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Pure Appl. Chem., 2010, Vol. 82, No. 9, pp. 1735-1748

http://dx.doi.org/10.1351/PAC-CON-09-11-14

Published online 2010-06-04

Lessons from the total synthesis of (±)‑phalarine: Insights into the mechanism of the Pictet–Spengler reaction

John D. Trzupek1, Chaomin Li2, Collin Chan2, Brendan M. Crowley1, Annekatrin C. Heimann1 and Samuel J. Danishefsky2,1*

1 Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA
2 Department of Chemistry, Columbia University, Havemeyer Hall, 3000 Broadway, New York, NY 10027, USA

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  • 33. The ratio of regioisomers was dependent on reaction conditions. A 4:1 ratio of regioisomers favoring the desired regioisomer was observed in DMF with sodium carbonate as base, however the yield was variable (50–90 %). The procedure described in the Supplementary Information was highly reproducible, albeit with a decreased level of regioselectivity. For interesting discussions on the regioselectivity of the Larock indolization reaction, see refs. [32,34].
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  • 35. Note that compound 60 was remarkably unstable to both chromatography and storage at room temperature. The half-life of this compound in organic solvents was less than 30 min as observed by TLC.
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  • 38. The amine was free-based by treatment with sodium bicarbonate. Surprisingly, in protocols where this step was avoided, an undesirable chlorination of the methoxy-bearing aryl ring was observed at the nucleophilic carbon alpha to the methoxy group and para to the phenol. This product was characterized by 1H NMR, COSY, NOESY, and mass spectrometry where the characteristic 3:1 ratio of molecular ions was observed.
  • 39. Encouragingly, using the optimized conditions for compound 61, compound 60 was persuaded to directly forge 35 in modest yield (40 %) where certainly a kinetically competitive degradation of compound 60 accounted for a majority of the loss in conversion for this substrate.
  • 40. A. Pictet, T. Spengler. Ber. Dtsch. Chem. Ges. 44, 2030 (1911). (http://dx.doi.org/10.1002/cber.19110440309)
  • 41. Compound 24 was prepared from an aryl lithium insertion into the corresponding oxindole and not from a Mannich-like process (see ref. [22]).
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  • 43. Note that in Woodward’s synthesis of strychnine, the iminium precursor used was beneficially inactive to Mannich capture, likely due to both the presence of a C2 aryl blocking group and an additional deactivating ethyl ester on the imine (derived from ethyl glyoxylate). Instead, this intermediate was isolated via trapping the azaspiroindolenine by invoking a base-promoted Mannich cyclization with concomitant tosylation of the imine nitrogen in a system that was blocked from further reaction. Our work utilizes no such blocking mechanism and suggests that C2-aryl tryptamine derivatives will only serve as blocking groups in the absence of a suitable trap for the transient benzylic carbocation generated upon 1,2-alkyl migration. It also seems that the blocking capacity of these systems is more a function of the unique stereoelectronics of an unprotected C2-aryl azaspiroindolenine as discussed in this section.
  • 44. Interestingly, upon treatment of desmethoxy 67 to identical conditions, the azaspiroindolenine intermediate was not isolable, and could only be observed in the crude 1H NMR (1:1 ratio with starting material, data not shown).