Accepted Manuscript Protection-free, short and stereoselective synthesis of ieodomycin A and B

Please download to get full document.

View again

of 5
8 views
PDF
All materials on our website are shared by users. If you have any questions about copyright issues, please report us to resolve them. We are always happy to assist you.
Document Description
Accepted Manuscript Protection-free, short and stereoselective synthesis of ieodomycin A and B
Document Share
Document Tags
Document Transcript
  Accepted Manuscript Protection-free, short and stereoselective synthesis of ieodomycin A and BN. Nageswara Rao, H. M. MeshramPII:S0040-4039(13)01038-1DOI:http://dx.doi.org/10.1016/j.tetlet.2013.06.071Reference:TETL 43124To appear in: Tetrahedron Letters  Received Date:9 May 2013Revised Date:13 June 2013Accepted Date:15 June 2013Please cite this article as: Nageswara Rao, N., M. Meshram, H., Protection-free, short and stereoselective synthesisof ieodomycin A and B, Tetrahedron Letters   (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.06.071This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customerswe are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, andreview of the resulting proof before it is published in its final form. Please note that during the production processerrors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.    Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered. Protection-free, short and stereoselective synthesis of ieodomycin A and B  N. Nageswara Rao, H. M. Meshram * OH OHOO IeodomycinA OOHO Ieodomycin B OHNOSS 9 OH Total 7 Steps  Leave this area blank for abstract info.    Tetrahedron Letters 1 Protection-free, short and stereoselective synthesis of ieodomycin A and B  N. Nageswara Rao, H. M. Meshram *   Medicinal Chemistry and Pharmacology Division Indian Institute of Chemical Technology, Hyderabad  –  500 007, India. hmmeshram@yahoo.com, Ph. No. 9140271640 Abstract. A   concise, protection-free and improved stereoselective total synthesis of ieodomycin A and ieodomycin   B is described. The key steps involved in the synthesis are Evans aldol reaction and nucleophilic addition of potassium salt of mono methyl malonate .   Keywords : Evans aldol, ieodomycin, 4-pentyn-1-ol, lactonization, protection-free.   Marine life serves as a good resource of food, medicine and other raw materials that are important to mankind. 1  For decades, many biological active compounds which possess antitumor and antimicrobial activities have been discovered that are produced by a variety of marine organisms. 2  Of late, new compounds called ieodomycins A - D  (Figure 1) were isolated from marine bacteria belonging to  Bacillus species and are known to exhibit broad spectrum of antibacterial activity through inhibiting the growth of both gram positive and gram negative bacteria. 3  Due to their promising biological activity, unique structure, and scarce availability from the natural source, the ieodomycins have attracted the attention to synthetic organic chemists. Recently, ieodomycin C  and D  were synthesized from propylene epoxide 4  and later ieodomycin A  and B  were synthesized from D-glucose based on chiral pool approach in as many as 15 steps. 5  Based on promising biological activity of ieodomycin A  & B , we herein reported a short stereoselective synthesis of the ieodomycin A  and B . OOHOIeodomycin  B  ( 2 )OH OHOOIeodomycin  A  ( 1 )OH OHOHO OHOHOIeodomycin  C  ( 3 ) Ieodomycin  D  ( 4 )   Figure1.  Chemical structure of ieodomycin products 1-4 . The retrosynthetic analysis of the target molecule was outlined in the Scheme 1. The synthesis of the target compound 2  was envisioned to be obtained from the anti-1,3-diol 1 ,   which could be derived from 10  by anti -hydroxy induced reduction. Compound 10  would be constructed by nucleophilic addition of aldol adduct 9  with potasium salt of mono methyl malonate. Precursor 9  was proposed to obtain from by asymmetric aldol addition of acetylthiazolidinethione onto aldehyde 7. The compound 7 can be easily prepared by 4-pentyne-1-ol by using known literature procedures. In a word, the proposed synthesis aims to better the existing synthesis by reducing the number of steps involved and it takes only 7 steps. O OOH 2 OH OHOO 1 OH OOO 10 OHNOSS 9 OH 6 OH   Scheme 1.  Retrosynthetic analysis to 1  and 2 The synthesis of target compounds ieodomycin A  and B  was illustrated in the Scheme 2.   The synthesis started with 4- pentyne-1-ol converted to a methylaluminated intermediate using trimethyl aluminium and zirconcene dichloride which on treatment with iodine gave desired vinyl iodide. Coupling of vinyliodide with vinyltributyltin 6  catalyzed by palladium catalyst afforded diene 6  in 75% yield as a single isomer. The  primary alcoholic functionality of compound 6  was subjected to Swern oxidation to afford the aldehyde 7 . 7   After the usual workup procedures, the aldehyde was used for    the next step without further purification. Secondary alcohol 9  can be obtained by an asymmetric aldol addition of known acetylthiazolidine  –  thione 8  and aldyhde 7 . 8 The titanium enolate generated with titanium tetrachloride and DIPEA gave the predominantly desired isomer 9  in excellent yield. The thiazolidinethione auxiliary of compound 9a  can be displaced by a carbon nucleophile without the need for  protection of the free hydroxyl group. This protocol is adopted from an existing method. 9  Thus, treatments of aldol adduct 9  with the potassium salt of mono methyl malonate 10  and MgCl 2  in the presence of imidazole led to  β  -keto-ester 10 . But the reaction was too sluggish with an unacceptable yield. To enhance the rate of the reaction and yield, the reaction was  performed with MgI 2.  The reaction was completed within 8 h    Tetrahedron Letters 2 with 87% yield. The β -hydroxy ketone was subjected to hydroxyl-directed reduction to give anti -1, -3-diol 1 in good yield and diastereoselectivity (85%). 11  The acid mediated lactonization of the compound afforded the target compound  2 (Scheme 2). Finally, the compound 1  was readily lactonized to compound 2  by  p -toluene sulfonic acid or camphor sulfonic acid in benzene in 87% yield. 5  The anti -1, -3-diol undergoes lactonization even with silica gel to afford the target compound 2. The optical rotation and spectral data of synthetic compounds 1  and 2  ( 1 H NMR and 13 C NMR) were found to be in good agreement with those of isolated natural  products. 3   OHOHNOSSOH OOOOHIOHOO OOHNOSSKOOOO 925 67 OH OHOO 1ab  (85%) cd ef gh 75% (9:1)87% 85%88%75%85% 810  Scheme 2. Synthesis of iedomycin A  ( 1 ) and ieodomycin B  ( 2 ). Reagents and conditions: (a) Cp 2 ZrCl 2 , AlMe 3 , CH 2 Cl 2  -15 0 C-r.t, 12 h; (b) I 2 , THF, -30 0 C, K  2 CO 3 , 1 h; (c) Vinyl tributyltin, Pd(PPh 3 ) 2 Cl 2 , DMF, rt, 8 h; (d) (COCl) 2 , DMSO, Et 3  N, -78 0 C, 2 h; (e) TiCl 4 , CH 2 Cl 2 , DIPEA, -78 0 C; 7 h; (f) MgI 2 , Imidazole, THF, 5 h; (g) Me 4  NBH(OAc) 3 , AcOH/CH 3 CN (1:2), -40 0 C, 10 h; (h) (5 mol%) p-TsOH or CSA, C 6 H 6 , 0 0 C. In conclusion, we have successfully completed the stereoselective total synthesis of ieodomycin A  and   B from commercially available 4-pentyne-1-ol in a highly concise way and the overall yield is 26.44%. The present strategy improved an existing synthesis by achieving the target in lesser steps. A modified form of an existing methodology of chopping the auxiliary after the Evans aldol reaction was found extremely useful in this synthesis. Acknowledgments   N N R thanks UGC for the award of a fellowship and Dr. A. Kamal, HOD, MCP Division for his support and encouragement. References 1.   Blunt, J. W.; Copp, B. R.; Hu, W. P.; Munro, M. H. G.;  Northcote, P. T.; Prinsep, M. R.  Nat. Prod. Rep.   2009 , 26  , 170. 2.   (a) Oguntoyinbo, F. A.  Afr.    J. Biotechnol  . 2007 , 6  , 163; b) Devi, P.; Wahidullah, S.; Rodrigues, C.; Souza, L. D.  Mar. Drugs   2010 , 8 , 1203; c) Lu, X. L.; Xu, Q. Z.; Liu, X. Y.; Cao, X.; Ni, K. Y.; Jiao, B. H. Chem. Biodiversity   2008 , 5 , 1669. 3.   Mondol, M. A. M.; Kim, J. H.; Lee, M. A.; Tareq, F. S.; Lee, H. S.; Lee. Y. J.; Shin. H. J.  J. Nat. Prod.   2011 , 74 , 1606. 4.   Chinnababu, B.; Reddy, S. P.; Reddy, D. K.; Rao, D. C.; Venkateswarlu, Y. Synthesis   2012 , 44 , 311. 5.   Videsh, T. S.; Sandeep, B.; Prasad, P.; Debnath, B.; Summon, K. Tetrahedron Lett. 2013 , 54 , 2489. 6.   Parkinson, C. J.; Stoermer, M. J.  J. Organomet. Chem.   1996 , 507  , 207. 7.   (a) Wender, P. A.; Tebbe, M. J. Synthesis   1991 , 1089; (b) Clausen, D. J.; Wan, S.; Floreancig, P. E.  Angew. Chem.,  Int. Ed.   2011 , 50 , 5178. 8.   (a) Kanada, R. M.; Itoh, D.; Nagai, M.; Niijima J., Asai,  N.; Mizui, Y.; Abe, S.; Kotake, Y.  Angew. Chem., Int. Ed.   2007 , 46  , 4350; (b) Skaanderup, P. R.; Jensen, T. Org.  Lett.   2008 , 10 , 2821. 9.   (a) Smith, T. E.; Djang, M.; Velander, A. J.; Downey, C. W.; Carroll, K. A.; Van Alphen, S. Org. Lett. 2004  , 6, 2317; (b) Brooks, D. W.; Lu, D. -L.; Masamune, S.  Angew. Chem., Int. Ed. Engl.   1979 , 18 , 72. 10.   Shang, R.; Ji, D.-S.; Fu, Y.; Liu, L.  Angew. Chem., Int. Ed.   2011 , 50 , 4470; 11.   Evans, D. A.; Chapman, K. T.; Carreira, E. M.  J. Am. Chem. Soc.   1988 , 110 , 3561. Spectral data of representative compounds:   (E)-5-iodo-4-methylpent-4-en-1-ol ( 5 ):   IR  : ν max  3377, 2940, 2873, 1616, 1443, 1269, 1044, 765 cm -1 ; 1 H NMR (300MHz, CDCl 3 ): δ  5.91 (s, 1H), 3.60 (t,  J   = 6.4 Hz, 2H), 2.50 (br. s, 1H), 2.29 (t,  J   = 7.6 Hz, 2H), 1.84 (s, 3H), 1.63-1.75 (m, 2H); 13 C NMR (75 MHz, CDCl 3 ): δ  147.4, 75.0, 61.7, 35.7, 30.4, 23.8; m/z (ESI); 227 [M+H] + . (E)-4-methylhepta-4,6-dien-1-ol ( 6  ) : IR:  ν max  3356, 2931, 2869, 1646, 1434, 1056, 989, 898 cm -1 ; 1 H NMR (300MHz, CDCl 3 ): δ  6.57 (ddd,  J   = 10.5,  J   = 10.5,  J   = 16.6 Hz, 1H), 5.88 (d,  J   = 10.5 Hz, 1H), 5.10 (d,  J   = 16.6 Hz, 1H), 5.00 (d,  J   = 10.5 Hz , 1H), 3.64 (q,  J   =12.0 Hz, 2H), 2.14 (t,  J   = 7.5 Hz, 2H), 1.77 (s, 3H), 1.62-1.75 (m, 2H); 13 C NMR (75 MHz, CDCl 3 ): δ  133.1, 125.7, 114.9, 62.5, 35.9, 30.5, 16.4; m/z (ESI); 127 [M+H] + . (R, E)-1-((R)-4-benzyl-2-thioxothiazolidin-3-yl)-3-hydroxy-6-methylnona-6,8-dien-1-one ( 9 ): [α] 25D  = -110 (c 1.9, CHCl 3 ); IR  : ν max  3447, 2925, 1696, 1341, 765 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ  7.24-7.38 (m, 5H), 6.57 (ddd,  J   = 10.5,  J   = 10.5,  J   = 16.6 Hz, 1H), 5.91 (d,  J   = 10.5 Hz, 1H), 5.35-5.44 (m, 1H), 5.11 (d,  J   = 16.6 Hz, 1H), 5.00 (d,  J   = 10.5 Hz, 1H), 4.08-4.19 (m, 1H), 3.65 (dd,  J   = 3.0,  J   = 17.3 Hz, 1H), 3.41 (dd,  J   = 7.5,  J   = 11.3 Hz, 1H), 3.22 (dd,  J   = 3.7,  J   = 11.3 Hz, 1H), 2.99-3.18 (m, 2H), 2.89 (d,  J   = 11.3 Hz, 1H), 2.68 (br. s,    Tetrahedron Letters 3 1H), 2.10-2.31 (m, 2H), 1.78 (s, 3H), 1.61-1.76 (m, 2H); 13 C  NMR (75 MHz, CDCl 3 ): δ  201.2, 172.9, 138.5, 136.2, 130.0, 129.2, 128.7, 127.1, 125.7, 114.8, 68.1, 67.2, 45.7, 36.6, 35.5, 34.1, 31.9, 16.5; m/z (ESI); 398 [M+Na] + . HRMS: m/z   calc. for C 20 H 25  NO 2 S 2  Na: 398.1222, found: 398.1218. (R,E)-methyl-5-hydroxy-8-methyl-3-oxoundeca-8,10-dienoate ( 10 ): [α] 25D  = -33 (c 1.5, CHCl 3 ); IR  : ν max  3445, 2926, 1713, 1647, 1258, 760 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ  6.56 (ddd,  J   = 10.5,  J   = 10.5,  J   = 16.7 Hz, 1H), 5.89 (d,  J   = 10.5 Hz, 1H), 5.10 (d,  J   = 16.7 Hz, 1H), 5.00(d,  J   = 10.5 Hz, 1H). 4.03-4.10 (m, 1H), 3.75 (s, 3H), 3.28 (d,  J   = 4.5 Hz, 1H), 2.81 (br, 1H), 2.73 (d,  J   = 3.2 Hz, 1H), 2.70 (d,  J   = 8.6 Hz, 1H), 2.17-2.25 (m, 1H), 2.09-2.16 (m, 1H), 1.72-1.82 (m, 1H), 1.77 (s, 3H), 1.62-1.68 (s, 1H), 1.52-1.60 (M, 1H); 13 C NMR (75 MHz, CDCl 3 ): δ  203.4, 167.2, 133.0, 125.8, 119.3, 115.0, 76.9, 67.0, 49.5, 41.3, 35.5, 34.3, 16.5; m/z (ESI); 263 [M+H] + . HRMS: m/z   calc. for C 13 H 20 O 4  Na: 263.1252, found: 263.1253. (3S,5R,E)-methyl-3,5-dihydroxy-8-methylundeca-8,10-dienoate (  1   ):   [α] 25D  = +17.42 (c 0.7, CHCl 3 ); IR  : ν max  3422, 2925, 2855, 1730, 1250, 1076 cm -1 ; 1 H NMR (500 MHz, CD 3 OD): δ  6.57 (ddd,  J   = 10.5,  J   = 10.5,  J   = 16.7 Hz, 1H) 5.86 (d,  J   = 10.5 Hz, 1H), 5.04 (d,  J   = 16.7 Hz, 1H), 4.93 (d,  J   = 10.5 Hz, 1H), 4.22-4.28 (m, 1H), 3.73-3.79 (m, 1H), 3.66 (s, 3H), 2.40-2.59 (m,  J   = 4.9,  J   = 9.9 Hz, 2H), 2.16-2.21 (m, 1H), 2.07-2.14 (m, 1H), 1.75 (s, 3H), 1.49-1.58 (m, 4H); 13 C  NMR (125 MHz, CD 3 OD): δ  173.9, 140.0, 134.6, 126.9, 115.0, 68.7, 66.5, 52.0, 45.2, 43.8, 37.4, 36.9, 16.7; m/z (ESI); 265 [M+H] + . HRMS: m/z   calc. for C 13 H 22 O 4  Na: 265.1405, found: 265.1410. (4S,6R)-4-hydroxy-6-((E)-3-methylhexa-3,5-dienyl) tetrahydro-2H-pyran-2-one (  2   ):   [α] 25D  = +19.63 (c 0.9, CHCl 3 ); IR  : ν max  3425, 2961, 2925, 1725, 1260, 1088, 1021, 799 cm - 1; 1H NMR (300 MHz, CD 3 OD): δ  6.58 (ddd,  J   = 10.6,  J = 10.6,  J   = 16.6 Hz, 1H), 5.88 (d,  J   = 10.6 Hz, 1H), 5.07 (d,  J   = 16.6 Hz, 1H), 4.97 (d,  J   =10.6 Hz, 1H), 4.13-4.32 (m, 2H), 2.86 (dd,  J   = 5.3,  J   = 16.6 Hz, 1H), 2.36 (dd,  J   = 7.2,  J   = 16.8 Hz, 1H), 2.21-2.31 (m, 2H), 2.10-2.21 (m, 1H), 1.77 (s, 3H), 1.78-1.85 (m, 1H), 1.45-1.58 (m, 1H); 13 C NMR (75 MHz, CD 3 OD): δ  173.9, 140.0, 134.6, 126.9, 115.0, 68.7, 66.5, 52.0, 45.2, 43.8, 37.4, 36.9, 16.7; m/z (ESI); 233 [M+H] + . HRMS: m/z   calc. for C 15 H 14  N 2 O 2 F: 233.1145, found: 233.1144.
Similar documents
View more...
Search Related
We Need Your Support
Thank you for visiting our website and your interest in our free products and services. We are nonprofit website to share and download documents. To the running of this website, we need your help to support us.

Thanks to everyone for your continued support.

No, Thanks