On the enhancement of stereoselection by cooperation between chiral auxiliaries. Asymmetric diels-alder reactions with fumaric acid bis ((S)-proline benzyl ester) amide

Abstract Fumaric acid bis ((S)-proline benzyl ester) amide reacts with cyclopentadiene in thermal and Lewis acid catalyzed Diels-Alder reactions to give the cycloadducts with high yields and diastereomeric ratios up to 100:1.

Der Phenylacetyl-(PhAc-)Rest als enzymatisch ablösbare Schutzgruppe für Peptide und Kohlenhydrate: Selektive Schutzgruppenabspaltungen mit Penicillin-Acylase

N-Phenylacetyl-(PhAc-)-aminosauren werden mit Aminosauremethyl-, -benzyl-, -allyl- und -tert-butylestern mit Hilfe des modifizierten Carbodiimidverfahrens oder unter Verwendung von EEDQ in guten Ausbeuten zu vollgeschutzten Dipeptiden verknupft. Der PhAc-Rest ist bei den Abspaltungen der C-terminalen Schutzgruppen stabil, kann jedoch aus den Peptiden unter nahezu neutralen Bedingungen selektiv mit Penicillin-Acylase (EC 3.5.1.11) abgelost werden. Das Enzym hydrolysiert den PhAc-Rest auch aus der 2-Position von acetylgeschutzter Glucose, der 3-Position von Di-O-isopropylidenglucose und der primaren OH-Gruppe von Di-O-isopropyliden-L-sorbose. Bei den enzymatischen Abspaltungsreaktionen bleibe…

Protecting Groups

There is hardly any area of preparative organic chemistry in which the proper use of protecting groups is not a prerequisite for the successful achievement of the goals aimed at. For this reason such blocking functions have been developed for nearly 100 years by numerous researchers from all disciplines of organic chemistry, and consequently solutions to the existing problems have been devised, making use of various synthetic transformations. It was Fischer who, among his many important contributions to chemistry, first realized that the application of protecting functions is often a necessity for a successful synthesis. Thus, he introduced the isopropylidene ketal in carbohydrate chemistry…

Naturstoffsynthese am polymeren Träger – Synthese und biologische Evaluierung einer Indolactam-Bibliothek

Als wirksame Aktivatoren der Proteinkinease C in Mausefibroblasten erwiesen sich einige Indolactam-V-Analoga 1, wie mit einem neuen biologischen Assay nachgewiesen wurde. Die Derivate dieses tumorpromovierenden Indolalkaloids wie auch der Naturstoff selbst wurden effizient durch eine kombinatorische Festphasensynthese hergestellt, deren Schlusselschritte eine regioselektive Aminierung des Indolrings und eine enantiodifferenzierende enzymatische Umsetzung sind.

Cycloaddition Reactions in Organic Synthesis. VonW. Carruthers. Pergamon Press, Oxford 1990. VIII, 373 S., Paperback $ 30.00. - ISBN 0-08-034712-6

ChemInform Abstract: SYNTHESIS OF THE GLYCOPEPTIDE PARTIAL SEQUENCE A80-A84 OF HUMAN FIBROBLAST INTERFERON

The glycopentapeptide H-(GlcNAcβ1-)Asn-Glu-Thr-Ile-Val-OH (10) representing the partial sequence A80–A84 of human fibroblast interferon was synthesized using the newly developed allyl-ester protection of carboxy functions. The allyl esters, which are stable to acids and to bases, can be cleaved under very mild, neutral conditions using tris(triphenylphosphine)rhodium(I) chloride or tetrakis(triphenylphosphine)palladium(0) as a catalyst. This synthetic method opens up a preparative route to glycopeptide model structures of glycoproteins of high biological interest.

Book Review: Cycloaddition Reactions in Organic Synthesis. By W. Carruthers

Prolin-benzylester als chirale Hilfsgruppen in asymmetrischen 1,3-dipolaren Cycloadditionen mit Nitriloxiden

Proline Benzyl Esters as Chiral Auxiliaries in Asymmetric 1,3-Dipolar Cycloadditions N-Acryloylproline benzyl ester (1b) reacts with nitrile oxides at temperatures from −78 to 0°C to give isoxazolines 4/5 with diastereomeric ratios of ca. 3:1 and with the (5S) isomer as the predominating. The corresponding N-methacryloylproline benzyl ester (1c) gives inferior results. The diastereoselectivity is not influenced by the temperature and the substituents of the nitrile oxides. To prove the absolute configuration of the predominating stereoisomer, a reaction sequence is developed which makes use of an enantioselective hydrolysis with pig liver esterase as the key step to generate an optically ac…

Aminosäureester als chirale Hilfsgruppen in Lewis-Säure-katalysierten Diels-Alder-Reaktionen

Amino Acid Esters as Chiral Auxiliaries in Lewis Acid Catalyzed Diels-Alder Reactions Cyclopentadiene, cyclohexadiene and alkyl-substituted butadienes react with N-acryloyl-, N-crotonoyl- and N-(4-nitro-cinnamoyl)-(S)-proline benzyl and allyl ester in the presence of Lewis acids to give the cycloadducts in high yields and with stereoselectivities of up to 97:3 for the endo isomers. The sense of the asymmetric induction in these reactions can be directed by the use of differently coordinating catalysts (e.g. TiCl4: (2R):(2S) = 96:4; EtAlCl2: (2R):(2S) = 10:90 at 0°C). In the TiCl4-catalyzed reactions with the fumaric acid derivatives the ratio of the diastereomers reaches values of up to 112…

Tumor-Associated MUC1 Tandem-Repeat Glycopeptide Microarrays to Evaluate Serum- and Monoclonal-Antibody Specificity

Aminosäureester als chirale Hilfsgruppen in Lewis-Säure-katalysierten Umsetzungen elektronenreicher Siloxydiene mit Iminen

The Allyl Ester as Carboxy-Protecting Group in the Stereoselective Construction of Neuraminic-Acid Glycosides

The application of the allyl-ester moiety as protecting principle for the carboxy group of N-acetylneuraminic acid is described. Peracetylated allyl neuraminate 2 is synthesized by reacting the caesium salt of the acid 1 with allyl bromide. Treatment of 2 with HCl in AcCl or with HF/pyridine gives the corresponding 2-chloro or 2-fluoro derivatives 3 and 4, respectively (Scheme 1). In the presence of Ag2CO3, the 2-chloro carbohydrate 3 reacts with di-O-isopropylidene-protected galactose 5 to give the 2–6 linked disaccharide with the α-D-anomer 6a predominating (α-D/β-D = 6:1; Scheme 2). Upon activation of the 2-fluoro derivative 4 with BF3 · Et2O, the β-D-anomer 6b is formed preferentially (…

Allylester als selektiv abspaltbare Carboxyschutzgruppen in der Peptid- undN-Glycopeptidsynthese

Allylester eignen sich als Schutz der Carboxyfunktion bei Peptid- und N-Glycopeptidsynthesen und konnen von Aminosauren einfach hergestellt werden. Unter den Bedingungen der Boc- und Z-Gruppenabspaltung im Sauren sind die Allylester bestandig. Durch Behandlung mit katalytischen Mengen von Tris(triphenylphosphan)rhodium(I)-chlorid in Ethanol/wasser (9:1) werden sie im neutralen bis schwach basischen Milieu schonend gespalten. Der N-terminale Schutz und die N-glycosidische Bindung bleiben dabei unverandert erhalten. Die dadurch mogliche selektive Deblockierung der α-Carboxyfunktion geschutzter N-glycosylierter Asparagin-Derivate 15 wird zur gezielten C-terminalen Kettenverlangerung zu N-Glyco…

Natural Product Synthesis on Polymeric Supports—Synthesis and Biological Evaluation of an Indolactam Library

Potent activators of protein kinase C in fibroblasts: This property was determined for several indolactam V analogues (1) with a new cell-based assay system. This tumor-promoting indole alkaloid and analogues thereof can be synthesized efficiently on the solid phase. The key steps of the combinatorial approach are a regioselective amination of the indole ring and an enantioselective enzymatic reaction.

Synthesis of the Glycopeptide Partial Sequence A80-A84 of Human Fibroblast Interferon

The glycopentapeptide H-(GlcNAcβ1-)Asn-Glu-Thr-Ile-Val-OH (10) representing the partial sequence A80–A84 of human fibroblast interferon was synthesized using the newly developed allyl-ester protection of carboxy functions. The allyl esters, which are stable to acids and to bases, can be cleaved under very mild, neutral conditions using tris(triphenylphosphine)rhodium(I) chloride or tetrakis(triphenylphosphine)palladium(0) as a catalyst. This synthetic method opens up a preparative route to glycopeptide model structures of glycoproteins of high biological interest.

Asymmetric synthesis of bicyclic amino acid derivatives by Aza-Diels-Alder reactions in aqueous solution

Derivatives 7–10 and 13–16 of methyl and ethyl 2-azabicyclo[2.2.1]heptane-3-carboxylates are synthesized by Aza-Diels-Alder reactions of chiral iminium ions, formed in situ from glyoxylic acid and chiral amines, with cyclopentadiene. Whereas the heterodienophiles derived from phenylglycinol and esters of sterically more demanding amino acids fail to undergo asymmetric cycloadditions, with alanine methyl ester and (R)-1-phenylethylamine hydrochoride the cycloadducts are formed in yields of 15 and 52%, respectively, reaching de values of up to 90:10 for the exo isomers.

ChemInform Abstract: Amino Acid Esters as Chiral Auxiliaries in Asymmetric Cycloadditions

Preparation of Biomolecule Microstructures and Microarrays by Thiol-ene Photoimmobilization

A mild, fast and flexible method for photoimmobilization of biomolecules based on the light-initiated thiol-ene reaction has been developed. After investigation and optimization of various surface materials, surface chemistries and reaction parameters, microstructures and microarrays of biotin, oligonucleotides, peptides, and MUC1 tandem repeat glycopeptides were prepared with this photoimmobilization method. Furthermore, MUC1 tandem repeat glycopeptide microarrays were successfully used to probe antibodies in mouse serum obtained from vaccinated mice. Dimensions of biomolecule microstructures were shown to be freely controllable through photolithographic techniques, and features down to 5 …

Titelbild: Tumor-Associated MUC1 Tandem-Repeat Glycopeptide Microarrays to Evaluate Serum- and Monoclonal-Antibody Specificity (Angew. Chem. 44/2009)

ChemInform Abstract: The Allyl Ester as Carboxy-Protecting Group in the Stereoselective Construction of Neuraminic Acid Glycosides.

The application of the allyl-ester moiety as protecting principle for the carboxy group of N-acetylneuraminic acid is described. Peracetylated allyl neuraminate 2 is synthesized by reacting the caesium salt of the acid 1 with allyl bromide. Treatment of 2 with HCl in AcCl or with HF/pyridine gives the corresponding 2-chloro or 2-fluoro derivatives 3 and 4, respectively (Scheme 1). In the presence of Ag2CO3, the 2-chloro carbohydrate 3 reacts with di-O-isopropylidene-protected galactose 5 to give the 2–6 linked disaccharide with the α-D-anomer 6a predominating (α-D/β-D = 6:1; Scheme 2). Upon activation of the 2-fluoro derivative 4 with BF3 · Et2O, the β-D-anomer 6b is formed preferentially (…

ChemInform Abstract: Asymmetric Synthesis of Bicyclic Amino Acid Derivatives by Aza-Diels- Alder Reactions in Aqueous Solution.

Derivatives 7–10 and 13–16 of methyl and ethyl 2-azabicyclo[2.2.1]heptane-3-carboxylates are synthesized by Aza-Diels-Alder reactions of chiral iminium ions, formed in situ from glyoxylic acid and chiral amines, with cyclopentadiene. Whereas the heterodienophiles derived from phenylglycinol and esters of sterically more demanding amino acids fail to undergo asymmetric cycloadditions, with alanine methyl ester and (R)-1-phenylethylamine hydrochoride the cycloadducts are formed in yields of 15 and 52%, respectively, reaching de values of up to 90:10 for the exo isomers.

Asymmetrische Hetero-Diels-Alder-Reaktionen in wäßriger Lösung unter Verwendung von Aminosäureestern als chiralen Auxiliaren

(R)- und (S)-Aminosaure-methylester-hydrochloride bilden mit Formaldehyd in THF/Wasser-Gemischen Iminium-Ionen, die als elektronenarme Dienophile mit Cyclopentadien, 1,3-Cyclohexadien und Alkyl-substituierten Butadienen bereits bei 0°C Hetero-Diels-Alder-Reaktionen eingehen. Die Cycloaddukte werden mit hohen Ausbeuten im Multigrammasstab und mit Diastereomerenverhaltnissen (bis zu 93:7) gebildet, die mit anderen chiralen Aminen bisher nicht erreicht werden konnten. Mit Hilfe von NOE-Experimenten werden die absoluten Konfigurationen der Hauptdiastereomeren zugeordnet. Aus den Phenylglycin- und den Serin-Derivaten konnen die chiralen Hilfsgruppen mittels hydrogenolytischer Methoden bzw. unter…

ChemInform Abstract: Synthesis of Glycopeptide Partial Structures of Virus Coat Glycoproteins

Amino Acid Esters as Chiral Auxiliary Groups in Lewis Acid Catalyzed Reactions of Electron-rich Siloxydienes with Imines

Selektive enzymatische Schutzgruppenabspaltungen: Der n-Heptylester als Carboxylschutzgruppe in der Peptidsynthese

Selective Enzymatic Removal of Protecting Groups: n-Heptyl Esters as Carboxy Protecting Functions in Peptide Synthesis Amino acid heptyl (Hep) esters are accessible as generally crystalline hydro tosylates 3 from the amino acids by azeotropic esterification with 1-heptanol in high yields. They can be condensed with Z-, Boc-, and Aloc-protected amino acids to give the dipeptides 7–9 in the presence of 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). From the fully protected dipeptides the N-terminal protecting groups are cleaved by chemical methods without affecting the Hep esters. On the other hand, the heptyl esters can be hydrolyzed under mild conditions (pH = 7.0, 37°C) and with hi…

Synthese vonN-Glycopeptid-Partialstrukturen der Verknüpfungsregion sowohl der Transmembran-Neuraminidase eines Influenza-Virus als auch des Faktors B des menschlichen Komplementsystems

Mit Hilfe der Schutzgruppenkombination Boc-Gruppe/Allylester und Acetylschutz im Kohlenhydratteil wurden die geschutzten N-Chitobiosyl-asparagin-peptide 12a und 14 synthetisiert, die der Verknupfungsregion des Faktors B des menschlichen Komplementsystems und einer Influenza-Virus-Neuraminidase entsprechen. Aus dem vollgeschutzten Glycopeptid 12a liesen sich der Allylester und die Acetylschutzgruppen simultan mit methanolischem Ammoniak und die Boc-Schutzgruppe mit wasserfreier Trifluoressigsaure ohne storende Nebenreaktionen entfernen. Versuche, die Boc-Gruppe aus an den Kohlenhydrat-Hydroxyfunktionen deblockierten Glycopeptiden abzulosen, fuhrten uberwiegend zur Spaltung der O-glycosidisch…

Stereospecific CC-bond formation with rabbit muscle aldolase - A chemoenzymatic synthesis of (+)-exo-brevicomin

Abstract (+)-(1S,5R,7S)-Exo-brevicomin 9, a sex pheromone of the western pine bark beetle, is synthesized using an aldol reaction catalyzed by fructose-1,6-diphosphate aldolase (EC 4.1.2.13) from rabbit muscle as the key step by which the absolute configuration of the target is established.

Aminosäureester als chirale Hilfsgruppen bei Barbier-Reaktionen in wäßriger Lösung

Amino Acid Esters as Chiral Auxiliaries in Barbier-Type Reactions in Aqueous Solution Valine and proline benzyl ester are converted into the aliphatic and aromatic α-oxo amides 5 by activation of the respective α-oxo acid by means of N,N′-diisopropylcarbodiimide. The α-oxo amides 5 undergo Barbier-type reactions with differently substituted allyl halides in the presence of zinc and pyridinium toluenesulfonate in water/THF (2:1, v/v) at 4°C. Thereby, the α-hydroxy amides 8/9 are formed in high yields and, in the case of the proline ester amides, with diastereomer ratios of 4–6:1. In the absence of any allyl halide, or if the addition of the allyl moiety to the carbonyl groups is only slow, t…

Solid-Phase Synthesis and Biological Evaluation of a Teleocidin Library—Discovery of a Selective PKC Down Regulator

Protein kinaseC (PKC) is linked to the signal-induced modulation of a wide variety of cellular processes, such as growth, differentiation, secretion, apoptosis, and tumor development. The design and synthesis of small molecules that regulate these different cellular signaling systems is at the forefront of modern drug design. Herein we report a) an efficient method for the synthesis of indolactamV (6), a PKC activator, and its N13-des(methyl) analogues (19) using a regioselective organometallic transformation, a convenient aminomalonate derivative (10) to introduce the appropriate functionality and an enantiospecific enzymic hydrolysis as key steps; b) the use of this method in the first so…

Chemoenzymatische „Chiral-Pool”-Synthese von (+)-exo-Brevicomin aus Kohlenhydraten mit Fructose-1,6-diphosphat-Aldolase

Chemoenzymatic “Chiral-Pool” Synthesis of (+)-exo-Brevicomin from Carbohydrates Using Fructose 1,6-Diphosphate Aldolase Fructose-1,6-diphosphate aldolase (EC 4.1.2.13) catalyzes the stereospecific aldol reaction between 1,3-dihydroxyacetone phosphate (4) and 5-oxohexanal (3) or its 5-dithiane-protected analog 8. The products of the aldol reactions are dephosphorylated with acid phosphatase (EC 3.1.3.2). Whereas the aldol adduct of 3 cyclizes spontaneously to give the bicyclic brevicomin precursor 3, the adduct of 8 first has to be deprotected with sulfuryl chloride and wet silica gel. The resulting bicyclic α-hydroxy ketone 3 is reduced with LiAlH4 to form the 1,2-diol 14 which is then deox…

ChemInform Abstract: Amino Acid Esters as Chiral Auxiliary Groups

Organische Chemie. Ein kurzes Lehrbuch. Von H. Hart. Übersetzt und ergänzt von J. Lehmann. VCH Verlagsgesellschaft, Weinheim 1989. XVI, 458 S., Broschur DM 58.00. – ISBN 3-527-26480-9

ChemInform Abstract: (S)-Proline Benzyl Ester as Chiral Auxiliary in Lewis Acid-Catalyzed Asymmetric Diels-Alder Reactions.

Asymmetric Diels-Alder reaction of cyclopentadiene (I) with (S)-proline benzyl ester (II) yields a mixture of the diastereomeric cycloadducts (R)-(III) and (S)-(IV).

Thermische Diels-Alder-Reaktionen mitN-(2-Alkenoyl)-(S)-prolinestern als chiralen Dienophilen in organischen und wäßrigen Reaktionsmedien

Thermal Diels-Alder Reactions with N-(2-Alkenoyl)-(S)-proline Esters as Chiral Dienophiles Cyclopentadiene reacts with N-acryloyl-(S)-proline benzyl and allyl ester in toluene at 0°C to give the bicycloheptene-carboxylic acid amides with a stereoselection of (2S):(2R) = 81:19. In the reactions with the N,N′-fumaroylbis(proline esters) the cycloadducts are formed in high yields and with isomer ratios of up to 97:3. The absolute configuration of N,N′-〈(1R,2R,3R,4S)-bicyclo[2.2.1]hept-5-ene-2,3-diyldicarbonyl〉bis-[(S)-proline benzyl ester] (6 a) has been determined by an X-ray analysis. In the reactions of the acrylamides with cyclopentadiene and of the fumaramides with cyclopentadiene, isopre…

ChemInform Abstract: Asymmetric Aza Diels-Alder Reactions of Amino Acid Ester Imines with Brassard′s Diene.

Cover Picture: Tumor-Associated MUC1 Tandem-Repeat Glycopeptide Microarrays to Evaluate Serum- and Monoclonal-Antibody Specificity (Angew. Chem. Int. Ed. 44/2009)

Chemoenzymatic synthesis of O-glycopeptides carrying the tumor associated TN-antigen structure

Abstract The application of the lipase-catalyzed C-terminal deprotection of heptyl esters for the construction of acid- and base-labile O -glycopeptides carrying the characteristic structural element of the tumor associated T N -antigen (GalNAc α→Ser/Thr) is described