(3R,4R,5R)-5-(Acetamidomethyl)-N-benzyl-3,4-dihydroxytetrahydrofuran-3-carboxamide

X-ray crystallographic analysis with Cu Kα radiation established the relative configurations of the stereogenic centers in the title compound, C15H20N2O5, and clarified mechanistic ambiguities in the synthesis. The conformation of the five-membered ring approximates twisted, about a C—O bond. The absolute configuration of this carbon-branched dipeptide isostere was known based on the use of d-ribose as the starting material. Refinement of the Flack parameter gave an ambiguous result but the refined Hooft parameter is in agreement with the assumed (d-ribose) absolute structure. The crystal structure consists of N—H⋯O and O—H⋯O hydrogen-bonded bi-layers, with the terminal methyl and phenyl groups forming a hydrophobic inter-layer interface. Some weak C—H⋯O interactions are also present.

Data collection: Gemini (Oxford Diffraction, 2006); cell refinement: CrysAlis RED (Oxford Diffraction, 2002); data reduction: CrysAlis RED; program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: CRYSTALS (Betteridge et al., 2003); molecular graphics: CAMERON (Watkin et al., 1996); software used to prepare material for publication: CRYS-TALS. Comment δ-Tetrahydrofuran sugar amino acids (THF SAAs) (Risseeuw et al., 2007;Smith and Fleet, 1999) have been extensively used as dipeptide isosteres (Long et al., 1998;Brittain et al., 2000) and incorporated into peptidomimetics Hungerford et al., 2000;Raunkjr et al., 2004). The secondary structural preferences induced by THF SAAs upon their incorporation into peptidomimetics have been investigated in a wide variety of systems Tuin et al., 2009). All these studies have been reported on linear carbon chains, however a number of approaches to branched carbohydrates have been developed Hotchkiss et al., 2004;Booth et al., 2008). This will allow the synthesis of THF SAAs with a branched carbon chain and allow a new family of foldamers to be created.
Compound (4) is a dipeptide isostere bearing a branching carbon substituent at position C-3 of the THF scaffold. The branched peptidomimetic (4) was synthesized in a number of steps from the suitably protected D-ribose derivative (1). A crossed aldol reaction of (1) with formaldehyde (Ho, 1985) gave the resulting lactol which was then further modified to give the carbon-branched lactone trifluoromethanesulfonate (2). Reaction of (2) in acidic methanol (Simone et al., 2008) afforded the branched δ-THF SAA (3). The dipeptide isostere (4) was synthesized from SAA scaffold (3) in four synthetic steps. The crystal structure of an isomeric branched peptidomimetic has been published previously (Punzo et al., 2005).
The crystal structure of (4) removes mechanistic ambiguities arising from the Ho crossed aldol condensation and successive modifications of the THF scaffold. Furthermore the crystal structure may provide information about the conformational preference of the scaffold (4) and its corresponding ability to induce any secondary structural features when incorporated into peptidomimetics. The use of D-ribose as the starting material enabled the determination of the absolute configuration of this carbon-branched dipeptide isostere (4).

Experimental
Compound (4) was dissolved in methanol, ethyl acetate and cyclohexane and then crystallized as the solvent (methanol) evaporated slowly to give crystals of (I) as very thin fragile colourless plates, which readily delaminated on handling. M.p. .
The H atoms were all located in a difference map, but those attached to carbon atoms were repositioned geometrically.
The H atoms were initially refined with soft restraints on the bond lengths and angles to regularize their geometry (