Chemoenzymatic approaches to glycoprotein synthesis

The construction of homogeneous glycoproteins presents a formidable challenge to the synthetic chemist. Over the past few years there has been an explosion in the number of methods developed to address this problem. These methods include the development of novel ligation technologies for the synthesis of the protein backbone, as well chemical and enzymatic approaches for introducing complex glycans into the peptide backbone. This tutorial review discusses the application of these techniques to the synthesis of peptides and proteins possessing well defined glycans.     

Synthetic approaches toward sesterterpenoids

Sesterterpenoids account for many bioactive natural products, often with unusual and complex structural features, which makes them attractive targets for synthetic chemists. This review surveys efforts undertaken toward the synthesis of sesterterpenoids, focusing on completed total syntheses and covering ca. 50 natural products in total.     

Three overlooked chemical approaches toward 3-naphthalimide amonafide N-derivatives

Three efficient strategies for derivatization of the anticancer drug candidate amonafide (Quinamed, originally AS1413) are described. Unprecedented reductive amination of aryl aldehydes, S_NAr, and addition–elimination reactions, while using readily available starting materials, give quick entry to potential libraries of novel 3-aryl, 3-benzyl N-derivatives of amonafide. The selective anticancer activity of this important DNA intercalation agent is expected to be enhanced by expanding the diversity of amonafide N-derivatives. The synthetic routes reported in this work are general and readily applicable.     

Synthetic approaches toward the reserpine

Reserpine is an indole alkaloid, antipsychotic, and antihypertensive drug that has been used for the control of high blood pressure and for the relief of psychotic symptoms. It was first isolated in 1952 from the dried root of Rauwolfia serpentina whose molecular structure was established in 1953 and natural configuration was published in 1955. The first total synthesis of reserpine was reported by Woodward in 1958. This review article updates current multistep synthetic approaches toward the reserpine natural product and its analogues.     

Chemoenzymatic approaches to lycorine-type Amaryllidaceae alkaloids: total syntheses of ent-lycoricidine, 3-epi-ent-lycoricidine, and 4-deoxy-3-epi-ent-lycoricidine

The readily available and enzymatically derived cis-1,2-dihydrocatechol 4 has been elaborated, over 11 steps including an Overman rearrangement, into the non-natural enantiomer, (-)-1, of the alkaloid lycoricidine [(+)-1]. Related chemistries have provided analogues 18, 19, and 26.     

Chemoenzymatic synthesis of azacycloalkan-3-ols

Optically active ω-bromocyanohydrins are easily synthesized through an enantioselective (R)-oxynitrilase-catalyzed reaction from their corresponding ω-bromoaldehydes. These cyanohydrins are starting materials for the preparation of medium size nitrogen heterocycles. The reduction of (R)-(+)-5-bromo-2-hydroxypentanenitrile affords, in one-pot, piperidin-3-ol. Azepan-3-ol and azocan-3-ol are readily obtained from their corresponding cyanohydrins in high enantiomeric excesses.     

Chemoenzymatic syntheses of iGb3 and Gb3

[STRUCTURE: SEE TEXT] Efficient chemoenzymatic syntheses of iGb3 and Gb3 have been developed. Isoglobotrihexose and globotrihexose were enzymatically synthesized by a three-enzyme system in both solid and solution phases. Then iGb3 and Gb3 were chemically synthesized by coupling of the corresponding trisaccharides with lipid.     

Chemoenzymatic approaches to the montanine alkaloids: a total synthesis of (+)-brunsvigine

The readily available and enzymatically derived cis-1,2-dihydrocatechols 3a and 3b have been elaborated over 17 steps, including a novel radical addition/elimination sequence, into the enantiomer, (+)-1, of the montanine alkaloid brunsvigine [(-)-1].     

Chemoenzymatic approaches to the montanine alkaloids: a total synthesis of (+)-nangustine

The synthesis of (+)-nangustine [(+)-2] has been achieved, for the first time, using the enantiomerically pure cis-1,2-dihydrocatechol 3 as starting material. The latter compound is available, in multi-gram quantities, through a whole-cell-mediated biotransformation of chlorobenzene using genetically engineered organisms that over-express the responsible enzyme, namely toluene dioxygenase. Since the enantiomer of compound 3 is available by related means, the present work also represents a formal total synthesis of the montanine alkaloid (−)-nangustine [(−)-2]. Single-crystal X-ray analyses of compounds 13 and (+)-2 are reported.     

Synthetic approaches toward macrocyclic sulfonyl crown formazans

Coupling of diazonium salts with ethyl sulfonylpyruvates 1–3 or arenesulfonylacetic acids 14,15 afforded good yields of the corresponding 1,5-symmetrically disubstituted-3-sulfonylformazans 4–11. The new sulfonyl macrocyclic crown formazans 25–32 were prepared by coupling of the appropriate bisdiazonium salts 22–24 with compounds 1–3 or 14,15. © 1996 John Wiley & Sons, Inc.     

Green chemical approaches toward high-quality semiconductor nanocrystals

Green chemistry principles have gradually been implemented into the development of the synthetic chemistry of high-quality semiconductor nanocrystals. In comparison with the original organometallic approach, the resulting alternative routes are safe, simple, inexpensive, reproducible, versatile, "user friendly", and yield nanocrystals with well-controlled size, shape, and size/shape distribution. Further developments in this direction will promote the understanding of crystallization in general.     

Chemoenzymatic synthesis of both enantiomers of 3-hydroxy- and 3-amino-3-phenylpropanoic acid

Ethyl (S)-3-hydroxy-3-phenylpropionate (S)-2 was obtained by the asymmetric reduction of ethyl 3-phenyl-3-oxopropionate 1 with the yeast Saccharomyces cerevisiae (ATCC 9080). The kinetic resolution of racemic ethyl 2-acetoxy-3-phenyl-propionate rac-3 with the same microorganism, gave after hydrolysis ethyl (R)- and (S)-3-hydroxy-3-phenylpropionates (R)-2 and (S)-2 which were converted by a straightforward series of reactions to the enantiomers of 3-amino-3-phenyl-propionic acids (S)-6 and (R)-6. The asymmetric reduction and hydrolytic kinetic resolution were also tested with several other whole cell systems under a variety of conditions.     

Chemoenzymatic synthesis of both enantiomers of 3-hydroxy-2,2-dimethylcyclohexanone

The stereoselective acetylation of meso-2,2-dimethyl-1,3-cyclohexanediol by vinyl acetate in the presence of three lipases gave the (1R,3S)-monoester in high enantiomeric excess (ee > or = 98%). The hydrolysis of the corresponding meso-diacetate in the presence of Candida antarctica lipase in phosphate buffer provided the opposite enantiomer. Optically active monoacetates were converted to both enantiomers of 3-hydroxy-2,2-dimethylcyclohexanone, a versatile chiral building block.     

Chemoenzymatic resolution of epimeric cis 3-carboxycyclopentylglycine derivatives

Epimeric 3-carboxycyclopentylglycines (+)-10/(−)-10 and (+)-11/(−)-11 were efficiently prepared by the way of a sequence of Diels-Alder and retro-Claisen reactions. The synthesis incorporates a concise and inexpensive chemoenzymatic resolution of racemic compounds 4,5a, the N,O-protected derivatives of amino acids 10,11. Systematic screening with different enzymes and microorganisms was performed to select a very efficient catalyst for the separation of the racemic mixtures. The reaction conditions allowing deprotection of both ester and amino functions and to avoiding epimerization processes were studied. Enantiomers (i.e., (+)-10/(−)-10 and (+)-11/(−)-11) were obtained in high enantiopurity. The absolute configuration of all stereocenters was unequivocally assigned.     

Recent synthetic approaches toward non-anomeric spiroketals in natural products

Many natural products of biological interest contain [6,5]- and [6,6]-spiroketal moieties that can adopt various configurations, benefiting or not from anomeric conformation stabilizing effects. The spiroketal fragments are often important for the biological activity of the compounds containing them. Most stable spiroketal stereoisomers, including those benefiting from conformational anomeric effects (gauche conformers can be more stable than anti conformers because of a contra-steric stabilizing effect), are obtained easily under acidic conditions that permit acetal heterolysis (formation of tertiary oxycarbenium ion intermediates). The synthesis of less stable stereoisomers requires stereoselective acetal forming reactions that do not permit their equilibration with their most stable stereoisomers or, in the case of suitably substituted derivatives, concomitant reactions generating tricyclic products that quench the less stable spiroketal conformers. Ingenuous approaches have been recently developed for the synthesis of naturally occurring [6,6]- and [5,6]-nonanomeric spiroketals and analogues. The identification of several parameters that can influence the stereochemical outcome of spirocyclization processes has led to seminal improvements in the selective preparation of the non-anomeric isomers that are discussed herein. This review also gives an up-dated view of conformational anomeric effect which represents a small fraction of the enthalpic anomeric effect that makes gem-dioxy substituted compounds much more stable that their 1,n-dioxy substituted isomers (n > 1). Although models assuming sp3-hybridized oxygen atoms have been very popular (rabbit ears for the two non-bonding electron pairs of oxygen atom), sp2-hybridized oxygen atoms are used to describe the conformational anomeric effect.     

Synthetic approaches toward piperidine related structures: A review

Abstract

The current review covers explosive development of various synthetic approaches for piperidine scaffold and its analogues in the last few decades. The piperidine ring system is a key motif in many natural alkaloids and synthetic organic compounds. Further, piperidine moiety has gained significant consideration in drug discovery due to its wide range of therapeutic applications.     

Chemoenzymatic synthesis of Park’s nucleotide: toward the development of high-throughput screening for MraY inhibitors

An efficient chemoenzymatic synthesis of UDP-N-acetylmuramyl-l-alanyl-γ-d-glutamyl-meso-diaminopimelyl-d-alanyl-d-alanine (Park’s nucleotide) is reported. UDP-MurNAc is efficiently synthesized by a minimum number of protecting strategies. One-pot amino acid ligation reactions catalyzed by MurC, D, E, and F enzymes are amenable to scale-up production.     

Chemoenzymatic resolution of rac-malathion

Malathion, diethyl 2-[(dimethoxyphosphorothioyl)sulfanyl]butanedioate, is an organophosphate used to control insect pests. Malathion contains a diethyl succinate moiety that is a known functional group susceptible to desymmetrizing enzymes such as esterases that selectively react with a single enantiomer. Purified rac-malathion was subjected to hydrolysis at the diethyl succinate moiety of malathion under various conditions using wild type pig liver esterase to form (S)-malathion (12% ee) and ∼3:2 mixture of α- and β-monoacids of (R)-malathion. Technical malathion could not be enriched due to the presence of esterase inhibitors. Further investigation of this resolution using a panel of six PLE isoenzymes also demonstrated the formation of (S)-malathion, however, an improvement of up to 56% ee was obtained.