Domino ether synthesis

The group ofWalborsky probably has described one of the first true anionic/radi-cal domino process in their synthesis of the spirocyclopropyl ether 2-733 starting from the tertiary allylic bromide 2-730 (Scheme 2.161) [369]. The first step is a Michael addition with methoxide which led to the malonate anion 2-731. It follows a displacement of the tertiary bromide and a subsequent ring closure which is thought to involve a SET from the anionic center to the carbon-bromine anti bonding orbital to produce the diradical 2-732 and a bromide anion. An obvious alternative Sn2 halide displacement was excluded due to steric reasons and the ease with which the reaction proceeded. 

Giomi s group developed a domino process for the synthesis of spiro tricyclic nitroso acetals using a, 3-unsaturated nitro compounds 4-163 and ethyl vinyl ether to give the nitrone 4-164, which underwent a second 1,3-dipolar cycloaddition with the enol ether (Scheme 4.35) [56]. The diastereomeric cycloadducts formed, 4-165 and 4-166 can be isolated in high yield. However, if R is hydrogen, an elimination process follows to give the acetals 4-167 in 56% yield. 

A domino Claisen/ene strategy was employed for the synthesis of (+)-9(l l)-dehy-droestrone [82] methyl ether, while an example of a domino aza-Cope rearrange-ment/Mannich reaction is the above-mentioned synthesis of (-)-preussin (4-14) [5]. 

To date, only a few examples are known where a domino reaction starts with an electrocydic reaction, although the value of this approach is clearly demonstrated by the beautiful synthesis of estradiol methyl ether 4-319 through a domino elec-trocyclic/cycloaddition process. There is also an impressive example of a double thermal electrocyclization being used however, the starting material for this domino reaction was prepared in situ by a transition metal-catalyzed transformation, and is therefore discussed in Chapter 6. 

Based on a transformation described by Catellani and coworkers [61], the Lautens group [62] developed a three-component domino reaction catalyzed by palladium for the synthesis of benzo annulated oxacycles 6/1-114 (Scheme 6/1.30). As substrates, these authors used a m-iodoaryl iodoalkyl ether 6/1-113, an alkene substi-... 

Leighton and coworkers [217] have also used this approach to develop efficient strategies for the synthesis of polyketide-derived natural products [218]. A main motif of these compounds is a skipped polyol structure, as in 6/2-94 this can easily be prepared by a novel Rh-catalyzed domino reaction of a diallylsilyl ether in the presence of CO, followed by a Tamao oxidation [219]. Thus, reaction of, for example, the silane 6/2-93, which is readily prepared from the corresponding ho-... 

Cu-catalyzed domino reactions have been used for the synthesis of carbocycles, as well as for heterocycles such as indoles, benzoxazoles, and quinoxalines. A very useful process is also the combination of the formation of allyl vinyl ethers, followed by a Claisen rearrangement. 

Today, multi-parallel synthesis lies at the forefront of organic and medicinal chemistry, and plays a major role in lead discovery and lead optimization programs in the pharmaceutical industry. The first solid-phase domino reactions were developed by Tietze and coworkers [6] using a domino Knoevenagel/hetero-Diels-Alder and a domino Knoevenagel/ene protocol. Reaction of solid-phase bound 1,3-dicarbonyl compounds such as 10-22 with aldehydes and enol ethers in the presence of piperidinium acetate led to the 1-oxa-1,3-butadiene 10-23, which underwent an intermolecular hetero-Diels-Alder reaction with the enol ethers to give the resin-bound products 10-24. Solvolysis with NaOMe afforded the desired dihydro-pyranes, 10-25 with over 90 % purity. Ene reactions have also been performed in a similar manner [7]. 

More recently, Tietze s group adapted the well-known domino Knoevenagel-Hetero-Diels-Alder MCR to the efficient synthesis of the deoxyaminosugar (-l-)-D-Forosamine starting from nitroacetone, aqueous formaline, and ethyl vinyl ether (Scheme 65) [169]. The expected racemic dihydropyran was obtained in 37% yield and further transformed to the optically pure product in eight steps in chiral resolution with chiral HPLC. 

Zhang J, Li C-J (2002) InCl3-catalyzed domino reaction of aromatic amines with cyclic enol ethers in water a highly efficient synthesis of new L2,3,4-tetrahydroquinoline derivatives. J Org Chem 67 3969-3971... 

Lin XF, Cui SL, Wang YG (2006) A highly efficient synthesis of 1,2,3,4-tetrahydro-quinolines by molecular iodine-catalyzed domino reactions of anilines with cylci enol ethers. Tetrahedron Lett 47 4509 1512... 

This three-component reaction as the key step of this synthesis is called a domino-Knoevenagel-hetero-Diels-Alder reaction. Domino reactions are defined as processes of two or more bond forming reactions in which a subsequent transformation takes place by virtue of the functionalities introduced in a former transformation.2,16 The tetrahydrocarbolinaldehyde 11 first reacts in a Knoevenagel type condensation with Meldrum s acid 14 and ethyleneammonium diacetate 41 as the catalyst to oxabutadiene 44 which then undergoes a Diels-Alder reaction with enol ether 13. 

Polysubstituted 1,3-oxazolidines were prepared in a one-pot diversity oriented four-component reaction (4-MCR), comprising two linked domino processes. Thus, domino synthesis of enol ethers 9 was followed by a sequential amine addition-cyclization sequence [74]. While strong microwave irradiation (900 W) of silica-gel absorbed conjugated alkynoates 9 and amines afforded tetrasubstituted pyrroles (via the skeletal rearrangement of 1,3-oxazolidines, see Sect. 2.1 and Scheme 5) [24], the use of milder microwave conditions (160 W power, 90 min) furnished 1,3-oxazolidines. Under these mild conditions the 1,3-oxazolidines did not rearrange to pyrroles and with respect to diastereoselectivity, the 1,3-oxazolidines were obtained as mixtures of syn/anti isomers. Overall, the formation of one C-C bond, one C-0 bond, two C - N bonds and a ring in this MCR required less than 3 hours and utilized simple and commercially available reagents (Scheme 26). 

As for the biaryl ether containing macrocycles, an array of bioactive macrocycles with an endo aryl-aryl bond exist in nature. A new palladium catalyzed reaction has been recently developed in which bis(pinacolato)diborane(4) mediated the process to reach such a structural motif. The reaction consists of a domino process involving a Miyaura s arylboronic ester synthesis and an intramolecular Suzuki-coupling. Synthesis of a bicyclic A-B-O-C ring system of RP-66453 273, a neurotensine receptor antagonist, with an endo aryl-aryl and an endo aryl-aryl ether bond was described (Scheme 53).141... 

The domino Knoevenagel condensation hetero-Diels-Alder reaction was used for the enantioselective total synthesis of the active anti-influenza A virus indole alkaloid hirsutine and related compounds by L.F. Tietze and co-workers. The Knoevenagel condensation was carried out between an enantiopure aldehyde and Meldrum s acid in the presence of ethyienediamine diacetate. The resulting highly reactive 1-oxa-1,3-butadiene underwent a hetero-Diels-Alder reaction with 4-methoxybenzyi butenyl ether ElZ = 1 1) in situ. The product exhibited a 1,3-asymmetric induction greater than 20 1. 

Figure 2.69 Domino reaction for the synthesis of an ether fragrance. Source adapted from Corma et al. [320, 343],...

An interesting example of catalytic domino reaction is the synthesis of an ether fragrance reported by Corma and Renz [343] using either Sn-beta or Zr-beta, although the latter is preferable, giving at 100 °C (8h) complete conversion with virtually 100% overall selectivity, while the Sn-beta is equally selective but less active. Figure 2.69 reports the scheme of this reaction. In a first step, the alcohol is produced by a Meerwein-Ponndorf-Verley reduction at 100 °C. 

Hayashi and co-workers took advantage of the organocatalyzed reaction for the stereoselective synthesis of the cyclohexane structure. Diphenylprolinol silyl ether ent-6a proved to be effective for the domino Michael reaction/Horne-Wardsworth-Emmons reaction. They synthesized (-)-oseltamivir by three one-pot operations, with a total yield of 57% (Scheme 10.4) [38]. 

The diester 87 with the same tetracyclic skeleton as 83 had previously been prepared by Paquette et al. via a domino Diels-Alder reaction of 5,5 -bicyclo-pentadienyl 84 with dimethyl acetylenedicarboxylate (Scheme 20) [73]. The key precursor 84 was obtained by iodine-induced oxidative coupling of the copper cyclopentadienide derived from the sodium derivative. The diester 85 formed along with 86 was transformed into a bissilyl bisenol ether by reductive cleavage of the central bond in the succinate moiety with sodium in the presence of trimethylsilyl chloride. Subsequent hydrolysis of the bisenol ether - actually a bisketene acetal - gave the dienic tetraquinacenedicarboxylate 87. This compound served as the key intermediate in the first synthesis of dodecahedrane 88 [74]. 

The synthesis and use of the resin-bound enol ether in the domino cydoaddition is described in... 

---