that a carbonyl to oxetane switch can be a viable approach to mitigate epimerization at adjacent stereocenters.
Table 2.2 Physicochemical and biochemical properties of selected oxetanes, and their carbonylated and gem‐dimethyl counterparts.
Source: Based on Wuitschik et al. [55].
|
|
|
|
|
|
|
|
|
|
|
|---|---|---|---|---|---|---|---|---|---|
| Solubility (μg ml−1) | 4000 | 1400 | 220 | 4100 | 730 | 40 | n.d. | 24 000 | 290 |
| Lipophilicity logD (logP) | 1.2 (1.6) | 1.0 (2.0) | 2.3 (4.4) | −0.1 (−0.1) | 0.7 (1.5) | 1.4 (3.7) | n.d. | 0.5 (1.2) | 0.8 (3.1) |
| hCLint (min−1 mg−1 μl) | 120 | 6 | 23 | 100 | 2 | 10 | n.d. | 3 | 0 |
| mCLint (min−1 mg−1 μl) | 88 | 22 | 31 | 580 | 27 | 39 | n.d. | 7 | 16 |
| pK a amine | 7.5 | 8.3 | 9.5 | 6.1 | 8.1 | 9.7 | n.d. | 8.0 | 9.6 |
Figure 2.6 (a) Spiro‐oxetane as a morpholine bioisostere.
Sources: Based on Carreira and Fessard [48]; Burkhard et al. [56];
(b) comparison of exit vectors in the piperidine motif and its spiro counterpart; (c) spirocyclic oxetane based on mimics of morpholine.
Table 2.3 Comparison of the properties of spirocyclic oxetanes with their morpholine parent.
Source: Adapted from Carreira Wuitschik et al. [55].
|
|
|
|
|
|---|---|---|---|
| Solubility (μg ml−1) | 730 | 8000 | 24 000 |
| Lipophilicity logD (logP) | 0.7 (1.5) | 1.5 (1.6) | 0.5 (1.2) |
| hCLint (min−1 mg−1 μl) | 2 | 9 | 3 |
| mCLint (min−1 mg−1 μl) | 27 | 8 | 7 |
| pK a amine | 8.1 | 7.0 |
8.0
|