Prochiral Environments

Introduction to Strategies for Organic Synthesis, First Edition. Laurie S. Starkey. 2012 John Wiley Sons, Inc. Published 2012 by John Wiley Sons, Inc. 

Since an asymmetric synthesis is one that preferentially involves only one prochiral face of a planar substrate or reacts with only one prochiral group on a tetrahedral atom, some terminology is needed to unambiguously describe such species. 

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We can view this reaction as the replacement of one or the other of the two methylene protons at C 2 of butane These protons are prochiral atoms and as the red and blue protons m the Newman projection indicate occupy mirror image environments... 

Figure 9.18 (a) When a prochiral molecule is held in a chiral environment, the two seemingly identical substituents (red) are distinguishable, (b) Similarly, when an achiral coffee mug is held in the chiral environment of your hand, it s much easier to drink from one side than the other because the two sides of the mug are now distinguishable. 

The enantioselective hydrogenation of C=C bonds is included in Chapter 3, where the general nature of heterogeneous enantioselective hydrogenation is fully explored, so here we examine only the narrow subject. Enantioselective hydrogenation of C=C bonds occurs only on prochiral double bonds (at least one of the carbons substituted with two different groups other than hydrogen). A chiral environment is required. 

To create a chiral center at an sp3-hybridized carbon requires a chiral environment to stereodirect the reaction. This chiral environment may exist as a chirally substituted sp3-hybridized carbon, on which appropriate substitution creates a new molecule with the same or inverted chirality at the former chiral center or as a chiral arrangement near a prochiral (prechiral) sp2 carbon. 

It is well recognized that chiral tridentate ligands generally form a deeper chiral cavity around the metal center than a bidentate ligand. For example, as mentioned in previous chapters, the chiral tridentate ligand Pybox 120 has been used in asymmetric aldol reactions (see Section 3.4.3) and asymmetric Diels-Alder reactions (see Section 5.7). The two substituents on the oxazoline rings of 120 form a highly enantioselective chiral environment that can effectively differentiate the prochiral faces of many substrates. 

If stoichiometric quantities of the chiral auxiliary are used (i.e., if the chiral auxiliary is covalently bonded to the molecule bearing the prochiral centres) there are in principle three possible ways of achieving stereoselection in an aldol adduct i) condensation of a chiral aldehyde with an achiral enolate ii) condensation of an achiral aldehyde with a chiral enolate, and iii) condensation of two chiral components. Whereas Evans [14] adopted the second solution, Masamune studied the "double asymmetric induction" approach [22aj. In this context, the relevant work of Heathcock on "relative stereoselective induction" and the "Cram s rule problem" must be also considered [23]. The use of catalytic amounts of an external chiral auxiliary in order to create a local chiral environment, will not be considered here. 

Enantioselective condensation of aldehydes and enol silyl ethers is promoted by addition of chiral Lewis acids. Through coordination of aldehyde oxygen to the Lewis acids containing an Al, Eu, or Rh atom (286), the prochiral substrates are endowed with high electrophilicity and chiral environments. Although the optical yields in the early works remained poor to moderate, the use of a chiral (acyloxy)borane complex as catalyst allowed the erythro-selective condensation with high enan-tioselectivity (Scheme 119) (287). This aldol-type reaction may proceed via an extended acyclic transition state rather than a six-membered pericyclic structure (288). Not only ketone enolates but ester enolates... 

Certain chiral organic compounds create crystalline environments and act as enantio-controlling media (7) even though they do not function as true catalysts. Natta s asymmetric reaction of prochiral trans-1,3-pentadiene, which was included in the crystal lattice of chiral perhydro-triphenylene as a host compound, to form an optically active, isotactic polymer on 7-ray irradiation, is a classic example of such a chiral molecular lattice (Scheme 1) (2). Weak van der Waals forces cause a geometric arrangement of the diene monomer that favors one of the possible enantiomeric sequences. 

A similar chiral environment is given by inclusion to cyclodextrins (CDs), cyclic oligosaccharides (3). The outside of the host molecule is hydrophilic and the inside hydrophobic. The diameters of the cavities are approximately 6 (a), 7-8 (j3), and 9-10 A (7), respectively. Reduction of some prochiral ketone-j3-CD complexes with sodium boro-hydride in water gives the alcoholic products in modest ee (Scheme 2) (4). On the other hand, uncomplexed ketones are reduced with a crystalline CD complex of borane-pyridine complex dispersed in water to form the secondary alcohols in up to 90% ee, but in moderate chemical yields. Fair to excellent enantioselection has been achieved in gaseous hydrohalogenation or halogenation of a- or /3-CD complexes of crotonic or methacrylic acid. These reactions may seem attractive but currently require the use of stoichiometric amounts of the host CD molecules. 

Iwo double bonds are available to palladium for oxidative addition in alkyl Pd complex 23. Both double bonds arc prochiral in the absence of chiral ligands on the palladium, but they differ in their to-picity Introduction of a BINAP ligand provides a chiral environment around palladium in complex 23, so one of the double bonds in the cyclopentadicne is attacked preferentially. This differentiation within the previously prochiral cyciopentadiene unit of compound 23 leads to an enantiomeric excess of 87 ft in favor of the (+)-(45,105,115 ) enantiomer 13. 

Topochemical Polymerization The chiral crystalline environment of a monomer itself can be a source of asymmetric induction in solid-state polymerization [69-72], Prochiral monomers such as 37 give enantiomorphic crystals, one of which can be preferentially formed by recrystallization with a trace amount of optically active compounds. Photoir-... 

In this approach (17), the prochiral fragment was attached to the auxiliary at only one point making the acid-catalysed release after transformation a simple procedure. Chirality was induced by the borohydride reduction of a carbonyl group on the pro-chiral fragment in the asymmetric environment created by complexation of calcium ions between the Cl and C2 oxygens of the hexose. The diastereomeric purity was good (-70%) but separation of the diastereomers was more problematic. 

Acrylanilides also undergo this photoinduced process the reaction can occur either in the solid state or in aqueous suspension. In this way, optically active photoproducts can be obtained by irradiating prochiral substrates in the presence of optically active partners (1 1 complexes) (see Scheme 9.27). The substrate is highly oriented and immobilized in the chiral environment. Although photocyclization in the solid state takes a long time (close to 150 h), the photoreaction of a powdered complex in a water suspension containing sodium alkylsulfate as a surfactant proceeds more efficiently (less than 50h) [40],... 

In solution, the great conformational mobility of molecules does not favor tight transition states. For a good asymmetric induction, there is a need to decrease this mobility and to introduce the chiral information as close as possible from the prochiral centers. An efficient way to introduce the chiral environment in asymmetric [2 4- 2]-photocycloadditions is to connect chiral auxiliaries to the reactants. When removable chiral auxiliaries are attached to the starting molecules before the photochemical step, photocycloadditions proceed diastereoselectively. After removal of the chiral auxiliary, the overall process can be considered as a byroad for an enantioselective reaction. 

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