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An acyclic approach to synthesize thiofuranoside N-glycosides bearing an adenine nucleobase is presented herein. This approach provides a significant improvement in terms of regio- and diastereoselectivity compared with the current paradigms used for their formation. Activation of acyclic dithioacetal substrates bearing either a C2′-alkoxy or fluoro group and coupling with purine nucleobases selectively generates 1′,2′-syn thioaminals. The regiochemistry of the nucleobase coupling (N7 or N9) can also be controlled by using either silylated or unsilylated purines. A subsequent SN2-like cyclization of these 1′,2′-syn acyclic thioaminals results in the desired 1′,2′-cis thionucleoside analogues.

The progress towards the development of a nucleoside analogue with inhibitory properties against SETDB1, a histone methyltransferase (HMT), is described. Based on the structure of the natural cofactor S-adenosyl-L-methionine (SAM), novel fluorinated nucleoside analogues were synthesized. Two of these compounds bearing a C2′-F and C5′-primary amine moiety showed moderate inhibition of SETDB1, a lysine HMT for which there is only one reported inhibitor.

The synthesis of novel nucleoside analogues bearing a C3′ all-carbon quaternary center and a C2′-hydroxy substituent is described. The all-carbon stereogenic center was generated through an intramolecular 7-endo attack of a silyl-tethered allyl moiety on a tertiary radical using photoredox catalysis. Subsequent allylic oxidation and diastereoselective hydride reductions provided the hydroxy substituent at C2′, which then controls the stereoselective introduction of pyrimidine nucleobases on the corresponding furanose scaffold. Density functional theory (DFT) calculations provided insights into the origin of the high syn diastereoselectivity resulting from the radical cyclization. This original methodology grants access to a wide range of 1′,2′-cis and 1′,2′-trans arabino- and ribo-like analogues bearing an all-carbon quaternary center at C3′. These molecules are currently being tested for their antiviral and anticancer properties.

Reported herein is the synthesis of sialyl LewisX analogues bearing a trans-bicyclo[4.4.0] dioxadecane-modified 3- O,4- C-fused galactopyranoside scaffold that locks the carboxylate pharmacophore in either the axial or equatorial position. This novel series of bicyclic galactopyranosides are prepared through a stereocontrolled intramolecular cyclization reaction that has been evaluated both experimentally and by density functional theory calculations. The cyclization precursors are obtained from β-d-galactose pentaacetate in a nine-step sequence featuring a highly diastereoselective equatorial alkynylation and Cu(I) catalyzed formation of the acetylenic α-ketoester moiety. Preliminary biological evaluations indicate improved activity as P-selectin antagonists for the axially configured analogues as compared to their equatorial counterparts.

The design of novel nucleoside analogues bearing a C2' all-carbon quaternary center is described. The construction of this all-carbon stereogenic center involves the use of photoredox catalysis to initiate an intramolecular attack of a silyl-tethered vinyl functionality on a tertiary radical. Density functional theory calculations were performed to explore the origin of the high syn diastereoselectivity obtained through the preferred 5-exo-trig cyclization mode. The intramolecular vinyl addition also enables the preparation of the complementary configuration of the C2' all-carbon stereocenter when performed after lactonization.

Reported herein is the synthesis of sialyl Lewis

Nucleoside analogues bearing a fluorine in the C2′-position have been synthesized by SN2-like cyclizations of acyclic thioaminal precursors. This strategy provides access to two scaffolds, d-1′,2′-cis-thiofuranosides and d-1′,2′-trans-furanosides, which are difficult to generate using the standard approach for nucleoside synthesis. The addition of silylated nucleobases onto model C2-fluorinated dithioacetal substrates resulted in 1,2-syn diastereoselectivity, which is consistent with the C2–F and S-alkyl moiety being in close proximity. A new series of analogues bearing a C3′ all-carbon quaternary center along with a C2′–F atom have also been synthesized using this approach and are being investigated as potential antimetabolites.

A synthetic strategy to access a novel family of nucleoside analogues bearing a C3'-nitrile substituted all-carbon quaternary center is presented herein. These purine bearing scaffolds were tested in two pancreatic cancer cell lines harboring either wild-type (BxPC3) or G12V KRAS (Capan2) mutations. A promising compound was shown to have significantly greater efficacy in the Capan2 cell line as compared to Gemcitabine, the clinical gold standard used to treat pancreatic cancer.

Reported herein is the total synthesis of zincophorin methyl ester, a polyketide ionophore. Of particular interest is the use of sterically hindered nucleophiles to surmount the unfavorable stereochemical outcome, leading to acetate aldol adducts, in nucleophilic addition to the aldehyde derived from propionates. The approach is based on the addition of an enoxysilane (bearing a removable phenylselenide moiety) to generate selectively Felkin–Anh adducts in a BF 3 ⋅OEt 2 -mediated Mukaiyama aldol reaction. Subsequent reduction of the selenide group led to the corresponding syn -aldol acetate motif, and this approach was applied to induce selectively the C12–C13 relationship of zincophorin.

Reported herein is an experimental and theoretical study that elucidates why silylated nucleobase additions to acyclic α-alkoxythiacarbenium intermediates proceed with high 1,2-syn stereocontrol (anti-Felkin-Anh), which is opposite to what would be expected with corresponding activated aldehydes. The acyclic thioaminals formed undergo intramolecular cyclizations to provide nucleoside analogues with anticancer and antiviral properties. The factors influencing the selectivity of the substitution reaction have been examined thoroughly. Halothioether species initially form, ionize in the presence (low dielectric media) or absence (higher dielectric media) of the nucleophile, and react through SN2-like transition structures (TS A and D), where the α-alkoxy group is gauche to the thioether moiety. An important, and perhaps counterintuitive, observation in this work was that calculations done in the gas phase or low dielectric media (toluene) are essential to locate the product- and rate-determining transition structures (C-N bond formation) that allow the most reasonable prediction of selectivity and isotope effects for more polar solvents (THF, MeCN). The ΔΔG(⧧) (G(TSA-TSD)) obtained in silico are consistent with the preferential formation of 1,2-syn product and with the trends of stereocontrol displayed by 2,3-anti and 2,3-syn α,β-bis-alkoxydithioacetals.

The design of a novel nucleoside scaffold that exhibits an all-carbon quaternary center is reported. This allows for both α- and β-anomers of a given 2'-deoxy-2',2'-difluoro nucleoside analog (NA) to have potential biological activity. Using an intramolecular atom-transfer reaction, an all-carbon quaternary center was obtained without the use of heavy metals and/or harsh conditions. The chemistry developed is efficient, easily scalable and leads to novel libraries of molecules.

Reported herein is the synthesis of all possible stereotriad propionates derived from L-lactic acid and L-alanine. The approach is based on a stereocontrolled Mukaiyama aldol reaction followed by a free radical-mediated hydrogen transfer, for which the choice of Lewis acid (monodentate or bidentate) dictates the stereochemical outcome in each reaction. The sequential process has been applied iteratively for the synthesis of eight stereopentad motifs derived from β,γ-alkoxyaldehydes. New experimental data and DFT calculations (BHandHLYP/TZVP) of the transition states involved in the radical reduction of aluminate intermediates support the proposed model of the endocyclic effect leading to high 2,3-syn selectivities for the synthesis of propionates and subunits thereof.

We report on the design and synthesis of molecules having E- and P-selectins blocking activity both in vitro and in vivo. The GlcNAc component of the selectin ligand sialyl Lewis(X) was replaced by an acyclic tether that links two saccharide units. The minimization of intramolecular dipole-dipole interactions and the gauche effect would be at the origin of the conformational bias imposed by this acyclic tether. The stereoselective synthesis of these molecules, their biochemical and biological evaluations using surface plasmon resonance spectroscopy (SPR), and in vivo assays are described. Because the structure of our analogues differs from the most potent E-selectin antagonists reported, our acyclic analogues offer new opportunities for chemical diversity.

Radical reductions of halogenated precursors bearing a heterocycle exo (α) to the carbon-centered radical proceed with enhanced anti-selectivity, a phenomenon that we termed "exocyclic effect". New experimental data and DFT calculations at the BHandHLYP/TZVP level demonstrate that the origin of the exocyclic effect is linked to the strain energy required for a radical intermediate to reach its reactive conformation at the transition state (ΔE(≠)(strain)). Furthermore, radical reductions of constrained THP systems indicate that high 2,3-anti inductions are reached only when the radical chain occupies an equatorial orientation. Hydride deliveries to different acyclic substrates and calculations also suggest that the higher anti-selectivities obtained with borinate intermediates are not related to the formation of a complex mimicking an exocycle. From a broader standpoint, this study reveals important conformational factors for reactions taking place at a center vicinal to a heterocycle or an α-alkoxy group.

The activation and ring-opening of methyl furanosides in the four natural sugar scaffolds (ribo, lyxo, arabino, and xylo) efficiently afforded acyclic thioacetals with high S(N)2-like selectivity at the acetal center in the presence of Me2BBr and thiophenol. The stereochemical outcome of these reactions provides important mechanistic insights into the activation pathway of five-membered semicyclic acetals. The thioacetal products should find applications in oligosaccharides synthesis and allow further development of acyclic strategies for the synthesis of novel nucleoside analogues.

Reported herein are the first diastereoselective and Lewis acid-mediated radical reactions of N-heterocyclic carbene (NHC) boranes. We applied these reactions to the synthesis of four propionate diastereoisomers combining an aldol reaction, followed by a stereoselective radical-based reduction in which the NHC borane serves as the hydrogen donor, thus obviating the use of tin-based reagents. The 2,3-syn isomer is obtained by combining an NHC-borane and a Lewis acid (MgBr2·OEt2), while using a reverse polarity strategy provides the 2,3-anti isomer.

The discovery of molecules that interfere with the binding of a ligand to a receptor remains a topic of great interest in medicinal chemistry. Herein, we report that a monosaccharide unit of a polysaccharide ligand can be replaced advantageously by a conformationally locked acyclic molecular entity. A cyclic component of the selectin ligand Sialyl Lewis(x), GlcNAc, is replaced by an acyclic tether, tartaric esters, which link two saccharide units. The conformational bias of this acyclic tether originates from the minimization of intramolecular dipole-dipole interaction and the gauche effect. The evaluation of the binding of these derivatives to P-selectin was measured by surface plasmon resonance spectroscopy. The results obtained in our pilot study suggest that the discovery of tunable tethers could facilitate the exploration of the carbohydrate recognition domain of various receptors.

Zincophorin C1-C9 fragment and seven tetrahydropyran analogues were prepared diastereoselectively by sequential iodoetherification and radical hydrogen-transfer reactions. Stereoselective formation of 3,7-trans or 3,7-cis rings was rationalized through minimization of allylic-1,3 strain in chair-like transition states. Subsequent hydrogen-transfer provided 7,8-anti or 7,8-syn isomers under acyclic stereocontrol or endocyclic control respectively. The latter approach relies on the formation of a [4.4.0] bicyclic complexes resulting from the chelation of the oxygen of the tetrahydropyran ring and the ester by a bidentate Lewis acid.

The structure-activity study of a bioactive natural product containing polypropionate subunits requires that its stereoisomers also be evaluated. Therefore, a general approach to synthesize these motifs is necessary. We describe herein the synthesis of the C1-C13 polypropionate subunit of zincophorin and isomers thereof using a two-reaction sequence: an aldol reaction using a mixture of tetrasubstituted enoxysilanes and a hydrogen-transfer reaction, both under Lewis acid control. Selection of the appropriate Lewis acid dictates the stereochemical outcome of these reactions. From a tactical standpoint, this study shows how a polypropionate sequence can be read and constructed in two directions, either the east-west or the west-east approaches. The choice of the optimal route is influenced by the number of complexation sites that can interfere in the aldol step under bidentate Lewis acid control.

A novel strategy for the stereoselective construction of all-carbon quaternary centers on acyclic molecules using a two-step tandem process is reported. The first step involves an intramolecular and stereoselective atom transfer radical cyclization reaction from an allyl or vinyl subunit attached on a silyloxy, serving as a tether, to a tertiary radical alpha to an ester. A subsequent mild acidic elimination leads stereoselectively to a quaternary center bearing an allyl or a vinyl in high yield.

Reported herein is the iteration of a strategy employing a Mukaiyama reaction in tandem with a hydrogen transfer reaction for the elaboration of four polypropionate motifs containing the anti – anti unit. In this process, Lewis acid acts as the key element in controlling the diastereoselectivity of each step, the outcome of which is >20:1 for all of the reactions performed.

The work described herein considers the impact of stereoelectronic effects and allylic 1,3-strain in controlling the cyclofunctionalization reaction when a hydroxyl group is at the allylic position. The stereoelectronic arguments are supported by independent iodocyclization reactions performed using two secondary alcohols. The transition-state pathways involved in these reactions are established through a comparison of relative reaction rates. A bi-directional approach is used to demonstrate the potential of the iodocyclization reaction to differentiate a terminus in molecules with a pseudo C(2) axis of symmetry, showing that two-directional synthesis can be used to differentiate between alternative transition-state pathways.

anti Relative stereochemistry is achieved in the hydrogen-transfer reaction of a lactam adjacent to the carbon-centered radical. The sense of diastereoselectivity is reversed using N-substituted lactams, and optimal results favoring syn reduced products are obtained with an α-methylbenzyl group and a Boc group.

The radical allylation of a series of α-halo or α-phenylseleno-β-alkoxy esters in the presence of MgBr2·OEt2 is reported and compared with analogous reactions under non-chelating conditions. The addition of MgBr2·OEt2 gives excellent selectivity favoring anti products; in some cases ratios >100:1 are obtained. Varying the substrate substituents reveals that these reactions are quite tolerant of alkyl functionalities at the β-position. Changes to the alkoxy function indicate that a chelate is involved in the reaction. The reactions are successful with secondary iodides, bromides, and phenylselenides, as well as tertiary iodides, which all give very high ratios under chelation control. Performing less well under the same conditions are substrates with a radical exocyclic to a tetrahydrofuran ring. EDTA titration is used to determine the amount of Mg2+ dissolved in the allylation reaction mixture, and 13C NMR is employed to better define the nature of the complex formed (chelate or monodentate) prior to the reaction. Competition experiments suggest that the chelate and monodentate pathways are in competition for the radical allylation with allyltributyltin.Key words: allylation, radicals, Lewis acid, stereoselectivity, 1,2-induction.

The radical reduction of a series of α-bromo-β-alkoxy esters under chelation-controlled conditions is reported. Proceeding with high stereoselectivity in the presence of MgBr2·OEt2, reductions give access to syn products. Systematic variations in substrate substituents show that these reactions tolerate a wide variety of alkyl functionalities at positions 2 and 3 and are relatively unaffected by the nature of the ester group. Changes to the alkoxy function indicate that a bidentate chelate is involved in the reaction and that an excess of MgBr2·OEt2 is required for optimum selectivity by favoring this species in preference to the anti-selective monodentate or nonchelated pathways. Competition experiments suggest that the monodentate pathway is kinetically favored over the bidentate one. The suppressibility of the reaction by radical chain inhibitors and the need for initiation indicate the intermediacy of radicals. Further support for this mechanism includes both radical addition to α,β-unsaturated esters...

The efficiency of a tandem process featuring an oxy radical cyclization and hydrogen transfer reaction of the resultant carbon-based radical has been demonstrated. This methodology affords 2,3- trans -disubstituted tetrahydrofurans by creating two new contiguous stereogenic centers with high levels of 1,2-induction in each step.

To enhance the diastereoselectivity of the hydrogen transfer reaction of acyclic substrates bearing 1,2- or 1,3-diols, the feasibility of a strategy employing bifunctional protecting groups has been demonstrated. This strategy is based upon the “exocyclic effect” or the significant improvement of anti-selectivity exhibited by the reductions of substrates in which the two substituents (R1 and Y) at the stereogenic center α to the radical center are linked together. A rationale for the excellent facial discrimination of these exocyclic radicals is offered based on an analysis of transition state models, which considers both steric and electronic factors.

Palinavir is a potent peptidomimetic-based HIV protease inhibitor. We have developed a highly convergent and stereoselective synthesis which is amenable to the preparation of multikilogram quantities of this compound. The synthetic sequence proceeds in 24 distinct chemical steps (with several integrated, multistep operations) from commercially available starting materials. No chromatographies are required throughout the process, and the final product is purified by crystallization of its dihydrochloride salt to >99% homogeneity.

Exocyclic radical reductions were thoroughly investigated in the context of the synthesis of polysubstituted tetrahydropyrans, which are found in numerous macrolides. The radical precursors studied herein were generated by tandem cycloetherification and iodoetherification reactions or, alternatively, by semicyclic acetals substitutions. DFT calculations (BHandHLYP/TZVP) performed at the transition-state level for the hydrogen radical delivery are in good accordance with the experimental data and enabled the identification of important conformational factors that govern the selectivities obtained. This study demonstrates that both the preferred reactive conformation of the radical and steric interactions with the incoming hydride have to be considered in order to fully rationalize the levels of diastereoselection generated in acyclic free-radical processes.

The radical allylation of a series of β-alkoxy esters using allyltrimethylsilane in the presence of MgBr2· OEt2 is described. Under bidentate chelation-controlled conditions, allyltrimethylsilane r...

(2S,3S)-N-Boc-3-amino-1,2-epoxy-4-phenylbutane is prepared in four steps from commercially available N,N-dibenzyl-L-phenylalaninol. The synthesis is amenable to the preparation of kilogram quantities of enantiomerically pure material.

Reported herein is a novel and versatile strategy for the stereoselective synthesis of unnatural β-L-arabinofuranosyl nucleoside analogues from acyclic N,OTMS-acetals bearing pyrimidine and purine bases. These unusual acetals undergo a C1' to C4' cyclization where the OTMS of the acetal serves as the nucleophile to generate 2'-oxynucleosides with complete retention of configuration at the C1' acetal center. N,OTMS-acetals are obtained diastereoselectively from additions of silylated nucleobases onto acyclic polyalkoxyaldehydes in the presence of MgBr(2)·OEt(2). The strategy reported is addressing important synthetic challenges by providing stereoselective access to unnatural L-nucleosides starting from easily accessible pools of D-sugars and, as importantly, by allowing the formation of the sterically challenging 1',2'-cis nucleosides. A wide variety of nucleoside analogues were synthesized in 7-8 steps from easily accessible D-xylose.

The tandem iodoetherification reaction and stereoselective reduction of acyclic radicals has been used in the stereocontrolled synthesis of substituted tetrahydrofurans. Such a tetrahydrofuran intermediate is regioselectively cleaved using Me 2 BBr to reveal the acyclic array 2 which represents the C 17 -C 22 subunit of ionomycin. In experiments that provide for a better understanding of hydrogen transfer reactions involving acyclic radicals, a significant improvement in the stereoselectivity is observed when the two substituents at the stereogenic center a to the radical are imbedded in a cycle («cycle effect»). A mechanistic rationale is discussed

ESR measurements and AM1 calculations show that ester substituted radicals 2 and 6 prefer conformation A as a result of allylic strain effects. But dipolar repulsion between substituents X and CO2Et In 2 and 6 has a pronounced effect on the conformation and the stereoselectivity of radicals 2 and 6.

Radical-based reduction of β-methoxy- or β-fluoro-α-bromo esters could be achieved with good stereoselection at low temperatures. A systematic evaluation of this reaction is presented and possible transition state models are discussed.

(2S,3S)-N-Boc-3-amino-1,2-epoxy-4-phenylbutane is prepared in four steps from commercially available N,N-dibenzyl-L-phenylalaninol. The synthesis is amenable to the preparation of kilogram quantities of enantiomerically pure material.

We are reporting a highly diastereoselective route to 1',2'-cis-nucleoside analogues in the D-ribo, D-lyxo, D-xylo, and D-arabinoside series. Five-membered ring lactols undergo highly selective N-glycosidation reactions in the presence of dimethylboron bromide with different silylated nucleobases. Stereoelectronic control plays a crucial role for the observed induction, and the products are proposed to be formed through S(N)2 "exploded" transition states. This approach shows great potential considering its simplicity and selectivity for the synthesis of nucleoside analogues, an important class of molecules in medicinal chemistry.