Centrally chiral

Ahn et al. [20] reported the synthesis of homochiral bis(oxazolinyl)-biferrocene ligands (structure 11 in Scheme 7), which also have both planar and central chirality. With these complexes, 2-(phenyl)cyclopropane carboxy-lates were obtained in up to 99% ee and a trans/cis ratio of 88/12. 

Although the vast majority of centrally chiral diphosphine ligands to be employed in enantioselective rhodium-catalyzed hydroborations possess -symmetry, there are a few examples of ( -symmetric diphosphine ligands. Buono prepared bis(aminophosphine) ligands 35-38,81 while Bianchini reported (R, i )-BDPBzP 39 (Figure 5).82... 

Central Chirality. The system Cxyzw (5) has no symmetry when x, y, z, and w are different groups, and this system is referred to as a central chiral system. 

Axial Chirality. For a system with four groups arranged out of the plane in pairs about an axis, the system is asymmetric when the groups on each side of the axis are different. Such a system is referred to as an axial chiral system. This structure can be considered a variant of central chirality. Some axial chiral molecules are allenes, alkylidene cyclohexanes, spiranes, and biaryls (along with their respective isomorphs). For example, compound 7a (binaphthol), which belongs to the class of biaryl-type axial chiral compounds, is extensively used in asymmetric synthesis. Examples of axial chiral compounds are given in Figure 1-5. 

The nomenclature for biaryl, allene, or cyclohexane-type compounds follows a similar rule. Viewed along the axis, the nearer pair of ligands receives the first two positions in the order of preference, and the farther ligands take the third and fourth position. The nomination follows a set of rules similar to those applied in the central chiral system. In this nomination, the end from which the molecule is viewed makes no difference. From whichever end it is viewed, the positions remain the same. Thus, compound 7a has an ( -configuration irrespective of which end it is viewed from. 

Besides the function of the l,l -binaphthyl backbone, which is very important for high enantioselectivity, configuration of the central chirality on the... 

Figure 8.17 Reaction of an alkyl halide with hydroxide ion. (a) A primary halide reacts by an SN2 mechanism, causing Walden inversion about the central, chiral carbon, (b) A tertiary halide reacts by an SN1 mechanism (the rate-determining step of which is unimolecular dissociation, minimizing the extent of Walden inversion and maximizing the extent of racemization). Secondary alcohols often react with both Sn 1 and SN2 mechanistic pathways proceeding concurrently...

A propargyl substrate having a substituent at the propargyl position is centrally chiral and an allenic product from the SN2 substitution reaction will be axially chiral. Chirality transfer in the SN2 reaction, accordingly, may be achieved starting from an enantiomerically enriched propargyl electrophile [29]. The reactions in Scheme 3.11 are some recent examples of the center to axis chirality transfer by Pd-catalyzed SN2 reactions [41, 42]. 

Efficient chirality transfer was reported for the reactions of enantiomerically enriched 75 with Grignard reagents [85], Using 10mol% of CuBr or CuCN-2LiBr, the axially chiral allenes 76 are obtained from the centrally chiral 75 with nearly complete chirality transfer (Scheme 3.39). 

The axially chiral (allenylmethyl) silanes 110 were also prepared in optically active form using chiral Pd catalysts [98]. For the asymmetric synthesis of 110, a Pd/(R)-segphos system was much better in terms of enantioselectivity than the Pd/(R)-binap catalyst. Under the optimized conditions, 110m and llOt were obtained in 79% ee (57% yield) and 87% ee (63% yield), respectively (Scheme 3.56). The enantio-merically enriched (allenylmethyl) silanes 110 served for Lewis acid-promoted SE reaction with tBuCH(OMe)2 to give conjugated dienes 111 with a newly formed chiral carbon center (Scheme 3.56). During the SE reaction, the allenic axial chirality was transferred to the carbon central chirality with up to 88% transfer efficiency. 

The stereoselective elimination reaction of suitably substituted allylic compounds is a reasonable approach to the construction of the propadiene framework. Central chirality at the allylic position is transferred to axial chirality of the allene by stereoselective /3-elimination (Scheme 4.53). 

The stereospecificity of the reaction was already mentioned around 1990 [34, 35]. Since enantiomerically pure allenes are available by a number of methods [36, 37], this clean axial to central chirality transfer is very useful in organic synthesis. Several further examples can be found in the literature [38, 39], one example being the cydi-zation of 74 to 75 (Scheme 15.17) [40]. 

Further applications include the synthesis of ( )-pinidine 132 (Scheme 15.41) [91] and the synthesis of (K)-(-)-coniine via an axial to central chirality transfer in the cydization of enantiomerically pure 133 to 134 [92]. 

In these reactions a clean axial to central chirality transfer can be achieved. The phosphine oxide 232 cleanly delivers 234 as a single diastereomer the relative configuration shown was determined by single-crystal X-ray analysis (Scheme 15.73) [143]. 

The relative importance of the planar and central elements of chirality within the Josi-phos skeleton has also been established. Diastereomeric ligands 13 and 22 bear the same R) central chirality but have the opposite planar chirality (Fig. 9.4). Under standard reaction conditions with methanol as the nucleophile, the (R),(S)-ligand 13 gives 100% conversion after approximately 7 min. Conversely, the (i ),(i )-diastereomer 22 gives incom-... 

Many syntheses of chiral allenes of high enantiomeric purity start from chiral precursors, notably propynyl compounds, with the central chirality being converted into allene axial chirality by a mechanism-controlled reaction. 

Intramolecular pinacol coupling of 2,2 -biaryldicarbaldehyde with samarium(ll) iodide shows that axial chirality transfer to central chirality proceeds in a stereospecific manner. ... 

The use of planar-chiral [7] and central-chiral ligands based on paracyclophane systems was still a relatively unexplored frontier, with notable exceptions in the reactions examined by the Rozenberg group [8] and the Berkessel group [9]. 

These, in turn, can be condensed with amines to give imines 4 or ketimines 5 and 6, or reduced to give amino alcohols 7-9, respectively. The ligand structure is therefore vastly variable. Steric factors, such as flexibility of backbone and side-chains, as well as electronic factors (for example sp versus sp conflguration of the N-donors) can be easily modulated. The introduction of central chirality via chiral amine side-chains is also possible. The interaction of planar and central chirality, usually referred to as chiral cooperativity [11-13], can thus be studied in a ligand system which has both planar and central chiral elements. 

Scheme 2.1.3.1 Synthesis of planar-chiral and central chiral imines 4a-4c and 5a-5c. 1) Primary amine (2-5 equiv), toluene/EtOH, MS 4A, A, 3 h. 2) Primary amine (2-5 equiv.), cat. Bu2SnCl2, toluene, MS 4A, A, 40 h [15].

The well-established planar- and central-chiral ferrocenyl ligands have shown high activity and selectivity in the reaction. However, to the best of our knowledge, these ligands have no central-chiral equivalent with similar bond length and bond angles. In comparison, the [2.2]paracyclophane structure creates central-chiral structures with similar properties, which offer the great opportunity to study its influence on different kinds of chiral elements. 

The best results observed so far were with the central- and planar-chiral ketimine ligands, all of which were synthesized with the same chiral amine, (S)- or (R)-phenylethylamine, to result in the same central-chiral side-chain. The second generation of these ligands was synthesized with the various chiral amines depicted in Fig. 2.1.3.5 based on the AHPC 2 and BHPC 3. 

In summary, the configuration of the desired product is controlled by the planar-chiral imine and ketimine ligand backbone. The selectivity of the reaction depends on both the chiral center and the communication of the side-chain with the ligand backbone. We tuned the side-chain to increase the enantioselectivity up to 90% ee. In the case of the amino alcohol ligands, chiral cooperativity is also observed. However, the influence of the planar chirality is much lower, whereas central chirality is dominant in this instance. In most cases the enantioselectivity is lower than for the ketimines. 

For studies on chiral cooperativity in axial- and central-chiral ligands, see ... 

The modular synthetic approach has allowed the preparation of many QUINAPHOS derivatives in both diastereomeric forms. Testing of the single diastereo-mers in catalysis has been revealed to be of crucial importance. Thus, a pronounced interplay between the axial and central chirality has been observed in all applications of QUINAPHOS in catalysis, whereby the choice of the diastereomer may affect not only the enantioselectivity but also the activity and the chemoselectivity of a catalyzed reaction. 

The values given in column 3 of Table IV were obtained from the data in column 2 ((2) and (6)]. A comparison of the results for 14 and 15 indicates that the introduction of methyl groups at sites 4 and 5 (see 12), leading to central chirality R at both carbon atoms, is the main cause of enantiomer selectivity. This is in agreement with the only slightly different enantiomer selectivity of 16 relative to 15. As expected, the effect of 17 is reversed by 18. Although valinomycin 1 is chiral, no enantiomer selectivity was detectable (see Table IV). The potentiometrically determined enantiomer selectivity AEMF is correlated to the transport selectivity [(2), (6), (10), and (11)]... 

---