Synthesis of fused heteroarylprolines and pyrrolopyrroles

The Journal of Organic Chemistry
Guillaume Jeannotte, William D Lubell

Abstract

Fused heteroarylprolines were prepared starting from 4-oxo-N-(PhF)proline benzyl ester (6, PhF = 9-(9-phenylfluorenyl)) following two approaches. First, allylation of oxoproline 6 followed by Wacker oxidation gave 1,4-dione 8 that was selectively converted to pyrroloproline 10b, pyrrolopyrrole 12, and pyridazinoproline 9. Second, aldol condensation of oxoproline 6 with a series of N-(Boc)-alpha-amino aldehydes 15a-e and acid-catalyzed cyclization gave pyrroloprolines 17a-e possessing a variety of pyrrole 5-position substituents. Conditions for the selective deprotection and alkylation of the pyrrole nitrogen of pyrroloprolines 17 were developed to expand the diversity of the heteoaryl systems. Finally, hydrogenolytic cleavage of the PhF and benzyl groups followed by subsequent protection with Boc, Fmoc, and Moz groups was performed to obtain analogues suitable for peptide synthesis. The enantiomeric purity of N-(Boc)pyrrolo-proline 21a was ascertained by coupling to l- and d-phenylalanine methyl ester and examination of the diastereotopic pyrrole protons, which demonstrated the dipeptides to be of >99% diastereomeric purity. These approaches have thus delivered the first series of enantiopure fused arylprolines for application ...Continue Reading

References

Sep 1, 1983·Journal of Medicinal Chemistry·N GruenfeldC F Huebner
Apr 27, 2000·Bioorganic & Medicinal Chemistry Letters·D RondeauW D Lubell
Jan 19, 2002·The Journal of Organic Chemistry·Oliver Gaertzen, Stephen L Buchwald

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Citations

Aug 19, 2007·Amino Acids·A TrabocchiA Guarna
Jun 11, 2011·Organic Letters·Benjamin B Thompson, John Montgomery
Dec 17, 2005·Biopolymers·Ye Che, Garland R Marshall
Nov 23, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Khidmet ShikhalievKristina Yankina
Oct 2, 2008·The Journal of Organic Chemistry·Vincenzo Giulio AlbanoDiego Savoia
Jan 6, 2006·Journal of Medicinal Chemistry·Ye Che, Garland R Marshall
Dec 12, 2012·The Journal of Physical Chemistry. B·Robel B TeklebrhanFrank Schweizer
Nov 4, 2004·Journal of the American Chemical Society·Guillaume Jeannotte, William D Lubell
Mar 14, 2007·Inorganic Chemistry·Candace N Cornell, Matthew S Sigman
Jun 1, 2007·The Journal of Organic Chemistry·Neil W OwensFrank Schweizer

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