**4. Conclusions**

Application of an integrated program of cultivation (MATRIX) and chemical (HPLC-DAD and GNPS) profiling to the marine-derived fungus *Talaromyces* sp. CMB-TU011 enabled access to talarolide A (**1**), along with three new analogues, talarolides B–D (**2**–**4**). Detailed spectroscopic analysis, supported by chemical degradation and derivatization, and partial and total syntheses, permitted assignment of structures to **1** (revised) and **2**–**4**. The talarolides include rare examples of natural cyclic peptides incorporating a hydroxamate moiety, with a solution structure on **1** revealing H-bonding from the *N*-OH-Gly1 across the macrocyclic ring to the D-Ala5 carbonyl oxygen, which both defined and stabilized a unique conformation. This contrasts with the deoxy analogue **2** (i.e., Gly1) where the NMR data indicate two interconverting conformers. Knowledge of the talarolides draws attention to the possible inclusion of hydroxamate moieties in other cyclic peptides (natural and synthetic), as a means to access new and unusual conformations with potentially new biological properties including improved oral bioavailability [16].

**Supplementary Materials:** The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/md21090487/s1. MATRIX study of CMB TU011; NMR spectroscopic data (tabulated data and spectra), Marfey's analysis, and MS/MS spectra of **1**–**4**; NMR spectra comparison of natural and synthetic talarolide B (**2**); 3D calculations of talarolide A (**1**).

**Author Contributions:** R.J.C. conceptualized the research; P.D. carried out the MATRIX study; P.D. and Z.G.K. analyzed NMR data and assigned the structures; W.M.H. and Y.Z. synthesized the dipeptides and talarolide B; K.S. cultivated the microbe and isolated talarolides, H.N.H. and D.P.F. performed 3D structure calculation; A.A.S. analyzed MS/MS data, revised NMR data, developed revised Marfey's method and prepared Supplementary Materials, R.J.C. writing—original draft, R.J.C. and A.A.S.; writing—review and editing. All authors have read and agreed to the published version of the manuscript.

**Funding:** D.P.F. and H.N.H. were supported by Australian Research Council (CE200100012) and NHMRC Investigator (2009551) grants.

**Institutional Review Board Statement:** Not applicable.

**Data Availability Statement:** Raw NMR data have been deposited in the Natural Product Magnetic Resonance Database Project (NP-MRD).

**Acknowledgments:** We thank R. Damodar for collection of CMB-TU011 and the University of Queensland (UQ), Institute for Molecular Bioscience for supporting this research. P.D. and K.S. acknowledge UQ for provision of postgraduate research scholarships.

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