The thesis entitled “Enantioselective synthesis of didemniserinolipid, cladospolides, aspercyclide and muricatacin” is divided into three chapters. First chapter of the thesis deals with the formal total synthesis both enantiomers didemniserinolipid B from L-(+)-tartaric acid. Fused bicyclic acetals containing 6,8-dioxabicyclo[3.2.1]octane structural unit are wide spread in bio active natural products. Didemniserinolipids A-C possessing similar framework were isolated from a methanol extract of Didemnum sp., and some of the analogous compounds were found to be cytotoxic against P388, A549, and HT29 tumor cell lines. Pivotal reactions en route to the natural product include the elaboration of a γ-hydroxy amide derived from tartaric acid, olefin cross metathesis and Wittig olefination (Scheme 1). (+)-didemniserinolipid B Scheme 1: Retrosynthesis of both enantiomers of didemniserinolipid B. Second chapter of the thesis describes an enantiodivergent synthesis of macrolactones: In section A, enantiodivergent approach for the synthesis of cladospolides B, C and iso-cladospolide B is described. The cladospolides A-D are a class of 12-membered macrolactones, isolated from various cladosporium species of fungi and posseses a range of biological activities. Key reaction in the synthetic sequence involve formation of the required side chain by olefin cross metathesis. Selective Wittig olefination and lactonization afforded cladospolides (Scheme 2). Scheme 2: Enantiodivergent synthesis of cladospolide B, C and iso-cladospolide B. In section B, synthesis of bio-active biaryl ether lactone aspercyclide is described. Aspercyclides A-C are 11-membered biaryl ether lactones isolated from the extraction of the fermentation broth of an Apergillus. Sp.. Aspercyclides are reported to be moderately active (IC50 of 200 M for aspercyclide A) in the IgE receptor binding, which is key for the understanding of allergic disorders. A combination of Boord elimination and Mitsunobu reactions were employed to synthesize the key homoallylic alcohol from γ-hydroxy amide derived from tartaric acid. Elaboration of γ-hydroxy amide derived from L-(+)-tartaric acid is the key step for the synthesis of both enantiomers of the chiral homoallylic alcohol part, while Ullmann coupling reaction is employed to construct biaryl linkage. Ring closing metathesis (RCM) of the diene furnished required macrolactone (Scheme 3). Scheme 3: Enantiodivergent formal total synthesis of aspercyclide C. Last chapter of the thesis describes the enantioselective synthesis of muricatacin, a bio-active butanolide isolated as the major component of a scalemic mixture from the seeds of Annona muricata. Muricatacin was found to exhibit potent cytotoxicity toward several human tumor cell lines with SAR studies showing that activity is influenced significantly by the nature of the side chain. Stereoselective synthesis of ()-Muricatacin and structurally similar butanolide L-Factor has been accomplished from L-(+)-tartaric acid. Pivotal strategy in the synthesis is the elaboration of -hydroxy amide to the required allylic alcohol which on further reactions (including RCM) provided muricatacin (Scheme 4). Scheme 4: Stereoselective synthesis of Muricatacin and L-Factor. (For structural formula pl refer the thesis)

The thesis entitled “Total synthesis of bio-active macrolide natural products and sulphonamide based ligands in asymmetric catalysis” is divided into two chapters. First chapter of the thesis describes the total synthesis of bio-active macrolide natural products cladospolide A 1, seimatopolide A 2 and synthetic studies towards aetheramides A 3 and B 4 (Figure 1). Figure 1: Bio-active macrolide natural products. Section A of chapter 1 describes the enantiospecific total synthesis of cladospolide A (ent-1). Cladospolide A was isolated from three different sources such as culture filtrate of cladosporium fulvam FI-113, Fungus cladosporium tenuissimum and Fermentation broath of cladosporium sp. FT-0012. Cladospolide A is shown to inhibit the root growth of lettuce seedlings. Enantiospecific total synthesis of cladospolide A ent-1 was accomplished in 9% overall yield in 11 linear steps using D-ribose as a chiral pool precursor. Key reactions in the present approach include olefin cross metathesis and Yamaguchi macrolactonization reactions (Scheme 1). Scheme 1: Total synthesis of cladospolide A (ent-1). Section B of chapter 1 describes the use of furan as a surrogate for the E-but-2-ene-1, 4-dione unit in the total synthesis of seimatopolide A 2. Seimatopolide A 2 was isolated by Heip and co-workers from the fungus Seimatosporium discosioides in 2012 and is shown to activate the γ-subtype peroxysome proliferator-activated receptors (PPAR-γ), which is a pivotal process in the type-2 diabetes. Total synthesis of ent-seimatopolide A was accomplished in 7.8% overall yield in 14 linear steps from furfural. Nagao acetate aldol and Shiina macrolactonization reactions were employed as key reactions for the synthesis of ent-seimatopolide A (ent-2) (Scheme 2). Scheme 2: Stereoselective total synthesis of seimatopolide A (ent-2). In section C of Chapter 1, studies towards the synthesis of aetheramides A 3 and B 4 are described. Aetheramides A 3 and B 4 are isolated by Müller’s group in 2012 from the novel myxobacterial genus “Aetherobacter”. Aetheramides are cyclic depsipeptides, which are shown to inhibit the HIV-I infection with IC50 values of ∼0.015 μM and cytostatic activity against human colon carcinoma (HCT-116) cells with IC50 values of 0.11 μM. Stereochemistry at two chiral centers present in the molecules is unassigned. The first approach (Scheme 3) relied on macrolactonization as the key step while the second approach (Scheme 4) relied on RCM to accomplish the macrolactonization. The required precursors were synthesized from elaboration of chiral furyl carbinol, while synthesis of the RCM precursor was accomplished employing the aldol reaction. Scheme 3: Macrolactonization strategy for synthesis of 3 from chiral furyl carbinol. Scheme 4: RCM strategy for synthesis of 3 from chiral furyl carbinol. The successful synthesis of the macrolactone core of aetheramide A 1 is accomplished by employing the ring closing metathesis reaction to construct the C18-C19 bond. RCM precursor has been synthesized by the amidation of the amine derived from R-mandelic acid, while the acid fragment is synthesized from allyl trityl ether (Scheme 5). Scheme 5: RCM strategy for synthesis of 3 from R-mandelic acid. Second chapter of the thesis describes the synthesis and application of novel sulfinamide ligands in asymmetric catalysis. In section A of chapter 2, chiral 2-pyridylsulfinamides are shown to be effective catalysts in the alkylation of aryl and alkyl aldehydes with diethylzinc providing the corresponding alcohols in excellent enantioselectivity. It was found that the chirality present at sulfur in the ligand is pivotal for the asymmetric induction (Scheme 6). Scheme 6: Asymmetric alkylation of benzaldehyde with some of the 2-Pyridyl sulfinamide catalysts. Second section of chapter 2 describes the synthesis and application of C2-symmetric bis-sulfinamides in Rh (I) catalyzed conjugate addition of PhB(OH)2 to enones. Chirality present at sulphur in sulfonamide as well as symmetry present in the ligand plays crucial role in the outcome of the reaction (Scheme 7). Scheme 7: Asymmetric arylation of enones using C2-symmetric bis-sulfinamide/olefin ligands. The thesis entitled “Total synthesis of bio-active macrolide natural products and sulphonamide based ligands in asymmetric catalysis” is divided into two chapters. First chapter of the thesis describes the total synthesis of bio-active macrolide natural products cladospolide A 1, seimatopolide A 2 and synthetic studies towards aetheramides A 3 and B 4 (Figure 1). Figure 1: Bio-active macrolide natural products. Section A of chapter 1 describes the enantiospecific total synthesis of cladospolide A (ent-1). Cladospolide A was isolated from three different sources such as culture filtrate of cladosporium fulvam FI-113, Fungus cladosporium tenuissimum and Fermentation broath of cladosporium sp. FT-0012. Cladospolide A is shown to inhibit the root growth of lettuce seedlings. Enantiospecific total synthesis of cladospolide A ent-1 was accomplished in 9% overall yield in 11 linear steps using D-ribose as a chiral pool precursor. Key reactions in the present approach include olefin cross metathesis and Yamaguchi macrolactonization reactions (Scheme 1). Scheme 1: Total synthesis of cladospolide A (ent-1). Section B of chapter 1 describes the use of furan as a surrogate for the E-but-2-ene-1, 4-dione unit in the total synthesis of seimatopolide A 2. Seimatopolide A 2 was isolated by Heip and co-workers from the fungus Seimatosporium discosioides in 2012 and is shown to activate the γ-subtype peroxysome proliferator-activated receptors (PPAR-γ), which is a pivotal process in the type-2 diabetes. Total synthesis of ent-seimatopolide A was accomplished in 7.8% overall yield in 14 linear steps from furfural. Nagao acetate aldol and Shiina macrolactonization reactions were employed as key reactions for the synthesis of ent-seimatopolide A (ent-2) (Scheme 2). Scheme 2: Stereoselective total synthesis of seimatopolide A (ent-2). In section C of Chapter 1, studies towards the synthesis of aetheramides A 3 and B 4 are described. Aetheramides A 3 and B 4 are isolated by Müller’s group in 2012 from the novel myxobacterial genus “Aetherobacter”. Aetheramides are cyclic depsipeptides, which are shown to inhibit the HIV-I infection with IC50 values of ∼0.015 μM and cytostatic activity against human colon carcinoma (HCT-116) cells with IC50 values of 0.11 μM. Stereochemistry at two chiral centers present in the molecules is unassigned. The first approach (Scheme 3) relied on macrolactonization as the key step while the second approach (Scheme 4) relied on RCM to accomplish the macrolactonization. The required precursors were synthesized from elaboration of chiral furyl carbinol, while synthesis of the RCM precursor was accomplished employing the aldol reaction. Scheme 3: Macrolactonization strategy for synthesis of 3 from chiral furyl carbinol. Scheme 4: RCM strategy for synthesis of 3 from chiral furyl carbinol. The successful synthesis of the macrolactone core of aetheramide A 1 is accomplished by employing the ring closing metathesis reaction to construct the C18-C19 bond. RCM precursor has been synthesized by the amidation of the amine derived from R-mandelic acid, while the acid fragment is synthesized from allyl trityl ether (Scheme 5). Scheme 5: RCM strategy for synthesis of 3 from R-mandelic acid. Second chapter of the thesis describes the synthesis and application of novel sulfinamide ligands in asymmetric catalysis. In section A of chapter 2, chiral 2-pyridylsulfinamides are shown to be effective catalysts in the alkylation of aryl and alkyl aldehydes with diethylzinc providing the corresponding alcohols in excellent enantioselectivity. It was found that the chirality present at sulfur in the ligand is pivotal for the asymmetric induction (Scheme 6). Scheme 6: Asymmetric alkylation of benzaldehyde with some of the 2-Pyridyl sulfinamide catalysts. Second section of chapter 2 describes the synthesis and application of C2-symmetric bis-sulfinamides in Rh (I) catalyzed conjugate addition of PhB(OH)2 to enones. Chirality present at sulphur in sulfonamide as well as symmetry present in the ligand plays crucial role in the outcome of the reaction (Scheme 7). Scheme 7: Asymmetric arylation of enones using C2-symmetric bis-sulfinamide/olefin ligands.