Download Mechanisms of Aspartimide Formation: The Effects of Protecting

yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the work of artificial intelligence, which forms the content of this project

Document related concepts

Biochemistry wikipedia, lookup

Nucleic acid analogue wikipedia, lookup

Proteolysis wikipedia, lookup

Fatty acid metabolism wikipedia, lookup

Genetic code wikipedia, lookup

Amino acid synthesis wikipedia, lookup

Fatty acid synthesis wikipedia, lookup

Metalloprotein wikipedia, lookup

Peptide synthesis wikipedia, lookup

Metabolism wikipedia, lookup

Biosynthesis wikipedia, lookup

Oligonucleotide synthesis wikipedia, lookup

Citric acid cycle wikipedia, lookup

Hepoxilin wikipedia, lookup

Butyric acid wikipedia, lookup

Specialized pro-resolving mediators wikipedia, lookup

15-Hydroxyeicosatetraenoic acid wikipedia, lookup

Ribosomally synthesized and post-translationally modified peptides wikipedia, lookup

Figure 2. Synthesis of Boc-Asp (O,~;Hex)-OH from cyclohexene by acid catalysis.
Boc-Aap-OBzl _ _ _K;.;.F;._--4•
Figure 3. Synthesis of Boc-Asp (O~Hex)-OH by displacement of cyclohexyl bromide.
Figure 4. Synthesis of Boc-Asp(O,Hex) by carbodiimide condensation of cyclohexanol.
H-Asp-OH _ __.,.. NH
£_Hex, R2 = H
H, R2 = £_Hex
R2 = £_Hex
FigureS. Synthesis of Asp(O.cHex) from aspartic acid.
slow and led to significant amounts of
N-acylurea byproducts 5. The formation of the symmetrical anhydride or
the use of an additive such as 1hydroxybenzotriazole (HOBt) did not
accelerate the reaction or alter the
amount of side products. It has been
reported that 4-dimethylaminopyridine
is a powerful acylation accelerating
reagent that also suppresses the formation of N-acyl urea (14,27). When 1020 mol% of this catalyst in methylene
chloride was used, the esterification
proceeded extremely rapidly and was
complete in 1 h. However, theN-acyl
urea side product still accounted for 35% of the yield. It was nonsuppressible, even with additives such as
HOBt, or by maintaining a low temperature. In order to avoid the need for
extensive chromatographic purification, a water soluble carbodiimide was
used, since the side product 6 could be
removed in an aqueous workup. The
diester 3 was thus obtained in 90%
yield. After hydrogenolytic removal of
the a-benzyl ester, Boc-Asp-(O~Hex)­
OH 4 was obtained as a solid in 85%
yield. Similarly, Boc-Glu(O~Hex)-OH
was obtained in 82% yield. To test for
racemization that might occur during
this preparation, Boc-Asp-(O~Hex)­
OH was treated with HF to remove all
the protecting groups. The free Asp
was shown to be free from racemization using the Manning and Moore procedure (19,24). This synthetic procedure is efficient and gives high yields
and produces pure products.
A practical and direct laboratory
synthesis of Boc-Asp(O~Hex)-OH (4)
was also undertaken, starting from
aspartic acid and cyclohexanol, using
concentrated sulfuric acid as the catalyst (Figure 5) (3). The reaction
proceeded much too slowly at room
temperature and required elevated tern.
perature (50° C) for satisfactory yield.
After 24 h, the yield of desired product
1 was found to be 75% based on the
ion-exchange chromatography analysis
of the reaction mixture. Fractional
crystallization of the correct product in
the presence of the starting material
(Asp), the a-isomer (AspO~Hex) and
the diester 9 was found to be difficult,
and 35% of Asp(O~Hex) was obtained
by ion-exchange chromatography. The
product 7, when examined under analytical ion-exchange chromatography
(r.t. 124 min), was found to be free of
Asp (r.t. 29 min) and its diester, but
contained 0.5 to 1.5% of Asp-O~Hex 8