Self-immolative reaction

FIGURE 5.43 Signal transduction mechanism for dendritic molecule 42, through a self-immolative reaction sequence. 

As the central feature, the substrate contains a configurationally pure stereogenic center, which is sacrificied during the process ( self-immolative reaction ) The reaction itself transfers chirality intramolecularly from the existing stereogenic center to a new one via an unambiguous stereochemical pathway which is... 

In modem terminology, the core of Marckwald s definition is the conversion of an achiral substance into a chiral, nonracemic one by the action of a chiral reagent. By this criterion, the chiron approach falls outside the realm of asymmetric synthesis. Marckwald s point of reference of course, was biochemical processes, so it follows that modern enzymatic processes [30-32] are included by this definition. Marckwald also asserted that the nature of the reaction was irrelevant, so a self-immolative reaction or sequence such as an intermolecular chirality transfer in a Meerwein-Pondorf-Verley reaction would also be included ... 

The design of a first generation domino dendron is based on a molecular adaptor with three functional groups. Two identical functionalities are finked to reporter molecules and the third is attached to a trigger (Fig. 2 1). The cleavage of the trigger, initiates a self-immolative reaction sequence that... 

Scheme 22 Suggested mechanism for drug release from the dendritic platform. The enzymatic cleavage initiates a self-immolative reaction sequence based on an internal cyclization and a triple quinone-methide rearrangement...

The kinetic constants K(obs) for the three reactions were calculated by linear correlation with the measured plots (Table 2). The phenomenon of dendron 39 releasing its reporter group faster than dendron 38 occurs since the enzymatic substrate concentration in dendron 39 is twice that of dendron 38. The followed self-cyclization step is relatively fast and therefore the rate-hmiting step is cleavage of the enzymatic substrate. In dendron 40, additional self-immolative reactions occurred in order to complete the release of the reporter group (another intra-cyclization and 1,6-quinone-methide elimination). The overall rate of these reactions is slower than the rate of the enzymatic substrate cleavage and therefore the K( obs) for dendron 40 is relatively smaller. 

We also wanted to evaluate the disassembly of our dendritic system under physiological conditions. Thus, we synthesized a self-immolative AB6 dendron 32 with water-soluble tryptophan tail units and a phenylacetamide head as a trigger (Fig. 5.26) to evaluate disassembly in aqueous conditions. The phenylacetamide is selectively cleaved by the bacterial enzyme penicillin G amidase (PGA). The trigger was designed to disassemble through azaquinone methide rearrangement and cyclic dimethylurea elimination to release a phenol intermediate that will undergo six quinone methide elimination reactions to release the tryptophan tail units. 

Fig. 8.17. Mechanism of bioactivation of self-immolative carbamate prodrugs of cytotoxic amines. A bacterial nitroreductase coupled to a tumor-directed antibody reduces the prodrug to a hydroxylamine (Reaction a), which breaks down spontaneously to liberate the antitumor...

This type of stereoselective reaction, in which a chiral unit is created and another destroyed, has been termed self-immolative by Mislow39 and an asymmetric transfer process by Pracejus40. Both terms are in use. but the latter is gaining ground in the mutated form of "chirality transfer 41, which is most often applied to sigmatropic rearrangement reactions such as the following37 ... 

These reactions are characterized by the phenomenon that the frontier orbitals of the reactants maintain a defined stereochemical orientation throughout the w hole reaction. Most noteworthy in this respect, is the principle of orbital symmetry conservation ( Woodward-Hoffmann rules la), but the phenomenon is much more general, as shown by the following examples of Self-Immolative Stereoconversion or Chirality Transfer . This term describes processes by which a stereocenter in the starting material is sacrificed to generate a stereocenter in the product in an unambiguous fashion. This is, of course, the case in classical SN2-displacements. 

In these reactions the stereoselective formation of a new chiral unit is linked to the elimination of another (self-immolative asymmetric synthesis138). As far as the determination of configuration of the reaction products is concerned, a number of cases are discernible and these are described in Sections 4.3.3.2.4.1. and 4.3.3.2.4.2. 

Up to three chiral centers can directly be involved in the Claisen reairangonent (Equation 27). The configuration of the allylic chiral center at C-4 in (269) specifically relates to the configuration of the newly formed chiral centers in (271) and (273). Moreover, the ratio of diastereomeric transition states (270) and (272) greatly depends on die relative steric bulk of substituents R and Thus, generally a highly selective course of the reaction via pathway A or pathway B can be predicted. It is important to note that the primary chiral center is destroyed in die rearrangement ( self-immolative process ) and... 

The transfer of chirality from nitrogen to carbon has been observed for the [1,2] Stevens rearrangement of (/ )-benzyl(methyl)phenyl(2-propenyl)ammonium iodide55. The product of the reaction was assigned the S configuration based on degradation studies unfortunately, details regarding the extent of asymmetric induction in this unusual example of self-immolative chirality transfer are unavailable. 

Self-immolative processes are those that generate a new stereocenter at the expense of an existing one, either in a single reaction or in a sequence whereby the controlling stereocenter is deliberately destroyed in a subsequent step. 

From the viewpoint of organic chemistry, the present system is quite interesting the system involves self-immolative transfer of the axial chirality at the carbonyl group of the oxidized form into the central chirality at the 4 position of the corresponding reduced form and vice versa. In this sense, this reaction system may be claimed as asymmetric inductions of a brand-new type (chirality sink). There are a few reports of one-way transfer of a chirality into another chirality of different type (Meyers and Wettlaufer 1984). 

Performing a similar analysis as for the G1 amine-intermediate All, the HPLC results obtained ftom the G2 self-immolative dendrimer are shown in Fig 23a, in terms of PDFs. The self-immolative mechanism of the G2 dendrimer to release two All ftagments shows a similar kinetic pattern to the one observed for the G1 SID namely, an exponential temporal decay for AI2 concentration. As we expected the value of the rate constant for AI2 degradation was found to be equal to the one calculated for All (Figure 23b). This can be rationalized when one considers that in both G1 and G2 Aagmentation reactions, the rate-limiting step is the cyclization of the amine intermediate. An excellent... 

The core of the self-immolative polymer structure is an amino-benzylal-cohol that is connected via carbamate bonds. Reaction of the amine group with phenylchloroformate converts it into a phenylcarbamate which can be polymerised in a tin-catalysed reaction under exclusion of water. After... 

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