Naturally Occurring Proline Analogues

Mauger, Anthony B.

doi:10.1021/np9603479

Cited by 92 publications

(56 citation statements)

References 172 publications

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“…A few chlorinated proline moieties have been found in natural products, all of which are cyclic peptides. 52 Cyclochloritine 53 and astins A-C, [54][55][56][57] which are cyclic pentapeptide toxins from Penicillium islandicum and Aster tataricus, respectively, contain a (2R,3S,4R)-3,4-dichloroproline moiety (which is a derivative of L-proline with all three substituents on the same side of the pyrrolidine ring). Likewise, (2S,3S,4R)-3-hydroxy-4-chloroproline is a component of astin I.…”

Section: Introductionmentioning

confidence: 99%

4‐Chloroprolines: Synthesis, conformational analysis, and effect on the collagen triple helix

2007

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Collagen is an abundant, triple-helical protein comprising three strands of the repeating sequence: Xaa-Yaa-Gly. (2S)-Proline and (2S,4R)-4-hydroxyproline (Hyp) are common in the primary structure of collagen. Here, we use nonnatural proline derivatives to reveal determinants of collagen stability. Specifically, we report high-yielding syntheses of (2S,4S)-4-chloroproline (clp) and (2S, 4R)-4-chloroproline (Clp). We find that the crystal structure of Ac-Clp-OMe is virtually identical to that of Ac-Hyp-OMe. In contrast, the conformational properties of Ac-clp-OMe are similar to those of Ac-Pro-OMe. Ac-Clp-OMe has a stronger preference for a trans amide bond than does Ac-ProOMe, whereas Ac-clp-OMe has a weaker preference. (Pro-Clp-Gly) 10 forms triple helices that are significantly more stable than those of (Pro-Pro-Gly) 10 . Triple helices of (clp-Pro-Gly) 10 have stability similar to those of (Pro-Pro-Gly) 10 . Unlike (Pro-Clp-Gly) 10 and (clp-Pro-Gly) 10 , (clpClp-Gly) 10 does not form a stable triple helix, presumably due to a deleterious steric interaction between proximal chlorines on different strands. These data, which are consistent with previous work on 4-fluoroprolines and 4-methylprolines, support the importance of stereoelectronic and steric effects in the stability of the collagen triple helix and provide another means to modulate that stability.

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Section: Introductionmentioning

confidence: 99%

4‐Chloroprolines: Synthesis, conformational analysis, and effect on the collagen triple helix

2007

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“…The use of proline derivatives as organocatalysts13 and as key building blocks of many pharmaceuticals and natural products14 ensures its status as a privileged structural motif. Chiral 2,3-dehydroproline (3-pyrroline) products commonly originate from natural 3-hydroxy proline,15 a neglected family of chiral proline products emerged as an ideal target for our new methodology.…”

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confidence: 99%

Stereospecific Ring Expansion of Chiral Vinyl Aziridines

et al. 2011

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In this report, it is demonstrated that chiral vinyl aziridines can be stereospecifically ring expanded. This synthetic approach allows controlled access to chiral 2,5-cis or 2,5-trans-3-pyrroline products from starting materials with the appropriate aziridine geometry. Twenty three ring expansion examples, most of which feature a stereospecific cyclization, are presented.A cursory review of the structural motifs of the top 200 top selling drugs 1 reveals that around 90% contain at least one nitrogen atom and approximately 65% are decorated with a heterocycle. Not surprisingly, the majority of these heterocycles are nitrogenous, with pyrrolidines a commonly occurring heterocyclic scaffold. Given the success of chiral pyrrolidines as important pharmaceutical building blocks it follows that a range of practical synthetic methods are needed 2 to provide access to any targeted structural and stereochemical pyrrolidine pattern.We have chosen to tackle the challenge of developing useful pyrrolidine forming methods by revisiting the ring expansion of vinyl aziridines, first reported by Atkinson. 3 Surprisinigly, despite the potential usefulness of converting a vinylaziridine into a 3-pyrroline, there had only been a single study focused on using metal catalysts to aid the rearrangement prior to our contribution to this field. 4 Oshima and coworkers found that tosylated dieneaziridines could be ring expanded in the presence of a palladium catalyst to the 3-pyrrolines. Both the N-tosyl group and the diene moiety were reported to be essential for the success of this rearrangement. Simple non-dienic vinyl aziridines did not ring expand, furnishing instead a complex mixture of products. In our recent report, we demonstrated that this significant substrate limitation could be solved using Cu(hfacac) 2 as a catalyst. 5 The substrate scope of this new transformation, which we demonstrated for a range of tosyl (Ts) and N-phthalimide (NPhth) protected vinyl aziridines, was shown to be quite broad. In this report we expand these investigations further and focus our attention on stereospecific vinyl aziridine ring expansions and application of this new methods towards accessing chiral pyrroline products.njardars@email.arizona.edu. Supporting Information Available Full experimental details for all new compounds reported in this article including X-ray data for compounds 15d, 15j, 15l, 21d and 21f are available free of charge via the Internet at http://pubs.acs.org. In order to maximize the synthetic potential of our method for preparing chiral pyrroline products, it is essential that reliable, asymmetric, convergent, and scalable routes be available to access the requisite starting materials (chiral vinyl aziridines). 6 The union of an imine and suitably activated nucleophile quickly emerged as the optimal approach (Scheme 1). The imine based retrosynthetic analysis is highlighted for chiral pyrroline 3, which we envisioned would originate from the copper catalyzed ring expansion of a trans-or cis-vinyl aziridine (4 and ...

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“…Likewise, the amino acid L-proline is ubiquitous in biologically important peptides and proteins, as well as other natural products. In addition, numerous naturally occurring compounds incorporating derivatives of proline have been identified [31]. Detailed mechanisms for some of the intricate biosynthetic pathways responsible for pyrrole ring formation and incorporation of pyrrole units in natural products have been formulated [32].…”

Section: Relevant Natural And/or Useful Compoundsmentioning

confidence: 99%