SUMMARYNeurons from layer II of the entorhinal cortex (ECII) are the first to accumulate tau prot... more SUMMARYNeurons from layer II of the entorhinal cortex (ECII) are the first to accumulate tau protein aggregates and degenerate during prodromal Alzheimer’s disease. Here, we use a data-driven functional genomics approach to model ECII neuronsin silicoand identify the proto-oncogene DEK as a potential driver of tau pathology. By modulating DEK levels in EC neuronsin vitroandin vivo, we first validate the accuracy and cell-type specificity of our network predictions. We then show thatDeksilencing changes the inducibility of immediate early genes and alters neuron excitability, leading to dysregulation of neuronal plasticity genes. We further find that loss of function of DEK leads to tau accumulation in the soma of ECII neurons, reactivity of surrounding microglia, and eventually microglia-mediated neuron loss. This study validates a pathological gene discovery tool that opens new therapeutic avenues and sheds light on a novel pathway driving tau pathology in vulnerable neurons.
F1000 - Post-publication peer review of the biomedical literature, 2010
Chemical reactions that facilitate the attachment of synthetic groups to proteins are useful tool... more Chemical reactions that facilitate the attachment of synthetic groups to proteins are useful tools for the field of chemical biology and enable the incorporation of proteins into new materials. We have previously reported a pyridoxal 5′-phosphate (PLP) mediated reaction that site-specifically oxidizes the N-terminal amine of a protein to afford a ketone. This unique functional group can then be used to attach a reagent of choice through oxime formation. Since its initial report, we have found that the N-terminal sequence of the protein can significantly influence the overall success of this strategy. To obtain short sequences that lead to optimal conversion levels, an efficient method for the evaluation of all possible N-terminal amino acid combinations was needed. This was achieved by developing a generalizable combinatorial peptide library screening platform suitable for the identification of sequences that display high levels of reactivity toward a desired bioconjugation reaction. In the context of N-terminal transamination, a highly reactive alanine-lysine motif emerged, which was confirmed to promote the modification of peptide substrates with PLP. This sequence was also tested on two protein substrates, leading to substantial increases in reactivity relative to their wild type termini. This readily-encodable tripeptide thus appears to provide a significant improvement in the reliability with which the PLPmediated bioconjugation reaction can be used. This study also provides an important first example of how synthetic peptide libraries can accelerate the discovery and optimization of protein bioconjugation strategies.
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Many of the Annonaceous acetogenins, particularly those containing a bis-THF moiety, exhibit outs... more Many of the Annonaceous acetogenins, particularly those containing a bis-THF moiety, exhibit outstanding cytotoxicity and pesticidal activity. Their remarkable structural diversity suggests that a complete chemical library of these compounds should be prepared and systematically screened. We show here several approaches to meet this synthetic challenge using the naked carbon skeleton strategy as well as a convergent synthesis. The key transformations include the Sharpless asymmetric dihydroxylation reaction, the Mitsunobu inversion of alcohols and ligand-assisted chirality transfer methods based on rhenium and vanadium oxides. These approaches provide an easy access to naturally occurring acetogenins (e.g. asimicin, bullatacin, trilobacin, rolliniastatin and solamin) as well as the non-natural isomers. Jntroduction To date, more than 230 different acetogenins have been isolated from 26 plants of the Annonaceae.[l] Many of these Annonaceous acetogenins have exhibited remarkable cytotoxic, antitumor, antimalarial, immunosuppressive, pesticidal and antifeedant activities.[2] For example, studies with human solid-tumor cell-lines show that some of the bis-THF derivatives, such as compounds 1-4 (Scheme 1), are many orders of magnitude more cytotoxic than adriamycin.[s] Interestingly, these fatty acid derivatives share very similar carbon skeletons, with their striking diversity originating mainly from the relative and absolute configuration of their various stereogenic oxygen functions.
An attempt was made to mimic cytochrome P-450-like activity using antibodies elicited against met... more An attempt was made to mimic cytochrome P-450-like activity using antibodies elicited against metallo-porphyrins. Monoclonal antibodies raised against a water-soluble Sn(1V) porphyrin complex (1) exhibited Specificity for a variety of monomeric metalloporphyrins, as well as for the b-0x0-Fe(II1) porphyrin dimer 2. Some antibodies were found to be more selective for the monomer 1 than for the dimer 2 , suggesting an "edge-on" recognition of the planar porphyrin molecule. The catalytic activity of the antibody-metalloporphyrin complexes was investigated using the epoxidation of styrene by iodosobenzene as a model reaction. Three biphasic media were studied for this reaction: reverse micelles, microemulsions, and solid catalyst in organic solvent. The most promising results were obtained with solid catalyst (obtained via lyophilization of equimolar amounts of Mn(TCP)Cl and specific antibody) in dry CHzClz at room temperature, as indicated by the high turnover numbers of the catalyst. A difference in the relative activity of the various monoclonal antibodies (MABs) was noted. The anti-1 antibodies displayed ca. 30-60% higher activity compared to a nonrelevant MAB.
The consecutive oxidative polycyclization reaction with rhenium(VII) oxides represents a highly s... more The consecutive oxidative polycyclization reaction with rhenium(VII) oxides represents a highly stereoselective synthetic tool by which polyenes that contain a bis-homoallylic alcohol can be transformed into poly-THF products in a single step. On the basis of a detailed study with model substrates, a set of rules is proposed to predict product configurations in the polycyclization reactions with trifluoroacetylperrhenate. This methodology is exceptionally useful for the synthesis of polyoxygenated carbon skeletons that contain many stereogenic centers, and for the Annonaceous acetogenins in particular. Many of these potent antitumor agents, including solamin, reticulatacin, asimicin, bullatacin, trilobin, trilobacin, squamotacin, rolliniastatin, uvaricin, rollidecins C and D, mucocin, goniocin, and cyclogoniodenin T, as well as chemical libraries of non-natural analogs, were synthesized using the oxidative polycyclization reaction in combination with the Sharpless AD and AE reactions.
Proceedings of the National Academy of Sciences, 2003
Proposing that a blend of the chemical diversity of small synthetic molecules with the immunologi... more Proposing that a blend of the chemical diversity of small synthetic molecules with the immunological characteristics of the antibody molecule will lead to therapeutic agents with superior properties, we here present a device that equips small synthetic molecules with both effector function and long serum half-life of a generic antibody molecule. As a prototype, we developed a targeting device that is based on the formation of a covalent bond of defined stoichiometry between a 1,3-diketone derivative of an integrin α v β 3 and α v β 5 targeting Arg-Gly-Asp peptidomimetic and the reactive lysine of aldolase antibody 38C2. The resulting complex was shown to ( i ) spontaneously assemble in vitro and in vivo , ( ii ) selectively retarget antibody 38C2 to the surface of cells expressing integrins α v β 3 and α v β 5 , ( iii ) dramatically increase the circulatory half-life of the Arg-Gly-Asp peptidomimetic, and ( iv ) effectively reduce tumor growth in animal models of human Kaposi's ...
Proceedings of the National Academy of Sciences, 2004
Prodrugs of dynemicin analogs were synthesized, and their activation by aldolase antibody (Ab) 38... more Prodrugs of dynemicin analogs were synthesized, and their activation by aldolase antibody (Ab) 38C2 was evaluated by DNA-cleaving activity, as well as tumor cell growth inhibition. Further, we provide evidence that the activated enediynes underwent covalent crosscoupling with the aldolase Ab, which appears to be a limiting factor of their tumor cell growth-inhibiting activity and should be of general interest in the field of enediyne chemotherapy. These findings might open new avenues for defined conjugations of small molecule drugs to mAbs in general and aldolase Abs in particular.
The structures of two isomeric C 28 -sterols isolated from Physalis minima Linn. var. indica were... more The structures of two isomeric C 28 -sterols isolated from Physalis minima Linn. var. indica were elucidated as ergosta-5,25-dien-3?,24?,-diol and ergosta-5,24(28)-dien-3?,25-diol on the basis of detailed spectral analysis. The isolated sterols are regarded as precursors in the ...
The structure of withaminimin, a new ergostane-type steroid from Physolis minima, was established... more The structure of withaminimin, a new ergostane-type steroid from Physolis minima, was established by spectral analysis ('H and 13C NMR, MS) and chemical transformations, as (2OS, 22R)-15a-acetoxy-5a,6j?.14atrihydroxy-1-oxowitha-2,16,24-trienolide. An unusual MH20t quasi-molecular ion was observed in the chemical ionization mass spectrum of the natural product.
Dibutylboron triflate/diisopropylethylamine mediated aldol-type cyclization provides an expedient... more Dibutylboron triflate/diisopropylethylamine mediated aldol-type cyclization provides an expedient route for the stereoselective synthesis of cyclic ethers in a single step. The method is highly efficient for the stereoselective synthesis of 4-cis-tetrahydropyranones. The reaction is proposed to proceed via an S N 1-type mechanism through a chair-like transition state, in which both substituents occupy equatorial positions. The aldol addition reaction is undoubtedly among the most powerful methods for the formation of carbon-carbon bonds. 1 A number of new methods, including enantioselective and catalytic processes, have been developed. 1a,b Despite these developments, however, the aldol-type reaction between a carbonyl compound and an acetal has remained less explored. In 1974, Mukaiyama discovered the Ti(IV)catalyzed reaction of silyl enol ethers with acetals to produce-alkoxy carbonyl compounds (eq 1). 2 The process, 3,4 which requires preformation of the silyl enol ethers, can also be accomplished in a single step by in situ generation of corresponding enol ethers (eq 2). 5,6 Nonetheless, the im
Metal ions in the active sites of many metalloenzymes exhibit distinctive spectral and chemical f... more Metal ions in the active sites of many metalloenzymes exhibit distinctive spectral and chemical features which are different from those of small inorganic complexes. These features are the result of the unusual geometric and electronic constraints that are imposed on the metal ion within the protein environment. Much effort has been invested to try to mimic this feature of metalloenzymes in synthetic systems, but this remains a formidable task. Here we show that one of the key lessons learned from the science of catalytic antibodies--that binding energy can be converted into chemical energy--can be exploited to 'fine-tune' the physicochemical properties of a metal complex. We show that an antibody's binding site can reversibly perturb the coordination geometry of a metal ion, and can stabilize a high-energy coordinated species. Specifically, antibodies designed to bind the organosilicon compound 1 also bind the geometrically similar Cu(I) complex 2. However, the antibody binds a slightly compressed form of 2, which is closer in size to 1. This distortion is manifested by a spectral shift--an 'immunochromic' effect.
Since its inception, not too long ago, the science of catalytic antibodies has undergone a remark... more Since its inception, not too long ago, the science of catalytic antibodies has undergone a remarkable maturation process.' From initial "proof of concept" and demonstration of fundamental, enzyme-like characteristics, antibodies have been shown to catalyze a broad scope of organic transformations, including difficult and unfavorable chemical reactions2 The relevance of the field to synthetic organic chemistry has been demonstrated recently by the ability to run these reactions with gram-scale q~antities.~ Here we go one step further and show for the first time that catalytic antibodies can be effectively used in natural product synthesis. (-)-a-Multistriatin, 1, is an essential component of the aggregation pheromone of the European elm bark beetle, Scolytus multistriatus (Marsham), which is the principal vector of Dutch elm d i~e a s e .~ The severe devastation of the elm population in the northeastem United States has resulted in extensive studies of the synthesis5 and field ~t i l i z a t i o n~*~ of 1. In order to achieve the required absolute configuration in all four asymmetric centers (lS,2R,4S,5R), most of the previous syntheses of 1 employ enantiomerically pure natural products as starting material^.^ We focused on the opportunity to achieve the required chirality via asymmetric synthesis of ketone 2 using antibody catalysis. Monoclonal antibody 14D9 has already been proven an effective catalyst for hydrolysis of a variety of substrates that are structurally related to 2, including a cyclic acetal,8 k e t a l~,~ epoxides,I0 and enol One could therefore expect that ketone 2 would be readily available by
SUMMARYNeurons from layer II of the entorhinal cortex (ECII) are the first to accumulate tau prot... more SUMMARYNeurons from layer II of the entorhinal cortex (ECII) are the first to accumulate tau protein aggregates and degenerate during prodromal Alzheimer’s disease. Here, we use a data-driven functional genomics approach to model ECII neuronsin silicoand identify the proto-oncogene DEK as a potential driver of tau pathology. By modulating DEK levels in EC neuronsin vitroandin vivo, we first validate the accuracy and cell-type specificity of our network predictions. We then show thatDeksilencing changes the inducibility of immediate early genes and alters neuron excitability, leading to dysregulation of neuronal plasticity genes. We further find that loss of function of DEK leads to tau accumulation in the soma of ECII neurons, reactivity of surrounding microglia, and eventually microglia-mediated neuron loss. This study validates a pathological gene discovery tool that opens new therapeutic avenues and sheds light on a novel pathway driving tau pathology in vulnerable neurons.
F1000 - Post-publication peer review of the biomedical literature, 2010
Chemical reactions that facilitate the attachment of synthetic groups to proteins are useful tool... more Chemical reactions that facilitate the attachment of synthetic groups to proteins are useful tools for the field of chemical biology and enable the incorporation of proteins into new materials. We have previously reported a pyridoxal 5′-phosphate (PLP) mediated reaction that site-specifically oxidizes the N-terminal amine of a protein to afford a ketone. This unique functional group can then be used to attach a reagent of choice through oxime formation. Since its initial report, we have found that the N-terminal sequence of the protein can significantly influence the overall success of this strategy. To obtain short sequences that lead to optimal conversion levels, an efficient method for the evaluation of all possible N-terminal amino acid combinations was needed. This was achieved by developing a generalizable combinatorial peptide library screening platform suitable for the identification of sequences that display high levels of reactivity toward a desired bioconjugation reaction. In the context of N-terminal transamination, a highly reactive alanine-lysine motif emerged, which was confirmed to promote the modification of peptide substrates with PLP. This sequence was also tested on two protein substrates, leading to substantial increases in reactivity relative to their wild type termini. This readily-encodable tripeptide thus appears to provide a significant improvement in the reliability with which the PLPmediated bioconjugation reaction can be used. This study also provides an important first example of how synthetic peptide libraries can accelerate the discovery and optimization of protein bioconjugation strategies.
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Many of the Annonaceous acetogenins, particularly those containing a bis-THF moiety, exhibit outs... more Many of the Annonaceous acetogenins, particularly those containing a bis-THF moiety, exhibit outstanding cytotoxicity and pesticidal activity. Their remarkable structural diversity suggests that a complete chemical library of these compounds should be prepared and systematically screened. We show here several approaches to meet this synthetic challenge using the naked carbon skeleton strategy as well as a convergent synthesis. The key transformations include the Sharpless asymmetric dihydroxylation reaction, the Mitsunobu inversion of alcohols and ligand-assisted chirality transfer methods based on rhenium and vanadium oxides. These approaches provide an easy access to naturally occurring acetogenins (e.g. asimicin, bullatacin, trilobacin, rolliniastatin and solamin) as well as the non-natural isomers. Jntroduction To date, more than 230 different acetogenins have been isolated from 26 plants of the Annonaceae.[l] Many of these Annonaceous acetogenins have exhibited remarkable cytotoxic, antitumor, antimalarial, immunosuppressive, pesticidal and antifeedant activities.[2] For example, studies with human solid-tumor cell-lines show that some of the bis-THF derivatives, such as compounds 1-4 (Scheme 1), are many orders of magnitude more cytotoxic than adriamycin.[s] Interestingly, these fatty acid derivatives share very similar carbon skeletons, with their striking diversity originating mainly from the relative and absolute configuration of their various stereogenic oxygen functions.
An attempt was made to mimic cytochrome P-450-like activity using antibodies elicited against met... more An attempt was made to mimic cytochrome P-450-like activity using antibodies elicited against metallo-porphyrins. Monoclonal antibodies raised against a water-soluble Sn(1V) porphyrin complex (1) exhibited Specificity for a variety of monomeric metalloporphyrins, as well as for the b-0x0-Fe(II1) porphyrin dimer 2. Some antibodies were found to be more selective for the monomer 1 than for the dimer 2 , suggesting an "edge-on" recognition of the planar porphyrin molecule. The catalytic activity of the antibody-metalloporphyrin complexes was investigated using the epoxidation of styrene by iodosobenzene as a model reaction. Three biphasic media were studied for this reaction: reverse micelles, microemulsions, and solid catalyst in organic solvent. The most promising results were obtained with solid catalyst (obtained via lyophilization of equimolar amounts of Mn(TCP)Cl and specific antibody) in dry CHzClz at room temperature, as indicated by the high turnover numbers of the catalyst. A difference in the relative activity of the various monoclonal antibodies (MABs) was noted. The anti-1 antibodies displayed ca. 30-60% higher activity compared to a nonrelevant MAB.
The consecutive oxidative polycyclization reaction with rhenium(VII) oxides represents a highly s... more The consecutive oxidative polycyclization reaction with rhenium(VII) oxides represents a highly stereoselective synthetic tool by which polyenes that contain a bis-homoallylic alcohol can be transformed into poly-THF products in a single step. On the basis of a detailed study with model substrates, a set of rules is proposed to predict product configurations in the polycyclization reactions with trifluoroacetylperrhenate. This methodology is exceptionally useful for the synthesis of polyoxygenated carbon skeletons that contain many stereogenic centers, and for the Annonaceous acetogenins in particular. Many of these potent antitumor agents, including solamin, reticulatacin, asimicin, bullatacin, trilobin, trilobacin, squamotacin, rolliniastatin, uvaricin, rollidecins C and D, mucocin, goniocin, and cyclogoniodenin T, as well as chemical libraries of non-natural analogs, were synthesized using the oxidative polycyclization reaction in combination with the Sharpless AD and AE reactions.
Proceedings of the National Academy of Sciences, 2003
Proposing that a blend of the chemical diversity of small synthetic molecules with the immunologi... more Proposing that a blend of the chemical diversity of small synthetic molecules with the immunological characteristics of the antibody molecule will lead to therapeutic agents with superior properties, we here present a device that equips small synthetic molecules with both effector function and long serum half-life of a generic antibody molecule. As a prototype, we developed a targeting device that is based on the formation of a covalent bond of defined stoichiometry between a 1,3-diketone derivative of an integrin α v β 3 and α v β 5 targeting Arg-Gly-Asp peptidomimetic and the reactive lysine of aldolase antibody 38C2. The resulting complex was shown to ( i ) spontaneously assemble in vitro and in vivo , ( ii ) selectively retarget antibody 38C2 to the surface of cells expressing integrins α v β 3 and α v β 5 , ( iii ) dramatically increase the circulatory half-life of the Arg-Gly-Asp peptidomimetic, and ( iv ) effectively reduce tumor growth in animal models of human Kaposi's ...
Proceedings of the National Academy of Sciences, 2004
Prodrugs of dynemicin analogs were synthesized, and their activation by aldolase antibody (Ab) 38... more Prodrugs of dynemicin analogs were synthesized, and their activation by aldolase antibody (Ab) 38C2 was evaluated by DNA-cleaving activity, as well as tumor cell growth inhibition. Further, we provide evidence that the activated enediynes underwent covalent crosscoupling with the aldolase Ab, which appears to be a limiting factor of their tumor cell growth-inhibiting activity and should be of general interest in the field of enediyne chemotherapy. These findings might open new avenues for defined conjugations of small molecule drugs to mAbs in general and aldolase Abs in particular.
The structures of two isomeric C 28 -sterols isolated from Physalis minima Linn. var. indica were... more The structures of two isomeric C 28 -sterols isolated from Physalis minima Linn. var. indica were elucidated as ergosta-5,25-dien-3?,24?,-diol and ergosta-5,24(28)-dien-3?,25-diol on the basis of detailed spectral analysis. The isolated sterols are regarded as precursors in the ...
The structure of withaminimin, a new ergostane-type steroid from Physolis minima, was established... more The structure of withaminimin, a new ergostane-type steroid from Physolis minima, was established by spectral analysis ('H and 13C NMR, MS) and chemical transformations, as (2OS, 22R)-15a-acetoxy-5a,6j?.14atrihydroxy-1-oxowitha-2,16,24-trienolide. An unusual MH20t quasi-molecular ion was observed in the chemical ionization mass spectrum of the natural product.
Dibutylboron triflate/diisopropylethylamine mediated aldol-type cyclization provides an expedient... more Dibutylboron triflate/diisopropylethylamine mediated aldol-type cyclization provides an expedient route for the stereoselective synthesis of cyclic ethers in a single step. The method is highly efficient for the stereoselective synthesis of 4-cis-tetrahydropyranones. The reaction is proposed to proceed via an S N 1-type mechanism through a chair-like transition state, in which both substituents occupy equatorial positions. The aldol addition reaction is undoubtedly among the most powerful methods for the formation of carbon-carbon bonds. 1 A number of new methods, including enantioselective and catalytic processes, have been developed. 1a,b Despite these developments, however, the aldol-type reaction between a carbonyl compound and an acetal has remained less explored. In 1974, Mukaiyama discovered the Ti(IV)catalyzed reaction of silyl enol ethers with acetals to produce-alkoxy carbonyl compounds (eq 1). 2 The process, 3,4 which requires preformation of the silyl enol ethers, can also be accomplished in a single step by in situ generation of corresponding enol ethers (eq 2). 5,6 Nonetheless, the im
Metal ions in the active sites of many metalloenzymes exhibit distinctive spectral and chemical f... more Metal ions in the active sites of many metalloenzymes exhibit distinctive spectral and chemical features which are different from those of small inorganic complexes. These features are the result of the unusual geometric and electronic constraints that are imposed on the metal ion within the protein environment. Much effort has been invested to try to mimic this feature of metalloenzymes in synthetic systems, but this remains a formidable task. Here we show that one of the key lessons learned from the science of catalytic antibodies--that binding energy can be converted into chemical energy--can be exploited to 'fine-tune' the physicochemical properties of a metal complex. We show that an antibody's binding site can reversibly perturb the coordination geometry of a metal ion, and can stabilize a high-energy coordinated species. Specifically, antibodies designed to bind the organosilicon compound 1 also bind the geometrically similar Cu(I) complex 2. However, the antibody binds a slightly compressed form of 2, which is closer in size to 1. This distortion is manifested by a spectral shift--an 'immunochromic' effect.
Since its inception, not too long ago, the science of catalytic antibodies has undergone a remark... more Since its inception, not too long ago, the science of catalytic antibodies has undergone a remarkable maturation process.' From initial "proof of concept" and demonstration of fundamental, enzyme-like characteristics, antibodies have been shown to catalyze a broad scope of organic transformations, including difficult and unfavorable chemical reactions2 The relevance of the field to synthetic organic chemistry has been demonstrated recently by the ability to run these reactions with gram-scale q~antities.~ Here we go one step further and show for the first time that catalytic antibodies can be effectively used in natural product synthesis. (-)-a-Multistriatin, 1, is an essential component of the aggregation pheromone of the European elm bark beetle, Scolytus multistriatus (Marsham), which is the principal vector of Dutch elm d i~e a s e .~ The severe devastation of the elm population in the northeastem United States has resulted in extensive studies of the synthesis5 and field ~t i l i z a t i o n~*~ of 1. In order to achieve the required absolute configuration in all four asymmetric centers (lS,2R,4S,5R), most of the previous syntheses of 1 employ enantiomerically pure natural products as starting material^.^ We focused on the opportunity to achieve the required chirality via asymmetric synthesis of ketone 2 using antibody catalysis. Monoclonal antibody 14D9 has already been proven an effective catalyst for hydrolysis of a variety of substrates that are structurally related to 2, including a cyclic acetal,8 k e t a l~,~ epoxides,I0 and enol One could therefore expect that ketone 2 would be readily available by
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