Literature Report (11) Total Synthesis of Rubriflordilactone B Reporter: Yue Ji Checker: Mu-Wang Chen Date: 2016/12/26 Yang, P.; Yao, M.; Li, J.; Li, Y.; Li, A.* Angew. Chem. Int. Ed. 2016, 55, 6964. Laboratory of Asymmetric Catalysis, 201 1
Content Introduction Asymmetric Total Synthesis of Rubriflordilactone B Total Synthesis of (+/-)-Schindilactone A Summary 2
Introduction Sun,.-D. et al. rg. Lett. 2006, 8, 991. Sun,.-D. et al. Nat. Prod. Rep. 2008, 25, 871. 3
Introduction Shi Schisandra rubriflora bifl Biological activity: an EC 50 value of 9.75 ug/ml against IV-1 replic- ation with low cytotoxicity Structure features: a heptacyclic bisnortriterpenoid backbone, 8 stereogenic centers, 5 contiguous chiral centers, a seven membered ring, a tetrasubstituted arene moiety https://en.wikipedia.org/wiki/schisandra Sun,.-D. et al. rg. Lett. 2006, 8, 991. 4
Retrosynthetic Analysis of Rubriflordilactone B 6 -electrocyclization aromatization Rubriflordilactone B 5 Sonogashira coupling Tf + 6 7 NC 10 TES 8 P Et Et 13 + 12 9 11 TBS TBS 15 14 TMS Li, A. et al. Angew. Chem. Int. Ed. 2016, 55, 6964. 5
Synthesis of the left-hand fragment ZnI 2, P(Et) 3 (Et) 2 P 3, 2 S then K 2C 3 (aq.) 94% 54% Arbuzov-type reaction 11 16 17 N 1) LDA, Ph S Cl t Bu TMSCN, AlEt 3 then Na (aq.) 2) L-Selectride 84% 50% 9 NC 19 C 6
Synthesis of the left-hand fragment NC 1) Co(acac) 2 1) Ph 3 P=C 2 TES X PhSi 3, 2 2) KMDS, 21; 2) Na (aq.) TESTf 76% 63% 19 20 Ph 22: X = C 2 N 8: X= Ph 2 S 21 3 (96%) 1) LiMDS, PhNTf 2 2) Sc(Tf) 3,Ac 2 85% Ac Tf 1) LiMDS 2) Et 3 Si, BF 3 Et 2 60% 23 24 Tf NBS, BP 90% Tf 1) NaB 4,ArSeCN 2) 2 2 (aq.), pyridine Ar = 4-N 2 C 6 4 A B C Tf Br 50% 25 6 7
Synthesis of the right-hand fragment 8
Johnson-Clainsen rearrangement TMS o-n 2 C 6 4 EtC() o 3, 180 C TMS C 2 83% TBS 14 27 TBS chanism: R R R R R A R -R I II III [3,3] R R IV V 9
Asymmetric Total Synthesis of Rubriflordilactone B 10
Asymmetric Total Synthesis of Rubriflordilactone B Lindlar cat., 2 60% 31 5 (3-Am)Si 2 87% Si Si Pt 32 DDQ, 80 o C 87% R 1 R 2 33, R 1 = (3-Am)Si 2,R 2 = 34, R 1 =,R 2 = (3-Am)Si 2 1) DDQ, 135 o C 2) AgF 73% D 4: Rubriflordilactone B 11
Total Synthesis of (+/-)-Schindilactone A Pauson-Khand reaction Dieckmann-type condesation RCM reaction A B C E D F G Coupling reaction Carbonylative annulation Schindilactone A (1) Structuret features: a highlyhl oxygenated octacyclic framework bearing 12 stereogenic centers, 8 contiguous chiral centers, an oxabridged ketal that lies within an unprecedented fused core. Sun,.-D. et al. Nat. Prod. Rep. 2008, 25, 871. Tang, Y.-F.; Chen, J.-.; Yang, Z. et al. Angew. Chem. Int. Ed. 2011, 50, 7373. 12
Total Synthesis of (+/-)-Schindilactone A Tang, Y.-F.; Chen, J.-.; Yang, Z. et al. Angew. Chem. Int. Ed. 2011, 50, 7373. 13
Total Synthesis of (+/-)-Schindilactone A 14
Total Synthesis of (+/-)-Schindilactone A 15
Total Synthesis of (+/-)-Schindilactone A TES KMDS,TF TES C then I TMS 88% Bn Bn 19 20 TMS C 1) DIBAL,C 2 Cl 2 2) DMP, NaC 3 70% TES 21 Bn TMS Br Mg TES 1) TBAF, Ac, TF TF, -78 o C 2) LiAl 2 2( () 2, TF 88% TMS 56% Bn 22 16
Total Synthesis of (+/-)-Schindilactone A TES Pd(Ac) 2, ligand A LiMDS, TF CuCl 2,C(1atm),TF TES then I 78% 80% Bn A Bn 23 24 N N S TES 25 Bn Li + N - TF then N 4 Cl (aq.) 76% TES 26 G Bn 17
Total Synthesis of (+/-)-Schindilactone A TES Ac Ac 2, Sc(Tf) 3,C 3 CN 92% Bn Bn 26 27 1) Pd() 2, 2 (1 atm) 2) LiMDS, TF 3) DMP, NaC 3,C 2 Cl 2 54% (+/-)-Schindilactone A (1) 18
Summary A B D C E F Rubriflordilactone B G Li's work 1. Asymmetric total synthesis, 20 steps, 0.20% yield 2. ighly convergent strategy for total synthesis 3. Sonogashira-hydrosilylation-electrocyclization-aromatization sequence for pentasubstituted arenes A B C E D F G Schindilactone A Yang's work 1. Racemic total synthesis, 29 steps, 0.17% yield 2. Silver-mediated cyclopropane rearrangement to generate the C ring 3. RCM reaction for the formation of the fully functionalized eight-membered E ring 4. Thiourea/cobalt-catalyzed t l PKR for the F ring 5. Thiourea/palladium-catalyzed carbonylative annulation for G ring 19
Constructing multisubstituted arenes remains a challenge in natural product synthesis. Conventional strategies t based on substitutiontype reactions, such as Friedel Crafts, S N 2Ar, and cross-coupling reactions, are limited by the availability and electronic properties of the corresponding substrates and the positional selectivity of these transformations, despite being recently reinforced by transitionmetal- or radical-mediated C- bond functionalization. The groups of Nicolaou and others have elegantly demonstrated the power of electrocyclization in natural product synthesis. The combination of 6π electrocyclization and oxidative aromatization for constructing multisubstituted arenes is of significant advantage from the following aspects: 1) strong driving force, 2) no functionalization (e.g., halogenation or metalation) required, 3) separating stereochemical problems from connectivity issues, 4) eliminating torquoselectivity issues, and 5) enhanced convergence. 20
Thus, such strategies were creatively applied by a number of groups in synthesizing natural products containing multisubstituted arenes, which recently inspired us to explore this area. owever, the geometrically controlled formation of the prerequisite triene substrates is a considerable challenge for executing the electrocyclization strategy. Partial-hydrogenation reagents (e.g., Lindlar catalyst, diazene, activated Zn) suffer from incompatibility issues with functionalized diene-ynes and result in poor yields of the desired cis-trienes. Precursors of penta- and hexasubstituted arenes pose even greater difficulties in controlling the geometry of the more substituted olefin substrates 21
In summary, we have accomplished the total synthesis of rubriflordilactone B in a highly convergent fashion. A 6π electrocyclization aromatization sequence served as a key step. ydrosilylation y of aconjugated triene-yne intermediate defined the cis geometry of the electrocyclization precursor, which constitutes a superior approach to the conventional method of partial hydrogenation. The Sonogashira hydrosilylation electrocyclization aromatization sequence could be streamlined as a general and robust approach towards the synthesis of pentasubstituted arenes bearing silyl groups as versatile handles, considering that the regioselectivity of the hydrosilylation can be tuned by varying the ligands. The total synthesis suggests the existence of a naturally occurring sibling of rubriflordilactoneb bifl and provides efficient i and flexible access to analogues of potential biological interest. 22