Applica'on  of  Cross-­‐ConjugatedHeteroaroma'c  Betaines  to  theSynthesis  of  the  SchizozyganeAlkaloid  (±)-­‐StrempeliopineDrew  R.  Bobeck,  Hyoung  Ik  Lee,  Andrew  C.  Flick,

and  Albert  Padwa

JOC,  ASAP,  DOI:  10.1021/jo901336z

Gary  Davis  Current  Lit.  9-­‐12-­‐2009

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Basic  Family  Members

• Isolated  from  Cuban  species  Strempeliopis  strempelioides  K.  Schum  and  East-­‐Africanshrub  Schizozygia  coffaeoides  (Boj.)  Baill.

• Tradi'onal  medicine  for  variety  of  skin  diseases.

• Some  exhibit  an'fungal  and  an'microbial  ac'vity.

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Proposed  Biosynthesis

Hájícek,  J.;  Tamir,  J.;  Budësinsky,  M.  Tet.  Le7.  1998,  39,  505.

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Synthesis  of  (±)-­‐Isoschizogamine

Key  Points• First  concise  total  synthesis  of  isoschizogamine• Based  on  proposed  biosynthe'c  pathway• Michael  addi'on  of  enamine  tautomer• Cycliza'on  expunges  acetone  and  CO2

Hubbs,  J.  L.;  Heathcock,  C.  H.  Org.  Le7.  1999,  1,  1315.

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Synthesis  of  Strempeliopine

Key  Points

• First  and  only  synthesis  prior  to  'tle  paper

• Key  step:  reduc've  rearrangement  ofindolenine  using  Zn-­‐CuSO4

Mauperin,  P.;  Levy,  J.;  Le  Men,  J.  Tet.  Le7.  1971,  999.

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1,3-­‐Dipolar  Addi'on  Approach

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1,4-­‐Dipolar  Addi'on

• Existence  first  postulated  in  1967

• Incorporated  in  cross-­‐conjugated  heteroaroma'c  betaines  in‘82  &  ’85

• Cycloaddi'ons  give  bi-­‐  and  tricyclic  heterocycles  not  easyaccesible  by  other  routes

• Obstacle:  cycloadducts  can  be  difficult  to  convert  to  usefulstructures

Topics  in  Heterocyclic  Chemistry,  1969,  Chap.  8.Heterocycles  1982,  19,  1083.Tetrahedron  1985,  41,  2239.JOC  1972,  37,  1422.JOC  1989,  54,  1077.

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Padwa’s  Earlier  Work

Padwa,  A.;  Coats,  S.  J.;  Semones,  M.  A.  Tetrahedron  1995,  51,  6651.

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Applica'on  to  Isoschizozygane  Core

KeysConstruc'ng  appropriately  subs'tuted  1,4-­‐dipolesAllow  for  the  elimina'on  of  a  small  stable  fragment  (ie  COS,  CO2,  HOCN)

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Retrosynthesis

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Title  Paper  Synthesis

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Title  Paper  Synthesis

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Summary  &  Future  Work

• Successfully  synthesized  both  the  isoschizozygane  skeletonand  (±)-­‐strempeliopine.

• (±)-­‐Strempeliopine  was  synthesized  in  14  steps  from  δ-­‐valerolactam.

• Expands  the  use  of  1,4-­‐dipolar  addi'ons.

• Method  could  poten'ally  be  used  to  access  other  members  ofthis  family.

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