THE CHIRAL TEMPLATE APPROACH

CONNECTIVITY FRAMEWORK FUNCTIONALITY PROBLEM CENTERS STEREOCHEMISTRY 

BIOMIMETICALLY-BASED CONCEPT-BASED KEY TRANSFORMATIN-BASED I LL DO IT MY WAY APPROACH 

CHOOSE STARTING MATERIAL EVALUATE CRITICAL STEPS PRACTICALITY/INNOVATION 

COST/FEASIBILITY LOGISTICSATIMING METHODOLOGY PROTECTIVE GROUPS REACTION/REAGENT DESIGN 

Partially hidden chiral templates in punctatin A, a-kainic acid, forskolin and an amino acid from pepstatin 

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Structure goal strategies. Identify a potential starting material, building block, retrosynthetic subunit, or initiating chiral element (.see the chiral template approach in sec. 10.9). 

The last approach to chiral synthesis begins with a chiral precursor whose components will be integrated into the final product, which is the chiral template approach (sec. 10.9). The examples of asymmetric syntheses involving Diels-Alder templates are as varied as the targets. One typical example is by Oppolzer, who reported an asymmetric synthesis of pumiliotoxin C via Diels-Alder cyclization of 303, prepared from (/ )-norvaline, to give 304.248... 

Carbohydrates are efficient chiral templates and have been used in the Diels-Alder reaction. Sherbum used L-ascorbic acid as a template to synthesize 305.249 Heating this compound in refluxing toluene led to a 96 4 mixture of 306 and 307 (68% yield). The chirality inherent in the carbohydrate precursor provides the needed facial selectivity that is transferred to the cycloadduct product. The use of chiral templates for preparing Diels-Alder precursors will undoubtedly increase in importance. As the need for enantiomerically pure material increases, the chiral template approach coupled with the power of the Diels-Alder reaction will be an effective combination. 

In the chiral template approach you fix one or more as3nnmetric centres at the outset and carry the chirahty through to the product. 

Last year, a short enantioselective total synthesis of herbarumin III (42) in 11% overall yield was published the approach applied uses Keck s asymmetric allylation and Sharpless epoxidation to build the key fragment. Esterification with 5-hexenoic acid and a RCM was used to yield 42. Finally, another asymmetric synthesis of herbarumin III (42) was carried out using (R)-cyclohexylidene glyceraldehyde as the chiral template. The key steps of the synthesis were the enantioselective preparation of the... 

There have been two main approaches to the development of dipolarophile facial selectivity (1) the use of chiral substrates, templates, and auxiharies and (2) the use of chiral rhodium catalysts [35]. In one of the earhest examples of chiral substrate selectivity, Pirmng and Lee reported a selective hydroxy-directed cycloaddition with chiral hydroxy-substituted vinyl ethers [95]. This effort was followed by a number of chiral template approaches to diastereocontrol, including the use of (R)- or (S)-phenylglycinol to form a cycHc phenyloxazinone for the facially selective cycloaddition of isomtinchnones [96, 97]. Padwa and Prein demonstrated acycHc diastereofacial control in the cycloaddi-... 

For intramolecular 1,3-dipolar cycloadditions, the application of nitrones and nitrile oxides is by far most common. However, in increasing frequency, cases intramolecular reactions of azomethine ylides (76,77,242-246) and azides (247-259) are being reported. The previously described intermolecular approach developed by Harwood and co-workers (76,77) has been extended to also include intramolecular reactions. The reaction of the chiral template 147 with the alkenyl aldehyde 148 led to the formation of the azomethine ylide 149, which underwent an intramolecular 1,3-dipolar cycloaddition to furnish 150 (Scheme 12.49). The reaction was found to proceed with high diastereoselectivity, as only one diaster-eomer of 150 was formed. By a reduction of 150, the proline derivative 151 was obtained. 

In another study,a chiral templating procedure was employed to direct the helicity of an oligo-bipyridine, double-stranded copper(I) helicate. The strategy employed is illustrated in Figure 6.29 in which spiro-bisindanol 71 and dimethyl-biphenic acid 72 were employed as the chiral template starters for the twisting process inherent in helicate formation. The above approach serves as a model for a general route towards the synthesis of enantio-pure helicates and is also of considerable intrinsic interest since it illustrates the manner by which stereochemical information may be transmitted over nanometer distances. 

In this work a new approach is desribed, which can help to understand ED over heterogeneous catalysts We also hope that this approach can be used to find new modifiers for enantioselective heterogeneous catalytic reactions. The basis for this approach is the steric shielding known in organic chemistry [7,8]. A chiral template molecule can induce shielding effect (SE) in such a way that it preferentially interacts with one of the prochiral sites of the substrate. If a substrate is preferentially shielded its further reaction can take place only fi"om its unshielded site resulting in ED. 

Harwood and co-workers (105) utihzed a phenyloxazine-3-one as a chiral derived template for cycloaddition (Scheme 4.50). An oxazinone template can be formed from phenylglycinol as the template precursor. The diazoamide needed for cycloaddition was generated by addition of diazomalonyl chloride, trimethyl-dioxane-4-one, or succinimidyl diazoacetate, providing the ester, acetyl, or hydrogen R group of the diazoamide 198. After addition of rhodium acetate, A-methylmaleimide was used as the dipolarophile to provide a product that predominantly adds from the less hindered a-face of the template in an endo fashion. The cycloaddition also provided some of the adduct that approaches from the p-face as well. p-Face addition also occurred with complete exo-selectivity. Mono- and disubstituted acetylenic compounds were added as well, providing similar cycloadducts. 

Using an elegant approach, Che et al. prepared chiral mesoporous silica using bio-inspired surfactants [63]. The trimethylammonium group of the quaternary amine used as a surfactant in the synthesis of MCM-41 (CTAB) was replaced by L-alanine. The chirality of the amino acid in the polar head of the surfactant induces chirality in the micelle used as template (see Figure 3.15). This simple modification in the surfactant allowed the preparation of the first chiral mesoporous silica with tunable pore size and ordered porosity. A key step in this synthesis is the transfer of the chirality from the surfactant to the solid, which was accomplished by electrostatic interaction between the terminal amino acid and the... 

While technically simpler than the covalent approach, the self-assembly approach creates more heterogeneous sites and also requires templates with specific functional groups.8 Since sol-gel chemistry is aqueous based, H-bonding interactions are significantly weaker compared to the conventional organic polymerization methods. Often, hydrophobic effects and ionic interactions are utilized. A number of other examples of the noncovalent approach to imprinting in sol-gel-derived materials are provided in recent reviews.5 17 In the sections below, the focus will be on some of the newer aspects of small molecule imprinting in silica that involve the use of chiral templates... 

Although the trend is changing, the use of chiral auxiliaries, such as oxazolidinones, is often thought of as too expensive. There are examples where this approach has been taken to large scale (Chapters 23 and 24). The use of a cheap chiral template can also have advantages (Chapter 25). 

As with another class of compounds, the scale of synthesis and time required at the research stage before product can be made influence which method is finally used. At small scale, a plethora of methods exist to prepare amino acids, in addition to isolation of the common ones from natural sources. The majority of these small-scale reactions rely on the use of a chiral auxiliary or template. At larger scale, asymmetric hydrogenation and biocatalytic processes come into their own. For the amino acids approaching commodity chemical scales, biological approaches, either as biocatalytic or total fermentation, provide the most cost-efficient processes. 

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