Utilization of Ring Closing Metathesis in Alkaloid Synthesis I. Synthetic Studies on the Immunosuppressant FR II. Toward the Total Synthesis of Lundurines A-C Suvi T. M. Simila Martin Group, University of Texas at Austin Group Meeting, Research September 17, 2007

Utilization of Ring Closing Metathesis in Alkaloid Synthesis I. Synthetic Studies on the Immunosuppressant FR II. Toward the Total Synthesis of Lundurines A-C Suvi T. M. Simila Martin Group, University of Texas at Austin Group Meeting, Research September 17, 2007

Retrosynthetic Analysis

Addition of the Allylzinc to the Chiral Imine Simila, S. T. M.; Martin, S. F. J. Org. Chem. 2007, 72, Model studies: Simila, S. T. M.; Reichelt, A.; Martin, S. F. Tetrahedron Lett. 2006, 47, 2933.

Weinreb’s Results Overshadowing Our Endgame Weinreb. et al. J. Org. Chem. 2006, 71, 2046.

Summary Part I A new route to azaspirane core structure of FR was developed via a nucleophilic addition to an acyl iminium ion followed by a ring-closing metathesis Lactone-lactam rearrangement gave the azatricyclic core structure of FR Ethylallylcarbamate protecting group and its cleavage was developed Allylzinc reagent was developed and it was successfully added to the chiral imine, however with lack of diastereoselectivity that persuaded us to divert our initial studies toward (-)-FR901483

II. Toward the Total Synthesis of Lundurines A-C Isolation and Biological Activity - Isolated in 1995 from the leaf extract of the Borneo species Kopsia tenuis - Biological studies were reported in Lundurine B is cytotoxic against B16 melanoma cells (in vitro); 2.8 µg/mL - Unique hexacyclic core containing dihydroindole-cyclopropane moiety - No reported total syntheses to date Kam, T. S.; Yoganathan, K.; Chuah, C. H. Tetrahedron Lett. 1995, 36, 759. Kam, T. S.; Lim, K.; Yoganathan, K.; Hayashi, M.; Komiyama, K. Tetrahedron 2004, 60,

Retrosynthetic Analysis

Synthesis of the Ugi Components: 2-Vinyltryptamine Trivinylboroxane: O’Shea, et. al. J. Org. Chem. 2002, 67, 4968.

Synthesis of the Ugi Components: Masked Divinylketone Blicke, F.; McCarty, F. et. al. J. Org. Chem. 1959, 24, Sapi, J. et. al. Synthesis 1988, 619. Ward, D. E. et. al. J. Org. Chem. 2002, 67, Detty, M. L. et. al. Organometallics 1992, 11, Angiolini, L. et al. Polymer 1989, 30, 564.

Successful Ugi Reactions Convertible isocyanide: Armstrong, R. W.; Keating, T. A. J. Am. Chem. Soc. 1999, 118, Hoffmann type elimination trials of the methyl piperidine ring unsuccessful

Ugi with the Thiopyranone Sulfoxide eliminations: Rapoport, H. et. al. J. Org. Chem. 1980, 45, Galons, H. et. al. Synth. Commun, 1991, 21, 1743.

Ugi with Bisthiophenylpentanone

Ugi with the 5-Methoxy-2-vinyltryptamine

Protected Tryptamine Piece

Ugi with the 5-Methoxy-2-vinyltryptamine

Synthesis of the RCM Precursor

Execution of the Back-up Plan

Preparation of the Divinylglycine Piece Bis-conjugate addition: Galons, H. et. al. Synth. Commun, 1991, 21, 1743.

Preparation of the Divinylglycine Piece Bis-conjugate addition: Galons, H. et. al. Synth. Commun, 1991, 21, 1743.

Successful Formation of the RCM Precursors

Tandem-RCM Attempts Grubbs catalysts: Grubbs, R. H. Angew. Chem. Int. Ed, 2006, 45, Lance: Grubbs, R. H. et. al. Org. Lett. 2007, 9, Schrock catalysts: Schrock, R. R. Angew. Chem. Int. Ed. 2006, 45, 3748.

Possible Explanations for Unsuccessful RCM Modes of catalyst inhibition: Grubbs, R. H. Acc. Chem. Res, 1995, 28, 446.

Troubleshooting the Functional Group Problems

Examples of 8-membered RCM: Martin, S. F. et. al. Tetrahedron Lett. 1994, 35, 691. Lubell, W. D. et. al. J. Org. Chem. 2005, 70, Rodriguez, J. Angew. Chem. Int. Ed. 2006, 45, Bennasar, M.-L. Tetrahedron, 2007, 63, 861.

Ts-indole and Cyanide in Place of the t-Butyl Ester //

Methyl Ester in Place of the t-Butyl Ester

Reduction of the Ester

Substrate for 8-Membered Ring Closure

End Game

Summary Part II Ugi reactions with cyclic ketones appeared to give better results than acyclic Successful route to the RCM precursor via Ugi was developed; however, the low yielding Ugi step steered us to develop another route Bisalkylation of an imine, reductive amination and acylation/alkylation provided an efficient route to the RCM precursors Preliminary experiments to cyclize 5- and 8-membered rings have been accomplished and further studies are in progress

Acknowledgements University of Texas at Austin Prof. Stephen F. Martin Martin Group Lab 1 $$$$$$ Robert A. Welch Foundation NIH (GM 25439) RochePfizerMerck Materia Inc. for catalyst support Prof. Robert H. Grubbs for catalyst support

Woerpel: Inside Addition Woerpel K. A. et al. J. Am. Chem. Soc. 1999, 121,

Addition to the Acyl Iminium Ion Woerpel’s Model Stereoselective additions to oxonium ions: Woerpel, K. A. et al. J. Am. Chem. Soc. 1999, 121, Stereoselective additions to iminium ions: Martin, S. F.; Bur, S. K. Org. Lett. 2000, 2, 3445; Tetrahedron Lett. 1997, 38, 7641.

Hydroboration of the Azaspirane Predicted selectivity:

Development of a New Protecting Group Substituted Alloc

Development of the Deprotection Conditions EntryNucleophileSolventTime (25 °C)Yield 1MorpholineCH 2 Cl 2 /EtOAc4 h>99% 2MorpholineCH 2 Cl 2 3 h>99% 3PyrrolidineCH 2 Cl 2 1 h>99% 4PhthalimideCH 2 Cl 2 >18 hN/A 5Phthalimide K-saltCH 2 Cl 2 >18 hN/A 6HoBt/DIEACH 2 Cl 2 >18 hN/A 7BenzotriazoleCH 2 Cl 2 45 min>99% 8*Benzotriazole (1 equiv)CH 2 Cl 2 /[0.45 M]45 min>99% *) 10-mol% Pd(PPh 3 ) 4

Allylsilane Addition Allylsilane acid synthesis: Weiler, L. Can. J. Chem. 1983, 61, 2530.

Staudinger/Aza-Wittig/Ugi

Towards the Divinyl Functionality