A study on the synthesis of β-amino acids: the first synthesis of a bicyclic hemiaminal (3,3-dimethyl-1- (2,4,5-trifluorophenyl) tetrahydro-3H,5H-oxazolo[3,4- c] [1,3] oxazin-5-one)

We synthesized (4S)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(2,4,5-trifluorophenyl) oxazolidin-2-one and examined its Pd/C-catalyzed hydrogenation reaction. The condensation and rearrangement reaction of acetone with (4S)-4-(2-((tert-butyl dimethylsilyl)oxy)ethyl)-5-(2,4,5-trifluorophenyl)oxazolidin-2-one resulted in the formation of a hemiaminal structure containing a fused oxazine-oxazole ring, whose exact configuration was determined by X-ray crystal analysis. A mechanism was proposed to explain the formation of the fused oxazine-oxazole ring, which has a hemiaminal structure.


Introduction
The synthesis of amino acids still represents a great challenge and they are seen as target molecules due to their biological and toxicological properties. β-Amino acids are key components of many natural compounds. Thus, they are one of the most important classes of compounds in synthetic and medicinal chemistry [1][2][3][4]. The β-amino acids do not participate in the protein structure but are involved as secondary metabolites in biochemical processes. Amino acids are systematically added to peptide drugs to increase their stability and incur conformational biases [5][6][7]. It is well known that the use of β-amino acids in peptides improves their metabolic lability and therefore enhances their stability against proteolytic degradation [8][9][10][11]. β-Peptides have thus been used to mimic natural peptide-based drugs in medicinal and pharmacological studies. For example, sitagliptin containing the β-amino acid unit is known as dipeptidyl peptidase IV (DPP-IV) enzyme [12][13]. Many methods have been developed for the synthesis of the amino acid unit of sitagliptin in the literature (Fig. 1) [14]. In our previous studies we developed new methods for the synthesis of β-amino and βhydroxy acids [15][16][17][18]. Very recently, we also reported the synthesis of γ-keto-β-amino acids via the ringopening reaction of homoserine lactone, which is readily available from (S)-methionine [19]. Following on from the study of the synthetic applications of the ring-opening reaction of homoserine lactone with Grignard reagent, further reactions of the ring opening products were performed for the synthesis of β-amino acid derivatives in these studies. As part of our current studies on the synthesis of amino acid derivatives from readily available building blocks, herein we report interesting results obtained from the reduction reaction of amino keto-alcohol derivative and their transformation.
Thus, amino-keto alcohol 5, the precursor compound of homophenylalanine, was synthesized by this methodology. For the synthesis of homophenylalanine, we decided to reduce amino-keto alcohol 5 to amino diol 8 or amino alcohol 9. It is well known that H2/Pd (in catalytic reduction) and metal hydrides are very useful reduction reagents.
Firstly, the primary hydroxyl of amino-keto alcohol 5 was protected with tert-butyldiphenylsilyl (TBDPS) to give silyl ether 6. Subsequently, silyl ether 6 was reacted with NaBH4 to give benzylic alcohols 7 in high yield as a mixture of diastereoisomers (Scheme 2).

Scheme 2. Synthesis of benzylic alcohols 7.
For practical reasons, the diastereomeric alcohols 7 were not isolated but directly subjected to a further reaction. The reduction of the benzylic OH group was carried out by various methods [22]. One of these methods was direct Pd/C catalyzed hydrogenation of benzylic ketones or alcohols. However, this methodology was not suitable to reduce the benzylic OH group of 7. However, compound 8 was obtained by removal of the protecting group (Cbz-) from 7 in this reaction (Scheme 3).

Scheme 3. Pd/C catalyzed hydrogenation of benzylic alcohols 7.
Therefore, we planned to use a different modification for the reduction reaction of benzyl alcohol. The reduction reactions of the urethane ring containing the benzylic group are known in the literature. During this reaction, the reduction product is formed by the release of carbon dioxide from the molecule. In this context, we synthesized benzylic urethane 10 using two methods. First, the ketone was subjected to direct hydrogenation to give amino alcohol 8. Next, amino alcohol 8 was converted to benzylic urethane 10 with trichloroacetyl chloride in the presence of NEt3 in 55% yield.

Scheme 4. Synthesis of benzylic urethane 10.
As can be seen from Scheme 4, we used DCM as the solvent for the synthesis of the urethane ring. We obtained urethane with an average yield (55%). In order to increase the amount of product formed, the synthesis of the urethane ring was examined in different solvents. When using acetone, a very interesting rearrangement product including two methyl groups and a different urethane ring was obtained in the urethane synthesis reaction of amino alcohol 8 in acetone (Scheme 5). After separation, the 1 H 5 and 13 C NMR spectroscopic data indicated that a product different from what was expected was formed. The 1 H NMR spectra interestingly showed two methyl and two different methylene protons. In addition, three different carbon signals, i.e., quaternary, tertiary, and carbonyl carbon, appeared in the 13 C-NMR spectra. In particular, the presence of two methyl groups and one saturated quaternary carbon in the 1 H and 13 C NMR indicate that acetone reacts with molecule 10 and any molecule. On the other hand, butyl and phenyl protons belonging to the silyl group were not seen in the 1 H NMR spectra.

Scheme 5. Synthesis of the hemiaminal 11.
Although the 1 H and 13 C NMR spectra support the formation of an acetal ring and a different urethane ring, to gain more insight about the compound 11, we decided to confirm its exact structure by single-crystal X-ray diffraction techniques [23].   We performed X-ray structure analysis of the molecule 3,3-dimethyl-1-(2,4,5trifluorophenyl)tetrahydro-3H,5H- [1,3]oxazolo [3,4-c] [1,3]oxazin-5-one (11) to identify the conformation and possible interactions (Fig. 2a). The structure has a racemic form and crystallizes in the triclinic centrosymmetric space group P-1 with two enantiomers in the unit cell. There are two molecules in the asymmetric unit and their circumference of each one is different (Fig. 2b) In the second step, the synthesized benzylic urethane 10 was submitted to Pd-C catalyzed hydrogenation to give its reduction product 9. The reduction reaction of urethane 10 was examined in different solvents such as ethanol, methanol, ethyl acetate, and chloroform. However, this methodology was unsuccessful in reducing the benzylic OH group of 10 (Scheme 6). Additionally, the Pd-C catalyzed hydrogenation reaction was examined at 25 °C for 10 h in a Parr apparatus, but the desired reduction product 9 was not formed and the molecule was degraded in this condition. Scheme 6. Pd-C catalyzed hydrogenation reaction of 10.

Conclusion
For the first time, we synthesized a five-membered urethane (10), a -amino acid precursor compound. We demonstrated the condensation reaction of acetone to the system of benzylic urethane 10. We obtained the hemiaminal structure containing the fused oxazine-oxazole ring and determined the reaction mechanism of the acetalization product 11. Such an acetalization reaction is a unique example for the formation of an oxazine-oxazole ring.
The chemical transformations of amino-keto alcohol 5 and urethane ring 10 to the related compounds are currently under investigation. We think that this simple and straightforward method will find application in the synthesis of pharmacologically important -amino acid derivatives.

General
All reagents and substrates were purchased from commercial sources and used without further purification. Solvents were purified and dried by standard procedures before use. 1H and 13C NMR spectra were recorded on Varian 400 and Bruker 400 spectrometers. Elemental analysis were performed on a Leco CHNS-932 instrument.