The  bis-spiroepoxide  dithiane  dioxide  has  been attempted  to  be  synthesised  as  its  role  as  an  intermediate  in the  synthesis  of  diaminopimelic  acid  (DAP).  The  first  method was  carried  out  by  reacting  the  3-dithiane-2-diethylphosphonate  4  with  an  aqueous  solution  of  the commercially  available  glutaraldehide  resulting  the  bis-ketene dithiane  dioxide  5.  The  second  alternative  method  was involving  the  ozonolysis  of  cyclopentene   7  in  the  synthesis  of bis-ketene dithiane dioxide  5 in  four step reactions  which gave moderate to good yield. Unfortunately, epoxidation process  for the bis-ketene dithiane dioxide 5 was still unsuccess yet.Key  words:  synthesis,  diaminopimelic  acid,  bis-spiroepoxide  dithiane dioxid

Aggarwal, Varinder K.

Ritmaleni, Ritmaleni

English

Indonesian Journal of Pharmacy

 Research Article Volume 23 Issue 3 (2012) 188 Indonesian J. Pharm. Vol. 23 No. 3 : 188 – 192   ISSN-p : 0126-1037 ATTEMPTED SYNTHESIS OF BIS-SPIROEPOXIDE DITHIANEDIOXIDE   Ritmaleni1*, Varinder K. Aggarwal2   1Dep. Pharmacy Chemistry  Faculty of Pharmacy, Universitas Gadjah Mada, Sekip Utara, Jogjakarta, 55281, Indonesia 2School of Chemistry, University of Bristol, Cantocks Close, Bristol, BS8 1TS, UK  Submitted: 12-07-2012 Revised: 17-07-2012 Accepted: 08-08-2012  Coresponding Authors Ritmaleni E-mail : ritmaleni@ymail.com ABSTRACT  The bis-spiroepoxide dithiane dioxide has been attempted to be synthesised as its role as an intermediate in the synthesis of diaminopimelic acid (DAP). The first method was carried out by reacting the 3-dithiane-2-diethylphosphonate 4 with an aqueous solution of the commercially available glutaraldehide resulting the bis-ketene dithiane dioxide 5. The second alternative method was involving the ozonolysis of cyclopentene  7 in the synthesis of bis-ketene dithiane dioxide 5 in four step reactions which gave moderate to good yield. Unfortunately, epoxidation process for the bis-ketene dithiane dioxide 5 was still unsuccess yet.   Key words: synthesis, diaminopimelic acid, bis-spiroepoxide dithiane dioxide   INTRODUCTION Spiroepoxide dithianedioxides (Ritmaleni and Aggarwal, 2008) has been successfully synthesised in only one diastereomeric form (Aggarwal et al., 2003). These novel structures can potentially be used in the synthesis of  some important biologically active compounds, such as aza β-lactams and diaminopimelic acids. This spiroepoxide has been succesfully applied to the synthesis of  racemic (Ritmaleni and Aggarwal, 2005)  and asymmetric (Ritmaleni and Aggarwal, 2009) of  aza β-Lactam.   NNMeMeOSSOOO1 2Ph Ph(a)  Figure 1. (a) MeNHNHMe·2HCl, NEt3, THF, r.t., 24 h, 40 %.  This research was aimed to synthesis the bis spiroepoxide dithiane dioxide and to applied it as intermediate in the synthesis of  diaminopimelic acid. Wade et al., isolated α-aminopimelic acid as a component of  green plants in milligram quantities. They characterised the compound successfully except for its optical rotation and configuration. (Wade et al., 1957) Work et al., (1955) also observed that the symmetrical diaminopimelic acids exist in two racemic modifications, (L, L)-form and the other as meso-(D, L)-form. One member of  this class is 2,6-diaminopimelic acid (DAP) (Figure 1), which is of  particular contemporary interest due to its presence in bacterial products, and because of  its role as a precursor in the biosynthesis of  lysine. (Williams and Yuanm 1992)    Figure 2 . DAP structure.  Diaminopimelic acid (DAP) is an important, naturally occurring amino acid biosynthesised in bacteria and higher plants. L, L- and meso-DAP serve as the penultimate biosynthetic precursors of  the essential amino acid L-lysine. (Coc, 1996) meso-DAP functions as a cross-linking constituent of  virtually          all Gram-negative and some Gram-             positive bacterial peptidoglycans and also serves to anchor various membrane-associated macromolecules, such as lipoprotein to the cell wall. Recognition of  the pivotal roles DAP plays in microbial metabolism and cell wall structure has resulted in an increased level of  interest in possible means to selectively disrupt the DAP biosynthetic pathway. DAP also acts Ritmaleni and Varindel K. Aggarwal Volume 23 Issue 3 (2012) 189 as bacterial toxin, a sleep-inducing factor and antitumor agent (Gao et al., 1998).  METHODOLOGY Synthesis  of  5,5-Dimethoxypentanal  8 A 1000 mL three necked round-bottomed flask was fitted with a glass frit to admit ozone, a calcium hydride drying tube, a glass stopper and a magnetic stirrer bar and was charged with cyclopentene (150 mmol, 10.22 g; 13.20 mL), anhydrous DCM  (500 mL)  and  anhydrous  methanol (100 mL).  The  flask  was  cooled  to –78°C, and ozone was bubbled through the solution with stirring until a blue colour remained. Nitrogen was passed through the solution until the blue colour was discharged and then the cold bath was removed. The drying tube and ozone inlet were replaced with a glass stopper and a rubber septum, and p-toluene sulfonic acid monohydrate (10 % w/w) (11.56 mmol, 2.2 g) was added. The solution was allowed to warm to room temperature as it stirred under nitrogen for 90 minutes. Anhydrous sodium hydrogen carbonate (46.2 mmol, 3.88 g) was then added to the flask and the mixture was stirred for 15 minutes after which time dimethyl sulfide (300 mmol, 24 mL) was added. After stirring for 13 hours the heterogeneous mixture was washed with water (100 mL). The aqueous layer was extracted with DCM (2 x 250 mL) and the combined organic layers were               dried over MgSO4, filtered and concentrated            in vacuo. Flash column chromatography (2:1 petrol/ether) on silica gave aldehyde 8 as a colourless oil (8.44 g; 39 %); Rf 0.21 (2:1 petrol/ether); υmax (thin film)/cm-1 1723 (C=O), 1453, 1387, 1127, 1050; δH (400 MHz, CDCl3) 1.60-1.75 (4H, m, 3-CH2 and4-CH2) 2.49 (2H, dt, J 6.4; 1.0, 2-CH2) 3.32 (6H, s, 2 x OCH3) 4.37 (1H, t, J 5.3, 5-H) 9.77 (1H, t, J 1.0, CHO) [lit. (Schreiber et al., 1982)  (270 MHz; CDCl3) 9.77 (1H, t, J 1.3, CHO)].   Synthesis of (±)-2-(5,5-dimethoxy-pentylidene)-[1RS,3RS]-1,3-dioxo-1,3-dithiane 9 To a stirred solution of  aldehyde 8 (9.85 mmol, 1.44 g) in anhydrous THF (10 mL) under nitrogen at room temperature, were added racemic phosphonate 4 (6.57 mmol, 1.89 g) and lithium hydroxide monohydrate (6.50 mmol, 273 mg). The stirring reaction mixture was heated at 70°C for 4 hours before being allowed to cool to room temperature, then the solvent was removed in vacuo to give a white solid residue. Flash column chromatography (5 % EtOH/DCM) afforded 9 as a colorless oil (1.65 g; 90 %); Rf  (10% EtOH/DCM) 0.46; δH (400 MHz, CDCl3) 1.54-1.68 (4H, m, 2x CH2) 2.33-2.41 (1H, m) 2.45-2.56 (1H, m) 2.59-2.71 (2H, m) 2.75-2.82 (1H, m) 3.01-3.14 (1H, m) 3.19-3.27 (1H, m) 3.33 (6H, s, 2 x OCH3) 3.61-3.67 (1H, m) 4.36 (1H, t, J 5.1, OCHO) 6.67 (1H, t, J 7.7, C=CH) [Lit. (Aggarwal et al., 2002) (400 MHz, CDCl3) 6.68 (1H, t, J 7.7, C=CH)]; δC  (100 MHz; CDCl3) 14.9 (t), 24.0 (t), 28.7 (t), 32.0 (t), 49.0 (t), 53.1(q), 53.2 (q), 55.6 (t), 104.3 (d), 140.4 (d), 145.0 (s).   Synthesis of (±)-5-([1RS,3RS]-1,3-dioxo-1,3-dithian-2-ylidene)-pentanal 6  Bisacetonitrilepalladium (II) chloride (1 mol %) (4.24 x 10-5 mmol, 10.3 mg) was added to a stirring solution of  racemic acetal 9 (4.21 mmol, 1.18 g) in distilled acetone (150 mL) under nitrogen. The stirring orange solution was heated under reflux for two hours before the reaction mixture was allowed to cool to room temperature and   concentrated in vacuo to give an orange oil. Flash column chromato-graphy (7% EtOH /DCM) gave the aldehyde 6 as orange oil (875 mg, 89%); Rf (10% EtOH/DCM) 0.22; δH (400 MHz; CDCl3) 1.84-1.92 (2H, m, 9-CH2) 2.35-2.43 (1H, dm, J 16.1, 5-Heq) 2.47-2.58 (1H, m, 4-Hax) 2.61-2.69 (2H, m, 8-CH2) 2.74 (1H, ddd, J 16.7, 16.7, 2.8, 6-Hax) 2.81 (2H, dd, J 13.2, 11,7, 10-CH2) 3.01-3.13 (1H, m, 5-Hax) 3.23 (1H, dt, J 13.8, 2.6, 4-Heq) 3.61-3.67 (1H, dm, J 16.5, 6-Heq) 6.64 (1H, t, J 8.4, 7-H) 9.79 (1H, s, CHO) [Lit. (Aggarwal et al., 2002)  (400 MHz, CDCl3) 9.79 (1H, s, CHO)]; δC  (100 MHz; CDCl3) 14.9 (t), 21.1 (t), 28.1 (t), 42.7 (t), 49.0 (t), 55.4 (t), 139.2 (d), 145.9 (s), 201.1 (d).  Synthesis of 1’,5’-pentylidene-bis-[1RS, 3RS]-1,3-dioxo-2-ylidene 5 Method A, to a suspension of  the pho-phonate 4 (1.39 mmol, 400 mg) in 1,4-dioxane (8.63 mL),was added Mg (OH)2 (1.5 mmol, 90.45 mg) and glutaraldehyde (25% solution in water),  (0.695 mmol, 277 μL)  under  nitrogen.  Synthesis of Bis-Spiroepoxide Dithianedioxide Volume 23 Issue 3 (2012) 190 The reaction was heated to reflux  for 4 hours and allowed to cool to roomtemperature. The solvent was then removed under reduced pressure and the residue was extracted with chloroform (5 x 20 mL). The combined organic extracts were dried over MgSO4, filtered and the solvent removed under reduced pressure. Flash column chromatography (10% EtOH/ CHCl3) yielded 5 as a white foam (151 mg, 29%); Rf  (10% EtOH/CHCl3) 0.09; δH (270 MHz; CDCl3) 1.55-1.86 (4H, m, 2 x CH2), 2.34-2.44 (2H, dm, J 15.4, 2 X 5-Heq), 2.49-2.57 (2H, dt, J 14.5, 7.3, CH2), 2.58-2.90 (4H, m, 2 x 4-Hax, 2 x 6-Hax), 3.00-3.12 (2H, m, 2 x 5- Hax), 3.18-3-27 (2H, dm, J 13.5, 2 x 4-Heq), 3.60-3.67 (2H, ddm, J 11.6, 5.2, 2 x 6- Heq), 6.64 (2H, dd, J 7.5, 7.2, 2 x CH) [lit. (Ritmaleni and Aggarwal, 2011) (250 MHz; CDCl3) 6.62 (2H, dd, J 8.6, 7.0,  2 x CH)]. Method B, to a stirred solution of  aldehyde 6 (1.15 mmol, 270 mg;) in anhydrous THF (2 mL) under nitrogen at room temperature was added racemic phosphonate (1.72 mmol, 496 mg) and lithium hydroxide monohydrate (1.72 mmol, 72 mg). The stirring reaction mixture was heated at 70°C for 4 H HO O SSOOSSSSOO+564SSOOP(O)(OEt)2 (a)OOO  Figure 3.  Reagents  and  Conditions: (a) Mg(OH)2, dioxane, reflux, 4 h (5, 29 %; 6, 11 %).  78 9(a)SSOOP(O)(OEt)2OMeO OMe(b)4 SSOO(c)6SSOOSSOOP(O)(OEt)2(d)45SSOOSSOMeOMeOOO  Figure 4.   Reagents  and  Conditions:  (a) O3,  MeOH, -78°C, p-TsOH, DMS, 39%; (b) LiOH·H2O, THF, 70°C, 90%;  (c) Cl2Pd(CN)2  (1.0 mol%),  acetone,  H2O, 70°C, 89%; (d) ) LiOH·H2O, THF, 70°C, 56%.  Ritmaleni and Varindel K. Aggarwal Volume 23 Issue 3 (2012) 191 hours and then cooled down to room temperature. Water (15 mL) was added to the reaction mixture and extracted with CHCl3 (5 x 30 mL). The combined organic extract was dried over MgSO4, filtered and the solvent removed under reduced pressure to give a white solid. Flash column chromatography (20% EtOH/ CHCl3) afforded 5 as white foam (240 mg; 56%); Rf  (10% EtOH/ CHCl3) 0.10; with identical 1H-NMR to the compound on method A as before.  SS5OSS(a)SS10OSSOor (b)OOOOOOO  Figure 5.   Reagents  and  Conditions: (a) H2O2,  NaOH,  -10°C,  20 min.; (b) t-BuOOH, n-BuLi, THF,  -78°C to r.t,  RESULT AND DISCUSSION  To synthesise diaminopimelic acid, the epoxide 10 was required which could be obtained from bis-ketene-dithiocatal-dioxide 5: the precursor to bis-epoxide-dithioacetal-dioxide 10 (Figure 3). The first attempt to synthesise 15 involved the reaction of  an aqueous solution of  the commercially available glutaraldehyde, with a solution of  1,3-dithiane-2-diethylphosphonate 4 with magnesium hydroxide as base, in dioxane. A yield of  29% was the best result that was achieved. This was due to an incomplete reaction, as 11% of  6 was isolated as a by-product (Figure 3). The yields obtained were very low, therefore an alternative procedure was tried. Starting from cyclopentene 7, ozonolysis was carried out, in the presence of  methanol, to give the aldehyde 8 in 39 % yield. HWE reaction of  8 and 4 gave the ketene-dithioacetal-dioxide-dimethylacetal 9 in 90% yield. Hydrolysis of  9 using a palladium catalyst generated ketene-dithioacetal-dioxide-aldehyde 6 (Newman et al., 1954) in an 89% yield. A second HWE reaction was then performed with 4 to give 5, in reasonable yield (Scheme Figure 3).    Figure 6. Reagents and Conditions: (a) H2O2, NaOH, -10°C, 20 min.; (b) CH2Cl2, r.t.    Figure 7.  Reagents  and  Conditions:  (a) Boc-NHNH-Boc,  n-BuLi, 0°C to  –78°C, NH4Cl, 20 min.; (b) MeNHNHMe·2HCl, n-BuLi,  THF, 0°C to –78°C, NH4Cl, 20 min.;                    (c) MeNHNHMe·2HCl, Hünig’s base, CH2Cl2  The above results show that both are reliable routes towards the synthesis of  bis-ketene 5. The first method gave a 17.7% overall yield in a 3-step reaction sequence while the second method gave a 17.5% overall yield in 4 steps. Attempts were made at using basic hydrogen peroxide as an oxidant for the epoxidation reaction of  5. Unfortunately, no product was observed. Monitoring by TLC showed only decomposition products. In addition, tert-butyl-hydrogen peroxide and n-BuLi in THF at –78°C were used as an Synthesis of Bis-Spiroepoxide Dithianedioxide Volume 23 Issue 3 (2012) 192 alternative oxidation system to prepare 10 from 5. However, no reaction occurred and only starting material remained at the end of  the reaction (Figure 5). It is difficult to understand why 5               was unreactive to the epoxidation whereas              the related substrate gave good yields of  the corresponding epoxide. Using basic hydrogen peroxide, the bis-ketene-dithioacetal 5 was consumed and direct reaction with the              amino alcohol 11 was attempted but the  desi-red product could not be isolated (Figure 6). Another route to the diaminopimelic acids was proposed by addition of  a hydrazine derivative to 5. The addition to 5 has been attempted using several different methods. Addition of  Boc-hydrazine or hydrazine dihydrochloride salt to 5, using n-BuLi as a base at -78°C, gave only the decomposi-                   tion products. Attempts to synthesise 14, involved the use of  dimethyl hydrazine dihydrochloride salt with Hünig’s base at room temperature in CH2Cl2 but no reaction occurred even when the reaction was heated up (Figure 6).  CONCLUSION  The synthesis of  bis-spiroepoxide dithianedioxides has been attempted, unfortunately no one of  the routes that have been tried gave the desired product.    ACKNOWLEDGEMENTS We thank QUE Project Faculty of   Pharmacy, Gadjah Mada University, for funding.   REFERENCES Aggarwal, V. K., Roseblade, S. J., Barrell, J. K., Allexander, R., 2002, Highly Diastereoselective Nitrone Cycloaddition onto a Chiral Ketene Equivalent:   Asymmetric Synthesis of  Cispentacin, Org. Lett. 4  1227-1229 Aggarwal, V. K.; Steel, R. M.; Ritmaleni; Barrell, J. K., Grayson I., 2003, Highly EnantioselectiveOxidations of  Ketene Dithioacetals Leading to Trans Bis-sulfoxides, J. Org. Chem., 68 10, 4087-4090 Cox, R. J., 1996, The DAP Pathway to Lysine as a Target for Antimicrobial Agents, Nat. Prod. Rep. 13, 29-43 Gao, Y., Lane-Bell, P.,  Vederas, J. C., 1998, Stereoselective Synthesis of  meso-2,6-Diaminopimelic Acid and Its Selectively Protected Derivatives, J. Org. Chem.  63, 2133-2143 Newman, S. N., Edwards, W. M., 1954, New Reactions Involving Alkaline Treatment of  3-Nitroso-2-oxazolidones. II, J. Am. Chem. Soc. 76 , 1840-1845 Ritmaleni and Aggarwal V. K., 2011, Ring opening of  spiroepoxides dithiane-dioxide with bis-nucleophiles: attempted synthesis of  amino acids, J. of  Scientific Research, 3, 3, 575-586  Ritmaleni and Aggarwal, V. K., 2008, Application of  Spiro-epoxide in the synthesis of  aza β-Lactam, proceeding International Seminar on Chemistry, UNPAD, Bandung, Indonesia Ritmaleni and Aggarwal, V. K., 2009, Asymmetric synthesis of  phenethyl aza-β-Lactam, proceeding Seminar Nasional Pharmacy, UNPAD, Bandung, Indonesia Ritmaleni, Aggarwal, V. K., 2005, Synthesis of  Phenethyl-Aza β-Lactam (1,2-Dimethyl-4(R,S)-Phenethyl-[1,2] Diazetidin-3-one, Indonesian J Pharm., 16, 3, 162-167  Schreiber, S. L., Claus, R. E.,  Reagan, J., 1982, Ozonolytic cleavage of  cycloalkenes to terminally differentiated products, Tet. Lett. 23,  3867-3870 Wade, R., Birnbaum, S. M.,  Winitz, M., Koegel,  R.J.,  Greenstein, J. P., 1957, Preparation  and Properties of  the Isomeric Forms of  α-Amino- and α,[UNK]-Diamin-opimelic Acid, J. Am. Chem. Soc. 79,  648-652 Williams, R. M., Yuan, C., 1992, Asymmetric synthesis of  2,6-diaminopimelic acids, J. Org. Chem. 57,  6519-6527 Work, E., Birnbaum, S. M., Winitz, M., Greenstein, J. P., 1955, Separation of  the Three Isomeric Components of  Synthetic α,ε-Diaminopimelic Acid1, J. Am. Chem. Soc. 77, 1916-1918  

ATTEMPTED SYNTHESIS OF BIS-SPIROEPOXIDE  DITHIANEDIOXIDE

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ATTEMPTED SYNTHESIS OF BIS-SPIROEPOXIDE DITHIANEDIOXIDE

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