FULL PAPER DOI: 10.1002/ejoc.201500603 Divergent and Concise Syntheses of Spiroisoxazolines: First Total Synthesis of 11-Deoxyfistularin-3 Prasanta Das [a] and Ashton T. Hamme II* [a] Keywords: Total synthesis / Natural products / Spiro compounds A divergent and concise base-promoted Dieckmann-type keto-ester condensation strategy is demonstrated to generate two unique spiro[cyclohexadiene-isoxazoline] moieties. The consecutive di-bromination–elimination–bromination of the corresponding spiro moiety has been successfully utilized to furnish the desired core structure of many bromotyrosine de- rived spiroisoxazoline natural products. The spiroisoxazoline Introduction The natural occurrence and the discovery of new syn- thetic agents displaying antineoplastic activity are impor- tant topics of research in medicinal chemistry. [1] Since the first reports pertaining to the herbicidal and plant hor- monal activity, [2] spiroisoxazoline containing natural prod- ucts and their analogues have stimulated a great deal of interest in biomedicinal chemistry. [3] Among the broad spectrum of α-oximinotyrosine derived natural products isolated from marine sponges, in particular 11-deoxy- fistularin-3 (1), [4a] purealidin P (6), [4b] and Q (7) [4d] are cyto- toxic against the MCF-7 breast cancer cell line (LD 50 = 17 μg/L), [4a] murine lymphoma K1210 (IC 50 2.8 and 0.95 μg mL –1 , respectively), [4b] and human epidermal carcinoma KB (nasopharynx) (IC 50 7.6 and 1.2 μg mL –1 , respective- ly) [4d] cell lines (Figure 1). The other members from the same family are also widely known for their diverse phar- macological activities including antiviral, [5] antimicrobial, [6] anti-HIV, [7] antifungal, [8] antifouling, [9] Na + /K + ATPase in- hibition, [10] HDAC inhibition, [11] histamine H 3 antago- nism, [12] mycothiol S-conjugate amidase inhibition, [13] and isoprenylcysteine carboxymethyl transferase (Icmt) inhibi- tion. [14] The distinguishable molecular diversity arises due to several prominent structural features including; (a) brominated spiroisoxazoline core that contains a cyclohexa- diene, a bromo epoxy ketone, or a bromohydrin moiety, (b) the R or S absolute stereochemistry of the spiro stereogenic center of spiroisoxazoline amide core, (c) the presence of a [a] Department of Chemistry & Biochemistry, Jackson State University, Jackson, MS 39217, USA E-mail: ashton.t.hamme@jsums.edu http://www.jsums.edu/chemistry/ashton-t-hamme-ii/ Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201500603. Eur. J. Org. Chem. 2015, 5159–5166 © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5159 acid was further coupled with the desired diamine to ac- complish the first total synthesis of 11-deoxyfistularin-3. This strategy could serve as an efficient alternative to previously developed oxidative dearomatizing spirocyclization of phenol as the essential step to synthesize this class of natural products. diverse range of amine and diamine spacers attached to the spiroisoxazolines. Owing to the diverse biological activity along with structural diversity, the synthesis of this unique and challenging spiro-skeleton has been of great interest to many chemists. [15,16] Hitherto, the most reported synthetic methodology to this class of natural products fundamentally relies on classi- cal aromatic oxidation. [16a,16b,16c,16d] Since the first synthesis of spiroisoxazolines via oxidative dearomatization achieved by a toxic metal [16a,16b] and electroorganic oxidation, [16c,16d] further modification was also reported using other oxidiz- ing agents (NBS, and PIDA) [16f,16j] shortly thereafter. How- ever, the oxidative methods for spiroisoxazoline synthesis remain restricted to aromatic systems with moderate iso- lated yields, and often required the use of toxic metallic based oxidants. [16a–16d] However, the oxidative cyclization of oxime esters using diacetoxyiodosobenzene was proven to be the most suitable oxidation reagent for phenolic α- oximino ester to date. [16e,16g–16i] Very recently we also re- ported an efficient and alternative process to access spiro- isoxazoline core structures as a model study toward this family of natural products. [17] The rich background for the synthesis of the challenging spiroisoxazoline moiety, in conjunction with their potential as precursors to a range of alkaloid derivatives with diverse biological activity, stimulated our desire to develop a new synthetic route for this unique spiro-moiety. Having experi- enced the efficacy of our multifunctionalization approach towards model spiroisoxazoline core structures, [17] we fo- cused on synthesizing the appropriate functionalized syn- thetic precursors, which would allow us to access the natu- ral product. In this paper, we further exploit our preceding approach [17] to accomplish the first total synthesis of 11- deoxyfistularin-3 (1) (Figure 1). This synthetic approach also facilitates the construction of a new class of spiroisox-