Cycloaddition Of Dichloroketene Research Articles

Synthesis and Reactivity of Spirocarbocycles as Scaffolds for Nucleoside Analogues.

A novel class of substituted spiro[3.4]octanes can be accessed via a [2 + 2]-cycloaddition of dichloroketene on a readily prepared exo-methylene cyclopentane building block. This reaction sequence was found to be robust on a multigram scale and afforded a central spirocyclobutanone scaffold for carbocyclic nucleosides. The reactivity of this constrained building block was evaluated and compared to the corresponding 4'-spirocyclic furanose analogues. Density functional theory calculations were performed to support the observed selectivity in the carbonyl reduction of spirocyclobutanone building blocks. Starting from novel spirocyclic intermediates, we exemplified the preparation of an undescribed class of carbocyclic nucleoside analogues and provided a proof of concept for application as inhibitors for the protein methyltransferase target PRMT5.

Preparation of 4'-Spirocyclobutyl Nucleoside Analogues as Novel and Versatile Adenosine Scaffolds.

Despite the large variety of modified nucleosides that have been reported, the preparation of constrained 4'-spirocyclic adenosine analogues has received very little attention. We discovered that the [2+2]-cycloaddition of dichloroketene on readily available 4'-exo-methylene furanose sugars efficiently results in the diastereoselective formation of novel 4'-spirocyclobutanones. The reaction mechanism was investigated via density functional theory (DFT) and found to proceed either via a non-synchronous or stepwise reaction sequence, controlled by the stereochemistry at the 3'-position of the sugar substrate. The obtained dichlorocyclobutanones were converted into nucleoside analogues, providing access to a novel class of chiral 4'-spirocyclobutyl adenosine mimetics in eight steps from commercially available sugars. Assessment of the biological activity of designed 4'-spirocyclic adenosine analogues identified potent inhibitors for protein methyltransferase target PRMT5.

Formation of β-Lactones by [2+2] Cycloaddition of Dichloroketene with Unreactive Carbonyl Compounds

We report a modified process that dichloroketene generated in situ from trichloroacetyl chloride and Zn powder reacts with unreactivate carbonyl groups to afford dichloro-β-lactones in moderate to good yields. Subse-quently, monochloro-β-lactones, β-lactones and β-hydroxy ester are obtained by dechlorination under different reac-tion conditions.

C12H12 interconversions: Two non-pyrolytic syntheses of tricyclo[5.3.2.04,8]dodeca-2,5,9,11-tetraene

Herein, we describe two independent and non-pyrolytic syntheses of an important C12H12 hydrocarbon which had been prepared previously by gas phase thermolysis of compound 6. The first method is based on an unusual dipolar cycloaddition of dichloroketene onto bullvalene. After reductive dechlorination, a Shapiro-Heath reaction of the tosylhydrazone gave the title compound. Alternatively, compound 13 is also obtained from its isomer 6 by a Ag+ catalyzed reaction.

Simple synthesis of conformationally fixed glycosamine analogues by beckmann rearrangement at the carbohydrate ring.

Conformationally fixed carbohydrate analogues are promising small-molecule inhibitors for hydrolases like O-GlcNAcase (OGA); however, their synthesis usually requires many steps. Herein we describe cycloadditions of dichloroketene to various glycals and subsequent Beckmann rearrangements, which offer an easy and stereoselective entry to glycosamine derivatives in good yields. The reactions are applicable for hexoses, pentoses, and disaccharides, and transformations to the corresponding imidates proceed smoothly. First biological tests reveal that such imidates indeed inhibit human OGA.

Total Synthesis of (+)-Hyacinthacine A6 and (+)-Hyacinthacine A7

(+)-Hyacinthacines A₆ and A₇ have been synthesized from a common, late-stage intermediate, prepared in high yield through stereoselective [2+2] cycloaddition of dichloroketene to a chiral enol ether. The flexibility of aminonitrile chemistry is central to the approach.

ChemInform Abstract: An Efficient Method for Hydroazulenone from Bicyclo(3.3.0)octanone via Two Carbon Annulation.

Abstract Hydroazulenones and hydroazulenediones are prepared efficiently from bicyclo[3.3.0]octanones via two carbon annulation utilizing thermal [2+2] cycloaddition of dichloroketene and fluoride or chloride induced fragmentation of the cycloadduct.

ChemInform Abstract: Sterically Hindered Halogenocyclobutanones. Part 11. (2 + 2) Cycloaddition of Dichloroketene to (Bromomethylene)cyclopropane and Some Transformations of the Adduct.

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Nonchiral-Pool Synthesis of (+)-Hyacinthacine B1

The first nonchiral-pool total synthesis of (+)-hyacinthacine B1 has been achieved. The synthesis uses as key steps an efficient [2+2] cycloaddition of dichloroketene to a chiral enol ether, two diastereoselective Bruylants-like alkylations, and an effective double Tamao-Fleming oxidation.

Approach to the hyacinthacines: first non-chiral pool synthesis of (+)-hyacinthacine A1

The first non-chiral pool total synthesis of (+)-hyacinthacine A(1) is described. This synthesis is based on an effective [2 + 2] cycloaddition of dichloroketene to a Stericol-based enol ether, a diastereoselective dihydroxylation, and an efficient Tamao-Fleming oxidation.

Asymmetric [2 + 2] Cycloaddition: Total Synthesis of (−)-Swainsonine and (+)-6-Epicastanospermine

[reaction: see text] An asymmetric total synthesis of (-)-swainsonine and (+)-6-epicastanospermine is described from a common intermediate, which is obtained through diastereoselective [2 + 2] cycloaddition of dichloroketene to a chiral enol ether.

Abnormal Beckmann rearrangement of steroidal α-chlorocyclobutanone oximes: the fragmentation–substitution reaction

α,α-Dichlorocyclobutanones of various substitution patterns, readily available by the thermal cycloaddition of dichloroketene to steroid olefins, were selectively dehalogenated and further transformed to α-chlorocyclobutanone oximes. In contrast to the Beckmann rearrangement of the α-unsubstituted oximes, α-chlorocyclobutanone oximes, on treatment with thionyl chloride in benzene, gave normal and abnormal reaction products. In all reactions studied, the Beckmann fragmentation–substitution was the major process. The rearrangement of α-chlorocyclobutanone oximes is the key step of the novel method for geminal functionalization of carbonyl carbon atom in ketones and regioselective vicinal functionalization of unsymmetrical olefins. The regiochemistry observed in the rearrangements is supported by semiempirical calculations (AM1).

Unusual Dimethyl Ketal from Cycloadduct of 4,6‐O‐Benzylidene‐D‐allal and Dichloroketene.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Extending the Scope of the [2 + 2] Cycloaddition of Dichloroketene to Chiral Enol Ethers: Synthesis of (‐)‐Detoxinine.

AbstractFor Abstract see ChemInform Abstract in Full Text.

New Asymmetric Approach to Natural Pyrrolizidines: Synthesis of (+)-Amphorogynine A, (+)-Amphorogynine D, and (+)-Retronecine

Three natural pyrrolizidines, (+)-amphorogynines A and D and (+)-retronecine, have been prepared from a common lactam intermediate. This central compound, in turn, was synthesized in diastereomerically enriched form through a highly selective [2 + 2]-cycloaddition of dichloroketene with a chiral enol ether, followed by Beckmann ring expansion and reduction. Subsequent stereocenters were then cleanly introduced through internal induction.

Unusual Dimethyl Ketal from Cycloadduct of 4,6-O-Benzylidene-D-allal and Dichloroketene

Glycal derivatives are useful building blocks in organic synthesis as well as in carbohydrate chemistry. Cycloadditions of dichloroketene to tri-O-benzyl or tri-O-acetylD-glucal and D-galactal were reported to produce α-oriented cyclobutanone ring, and the resulting bicyclic cyclobutanones were converted into lactone compounds by oxidation. Although they showed high stereo and regioselectivity with moderate yield, this methodology has not been widely applied for synthetic purpose. For the last few years, we have studied the cycloaddition of ketene to glucal, galactal, and allal derivatives and their application for the synthesis of C-glycoside derivatives and modified nucleosides. Even though, in case of allal, β-oriented cyclobutane ring formation is reported, no direct evidence supporting the face selectivity of dichloroketene cycloaddition to allal derivatives has been reported yet. Thus herein we report the X-ray structure of an unusual ketal from allal-derivative as the evidence that the facial selectivity of cycloaddition to glycal is controlled by the stereochemistry of C-3 constituent and discuss the mechanism for the formation of the unsual dimethyl ketal. To substantiate the evidence for facial selectivity, glucal and allal derivatives (1 and 3, respectively) were subject to dichloroketene cycloaddition reaction and treated with sodium methoxide in methanol. As expected, 3-O-benzyl4,6-O-benzilidene-D-glucal (1) was converted to C-1 and C-2 dialkylated C-glycoside, 3-O-benzyl-4,6-O-benzylidene1-dichloromethyl-2-methoxycarbonyl-1,2-dideoxy-α-D-glucopyranoside (2) in 73% yield. To our surprise, 3-O-benzyl4,6-O-benzylidene-D-allal (3) provided two products, O-benzyl-4,6-O-benzylidene-1-dichloromethyl-2-methoxycarbonyl-1,2-dideoxy-β-D-altropyranoside (4a) and dimethyl ketal (5a), in 36% and 29% isolated yield from allal (3), respectively (Scheme 1). The stereochemistry of C2 of 2 was determined by coupling constant between H2 and H3 (9.3 Hz, 1,2-diaxial orientation) and the previous results from glucal and galactal. Although C-glycoside from allalderivative has not been reported in the literature, methoxy carbonyl group on C2 of 4a was determined to orient axially based on coupling constant between H2 and H3 (3 Hz, 1,2diequatorial). This assignment of stereochemistry of C2 was confirmed by X-ray structure of 5a. In solid state the ketal (5a) has chair conformation of benzlylidene unit, twisted chair conformation of six membered sugar ring, and axial orientation of C3 benzyloxy substituent. Besides, more importantly, cyclobutanone is located on β-face of sugar ring, showed in Figure 1. This stereochemistry is attributed to the steric hindrance of bulky group on C3, which prevented dichloroketene from reacting on the α-face of allal effectively. To the best of our knowledge, the x-ray structure of allal-derived cycloaddition products has not been disclosed yet. Accordingly, we can

Formal Synthesis of (+)-Anatoxin-a by Asymmetric [2+2] Cycloaddition

A formal asymmetric synthesis of (+)-anatoxin-a, a neurotoxic alkaloid from Anabaena flos aquae, has been achieved through a highly diastereoselective [2+2] cycloaddition of dichloroketene with a chiral enol ether.

Cyclobutanone Approach to the Synthesis of Cardenolides

Abstract17β‐(3‐Oxocyclobutyl)androstane, prepared by the thermal [2 + 2] cycloaddition of dichloroketene to 3β‐acetoxypregna‐5,20‐diene, is the key intermediate in the new, efficient synthesis of steroids bearing the 17β‐butenolide fragment that characterizes cardenolides. The six‐step synthesis of 3β‐tert‐butyldimethylsilyloxy‐14α‐carda‐5,20(22)‐dienolide was achieved with a total yield of 32%. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Extending the Scope of the [2+2] Cycloaddition of Dichloroketene to Chiral Enol Ethers: Synthesis of (-)-Detoxinine

Allylic oxidation of a known lactam, obtained by asymmetric [2+2] cycloaddition of dichloroketene to a chiral enol ether, followed by Beckmann ring expansion and dechlorination, affords a potential intermediate for the synthesis of various natural products. The usefulness of this intermediate is first demonstrated by an asymmetric synthesis of (-)-detoxinine.

First Comprehensive Bakkane Approach: Stereoselective and Efficient Dichloroketene‐Based Total Syntheses of (.+‐.)‐ and (‐)‐9‐Acetoxyfukinanolide, (.+‐.)‐ and (+)‐Bakkenolide A, (‐)‐Bakkenolides III, B, C, H, L, V, and X, (.+‐.)‐ and (‐)‐Homogynolide A, (.+‐.)‐Homogynolide B, and (.+‐.)‐Palmosalide C.

AbstractFor Abstract see ChemInform Abstract in Full Text.