Synthesis of Atisine-type Alkaloids

Transcription

1 Literature Report III Synthesis of Atisine-type Alkaloids Reporter : Yang Zhao Checker : Zhou-ao Zhu Date : Ma, D. et al. Angew. Chem. Int. Ed. 2018, 57, 6676 Baran, P. S. et al. J. Am. Chem. Soc. 2014, 136, 12592

2 CV of Prof. Dawei Ma Research: Total synthesis of complex natural products ew synthetic methodologies: Copper-catalyzed coupling reactions; Asymmetric Michael additions, enry reaction; Intramolecular Dearomative xidative Coupling Biochemistry Education: B.S., Shandong University Ph.D., Shanghai Institute of rganic Chemistry (Xiyan Lu) Postdoc., University of Pittsburgh and Mayo Clinic, U.S.A now Prof., Shanghai Institute of rganic Chemistry 2

3 Contents 1 Introduction 2 3 Semisynthesis of (-)-Isoatisine Total Syntheses of Azitine 4 Summary 3

4 Introduction C 20 diterpenoid alkaloids hetisine-type nominine hetidine-type (-)-spirafine III atisine-type (-)-isoatisine azitine 4

5 Introduction (-)-Isoatisine Aconitum Atisine-type diterpenoid alkaloids isolated from Aconitum Folk medicine for the treatments of rheumatism and neuralgia Bicycle[2,2,2]octane system with the attached allylic alcohol Yao, B.-. et al. J. Pharm. Anal. 2011, 1, 57 Baran, P. S. et al. J. Am. Chem. Soc. 2014, 136,

6 Retrosynthetic Analysis 20 ofmann-löffler- Freytag Reaction 7 20 P()(Et)2 Ac (-)-Isoatisine Mukaiyama xidation/ Fragmentation (-)-Steviol 4 20 P()(Et)2 6

7 Barton-McCombie Deoxygenation Reaction R Base S Y X S R Y thioxoester ( n- Bu)3Sn AIB, PhC 3 reflux R Initiation step: C C heat C (n-bu)3sn C Propagation step: S Sn( n -Bu)3 R Y C + S Sn(n -Bu)3 R Y (n-bu)3sn Sn( n -Bu)3 S Y R Sn( n -Bu)3 R + Sn( n -Bu)3 X = Cl, imidazolyl; Y=S, imidazolyl, Ph, ; R- = 1 o, 2 o or 3 o alcohol 7

8 ofmann-löffler-freytag Reaction X or hv or radical initiator acidic or neutral or weakly basic medium X Base -X X X or hv or radical initiator X - X 1,5- abstraction alkyl radical + X X δ -halogenated amine :B -B X : - X :B -B X = Cl, Br, I 8

9 Semisynthesis of (-)-Isoatisine EDCl, Bt, 4 80% 2 LiAl % 2 P(Et)2()Cl, DIPEA 93% Co(acac)2, Et 3 Si, % 4 P()(Et)2 Mukaiyama xidation/ Fragmentation 5 ecessary directing group for C20 C- activation P()(Et)2 Amberlyst 15 87% P()(Et)2 Ac 2, Et 3, DMAP 90% Ac ab 4 6 P()(Et)2 7 P()(Et)2 8 47% Ac 9

10 Semisynthesis of (-)-Isoatisine 20 P()(Et)2 13 Ac 8 1) thio CDI 2) (TMS)3Si, AIB 85% Barton-McCombie deoxygenation P()(Et)2 9 Ac PIDA, I 2, 90-W sunlamp ofmann-löffler- Freytag reaction 2 Ac 6 20 I 10 P()(Et)2 Selective C20 C- activation then K 2 C 3, Martin's Sulfurane Se 2, tbu 71% I 11 91% C(CF3)2C 6 5 I 12 63% (C6 5)2S C(CF3)2C 6 5 I 13 95% 2 + (-)-isotisine epi-minor 10

11 Introduction Atisine-type (-)-Isoatisine Azitine C (-)-Steviol α,β-unsaturated nitrile Ma, D. et al. Angew. Chem. Int. Ed. 2018, 57,

12 Retrosynthetic Analysis Reductive Cyclization C C 14 Azitine a) xidative Dearomatization b) Diels-Alder Cycloaddition C Ac C 1 6 C + TBS Chelation-Controlled Conjugate Addition C 2 ClMg 8 Ac 6 12

13 Luche Reduction ab 4, CeCl 3, R B R [B3(R)] Ce 3+ [B2(R)2] R R R B R Ce 3 + R Both acyclic and cyclic enones are reduced to corresponding allylic alcohols 13

14 Chelation-Controlled Conjugate Addition C tbumgcl, MgX then R 3 X C R 3 C tbumgcl MgX Mg C MgX2 MgX2 Mg C R 3 X R 3 C γ-hydroxy group in an α,β-unsaturated nitrile could promote the conjugate addition by chelation to the Grignard reagent Steward,. W. et al. Angew. Chem. Int. Ed. 2004, 43,

15 Swern xidation (CCl)2 or TFAA, DMS then Et 3 R Low 2 temperature/ R Solvent 2 1 o or 2 o alcohols S (CCl)2 S Cl Cl C, C 2 Cl - S Cl S B S 2 15

16 Van Leusen Reaction S 2 C 2 =C tbuk C tbuk TosC 2 C TosC C Tos C 5-endo-dig Tos I Tos Tos -Tos C II R C R -CR C III C Van Leusen, A. M. et al. J. rg. Chem. 1977, 42,

17 Total Syntheses of Azitine C C ab 4, CeCl 3 tbumgcl then 8 97% Luche Reduction 1 2 Chelation-Controlled Conjugate Addition Mg C 3 TBS then AcCl then ab 4, Ac C TBS 61% Ac C TBS 4 5 Matin's sulfurane then TBAF 74% Ac C PIDA, ac 3 then toluene, 105 o C 88% Ac C (C6 5)2S C(CF3)2C 6 5 C(CF3)2C

18 Preparation of Grignard Reagent 8 TBS TBS TBS SCl 2, pyridine 81% Mg, 90 o C Cl ClMg

19 Total Syntheses of Azitine Ac C 7 SmI 2 (4 eq.) Ac C 9 (C2)2 Ac C 10 Dibal- C 11 (CCl)2, DMS then Et 3 88% for 4 steps Swern xidation 4 C 12 Van Leusen Reaction TosMic, tbuk tbu S C C 4 C 13 LDA, I 68% for 2 steps 4 C C 14 LA 15 19

20 Total Syntheses of Azitine 15 Li/ 3(l) TF/iPr path a Li e - path b 16 path b path a Li % yield (2 steps) 19 : 20 = 1 : 2 18 further reduction 20 46% yield (2 steps) 20

21 Total Syntheses of Azitine 20 Ts, Acetone/ 2 21 PPh 3 Br, nbuli 91% for 2 steps Se 2, TBP 22 56% azitine 21

22 Summary Semisynthesis of (-)-Isoatisine (-)-Steviol 20 P()(Et)2 P()(Et)2 Ac (-)-Isoatisine Baran, P. S. et al. J. Am. Chem. Soc. 2014, 136, Total Syntheses of Azitine C Ac C 4 C 10 C Azitine Ma, D. et al. Angew. Chem. Int. Ed. 2018, 57,

23 Summary Semisynthesis of (-)-Isoatisine (-)-Isoatisine 13 steps, 4.6% overall yield Mukaiyama oxidation/fragmentation ofmann-löffler-freytag reaction (Suárez modification) Baran, P. S. et al. J. Am. Chem. Soc. 2014, 136, Total Syntheses of Azitine 17 steps, 5.4% overall yield Chelation-trigged conjugate addition Azitine xidative dearomatization/ Diels-Alder cycloaddition Reduction of a dinitrile intermediate Ma, D. et al. Angew. Chem. Int. Ed. 2018, 57,

24 The First Paragraph wing to their caged and polycyclic ring systems, the C 20 diterpenoid alkaloids are recognized among the most architecturally complex natural products, and have elicited considerable interest from the synthetic community over the past several decades. These synthetic campaigns culminated in the completion of formal and total syntheses of a subset of C 20 diterpenoid alkaloids, namely nominine, atisine, isoatisine and so on. owever, most of these synthetic routes require a large number of steps and are restricted to a very particular structure. There is plenty of room for developing more concise total syntheses towards atisine- and hetidine-type alkaloids. erein, we report a short and efficient approach for the assembly of a tetracyclic dinitrile compound. By making use of this common intermediate, we achieved the first total synthesis of azitine, an antileishmanial atisine-type diterpenoid alkaloid that was first isolated from Consolida hellespontica. 24

25 The Last Paragraph In conclusion, we have described a unified approach towards the atisane-type C 20 diterpenoid alkaloids, as exemplified by the first total syntheses of azitine. The syntheses feature a number of key transformations, including a) chelation-triggered conjugate addition to control the contiguous three stereogenic centers in the cyclohexane unit, b) oxidative dearomatization/diels Alder cycloaddition to forge the crucial bicyclo[2.2.2]octane moiety with a free cyano group at the C 20 position, c) reduction of a dinitrile intermediate to form an -heterocycle with the correct oxidation state at the C 20 position. If other Grignard reagents with functional groups at C 6 /C 7 and functionalized α,β-unsaturated nitriles were employed in the chelation-controlled conjugate addition, it should be facile to assembly other functionalized diterpenoid alkaloids. Thus the present synthetic strategy provides a reliable and efficient approach for diverse syntheses of diterpenoid alkaloids and their analogues. 25

26 Acknowledgement 26

27 Mukaiyama ydration SiEt 3 L 2 Co 2 + R R 2, Et 3 Si L 2 Co 3 + R Et 3 Si L 2 Co 3 + L 2 Co 3 + R R L 2 Co 2 + L 2 Co 2 + R R 2 From Fan-Jie ng 27

28 Allylic ydroxylation of Alkenes with Se 2 Se 2 Se ene Se [2,3]-sigmatropic Se 28

29 Removal of Two thoxyl Group with SmI 2 SmI 2 SmI 2 SmI 2 SmI 2 R1 29