Advancements in Carbohydrate Scaffold Synthesis: Exploring Prins Cyclization Methodology

Abstract

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.

1. Introduction

Carbohydrates are fundamental biomolecules that play a multitude of vital roles in living systems, including cell growth, proliferation, immune responses, cell adhesion, and cell–cell communication [1,2,3,4,5,6,7]. Their diverse functions make them crucial for maintaining the structural and functional integrity of biological processes. In biological systems, carbohydrates exist in various forms, with many found as oligosaccharides bound to lipids or proteins. These complexes, collectively termed glycoconjugates, are essential for mediating biological recognition events such as immune signaling and pathogen-host interactions. Glycoconjugates are classified based on the nature of their glycosidic linkages, which can be N-, O-, C-, or S-linked glycosides [8,9,10,11,12]. The synthesis and modification of these carbohydrate structures remain a cornerstone of chemical biology and medicinal chemistry, as their applications span pharmaceuticals, materials science, and biotechnology.

Designing novel synthetic strategies for carbohydrates is an active area of research due to their immense structural complexity and the challenges of achieving stereoselectivity during synthesis. One of the most critical challenges in carbohydrate chemistry is the construction of pyran (six-membered) and furan (five-membered) rings, which are common structural motifs in natural products, glycoconjugates, and various biologically active compounds [13,14,15,16,17,18]. Achieving the stereoselective synthesis of these rings under mild conditions is a central goal in organic synthesis. Among the various approaches developed to address this challenge, the Prins reaction stands out as a highly efficient and versatile method.

The Prins reaction [19,20,21,22,23,24,25,26,27] 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 functionalized cyclic compounds. Numerous natural products and bioactive molecules containing THP rings have been synthesized using Prins methodology (Figure 1) such as Clavosolide A 1, Cryptophycin-24 2, and (-)-Ploycaverrnoside A 3 [28,29,30].

The renewed interest in the Prins reaction stems from its ability to generate multifunctionalized carbohydrate scaffolds with diverse applications. A typical (Scheme 1) reaction 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 oxocarbenium 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 [33,34,35]. Rare sugars such as altrose and allose, while less abundant in nature, exhibit unique biological properties that make them attractive for therapeutic 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].

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 [40,41,42] 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 carbohydrate 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 underscores 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 involves an intermediate X and a highly reactive carbocation Y. This carbocation Y is subsequently captured by an iodide ion, resulting in the formation of the sugar-annulated iodotetrahydropyran compound 12.

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 various carbonyl compounds 11, employing BF₃·OEt₂ as a catalyst and various arene (Scheme 3).

In a subsequent study, the same research group [48] conducted an in-depth investigation 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 carbonyl compounds 11, using benzene as the solvent and a catalytic amount of BF₃·OEt₂ (0.1 equiv). The reaction proceeded efficiently at 25 °C, yielding the corresponding 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 specifically aimed to trap the tetrahydropyranyl carbocation using benzene as the C-nucleophile. Notably, they also investigated the reaction in other arene solvents, including benzene, toluene, o-xylene, and anisole. The reaction demonstrated compatibility with a wide range of aryl and alkyl aldehydes as well as cyclohexanone. Interestingly, one of the products was further converted into diaryl dihydroxytetrahydropyran 14, a C-aryl glycoside (Scheme 4).

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 aldehydes 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 cyclohexylidene protected O-prenyl tethered carbohydrate-derived aldehyde to furnish the product tricyclic sugar derivative 16 (Scheme 5).

First, cyclization of O-prenyl tethered carbohydrate-derived aldehyde 15 is proposed, facilitated by carbonyl ene reaction and led to homoallylic alcohol A, with this being 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 proton from methyl group and led to product 16 (Scheme 6).

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-oxadecalines 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.

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.

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. Oikawa 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 substrate 24 with variety of aldehydes and nitrile solvent 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.

Vankar and co-workers [53] developed an efficient synthesis of bridged tricyclic ketals 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 plausible 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.

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 intermediate 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.

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).

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 dihydropyran F. This dihydropyran F treated with PTSA gives tertiary carbocation G, which is in equilibrium with intermediate E. Then, intermediate E may directly give the product 34 (Scheme 15).

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-derived homoallylic alcohol 35 was treated with various carbonyl compounds in the presence 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).

Using similar reaction conditions, but with a D-mannitol-derived homoallylic alcohol 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 abstraction 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 bicyclic vinyl chloride, vinyl bromide, or vinyl iodide derivatives, respectively (Scheme 18).

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).

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 pinacol-type rearrangement [56]. This transformation involved an –OTBDPS-protected homoallylic alcohol 45, derived from D-mannitol, reacting with various carbonyl compounds 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.

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.

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.

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 versatility 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).

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 reaction 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 obtained via intermediate 66a in moderate to excellent yields. This transformation occurred from D-glucose-derived homopropargyl alcohol 65 and several aldehydes (Scheme 27).

In 2008, Oikawa and co-workers reported [59] the Prins reaction of glucose-derived enetiomerically 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 derivatives 69-71 (Scheme 28).

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 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 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, purification, 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 construction 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 of TMSOTf and TMSOAc/AcOH, resulting in the formation of silyltetrahydropyran 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 synthesis of cryptophycin-24. The key step for constructing the core center involved a Prins cyclization of homoallylic alcohol 92 with aldehyde 93 in the presence of TFA in DCM, yielding core sugar skeleton 94. Furthermore, this methodology was extended for the total synthesis 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 presence 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 (-)-Polycavernoside A 7 (Scheme 33).

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 traditional carbohydrate precursors and alternative non-carbohydrate starting materials.