Diaster eomers

Multiple Chiral Centers. The number of stereoisomers increases rapidly with an increase in the number of chiral centers in a molecule. A molecule possessing two chiral atoms should have four optical isomers, that is, four structures consisting of two pairs of enantiomers. However, if a compound has two chiral centers but both centers have the same four substituents attached, the total number of isomers is three rather than four. One isomer of such a compound is not chiral because it is identical with its mirror image it has an internal mirror plane. This is an example of a diaster-eomer. The achiral structure is denoted as a meso compound. Diastereomers have different physical and chemical properties from the optically active enantiomers. Recognition of a plane of symmetry is usually the easiest way to detect a meso compound. The stereoisomers of tartaric acid are examples of compounds with multiple chiral centers (see Fig. 1.14), and one of its isomers is a meso compound. 

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. 

Schemes 3-7 describe the synthesis of cyanobromide 6, the A-D sector of vitamin Bi2. The synthesis commences with an alkylation of the magnesium salt of methoxydimethylindole 28 to give intermediate 29 (see Scheme 3a). The stereocenter created in this step plays a central role in directing the stereochemical course of the next reaction. Thus, exposure of 29 to methanol in the presence of BF3 and HgO results in the formation of tricyclic ketone 22 presumably through the intermediacy of the derived methyl enol ether 30. It is instructive to point out that the five-membered nitrogen-containing ring in 22, with its two adjacent methyl-bearing stereocenters, is destined to become ring A of vitamin Bi2. A classical resolution of racemic 22 with a-phenylethylisocyanate (31) furnishes tricyclic ketone 22 in enantiomerically pure form via diaster-eomer 32.

Brunow, G. Karlsson, O. Lundquist, K Sipila, J. On the distribution of the diaster-eomers of the structural elements in lignins the steric course of reactions mimicking lignin biosynthesis. Wood Sci. Technol. 1993, 27, 281-286. 

FIGURE 14.5 Separations involving voriconazole (1), its mirror image (2), related diaster-eomers (3), chlorinated impurities (4), and an achiral impurity 5. (a) Achiral separation of compounds 1-5 on an amino column with hexane/ethanol mobile phase (b) Chiral separation of compounds 1-5 on Chiralpak As column with hexane/ethanol mobile phase (c) Achiral-chiral multidimensional separation with the amino and chiral column coupled in series. Reprinted from Ferretti et al. (1998) with permission from Vieweg Verlag. 

The 2, 4-dimethylpyrrolidine analog 44 (as a mixture of four diaster-eomers) is a selective inhibitor of GlyT-1 (IC50 = 800 nM). Modification led to optimized analog 45, which demonstrated good potency and selectivity but poor microsomal clearance and oral bioavailability [83]. 

Very recently, Reetz, Ma and Goddard reported phosphoramidites based on BINOL bearing a single ortho-substituent (Scheme 28.10) [69]. These ligands are also chiral on phosphorus, such that the synthesis results mostly in diastereo-mers which have to be separated. In several cases, however, one of the diaster-eomers was formed exclusively. Some of the ligands afford high ee-values in the hydrogenation of methyl N-acyl dehydroalanine and dimethyl itaconate. 

In an asymmetric reaction, substrate and reagent combine to form diaster-eomeric transition states. One of the two reactants must have a chiral element to induce asymmetry at the reaction site. Most often, asymmetry is created upon conversion of trigonal carbons to tetrahedral ones at the site of the functionality. Such asymmetry at carbon is currently a major area of interest for the synthetic organic chemists. 

Six-Membered Ring (exo-Cyclic). The diastereoselective alkylation reactions of exo-cyclic enolates involving 1,2-asymmetric inductions are anti-inductions. In Scheme 2-2, there are two possible enolate chair conformations in which the two possible transition-state geometries lead to the major diaster-eomer 9e (where the substituent takes the equatorial orientation). However, for the case in which R = methyl and X = alkoxyl or alkyl, one would expect the... 

Although relatively weak, it is this last interaction that is essential for determining chiral discrimination. The superior chiral recognition achieved when ref has an aromatic side chain (Table 10) suggests that 7r-cation interactions play an important role in the stereoselectivity. Evidence for such a rr-cation interaction is observed in the CID spectra of the dimeric [A Me° ref-H]and [A -Me -ref-H] diaster-eomers, in which one ligand is an aromatic amino acid, and is supported by ab initio calculations. When an L-aromatic amino acid, such as L-phenylalanine, is used as ref, these interactions are disrupted by the side group on the a-asymmetric carbon of the L-analyte, whereas the side-chain group in the D-analyte has little steric effect on... 

The synthesis of tacamonine, an indole alkaloid of the Iboga type, was accomplished in both racemic and homochiral forms, by incorporating a classical 6-exo-trig radical cyclization in the key step of the synthesis (Reaction 7.57) [52], The cyclization produced piperidinone in a 72% yield as a diaster-eomeric mixture. 

Many drugs are racemates, including 13-blockers, nonsteroidal anti-inflammatory agents, and anticholinergics (e.g benzetimide A). A racemate consists of a molecule and its corresponding mirror image which, like the left and right hand, cannot be superimposed. Such chiral ( handed ) pairs of molecules are referred to as enantiomers. Usually, chirality is due to a carbon atom (C) linked to four different substituents ( asymmetric center ). Enantiomerism is a special case of stereoisomerism. Non-chiral stereoisomers are called diaster-eomers (e.g., quinidine/quinine). 

Intramolecular cycloadditions of alkenyl-substituted nitrile oxides produce bicyclic isoxazolines. When monocyclic olehns are used, tricyclic structures are obtained. This approach was pioneered by both Kozikowski s and Curran s groups. A typical case involves the cycloaddition of nitro compound 191 [mixture of diastereomers derived from pentenose pyranoside 190], which produced a diaster-eomeric mixture of isoxazolines that contain cis-fused rings (i.e., 192) in near quantitative yield (326) (Scheme 6.85). Further elaboration of this mixture led to epoxycyclopentano-isoxazoline 193, which was then converted to the aldol product in the usual manner. The hydrogenation proceeded well only when rhodium on alumina was used as the catalyst, giving the required p-hydroxyketone 194. This... 

For intramolecular 1,3-dipolar cycloadditions, the application of nitrones and nitrile oxides is by far most common. However, in increasing frequency, cases intramolecular reactions of azomethine ylides (76,77,242-246) and azides (247-259) are being reported. The previously described intermolecular approach developed by Harwood and co-workers (76,77) has been extended to also include intramolecular reactions. The reaction of the chiral template 147 with the alkenyl aldehyde 148 led to the formation of the azomethine ylide 149, which underwent an intramolecular 1,3-dipolar cycloaddition to furnish 150 (Scheme 12.49). The reaction was found to proceed with high diastereoselectivity, as only one diaster-eomer of 150 was formed. By a reduction of 150, the proline derivative 151 was obtained. 

In all cases, the initial addition to generate 520 was diastereospecific, that is, the isocyanate always adds to 519 from the face opposite to the 4-ethyl substituent of the oxazoline. In the cases wherein 521 was isolated (Entries 17-20 from Table 8.33), the stereochemistry of the two additional chiral centers from the secondary [2 + 2] cycloaddition was controlled by the chiral center formed during the initial reaction, that is, the isocyanate reacts with 520 from the opposite face of the neighboring Ri group. For Ri = H, R2 = Me, 519 reacted with an arylisocyanate (R3 = Ar) to give tricyclic adducts 521a and 521b as a 1.7 1 mixture of diaster-eomers (Entries 18-20). For Rj = Ph, R2 = Me, 519 reacted with phenylisocyanate... 

Many reactions of this type are known, in some of which the extent of favoritism approaches 100% (for an example see 2-11).90 The farther away the reaction site is from the chiral center, the less influence the latter has and the more equal the amounts of diaster-eomers formed. 

Conjugate addition of 1 to a,(3-unsaturated esters, ketones, or aldehydes followed by reaction with an alkyl iodide (or bromide) proceeds by stereoselective attack anti to the silyl group, apparently because of electronic effects.2 Protonation of the (3-silyl enolate of 5 proceeds in the same sense to give the opposite diaster-eomer (Chart I). 

In 1994, Balueva described the preparation of the phosphine-boronate 55 featuring a 1,3,2-dioxaborinane skeleton (Scheme 34). Diphenylpho-sphine spontaneously adds to the racemic aldol 54 and the ensuing intermediate is condensed in situ with phenylboronic acid. The resulting phosphine-boronate 55 was isolated as a 3 1 mixture of cis/trans diaster-eomers in 32% overall yield.64... 

A regioselective synthesis of pyrazoloquinolines 225 by the multicomponent reaction of 3-aryl-5-aminopyrazole 222 with 1,3-diketones and aromatic aldehydes in ethanol in the presence of Et3N under microwave irradiation at 150°C (Scheme 3.62, reaction i) was described in [193,194]. In the presence of a strong base such as EtONa (KOH), the three-component treatment proceeded via a different pathway and led to novel and unusual reaction products—quinolizi-nones 226 (Scheme 3.62, reaction ii) [193]. The formation of only one diaster-eomeric pair from two possible ones with trans relative configuration of the... 

Reduction of 2,-4-diphenyl-2,3-dihydro- 1H-1,5-benzodiazepine 103 (R is H, Ar is Ph) by sodium borohydride leads to an equimolar mixture of the diaster-eomeric tetrahydro derivatives 105 (Scheme 4.34), whereas under analogous... 

Use of hydroxyacetone as donor in the asymmetric Mannich reaction led to the formation of optically active syn /i-amino alcohols bearing two stereogenic centers [22, 23], In the presence of 35 mol% L-proline as organocatalyst several types of syn / -amino alcohol syn-35 were successfully synthesized with enantioselectivity up to 99% ee and high diastereomeric ratio. For example, a high yield of 92%, a diaster-eomeric ratio of 20 1, and enantioselectivity >99% ee were observed by List et al. for formation of the syn yfi-amino alcohol 35a (Scheme 5.17) [23]. In addition to hydroxyacetone the methylated derivative methoxyacetone was also applied successfully in this reaction (93% yield, d.r. > 39 1, >99% ee). 

One last example in this section is the observation that for a particular OC-6 Co(III) complex, an atropisomer with rotamer conformation can be obtained as the diaster-eomeric trans- CoC12py4 (hydrogen L-dibenzoyltartrate) compound in solid powder, but in solution the racemization is too fast to observe the CD spectrum.48... 

---