Synthesis of Glycosyl Amino Acids, Glyco Amino Acids & α-Amino γ-Lactams from Carbohydrate Derived Donor-Acceptor Cyclopropanes

Abstract

Synopsis The thesis entitled “Synthesis of Glyco-amino-acids, Glycosyl-amino-acids, and α-Amino γ-Lactams from Carbohydrate Derived Donor-Acceptor Cyclopropanes” is divided into five chapters. Chapter 1: Introduction and Background: Carbohydrate Derived Cyclopropanes and Glycoconjugates of Amino Acids and Peptides In this chapter, introduction and background on cyclopropanes, carbohydrate derived DA-cyclopropanes, glycopeptides and its mimetics is discussed Chapter 2: Efficient Synthesis of Glycosyl Esters of Amino Acids from Carbohydrate Derived Cyclopropanecarboxylates In this chapter, the N-iodosuccinimide (NIS) mediated ring opening of carbohydrate derived donor-acceptor (DA) cyclopropanes with carboxylic group of various N-protected amino acids is discussed. Under mild conditions, glucosyl esters of amino acids have been synthesized in moderate to good yields. This methodology has also been applied to galactose derived DA-cyclopropanes for the synthesis of galactosyl-amino-acid derivative. Among three N-protected valine derivatives (–Fmoc, –Boc, and –Cbz), the reaction of N-Fmoc protected valine derivative of glycosyl-amino-acid has not been successful due to the steric hindrance of bulky Fmoc group. Chapter 3: Synthesis of O–Linked Glycosyl-amino-acids & C–Linked Glyco-amino-acids. In this chapter, the synthesis of glycosyl-amino-acids and glyco-amino-acids by the NIS mediated ring opening of carbohydrate derived DA-cyclopropanes is reported. To synthesize the precursors of glycopeptides, deprotection of NHBoc has been performed with trifluoroacetic acid (TFA) and trimethylsilyl chloride (TMSCl). Trimethylsilyl chloride is found to be a better reagent than trifluoroacetic acid for this reaction. The synthesis of both O–linked glycosyl-amino acids and C–linked glycopeptides from single starting material using the orthogonal strategy at amine groups has been achieved. In these glycoconjugates of amino acids, the azide group (–N3) has been used as a masked amine (–NH2) which circumvents the protection and deprotection steps. Chapter 4: Synthesis of Carbohydrate Fused α-Amino γ-Lactams. In this chapter a flexible protocol for the synthesis of carbohydrate fused α-Amino γ-Lactams from carbohydrate derived cyclopropanecarboxylates has been disclosed. Also, the synthesis of carbohydrate fused γ-Lactams in a single-step from the iodo-azide by reductive cyclization has been reported. The formation of -lactam is achieved in low yield using both methods (A & B). The utility of the carbohydrate fused α-Amino γ-Lactams in the synthesis of Agl-bridged glycopeptide conjugates in a single-step with high efficiency has been demonstrated. Chapter 5: Studies on the Synthesis of Septanosides from Carbohydrate Derived DA-Cyclopropanes In carbohydrate derived DA 1,2-cyclopropanes, generally, the electron withdrawing group is attached at C-7 (type-I), C-2 (type-II), or C-3 (type-III). In this chapter, studies on the synthesis and use of carbohydrate derived DA-cyclopropanes of type-II & -III to form the the septanoside derivatives have been described. Attempts at the synthesis of 3,4,6-tri-O-methyl-D-glucal derived cyclopropanecarboxylates of type-II have not been successful. The failure of the cyclopropanation reactions might be due to presence of the carbmethoxy group at C-2 causing steric hindrance on the olefinic bond of 3,4,6-tri-O-tri-methyl-D-glucal methyl ester. It was then speculated that replacement of the of the carboxylate group in tri-O-methyl-glucal with hydroxymethyl group can promote the cyclopropanation reaction. Cyclopropanation of benzyl protected corresponding alcohol furnished the desired cyclopropane derivative in moderate yield (48%) as an inseparable mixture of diastereomers (1:1). Hence the synthesis of cyclopropanecarboxylates of type-II has not been achieved using this methodology. Glucose derived 3-oxo-1,2-cyclopropanes is synthesized from 3,4,6-tri-O-acetyl-D-glucal in good yield. This glucose derived cyclopropane of type-III did not furnish the septanoside derivative under different conditions. The synthesis of 3-oxo-1,2-cyclopropanated galactose derivative has been achieved in reasonably good yield from D-galactal with in three steps. When the galactose derived DA-cyclopropane is reacted with NIS and MeOH in the presence of catalytic amount of TMSOTf, it furnished the desired septanoside along with many side-products. The attempts at separation and identification of the septanoside in pure form have not been successful.