An In-Depth Study on Ring-Closing Metathesis of Carbohydrate-Derived α-Alkoxyacrylates:  Efficient Syntheses of DAH, KDO, and 2-Deoxy-β-KDO

Hekking, Koen F. W.; Moelands, Marcel A. H.; Delft, Floris L. van; Rutjes, Floris P. J. T.

doi:10.1021/jo060913x

Cited by 30 publications

(19 citation statements)

References 33 publications

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“…1) has been significantly increased. A phosphorylated form of DHA (7-phospho DHA) is an important intermediate in the shikimate pathway for the biosynthesis of aromatic amino acids (48), and there has been much interest in the preparation of DHA, and other 3-deoxy-2-ulosonic acids, due to their potential as starter units for complex oligosaccharide syntheses (42,(48)(49)(50). Our structural studies showed that the noncanonical amino acid is perfectly shaped and functionalized to interpose between Asp141 and Glu192, reducing the active site volume and causing a remodeling of the active site to stabilize better the transition state of the DHA-producing reaction.…”

Section: Discussionmentioning

confidence: 99%

Extending enzyme molecular recognition with an expanded amino acid alphabet

Windle

Simmons

Ault

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Natural enzymes are constructed from the 20 proteogenic amino acids, which may then require posttranslational modification or the recruitment of coenzymes or metal ions to achieve catalytic function. Here, we demonstrate that expansion of the alphabet of amino acids can also enable the properties of enzymes to be extended. A chemical mutagenesis strategy allowed a wide range of noncanonical amino acids to be systematically incorporated throughout an active site to alter enzymic substrate specificity. Specifically, 13 different noncanonical side chains were incorporated at 12 different positions within the active site of N-acetylneuraminic acid lyase (NAL), and the resulting chemically modified enzymes were screened for activity with a range of aldehyde substrates. A modified enzyme containing a 2,3-dihydroxypropyl cysteine at position 190 was identified that had significantly increased activity for the aldol reaction of erythrose with pyruvate compared with the wild-type enzyme. Kinetic investigation of a saturation library of the canonical amino acids at the same position showed that this increased activity was not achievable with any of the 20 proteogenic amino acids. Structural and modeling studies revealed that the unique shape and functionality of the noncanonical side chain enabled the active site to be remodeled to enable more efficient stabilization of the transition state of the reaction. The ability to exploit an expanded amino acid alphabet can thus heighten the ambitions of protein engineers wishing to develop enzymes with new catalytic properties.protein engineering | aldolases | chemical modification E nzymes are phenomenally powerful catalysts that increase reaction rates by up to 10 18 -fold (1, 2), and a new era of enzyme applications has been opened by the advancement of protein engineering and directed evolution to provide new, or improved, enzymes for industrial biocatalysis. Enzymes are attractive catalysts because they are highly selective, carrying out regio-, chemo-, and stereoselective reactions that are challenging for conventional chemistry. Moreover, enzymes are efficient catalysts, function under mild conditions with relatively nontoxic reagents, and enable the production of relatively pure products, minimizing waste generation. In recent years, there has been much success in engineering enzymes for desired reactions (3-5) using methods such as rational protein engineering (6-8), directed evolution (9-11), and, most recently, computational enzyme design (12-15).Enzymes found in Nature achieve catalysis using active sites generally composed of only 20 canonical amino acids, which are encoded at the genetic level, plus the rarer selenocysteine and 1-pyrrolysine. However, many enzymes also rely on one or more of 27 small organic cofactor molecules and/or 13 metal ions for their function (16). In addition, in some cases, Nature has exploited noncanonical amino acids (Ncas) in catalysis to extend its catalytic repertoire: for example, the quinones TPQ, LTQ, TTQ, and CTQ, respectively, in ...

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Section: Discussionmentioning

confidence: 99%

Extending enzyme molecular recognition with an expanded amino acid alphabet

Windle

Simmons

Ault

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…[1] In this context, Postema and co-workers designed an approach based on an enol ether-olefin ring closing metathesis protocol (Scheme 1c), [8,14,35,[36][37][38] whereas Mootoo and coworkers employed an intramolecular oxocarbenium ion-alkene cyclization on an acetal-enol ether precursor, as the key step in the ring forming reaction (Scheme 1d). [39] Base-induced elimination of 1-CN glycosides has been used in the preparation of 1-cyanoglycals (Scheme 1e, X = CN), which are useful precursors of heterocyclic C-1 glycals.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of C‐1 Alkyl and Aryl Glycals from Pyranosyl or Furanosyl Chlorides by Treatment with Organolithium Reagents

et al. 2009

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“…This behaviour, including the isomerization, is comparable to that observed during earlier work by our group on the RCM of a-alkoxyacrylates. [3] Interestingly, ring-closing metathesis of 10 proceeded without problems in a yield of 79 %. Apparently, the impossibility of isomerization of 10 in combination with a constrained geometry eliminates all side reactions.…”

Section: Resultsmentioning

confidence: 99%

“…[2] Conceptually, a dehydroalanine fragment consists of a double bond substituted with both an electron-donating and an electron-withdrawing group, similar to the a-alkoxyacrylate systems that have previously been reported by us. [3] Since ring-closing metathesis (RCM) of the latter systems appeared to be a particularly versatile process and successful RCM of regular enamides had already been developed by our group, [4] we also set out to investigate the metathesis behaviour of dehydroamino acids. [5] Initially, our efforts were focused on the generation of nitrogen heterocycles 1 from the corresponding precursors 2 via RCM.…”

Section: Introductionmentioning

confidence: 99%

A Ring‐Closing Metathesis Approach to Cyclic α,β‐Dehydroamino Acids

et al. 2008

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A comprehensive study on the synthesis and ring-closing metathesis (RCM) of a,b-dehydroamino acids is described. This sequence has led to the formation of a range of biologically relevant functionalized nitrogen heterocycles. The incorporation of chiral building blocks in the RCM precursors eventually resulted in the formation of optically active 4-substituted cyclic dehydroamino acids. In ad-dition, olefin isomerization under metathesis conditions was observed for a number of compounds, which could be successfully inhibited either by the introduction of allylic substituents or by the addition of a ruthenium hydride scavenger. Scheme 1. Ring-closing metathesis of dehydroamino acids.Scheme 4. Synthesis of allylically substituted RCM precursors.Scheme 5. RCM of allylically substituted dehydroamino acid-based precursors.

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An In-Depth Study on Ring-Closing Metathesis of Carbohydrate-Derived α-Alkoxyacrylates: Efficient Syntheses of DAH, KDO, and 2-Deoxy-β-KDO

Cited by 30 publications

References 33 publications

Extending enzyme molecular recognition with an expanded amino acid alphabet

Extending enzyme molecular recognition with an expanded amino acid alphabet

Synthesis of C‐1 Alkyl and Aryl Glycals from Pyranosyl or Furanosyl Chlorides by Treatment with Organolithium Reagents

A Ring‐Closing Metathesis Approach to Cyclic α,β‐Dehydroamino Acids

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