Synthesis of Carbohydrate Building Blocks Via Regioselective Uniform Protection/Deprotection Strategies Tinghua Wang and Alexei V
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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, Mis- souri 63121, USA 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 process need to be left unprotected or regioselectively liberated. Therefore, it is significant to develop regioselective methods to 1. Introduction and basic considerations simplify the preparation of partially or differentially substituted 2. Synthesis of partially substituted building blocks by uni- synthetic intermediates.4 As a consequence, regioselective protec- form regioselective protection tion and deprotection of carbohydrates has been a vibrant area of 2.1 Ester groups research. Orthogonal or selectively removable protecting group 2.2 Alkyl and silyl groups manipulations have been extensively employed in oligosaccharide 2.3 Cyclic groups synthesis.5,6 However, these strategies require a specialized 3. Synthesis of partially substituted building blocks by re- knowledge of various protecting groups, reaction conditions for gioselective deprotection of uniformly protected sub- their installation and removal, and application strategies to differ- strates ent sugar series. 3.1 Ester group removal and migration 3.2 Ether group removal Despite a significant progress in this area, and the availability of 3.3 Cyclic group removal and opening streamlining one-pot processes,7-12 in a majority of the applications 4. Conclusions and outlook a large number of protecting group manipulation steps are required 5. References to obtain the desired regioselectively substituted product. While or- thogonal, semi-orthogonal, or selectively removable protecting groups represent a very important direction of carbohydrate synthe- 1. Introduction and basic considerations sis, discussed herein in the synthesis of partially protected carbo- hydrates by manipulating only one type of a protecting group for a Carbohydrates are the most abundant molecules among the four es- given derivative. While some overlap with orthogonal protecting sential classes of biomolecules that also include nucleic acids, li- group strategies is inevitable, a more comprehensive coverage of pids, and proteins. Unlike proteins and nucleic acids, which follow the topic is available in a number of excellent recent reviews.5,10,13- template-driven synthetic pathways, there is no general route to the 16 Two major focuses of this review article are depicted in Scheme synthesis of carbohydrates. Monosaccharides are polyhydroxylated 1. The first focus is the protection of the unprotected starting mate- molecules, and regioselective protection and deprotection of spe- rial in the way that only one (or two) hydroxyl groups remain un- cific hydroxyl groups over others represents one of the major chal- 1-3 protected. The second focus leads to the formation of the same type lenges in carbohydrate chemistry. During sequencing of simple of derivatives, but it rather involves regioselective partial deprotec- monosaccharides into larger oligomeric networks, most of the func- tion of uniformly protected compounds. At times, we chose to dis- tional groups need to be temporarily blocked by protecting groups. cuss these two major focus areas in application to differentially On the other hand, functional groups involved in the coupling protected carbohydrates. These examples include some new reac- This section is focused on discussing those methods wherein the tions that have only been applied to such molecules, but in our opin- unprotected (or polyol) starting material is regioselectively pro- ion could also be generally relevant to the uniformly protected sys- tected in the way that only one (or two) hydroxyl groups remain tems. unprotected. Scheme 1. The overview of protecting group strategies de- 2.1. Ester groups scribed herein Ester protecting groups are ubiquitous in carbohydrate chemistry because acylation of hydroxyl groups is typically an efficient and high-yielding process. Common methods of esterification utilize an acid chloride or an acid anhydride as the acylating reagent in the presence of pyridine. Sometimes, more reactive nucleophilic cata- lysts such as DMAP are also employed. In 1975, Williams and co- workers observed that benzoylation of α-D-glucose with benzoyl chloride (4.2 equiv) in anhydrous pyridine at -35 oC provided 1,2,3,6-tetrabenzoate (4-OH derivative) 2 in 37% yield (Scheme 3). The application of partially protected building blocks is fundamen- When similar conditions were applied to α-D-mannose, the respec- tal to oligosaccharide synthesis. Mono-hydroxylated building tive 4-OH derivative 3 was obtained in 51% yield.21 The synthesis blocks can be directly utilized as glycosyl acceptors in glycosyla- of 1,2,3,6-tetrabenzoate 4 from α-D-galactose using benzoyl chlo- tion reactions. Di-hydroxylated building blocks can also be utilized ride in pyridine at low temperature was achieved in 38% yield.22,23 as glycosyl acceptors, for example, for the synthesis of branched These results clearly demonstrate that 4-OH is typically the least glycan sequences. Alternatively, the diols are useful synthetic in- reactive hydroxyl access these sugar series. In contrast, a very re- termediates for further transformations because the differentiation cent report describes selective benzoylations of various α-D-galac- between two hydroxyls is typically much simpler than that of fully topyranosides 5 with benzoyl cyanide to produce 3-OH compound unprotected sugars containing four or more hydroxyls. 6 in good yields of 61-67%.24 The regioselectivity achieved was Inherent difference in reactivity of various hydroxyl groups in car- rationalized by the existence of the “cyanide effect” that favors 4- bohydrates have been investigated to achieve selective protection. O-benzoylation and “the alkoxy group mediated diol effect” that Primary hydroxyl groups are sterically less hindered than their sec- favors 2-O-benzoylation with BzCN in the presence of DMAP. ondary counterparts, which offers an opportunity for their regiose- An efficient method for regioselective benzoylation of diols and lective protection.17 The best-known examples is the use of bulky polyols was developed by Dong and co-workers.25 This regioselec- (trityl, silyl) protecting groups to selectively protect primary hy- tive method does not rely on any amine bases or metal-based cata- droxyl groups in the presence of secondary ones. Steric hindrance, lysts. Thus, benzoylation of methyl glycosides of the D-gluco, D- as well as the electronic effects, can also be utilized to some extent galacto, and D-manno series with benzoic anhydride catalyzed by to discriminate between certain secondary hydroxyl groups.18 In tetrabutylammonium benzoate led to 2,4-diols in 70-91% yield. addition, hydrogen bond networks were also proposed as a possible driving force for the regioselective protection. Tin-mediated acylation was initially developed and used for mon- oacylations of polyhydroxylated compounds.26,27 The tin-mediated Early studies by Williams and co-workers revealed general reactiv- reactions of carbohydrates with acylating reagents has been an ity trends of various hydroxyls.19 These studies also gave an appre- effective way to acheive differentiation between 1,2- and 1,3-diol ciation that even similarly positioned hydroxyls of different sugar pairs.28 More recently, Zhang and Wong performed regioselective series may have different reactivities towards regioselective protec- polyacylation reactions of various sugars using an excess of BzCl tion. Thus, the order of reactivity towards benzoylation was deter- o 29 and Bu2SnO at higher temperatures (70-100 C). The stannylene mined to be: 2-OH > 3-OH > 4-OH for D-gluco, 3-OH > 2-OH > acetal was proposed as an intermediate of the reaction of methyl α- 4-OH for D-manno, and 2-OH, 3-OH > 4-OH for the D-galacto se- D-glucopyranoside 1 with O-2 coordinating with the anomeric ries. In 1990, Hanessian attempted partial acetylation of methyl α- methoxy and O-6 coordinating with the ring oxygen. This reaction D-glucopyranoside 1 with and without the use of zinc chloride ad- produced 4-OH glucoside 7 with high regioselectivity in 91% yield ditive.20 Compared with the control experiment, the addition 1 (Scheme 3). Interestingly, while a comparable outcome was equiv of zinc(II) chloride enhanced the selectivity of the formation achieved with the D-manno substrate, the D-galacto counterpart of the 3,4-diol product (Scheme 2). However, the regioselectivity gave much lower regioselectivity.29 Tosylation and benzylation can and the product distribution was below preparative value for main- also be achieved regioselectively using a similar approach.30 The stream application in carbohydrate synthesis. This example clearly principles and applications of tin-mediated reactions