1) The document describes a methodology for synthesizing chiral anti-1,2-diols from α-oxyaldehydes using organocatalytic α-oxygenation. This provides a convenient route to access these important building blocks. 2) Key reactions include the addition of organometallic reagents like Grignard reagents to α-oxyaldehydes, which proceeds with high diastereoselectivity through chelation control. 3) The anti diol configuration of products is determined by NMR spectroscopy, exploiting the difference in chemical shifts of the hydroxyl protons between the anti and syn diastereomers.

1. Chiral anti-1,2-Diols from
α-Oxyaldehydes
Gayan Abeykoon, Shreyosree Chatterjee, Jason Chen*
Iowa State University
Abeykoon, G. A.; Chatterjee, S.; Chen, J. S. Org. Lett. 2014, 16, 3248 – 3251
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2. Chiral-1,2-Diols
• Common in natural products like carbohydrates and polyketides
• Important as chiral ligands used in asymmetric catalysis.
• Our goal is to develop a methodology to generate chiral-1,2-diols with
stereoflexibility
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3. Sharpless Asymmetric
Dihydroxylatation (SAD)
• SAD converts trans alkenes to chiral syn-1,2-diols with high
enantioselectivity.
• Modest enantioselectivities are observed when cis alkenes are converted
to anti-1,2-diols.
Sharpless et al. J. Org. Chem. 1992, 57, 2768 – 2771.
Sharpless et al. J. Am. Chem. Soc. 1992, 114, 7568 – 7570.
Sharpless et al. Chem. Rev. 1994, 94, 2483 − 2547.
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4. Strategies to Construct anti-1,2-Diols
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• Nucleophilic attack on an
aldehyde setting both stereo
centers same time
• Nucleophiles
- α-Oxycarbonyl compounds
- Functionalized allyl reagents
Nucleophilic attack on chiral
hydroxy epoxide
• Nucleophilc attack on chiral α-oxyaldehyde
• More appealing: broader substrate scope
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Jamison et al. Org. Lett. 2005, 7, 2937 – 2940.
Guiry et al. Med. Chem. 2007, 50, 5894 − 5902.

5. Enantioselective α-Oxygenation
• Addition to α-oxyaldehydes is appealing in diol synthesis because of
– broad range of nucleophiles
– substrate-controlled stereoinduction
• TBS ether for polar Felkin–Anh control
• Benzyl ether for chelation control
• Chiral α-oxyaldehydes often require multiple steps to prepare with
suitable protecting groups at alpha position to alter the selectivity
• Direct aldehyde α-oxygenation
– most convenient route
– organocatalytic methods via enamine catalysis
• Proline Catalysis
• Imidazolidinone Catalysis
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6. α-Oxygenation
• Proline catalysis
• Imidazolidinone catalysis
Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247 – 4250.
Macmillan et al. J. Am. Chem. Soc. 2003, 125, 10808 – 10809.
Hayshi et al. Tetrahedron Lett. 2003, 44, 8293 – 8296.
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• not reproducible
• unstable α-oxyaldehydes
• reproducible
• stable α-oxyaldehydes
Sibi et al. J. Am. Chem. Soc. 2007, 129, 4124 – 4125.
MacMillan et al. Chem. Sci. 2012, 3, 58 – 61.

7. Chelation and Polar Felkin-Ahn Control
• Grignard addition: Chelation control
• Aldol reaction: Polar Felkin-Ahn control
• Stereochemical oddity
MacMillan et al. Chem. Sci. 2012, 3, 58 – 61.
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8. Determination of Diol Configuration
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9. Determination of Diol Configuration
• anti diol configuration was determined by
– Optical rotation
– 1H NMR
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10. Optimizing the Diastereoselectivity
Entry M Solvent Temp. / °C dr Yield/ %
1 MgCl Et2O 0 4:1 60
2 MgCl THF 0 6:1 70
3 MgCl THF –78 10:1 86
4 Li THF –78 6:1 81
5 Li hexanes –78 12:1 84
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11. Scope of Carbon Nucleophiles
Entry R dr Yielda / %
1 nBu 10:1 86
2 iPr 10:1 35
3 CH=CH2 >20:1 89 (78)b
4 C(Me)=CH2 >20:1 84 (79)b
5 Ph 14:1 77 (73)b
6 C≡CH 8:1 83 (67)b
a Isolated yield of a mixture of diastereomers.
b Isolated yield of a single diastereomer.
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12. Effect of Chelation
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13. Determination of Diastereoselectivity
Using NMR
• Chemical shift of hydroxyl proton of masked 1,2-diols in CDCl3,
– ca. 2 ppm anti-diastereomer (major)
– ca. 7 ppm syn-diastereomer (minor)
• This is general and holds for most of the NMR solvents
Major
Minor
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14. Oxylipins from Dracontium loretense
• Oxylipin 2 has shown immunostimulatory effect.
• Absolute configuration of chiral centers were not assigned.
• Four total synthesis of oxylipins has been reported.
Pizza et al. J. Nat. Prod. 2009, 72, 813 – 817.
Sharma et al. Tetrahedron: Asymmetry. 2011, 22, 367 – 372.
Narsaiah et al. Tetrahedron Lett.2012, 53, 3955 – 3958.
Barua et al. Tetrahedron 2013, 69, 2157− 2166.
Reddy et al. Helv. Chim. Acta 2014, 97, 546−555.
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15. Application in the Synthesis of
Oxylipins
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16. Application in the Synthesis of
Oxylipins
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17. Conclusions
• Developed a method to
– access anti-1,2-diols with high diastereoselectivity.
– with differential protection.
• Built-in stereochemical probe using 1HNMR to determine the diastereomeric
ratio of masked syn and anti-1,2-diols.
• Currently, we are working on optimizing the Grignard addition to α-
oxyaldehydes to get syn-1,2-diols.
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18. Acknowledgment
• Department of Chemistry, Iowa state University
• Prof. Jason Chen
• Chen group members
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