Titolo della tesi: Studies on the synthesis and properties of natural and unnatural products for therapeutic and agrochemical applications.
This work focused mainly on the development of synthetic strategies to obtain complex molecules that could be useful in the therapeutic and agro-industrial fields.
The first part of this work summarizes the studies on the different synthetic approaches carried out to obtain two natural products with promising biological activities: Malaymycin (1) and (+)-Oryzalexin-S (2). 1 is a tetrahydroquinoline alkaloid with a cyclopentenone ring isolated in 2021 from a family of actinomycetes (i). Preliminary tests on the biological activity of 1 have highlighted its high cytotoxicity and its ability to inhibit the transcription of key androgen receptor genes involved in the growth and development of prostate cancer (ii). Although the structure of 1 was elucidated by NMR studies, the absolute configuration of its two chiral centers was determined by comparing the theoretical circular dichroism spectrum calculated for 1 with the experimentally obtained spectrum. The peculiar structure of 1 makes it a structural analog of the non-natural enantiomer of virantmycin (3), a molecule with no biological activity (compared to its natural enantiomer) that was synthesized enantioselectively only twice (iii,iv).
Therefore, with the idea of proposing the first synthetic strategy for this promising chemotherapeutic agent and confirming the initially proposed structural interpretation, I considered 1 as a valid synthetic target for a PhD project. The state-of-the art briefly described above was discussed in detail in Chapter I. Chapter II discussed instead the retrosynthetic analysis of 1, the corresponding synthetic proposals and the synthetic problems identified.
2 is instead an interesting stemaranic phytoalexin with great antifungal activity that can potentially be used for the treatment of fungal infections in rice plants. Our research group recently proposed a retrosynthetic plan to obtain the first key intermediate (4) in the total synthesis of 2 (v). However, the final reaction of the proposed synthetic strategy to obtain 4 unexpectedly led to its enantiomer. This interesting reversal of enantioselection compared to similar reactions commonly reported in the literature represents a rare precedent that deserves further investigation (vi-viii).
In Chapter I, this section of the work was placed in the appropriate literature context. Chapter III then describes the new synthetic plan proposed to obtain 4 and the investigations to elucidate the rare inversion of enantioselection observed in the intramolecular aldol condensation generating this intermediate.
As reported in the literature, trifluoromethyl aryl diazirines are molecules that can release N2 upon photoexcitation and form an extremely reactive carbene intermediate. The latter has been used extensively over the last 50 years for the development of photolabeling agents (PALs) to study protein systems (ix). However, most of these studies were in vitro experiments. The in vivo application of diazirines as PALs is limited due to the activation wavelength of these systems (350-390 nm), which is extremely damaging to cellular structures. To overcome this problem, one could think of coordinating a chromophore group to the diazirine that can shift its activation wavelength. However, the sp3 hybridization state in which diazirines are thought to exist in the literature would make electronic coordination between these two systems impossible. Interestingly, the work of Musolino et al. recently published in 2021 has provided some experimental evidence for such electronic coordination (x).
Among the different classes of chromophores, the push-pull class has recently emerged in the literature due to its versatility. These chromophores are often characterized by a 9,9-dimethyl fluorene scaffold in which an EDG and an EWG group are installed in positions 2 and 7, respectively (xi). The electronic coordination between these two groups which extends across the π system of the molecular scaffold, makes the molecule an efficient chromophore. With the idea of exploiting this interesting property of push-pull systems to investigate the actual existence of electronic coordination between a diazirine system and a chromophore, and at the same time with the idea of extending the activation wavelength of diazirine towards the visible region, we decided to synthesize the trifluoromethyl aryl diazirine 8 and investigate its properties.
While the quickly described contextualization of the state-of-the art for 8 was discussed in detail in Chapter IV, the synthesis, properties investigation, and photochemical activation of 8 were examined in Chapter V.
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(viii) For a detailed review on the diasteroselection of aldol intramolecular condensation leading to Wieland Miescher ketone analogs see: F. Vetica, F. Pandolfi, L. Pettazzoni, F. Leonelli, M. Bortolami, Symmetry, 2022, 14, 355.
(ix) J. R. Hill, A. A. B. Robertson, J. Med. Chem., 2018, 61, 6945−6963.
(x) S. F. Musolino, Z. Pei, L. Bi, G. A. Di Labio, J. E. Wulff, Chem. Sci., 2021, 12, 12138-12148.
(xi) J. Shaya, F. Fontaine-Vive, B. Y. Michel, A. Burger, Chem. Eur. J., 2016, 22, 10627-10637.