A Highly Convergent and Biomimetic Total Synthesis of Portentol

Transcription

1 A ighly Convergent and Biomimetic Total Synthesis of Portentol portentol B. Cheng, D. Trauner, J. Am. Chem. Soc. 2015, 137, Departement of Chemistry and Center for Integrated Protein Science Ludwig-Maximilians-Universität München, Germany DI: /jacs.5b10009 Samuel Rieder, 25 th Nov. 2015

2 Dirk Trauner : Born in Linz, Austria : Studied Biology, Vienna : Studied Biochemistry, Vienna : Studied Chemistry, Berlin : PhD, Prof. J. Mulzer, Berlin & Vienna : Postdoc, Prof. S. Danishefsky, New York : Assistant Professor, Berkeley : Associate Professor, Berkeley : Full Professor, Munich Research Interest: - Chemical Synthesis - Cell Biology - Natural Product Chemistry - Neuroscience - Photopharmacology 2

3 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, D. J. Aberhart, A. Corbella, K.. verton, J. Chem. Soc. D 1970,

4 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

5 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

6 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,

7 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, M. Chen, W. R. Roush, J. Am. Chem. Soc. 2012, 134,

8 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

9 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,

10 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

11 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, % (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

12 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,

13 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

14 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

15 Boron Enolate 15