Burke Group Literature Seminar7 September 2007

433 Roger Adams LabHosted by Dan PalaciosThe Synthesis of diazonamide A

1) Nicolaou, K.C.; Bella, M.; Chen, D.Y.-K.; Huang, X.; Ling, T. Snyder, S.A.Angew. Chem. Int. Ed. Engl. 2002, 41, 3495-3499. (TMA, ID, HCT, SGB)

2) Nicolaou, K.C. et. al. Angew. Chem. Int. ed. Engl. 2001, 40, 4705-4709. Nicolaou, K.C. et. al.Angew. Chem. Int. Ed. Engl. 2003, 42, 1753-1758. (EPG, KCG, DWR, BCW, SJL)

3) Burgett, A.W.G.; Li, Q.; Wei, Q.; Harran, P.G.; Angew. Chem. Int. Ed. Engl. 2003, 42, 4961-4966.(DMK, EMW, PW, JP)

For reviews of the syntheses see: Nicolaou, K.C.; Chen, D.Y.-K.; Huang, X.; Ling, T.; Bella, M.; Snyder,S.A. J. Am. Chem. Soc. 2004, 126, 12888-12896. Nicolaou, K.C. et. al. J. Am. Chem. Soc. 2004, 126,12987-12906. Ritter, T.; Carreira, E.M. Angew. Chem. Int. Ed. Engl. 2002, 41, 3495-3499

Isolation of the diazonamides

Linquist, N.; Fenical, W.; Van Duyne, G.D.; Clardy, J. J. Am. Chem. Soc. 1991, 113, 2303-2304

Initial Synthesis of “Diazonamide A”

“Remarkably, this material is different from a sample of natural (–)-diazonamide A,Particularly by qualitative measures such as its stability and its mobility on a thin-layer chromatography plate. The former issue is most troubling”.

Li, J.; Jeong, S.; Esser, L.; Harran, P.G. Angew. Chem. Intl. Ed. Engl. 2001, 40, 4765-4769

Revising the Structure

Li, J.; Burgett, A.W.G.; Esser, L.; Amezcua, C.; Harran, P.G. Angew. Chem. Int. Ed. Engl. 2001, 40, 4770-4773

Revising the Structure

Li, J.; Burgett, A.W.G.; Esser, L.; Amezcua, C.; Harran, P.G. Angew. Chem. Int. Ed. Engl. 2001, 40, 4770-4773

Synthetic Challenges

Installation of aryl chlorides Macrocylic ring closure

Formation of quaternary carbon Heterocylic core

Synthesis of aminal motif

Atropisomerism at C16-C17 and C24-C26

Nicolaou’s Gen 1 Retrosynthesis

EPGNicolaou, K. C. et al. Angew. Chem. Int. Ed. 2002, 41, 3495-3499

Formation of the Quaternary Center

DMK

Oxazole Formation

JP

The Crucial Witkop Cyclization

EMW, HCT

Nicolaou’s Gen 2 Retrosynthesis

KCGNicolaou, et al. Angew. Chem. Int. Ed. Engl. 2003, 42, 1753-1758

Model Studies

PW

Samarium Iodide mediated cyclization

SGB

Samarium Iodide mediated cyclization

SGB

Robinson-Gabriel Cyclodehydration

TMA

Completing the Synthesis

BEU

Harran’s Retrosynthesis

IDHarran, et. al. Angew Chem. Int. Ed. Engl. 2003, 42, 4961-4966

An Interesting Oxidative Cyclization

BCW

Forming the desired heterocycle

BCW

The Crucial Witkop Cyclization

EMW, HCT