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Synlett 2024; 35(15): 1745-1762
DOI: 10.1055/a-2214-7557
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Stereo- and Site-Selective Acylation in Carbohydrate Synthesis

Stephanie A. Blaszczyk
a   School of Pharmacy, University of Wisconsin-Madison, 777 Highland Ave, Madison, WI 53705, USA
b   Department of Chemistry, University of Wisconsin-Madison, 1101 University Ave, Madison, WI 53706, USA
,
Xiaolei Li
a   School of Pharmacy, University of Wisconsin-Madison, 777 Highland Ave, Madison, WI 53705, USA
,
Peng Wen
a   School of Pharmacy, University of Wisconsin-Madison, 777 Highland Ave, Madison, WI 53705, USA
,
Weiping Tang∗
a   School of Pharmacy, University of Wisconsin-Madison, 777 Highland Ave, Madison, WI 53705, USA
b   Department of Chemistry, University of Wisconsin-Madison, 1101 University Ave, Madison, WI 53706, USA
› Author Affiliations

S.A.B. was funded by the NSF GRFP and the NIH Chemistry-Biology Interface training grant (T32 GM008505). W.T. thanks the NIH (U01 GM125290 and R35 GM148266) for financial support.
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Abstract

Carbohydrates are synthetically challenging molecules with vital biological roles in all living systems. To better understand the biological functions of this fundamentally important class of molecules, novel methodologies are needed, including site-selective functionalization and glycosylation reactions. This account describes our efforts toward the development of novel methodologies for site-selective functionalization of carbohydrates and stereoselective glycosylation through various acylation reactions.


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Keywords

carbohydrate - esterification - catalysis - site-selective functionalization - stereoselective

Biographical Sketches

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Stephanie Blaszczyk is a medical writer and science communicator, the former editor-in-chief of Chembites, a former AAAS Mass Media Science and Engineering Fellow for the Milwaukee Journal Sentinel, and a former WISCIENCE Public Service Fellow. Stephanie studied chemistry at Rockford University, where she earned her B.S. degree in 2013. She then worked in industry, first at a small company then at a global corporation, before returning to the University of Wisconsin–Madison in 2016 to pursue graduate studies under the direction of Professor Weiping Tang. Her research focused on developing more efficient methods for the chemical synthesis of carbohydrates. Her appreciation for accurate science information guided her development from a cheeky adolescent to a passionate scientist and science communicator. In both roles, she values evidence-based science, transparency, and integrity.

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Xiaolei Li received his B.S. degree from Peking University in 2017, where he did his undergraduate research in Prof. Zhang-Jie Shi’s lab. After that, he obtained his Ph.D. degree from the University of Wisconsin-Madison under the supervision of Professor Weiping Tang in 2023. During his Ph.D. study, he worked on developing novel methodologies for carbohydrate synthesis, as well as synthesis of small molecule protein degraders. He is now a medicinal chemist in the pharmaceutical industry.

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Peng Wen obtained his bachelor’s degree in bioengineering from Southwest Jiaotong University, China, in 2009. He continued his study at the same university where he received his master’s degree in biochemical engineering in 2012 under the supervision of Professor Qun Lu. He then joined Wayne State University and earned his Ph.D. degree in organic chemistry in 2018 under the direction of Professor David Crich. He then pursued his postdoctoral training with Professor Weiping Tang at University of Wisconsin-Madison before he moved to his current position in pharmaceutical industry in 2021.

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Weiping Tang received his B.S. degree from Peking University, M.S. degree from New York University, and Ph.D. degree from Stanford University. He was a HHMI postdoctoral fellow at Harvard University. He is currently Janis Apinis Professor and Vilas Distinguished Achievement Professor in the School of Pharmacy and a joint faculty member in the Department of Chemistry at the University of Wisconsin-Madison. His group is currently interested in carbohydrate chemistry, medicinal chemistry, and chemical biology, with a focus on new strategies for drug discovery.

Introduction

The prevalent roles of carbohydrates in physiological and pathological processes have necessitated that chemists investigate and expedite their chemical synthesis so that glycobiologists can better elucidate carbohydrate function.[1] However, compared to other classes of biopolymers, carbohydrates pose significantly more synthetic burdens than their protein and nucleic acid counterparts, which are produced through templated biosynthetic pathways or well-established automated chemical synthesis platforms. One of the major issues associated with carbohydrate synthesis is the fact that each carbohydrate building block is usually a densely functionalized molecule bearing multiple hydroxyl groups. These hydroxyls have similar reactivities so modifying one hydroxyl while leaving the others unchanged is difficult. In fact, site-selective functionalization has been termed a ‘Holy Grail’ in chemistry.[2] Another longstanding knowledge gap in carbohydrate chemistry is a general and efficient method for stereoselective functionalization of the anomeric hydroxyl group including glycosylation.

This account will detail how we have developed stereo- and site-selective acylation methods to improve the stereoselectivity and efficiency for the synthesis of carbohydrate building blocks. To expedite the synthesis of rare sugars and carbohydrate analogs, we have frequently drawn upon the Achmatowicz rearrangement[3] to form dihydropyranone intermediates. Our group took advantage of the equilibrium between two lactol stereoisomers to preferentially acylate one stereoisomer via a dynamic kinetic process. We have used both transition-metal catalysts and chiral organocatalysts to control the traditionally challenging stereoselective transformations, finding chiral benzotetramisole (BTM) organocatalysts particularly useful. The utility of BTM catalysts was further extended from the stereoselective acylation of the anomeric hydroxyl group to the site-selective acylation of carbohydrate hydroxyl groups. Recently, we also employed isoquinolinic and picolinic esters for the preparation of glycosides and glycosyl halides under mild conditions. An overview of the reactions covered in this review can be found in Scheme [1]. We hope the reader will enjoy the story behind how our lab used the seemingly simple acylation reaction to solve some of the challenging problems in carbohydrate chemistry and continue pushing its boundaries.


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Dynamic Kinetic Transformations Mediated by Transition-Metal Catalysts Prompt Our Carbohydrate Research

The first work that we will delve into is our stereoselective iridium-catalyzed dynamic kinetic internal transfer hydrogenation.[4] In 2015 we reported this research, which was one of our initial publications in the area of carbohydrate chemistry, and believe it or not, these findings were actually serendipitous. When a group member was trying to develop stereoselective allylic alkylation reactions using allylic alcohol 2 as the substrate and different nucleophiles, he noticed an unexpected spot on the TLC plate. Rather than ignoring this by-product and moving forward, he purified the reaction mixture and isolated this unexpected spot. He later determined that the spot corresponded to an isomerization product that occurred when trying to optimize the originally studied allylic alkylation reaction. We found this isomerization process interesting because we started with a 3:1 ratio of cis-2/trans-2, but after optimization, we were able to boost that ratio to favor the cis isomer by >20:1.

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Scheme 1 Summary of the reactions covered in this review

Our investigation into the isomerization pathway began with the preparation of starting material 1 by an asymmetric reduction of 2-acylfuran and subsequent Achmatowicz rearrangement of alcohol 1 to form dihydropyranones 2, which existed as a mixture of epimers. These dihydropyranones could then undergo internal redox isomerizations and result in the stereoselective synthesis of lactone 3, the cis isomer, as the major product (Scheme [2]).

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Scheme 2 Overview of the iridium(I)-catalyzed dynamic kinetic stereoselective isomerization (top) and partial substrate scope (bottom)

Though we knew an isomerization occurred from 2 to 3, we still had to optimize the reaction. After screening various transition-metal catalysts, we observed that only iridium-based catalysts provided the desired product. Further optimization prompted some interesting insights. When we subjected a 3:1 ratio of cis-2/trans-2, where R = Me, to the reaction with only the iridium catalyst, we obtained 4 but only in a 3:1 ratio favoring the cis product. This result suggested that the metal catalyst played no role in the equilibration between the dihydropyranones. However, as we screened various Brønsted acids in an attempt to accelerate the rate of equilibration between cis-2 and trans-2, we noticed the diastereoselectivity of the products began to more heavily favor the cis product. In the end, we found that using 2,6-dichlorobenzoic acid as a co-catalyst provided the cis isomer in a >20:1 ratio. As we move forward in this review, we will see how a carboxylic acid additive biases the reaction to improve the diastereoselectivity.

The isomerization from 2 to 3 worked well when R was various alkyl and silyl ether groups. Aryl groups also worked regardless of the presence of electron-donating or electron-withdrawing substituents. When a gem-dimethyl group, as seen in 9, was used in the isomerization reaction, the product 10 can undergo methylation, reduction, and dihydroxylation to complete the de novo formal synthesis of the carbohydrate noviose (Scheme [3]).[5]

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Scheme 3 Formal synthesis of the carbohydrate noviose

As an added advantage, the stereochemical configuration maintained high fidelity through the isomerization even in gram-scale reactions (14, 0.95 g, 98% ee). Using 14 as a key intermediate, this method yielded l-rhodinose and allowed for the formal synthesis of numerous deoxy sugars (Scheme [4]), of which intermediates 14 and 16 have been converted into amino sugar derivatives.[6] Other groups have used this isomerization reaction to complete the total synthesis of the natural product angiopteralactone B,[7] (+)/(–)-cis-osmundalactone,[8] and phosdiecin A.[9]

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Scheme 4 Formal synthesis of deoxy sugars using the iridium-catalyzed isomerization to obtain necessary intermediates. Reagents and conditions: (a) [Cp*RhCl2]2 (0.05 mol%), (R,R)-TsDPEN (0.12 mol%), HCO2Na, 40 °C, 98%; (b) NBS, 85%; (c) [Ir(COD)Cl]2 (2.5 mol%), rt, 76%; (d) H2, Pd/C; (e) DIBAL-H, 40% over 2 steps; (f) PPh3, p-O2NC6H4CO2H, DEAD, then MeOH, Et3N, 75% over 2 steps.

When we originally started the iridium-catalysis work, we were devising efficient methods to access allylic alkylation products directly from allylic alcohols derived from Achmatowicz rearrangement and different nucleophiles. We did not try any alcohol nucleophiles because we thought it would be difficult to differentiate the allylic alcohol substrate, which itself is also an alcohol, and the external alcohol nucleophile. We previously discussed the detour of finding and publishing the isomerization reaction, which was performed best using chloroform as the solvent. The commercially available chloroform is stabilized with either amylene or ethanol. When we accidentally used chloroform stabilized with ethanol, we obtained a mixture of isomerization product and allylic etherification product derived from the nucleophilic attack of ethanol to the metal-π-allyl complex. We subsequently began investigating the allylic etherification reaction using different alcohols as the nucleophiles and chloroform stabilized by amylene. However, isomerization was the dominant pathway under most conditions. Finally, in 2017, we reported that the addition of a triphenyl phosphite ligand can suppress the isomerization pathway and promote the allylic etherification pathway (Scheme [5]).[10]

In optimizing the allylic etherification reaction, we started with a 3:1 ratio of cis/trans-21 and used benzyl alcohol as the nucleophile to obtain the desired product 22 (Scheme [5], top). We found that phosphine ligands resulted in no reaction, but phosphite ligands suppressed the isomerization reaction we previously reported, with triphenyl phosphite being superior. We also knew from our previous work that Brønsted acids could influence the degree of diastereoselectivity. After screening different Brønsted acid additives, we determined that diphenyl phosphate provided the best dr (10:1 for cis/trans-22).

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Scheme 5 Optimized conditions (top) and selected products (bottom) for the iridium-catalyzed dynamic kinetic stereoselective allylic etherification

It’s interesting to note just how much the acid additive and solvent choice can affect the iridium-catalyzed isomerization and allylic etherification. With the isomerization, 2,6-dichorobenzoic acid was the best for maximizing the yield and diastereoselectivity, but in the allylic etherification, the same acid additive resulted in either no reaction or a poor yield (41%).

Furthermore, even though diphenyl phosphate was sufficient for maximizing the diastereoselectivity in the etherification reaction, the solvent choice could negate any gains made by the addition of the appropriate acid. For example, using triphenyl phosphite and diphenyl phosphate gave a 10:1 dr favoring cis-22 over trans-22 using chloroform, but no diastereoselectivity resulted when the same reaction was run in dichloromethane.

Following optimization, we explored the scope of the reaction, which was tolerant of a diverse range of alcohols (Scheme [5], bottom). Glycosyl acceptors with primary and secondary hydroxyls were also successful in this reaction. Sterically less encumbered acceptors tended to promote the formation of the cis-isomers or β-anomers as the major product, and sterically bulky acceptors tended to promote the formation of the trans-isomers or α-anomers as the major product.

Because the same starting materials were used for the iridium-catalyzed dynamic kinetic isomerization and allylic etherification,[4] the proposed mechanisms for both are shown in Scheme [6]. In both cases, there is a rapid acid-catalyzed mutarotation of the hemiacetals cis-2 and trans-2 for which the equilibrium favors cis-2. For the isomerization, we propose that the dehydrogenation of cis-2 and trans-2 forms iridium-hydride species 29 and 30. The stereoselective iridium-catalyzed transfer hydrogenation then leads to 3 and 31. When an acid co-catalyst is absent from the reaction, the product ratio of 3/31 is approximately 3:1, which is similar to the ratio of cis-2 and trans-2 at equilibrium. This observation suggests that when an acid is absent, the rate of internal transfer hydrogenation is faster than the equilibration of the two hemiacetals.

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Scheme 6 Proposed mechanism for the iridium-catalyzed dynamic kinetic isomerization (dotted lines) and the iridium-catalyzed dynamic kinetic stereoselective allylic etherification (solid line)

To avoid the formation of 29 and 30, triphenyl phosphite was added to promote the formation of the iridium-π-allyl species 32 and 33. When sterically unencumbered nucleophiles are used, the iridium complex will approach the alkene from the side opposite to the R group to minimize steric interactions. This leads to intermediate 32 and results in product 34. However, when sterically demanding nucleophiles are present, the reaction proceeds through intermediate 33 to avoid steric interactions between the alcohol nucleophile and the R-group. This results in product 35, which has opposite diastereoselectivity compared to 34. These trends can be seen when observing the product distribution ratios for the various nucleophiles shown at the bottom of Scheme [5].


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Continuation of the Dynamic Kinetic Transformations using Chiral Organocatalysts for Carbohydrate Synthesis

Although our iridium-catalyzed dynamic allylic etherification provides the glycosylation products directly from allylic alcohol 21, it should be noted that the glycosyl donor was mostly limited to substrates with the -OTBS protecting group at the C6 position, and the diastereoselectivity often varies depending on the glycosyl acceptor. The O’Doherty group has used a wide range of glycosyl donors and glycosyl acceptors for the palladium-catalyzed stereospecific glycosylation reactions,[11] but the issue of developing efficient and diastereoselective methods to prepare allylic carbonates or allylic esters from the allylic alcohol remains. Building upon our previous success with the dynamic kinetic stereoselective transformations with lactols, we speculated that we could use chiral organocatalysts to improve the diastereoselectivity for the formation of anomeric esters, which has been a significant bottleneck in de novo carbohydrate synthesis.

We envisioned that we could improve the diastereoselectivity of anomeric acylation of cis-2 and trans-2 by either reinforcing or overriding the intrinsic diastereoselectivity through a chiral catalyst-directed dynamic kinetic diastereoselective acylation (DKDA), shown in Scheme [7].[12]

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Scheme 7 Overview of the dynamic kinetic diastereoselective acylation (DKDA) of lactols

Our initial conditions optimization used chiral lactol 13, prepared enantioselectively in two steps, and commercially available chiral organocatalyst (S)-levamisole 38. In retrospect, the fact that we identified (S)-levamisole as a potential catalyst was rather lucky because when a group member was doing background research for this project,[13] he just happened to find that (S)-levamisole was one of the cheapest chiral nucleophilic catalysts so we tried it first.

We screened various anhydrides and were pleased to see that the acetic anhydride led to 39 in quantitative yield with a diastereomeric ratio of 8:1 favoring the trans isomer. Furthermore, more hindered anhydrides increased this ratio, an observation that paralleled those of Birman.[14] Using isobutyric anhydride, we were able to obtain 40 in great yield with 15:1 dr, also favoring the trans isomer (Scheme [8]). Unfortunately, only (S)-levamisole was commercially available at that time, and (R)-levamisole was not readily available.

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Scheme 8 Screening of anhydrides for the DKDA of lactols using (S)-levamisole

Inspired by Birman’s use of benzotetramisole (BTM) catalysts[14] 41 and 42, of which both enantiomers are commercially available, and Shiina’s mixed anhydride method,[15] we decided to investigate the feasibility of acylating 43 with BTM catalysts, pivalic anhydride, and a readily available carboxylic acid to obtain the desired product in both matched and mismatched scenarios (Scheme [9]). Using the BTM catalysts and the mixed anhydride method, we were able to improve the diastereoselectivity of both matched and mismatched reactions.

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Scheme 9 Results of using Birman’s benzotetramisole catalysts and Shiino’s mixed anhydride method for the DKDA of lactols and results from palladium-catalyzed glycosidation. Reagents and conditions: (a) (R)-BTM 41 (10 mol%), PhCH2CO2H (1.3 equiv), Piv2O (1.3 equiv), i-Pr2NEt (2.5 equiv); (b) (S)-BTM 42 (10 mol%), PhCH2CO2H (1.3 equiv), Piv2O (1.3 equiv), i-Pr2NEt (2.5 equiv); (c) Pd2(dba)3 (2.5 mol%), PPh3 (10 mol%), BnOH; (d) Pd2(dba)3 (2.5 mol%), PPh3 (10 mol%), BnOH, i-Pr2NEt.

We were then able to use 44 and 45 in a palladium-catalyzed glycosidation to synthesize the corresponding benzyl ethers 46 and 47. This two-step strategy of using DKDA developed by us and Pd-catalyzed glycosidation pioneered by O’Doherty[16] afforded us complete stereochemical control of the anomeric position and allowed us to easily achieve a starting point for the de novo synthesis of many natural and non-natural carbohydrates. Later in the review, we will demonstrate how the diastereoselective acylation of lactols guided our way further into synthetic methodology development for carbohydrate synthesis.

Our lactol acylation work was published concurrently with a research group from Bristol-Myers Squibb (BMS), which reported a similar transformation using 38.[17] In fact, one of the co-authors on the paper from BMS was an alumnus of the University of Wisconsin-Madison, which is home to our research group. This co-author, Tamas Benkovics, actually returned to UW-Madison to give a seminar where he reported that BMS scientists tried numerous different catalysts before discovering that 38 worked for their synthesis of the key intermediate used for the preparation of a drug candidate. Knowing this, we were pleased that our first catalyst choice worked, and even more happy that paired BTM catalysts could be used as well.

Since the early days of Emil Fisher, synthetic chemists still lack a systematic way to access all stereoisomers of particular monosaccharides, especially rare sugars. However, continuing with our use of reagent control, we exploited a chiral catalyst-based divergent strategy to access all eight stereoisomers of 2,3,6-trideoxyhexopyranosides, which includes the rhodinopyranosides and amicetopyranosides.[18]

From work already presented in this review, we’ve repeatedly used the Achmatowicz rearrangement to convert inexpensive feedstock furan 8 into valuable dihydropyranone intermediates 13, and we’ve also taken advantage of O’Doherty’s palladium-catalyzed glycosidation[16] to prepare anomeric ethers 48 and 49 through Pd-π-allyl intermediates (Scheme [10]). We will discuss the details for the formation of the carbonate or ester intermediates from key intermediate 13 later to have a better comparison.

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Scheme 10 Preparation of key intermediates 48 and 49 for the synthesis of all eight stereoisomers of 2,3,6-trideoxyhexopyranosides. Reagents and conditions: (a) Boc2O, DMAP, –78 °C; (b) Pd2(dba)3 (0.5 mol%), PPh3 (2 mol%), BnOH; (c) Boc2O, NaOAc, 80 °C.

In 2015, as we were thinking about ways to access the 2,3,6-trideoxyhexopyranoside stereoisomers, our literature review indicated that there was no known way to go directly from 48/49 to 53–56 (Scheme [11]). We hypothesized that we could complete a chiral catalyst-controlled tandem reduction to obtain the eight 2,3,6-trideoxyhexopyranoside stereoisomers. Because the reduction of 48 and 49 with an achiral Ts-ethylenediamine ligand 50 showed low intrinsic diastereoselectivity, we were further convinced that a chiral catalyst strategy with chiral ligands 51 and 52 could be successful.

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Scheme 11 Preparation of four 2,3,6-trideoxyhexopyranoside stereoisomers. When achiral ligand 50 was used, low intrinsic diastereoselectivity was observed. When chiral ligand 51 or 52 was used (depending on the desired product), complete stereoselectivity was observed. Reagents and conditions: (a) Low intrinsic diastereoselectivity with achiral ligand 50; [Cp*RhCl2]2 (0.5 mol%), 50 (1.2 mol%), HCO2Na, 40 °C; (b) Complete stereoselectivity with chiral ligands 51 or 52; [Cp*RhCl2]2 (0.5 mol%), 51 or 52 (1.2 mol%), HCO2Na, 40 °C.

We were pleased that our hypothesis was correct. Depending on the choice of substrate (48, 49, 57, 58) and chiral ligand (51, 52), we were able to use rhodium-catalysis to obtain eight single stereoisomers (Scheme [12]).[18] In each case, hydroxyl groups with (S) configurations resulted from using the (S,S)-Ts-DPEN ligand, and hydroxyl groups with (R) configurations resulted from using the (R,R)-Ts-DPEN ligand. This work demonstrated that the absolute or relative stereochemistry of the enone starting materials (48, 49, 57, 58) had no effect on the stereochemistry of the final product.

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Scheme 12 Divergent de novo synthesis of all eight stereoisomers of 2,3,6-trideoxyhexopyranosides using a chiral catalyst-controlled reduction. Reagents and conditions: [Cp*RhCl2]2 (0.5 mol%), ligand 51/52 (1.2 mol%), HCO2Na, 40 °C.

Mechanistic studies using the standard reaction conditions except a reduced amount of sodium formate resulted in 50% of unreacted starting material 49, 40% of alcohol 55, and 10% of ketone 63, based on NMR analysis of the crude product mixture (Scheme [13]). Considering no allylic alcohol 64 was observed, this suggests that the 1,4-reduction of enone starting material 49 is significantly faster than the 1,2-reduction of 49.

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Scheme 13 Product distribution resulting from the reduction of enone 49 as a way to investigate the mechanism of the chiral catalyst-controlled reduction. Reagents and conditions: a) [Cp*RhCl2]2 (0.5 mol%), (R,R)-Ts-DPEN 52 (1.2 mol%), HCO2Na (1.0 equiv).

Using a sequence of palladium-catalyzed glycosidation and a divergent chiral catalyst-controlled reduction, we synthesized all eight stereoisomers of the 2,3,6-trideoxyhexopyranosides. We also demonstrated the utility of this method by synthesizing both isomers of narbosine B 65 and 66 while also making tetrasaccharide 67 (Scheme [14]).

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Scheme 14 Selected bioactive natural products and saccharides made using a palladium-catalyzed glycosidation and divergent chiral catalyst-directed tandem reduction

While our previous divergent synthesis was useful, we published an update to this method in 2018.[19] Formation of the products shown in Scheme [12] originally proceeded through carbonate intermediates 68 and 69, and suffered from poor stereoselectivity (no greater than roughly 3:1) in the transformation from 13 (Scheme [15]). We thought our previously published dynamic kinetic stereoselective acylation of lactols using chiral benzotetramisole catalysts[12] could be used instead to prepare 53–56 and their respective enantiomers. But in this case, the desired products would go through a completely stereoselective acylation to yield intermediates 71 and 72 and their enantiomers using BTM catalysts. Using the new method shown at the bottom of Scheme [15], we were able to access the enone starting materials 48, 49, 57, and 58 needed to access all of the 2,3,6-trideoxyhexopyranosides stereoisomers shown in Scheme [12].

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Scheme 15 Comparison of old and new methods to access enone intermediates to obtain all stereoisomers of 2,3,6-trideoxyhexopyranosides. Reagents and conditions: (a) Boc2O, DMAP, –78 °C, 59%; (b) Boc2O, NaOAc, 80 °, 50%; (c) Pd2(dba)3 (0.5 mol%), PPh3 (2.0 mol%), BnOH; (d) BTM 41 or 42 (10 mol%), Piv2O (1.3 equiv), PhCH2CO2H (1.3 equiv), i-Pr2NEt (2.5 equiv), CHCl3; (e) Pd2(dba)3 (2.5 mol%), PPh3 (10.0 mol%), BnOH (1.5 equiv), i-Pr2NEt (1.5 equiv.).

With a more efficient synthesis in hand for the production of 2,3,6-trideoxyhexopyranosides, we looked to produce their corresponding deoxyamino sugars through a Mitsunobu reaction to introduce the azido group and a subsequent reduction (Scheme [16]).

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Scheme 16 Synthesis of all possible 2,3,4,6-tetradeoxy-4-aminopyranosides

Deoxyaminosugars are commonly part of natural products, including anthracyclines, macrolides, and aminoglycosides.[20] Specifically, examples of natural products containing 2,3,4,6-tetradeoxy-4-aminopyranosides can be found in Scheme [17]. In fact, using a reductive amination protocol we introduced the N,N-dimethyl group to 73 to synthesize 74 O-benzyl-β-d-forosaminide, which is the glycone portion of spinosyn A (75). Additionally, 76 is the glycon moiety found in grecocycline A 79, and using 76 with the same reductive amination protocol we synthesized O-benzyl-α-l-ossaminide 77, the glycone in ossamycin 78. Continuing with the theme of the work in this review, reagent control is the key to achieving the stereodivergent synthesis of the deoxysugars and deoxyaminosugars presented here.

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Scheme 17 Synthesis of 2,3,4,6-tetradeoxy-4-aminopyranoside derivatives found in natural products

Although some time had passed since we published our work on the DKDA of allylic lactols, we did not pay too much attention to the detailed mechanism of this reaction. We always thought a cation-π interaction between the cationic acylated-BTM catalyst and the π system of the substrates was the driving force for the high selectivity. This was what Houk and Birman proposed for the BTM-catalyzed kinetic resolution of benzylic, allylic, and propargylic secondary alcohols,[21] which states the enantioselectivity in these reactions results from interactions between the cationic acylated-BTM catalyst and the π system of the substrates. We also had a π system in our allylic lactol substrates and thought our reaction should just follow the same mechanism.

However, there was a flaw in this logic because the π system in our substrates, such as 43, was an enone and the electron-withdrawing carbonyl group makes the alkene π system electron-deficient. Thus, it would be difficult for our π component to interact with the cationic acylated catalyst through the cation-π interaction. But we did not realize this until we figured out the actual interaction that governed the selectivity later. As discussed later, we had some very interesting results for the BTM-catalyzed site-selective acylation of α-glucosides, but we could not rationalize the results we observed using well-known interactions. We then had to come back to the BTM-catalyzed stereoselective acylation reaction and start asking ourselves if we really understood this reaction that we had already published.

One day, out of nowhere, in the midst of our ponderings, we took out our molecular modeling kit that had been collecting dust for a while. We used the kit to build the structures for both (R)-BTM and substrate 80 to try to predict the reaction outcome based on a cation-π interaction. The model predicted 81, but our experimental results indicated that 82 was the major product (Scheme [18])!

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Scheme 18 Models comparing the acylation product of 80 via a cation-π interaction or a cation-n interaction

To get the experimentally observed product 82, we had to place the ring oxygen instead of the alkene on the top of the π-system of the acylated BTM catalyst. It appears that if there is a cation–lone pair or cation–n interaction between the lone pair of the oxygen atom on the pyranose ring, we can then predict the correct reaction outcome. One way to evaluate this hypothesis was to try a monosaccharide substrate, where we eliminate the enone moiety, which was previously thought to be the directing group, but retain the pyranose ring. With a monosaccharide substrate, we could test whether or not it was actually the ring oxygen that dictated the reaction outcome.

In 2017, we demonstrated that our DKDA method could be applied to saturated pyranosides.[22] This was a significant step forward in the realm of carbohydrate synthesis because, until this work, chemists lacked a general, catalyst-controlled method for the stereoselective acylation of anomeric hydroxyl groups (Scheme [19]).

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Scheme 19 Overview of the BTM-catalyzed dynamic kinetic diastereoselective acylation of anomeric hydroxyl groups

We screened commercially available chiral catalysts for the DKDA of glucose derivative 85 (Scheme [20]). We determined that (S)-tetramisole 38 and (S)-BTM 42 were the best catalysts for producing the β-anomer as the major product while (R)-BTM 41 provided the α-anomer as the major product. Although using the anhydride method with isobutyric anhydride for the catalyst screening worked well enough, favoring a 1:13 ratio of 86/87, we once again turned to Shiina’s mixed anhydride method. And again, the mixed anhydride method, which used isobutyric acid and pivalic anhydride, proved superior and increased the ratio of 86/87 to <1:20 with (S)-BTM.

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Scheme 20 Screening of catalysts and conditions for the BTM-catalyzed dynamic kinetic diastereoselective acylation of anomeric hydroxyl groups

The mixed anhydride method also allows for a greater variety of anomeric esters to be formed because it uses many readily available carboxylic acids. The mixed anhydride method worked great in conjunction with (S)-BTM and phenylacetic acid to make β-anomer 101, but the results for the formation of the α-anomer 100 left room for improvement since the ratio of 100/101 was only 7:1. To increase the selectivity for the α-anomer we examined BTM catalysts with varying steric and electronic properties, but (R)-BTM remained the best option. Solvent screening showed that chloroform, which was used in our previous acylation work, was still our best option.

A variety of carboxylic acids were amenable to this reaction, including acetic acid, long alkyl chain carboxylic acids, and unsaturated acids. The β-anomers were consistently obtained with high selectivity, and the selectivity for the α-anomer ranged from 6:1 to 8:1. The scope of carbohydrates for this method is also shown in Scheme [21]. When an achiral catalyst, DMAP 90, was used for this reaction, the intrinsic selectivity was generally low. However, we were able to show that chiral catalysts could enhance or even override the intrinsic selectivity in the case of β-mannoside 91c and β-xyloside 91d. We also showed that the α- or β-acyl sugars 92 and 93 formed via this method exhibited different reactivity to the same reduction protocol. In fact, only 89 can undergo controlled reduction to form 94.

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Scheme 21 Scope of carbohydrates for the BTM-catalyzed dynamic kinetic diastereoselective acylation of anomeric hydroxyl groups

The diastereoselective anomeric hydroxyl acylation is another example of how we have used chiral catalysts to solve a longstanding problem in carbohydrate synthesis. Furthermore, since carbohydrates are prevalent in natural products and pharmaceuticals, the ability to predictably functionalize the anomeric position is essential for downstream transformations. The stereoselectivity we observed for these carbohydrate substrates without any π-system in the ring is consistent with the cation–n interaction model proposed in Scheme [18]. The more rigorous analysis of the cation–n interaction with the support of computational chemistry is illustrated later.

We also applied the developed method to non-carbohydrate substances. 2-Chromanols, which are important intermediates for the synthesis of various bioactive pharmaceuticals, can also be enantioselectively acylated under BTM catalysis, following the same mechanism and a dynamic kinetic enantioselective acylation process.[23] This work showed that our developed method can be widely used in the synthesis of bioactive pharmaceuticals beyond carbohydrates.

Our work with carbohydrates, however, was far from over. In fact, the rest of this review will focus on how acylation reactions may provide some solutions for two major questions in carbohydrate chemistry – the site-selective functionalization of carbohydrates and the glycosylation reaction.


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Using the Same Chiral Organocatalysts for Site-Selective Acylation

While working on the BTM-catalyzed stereoselective acylation of the anomeric hydroxyl group, we started thinking if there were other places we could use the BTM catalysts. As discussed earlier, site-selective functionalization of carbohydrates is essential for the efficient synthesis of carbohydrate building blocks. Historically, most attention has been given to differentiating cis-diols in carbohydrates.[2`] [e] , [24] This differentiation is possible because the intrinsic reactivity of axial and equatorial hydroxyl groups in a cis-diol is different, and this difference can be further amplified by chelation with metals.[25] trans-Diols are much harder to site-selectively functionalize in a systematic way because both hydroxyl groups are in equatorial positions.

We once again relied on reagent control, employing paired chiral BTM catalysts, to differentiate trans-diols in O-glycosides and more complicated substrates through a cation–lone pair interaction discussed previously.[26]

We first used (R)-BTM 41 and isobutyric anhydride to functionalize commercially available α-glycoside 95. We obtained C3-acylated product 96 in 92% yield with greater than 20:1 selectivity (Scheme [22]). Interestingly, when we used (S)-BTM 42 as the catalyst, the major product was the C2-acylated glucoside 97, which was obtained in 94% yield and favored in 17:1 ratio over 96. The site-selectivity of this method is even more impressive considering that there was no intrinsic selectivity when achiral DMAP was used as the catalyst.

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Scheme 22 Paired chiral BTM-catalyzed site-selectively functionalization of hydroxyl groups in a monosaccharide

We had the above nearly perfect site-selective acylation result right after we published the stereoselective acylation method in 2015. However, when we applied the same conditions on β-glucoside, no site-selectivity was observed using either (R)- or (S)-BTM catalyst. We thought this reaction was limited to α-glycosides and then tried α-galactoside. Again, neither (R)- nor (S)-BTM catalyst provided any site-selectivity. We stuck with one substrate, α-glucoside, for a long time without being able to extend the scope of the reaction. We realized that we needed to understand the mechanism of the reaction and the source of the site selectivity in order to make any progress. However, we could not rationalize it using any known interactions reported for chiral organocatalysts. We started going back to our previously reported stereoselective acylation to examine whether it was really directed by a cation–π interaction. As discussed before, a cation–π interaction does not lead to the observed stereoisomer, and we recognized a cation–n interaction as the controlling factor for stereoselectivity. Does the same type of cation–n interaction govern the site-selective acylation of α-glucoside? After using the molecular modeling kit with chiral BTM-catalysts, α-glucoside, β-glucoside, and α-galactoside, we determined that all of the results we obtained, either positive or negative, made perfect sense if we introduced the cation–n interaction to the system.

The top half of Scheme [23] shows the catalytic cycle for (R)-BTM-catalyzed selective acylation of the C3-OH group, which was facilitated by the lone pair on the C4-oxygen. A cation was generated after the acylation of the BTM catalyst to form an active catalyst 104. The acyl group remained in the same plane as the heterocycle due to the non-bonding interaction between the oxygen and sulfur.[27] The C3-OH group attacks the carbonyl in 105 from the top face of the heterocycle to avoid a steric clash with the phenyl group located on the bottom of the ring. This will place the lone pair on the equatorial C4-oxygen pointing towards the cationic (R)-BTM catalyst and make the C4-oxygen an ‘anchor’ atom for the acylation of C3-OH group, as shown in the bottom half of Scheme [23]. On the other hand, for C2-OH acylation, the lone pair on the axial anomeric oxygen, which is located on the top face of the heterocycle, points away from the cationic catalyst for the acylation of the C2-OH group. Because of the wrong geometry of axial anomeric oxygen, it cannot work as an ‘anchor’ atom to facilitate the acylation of adjacent C2-OH group. On the other hand, the C3-OH group cannot be an ‘anchor’ for the acylation of the C2-OH group, because of significant steric repulsions between the acylated catalyst and the substrate. The (R)-BTM catalyst-mediated acylation of the C3-OH group is therefore favored, while the acylation of the C2-OH group is disfavored. This rationalized why selective acylation of the C3-OH group was observed for α-glucoside, when the (R)-BTM catalyst was employed. This is summarized in Ia and Ib (Scheme [24]A) with the arrow indicating how the lone pair in the right direction can or cannot facilitate the acylation of the corresponding OH group.

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Scheme 23 Mechanism for the site-selective acylation of trans-1,2-diols in α-glucoside

When the (S)-BTM catalyst was employed for the acylation of α-glucoside, the axial anomeric methoxy group can create a steric clash with the catalyst and disable the cation–n interaction between the lone pair on the C2-oxygen and the cationic catalyst for C2-OH acylation (Ic, Scheme [24]B). When using C4-oxygen as the ‘anchor’ atom, DFT calculations again showed steric repulsion between the substrate and BTM catalyst. Thus, C3-OH acylation is disfavored. In contrast, selective C2-OH acylation was observed in this case. It can be rationalized by a favorable transition state in which C3-oxygen acts as an ‘anchor’ atom, as shown in Id (Scheme [24]B). The disfavored situation in Ib and Ic is due to the axial anomeric OMe group. In the case of β-glucoside, the chemical environments of both hydroxy groups are similar, in which case all four situations (IIa–d, Scheme [24]C/D) are favored. This explains why no selectivity was observed for β-glucoside using either enantiomer of the catalyst.

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Scheme 24 Predictive models for the site-selective acylation of trans-1,2-diols

We generalized the above DFT calculations to a predictive working model that can be easily applied to other monosaccharides (Scheme [24]E). We can use our right hand to predict the site-selectivity of (R)-BTM-catalyzed acylation and our left hand to predict the site-selectivity of (S)-BTM-catalyzed acylation. If the thumb aligns with the C–H bond on the dotted carbon and points to the hydrogen atom, the rest of the fingers will curve towards the adjacent anchor OH or OR that is supposed to interact with the acylated catalyst. If the anchor OH or OR is on the equatorial position and there is no adjacent axial substituent, it is a favored situation (e.g., I and IV). If the anchor OH or OR is in the axial position (e.g., II) or in the equatorial position with an adjacent axial substituent (e.g., III), the anchor is not able to interact with the catalyst (defined as disabled O). It is therefore a disfavored situation. It is also a disfavored situation if the anchor OH or OR is replaced by a group without any lone pair, such as the anomeric position in C-glycosides. One would also expect a disabled anchor if the oxygen is attached to an electron-withdrawing or sterically demanding group. By using this model, we are able to predict what substrates can or cannot undergo selective acylation using which catalyst. Indeed, we observed high selectivity for all substrates that were predicted to be selective and low selectivity for all substrates that were predicted to be unselective. This was further elaborated in 2021 by more detailed calculations.[28]

We were able to functionalize a broad range of trans-1,2-diols in common sugars including glucosides, galactosides, mannosides, rhamnosides, and also xylosides. This strategy could even be extended to more complex substrates, including trehalose derivative 98 and disaccharide 101, which have two hydroxyl groups in two different monosaccharides (Scheme [25]).

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Scheme 25 Site-selectivity for complex substrates

Overall, our theoretical predictions were consistent with experimental evidence. We could now systematically and predictably achieve the site-selective acylation of trans-diols in carbohydrates. It is worth mentioning that our method was applied by the Wan group to the synthesis of complicated oligosaccharides with a macrolactone group in 2020.[29]

When we were considering how to extend the scope of the cation–lone pair directed acylation of O-glycosides, we wondered if we could similarly acylate S-glycosides through the same interaction because they’re isoelectronic with O-glycosides. Already thinking ahead, we knew if this method could be applied to S-glycosides, then we could significantly streamline the synthesis of oligosaccharides. S-Glycosides are extremely valuable in carbohydrate chemistry because they are quickly synthesized, stable to many protecting group manipulations, and can be easily converted into other glycosyl donors.[30] In 2019, we reported that we could indeed use S-glycosides to direct site-selective acylation.[31]

We synthesized various S-glycosides with thioalkyl and thioaryl substituents and used them in our previous site-selective acylation protocol with chiral BTM catalysts to determine the best directing group. Based on our previous cation–lone pair interaction work, we anticipated that sterically unencumbered thiosubstituents, such as S-ethyl and S-phenyl, would lead to the best selectivity; but they only resulted in minimal selectivity enhancements compared to results using the achiral catalyst DMAP. We later determined that the sterically bulky adamantyl substituent was the best directing group, favoring C2-acylated product 107 in a >20:1 ratio over its C3-acylated counterpart (Scheme [26]). Additionally, the 1-adamantanethiol used to synthesize the substrates is a solid thiol that does not exhibit the offensive odors that many liquid thiols boast.[32] Furthermore, adamantyl-substituted S-glycosides avoid undesired aglycon-transfer reactions that can occur between trichloroimidate glycosyl donors and thioglycoside acceptors,[33] and they are more reactive than other S-glycoside donors such as S-phenyl.[34]

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Scheme 26 S-Adamantyl group directed site-selective acylation

We were happy with the selectivity results, but we were perplexed because they were counterintuitive to our previous site-selectivity model. To better understand what factors contributed to the high C2-selectivity, our collaborators once again performed DFT calculations. They determined that dispersion interactions between the C–H bonds of the adamantyl group and the π system of the cationic acylated BTM catalyst were to credit. Since the bulky adamantyl group is effectively locked into the exo-syn-conformation by the exo-anomeric effect[35] and multiple C–H bonds from adamantane are available for the C-H-π interactions, it was not surprising that we only saw high selectivity for the C2 position.

We also wanted to investigate the relative strength of the cation–lone pair interaction we previously reported versus the newly discovered dispersion interactions (Scheme [27]). Substrates 108 and 111 were used to compare the interactions. Compound 108 can engage in a cation–lone pair interaction because of the C4 oxygen’s lone pair, but it can also participate in dispersion interactions because of the adamantyl group’s presence. We observed that the cation–lone pair interaction slightly outcompetes the dispersion interactions because the C3-acylated product 109 was favored over the C2-acylated product 110. However, in substrate 111, the para-nitrobenzylidene group electronically decreases the ability of the C4 oxygen lone pair to interact with the cationic catalyst so the C2 acylated product 113 becomes favored over the C3 acylated product 112.

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Scheme 27 Comparison of the relative strength of cation–lone pair and dispersion interactions. Reagents and conditions: (a) 41, (R)-BTM (10 mol%), isobutyric anhydride (2.5 equiv), i-Pr2NEt (3.0 equiv), CHCl3, rt, Ar.

We found that this method could be used to introduce various acyl groups to the final product, depending on the carboxylic acid used to make the mixed anhydride, and site-selectivities often exceeded 20:1 for the C2-acylated product (Scheme [28]). Furthermore, the carboxylic acids could include alkene, alkyne, and ketone functionalities for use in further transformations. Because this method always resulted in preferential acylation of the C2 hydroxyl, 1,2- and 1,3- diols could be functionalized equally well.

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Scheme 28 Partial substrate scope for S-adamantyl directed acylation. Reagents and conditions: (a) 41, (R)-BTM (10 mol%), carboxylic acid (2.5 equiv), Piv2O (2.5 equiv), i-Pr2NEt (3.0 equiv), CHCl3, rt, Ar; (b) C2/C3 or C2/C3/ C2+C3 for C2,C3-diols; C2/C4 or C2/C4/C2+C4 for C2,C4-diols. The values within parentheses are the ratios obtained when DMAP (10 mol%) was used as a catalyst. (c) 42 (S)-BTM was used as the catalyst for l-fucose.

With the development of a method for the site-selective acylation of S-glycosides behind us, we anticipated that the acylated products could be easily activated for use as glycosyl donors for glycosylation reactions. Additionally, the presence of the newly installed C2 acyl group allows for neighboring group participation to provide an intrinsic driving force for the formation of β-glycosidic bonds. This is demonstrated by the formation of products 125a–e from the reaction between glycosyl donor 123 and glycosyl acceptors 124a–e in Scheme [29]. Finally, this method was used to streamline the synthesis of the protected carbohydrate core 126 of isoglobotrihexosylceramide, a glycolipid that has been shown to be an antigen for natural killer T cells.[36]

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Scheme 29 Demonstration of the S-glycoside’s ability to promote β-glycosidic bond formation through the presence of a C2 acyl group

The S-adamantyl group-directed C2 hydroxyl acylation allows for the elimination of tedious protection and deprotection steps often required for site-selective functionalizations. Because of the regioselectivity, we anticipate that this method can also be applied to the function of minimally protected sugars.

Now with our ability to site-selectively acylate trans-1,2-diols, we wondered if we could successfully execute other types of site-selective functionalization. We chose site-selective phosphoramidation as our next target because phosphoramidated carbohydrates have found use in prodrugs[37] and have been studied as anti-tumor agents.[38] While the site-selective acylation of O- and S- glycosides was relatively straightforward, successful phosphoramidation would pose more of a challenge. Since phosphoramidates are chiral at the phosphorous center, a high degree of both site- and stereoselectivity would have to be obtained in order for our method to be widely useful.

Bicycloimidazole-based catalysts have been used for the dynamic kinetic resolution of phosphorous centers[39] and to install phosphoramidates on primary alcohols of nucleotides,[40] so we reasoned these catalysts would be a good place to start. In 2019, after screening multiple chiral catalysts and chiral electrophiles, we reported that bicycloimidazole-based catalyst 128 and (d)-alanine-derived chiral electrophile 129 could be used to achieve the site-selective phosphoramidation of α-glucosides and β-galactosides (Scheme [30]).[41] A dynamic kinetic resolution at the phosphorus center contributes to the stereoselectivity of the reaction. Then, the high stereoselectivity promotes the high site selectivity.

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Scheme 30 Site-selective phosphoramidation of carbohydrates using a chiral catalyst and chiral electrophile (top) and partial substrate scope (bottom)

The method worked well for α-glucoside 95, favoring the formation of 130 over 131. However, for β-glucoside 132 no selectivity resulted. We presume this is because of the high degree of symmetry within the molecule, which doesn’t allow the formation of the chiral catalyst/electrophile system to differentiate between the diols because they’re too similar. This method was rather limited to benzylidene-protected pyranosides that featured O-methyl or O-allyl groups at the anomeric position. To our knowledge, this was the first reported site- and stereoselective phosphoramidation reported in the literature, and we hope it will find use in streamlining the synthesis of phosphoramidated carbohydrates.

Aside from using chiral catalysts to direct site-selective acylation and phosphoramidation, we’ve also had success using anomeric esters and copper salts to promote stereoselective glycosylation reactions under very mild conditions.


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Glycosylation under One of the Mildest Conditions Using an Ester as the Leaving Group

Traditionally, stereoselective glycosylations rely on strong Lewis acids, Brønsted acids, or reactive electrophiles to proceed efficiently.[42] However, glycosyl donors that can be easily activated under mild and neutral conditions are extremely attractive. In 2017, we reported that isoquinoline-1-carboxylate was a glycosyl donor that could do just that (Scheme [31]).[43]

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Scheme 31 Isoquinoline-1-carboxylate as a traceless leaving group for chelation-assisted glycosylation

We knew of reports[44] where transition metals could activate anomeric ester donors for glycosylation, but these cases all require purification post-reaction. Our thought was to improve upon these methods by having the carboxylate precipitate out of the solution after the reaction through chelation,[45] thereby rendering it a traceless leaving group.

We first used Cu(OTf)2 to examine anomeric picolinic esters as the glycosyl donor, but we observed significant amounts of transesterification products. We reasoned that a bulkier substituent on the 3-position of the picolinic ester could help prevent nucleophilic attack of the acceptor on the carbonyl carbon, which would minimize the transesterification product.

We identified isoquinoline-1-carboxylic acid as the most inexpensive yet sterically encumbered reagent.[43] The isoquinolinic esters were easily prepared, and they provided the desired products using 60 mol% Cu(OTf)2. We also completed a competition experiment between anomeric picolinic and isoquinolinic esters to determine their relative reactivity and determined that the isoquinolinic ester was far more reactive. Additionally, this ester was benchtop stable for months at room temperature. Our new anomeric ester worked well as the glycosyl donor when present within a variety of monosaccharides and with both primary and secondary alcohols as acceptors of varying complexities (Scheme [32]). Because our isoquinolinic ester activated by copper was orthogonal to the anomeric ester activated by gold, reported by Yu,[44c] [46] we used these complementary approaches to complete an iterative synthesis of tetrasaccharide 136.

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Scheme 32 Partial substrate scope using isoquinoline-1-carboxylate as a traceless leaving group (top) and tetrasaccharide synthesized (bottom)

Even though picolinic esters didn’t work well for glycosylation reactions, in 2020 we reported that they could be used to make glycosyl chlorides and glycosyl bromide under mild and neutral conditions, just like our previous isoquinolinic esters.[47] Picolinic esters are stable glycosyl donors that are activated by nontoxic copper(II) salts under mild conditions.[48] As we screened copper(II) sources for the activation of isoquinolinic esters in our previous work, we observed that glycosyl chlorides were produced instead of the desired O-glycoside product. As an added advantage, the glycosyl chloride was produced under mild enough conditions that historically acid-labile protecting groups could be present on the substrate.

The substrate scope for this work was rather large; therefore, only a small portion is shown in Scheme [33]. All benzylated sugars led to the α-isomer as the major product in high yield, and this configuration was achieved independent of the anomeric picolinic ester’s stereochemistry, which suggests the involvement of an oxocarbenium intermediate. In most cases, the crude glycosyl halide product could be used for further derivatization without purification. When electron-withdrawing protecting groups were present on the starting materials, the reactions required longer reaction times and an increased amount of CuCl2, but they still produced the glycosyl chlorides in good yield. However, starting materials with gluco-configurations resulted in β-isomers as the major product, such as in 146, which indicates that C2 neighboring group participation is the major contributor to anomeric stereoselectivity.

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Scheme 33 Synthesis of glycosyl chlorides and glycosyl bromides through chelation-assisted activation of picolinic esters (top) and partial substrate scope (bottom)

Glycosyl bromides could also be accessed easily using CuBr2, but regardless of the presence of armed/disarmed protecting groups on the starting materials, only α-glycosyl bromides were produced. These results are logical considering that the bromide ion is a better leaving group compared to the chloride ion, and the high reactivity of β-glycosyl bromides. Unfortunately, we were unable to produce glycosyl fluorides or iodides in the same manner, using copper(II) fluoride and copper(I) iodide, respectively. We were, however, able to demonstrate the utility of this method by synthesizing two disaccharides from glycosyl bromides, including 135a and 149 (Scheme [34]).

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Scheme 34 Glycosyl bromide donors for the synthesis of disaccharides

We further showed that anomeric picolinic esters can be used as glycosyl donors for C-glycosylation reactions in 2020.[49] With the activation of corresponding picolinic esters by Cu(OTf)2, different C-glycosides were obtained in up to 95% yield with moderate to excellent stereoselectivities (Scheme [35]). Both allyltrimethylsilane and silyl enol ethers can be used as nucleophiles, however, allylations of various armed glycosyl picolinates afforded the corresponding C-glycosides in excellent stereoselectivities (150–154), while glycosylations of armed glycosyl picolinates with silyl enol ethers exhibited only moderate stereoselectivities in most cases (155–158). The glycosylation reactions were performed under mild neutral conditions and the use of harsh Lewis acids was avoided. Considering the good yields, high synthetic efficacy, availability of starting materials, and relatively low cost of copper salts, picolinic esters are promising glycosyl donors for C-glycosylation.

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Scheme 35 Partial substrate scope using picolinic esters as glycosyl donors for C-glycosylation

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Conclusion

In order for glycobiologists to better understand the roles of carbohydrates in human health and diseases, chemists are tasked with finding new methods to expedite the synthesis of carbohydrates. This task will require current members of the field to be creative and think outside of their wheelhouse to address the two problems that consistently plague carbohydrate chemists – site-selective functionalization for efficient preparation of building blocks and stereoselective glycosylation to connect the building blocks together. We hope this review has been informative and has shown the reader how our group has approached carbohydrate synthesis using a simple acylation reaction. We have recently expanded the toolbox to include site-selective alkylation reaction by a Rh-catalyzed carbene OH insertion[50] and epimerization reaction by a Ru-catalyzed redox process.[51] We look forward to the introduction of additional methods for efficient and selective carbohydrate synthesis in the future.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The research detailed in this review was completed thanks to the critical thinking, planning, and experimental execution of several postdoctoral fellows, graduate students, visiting students and scholars, and our collaborators. Their curiosity, intellectual prowess, resiliency, and loyalty to each other will always be remembered. We offer a special thank you to Dr. Haoyaun Wang for recounting many of his lab memories as the first group member working on carbohydrate chemistry. We would like to thank the University of Wisconsin—Madison School of Pharmacy for their support.


Corresponding Author

Weiping Tang
Department of Chemistry, University of Wisconsin-Madison
1101 University Ave, Madison, WI 53706
USA   

Publication History

Received: 21 October 2023

Accepted after revision: 20 November 2023

Accepted Manuscript online:
20 November 2023

Article published online:
10 January 2024

© 2024. Thieme. All rights reserved

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Scheme 1 Summary of the reactions covered in this review
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Scheme 2 Overview of the iridium(I)-catalyzed dynamic kinetic stereoselective isomerization (top) and partial substrate scope (bottom)
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Scheme 3 Formal synthesis of the carbohydrate noviose
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Scheme 4 Formal synthesis of deoxy sugars using the iridium-catalyzed isomerization to obtain necessary intermediates. Reagents and conditions: (a) [Cp*RhCl2]2 (0.05 mol%), (R,R)-TsDPEN (0.12 mol%), HCO2Na, 40 °C, 98%; (b) NBS, 85%; (c) [Ir(COD)Cl]2 (2.5 mol%), rt, 76%; (d) H2, Pd/C; (e) DIBAL-H, 40% over 2 steps; (f) PPh3, p-O2NC6H4CO2H, DEAD, then MeOH, Et3N, 75% over 2 steps.
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Scheme 5 Optimized conditions (top) and selected products (bottom) for the iridium-catalyzed dynamic kinetic stereoselective allylic etherification
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Scheme 6 Proposed mechanism for the iridium-catalyzed dynamic kinetic isomerization (dotted lines) and the iridium-catalyzed dynamic kinetic stereoselective allylic etherification (solid line)
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Scheme 7 Overview of the dynamic kinetic diastereoselective acylation (DKDA) of lactols
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Scheme 8 Screening of anhydrides for the DKDA of lactols using (S)-levamisole
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Scheme 9 Results of using Birman’s benzotetramisole catalysts and Shiino’s mixed anhydride method for the DKDA of lactols and results from palladium-catalyzed glycosidation. Reagents and conditions: (a) (R)-BTM 41 (10 mol%), PhCH2CO2H (1.3 equiv), Piv2O (1.3 equiv), i-Pr2NEt (2.5 equiv); (b) (S)-BTM 42 (10 mol%), PhCH2CO2H (1.3 equiv), Piv2O (1.3 equiv), i-Pr2NEt (2.5 equiv); (c) Pd2(dba)3 (2.5 mol%), PPh3 (10 mol%), BnOH; (d) Pd2(dba)3 (2.5 mol%), PPh3 (10 mol%), BnOH, i-Pr2NEt.
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Scheme 10 Preparation of key intermediates 48 and 49 for the synthesis of all eight stereoisomers of 2,3,6-trideoxyhexopyranosides. Reagents and conditions: (a) Boc2O, DMAP, –78 °C; (b) Pd2(dba)3 (0.5 mol%), PPh3 (2 mol%), BnOH; (c) Boc2O, NaOAc, 80 °C.
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Scheme 11 Preparation of four 2,3,6-trideoxyhexopyranoside stereoisomers. When achiral ligand 50 was used, low intrinsic diastereoselectivity was observed. When chiral ligand 51 or 52 was used (depending on the desired product), complete stereoselectivity was observed. Reagents and conditions: (a) Low intrinsic diastereoselectivity with achiral ligand 50; [Cp*RhCl2]2 (0.5 mol%), 50 (1.2 mol%), HCO2Na, 40 °C; (b) Complete stereoselectivity with chiral ligands 51 or 52; [Cp*RhCl2]2 (0.5 mol%), 51 or 52 (1.2 mol%), HCO2Na, 40 °C.
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Scheme 12 Divergent de novo synthesis of all eight stereoisomers of 2,3,6-trideoxyhexopyranosides using a chiral catalyst-controlled reduction. Reagents and conditions: [Cp*RhCl2]2 (0.5 mol%), ligand 51/52 (1.2 mol%), HCO2Na, 40 °C.
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Scheme 13 Product distribution resulting from the reduction of enone 49 as a way to investigate the mechanism of the chiral catalyst-controlled reduction. Reagents and conditions: a) [Cp*RhCl2]2 (0.5 mol%), (R,R)-Ts-DPEN 52 (1.2 mol%), HCO2Na (1.0 equiv).
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Scheme 14 Selected bioactive natural products and saccharides made using a palladium-catalyzed glycosidation and divergent chiral catalyst-directed tandem reduction
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Scheme 15 Comparison of old and new methods to access enone intermediates to obtain all stereoisomers of 2,3,6-trideoxyhexopyranosides. Reagents and conditions: (a) Boc2O, DMAP, –78 °C, 59%; (b) Boc2O, NaOAc, 80 °, 50%; (c) Pd2(dba)3 (0.5 mol%), PPh3 (2.0 mol%), BnOH; (d) BTM 41 or 42 (10 mol%), Piv2O (1.3 equiv), PhCH2CO2H (1.3 equiv), i-Pr2NEt (2.5 equiv), CHCl3; (e) Pd2(dba)3 (2.5 mol%), PPh3 (10.0 mol%), BnOH (1.5 equiv), i-Pr2NEt (1.5 equiv.).
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Scheme 16 Synthesis of all possible 2,3,4,6-tetradeoxy-4-aminopyranosides
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Scheme 17 Synthesis of 2,3,4,6-tetradeoxy-4-aminopyranoside derivatives found in natural products
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Scheme 18 Models comparing the acylation product of 80 via a cation-π interaction or a cation-n interaction
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Scheme 19 Overview of the BTM-catalyzed dynamic kinetic diastereoselective acylation of anomeric hydroxyl groups
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Scheme 20 Screening of catalysts and conditions for the BTM-catalyzed dynamic kinetic diastereoselective acylation of anomeric hydroxyl groups
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Scheme 21 Scope of carbohydrates for the BTM-catalyzed dynamic kinetic diastereoselective acylation of anomeric hydroxyl groups
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Scheme 22 Paired chiral BTM-catalyzed site-selectively functionalization of hydroxyl groups in a monosaccharide
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Scheme 23 Mechanism for the site-selective acylation of trans-1,2-diols in α-glucoside
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Scheme 24 Predictive models for the site-selective acylation of trans-1,2-diols
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Scheme 25 Site-selectivity for complex substrates
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Scheme 26 S-Adamantyl group directed site-selective acylation
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Scheme 27 Comparison of the relative strength of cation–lone pair and dispersion interactions. Reagents and conditions: (a) 41, (R)-BTM (10 mol%), isobutyric anhydride (2.5 equiv), i-Pr2NEt (3.0 equiv), CHCl3, rt, Ar.
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Scheme 28 Partial substrate scope for S-adamantyl directed acylation. Reagents and conditions: (a) 41, (R)-BTM (10 mol%), carboxylic acid (2.5 equiv), Piv2O (2.5 equiv), i-Pr2NEt (3.0 equiv), CHCl3, rt, Ar; (b) C2/C3 or C2/C3/ C2+C3 for C2,C3-diols; C2/C4 or C2/C4/C2+C4 for C2,C4-diols. The values within parentheses are the ratios obtained when DMAP (10 mol%) was used as a catalyst. (c) 42 (S)-BTM was used as the catalyst for l-fucose.
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Scheme 29 Demonstration of the S-glycoside’s ability to promote β-glycosidic bond formation through the presence of a C2 acyl group
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Scheme 30 Site-selective phosphoramidation of carbohydrates using a chiral catalyst and chiral electrophile (top) and partial substrate scope (bottom)
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Scheme 31 Isoquinoline-1-carboxylate as a traceless leaving group for chelation-assisted glycosylation
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Scheme 32 Partial substrate scope using isoquinoline-1-carboxylate as a traceless leaving group (top) and tetrasaccharide synthesized (bottom)
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Scheme 33 Synthesis of glycosyl chlorides and glycosyl bromides through chelation-assisted activation of picolinic esters (top) and partial substrate scope (bottom)
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Scheme 34 Glycosyl bromide donors for the synthesis of disaccharides
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Scheme 35 Partial substrate scope using picolinic esters as glycosyl donors for C-glycosylation