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Synopsis 1 SYNOPSIS This thesis entitled “Synthesis of some biological active compounds containing chiral vicinal amino alcohols” is divided in to three chapters. The first chapter deals with the “ Stereoselective synthesis of (-)-Cytoxazone, (+)5-epi-Cytoxazone and its analogue”. The second chapter deals with the “ Synthesis of (3S, 4S)-3-methoxy-4methylamino pyrrolidine and (3S, 4R)-3-methoxy-4-methylamino pyrrolidine”. The third chapter deals with the “ Synthesis of protected (2R, 3R, 4S)-4,7- diamino-2,3-dihydroxyheptanoic acid, a constituent of Callipeltins A and D”. CHAPTER-I: “ Stereoselective synthesis of (-)-Cytoxazone, (+)-5-epi-Cytoxazone and its analogue”. Enantiomerically pure substituted 2-oxazolidinones are important target molecules in organic synthesis. Some of them act as antibiotics against highly resistant gram-positive bacteria. In 1998 Osada etal, isolated a novel cytokine modulator from streptomyces species. Fig-I OMe OMe HO HO HO NH O H H H H H H NH O NH O O O O 1 2 3 Synopsis 2 This new 4,5-disubstituted oxazolidinone was named as (-)-cytoxazone 1 (Fig.I). It interferes with cytokine IL4; IL10 and IgG production by selective inhibition of signaling pathway of Th2 cells, but not Th1 cells. Inhibition of Th2 dependent cytokine products would be potent chemotherapeutic agents in the field of Immunotherapy. Scheme-I NH2 COOH AcCl, MeOH (Boc)2O, Et3N, THF HO NHBoc OMe 4 DMF 5 NHBoc OMe O MeO O HO CH3I, K2CO3 NHBoc OH LiCl, NaBH4 EtOH, THF DMSO, (COCl)2 CH2=CH-MgBr, THF MeO 7 6 O HN NHBoc O O3, CH2Cl2 NaH, THF OH MeO NaBH4, MeOH MeO 9 8 O HN O OH MeO 2 Cytoxazone 1 is different from known immunomodulators such as FK 506 and rapamycin in respect of structure and biological activity. Therefore 1 and its analogues have been a new subject of synthetic studies for the development of a cytokine modulators. Synopsis 3 Due to its potent biological activity, several syntheses of 1 and its isomers have been described in the literature. Very recently we reported a stereoselective synthesis of 1 via stereoselective Grignard addition of p-methoxyphenylmagnesium bromide to Nbenzylimine derived from (S)-2,3-O-isopropylidine glyceraldehyde followed by a single step conversion of N-Boc amine diol to oxazolidinone. Herein we report a short and stereoselective synthesis of (-)-cytoxazone 1, (+)-5-epi-cytoxazone 2 which is a C-5epimer of cytoxazone and its analogue 3. The commercially available p-hydroxy-D-phenylglycine 4 was converted to N-Boc methyl ester 5 using AcCl, MeOH followed by treatment with (Boc)2O and Et3N (schemeI). Treatment of 5 with methyl iodide, potassium carbonate in DMF gave 6. Scheme-II NHBoc NHBoc OH O3, CH2Cl2 OH MeO NaBH4, MeOH OH MeO TBSCl imidazole, DCM 10 8 NHBoc NHBoc OTBS OTBS OH MeO TPP, DIAD O PNBA, THF O2N 11 O OH HN NaH, THF O OH OH MeO 13 TBAF, DCM 12 NHBoc MeO LiOH, THF-H2O O MeO 1 4 Synopsis The next step in the sequence is to convert the ester to aldehyde followed by stereoselective addition of vinylmagnesium bromide to get syn N-Boc amino alcohol based on the well-established protocol. Thus the ester 6 was reduced to alcohol 7 under LiBH4 conditions. Swern oxidation of 7 followed by in-situ reaction of the resulting aldehyde with vinylmagnesium bromide yielded the syn 1,2-amino alcohol 8. Intramolecular cyclization of compound 8 in the presence of NaH in THF yielded the oxazolidinone 9. Oxidative cleavage of the double bond with ozone followed by immediate reduction afford the (+)-5-epi-cytoxazone 2 whose 1H, 13 C NMR spectral data are in agreement with the assigned structure. The synthesis of (-)-cytoxazone 1 from 8 was achieved as follows (scheme-II): Oxidative cleavage of 8 with O3 followed by reduction with NaBH4 gave diol 10. Primary hydroxyl in 10 was protected as TBS ether 11. When compound 11 was subjected to mitsunobu reaction conditions gave 12 as a p-nitrobenzoic ester with inverted configuration. Hydrolysis of ester and deprotection of TBS ether in one pot yielded 13 whose NMR and rotational values are in agreement with the reported compound. Treatment of compound 13 with NaH in THF gave (-)-cytoxazone 1 whose spectral data was in agreement with the reported compound. Some compounds contain oxazolidinone unit shows antibacterial activity against gram positive and gram-negative bacteria. Keeping this criterion in view antibacterial testing was done for both compounds. Interestingly we observed that (+)-5-epi-cytoxazone 2 and (-)-cytoxazone 1 shows some antibacterial activity against gram-positive (G+ve) Bacillus subtilis and gram-negative (Gr-ve) Escherichia coli. by paper disc method. The activity has been compared with standard streptomycin disc (10 Mcg). (+)-5-epi- Synopsis 5 Cytoxazone 2 shows somewhat more antibacterial activity compared to the (-)-cytoxazone 1 against gram positive and gram-negative bacteria. S. No Samples Diametre of Inhibition zone Basillus subtilis Escherichia coli 1 (-)-Cytoxazone (100 Mcg) 12 14 2 (+)-5-epi-Cytoxazone (100 Mcg) 16 20 3 Streptomycin (10Mcg) 18 22 Scheme-III COOH NH2 COOMe AcCl, MeOH NHBoc (Boc)20, TEA, THF LiCl, NaBH4 EtOH, THF 15 14 OH OH NHBoc NaH, THF DMSO, (COCl)2 NHBoc CH2=CH-MgBr, THF 17 16 OH O3, CH2Cl2 O HN O 18 NaBH4, MeOH O HN O 3 Keeping the above results in view similarly we synthesized the analogue of 5-epicytoxazone 3 from phenylalanine (scheme-III), which is a naturally available amino acid Synopsis 6 and we evaluated antibacterial activity for this compound. This analogue also possessing good antibacterial activity against the microorganism candida albicans and p.auraginosa. Sl. Samples No Diametre of inhibition zone Candida albicans p.auraginosa 1 (-)-Compound 3 (100 Mcg) 11 22 2 Streptomycin (10Mcg) 18 22 CHAPTER-II: “ Synthesis of (3S, 4S)-3-methoxy-4-methylamino pyrrolidine and (3S, 4R)-3-methoxy-4-methyl amino pyrrolidine”. Biologically active chiral and non-racemic pyrrolidines are commonly found in subunits of natural and unnatural products. Okada et.al showed that a new series of quinoline compounds e.g., 22 (Fig-II), bearing a 3-methoxy-4-amino chiral pyrrolidine derivatives at C-7 showed higher in vivo and in vitro antibacterial activity against gram +Ve and gram – Ve bacteria. The pyrrolidine skeleton possesses 3-methoxy-4-amino or 3methoxy-4-methyl amino groups both in syn and anti form. Tsuzuki also showed that (3S,4S)-3-methoxy-4-methyl amino pyrrolidines attached to the naphthyridine ring at C-7 in AG-7352 19, a new type of antitumor agent, showed potent activity equal or superior to those of cisplatin and etoposide. Synopsis 7 Fig-II O MeHN N N N N MeO NH2 OMe COOH RHN S N N R1 R1 O COOH F MeHN N N F (S,S) AG-7352 (+) 19 OMe RHN MeO (S,R) 20 a R = Me, R1 = H 20 b R = R1 = Boc 22 21 a R = Me, R1 = H 21 b R = R1 = Boc The amino hydroxy moiety in erythro form is also present in a pyrrolidine containing balanol analogue, which is a very effective inhibitor of protein kinase C (PKC). Scheme-IV OH D-Isoascorbic acid COOEt O O HO OTs NaN3, DMF O O MeO N3 MeO MeI, NaH DMF O O OH DCM 29 OTs 30 BocHN OMe EtOH, (Boc)2o (Boc)2O, THF OMe N Boc 31 OMe Pd/C, H2 N MeOH, PTSA O TsO N3 TPP, MeOH TsO N3 28 MeO N3 DCM 25 TsCl, Et3N, N3 O 27 26 HO TsCl, Et3N, 24 HO OH LAH, THF O 23 O HO N Boc Boc 32 20 b NaN3, DMF 8h 8 Synopsis Hence these novel pyrrolidine moieties must certainly contribute to the activity of the above compounds. Therefore we undertook the synthesis of these 3,4-disubstituted pyrrolidines and developed a new general strategy for the preparation of both syn and anti compounds 21a and 20 a. Although an approach for the synthesis of 21 a is known, it is racemic and the chiral pyrrolidine 21a was obtained after resolution. Also two approaches are known for 20a based on SN2 displacement reaction and chiral resolution from tartaric acid. Herein we represent a short stereoselective and general approach for the synthesis of both 20a and 21a starting from Isoascorbic acid and ascorbic acid respectively. Our approach to the synthesis of trans (S,S)-pyrrolidine 20b is outlined in (Scheme IV). D-Isoascorbic acid was converted into the ester 24 by a sequence of reactions reported earlier. Ester functionality was reduced using LAH to give diol 25. The primary alcohol was converted into its azide 27 via the tosylate 26 using TsCl-Py and NaN3 in DMF. The azidoalcohol thus obtained was protected as the methylether using MeI/ NaH to give compound 28. Under the acidic conditions (cat. amount of p-TSA in MeOH) compound 28 underwent isopropylidine cleavage to furnish the diol 29, which was converted into ditosyl derivative 30 using TsCl/Et3N. Reaction of compound 30 in TPP/ MeOH at reflux resulted in azide reduction and regioselective cyclization to give the pyrrolidine derivative, which was subsequently treated with (Boc)2O to give 31. Next, the tosyl group in compound 31 underwent SN2 displacement with NaN3 in DMF to furnish azide 32, which on further reduction with Pd/C, H2 and protection with (Boc)2O afforded compound 20b whose spectral and analytical data were in agreement with the reported values. Compound 20b, after N-methylation and Boc deprotection was coupled with the naphthyridine moiety to give AG-7352, which has been reported in the literature. Synopsis 9 Scheme-V OH COOEt L-Ascorbic acid O O TsCl, Et3N, O 35 NaN3, DMF O MeI, NaH DMF O O TsO TsCl, Et3N, HO OH DCM BocHN OMe Pd/ C, H2 N Boc 42 OTs TPP, MeOH N (Boc)2O, THF Boc 40 39 N3 TsO EtOH, (Boc)2o NaN3, DMF 3 days 41 OMe N Boc 43 OMe N3 MeO N3 MeO MeOH, PTSA O 38 37 36 N3 MeO N3 HO O DCM O 34 OTs HO LAH, THF O 33 OH HO BocMeN OMe MeI, NaH DMF N Boc 21 b Cis pyrrolidine derivative 21b was synthesized from L-ascorbic acid using the similar strategy described in (Scheme-V). In this case conversion of compound 41 to its azide 42 required heating reaction mixture for 3 days at 80oC, this may be due to the steric hindrance of the ‘trans’ configuration in compound 41. On treatment with Pd/C, H2 the azide group in 42 was reduced to the amine, and was subsequently, protected as its Boc derivative 43. On treatment with NaH, MeI in DMF compound 43 was N-methylated to give 21b whose spectral and analytical data were in agreement with the assigned structure. Synopsis 10 Tsuzuki et.al reported that compound 21b, after Boc deprotection, was coupled with the quinoline moiety, to give 22. CHAPTER-III: “Synthesis of protected (2R, 3R, 4S)-4,7-diamino-2,3- dihydroxyheptanoic acid, a constituent of Callipeltins A and D”. Cyclic depsipeptides have emerged as very important classes of bioactive compounds in marine natural products. Among these cyclic depsipeptides callipeltin A 44a (Fig.III) shows anti-HIV, antifungal and cytotoxic activities against selected human carcinoma cell lines. The isolation of callipeltin A 44a was reported by Minale et.al in 1996 from a shallow water sponge of the calipelta species and later by D’Auria and coworkers from Latruncula sp. It shows marked activity in cytotoxic assays against KB and P388 cells and recently it was found that callipeltin A 44a is a selective and powerful inhibitor of Na/ Ca cardiac exchange and a positive inotropic agent in guinea pig left atria. It contains a number of novel amino acid residues: methoxy-tyrosine, (2R, 3R, 4S)-4amino-7-guanidino-2,3-dihydroxy heptanoic acid (AGDHE) and (3S,4R)-3,4-dimethyl-Lglutamine. Recent reports have revealed that the side-chain attached to the macrocycle in callepeltin A 44a is essential for anti-HIV activity and it is also present in callipeltin D 44b. The key residue in the side-chain is the novel amino acid (2R,3R,4S)-4-amino-7guanidino-2,3-dihydroxy heptanoic acid (AGDHE). Synopsis 11 Fig.III CONH 2 L-dlMe-Gln 2R, 3R, 4S AGDHE O OH NH OH O L-Thr H N H 2N N H N H NH O NH N H L-Thr O OH HN N H O O L-Ala CONH 2 D-Arg O NH O L-MeAla HN N Me O O NMe N H O MeO L-Leu O OH NH 2 L-MeGln B-MeOTyr OH Callipeltin A 44a CONH 2 L-dlMe-Gln 2R, 3R, 4S AGDHE O OH NH O H N H 2N N H N H NH OH L-Thr NH 2 O HO O L-Ala HN O OH Callipeltin D 44b Two syntheses have been reported for this fragment to date and one of these was from our lab starting from D-glucose. Recently Lipton et.al reported this fragment from protected L-ornithine. Herein we report an efficient synthesis of AGDHE fragment starting from readily available D-ribose. Synopsis 12 D-Ribose 45 was converted into compound 46 via a reported procedure in one step (Scheme-VI). Compound 46 underwent Swern oxidation and Wittig olefination to afford 48, whose NMR spectral data are in agreement with the literature. Reduction of 48 using LAH gave compound 49, which was subsequently converted to azide 51. Scheme-VI D-RIBOSE Acetone, MeOH H2SO4 (cat) O O HO O 45 OMe O O H (COCl)2, DMSO Et3N, -78oC, 30 min O 46 OMe O 47 O Ph3P=CH-COOEt O EtO DCM, 0oC to rt, 1 h OMe LiAlH4, THF O O O HO 0oC to rt, 6 h, 87 % O 48 TsCl, DCM, Et3N 0oC -rt, 6 h NaN3, DMF O O O 49 OMe O TsO OMe 90oC, 8 h O N3 O 50 OMe O 51 Under acidic conditions compound 51 underwent isopropylidine cleavage to give anomeric mixture of diol 52 (scheme-VII), which was protected as the dibenzyl ether 53. Hydrolysis of the O-glycosidic bond of 53 afforded the corresponding lactol 54. Synopsis 13 Scheme-VII 51 MeOH, Conc. HCl O N3 OMe BnBr, NaH HO 60oC, 4 h DMF, 0oC-rt, 2 h OH O N3 BnO O N3 HCl (cat), 60oC, 2 h BnO OBn 53 52 60% AcOH-H20 OMe OH OBn 54 Compound 54 when treated with LAH, resulted in opening of the lactol and reduction of azide to the corresponding amine (scheme-VIII) to give 55. Scheme-VIII O N3 BnO OBn OH OBn 54 LAH, THF, 0oC, 30 min 15% NaOH, H20, (Boc)20, 12 h BocHN OBoc OH OBn 55 The reaction was quenched with 15% NaOH solution and immediately (Boc)2O was added to convert the amine in to the N-Boc derivative. Interestingly, it was found that the primary hydroxy was also protected as its Boc ester to give 55, selectively, in good yields. Compound 55 was converted into azide derivative 56 in 90% yield by SN2 displacement of the intermediate mesylate. When compound 56 was treated with NaH/ BnBr in DMF for N-benzylation, it also resulted in O-Boc ester cleavage to give 57. Synopsis 14 Scheme-IX OBn 55 MsCl, Et3N, DCM NaN3, DMF, 80oC, 8 h NaH, BnBr, DMF BocHN OBoc N3 OBn OBn Bn N 0oC- rt, 6 h Boc 56 TPP, Benzene-H2O Et3N, (Boc)2O, 12 h N OBn O Boc Bn OH NH OBn Boc 58 OBn 57 OBn Bn OH N3 Jones reagent OMe N Boc NH OBn Boc 59 Azido alcohol 57 was reduced to the corresponding amine using TPP/ BenzeneH2O and was immediately protected as the Boc derivative 58, []D25 = - 14.2 (c 0.8, CHCl3), [lit []D25 = - 14.8 (c 0.7, CHCl3)], whose NMR spectral data were in agreement with the literature. Compound 58 is already known to give methyl ester 59 in one step.