Stereoselectivity cyclohexenone reductions

Selective reductions This complex borohydride is particularly useful for selective 1,2-reduction of acyclic a,/ -cnones and of conjugated cyclohexenones to allylic alcohols. However, the 1,2-selectivity is less marked with conjugated cyclopentenones. The reagent reduces unhindered cyclic ketones to the more stable (equatorial) alcohols with stereoselectivity greater than that of sodium borohydride. 

The pyridyl analog (51) leads to the opposite asymmetric orientation in most cases. Asymmetric reduction of 2-cyclohexenone affords (/ )-2-cyclohexenol with 98% ee. Other cyclic ketones are also converted to (f )-carbinols in high optical yields (Scheme 9), but the reduction of acyclic ketones is only moderately stereoselective. ... 

The stereoselectivity of the hydride reduction of conjugated cyclohexenones has also been subjected to close examination from both experimental and theoretical viewpoints. Much of the work has involved polycyclic systems, e.g.. steroids which have little conformational flexibility and in which axial and equatorial directions of approach can be clearly defined. With small" hydride donors, these substrates show an even clearer preference for axial attack than the corresponding cyclohexanones. For examples involving reductions with lithium aluminum hydride and sodium borohydride, see Table 10. 3/(-Acetylcholest-5-en-7-one and cholest-2-en-l-one are notable in that the analogous saturated substrates are attacked from the equatorial direction115 l16. The reduction of 17/i-hydroxy-4-androsten-3-one (testosterone) to 4-androstene-3/1,17/j-diol with d.r. 90 10 can be compared with the sodium borohydride reduction of 17/i-hy-droxyandrostan-3-one (dihydrotestosterone) to androstane-3/ ,17/ -diol with d.r. 81 19 (see p 4030). 

An interesting approach to the synthesis of highly oxygenated cyclohexane derivatives has been developed by Ichihara. Benzoquinone epoxides and epox-ycyclohexenones were obtained by the thermal retro Diels-Alder reaction of epoxide 511, obtained from quinones and dimethylfulvene without isolation of the primary adduct. Intermediate 512 (R = Ac), obtained in this way from hydroxymethyl-benzoquinone, was converted into the natural compound sene-poxide (514) as shown in Scheme 6. Reductive, regioselective cleavage of the diepoxide 513 was achieved by treatment with hydrazine hydrate. The stereoselective total synthesis of crotoepoxide (515) from cyclohexenone 512 (R = Ms), and of other natural compounds with related structure, was described. ... 

A stereoselective [3 + 3] annulalion by a Michael-Wittig reaction on the enal 82 derived from 2,3-0-isopropylidene-(/ )-glyceraldehyde and ethyl-3-oxo-(triphenyl phosphoryU-dene) butanoate (69)" in one pot gave the cyclohexenone derivative 83. Enone reduction and stereoselective dihydroxylation led to formation of highly functionalized cyclohexane systans (85a to 85c) (Schone 22.19). 

In 1991, the Danishefsky group disclosed the synthesis of the C-28-C-49 subunit of rapamycin utilizing the combination of the Perrier carbocyclization reaction and an Ireland-Claisen rearrangement (see Section 12.3.3. Scheme 12.21T The Perrier carbocyclization of 5-enopyranoside 86, prepared from 2-deoxy-d-glucose derivative (Section 12., Scheme 12.2ST followed by elimination of the p-hydro group gave cyclohexenone 152 tScheme 12.40T Luche reduction of 152 afforded cyclohexenol 83 stereoselectively. Condensation of 83 with carboxylic acid 84, prepared from (i )-3-(benzylojg )-2-methylpropanal, provided ester 82 in 75% yield. 

Total syntheses of diterpenoid hydrokempenones have been accomplished by Paquette et al.,f using the Pd-catalyzed [3 + 2] cycloaddition methodology. One example is outlined on Scheme 43 and describes the synthesis of an isomeric compound 208 of 3/3-hydroxy-7/3-kemp-8(9)-en-6-one, a defense secretion agent of the neotropical species Nasutitermes octopilis. 3-AUcoxy-2-cyclohexenone 204 was efficiently functionalized and transformed to bicylic adduct 205 via a Robinson annulation reaction. Reduction of the double bond followed by condensation of dimethyl carbonate and oxidation gave the keto ester 206, which was treated with [2-(acetoxymethyl)-3-allyl]trimethylsilane, palladium acetate, and triisopropyl phosphite in refluxing tetrahydrofuran to afford a 98% yield of 207. Substituted methylenecyclopentane 207 was then functionalized by stereoselective reduction and protections, and final closure was done under basic conditions after an ozonolysis step. A modified Barton-McCombie reaction produced the desired tetracyclic adduct 208. 

A Birch reduction of 40, followed by acylation of the amino group in the resulting dihydro derivatives 41 with cyanoacetic acid and subsequent hydrolysis of the enol ether moiety gave cyclohexenones 42. Treatment of 42 with a substoichiometric amount of NaOEt caused the isomerization of the carbon—carbon double bond to give an a,P-enone and the closure of the piperidine B ring by an intramolecular Michael addition, leading to the ds-fused perhydroisoquinoUne derivatives 43 as mixtures of C-9 epi-mers. A stereoselective allylation from the most accessible face of 43... 

An early example of protein engineering of an OYE pertains to the reductase from S. pastorianus as a catalyst in the stereoselective reduction of hulky 3-aIkyl-suhstituted 2-cyclohexenone derivatives in the presence of an NADPH regeneration system [35]. 

Synthetic analogues have been prepared as exemplified in Scheme 14 [95]. A first Wittig-Homer olefination of aldehyde 107, followed by acidic treatment, generates cyclohexenone 108. Chemo- and stereoselective reduction of the latter with 9-BBN followed by sy -selective epoxidation of the allylic alcohol (lateral hydroxyl group control) by w-chloroperbenzoic acid gives 109. Selective tosylation of its secondary alcohol moiety (steric hindrance makes the tosylation of the tertiary alcoholic moiety difficult) and subsequent deprotonation of the tertiary alcohol with NaH provide an alcoholate that undergoes an intramolecular displacement reaction. 

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