Peptide alcohols

Mergler, M. Nyfeler, R. Rapid Synthesis of fully Protected Peptide Alcohols, Communication from Bachem, Bubendorf, CH, 1990. 

Peptide aldehydes 1 can be synthesized effectively by the oxidation of peptide alcohols 15, which are readily available without racemization by reduction of peptide esters 9 with sodium borohydride-lithium chloride (Scheme 5). The peptide alcohols 15 can be readily oxidized to afford enantiomerically pure aldehydes using Parikh-Doering or Dess-Martin reagents. This route is less popular than the previously described reductive methods due to (1) the sensitivity of the aldehydes to further oxidation, (2) racemization under the reaction conditions, and (3) instability of the products under the reaction conditions. 

Popular oxidation reactions of peptide alcohols such as the Parikh-Doering or Dess-Martin in addition to older oxidation reactions such as Collins, pyridinium chlorochromate, or Swern oxidation afford racemization free productsJ9121415 37-39 Oxidations using pyridinium dichromate results in racemization and low yields of product.[l3 Oxidation reactions have also been utilized in semisynthetic pathways of peptide aldehydes (1) peptide aldehydes are obtained through the enzymatic acylation of a peptide ester to an amino alcohol with subsequent oxidation of the peptide alcohol to afford the aldehyde, and (2) peptide aldehydes can also be obtained by direct enzymatic oxidation of the peptide alcohol by alcohol de-hydrogenaseJ40 41 ... 

Scheme 6 Dess-Martin Oxidation of a Peptide Alcohol 391...

Semisynthetic enzymatic oxidation of peptide alcohols employs equine liver alcohol dehydrogenase. Amino alcohols with nonpolar side chains and Z-Om[CH2OH] worked as effective substrates while polar amino alcohols such as H-Arg[CH2OH] and H-Lys[CH2OH] failed as substrates. To attain complete oxidation, semicarbazide was present in the reaction mixture to immediately trap the aldehyde, and flavin mononucleotide was used to oxidize the NADH to NAD+, which serves to oxidize the alcohol 41] Configurational stability was confirmed by NMR spectroscopy as in the case of Ac-Phe[CH2OH], which was prepared by sodium borohydride reduction of Ac-Phe-H 4 1... 

A different semisynthetic method involves the acylation of an amino alcohol with a peptide ester and the resulting amino alcohol is subsequently oxidized to the aldehyde 40 The acylation of H-Phe[CH2OH] with the peptide ester Z-Ala-Ala-Leu-OMe is carried out in 5% DMF/MeCN with the subtilisin distributed on the surface of macroporous silica gel. The resulting peptide alcohol is oxidized under mild conditions using anhydrous dimethyl sulfoxide and 20-fold excess of acetic anhydride with purification via flash chromatography 40] Z-Phe[CH2OH] has been oxidized under these conditions and the optical rotation indicates little epimerization as compared to literature values 11 40 ... 

The peptide aldehydes, Boc-Tyr-G Iy-GIy-Phe-Leu-H, and Boc-Tyr-Gly-Gly-Phe-Met-H, can be oxidized in the same manner as the above peptide alcohols except that S03-Py complex (4 equiv) and TEA (4 equiv) were used. 

The application of antibiotics as chiral selectors has resulted in the successful resolution of almost all types of neutral, acidic, and basic racemic molecule. These antibiotics have been used for the enantiomeric resolution of amino acids, their derivatives, peptides, alcohols, and other pharmaceuticals. The selectivities of the most commonly used antibiotic-based (vancomycin, teicoplanin, and ristocetin A) CSPs varied from one racemate to another and are given in Table 1. Vancomycin was used for the chiral resolution of amino acids, amines, amides, imides, cyclic amines, amino alcohols, hydantoins, barbiturates, oxazolidinones, acids, profens, and other pharmaceuticals. Teicoplanin was found to be excellent chiral selector for the enantiomeric resolution of amino acids, amino alcohols, imides, peptides, hydantoins, a-hydroxy and halo acids, and oxazolidinones, whereas ristocetin A is capable of chiral resolution of amino acids, imides, amino... 

Key Words Acidolytic cleavage backbone amide linkage bioconjugate chemical ligation combinatorial chemistry handle linker peptide alcohol peptide aldehyde peptide ester peptide thioester protecting group solid support. 

Besides C-terminal and side-chain attachment of the first amino acid derivative onto the solid support, there is a third possibility, which involves attachment of a backbone amide nitrogen to an appropriate handle/support, as shown in Scheme This strategy represents a novel and general concept for the solid-phase preparation of peptides having a variety of C-terminal functionalities, including peptide alcohols, A,A-dialkylamides, esters, thioesters, aldehydes, and head-to-tail cyclic peptides. 

Besides the methods described above for the side-chain anchoring of Ser and Thr, the 3,4-dihydro-2//-pyran-2-functionalized-resin and handle 331 23,124] Table 3) allows the preparation of peptide alcohols by treatment with TEA in the presence of scavengers. Furthermore, the alkylation of Fmoc amino alcohols with a diphenyldiazomethane polymeric resin 34 gives rise to a benzhydryl ether, which can be cleaved with TFA/CH2CI2 (2 98) to give protected peptide alcohols. 

Peptide aldehydes can be synthesized by backbone attachment of the corresponding amino acetal to a BAL resin 30.b A modification of this method involves the preparation of a peptide alcohol (with the free alcohol group) by side-chain attachment, and after elongation of the peptide chain the alcohol is converted into the aldehyde using sulfur trioxide and pyridine.t l... 

Stir the peptide-resin (l.Og, 0.4mmol) in anhyd, peroxide-free THF (30mL), ensuring the exclusion of moisture. (Check the THF for peroxides and purify as described in Section 4.3.5.1.12). Add LiBHt (58 mg, 2nunol) slowly in portions and stir at rt for 1 h. Slowly add glacial AcOH (l.OmL) to destroy excess hydride, filter on a fritted funnel, wash the resin with small portions of AcOH, and lyophUize the soln directly. Purify the peptide alcohol by a suitable procedure. The whole procedure converts Asp and Glu esters into alcohols and deblocks Tyr[Z(Br)] groups. 

A 9-phenylfluoren-9-yl-based linker can also be used for the attachment of alcohols. This Hnker shows improved acid stability compared with the trityl Hnker. The Hnker has been appHed to the synthesis of a peptide alcohol [71]. 

Diacid-based linkers, such as the succinic linker 21, have been described to prepare alcohols. The procedure involves the esterification of the starting alcohol with succinic anhydride and DMAP to yield the hemiester that is anchored to an amino containing-resin by means of an amide bond. The bound alcohol is then elaborated and finally released with a nucleophile. Oligosaccharides have been assembled following this approach and released with aqueous ammonia or sodium methoxide in methanol-dioxane [73, 74]. Peptide alcohols have also been prepared with the succinic linker on BHA resin and released by treatment with NH3 in MeOH for 72-96h or hydrazine in DMF for 24h [75]. Similarly, hydroquinone-0,0 -diacetic acid (linker 22) has been used to link nucleosides to polystyrene or CPG supports. Cleavage of oligonucleotides was carried out with aqueous ammonia [76]. Other diacids with a similar function have also been described [77]. 

HMBA resin, an aminomethyl polystyrene resin acylated with 4-(hydro-xymethyl)benzoic acid. It is completely resistant towards treatment with acids (even liquid HE), and enables on-resin side-chain deprotection. The highly versatile linker is cleaved by a variety of nucleophiles such as hydroxide ions (to give peptide acids), alcohols (to give esters), ammonia or amines (to give amides), hydrazine (to give peptide hydrazides), or UBH4 (to give peptide alcohols) [R. C. Sheppard, B. J. Williams, Int.J. Pept. Protein Res. 1982, 20, 451]. 

Peptide aldehydes have been synthesized both by oxidation of peptide alcohols and by reduction of peptide acids. Both routes are restricted to peptides that do not contain other functional groups sensitive to the reducing and oxidizing reagents, and the oxidative route at least, subjects the whole peptide to a reaction which sometimes gives only poor yields. To provide increased flexibility of synthesis of peptide aldehydes, I have explored another synthetic route, which involves the preparation from a-amino alcohols of suitably protected a-amino aldehydes, the coupling of the protected aldehydes to preformed peptides, and the subsequent removal of protection from the aldehyde group. This type of synthesis has... 

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