Journal Club Topic of the Week

Recent Advances in Asymmetric Transfer Hydrogenation via Dynamic Kinetic Resolution

Grenning Research Lab

February 18th, 2021 Journal Club: Asymmetric transfer Introduction Hydrogenation via DKR

➢ Asymmetric hydrogenation (AH, hydrogen source = H2 gas) and asymmetric transfer hydrogenation (ATH, hydrogen source ≠ H2 gas) are efficient, environmentally friendly techniques for synthesizing diastereomerically and enantiomerically pure alcohols and amines.

➢ In combination with dynamic kinetic resolution (DKR), AH and ATH can be used to transform a substrate bearing a labile stereocenter into a single, enantiomerically pure diastereomer.

Sara E. Kearney February 18th, 2021 Journal Club: “Asymmetric Transfer Hydrogenation of α-Substituted-β-Keto Asymmetric transfer Carbonitriles via Dynamic Kinetic Resolution” Hydrogenation via Fangyuan Wang, Tilong Yang, Ting Wu, Long-Sheng Zheng, Congcong Yin, Yongjie Shi, Xiang-Yu Ye, Gen- DKR Qiang Chen, and Xumu Zhang

✓ Dynamic kinetic resolution ✓ Up to 99% yield ✓ Up to >99% ee, up to >99:1 dr ✓ Wide substrate scope ✓ Valuable synthetic applications

Hydrogen donors: HCO2H : Et3N (5:2, 3:2, 1:1), HCO2H : DBU (1:1), HCO2H : DIPEA (1:1), iPrOH, HCO2Na

Solvents: DCM, MeOH, iPrOH, THF, dioxane, EA, DMF, hexane, PhMe, iPrOH : H2O (1:1)

Optimal conditions: cat. 4, HCO2H : Et3N (5:2), PhMe (>99% ee, 97:3 dr, anti-selective)

J. Am. Chem. Soc. 2021, 143, 6, 2477–2483. Sara E. Kearney February 18th, 2021 Journal Club: “Asymmetric Transfer Hydrogenation of α-Substituted-β-Keto Asymmetric transfer Carbonitriles via Dynamic Kinetic Resolution” Hydrogenation via Fangyuan Wang, Tilong Yang, Ting Wu, Long-Sheng Zheng, Congcong Yin, Yongjie Shi, Xiang-Yu Ye, Gen- DKR Qiang Chen, and Xumu Zhang

➢ DFT calculations were performed to rationalize the origin of diastereoselectivity.

➢ Transition state calculations reveal edge-to-face interactions between the η5 arene of the ligand and the aryl group of the substrate which can stabilize the transition state for the ketone reduction process; the tosyl group can affect diastereoselectivity through hydrogen bonding.

J. Am. Chem. Soc. 2021, 143, 6, 2477–2483. Sara E. Kearney February 18th, 2021 “Ruthenium-Catalyzed Highly Enantioselective Synthesis of cis-3- Journal Club Quinuclidinols via DKR Asymmetric Transfer Hydrogenation” Topic of the Week Grenning Lab (University of Florida)

>99% conv. >99% conv. >99% conv. >99% conv. >99% conv. >99% conv. >99% conv. >99% conv. >99% conv. >99% conv. 96% yield 98% yield 97% yield 98% yield 96% yield 91% yield 96% yield 97% yield 99% yield 97% yield >99% ee, >99% ee, >99% ee, >99% ee, >99% ee, >99% ee, 97% ee, 98% ee, 99% ee, >99% ee, >99:1 dr >99:1 dr >99:1 dr >99:1 dr >99:1 dr >99:1 dr >99:1 dr >99:1 dr >99:1 dr >99:1 dr

J. Org. Chem. 2020, 85, 11309-11330 Anghelo Gangano February 18th, 2021 “Ruthenium-Catalyzed Highly Enantioselective Synthesis of cis-3- Journal Club Quinuclidinols via DKR Asymmetric Transfer Hydrogenation” Topic of the Week Grenning Lab (University of Florida)

Chlorine dissociation stabilized by ammonium cation

Hydride transfer A proposed catalytic cycle for the asymmetric transfer hydrogenation of 3- keto-quinuclidines

[Ru] (1mol%) Reformation of activated catalyst Favorable edge to face interaction

IPA/DCM=1:1 HCO2NH4, 50◦C 72hr

Isopropanol as H2 source

J. Org. Chem. 2020, 85, 11309-11330 Anghelo Gangano February 18th, 2021 “Multiple Absolute Stereocontrol in Cascade Lactone Formation via Dynamic Journal Club Kinetic Resolution Driven by the Asymmetric Transfer Hydrogenation of Topic of the Week Keto Acids with Oxo-Tethered Ruthenium Catalysts” Taichiro Touge, Kazuhiko Sakaguchi, Nao Tamaki, Hideki Nara, Tohru Yokozawa, Kazuhiko Matsumara, and Yoshihito Kayaki

J. Am. Chem. Soc. 2019, 141, 16354-16361 Kenneth Ko February 18th, 2021 “Multiple Absolute Stereocontrol in Cascade Lactone Formation via Dynamic Journal Club Kinetic Resolution Driven by the Asymmetric Transfer Hydrogenation of Topic of the Week Keto Acids with Oxo-Tethered Ruthenium Catalysts” Taichiro Touge, Kazuhiko Sakaguchi, Nao Tamaki, Hideki Nara, Tohru Yokozawa, Kazuhiko Matsumara, and Yoshihito Kayaki

J. Am. Chem. Soc. 2019, 141, 16354-16361 Kenneth Ko February 18th, 2021 Journal Club: Asymmetric transfer Hydrogenation via References DKR

Featured in this presentation: Additional references:

1. Synthesis, 2021, 53, 30-50. 1. Angew. Chem. Int. Ed. 2004, 43, 6660 –6662. 2. J. Am. Chem. Soc. 2012, 134, 20197–20206. 2. J. Am. Chem. Soc. 1989, 111, 25, 9134–9135. 3. Org. Lett. 2019, 21, 2998–3002. 3. J. Am. Chem. Soc. 1950, 72, 631. 4. Org. Lett. 2019, 21, 3644–3648. 4. J. Am. Chem. Soc. 2005, 127, 1, 32–33. 5. Org. Lett. 2019, 21, 4266–4270. 5. Tetrahedron:Asymmetry. 2002, 13, 2485–2490. 6. Chem. Commun. 2009, 571-573. Reviews: 7. Chem. Commun. 2014, 50, 12526-12529. 8. Chem. Commun. 2017, 53, 6113-6116. 1. Chem. Eur. J. 2021, 27, 39–53. 9. J. Org. Chem. 2020, 85, 11309-11330. 2. Synthesis. 2021, 53, 30-50. 10. J. Am. Chem. Soc. 2019, 141, 16354-16361. 3. Synthesis. 2020, 52, 504-520.

February 18th, 2021