/-)-9a-e almost according to the reported route.     

STUDIES ON STEROIDAL PLANT-GROWTH REGULATORS (ⅩⅦ)——A NEW SYNTHESIS OF HOMOBRASSINOLIDE AND (22S,23S)-22,23-EPI-HOMOBRASSINOLIDE

Homobrassinolide (2) and (22S, 23S)-22,23-epi-homobrassinolide (4) were synthesized fromstigmasterol in seven steps respectively in 4.7% and 24.1% overall yields. The ratio of 2 to 4is 1:5. The key step is the highly regioselective formation of the B--homo-7-oxa-lactone ringby oxidation of an enol silyl ether with 3--chloro-peroxybenzoic acid.     

5-(2’-羧乙基)-6-烷基-3,4-二氢吡喃酮的合成

吡喃酮是许多天然产物的结构单元,我们曾由4-异丁酰基庚二酸在过量醋酸酐及乙酰氯存在下回流得到7-氧代-8,8-二甲基-△~9-六氢香豆素.本文由二氰乙基-β-二酮进行酮解水解反应得到4-酰基庚二酸1_(a-c)。 在过量醋酸酐、乙酰氯存在下由1_a、1_c为底物进行反应没有得到双环的香豆素衍生物.其产物和单纯以乙酐为缩合剂时的产物2_a、2_c相同,产率分别为68％、63％。2_c可在硫酸铁催化     

Facile, efficient, and enantiospecific syntheses of 1,1'-N-linked pseudodisaccharides as a new class of glycosidase inhibitors

This article describes an efficient synthesis of a potent trehalase inhibitor, 1,1'-N-linked pseudodisaccharide 1 (consisting of two valienamines), in 14 steps with an overall yield of 12% and a first synthesis of 2 (consisting of two 2-epi-valienamines) in 15 steps with an overall yield of 24% from (-)-quinic acid. The synthesis involves a stereospecific palladium-catalyzed coupling reaction between an allylic amine and an allylic chloride as the crucial step. The acetonide blocking groups were shown to be the best hydroxyl protecting groups, compatible with the palladium-catalyzed allylic amination reaction that afforded high yields of the 1,1'-N-linked pseudodisaccharides with a minimum amount of an elimination diene side product.     

An efficient access to novel enantiomerically pure steroidal delta-amino acids

A highly chemoselective sequence of Stille and Heck couplings on the heterocyclic bromoenol triflates 2 a-c with the bicycloalkenylstannanes cis-3 and trans-3 furnished the intermediate bromobutadienes 4 a-c in good yields ranging from 73-94 %. A modified Heck coupling protocol employing the palladacycle 8 and an additional bidentate ligand such as 1,4-bis(diphenylphosphinyl)butane allowed a significant reduction in catalyst loading while still obtaining the heterocyclic 1,3,5-hexatrienes 5 a-c in good yields (71-94 %). The unsymmetrically substituted 1,3,5-hexatrienes 5 a-c in solution underwent 6pi-electrocyclizations following an optimized microwave-heating protocol to yield the steroidal tetracycles cis-7 a-c and trans-7 b (59-69 %). Tetracycles cis-7 a-c are the products of a subsequent 1,5-hydrogen shift to the thermodynamically more stable, more highly substituted diene units. Removal of the tert-butyl groups provided the novel steroidal delta-amino acid 9 a and the delta-amino acid derivatives 9 b, c in good yields (76-86 %).