Ka Wai Choi

Synthesis of spiroacetal-triazoles as privileged natural product-like scaffolds using “click chemistry”

The elaboration of a 6,6-spiroacetal scaffold to incorporate a triazole unit as a peptide bond surrogate at the anomeric position is described. The novel spiroacetal-triazole hybrid structures were generated via cycloaddition of a spiroacetal azide to a series of alkynes. The spiroacetal framework was constructed via Barbier reaction of bromide 10 with Weinreb amide 11, followed by acid-catalysed deprotection and cyclisation to afford the 6,6-spiroacetal ring system. The resultant ethoxy-spiroacetal 8 was converted to spiroacetal azide 5, which was then elaborated into a series of spiroacetal-triazole derivatives 7.

Synthesis of spiroacetal-nucleosides as privileged natural product-like scaffolds

The elaboration of a 6,6-spiroacetal scaffold to incorporate a nucleoside unit at the anomeric position is described. The novel spiroacetal-nucleoside hybrids were generated via nucleosidation of acetoxy-spiroacetal with a series of silylated nucleobases under Vorbrüggen conditions.

Synthesis of a 6,6‐Spiroketal Amino Acid and Its Incorporation into a Peptide Turn Sequence Using Solid‐Phase Peptide Synthesis

Spiropins for SPPS: The rigid structure of an anomerically stabilised spiroketal motif enables the appendage of substituents in a fixed conformation. To assess the ability of a spiroketal motif to induce a turn structure and participate in solid-phase peptide synthesis (SPPS), an Fmoc-spiroketal amino acid was synthesised and incorporated into a spiroketal-containing cyclic peptide.

(±)-1-{8′-(tert-Butyl­diphenyl­silyloxy­meth­yl)-1′,7′-dioxaspiro­[5.5]undecan-2′-yl}uridine

The crystal structure of the title compound, C30H38N2O5Si, has been investigated to establish the relative stereochemistry at the spiro ring junction and the two anomeric centres. Each of the O atoms in the tetrahydropyran rings adopts an axial position on the neighbouring ring. This bis-diaxial conformation is adopted, thus gaining maximum stablization from the anomeric effect. The silyl-protected hydroxymethyl and uracil substituents adopt equatorial positions on their associated tetrahydropyran rings, thereby minimizing unfavourable steric interactions. The dimeric (2′R*,6′R*,8′R*)- and (2′S*,6′S*,8′S*)-uridine units are connected to each other across crystallographic inversion centres via intermolecular N—H⋯O hydrogen bonds.

Synthesis of a Novel Nucleoside Based on a Spiroacetal Framework

The first synthesis of a nucleoside analogue 1 is reported wherein the nucleobase 5-fluorocytosine is attached to a 1,6-dioxaspiro[5.5]undecane spiroacetal ring system. The spiroacetal system acts as a substitute for the sugar unit of natural nucleosides and provides a conformationally restricted framework upon which to append nucleobases in a well defined geometry. Trimethylsilyl triflate promoted Vorbruggen-type coupling of bis(trimethylsilyl)-5-fluorocytosine 3 with spiroacetal acetate 2 provided spiroacetal nucleoside 1 in which the nucleobase occupied an equatorial position together with the ring opened (Z)-alkene 10. Spiroacetal acetate 2 serves as the spiroacetal donor and was prepared from the readily available starting materials δ-valerolactone and but-3-yn-1-ol 4.

(1R,1′R,3S,3′S)-5,5′,10,10′-Tetra­meth­oxy-1,1′,3,3′-tetra­methyl-3,3′,4,4′-tetra­hydro-1H,1′H-8,8′-bi[benzo[g]isochromene]

In the title compound, C34H38O6, the methyl groups on each pyran ring exhibit 1,3-cis stereochemistry, established during synthesis by pseudo-axial delivery of hydride during a lactol reduction step. In the crystal structure, the molecule lies on a twofold rotation axis and the torsion angle about the central diaryl bond is 41.3 (1)°. The molecules pack in a herringbone arrangement.

(±)-Cyclo-hexane-1,2-diyl bis-(4-nitro-benzoate).

The crystal structure of the title compound, C20H18N2O8, has been investigated to establish the relative stereochemistry between the ester groups. The cyclohexane ring adopts a chair conformation, in which the two ester groups occupy the adjacent equatorial positions in a trans relationship with each other. The molecules assemble in the crystal as chains along the c axis via C—H⋯π interactions between the cyclohexane ring and a pair of nitrophenyl rings of the neighbouring molecule. Also observed are π–π stacking interactions between the nitrophenyl rings of neighbouring chains, with a perpendicular distance between these rings of 3.409 Å and a slippage of 0.969 Å.

(1R,6R)-1-Methyl-8-aza-spiro-[5.6]dodecan-7-one.

The crystal structure of the title compound, C12H21NO, has been investigated to establish the absolute stereochemistry at position 1. The absolute stereochemistry at the quaternary centre at position 6 is established to be R using an asymmetric Birch reductive alkylation reaction for which the stereochemical outcome is known. The crystal structure indicates the presence of two conformers of the bicyclic (1R,6R)-spirolactam ring system that differ in the conformation adopted by the six-membered ring. In one conformer, the methyl group adopts an axial position whereas in the other conformer, the same methyl group adopts an equatorial position. In both conformers, the seven-membered ring adopts a chair conformation. The two conformers of the bicyclic spirolactam are connected to each other via intermolecular N—H⋯O hydrogen bonds forming a heterodimer. The asymmetric unit contains two such dimers.

(±)-N-(3-Hydr-oxy-1,2-diphenyl-prop-yl)-4-methyl-benzene-sulfonamide.

In the title compound, C22H23NO3S, the relative stereochemistry of the two stereogenic centres is anti with respect to the H atoms. The molecular packing of the crystal shows a double-strand arrangement, consisting of one strand of (S*,S*) enantiomers and one strand of (R*,R*) enantiomers. Both strands lie parallel to each other along the a axis. Each strand is made up of dimers in which the molecules are connected to each other via an intermolecular O—H⋯O hydrogen bond between the hydroxyl groups and an O—H⋯π interaction with the aromatic ring. These units are then connected to neighbouring dimers via N—H⋯O hydrogen bonds and C—H⋯O interactions. Intramolecular C—H⋯O interactions are also observed.

3-Allyl-2-hydr­oxy-5,6,8-trimethoxy­naphthalene-1,4-dione

In the crystal structure of the title compound, C(16)H(16)O(6), a pair of naphthoquinone rings are linked via O-H⋯O-C hydrogen bonds in a nearly orthogonal arrangement. This dimeric unit is linked to a neighbouring dimer by π-π stacking inter-actions between the naphthoquinone rings, where the distance between the mean plane of the naphtoquinone backbones is 3.468 Å, and O-H⋯O-C hydrogen bonds.