A new route to diastereomerically pure cyclopropanes utilizing stabilized phosphorus ylides and gamma-hydroxy enones derived from 1, 2-dioxines: mechanistic investigations and scope of reaction

A new chemical transformation for the construction of diversely functionalized cyclopropanes utilizing 1,2-dioxines and stabilized phosphorus ylides as the key precursors is presented. Through a series of mechanistic studies we have elucidated a clear understanding of the hitherto unknown complex relationship between 1, 2-dioxines 1a-e, and their isomeric cis/trans gamma-hydroxy enones (23 and 21a-e), cis/trans hemiacetals 24a-e, and beta-ketoepoxides (e.g., 26), and how these precursors can be utilized to construct diversely functionalized cyclopropanes. Furthermore, several new synthetically useful routes to these structural isomers are presented. Key features of the cyclopropanation include the ylide acting as a mild base inducing the ring opening of the 1,2-dioxines to their isomeric cis gamma-hydroxy enones 23a-e, followed by Michael addition of the ylide to the cis gamma-hydroxy enones 23a-e and attachment of the electrophilic phosphorus pole of the ylide to the hydroxyl moiety, affording the intermediate 1-2lambda(5)-oxaphospholanes 4 and setting up the observed cis stereochemistry between H1 and H3. Cyclization of the resultant enolate (30a or 30b), expulsion of triphenylphosphine oxide, and proton transfer from the reaction manifold affords the observed cyclopropanes in excellent diastereomeric excess. The utilization of Co(SALEN)(2) in a catalytic manner also allows for a dramatic acceleration of reaction rates when entering the reaction manifold from the 1,2-dioxines. While cyclopropanation is favored by the use of ester-stabilized ylides, the use of keto- or aldo-stabilized ylides results in a preference for 1,4-dicarbonyl formation through a competing Kornblum-De La Mare rearrangement of the intermediate hemiacetals. This finding can be attributed to subtle differences in ylide basicity/nucleophilicity. In addition, the use of doubly substituted ester ylides allows for the incorporation of another stereogenic center within the side chain. Finally, our studies have revealed that the isomeric trans gamma-hydroxy enones and the beta-keto epoxides are not involved in the cyclopropanation process; however, they do represent an alternative entry point into this reaction manifold.     

Mechanistic investigations on the reaction between 1,2-dioxines and bulky stabilized phosphorus ylides: an efficient route to closely related cyclopropane stereoisomers.

The bulky stabilized ylides (2a-d) react with a range of 1,2-dioxines (1a-d) to afford the diversely functionalized cyclopropanes 7 in excellent yield and diastereomeric excess. This is in direct contrast to the situation when nonbulky ester ylides are utilized which results in a completely different cyclopropyl series. Through a combination of isolation, spectroscopic, temperature, and deuterium and additive effects studies, the mechanism of cyclopropane formation from this second pathway can be proposed. Importantly, enolate quenching of the intermediate 1-2lambda(5)-oxaphospholanes 4 prior to collapse results in an equilibrium mixture of intermediates 10 and 11 which have been fully characterized, and their formation is primarily a result of the steric bulk of the stabilized ester ylide. These intermediates (10/11) then collapse further and result in formation of the observed closely related cyclopropyl stereoisomers 7 and 8. Moreover, the addition of LiBr to these reactions allows for the control of which of the two possible cyclopropanation pathways will be dominant. Finally, optimal protocols that demonstrate the potential of this new cyclopropanation methodology for the ready construction of closely related cyclopropyl stereoisomers are presented.     

Density functional theory investigations on sulfur ylide promoted cyclopropanation reactions: insights on mechanism and diastereoselection issues

The mechanism and diastereoselectivity of synthetically useful sulfur ylide promoted cyclopropanation reactions have been studied using the density functional theory method. Addition of different substituted ylides (Me2S+CH-R) to enone ((E)-pent-3-en-2-one, MeHC=CH-COMe) has been investigated. The nature of the substituent on the ylidic carbon brings about subtle changes in the reaction profile. The stabilized (R=COMe) and semistabilized (R=Ph) ylides follow a cisoid addition mode, leading to 1,2-trans and 1,2-cis cyclopropanes, respectively, via syn and anti betaine intermediates. The simplest and highly reactive model ylide (R=H) prefers a transoid addition mode. Diastereoselectivity is controlled by the barrier for cisoid-transoid rotation in the case of stabilized ylides, whereas the initial electrophilic addition is found to be the diastereoselectivity-determining step for semistabilized ylides. High selectivity toward trans cyclopropanes with stabilized ylides are predicted on the basis of the relative activation energies of diastereomeric torsional transition states. The energy differences between these transition states could be rationalized with the help of weak intramolecular as well as other stereoelectronic interactions.     

Rhodium(I)/Zn(OTf)2‐Catalyzed Asymmetric Ring Opening/Cyclopropanation of Oxabenzonorbornadienes with Phosphorus Ylides

The strong binding ability of P‐ylides with transition metals limits the utilization of stabilized P‐ylide as nucleophiles in asymmetric organometallic catalysis. Herein we describe the first rhodium‐catalyzed asymmetric ring‐opening reaction of P‐ylides utilizing oxabicyclic alkenes as the electrophilic partner. Various P‐ylides including ester‐, ketone‐ and amide‐style P‐ylides are all applicable. This asymmetric reaction occurs through the cleavage of two bridgehead C?O bonds and the formation of two C?C bonds, and oxabenzonorbornadienes are used as 1,4‐biselectrophiles, thus providing access to benzonorcaradienes in good yields with high enantioselectivity and perfect diastereoselectivity. The present protocol also constitutes the first highly enantioselective direct catalytic asymmetric cyclopropanation of stabilized P‐ylide nucleophiles.     

1,2-dioxines as masked cis gamma-hydroxy enones and their versatility in the synthesis of highly substituted gamma-lactones

Addition of highly stabilized ester nucleophiles to 1,2-dioxines affords good to high yields of gamma-lactones with high diastereoselectivity. Heterolytic or homolytic cleavage of the 1,2-dioxines under appropriate conditions generates the key reactive cis gamma-hydroxy enones, which ultimately afford the observed gamma-lactones. Diastereoselectivity is installed as a result of anti 1,4-addition by the ester enolate to the cis enones followed by intramolecular cyclization. The reaction is tolerant of a range of substitution patterns on the 1,2-dioxine while a broad range of esters are also accommodated. In addition to the synthesis of racemic gamma-lactones, highly enantioenriched gamma-lactones can also be synthesized when chiral cobalt(II) catalysts are employed for the initial homolytic ring-opening of the 1,2-dioxine.     

Asymmetric cyclopropanation of β,γ-unsaturated α-ketoesters with stabilized sulfur ylides catalyzed by C2-symmetric ureas

A novel organocatalytic asymmetric cyclopropanation of β,γ-unsaturated α-ketoesters with stabilized sulfur ylides using C(2)-symmetric urea as a hydrogen-bond catalyst has been described. This reaction allows an efficient access to 1,2,3-trisubstituted cyclopropane derivatives in moderate to good yields with up to 16:1 dr and 90:10 er under mild reaction conditions. The mechanism study proved that the high stereoinduction originated from the cooperative effect of the hydrogen-bond catalyst.     

Ozonolysis of bicyclic 1,2-dioxines: initial scope and mechanistic insights

The ozonolysis of bicyclic 1,2-dioxines was investigated using a variety of 1,4-disubstituted 1,2-dioxines along with a 1,3-dialkyl and steroidal example, with yields ranging from moderate to excellent. Two different pathways were observed upon reaction of the 1,4-disubstituted 1,2-dioxines with ozone; one pathway saw the "expected" results, that is, cleavage of the olefinic moiety with generation of 1,4-dicarbonyl 1,2-dioxines, while the other pathway revealed a previously unobserved rearrangement involving cleavage of the peroxide linkage along with loss of either CO or CO(2). Several unsymmetrical ozonolyses were also performed to further investigate the origins of this rearrangement, and initial mechanistic insights into the fragmentation pathways are discussed.     

Synthesis of α‐phosphonylated phosphonium and sulfonium ylides: Study of their thermal behavior

The additions of two equivalents of trialkylphosphites onto phosphonodithioformates produce stabilized α‐sulfanyl‐α‐phosphonyl phosphonium ylides. Their subsequent reaction with alkyl or benzyl halides gives stabilized sulfonium ylides. Thermal treatment of these phosphonium and sulfonium ylides leads to α‐sulfanyl methylene bis‐phosphonates through protonation–dealkylation intramolecular reactions. © 2009 Wiley Periodicals, Inc. Heteroatom Chem 20:164–171, 2009; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20530     

Strained azetidinium ylides: new reagents for cyclopropanation

Azetidinium ylides showed a remarkable ability to perform the cyclopropanation of Michael acceptors. Ephedrine-derived azetidinium ylides allowed the formation of substituted cyclopropanes in good yields and at a high level of stereoselectivity. The determination of the relative stereochemistries in the produced cyclopropanes gave some insight into the reaction mechanism.     

Base- and Co(II)-catalyzed ring-opening reactions of perhydrooxireno[2,3-d][1,2]dioxines: an efficient route to 4-hydroxy-2,3-epoxy-ketones

A series of 3,4,6-substituted 3,6-dihydro-1,2-dioxines were epoxidized with m-chloroperbenzoic acid to furnish perhydrooxireno[2,3-d][1,2]dioxines (epoxy-1,2-dioxines) in yields ranging from 51% to 93% with de's from 26% to 100%. Unsymmetrical epoxy-1,2-dioxines were ring-opened using triethylamine to yield 4-hydroxy-2,3-epoxy-ketones quantitatively, and meso-epoxy-1,2-dioxines were ring-opened using Co(II) salen complexes to afford 4-hydroxy-2,3-epoxy-ketones in 77-98% yield. The first reported examples of the catalytic asymmetric ring-opening of meso-epoxy-1,2-dioxines using a range of chiral Co(II) salen and beta-ketoiminato complexes to afford highly enantio-enriched 4-hydroxy-2,3-epoxy-ketones are also presented.     

Triphenylphosphine-Catalyzed Simple Synthesis of Vinyl-Substituted Saccharins

Saccharin (1,1-dioxo-1,2-dihydro-1 u 6 -benzo[ d ]-isothiazol-3-one) undergoes a smooth reaction with dialkyl acetylenedicarboxylates in the presence of triphenylphosphine to produce highly-functionalized salt-free sulfur-containing ylides in nearly quantitative yields. These stabilized phosphorus ylides exist as a mixture of two geometrical isomers as a result of restricted rotation around the carbon-carbon partial double bond resulting from conjugation of the ylide moiety with the adjacent carbonyl group. These ylides are converted to dialkyl 2-(1,1-dioxo-1 H -1 u 6 -benzo[ d ]-isothiazol-3-yl)-but-2-enedioates in boiling toluene.     

Triphenylphosphine-induced ring contraction of 1,2-dioxines

Triphenylphosphine inserts into the peroxide bond of 1,2-dioxines, initiating ring contraction with loss of triphenylphosphine oxide. This process yields dihydrofuran oxides in 54-97% yield from oxirenyl[2,3-c][1,2]dioxines and dihydrofurans from 3,6-dihydro-1,2-dioxines with inversion of stereochemistry at either the 2 or 5 position in the furan product.     

3,3]-rearrangements of phosphonium ylides

Allylic phosphonium ylides are readily generated by the combination of an allylic alcohol, a carbene, and a chlorophosphite. Here we demonstrate that these intermediates undergo a thermal [3,3]-rearrangement to provide single isomers of homoallylic phosphonates in good to excellent yields. This new reaction manifold for phosphorus ylides is tolerant of a range of substitution patterns on the reactants and provides access to structurally complex intermediates for the synthesis of enzyme inhibitors, aminophosphonic acids, and natural products.     

Organocatalytic asymmetric cyclopropanation of α,β-unsaturated aldehydes with arsonium ylides

A novel organocatalytic asymmetric cyclopropanation of α,β-unsaturated aldehydes with arsonium ylides using diphenylprolinol silylether as a catalyst is described. A variety of chiral cyclopropyl aldehydes are obtained in moderate to good yields with up to 99:1 dr (diastereomeric ratio) and 99% ee under simple and mild reaction conditions.     

Three-Component Reaction Between Trivalent Phosphorus,Dimethyl Acetylenedicarboxylate,and Amide Derivatives

Stabilized phosphoranes were synthesized from the reaction between dimethyl acetylenedicarboxylate and amide derivatives in the presence of triphenylphosphine. Dimethylurea containing a phosphorus ylide underwent a smooth reaction in boiling toluene to produce hydantoin and oxo-oxazolidin containing stable phosphorus ylides in good yields. Phosphorus ylides derived from (PhO)₃P were not stable and converted to diastereoisomeric phosphonates and phosphorimidate. The nature of the amide derivatives and type of trivalent phosphorus compounds, as well as solvents, determined the distribution of products.     

Ring-opening of unsymmetrical 1,2-dioxines using cobalt(II) salen complexes

The regioselectivity of the metal-catalyzed ring opening of unsymmetrical 1,2-dioxines to cis-gamma-hydroxyenones was investigated using two different Co(II) salen complexes. Regioselectivity was determined by direct examination of the enone ratios and by derivitization with a stabilized phosphorus ylide. The steric influence of the substituents on the 1,2-dioxine was the primary influence on regioselectivity. Temperature played little role; however, solvent and selection of Co(II) complex could be used to mildly influence the outcome of the rearrangement for selected substrates. The origins of the selectivity for the reaction are discussed.     

Hypervalent iodine(III) reagents as safe alternatives to alpha-nitro-alpha-diazocarbonyls

A cyclopropanation reaction involving iodonium ylides generated in situ allows for efficient preparation of substituted 1-nitro-1-carbonyl cyclopropanes. This robust cyclopropanation reaction can be performed in organic solvents, biphasic aqueous media, or under solvent-free conditions with alkene substrates. The iodonium ylides generated in situ display some surprising differences in reactivity when compared to alpha-nitro-alpha-diazocarbonyl compounds. They do not undergo O-H insertion reactions and exhibit reduced reactivity with certain alkenes. [reaction: see text]     

1,2-dioxines containing tethered hydroxyl functionality as convenient precursors for pyran syntheses

A new method for the construction of tetrahydropyrans derived from readily available 1,2-dioxines containing a tethered hydroxyl moiety is described. The reaction proceeds via a base-catalyzed rearrangement of the 1,2-dioxines to either the isomeric cis or trans gamma-hydroxy enones followed by intramolecular oxa-Michael addition of the tethered hydroxyl group.     

DFT study of the mechanism of Cu(I)-catalyzed and uncatalyzed intramolecular cyclopropanation of iodonium ylides

The mechanism of the Cu(I)-catalyzed and uncatalyzed intramolecular cyclopropanation of ketoesteric and diesteric iodonium ylides has been thoroughly explored by means of electronic structure calculation methods (DFT). All crucial reaction steps encapsulated in the entire catalyzed and uncatalyzed reaction pathways were scrutinized, while the elementary steps, the intermediates and transition states were identified through monitoring the geometric and energetic reaction profiles. It was found that CuCl efficiently catalyze the cyclopropanation of iodonium ylides only for their diesteric derivatives and their diazo analogues via stabilization of the respective carbene upon complexation with the metal center. For the ketoesteric iodonium ylides the CuCl catalyst does not affect the kinetics of the intramolecular cyclopropanation reactions which could proceed easily without the catalyst, in line with available experimental observations.     

Asymmetric Cyclopropanation of Optically Active Vinyl Sulfoxides: A New Synthetic Approach to Biologically Active Compounds

Abstract

The influence of adjacent substituents on stereochemical course of cyclopropanation of vinyl sulfoxides with stabilized and nonstabilized ylides, as well as dependence on reaction conditions, was investigated. Application of optically active cyclopropanes obtained in the synthesis of conformationally constrained analogs of L-glutamic acid, the useful pharmacological tools in investigation of excitatory amino acid receptors, is presented.