Periodic Reporting for period 1 - NOVOFLAT (Escaping from Flatland by “de novo” Catalytic Decarboxylation Techniques)
Periodo di rendicontazione: 2020-11-01 al 2022-04-30
NOVOFLAT aims at designing a de novo technology for forging sp3 architectures via novel C-C bond-functionalization events. In order to do so, NOVOFLAT offers a pioneering approach for forging sp3-sp3 linkages via dual catalysis that combines the flexibility of synthetic design exerted by Ni catalysis and the generation of open-shell intermediates via photoexcitation under light irradiation. In this manner, the technology offers an unprecedented look at rapidly accessing sp3-sp3 linkages with different steric and electronic requirements, providing an invaluable opportunity to streamline the discovery of new architectures with applications acsoss the molecular sciences. Unlike other technologies aimed at forging sp3 architectures, NOVOFLAT will make use of native functionality present in a myriad of different organic molecules without recourse to utilize prefunctionalized building blocks that need to be prepared prior to their use for forging sp3 architectures. In this way, NOVOFLAT will not only provide new dogmas in retrosynthetic analysis by fundamentally altering the way sp3-sp3 bonds are made, but also offer new opportunities to access scaffolds that are beyond reach using classical approaches within the field of cross-coupling reactions.
The main objectives to be accomplished during the execution of NOVOFLAT are the following:
(1) Assembling sp3-sp3 architectures via C-C bond-functionalization of carbonyl compounds.
(2) Enantioselective sp3-sp3 bond-formation at remote sp3 sites.
(3) Forging sp3-sp3 bonds are remote sp3 sites with stereochemistry control.
(4) Ring-contractions of lactones.
(5) Late-stage diversification via C-C bond-functionalization en route to sp3-sp3 linkages.
The main objectives to be accomplished during the execution of NOVOFLAT are the following:
(1) Assembling sp3-sp3 architectures via C-C bond-functionalization of carbonyl compounds.
(2) Enantioselective sp3-sp3 bond-formation at remote sp3 sites.
(3) Forging sp3-sp3 bonds are remote sp3 sites with stereochemistry control.
(4) Ring-contractions of lactones.
(5) Late-stage diversification via C-C bond-functionalization en route to sp3-sp3 linkages.
Given the challenges posed by NOVOFLAT, we decided to focus on understanding the factors that contribute to C-C functionalization followed by sp3-sp3 bond-formation. To this end, we have found recently the following:
(1) We have reported a catalytic dual Ni/photoredox technology that demonstrates the ability of simple carbonyl compounds to promote a C-C bond-functionalization followed by sp3 coupling via the intermediacy of precursors amenable to photoexcitation. This technique demonstrates the ability of our approach by using simple carbonyl groups as latent nucleophiles for sp3-sp3 bond-forming reactions (Nature communications 2022, 13, 2394)
(2) Taking into consideration the above considerations, we have recently took these conceptions one step-further for enabling sp3-sp3 bond-forming reactions within the context of trifluoromethylation events via C-C bond-functionalization by combining the virtues of photoredox catalysis to generate open-shell species and the flexibility exerted by simple and readily available Cu catalysts to incorporate the trifluoromethyl group into sp3 backbones (J. Am. Chem. Soc. 2022, in revision). In addition to this, we have demonstrated that photoredox catalysis is a perfect vehicle to incorporate difluorinated backbones into sp3 architectures, constituting an opportunity to rapidly and reliably build up molecular backbones of interest in medicinal chemistry programs (Org. Lett. 2022, accepted).
(3) Very recently, we have demonstrated the main idea delineated in NOVOFLAT by taking ester derivatives from proline and being able to extrude carbon dioxide while forming a new sp3-sp3 bond. Interestingly, this technique can be promoted by either Ni/photoredox dual catalysis or by simple sulfinate salts under light irradiation. We are currently exploring the scope of the transformation and the results will be reported in due course. In addition, we have shown the viability of enabling C-C bond-functionalization on simple aminoacid derivatives (Synlett 2022, 33, 52).
(4) Following up our interest on the development of C-C bond-functionalization events by virtue of dual catalysis, we have recently taken the conceptions delineated in (1) and show the possibilities that this might have to build up other sp3 architectures. Specifically, we have shown the possibility of promoting a sp3 amination event by means of C-C bond-functionalization of carbonyl derivatives, offering a complementary reactivity mode to classical sp3 C-N bond-forming reactions that require the utilization of prefunctionalized organic halides or harsh reaction conditions (manuscript in preparation).
(5) The virtues of Ni catalysis and photoredox endeavors have been explored a bit further in our group for building up sp3-sp3 architectures. In particular we have found the possibility to promote b-fragmentation beyond the realm of C-C functionalization (reported by our group recently: J. Am. Chem. Soc. 2020, 142, 20594), but allowing the establishing of a technique capable of promoting unconventional sp3 C-O bond-cleavage as well, certainly an enormous step-forward for building up sp3 architectures from simple building blocks (J. Am. Chem. Soc. 2022, 144, DOI:10.1021/jacs.2c04513).
(1) We have reported a catalytic dual Ni/photoredox technology that demonstrates the ability of simple carbonyl compounds to promote a C-C bond-functionalization followed by sp3 coupling via the intermediacy of precursors amenable to photoexcitation. This technique demonstrates the ability of our approach by using simple carbonyl groups as latent nucleophiles for sp3-sp3 bond-forming reactions (Nature communications 2022, 13, 2394)
(2) Taking into consideration the above considerations, we have recently took these conceptions one step-further for enabling sp3-sp3 bond-forming reactions within the context of trifluoromethylation events via C-C bond-functionalization by combining the virtues of photoredox catalysis to generate open-shell species and the flexibility exerted by simple and readily available Cu catalysts to incorporate the trifluoromethyl group into sp3 backbones (J. Am. Chem. Soc. 2022, in revision). In addition to this, we have demonstrated that photoredox catalysis is a perfect vehicle to incorporate difluorinated backbones into sp3 architectures, constituting an opportunity to rapidly and reliably build up molecular backbones of interest in medicinal chemistry programs (Org. Lett. 2022, accepted).
(3) Very recently, we have demonstrated the main idea delineated in NOVOFLAT by taking ester derivatives from proline and being able to extrude carbon dioxide while forming a new sp3-sp3 bond. Interestingly, this technique can be promoted by either Ni/photoredox dual catalysis or by simple sulfinate salts under light irradiation. We are currently exploring the scope of the transformation and the results will be reported in due course. In addition, we have shown the viability of enabling C-C bond-functionalization on simple aminoacid derivatives (Synlett 2022, 33, 52).
(4) Following up our interest on the development of C-C bond-functionalization events by virtue of dual catalysis, we have recently taken the conceptions delineated in (1) and show the possibilities that this might have to build up other sp3 architectures. Specifically, we have shown the possibility of promoting a sp3 amination event by means of C-C bond-functionalization of carbonyl derivatives, offering a complementary reactivity mode to classical sp3 C-N bond-forming reactions that require the utilization of prefunctionalized organic halides or harsh reaction conditions (manuscript in preparation).
(5) The virtues of Ni catalysis and photoredox endeavors have been explored a bit further in our group for building up sp3-sp3 architectures. In particular we have found the possibility to promote b-fragmentation beyond the realm of C-C functionalization (reported by our group recently: J. Am. Chem. Soc. 2020, 142, 20594), but allowing the establishing of a technique capable of promoting unconventional sp3 C-O bond-cleavage as well, certainly an enormous step-forward for building up sp3 architectures from simple building blocks (J. Am. Chem. Soc. 2022, 144, DOI:10.1021/jacs.2c04513).
During the next months we will consolidate our position for building up sp3-sp3 architectures via catalytic C-C functionalization enabled by dual or triple cascade processes. In particular, we aim at exploring the preparative scope of our decarboxylative sp3-sp3 bond-forming reaction and publish these results as soon as possible.
In order to tackle the challenge of combining C-C bond-functionalization with chain-walking reactions for studying the possibility of promoting bond-formation at remote sp3 sites in a stereoselective manner, we have recently shown the ability to discriminate at will the possibility for promoting C-C bond-formation at a saturated hydrocarbon side-chain by harnessing the propensity of carbonyl groups to direct functionalization at different sp3 sites (manuscript in preparation). These results will certainly set the basis for studying the possibility of enabling enantioselective transformations within the context of both C-C functionalization as well as sp3-sp3 bond-forming events.
Special attention will be devoted to study the intramolecular sp3-sp3 bond-forming reaction of lactones, as this technology will lead to a de novo technique for ring-contraction events. We have gathered preliminary results that show the viability of this approach (<30% yield), and we aim at utilizing high-throughput experimentation to speed up the optimization of these processes.
In order to tackle the challenge of combining C-C bond-functionalization with chain-walking reactions for studying the possibility of promoting bond-formation at remote sp3 sites in a stereoselective manner, we have recently shown the ability to discriminate at will the possibility for promoting C-C bond-formation at a saturated hydrocarbon side-chain by harnessing the propensity of carbonyl groups to direct functionalization at different sp3 sites (manuscript in preparation). These results will certainly set the basis for studying the possibility of enabling enantioselective transformations within the context of both C-C functionalization as well as sp3-sp3 bond-forming events.
Special attention will be devoted to study the intramolecular sp3-sp3 bond-forming reaction of lactones, as this technology will lead to a de novo technique for ring-contraction events. We have gathered preliminary results that show the viability of this approach (<30% yield), and we aim at utilizing high-throughput experimentation to speed up the optimization of these processes.