First Total Synthesis of Suillusin (28) and Confirmation of Absolute Stereochemistry

The successful synthesis of suillusin allowed for the comparison of the enantiopure specific rotation ([α]D22.0 = -822, c 1.0, MeOH) with the values published in the original isolation

paper ([α]D = 4, c 1.0, MeOH). The racemic nature of the original sample was confirmed

upon comparison of the specific rotation of the natural isolate and the synthetic sample. Furthermore, the absolute stereochemistry of (-)-(3aR,8bS)-suillusin was unequivocally determined through X-ray crystallography (see Appendix page 172 for details).56,57

Successful chiral HPLC separation of the racemic material enabled us to validate the hypothesis discussed in Chapter One that the biosynthesis of suillusin involves a spontaneous oxidative rearrangement.

Overall, the work presented in this thesis details our pursuits in constructing polyoxygenated heterocyclic frameworks through the synergy of method development and natural product synthesis. With viable synthetic routes in hand, we have now set the stage to probe the biological activity and the biosynthetic origin of these unique fungal natural products. The

synthetic methodology as an enabling tool for total synthesis, and also showcases how judicious synthetic planning can be the key to simplifying a problem.

From a fundamental standpoint, studies in total synthesis encourage novel bond disconnections that help identify uncharted areas of chemical reactivity and lead to new reaction development. Those strategies and concepts can be tested in the construction of complex natural products—a proving ground for new synthetic methodologies. Total synthesis can also be applied effectively to obtain sufficient quantities of material necessary for ensuing investigations, whether that is structure determination of natural products or evaluation of bioactivity. A modular synthetic route can allow access to a diverse library of structural analogues to pursue exhaustive high-throughput screening. Oftentimes, serendipitous discoveries that are identified during these synthetic undertakings can foster new ideas that ultimately push the boundaries of this ever-expanding field. Above all, the entire enterprise is an excellent platform for training chemists to be persistent, adventurous and creative.

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Appendix

X-ray Structure Report of (-)-(3aR,8bS)-Suillusin

The image for (-)-(3aR,8bS)-suillusin was measured on a diffractometer (Cu Kα, mirror monochromator, λ = 1.54184 Å) fitted with an area detector and the data extracted using the CrysAlis package.1 _{The structure of this compound was solved with ShelXT}2 _{and refined}

using ShelXL3 _{in OLEX2.}4 _{Atomic coordinates, bond lengths and angles, and displacement}

parameters have been deposited at the Cambridge Crystallographic Data Centre (CCDC no. 1873655).

Crystallographic Data for (-)-(3aR,8bS)-suillusin

C19H14O8, M = 370.30, T = 150 K, orthorhombic, space group P212121, Z = 4, a = 7.4131(2),

b = 14.2088(3), c = 15.2437(4) Å, V = 1605.64(7) Å3_{, D}

x = 1.532 g cm-3, 3218 unique data

(2σmax = 149.2°), R = 0.040 [for 3046 reflections with I > 2.0σ(I)]; Rw = 0.113 (all data), S =

1.07. References

1. Agilent (2014). CrysAlis PRO. Agilent Technologies Ltd, Yarnton, Oxfordshire, England.

2. G. M. Sheldrick, 2015, Acta Cryst., A71, 3–8. 3. G. M. Sheldrick, 2015, Acta Cryst., C71, 3–8.

4. O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard and H. Puschmann, 2009, J. Appl. Cryst., 42, 339-341.