From the Chiral Pool

As resolution procedures are often tedious, and asymmetric synthesis provides chiral products with only limited enantiomeric excess, it seems an obvious strategy to use an enantiomerically pure material from the chiral pool to construct chiral ferrocenes by incorporating these compounds in the final product. As such chiral materials, cheap terpenes (menthone, a- and -pinene, and camphor) were chosen. The reaction of ferrocene with carbonyl compounds under acidic conditions is a very convenient way to obtain directly a-ferrocenylalkyl carbocations. The starting materials were therefore converted to aldehydes or their enol ethers (menthone and camphor are too sterically hindered and do not react with ferrocene). Joint dissolution of the aldehydes and ferrocene in trifluoroacetic acid or in the trichloroacetic acid/ fluorosulfonic acid system gives a-ferrocenylalkyl carbocations, which can either 

as shown in Fig. 4-10, three isomeric enantiomerically pure amines can be prepared from the same starting material by the appropriate choice of the reaction conditions [76]. 

An enantiomerically pure aldehyde, (lR,2R,3R)-2,7,7-trimethylbicyclo[3.1.1]hep-tane-2-aldehyde, is produced from a-pinene by rhodium-catalyzed hydroformylation [79, 80]. Initially, reaction with ferrocene under acidic conditions leads to a 1 1 mixture of diastereoisomeric cations, but on standing for a few hours at room temperature, isomerization by rotation around the ferrocene — cationic carbon bond to the thermodynamically more stable cation (with configuration (R) at the cationic center) occurs (Fig. 4-11). An enantiomerically pure amine is available by trapping of this cation by azide and reduction [75]. Analogously, the isomeric aldehyde with the bicyclo [2.2.1] heptane structure is formed by hydroformylation of a-pinene with cobalt catalysts [79, 80] and was used as the starting material for an isomeric series of chiral amines [75]. 

So far, all approaches to chiral ferrocenes have started with unsubstituted ferrocene and the chirality introduced later. If a chiral derivative of cyclopentadiene could be prepared, it would be possible to obtain a chiral ferrocene derivative by simple reaction with FeClj and base. This concept has been realized by several groups. 

Chiral starting materials are not only accessible from natural products, but also by asymmetric synthesis. Thus, as shown in Fig. 4-12c, a prochiral fulvene was 

From tartaric acid, a chiral cyclopentadiene was derived that gave a ferrocene derivative having a phosphine-substituted dioxolane in each ring (Fig. 4-12 b) 

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Clearly, there is a need for techniques which provide access to enantiomerically pure compounds. There are a number of methods by which this goal can be achieved . One can start from naturally occurring enantiomerically pure compounds (the chiral pool). Alternatively, racemic mixtures can be separated via kinetic resolutions or via conversion into diastereomers which can be separated by crystallisation. Finally, enantiomerically pure compounds can be obtained through asymmetric synthesis. One possibility is the use of chiral auxiliaries derived from the chiral pool. The most elegant metliod, however, is enantioselective catalysis. In this method only a catalytic quantity of enantiomerically pure material suffices to convert achiral starting materials into, ideally, enantiomerically pure products. This approach has found application in a large number of organic... 

Stork and Takahashi took -glyceraldehyde synthon from the chiral pool and condensed it with methyl oleate, using lithium diisopropyl amide as catalyst for the mixed aldol reaction, leading to The olefinic linkage is a latent form... 

Catalytic kinetic resolution can be the method of choice for the preparation of enantioenriched materials, particularly when the racemate is inexpensive and readily available and direct asymmetric routes to the optically active compounds are lacking. However, several other criteria-induding catalyst selectivity, efficiency, and cost, stoichiometric reagent cost, waste generation, volumetric throughput, ease of product isolation, scalability, and the existence of viable alternatives from the chiral pool (or classical resolution)-must be taken into consideration as well... 

Highly uMtr-diastereofacial selective cycloaddition of isoprene (2) with 4-isopropyl-2-cyclohexenone allowed a short regiocontrolled and stereocon-trolled synthesis [13] of jS-cadinene and (y2-cadinene, Scheme 3.3). High anti-diastereofacial selectivity also occurs in the Diels-Alder reaction of optically active cyclohexenones 6-9 (Figure 3.2), readily available from the chiral pool, with open chain dienes [14-16]. Their cycloadducts are valuable intermediates in the synthesis of optically active sesquiterpenes in view of the easy conversion of the gem-dimethylcyclopropane and gem-dimethylcyclobutane in a variety of substituents. 

In conclusion, many chiral pyridine-based ligands have been prepared from the chiral pool and have been successfully tested as ligands for the copper- or rhodium-catalyzed cyclopropanation of olefins. Alfhough efficient systems have been described, sometimes leading interestingly to the major cis isomer, the enantioselectivities usually remained lower than those obtained with the copper-bis(oxazoline) system. 

A review was published covering recent progress in the stereoselective synthesis of piperidines <00S1781>. Routes described in detail include those derived from the chiral-pool, chiral auxiliaries, and catalytic asymmetric methodology. 

One of the fundamental operations in organic synthesis remains the stereoselective reduction of carbonyl groups1241. In a process related to that reported by Hosomi et u/.[25], using hydrosilanes as the stoichiometric oxidant and amino acid anions as the catalytic source of chirality, a variety of ketones were reduced in good to excellent yield and with good stereoselectivity1261. This process reduces the amount of chiral catalyst needed and utilizes catalysts from the chiral pool that can be used directly in their commercially available form. 

At that time, as now, the enantiomers of many chiral amines were obtained as natural products or by synthesis from naturally occurring amines, a-amino acids and alkaloids, while others were only prepared by introduction of an amino group by appropriate reactions into substances from the chiral pool carbohydrates, hydroxy acids, terpenes and alkaloids. In this connection, a recent review10 outlines the preparation of chiral aziridines from enantiomerically pure starting materials from natural or synthetic sources and the use of these aziridines in stereoselective transformations. Another report11 gives the use of the enantiomers of the a-amino acid esters for the asymmetric synthesis of nitrogen heterocyclic compounds. 

One purpose of our work is to mimic the chiral environment of the enzymes. Therefore, we thought it a reasonable goal to supply chiral models for the active sites of metalloenzymes. This was achieved before by Alsfasser et al. 113) or Vahrenkamp et al. 114) via amino acids that have been incorporated into the ligand systems. Modification of Tp ligands by chiral pyrazoles derived from the chiral pool is another way to chiral W,W,iV tripod ligands and has been achieved before by W. B. Tolman and coworkers (115). Thus, first we focused on the synthesis of a racemic mixture of a chiral NJtl,0 scorpionate... 

Modification of Tp ligands by chiral pyrazoles derived from the chiral pool is another way to chiral N,N,N tripod ligands and has been achieved before by Tolman and coworkers (115). 

TABLE 11.1. Representative substances from the chiral pool ... 

In connection with the synthetic work directed towards the total synthesis of polyene macrolide antibiotics -such as amphotericin B (i)- Sharpless and Masamune [1] on one hand, and Nicolaou and Uenishi on the other [2], have developed alternative methods for the enantioselective synthesis of 1,3-diols and, in general, 1, 3, 5...(2n + 1) polyols. One of these methods is based on the Sharpless asymmetric epoxidation of allylic alcohols [3] and regioselective reductive ring opening of epoxides by metal hydrides, such as Red-Al and DIBAL. The second method uses available monosaccharides from the "chiral pool" [4], such as D-glucose. 

Most of the useful auxiliaries are chiral amine or alcohol derivatives readily available from the chiral pool, and most of them possess rigid cyclic or bicyclic structures to allow efEcient differentiation of the two competing diastereomorphic transition states. In some cases, additional rigidity was achieved with the aid of an external chelating Lewis acid (entries 6, 10, 12). In certain cases, however, acyclic auxiliaries may also be useful (see entry 15). 

Chiral benzamides I and the pyrrolobenzodiazepine-5,11-dio-nes n have proven to be effective substrates for asymmetric organic synthesis. Although the scale of reaction in our studies has rarely exceeded the 50 to 60 g range, there is no reason to believe that considerably larger-scale synthesis will be impractical. Applications of the method to more complex aromatic substrates and to the potentially important domain of polymer supported synthesis are currently under study. We also are developing complementary processes that do not depend on a removable chiral auxiliary but rather utilize stereogenic centers from the chiral pool as integral stereodirectors within the substrate for Birch reduction-alkylation. 

Consequently, a number of stereoselective syntheses have been developed leading to a variety of paraconic acids either in racemic or in enantiopure form, using starting materials from the chiral pool, chiral auxiliaries or applying catalytic asymmetric methodology. Moreover, a number of strategies leading to paraconic acids in a non-stereoselective way have been reported, which will not be described in detail in this review [4, 5]. 

Carbohydrates are configurationally stable, easily available in enantiopure forms from the chiral pool, and they show a high density of chiral information per molecular unit. Their polyfunctionality and structural diversity fadhtate their tailor-made modification, derivatization, and structural optimization for a broad spectrum of synthetic applications. While derivatives of various saccharides have already been utilized as versatile starting materials and building blocks for chiral auxiliaries, ligands, and reagents [330] their obvious role as precursors for the... 

Stereocontrol in the synthesis of such compounds is quite challenging and the use of synthons from the chiral pool in stereocontrolled transformations might be an attractive alternative to be considered, as shown recently [94]. 

In planning the synthesis of biologically active compounds, strategies using aldonolactones or other compounds from the chiral pool should therefore continue to be considered, since they can provide attractive routes in comparison with alternative methods by asymmetric synthesis. 

Further research on mixed IL stationary phases will allow for the chroma-tographer to tune the stationary phase composition to provide enhanced control over the separation selectivity and analyte elution order, particularly for complicated analyte mixtures. The development of models that correlate analyte retention with the IL composition will prove useful for multidimensional GC. Micellar GC utilizing IL solvents presents an exciting class of highly selective stationary phases. The development of CSPs will likely mature as more chiral ILs are synthesized and evaluated from the chiral pool. 

Economic and practical reasons, in addition to green concerns, have meant that many of the first generation of asymmetric organocatalysts have been either natural molecules, such as nomicotine [52] and proline [40], derived directly from the chiral pool (Figure 7.1), or simple derivatives thereof, such as quinine acetate [53] and 5,5-dimethyl thiazolidinium-4-carboxylate (DMTC) [54], which are expected to be either biodegradable or biotransformable, with little impact on the environment. [54]. 

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