Organocatalytic Chiral Oxygenations: anti 1,2-Diols from

α-Oxyaldehydes and α,β,-Trioxygenation of Enals Gayan A. Abeykoon, Shreyosree Chatterjee and Jason S. Chen

Department of Chemistry, Iowa State University, Ames, Iowa, 50010

Abstract

anti 1,2-Diols were prepared by enantioselective α-oxygenation of aldehydes catalyzed by salts of chiral

imidazolidinones using stoichiometric TEMPO followed by organomagnesium or –lithium addition. Excellent

yields and diastereoselectivities were observed regardless of the branched/unbranched nature or hybridization

of the carbon nucleophile. Subjecting an enal to the above α-oxygenation condition led to the first ever α,β,-

trioxygenation of enals. Moderate yields and enantiomeric ratios were observed when a tryptophan-derived

imidazolidinone catalyst in fluorinated aromatic solvents was used. Initial incorporation of TEMPO at position

was followed by rapid racemization and reversible conjugate addition of water. Finally, α-incorporation of

TEMPO set three chiral centers with double dynamic kinetic resolution to form the α,β,-trioxyaldehyde.

α,β,-Trioxygenation of Enals

• Chiral oxygenations using organocatalysis

• Organocascade reactions

• Catalysis of chiral imidazolidinones

Mismatch in catalytic modes

• What if an enal?

• Discovery of first ever α,β,-Trioxygenation of Enals

• Troubleshooting and optimization of trioxygenation5

• Mechanistic insight5

Dynamic kinetic resolution

12.5% from (R)-A

+

52% from major enantiomer of B with (R) configuration at -position

64.5% combined yields of compounds with (R) configuration at -position

anti-1,2-Diols

• Sharpless Dihydroxylation

• syn 1,2-diols: excellent selectivity from trans alkenes

• anti 1,2-diols: modest selectivity from cis alkenes (major limitation)

• Alternative methods for anti-1,2-Diols

• Published reactions of α-oxyaldehydes to get 1,2-diols1

Stereochemical oddity

• Determination of relative stereochemical outcome of Grignard addition to α-

oxyaldehydes2

Corrected the stereochemical outcome of Grignard addition to α-oxyaldehydes to be anti

Table 1:Tunning the Diastereoselectivity of Grignard addition to α-oxyaldehydes

• anti 1,2-diol synthesis varying the carbon nucleophile2

Grignard Solvent Temp (C) dr Yield %

BuMgCl E2O 0 4:1 60

BuMgCl THF 0 6:1 70

BuMgCl THF -78 10:1 86

BuLi THF -78 6:1 81

BuLi hexanes -78 12:1 84

excellent

diastereoselectivity

Amine Solvent Yield % dr er

Acetone 78 (57) 4.1:1 61:39

THF 39 9.0:1 64:39

DMSO 0 ND ND

CHCl3 0 ND ND

PhMe 42 5.5:1 73:27

PhCF3 69 (52) 5.0:1 71:29

Pentafluoro

benzene

66 (59) >20:1 70:30

PhCF3 45 (36) 6.4:1 84:16

Pentafluro

benzene

59 (51) 8.9:1 85:15

Conclusions

• Developed a method to access anti 1,2-diols with high diastereomeric ratio

• Discovery of the first ever catalytic, enantioselective α,β,-trifunctionalization of enals with moderate ee

• Development of mechanistic insight on the novel trioxygenation.

References

1. Simonovich, S. P.; Van Humbeck, J. F.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 58.

2. Abeykoon, G. A.; Chatterjee, S.; Chen, J. S. Org. Lett. 2014, 16, 3248.

3. Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W.C. J. Am. Chem. Soc. 2000, 122, 4243.

4. Chen, J.S.; Abeykoon G. A. Org. Lett. 2015, 17, 6050.

5. Ho, X.-H.; Jung, W.-J.; Shyam, P. K.; Jang, H.-Y. Catal. Sci.Technol. 2014, 4, 1914.

6. Fought, E. L.; Chatterjee, S.; Windus, T. L.; Chen, J. S. J. Org. Chem. 2015, 80, 9967.

Funding • National Science Foundation