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Succinate- and cyclopropane-derived phosphotyrosine (pY) replacements are incorporated into a series of Grb2 SH2 binding ligands wherein the pY+1 residue is varied in order to determine the impact of variations in ligand preorganization on binding energetics and structure. Crystallographic b-factors in the complexes of constrained ligands are greater than those of their flexible counterparts and the studies have highlighted the profound challenges associated with predicting the effect of structural changes in a ligand on enthalpies, entropies and structure in protein-ligand interactions.

Highly stereoselective synthesis of (-)-nakadomarin A is developed by using catalyst-controlled bond formations, one-pot multistep procedures and powerful route-shortening reaction cascades. Many unprecedented chemical transformations are developed, which have included a highly Z-selective, eight-membered-ring-forming intramolecular Julia-Kocienski reaction, a highly diastereoselective intramolecular furan/iminium ion cyclization, and a sulfonic acid-controlled Z-selective macrocyclic ring-closing metathesis.

The synthesis of [n,5]-spiroketals (n = 5, 6) via use of exocyclic enol ethers as starting materials is reported. Addition of catalytic amounts of the Lewis acid [Yb(OTf).sub.3] is observed to facilitate the ring enlargement and increase the yield of the corresponding spiroketal in many synthesis examples.

Two approaches to eliminate the generation of unexpected products during the free-radical cyclization process to obtain expected cyclization-reduction products are reported. The secondary cyclization reaction could be avoided by use of a cyclopropylcarbinyl fragmentation and use of an allene as a radical acceptor avoided the atom-transfer reaction altogether.

The preparation of Julia-Kocienski olefination reagents 1-fluoropropyl, (cyclopropyl)fluoromethyl, 1-fluoro-2-methyl-2-propenyl, and 1-fluoro-5-hexenyl 1-phenyl-1H-tetrazol-5-yl (PT) sulfones via metalation followed by electrophilic fluorination is reported. Screening of olefination conditions showed that stereoselectivity which depended on reagent and carbonyl structure could be tuned either toward E- or Z-selectivity.

The enantioinduction process of chiral Rh(II)-carboxylate catalysts are described in the first catalytic cyclopropanation of alkenes with [alpha]-nitro diazoacetophenones. The catalyst's 'All-Up' reactive conformation has helped in obtaining good stereoselectivity and the resulting products are shown to be key intermediates in a concise synthesis of highly enantioenriched cis-cyclopropane [alpha]-amino acids.

B3LYP/6-31G* calculations are performed to compute the kinetic isotope effects (KIEs) on the rate of ring opening of cyclopropylcarbinyl radical to 3-buten-1-yl radical at 20 K by tunneling. The increase in the rate of reaction by substitution of [D.sub.2] for [H.sub.2] at [C.sup.1] and origin of inverse KIE on the rate of tunneling are also discussed.

Lewis acid catalyzed ring opening of 1,1-cyclopropanediesters by the hydroxyl group of a propargyl alcohol sets up a subsequent Conia-ene cyclization to produce substituted tetrahydropyrans in a one-pot, high-yielding procedure.

The cycloadditions of vinylidenecyclopropanes with aldehydes are described for the preparation of tetrahydrofurans. The cycloadditions of vinylidenecyclopropanes with aldehydes and the transformations of the cycloadducts have provided an efficient protocol for constructing various medium- and large-size ring-fused tetrahydrofuran, furan, and benzo[c]fluorene derivatives.

The asymmetric cyclopropanation of allylic alcohols using gem-dizinc carbenoids is described, which has allowed the preparation of 1,2,3-substituted cyclopropane derivatives in high yields and enantio- and diastereoselectivities. The cyclopropylzinc has undergone an in situ B/Zn exchange with the stoichiometric chiral ligand to generate a cyclopropyl borinate that is directly engaged in a Suzuki-Miyaura cross-coupling reaction.

Alkylidenecyclopropanes containing a chelation assistant at the terminal carbon atom of the olefinic moiety have undergone an Os- or Ru-promoted ring expansion reaction to produce metal cyclobutylidene derivatives. The process has taken place on a metallaheterocyclopentene intermediate that is generated from an [[eta].sup.2]-methylenecyclopropane species stabilized by coordination of the chelation assistant.

The mechanisms involved in the crossed [2+2] cycloaddition reactions of 1-phenylcyclopropene and 1-bromo-2-phenylcyclopropene are discussed. The various steps and procedures involved in the reactions are also discussed.

Several studies are conducted to explain the various mechanisms that are involved in the switchable reactions of cyclopropanes with enol silyl ethers. The reactions are shown to be extremely useful for the synthesis of substituted cyclopentane derivatives in high yield.

A highly selective convergent coupling reaction between alkynes for the synthesis of stereodefined trisubstituted (E,E)-1,3-dienes-structural motifs commonly found embedded in the skeletons of bioactive polyketide-derived natural products is described. The preparation of complex 1,3-dienes relevant for the synthesis of polyketide-derived natural products of varying stereochemistry with typically [greater than equal to] 20:1 selectivity defined the important role of an alkoxide directing group located [delta] to preformed titanacyclopropenes is also reported.

Several studies are conducted to explain the various mechanisms involved in the synthesis of endo- and exo-configured cyclopropylidenes, which are annelated to the nonbornadiene skeleton. The rearrangement of the carbenes, as well as the impact of the remote substituents on the stability is also discussed.

A practical large-scale chromatography-free synthesis of EP4 antagonist MF-310, a new treatment for chronic inflammation, is described. The key features of the sequence has included a regioselective reduction of succinimide controlled by the electronic properties of a remote pyridine ring, preparation of cyclopropane carboxylic acid via a Corey-Chaykovsky cyclopropanation and a short synthesis of sulfonamide.

The aromatic rings of perfluoro[2.2]paracyclophane are reactive with respect to nucleophilic substitution reactions. The reactions have proceeded via [S.sub.N]Ar mechanisms and the reactivity issues are discussed including the effect of substituents on reactivity and regiochemistry of substitution.

The mechanism of rhodium-catalyzed cyclopropanation and C-H functionalization reactions with methyl phenyldiazoacetate and methyl diazoacetate is computationally studied by using density functional theory (DFT). The analyses of transition state geometries have helped in developing a rational model for predicting the stereochemical outcome of intermolecular C-H insertions with donor/acceptor rhodium carbenoids.

The catalytic activity of heterobimetallic Bi-Rh paddlewheel carboxylate complexes is studied in the context of metal carbenoid chemistry. The Bi-Rh carboxylate complexes have catalyzed cyclopropanation reactions and C-H insertions as well as reactions involving ylide intermediates with similar selectivity profiles to analogous dirhodium complexes.

A highly efficient triflic acid catalyzed ring opening of a wide variety of 1-cyclopropyl-2-propyn-1-ols with alcohols as an efficient synthetic route to conjugated enynes is reported. The mechanism involved protonation of the alcohol substrate by the TfOH catalyst, followed by ionization of the starting material to causes ring opening of the cyclopropane moiety and trapping by the alcohol nucleophile to yield the conjugated enyne product.

The radical clock, intramolecular kinetic isotope effect, and laser flash photolysis (LFP) experiments as well as density functional theory (DFT) and ab initio computations were utilized to study the mechanism of the photochemical [C.sup.2]-[C.sup.6] cyclization of enyne- allenes . The results for enyne-allene provides evidence for an allene triplet excited state (transient A) as a primarily formed short-lived intermediate and the formation of a diphenylmethyl-type diradical resulting from ring opening of a diphenylcyclopropane ring.

The ring opening utrasonification of gem-dichlorocyclopropane (gDCC) copolymers derived from polybutadiene to form 2,3-dichloroalkenes is reported. The ability to specifically and significantly alter the structure of the polymer backbone through a coupled restoring force suggested a new pathway to postsynthetic polymer modification and motivated the design of easily scalable mechanophores for applications in stress-responsive polymers.

A concise and convergent route to (+)-polyanthellin A which features a diastereoselective cyclopropane/aldehyde [3+2] cycloaddition to install the hydroisobenzofuran core is described. The key steps in the synthesis include a ring-closing metathesis and a selective olefin oxidation in presence of MADNT[f.sub.2] as a potent, bulky Lewis acid required to facilitate a labile [beta]-silyloxy aldehyde to be used in the cycloaddition.

Catalyzed by Lewis acid, 1,2-dipehnyldiselane or 1,2-di-p-tolyldisulfane is added to methylenecyclopropanes smoothly. A four-membered carbon ring is constructed to give cyclobutane-1,1-diylbis(phenylselane) derivatives or cyclobutane-1,1-diylbis(p-tolylsulfane) derivatives as products.

Catalyzed by N-heterocyclic carbenes (NHCs), domino ring-opening/redox amidation/cyclization reactions of the formylcyclopropane 1,1-diesters with 2-chloro-1H-indole-3-carboaldehydes are described. This method has provided a direct construction of a 6-5-6-tricyclic hydropyrido[1,2-a]indole skeleton, which is applied for the synthesis of many types of polycyclic indole alkaloids.

1(2-Pyrrolidinyl)cyclopropanecarboxylic acids ([alpha]-cyclopropyl-[beta]-homoprolines) are prepared by 1,3-dipolar cycloadditions of cyclic nitrones onto bicycloproppylidene followed by trifluoroacetic acid induced thermal fragmentive rearrangement. The sterically hindered nitrogen atom of the highly substituted pyrrolidine is acylated through the intermediate formation of a mixed anhydride.

Crystallographic and computational evidence has shown that Hashimoto's [Rh.sub.2][(S-PTTL).sub.4] catalyst has adopted a 'chiral crown' conformation with a reactive chiral face and an unreactive achiral face. [alpha]-Alkyl-[alpha]-diazoesters are used for describing an enantioselective and diastereoselective proton for intermolecular [Rh.sub.2][(S-PTTL).sub.4]-catalyzed cyclopropanation.

The addition of diazomethane and diazoethane to enantiopure (S)-(+)-3-[(methylphenyl)sulfinyl]-5,6-dihydropyran-2-one has produced the corresponding pyrazolines with almost complete [pi]-facial selectivity. The results are improved starting from sulfonyl pyrazolines, which has produced pure 3-oxabicyclo[4.1.0] heptan-2-ones.

A practical application of 1-alkenyl-1,1-heterobimetallic intermediates as a valuable building blocks in the synthesis of versatile cyclopropyl alcohol boronate esters is presented. The method could also be applied in the synthesis of quercus lactones A and B.

A diastereoselective procedure is developed for the Cu-catalyzed addition of diorganozinc reagents to cyclopropene derivatives. The scope of this method is broadened by using organozinc reagents that are generated in situ from Grignard reagents and the chiral oxazolidinone auxilaries are effective in controlling the diastereoselectivity of the carbometalation reactions.

Aryl cyclopropyl ketones have undergone nickel-catalyzed borylative ring opening with bis(pinacolato)diboron to produce 4-oxoalkylboronates.

Pentosyl and hexosyl vinyl sulfone-modified carbohydrates having the terminal double bond and a suitably positioned leaving group are reacted in a stereoselective way with a series of nucleophiles in order to produce a myriad of cyclopropanes substituted at all three ring carbon atoms.

A cascade epoxidation and nucleophilic addition process under mild conditions was used to prepare cyclobutylmethanone and cyclopropylmethanone derivatives in moderate to good yields. The synthesis involved reaction of monoaryl-substituted methylenecyclobutanes (MCBs) and methylenecyclopropanes (MCPs) with 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), and 1-hydroxysuccinimide (HOSu).

A cascade ring-opening reaction/Diels?Alder cycloaddition along with Al(III) as catalyst was employed to produce the Diels-Alder adducts from arylvinylcyclopropenes and alpha],[beta]-unsaturated substrates. The acidity of the Al(III) catalyst plays a key role in these ring-opening reaction.

Samarium diiodide promoted reaction of various [alpha]-bromomethyl cycloalkanones, followed by subsequent treatment with trimethylsilyl chloride, which leads to the production of cyclopropyl silyl ethers embedded in bicyclo[m.1.0]alkane frameworks is described. The regioselectivities of cyclopropane ring opening in the bicyclic substrates is found to depend on the oxidizing agents used.

Rhodium-catalyzed cyclization of an [alpha]-diazoester which provided an intermediate cyclopentanone was used for an enantioselective synthesis of (+)-coronafacic acid. Subsequent Fe-mediated cyclocarbonylation of a derived alkenyl cyclopropane led to formation of a bicyclic enone which was hydrogenated and carried on to the natural product.

A highly diastereoselective dynamic kinetic asymmetric transformation of racemic 1,1-cyclopropane diesters is developed in order to prepare enantioenriched tetrahydrofuran (THF) derivatives. Asymmetric [3+2] cycloaddition of activated donor-acceptor (D-A) cyclopropanes and aldehydes catalyzed by ([super t]Bu-pybox)Mg[I.sub.2] has produced THF products as single diastereomers.

The magnesium halide salts promoted ring-opening reactions of bis-activated cyclopropenes to obtain trisubstituted alkenyl halides with high stereoselectivities are reported. The magnesium enolates produced during reactions might be trapped with enones to yield more highly functionalized products.

A series of experimental examples and mechanistic studies based on the research related to the triplet photochemistry of vinyl cyclopropenes that deals with a diverse series of systems is discussed. The studies provide evidence for control by a critical [T.sub.1] diradical intermediate which have a high spin-orbit coupling with [S.sub.0] ground-state along the mechanistic pathway.

The total synthesis and evaluation of iso-duocarmycin SA and iso-yatakemycin are described. The implications of the results on the source of the DNA alkylation selectivity and catalysis for this class of natural products incorporating an isomeric alkylation subunit are discussed.

A highly enantio- and diastereoselective one-pot synthesis of halocyclopropyl alcohols is described. The studies have shown that the iodocyclopropanols are metalated with LiCu[(n-bu).sub.2] and quenched with allylbromides to produce allylated cyclopropyl alcohols with high diastereoselectivity.

A novel Ru-catalyzed ring expansion of alkynylcyclopropanols is developed. The exclusive obtention of the (Z)-alkylidene cyclobutanone isomers through the cyclopropanol/cyclobutanone expansion manifold are unprecedented and have served to distinguish Ru from other, alkynophilic transition metals.

A study is conducted to gain insight into the ring-opening reaction mechanism of the distal and proximal bond of difluoro(methylene)cyclopropanes ([F.sub.2]MCPs) with halogens and amines. The simple ring-opening reaction of ([F.sub.2]MCPs) could be applied to obtain a number of fluorine-containing compounds.

A [super 1]H NMR spectroscopy is used to study the kinetics of the Curtius rearrangements of methyl 1-azidocarbonyl cycloprop-2-enel-carboxylate and methyl 1-azidocarbonyl cyclopropane-1-carboxylate. The results from the comparison of reaction pathways at the CBS-QB3 level for the Curtius rearrangement versus the loss of [N.sub.2] to form a nitrene intermediate has provided strong evidence for the dominant process of the concerted Curtius rearrangement.

The first regio- and diastereoselective intermolecular rhodium-catalyzed [3+2+2] carbocyclization reaction of alkenylidenecyclopropanes (ACPs) with activated alkynes is described for the construction of the bicycloheptadienes. The studies have shown that E-alkenes can be incorporated in a stereospecific manner to afford products with up to three new stereogenic centers.

The mechanisms involved in the tetramerization of 3-methyl-cyclopropene-3-carbonitrile are studied to explain the novel CN-Alder-ene oligomerization reactions. The results prove that a stepwise process involving a biradical intermediate can be easily employed for the CN-Alder-ene reaction.