Evaluation of in-batch and in-flow synthetic strategies towards the stereoselective synthesis of a fluorinated analogue of retro-thiorphan
M. Pirola, A. Puglisi, L. Raimondi, A. Forni, M. Benaglia Molecules, 2019, 24 2260-2269 [Link]
. Abstract: A stereoselective synthetic strategy for the preparation of trifluoromethylamine mimics of retro-thiorphan, involving a diastereoselective, metal-free catalytic step, has been studied in batch and afforded the target molecule in good yields and high diastereoselectivity. A crucial point of the synthetic sequence was the catalytic reduction of a fluorinated enamine with trichlorosilane as reducing agent in the presence of a chiral Lewis base. The absolute configuration of the key intermediate was unambiguously assigned by X-ray analysis. The synthesis was also investigated exploiting continuous flow reactions; that is, an advanced intermediate of the target molecule was synthesized in only two in-flow synthetic modules, avoiding isolation and purifications of intermediates, leading to the isolation of the target chiral fluorinated amine in up to an 87:13 diastereoisomeric ratio.
A continuous flow, two-steps, metal-free process for the synthesis of differently substituted chiral 1,2-diamino derivatives
M. Pirola, M. Benaglia, M. E. Compostella, L. Raimondi, A. Puglisi Synthesis, 2018, 50, 1430-1438 [Link]
. Abstract: The enantioselective organocatalytic reduction of aryl-substituted nitroenamines was successfully performed under continuous-flow conditions. After a preliminary screening with a 10 ul microreactor, to establish the best reaction conditions, the reduction was scaled-up in a 0.5 ml mesoreactor, without appreciable loss of enantioselectivity, that remained constantly higher than 90%. The in-flow nitro reduction was also accomplished, either by Raney-Ni catalyzed hydrogenation, and by a metal-free methodology based on the use of the. very inexpensive and readily available reducing agent trichlorosilane. The final aim is to develop a two-step, continuous-flow process for the stereoselective, metal-free, catalytic synthesis of differently functionalized chiral 1,2-diamines
Organocatalytic α-trifluoromethylthiolation of silylenol ethers: batch vs continuous flow reactions
S. S. Abubakar, M. Benaglia, S. Rossi, R. Annunziata Cat. Today, 2017, accepted, doi:10.1016/j.cattod.2017.09.013 [Link]
Abstract: This work describes the organocatalytic a-trifluoromethylthiolation of silylenol ethers using N-(trifluoromethylthio)saccharin as trifluoromethylthiolating reagent that is activated by the presence of catalytic amounts of a Lewis base. Tetrahydrothiophene was identified as the best organocatalyst and it was successfully employed to promote the synthesis of different α-trifluoromethylketones; the reaction has been performed under a traditional batch methodology and under continuous flow conditions. In general, yields obtained using the traditional batch process were higher than those observed when the reaction was performed under flow conditions. However, short reaction times, higher productivity and higher space time yields were observed when a flow system process was employed. Preliminary DFT calculations were also performed in order to elucidate the mechanism of the reaction.
Solid supported chiral N-picolylimidazolidinones: recyclable catalysts for the enantioselective, metal- and H2-free reduction of imines in batch and in flow mode
R. Porta, M. Benaglia, R. Annunziata, A. Puglisi, G. Celentano Adv. Synth. Catal, 2017, 359, doi:10.1002/adsc.201700376 [Link]
Abstract: A new class of solid supported chiral imidazolidinones organocatalysts for the catalytic reduction of imines with trichlorosilane was developed. Polystyrene proved to be a more effective support than silica in terms of both chemical and stereochemical efficiency. Even with a loading as low as 1 mol % the best performing supported catalyst showed a remarkable activity and stereocontrol ability, promoting the reduction with stereoselectivities reaching 98% e.e. and in most cases ranging between 90-95% e.e. The general scope of the methodology and the good recyclability of the immobilized catalyst were demonstrated. The polystyrene-anchored chiral catalyst was also used to prepare packed bed reactors for the continuous flow synthesis of chiral amines, that were obtained in excellent yields and enantioselectivities. By exploiting the chiral organocatalytic reactor, the in-flow stereoselective synthesis of a common, immediate precursor of rivastigmine, of the calciomimetic (R)-NPS 568 and of Acrylamide (S)-A, currently under study for the treatment of neuropathic pain, was successfully accomplished.
Flow chemistry: recent developments in the synthesis of pharmaceutical products.
R. Porta, M. Benaglia, A. Puglisi Org. Process Res. Dev. , 2016, 20, 2-25 accepted
Abstract: In this review we focused our attention only on very recent advances in the continuous flow multistep synthesis of organic molecules which found application as APIs, especially highlighting the contributions described in the literature from 2013 to 2015, including very recent examples not reported in any published review. Without claiming to be complete, we will give a general overview of different approaches, technologies and synthetic strategies used so far, thus hoping to contribute to minimize the gap between academic research and pharmaceutical manufacturing. A general outlook about a quite young and relatively unexplored field of research, like stereoselective organocatalysis under flow conditions will be also presented, and most significant examples will be described; our purpose is to illustrate all the potentialities of continuous flow organocatalysis and offer a starting point to develop new methodologies for the synthesis of chiral drugs. Finally, some considerations on the perspectives and the possible, expected developments in the field are briefly discussed.
Solid supported 9-amino-9-deoxy-epi-quinine as efficient organocatalysts for stereoselective reactions in batch and under continuous flow conditions.
R. Porta, M. Benaglia, F. Coccia, F. Cozzi, A. Puglisi Adv. Synth. Catal , 2015, 357, 377-383 [Link]
Abstract: Polystyrene supported 9-amino-9-deoxy-epi-quinine was synthesized through co-polymerization of an ad hoc-designed chiral monomer with divinylbenzene, in the presence of AIBN as radical initiator and toluene and 1-dodecanol as porogenic solvents. The heterogenized catalyst efficiently promoted the reaction of i-butyric aldehyde with β-nitrostyrene, in very high yield and enantioselectivity, comparable or even higher than that of the homogeneous counterpart (up to 95% ee). The recyclability of the catalyst, its general applicability and its successful application to other reactions was also demonstrated. Finally, for the first time, a 9-amino-epi-quinine derivative was employed to perform an enantioselective Michael reaction under continuous-flow conditions; by using a home-made, packed-bed catalytic reactor, the aldehyde.
A catalytic reactor for organocatalyzed enantioselective continuous flow alkylation of aldehydes
R. Porta, M. Benaglia, A. Puglisi, A. Mandoli, A. Gualandi, P.G. Cozzi ChemSusChem , 2014, 7, 3534-3540. [Link]
Abstract: The use of immobilized metal-free catalysts offers the unique possibility to develop sustainable processes in flow mode. A challenging transformation like the intermolecular organocatalyzed aldehyde enantioselective alkylation was performed for the first time under continuous flow conditions. By using a packed-bed catalytic reactor filled with readily available and relatively inexpensive solid-supported enantiomerically pure imidazolidinone, different aldehydes were reacted with three distinct cationic electrophiles. In the organocatalyzed α-alkylation of aldehydes with 1,3-benzodithiolylium tetrafluoroborate excellent enantioselectivities, in some cases even better than in the flask process (up to 95% e.e. at 25 °C) and high productivity (more than 3800 h-1) were obtained, thus showing that the catalytic reactor may efficiently work and continuously produce enantiomerically enriched compounds. The treatment of the alkylated products with Raney Nickel allows to obtain enantiomerically enriched α-methyl derivatives, key intermediates for the production of APIs and natural products.
A chiral organocatalytic polymer-based monolithic reactor
V. Chiroli, M. Benaglia, A. Puglisi, R. Porta, R. P. Jumde, A. Mandoli Green Chem, 2014, 16, 2798-2806. [Link]
Abstract: Radical copolymerisation of divinylbenzene and a properly modified enantiomerically pure imidazolidinone inside a stainless steel column in the presence of dodecanol and toluene as porogens afforded the first example of a chiral organocatalyst immobilized onto a monolithic reactor. Organocatalyzed cycloadditions between cyclopentadiene and cinnamic aldehyde were performed under continuous-flow conditions; by optimizing the experimental set up, excellent enantioselectivities (90% ee at 25 у) and high productivities (higher than 330) were obtained, thus showing that a catalytic reactor may work efficiently to continuously produce enantiomerically enriched compounds. The same catalytic reactor was also employed to carry out three different stereoselective transformations in continuo, sequentially, inside the chiral column (Diels-Alder, 1,3-dipolar nitrone-olefin cycloaddition, and Friedel-Crafts alkylation); excellent results were obtained in the case of the former two reactions (up to 99% yield, 93% ee and 71% yield, 90% ee, at 25у, respectively). In addition to simplify the product recovery, the monolithic reactor performed better than the same supported organocatalyst in a stirred flask and could be kept working continuously for more than 8 days.
Stereoselective Diels-Alder reactions promoted under continuous-flow conditions by silica supported chiral organocatalysts
R. Porta, M. Benaglia, V. Chiroli, F. Coccia, A. Puglisi Isr. J. Chem., 2014, 54, 381-394. [Link]
Abstract: Silica nanoparticles of different morphological properties were functionalized with enantiomerically pure imidazolidinones, through different immobilization techniques; stainless steel columns were then loaded with silica bearing the chiral organocatalysts, to realize chiral “homemade” reactors. The influence of the material properties and of the immobilization procedures on the chemical and stereochemical activities of the chiral HPLC columns was studied, by performing organocatalyzed Diels-Alder reactions under continuous-flow conditions between cyclopentadiene and α,β-unsaturated aldehydes. In some cases, excellent enantioselectivities were obtained, thus showing that a catalytic reactor may work efficiently to continuously produce enantiomerically enriched cycloadducts for more than 200 hours. The regeneration of the organocatalytic column was also partially accomplished, although associated with a slightly lower enantioselectivity, thus prolonging the “life” of the reactor to more than 300 hours.
Continuous-Flow Stereoselective Organocatalyzed Diels-Alder Reactions in a Chiral Catalytic "Homemade" HPLC Column
V. Chiroli, M. Benaglia, F. Cozzi, A. Puglisi, R. Annunziata, G. Celentano Org. lett., 2013, 15,3590-3593. [Link]
Abstract: Continuous-flow organocatalyzed Diels-Alder reactions have been performed with excellent enantioselectivity for the first time in a chiral “homemade” HPLC column, packed with silica on which a MacMillan catalyst has been supported by a straightforward immobilization procedure. The versatility of the system was also proven by running with the same column continuous-flow stereoselective reactions with three different substrates, showing that the catalytic reactor may efficiently work in continuo for more than 150 h; the regeneration of the HPLC column was also demonstrated, allowing to further extend the activity of the reactor to more than 300 operating hours.
Stereoselective organic reactions promoted by immobilized chiral catalysts in continuous flow systems
A. Puglisi, M. Benaglia, V. Chiroli Green Chemistry, 2013, 15, 1970-1813. [Link]
Abstract: The immobilization of the catalyst on a support with the aim of facilitating the separation of the product from the catalyst, and thus the recovery and recycling of the latter, can be regarded as an important improvement for a catalytic process. However, a system where a catalyst must not be removed from the reaction vessel is even more attractive: in continuous flow methods the immobilized catalyst permanently resides in the reactor where it transforms the entering starting materials into the desired products. The retention of the catalytic species inside the reaction vessel can be achieved by different techniques ranging from ultrafiltration through a MW-selective membrane to immobilization on different supports. In this review we will discuss the most significant examples of stereoselective reactions promoted by immobilized chiral catalysts and performed under continuous flow conditions, with particular attention to the more recent contributions of the last few years.