Diene synthesis aldehydes

The total synthesis of palytoxin (1) is a landmark scientific achievement. It not only extended the frontiers of target-oriented synthesis in terms of the size and complexity of the molecules, but also led to new discoveries and developments in the areas of synthetic methodology and conformational analysis. Among the most useful synthetic developments to emerge from this synthesis include the refinement of the NiCh/CrC -mediated coupling reaction between iodoolefins and aldehydes, the improvements and modifications of Suzuki s palladium-catalyzed diene synthesis, and the synthesis of A-acyl vinylogous ureas. 

A useful application of the silver-mediated additions is 1,3 -diene synthesis by three-carbon elongation of aldehydes [48,51,53]. The bimetallic reagent 3-trimethylsilyl-l-propenylzirco-nocene chloride (A Scheme 8.23) reacts with aldehydes under the influence of a catalytic amount of Ag+ to give the intermediate zirconocene-alkoxide B, which then undergoes a Peterson-type 1,4-elimination of TMS alkoxide to stereoselectively afford ( )-dienes (fc/Z > 96 4) (Scheme 8.23). A Wittig reaction yields the same products without stereoselectivity (ca. 1 1 mixtures of E- and Z-isomers). 

Bednarski, M, Danishefsky, S, Interactivity of chiral catalysts and chiral auxiliaries in the cycloaddition of activated dienes with aldehydes a synthesis of L-glucose, J. Am. Chem. Soc., 108, 7060-7067, 1986. 

The cycloadditions of achiral oxy-substituted dienes with aldehydes in the presence of enantiomerically pure (+)-Eu(hfc)3 [hfc = 3-(heptafluoropropylhydroxymethylene)-(+)-cam-phorate] shows only modest enantioselectivities. Similarly, modest diastereoselectivities are observed for the reactions of chiral oxy-substituted dienes with aldehydes in the presence of achiral Eu(fod)3 (fod = 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedienoate). However, the combination of chiral dienes with chiral (+)-Eu(hfc)3 catalyst shows interesting interactivities, resulting in some instances in diastereoselectivities of 97 3. This has permitted a total synthesis of L-glucose [336,337,338]. 

Keck, G. E., Li, X.-Y., Krishnamurthy, D. Catalytic Enantioselective Synthesis of Dihydropyrones via Formal Hetero Diels-Alder Reactions of "Danishefsky s Diene" with Aldehydes. J. Org. Chem. 1995, 60, 5998-5999. 

Dihydropyrans. Either by cycloaddition of dienes with aldehydes (electron-rich aldehydes not suitable) or by sequential oxo-ene reaction, the synthesis is catalyzed by TfOH. 

The reaction of activated dienes with aldehydes is emerging as a powerful tool in the synthesis of natural products. This chapter reviews the major contributions that have led to the discovery and use of this reaction in organic synthesis. The first part of the chapter discusses the mechanism of the reaction, the second part describes the use of chiral aldehydes, chiral dienes and chiral catalysts in controlling stereochemistry, and the last section outlines applications in the synthesis of natural products. 

An important development in the hetero Diels-Alder reaction came when Jurczak used high pressure to help improve the reactivity of dienes with aldehydes. 1-Methoxybutadiene, for example, was shown to react at 15-25 kbar (I bar = l(X) kPa) with a variety of unactivated aldehydes. - These reactions give predominantly endo adducts and allow for the use of simple alkyl and aromatic aldehydes as dienophiles. Jurczak also realized the importance of this reaction in the synthesis of carbohydrates and applied it to the construction of simple monosaccharide derivatives (see Section 2.5.2. ). " ... 

The synthesis of more complex monosaccharides requires the construction of more complex and highly functionalized dienes and aldehydes. Furyl diene (124) serves as an important starting material in syntheses of KDO and NeuAc. This diene is easily synthesized from the condensation of benzoyloxy acetyl chloride with acetylfuran, followed by treatment with diazomethane. Cyclocondensation of diene (124) with chiral aldehyde (125a) using BFa-OEta as a catalyst gives the CF-type products (126) in a S l ratio of syn and anti isomers (126a and 126b). Aldehyde (125) is also available in optically pure form from... 

In summary, the condensation of activated dienes with aldehydes is a versatile tool in organic synthesis. The reaction is applicable to both complex and simple aldehydes and dienes a list of the dienes which were used in cyclocondensation reactions is given in Figure 5. The high degree of stereoselectivity also makes the cyclocondensation of activated dienes with aldehydes a useful synthetic tool. 

A study comparing, under a range of conditions, diene synthesis by the two alternative Wittig routes, allylic ylide-saturated aldehyde (route 1) and reactive ylide-a,P-unsaturated aldehyde (route 2), has been reported. 9 por the system chosen (Scheme 2) the reactive ylide-a,P-unsaturated aldehyde route is clearly preferred in that the stereochemistry of the new double bond can be controlled more easily and there is little or no isomerisation of the double bond already present in the aldehyde. A route to symmetrically substituted polyenes containing an odd or even number of double bonds has been reported (Scheme 3).20 The Wittig reactions of ylides derived from... 

Hetero-Diels-Alder reaction/ Dihydropyran synthesis, in the manner reported by Danishefsky, from monoactivated dienes and aldehydes is best catalyzed by BF -OEtj. The Mukaiyama aldol condensation pathway does not operate in such cases. 

The hetero Diels-Alder reaction of activated dienes with aldehydes is a useful tool for the synthesis of dihydropyrans [21] (Scheme 8). In the synthesis of marine macrohdes, for example, Forsyth reported the diastereoselective... 

For a review, see Bednarski MD, Lyssikatos JP (1991) Reactions of Activated Dienes with Aldehydes. In Trost BM (ed) Comprehensive Organic Synthesis, vol 2. Pergamon Press, Oxford, p 661 Cink RD, Forsyth CJ (1997) J Org Chem 62 5672 Keck GE, Li XY, Krishnamurthy D (1995) J Org Chem 60 5998 Danishefsky (1981) Acc Chem Res 14 400... 

Du HF, Zhao DB, Ding KL (2004) Enantioselective Catalysis of the Hetero-Diels-Alder Reaction Between Brassard s Diene and Aldehydes by Hydrogen-Bonding Activation A One-Step Synthesis of (5)-(-t)-Dihydrokawain. Chem Eur J 10 5964... 

Michael addition with j -acoxyketones, and 2-acoxynitro compounds, diene synthesis with 2-acoxynitro compounds s. 17, 814 a, -Ethyleneketones from aldehydes GHO GH G GOR... 

The CAB process is quite general for simple dienes and aldehydes. The a-sub-stituent on the dienophile increases the enantioselectivity (acrolein vs methacrolein). When there is a P-substitution in the dienophile, as in crotonaldehyde, the cycloadduct is nearly racemic. Conversely, for a substrate with substituents at both a-and P-positions, high ees are observed, as with 2-methylcrotonaldehyde and cy-clopentadiene (90% ee, exo endo = 97 3). a-Bromoacrolein is a useful dienophile in the Diels-Alder process because of the exceptional synthetic versatility of its resulting adducts e.g., an important intermediate for prostaglandin synthesis [19a]. In the presence of 10 mol% of 3a, a-bromoacrolein and cyclopentadiene in dichloro-methane undergo a smooth Diels-Alder reaction to give the (S)-bromoaldehyde cycloadduct in quantitative yield, 95% ee and 94 6 (exo endo CHO) diastereoselectivity (Equation 20). Similar results are obtained for the catalyst 3b in propionitrile. Other examples are listed below [20]. 

A new stereocontrolled diene synthesis via a palladium-catalysed decarboxy-lative elimination of the adducts from a,jS-unsaturated aldehydes and carboxylate enolate has been reported and applied to the synthesis of insect pheromones and to regiospecifically substituted cyclohexadienes (Scheme 32). ... 

Stereoselective synthesis of 1,4-disubstituted 1,3-dienes from aldehydes has also been reported [232, 233]. The stereoselective synthesis of j8-hydroxy-a-(l-alkenyl)-... 

Another intriguing application reported by Scettri was the trans- and enantiose-lective synthesis of 2,3-disubstituted 2,3-dihydropyran-4-ones through the 2-catalyzed aldol reaction of the siloxy diene with aldehydes followed by acidic treatment for the subsequent ring closure (Scheme 7.7) [9]. 

In addition to the studies mentioned above, chiral alcohols have been used as H-bonding catalysts in a vinylogous aldol reaction of Chan s diene with aldehydes [73], in an enantioselective Strecker reaction [74], and in the enantioselective addition of aza-enamines to imines [75]. Taddol has also found use as a memory of chirality enhancer in the stereoselective synthesis of (i-lactams from amino acid derivatives [76, 77]. 

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