I. DEVELOPMENT OF A 2ND-GENERATION SYNTHESIS OF CJF-III-288, A HIGHLY POTENT HIV-1 ENTRY INHIBITOR FOR IN-VIVO STUDIESAs of 2023, 39.9 million people worldwide were living with the human immunodeficiency virus (HIV). The current state of the art for treatment of HIV is Highly Active Antiretroviral Therapy (HAART), which consists of several compounds in multiple categories of antiretroviral drugs. While this treatment results in almost total restoration of normal immune function and a normal lifespan, it does not eliminate viral reservoirs, necessitating lifelong adherence to treatment. Thus, to end the HIV epidemic, curative treatment is needed. CD4-mimetic compounds (CD4mcs) developed in the Smith Group directly address this issue. Our previous lead CD4-mimetic compound, BNM-III-170, inhibited HIV-1 viral entry in-vitro with low micromolar potency and protected monkeys from intrarectal SHIV challenge. However, the activity of BNM-III-170 was not sufficient for clinical use and some primary HIV-1 strains were completely resistant, so the need arose to develop new CD4mcs that inhibited a broader range of HIV strains with enhanced potency. Our new lead CD4-mimetic compound, CJF-III-288, displays enhanced potency against strains inhibited previously by BNM-III-170, and activity against strains of HIV previously not susceptible to inhibition by BNM-III-170. Compared to BNM-III-170, CJF-III-288 also increases the binding of HIV+ plasma to HIV infected cells and increases HIV+ plasma mediated antibody-dependent cellular cytotoxicity (ADCC). These results justified the development of a more efficient synthesis of CJF-III-288 to access larger quantities of the compound to assess CJF-III-288’s ability to sensitize HIV-1 infected cells to ADCC in animal models. The 2nd-Generation synthesis of CJF-III-288, utilizes new photoredox catalysis methods which overcome the limitations of 2-electron transformations and obviate the need for excessive protecting group and functional group manipulations. The new route allows one to begin on over a hundred-gram scale, and proceed in 10 steps to yield CJF-III-288 in an overall yield of 3%. This reduces the step count almost by half compared to the original of 18 steps, and the overall yield has increased 9.41-fold compared to the original of 0.3%. II. SYNTHETIC EFFORTS TOWARDS THE TOTAL SYNTHESIS OF SEQUOIAMONASCIN A EMLPLOYING RADICAL RELAY CHEMISTRYAnion Relay Chemistry (ARC) is a synthetic method which comprises the union of a nucleophile, the ARC “linchpin”, and an electrophilic reaction partner, in a multicomponent coupling protocol utilizing [1,4]-Brook rearrangement, giving rise to diverse 1,3,5- or 1,5-polyol precursors, which has been utilized in the Smith laboratory for the total synthesis of natural products, most recently the Peniciketals A and B6 and (-)-Enigmazole A. The corresponding [1,5]-Brook rearrangements that would lead to 1,4,n-polyol fragments, while having been studied by our group, have not been applied to a total synthesis due to the harsh conditions needed to trigger the Brook rearrangement. We turn instead to the distal functionalization of C(sp3)-H bonds by intramolecular [1,5]-hydrogen atom transfer (HAT). An alkoxyl radical generated from the corresponding N-alkoxyphthalimide via a single electron transfer from a photocalayst, can “relay” the radical to a carbon center by intramolecular [1,5]- or [1,6]-HAT, affording a stabilized radical which captures a radical acceptor in a Giese-type addition to afford 1,4,7- or 1,5,7-triol precursors. These precursors are transformed into a variety of synthetic fragments, such as [5.5]- and [5.6]-spiroketals, important pharmacophores found in many biologically active natural products. Continuing our program in Radical Relay Chemistry (RRC), the [5.6]-spiroketallactone in Sequoiamonascin A was an excellent target to demonstrate the RRC tactic. The construction of the α,β-unsaturated cyclohexenone scaffold for the proposed radical-relay tactic proved to be more challenging than anticipated. While the proposed tactic has merit, improving the yield of the beginning portion of the synthesis is crucial to ensuring sufficient material throughput for the rest of the synthesis, including optimizing conditions for the Johnson-Claisen rearrangement, dihydroxylation, and synthesis of the [4.3]-trans-fused lactone.