New approaches toward the synthesis of (D-homo) steroid skeletons using Mukaiyama reactions

New, short, and flexible procedures have been developed for syntheses of steroid and D-homo steroid skeletons. A Mukaiyama reaction between the silyl enol ether of 6-methoxytetralone and 2-methyl-2-cyclopentenone or carvone, with transfer of the silyl group to the receiving enone, gave a second silyl enol ether. Addition of a carbocation, generated under Lewis acid conditions from 3-methoxy-2-butenol, 3-ethoxy-3-phenyl-2-propenol or 3-methoxy-2-propenol to this second silyl enol ether gave adducts, which could not be cyclized by aldol condensation to (D-homo) steroid skeletons. The Mukaiyama-Michael reaction of the silyl enol ether of 6-methoxy tetralone with 2-methyl-2-cylopentenone gave a second silyl enol ether, which reacted in high yield with a carbocation generated from 3-hydroxy-3-(4-methoxyphenyl)propene. Ozonolysis of the double bond in this adduct gave a tricarbonyl compound (Zieglers triketone), which has been used before in the synthesis of 9,11-dehydroestrone methyl ether. A second synthesis of C17 substituted CD-trans coupled (D-homo) steroid skeletons has been developed via addition of a carbocation, generated with ZnBr₂ from a Torgov reagent, to a silyl enol ether containing ring D precursor. The obtained seco steroids have been cyclized under formation of the 8-14 bond by treatment with acid. The double bonds in one of the cyclized products have been reduced to a C17-substituted all trans steroid skeleton.     

Enantioselective synthesis of 2-alkylidenetetrahydrofurans based on a ‘cyclization/enzymatic resolution’ strategy

Enantiomerically pure 2-alkylidenetetrahydrofurans have been prepared by TiCl₄ mediated enantiospecific reactions of 1,3-bis-silyl enol ethers with enantiomerically pure epichlorohydrin. In addition, the enzymatic kinetic resolution of 2-alkylidenetetrahydrofurans, using Candida antarctica lipase B (CAL-B), was studied. Enzymatic kinetic resolution of monocyclic 5-vinyl-2-alkylidenetetrahydrofuran with CAL-B afforded the enantiomerically pure ester with 97% ee. For a bicyclic 2-alkylidenetetrahydrofuran, this proceeded with excellent enantioselectivity (E >100) affording the enantiomerically pure acid with 98% ee. 2-Alkylidenetetrahydrofurans were prepared by [3+2] cyclization reactions of 1,3-dicarbonyl dianions (‘free dianions’) or 1,3-bis-silyl enol ethers (‘masked dianions’).     

Reaction of Ph3P(SCN)2 with Further Orthohydroxy Carboxylic Acid Systems,Including Substituted β-Keto Acids: Synthesis of Novel 2-Thio-1,3-oxazines and Their Subsequent Transformation with Amines

We now report the first reaction of Ph₃P(SCN)₂ with 4,6-dihydroxy-5-methylisophthalic acid to give 10-methyl-2,8-dithio-1,3-oxazino-1,3-benzoxazine-4,6-dione. Also, the enol tautomer has been utilized in the reaction of β-keto acids with Ph₃P(SCN)₂ to give novel 2-thio-1,3-oxazines. Subsequent reaction of the 2-thio-1,3-oxazines with benzylamine resulted in opening of the oxazine ring and gave novel dibenzylamino-enamides, which could be cyclized to thiouracils. The reaction of 2-thio-1,3-oxazines with morpholine at low temperature led to the production of unstable 2-Mercapto-2-morpholino-1,3-oxazines. 2-Mercapto-2-morpholin-4-yl-2,3,5,6,7,8-hexahydro-4H-1,3-benzoxazin-4-one was observed to lose H₂S at room temperature to give 2-morpholin-4-yl-5,6,7,8-tetrahydro-4H-1,3-benzoxazin-4-one, which was subsequently tested and found to exhibit some antiplatelet activity.     

双环烯醚的合成及其性质的研究

由内酯2和Tebbe试剂反应合成了双环烯醚化合物5-苄氧基-2,8-二亚甲基-3,4,9,10-四氢-2H,8H-苯并[1,2-b; 3,4-b']二吡喃(3), 环烯醚在酸性条件下很容易水解和异构化, 在酸存在下外环烯醚3于10 min内转化为内环烯醚4, 较长的反应时间只能得到水解物或其它分解产物.     

BF3·OEt2-initiated polymerization of 2-methylene-1,3-dioxepanes

BF₃·OEt₂-initiated polymerizations of 2-methylene-1,3-dioxepane gave polymers composed of both ring-retained and ring-opened structures. The ring-opening content increased with an increase in polymerization temperature. Poly(4,7-dimethyl-2-methylene-1,3-dioxepane) propagated slower during BF₃·OEt₂-initiated polymerization and had a lower ring-opened content than poly(2-methylene-1,3-dioxepane). The type of acid initiator used also affected the amount of ring opening observed. Stronger acids gave less ring opening. Attempted BF₃·OEt₂-initiated copolymerizations of these seven-membered ring cyclic ketene acetals with isobutyl vinyl ether at room temperature resulted in formation of the two homopolymers. © 1998 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 36: 873–881, 1998     

A practical approach to the synthesis of insect antifeedant tonghaosu analogs

Tonghaosu and its analogs are a class of structurally interesting spiroketal enol‐ether compounds. A practical route to furandiol, a key intermediate for their syntheses, was developed. Using Friedel‐Crafts benzoylation of 3‐(2‐fury I) propyl acetate, a diarylketone was obtained in high yield, which was further transformed into corresponding furandiol by reduction with NaBH₄ in basic medium with simultaneous ester hydrolysis. The furandiol was then cyclized into the desired spiroketal enol‐ether compound in the presence of CuSO₄ 5H₂O.     

Synthesis of coruscanones A and B,metabolites of <Emphasis Type="Italic">Piper coruscans</Emphasis>, and related compounds

Base-catalyzed rearrangements of both individual 4-(acylmethylidene)butenolides and their mixtures prepared by condensation of citraconic anhydride with various phosphoranes occur successfully only in the presence of 5.2% MeONa in MeOH (molar ratio MeONa: substrate ≤ 10: 1, room temperature, 1–2 h). Under these conditions, the yields of 2-cinnamoyl-4-methylcyclopent-4-ene-1,3-dione (coruscanone B) and 2-acetyl-4-methylcyclopent-4-ene-1,3-dione are 56 and 65%, respectively. With a considerable increase in the reaction temperature or the molar ratio MeONa: substrate, formal addition of MeOH to the C(4)=C(5) double bond of these triketones becomes an appreciable (or predominant) process. A reaction of coruscanone B with CH₂N₂ in ether gives coruscanone A as a ~3: 2 mixture of (Z)- and (E)-methyl enolates (43%); other products (10%) result from the expansion and aromatization of the five-membered ring of the triketone. The simplest analog of coruscanone B, 2-acetyl-4-methylcyclopent-4-ene-1,3-dione, reacts with CH₂N₂ in a similar way.     

Regioselectivity of the hydrolysis of 2-(1-alkoxyvinyl)-substituted imidazolidines, 1,3-thiazolidines,and 1,3-oxazolidines

2-(1-Alkoxyvinyl)-1,3-thiazolidines reacted with H₂O or D₂O in the presence of 105 mol % of p-toluenesulfonic acid or trifluoroacetic acid (20°C, 1 h) to give 2-acetyl-1,3-thiazolidine in quantitative yield. 2-(1-Alkoxyvinyl)-3,5-diphenylimidazolidines underwent hydrolysis in the presence of 20 mol % of an acid (20°C, 24 h) at the vinyloxy group with high regioselectivity yielding 2-acetylimidazolidines. Hydrolysis of 2-(1-alkoxyvinyl)-3-phenyl-1,3-oxazolidines in the presence of 10 mol % of p-toluenesulfonic acid (20°C, 5 days) takes two pathways, one of which involves the endocyclic C-O bond with ring opening and the other involves the vinyloxy group to produce 2-acetyl-3-phenyl-1,3-oxazolidine. Unlike phenyl-substituted 1,3-thiazolidines and imidazolidines, hydrolysis of their 3-methyl- and 3,5-dimethyl-substituted analogs in acid medium occurs mainly via ring opening. The observed hydrolysis pathways were interpreted in terms of B3PW91/6-311G(d,p) quantum-chemical calculations.     

Chemistry of pleuromutilins - 12 : A cyclopropyl conjugated system within the tricyclic skeleton of the diterpene pleuromutilin: formation and synthetic use

The conversion of γ-substituted enol ethers to conjugated cyclopropyl ketones which are part of the skeleton of pleuromutilin is described. The nucleophilic opening of the cyclopropane ring is shown to proceed in a highly stereospecific manner. The cyclopropane bond which is cleaved (C₈-C₄) is the one exhibiting the maximum overlap with the π-orbital of the carbonyl group. This reaction offers a convenient method for the stereospecific introduction of an equatorial fluorine at C₈.     

Synthese de nouveaux derives silicies cycliques fonctionnels

Methyl or trimethylsilyl ether derivatives of mono- or di-phenols easily undergo disilylation to give disilylated enol ethers or bis(enoxysilanes) with a 1,4-cyclohexadienic ring which are new classes of intermediates in synthesis. In the case of monophenol derivatives hydrolysis affords stable δ-silyl-β,γ-unsaturated ketones, which are converted to the corresponding conjugated cyclohexenones by desilylation (e.g. 4-allyl-2-cyclohexenone which was previously difficult to prepare). In the case of diphenol derivatives cyclohexanediones are obtained upon hydrolysis. Polysilylation occurs with methyl phenyl thio ether, pyrocatechol and even with o-cresol derivatives, to give new products.     

Functionalization of the Methyl Ketone Fragment in 1-[(1S,3R)-2,2-Dimethyl-3-(2-methoxymethyloxyethyl)cyclopropyl]-2-propanone

Deprotonation of 1-[(1S,3R)-2,2-dimethyl-3-(2-methoxymethyloxyethyl)cyclopropyl]-2-propanone with lithium diisopropylamide in THF at -78°C and subsequent treatment of the resulting enolate with Me₃SiCl yielded mainly the corresponding terminal silyl enol ether. The condensation of intermediate enolate with benzaldehyde regioselectively afforded a mixture of the corresponding aldol and its dehydration product. The reactions of the title ketone with NBS, as well as of the silyl enol ethers derived therefrom with I₂, led to formation of mixtures of products via opening of the cyclopropane ring.     

FeCl3·6H2O-catalyzed selective conjugate reduction of alkylidene-β-keto esters and alkylidene-1,3-diketones

FeCl₃·6H₂O/triethylsilane composite catalyst system is successfully developed for the selective conjugate reduction of carbon-carbon double bond of Michael acceptor-alkylidene-β-keto esters and alkylidene-1,3-diketones under mild reaction conditions to afford the corresponding saturated β-keto esters and 1,3-diketones. The process involves the iron-catalyzed hydrosilylation, followed by in situ hydrolysis of silyl enol ether. The optimal reaction conditions include 20?mol% of FeCl₃·6H₂O and triethylsilane in dichloromethane at room temperature. A broad range of substrates undergoes the reduction in 1, 4-selective manner to afford the corresponding saturated compounds in excellent yields.     

Photoreactions of benzonitrile with cyclic enol ethers

Upon irradiation, cyclic enol ethers such as 1-methoxy-cyclopentene (4) mainly add across the cyano group of benzonitrile (1), under formation of 2-azabutadienes of an imidoester type. This is in agreement with the so-called Δ G-correlation which was reported earlier (ref. 5 and 6). 4-Phenyloxazole (9) is formed from 1 and 1,3-dioxole (5) probably by a similar photochemical process followed by electrocyclic ring opening and hydrolysis. The low yield of the latter photoreaction and the almost exergonic electron transfer between 5 and 1 may point to back electron transfer as the main energy wasting process. From 1 and 2,3-dihydrido-furan (2) only the ortho cycloadduct 6 has been isolated in low yields.     

Synthesis of bicyclo[3.2.1]octanes by a tandem Diels-Alder-carbocation cyclization strategy

The bicyclo[3.2.1]octane ring system is assembled by a three-step process featuring a thermally induced [4+2] cycloaddition followed by a 1,3-benzodithiolium ion mediated cyclization onto an enol or silyl enol ether double bond.     

The synthesis of 6,6′-cyclo-6′-deoxyhexofuranosyluracils via a diazomethane-promoted ring-enlargement reaction

The protected 5′-oxo-6,5′-cyclouridine 13 reacts with diazomethane to afford mostly the spiro-epoxide 18 (79%), but it also undergoes ring-expansion to give the corresponding 5′-oxo-6,6′-cyclonucleoside 16. Under the conditions of the reaction, ketone 16 reacts further with diazomethane to give the enol ether 20 (12% overall), the isomeric 4-methoxy nucleoside 15 (2%), and the spiro-epoxide 19 (4.4%). Acid hydrolysis of the enol ether 20 , followed by reduction of the resulting ketone with sodium borohydride, affords a separable mixture of the 5′S (L-talo) and 5′R (D-allo) methylene-bridged cyclonucleosides 7 and 8 , respectively. From proton nmr measurements, it appears that the 6′-methylene groups of these cyclonucleosides project towards the 2′,3′-edge of the furanose ring.     

Synthesis and Biological Activity of 7,8,9‐Trideoxy‐ and 7R DesTHP‐Peloruside A

The stereoselective syntheses of 7,8,9‐trideoxypeloruside A ( 4 ) and a monocyclic peloruside A analogue lacking the entire tetrahydropyran moiety ( 3 ) are described. The syntheses proceeded through the PMB‐ether of an ω‐hydroxy β‐keto aldehyde as a common intermediate which was elaborated into a pair of diastereomeric 1,3‐syn and ‐anti diols by stereoselective Duthaler–Hafner allylations and subsequent 1,3‐syn or anti reduction. One of these isomers was further converted into a tetrahydropyran derivative in a high‐yielding Prins reaction, to provide the precursor for bicyclic analogue 4 . Downstream steps for both syntheses included the substrate‐controlled addition of a vinyl lithium intermediate to an aldehyde, thus connecting the peloruside side chain to C15 (C13) of the macrocyclic core structure in a fully stereoselective fashion. In the case of monocyclic 3 macrocyclization was based on ring‐closing olefin metathesis (RCM), while bicyclic 4 was cyclized through Yamaguchi‐type macrolactonization. The macrolactonization step was surprisingly difficult and was accompanied by extensive cyclic dimer formation. Peloruside A analogues 3 and 4 inhibited the proliferation of human cancer cell lines in vitro with micromolar and sub‐micromolar IC₅₀ values, respectively. The higher potency of 4 highlights the importance of the bicyclic core structure of peloruside A for nM biological activity.     

d-生物素的不对称全合成研究(Ⅱ)

1,3－二苄基咪唑啉－2－酮－顺－4,5－二羟酸经脱水、单酯化,折分成分（4S,5R）－顺1,3－二苄基－5－甲氧基羧基－2－氧代咪唑啉－4－羧酸,再经还原环合,硫代成(3aS,6aR)-1,3－二苄基－四氢－4H－噻吩并[3,4-d)咪唑－2,4（1H)-二酮（7）,后者经格氏反应、脱水、还原、裂解环合一锅合成（3aR,8aS,8bS)－1,3－二苄基－2－氧代十氢咪唑[3,4-d]噻吩并[1,2-a]锍翁溴化物（11）,继而经缩合、开环、水解、脱羧、脱苄而得d－生物素（1）,总收率为14．5％。     

Rhodium-catalyzed phenylthiolation reaction of heteroaromatic compounds using α-(phenylthio)isobutyrophenone

In the presence of catalytic amounts of RhH(PPh₃)₄ and 1,2-bis(diphenylphosphino)ethane (dppe), 1,3-benzothiazoles, 1,3-benzoxazoles, and benzothiophene reacted with α-(phenylthio)isobutyrophenone giving 2-phenylthio derivatives. Reactive monocyclic heteroaromatics, 1-methyl-1,2,3,4-tetrazole and 2-cyanothiophene were also converted into the 5-phenylthio derivatives. The use of an appropriate phenylthio transfer reagent is crucial for the efficient catalyzed conversion of heteroaromatic C-H bonds into C-S bonds.     

The reaction of Grignard reagents with 1,3-dioxolanes : III. A novel synthetic route to β-hydroxyalkyl enol ethers

The reaction of ethylmagnesium bromide, prepared in benzene with one or more molar equivalents of triethylamine, with 2-, 2,4- and 2,4,5-substituted 1,3-dioxolanes has been investigated. Besides β-hydroxyethyl sec-alkyl ethers, the normal products of the ring opening/addition reaction encountered with other Lewis bases, 2-hydroxyethyl enol ethers were formed as products of a ring opening/elimination reaction. Kinetic studies suggest an E₁ mechanism for this novel reaction.     

Catalytic opening of the diaziridine fragment in 6-aryl-1,5-diazabicyclo[3.1.0]hexanes

Treatment of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes with Lewis acids [BF₃·Et₂O or In(OTf)₃] promotes opening of the diaziridine ring, followed by formation of 1,3-dipolar cycloaddition products with N-arylmaleimides. The conversion of the initial diaziridine depends on the nature of the 6-aryl group. Diazabicyclohexanes with donor substituents react quantitatively to give (in the absence of dipolarophiles) the corresponding azomethine imine dimers, 1,2,4,5-tetrazine derivatives. The conversion of diazabicyclohexanes having acceptor substituents is poor; simultaneously, the fraction of the hydrolysis products increases. The stereoselectivity in the 1,3-dipolar cycloaddition, i.e. the ratio of the cis-and trans-adducts, depends on the catalyst and solvent. Azomethine imine dimers react with N-arylmaleimides in the presence of indium(III) trifluoromethanesulfonate to give the same 1,3-dipolar cycloaddition products as those obtained from parent 1,5-diazabicyclohexanes.