Direct asymmetric organocatalytic de novo synthesis of carbohydrates

A biomimetic organocatalytic asymmetric synthesis of carbohydrates can be accomplished by a proline catalyzed aldol reaction with the dihydroxyacetone equivalent 2,2-dimethyl-1,3-dioxan-5-one and various aldehydes. The biomimetic C₃+C_n strategy directly generates selectively protected carbohydrates in one step, which can be easily deprotected. Additionally, the stereoselective reduction of the keto functions allows a direct entry to different aldopentoses.     

Amino acid catalyzed neogenesis of carbohydrates: a plausible ancient transformation

Hexose sugars play a fundamental role in vital biochemical processes and their biosynthesis is achieved through enzyme-catalyzed pathways. Herein we disclose the ability of amino acids to catalyze the asymmetric neogenesis of carbohydrates by sequential cross-aldol reactions. The amino acids mediate the asymmetric de novo synthesis of natural L- and D-hexoses and their analogues with excellent stereoselectivity in organic solvents. In some cases, the four new stereocenters are assembled with almost absolute stereocontrol. The unique feature of these results is that, when an amino acid is employed as the catalyst, a single reaction sequence can convert a protected glycol aldehyde into a hexose in one step. For example, proline and its derivatives catalyze the asymmetric neogenesis of allose with >99 % ee in one chemical manipulation. Furthermore, all amino acids tested catalyzed the asymmetric formation of natural sugars under prebiotic conditions, with alanine being the smallest catalyst. The inherent simplicity of this catalytic process suggests that a catalytic prebiotic "gluconeogenesis" may occur, in which amino acids transfer their stereochemical information to sugars. In addition, the amino acid catalyzed stereoselective sequential cross-aldol reactions were performed as a two-step procedure with different aldehydes as acceptors and nucleophiles. The employment of two different amino acids as catalysts for the iterative direct aldol reactions enabled the asymmetric synthesis of deoxysugars with >99 % ee. In addition, the direct amino acid catalyzed C(2)+C(2)+C(2) methodology is a new entry for the short, highly enantioselective de novo synthesis of carbohydrate derivatives, isotope-labeled sugars, and polyketide natural products. The one-pot asymmetric de novo syntheses of deoxy and polyketide carbohydrates involved a novel dynamic kinetic asymmetric transformation (DYKAT) mediated by an amino acid.     

Organocatalytic Synthesis of Higher‐Carbon Sugars: Efficient Protocol for the Synthesis of Natural Sedoheptulose and d‐Glycero‐l‐galacto‐oct‐2‐ulose

Herein we report a short and efficient protocol for the synthesis of naturally occurring higher‐carbon sugars—sedoheptulose (d‐altro‐hept‐2‐ulose) and d‐glycero‐l‐galacto‐oct‐2‐ulose—from readily available sugar aldehydes and dihydroxyacetone (DHA). The key step includes a diastereoselective organocatalytic syn‐selective aldol reaction of DHA with d‐erythrose and d‐xylose, respectively. The methodology presented can be expanded to the synthesis of various higher sugars by means of syn‐selective carbon–carbon‐bond‐forming aldol reactions promoted by primary‐based organocatalysts. For example, this methodology provided useful access to d‐glycero‐d‐galacto‐oct‐2‐ulose and 1‐deoxy‐d‐glycero‐d‐galacto‐oct‐2‐ulose from d‐arabinose in high yield (85 and 74 %, respectively) and high stereoselectivity (99:1).     

Total syntheses of carbohydrates: organocatalyzed aldol additions of dihydroxyacetone

The selective total synthesis of carbohydrates with defined configuration has been of great interest for a long time. This field has been the domain of enzymatic methods so far. But now the recent development of several organocatalyzed aldol methodologies has made a selective synthetic approach to configuratively defined carbohydrates possible. This development and different strategies will be discussed in this concept article.     

A Designer Axially Chiral Amino Sulfonamide as an Efficient Organocatalyst for Direct Asymmetric anti‐Selective Mannich Reactions and syn‐Selective Cross‐Aldol Reactions

Amino sulfonamide catalyst : A distal proton of the axially chiral amino sulfonamide (S)‐ 1 realized the opposite diastereoselectivity in Mannich and cross‐aldol reactions compared with that observed in proline‐catalyzed reactions. The reactions catalyzed by (S)‐ 1 proceeded smoothly to give the anti‐Mannich and syn‐aldol adducts in excellent enantioselectivity (see scheme).

     

A Direct,Concise, and Enantioselective Synthesis of 2‐Substituted 4,4,4‐Trifluorobutane‐1,3‐diols Based on the Organocatalytic In Situ Generation of Unstable Trifluoroacetaldehyde

A direct, concise, and enantioselective synthesis of 2‐substituted 4,4,4‐trifluorobutane‐1,3‐diols based on the organocatalytic asymmetric direct aldol reaction of an ethyl hemiacetal of trifluoroacetaldehyde with various aldehydes was examined. A catalytic amount (30 mol %) of commercially available and inexpensive l ‐prolinamide is quite effective as an organocatalyst for the catalytic in situ generation of gaseous and unstable trifluoroacetaldehyde from its hemiacetal, and a successive asymmetric direct aldol reaction with various aldehydes in dichloromethane at 0 °C, followed by reduction with sodium borohydride, gives 2‐substituted 4,4,4‐trifluorobutane‐1,3‐diols in moderate to good yields (31–84 %) with low diastereoselectivities and good to excellent enantioselectivities (64–97 % ee).     

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.     

Diarylprolinol‐Mediated Asymmetric Direct Cross‐Aldol Reaction of α,β‐Unsaturated Aldehyde as an Electrophilic Aldehyde

The diarylprolinol‐mediated asymmetric direct cross‐aldol reaction of α,β‐unsaturated aldehyde as an electrophilic aldehyde was developed. The reaction becomes accelerated by an acid when a carbonyl group is introduced at the γ‐position of the α,β‐unsaturated aldehyde. Synthetically useful γ,δ‐unsaturated β‐hydroxy aldehydes were obtained with high anti‐selectivity and excellent enantioselectivity.