Ketomethylene isosteres

In 2003, a new Sml2-mediated carbon carbon bond-forming reaction was reported by Skrydstrup for the direct synthesis of peptide mimics for evaluation as protease inhibitors.90 For example, the low-temperature coupling of 4-thiopyridyl ester 100, derived from Cbz-protected phenylalanine, with the dipeptide acrylamide 101 gave the peptide analogue 102 in a 61% yield (Scheme 7.43). Ketone 102 represents a ketomethylene isostere of the tetra-peptide Phe Gly Leu Phe. Ketomethylene isosteres and the corresponding reduced analogues, hydroxyethylene isosteres, represent important and pharmaceutically relevant classes of protease inhibitors.91,92... 

Stteinmetzer T, Zhu BY, Konishi Y (1999) Potent bivalent thrombin inhibitors replacement of the scissile peptide bond at P(l)-P(l) with arginyl ketomethylene isosteres. J Med Chem 42 3109-3115... 

We synthesized the ketomethylene, , and hydroxyethylene,8, isosteres of a Leu-Ala dipeptide sequence in order to explore the importance of the two extra atoms in statine relative either to substrate or to the tetrahedral intermediate (Figure 1) in another aspartyl protease system. The compounds were synthesized by the routes outlined in Scheme I. This route was chosen so as to provide steric control at C-2 and C-5 of both 7 and 8 as well as to provide ready access to C-4 labeled analogs. Details of the synthesis have been described else-where.(23.24) Inhibitors were synthesized in which Leu-Ala dipeptide Isosteres replaced either Sta or Sta-Ala in known pepstatin analogs. Inhibition of porcine pepsin was determined using the reported spectrophotometric assay (Table I).(25)... 

J. V. N. Vara Prasad and D. H. Rich, Addition of allylic metals to ot-amino aldehydes. Application to the synthesis of statine, ketomethylene and hydroxyethylene dipeptide isosteres. Tetrahedron Lett. 37 1803 (1990). 

Biologically active molecules containing amide bonds suffer usually of pharmacokinetic liability. In order to increase their stability, bioisosteric transformation of the carboxamide have been performed and yielded a lot of successful examples especially in the area of petidomimetic. The isosteric replacements for peptidic bonds have been summarized by Spatola and by Fauchere. " The most used and well-established modihcations are iV-methylation, configuration change (o-conhguration at Ca), formation of a retroamide or an a-azapeptide, use of aminoisobutyric or dehydroamino acids, replacement of the amidic bond by an ester [depsipeptide], ketomethylene, hydroxyethyl-ene or thioamide functional group, carba replacement of the amidic carbonyl, and use of an olefinic double bond (Figure 15.33). 

A simple, steieocontrolled synthesis of monofluoro ketomethylene dipepdde isosteres has been developed. N-Tritylated ketomethylene dipeptide isosteres, prepared from N-tritylated amino acids, are converted to their Z-TMS enol ethers and fluorinated with Selectfluor. There is cooperative stereocontrol between the allylic N-tritylamine group and the alkyl group at C-2. The method is short (6 steps) and diastereoselective (85->9S%) and enantioselective (>95%),... 

In the last several years we have developed a new general strategy for the synthesis of peptide isosteres that utilizes an acetoacetic ester synthesis to assemble the y-ketoester core unit.(9-i7) By using Cbz-protected amino acids 1 and scalemic a-triflyloxy esters 2 as alkylating agents, the densely functionalized, fiilly elaborated ketomethylene peptide isosteres 3 can be assembled quickly, efficiendy and with good stereocontrol at both C-2 and C-5 (Scheme l).(i2)... 

These model studies provided the impetus to extend this methodology to the preparation of monofluoro ketomethylene peptide isosteres. Monofluoro ketomethylene peptide isosteres 15 (Figure 3) could be very interesting peptide mimetics since they are true peptide isosteres whose binding region can be extended in both the P and P directions by standard methods. Moreover the ketone carbonyl group is rendered more electrophilic by the fluoro substituent but yet is only partially hydrated ( 20-50%) upon treatment with water so that interaction with several different types of proteases is possible. The first synthesis of a monofluoro ketomethylene peptide isostere utilized a homoenolate equivalent to assemble the isostere skeleton and fluorination of a silyl enol ether to introduce the C-3 fluorine substituent.(20) Overall this route was long (>10 steps) and the introduction of fluorine was completely non-stereoselective. 

A series of (2R, 55)-N-tritylated ketomethylene peptide isosteres 4a-e were converted to their corresponding TMS-enol ethers 16a-e with NaHMDS/ TMSCl (Scheme 7). Only a single enol geometry could be detected in the nmr and it was assigned as the Z-isomer because of Ae base employed.(i9) These were fluorinated with Selectfluor to give monofluoro ketomethylene peptide isosteres 17a in good yields. 

When ketomethylene isosteies 4f,g (25,55) which have the opposite (and unnatural) 25 stereochemistry at C-2, were used in the same sequence, comparable yields of monofluoro ketomethylene peptide isosteres were obtained, however the diastereoselectivity was much lower (Scheme 8). Since only a single TMS-enol ether 16 was produced on enolization, the reduced diastereoselectivity must occur in the fluorination step. The major diastereomer was assigned the 35 configuration on the basis of nmr. 

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