Trimethylsilyl Cyanide, a Reagent and (Co)Solvent “par Excellence” for Homogeneous Peptide Synthesis. A Strategy Circumventing Classical Drawbacks?

We have recently reported on the resistance of silylated (thio)ethers and esters against acid chlorides and anhydrides allowing even Head-to-Tail peptide syntheses (1). Selective N-amide and urethane formation in general are very easily performed after the amino acid has been simply pretreaeted with trimethylsilyl cyanide ("US-CN) shortly before the acylation reaction, and no other precautions have to be taken for side-chain protection except for amino-type functionalities (2). We want to report shortly on our prelimenary findings that the scope of possible N-acylations performed selectively without accompanying 0-acylatione with polyfunctional amino alcohols can be generalized leading to improved reaction conditions and yields. -5 5 5 -

Chemoselective N‐Acylations of Amino Alcohols Mediated by Trimethylsilyl Cyanide

Anteunis¹,

Becu²

1987

Simultaneous Use of N‐Fmoc and OTmse Protective Groups in the Synthesis of Peptolytic Sensitive Peptides

Vanfleteren

Anteunis

1988

Self Cite

ABSTRACT.The combined use of Fmoc (fluorenylmethoxycarbonyl) as N-protection and Tmse (trimethylsilylethyl) as 0-protection during demanding fragment condensation mediated by Bop-C1 (N,N'-bis(3-oxo-2-oxazolidinyl)phosphinyl chloride) has been explored in the preparation of useful synthons that are sensitive to acidic and even basic hydrolyBes. Stepwise deprotection by morfoline (Fmoc-deprotection) followed by F -mediated removal of Tmse results in a very effective peptide synthesis strategy, as exemplified by the preparation of i.a. Phg-MePhe-Thz. Similarly, combinations of N-B$c, 0-Tmse peptide esters are also possible that allow the preparation of H2-MePhe-Thz-OTmse (via Boc-MePhe-Thz-OTmse) without competitive DKP formation. I "Many bioactive (cyclic) peptides produced in nature possess a repetitive succession of N-alkylated aminoacid residues.We have demonstrated (1, 2) that such chain fragments are extremely sensitive to acid-catalyzed peptolysis (endopeptolysis), a fact which can be exploited for deliberate peptide chain rupture ( 3 ) . Although much slower, and therefore controlable, C'-terminal secondary aminoacids also can be splitt off from peptide acids in acidic conditions (4). These features are important in planning strategies for the preparation of N-alkylated peptides. In addition, the coupling of secondary aminoacids often demands strong activation. Mixed pivalic anhydrides ( 5 ) and phosphorous anhydrides (5-7) have been found superior in these cases. In our own laboratory we have gained experience in using N,N'-bis(Z0x0-3-oxazolidinyl)phosphinic chloride (Bop-C1) (6,9) although appreciable epimerization has been found ( 8 , 9) to occur in fragment condensations.We have recently reported on the synthesis of a linear precursor of Virginiamycin analog (10) (VS-analog) whereby 2 and BOC aminoprotection, combined with But ester protection was adapted in the strategy for the synthesis of the peptide material containing N-alkylated aminoacid residues. Other (orthogonal) protections would be wellcome and suitable groupings should meet following characteristics: (i) they should be cleavable by non-acidolytic methods and (ii) be removed by non-reductive procedures (this would allow concomittant use of a 2 group as a permanent blocking group); (iii) deprotection should leave an ester bond intact; and (iv) finally the protective groupings must be compatible with strong activation (11) e.g. mediated by BOP-C1.-505 -

”In situ“ Silylation with Trimethylsilyl Cyanide an Outstanding Protocol for Fast Peptide Synthesis a Synopsis

Anteunis

Becu

1990

The use of trimethylsilyl cyanide as a potent "in situ" silylating agent and its compatibility with most classical functionalities employed during solution phase peptide syntheses allows repetitive peptide chain elongations (including linear Head-to-Tail) with a minimum of chemical steps and manipulations. The outstanding features are: the upscaling facilities, the simplicity and the high purity of the final peptides exempt of stereomutation.