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New Stereodivergent Approach to 3-Amino-2,3,6-trideoxysugars. Enantioselective Synthesis of Daunosamine, Ristosamine, Acosamine, and Epi-daunosamine
Abstract
[reaction: see text] An enantioselective preparation of the four diastereomeric 3-amino-2,3,6-trideoxy-hexoses, key components of anthracycline antibiotics, has been developed. Sharpless catalytic asymmetric epoxidation of the (2E)-2,5-hexadien-1-ol, regioselective ring opening with azide, followed by convenient functional group transformations, afforded the key aldehydes cis- or trans-6 in any configuration. The diastereoselective addition of methylmetal reagents to these aldehydes followed by ozonolysis gives access in a completely stereocontrolled manner to the four isomeric trideoxyaminosugars.
... Henry reaction [10] (i.e., nitroaldol condensation) is one of the prominent transformations to access a wide range of strategically fundamental molecular structures such as β-hydroxy nitro alkanes, α-hydroxy carboxylic acids and 1,2-amino-alcohols, etc., in a forthright fashion [9,11]. Henry reaction also provides a facile and direct access of various versatile building block β-nitro alcohols [10,12,13] which are the vital skeleton found in many biologically active compounds, such as antibiotics L-acosamine [14], anti-asthmatic drug (R)-salmeterol [15], fungicide (S)-spirobrassinin [16] and bestatin [17]. Due to the dual functionality of β-nitro alcohol, it can be easily transformed into various functionalities via a several roots such as reduction of nitro group into amine, dehydration leads to nitro-olefin, denitration, or other transformations such as Nef reaction and retro-Henry reaction (Figure 1) [18]. ...
Citation: Alammari, A.S.; Al-Majid, A.M.; Barakat, A.; Alshahrani, S.; Ali, M.; Islam, M.S. Asymmetric Henry Reaction of Nitromethane with Substituted Aldehydes Catalyzed by Novel In Situ Generated Chiral Bis(β-Amino Alcohol-Cu(OAc) 2 ·H 2 O Complex. Catalysts 2021, 11, 1208. Abstract: Novel chiral thiophene-2,5-bis(β-amino alcohol) ligands (L1-L5) were designed and synthesized from thiophene-2,5-dicarbaldehyde (3) with chiral β-amino alcohols (4a-e) in 4 steps with overall 23% yields. An in situ generated L-Cu(OAc) 2 ·H 2 O catalyst system was found to be highly capable catalyst for the asymmetric Henry reaction of nitromethane (7) with various substituted aromatic aldehydes (6a-m) producing chiral nitroaldols product (8a-m) with excellent enantiomeric purity (up to 94.6% ee) and up to >99% chemical yields. 20 mol% of L4-Cu(OAc) 2 catalyst complex in EtOH was effective for the asymmetric Henry transformation in 24 h, at ambient temperature. Ease of ligand synthesis, use of green solvent, base free reaction, mild reaction conditions, high yields and excellent enantioselectivity are all key factors that make this catalytic system robust and highly desirable for the access of versatile building block β-nitro alcohol in practical catalytic usage via asymmetric Henry reaction.
... The reaction is named Henry reaction according to its discoverer [4] and because of its similarity with the aldol reaction it is also referred as the nitroaldol reaction. A significant feature of the Henry reaction is a possibility to conduct the reaction enantio-or diastereoselectively. Chiral products of the Henry reaction, 2-nitroalcohols, are important intermediates in syntheses of many biologically active compounds, such as antiasthmatic drug (R)-salmeterol [5], antibiotics L-acosamine [6] and bestatin [7], or fungicide (S)-spirobrassinin [8]. In the past, development of the field of stereoselective Henry reaction had been rather slow [9]. ...
Copper(II) complex of the ligand possessing two enantiomerically pure trans-cyclohexane-1,2-diamine units proved to be an efficient catalyst for the enantioselective Henry reaction of aromatic aldehydes with nitromethane. The effect of various reaction conditions on yield and enantioselectivity of the Henry reaction was studied. The results suggest that only one cyclohexane-1,2-diamine unit is involved in catalysis of the Henry reaction.
Amino deoxysugars are abundant in nature and play an important role in various biological functions, promoting numerous efforts to synthesize their structurally unique motifs. In this report, a de novo approach from a readily available lactic acid derivative is devised to construct several amino deoxysugars embedded in natural products, featuring a novel nitroso-ene-type cyclization to introduce a nitrogen atom into the carbon framework. This efficient synthesis provides an unprecedented synthetic route to explore the nitroso-ene cyclization to accumulate intriguing amino deoxysugars.
Synthesis of 3,5-cis-3-amino glycals with a cis-fused cyclic sulfamidate group has been achieved by selective reduction of sulfamidate ketimine groups. The efficient access to the structurally unique glycals allowed the subsequent divergent synthesis of various naturally occurring 3-amino-2,3,6-trideoxysugars. In addition, Lewis acid-promoted glycosylation of the glycals provided a simple solution for the stereoselective installation of O- and C-linked aglycons on the amino sugar scaffolds.
Catalyst supports were modified using a variety of matrices, and cellulose showed the best modification effect, with an enantioselectivity up to 99% in the asymmetric Henry reaction.
This chapter provides a summary of olefination, metathesis, and epoxidation reactions applied in modern organic chemistry and drug synthesis. The summary includes valuable information on reaction details, step‐by‐step mechanism, experimental procedures, applications, and (patent) references. The reactions covered include Corey–Winter olefin synthesis, Horner–Wadsworth–Emmons reaction, Julia–Lythgoe olefination, Julia–Kocienski olefination, Kauffmann olefination, Peterson olefination, Petasis olefination, Tebbe olefination, Wittig reaction, olefin metathesis, ring‐closing metathesis, cross metathesis, ring‐opening metathesis, sharpless asymmetric epoxidation, sharpless asymmetric aminohydroxylation, Woodward cis‐dihydroxylation, Prevost trans‐dihydroxylation reaction. By providing mechanistic information and representative experimental procedures, the chapter is an indispensable guide for researchers and professionals in organic chemistry, natural product synthesis, pharmaceutical, and medicinal chemistry, as well as post‐graduates preparing themselves for a job in the pharmaceutical industry.
This review covers diastereo- and enantiodivergent catalyzed reactions in acyclic and cyclic systems using metal complexes or organocatalysts. Among them, nucleophilic addition to carbon–carbon and carbon–nitrogen double bonds, α-functionalization of carbonyl compounds, allylic substitutions, and ring opening of oxiranes and aziridines are considered. The diastereodivergent synthesis of alkenes from alkynes is also included. Finally, stereodivergent intramolecular and intermolecular cycloadditions and other cyclizations are also reported.
Invited for the cover of this issue is the group of Alexey Sukhorukov at the N. D. Zelinsky Institute of Organic Chemistry. The image depicts the reaction pathways taken by metal azides as a “chemical billiard” game. Read the full text of the article at 10.1002/chem.201605390.
In the “chemical billiard” reaction shown on the front cover, a counter ion directs the attack of the azide anion to one or another electrophilic center of the organic substrate. Covalently bonded metal azides transfer N3⁻ to the β-carbon atom through a Lewis-acid-promoted SN’ process, while ionic azides react through SN2 attack on the silicon. These two pathways lead to entirely different products. More information can be found in the Full Paper by A. Yu. Sukhorukov et al. (DOI: 10.1002/chem.201605390).
Metal azides generated in situ by ion exchange exhibit divergent reactivity in reaction with cyclic N-alkoxy,N-siloxy-enamines. Depending on the nature of metal and the [M]/N3- ratio, addition of the azide ion to the С,С-double bond proceeds with regioselective cleavage of either exo- or endo-cyclic N-O bond leading to cyclic or open-chain a-azidooxime derivatives, respectively. Mechanistic studies in combination with solvent state FTIR spectroscopy and DFT calculations revealed that covalently bound metal azides (Co, Cu, Zn) transfer N3- to the С,С-double bond through a Lewis acid-assisted SN' substitution of silyloxy-group. More ionic metal azides (Mg, Al, Sc, Ni, Yb) tend to react via initial nucleophilic attack of N3- on the silicon atom generating conjugated nitrosoalkenes. a-Azidooxime derivatives prepared using the designed protocols were stereoselectively reduced to valuable 1,2-diaminoalcohols bearing up to four contiguous stereogenic centers. By reducing the a-azidooxime fragment in a stepwise manner site-selective protection and reductive amination of each of the emerging primary amino groups was achieved.
Amino sugars are important constituents of a number of biomacromolecules and products of microbial secondary metabolism, including antibiotics. For most of them, the amino group is located at the positions C1, C2 or C3 of the hexose or pentose ring. In biological systems, amino sugars are formed due to the catalytic activity of specific aminotransferases or amidotransferases by introducing an amino functionality derived from L-glutamate or L-glutamine to the keto forms of sugar phosphates or sugar nucleotides. The synthetic introduction of amino functionalities in a regio- and stereoselective manner onto sugar scaffolds represents a substantial challenge. Most of the modern methods of for the preparation of 1-, 2- and 3-amino sugars are those starting from "an active ester" of carbohydrate derivatives, glycals, alcohols, carbonyl compounds and amino acids. A substantial progress in the development of region- and stereoselective methods of amino sugar synthesis has been made in the recent years, due to the application of metal-based catalysts and tethered approaches. A comprehensive review on the current state of knowledge on biosynthesis and chemical synthesis of amino sugars is presented.
Written by world-renowned and best-selling experts, Nobel Laureate E. J. Corey and Laszlo Kurti, Enantioselective Chemical Synthesis offers an authoritative and comprehensive overview of the field's progress; the processes and tools for key formations; future development for complex, stereocontrolled (enantiomeric or diastereoisomeric) molecules; and valuable examples of multi-step syntheses. Utilizing a color-coded scheme to illustrate chemical transformations, Enantioselective Chemical Synthesis provides clear explanation and guidance through vital asymmetrical syntheses and insight into the next steps for the field. Researchers, professionals, and academics will benefit from this valuable, thorough, and unique resource. © 2010 Elias J. Corey & Laszlo Kurti Published by Elsevier Inc. All rights reserved.
Enantioselective syntheses of cis-4- and trans-3-hydroxypipecolic acids from 2,3-epoxy-5-hexen-1-ol (7) are described. Regioselective C-3 or C-2 ring opening of the epoxide by the appropriate nitrogen nucleophile is the key step in each route. As enantiomerically enriched epoxy alcohols are readily available in any configuration by Sharpless epoxidation, both enantiomers are equally accessible. This approach was also employed to synthesize the natural product baikiain and the important synthetic intermediate trans-3-hydroxy-2-hydroxymethylpiperidine. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
Ab initio asymmetric syntheses of methyl N,O-diacetyl-D-3-epi-daunosaminide and methyl N,O-diacetyl-D-ristosaminide, employing diastereoselective epoxidation and dihydroxylation, respectively, of alkyl (3S,alphaR,Z)-3-[N-benzyl-N-(alpha-methylbenzyl)amino]hex-4-enoates as the key steps, are reported. The requisite substrates were readily prepared using the conjugate additions of lithium (R)-N-benzyl-N-(alpha-methylbenzyl)amide to methyl and tert-butyl (E)-hexa-2-en-4-ynoates followed by diastereoselective alkyne reduction. syn-Dihydroxylation using OsO4 proceeded under steric control on the 4Re,5Re face of the olefin to give the corresponding diol, which subsequently underwent lactonisation. Meanwhile, epoxidation using F3CCO3H in conjunction with F3CCO2H proceeded on the opposite 4Si,5Si face of the olefin, under hydrogen-bonding control from the in situ formed ammonium-ion. Treatment of the intermediate epoxide with conc aq H2SO4 promoted highly regioselective ring-opening (distal to the in situ formed ammonium moiety) to give the corresponding diol (completing overall the formal anti-dihydroxylation of the olefin), which then underwent lactonisation under the reaction conditions. Elaboration of these diastereoisomeric lactones through hydrogenolysis, N-Boc protection, reduction, methanolysis and acetate protection gave methyl N,O-diacetyl-D-3-epi-daunosaminide and methyl N,O-diacetyl-D-ristosaminide.
Diastereoselective aza-Wacker cyclization of O-allyl hemiaminals under aerobic conditions enables efficient access to 1,2-aminoalcohol derivatives from allylic alcohols. The scope of this method is presented and its utility is highlighted in a streamlined synthesis of the biologically important aminosugar (-)-acosamine. Cbz=benzyloxycarbonyl, TBDPS=tert-butyldiphenylsilyl, TBS=tert-butyldimethylsilyl.
We published a review concerning the scope and application of the conjugate addition of enantiomerically pure lithium amides in 2005. This review comprehensively updates recent developments of this reaction, all the new reports of this methodology, and its applications in synthesis since the publication of our first review up to the end of 2011.
Starting from a single suitable functionalised epoxide, a highly efficient stereoselective synthesis of d-erythro-sphingosine and d-lyxo-phytosphingosine is described. The approach allows the formal preparation of all stereoisomers of these sphingoid structures.
3-Amino- and 3-nitro-2,3-dideoxy sugars, which are structurally diverse and uncommon sugars bearing an amino substitution on a sugar scaffold, have been shown to play crucial roles in the biological activities of aminoglycoside antibiotics and aminoglycoside containing natural products. Over the past few decades, there have been continuing efforts on the convenient synthesis of monosaccharides and oligosaccharides containing 3-amino- and 3-nitro-2,3-dideoxysugar motifs, beginning from either carbohydrate or non-carbohydrate precursors. This review article is intended to provide an updated overview of the most striking contributions in this field, based on the various strategies to construct the 3-amino sugar ring.
Diastereoselective conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl sorbate and subsequent chemo- and diastereoselective ammonium-directed olefinic oxidation of the resultant conjugate addition product {tert-butyl (3S,αR)-3-[N-benzyl-N-(α-methylbenzyl)amino]hex-4-ene} have been used as the key steps in a concise and highly selective asymmetric synthesis of the 2,3,6-trideoxy-3-aminohexose l-acosamine. This sequence of two chemical operations allows rapid assembly of the molecular architecture and facilitates the de novo asymmetric synthesis of methyl N,O-diacetyl-α-l-acosaminide in only 7 steps from commercially available sorbic acid in 15% overall yield.
Four 3-amino-2,3,6-trideoxysugars were synthesized by a divergent route from a single enone 9a. The Migita-Stille coupling introduced a methyl group at the 3-position. Stereoselective reduction of enone and the Mitsunobu reaction provided both beta- and alpha-hydroxy groups at the 4-position. Stereospecific radical cyclization of the C4 carbamoyl moiety furnished the desired 5a, 5b and 6a, 6b, respectively.
An alternative strategy has been developed for producing 3-azido-2,3,6-trideoxy-l-hexoses, protected forms of daunosamine, ristosamine, acosamine, and epi-daunosamine. This method involved BF3·OEt2-induced peroxidation of rhamnal to construct key intermediate α,β-unsaturated lactone as the common precursor. After further derivatization, four 3-azido hexoses were successfully synthesized.
Studies of stereocontrol in two types of radical equivalents of Mannich addition reactions offer new insights for application to aminosugar synthesis. In the first method, haloacetal addition (Ueno–Stork reaction) is extended to dihydroxyhydrazones, leading to an adduct with the unexpected 3-epi-l-daunosamine configuration. A neighboring α-benzyloxy substituent causes a dramatic reversal of stereocontrol compared with hydrazones where this substituent is absent; vicinal dipole repulsion is proposed to account for the diastereoselectivity. In the second method, radical addition–cyclization with thiophenol and treatment with fluoride leads to diastereoselective group transfer from a silicon-tethered ethynyl group to the CN bond of hydrazones, affording anti-hydrazino alcohols with a trans-2-(phenylthio)vinyl substituent. The one-pot process occurs under neutral, tin-free radical conditions, and offers stereocontrol which is complementary to the haloacetal method. Synthetic utility of the radical Mannich concept is demonstrated in a brief asymmetric synthesis of N-trifluoroacetyl-l-daunosamine from achiral precursors.
A new and very concise strategy has been formulated for the synthesis of 3-amino-2,3,6-trideoxyhexoses, daunosamine, acosamine, ristosamine and 3-epi-daunosamine, via cis- and trans-oxazoline intermediates assembled by a novel intramolecular conjugate addition of γ-trichloroacetimidoyloxy-α,β-unsaturated esters in an acyclic system.
The first total synthesis of dinemasone A, a bioactive metabolite with a spiroketal moiety, is described. The main strategy for the construction of the spiroketal unit involves a double intramolecular hetero-Michael addition (DIHMA) of an ynone moiety. The thus obtained axial-equatorial mono anomeric spiroketal, on spiroepimerization with ZnBr(2), was converted into the requisite axial-axial double anomeric spiroketal. The ynone moiety with four stereocentres, was prepared from a chiral propargylic alcohol (C5-C11 fragment) and a dihydroxy aldehyde (C1-C4 fragment), which in turn were obtained from d-mannitol and crotyl alcohol respectively.
Seit der Entdeckung der organischen Azide vor über einhundertvierzig Jahren durch Peter Grieß wurde eine Reihe von Synthesen für diese energiereichen Moleküle entwickelt. In letzter Zeit haben sich völlig neue Perspektiven durch Anwendungen in der Peptidchemie, der kombinatorischen Chemie und der Heterocyclensynthese ergeben. Auf dem interdisziplinären Gebiet zwischen Chemie, Biologie, Medizin und Materialwissenschaften nehmen organische Azide inzwischen einen wichtigen Raum ein. In diesem Aufsatz werden die Grundzüge der Azid-Chemie dargelegt und aktuelle Entwicklungen auf diesem Gebiet beleuchtet. Der Schwerpunkt liegt dabei auf Cycloadditionen (Huisgen-Reaktion), Aza-Ylidchemie und der Synthese von Heterocyclen. Weitere Reaktionen wie die Aza-Wittig-Reaktion, Sundberg-Umlagerung, Staudinger-Ligation, Boyer- und Boyer-Aubé-Umlagerung, Curtius-Umlagerung, Schmidt-Umlagerung sowie die Hemetsberger-Umlagerung zeugen von der Vielfältigkeit moderner Azid-Chemie.
Enantiomerically pure cyanohydrins derived from 2-p-tolylsulfinyl benzaldehyde can be obtained by reaction with different hydrocyanating reagents in the presence of Yb(OTf)3 or Y(OTf)3.
Biological activity of the anthracycline antibiotics, which have found wide application in clinical
oncology, is strongly related to their glycosidic structure. Modification or switch of the saccharide moiety
became an important line of new drug discovery and study of their mechanism of action. Natural glycons
(sugar moieties) of the anthracycline antibiotics belong to the 2,6-dideoxypyranose family and their principal
representative, daunosamine, is 3-amino-2,3,6-trideoxy-l-lyxo-pyranose. Some newer chemical syntheses of this sugar, from achiral
pool as well as from achiral starting materials, are presented and their capability for scale-up and process
development are commented upon. Rational sugar structural modifications, which are either useful for synthetic
purposes or offer advantages in experimental therapy of cancer, are discussed from the chemical point of
view.
The 3-aminoglycosides are ubiquitous in biologically important classes of glycoconjugates and naturally occurring oligosaccharides. Despite the rapid growth in the development of synthetic method of 3-amino glycosides, the current state-of-the art suffers from limited substrate scope, low yields, long reaction times, and anomeric mixtures. This work presents a novel direct method for the synthesis of 1,3-cis-3-arylsulphonaminodeoxydisaccharides and oligosaccharides via α-selective glycosylation and hydroamination of glycal in a one-pot manner. This efficient multicomponent reaction methodology provides ready access to 1,3-cis-3-arylsulphonaminodeoxydisaccharides and oligosaccharides and allows derivatization by variation of each component.
Titanium(IV)-promoted regioselective ring-opening reaction of chiral epoxy-allyl alcohols (Sharpless conditions as the key strategic step) is developed as a tool for ready access to chiral 5,6-dihydroxyoct-7-en-4-yl alkoxylates. Later, the synthetic utility of products thereof was demonstrated through the RCM based stereoselective synthesis of various natural products.
Free radical additions to imino compounds offer increased synthetic accessibility of chiral amines, but lack of general methods for stereocontrol has hindered their development. This review focuses on two asymmetric amine synthesis strategies designed to address this problem, with emphasis on addition of functionalized radicals which may facilitate applications to synthesis of complex targets. First, chiral N-acylhydrazones are acceptors for intermolecular radical additions of a wide range of primary, secondary, and tertiary alkyl halides to the C=N bond, with radicals generated under manganese-, tin-, or boron-mediated conditions. A variety of aldehydes and ketones serve as viable precursors for the chiral hydrazones, and the highly stereoselective reactions tolerate electrophilic functionality in both coupling components. Second, radical precursors may be linked to chiral α-hydroxyhydrazones via a silicon tether to the hydroxyl group; conformational constraints impart stereocontrol during 5-exo radical cyclization under stannyl- or thiyl-mediated conditions. The silicon tether may later be removed to reveal the formal adducts of hydroxymethyl, vinyl, acetyl, and 2-oxoethyl radicals to the C=N bond. Methodology development and applications to biologically important targets are discussed.
A highly stereoselective BF(3)·OEt(2)-promoted tandem hydroamination-glycosylation on a glycal scaffold has been developed to form 3-amino-2,3-dideoxysugars in a one-pot procedure. This efficient multicomponent reaction protocol offers simplicity and general applicability to a broad range of variations on each component.
A highly efficient synthesis of L-ristosamine and L-epi-daunosamine glycosides via BF(3)·OEt(2) promoted tandem hydroamination/glycosylation of 3,4-di-O-acetyl-6-deoxy-L-glucal and L-galactal has been developed. The new method proceeds in a completely stereocontrolled manner within a short reaction time. Preparation of a library of L-ristosamine and L-epi-daunosamine glycosides with potential biochemical applications, by varying each component, exemplified the generality of the reaction.
An overview of the synthesis and applications of chiral 2,3-epoxy alcohols containing unsaturated chains is presented. One of the fundamental synthetic routes to these compounds is Sharpless asymmetric epoxidation, which is reliable, highly chemoselective and enables easy prediction of the product enantioselectivity. Thus, unsaturated epoxy alcohols are readily obtained by selective oxidation of the allylic double bond in the presence of other carbon-carbon double or triple bonds. The wide availability of epoxy alcohols with unsaturated chains, the versatility of the epoxy alcohol functionality (e.g. regio- and stereo-selective ring opening; oxidation; and reduction), and the arsenal of established alkene chemistries, make unsaturated epoxy alcohols powerful starting materials for the synthesis of complex targets such as biologically active molecules. The popularization of ring-closing metathesis has further increased their value, making them excellent precursors to cyclic compounds.
Reactions of amines and carbon nucleophiles with 4-sulfonyl-hex-3-enopyranoside generate a range of C-3 amino- and C-3 branched-chain sugars, which are analogues of 3-amino-3,6-dideoxy sugars and 3-C-branched-chain-3,6-dideoxy sugars. The diastereoselectivity of addition reaction is nucleophile dependent; while both nitrogen and carbon nucleophiles added in cis-fashion, amines generated C3-C4 trans-diaxial products (gulo-derivatives), and carbon nucleophiles afforded C3-C4 trans-diequatorial products (gluco-analogues).
C-Glycoside analogs of α-galactosylceramide (KRN7000) were synthesized in 19 linear steps with Sharpless asymmetric epoxidation as a key reaction. Opening of a hydroxy epoxide with sodium azide provided an anti vicinal azido diol with inversion of configuration at the azide-bearing carbon while opening with Ti(O-i-Pr)2(N3)2 gave syn vicinal azido diol with retention. The latter, unusual outcome could be rationalized either by invoking Ti-catalyzed intramolecular double SN2 inversion or by epoxide opening/intramolecular delivery of azide from the Ti complex.
Stereocontrolled additions of hydroxymethyl and vinyl groups to chiral alpha-hydroxyhydrazones can be achieved by radical cyclizations using bromomethyl or vinyl radical precursors tethered via a temporary silicon connection. Tin-mediated 5-exo radical cyclization of alpha-hydroxyhydrazones using a silicon-tethered bromomethyl group, followed by oxidative removal of the tether, provides anti-2-hydrazino 1,3-diols in good yield. Tandem thiyl radical addition-cyclization of alpha-hydroxyhydrazones using a silicon-tethered vinyl group, followed by treatment with potassium fluoride, affords acyclic allylic anti-hydrazino alcohols in good yield. The thiyl addition-cyclization method has been successfully extended to the use of alpha,beta-dihydroxyhydrazones without prior protection or hydroxyl differentiation. Diastereoselection in both reaction types increases with increasing A values of the appended groups, consistent with prediction by the Beckwith-Houk model for stereocontrol in 5-hexenyl radical cyclizations.
Three-component reactions of aldehydes, ammonia, and allylboronates were found to provide homoallylic primary amines in high yields with high chemo- and stereoselectivities. A two-step, one-pot, stereoselective synthesis of an uncommon alpha-amino acid, alloisoleucine, was achieved utilizing this reaction.
Since the discovery of organic azides by Peter Griess more than 140 years ago, numerous syntheses of these energy-rich molecules have been developed. In more recent times in particular, completely new perspectives have been developed for their use in peptide chemistry, combinatorial chemistry, and heterocyclic synthesis. Organic azides have assumed an important position at the interface between chemistry, biology, medicine, and materials science. In this Review, the fundamental characteristics of azide chemistry and current developments are presented. The focus will be placed on cycloadditions (Huisgen reaction), aza ylide chemistry, and the synthesis of heterocycles. Further reactions such as the aza-Wittig reaction, the Sundberg rearrangement, the Staudinger ligation, the Boyer and Boyer-Aubé rearrangements, the Curtius rearrangement, the Schmidt rearrangement, and the Hemetsberger rearrangement bear witness to the versatility of modern azide chemistry.
[reaction: see text] Optically pure functionalized cyanohydrins derived from 1-[2-(p-tolylsulfinyl)phenyl] ethanone can be obtained by the reaction of 2-p-tolylsulfinyl benzaldehyde derived cyanohydrins with bases and further treatment with suitable electrophiles. High yields and excellent stereoselectivities (up to de >98%) were obtained for these remote 1,4-asymmetric induction processes controlled by a sulfinyl chiral inductor.
An overview is given of the impressive amount of enantioselective synthetic uses that have been found for titanium catalyst and/or reagents in the last few years, from classical reactions such as 1,2- and 1,4-additions, Diels-Alder reactions, or oxidations and reductions to new procedures such as the enantioselective nucleophilic addition of unreactive organozinc reagents to poor electrophilic ketones, or the electrophilic α-halogenation of carbonyl compounds. Completely new reactions have been exclusively promoted by titanium complexes. The economical, health, and environmental benefits compared to the use of other metal-based procedures are very significant.
[reaction: see text] The diastereomers of 6-amino-cyclohex-3-ene-1,2-diols 1 (4-deoxy-3-conduramines), key building blocks for the syntheses of a large range of natural products, have been enantioselectively prepared. Diastereoselective dihydroxylation of the compounds provided a new family of aminocyclitols 2 (deoxyinosamines). The key reactions of our syntheses are Sharpless catalytic asymmetric epoxidation, diastereoselective addition of vinylmetal reagents to the aldehydes, and ring-closing metathesis (RCM).
Application of photoinduced acylnitrene aziridination to the syntheses of L-daunosamine and L-ristosamine glycosides is reported. Photoreaction of methyl 4-O-azidocarbonyl-2,3,6-trideoxy-L-hex-2-enopyranosides, followed by aziridine opening, leads to 3-amino-3-N-,4-O-carbonyl-2,3,6-trideoxy precursors to the aminosugar methyl glycosides. Conversion of these precursors to their thioglycoside analogues followed by N-acetylation of the carbamate moiety permits high yielding and, in some cases, stereoselective glycosylations using the 1-benzenesulfinylpiperidine-triflic anhydride activation method developed by Crich and co-workers. Glycosylations involving activation with N-iodosuccinimide and silver triflate were also successful, but the stereoselectivities of these reactions in general were lower.
For the efficient synthesis of divergent nitrogen-containing compounds of pharmaceutical and agricultural importance, the development of efficient, complementary, and new synthetic methodologies is essential. One of the key subjects is how to introduce nitrogen atoms in to organic molecules. This review summaries our recent efforts on this issue, focusing on the use of carbamates, acylhydrazines, and ammonia as nitrogen sources.
[reaction: see text] Asymmetric dihydroxylation, thiyl radical mediated transfer of a silicon-tethered vinyl group to a hydrazone and an unconventional aldehyde-selective Wacker oxidation are sequenced for an efficient synthesis of methyl N-trifluoroacetyl-L-daunosaminide in 32% overall yield from crotonaldehyde.
[reaction: see text] The tungsten-catalyzed cycloisomerization of alkynyl alcohols can be conducted without using photochemistry, using a stable tungsten Fischer carbene as the precatalyst for this transformation. A variety of alkynyl alcohols undergo cycloisomerization under these conditions to provide endocyclic enol ethers of five-, six-, and seven-membered ring sizes. The utility of this method is further demonstrated in the stereoselective synthesis of the disaccharide substructure of altromycin B.
An asymmetric synthesis for the preparation of both enantiomers of trans-methylpipecolic acids is described. It is based on Sharpless epoxidation as a chirality source, regioselective ring opening with allylamine, and ring-closing metathesis to construct the piperidine ring. The stereogenic center at C-4 is set by stereoselective hydrogenation that is directed by the alcohol functionality of an intermediate and proceeds with good diastereomeric control (trans/cis 16/1). Crystallization of the Boc-protected amino acid afforded the target products with excellent chemical (98% de) and enantiomeric purity (99% ee).
N-Benzoyl-L-daunosamine was synthesized with high stereoselectivity utilizing a 1, 3-addition of ketene silyl acetal to the chiral nitrone, (Z)-[(4S, 5S)-2, 2, 5-trimethyl-1, 3-dixolan-4-yl]methylene[(1S)-1-phenylethyl]amine N-oxide, followed by a silyl group-transfer reaction in acetonitrile under mild conditions.
We tested the ability of vaccination with virus-like particles (VLPs) to protect domestic rabbits against papillomas induced by the cottontail rabbit papillomavirus (CRPV). A recombinant baculovirus system that expressed only the L1 major papillomavirus structural protein or L1 plus the minor L2 protein was used in insect cells as the source of VLPs. Groups of 10 rabbits were immunized with native or denatured VLPs from CRPV or type 1 bovine papillomavirus by using Freund's adjuvant. Alum was used as the adjuvant for an additional group immunized with CRPV L1-L2 VLPs. Animals were challenged with 5 x 10(10) and 2 x 10(11) particles on opposing flanks. No protection was seen in rabbits immunized with native or denatured bovine papillomavirus L1-L2 or with denatured CRPV L1-L2. In these groups, the lower and higher challenge doses resulted in 27 of 30 animals with extensive papillomas, with each of the remaining animals having a smaller number of persistent papillomas. Progression to carcinoma developed in 20 rabbits. Animals inoculated with native CRPV VLPs composed of L1 alone or L1-L2 developed many fewer lesions; the lower and higher challenge doses resulted in 17 of 29 and 5 of 29 rabbits, respectively, with no lesions, and the remainder developed only one to eight papillomas, which all regressed except for those on 1 rabbit. None developed cancer within 1 year of infection. Rabbits vaccinated with native CRPV VLPs developed high-titer antibodies in an enzyme-linked immunosorbent assay based on native VLPs, and passive transfer of serum or immunoglobulin G from rabbits immunized with CRPV VLPs protected against CRPV challenge. We conclude that native VLPs can induce antibody-mediated, type-specific protection against experimental papillomavirus infection.
Infection of mucosal epithelium by papillomaviruses is responsible for the induction of genital and oral warts and plays a critical role in the development of human cervical and oropharyngeal cancer. We have employed a canine model to develop a systemic vaccine that completely protects against experimentally induced oral mucosal papillomas. The major capsid protein, L1, of canine oral papillomavirus (COPV) was expressed in Sf9 insect cells in native conformation. L1 protein, which self-assembled into virus-like particles, was purified on CsCl gradients and injected intradermally into the foot pad of beagles. Vaccinated animals developed circulating antibodies against COPV and became completely resistant to experimental challenge with COPV. Successful immunization was strictly dependent upon native L1 protein conformation and L1 type. Partial protection was achieved with as little as 0.125 ng of L1 protein, and adjuvants appeared useful for prolonging the host immune response. Serum immunoglobulins passively transferred from COPV L1-immunized beagles to naive beagles conferred protection from experimental infection with COPV. Our results indicate the feasibility of developing a human vaccine to prevent mucosal papillomas, which can progress to malignancy.
To assess the potential for cross-protection among genital human papillomavirus (HPV) types in virus-like particle (VLP)-based vaccinations, inhibition of HPV VLP-mediated hemagglutination by rabbit antisera raised against HPV type 6b (HPV-6b), HPV-11, HPV-16, HPV-18, HPV-31, HPV-33, and HPV-45 was analyzed. Only highly homologous types (HPV-6b and HPV-11, and HPV-18 and HPV-45) exhibited detectable serological cross-reaction for the class of antibodies that inhibit virion-to-cell surface binding. However, analysis of neutralizing monoclonal antibodies to several animal and human papillomaviruses indicated that over half of these antibodies do not prevent cell surface binding, but these latter antibodies do not appear to be more cross-reactive in enzyme-linked immunosorbent assays than those that mediate inhibition of hemagglutination. The data strongly suggest that while there may be limited cross-protection between highly (>85% L1 amino acid identity) homologous types, protection by HPV VLP-based vaccines will be predominantly type specific.
We report a system for generating infectious papillomaviruses in vitro that facilitates the analysis of papillomavirus assembly, infectivity, and serologic relatedness. Cultured hamster BPHE-1 cells harboring autonomously replicating bovine papillomavirus type 1 (BPV1) genomes were infected with recombinant Semliki Forest viruses that express the structural proteins of BPV1. When plated on C127 cells, extracts from cells expressing L1 and L2 together induced numerous transformed foci that could be specifically prevented by BPV neutralizing antibodies, demonstrating that BPV infection was responsible for the focal transformation. Extracts from BPHE-1 cells expressing L1 or L2 separately were not infectious. Although Semliki Forest virus-expressed L1 self-assembled into virus-like particles (VLPs), viral DNA was detected in particles only when L2 was coexpressed with L1, indicating that genome encapsidation requires L2. Expression of human papillomavirus type 16 (HPV16) L1 and L2 together in BPHE-1 cells also yielded infectious virus. These pseudotyped virions were neutralized by antiserum to HPV16 VLPs derived from European (114/K) or African (Z-1194) HPV16 variants but not by antisera to BPV VLPs, to a poorly assembling mutant HPV16 L1 protein, or to VLPs of closely related genital HPV types. Extracts from BPHE-1 cells coexpressing BPV L1 and HPV16 L2 or HPV16 L1 and BPV L2 were not infectious. We conclude that (i) mouse C127 cells express the cell surface receptor for HPV16 and are able to uncoat HPV16 capsids; (ii) if a papillomavirus DNA packaging signal exists, then it is conserved between the BPV and HPV16 genomes; (iii) functional L1-L2 interaction exhibits type specificity; and (iv) protection by HPV virus-like particle vaccines is likely to be type specific.
The human papillomavirus type 16 (HPV-16) L1 capsid protein is the major component of the HPV virion. We prepared L1 protein of HPV-16 in a cell-free system. The L1 gene was cloned in an expression plasmid and transcribed and translated in vitro in a rabbit reticulocyte lysate. The expressed protein had the molecular mass (55 kDa) expected for the L1 protein, and it assembled into virus-like particles that closely resembled papillomavirus virions. The protein retained conformational epitopes, as evidenced by its reactivity with monoclonal antibodies which recognize only intact viral particles. In radioimmunoprecipitation assays with sera from college women grouped by their genital tract HPV DNA status, high reactivity was found in 68% of HPV-16 DNA-positive women, in 23% of women with other HPVs, and in 19% of HPV-negative women. In comparison, none of the sera of children were reactive. The results of the radioimmunoprecipitation assays showed a significant correlation with results obtained with the same sera in an enzyme-linked immunosorbent assay with virus-like particles produced in baculovirus (chi-square test for linear trend, P = 0.0023). Although the amounts of L1 protein obtained are small, the ability to produce virus-like particles by in vitro translation may be useful in the study of virus assembly, virus binding, and the immunological response to HPV infection.
A highly stereocontrolled enantiospecific synthesis of d-daunosamine in six steps through a diastereoselecrive C-C bond formation and a stereocontrolled cis-dihydroxylation reaction employing chiral 1,3-oxathiolan-5-one as a chiral acetate equivalent is described.
A general route for the stereoselective synthesis of 3-amino-4,5-dihydroxyaldehydes, with almost any desired configuration at the three stereogenic centers, is described by applying a combination of enzymatic and chemical steps. l-Daunosamine 1, for example, the glycosidic fragment of many important anthracycline antibiotics has been prepared by this route starting from O-allyl-l-lactaldehyde (S)-6a. (R)-Hydroxynitrile lyase (HNL) catalyzed addition of HCN to (S)-6a yields the 2,3-dihydroxynitrile (2S,3S)-7a with high stereoselectivity (91% de) in 75% yield. The addition of allyl Grignard to the O-protected 2,3-dihydroxynitrile (2S,3S)-9a and subsequent hydrogenation of the imino intermediate leads to 4-amino-2,3-dihydroxy-1-heptene (4S,5S,6S)-12a, which after ozonization and deprotection gives N-acetylated l-daunosamine 14a in a total yield of 15% referring to (S)-6a. The general applicability of this chemoenzymatic multistep procedure is demonstrated in the stereoselective synthesis of the unnatural aminodeoxy sugar (2S,3S,4S)-14b, starting from isovaleraldehyde 3.
-Daunosamine has been synthesised from -Glucurono-6,3-lactone in which carbon atoms C- of the lactone are transformed into C- of aminosugar by a new approach.
The title compounds were prepared from tartraldehyde dithioacetals and using Wittig chain elongation, amino functionalization of the double bond and removal of the protective groups.
A new and efficient enantioselective synthesis of Boc-α-amino acids has been developed. Starting from an enantiomerically enriched epoxy alcohol the sequence involves a regioselective nucleophilic epoxide opening by diphenylmethylamine (benzhydrilamine), hydrogenolysis/protection of the amino group, and oxidation of the diol moiety.
A versatile, non-alkylative enantioselective synthesis of unsaturated α-amino acids based on the Sharpless asymmetric epoxidation has been developed. Enantiomerically enriched trans epoxy alcohols bearing unsaturated substituents were prepared and submitted to regio- and stereospecific ring-opening with p-methoxybenzylamine as a nucleophile, leading to anti-3-(p-methoxybenzylamino)-1,2-diols which were further protected by reaction with Boc2O. The 1,2-diol fragment was then oxidatively cleaved by a sequential treatment with sodium periodate and sodium chlorite to afford the corresponding amino acid. Using this methodology, doubly N-protected (p-methoxybenzyl and Boc) allyl glycine, 3-butenyl glycine and 4-pentenyl glycine have been prepared in three synthetic steps from the corresponding allyl alcohols. As a demonstration of the orthogonal nature of the nitrogen protection, both protecting groups have been selectively removed from the fully protected amino ester.
New enantioselective syntheses of N-protected baikiain and pipecolic acid have been developed. The starting material is 2,3-epoxy-5-hexen-1-ol (4) readily available in high ee by Sharpless epoxidation. The regio- and stereoselective epoxide ring-opening by allylamine afforded a doubly unsaturated amine that was converted into a carbamate (Boc) and submitted to ring-closing metathesis. The resulting cyclic amino diol 6 is a key intermediate that was converted into N-Boc-baikiain and several pipecolic acid derivatives.
Conjugate addition-rearrangement of N-benzylhydroxylamine to lactones 11 and12 provided respective isoxazolidin-5-ones 13 and 14 which were in turn mesylated at the hydroxy group and subjected to the next skeleton rearrangement to afford N,3,4,5-tetrasubstituted isoxazolidines 18 and 19 in such a way that inversion of configuration at C-5 of the sugar chains occured. Standard transformation of isoxazolidines 18 and 19 provided methyl glycoside of N,O-diacetate of acosamine 33 and daunosamine 34, respectively.
In a convenient simple sequence, treatment of azides with tri-n-butylphosphine, followed by addition of di-t-butyl dicarbonate, yields N-(t-Butoxycarbonyl)amines in moderate to good overall yields.
Highly enantioenriched cis and transN-Boc-2,2-dimethyl-oxazolidine-5-carbaldehydes have been efficiently prepared from N-Boc-3-amino-1,2-alkanediols, readily available in enantiopure or enantioenriched form by Sharpless epoxidation methodology. These compounds have been converted into N-Boc-(S)-γ-[(S)-1-aminoalkyl]-γ-lactones which are key intermediates of hydroxyethylene dipeptide isosteres.
N,O-Dibenzyl-N-tert-butoxycarbonyl-l-homoserinal (7), obtained from l-aspartic acid, reacts with vinylmagnesium chloride to afford with high stereoselectivity compound 6 which is subsequently transformed into the derivative of l-daunosamine 15.
An asymmetric aldol strategy has been developed for the synthesis of l-daunosamine and d-ristosamine derivatives starting from noncarbohydrate precursors. Lithium and boron enolate mediated aldol reactions of 12 with O-TBS lactaldehyde gave non-Evans syn and Evans syn aldol products, respectively, with high selectivity. The chemical efficiency of the lithium enolate reactions were higher than the corresponding reactions with the boron enolates. Curtius rearrangement of lactone acids 23 and 26 gave the corresponding N-BOC amino lactones 30 and 32 in 64% and 62%, respectively, with complete retention of configuration. Lactone 30 was converted by a two-step sequence to N-benzoyldaunosamide 40. The overall yield for the amino sugar 40 was 18% over six steps. Similarly, lactone 32 was converted to N-benzoylristosamide 42 with an overall yield of 18% starting from 12.
Methyl l-N,O-diacetyldaunosaminide was prepared from 3-nitro-4,5-dihydroisoxazole in 8.5% overall yield. A key step in the synthesis involved the AD reaction of (E)-3-(1-propenyl)-4,5-dihydroisoxazole (2b), affording the corresponding diol in 76% yield (92% ee). A second key step involved reductive cleavage of the dihydroisoxazole 4a and subsequent N-acetylation to afford separable diastereomeric γ-(acetylamino)alcohols 7a and 8a in 62% yield (72:28, 7a/8a). Swern oxidation of 7a and subsequent methanolysis followed by acetylation provided methyl l-N,O-diacetyldaunosaminide as an anomeric mixture. The AD reactions of chiral alkenyl dihydroisoxazole 16 with (DHQ)2−PHAL and (DHQD)2−PHAL afforded diastereomeric diol products, isolated as the acetates 18 and 19 (98:2 and 5:95 ratios, respectively, depending on the chiral auxiliary).
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Dimethyl sulfoxide "activated" by oxalyl chloride at low temperatures in methylene chloride reacts rapidly with alcohols to give alkoxysulfonium salts, convertible to carbonyls in high to quantitative yields upon addition of triethylamine. Oxalyl chloride is the most efficient and generally useful Me2SO "activator" thus far reported. The mild, high yield oxidation of long-chain saturated, unsaturated, acetylenic, and steroidal alcohols to carbonyls utilizing Me2SO "activated" by oxalyl chloride is described.
Highly diastereoselective syntheses of L-N-acetylacosamine (1b) and L-N-benzoylristosamine (2b), two isomeric L-3-amino-2,3,6-trideoxyhexoses, were achieved by utilizing the intramolecular conjugate addition of carbamate group in the Z-α,β-unsaturated esters 4a and 4b, respectively. 4a and 4b were prepared from the common intermediate, 4,5-dihydroxy-2-hexynoate derivative 7a, readily available by the non-chelation-controlled addition of methyl propiolate to O-(tert-butyldimethylsilyl)lactaldehyde 3.
1,2,2,2-Tetrachloroethyl chloroformate reacts with substituted phenols or N-hydroxy imides to yield crystalline and stable mixed aryl or oximido tetrachloroethyl carbonates. When allowed to react with an N-protected amino acid derivative, these compounds proved to be efficient for the syntheses of the corresponding active esters. A series of active esters including p-nitrophenol, trichlorophenol, pentafluorophenol, and N-hydroxysuccinimide derivatives were prepared by this new procedure.
Syntheses of 1,1-dimethylethyl (S)-4-formyl-2,2-dimethyl-3-oxazolidinecarboxylate (5) and 1,1-dimethylethyl (4S-trans)-4-formyl-2,2,5-trimethyl-3-oxazolidinecarboxylate (6) from commercially available serine and threonine derivatives are described. The method involves selective reduction of the corresponding oxazolidine esters 3 and 4 using diisobutylaluminum hydride at low temperature. These differentially protected β-hydroxy-α-amino aldehydes are also shown to be produced in 93-95% enantiomeric excess (via NMR and HPLC analysis of the Mosher ester derivatives 8 and epi-8) - thus making them useful as chiral, nonracemic synthons for asymmetric synthesis.
Completely stereocontrolled synthesis of N-benzoyl-L-daunosamine (1a) is described. The synthesis starts with 4-O-benzyl-2,3-O-bis(methoxymethyl)-L-threose (12), readily accessible from L-tartaric acid, and proceeds via the xylo alcohol 14 which is formed by an extremely high degree of chelation controlled addition of the acetal-containing Grignard reagent to 12. The Mitsunobu reaction of 14 gives the phthalimide 15 which undergoes debenzylation followed by tosylation, iodination, and deiodination. The resulting 6-deoxyphthalimide 19 is converted to the N-benzoyl derivative 20. Deprotection of 20 by treatment with BF3·Et2O-EtSH followed by HgCl2-HgO provides N-benzoyl-L-daunosamine (1a).
Treatment of 2,3-epoxy alcohols with [Ti(O-i-Pr)2(N3)2] affords the corresponding 3-azido 1,2-diols, which are readily transformed in two steps to the α-amino acids.
The presence of Ti(O-i-Pr)4 during the openings of 2,3-epoxy alcohol 1 with a variety of nucleophiles markedly increases the rates and regioselectivities of these processes. The magnitude of these effects was found to be nucleophile dependent.
The thermolysis of monomethylsilane (MMS) has been studied as a function of pressure (33-400 Torr), temperature (340-440°C), and conversion. Under conditions of very low (typically, 0.5%) conversion and in a carefully seasoned vessel the major products are H2 and dimethyldisilane (DMDS). Dimethylsilane (DMS) comprises ∼5% of the major products. MMS-d3 generates D2 exclusively. In the presence of ∼10% C2H4 the yields of H2 and DMDS are considerably reduced and both products follow first-order kinetics in their formation. Also, the formation of DMS is completely suppressed, and the Arrhenius parameters for the molecular process CH3SiH3 → CH3S̈iH + H2 (1a) when determined from the rate of H2 production and from (CH3S̈iH + CH3SiH3 → DMDS) production are log k1a = (15.02 ± 0.10) - (63270 ± 310)/2.3RT and (14.87 ± 0.12) - (63150 ± 350)/2.3RT, respectively. The "molecular" rate constant for H2, however, includes a small contribution from radical processes that cannot be completely suppressed. When the latter expression for k1a is used, the rate data for H2 in the unscavenged reaction can be fitted to a mechanism incorporating a second primary step, a slow, surface-catalyzed reaction generating H• and CH3SiH2• radicals, which then set up a short chain: CH3SiH2• + CH3SiH3 → DMDS + H H + CH3SiH3 → H2 + CH3SiH2• On the basis of kinetic analysis of the data it is concluded that the chain is terminated linearly by CH3SiH2• radicals at the surface, with log A (s-1) = 11.7 and Ea ≈ 32.3 kcal mol-1. The derived rate expression for the surface-catalyzed radical initiation step CH3SiH3 → CH3SiH2• + H (1b) is log k1b = 12.7 - 57900/2.3RT. From the measured kinetic data the following thermochemical values were derived: D(CH3ṠiH-H) = 73.5 kcal mol-1 and ΔHf(CH3S̈iH) = 51.9 kcal mol-1.
The use of 3A or 4A molecular sieves (zeolites) substantially increases the scope of the titanium(IV)-catalyzed asymmetric epoxidation of primary allylic alcohols. Whereas without molecular sieves epoxidations employing only 5 to 10 mol % Ti(O-i-Pr)â generally lead to low conversion or low enantioselectivity, in the presence of molecular sieves such reactions generally lead to high conversion (>95%) and high enantioselectivity (90-95% ee). The epoxidations of 20 primary allylic alcohols are described. Especially noteworthy are the epoxidations of cinnamyl alcohol, 2-tetradecyl-2-propen-1-ol, allyl alcohol, and crotyl alcohol - compounds which heretofore had been considered difficult substrates for asymmetric epoxidation. In the case of allyl alcohol, the use of cumene hydroperoxide substantially increases both the reaction rate and the conversion, even in the absence of molecular sieves. In general, enantioselectivities are slightly depressed (by 1-5% ee) relative employing 50-100 mol % Ti(O-i-Pr)â. The epoxidation of low molecular weight allylic alcohols is especially facilitated and, in conjunction with in situ derivatization, provides for the synthesis of many epoxy alcohol synthons which were previously difficult to obtain. The kinetic resolution of four secondary allylic alcohols with 10 mol % Ti(O-i-Pr)â is also described. The role of molecular sieves in the reaction and the effects of variation in reaction stoichiometry, oxidant, and tartrate are discussed.
trans-4-Hexenal-((2R, 3R)-weinsäure-dimethylester-acetal) (6) liefert nach allylischer Aminierung mit metallischem Selen und Chloramin-T die gut trennbaren 3-Tosylamino-Derivate mit D- (7) und L-glycero-Konfiguration (8) an C-3. 7 wird mit Osmiumtetroxid hoch selektiv zum 4,5-Dihydroxy-3-tosylamino-D-xylo-hexanal-acetal 9 hydroxyliert, aus dem durch Abspaltung der Carbonylschutzgruppe mit HCl in Methanol das Methyl-2,3,6-tridesoxy-3-tosylaminohexosid 11 entsteht. Dessen Detosylierung mit Natrium in flüssigem Ammoniak führt nach Peracetylierung zum D-konfigurierten Methyl-4-O-acetyl-3-acetylamino-2,3,6-tridesoxyhexosid 13, dessen Konstitution durch Massenspektrometrie und dessen α-xylo-Konfiguration durch 1H-NMR-Untersuchungen bewiesen wird.
Syntheses of Biologically Important Carbohydrates, 21 Asymmetrically Induced Synthesis of Amino Sugars: Methyl 4-O-Acetyl-3-acetylamino-2,3,6-trideoxy-α-D-xylo-hexopyranoside
trans-4-Hexenal-((2R, 3R)tartaric acid dimethyl ester acetal) (6) is aminated in allylic position with metallic selenium and chloramine-T yielding the easily separable 3-tosylamino derivatives with D-(7) and L-glycero-configuration (8) at C-3. 7 is hydroxylated with osmium tetroxide giving the 4,5-dihydroxy-3-tosylamino-D-xylo-hexanal acetal 9 with high selectivity. By splitting off the carbonyl protecting group from 9 with HCl in methanol methyl 2,3,6-trideoxy-3-tosylamino-hexoside 11 is obtained. Detosylation of 11 with sodium in liquid ammonia and peracetylation gives methyl 4-O-acetyl-3-acetylamino-2,3,6-trideoxyhexoside 13 with D-configuration. The constitution of 11 and 13 is proved by mass spectrometry and the α-xylo-configuration is determined by means of the 1H-NMR spectra.
5-Substituted 4-alkoxycarbonyloxazoles 13a-c have been easily prepared by direct C-acylation of isocyanoacetic esters with O-protected α-hydroxycarboxylic acids 12a-c by use of diphenyl phosphorazidate (DPPA). Acid treatment of the oxazole derivatives 13a-c affords 5-substituted 3-aminotetronic acids 14a-c, which are stereoselectively hydrogenated to give 5-substituted 2-amino-3-hydroxy-1,4-lactones 15a,16b, and so on. From the L-lyxo-1,4-lactone 15a, three 3-amino-2,3,6-trideoxyhexoses, L-daunosamine (7), L-vancosamine (8), and D-ristosamine (9) have been conveniently prepared by use of the Wittig homologation. Similar treatment of the D-ribo-1,4-lactone 16b has produced a hydroxy amino acid moiety A of Al-77-B (11) as its protected form 10.
Computational chemistry made possible the prediction of the three-dimensional structures of γ-lactam analogues of penems and carbapenems before the analogues were made. Molecular superpositioning showed that these novel structures with a 7β-acylamino side-chain present the pharmacophoric groups in close spatial similarity to the groups in biologically active cephalosporin and penicillin antibiotics. This suggests that 8-oxo-7-acylamino-1-azabicyclo[3.3.0]-oct-2-ene-2-carboxylates and the 4-thia-analogues can be accommodated in the same active sites of essential bacterial penicillin-binding proteins where cephalosporins and penicillins are recognized. The syntheses of these compounds are reported. The γ-lactams exhibit low, but detectable levels of antibacterial activity and suggest promise that substantial activity can be achieved with other γ-lactams.
The "naked sugars" are optically pure synthetic intermediates. Their advantage compared with natural sugars is that they possess a number of unsubstituted carbon atoms that can be substituted stereospecifically through direct procedures. (1S,2R,4S)-2-[(-)-Camphanoyloxy]-7-oxabicyclo[2.2.1]hept-5-ene-2-carbonitrile ((+)-1) is an example of a "naked sugar". Electrophilic reagents add to the C(5),C(6) double bond, giving the corresponding adducts where the electrophile substitutes the exo position of C(6) and the nucleophile the endo position at C(5). This principle was used to prepare (1R,4R,5R)-5-endo-chloro-7-oxa-2-bicyclo[2.2.1]heptanone (13), which was monomethylated stereoselectively in the exo position at C(3), giving (+)-(1R,3S,4R,5R)-5-endo-chloro-3-exomethyl-7-oxa-2-bicyclo[2.2.1]heptanone (14). The latter was transformed stereospecifically into L-daunosamine (3-amino-2,3,6-trideoxy-L-lyxo-hexose). The (-)-camphanic acid used to engender asymmetry was recovered at an early stage of the synthesis.
The synthesis of 4'-epi-daunorubicin and of 4'-epi-adriamycin was performed by condensation of 2,3,6-trideoxy-3-trifluoroacetamido-4-O-trifluoroacetyl-alpha-L-arabino-hexopyranosyl chloride with daunomycinone or the protected adriamycinone derivative 17, respectively. Both the alpha and beta anomers were obtained and characterized. All new compounds are biologically active in cultured cells and the alpha anomers display noticeable activity in experimental tumors in mice. Interestingly, 4'-epi-adriamycin (4) appears nontoxic to cultured heart cells up to a concentration of 5 mug/ml.
Monoclonal (MAbs) and polyclonal antibodies were produced against the major capsid protein of detergent-disrupted, purified
bovine papillomavirus type 1 (BPV-1). The precise locations of the corresponding epitopes were identified by the reactivity
of MAbs and selected polyclonal antibodies with synthetic, overlapping, hexameric peptides corresponding with 95% of the BPV-1
major capsid protein. The topography of these epitopes was determined by reactivity of antibodies with intact (conformational
and nonconformational surface epitopes) and disrupted (external or internal nonconformational epitopes) BPV-1 virions. The
distribution of epitopes in various papillomaviruses of 13 different species was determined by reactivity ofthe MAbs and polyclonal
sera with productively infected, formalin-fixed papillomas, fibropapillomas, and fibromas. Epitope scanning, using MAbs and
polyclonal antisera, resulted in the precise location of BPV-1 hexameric epitopes that could becorrelated with their topography
on the capsid and distribution in papillomatous lesions of various species.
Sera from cattle that had been inoculated with BPV-1 virions or with recombinant L1 proteins and serum from a rabbit that had been immunized with SDS-denatured virions were evaluated for their reactivity with 466 overlapping synthetic peptides corresponding to 95% of the BPV-1 L1 protein. The late serological response of cattle to both intact virions and recombinant L1 proteins exhibited a similar profile of reactivity with approximately 70% (7 of 10) of L1 antigenic sites. However, the L1 serological response of the rabbit to SDS-denatured virions exhibited a significant difference from bovine serum antibodies in the profile of epitopes recognized, including a relative lack of response to major bovine epitopes located between L1 amino acids (AAs) 300-400. Importantly, only the sera from animals inoculated/immunized with intact virions was capable of neutralizing BPV-1 infectivity of murine C127 cells, suggesting that nonlinear epitopes are important for papillomavirus neutralization.
A highly stereoselective synthesis of 2(R)-[5(R)-[1(S)-[(tert-butyloxycarbonyl)amino]-3-methylbutyl]-2,2- dimethyl-4(R)-dioxolanyl]-3-methylbutanoic acid is described. This is a suitably protected carboxylic acid useful as an intermediate for the preparation of renin inhibitory peptides. Angiotensinogen analogues such as peptides IX and X that contain the dipeptide isostere (2R,3R,4R,5S)-5-amino-3,4-dihydroxy-2-isopropyl-7-methyloctanoic acid residue at the scissile site are shown to be potent inhibitors of human plasma renin. The glycol moiety in this novel acid, dihydroxyethylene isostere, is suggested to act as a transition-state analogue and mimics the tetrahedral intermediate formed during the enzyme-catalyzed hydrolysis of the peptidic bond.
The alpha- and beta-D-lyxofuranosyl analogues of the naturally occurring nucleosides have been synthesized and their antiviral properties examined. The alpha anomers were prepared by glycosylation of purine and pyrimidine aglycons with tetra-O-acetyl-alpha-D-lyxofuranose, followed by removal of the blocking groups. The beta anomers were obtained by sequential oxidation and reduction of 3',5'-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-beta-D-x ylofuranosyl nucleosides. The lyxofuranosyl nucleosides were tested for their activity against a variety of RNA and DNA viruses and for inhibition of cell growth. One compound, 9-alpha-D-lyxofuranosyladenine, showed activity against herpes simplex virus types 1 and 2 both in vitro and in vivo.
The following 14-O-acyl derivatives of adriamycin were synthesized: acetate, propionate, octanoate, benzoate, phenylacetate, and nicotinate. The compounds were evaluated for cytotozic, antiviral, and antitumor activities.
Here, we describe assembly PCR as a method for the synthesis of long DNA sequences from large numbers of oligodeoxyribonucleotides (oligos). The method, which is derived from DNA shuffling [Stemmer, Nature 370 (1994a) 389-391], does not rely on DNA ligase but instead relies on DNA polymerase to build increasingly longer DNA fragments during the assembly process. A 1.1-kb fragment containing the TEM-1 beta-lactamase-encoding gene (bla) was assembled in a single reaction from a total of 56 oligos, each 40 nucleotides (nt) in length. The synthetic gene was PCR amplified and cloned in a vector containing the tetracycline-resistance gene (TcR) as the sole selectable marker. Without relying on ampicillin (Ap) selection, 76% of the TcR colonies were ApR, making this approach a general method for the rapid and cost-effective synthesis of any gene. We tested the range of assembly PCR by synthesizing, in a single reaction vessel containing 134 oligos, a high-molecular-mass multimeric form of a 2.7-kb plasmid containing the bla gene, the alpha-fragment of the lacZ gene and the pUC origin of replication. Digestion with a unique restriction enzyme, followed by ligation and transformation in Escherichia coli, yielded the correct plasmid. Assembly PCR is well suited for several in vitro mutagenesis strategies.
Epidemiologic studies have shown that the association of genital human papillomavirus (HPV) with cervical cancer is strong, independent of other risk factors, and consistent in several countries. There are more than 20 different cancer-associated HPV types, but little is known about their geographic variation.
Our aim was to determine whether the association between HPV infection and cervical cancer is consistent worldwide and to investigate geographic variation in the distribution of HPV types.
More than 1000 specimens from sequential patients with invasive cervical cancer were collected and stored frozen at 32 hospitals in 22 countries. Slides from all patients were submitted for central histologic review to confirm the diagnosis and to assess histologic characteristics. We used polymerase chain reaction-based assays capable of detecting more than 25 different HPV types. A generalized linear Poisson model was fitted to the data on viral type and geographic region to assess geographic heterogeneity.
HPV DNA was detected in 93% of the tumors, with no significant variation in HPV positivity among countries. HPV 16 was present in 50% of the specimens, HPV 18 in 14%, HPV 45 in 8%, and HPV 31 in 5%. HPV 16 was the predominant type in all countries except Indonesia, where HPV 18 was more common. There was significant geographic variation in the prevalence of some less common virus types. A clustering of HPV 45 was apparent in western Africa, while HPV 39 and HPV 59 were almost entirely confined to Central and South America. In squamous cell tumors, HPV 16 predominated (51% of such specimens), but HPV 18 predominated in adenocarcinomas (56% of such tumors) and adenosquamous tumors (39% of such tumors).
Our results confirm the role of genital HPVs, which are transmitted sexually, as the central etiologic factor in cervical cancer worldwide. They also suggest that most genital HPVs are associated with cancer, at least occasionally.
The demonstration that more than 20 different genital HPV types are associated with cervical cancer has important implications for cervical cancer-prevention strategies that include the development of vaccines targeted to genital HPVs.
The L1 major capsid protein-coding sequences of human papillomavirus (HPV) types 11, 16 and 18 were expressed in the baculovirus system. Virus-like particles (VLPs) were purified from recombinant-infected Spodoptera frugiperda Sf9 cells and cell-free culture supernatants. Rabbits immunized with purified VLPs developed antibodies that reacted only with the specific VLP type used as the immunogen. In addition, rabbit antibodies raised against infectious HPV-11 virions only reacted with HPV-11 L1 VLPs and not with VLPs derived from either HPV-16 or HPV-18. These results suggest that HPV-11, HPV-16 and HPV-18 virions are antigenically distinct from one another. This observation should be considered in future studies of immune responses to HPV.
Characterization of virus binding by neutralizing antibodies is important both in understanding early events in viral infectivity and in development of vaccines. Neutralizing monoclonal antibodies (MAbs) to human papillomavirus type 11 (HPV11) have been described, but mapping the binding site has been difficult because of the conformational nature of key type-specific neutralization epitopes on the L1 coat protein. We have determined those residues of the L1 protein of HPV11 which confer type specificity to the binding of HPV11-neutralizing MAbs. Binding of three HPV11-specific neutralizing MAbs could be redirected to HPV6 L1 virus-like particles in which as few as two substitutions of corresponding amino acid residues from HPV11 L1 have been made, thus demonstrating the importance of these residues to MAb binding through the transfer of a conformationally dependent epitope. In addition, a fourth neutralizing MAb could be distinguished from the other neutralizing MAbs in terms of the amino acid residues which affect binding, suggesting the possibility that it neutralizes HPV11 through a different mechanism.
A panel of 24 monoclonal antibodies (MAbs) was generated against human papillomavirus (HPV) types 16 and 18 L1 virus-like particles (VLPs). The MAbs were screened for reactivity to a variety of VLPs prepared from HPV-6, -11, -16, -18, -31, -33, -35, and -45, cottontail rabbit papillomavirus, bovine papillomavirus type 1, and a set of 35 overlapping 20-amino-acid peptides spanning the entire HPV-16 L1 gene. Type-specific linear and conformational surface epitopes were detected as well as several cross-reactive linear epitopes that showed various levels of cross-reactivity between different genital HPV and animal papillomavirus L1s. Most of the linear epitopes were mapped using synthetic peptides, and the epitopes were identified as being either surface or buried within the VLP as defined by the pattern of reactivity in ELISA using intact and disrupted VLP antigen. These MAbs may be useful reagents to help define neutralizing epitopes of HPV-16 and -18 when infectivity assays become available, and to define the regions of L1 that are exposed on the surface or buried within the assembled capsid.
A set of 13 monoclonal antibodies (MAbs) was generated against HPV-6 L1 virus-like particles (VLPs), screened for reactivity to HPV-6 and HPV-11 L1 VLPs by ELISA, and tested for neutralization of HPV-11 infection. Both cross-reactive and type-specific epitopes were detected such that 4 of 13 MAbs reacted to surface conformational sites on HPV-6 L1 VLPs and the remaining 9 MAbs were cross-reactive to both HPV-6 and HPV-11 L1 VLPs. four of the 9 cross-reactive MAbs were able to neutralize HPV-11 infectivity, and 3 of 4 of these neutralizing MAbs (N-MAbs) identified shared surface conformational sites. One N-MAb therefore recognized a surface linear epitope as judged by positive binding to L1 in a Western blot assay. The neutralization status of these cross-reactive MAbs with regard to HPV-6 could not be assayed. These results demonstrated that the closely related HPV types 6 and 11 contain both type-specific and shared neutralizing epitopes.
Since human papillomaviruses (HPV) cannot be propagated in cell culture, the generation of infectious virions in vitro is a highly desirable goal. Here we report that pseudovirions can be generated by the assembly of virus-like particles (VLPs) in COS-7 cells containing multiple copies of a marker plasmid. Using recombinant vaccinia viruses, we have obtained spherical VLPs of HPV type 33 (HPV-33) which fractionate into heavy and light VLPs in cesium chloride density gradients. VLPs in the heavy fraction (1.31 g/cm3) carry the plasmid in DNase-resistant form and are capable of transferring the genetic marker located on the plasmid to COS-7 cells in a DNase-resistant way (pseudoinfection). The minor capsid protein L2 is not required for encapsidation but is essential for efficient pseudoinfection. Antiserum to HPV-33 VLPs inhibits VLP-mediated DNA transfer with high efficiency. Antisera to VLPs of HPV-18 and HPV-16 are not neutralizing, although the HPV-16 antiserum exhibited some cross-reactivity with HPV-33 VLPs in an enzyme-linked immunosorbent assay. In a cell binding assay, the titer of the HPV-33 VLP antiserum was 1:200 compared to the neutralization titer of 1:10(5). This indicates that neutralization is essentially due to the inhibition of cellular processes after VLP binding to cells. The encapsidation of marker plasmids into VLPs provides a sensitive and fast assay for the evaluation of neutralizing potentials of antisera against papillomavirus infections.