Programmable synthesis of 2-deoxyglycosides. - ACS Publications

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Programmable synthesis of 2-deoxyglycosides. Kevin M. Hoang, Nicholas Robert Lees, and Seth B Herzon J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 06 May 2019 Downloaded from http://pubs.acs.org on May 6, 2019

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Journal of the American Chemical Society

Programmable synthesis of 2-deoxyglycosides. Kevin M. Hoang,1 Nicholas R. Lees,1 and Seth B. Herzon*1,2 1

Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States. Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut 06520, United States. Supporting Information Placeholder 2

ABSTRACT: Control of glycoside bond stereochemistry is the central challenge in the synthesis of oligosaccharides. 2-Deoxyglycosides, which lack a C2 substituent to guide stereoselectivity, are among the most difficult classes of glycoside bond constructions. Here we present a method to synthesize 2-deoxysaccharides with specified glycoside bond stereochemistry using a nucleophilic carbohydrate residue and the synthetic equivalent of an alcohol electrophile. Because the configuration of the nucleophile can be precisely controlled, both α- and β-glycosides can be synthesized from the same starting material in nearly all cases examined. Stereoselectivities in these reactions are often greater than 50:1 and yields typically exceed 70%. This strategy is amenable to the stereocontrolled syntheses of trisaccharide diastereomers, and a tetrasaccharide. This method may be extensible to other classes of carbohydrates.

Control of glycoside bond stereochemistry has been called the “central topic” of carbohydrate chemistry.1 Most synthetic glycosylations involve the addition of a nucleophilic alcohol (acceptor) to a carbohydrate electrophile (Figure 1, left) and lie along a continuum bound by SN1 and SN2 pathways.2 The anomeric (C1) stereoselectivity then derives from the facial selectivity in this addition. Many effective strategies to control selectivity based on the nature of the C2 substituent have now been developed. 3 2-Deoxyglycosides, such as olivose and digitoxose, are an important constituent of biological polysaccharides and natural products.4 In the absence of a C2 oxygen, control of anomeric stereochemistry is considerably more challenging. In particular, synthetic methods to directly access the thermodynamically- and kinetically disfavored β-glycoside are rare, but this linkage is very common in nature (for selected examples, see refs. 5; for a review, see ref. 6). More broadly, methods that provide controlled access to either diastereomer from a single precursor do not exist, to our knowledge, although nature flexibly combines both linkages into single polymers. We considered alternative mechanistic manifolds7 to circumvent the recurring challenges associated with the direct synthesis of 2-deoxyglycosides. After evaluating several strategies, we developed an approach based on the coupling of a nucleophilic anomeric anion with the synthetic equivalent of an alcohol electrophile (Figure 1, right). This approach was inspired by several key findings. In 1980, Cohen reported that axial 2-lithiotetrahydropyrans are accessible by reductive lithiation of 2-phenylthio-tetrahydropyrans8 and later demonstrated9 that the kinetically-favored axial anion could be thermally equilibrated to the equatorial diastereomer in conformationally-restricted pyrans. In an important advance, Rychnovsky showed that both axial and equatorial anions were accessible in high diastereoselectivity from a range of flexible monocyclic tetrahydropyrans, including a glycoside derivative. 10

Figure 1. Left: The conventional approach to O-glycoside synthesis involves the addition of a nucleophilic alcohol to an electrophilic carbohydrate donor. When X  H, the C2 substituent may be used strategically to control diastereoselectivity. Right: Anomeric anions can be generated as α- or β-diastereomers by reductive lithiation of phenyl thioglycosides. We envisioned that reaction with an electrophilic alcohol equivalent would provide access to either α- or β-glycoside products. Anomeric anions undergo stereoretentive addition to a range of electrophiles,11 and have found use in the preparation glycosylsulfides.12 Thus, we recognized that these anomeric anions might form the basis for a method to access both α- and β-2-deoxyglycosides from a single starting material. As a collateral benefit, the configuration of the starting phenyl thioglycoside is inconsequential because the reductive lithiation proceeds by stepwise electron transfer.9 To realize this strategy, the synthetic equivalent of an alcohol electrophile needed to be identified. Reagents that transfer “R–O+” to carbanions are rare. Tetrahydropyranyl (THP) monoperoxy acetals, pioneered by Dussault, have emerged as perhaps the most useful and general reagents for formal alkoxenium ion transfer to organolithium and Grignard reagents (typical yields of 50– 70%).13,14 Accordingly, we evaluated the reductive lithiation of phenyl 3,4-di-O-methyl-1-thio-L-olivopyranoside (1, Figure 2A) with lithium di-tert-butylbiphenylide (LiDBB),15 followed by the addition of benzyl tetrahydropyranyl monoperoxy acetal (2).

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Figure. 2. A–C. Optimization of the glycosylation of the α-anomeric anion derived from 1 using alkyl THP and alkyl MTHP monoperoxy acetals. D. Optimized conditions for the generation of the β-glycoside 8β (see also Table S1). Under these conditions, the product 3 was isolated in 6% yield as a single detectable α-diastereomer (1H NMR analysis). Benzaldehyde and the protodethiolated sugar 4 were each formed in 34% yield, presumably by Kornblum–DeLaMare elimination.16 To circumvent proton abstraction from the acidic benzylic position, we employed the 3-phenylpropyl monoperoxy acetal 5a (Figure 2B). The addition of 5a to the α-anion derived from 1 provided the αglycoside 6 in 81% yield and >50:1 α:β selectivity. A 91% yield of 6 (>50:1 α:β) was obtained when the novel 2-methyl-tetrahydrofuranyl (MTHP) monoperoxy acetal 5b was used as the electrophile, presumably by suppressing minor amounts of proton abstraction from the THP ring. This modification may also improve the yields of product when more hindered coupling partners are employed (see below). To test the feasibility of this reaction in the synthesis of a disaccharide, we prepared the carbohydrate-derived MTHP monoperoxy acetal 7 (Figure 2C). Glycosylation with the anomeric anion derived from 1 generated the product 8α in 77% yield and >50:1 dr. Increasing the reaction time to 3 h increased the yield of the product to 89% (>50:1 α:β). We then proceeded to optimize formation of the β-product with respect to yield and stereoselectivity (Figure 2D and Table

S1). The α-anion formed upon reductive lithiation of 1 at –78 °C could be equilibrated to the β-isomer by warming to –20 °C. In accord with Rychnovsky’s observations,10 we found that a tetrahydrofuran–pentane solvent mixture provided the fastest equilibration rates while minimizing proton transfer from the solvent. Under optimized conditions, the β-linked product 8β was obtained in 82% yield and >50:1 dr by reductive lithiation of 1 (1.5 equiv), equilibration to the β-anion (–20 °C, 1 h), re-cooling to –78 °C, and addition of the MTHP monoperoxy acetal 7. The preliminary scope of this reaction is shown in Figure 3. The 2,6-dideoxyglycosides 8 and 16 were obtained in 79–90% yield using the primary MTHP monoperoxy acetal 7 as the electrophile and the phenyl thioglycosides 1 or 9 as pronucleophiles (Figure 3C). The secondary MTHP monoperoxy acetals 14 and 15 were also competent and provided the α- or β-linked 2,6- dideoxyglycosides 17–20 in 53–90% yield (Figure 3D). As expected, the lesshindered MTHP monoperoxy acetal 14 transformed more efficiently than 15. The selectivities in the formation of 8 and 16–20 exceeded 19:1, and were >50:1 in most cases. 2-Deoxydonors such as 10, 11, and 12 also reacted smoothly. For example, both the α- and β-products derived from reaction of the trimethoxy donor 10 with the primary MTHP monoperoxy acetal 7 were prepared in high yield and with complete control of anomeric stereochemistry (21α: 84%, >50:1 α:β; 21β: 75% >20:1 β:α, Figure 3E). However, reactions of the 2-deoxydonor 10 with secondary MTHP monoperoxy acetals were challenging (Figure 3F). While the α-linked products 24α and 25α were obtained in 87% (>50:1 α:β ) and 37% (>50:1 α:β) yields, respectively, reactions of the β-anions proceeded more slowly. The yields of the β-linked products 24β or 25β were 58% and 21%, respectively, although the stereoselectivities remained high (>50:1 β:α). The α-linked glycosides 22α and 23α could be prepared in 80% (>30:1 α:β) and 74% (>30:1 α:β) yields, respectively, but attempts to form the diastereomeric β-products were unsuccessful (Figure 3E). To gain insight into the relative reactivity of the 2-deoxy and 2,6-dideoxy donors we calculated the energies of the C1-lithio derivatives in a C-PCM solvation model ( = 7.43) and in the gas phase (MP2/6-311+G(d,p); Figure 4).17 For both series’, the β-anion was found to be lower in energy than the α-anion, as expected, but the lowest energy conformations of the β-anion were unanticipated. In the 2,6-dideoxyglycoside series, the all-axial β-anion was 1.9 kcal/mol lower in energy than the equatorial β-anion in the CPCM model, while in the gas phase the equatorial β-anion was 1.6 kcal/mol lower in energy than the all-axial isomer. However, in the 2-deoxyglycoside series the all-axial β-anion was 9.7 and 10.7 kcal/mol lower in energy than the equatorial β-anion in the C-PCM model and in the gas phase, respectively. Thus, in the 2-deoxy series the β-anion adopts an all-axial chair conformation, likely due to a stabilizing interaction between the C6(O) and C2(O) substituents with the axial lithium atom (interatomic distances = 1.91 and 1.97 Å, respectively). The lowest energy conformation of the 2,6dideoxy-β-anion is not unambiguous, but given the similar energies of the axial and equatorial conformers, both are plausibly accessible in solution. The formation of a stable all axial β-anion in the 2deoxyglycoside series provides an explanation for the lower reactivity of these substrates. To investigate if conformationally-restricting the system might inhibit formation of the stable, all-axial β-anion, we prepared the 2,3-butanedione acetal derivatives 13a and 13b (Figure 3A). However, both substrates failed to produce the desired β-linked disaccharides. These results point to a deeper effect invoked by the C6 oxygen atom. Further investigation led us to the C6 free hydroxy derivative 13c, whereupon we reasoned that prior removal of the acidic C6 hydroxyl proton would allow the glycosylation to


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Journal of the American Chemical Society

Figure 3. Preliminary scope of the inverse glycosylation reaction. A. Structures of phenyl thioglycosides used in this study. B. Structures of the MTHP monoperoxy acetals used in this study. C. Products derived from coupling of 2,6-dideoxy donors and primary MTHP monoperoxy acetals. D. Products derived from 2,6-dideoxydonors and secondary MTHP monoperoxy acetals. E. Products derived from 2-deoxy donors and primary MTHP monoperoxy acetals. F. Products derived from 2-deoxy donors and secondary MTHP monoperoxy acetals. G. Products derived from 2-deoxy-6-hydroxy donors and primary MTHP monoperoxy acetals.



Figure 4. Relative energies and structures of the β axial, α axial, and β equatorial 2,6-dideoxyglycoside and 2-deoxyglycoside anions. Geometries and energies were optimized [MP2/6-311+G(d,p)] in a C-PCM solvation model ( = 7.43) or in the gas phase. proceed. To our delight, we were able to restore β-reactivity and synthesize the glycosides 26α and 26β in 77% and 68% yields, respectively, with >50:1 α:β and >8:1 β:α stereoselectivities (Figure 3G). Furthermore, the presence of free hydroxyl groups (and especially a primary C6 hydroxyl group)in synthetic glycosylations is rare.18 Thus, this approach provides a handle for installation of a third sugar and suggests that application of this chemistry to 2-hydroxy or 2-acetamido thioglycosides may also be possible. We recognized that the addition of carbohydrate-based MTHP monoperoxy acetals containing an anomeric phenylthio residue (see 14 and 15, Figure 3B) might allow us to extend our method to sequential glycosylations in one flask.19 The synthesis of oligosaccharides in one flask from carbohydrate monomers is a longstanding goal in synthetic carbohydrate chemistry, and significant advances toward this end have been recorded.20 However, in most instances stereocontrol derives from the mode of activation or carbohydrate protecting group strategy. In our approach we envisioned the generation of oligosaccharides with control over the newly-formed glycoside linkages would be possible. Toward this end, we synthesized the products shown in Figure 5. Reductive lithiation of 1 and addition of the MTHP monoperoxy acetal 14, followed by sequential reductive lithiation of the resulting disaccharide and addition of the MTHP monoperoxy acetal 7, resulted in the formation of the α,α-linked trisaccharide 27α,α in 54% yield (>73% per iteration) as a single detectable diastereomer by 1H NMR analysis (out of four possible diastereomers). As a benchmark, Kahne’s pioneering sulfoxide-based one-step synthesis of the related α,α-linked cyclamycin trisaccharide proceeds in 25% yield.20b Following our equilibration procedure for the first

glycosylation, the diastereomer 27β,α was also accessible (30%, four possible diastereomers, single detectable diastereomer by 1H NMR analysis). Alternatively, reductive lithiation of 1 and addition of the MTHP monoperoxy acetal 14, followed by a second reductive lithiation and equilibration to the β-anion, provided 27α,β in 13% yield (four possible diastereomers, single detectable diastereomer by 1H NMR analysis). The lower yield obtained when the second glycosylation involves equilibration to the β diastereomer was not entirely unexpected; in earlier optimization studies, we had observed that the MTHP leaving group can act as an electrophile and proton source. Warming to −20 °C in the presence of this leaving group from the first iteration results in competitive protonation of the anomeric anion (we recovered 43% of protodethiolated disaccharide). Alternative electrophiles that circumvent this issue are currently under development. By executing three sequential reductive lithiations using the MTHP monoperoxy acetal 14 twice as a building block we obtained the tetrasaccharide 28α,α,α in 25% yield (>63% per iteration, eight possible diastereomers, single detectable diastereomer by 1H NMR analysis). The high stereoselectivities in this glycosylation reaction confer a practical advantage to this approach, as the diastereomers of 27 (and 28) would be difficult to separate on preparative scales (see Figure S3). In conclusion, we have developed an O-glycosylation protocol that provides efficient access to both α and β anomers of 2-deoxy and 2,6-dideoxyglycoside products from simple carbohydrate donors that are free of directing groups and glycosyl promotors. Additionally, computational studies have proven useful in elucidating the conformations and understanding the relative reactivity of anomeric anions, and we used these to guide the

Figure 5. Single-flask synthesis of the trisaccharides 27α,α, 27β,α, 25α,β, and the tetrasaccharide 28α,α,α.


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Journal of the American Chemical Society glycosylation of carbohydrates bearing a C6 hydroxyl group. We envision that this methodology will be amenable to the iterative construction of polysaccharides with control over anomeric stereochemistry.

ASSOCIATED CONTENT Supporting Information Detailed experimental procedures and characterization data for all new compounds (PDF). The Supporting Information is available free of charge on the ACS Publications website.

AUTHOR INFORMATION Corresponding Author [email protected]

ACKNOWLEDGMENT Financial support from Yale University and the National Science Foundation (Graduate Research Fellowship to K.M.H.) is gratefully acknowledged. We thank Dr. Fabian Menges for HRMS analysis.

REFERENCES 1. For a recent review, see: Krasnova, L.; Wong, C.-H. Oligosaccharide Synthesis and Translational Innovation. J. Am. Chem. Soc. 2019, 141, 3735. 2. For a review, see: Adero, P. O.; Amarasekara, H.; Wen, P.; Bohé, L.; Crich, D. The Experimental Evidence in Support of Glycosylation Mechanisms at the SN1–SN2 Interface. Chem. Rev. 2018, 118, 8242. 3. For a review, see: Nigudkar, S. S.; Demchenko, A. V. Stereocontrolled 1,2-cis glycosylation as the driving force of progress in synthetic carbohydrate chemistry. Chem. Sci. 2015, 6, 2687. 4. For a review, see: Bennett, C. S.; Galan, M. C. Methods for 2Deoxyglycoside Synthesis. Chem. Rev. 2018, 118, 7931. 5. Selected examples: (a) Guo, Y.; Sulikowski, G. A. Synthesis of the Hexasaccharide Fragment of Landomycin A: Application of Glycosyl Tetrazoles and Phosphites in the Synthesis of a Deoxyoligosaccharide. J. Am. Chem. Soc. 1998, 120, 1392. (b) Tanaka, H.; Yoshizawa, A.; Takahashi, T. Direct and Stereoselective Synthesis of β-Linked 2,6Deoxyoligosaccharides. Angew. Chem., Int. Ed. 2007, 46, 2505. (c) Kaneko, M.; Herzon, S. B. Scope and Limitations of 2-Deoxy and 2,6Dideoxyglycosyl Bromides as Donors for the Synthesis of β-2-Deoxy and β-2,6-Dideoxyglycosides. Org. Lett. 2014, 16, 2776. (d) Issa, J. P.; Bennett, C. S. A Reagent-Controlled SN2-Glycosylation for the Direct Synthesis of β-Linked 2-Deoxy-Sugars. J. Am. Chem. Soc. 2014, 136, 5740. (e) Park, Y.; Harper, K. C.; Kuhl, N.; Kwan, E. E.; Liu, R. Y.; Jacobsen, E. N. Macrocyclic bis-thioureas catalyze stereospecific glycosylation reactions. Science 2017, 355, 162. 6. Borovika, A.; Nagorny, P. Recent Advances in the Synthesis of Natural 2-Deoxy-β-glycosides. J. Carbohydr. Chem. 2012, 31, 255. 7. Synthetic methods that establish glycoside bond stereochemistry by other mechanistic manifolds have proven useful in constructing β-2deoxyglycosides. The stereoselective reduction of anomeric radicals exemplies the merits of alternative approaches. See: (a) Crich, D.; Ritchie, T. J. Stereoselective free radical reactions in the preparation of 2-deoxy-βD-glucosides. J. Chem. Soc., Chem. Commun. 1988, 1461. (b) Kahne, D.;

Yang, D.; Lim, J. J.; Miller, R.; Paguaga, E. The use of alkoxy-substituted anomeric radicals for the construction of .beta.-glycosides. J. Am. Chem. Soc. 1988, 110, 8716. 8. Cohen, T.; Matz, J. R. A general preparative method for α-lithioethers and its application to a concise, practical synthesis of brevicomin. J. Am. Chem. Soc. 1980, 102, 6900. 9. Cohen, T.; Lin, M. T. Two-flask preparation of α-lithio cyclic ethers from γ- and δ-lactones. Reductive lithiation as a route, via radical intermediates, to axial 2-lithiotetrahydropyrans and their equilibration to the equatorial isomers. J. Am. Chem. Soc. 1984, 106, 1130. 10. Rychnovsky, S. D.; Mickus, D. E. Preparation of 2lithiotetrahydropyrans: Kinetic and thermodynamic generation of alkyllithium reagents. Tetrahedron Lett. 1989, 30, 3011. 11. For a review, see: Somsák, L. Carbanionic Reactivity of the Anomeric Center in Carbohydrates. Chem. Rev. 2001, 101, 81. 12. Baryal Kedar, N.; Zhu, D.; Li, X.; Zhu, J. Umpolung Reactivity in the Stereoselective Synthesis of S‐Linked 2‐Deoxyglycosides. Angew. Chem., Int. Ed. 2013, 52, 8012. 13. Kyasa, S.; Meier, R. N.; Pardini, R. A.; Truttmann, T. K.; Kuwata, K. T.; Dussault, P. H. Synthesis of Ethers via Reaction of Carbanions and Monoperoxyacetals. J. Org. Chem. 2015, 80, 12100. 14. Caution: While we have not encountered any laboratory incidents in carrying out this work, organic peroxides are potentially explosive and should be protected from light and metal salts. It is recommended that organic peroxides are stored in the presence of an inhibitor. See: (a) Dussault, P.; Sahli, A. 2-Methoxy-2-propyl hydroperoxide: a convenient reagent for the synthesis of hydroperoxides and peracids. J. Org. Chem. 1992, 57, 1009. For a comprehensive discussion of the hazards and safe handling of peroxides, see: (b) Clark, D. E. Peroxides and peroxide-forming compounds. J. Chem. Health Saf. 2001, 8, 12. 15. (a) Hill, R. R.; Rychnovsky, S. D. Generation, Stability, and Utility of Lithium 4,4′-Di-tert-butylbiphenylide (LiDBB). J. Org. Chem. 2016, 81, 10707. For a review, see: (b) Perry, M. A.; Rychnovsky, S. D. Generation, structure and reactivity of tertiary organolithium reagents. Nat. Prod. Rep. 2015, 32, 517. 16. Kornblum, N.; DeLaMare, H. E. The base catalyzed decomposition of a dialkyl peroxide. J. Am. Chem. Soc. 1951, 73, 880. 17. For earlier computational studies of α-alkoxyanions, see: Rychnovsky, S. D.; Buckmelter, A. J.; Dahanukar, V. H.; Skalitzky, D. J. Synthesis, Equilibration, and Coupling of 4-Lithio-1,3-dioxanes: Synthons for synand anti-1,3-Diols. J. Org. Chem. 1999, 64, 6849. 18. (a) Taylor, M. S. Catalysis Based on Reversible Covalent Interactions of Organoboron Compounds. Acc. Chem. Res. 2015, 48, 295. (b) Tanaka, M.; Nakagawa, A.; Nishi, N.; Iijima, K.; Sawa, R.; Takahashi, D.; Toshima, K. Boronic-Acid-Catalyzed Regioselective and 1,2-cis-Stereoselective Glycosylation of Unprotected Sugar Acceptors via SNi-Type Mechanism. J. Am. Chem. Soc. 2018, 140, 3644. 19. For sequential sterecontrolled coupling of carbanions, see: Burns, M.; Essafi, S.; Bame, J. R.; Bull, S. P.; Webster, M. P.; Balieu, S.; Dale, J. W.; Butts, C. P.; Harvey, J. N.; Aggarwal, V. K. Assembly-line synthesis of organic molecules with tailored shapes. Nature 2014, 513, 183. 20. For selected examples, see: (a) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B. Armed and disarmed n-pentenyl glycosides in saccharide couplings leading to oligosaccharides. J. Am. Chem. Soc. 1988, 110, 5583. (b) Raghavan, S.; Kahne, D. A one step synthesis of the ciclamycin trisaccharide. J. Am. Chem. Soc. 1993, 115, 1580. (c) L. Douglas, N.; V. Ley, S.; Lücking, U.; L. Warriner, S. Tuning glycoside reactivity: New tool for efficient oligosaccharide synthesis. J. Chem. Soc., Perkin Trans. 1 1998, 51. (d) Pongdee, R.; Wu, B.; Sulikowski, G. A. OnePot Synthesis of 2-Deoxy-β-oligosaccharides. Org. Lett. 2001, 3, 3523. See also ref. 1.




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Programmable synthesis of 2-deoxyglycosides. - ACS Publications

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