Proline functional group

The gelation molecule is basically composed of short a-hehcal segments in the form of a triple helix with numerous intramolecular bonds at room temperature see Section 9.13. The a-helical segments are interrupted by prohne and hydroxy proline functional groups. These groups disrupt the helical structure, yielding intervening portions of chain that behave hke random coUs, and which may be relatively free to develop intermolecular bonds. The subject has been reviewed by Djabourov (A7) and Mel nichenko et al. (A8). 

Treatment of the iV-protected 4-chloro-2-pyridone 151 with sodium prolinate in hot DMSO gives a prolinylpyr-idone, which may then be cyclodehydrated by acetic anhydride to give the pyridopyrrolizinone 152 <1994TL6985> (Scheme 42). The acetoxy group in 152 forms the basis for further functional group transformations, as outlined in... 

The formation of a dipeptide, for example, thus involves the condensation of the carboxyl group of one amino acid with the amino group of another. To achieve this apparently simple synthetic objective efficiently however, a number of reaction steps, requiring the use of appropriate functional group protection procedures (see p. 13), must be carried out. An illustrative synthesis is that of l-prolylglycine described in Expt 5.188, where the sequence is formulated in full. Note that proline is actually a secondary rather than a primary a-amino acid,... 

Functional group protection. The NH— group in proline is protected by acylation in the usual Schotten-Baumann manner with benzyl chloroformate to yield the benzyloxycarbonyl derivative (42). Correspondingly the —C02H group in glycine is protected by esterification in ethanol to form the ethyl ester, obtained as the hydrochloride (43) under Fischer-Speier conditions. 

This reaction is particularly suitable for the preparation of the Wieland-Miescher ketone 96, a very useful building block for construction of a broad variety of biologically active compounds such as steroids, terpenoids, and taxol. On the basis of the proline-catalyzed approach described above Barbas et al. recently reported an optimized procedure for formation of the chiral Wieland-Miescher ketone, 96 [105]. It has been shown that this synthesis (which comprises three reactions) can be performed as a one-pot synthesis. The desired product is obtained in 49% yield with enantioselectivity of 76% ee (Scheme 6.43). Here L-proline functions as an efficient catalyst for all three reaction steps (Michael-addition, cydiza-tion, dehydration). It is also worth noting that although many other amino adds and derivatives thereof were tested as potential alternative catalysts, L-proline had the best catalytic properties for synthesis of 96. This result emphasizes the superior catalytic properties of proline reported after previous comparative studies by the Hajos group [100, 101]. 

S )-Proline has been used in the synthesis of (fC)-clomoxir (44), a powerful hypoglycemic agent (Scheme 23.13).61 A proline derivative was used for the diastereoselective bromolactonization step. After hydrolysis of the auxiliary and further functional group transformations, the desired product was obtained in an overall yield of 45%. 

For subsequent transformations, it was necessary to protect the amino and C-2 carboxyl groups of fra/w-4-hydroxy-L-proline 34. Throughout all of the synthetic work to be described, A-benzoyl amide protection was chosen as it was felt likely that such a functional group would be resistant to most reaction conditions. Initially, a C-2 terf-butyl ester was chosen in an attempt to maximize the stereoselectivity in the planned enamine alkylation reaction however, later experiments revealed that the more straightforward to introduce C-2 methyl ester was equally effective. The preparations for all of the derivatives used are described here. 

Modelling can pinpoint functional groups and analyse catalytic interactions. In several enzymes, catalytic interactions have been identified via calculation. For example, in the flavin-dependent monooxygenases, para-hydroxybenzoate hydroxylase and phenol hydroxylase, a conserved proline residue was found from QM/MM modelling, which specifically stabilizes the transition state for aromatic hydroxy-lation.12,13... 

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