Chirality control

The frequent use of chiral controller or auxiliary groups in enantioselective synthesis (or diastereoselective processes) obviously requires the addition of such units retrosynthetically, as illustrated by the antithetic conversion 34 =i> 35. 

Spatial and/or coordinative bias can be introduced into a reaction substrate by coupling it to an auxiliary or controller group, which may be achiral or chiral. The use of chiral controller groups is often used to generate enantioselectively the initial stereocenters in a multistep synthetic sequence leading to a stereochemically complex molecule. Some examples of the application of controller groups to achieve stereoselectivity are shown retrosynthetically in Chart 19. 

There are a number of powerful synthetic reactions which join two trigonal carbons to form a CC single bond in a stereocontrolled way under proper reaction conditions. Included in this group are the aldol, Michael, Claisen rearrangement, ene and metalloallyl-carbonyl addition reactions. The corresponding transforms are powerfully stereosimplifying, especially when rendered enantioselective as well as diastereoselective by the use of chiral controller groups. Some examples are listed in Chart 20. 

Chiral Controller. (Synonymous with Chiral Auxiliary). A chiral structural unit which when attached to a substrate enhances stereoselectivity in the formation of new stereocenter(s). 

Kanemasa et al.63 reported that cationic aqua complexes prepared from the /ram-chelating tridentate ligand (i ,f )-dibenzofuran-4,6-diyl-2,2,-Mv(4-phcnyloxazolinc) (DBFOX/Ph) and various metal(II) perchlorates are effective catalysts that induce absolute chiral control in the Diels-Alder reactions of 3-alkenoyl-2-oxazolidinone dienophiles (Eq. 12.20). The nickel(II), cobalt(II), copper(II), and zinc(II) complexes are effective in the presence of six equivalents of water for cobalt and nickel and three equivalents of water for copper and zinc. 

Skourtis SS, Beratan DN, Naaman R, Nitzan A, Waldeck DH (2008) Chiral control of electron transmission through molecules. Phys Rev Lett 101(23) 238103... 

Corey et al.39 introduced a chiral controller system, chiral auxiliary 55, which has shown excellent practical potential because of its availability, recoverability, and high enantioselectivity. Furthermore, using conformation analysis,... 

Diels-Alder disconnection will have been eliminated, and the rctrosynthetic search becomes highly focused. Having selected both the transform and the mapping onto the TGT, it is possible to sharpen the analysis in terms of potentially available dienophile or diene components, variants on the structure of the intermediate for Diels-Alder disconnection, tactics for ensuring stereocontrol and/or position control in the Diels-Alder addition, possible chiral control elements for enantioselective Diels-Alder reaction, etc. 

In the neutral BIPHEP-Pt complex, the axial chirality of BIPHEP moiety is controlled by chiral diol BINOL as shown in Scheme 8.29. However, the diastereo-meric purity is not high enough (95 5). Therefore, recrystallization is essential to obtain the single BIPHEP-Pt diastereomer and subsequent enantiomer. It has thus been required that complete chirality control of both neutral and cationic BIPHEP-Pt complexes without recrystallization and its application to asymmetric Lewis acid catalysis (Scheme 8.32)." Interestingly, both enantiopure (5)- and (7 )-BIPHEP-Pt complexes can be obtained quantitatively through the... 

In ketone 26, the chiral control elements are close to the reacting carbonyl, thus enhancing the stereochemical communications between the catalyst and the substrate. The fused ring or quaternary centers are placed at the a-position to the carbonyl group, which minimizes potential epimerization of the stereogenic centers. Electron-withdrawing oxygen substituents inductively activate the carbonyl. 

Improved selectivities were observed with the enone 148 using the dibenzyl amine as the chiral controlling unit at the y-position, delivering essentially a single product from the reaction (Scheme 3.43). 

In synthetic efforts toward the DNA reactive alkaloid naphthyridinomycin (164), Gamer and Ho (41) reported a series of studies into the constmction of the diazobicyclo[3.2.1]octane section. Constmction of the five-membered ring, by the photolytic conversion of an aziridine to an azomethine ylide and subsequent alkene 1,3-dipolar cycloaddition, was deemed the best synthetic tactic. Initial studies with menthol- and isonorborneol- tethered chiral dipolarophiles gave no facial selectivity in the adducts formed (42). However, utilizing Oppolzer s sultam as the chiral controlling unit led to a dramatic improvement. Treatment of ylide precursor 165 with the chiral dipolarophile 166 under photochemical conditions led to formation of the desired cycloadducts (Scheme 3.47). The reaction proceeded with an exo/endo ratio of only 2.4 1 however, the facial selectivity was good at >25 1 in favor of the desired re products. The products derived from si attack of the ylide... 

The reaction protocol was further developed by alterations to the chiral controlling element of the reaction (49). Use of the precursor 183 under the standard ylide generation and cycloaddition conditions gave a greatly improved diastereomeric excess of >95%, an endo/exo ratio 1 15 and an isolated yield of 62%, with A-phenylmaleimide as the dipolarophile. The improvement in the reaction was rationalized by both endo and exo attack of the dipolarophile to the same diastereomerically favored face of the conformationally restricted U-shaped ylide 184 (Scheme 3.52). 

By attachment of a chiral controlling unit, the reaction could also be carried out asymmetrically (100). Subjecting 352 (R = 2-naphthyl, R = H) to cycloaddition with 353 in the presence of AgOAc (1.5 M equiv) and EtaN (1.0 M equiv) furnished the enantiopure adduct 354 in 50%, with no other reaction products being observed. The reaction could be improved by alteration of the metal salt. Treatment of 352 (R = R = Ph) with dipolarophile 353 in the presence of LiBr and EtsN delivered the expected, enantiomerically pure adduct 354 in >90% yield, while 352 (R = 2-naphthyl, R = H) gave rise to 354 in quantitative yield with TINO3 and EtaN (Scheme 3.119). 

A new dipolarophile bearing a chirality-controlling heterocyclic auxiliary at the p-position is readily accessible from (5)-A -benzylvalinol and methyl ( )-4-oxo-2-propenoate. However, the dipolarophile is available only as an 86 14 equilibrium mixture of trans and cis stereoisomers (Scheme 11.20) (84). When this is used without separation in the reaction with the Al-hthiated azomethine ylide derived from methyl (benzylideneamino)acetate in THE at 78 °C for 3.5 h, a mixture of two diastereomeric cycloadducts (75 25) was obtained in 82% yield. These two cycloadducts are derived from the trans and cis isomers of acceptor, indicating that both cycloadditions were highly diastereoselective. 

Other chiral azomethine ylide precursors such as 2-(ferf-butyl)-3-imidazolidin-4-one have been tested as chiral controllers in 1,3-dipolar cycloadditions (89). 2-(ferf-Butyl)-3-imidazolidin-4-one reacted with various aldehydes to produce azomethine ylides, which then were subjected to reaction with a series of different electron-deficient alkenes to give the 1,3-dipolar cycloaddition products in moderate diastereoselectivity of up to 60% de. 

Mukund Sibi of North Dakota State University has developed (J. Am. Chem. Soc. 2004,126,718) a powerful three-component coupling, combining an a,(5-unsaturated amide 9, a hydroxylamine 10, and an aldehyde 11. The hydroxylamine condenses with the aldehyde to give the nitrone, which then adds in a dipolar sense to the unsaturated ester. The reaction proceeds with high diastereocontrol, and the absolute configuration is set by the chiral Cu catalyst. As the amide 9 can be prepared by condensation of a phosphonacetate with another aldehyde, the product 12 can be seen as the product of a four-component coupling, chirally-controlled aldol addition and Mannich condensation on a starting acetamide. 

Ali, M.M. and MacDonnell, F.M. (2000) Topospecific self assembly of mixed-metal molecular hexagons with diameters of 5.5 nm using chiral control. J. Am. Chem. Soc., 122 (46), 11527-11528. 

Peptide-like compounds raise the further significant issue of chirality control. When all the chiral fragments consist of natural amino acids, the chiral sources are natural amino acids themselves. However, when chiral non-natural amino acids are used as bioisosteres of amino acid residues to construct peptide mimetic compounds, the chirality needs to be constructed as efficiently as possible. Multi-step or low-yielding processes resulting from the necessity to control chirality often lead to the potential risk of large amounts of waste and a high environmental burden. 

In the following section, taking diabetic drug candidates 1 and 2 [8, 9] as case studies (Figure 9.3), the purification and chirality control issues of peptide-hke API manufacturing are considered from a Green Chemistry perspective. 

However, the method has not generally been adopted for the preparation of 3-branched-a-amino acids that require simultaneous chirality control of the adjacent asymmetric centers, because the preparation of j3,j3-disubstituted a-enamide... 

---