Stereocontrolled*Total*Synthesis*of*( ) Stemaphylline*ccc.chem.pitt.edu/wipf/Current Literature/Keita_3.pdf · 2017-03-04 · Conclusion # They completed the total synthesis of (‒)-stemaphylline

Stereocontrolled  Total  Synthesis  of  (‒)-­‐Stemaphylline  

Ana  Varela,  Lennart  K.  B.  Garve,  Daniele  Leonori,*  and  Varinder  K.  Aggarwal*  

Angew.  Chem.  Int.  Ed.  2017,  56,  2127–2131

Current  Literature        March  4  2017  Keita  Takubo  -­‐Wipf  group-­‐

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Stemona alkaloids

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ü  Isolation: A root extract of Stemona aphylla.

ü  Biological activity: Insecticidal and antiparasitic properties.

ü  Structure: Pyrrolo-[1,2-a]azepine core as well as a γ-lactone and five stereogenic centers, three of which are contiguous.

Pitchaya  M.  et.  al.,  J.  Nat.  Prod.  2009,  72,  848–851.  

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Synthesis of (-)-stemaphylline

C.  W.  Lindsley  et.  al.,  Chem.  Eur.  J.  2013,  19,  11847-­‐11852.  

n  Previous work

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Homologation through lithiation-borylation

Fandrick,  K.  R.    et.  al.,  Org.  Le?.  2014,  16,  4360–4363.  

n  Large-scale lithiation-borylation reaction

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Application in the synthesis of natural product

Acc.  Chem.  Res.  2014,  47,  3174−3183.

Retrosynthetic analysis

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Optimization of the 1,2-migration

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8

Homologation of chiral boronic ester

Synthesis of Allyl Pyrroridine

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10

Construction of pyrrolo-[1, 2a]azepine core

Optimization of lithiation of TIB ester

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Endgame

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Conclusion

l  They completed the total synthesis of (‒)-stemaphylline in 11 steps, with high stereocontrol (>20:1 d.r.) and 11% overall yield.

l  The synthesis features a late-stage lithiation–borylation reaction with a tertiary amine containing carbenoid.

l  By performing a solvent switch from Et2O to CHCl3, efficient 1,2-metalate rearrangement of the intermediate boronate occurs with both halide and ester leaving groups.

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Synthesis of Boronic esters 4 and 26

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Synthesis of Boronic ester 7

Natural charge (NBO) calculations

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Optimization of Deprotonation Condition

J.  Am.  Chem.  Soc.  2013,  135,  16054−16057.

Solution structure of i-PrLi2/(-)-sparteine

J.  Am.  Chem.  Soc.  1994,  116,  3231-­‐3239.