Natural epimeric

Maltese, F. Erkelens, C. Kooy, F.V.D. Choi, Y.H. Verpoorte, R. 2009. Identification of natural epimeric flavanone glycosides by NMR spectroscopy. Food Chem. 116 575-579. 

L-Nucleosides represent a class of nucleoside analogs with an excellent profile for antiviral activity combined with minimal host toxicity [105]. Synthesis of new L-nucleosides can use L-ribose and 2-deoxy-L-ribose as starting materials. Synthetic preparations of L-ribose from natural epimeric L-aldopentoses such as L-arabinose or L-xylose has recently been reviewed [106]. The simpler approach used an oxidation-reduction at C-2 from L-arabinose as depicted in Scheme 18 [107, 108]. 

Ephedrine and pseudoephedrine (2-methylamino-l-phenylpropan-l-ol) are natural epimeric amino alcohols extracted from various species of the family of plants Ephedra. These plants have been used for millennia in China as stimulants and nasal decongestants. The structures of natural (—)-ephedrine and (+)-pseudoephedrine are depicted in Figure 3.3. The figure also shows norephedrine, which is the nitrogen-unsubstituted counterpart of ephedrine. These compounds are nowadays commercially available as inexpensive crystalline white solids and have been extensively used in phosphorus chemistry, as detailed in the next sections. 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

Epimerization at C(5) has not been observed under the conditions discussed for the preparation of C(6) epimers (see Section 5.11.3.8.4). It is possible to prepare 5 -epipenicillins, however, as shown in Scheme 28. Note particularly the successful removal of the phthaloyl group (step iii) in this sequence, a procedure which leads to /3-lactam cleavage when C(5) is the R, or natural, configuration. Silylation of (35) followed by DBN treatment afforded (36), which corresponds to epimerization at C(3), and (37), which corresponds to epimerization at C(3) and C(6). No product corresponding to only C(6) epimerization was observed (76JOC2561). 

A classic diagnostic use of such stereochemical requirements, due to Ruzicka, is the ring contraction induced in natural products containing the 4,4-dimethyl-5a-3 -ol system (94). The epimeric, axial 3a-alcohols (95) dehydrate without ring contraction. Barton suggested that it is necessary for the four reacting centers (hydroxyl, C-3, C-4, C-5) to be coplanar for ring contraction to occur, and this is only the case with the 3)5-alcohol. 

Acetoxy-21-nor-5a-cholestan-20-one (73a) as well as the free alcohol (73b) react with methylmagnesium iodide to give a mixture of epimeric diols (74). After treatment with acetic anhydride and subsequent hydrogenation over reduced platinum oxide this mixture alfords 3j5-acetoxy-5oc-cholestane (75) which is identical with the natural product. This synthesis has been used to prepare the 21- C compound (75) in a total yield of 18... 

Oxidation of the hydroxy group in (10) to the ketone followed by isomerization affords the 10oc-methyl-A -3-ketone (11). In contrast, methylenation of 3)5-hydroxy-A ° -compounds proceeds in refluxing ether solution to give, after oxidation and acid rearrangement, the natural 10/5-methyl-A -3-keto steroids. With an epimeric mixture of 3fi- and 3a-A ° -alcohols only the )5-alcohol reacts under these imild conditions. ... 

Treatment of 14 with hydrogen and a catalyst converts it to a mixture of epimeric 6-deoxy-5-oxytetracyclines (15 and 16), each of which is active as an antibiotic. The more active isomer has the natural tetracycline configuration of the methyl group at Ce and is in clinical use as a 6-deoxyoxytetracycline (15). ... 

The chlorophylls produced by bacteria, algae and plants are a natural source of chlorins. The isolation of chlorophylls from natural material is known to be difficult because of their extreme sensitivity to various reactions, such as enolization, epimerization, allomerization, de-methoxycarbonylation, solvolysis, demctalation, dephytylation, photooxidation, etc. Often the... 

As described in Section 2.3.2, vinylaziridines are versatile intermediates for the stereoselective synthesis of (E)-alkene dipeptide isosteres. One of the simplest methods for the synthesis of alkene isosteres such as 242 and 243 via aziridine derivatives of type 240 and 241 (Scheme 2.59) involves the use of chiral anti- and syn-amino alcohols 238 and 239, synthesizable in turn from various chiral amino aldehydes 237. However, when a chiral N-protected amino aldehyde derived from a natural ot-amino acid is treated with an organometallic reagent such as vinylmag-nesium bromide, a mixture of anti- and syn-amino alcohols 238 and 239 is always obtained. Highly stereoselective syntheses of either anti- or syn-amino alcohols 238 or 239, and hence 2,3-trans- or 2,3-as-3-alkyl-2-vinylaziridines 240 or 241, from readily available amino aldehydes 237 had thus hitherto been difficult. Ibuka and coworkers overcame this difficulty by developing an extremely useful epimerization of vinylaziridines. Palladium(0)-catalyzed reactions of 2,3-trons-2-vinylaziri-dines 240 afforded the thermodynamically more stable 2,3-cis isomers 241 predominantly over 240 (241 240 >94 6) through 7i-allylpalladium intermediates, in accordance with ab initio calculations [29]. This epimerization allowed a highly stereoselective synthesis of (E) -alkene dipeptide isosteres 243 with the desired L,L-... 

Quinidine, a natural product epimeric with quinine at Cg and C9, was accessed through the diastereoisomeric trans epoxide prepared from 86 by SAD, in this case by using AD-mix a [2b, 41]. 

Commercial A -acetylneuraminic acid aldolase from Clostridium perfringens (NeuAcA EC 4.1.3.3) catalyzes the addition of pyruvate to A-acetyl-D-mannosamine. A number of sialic acid related carbohydrates are obtained with the natural substrate22"24 or via replacement by aldose derivatives containing modifications at positions C-2, -4, or -6 (Table 4)22,23,25 26. Generally, a high level of asymmetric induction is retained, with the exception of D-arabinose (epimeric at C-3) where stereorandom product formation occurs 25 2t The unfavorable equilibrium constant requires that the reaction must be driven forward by using an excess of one of the components in order to achieve satisfactory conversion (preferably 7-10 equivalents of pyruvate, for economic reasons). 

Intramolecular Diels-Alder reactions employing furan as the diene component are an effective step in the synthesis of many natural products, but difficulties are sometimes encountered due to the poor dienic character of the aromatic ring. Using CDs can help to overcome this problem. Thus, when 73 is heated in water at 89 °C for only 6h a 20% epimeric 1 2 mixture of 74 and 75 is... 

Extensive studies have indicated that only pyruvate is acceptable as the NeuA donor substrate, with the exception of fluoropyruvate [49], but that the enzyme displays a fairly broad tolerance for stereochemically related aldehyde substrates as acceptor alternatives, such as a number of sugars and their derivatives larger or equal to pentoses [36,48,50,51]. Permissible variations include replacement of the natural D-manno configured substrate (4) with derivatives containing modifications such as epimerization, substitution, or deletion at positions C-2, -4, or -6 [16,27]. Epimeriza-tion at C-2, however, is restricted to small polar substituents owing to strongly... 

However, upon dissolution, an epimerization of the anions can occur in the presence of acidic counter-ions. This is particularly true for 16a-16d [39]. The nature of the solvent (MeOH, CHCI3) plays a crucial role on the kinetics of epimerization and the position of the resulting equilibrium. For anions made with a 2R, 3R) tartaric backbone, a A configuration is always preferred in MeOH the selectivity, obtained after a slow equilibration, being independent of the nature of the ester alkyl chain (diastereomeric ratio (d.r.) 3 1). However, in chloroform, the A diastereomer is rapidly obtained and the selectivity is best if the ester side chain is sterically demanding (d.r. 2 1 to 9 1 from 16a to 16d) (Scheme 16). 

Epimerization of 4 at C-2 provided 5a-carba-a-DL-galactopyranose (6). When the pentaacetate IS was heated in acetic acid containing sulfuric acid, epimerization occurred at C-2 through an intermediary cyclic acetoxonium ion (18), with anchimeric assistance of the vicinal, axial acetoxyl group. After acetylation, 5a-carba-a-DL-galactopyranose pentaacetate (19) was obtained in a yield of 14% it was converted into 6 by hydrolysis. The antimicrobial activity of the racemate 6 was found to be about half that of the natural antibiotic 7 in the same assay system, indicating that the L-antipode is probably inactive. " ... 

Sodium borohydride reduction of aknadinine gave a pair of epimeric alcohols, one of which was found to be identical to natural epihernandolinol and the other identical to the known alkaloid hemandolinol (10) (28). As the structure of hemandolinol (10) had been proposed without resolution of the stereochemistry (28), the stereochemistry of epihernandolinol (9) was not definitely established (27). 

Ishikawa s synthesis of ( )-0-methylkinamycin C (54) represents a distinct approach to the kinamycins that hinges on a key Diels-Alder reaction to establish the tetracyclic skeleton of the natural products. Additional key steps in the sequence include a substrate-directed dihydroxylation, substrate-directed reduction, and spontaneous epimerization of an a-hydroxyketone intermediate. 

When pyridinium salt 187 was transformed to an indolo[2,3-a]quinolizidine compound in a similar way and the unsaturated lactone 188 was hydrogenated over platina catalyst, a mixture of vallesiachotamine-type compounds (189 di-astereomers) epimeric at C-20 was formed (134). These compounds have also been prepared in optically active form from vallesiachotamine (9), thus producing the first chemical correlation between synthetic and natural vallesiachotamine derivatives (134). 

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