Chiral fragments

In the synthesis of six-membered cyclic nitronates (35) by the (42 + 43) cycloaddition, facial discrimination can be achieved by introducing enantiomerically pure chiral fragments into nitro olefin (42) (147, 157) enamine (117), or enol (134). In addition, Prof. Seebach (96) and postgraduate students supervised by Prof. Denmark (158) successfully used chiral LA for facial discrimination. 

Two research groups examined the approach to the synthesis and the use of six-membered cyclic nitronates by introducing chiral inductors into the molecule of the starting a-nitroalkene. (Here, it is incorrect to use the term auxiliaries because the chiral fragment is not eliminated and is involved in the target product.)... 

As an example of spectra of molecules containing the CH2CH2C H chiral fragment, the spectra of (—)-menthone and (-t-)-isomenthone are shown in Figure 5. (—)-Menthone has two bulky substituents and the favored chair conformation is 16, which corresponds to 14 with both substituents in equatorial positions. The observed (-1— +) VCD pattern is that predicted for this fragment geometry. For isomenthone both chair conformations 18 and 19 are populated since, in each, one alkyl substituent is axial and one equatorial. However, the... 

The D-fructose-derived, chiral, nonracemic l,3-oxazin-2-one derivative 260 exerted smooth stereocontrol, resulting in high levels of asymmetric induction and good chemical yields in various synthetic transformations. The chiral fragments 256 and 261 formed in the aldol or a-bromination reactions of the A -propionyl derivative 257 could easily be removed from the parent auxiliary by mild hydrolysis (Scheme 48). The Diels-Alder cyloadditions of the A -acryloyl and A -cinnamoyl derivatives of 260 were also characterized by excellent diasterofacial selectivity <1998T9765>. 

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 this approach (17), the prochiral fragment was attached to the auxiliary at only one point making the acid-catalysed release after transformation a simple procedure. Chirality was induced by the borohydride reduction of a carbonyl group on the pro-chiral fragment in the asymmetric environment created by complexation of calcium ions between the Cl and C2 oxygens of the hexose. The diastereomeric purity was good (-70%) but separation of the diastereomers was more problematic. 

The asymmetric cis dihydroxylation of alkenes covalently bound to chiral fragments, which can be cleaved after the osmylation step, has been the subject of several reports2-5. The subsequent removal of the chiral auxiliary can be effected by various methods and allows the preparation of enantiomerically pure hydroxylated compounds. 

Ethyl lactate has also been used as a chiral fragment for numerous other studies. Included are synthetic efforts relating to salenomycin, (-)-biopterin, (+)-polyoxamic acid, jaspamide, the enantiomeric 2-pentanols, pumilitoxin B, D-ristosamine, protomycinolide IV, and tirandamycin. ... 

Chiral Pool Reagent. (7 )-Pantolactone has been used as a source of chiral fragments for synthesis. Applications include use in the syntheses of the elfamycins (eq 12) and the bryostatins (eq IS). It has also been used to prepare potentially useful chiral epoxide synthons possessing a quaternary gem-dimethyl carbon. ... 

One means of stereoselective cleavage of biaryl lactones [53] is activation of the carbonyl group with a Lewis acid and subsequent attack with a chiral nucleophile. Conversely, activation can be effected with a chiral Lewis acid followed by attack of an achiral nucleophile. Complexation of a biaryl lactone to the chiral fragment [CpRe (NO)(PPh3)j then reduction with K(s-Bu)3BH (K-selectride) and ring opening of the intermediate rhenium lactolate gives the metalated aldehyde (dr = 75 25) which is converted to the alcohol without essential loss of optical purity (Sch. 6) [54]. 

Protein kinase inhibitors are in the news as cancer drugs but Eli Lilley have a saturosporinone analogue 220 to help diabetes patients overcome problems such as sight loss from retinopathy. The bis-indole portion 221 does not concern us but the chiral fragment 222 does. 

Initial achievements in this field were carried out by Kobayashi as early as 1978. Copolymerization of 71 with acrylonitrile produced linear polymers 72 (Scheme 10.14), which are soluble in polar aprotic solvents, that were assayed for different Michael additions. In general, good conversions were obtained, but enantioselec-tivities were always below 60% ee [204-206]. In a related approach by Oda, different spacers were introduced between the polyacrylonitrile backbone and the chiral fragment, which resulted in an increase of selectivity up to 65% ee [207]. Addition of thiol groups in PS-DVB resins to the double bond allowed the preparation of the corresponding insoluble polymers 73, which were assayed by Hodge for the addition of thiols to unsaturated ketones and nitrostyrene. Again, selectivities were... 

Figure 10.7 Chiral fragments derived from cinchona alkaloids.

Cinchona alkaloids are by far the chiral fragments most used for the challenge of achieving chiral PTC using insoluble supports. For this purpose, one of the nitrogen atoms of 71, usually the aliphatic one, is quaternized, either by using this atom to anchor the polymeric backbone (92, Scheme 10.17) or by its appropriate... 

Other chiral fragments such as N-methylephedrine, N,N-dimethyl a-methylben-zylamine or strychnine have been immobilized, as quaternary ammonium salts, on PS-DVB and tested for different reactions under PTC conditions, but only low levels of enantioselectivity were obtained [262-264]. 

How might we obtain enantiomerically pure compounds Historically, the best answer to that question has been to isolate them from natural sources. Hence the dependence on natural product isolation for the production of enantiomerically pure pharmaceuticals. Derivatization of natural products or their use as synthetic starting materials has long been a useful tool in the hands of the synthetic chemist, but it has now been raised to an art form by practitioners of the Chiron approach to total synthesis, wherein complex molecules are dissected into chiral fragments that may be obtained from natural products [17-25]. 

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