27345-71-7

The invention discloses a class of new polymers, trans-ring-fused poly(4-hydroxybutyrate)s (RF-P4HB) that exhibit a unique set of properties, including robust thermal stability and mechanical strength, quantitative recyclability to the building block monomers via thermolysis and/or chemical catalysis, and convenient production from the chemical ring-opening polymerization under ambient temperature and pressure. Another unique property is the formation of crystalline stereocomplexed polymers with high melting temperature upon mixing the two enantiomeric RF-P4HB chains via stereocomplexing co-crystallization. This invention also provides the corresponding ring-fused lactone monomer structures that enable the synthesis of the RF-P4HB polymers, through trans-fusing of rings to the parent γ-butyrolactone ring. Furthermore, a polymerization or copolymerization process for the synthesis of RF-P4HB polymers and copolymers is disclosed.

(HMe 2 SiCH 2) 2 has been utilized as a useful reagent for B(C 6 F 5) 3 -catalyzed reduction-lactonization of keto acids to synthesize γ- and δ-lactones. The process led concisely to (-)- cis -whisky and (-)- cis -cognac lactones in respective overall yields of 32% and 36%.

An environmentally friendly oxidative cleavage of tetrahydrofuran-2-methanols to the corresponding γ-lactones using a catalytic amount of 2-iodo-N-isopropylbenzamide has been developed. The reaction of various tetrahydrofuran-2-methanols with the catalyst in the presence of Oxone (2 KHSO5·KHSO4·K2SO4) as a co-oxidant in DMF at room temperature successfully affords the corresponding lactones in good to high yields, and recovery of the catalyst is readily accomplished using a reductive work-up. This method is notable because it enables the transformation of tetrahydrofuran-2-methanols to γ-lactones under mild conditions without the use of any toxic heavy metals.

Model compounds 3 and 5 have been studied to determine the orientation of the reacting double bonds in the transition state of the allylmetal-aldehyde addition. These models were designed to remove any intrinsic steric bias for the formation of the bicyclic products that would obfuscate a stereoelectronic contribution to the transition states. Model system 3 revealed a modest preference for the synclinal transition state, albeit in very low yields. Model system 5 underwent selective and largely Lewis acid independent cyclization primarily via a synclinal transition state. The high proximal selectivity observed in these cyclizations likely reflects the selectivity of an unhindered allylmetal-aldehyde addition for the synclinal transition state and results from a stereoelectronic preference, not an intrinsic steric bias, for the synclinal arrangement of double bonds.

The decomposition of cyclohexyl diazo(triethylsilyl)acetate 2a and the t-butyl derivatives 3a,b with [Rh2{(S)-nttl}4] and similar chiral Rh(II)-catalysts proceeds in toluene at room temperature to produce silylated lactones in up to 90% yield. The reaction is highly stereoselective. Enantioselectivities of up to 79% have been observed.

Evidence is provided that nucleophilic attack on five-membered ring oxocarbenium ions occurs from the inside face of the envelope. An eight-five fused-bicyclic system in which two substituents are constrained to pseudoequatorial positions underwent nucleophilic addition with selectivity that was comparable to an unconstrained monocyclic system. On the other hand, a bicyclic six-five analogue underwent reaction with low selectivity. This observation indicates that minimization of eclipsing interactions by attacking inside the envelope is not enough to control selectivity, but that the changes in the overall three-dimensional structure of the ring must be favorable as well. In the bicyclic six-five series, the six-membered ring is accommodated in the cation, but it destabilizes the transition state structure leading to the first-formed product of inside attack.

A new synthetic route to γ-substituted γ-butyrolactones from alkenes and α-dichloro ester, in the presence of CuCl (catalytic) and Fe(0) (stoichiometric) in acetonitrile, was established. A study of this reaction has demonstrated that the overall process consists of the following reaction steps: (a) addition of the dichloro ester to the olefin via CuCl catalysis; (b) selective reduction of the α-chloro atom in the resulting adduct by Fe(0); (c) cyclization of the resulting γ-chloro ester to γ-butyrolactone. Yields were improved by first carrying out step (a), then steps (b) and (c) in one pot. Selectivity was improved in the presence of a small amount of water. α-Trichloro esters also generated the γ-substituted γ-butyrolactone, albeit in lower yields and selectivity. The latter reaction gave rise to the formation of interesting by-products, namely new unsaturated bis-lactones.

(Graph presented) Treatment of allyl β-iodoacetals with ethylmagnesium bromide in THF provided tetrahydrofuran derivatives in good yields. On the other hand, the reaction in DME provided tetrahydrofuranylmethylmagnesium compounds in good yields.

Olefins undergo cyclopropanation with diphenylsulfonium (ethoxycarbonyl)methylide (=diphenyl-sulfonium 2-ethoxy-2-oxoethylide; 3a) in the presence of chiral Cu(I) or Rh(II) catalysis, trans/cis Ratios and ee's of the cyclopropanes 6 obtained with this ylide in the presence of a chiral Cu(I) catalyst 7 are identical with those obtained with ethyl diazoacetate (4). In the case of catalysis with Rh(II), the trans/cis ratios of the cyclopropanes as well as the enantioselectivity change slightly upon going from the ylide 3a to diazoacetate 4.

Reduction of Li2-MnCl4 with magnesium in THF afforded a fairly active manganese species which readily initiated radical cyclization of 2- iodoethanal allylic acetals at room temperature. The corresponding 2- bromoethanal acetals also provided the same cyclized products upon treatment with the activated manganese reagent at reflux in THF. This reagent can also be used to induce tandem radical cyclizations, and the 5-exo/6-endo and 5- exo/6-exo modes are both available to give the products with trans- stereochemistry with regard to ring-junction. Further, the intramolecular type of sequential generation and utilization of radical and anionic species with this reagent have also been studied.

Synthesis of γ-butyrolactones using radical cyclization on solid-phase has been achieved. Polymer-supported β-bromoethylacetals were treated with tributyltin hydride in the presence of a catalytic amount of α,α'- azobisisobutyronitrile to generate intermediate carbon radicals which cyclize onto the intramolecular carbon-carbon double bond. The cyclization products were released by Jones oxidation from resin to give γ-butyrolactones in good yields.

The 1H and 13C NMR resonances often bicyclo[4.3.0]-and bicyclo[6.3.0]-γ-lactones and α-carbomethoxy-γ-lactones were completely and unambiguously assigned by a combination of homonuclear (gs-COSY), 1H-detected heteronuclear one-bond (gs-HMQC) and long-range (gs-HMBC) gradient-selected correlation experiments.

Photosensitized one-electron reductive activation of aldehydes/ketones tethered with activated olefins leads to efficient cyclization to give diastereoselective cycloalkanols in high yield. The activation is promoted by secondary and dark electron transfer from visible light (405 nm) initiated photosensitized electron transfer generated 9,10-dicyanoanthracene radical anion (DCA.-). The DCA.- is produced by electron transfer using either triphenylphosphine (Ph3P) as sacrificial electron donor (PS-A) or 1,5-dimethoxynaphthalene (DMN) as primary electron donor and ascorbic acid as sacrificial electron donor (PS-B), to light-absorbing DCA. The cyclization is suggested to involve ketyl radical intermediate. High trans diastereoselectivity is observed during the formation of cycloalkanols. This cyclization strategy is further extended for the stereoselective synthesis of optically pure C-furanoside (41), starting from naturally occuring L-tartaric acid. The stereochemistry of 41 is suggested based on the single-crystal X-ray diffraction data.

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Dirhodium(II) tetrakis, Rh2(4S-MPPIM)4, provides significant enhancement in enantiocontrol for intramolecular cyclopropanation reactions of allylic diazoacetates and optimal enantiocontrol/diastereocontrol for intramolecular C-H insertion reactions of secondary alkyl diazoacetates.

Sodium-hexamethylphosphoric triamide (HMPA) mediated electron transfer induced reductive cleavage of 1 -> 3 and 1 -> 2 γ-lactones fused in cyclohexane ring gives the corresponding carboxylic acids in good yields.

A method for the synthesis of γ-butyrolactones 6 is described in which the key step is a free-radical cyclization of α-bromoacetals 4 to 2-alkoxytetrahydrofurans 5 in 54-93percent yield induced by activated chromium(II)-acetate.Four new methods have been developed in order to activate the transition metal.Two of them require only catalytic amounts of chromium(II)-acetate, because it can be regenerated in situ chemically or electrochemically.The diastereoselectivity of the cyclization depends on the substitution pattern of 4 and ranges between 30.4:1 and 1:54.8.

A variety of substituted γ-hydroxy olefins 1 have been converted to butanolides 4 in very high yield in a three-step sequence involving bromoetherification, elimination, and oxidative cleavage.The key step in the overall transformation is the highly selective oxidative cleavage of enol ethers 3 with PCC under very mild reaction conditions.Application of this methodology has been exemplified in the synthesis of the Japanese beetle pheromone.

The preparation and free-radical cyclization reactions of unsaturated α-iodo esters, ketones, and malonates have been investigated.For example, sunlamp irradiation of methyl 2-iodo-6-heptenoate in benzene in the presence of 10 mol percent hexabutylditin produces methyl 2-(iodomethyl)cyclopentanecarboxylate (cis and trans) and methyl 3-iodocyclohexanecarboxylate in a ratio of 93/7 in a combined yield of 86percent.The γ-iodo carbonyl products can either be isolated (in most cases) or converted in situ to deiodinated products (with Bu3SnH) or lactones (by heating).Five-, six-, or seven-membered rings selectively form, depending on chain length and alkene substitution.Terminal alkene substituents favor exo cyclization while internal alkene substituents promote endo cyclization.A preference for endo closure is also observed when there is a carbonyl group "inside" the forming ring.A detailed analysis of reaction rates indicates that these isomerizations proceed by an iodine atom transfer chain mechanism, and thus the observed selectivities are due to the kinetic substituent effects.The results contrast the thermodynamically controlled hydrogen atom transfer cyclizations of Julia.A new procedure for the removal of tin byproducts is described.

β-hydroxy esters have been converted into fused and spiro γ-butyrolactones in 50-90percent yield by refluxing with Amberlyst-15 resin in hydrocarbon solvent.Fused-ring lactones are formed with the cis geometry at the ring junction and the regiochemistry of the closure is that expected from a process proceeding through the most stabilized carbocation.The use of an acidic resin offers several advantages over standard aqueous acid conditions: (1) easier monitoring of the reaction, (2) convenient workup, and (3) higher yields.

An aldehyde or a ketone connected by a tether to an olefin efficiently cyclizes in a free radical reaction mediated by tributyltin hydride.The effects of activated olefins on this reaction, which provides functionalized cyclopentane rings and γ-lactones from O-stannyl ketyls in a mild and regiocontrolled manner, were also studied.

The intramolecular electrochemically initiated cyclization of a variety of α,β-unsaturated esters and one nitrile, each of which is tethered to an aldehyde or a ketone, has been investigated.Good yields (70-79percent) of mono- and bicyclic products, resulting from closure between the β-carbon of the α,β-unsaturated unit and the aldehyde or ketone carbonyl carbon, were obtained.Cyclic voltammetry was used to determine that the α,β-unsaturated unit corresponded to the electrophore.In all but one instance, cyclization favored formation of the product wherein the hydroxy and (methoxycarbonyl)methyl units were trans to one another.The stereoselectivity was studied as a function of temperature, nature of the proton donor, proton availability, and percent conversion (i.e., as a function of time).Attempts to use the reaction to synthesize the marine natural product ambliol A were unsuccessful.A mechanistic scheme in which a reversible cyclization of the initially formed radical anion is followed by an irreversible proton transfer is suggested to account for the experimental observations.

The free radical isomerization of unsaturated α-iodo carbonyls to cyclic γ-iodo carbonyls is described.Iodine atom abstraction from the starting iodide by the cyclic radical is the key chain transfer step.

A new one pot procedure to synthesize γ- and δ-lactones, in a 76-84percent yield, is accomplished by the reductive cyclization of 1,4- and 1,5-ketoesters, utilizing sodium cyanoborohydride.The procedure is generally applicable to a wide variety of ketoesters with the exception of the ethyl ester of alkyl 1,5-ketoesters and α,β-unsaturated 1,4- and 1,5-ketoesters.

Primary alcohols undergo oxidative condensation upon treatment with RuH2(PPh3)4 catalyst to give esters and molecular hydrogen.Similarly, 1,4- and 1,5-diols can be converted into the corresponding γ- and δ-lactones, respectively.The lactonization is greatly enhanced by accepting hydrogen with an appropriate hydrogen acceptor such as acetone.Primary alcohols are oxidized chemoselectively in the presence of secondary alcohols to give the corresponding lactones.These reactions are operationally simple and highly efficient for synthesis of esters and lactones from alcohols.The principle of the oxidative condensation of alcohols can be extended to ester formation from aldehydes and alcohols.The ruthenium-catalyzed reaction of aldehydes with water gives esters, while the same reaction in the presence of a hydrogen acceptor gives carboxylic acids.The key step of these reactions is the oxidative addition of ruthenium into the OH bonds of alcohols and subsequent β-elimination of (RuH) species to give the corresponding carbonyl compounds.

Treatment of unsaturated keto- or aldo-esters with SmI2 in tetrahydrofuran (THF) or THF-hexamethylphoshoramide affords bicyclic γ-lactones in moderate to good yields.

Treatment of primary, secondary or tertiary γ- and δ-hydroxyolefins with cetyltrimethylammonium permanganate gives good yields of γ- and δ-lactones by oxidative cyclization, with loss of one carbon.

The annulation of a γ-lactone ring onto an alkene by manganese(III) acetate oxidation of acetic acid was investigated.The regioselectivity of addition to unsymmetrically substituted alkenes is reported along with the stereoselectivity of addition to various acyclic and cyclic alkenes.Alkenes with ionization potentials above 8.2 eV were found to react in good yield.The role of acetic anhydride in these reactions was studied, and it was shown to be oxidized faster than acetic acid and also led to different products.The fate of oxidized acetic acid or anhydridein the absence of suitable acceptor molecule has also been quantitatively identified.The relationship of enolizability, or C-H acidity, of the carboxylic acid being oxidized was established quantitatively.

Cyclopropanecarboxylic acids when heated at 150 deg C with pyridinium chloride (molten salt) or iodide undergo ring fission giving γ-lactones in one step.Saturated bicyclic substrates give cis products, while an α,β-unsaturated compound does not undergo ring opening and produces a mixture of tricyclic γ- and δ-lactones.

The preparation of a new aluminium reagent, dimethylaluminium methaneselenolate (Me2AlSeMe) is described.The reactivity of this aluminium reagent toward a variety of organic substrates has been studied.Me2AlSeMe will convert O-alkyl esters to selenoesters in high yield.These selenoesters function as extremely reactive acyl transfer agents and are converted to acids, esters, and amides on reaction with water, alcohols or amines in the presence of a selenophilic metal cation.The selenoesters will, moreover, acylate reactive arenes and heterocyclic compounds when cuprous triflate is employed as the selenophilic metal cation.This latter transformation constitutes a new transition metal promoted variant of the Friedel-Crafts acylation reaction.

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The cycloaddition of dichloroketene to a series of 1-substituted cyclohexanes is shown to proceed in a highly regio- and stereospecific manner.The structures of the cycloadducts were determined by reductive dechlorination to the cyclobutanones, and the structures and stereochemistry of the latter as cis-bicyclooctan-7-ones (4) were established by an oxa-ring expansion to the corresponding cis-octahydrobenzofuran-2-ones (6).The structures of the lactones 6 were established by 1H and 13C NMR studies which further indicated that these compounds exist in conformation 6a rather than 6b.The success of the regio- and stereospecific cycloaddition of dichloroketene to the 1-substitutd cyclohexenes discussed is found to be critically dependent on utilizing the zinc dehalogenation procedure for its in situ generation.Additional examples of the cycloaddition of dichloroketene to indene, 1,4,-dihydronaphthalene and 1,2-dihydronaphthalene is also presented.

It is shown that a conveniently placed internal nucleophile (carboxyl group) is not involved with the rearrangement of a diclorocyclopropane into an allylic chloride.This result appears to support a concerted mechanism of a ?s2 + ?a2 type for this rearrangement.In the products obtained, the allylic chloride may undergo displacement either by solvent (H2O), leading to alcohols, or by the internal carboxyl group, leading to a lactone.

Cyclopropyl esters derived from olefins undergo ring opening with iodotrimethylsilane and, after base treatment, γ-butyrolactones are obtained.

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Preparative and mechanistic details are described for the conversion of selenides into hydrocarbons RH> by heating with triphenyltin hydride at about 120 deg C.The process has been extended to selenoacetals in a form that constitutes a reduction methods for carbonyl compounds RR'C(SePh)2 -> RR'CH2>.Selective reduction of selenoacetals in the presence of thioacetals is possible.Cold-labeled species can be prepared by using triphenyltin deuteride.Tellurides are available easily without problems arising from exposure to air provided that the work is done in a photographic darkroom equipped with a red safety light.These tellurides, as well as the corresponding dichlorides , are reduced under very mild conditions (25-80 deg C) by triphenyltin hydride.The selenium- and tellurium-based chemistry has been used for the unusual process of reducing an epoxide in the presence of a ketone carbonyl.

Enantiomerically pure bicyclic lactones 1-3 and tricyclic lactones 4 and 5 have been prepared by either of two procedures, each hinging upon the liquid chromatographic seperation of rationally selected diastereomeric derivatives.After seperation, the diastereomers are converted by a simple high-yield reaction sequence to the enantiomeric multiring lactones, none of which has been previously reported in optically active form. The relative strengths and weaknesses of each approach are discussed.Lactones 4 and 5 were α-methylated, these derivatives being suitable for the determination of enantiomeric purity and absolute configuration using the chiral solvating agent (S)-(+)-2,2,2-trifluoro-1-(9-anthryl)ethanol.