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. 2009 Jun 10;131(22):7560-1.
doi: 10.1021/ja9029736.

Nazarov cyclization initiated by peracid oxidation: the total synthesis of (+/-)-rocaglamide

John A Malona  1 , Kevin Cariou, Alison J Frontier
Affiliations

Nazarov cyclization initiated by peracid oxidation: the total synthesis of (+/-)-rocaglamide

John A Malona et al. J Am Chem Soc. .

Abstract

The total syntheses of aglafolin, rocagloic acid, and rocaglamide using Nazarov cyclization are described. Generation of the necessary oxyallyl cation intermediate was accomplished via peracid oxidation of an allenol ether to generate an unusual oxycarbenium ion species that undergoes cyclization. The synthesis is efficient, highly diastereoselective, and strategically distinct from previous syntheses of rocaglamide.

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Figures

Scheme 1
Scheme 1
Initial approach: Interrupted Nazarov Cyclization
Scheme 2
Scheme 2
Alternative analysis of pentadienyl cation polarization
Scheme 3
Scheme 3
Synthesis of propargyl ethers 13a Reagents and conditions: (a) CeCl3, vinyl magnesium bromide, then HCl 1M, 65%; (b) (i) OsO4 (4 mol%), NMO (1.2 equiv.), acetone/t-BuOH/H2O; (ii) NaIO4, THF/H2O; (c) phenylacetylene, n-BuLi, THF; (d) KH, EtI, THF, 64% or KH, NaI, PMBCl, THF, 69% (over three steps).
Scheme 4
Scheme 4
Nazarov cyclization initiated by epoxide openinga Reagents and conditions: (a) t-BuLi, Bu3SnCl, Et2O, −40°C (b) m-CPBA (4 equiv.), DMF, rt, 40–50% over two steps.
Scheme 5
Scheme 5
Completion of the rocaglamide skeleton Reagents and conditions: (a) DDQ (4 equiv.), DCM, 71% (b) KHMDS, PhNTf2, THF, 0°C, 83% (c) Pd(PPh3)4, CO, MeOH, Hünig's base, THF, 65°C, 79%.
Scheme 6
Scheme 6
Completion of the synthesisa Reagents and conditions: (a) PtO2, H2, EtOH, rt, 65% (b) NaHB(OAc)3, MeCN/AcOH, 56% (c) LiOH, THF/H2O, 82%; (d) Me2NH•HCl, DCC, DMAP, 60%.
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