XWH - 06 - 1 - 0300 TITLE : Novel and Efficient Synthesis of the Promising Drug Candidate Discodermolide

Asymmetric catalysis and chirality transfer by the 2,3-Wittig rearrangement were combined to provide a syn, anti stereotriad-containing olefinicalcohol in five steps from inexpensive starting materials. Development of this compound, a versatile intermediate for polypropionate synthesis,gave known building blocks for discodermolide. The biosynthetic cascades controlled by the type I polyketidesynthases produce a large and diverse family of naturalproducts, in which the key structural feature is a long, methyl-and oxygen-substituted carbon chain.1 Many of these me-tabolites are important medicinals, and many more havepromising activity.The construction of the long, multiply substituted chainsrequired for the chemical synthesis of the nonaromaticpolyketides is usually based on the iterative lengthening ofan acyclic substituted chain and/or the coupling of severalappropriately substituted chains. In this context, stereotriad-containing building blocks2,3 have found widespread use. Theanti, syn stereotriad that appears in antibacterial (e.g.,erythromycin, streptovaricin) and antifungal (amphotericin)macrolides has been the subject of the most attention. Itappears three times in the structure of the important non-macrolide (+)-discodermolide (1, Figure 1). (+)-Discodermolide is a marine natural product, isolatedin truly meager amounts from the Caribbean sponge Disco-derma dissolute.4 Originally identified in an immunosup-(1) McDaniel, R.; Welch, M.; Hutchinson, C. R. Chem. ReV. 2005, 105,543.(2) Related reviews: (a) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl.1987, 26, 489. (b) Hoffmann, R. W.; Dahmann, G.; Andersen, M. W.Synthesis 1994, 629. (c) Kolodiazhnyi, O. I. Tetrahedron 2003, 59, 5953.(3) For a recent review on the occurrence of stereotetrads in naturalproducts and selected examples of stereotetrad building blocks, see:Koskinen, A. M. P.; Karisalmi, K. Chem. Soc. ReV. 2005, 34, 677.Figure 1. (+)-Discodermolide (1).ORGANICLETTERS 2006Vol. 8, No. 163541-3544 10.1021/ol0612612 CCC: $33.50 © 2006 American Chemical SocietyPublished on Web 07/11/2006 pressant screen, discodermolide was later shown to haveantimitotic activity that results from its binding to microtu-bules.5 Discodermolide is a particularly attractive drugcandidate because it maintains activity against multidrugresistant organisms6 and because it demonstrates synergismwith taxol.7,8 Because of the difficulty in obtaining thisvaluable compound from its deep-sea source, drug develop-ment has necessitated its preparation by total synthesis.Among the impressive total syntheses that have beenreported,9,10 Schreiber’s original synthesis,11 the “gram-scale”preparation by Smith,12 and the subsequent “practical”synthesis of Paterson13 are noteworthy for having suppliedmaterials for biological testing. Proceeding on the premisethat discodermolide will indeed become available in sub-stantial amounts, the Novartis group has scaled up a “hybrid”synthesis and, with synthetic material, advanced discoder-molide to phase I clinical trials.14Retrosynthesis of discodermolide quickly reveals probabledisconnects through or adjacent to the 8,9and 13,14-olefinicbonds. Consequently, the total syntheses of this target havegenerally relied on strategies in which an anti, syn stereotriad-containing building block, functionalized on both ends(Figure 2), is parlayed into three more advanced intermediates, appropriately extended and/or activated for sequentialcoupling.In general, the stereotriad-containing building blocks fordiscodermolide synthesis have been prepared by variationson the chiral aldol strategy for the chain extension of analdehyde derived from the Roche ester 3 (Figure 3). For example, Smith’s “common precursor” or “CP” 2 wasprepared in eight steps from the Roche ester 3.15 There aretwo notable exceptions to this rule. In almost simultaneousdisclosures, Dias16 and Day17 and later the Novartis group18have described the use of recoverable auxiliaries (see 6,Figure 3) as the sources of chiral induction in Evans aldolcondensations with methacrolein. The resulting stereodiadswere then converted to the stereotriad-containing lactone 5.Lactone 5 has been converted to the more advanceddiscodermolide intermediate 4 (see 6 f 5 f 4), a precursorto both the C-1-C-6 and C-9-C-14 synthons in the Smith19and Novartis20 syntheses. It has also been employed in a totalsynthesis of sanglifehrin A21 and converted to a usefulHorner-Wadsworth-Emmons reagent.22 Recently, Myles(4) Gunasekera, S. P.; Gunasekera, M.; Longley, R. E.; Schulte, G. K.J. Org. Chem. 1990, 55, 4912. Additions and corrections: J. Org. Chem.1991, 56, 1346.(5) (a) ter Haar, E.; Kowalski, R. J.; Hamel, E.; Lin, C. M.; Longley, R.E.; Gunasekera, S. P.; Rosenkranz, H. S.; Day, B. W. Biochemistry 1996,35, 243. (b) Hung, D. T.; Chen J.; Schreiber S. L. Chem. Biol. 1996, 3,287. (c) Klein, L. E.; Freeze, B. S.; Smith, A. B., III; Horwitz, S. B. CellCycle 2005, 4, 501. (d) Escuin, D.; Kline, E. R.; Giannakakou, P. CancerRes. 2005, 65, 9021.(6) Kowalski, R. J.; Giannakakou, P.; Gunasekera, S. P.; Longley, R.E.; Day, B. W.; Hamel, E. Mol. Pharmacol. 1997, 52, 613.(7) Huang, G. S.; Lopez-Barcons, L.; Freeze, B. S.; Smith, A. B., III;Goldberg, G. L.; Horwitz, S. B.; McDaid, H. M. Clin. Cancer Res. 2006,12, 298.(8) (a) Honore, S.; Kamath, K.; Braguer, D.; Horwitz, S. B.; Wilson, L.;Briand, C.; Jordan, M. A. Cancer Res. 2004, 64, 4957. (b) Martello, L. A.;McDaid, H. M.; Regl, D. L.; Yang, C.-P. H.; Meng, D.; Pettus, T. R. R.;Kaufman, M. D.; Arimoto, H.; Danishefsky, S. J.; Smith, A. B., III; Horwitz,S. B. Clin. Cancer Res. 2000, 6, 1978.(9) A review of the total syntheses prior to 2003: Paterson, I.; Florence,G. J. Eur. J. Org. Chem. 2003, 12, 2193.(10) For contributions that describe improvements on the reports citedin ref 9, see: (a) Smith, A. B., III; Freeze, B. S.; Xian, M.; Hirose, T. Org.Lett. 2005, 7, 1825-1828. (b) Smith, A. B.; Freeze, B. S.; Brouard, I.;Hirose, T. Org. Lett. 2003, 5, 4405. (c) Paterson, I.; Lyothier, I. J. Org.Chem. 2005, 70, 5494. (d) Paterson, I.; Delgado, O.; Florence, G. J.;Lyothier, I.; O’Brien, M.; Scott, J. P.; Sereinig, N. J. Org. Chem. 2005, 70,150. (e) Paterson, I.; Lyothier, I. Org. Lett. 2004, 6, 4933.(11) (a) Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem.Soc. 1996, 118, 11054. (b) Nerenberg, J. B.; Hung, D. T.; Somers, P. K.;Schreiber, S. L. J. Am. Chem. Soc. 1993, 115, 12621.(12) Smith, A. B., III; Kaufman, M. D.; Beauchamp, T. J.; LaMarche,M. J.; Arimoto, H. Org. Lett. 1999, 1, 1823.(13) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N.J. Am. Chem. Soc. 2001, 123, 9535.(14) Mickel, S. J.; Niederer, D.; Daeffler, R.; Osmani, A.; Kuesters, E.;Schmid, E.; Schaer, K.; Gamboni, R.; Chen, W.; Loeser, E.; Kinder, F. R.,Jr.; Konigsberger, K.; Prasad, K.; Ramsey, T. M.; Repic, O.; Wang, R.-M.;Florence, G.; Lyothier, I.; Paterson, I. Org. Process Res. DeV. 2004, 8,122.(15) Smith, A. B., III; Kaufman, M. D.; Beauchamp, T. J.; LaMarche,M. J.; Arimoto, H. Org. Lett. 1999, 1, 1823.(16) Dias, L. C.; Bau, R. Z.; de Sousa, M. A.; Zukerman-Schpector, J.Org. Lett. 2002, 4, 4325.(17) Day, B. W.; Kangani, C. O.; Avor, K. S. Tetrahedron: Asymmetry2002, 13, 1161.(18) Loiseleur, O.; Koch, G.; Wagner, T. Org. Process Res. DeV. 2004,8, 597.(19) Smith, A. B., III; Beauchamp, T. J.; LaMarche, M. J.; Kaufman,M. D.; Qiu, Y.; Arimoto, H.; Jones, D. R.; Kobayashi, K. J. Am. Chem.Soc. 2000, 122, 8654.Figure 2. Functionalized syn, anti stereotriad building blocks forpolypropionate construction.Figure 3. Origins of key building blocks in the chiral pool. 3542Org. Lett., Vol. 8, No. 16, 2006 and co-workers at Kosan prepared this key lactone bychemical modification of a fermentation product (see 7 f5, Figure 3) from a genetically engineered Streptomyces.23In this paper, we describe the preparation of key disco-dermolide intermediates 5 and 9 from the stereotriad-containing alcohols 8 (Figure 4). Each of these chiral alcohols 8 is readily available by the catalytic asymmetric synthesisof a chiral cis allylic alcohol and then elaboration by theremarkably efficient and totally overlooked “Midland se-quence” (methallylation, 2,3-Wittig rearrangement, protec-tion, and hydroboration).24In 1984, when this efficient chemistry was demonstrated,chiral cis allylic alcohols could be obtained only indi-rectly.25,26 More recently introduced methodology for thecatalytic asymmetric synthesis of allylic alcohols in combi-nation with the Midland sequence allows the preparation ofstereotriad building blocks 8 in only five steps frominexpensive, commercially available starting materials (Scheme1). In this work, we used cyclohexanecarboxaldehyde-derivedintermediates for convenience in handling.Thus, treatment of cyclohexanecarboxyaldehyde (10) withthe complex prepared from Z-propenylzinc bromide andlithiated (+)-N-methylephedrine, according to Oppolzer’sasymmetric addition protocol,27 afforded the cis allylicalcohol 11 in 82% yield (92% ee).28 Alkylation of the alcohol11 gave the doubly allylic ether 12 which, on treatment withtheKOtBu/nBuLi reagent, underwent the 2,3-Wittig rear-rangement to provide alcohol 13 with two chiral centersestablished. The ratio of the syn/anti diastereomers of thisrearrangement product was, as judged by analysis of the 1HNMR spectrum, 97:3.29 Silylation and hydroboration pro-vided the key intermediate 8a. Alternatively, MOM alkyla-tion followed by hydroboration gave alcohol 8b. This strategyallows the preparation of these versatile intermediates in highoverall yield and high enantiomeric excess without thesacrifice of a chiral starting material or the need to recyclea chiral auxiliary.Alcohols 8 are versatile stereotriad-containing buildingblocks. To illustrate the potential of this approach for thepractical synthesis of complex polyketides, we have appliedit in the synthesis of lactone 5 and of vinyl iodide 9, whichare both intermediates in established syntheses of discoder-molide.The TBS monoprotected diol 8a was easily converted tolactone 5 in two steps (Scheme 2). Ozonolysis with dimethyl sulfide workup followed by MnO2 oxidation of the crude(20) Mickel, S. J.; Sedelmeier, G. H.; Niederer, D.; Schuerch, F.; Grimler,D.; Koch, G.; Daeffler, R.; Osmani, A.; Hirni, A.; Schaer, K.; Gamboni,R.; Bach, A.; Chaudhary, A.; Chen, S.; Chen, W.; Hu, B.; Jagoe, C. T.;Kim, H.-Y.; Kinder, F. R., Jr.; Liu, Y.; Lu, Y.; McKenna, J.; Prashad, M.;Ramsey, T. M.; Repic, O.; Rogers, L.; Shieh, W.-C.; Wang, R.-M.; Waykole,L. Org. Process Res. DeV. 2004, 8, 101.(21) Dias, L. C.; Salles, A. G., Jr. Tetrahedron Lett. 2006, 47, 2213.(22) Kagani, C. O.; Bruckner, A. M.; Curran, D. P. Org. Lett. 2005, 7,379.(23) Burlingame, M. A.; Mendoza, E.; Ashley, G. W.; Myles, D. C.Tetrahedron Lett. 2006, 47, 1209.(24) (a) Tsai, D. J. S.; Midland, M. M. J. Org. Chem. 1984, 49, 1842.(b) Tsai, D. J. S.; Midland, M. M. J. Am. Chem. Soc. 1985, 107, 3915.(25) First, a propargyl alcohol was oxidized to an ynone that was thenreduced with a chiral reagent (Midland used R-alpine-borane); thensemihydrogenation provided the allylic alcohol. See: (a) Midland, M. M.;McDowell, D. C.; Hatch, R. L.; Tramontano, A. J. Am. Chem. Soc. 1980,102, 867. (b) Midland, M. M.; Kazubski, A. J. Org. Chem. 1982, 47, 2814.(26) Brinkmeyer, R. S.; Kapoor, V. M. J. Am. Chem. Soc. 1977, 99,8339.(27) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1991, 32, 5777.(28) The ee was obtained by Mosher ester analysis; see SupportingInformation.(29) Careful integration of the 3-4 ppm region of the 1H NMR spectrum(300 Hz) revealed the ratio of syn diastereomer (d, J ) 6.0 Hz centered at3.87 ppm) to anti diastereomer (d, J ) 8.4 Hz, centered at 3.66 ppm) to be97:3. For the assignment, see ref 24a.Figure 4. Examples of polypropionate building blocks availablefrom alcohols 8.Scheme 1. Asymmetric Catalysis Route to Chiral StereotriadBuilding Blocks Scheme 2. Preparation of Lactone 5 Org. Lett., Vol. 8, No. 16, 20063543 lactol 15 gave lactone 5 directly (recrystallized product, 80%for two steps).The MOM-protected diol 8b has been converted to vinyliodide 9, an intermediate in Smith’s later generation disco-dermolide syntheses in which it serves as the precursor tothe C-9-C-14 moiety.10a,b Preparation of vinyl iodide 9 fromalcohol 8b was achieved in three steps (Scheme 3). Introduction of the PMB group was followed by ozonolysis to givethe aldehyde 17. Then, the Stork-Zhao procedure gave theknown building block 9.Thus, chiral syn, anti stereotriad building blocks, usefulfor the preparation of polypropionate antibiotics, may beefficiently accessed by short schemes from inexpensivestarting materials. Asymmetric catalysis replaces the needfor the stoichiometric consumption of a chiral startingmaterial or a chiral reagent or the recycling of a chiralauxiliary. Extension of this strategy to the preparation ofadvanced intermediates for antibiotic synthesis will bedescribed in due course. Acknowledgment. The work described in this com-munication was supported by the National Institutes of Health(CA-87503), the Army Breast Cancer Initiative (BC 051816),and the National Science Foundation (CHE-0131146, NMRinstrumentation). Note Added after ASAP Publication. Figure 2 wasreferenced in error twice in the version posted July 11, 2006;this error was corrected July 13, 2006. Subsequently, an errorwas discovered in the abstract graphic. A corrected versionwas posted July 17, 2006. Supporting Information Available: Detailed descrip-tions of the experimental procedures and complete analyticaldata for all new compounds. This material is available freeof charge via the Internet at http://pubs.acs.org. OL0612612Scheme 3. Preparation of Vinyl Iodide 9 3544Org. Lett., Vol. 8, No. 16, 2006 Asymmetric Catalysis Route to anti,antiStereotriads, Illustrated by Applications Kathlyn A. Parker* and Qiuzhe Xie Department of Chemistry, State UniVersity of New York at Stony Brook,Stony Brook, New York, 11794 [email protected] Received December 12, 2007