Epimerization base-catalyzed

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). 

The most recent, and probably most elegant, process for the asymmetric synthesis of (+)-estrone appHes a tandem Claisen rearrangement and intramolecular ene-reaction (Eig. 23). StereochemicaHy pure (185) is synthesized from (2R)-l,2-0-isopropyhdene-3-butanone in an overall yield of 86% in four chemical steps. Heating a toluene solution of (185), enol ether (187), and 2,6-dimethylphenol to 180°C in a sealed tube for 60 h produces (190) in 76% yield after purification. Ozonolysis of (190) followed by base-catalyzed epimerization of the C8a-hydrogen to a C8P-hydrogen (again similar to conversion of (175) to (176)) produces (184) in 46% yield from (190). Aldehyde (184) was converted to 9,11-dehydroestrone methyl ether (177) as discussed above. The overall yield of 9,11-dehydroestrone methyl ether (177) was 17% in five steps from 6-methoxy-l-tetralone (186) and (185) (201). 

Table 2 summarizes some of the transformations of substituents which have been carried out on azetidines without effect on the ring <79CRV33l). Other transformations of interest are the base catalyzed epimerization, H exchange and alkylation of the activated H-3 in azetidines (26) (69JHC153) and the nitration, reduction, diazotization and hence further modification of the aromatic ring in 3-phenyl-fV-acetylazetidine (27) (61LA 647)83). 

The synthesis in Scheme 13.49 features use of an enantioselective allylic boronate reagent derived from diisopropyl tartrate to establish the C(4) and C(5) stereochemistry. The ring is closed by an olefin metathesis reaction. The C(2) methyl group was introduced by alkylation of the lactone enolate. The alkylation is not stereoselective, but base-catalyzed epimerization favors the desired stereoisomer by 4 1. 

Recently, Porter et al. (1986b, 1988) have reported the synthesis of both meso- and ( )-forms of a series of two-chain carbonyl diacids made by joining two pentadecanoic acid units by a carbonyl group at the 3,3, 6,6, 9,9 and 12,12 positions, 3,5-didodecyl-4-oxoheptanedioic acid (C-15 3,3 ), 6,8-dinonyl-7-oxotridecanedioic acid (C-15 6,6 ), 9,11-dihexyl-10-oxononadecanedioic acid (C-15 9,9 ) and 12,14-dipropyl-13-oxopentacosanedioic acid (C-15 12,12 ), respectively. The diacids were used to probe further the question of stereochemical preference in two-chain amphiphiles. The method used for examining the diastereomeric preference was equilibration by base-catalyzed epimerization in homogeneous, bilayer and micellar media. This method allows for stereoselection based on hydrophobic/hydrophilic considerations rather than classic steric size effects. 

Fig. 5.10. Base-catalyzed epimerization at C(5) in penicilloic acids involves opening the thiazolidine ring by CS bond fission, followed by reclosure with inversion of configuration at...

Fig. 5.13. Base-catalyzed epimerization at C(7) in cephalosporins involves the removal of the acidic H-atom at C(7) (Pathway b). Electron-withdrawing substituents at C(3 ) enhance the acidity of the C(7) proton and, thus, favor epimerization compared to hydrolysis (Pathway a) [113][114]. 

At pH 10 and 70°, the hexapeptides had tm values for degradation of ca. 30-40 h, with the exception of Val-Tyr-Pro-Asp-Val-Ala, the stability of which was much greater (t1/2 ca. 800 h). Here, the hexapeptides containing Asp-Gly or Asp-Ser were clearly much more reactive than the Asp-Val hexapeptide. Interestingly, the D,L-iso-aspartic hexapeptide was the only product formed from the Asp-Gly hexapeptides, and it was the major product from the Asp-Ser hexapeptide (Fig. 6.28,a and c). Formation of the D-Asp hexapeptide was observed for the Asp-Ser hexapeptide, and it was the major one for the Asp-Val hexapeptide, presumably because base-catalyzed epimerization had ample time to occur given the very slow rate of other breakdown reaction. 

Fig. 7.13. HO -Catalyzed ring opening of pilocarpine (7.76) and isopilocarpine (7.77) to pilocarpic acid and isopilocarpic acid, respectively, and proton-catalyzed lactonization of the two acids to the respective lactone. Note that pilocarpine and isopilocarpine interconvert by a base-catalyzed reaction of epimerization (Reaction a).

The cyclizations of /3-hydroxycarboxamides with aldehydes, ketones, or their equivalents results in l,3-oxazin-4-one derivatives <1996CPB734, 2006BMC584, 2006BMC1978>. In the acid-catalyzed condensation of salicylamide 422 with (—)-menthone, a 2 1 mixture of C-2-epimeric 27/-l,3-benzoxazin-4(37r)-ones 202 and 423 was formed, the equilibrium of which could be shifted toward the (23 )-enantiomer 202 by base-catalyzed isomerization with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in A -methyl-2-pyrrolidone (NMP) to yield a 14 1 mixture of 202 and 423 (Equation 44) <1996TL3129>. 

Cyclic dipeptides, especially when N-alkylated, undergo extremely fast epimerization (79JA1885). For example, cyclo(L-Pro-L-Phe) is rapidly converted to its diastereomer, cyclo(D-Pro-L-Phe) (80% conversion), by treatment with 0.5 N NaOH at 25°C for 15 min. This diastereomer is the one in which the proline residue has epimerized and not the more activated phenylalanine. CNDO/2 calculations seem to provide a rationale for this. It is not yet completely clear why such base-catalyzed epimerizations of piperazinediones are so easy the conformation of the molecule may play a role in this (79MI1). It is also worth noting that even in linear peptides, rm-amides of N-alkyl-amino acids, which consist of s-trans and s-cis rotamers of almost equal energy, are more prone to racemization than the sec-amides, which exist only in the s-trans configuration. Of course, the amide functions of piperazine-2,5-diones are obliged to assume the s-cis conformation. 

Several cyclodipeptides have been subjected to base-catalyzed epimerization (EtOH/NaOEt at 30-75°C) and the ratio of cis-to-trans isomers at equilibrium has been determined (74JA3985). The results have been correlated with the conformation of the molecules. Thus, cyclo(Pro-Pro) NMR studies (73JA6142) have indicated a boat form in the cis and a planar form in the trans diastereomer. In the latter, the pyrrolidine rings take up a half-chair conformation, which is greatly strained as long as the amide bonds are planar. This renders the trans less stable than the cis diastereomer. Consequently, at equilibrium, only cis diastereomer is found the trans isomer occurs to the extent of less than 0.5%. 

C-l, obviously owing to base-catalyzed epimerization at the aldehyde stage. As compared with nitromethane cyclizations (wherein such epi-merizations have not been observed), nitroalkanes react less readily, thus providing longer exposure of the dialdehyde to the alkaline conditions required for cyclization. 

Unless a substrate or reagent contains an acidic or basic site, the conditions for most radical reactions are neutral. Thus, ionic side reactions such as base-catalyzed epimerization are rarely a problem. While radical reactions are typically conducted at temperatures above ambient, this is often solely for experimental convenience most commercially available initiators require heating to generate radicals. Many radical reactions should succeed at lower temperatures provided that the chain is maintained (in chain methods) or that the rate of generation of radicals is sufficiently rapid (in nonchain methods). Low temperature initiators are available.30,31... 

Starting from D-galactono-1,4-lactone, 2-keto-3-deoxy-D-hexonic acids with either the D-erythro (119) or D-threo configuration (120) were obtained in only three steps.318 Epimerization at C-4 occurred during the base-catalyzed /1-elimination reaction on the galactonolactone derivative 136. 

Figure 4. Froposed retro-aldol mechanism for the base-catalyzed epimerization...

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