CarbonCarbon Bond Formations Involving OrganochromiumIII Reagents

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Carbon-Carbon Bond Formations Involving
Organochromium(III) Reagents

• Seminar 12.10.2004
• Roland Barth

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Organochromium (III) Reagents

• Alkenylchromium (III) Reagents
• Nozaki-Hiyama-Kishi coupling, Stoichiometric and
  catalytic processes
• Alkynylchromium (III) Reagents
• Allylchromium (III) Reagents
• More Organochromium Methodology and
  Applications
• Enantioselective additions, Cr(II) mediated
  Reformatzkij reaction, Takai Reaction

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Preparation

• a transmetallation with organo-MgX or organo-Li
  reagents
• b direct reaction of organic halide with a CrII
  species
• (usually allylic, propargylic and alkenyl
  halides)

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Reactions with Alkenyl Halides and Triflates
Addition to Carbonyl Groups
Reaction conditions room temperature polar,
aprotic solvent
Advantage high chemoselectivity!
a,b-unsaturated aldehydes 1,2-addition only
geometry of double bond is
maintained for disubstituted olefins
trisubstituted olefins give the
(E)-configurated allyl alcohol
CrCl2 commercially available or generated in
situ
CrCl3 LiAlH4 CrCl3 Na(Hg) CrCl3 Zn or Mn
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Traces of Nickel are necessary!The
Nozaki-Hiyama-Kishi (NHK) Coupling
Stoichiometric amounts of CrCl2 with 1 NiCl2 or
Ni(AcAc)2
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Application of CrII-promoted Couplingin Total
Synthesis

• Palytoxin

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• Brevetoxin B
• Application of lactone-derived enoltriflates in
  the NHK-coupling
• Halichondrin B

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• Brefeldin
• An intramolecular version of the NHK-coupling

Macrocyclisation is successful by an
intramolecular NHK-coupling
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Stoichiometric Setup versus Chromium-catalysed
Reactions
Stoichiometric reactions
Cr(II).(large) excess (gt2 eq.) polar, aprotic
solvent (DMF, THF, DMSO,)
donor ligands for complexation (TMEDA,) 4-tert.-b
utylpyridine
Chromium-catalysed processes
Advantage
Only 15 mol CrCl2 MnCl2 weak Lewis acid
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Alkynylchromium(III) Reagents

• Reductive dimerisation
• Addition to aldehydes

excellent chemoselectivity stoichiometric or
catalytic
selective 1,2-addition
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Application in Total Synthesis

• Discodermolide
• Enediyne toxins

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Allylchromium(III) Reagents

• stoichiometric or catalytic, no Ni necessary
• regioselectivity with substrates bearing ketone
  and aldehyde group
• but ketones can also be used ester groups are
  not reactive
• allylic rearrangement
• primary allylic halides (tosylates) exclusively
• new stereocenters ? good stereocontrol
• a,b-unsaturated aldehydes 1,2-addition
• (E) and (Z) isomers give same product mixture, no
  effect on configuration of new stereocenters

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Allylchromium (III) Reagents
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Stereochemistry (1)

• (E)- and (Z)-crotyl halides give the anti
  addition product

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Stereochemistry (2) Substrate-Controlled
Stereoselectivity
addition governed by steric factors, (almost) no
chelation control
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Examples from Total Synthesis

• ent-Castanospermine
• Asperdiol

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More OrganochromiumEnantioselective Additions
No general solution up to now!
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More OrganochromiumCr(II)-Mediated Reformatzkij
Reaction
Syn gtgt Anti
Also a-halo esters, -lactones, -nitrils, -amides
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More OrganochromiumThe Takai Reaction
Iodoolefination
(E) gtgt (Z)
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References

• General literature
• A. Fürstner Chem. Rev. 1999, 99, 991-1045
• M. Schlosser Organometallics in Synthesis
  Wiley 2002
• Synthesis
• Palytoxin JACS 1986, 108, 5644-5646
• Brevetoxin B JACS 1995, 117, 1171
• Halichondrin B TH Lett., 1996, 37, 8643
• Brefildin JACS 1988, 110, 5198
• Discodermolide JACS 1996, 118, 11054
• Enediyne toxins TH Lett., 1997, 38, 5583
• Ent-Castanospermine JOC, 1992, 57, 3194-3202
• Asperdiol JOC, 1983, 48, 4785
• Takai Reaction
• JACS 1986, 108, 7408-7410