Volume 72, Issue 9

A highly effective method for the synthesis of formyl C-glycosides is described via addition of 2-lithiothiazole or 2-lithiobenzothiazole to sugar lactones, deoxygenation of the resulting ketols, and releasing of the formyl group from the heterocyclic ring. The synthetic utility of these sugar aldehydes is demonstrated by the development of synthetic methods to more elaborate C-glycosides. These include various (1-6)-C-disaccharides and some higher oligomers up to a C,C,C,C-pentasaccharide; C-glycosyl amino acid isosteres of N-glycosyl asparagines; the methylene isostere of β-Δ-galactosyl ceramide; linear and cylic (2-1)-ketoside oligomers. An alternative synthesis of ethylene-bridged glycosyl asparagine isosteres is illustrated by the use of ethynyl C-glycosides as starting materials.

Synthesis of chiral derivatives of glyoxylic acid with special emphasis on N-glyoxyloyl-(2R)-bornane-10,2-sultam is presented. Investigation of glyoxylic acid chiral derivatives in various stereocontrolled organic syntheses showed their excellent ability to provide products of high optical purity. Application of our methodology to the synthesis of natural products and their analogs is presented.

Benzotriazole-mediated methodology was successfully applied for the preparation of many classes of polyfunctional organic compounds.

This article reviews our contribution in the field of radical synthetic chemistry, focusing on cascades relying on the use of propargylic BMDMS ethers and asymmetric synthesis using enantiopure vinylsulfoxides.

A novel approach to developing enantioselective enzymes for use in organic chemistry has been devised which is independent of structural or mechanistic aspects. The underlying idea is to combine appropriate methods of random mutagenesis, gene expression, and high-throughput screening for enantioselectivity. If these actions are performed in repetitive cycles, an evolutionary pressure is created that leads to sequential improvements of the enantioselectivity of a given enzyme-catalyzed reaction. The concept is illustrated by an example involving the lipase-catalyzed hydrolytic kinetic resolution of an α-chiral ester, the enantio-selectivity increasing from ee = 2% (E =1.1) for a wild-type enzyme to ee = 90-93% (E = 25) for the best mutants.

The formation of C,C-bonds via photolytically generated biradicals can occur with high stereoselectivity. If triplet biradicals are involved, chiral induction is highly likely. Syntheses that occur only via singlet biradicals have a good chance to show a memory effect of chirality.

A formal total synthesis of the polyketide herboxidiene (1) has been achieved by Horner-Wittig coupling of the side-chain fragment 12- epi -(2) with the tetrahydropyran-2-acetic acid derivative (3) followed by desilylation of the resulting triene (19) and hydroxyl-directed mono-epoxidation of the ensuing bis -homoallylic alcohol (20).

A furofuran annulation/oxidative rearrangement strategy was used to construct the basic skeleton of the pyranonaphthoquinone family of antibiotics. This synthetic methodology has been applied to the synthesis of the spiroacetal-containing pyranonaphthoquinone antibiotic griseusin A, to an analog of the C-glycoside medermycin, and to a dimeric pyranonaphthoquinone.

Reductive allylation of certain nitrogen heterocycles (indoles, isoquinoline, 4-vinylpyridine, and lactams) with allylic boron and zinc derivatives is presented.

A versatile, readily accessible triad of 2-enoxy silane synthons derived from furan, pyrrole, and thiophene is presented. These heterocycles, in reacting with carbonyl and carbonyl-related acceptors, act as vinylogous nucleophile modules, giving rise to diverse, functionality-rich, γ-substituted α,β-unsaturated carbonyl constructs. These, in turn, are invaluable platforms onto which further functional elements and chirality may be introduced. A couple of appealing applications—the variable construction of a repertoire of carbasugars and a library of annonaceous acetogenin segments—have been chosen to illustrate the viability of this vinylogous aldol approach.

Fluorous molecules partition out of an organic phase and into a fluorous (highly fluorinated) phase in a liquid-liquid extraction. New fluorous techniques allow simple yet substantive separations of organic reaction mixtures based on the presence or absence of a fluorous tag. Fluorous-tagged molecules can also be separated from nontagged molecules by solid phase extraction over fluorous reverse-phase silica gel. This technique is ideal for solution-phase parallel synthesis because it allows simple yet substantive separations of organic reaction mixtures.

Siloxane methodology is extended to couplings with iodo- and bromoanilines, hindered arylbromides, and substituted siloxanes as substrates. Additionally, initial studies with 5-bromoindole and other heteroaromatics suggest that the siloxane-mediated cross coupling methodology will also be applicable in these systems.

After a brief summary of our asymmetric total syntheses of A83586C and 4- epi -A83586C, we will go on to describe some of our synthetic work on the monamycins, and our most recent total synthesis studies on the bryostatin antitumor macrolides.

This lecture describes some of our studies of lithio derivatives of allyl sulfone carbanions which add α-regioselectively as well as anti diastereoselectively to Michael acceptor olefins. This can be ascribed to chelation in the Michael addition step. When the reaction leads to subsequent ring closure by using a bromoallyl sulfone, the latter acts as a methylenemethane synthon in a (3+2) Michael-initiated ring closure, affording highly functionalized cyclopentane derivatives. Such additions proceed with high stereoselectivity and with asymmetric induction leading to nonracemic substituted cyclopentanones. Additions of allyl sulfone carbanions also proceed stereoselectively to C=N systems containing a chiral auxiliary on N. These can be used in the synthesis of optically active five- and six-membered ring N-heterocycles. Furthermore, chiral groups on the allyl sulfone moiety can induce significant remote asymmetric induction, made possible by the presence of an aromatic π-system which promotes intramolecular chelation to the Li cation.

By using the properties of fluorine such as electronic effects and leaving-group ability, two types of ring-forming reactions have been achieved starting from fluoroolefins: (i) fluorinated vinyl ketones with a vinyl and/or an aryl group, which undergo fluorine-directed and/or -activated Nazarov, Friedel-Crafts, and tandem cyclizations in their combination to construct highly functionalized and fused ring systems and (ii) gem-difluoroolefins bearing a nucleophilic center on the carbon δ to the flourines undergo intramolecular substitution for the fluorine via "anti-Baldwin" 5-endo-trig closures leading to ring-fluorinated heterocycles. Throughout these reactions, fluorines function as an activator of the substrates and a controller over the reaction pathways.

Stereo differentiated asymmetric syntheses have been achieved by S -indoline derivations. Diels-Alder cycloadditions of S -indoline chiral acrylamides with cyclopentadiene proceed with high diastereofacial selectivity, giving either endo-R or endo-S products depending on Lewis acid and the structures of chiral dienophiles. Diastereo- and enantio-selective pinacol coupling reactions of chiral α-ketoamides mediated by samarium diiodide afforded extremely high diastereoselectivities. Enantiopure ( S , S )- or ( R , R )-2,3-dialkyltar-taric acid and derivatives can be synthesized for the first time depending on the structure of α-ketoamides.

Main-group organometallics are useful intermediates for the chemoselective and diastereoselective C-C bond formation. The boron-zinc exchange is a unique way for preparing chiral secondary alkylzinc reagents which are configurationally stable over a wide temperature scale. Coupled with the thermal rearrangement of tertiary organoboranes, a broad range of open-chain and cyclic polyfunctional molecules have been prepared. In addition, several examples of a diastereoselective remote C-H activation have been studied. The second part shows that the main-group metallic alkoxides such as t-BuOK can be used for the performance of catalytic reactions such as a new indole synthesis.

In view of the importance of nucleoside analogs as enzyme inhibitors and adenosine receptor (ant)agonists, new adenosine analogs were prepared and their activities studied on adenosine deaminase in vitro and on A 1 , A 2A , and A 3 receptors. Particularly useful for the synthesis of new analogs were the applications of the Pd-catalyzed Buchwald reaction and a radical nitration reaction of purine- and 1-deazapurine nucleosides.

Selenium chemistry became, over the last 30 years, particularly useful for synthetic organic chemistry [1]. Inorganic as well as organic selenium compounds allow transformation which otherwise cannot be done or require much more drastic conditions to proceed. We have over the last 25 years explored the reactivity of elemental selenium as well as its inorganic and organic derivatives. We report here our recent finding concerning (i) organic diselenols and -diselenolates and (ii) the role of selenoxides in the enantioselective dihydroxylation of C,C double bonds using catalytic amounts of osmium tetroxide.

Dialkoxytitanacyclopropane intermediates [or titanium (II)-olefin complexes] generated in situ from ethylmagnesium bromide and titanium (IV) isopropoxide react with allylic alcohols and allylic ethers to afford S N 2' allylic ethylation products. The reaction proceeds with high regioselectivity and with low to high trans-/cis -stereoselectivity. This observation and others suggest a reaction mechanism involving an EtMgBr-initiated formation of titanacyclopentane ate complex 10 from titanacyclopropane-olefin complex 7 as a key step. Based on this assumption, a modified mechanism of titanium-mediated cyclopropanation of esters with Grignard reagents is proposed.

Camphor-derived oxazoline-N-oxides are versatile dipoles in a new kind of asymmetric [2+3] cycloadditions. Recent applications of this methodology allowed the stereoselective syntheses of several b-lactones natural products such as 1233A and tetrahydrolipstatine. Two formal syntheses of b-lactams antibiotics, b-methyl thienamycin and carpetimycin A, have also been achieved using this type of cycloaddition.

The hydrohalogenation reactions of electron-deficient allenes, such as 1,2-allenyl ketones, carboxylic acids, esters, amides, nitriles, sulfoxides, sulfones, and phosphine oxides with MX in HOAc, CF 3 COOH-HOAc, CF 3 COOH or AlCl 3 /H 2 O, afforded β-halo-β,γ-unsaturated functionalized alkenes. The regioselectivity of the reaction could be controlled by the reaction conditions.

Bicyclopropylidene ( 4 ), now readily available in preparatively viable quantities, is evolving as a useful C 6 building block for organic synthesis due to its enhanced reactivity at the C-H, the C=C, as well as both types of C-C single bonds. Monosubstituted derivatives are accessible by deprotonation/electrophilic substitution. Di- and tetrasubstituted bicyclopropylidenes are best made by copper-mediated reductive dimerization of bromolithiocarbenoids. The 1,3-dipolar cycloadducts of nitrones rearrange to spirocyclopropanated piperidones, palladium-catalyzed codimerizations with acrylates occur with opening of one of the rings to yield precursors to bicyclo[3.3.0]octene and bicyclo[5.3.0]decene skeletons. Silicon-heteroatom bonds can be added across the double bond of 4 under palladium catalysisjust like across a C텡C triple bond, and carbopalladation of the double bond in 4 occurs more rapidly than that in an acrylate. A variety of new three-component reactions of 4 with alkenyl as well as aryl halides and dienophiles have been developed and extended to be carried out in a combinatorial sense, even on a polymer support, with an additional dimension added in the cleavage step. Most of the reported reactions of bicyclopropylidene ( 4 ) proceed with good to excellent yields.

Metallocene complexes of the Group 3 metals and lanthanides have been utilized for cyclization/silylation reactions of polyunsaturated organic substrates. Acyclic dienes, trienes, enynes, and dienynes can be selectively cyclized to provide five- and six-membered rings in high yields.

The diastereoselective [2+2] cycloaddition of α-hydroxyketene equivalents with chiral α,ω-oxyaldehyde-derived imines followed by the 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO)-promoted ring expansion of the resulting α-hydroxy β-lactam adducts provides an unconventional and short route to α-amino acid N-carboxy anhydrides (NCAs). The required enantiopure α,ω-oxyaldehydes were obtained either from the chiral pool or through the Sharpless AD methodology. Following the present strategy, several nonproteinogenic NCAs were synthesized, which were further coupled with α-amino acid esters giving rise to key fragments of some nucleoside antibiotics and macrocyclic peptides.

Phosphatriafulvenes readily react with kinetically stabilized phosphaalkynes. Depending on the substituent at the phosphorus atom of the phosphatriafulvene, different six-membered phosphaheterocycles can be isolated. On the one hand, 1,3-diphosphabenzenes are formed, which can be isomerized thermally to diphospha dewarbenzenes or complexed by Cr(CO) 3 . On the other hand, 1,3-diphosphaisobenzenes are thus available. They are converted to bicyclic six-membered allenes via 1,3-dipolar cycloaddition to the P/C double bond.

Hexahydro-1 H -indol-3-one can be used as a building block for alkaloid synthesis. Radical and anionic cyclization approaches toward this useful structure were developed. Approaches toward total synthesis of montanine-type Amaryllidaceae alkaloids using hexahydro-1 H -indol-3-one as a key intermediate were studied.

Earlier observation that stereoregular All-R p -PS -oligonucleotides in the presence of nonsequence-specific Serratia endonuclease undergo nucleolytic degradation, confronted with recently published results on the active-site architecture of this enzyme, strongly supports an involvement of 3'-bridging and pro-Sp -nonbridging oxygen atoms of scissile internucleotide bond in the interactions with hydrated magnesium ion anchored by Asn-119 residue of this endonuclease.

Strategies and tactics associated with the total synthesis of hybrid natural products are discussed. The target is ravidomycin ( 2 ), one of the gilvocarcin-class antitumor antibiotics with an aryl C -glycoside structure. The first total synthesis of 2 , which was achieved along similar lines of that of gilvocarcin V ( 1 ), served for the determination of the relative as well as the absolute stereochemistry of 2 . Also revealed was a limitation of the synthetic scheme so long as the amino sugar congener was concerned. A preliminary result is discussed on the [2+2+2] approach that relies on the ready availability of various benzocyclobutene derivatives via regioselective [2+2] cycloaddition of α-alkoxybenzynes and ketene silyl acetals.

Titanium oxide catalysts were implanted with various transition-metal ions by a high-voltage acceleration technique, then calcined in O 2 at around 723 K to produce photocatalysts capable of absorbing visible light, the extent of the red shift depending on the amount and kind of metal ions implanted. Such metal ion-implanted titanium oxide photocatalysts, specifically using Cr or V ions, were successful in carrying out various photocatalytic reactions such as the decomposition of NO into N 2 , O 2 , and N 2 O at 293 K, significantly under irradiation with visible light longer than 450 nm. In outdoor field tests, these Cr and V ion-implanted titanium oxide photocatalysts showed three to four times higher photocatalytic reactivity for the decomposition of NO under solar beam irradiation, as compared with the original unimplanted titanium oxide photocatalyst.

Dimethylcarbonate (DMC), an environmentally friendly substitute for dimethylsulfate and methyl halides in methylation reactions, is also a very selective reagent. Under batch conditions, with potassium carbonate as the catalyst, the reactions of DMC, used as the solvent of the reactions, with methylene-active compounds (arylacetonitriles and arylacetoesters, aroxyacetonitriles and methyl aroxyacetates, benzylaryl- and alkylaryl-sulfones) produce monomethylated derivatives, with a selectivity not previously observed (i. e., >99%). These are examples of "green chemistry".