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Total Synthesis Blog: Lycoricidine

The Sarlah lab this week published the total synthesis of two isocarbostyril alkaloids1, lycoricidine and the closely related narciclasine, impressively starting from the quite cheap commercially available bromobenzene. Both products have useful biological properties2, but as always the utility of natural products lies in their availability. The latest synthesis obviates reliance on Stille-type couplings3 (and the organotin reagents that come with them), further cementing its utility.

Structures

Fig 1. Structures

The Sarlah et al. synthesis begins with generating the cis-dihydrodiol through a modified Sharpless reaction, the Naraska-Sharpless dihydroxylation. Using the arenophile MTAD with visible light illumination, followed by osmium tetroxide and NMO (as one would usually see in Upjohn and Sharpless procedures) the team introduces the aryl boronic acid to obtain the bicyclic adduct. The researchers at the University of Illinois then utilised a quite nice Suzuki coupling with their boronate ester, using Pd(dppf)Cl2 as a catalyst. The boronate ester likely ‘fragments’ in a sense, and the aryl bromide and boronic acid act in the Suzuki, transposing to yield the diol. Diol protection as the acetonide follows using 2,2,-dimethoxypropane in the presence of the pyridinium salt of p-toluenesulfonic acid, PPTS. This enables the base hydrolysis of the methyl ester to the relevant acid.

First synthetic section

Scheme 1.

They make the call to install the required amino-alcohol through a nitroso Diels-Alder. In order to line up deprotection of the resulting amide nitrogen, the team used a TIPS-protected reagent in the nitroso Diels-Alder. This furnishes the 1,4-syn product with good stereocontrol following a dissolving metal reduction with zinc and acetic acid. To finish off, a one-pot oxidative cleavage using the hypervalent iodine (III) reagent, PIFA, followed by exhaustive acetonide deprotection with trifluoroacetic acid yields (±)-lycoricidine.

Second synthetic section

Scheme 2.

Where the paper really comes into its own is the transformation into narciclasine following the nitroso Diels-Alder – but to see how they do it, check out the published work (DOI: 10.1002/anie.201709712). Displaying increased atom economy and yields relevant to earlier work, the Sarlah approach facilitates analogue synthesis from readily available starting materials.

References

  1. E. H. Southgate, D. R. Holycross and D. Sarlah, Angew. Chem. Int. Ed. Engl., 2017, 56, 15049–15052.
  2. a) T. Okamoto, Y. Torii, Y. O. Isogai, Chem. Pharm. Bull. 1968,
    16, 1860–1864; b) G. Ceriotti, Nature 1967, 213, 595; c) G. R.
    Pettit, V. Gaddamidi, G. M. Cragg, J. Nat. Prod. 1984, 47, 1018;
    d) S. Ghosal, S. K. Singh, Y. Kumar, R. S. Srivastava, Phytochemistry
    1989, 28, 611.
  3. H. Zhang and A. Padwa, Org. Lett., 2006, 8, 247–250.
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