Exploiting morph-DAST mediated ring-expansion of substituted cyclic β-amino alcohols for the preparation of cyclic fluorinated amino acids. Synthesis of 5-fluoromethylproline and 5-fluoropipecolic acid

doi:10.1016/j.tet.2011.02.082

Tetrahedron

Volume 67, Issue 17, 29 April 2011, Pages 3091-3097

https://doi.org/10.1016/j.tet.2011.02.082 Get rights and content

Abstract

The synthesis of proline analogues bearing a fluorine-containing substituent at the fifth position of the pyrrolidine ring, racemic trans- and cis-5-fluoromethyl prolines, was performed. The key step of the synthesis is a transformation of the CH₂OH-group into the CH₂F-one using morpholinosulfur trifluoride. During the synthesis, an efficient procedure to prepare trans- and cis-5-fluoropipecolic acids was elaborated.

Graphical abstract

Introduction

4-Fluoroprolines and large molecules containing them have gained widespread popularity in the last decades. For example, they were used in the applications, such as biochemical probes, enzyme inhibitors, and enzyme substrates.1, 1(a), 1(b), 1(c), 1(d) In particular, they were shown to control cis–trans isomerization of the amide bonds, which is closely related to biologically relevant processes, primarily to protein folding and unfolding.² Moreover, proline analogues bearing fluoro-containing substituents at the position 4 of the pyrrolidine ring became very popular within the drug discovery programs (Fig. 1).³ In part, this is due to a number of the well-documented and well-elaborated synthetic protocols toward such compounds.4, 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), 4(h), 4(i), 4(j), 4(k)

Practical applications of prolines with fluorinated substituents at the positions 28, 8(a), 8(b), 8(c) and 39, 9(a), 9(b), 9(c), 9(d), 9(e) of the pyrrolidine ring, however, received much less development, since the first synthetic approaches to these compounds appeared in the literature only recently.

In contrast to the other isomers, chemistry of prolines with fluorine-containing substituents at the position 5 of the pyrrolidine ring attracted almost no attention so far. In only 2010 Brigaud et al. described the synthesis of 5-trifluoromethylpseudoprolines and studied their conformational behavior.¹⁰ Hence, the development of synthetic methodologies for a facile and practical preparation of the prolines, containing fluorinated substituents at the position 5 of the pyrrolidine ring is still a challenge. Our interest in such compounds was additionally stimulated by recent work on the application of fluorinated prolines as the solid state ¹⁹F NMR labels to study the membrane active peptides.¹¹ In this strategy, the both enantiomerically pure and racemic ¹⁹F-amino acids are used.12(c), 12(d), 12(e), 12, 12(a), 12(b) In this context, the original aim of this work was to develop a reliable synthetic strategy toward prolines having a common fluorine-containing substituent—CH₂F—at the fifth position: trans-(1a) and cis-5-fluoromethyl prolines (1b, Fig. 2).¹³

Section snippets

Results and discussion

Our retrosynthetic approach to the both 1a and 1b was based on trans- and cis-N-benzyl-2,5-dicarbomethoxy pyrrolidines 2a and 2b as the starting materials (Scheme 1). The key step of the synthesis—the transformation of the CH₂OH-group into CH₂F-one—was expected to be performed with readily available morpholinosulfur trifluoride (morph-DAST, O(CH₂CH₂)₂NSF₃)14(c), 14(d), 14, 14(a), 14(b) analogously to the reported literature procedures.15, 15(a), 15(b)

The compounds 2a/2b were readily prepared

Conclusion

In summary, we have performed the synthesis of racemic trans-(1a) and cis-5-fluoromethyl prolines (1b). During the synthesis we found an effective strategy for the preparation of cyclic fluorinated amino acids: morph-DAST mediated ring-expansion of the correspondingly substituted cyclic β-amino alcohols. In particular, synthesis of racemic trans-(9a) and novel cis-5-fluoropipecolic acids (9b) was elaborated. We hope that the discovered strategy will find wide applications in the synthesis of

General

¹H, ¹³C, and ¹⁹F NMR spectra were recorded on a Bruker Avance 500 spectrometer at 499.9 MHz, 124.9 MHz, and 470.3 MHz, respectively. Chemical shifts are reported in parts per million downfield from TMS (¹H, ¹³C) or CFCl₃ (¹⁹F) as internal standards. Mass spectra were recorded on an Agilent 1100 LCMSD SL instrument by chemical ionization (CI).

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Exploiting morph-DAST mediated ring-expansion of substituted cyclic β-amino alcohols for the preparation of cyclic fluorinated amino acids. Synthesis of 5-fluoromethylproline and 5-fluoropipecolic acid

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusion

General

Angew. Chem., Int. Ed.

Angew. Chem., Int. Ed.

J. Pept. Sci.

ChemBioChem

Biophys. J.

J. Am. Chem. Soc.

J. Fluorine Chem.

Synlett

J. Am. Chem. Soc.

J. Fluorine Chem.

J. Chem. Soc., Perkin Trans. 1

J. Org. Chem.

Biochemistry

J. Am. Chem. Soc.

Angew. Chem., Int. Ed.

J. Org. Chem.

Nature

J. Org. Chem.

Angew. Chem., Int. Ed.

J. Chem. Soc., Perkin Trans. 1

Tetrahedron Lett.

J. Fluorine Chem.

Org. Lett.

Tetrahedron

Chem. Ber.

Synthesis

J. Org. Chem.

Org. Lett.

J. Pharmacol. Exp. Ther.

J. Med. Chem.

J. Med. Chem.