Review y Addition of Heteroatom Radicals to endo-Glycals Torsten Linker Department of Chemistry, University of Potsdam, Karl-Liebknecht-Str. 24-25, 14476 Golm, Germany; [email protected]; Tel.: +49 331 9775212 Dedicated to Bernd Giese on the occasion of his 80th birthday and his pioneering work on radicals in y carbohydrate chemistry. Received: 6 February 2020; Accepted: 18 February 2020; Published: 20 February 2020 Abstract: Radical reactions have found many applications in carbohydrate chemistry, especially in the construction of carbon–carbon bonds. The formation of carbon–heteroatom bonds has been less intensively studied. This mini-review will summarize the efforts to add heteroatom radicals to unsaturated carbohydrates like endo-glycals. Starting from early examples, developed more than 50 years ago, the importance of such reactions for carbohydrate chemistry and recent applications will be discussed. After a short introduction, the mini-review is divided in sub-chapters according to the heteroatoms halogen, nitrogen, phosphorus, and sulfur. The mechanisms of radical generation by chemical or photochemical processes and the subsequent reactions of the radicals at the 1-position will be discussed. This mini-review cannot cover all aspects of heteroatom-centered radicals in carbohydrate chemistry, but should provide an overview of the various strategies and future perspectives. Keywords: radicals; carbohydrates; heteroatoms; synthesis 1. Introduction Radical reactions of carbohydrates are important for chemistry, biology, and medicine. For example, free radicals are involved in several biosynthetic pathways or are used for cancer-treatment [1–4]. On the other hand, radiation can cause DNA strand break by H atom abstraction and radical generation at the sugar backbone [5–7]. Bernd Giese’s group proved that radical cations are involved in the mechanism [8] and investigated how the positive charge is transferred through the DNA [9]. For synthetic applications, Bernd Giese’s group also made carbohydrate radicals available for the formation of carbon–carbon bonds under mild conditions [10]. Due to steric interactions, carbohydrates provide high stereoselectivities [11,12], and the importance of such reactions has been reviewed many times [13–18]. Furthermore, under appropriate conditions, 2-deoxy sugars can be synthesized from bromo sugars in only one step [19]. To develop efficient radical reactions, it is important to understand the reactivities of the corresponding radicals [12,20,21]. Thus, such reactive species can have a nucleophilic or an electrophilic character [22], which controls their addition to alkenes. Applied to the anomeric center of carbohydrates, the radicals 1 exhibit a nucleophilic character due to the adjacent oxygen atom, and add preferentially to electron poor double bonds with electron withdrawing (EWG) and nondonating (EDG) groups (Scheme1a). If the carbohydrate is used as radical acceptor, unsaturated carbohydrates like endo-glycals 2 become attractive substrates, which can be easily synthesized on a large scale [23]. However, once the double bond becomes electron rich the reaction proceeds only with electrophilic radicals (Scheme1b). Chemistry 2020, 2, 80–92; doi:10.3390/chemistry2010008 www.mdpi.com/journal/chemistry Chemistry 2020, 2, 80–92 81 Chemistry 2020, 2 81 Chemistry 2020, 2, 80–92 81 Scheme 1. Examples for radical reactions in carbohydrate chemistry: (a) starting from a carbohydrate radical 1 and (b) radical additions to glycals 2. Scheme 1. ExamplesExamples for radical reactions in carbohydrate chemistry: ( a)) starting starting from from a carbohydrate carbohydrate radical 1 and (b) radical additions to glycals 2.. During the last 25 years, we developed C-C bond formations by the addition of electrophilic radicals,During mainly thethe last derivedlast 25 25 years, years, from we malonates,we developed developed to C-C glycals C-C bond bond formations2 with formations various by the further by addition the synthetic addition of electrophilic transformations of electrophilic radicals, [24–27].radicals,mainly derivedHowever, mainly fromderived the malonates,addition from malonates, ofto heteroatom glycals to2 glycalswith radicals various 2 with to glycals furthervarious is synthetic veryfurther attractive synthetic transformations as transformationswell, since [24 such–27]. radicals[24–27].However, However,exhibit the addition the the required addition of heteroatom electrophilic of heteroatom radicals characte toradicals glycalsr [22,28]. to is glycals very On attractivethe is very other attractive ashand, well, heteroatom sinceas well, such since radicals such areradicalsexhibit prone the exhibit to required undergo the electrophilicrequired H atom electrophilic abstraction, character [characte22 which,28]. Onr is[22,28]. theproblematic other On hand, the inother heteroatom carbohydrate hand, heteroatom radicals chemistry are proneradicals with to variousareundergo prone functional H to atom undergo abstraction, groups. H atom Thus, which abstraction, although is problematic al koxylwhich inradicals is carbohydrate problematic [29] can chemistrybein generatedcarbohydrate with from various chemistry carbohydrates functional with andvariousgroups. undergo functional Thus, fast although fragmentations groups. alkoxyl Thus, radicals although[30,31], [of29 al the]koxyl can way be radicals in generated which [29] such fromcan radicals be carbohydrates generated can be from added and carbohydrates undergo to glycals fast is unknown.andfragmentations undergo Since fast [30halogen fragmentations,31], of atoms, the way nitrogen-, [30,31], in which of phosphorthe such way radicals inus-, which and can suchsulfur-centered be added radicals to glycals can radicals be isadded unknown. are to less glycals prone Since is tounknown.halogen undergo atoms, Since H atom nitrogen-, halogen abstraction, atoms, phosphorus-, nitrogen-, this mini-review and phosphor sulfur-centered wius-,ll focusand radicals sulfur-centered on the are lessaddition prone radicals of to such undergo are radicals less H prone atom to endotoabstraction, undergo-glycals. this H atom mini-review abstraction, will focusthis mini-review on the addition will of focus such radicalson the addition to endo-glycals. of such radicals to endo-glycals. 2. Addition Addition of of Halogen Halogen Atoms Atoms 2. AdditionThe halogenation of Halogen of ofAtoms endoendo-glycals-glycals 22 isis one of the oldest transformationstransformations of such unsaturated carbohydrates,The halogenation already already ofdescribed described endo-glycals by by Lemieux 2 is one inof 1965the oldest [[32].32]. Thus, Thus,transfor tri- tri-mationsOO-acetyl--acetyl- ofDd-glucal -glucalsuch unsaturated ( (2a2a)) or or the corresponding isomer tri-O-acetyl-Dd-galactal (2b) reacted with chlorine or bromine in high yields to carbohydrates,corresponding isomeralready tri- describedO-acetyl- by-galactal Lemieux (2b in) reacted1965 [32]. with Thus, chlorine tri-O or-acetyl- bromineD-glucal in high (2a yields) or the to the main products 3a and 3b (Scheme 2). correspondingthe main products isomer3a and tri-O3b-acetyl-(SchemeD-galactal2). (2b) reacted with chlorine or bromine in high yields to the main products 3a and 3b (Scheme 2). Scheme 2. HalogenationHalogenation of of glycals glycals 2a2a andand 2b2b.. Scheme 2. Halogenation of glycals 2a and 2b. Although the authors proposed an ionic pathway via halonium ions, the 1,2-cis-configurations-configurations might bebe explained explained by by homolysis homolysis of the of labile the halogenlabile halogen bonds andbonds addition and ofaddition the resulting of the electrophilic resulting radicals.Although To distinguish the authors between proposed a radical an ionic or an pathway ionic pathway, via halonium halogen ions, azides the are 1,2- attractivecis-configurations precursors electrophilicmight be explained radicals. byTo homolysisdistinguish of between the labile a radical halogen or anbonds ionic and pathway, addition halogen of the azides resulting are attractivebecause they precursors easily undergo because homolysis they easily and are undergo used in regio-homolysis and stereoselective and are used syntheses in regio- [33]. Thus,and electrophilicreaction of tri- radicals.O-acetyl- Tod-glucal distinguish (2a) with between chlorine a azideradical aff ororded an ionic regioisomers pathway,4 and halogen5, depending azides are on stereoselectiveattractive precursors syntheses because [33]. Thus,they easilyreaction undergo of tri- Ohomolysis-acetyl-D-glucal and are(2a) usedwith chlorinein regio- azide and affordedthe reaction regioisomers conditions 4 (Scheme and 5, depending3)[34]. on the reaction conditions (Scheme 3) [34]. stereoselective syntheses [33]. Thus, reaction of tri-O-acetyl-D-glucal (2a) with chlorine azide afforded regioisomers 4 and 5, depending on the reaction conditions (Scheme 3) [34]. Chemistry 2020, 2, 80–92 82 Chemistry 2020, 2, 80–92 82 Scheme 3. Reaction of tri-O-acetyl-D-glucal (2a) with chlorine azide. Scheme 3. ReactionReaction of tri- O-acetyl--acetyl-Dd-glucal ( 2a) with chlorine azide. In the dark, 2-chloro-2-deoxy sugars 4 were isolated as main products, whereas irradiation gave In the dark, 2-chloro-2-deoxy sugars 4 were isolated as main products, whereas irradiation gave the 2-azido-2-deoxy isomer 5. Such different regioselectivities were explained by an ionic pathway the 2-azido-2-deoxy2-azido-2-deoxy isomerisomer5 5.. Such Such di differentfferent regioselectivities regioselectivities