Total Synthesis of Hexaacetylcelenamide A

Abstract

both the pure Eas well as the pure Z-isomer of the cyclic phosphinate l a with trifluoroacetate acid'']. 2a adds nucleophiles such as water, methanol or ethanol at C-4 to give the E/Z-mixture 3s (R= H, Me, Et); hydride ions add at C-2 to give the E/Z-mixture 4a.The 57c delocalization, competing for the destabilization by the phosphinic acid group, accounts for the stability of the carbocation of 2. The species 2b is kno~n['"~~]. Recent, independent experiment^[^*^' encouraged us to prepare the salts 2c and 26 (containing deep-blue and deep-red cations, respectively161) from l c and Id by reaction with trifluoroacetic acid or aluminum chloride in dichloromethane. 2c and 2d likewise add nucleophiles such as water, methanol or ethanol to give the E/Z mixture of 3c and 3d, respectively (R=H, Me, Et); hydride ions add to C-2 to give 4c and 46, respectively. 4c and 4d react with potassium hydride in tetrahydrofuran (THF) to give the salts 5c and 5d containing stable delocalized anions. A mixture of equimolar amounts of 2c and 2d in dichloromethane and of 5c and 5d, respectively, in THF at room temperature, leads to formation of the radicals 6c and 6d, respectively, which are stable for days in the absence of air; their phosphorus coupling constants up=2.3 mT compare very well with those of the well known radicals 6a (u,=2.31 m v , and 6, R' = tBu, R2 = C6H3(tBu),(3,5) (up = 2.35 I~T)['~. Angew. Chem. Int. Ed. Engl. 23 (1984) No. I 2 0 Verlag Chemie GmbH, 0-6940 Weinheim, 1984 0570-0833/84/12 12-0993 $ 02.50/0

Chemical Synthesis of Natural Product Peptides: Coupling Methods for the Incorporation of Noncoded Amino Acids into Peptides

“…95 Galpin's ring disconnection 110 between the hindered cyclosporine 1 and 11 positions (Chart 44) was designed to enable the facile preparation of cyclosporine analogues differing from the natural compound at position 1, which had been implicated as being central to the immunosuppressant activity. That this 36), obtaining only 30% of the desired product. 75 Interestingly, the reaction proceeded at high dilution via the trichlorophenyl ester in refluxing pyridine, but no desired product was obtained at ambient temperatures.…”

“…The precursor phosphonoglycine (Chart ) is extended on either side with standard coupling procedures to give a phosphonopeptide, which is then smoothly converted into a dehydropeptide in excellent yield via the Horner Emmons reaction (Chart ). A variety of aromatic and aliphatic aldehydes have been employed, and the utility of this method was demonstrated in the synthesis of natural products such as chlamydocin (Chart ) and hexaacetylcelenamide A (Chart ). , This method was recently adapted to the preparation of N- methyl Dhaa's in our synthesis of microcystin LA (Charts and ) 37 Dehydropeptides by the Horner Emmons Reaction …”

“…A variety of aromatic and aliphatic aldehydes have been employed, and the utility of this method was demonstrated in the synthesis of natural products such as chlamydocin (Chart 18) and hexaacetylcelenamide A (Chart 38). 35,36 This method was recently adapted to the preparation of N-methyl Dhaa's in our synthesis of microcystin LA (Charts 37 and 48). 163…”

“…Enzymatic methods of peptide bond formation will not be covered. The synthesis of unusual amino acids will also not be discussed here, since there are numerous publications covering this topic. − Additionally, Roberts and Vellaccio have prepared a useful compilation of unusual amino acids used in peptide synthesis . The cyclopeptide alkaloids − and the oxazole/thiazole ,− containing peptides have also received extensive coverage that will not be reiterated here.…”

The total synthesis of frangulanine

“…17a: 1H NMR (250MHz, (d,J6.7Hz, 3H), 1.06 (d, J6.8Hz, 3H), 1.18-1.39 (m, 3H), 1.34(s, 9H), 2.04-2.13 (m, lH), 2.43 (s, br, lH), 2,98 (d, J 14.1 Hz, lH), 3.90 (dd,JS.O, 6.3 Hz, 1H),3.98(d7J8.8Hz, 1H),4.18(dd,J14.174.1 Hz, lH), 4.60 (dd, J 8.7, 1.2 Hz, lH), 5.07 (d, J 3.4 Hz, lH), 6.75 (dd, J 8.4,2.4Hz,lH),6.84(dd,J7.6,2.4Hz,lH),6.93(dd,J8.4,2.1Hz, lH), 7.34 (dd, J 7.6, 2.1Hz7 1H); 17b: lH NMR (250MHz, (d,J6.7Hz,3H),1.07(d,J6.3Hz73H),1.14-1.37(m,3H),1.34(s, 9H), 1.95-2.11 (m, lH), 3.14 (dd, J 13.3, 6.4Hz, lH), 3.81 (d, J2.5 Hz, lH), 3.82 (d, J 13.3 Hz, lH), 3.95 (d, J8. 8 Support of this research work by BASF AG, the Fonds der Chemischen Industrie and the Deutsche Forschungsgemeinschaft is gratefully acknowledged. We thank Dr W. Rozdzinski for mass spectra and Prof. E. Haslinger for a sample of natural frangulanine to compare with the synthetic product.…”