Chapter I. Sterically Strained Brønsted Salts and Their Utility
Scheme 2: Hydration on Glycal
C−H···Anion Interactions Assisted Addition of Water to Glycals by Sterically Hindered 2,4,6-Tri-tert-butylpyridinium Hydrochloride
2.1 Introduction:
There are sufficient studies on the hydration of terminal olefin styrene and substituted styrene and from the evidences it was demonstrated that the reaction is carried out in the presence of an acid catalyst and the carbonium ion intermediate generated in situ forms the Markovnikov addition product irreversibly (scheme 1).1 The hydration mechanism of styrene reveals that the proton transfer from H3O+ to styrene, which is also the rate determining step, results in the formation of the carbonium ion which is followed by the formation of corresponding (substituted) phenylethan-1-ol.2
trideoxy sugars are present in naturally available and biologically important molecules.3 Fucose or 6- deoxy-L-galactose is the main component of fucoidan of brown algae and is found in N-linked glycans.
Moreover, rhamnose or 6-deoxy-L-mannose is a 2,6-dideoxy sugar and is commonly found in plant glycosides.
2-Deoxy Sugars: One of the most important 2-deoxy sugar is 2-deoxy-D-erythro-pentose (2- deoxyribose) which is the main constituent of deoxyribonucleic acids (DNA). Moreover, 2-deoxy- D- arabino-hexose (2-deoxyglucose) is known as an energy restriction mimetic agent.4 Besides, synthesis of 2-deoxy glycosides are also challenging as they are very tough to handle, sensitive towards hydrolysis and prone to 1,2-elimination reaction.
2.1.2 2,6-Dideoxy Sugars:
These are one of the most highly abundant carbohydrates in nature and they have antibiotic and antitumor activity. Among them, 2,6-dideoxy-3-methoxy-hexopyranoses and 2,6-dideoxy-3-amino- hexopyranoses are found as components of various natural products in medicinal chemistry. D- Boivinose, which can be isolated from the seeds of Corchorus olitorius L, was found as a component of a cardenolide glycoside.5 L-boivinose is the least abundant of the three and is found in corn (Zea mays).6
D-digitoxose is the main constituents of plant cardiac and other steroidal glycosides7 whereas L- digitoxose has been found in actinomycetes, particularly as a unique family of antibiotics, the jadomycins. L-olivose is the main constituent of the trisaccharide chain of the anthracycline Aclacinomycin A. Interestingly, L-olivose is not available in nature but its 3-methoxy derivative, i.e. L- oleandrose has been isolated in oleandomycin which is a macrolide antibiotic produced by Streptomyces antibioticus (Figure 2).7
Figure 2: Naturally Occurring 2,6-Dideoxy Sugars 2.1.3 Biological Importance of Deoxy Sugars:
Deoxysugars are found in various natural products and also as structural components in several glycoproteins, bacterial endotoxins and secondary metabolites etc. Deoxy sugars are found to be involved with intercellular communications, immunogenic responses to pathogenic bacteria and also in many biologically important antibiotics.8 The change in the number or structure of the deoxysugar unit present in these natural products can affect their activity. Also, by modifying the sugar unit one can enhance the activity of antibiotics. Thus, to develop useful drugs or to design new and effective therapeutic strategies, it is crucial to understand both the genetic and mechanistic aspects of deoxysugar biosynthesis. Thus, developing new biologically important medicinal products containing deoxy sugar units as well as studying the mechanistic information are always areas of interest to organic chemists.
Naturally, 2-deoxy sugars are found in biologically active molecules. Most of them have antitumor and anticancer activities.8 Deoxysugar plasmids were exploited to synthesize the clinically relevant aureolic acid anticancer drug derivatives i.e. mithramycin analogues (Figure 3).9-13
Figure 3: Anticancer Drug Mithramycin
In addition, deoxysugars also seem to play a significant role in the DNA-binding properties of antitumor anthracycline antibiotics (Figure 4). Hutchison and coworkers exploited the same and attempted to synthesize various deoxyaminosugars to attach them anthracycline-type aglycones in pursuit of developing new antitumor drugs.14Antitumor antibiotics such as Anthracycline are a class of natural products containing tetracyclic aglycone units linked to the 2-deoxy sugar. Daunomycin, Adriamycin and Robumycin form noncovalent complexes with DNA through intercalation and inhibit DNA replication and RNA transcription.11,12
Figure 4: Antitumor Antibiotics
Doxorubicin is a well-known drug for antitumor activity. Anthracycline derivatives (Figure 5), e.g. Marcellomycin and Aclacinomycin A containing long carbohydrate chains are known for their lower toxicity.14
Figure 5: Naturally Occurred Anthracycline Antitumor Drugs 2.2 Literature Reports
2.2.1 Literature Preview on Organocatalytic Stereoselective Synthesis of 2-Deoxy Glycosides Catalysis in which the rate of the chemical reaction is increased by an organic molecule is termed as organocatalysis. These molecules consist of carbon, hydrogen, sulfur and other non-metal elements that are found in organic compounds. Enantioselective organocatalysis is a most established synthetic method to catalyze challenging transformations in synthetic organic chemistry. It is critical in the development of methods to synthesize chiral molecules with exclusive regio-, chemo-, and stereoselectivity. Organocatalysis is known for its easy to handle and simple operational purpose. These catalysts are readily commercially available, easy to prepare, and have low toxicity. These important features make organocatalysis an attractive method to synthesize complex organic molecules, including oligosaccharides, in a stereoselective fashion.
In literature, there are various reports on the synthesis of 2-deoxy α-glycosides. Xin-Shan Ye and coworkers explored an efficient pre-activation method to activate anomeric thioglycosides towards the formation of highly α-selective glycosylation of deoxysugars (Scheme 3).15 They have used 2- deoxy- and 2,6-dideoxythioglycosides as glycosyl donors. They have shown a variety of glycosyl acceptors and donors can be used in this method.The presence of a 3,4-O-carbonate group in glycosyl donors enhances the α-selectivity in the product outcome. The above mentioned donor is activated in the presence of 4 Å MS in DCM solvent with a combination of triflic anhydride and benzenesulfinyl morpholine (BSM) at -72 °C. This pre-activated donor when treated with any glycosyl acceptor provides the corresponding α-glycoside.
Scheme 3: α-Selective Glycosylation of 3,4-O-Carbonate-Protected Deoxythioglycosides
Taylor and coworkers have showcased regio- and stereo-selective synthesis of β-deoxy glycosides. They have chosen gluco-, galacto- and rhamno- based per-acetate donors and converted them into anomeric chloride. The thus obtained anomeric chloride was then reacted with cis-1,2- and 1,3-diol acceptors using an organo-boron catalyst in presence of Ag2O (scheme 4).16 In this method, they were able to synthesize partially protected disaccharides with regio- and β-stereoselectivity.