A Short and Efficient Protocol for the Solid-Phase Synthesis of Retro-Inverso Surrogates

Abstract

A novel and straightforward synthesis of malondiamides on solid-phase has been developed. These compounds, which are obtained in good yield and excellent purity, can be used for the synthesis of large lead-finding split-and-mix-libraries.

combinatorial chemistry - solid-phase synthesis - amides - acylations - peptides

References

<A NAME="RG43704ST-1A">1a</A> Boeijen A. Liskamp RMJ. Eur. J. Org. Chem.  1999,  2127 

<A NAME="RG43704ST-1B">1b</A> Georgiadis TM. Bainjdur N. Player MR. J. Comb. Chem.  2004,  224 

<A NAME="RG43704ST-1C">1c</A> Hamper BC. Snyderman DM. Owen TJ. Scates AM. Owsley DC. Kesselring AS. Chott RC. J. Comb. Chem.  1999,  224 

<A NAME="RG43704ST-2">2</A> Fletcher MD. Campbell MM. Chem. Rev.  1998,  98:  763 ; and references therein

<A NAME="RG43704ST-3A">3a</A> Pessi A. Pinori M. Verdini AS. Viscomi GC. J. Chem. Soc., Chem. Commun.  1983,  195 

<A NAME="RG43704ST-3B">3b</A> Bonelli F. Pessi A. Verdini AS. Int. J. Pept. Protein Res.  1984,  553 

<A NAME="RG43704ST-4">4</A> Pallai PV. Struthers RS. Goodman M. Moroder L. Wunsch E. Biochemistry  1985,  1933 

<A NAME="RG43704ST-5">5</A> Aleman C. Perez JJ. Int. J. Pept. Protein Res.  1994,  258 

<A NAME="RG43704ST-6A">6a</A> Jensen KJ. Alsina J. Songster MF. Vagner J. Albericio F. Barany G. J. Am. Chem. Soc.  1998,  5441 

<A NAME="RG43704ST-6B">6b</A> Alsina J. Jensen KJ. Albericio F. Barany G. Chem.-Eur. J.  1999,  2787 

<A NAME="RG43704ST-7">7</A> Reagents: e.g., HCTU, HATU, PyBOB. For a recent review see: Albericio F. Curr. Opin. Chem. Biol.  2004,  211 

<A NAME="RG43704ST-8">8</A> Duckworth AC. J. Am. Chem. Soc.  1962,  3146 

<A NAME="RG43704ST-9A">9a</A> Zirvi KA. Jarboe CH. J. Am. Chem. Soc.  1968,  183 

<A NAME="RG43704ST-9B">9b</A> Zirvi KA. Jarboe CH. J. Am. Chem. Soc.  1969,  926 

<A NAME="RG43704ST-10">10</A>

The purity was determined by HPLC at 254 nm and 214 nm and ¹H NMR.

<A NAME="RG43704ST-11">11</A>

Under the same conditions up to 90% cross-linking was found when phthaloyldichloride, isophthaloyldichloride or terephthaloyldichloride were used as diacidchlorides.

<A NAME="RG43704ST-12">12</A>

The results of more complex and non-symmetric acid and acid chlorides will be reported in due course.

<A NAME="RG43704ST-13">13</A>

The ratio was determined by HPLC at 254 nm and 214 nm and ¹H NMR.

<A NAME="RG43704ST-14">14</A>

The investigation of mono Boc-protected diamines as reactant and their subsequent deprotection on solid-phase is underway in our laboratories and will be reported in due course.