The asymmetric Henry reaction as synthetic tool for production of drugs Linezolid and Rivaroxaban

The human drugs – antibiotic Linezolid (1) and anticoagulant Rivaroxaban (2) – belongs among modern pharmaceutics, which contain oxazolidine-2-one moiety bearing stereogenic centre. The chirality of these drugs is fundamental attribute of their biological activity. Herein, one of the efficient asymmetric syntheses of those drugs was studied in detail. High enantioselective catalysts were tested in the key step of the synthetic procedure, i.e. asymmetric Henry reaction, under different reaction conditions, using several starting aldehydes. The corresponding nitroaldols as chiral intermediates of those drugs were obtained in high yields and enantiomeric excess up to 91% ee.


Introduction
Oxazolidine-2-one derivatives belong among important branch of pharmaceutical substances [1,2]. This class includes for instance many of oxazolidine-type antibioticse.g. Linezolid (1) [3] (sold under the trade name Zyvox ® (Chart. 1), Tedizolid [4], Radezolid [5]) and the anticoagulant Rivaroxaban (2) [6,7] (Chart. 1), the member of DOACs (direct oral anticoagulants). All these human drugs can be considered as modern medicaments, which were developed and approved during past three decades [8]. Chirality of the mentioned oxazolidine-2-ones is crucial factor of their therapeutic effect, because only single enantiomer affords desired biological activity. Hence, only S-enantiomer of Rivaroxaban (2) (sold under trade name Xarelto ® ) exhibits strong inhibitory activity against coagulant factor Xa, whereas Renantiomer is almost inactive (IC50 = 0.7 nM for S-vs. 2300 nM for R-) [7]. Similarly, in the case of the oxazolidine-2-one antibiotics only S-enantiomers are able to block the bacterial ribosomes, what leads to the prevention of translation processes in bacteria [9,10]. With regards to these facts, high enantiomeric purity is one of the fundamental requirements in the production of such pharmaceutical substances, because the reduction of abundance of undesirable stereoisomer to a minimum can supress possible side effects.
The oxazolidine-2-one-type drugs are usually prepared according to the synthetic methods, that utilizes available chiral building blocks (e.g. epichlorohydrine, glycidol, 3-chloropropane-1,2diol etc.) [11]. Beside this, the approaches in which the asymmetric synthesis takes place are also applicable. Recently, the utilization of asymmetric Henry reaction for the preparation of two oxazolidine-type drugs -Linezolid (1) and Rivaroxaban (2)was described [12,13]. These published papers confirmed that the application of asymmetric Henry reaction represents the promising alternative route for feasible production of these compounds. Nevertheless, these studies gave only preliminary results, because it was included only one enantioselective catalyst 3 in the case of preparation of Rivaroxaban (1) [12] and the study of the Linezolid (2) synthesis used only commercially unavailable and poor enantioselective catalysts (max ee 72%) [13].
In this paper, we focused on the application of asymmetric Henry reaction for the preparation of oxazolidine-2-one-type drugs Linezolid (1) and Rivaroxaban (2)

Results and discussion
The aldehydes 15-20 were prepared by analogical methods, which were described previously [12,13]. The starting L-menthyl (7) and (-)-bornyl chloroformate (8) were obtained according to the modified synthetic procedure [14]. Here, it was included the chromatographic purification of final chloroformates, what led to removing of corresponding alkyl chlorides formed as by-4 products. The aldehyde 17 was prepared by different way, because the acid-catalysed hydrolysis of its acetal intermediate 11 was accompanied with simultaneous cleavage of Boc group.

Scheme 1. The syntheses of aldehydes 15-20
For the catalytic study of the asymmetric Henry reaction of aldehydes 15-20 with nitromethane were chosen highly enantioselective catalysts based on copper(II) complexes of chiral nitrogen ligands. Generally, the chiral complexes of copper possess many advantages valuable for pharmaceutical industry, e.g. low toxicity, low-cost, possibility of recycling [19]. Therefore, they represent very useful tool for many of asymmetric transformations, including Henry reaction. The pilot study of the synthesis Rivaroxaban via asymmetric Henry reaction [12] described the application of only one copper complex of 2-(pyridine-2-yl)imidazolidin-4-one derivative. In this work, we extent the series of catalysts with the copper complexes of another [20][21][22], four bis-oxazolines IV-VII [23,24] and chiral diaminealkaloid (+)-sparteine VIII [25] (Chart 2). All Henry reactions were performed on sub-millimolar scale. The obtained products 21-26 were separated from starting aldehydes 15-20 by column chromatography. The reaction conditions (i.e. temperature, reaction time, amount of catalyst, solvent) were adopted from the pilot study [12] for relevant comparison of catalyst's characteristics. Subsequently, the reaction temperature and loading of catalyst was tuned using aldehyde 15 to achieve satisfactory chemical yields and ee in nitroaldol 21 (Table 1).
6 Chart 2. The survey of chiral ligands used for the study of the asymmetric Henry reaction  From the obtained results summarized in Table 1 was found out, that the highest enantioselectivity exhibit the copper(II) complexes of ligands Ia, IIa, IIIa and IV. Fortunately, these catalysts provide the R-enantiomer of nitroaldol 21 as a major product, which can be subsequently transformed to S-Linezolid (1) (the active stereoisomer). On the other hand, the catalysts derived from 2-(pyridine-2-yl)imidazolidine-4-ones Ib-IIIb, bis-oxazoline ligands V-VII and (+)-sparteine (VIII) show only insufficient enantioselectivity, therefore, they were excluded for further catalytic study. Obviously, the higher catalyst loading does not affect enantioselectivity, however, it enables the achievement of high chemical yield. Performing of the reaction at room temperature also increases the yield, nevertheless, the certain drop of ee was observed, especially in the case of catalyst IIa. From this point of view, the 10 mol % of catalyst derived from ligands Ia, IIa, IIIa and IV and reaction temperature 6 °C were evaluated as optimal reaction conditions for studied asymmetric Henry reaction.
Further, the asymmetric Henry reaction of the other aldehydes 16-20 was studied ( Table 2).
The bulky (R 2 = t-Bu) or chiral (R 2 = L-menthyl or (-)-bornyl) alkoxy group was introduced into the carbamate moiety instead of ethyl group in aldehydes 15 and 19. Of note, the nitroaldols 22, 24 and 26 were formed as a pair of epimers, therefore, possible separation of the individual stereoisomers of these compounds was assumed. Hence, it should be noted that the R 2 O-part of the carbamate group does not modify the structure of Linezolid (1), because this molecular moiety is cleaved by intramolecular nucleophilic substitution within the final reaction step (Scheme 2). The catalysts derived from ligands Ia, IIa, IIIa and IV were also tested in asymmetric Henry reaction using two substrates 19-20, which afford the chiral intermediates 25-26 applicable for Rivaroxaban (2) synthesis.  Next, the synthetic method [12,13]

Conclusion
In conclusion, the synthetic approach to the production of the antibiotic Linezolid (1) and the anticoagulant Rivaroxaban (2) based on the asymmetric Henry reaction was studied in detail.
The series of 11 efficient enantioselective catalysts was tested to obtain the corresponding nitroaldol 21 in the enantiomeric excess as high as possible. Four of them based on chiral ligands Ia, IIa, IIIa and IV were evaluated as the most effective catalysts. They exhibit the mutually comparable enantioselectivity in the range of 83-91% ee. It was found out, that the enantioselectivity does not vary with the substitution in the carbamate group of used aldehydes 15-20. However, all nitroaldols 21-24 prepared as chiral intermediates suitable for the Linezolid (1) synthesis were obtained with higher ee (83-90%) than in the previously published study (up to 72% ee) [13]. The introduction of chiral moiety into the structure of aldehydes 16,