Dual Photoredox/HAT Chemistry in Carbohydrate

Dual Photoredox/HAT Chemistry in Carbohydrate Functionalization

by

Nicholas Rosano

A thesis submitted in conformity with the requirements for the degree of Master of Science

Department of Chemistry University of Toronto

© Copyright by Nicholas Rosano 2021

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Dual Photoredox/HAT Chemistry in Carbohydrate Functionalization

Nicholas Rosano

Master of Science

Department of Chemistry University of Toronto

2021

Abstract

Chemical synthesis of carbohydrate derivatives has attracted much attention due to their

prevalence in natural products. The methods for the derivatization of carbohydrate monomers

are, however, still mainly focused on the functionalization of hydroxyl groups rather than the

carbon-backbone. This thesis describes the exploration of a method for the regioselective C-H

alkylation of the anomeric position of 1,2-unprotected carbohydrate diols using hydrogen-atom

transfer (HAT)/photoredox chemistry and borinic acid catalysis. Initial experiments yielded

mixtures of alkylated products, culminating in the investigation of reaction kinetics and stability

of radical intermediates by computational analysis. A second research direction aimed at the

transformation of 2-O-acylated pyranosides to 3-keto-2-deoxypyranosides using another

HAT/photoredox system is also described. These products are suggested to arise by hydrogen-

atom abstraction at the C3-position of the pyranoside, followed by C2-O bond cleavage via spin-

center shift. Compatibility with variously configured mono-acylated substrates suggest wide

applicability for the preparation of rare, deoxygenated carbohydrates.

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Acknowledgments

Throughout the writing of this thesis, I have received a great deal of support and assistance. I

would like to thank Professor Mark S. Taylor, the Taylor group, family, and my friends for

making this work possible.

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Table of Contents

Abstract………………………………………………………………………….…………….....ii Acknowledgments……………………………………………………………………………….iii Table of Contents………………………………………………………………………………..iv List of Abbreviations…………………………………………………………………………….v List of Schemes………………………………………………………………………………..…vi List of Tables……………………………………………………………………………………vii 1 Introduction……………………………………..…………..……..…………………………...1 1.1.0 Properties and Applications of Carbohydrate Radicals….………………………….1 1.2.0 Dual Photoredox/HAT Catalysis……………………………………………………4

1.2.1 Cocatalysts for α-hydroxy C-H bond Weakening…………………………………..7 1.3.0 Photoredox-Mediated Functionalization of Carbohydrates…………………………8

1.4.0 Research Objectives………………………………………………………….…….10 2 Results and Discussion……………………………………………………………………….12

2.1 Regioselective C-H Alkylation of Carbohydrate Derivatives using Borinic Acid/Photoredox Catalysis……………………………………………………….12 2.1.1 Reaction Development and Optimization………………………….…….12 2.1.2 Computational Analysis………………………………………………….17

2.2 Site-Selective Redox Isomerizations of Pyranosides…………………………….19 2.2.1 Reaction Development and Optimization……………………………..…19 2.2.2 Scope Studies…………………………………………………………….22

3 Summary…………………………………………………………………………..…….26 4 Experimental……………………………………………………………………………27

4.1 Materials and Methods………………………………………………….………..27 4.1.1 General Information………………………………………..…………….27 4.1.2 Materials…………………………………………………………………27 4.1.3 Instrumentation…………………………………………………………..27

4.2 General Experimental Procedures………………..………………………………28 4.2.1 General Procedure for Diol Alkylation on 0.1 mmol Scale…………...…28 4.2.2 General Procedure for Constructing Diols………………………….……28

4.2.3 General Procedure for Pyranoside Transformation on 0.1 mmol Scale…29 4.2.4 General Procedure for Monoacylation of Carbohydrates A…………..…30 4.2.5 General Procedure for Monoacylation of Carbohydrates B…………..…30 4.2.6 General Procedure for Disaccharide Synthesis…………………..………31

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List of Abbreviations

Ac acetyl Bn benzyl Boc tert-butyloxycarbonyl br broad Bu4N tetrabutylammonium Bu n-butyl BzO benzoyl C carbon Cu copper d doublet DART direct analysis in real time DCM dichloromethane DMAP 4-(dimethylamino)pyridine DMF N-N-dimethylformamide DBP dibutyl phosphate DPP diphenyl phosphate equiv. equivalents Et ethyl EtOAc ethyl acetate h hour(s) M molarity m multiplet Me methyl MeCN acetonitrile MeOH methanol MS molecular sieve NIS N-iodosuccinimide NMR nuclear magnetic resonance O oxygen OH hydroxyl Piv pivaloyl ppm parts per million q quartet rt room temperature t triplet TBS tert-butyldimethylsilyl TLC thin-layer chromatography

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List of Schemes

Scheme 1: Examples of C-glycosides in pharmaceuticals and natural products………………….1

Scheme 2: Direction of attack on glycosyl radicals……………………………………………….2

Scheme 3: Classical methods for C-glycoside linkages………………….………………….……3

Scheme 4: Carbohydrate derivatives for use synthetically and biologically……………...………4

Scheme 5: Initial photoredox works………………………………………………………………5

Scheme 6: Early dual photoredox/HAT catalysis methods……………………………………….6

Scheme 7: Various methods for α-hydroxy C(sp3)−H bond weakening………………………….7

Scheme 8: Photoredox strategies for C-glycoside synthesis………………………………………8

Scheme 9: C-H activation of carbohydrates using photoredox/HAT hybrid systems…………...10

Scheme 10. Proposed mechanism for the alkylation of the anomeric position of monomers…...11

Scheme 11. Proposed scheme for isomerization of pyranosides via spin-center shift…………..11

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List of Tables

Table 1. Initial results of alkylating Diol 1 with previously developed conditions……...………12

Table 2. Investigation into compatible diols…………………………………….……………….13

Table 3. Varying SOMOphile and photocatalyst components.………………………………….14

Table 4. Varying borinic acid and HAT mediator components…………………………...……..16

Table 5. 3,4,6-Tri-O-methyl glucopyranose results……………………………………..……….17

Table 6. Bond-dissociation energy (BDE) studies: 3,4,6-Tri-O-methyl glucopyranose 6………18

Table 7. Bond-dissociation energy (BDE) and transition state studies: galactose diols…………19

Table 8. Optimization of phosphate salt component………………………………….…………20

Table 9. Effect of the ratio of phosphate salt to quinuclidine ………………………...…………21

Table 10. Substrate investigation………………………………………………………...………22

Table 11. Comparison between optimized conditions……………………………………..…….24

Table 12. Substrate scope………………………………………..………………………………25

1

Introduction

1.1 Properties and Applications of Carbohydrate Radicals

Carbohydrates are ubiquitous in nature and their diverse roles in biological systems make them

interesting objects of study for the chemical and biological communities.1 Due to their

importance as building blocks, synthetic targets, and biological tools, new methodologies for

their synthesis and derivatization are of interest.2 The applications of carbon-centered radicals

derived from carbohydrates have been on the rise for some time by facilitating the preparation of

scaffolds that have not been accessible following classical synthetic routes.3 Carbohydrate-based

radicals have been used to prepare C-linked glycoconjugate compounds, enantiomerically pure

starting materials4 and tools to investigate biochemical pathways.5

Scheme 1: Examples of C-glycosides in pharmaceuticals and natural products.

C-linked glycosides are core units within several natural products and bioactive compounds

(Scheme 1). They consist of a carbohydrate unit attached to an aglycone or another carbohydrate

unit through a C-C bond linkage. Structurally similar to their O-linked analogues, they are more

inert towards enzymatic degradation, an advantage in applications as therapeutic agents.6

Various approaches have been developed for the synthesis of C-glycosides, including

intermolecular additions of glycosyl radicals to π-systems as discussed below.6

Glycosyl radicals are among the most well studied and versatile species in carbohydrate

chemistry.7 They are readily generated from the homolytic cleavage of halides, xanthates,

thioethers, selenides and nitro compounds and more recently by C-H activation methods.8

Furthermore, they react with predictable stereoselectivity. Glycosyl radicals react with

electrophilic acceptors to give preferential axial-substituted adducts (Scheme 2A), in contrast to

2

cyclohexyl radicals which favor equatorial approach.9-11 The behavior of the anomeric-radical

depends on two main stereoelectronic effects: the anomeric effect (interaction of the semi-filled

p-orbital with the ring-oxygen lone pair) and the -oxygen effect (interaction of the semi-

occupied p-orbital with the * orbital of the co-planar -C-OR bond). The combination of these

effects induce conformational changes in the glycosyl radical with respect to the original

carbohydrate in order to maximize orbital interactions.9-11 Factors, particularly the protecting

groups, that sterically hinder access to one face or restrict conformation-shifting are capable of

altering the stereoselectivity (Scheme 2B).12,13

Scheme 2: Arrows indicate preferred direction of attack on acrylonitrile. A: Stereoselectivity of

anomeric radical. B: Conformation restriction can affect the stereoselectivity.

Intermolecular additions of glycosyl radical donors to electron-deficient alkenes is the core

synthesis of C-linked glycosides. For instance, the addition of a glycosyl radical, generated by

tributyltin hydride from glucosyl bromide 1, to the exocyclic double bond of a methylene lactone

2 provides direct access to α-(1,2)-linked C-disaccharides 3 with high diastereoselectivity

(Scheme 3A).14 Approaches to the synthesis of -linked C-glycosides include using bulky

protecting groups which causes the α-face to be more sterically hindered; metal-mediated

reductive coupling reactions; and the use of silicon tethers (Scheme 3B).12,15,16 Branched-chain

sugars can also be prepared by the intermolecular addition of non-anomeric radicals to π-systems

with the stereoselectivity of the reaction being sterically controlled by the substituents adjacent

to the radical center (Scheme 3C).17

3

Scheme 3: Classical methods for C-glycoside linkages. A: Addition of glycosyl radical to an

alkene to form on α-linked C-glycoside. B. Various methods for -linked C-glycoside formation

i: Use of bulky protecting group to block α-addition. ii: Metal-mediated reductive coupling

reaction. iii: Use of silyl-tethers as a directing group. C: Formation of branched-chain

carbohydrate with C-C bond linkage.

Other interesting uses of carbohydrate-based radicals include processes involving -

fragmentation reactions. Alkoxyl radicals undergo -fragmentation transforming the anomeric

carbon into a formate group. The carbohydrate is degraded into an acyclic product, which can

allow access to functionalized chiral synthons (Scheme 4A).18 Furthermore, radical elimination

products can be used to investigate molecular processes and mechanisms. For instance,

ribonucleotide reductase catalyzes the key transformation of ribonucleotides to the corresponding

2’-deoxyribonucleotidues providing the monomeric precursors required for DNA biosynthesis.

4

The key steps involve the formation of a C-3’ nucleotide radical via hydrogen atom abstraction

by a sulfur based radical, protonation of the 2’-hydroxyl group and sequential spin-center shift to

eliminate water eventually leading to the 2’-deoxy-3’-ketonucleotide (Scheme 4B).19 In order to

model certain steps in this mechanism, Giese and co-workers synthesized a 3’-selenocarbonyl

nucleoside which allowed for the selective generation of a C-3’adenosyl radical under mild

conditions (Scheme 4C).20 Using competition kinetic methods, it was demonstrated that these

radicals rapidly eliminate the 2’-hydoxyl group providing additional support for the biosynthesis

mechanism of 2’-deoxyribonucleides in which C-3’ nucleotide radicals represent key

intermediates.20 The application of radicals in carbohydrate chemistry not only provides high

value synthetic products but also contributes to the understanding of biological processes and the

importance of stereoelectronic effects.

Scheme 4. A: -fragmentation of carbohydrates to generate chiral azirines. B: Ribonucleotide

reductase mechanism as proposed by Stubbe. C: Synthetic model for ribonucleotide reductase.

1.2 Dual Photoredox/HAT Catalysis

Over the last century, light-mediated catalysis has enabled the construction of various

unconventional bonds formations in organic chemistry.21 Recently, the field of modern

photoredox catalysis has allowed access to a variety of novel synthetic methodologies.22 As a

complement to conventional thermal methods, photocatalysis offers a unique activation mode to

generate reactive intermediates, such as radicals and radical ions. These intermediates are

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difficult to generate using typical thermal conditions alone. A key factor in the rapid growth of

this platform has been the readily accessible organic compounds and metal complexes capable of

facilitating the conversion of visible light into chemical energy.23 This irradiation occurs at

wavelengths where common organic molecules do not absorb, allowing for the selective

excitation of the photoredox catalyst. Upon excitation, these molecules engage in single-electron

transfer (SET) events with organic substrates, providing direct access to reactive species. These

excited species generated can exist as both an oxidant and reductant simultaneously, creating

distinct organic reaction conditions.24

Scheme 5. Initial photoredox work. A: Seminal work by Kellogg. B: Work by Okada. C: Dual

Photoredox/Organocatalysis strategy by Nicewicz and MacMillan

Seminal work by Kellogg in 1978 provided the groundwork for recent developments in

photoredox catalysis. Kellogg demonstrated that the reduction of sulfonium ions to the

corresponding alkanes could be accelerated by the addition of [Ru(bpy)3]Cl2 which displayed

photocatalytic characteristics (Scheme 5A).25 Okada and co-workers would later build upon this

work by demonstrating that N-(acyloxy)phthalimides could be used as a source of alkyl radicals.

Following single electron reduction and sequential decarboxylation, the alkyl radicals formed

could be used in a variety of transformations such as chlorination, selenylation, hydrogen atom

6

abstraction and the ability to engage in conjugate additions with Michael acceptors (Scheme

5B).26 In 2008, Yoon, Nicewicz and MacMillan would demonstrate the underlying potential of

photoredox organocatalytic hybrid protocols.27,28 For instance, the direct asymmetric alkylation

of aldehydes using a catalytically generated chiral enamine intermediate proved to be a solution

to the problem of asymmetric α-carbonyl alkylation (Scheme 5C).28 These reports would

collectively trigger significant interest in the field of dual photoredox strategies.

Scheme 6. A: First dual photoredox/HAT catalysis method: hydroetherification of alkenols. B:

Alkylation of α-alcohol C-H bonds.

Hydrogen atom transfer (HAT) in a photocatalytic approach represents a unique opportunity in

organic free radical chemistry, allowing for greater versatility in the activation and

functionalization of R-H bonds. Several groups have exploited HAT catalysts for the

establishment of various dual photoredox/HAT transformations.29 Pioneering studies from the

Nicewicz group demonstrated that intermediates that do not readily interact with the

photocatalyst can be converted to products via hydrogen atom transfer with 2-phenylmalonitrile.

In their initial report, they displayed this new dual photoredox/HAT strategy by the anti-

Markovnikov hydroetherification of alkenols (Scheme 6A).30 Utilizing this catalytic strategy,

future works would entail the activation and sequential fluorination, oxygenation, alkylation and

amination of C-H bonds.31 The MacMillan group would later exploit this new approach for the

development of photoredox/HAT methodologies with the capacity to activate strong C-H

bonds.32 In 2015, MacMillan and co-workers described the use of photoredox, HAT and

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hydrogen bonding catalysis for the selective alkylation of α-alcohol C-H bonds with Michael

acceptors in the presence of other weaker C-H bonds (Scheme 6B).33 In this protocol, a

phosphate hydrogen bonding catalyst coordinates to an alcohol group, that induces a drastic

weakening of the α-hydroxy C−H bond known as the “oxyanionic substituent effect”. The

oxidized HAT catalyst, such as a tertiary amine, phosphate, or thiol, then proceeds to abstract a

hydrogen atom at that position.34 The resultant α-hydroxy radical is then readily trapped by an

electron-deficient alkene to furnish the product. This protocol provided the fundamentals to

achieve previously elusive synthetic transformations on aliphatic and hydroxylated systems.35

1.2.1 Cocatalysts for α-Hydroxy C-H bond Weakening

Alcohols represent one of the most abundant functionalities among organic molecules. The

functionalization of α-hydroxy C(sp3)−H bonds via dual photoredox/HAT catalysis is innovative

for synthetic routes and for the late-stage derivatization of complex molecules.36 Despite the

advances by MacMillan, the methodologies for the activation of alkyl alcohols as a source of

carbon-centered radicals remain relatively underdeveloped.37 The development of novel α-C-H

bond-weakening catalysts would provide great potential for exploring unprecedented reactivity,

selectivity and substrate range in C(sp3)-H functionalizations. In recent years, various methods

have been used to alkylate the C-H bonds adjacent to alkyl alcohol groups in conjunction with

dual photoredox/HAT catalysis (Scheme 7). To name a few, MacMillan and co-workers

introduced using metal alkoxides such as zinc chloride as cooperative catalysts to accelerate the

C–H alkylation of benzyl alcohols.38 Kanai has reported the use of Martin’s spirosilane as a

bond-weakening catalyst by forming a silicate to promote the C–H alkylation of various aliphatic

alcohols.39 Recently, Taylor and co-workers have reported the use of borinic and boronic acids in

combination with cis-1,2-diol moieties to induce C-H bond weakening in carbohydrates.40,41

Scheme 7. Various methods for α-hydroxy C(sp3)−H bond weakening.

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1.3 Photoredox-Mediated Functionalization of Carbohydrates

With the advent of light-mediated catalysis, the functionalization of complex molecules such as

carbohydrates has shown great promise.42 Currently, the majority of photoinduced strategies

have been reserved for the synthesis of oligosaccharides and glycoconjugates. Such methods

include O-glycosylations, S-glycosylations, O-arylations, dethiolations, and thiol-ene reactions.42

The use of these glycosylation protocols allow for the construction of glycosidic bonds which are

no longer confined to neighboring group participation, or the anomeric effect for directing newly

formed anomeric linkages.42 However these reaction types, while being versatile, do not

diversify the carbon-backbone of the carbohydrate itself. The application of photoredox hybrid

systems to the carbohydrate scaffold is underdeveloped.43 This represents a knowledge gap, and

only recent studies have outlined the promise of this approach.

Scheme 8. Photoredox strategies for C-glycoside synthesis. A: Conjugate addition using

glycosyl halides and electron-deficient alkenes. B: NHP-esters to activated alkenes. C: Dual

nickel/photoredox catalysis using carboxylic acid functionalized carbohydrates as coupling

partners

Synthesis of C-glycosides using photoredox catalysis was first introduced by Gagne in 2010.

Gagne and co-workers developed a reductive conjugate addition of glucosyl halides to activated

9

alkenes, leading to fully saturated C-glycosides with exclusive α-selectivity (Scheme 8A).44

Wang, Witte, and Minnaard would later build upon this approach in sequential years using

photoredox mediated additions of sugar-derived NHP-esters to activated alkenes (Scheme

8B).45,46 In 2018, Molander would introduce the synthesis of C-acyl glycosides using dual

nickel/photoredox catalysis and carboxylic acid functionalized carbohydrates as coupling

partners. Glycosyl radicals are generated via the decarboxylation of glycosyl carboxylic acids

with the organic photocatalyst, which efficiently couple with a variety of carboxylic acids under

nickel catalysis (Scheme 8C).47 Although useful, the methods to selectively functionalize

carbohydrates using photoredox catalysis are nonetheless very limited and focused mainly on the

anomeric and C-6 positions.

The currently developing photocatalytic HAT strategies for C−H bond activation has found

particular use for the modification of carbohydrates.48 As previously described, MacMillan

disclosed that HAT can occur from α-hydroxyl C-H bonds even in the presence of weaker C-H

bonds adjacent to ethers and acetals. This concept was demonstrated by the alkylation of a

protected galactose derivative in which the primary hydroxyl group remained unprotected

(Scheme 9A).33 The same catalytic system was then applied to the site-selective modification of

unprotected carbohydrates by Minnaard and co-workers. The transformation proceeds with C-3

alkylation on unprotected sugars being primarily favored (Scheme 9B).49 This selectively was

also used for the synthesis of rare sugar isomers through site-selective epimerization by

Wendlandt and co-workers.50 In 2019, the Taylor group achieved the stereo- and site-selective

alkylation of carbohydrates employing borinic acid and photoredox/HAT catalysis (Scheme

9C).40 These alkylated products arise from the unique interaction between cis-1,2-diols and the

organoboron cocatalyst. This interaction allows for equatorial C-H bonds to become weaker,

eventually leading to their homolytic cleavage. Due to the bicyclic nature of the borinate-

complex intermediate, the reaction proceeds with net configuration of the starting material.

Using a similar photoredox system, Taylor and co-workers also accomplished the direct

transformation of furanosides to 2’-keto-3’-deoxyfuranosides via spin-center shift (Scheme

9D).41 These products occur by boronic acid promoted hydrogen atom abstraction at the C-2’

position, followed by C-3’-O bond cleavage analogous to the previously shown mechanism of

ribonucleotide reductase enzymes.

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Scheme 9. Functionalization of C-H bonds of carbohydrates using photoredox/HAT hybrid

systems. A: Alkylation of C6 position of galactose. B: Site-selective alkylation of unprotected

sugars. C: Site-selective alkylation of 1,2-diols using borinic acids. D: Isomerization of

furanosides to 2’-keto-3’-deoxyfuranosides via spin-center shift.

1.4 Research Objectives

Recently, colleagues in our group have developed a method to achieve site-selective C-H

alkylation of carbohydrates via diarylborinic acid and photoredox catalysis.40 However, the

scope of this reaction has yet to be applied to the anomeric position of carbohydrates. As an

ongoing effort in our laboratory, we aimed to develop a new methodology for the regioselective

C-H alkylation of the anomeric position of carbohydrate derivatives using dual hydrogen-atom

transfer (HAT)/photoredox chemistry to generate spiro-fused butyrolactones (Scheme 10). These

products would arise from the unique interaction between cis-1,2-diols and the diphenylborinic

acid cocatalyst. The resulting tetracoordinate borinic ester should only form with the α-anomer

of a carbohydrate mixture therefore selectively generating only α-products. The development of

a methodology for the formation of quaternary centers on the anomeric position would provide

access to a useful class of carbohydrate products.51 For instance, quaternary centers allow

11

carbohydrates to adopt frozen conformations which can be used to investigate molecular

recognition processes.51 Moreover, inhibitors of carbohydrate-active enzymes are often derived

from glycosides containing a quaternary anomeric position.53

Scheme 10. Proposed mechanism for the alkylation of the anomeric position of monomers.

In addition to the C-H alkylation project, another research direction we have undertaken is the

site-selective redox isomerizations of 2-O-acylated pyranosides to ketodeoxypyranosides using

another HAT/photoredox system. Previously, colleagues in our group have accomplished

applying similar chemistry for the successful isomerization of furanosides to

ketodeoxyfuranosides.41 However due to high-energy intermediates in the reaction, their protocol

gave low yields for pyranosides. By introducing a leaving group at the site of deoxygenation, we

performed the desired site-selective redox transformation via spin-center shift on pyranosides

(Scheme 11). The formation of these sugars occurs in the presence of a hydrogen-bond acceptor

catalyst and HAT/photoredox conditions. The reaction proceeds with the generation of an α-oxy

carbon radical which subsequently eliminates an adjacent leaving group to furnish the

ketodeoxypyranoside product. A potential application of this chemistry is the ability to control

the stereoselectivity in the synthesis of 2-deoxyglycosides, such as digitoxin, after a 2-O-acylated

building block is used to control the stereochemistry of the glycosidic linkage. This would be an

uncommon approach compared to other deoxygenative methods.54

Scheme 11. Proposed scheme for isomerization of pyranosides via spin-center shift.

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Results and Discussion

2.1 Regioselective C-H Alkylation of Carbohydrate Derivatives using Borinic Acid/Photoredox Catalysis

2.1.1 Reaction Development and Optimization

Investigations into the alkylation of the anomeric position of carbohydrates first began by

identifying a class of suitable model substrates. For this reaction to take place, the hydroxyl

groups other than those in the C-1 and C-2 positions require some protection to generate the

desired borinate complex. In 2019, Takemoto demonstrated the synthesis of 1,2-cis-glycosides

by anomeric O-alkylation using borinic acid catalysis.55 The borinate complex formed in this

reaction would be analogous to the intermediate we would be interested in for weakening the

equatorial C-H bond on the anomeric position. The substrates used in that protocol involved the

protection of the O-3, O-4 and O-6 positions of carbohydrate monomers with benzylic protecting

groups. These O-alkylated sugars could be donating electron-density into the pyranose ring,

influencing the reactivity of the borinic ester intermediate towards glycosyl acceptors or C-H

bond cleavage. 3,4,6-Tri-O-benzyl glucopyranose 1 was synthesized and then subjected to the

conditions previously reported by our group for C-H activation on carbohydrates (Table 1).

Table 1. Initial results of alkylating Diol 1 with previously developed conditions.

Entry Equiv. 1 Equiv. Acrylate Yielda

1 2 1 15%

2 1 1 22%

3 1 2 24%

aYields determined by 1H NMR spectroscopic analysis of the unpurified reaction mixture using 1,3,5-trimethoxybenzene as an internal standard.

The reactions were run on a 0.1 mmol scale with Ir[dF(CF3)ppy]2(tbbpy)PF6 as the photocatalyst,

diphenylborinic acid as the cocatalyst and quinuclidine as the HAT mediator. 2 was generated in

13

poor yield. Inverting the stoichiometries of methyl acrylate to sugar did not significantly alter the

yield, neither did heating the crude mixture in acid resin for 3 hours to close any potential acyclic

alkylated product (result not displayed). The conversion of the reaction is considerable, with an

approximate 60-70% conversion in these instances. The remaining mass balance of the reaction

was complicated with numerous products being formed. Preparative TLC better enabled the

isolation and characterization of 2, whereas the identification of the other products appears to be

over-alkylation, fragmentation, degradation and seemingly dimerization. The α:β ratio of the

recovered starting material is still 1:1, suggesting that the rate of anomerization is sufficient for

the α-anomer to be replenished after capture of the borinic acid catalyst and sequential

alkylation.

Table 2. Investigation into compatible diols.


Due to the meager yield of 2, other diol substrates were synthesized to investigate substrate

compatibility with the reaction conditions (Table 2). The substrates were submitted to the

conditions as previously shown in Table 1., however 2 equivalents of methyl acrylate to 1

equivalent of carbohydrate were used. Once again there was little success in determining an ideal

Entry Carbohydrate Yielda Conversion

1

24% ~70%

2

26% ~60%

3

~20% >90%

14

candidate for further optimizations. The diols faced similar issues as before such as high

conversion with meager yields and complex reaction mixtures. Acylated diols proved not only

difficult to make but tended to undergo acyl migration under reaction conditions with little to no

alkylation observed (not depicted). It was determined that tri-O-benzyl galactopyranose 3 (Entry

2) would serve as the model substrate in our endeavor to optimize this reaction.

Table 3. Varying SOMOphile and photocatalyst components.

Entry SOMOphile Photocatalyst Yielda

1 R=CO2Me, R’=R’’=H Ir[dF(CF3)ppy]2(tbbpy)PF6 26%

2 R=CN, R’=R’’=H Ir[dF(CF3)ppy]2(tbbpy)PF6 11%

3 R=SO2Ph, R’=R’’=H Ir[dF(CF3)ppy]2(tbbpy)PF6 <5%

4b R=H, R’=NO2, R’’=Ph Ir[dF(CF3)ppy]2(tbbpy)PF6 0%

5c R=R’=CO2Me, R’’=Ph Ir[dF(CF3)ppy]2(tbbpy)PF6 0%

6c R=CN, R’=CO2Me, R’’=Ph Ir[dF(CF3)ppy]2(tbbpy)PF6 0%

7c R=R’=CN, R’’=Ph Ir[dF(CF3)ppy]2(tbbpy)PF6 0%

8 R=CO2Me, R’=R’’=H Ir[dF(CF3)ppy]2(bpy)PF6 28%

9 R=CO2Me, R’=R’’=H

0%

10 R=CO2Me, R’=R’’=H Ru(bpy)3Cl2 0%

aYields determined by 1H NMR spectroscopic analysis of the unpurified reaction mixture using 1,3,5-trimethoxybenzene as an internal standard. bResulted in reduction of somophile. cResulted in polymerization of somophile.

15

As part of our optimizations, the photocatalyst and SOMOphile components were addressed. It

was initially believed the radical generated at the anomeric position could not successfully be

captured by methyl acrylate and instead other more electron withdrawing SOMOphiles were

explored (Table 3). In addition, other photocatalysts were surveyed to determine the effect of

their redox potential on the reaction. As depicted in Table 3., it seems that the most ideal

SOMOphile is methyl acrylate. Popular SOMOphiles such as acrylonitrile and vinyl phenyl

sulfone saw a significant decrease in the formation of 4. These results coincide to an extent with

what was observed by our group during their optimizations of the cis-1,2-diol alkylation

project.40 It was also observed that nitrostyrenes, and various benzylidene malonates were

incompatible. These SOMOphiles would undergo reduction and polymerization, respectively. Of

the photocatalysts tested it appears that only the iridium-based photocatalysts influence the

reaction, with no significant difference between the iridium catalysts tested. Photocatalysts with

strong oxidizing and reduction potentials such as the acridinium (Entry 9) and ruthenium

catalysts (Entry 10), respectively, did not appear to form 4. These results seem to suggest that

Ir[dF(CF3)ppy]2(bpy)PF6 as the photocatalyst and methyl acrylate as the SOMOphile are the most

compatible pairings for the alkylation at the anomeric carbon.

Further optimizations were warranted to further increase the butyrolactone yield. To this end, the

borinic acid cocatalyst and HAT mediator aspect of this reaction were investigated (Table 4.). As

previously shown, standard conditions give 26% yield of 5. Concentrating the reaction to 0.50 M

has no noticeable effect on product yield. As a control to investigate the background reaction, no

borinic acid was added. As expected, no alkylation nor fragmentation of 3 was observed.

Switching the cocatalyst to a conformationally-locked borinic acid (Entry 4) halved the yield.

This may suggest that the flexibility imparted by the diphenylborinic acid may be an enhancing

factor for binding to the cis-1,2-diol moieties of carbohydrates. A couple of HAT mediators were

explored to determine if the hydrogen atom abstraction or protonation step of the mechanism

could be influencing the yield through pathways unknown. 3-Quinuclidinol, a less basic form of

quinuclidine, appears to give comparative yields as quinuclidine. The use of methyl thioglycolate

gives no observed product formation. This can be attributed to S-based HAT mediators generally

being used for hydrogen atom abstraction on weak C-H bonds such as benzylic positions.56

16

Table 4. Varying borinic acid and HAT mediator components.

Entry Borinic Acid HAT Mediator Yielda

1 (Ph2B)2O (5 mol%) Quinuclidine 26%

2b (Ph2B)2O (5 mol%) Quinuclidine 22%

3 -- Quinuclidine 0%

4

(10 mol%)

Quinuclidine 13%

5 (Ph2B)2O (5 mol%) 3-Quinuclidinol 28%

6 (Ph2B)2O (5 mol%) Methyl thioglycolate 0%

aYields determined by 1H NMR spectroscopic analysis of the unpurified reaction mixture using 1,3,5-trimethoxybenzene as an internal standard. bReaction was carried out at a concentration of 0.5 M.

Varying the components within this system does not showcase any alternatives to the already

established conditions. The conversion is high with various minor side-products unable to be

isolated or too complex to elucidate. As an effort to identify the side-products generated, 3,4,6-

tri-O-methyl glucopyranose 6 was synthesized. The rationale for the synthesis of a methylated

substrate rather than benzylated is due to two reasons. One reason is that there existed suspicion

of alkylation at the benzylic positions, leading to the various alkylated products observed.

Another reason is that the benzylic protons add another layer of complexity to the 1H NMR

spectrum. The range they occupy (5.2 – 4.2 ppm) could be overlapping upon important

carbohydrate peaks which can cause identification of side-products to be difficult. Indeed, using

6 resulted in the identification of products 7 and 8 (Table 5). The formation of butyrolactone

product 7 to 8 in a ratio of approximately 1:1 was unanticipated give given our current

understanding of the reaction mechanism. It is assumed that equatorial hydrogen atoms should

undergo hydrogen atom abstraction in preference over axial hydrogen atoms. Additionally, given

the assumed hydridicity of the anomeric position, the formation of a C-2 product should not be

17

favored kinetically or thermodynamically. Removal of the borinic acid cocatalyst did not result

in the formation of either product suggesting that the organoboron catalyst is directly responsible

for the formation of this product. The identification of isomeric product 8 motivated the

investigation of radical stabilities at the C-1 and C-2 positions as well as HAT transitions-states

studies.

Table 5. 3,4,6-Tri-O-methyl glucopyranose results

Entry Borinic Acid 7 Yielda 8 Yielda

1 Yes 24% 18%

2 No 0% 0%


2.1.2 Computational Analysis

Initially we sought to evaluate the bond-dissociation energies at the C-1 and C-2 positions of

3,4,6-tri-O-methyl glucopyranose 6 (Table 6). Calculations applied to the α-anomer display that

the most stable radical appears to form on the C-2 position (α-anomer) of both the free and

boron-bound sugar rather than the anomeric position, as had been assumed. However, the

magnitude of the difference was relatively low. A possible explanation for the unexpected

stability of the C-2 position in comparison to the anomeric position could be due to a variety of

factors such as the β-oxygen effect and intramolecular hydrogen bonding. Currently there are no

significant computational or experimental studies on the subject to support this rationale. In

2020, Linker described the use of a radical clock to determine the stability of carbohydrate

radicals in the C-1 and C-2 positions.57 This resulted in the preference for the C-1 radical,

however, these findings do not include hydroxyl groups at the designated positions which may

stabilize the C-2 radical to a greater extent than the C-1 radical. Efforts are underway in our

group to computationally describe the bond-dissociation energies on the carbon-backbone of

carbohydrates and their preferred HAT transition-states.

18

Table 6. Bond-dissociation energy (BDE) studies: 3,4,6-Tri-O-methyl glucopyranose 6

Position of C-H bond BDE (kcal/mol)

C-1 Position (Alpha) 82.7

C-1 Position (Beta) 81.7



Calculations were carried out using B97-D3/Def2-TZVP (level of theory/basis set). Solvent:

acetonitrile.

For comparison, the bond-dissociation energies of the C-1 and C-2 positions on 3,4,6-tri-O-

methyl galactopyranose were also determined (Table 7). It was found that the difference in

radical stability at the C-1 and C-2 positions was insignificant as previously observed with 3,4,6-

tri-O-methyl glucopyranose 6. Changing the protecting groups on tri-protected galactose appears

to affect the radical stabilities at those two positions. Methyl protecting groups display an

insignificant difference between the radical stabilities between the two positions. Acyl protecting

groups show a preference for the C-2 position. TMS protecting groups show a preference for the

C-1 position. The stabilization of a radical at the C-2 position when using acyl protecting groups

may occur due to the adjacent ester oxygen accepting a hydrogen bond from the O-2 hydrogen.

In combination with the thermodynamics aspect, several HAT transition-states have been

modelled for the hydrogen atom abstraction at the C-1 and C-2 positions of 3,4,6-tri-O-methyl

galactopyranose. The results indicate that the HAT at the C-1 position is only favorable by 1.2

kcal/mol over the C-2 position. This is a relatively small difference for HAT at an axial versus

equatorial position on a carbohydrate. For context, Taylor and co-workers reported differences of

greater than 3.0 kcal/mol for relative HAT activation energies on methyl α-L-

rhamnopyranoside.40 Ongoing investigations into the computational analysis of the

thermodynamics and kinetics of the reaction may provide some insight into the mechanism of

HAT on the C-1 and C-2 positions of carbohydrates.

19

Table 7. Bond-dissociation energy (BDE) and transition state studies: galactose diols

Position of C-H bond BDE (kcal/mol) R = Me BDE (kcal/mol) R = Acetyl BDE (kcal/mol) R = TMS

C-1 Position (Alpha) 82.4 81.9 80.0

C-1 Position (Beta) 82.2 82.3 82.7

C-2 Position (Alpha) 82.5 81.9 82.6

C-2 Position (Beta) 82.1 79.1 82.5

Radical Position Relative Energy (kcal/mol)

C-1 Position (Alpha) 0

C-1 Position (Beta) --



Calculations were carried out using B97-D3/Def2-TZVP (level of theory/basis set). Solvent:

acetonitrile. Transition states are in gas phase.

2.2 Site-Selective Redox Isomerizations of Pyranosides

2.2.1 Reaction Development and Optimization

As another research direction to complement the alkylation project, we have been working on the

photoredox-mediated transformation of pyranosides to ketodeoxypyranosides via spin-center

shift. As previously discussed, pyranosides were a limitation of the first-generation protocol and

20

could not isomerize pyranosides in high yields. However, this transformation may be plausible

with the assistance of a leaving group at the site of deoxygenation. Our inquiry into this subject

began when another member of this project, Julia Turner, observed that 2-O-pivaloyl-α-D-

glucopyranoside 9 undergoes isomerization to the 3-keto-2-deoxypyranoside product 10 using

tetrabutylammonium phosphate monobasic (TBAP) as a hydrogen-bond acceptor (HBA)

catalyst. Although the yield was modest, this prompted our investigation into this reaction. 9 was

chosen as our model substrate due to its ease of synthesis using methods developed by our

laboratory and its clean conversion to 10.58

Table 8. Optimization of phosphate salt component.

Salt Base Yielda

None - 27% bTBAP KHCO3 40%

Na DBP - 37%

Na DBP K2CO3 56%

K DBP K2CO3 44%

(Bu4N) DBP - 57%

(Bu4N) DBP KHCO3 46%

(Bu4N) DBP K2CO3 76%

(Bu4N) DPP - 22%

DBP K2CO3 51% aYields determined by 1H NMR spectroscopic analysis of the unpurified reaction mixture using 1,3,5-trimethoxybenzene as an internal standard. bCredit due to Julia Turner for this reaction.

Due to recent attention devoted to applications of dibutyl phosphates and electron-deficient

carboxylates as hydrogen-bond catalysts in combination with photoredox/HAT catalysis, we

began investigations into these two avenues.59,50 As part of our study, we screened a variety of

dibutyl phosphate salts in conjunction with base additives (Table 9). It appears that using K2CO3

21

as a base with the phosphates significantly increases the yield of the reaction. This is perhaps due

to the base additives neutralizing pivalic acid that presumably builds up over the reaction, which

may be detrimental to hydrogen bonding interactions between the phosphate and hydroxyl

groups. It is unknown why KHCO3 and other bicarbonates (not shown) seem to hinder the

reaction in combination with phosphates. From these findings, it appears that

tetrabutylammonium dibutyl phosphate ((Bu4N) DBP) is the most effective phosphate catalyst

for this transformation, which may be in part due to an enhanced solubility in comparison to the

other salts. The conversion of this reaction is directly correlated with the yield with no other

apparent side-products being generated when using 9 as a substrate. In addition to the

optimization of the salt and base component of the reaction, we have also been interested in

varying the salt and quinuclidine loading (Table 9). It appears that increasing and decreasing the

loading of (Bu4N) DBP has a detrimental effect on the yield of the reaction. A similar trend is

observed for varying the quinuclidine loading as well. These results suggest that the ideal salt

loading is 25 mol% with a quinuclidine loading of 20 mol%.

Table 9. Effect of the ratio of phosphate salt to quinuclidine on the yield of 10


Phosphate (mol%)

5% 10% 25% 50% 100%

10% - - 28% - -

Quinuclidine (mol%) 20% 43% 45% 57% 48% 38%

30% - - 40% - -

40% - - 34% - -

22

2.2.2 Scope Studies

The use of (Bu4N) DBP and K2CO3 for this reaction may be used as alternative to our current

conditions. Our conditions going forward involves the use of tetrabutylammonium 4-

chlorobenzoate (Bu4N 4-ClOBz) and KHCO3 as our HBA catalyst and base, respectively

(optimizations by Julia Turner). This system can form 3-keto-2-deoxypyranoside 10 in 79%

yield based on NMR yield using similar conditions to those shown previously. As such, my

focus has shifted from phosphate optimizations to substrate synthesis, whereas Julia Turner

would be running these reactions as well as synthesizing some substrates (where specified). With

optimized conditions in hand, we sought to evaluate the substrates and leaving groups that would

be compatible with the conditions developed (Table 10.). It appears that 2-O-benzoyl-α-D-

glucopyranoside (Entry 3) can transform into 3-keto-2-deoxypyranoside 10 although at

diminished yields in comparison to its pivaloyl counterpart. 4,6-Benzylidine groups (Entry 2)

affects the efficiency of the reaction. Currently developing computational studies may suggest

that the transition state involves a boat or half-chair conformation which may be required for

effective spin-center shift. This theory can account for the diminished yields of conformationally

locked carbohydrates such as 4,6-benzylidenes and conformationally labile carbohydrates such

as arabinose (Entry 6). Diminished yields are observed when using tert-butyloxycarbonyl (Boc)

and tosyl (Ts) groups as leaving groups. Based on the understood mechanism of the reaction,

these leaving groups should theoretically be more efficient at eliminating from the molecule

contrary to what is observed. Perhaps these leaving groups hinder the formation of the adjacent

α-oxy radical or are unable to eliminate from the molecule in the proposed concerted fashion.

Table 10. Substrate investigation.

Entry Carbohydrate Yieldc

1a,b

67%

23

2c

~15%

3a,b

47%

4b

<5%

5b

~30%

6c

~30%

aIsolated yields. Yields determined by 1H NMR spectroscopic analysis of the unpurified reaction mixture using 1,3,5-trimethoxybenzene as an internal standard. bPersonally synthesized substrates. cCredit due to Julia Turner for running these reactions and the substrates synthesized.

To broaden substrate compatibility, I compared our alternative phosphate conditions to substrates

which produced the desired keto-deoxypyranosides in poor yield using our optimized

carboxylate conditions. As shown in Table 11, there appears to be few differences between the

two conditions developed. However there exists a noticeable discrepancy in Entry 4. The

phosphate conditions can generate the keto-deoxypyranoside product from 2-O-benzoyl-α-L-

fucopyranoside in a combined yield of 75% in comparison to the carboxylate conditions

combined yield of 20%. Unfortunately, the axial O-4 undergoes epimerization to generate the

keto-deoxyrhamnoside product. Attempts at tuning the reaction conditions to favor the non-

epimerized product were unproductive (results not shown). Efforts to shorten the reaction time to

impede the epimerization of the product were unsuccessful as the rate of epimerization proceeds

quickly as the reaction progresses. However, the results gathered from this optimization did

display that the phosphate catalyzed conditions can produce the keto-deoxypyranoside product in

6 h. Going forward, products that may prove to be difficult to produce from the carboxylate

conditions may prove to be more compatible with our alternative phosphate conditions as shown

in Entry 4.

24

Table 11. Comparison between optimized conditions

Entry Carbohydrate Product Conditions A

Yielda,f

Conditions B

Yielda

1c

11% 10%

2b,f

20% (Mixture) 31% (Mixture)

3c

47% 40%

4c

15%d (5%)e 52%d (23%)e

5c

10% (Mixture) 12% (Mixture)

aYields determined by 1H NMR spectroscopic analysis of the unpurified reaction mixture using 1,3,5-trimethoxybenzene as an internal standard. bMixture of keto-deoxypyranoside isomers. cPersonally synthesized substrates. dNon-epimerized product. eEpimerized product at C-4. fCredit due to Julia Turner for running these reactions and the substrate synthesized.

Scope investigations are still underway for this reaction; however, we have found it successful

with various sugars (Table 12). As shown previously, this transformation works well with 2-O-

acylated glucose including those substituted at the 6-position with TBS groups. 2-O-benzoylated

mannose (Entry 2) produces the 3-keto-2-deoxypyranoside product in approximately 70% yield.

Monomers containing unprotected axial hydroxyl groups appear to undergo epimerization to the

more thermodynamically stable equatorial position. This is observed with substrates such as 2-O-

25

acylated galactose (Entry 3) and 4-O-acylated mannose (Entry 4) producing the epimerized

products in 42% and 57% yield, respectively. These conditions are also compatible with 6-deoxy

sugars; we can selectively acylate rhamnose at either the O-2 or O-4 position to give 2- or 4-

deoxy rhamnose in approximately 65% yield each. There are current investigations into the

disaccharide scope (general synthesis of these disaccharides described in experimental);

preliminary results suggest some compatibility as our initial attempt produced approximately

19% yield of the 3-keto-2-deoxy disaccharide (Entry 7). This substrate may not have worked due

to observed acetyl migration within the 1H NMR of the unpurified reaction mixture, effectively

shutting down the reaction. We have found that substrates containing acyl groups at the O-3

position are incompatible, giving little to no product. Previous research from the Minnaard and

Wendlandt groups suggest that hydrogen atom abstraction predominately occurs at the C-3

position of an unprotected carbohydrate.49,50 This coincides with what is observed; the ideal

radical is unable to form at the C-3 position and therefore cannot eliminate the leaving group

installed at the O-3 position via spin-center shift.

Table 12. Substrate scope for the transformation of pyranosides to 3-keto-2-deoxypyranosides.

Entry Carbohydrate Product Yieldc

1a,c

67%

2c

70%

3b

42% + 10%

26

4a,b,c

57%

5a,c

65%

6c

62%

7b

19%

8b

30%

aIsolated yields. Yields determined by 1H NMR spectroscopic analysis of the unpurified reaction mixture using 1,3,5-trimethoxybenzene as an internal standard. bPersonally synthesized substrates. cCredit due to Julia Turner for running these reactions and the substrate synthesized.

Summary

In summary, the regioselective C-H alkylation of the anomeric position of carbohydrate

derivatives is more difficult than expected. Alkylation at both the C-1 and C-2 positions in

similar ratios was unexpected given our current understanding of the reaction mechanism and

assumed radical stabilities. Additionally, the manipulation of protecting groups on the diol may

produce results different than those shown here. Future computational and mechanistic studies

will be able to shed some light on the preference for HAT on carbohydrate monomers containing

a hemiacetal. The photoredox-mediated transformation of acylated pyranosides into keto-

deoxypyranosides can proceed in 19-70% yield. These conditions appear to be compatible with a

wide variety of sugars. This method would allow for the formation of rare sugars and the ability

to control the stereochemical outcome of glycosylation with 2-deoxy sugars. There is currently

an ongoing expansion of the substrate scope in addition to computational studies on the radical

stabilities within this system.

27

Experimental

4.1.1 Materials and Methods

4.1.1.1 General Information

All reactions were stirred using teflon-coated magnetic stir bars at room temperature (23 °C)

unless otherwise stated. Stainless steel needles and gas-tight syringes were used to transfer air

and moisture-sensitive liquids. Schlenk flasks and 4 Å molecular sieves were stored at 140 ℃ for

at least 24 hours before use. Flash column chromatography was carried out using neutral silica

gel (60 Ǻ, 230-400 mesh) (Silicycle) using reagent grade solvents. Analytical TLC was carried

out using aluminium-backed silica gel 60 F254 plates (EMD Milipore) and visualized with a

UV254 lamp or with aqueous basic permanganate stain.

4.1.1.2 Materials

Where indicated, dry solvents are HPLC grade and purified using a solvent purification system

equipped with columns of activated alumina under nitrogen (Innovative Technology, Inc.).

Distilled water was obtained from an in-house supply. Nuclear magnetic resonance (NMR)

solvents were obtained from Cambridge Isotope Laboratories. Carbohydrate starting materials

were purchased from Sigma Aldrich or Carbosynth Ltd. (Berkshire, UK) or synthesized

according to literature procedures. All other reagents and solvents otherwise not indicated were

purchased from Sigma Aldrich or Caledon and used without further purification.

4.1.1.3 Instrumentation

1H, 13C and 2D NMR spectra were recorded using an Agilent DD2-600 (600MHz), Agilent DD2-

500 (13C, 126 MHz), Varian Mercury 400 (400MHz), or Bruker Avance III (400 MHz)

instrument at the Centre for Spectroscopic Investigation of Complex Organic Molecules and

Polymers (CSICOMP) at the University of Toronto. 1H NMR are reported in parts per million

(ppm) relative to tetramethylsilane and referenced to residual protium in the dominant solvent.

Spectral features are reported in the following order: chemical shift (δ, ppm); multiplicity (s-

singlet, d-doublet, t-triplet, q-quartet, m-complex multiplet, br.- broad); number of protons;

coupling constants (J, Hz); assignment. Where reported, assignments were made based on

coupling constants and 2D (gCOSY/HSQC/HMBC) NMR spectra. High-resolution mass spectra

(HRMS) were obtained on JEOL AccuTOF JMS-TL1000LC for DART+ at the Advanced

28

Instrumentation for Molecular Structure (AIMS) Mass Spectrometry Laboratory at the

University of Toronto.

4.1.2 General Experimental Procedures

4.1.2.1 General Procedure for Diol Alkylation on 0.1 mmol Scale

Carbohydrate/diol (0.1 mmol, 1 equiv.), (Ir[dF(CF3)ppy]2(dtbpy))PF6 (1 mg, 0.001 mmol, 1

mol%), quinuclidine (2.2 mg, 0.02 mmol, 20 mol%), and (Ph2B)2O borinic acid (1.7 mg, 0.005

mmol, 5 mol%) were combined in a ½ dram vial. A rubber septum was used to seal the vial,

which was then evacuated and backfilled with argon three times on a Schlenk line. Dry, degassed

acetonitrile (0.4 mL) was added under a balloon of argon. The balloon was removed, and methyl

acrylate was added to the vial using an airtight glass syringe. The rubber septum was quickly

replaced with the vial cap and sealed with Teflon tape. The vial was placed 5 inches from a blue

LED Kessil lamp and stirred at 1050 rpm at ~25 °C. After 16 hours, the crude reaction mixture

was concentrated under reduced pressure, and analyzed by 1H NMR spectroscopy.

4.1.2.2 General Procedure for Constructing Diols

A solution of pentaacetylated carbohydrate monomer A (2.00 mmol, 1 equiv.) in DCM (6 mL)

was treated with I2 (2.80 mmol, 1.4 equiv.) and Et3SiH (2.8 mmol, 1.4 equiv.). The mixture was

heated at reflux for 1 h, cooled to RT and treated with 2,6-lutidine (0.93 mL, 4 equiv.), EtOH

(0.68 mL, 6 equiv.) and TBAI (0.8 mmol, 0.4 equiv.). The mixture was heated at reflux for 3 h,

29

the volatiles were removed under reduced pressure and the residue was purified by flash

chromatography on silica gel to afford B.60

A solution of the acetylated orthoester B (1.23 mmol, 1 equiv.) in MeOH (5 mL) was treated

with NaOMe (0.12 mmol, 0.1 equiv.) in one portion and the resulting mixture was stirred at RT

until consumption of the starting material (ca. 45 min). The volatiles were removed under

reduced pressure and dried by azeotropic removal of water with toluene. The residue was

dissolved in dry DMF (5 mL). The mixture was cooled to 0 °C and NaH (5.32 mmol, 4 equiv.,

60% in mineral oil) was added in one portion. The alkyl halide (5.96 mmol, 4.5 equiv.) was

added via syringe and the resulting mixture was stirred overnight at RT. The reaction was

quenched with ice and extracted twice with EtOAc. The combined organic phases were washed

with brine, dried, concentrated and the residue was purified by flash column chromatography on

silica gel to afford C.60

Concentrated H2SO4 (0.13 mL) was added to a stirred solution of tri-O-alkylated orthoester (1.3

mmol, 1 equiv.) in 1,4-dioxane (4.80 mL) and H2O (2.55 mL), and the solution was refluxed for

7 h. Then, the reaction mixture was cooled down to room temperature, and solid NaHCO3 was

added until the mixture was neutralized. EtOAc and H2O were added and separated. The organic

layer was washed with water and brine. The organic layer was dried over Na2SO4, filtered, and

concentrated under reduced pressure. The crude product was purified by flash column

chromatography over silica gel to afford D.61,55

4.1.2.3 General Procedure for Pyranoside Transformation on 0.1 mmol Scale

O-acylated pyranoside (0.10 mmol), (Ir[dF(CF3)ppy]2(dtbpy))PF6 (1 mg, 0.001 mmol, 1 mol %),

quinuclidine (2.2 mg, 0.02 mmol, 20 mol %), salt additive (0.025 mmol, 25 mol%) and a small

magnetic stir bar were added to a ½ dram vial. A rubber septum was used to seal the vial, which

was then evacuated and backfilled with argon three times on a Schlenk line. Dry, degassed

30

acetonitrile (0.8 mL) was added to the vial under a balloon of argon. The rubber septum was

removed and quickly replaced with the vial cap which was sealed with Teflon tape and parafilm.

The vial was placed 5 inches away from a blue LED Kessil lamp and stirred at 1050 rpm for 24

hours at 25 ℃. After 24 hours the crude reaction was concentrated under reduced pressure and

analyzed by 1H NMR Spectroscopy.

4.1.2.4 General Procedure for Monoacylation of Carbohydrates

Prepared from an adapted literature procedure.58 To a round-bottomed flask containing

carbohydrate derivative (1.99 mmol, 1 equiv.) was added phenylboronic acid (1.99 mmol,1

equiv.) and toluene (10 mL). The reaction mixture stirred for 16 hours under reflux. The mixture

was then concentrated under reduced pressure and dried by azeotropic removal of water with

toluene. To the resulting colourless oil was added pyridine (4 mL), and the solution was cooled

to 0°C and acyl chloride (2.99 mmol, 1.5 equiv.) was added dropwise. The reaction was stirred at

RT until consumption of the starting material by TLC, after which it was quenched with

methanol (1 mL) and then concentrated under reduced pressure. The crude material was then

dissolved in EtOAc and transferred to a separatory funnel along with a sorbitol: sodium

carbonate solution (1M:1M) and hand shaken vigorously for 5 minutes. The aqueous layer was

extracted with EtOAc and the combined organic extracts were dried and concentrated under

reduced pressure. The resulting crude material was purified by flash chromatography on silica

gel.

4.1.2.5 General Procedure for Monoacylation of Carbohydrates

To a round-bottom flask equipped with a magnetic stir bar was added the pyranoside derivative

(1.00 mmol, 1 equiv.), copper (II) trifluoroacetic acid (1.30 mmol, 1.3 equiv.), and dissolved in

31

dry MeCN (8 mL). The anhydride (1.30 mmol, 1.3 equiv.) was added then 2,4,6-collidine (1.30

mmol, 1.3 equiv.) was added dropwise. The reaction stirred at 25 ℃ for 6 hours. The reaction was

then diluted with DCM and washed with 1 M HCl, saturated NaHCO3, then H2O. The organic

layer was dried over MgSO4 and concentrated under reduced pressure. The crude material was

then purified by flash column chromatography on silica gel.62

4.1.2.6 General Procedure for Disaccharide Synthesis

To a vigorously stirred, cooled (ice bath) biphasic solution of A63 (3.00 mmol) in DCM (12 mL),

acetone (1.2 mL) and sat. aq, NaHCO3 (20 mL), a solution of Oxone (3.59 g) in H2O (14 mL)

was added dropwise over 15 min. The mixture was vigorously stirred at 0°C for 30 min and then

at RT for an additional 2 h. The reaction was then extracted with DCM. The combined organic

phases were dried and concentrated to afford B (90%) as a white solid.64

B (1.4 mmol) was dissolved in DCM (1.2 mL), and EtSH (1 mL) was added. The mixture was

cooled to -78 °C, and trifluoroacetic acid anhydride (17 µL) was added dropwise. The reaction

mixture was stirred at -78°C for 20 min and then warmed up to RT. The volatiles were removed

under reduced pressure and the residue was purified by flash chromatography on silica gel (10%

to 50% ethyl acetate in hexane) to provide C (70%).65 C (0.5 mmol) and DMAP (5 mol%) was

dissolved in pyridine (5 mL) and cooled to 0°C. PivCl (3 equiv.) were added dropwise and the

reaction mixture was heated to 40°C for several days until TLC revealed consumption of the

starting material (ca. 4 days). The reaction was then extracted with DCM, washed with sat. aq.

NaHCO3, dried and concentrated under reduced pressure. The resulting residue was purified by

flash chromatography on silica gel (5% to 20% ethyl acetate in hexane) to give glycosyl donor

16 (85%).

A mixture containing the glycosyl donor 16 (0.10 mmol), glycosyl acceptor (0.11 mmol), and

freshly activated 4 Å molecular sieves (200 mg) in DCE (1.6 mL) was stirred under argon for 1 h

32

followed by the addition of Cu(OTf)2 (20 mol%). The reaction mixture was cooled to 0°C and

NIS (2.2 equiv.) was added in one portion. The reaction was stirred at 0°C until TLC revealed

consumption of the starting material (ca. 20 min). The reaction mixture was then diluted with

DCM and transferred to a separatory funnel. The organic layer was washed with 20% aq

NaHCO3, 10% sodium thiosulfate and water. The organic phase was separated, dried, and

concentrated under reduced pressure. The residue was purified by column chromatography on

silica gel (ethyl acetate/hexane gradient) to afford D.66

D was dissolved in EtOH, and Pd/C (10 % w/w) was added. The reaction mixture was purged

with nitrogen, then the flask was purged with hydrogen three times. The reaction mixture was

stirred at RT under hydrogen until TLC revealed consumption of the starting material (ca. 16 h).

The solution was filtered through Celite®, and the filtrate was concentrated under vacuum. The

residue was purified by column chromatography on silica gel (acetone/DCM gradient) to afford

the final disaccharide substrate.

3,4,6-Tri-O-benzyl-D-glucopyranose 1

Prepared according to general procedure (4.1.2.2). 1 was obtained as a white solid (343 mg, 69%) after flash column chromatography on silica (50% to 66% ethyl acetate in hexane). Spectral data agreed with those previously reported.55

Rf = 0.10 (EtOAc/Hexanes, 1:1)

1H NMR (400 MHz, CDCl3, 50:50 mixture of anomers): δ (ppm) = 7.377.13 (m, 15H), 5.24 (t, J = 3.5 Hz, 0.5H), 4.9079 (m, 3H), 4.6047 (m, 3.5H), 4.19 (d, J = 6.4 Hz, 0.5H), 4.04 (td, J = 6.7, 3.3 Hz, 0.5H), 3.79 (t, J = 9.0 Hz, 0.5H), 3.7046 (m, 5.5H), 2.59 (d, J = 2.3 Hz, 0.5H), 2.28 (d, J = 7.5 Hz, 0.5H)

13C NMR (126 MHz, CDCl3, 50:50 mixture of anomers): δ (ppm) = 138.5, 138.4, 138.0, 137.8, 137.6 (2C), 128.5, 128.4, 128.0 (2C), 127.9 (3C), 127.8 (4C), 96.7, 92.3, 84.3, 82.4, 77.6, 77.5, 77.2, 75.5, 75.3, 75.2, 74.9, 74.8, 73.5, 73.4, 72.7, 70.4, 68.7 (2C)

α:β = 1:1

33

(5R,7R,8R,9R,10R)-8,9-bis(benzyloxy)-7-((benzyloxy)methyl)-10-hydroxy-1,6-dioxaspiro[4.5]decan-2-one 2

Prepared from 1 according to general procedure (4.1.2.1). 2 was obtained as a white solid after Prep TLC (7% acetone in DCM). Purification of the sugar lactones was challenging.

Rf = 0.40 (Acetone/DCM, 7:93)

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.40-77.27 (m, 13H), 7.20-7.16 (m, 2H), 4.92 (d, J=11.8 Hz, 1H), 4.79 (dd, J=23.8, J=11.2 Hz, 2H), 4.63-5.53 (m, 2H), 4.49 (d, J=12.2 Hz, 1H), 3.91 (d, J=8.5 Hz, 1H), 3.84-3.71 (m, 3H), 3.69-3.52 (m, 3H), 2.73-2.52 (m, 3H), 2.20-2.15 (m, 1H)

HRMS (DART+, m/z): calculated for C30H36NO7 [M+H]+: 522.24918, found: 522.24863.

Partial characterization data obtained for products whose yields could not be optimized to synthetically useful levels.

3,4,6-Tri-O-benzyl-D-galactopyranose 3

Prepared according to general procedure (4.1.2.2). 3 was obtained as a white solid (343 mg, 69%) after flash column chromatography on silica (50% to 66% ethyl acetate in hexane). Spectral data agreed with those previously reported.55

Rf = 0.15 (EtOAc/Hexanes, 2:1)

1H NMR (500 MHz, CDCl3, 70:30 mixture of anomers): δ (ppm) = 7.377.26 (m, 15H), 5.32 (d, J = 2.9 Hz, 0.7H), 4.87 (d, J = 11.5 Hz, 1H), 4.744.40 (m, 5.3H), 4.154.13 (m, 1.5H), 3.933.86 (m, 1H), 3.72 (dd, J = 10.0, 2.6 Hz, 0.7H), 3.613.44 (m, 2.6H), 3.40 (dd, J = 9.7, 2.9 Hz, 0.3H), 2.71 (br s, 0.3H), 2.37 (br s, 0.7H), 1.72 (br s, 1.0H)

13C NMR (125 MHz, CDCl3, 70:30 mixture of anomers): δ (ppm) = 138.3, 138.2, 138.0, 137.8, 137.6 (2C), 128.5 (2C), 128.4 (2C), 128.3, 128.2 (2C), 128.0 (2C), 127.9 (2C), 127.8 (2C), 127.7 (2C), 97.2, 92.7, 81.9, 79.1, 74.6, 74.5, 73.8, 73.7, 73.5 (2C), 72.9, 72.5, 72.4, 72.3, 69.6, 69.2, 68.9, 68.6

34

α:β = 7:3

(5R,7R,8S,9R,10R)-8,9-bis(benzyloxy)-7-((benzyloxy)methyl)-10-hydroxy-1,6-dioxaspiro[4.5]decan-2-one 5

Prepared from 3 according to general procedure (4.1.2.1). 5 was obtained as a white solid after Prep TLC (7% acetone in DCM). Purification of the sugar lactones was challenging.

Rf = 0.50 (Acetone/DCM, 7:93)

1H NMR (500 MHz, CDCl3): δ (ppm) = 7.36-7.27 (m, 15H), 4.86 (d, J=12.0 Hz, 1H), 4.72 (d, J=11.4 Hz, 1H), 4.60-4.54 (m, 2H), 4.48 (d, J=5.1 Hz, 2H), 4.13-4.07 (m, 4H), 3.78 (dd, J=7.4, 2.7 Hz, 1H), 3.66 (m, 1H), 3.61 (m, 1H), 3.52 (dd, J=5.6, 3.7 Hz, 1H), 2.69-2.57 (m, 3H), 2.18-2.12 (m, 1H)

13C NMR (125 MHz, CDCl3): δ (ppm) = 176.0, 138.3, 137.7, 137.6, 128.7, 128.5, 128.3, 128.1, 127.9, 127.8, 108.71, 80.0, 77.2, 74.8, 73.5, 73.0, 72.8, 72.2, 70.4, 68.0, 30.3, 28.2.


3,4,6-Tri-O-methyl-D-glucopyranose 6

Prepared according to general procedure (4.1.2.2). 6 was obtained as a white solid (63 mg, 77%) after flash column chromatography on silica (0% to 10% methanol in ethyl acetate).

Rf = 0.30 (EtOAc)

1H NMR (500 MHz, CDCl3): δ (ppm) = 5.12 (d, J=3.6 Hz, 1H), 4.44 (d, J=7.8 Hz, 1H), 3.83 (ddd, J=10.1, 4.3, 2.7 Hz, 1H), 3.58 (d, J=2.3 Hz, 3H), 3.55 (dd, J=10.4, 2.1 Hz, 1H), 3.51-3.45 (m, 2H), 3.44 (d, J=1.6 Hz, 3H), 3.39-3.34 (m, 2H), 3.32 (d, J=2.1 Hz, 3H), 3.30-3.24 (m, 1H), 3.14-3.02 (m, 1.5H)

13C NMR (125 MHz, CDCl3): δ (ppm) = 96.6, 92.2, 86.1, 83.7, 79.6, 79.5, 74.7, 74.3, 72.2, 71.4, 69.1, 60.7 (2C), 60.2, 60.1, 59.0 (2C), 50.3

35

(5R,7R,8R,9R,10R)-10-hydroxy-8,9-dimethoxy-7-(methoxymethyl)-1,6-dioxaspiro[4.5]decan-2-one 7

Prepared according to general procedure (4.1.2.1). 7 was obtained as a clear oil after flash column chromatography on silica (5% methanol in ethyl acetate). Purification of the sugar lactones was challenging.

Rf = 0.60 (MeOH:EtOAc 5:95)

1H NMR (500 MHz, CDCl3): δ (ppm) = 3.75 (ddd, 10.0, 3.3, 2.0 Hz, 1H), 3.65 (s, 3H), 3.58-3.54 (m, 3H), 3.52 (s, 3H), 3.50-3.46 (m, 1H), 3.39 (s, 3H), 3.35-3.31 (m, 1H), 2.73-2.55 (m, 3H), 2.20-2.15 (m, 1H)

13C NMR (125 MHz, CDCl3): δ (ppm) = 175.8, 108.1, 84.3, 78.9, 73.8, 73.6, 70.4, 61.0, 60.2, 59.2, 29.9, 28.0


(5R,8R,9R,10S)-6-hydroxy-9,10-dimethoxy-8-(methoxymethyl)-1,7-dioxaspiro[4.5]decan-2-one 8

Prepared according to general procedure (4.1.2.1). 7 was obtained as a clear oil after flash column chromatography on silica (5% methanol in ethyl acetate). Purification of the sugar lactones was challenging.

Rf = 0.65 (MeOH:EtOAc 5:95)

1H NMR (500 MHz, CDCl3): δ (ppm) = 4.78 (d, J=4.7 Hz, 1H), 4.15 (d, J=4.7 Hz, 1H), 3.62-3.60 (m, 2H), 3.58 (s, 3H), 3.54-3.51 (m, 2H), 3.51 (s, 3H), 3.39 (s, 3H), 2.98 (dd, J=9.9, 9.4 Hz, 1H), 2.68 (ddd, J=17.9, 10.9, 8.3 Hz, 1H), 2.53 (ddd, J=17.9, 11.0, 4.5 Hz, 1H), 2.35-2.16 (m, 2H)

13C NMR (125 MHz, CDCl3): δ (ppm) = 177.7, 95.7, 87.6, 85.6, 78.7, 74.8, 71.3, 61.6, 60.6, 59.3, 29.4, 19.5

36


Methyl 2-O-pivaloyl-α-D-glucopyranoside 9

Prepared from methyl α-D-glucopyranoside (Carbosynth Ltd) according to general procedure (4.1.2.4). 9 was obtained as a white solid (343 mg, 72%) after flash column chromatography on silica (0% to 50% acetone in DCM). Spectral data agreed with those previously reported.58

Rf = 0.10 (Acetone:DCM 3:7)

1H NMR (400 MHz, CDCl3): δ (ppm) = 4.90 (d, J=3.7 Hz, 1H), 4.60 (dd, J=10.0, 3.7 Hz, 1H), 4.03–3.95 (m, 1H), 3.90–3.83 (m, 2H), 3.71–3.62 (m, 2H), 3.37 (s, 3H), 1.24 (s, 9H).

Methyl 3-keto-2-𝛂-D-deoxyglucopyranoside 10

Prepared according to general procedure (4.1.2.3). 10 was obtained as a white solid (67%) after flash column chromatography on silica (20% to 40% Acetone in DCM).


1H NMR (500 MHz, CDCl3): δ (ppm) = 5.17 (d, J = 4.4 Hz, 1H), 4.23 (dd, J = 9.8, 2.2 Hz), 3.98 (dd, J = 11.9, 2.8 Hz, 1H), 3.92 (dd, J = 12.0, 3.7 Hz, 1H), 3.76–3.72 (m, 1H), 3.35 (s, 3H), 2.82 (ddd, J = 14.0, 4.6, 1.4 Hz, 1H), 2.70 (dd, J = 14.0, 1.1 Hz, 1H).

13C NMR (125 MHz, CDCl3): δ (ppm) = 205.4, 100.1, 74.8, 73.3, 62.6, 55.1, 45.2.

IR (neat, cm-1): 3438 (w), 2930 (w), 1724 (s), 1365 (s), 1290 (s), 1194 (s), 1116(s), 1099 (s), 1034 (s), 1002 (s), 955 (s), 878 (s), 840 (s).

HRMS (DART+, m/z): calculated for C7H16NO5 [M+NH4]+: 194.10230, found: 19410223.

[𝛂]𝐃𝟐𝟎 = + 117.1 (c = 11.75 mg/mL, CHCl3)

37

Methyl 2-O-benzoyl-α-D-glucopyranoside 11

Prepared from methyl α-D-glucopyranoside (Carbosynth Ltd). Synthesized and characterized as previously reported using dibutyltin chloride.67 11 was obtained as a white solid (70%) after flash column chromatography on silica (10% Methanol in DCM).

Rf = 0.30 (MeOH;DCM 1:9)

1H NMR (400 MHz, CDCl3): δ (ppm) = 8.09 (d, J=6.9 Hz, 2H), 7.60 (t, J=7.5 Hz, 1H), 7.47 (t, J=7.5 Hz, 2H), 5.04 (d, J = 3.6 Hz, 1H), 4.91 (dd, J=3.6, 9.9 Hz, 1H), 4.16 (t, J=3.6 Hz, 1H), 3.92-3.89 (m, 2H), 3.75-3.72 (m, 2H), 3.40 (s, 3H), 2.62 (br s, 1H), 2.50 (br s, 1H), 2.00 (br s, 1H).

Methyl 2-O-tosyl-α-D-glucopyranoside 12

Prepared from methyl α-D-glucopyranoside (Carbosynth Ltd). Synthesized using a modified procedure using dibutyltin chloride.67 12 was obtained as an off white solid (14%) after flash column chromatography on silica (10% Methanol in DCM). Spectral data agreed with those previously reported.68

Rf = 0.32 (MeOH;DCM 1:9)

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.84 (d, J=8.3 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 4.65 (d, J=3.7 Hz, 1H), 4.36 (dd, J=9.7, 3.7 Hz, 1H), 4.14 (br s, 1H), 3.96-3.87 (m, 1H), 3.81 (dd, J=13.9, 2.9 Hz, 1H), 3.66-3.51 (m, 1H), 3.25 (s, 1H), 2.94 (br s, 1H), 2.43 (s, 3H)

38

Methyl 4-O-pivaloyl-6-O-(tert-butyldimethylsilyl)-𝛂-D-mannopyranoside 13

Prepared from methyl 6-O-(tert-butyldimethylsilyl)-α-D-mannopyranoside69 according to general procedure (4.1.2.4). 14 was obtained as a yellow solid (78%) after flash column chromatography on silica (30% to 50% ethyl acetate in hexanes).

Rf = 0.47 (EtOAc:Hexanes 4:6)

1H NMR (500 MHz, CDCl3): δ (ppm) = 4.93 (tt, J = 9.5, 2.0 HZ, 1H), 4.77 (d, J = 1.5 Hz, 1H), 3.92–8.85 (m, 2H), 3.7–3.67 (m, 3H), 3.39 (s, 3H), 1.22 (s, 9H), 0.88 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H).

13C NMR (125 MHz, CDCl3): δ (ppm) = 179.8, 100.4, 71.0, 70.8, 70.8, 70.6, 62.6, 55.1, 39.1, 27.2, 26.0, 18.4, -5.2, -5.2.

IR (neat, cm-1 ): 3444 (w), 2934 (w), 1731 (s), 1249 (s), 1150 (s), 1110 (s), 1038 (s), 972 (s), 836 (s), 776 (s), 569 (s).

HRMS (DART+, m/z): calculated for C18H37O7Si [M+NH4]+: 393.23031; found: 393.23089

Methyl 2-O-(tert-butyloxycarbonyl)-𝛂-D-glucopyranoside 14

Prepared from methyl α-D-glucopyranoside (Carbosynth Ltd) according to modified general procedure (4.1.2.4). Boc2O was used as the acylating agent, DMAP (10 mol%) was added. 18 was obtained as an off white solid (30%) after flash column chromatography on silica (20% to 50% acetone in DCM).


1H NMR (500 MHz, CDCl3): δ (ppm) = 4.95 (d, J=3.6 Hz, 1H), 4.47 (dd, J=10.0, 3.6 Hz, 1H), 3.96 (t, J=8.8 Hz, 1H), 3.86 (s, 2H), 3.69-3.59 (m, 2H), 3.58 (s, 1H), 3.39 (s, 3H), 3.31 (s, 1H), 1.49 (s, 9H)

13C NMR (125 MHz, CDCl3): δ (ppm) = 153.2, 97.1, 83.2, 75.7, 71.7, 70.8, 70.5, 61.9, 55.3, 27.7

IR (neat, cm-1): 3422 (w), 2989 (w), 2940 (w), 1739 (s), 1278 (s), 1154 (s), 1038 (s), 820 (s)

39

HRMS (DART+, m/z): calculated for C12H24O8 [M+NH4]+: 312.16584; found: 312.16529

[𝛂]𝐃𝟐𝟎 = +32.0 (c = 13.3 mg/mL, CHCl3)

Methyl 2-O-benzoyl-α-L-fucopyranoside 15

Prepared from methyl α-L-fucopyranoside (Carbosynth Ltd) according to general procedure (4.1.2.5). 15 was obtained as a white solid (56%) after flash column chromatography on silica (30% acetone in hexane). Spectral data agreed with those previously reported.

Rf = 0.18 (Acetone:Hexane 3:7)

1H NMR (500 MHz, CDCl3): δ (ppm) = δ 8.08–8.06 (m, 2H), 7.59–7.55 (m, 1H), 7.45–7.41 (m, 2H), 5.21 (dd, J=10.0, 4.0 Hz, 1H), 4.98 (d, J=4.0 Hz, 1H), 4.17 (dd, J=10.0, 3.2 Hz, 1H), 4.04 (q, J=6.4 Hz, 1H), 3.87 (d, J=3.2 Hz, 1H), 3.39 (s, 3H), 1.83 (br s, 2H), 1.34 (d, J=6.4 Hz, 3H)

Ethyl 3,4,6-tri-O-benzyl-2-O-pivaloyl-thio-β-D-glucopyranoside 16

Prepared according to general procedure (4.1.2.6). 16 was obtained as an off white solid (85%) after flash column chromatography on silica (5% to 20% ethyl acetate in hexane).

Rf = 0.65 (EtOAc:Hexane 2:8)

1H NMR (500 MHz, CDCl3): δ (ppm) = 7.38-7.26 (m, 13H), 7.19-7.16 (m, 2H), 5.16-5.09 (m, 1H), 4.79 (dd, J=11.0, 4.0 Hz, 2H), 4.72 (d, J=11.0 Hz, 1H), 4.63 (d, J=12.1 Hz, 1H), 4.58-4.55 (m, 2H), 4.41 (d, J=10.0 Hz, 1H), 3.78 (dd, J=11.0, 2.1 Hz, 1H), 3.75-3.71 (m, 3H), 3.54 (ddt, J=6.7, 4.7, 1.9 Hz, 1H), 2.81-2.64 (m, 2H), 1.28 (t, J=7.5, 3H), 1.22 (s, 9H)

13C NMR (125 MHz, CDCl3): δ (ppm) = 177.9, 138.2 (2C), 138.0, 128.4 (3C), 128.0, 127.8, 127.7, 127.6, 127.6, 127.4, 84.7, 83.5, 79.5, 77.8, 75.2, 75.0, 73.5, 71.5, 68.9, 38.7, 27.2, 23.6, 15.0

IR (neat, cm-1): 2976 (s), 2931 (s), 2973 (s), 1735 (s), 1503 (s), 1453 (s), 1362 (s). 1277 (s), 1134 (s), 1092 (s) 1071 (s), 749 (s) 696 (s)

40

HRMS (DART+, m/z): calculated for C34H42O6S [M+NH4]+: 596.30459; found: 596.30404

[𝛂]𝐃𝟐𝟎 = -58.0 (c = 11.0 mg/mL, CHCl3)

2-O-Pivaloyl-β-D-glucopyranoside-(1-6)-methyl 2,3,4-tri-O-acetyl-α-D-glucopyranoside 17

Prepared according to general procedure (4.1.2.6) from 16 and methyl 2,3,4-tri-O-acetyl-α-D-glucopyranoside.70 17 was obtained as a white solid (48%) after flash column chromatography on silica (0% to 10% methanol in ethyl acetate).70

Rf = 0.10 (EtOAc)

1H NMR (500 MHz, CDCl3): δ (ppm) = 5.47 (dd, J=10.2, 9.2 Hz, 1H), 4.97 (dd, J=10.1, 9.2 Hz, 1H), 4.89 (d, J=3.6, 1H), 4.83 (dd, J=10.2, 3.6 Hz, 1H), 4.73-4.69 (m, 1H), 4.51 (d, J=7.9 Hz, 1H), 3.94-3.89 (m, 2H), 3.87 (dd, J=10.5, 3.2 Hz, 1H), 3.84-3.79 (m, 1H), 3.63-3.60 (m, 2H), 3.57 (dd, J=10.6, 5.7 Hz, 1H), 3.38 (s, 3H), 2.82-2.79 (m, 2H), 2.41 (br s, 1H), 2.05 (s, 3H), 2.04 (s, 3H), 1.99 (s, 3H), 1.24 (s, 9H)

13C NMR (125 MHz, CDCl3): δ (ppm) = 178.8, 170.2, 170.0, 100.5, 96.4, 75.7, 75.3, 73.8, 71.2, 70.8, 70.0, 69.7, 68.0, 67.9, 62.1, 55.4, 39.0, 27.0, 16.3

2-O-Pivaloyl-β-D-glucopyranoside-(1-6)-1,2:3,4-di-O-isopropylidene-α-D-galactopyranoside 18

Prepared according to general procedure (4.1.2.6) from 16 and 1,2:3,4-Di-O-isopropylidene-α-D-galactopyranose (Sigma Aldrich). 18 was obtained as an off white solid (80%) after flash column chromatography on silica (20% to 50% acetone in DCM).


41

1H NMR (500 MHz, CDCl3): δ (ppm) = 5.49 (d, J=5.0 Hz, 1H), 4.69 (td, J=7.7, 2.5 Hz, 1H), 4.59 (dd, J=7.9, 2.5 Hz, 1H), 4.56 (d, J=7.8 Hz, 1H), 4.29 (dd, J=5.0, 2.4 Hz, 1H), 4.26 (dd, J=12.5, 6.0 Hz, 1H), 4.00 (dd, J=10.3, 6.1 Hz, 1H), 3.94-3.88 (m, 2H), 3.78 (dd, J=12.5, 6.0 Hz, 1H), 3.68 (dd, J=10.3, 6.1 Hz, 1H), 3.63-3.56 (m, 2H), 3.40 (ddd, J=9.0, 5.6, 3.2 Hz, 1H), 2.95 (br s, 1H), 2.90 (br s, 1H), 2.55 (br s, 1H), 1.50 (s, 3H), 1.44 (s, 3H), 1.34 (s, 3H), 1.31 (s, 3H), 1.24 (s, 9H)

13C NMR (125 MHz, CDCl3): δ (ppm) = 179.1, 109.4, 108.6, 101.0, 96.3, 75.9, 75.2, 74.3, 71.5, 70.9, 70.6, 70.5, 68.6, 66.8, 62.35, 53.8, 39.0, 29.3, 27.1, 26.1, 25.9, 24.9, 24.4

IR (neat, cm-1): 3422 (w), 2989 (s), 1739 (s), 1266 (s), 1391 (s), 1266 (s), 1182 (s), 1070 (s), 1008 (s)


[𝛂]𝐃𝟐𝟎 = -37.6 (c = 5.0 mg/mL, CHCl3)

Methyl 2-O-pivaloyl-β-D-glucopyranoside 19

Prepared according to a modified general procedure (4.1.2.6). B was treated with MeOH followed by pivaloylation. 19 was obtained as an off white solid (81%) after flash column chromatography on silica (10% to 50% acetone in DCM).


1H NMR (500 MHz, CDCl3): δ (ppm) = 4.70 (dd, J=9.5, 7.9 Hz, 1H), 4.38 (d, J=7.9 Hz, 1H), 3.95-3.84 (m, 2H), 3.72-3.57 (m, 3H), 3.50 (s, 3H), 3.43-3.34 (m, 2H), 2.72 (br s, 1H), 1.22 (s, 9H)

13C NMR (125 MHz, CDCl3): δ (ppm) = 178.7, 102.1, 75.5, 75.3, 73.9, 70.7, 61.9, 57.2, 38.9, 27.0

IR (neat, cm-1): 3412 (b), 2985 (s), 1738 (s), 1405 (s), 1485 (s), 1289 (s), 1161 (s), 1060 (s)


[𝛂]𝐃𝟐𝟎 = -19.4 (c = 5 mg/mL, CHCl3)

42

Sodium dibutyl phosphate 20

Prepared from dibutyl phosphoric acid (Sigma Aldrich). Synthesized as previously reported.71

1H NMR (400 MHz, CDCl3): δ (ppm) = 3.79 (q, J=6.5 Hz, 2H), 1.59 (dq, J=12.4, 7.0 Hz, 2H), 1.44-1.30 (m, 2H), 0.94 (t, J=7.3 Hz, 3H)

13C NMR (125 MHz, CDCl3): δ (ppm) = 33.0, 32.9, 19.1, 13.9

31P NMR (121 MHz, CDCl3): δ (ppm) = 1.50

Tetrabutylammonium dibutyl phosphate 21

Prepared from dibutyl phosphoric acid (Sigma Aldrich). Synthesized and characterized as previously reported.72

1H NMR (400 MHz, CDCl3): δ (ppm) = 3.85-3.80 (m, 4.2H), 3.42-3.35 (m, 8H), 1.70-1.60 (m, 12.4H), 1.49-1.35 (m, 12.4 H), 0.99 (t, J=7.4 Hz, 12H), 0.89 (t, J = 7.4 Hz, 6.5H)

Potassium dibutyl phosphate 22

Prepared from dibutyl phosphoric acid (Sigma Aldrich). Synthesized as previously reported.71

1H NMR (400 MHz, CDCl3): δ (ppm) = 3.81 (q, J=6.6 Hz, 2H), 1.59 (m, 2H), 1.45-1.33 (m, 2H), 0.94 (t, J=7.4 Hz, 3H)

13C NMR (125 MHz, CDCl3): δ (ppm) = 65.3 (2C), 32.9 (2C), 19.0, 13.8

31P NMR (121 MHz, CDCl3): δ (ppm) = -0.1

43

Tetrabutylammonium diphenyl phosphate 23

Prepared from diphenyl phosphoric acid (Sigma Aldrich). Synthesized as previously reported.72

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.28=7.17 (m, 4H), 7.05 (m, 1H), 3.21-3.12 (m, 2H), 1.54 (p, J=8.1, 7.6 Hz, 2H), 1.32 (h, J=7.3 Hz, 2H), 0.90 (t, J=7.3 Hz, 3H)

13C NMR (125 MHz, CDCl3): δ (ppm) = 152.3, 152.2, 129.2, 123.6 (2C), 120.4 (2C), 58.63, 23.8, 19.6, 13.6

31P NMR (121 MHz, CDCl3): δ (ppm) = -12.9

44

References

1. de Armas, P.; Francisco, C. G.; Suarez, E. J. Am. Chem. Soc. 1993, 115(19), 8865-8866. 2. Hanessian, S.; Rancourt, G. Carbohydrate Chemistry. 1977, 1201-1214, Pergamon. 3. Pérez‐Martín, I.; Suárez, E. Radicals and carbohydrates. 2012. Wiley, Encyclopedia of

Radicals in Chemistry, Biology and Materials. 4. Suárez, E.; Rodriguez, M. S. Radicals in Organic Synthesis. 2001. Wiley, 440-454. 5. Nicolaou, K. C.; Dai, W. M. Angew. Chem. Int. Ed. 1991, 30(11), 1387-1416. 6. Koester, D. C.; Holkenbrink, A.; Werz, D. B. Synthesis. 2010, 3217−3242. 7. Xu, L. Y.; Fan, N. L.; Hu, X. G. Org. Biomol. Chem. 2020, 18, 5095-5109 8. Giese, B. Angew. Chem. Int. Ed. 1985, 24, 553-565. 9. Giese, B. Pure Appl. Chem. 1988, 60(11), 1655-1658. 10. Giese, B. Angew. Chem. Int. Ed. 1989, 28(8), 969-980. 11. Dupuis, J.; Giese, B.; Rüegge, D.; Fischer, H.; Korth, H. G.; Sustmann, R. Angew. Chem.

Int. Ed. 1984, 23(11), 896-898. 12. Roe, B. A.; Boojamra, C. G.; Griggs, J. L.; Bertozzi C. R. J. Org. Chem. 1996, 61, 6442–

6445. 13. Abe, H.; Shuto, S.; Matsuda, A. J. Am. Chem. Soc. 2001, 123, 11870–11882. 14. Giese, B.; Witzel, T. Angew. Chem. 1986, 98, 459-460. 15. Miquel, N.; Doisneau, G.; Beau, J. M. Angew. Chem. Int. Ed. 2000, 39(22), 4111-4114. 16. Rubinstenn, G.; Mallet, J. M.; Sinaÿ, P. Tetrahedron Lett., 1998, 39, 3697–3700. 17. Giese, B.; Witzel. T. Angew. Chem. Int. Ed. 1986, 25, 450-451. 18. Alonso-Cruz, C. R.; Kennedy, A. R.; Rodríguez, M. S.; Suárez, E. Org. Lett. 2003, 5(20),

3729-3732. 19. Stubbe, J. Enzymol. Relat. Areas Mol. Biol. 1990, 63, 349-417.; Stubbe, J.; van der Donk,

W. A. Chem. Biol. 1995, 2, 793-801. 20. Lenz, R.; Giese, B. J. Am. Chem. Soc. 1997, 119(12), 2784-2794.

21. Shaw, M. H.; Twilton, J.; MacMillan, D. W. J. Org. Chem. 2016, 81(16), 6898-6926.

22. Kärkäs, M. D.; Porco, J. A., Jr.; Stephenson, C. R. J. Chem. Rev. 2016, 116(17), 9683-9747

23. Romero, N. A.; Nicewicz, D. A. Chem. Rev. 2016, 116(17), 10075-10166 24. Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102−113 25. Hedstrand, D. M.; Kruizinga, W. M.; Kellogg, R. M. Tetrahedron Lett. 1978, 19,

1255−1258. 26. Okada, K.; Okamoto, K.; Morita, N.; Okubo, K.; Oda, M. J. Am. Chem. Soc. 1991, 113,

9401−9402. 27. Ischay, M. A.; Anzovino, M. E.; Du, J.; Yoon, T. P. J. Am. Chem. Soc. 2008, 130,

12886−12887. 28. Nicewicz, D. A.; MacMillan, D. W. C. Science. 2008, 322, 77−80. 29. Capaldo, L.; Ravelli, D. Eur. J. Org. Chem. 2017, 15, 2056-2071.; Capaldo, L.; Quadri,

L. L.; Ravelli, D. Green Chem. 2020, 22, 3376-3396 30. Hamilton, D. S.; Nicewicz, D. A. J. Am. Chem. Soc. 2012, 134, 18577−18580. 31. Ohkubo, K.; Kobayashi, T.; Fukuzumi, S. Angew. Chem., Int. Ed. 2011, 50, 8652−8655.;

Ohkubo, K.; Fujimoto, A.; Fukuzumi, S. J. Phys. Chem. A. 2013, 117, 10719−10725.; Romero, N. A.; Margrey, K. A.; Tay, N. E.; Nicewicz, D. A. Science 2015, 349, 1326−1330.

45

32. Qvortrup, K.; Rankic, D. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2014, 136, 626−629.

33. Jeffrey, J. L.; Terrett, J. A.; MacMillan, D. W. C. Science, 2015, 349, 1532−1536. 34. Skubi, K. L.; Blum, T. R.; Yoon, T. P. Chem. Rev. 2016, 116(17), 10035-10074. 35. Twilton, J.; Christensen, M.; DiRocco, D. A.; Ruck, R. T.; Davies, I. W.; MacMillan, D.

W. Angew. Chem. 2018, 130(19), 5467-5471. 36. Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S. W. Chem. Soc. Rev.

2016, 45, 546–576. 37. Kim, S. W.; Zhang, W.; Krische, M. J. Acc. Chem. Res. 2017, 50, 2371; Alam, R.;

Molander, G. A. J. Org. Chem. 2017, 82(24), 13728-13734. 38. Twilton, J.; Christensen, M.; DiRocco, D. A.; Ruck, R. T.; Davies, I. W.; MacMillan, D.

W. Ange. Chem. 2018, 130(19), 5467-5471. 39. Sakai, K.; Oisaki, K.; Kanai, M. Adv. Synth. Catal. 2020, 362(2), 337-343. 40. Dimakos, V.; Su, H. Y.; Garrett, G. E.; Taylor, M. S. J. Am. Chem. Soc. 2019, 141(13),

5149-5153. 41. Dimakos, V.; Gorelik, D.; Su, H. Y.; Garrett, G. E.; Hughes, G.; Shibayama, H.; Taylor,

M. S. Chem. Sci. 2020, 11(6), 1531-1537.

42. Zhao, G.; Wang, T. Angew. Chem. Int. Ed. 2018, 57(21), 6120-6124. Spell, M. L.; Deveaux, K.; Bresnahan, C. G.; Bernard, B. L.; Sheffield, W.; Kumar, R.; Ragains, J. R. Angew. Chem. Int. Ed. 2016, 55(22), 6515-6519.; Ye, H.; Xiao, C.; Zhou, Q. Q.; Wang, P. G.; Xiao, W. J. J. Org. Chem. 2018, 83(21), 13325-13334.; Sangwan, R.; Mandal, P. K. RSC Adv. 2017, 7(42), 26256-26321.; Zhao, G.; Kaur, S.; Wang, T. Org. Lett. 2017, 19(12), 3291-3294.

43. Zhu, F.; Zhang, S. Q.; Chen, Z.; Rui, J.; Hong, X.; Walczak, M. A. J. Am. Chem. Soc. 2020, 142, 25, 11102–11113

44. Andrews, R. S.; Becker, J. J.; Gagné, M. R. Angew. Chem. 2010, 122(40), 7432-7434. 45. Ji, P.; Zhang, Y.; Wei, Y.; Huang, H.; Hu, W.; Mariano, P. A.; Wang, W. Org. Lett.

2019, 21(9), 3086-3092. 46. Wan, I. C. S.; Witte, M. D.; Minnaard, A. J. Org. Lett. 2019, 21, 7669–7673. 47. Badir, S. O.; Dumoulin, A.; Matsui, J. K.; Molander, G. A. Angew. Chem. Int. Ed. 2018,

57(22), 6610-6613. 48. Shaw, M. H.; Twilton, J.; MacMillan, D. W. C. J. Org. Chem. 2016, 81, 6898–6926. 49. Wan, I. C. S.; Witte, M. D.; Minnaard, A. J. Chem. Comm. 2017, 53(36), 4926-4929. 50. Wang, Y.; Carder, H. M.; Wendlandt, A. E. Nature. 2020, 578(7795), 403-408. 51. Awan, S. I.; Werz, D. B. Bioorg. Med. Chem. 2012, 20, 1846. 52. Lei, P. S.; Duchaussoy, P.; Sizun, P.; Mallet, J. M.; Petitou, M.; Sinaÿ, P. Bioorg. Med.

Chem. 1998, 6(8), 1337-1346. 53. Noort, D.; Van Straten, N. C. R.; Boons, G. J. P. H.; Van der Marel, G. A.; Bossuyt, X.;

Blanckaert, N.; ... Van Boom, J. H. Bioorg. Med. Chem. Lett. 1992, 2(6), 583-588. 54. Bennett, C. S.; Galan, M. C. Chem. Rev. 2018, 118(17), 7931-7985. 55. Izumi, S.; Kobayashi, Y.; Takemoto, Y. Org. Lett. 2019, 21(3), 665-670. 56. Hager, D.; MacMillan, D. W. J. Am. Chem. Soc. 2014, 136(49), 16986-16989. 57. Mai-Linde, Y.; Linker, T. Org. Lett. 2020, 22(4), 1525-1529. 58. Mancini, R. S.; Lee, J. B.; Taylor, M. S. Org. Biomol. Chem. 2017, 15(1), 132-143. 59. Choi, G. J.; Zhu, Q.; Miller, D. C.; Gu, C. J.; Knowles, R. R. Nature. 2016, 539(7628),

268-271.

46

60. Loscher, S.; Schobert, R. Eur. J. Chem. 2013, 19(32), 10619-10624. 61. Asai, N.; Fusetani, N.; Matsunaga, S. J. Nat. Prod. 2001, 64, 1210 62. Evtushenko, E.V. Carbohydr. Res. 2012, 359, 111-119. 63. Singh, A. K.; Kandasamy. J. Org. Biomol. Chem. 2018, 16(28), 5107-5112. 64. Cheshev, P.; Marra, A.; Dondoni, A. Carbohydr. Res. 2006, 341(16), 2714-2716. 65. Seeberger, P. H.; Eckhardt, M.; Gutteridge, C. E.; Danishefsky, S. J. J. Am. Chem. Soc.

1997, 119(42), 10064-10072. 66. Premathilake, H. D.; Mydock, L. K.; Demchenko, A. V. J. Org. Chem. 2010, 75(4),

1095-1100 67. Demizu, Y.; Kubo, Y.; Miyoshi, H.; Maki, T.; Matsumura, Y.; Moriyama, N.; Onomura,

O. Org. Lett. 2008, 10(21), 5075-5077. 68. Muramatsu, W. J. Org. Chem. 2012, 77(18), 8083-8091. 69. Doris, L.; Taylor, M. S. J. Am. Chem. 2011, 133(11), 3724 - 3727 70. Wahlstrom, J. L., & Ronald, R. C. J. Org. Chem. 1998, 63(17), 6021-6022. 71. Chen, K.; Schwarz, J.; Karl, T. A.; Chatterjee, A.; König, B. Chem. Comm. 2019, 55(87),

13144-13147. 72. Zhu, Q.; Graff, D. E.; Knowles, R. R. J. Am. Chem. Soc. 2018, 140(2), 741-747.

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