Ring Strain Research Articles

Metal‐Free Ring‐Opening of Epoxides

AbstractEpoxide ring is considered as an efficient structural toolbox to access 1,2‐difunctionalised compounds. Epoxide precursors are highly susceptible towards nucleophiles owing to its inherent ring strain. Metal free methodologies for epoxides ring opening with various nucleophiles provide an easy, economic and sustainable access to synthetically and biologically important 1,2‐difunctionalized compounds without harming the environment. This article highlights step by step development of various strategies for the ring opening of epoxides without the use of metal from last two decades. Use of water, ionic liquids, cyclodextrins and organocatalyts for the ring opening reactions of epoxide have been discussed in detail.

Strain‐Driven Formal [1,3]‐Aryl Shift within Molecular Bows

AbstractDelving into the influence of strain on organic reactions in small molecules at the molecular level can unveil valuable insight into developing innovative synthetic strategies and structuring molecules with superior properties. Herein, we present a molecular‐strain engineering approach to facilitate the consecutive [1,2]‐aryl shift (formal [1,3]‐aryl shift) in molecular bows (MBs) that integrate 1,4‐dimethoxy‐2,5‐cyclohexadiene moieties. By introducing ring strain into MBs through tethering the bow limb, we can harness the intrinsic mechanical forces to drive multistep aryl shifts from the para‐ to the meta‐ to the ortho‐position. Through the use of precise intramolecular strain, the seemingly impractical [1,3]‐aryl shift was realized, resulting in the formation of ortho‐disubstituted products. The solvent and temperature play a crucial role in the occurrence of the [1,3]‐aryl shift. The free energy calculations with inclusion of solvation support a feasible mechanism, which entails multistep carbocation rearrangements, for the formal [1,3]‐aryl shift. By exploring the application of molecular strain in synthetic chemistry, this research offers a promising direction for developing new tools and strategies towards precision organic synthesis.

Strain-Driven Formal [1,3]-Aryl Shift within Molecular Bows.

Delving into the influence of strain on organic reactions in small molecules at the molecular level can unveil valuable insight into developing innovative synthetic strategies and structuring molecules with superior properties. Herein, we present a molecular-strain engineering approach to facilitate the consecutive [1,2]-aryl shift (formal [1,3]-aryl shift) in molecular bows (MBs) that integrate 1,4-dimethoxy-2,5-cyclohexadiene moieties. By introducing ring strain into MB through tethering the bow-limb, we can harness the intrinsic mechanical forces to drive multistep aryl shifts from para- to meta- to ortho-position.Through exercise of precise intramolecular strain, the seemingly impractical [1,3]-aryl shift was realized, resulting in the formation of ortho-disubstituted products. The solvent and temperature play a crucial role in the occurrence of the [1,3]-aryl shift.The free energy calculations with inclusion of solvation support a feasible mechanism, which entails multistep carbocation rearrangements, for the formal [1,3]-aryl shift. By exploring the application of molecular strain in synthetic chemistry, this research offers a promising direction for developing new tools and strategies towards precision organic synthesis.

Electrochemical Synthesis and Reactivity of Three-Membered Strained Carbo- and Heterocycles.

Three-membered carbocyclic and heterocyclic ring structures are versatile synthetic building blocks in organic synthesis with biological importance. Moreover, the inherent strain of these three-membered rings leads to their ring-opening functionalization through C->C, C->N, and C-O bond cleavage. Traditional synthesis and ring-opening methods for these molecules require the use of acid catalysts or transition metals. Recently, electro-organic synthesis has emerged as a powerful tool for initiating new chemical transformations. In this review, the synthetic and mechanistic aspects of electro-mediated synthesis and ring-opening functionalization of three-membered carbo- and heterocycles are highlighted.

Experimental and numerical assessment of two reconstructive techniques for the fragility fractures of the pelvis type Ia.

Anterior pelvic ring fractures are common in geriatric patients. The Supraacetabular External Fixator (SEF) is a relatively simple and effective surgical procedure. On the other hand, there is the option of a Subcutaneous Iliopubic Plate (SIP) osteosynthesis. Only limited comparative biomechanical data of these two devices are available. Therefore, this biomechanical study's objective was to compare the stabilizing effect of the SEF versus the SIP in a model of Fragility Fractures of the Pelvis (FFP) type Ia. A test stand for pelvic biomechanics testing that emulates the gait loading cycle with physiological relevance was used. The osteotomy on the right pelvic ring was stabilized either with the SEF or the SIP. Strain gauges were used to measure strain in the pelvic ring. The osteotomy's spatial interfragmentary displacement (SID) was monitored using a 3D digital image correlation system. The SEF stabilization reduced the SID by approximately 10%, whereas the locking SIP could reduce displacement by about 62%. Additionally, the SIP reduced the stress/strain levels by 67% in the posterior pelvic ring. We could demonstrate that the SIP is superior to SEF in treating FFP type Ia as it significantly reduced the osteotomy's SID and the strain in the posterior pelvic ring.

Strain-Inducing Positional Alkene Isomerization.

Small, strained ring systems are important pharmacophores in medicinal chemistry and versatile intermediates in organic synthesis. However, the kinetic and thermodynamic instability of many strained organic molecules renders them challenging to prepare. Here, we report a strain-inducing positional alkene isomerization reaction that provides mild and selective access to cyclobutene building blocks from readily obtained cyclobutylidene precursors. This endergonic isomerization relies on the sequential and synergistic action of a decatungstate polyanion photocatalyst and cobaloxime co-catalyst to store potential energy in the form of ring strain. The versatility of the cyclobutene products is demonstrated through diverse subsequent strain-releasing transformations. Mechanistic studies reveal a steric basis for strain-selective product formation.

Theoretical Investigations of the Crystal Structures and Molecular Energetics of High Quality Silicon Carbide (β-SiC) Precursor Compound 1,4-bis(trimethylsilyl)benzene

Over the last decades, the rapidly growing theoretical methods have revolutionized whole scientific paradigm, developed state-of-art analyses, and created substantial computational platforms through the huge support of outstanding mathematical algorithms. The self-consistent-charge density-functional based tight-binding (SCC-DFTB) scheme is one of them that offers versatile and efficient quantum mechanical calculations with some unique features compatible especially to the crystalline solid even at low computational resources. Its effective parametrizations and computational implementations under the Gaussian standardized interface as an "External program" via the users' script (Gaussian- External methodology; GEM) has added an additional value because of which various in-built high-level Gaussian computations are directly accessible. Herewith, the Gaussian offered geometry optimization algorithms and convergence criteria plus the ModRedundant type relaxed potential energy surface (PES) scanning techniques are assessed through the GEM, and characterized the crystal structures with concerned molecular energetics and PES of the experimentally synthesized 1,4-bis (trimethylsilyl) benzene (1,4-BTMSB) compound; a potential precursor for the high quality Silicon Carbide (β-SiC) coating particles, and an ideal "Internal Standard" for the quantitative spectroscopic analyses. The general results reveal that the 1,4- BTMSB molecules in its unit-cell and crystal lattice experience significant non-bonding interactions that induces them to attain the definite molecular geometry with recognizable ring, angle, torsional, and steric strains. The quantitative analyses of its PES depict that the phenylene ring has to overcome multiple yet unidentical energy barriers with the tallest Ea1= 5.3 kcal/mol in order to undergo internal 2π angular rotation around the 1,4-(C-Si) axes. And, exhibiting such type internal rotation of its phenylene ring is energetically highly probable as this compound is widely employed in coating high temperature reactors, and in quantizing analyte in high energy run spectroscopic facilities. The same quantification is referred here in order to underscore the significance of adopting perfectly closed topological molecular architectures while designing/synthesizing amphidynamic type crystalline free molecular gyrotops and their prototypes.

Magnetic Properties of Amorphous Ta/CoFeB/MgO/Ta Thin Films on Deformable Substrates with Magnetic Field Angle and Tensile Strain.

Recently, the application of cobalt iron boron (CoFeB) thin films in magnetic sensors has been widely studied owing to their high magnetic moment, anisotropy, and stability. However, most of these studies were conducted on rigid silicon substrates. For diverse applications of magnetic and angle sensors, it is important to explore the properties of ferromagnetic thin films grown on nonrigid deformable substrates. In this study, representative deformable substrates (polyimide (PI), polyethylene naphthalate (PEN), and polydimethylsiloxane (PDMS)), which can be bent or stretched, were used to assess the in-plane magnetic field angle-dependent properties of amorphous Ta/CoFeB/MgO/Ta thin films grown on deformable substrates. The effects of substrate roughness, tensile stress, deformable substrate characteristics, and sputtering on magnetic properties, such as the coercive field (Hc), remanence over saturation magnetization (Mr/Ms), and biaxial characteristics, were investigated. This study presents an unconventional foundation for exploring deformable magnetic sensors capable of detecting magnetic field angles.

Calix[3]Pyrrole and Related Macrocycles: Synthesis and Properties

Calix[4]pyrrole is a porphyrinogen-like macrocycle in which four pyrrole units are linked by four sp3-hybridized carbon atoms at the α-positions. While such tetrapyrrolic macrocycles are readily synthesized by acid-catalyzed condensation reactions of pyrrole monomer and carbonyl compound, analogous macrocycles composed of three pyrrole units are always not observed. Calix[3]pyrrole is a ring-contracted analogue of calix[4]pyrrole, and has been missing in porphyrin-related chemistry. In this presentation, the first synthesis of calix[3]pyrrole and its furan-embedded analogues is reported, and their unique reactivity derived from their macrocyclic ring strain will be discussed.Synthesis of calix[3]pyrrole started with a linear trimer of 3,3-dimethylpentane-2,5-dione. Intramolecular cyclization of the linear hexaketone was accomplished in 5 steps to give a cyclic hexaketone precursor. Paal–Knorr type pyrrole formation reaction of cyclic hexaketone gave calix[3]pyrrole in 41% yield (Scheme 1). Using similar strategies, analogous calix[3]-type macrocycles, namely, calix[1]furan[2]pyrrole, calix[2]furan[1]pyrrole, and calix[3]furan, were successfully synthesized. Single crystal X-ray diffraction analysis of calix[3]pyrrole revealed its strained structure, and the theoretical calculations showed the strain energy of calix[3]pyrrole is 22.1 kcal/mol per unit higher than that of calix[4]pyrrole. Such strain energy tends to decrease as the number of pyrrole unit decreased.Calix[3]pyrrole exhibited unique reactivity derived from macrocyclic ring strain under acidic (Rothemund–Lindsey) conditions that are frequently used for porphyrin synthesis. When calix[3]pyrrole was dissolved in 10 mM solution of trifluoroacetic acid in dichloromethane, calix[6]pyrrole was quantitatively formed within 30 seconds (Scheme 1). Similar strain-induced ring expansion was observed for calix[1]furan[2]pyrrole, but full conversion took approximately 5 minutes. On the other hand, calix[2]furan[1]pyrrole and calix[3]furan did not show ring expansion. Detailed mechanistic analysis revealed that protonation at a pyrrole unit in calix[3]pyrrole triggers irreversible ring-cleavage to give a linear tripyrrane moiety which undergoes cyclodimerization under acidic conditions.The strain-induced ring expansion reaction of calix[3]pyrrole solved a long-standing question in porphyrin-related chemistry. Tripyrrolic macrocycles such as calix[3]pyrrole are, even formed, not isolable from pyrrole condensation reaction using acid, because the strain-induced conversion to calix[6]pyrrole is too fast. Besides, this reaction provided a novel approach to ring-expanded calix-type macrocycles. Figure 1

Intramolecular Hydrogen Bonding Enables a Zwitterionic Mechanism for Macrocyclic Peptide Formation: Computational Mechanistic Studies of CyClick Chemistry

AbstractMacrocyclic peptides have become increasingly important in the pharmaceutical industry. We present a detailed computational investigation of the reaction mechanism of the recently developed “CyClick” chemistry to selectively form imidazolidinone cyclic peptides from linear peptide aldehydes, without using catalysts or directing groups (Angew. Chem. Int. Ed. 2019, 58, 19073–19080). We conducted computational mechanistic to investigate the effects of intramolecular hydrogen bonds (IMHBs) in promoting a kinetically facile zwitterionic mechanism in “CyClick” of pentapeptide aldehyde AFGPA. Our DFT calculations highlighted the importance of IMHB in pre‐organization of the resting state, stabilization of the zwitterion intermediate, and the control of the product stereoselectivity. Furthermore, we have also identified that the low ring strain energy promotes the “CyClick” of hexapeptide aldehyde AAGPFA to form a thermodynamically more stable 15+5 imidazolidinone cyclic peptide product. In contrast, large ring strain energy suppresses “CyClick” reactivity of tetra peptide aldehyde AFPA from forming the 9+5 imidazolidinone cyclic peptide product.

Intramolecular Hydrogen Bonding Enables a Zwitterionic Mechanism for Macrocyclic Peptide Formation: Computational Mechanistic Studies of CyClick Chemistry.

Macrocyclic peptides have become increasingly important in the pharmaceutical industry. We present a detailed computational investigation of the reaction mechanism of the recently developed "CyClick" chemistry to selectively form imidazolidinone cyclic peptides from linear peptide aldehydes, without using catalysts or directing groups (Angew. Chem. Int. Ed. 2019, 58, 19073-19080). We conducted computational mechanistic to investigate the effects of intramolecular hydrogen bonds (IMHBs) in promoting a kinetically facile zwitterionic mechanism in "CyClick" of pentapeptide aldehyde AFGPA. Our DFT calculations highlighted the importance of IMHB in pre-organization of the resting state, stabilization of the zwitterion intermediate, and the control of the product stereoselectivity. Furthermore, we have also identified that the low ring strain energy promotes the "CyClick" of hexapeptide aldehyde AAGPFA to form a thermodynamically more stable 15+5 imidazolidinone cyclic peptide product. In contrast, large ring strain energy suppresses "CyClick" reactivity of tetra peptide aldehyde AFPA from forming the 9+5 imidazolidinone cyclic peptide product.

Azetidines with All-Carbon Quaternary Centers: Merging Relay Catalysis with Strain Release Functionalization.

Given the importance and beneficial characteristics of decorated azetidines in medicinal chemistry, efficient strategies for their synthesis are highly sought after. Herein, we report a facile synthesis of the elusive all-carbon quaternary-center-bearing azetidines. By adopting a well-orchestrated polar-radical relay strategy, ring strain release of bench-stable benzoylated 1-azabicyclo[1.1.0]butane (ABB) can be harnessed for nickel-catalyzed Suzuki Csp2-Csp3 cross-coupling with commercially available boronic acids in broad scope (>50 examples), excellent functional group tolerance, and gram-scale utility. Preliminary mechanistic studies provided insights into the underlying mechanism, wherein the ring opening of ABB with a catalytic quantity of bromide accounts for the conversion of ABB into a redox-active azetidine, which subsequently engages in the cross-coupling reaction through a radical pathway. The synergistic bromide and nickel catalysis could intriguingly be derived from a single nickel source (NiBr2). Application of the method to modify natural products, biologically relevant molecules, and pharmaceuticals has been successfully achieved as well as the synthesis of melanocortin-1 receptor (MC-1R) agonist and vesicular acetylcholine transporter (VAChT) inhibitor analogues through bioisosteric replacements of piperidine with azetidine moieties, highlighting the potential of the method in drug optimization studies. Aside from the synthesis of azetidines, we demonstrate the ancillary utility of our nickel catalytic system toward the restricted Suzuki cross-coupling of tertiary alkyl bromides with aryl boronic acids to construct all-carbon quaternary centers.

Photochemical Isomerization of Cyclohept-1-ene-1-carbaldehyde: Strain-Release Cycloadditions and Ene Reactions.

Cyclohept-1-ene-1-carbaldehyde undergoes photoinduced E → Z isomerization at λ = 350 nm. The ring strain facilitates Diels-Alder cycloaddiions with 1,3-dienes, [3 + 2] cycloadditions with 1,3-dipoles, and ene reactions with olefins. Products are trans-fused at the cycloheptane core and were obtained in yields of up to 82%. Single crystal X-ray analyses corroborated the constitution and relative configuration of key products. With BF3 as a Lewis acid and 2,3-dimethylbuta-1,3-diene, cyclohept-1-ene-1-carbaldehyde reacted in the dark and rearranged stereoselectively to a tricyclic ketone (87%).

Sustainable biobased composites from norbornylized linseed oil and biomass sorghum fillers

Thermosets and composites sourced from environmentally benign natural sources are in huge demand. In that context, norbornylized linseed oil was used as the key sustainable polymer precursor for thermosets and glass fiber reinforced hybrid biocomposites via three different curing techniques. At first, norbornylized linseed oil was copolymerized by dicyclopentadiene whereas its epoxides were cured via latent cationic initiator, and copolymerization with disulfide containing acid moieties. Further, biomass sorghum fillers were incorporated into the epoxides to fabricate stronger, cheaper, light weight and more sustainable products. The activation energies and crosslink efficiency of the thermosets were calculated first. To evaluate the commercial significance of the products fabricated, synthetic bisphenol-A based epoxides and commercial standards of epoxidized linseed oil-based thermosets and composites were analyzed side by side. Finally, natural flax fiber reinforced composites were also fabricated to make green composites. The thermo-mechanical properties of the composites were investigated using universal testing machine and thermogravimetric analysis. Steric hindrance and ring strain energies seem to have tangible role in the curing process whereas the presence of ring structures increased the crosslink density and mechanical strength. Fine tunability of composite properties by the selection of a specific curing technique was demonstrated by virtue of different curing mechanisms. While outperforming commercial linseed oil epoxides, the norbornylized linseed epoxides-natural fiber composites exhibited comparable performance properties to synthetic bisphenol-A epoxy-glass fiber composites. Therefore, such biocomposites can be viable replacements of harmful bisphenol-A epoxides in the composite industry, especially in the non-structural automotive composite parts.

SN 2 versus E2 Competition of Cyclic Ethers.

We have quantum chemically studied the influence of ring strain on the competition between the two mechanistically different SN 2 and E2 pathways using a series of archetypal ethers as substrate in combination with a diverse set of Lewis bases (F- , Cl- , Br- , HO- , H3 CO- , HS- , H3 CS- ), using relativistic density functional theory at ZORA-OLYP/QZ4P. The ring strain in the substrate is systematically increased on going from a model acyclic ether to a 6- to 5- to 4- to 3-membered ether ring. We have found that the activation energy of the SN 2 pathway sharply decreases when the ring strain of the system is increased, thus on going from large to small cyclic ethers, the SN 2 reactivity increases. In contrast, the activation energy of the E2 pathway generally rises along this same series, that is, from large to small cyclic ethers. The opposing reactivity trends induce a mechanistic switch in the preferred reaction pathway for strong Lewis bases from E2, for large cyclic substrates, to SN 2, for small cyclic substrates. Weak Lewis bases are unable to overcome the higher intrinsic distortivity of the E2 pathway and, therefore, always favor the less distortive SN 2 reaction.

Rh-Catalyzed [4 + 1] Reaction of Cyclopropyl-Capped Dienes (but not Common Dienes) and Carbon Monoxide: Reaction Development and Mechanistic Study.

Transition-metal-catalyzed [4 + 1] reaction of dienes and carbon monoxide (CO) is the most straightforward and easily envisioned cyclization for the synthesis of five-membered carbocycles, which are ubiquitously found in natural products and functional molecules. Unfortunately, no test of this reaction was reported, and consequently, chemists do not know whether such kind of reaction works or not. Herein, we report that the [4 + 1] reaction of common dienes and CO cannot work, at least under the catalysis of [Rh(cod)Cl]2. However, using cyclopropyl-capped dienes (also named allylidenecyclopropanes) as substrates, the corresponding [4 + 1] reaction with CO proceeds smoothly in the presence of [Rh(cod)Cl]2. This [4 + 1] reaction, with a broad scope, provides efficient access to five-membered carbocyclic compounds of spiro[2.4]hept-6-en-4-ones. The [4 + 1] cycloadducts can be further transformed into other molecules by using the unique chemistry of cyclopropyl groups present in these molecules. The mechanism of this [4 + 1] reaction has been investigated by quantum chemical calculations, uncovering that cyclopropyl-capped dienes are strained dienes and the oxidative cyclization step in the [4 + 1] catalytic cycle can release this (angular) strain both kinetically and thermodynamically. The strain release in this step then propagates to all followed CO coordination/CO insertion/reductive elimination steps in the [4 + 1] catalytic cycle, helping the realization of this cycloaddition reaction. In contrast, common dienes (including cyclobutyl-capped dienes) do not have such advantages and their [4 + 1] reaction suffers from energy penalty in all steps involved in the [4 + 1] catalytic cycle. The reactivity of ene-allenes for the [4 + 1] reaction with CO is also discussed.

Synthesis and characterization of high-density biosynthetic fuels from myrtenal

Apopinene was synthesized from myrtenal by catalytic decarbonylation followed by either hydrogenation to generate dihydroapopinene or Simmons-Smith cyclopropanation to generate exo-(1R,2R)-7,7-dimethyltricyclo[4.1.1.02,4]octane (cyclopropanated apopinene, CPA). Key fuel properties of apopinene and the two derivative fuels were evaluated including density, heat of combustion, and low temperature viscosity. CPA exhibited a density of 0.918 g mL−1 and a volumetric net heat of combustion (NHOC) 20 % higher than the lower limit for conventional jet fuel. This exceptional NHOC is a result of the high density of the tricyclic compound and the ring strain of the bridging cyclobutane and fused cyclopropane groups. Dihydroapopinene exhibited a high freezing point that will limit its applications as a jet fuel blendstock. In contrast, no freezing point down to −80 °C was observed for CPA via differential scanning calorimetry (DSC). In addition, CPA exhibited a moderate kinematic viscosity of 10.11 mm2 s−1 at −20 °C and 22.76 mm2 s−1 at −40 °C. This work demonstrates that fuels with both high energy densities and excellent low temperature properties can be generated from bio-based substrates through cyclopropanation reactions.

The effect of functional orthotic rearfoot posting on in-vivo tibial strain

Medial tibial stress fractures occur secondary to failure in shear. It has been proposed that the use of functional foot orthotics (FFOs) may decrease their incidence by positioning the subtalar joint in the neutral position at heel strike. The purpose of this study was to evaluate the scientific basis of this concept by in-vivo measurement of tibial principal strain, the principal strain angle and shear strains during treadmill walking from rosette strain gauges bonded to the tibia of a male subject at two sites prone to stress fracture. Recordings were made while wearing Rockport walking shoes without orthotics, with non-posted graphite orthotics, with neutral rearfoot posted polypropylene orthotics, with 4° varus rearfoot posted polypropylene orthotics, and with neutral rearfoot posted kinetic wedge polypropylene orthotics designed to treat hallux limitus. None of the various modifications of FFOs tested in this study had a statistically significant effect on the compression strains during treadmill walking compared to the walking shoe alone, indicating that they were not affective in attenuating the ground reaction force. Their use was associated with a 22–51% increase in principal (p < .001) and a 9–35% increase in tibial shear strains (p = .003). The compression and shear strains and the angle of the principal strains (p < .001) were higher at the distal than at the proximal recording site, (p < .001 for all). The findings do not support the use of FFOs in any of the posting configurations tested as a means for lowering tibial shear strains or the concept of the biomechanical importance of the neutral position of the subtalar joint at heel strike.

Neural network based rate- and temperature-dependent Hosford–Coulomb fracture initiation model

The accurate description of the strain rate and temperature dependent response of metals is a perpetual quest in crashworthiness and forming applications. In the present study, experiments are carried out to probe the onset of ductile fracture for an aluminum alloy AA7075-T6 for 136 combinations of stress state, strain rate and temperature. The experimental campaign covers strain rates ranging from 0.001/s to 100/s, and temperatures ranging from 20 °C to 360 °C. We combine a YLD2000 yield surface with a neural network based hardening law to describe the large deformation plasticity response of the material. The NN-based hardening law is trained on experimental data, achieving 3.9% accuracy on force predictions including the post-necking regime. The loading paths to fracture are extracted for each simulation, showcasing non-proportionally evolving stress triaxiality, Lode angle parameter, strain rate and temperature. A neural network parameterized Hosford–Coulomb fracture locus is proposed, which is trainable using these evolving loading histories. The accuracy of the proposed fracture model is validated against the experimental onset of fracture, predicting the fracture onset at an error of 8%.

A Stereoselective Synthesis of 4′‐α‐Fluoro‐methyl Carbocyclic Nucleoside Analogs

AbstractThe 4′ position modifications in carbocyclic nucleosides have not been investigated much as potential antiviral agents. Due to the higher ring strain and torsion of the cyclopentyl carbocyclic ring, it is not easy to carry out the modification at the 4′ position. Therefore, there is a need for a procedure that may tackle the synthesis of 4′ position substituted carbocyclic pentyl ring. In this communication, a stereoselective synthesis of 4′‐α‐fluoro‐methyl carbocyclic nucleosides has been reported. A stereoselective synthesis of the 4‐α‐fluoro‐methyl carbocyclic sugar moiety (16) was carried out via carbocyclic ketone 1. The oxidation of the 5‐methyl hydroxy of 9 followed by the aldol condensation gave a diol 11, which via selective protection followed by selective fluorination, yielded a MOM‐protected 4‐α‐fluoro‐methyl carbocyclic ring (16). Compound 16 served as a key intermediate for the synthesis of purines (21&amp;24) and pyrimidine (28&amp;31) nucleosides. The described synthesis may be utilized to construct the various 4′ position modified carbocyclic nucleos(t)ides for an elaborated structure‐activity relationship (SAR) as an antiviral and anticancer agent.