Different intra- and intermolecular hydrogen-bonding patterns in (3S,4aS,8aS)-2-[(2R,3S)-3-(2,5-X 2-benzamido)-2-(2,5-X 2-benzoyloxy)-4-phenylbutyl]-N-tert-butyldecahydroisoquinoline-3-carboxamides (X = H or Cl): compounds with moderate aspartyl protease inhibition activity

The closely related title compounds show different intra- and intermolecular hydrogen-bonding patterns.


Chemical context
Malaria remains one of the most devastating infectious diseases with over 200 million cases and more than 600 000 deaths each year -primarily children under the age of five in sub-Saharan Africa. There is an urgent need for effective drugs with new mechanisms of action, due to the high rate of mutation of the parasite, which leads to the development of resistance of current drugs.
One of the critical stages of the life cycle of the parasite during human infection is the degradation of haemoglobin, which provides nutrients for its growth and maturation (Coombs et al., 2001). Plasmepsins are a family of aspartic proteases involved in the degradation of human haemoglobin by Plasmodium falciparum (Huizing et al., 2015). As the parasite needs the resulting amino acid building blocks for its growth and development, plasmepsins are an important antimalarial drug target. Secondary alcohols (Muthas et al., 2005;Ersmark et al., 2006) and tertiary alcohols (Motwani et al., 2015) have been successfully used to develop potent inhibitors of these enzymes. ISSN 2056-9890 Cunico et al. (2008 reported the moderate in vitro antimalarial activities of the products of reactions of the 2-aminoethyl compound, 3 (see Scheme 1) with various sulfonyl chlorides and acyl chlorides. In the present article, we report the crystal structures of two compounds (see Scheme 2), C 38 H 47 N 3 O 4 , (I), and C 38 H 43 Cl 4 N 3 O 4 , (II), obtained in that study from reactions with acyl chlorides.

Structural commentary
Compound (I) crystallizes in the space group P2 1 with a single molecule in the asymmetric unit (Fig. 1). The absolute structure was not definitively established based on refinement of the Flack parameter (Parsons et al., 2013) and the configurations of the stereogenic centres (C2 R, C3 S, C7 S, C9 S, C14 S) were set to match those in (II): they are those expected based on the known starting materials. Each atom in the C1-C2-C3-C4 'backbone' of (I) bears a different substituent: C1 is attached to a piperidine+cyclohexane fused-ring system, which in turn bears a tert-butylamide group. C2 is attached to a benzoate group and C3 bears a benzamide group. Finally, C4 is attached to a simple phenyl ring, i.e. a benzyl group. Some key torsion angles are presented in Table 1. These show that with respect to the C2-C3 bond, the C1 + C4, C1 + N3 and N3 + O4 pairings are gauche, whereas the C4 + O4 atoms are mutually anti. In terms of the H atoms, H2 is anti to N3 (171 ) and H3 is anti to C1 (176 ); the gauche torsion angle between the H atoms is 54 . The N1-C1-C2-C3 torsion angle of 170.4 (3) indicates an anti conformation and the N1/C7/C8/ C9/C14/C5 and C9-C14 rings have a cis-fused junction (H9-C9-C14-H14 = À52 ). The amide torsion angles C3-N3-C5-C27 and C17-N2-C16-C7 are À178.3 (3) and À164.7 (4) , respectively, which reflect the expected nearplanar conformations for these groups. The dihedral angles between the aromatic rings C21-C26 (A), C27-C32 (B) and C33-C38 (C) are A/B = 85.7 (2), A/C = 79.2 (2) and B/C = 17.3 (2) . The conformation of (I) is supported by a bifurcated intramolecular N-HÁ Á Á(N,O) hydrogen bond (Table 2) arising from the tert-butylamide group: the acceptor atoms are the N atom of the piperidine ring and the O atom of the C O group of the benzoate group. The bifurcated bond is very asymmetric in terms of angles and the HÁ Á ÁO link is long, but given that the assemblage is close to planar (bond-angle sum for the H atom = 353 ), we regard it as being just significant.
Compound (II) crystallizes in the space group P2 1 2 1 2 1 with one molecule in the asymmetric unit (Fig. 2). Here, the absolute structure is very well established (C2 R, C3 S, C7 S, C9 S, C14 S) and is consistent with the starting materials (Cunico et al., 2008). The C1-C2-C3-C4 backbone bears the equivalent substituents to (I), with the difference that the benzyl and amide rings both bear a pair of Cl atoms at the The asymmetric unit of (I), showing 50% probability displacement ellipsoids, with most H atoms omitted for clarity. The bifurcated intramolecular hydrogen bond is shown as a double-dashed line.

Supramolecular features
In the crystal of (I), molecules are linked by classical C(4) amide N-HÁ Á ÁO hydrogen bonds into chains propagating in the [010] direction, with adjacent molecules related by the 2 1 screw axis. Both donor and acceptor are part of the benzamide group (Fig. 3). Two weak C-HÁ Á ÁO interactions are also observed.
In the extended structure of (II), C(11) [010] N-HÁ Á ÁO chains arise, with the donor being the tert-butylamide NH group and the acceptor being the O atom of the benzamide ring (Fig. 4). Adjacent molecules are again related by a 2 1 screw axis.
In short, for (I), the tert-butylamide NH moiety forms an intramolecular hydrogen bond and the benzamide NH group forms an intermolecular link, whereas for (II), the situation is reversed: the benzamide NH group forms the intramolecular The asymmetric unit of (II), showing 50% probability displacement ellipsoids, with most H atoms omitted for clarity. The intramolecular hydrogen bond is shown as a double-dashed line. Table 3 Selected torsion angles ( ) for (II).  bond and the tert-butyl NH group forms the intermolecular link.

Database survey
A survey of of the Cambridge Structural Database (Groom et al., 2016: updated to April 2017 for the grouping of atoms about the C1-C2-C3-C4 fragment in (I) and (II) yielded 24 matches. The most similar are the isostructural halide salts YURSUB and YURTAI of the anti-HIV drug saquinavir mesylate (Fandaruff et al., 2015), which also act as protease inhibitors. The other hits have little similarity to the title compounds.

Synthesis and crystallisation
As summarized in Scheme 1, compounds (I) and (II) were prepared as described previously (Cunico et al., 2008)

Figure 4
A fragment of a [010] hydrogen-bonded chain in (II), showing 20% probability displacement ellipsoids; the pendant rings and C-bound H atoms have been omitted for clarity. [Symmetry code as in Table 4; additionally (ii) Àx + 1, y À 1 2 , Àz + 1 2 .] constraint U iso (H) = 1.2U eq (C) or 1.5U eq (methyl C) was applied in all cases. The methyl groups were allowed to rotate, but not to tip, to best fit the electron density.

Computing details
For both compounds, data collection: CrysAlis PRO (Rigaku, 2014); cell refinement: CrysAlis PRO (Rigaku, 2014); data reduction: CrysAlis PRO (Rigaku, 2014); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: ORTEP-3 (Farrugia, 2012); software used to prepare material for publication: publCIF (Westrip, 2010). Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )