*3.7. X-ray Crystal Structure Analysis*

High-resolution crystallographic data for compound **8** were collected using redundant ω scans on a Rigaku XtaLabPro single-crystal diffractometer using microfocus Mo Kα radiation and a HPAD PILATUS3 R 200K detector. Its structure was readily solved by intrinsic phasing methods (*SHELXT*) and by full-matrix least-squares methods on F2 using *SHELX-L* [43,44]. The non-hydrogen atoms were refined anisotropically, and hydrogen atoms, all identified in difference maps, were positioned geometrically and refined with Uiso set to xUeq of the parent atom (x = 1.5 for methyl carbons or hydroxy oxygens and 1.2 for all others). Despite extremely weak anomalous signal and ambiguous Flack parameter [45] obtained with that radiation, the Bijvoet analysis using likelihood methods showed strong probabilities that this characterized enantiopure natural product is (*R*)-2,3,7-trihydroxy-1,8,8,9-tetramethyl-8,9-dihydro-4*H*,6*H*-benzo[*de*]furo[2,3-*g*] isochromene-4,6-dione. Duplicated measurements using a Rigaku mm007 rotating anode consolidated our statement (data not deposited).

Crystallographic data for this structure, **8**, have been deposited in the Cambridge Crystallographic Data Centre database (CCDC) (deposition number CCDC 1963851). Copies of the data can be obtained free of charge from the CCDC at www.ccdc.cam.ac.uk.

Crystal data for **8**: C18H16O7, *M* = 344.31, Orthorhombic, a = 6.6249(2) Å, b = 10.0615(3) Å, c = 22.5473(6) Å a = b = g = 90◦, V = 1502.92(8) Å3, T = 293(2) K, space group *P*212121, Z = 4, μ(Mo Kα) = 0.118 mm−1, 47,173 reflections measured, 4370 independent reflections (Rint = 0.0456). The final R1 values were 0.0389 (I > 2σ(I)). The final *wR* (F2) values were 0.1093 (all data). The goodness of fit on F2 was 1.072. Flack parameter = −0.2 (2). Bijvoet Pairs = 1854 (100% coverage): P2 (true) = 1.000. P3 (true) <sup>=</sup> 0.987, P3 (rac-twin) <sup>=</sup> 0.013, P3 (false) <sup>=</sup> 0.8.10<sup>−</sup>6. Hooft parameter <sup>=</sup> <sup>−</sup>0.1 (2) [35].

**Supplementary Materials:** The following are available online at http://www.mdpi.com/1660-3397/17/12/678/s1, S1 to S4, spectroscopic characterization of compound **1**; S5 to S11, spectroscopic characterization of compounds **2** + **3**; S12 to S18, spectroscopic characterization of compound **4**; S19 to S25, spectroscopic characterization of compound **5**; S26 to S29, spectroscopic characterization of compound **6**, S30 to S34, spectroscopic characterization of compound **7**; S35 to S42, spectroscopic characterization of compound **8**; S43 to S46, spectroscopic characterization of compound **9**; S47 to S50, spectroscopic characterization of compound **10**; S51 to S57, crystallographic data for compound **8**; S58-S72, crystallographic data for compounds **7** and **10**.

**Author Contributions:** G.L.G. designed, managed, and implemented the microbial and chemical experiments and elucidated the structures of the reported compounds. She wrote all the technical parts of the paper. P.L. and P.V. participated in the microbial and analytical experiments; P.L. and G.A. participated in compound purification and chromatographic analysis; E.V.E. and P.R. did the crystallographic studies; J.-F.G. recorded the NMR spectra; M.W. and Y.B. collected and identified the sponge *Acanthella cavernosa*; N.F. reviewed and discussed the manuscript; and J.O. coordinated the work and finalized the writing and editing of the manuscript.

**Funding:** This work was supported and conducted in the frame of the H2020 TASCMAR project, which is funded by the European Union under grant agreement number 634674 (www.tascmar.eu).

**Acknowledgments:** The photos are the property of CNRS images, they were taken by Cyril Frésillon (© Cyril Frésillon/ICSN/CNRS Photothèque). We thank the Interuniversity Institute for Marine Sciences in Eilat (IUI) for the use of the Sam Rothberg R/V and the professional assistance of its crew members. We are indebted to EcoOcean staff members for operating the ROV. We acknowledge E. Shoham and R. Liberman for their help in the field work. We thank Nicole J. de Voogd from Naturalis, Biodiversity Research Center, Leiden, the Netherlands, for taxonomic identification of the sponge. The Israel Nature and National Parks Protection Authority is acknowledged for issuing collection permits.

**Conflicts of Interest:** The authors declare no conflict of interest.
