Direct one-pot highly enantioselective assembly of polyketide and carbohydrate synthons

A short, direct, catalytic, enantioselective synthesis of polyketide segments and carbohydrates is presented. The novel, direct, one-pot, organocatalytic asymmetric tandem cross-aldol/Horner-Wittig-Emmons reactions assemble polyketide and carbohydrate derivatives in good yield with 93-98% ee. The one-pot catalytic asymmetric tandem reaction was applied to a highly enantioselective formal de novo synthesis of the rare carbohydrate, l-altrose.     

Direct asymmetric intermolecular aldol reactions catalyzed by amino acids and small peptides

In nature there are at least nineteen different acyclic amino acids that act as the building blocks of polypeptides and proteins with different functions. Here we report that alpha-amino acids, beta-amino acids, and chiral amines containing primary amine functions catalyze direct asymmetric intermolecular aldol reactions with high enantioselectivities. Moreover, the amino acids can be combined into highly modular natural and unusual small peptides that also catalyze direct asymmetric intermolecular aldol reactions with high stereoselectivities, to furnish the corresponding aldol products with up to >99 % ee. Simple amino acids and small peptides can thus catalyze asymmetric aldol reactions with stereoselectivities matching those of natural enzymes that have evolved over billions of years. A small amount of water accelerates the asymmetric aldol reactions catalyzed by amino acids and small peptides, and also increases their stereoselectivities. Notably, small peptides and amino acid tetrazoles were able to catalyze direct asymmetric aldol reactions with high enantioselectivities in water, while the parent amino acids, in stark contrast, furnished nearly racemic products. These results suggest that the prebiotic oligomerization of amino acids to peptides may plausibly have been a link in the evolution of the homochirality of sugars. The mechanism and stereochemistry of the reactions are also discussed.     

Amino acid-catalyzed dynamic kinetic asymmetric transformations (DYKAT): one-step de novo synthesis of polyketide sugars from racemic β-hydroxy aldehydes

The ability of amino acids to catalyze dynamic kinetic asymmetric transformation (DYKAT) with excellent stereoselectivity is presented. The novel DYKAT process was applied in the proline-catalyzed one-step de novo synthesis of triketide- and deoxysugars, which were formed with excellent diastereoselectivity and up to 99% ee. The de novo synthesis is accomplished via an enzyme-like DYKAT process, which includes continuous amino acid-mediated racemization of the acceptor β-hydroxy aldehyde in combination with amino acid-catalyzed direct selective aldol addition.     

Direct organocatalytic aldol reactions in buffered aqueous media

Organocatalytic cross-aldol reactions catalyzed by cyclic secondary amines in aqueous media provide a direct route to a variety of aldols including carbohydrate derivatives and may warrant consideration as a prebiotic route to sugars.     

Enantioselective de novo synthesis of 4-deoxy-D-hexopyranoses via hetero-Diels-Alder cycloadditions: total synthesis of ezoaminuroic acid and neosidomycin

The de novo synthesis of carbohydrates constitutes an important aspect of organic chemistry, and its application toward deoxy sugars is particularly noteworthy in targeting biologically active compounds. The enantioselective preparation of 4-deoxy-D-ribo-, 4-deoxy-D-lyxo-, and 4-deoxy-D-xylo-hexopyranosides, along with their uronate counterparts has been successfully accomplished using hetero-Diels-Alder reactions as the key step. Jacobsen chromium(III) catalyst and a titanium-binaphthol complex have been used to successfully catalyze diene and aldehyde cycloadditions, leading to optically active dihydropyran templates. 6-Hydroxydesosamine, orthogonally protected ezoaminuroic acid, and neosidomycin were synthesized using a comparative study. Also, a novel chiron approach to 4-deoxy-lyxo-hexopyranosiduronic acid methyl ester derivatives was efficiently accomplished starting from readily accessible starting materials. This work represents a systematic and comprehensive study toward a de novo synthesis of 4-deoxy-hexopyranoses via enantioselective hetero-Diels-Alder reactions.     

A highly enantioselective amino acid-catalyzed route to functionalized alpha-amino acids

The development of syntheses providing enantiomerically pure alpha-amino acids has intrigued generations of chemists and been the subject of intense research. This report describes a general approach to functionalized alpha-amino acids based on catalytic asymmetric synthesis. Proline catalyzed Mannich-type reactions of N-PMP-protected alpha-imino ethyl glyoxylate with a variety of unmodified ketones to provide functionalized alpha-amino acids in high yields with excellent regio-, diastereo-, and enantioselectivities. Study of seven examples yielded six with product ee values of > or = 99%. In reactions involving ketone donors where diastereoisomeric products could be formed, two adjacent stereogenic centers were created simultaneously upon carbon-carbon bond formation with complete syn-stereocontrol. Significantly, this methodology utilizes readily available and rather inexpensive starting materials, does not require any preactivation of substrates or metal ion assistance, and can be carried out on a gram scale under operationally simple reaction conditions. The keto-functionality present in the products provides a particularly attractive site for versatile modifications. This study compliments and extends our bioorganic approach to asymmetric synthesis to a versatile synthon class. Given that we have shown that a variety of optically active amino acids can be synthesized with proline catalysis, where an L-amino acid begets other L-amino acids, our results may stimulate thoughts concerning prebiotic syntheses of optically active amino acids based on this route.     

Asymmetric syn-selective direct aldol reaction of protected hydroxyacetone catalyzed by primary amino acid derived bifunctional organocatalyst in the presence of water

A new series of water compatible primary-tertiary diamine catalysts derived from natural primary amino acids bearing a hydrophobic side chain have been synthesized. These new primary-tertiary diamine-Br?nsted acid conjugates bifunctional organocatalysts efficiently catalyzes the asymmetric direct syn selective cross-aldol reaction of different protected hydroxyacetone with various aldehydes in high yield (94%) and high enantioselectivity (up to 97% ee of syn) and dr of 91 : 9 (syn/anti) under mild reaction conditions.     

Asymmetric cyclization via memory of chirality: a concise access to cyclic amino acids with a quaternary stereocenter

N-(omega-Bromoalkyl)-amino acid derivatives, readily prepared from natural alpha-amino acids, gave cyclic amino acids with a quaternary stereocenter by treatment with potassium hexamethyldisilazaide in DMF. The chirality of parent amino acids was almost completely preserved during an enolate-formation and cyclization process, giving aza-cyclic amino acids in up to 98% ee in retention of configuration. This method is applicable to the asymmetric synthesis of azetidine, pyrrolidine, piperidine, and azepane derivatives. The asymmetric cyclization seems to proceed via an axially chiral enolate intermediate and not through a concerted SEi process.     

手性口恶唑硼烷酮催化不对称Aldol反应的研究

以廉价易得的手性氨基酸为原料合成了一系列氮磺酰化氨基酸配体,并将之与硼烷原闰制备成手性恶唑硼烷酮催化苯甲醛与烯醇硅醚的不对称Aldol反应,获得了较好的效果。对各种影响反应结果的因素进行了讨论,并对其不对称诱导机理进行了探讨。结果表明D-苯基甘氨酸衍生的手性恶唑硼烷酮催化剂对这种反应的催化效明显好于L-缬氨酸、L-亮氨酸、L-异亮氨酸等其它脂肪侧链氨基酸衍生的恶唑硼烷酮催化剂。其所得产物的化学产率和ee值分别为38.7%和81.7%。     

Proline-catalyzed asymmetric assembly reactions: enzyme-like assembly of carbohydrates and polyketides from three aldehyde substrates

Directed asymmetric assembly of simple achiral building blocks into stereochemically complex molecules like triketides has been described for the first time using l-proline catalyzed asymmetric double aldol reactions. The product pyranoses contain four asymmetric centers constructed under proline catalysis in a highly diastereoselective and modestly enantioselective fashion from three aldehyde molecules. These results suggest that the construction of complex products from simple starting materials is within the realm of organocatalysis involving the simple naturally occurring amino acid l-proline. Our successful assembly of pyranoses from simple aldehydes under proline catalysis suggests that this approach may warrant consideration as a prebiotic route to sugars and polyketides.     

Acyclic chiral amines and amino acids as inexpensive and readily tunable catalysts for the direct asymmetric three-component Mannich reaction

The direct three-component asymmetric Mannich reaction catalyzed by acyclic chiral amines or amino acids is presented. Simple acyclic chiral amines and amino acids--such as alanine-tetrazole (9), alanine, valine, and serine-catalyzed the three-component asymmetric Mannich reactions between unmodified ketones, p-anisidine, and aldehydes with high chemo- and stereoselectivity, furnishing the corresponding Mannich bases with up to >99 % ee. This study demonstrates that the whole range of amino acids in nature, as well as nonproteogenic amino acid derivatives, can be considered in the design and tuning of novel, inexpensive organocatalysts for the direct asymmetric Mannich reaction.     

手性伯胺催化剂用于顺式选择性的不对称Cross-Aldol反应

基于酸碱作用,将手性伯胺与质子酸原位结合制得有机小分子催化剂,并用于醛与醛的不对称Cross-aldol反应.与一般手性仲胺催化剂不同,该类伯胺催化剂得到的是顺式选择性构型的Cross-aldol产物,其产率达90%,顺反比和ee值分别为9:1和90%.相比而言,采用简单易得的(1S,2S)-(+)-环己二胺即可得到较高选择性的顺式产物.     

Direct catalytic asymmetric aldol reactions of pyruvates: scope and mechanism

The direct aldol reaction of 2-ketoesters catalyzed by chiral bisoxazoline copper(II) complexes has been investigated. First the direct homo-aldol reaction of ethyl pyruvate is reported which proceeds to give diethyl 2-hydroxy-2-methyl-4-oxoglutarate. This was isolated as the more stable optically active isotetronic acid in good yield and enantiomeric excess in the absence of bases such as amines. Detailed investigations of the use of different chiral Lewis acids as the catalyst, amines, ratios of chiral bisoxazoline copper(II) salts:amine, and solvents gave up to 96% ee of the isotetronic acid. Then the reaction was extended to a cross-aldol reaction of various 2-ketoesters with activated carbonyl compounds to give the cross-aldol adduct with excellent enantiomeric excess. Furthermore, the synthesis of the isotetronic acids was investigated from these cross-aldol adducts giving important information about the formation of the stereogenic centers during the aldol reaction. Based on the absolute configuration of the homo-aldol adduct the mechanism for the aldol reaction is discussed.     

Acyclic amino acid-catalyzed direct asymmetric aldol reactions: alanine, the simplest stereoselective organocatalyst

The linear amino acid-catalyzed direct asymmetric intermolecular aldol reaction is presented; simple amino acids such as alanine, valine, isoleucine, aspartate, alanine tetrazole and serine catalyzed the direct catalytic asymmetric intermolecular aldol reactions between unmodified ketones and aldehydes with excellent stereocontrol and furnished the corresponding aldol products in up to 98% yield and with up to > 99% ee.     

De Novo Synthesis of Furanose Sugars: Catalytic Asymmetric Synthesis of Apiose and Apiose‐Containing Oligosaccharides

A de novo synthetic method towards apiose, a structurally unusual furanose, is reported. The key feature is sequential metal catalysis consisting of the palladium‐catalyzed asymmetric intermolecular hydroalkoxylation of an alkoxyallene and subsequent ring‐closing metathesis (RCM). This strategy enabled the efficient synthesis of various apiose‐containing disaccharides and a unique convergent synthesis of trisaccharides.     

Intramolecular Diels-Alder reactions using chiral ruthenium Lewis acids and application in the total synthesis of ent-ledol

One-point binding chiral ruthenium Lewis acids incorporating the C(2)-symmetric electron-poor bidentate phosphinite ligand BIPHOP-F and a Cp or an indenyl 'roof' can efficiently catalyze asymmetric intramolecular Diels-Alder reactions of trienes to form bicyclic adducts with good to excellent asymmetric induction. This reaction forms the key step in a total synthesis of ent-ledol in 96% ee. The synthesis also helps to clarify the stereochemical assignment of ledol and inconsistencies in the measured optical rotation.     

Enantioselective Alkynylation of Benzaldehyde Catalyzed by New Chiral Lewis Acid Ligand: Zinc-Amide Complex

The enantioselective alkynylzinc addition to aldehydes is very useful for the synthesis of chiral propargyl alcohols which are important versatile building blocks of many biologically active compounds and natural products1. A series of chiral oxazolidines were conveniently synthesized from amino acids in three steps with good yields. The use of chiral Lewis acid ligand: zinc-amide complex in situ generated from this oxazolidine with alkylzinc as chiral catalysts for the enantioselective alkyny…     

Catalytic, enantioselective alkylation of alpha-imino esters: the synthesis of nonnatural alpha-amino acid derivatives.

Methodology for the practical synthesis of nonnatural amino acids has been developed through the catalytic, asymmetric alkylation of alpha-imino esters and N,O-acetals by enol silanes, ketene acetals, alkenes, and allylsilanes using chiral transition metal-phosphine complexes as catalysts (1-5 mol %). The alkylation products, which are prepared with high enantioselectivity (up to 99% ee) and diastereoselectivity (up to 25:1/anti:syn), are protected nonnatural amino acids that represent potential precursors to natural products and pharmaceuticals. A kinetic analysis of the catalyzed reaction of alkenes with alpha-imino esters is presented to shed light on the mechanism of this reaction.     

Resolution of racemic 2-aminocyclohexanol derivatives and their application as ligands in asymmetric catalysis

A preparatively easy and efficient protocol for the resolution of racemic 2-aminocyclohexanol derivatives is described, delivering both enantiomers with >99% enantiomeric excess (ee) by sequential use of (R)- and (S)-mandelic acid. A simple aqueous workup procedure permits the isolation of the amino alcohols in analytically pure form and the almost quantitative recovery of mandelic acid. Debenzylation of enantiopure trans-2-(N-benzyl)amino-1-cyclohexanol by hydrogenation and subsequent derivatization give access to a broad variety of diversely substituted derivatives. Furthermore, the corresponding cis isomers are readily available. Applications of these optically active aminocyclohexanols in catalyzed asymmetric phenyl transfer reactions to benzaldehydes and transfer hydrogenations of aryl ketones lead to products with up to 96% ee.     

Mimicking enzymatic transaminations: attempts to understand and develop a catalytic asymmetric approach to chiral alpha-amino acids

Attempts are made to build a bridge between asymmetric catalysis and enzymatic reactions by mechanistic investigations and the development of a catalytic and enantioselective approach to amination of alpha-keto esters by primary amines catalyzed by chiral Lewis acids as a model for transamination enzymes. Different Lewis acids can catalyze the half-transamination of alpha-keto esters using primary amine nitrogen sources such as pyridoxamine and 4-picolylamine. The mechanistic studies of the Lewis-acid catalyzed half-transamination using deuterium-labelled compounds show the incorporation of deuterium atoms in several positions of the alpha-amino acid derivative, indicating that the enol of the alpha-keto ester plays an important role along the reaction path. The catalytic enantioselective reactions are dependent on the pKa-value of the solvent since enantioselectivities were only obtained in solvents with high pKa-values relative to methanol. However, stronger acidic conditions generally gave better yields, but poor enantioselectivities. A series of chiral Lewis acids were screened as catalysts for the enantioselective half-transamination reactions and moderate yields and enantioselectivities of up to 46% ee were obtained.