5-Carboxy-2-azabicyclo[2.1.1]hexanes as Precursors of 5-Halo, Amino, Phenyl, and 2-Methoxycarbonylethyl Methanopyrrolidines

Prolyl 4-hydroxylase (P4H) catalyzes the post-translational hydroxylation of (2S)-proline (Pro) residues in procollagen strands. The resulting (2S,4R)-4-hydroxyproline (Hyp) residues are essential for the folding, secretion, and stability of the collagen triple helix. Even though its product (Hyp) differs from its substrate (Pro) by only a single oxygen atom, no product inhibition has been observed for P4H. Here, we examine the basis for the binding and turnover of substrates by human P4H. Synthetic peptides containing (2S,4R)-4-fluoroproline (Flp), (2S,4S)-4-fluoroproline (flp), (2S)-4-ketoproline (Kep), (2S)-4-thiaproline (Thp), and 3,5-methanoproline (Mtp) were evaluated as substrates for P4H. Peptides containing Pro, flp, and Thp were found to be excellent substrates for P4H, forming Hyp, Kep, and (2S,4R)-thiaoxoproline, respectively. Thus, P4H is tolerant to some substitutions on C-4 of the the pyrrolidine ring. In contrast, peptides containing Flp, Kep, or Mtp did not even bind to the active site of P4H. Each proline analog that does bind to P4H is also a substrate, indicating that discrimination occurs at the level of binding rather than turnover. As the iron(IV)-oxo species that forms in the active site of P4H is highly reactive, P4H has an imperative for forming a snug complex with its substrate, and appears to do so. Most notably, those proline analogs with a greater preference for a C γ -endo pucker and cis peptide bond were the ones recognized by P4H. As Hyp has a strong preference for C γ -exo pucker and trans peptide bond, P4H appears to discriminate against the conformation of proline residues in a manner that diminishes product inhibition during collagen biosynthesis.Collagens are the major structural proteins in the extracellular matrix. All collagens are comprised of three polypeptide strands that coil together into a right-handed triple helix. Each strand contains a repeating three amino-acid sequence in which every third residue is a glycine (Gly 1 ): Xaa-Yaa-Gly. The Xaa position is often (2S)-proline (Pro), and the Yaa position is often (2S,4R)-4-hydroxyproline (Hyp) (1). Hyp is produced by the action of prolyl 4-hydroxylase (P4H; EC 1.14.11.2). This post-translational modification is the most prevalent † This work was supported by Grants AR044276 (NIH to R.T.R) and CHE 0515635 (NSF to G.R.K.). K.L.G. was supported by ChemistryBiology Interface Training Grant T32 BM008505 (NIH). MALDI-MS experiments were performed at the University of WisconsinMadison Biophysics Instrumentation Facility, which was established with Grants BIR-9512577 (NSF) and RR13790 (NIH).*To whom correspondence should be addressed: Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706-1544. Telephone: 608-262-8588. Fax: 608-262-3453. rtraines@wisc.edu. NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2010 January 22. in the kingdom Animalia, where Hyp is more common than seven of the "common" aminoacid residues: Cys, Gln, His, Met, P...

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“…Briefly, carbamate 1 was prepared as in ref. 46, and then used in a manner similar to that in ref. 47.…”

Section: Methodsmentioning

confidence: 99%

Conformational Preferences of Substrates for Human Prolyl 4-Hydroxylase

et al. 2008

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“…14,15 The 5- anti -bromo,6- anti -fluoro azabicycle 22 was reductively debrominated to give 5- anti -fluoride 23 . Reductive removal and reprotection, as described above for fluoride 20 , afforded either the N -BOC-5- anti- fluoro synthon 11a 16 or the N -acetyl fluoride 11b .…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Conformationally Constrained 5-Fluoro- and 5-Hydroxymethanopyrrolidines. Ring-Puckered Mimics of Gauche- and Anti-3-Fluoro- and 3-Hydroxypyrrolidines

et al. 2011

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N-Acetylmethanopyrrolidine and its four 5-syn/anti-fluoro and hydroxy derivatives have been synthesized from 2-azabicyclo[2.2.0]hex-5-ene, a 1,2-dihydropyridine photoproduct. These conformationally constrained mimics of idealized Cβ-gauche and Cβ-anti conformers of pyrrolidines were prepared in order to determine the inherent bridge bias and subsequent heteroatom substituent effects upon trans/cis amide preferences. The bridgehead position and also the presence of gauche(syn)/anti-5-fluoro or 5-hydroxy substituents have minimal influence upon KT/C values of N-acetylamide conformers in both CDCl3 (43–54% trans) and D2O (53–58% trans). O-Benzoylation enhances the trans amide preferences in CDCl3 (65% for a syn-OBz, 61% for a trans-OBz) but has minimal effect in D2O. The synthetic methods developed for N-BOC-methanopyrrolidines should prove useful in the synthesis of more complex derivatives containing α-ester substituents. The KT/C results obtained in this study establish baseline amide preferences that will enable determination of contributions of α-ester substituents to trans-amide preferences in methanoprolines.

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“…141 However, the yields of these products were substantially low (186−188). Some dichloroalkanes were prepared from the corresponding diacids in moderate yield (165,174,175); however, the chlorodecarboxylation of 1,2-dicarboxylic acids usually furnished the products in low yields. 122,135,140 Interestingly, even quadruple, one-pot chlorodecarboxylation was achieved in 20% yield (182).…”

Section: Modifications Of the Hunsdiecker−borodin Reactionmentioning

confidence: 99%

Decarboxylative Halogenation of Organic Compounds

2020

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Decarboxylative halogenation, or halodecarboxylation, represents one of the fundamental key methods for the synthesis of ubiquitous organic halides. The method is based on conversion of carboxylic acids to the corresponding organic halides via selective cleavage of a carbon–carbon bond between the skeleton of the molecule and the carboxylic group and the liberation of carbon dioxide. In this review, we discuss and analyze major approaches for the conversion of alkanoic, alkenoic, acetylenic, and (hetero)aromatic acids to the corresponding alkyl, alkenyl, alkynyl, and (hetero)aryl halides. These methods include the preparation of families of valuable organic iodides, bromides, chlorides, and fluorides. The historic and modern methods for halodecarboxylation reactions are broadly discussed, including analysis of their advantages and drawbacks. We critically address the features, reaction selectivity, substrate scopes, and limitations of the approaches. In the available cases, mechanistic details of the reactions are presented, and the generality and uniqueness of the different mechanistic pathways are highlighted. The challenges, opportunities, and future directions in the field of decarboxylative halogenation are provided.

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5-Carboxy-2-azabicyclo[2.1.1]hexanes as Precursors of 5-Halo, Amino, Phenyl, and 2-Methoxycarbonylethyl Methanopyrrolidines

Cited by 17 publications

References 43 publications

Conformational Preferences of Substrates for Human Prolyl 4-Hydroxylase

Conformational Preferences of Substrates for Human Prolyl 4-Hydroxylase

Synthesis of Conformationally Constrained 5-Fluoro- and 5-Hydroxymethanopyrrolidines. Ring-Puckered Mimics of Gauche- and Anti-3-Fluoro- and 3-Hydroxypyrrolidines

Decarboxylative Halogenation of Organic Compounds

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