A synthesis of strychnine. by a longest linear sequence of six steps. Chem. Sci. 2011, 2, David B. C. Martin and Christopher D.

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1 A synthesis of strychnine by a longest linear sequence of six steps David B. C. Martin and Christopher D. Vanderwal Chem. Sci. 2011, 2,

2 ABUT STRYCIE Member of the Strychnos alkaloids isolated in 1818 by Pelletier and Caventou Is best known as a poison (antagonist of glycinereceptor) but also used medicinally as a CS-stimulant as a fascinating complex heptacyclic structure The pioneer was Woodward in 1954 Until 4 months ago, the fastest synthesis was completed by Viresh Rawal in 14 steps P. J. Pelletier, J. B. Caventou, Ann. Chim. Phys., 1818, 8, 323

3 TEIR PREVIUS WRK Synthesis of itrogen eterocycles by the Ring pening of Pyridinium Salts A: Generic activating group Angew. Chem. Int. Ed., 2006, 45,

4

5 TEIR PREVIUS WRK Synthesis of itrogen eterocycles by the Ring pening of Pyridinium Salts Example : Conversion of pyridinyl anilines into indoles Angew. Chem. Int. Ed., 2006, 45,

6 TEIR PREVIUS WRK Stereocontrolled Synthesis of Z-Dienes via an Unexpected Pericyclic Cascade Rearrangement of 5-Amino-2,4-pentadienals J. Am. Chem. Soc., 2008, 45,

7 TEIR PREVIUS WRK Efficient Access to the Core of the Strychnos, Aspidosperma and Iboga Alkaloids A short Synthesis of orfluorocurarine J. Am. Chem. Soc., 2009, 131,

8 SYTESIS F STRYCIE RETRSYTETIC PLA Chem. Sci. 2011, 2, 649

9 SYTESIS F STRYCIE Synthesis of the b -Allyltryptamine 9 from tryptophyl bromide : PBr 3 Br 2 tryptophanol commercial available Tryptophyl bromide -Allyltryptamine Martin et al. J. rg. Chem. 1983, 48,

10 SYTESIS F STRYCIE Conversion of 9 to the Zincke aldehyde 11 : 2 2 Cl - 2.Cl -.Cl Cl - - / 2 11 Zincke et al. Liebigs Ann. Chem. 1903, 330, Vanderwal et al. Angew. Chem. Int. Ed. 2006, 45,

11 SYTESIS F STRYCIE Synthesis of 14 by a ruthenium-catalyzed trans-hydrosilylation of the propargylic diol 13 : cat. Cp*Ru(MeC) 3 PF 6 Me 2 (Et)Si- Trans-addition Et Si Si + Et Trost and Ball, J. Am. Chem. Soc., 2005, 127,

12 SYTESIS F STRYCIE Synthesis of the vinylsilane 15 : Me 2 Si Et 3 - Me 2 Si Ms-Cl S Me 2 Si Li-Br Br Me 2 Si S Li Br Br Me-MgBr 4 Cl Me 3 Si Me 3 Si

13 SYTESIS F STRYCIE Chem. Sci. 2011, 2, 650

14 SYTESIS F STRYCIE Pd(PPh 3 ) 4 Br DIPEA SiMe 3 SiMe 3 C C C Deallylation of 12 : Pd(PPh 3 ) 4 Pd(PPh 3 ) PPh 3 RR' RR' Pd(PPh 3 ) 2 RR' Pd Ph 3 P PPh 3 RR' Guibé et al., J. rg. Chem. 1993, 58,

15 SYTESIS F STRYCIE Brook rearrangement of the free alcohol of 16 followed by an intramolecular conjugate addition (1) : SiMe 3 adms SiMe 3 - Me 3 Si C C Brook Rearrangement C Brook Rearrangement C SiMe 3 CuBr.SMe 2 Transmetalation A. G. Brook, Acc. Chem. 1974, 7, Cu Cu

16 SYTESIS F STRYCIE Brook rearrangement of the free alcohol of 16 followed by an intramolecular conjugate addition (2) : Cu - Cu Cu Cu A. G. Brook, Acc. Chem. 1974, 7, 77-84

17 SYTESIS F STRYCIE Conversion of 2 to Strychnine via the protocol of Robinson and Anet : Ac Ac -Ac Ac Ac Ac Ac +, 120 C -C 2 Ac F. A. L. Anet and R. Robinson, Chem. Ind. 1953, 245

18 SYTESIS F STRYCIE To conclude : Shortest synthesis to date which put into practice their strategy deployed in their lab and documents the utility of Zincke Aldehydes The starting materials used are commercially available, and inexpensive compounds ne drawback : the overall yield is not so high owing to the next to last step (Brook Rearrangement followed by conjugate addition) which has not worked as expected (only 5-10% yield)