Allylic Strain Research Articles

The Role of Allylic Strain for Conformational Control in Medicinal Chemistry.

It is axiomatic in medicinal chemistry that optimization of the potency of a small molecule at a macromolecular target requires complementarity between the ligand and target. In order to minimize the conformational penalty on binding, both enthalpically and entropically, it is therefore preferred to have the ligand preorganized in the bound conformation. In this Perspective, we highlight the role of allylic strain in controlling conformational preferences. Allylic strain was originally described for carbon-based allylic systems, but the same principles apply to other types of structure with sp2 or pseudo-sp2 arrangements. These systems include benzylic (including heteroaryl methyl) positions, amides, N-aryl groups, aryl ethers, and nucleotides. We have derived torsion profiles from small molecule X-ray structures for these systems. Through multiple examples, we show how these effects have been applied in drug discovery and how they can be used prospectively to influence conformation in the design process.

Crystal structure analysis of N-acetylated proline and ring size analogs.

Crystal structures of N-acetylated proline and homologs with four- and six-membered rings (azetidine carboxylic acid and piperidine carboxylic acid) were obtained and compared. The distinctly different conformations of the four-, five-, and six-membered rings reflect Bayer strain, n → π* interaction, and allylic strain, and result in crystal lattices with a zigzag structure.

Modulating Conformational Preferences by Allylic Strain toward Improved Physical Properties and Binding Interactions.

The preference of the axial over the equatorial orientation of 2-substitutent for both phenyl-1-piperidines and N-acylpiperidines is studied at the M06-2X level of theory. For phenyl-1-piperidines, the axial 2-substituent is modestly favored over the equatorial one. In contrast, the pseudoallylic strain in N-acylpiperidines dictates the axial orientation of 2-substituent with a ΔG up to −3.2 kcal/mol. The calculations agree well with the statistics from both the Cambridge Structural Database of small-molecule organic crystal structures and the Protein Data Bank. The equilibrium between the twist-boat and chair conformations for N-acylpiperidines with a 2-substituent was further investigated. The twist-boat conformation is found to be around 1.5 kcal/mol less favorable. Finally, the three-dimensionality in shape resulting from minimization of the pseudoallylic strain is characterized, and its implication in protein–ligand interactions is briefly reviewed.

Stereochemical Control Yields Mucin Mimetic Polymers.

All animals except sponges produce mucus. Across the animal kingdom, this hydrogel mediates surface wetting, viscosity, and protection against microbes. The primary components of mucus hydrogels are mucins—high molecular weight O-glycoproteins that adopt extended linear structures. Glycosylation is integral to mucin function, but other characteristics that give rise to their advantageous biological activities are unknown. We postulated that the extended conformation of mucins is critical for their ability to block microbial virulence phenotypes. To test this hypothesis, we developed synthetic mucin mimics that recapitulate the dense display of glycans and morphology of mucin. We varied the catalyst in a ring-opening metathesis polymerization (ROMP) to generate substituted norbornene-derived glycopolymers containing either cis- or trans-alkenes. Conformational analysis of the polymers based on allylic strain suggested that cis- rather than trans-poly(norbornene) glycopolymers would adopt linear structures that mimic mucins. High-resolution atomic force micrographs of our polymers and natively purified Muc2, Muc5AC, and Muc5B mucins revealed that cis-polymers adopt extended, mucin-like structures. The cis-polymers retained this structure in solution and were more water-soluble than their trans-analogs. Consistent with mucin’s linear morphology, cis-glycopolymers were more potent binders of a bacterial virulence factor, cholera toxin. Our findings highlight the importance of the polymer backbone in mucin surrogate design and underscore the significance of the extended mucin backbone for inhibiting virulence.

Contra-thermodynamic E → Z isomerization of cinnamamides via selective energy transfer catalysis

A bio-inspired, photocatalytic E → Z isomerization of cinnamides is reported using inexpensive (−)-riboflavin (vitamin B2) under irradiation at λ = 402 nm. This operationally simple transformation is compatible with a range of amide derivatives including –NR2, –NHSO2R and N(Boc)2 (up to 99:1 Z:E). Selective energy transfer from the excited state photocatalyst to the starting E-isomer ensures that directionality is achieved: The analogous process with the Z-isomer is inefficient due to developing allylic strain causing chromophore deconjugation. This is supported by X-ray analysis and Stern-Volmer photo-quenching studies. Preliminary validation of the method in manipulating the conformation of a simple model Leu-enkephalin penta-peptide is disclosed via the incorporation of a cinnamamide-based amino acid.

Enantioselective syntheses of (E)-γ,δ-disubstituted homoallylic alcohols via BF3·OEt2-catalyzed aldehyde allylboration and analysis of the origin of E-selectivity: A1,2 allylic strain vs. syn-pentane interaction

Enantioselective allylboration of aldehydes with α-substituted β-methyl allylboronate was reported. By using BF3·OEt2 as the catalyst, γ,δ-disubstituted homoallylic alcohols were obtained in good yields with high E-selectivities and enantioselectivities. Transition state analysis revealed that the disfavored transition state suffers from a syn-pentane interaction between the BF3 catalyst and axially oriented α-substituent of the allylboron reagent. Such a syn-pentane interaction is severe enough to overcome the A1,2 allylic strain between the β-methyl group and the α-substituent of the boron reagent that is present in the favored competing transition state. Consequently, the reaction proceeded with equatorial placement of the α-substituent to furnish γ-methyl substituted homoallylic alcohols with high E-selectivity.

Syntheses of Unsymmetrical 1,4-Bifunctional Allylboron Reagents via Cu-catalyzed Highly Regio- and Stereoselective 1,4-Protoboration of Dienylboronates and Analysis of the Origin of Chemoselective Aldehyde syn-(Hydroxymethyl)allylation.

The syntheses of unsymmetrical 1,4-bifunctional allylboron reagents via Cu-catalyzed highly regio- and stereoselective 1,4-protoboration of dienylboronates were developed. The resulting allylboronates underwent chemoselective allylboration with aldehydes followed by oxidative workup to give diol products with high diastereoselectivity. Transition state analysis revealed that the disfavored transition states suffer from either a severe A1,3 allylic strain or 1,3- syn-pentane interactions. Minimization of such nonbonding 1,3- syn-pentane interactions is proposed to be the origin of observed chemoselectivity of the reaction.

Allylic strain as a stereocontrol element in the hydrogenation of 3-hydroxymethyl-cyclohex-3-en-1,2,5-triol derivatives. Synthesis of the carbasugar pseudo-2-deoxy-α-d-glucopyranose

By adaptation of a literature method developed in the glucose series and standard protecting group manipulations a 2-deoxy-d-glucose derivative is converted to a series of 1R,2R,5R-3-hydroxymethyl-cyclohexen-1,2,5-triol derivatives whose reduction to the corresponding diastereomeric d-gluco and l-ido-2-deoxy carbasugars is studied. When the hydroxymethyl group is tied up in a cyclic isopropylidene acetal with the adjacent 6-hydroxy group the cis-fused products with the ido-configuration are formed preferentially whereas protection of the hydroxymethyl group as a methoxymethyl ether results in the formation of the d-gluco isomer on hydrogenation over Raney nickel. This result is rationalized in terms of the minimization of allylic strain in the course of the reduction, enables the preparation of the carbasugar pseudo-2-deoxy-α-d-glucopyranose, and suggests that the conformation of the side chain is an important control element in the chemistry of the pseudosugars as it is in the sugars themselves.

Acyclic 1,4-Stereocontrol via the Allylic Diazene Rearrangement: Development, Applications, and the Essential Role of Kinetic E Stereoselectivity in Tosylhydrazone Formation

We report full details of a method for 1,3-reductive transposition of α-alkoxy-α,β-unsaturated hydrazones to provide E-alkenes with high 1,4-stereocontrol between the two respective allylic stereocenters. The process couples a chelation-controlled reduction of the hydrazone with an in situ allylic strain controlled retro-ene reaction of an allyl diazene, i.e., an allylic diazene rearrangement. Such stereotriads are frequently observed motifs in natural products. We observed a fortuitous kinetic preference for the E-hydrazone geometry during the hydrazonation reaction, as only the E-isomers could undergo chelation-controlled reduction.

Alkyne hydroacylation: switching regioselectivity by tandem ruthenium catalysis.

By using tandem Ru-catalysis, internal alkynes can be coupled with aldehydes for the synthesis of β,γ-unsaturated ketones. The catalyst promotes alkyne transformations with high regioselectivity, with examples that include the differentiation of a methyl vs ethyl substituent on the alkyne. Mechanistic studies suggest that the regioselectivity results from a selective allene formation that is governed by allylic strain.

Molecular Design Exploiting a Fluorine gauche Effect as a Stereoelectronic Trigger

AbstractAcyclic conformational control often relies on destabilising noncovalent interactions to give rise to predictable conformer populations. Pertinent examples of such strategies include allylic strain (A1,2 and A1,3) and syn‐pentane interactions. However, the incorporation of fluorine vicinal to an electron‐withdrawing group (F–Cβ–Cα–X) can lead to predictable conformations as a consequence of stabilising hyperconjugative and/or electrostatic interactions. Herein, we describe the application of a fluorine gauche effect to predictably control torsional rotation in a class of fluorinated 4‐(dimethylamino)pyridine (DMAP) analogues. Intramolecularisation, such as protonation or acylation, generates an electropositive nitrogen centre vicinal to the fluorine atom at a molecular hinge (F–Cβ–Cα–N+); this is the only rotatable sp3–sp3 bond. In so doing, this “substrate binding” triggers a conformational change akin to the induced fit process inherent to enzymatic systems. Herein, we validate this design approach to control molecular space. A number of X‐ray structures are documented that display this gauche preference (φNCCF ≈ 60°). Preliminary catalysis experiments are disclosed together with a kinetic and reactivity analysis.

Tandem diastereo- and enantioselective preparation of aryl and alkyl cyclopropyl carbinols with three adjacent stereocenters using perhydrobenzoxazines and diethylzinc

The enantio- and diastereoselective one-pot ethylation/cyclopropanation is efficiently promoted by a chiral perhydrobenzoxazine. The catalytic system tolerates a wide range of di- and trisubstituted α,β-unsaturated aldehydes and has been found to be highly diastereo- and enantioselective. Enals leading to intermediates lacking allylic strain or with either A(1,2) or A(1,3) strain afford the corresponding syn hydroxycyclopropanes very selectively. While α-methyl enals are successfully ethylated/cyclopropanated, the presence of bulky substituents at the alpha position of the enal constitutes a limitation to the substrate scope. The use of 1,1-diiodoethane allows the obtention of the corresponding enantioenriched cyclopropylcarbinol, which bears carbon-substituents at all three positions of the ring, with good enantiocontrol, although moderate diastereoselectivity. A procedure for the asymmetric one-pot arylation/cyclopropanation of enals is proposed, which involves the use of triarylboroxin, diethylzinc and diiodomethane.

Intramolecular Enolate Alkylation: From Steroids through Cladiellins to Isolaurallene

This account of the author’s contributions over his career attempts to sketch out a research arc that stretches all the way from very simple beginnings, taking inspiration from the steroidal <i>trans</i>-hydrindane problem, to the development of a general strategy for the stereoselective construction of cycloalkanecarboxylates via a folding and allylic strain controlled intramolecular ester enolate alkylation, with applications thereof to the total syntheses of natural products of modest complexity. Examination of the corresponding S_N2′ version of this methodology led to a serendipitous discovery that ultimately produced the olefin geometry dependent intramolecular amide enolate alkylation. Applications and extensions of this methodology have enabled completely substrate-controlled asymmetric total syntheses of diverse medium-ring oxacyclic marine natural products, and a fortuitous discovery along the way involving an organoselenium-based method led to an intriguing biomimetic synthesis of <i>Laurencia</i> metabolites. Observations are made regarding aspects of a research career in retrospect. 1 Introduction 2 Intramolecular S_N2 Enolate Alkylation 3 Intramolecular S_N2′ Enolate Alkylation 4 Synthesis of α,α′-<i>cis</i>-Disubstituted Medium-Ring Oxa­cyclic Marine Natural Products 5 Synthesis of α,α′-<i>trans</i>-Disubstituted Medium-Ring Oxa­cyclic Marine Natural Products 6 General Synthetic Plan for Dioxabicyclic Bromoallene ­Marine Natural Products Having either a 2,10-Dioxabi­cyclo[7.3.0]dodecene or 2,9-Dioxabicyclo[6.3.0]undecene Skeleton 7 Conclusion

Synthesis of (−)-Epi-Indolactam V by an Intramolecular Buchwald–Hartwig C–N Coupling Cyclization Reaction

The synthetic efforts toward the concise synthesis of (-)-indolactam V from simple and commercially available starting materials using palladium- and copper-catalyzed intramolecular N-arylation strategy for the elaboration of the requisite nine-membered lactam ring as the key step are described. The incorporation of a turn-inducing structural element along the linear precursor was fundamental to achieve the heterocyclization step as well as obtain the correct regio- and chemoselectivity. The stereoselective nature in the C-N coupling cyclization reaction is interpreted in terms of minimization of allylic strain at the transition state for the palladium-amido complex formation. Meanwhile, the synthesis of the (-)-epi-indolactam V and its enantiomer have been accomplished.

Enantioselective One‐Pot Catalytic Synthesis of 4,5‐Epoxy‐3‐alkanols and 1‐Phenyl‐2,3‐epoxy‐1‐alkanols from α,β‐Unsaturated Aldehydes

AbstractConformationally restricted perhydrobenzoxazines have been demonstrated to be good chiral ligands for one‐pot asymmetric ethylation/epoxidation, and the unprecedented arylation/epoxidation of trisubstituted α,β‐unsaturated aldehydes. The scope of the reaction has been studied and a wide set of substrates with allylic strain of different nature has been explored, obtaining good or total diastereoselectivities in all cases. The enantiocontrol was good or high for the ethylation/epoxidation reaction, whereas it remained at moderate or good levels for the arylation/epoxidation. The reaction is general for trisubstituted enals, and alkylic and aromatic substituents are tolerated at both the α‐ and β‐position of the unsaturated aldehyde; however, disubstituted enals remain challenging substrates. When the one‐pot and two‐pot protocols were compared, no significant differences concerning the stereocontrol were found, so the advantages of the one‐pot procedure are clear.

Opposing Auxiliary Conformations Produce the Same Torquoselectivity in an Oxazolidinone-Directed Nazarov Cyclization

Most applications of chiral oxazolidinone auxiliaries in asymmetric synthesis operate through a common set of stereocontrol principles. That is, the oxazolidinone is made to adopt a specific, coplanar conformation with respect to the prochiral substrate, and reaction occurs preferentially at whichever stereoheterotopic face is not blocked by the substituents on the oxazolidinone. In contrast to these principles, we report here the discovery of an alternative mechanism of oxazolidinone-based stereocontrol that does not require coplanarity and is driven instead by allylic strain. This pathway has been uncovered through computational studies of an asymmetric Nazarov cyclization. Chiral oxazolidinone auxiliaries provide essentially complete control over the torquoselectivity of ring closure and the regioselectivity of subsequent deprotonation. Density functional theory calculations (M06-2X//B3LYP) reveal that in the transition state of 4π electrocyclic ring closure, the oxazolidinone ring and the cyclizing pentadienyl cation are distorted from coplanarity in a manner that gives two transition state conformations of similar energy. These two conformers are distinguished by a 180° flip in the auxiliary orientation such that in one conformer the oxazolidinone carbonyl is oriented toward the OH of the pentadienyl cation (syn-conformer) and in the other it is oriented away from this OH (anti-conformer). Surprisingly, both conformations induce the same sense of torquoselectivity, with a 3-5 kcal/mol preference for the C5-β epimer of the ring-closed cation. In both conformations, the conrotatory mode that leads to the C5-α epimer is disfavored due to higher levels of allylic strain between the oxazolidinone substituent and adjacent groups on the pentadienyl cation (R(4) and OH). The excellent torquoselectivities obtained in the oxazolidinone-directed Nazarov cyclization suggest that the allylic strain-driven stereoinduction pathway represents a viable alternative mechanism of stereocontrol for reactions of sterically congested substrates that lie outside of the traditional coplanar (N-acyloxazolidinone) paradigm.

Origins of 1,6-Stereoinduction in Torquoselective 6π Electrocyclizations

A novel stereoselective electrocyclization developed for the total synthesis of reserpine has been explored by both experiment and theory. A stereocenter six atoms away from the newly forming chiral center is responsible for the diastereoselectivity of the ring closure. This stereogenic center, lying at the junction of two six-membered rings, defines the conformation of the substrates' fused ring skeleton that ultimately distinguishes between the two allowed, disrotatory triene geometries at the transition state. The presence of allylic strain in the disfavored transition state results in a torquoselective ring closure (dr up to 15.7:1).

ChemInform Abstract: Asymmetric Pd—NHC‐Catalyzed Coupling Reactions

AbstractReview: 55 refs.

Asymmetric Pd-NHC*-catalyzed coupling reactions

Very high asymmetric inductions result in the Pd-catalyzed intramolecular arylation of amides to give 3,3-disubstituted oxindoles when new in situ-generated chiral N-heterocyclic carbene (NHC*) ligands are employed. Structural studies show that conformational locking to minimize allylic strain is the key to understanding the function of these ligands. New applications of these ligands in the frontier area of asymmetric coupling reactions involving C(sp3)–H bonds are detailed. Highly enantioenriched fused indolines are accessible using either preformed- or in situ-generated Pd-NHC* catalysts. Remarkably, this occurs at high temperature (140–160 °C) via excellent asymmetric recognition of an enantiotopic C–H bond in an unactivated methylene unit.

A Stereoselective Oxidative Polycyclization Process Mediated by a Hypervalent Iodine Reagent

Activation of phenol derivatives with a hypervalent iodine reagent promotes the formation of bicyclic and tricyclic products via a cationic cyclization process. The method allows efficient one-step syntheses of scaffolds present in several natural products and occurs with total stereocontrol, governed by 1,3 allylic strain interactions and by the configuration of the side chain double bonds.