Short Literature 8/9/10

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1 Short Literature 8/9/10 Reiter, M.; Torssell, S.; Lee, S.; MacMillan, D. W. C. The organocatalytic three-step total synthesis of ()-frondosin B Chem. Sci. 2010, Spangler, J. E.; Carson, C. A.; Sorensen, E. J. Synthesis enables a structural revision of the Mycobacterium tuberculosis-produed diterpene, edaxadiene Chem Sci. 2010, John Roberts

2 Chemical Science aims to deliver a new and progressive format in which to publish leading edge research in chemistry and to become a top tier, high impact journal Introduces a new article type: the ʻEdge Articleʼ This format has no page restrictions Prof. David MacMillan, Editor-in-Chief Associate Editors of note: - Stephen Buchwald - Christopher Cummins - David Leigh - Jeff Long - Teri dom - Dean Toste

3 ()-Frondosin B Isolated from marine sponge Dysidea frondosa 1997 µm inhibitor of IL-8 receptors and PKC IL-8 promotes neutrophils, a chemotype implicated in autoimmune diseases Also has anti-cancer and anti-iv activity 3 enantioselective total syntheses: Danishefsky, Trauner, and vaska Patil, A. D.; Freyer, A. J.; Killmer, L.; ffen, P.; Carte, B.; Jurewicz, A. J.; Johnson, R. K. Tetrahedron, 1997, 5047

4 Prior Syntheses Danishefsky (2001): 17 Steps, 1% yield Retro Synthesis: Diels Alder Friedel Crafts C 2 I C 2 Installation of 2 benzylic stereocenter: C 2 Al 3, -78 C, 3 d, 60% C 2 1) ai 4 2) Gilbert Seyferth 71% (2 Steps) C 2 Assigns absolution confirmation of natural material as ()-Frondosin B Inoue, M.; Carson, M. W.; Frontier, A. J.; Danishefsky, S. J. J. Am. Chem. Soc. 2001,

5 Prior Syntheses Trauner (2002): 20 Steps, 7% yield Retro Synthesis: Tf Pd 0 Alkylation I Li Br PMB Ac Installation of 2 benzylic stereocenter: PMB Al 3, -0 C, PMB 1) ai 4, then CBr 4, PPh 3 PMB 16 h, 77% 2) nbuli 84% (3 Steps) owever, Trauner synthesizes the opposite enantiomer, ( ) Frondosin B, and proposes this is the natural material ughes, C. C.; Trauner, D. Angew. Chem. Int. Ed. 2002,

6 vaska (2009): 10 Steps, 13% yield Retro Synthesis: Prior Syntheses 5-exo-dig, Claisen Br I Installation of 2 benzylic stereocenter: 5-exo-dig Claisen 98% ee cat. Li (0.15 equiv) phenetole, µwave, 210 C vaska, T. V.; Sullivan, J. A.; vaska, S. I.; Winegrad, J. B.; Fair, J. D. rg. Lett. 2009, %, ~4:1 dr 95% ee 1) LiMDS 2) I 85%, 97% ee

7 MacMillanʼs 1st Synthesis Installation of 2 benzylic stereocenter: Iminium Formation Asymmetric Friedel-Crafts Cat = Bn t Bu Bn t Bu K BF 3 94%, 92% ee Re-face Attack Forward Synthesis: K BF 3 20 mol % Cat Cl, 1 equiv F, 24 h 94%, 92% ee Tris t BuLi, -78 C BBr 3 91% 10 mol % [Mo(C) 4 Br 2 ] 2 ()-Frondosin B 83%, 2.5:1 olefin isomers 86%

8 MacMillanʼs Revised Synthesis MacMillian wanted to use commercial reagents Commercially available B() 2 1 equiv F, 24 h 20 mol % Cat DCA, DCA = dichloro acetic acid 84%, 93% ee Tris BBr 3 88%, 3.6:1 olefin isomers ()-Frondosin B 86% t BuLi, -78 C 50 % overall The alkylation and olefin isomerization proceeded under acidic conditions Demethylation creates one equivalent of Br, so the demethylation/ alkylation/olefin isomeriztion was attempted ʻone-potʼ

9 Assignment of Frondosin B Danishefsky tested the stability of the 2 benzylic center in his report assigning the confirmation D LiMDS, D LiMDS, TMSCl 95% D, 84% ee TMS 1) TiCl 4, 2 C, 70% ()-Frondosin B 75% 2) i. MsCl, Et 3, ii. PdCl 2 (C) 2, 93 %, 84% ee Trauner asserts the (perceived) inversion of stereochemistry must have happened earlier Al 3 C 2 Al C 2 eighboring group interaction Retention of stereochemistry Danishefsky does observe this at - 50 C Suzuki, T.; Saimoto,.; Tomioka, K.; ozaki,. Tet. Lett. 1982,

10 Assignment of Frondosin B X-ray from a racemic analog of the CBS reduction product shows vaska has made ( ) Frondosin B vaska 2007: 5-exo dig/claisen, X-ray then methylation racemic vaska 2009: Ph Ph catechol borane B 5-exo dig/claisen, 68%, 98% ee then methylation 95% ee Unlikely to invert in subsiquent steps Li, X.; vaska, T. V. rg. Lett. 2007,

11 Assignment of Frondosin B MacMillan carries out 3 experiments to support Danishefskyʼs initial assignment MacMillan Intermediate 2 Steps ()-Frondosin B ab 4 Trauner Intermediate 8 Steps ( )-Frondosin B 99%, (X-ray) 86% ee, from opposite enantiomer catalyst 1) 2 C P Et Et 2) Lindlar, 2 87% C 2 Enantiomer of Daniskefsky Int., has opposite optical rotation K BF 3 D (> 95% D) 20 mol % Cat Cl, 1 equiv F, 24 h Cat = Ph 73%, 84% ee t Bu D 1st gen. route D 48%, >95% D

12 What Likely appened Syn elimination of Pd- species generates an exocyclic enol ether This intermediate is likely rearomatized in a selective manner Tf Pd Pd 0 Insertion Pd Syn Elim. Selective rearomatization ( ) Frondosin B Exocyclic enol ether

13 Edaxadiene Produced from halimadienyl diphosphate by an enzyme (Rv3378c) in M. tuberculosis Also produced by biomimetic conversion of a related compound (tuberculosinol) Arrests maturation of the endocytic phagosomal compartment Similar to action of M. tuberculosis in causing disease M. tuberculosis mutants unable to make edaxadiene exhibit delayed proliferation Mann, F. M.; Xu, M.; Chen, X.; Fulton, D. B.; Russell, D. G.; Peters, R. J. J. Am. Chem. Soc. 2009, akano, C.; kamura, T.; Sato, T.; Dairi, T.; oshino, T. Chem. Commun. 2005,

14 Sorensenʼs Approach Retro synthesis: deoxygenation annulation X Intramolecular ketone allylation

15 Sorensenʼs Approach Forward synthesis: R 1 R 2 C Ph, 120 C TBS 80% C TBS Ph 3 PC 3 Br 67% TBS 1) 9-BB, then PdCl 2 (dppf) and 1 or 2 2) TBAF Br 1) 2) Br 86% using 1 (R 1 =, R 2 = ) 100% using 2 (R 1 =, R 2 = ) Mn(Ac) 3, Cu(Ac) 2 Mn 3 13 C Shifts not close to matching Edaxadiene Mn(Ac) 3, Cu(Ac) 2 A(1,3) min. Mn 3 A(1,2) min. 57%, 1.4:1 dr 51%, 1.4:1 dr 1) ab 4 2) LiAl 4 3) Martin Sulfurane 20% 25%

16 Red flags about structure Discrepancies in 13 C MR: δ = 41.4 δ = 40.3 δ = 73.0 δ = 72.9 nosyberkol C 2 Et 1) 160 C, neat 71%, 2:1 exo:endo 2) LiAl, 56% (24% endo) 3) S 3 Pyr, 86% C 1) 2 C, amds, 87% 2)Rh(PPh 3 ) 3 Cl, SiEt, 83% MgBrCC 2 93%, 1.5:1 dr PPh 3 C 3 Br nosyberkol 9-BB, then PdCl 2 (dppf), Ph 3 As, and 5 I 5 73% tuberculosinol CuCl 2 20%, 1:1 dr

17 Sniderʼs skepticism and subsequent synthesis Mass spec indicated C2032 Insertion of allylic cation into allylic C bond and proton loss unlikely enzymatically PP halimadienyl diphosphate enzymatic dephosphorylation tuberculosinol CuCl 2, DCC Should not happen with CuCl2 & DCC Rv3378c CuCl 2, DCC Rv3378c Also noticed MR discrepancies edaxadine nosyberkol 1) Al 2 Cl (1.9 equiv) 54%, 10:1 exo:endo 2) LiB 4, 82% 3) DMP, 94% C 1) 2 C, a, 60% 2) Li, 3, then Jones x., 90% (Minor) Differences between Sorensenʼs and Sniderʼs Syntheses Different Diels-Alder Different Reduction of enone Different appending of allylic alcohol Snider does not convert tuberculosinol to nosyberkol Et 2 C a, Et 2 C 84%, ( 12 % Z-isomer) P MgBrCC 2 Et Et DIBAL- 88%, 2:1 dr nosyberkol 92% tuberculosinol Maugel,.; Mann, F. M.; illwig, M. L.; Peters, R. J., Snider, B. B. rg. Lett. 2010,