Formation of Diastereomers

Diastereomers are defined as compounds which have the same molecular formula and sequence of bonded elements but which are nonsuperimposable, non-mirror 

One of the most direct ways to produce diastereomers is by addition reactions across carbon-carbon double bonds. If the structure of the olefin substrate is such that two new chiral centers are produced by the addition of a particular reagent across the double bond, then diastereomers will result. For example, the addition of HBr to Z-3-chloro-2-phenyl-2-pentene produces 2-bromo-3-chloro-2-phenylpentane as a mixture of four diastereomers. Assuming only Markovnikov addition, the diastereomers are produced by the addition of a proton to C-3 followed by addition of bromide to the carbocation intermediate at C-2. Since the olefin precursor is planar, the proton can add from either face, and since the carbocation intermediate is also planar and freely rotating, the bromide can add to either face to give diastereomeric products. The possibilities are delineated schematically (but not mechanistically) below. 

The diastereoselectivity for any process is often reported as a diastereomeric excess (de%), which is analogous to the optical purity reported for mixtures of enantiomers. The de% is given by de% = % major diastereomer — % minor diastereomer. For diastereospecific reactions in which a single diastereomer is produced, de = 100%, while for reactions in which there is no selectivity and diastereomers are produced in equal amounts, de = 0%. 

A typical example of a stereospecific olefin addition reaction is the addition of bromine to olefins. If d.v-2-pentene is used as the substrate, only the 2R,3R and 2S,3S pair will be produced (they are enantiomers). 

Because the addition of bromine is stereospecifically trails or anti, one bromine atom adds to each face of the olefin and can go to either carbon. If traw.v-2-pcntcnc is used as the substrate, then only the 2R,3S and 2S,3R pair is produced (they are also enantiomers.). However, the pair from cw-2-pentene is diastereomeric with die pair from fraws-2-pentene. 

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The introduction of a THP ether onto a chiral molecule results in the formation of diastereomers because of the additional stereogenic center present in the tetrahy-dropyran ring (which can make the interpretation of NMR spectra somewhat troublesome at times). Even so, this is one of the most widely used protective groups employed in chemical synthesis because of its low cost, the ease of its installation, its general stability to most nonacidic reagents, and the ease with which it can be removed. 

Reaction of 2-[A -(rra -crotyl)-A -benzylamino]-3-formyl-4/f-pyrido[l,2-n]pyrimidin-4-one (269) with chiral primary amines 270 and 271 gave mixtures of diastereoisomers of tetracyclic compounds 273 and tricyclic 275 (96T131]]). The chiral centers in 272 and 274 did not provide any stereocontrol for the formation of diastereomers 273 and 275, respectively. 

In the 1,3-dipolar cycloaddition reactions of especially allyl anion type 1,3-dipoles with alkenes the formation of diastereomers has to be considered. In reactions of nitrones with a terminal alkene the nitrone can approach the alkene in an endo or an exo fashion giving rise to two different diastereomers. The nomenclature endo and exo is well known from the Diels-Alder reaction [3]. The endo isomer arises from the reaction in which the nitrogen atom of the dipole points in the same direction as the substituent of the alkene as outlined in Scheme 6.7. However, compared with the Diels-Alder reaction in which the endo transition state is stabilized by secondary 7t-orbital interactions, the actual interaction of the N-nitrone p -orbital with a vicinal p -orbital on the alkene, and thus the stabilization, is small [25]. The endojexo selectivity in the 1,3-dipolar cycloaddition reaction is therefore primarily controlled by the structure of the substrates or by a catalyst. 

D-mannopyranoside [41]. All these anions were isolated as their dimethylam-monium salts in good yields and chemical purity. The presence of the stereo-genic centers of the chiral ligands induces the formation of diastereomers. In essentially all cases, the initial salts are obtained in high diastereomeric purity. Figure 20 shows the diastereomeric ratios and, when known, the relative configuration of the major isolated compounds. 

The allene moiety of the products 70b, 72 and 75 is in each case chiral and, furthermore, an additional chiral center is created in 72a,b and 75b,e-g, thereby leading to the possible formation of diastereomers. However, the concerted nature of such sigmatropic processes should result in suprafacial migrations and formation of the racemate of only one diastereomer in each case, as shown for 74 — 75 in Scheme 7.10. High stereoselectivity can really be found for the reaction of (fc)-71a and 74b,e,f, but not for other examples of type 71 and for 74g, which lead to mixtures of diastereomers. 

Investigations on the stereochemistry of chiral semiochemicals may be carried out by (gas) chromatographic separation of stereoisomers using chiral stationary phases, e.g. modified cyclodextrins [32]. Alter natively, formation of diastereomers (e.g. Mosher s ester or derivatives involving lactic acid etc.) may be followed by separation on conventional achiral stationary phases. Assignment of the absolute configuration of the natural product will again need comparison with an authentic (synthetic) reference sample. 

One can try to figure out from the pictures how two diastereomeric intermediates are formed. It is more convenient to adopt a formal approach. We can explain the formation of enantiomers when a metal (even a bare Ag+ ion would do) co-ordinates to our alkene substrate, and equally so the formation of diastereomers in Figure 4.5. 

A third class of compounds that can be hydrogenated are ketones or aldehydes containing another polar group. The pressures used are high (50-100 bar H2) but the enantioselectivities are excellent. The general reaction (R can be varied extensively) is shown in Figure 4.16. Since these B-substituted ketones are easy to make, this method is extremely powerful for the synthesis of enantiomers. Furthermore, the catalyst is also very selective in the formation of diastereomers. An industrial application is shown below [19],... 

Acetals and ketals are very important protecting groups in solution-phase synthesis, but only a few constructs have been used as linkers in solid-phase synthesis (Tab. 3.3). The THP-linker (22) (tetrahydropyran) was introduced by Ellman [54] in order to provide a linker allowing the protection of alcohols, phenols and nitrogen functionalities in the presence of pyridinium toluene sulfonate, and the resulting structures are stable towards strong bases and nucleophiles. Other acetal-linkers have also been used for the attachment of alcohols [55, 56]. Formation of diastereomers caused by the chirality of these linkers is certainly a drawback. Other ketal tinkers tike... 

We explain the selective formation of diastereomer 52 on the basis of conformational arguments. The two likely conformers of 50 should have an essentially planar allyl moiety, whereas the six-membered ring should exist in two quasi-chair conformers with either the isopropyl or the methoxy group in the quasi-axial position. The conformer with the (bulkier) isopropyl group in a quasi-equatorial position is preferred. While access to the terminal allylic carbon (which leads to 51) appears to be unhindered, the quasi-axial substituent at the chiral carbon will interfere with the attack on the internal allylic center, directing the attack to the face opposite to the quasi-axial methoxy function, (- 52). These considerations account for the preference of 51 over 52 as well as for the suppression of the diastereomer. 

The reaction of m-3,4-di- /t-butylthiolone-3,4-diol 74 with thionyl chloride and base (triethylamine or pyridine) produced two diastereomeric cyclic sulfites 3a and 3b. The ratio of 3a to 3b is dependent on the solvent used (Table 3). These teactions are generally high yielding with a greater tendency for the formation of diastereomer 3a (Equation 25) <2003HAC587>. 

However, in order to separate enantiomers via formation of diastereomers, the chiral selector (CDA) must be optically pure, e.g., 99.9% of ( )-SO, otherwise the separated diastereomeric reaction products will still be contaminated with the reaction products derived from (S)-SO, leading to optically impure reaction products (mixture of enantiomers) and false results when evaluating the optical purity data of the analyte. 

Whenever possible, the chemical reactions involved in the formation of diastereomers and their conversion to separate enantiomers are simple acid-base reactions. For example, naturally occurring (S)-(-)-malic acid is often used to resolve amines. One such amine that has been resolved in this way is 1-phenylethylamine. Amines are bases, and malic acid is an acid. Proton transfer from (S)-(-)-malic acid to a racemic mixture of (/ )- and (5)-1-phenylethylamine gives a mixture of diastereomeric salts. 

Lactone 5 can be obtained in both enantiomeric forms or as a racemate according to the described procedure. The reaction sequence includes the in situ formation of an alkylidene-1,3-dicarbonyl system 7 which can act as a heterodiene in an intramolecular hetero-Diels-Alder addition. A small amount of the ene product 4 with de > 98% is formed at room temperature as well. The remarkable selectivity in formation of diastereomer 3 is explained by an energetically more favorable exo transition state 8 with a pseudo-chair arrangement having the methyl group quasi-equatorial. Polycyclic cis-fused compounds can also be synthesized by the procedure above,9 and a related sequence to the cannabinoid skeleton has been described using appropriate 1,3-dicarbonyl reactants.10... 

Preferred formation of a double bond with the Z configuration is explained by Corey as follows. In solution there exists an equilibrium between lithiated alkync 44 and allene 45. The latter adds to the aldehyde with minimization of stcric interactions to give intermediate 46. Two stereocentcrs at C-3 and C-4 are thereby created in a single step. Simple diaslereoselectivity is observed leading to preferential formation of diastereomer 46a over 46b because of stenc interactions. 

By analogy, die formation of diastereomers is observed for additions to other trigonal systems, such as olefins, which have a chiral center elsewhere in the molecule. In these cases, if optically active starting materials are used, then the diastereomers will be optically active. If racemic starting materials are employed, the diastereomeric mixture will be optically inactive. In either case it is common to find different amounts of the two diastereomers. 

The formation of diastereomers is also possible when two new chiral centers are produced from achiral starting materials. A pertinent example is found in aldol-type reactions between enolates and carbonyl compounds. The achiral enolate and the achiral aldehyde or ketone gives a product with two new... 

With substituted nitroalkanes, the formation of diastereomers becomes a possibility. 

This type of photocyclization strategy has also been utilized [80] to construct indoline substructures 157 and 159 by irradiating enamine derivatives bearing an electron-withdrawing substituent on the olefinic double bond, such as 156. This was produced as a mixture of cis and trans diastereomeric indolines, as shown in Scheme 8.45. The formation of diastereomers (157 and 159) is explained by... 

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