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One-‐Pot Zinc-‐Promoted Asymmetric Alkynyla5on/Brook-‐Type Rearrangement/Ene-‐Allene Cycliza5on: Highly Selec5ve Forma5on of Three New Bonds and Two
Stereocenters in Acyclic Systems Polina Smirnov, Jomon Mathew, Anne Nijs, Einat Katan, Miriam Karni, Casten Bolm, Yitzhak
Apeloig, and Ilan Marek Angew. Chem. Int. Ed. 2013, 52, 1-‐6
Nicholas Reed Wipf Group Current Literature
June 8, 2013
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Rapidly Building Complexity
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J. Am. Chem. Soc. 2007, 129, 3790
Tetrahedron: Asymmetry, 1996, 7 443
Asymmetric one-‐pot reac5ons are extremely a^rac5ve transforma5ons for their ability to impart stereoselec5vity and for their ability to rapidly build up complexity
New challenges are encountered when several different types of reac5ons are a^empted in one pot processes
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Proposed Chemical Transforma5on
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1. Does the Brook rearrangemenet proceed in the presence of stoichiometric base? 2. Does complete transfer of chirality occur? 3. Would the propargyl zinc species be configura5onally stable? 4. What is the stereochemical outcome and mechanis5c implica5ons of such a
transforma5on? 5. Would the intermediate species then undergo an enan5oselec5ve Zn-‐ene-‐allene
cycliza5on?
Angew. Chem. Int. Ed. 2013, 52, 1-‐6
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Previous Work
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Nature Prot. 2013, 8, 749-‐754
J. Am. Chem. Soc. 2006, 128, 4642-‐4649
Angew. Chem. Int. Ed. 2007, 46, 9291-‐9294
Limita-ons: • Diastereoselec5vity is good (>95:5 d.r. in most cases) but yields are moderate (50-‐70%) • Previous methods rely on chiral auxiliaries that must be added and removed
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Asymmetric Alkynyla5on
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• Catalyst sensi5ve to: Size of R: Reducing the steric bulk lowers e.r., increasing steric bulk lowers yield Electronic environment: Electron-‐dona5ng/electron-‐withdrawing groups lower yield and e.r.
• Tolerates some different subs5tu5on on silyl ketone with similar levels of stereoinduc5on
Angew. Chem. Int. Ed. 2013, 52, 1-‐6
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Scope
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• Rela5vely small number of examples with homogeneous substrates • Difficult to determine limits of promising methodology
Angew. Chem. Int. Ed. 2013, 52, 1-‐6
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Configura5onal Stability of Propargyl Zinc Species and its Implica5ons
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J. Org. Chem. 1994, 59, 2925-‐2926
Alkyl zincs are usually unstable in the absence of a heteroatom or at high temperatures!
Tetrahedron, 1994, 50, 2415-‐2432
Why is the proposed propargyl zinc species configura-onally stable?
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Calculated Mechanis5c Pathway
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Hybrid PBE0 func5onal, 6-‐311G(d,p) basis set
Angew. Chem. Int. Ed. 2013, 52, 1-‐6
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Conclusions and Future Work • Ini5al development of an a^rac5ve cascade process that forms three new bonds
and two stereocenters
• Uses a cataly5c amount of chiral organo-‐catalyst as the only source of chirality
• Calcula5ons suggest an allenyl Zn-‐Brook rearrangement as the opera5ve mechanis5c pathway (in agreement with observed experimental results).
• Limited substrate scope makes it difficult to know the limits of such an a^rac5ve transforma5on
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Asymmetric Alkynyla5on Cataly5c Cycle
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J. Am. Chem. Soc. 2006, 128, 8-‐9
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