Pyrrolam A

Synthesis of (R)‐(‐)‐Pyrrolam A (I) and Studies on Its Stability: A Caveat on Computational Methods[Reference: WebLink]

The Journal of Organic Chemistry,2004, 69(18):6105-14.

The asymmetric synthesis of (-)-(R)-Pyrrolam A was achieved in three operations from N-Boc pyrrolidine via an alpha-(N-carbamoyl)alkylcuprate vinylation reaction followed by N-Boc deprotection and cyclization. One-pot deprotection-cyclization procedures led to mixtures of Pyrrolam A and its double bond isomers. These isomerization events could be circumvented by use of a two-step procedure.
METHODS AND RESULTS:
To guide aspects of the experiments, a series of computational energy evaluations and chemical shift predictions were performed with molecular mechanics, semiempirical, ab initio, and density functional methods. The relative stabilities of the double bond isomers, as estimated by experiment, challenged a number of computational methods, and only the MP2 model with its moderate degree of electron correlation came close to matching the experimental data. The MP2 method was further applied to an unusual aspect of the double bond migration between Pyrrolam A and its isomer 9.
CONCLUSIONS:
The reaction (1 to 9) on neat samples is irreversible without racemization, and the alumina-mediated equilibration is accompanied by complete loss of enantiomeric excess. The source of the irreversibility was traced to asymmetric charge distribution in the intermediate dienolate anion. The analysis ultimately led to a semiquantitative sketch of the pyrrolam energy surface.

Org Lett. 2014 Jul 18;16(14):3780-3.

Enantioselective catalytic desymmetrization of maleimides by temporary removal of an internal mirror plane and stereoablative over-reduction: synthesis of (R)-pyrrolam A.[Pubmed: 24972082]

METHODS AND RESULTS:
A highly enantioselective (>95% ee) strategy to affect the desymmetrization of a maleimide has been performed by temporary attachment to an anthracene template followed by asymmetric reduction with an oxazaborolidine catalyst. A stereoablative over-reduction process was partially responsible for the high levels of enantioselectivity.
CONCLUSIONS:
Exemplification of the strategy by stereoselective functionalization and retro-Diels-Alder reaction provided the natural product Pyrrolam A.

Tetrahedron,1996,52(3): 869–876.

First total synthesis of pyrrolam A.[Reference: WebLink]

METHODS AND RESULTS:
First synthesis of Pyrrolam A (1), a pyrrolizidine alkaloid from Streptomyces olivaceus, was accomplished. The SmI2-mediated intramolecular coupling reaction between a bromoalkyl and ynamide group gave solely a cyclized product, which was converted to Pyrrolam A (1) efficiently.