Diastereoselective Alkylation Research Articles

Practical and Scalable Total Syntheses of (+)-Dysidavarones A–C

AbstractA practical and scalable enantioselective total syntheses of the marine anticancer sesquiterpene quinone meroterpenoids (+)-dysidavarones A–C has been accomplished. The central bridged bicyclo[3.3.1]nonane structure of dysidavarones was efficiently established by a one-pot intermolecular diastereoselective alkylation and intramolecular α-arylation of a Wieland–Miescher ketone derivative with a substituted benzylic bromide, without protection of the more-reactive C(4) carbonyl group. (+)-Dysidavarones A and ‘E’ were prepared on a 150-mg scale, demonstrating the efficiency and reliability of our synthetic route and providing sufficient amounts of the dysidavarones for further bioactivity evaluation.

Stereocontrolled Access to Quaternary Centers by Birch Reduction/Alkylation of Chiral Esters of Salicylic Acids.

8-Phenylmenthol esters of salicylic acid derivatives undergo efficient Birch reduction and in situ diastereoselective alkylations to afford methoxycyclohexadienes bearing new quaternary stereogenic centers. The use of an ester-based auxiliary is a designed improvement over the use of prolinol-derived amides, which are expensive and often very difficult to cleave.

Diastereoselective Alkylation of Activated Nitrogen Heterocycles with Alkenyl Boronate Complexes

AbstractAlkenyl boronate complexes react with acylated quinolines and isoquinolines via 1,2‐metalate rearrangement to give alkylated, dearomatized heterocycles in good yields, diastereoselectivities, and regioselectivities. This multi‐component coupling is highly modular and can be used to access a wide scope of heterocyclic scaffolds. Chiral boronic esters made through this methodology possess high synthetic potential and can be transformed into various functional groups in one step without racemization.

Diastereoselective Alkylation of Activated Nitrogen Heterocycles with Alkenyl Boronate Complexes.

Alkenyl boronate complexes react with acylated quinolines and isoquinolines via 1,2-metalate rearrangement to give alkylated, dearomatized heterocycles in good yields, diastereoselectivities, and regioselectivities. This multi-component coupling is highly modular and can be used to access a wide scope of heterocyclic scaffolds. Chiral boronic esters made through this methodology possess high synthetic potential and can be transformed into various functional groups in one step without racemization.

Convenient synthesis of perhydrobenz[e]indene triketone, a key intermediate for the total synthesis of stelletins.

A complementary strategy for the formal total synthesis of (±)-stelletins is reported. Key reactions include a diastereoselective Eschenmoser-Claisen rearrangement, a highly diastereoselective alkylation of decalin-nitrile, and an intramolecular [3 + 2] cycloaddition/N-O reductive bond cleavage to construct the strained functionalized tricyclic core of (±)-stelletins.

Synergistic Effect of Cerium in Dual Photoinduced Ligand-to-Metal Charge Transfer and Lewis Acid Catalysis: Diastereoselective Alkylation of Coumarins.

We report the dual role of cerium to promote the photoinduced ligand-to-metal charge transfer (LMCT) process for the generation of the alkyl radical and subsequent Lewis acid catalysis to construct stereodefined C-C bonds. This paradigm utilized ubiquitous carboxylic acids as alkyl radical surrogates and offers excellent diastereoselectivity for the formation of C-4 alkylated coumarins in good to excellent yield. UV-vis spectroscopy studies in combination with in situ Fourier transform infrared spectroscopy are consistent with the proposed mechanism, supporting the participation of the CeIV-carboxylate complex in photoinduced LMCT and its subsequent homolysis to generate the alkyl radial through the exclusion of CO2. Finally, the oxophilicity of cerium enables a two-point complexation with the in situ generated enolate intermediate and facilitates the diastereoselective protonation to form the desired product. Furthermore, this mild and atom-economical catalytic manifolds allow the late-stage modification of pharmaceuticals.

Synthesis of β2,2-Amino Acids by Stereoselective Alkylation of Isoserine Derivatives Followed by Nucleophilic Ring Opening of Quaternary Sulfamidates.

Chiral bicyclic N,O-acetal isoserine derivatives have been synthesized by an acid-catalyzed tandem N,O-acetalization/intramolecular transcarbamoylation reaction between conveniently protected l-isoserine and 2,2,3,3-tetramethoxybutane. The delicate balance of the steric interactions between the different functional groups on each possible diastereoisomer controls their thermodynamic stability and hence the experimental product distribution. These chiral isoserine derivatives undergo diastereoselective alkylation at the α position, proceeding with either retention or inversion of the configuration depending on the relative configuration of the stereocenters. Quantum mechanical calculations revealed that a concave-face alkylation is favored due to smaller torsional and steric interactions at the bicyclic scaffold. This synthetic methodology gives access to chiral β2,2-amino acids, attractive compounds bearing a quaternary stereocenter at the α position with applications in peptidomimetic and medicinal chemistry. Thus, enantiopure α-alkylisoserine derivatives were produced upon acidic hydrolysis of these alkylated scaffolds. In addition, α-benzylisoserine was readily transformed into a five-membered ring cyclic sulfamidate, which was ring opened regioselectively with representative nucleophiles to yield other types of enantiopure β2,2-amino acids such as α-benzyl-α-heterofunctionalized-β-alanines and α-benzylnorlanthionine derivatives.

Catalytic Asymmetric Cyanoalkylation of Electron-Deficient Olefins with Potassium Cyanide and Alkyl Halides.

The stereoselective cyanoalkylation of electron-deficient olefins with potassium cyanide and alkyl halides was developed based on the utilization of modular chiral 1,2,3-triazolium salts featuring a hydrogen bond-donor ability as catalysts. The reaction involving multiple carbon-carbon bond formations proceeds via the enantioselective conjugate addition of a cyanide ion and the consecutive catalyst-controlled diastereoselective alkylation of intermediary chiral triazolium enolates. Control experiments revealed that the use of a properly tuned chiral triazolium ion as a catalyst and the presence of the cyano functionality in the intermediary enolate are of crucial importance for achieving high levels of acyclic absolute and relative stereocontrol.

Practical Gram-Scale Synthesis of Iboxamycin, a Potent Antibiotic Candidate.

A gram-scale synthesis of iboxamycin, an antibiotic candidate bearing a fused bicyclic amino acid residue, is presented. A pivotal transformation in the route involves an intramolecular hydrosilylation-oxidation sequence to set the ring-fusion stereocenters of the bicyclic scaffold. Other notable features of the synthesis include a high-yielding, highly diastereoselective alkylation of a pseudoephenamine amide, a convergent sp3-sp2 Negishi coupling, and a one-pot transacetalization-reduction reaction to form the target compound's oxepane ring. Implementation of this synthetic strategy has provided ample quantities of iboxamycin to allow for its in vivo profiling in murine models of infection.

Diastereoselective Synthesis of Alkylated 1,4-Cyclohexadiene Esters Using Epimeric Pyrroloimidazolones

A pair of ortho-benzoate esters containing epimeric pyrroloimidazolones undergo sequential Birch reduction and diastereoselective alkylation to provide products ranging from 88:12 to >95:5 diastereomeric ratio (dr) for the syn-epimer, and 50:50 to 95:5 dr for the anti-epimer. The stereochemistry of the products is confirmed by a combination of X-ray crystallography on a key anti-epimer-derived product, in combination with specific rotation measurements of enantiomers that are prepared from the syn or anti starting materials. A diastereomerically pure allyl-substituted substrate is shown to undergo Cope rearrangement, which transposes the quaternary chiral center to a remote position without racemization. This work is complementary to asymmetric reductive alkylation reported previously by Schultz using anisole substrates with chiral benzamide auxiliaries in that the pyrroloimidazolones act as surrogates for the methoxy group.

Structure-activity relationship studies on the inhibition of the bacterial translation of novel Odilorhabdins analogues

A structure–activity relationship (SAR) study of NOSO-95179, a nonapeptide from the Odilorhabdin class of antibacterials, was performed by systematic variations of amino acids in positions 2 and 5 of the peptide. A series of non-proteinogenic amino acids was synthesized in high enantiomeric purity from Williams’ chiral diphenyloxazinone by highly diastereoselective alkylation or by aldol-type reaction. NOSO-95179 analogues for SAR studies were prepared using solid-phase peptide synthesis. Inhibition of bacterial translation by each of the synthesized Odilorhabdin analogues was measured using an in vitro test. For the most efficient analogues, antibacterial efficacy was measured against two wild-type Enterobacteriaceae (Escherichia coli and Klebsiella pneumoniae) and against an efflux defective E. coli strain (ΔtolC) to evaluate the impact of efflux on the antibacterial activity.

Chromium(II)-Catalyzed Diastereoselective and Chemoselective Csp2-Csp3 Cross-Couplings Using Organomagnesium Reagents.

A simple protocol for performing chromium-catalyzed highly diastereoselective alkylations of arylmagnesium halides with cyclohexyl iodides at ambient temperature has been developed. Furthermore, this ligand-free CrCl2 enables efficient electrophilic alkenylations of primary, secondary, and tetiary alkylmagnesium halides with readily available alkenyl acetates. Moreover, this chemoselective C-C coupling reaction with stereodefined alkenyl acetates proceeds in a stereoretentive fashion. A wide range of functional groups on alkyl iodides and alkenyl acetates are well tolerated, thus furnishing functionalized Csp2-Csp3 coupling products in good yields and high diastereoselectivity. Detailed mechanistic studies suggest that the in situ generated low-valent chromium(I) species might be the active catalyst for these Csp2-Csp3 cross-couplings.

Enantioselective Redox-Neutral Coupling of Aldehydes and Alkenes by an Iron-Catalyzed "Catch-Release" Tethering Approach.

The reductive coupling of aldehydes and alkenes is an emerging technology that holds the potential to reinvent carbonyl addition chemistry. However, existing enantioselective methods are limited to form “branched” products. Herein, we present a directed enantio- and diastereoselective alkylation of aldehydes with simple olefins to selectively yield linear coupling products. This is achieved by redox-neutral remote functionalization, whereby a tethering “catch–release” strategy decisively solves the key problems of reactivity and selectivity.

A Computational Determination of the Origins of Diastereoselective Alkylations of a Cysteinesulfenate Anion

Sulfenic acid anions (RSO–) represent an untapped functional group for the formation of sulfoxides and other organic compounds. Their stereoselective alkylation is an important component of this chemistry, but factors governing reaction outcomes are not fully understood. The current study uses Density Functional Theory methods to break down the influencing roles of substituents attached to 2‐aminoethanesulfenate. The lithium counterion can be coordinated to pendant ester or carbamate carbonyl groups, whereas the sulfenate oxygen readily participates in hydrogen bonding with proximal hydrogen atoms of the (protected) amino group. A Moc‐protected, ester substituted, 2‐aminoethanesulfenate adopts both lithium coordination and hydrogen bonding in the lowest energy form and demonstrates stereoselective methylation and benzylation consistent with experiments from the literature.

Diastereoselective Synthesis of Unnatural Amino Acids by Alkylation of α-tert-Butanesulfinamide Auxiliary-Bound Enolates

A new chiral auxiliary for the diastereoselective alkylation of amino ester enolates that takes advantage of chiral information stored on the enolate side of the amino ester substrate has been developed. Chiral α-sulfinamido esters were alkylated under basic conditions in good yields (up to 90%) and good to high diastereoselectivities (generally >6:1) to provide unnatural mono- and α,α-disubstituted amino acid derivatives. This auxiliary allowed for the ready conversion of ester functionality without the need for esoteric reagents. Furthermore, the auxiliary is easily removed to provide enantiopure amino acids. Computational studies revealed that a chelated transition state governs electrophile addition from the convex face of a transient bicyclic intermediate. This method allows ready access to enantioenriched natural and unnatural amino acids.

Electrophile-Dependent Alkylations of Lithiated 4-Alkoxyalk-4-enenitriles.

Alkylations of acyclic, lithiated 4-alkoxyalk-4-enenitriles are highly diastereoselective with an unusual electrophile-dependent preference. Alkyl halides, sulfur, chlorine, and acyl cyanide electrophiles intercept a series of lithiated 4-alkoxyalk-4-enenitriles to install contiguous tertiary-quaternary stereocenters with high diastereoselectivity, whereas acylations with ester and carbonate electrophiles are modestly selective. The diastereoselectivity is consistent with electrophilic attack on the most accessible face of the lithated nitrile for most electrophiles except ester and carbonate electrophiles, which likely precoordinate the lithiated nitrile before acylation. Intercepting the lithiated 4-alkoxyalk-4-enenitriles with a range of electrophiles provide insight into the criteria for otherwise challenging diastereoselective alkylations and acylations of acyclic nitriles.

Electrophile-Directed Diastereoselective Oxonitrile Alkylations.

Diastereoselective alkylation of prochiral oxonitrile dianions with secondary alkyl halides efficiently installs two contiguous stereogenic centers. The confluence of nucleophilic trajectory and the electrophile chirality causes distinct steric differences that allow efficient discrimination for one of the six possible conformers. Numerous oxonitrile-derived dianions efficiently displace secondary alkyl halides propagating the electrophile chirality to efficiently install two contiguous tertiary centers. The prevalence of chiral, secondary electrophiles makes the interdigitated alkylation of chiral electrophiles a particularly attractive route because the resulting oxonitriles are readily transformed into bioactive heterocycles.

Chiral Camphor-Based 1,3- and 1,4-Amino Alcohols and Aminodiols as Ligands for Diethylzinc Addition to Aldehydes

Syntheses of (1R,2S,3R,4S)-1,7,7-trimethyl-2-pyridin-2-ylmethylbicyclo[2.2.1]-heptane-2,3-diol (7), (1R,2S,3R,4S)-1,7,7-trimethyl-2-[(6-methyl)-pyridin-2-ylmethyl-bicyclo-[2.2.1]heptane-2,3-diol (13), and (1R,2S,2’R,4R)-1,7,7-trimethyl-2-piperidin-2-ylmethyl-bicyclo[2.2.1]heptan-2-ol (19b) from commercially available (d)-camphor (1) are described. Key steps of the syntheses involved substrate-controlled diastereoselective alkylation and platinum oxide-catalyzed hydrogenation reactions. These compounds, and other intermediate amino alcohols in their syntheses, were successfully utilized as ligands in enantioselective diethyl zinc (Et2Zn) addition to benzaldehyde with moderate enantioselectivity.

Asymmetric total synthesis of (+)-ovafolinins A and B.

(+)-Ovafolinins A and B are two homologous lignans containing unique polycyclic skeletons. Benefiting from a highly diastereoselective alkylation of (S)-Taniguchi lactone, a double Friedel-Crafts reaction, a global debenzylation and a Cu(OAc)2-enabled benzylic oxidative cyclization, we present herein an efficient synthetic approach to (+)-ovafolinins A and B.

Quaternized α,α'-Amino Acids via Curtius Rearrangement of Substituted Malonate-Imidazolidinones.

An efficient synthesis protocol is presented for accessing quaternized α-amino acids in chiral, nonracemic form via diastereoselective malonate alkylation followed by C- to N-transposition. The key stereodifferentiating step involves a diastereoselective alkylation of an α-monosubstituted malonate-imidazolidinone, which is followed first by a chemoselective malonate PMB ester removal and then a Curtius rearrangement to provide the transposition. The method demonstrates a high product ee (89-99% for eight cases) for quaternizing a range of proteinogenic α-amino acids. The stereogenicity in targets 5a-i supports previous conclusions that the diastereoselective alkylation step proceeds via an α-substituted malonate-imidazolidinone enolate in its Z-configuration, with the auxiliary in an s-transC-N conformation.