Chiral Synthons Research Articles

One-Handed Covalent Helical Ladder Polymers: The Dawn of a Tailorable Class of Chiral Functional Materials.

In the last decades, chemists have developed methods to synthesize helical molecular architectures using a combination of covalent and non-covalent interactions. Very recently, the new class of completely covalent, one-handed helical ladder polymers has vigorously emerged. Such polymers can be rationally and programmably obtained through an approach guided by the principles of chirality-assisted-synthesis (CAS) and making use synergically of two disciplines that have so far rarely interacted: non-planar chiral π-conjugated synthons and ladder polymer chemistry. The precise programmability of the 3D structure and new mechanical and chiroptical properties will lead to potential applications in areas such as enantiorecognition, catalysis, spintronics and chiral-related optoelectronics. This minireview examines the emerging field of one-handed helical ladder polymers, analyzing their synthesis, applications, and limitations.

Carbohydrate Derived α,β-Unsaturated Enals (Perlin’s Aldehyde) as Chiral Synthon for the Synthesis of Privileged Scaffolds

Perlin’s aldehyde is an α,β-unsaturated carbonyl compound with two well-defined chiral centres and a free hydroxy group. Since its discovery and synthesis by A. S. Perlin in 1975, it has been used as a flexible chiral synthon for synthesising natural products, its scaffolds and biologically significant compounds. Perlin’s aldehydes serve as useful starting materials in diversity-oriented synthesis (DOS) and chiral building blocks in organic synthesis. Currently, synthesising frameworks based on carbohydrates is at the forefront of organic synthesis. Inspired by the reactivity of Perlin’s aldehyde, various research groups worldwide used this molecule as a chiral synthon and published a number of research papers and a review article covering literature until 2012. This review covers recent advances in the synthesis of natural products, their scaffolds and other molecules, starting from perlin aldehyde, covering the literature from 2013 till date.

Helical Ni‐Cluster Organic Framework Constructed from Enantiopure Lactate Derivative: Synthesis, Structure and Properties

AbstractUnder hydrothermal condition, lactate derivative (R)‐4‐(1‐ carboxyethoxy)‐2‐methylbenzoic acid ((R)‐H2cma) as chiral synthon assembled with 4,4′‐di(1H‐imidazol‐1‐yl)‐1,1′‐biphenyl (4,4’‐dib) and Ni(II) ions to obtain complex {[Ni2((R)‐cma)2(4,4’‐dib)2(H2O)] ⋅ 2H2O}n (HU20‐R). In complex HU20‐R, carboxyl group from lactate unit of (R)‐cma2− anion and coordinating H2O molecule adopt a μ2‐coordination mode to obtain dinuclear [Ni2(CO2)2(H2O)]2+ cluster. (R)‐cma2− anions and Ni(II) ions build single left‐handed (R)‐cma‐Ni‐chain, while 4,4’‐dib ligands are bridged by different Ni(II) centers to form double left‐handed 4,4’‐dib‐Ni‐chain. These helical secondary structures are further connected together to result in an 8‐connected 3D framework. PXRD tests indicated that complex HU20‐R has well hydro‐stability. UV‐vis absorption experiment confirmed that HU20‐R is a semi‐conducting material with strong absorption capacity for ultraviolet‐visible (UV‐vis) light. Additionally, electrochemical experiment revealed that HU20‐R has low impedance and high charge transport capacity. Further test results confirm that HU20‐R has noticeable photo‐catalytic effect in photodegradation of Rhodamine B (RhB) and antiferromagnetic property.

Catalytic Asymmetric Aza-Electrophilic Additions of 1,1-Disubstituted Styrenes.

Electrophilic addition of alkenes is a textbook reaction that plays a pivotal role in organic chemistry. In the past decades, catalytic asymmetric variants of this important type of reaction have witnessed great achievements by the development of novel catalytic systems. However, enantioselective aza-electrophilic additions of unactivated alkenes, which could provide a transformative strategy for the preparation of synthetically significant nitrogen-containing compounds, still remain a formidable challenge. Herein, we have developed unprecedented Au(I)/NHC-catalyzed asymmetric aza-electrophilic additions of unactivated 1,1-disubstituted styrenes by the utilization of readily available dialkyl azodicarboxylates as electrophilic nitrogen sources. Based on this approach, a series of transformations, including [2 + 2] cycloaddition, intermolecular 1,2-oxyamination, and several types of intramolecular hydrazination-induced cyclizations, have been realized. These transformations provide a previously unattainable platform for the divergent synthesis of hydrazine derivatives, which could also be converted to other nitrogen-containing chiral synthons. Experimental and computational studies support the idea that carbocation intermediates are involved in reaction pathways.

Solvent-controlled assembly of helical coordination polymers based on lactate synthon from two-dimensional layer to three-dimensional framework

Compound (R)-4-(1-carboxyethoxy)-2-methylbenzoic acid ((R)-H2cma) was prepared from (S)-methyl lactate and 4-hydroxy-2-methylbenzoic acid. (R)-H2cma as chiral synthon assembled with 1,3-di(pyridin-4-yl)propane (1,3-dpp) and Ni2+ ions to obtain helical chiral complexes {[Ni2((R)-cma)2(1.3-dpp)2]·H2O}n (HU18-R) and {[Ni2((R)-cma)2(1.3-dpp)2(H2O)]·3H2O}n (HU19-R) in different solvent systems. Single crystal tests revealed that HU18-R is a two-dimensional (2D) structure with two independent Ni2+ centers and HU19-R is a three-dimensional (3D) framework containing dinuclear [Ni2(CO2)2(H2O)]2+ clusters. Four types of helices were formed in HU18-R and HU19-R by chiral transfer or induction. In HU18-R, small right-handed (R)-cma-Ni chain and large right-handed (R)-cma-Ni-1.3-dpp chain were constructed by chiral transfer. For HU19-R, helical nano-channel based on achiral 1.3-dpp ligands and Ni2+ ions was obtained from chiral induction method and small (R)-cma-Ni chain was built from chiral transfer. As semi-conducting materials, HU18-R and HU19-R indicate strong absorption capacity for UV–vis light and low-impedance properties. Under UV light, they have noticeable catalytic effects for degradation of methylene blue (MB). Moreover, magnetic tests confirmed that HU18-R and HU19-R have ferromagnetic and antiferromagnetic properties, respectively.

Modulating regioselectivity of CYP107J3-catalyzed isophorone hydroxylation by disrupting the hydrophobic balance of the substrate binding pocket

4-Hydroxyisophorone (4HIP) is an oxygenated intermediate derived from isophorone, serving as an important flavor and fragrance and chiral synthon of pharmaceutical drugs. In this study, a newly identified P450CYP107J3 from Bacillus cereus was found to prefer 4-hydroxylation of isophorone (80% regioselectivity) with 4HIP as the predominant product (59% product proportion). Bioinformatic analyses, including homologous modelling and molecular docking, reveal that four potential “hotspot” residues (L98, T300, M401 and V296) located on both sides of the substrate in the active pocket may control regioselectivity. By introducing polar residues to these hotspots to disrupt the hydrophobic balance, significant improvement in C4-regioselectivity was achieved by variants of L98, T300, and M401, with the most effective L98N exhibiting a notable enhancement of 93% C4-regioselectivity including 81% of 4HIP. Following, the double mutant L98N-M401F further improved both C4-regioselectivity (97%) and the proportion of 4HIP (86%). Remarkably, variant V296T essentially shifted regioselectivity from 4HIP to 6-hydroxyisophorone (6HIP) with an 80% preference for the latter, indicating the crucial role of V296 in controlling regioselectivity. Subsequently, the mechanism of regioselectivity of isophorone hydroxylation catalyzed by CYP107J3 was revealed by computational analysis. Furthermore, we demonstrated the generality of conserved hotspots L98 and V296 in mediating regioselectivity control in the CYP107J family members like CYP107J1 and CYP107J5. Overall, our study not only expands the biocatalytic toolbox for producing 4HIP and the α-hydroxy ketone 6HIP but also provides efficient engineering strategy and knowledge for the regioselectivity control of P450s in potential applications.

Developments in the stereoselective synthesis of benzopyran, benzopyrone and flavonoid based natural product analogues using C-glycosides as an intrinsic chiral synthon

Stereoselective synthesis is essential for propelling mainstream academia toward a relentless pursuit of novel and cutting-edge strategies for constructing molecules with unparalleled precision. Naturally derived benzopyrans, benzopyrones, and flavonoids are an essentially prominent group of oxa-heterocycles, highly significant targets in medicinal chemistry owing to their extensive abundance in biologically active natural products and pharmaceuticals. The molecular complexity and stereoselectivity induced by heterocycles embedded with C-glycosides have attracted considerable interest and emerged as a fascinating area of research for synthetic organic chemists. This present article emphasizes the existing growths in the strategies involving the diastereoselective synthesis of C-glycosylated benzopyrans, benzopyrones, and flavonoids using naturally acquired glycones as chiral synthons.

Enantioselective remote methylene C-H (hetero)arylation of cycloalkane carboxylic acids.

Stereoselective construction of γ- and δ-stereocenters in carbonyl compounds is a pivotal objective in asymmetric synthesis. Here, we report chiral bifunctional oxazoline-pyridone ligands that enable enantioselective palladium-catalyzed remote γ-C-H (hetero)arylations of free cycloalkane carboxylic acids, which are essential carbocyclic building blocks in organic synthesis. The reaction establishes γ-tertiary and α-quaternary stereocenters simultaneously in up to >99% enantiomeric excess, providing access to a wide range of cyclic chiral synthons and bioactive molecules. The sequential enantioselective editing of two methylene C-H bonds can be achieved by using chiral ligands with opposite configuration to construct carbocycles containing three chiral centers. Enantioselective remote δ-C-H (hetero)arylation is also realized to establish δ-stereocenters that are particularly challenging to access using classical methodologies.

Vicinal Diones and α‐Keto Esters as Electrophiles of Aldolases for Stereoselective Construction of Tertiary Alcohols

AbstractAldolases are powerful C−C bond‐forming enzymes with high stereoselectivity and broad substrate scope in biocatalysis, but their ability to stereoselectively construct tertiary alcohols has not been fully explored. Herein, we demonstrate that vicinal diones and α‐keto esters are electrophiles that can be accepted by both natural and computationally designed aldolases via various catalytic mechanisms. This method allows for the efficient asymmetric synthesis of small molecules with tertiary alcohols, including noncanonical amino acids. This study presents the first types of generic nonnatural substrates of aldolases and reveals new opportunities for the use of aldolases in the synthesis of versatile chiral synthons.

Peroxygenase-Enabled Reductive Kinetic Resolution for the Enantioenrichment of Organoperoxides.

Enantiomerically pure organoperoxides serve as valuable precursors in organic transformations. Herein, we present the first examples of unspecific peroxygenase catalyzed kinetic resolution of racemic organoperoxides through asymmetric reduction. Through meticulous investigation of the reaction conditions, it is shown that the unspecific peroxygenase from Agrocybe aegerita (AaeUPO) exhibits robust catalytic activity in the kinetic resolution reactions of the model substrate with turnover numbers up to 60000 and turnover frequency of 5.6 s-1. Various aralkyl organoperoxides were successfully resolved by AaeUPO, achieving excellent enantioselectivities (e.g., up to 99 % ee for the (S)-organoperoxide products). Additionally, we screened commercial peroxygenase variants to obtain the organoperoxides with complementary chirality, with one mutant yielding the (R)-products. While unspecific peroxygenases have been extensively demonstrated as a powerful oxidative catalysts, this study highlights their usefulness in catalyzing the reduction of organoperoxides and providing versatile chiral synthons.

Peroxygenase‐Enabled Reductive Kinetic Resolution for the Enantioenrichment of Organoperoxides

AbstractEnantiomerically pure organoperoxides serve as valuable precursors in organic transformations. Herein, we present the first examples of unspecific peroxygenase catalyzed kinetic resolution of racemic organoperoxides through asymmetric reduction. Through meticulous investigation of the reaction conditions, it is shown that the unspecific peroxygenase from Agrocybe aegerita (AaeUPO) exhibits robust catalytic activity in the kinetic resolution reactions of the model substrate with turnover numbers up to 60000 and turnover frequency of 5.6 s−1. Various aralkyl organoperoxides were successfully resolved by AaeUPO, achieving excellent enantioselectivities (e.g., up to 99 % ee for the (S)‐organoperoxide products). Additionally, we screened commercial peroxygenase variants to obtain the organoperoxides with complementary chirality, with one mutant yielding the (R)‐products. While unspecific peroxygenases have been extensively demonstrated as a powerful oxidative catalysts, this study highlights their usefulness in catalyzing the reduction of organoperoxides and providing versatile chiral synthons.

Chiral Ni(Ⅱ)-Based coordination polymers with helixes and dinuclear clusters constructed from lactate synthons

Chiral coordination polymers [Ni((R)-ceba) (1,3-dpp) (H2O)0.5] (HU15-R), [Ni((R)-ceba) (1,3-dpp) (H2O)0.5] (HU15–S), [Ni((R)-ceba) (4,4′-dib) (H2O)0.5] (HU16-R) and [Ni((S)-ceba) (4,4′-dib) (H2O)0.5](HU16–S) were prepared from lactate-derived synthons and different N-donor linkers under hydrothermal conditions (H2ceba = 4-(1-carboxyethoxy)benzoic acid, 1,3-dpp = 1,3-di(pyridine-4-yl)propane, 4,4′-dib = 4,4′-di (1H-imidazole-1-yl)-1,1′-biphenyl). Structural analysis confirmed that that all complexes are three-dimensional frameworks containing dinuclear [Ni2(CO2)2(H2O)]2+ clusters. In addition, four types of helical structures were also obtained though chiral transfer and asymmetric induction from chiral synthons among them. (R)-ceba2- anions and Ni(Ⅱ) ions were bridged together to construct right-handed (R)-ceba-Ni chains in HU15-R and HU16-R, while (S)-ceba2- anions were linked by Ni(Ⅱ) ions to build right-handed (S)-ceba-Ni chains in HU15–S and HU16–S. Apart from chiral synthons, achiral linkers 1,3-dpp and 4,4′-dib assembled with Ni(Ⅱ) ions to form single 1,3-dpp-Ni chains in HU15-R and HU15–S and double 4,4′-dib-Ni chains in HU16-R and HU16–S, respectively. Meanwhile, the introductions of N-donor ligands resulted in varied topological structures. HU15-R and HU15–S are 4-connected dia nets, while HU16-R and HU16–S are 8-connected frameworks. Moreover, magnetic experiments indicated that antiferromagnetic interactions exist in these complexes.

Cobalt-Catalyzed Enantioselective Hydroboration of α-Substituted Acrylates.

Even though metal-catalyzed enantioselective hydroborations of alkenes have attracted enormous attention, few preparatively useful reactions of α-alkyl acrylic acid derivatives are known, and most use rhodium catalysts. No examples of asymmetric hydroboration of the corresponding α-arylacrylic acid esters are known. In our continuing efforts to search for new applications of earth-abundant cobalt catalysts for broadly applicable organic transformations, we have identified 2-(2-diarylphosphinophenyl)oxazoline ligands and mild reaction conditions for efficient and highly regio- and enantioselective hydroboration of α-alkyl- and α-aryl- acrylates, giving β-borylated propionates. Since the C-B bonds in these compounds can be readily replaced by C-O, C-N, and C-C bonds, these intermediates could serve as valuable chiral synthons, some from feedstock carbon sources, for the synthesis of propionate-bearing motifs including polyketides and related molecules. Two-step syntheses of "Roche" ester from methyl methacrylate (79%; er 99:1), arguably the most widely used chiral fragment in polyketide synthesis, and tropic acid esters (∼80% yield; er ∼93:7), which are potential intermediates for several medicinally important classes of compounds, illustrate the power of the new methods. Mechanistic studies confirm the requirement of a cationic Co(I) species [(L)Co]+as the viable catalyst in these reactions and rule out the possibility of a [L]Co-H-initiated route, which has been well-established in related hydroborations of other classes of alkenes. A mechanism involving an oxidative migration of a boryl group to the β-carbon of an η4-coordinated acrylate-cobalt complex is proposed as a plausible route.

Asymmetric α-benzylation of cyclic ketones enabled by concurrent chemical aldol condensation and biocatalytic reduction

Chemoenzymatic cascade catalysis has emerged as a revolutionary tool for streamlining traditional retrosynthetic disconnections, creating new possibilities for the asymmetric synthesis of valuable chiral compounds. Here we construct a one-pot concurrent chemoenzymatic cascade by integrating organobismuth-catalyzed aldol condensation with ene-reductase (ER)-catalyzed enantioselective reduction, enabling the formal asymmetric α-benzylation of cyclic ketones. To achieve this, we develop a pair of enantiocomplementary ERs capable of reducing α-arylidene cyclic ketones, lactams, and lactones. Our engineered mutants exhibit significantly higher activity, up to 37-fold, and broader substrate specificity compared to the parent enzyme. The key to success is due to the well-tuned hydride attack distance/angle and, more importantly, to the synergistic proton-delivery triade of Tyr28-Tyr69-Tyr169. Molecular docking and density functional theory (DFT) studies provide important insights into the bioreduction mechanisms. Furthermore, we demonstrate the synthetic utility of the best mutants in the asymmetric synthesis of several key chiral synthons.

Multigram-scale chemoenzymatic synthesis of diverse aminopolycarboxylic acids as potential metallo-β-lactamase inhibitors.

Toxin A, a precursor to naturally occurring aspergillomarasmine A, aspergillomarasmine B, lycomarasmine and related aminopolycarboxylic acids, was synthesized as the desired (2S,2'S)-diastereomer on a multigram-scale (>99% conversion, 82% isolated yield, dr > 95 : 5) from commercially available starting materials using the enzyme ethylenediamine-N,N'-disuccinic acid lyase. A single-step protection route of this chiral synthon was developed to aid N-sulfonylation/-alkylation and reductive amination at the terminal primary amine for easy derivatization, followed by global deprotection to give the corresponding toxin A derivatives, including lycomarasmine, in moderate to good yields (23-66%) and with high stereopurity (dr > 95 : 5). Furthermore, a chemoenzymatic route was developed to introduce a click handle on toxin A (yield 72%, dr > 95 : 5) and its cyclized congener for further analogue design. Finally, a chemoenzymatic route towards the synthesis of photocaged aspergillomarasmine B (yield 8%, dr > 95 : 5) was established, prompting further steps into smart prodrug design and precision delivery. These new synthetic methodologies have the prospective of facilitating research into the finding of more selective and potent metallo-β-lactamase (MBL) inhibitors, which are urgently needed to combat MBL-based infections.

Chiral auxiliary-induced asymmetric synthesis of (R)- and (S)-Garner’s aldehydes

This article describes the synthesis of optically pure four N-Boc and N-Cbz-protected (R)- and (S)-isomers of Garner’s aldehyde. The key step involves TiCl4-catalyzed Evans' aldol reaction of the uncommon chiral synthon “glycine enolate equivalent” of N-(N-Boc/Cbz-glycinyl) oxazolidinone with gaseous formaldehyde. The chromatographically separable Evans and non-Evans adduct formation takes place through the installation of hydroxymethyl functionality on chiral glycine enolate in good yields. The orthogonality of the reaction was maintained via the “reverse addition” in the aldol reaction on Evans chiral auxiliary. This method provides a promising opportunity for the synthesis of expensive (R)-Garner’s aldehyde evading the use of unnatural d-serine. Moreover, asymmetric alkylation of Li-enolate of N-(N-Boc-glycinyl) oxazolidinone is a promising opportunity for the formation of an exclusive single isomer of (R)-Garner’s aldehyde.

Reducing the vicissitudes of heterologous prochiral substrate catalysis by alcohol dehydrogenases through machine learning algorithms

Alcohol dehydrogenases (ADHs) are popular catalysts for synthesizing chiral synthons a vital step for active pharmaceutical intermediate (API) production. They are grouped into three superfamilies namely, medium-chain (MDRs), short-chain dehydrogenase/reductases (SDRs), and iron-containing alcohol dehydrogenases. The former two are used extensively for producing various chiral synthons. Many studies screen multiple enzymes or engineer a specific enzyme for catalyzing a substrate of interest. These processes are resource-intensive and intricate. The current study attempts to decipher the ability to match different ADHs with their ideal substrates using machine learning algorithms. We explore the catalysis of 284 antibacterial ketone intermediates, against MDRs and SDRs to demonstrate a unique pattern of activity. To facilitate machine learning we curated a dataset comprising 33 features, encompassing 4 descriptors for each compound. Subsequently, an ensemble of machine learning techniques viz. Partial Least Squares (PLS) regression, k-Nearest Neighbors (kNN) regression, and Support Vector Machine (SVM) regression, was harnessed. Moreover, the assimilation of Principal Component Analysis (PCA) augmented precision and accuracy, thereby refining and demarcating diverse compound classes. As such, this classification is useful for discerning substrates amenable to diverse alcohol dehydrogenases, thereby mitigating the reliance on high-throughput screening or engineering in identifying the optimal enzyme for specific substrate.

Deconstruction of 18β-glycyrrhetinic acid into gram scale multifunctional chiral synthons

The transformation of 18β-glycyrrhetinic acid into two significant chiral synthons has been successfully showcased employing gentle reaction conditions. The effectiveness of one of these chiral synthons has been exhibited by utilizing it as a key building block for the synthesis of tetracyclic meroterpenoid natural products (+)-hongoquercins A and B.

An Easy and Straight Forward Approach Towards the Synthesis of N-Benzyl-5(S)-Substituted Pyrrolidin-2-ones from N-Benzyl-5(S)-pyroglutaminol through Mitsunobu Reaction

Background: Pyroglutamic acid is one of the cheapest chiral synthon for the synthesis of a variety of bioactive molecules ranging from synthetic to natural origin. Derived from glutamic acid by internal cyclization pyroglutamic acid can serve easily as a precursor for prolines or pyroglutaminols by the selective reduction of lactam carbonyl or carboxylic group, respectively. Pyroglutamic acid has two differential carbonyls and a lactam NH group. All these can differentially be modified to get a variety of compounds. These applications coupled with the easy availability of pyroglutamic acid have made it a choice of interest for various research groups in recent years to get a range of bioactive compounds both of natural as well as synthetic origins. In our ongoing research programme, we were interested to develop an easy route for the synthesis of 5-substituted pyrrolidin-2-ones exploiting the chemistry of pyroglutamates, whose synthetic potential is well established. Objective: To develop a simple and efficient methodology for the synthesis of 5-sustituted- pyrrolidin-2-ones as bioactive molecules/intermediate to bioactive molecules. Methods: N-Benzyl-5(S)-pyroglutaminol 1, (0.96 g, 5.0 mmol) was taken in THF (15 mL) and diethylazodicarboxylate (DEAD) (1.21 g, 1.4 eq) and triphenylphosphine (Ph3P) (1.72 g, 1.4 eq), were added to it and the reaction mixture was stirred at RT for 30 min. After 30 min a solution of the substituted pyrazole/imidazole derivative (1.2 eq) in THF (10 mL) was added and the reaction mixture was stirred again at RT for 7 hr. The progress of the reaction was monitored by thin layer chromatography (TLC). At the completion of the reaction, the solvents were evaporated under a vacuum to give a liquid which was poured into water (15 mL) and extracted twice with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine solution (15 mL), dried over sodium sulfate, concentrated and purified by column chromatography on silica gel using 20% EtOAc-hexane as eluent to give pure compounds 2 a-d, 3 and 4, respectively in satisfactory yields. Results: Herein, we wish to describe the synthesis of new 5(S)-substituted pyrrolidin-2- one derivatives through Mitsunobu reaction of N-benzyl-5(S)- pyroglutaminol with substituted pyrazole and imidazole derivatives. Conclusion: An easy and straightforward approach towards the synthesis of enantiomerically pure N-benzyl- (S)-5-substituted pyrrolidin-2-ones from N-benzyl-5(S)- pyroglutaminol through Mitsunobu reaction has been developed. These N-benzyl-(S)-5-substituted pyrrolidin-2-ones could be useful for the synthesis of bioactive natural products requiring pyrazole/imidazole moiety attached at C-5 position of native pyrrolidin-2- one moiety.

Synthesis of Antiepileptic Drug (R)-Lacosamide and Chronic Pain Reliever (S)-Lacosamide from Chiral Glycine Enolate Equivalent.

A short enantioselective and azide-free synthesis of antiepileptic drug (R)-lacosamide and pain reliever (S)-lacosamide on a large scale has been articulated from an uncommon chiral synthon "glycine enolate equivalent of 4-benzyl-N-glycinyl oxazolidinone". Evans' asymmetric alkylation using N-(N-Boc-glycinyl) oxazolidinone was standardized to ensure the stereoselective formation of (Z)-enolate for a diastereofacial selection in the C-alkylation process of chiral glycine enolate equivalent with different alkyl halides such as methyl iodide, methoxymethyl chloride, benzyl bromide, p-NO2C6H4CH2Br, allyl bromide, and p-OCH3C6H4CH2Br in the presence of lithium diisopropyl amide at -78 °C in THF. This optimized asymmetric C-alkylation method with methoxymethyl chloride on lithium-mediated (Z)-enolate of (4S/4R)-4-benzyl-N-glycinyl oxazolidinones was extended following other subsequent reactions to produce the final lacosamides with no racemization in ∼36 to 45% overall yields from commercially available 4-benzyl-2-oxazolidinone and N-Boc-glycine.