Hydroxy carbonyls, reduction

There are very few reactions of real synthetic significance which proceed via condensation of two 1,3-electrophile-nucleophile species. Probably the most important of this latter type of reaction is the synthesis of pyrazines by self-condensation of an a-acylamino compound to the dihydropyrazine followed by aromatization (equation 132). The a-acylamino compounds, which dimerize spontaneously, are normally generated in situ, for example by treatment of a- hydroxy carbonyl compounds with ammonium acetate or by reduction of a-azido, -nitro or -oximino carbonyl compounds. Cyclodimerization of a-amino acids gives 2,5-dioxopiperazines (equation 133), many derivatives of which occur as natural products. Two further reactions which illustrate the 1,3-electrophile-nucleophile approach are outlined in equations (134) and (135), but su i processes are of little general utility. 

Diastereomeric 1,3-amino alcohols 1 have been obtained by reduction of 4,5-dihydroisoxa-zoles350-353. 3C chemical shifts allow a stereochemical differentiation due to the formation of energetically preferred chelated conformations. Similar to /3-hydroxy carbonyl compounds and 1,3-diol derivatives, the chemical shifts of the backbone carbons are larger in the syn 1,3-amino alcohols than in the awn -isomers353. 

An entirely different approach to the introduction of isolated double bonds is illustrated by the selective silylation of the 3-hydroxy group of 155 and Swern oxidation at C-2 to give 156 following spontaneous elimination. Final conversion of the enone to the free sugar 157 is accomplished by carbonyl reduction that induces an ester migration (Scheme 17).176... 

Miyashita, M. Suzuki, T. Hoshino, M. Yoshi-koshi, A. The organoselenium-mediated reduction of a,fl-epoxy ketones, a,fl-epoxy esters, and their congeners to /J-hydroxy carbonyl compounds novel methodologies for the synthesis of aldols and their analogs. Tetrahedron 1997, 53, 12469-12486. 

The N—O bond of isoxazolines can easily be cleaved via reduction. It is for this reason that isoxazolines are interesting synthetic intermediates. y-Amino alcohols are formed by reduction with LiAlH4 (for an example, see Figure 15.46, left). Hydrogenolysis of isoxazolines catalyzed by Raney nickel yields /j-hydroxy imines, which undergo hydrolysis to / -hydroxy-carbonyl compounds in the presence of boric acid (Figure 15.46, right). 

Hydrocarbons 407 can be used as precursors in hydroxyalkylation reactions of a,p-unsaturated carbonyl compounds 408 in the presence of molecular oxygen (Fig. 95) [438]. The reactions are catalyzed by 0.3-1 mol% Co(acac)3 and 30 mol% 398. Alkylated a-hydroxy carbonyl compounds 409 and a-keto carbonyl compounds 410 were obtained in 42-98% yield in a 1-100 1 ratio. The reactions showed a considerable induction period. Co(acac)2, in contrast, initiated the reaction very quickly, but conversion soon ceased. The success using the unreactive Co(III) complex consists of gradual reduction to catalytically active Co(II). 

In addition to accelerating the rate of carbonyl reduction, chelation can be used to control the diastereoselectivity of reductions and carbon-carbon bondforming reactions through highly organised transition states. Keck showed that appropriately subsituted p-hydroxy ketones are stereoselectively reduced by... 

Cathodic reduction of diphenyl diselenide produces a benzeneselenolate, which catalyzes the reduction of a, -epoxy carbonyl compounds into -hydroxy carbonyl compounds in the presence of a proton source (Scheme 16) [21]. This electrochemical method is applicable to the selenation of haloalkanes, epoxides, and enones [22]. Electrochemical reduction of elemental selenium to diselenide dianion (Se ) and selenide dianion (Se ) is also possible [23]. 

The reaction with a, -epoxy carbonyl compounds 12 leads to the corresponding reductive ring-opened products, -hydroxy carbonyl compounds 13, in good yields (Scheme 22). Electrochemically generated benzeneselenolate [21,22] and sodium phenylseleno(triethoxy)borate (1) [35, 36], have been applied for this type of reaction as a nucleophilic selenolate. In the latter case, the reaction mechanism was suggested as shown in Scheme 23 [36]. Reaction of 1 with 12 first produces the ring-opened adduct 14, which is then reacted with an excess amount of 1 to produce the final product 13. This method is important as a simple synthetic procedure to aldols and -hydroxy esters that are rather difficult to obtain by other methods. The reactions have been extended to the reduction of more functionalized a, -epoxy carbonyl compounds [37] and have been successfully applied for the synthesis of several natural products [38]. 

The p-hydroxy carbonyl compound formed from the crossed aldol reaction can be reduced with NaBH4, CH3OH (Section 20.4A) to form a 1,3-diol (Reaction [1]) or dehydrated to form an a,p-unsaturated carbonyl compound (Reaction [2]). Reduction of the c(,p-unsaturated carbonyl compound forms an allylic alcohol with NaBHi (Reaction [3]), or a ketone with H2 and Pd-C (Reaction [4]) see Section 20.4C. Reaction of the a,p-unsaturated carbonyl compound with an organometalllc reagent forms two different products depending on the choice of RM (Reaction [5]) see Section 20.15. 

A simultaneous reduction-oxidation sequence of hydroxy carbonyl substrates in the Meerwein-Ponndorf-Verley reduction can be accomplished by use of a catalytic amount of (2,7-dimethyl-l,8-biphenylenedioxy)bis(dimethylaluminum) (8) [33], This is an efficient hydride transfer from the sec-alcohol moiety to the remote carbonyl group and, because of its insensitivity to other functionalities, should find vast potential in the synthesis of complex polyfunctional molecules, including natural and unnatural products. Thus, treatment of hydroxy aldehyde 18 with 8 (5 mol%) in CH2CI2 at 21 °C for 12 h resulted in formation of hydroxy ketone 19 in 78 % yield. As expected, the use of 25 mol% 8 enhanced the rate and the chemical yield was increased to 92 %. A similar tendency was observed with the cyclohexanone derivative. It should be noted that the present reduction-oxidation sequence is highly chemoselective, and can be utilized in the presence of other functionalities such as esters, amides, rert-alco-hols, nitriles and nitro compounds, as depicted in Sch. 10. 

When 2-heptanone (950 mg kg was administered orally to rabbits, 40% of administered dose was excreted as heptyl-2-glucuronide, and traces of the unchanged ketone were also found in the urine. Compound undergoes carbonyl reduction to a secondary alcohol and co-l oxidation to a hydroxy-ketone which is further oxidized to 2,6-heptadione. 

Hydroxy carbonyl compounds The oxirane ring of a,P-epoxy carbonyl compounds undergo reductive cleavage (29 examples, 80-100%). 

A simultaneous reduction/oxidation sequence of hydroxy carbonyl substrates in the Meerwein-Ponndorf-Verley reduction can be accomplished by use of a catalytic amount of (2,7-dimethyl-l,8-biphenylenedioxy)bis(dimethylaluminum) (49). This represents an efficient hydride transfer from the sec-alcohol moiety to the remote carbonyl group and, due to its insensitivity to other functionalities, should find vast potential in the synthesis of complex polyfunctional molecules including both natural... 

Scheme 1-24. Chemoselective simultaneous reduction/oxidation of hydroxy carbonyl substrates.

Synthesis of (—)-Laulimalide. Different approaches to the (3-hydroxy sulfone moiety needed for the olefination reaction are frequently used in the synthesis of natural products. For instance, a very common strategy consists of carbonyl reduction of the corresponding a-ketosulfone followed by reductive elimination. This sequence is employed in the synthesis of polyhydroxylated indolizidine alkaloids (Eq. 121),207 (+)-dihydromevinolin,268 pleraplysillin-1,269 amphidino-lide B,270 and the novel antitumor agent (—)-laulimalide (Eq. 158).271... 

Since n-butyl alcohol is a four-carbon compound and "6-12" (2-ethyl-l,3-hexandiol) is an eight-carbon compound, it is reasonable to think that the main reaction is a condensation reaction. However, this condensation reaction requires two carbonyl compounds. This can be obtained by oxidizing the alcohol into an aldehyde, subsequently, aldehydes can be combined by aldol condensation to form a hydroxy-carbonyl compound. A reduction of this compound will result in the desired diol. 

Reduction of a-Ketolsf Carbonyl compounds containing a-hydroxy, a-acetoxy, or a-halo groups react with excess TMS-I to give the parent ketone. a-Hydroxy ketone reductions proceed via the iodide, which is then reduced with iodide ion to form the parent ketone (eq 32). 

Likewise, this procedure provides a route for the reduction of a,/3-epoxy ketones and a, -epoxy esters to generate the corresponding /3-hydroxy carbonyl compounds (eqs 7 and 8). The epoxy ketone substrates may be derived from Sharpless asymmetric epoxidation. Consequently, this procedure provides a means to prepare a variety of chiral, nonracemic 8-hydroxy carbonyl compounds that are difficult to acquire by more traditional procedures. 

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