Natural product synthesis domino reactions

Tietze L. F. Domino-Reactions the Tandem-Knoevenagel-Hetero-Diels-Alder Reaction and Its Application in Natural Product Synthesis J. Heterocycl. Chem. 1990 27 47-69... 

One of the first enantioselective transition metal-catalyzed domino reactions in natural product synthesis leading to vitamin E (0-23) was developed by Tietze and coworkers (Scheme 0.7) [18]. This transformation is based on a Pdn-catalyzed addition of a phenolic hydroxyl group to a C-C-double bond in 0-20 in the presence of the chiral ligand 0-24, followed by an intermolecular addition of the formed Pd-spe-cies to another double bond. 

The domino process probably involves the chiral enamine intermediate 2-817 formed by reaction of ketone 2-813 with 2-815. With regard to the subsequent cy-doaddition step of 2-817 with the Knoevenagel condensation product 2-816, it is interesting to note that only a normal Diels-Alder process operates with the 1,3-bu-tadiene moiety in 2-817 and not a hetero-Diels-Alder reaction with the 1-oxa-l,3-butadiene moiety in 2-816. The formed spirocydic ketones 2-818/2-819 can be used in natural products synthesis and in medidnal chemistry [410]. They have also been used in the preparation of exotic amino adds these were used to modify the physical properties and biological activities of peptides, peptidomimetics, and proteins... 

As model studies and radical reactivity control have improved, the so-called cascade (or domino) reactions have emerged as a very powerful method for natural product synthesis, since they offer a unique route to prepare complex backbones from appropriately designed but quite simple precursors. A few selected reactions will be presented here. 

Tietze LF (1990) Domino-reactions - the tandem-Knoevenagel-hetero-Diels-Alder reaction and its application in natural product synthesis. J Heterocycl Chem 27 47-69... 

Snider et al. have synthesised the antiinsectan ( )-leporin [496] 7-26 using the domino-Knoevenagel-hetero Diels-Alder sequence. The intermediate 1-oxa-1,3-butadiene 7-25 was formed in situ by condensation of the pyridone 7-23 and the dienal 7-24. Subsequently, a hetero Diels-Alder reaction occurred accompanied by minor side reactions. Thus, the desired cycloadduct 7-27 was formed only in moderate yield as 5 1 mixture with its trans-fused diastereomer (Fig. 7-6). Functionalisation of the nitrogen atom yielded the natural product. A similar reaction sequence occurred in the synthesis of the structurally related free radical scavenger ( )-pyridoxatin, however, in this approach the hetero Diels-Alder reaction represented only a side reaction competing with the desired intramolecular ene reaction [497]. 

Nina Tolle, born in 1981 in Osnabriick, Germany, started studying chemistry at the University of Gottingen, Germany, in 2001. She joined the research group of Professor Tietze in 2005 and received her diploma in 2006. She stayed in the same group for her doctoral research which deals with Lewis-acid mediated domino-reactions for the synthesis of spiroamine structures with the objective of natural product synthesis. 

Enyne metathesis/metallotropic [l,3]-shift domino processes are also valuable for natural product synthesis [33c,d]. Reaction of substrate 168 with cis-l,4-diacetoxy-2-butene in the presence of Grubbs catalyst 2 generated the intermediate ruthenium alkinyl carbene through a relay RCM with the hberation of 2,5-dihydrofuran followed by metallotropic [l,3]-shift and terminating (Z)-selective CM with the co-olefin to yield the conjugated enediyne 169 (Scheme 2.58) [33c]. The antitumor active Panax ginseng constituent (3R,9R,10R)-panaxytriol was readily synthesized from 169 in six steps. 

The third section of the chapter describes recently developed anion relay chemistry (ARC) involving threefold domino Sj -Brook rearrangement/ reactions, discovered by Tietze and extensively explored by Amos Smith 111 and his group. These reactions are also initiated by nucleophihc ring opening of epoxides, usually by silyl-substituted dithiane anions, and find useful apphcation in natural product synthesis. 

Another natural product synthesis features that of a key domino ene-yne coupling/Michael reaction to a tetrahydropyran ring (Scheme 7.29) [22]. An in-depth Trost domino ene-yne/oxa-Michael reaction methodology process was first carried out prior to using the key substrates 143 and 144, with [CpRu(MeCN)3]PFg 145 as the catalyst The product 146 contained almost all the carbons of the natural product target (—)-exiguolide as well as most of its asymmetric centers. 

Carbopalladation of dienes yields 7r-allylpalladium intennediates capable of capturing nucleophiles. An example of this type of reaction in natural product synthesis is the conversion of the aryl iodide 168 into pentacycle 169. After 6-exo carbopalladation the free phenol is captured by the resultant Tr-allylpaUadium intermediate to yield aUyUc ether 169 en route to (-)-morphine 120. The domino reaction closes a srx-membered ring, forges a quaternary center, and forms a five-membered furan ring. The reaction sequence has also been effectively reversed in a construction of (+)-y-lycorane 172. Treatment of aUylic benzoate 170 with a palladium catalyst in the presence of sodium hydride triggers tt-allylpalladium formation and intramolecular amide capture. rr-Allylpalladium formation occurs with inversion, as does reaction with the pendant amide, resulting in a net retentive 1,3-transposition of stereochemical information. Subsequent addition of base and thermolysis induces 6-exo intramolecular carbopalladation to yield alkene 171. 

Usually, carbodiimides obtained by an aza-Wittig reaction of A-vinyUc phosphazenes with isocyanates cannot be isolated. Therefore, the very reactive carbodiimides can be used as synthetic intermediates of polyheterocyclic natural products by domino processes involving aza-Wittig/intramolecuIar cycUzation (AW-IC). In the synthesis of variolin B (58), the formation of the annulated 2-aminopyrimidine ring 57 is achieved from phosphazene 56 by a tandem aza-Wittig/carbodiimide-mediated intramolecular cyclization process (Scheme 15.12). 

Phillips laboratory also extended the domino process in natural product synthesis by combining ROM, RCM, and CM. For this cascade reaction, regioselectivity... 

The Bernet-Vasella reductive ring opening has found many applications in carbohydrate chemistry and is a key step in several natural product synthesis [25,26]. However, the instability of the liberated aldehyde can be a problem, leading to side reactions and decomposition [27,28]. To overcome this limitation, the aldehyde has been trapped in situ by nitrogen or carbon nucleophiles. As a result, a series of domino reactions based on the Bernet-Vasella reaction has been described and applied to the total synthesis of chemically and biologically relevant products. 

The total synthesis of alkaloid (+)-lycoricidine reported by Yadav et al. represents a further application of the sequence domino reductive fragmentation/allylation followed by ring-closing metathesis in the synthesis of bioactive natural products [42], Thus, reaction of co-iodoglycoside 29 with zinc/allyl bromide in THF/HjO afforded diene 30 (87%, dr 85 15). Ring-closing metathesis of diene 30 followed by acetylation furnished cyclohexene 31. Treatment of the acetate 31 with PhINTs in the presence of Cu(acac)2, followed by sodium naphthalenide, afforded the aziridine 32 (67%), from which (-i-)-lycoricidine (33) can be easily obtained (Scheme 3.11). 

Another very interesting category of the domino/cascade reactions worth mentioning is that of three component reactions. Its application to the synthesis of many molecules of biological interest and templates for natural products synthesis is particularly appealing. This strategy is well exemplified and detailed in Chapter 7. 

Over the past decade, domino palladium-catalyzed reactions have been used extensively in natural product synthesis and for the synthesis of other complex carbon... 

Tietze L. F., Modi A. Multicomponent Domino Reactions for the Synthesis of Biologically Active Natural Products and Drugs Med. Res. Rev. 2000 20 304-322 Keywords Diels-Alder reactions... 

Tietze, L.R Rackelmann, N. (2004) Domino Reactions in the Synthesis of Heterocyclic Natural Products and Analogs. Pure and Applied Chemistry, 76, 1967-1983. 

An unusual cationic domino transformation has been observed by Nicolaou and coworkers during their studies on the total synthesis of the natural product azadirachtin (1-105) [30]. Thus, exposure of the substrate 1-106 to sulfuric acid in CHjClj at 0°C led to the smooth production of diketone 1-109 in 80% yield (Scheme 1.27). The reaction is initiated by proto nation of the olefinic bond in 1-106, affording the tertiary carbocation 1-107, which undergoes a 1,5-hydride shift with concomitant disconnection of the oxygen bridge between the two domains of the molecule. Subsequent hydrolysis of the formed oxenium ion 1-108 yielded the diketone 1-109. 

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