A ighly Convergent and Biomimetic Total Synthesis of Portentol portentol B. Cheng, D. Trauner, J. Am. Chem. Soc. 2015, 137, 13800 13083 Departement of Chemistry and Center for Integrated Protein Science Ludwig-Maximilians-Universität München, Germany DI: 10.1021/jacs.5b10009 Samuel Rieder, 25 th Nov. 2015
Dirk Trauner - 1967: Born in Linz, Austria - 1986-88: Studied Biology, Vienna - 1988-91: Studied Biochemistry, Vienna - 1992-95: Studied Chemistry, Berlin - 1995-97: PhD, Prof. J. Mulzer, Berlin & Vienna - 1998-00: Postdoc, Prof. S. Danishefsky, New York - 2000-06: Assistant Professor, Berkeley - 2006-10: Associate Professor, Berkeley - 2008- : Full Professor, Munich Research Interest: - Chemical Synthesis - Cell Biology - Natural Product Chemistry - Neuroscience - Photopharmacology 2
Portentol Isolation and Characterisation - First isolated in 1967 from Roccella portentosa (lichen) - Moderate growth inhibition against several cancer cell lines - Densley functionalized spiro tricyclic core (9 consecutive stereocenters) - Biosynthetic Speculation (verton) portentol C 2-14C labelling: Carbon chain from acetate and malonate - C2 from acetate, other from methionine D. J. Aberhart, K.. verton, S. uneck, J. Chem. Soc., C 1970, 1612 1623. D. J. Aberhart, A. Corbella, K.. verton, J. Chem. Soc. D 1970, 664 665. 3
Biosynthetic Analysis Speculations - Cationic Cyclization Cascade portentol SR - Lactone assembled by type II polyketide synthase (PKS) - Containing two anti-anti triads (synthetically challenging) - PKS (thioesterase domain) might also catalyze subsequent cationic cyclization 4
Polyketides Stereotriades; Propionate Triades - Biosynthesis (polyacylation) SCoA SCoA SCoA n SCoA Acetyl-CoA Malonyl-CoA Polyketide - Biosynthesis (thylation, Reduction) n SCoA n SCoA - Biosynthesis (Selectivity) syn, syn syn, anti anti, syn anti, anti 5
anti,anti-triade Previous Approaches - Desymmetrization (soforms) Si 2 t-bu 9-BBN Si 2 t-bu 3 steps - Asymmetric Epoxidation 4:1 Bn 3 steps Bn 2 CuLi Bn - Crotylboration R Bpin 72-84%, 8:1 to > 100:1 R R major minor T. arada, A. Inoue, I. Wada, J. Uchimura, S. Tanaka, A. ku, J. Am. Chem. Soc. 1993, 115, 7665 7674. 6
anti,anti-triade Previous Approaches - Double Mismatched Crotylboraion R B( d ipc) 2 SnBu 3 R SnBu 3 - Aldol reaction (anti-selective) Cy 2 B Bn Bn Bn I. Paterson, D. J. Wallace, S. M. Velázquez, Tetrahedron Lett. 1994, 35, 9083 9086. M. Chen, W. R. Roush, J. Am. Chem. Soc. 2012, 134, 3925 3931. 7
Retrosynthetic Analysis oxocarbenium/ β-keto lactone cyclization R R' portentol aldol TMS TMS A PMB N Bn B aldol aldol TES C D Bz TES E N Bn F 8
Synthesis of Fragment A Synthesis of C & D; Paterson Aldol Reaction 1. LDA 2. I DMI 3. TESCl 87% TES C 1. ()N Cl i-prmgcl; then EtMgBr 2. BzCl, DMAP, Et 3 N 43% D Bz TES Cy 2 BCl, Et 3 N; TES then C Bz Bz 65% (dr ~ 4:1) C D TMSCl, TMS 2 N pyridine 99% TES TMS Bz TES TMS SmI 2 97% A I. Paterson, D. J. Wallace, S. M. Velázquez, Tetrahedron Lett. 1994, 35, 9083 9086. 9
Synthesis of Fragment B Evans Aldol Reaction TES Bn N Bu 2 BTf, Et 3 N; then E TES Bn N E F PMB-C(N)CCl 3, Sc(Tf) 3 TES PMB DMS, (CCl) 2, Et 3 N PMB 52% (2 steps) Bn N 94% Bn N B R X* BBu 2 10
Synthesis Lactone Precursor Key Coupling Reaction TES TMS PMB Bn N Cy 2 BCl, Et 3 N, Et 2 ; then B 78 to 40 C; then p 7 buffer, TF, 2 2 71% (dr ~ 4:1) TES TMS PMB A B - Lactone directly obtained after removal of auxiliary when adding TF during wu - Separation by FC (recovered fragment A) - Confirmation of stereochemistry by NMR - Removing PMB with DDQ (84%) à adding 2 or p 7 buffer lead to byproduct formation 11
Final Step Double Cyclization Cascade - xidation of β-hydroxy lactone under Swern conditions TES TMS DMS, TFAA; Et 3 N, 78 C;, rt portentol (35%) 55% - Acid formed in-situ during wu - Spectroscopic data and X-ray structures N. Sakai, Y. hfune, J. Am. Chem. Soc. 1992, 114, 998 1010. 12
Cationic Cascade chanism 2 portentol 2 side-product - C2 and C7 bond formation slow (steric hindrance) - A 1,3 -strain of C6 and C8 methyl groups 13
Conlusion - Due to high yield and ease of the cascade à similar process in nature - Enzymatic vs. Spontaneous - Side-product never isolated à points to catalysis - Brief, and efficient synthesis due to biomimetic key step and convergent synthetic plan - Three diastereoselective boron aldol reactions (one syn, two anti) - First total synthesis 14
Boron Enolate 15