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DOI: 10.1055/a-2616-1628
Hydrogen-Bonding Cyclodiphosphazane Organocatalysts in Enantioselective Michael Additions
Supported by: DFG GO-930-13-1
Funding Information This project was funded by the Deutsche Forschungsgemeinschaft (DFG), GO-930-13-1.

Dedication
Dedicated to Prof. Dr. Paul Knochel on the occasion of his 70th birthday.
Abstract
Chiral aryl-(1R,2R)-N,N-dimethyldiamino-cyclohexane (DMDACH)-substituted cyclodiphosphazanes are demonstrated to be efficient bifunctional hydrogen-bonding organocatalysts for the enantioselective Michael additions of 2-hydroxy-1,4-naphthoquinone (<90% ee), Meldrum’s acid (<55% ee), and kojic acid chloride (<80% ee) to β-nitrostyrene. The parent, unsubstituted phenyl-cyclodiphosphazane with PO functions shows superior enantioselectivity in most cases and even exceeds, with 55% ee, the enantioselectivity of Takemoto’s thiourea catalyst for the challenging Meldrum’s acid substrate (46% ee). For Michael additions of kojic acid chloride, the meta-CH3-substituted cyclodiphosphazane with PS functions is the most enantioselective (< 80% ee) catalyst. This highlights the benefits of modular cyclodiphosphazane structures, which can be tailored for specific substrates.
Keywords
Asymmetric catalysis - Michael additions - Enols - Stereoselective synthesis - Phosphates - Hydrogen bonding - Cyclodiphosphazanes - Organocatalysis - Enantioselectivity - Hydroxyquinones - Meldrum’s acid - Kojic acid - NitrostyrenePublication History
Received: 04 April 2025
Accepted after revision: 15 May 2025
Article published online:
24 July 2025
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References
- 1a Sigman MS, Jacobsen EN. J Am Chem Soc 1998; 120: 4901-4902
- 1b Schreiner PR. Chem Soc Rev 2003; 32: 289-296
- 1c Okino T, Hoashi Y, Takemoto Y. J Am Chem Soc 2003; 125: 12672-12673
- 2a Malerich JP, Hagihara K, Rawal VH. J Am Chem Soc 2008; 130: 14416-14417
- 2b Chauhan P, Mahajan S, Kaya U, Hack D, Enders D. Adv Synth Catal 2015; 357: 253-281
- 2c Wolf FF, Klare H, Goldfuss B. J Org Chem 2016; 81: 1762-1768
- 3a Klare H, Neudörfl JM, Goldfuss B. Beilstein J Org Chem 2014; 10: 224-236
- 3b Klare H, Hanft S, Neudörfl JM. et al. Chem. – Eur. J. 2014; 20: 11847-11855
- 3c Wolf FF, Neudörfl J-M, Goldfuss B. New J Chem 2018; 42: 4854-4870
- 4a For applications of cyclodiphosphazanes see. Sim Y, Leon F, Hum G. et al. Comm Chem 2022; 5: 1
- 4b Shi X, León F, Sim Y. et al. Angew Chem Int Ed 2020; 59: 22100-22108
- 4c Plajer AJ, Lee S, Bond AD, Goodman JM, Wright DS. Dalton Trans 2020; 49: 3403-3407
- 4d Davis JT, Gale PA, Quesada R. Chem Soc Rev 2020; 49: 6056-6086
- 4e Plajer AJ, Bond AD, Wright DS. Chem. – Eur. J. 2020; 27: 289-297
- 4f Pandey MK, Kunchur HS, Ananthnag GS, Mague JT, Balakrishna MS. Dalton Trans 2019; 48: 3610-3624
- 4g Plajer AJ, Zhu J, Pröhm P. et al. J Am Chem Soc 2019; 142: 1029-1037
- 4h Plajer AJ, Zhu J, Proehm P. et al. J Am Chem Soc 2019; 141: 8807-8815
- 4i Plajer AJ, Rizzuto FJ, Niu H-C. et al. Angew Chem Int Ed 2019; 58 (31) 10655-10659
- 4j Tan D, Ng ZX, Sim Y, Ganguly R, García F. CrystEngComm 2018; 20: 5998-6004
- 4k Sim Y, Tan D, Ganguly R, Li Y, García F. Chem Commun 2018; 54: 6800-6803
- 4l Bawari D, Prashanth B, Jaiswal K, Choudhury AR, Singh S. Eur J Inorg Chem 2017; 35: 4123-4130
- 4m Balakrishna MS. Dalton Trans 2016; 45: 12252-12282
- 4n Otang ME, Lief GR, Stahl L. J Organomet Chem 2016; 820: 98-110
- 5a García Mancheño O. ed Anion-Binding Catalysis. Weinheim: Wiley-VCH; 2022
- 5b Dalko PI. ed Comprehensive Enantioselective Organocatalysis. Weinheim: Wiley-VCH; 2013
- 5c Berkessel A, Gröger H. Asymmetric Organocatalysis. Weinheim: Wiley-VCH; 2005
- 6a Okino T, Hoashi Y, Takemoto Y. J Am Chem Soc 2003; 125: 12672
- 6b Berkessel A, Seelig B. Synthesis 2009; 12: 2113
- 7a Piccart M, Rozencweig M, Abele R. et al. Eur J Cancer Clin Oncol 1981; 17: 775-779
- 7b Lown JW. Pharmacol Ther 1993; 60: 185-214
- 7c Scott LJ, Figgitt DP. CNS Drugs 2004; 18: 379-396
- 8 Meldrum NA. J Chem Soc Trans 1908; 93: 598-601
- 9 Bassas O, Huuskonen J, Rissanen K, Koskinen AMP. Eur J Org Chem 2009; 2009: 1340-1351 with a quinidine derived thiourea catalyst, 75% ee of (S)-pregabalin are achieved
- 10 Okino T, Hoashi Y, Furukawa T, Xu X, Takemoto Y. J Am Chem Soc 2005; 127: 119-125
- 11a Yamato M, Hashigaki K, Yasumoto Y. et al. J Med Chem 1987; 30: 1897-1900
- 11b Alverson J. J Invertebr Pathol 2003; 83: 60-62
- 11c Higa Y, Kawabe M, Nabae K. et al. J Toxicol Sci 2007; 32: 143-159
- 11d Fassihi A, Abedi D, Saghaie L. et al. Eur J Med Chem 2009; 44: 2145-2157
- 12 Kucherenko AS, Kostenko AA, Komogortsev AN. et al. J Org Chem 2019; 84: 4304-4311
- 13 We found that scalemic mixtures of the adduct of kojic acid chloride and β-nitrostyrene yield, via crystallization, a racemic product, which leads to increased enantiomeric purity of the remaining solution
- 14 Zhou W-M, Liu H, Du D-M. Org Lett 2008; 10: 2817-2820
- 15 Anderson JC, Kalogirou AS, Tizzard GJ. Tetrahedron 2014; 70: 9337-9351