Enantiotopic Ligands and Faces

Just as one divides stereoisomers into two sets, enantiomers (Greek enantios = opposite) and diastereomers, so it is convenient to divide heterotopic (non-equivalent) groups or faces into enantiotopic and diastereotopic moieties. Enantiotopic ligands are ligands which find themselves in mirror-image positions whereas diastereotopic ligands are in stereochemically distinct positions not related in mirror-image fashion similar considerations relate to planes of double bonds. 

The two criteria used to spot homotopic ligands and faces may also be used to detect those which are enantiotopic. 

---

Enantiotopic ligands and faces are not interchangeable by operation of a symmetry element of the first kind (Cn, simple axis of symmetry) but must be interchangeable by operation of a symmetry element of the second kind (cr, plane of symmetry i, center of symmetry or S , alternating axis of symmetry). (It follows that, since chiral molecules cannot contain a symmetry element of the second kind, there can be no enantiotopic ligands or faces in chiral molecules. Nor, for different reasons, can such ligands or faces occur in linear molecules, QJV or Aoh )... 

Constitutionally heterotopic ligands are in principle always distinguishable, just as constitutional isomers are. Diastereotopic and enantiotopic ligands or faces may be lumped together under the term stereoheterotopic just as diastereomers and enantiomers are both called stereoisomers. 

In Chapter 32, the students find that what they have learned about stereoselectivity and stereospecificity applies not only to stereochemically different molecules, but also to stereochemically different parts of the same molecule. They find that portions of a molecule may be stereochemically equivalent or non-equivalent, and that they must be able to distinguish between these if they are to understand subjects as widely different as NMR spectroscopy and biological oxidation and reduction. They must leam the concepts of enantiotopic and diastereotopic ligands and faces. 

The proposed descriptors of homotopic/diastereotopic faces/ligands establish a common basis for the discussion of their reactivities and selectivities (vide infra). These descriptors are not intended to replace either the pro-R, pro-S, pro-r, pros descriptors for ligands, or the Re/Si/re/si descriptors for faces. The proposed specifications are short, concise, and universal they emphasize the similarities in reactivity for ligands and faces further, they reveal the stereotopic nature of the ligands (homotopic vs. enantiotopic vs. diastereotopic), as well as the chirotopicity vs. achirotopicity of the molecular environment. 

The enzyme-catalyzed interconversion of acetaldehyde and ethanol serves to illustrate a second important feature of prochiral relationships, that ofprochiral faces. Addition of a fourth ligand, different from the three already present, to the carbonyl carbon of acetaldehyde will produce a chiral molecule. The original molecule presents to the approaching reagent two faces which bear a mirror-image relationship to one another and are therefore enantiotopic. The two faces may be classified as re (from rectus) or si (from sinister), according to the sequence rule. If the substituents viewed from a particular face appear clockwise in order of decreasing priority, then that face is re if coimter-clockwise, then si. The re and si faces of acetaldehyde are shown below. 

The concept of heterotopic atoms, groups, and faces can be extended from enantiotopic to diastereotopic types. If each of two nominally equivalent ligands in a molecule is replaced by a test group and the molecules that are generated are diaster-eomeric, then the ligands are diastereotopic. Similarly, if reaction at one face of a trigonal atom generates a molecule diastereomeric with that produced at the alternate face, the faces are diastereotopic. 

If the test ligands are chiral, the products of replacing first one and then the other of two enantiotopic ligands by them will be diastereomeric. Similar considerations apply to addition of chiral ligands to enantiotopic faces. 

Z)-l,2-disubstituted alkenes proved to be the most difficult class. In fact, they are not osmylated efficiently with the all purpose ligands 1F/2 F. Further studies, however, led to the discovery of the indolinyl ligands 11/21 that allowed cis dihydroxylation of these alkenes in up to 80% eel0. It should be kept in mind, however, that in the case of 1,1-disubstituted alkenes and of (Z)-l,2-disubstituted alkenes, a lowering of difference in steric requirement between the two vicinal substituents inevitably means a drop in the 7t-face discrimination since the two enantiotopic alkene 7t-faces lend to become quasi-homotopic . 

Intramolecular cyclopropanations with unsaturated diazo ketones have also been reported. Furthermore, enantioselective cyclopropanation with diazomethane can be achieved in up to 75% ee. In detailed mechanistic discussions, a copper(I) species, complexed with only one semicorrin ligand, and formed by reduction and decomplcxation, is suggested as the catalytical-ly active species, cisjtrans Stereoselection and discrimination of enantiotopic alkene faces should take place within a copper-carbene-alkene complex25-54"56. According to these interpretations, cisjtrans selectivity is determined solely by the substituents of the alkene and of the diazo compound (especially the ester group in diazoacetates) and is independent of the chiral ligand structure (salicylaldimine or semicorrin)25. 

Some of the earliest DNMR observed for organometallics involved the planar rotation of olefins. This process effectively involves a rotation about an axis from the metal to the midpoint of an -alkene and is sometimes called a propeller rotation. In unsymmetrical metal complexes, there is the possibility of several conformers based on orientations of the olefin. This can generally be attributed to differing donor properties of non-equivalent other ligands. The faces of many substituted olefins are enantiotopic, and binding to the metal produces... 

Over the past 20 years, there has been a growing interest in the use of acyclic (or open) ( 7 -pentadienyl)iron cations 1 (Scheme 1) as synthetic tools for G-C bond formation. Complexation of Fe(CO)3 to a diene distinguishes between two enantiotopic faces of the ligand and directs diastereoselective bond formation at unsaturated centers adjacent to the coordinated diene. In addition, the electron-donor ability of the carbonyliron group allows for the generation of cationic centers adjacent to the coordinated diene. ... 

An achiral reagent cannot distinguish between these two faces. In a complex with a chiral reagent, however, the two (phantom ligand) electron pairs are in different (enantiotopic) environments. The two complexes are therefore diastereomeric and are formed and react at different rates. Two reaction systems that have been used successfully for enantioselective formation of sulfoxides are illustrated below. In the first example, the Ti(0-i-Pr)4-f-BuOOH-diethyl tartrate reagent is chiral by virtue of the presence of the chiral tartrate ester in the reactive complex. With simple aryl methyl sulfides, up to 90% enantiomeric purity of the product is obtained. 

The highly efficient asymmetric cyclization of 97 using (i )-BINAP as a chiral ligand based on the differentiation of enantiotopic faces gave the tetralin system 98 with 93% ee and has been applied to the synthesis of (—)-eptazocine (99) [45]. 

---