An Unusual Rearrangement of a Lithiated N-Acyl-tetrahydroisoquinoline to an Amino-indan Skeleton and Structural Comparison of 3-Amino-2-methylindan- and -tetrahydronaphthalene-2-carboxylic Acids as Possible Building Blocks for Peptide-Turn Mimics
✍ Scribed by Thomas Gees; W. Bernd Schweizer; Dieter Seebach
- Book ID
- 102857319
- Publisher
- John Wiley and Sons
- Year
- 1993
- Tongue
- German
- Weight
- 956 KB
- Volume
- 76
- Category
- Article
- ISSN
- 0018-019X
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✦ Synopsis
Lithium 1-lithio-6,7-dimethoxy-3-methyl-2-pivaloyl-l,2,3,4-tetrahydroisoquinoline-3-carboxylate rearranges to the dilithio derivative of 5,6-dimethoxy-2-methyl-l-(pivaloylamino)indan-2-carboxylic acid (2, 2]-sigmatropic shift with retention of configuration) by 1,2-migration resembling the Wittig rearrangement of deprotonated ethers (Scheme 2). The structure, including absolute configuration of the rearrangement product, was determined by X-ray diffraction. Structural conditions for the rearrangement to occur are tested by subjecting various other tetrahydroisoquinoline derivatives (6,7,10,15) to the metalating conditions. Only one other compound was found to undergo the same rearrangement (15 + 16). Possible mechanisms of the rearrangement are discussed (BG). Due to the presence of a tetrasubstituted C-atom, the indan-type P-amino-acid derivative 2 has a conformationally locked structure (N-C-C-CO,R dihedral angle 44"). For comparison, the corresponding tetralin-type B-aminoacid derivatives 19-22 were prepared, and it was shown by X-ray analysis (of the ester 21) that these have larger dihedral angles (ca. 60"). It is proposed that p-amino acids of the type described here could be incorporated into peptides, providing bents of known angles along the peptide backbone.
') *)
Part o f the Dissertation of Th.G., ETH Zurich, No.9948 (1992). Simple bis-THIQ derivatives are known since the beginning o f the century. They have been prepared by reductive coupling of the corresponding iminium salts [2], by Bischler-Napieralsky ring closure of the appropriate oxalic-acid diamides [3], or by oxidative coupling of I-lithio-2-acyl-or -2-phorphoryl-THIQs [4] (cJ 1 +A!). HELVETICA CHIM~CA ACTA -Vol. 76 (1 993) Scheme I 2641 H.C / 1) 2.5 t-BuLi 2) D@ I (i-W,)-I A CH30
employed') to cause the lithiated THIQ to dimerize, without success. Careful analysis of the reaction mixture, obtained with various oxidants, and chromatographic separation of its numerous components revealed the presence of a main product X the spectra of which were not compatible with the dimeric structure. Ironically, compound X was also formed, simply by letting a solution of lithiated 1 stand long enough at dry-ice temperature or by allowing it to warm up to room temperature overnight. The best conditions for preparing compound X gave reproducibly 30-35 YO yields of chromatographically separated and recrystallized material, with 40-50 % of starting material 1 being recovered. Mass spectra, osmometric molecular-weight determination, and elemental analysis proved that the new compound was an isomer of the original THIQ derivative 1. Compound X was still enantiomerically pure, with a specific rotation of [a],, = -30 which did not change after repeated recrystallizations. The crystals were suitable for X-ray structure analysis; the surprising result is shown in Fig. . A rearrangement had occurred, with ring contraction of the THIQ skeleton 1 to an amino-indan system 2, having cis-configuration of the CO,H and NHCO(t-Bu) substituents!
The absolute configuration of 2 was determined by crystal structure analysis of the ammonium salt obtained with (R)-1-(p-nitropheny1)ethylamine [7] (see Fig. ). This establishes that the ring contraction has taken place with retention of configuration. The only other product we could isolate, besides 2, from a crystallization experiment was the 3, Cu', and Cu" salts, Br2, I,, K,[Fe(CN),], NiCI,, CoCI,, HgCI,, AgOAc, PtCI,, PdCl, were used. The parent N-pivaloyl-THIQ could be dimerized by sequential treatment with t-BuLi and NiCI, in 70 % yield. Previously, we used I, or Ti(OCHMe,),Cl for dimerizing simple THIQ derivatives 141. ' ) ' ) *) We thank Dr. S. KO and the Sundoz Phurma AG (Basel), Preclinical Research Division, for allowing us to communicate these hitherto unpublished results herein