Oxazolidinones as chiral auxiliaries in asymmetric aldol reactions applied to total synthesis

Asymmetric aldol reactions of oxazolidinones as chiral auxiliaries have been achieved and attracted significant consideration as one of the most powerful synthetic tools for the carbon–carbon bond-forming reactions. The methodology has been highly successful in the stereoselective construction of a number of natural products, antibiotics, and other medicinally important compounds. The present review is focused on the utility and versatility of oxazolidinones (Evans chiral auxiliaries) in the asymmetric aldol condensations for the total synthesis of natural products and complex targets.     

Partial reduction of pyrroles: application to natural product synthesis

The partial reduction of N-Boc pyrroles has been explored giving stereoselective routes to disubstituted pyrrolines in good yields and with excellent diastereoselectivities. A novel methodology has been developed to carry out reductive aldol reactions on 2-substituted N-Boc pyrroles; use of aldehydes under reductive aldol conditions gave the anti aldol product in good selectivity. This chemistry was used as the key transformation in a synthesis of omuralide, which was achieved in 13 steps and 14% overall yield. We also report a methodology for selectively forming either cis or trans 2,5-disubstituted pyrrolines via a partial reduction of an electron-deficient N-Boc pyrrole. The trans pyrroline formed using this route was utilized in the syntheses of the polyhydroxylated pyrrolizidine natural products hyacinthacine A1 and 1-epiaustraline. Further investigation has led to the development of routes to enantiopure substituted pyrroline compounds. This has been achieved via a chiral protonation approach using easily accessible chiral acids, such as ephedrine and oxazolidinones, to quench enolates formed during the partial reduction process. Alternatively, enzymatic desymmetrization of symmetrical diol compounds formed from the partial reduction products of substituted pyrroles is also reported. This leads to formation of both enantiomers of 2,2- and 2,5-disubstituted N-Boc pyrrolines in excellent ee and yields.     

Fluorous mixture synthesis of stereoisomer libraries: total syntheses of (+)-murisolin and fifteen diastereoisomers

The synthesis of a stereoisomer library of 16 murisolins in individual pure form by fluorous mixture synthesis is reported. Four stereoisomeric precursors are tagged with different fluorous tags, and the resulting mixture is taken through the synthesis with four splits and late stage demixing and detagging to give all 16 products. These products exhibit only six different sets of NMR spectra, but all can be differentiated by chiral HPLC. The structure of murisolin is confirmed, but the structures of murisolin A and 16,19-cis-murisolin may never be known with certainty because insufficient data were collected on natural samples to differentiate each of them from one other isomer.     

Solution-phase preparation of a 560-compound library of individual pure mappicine analogues by fluorous mixture synthesis

Solution-phase mixture synthesis has efficiency advantages and favorable reaction kinetics. Applications of this technique, however, have been discouraged by the difficulty in obtaining individual, pure final products by using conventional separation and identification processes. Introduced here is a new strategy for mixture synthesis that addresses the separation and identification problems. Members of a series of organic substrates are paired with a series of fluorous tags of different chain lengths. The tagged starting materials are then mixed and taken through a multistep reaction process. Fluorous chromatography is used to demix the tagged product mixtures on the basis of the fluorine content of the tags to provide the individual pure components of the mixture, which are detagged to release the final products. The utility of fluorous mixture synthesis is demonstrated by the preparation of a 560-membered library of analogues of the natural product mappicine. A seven-component mixture is carried through a four-step mixture synthesis (two one-pot and two parallel steps) to incorporate two additional points of diversity onto the tetracyclic core. Methods for analysis and purification of the intermediates are established for the quality control of the mixture synthesis.     

Asymmetric halo aldol reaction (AHA)

[reaction: see text] The asymmetric halo aldol reaction (AHA) using Evans oxazolidinones as chiral auxiliaries has been established for tandem I-C/C-C bond formations. The new asymmetric reaction provides a practical approach to a variety of halo aldols of a non-Evans type that cannot be easily synthesized by other methods. Excellent diastereoselectivity (>95%) and yields (80-93%) have been obtained for eight examples.     

Asymmetric synthesis and absolute configuration of streptophenazine G

The asymmetric synthesis of the antibacterial natural product, streptophenazine G, has been achieved by employing asymmetric alkylation and asymmetric aldol reactions using chiral oxazolidinones as the key steps. The originally proposed structure for streptophenazine G has been revised, and its absolute configuration has been determined to be 1'S,2'R,6'S. The asymmetric total synthesis of 6'-epi-streptophenazine G is also described.     

Adsorptive detagging of poly-histidine tagged protein using hexa-histidine tagged exopeptidase

The ubiquitous use of poly-histidine fusion tags has made the purification of the recombinant target proteins much simpler, although the presence of residual fusion tags can generate immunogenic products or products with changed biological activities. This work presents a generic method of removing poly-histidine fusion tags from recombinant proteins through the use of a hexa-histidine tagged exopeptidase (DAPase) when both tagged species are adsorbed to the immobilized metal affinity chromatography (IMAC) adsorbent. Adsorptive detagging was performed in the presence of 50mM imidazole in order to allow the cleavage reaction by the hexa-histidine tagged DAPase to occur. The progress of batch and adsorptive detagging by DAPase of maltose binding protein (MBP) tagged with two variants of hexa-histidine fusion tag was successfully monitored using cationic exchange chromatography. A single-step, column-based detagging strategy was then optimized to maximize the recovery of native MBP. The kinetics of batch and on-column digestion for both HT6 and HT15 fusion tags were investigated. The process involved the sequential removal of dipeptides during the digestion of full-length fusion protein down to its fully detagged native form. During the course of tag digestion, 4 and 7 different intermediates were detected for HT6 and HT15 tagged MBP respectively. The characteristics of on-column cleavage of poly-histidine fusion tags by DAPase as a function of incubation temperature and amount of protease activity used were examined. It was found that the influence of fusion tag design on the batch and column-based detagging yield and efficiency was substantial. In addition, the structural difference of fusion tags affects the binding strength of the fusion protein, which can influence the resulting product purity. Despite being a longer tag, HT15 fusion tag was the preferred sequence for shortening the time needed for on-column detagging. These results can be applied to the wider use of the proposed platform protocol for the on-column cleavage of poly-histidine tagged proteins using exopeptidases.     

Direct observation of enantioselective synergism at trimetallic centers

[structure: see text] [structure: see text] New oligomeric chiral macrocyclic ligands have been synthesized using an efficient self-assembly method. High enantioselective cooperativity in the catalytic asymmetric aldol reactions was directly observed using the conceptually novel chiral multinuclear complex catalysts.     

Preparative fluorous mixture synthesis of diazonium-functionalized oligo(phenylene vinylene)s

[structure: see text] A series of building blocks for the synthesis of oligo(phenylene vinylene)s (OPVs) and hybrid oligomers were prepared, and alternating Heck coupling and Horner-Wadswoth-Emmons (HWE) reactions were used to couple the building blocks. Model studies were carried out to optimize the reaction strategies. The products were made to bear aryl diazonium functionalities that allow them to be used as surface grafting moieties in hybrid silicon/molecule assemblies. A library of OPV and hybrid oligomer tetramers was synthesized using fluorous mixture synthesis (FMS). The fluorous tags, which are secondary amines bearing different numbers of fluorine atoms, were synthesized and used as phase tags in mixture synthesis. The tags and substrates were anchored together by triazene linkages. The mixture synthesis was monitored by analytical HPLC on a fluorous column, and isolation of final OPV and hybrid oligomer tetramers was achieved by preparative HPLC. At the end of the FMS, after demixing, the tagged products were detagged by cleaving the triazene linkage and generating a series of aryl diazonium compounds. The fluorous tags could be recovered and reused. The NMR spectra of the 1-aryl-3,3-dialkyltriazenes are discussed.     

Enantioselective aldol reaction of chiral acyl thiazolidine thione derived boron enolates

The compatability of an acyl thiazolidine thione as a chiral auxillary in boron enolate chemistry has been demonstrated by an enantioselective aldol condensation. The aldol products provide direct access to chiral β-lactams.     

Asymmetric aldol additions: use of titanium tetrachloride and (-)-sparteine for the soft enolization of N-acyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones.

Asymmetric aldol additions using chlorotitanium enolates of N-acyloxazolidinone, oxazolidinethione, and thiazolidinethione propionates proceed with high diastereoselectivity for the Evans or non-Evans syn product depending on the nature and amount of the base used. With 1 equiv of titanium tetrachloride and 2 equiv of (-)-sparteine as the base or 1 equiv of (-)-sparteine and 1 equiv of N-methyl-2-pyrrolidinone, selectivities of 97:3 to > 99:1 were obtained for the Evans syn aldol products using N-propionyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones. The non-Evans syn aldol adducts are available with the oxazolidinethione and thiazolidinethiones by altering the Lewis acid/amine base ratios. The change in facial selectivity in the aldol additions is proposed to be a result of switching of mechanistic pathways between chelated and nonchelated transition states. The auxiliaries can be reductively removed or cleaved by nucleophilic acyl substitution. Iterative aldol sequences with high diastereoselectivity can also be accomplished.     

Solution-phase parallel synthesis with oligoethylene glycol sorting tags. Preparation of all four stereoisomers of the hydroxybutenolide fragment of murisolin and related acetogenins

The principles of the oligoethylene glycol (OEG) mixture synthesis are illustrated with the synthesis of all four possible stereoisomers of a hydroxybutenolide fragment common to murisolin and many other acetogenins. Modified dimethoxybenzyl groups with varying numbers of OEG units (-CH2CH2O-) are used to protect alcohols and serve as codes for configurations at two stereocenters. The encoded isomers are carried through several steps in a sequence of mixing prior to the reaction and then demixing during the separation to give individual pure products. A new tagging scheme is introduced in which a stereocenter bearing a hydroxy group is given two different tags. These initially redundant tags then serve to encode the configuration of another (untagged) stereocenter by appropriate pairwise reactions of the tagged precursors. The experimental features (reaction, analysis, separation, and characterization) of OEG mixture synthesis are detailed and are compared to and contrasted with those of fluorous mixture synthesis.     

Storable, powdered chiral zirconium complex for asymmetric aldol and hetero Diels-Alder reactions

A storable, powdered chiral zirconium catalyst for asymmetric aldol and hetero Diels-Alder reactions has been developed. The catalyst has the same activity as that prepared in situ even after being stored for 3 months. Moreover, this chiral Zr catalyst worked efficiently not only for asymmetric aldol reactions but also for asymmetric hetero Diels-Alder reactions affording the corresponding addition products with high enantioselectivities.     

Direct asymmetric aldol reactions inspired by two types of natural aldolases: water-compatible organocatalysts and Zn(II) complexes

In this article the utility of water-compatible amino-acid-based catalysts was explored in the development of diastereo- and enantioselective direct aldol reactions of a broad range of substrates. Chiral C(2)-symmetrical proline- and valine-based amides and their Zn(II) complexes were designed for use as efficient and flexible chiral catalysts for enantioselective aldol reactions in water, on water, and in the presence of water. The presence of 5 mol % of the prolinamide-based catalyst affords asymmetric intermolecular aldol reactions between unmodified ketones and various aldehydes to give anti products with excellent enantioselectivities. We also demonstrate aldol reactions of more demanding substrates with high affinity to water (i.e., acetone and formaldehyde). Newly designed serine-based organocatalyst promoted aldol reaction of hydroxyacetone leading to syn-diols. For presented catalytic systems organic solvent-free conditions are also acceptable, making the elaborated methodology interesting from a green chemistry perspectives.     

Synthesis of chiral organocatalysts derived from aziridines: application in asymmetric aldol reaction

We report the synthesis of a new series of highly efficient chiral organocatalysts derived via the regio- and stereoselective ring opening of chiral aziridines with azide anions. The catalysts have proved to be very efficient for a direct asymmetric aldol reaction, both with cyclic as well as acyclic ketones in brine with 2 mol % of catalyst loading, and afforded the products in excellent yields (up to 99%) and enantioselectivities (up to >99%). The chiral aldol adduct obtained has further been converted to a chiral azetidine ring via a convenient pathway.     

Iodine-catalyzed direct allylation of chiral oxazolidinones by the amide-aldehyde-alkene condensation

An iodine-catalyzed direct allylation of chiral oxazolidinones with aldehydes and alkenes has been developed. The reaction proceeds, without use of any bases or metals, directly converted the 3-chiral oxazolidinones into N-allylated oxazolidinones. Additionally, the 3-chiral allylamine skeleton was constructed and the diastereomers were isolated by simple column chromatography.     

Ring Opening of Homochiral Bicyclic Oxazolidinones: Synthesis of Allylglycinol Derivatives

(4R,6aS)-2-Oxo-4-phenyl-2,4,5,6a,7-hexahydrooxazolo[3,2-c]oxazole and its 4-methyl analog were synthesized using (R)-phenylglycinol and (S)-alaninol as the chiral source, respectively. The ring opening reaction of the bicyclic oxazolidinones by an allyltrimethylsilane–titanium tetrachloride mixture afforded the corresponding substitution products with diastereoselectivity of up to ～3:1. The major substitution product was readily converted to allylglycinol derivatives.     

Kinetic Resolution of Tertiary 2‐Alkoxycarboxamido‐Substituted Allylic Alcohols by Chiral Phosphoric Acid Catalyzed Intramolecular Transesterification

A highly enantioselective kinetic resolution of tertiary 2‐alkoxycarboxamido allylic alcohols has been achieved through a chiral phosphoric acid catalyzed intramolecular transesterification reaction. Both alkyl,aryl‐ and dialkyl‐substituted tertiary allylic alcohols were resolved with excellent efficiencies, affording both the recovered tertiary alcohols and the carbamate products with high enantioselectivities (with s factors up to 164.6). A gram‐scale reaction with 1 mol % catalyst loading and the facile conversion of the enantioenriched products into useful chiral building blocks, such as chiral oxazolidinones and β‐amino alcohols, demonstrate the value of this reaction.     

Current applications of organocatalysts in asymmetric aldol reactions: An update

The aldol reaction is one of the most important carbon–carbon bond formations in synthetic organic chemistry. An enantioselective aldol reaction should provide an enantioenriched product. The organocatalytic asymmetric aldol reaction via an in situ generated enamine intermediate is one of the most powerful synthetic tools to achieve enantiomerically pure products. This approach is often used to obtain chiral β-hydroxycarbonyl compounds with excellent enantioselectivity. In this report, we update our previous review regarding the applications of organocatalysts in asymmetric aldol reactions leading to chiral β-hydroxycarbonyl compounds as versatile synthetic motifs frequently found in pharmaceutically desired intermediates and biologically active naturally occurring compounds.     

Convenient synthesis of oxazolidinones by the use of halomethyloxirane, primary amine, and carbonate salt

[reaction: see text] Primary amines reacted with carbonate salts (Na2CO3, K2CO3, Cs2CO3, and Ag2CO3) and halomethyloxiranes in the presence of a base such as DBU or TEA to give oxazolidinones in high yields. The use of K2CO3 among these carbonate gave the best yield in this synthesis. A reaction mechanism was proposed that the oxazolidinone was obtained from an oxazinanone intermediate via a bicyclo[2.2.1] intermediate. The present reaction can be widely applied to convenient synthesis of useful N-substituted oxazolidinones and chiral oxazolidinones.