This review rationalizes the varied designs of systems for incorporation of UAAs into proteins via canonical codons.

Posttranslational modification of proteins expands their structural and functional capabilities beyond those directly specified by the genetic code. However, the vast diversity of chemically plausible (including unnatural but functionally relevant) side chains is not readily accessible. We describe C (sp)-C (sp) bond-forming reactions on proteins under biocompatible conditions, which exploit unusual carbon free-radical chemistry, and use them to form Cβ-Cγ bonds with altered side chains. We demonstrate how these transformations enable a wide diversity of natural, unnatural, posttranslationally modified (methylated, glycosylated, phosphorylated, hydroxylated), and labeled (fluorinated, isotopically labeled) side chains to be added to a common, readily accessible dehydroalanine precursor in a range of representative protein types and scaffolds. This approach, outside of the rigid constraints of the ribosome and enzymatic processing, may be modified more generally for access to diverse proteins.

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N-Sulfonyl 1,2,3-triazoles readily form rhodium(II) azavinyl carbenes, which react with olefins to produce cyclopropanes with excellent diastereo-and enantioselectivity and in high yield.Diazocarbonyl compounds 1 are well known precursors to metal carbenes 2 (eq 1). 1 The versatile reactivity of the latter is recognized by numerous synthetic applications. 2 In contrast, related azavinyl carbenes 3 have not been employed in synthesis, 3 primarily due to the limited availability of corresponding α-diazoimines. 4 These reactive intermediates can be viewed as synthetic equivalents of formyl carbenes, in which both amine and aldehyde functions can be revealed by simple transformations, thus significantly expanding the repertoire of chiral molecules that may be accessed via carbene-based synthetic methods. Herein we wish to report a first example of highly diastereo-and enantioselective Rh(II)-catalyzed cyclopropanation employing azavinyl carbenes 3 derived from 1-sulfonyl 1,2,3-triazoles 4. The latter can be obtained using the copper-catalyzed cycloaddition reaction of alkynes with sulfonyl azides. 5 fokin@scripps.edu. Supporting Information Available: Experimental details, characterization data and NMR spectral charts. This material is available free of charge via the Internet at http://pubs.acs.org. Our recent success in the Rh-catalyzed transannulation of N-sulfonyl 1,2,3-triazoles had proven that these easily available, reasonably stable and seemingly unreactive compounds are reliable precursors of azavinyl carbenes. 6 Accordingly, we further explored the Rh(II) catalysis with 1,2,3-triazoles targeting enantioselective transformations. To this end, we examined the cyclopropanation of styrene with 1-sulfonyl-4-phenyl-1,2,3-triazoles 4 in the presence of various chiral Rh(II) complexes 7 (Figure 1) in 1,2-dichloroethane at 80 °C (Table 1). The resulting sulfonyl imine 5 was smoothly converted into the corresponding aldehyde 6a by treatment with K 2 CO 3 in wet methanol. NIH Public AccessFirst, we found that the use of 1-toluenesulfonyl derivative 4a with Rh 2 (S-DOSP) 4 8 catalyst afforded cyclopropane-carboxaldehyde 6a in high yield and excellent transdiastereoselectivity. However, enantioselectivity of the reaction was low (Table 1, entry 1). Next, Rh 2 (S-PTAD) 4 9 and Rh 2 (S-PTTL) 4 10 catalysts were examined, providing 6a with over 70% ee (entries 2 and 3). Increased steric demand of the ligands on rhodium resulted not only in very sluggish reaction, but also in drastic erosion of the diastereoselectivity (entry 4). We hypothesized that switching to a less sterically encumbered carbene precursor might improve the overall performance of the reaction. Indeed, 1-mesyl triazole 4b reacted smoothly in the presence of Rh 2 (S-PTTL) 4 catalyst furnishing the cyclopropane product with 88% ee (entry 5). To our great delight, Rh 2 (S-NTTL) 4 ,11 in combination with sulfonyl triazole 4b allowed for excellent enantioselectivity (96% ee) and yield, 95% (entry 6). Remarkably, n-octylsulfonyl and isopropylsulfonyl t...

Cross-metathesis (CM) has recently emerged as a viable strategy for protein modification. Here, efficient protein CM has been demonstrated through biomimetic chemical access to Se-allyl-selenocysteine (Seac), a metathesis-reactive amino acid substrate, via dehydroalanine. On-protein reaction kinetics reveal a rapid reaction with rate constants of Seac-mediated-CM comparable or superior to off-protein rates of many current bioconjugations. This use of Se-relayed Seac CM on proteins has now enabled reactions with substrates (allyl GlcNAc, N-allyl acetamide) that were previously not possible for the corresponding sulfur analogue. This CM strategy was applied to histone proteins to install a mimic of acetylated lysine (KAc, an epigenetic marker). The resulting synthetic H3 was successfully recognized by antibody that binds natural H3-K9Ac. Moreover, Cope-type selenoxide elimination allowed this putative marker (and function) to be chemically expunged, regenerating an H3 that can be rewritten to complete a chemically enabled “write (CM)–erase (ox)–rewrite (CM)” cycle.

Transcription factor binding and high resolution crystallographic studies (1.3 Å) of Dickerson-Drew duplexes with cytosine, methylcytosine and hydroxymethylcytosine bases provide evidence that C-5 cytosine modifications could regulate transcription by context dependent effects on DNA transcription factor interactions.

The formation of all-carbon quaternary stereocentres in acyclic systems is one of the most difficult contemporary challenges in modern synthetic organic chemistry. Particularly challenging is the preparation of all-carbon quaternary stereocentres in aldol adducts; this difficulty is problematic because the aldol reaction represents one of the most valuable chemical transformations in organic synthesis. The main problem that limits the formation of these stereocentres is the absence of an efficient method of preparing stereodefined trisubstituted enolates in acyclic systems. Here we describe a different approach that involves the formation of two new stereogenic centres--including the all-carbon quaternary one--via a combined carbometalation-oxidation reaction of an organocuprate to give a stereodefined trisubstituted enolate. We use this method to generate a series of aldol and Mannich products from ynamides with excellent diastereomeric and enantiomeric ratios and moderate yields.