The synthesis of a variety of enantiomerically pure chiral auxiliaries based on (S)‐proline and bearing sterically demanding side chains at the pyrrolidine moiety, such as the secondary amines (S)‐3,5 and 7 and the hydrazines (S)‐6, is described on a molar scale. As key step, the Grignard or RLi addition to the N‐benzylated proline ester (S)‐1 is used.

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The synthesis of a variety of enantiomerically pure chiral auxiliaries based on (S)-proline and bearing sterically demanding side chains at the pyrrolidine moiety, such as the secondary amines (s)-2,5 and 2 and the hydrazines (S)-a, is described on a molar scale. As key step, the Grignard or RLi addition to the N-benzylated proline ester ( S ) -l is used.Among the enantiomerically pure natural products used as starting materials for the preparation of chiral auxiliaries in the field of asymmetric synthesis, aminoacids2 have been employed extensively. Since the pioniering work of S. Yamada et al.3 and the discovery of the so called Eder-Sauer-Wiechert-Hajos reaction4, proline, with its conformationally rigid five membered pyrrolidine ring, has gained special attraction. This may be exemplified with the chiral ligands PPM and BPPM for ligands a la MUkaiyamag . Recently, independent reports form several groups indicate the great utility of such bulkier pyrrolidine auxiliaries in enantioselective synthesis 10-15. In this paper we describe in detail the large scale preparation of twelve of these versatile chiral auxiliaries.In order to prevent any side reactions during the Grignard or RLi additions to the proline ester functionality -the key step of the reaction sequence -we focused on the N-benzyl protecting group, which is easily cleaved off by hydrogenolysis. Thus, in a simple one pot procedure (S)-proline was esterified with thionylchloride/ethanol and after addition of triethylamine the resulting crude ( Alternatively, the alcohol group was readily converted to the methylethers (S)-&-g by treatment with sodium hydride and methyliodide in tetrahydrofuran. Deprotection by hydrogenation gave rise to the aminoethers ( S ) -& -g , which could easily be converted further to the corresponding hydrazines ( S ) -@ -a employing the nitrosation (t-BuONO, THF)/reduction (LAH, THF) sequence. In addition, the key intermediates ( S 1 -2 open the possibilities to prepare oxygenfree auxiliaries, such as ( S 1 -G and a. For instance, ( S ) -a was obtaines by dehydration of ( S 1 -a with thionylchloride in tetrahydrofuran in the presence of triethylamine, followed by hydrogenation (benzyl deprotection and reduction of the double bond). In the case of the phenylderivative ( S ) -a direct reduction with lithium in followed by benzyl deprotection to give ( S ) -a .liquid ammonia was usedl8,The enantiomeric purity of all chiral auxiliaries 2,5,6 and 1 described in this paper were checked by conversion to the corresponding Mosher-derivatives. The 13C NMR data showed enantiomeric excesses of ee298%. The enantiorneric auxiliaries of (R)-configuration were prepared in the same way starting from (R)-proline.In conclusion, the reaction sequence described here allows the large scale preparation of very useful chiral secondary amine and hydrazine auxiliaries, as has been tested many times with reproducable yields and quality by our student beginners in their experimental laboratory course. Further successful applications of these reage...

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