Chiral memory, example

In 2008, Sakamoto and coworkers have reported the synthesis of optically active (3-lactams via photochemical intramolecular y-hydrogen abstraction reaction of thioimides [177]. This reaction provides the first example of a chiral-memory effect for the photochemical y-hydrogen abstraction reaction of thiocarbonyl or carbonyl compounds, and a useful synthetic methodology for preparing optically active (5-lactams (Scheme 78). 

Interestingly, a high chiral memory has been observed for this photochemical reaction, which probably involves triplet biradicals. For example, triplet-photosensitized electron transfer in the substrate of Scheme 9.4 leads to decarboxylation, followed by cyclization to a pyrrolobenzodiazepine with 86% enantiomeric excess... 

In certain cases, seemingly simple enolates can have a chiral memory effect . For example, treatment of a-imino lactam (5)-88 with f-BuOK in CD3OD for 6-13 days at 25°C gave the corresponding enantiomerically deuteriated a-imino lactam l-d-(S)-89 in quantitative yield with 98% D incorporation and ee 97% (equation 15) , via a conformationally chiral enolate. This methodology has been extended towards enan-tioselective alkylation of enolates. Excellent levels of enantioselectivity (ee 88%) were achieved for a-imino lactam (S)-SS using KHMDS as Brpnsted base and benzyl iodide as the electrophile . Interestingly, to prevent unwanted racemization of the intermediate enolate, the reaction time for deprotonation was lowered to 10 seconds, and to ensure rapid alkylation, 20 equivalents of Bnl were used . 

This method can be regarded as an example of memory of chirality,71 a phenomenon in which the chirality of the starting material is preserved in a reactive intermediate for a limited time. The example in Scheme 2-35 can also be explained by the temporary transfer of chirality from the a-carbon to the t-BuCH moiety so that the newly formed chiral center t-BuCH acts as a memory of the previous chiral center. The original chirality can then be restored upon completion of the reaction. 

Rychnovsky et al. considered the formation of achiral conformers from chiral molecules and trapping the prochiral radical with a hydrogen atom donor based on memory of chirality (Scheme 12) [41], The photo-decarboxylation of optically active tetrahydropyran 40 leads to an intermediate 43, which now does not contain a stereocenter. If the intermediate 43 can be trapped by some hydrogen atom source before ring inversion takes place, then an optically active product 41 will be formed. This is an example of conformational memory effect in a radical reaction. It was reported that the radical inversion barrier is low (< 0.5 kcal/mol) while the energy for chair flip 43 44 is higher (5 to... 

Many of the reactions discussed are not suitable to establish such a relationship, either because of the general stereochemical course of the reaction type, or because of the inherent symmetry of the substrate. Any reaction in which the pyramidal sp hybridized cyclopropane centers are converted to planar sp hybridized ones will lose any memory of the radical cation chirality or stereochemistry, unless it is transferred to a new chiral center generated in the course of the conversion. On the other hand, there are several reaction types which, given appropriate substrates, may be used to probe the stereochemical course of a cyclopropane radical cation reaction. For example, several hydrogen migrations have shown elements of stereoselectivity. Similarly, oxygenation reactions may have the potential to reveal some degree of stereoselectivity. 

The first reported attempt of using MIPs to control the stereochemical course of a reaction dates back to 1980, when the two research groups of Neckers and Shea published, simultaneously, examples of bulk polymers able to control the formation of the product by using a chiral template. Shea et al. reported that bulk polymers imprinted with stereochemically pure ( )-/ra/w-l,2,cyclobutane-dicarboxyilic acid (6) were able to keep a molecular memory of the asymmetry of the template [8]. In fact, this was transferred to an achiral substrate, such as fumaric acid (7), inducing a diastereoselective methylation, which led to trans-1,2,cyclopropane-dicarboxyilic... 

The third example clarifies the special feature of singlet photochemistry. In contrast with 34 and 36, the a-ketoester 39 reacts from the singlet state if irradiated in the presence of naphthalene as triplet quencher. Despite the low diastereoselectiv-ity, the chirality of the alanine derivative 39 is completely conserved during cycli-zation to the pyrrolidines 40a and 40b. This approach has been called the memory effect of chirality [16]. 

The imbalance between the two diastereoisomers is prolonged when the chiral D-tartrate is removed by precipitation with ethylendiamine thus leading to an enantioenriched chiral double-rosette made of achiral components with 90% e.e. The memory effect in this case is even stronger then in the former example with activation energy towards racemization as high as 119 KJ/mol and a half-life time of one week at room temperature. 

The phenomenon of memory of chirality [60] was recently extended to PET-cyclization reactions. An interesting example was the highly... 

Finally, we feel it is worthwhile to stress one more time the importance of the kinetic inertia in the (reversible) chiral transfer and memory processes of our porphyrin systems. Inertia provides evidence that the system is trapped in an energy minimum. In the above examples the minimum is local the real minimum is that reached from the achiral system whose formation involves the same enthalpic contribution of the chiral one but a more favourable entropic contribution. In particular, the network of electrostatic interactions ensures a quite deep local energy minimum (that is a high value of EA). 

Memory of chirality signifies asymmetric transformation in which the chirality of the starting materials is preserved in the configurationally labile intermediates (typically enolates) during the transformation. A typical example of memory of chirality is the alkylation of ketone 23 and a-amino acid ester 40. Before and after our first report on the memory of chirality in 1991, several related phenomena have been reported. 

In the early twentieth century Leuchs reported a surprising example of the a-chlorination of chiral ketone 73, which gave optically active 74 in the absence of additional chiral sources.36 From a mechanistic point of view, however, there remains some ambiguity. Possible mechanisms for the formation of optically active 74 include (1) asymmetric chlorination via an enol intermediate (i.e., memory of chirality), (2) direct electrophilic chlorination of the C-H bond at the stereogenic carbon center, (3) complex formation of an achiral enol intermediate with optically active 73, (4) resolution of dl-74 by co-crystallization with optically active 73, and (5) simultaneous resolution of dl-74. 

Chiral monomers of PHA can also be used for the synthesis of drugs or others used for fine chemicals [5, 6]. For example, one of the most common PHA monomers, 3-hydroxybutyrate (3HB), is a potential memory-enhancing drug when turned into 3HB methyl ester [32] (Fig. 6). Several amphiphilic proteins, namely PhaP or phasin attached to hydrophobic PHA granules, were used to aehieve protein purification or specific drug delivery (targeting) [26,28] (Fig. 7). It appears that PHA has many potential applications waiting to be exploited. 

Memory of chirality is an intriguing and powerfiil strategy in stereoselective organic synthesis" that has been applied to enolate chemistry,radical and photochemical processes, and reactions involving carboca-tion intermediates. Several examples of MOC are provided in Scheme 1.3. 

The following examples of transannular cyclizations in the context of natural product total synthesis and related settings are grouped according to the reaction types except the last section where memory of chirality is discussed. Because of space limitations, the authors apologize for the omission of many excellent examples. 

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