Cascade synthesis

Westman, J. and Orrling, K., Cascade synthesis with (triphenylphosphoranylidene)-ethenone as a versatile reagent for fast synthesis of heterocycles and unsaturated amides under microwave dielectric heating, Comb. Chem. High Throughput Screening, 2002, 5, 571-574. 

The first correctly dendritically branched molecules were termed cascade molecules and could be prepared divergently by a cascade synthesis (Section 1.1). 

The only mass spectrometric methods available during the era of the first cascade synthesis in 1978 [30] were electron impact (El) and field desorption (FD) mass spectrometry [31]. Fast atom bombardment (FAB) mass spectrometry is limited to fairly low mass ranges and not very suitable for compounds of low polarity. It was not until the development of new and gentle ionisation methods such as MALDI (matrix-assisted laser desorption ionization) [32] and ESI (electrospray ionization) [33] that the conditions were fulfilled for the start of intense research in the field of dendrimer chemistry. The following section will present the special features of these mass-spectrometric methods and their importance in dendrimer analysis. 

The essence of the cascade synthesis is depicted in Scheme 2.1. Two procedures, alkylation and reduction, comprised the [a — b — a — b — ] sequence. Thus, treatment of a diamine with acrylonitrile afforded tetranitrile 3. Cobalt-mediated nitrile reduction gave tetraamine 4. Further amine alkylation provided the second generation octanitrile 5. The nonskid-chain-like [2] synthesis is shown in Scheme 2.2. Construction of polycyclic 6 was accomplished by repetitive alkylation, reduction, acylation, and reduction (a — b c— d—>a- b— ...) sequences. Again, repetitive and multiple reaction sequences were employed for the generation of new molecular assemblies. Most notable about these syntheses is that for the first time, generational molecules were prepared and characterized at each stage of the construction process. 

Scheme 4.50. Cascade synthesis employing a pentavalent, neutral phosphorus core.

Dendrimers are macromolecules with a regular and highly branched three-dimensional architecture. The first example of an iterative synthetic procedure toward well-defined branched structures has been reported by Vogtle et al. [1], who named this procedure a cascade synthesis . The paper concerning den-... 

Cascade Synthesis of Enynes/Pauson-Khand Reaction. 221... 

The radical cascade synthesis was applied to the preparation of drugs such as irinotecan [62], and drug candidates such as lurtotecan [66], silatecan DB-67 [67] and homosilatecans [68]. Moreover, a convergent synthesis could be applied to a combinatorial synthesis, in which over one hundred homosilatecans were prepared by parallel synthesis and automated purification [69]. 

Kim developed a new entry into A -heterocycles by radical cyclizations onto alkyl azides. Iodides, bromides and thionocarbonates (Scheme 28, Eq. 28.1) are suitable radical precursors. 5-Exo cyclizations afford 3,3-triazenyl radicals that lose N2 to furnish an aminyl radical [79]. Following this work, Kilburn has applied this strategy to the formation of spiro-heterocycles from methylenecyclopropanes [80]. Finally, this reaction was applied as a key step in a very elegant cascade synthesis of aspi-dospermidine developed by Murphy (Scheme 28, Eq. 28.2) [81]. 

Tomalia, Denkewalter and Newkome followed the cascade synthesis for the preparation of Starburst polyamidoamines, polylysines, and arborols during the 80 s and developed the dendrimer chemistry to a high skill. [1]... 

Figure 3. The first cascade synthesis of dendrimers by iterative cycles of Michael-type addition of acrylo-nitril and reduction to the amine.

Heise, Palmans, de Geus, Villarroya and their collaborators (17,41,42) have been working on a chemoenzymatic cascade synthesis to prepare block copolymers. They combine enzymatic ring-opening polymerization (eROP) and atom transfer radical polymerization (ATRP). The synthesis of block copolymers was successful in two consecutive steps, i.e., eROP followed by ATRP. In the one-pot approach, block copolymers could be obtained by sequential addition of the ATRP catalyst, but side reactions were observed when all components were present from at the onset of reactions. A successful one-pot synthesis was achieved by conducting the reaction in supercritical carbon dioxide. 

The ideal of cascade synthesis was first introduced in 1978 by Vogtle [41] etal., who reported reactions involving Michael additions of an amine to acrylonitrile, followed by reduction of the nitrile group to an amino group. In 1979 [40] a Dow research group reported that a variety of amines could be added to methyl acrylate and the products subsequently amidated with a, co-diaminoalkane to give cascade products . Further work by the Dow group has expanded this area to produce the Starburst system [40]. An in depth review by Tomalia [40] et al. should be consulted. 

I. G. Ovchinnikova, O. V. Fedorova, Eugenia G. Matochkina, M. I. Kodess, A. A. Tumashov, P. A. Slepukhin, Gennady L. Rusinov, V. N. Charushin, The first example of cascade synthesis of alkaloid-like subunit incorporated into crown ethers. Macroheterocycles 3 (2012) 108-113. 

Diickert, H., Pries, V., Khedkar, V., Menninger, S., Brass, H., Bird, A.W, Maliga, Z., Brockmeyer, A., Janning, P, Hyman, A., Grimme, S., Schiirmann, M, Preut, H., Hubei, K., Ziegler, S, Kumar, K., and Waldmaim, H. (2012) Natural product-inspired cascade synthesis yields modulators of centrosome integrity, Nat Chem. Biol, 8, 179-184. 

The cascade synthesis of tetrahydrofuran-containing oxacyclic molecules takes place by a 2-oxonia[3,3]-sigmatropic-aldol mechanism rather than by a Prins cyclization-pinacol rearrangement sequence (Scheme 6). ... 

A number of procedures for the preparation of 2-substituted quinazo-lines were reported in 2013. Wu and coworkers prepared 2-substituted quinazolines via a copper-catalyzed cascade synthesis by treating (2-ami-nophenyl) methanols 68 with aromatic aldehydes in the presence of copper(I) chloride, cerium nitrate hexahydrate, ammonium chloride, and potassium hydroxide in acetonitrile in moderate-to-high yields (Scheme 31) (13JOC11342). Electron-withdrawing substituents on either the (2-aminophenyl)methanol or the aromatic aldehyde resulted in a decrease in yield. 

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