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Synthesis of Carbohydrate Building Blocks Via Regioselective Uniform Protection/Deprotection Strategies

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Synthesis of Carbohydrate Building Blocks Via Regioselective Uniform Protection/Deprotection Strategies Organic & Biomolecular Chemistry Synthesis of carbohydrate building blocks via regioselective uniform protection/deprotection strategies Journal: Organic & Biomolecular Chemistry Manuscript ID OB-REV-03-2019-000573.R1 Article Type: Review Article Date Submitted by the 21-Apr-2019 Author: Complete List of Authors: Wang, Tinghua; University of Missouri - St. Louis, Deparment of Chemistry and Biochemistry Demchenko, Alexei; University of Missouri - St. Louis, Deparment of Chemistry and Biochemistry Page 1 of 14 Organic & Biomolecular Chemistry Synthesis of carbohydrate building blocks via regioselective uniform protection/deprotection strategies Tinghua Wang and Alexei V. Demchenko* Department of Chemistry and Biochemistry, University of Missouri – St. Louis, One University Boulevard, St. Louis, Missouri 63121, USA O Scope 1 HO O n R PO O n-1 R Scope 2 OH PO n R P = protecting group R = anomeric substituent Scope 1: sugar is uniformly protected leaving only one (or two) free hydroxyl; Scope 2: uniformly protected sugar is deprotected to liberate only one (or two) hydroxyl ABSTRACT: Discussed herein is the synthesis of partially protected carbohydrates by manipulating only one type of a protecting group for a given substrate. The first focus of this review is the uniform protection of the unprotected starting material in the way that only one (or two) hydroxyl groups remain unprotected. The second focus involves regioselective partial deprotection of uniformly protected compounds in the way that only one (or two) hydroxyl groups become liberated.. Contents challenges in carbohydrate chemistry.1-3 During sequencing of simple monosaccharides into larger oligomeric networks, 1. Introduction and basic considerations most of the functional groups need to be temporarily blocked 2. Synthesis of partially substituted building blocks by by protecting groups. On the other hand, functional groups uniform regioselective protection involved in the coupling process need to be left unprotected 2.1 Ester groups or regioselectively liberated. Therefore, it is significant to 2.2 Alkyl and silyl groups develop regioselective methods to simplify the preparation of 2.3 Cyclic groups partially or differentially substituted synthetic intermediates.4 3. Synthesis of partially substituted building blocks by As a consequence, regioselective protection and deprotection regioselective deprotection of uniformly protected of carbohydrates has been a vibrant area of research. substrates Orthogonal or selectively removable protecting group 3.1 Ester group removal and migration manipulations have been extensively employed in 3.2 Ether group removal oligosaccharide synthesis.5,6 However, these strategies require 3.3 Cyclic group removal and opening a specialized knowledge of various protecting groups, reaction 4. Conclusions and outlook conditions for their installation and removal, and application 5. References strategies to different sugar series. Despite a significant progress in this area, and the availability 1. Introduction and basic considerations of streamlining one-pot processes,7-12 in a majority of the applications a large number of protecting group manipulation Carbohydrates are the most abundant molecules among the steps are required to obtain the desired regioselectively four essential classes of biomolecules that also include nucleic substituted product. While orthogonal, semi-orthogonal, or acids, lipids, and proteins. Unlike proteins and nucleic acids, selectively removable protecting groups represent a very which follow template-driven synthetic pathways, there is no important direction of carbohydrate synthesis, discussed general route to the synthesis of carbohydrates. herein in the synthesis of partially protected carbohydrates by Monosaccharides are polyhydroxylated molecules, and manipulating only one type of a protecting group for a given regioselective protection and deprotection of specific derivative. While some overlap with orthogonal protecting hydroxyl groups over others represents one of the major group strategies is inevitable, a more comprehensive coverage Organic & Biomolecular Chemistry Page 2 of 14 of the topic is available in a number of excellent recent chemists dealing with regioselective protection of reviews.5,10,13-16 Two major focuses of this review article are carbohydrates face. depicted in Scheme 1. The first focus is the protection of the Scheme 2. Partial acetylation of methyl α-D- unprotected starting material in the way that only one (or glucopyranoside 1 provides a mixture of products two) hydroxyl groups remain unprotected. The second focus leads to the formation of the same type of derivatives, but it OH Additive none ZnCl2 tetra-Ac 7% 4% rather involves regioselective partial deprotection of O 2.4 equiv. Ac O HO 2 4-OH 7% 9% HO 2.8 equiv. pyridine uniformly protected compounds. At times, we chose to 3-OH 18% 21% HO DMF, rt, 3 days discuss these two major focus areas in application to OMe 2-OH 8% trace differentially protected carbohydrates. These examples 1 99% 3,4-diol 9% 65% 2,4-diol 28% trace include some new reactions that have only been applied to 2,3-diol 20% - such molecules, but in our opinion could also be generally mono-Ac 12% - relevant to the uniformly protected systems. Scheme 1. The overview of protecting group strategies 2. Synthesis of partially substituted building described herein blocks by uniform regioselective protection O Scope 1 This section is focused on discussing those methods wherein HO O n R the unprotected (or polyol) starting material is PO O n-1 R regioselectively protected in the way that only one (or two) Scope 2 OH PO hydroxyl groups remain unprotected. n R P = protecting group 2.1. Ester groups R = anomeric substituent Ester protecting groups are ubiquitous in carbohydrate The application of partially protected building blocks is chemistry because acylation of hydroxyl groups is typically an fundamental to oligosaccharide synthesis. Mono- efficient and high-yielding process. Common methods of hydroxylated building blocks can be directly utilized as esterification utilize an acid chloride or an acid anhydride as glycosyl acceptors in glycosylation reactions. Di-hydroxylated the acylating reagent in the presence of pyridine. Sometimes, building blocks can also be utilized as glycosyl acceptors, for more reactive nucleophilic catalysts such as DMAP are also example, for the synthesis of branched glycan sequences. employed. In 1975, Williams and co-workers observed that Alternatively, the diols are useful synthetic intermediates for benzoylation of α-D-glucose with benzoyl chloride (4.2 equiv) further transformations because the differentiation between in anhydrous pyridine at -35 oC provided 1,2,3,6-tetrabenzoate two hydroxyls is typically much simpler than that of fully (4-OH derivative) 2 in 37% yield (Scheme 3). When similar unprotected sugars containing four or more hydroxyls. conditions were applied to α-D-mannose, the respective 4-OH 21 Inherent difference in reactivity of various hydroxyl groups in derivative 3 was obtained in 51% yield. The synthesis of carbohydrates have been investigated to achieve selective 1,2,3,6-tetrabenzoate 4 from α-D-galactose using benzoyl protection. Primary hydroxyl groups are sterically less chloride in pyridine at low temperature was achieved in 38% 22,23 hindered than their secondary counterparts, which offers an yield. These results clearly demonstrate that 4-OH is opportunity for their regioselective protection.17 The best- typically the least reactive hydroxyl access these sugar series. known examples is the use of bulky (trityl, silyl) protecting In contrast, a very recent report describes selective groups to selectively protect primary hydroxyl groups in the benzoylations of various α-D-galactopyranosides 5 with presence of secondary ones. Steric hindrance, as well as the benzoyl cyanide to produce 3-OH compound 6 in good yields 24 electronic effects, can also be utilized to some extent to of 61-67%. The regioselectivity achieved was rationalized by discriminate between certain secondary hydroxyl groups.18 In the existence of the “cyanide effect” that favors 4-O- addition, hydrogen bond networks were also proposed as a benzoylation and “the alkoxy group mediated diol effect” that possible driving force for the regioselective protection. favors 2-O-benzoylation with BzCN in the presence of DMAP. Early studies by Williams and co-workers revealed general An efficient method for regioselective benzoylation of diols 25 reactivity trends of various hydroxyls.19 These studies also gave and polyols was developed by Dong and co-workers. This an appreciation that even similarly positioned hydroxyls of regioselective method does not rely on any amine bases or different sugar series may have different reactivities towards metal-based catalysts. Thus, benzoylation of methyl regioselective protection. Thus, the order of reactivity towards glycosides of the D-gluco, D-galacto, and D-manno series with benzoylation was determined to be: 2-OH > 3-OH > 4-OH for benzoic anhydride catalyzed by tetrabutylammonium D-gluco, 3-OH > 2-OH > 4-OH for D-manno, and 2-OH, 3-OH benzoate led to 2,4-diols in 70-91% yield. > 4-OH for the D-galacto series. In 1990, Hanessian attempted Tin-mediated acylation was initially developed and used for partial acetylation of methyl α-D-glucopyranoside 1 with and monoacylations of polyhydroxylated compounds.26,27 The tin- without the use of zinc chloride additive.20 Compared with the mediated reactions of carbohydrates with
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