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Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX
Concise Modular Synthesis of Thalassotalic Acids A−C Joseph M. Schulz,†,§ Hunter T. Lanovoi,‡,§,⊥ Amanda M. Ames,‡,∥ Phillip C. McKegg,‡,Δ and James D. Patrone*,†,‡ †
Department of Chemistry and ‡Program in Biochemistry and Molecular Biology, Rollins College, Winter Park, Florida 32789, United States
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ABSTRACT: The novel N-acyldehydrotyrosine analogues known as thalassotalic acids A−C were isolated from a marine bacterium by Deering et al. in 2016. These molecules were shown to have tyrosinase inhibition activity and thus are an attractive set of molecules for further study and optimization. To this end, a concise and modular synthesis has been devised and executed to produce thalassotalic acids A−C and two unnatural analogues. This synthesis has confirmed the identity and inhibitory data of thalassotalic acids A−C, more potent synthetic analogues (IC50 = 65 μM), and provides a route for further structure−activity relationship studies to optimize these molecules.
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of a dehydrotyrosine derivatized with an amide bond containing a long nine to ten carbon alkyl chain. Interestingly, thalassotalic acid A (1) was shown to be a moderate inhibitor of tyrosinase, with an IC50 value of 130 μM.15 Based upon its initial isolation and discovery of tyrosinase inhibition, thalassotalic acid A was an attractive target for synthesis and further study and optimization.
elanogenesis is the near-universal biosynthetic pathway responsible for producing melanin, the brownish-red polymer responsible for providing protection in humans, animals, and plants.1−4 Tyrosinase (EC 1.14.18.1) is a coppercontaining oxidase operating at the beginning of the melanogenesis pathway.5,6 Specifically, tyrosinase is a copper III oxidase responsible for the rate-limiting oxidation of tyrosine into L-DOPA, then further oxidation to dopaquinone and subsequent cyclization to dopachrome in melanin production.7 As the enzyme responsible for catalyzing this oxidative process in melanogenesis, tyrosinase is consequently responsible for the hyperpigmentation of skin in humans, coloring the exoskeleton of insects, and the browning of fruits such as bananas and avocados.1,4,8 Due to its critical role in the melanin biosynthetic pathway across a wide range of organisms, tyrosinase has been the focus of numerous studies to identify inhibitors in both the cosmetic and agricultural sectors.9 These studies have afforded many different inhibitors across a range chemical space from both natural and synthetic sources.10−13 However, many of these molecules have not made it into widespread use or have been taken out of use due to either being ineffective or possessing toxic side effects.7,14 This combination of a clear need in the cosmetic and agricultural fields for a widespread tyrosinase inhibitor along with the lack of current appropriate options continues to drive research into discovering novel tyrosinase inhibitors from a myriad of sources and techniques. In an effort to identify novel tyrosinase inhibitors, Deering et al. isolated a series of N-acyldehydrotyrosine analogues from the marine bacterium Thalassotalea sp. PP2-459.15 These molecules were reclassified as thalassotalic acids A−C (1−3) based upon the bacterial species from which they were isolated.15 This family of molecules share the common motifs © XXXX American Chemical Society and American Society of Pharmacognosy
In an effort to synthesize the recently discovered natural products and analogues thereof, a three-step synthesis was devised that would set the desired Z-alkene in a stereospecific fashion and allow for the incorporation of diversity at each of the three steps (Scheme 1). The key step in this modular scheme is the second step, in which an Erlenmeyer-azlactone derived from the appropriate glycine derivative is treated with an aldehyde to afford the desired Z-double bond. Further, this step allows for the second point of diversity in the final molecule, as one can choose from any of the numerous commercially available aldehydes. The synthesis begins with the derivatization of glycine (4) to amides 5b−e, which incorporate the R-groups that will eventually differentiate thalassotalic acids A−C and the unnatural analogues. These amide bond formations were performed in excellent yields (91−97%) even in the case of 5d, where due to lack of commercial availability, the acyl chloride Received: January 9, 2019
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DOI: 10.1021/acs.jnatprod.9b00028 J. Nat. Prod. XXXX, XXX, XXX−XXX
Journal of Natural Products
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Scheme 1. Synthesis of Thalassotalic Acids A−C
was synthesized from the carboxylic acid.16,17 Based on extensive literature precedent, the next step of installing the Z-alkene was accomplished through the use of an Erlenmeyerazlactone formation.18−21 While there are a vast number of examples in the literature, there were surprisingly none utilizing either 4-acetoxybenzaldehyde or an alkyl chain longer than three methylene units. As such, it was prudent to attempt the azlactone formation using R = methyl (5a) and phenyl (5b) as model compounds. The formation of azlactones 6a and 6b in the presence of sodium acetate and 4acetoxybenzaldehyde went smoothly and yielded pure product upon precipitation in 63% and 72%, respectively. Unfortunately, as expected, the incorporation of the long alkyl chain in the amides 5c−e caused difficulties with both the formation of the azlactone and its purification. When performing the reaction of 5c to form 6c under the aforementioned standard conditions, NMR of the reaction mixture revealed some desired product formation (∼30%), as judged by the integration of the aldehydic proton of the starting material versus the vinyl proton of the product.19 Increasing the equivalencies of the starting amide 5c and sodium acetate and elongating the reaction time to 24 h resulted in a 75% yield for 6c by NMR of the crude product.21,22 Purification of the desired product was attempted using silica and alumina, but the desired product was not stable under these conditions, resulting in an even lower yield (
