Thiwanka Bandara Samarakoon

Scaling out by microwave-assisted, continuous flow organic synthesis (MACOS): multi-gram synthesis of bromo- and fluoro-benzofused sultams benzthiaoxazepine-1,1-dioxides.

Sultams (cyclic sulfonamides) are an important class of molecules that exhibit widespread biological activity against a variety of biological targets.[1] In particular, the benzoxaze-pine-1,1-dioxide motif has exhibited activity towards a variety of targets including: histone deacetylase inhibition (for treatment of cognitive disorders such as Alzheimer’s disease),[2] glucokinase activation,[3] serotonin 5-HT2C activation,[4] modulation of the histamine H3 receptor,[5] inhibition of MDM2-p53,[6] inhibition of sodium–proton exchange, bradykinin B1 receptor antagonism (for treating Alzheimer’s disease),[7] AMPA receptor agonism,[8] and inhibition of metalloproteinase.[9] As a consequence, there is interest in the development of general strategies for the synthesis of organized collections (libraries) of these compounds to serve as probes for biological pathways and as potential therapeutic agents. Diversity-oriented synthesis (DOS)[10,11] has emerged as an effective strategy to synthesize structurally varied compound collections. The development of strategies that allow the production of versatile core scaffolds in a highly efficient manner is crucial for DOS-based strategies. The advent of rational DOS whereby ‘privileged structures’ are utilized as core scaffolds in DOS approaches has presented opportunities in this regard.[12] The desire to utilize benzofused sultam cores for DOS approaches has prompted the investigation of strategies that would allow facile access to these scaffolds. In this regard α-fluorobenzenesulfonyl chlorides represent a versatile building block synthon. The electron-withdrawing SO2 moiety imparts enhanced electrophilicity at the β-carbon atom, and α-fluorobenzenesulfonyl chlorides may therefore be viewed as bis-electrophiles. Pairing of these bis-electrophilic synthons with amino alcohols (bis-nucleophiles) in a complementary fashion would allow access to benzofused sultams bearing a secondary sulfonamide in a highly efficient manner. The reaction potential of this versatile functionality can be harnessed for functionalization, while placement of halides on the aromatic ring allows either SNAr or metal-catalyzed cross-coupling pathways of diversification; stereochemical and skeletal diversity can be achieved by utilizing a variety of chiral amino alcohols (Figure 1). Additionally, the ability to functionalize around the periphery of the molecule along with access to stereo-chemical diversity allows maximal interactions with macromolecules within biological systems. Figure 1 Pairing strategy to benzofused sultams. The use of an intramolecular SNAr O-arylation route to benzothiazepine-1,1-dioxides containing a secondary sulfonamide was explored. Investigations commenced with the nucleophilic substitution of the sulfonyl chloride (first Click reaction) by a variety of 1,2-amino alcohols by employing modified Schotten–Bauman conditions. Accordingly, addition of α-fluorobenzenesulfonyl chloride to a vigorously stirring CH2Cl2/H2O biphasic system of 1,2-amino alcohols in the presence of NaHCO3 furnished the β-hydroxy α-fluorobenzene sulfonamides in excellent yields. These products were thereafter subjected to microwave irradiation at 140°C for 30 min in DMF in the presence of Cs2CO3 to produce a variety of chiral benzothiaoxazepine-1,1-dioxides in excellent yields (Table 1). Table 1 Click–cyclize protocol to diverse benzothiaoxazepine-1,1-dioxides. With a successful two-step protocol in hand, we next turned our attention to the quantity of final core structure that could be produced. As the building blocks still have to undergo two further diversification steps, it would be necessary to produce these scaffolds on (at least) a 5-gram scale to allow larger library synthesis. The cyclization step worked best (cleanest and highest yielding) when performed under microwave heating while keeping the concentration of 3 at 0.1M. Given the vessel size limitation imposed by the Biotage Initiator Microwave Synthesizer, and the relatively dilute reaction conditions, the only way to obtain the desired quantity of 4 would be to run the reaction repeatedly on small scale in batches and pool the product. Not only is this undesirable, but it dramatically increases the handling and consumables required (e.g., high-pressure reaction tubes) and occupies the microwave synthesizer for prolonged periods (days) of time just to obtain one single scaffold. Movement of the cyclization step (at least) to a flow platform would remove the limitations imposed by scale up. With this goal in mind, we set out to employ a microwave-assisted, continuous flow organic synthesis (MACOS) platform for the scale-up synthesis of sultam 4. Conducting chemical synthesis in a moveable (flowing) platform offers several significant advantages that make its implementation desirable from a strategic point of view.[13,14] The compartmentalization of starting materials, reagents, and/or catalysts from the site of reaction minimizes their contact with the final product, which, as a result, minimizes side reactions that reduce yield and complicate purification. This means that flowed synthesis is controllable both in terms of space and time. Keeping reactants separate, providing that they are stable in their reservoir (e.g., in a syringe pump or in a larger tank) for extended periods of time, means that the same level of conversion is sustainable, in principle, indefinitely. This means that only a single drop of product mixture is necessary to ascertain how a given set of reaction conditions are going to perform, dramatically reducing the time and waste associated with process optimization. Once a desired set of conditions has been realized, then all that is necessary is to simply collect the effluent from the reaction tube for as long as is necessary to accrue the desired quantity of product. This approach to raising larger amounts of product is termed ‘scaling out’, rather than the conventional ‘scaling up’ process chemistry that has historically dominated the production of fine chemicals. Of course, this is only useful if the reaction proceeds to a high level of conversion; to meet these criteria, microwave irradiation can be applied to the flowing reactant stream to help drive the reaction to completion during the time that any plug of reactant spends flowing through the reactor. We next sought to optimize the MACOS process for the multi-gram preparation of 4 keeping in mind the brief residence time in the flow tube, while addressing the heterogeneous reaction conditions in Table 1 that are not ideal for flow. To begin, we examined the cyclization of homogeneous mixtures in batches, where the reaction was heated for 60 s to simulate the approximate time that any single plug of moving reaction stream would be receiving microwave irradiation during flow (Table 2). Table 2 Optimization of base using batch microwave.[a] While amine-derived bases proved ineffective (entries 1 and 2, Table 2),[15] Cs2CO3 solubilized in DMF/water provided reasonable conversion to 4 (entry 3). Potassium silanoxide (entry 4) worked nicely and full conversion was achieved with tBuOK (entry 5); both bases were fully soluble in DMF. This proved that cyclization was a very efficient transformation and the optimized conditions using DMF and tBuOK base could be applied to flow. Under the conditions given in Table 3, the above solvent and base indeed led to excellent conversion to product using MACOS (entry 1, Table 3). However, while the crude mass was as expected and the crude NMR spectra showed the presence of what appeared to be only product, recovery of 4i was disappointing. With this knowledge, we explored a variety of other solvents (entries 2–4, Table 3) to improve recovery and DMSO provided consistently the best mass balance of product. Moving forward with these conditions, a collection of 19 sultam building blocks was obtained in 5–10 gram quantities each. Table 3 Final solvent optimization for MACOS preparation of sultam (4) sublibrary. In summary, an effective microwave-assisted flow synthesis protocol for the preparation of multi-gram quantities of benzofused sultams has been developed. The production runs to generate each sultam took approximately 2.5 h. Thus, all compounds were obtained in approximately two weeks, including the time required to optimize the flow process. The preparation of the same number and gram quantity of these compounds using a robotically fed batch microwave would have taken more time and consumables. The bulk sultams thus produced will be elaborated into approximately 1000 compounds using a combination of alkylation and substitution or cross-coupling chemistry. This work is ongoing and will be reported in due course.

A Formal [4 + 4] Complementary Ambiphile Pairing Reaction: A New Cyclization Pathway for ortho-Quinone Methides

A formal, one-pot [4 + 4] cyclization pathway for the generation of eight-membered sultams via in situ generation of an ortho-quinone methide (o-QM) is reported. The pairing of ambiphilic synthons in a complementary fashion is examined whereby o-fluorobenzenesulfonamides are merged with in situ generated o-QM in a formal [4 + 4] cyclization pathway to afford 5,2,1-dibenzooxathiazocine-2,2-dioxide scaffolds under microwave (mW) conditions. The method reported represents the first use of an o-QM in a formal hetero [4 + 4] cyclization.

Reaction Pairing: A Diversity-Oriented Synthesis Strategy for the Synthesis of Diverse Benzofused Sultams

A reaction pairing strategy centered on utilization of a reaction triad (sulfonylation, SNAr addition and Mitsunobu alkylation) generating skeletally diverse, tricyclic and bicyclic benzofused sultams is reported. Pairing sulfonylation and SNAr reactions yields bridged, tricyclic and bicyclic benzofused sultams. Application of the Mitsunobu reaction in a sulfonylation–Mitsunobu–SNAr pairing allows access to benzthiazocine-1,1-dioxides, while a simple change in the order of pairing to sulfonylation–SNAr–Mitsunobu affords structurally different, bridged tricyclic benzofused sultams.A reaction pairing strategy centered on utilization of a reaction triad (sulfonylation, S(N)Ar addition and Mitsunobu alkylation) generating skeletally diverse, tricyclic and bicyclic benzofused sultams is reported. Pairing sulfonylation and S(N)Ar reactions yields bridged, tricyclic and bicyclic benzofused sultams. Application of the Mitsunobu reaction in a sulfonylation-Mitsunobu-S(N)Ar pairing allows access to benzthiazocine-1,1-dioxides, while a simple change in the order of pairing to sulfonylation-S(N)Ar-Mitsunobu affords structurally different, bridged tricyclic benzofused sultams.

Monomer-on-Monomer (MoM) Mitsunobu Reaction: Facile Purification Utilizing Surface-Initiated Sequestration

A monomer-on-monomer (MoM) Mitsunobu reaction utilizing norbornenyl-tagged (Nb-tagged) reagents is reported, whereby purification was rapidly achieved by employing ring-opening metathesis polymerization, which was initiated by any of three methods utilizing Grubbs catalyst: (i) free catalyst in solution, (ii) surface-initiated catalyst-armed silica, or (iii) surface-initiated catalyst-armed Co/C magnetic nanoparticles.

Facile (triazolyl)methylation of MACOS-derived benzofused sultams utilizing ROMP-derived OTP reagents.

A combination of MACOS scale-out and ROMP-derived oligomeric triazole phosphates (OTP(n)) have been successfully utilized for the preparation of a 106-member library of triazole containing benzothiaoxazepine-1,1-dioxides. This report demonstrates the utilization of a suite of soluble OTP(n) reagents for facile (triazolyl)methylation of 10 MACOS-derived sultam scaffolds in purification-free process for parallel synthesis of small molecule collections for HTS.

ROMP-derived Oligomeric Phosphates for Application in Facile Benzylation

The development of new ROMP-based oligomeric benzyl phosphates (OBP(n)) is reported for use as soluble, stable benzylating reagents. These oligomeric reagents are readily synthesized from commercially available materials and conveniently polymerized and purified in a one-pot process, affording bench-stable, pure white, free-flowing solids on multigram scale. Utilization in benzylation reactions with a variety of nucleophiles is reported.

Intramolecular monomer-on-monomer (MoM) Mitsunobu cyclization for the synthesis of benzofused thiadiazepine-dioxides.

The utilization of a monomer-on-monomer (MoM) intramolecular Mitsunobu cyclization reaction employing norbornenyl-tagged (Nb-tagged) reagents is reported for the synthesis of benzofused thiadiazepine-dioxides. Facile purification was achieved via ring-opening metathesis (ROM) polymerization initiated by one of three metathesis catalyst methods: (i) free metathesis catalyst, (ii) surface-initiated catalyst-armed silica, or (iii) surface-initiated catalyst-armed Co/C magnetic nanoparticles.

Modular, One-Pot, Sequential Aziridine Ring Opening-S(N)Ar Strategy to 7-, 10-, and 11-Membered Benzo-Fused Sultams.

The generation of common and stereochemically rich medium-sized benzo-fused sultams via complementary pairing of heretofore-unknown (o-fluoroaryl)sulfonyl aziridine building blocks with an array of amino alcohols/amines in a modular one-pot, sequential protocol using an aziridine ring opening and intramolecular nucleophilic aromatic substitution is reported. The strategy employs a variety of amino alcohols/amines and proceeds with 6 + 4/6 + 5 and 6 + 1 cycloetherification pathways in a highly chemo- and regioselective fashion to obtain skeletally and structurally diverse, polycyclic, 10- to 11- and 7-membered benzo-fused sultams for broad-scale screening.

Rapid, Scalable Assembly of Stereochemically Rich, Mono- and Bicyclic Acyl Sultams

A one-pot, sequential protocol is reported that involves complementary ambiphile pairing (CAP) of a vinyl sulfonamide with a variety of unprotected amino acids via aza-Michael addition and subsequent intramolecular amidation. The method generates diverse, sp(3)-rich mono- and bicyclic acyl sultams in a highly scalable manner. Modular pairing of stereochemically rich building blocks allows quick access to all possible isomers. Extension to include one-pot, sequential 3-, 4-, and 5-multicomponent protocols is also discussed.

Synthesis of Amino-Benzothiaoxazepine-1,1-dioxides Utilizing a Microwave-Assisted, SNAr Protocol

The development of a microwave-assisted, intermolecular S(N)Ar protocol for the synthesis of a 126-member benzothiaoxazepine-1,1-dioxide library is reported. Diversification of 12 benzothiaoxazepine-1,1-dioxides was achieved in rapid fashion utilizing a variety of 2° amines and amino alcohols to generate an 80-member library. A second 48-member library was subsequently generated via a two-step alkylation, intermolecular S(N)Ar diversification protocol.