thods to Spiroketals: Classic and Modern Approaches 2 C kadaic Acid Problem Set September 3, 2010 12:00pm, 3005 Malott
Significance of Spiroketals in Nature Ac 12 Cl Ac Spongistatin 1 isolated from Spongia Inhibit tumor growth of 60 human carcinoma cell lines GI 50 values in nm and pm ranges (-)-Aculeatin A isolated from Amomun aculeatum Anti-malarial and some cancer inhibition effects Et 2 C ( )-Berkelic Acid Selective activity toward ovarian cancer VCAR-3 C5 11 C 2 N N Bistramide A Antiproliferative activity against the A2780 ovarian cancer cell line Spongistatin 1: Pettit, G. R.; Cichacz, Z. A.; Gao, F.; erald, C. L.; Boyd, M. R.; Schimdt, J. M.; ooper, J. N. A. J. rg. Chem. 1993, 58, 1302-1304. ( )-Berkelic Acid: Stierle, A. A.; Stierle, D. B.; Kelly, K. J. rg. Chem. 2006, 71, 5357-5360. ( )-Aculeatin A: Salim, A. A.; Su, B.-N.; Chai,.-B.; Riswan, S.; Kardono, L. B. S.; Riskandi, A.; Farnsworth, N. R.; Swanson, S. M.; Kinghorn, A. D. Tetrahedron Lett. 2007, 48, 1849-1853. Bistramide A: Gouiffes, D.; Moreau, S.; elbecque, N.; Bernier, J. L.; enichart, J. P.; Barbin, Y.; Laurent, D.; Verbist, J. F. Tetrahedron 1988, 44, 451-459. 2
Common Approach to Spiroketal Synthesis 3 + Common synthesis of these motifs are through acid-mediated processes. Please propose a mechanism and the two potential stereoisomers that could arise from this reaction. Lastly, identify under thermodynamic conditions, which isomer is favored and why. 3
Acid-diated Spiroketalization + + Proton Transfer Thermodynamic Kinetic - + psuedoaxial psuedoequatorial - 2 2 Why is the conformer with the oxygen in the axial position lower in energy than the equatorial? 4
Anomeric Effect Prefers Antiperiplanar Arrangement n! " interaction! " C Stabilized from overlapping of the oxygen lone pair and the! " orbital of the adjacent C bond. x Equatorial Bond Cannot Experience Interaction Approximate how much energy is gained per anomeric stabilization: 1.4-2.4 kcal/mol Reviews on Spiroketals in Natural Products: (a) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. Rev. 2005, 105, 4406-4440. (b) Favre, S.; Vogel, P.; Gerber-Lemaire, S. Molecules 2008, 13, 2570-2600. 5
Spiroketal Natural Products with Non-Anomeric Acetals A B Pectenotoxin 1 C 2 scillatoxin B R 1 A B R 2 Anomeric Ac Ac Non-Anomeric Cl Spongistatin 1 Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. Rev. 2005, 105, 4406-4440. 6
Conformational Locking to Access Non-Anomeric Motifs 1. Must be a clear difference between the anomeric and non-anomeric configuration. 2. The ring confirmation must be effectively locked to prevent ring-flipping to the anomeric conformer. R R 3. Intramolecular -Bonding. 4. Macrocyclic structures can favor non-anomeric spiroketals. Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. Rev. 2005, 105, 4406-4440. 7
Stereocontrolled Spiroketalization: Kinetic Control Please Rationalize the utcomes TBDPS TIPS Conditions A Ts, RT Conditions B, -63 ºC TIPS TBDPS TIPS TBDPS A: B: < 2% 92% 98% 0% (other 8% from by-pdt) Potuzak, J. S.; Moilanen, S. B.; Tan, D. S. J. Am. Chem. Soc. 2005, 127, 13796-13797. TBDPS TIPS 2 eq. Ti(i-Pr) 4 1:1 C 2 Cl 2 /Acetone -78 ºC to RT P = TIPS P TBDPS >98:2 dr 81% yield P TBDPS Moilanen, S. B.; Potuzak, J. S.; Tan, D. S. J. Am. Chem. Soc. 2006, 128, 1792-1793. 8
Inversion Formal Inversion vs. Retention via Chelation Control TIPS R 3 TIPS R 3 TIPS R 3 Retention X R 2 R 1 R 3 X = or Ti(i-Pr) n R 3 = (C 2 ) 2 TBDPS R 1 X R 2 R 3 R 1 = TIPS for R 2 = TIPS for Ti(i-Pr) n X R 1 R 2 R 3 Kinetic Control From Chelation Potuzak, J. S.; Moilanen, S. B.; Tan, D. S. J. Am. Chem. Soc. 2005, 127, 13796-13797. Moilanen, S. B.; Potuzak, J. S.; Tan, D. S. J. Am. Chem. Soc. 2006, 128, 1792-1793. 9
ther Chelation-Controlled Strategies To Accessing Non-Anomeric Spiroketals Np L n M ML n R Np Acid CSA CSA ZnBr 2 MgTf 2 ZnCl 2 Solvent :C 2 Cl 2 C 2 Cl 2 C 2 Cl 2 C 2 Cl 2 C 2 Cl 2 Anomeric:Non 6:1 1:1 1:2.3 1:2.6 1:4.3 Kinetic Control Evans, D. A.; Trotter, B. W.; Cote, B.; Coleman, P. J.; Dias, L. C.; Tyler, A. N. Angew. Chem. Int. Ed. 1997, 36, 2744. Bn TBS TBS S S 1) Cl,, 85% 2) g(cl 4 ) 2, CaC 3 CN: 2 (9:1) Bn Bn Bn Ca 2+ 10:1 ratio Residual Ca 2+ ions Cl 4 C 2 Cl 2 :CN (10:1) 87% over 2 steps 2:1 ratio Treated with Cl 4 Prior To Purification Resulting in Ca 2+ ions Smith, A. B., III; Doughty, V. A. ; Lin, Q.; Zhaung, L.; McBriar, M. D.; Boldi, A. M.; Moser, W..; Murase, N. Nakayama, K.; Sobukawa, M. Angew. Chem. Int. Ed. 2001, 40, 191. 10
Reductive Cyclization Approach: Rychnovsky Group n-c 5 11 CSA, 31% n-c 5 11 TMSCN BF 3 Et 2-78 ºC 75% n-c 5 11 CN Single Diastereomer 1) MsCl, pyr. 2) LiCl, DMF 82% over 2 steps n-c 5 11 CN Cl LiDBB TF, -78 ºC 63% yield n-c 5 11 btained as single Diastereomer Predict Which ne Cl 2 SET n-c 5 11 n-c 5 11 Li t-bu t-bu Li Formal Retention of Configuration lithium 4',4'-ditert-butylbiphenylide LiDBB Takaoka, L. R.; Buckmelter, A. J.; LaCruz, T. E.; Rychnovsky, S. D. J. Am. Chem. Soc. 2005, 127, 528-529. 11
chanism of Reductive Cyclization R 1 CN R 2 LiDBB R 1 R 2 Fast Li, 1e - pathway a R 1 ΔG = 1.86 kcal/mol R 2 Li R 1 Li R 3 Retention R 1 Li R 3 Pdt A Pdt B R 2 = (C 2 ) 3 P()(Et) 2 R 1 R 2 Li, 1e - pathway b R 1 R 2 Li Inversion R 1 R 1 R 3 = P()(Et) 2 R 1 Li R 3 Pdt B Product A Non-Anomeric Product B Anomeric Retention What is the relative energies of the axial and equatorial radicals? La Cruz, T. E.; Rychnovsky, S. D. J. rg. Chem. 2007, 72, 2602-2611. 12
Application in the Total Synthesis of Attenol A TBS PhS (Et) 2 P() TBS CN LiDBB -78 ºC Attenol A Shows Moderate Cytotoxicity Against P388 Cells 78:1 ratio by GC 94% yield TBS La Cruz, T. E.; Rychnovsky, S. D. J. rg. Chem. 2007, 72, 2602-2611. 13
Can the Non-Anomeric Core of Attenol Act as a Prodrug? TBAF p buffer TBS time p T (ºC) time (h) ratio (nonanomeric:anomeric) 5.8 5 4 23 23 23 72 48 22 no epimerization no epimerization 10:1 Solid tumors have low extracellular p (ca. 6.8), where acidic media could trigger epimerization. Because no epimerization occurs close to physiological p, it was determined too stable and not a proper pro-drug candidate. La Cruz, T. E.; Rychnovsky, S. D. J. rg. Chem. 2007, 72, 2602-2611. 14
Cycloaddition Approach to Berkelic Acid 2 C Et Et C 5 11 C 2 1) AgSbF 6, Et 2 RT, 2 h 2) (Bu 3 Sn) 2 (35 eq.) PhC 3, reflux, 8 h 35% over 2 steps Et 2 C ( )-Berkelic Acid C 2 C5 11 2 C Ag + Ag + C 2 Et C 2 C 2 Et C 5 11 C 5 11 Bender, C. F.; Yoshimoto, F. K.; Paradise, C. L.; De Brabander, J. K. J. Am. Chem. Soc. 2009, 131, 11350-11352. 15
TBDPS If Time Permits: Furstner Approach to Berkelic Acid C 2 TBS TBS Cl :C 2 Cl 2 0 ºC to RT 94% yield C5 11 C 2 ent-berkelic Acid in situ generation of 3 + C 5 11 C 2 dr = >12.5:1 Spiroketalization C 5 11 C 2 C 2 Michael and Acyl Migration C 5 11 Buchgraber, P.; Snaddon, T. N.; Wirtz, C.; Mynott, R.; Goddard, R.; Furstner, A. Angew. Chem. Int. Ed. 2008, 47, 8450-8454. C 5 11 16