The use of HMQC-TOCSY experiments for elucidating the structures of bicyclic lactams: Uncovering a surprise rearrangement in the synthesis of a key prophe building block
✍ Scribed by Kevin D. Moeller; Cathleen E. Hanau; Andrè d'Avignon
- Publisher
- Elsevier Science
- Year
- 1994
- Tongue
- French
- Weight
- 347 KB
- Volume
- 35
- Category
- Article
- ISSN
- 0040-4039
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✦ Synopsis
HMQC-TOCSY experiments were used to unequivocally assign the ring skeletons of several bicyclic lactams. This work demonstrated the power of these techniques for establishing the complete carbon connectivity of peptide building blocks with closely overlapping protons. In addition, it has led to the discovery of a surprise rearrangement reaction and allowed for the correction of a previously r&assigned Pro-Phe building block ring skeleton.
Recently, we reported that the titanium tetrachloride initiated cyclization of the a-methoxyalkyl amide la (R= CH3) led to the formation of the bicyclic seven-membered ring lactam 2 (Scheme l).l Scheme l* I la eta, 2 a lb. R=CH~Ptl 3 IP R==cH~ 92% 5r R-CES Ib. R=H 81% Sb. R=TDDMS 6. R-TBDMS Recrgenrs: a. TiC14. CH2Cl2, -780C to room temperature; b. H2,5% Pd/C, NaOMe, MeOH, 88% (R=CH3) aud 89% (R=H); c. i. LDA, THF, -50 to 40°C, ii. (+)-(2RJaS)-(campbordfbnyi)oxazitidine (Davis' reagent), 780/o; d. i. NCS, DMS, CH2Cl2. -30 to -20°C, ii. Et3N 76%; e. NH3, MeOH, 69% (R=Me) and 75% (R=TBDMS/ the bridgehead isomers could be separated here), f. TBDMSCI, imidazole, DMF, 81?4& g. i. LDA, THF, -78oC, ii. 02, 6056, h. pyroglutamic acid, EDC, HOBt, We-thyhnorphiline. 25% (uaoptimizcd, R=l%DMS). Compound 2 was then converted into what we assigned as the peptide building compounds were obtained as an inseparable mixture of isomers at the bridgehead block 3. Both of these position; a minor issue