Site-Selective and Stereoselective O-Alkylation of Glycosides by Rh(II)-Catalyzed Carbenoid Insertion

doi:10.1021/jacs.9b11262

. 2019 Dec 18;141(50):19902-19910.

doi: 10.1021/jacs.9b11262. Epub 2019 Dec 3.

Site-Selective and Stereoselective O-Alkylation of Glycosides by Rh(II)-Catalyzed Carbenoid Insertion

Jicheng Wu¹, Xiaolei Li¹, Xiaotian Qi², Xiyan Duan¹, Weston L Cracraft³, Ilia A Guzei³, Peng Liu^{2

4}, Weiping Tang^{1

3}

Affiliations

¹ School of Pharmacy , University of Wisconsin-Madison , Madison , Wisconsin 53705 , United States.
² Department of Chemistry , University of Pittsburgh , Pittsburgh , Pennsylvania 15260 , United States.
³ Department of Chemistry , University of Wisconsin-Madison , Madison , Wisconsin 53706 , United States.
⁴ Department of Chemical and Petroleum Engineering , University of Pittsburgh , Pittsburgh , Pennsylvania 15261 , United States.

PMID: 31739665
PMCID: PMC6920555
DOI: 10.1021/jacs.9b11262

Site-Selective and Stereoselective O-Alkylation of Glycosides by Rh(II)-Catalyzed Carbenoid Insertion

Jicheng Wu et al. J Am Chem Soc. 2019.

. 2019 Dec 18;141(50):19902-19910.

doi: 10.1021/jacs.9b11262. Epub 2019 Dec 3.

Authors

Jicheng Wu¹, Xiaolei Li¹, Xiaotian Qi², Xiyan Duan¹, Weston L Cracraft³, Ilia A Guzei³, Peng Liu^{2

4}, Weiping Tang^{1

3}

Affiliations

¹ School of Pharmacy , University of Wisconsin-Madison , Madison , Wisconsin 53705 , United States.
² Department of Chemistry , University of Pittsburgh , Pittsburgh , Pennsylvania 15260 , United States.
³ Department of Chemistry , University of Wisconsin-Madison , Madison , Wisconsin 53706 , United States.
⁴ Department of Chemical and Petroleum Engineering , University of Pittsburgh , Pittsburgh , Pennsylvania 15261 , United States.

PMID: 31739665
PMCID: PMC6920555
DOI: 10.1021/jacs.9b11262

Abstract

Carbohydrates are synthetically challenging molecules with vital biological roles in all living systems. Selective synthesis and functionalization of carbohydrates provide tremendous opportunities to improve our understanding on the biological functions of this fundamentally important class of molecules. However, selective functionalization of seemingly identical hydroxyl groups in carbohydrates remains a long-standing challenge in chemical synthesis. We herein describe a practical and predictable method for the site-selective and stereoselective alkylation of carbohydrate hydroxyl groups via Rh(II)-catalyzed insertion of metal carbenoid intermediates. This represents one of the mildest alkylation methods for the systematic modification of carbohydrates. Density functional theory (DFT) calculations suggest that the site selectivity is determined in the Rh(II)-carbenoid insertion step, which prefers insertion into hydroxyl groups with an adjacent axial substituent. The subsequent intramolecular enolate protonation determines the unexpected high stereoselectivity. The most prevalent trans-1,2-diols in various pyranoses can be systematically and predictably differentiated based on the model derived from DFT calculations. We also demonstrated that the selective O-alkylation method could significantly improve the efficiency and stereoselectivity of glycosylation reactions. The alkyl groups introduced to carbohydrates by OH insertion reaction can serve as functional groups, protecting groups, and directing groups.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Scheme 1.**
Selective Functionalization of Glycosides

**Scheme 2.. Determination of the Stereochemistry^a**
^a Reaction conditions: See Table 1 for conditions. α-diazo compounds **14a** or **14b** (0.3 mmol, 1.5 equiv) was used.

**Scheme 3.**
DFT Calculations and Working Model for Site-selective Alkylation

**Scheme 4.. Tuning the Site-selectivity by Protecting Groups^a**
^a See Table 1 for conditions, α-diazo compound 2 (0.3 mmol, 1.5 equiv) was used.^b Rh₂(oct)₄ (1 mol%) was used.

**Scheme 5.. Evaluation of Chiral Rh(II) Catalysts^a**
^a See Table 1 for conditions, α-diazo compound (0.3 mmol, 1.5 equiv) was used, 10 min - 2 h.^b α-diazo compound 2 was used, 10 min - 2 h. Rh₂(R-DOSP)₄: dirhodium(II) tetrakis[(R)-N-(p-dodecylphenylsulfonyl)prolinate]. Rh₂(R-PTAD)₄: dirhodium(II) tetrakis[(R)-(−)-(1-adamantyl)-(N-phthalimido)acetato]. Rh₂(5R-MEPY)₄: dirhodium(II) tetrakis[methyl 2-pyrrolidone-5(R)-carboxylate].

**Scheme 6.. Alkyl Group as the Directing Group for Stereoselective Glycosylation Reactions**
Conditions: a) See Table 1 for standard conditions. b) DMAP, NEt₃, Piv₂O, AcOH, DCM, rt. c) PdCl₂, NaOAc/AcOH/H₂O, rt. d) CCl₃CN, DBU, DCM, rt. e) TMSOTf, 4Å MS, DCM, −78 °C - rt.

**Scheme 7.. Alkyl Group as the Protecting Group for Glycosylation Reactions**
Conditions: a) KHMDS, −78 °C, THF, 30 min. b) Oxaziridine, −78 °C, 1 – 3 h; r.t., 45 min. c) TMSOTf, DCM, −78 °C - rt. d) NIS, TMSOf, DCM, −78 °C - rt, 4 Å MS. e) NaOMe, MeOH, rt.

**Scheme 8:. Alkyl Group as the Functional Group**
Conditions: a) TBSCl, imidazole, DMF, rt, 6 h. b) LiOH·H₂O, THF/H₂O (v/v, 5:1), rt, 4 h. c) HATU, DIPEA, DCM, rt, 5 h. d) DMAP, DCC, DCM, rt, 5 h.

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References

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3. Danishefsky SJ; Shue Y-K; Chang MN; Wong C-H Development of Globo-H cancer vaccine. Acc. Chem. Res 2015, 48, 643–652. - PubMed
1. Varki A Biological roles of glycans. Glycobiology 2017, 27, 3–49. - PMC - PubMed
1. Crich D Modern synthetic methods in carbohydrate chemistry: From monosaccharides to complex glycoconjugates. Wiley-VCH, 2013.
2. Cossy J; Arseniyadis S Modern tools for the synthesis of complex bioactive molecules. Wiley-VCH, 2012.
1. For recent reviews, see:
2. Nielsen MM; Pedersen CM Catalytic glycosylations in oligosaccharide synthesis. Chem. Rev 2018, 118, 8285–8358. - PubMed
3. Panza M; Pistorio SG; Stine KJ; Demchenko AV Automated chemical oligosaccharide synthesis: novel approach to traditional challenges. Chem. Rev 2018, 118, 8105–8150. - PMC - PubMed
4. Kulkarni SS; Wang C-C; Sabbavarapu NM; Podilapu AR; Liao P-H; Hung S-C “One-pot” protection, glycosylation, and protection–glycosylation strategies of carbohydrates. Chem. Rev 2018, 118, 8025–8104. - PubMed
5. Bennett CS; Galan MC Methods for 2-deoxyglycoside synthesis. Chem. Rev 2018, 118, 7931–7985. - PMC - PubMed
6. Adero PO; 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, 8242–8284. - PMC - PubMed
7. Leng W-L; Yao H; He J-X; Liu X-W Venturing beyond donor-controlled glycosylation: New perspectives toward anomeric selectivity. Acc. Chem. Res 2018, 51, 628–639. - PubMed
8. Peng P; Schmidt RR Acid–base catalysis in glycosidations: a nature derived alternative to the generally employed methodology. Acc. Chem. Res 2017, 50, 1171–1183. - PubMed
9. Shugrue CR; Miller SJ Applications of nonenzymatic catalysts to the alteration of natural products. Chem. Rev 2017, 117, 11894–11951. - PMC - PubMed
10. Blaszczyk SA; Homan TC; Tang W Recent advances in site-selective functionalization of carbohydrates mediated by organocatalysts. Carbohydr. Res 2019, 471, 64–77. - PMC - PubMed
11. Wang H-Y; Blaszczyk SA; Xiao G; Tang W Chiral reagents in glycosylation and modification of carbohydrates. Chem. Soc. Rev 2018, 47, 681–701. - PubMed
12. Dimakos V; Taylor MS “Site-Selective Functionalization of Hydroxyl Groups in Carbohydrate Derivatives” Chem. Rev 2018, 118, 11457. - PubMed
1. David S; Hanessian S Regioselective manipulation of hydroxyl groups via organotin derivatives. Tetrahedron 1985, 41, 643–663.
2. Oshima K; Kitazono E; Aoyama Y Complexation-induced activation of sugar OH groups. Regioselective alkylation of methyl fucopyranoside via cyclic phenylboronate in the presence of amine. Tetrahedron Lett. 1997, 38, 5001–5004.
3. Taylor MS Catalysis based on reversible covalent interactions of organoboron compounds. Acc. Chem. Res 2015, 48, 295–305. - PubMed
4. Sculimbrene BR; Miller SJ Discovery of a catalytic asymmetric phosphorylation through selection of a minimal kinase mimic: A concise total synthesis of d-myo-inositol-1-phosphate. J. Am. Chem. Soc 2001, 123, 10125–10126. - PubMed
5. Sun X; Lee H; Lee S; Tan KL Catalyst recognition of cis-1,2-diols enables site-selective functionalization of complex molecules. Nat. Chem 2013, 5, 790–795. - PMC - PubMed
6. Sun X; Worthy AD; Tan KL Scaffolding catalysts: Highly enantioselective desymmetrization reactions. Angew. Chem. Int. Ed 2011, 50, 8167–8171. - PMC - PubMed
7. Lee D; Taylor MS Borinic acid-catalyzed regioselective acylation of carbohydrate derivatives. J. Am. Chem. Soc 2011, 133, 3724–3727. - PubMed
8. Gouliaras C; Lee D; Chan L; Taylor MS Regioselective activation of glycosyl acceptors by a diarylborinic acid-derived catalyst. J. Am. Chem. Soc 2011, 133, 13926–13929. - PubMed
9. Lee D; Williamson CL; Chan L; Taylor MS Regioselective, borinic acid-catalyzed monoacylation, sulfonylation and alkylation of diols and carbohydrates: Expansion of substrate scope and mechanistic studies. J. Am. Chem. Soc 2012, 134, 8260–8267. - PubMed
10. D’Angelo KA; Taylor MS Borinic acid catalyzed stereo- and regioselective couplings of glycosyl methanesulfonates. J. Am. Chem. Soc 2016, 138, 11058–11066. - PubMed

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[1] Wong C-H Carbohydrate-based drug discovery. Wiley-VCH, 2006.

Gabius H-J The sugar code: fundamentals of glycosciences. Wiley-VCH, 2011.

Danishefsky SJ; Shue Y-K; Chang MN; Wong C-H Development of Globo-H cancer vaccine. Acc. Chem. Res 2015, 48, 643–652. - PubMed

[2] Wong C-H Carbohydrate-based drug discovery. Wiley-VCH, 2006.

[3] Gabius H-J The sugar code: fundamentals of glycosciences. Wiley-VCH, 2011.

[4] Danishefsky SJ; Shue Y-K; Chang MN; Wong C-H Development of Globo-H cancer vaccine. Acc. Chem. Res 2015, 48, 643–652. - PubMed

[5] Varki A Biological roles of glycans. Glycobiology 2017, 27, 3–49. - PMC - PubMed

[6] Varki A Biological roles of glycans. Glycobiology 2017, 27, 3–49. - PMC - PubMed

[7] Crich D Modern synthetic methods in carbohydrate chemistry: From monosaccharides to complex glycoconjugates. Wiley-VCH, 2013.

Cossy J; Arseniyadis S Modern tools for the synthesis of complex bioactive molecules. Wiley-VCH, 2012.

[8] Crich D Modern synthetic methods in carbohydrate chemistry: From monosaccharides to complex glycoconjugates. Wiley-VCH, 2013.

[9] Cossy J; Arseniyadis S Modern tools for the synthesis of complex bioactive molecules. Wiley-VCH, 2012.

[10] For recent reviews, see:

Nielsen MM; Pedersen CM Catalytic glycosylations in oligosaccharide synthesis. Chem. Rev 2018, 118, 8285–8358. - PubMed

Panza M; Pistorio SG; Stine KJ; Demchenko AV Automated chemical oligosaccharide synthesis: novel approach to traditional challenges. Chem. Rev 2018, 118, 8105–8150. - PMC - PubMed

Kulkarni SS; Wang C-C; Sabbavarapu NM; Podilapu AR; Liao P-H; Hung S-C “One-pot” protection, glycosylation, and protection–glycosylation strategies of carbohydrates. Chem. Rev 2018, 118, 8025–8104. - PubMed

Bennett CS; Galan MC Methods for 2-deoxyglycoside synthesis. Chem. Rev 2018, 118, 7931–7985. - PMC - PubMed

Adero PO; 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, 8242–8284. - PMC - PubMed

Leng W-L; Yao H; He J-X; Liu X-W Venturing beyond donor-controlled glycosylation: New perspectives toward anomeric selectivity. Acc. Chem. Res 2018, 51, 628–639. - PubMed

Peng P; Schmidt RR Acid–base catalysis in glycosidations: a nature derived alternative to the generally employed methodology. Acc. Chem. Res 2017, 50, 1171–1183. - PubMed

Shugrue CR; Miller SJ Applications of nonenzymatic catalysts to the alteration of natural products. Chem. Rev 2017, 117, 11894–11951. - PMC - PubMed

Blaszczyk SA; Homan TC; Tang W Recent advances in site-selective functionalization of carbohydrates mediated by organocatalysts. Carbohydr. Res 2019, 471, 64–77. - PMC - PubMed

Wang H-Y; Blaszczyk SA; Xiao G; Tang W Chiral reagents in glycosylation and modification of carbohydrates. Chem. Soc. Rev 2018, 47, 681–701. - PubMed

Dimakos V; Taylor MS “Site-Selective Functionalization of Hydroxyl Groups in Carbohydrate Derivatives” Chem. Rev 2018, 118, 11457. - PubMed

[11] For recent reviews, see:

[12] Nielsen MM; Pedersen CM Catalytic glycosylations in oligosaccharide synthesis. Chem. Rev 2018, 118, 8285–8358. - PubMed

[13] Panza M; Pistorio SG; Stine KJ; Demchenko AV Automated chemical oligosaccharide synthesis: novel approach to traditional challenges. Chem. Rev 2018, 118, 8105–8150. - PMC - PubMed

[14] Kulkarni SS; Wang C-C; Sabbavarapu NM; Podilapu AR; Liao P-H; Hung S-C “One-pot” protection, glycosylation, and protection–glycosylation strategies of carbohydrates. Chem. Rev 2018, 118, 8025–8104. - PubMed

[15] Bennett CS; Galan MC Methods for 2-deoxyglycoside synthesis. Chem. Rev 2018, 118, 7931–7985. - PMC - PubMed

[16] Adero PO; 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, 8242–8284. - PMC - PubMed

[17] Leng W-L; Yao H; He J-X; Liu X-W Venturing beyond donor-controlled glycosylation: New perspectives toward anomeric selectivity. Acc. Chem. Res 2018, 51, 628–639. - PubMed

[18] Peng P; Schmidt RR Acid–base catalysis in glycosidations: a nature derived alternative to the generally employed methodology. Acc. Chem. Res 2017, 50, 1171–1183. - PubMed

[19] Shugrue CR; Miller SJ Applications of nonenzymatic catalysts to the alteration of natural products. Chem. Rev 2017, 117, 11894–11951. - PMC - PubMed

[20] Blaszczyk SA; Homan TC; Tang W Recent advances in site-selective functionalization of carbohydrates mediated by organocatalysts. Carbohydr. Res 2019, 471, 64–77. - PMC - PubMed

[21] Wang H-Y; Blaszczyk SA; Xiao G; Tang W Chiral reagents in glycosylation and modification of carbohydrates. Chem. Soc. Rev 2018, 47, 681–701. - PubMed

[22] Dimakos V; Taylor MS “Site-Selective Functionalization of Hydroxyl Groups in Carbohydrate Derivatives” Chem. Rev 2018, 118, 11457. - PubMed

[23] David S; Hanessian S Regioselective manipulation of hydroxyl groups via organotin derivatives. Tetrahedron 1985, 41, 643–663.

Oshima K; Kitazono E; Aoyama Y Complexation-induced activation of sugar OH groups. Regioselective alkylation of methyl fucopyranoside via cyclic phenylboronate in the presence of amine. Tetrahedron Lett. 1997, 38, 5001–5004.

Taylor MS Catalysis based on reversible covalent interactions of organoboron compounds. Acc. Chem. Res 2015, 48, 295–305. - PubMed

Sculimbrene BR; Miller SJ Discovery of a catalytic asymmetric phosphorylation through selection of a minimal kinase mimic: A concise total synthesis of d-myo-inositol-1-phosphate. J. Am. Chem. Soc 2001, 123, 10125–10126. - PubMed

Sun X; Lee H; Lee S; Tan KL Catalyst recognition of cis-1,2-diols enables site-selective functionalization of complex molecules. Nat. Chem 2013, 5, 790–795. - PMC - PubMed

Sun X; Worthy AD; Tan KL Scaffolding catalysts: Highly enantioselective desymmetrization reactions. Angew. Chem. Int. Ed 2011, 50, 8167–8171. - PMC - PubMed

Lee D; Taylor MS Borinic acid-catalyzed regioselective acylation of carbohydrate derivatives. J. Am. Chem. Soc 2011, 133, 3724–3727. - PubMed

Gouliaras C; Lee D; Chan L; Taylor MS Regioselective activation of glycosyl acceptors by a diarylborinic acid-derived catalyst. J. Am. Chem. Soc 2011, 133, 13926–13929. - PubMed

Lee D; Williamson CL; Chan L; Taylor MS Regioselective, borinic acid-catalyzed monoacylation, sulfonylation and alkylation of diols and carbohydrates: Expansion of substrate scope and mechanistic studies. J. Am. Chem. Soc 2012, 134, 8260–8267. - PubMed

D’Angelo KA; Taylor MS Borinic acid catalyzed stereo- and regioselective couplings of glycosyl methanesulfonates. J. Am. Chem. Soc 2016, 138, 11058–11066. - PubMed

[24] David S; Hanessian S Regioselective manipulation of hydroxyl groups via organotin derivatives. Tetrahedron 1985, 41, 643–663.

[25] Oshima K; Kitazono E; Aoyama Y Complexation-induced activation of sugar OH groups. Regioselective alkylation of methyl fucopyranoside via cyclic phenylboronate in the presence of amine. Tetrahedron Lett. 1997, 38, 5001–5004.

[26] Taylor MS Catalysis based on reversible covalent interactions of organoboron compounds. Acc. Chem. Res 2015, 48, 295–305. - PubMed

[27] Sculimbrene BR; Miller SJ Discovery of a catalytic asymmetric phosphorylation through selection of a minimal kinase mimic: A concise total synthesis of d-myo-inositol-1-phosphate. J. Am. Chem. Soc 2001, 123, 10125–10126. - PubMed

[28] Sun X; Lee H; Lee S; Tan KL Catalyst recognition of cis-1,2-diols enables site-selective functionalization of complex molecules. Nat. Chem 2013, 5, 790–795. - PMC - PubMed

[29] Sun X; Worthy AD; Tan KL Scaffolding catalysts: Highly enantioselective desymmetrization reactions. Angew. Chem. Int. Ed 2011, 50, 8167–8171. - PMC - PubMed

[30] Lee D; Taylor MS Borinic acid-catalyzed regioselective acylation of carbohydrate derivatives. J. Am. Chem. Soc 2011, 133, 3724–3727. - PubMed

[31] Gouliaras C; Lee D; Chan L; Taylor MS Regioselective activation of glycosyl acceptors by a diarylborinic acid-derived catalyst. J. Am. Chem. Soc 2011, 133, 13926–13929. - PubMed

[32] Lee D; Williamson CL; Chan L; Taylor MS Regioselective, borinic acid-catalyzed monoacylation, sulfonylation and alkylation of diols and carbohydrates: Expansion of substrate scope and mechanistic studies. J. Am. Chem. Soc 2012, 134, 8260–8267. - PubMed

[33] D’Angelo KA; Taylor MS Borinic acid catalyzed stereo- and regioselective couplings of glycosyl methanesulfonates. J. Am. Chem. Soc 2016, 138, 11058–11066. - PubMed

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Site-Selective and Stereoselective O-Alkylation of Glycosides by Rh(II)-Catalyzed Carbenoid Insertion

Affiliations

Site-Selective and Stereoselective O-Alkylation of Glycosides by Rh(II)-Catalyzed Carbenoid Insertion

Authors

Affiliations

Abstract

Conflict of interest statement

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Abstract

Conflict of interest statement

Figures

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References

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