Practical Synthesis of 6-Amino-1-hydroxy-2,1-benzoxaborolane: A Key Intermediate of DNDI-6148.

Visceral leishmaniasis (VL), a parasitic, poverty-linked, neglected disease, is endemic across multiple regions of the world and fatal if untreated. There is an urgent need for a better and more affordable treatment for VL. DNDI-6148 is a promising drug candidate being evaluated for the treatment of VL; however, the current process for producing the key intermediate of DNDI-6148, 6-amino-1-hydroxy-2,1-benzoxaborolane, is expensive and difficult to scale up. Herein, we describe two practical approaches to synthesizing 6-amino-1-hydroxy-2,1-benzoxaborolane from inexpensive and readily available raw materials. Starting with 4-tolunitrile, the first approach is a five-step sequence involving a Hofmann rearrangement, resulting in an overall yield of 40%. The second approach utilizes 2-methyl-5-nitroaniline as the starting material and features borylation of aniline and continuous flow hydrogenation as the key steps, with an overall yield of 46%. Both routes bypass the nitration of 1-hydroxy-2,1-benzoxaborolane, which is challenging and expensive to scale. In particular, the second approach is more practical and scalable because of the mild operating conditions and facile isolation process.

Highly Regioselective Protecting-Group-Free Synthesis of the Antimalarial Drug MMV693183.

MMV693183 is a promising antimalarial drug candidate that works for uncomplicated malaria treatment and resistance management. Herein, we report an efficient and highly regioselective synthesis of MMV693183. This novel synthetic method highlights a three-step route with an overall yield of 46% from readily available starting materials. The key to the success lies in (1) utilizing the subtle difference of the two amino groups in the starting material (S)-propane-1,2-diamine dihydrochloride without amino protection and (2) identifying the L-(+)-tartaric acid as the counter acid for the organic salt formation, yielding the desired regioisomer up to 100:0. The efficient and scalable three-step protocol operates under mild conditions with a high chemo/regioselectivity, providing effective access to MMV693183.

Application of Chiral Transfer Reagents to Improve Stereoselectivity and Yields in the Synthesis of the Antituberculosis Drug Bedaquiline.

Bedaquiline (BDQ) is an important drug for treating multidrug-resistant tuberculosis (MDR-TB), a worldwide disease that causes more than 1.6 million deaths yearly. The current synthetic strategy adopted by the manufacturers to assemble this molecule relies on a nucleophilic addition reaction of a quinoline fragment to a ketone, but it suffers from low conversion and no stereoselectivity, which subsequently increases the cost of manufacturing BDQ. The Medicines for All Institute (M4ALL) has developed a new reaction methodology to this process that not only allows high conversion of starting materials but also results in good diastereo- and enantioselectivity toward the desired BDQ stereoisomer. A variety of chiral lithium amides derived from amino acids were studied, and it was found that lithium (R)-2-(methoxymethyl)pyrrolidide, obtained from d-proline, results in high assay yield of the desired syn-diastereomer pair (82%) and with considerable stereocontrol (d.r. = 13.6:1, e.r. = 3.6:1, 56% ee), providing BDQ in up to a 64% assay yield before purification steps toward the final API. This represents a considerable improvement in the BDQ yield compared to previously reported conditions and could be critical to further lowering the cost of this life-saving drug.

Diastereoselective addition of monoorganocuprates to a chiral fumarate: reaction development and synthesis of (-)-dihydroprotolichesterinic acid.

Recent studies of diastereoselective conjugate additions of monoorganocuprates, Li[RCuI], to chiral γ-alkoxycrotonates and fumarates are disclosed. This methodology was applied to the shortest total synthesis of (-)-dihydroprotolichesterinic acid to date, but several attempts to prepare other succinate-derived natural products, such as pilocarpine and antrodin E, were unsuccessful.

A survey of enoldiazo nucleophilicity in selective C-C bond forming reactions for the synthesis of natural product-like frameworks.

A survey of in situ, catalytically generated carbocations for coupling with enoldiazoacetate nucleophiles was performed. These couplings facilitate the rapid assembly of complex organodiazo compounds that provide a template for the synthesis of a variety of carbocyclic and heterocyclic ring systems.

Asymmetric Formal Total Synthesis of the Stemofoline Alkaloids: The Evolution, Development and Application of a Catalytic Dipolar Cycloaddition Cascade.

A formal synthesis of didehydrostemofoline and isodidehydrostemofoline has been accomplished by preparing an intermediate in the Overman synthesis of these alkaloids from commercially available 2-deoxy-D-ribose. The work presented in this account chronicles the evolution of our explorations to identify the optimal steric and electronic control elements necessary to generate the tricyclic core structure of these alkaloids in a single operation from an acyclic precursor. The key step in the synthesis is a novel dipolar cycloaddition cascade sequence that is initiated by cyclization of a rhodium-derived carbene onto the nitrogen atom of a proximal imine group to generate an azomethine ylide that then undergoes spontaneous cyclization via dipolar cycloaddition. The synthesis features several other interesting reactions, including a Boord elimination to prepare a chiral allylic alcohol, a highly diastereoselective Hirama-Itô cyclization, and a useful modification of the Barton decarboxylation protocol.

Diazoacetoacetate enones for the synthesis of diverse natural product-like scaffolds.

Diazoacetoacetate enones are a new class of Michael acceptors that enable the efficient construction of natural product-like scaffolds. Through their Michael addition reactions, including those with silyl enol ethers, indoles, pyrroles, and amines, δ-functionalized diazoacetoacetates are formed in high yield and with overall operational efficiency. Subsequent catalytic dinitrogen extrusion reactions provide access to a diverse series of natural product-like carbo- and heterocyclic ring systems in only three steps from commercial materials.

Total synthesis of (-)-dihydroprotolichesterenic acid via diastereoselective conjugate addition to chiral fumarates.

A diastereoselective conjugate addition of a variety of monoorganocuprates, Li[RCuI], to chiral fumarates to provide funtionalized succinates has been developed. The utility of this reaction is demonstrated in a concise total synthesis of (-)-dihydroprotolichesterenic acid that required only four steps and proceeded in an overall 31% yield.

Enantioselective formal total syntheses of didehydrostemofoline and isodidehydrostemofoline through a catalytic dipolar cycloaddition cascade.

Sweet to the core: Enantioselective formal total syntheses of the title compounds were accomplished in 24 steps from 2-deoxy-D-ribose. The synthesis features a novel cascade of reactions culminating in an intramolecular dipolar cycloaddition to form the tricyclic core of the stemofoline alkaloids from an acyclic diazo imine intermediate.

Divergent stereocontrol of acid catalyzed intramolecular aldol reactions of 2,3,7-triketoesters: synthesis of highly functionalized cyclopentanones.

The intramolecular acid catalyzed aldol cyclization of 2,3,7-triketoesters formed from ζ-keto-α-diazo-ß-ketoesters provides highly functionalized cyclopentanones with good diastereoselectivity in high overall yields via kinetically controlled and stereodivergent catalytic processes. Lewis acid catalysis gives high selectivity for the 1,2-anti tetrasubstituted cyclopentanones, whereas Brønsted acid catalysis produces the corresponding 1,2-syn diastereomer.

Toward a total synthesis of the stemofoline alkaloids: Advancement of a 1,3-dipolar cycloaddition strategy.

Novel, intramolecular 1,3-dipolar cycloadditions of azomethine ylides have been applied to the synthesis of functionalized core structures of the stemofoline alkaloids. In an effort to maximize the efficiency of this key transformation in the context of an eventual total synthesis of these complex natural products, a number of strategic modifications to the cycloaddition substrate were investigated. These collective efforts have provided useful insights into the operative, regiochemical control elements for 1,3-dipolar cycloadditions leading to stemofoline alkaloids. A potential intermediate in the synthesis of these alkaloids was prepared.

Convergent synthesis of geometrically disassembling dendrimers using Cu(I)-catalyzed C-O bond formation.

The convergent synthesis of geometrically degradable dendrimers based on the 2,4-bis(hydroxymethyl)phenol subunit is presented. The key step of the synthetic scheme involves the CuI/3,4,7,8-tetramethyl-1,10-phenanthroline-catalyzed coupling of aryl iodides and alcohols. The synthesis and disassembly of these compounds is discussed.

Improved iterative synthesis of linearly disassembling dendrons.

We report a significant improvement in the synthesis of disassembling dendritic structures by using 4-hydroxy-3-nitrobenzoic acid as the building block. We have prepared multigram quantities of first- through third-generation linearly disassembling dendrons containing a [3-N,4-O]-benzylaryl ether disassembly pathway, capped by a vanillin-derived phenyl allyl ether trigger, and a p-nitrophenoxy (PNP) reporter group. The disassembly process of these materials was initiated by allyl deprotection and monitored by the absorbance of the PNP reporter unit in the UV-vis. Modification of the disassembly conditions for the allyl trigger resulted in decreased disassembly times, decreased incubation time for onset of disassembly from minutes to seconds, and allowed observation of indicative rate differences between generations not seen with the previously reported conditions.

The Pauson-Khand Reaction as a New Entry to the Synthesis of Bridged Bicyclic Heterocycles: Application to the Enantioselective Total Synthesis of (-)-Alstonerine.

The first application of the Pauson-Khand reaction (PKR) to the synthesis of azabridged bicyclic structures is described. Compounds containing azabicyclo[3.3.1]nonane and azabicyclo[3.2.1]octane rings fused to cyclopentenones were efficiently constructed via the PKR of cis-2,6-disubstituted N-acyl piperidine enyne substrates, many of which can be readily prepared from 4-methoxypyridine in a few steps. Moreover, the PKR of cis-2,6-disubstituted piperazine enynes allowed the preparation of diazabicyclo[3.3.1]nonanes fused to cyclopentenones. This new strategy for the synthesis of azabridged bicyclic frameworks was exploited as a key step in a concise, enantioselective total synthesis of the macroline alklaoid (-)-alstonerine.

Synthesis and characterization of BHT-derived tert-butyl dendrons.

A series of 3,5-poly(aryl ether) dendrons was prepared up to the third generation using inexpensive 3,5-di-tert-butyl-4-hydroxytoluene (BHT, 1) as a starting material.