Novel Carboxylic Acid and Carboxamide Protective Groups Based on the Exceptional Stabilization of the Cyclopropylmethyl Cation

Abstract

The facile solvolysis of cyclopropylmethyl substrates has long been recognized as being exceptional, an a-cyclopropyl substituent being even more effective, in many situations, than the a-phenyl residue in cationic stabi-1ization.l Surprisingly, little practical application of this unusual effect has been made in spite of the fact that no moiety of lower molecular weight comes close to equaling the effect of this simple three-carbon unit. In 1977, Brady, Hirschmann, and Veber2 examined the [(cyclopropylmethyl)oxylcarbonyl and [(1-cyclopropylethyl)oxylcarbonyl groups as potential N-a-amino acid protectants. A deficiency of the former, noted by Veber and coworkers, is the rearrangement of a portion of the substrate under acidic deblocking conditions to the (1-cyclobuty1oxy)carbonyl system with consequent partial early termination of the deblocking process.In the present paper it is demonstrated that the secondary system 1 incorporating two a-cyclopropyl units or the tertiary system 2 having one cyclopropyl and two methyl residues give rise to two widely applicable protective systems for carboxyl and amide protection, respectively. The dicyclopropylmethyl (Dcpm) group can be used for carboxylic acid protection where selective removal is necessary in the presence of tert-butyl-derived or N-trityl side chain protection. t On leave from the 1 2 A typical example involved assembly of the protected hexapeptide acid 33 from Fmoc-Tyr(t-Bu)-ODcpm by the rapid, continuous Fmodtris(2-aminoethy1)amine (TAEA) solution method of peptide ~y n t h e s i s .~,~ Except for Arg, which was coupled via N-[[(dimethylamino)-lH-1,2,3triazolo[4,5-blpyridin-l-yllmethylenel-N-methylmethanaminium hexafluorophosphate N-oxide (HATU),6 all acylations were carried out via the appropriate Fmoc amino acid fluorides' which were employed in the presence of base (DIEA). The final deblocking step involved short time (15 min) treatment of the Dcpm ester with 1% trifluoroacetic acid (TFA) in DCM. Fmw-lle-Thr( t-Bu)-Arg( Pn-c)-Gln(Tlt)-Arg( Pm)-Tyr( t-Bu)-OH 3Comparable amide protection, useful for avoidance of dehydration, to enhance solubility or interfere with aggregation8 can be achieved similarly. Although the Dcpm residue can be used for this purpose, its removal from nitrogen is somewhat sluggish and it is preferable to use a tertiary system, such as the dimethylcyclopropylmethyl (Dmcp) residue 2, which provides the desired level of rea~tivity.~ Table 1 collects some relevant halftimes for conversion of simple N-alkyl derivatives to acetamide by treatment with TFA and provides comparison with analogous phenylated systems. Comparison between 5 and 6 shows the cyclopropyl system to be about 10 times more reactive than the phenyl analog. A further deficiency of phenylated systems was noted in the case of 7, which was somewhat more reactive than 5, namely separation from the reaction mixture of an insoluble sticky material, presumably a polymer of the corresponding olefin.1° Under the conditions of Table 1,12 N-(3) Riniker, B.; Florsheimer, A.; Fretz, ...

Ring Opening of Spiroepoxides Dithianedioxide with Bis-nucleophiles

“…In order to carry out this, morpholine 9 was subjected to various conditions (a-g), but none gave the amino acid 14. Instead, the reactions generated the protonated product (a, d and g) [8], starting material (f) [9,10,11,12], decomposition of starting material (b) [13] or some unidentifiable compounds (c and e) [14]. It was assumed, from the above results, that the C-N bond was too strong to be cleaved.…”

Synthesis and binding studies of two new macrocyclic receptors for the stereoselective recognition of dipeptides

“…The best results for the coupling reactions were obtained when using a combination of HATU/NMM [31–32] in DMF at room temperature (Scheme 3). The analysis of the crude reaction mixtures by HPLC and 1 H NMR spectroscopy revealed that both tetrapeptides, 12 and 13 , were obtained as mixtures of two diastereoisomers.…”

Peptide Synthesis

“…The dicyclopropylmethyl group (Dcpm) can be cleaved with 1% TFA in dichloromethane, even in the presence of side chain-protecting groups of the tert-butyl type [86]. The hydroxy groups of serine or threonine are transformed under these conditions into the tert-butyl ethers.…”