Self-immolative process

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 chiral pool has provided the backbone of many products. Carbohydrates [17] and amino acids are often used because of the high degree of functionality and the ready availability of these compounds from natural sources. Enalapril maleate contains the dipeptide L-alanyl-L-proline (Figure 16.1a) [18]. Aztreonam is derived from L-threonine (Figure 16.1b) [19].The chiral ester 2 was prepared from an amino acid derivative 1 (Figure 16.1c) [20]. In this transformation the original chiral center from L-cysteine was destroyed, similar to self-immolative processes [21]. 

As already discussed for Claisen rearrangements, Cope rearrangements as self-immolative processes are combined with conservation of chirality. In contrast to the Claisen rearrangements, however, only a few examples of the 1,3-chirality transfer in Cope rearrangements of acyclic systems have been reported in the literature. This is probably due to the fact that the synthesis of the optically substrates is as difficult as that of the products. 

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. 

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. 

The second example has been used in a stereoselective synthesis of a-alkylbenzylamines, as shown by the example illustrated in Scheme 20. Note that this sequence destroys the existing stereocenter. Because the original stereocenter is deliberately destroyed after the creation of a new one, the overall process constitutes a self-immolative chirality transfer . ... 

The stereoselective alkylation of tetrahydroisoquinoline pivalamides containing a stereocenter at the 3-position was reported in 1987 by Seebach. The self-immolative chirality transfer process illustrated in Scheme 26 affords only one diastereomer. Oxidative decarboxylation and reduction afford the alkylation products in 5% ee. 

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... 

Due to the concerted, suprafacial nature of the Claisen rearrangement a new stereogenic center (stereocenter) is created in the C-6 position in those cases where the, vp -hybridized C-4 carbon and the terminus of the allylic moiety is asymmetrically substituted, while the stereogenic center at C-4 is destroyed. What is transferred in "1.3-chirality transfer processes" is stereogenicity from C-4 to C-6. These processes have been called self-immolative processes372. 

Chirality transfer for the self-immolative [2,3] sigmatropic process is reversed upon inversion of the directing allylic center, an observation that has been employed effectively in the development of remote acyclic stereocontrol in the synthesis of several steroidal systems24-26, e.g., 18 or 19. 

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 dendrimers platform is designed to disassemble upon triggering through a process of self-immolative chain fragmentation, based on cycli-... 

Fluoropyruvaldehyde N,S-ketah (R)-32 can be prepared in good yields (up to 88%) and e.e. s (up to 82%) from a-(fluoroalkyl)-p-sulfmylenamines (7 )-2-19a-c (Scheme 9), through an unprecedented self-immolative tandem sequential process (34,35), consisting in a Pummerer reaction promoted by TFAA (.step 1) that provides the intermediate a-trifluoroacetoxy A -Cbz imine 36, followed by a 1,2-migration of the / -tolylthio group (step 2), triggered by addition of silica gel or aqueous base. 

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