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. 2004 Aug 17;101(33):12030-5.
doi: 10.1073/pnas.0401932101. Epub 2004 Jun 21.

Unified synthesis of caged Garcinia natural products based on a site-selective Claisen/Diels-Alder/Claisen rearrangement

Eric J Tisdale  1 , Irina Slobodov, Emmanuel A Theodorakis
Affiliations

Unified synthesis of caged Garcinia natural products based on a site-selective Claisen/Diels-Alder/Claisen rearrangement

Eric J Tisdale et al. Proc Natl Acad Sci U S A. .

Abstract

A unified synthetic strategy toward caged Garcinia natural products has been designed and implemented. Central to the strategy is a tandem Claisen/Diels-Alder/Claisen rearrangement of a suitably substituted xanthone precursor to form forbesione (1a). Serving as a template, forbesione is then used to deliver representative members of this family, including desoxygaudichaudione A (4), desoxymorellin (5), and gambogin (10). Studies on the timing of this reaction cascade suggest that the C-ring Claisen/Diels-Alder rearrangement proceeds initially and is followed by the A-ring Claisen reaction. The electronic and steric effects that govern the outcome of this cascade are presented.

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Figures

Fig. 1.
Fig. 1.
Representative structures of caged Garcinia natural products.
Fig. 2.
Fig. 2.
Structural motifs arising from the Claisen/Diels–Alder reaction on 12.
Fig. 3.
Fig. 3.
Retrosynthetic analysis of 1a, 4, 5, and 10.
Scheme 2.
Scheme 2.
Reagents and conditions: reaction a, 3.0 eq of K2CO3,20 eq of 21, 1.5 eq of KI, 10 mol % CuI, Me2CO, 55°C, 4 h, 67% yield; reaction b, 10% Pd/BaSO4, quinoline, EtOAc, 25°C, 15 min, 66% yield; reaction c, DMF, 120°C, 2 h, 78% yield; reaction d, DMF, 120°C, 4 h, 91% yield; and reaction e, 3.0 eq of triethylamine, 3.0 eq of 24, 2.0 eq of CaCl2·H2O, MeOH (sealed tube) 3 h, 75% yield.
Scheme 3.
Scheme 3.
Timing of the Claisen/Diels–Alder/Claisen rearrangement.
Scheme 1.
Scheme 1.
Reagents and conditions: reaction a, 1.0 eq of 19, 1.0 eq of 20, 6.5 eq of ZnCl2, POCl3,65°C, 3 h, 46% yield; reaction b, 3.3 eq of K2CO3, 5.1 eq of 21, 3.3 eq of KI, 10 mol % CuI, Me2CO, 45°C, 6 h, 25% yield; reaction c, 10% Pd/BaSO4, quinoline, EtOAc, 25°C, 6 h, 75% yield; reaction d, 25 eq of Ac2O, 25 eq of pyridine, 10 mol % N,N-dimethylaminopyridine, CH2Cl2, 35°C, 24 h, 85% yield; reaction e, 5.0 eq of Cs2CO3, 5.0 eq of MeI, DMF, 25°C, 15 min, 61% yield; reaction f, DMF, 120°C, 1 h, 49% yield of 1a, 35% yield of 22a;, 79% of 1b; 51% of 1c, 24% of 23c; and reaction g, 0.5 M K2CO3 (aq), MeOH, 25°C, 6 h, 91% yield. ND, not detected.
Scheme 4.
Scheme 4.
Potential Claisen rearrangement intermediates.
Scheme 5.
Scheme 5.
Reagents and conditions: reaction a, DMF, 125°C, 1 h, 41% yield of 33a, 39% yield of 34a; 75% yield of 33b; 82% yield of 33c. ND, not detected.
Fig. 4.
Fig. 4.
Survey of natural products from Garcinia bracteata.
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References

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