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Diastereoselective Synthesis ofAryl C-Glycosides via Radical Pathway

2024/1/11 (Thu) B4 Takashi Koyama

2Outline

1. Introduction

2. Contents
2-1. Homolytic activation of hydroxyl group and formation of radicals

2-2. Stereoselective C-aryl glycosylation by catalytic cross-coupling of heteroaryl glycosyl sulfones
2-3. Direct synthesis of unprotected aryl C-glycosides by photoredox Ni-catalysed cross-coupling

3. Summary

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Conventional glycosyl donors (ionic pathway)(a) C-Glycosylation via glycosyl electrophilic/cationic species(b) C-Glycosylation via glycosyl anionic species

Challenges
・Dependence on the structures of donors/acceptors.
・Unstable glycosyl donors.
・Harsh reaction conditions.
・Incompatible with free hydroxyl group.
・Byproduct (ex. glycal, glycosidic bonds )・Stereochemical purity of the glycosyl donors.

Y. Yang, B. Yu, Chem. Rev. 2017, 117, 12281–12356.

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Reactive glycosyl intermediates

Regardless of the stereochemical purity of the glycosyl donors, both anomers
will eventually converge to the sugar radical of the same conformation.

Y. Yang, B. Yu, Chem. Rev. 2017, 117, 12281–12356.
Y. jiang. et al. Angew. Chem. Int. Ed. 2023, 62, e202305138.

5Factors determining stereoselectivity① Anomeric effect

The axial radical is more stable and nucleophilic because of the interaction
between the lone pair on the ring oxygen and the radical orbital.

② SOMO-LUMO interaction

Stabilizing interaction between SOMO and LUMO of the neighboring C-O bond
H. Togo, W. He, Y. Waki, M. Yokoyama, Synlett, 1998, 700–717.
Giese, B. Angew. Chem. Int. Ed. 1989, 28, 969–980.
H. Abe, S. Shuto, A. Matsuda, J. Am. Chem. Soc. 2001, 123, 11870.

6Factors determining stereoselectivity③ Conformation restriction

1(2.70 kcal/mol)*
5(0.00 kcal/mol)**relative energy

23(0.94 kcal/mol)*(0.00 kcal/mol)*4

H. Abe, S. Shuto, A. Matsuda, J. Am. Chem. Soc. 2001, 123, 11870.
L. Y. Xu, N. L. Fan, X.-G. Hu, Org. Biomol. Chem. 2020, 18, 5095–5109.

6(3.55 kcal/mol)*
Conformational restriction of the pyranose ring changes
the stereoselectivity in the anomeric radical reaction.

7Factors determining stereoselectivity④ Ligands effect in transition metal-catalyzed reactions

J. Liu, H. Gong, Org Lett, 2018, 20, 7991–7995.

J. Liu, C. Lei, H. Gong, Sci. China: Chem., 2019, 62, 1492–1496.

Bulky Ni-tridentate ligand complex seems to overcome the α-stereoselectivity
F. Zhu, M. A. Walczak, J. Am.Chem.Soc. 2020,142,15127–15136.

8Outline

1. Introduction

2. Contents
2-1. Homolytic activation of hydroxyl group and formation of radicals

2-2. Stereoselective C-aryl glycosylation by catalytic cross-coupling of heteroaryl glycosyl sulfones
2-3. Direct synthesis of unprotected aryl C-glycosides by photoredox Ni-catalysed cross-coupling

3. Summary

9Formation of carbon radicals from alcohols via C-O bond cleavage(a) Homolytic activation of C-O bonds via redox-active groups(b) Carbon radicals from aldehydes via C-C bond cleavage(d) Carbon radicals from alcohols via C-O bond cleavage(c) Carbamoyl radicals from amines via C-C bond cleavage(a) Á. Gutiérrez-Bonet. et al. ACS Catal. 2016, 6, 8004.
(b) Á. Gutiérrez-Bonet. et al. J. Am. Chem. Soc. 2017,139, 12251.
(c) N. Alandini. et al. Angew. Chem. Int. Ed. 2020, 59, 5248.
(d) Wei, Y., Ben-Zvi, B., Diao, T. Angew. Chem. Int. Ed. 2021, 60, 9433.

10Proposed mechanism and optimized conditions
G. Ya. Dubur, Ya. R. Uldrikis, Chem. Heterocycl. Compd. 1972, 5, 762.

(A) Proposed mechanism for C-aryl glycosylation based on DHP derived estes(B) Optimized conditions

・High temperature is required to facilitate DHP fragmentationand the subsequent decarboxylation.
・High α-selectivity because of C2, C3 and C4 substituents

Wei, Y., Ben-Zvi, B., Diao, T. Angew. Chem. Int. Ed. 2021, 60, 9433.

11Substrate scope・Performing the synthesis of 17 on a 1.94-gramscale afforded 21 in 82% isolated yield.
・A lower temperature led to the formation of a byproduct derived from the coupling of 7 to PhBr.

Wei, Y., Ben-Zvi, B., Diao, T. Angew. Chem. Int. Ed. 2021, 60, 9433.

12Stereoselectivity

・Mannopyranoses display α-selectivity.

Derivatization of (+)-sclareolide from deoxygenative cross coupling

・Glucopyranoses display poor reactivity
and stereoselectivity.
・The poor selectivity can be attributed to the contradictory
preferences by the steric and the stereoelectronic effect.

Wei, Y., Ben-Zvi, B., Diao, T. Angew. Chem. Int. Ed. 2021, 60, 9433.

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Factor causing poor stereoselectivity of glucopyranoside
J. Dupuis, et al. Angew. Chem. Int. Ed, 1984, 23, 896–898.
H. Abe, S. Shuto, A. Matsuda, J. Am. Chem. Soc. 2001, 123, 11870.
H. Togo, W. He, Y. Waki, M. Yokoyama, Synlett, 1998, 700–717.

planar radical center

・B2,5 conformation has a planar (sp2-like) radical center with a radical orbital having high p-character.
・B2,5 conformation has potential to form both anomers through α- and β- attack.
・In the transition state the radical center has more pyramidal (sp3-like) radical center.

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Factor causing poor stereoselectivity of glucopyranoside・Fluctuating conformational changes of the glucosyl radical leads to varied α/β selectivity.

・Contradictory preferences by the steric and the stereoelectronic effect are the factor offluctuating conformational changes.
Adak, L. et al. J. Am. Chem. Soc. 2017, 139, 10693–10701.

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Short summary
Homolytic activation of hydroxyl group and formation of radicals✓ Bench-stable.
✓ Easily accessible.
✓ Diastereoselective in furanoside.

 Stereoselectivity of glucopyranose.
 Protection of the hydroxyl groups.
 High temperature.

Wei, Y., Ben-Zvi, B., Diao, T. Angew. Chem. Int. Ed. 2021, 60, 9433.

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Outline1. Introduction

2. Contents
2-1. Homolytic activation of hydroxyl group and formation of radicals

2-2. Stereoselective C-aryl glycosylation by catalytic cross-coupling of heteroaryl glycosyl sulfones
2-3. Direct synthesis of unprotected aryl C-glycosides by photoredox Ni-catalysed cross-coupling

3. Summary

17Heteroaryl glycosyl sulfones as practical donors for C-aryl glycosylation

Q. Wang, et al. Angew. Chem. Int. Ed. 2023, 62, e202301081.
J. Corpas, et al. Chem. Soc. Rev. 2022, 51, 6774–6823.

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Optimized conditions

Conditions A
・The reactions proceed under room temperature.
・2-Pyridyl sulfinate salt was detected as a byproduct.

Conditions B
・Benzothiazole and 2,2-bibenzothiazole were detected. W. Miao. et al. J. Am. Chem. Soc. 2018, 140, 880–883.

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Mechanistic studies

Q. Wang, et al. Angew. Chem. Int. Ed. 2023, 62, e202301081.

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Proposed mechanisms for Fe- and Ni-catalyzed C-aryl glycosylationa.
・Aryl iron speciesⅰcould serve as a reducing agent by SET to the electrophilic heteroaryl sulfone.
・Radical anion undergoes direct S-C(glycosyl) bond cleavage to form glycosyl radical and sulfinate.
W. Miao, et al. J. Am. Chem. Soc. 2018, 140, 880–883.

b.
・Zn could serve as a reducing agent by SET to the more electrophilic heteroaryl sulfone.
・Radical anion undergoes S-C(2-benzothiazoyl) bond cleavage to give glycosylsulfonyl radicaland 2-benzothiazoyl anion.

J. M. E. Hughes, P. S. Fier, Org. Lett. 2019, 21, 5650–5654.

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Fe-catalyzed desulfonylative arylation with diaryl zinc reagents

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Ni-catalyzed desulfonylative arylation with aryl iodides

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Stereodivergent C-aryl glycosylation

Q. Wang, et al. Angew. Chem. Int. Ed. 2023, 62, e202301081.
A. G. Orpen, et al. J. Chem. Soc. Dalton Trans. 1989, S1–S83.

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Outline1. Introduction

2. Contents
2-1. Homolytic activation of hydroxyl group and formation of radicals

2-2. Stereoselective C-aryl glycosylation by catalytic cross-coupling of heteroaryl glycosyl sulfones
2-3. Direct synthesis of unprotected aryl C-glycosides by photoredox Ni-catalysed cross-coupling

3. Summary

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Direct synthesis of aryl C-glycosides by photoredox Ni-catalysed cross-couplinga. Classical routes to aryl C-glycosides that use protected intermediates

Takeda, D. et al. Org. Lett, 2021, 23, 1940–1944.
Liu, J., Lei, C., Gong, H. Sci. China Chem, 2019, 62, 1492–1496.

b. Direct, stereoselective synthesis of unprotected aryl C-glycosides

Zhang, C., Xu, SY., Zuo, H. et al. Nat. Synth, 2023, 2, 251–260.

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Mechanistic studies
Markovic, T. et al. J. Am. Chem. Soc, 2018, 140, 15916–15923.

a.

The trap of the allyl group in 16 to form a tetrahydrofuran ring in 17 suggests
the intermediacy of glycosyl radical 18.
b.
Glycosyl radicals is triggered by initial generation of a tolyl sulfonyl radical.
→ Tolyl sulfonyl radical subsequently adds to the terminal alkene group of 19.
(Not a Ni-catalyzed allylic substitution process.)
Zhang, C., Xu, SY., Zuo, H. et al. Nat. Synth, 2023, 2, 251–260.

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Proposed mechanismc.

Product 15e was formed in excellent yield and stereoselectivity, supporting the intermediacy of 22.
d.
An alternative pathway involving glycosyl radical addition to Ni(0) could be operating as well.
Gutierrez, O. et al. J. Am. Chem. Soc, 2015, 137, 4896–4899.
Zhang, C., Xu, SY., Zuo, H. et al. Nat. Synth, 2023, 2, 251–260.

28Condition optimization

・The potentially competing reactions was not observed.
(a) C–O coupling between the free hydroxyl groups in 8 with 9Terrett, J. A. et al. Nature, 2015, 524, 330–334.
MacQueen, P. M. et al. J. Am. Chem. Soc, 2018, 140, 5023–5027.

(b) C–S coupling between TolSO2Na with 9Cabrera-Afonso, M. et al. Chem. Sci, 2018, 9, 3186–3191.

・The direct C–S coupling with 9 to form 12 became the dominant
process using pyridine-2-thiol instead of TolSO2Na (entry9).

Zhang, C., Xu, SY., Zuo, H. et al. Nat. Synth, 2023, 2, 251–260.

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Substrate scope of aryl halides

Zhang, C., Xu, SY., Zuo, H. et al. Nat. Synth, 2023, 2, 251–260.

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Substrate scope of glycosyl donor

Zhang, C., Xu, SY., Zuo, H. et al. Nat. Synth, 2023, 2, 251–260.

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Computed pathway of the reaction between glucopyranosyl radical and OA complex

steric hinderance

The ligated metal unit clashes with both the sugar ring system and the C2-hydroxyl group.
Zhang, C., Xu, SY., Zuo, H. et al. Nat. Synth, 2023, 2, 251–260.

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Comparing the activation free energies of reactions

steric hinderance

The radical addition using protected radical to the OA complex becomes considerably more difficult.
Zhang, C., Xu, SY., Zuo, H. et al. Nat. Synth, 2023, 2, 251–260.

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Conformational stability of protected and unprotected glucosyl radicals

・The most stable conformation for the tetraacetyl glucosyl radical is B2,5 ( or 1S5) conformation.
・The most stable conformation for the protecting-group-free glucosyl radical is 4C1 conformation.

・The 2-OP and 3-OP groups of the protected glucosyl radical adopt a pseudo-axial position
to reduce steric repulsion, resulting in the formation of the B2,5 conformation.
・Steric factors are negligible in the unprotected glucosyl radical,
leading to the preferable existence of the 4C1 conformation.
T. Miura, et al. Chem. Commun, 2023, 59, 8564.
H. Abe, S. Shuto, A. Matsuda, J. Am. Chem. Soc. 2001, 123, 11870.

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Outline1. Introduction

2. Contents
2-1. Homolytic activation of hydroxyl group and formation of radicals

2-2. Stereoselective C-aryl glycosylation by catalytic cross-coupling of heteroaryl glycosyl sulfones
2-3. Direct synthesis of unprotected aryl C-glycosides by photoredox Ni-catalysed cross-coupling

3. Summary

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Summary
Synthesis of Aryl C-Glycosides via Radical Pathway✓ Independence on the structures of donors.
✓ Mild conditions.
✓ Functional group tolerant.

2-2. Stereoselective C-aryl glycosylation by catalytic cross-coupling of heteroaryl glycosyl sulfones✓ Bench-stable and easily accessible donors.
✓ Distinct mechanisms and activation modes.
✓ Access to both α and β isomers for key sugars.

2-3. Direct synthesis of unprotected aryl C-glycosides by photoredox Ni-catalysed cross-coupling✓ Stereoconvergent, diastereoselective✓ Protecting groups unnecessary✓ Bench-stable and easily accessible donors

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Appendix: Aryl C-glycosides(a) Previously reported method Three steps

 Harsh conditions(b) New method via glycosyl radical
SGLT2 inhibitors against typeⅡdiabetes✓ One step✓ Mild conditions
Chao, E. C.; Henry, R. R. Nat. Rev. Drug Discovery 2010, 9, 551−559.
(a) Aguillón, A. R. et al. Org. Proc. Res. Dev. 2018, 22, 467–488.
(b) Zhang, C., Xu, SY., Zuo, H. et al. Nat. Synth, 2023, 2, 251–260.

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Appendix : Optimization of the coupling reaction

Wei, Y., Ben-Zvi, B., Diao, T. Angew. Chem. Int. Ed. 2021, 60, 9433.

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Appendix: Extended reaction scopes of 2-2Q. Wang, et al. Angew. Chem. Int. Ed. 2023, 62, e202301081.

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Appendix: Screen of photocatalyst and ligands

Zhang, C., Xu, SY., Zuo, H. et al. Nat. Synth, 2023, 2, 251–260.

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Appendix: Screen of nickel catalysts and solvents

Zhang, C., Xu, SY., Zuo, H. et al. Nat. Synth, 2023, 2, 251–260.

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Appendix: Screen of RSO2Na additive

Zhang, C., Xu, SY., Zuo, H. et al. Nat. Synth, 2023, 2, 251–260.

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Appendix: Synthetic applicationsa.

Mamidyala, S. K. et al. J. Am. Chem. Soc. 2012, 134, 1978–1981b.

a. Synthesis of ASGPR ligand by literature methods
compared with this work.

b. Synthesis of gliflozins.

Aguillón, A. R. et al. Org. Proc. Res. Dev. 2018, 22, 467–488.
Zhang, C., Xu, SY., Zuo, H. et al. Nat. Synth, 2023, 2, 251–260.

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Appendix: Relative free energies of intermediates and transition structures

Zhang, C., Xu, SY., Zuo, H. et al. Nat. Synth, 2023, 2, 251–260.