Toward the gram -scale total synthesis of (+)-spongistatin 1

This dissertation describes the evolution of a large-scale synthetic campaign directed at the total synthesis (+)-spongistatin 1, one of the most potent and architecturally complex antitumor marine macrolides discovered to date. Chapter one provides an introduction to the spongistatin family of natural products. Specifically, the isolation, structure elucidation, and biological activity of the spongistatins are discussed. Furthermore, relevant synthetic approaches toward the spongistatins are delineated.* Chapter two provides a critical analysis of our previous syntheses of the spongistatins in the form of a detailed retrosynthesis, and describes our latest synthetic strategy for overcoming the deficiencies associated with our earlier work. The (+)-spongistatin 1 macrolide framework was assembled via Wittig union of an EF phosphonium salt and an ABCD aldehyde. For construction of the advanced ABCD fragment, disconnection at the C(15)-C(16) aldol linkage revealed the AB aldehyde and CD ketone. The linear precursors of both spiroketal moieties were assembled in a highly efficient manner via methods developed in our laboratories, namely the three component union of 2-silyl-1,3-dithianes with terminal epoxides.* As anticipated from the precedent set forth by Evans, aldol union of the AB and CD fragments proceeded in both good yield (72%) and with high selectivity (9:1). The complex aldol reaction was ultimately performed on a 2 g scale; approximately 5 g of coupled product were prepared. The synthesis of the advanced ABCD aldehyde was achieved with a longest linear sequence of 22 steps (6.5% overall yield) and is 15 steps shorter than our previous synthesis.* Chapters three and four describe our long-standing efforts toward an efficient and scalable synthesis of the EF Wittig salt. The difficulty in this regard lies in the installation of the highly sensitive chlorodiene side chain moiety present in (+)-spongistatin 1. In response, we have developed a novel method for side chain introduction via cyanohydrin alkylation. Construction of the EF bis-tetrahydropyran subunit was achieved via dithiane alkylation to an F-ring aldehyde, using chelation control to establish the requisite C(38) stereochemistry.* Successful installation of the chlorodiene side chain was achieved via cyanohydrin alkylation of an appropriately functionalized EF bis-tetrahydropyran allyl iodide. Subsequent synthetic operations, involving cyanohydrin hydrolysis, elimination to afford the diene moiety, asymmetric ketone reduction, and phosphonium salt formation completed the synthesis of the EF Wittig salt.* (Abstract shortened by UMI.) *Please refer to dissertation for diagrams

Mechanistic Insights into the Vanadium-Catalyzed Achmatowicz Rearrangement of Furfurol

The Achmatowicz rearrangement is a powerful method for the construction of pyranones from simple furan derivatives. Here, we describe the development of improved reaction conditions and an interrogation into the fate of the metal center during this interesting transformation. The reaction to form the synthetically important lactol, 6-hydroxy-2<i>H</i>-pyran-3­(6<i>H</i>)-one (<b>3</b>), proceeds cleanly in the presence of <i>tert</i>-butyl hydroperoxide (TBHP, <b>2</b>) using low loadings of VO­(O^<i>i</i>Pr)₃ as catalyst. The nonaqueous conditions developed herein allow for easy isolation of product <b>3</b> and synthetically important derivatives, a key advantage of this new protocol. Detailed experimental, spectroscopic, and kinetic studies along with kinetic modeling of the catalytic cycle support a positive-order dependence in both furfurol and TBHP concentrations, first-order dependence in catalyst (VO­(O^<i>i</i>Pr)₃), and a <i>negative</i> dependence on the 2-methyl-2-propanol (<b>4</b>) concentration. ⁵¹V-NMR spectroscopic studies revealed that 2-methyl-2-propanol (<b>4</b>) competes with substrates for binding to the metal center, rationalizing its inhibitory effect

Development of a Concise Multikilogram Synthesis of LPA‑1 Antagonist BMS-986020 via a Tandem Borylation–Suzuki Procedure

The process development for the synthesis of BMS-986020 (<b>1</b>) via a palladium catalyzed tandem borylation/Suzuki reaction is described. Evaluation of conditions culminated in an efficient borylation procedure using tetrahydroxydiboron followed by a tandem Suzuki reaction employing the same commercially available palladium catalyst for both steps. This methodology addressed shortcomings of early synthetic routes and was ultimately used for the multikilogram scale synthesis of the active pharmaceutical ingredient <b>1</b>. Further evaluation of the borylation reaction showed useful reactivity with a range of substituted aryl bromides and iodides as coupling partners. These findings represent a practical, efficient, mild, and scalable method for borylation

Stereoselective Bulk Synthesis of CCR2 Antagonist BMS-741672: Assembly of an All-<i>cis</i> (<i>S,R,R</i>)‑1,2,4-Triamino­cyclohexane (TACH) Core via Sequential Heterogeneous Asymmetric Hydrogenations

A concise bulk synthesis of stereochemically complex CCR2 antagonist BMS-741672 is reported. A distinct structural feature is the chiral all-<i>cis</i> 1,2,4-triamino­cyclohexane (TACH) core, which was assembled through consecutive stereocontrolled heterogeneous hydrogenations: efficient Pt-catalyzed reduction of a β-enaminoester, directed by (<i>S</i>)-α-methyl­benzyl­amine as a low-cost chiral template, and reductive amination of a 3,4-<i>cis</i>-disubstituted cyclohexanone over sulfided Pt/C introduced a <i>tert-</i>amine, setting the third stereocenter in the all-<i>cis</i> cyclohexane core. The heterogeneous catalysts were recycled. Ester hydrolysis produced a γ-amino acid, isolated as its Na salt. A challenging Curtius reaction to introduce the remaining C–N bond at C-2 was strongly influenced by the presence of the basic <i>tert-</i>amine, providing a stereoelectronically highly activated isocyanate. Detailed mechanistic and process knowledge was required to enable clean trapping with an alcohol (<i>t</i>-BuOH) while avoiding formation of side products, particularly an unusual carbamoyl phosphate. Deprotection, <i>N</i>-acetylation, and uncatalyzed S_NAr coupling with known 4-chloroquinazoline provided the final product. The resulting 12-step synthesis was used to prepare 50 kg of the target compound in an average yield of 82% per step

Process Development of a Macrocyclic Peptide Inhibitor of PD-L1

This article outlines the process development leading to the manufacture of 800 g of BMS-986189, a macrocyclic peptide active pharmaceutical ingredient. Multiple N-methylated unnatural amino acids posed challenges to manufacturing due to the lability of the peptide to cleavage during global side chain deprotection and precipitation steps. These issues were exacerbated upon scale-up, resulting in severe yield loss and necessitating careful impurity identification, understanding the root cause of impurity formation, and process optimization to deliver a scalable synthesis. A systematic study of macrocyclization with its dependence on concentration and pH is presented. In addition, a side chain protected peptide synthesis is discussed where the macrocyclic protected peptide is extremely labile to hydrolysis. A computational study explains the root cause of the increased lability of macrocyclic peptide over linear peptide to hydrolysis. A process solution involving the use of labile protecting groups is discussed. Overall, the article highlights the advancements achieved to enable scalable synthesis of an unusually labile macrocyclic peptide by solid-phase peptide synthesis. The sustainability metric indicates the final preparative chromatography drives a significant fraction of a high process mass intensity (PMI)

Process Development of a Macrocyclic Peptide Inhibitor of PD-L1

This article outlines the process development leading to the manufacture of 800 g of BMS-986189, a macrocyclic peptide active pharmaceutical ingredient. Multiple N-methylated unnatural amino acids posed challenges to manufacturing due to the lability of the peptide to cleavage during global side chain deprotection and precipitation steps. These issues were exacerbated upon scale-up, resulting in severe yield loss and necessitating careful impurity identification, understanding the root cause of impurity formation, and process optimization to deliver a scalable synthesis. A systematic study of macrocyclization with its dependence on concentration and pH is presented. In addition, a side chain protected peptide synthesis is discussed where the macrocyclic protected peptide is extremely labile to hydrolysis. A computational study explains the root cause of the increased lability of macrocyclic peptide over linear peptide to hydrolysis. A process solution involving the use of labile protecting groups is discussed. Overall, the article highlights the advancements achieved to enable scalable synthesis of an unusually labile macrocyclic peptide by solid-phase peptide synthesis. The sustainability metric indicates the final preparative chromatography drives a significant fraction of a high process mass intensity (PMI)

Process Development of a Macrocyclic Peptide Inhibitor of PD-L1

This article outlines the process development leading to the manufacture of 800 g of BMS-986189, a macrocyclic peptide active pharmaceutical ingredient. Multiple N-methylated unnatural amino acids posed challenges to manufacturing due to the lability of the peptide to cleavage during global side chain deprotection and precipitation steps. These issues were exacerbated upon scale-up, resulting in severe yield loss and necessitating careful impurity identification, understanding the root cause of impurity formation, and process optimization to deliver a scalable synthesis. A systematic study of macrocyclization with its dependence on concentration and pH is presented. In addition, a side chain protected peptide synthesis is discussed where the macrocyclic protected peptide is extremely labile to hydrolysis. A computational study explains the root cause of the increased lability of macrocyclic peptide over linear peptide to hydrolysis. A process solution involving the use of labile protecting groups is discussed. Overall, the article highlights the advancements achieved to enable scalable synthesis of an unusually labile macrocyclic peptide by solid-phase peptide synthesis. The sustainability metric indicates the final preparative chromatography drives a significant fraction of a high process mass intensity (PMI)

Challenges with the Synthesis of a Macrocyclic Thioether Peptide: From Milligram to Multigram Using Solid Phase Peptide Synthesis (SPPS)

We describe an optimization and scale-up of the 45-membered macrocyclic thioether peptide BMS-986189 utilizing solid-phase peptide synthesis (SPPS). Improvements to linear peptide isolation, macrocyclization, and peptide purification were demonstrated to increase the throughput and purification of material on scale and enabled the synthesis and purification of >60 g of target peptide. Taken together, not only these improvements resulted in a 28-fold yield increase from the original SPPS approach, but also the generality of this newly developed SPPS purification sequence has found application in the synthesis and purification of other macrocyclic thioether peptides