Tetrahydrolipstatin (1) and its analogue 2 are representatives of a new class of pancreatic-lipase inhibitors. Two stereoselective synthetic approaches are described.
Early syntheses of tetrahydrolipstatin (l), in connection with the determination of its absolute configuration, have already been described [ 11. Our continued interest in pancreatic-lipase inhibitors has led us to prepare tetrahydrolipstatin (1) as well as several analogues, e.g. 2, by stereoselective syntheses'). ,rNHCHO x O=A h.....KCH2& ,..NHCHO CHI(CH2)$%N'2 J c (CH,),CH3 CHdCH21, 1 1 2
1. Tetrahydrolipstatin (1).
-As a key step in this synthesis, the TiC14-mediated condensation of ketene silyl acetal derivative 7 of (-)-N-methylephedrine with aldehyde 5 was used, following a procedure of Gennari et al. [2].
Hydroxy ester 3 [3] (e.e. 98%, determined by GC of a probe esterified with (-)-Masher's reagent) was transformed into the benzyl derivative 4 according to a novel procedure [4], and reduction of 4 with diisobutylaluminium hydride (DIBAH) yielded aldehyde 5 (Scheme I ) . The other component in the condensation was ketene silyl acetal 7 which was obtained by silylation of ester 6. Condensation of 7 with 5 in the presence of TiC1, yielded only two hydroxy esters in the proportion of 3 : 1. The major one, 8, has the desired (2S, 3S)-configuration, as shown by its transformation into tetrahydrolipstatin (1). The minor isomer 8' has erythro-configuration at C(2),C(3), as indicated by its transformation into cis-/j'-lactone 11' (the cis-conformation was established by NMR spectroscopy, see Exper. Purl). Ester 8 was saponified to hydroxy acid 9 which, by ring closure with benzenesulfonyl chloride and pyridine, furnished /j'-lactone 10 in good yield. By hydrogenolysis, hydroxy-P-lactone 11 was obtained which was reacted with ( S ) -Nformylleucine under Mitsunabu's conditions to yield tetrahydrolipstatin (1) without racemisation of the amino-acid moiety.
') The synthesis of further derivatives, in connection with structure-activity relationships, will be described elsewhere.
' ) ')
No reaction occurred, if octadecanal was used, presumably due to its low solubility in THF at -78". Cleavage of crude 18 with pyridinium p-toluenesulfonate in EtOH at 55-60" yielded the corresponding diol. Both H-C(3) and H-C(5) were found as 2 broad m in a ratio of4:I. The same ratio was found for H-C(2) of the chiral auxiliary moiety. Since the first diastereoselective condensation step 13+14 gave 14 with a d.e. of ca. 8O%, a similar value may be calculated for the second condensation 17-18. Our thanks are due to Dr. E. Broger from Hoffmann-La Roche & Co. AG, Central Research, for making available to us hydroxy ester 3 in large amounts and to Mr. C. Bardranu, S. Burner, and R. Simon for their excellent technical assistance. We thank our colleagues from Hojj'iiann-La Roche & Co. AG, Central Research, for spectral data and elemental analysis.