Carbasugar Synthesis via Vinylogous Ketal: Total Syntheses of (+)-MK7607, (−)-MK7607, (−)-Gabosine A, (−)-Epoxydine B, (−)-Epoxydine C, <i>epi</i>-(+)-Gabosine E and <i>epi</i>-(+)-MK7607

Carbasugars, the carbocyclic analogues of sugars, constitute an important class of natural products with more than 140 members known and have attracted much attention due to their diverse biological activities like anticancer, antibacterial, herbicidal, and various enzyme inhibitory activities. As many carbohydrates are involved in various cellular signaling pathways, there is great interest in synthesis and biological exploration of carbasugars. Herein, we have developed a methodology to install an α,β-unsaturated aldehyde functionality on different inositols and derivatives by vinylogous elimination of the O-protecting group under mildly acidic condition. We have illustrated the versatility and utility of our methodology by the total syntheses of seven carbasugars viz. (−)-MK7607, (−)-gabosine A, (−)-epoxydine B, (−)-epoxydine C, (+)-MK7607, 1-<i>epi</i>-(+)-MK7607 and 1-<i>epi</i>-(+)-gabosine E

Strength from Weakness: Conformational Divergence between Solid and Solution States of Substituted Cyclitols Facilitated by CH···O Hydrogen Bonding

We have investigated the conformational preferences of a series of cyclitol derivatives, namely mono- and diesters of 1,2:5,6-di-<i>O</i>-isopropylidene-<i>myo</i>-inositol and 1,2:5,6-di-<i>O</i>-cyclohexylidene-<i>myo</i>-inositol, in both solid and solution states. The solid-state conformations were determined by single-crystal X-ray analysis. The solution-state conformations were determined by using NMR. The experimental ³<i>J</i>_HH values were applied in the Haasnoot–Altona equation to calculate the dihedral angle (ϕ) between the respective vicinal protons. By fixing the dihedral angle between different sets of vicinal protons, the molecules were energy-minimized by MM2 method to visualize their conformation in solution. As the solvent polarities can influence the conformational preference, we have determined the conformations of these molecules in various solvents of different polarities such as benzene-<i>d</i>₆, chloroform-<i>d</i>, acetonitrile-<i>d</i>₃, acetone-<i>d</i>₆, methanol-<i>d</i>₄, and DMSO-<i>d</i>₆. All of the compounds adopted boat conformations in solution irrespective of the solvents, acyl groups, or alkylidene protecting groups. This conformation places H6 and O3 of the cyclitol ring in proximity, such that an intramolecular CH···O hydrogen bond between them stabilizes this otherwise unstable conformation. However, in the solid state, several intermolecular CH···O hydrogen bonds force these molecules to adopt the chair conformation. This study uncovers the role of weak noncovalent interactions in influencing the molecular conformations differentially in different states

Topochemical Azide–Alkyne Cycloaddition Reaction in Gels: Size-Tunable Synthesis of Triazole-Linked Polypeptides

Though topochemical reactions are attractive, the difficulty associated with crystallization such as low yield, unsuitability for large-scale synthesis, etc. warranted the exploitation of other self-assembled media for topochemical reactions. We synthesized a dipeptide gelator decorated with azide and alkyne at its termini, N₃-Ala-Val-NHCH₂-CCH, which is designed to self-assemble through intermolecular hydrogen bonds to β-sheets thereby placing the azide and alkyne motifs in proximity. As anticipated, this peptide forms gels in organic solvents and water via hydrogen-bonded β-sheet assembly as evidenced from IR spectroscopy and PXRD profiling. The microscopic fibers present in organogel and hydrogel have different morphology as was evident from scanning electron microscopy (SEM) imaging of their xerogels, XG_h (xerogel made from hydrogel) and XG_o (xerogel made from organogel). Heating of xerogels at 80 °C resulted in the topochemical azide–alkyne cycloaddition (TAAC) polymerization to 1,4-triazole-linked oligopeptides. Under identical conditions, XG_o produced larger oligopeptides, and XG_h produced smaller peptides, as evidenced from MALDI-TOF spectrometry. We have also shown that degree of TAAC polymerization can be controlled by changing gel fiber thickness, which in turn can be controlled by concentration. SEM studies suggested the morphological intactness of the fibers even after the reaction, and their PXRD profiles revealed that both XG_h and XG_o undergo fiber-to-fiber oligomerization without losing their crystallinity. In contrast to crystals, the xerogels undergo TAAC polymerization in two distinct stages as shown by DSC analyses. Interestingly, XG_h and XG_o undergo spontaneous TAAC polymerization at room temperature; the latter shows faster kinetics. This is not only the first demonstration of the use of xerogels for thermally induced topochemical polymerization but also the first report on a spontaneous topochemical reaction in xerogels

A Spontaneous Single-Crystal-to-Single-Crystal Polymorphic Transition Involving Major Packing Changes

4,6-<i>O</i>-Benzylidene-α-d-galactosyl azide crystallizes into two morphologically distinct polymorphs depending on the solvent. While the α form appeared as thick rods and crystallized in <i>P</i>2₁ space group (monoclinic) with a single molecule in the asymmetric unit, the β form appeared as thin fibers and crystallized in <i>P</i>1 space group (triclinic) with six molecules in the asymmetric unit. Both the polymorphs appeared to melt at the same temperature. Differential scanning calorimetry analysis revealed that polymorph α irreversibly undergoes endothermic transition to polymorph β much before its melting point, which accounts for their apparently same melting points. Variable temperature powder X-ray diffraction (PXRD) experiments provided additional proof for the polymorphic transition. Single-crystal XRD analyses revealed that α to β transition occurs in a single-crystal-to-single-crystal (SCSC) fashion not only under thermal activation but also spontaneously at room temperature. The SCSC nature of this transition is surprising in light of the large structural differences between these polymorphs. Polarized light microscopy experiments not only proved the SCSC nature of the transition but also suggested nucleation and growth mechanism for the transition

Organogel-Derived Covalent–Noncovalent Hybrid Polymers as Alkali Metal-Ion Scavengers for Partial Deionization of Water

We show that crown ethers (CEs) <b>1</b>–<b>5</b> congeal both polar and nonpolar solvents via their self-assembly through weak noncovalent interactions (NCIs) such as CH···O and CH···π interactions. Diisopropylidene-mannitol (<b>6</b>) is a known gelator that self-assembles through stronger OH···O H bonding. These two gelators together also congeal nonpolar solvents via their individual self-assembly. Gelator <b>6</b> self-assembles swiftly to fibers, which act as templates and attract CE to their surface through H bonding and thereby facilitate their self-assembly through weak NCI. Polymerization of styrene gels made from CE and <b>6</b>, followed by the washing off of the sacrificial gelator <b>6</b>, yields robust porous polystyrene-crown ether hybrid matrices (PCH), having pore-exposed CEs. These PCHs not only were efficient in sequestering alkali metal ions from aqueous solutions but also can be recycled. This novel use of organogels for making solid sorbents for metal-ion scavenging might be of great interest

Vinylogy in Orthoester Hydrolysis: Total Syntheses of Cyclophellitol, Valienamine, Gabosine K, Valienone, Gabosine G, 1-<i>epi</i>-Streptol, Streptol, and Uvamalol A

C7-cyclitols represent an important category of natural products possessing a broad spectrum of biological activities. As each member of these compounds is structurally unique, the usual practice is to synthesize them individually from appropriate polyhydroxylated chiral pools. We have observed an unusual vinylogy in acid mediated hydrolysis of enol ethers of <i>myo</i>-inositol 1,3,5-orthoesters giving a synthetically versatile polyhydroxylated cyclohexenal intermediate. We have exploited this unprecedented reaction for developing a general strategy for the rapid and efficient syntheses of several structurally diverse natural products of C7-cyclitol family. We have made an appropriately protected advanced intermediate 25 in five steps from the cheap and commercially available <i>myo</i>-inositol, and this common intermediate has been used to synthesize eight natural products in racemic form. We could synthesize (±)-cyclophellitol in seven steps, (±)-valienamine in five steps, (±)-gabosine I in five steps, (±)-gabosine G in six steps, (±)-gabosine K in three steps, (±)-streptol in six steps, (±)-1-<i>epi</i>-streptol in two steps, and (±)-uvamalol A in five steps from this intermediate

Organogel-Derived Covalent–Noncovalent Hybrid Polymers as Alkali Metal-Ion Scavengers for Partial Deionization of Water

We show that crown ethers (CEs) <b>1</b>–<b>5</b> congeal both polar and nonpolar solvents via their self-assembly through weak noncovalent interactions (NCIs) such as CH···O and CH···π interactions. Diisopropylidene-mannitol (<b>6</b>) is a known gelator that self-assembles through stronger OH···O H bonding. These two gelators together also congeal nonpolar solvents via their individual self-assembly. Gelator <b>6</b> self-assembles swiftly to fibers, which act as templates and attract CE to their surface through H bonding and thereby facilitate their self-assembly through weak NCI. Polymerization of styrene gels made from CE and <b>6</b>, followed by the washing off of the sacrificial gelator <b>6</b>, yields robust porous polystyrene-crown ether hybrid matrices (PCH), having pore-exposed CEs. These PCHs not only were efficient in sequestering alkali metal ions from aqueous solutions but also can be recycled. This novel use of organogels for making solid sorbents for metal-ion scavenging might be of great interest

Vinylogy in Orthoester Hydrolysis: Total Syntheses of Cyclophellitol, Valienamine, Gabosine K, Valienone, Gabosine G, 1-<i>epi</i>-Streptol, Streptol, and Uvamalol A

C7-cyclitols represent an important category of natural products possessing a broad spectrum of biological activities. As each member of these compounds is structurally unique, the usual practice is to synthesize them individually from appropriate polyhydroxylated chiral pools. We have observed an unusual vinylogy in acid mediated hydrolysis of enol ethers of <i>myo</i>-inositol 1,3,5-orthoesters giving a synthetically versatile polyhydroxylated cyclohexenal intermediate. We have exploited this unprecedented reaction for developing a general strategy for the rapid and efficient syntheses of several structurally diverse natural products of C7-cyclitol family. We have made an appropriately protected advanced intermediate 25 in five steps from the cheap and commercially available <i>myo</i>-inositol, and this common intermediate has been used to synthesize eight natural products in racemic form. We could synthesize (±)-cyclophellitol in seven steps, (±)-valienamine in five steps, (±)-gabosine I in five steps, (±)-gabosine G in six steps, (±)-gabosine K in three steps, (±)-streptol in six steps, (±)-1-<i>epi</i>-streptol in two steps, and (±)-uvamalol A in five steps from this intermediate

Crystal-to-Crystal Synthesis of Triazole-Linked Pseudo-proteins via Topochemical Azide–Alkyne Cycloaddition Reaction

Isosteric replacement of amide bond(s) of peptides with surrogate groups is an important strategy for the synthesis of peptidomimetics (pseudo-peptides). Triazole is a well-recognized bio-isostere for peptide bonds, and peptides with one or more triazole units are of great interest for different applications. We have used a catalyst-free and solvent-free method, viz., topochemical azide–alkyne cycloaddition (TAAC) reaction, to synthesize pseudo-proteins with repeating sequences. A designed β-sheet-forming l-Ala-l-Val dipeptide containing azide and alkyne at its termini (N₃-Ala-Val-NHCH₂CCH, <b>1</b>) was synthesized. Single-crystal XRD analysis of the dipeptide <b>1</b> showed parallel β-sheet arrangement along the <i>b</i>-direction and head-to-tail arrangement of such β-sheets along the <i>c</i>-direction. This head-to-tail arrangement along the <i>c</i>-direction places the complementary reacting motifs, viz., azide and alkyne, of adjacent molecules in proximity. The crystals of dipeptide <b>1</b>, upon heating at 85 °C, underwent crystal-to-crystal polymerization, giving 1,4-triazole-linked pseudo-proteins. This TAAC polymerization was investigated by various time-dependent techniques, such as NMR, IR, DSC, and PXRD. The crystal-to-crystal nature of this transformation was revealed from polarizing microscopy and PXRD experiments, and the regiospecificity of triazole formation was evidenced from various NMR techniques. The MALDI-TOF spectrum showed the presence of pseudo-proteins >7 kDa

Cascading Effect of Large Molecular Motion in Crystals: A Topotactic Polymorphic Transition Paves the Way to Topochemical Polymerization

A topochemical polymerization governed by a topotactic polymorphic transition is reported. A monomer functionalized with azide and an internal alkyne crystallized as an unreactive polymorph with two molecules in the asymmetric unit. The molecules are aligned in a head-to-head fashion, thereby avoiding the azide–alkyne proximity for the topochemical azide–alkyne cycloaddition (TAAC) reaction. However, upon heating, one of the two conformers underwent a drastic 180° rotation, leading to a single-crystal-to-single-crystal (SCSC) polymorphic transition to a reactive form, wherein the molecules are head-to-tail arranged, ensuring azide–alkyne proximity. The new polymorph underwent TAAC reaction to form a trisubstituted 1,2,3-triazole-linked polymer. These results, showing unexpected topochemical reactivity of a crystal due to the intermediacy of an SCSC polymorphic transition from an unreactive form to a reactive form, highlight that predicting topochemical reactivity by relying on the static crystal structure can be misleading