Science, Faculty of
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Earth, Ocean and Atmospheric Sciences, Department of
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Reactions 6 (1): 3 (2025)
Dubbu, Sateesh
Jampani, Santhi
The synthesis of natural and unconventional compounds with carbohydrate structures is of great interest to glycochemists due to their vital biological roles. In recent years, there has been significant progress in developing direct and indirect synthetic strategies for constructing sugar moieties. Among these methods, the Prins reaction, employing homoallylic alcohols and carbonyl compounds, has proven invaluable for directly creating sugar skeletons. This review discusses approaches for crafting carbohydrate frameworks using the Prins reaction, utilizing both carbohydrate and non-carbohydrate starting materials.
Academic Editor: Silvana PedatellaReceived: 10 November 2024Revised: 21 December 2024Accepted: 24 December 2024Published: 3 January 2025Citation: Dubbu, S.; Jampani, S.Advancements in CarbohydrateScaffold Synthesis: Exploring PrinsCyclization Methodology. Reactions2025, 6, 3. https://doi.org/10.3390/reactions6010003Copyright: © 2025 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license(https://creativecommons.org/licenses/by/4.0/).ReviewAdvancements in Carbohydrate Scaffold Synthesis: ExploringPrins Cyclization MethodologySateesh Dubbu 1,* and Santhi Jampani 21 Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, IL 61801, USA2 Department of Earth, Ocean & Atmospheric Sciences, The University of British Columbia,Vancouver, BC V6T 1Z1, Canada* Correspondence: sateeshd@illinois.eduAbstract: The synthesis of natural and unconventional compounds with carbohydrate struc-tures is of great interest to glycochemists due to their vital biological roles. In recent years,there has been significant progress in developing direct and indirect synthetic strategies forconstructing sugar moieties. Among these methods, the Prins reaction, employing homoal-lylic alcohols and carbonyl compounds, has proven invaluable for directly creating sugarskeletons. This review discusses approaches for crafting carbohydrate frameworks usingthe Prins reaction, utilizing both carbohydrate and non-carbohydrate starting materials.Keywords: carbohydrates; Prins reaction; 2-deoxysuagrs; homoallylic alcohols; rare sugars1. IntroductionCarbohydrates are fundamental biomolecules that play a multitude of vital roles inliving systems, including cell growth, proliferation, immune responses, cell adhesion, andcell–cell communication [1–7]. Their diverse functions make them crucial for maintainingthe structural and functional integrity of biological processes. In biological systems, carbo-hydrates exist in various forms, with many found as oligosaccharides bound to lipids orproteins. These complexes, collectively termed glycoconjugates, are essential for mediatingbiological recognition events such as immune signaling and pathogen-host interactions.Glycoconjugates are classified based on the nature of their glycosidic linkages, which canbe N-, O-, C-, or S-linked glycosides [8–12]. The synthesis and modification of these carbo-hydrate structures remain a cornerstone of chemical biology and medicinal chemistry, astheir applications span pharmaceuticals, materials science, and biotechnology.Designing novel synthetic strategies for carbohydrates is an active area of researchdue to their immense structural complexity and the challenges of achieving stereoselec-tivity during synthesis. One of the most critical challenges in carbohydrate chemistry isthe construction of pyran (six-membered) and furan (five-membered) rings, which arecommon structural motifs in natural products, glycoconjugates, and various biologicallyactive compounds [13–18]. Achieving the stereoselective synthesis of these rings undermild conditions is a central goal in organic synthesis. Among the various approachesdeveloped to address this challenge, the Prins reaction stands out as a highly efficient andversatile method.The Prins reaction [19–27] has emerged as a key tool for the stereoselective forma-tion of tetrahydropyran (THP) and tetrahydrofuran (THF) rings. This reaction involvesthe condensation of homoallylic alcohols with carbonyl compounds in the presence of aBrønsted or Lewis acid catalyst. Over the last few decades, the Prins reaction has gainedconsiderable attention due to its ability to provide access to a wide variety of functionalizedReactions 2025, 6, 3 https://doi.org/10.3390/reactions6010003Reactions 2025, 6, 3 2 of 22cyclic compounds. Numerous natural products and bioactive molecules containing THPrings have been synthesized using Prins methodology (Figure 1) such as Clavosolide A 1,Cryptophycin-24 2, and (-)-Ploycaverrnoside A 3 [28–30].Reactions 2025, 6, x FOR PEER REVIEW 2 of 23 The Prins reaction [19–27] has emerged as a key tool for the stereoselective formation of tetrahydropyran (THP) and tetrahydrofuran (THF) rings. This reaction involves the condensation of homoallylic alcohols with carbonyl compounds in the presence of a Brønsted or Lewis acid catalyst. Over the last few decades, the Prins reaction has gained considerable attention due to its ability to provide access to a wide variety of functional-ized cyclic compounds. Numerous n tural products and bioactive mol cules containing THP rings have bee synthesized using Prins methodology (Figure 1) such as Clavosolide A 1, Cry tophycin-24 2, and (-)-Ploycaverrnoside A 3 [28–30]. Figure 1. Synthesis of natural products by using Prins reaction. The renewed interest in the Prins reaction stems from its ability to generate multi-functionalized carbohydrate scaffolds with diverse applications. A typical (Scheme 1) re-action pathway [31,32] involves the interaction of homoallylic alcohols 4 and carbonyl compounds in the presence of an acid catalyst, leading to the formation of an oxocarbe-nium ion intermediate 5. This intermediate undergoes π-cation cyclization, resulting in the formation of a tetrahydropyran intermediate 5a; then, through a nucleophilic attack, either the reaction proceeds intramolecularly or intermolecularly, which subsequently produces a highly functionalized and more complex molecular architecture 6. On the other hand, this intermediate 5a may undergo a pinacol-type rearrangement through 7, yielding tetrahydrofuran derivatives 8. Alternatively, the tetrahydropyran intermediate 5a C2-H elimination yields cycloalkene products or Ferrier products 9. This versatility makes the Prins reaction a valuable tool in synthetic organic chemistry Developing efficient methods for synthesizing rare sugars is another crucial aspect of carbohydrate chemistry [33–35]. Rare sugars such as altrose and allose, while less abun-dant in nature, exhibit unique biological properties that make them attractive for thera-peutic and industrial applications. The Prins reaction has proven to be a versatile method for accessing these rare sugar scaffolds, enabling chemists to explore their potential in drug discovery and other fields [36]. Figure 1. Synthesis of natural products by using Prins reaction.The renewed interest in the Prins reaction stems from its ability to generate multi-functionalized carbohydrate scaffolds with diverse applications. A typical (Scheme 1)reaction pathway [31,32] involves the interaction of homoallylic alcohols 4 and carbonylcompounds in the presence of an acid catalyst, leading to the formation of an oxocarbe-nium ion intermediate 5. This intermediate undergoes π-cation cyclization, resulting inthe formation of a tetrahydropyran intermediate 5a; then, through a nucleophilic attack,either the reaction proceeds intramolecularly or intermolecularly, which subsequentlyproduces a highly functionalized and more complex molecular architecture 6. On the otherhand, this intermediate 5a may undergo a pinacol-type rearrangement through 7, yieldingtetrahydrofuran derivatives 8. Alternatively, the tetrahydropyran intermediate 5a C2-Helimination yields cycloalkene products or Ferrier products 9. This versatility makes thePrins reaction a valuable tool in synthetic organic chemistry.Developing efficient methods for synthesizing rare sugars is another crucial aspect ofcarbohydrate chemistry [33–35]. Rare sugars such as altrose and allose, while less abundantin nature, exhibit unique biological properties that make them attractive for therapeuticand industrial applications. The Prins reaction has proven to be a versatile method foraccessing these rare sugar scaffolds, enabling chemists to explore their potential in drugdiscovery and other fields [36].Although various reviews have covered synthetic transformations of unique carbohydrate-based scaffolds, such as the carbohydrate dienes [37], 1,2- and 1,6-anhydrosugars [38,39],glycal functionalization [40–42] and C-H activations [43,44], hypervalent iodine in glyco-chemistry [45], and functionalization of 3-oxo-glycals [46], to the best of our knowledge, thechemistry of the Prins reaction in carbohydrate chemistry has not been reviewed recently.Given the progress made over the past several decades, and the great utility of the Prinsreaction in carbohydrate chemistry as important building blocks, this review highlights theReactions 2025, 6, 3 3 of 22strategic importance of the Prins reaction in the synthesis of carbohydrate moieties. Thediscussion is structured around the methods used to construct the extended carbohydratecore, with a focus on the number and type of bonds formed during the critical syntheticstep. By providing an overview of the main strategies, this work underscores the utility ofthe Prins reaction as a cornerstone for advancing carbohydrate chemistry.Reactions 2025, 6, x FOR PEER REVIEW 3 of 23 Scheme 1. General mechanism for the synthesis of carbohydrate skeleton through Prins reaction. Although various reviews have covered synthetic transformations of unique carbo-hydrate-based scaffolds, such as the carbohydrate dienes [37], 1,2- and 1,6-anhydrosugars [38,39], glycal functionalization [40–42] and C-H activations [43,44], hypervalent iodine in glycochemistry [45], and functionalization of 3-oxo-glycals [46], to the best of our knowledge, the chemistry of the Prins reaction in carbohydrate chemistry has not been reviewed recently. Given the progress made over the past several decades, and the great utility of the Prins reaction in carbohydrate chemistry as important building blocks, this review highlights the strategic importance of the Prins reaction in the synthesis of carbo-hydrate moieties. The discussion is structured around the methods used to construct the extended carbohydrate core, with a focus on the number and type of bonds formed during the critical synthetic step. By providing an overview of the main strategies, this work un-derscores the utility of the Prins reaction as a cornerstone for advancing carbohydrate chemistry. There is currently a wealth of inter and intramolecular Prins reactions available within the modern synthetic chemist’s “toolbox.” However, among the most prevalent Prins reaction types is the addition of a nucleophiles to a secondary carbocation (typically alkenes or alkynes), pinacol-type rearrangement, Sakurai–Prins reaction, and Ritter–Prins reaction. Within the context of sugar moiety synthesis via Prins cyclization and based on the origin synthon of homoallylic alcohols, these reactions are divided into two distinct subclasses: those in which a synthesis of carbohydrate scaffolds from carbohydrate synthons (2) and those in which a carbohydrate scaffolds from non-carbohydrate synthons (3). 2. Carbohydrate Synthons to Carbohydrate Scaffolds This section summarizes research that focuses on generating valuable carbohydrate scaffolds or structural units using carbohydrate-derived starting materials, particularly carbohydrate-derived homoallylic alcohols, through a process called Prins cyclization. In this specific study conducted by Yadav and colleagues, they reported [47] the synthesis of a sugar-annulated iodotetrahydropyran compound 12 by employing Prins cyclization. They combined a D-glucose-derived homoallylic alcohol 10 with an aldehyde 11 in their synthetic approach (Scheme 2). The researchers explored the use of a variety of aromatic and aliphatic aldehydes as reactants in their experiments. Importantly, they successfully obtained the desired products in moderate to good yields, indicating the effectiveness of their synthesis method. The authors of this study proposed a reaction mechanism that Sche e 1. General mechanis for the synthesis of carbohydrate skeleton through Prins reaction.There is currently a wealth of inter and intramolecular Prins reactions available withinthe modern synthetic chemist’s “toolbox.” However, among the most prevalent Prinsreaction types is the addition of a nucleophiles to a secondary carbocation (typically alkenesor alkynes), pinacol-type rearrangement, Sakurai–Prins reaction, and Ritter–Prins reaction.Within the context of sugar moiety synthesis via Prins cyclization and based on the originsynthon of homoallylic alcohols, these reactions are divided into two distinct subclasses:those in which a synthesis of carbohydrate scaffolds from carbohydrate synthons (2) andthose in which a carbohydrate scaffolds from non-carbohydrate synthons (3).2. Carbohydrate Synthons to Carbohydrate ScaffoldsThis section summarizes research that focuses on generating valuable carbohydratescaffolds or structural units using carbohydrate-derived starting materials, particularlycarbohydrate-derived homoallylic alcohols, through a process called Prins cyclization. Inthis specific study conducted by Yadav and colleagues, they reported [47] the synthesisof a sugar-annulated iodotetrahydropyran compound 12 by employing Prins cyclization.They combined a D-glucose-derived homoallylic alcohol 10 with an aldehyde 11 in theirsynthetic approach (Scheme 2). The researchers explored the use of a variety of aromaticand aliphatic aldehydes as reactants in their experiments. Importantly, they successfullyobtained the desired products in moderate to good yields, indicating the effectiveness oftheir synthesis method. The authors of this study proposed a reaction mechanism thatinvolves an intermediate X and a highly reactive carbocation Y. This carbocation Y issubsequently captured by an iodide ion, resulting in the formation of the sugar-annulatediodotetrahydropyran compound 12.Reactions 2025, 6, 3 4 of 22Reactions 2025, 6, x FOR PEER REVIEW 4 of 23 involves an intermediate X and a highly reactive carbocation Y. This carbocation Y is sub-sequently captured by an iodide ion, resulting in the formation of the sugar-annulated iodotetrahydropyran compound 12. Scheme 2. Synthesis of sugar annulated iodotetrahydropyrons. In a subsequent study, the same research group delved deeper into the Prins reaction of homoallylic alcohol 10, as shown in Scheme 3. They investigated this reaction with var-ious carbonyl compounds 11, employing BF3·OEt2 as a catalyst and various arene (Scheme 3). Scheme 2. Synthesis of sugar annulated iodotetrahydropyrons.In a subsequent study, the same research group delved deeper into the Prins reaction ofhomoallylic alcohol 10, as shown in Scheme 3. They investigated this reaction with variouscarbonyl compounds 11, employing BF3·OEt2 as a catalyst and various arene (Scheme 3).Reactions 2025, 6, x FOR PEER REVIEW 4 of 23 involves an intermediate X and a highly reactive carbocation Y. This carbocation Y is sub-sequently captured by an iodide ion, resulting in the formation of the sugar-annulated iodotetrahydropyran compound 12. Scheme 2. Synthesis of sugar annulated iodotetrahydropyrons. In a subs quent study, th same resea ch group delved deeper into the Prins reaction of homoallylic alcohol 10, as shown in Scheme 3. They investigated this reaction with var-ious carbonyl compounds 11, employing BF3·OEt2 as a catalyst and various arene (Scheme 3). Scheme 3. Synthesis of sugar-fused diaryl hexahydro-2H-furo [3,2-b]pyran.Reactions 2025, 6, 3 5 of 22In a subsequent study, the same research group [48] conducted an in-depth investi-gation of the Prins/Friedel–Crafts cyclization of homoallylic alcohol 10, as illustrated inScheme 3. They explored the reaction of a homoallylic alcohol 10 derived from D-glucosewith various carbonyl compounds 11, using benzene as the solvent and a catalytic amountof BF3·OEt2 (0.1 equiv). The reaction proceeded efficiently at 25 ◦C, yielding the corre-sponding sugar-fused diaryl hexahydro-2H-furo [3,2-b]pyran 13 via intermediate III ingood to excellent yields, with complete cis-selectivity (Scheme 3).The authors specifically aimed to trap the tetrahydropyranyl carbocation using ben-zene as the C-nucleophile. Notably, they also investigated the reaction in other arenesolvents, including benzene, toluene, o-xylene, and anisole. The reaction demonstratedcompatibility with a wide range of aryl and alkyl aldehydes as well as cyclohexanone. Inter-estingly, one of the products was further converted into diaryl dihydroxytetrahydropyran14, a C-aryl glycoside (Scheme 4).Reactions 2025, 6, x FOR PEER REVIEW 5 of 23 Scheme 3. Synthesis of sugar-fused diaryl hexahydro-2H-furo [3,2-b]pyran. In a subsequent study, the same research group [48] conducted an in-depth investi-gation of the Prins/Friedel–Crafts cyclization of homoallylic alcohol 10, as illustrated in Scheme 3. They explored the reaction of a homoallylic alcohol 10 derived from D-glucose with various carbon l compounds 11, sing be zene s the solvent and a catalytic amount of BF3·OEt2 (0.1 equiv). The reaction proceeded efficiently at 25 °C, yielding the corre-sponding sugar-fused diaryl hexahydro-2H-furo [3,2-b]pyran 13 via intermediate III in good to excellent yields, with complete cis-selectivity (Scheme 3). The authors specificall aimed t trap the tetrahydropyr nyl carbocation using ben-zene as the C-nucleophile. Notably, they also investigated the reaction in other arene sol-vents, including benzene, toluene, o-xylene, and anisole. The reaction demonstrated com-patibility with a wid rang f aryl an lkyl ald hydes as well s cyclohexanone. Inter-estingly, one of the products was further converted into diaryl dihydroxytetrahydropyran 14, a C-aryl glycoside (Scheme 4). Scheme 4. Synthesis of sugar-fused diaryl hexahydro-2H-furo [3,2-b]pyran 14. Reddy et al. reported [49] the synthesis of the hexahydro-2H-furo [3,2-b]pyranopyran scaffold 16 from O-prenyl tethered carbohydrate-derived aldehyde 15 with various alde-hydes in the presence of 10 mol% Sc(OTf)3 in dichloromethane at 0 °C to room temperature (Scheme 5). Further, this reaction was studied with a variety of aryl and alkyl aldehydes. Eventually, this reaction was quite successful with p-bromobenzaldehyde and cyclo-hexylidene protected O-prenyl tethered carbohydrate-derived aldehyde to furnish the product tricyclic sugar derivative 16 (Scheme 5). Scheme 4. Synthesis of sugar-fused diaryl hexahydro-2H-furo [3,2-b]pyran 14.Reddy et al. reported [49] the synthesis of the hexahydro-2H-furo [3,2-b]pyranopyranscaffold 16 from O-prenyl tethered carbohydrate-derived aldehyde 15 with various aldehy-des in the presence of 10 mol% Sc(OTf)3 in dichloromethane at 0 ◦C to room temperature(S heme 5). Further, this reaction was studied with a variety of aryl and alkyl aldehyd s.Eventually, this reaction was quite successful with p-bromobenzaldehyde and cyclohexyli-dene protected O-prenyl tethered carbohydrate-derived aldehyde to furnish the producttricyclic sugar derivative 16 (Scheme 5).First, cyclization of O-prenyl tethered carbohydrate-derived aldehyde 15 is proposed,facilitate by carbonyl ene reaction and led to homoallylic alcohol A, with this being thePrins reaction defining step. Then A condes with aldehyde in presence of Sc(OTf)3 couldgive tertiary carbocation C via oxocarbenium ion B. Further C could eliminate proton frommethyl group and led to product 16 (Scheme 6).In 2014, Lumba and Mukherjee [50] developed a practical protocol for the conver-sion of tri-O-acetyl-D-glucal-derived 2-C-branched sugars 17 to the corresponding cis-1-oxadecalines 18. By using FeCl3 as a catalyst system at room temperature, the targetmolecules could be afforded (Scheme 7). The advantages of this protocol are the use of avariety of 2-C-branched sugars.Reactions 2025, 6, 3 6 of 22Reactions 2025, 6, x FOR PEER REVIEW 6 of 23 Scheme 5. Synthesis of hexahydro-2H-furo [3,2-b]pyranopyran scaffold. First, cyclization of O-prenyl tethered carbohydrate-derived aldehyde 15 is pro-posed, facilitated by carbonyl ene reaction and led to homoallylic alcohol A, with this be-ing the Prins reaction defining step. Then A condes with aldehyde in presence of Sc(OTf)3 could give tertiary carbocation C via oxocarbenium ion B. Further C could eliminate pro-ton from methyl group and led to product 16 (Scheme 6). Scheme 6. Mechanism for the formation of hexahydro-2H-furo [3,2-b]pyranopyran. In 2014, Lumba and Mukherjee [50] developed a practical protocol for the conversion of tri-O-acetyl-D-glucal-derived 2-C-branched sugars 17 to the corresponding cis-1-oxa-decalines 18. By using FeCl3 as a catalyst system at room temperature, the target molecules could be afforded (Scheme 7). The advantages of this protocol are the use of a variety of 2-C-branched sugars. Scheme 5. Synthesis of hexahydro-2H-furo [3,2-b]pyranopyran scaffold.Reactions 2025, 6, x FOR PEER REVIEW 6 of 23 Scheme 5. Synthesis of hexahydro-2H-furo [3,2-b]pyranopyran scaffold. First, cyclization of O-prenyl tethered carbohydrate-derived aldehyde 15 is pro-posed, facilitated by carbonyl ene reaction and led to homoallylic alcohol A, with this be-ing the Prins reaction defining step. Then A condes with aldehyde in presence of Sc(OTf)3 could give tertiary carbocation C via oxocarbenium ion B. Further C could eliminate pro-ton from methyl group and led to product 16 (Scheme 6). Scheme 6. Mechanism for the formation of hexahydro-2H-furo [3,2-b]pyranopyran. In 2014, Lumba and Mukherjee [50] developed a practical protocol for the conversion of tri-O-acetyl-D-glucal-derived 2-C-branched sugars 17 to the corresponding cis-1-oxa-decalines 18. By using FeCl3 as a catalyst system at room temperature, the target molecules could be afforded (Scheme 7). The advantages of this protocol are the use of a variety of 2-C-branched sugars. Scheme 6. Mechanism for the formation of hexahydro-2H-furo [3,2-b]pyranopyran.Padrón and co-workers [51] reported a simple preparation method for trans-fusedbicyclic tetrahydropyran 21 by iron(lll) catalyzed tandem reaction using tri-O-acetyl-D-glucal-derived homoallylic alcohol 16 and iso-valeraldehyde (Scheme 8). This reactionwas further studied with more complex molecule 19, which is derived from a-methyl-D-glu opyranoside with aldehydes and led to the trans-fus d bicyclic tetrahydropyrans 20.Here, the features are the good substrate generality and the mild reaction conditions.Reactions 2025, 6, 3 7 of 22Reactions 2025, 6, x FOR PEER REVIEW 7 of 23 Scheme 7. Synthesis of cis-1-oxadecalines 17 from 2-C-branched sugar 18. Padrón and co-workers [51] reported a simple preparation method for trans-fused bicyclic tetrahydropyran 21 by iron(lll) catalyzed tandem reaction using tri-O-acetyl-D-glucal-derived homoallylic alcohol 16 and iso-valeraldehyde (Scheme 8). This reaction was further studied with more complex molecule 19, which is derived from a-methyl-D-glucopyranoside with aldehydes and led to the trans-fused bicyclic tetrahydropyrans 20. Here, the features are the good substrate generality and the mild reaction conditions. Scheme 8. Synthesis of trans-fused bicyclic tetrahydropyrans 21 from tri-O-acetyl-D-glucal and α-methyl-D-glucopyranoside. Scheme 7. Synthesis of cis-1-oxadecalines 17 from 2-C-branched sugar 18.Reactions 2025, 6, x FOR PEER REVIEW 7 of 23 Scheme 7. Synthesis of cis-1-oxadecalines 17 from 2-C-branched sugar 18. Padrón and co-workers [51] reported a simple preparation method for trans-fused bicyclic tetrahydropyran 21 by iron(lll) catalyzed tandem reaction using tri-O-acetyl-D-glucal-derived homoallylic alcohol 16 and iso-valeraldehyde (Scheme 8). This reaction was further studied with more complex molecule 19, which is derived from a-methyl-D-glucopyranoside with aldehydes and led to the trans-fused bicyclic tetrahydropyrans 20. Here, the features are the good substrate generality and the mild reaction conditions. Scheme 8. Synthesis of trans-fused bicyclic tetrahydropyrans 21 from tri-O-acetyl-D-glucal and α-methyl-D-glucopyranoside. Scheme 8. Synthesis of trans-fused bicyclic tetrahydropyrans 21 from tri-O-acetyl-D-glucal andα-methyl-D-glucopyranoside.Cis-fused heterobicyclic systems are very important substrates in neuronally activeagents such as marine-derived dysiherbaine and their analogues IKM-159 and MC-27.Reactions 2025, 6, 3 8 of 22Oikawa and co-workers [52] reported a BF3·OEt2 catalyzed condensation reaction betweenglucose-derived enetiomerically pure homoallylic alcohol 22 with aldehydes 11 and nitrilesolvent 23; the intended cis-fused 4-amidotetrahydropyrans 24 were obtained in a one-potmanner under relatively mild conditions (Scheme 9). Based on these results and the scopewas extended to substrate 24 with variety of aldehydes and nitrile solvent via Prins-Ritterreaction to obtained cis-fused heterobicyclics 24 which were further subjected to acidhydrolysis led to the formation for novel glutamates 25.Reactions 2025, 6, x FOR PEER REVIEW 8 of 23 Cis-fused heterobicyclic systems are very important substrates in neuronally active agents such as marine-derived dysiherbaine and their analogues IKM-159 and MC-27. Oi-kawa and co-workers [52] reported a BF3·OEt2 catalyzed condensation reaction between glucose-derived enetiomerically pure homoallylic alcohol 22 with aldehydes 11 and nitrile solvent 23; the intended cis-fused 4-amidotetrahydropyrans 24 were obtained in a one-pot manner under relatively mild conditions (Scheme 9). Based on these results and the scope was extended to substrat 24 with variety of ald hydes and itrile solve t via Prins-Ritter reaction to obtained cis-fused heterobicyclics 24 which were further subjected to acid hydrolysis led to the formation for novel glutamates 25. Scheme 9. Cis-fused 4-amidotetrahydropyrans towards a precursor for possible neuronal receptor ligands via Prins-Ritter reaction. Vankar and co-workers [53] developed an efficient synthesis of bridged tricyclic ket-als 28/29 with good substrate generality starting from homoallylic alcohols 26/27 derived from 1,2-anhydro and aldehydes; they used BF3·OEt2 as the catalyst (Scheme 10). Here, the main advantages include the stereoselectivity and good yields. They proposed the plau-sible mechanism for the formation of bridged tricyclic ketals 28/29. It is presumed(Scheme 11) that after initial formation of the oxocarbenium ion A, it can either undergo Oxonia-Cope rearrangement to form B or simply a π-cation cyclization to form C. Both of these intermediates will then undergo 7-exo trig cyclization or pinacol-type rearrangement via the transition state D, followed by cleavage of the C4-OBn participation resulting in the form of bridged tricyclic ketals 28/29. Later, these bridged tricyclic ketals were converted to (Scheme 12) tetrahydrofuran ring-fused heptose 31 and 2C-branched heptose 32. Scheme 9. Cis-fused 4-amidotetrahydropyrans towards a precursor for possible neuronal receptorligands via Prins-Ritter reaction.Vankar and co-workers [53] developed an efficient synthesis of bridged tricyclic ketals28/29 with good substrate generality starting from homoallylic alcohols 26/27 derivedfrom 1,2-anhydro and aldehydes; they used BF3·OEt2 as the catalyst (Scheme 10). Here, themain advantages include the stereoselectivity and good yields. They proposed the plausiblemechanism for the formation of bridged tricyclic ketals 28/29. It is presumed(Scheme 11)that after initial formation of the oxocarbenium ion A, it can either undergo Oxonia-Cope rearrangement to form B or simply a π-cation cyclization to form C. Both of theseintermediates will then undergo 7-exo trig cyclization or pinacol-type rearrangement viathe t ansition state D, followed by cleavage f the C4-OB par icipation r sulting in theform of bridged tricyclic ketals 28/29. Later, these bridged tricyclic ketals were convertedto (Scheme 12) tetrahydrofuran ring-fused heptose 31 and 2C-branched heptose 32.Reactions 2025, 6, 3 9 of 22Reactions 2025, 6, x FOR PEER REVIEW 9 of 23 Scheme 10. Synthesis of bridged tricyclic ketals 28/29 through Prins-pinacol-type rearrangement and C4-OBn participation. Scheme 11. Mechanism for the formation of bridged tricyclic ketals 30/31. To gain further insights into the proposed mechanism, homoallylic alcohol 26 was treated with acetaldehyde using p-xylene as a solvent and two equivalents of BF3·OEt2 at 0 °C. After 30 min, the p-xylene-trapped product was observed (Scheme 13). This interme-diate was then subjected to hydrogenolysis using Pd(OH)2/C, followed by benzoylation of the resulting alcohol with p-nitrobenzoyl chloride in the presence of Et3N, yielding the corresponding annulated sugar 30. Scheme 10. Synthesis of bridged tricyclic ketals 28/29 through Prins-pinacol-type rearrangementand C4-OBn participation.Reactions 2025, 6, x FOR PEER REVIEW 9 of 23 c e e . t esis f 29 t i l-t e e t a - rti i ti . Scheme 11. Mechanism for the formation of bridged tricyclic ketals 30/31. To gain further insights into the proposed mechanism, homoallylic alcohol 26 was treated with acetaldehyde using p-xylene as a solvent and two equivalents of BF3·OEt2 at 0 °C. After 30 min, the p-xylene-trapped product was observed (Scheme 13). This interme-diate was then subjected to hydrogenolysis using Pd(OH)2/C, followed by benzoylation of the resulting alcohol with p-nitrobenzoyl chloride in the presence of Et3N, yielding the corresponding annulated sugar 30. Sche e 11. echanis for the for ation of bridged tricyclic ketals 30/31.Reactions 2025, 6, x FOR PEER REVIEW 10 of 23 Scheme 12. Derivatization of bridged tricyclic ketal. Scheme 13. Trapping with p-xylene. In 2017, Vankar et al. [54] reported an efficient synthetic route for the preparation of 1C-aryl/alkyl 2C-branched sugar-fused isochroman derivatives 34. The method involved the reaction of homoallylic alcohol 33 and various aldehydes in the presence of BF3·OEt2 in DCM, leading to the formation of 1C-aryl/alkyl 2C-branched sugar-fused isochroman derivatives 34 and intermediate F. Then, the crude reaction mixture was further treated with p-TSA in toluene, yielding exclusively the desired derivative 34. This process achieved moderate reaction times (1 h) with yields ranging from 60–70% (Scheme 14). Scheme 14. Synthesis of 1C-aryl/alkyl 2C-branched sugar-fused isochroman derivatives. In the presence of the BF3·OEt2, substrate 33 and aldehyde were condensed to produce intermediate E, which would undergo elimination of adjacent proton and generate dihy-dropyran F. This dihydropyran F treated with PTSA gives tertiary carbocation G, which Sche e 12. erivatization of bridged tricyclic ketal.Reactions 2025, 6, 3 10 of 22To gain further insights into the proposed mechanism, homoallylic alcohol 26 wastreated with acetaldehyde using p-xylene as a solvent and two equivalents of BF3·OEt2 at0 ◦C. After 30 min, the p-xylene-trapped product was observed (Scheme 13). This interme-diate was then subjected to hydrogenolysis using Pd(OH)2/C, followed by benzoylationof the resulting alcohol with p-nitrobenzoyl chloride in the presence of Et3N, yielding thecorresponding annulated sugar 30.Reactions 2025, 6, x FOR PEER REVIEW 10 of 23 Scheme 12. Derivatization of bridged tricyclic ketal. Scheme 13. Trapping with p-xylene. In 2017, Vankar et al. [54] reported an efficient synthetic route for the preparation of 1C-aryl/alkyl 2C-branched sugar-fused isochroman derivatives 34. The method involved the reaction of homoallylic alcohol 33 and various aldehydes in the presence of BF3·OEt2 in DCM, leading to the formation of 1C-aryl/alkyl 2C-branched sugar-fused isochroman derivatives 34 and intermediate F. Then, the crude reaction mixture was further treated with p-TSA in toluene, yielding exclusively the desired derivative 34. This process achieved moderate reaction times (1 h) with yields ranging from 60–70% (Scheme 14). Scheme 14. Synthesis of 1C-aryl/alkyl 2C-branched sugar-fused isochroman derivatives. In the presence of the BF3·OEt2, substrate 33 and aldehyde were condensed to produce intermediate E, which would undergo elimination of adjacent proton and generate dihy-dropyran F. This dihydropyran F treated with PTSA gives tertiary carbocation G, which Scheme 13. Trapping with p-xylene.In 2017, Vankar et al. [54] reported an efficient synthetic route for the preparation of1C-aryl/alkyl 2C-branched sugar-fused isochroman derivatives 34. The method involvedthe reaction of homoallylic alcohol 33 and various aldehydes in the presence of BF3·OEt2in DCM, leading to the formation of 1C-aryl/alkyl 2C-branched sugar-fused isochromanderivatives 34 and intermediate F. Then, the crude reaction mixture was further treatedwith p-TSA in toluene, yielding exclusively the desired derivative 34. This process achievedmoderate reaction times (1 h) with yields ranging from 60–70% (Scheme 14).Reactions 2025, 6, x FOR P I 10 of 23 Sch me 12. Derivatizati n of bridged tricyclic ketal. Scheme 13. Trapping with p-xylene. In 2017, Vankar et al. [54] reported an efficient synthetic route for the preparation of 1C-aryl/alkyl 2C-branched sugar-fused isochroman derivatives 34. The method involved the eaction of homoallylic alcohol 33 and various aldehyd s in the pres nce of BF3·OEt2 in DCM, leading to the formation of 1C-aryl/alkyl 2C-branched sugar-fused isochroman derivatives 34 and intermediate F. Then, the crude reaction mixture was further treated with p-TSA in toluene, yielding exclusively the desired derivative 34. This process achieved moderate reaction times (1 h) with yields ranging from 60–70% (Scheme 14). Scheme 14. Synthesis of 1C-aryl/alkyl 2C-branched sugar-fused isochroman derivatives. In the presence of the BF3·OEt2, substrate 33 and aldehyde were condensed to produce intermediate E, which would undergo elimination of adjacent proton and generate dihy-dropyran F. This dihydropyran F treated with PTSA gives tertiary carbocation G, which Scheme 14. Synthesis of 1C-aryl/alkyl 2C-branched sugar-fused isochroman derivatives.In the presence of the BF3·OEt2, substrate 33 and aldehyde were condensed to produceintermediate E, which would undergo elimination of adj cent proton and g n rate dihy-dropyran F. This dihydropyran F treated with PTSA gives tertiary carbocation G, which isin equilibrium with intermediate E. Then, intermediate E may directly give the product 34(Scheme 15).Reactions 2025, 6, 3 11 of 22Reactions 2025, 6, x FOR PEER REVIEW 11 of 23 is in equilibrium with intermediate E. Then, intermediate E may directly give the product 34 (Scheme 15). Scheme 15. Mechanism for the formation of 1C-aryl/alkyl 2C-branched sugar-fused isochroman de-rivatives. Later, Dubbu and Vankar strategically synthesized [55] a series of 2-deoxy-3,4-fused-C-aryl/alkylglycosides through a cascade Prins cyclization of a D-mannitol-derived homoallylic alcohol, using BF₃·OEt₂ as a catalyst. Initially, (Scheme 16) D-mannitol-de-rived homoallylic alcohol 35 was treated with various carbonyl compounds in the pres-ence of BF₃·OEt₂ in DCM, yielding 2-deoxy-3,4-fused isochroman derivatives 36/37 in good to excellent yields. The authors further modified these products to obtain potentially bioactive scaffolds 38, 39, and 40 (Scheme 17). Scheme 16. Synthesis of 1C-aryl/alkyl-fused isochroman derivatives. Sche e 15. echanis for the formation of 1C-aryl/alkyl 2C-branched sugar-fused isochromanderivatives.Later, Dubbu and Vankar strategically synthesized [55] a series of 2-deoxy-3,4-fused-C-aryl/alkylglycosides through a cascade Prins cyclization of a D-mannitol-derived ho-moallylic alcohol, using BF3·OEt2 as a catalyst. Initially, (Scheme 16) D-mannitol-derivedhomoallylic alcohol 35 was treated with various carbonyl compounds in the presence ofBF3·OEt2 in DCM, yielding 2-deoxy-3,4-fused isochroman derivatives 36/37 in good toexcellent yields. The authors further modified these products to obtain potentially bioactivescaffolds 38, 39, and 40 (Scheme 17).Reactions 2025, 6, x FOR PEER REVIEW 11 of 23 is in equilibrium with intermediate E. Then, intermediate E may directly give the product 34 (Scheme 15). Scheme 15. Mechanism for the formation of 1C-aryl/alkyl 2C-branched sugar-fused isochroman de-rivatives. Later, Dubbu and Vankar strategically synthesized [55] a series of 2-deoxy-3,4-fused-C-aryl/alkylglycosi es th ough a cascade Prins cyclization of a D-mannitol-derived homoallylic alc hol, using BF₃·OEt₂ as a catalyst. I itially, (Scheme 16) D-mannitol-de-rived homo llylic alcohol 35 was treated with various carbonyl co pounds in the pres-enc of BF₃·OEt₂ in DCM, yielding 2-deoxy-3,4-fused isochr man derivatives 36/37 in good to excellent yields. The authors further modified these products to obtain potentially bioactive scaffolds 38, 39, and 40 (Scheme 17). Scheme 16. Synthesis of 1C-aryl/alkyl-fused isochroman derivatives. Scheme 16. Synthesis of 1C-aryl/alkyl-fused isochroman derivatives.Reactions 2025, 6, 3 12 of 22Reactions 2025, 6, x FOR PEER REVIEW 12 of 23 Scheme 17. Derivatization of sugar-fused isochroman derivatives. Using similar reaction conditions, but with a D-mannitol-derived homoallylic alco-hol protected with a propargyl group, Dubbu and Vankar obtained [55] 1C-aryl/alkyl-fused bicyclic vinyl halide derivatives 42 in good to excellent yields. The halogen abstrac-tion was achieved through the use of halogenated solvents. Depending on the solvent used—CH₂Cl₂, CH₂Br₂, CH₃I, etc.—the products obtained were 1C-aryl/alkyl-fused bicy-clic vinyl chloride, vinyl bromide, or vinyl iodide derivatives, respectively (Scheme 18). Scheme 18. Synthesis of 1C-aryl/alkyl-fused bicyclic vinyl halide derivatives. By applying similar reaction conditions, Dubbu and Vankar further transformed [55] the D-mannitol-derived homoallylic alcohol 35, protected with allyl and substituted allyl groups, to synthesize 1C-aryl/alkyl-fused bicyclic fluorine-substituted tetrahydropyran and furan derivatives 43/44, achieving good to excellent yields (Scheme 19). Scheme 17. Derivatization of sugar-fused isochroman derivatives.Using similar reaction conditions, but with a D-mannitol-derived homoallylic alcoholprotected with a propargyl group, Dubbu and Vankar obtained [55] 1C-aryl/alkyl-fusedbicyclic vinyl halide derivatives 42 in good to excellent yields. The halogen abstractionwas achieved through the use of halogenated solvents. Depending on the solvent used—CH2Cl2, CH2Br2, CH3I, etc.—the products obtained were 1C-aryl/alkyl-fused bicyclic vinylchloride, vinyl bromide, or vinyl iodide derivatives, respectively (Scheme 18).Reactions 2025, 6, x FOR PEER REVIEW 12 of 23 Scheme 17. Derivatization of sugar-fused isochroman derivatives. Using si ilar reactio co itio s, b t ith a D-ma nitol-derived homoallylic alco-hol protected with a propar yl group, Dubbu and Vankar obt ined [55] 1C-aryl/alkyl-fused bicyclic vinyl halide derivatives 42 in go d to excellent yields. T e halogen abstrac-tion was achieved through the use f halogenated solvents. Depending on the solvent used—CH₂Cl₂, CH₂Br₂, CH₃I, etc.—the products obtained were 1C-aryl/alkyl-fused bicy-clic vinyl chloride, vinyl bromide, r vinyl iodide derivatives, respectively (Scheme 18). Scheme 18. Synthesis of 1C-aryl/alkyl-fused bicyclic vinyl halide derivatives. By applying similar reaction conditions, Dubbu and Vankar further transformed [55] the D-mannitol-derived homoallylic alcohol 35, protected with allyl and substituted allyl groups, to synthesize 1C-aryl/alkyl-fused bicyclic fluorine-substituted tetrahydropyran and furan derivatives 43/44, achieving good to excellent yields (Scheme 19). Scheme 18. Synthesis of 1C-aryl/alkyl-fused bicyclic vinyl halide derivatives.By applying similar reaction conditions, Dubbu and Vankar further transformed [55]the D-mannitol-derived homoallylic alcohol 35, protected with allyl and substituted allylReactions 2025, 6, 3 13 of 22groups, to synthesize 1C-aryl/alkyl-fused bicyclic fluorine-substituted tetrahydropyranand furan derivatives 43/44, achieving good to excellent yields (Scheme 19).Reactions 2025, 6, x FOR PEER REVIEW 13 of 23 Scheme 19. Synthesis of 1C-aryl/alkyl-fused bicyclic fluorine substituted tetrahydropyrans and fu-ran derivatives. In 2019, Vankar reported the stereoselective synthesis of 3-deoxy-3C-formyl β-C-aryl/alkyl furanosides 46 (Scheme 20) through a cascade Prins reaction followed by a pi-nacol-type rearrangement [56]. This transformation involved an –OTBDPS-protected homoallylic alcohol 45, derived from D-mannitol, reacting with various carbonyl com-pounds in the presence of BF₃·OEt₂ in DCM. The reaction provided excellent yields and high selectivity. The author proposed that this reaction proceeds via a cyclic transition state, 46a. Scheme 20. Synthesis of 2,3-dideoxy-3C-formyl β-C-aryl/alkyl furanosides 48. Furthermore, (Scheme 21) this method was effectively applied to synthesize a fused-bicyclic β-C-aryl furanoside moiety 47 and a 2,3-dideoxy-3C-methyl β-C-aryl furanoside 48, both of which are found in the core structures of bioactive molecules. Scheme 19. Synthesis of 1C-aryl/alkyl-fused bicyclic fluorine substituted tetrahydropyrans andfuran derivatives.In 2019, Vankar reported the stereoselective synthesis of 3-deoxy-3C-formyl β-C-aryl/alkyl furanosides 46 (Scheme 20) through a cascade Prins reaction followed by apinacol-type rearrangement [56]. This transformation involved an –OTBDPS-protectedhomoallylic alcohol 45, derived from D-mannitol, reacting with various carbonyl com-pounds in the presence of BF3·OEt2 in CM. The reaction provided excellent yields andhigh selectivity. The author proposed that this reaction proceeds via a cyclic transitionstate, 46a.Reactions 2025, 6, x FOR PEER REVIEW 13 of 23 Sche e 19. Synthesis of 1C-aryl/alkyl-fused bicyclic fluorine substituted tetrahydropyrans and fu-ran derivatives. , a r re rt t stere s l ti t - l alkyl furanosides 46 (Scheme 20) through a cascade Prins reaction foll wed by a pi-nacol-type rearrangement [56]. This transformation i l e – T S- r t t ll li l l , i f - it l, ti it i l - i t e presence of BF₃· t₂ i D . ti i ll t i l i l ti it . t t t t i ti i c cli tr siti t t , . Scheme 20. Synthesis of 2,3-dideoxy-3C-formyl β-C-aryl/alkyl furanosides 48. Furthermore, (Scheme 21) this method was effectively applied to synthesize a fused-bicyclic β-C-aryl furanoside moiety 47 and a 2,3-dideoxy-3C-methyl β-C-aryl furanoside 48, both of which are found in the core structures of bioactive molecules. Scheme 20. Synthesis of 2,3-dideoxy-3C-formyl β-C-aryl/alkyl furanosides 48.Reactions 2025, 6, 3 14 of 22Furthermore, (Scheme 21) this method was effectively applied to synthesize a fused-bicyclic β-C-aryl furanoside moiety 47 and a 2,3-dideoxy-3C-methyl β-C-aryl furanoside48, both of which are found in the core structures of bioactive molecules.Reactions 2025, 6, x FOR PEER REVIEW 14 of 23 Scheme 21. Derivatization of 2,3-dideoxy-3C-formyl β-C-aryl/alkyl furanosides. Later, Vankar and co-workers optimized (Scheme 22) the Sakurai–Prins reaction of a D-mannitol-derived homologated allylsilane homoallylic alcohol 48 with p-tolualdehyde 51 in the presence of BF₃·OEt₂ [56]. This reaction yielded 2-deoxy-2C-branched β-C-aryl furanosides in good yield (84%) as an inseparable diastereomeric mixture (α:β = 0.8:1 ratio) (Scheme 22). To separate the stereoisomers, compound 48 was subsequently deprotected at the –OPiv group using NaOMe/MeOH, resulting in diastereomers 53 and 54, which were then separated by column chromatography with yields of 43% and 35%, respectively. Scheme 22. Synthesis of 2-deoxy-2C-branched β-C-aryl furanosides 53 and 54. Vankar and co-workers further synthesized [57] a non-participating protecting group at allylic position of D-mannitol-derived homoallylic alcohol 55 and which was subjected to the Prins reaction with a vairy of aldehydes in the presence of BF3·OEt2 as a catalyst and led to stereoselective 2-deoxy-C-aryl/alkyl glycosides 56 (Scheme 23). The synthetic ver-satility of this approach has been demonstrated in the synthesis of C-disaccharide and O-linked disaccharides 58, and differently protected 2-deoxy-β-C-aryl glycosides 59,60 (Scheme 24). Scheme 21. Derivatization of 2,3-dideoxy-3C-formyl β-C-aryl/alkyl furanosides.Later, Vankar and co-workers optimized (Scheme 22) the Sakurai–Prins reaction of aD-mannitol-derived homologated allylsilane homoallylic alcohol 48 with p-tolualdehyde51 in the presence of BF3·OEt2 [56]. This reaction yielded 2-deoxy-2C-branched β-C-arylfuranosides in good yield (84%) as an inseparable diastereomeric mixture (α:β = 0.8:1 ratio)(Scheme 22). To separate the stereoisomers, compound 48 was subsequently deprotected atthe –OPiv group using NaOMe/MeOH, resulting in diastereomers 53 and 54, which werethen separated by column chromatography with yields of 43% and 35%, respectively.Reactions 2025, 6, x FOR PEER REVIEW 14 of 23 Scheme 21. Derivatization of 2,3-dideoxy-3C-formyl β-C-aryl/alkyl furanosides. Later, Vankar and co-workers optimized (Scheme 22) the Sakurai–Prins reaction of a D-mannitol-derived homologated allylsilane homoallylic alcohol 48 with p-tolualdehyde 51 in the presence of BF₃·OEt₂ [56]. This reaction yielded 2-deoxy-2C-branched β-C- ryl furanosides in good yield (84%) as an insepar ble diastereomeric mixture (α:β = 0.8:1 ratio) (Scheme 22). To separate the st reoisomers, comp und 48 was subsequently deprot cted at the –OPiv group using NaOMe/MeOH, resulting in diastereomers 53 and 54, which were then separat d by column chromatography with yields of 43% and 35%, respectively. Scheme 22. Synthesis of 2-deoxy-2C-branched β-C-aryl furanosides 53 and 54. Vankar and co-workers further synthesized [57] a non-participating protecting group at allylic position of D-mannitol-derived homoallylic alcohol 55 and which was subjected to the Prins reaction with a vairy of aldehydes in the presence of BF3·OEt2 as a catalyst and led to stereoselective 2-deoxy-C-aryl/alkyl glycosides 56 (Scheme 23). The synthetic ver-satility of this approach has been demonstrated in the synthesis of C-disaccharide and O-linked disaccharides 58, and differently protected 2-deoxy-β-C-aryl glycosides 59,60 (Scheme 24). Scheme 22. Synthesis of 2-deoxy-2C-branched β-C-aryl furanosides 53 and 54.Vankar and co-workers further synthesized [57] a non-participating protecting groupat allylic position of D-mannitol-derived homoallylic alcohol 55 and which was subjectedto the Prins reaction with a vairy of al ehydes in the presence of BF3·OEt2 as a catalystand led to stereoselective 2-deoxy-C-aryl/alkyl glycosides 56 (Scheme 23). The syntheticversatility of this approach has been demonstrated in the synthesis of C-disaccharide andO-linked disaccharides 58, and differently protected 2-deoxy-β-C-aryl glycosides 59, 60(Scheme 24).Reactions 2025, 6, 3 15 of 22Reactions 2025, 6, x FOR PEER REVIEW 15 of 23 Scheme 23. Synthesis of 2-deoxy-β-C-aryl glycosides 52 from D-mannitol-derived homoallylic alco-hol 51. Scheme 24. Derivatization of 2-deoxy-β-C-aryl glycosides 56. Furthermore, Vankar and co-workers reported [58] (Scheme 25) the synthesis of 1,2-annulated tetrahydropyran-fused sugar derivatives 62 via intermediate 62a by the reac-tion of a D-glucose-derived alcohol 61 with various carbonyl compounds in the presence of BF3 Et2O, via Prins cyclization. The obtained products were converted to more useful scaffolds cis-sugar-fused pyrano [3,2-c][1]benzopyran 63 and cis-sugar-fused 4H-naptho [1,2-b]pyran 64 (Scheme 26). Furthermore, they investigated the reaction in the presence of TMSOTf, where 1,2-annulated tetrahydrofuran-fused sugar derivatives 66 were ob-tained via intermediate 66a in moderate to excellent yields. This transformation occurred from D-glucose-derived homopropargyl alcohol 65 and several aldehydes (Scheme 27). Scheme 23. Synthesis of 2-deoxy-β-C-aryl glycosides 52 fro D-mannitol-derived homo llylicalcohol 51.Reactions 2025, 6, x FOR PEER REVIEW 15 of 23 Scheme 23. Synthesis of 2-deoxy-β-C-aryl glycosides 52 from D-mannitol-derived homoallylic alco-hol 51. Scheme 24. Derivatization of 2-deoxy-β-C-aryl glycosides 56. Furthermore, Vankar and co-workers reported [58] (Scheme 25) the synthesis of 1,2-annulated tetrahydropyran-fused sugar derivatives 62 via intermediate 62a by the reac-tion of a D-glucose-derived alcohol 61 with various carbonyl compounds in the presence of BF3 Et2O, via Prins cyclization. The obtained products were converted to more useful scaffolds cis-sugar-fused pyrano [3,2-c][1]benzopyran 63 and cis-sugar-fused 4H-naptho [1,2-b]pyran 64 (Scheme 26). Furthermore, they investigated the reaction in the presence of T SOTf, where 1,2-annulated tetrahydrofuran-fused sugar derivatives 66 were ob-tained via intermediate 66a in moderate to excellent yields. This transformation o curred from D-glucose-derived homopropargyl alcohol 65 and several aldehydes (Scheme 27). Scheme 24. Derivatization of 2-deoxy-β-C-aryl glycosides 56.Furthermore, Vankar and co-workers reported [58] (Scheme 25) the synthesis of1,2-annulated tetrahydropyran-fused sugar derivatives 62 via intermediate 62a by thereaction of a D-glucose-derived alcohol 61 with various carbonyl compounds in thepresence of BF3 Et2O, via Prins cyclization. The obtained products were converted tomore useful scaffolds cis-sugar-fused pyrano [3,2-c][1]benzopyran 63 and cis-sugar-fused4H-naptho [1,2-b]pyran 64 (Scheme 26). Furthermore, they investigated the reaction in thepresence of TMSOTf, where 1,2-annulated tetrahydrofuran-fused sugar derivatives 66 wereobtained via intermediate 66a in moderate to excellent yields. This transformation occurredfrom D-glucose-derived homopropargyl alcohol 65 and several aldehydes (Scheme 27).Reactions 2025, 6, 3 16 of 22Reactions 2025, 6, x FOR PEER REVIEW 16 of 23 Scheme 25. Synthesis of 1,2-annulated sugars having substituted tetrahydropyrans 62. Scheme 26. Synthesis of cis-sugar-fused pyrano [3,2-c][1]benzopyran 63 and cis-sugar-fused 4H-naptho [1,2-b]pyran 64. Scheme 25. Synthesis of 1,2-annulated sugars having substituted tetrahydropyrans 62.Reactions 2025, 6, x FOR PEER REVIEW 16 of 23 Scheme 25. Synthesis of 1,2-annulated sugars having substituted tetrahydropy ans 62. Scheme 26. Synthesis of cis-sugar-fused pyrano [3,2-c][1]benzopyran 63 and cis-sugar-fused 4H-naptho [1,2-b]pyran 64. Scheme 26. Synthesis of cis-sugar-fused pyrano [3,2-c][1]benzopyran 63 and cis-sugar-fused 4H-naptho [1,2-b]pyran 64.Reactions 2025, 6, x FOR PEER REVIEW 16 of 23 Scheme 25. Synthesis of 1,2-annulated sugars having substituted tetrahydropyrans 62. Scheme 26. Synthesis of cis-sugar-fused pyrano [3,2-c][1]benzopyran 63 and cis-sugar-fused 4H-naptho [1,2-b]pyran 64. Scheme 27. Synthesis of 1,2-annulated sugars having substituted tetrahydrofurans 66.Reactions 2025, 6, 3 17 of 22In 2008, Oikawa and co-workers reported [59] the Prins reaction of glucose-derivedenetiomerically pure homoallylic alcohol 67 with unreactive formaldehyde equivalent,i.e., 1,3,5-trioxane 68 to trisubstituted cis-fused hexahydro-2H-furo[3,2-b]pyran derivatives69–71 (Scheme 28).Reactions 2025, 6, x FOR PEER REVIEW 17 of 23 Scheme 27. Synthesis of 1,2-annulated sugars having substituted tetrahydrofurans 66. I , i - rs t [ ] t i ti f l - i ti erically re ll lic lc ol 7 it ti f l e y e e ivalent, i. ., , , -t i 68 to trisubstituted cis-fused hexahydro-2H-furo[3,2-b]pyran deri a-tives 69-71 (Scheme 28). Scheme 28. Synthesis of trisubstituted cis-fused hexahydro-2H-furo [3,2-b]pyran derivatives 69–71. 3. Non-Carbohydrate Synthons to Carbohydrate Scaffolds Besides exhibiting excellent biological activities, the carbohydrate-derived deoxy-C-aryl glycosides were found to be versatile substrates for the synthesis of various skeletal frameworks. Deoxy-C-aryl glycoside is a common structural motif found in a number of biologically relevant compounds, such as aquayamycin Adriamycin, pluramycin A, and kidamycin [60]. An efficiently non-carbohydrate synthons source to sugar skeletons by ap-plying the Prins reaction is a topic which has seen extensive study since the mid-twentieth century [60]. Within this reaction manifold, Migaud and co-workers reported [61] stereose-lective synthesis of a non-carbohydrate-based core sugar skeleton 73 via Sakuri–Prins cy-clization of alcohol 72 with crotanaldehyde. Further, the core sugar skeleton 73 hydroxyl groups at C-6 and C-3 were introduced by oxidative cleavage of the alkenes in 73 followed by reduction of the dicarbonyl intermediate. Subsequent acetylation of these hydroxyls, pu-rification, and acetyl removal then yielded the final C-nucleosides 74 and 75. Following the same reaction sequences and protocols, the synthesis of deoxy-C-aryl glycosides 77, 81, 82 and 84 was achieved using alcohol 72, 78 as a building blocks, respectively (Scheme 29). In 2016, Galan and co-workers reported [36] a de novo approach for the rapid con-struction of orthogonally protected L- and D-deoxysugars and analogues via Prins cy-clization. In this approach, homoallylic alcohol 85 was treated with aldehyde 86 in the presence of TMSOTf and TMSOAc/AcOH, resulting in the formation of silyltetrahydro-pyran 87 in good to excellent yield. This compound was subsequently subjected to Tamao–Fleming oxidation, leading to the formation of 2,4-dideoxysugar 88. By applying a similar reaction, compound 89 was converted into the 2,6-dideoxysugar 91 (Scheme 30). In 2016, Yadav and co-workers [29] demonstrated a diastereoselective formal synthe-sis of cryptophycin-24. The key step for constructing the core center involved a Prins cy-clization of homoallylic alcohol 92 with aldehyde 93 in the presence of TFA in DCM, yield-ing core sugar skeleton 94. Furthermore, this methodology was extended for the total syn-thesis of the natural product cryptophycin-24 (Scheme 31). In 2012, Floreancig and Peh reported [28] a DDQ-mediated oxidative intramolecular Prins cyclization of compound 95, yielding sugar core 96 in moderate yield (Scheme 32). This reaction proceeds via a diene-type intermediate. In 2010, Lee and Woo reported [30] an intramolecular Prins reaction of 97 in the pres-ence of TMSOTf and TMSOAc/AcOH, resulting in the formation of sugar core 98 in good yield. This compound was further subsequently used for the total synthesis of (-)-Poly-cavernoside A 7 (Scheme 33). Sche e 28. Synthesis of trisubstituted cis-fused hexahydro-2H-furo [3,2-b]pyran derivatives 69–71.3. Non-Carbohydrate Synthons to Carbohydrate ScaffoldsBesides exhibiting excellent biological activities, the carbohydrate-derived deoxy-C-aryl glycosides were found to be versatile substrates for the synthesis of various skeletalframeworks. Deoxy-C-aryl glycoside is a common structural motif found in a numberof biologically relevant compounds, such as aquayamycin Adriamycin, pluramycin A,and kidamycin [60]. An efficiently non-carbohydrate synthons source to sugar skeletonsby applying the Prins reaction is a topic which has seen extensive study since the mid-twentieth century [60]. Within this reaction manifold, Migaud and co-workers reported [61]stereoselective synthesis of a non-carbohydrate-based core sugar skeleton 73 via Sakuri–Prins cyclization of alcohol 72 with crotanaldehyde. Further, the core sugar skeleton 73hydroxyl groups at C-6 and C-3 were introduced by oxidative cleavage of the alkenesin 73 followed by reduction of the dicarbonyl intermediate. Subsequent acetylation ofthese hydroxyls, purification, and acetyl removal then yielded the final C-nucleosides 74and 75. Following the same reaction sequences and protocols, the synthesis of deoxy-C-aryl glycosides 77, 81, 82 and 84 was achieved using alcohol 72, 78 as a building blocks,respectively (Scheme 29).In 2016, Galan and co-workers reported [36] a de novo approach for the rapid construc-tion of orthogonally protected L- and D-deoxysugars and analogues via Prins cyclization.In this approach, homoallylic alcohol 85 was treated with aldehyde 86 in the presence ofTMSOTf and TMSOAc/AcOH, resulting in the formation of silyltetrahydropyran 87 ingood to excellent yield. This compound was subsequently subjected to Tamao–Flemingoxidation, leading to the formation of 2,4-dideoxysugar 88. By applying a similar reaction,compound 89 was converted into the 2,6-dideoxysugar 91 (Scheme 30).In 2016, Yadav and co-workers [29] demonstrated a diastereoselective formal synthesisof cryptophycin-24. The key step for constructing the core center involved a Prins cycliza-tion of homoallylic alcohol 92 with aldehyde 93 in the presence of TFA in DCM, yieldingcore sugar skeleton 94. Furthermore, this methodology was extended for the total synthesisof the natural product cryptophycin-24 (Scheme 31).In 2012, Floreancig and Peh reported [28] a DDQ-mediated oxidative intramolecularPrins cyclization of compound 95, yielding sugar core 96 in moderate yield (Scheme 32).This reaction proceeds via a diene-type intermediate.In 2010, Lee and Woo reported [30] an intramolecular Prins reaction of 97 in thepresence of TMSOTf and TMSOAc/AcOH, resulting in the formation of sugar core 98in good yield. This compound was further subsequently used for the total synthesis of(-)-Polycavernoside A 7 (Scheme 33).Reactions 2025, 6, 3 18 of 22Reactions 2025, 6, x FOR PEER REVIEW 18 of 23 Scheme 29. Synthesis of deoxy-C-aryl glycosides from non-carbohydrate-based starting materials. Scheme 29. Synthesis of deoxy-C-aryl glycosides from non-carbohydrate-based starting materials.Reactions 2025, 6, x FOR PEER REVIEW 19 of 23 Scheme 30. Synthesis of dideoxysugars from silyltetrahydropyrans and non-carbohydrate-based starting materials via Prins reaction. Scheme 31. Synthesis of cryptophycin-24 2 from non-carbohydrate-based starting materials via Prins reaction. cheme 30. Synthesis of dideoxysugars from silyltetrahydropyrans and non-c rbohydrate-basedtarting materials via P ins reaction.Reactions 2025, 6, 3 19 of 22Reactions 2025, 6, x FOR PEER REVIEW 19 of 23 Scheme 30. Synthesis of dideoxysugars from silyltetrahydropyrans and non-carbohydrate-based starting materials via Prins reaction. Scheme 31. Synthesis of cryptophycin-24 2 from non-carbohydrate-based starting materials via Prins reaction. Scheme 31. Synthesis of cryptophycin-24 2 from non-carbohydrate-based starting materials via Prinsreaction.Reactions 2025, 6, x FOR PEER REVIEW 19 of 23 Scheme 30. Synthesis of dideoxysugars from silyltetrahydropyrans and non-carbohydrate-based starting materials via Prins reaction. Sche e 31. Synthesis of cryptophycin-24 2 from non-carbohydrate-based starting materials via Prins reaction. Scheme 32. Total synthesis of Clavosolide A 7 via Prins reaction.Reactions 2025, 6, x FOR PEER REVIEW 20 of 23 Scheme 32. Total synthesis of Clavosolide A 7 via Prins reaction. Scheme 33. Total synthesis of (-)-Polycavernoside A 9 via Prins reaction. 4. Conclusions Carbohydrate-based structures are of high interest in glycochemistry due to their crucial roles in biological systems. Recent innovations have introduced both direct and indirect methods to synthesize sugar moieties effectively. Notably, the Prins reaction—a process involving homoallylic alcohols and carbonyl compounds—has become a valuable approach for constructing sugar backbones. This review delves into various Prins reaction techniques for assembling carbohydrate frameworks, highlighting the use of both tradi-tional carbohydrate precursors and alternative non-carbohydrate starting materials. Author Contributions: S.D.: writing—review and editing, writing—original draft, visualization, super-vision, methodology, and conceptualization. S.J.: writing—review and editing, and writing—original draft. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Data Availability Statement: No new data were created or analyzed in this study. Acknowledgments: S.D. gratefully acknowledges the University of Illinois Urbana-Champaign for infrastructure. S.J. gratefully acknowledges The University of British Columbia for infrastructure. Conflicts of Interest: The authors declare no conflict of interest. References 1. Varki, A. Biological roles of oligosaccharides: All of the theories are correct. Glycobiology 1993, 3, 97. 2. Seeberger, P.H.; Werz, D.B. Synthesis and medical applications of oligosaccharides. Nature 2007, 446, 1046–1051. 3. Dwek, R.A. Glycobiology: Toward Understanding the Function of Sugars. Chem. Rev. 1996, 96, 683–720. 4. Rudd, P.M.; Elliott, T.; Cresswell, P.; Wilson, I.A.; Dwek, R.A. Glycosylation and the Immune System. Science 2001, 291, 2370–2376. 5. Galonic, D.P.; Gin, Y.D. Chemical glycosylation in the synthesis of glycoconjugate antitumour vaccines. Nature 2007, 446, 1000–1007. 6. Ernst, B.; Magnani, J.L. From carbohydrate leads to glycomimetic drugs. Nat. Rev. 2009, 8, 661–677. 7. Gloster, T.M.; Vocadlo, D.J. Developing inhibitors of glycan processing enzymes as tools for enabling glycobiology. Nat. Chem. Biol. 2012, 8, 683–694. Scheme 3. Total synthesis of (-)-Polycavernoside A 9 via Prins reaction.4. ConclusionsCarbohydrate-based structures are of high interest in glycochemistry due to theircrucial roles in biological systems. Recent innovations have introduced both direct andReactions 2025, 6, 3 20 of 22indirect methods to synthesize sugar moieties effectively. Notably, the Prins reaction—aprocess involving homoallylic alcohols and carbonyl compounds—has become a valuableapproach for constructing sugar backbones. This review delves into various Prins reac-tion techniques for assembling carbohydrate frameworks, highlighting the use of bothtraditional carbohydrate precursors and alternative non-carbohydrate starting materials.Author Contributions: S.D.: writing—review and editing, writing—original draft, visualization,supervision, methodology, and conceptualization. S.J.: writing—review and editing, and writing—original draft. 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carbohydrates
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Advancements in Carbohydrate Scaffold Synthesis : Exploring Prins Cyclization Methodology
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