MATRIMONIO CELESTIAL
LEYES QUE GOBIERNAN EL MATRIMONIO ETERNO
Subjecting δ-amino-δ-ketoester 144 to the standard spirocyclisation conditions (Scheme 39) of 4 M HCl followed by treatment with a ketone and NaHCO3 gave rise to C-6 unsubstituted 2,2-dimethyl piperidine 145 and 2-spiropiperidine 146 (Figure 14).
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2.5 Determination of the Stereochemistry
It had initially been assumed that the stereochemistry of the major diastereomer was replicant of the results reported by Clarke for 2,6-di-substituted piperidines, positioning the C-3 ester and the C-6 substituent in an anti relationship.95 Upon analysis of the 1H NMR, the correct relative stereochemistry of the major diastereomer was confirmed to place the C-3 ester and the C-6 substituent in a syn relationship. The 1H NMR spectrum of spirocycle 138a is shown in Figure 15, with expansions of two key regions of the spectrum shown in Figure 16.
Figure 15. 1H NMR spectrum of spirocycle 138a.
In the expansion of 3.40-2.90 ppm, two protons H-3 and H-6 (Figure 16, A and B) are observed, and in the expansion of 2.65-2.15 ppm, two protons H-5ax and H-5eq (Figure 16, C and D) are observed.
The doublet at δ 3.26 ppm for H-3 has a 4J coupling of 1.0 Hz indicating a ‘W-coupling’ (Figure 16, A). The ddd at δ 2.30 ppm also exhibits a 4J coupling of 1.0 Hz, indicating an equatorial
57 proton at C-5 and thus identifying H-5eq (Figure 16, D). Also in the ddd at δ 2.30 ppm, a 2J geminal coupling to H-5ax of 13.5 Hz is observed, as well as a 3J coupling of 3.7 Hz indicating an axial-equatorial coupling with H-6. The H-5ax was confirmed by the 2J geminal coupling of 13.5 Hz with H-5eq, and the axial-axial 3J coupling of 10.5 Hz with H-6 (Figure 16, C). The dqd at δ 3.06 ppm has a 3J coupling of 3.7 Hz confirming the axial-equatorial coupling with H-5
eq, and a 3J coupling of 10.5 Hz confirming the axial-axial coupling with H-5
ax (Figure 16, B). With these couplings, it was deduced that the major diastereomer had a syn relationship between C-3 and C-6.
58 The relative stereochemistry of the major diastereomer from spirocyclisation was later confirmed with a crystal structure of spirocycle 138b (Figure 17). Interestingly, the C-3/C-6
syn relationship places the ester in a seemingly unfavourable axial configuration. Presumably
this is to avoid a destabilising steric interaction with the hydrogens on the adjacent spirocyclic ring. The wide range of diastereomeric ratios obtained from the cyclisation procedure was also believed to be a consequence of the 2-spiropiperidines undergoing a retro-Mannich reaction. It was then believed that during the room temperature reaction, the system was slowly equilibrating, consequently giving a mixture of diastereomers. The electronics of the C-6 substituent also appeared to be a key factor, with the methyl substitutent giving much greater diastereomeric ratios than the aromatic C-6 subsitutents.
Figure 17. Crystal structure of the major diastereomer of spirocycle 138b.
2.6 PMI Analysis
A library of novel compounds consisting of 18 2-spiropiperidines and four 2,2-dimethyl piperidines had been constructed via a novel stepwise procedure. It was important to be able to observe the relative three-dimensionality of the 2-spiropiperidines, as an original aim of the project was to synthesise three-dimensional compounds. The 22 compounds were plotted onto a PMI plot using the LLAMA software,14 with the 75% line from the ZINC database plot still shown for reference (Figure 18). It can be seen that 20 out of 22 2-spiropiperidines
59 lay on or to the right of the ZINC 75% line, with many examples pushing towards the area of relatively unpopulated three-dimensional chemical space.
Unsurprisingly the 2-spiropiperidines bearing the aliphatic methyl group at C-6 were amongst the most three-dimensional. 2,2-Dimethyl piperidine 134a (Figure 18, A) was the best performing compound, reaching the spherical region of the PMI plot. The other stand out compound was 2-spiropiperidine 137a with a cyclobutane ring as the spirocycle (Figure 18, B). Of note is 2-spiropiperidine 135b with a phenyl ring at C-6 (Figure 18, C), which was more three-dimensional than similar sp2 C-6 substituents. 2-Spiropiperidine 140 was understandably the worst performer (Figure 18, D), containing an aromatic C-6 substitutent and a Cbz protecting group. The negative impact of the Cbz protecting group was recognised by the performance of the Cbz deprotected 2-spiropiperidine 142 (Figure 18, E).
60 The outcome of the PMI plot was promising, with the majority of the 2-spiropiperidines occupying the underrepresented region of chemical space. The next aim of the project was to utilise the 2-spiropiperidines as scaffolds for a fragment based drug discovery program. Iterations would be made to the 2-spiropiperidines, so it was interesting to see if the relative three-dimensionality of the functionalised 2-spiropiperidines was retained.
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3. Functionalisations
With a robust procedure in place for the synthesis of 2-spiropiperidines, and with the knowledge that they occupy the desired region of chemical space, attention turned to exploring their versatility for elaboration. The 2-spiropiperidines were identified as useful scaffolds for a fragment drug discovery programme. Whilst the C-6 substituents and the spirocycles could be readily varied, the 2-spiropiperidines also possessed three handles that could be used for further functionalisations; an ester, a ketone and an amine (Figure 19).
Figure 19. Highlighted handles for 2-spiropiperidine elaboration.
The functionalisations were deemed relevant to improve the lead-likeness of the 2- spiropiperidines. Planned functionalisations included the manipulation of the C-3 ester, which is an undesirable functional group to be present for screening,113 to give either decarboxylated 2-spiropiperidines or amidated 2-spiropiperidines. Methods for the introduction of fluorine at C-3 and C-4 were trialled to improve hydrophilicity and bioavailability.114 Derivatisation of the ketone via reductive methods would give a better Fsp3, which was therefore assumed that the respective three-dimensionality would also improve. Manipulation of the amine or the reduced ketone would introduce new vectors to allow further exploration of the underrepresented region of chemical space.
Consequently, a small library of structurally interesting, medicinally relevant 2- spiropiperidines was constructed with the implication for use in a fragment based drug discovery programme.
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3.1 Decarboxylation
Aliphatic esters have been flagged as an undesirable functional group to be present in clinical candidates.14,113 The electrophilic ester has the potential to be unintentionally reactive towards proteins and is susceptible to decomposition by solvolysis or hydrolysis. This can consequently lead to false-positives that can plague screening efforts.115 It was therefore deemed necessary to be able to manipulate the methyl ester of the 2-spiropiperidine. Investigations began with the decarboxylation of 2-spiropiperidine 138a through microwave irradiation, using known conditions developed in the group’s tetrahydropyran work (Scheme 43).116 Unfortunately, this led to decomposition of starting material and no decarboxylation was observed from the 1HNMR spectrum of the crude reaction mixture.