Chapter One (Part I) discusses the isolation of two new propionate-derived metabolites, dolabriferols B and C (II and III), in addition to the known compound dolabriferol (I) from the Caribbean mollusk Dolabrifera dolabrifera collected in Puerto Rico. The structures of dolabriferols B (II) and C (III) were established by comparison of their spectral data with those of I, and the absolute configuration of II was determined from chemical degradation studies. The structure of dolabriferol C (III) was confirmed by Xray analysis. In the Part II and III, two distinct samples of the sea hare Aplysia dactylomela from two different locations around Puerto Rico were investigated for their secondary metabolite content. In Part II (collection from Mona Island), the investigation resulted in the isolation of a new regular diterpene possessing an unusual 1,6-anti-3- methylcyclohex-2-en-1-ol ring system, this compound was trivially named dactyloditerpenol acetate (IV). The stereostructure of IV was elucidated by spectroscopic methods and the absolute configuration was determined as 1S, 6S, 7R, 10S, and 11R by application of Kishi’s method for the assignment of absolute configuration of alcohols. The new diterpene potently inhibited in vitro thromboxane B2 (TXB2) (IC50 0.4 μM) and superoxide anion (O €2) (IC50 1 μM) generation from Escherichia coli lipopolysaccharide (LPS)-activated rat neonatal microglia, with concomitant low shortterm toxicity. Lastly, in Part III (collection from Piñones), the investigation resulted in the isolation and structure elucidation of a fluorinated corticosteroid (V), which was previously known as a synthetic drug. Chapter Two discusses the reassignment of the absolute configuration of the marine natural product plakinidone, erroneously assigned as a perlactone (VI) by Faulkner’s group. Recent work by Wu’s group in connection with the first synthesis of plakinidone revealed that the most salient feature of its purported structure, a six-membered perlactone moiety, was in fact a five-membered lactone (i.e. a 3-methyl-4-hydroxy- 2(5H)-furanone or tetronic acid ring). With the planar structure of plakinidone confidently revised, we undertook a new investigation to establish its absolute configuration unambiguously. Upon preparing two stable derivatives, VII and VIII, from a sample of naturally occurring plakinidone extracted from the sponge association Plakortis halichondrioides–Xestospongia deweerdtae, the absolute configuration was assigned by synthesis and vibrational and electronic circular dichroism (VCD and ECD) measurements in combination with density functional theory calculations at the B3LYP/aug-cc-pVDZ/PCM(CH3CN) level of theory. Our combined efforts and the agreement between the experimental and calculated VCD/ECD spectra of VII revealed that the absolute configuration of plakinidone was in fact (10S,4R) and not the formerly reported (10S,4S) diastereomer assigned by Wu. Therefore, we propose that natural plakinidone is accurately represented by structure IX. Additionally, two new tetronic acids, plakinidone B (X) and plakinidone C (XI) were isolated and their stereostructures determined by comparison of their optical rotations and chemical shifts, as well as by chemical correlations. The antiplasmodial activity of these natural tetronic acids, along with various semi-synthetic analogues, was evaluated. Chapter Three discusses the isolation of plakorthiazole (XII), a modified polyketidedipeptide isolated from the sponge consortium Plakortis halichondrioides–Xestospongia deweerdtae. The structure of plakorthiazole (XII) was defined by spectroscopy and spectrometric data and the absolute configuration was determined using Marfey’s analysis. Due to the scarcity of this natural product, a synthetic approach was developed leading to dechloro-plakorthiazole (XIII), a synthetic analog of plakorthiazole. In 2015, during the completion of our synthetic approach, Costantino’s group reported the structure of smenothiazole A from the sponge Smenospongia aurea. The structure of smenothiazole A (including its absolute configuration) was identical to that of plakorthiazole. Plakorthiazole (XII) showed potent inhibitory activity toward the growth of Mycobacterium tuberculosis (H37Rv) with an IC50 value of 4.09 μg/mL with low toxicity against Vero cells (IC50 > 128 μg/mL). Thus, plakorthiazole represents a potentially promising lead. Chapter Three discusses the isolation of plakorthiazole (XII), a modified polyketidedipeptide isolated from the sponge consortium Plakortis halichondrioides–Xestospongia deweerdtae. The structure of plakorthiazole (XII) was defined by spectroscopy and spectrometric data and the absolute configuration was determined using Marfey’s analysis. Due to the scarcity of this natural product, a synthetic approach was developed leading to dechloro-plakorthiazole (XIII), a synthetic analog of plakorthiazole. In 2015, during the completion of our synthetic approach, Costantino’s group reported the structure of smenothiazole A from the sponge Smenospongia aurea. The structure of smenothiazole A (including its absolute configuration) was identical to that of plakorthiazole. Plakorthiazole (XII) showed potent inhibitory activity toward the growth of Mycobacterium tuberculosis (H37Rv) with an IC50 value of 4.09 μg/mL with low toxicity against Vero cells (IC50 > 128 μg/mL). Thus, plakorthiazole represents a potentially promising lead compound for antituberculosis drug discovery. Chapter Four discusses the isolation of three new polyketides, plakortilactone (XIV), 13-oxo-plakortide G (XV), and seco-plakortide F (XVI), along with the known 13-oxoplakortide F (XVII) from the free-living marine sponge Plakortis halichondrioides collected at Mona Island, Puerto Rico. These new polyketides, including their relative configurations, were determined on the basis of extensive analysis of spectroscopic data. Unfortunately, the relative configurations of the remote stereocenters at C-10 in compounds XIV-XV and XVII could not be determined. The absolute configuration of XVI was established by chemical correlations studies. The cytotoxic, antiplasmodial, and antitubercular properties of these polyketides were also investigated.