Total Synthesis of RK397

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• Total Synthesis of RK-397
• Scott E. Denmark and Shinji Fujimori
• Department of Chemistry, UniVersity of Illinois
  at Urbana-Champaign, Urbana, Illinois 61801
• Received April 7, 2005

J. AM. CHEM. SOC
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Editor

• Department of Chemistry university of Illinois
• highly selective reactions
• Focus on invent and develop new asymmetric
  reactions by studying the structure and
  reactivity relationships of a variety of organic
  and nonorganic species.
• ACS Award for Creative Work in Synthetic Organic
  Chemistryetc.

Scott E. Denmark
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Biological Activities

• Isolated from Streptomyces violaceusnigar.by
  Osada, in 1993. A member of a large family of
  polyene macrolides.
• RK-397 exhibitbroad antimicrobial activities
  against filamentous fungi, yeast, and bacteria at
  50-100 Ìg/mL.
• RK-397 is reported to have in vitro anticancer
  activity, inhibiting human leukemia cell lines
  K-562 and HL-60 at 50 and 25 Ìg/mL.

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Derivatives of RK-397
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Previous Synthesis of RK-397
Burova, S. A. McDonald, F. E. J. Am. Chem. Soc.
2004, 126, 2495-2500
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Modular Synthesis of Polyol Segment of RK-397
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Retrosynthesis of RK-397 (I)
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Retrosynthesis of RK-397 (II)
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Vilyogous Aldol Reaction
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Palladium-coupling
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Horner-Wadsworth-Emmons Olefination Protocol

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Prepare Ester 4 by Vinylogous Aldol Reaction

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Sodium bis(2-methoxyethoxy)aluminium hydride
(Red-Al)
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Vilyogous Aldol Reaction
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Prepare Key Intermedium--Methyl Ketone 2
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Prepare Aldehyde 3 by Witting Reaction
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Witting Reaction
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Prepare Compound 12 by The Use of (R,R)-13 as The
Catalyst
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The Boron Aldol Addition of 2 to 3 Afford
Compound 12
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Mosher Ester analysis

• A Mosher Ester analysis was performed on the
  enantiomerically pure propargyl alcohol, making
  both the R and the S esters. Using the spectra
  provided, assign the absolute configuration about
  the stereogenic center.

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Prepare Hydroxy Aldehyde 16 Using DDQ
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Retrosynthesis of RK-397 (I)
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Synthesis of Polyene Phosphonate 1
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Accomplished to RK-397
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Horner-Wadsworth-Emmons Olefination Protocol

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Conclusion

• RK-397 was synthesized by employing a convergent
  synthetic strategy that features the use of an
  8-carbon building block for 16 carbons in the
  polyol chain.
• The synthesis highlights the enantioselective
  vinylogous aldol addition using chiral
  phosphoramide 9 for the construction of the key
  intermediate 2. The stereogenic center created by
  this reaction established 8 of the 10 stereogenic
  centers in RK-397 by substrate control.

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Conclusion

• This synthesis also illustrated the sequential
  cross-coupling of bissilyldiene 17 to construct
  the conjugated polyene 1.
• The application of Lewis base-catalyzed aldol
  additions in syntheses of more complex molecules
  is currently under investigation.