Synthesis of functionalized heterocyclic and carbocyclic scaffolds VIA [3+2]-annulation of strained rings and [3+3]-cyclodimerization [3+3] of azomethine ylide

Abstract

Chapter 1: Introduction Heterocyclic or carbocyclic rings are common scaffolds found in the natural products and bioactive molecules. Due to the importance of these bioactive molecules, organic chemists are involved in development of efficient, economical and short routes for their synthesis from ancient time. In this context, strained molecules like cyclopropanes, epoxides, aziridines and 1,3-dipolar species like azomethine ylides are used as synthetic precursor for synthesis of heterocyclic or carbocyclic moieties. In this chapter, structure, bonding, reactivity, and some selected examples of cyclopropane, epoxide, and aziridine are explained in detail. The effect of substituents, Lewis acids, temperature, and solvents on mode of activation of these synthons is also highlighted in their respective part. Chapter 2: [3+2]-Annulation of Epoxide with Donor-Acceptor Cyclopropane Ring cleavage and mode of rearrangement of epoxide Epoxides are one of the most common synthetic equivalents in organic synthesis. Due to its easy handling, widespread preparation methods and predictable reactivity epoxides are frequently used in development of new methodologies for synthesis of natural products and bioactive molecules. Generally, it undergoes strain-induced and/or Lewis acid promoted selective C-O bond cleavage to give ring open intermediate (IM). Due to availability of lone pair of electrons on oxygen atom, IM has tendency to undergo rearrangement into new synthetic equivalent (Scheme 1). In presence of Lewis acid IM undergo Meinwald rearrangement i.e. hydride shift (route A, Scheme 1) and silicon assisted thermal rearrangement of epoxide into silyl enol ether i.e. Brook-type rearrangement (route B, Scheme 1) depending upon the reaction conditions. These types of rearrangements of epoxide entirely depend upon presence of substituents in it and applied reaction conditions. These extra advantages of epoxides further enhanced their utility in organic synthesis in greater extent for construction of pharmacologically and biologically active molecules. Meinwald rearrangement is most common in epoxide and it readily takes place in presence of Lewis acids in reaction medium. In this rearrangement 1,2-hydride shift takes place with the help of captodative effect of lone pair of electrons of oxygen atom in IM. Brook et al. has reported another type of rearrangement in thermal condition. This Brook-type rearrangement of epoxide via route B demands silicon assistance (Scheme 1). Silicon stabilized the β- carbocation (intermediate, IM) generated after C-O bond cleavage and also facilitated the rearrangement to produce silyl enol ether. In our investigations, we have developed a reaction conditions for Lewis acid control enolization of epoxide into enolate via deprotonation pathway (route C, Scheme 1). Section A contains a new synthetic approach for synthesis of tetrahydrofuran from [3+2]-cycloaddition reaction of epoxide with donoracceptor cyclopropane through Meinwald rearrangement. Furthermore, possible application of newly synthesized THF and asymmetric transformation of the titled methodology also presented. In section B, a new synthetic approach for enolization of epoxide and its implementation for synthesis of cyclopentane via [3+2]-annulation with donor-acceptor cyclopropane is documented. The plausible mechanism for this transformation is also proposed. Section A: Lewis Acid Catalyzed Tandem Meinwald Rearrangement/Intermolecular [3+2]-cycloaddition of Epoxides with Donor-Acceptor Cyclopropanes: Synthesis of Functionalized Tetrahydrofurans Tetrahydrofuran ring system is an important heterocyclic constituent in many bioactive natural products. Particularly, cis-2,5-disubstituted tetrahydrofurans are found in lignans, polyether antibiotics, fragrances (1), antibacterial terpenes (2) and Sclerophytin A (3) with potency against mouse leukemia cells (cytotoxic at 1 ng/mL versus L1210 cell line) (Figure 1). Several methods have been explored for synthesis of terahydrofuran (THF). Specially, cis-2,5-disubstituted tetrahydrofurans have attracted organic chemists for their synthesis due to importance in bioactive molecules. In this section, we have demonstrated a methodology for synthesis of varieties of cis-2,5- disubstituted tetrahydrofurans. In this context, epoxides are used as aldehyde reservoir due to its Lewis acid promoted Meinwald rearrangement and intimated to cycloaddition reaction with donor-acceptor cyclopropane under same Lewis acids catalyzed reaction condition. This method involved [3+2]-cycloaddition reaction of donor-acceptor cyclopropanes (DACs, 4) and epoxides (5) for synthesis of cis-2,5-tetrahydrofuran (6) (Scheme 2). This methodology is optimized with varieties of Lewis acids, solvents and also by temperature variation. It was observed that transformation worked well with InCl3 in dichloroethane at 60 °C. In this method, temperature and solvents played vital role. It was noticed that reactants decomposed at higher temperature and yield of product reduced at lower temperature. However, decomposition of reactants was slowed down at lower temperature. Scope and limitation of this methodology is also studied by varying substrates with respect to both epoxides and DACs. Electron rich aryl substituent in both epoxides and DACs favored good yield of the product. While yield of product was decrease when partially electron poor substrates were employed and progress of THF generation was completely ceased with electron poor substrates. Possible scope and limitation for asymmetric transformation of this tandem cyclization was also manifested with the help of InCl3-PyBOX catalytic system (7). Section B: Substituent and Lewis Acid Promoted Dual Behavior of Epoxides towards [3+2]-Annulation with Donor–Acceptor Cyclopropane: Synthesis of Functionalized Cyclopentane and Tetrahydrofuran In this section, a new route for epoxide rearrangement into enolate depending upon the use of varieties of Lewis acids in reaction medium and presence of substituents at geminal position of epoxide (8) is disclosed. This in situ generated enolate trapped with varieties of DACs (9) to produce cyclopentane derivatives (10). However, tetrahydrofuran (11) formation is also observed as a side product of the reaction (Scheme 3). In some cases only cyclopentane derivatives was observed and in some cases tetrahydrofuran was detected. These observations depend upon substituent present in epoxides and Lewis acids present in reaction medium. Lewis acids like MgI2, Yb(OTf)3, Sn(OTf)2, and TiCl4 were found effective catalysts for cyclopentane synthesis. However, BF3.OEt2, Sc(OTf)3, AlCl3, SnCl4 and GaCl3 gave both cyclopentane and tetrahydrofuran. BF3.OEt2 was found good catalysts for substrate variations as maximum amount of yield of the product was achieved with it. Therefore, deprotonation and hydride shift were found to be competitive with each other depending upon reaction conditions. Temperature also played important role for product. Scheme 3. Cycloaddition reaction of DAC (9) with in situ generated enol and aldehyde from epoxide formation and reaction worked well at room temperature. The newly synthesized cyclopentanes (12) and tetrahydrofuran (15) further converted into more demanding cyclopentanone (13), cyclopentene (14), and trisubstituted tetrahydrofuran (16) (Scheme 4). Chapter 3: One-pot Synthesis of Oxazolidine Derivatives via [3+2]-Cycloaddition Reaction of 1-Tosyl-2-phenyl/alkylaziridines with Epoxides Oxazolidines are important heterocyclic compounds and found as core structure in several natural products like opioid receptors, an antinociceptive SYK-146 (12), alkaloid Densiflorine (13), antitumor antibiotic Quinocarine (14) (Figure-2). Application of oxazolidine derivatives as chiral auxiliaries in asymmetric synthesis or as chiral ligands for transition metal catalysis further enhances their importance in large extent. In this chapter, one-pot synthesis of functionalized oxazolidine is described. In this context, aziridine (17) and epoxide (18) were taken as reactants and employed under Lewis acid catalyzed reaction condition. Due to strain in epoxide and aziridine ring opening became more facile under the given reaction condition and produced oxazolidine (19, 20) in excellent yield. In this transformation, epoxide underwent Meinwald rearrangement followed by [3+2]- cycloaddition reaction with aziridine (Scheme 5). BF3.OEt2 was found efficient catalyst for the reaction and worked well with all types of substrate employed in this study. Both electron rich and electron poor epoxides react efficiently with aziridine under BF3.OEt2 reaction conditions. However, reaction time is increased and yield of product decreased when 1-alkylN-tosylaziridine was subjected in reaction with epoxide. Chapter 4: Synthesis of Functionalized Dispiro-oxindoles through [3+3]- Cyclodimerization of Azomethine Ylide and Mechanistic Studies to Explain their Diastereoslectivity In continuation of our interest in synthesis of heterocyclic scaffolds, we further attempted to synthesize pharmacologically active piperazine derivatives9 and polycyclic fused dispirooxindole derivatives (23, 24). In this regard, a method of generation of azomethine ylide from condensation of isatin (21) and proline (22) is taken in consideration. The synthetic method proceeded in absence of dipolarophile due to its possibility of dimerization. In this chapter, optimization of reaction conditions, and substituent effects on in situ generated AMY dimerization is disclosed (Scheme 7). In this transformation, two diastereomers of the product viz, trans and cis are formed in quantitative yield, although trans was found as major. It is reported that trans isomer has anti-tuberculosis activity that escalated the importance of this methodology. Reaction underwent efficiently in polar solvent like methanol:dioxane (1:1) and reaction time was reduced (1 h) in compare to non polar solvent like toluene (4 h). Effect of substituent at nitrogen atom of isatin on dimerization of AMY is also studied. Steric hindrance and electron withdrawing character of substituent completely alter the dimerization of AMY. For better understanding of the this transformation, computational method (Density Functional Theory; DFT) is applied and found that substituent present at nitrogen atom of isatin changed activation energy (Ea) of the reaction in greater extent. Scheme 7. Dimerization of azomethine ylide