Anionic domino reactions

Anionic domino processes are the most often encountered domino reactions in the chemical literature. The well-known Robinson annulation, double Michael reaction, Pictet-Spengler cyclization, reductive amination, etc., all fall into this category. The primary step in this process is the attack of either an anion (e. g., a carban-ion, an enolate, or an alkoxide) or a pseudo anion as an uncharged nucleophile (e. g., an amine, or an alcohol) onto an electrophilic center. A bond formation takes place with the creation of a new real or pseudo-anionic functionality, which can undergo further transformations. The sequence can then be terminated either by the addition of a proton or by the elimination of an X group. 

Besides the numerous examples of anionic/anionic processes, anionic/pericydic domino reactions have become increasingly important and present the second largest group of anionically induced sequences. In contrast, there are only a few examples of anionic/radical, anionic/transition metal-mediated, as well as anionic/re-ductive or anionic/oxidative domino reactions. Anionic/photochemically induced and anionic/enzyme-mediated domino sequences have not been found in the literature during the past few decades. It should be noted that, as a consequence of our definition, anionic/cationic domino processes are not listed, as already stated for cationic/anionic domino processes. Thus, these reactions would require an oxidative and reductive step, respectively, which would be discussed under oxidative or reductive processes. 

Domino Reactions in Organic Synthesis. Lutz F. Tietze, Gordon Brasche, and Kersten M. Gericke Copyright 2006 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 3-527-29060-5 

Herein, the stereogenic center in 2-12 controls the stereochemistry in the way that the Michael addition occurs from the less-hindered a-face of the enolate to the si-side of the crotonate 2-13 according to transition structure 2-16. The second Michael addition occurs from the same face, again under chelation control, followed by an axial protonahon of the formed enolate to give the cis-compound 2-14a. It should be noted that after the usual aqueous work-up procedure an inseparable 

For a facial selective assembly ofthe stereogenic centers and the introduction of the amino functionality, chiral nitrogen-containing reagents, such as benzyl(2-pheny-lethyl)amine (2-19) and trimethylsilyl RAMP derivative 2-24 were applied. Treatment of diacrylates 2-18, 2-21, and 2-23 with 2-19 and 2-24, respectively, gave the protected amino acids 2-20, 2-22, and 2-25 in good yields as single isomers. 

Domino Michael/aldol addition processes unquestionably represent the largest group of domino transformations. Numerous synthetic applications - for example, in natural product synthesis as well as for the preparation of other bioactive compounds - have been reported. Thus, the procedure is rather flexible and allows the use of many different substrates [12]. In this process it is possible, in theory, to establish up to two new C-C-bonds and three new stereogenic centers in a single step. For example, Collin s group developed a three-component approach. 

Entry a,p-Unsaturated Aldehyde T[°C] Major product 2-33/2-34 Yield [%] ketone 2-29 2-32 2-33 

It was proposed that the biosynthetic pathway to 65 involved a similar intramolecu lar hetero-Diels-Alder cycloaddition [31, 33], but most biomimetic approaches so far have suffered from moderate stereoselectivity. Scheerer addressed this problem 

Kobayashi et al. [58] have applied a Ugi reaction to the formal synthesis of the proteasome inhibitor omuralide (147), which is derived from the natural product 

The substrate-specific reduction was rationalized by an activating intramolecular hydrogen bond present only in the two reacting diastereomers. The diastereomeric diols 153 (dr = 2.9 1) were further reacted to provide lactone 154, which closely resembles the guaianolide family of natural products. 

A modification of Hayashi s (—)-oseltamivir synthesis was recently reported by Ma et al. [64]. The group was able to replace the Michael acceptor ( )-tert-butyl 3-nitroacrylate (156) with acetyl-protected 2-amino-l-nitroethene, thereby eliminating the three-step conversion of the ester to the acetylamino group required thus far. 

A azabicycle 169 was further advanced to provide lycoposerramine Z (170) in only 10 steps with an overall yield of 20%. 

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Scheme 2.1. Twofold anionic domino reaction initiated by a Michael addition.

Besides the Michael addition-initiated domino reactions presented here, a multitude of other anionic domino reactions exist. Many of these take advantage of an incipient SN-type reaction (for a discussion, see above). In addition to the presented SN/Michael transformations [97, 98, 100], a SN/retro-Dieckmann condensation was described by Rodriguez and coworkers, which can be used for the construction of substituted cycloheptanes as well as octanes [123]. Various twofold SN-type domino... 

Ogasawara and coworkers have also published a complete series of threefold anionic domino reactions, all of which are based on an initial retro-aldol process. For instance, starting from chiral bicyclo[3.2.1]octenone 2-437, a formal total synthesis of (-)-morphine (2-445) [233] has been successfully performed (Scheme 2.103) [234]. Transformation of 2-437 into the substrate 2-488, necessary for the domino reaction, was achieved in seven linear steps. The domino process was then initiated by simply refluxing a solution of 2-438 in benzene in the presence of ethy-... 

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