Expanding donor-acceptor cyclopropane monocarbarbonyls to valued oxacycles

Abstract

Chapter 1: An Exordium to Oxygen Heterocycles and Reactivity of Cyclopropane Monocarbonyls Heterocycles irrespective of their class, circumscribe the major part of all bioactive molecules like natural products, biomolecules, vitamins, pigments, hormones, agrochemicals, dyes, pharmaceuticals and a lot more. Among them, the foremost contributors are the nitrogen heterocycles, whereas oxygen heterocycles represent a very specific and important section of all biologically active molecules especially in pharmaceuticals and agrochemicals. This chapter, in the beginning, discusses on the significance of oxygen heterocycles in our day-to-day life as well as its impact on world trade. Owing to their vast application in pesticides and medicinally important scaffolds, designing the synthesis of oxacycles using simpler routes in a sense to construct them from readily accessible precursors and to supplement their availability for research and application purposes is an absolute necessity. In this context, ring expansion of small-ring systems has also been recognized as a versatile route towards heterocyclic synthesis and the most exploited system for such ring-expansion reactions is the donor-acceptor cyclopropane, particularly with a diester group as an acceptor. The donor-acceptor reactivity of cyclopropanes could be made even more interesting if we can align it with the carbonyl group reactivity and replacing the diester group with an active monocarbonyl acceptor. This aspect of unique reactivity among donor-acceptor cyclopropane monocarbonyls is thoroughly described in this chapter. An account on general routes to the synthesis of various cyclopropane monocarbonyls followed by a brief discussion on literature reports for different modes of activation that have been employed for transformations of donor-acceptor cyclopropane monocarbonyls are also a part of this chapter. At the end, aim of this thesis and a short chapter-wise outline on the research work performed is described. Chapter 2: Prins Reaction and Cyclopropane Carbaldehydes: Perceiving the Alliance for a Facile Synthesis of Medium-Sized Heterocycles and Fused Bicyclics Prins reaction, a century old technique for the acid catalyzed addition of aldehydes to olefins is generally used as an efficient tool for the construction of various open chain as well as carbo- and heterocyclic derivatives. The cyclization process following the formation of an oxocarbenium ion is termed as Prins-type cyclization and commonly involves an intramolecular nucleophilic attack of an alkene or alkyne onto the oxocarbenium ion. The literature is full of reports on the synthesis of diverse five or sixmembered oxygen and nitrogen heterocycles using this conventional cyclization technique. On the other hand, a Prins-type cyclization process for a remote attack on positions other than the oxocarbenium carbon was unknown. This chapter demonstrates first such report on non-classical Prins-type cyclization that encompasses an intramolecular nucleophilic attack of an unsaturated carbon-carbon bond onto a remote cyclopropane ring for the construction of a medium-sized heterocycle. A titanium tetrachloride (TiCl4) catalyzed ring-expansion of trans-2-arylcyclopropane-1- carbaldehyde with 3-buten-1-ol furnished a nine-membered oxygen heterocycle having a trans double bond in it i.e., (E)-hexahydrooxonine. Here, TiCl4, in addition to an activator of the cyclopropane ring, also acted as a chloride source and so was needed in stoichiometric amount. The strategy also worked well in the presence of an external chloride source like trimethylsilylchloride (TMSCl) with lower loadings of the Lewis acid. In trials with differently substituted precursors, the moderately activated cyclopropane carbaldehydes represented the substrate scope of this reaction. Switching the alcohol to 3- butyn-1-ol prompted a similar route, followed by a second Prins cyclization within the ninemembered cyclic intermediate to afford a bicyclized product, i.e., 4,4-dihalo-5- aryloctahydrocyclopenta[b]pyran. This diastereoselective bicyclization of the cyclopropane carbaldehyde was compatible with both TiCl4 and TiBr4 to construct the respective geminal dichloro and dibromo derivatives. Effortless transformation of the acquired geminal dihalide to a vinyl halide and a ketone further supplemented the substance of this approach. Chapter 3: Cyclopropane Monocarbonyls in Cloke-Wilson-Type Annulations for Access to Dihydro-1,2-oxazine Frameworks The Cloke-Wilson rearrangement is heteroatomic version of the vinylcyclopropane rearrangement where under thermal activation, cyclopropane carbonyl or imine undergoes ring-expansion to a dihydrofuran or pyrroline respectively. Most reports on Cloke-Wilsontype rearrangements generally leads to the construction of a five-membered heterocyclic systems. This rearrangement of the cyclopropane ring is quite robust and is among one of the most commonly observed side-reactions of the active cyclopropane carbonyls. This section of the thesis presents our effort to put the Cloke-Wilson-type rearrangement of cyclopropane monocarbonyls into synthesis of non-dihydrofuran targets or larger heterocycles like the six-membered cyclic oxime ethers. Cyclic oxime ethers are an interesting class of compounds, owing to their potential application in the synthesis of various natural products and bioactive targets. These scaffolds in addition to representing the basic structure of many bio-relevant molecules, offers as intermediates for the synthesis of various amino alcohols, furan, pyrrole and pyrrolidine derivatives. The pyrrolo[1,2-b][1,2]oxazine subunit is the key structural core of the two novel alkaloids alsmaphorazine A and alsmaphorazine B. Clearly, the straightforward synthetic design of six-membered cyclic oxime-ethers and their bicyclic analogues and so their further examination is an important field of study. This chapter primarily focusses on binucleophilic annulation of cyclopropane monocarbonyls with hydroxylamine salts. Aryl substituted cyclopropane carbaldehydes were used as precursors for the in-situ generated aldoximes that undergo the anticipated Cloke-Wilson type ring expansion for a convenient additive-free synthesis of dihydro-4H- 1,2-oxazines. Cyclopropyl ketones which are comparatively less reactive, follows a similar protocol and produce disubstituted dihydro-4H-1,2-oxazine derivatives when supplemented by catalytic p-TSA.H2O at 50 °C. The transformation is performed in an open-to-air flask as it shows negligible sensitivity towards air/moisture. On cycloaddition with cyclopropane diester, the isolated dihydro-4H-1,2-oxazines formulate diastereoselective synthesis of the valued bicyclic hexahydro-2H-pyrrolo[1,2- b][1,2]oxazine derivatives. This bicyclization step was found to have a very general substrate scope with a variety of donor-acceptor cyclopropane diesters. A cascade one-pot variant of this two-step strategy also offered a comparable overall yield of the final product. Finally, to demonstrate the synthetic potential of the assembled pyrrolo-oxazine unit, the diester functionality in the molecule was subjected to monodecarboxylation in the presence of potassium hydroxide where an additional stereogenic centre was introduced in the product. Chapter 4: Cyclopropane Monocarbonyls as Intermediates: Direct Transformation of α,β-Unsaturated Carbonyls to 3,6-Dihydro-2H-pyrans In chapter 2 and 3, donor-acceptor cyclopropane monocarbonyls exhibited reactivity towards Prins and Cloke-Wilson type cyclizations with different binucleophilic species where the cyclopropane precursor behaved as a four-atom contributor towards the cyclized product. In this section, we intended to introduce another very specific and important class of reactivity that cyclopropane monocarbonyls are structured to display i.e., a [5+n] cyclization utilizing the cyclopropane unit as a five-atom contributor. Here, instead of a precursor, cyclopropane monocarbonyls were exploited as intermediates for direct conversion of α,β-unsaturated carbonyls to mono-, di- and trisubstituted 3,6-dihydro-2Hpyran derivatives. The Corey-Chaykovsky reaction is a well-studied approach for methylene transfer to olefins, imines and carbonyls to access various cyclopropane, aziridine and oxirane subunits respectively. In this chapter, we demonstrate two consecutive Corey-Chaykovsky reactions on α,β-unsaturated carbonyls to generate a cyclopropane monocarbonyl at first and then an epoxycyclopropane intermediate that follows a strain-induced ring expansion to the substituted dihydropyran. By simply subjecting α,β-unsaturated ketones to the carefully optimized Corey-Chaykovsky reaction conditions, efficient transition-metal free construction of di- and trisubstituted 3,6-dihydro-2H-pyran was achieved. The protocol resulted in moderate to excellent yields of the dihydropyran target and was reconcilable with a wide range of substrates. Similar developments were observed with α,β-unsaturated aldehydes to produce monosubstituted 3,6-dihydro-2H-pyran, however with compromised yields. Further, the synthetic utility of the developed strategy was verified by a number of derivatizations on the procured dihydropyran ring. Hydrogenation in the presence of palladium-charcoal in ethyl acetate solvent furnished the expected tetrahydropyran with practically high diastereoselectivity. A similar operation in methanol solvent manifested isomerization to 3,4-dihydro-2H-pyran in addition to the regular hydrogenated product. Treatment with pyridinium dichromate and sodium acetate resulted in allylic oxidation to a cyclic α,β-unsaturated lactone. Interestingly, the design also found usage in two-step synthesis of racemic goniothalamin which is widely being studied for its cytotoxic behaviour.