4-Hydroxy cyclopentenone

An efficient kinetic resolution of 4-hydroxy-2-cyclopentenone was achieved using [kh((/ )-UINAI))(CIIjOHl JCKT as catalyst.1 The reaction proceeded with a 5 1 discrimination rate between the two enantiomers, and (.S l-isoincr, which is a useful intermediate in prostaglandin synthesis, was obtained with 91% ee at 72% conversion (Scheme 31).54... 

Among many other excellent methods, convergent three-component coupling, the consecutive linking of the a- and co-side chains to an unsaturated 4-hydroxy-2-cyclopentenone derivative, is the most direct and effective synthesis. 

Such an isomerization of 4-hydroxy-2-cyclopentenone (2) results in 1,3-cyclopen-tanedione (3) via the keto enol. On exposure of racemic 2 to the optically active Rh-BINAP complex (R)-l, the (S)-enantiomer isomerizes more rapidly than (R)-2 to give, after 14 days at 0°, a mixture of 3 and (R)-2 in 91% ee. 

Hydrogen bonding also accounts for the stereoselectivity found in the cycloaddition to 4-substituted 4-hydroxy-2-cyclopentenones (175). The importance of this effect is evident by comparing the results from 26 with those of unprotected 25 as illustrated in Scheme 6.30. The acetylation of the hydroxy group causes a drop in the ratio of diastereoisomers from 85 15 to 57 43 (175). 

Hydroxy-2-cyclopentenone by Optical Resolution of 4-(Butanovloxy)-2-cyclopentenone Typical Procedure92 ... 

Oxidation of (15,47 )-4-/ert-butyldimethylsilyloxy-2-cyclohexenol (see p400) and subsequent silyl group removal gave 4-hydroxy-2-cyclopentenone (1) of known R configuration55. 

This method is particularly effective with cyclic substrates, and the combined effects of intramolecular and intermolecular asymmetric induction give up to 76 1 (kf/ks) differentiation between enantiomers of a cyclic allylic alcohol. This kinetic resolution provides a practical method to resolve 4-hydroxy-2-cyclopentenone, a readily available but sensitive compound. Hydrogenation of the racemic compound at 4 atm H2 proceeds with kf/ks =11, and, at 68% conversion, gives the slow-reacting R enantiomer in 98% ee. The alcoholic product is readily convertible to its crystalline, enantiomerically pure fert-butyldimethylsilyl ether, an important building block in the three-component coupling synthesis of prostaglandins (67). 

Scheme 21). Scheme 22 illustrates an example of kinetic resolution of a racemic allylic alcohol with a 1,3-hydrogen shift. When racemic 4-hydroxy-2-cyclopentenone is exposed to a cationic (/ )-BINAP-Rh complex in THF, the S enantiomer is consumed five times faster than the R isomer (32). The slow-reacting stereoisomer purified as the crystalline ferf-butyldimethylsilyl ether is an intermediate in prostaglandin synthesis (33). These isomerizations may occur via initial Rh-olefinic bond interaction (34). 

Scheme 3 illustrates retrosynthetic analysis of the E and F series of PGs. The widely used Corey synthesis (2) takes notice of the presence of the two olefinic bonds in the side chains of PGF2a. The actual synthesis consists of a two-fold Wittig-type chain extension of a chiral dialdehyde equivalent with four defined stereogenic centers derived from cyclopentadiene via a series of bicyclic intermediates. A similar sequential synthesis has been developed at Upjohn Co. (la). These chemical syntheses are much more economical than enzymatic methods and are used for commercial synthesis of certain PGs. An alternative pathway pioneered by Sih is the conjugate addition approach (3). Nucleophilic addition of an E-olefinic co side-chain unit to a cyclopentenone in which the a side chain is already installed leads directly to PGE-type compounds. Untch and Stork used an co chain unit with a Z-olefinic bond (4). The most direct and flexible synthesis is the convergent three-component coupling synthesis via consecutive linking of the two side chains to unsubstituted 4-hydroxy-2-cyclopentenone derivatives (5, 6). 

As outlined in Scheme 4, the ultimate goal of the three-component coupling synthesis is the organometallic-aided conjugate addition of an cj side-chain unit to an 0-protected (J )-4-hydroxy-2-cyclopentenone, followed by electrophilic trapping of the enolate intermediate by an oc... 

As shown in Figure 1.10, kinetic resolution of racemic acyclic and cyclic secondary alcohols can be achieved by the BINAP-Ru method with up to 74 1 differentiation between the enantiomers [139]. An application includes a practical resolution of a racemic 4-hydroxy-2-cyclopentenone, an important prostaglandin building block that is achievable on a multi-kilogram scale. Racemic methyl a-(hydroxyethyl)acrylate is reduced by hydrogen... 

Kaida, Y. and Okamoto, Y. (1992) Efficient optical resolution of 4-hydroxy-2-cyclopentenone derivatives by HPLC on 1-phenylethylcarbamates of cellulose and amylose, Chem. Lett., 85-88. 

The third type is common to monoepoxides of cyclic 1,3-dienes In five- to eight-membered rings and results in rearrangement to /3,y-unsaturated ketones in 55-80% yield. This isomerization can be utilized as one step in a route to 4-hydroxy-2-cycloenones. An example is a synthesis of 4-hydroxy-2-cyclopentenone formulated in equation (III). 

Hydroxy-3-boranone, 363 y-Hydroxybutenolides, 398 7-Hydroxybutyronitriles, 213-214 a-Hydroxy carboxylic acids, 105 7-IIydroxy carboxyUc acids, 504 2-Hydroxychalcones, 461 2 -Hydroxychalcones, 409 4-Hydroxy-2-cycloenones, 452 4-Hydroxy-2-cyclopentenone, 452, 453 (S)-2-Hydroxy-2,6-dimethyl-6-heptenal,... 

Chiral 4-hydroxy-2-cyclopentenones. Both (R)- and (S)-4-hydroxy-2-cyclo-pentenones can be obtained from phenol. The first step is alkaline hypochlorite oxidation to the acid 1, which is resolved with brucine. Oxidative decarboxylation of 1 gives 2, which is partially dechlorinated and protected as the silyl ether (3). The last step to 4 is reduction with zinc-silver (S, 760) or zinc-copper. ... 

Cationic Rh-(R)-BINAP complexes also catalyze the allylic hydrogen migration of racemic 4-hydroxy-2-cyclopentenone to 1,3-cyclopentanedione with 5 1 enantiomeric discrimination. The racemate is kinetically resolved to (R)-4-hydroxy-2-cyclopentenone of 91% ee at 72% conversion at 0 °C (eq 4). ... 

Geraniol or nerol can be converted to citronellol in 96-99% ee in quantitative yield without saturation of the C(6)-C(7) double bond (eq 6). The S C ratio approaches 50000. The use of alcoholic solvents such as methanol or ethanol and initial H2 pressure greater than 30 atm is required to obtain high enantioselectivity. Diastereoselective hydrogenation of the enantiomerically pure al-lylic alcohol with an azetidinone skeleton proceeds at atmospheric pressure in the presence of an (i )-BINAP-Ru complex to afford the (3-methyl product, a precursor of ip-methylcarbapenem antibiotics (eq 7). Racemic allylic alcohols such as 3-methyl-2-cyclohexenol and 4-hydroxy-2-cyclopentenone can be effectively resolved by the BINAP-Ru-catalyzed hydrogenation (eq 8). ... 

The cationic BINAP-Rh complexes catalyze asymmetric 1,3-hydrogen shifts of certain alkenes. Diethylgeranylamine can be quantitatively isomerized in THF or acetone to citronellal di-ethylenamine in 96-99% ee (eq 17). This process is the key step in the industrial production of (-)-menthol. In the presence of a cationic (R)-BINAP-Rh complex, (5)-4-hydroxy-2-cyclopentenone is isomerized five times faster than the (R) enantiomer, giving a chiral intermediate of prostaglandin synthesis. ... 

Kuhn, C, Florent, J-C, A carbohydrate approach to 4-hydroxy-2-cyclopentenone moiety of antitumor prostanoid punaglandin IV via alkylation of ester uronate, Tetrahedron Lett., 39, 4247-4250, 1998. 

Hydroxy-2-cyclopentenones. The reagent reacts with ketone enolates to form functionalized cyclopentenol derivatives which on exposure to TBAF leads to 4-hydroxy-2-cyclopentenones. A successfiil application of the method to the synthesis of the... 

Figure 6.10 illustrates the preparation of two key building blocks E and I. The former was synthesized by employing lipase-catalysed reaction, while the latter was derived from L-(+)-tartaric acid (F). The known ( )-4-hydroxy-2-cyclopentenone (A) was converted to C (as a mixture of four stereoisomers) via B. Treatment of C with pig-pancreatic lipase (PPL) afforded (—)-D in 25% yield. By this enzymatic hydrolysis of the acetate C, only the acetate corresponding to (—)-D was hydrolysed even in the presence of chlorine and silicone atoms in the molecule to give the desired (—)-D. The experimental simplicity of... 

---