ChemInform Abstract: Total Synthesis of (.+-.)-Otteliones A and B

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  ZUSCHRIFTEN 2502  ¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 0044-8249/02/11413-2502 $ 20.00+.50/0  Angew. Chem.  2002 ,  114 , Nr. 13 Total Synthesis of (  )-Otteliones A and B** Goverdhan Mehta* and Kabirul Islam The isolation of the two diastereomeric otteliones A and Bfrom the widely occurring but little studied fresh water plant Ottelia alismoides   and the determination of their structures,which include a unique 4-methylenecyclohex-2-enone sub-structure, was reported in 1998. [1] Collaborative effortsbetween US and Egyptian scientists, who employed high-field NMR spectroscopy techniques and modeling studies, ledto the stereostructure  1  for ottelione B. However, the OHHHOMeOOHHHOMeOOHHHOMeOOHHHOMeO 1 2a2b 2c 123456789101112131'2'3'4'5'6' structure of ottelione A could not be assigned unambiguously,and both  2a  and  2b  were considered as likely formulations,the former being more likely. [1] In 2000, scientists at Rho √ ne-Poulenc Rohrer reinterpreted [2] the NMR spectroscopic dataand proposed an alternate stereostructure  2c  for ottelione A(RPR 112378). Otteliones have attracted much attention asthey exhibit remarkable, broad-ranging biological activity. [1±4] Chinese scientists have reported the antitubercular effect of extracts of   Ottelia alismoid es, which is rich in otteliones, andhave shown in clinical trials that two cases of bilateraltuberculosis of the cervical lymph gland were cured in threemonths. [3] At the National Cancer Institute, in vitro screeningagainst a panel of 60 human cancer cell lines showed thatotteliones exhibited cytotoxicity at n  ±p   levels. [1, 4] Morerecent results have shown that ottelione A is an efficientinhibitor of tubulin polymerization (IC 50  1.2     ) and is ableto disassemble preformed microtubules in a manner reminis-cent of the colchicines, vinblastine, and vincristine. [2] Thecytotoxicity of otteliones can be attributed to the presence of  ters, GOF  1.081,  R 1  0.0463 [  I   2   (  I  )], w R 2  0.1350, min./max.residual electron density -0.989/0.599 eä  3 . Crystal structure deter-mination of   3  4 : C 9 H 12 FeN 2 O 3 ,  M  r  252.05 ( 3 ), C 16 H 24 FeN 4 O 4 ,  M  r  392.24 ( 4 ); orange cocrystals of   3  and  4  (molar ratio 1/1: chromato-graphic work-up of the product mixture of the reaction of [Fe 2 (CO) 9 ]with Me 2 N  C  C-NMe 2  containing the complexes  2 ,  3 ,  4  and[Fe 2 (CO) 6 (   -CNMe 2 ) 2 ] led to a fraction containing  3  and  4  fromwhich the cocrystals were grown from a pentane solution upon coolingfrom 20  30  C), triclinic, space group  P  1 ≈ ,  a  8.831(2),  b  8.944(2),  c  21.354(5) ä,    97.26(3),    95.31(3),    113.20(3)  , V   1519.0(7) ä 3 ,  Z   2,   calcd  1.409 gcm 3 ,  T   160(2) K, 2  max  52.48  ,    1.005 mm  1 ,  F  (000)  672, 13771 reflections, 5573 uniquereflections, 361 parameters, GOF  1.008,  R 1  0.0461[  I   2   (  I  )], wR 2  0.1311, min./max. residual electron density   0.504/0.524 eä  3 . Crystal structure determination of   5 : C 14 H 18 FeN 4 O 4 , M  r  362.17; violet crystals from pentane upon cooling from 20  78  C, triclinic, space group  P  1 ≈ ,  a  8.6326(12),  b  10.222(2),  c  11.114(3) ä,    113.15(2),    105.499(17),    99.58(3)  ,  V   827.2(3) ä 3 ,  Z   2,   calcd  1.454 gcm  3 ,  T   180(2) K, 2  max  53.9  ,    0.936 mm  1 ,  F  (000)  376, 5758 reflections, 3512 unique reflec-tions, 209 parameters, GOF  1.068,  R 1  0.0451[  I   2   (  I  )],  wR 2  0.1324, min./max. residual electron density   0.631/0.685 eä  3 . Crys-tal structure determination of   6 : C 11 H 13 F 3 FeN 2 O 7 S,  M  r  430.14;yellow crystals upon diffusion of diethyl ether in THF at 20  C,triclinic, space group  P  1 ≈ ,  a  6.6594(17),  b  10.490(3),  c  12.988(4) ä,    102.87(4),    100.02(3),    95.78(3)  ,  V   861.8(4) ä 3 ,  Z   2,   calcd  1.658 gcm  3 ,  T   180(2) K, 2  max  50.48  ,    1.062 mm  1 ,  F  (000)  436, 5674 reflections, 2892 unique reflec-tions, 226 parameters, GOF  1.109,  R 1  0.0776[  I   2   (  I  )],  wR 2  0.2197, min./max. residual electron density  0.725/1.778 eä  3 . Instru-ments: STOE STADI-4 four-circle diffractometer with scintillationcounter ( 2  and  5 ) and STOE-IPDS diffractometer with area detector( 3  and  6 ) at   (Mo K  )  0.71073 ä. CCDC-181665±181668 containsthe supplementary crystallographic data for this paper. These data canbe obtained free of charge via www.ccdc.cam.ac.uk/conts/retrie-ving.html (or from the Cambridge Crystallographic Data Centre, 12,Union Road, Cambridge CB21EZ, UK; fax: (  44)1223-336-033; ordeposit@ccdc.cam.ac.uk).[11] a) J. Park, J. Kim,  Organometallics  1995 ,  14 , 4431±4434; b) R.Schobert,  J. Organomet. Chem.  2001 ,  617±618 , 346±359; c) N.Le Gall, D. Luart, J.-Y. Sala¸n, H. des Abbayes, L. Toupet,  J.Organomet. Chem.  2001 ,  617  ± 618 , 483±494; d) Theoretical studiesare currently in progress to elucidate the nature of the Fe-C  interaction in  2 .[12] a) C. Sandorfy in  The Chemistry of the Carbon-Nitrogen Double Bond (Ed.: S. Patai), Interscience, London,  1970 .[13] Additional evidence for the Lewis acidic character of   2  is theformation of adducts with Lewis bases such as PMe 3 . The resultingoctahedral ferracyclobutenones  mer  /  fac -[Fe(CO) 3 PMe 3 (  1 :  1 -C(NMe 2 )C(NMe 2 )C(O))] are related to  1 : T. Rosenauer, A. C.Filippou, unpublished results.[14] a) N. Obata, T. Takizawa,  Tetrahedron Lett.  1969 , 3403±3406; b) N.Obata, T. Takizawa,  Chem. Commun.  1971 , 587±588; c) R. Breslow,F. A. McCormick, C. Werner,  Tetrahedron Lett.  1999 ,  40 , 2447±2448.[15] M. W. Kokkes, D. J. Stufkens, A. Oskam,  J. Chem. Soc. Dalton Trans. 1983 , 439±445.[*] Prof. G. Mehta, K. IslamDepartment of Organic Chemistry, Indian Institute of ScienceBangalore-560012 (India)Fax: (  91)80-360-0936E-mail: gm@orgchem.iisc.ernet.in[**] We would like to thank Professor Thomas R. Hoye for the NMRspectroscopic data for the otteliones for comparison purposes. K.I.thanks the CSIR (India) for a research fellowship.Supporting information for this article is available on the WWWunderhttp://www.angewandte.org or from the author.  ZUSCHRIFTEN  Angew. Chem.  2002 ,  114 , Nr. 13 ¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 0044-8249/02/11413-2503 $ 20.00+.50/0  2503the unique electrophilic 4-methylenecyclohex-2-enone moietythat engages the sulfhydryl groups of the cysteine residues onthe tubulin and disrupts the microtubule dynamics; thissuggests a mechanism of action similar to that of T138067, acytotoxic molecule with antitumor activity that reacts specif-ically with cysteine residue 239 in   -tubulin and is proposed tobind in the close vicinity of the colchicine-binding site. [2, 5±7] Inview of the structural ambiguity and complexity, exceptionaltherapeutic potential, and the desirability to access analogues,otteliones have aroused considerable synthetic interest. Thepresence of four contiguous stereogenic centers, the  cis -hydrindane moiety with side chains at C6 and C8, and the rareand sensitive 4-methylenecyclohex-2-enone functionalitymake otteliones challenging synthetic targets. We reportherein the first total synthesis of racemic otteliones A andB through a short and flexible strategy that fully securestheir structure and has potential for accessing diverseanalogues. [8, 9] The key to our synthetic strategy towards otteliones  1  and  2 was the choice of the readily available Diels±Alder adduct  3 of cyclopentadiene and benzoquinone as the starting point(Scheme 1). [10] We recognized that  3  embodies a readily Scheme 1. Reagents and conditions: a) LiAlH 4 , Et 2 O, 0  C, 78%; b) Zn±TiCl 4 ±CH 2 Br 2 , CH 2 Cl 2 , 0  C, 71%; c) 1) O 3 , MeOH,   78  C; 2) Me 2 S,room temperature, 70%; d) Ph 3 PCH 3  I  ,  n BuLi, THF, 0  C, 89%; e) PCC,CH 2 Cl 2 , 0  C, 91%. PCC  pyridinium chlorochromate. extractable  cis -hydrindane framework (see bold lines in  3 )whose functionalities can be differentiated and elaborated ina regio- and stereoselective manner to the substitution andfunctionalization pattern of the natural products. Lithiumaluminum hydride reduction of   3  led to both 1,4- and 1,2-reduction to furnish the tricyclic hydroxy ketone  4 . [11] Lombardo methylenation [12] of   4  smoothly delivered  5  andset the stage for unraveling the hydrindane moiety. Controlledozonolysis of   5  delivered  6  and  7  (8:1). [11] The major productof the reaction, the lactol aldehyde  6  srcinated through theintramolecular capture of one of the aldehyde moieties of theintermediate dialdehyde  8  by the appropriately positioned   -hydroxy group and concomitant epimerization of the secondaldehyde group to the thermodynamically more stable  exo orientation. The minor product of the ozonolysis reaction, thedome-shaped pentacyclic ether  7 , was derived through acascade intramolecular acetalization process in the intermedi-ate keto dialdehyde  9 , which is formed through the oxidativecleavage of both olefinic bonds of   5  (Scheme 1). Wittigolefination of   6  installed the vinyl side chain of   10  with thecorrect stereochemistry. PCC oxidation of lactol  10  deliveredthe crystalline lactone  11  whose stereostructure correspondedto the revised [2] formulation  2c  of ottelione A and wasfully secured through single-crystal X-ray structure determi-nation.We next focused on the introduction of the benzylic sidechain at C8 by utilizing the lactone functionality of   11 . Theorganolithium reagent derived from  12  readily added to  11  tofurnish  13 , which was further deoxygenated through lithium/ammonia reduction (Scheme 2). This protocol also releasedthe hydroxy group at C1 to yield  14 . PCC oxidation of   14  tothe cyclohexanone  15  was straightforward and set the stagefor the generation of the crucial 4-methylenecyclohex-2- Scheme 2. Reagents and conditions: a)  n BuLi, THF,   78  C  RT, 82%;b) Li, liquid NH 3 , THF,   33  C, 63%; c) PCC, CH 2 Cl 2 , 0  C, 89%;d) 1) LHMDS, PhSeCl, THF,   78  C; 2) H 2 O 2  (30%), CH 2 Cl 2 , 0  C, 61%over two steps; e) TBAF, THF, 0  C, 68%; f) DBU, benzene, 65  C, 83%.DBU  1,8-diazabicyclo[5.4.0]undec-7-ene, LHMDS  lithium 1,1,1,3,3,3-hexamethyldisilazane, TBAF  tetrabutylammonium fluoride. enone moiety, which was produced through the phenylsele-nation±selenoxide elimination sequence to give  16 (Scheme 2). Finally, fluoride-mediated cleavage of the TBSprotecting group in  16  furnished ottelione A ( 2c ), whosespectra are identical to those of the natural product. [1, 2] Synthetic  2c  smoothly underwent epimerization at C9 onexposure tobase (DBU)to give ottelione B ( 1 ), whose spectramatch those of the natural product (Scheme 2).To summarize, we have delineated an 11-step, regio- andstereocontrolled synthesis of the biologically potent naturalproducts otteliones A and B from commercially availablestarting materials in 5.4% overall yield, and have thus fullysecured their structures. Our approach is concise and flexible,  ZUSCHRIFTEN 2504  ¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 0044-8249/02/11413-2504 $ 20.00+.50/0  Angew. Chem.  2002 ,  114 , Nr. 13 [   -PMo 12 O 36 (OH) 4 {La(H 2 O) 4 } 4 ] 5  : The First   -PMo 12 O 40  Keggin Ion and Its Association withthe Two-Electron-Reduced   -PMo 12 O 40  Isomer Pierre Mialane, Anne Dolbecq, Laurent Lisnard,AlainMallard,Je¬ ro √ meMarrot,andFrancisSe¬ cheresse* Dedicated to Professor Dr. Gilbert Herve¬  Polyoxometalates, often considered as soluble metal oxides,have long attracted interest because of their large field of applications, especially in the domain of heterogeneouscatalysis. [1] The famous Keggin ion [  -PMo 12 O 40 ] 3  wasisolated nearly 200 years ago. Isomerization formally resultsfrom successive 60   rotations of the four basic Mo 3 O 13  groups.Although the five isomers   ,   ,   ,   , and    of the Kegginstructure have been postulated, only the  [2] and   [3] isomers of PMo 12 O 40  have been structurally characterized to date.However, the   -Keggin structure has been encountered inrelated compounds which are either polyoxocations, with anAl III12  core and a central tetrahedral Al III , [4] Ga III , or Ge III[5] center, or polyoxoions with Mo V12  and V V12  cores. In the case of Mo and V derivatives, [6] the highly negatively chargedstructure is stabilized by electrophilic capping groups. TheMo V12 O 40  skeleton has been crystallographically charac-terized in four polyoxometalates: the [(C 5 Me 5 Rh III ) 8 -(Mo V12 O 36 )(Mo VI O 4 )] 2  complex [7] has a central Mo VI O 42  tetrahedron and eight Rh III capping centers, the[NaMo 16 (OH) 12 O 40 ] 7  [8, 9] and [H 2 Mo 16 (OH) 12 O 40 ] 6  [8] polyoxo-metalates are stabilized by four capping Mo VI O 3  units andhave a central cavity encapsulating a sodium cation and twoprotons, respectively. Finally, the most recent example is the[Mo 12 O 30 (OH) 10 H 2 {Ni(H 2 O) 3 } 4 ] cluster [10] with two centralprotons and four Ni II capping centers. These compoundshighlight the capacity of the   -{Mo 12 O 40 } core to encapsulatevarious guests. We report here the synthesis and character-ization of the first   -Keggin cation with a central phosphorousatom, stabilized by four {La(H 2 O) 4 } 3  capping groups. Thiscation was isolated in the three different salts  1 ,  2  and  3 : [  -PMo 12 O 36 (OH) 4 {La(H 2 O) 4 } 4 ]Br 5 ¥16H 2 O  1 [  -PMo 12 O 36 (OH) 4 {La(H 2 O) 2.5 Cl 1.25 } 4 ]¥27H 2 O  2 K 3 [  -PMo 12 O 36 (OH) 4 {La(H 2 O) 4.25 Cl 0.75 } 4 ][  -PMo 12 O 40 ]¥28H 2 O  3 Compound  1  is the bromide salt of the [  -PMo 12 O 36 -(OH) 4 {La(H 2 O) 4 } 4 ] 5  polyoxocation. Compounds  2  and  3 have chloride ions directly bound to the capping La 3  centers; 2  is a neutral compound while  3  has an [  -PMo 12 O 40 ] 5  ion asthe counterion.Compounds  1  and  2  were characterized by  31 P NMR, IR,and UV/Vis spectroscopy, elemental analysis, potentiometricamenable to scale-up, geared to provide access to analogues,and involves only one protecting-group manipulation.  [13] Received: March 12, 2002 [Z18878][1] S. E. N. Ayyad, A. S. Judd, W. T. Shier, T. R. Hoye,  J. Org. Chem.  1998 , 63 , 8102.[2] C. Combeau, J. Provost, F. Lanceli, Y. Tournoux, F. Prod×homme, F.Herman, F. Lavelle, J. Leboul, M. Vuilhorgne,  Mol. Pharm .  2000 ,  57  ,553.[3] H. Li, H. Li, X. Qu, Y. Shi, L. Guo, Z. Yuan,  Zhongguo ZhongyaoZazhi (Chin. J. Chin. Mater. Med .  )  1995 ,  20 , 115, 128.[4] J. Leboul, J. Prevost, French Patent WO96/00205,  1996  [ Chem. Abstr  . 1996 ,  124 , 242296].[5] The 4-methylenecyclohex-2-enone moiety has been rarely reported, [6] and therefore the interaction of this electrophilic chromophore withbiological systems has remained unexplored.[6] a) D. F. Murray, M. W. Baum, M. Jones,  J. Org. Chem .  1986 ,  51 , 1;b) M. E. Jung, H. L. Rayle,  Synth. Commun .  1994 ,  24 , 197; c) H. Wild,  J. Org. Chem .  1994 ,  59 , 2748.[7] For the details of the interaction of tubulin with drugs and alkylatingagents, see: a) R. Kuriyama, H. Sakai,  J. Biochem. (Tokyo)  1974 ,  76 ,651; b) R. F. Luduena, M. C. Roach,  Biochemistry  1981 ,  20 , 4444; c) B.Shan, J. C. Medina, E. Shanta, W. P. Franckmoelle, T. C. Chau, R. M.Learned, M. R. Narbut, D. Stott, P. Wu, J. C. Jean, T. Rosen, P. B.Timmermans, H. Beckmann,  Proc. Natl. Acad. Sci. USA  1999 ,  96 ,5686.[8] Our synthetic efforts towards the otteliones began towards the end of 1998, and were initially targeted towards  2a , [9a] the then favoredstructure [1] of ottelione A, and subsequently towards the otherpossible formulation  2b . [9b] In January 2001, we became aware [2] of the alternate formulation  2c , and efforts were directed towards thistarget. We have completed the total synthesis of   2a ± c  and severalother diastereomers of otteliones A and B. Spectral data of   2a , b  didnot match those of the natural product ottelione A (K. Islam,unpublished results).[9] a) G. Mehta, D. S. Reddy,  Chem. Commun .  1999 , 2193; b) G. Mehta,K. Islam,  Synlett   2000 , 1473; for other approaches to the otteliones,see: L. Trembleau, L. Patiny, L. Ghosez,  Tetrahedron Lett.  2000 ,  41 ,6377.[10] a) O. Diels, J. M. Blom, W. Koll,  Justus Liebigs Ann. Chem.  1925 ,  443 ,247; b) R. C. Cookson, E. Crundwell, R. R. Hill, J. Hudec,  J. Chem.Soc .  1964 , 3062.[11] All new compounds reported herein are racemic and fully charac-terized on the basis of IR and  1 H and  13 C NMR spectroscopic data,mass spectrometry, and elemental analyses (see Supporting Informa-tion).[12] L. Lombardo,  Tetrahedron Lett.  1982 ,  23 , 4293.[13] Although the plant O ttelia alismoides  is regarded as a weed and iswidely distributed along irrigation canal linings and rice fields in theAfro-Asian region, otteliones A and B are present only at ppm levels;thus synthetic access through practical routes is necessary to evaluatetheir biological potential.[*] Prof. F. Se¬ cheresse, Dr. P. Mialane, Dr. A. Dolbecq, L. Lisnard,A. Mallard, Dr. J. MarrotInstitut Lavoisier, IREM, UMR 8637Universite¬  de Versailles Saint-Quentin45 Avenue des Etats-Unis, 78035 Versailles (France)Fax: (  33)1-39-25-43-81E-mail: secheres@chimie.uvsq.fr
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