Synthesis of LY503430 by using a selective rearrangement of β-amino alcohols induced by DAST

LY503430, an optically active β-fluoroamine, is a potential therapeutic agent for the Parkinson’s disease. Different strategies have been studied to synthesize this molecule using a regioselective and stereospecific rearrangement of β-amino alcohols into β-fluoroamines induced by DAST. This reaction allowed the synthesis of LY503430 with an excellent enantiomeric excess.


Introduction
LY503430, an optically active β-fluoroamine, which is a potential therapeutic agent for the Parkinson's disease, 1 has been prepared by Eli Lilly on gram scale 2 as well as on a kilogram scale 2 from racemic β-fluoroamine (±)-A.The two enantiomers of A were separated by using chiral chromatography or diastereomeric salt resolution (Scheme 1).Scheme 1. Retrosynthesis analysis of LY503430 by Eli Lilly.

First strategy
Our first synthetic strategy relies on a very late Suzuki cross-coupling of triflate D with a boronic acid to produce the biarylic substituent present in LY503430.The synthesis of β-fluoroamine D has been envisaged by utilizing an enantioselective rearrangement of β-amino alcohol E induced by DAST.A diastereoselective alkylation of F was chosen to control the quaternary stereocenter present in E and the synthesis of F was planned from 4-hydroxy-D-phenylglycine (Scheme 3).

Scheme 3. First retrosynthesis analysis of LY503430.
The synthesis of LY503430 started with the preparation of oxazolidinone 4 in four steps (Scheme 4).4-Hydroxy-D-phenylglycine was treated with two equivalents of methylchloroformate (NaOH/H2O) to furnish carbamate 1 and this carbamate was then transformed to a mixture of oxazolidinones 2 and 2' in a ratio of 5/1, by using benzaldehyde dimethyl acetal under acidic conditions (BF3•Et2O, CH2Cl2, 0 °C). 5 These two diastereoisomers were separated by chromatography on silica gel and compound 2 was isolated with an overall yield of 55% for the two steps.To control the quaternary center present in 4, oxazolidinone 2 was methylated.Depending on the conditions, the yield in 3 varied from 30% to 93%.Indeed, when 2 was treated with LDA (THF, -78 °C) followed by the addition of MeI, a degradation of the starting material was observed.The yield in 3 was improved to 31% when LDA was replaced by LiHMDS (THF, -78 °C) utilizing methyl iodide as the alkylating agent.When methyl iodide was replaced by methyl triflate, the yield in 3 reached 93% and the diastereoselectivity was up to 95/5.After reduction of 3 by L-selectride (10 equiv, THF, rt), oxazolidine 4 was formed in 74% yield, probably via intermediate G and G' (Scheme 4).
In order to obtain compound 8, the protected amino alcohol 4 was saponified (LiOH, EtOH/H2O 1:1, reflux) and a N,N-dibenzylation as well as the O-benzylation were tried [BnBr (3.1 equiv), K2CO3, acetone, reflux].Unfortunately, the desired amino alcohol 8 was not formed but instead tribenzylamine 6 was isolated, probably due to the formation of a tribenzylammonium phenolate intermediate H which has the propensity to eliminate the ammonium group (Scheme 5).To avoid this elimination, compound 4 was N-and O-benzylated (BnBr, K2CO3, MeCN, reflux) and then treated with LiOH (aqueous EtOH) to furnish 7 which after N-benzylation afforded the desired amino alcohol 8, however in a very poor yield, e.g. 5% over the three steps due to the poor conversion of oxazolidinone (τc = 15%) to produce 7 during the saponification step.As the non-protection of the phenol functionnality in one hand, and the protection of the amine on the other hand, revealed to be problematic during the transformation of oxazolidinone 4 to amino alcohol 8, we decided to prepare the protected oxazolidinone 9. Thus, 4 was selectively O-benzylated (BnBr, K2CO3, acetone, reflux), and the resulting oxazolidinone 9 (93%) was treated with LiOH to produce amino alcohol 10 with a total conversion.Finally, after N,N-dibenzylation of 10 (K2CO3, BnBr, MeCN, reflux), the desired amino alcohol 8 was isolated in 77% yield over the last two steps with an enantiomeric excess of 94% (Scheme 5).
The key intermediate in the synthesis of LY503430, amino alcohol 8 (ee 94%), was then submitted to DAST to produce β-fluoroamine 11 in 99% yield (Scheme 6).However, each attempt to purify 11 either on silica gel or alumina resulted in its degradation.Furthermore, a partial racemization occured during the process as the enantiomeric excess of 11 revealed to be only 24%.This racemization can be explained by the participation of the electronically enriched benzylated phenol group to the opening of an aziridinium intermediate, 6 intermediate I, formed after activation of the hydroxy group of amino alcohol 8 by DAST.Thus, the racemization proceeds probably through the formation of the achiral intermediate J (Scheme 6).
Due to the difficulties encountered to access β-fluoroamine 11 with good enantiomeric excess related to the racemization occurring during the rearrangement of amino alcohol 8 induced by DAST, a second strategy was planned to synthesize LY503430.

Second strategy
To avoid the racemization during the rearrangement of an amino alcohol by DAST, the synthesis of LY503430 was envisaged by introducing the biphenyl group, possessing an electronwithdrawing substituent, in an early stage of the synthesis of LY503430, before applying the rearrangement induced by DAST.Thus, 4 would be transformed to K which would be rearranged to L, precursor of LY503430 (Scheme 7).
As the deprotection of the N,N-dibenzyl group seems to be problematic, the use allyl groups to protect the amino group in 15 was planned.In consequence, β-amino alcohol 15 was transformed to N,N-diallyl amino alcohol 20 in 87% yield (AllylBr, K2CO3, n-Bu4NI, MeCN, reflux).The rearrangement of N,N-diallyl amino alcohol 20 induced by DAST (1.1 equiv) in THF (0 °C, 1 h) furnished the desired fluoroamine 21 (88%) and the amine was then deprotected by treatment with N,N-dimethyl barbituric acid (NMDBA) in the presence of Pd(PPh3)4 in CH2Cl2 8 leading to β-fluoroamine 22 (73% yield).To complete the synthesis of LY503430 from 22, this compound was sulfonylated (i-PrSO2Cl (1.5 equiv), Et3N (3 equiv), CH2Cl2) and the desired sulfonamide 23 was isolated with a moderate yield of 30% due to the limited conversion of 22 (τc = 44%).The last step to obtain LY503430 consisted of the transformation of the ester group in 23 to a methyl amide.A one-step procedure using either MeNH2 in EtOH or MeAlClNHMe (obtained by reaction of AlMe3 with MeNH3Cl) 9 as amidification reagents unfortunately led to the degradation of substrate 23 (Scheme 9).
Attempts utilizing a two-step procedure using a saponification followed by an amidification also failed.Indeed neither harsh conditions (KOH, EtOH/H2O, reflux) nor soft conditions (NaOH 1M, THF/MeOH, rt) led to the desired carboxylic acid 24.A degradation of the substrate was also observed along with the loss of the fluorine atom (Scheme 10).
As the benzylic position of the fluorine atom seems to decrease the energy of the C-F bond and entailed unwanted degradation, the introduction of the fluorine atom and the methyl amide present in LY503430, were planned at a late stage of the synthesis e.g. from 20.The transformation of the methyl ester in 20 to a methyl amide was realized in one step using Weinreb's conditions. 9Treatment of 20 with 2.0 equiv of MeAlClNHMe (obtained by reaction of AlMe3 MeNH3Cl) allowed the transformation of the methyl ester to a N-methyl amide, however the replacement of the allylamine by a N-methylamine was observed and compound 25 was isolated in 70% yield (Scheme 11).The formation of 25 could result from the activation of the hydroxyl group by MeAlClNHMe to furnish intermediate 26.The anchimeric assistance of the nitrogen atom associated with the nucleophilic displacement of the MeNH-Al-O moiety could entail an intramolecular rearrangement resulting in the formation of 25 (Scheme 11, route a).][12][13][14][15] Scheme 9. Synthesis of sulfonamide 23.

Conclusion
The synthesis of LY503430 was achieved successfully from 4-hydroxy-D-phenylglycine in 14 steps with an overall yield of 8.1%.The key steps were the construction of the quaternary center through a diastereoselective alkylation, a Suzuki coupling to introduce the biarylic function and the rearrangement induced by DAST to obtain the chiral β-fluoroamine moiety.It is worth noting that this highly enantio-and regioselective rearrangement is sensitive to the nature of the substituents present on the aromatic ring(s) of aryl or bis-aryl amino alcohols.

Experimental Section
General.Experimental procedure for the synthesis of compounds 2, 2', 3, 4, 12, 14, 15, 20, 27-29 and LY503430 with copies of their 1 H and 13 C NMR spectra were previously reported. 4 1H NMR spectra were recorded on a Bruker AVANCE 400 at 400 MHz and data are reported as follows: chemical shift in ppm from tetramethylsilane as internal standard, multiplicity (s = singulet, d = doublet, t = triplet, q = quartet, m = multiplet or overlap of non-equivalent resonances, integration). 13C NMR spectra were recorded on a Bruker AVANCE 400 at 100 MHz and data are reported as follows: chemical shift in ppm from tetramethylsilane with the solvent as internal standard (CDCl3, δ 77.0 ppm), multiplicity with respect to proton (deduced from DEPT experiments, s = quaternary C, d = CH, t = CH2, q = CH3).Mass spectra with electronic impact (MS-EI) were recorded from a Hewlett-Packard tandem 5890A GC (12 m capillary column) -5971 MS (70 eV).Infrared (IR) spectra were recorded on a Bruker TENSOR TM 27 (IRFT), wave-numbers are indicated in cm -1 .THF was distilled from sodiumbenzophenone.Reagents obtained from commercial suppliers were used as received.TLC was performed on Merck 60F254 silica gel plates and visualized with a UV lamp (254 nm), or by using solutions of KMnO4/K2CO3/NaOH in water or by using p-anisaldehyde/sulfuric acid/acetic acid in EtOH followed by heating.Column chromatography was performed with Merck Geduran Si 60 silica gel (40-63 µm).High resolution mass spectra (HRMS) were performed by the centre regional de microanalyse (Université Pierre et Marie Curie Paris VI).

General procedure for rearrangement of β-aminoalcohols induced by DAST.
To a solution of β-amino alcohol of type B in THF (0.05 M) was added DAST (1.1 to 2.2 equiv) at 0 °C.The mixture was stirred for 1 h at 0 °C and then warmed to rt.After addition of H2O, the mixture was extracted with twice CH2Cl2, dried over MgSO4, filtered and concentrated under reduced pressure.Purification of the residue by flash chromatography on silica gel afforded β-fluoroamines of type C.