Scheme 4.9 Examples of prolinol (a-c) and transition-metal (d) promoted domino reactions
A more limited number of cascade processes have been promoted by Bronsted acid [75, 76] or transition-metal catalysts and synthesis of vitamin E intermediate 16 through enantioselective Wacker oxidation followed by Heck reaction, reported by Tietze and coworkers  is a representative example of efficient palladium-catalyzed domino reactions (Scheme 4.9d).
In a biomimetic approach, suitable combinations of transition-metal or organo-catalysts could provide not only a sensible expansion in the range of chemical reactions feasible in one-pot protocol, but also improved reactivity and selectivity due to cooperative effects. Furthermore, the use of two chiral catalysts could enable selective access to any product enantiomer or diastereoisomer from a given sequence through judicious combination of catalysts' stereochemistry.
However, the design of effective multicatalyst reactions  is a big challenge since each catalyst need to be compatible with the other one as well as with other
CH3CN CH3CN CH3CN 17
(S,S)-18 (6%mol) Pd[n-C3H5)Cl]2 (2% mol) CH2Cl2, base,rt, 1h
Scheme 4.10 Synthesis of N- and O-heterocycles through sequential Ru-Pd catalysis
reaction components (substrates, reagents, intermediates generated in situ) and every step in the sequence should proceed with high selectivity in order to avoid side reactions and formation of mixtures of isomers, difficult to purify.
Multiple metal complexes are often unsuitable due to scrambling of ligands in their coordination with metals leading to unpredictable structure of the active catalysts, but good results have been achieved in some instances by sequential addition of catalysts and substrates, in a process better described as a tandem rather than cascade reaction [79-81]. As a selected example, the synthesis of several functionalized N- and O-heterocycles was achieved through combined action of [RuCp(CH3CN)3]PF6 17 and Pd-complex with ligand 18, providing that Pd-cat-alyst was added after completion of the Ru-promoted reaction. In such process the first step involved a Ru-promoted alkene/alkyne cross-coupling to give reactive allyl intermediates that were trapped by palladium and stereoselectively hetero-cyclised with simultaneous removal of p-nitrophenylether group initially present on olefin substrates. Large structural variety of alkynes was tolerated and further elaboration of the obtained enantio- and diastereo- pure heterocycles led to useful building blocks or natural compounds, as it was demonstrated with synthesis of 4-oxyproline derivatives, rose oil oxides or ring B of bryostatin  (Scheme 4.10).
MacMillans' group has recently developed a general strategy for organocascade reactions based on the coupling of imidazolidinones as specific iminium catalysts and proline as selective bifunctional enamine catalyst in the same vessel or sequentially added to reaction mixture. Exploiting the orthogonal reactivity profiles of these organocatalysts a variety of olefin hydro-, alkyl- or aryl-aminations
1 N T"Me
Ph H Me
(S,S)-19 (10% mol)
Me cbZ NH
Me Cbz NH
Me Cbz NH
Scheme 4.11 Examples of reactions with organocatalyst-organocatalyst combinations have been carried out in excellent yield and selectivity and reversal of dia-stereoselectivity was easily achieved changing l-proline with d-proline  (Scheme 4.11a). Coupling of J0rgenson catalyst 12 with achiral carbene 20 gave access to highly functionalized cyclopentanones from enals and acetylacetone or b-ketoesters with 3 contiguous stereocentres and a quaternary carbon through Michael addition/benzoin condensation sequence  (Scheme 4.11b). Compared with the two step protocol, the multicatalytic cascade gave increased yields and stereoselectivities, attributed to the suppression of prolinol-mediated retro Michael reaction of intermediate aldehydes that were shuttled to products by the simultaneous presence of carbene.
In order to avoid possible catalyst-catalyst or catalyst-reagent interferences, site-isolation techniques proved useful and microencapsulation or physical separation in distinct liquid phases of one or more reaction components have been explored. So, nucleophilic addition of N-methyl indole to 2-hexenal promoted by imidazolidinone 19 in the presence of p-toluensulphonic (pTSA) acid became compatible with subsequent enamine-catalyzed step by encapsulating the acid and prolinol 12, as the second catalyst, in star-branched polymers. In this way, small reagents and 19 freely diffused to the core of polymers whereas the activity of 12, that was not able to penetrate into pTSA core, was preserved from the detrimental
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