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Formal Semisynthesis of Demethylgorgosterol Utilizing A Full Papers doi.org/10.1002/ejoc.202100035 1 2 3 Formal Semisynthesis of Demethylgorgosterol Utilizing a 4 5 Stereoselective Intermolecular Cyclopropanation Reaction 6 [a] [a] [a, e] [b] [c] 7 Nicolai Rosenbaum, Lisa Schmidt, Florian Mohr, Olaf Fuhr, Martin Nieger, and [a, d] 8 Stefan Bräse* 9 10 11 In this study, we report a convenient and high yielding formal ester shows a trans/cis ratio of 89:11, with a diastereomeric 12 semisynthesis of demethylgorgosterol, a marine steroid with an ratio for the trans-diastereomers of >99:1. A reduction/ 13 intriguing sidechain containing a cyclopropane unit. This was oxidation sequence afforded the corresponding aldehyde, 14 achieved through the synthesis of an advanced ketone which was used in a Grignard reaction. A final oxidation step 15 intermediate. The synthetic route features a total of ten steps, then yielded the desired ketone. This novel route presents a 16 starting from commercially available stigmasterol, with an platform to further investigate the medicinal applications of 17 overall yield of 27%. The key step was a stereoselective gorgosterol-type steroids and to fully understand their role in 18 intermolecular cyclopropanation reaction. This reaction pro- coral symbiosis. 19 ceeded in 82% yield, the resulting cyclopropane carboxylic 20 21 Introduction One of these many natural products, gorgosterol (1a), was 22 first isolated by Bergmann et al. in 1943 from the soft coral 23 Corals and coral reefs, despite only covering about 1% of the Plexaura flexuosa.[7] Gorgosterol is also found in various other 24 ocean floor, are the most diverse aquatic ecosystems.[1] They are animals and their symbionts.[8] It had chemists puzzled due to 25 associated with an estimated 25% of all marine species and its unusual properties,[7,9] until its structure was elucidated 26 rivaled in biodiversity only by rain forests.[2] Their ecological, as unambiguously,[10] and its first derivative demethylgorgosterol 27 well as economic impact, is of global scale,[3] and they are a (1b) was discovered.[11] Nowadays, a plethora of derivatives are 28 source of countless natural products.[4] Yet, they are endangered known, e.g. 2–5 (Figure 1), showing a multitude of biological 29 by climate change in multiple ways,[5] as well as by environ- activities.[12] These include cytotoxicity against various cancer 30 mental pollution,[5a] amongst others.[6] cell lines,[12c,13] reversal of multidrug resistance in cancer cells,[14] 31 antitubercular activity[15], and antifungal activity.[16] A common 32 feature of these steroids is their distinctive sidechain, containing 33 [a] N. Rosenbaum, L. Schmidt, Dr. F. Mohr, Prof. Dr. S. Bräse 34 Institute of Organic Chemistry (IOC) Karlsruhe Institute of Technology (KIT) 35 Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany 36 E-mail: [email protected] 37 http://www.ioc.kit.edu/braese/index.php [b] Dr. O. Fuhr 38 Institute for Nanotechnology (INT) and Karlsruhe Nano Micro Facility 39 (KNMF) 40 Karlsruhe Institute of Technology (KIT) Hermann-von-Helmholtz Platz 1, 76344 Eggenstein-Leopoldshafen 41 [c] Dr. M. Nieger 42 Department of Chemistry 43 University of Helsinki P. O. Box 55, 00014 Helsinki, Finland 44 [d] Prof. Dr. S. Bräse 45 Institute of Biological and Chemical Systems – Functional Molecular 46 Systems (IBCS-FMS) Karlsruhe Institute of Technology (KIT) 47 Hermann-von-Helmholtz Platz 1, 76344 Eggenstein-Leopoldshafen 48 https://fms.ibcs.kit.edu 49 [e] Dr. F. Mohr New address: Pharmazeutisches Institut 50 Eberhard-Karls-Universität Tübingen 51 Auf der Morgenstelle 8, 72076 Tübingen 52 Supporting information for this article is available on the WWW under https://doi.org/10.1002/ejoc.202100035 53 © 2021 The Authors. European Journal of Organic Chemistry published by 54 Wiley-VCH GmbH. This is an open access article under the terms of the 55 Creative Commons Attribution Non-Commercial License, which permits use, Figure 1. Structures of Gorgosterol (1a), Demethylgorgosterol (1b), and 56 distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. selected derivatives 2–5. 57 Eur. J. Org. Chem. 2021, 1568–1574 1568 © 2021 The Authors. European Journal of Organic Chemistry published by Wiley-VCH GmbH Wiley VCH Donnerstag, 04.03.2021 2110 / 192789 [S. 1568/1574] 1 Full Papers doi.org/10.1002/ejoc.202100035 a C22/C23 cyclopropane ring and additional methyl groups at then cyclized to yield the known aldehyde 12 (Scheme 1c). 1 C23 and C24. These routes, despite involving more steps, produced the 2 The exact mechanism of the biosynthesis of the gorgosterol intermediary ketone 8 in a higher yield.[18] Ikekawa et al. also 3 family has not been fully elucidated yet. Several plausible routes presented a stereoselective semisynthesis of gorgosterol (1b) 4 have been proposed and discussed, with no final conclusion.[19] using a similar 3-exo-tet cyclization.[24] 5 However, biosynthesis is believed to be part of the complex 6 symbiotic relationship between corals and algae. Recently, it 7 was shown that corals depend on sterols provided by their Results and Discussion 8 symbionts and that their sterol composition varies substantially 9 to symbiont species and even cell line.[20] The biological The starting point for our semisynthesis was the commercially 10 function of gorgosterol is unknown, but it exhibits activity as a available stigmasterol (6). The latter phytosterol was trans- 11 growth inhibitor of human colon tumor cell lines.[21] Addition- formed into the alkene 19, which was needed for the enantio- 12 ally, it was identified as a new chemotype of farnesoid-X- and diastereoselective intermolecular cyclopropanation, accord- 13 receptor (FXR) antagonist,[12d] making it a potential target for ing to known procedures in five steps (Scheme 2). The first two 14 the treatment of cholestasis.[22] steps were necessary to protect the steroidal A- and B-rings in 15 In the past, several semisyntheses of demethylgorgosterol the form of the i-steroid methyl ether 16.[25] This was followed 16 (1b) and its stereoisomers, as well as one of gorgosterol (1a), by the cleavage of the side chain by ozonolysis,[26] and 17 were achieved by the groups of Djerassi and Ikekawa. The first subsequent transformation of the resulting aldehyde 17.[23] A 18 attempts to methylenate a suitable precursor using either a Julia-like, two-step alkene synthesis was employed, rather than 19 Simmons-Smith reaction or a Corey-Chaykovsky reaction did one step procedures like the Wittig reaction, since this resulted 20 not yield the desired configuration.[23] All of the following in higher yields.[27] Alkene 19 was obtained from stigmasterol 21 syntheses used an intramolecular 3-exo-tet ring-closure strategy (6) in up to 52% yield on a multi-gram scale. 22 to form the cyclopropane moiety in the desired configuration Since rhodium-based catalysts often show poor selectivity 23 (Scheme 1). The shortest route, developed by Djerassi et al., and yields for the cyclopropanation of aliphatic alkenes,[28] and 24 consists of a total of 15 steps. The key step was a domino asymmetric Corey-Chaykovsky- and Simmons-Smith-type reac- 25 cyclization/alkylation-reaction of 7 to 8 (Scheme 1a). However, tions were chemically not applicable to alkene 19, we opted for 26 the overall yield of the above-mentioned semisynthesis was Iwasa’s ruthenium-based procedure.[29] From their model for the 27 very low.[17] Ikekawa et al. developed three different routes, all chiral induction in this Ru-pheox catalyzed cyclopropanation we 28 leading to ketone 8 eventually and converging into Djerassi’s deduced that the (R)-configured catalyst would produce the 29 route. Starting from steroid 9, which was transformed into desired stereochemistry. The ligand 21 and catalyst 22 were 30 aldehyde 11 and then cyclized yielding 12. The cyclized synthesized according to literature from (R)-2-phenylglycinol 31 aldehyde 12 was then transformed into the known ketone 8 (20) in yields of 73% and 88% respectively (Scheme 3).[30] 32 (Scheme 1b).[18a] Alternatively, starting material 13 could either Scheme 4 shows the cyclopropanation carried out under 33 be transformed into 10 to join route (b) or into 14, which was optimized reaction conditions. A yield of 82% was achieved, 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 Scheme 1. Previous semisyntheses of demethylgorgosterol (1b). Routes developed by (a) Djerassi et al.[17] and (b), (c) Ikekawa et al.[18] 57 Eur. J. Org. Chem. 2021, 1568–1574 www.eurjoc.org 1569 © 2021 The Authors. European Journal of Organic Chemistry published by Wiley-VCH GmbH Wiley VCH Donnerstag, 04.03.2021 2110 / 192789 [S. 1569/1574] 1 Full Papers doi.org/10.1002/ejoc.202100035 1 2 3 4 5 6 7 8 9 10 Scheme 2. Synthesis of the alkene 19 starting from commercially available stigmasterol (6). Reaction conditions: a) TsCl, pyridine, rt, 16 h, quant. b) MeOH, 11 pyridine, reflux, 4 h, 78 %. c) i) O3, DCM, MeOH, À 78 °C, 45 min; ii) Zn, HOAc, rt, 1 h, 80 %. d) TsNHNH2, MS 3 Å, ethanol, rt, 30 min, 50 °C, 30 min, 95%. 12 e) Dimethyl sulfone, nBuLi, THF, 0 °C to rt, 16 h, 88%. 13 14 15 16 17 18 19 20 21 Scheme 3. Synthesis of (R)-Ru-pheox 22 from (R)-2-phenylglycinol (20). Reaction conditions: a) i) benzoyl chloride, Et N, DCM, 0 °C to rt, 16 h. 22 3 ii) SOCl2, CHCl3, 0 °C to rt, 24 h. iii) 2.5 m NaOH, 1,4-dioxan, 0 °C to rt, 4 h, 23 73%. b) benzeneruthenium(II) chloride dimer, 1 m NaOH, KPF6, MeCN, 80 °C, 24 48 h, 88 %.
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