Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Enantioselective Total Synthesis of (+)-Salimabromide Reveals Almost Racemic Nature of Natural Salimabromide Andre ́ Palm, Christopher Knopf, Björn Schmalzbauer, and Dirk Menche* Kekulé-Institut für Organische Chemie und Biochemie, Universität Bonn, Gerhard-Domagk-Str. 1, D-53121 Bonn, Germany
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ABSTRACT: The enantioselective total synthesis of (+)-salimabromide was accomplished by a concise two-step conversion of the fully functionalized dibromo-tetraline core, involving a one-pot Baeyer−Villiger/allylic oxidation by an innovative radical reagent combination. This route unequivocally resolves the stereochemistry and reveals the highly unusual, almost racemic nature of natural salimabromide. very recently, the first total synthesis in racemic form has been accomplished by the group of Magauer.4 Herein, we report the first enantioselective total synthesis of (+)-salimabromide (1) by a selective strategy that is based on the stereoselective generation of the fully functionalized dibrominated tetraline core. Its conversion to the targeted metabolite was then accomplished in a highly concise two-step fashion, involving a cycloaddition and a remarkable one-pot allylic and Baeyer−Villiger oxidation by an innovative radical reagent combination, which proceeds with high selectivity and demonstrates the critical importance of the two bromide atoms for late-stage reactivity and control.4 This route unequivocally resolves the stereochemistry of natural salimabromide and reveals a completely unexpected and highly unusual almost racemic nature of this unique metabolite. As shown in Scheme 1, our retrosynthetic approach was based on an early enantioselective generation of the fully functionalized tetraline core 5, which was planned to arise from procedures previously developed in our group.3 After further elaboration to ketene−imine 4 an intramolecular [2 + 2]cycloaddition was planned to forge the highly hindered C11, C13, and C15 bond in a joint fashion, before a late-stage oxidation was envisioned to conclude the enantioselective total synthesis of (+)-salimabromide. While a similar endgame strategy has been reported by the group of Magauer in their racemic synthesis, our enantioselective procedure is also distinctively different by the two additional bromine atoms already present in 4, which dramatically changes the reactivity during these challenging late-stage functionalization steps (vide infra). Also, an additional hydroxyl at C1 was planned to be
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alimabromide (1) presents one of the few secondary metabolites from marine myxobacteria.1 It was reported in 2013 by the group of König as the first natural product from Enhygromxya salina.2 As shown in Figure 1, its singular
Figure 1. Retrosynthetic analysis of (+)-salimabromide (1).
architecture is characterized by a congested tetracyclic system that is based on a bridged butyrolactone tetraline system. This structurally unique skeleton includes two vicinal quaternary centers, gives rise to four stereogenic centers, and also incorporates an unusual dibrominated benzene ring. While first biological data have revealed potent antibiotic activity, further evaluation has been severely hampered by the extremely low natural abundance, rendering a synthetic approach of vital importance to enable further studies. Its unique architecture in combination with these promising biological data render salimabromide an attractive synthetic target. Consequently, a first stereoselective assembly of the tricyclic core has been developed in 2015 in our group,3 and © XXXX American Chemical Society
Received: February 25, 2019
A
DOI: 10.1021/acs.orglett.9b00706 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
aldehyde 14 with acetate ester enalote. The required aldehyde 14 was readily obtained from Still−Gennari olefination product 13 by reduction and oxidation. In the subsequent cycloaddition studies (Table 1), it became quickly apparent that both the additional hydroxyl and the two
Scheme 1. Synthesis of the Tetraline Core of (+)-Salimabromide
Table 1. Development of the [2 + 2] Cycloaddition To Access Cyclobutanone 2
entry
base and Tf2O (equiv)
solvent
temp
yield (%)
1 2 3 4 5 6 7 8 9
2,4,6-collidine (1.3) 2,4,6-collidine (1.3) DBU (1.3) DBU (1.3) Et3N (1.3) Et3N (1.3) Et3N (3.0) Et3N (12.0) 2-F-pyridine (2.0)
DCE toluene DCE toluene DCE toluene toluene toluene toluene
80 °C 100 °C 80 °C 100 °C 80 °C 100 °C 120 °C 120 °C 140 °C
−a −a −a
