α -Amino cyclic dithioketal mediated asymmetric synthesis of ( S )-(-)- α -( N - p -toluenesulfonyl)aminopropiophenone ( N -tosyl cathinone)

The asymmetric synthesis of N -tosyl cathinone, a high reactive α -amino ketone, via the addition of 2-lithio-2-phenyl-1,3-dithiane to a sulfinimine ( N -sulfinyl imine), is described. It was found that the resistance of N -tosyl α -amino ketones to epimerization is related to the ability of this protecting group to stabilize anions at nitrogen.

ARKAT USA, Inc. (-)-Cathinone (6) obtained from the leaves of Catha edulis (Khat) exhibits cardiovascular activity 5 and is reported to have activity similar to amphetamines 6 and dopamine. 7Several targeted asymmetric syntheses of the N-tosyl and the hydrochloride salt of this material have been described because α-amino ketones are not stable unless suitably N-protected. 1 These methods include ring opening of aziridines, 8 asymmetric aminohydroxylation of silyl enol ethers and alkenes, 9 catalytic asymmetric aziridination of enols, 10 and Friedel-Crafts acylation. 11nfortunately these procedures are lengthy and the product is obtained with modest stereoselectivity.Because the amino 1,3-dithiane (S S ,S)-7 is generated in one step from a sulfinimine, our synthesis of (-)-6 or an N-protected 6 is expected to be highly efficient (Scheme 2).Furthermore, this protocol is amenable to the synthesis of amino ketone analogs that on reduction would provide enantiopure 1,2-amino alcohols, valuable chiral auxiliaries. 12

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OEt 2 and MgBr 2 , which result in lower de's and yields (Table 1, entries 2 and 3).The inability to separate diastereoisomers is occasionally observed in the addition of carbanion species to sulfinimines and can often be overcome by changing the Z group linked to sulfinyl moiety. 15Diverse enantiopure N-sulfinyl imines can be prepared using the N-sulfonyl-1,2,3-oxathiazolidine-2-oxide chiral auxiliary introduced by Senanayake and co-workers. 16This research group also reported that the diastereoselectivity for Grignard addition to sulfinimines improves as the steric size of the N-sulfinyl moiety increases.16b Importantly, we found that the reaction of (S S )-8b and (S S )-8c, showing in turn 2,4,6-trimethylphenyl (TMP) and 2,4,6triisopropylphenyl (TIPP) groups linked to sulfur atom, resulted in separable mixtures of isomers affording (S S ,S)-7b and (S S ,S)-7c in 65 and 80 % isolated yields, respectively (Scheme 3 and Table 1, entries 4 and 5).However, the effect of Z's size on the stereoselectivity was unclear.Best results were observed for the N-tert-butanesulfinyl group where only a single diastereoisomer was obtained.However, the reaction was slow resulting in only 30% of (S S ,S)-(+)-7d after 0.5 h.With two equiv of 2-lithio-2-phenyl-1,3-dithiane the yield of (+)-7d improved to 70% (Table 1, entry 7).
Next, we explored the selective hydrolysis of the thioketal moiety in 7a-d using DBDMH (3) and bis(trifluoroacetoxy)iodobenzene (Scheme 4).These results are summarized in Table 2.For Z = p-tolyl, earlier results had shown that 3 not only hydrolyzes the thioketal group but also oxidizes the p-toluenesulfinyl group to a tosyl group. 4Bis(trifluoroacetoxy)iodobenzene was more selective leaving the p-toluenesulfinyl group intact. 3In both examples there was no epimerization of the α-amino carbonyl compounds.The results summarized in Table 2 reveal that hydrolysis with PhI(O 2 CCF 3 ) 2 of 7a, 7b, and 7c, where the N-sulfinyl Z group is aryl, gives the corresponding N-sulfinyl α-amino ketones 9 in good yield.However, the only compound which did not experience some racemization was 9a where Z is p-tolyl (Table 2, entry 1), while 9b and 9c with the TMP and TIPP N-sulfinyl groups respectively exhibited some epimerization (Table 2, entries 3 and 5).For 7d where the Z group is tert-butyl (t-Bu) complete racemization occurred (Table 2, entry 7).For 7a, 7b, and 7c hydrolysis with 3 (DBDMH) afforded the corresponding sulfonamides 10a, 10b, and 10c in moderate yields (Table 2, entries 2, 4, and 6).However, with 7d decomposition was the result (Table 2, entry 8).
From the above studies, it appears that only the tosyl and sulfinyl N-protecting groups are able to prevent racemization of the α-amino carbonyl moiety under the conditions employed for thioketal hydrolysis (Table 2, entries 1 and 2).Racemization results from the removal of the αproton in the α-amino carbonyl compound forming the enol.Earlier we remarked on the superior protecting group abilities of the N-tosyl group for preventing racemization of α-amino carbonyl compounds because of its ability to stabilize anions at nitrogen. 4The lesser ability of the N-Boc group to stabilize anions at nitrogen is reflected in the epimerization (-)-12b under the hydrolysis conditions (Table 2, entries 10-13).In support of this argument there is the fact that hydrolysis of (-)-12c, which has the N-trifluoroacetyl protecting group, did not result in epimerization (Table 2, entry 14).The anion stabilizing effects of tosyl, Boc, and CF 3 C(O) can be estimated from Hammett σ p values of 0.72, 0.45, and 0.8 respectively. 21Since the σ p for MeS(O) is 0.49, similar to Boc, this strongly suggests that the arenesulfinyl groups in 7a-c are first oxidized by 3 to the corresponding arenesulfonyl groups prior to hydrolysis of the thioketal moiety.

Table 2 .
Hydrolysis of thioketals 7 and 12 a Isolated yield.bDetermined by 1 H NMR on the crude reaction mixture.cDetermined by comparison of the rotation with literature values.See ref. 10. d Determined using Eu(hfbc) 3 and 19 F NMR as previously described.See ref. 20.ARKAT USA, Inc.