Figure 1.
The GSK HTS campaign identified GSK2200150A, which is representative of the GSK Spiros family of anti-TB leads (A). (B) The optimised Spiros analogue developed by GSK [5]. (C) Existing anti-tubercular candidates that have a mode of action that involves MmpL3.
Figure 2.
Potential for the rapid synthesis of Spiros analogues via a common 2° amine intermediate 3.
(A) An existing oxa-Pictet–Spengler reaction can be used to form the spirocycle core (blue) as the 2° amine 3 [12]. (B) Strategy to diversify from the 2° core 3 to produce Spiros analogues (C) with variation at the piperidine nitrogen (red).
Figure 3.
Synthesis of the core 70 was attempted using conditions adapted from the literature [12].
(A) N -Debenzylation of 4 was achieved under palladium-catalysed transfer hydrogenation conditions [17]. (B) Reaction of the ketone 5 with thiopheneethanol 1 in the presence of strong Brønsted acids did not produce the expected spirocycle 3.
Figure 4.
Re-evaluating the route to the 2° amine core 3 (blue).
(A) The attempted route based on the patent literature procedure [12]. The dotted lines represent the additional step (red) required to attempt cyclisation strictly under the patent conditions. (B) The revised strategy: cyclise to give 6 followed by debenzylation to give the 2° amine 3 (blue).
Figure 5.
Executing the revised strategy towards the synthesis of spirocycle core as the 2° amine 3.
(A) The acid-mediated cyclisation. (B) Attempts to synthesise the 2° amine using catalytic hydrogenolysis. (C) 1-chloroethyl chloroformate was effective at producing the secondary amine 3. (D) 2-chloroethyl chloroformate resulted in incomplete deprotection of 6.
Figure 6.
Diversification in the final step.
The conditions for reductive amination (A) and acylation (B) of 3 to produce the final Spiros analogs 10–18 the yields reported are of pure material isolated following flash chromatography on silica.
Figure 7.
The piperidine nitrogen signals of the acylated products can be visualised by HSQC experiments.
The 1H-NMR and 13C{1H}-NMR spectra respectively displayed on the x- and y-axes of the HSQC spectra are projections of the corresponding one-dimensional NMR experiments and are displayed for clarity. (A) The aliphatic region of the 1H–13C{1H} HSQC spectrum of 16; the red arrows indicate the 1H signals corresponding to the piperidine protons (attached to the red ring of the structure). The corresponding piperidine carbon signals on the y-axis (circled red) are unclear in the 13C{1H} spectrum. (B) Rotation around the amide bond generates chiral rotamers (C and D) dictated by the π-system of the benzamide, which makes the methylene protons in the oxygen-containing ring diastereotopic, (E) Variable magnetic field temperature and NMR experiments showing coalescence of methylene signals for compound 16. At lower temperature the diastereotopic oxygen-containing ring protons (E) exhibited higher order coupling, arising from the individual rotamers (Figure S39) and the 13C{1H} NMR spectrum exhibited complete resolution of the piperidine ring carbon signals (Figure S40). Raw data may be found in Dataset S1.
Table 1.
Anti-tubercular activity of the synthesised Spiros analogues.