Acyclic Ketones and Aldehydes

In this chapter, we have outlined the progress made thus far in the use of DKRs based on enzyme-mediated reductions from both practical and fundamental viewpoints. 

Until today, the most common process in industry to obtain enantiomerically pure products is through the resolution of racemic mixtures. However, with this process, there is a maximum 50% yield of optically pure compounds. Therefore, from practical viewpoint, DKR strategies have attracted a great interest from academia as well as from the industry because they can solve the problem of the 50% limitation in yield. Since the last decade, there has been an increasing trend toward the use of metal-free catalysts, especially in the production of pharmaceutical products. 

Asymmetric reductions with enzymes from diverse sources have shown a great potential in successful DKR processes. The use of whole cells of microorganisms in DKR has been shown to provide alternative way when cofactors regeneration is required. The development of new biocatalysts has been greatly promoted from the utilization of enzymes expressed and the increased availability of genes in data bank. The increased number of commercially available oxidoreductases has also contributed a lot to the progress of asymmetric synthesis toward enantiomerically pure bioactive compounds. 

We finally believe that novel methodologies of multienzyme processes for dynamic resolutions will be developed, whereas the applications of DKR in organic synthesis will continue to fascinate researchers in academia as well as in pharmaceutical industry. 

1 (a) Stecher, H. and Faber, K (1997) Synthesis, 1—16 (b) Martin-Matute, B. and Backvall, J.-E. (2007) Curr. Opin. Chem. Biol, 11, 226-232 (c) Pellisier, H. (2008) Tetrahedron, 64,1563—1601 (d) Martm-Matute, B. and Backvall, J.-E. (2008) Asymmetric Organic Synth is with Enzymes (eds V. Gotor, I. Alfonso, and E. Garda-Urdiales), Wiley-VCH Verlag GmbH, Weinheim, pp. 89-113 (e) Kim, M.-J., 

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III. COMPILATION OF KETONE AND ALDEHYDE CD A. Acyclic Ketones and Aldehydes... 

This sequence transforms acyclic ketones and aldehydes into a-methylene ketones and a-methyl-a,)5-unsaturated ketones and aldehydes It has been illustrated by the synthesis of eucarvone, ( )-nuciferal and ( )-manicone This ring-opening of chlorosiloxycyc-lopropanes with ClSiMea elimination appears to be a practical route to Z or a,)5-ethylenic aldehydes and ketones depending on the stereochemistry of the reactants. For example, conversion in MeOH-NEta at 20°C of the 2-chloro-2-methyl-3-pentyl-l-trimethylsiloxycyclopropanes (derived from the addition of the chloromethylcarbene to the E and Z silyl enol ethers of n-heptanal) leads either to or Z 2-methyl-oct-2-enal (equation 65). ... 

Application of the MVK annulation procedure to enamines of acyclic ketones and aldehydes gives cyclohexenones. If the aldehyde carbonyl group is attached to a ring, the procedure provides a valuable stereoselective method for the spiroannulation of cyclic ketones (Scheme 138). The use of l-methoxybut-3-en-2-one in place of MVK provides a means for subsequent 1,2-transposition of a ketone carbonyl function (Scheme 139). Condensation of 2,2,2-trifluoroethyi vinyl ketone with enamines gives 2-trifluoromethylcyclohexenones °. 

Acyclic ketones and aldehydes having 3 or 4 carbon atoms between the azido and carbonyl group also undergo rearrangements to afford A-substituted lactams when treated... 

Table 7.2 Intramolecular Schmidt reactions of acyclic ketones and aldehydes...

Grignard reaction and similar transformations allow C-C bond formation without a palladium catalyst. Grignard reagents and organolithium compounds are very versatile carbanion sources used in the synthesis of acyclic, heterocychc and carbo-cychc compounds. The esters, ketones and aldehydes are more stable when the reaction takes place on solid supports than in the hquid-phase, because this immo-bihzed components are not so sensitive towards water or oxygen. In the total synthesis of (S)-zearalenone (155) on solid supports the Grignard reaction is one of the key steps (Scheme 3.16) [120]. 

Conjugated ketones and aldehydes have been reported to give [2 + 2] cycloadducts in a stercospccific manner in the presence of cthylaluminum diehloride. The reaction is sensitive to temperature with acyclic products being formed at higher temperatures.3... 

Aluminum atom reactions are relevant to interfacial chemistry associated with aluminum-polyimide junctions. Al deposited under ultra high vacuum will reduce surface carbonyl functional groups (22). MVS co-condensation experiments show that besides ketones, aldehydes and epoxides, atomic aluminum will deoxygenate ethers. Chapter 7 of the monograph by Klabunde (12) includes tables of deoxygenation products of a variety of cyclic and acyclic ketones and ethers. 

Both the (Z)-enolates from acyclic ketones and the (E)-enolates from cyclic ketones react with aldehydes to form P-hydroxy ketones with high. vvn-diastereoselectivity. Examples ... 

As shown in Scheme 38, several primary alkyl-substituted cyclohexanones have been prepared by Lewis acid catalyzed phenylthioalkylation of the TMS enol ether of cyclohexanone followed by reductive removal of a phenylsulfenyl group. The two-step neopentylation sequence is particularly noteworthy. This methodology has been used to prepare numerous a-alkylated cyclic and acyclic ketones. a-Alkylated aldehydes can be produced in a like manner. a-Alkylidenation can also be accomplished by oxidative removal of sulfur. Lee and coworkers have found that TMS triflate-catalyzed reactions of silyl enol ethers of cyclic ketones and aldehydes with saturated and unsaturated l,l-dimethoxy-(i>-tri-methylstannanes, followed by addition of titanium tetrachloride, provide novel routes to fused and spiro-cyclic ring systems. Phenylthiomethylstannylations of silyl enol ethers have also been reported. ... 

Asymmetric synthesis via chiral, nonracemic hydrazones have gained wide acceptance in the community of synthetic organic chemists. Some examples of asymmetric alkylations of acyclic, satu-rated and unsaturated cyclic ketones - and aldehydes, which are applicable in the natural products field, are shown in Scheme 55. Various methods of cleavage of the alkylated hydrazones are also illustrated in Scheme 55. 

In a very useful modification, simple ketones with CH2 adjacent to the carbonyl (cyclic ketones work much better than acyclic ketones) and ortfto-iodo-arylamines react under palladium catalysis to give indoles directly. The use of dimethylformamide as solvent and DABCO as the base are crucial to the success of the route. Mechanistically, the sequence certainly proceeds through the enamine. As well as being conceptually and practically simple, this method tolerates functional groups that would be sensitive to the acid of the traditional Fischer sequence. This method can also be applied to aldehydes, thus providing a direct route to 2-unsubstituted indoles, including side-chain-protected tryptophans. ... 

The stereochemistry of organometallic additions in acyclic carbonyl compounds has also been examined. Additions of Grignard reagents to ketones and aldehydes was one of the reactions that led to the formulation of Cram s rule (see p. 179). Many ketones and aldehydes have subsequently been subjected to studies to determine the degree of stereoselectivity. Cram s rule is obeyed when no special complexing functional groups are present near the reaction site. One series of studies is summarized in Table 7.5. These data show consistent agreement with Cram s rule and the Felkin TS, as discussed in Section 2.4.I.2. 

Enolates with Chiral Auxiliaries. Enantioselective alkylation of carbonyl derivatives encompassing chiral auxiliaries constitutes an important synthetic process. The anions derived from aldehydes, acyclic ketones, and cyclic ketones with (S)-l-Amino-2-methoxymethylpyrrolidine (SAMP) are used to obtain alkylated products in good to excellent yields and high enan-tioselectivity (e.g. eq 21). ... 

A previously described procedure, reported to be efficient for dioxolanes and noncyclic acetals, has been generalized for both cyclic and acyclic acetals of ketones and aldehydes, and it has been successfully applied to the opening of 1,3-dioxanes to enol ethers (eq 81). However, aromatization has occurred for 4-(A -benzoylamino)-4-phenyl-2,5-cyclohexadienone dimethyl ketal (eq 82). This method has also allowed the development of 1-methylcyclopropyl ether as a protecting group for the hydroxyl moiety which is prepared regioselectively from terminal acetonides. ... 

The simplest reaction occurs by using acetone as donor and nonenolisable aldehyde (eqn. (1) in Scheme 6.1), because a single regio- and diastereo-isomer is obtained. The reaction of symmetrically substituted cyclic or acyclic ketones only yields one regioisomer, but a mixture of diastereo-isomers could be formed (eqn. (2)), whereas mixtures of regio- and diastereo-isomers can be obtained by reaction of unsymmetrically substituted ketones and aldehydes (eqn. (3)). 

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