Squarate Ester Research Articles

Berichtigung: Squaramides and Ureas: A Flexible Approach to Polymerase‐Compatible Nucleic Acid Assembly

In this Research Article, a related patent by Hill et al. was not cited. The main text should accordingly be revised as detailed below, with the missing citation included as Ref. [41]. The authors are grateful to the reader who pointed out the missing citation and apologize for not discovering and citing this patent in the original report. Include Ref. [41] in paragraph 1: “Through the formation of stable pre-activated precursor oligonucleotides, a simple process,41 more controlled ligation can occur in reagent-free, mild buffered conditions.” Revise paragraph 2 as follows: “Structurally related carbamate,[24–26] thiourea,[27] urea,[26] and squaramides[28] have been introduced into oligonucleotides during solid phase synthesis by iterative coupling or as phosphoramidite dinucleotides. Interestingly, all of these backbones could be derived from unmodified or minimally modified oligonucleotides where the terminal 5′- or 3′-hydroxy groups are replaced by amino groups. Furthermore, the reagents (for example, 1,1′-carbonyldiimidazole (CDI) and squarate ester) used to generate these linkages become progressively less reactive upon each nucleophilic addition–elimination step,[29] allowing oligonucleotides to be pre-activated prior to ligation with another strand. Of these linkages, only the squaramide has been explored in a chemical ligation context mostly in a dual step pre-activation (pH 7.2) and template-dependent ligation (pH 9.2) system.41 The resulting squaramide linkage was shown to be read-through by polymerases (Herculase II and Phusion DNA polymerases),41 with the replication compared to unmodified oligonucleotides being described as ‘slightly less efficient’. Here we extensively study amine-based chemical ligation strategies and demonstrate their practical application.” Add Ref. [41] and a short text to paragraph 3: “On the other hand, squaramide- and urea-linked oligonucleotide ligation proceeded well using squarate ester and CDI, respectively (71 % and 46 %, respectively, Figure 2B; consistent with previous reports for the squaramide41).” Add Ref. [41] and an additional sentence to paragraph 5: “… was present (Figure 2E). These results support previous reports,41 which showed quantitative pre-activation around pH 7 and good subsequent ligation at pH 9. Finally, the 5′-amino pre-activated oligonucleotides gave slightly lower ligation efficiency (80 % vs. 88 % for the pre-activated 3′-amino oligonucleotide, Figure 2D, a full summary of squaramide ligation efficiency can be found in Table S10 in the Supporting Information), most likely due to the 3′-amino group being a more sterically hindered nucleophile.” Revise the second sentence of paragraph 7: “(…, respectively assuming 100 % PCR efficiency; see also Ref. [41] for information on the performance of Herculase II and Phusion DNA polymerases in this context).”

A hydroxamic-acid-containing nucleoside inhibits DNA repair nuclease SNM1A.

Nine modified nucleosides, incorporating zinc-binding pharmacophores, have been synthesised and evaluated as inhibitors of the DNA repair nuclease SNM1A. The series included oxyamides, hydroxamic acids, hydroxamates, a hydrazide, a squarate ester and a squaramide. A hydroxamic acid-derived nucleoside inhibited the enzyme, offering a novel approach for potential therapeutic development through the use of rationally designed nucleoside derived inhibitors.

N,N′-Diarylsquaramides: General, High-Yielding Synthesis and Applications in Colorimetric Anion Sensing

Zinc trifluoromethanesulfonate promotes efficient condensations of anilines with squarate esters, providing access to symmetrical and unsymmetrical squaramides in high yields from readily available starting materials. Efficient access to electron-deficient diaryl squaramides has enabled a systematic investigation of the colorimetric anion-sensing behavior of a p-nitro-substituted squaramide. Its behavior differs in dramatic and unexpected ways from that of structurally similar p-nitroaniline-based ureas, an effect that highlights the remarkable differences in acidity between the squaramide and urea functional groups. Computational studies illustrating the enhanced hydrogen bond donor ability and acidity of squaramides in comparison to ureas are presented.

Competitive Stereochemical Control Operative during Conrotatory Electrocyclization of Helically Equilibrating Diquinanyl-Substituted 1,3,5,7-Octatetraenyl Bisenolates

[Carbohydrate structure: see text] Activation of the squarate ester cascade by adding the lithiated bicyclo[3.3.0]octene 20 and vinyllithium sequentially to 1 results in the isolation of the four tetracyclic products 21-24. The structures of the topographically complex products were deduced by 2D NMR spectroscopy and X-ray diffraction studies. The mechanistic insights gained by these findings are discussed. The product distribution is telltale evidence for predominant 1,2-addition of the second alkenyl anion. Product stereochemistry is in turn diagnostic of the preferred mode of conrotatory ring closure operating within equilibrating helical intermediates of opposite pitch. A competing pathway for the elimination of methanol in these highly functionalized intermediates has been observed for the first time.

Applications of the squarate ester cascade to the expeditious synthesis of hypnophilin, coriolin, and ceratopicanol.

The first applications of the squarate ester cascade to natural products synthesis have been realized. Only 10 laboratory steps mediate the conversion of diisopropyl squarate to (+/-)-hypnophilin (8). Key reactions include a combination of chlorination, reduction, dehydration, and oxidation maneuvers in the proper sequence. A penultimate precursor to 8 has previously been converted into coriolin (9), thereby allowing a formal synthesis of racemic 9 also to be claimed. A rather different strategy was employed to arrive at (+/-)-ceratopicanol (10). Of the seven steps involved, three consisted of the use of lithium in liquid ammonia. The three divergent synthetic objectives realized in these experiments involved (a) generation of an extended enolate anion and its regioselective C-methylation at the gamma-carbon; (b) unprecedented reductive cleavage of a beta-isopropoxy group in a 2,3-diisopropoxy-2-cyclopentenone setting; and (c) conventional conversion of an alpha-alkoxy ketone to the parent carbonyl system. Thus, the appreciable enhancement in structural complexity offered by the squarate cascade holds considerable potential for the concise synthesis of constitutionally intricate targets.

Three-component coupling via the squarate ester cascade as a concise route to the bioactive triquinane sesquiterpene hypnophilin.

[reaction: see text] A squarate ester cascade is used to provide in one step, via the coupling of three reactants, a highly oxygenated linear triquinane product. The latter is transformed in nine steps into hypnophilin. The access route involves a combination of chlorination, reduction, dehydration, and oxidation maneuvers in the proper sequence.

ChemInform Abstract: Delineating the Possibilities for Intramolecular Interception of the Squarate Ester Cascade Through the Use of Metalated Enecarbamates.

Highly functionalized and annulated 2,4-cyclooctadienones are formed in a stereoselective manner by sequential treatment of squarate esters with a lithiated enecarbamate (six-membered ring or larger) and a cycloalkenyl- or 1-alkenyllithium reagent. The mechanistic details of this multistep process are presented. Particular attention is drawn to the step that involves intramolecular nucleophilic attack by a proximal oxido anion at the carbamate carbonyl and results in redirection of the cascade. This step is thwarted when five-membered cyclic enecarbamates are employed because of the excessive buildup of ring strain in the associated transition state.Key words: squarate esters, enecarbamates, conrotatory ring opening, intramolecular acylation, alkenyllithium reagents.

Synthesis of the Lewis b hexasaccharide and squarate acid–HSA conjugates thereof with various saccharide loadings

The Lewis b hexasaccharide, α- l-Fuc p-(1→2)-β- d-Gal p-(1→3)-[α- l-Fuc p-(1→4)]-β- d-Glc pNAc-(1→3)-β- d-Gal p-(1→4)-β- d-Glc p, has been synthesised using a convergent synthesis. Starting from ethyl 4,6- O-benzylidene-2-deoxy-2-phthalimido-1-thio-β- d-glucopyranoside, a thioglycoside tetrasaccharide donor block, was constructed through two orthogonal glycosylations with glycosyl bromide donors. First, the galactose moiety was introduced using silver triflate as a promoter and then the two fucose residues under halide-assisted conditions. Finally, this tetrasaccharide was linked to a spacer-equipped 3 I,4 I-diol lactose acceptor in a DMTST-promoted coupling to give, after deprotection, the Lewis b hexasaccharide as its 2-aminoethyl spacer-equipped derivative. This was coupled to human serum albumin (HSA), using the squarate ester methodology, in various saccharide–protein ratios, to give neoglycoconjugates with different saccharide loadings in about 50% efficiency.

Delineating the possibilities for intramolecular interception of the squarate ester cascade through the use of metalated enecarbamates

Highly functionalized and annulated 2,4-cyclooctadienones are formed in a stereoselective manner by sequential treatment of squarate esters with a lithiated enecarbamate (six-membered ring or larger) and a cycloalkenyl- or 1-alkenyllithium reagent. The mechanistic details of this multistep process are presented. Particular attention is drawn to the step that involves intramolecular nucleophilic attack by a proximal oxido anion at the carbamate carbonyl and results in redirection of the cascade. This step is thwarted when five-membered cyclic enecarbamates are employed because of the excessive buildup of ring strain in the associated transition state.Key words: squarate esters, enecarbamates, conrotatory ring opening, intramolecular acylation, alkenyllithium reagents.

Delineating the possibilities for intramolecular interception of the squarate ester cascade through the use of metalated enecarbamates

Highly functionalized and annulated 2,4-cyclooctadienones are formed in a stereoselective manner by sequential treatment of squarate esters with a lithiated enecarbamate (six-membered ring or larger) and a cycloalkenyl- or 1-alkenyllithium reagent. The mechanistic details of this multistep process are presented. Particular attention is drawn to the step that involves intramolecular nucleophilic attack by a proximal oxido anion at the carbamate carbonyl and results in redirection of the cascade. This step is thwarted when five-membered cyclic enecarbamates are employed because of the excessive buildup of ring strain in the associated transition state.Key words: squarate esters, enecarbamates, conrotatory ring opening, intramolecular acylation, alkenyllithium reagents.

Theoretical study of the molecular mechanism of the domino pathways for squarate ester sequential reactions

The PM3 semiempirical method was selected to study the stereoselectivity along the domino pathways corresponding to the twofold addition of the chiral (R)-3-tert-butylcyclopentenyllithium 2 and the achiral cyclopentenyllithium 5 to dimethyl squarate ester 1 as a model for squarate ester sequential reactions. Stationary points, reactants, intermediates, transition structures and products, on the reactive potential energy surface were characterized with analytical gradient techniques. The main steps of this consecutive chemical reaction can be classified as follows: (1) addition of 2 to 1 to obtain the ketoalkoxide products 3 and 4; (ii) a domino sequence corresponding to an initial addition of 5 to these products to yield dialkoxide intermediates IN1 and IN2; subsequent C—C bond breaking processes of IN1 and IN2, associated with electrocyclic four-membered ring cleavage, to yield the endo and exo octatetraene rotamers IN3 and IN4, respectively; the final cyclizations give the cyclooctatriene products 6 and 7, respectively; and (iii) hydrolysis and subsequent intramolecular aldolic condensation of these cyclooctatrienes to obtain the final products. The theoretical results show that the step controlling the product stereochemisty corresponds to the conrotatory cyclization of the exo octatetraene intermediate IN4. The large value of the barrier height associated with the cyclization of the endo octatetraene IN3 together with the easy interconversion between the octatetraene rotamers IN3 and IN4 indicate that the cyclization process takes place only through the exo octatetraene IN4. Copyright © 1999 John Wiley & Sons, Ltd.

Theoretical study of the molecular mechanism of the domino pathways for squarate ester sequential reactions

Theoretical study of the molecular mechanism of the domino pathways for squarate ester sequential reactions

Cascade Rearrangements Following Twofold Addition of Alkenyl Anions to Squarate Esters

The double 1,2-addition of alkenyl, cycloalkenyl, and alkynyllithium reagents to squarate esters constitutes a very expedient method for rapidly increasing structural complexity with formation of polycyclic end products. The simple one-pot process is amenable to regioselective operation, stereochemical control, self-immolative chirality transfer, 1,5-asymmetric induction, and chemical modulation.

Cascade Rearrangements Following Twofold Addition of Alkenyl Anions to Squarate Esters

The double 1,2-addition of alkenyl, cycloalkenyl, and alkynyllithium reagents to squarate esters constitutes a very expedient method for rapidly increasing structural complexity with formation of polycyclic end products. The simple one-pot process is amenable to regioselective operation, stereochemical control, self-immolative chirality transfer, 1,5-asymmetric induction, and chemical modulation.

1,5-Asymmetric Induction in Squarate Cascades. Conformational Control of Helicity by Chiral Amino Substituents during Conrotatory Octatetraene Cyclization Prior to β-Elimination

Both the sigmatropic and electrocyclic rearrangement pathways that can arise when a pair of alkenyl anions are added to a squarate ester have high stereochemical demands. The distinction is nontrivial. When cis addition occurs initially, the stereoinduction that materializes at this point is fully transmitted into the product(s). The more commonly observed trans addition exhibits fleeting stereochemical consequences because of rapid equilibration of the octatetraenyl intermediates. In this instance, product distribution is governed by the relative rates of conrotatory cyclization at this advanced stage. Herein reported is a complete dissection of a squarate cascade when a stereogenic center attached to an amino substituent effects 1,5-asymmetric induction prior to β-elimination of the entire fragment. Deuterium labeling permits a direct measure of the contrasting kinetic imbalances associated with the two possible modes of alkenyl anion addition. Furthermore, quantitative analysis of the partitioning experienced by the two helical octatetraenes is readily accomplished. This work constitutes the first example where a complete dynamic profile for these complex processes has been possible. The fact that long-range asymmetric induction has been instrumental in solving the mechanistic puzzle is noteworthy.

Evaluation of Amino Substituents as Nucleofugal Controllers of Regioselectivity and as Chelate Modulators of Stereoselectivity in Squarate Ester Cascades

The tandem addition of an alkenyllithium reagent and a 2-lithioallylamine to squarate esters has been systematically examined. The effect of the sequencing of this twofold addition has been investigated. The extent to which the amino group is eliminated was found to be dependent on the structural features of the companion nucleophile. Also assessed was the comparative ease with which the amino and methoxy groups experience competitive β-elimination from the highly reactive, medium-ring dianionic intermediates. Attempts were made to curtail the level of competing 1,4-addition, and success was achieved by increasing the effective size of the O-alkyl groups in the squarate ester. The highly stereocontrolled transformations described represent a notably direct means for producing highly fused polycyclic compounds. Mechanistic considerations surrounding these reactions, which are characterized by an impressive enhancement of molecular scaffolding, are discussed.

Enhanced Channeling of the Squarate Cascade through the Dianionic Oxy-Cope Option. Oxy Substitution Markedly Augments Syn Delivery of the Second Alkenyllithium

A general means for enhancing the extent to which squarate esters enter into cascade processes involving a dianionic oxy-Cope rearrangement as the key step is presented. Adoption of this sigmatropic process requires that the two alkenyllithium reagents being introduced add cis to each other, a kinetic bias which can be realized simply by the proper incorporation of ethereal oxygen substituents in the first organometallic reagent. Structural reorganization occurs via boat-like transition states such that stereoinduction manifests itself with high fidelity.

Probe of the Stereochemically Determining Step in Squarate Ester Cascades. Proof that Helical Equilibration within the Octatetraene Intermediate Is Responsible and Definition of Steric Control Elements

The stereoselectivity associated with the coaddition of a chiral and an achiral cycloalkenyl anion to a squarate ester has been examined. The selective formation of polycyclic ketones is observed in all cases, although dual protonation at both of the available enolate sites in their penultimate cyclooctatrienyl dianion precursors was sometimes noted. Proof that the stereoselection was the result of interconversion between a pair of helical octatetraene intermediates, with resultant erosion of original stereogenicity, was established by isolation of diastereomeric monoadducts and separate submission of these hydroxy cyclobutenones to the original reaction conditions. The final stages of the cascade proceed via the lower energy transition state option where nonbonded steric effects are skirted as much as possible. These features are coordinated with subsequent stereocontrolled trans/annular aldol reactions during the quenching process. The adherence to these mechanistic guidelines is so all-encompassing tha...

Reaction cascades based on squarate esters. 1,3-Dioxolane as a chaperone functional group for lithium ions

The consequences of adding enantiomerically pure 1-lithiocyclohexene-5,6-diol acetonide and 1-cyclopentenyllithium seriatim to diisopropyl squarate has been studied. The first-stage addition leads to a chromatographically separable mixture of diastereomeric keto alcohols, which are formed in a ratio approximating 1:1. Separate reaction of these intermediates with the second cycloalkenyl anion initiates a cascade of chemical steps. The consequences of the second-stage stereoselectivity are profound in dictating the manner in which the polycyclic end products are formed.

New transformations involving squarate esters. Multi-channel rearrangement options available to 2-(dimethoxy-methyl)-1-cycloalken-1-yl adducts

The Vilsmeier-Haack reaction of cyclic ketones with PBr3 and DMF is an effective means for generating β-bromo-α,β-unsaturated aldehydes, which are readily transformed into their dimethyl acetals. These bromides are conveniently amenable to halogen-metal exchange in the presence of tert-butyllithium. The resultant organometallic intermediates, when treated with an equimolar amount of diisopropyl squarate, undergo 1,2-addition to deliver α-hydroxy ketone adducts that have proven to be sensitive to different rearrangements when in the presence of silica gel or boron trifluoride etherate. Although both processes involve net ring expansion of the cyclobutene ring with loss of methanol, the similarity stops there. In the first instance, spirocyclic diketones are produced by 1,2-shift of either of two ring carbons. In the second, extensively conjugated lactones are generated. The behavior of the adduct originating from a lithiated quinone bisketal has also been scrutinized.