Diverse catalytic activation of smallest carbocycles towards valuable chiral and achiral organic scaffolds

Abstract

Chapter 1. Two smallest carbocycles donor-acceptor cyclopropanes and cyclobutanones and their activation by different catalysis In organic chemistry, carbocycles are the cyclic molecules where all the atoms composing the cycle are carbon atoms. They are ubiquitous in biologically active molecules, natural products, pharmaceuticals, and organic materials. The construction of intriguing carbocyclic frameworks like fused rings, spirocycles, and carbocycles containing multiple stereocenters always fascinated the synthetic community. The carbocycles can be of various ring sizes and among them, the three and four-membered carbocycles are called cyclopropanes and cyclobutanes respectively. These two carbocycles are the smallest and also among the most studied ones due to their intrinsic properties and reactivities. Over the years, these two smallest carbocycles achieved remarkable attention owing to their prevalence in a large number of bioactive molecules and natural products. Numerous catalytic and non-catalytic strategies have been developed over the past few decades for the construction of several chiral and achiral organic molecular frameworks via activation of these two carbocycles utilizing their strain-releasing reactivity. Different types of cyclopropanes and cyclobutanes are available in the literature according to their substitution pattern. Among them, vicinally substituted donor-acceptor cyclopropanes are the most explored ones. From the beginning of this 20th century, the field of donor-acceptor cyclopropanes experienced a renaissance as different catalytic activation methodologies have been developed so far to construct complex organic scaffolds. Though most of them deal with transition metal containing Lewis acid catalysis, a handful of examples could be found by environmental friendly approach like organocatalysis, whereas modern and sustainable methodologies like electro-organic and photoredox catalysis are rarely studied. Surprisingly, organocatalytic activation of racemic donor-acceptor cyclopropanes for the synthesis of chiral heterocyclic frameworks remains unexplored. On the other hand, out of different types of cyclobutanes, 3-donor cyclobutanones are widely studied via transition metal catalysis, Lewis acid catalysis, and even organocatalysis. However, no catalytic activation strategy has been still employed to coalesce the reactivities of the two smallest carbocycles, and catalytic Brønsted acid activation of 3-donor cyclobutanones is also not explored till date. Chapter 2: Asymmetric Organocatalytic Activation of Cyclopropane Carbaldehydes Towards the Construction of Enantioenriched Heterocycles Donor-acceptor cyclopropane carbaldehydes have not been previously employed to synthesize enantioenriched heterocyclic scaffolds via secondary amine organocatalysis. Here, we have demonstrated an asymmetric cycloaddition reaction of cyclopropane carbaldehydes with two different dipolar systems to construct valuable heterocyclic molecules. This chapter is divided into two parts. Chapter 2A will discuss (3+3) cycloaddition of cyclopropane carbaldehydes with aryl hydrazones to obtain chiral tetrahydropyridazine derivatives with good enantioselectivities. Whereas, chapter 2B will further expand the scope of the similar (3+3) cycloaddition with another dipolar system ortho-substituted nitrone to furnish enantioenriched oxazinanes. Chapter 2A: Organocatalytic Activation of Donor−Acceptor Cyclopropanes: A Tandem (3+3)-Cycloaddition/Aryl Migration toward the Synthesis of Enantioenriched Tetrahydropyridazines The construction of complex chemical entities from simpler building blocks is an essential and evergreen area of organic chemistry. Over the decades, various building blocks have been studied and utilized to access a large number of complex compounds using their typical reactivities. In this realm, donor−acceptor cyclopropane (DAC), a unique three-carbon building block, has been extensively employed to synthesize various important compounds in recent times. An array of cycloadditions of DACs with various dipoles, dienes, and double bonds have been reported. However, these methodologies are pre-eminently associated with metal-containing Lewis acid catalysts. In contrast, their enantioselective versions are less explored. Our laboratory has been working on the reactivity of DACs for more than a decade and developed various methodologies for the one-step synthesis of several carbo- and heterocycles. Keeping the unexplored enantioselective cycloaddition of DACs in mind, we envisioned that a chiral amine organocatalyst could asymmetrically activate cyclopropane carbaldehyde through the iminium ion pathway to render enantioselective cycloaddition. It should be noted that in the previous organocatalytic enantioselective ring-opening reactions, the cyclopropane carbaldehydes are meso in nature, and there has been no such report of organocatalytic enantioselective transformations with their racemic versions. In this chapter, we report the first asymmetric (3 + 3)-cycloaddition of racemic cyclopropane carbaldehyde with aryl hydrazones via organocatalytic activation. We commenced our optimization study with prolinol organocatalyst and obtained tetrahydropyridazine with an exocyclic double bond, where an intriguing aryl migration occurred just after the cycloaddition. After executing extensive optimization studies, we found that refluxing the reaction in carbon tetrachloride solvent in the presence of 30 mol% of prolinol gave the product in satisfactory yield with excellent enantiomeric excess. A wide variety of chiral tetrahydropyridazines were furnished by changing both the cyclopropane carbaldehydes and aryl hydrazones. From the control experiments, it was established that the enantioinduction from the racemic substrates has occurred via an unusual matched/mismatched kinetic resolution. It was also established that the ring-opening of cyclopropane followed a stereospecific SN2 pathway and the unusual 1,3-aryl migration was concerted and intramolecular in nature. Moreover, these findings were supported by computational studies which also unveiled that the aryl migration proceeds via a four-membered transition state. Chapter 2B: Organocatalytic (3+3)-cycloaddition of ortho-substituted phenyl nitrones with aryl cyclopropane carbaldehydes: A facile access towards the synthesis of enantioenriched 1,2-oxazinanes Nitrogen-containing enantioenriched heterocycles are ubiquitous structural frameworks that are present in a diverse range of biologically active molecules. Among them, chiral 1,2-oxazinanes gathered significant attention owing to their presence in several natural products which exhibit potent biological activities. Therefore, a number of methodologies flourished over the decades for their enantioselective construction by various research groups; however, most of them involve nitrones as a main precursor. Nitrones are one of the most useful and easily available starting materials for the construction of various biologically important nitrogen and oxygen-containing heterocycles. Especially its ability to undergo the 1,3-dipolar cycloaddition has achieved remarkable attention from synthetic organic chemists for the past few decades. In 2005, Sibi and coworkers reported the first enantioselective (3+3)-cycloaddition of nitrones with cyclopropane dicarboxylates in the presence of Ni(ClO4)2 and chiral ligand to obtain tetrahydro-1,2-oxazines with high enantiomeric excesses. Henceforth, several groups utilized this moiety for the asymmetric cycloaddition reaction to achieve enantioenriched heterocyclic frameworks, however, most of them are (3+2)-type cycloaddition. Evidently, organocatalytic enantioselective (3+3)-cycloaddition reactions with nitrones are still underexplored. We sought to develop an enantioselective (3+3)-cycloaddition of nitrones by utilizing organocatalysis with an appropriate three-carbon reacting partner. In line with the previous work, in this chapter, we employed cyclopropane carbaldehydes with ortho-substituted nitrones in the presence of a prolinol catalyst and obtained the (3+3) cycloadducts in good to moderate enantioselectivities. Here, we started our reaction with the same optimized reaction conditions which were established in Chapter 2A and obtained the desired product with moderate yield and enantioselectivity. Though further screening of various other catalysts, solvents, and additives was performed, none of them were fruitful in improving either the yield or the enantioselectivity further. Then, we started to explore the substrate scope variations for both cyclopropane and ortho-substituted nitrones. A range of chiral oxazinane derivatives were obtained with moderate yields and enantioselectivities. In all cases, the corresponding aryl aldehydes were also formed as a side product with a considerable amount, eventually decreasing the yield of the desired cycloadducts. Intriguingly, ortho-hydroxy substituted nitrones engendered an additional aryl migration and rendered novel tetrahydrochromeno-1,2-oxazine derivatives with moderate enantiomeric excesses. An unusual type of kinetic resolution was believed to be responsible for the enantioinduction. Chapter 3: Merging two strained carbocycles: Lewis acid catalyzed remote site-selective Friedel-Crafts alkylation of in situ generated β-naphthol Over the years, various strained carbo- and heterocycles have been studied extensively to synthesize a myriad of biologically and pharmaceutically important molecular architectures. However, methodologies exploiting a pair of different strained rings have remained underdeveloped. 3-Donor cyclobutanones are one of the important classes of four-membered carbocycles which can generate 1,4-zwitterionic intermediate in the presence of Lewis acid by regioselective cleavage of C2-C3 bond that further can undergo several transformation reactions. On the other hand, donor-acceptor cyclopropanes (DACs) have also similar strain-releasing reactivity. However, reports of merging DACs with other strained ring molecules are still scarce. In the last decade, our group and Trushkov et al. have worked on the reactivity of two different strained rings in the presence of Lewis acids and successfully obtained different heterocyclic frameworks. Encouraged by these affirmative experiences, we aim to utilize the reactivity of the two smallest carbocycles and reported the first tandem activation of donor-acceptor cyclopropane and 3-ethoxy cyclobutanone. Here, the Lewis acid-catalyzed rearrangement of cyclobutanones generated the 1-phenyl 2-naphthol in situ which further underwent a remote site-selective Friedel-Crafts alkylation via ring-opening of DAC to provide 1,6-disubstituted β-naphthol. After screening several reaction conditions, we found that performing the reaction taking 1:1 equivalent of both the starting materials in dichloromethane solvent at -15 °C in the presence of 20 mol% of SnCl4 is the optimized condition for this transformation. Then, substrate scope evaluation for the cyclopropane diester was executed to achieve a series of γ-naphthyl butyric acid derivatives with moderate to good yields. Several control experiments were conducted to get insights into the mechanism. From those, it was confirmed that the reaction was undergoing via in situ generation of 1-phenyl 2-naphthol derivative. However, diphenyl substitution on the cyclobutanone was also found to be crucial for the in-between rearrangement reaction. Finally, the site selectivity of the β-naphthol was also established for this developed protocol. At last, the gram-scale experiment and some late-stage derivatizations were performed to showcase the synthetic utility of our designed methodology. Chapter 4: Brønsted acid catalyzed cascade ring-opening/cyclization of 3-ethoxy cyclobutanones to access 2,8-dioxabicyclo[3.3.1]nonane derivatives The development of new methodologies to architect complex heterocyclic frameworks through small molecule activation has always fascinated the synthetic community. Out of numerous heterocycles embedded with two oxygen atoms, 2,8-dioxabicyclo[3.3.1]nonanes gathered significant attraction as these types of bicyclic moieties constitute several flavonoid compounds that serve as important drugs like procyanidin A1, dracoflavan C, dracoflavan D, ephedrannin B, and diinsinin which shows crucial biological activities like antiviral, anti-inflammatory, antioxidant, enzyme inhibition, and anticancer, etc. Various strategies have been engineered in the past few decades for the construction of this rigid diaryl substituted bicyclic ketals but utilization of small carbocyclic moieties has never been applied. 3-donor cyclobutanones remain distinguished among the four-membered carbocycles for their unique reactivity and explored for the ring-opening, rearrangement, and cycloaddition reactions mostly under Lewis acid catalysis. However, activation of these four-membered synthons via Brønsted acid (BA) catalysis is still scarce, and to the best of our knowledge, no reports were found on BA-catalyzed direct ring-opening or cyclization with these types of 3-ethoxy cyclobutanones. Herein, we report a Brønsted acid-catalyzed cascade ring-opening/cyclization of 3-ethoxy 2-substituted cyclobutanones with naphthols for the formation of 2,8-dioxabicyclo[3.3.1]nonane derivatives. We started our investigation by employing various Brønsted acids and solvents whereas changing the equivalency of substrate and catalyst loading also became fruitful to get our optimized reaction condition. A range of bicyclic ketal derivatives were synthesized varying both the aryl group of cyclobutanone and β-naphthols in this chapter. Apart from β-naphthols, α-naphthol was also found to be tolerated for this reaction but unfortunately, other phenol derivatives and electron-rich arenes failed to give the desired products. The control experiment confirms that these cyclobutanones can also be activated using mild Brønsted acids like PTSA. Further, a gram-scale experiment was conducted to display the practical utility, and also a 15-membered macrocycle was synthesized via ring-closing metathesis as a post-functional modification.