CADENAS DEL DRAMA, PARADIGMAS Y TRUBY

The extreme scarcity of the isolated solomonamides from the natural sources is a drawback for further pharmacological assays. This difficulty to access large amounts of these compounds from their natural sources makes quite difficult to gain insight into their biological profiles and mechanism of action and justifies the chemical synthesis of these natural products.Thus, the chemical synthesis of these unexplored cyclopeptides could represent a solution to provide enough amounts of material to carry out extensive biological studies and confirm their initially proposed structures. As a consequence, by the time we initiated this research project, the solomonamides had been elicited interest with the publication of some synthetic approaches,²⁸⁰ including the synthesis of a deoxy analogue of solomonamide B.²⁸¹ In parallel with the development of our research work, two new synthetic approaches were published,²⁸² culminating with the total synthesis of

279 For a review about the termed ‘problem of supply’ that has hampered the development of natural-products derived drugs see:

Newman, D.J. Pharmacol. Ther. 2016, 162, 19.

280 (a) Kashinath, K.; Vasudevan, N.; Reddy, D. S. Org. Lett. 2012, 14, 62226225. (b) Kavitha, N.; Kumar, V. P.; Chandrasekhar, S.

Tetrahedron Lett. 2013, 54, 21282130. (c) Reddy, D. S.; Kormirishetty, K.; Natrajan, V. WO Patent 2014083578 A1, Nov 27, 2013.

281 Vasudevan, N.; Kashinath, K.; Reddy, D. S. Org. Lett. 2014, 16, 61486151.

282 (a) Kashinath, K.; Dhara, S.; Reddy, D. S. Org. Lett. 2015, 17, 20902093. (b) Kavitha, N.; Chandrasekhar, S. Org. Biomol. Chem.

2015, 13, 62426248.

121 solomonamide B (578),²⁸³ and later solomonamide A (577),²⁸⁴ by the Reddy group. Very recently, the same group has reported the preparation of some stereoisomers of solomonamide macrocycles, by changing the stereochemical pattern of the non-peptide fragment AHMOA.²⁸⁵ More importantly, the total syntheses of solomonamides A and B led to the revision of the initially proposed structures for 577 and 578, with the correction of the configurations at C-3 and at C-4 positions to the (3S, 4S)-isomer (compound 580) instead of the proposed (3R, 4R) for solomonamide B (578) and the correction of the configuration at C-3, C-4 and C-5 to the (3S, 4S, 5S)-isomer (compound 579) instead of the proposed (3R, 4R, 5R) for solomonamide A (577) (Figure 12).

Figure 12. Revised Structures of Solomonamides A and B (Reddy et al. 2016 and 2018)^{283, 284}

From the retrosynthetic point of view, the total syntheses of solomonamides accomplished by Reddy et al. were based on a key intramolecular Heck reaction to obtain the macrocyclic core of the solomonamides, represented by compound 581 in Scheme 71. Thus, the synthesis started from D-methionine aldehyde 583, previously prepared from D-methionine 582, which was transformed into acid 584 in 5 steps, involving a Brown’s crotylation as the key reaction to generate the required syn-1,2-amino alcohol system. Then, acid 584 was coupled with the amine derived from peptide 585 to obtain iodo derivative 586 in a 73% yield over two steps, followed by the acetal deprotection to afford 587 in a modest 40% yield. The key intramolecular Heck reaction was then carried out by the action of Pd(OAc)2 in presence of triethylamine in a high diluted acetonitrile solution at 75 ºC to obtain compound 581 in a 53% yield. From macrocyclic 581, the synthesis of 578 was achieved in five additional steps in a 29% overall yield, involving a Boc deprotection, a peptide coupling with serine derivative 588, a key regioselective Wacker oxidation to install the ketone group and a final removal of protecting groups by hydrogenolysis and TFA (Scheme 71).

283 Kashinath, K.; Jachak, G. R.; Athawale, P. R.; Marelli, U. K.; Gonnade, R. G.; Reddy, D. S. Org. Lett. 2016, 18, 31783181.

284Jachak, G.; Athawale, P. R.; Agarwal, H.; Barthwal, M. K.; Lauro, G.; Bifulco, G.; Reddy, D. S. Org. Biomol. Chem. 2018, 16, 91389142.

285 Jachak, G. R.; Athawale, P. R.; Choudhury, R.; Kashinath, K.; Reddy, D. S. Chem. Asian J. 2019, just accepted. DOI:

10.1002/asia.201901075

122

Scheme 71. Total Synthesis of the Initially Proposed Structure of Solomonamide B (578) via Intramolecular Heck Reaction (Reddy et al. 2016)²⁸³

From the retrosynthetic point of view, the total syntheses of solomonamides accomplished by Reddy et al. were based on a key intramolecular Heck reaction to obtain the macrocyclic core of the solomonamides, represented by compound 581 in Scheme 71. Thus, the synthesis started from D-methionine aldehyde 583, previously prepared from D-methionine 582, which was transformed into acid 584 in 5 steps, involving a Brown’s crotylation as the key reaction to generate the required syn-1,2-amino alcohol system. Then, acid 584 was coupled with the amine derived from peptide 585 to obtain iodo derivative 586 in a 73% yield over two steps, followed by the acetal deprotection to afford 587 in a modest 40% yield. The key intramolecular Heck reaction was then carried out by the action of Pd(OAc)2 in presence of triethylamine in a high diluted acetonitrile solution at 75 ºC to obtain compound 581 in a 53% yield. From macrocyclic 581, the synthesis of 578 was achieved in five additional steps in a 29% overall yield, involving a Boc deprotection, a peptide coupling with serine derivative 588, a key regioselective Wacker oxidation to install the ketone group and a final removal of protecting groups by hydrogenolysis and TFA (Scheme 71). However, the spectroscopic data for synthetic solomonamide B did not match with those reported for the natural compound by Zampella

123 et al.²⁷⁸ Considering that the relative and absolute configurations of the three stereocenters contained in the polyketide fragment were established through computational methods, Reddy et al. planned to achieve the synthesis of the (3S, 4S)-isomer instead of the initially proposed (3R, 4R)-isomer. With this purpose, the authors started from the enantiomer of aldehyde ent-583 which was subjected to a Evans aldol reaction to construct the syn-1,2-amino alcohol system which contains the (3S, 4S)-stereochemistry upon the ADMOA fragment. Then, the same synthetic sequence described above was implemented to complete the synthesis of targeted compound 580 in a 0.4% over 15 steps from aldehyde ent-583. In this case, the spectroscopic data of synthetic 580 matched with those reported for the natural solomonamide B, therefore confirming the revised structure of solomonamide B (Scheme 72). present in solomonamide B should be contained in solomonamide A, thus leaving one stereocenter at the C5 position of the ADMOA fragment whose absolute stereochemistry needed to be fixed, initially established as 5R. With this aim, the authors carried out the synthesis of the (3S, 4S, 5S)-isomer instead of the initially proposed (3R, 4R, 5R)-configuration. Thus, macrocyclic compound 589, previously obtained through the synthesis of the revised solomonamide B was subjected to an Upjohn dihydroxylation to obtain triol 590 in a 74% yield as a single diastereoisomer. The reason for which this last reaction proceeded in a stereoselective manner could be explained by the rigid conformation of the macrocycle through intramolecular H-bonding. Subsequent selective bencylic oxidation by the use of Dess-Martin periodinane (DMP) afforded the -hydroxy ketone 591 in a 67% yield. From this ketone 591, compound 579 was obtained in four additional steps, and its spectroscopic data were matching with those reported for the natural solomonamide A. With the aim to confirm the absolute C5-configuration generated during the Upjohn dihydroxylation, the authors employed a QM/NMR approach based on comparison of the experimental ¹³C NMR chemical shift data and the predicted values calculated at the density functional theory (DFT) level for all the possible theoretical diastereoisomers, concluding the assignment of the C5-configuration as 5S (Scheme 73).

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Scheme 73. Total Synthesis of the Revised Structure of the Solomonamide A (579) (Reddy et al. 2018)²⁸⁴