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- Herausgeber: Wiley-VCH
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
The fields of glycochemistry and glycoscience are rich and varied and where much can be learned from Nature. As Nature is not always able to produce carbohydrates in quantities useful for not only in research but also as therapeutic agents, new ways need to be found to optimize the yield. This book presents an overview of the latest developments in the field of carbohydrates, ranging from de-novo approaches via cyclodextrin chemistry to the synthesis of such highly complex glycoconjugates as glycosphingolipids and GPI anchors.
The main emphasis remains on the synthetic aspects making the book an excellent source of information for those already involved in carbohydrate chemistry, as well as for those organic chemists who are beginners in this field. Equally of interest to synthetic chemists, as well as medicinal chemists and biochemists.
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Veröffentlichungsjahr: 2013
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Table of Contents
Related Titles
Title Page
Copyright
Foreword
Preface
List of Contributors
Chapter 1: De Novo Approaches to Monosaccharides and Complex Glycans
1.1 Introduction
1.2 De Novo Synthesis of Monosaccharides
1.3 Iterative Pd-Catalyzed Glycosylation and Bidirectional Postglycosylation
1.4 Synthesis of Monosaccharide Azasugar
1.5 Oligosaccharide Synthesis for Medicinal Chemistry
1.6 Conclusion and Outlook
1.7 Experimental Section
List of Abbreviations
Acknowledgments
References
Chapter 2: Synthetic Methodologies toward Aldoheptoses and Their Applications to the Synthesis of Biochemical Probes and LPS Fragments
2.1 Introduction
2.2 Methods to Construct the Heptose Skeleton
2.3 Synthesis of Heptosylated Oligosaccharides
2.4 Synthesis of Heptosides as Biochemical Probes
2.5 Conclusions
2.6 Experimental Part
List of Abbreviations
Acknowledgments
References
Chapter 3: Protecting-Group-Free Glycoconjugate Synthesis: Hydrazide and Oxyamine Derivatives in N-Glycoside Formation
3.1 Introduction
3.2 Glycosyl Hydrazides (1-(Glycosyl)-2-acylhydrazines)
3.3 O-Alkyl-N-Glycosyl Oxyamines
3.4 N,O-Alkyl-N-Glycosyl Oxyamines
3.5 Concluding Remarks and Unanswered Questions
3.6 Procedures
List of Abbreviations
Acknowledgment
References
Chapter 4: Recent Developments in the Construction of cis-Glycosidic Linkages
4.1 Introduction
4.2 Cis-Glycosylation
4.3 Conclusion
Acknowledgments
List of Abbreviations
References
Chapter 5: Stereocontrol of 1,2-cis-Glycosylation by Remote O-Acyl Protecting Groups
5.1 Introduction
5.2 Stereodirecting Influence of Acyl Groups at Axial and Equatorial O-3: Opposite Stereoselectivity Proves Anchimeric Assistance
5.3 Acyl Groups at O-4 in the galacto Series: Practical Synthesis of α-Glycosides: Complete Stereoselectivity
5.4 Lack of Stereocontrolling Effect of Acyl Groups at Equatorial O-4 in 4C1 Conformation
5.5 Effect of Substituents at O-6
5.6 Interplay of Stabilized Bicyclic Carbocation and Two H Conformations of Oxocarbenium Ions
5.7 Conclusion
5.8 Key Experimental Procedures
List of Abbreviations
References
Chapter 6: Synthesis of Aminoglycosides
6.1 Introduction
6.2 Amine-Protecting Group Strategies
6.3 Controlled Degradation of Aminoglycosides
6.4 Chemoselective Alcohol-Protecting Group Manipulations
6.5 Strategies for Glycosylation of Aminoglycoside Scaffolds
6.6 Synthesis of Amphiphilic Aminoglycosides
6.7 Chemoenzymatic Strategies for the Preparation of Aminoglycoside Analogs
6.8 Novel Synthetic Strategies to Overcome Resistance to Aminoglycosides
6.9 Conclusions and Future Perspectives
6.10 Selected Synthetic Procedures
Acknowledgments
List of Abbreviations
References
Chapter 7: Synthesis of Natural and Nonnatural Heparin Fragments: Optimizations and Applications toward Modulation of FGF2-Mediated FGFR Signaling
7.1 Introduction
7.2 Total Synthesis of Standard HPN Fragments
7.3 Total Synthesis of Modified HPN Fragments: Some Synthetic Clues
7.4 Alternative Synthetic Methods: Means to Build Libraries
7.5 Biological Evaluation
7.6 Conclusion and Outlook
7.7 Experimental Section (General Procedures)
Acknowledgments
List of Abbreviations
References
Chapter 8: Light Fluorous-Tag-Assisted Synthesis of Oligosaccharides
8.1 Introduction
8.2 Fluorous-Protecting Groups and Tags Amenable to Fluorous Solid-Phase Extraction in Carbohydrate Synthesis
8.3 Light Fluorous-Protecting Groups with Potential Use in Oligosaccharide Synthesis
8.4 “Cap-Tag” Strategies or Temporary Fluorous-Protecting Group Additions
8.5 Double-Tagging Carbohydrates with Fluorous-Protecting Groups
8.6 Other Advantages to Fluorous-Assisted Oligosaccharide Synthesis
8.7 Conclusions and Outlook
8.8 Experimental Section
Acknowledgments
List of Abbreviations
References
Chapter 9: Advances in Cyclodextrin Chemistry
9.1 Introduction
9.2 General Reactivity, Per- and Monofunctionalization
9.3 Capping Reagents for Direct Modification
9.4 Bulky Reagents for Direct Modifications
9.5 Selective Deprotections
9.6 Conclusion and Perspectives
9.7 Experimental Procedures
List of Abbreviations
References
Chapter 10: Design and Synthesis of GM1 Glycomimetics as Cholera Toxin Ligands
10.1 Introduction
10.2 Cholera Toxin and Its Specific Membrane Receptor, the GM1 Ganglioside
10.3 Rational Design of GM1-os Mimics as Cholera Toxin Inhibitors and Synthesis of First-Generation Ligands
10.4 Third Generation of GM1 Ganglioside Mimics: Toward Nonhydrolyzable Cholera Toxin Antagonists
10.5 Conclusions
10.6 Experimental Section
Acknowledgments
List of Abbreviations
References
Chapter 11: Novel Approaches to Complex Glycosphingolipids
11.1 Introduction
11.2 Syntheses of Complex Glycans of Gangliosides
11.3 Total Syntheses of Complex Gangliosides
11.4 Conclusion and Outlook
11.5 Experimental Section
List of Abbreviations
References
Chapter 12: Chemical Synthesis of GPI Anchors and GPI-Anchored Molecules
12.1 Introduction
12.2 Challenges in the Synthesis of GPIs
12.3 Tools for Synthesis of GPIs
12.4 Synthesis of GPIs with Linear Glycan Core
12.5 Synthesis of GPIs with Branched Glycan Core
12.6 GPI Derivatives for Biological Research
12.7 Synthesis of GPI-Anchored Peptides and Proteins
12.8 Conclusions and Outlook
Acknowledgments
List of Abbreviations
References
Index
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The Editors
Prof. Dr. Daniel B. Werz
Technische Universität Braunschweig
Institut für Organische Chemie
Hagenring 30
38106 Braunschweig
Germany
Dr. Sébastien Vidal
Université Claude Bernard Lyon 1
ICMBS-UMR-CNRS 5246
43 Boulevard du 11 Nov. 1918
69622 Villeurbanne
France
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Foreword
The ever-expanding field of glycoscience is driven by the vast diversity of biological processes mediated by carbohydrates, their oligomers, and conjugates, thereby providing enormous opportunities for the use of carbohydrates and their derivatives as research tools and as therapeutic agents. The difficulties in isolating homogeneous glycoforms from nature in any significant quantity and the limitations of such methods to naturally occurring glycoforms underline the need for efficient and effective chemical synthesis of such molecules. The superficially simple mechanism of the glycosidation reaction masks what is, in reality, a very difficult problem and one that drives the need for innovative chemical solutions, which in turn is attracting an increasing number of bright young (and not so young) researchers to the area. Against this background, Sébastien Vidal and Daniel B. Werz have assembled in this book an outstanding collection of work of talented authors to give their individual perspectives on “Modern Synthetic Methods in Carbohydrate Chemistry,” be they at the level of “simple” monosaccharides or complex glycosides. As the title suggests, oligosaccharide synthesis and carbohydrate chemistry, in general, are but one facet of modern organic chemistry. This is richly brought out in the content of the book from which it is clear that many recent advances in glycochemistry and indeed glycoscience depend very heavily on the power and ingenuity of contemporary synthetic organic methodology.
The first chapter, an authoritative contribution by George O'Doherty from Northeastern University in Boston, sets the tone by drawing the reader's attention to the fact that monosaccharides and complex glycans are not necessarily best prepared from actual sugars and that modern synthetic chemistry in the form of de novo synthetic approaches has an important role to play. The second chapter continues the theme as Stéphane Vincent from the University of Namur reminds us of the importance of the aldoheptoses and the need for their synthesis in terms of both biological probes and lipopolysaccharide (LPS) fragments. Mark Nitz from the University of Toronto then expounds on the protecting-group-free synthesis of glycoconjugates and in particular on the use of hydrazides and oxyamine derivatives for the synthesis of N-glycosides, before Alphert Christina, Gijs van der Marel, and Jeroen Codée from the Leiden University laboratory describe the recent evolution of the stereocontrolled synthesis of the 1,2-cis-glycosidic linkages, thereby nicely underlining the power of modern synthetic chemistry. Nikolay Nifantiev and his coauthors from the Zelinsky Institute of Organic Chemistry in Moscow continue with the theme of the stereocontrolled synthesis of the 1,2-cis-glycosides with particular emphasis on the role of participation by remote esters, a process for which the jury has yet to return a clear verdict. A chapter by Micha Fridman from Tel Aviv University then takes us into the realm of the aminoglycoside antibiotics and presents both useful chemistry and a perspective on novel applications of these compounds beyond their current use as antibacterials. Pierre-Alexandre Driguez at Sanofi in France takes us into the realm of complex oligosaccharide synthesis and tackles the vexing problems of the synthesis of heparin fragments, both natural and nonnatural, before Rajarshi Roychoudhury and Nicola Pohl from Indiana University set out the many advantages of light fluorous tag-assisted synthesis of oligosaccharides and the various strategies devised to date in order to take advantage of them. Samuel Guieu and Matthieu Sollogoub at the University of Aveiro and the Université Pierre and Marie Curie in Paris recount recent advances in cyclodextrin chemistry with an emphasis on selective functionalization methods, after which Anna Bernardi from the University of Milan takes up the theme of the design and synthesis of GM1 glycomimetics as cholera toxin ligands. This book continues with a chapter by Hiromune Ando and coworkers from Gifu University on recent advances in the synthesis of glycosphingolipids, from which much is to be learnt about the stereocontrolled synthesis of the once-difficult sialic acid glycosides. Finally, the volume closes with an important chapter from Daniel Varón Silva and his coauthors at the Max Planck Institute of Colloids and Interfaces in Berlin describing the need for, the many challenges in, and their numerous elegant solutions to, the synthesis of glycosylphosphatidylinositol (GPI) anchors and of GPI-anchored molecules.
The discerning reader will gain much from this volume not the least of which, hopefully, will be the recognition of the dynamic nature of the field of glycochemistry and of the many challenges still remaining. When viewed in the broader context, these many challenges are nothing more than problems in modern synthetic organic chemistry whose solution only awaits the arrival and ingenuity of fresh minds to the area.
Wayne State University
David Crich
November 2013
Preface
More than 100 years ago, pioneering achievements in carbohydrate chemistry were awarded the second Nobel Prize in Chemistry to Emil Fischer. Since that time this branch of organic chemistry has lost none of its fascination. The success story began with Fischer's brilliant logical deduction of the glucose structure (based on simple organic reactions performed with sugars) and was followed by basic glycosylation methods (such as the Fischer-Helferich or the Koenigs-Knorr procedures). Later, in 1937, another Nobel Prize was awarded for the investigation of disaccharides and vitamin C to Walter N. Haworth. After a long period of hibernation, carbohydrate chemistry has developed into an arsenal of highly sophisticated chemical methods, which have enabled the carbohydrate chemist to selectively build almost all of the possible glycosidic linkages. Since Nature has created an unbelievable variety of oligosaccharides and we can at least partially understand the biological significance of many of these structures today, it is very necessary to have a specialized chemical toolkit either to create mono- as well as oligosaccharides or to further modify any of these structures.
The present monograph comprises a fine selection of hot topics in carbohydrate chemistry that have found applications in biological studies and the preparation of complex natural glycans. The synthetic methodologies used for the preparation of these substrates have gathered modern skills from general organic chemistry to the more specific field of glycochemistry. Nevertheless, both organic chemistry and glycochemistry benefited from each other's experiences to push further the limits of the molecular architectures attainable.
In contrast to several other books dealing with carbohydrate chemistry, a collection of very recent synthetic developments in the field of carbohydrate chemistry are presented. Recent synthetic achievements including de novo synthesis of carbohydrates, highlights of cyclodextrin chemistry, synthesis of highly complex glycoconjugates such as glycosphingolipids and GPI anchors are treated, always with a strong focus on the synthetic aspects.
The idea for this book project came up at the European Young Investigators Workshop co-organized by us in April 2011 in Lyon (France). After this conference gathering young researchers in glycochemistry, we felt that putting together a book would help the scientific community to identify some key aspects of glycosciences in order to address the next scientific challenges in the post-genomics and post-proteomics era. Glycomics are now the next leap for scientists and this book is intended to bring together techniques from synthetic organic and carbohydrate chemistry so that each domain would benefit from each other.
This book was the collective work of a number of glycochemists. Most importantly, we would like to thank all contributors whose time, efforts, and expertise have made this book a useful scientific resource for beginners and advanced researchers both in organic chemistry and glycochemistry. We are grateful to Drs. Elke Maase and Lesley Belfit at Wiley-VCH for their help and useful advices in preparing this book.
Braunschweig, Germany
Daniel B. Werz
Lyon, France
Sébastien Vidal
November 2013
List of Contributors
Chapter 1
De Novo Approaches to Monosaccharides and Complex Glycans
Michael F. Cuccarese, Jiazhen J. Li, and George A. O'Doherty
1.1 Introduction
Over the years, considerable effort has been made toward the development of new synthetic routes to monosaccharides [1]. This interest came primarily from the medicinal chemistry community, as these new routes often provided access to unnatural sugars, which could be of use in structure–activity relationship (SAR) studies. In addition, the synthesis of monosaccharides, and in particular hexoses, has served as a challenge and a measuring stick to the synthetic organic community. Of particular interest are the routes to hexoses that start from achiral starting materials, where asymmetric catalysis is used to install the stereochemistry. In the synthetic organic community, these routes are described as “de novo” or “de novo asymmetric” routes to carbohydrates, whereas in the carbohydrate community, the term de novo takes up other meanings. For the purposes of this review, the term de novo asymmetric synthesis refers to the use of catalysis for the asymmetric synthesis of carbohydrates from achiral compounds [2]. This then precludes the inclusion of de novo process that produced sugars from molecules with preexisting chiral centers (e.g., Seeberger and Reißig) [3, 4].
The challenge of a de novo synthetic approach to carbohydrates has been met by many groups (Scheme 1.1). These approaches begin most notably with the seminal work by Masamune and Sharpless [5] (2 to 5), which utilized iterative asymmetric epoxidation of allylic alcohols to prepare all eight possible hexoses. More recently, Danishefsky [6] demonstrated the power of asymmetric hetero-Diels–Alder reaction for the synthesis of several glycals (3 and 4 to 5), which inspired further studies toward oligosaccharide synthesis. Johnson and Hudlicky [7] turned to the use of enzyme catalysis for the oxidation/desymmetrization of substituted benzene rings to achieve hexopyranoses (1 to 5). Alternatively, Wong and Sharpless [8] used a combination of transition metal catalysis (asymmetric dihydroxylation) and an enzyme-catalyzed aldol reaction for the synthesis of several 2-keto-hexoses. More recently, this challenge has been engaged by MacMillan who utilized an iterative aldol reaction approach (a proline-catalyzed aldol followed by a subsequent diastereoselective aldol reaction) to produce various hexoses (6 to 5) [3]. Of these approaches, only the iterative epoxidation strategy of Masamune and Sharpless provides access to all eight hexoses, but it is also noteworthy that their route required the most steps and protecting groups. It is this latter point, the reduction of steps and avoidance of protecting groups, which guided the development of these synthetic endeavors [9].
Scheme 1.1De novo approaches to hexoses.
We have also developed two practical methods for the de novo synthesis of hexoses. These efforts have resulted in the discovery of two orthogonal approaches to hexopyranoses with variable C-6 substitutions. These approaches entail an iterative dihydroxylation strategy to hexose sugar lactones (9 to 5) [10] and an Achmatowicz strategy that is amenable to all eight hexose diastereomers (7 or 8 to 5) [11] Of the two approaches, the iterative asymmetric dihydroxylation of dienoates (Scheme 1.1) is the most efficient in terms of steps (one step for racemic to three steps for asymmetric) and the minimal use of protecting groups. On the contrary, the Achmatowicz approach is superior in terms of synthetic scope. The potential of this approach can be seen in the highly efficient de novo route to various mono-, di-, tri- tetra-, and heptasaccharide motifs, allowing their use for biological and medicinal structure–activity studies.
Of the many ways to compare these de novo routes (e.g., number of steps, availability of starting materials, and atom economy), clearly the best metric is the scope of its use in synthetic and biological applications. The Achmatowicz approach is distinguished from the other approaches when it comes to practical application to rare sugars, medicinal chemistry, and more specially oligosaccharides. These features result from its compatibility with the Pd-π-allyl-catalyzed glycosylation for the stereospecific formation of the glycosidic bond [12, 13]. As outlined in Scheme 1.2, the Pd(0)-catalyzed glycosylation reaction is both general and stereospecific [14, 15]. The reaction occurs rapidly and in high yields for both the α-10 to α-11 and β-10 to β-11 systems and works best when Pd2(dba)3·CHCl3 is used as the Pd(0) source with triphenylphospine as the ligand in a 1 : 2 Pd/PPh3 ratio. While carboxylate-leaving groups also work, the t-butoxycarbonate group (BocO−) is critical for the successful implementation of this reaction with alcohol nucleophiles. For example, when the t-butoxycarboxy group was replaced with a benzoyl or pivaloyl group, the palladium-catalyzed glycosylation reaction was significantly slower.
Scheme 1.2 Stereospecific Pd-catalyzed glycosylation.
The de novo Achmatowicz approach to hexoses has great potential for preparing various D- and L-sugars because the starting 6-t-butoxycarboxy-2H-pyran-3(6H)-ones (10 and 13) can easily be prepared from optically pure furfuryl alcohols 12 (either (R) or (S) enantiomer) [16] by a one or two step procedure (Scheme 1.3). Depending on the temperature of the second step, the t-butylcarbonate acylation reaction can selectively give the α-Boc pyranones 10α and 13α at −78 °C, whereas at room temperature, a 1 : 1 ratio of the α- and β-Boc protected enones were produced. Thus, this procedure can be used to prepare multigram quantities of both α- and β-pyranones in either enantiomeric form. When the Pd-glycosylation reaction was coupled with the Achmatowicz oxidation of a furan alcohol and diastereoselective t-butylcarbonate acylation reaction, a net three-step stereo-divergent pyranone-forming reaction resulted. Key to the success of the de novo asymmetric Achmatowicz approach is the practical access to all four possible pyranone diastereomers from either furan alcohol enantiomers 12(R) or 12(S).
Scheme 1.3 Achmatowicz approach to the simplest hexoses.
An important aspect of this approach is the ease with which furan alcohols can be prepared in enantiomerically pure form from achiral furans (e.g., 7 and 8). There are many asymmetric approaches to prepare furan alcohols. The two most prevalent approaches are (i) the Noyori reduction of acylfurans (8 to 12) and (ii) the Sharpless dihydroxylation of vinylfurans (7 to 12) (Scheme 1.4) [17]. Both routes are readily adapted to 100 g scale synthesis and use readily available reagents. While the Sharpless route is most amenable to the synthesis of hexoses with a C-6 hydroxy group, the Noyori route distinguishes itself in its flexibility to virtually any substitution at the C-6 position. Herein, we review the development of the Achmatowicz approach to the de novo synthesis of carbohydrates, with application to oligosaccharide assembly and medicinal chemistry studies.
Scheme 1.4De novo asymmetric approaches to chiral furan alcohols.
1.2 De Novo Synthesis of Monosaccharides
Putting this together, a very practical de novo approach to manno-hexoses can be carried out in six steps from achiral acylfuran 15. The route began with a three-step synthesis of Boc-pyranone 18 in an ∼50% overall yield. Thus, in only three highly diastereoselective steps, pyranone 18 was converted into manno-pyranose 21 in 45% overall yield. The three-step sequence consists of a Pd-catalyzed glycosylation (18 to 19) and two postglycosylation reactions, a Luche reduction (NaBH4/CeCl3, 19 to 20) and Upjohn dihydroxylation (OsO4(cat)/NMO, 20 to 21) (NMO, N-methylmorpholine-N-oxide) (Scheme 1.5). This six-step sequence of achiral 15 to partially protected mannose 21 demonstrates the power of asymmetric synthesis. From the point of view of carbohydrate synthesis, this route consists of a three-step asymmetric synthesis of glycosyl donor 18, which in three additional steps is converted into manno-sugar 21. Viewing this approach from a synthetic perspective becomes more relevant in the subsequent schemes. Other hexose congeners were also prepared using other postglycosylation transformations [18]. Critical to the success of this approach is the chemoselective use of functionality of C–C and C–O π-bonds as atom-less protecting groups (i.e., enone as a protected triol) as well as an anomeric-directing group (via a Pd-π-allyl).
Scheme 1.5De novo asymmetric Achmatowicz approach to L-manno-hexoses.
1.3 Iterative Pd-Catalyzed Glycosylation and Bidirectional Postglycosylation
The synthetic efficiency of the approach reveals itself when the Pd(0)-catalyzed glycosylation was applied in an iterative manner for oligosaccharide synthesis (Scheme 1.6 and Scheme 1.7) [19]. The step savings occurred because of the bidirectional use of postglycosylation Luche and Upjohn reactions. While not always shorter, these routes compare favorably with more traditional carbohydrate approaches and offer exclusive access to enantiomers as well as D-/L-sugar diastereomers. In addition to reducing steps, this highly atom-economical approach avoids the extensive use of protection/deprotection steps. For example, the 1,6-manno-trisaccharide 23 was prepared from enone 18 in six steps (nine from achiral furan 15). The synthesis was accomplished by an iterative use of a t-butyldimethylsilyl (TBS)-deprotection/glycosylation strategy to prepare trisaccharide 22, followed by a tris-reduction and tris-dihydroxylation to install the manno-stereochemistry. By simply switching the order of the reduction and glycosylation steps, this route can also be used to prepare 1,4-manno-trisaccharide 23. Key to the success of this sequence was the highly stereoselective reduction and dihydroxylation reaction, which installed six stereocenters in one transformation (25 to 26). This approach was successfully used in the medicinal chemistry SAR study of digitoxin, an anticancer agent [20].
Scheme 1.6De novo asymmetric approach to 1,6- and 1,4-oligo-hexoses.
Scheme 1.7De novo asymmetric approach to branched 1,4- and 1,6-oligo-L-hexoses.
1.3.1 Bidirectional Iterative Pd-Catalyzed Glycosylation and Postglycosylation
The synthetic efficiency was magnified when the glycosylation reaction was also applied in a bidirectional manner [21]. For example, when the TBS group of pyran 20 was removed, the resulting diol 27 can be bis-glycosylated to form tris-pyran 28. This bidirectional application of ketone reduction and TBS deprotection gave tetraol 29. Once again, the tetraol of 29 can be per-glycosylated with excess pyranone 18 to give heptasaccharide 30. Finally, a ketone per-reduction and double bond per-dihydroxylation gave heptasaccharide 31. It is worth noting, while there is similar local symmetry around each alkene, they exist in different stereochemical environments.
1.3.2 Synthesis of Monosaccharide Aminosugar Library
While these bidirectional approaches do have some significant synthetic efficiency over traditional approaches, they do suffer from the fact that the routes tend to be linear in nature and do not readily adapt to convergent synthesis. On the contrary, these routes most readily adapt to divergent synthesis. In particular to divergent synthesis, as it is applied to the synthesis of unnatural sugars. This becomes particularly advantageous when it is being used to address problems associated with medicinal chemistry. An example of this application can be seen in our application of this de novo Achmatowicz approach for the synthesis of a library of glycosylated methymycin analogs for eventual medicinal chemistry SAR studies [22].
Methymycin is one of the several 12-membered ring-glycosylated macrolide antibiotics isolated from Streptomyces venezuelae ATCC 15439 (ATCC, American Type Culture Collection; Scheme 1.8). Similar to other macrolide antibiotics, the rare deoxy-aminosugar portion of methymycin (desosamine) is important for their bioactivity. Thus, its modifications hold promise as a valuable approach toward preparing new macrolide antibiotics with improved and/or altered biological properties. Our de novo approach to a library of methymycin analogs is retrosynthetically outlined in Scheme 1.8, where the macrolide aglycon 10-deoxymethynolide was glycosylated in a stereo-divergent manner (with D- or L-Boc pyranones 44 or ent-44, respectively) to give either α-D-glycoside 45 or its diastereomer α-L-glycoside 46. Subsequent postglycosylation transformations were used to provide various sugar congeners and stereoisomers, in particular, unnatural deoxy-aminosugar isomers.
Scheme 1.8De novo synthesis of a methymycin monosaccharide library.
The installation of amino-functional groups, in practice, was most easily accomplished at the C-4 position (Scheme 1.9). For instance, the α-D-pyranone ring on methymycin analog 45 could be converted into a 4-aminosugar 41 with α-D-rhodino-stereochemistry in four steps, via a reduction, activation of the resulting alcohol, azide inversion, and reduction strategy. Alternatively, this approach is also compatible with the installation of equatorial amino groups at the C-4 position. This is accomplished by means of a net retention of stereochemistry in the substitution reaction at the C-4 position. The reaction occurred via a Pd-catalyzed π-allyl reaction with trimethylsilyl azide (TMSN3) as the nucleophile to give allylic azide 47 from α-D methymycin analog 46. In turn, azide 47 could be converted into azido-/azasugar methymycin analogs with α-L-rhamno- (36 and 37) and α-L-amiceto-stereochemistries (34 and 35).
Scheme 1.9De novo synthesis of a methymycin monosaccharide aminosugar library.
1.4 Synthesis of Monosaccharide Azasugar
Among the polyhydroxylated indolizidine alkaloids, the most well-known member is D-swainsonine 60 (Scheme 1.10) [23–25]. Swainsonine is known as a potent inhibitor of both lysosomal α-mannosidase [26] and mannosidase II [27] and has shown promise as an anticancer agent [28]. Fleet et al. [29] have shown that the enantiomer (L-swainsonine) selectively inhibited narginase (L-rhamnosidase, = 0.45 μM), whereas the D-swainsonine showed no inhibitory activity toward this enzyme. Owing to the biological importance of both D- and L-swainsonines, several epimers and analogs have become attractive targets for syntheses [30, 31].
Scheme 1.10De novo synthesis of D-swainsonine.
Thus, we became interested in the de novo asymmetric synthesis of both enantiomers of swainsonine and various epimers for further biological studies [32]. We envisioned a similar postglycosylation transformation, in which the installation of the 4-amino-manno-stereochemistry in methymycin analog 47 could be instrumental in the development of a de novo Achmatowicz approach to the indolizidine natural product swainsonine 60 (Scheme 1.10). In practice, this required access to acylfuran 49, which was prepared in two steps from 2-lithiofuran and butyrolactone 48. After Noyori reduction, Achmatowicz reaction, and diastereoselective acylation, 49 was converted into pyranone 52. Glycosylation of benzyl alcohol with 52 installed the required C-1-protecting group. As before, Luche reduction, carbonate formation, and Pd-π-allyl allylic azide displacement installed the C-4 azido group in 56. Before the C-2/C-3 double bond was dihydroxylated, the TBS ether is converted into a mesylate-leaving group as in 58. Finally, a diastereoselective dihydroxylation (58 to 59) and exhaustive hydrogenolysis (59 to 60) cleanly provided D-swainsonine in an optically pure form. Thus, in only 13 steps, either D- or L-swainsonine can be prepared from achiral starting material. This is of particular note because both enantiomers have been valued as known inhibitors of glycosidase enzymes (D-swainsonine for α-D-mannosidases and α-L-swainsonine for α-L-rhamnosidases). This route has also been used to prepare various diastereoisomers of swainsonine, which are also known to be effective glycosidase inhibitors [32].
1.5 Oligosaccharide Synthesis for Medicinal Chemistry
As part of the continuing search for new antibiotics against bacterial resistance [33], the cyclic hexapeptide mannopeptimycin-ϵ 61 was isolated from the fermentation broths of Streptomyces hygroscopicus LL-AC98 and related mutant strains [34]. The key structural features of the mannopeptimycins are a cyclic hexapeptide core with alternating D- and L-amino acids, three of which are rare. Two of the amino acids (β-D-hydroxyenuricididine and D-tyrosine) are glycosylated with mannose sugars. The glycosylated amino acids are an N-glycosylated β-hydroxyenuricididine with an α-mannose, and an O-glycosylated tyrosine with an α-(1,4-linked)-bis-manno-pyranose disaccharide portion. The unique structure and unprecedented biological activity have inspired both biological [35] and synthetic studies from us and others.
Our de novo asymmetric Achmatowicz approach was also applied to the synthesis of the glycosylated tyrosine portion of the antibiotic mannopeptimycin-ϵ [36]. Specifically, we targeted a protected tyrosine with bis-manno-1,4-disaccharide with an isovalerate at the C-4′ position. This approach was used to prepare the amino acid portion of the natural product 62 as well as the disaccharide portion in the unnatural L/L-configuration. The linear route involved the application of the iterative bis-glycosylation, acylation, and bis-dihydroxylation of protected tyrosine in only six steps (Scheme 1.11).
Scheme 1.11 Assembly of the mannopeptimycin-ϵ disaccharide.
As part of further SAR studies of the antibiotic mannopeptimycin, access to the C-4 amide analogs 42 was also desired [37]. As before, this was also accomplished using the Pd-π-allyl-catalyzed allylic azide alkylation in conjunction with azide reduction and acylation. Specifically, allylic alcohol 66 was converted into methyl carbonate 67, and the allylic carbonate was converted into allylic azide 68. In turn, the azide was selectively reduced and the corresponding amine 69 was acylated. The remaining double bonds of 70 were dihydroxylated, and the TBS groups were removed to provide the desired target tyrosine disaccharide 71 (Scheme 1.12). Key to the success of this approach was the somewhat surprisingly selective ionization of the equatorial allylic carbonate in 67 without any sign of ionizing the anomeric phenol in the axial configuration.
Scheme 1.12 Elaboration to C-4″ aza-mannopeptidomycin.
1.5.1 Tri- and Tetrasaccharide Library Syntheses of Natural Product
As part of a high-throughput-based search for new natural products with unique structures and interesting biological activity, two partially acetylated trisaccharide (cleistrioside-5/-6, 72 and 73) and six partially acetylated tetrasaccharide (cleistetroside-2/-3/-4/-5/-6/-7, 74–81) natural products were discovered (Figure 1.1) from the leaves and bark of trees with a folk medicinal tradition [38–40]. These dodecanyl tri- and tetrarhamnoside structures with various degrees of acylation were isolated from Cleistopholis patens and Cleistopholis glauca [36, 37]. The structures of the cleistriosides and cleistetrosides were assigned by detailed NMR analysis and later confirmed by total synthesis by us [41] and others [42, 43]. In addition to clarifying the structural issues, our synthetic interest in these oligosaccharides was aimed at supplying sufficient material for SAR-type studies and as a test of our synthetic methodology [44].
Figure 1.1 The cleistriosides, cleistetrosides, and analogs.
The route began with pyranone ent-44, which was easily prepared in three steps from commercially available acetylfuran (Scheme 1.13). In four steps (glycosylation, reduction, dihydroxylation, and acetonide protection), glycosyl donor ent-44 was converted into protected rhamnose 83. A subsequent glycosylation, reduction, acylation, and dihydroxylation gave diol disaccharide 84. Unfortunately, when diol 84 was exposed to our typical Pd-catalyzed glycosylation conditions, the trisaccharide 85 with the wrong regiochemistry was formed. To our delight, this substrate regioselectivity (4 : 1) could be reversed via the formation of tin acetal 86. Thus, a tin-directed regioselective (7 : 1) glycosylation gave trisaccharide 87 with the required carbohydrate at the C-3 position. A subsequent chloro-acylation gave trisaccharide 88, which was ready for further elaboration into both the cleistrioside and cleistetroside natural products (Scheme 1.14, Scheme 1.16, and Scheme 1.17).
Scheme 1.13 Synthesis of trisaccharide 88.
Scheme 1.14 Synthesis of cleistrioside-5 and -6.
The pyranone ring in trisaccharide 88 is perfectly situated for further elaboration into a rhamnose ring with the desired acylation pattern for cleistrioside-5 and -6. This was accomplished by Luche reduction and acylation or chloro-acylation to give 89 and 90. A subsequent dihydroxylation and ortho-ester-mediated C-2 acylation gave trisaccharides 91 and 92, which could be converted into cleistrioside-5 and -6 (72 and 73) by a selective removal of the chloro-acetates over the other acetates (removed with thiourea) and acetonide-protecting groups (hydrolyzed with AcOH/H2O).
In addition, the trisaccharides 91 and 92 can be further converted into eight members of the cleistetroside family of natural products (Scheme 1.16 and Scheme 1.17). This divergent route began with the selective Pd-catalyzed glycosylation of the free C-3 alcohol in 91 and 92 and a subsequent Luche reduction to afford tetrasaccharides 93 and 94 (Scheme 1.15).
Scheme 1.15 Synthesis of tetrasaccharides 93 and 94.
As outlined in Scheme 1.16, tetrasaccharide 93 was divergently converted into five of the six desired cleistetroside-2, -3, -4, -6, and -7. This was accomplished in a range of three to five steps by subtle variations of the postglycosylation reactions (dihydroxylation, acylation, and chloro-acylation), followed by global deprotection (thiourea then AcOH/H2O).
By applying the same postglycosylation/deprotection reaction sequence on tetrasaccharide 94, the remaining cleistetroside-5 was prepared in three steps. In addition, the revised route was also used to prepare two previously unknown analogs, cleistetroside-9 and -10. This was accomplished in a range of one to three steps by modular application of the postglycosylation reactions (dihydroxylation, acylation, and chloro-acylation) (Scheme 1.17).
Scheme 1.16 Synthesis of cleistetroside-2, -3, -4, -6, and -7.
Scheme 1.17 Synthesis of cleistetroside-5, -8, and -10.
It is worth noting that the route to any of the cleistetrosides is quite comparable to the two previously reported routes to cleistetroside-2 in terms of total number of steps. What distinguished it from these more traditional routes is its flexibility to diverge to any of the possible natural product isomers. Thus, we have found that this divergent approach is particularly amenable to medicinal chemistry studies. In this regard, our synthetic access to these eight natural products (two trisaccharides and six tetrasaccharides) and additional two natural product analogs enabled detailed medicinal chemistry SAR studies. The divergent nature of the approach is graphically displayed in Scheme 1.18, where in only 13 steps and in 20% overall yield, the key trisaccharide 88 could be prepared from achiral furan 95. Trisaccharide 88 serves as the linchpin molecule that can, in 6–11 steps, be converted into any of the desired natural products, in sufficient quantities for further studies.
Scheme 1.18 Divergent synthesis retrosynthetic summary.
1.5.2 Anthrax Tetrasaccharide Synthesis
Possibly the most elaborate application of this de novo Achmatowicz approach to oligosaccharides was the synthesis of the anthrax tetrasaccharide 100. The approach to this tetrasaccharide natural product merged well with our efforts to C-4 aminosugars with the synthesis of rhamnose-containing oligosaccharides (Scheme 1.19) [45, 46]. Anthrax is a zoonotic disease caused by the spore-forming bacterium Bacillus anthracis [47]. In an effort to find a unique structural motif associated with the bacterium, the anthrax tetrasaccharide 100 was discovered. The tetrasaccharide 100 consists of three L-rhamnose sugars and a rare sugar, D-anthrose [48]. The uniqueness of the D-anthrose sugar and the resistance of carbohydrate structures to evolutionary change make the anthrax tetrasaccharide an interesting target for synthesis [49]. Several carbohydrate approaches to the anthrax tetrasaccharide and one to a related trisaccharide have been reported [49a, 50], which derive their stereochemistry from the known but less common sugar L-rhamnose and the rare D-fucose. Our de novo approach to the tetrasaccharide 100 was envisioned as occurring through a traditional glycosylation between trisaccharide 96 with
Scheme 1.19 Retrosynthesis of anthrax tetrasaccharide 100.
trichloroacetimidate 97 (Scheme 1.19). In turn, our de novo approach was planned to prepare both of these fragments (96 and 97) from the achiral acetylfuran 95, which it is worth noting are significantly less expensive than either L-rhamnose or D-fucose.
Our synthesis of the anthrose monosaccharide 97 is described in Scheme 1.20 and involved two Pd-π-allylation reactions. The route began with the synthesis of (p-methoxybenzyl) PMB-protected pyranone 101 from 95 via ent-44. Using the Pd-catalyzed C-4 allylic azide chemistry previously described, pyranone ent-44 was converted into allylic azide 104 and dihydroxylated to give rhamno-sugar 105. The 6-deoxy-gluco-stereochemistry is then installed by a protection/C-2 inversion strategy to give anthrose sugar 108. Finally, a Lev-protection, PMB-deprotection strategy, and trichloroacetimidate formation were used to convert 108 into the glycosyl donor sugar 97 (14 steps from achiral acetylfuran 95).
Scheme 1.20De novo synthesis of a D-anthrose sugar trichloroacetimidate.
The de novo Achmatowicz approach to the tris-rhamno portion of the anthrax tetrasaccharide began with the synthesis of disaccharide 115 from pyranone ent-44 and benzyl alcohol (Scheme 1.21). After glycosylation and postglycosylation transformations to install the rhamno-stereochemistry (ent-44 to 111), the 1,2-trans-diol of 111 was then protected with the Ley-spiroketal to provide monosaccharide 112 with a free C-2 hydroxyl group. After a similar three-step glycosylation (112 and 113) and postglycosylation sequence, 113 was converted into disaccharide 114, which in a one-pot ortho-ester protocol was protected to give disaccharide 115 with a free C-3 alcohol.
Scheme 1.21 Synthesis of disaccharide 115.
Simply repeating the same three-step glycosylation and postglycosylation sequence converted disaccharide 115 into trisaccharide 116 (Scheme 1.22). Once again the one-pot ortho-ester formation/acylation/hydrolysis sequence gave trisaccharide 117 with the free C-3 alcohol, ready for glycosylation with an anthrose sugar fragment. Unfortunately, any attempt at glycosylation of trisaccharide 117 failed because of the instability of the Ley-spiroketal to the Lewis acidic nature of
Scheme 1.22 Synthesis of tetrasaccharide 119.
the traditional glycosylation conditions. Undaunted, we turned to an alternative protecting group strategy. Thus, the C-3 hydroxyl group of 117 was protected as a levulinate ester, and the Ley-spiroketal-protecting group was removed to form 118. Then, the anthrose sugar was installed by an acylation, selective levulinate deprotection (using hydrazine), and glycosylation with anthrose monosaccharide 97 delivering the corresponding tetrasaccharide 119.
Finally, we turned to the deprotection of tetrasaccharide 119 into anthrax tetrasaccharide 100. Deprotection of levulinate-protecting groups followed by an etherification (MeI/Ag2O) delivered the methyl ether 120. A one-pot condition was employed to reduce and acylate azide 120 along with global deprotection of the acetate groups to generate the free alcohol (PEt3/LiOH/H2O), which upon selective peptide coupling of primary amine and 3-hydroxy-3-methylbutanoic acid (HBTU/Et3N) (HBTU, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) afforded amide 121. Removal of the benzyl groups in 121 under hydrogenolysis conditions provided the natural product anthrax tetrasaccharide 100 (Scheme 1.23).
Scheme 1.23 Synthesis of anthrax tetrasaccharide 100.
1.6 Conclusion and Outlook
For the last 25 years, various groups have been investigating the use of asymmetric catalysis for the synthesis of hexoses. When beginning with achiral starting materials and when asymmetric catalysis is used for the installation of asymmetry, these syntheses are called “de novo asymmetric” or “de novo” for short. While these de novo approaches have been quite impressive in terms of the scope of products prepared and the brevity of steps, they were lacking in terms of application to oligosaccharide synthesis. As part of these efforts, we have developed two orthogonal de novo asymmetric approaches to hexoses: an iterative dihydroxylation strategy and an Achmatowicz strategy. Owing to its compatibility with a Pd-catalyzed glycosylation reaction, this later Achmatowicz de novo approach to hexoses has seen significant application for the assembly of oligosaccharides.
Of particular note is the flexibility of the de novo Achmatowicz route to a myriad of carbohydrate motifs. The approach couples asymmetric catalysis with the Achmatowicz rearrangement for the synthesis of D- and L-pyranones and utilizes highly diastereoselective glycosylation and postglycosylation reactions for the assembly of oligosaccharides. Heavily featured in the glycosylation and postglycosylation reactions was the Pd-π-allyl-catalyzed allylic substitution reaction for substitution at both the anomeric C-1 and C-4 positions of the hexose. What made these allylic substitution reactions so powerful is the one-step double inversion mechanism of the Pd-catalyzed reaction, which in a highly stereospecific manner reliably provides products with net retention of stereochemistry.
Whether these approaches were used in linear and/or bidirectional manner, highly efficient syntheses of natural and unnatural mono-, di-, and oligosaccharides resulted. The overall efficiency of these approaches was the result of the strategic use of the enone functionality in the pyranone as atom-less protecting groups. While the use of atom-less protecting groups has been under-explored in carbohydrate chemistry, the success of the above-mentioned approaches suggest that this strategy should be given more attention from the synthetic organic chemistry community. The overall practicality of these syntheses can be seen in their ability to provide material for medicinal chemistry studies, often in ways that are not readily available by traditional carbohydrate syntheses [51].
1.7 Experimental Section
List of Abbreviations
Ac
Acetyl
AD-mix-α
3 equiv K
3
Fe(CN)
6
/K
2
CO
3
, 1 equiv MeSO
2
NH
2
, 5% OsO
4
,
and 6% (DHQ)
2
PHAL
AD-mix-β
3 equiv K
3
Fe(CN)
6
/K
2
CO
3
, 1 equiv MeSO
2
NH
2
, 5% OsO
4
,
and 6% (DHQD)
2
PHAL
ATCC
American Type Culture Collection
Bn
Benzyl
Boc
t
-Butoxycarbonyl
Bu
Butyl
Cbz
Carbobenzoxy
ClAc
Chloroacetyl
CTAB
Cetyltrimethylammonium bromide
DCC
Dicyclohexylcarbodiimide
DDQ
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
DMAP
Dimethylaminopyridine
DMP
Dess–Martin periodinane
dppb
1,4-Bis(diphenylphosphino)butane
Et
Ethyl
HBTU
O
-(Benzotriazol-1-yl)-
N
,
N
,
N
′,
N
′-tetramethyluronium
hexafluorophosphate
Lev
Levulinoyl
NBS
N
-Bromosuccinimide
NMO
N
-Methylmorpholine-
N
-oxide
Noyori
(
S
,
S
) (
R
)-Ru(η
6
-mesitylene)-(
S
,
S
)-TsDPEN
p
-TsOH
p
-Toluenesulfonic acid
Ph
Phenyl
PMB
p
-Methoxybenzyl
py
Pyridine
SAR
Structure Activity Relationship
TBAF
Tetrabutylammonium fluoride
TBS
t
-Butyldimethylsilyl
Tf
Trifluoromethanesulfonyl
THF
Tetrahydrofuran
TMS
Trimethylsilyl
TsDPEN
PhCH(TsN)CH(NH)Ph
Acknowledgments
We are grateful to NIH (GM090259) and NSF (CHE-0749451) for their support of our research programs. MFC also acknowledges the NSF for his fellowship from the NSF-IGERT Nanomedicine Program (DGE-0965843) at Northeastern University.
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