Domino asymmetric

Scheme 7.1. Domino asymmetric epoxidation/ring expansion reaction.

Cycloheptadiene (340) is obtained by the Cope rearrangement of cis-divinylcyclopropane (339.) Based on this reaction, highly diastereoselective and enantioselective construction of the 1,4-cycloheptadiene 343 (98% ee) was achieved by domino asymmetric cyclopropanation to generate cA-divinylcyclopropane... 

Reaction Scope Cascade (or Domino) Asymmetric Intramoiecuiar Mizoroki-Heck Reactions... 

Chiral oxazolidinones are the most popular auxiharies in the field of asymmetric synthesis. Chen and Sibi [76] employed this auxiliary for the domino asymmetric C-C/C-C single bond formation under convenient radical conditions (Scheme 5.51). During the reaction, the radical intermediates 240 was coordinated onto the Lewis acid Yb(OTf)3 at —78°C to form the desired s-cis conformation. Upon the treatment of this intermediate 240 by 2-methylallyl stannane, the product 241 was generated with a diastereoselectivity of >20 1. Similar radical conditions using a bromooxazolidinone imide source also resulted in allylated products with excellent diastereoselectivity (>50 1) and yield (>90%) even at room temperature. 

Carlone A, Cabrera S, Marigo M et al (2007) A new approach for an organocatalytic multi-component domino asymmetric reaction. Angew Chem Int Ed 46 1101—1104... 

A. Carlone, S. Cabrera, M. Marigo, K. A. Jprgensen, Angew. Chem. Int. Ed. 2007, 46, 1101-1104. A new approach for an organocatalytic multicomponent domino asymmetric reaction. 

Asymmetric carbopalladation can also be combined with other reactions to give domino asymmetric processes. A group selective example from a synthesis of ( capnellene 216 features the cyclization of the alkenyl triflate 210 (Scheme 32). The resultant TT-allylpalladium intermediate has effectively been captured with a variety of nucleophiles including acetate anion for the synthesis. A domino Suzuki coupling/in-tramolecular Heck reaction converts ditriflate 212 into tricycle 213 in modest yield with 85% The transformation accomplises an annnelation, two carbon-carbon bond... 

The subsequent epoxidation of these in situ formed allylic tertiary alcohols yielded the corresponding syn-e oxy alcohols with high levels of diastereo- and enantioselectivity, thus providing a novel one-pot asymmetric synthesis of acyclic chiral epoxyalcohols via a domino vinylation epoxidation reaction (Scheme 4.17). ... 

Scheme 4.17 Asymmetric domino alkylation epoxidation reactions.

For clarification, individual transformations of independent functionalities in one molecule - also forming several bonds under the same reaction conditions -are not classified as domino reactions. The enantioselective total synthesis of (-)-chlorothricolide 0-4, as performed by Roush and coworkers [8], is a good example of tandem and domino processes (Scheme 0.1). I n the reaction of the acyclic substrate 0-1 in the presence of the chiral dienophile 0-2, intra- and intermolecular Diels-Alder reactions take place to give 0-3 as the main product. Unfortunately, the two reaction sites are independent from each other and the transformation cannot therefore be classified as a domino process. Nonetheless, it is a beautiful tandem reaction that allows the establishment of seven asymmetric centers in a single operation. 

Feringa s group has demonstrated that cyclopentene-3,5-dione monoacetals as 2-47 can also be successfully applied as substrates in an asymmetric three-component domino Michael/aldol reaction with dialkyl zinc reagents 2-48 and aromatic aldehydes 2-49 [17]. In the presence of 2 mol% of the in-sitw-generated enantiomeri-cally pure catalyst Cu(OTf)2/phosphoramidite 2-54, the cyclopentanone derivatives 2-51 were formed nearly exclusively in good yields and with high ee-values (Scheme 2.11). 

The method has been used for a short asymmetric synthesis of (-)-prostaglandin Ej methyl ester (PGEj) (2-58) starting from 2-47, 2-55 and 2-56 (Scheme 2.12) [17]. The domino reaction provided 2-57 in 60 % yield as mixture of two diastereomers in reasonable stereoselectivity (trans-threo trans-erythro ratio 83 17). Further transformations led to 2-58 in an overall yield of 7% and 94% ee in seven steps. 

The group of Terashima [35] developed an asymmetric domino Michael/aldol process using the chinchona alkaloid (-)-cinchonidine (2-103), to prepare an intermediate for the synthesis of the natural product (-)-huperzine A (2-102) [36] (Scheme 2.22). 

An impressive organocatalytic asymmetric two-component domino Michael/ aldol reaction has been recently published by Jorgensen and coworkers (Scheme 2.23) [38]. 

Krische and coworkers [44] developed a Rh-catalyzed asymmetric domino Michael/aldol reaction for the synthesis of substituted cyclopentanols and cyclohex-anols. In this process, three contiguous stereogenic centers, including a quaternary center, are formed with excellent diastereo- and enantioselectivity. Thus, using an enantiopure Rh-BINAP catalyst system and phenyl boronic acid, substrates 2-108 are converted into the correspondding cyclized products 2-109 in 69-88% yield and with 94 and 95% ee, respectively (Scheme 2.24). 

Scheme 2.24. Rh-catalyzed asymmetric domino Michael/aldol process.

Recently, a first example of an organocatalytic asymmetric domino Knoevenagel/ Diels-Alder reaction was reported by Barbas and coworkers (Scheme 2.182) [409]. Spiro[5,5]undecane-l,5,9-triones of type 2-818/2-819 were obtained from comma-daily available 4-substituted-3-butene-2-ones 2-813, aldehydes 2-814, and Mel-drum s acid (2-801) in the presence of 20 mol% of the amino acid 2-815 with 80-95% ee and diastereoselectivity of dr> 12 1. 

Scheme 3.37. Domino radical addition/cyclization-reaction for the asymmetric synthesis of (3-aminobutyrolactones.

Serrano s group described asymmetric domino Diels-Alder/Cope reactions using 1,3-nitrocyclohexadienes containing a sugar moiety such as 4-39 and cy-... 

This chapter begins by classifying the combinations of oxidation/reduction processes with subsequent cationic transformations, though to date the details of only two examples have been published. The first example comprises an asymmetric epoxidation/ring expansion domino process of aryl-substituted cyclopropyl-idenes (e. g., 7-1) to provide chiral cyclobutanones 7-3 via 7-2, which was first described by Fukumoto and coworkers (Scheme 7.1) [2]. 

The reactions presented in this chapter show clearly that enzyme-triggered domino reactions offer a great potential in asymmetric synthesis. It remains to be seen, whether this methodology becomes a general tool, since the design of such enzyme-induced domino processes is not trivial. Nonetheless, this emerging field obviously has great potential. 

Certain examples are known for asymmetric induction in domino reactions using either chiral substrates or educts with removable chiral auxiliaries. In contrast, only a few enantioselective domino reactions have been developed so far. The first example was described by us using a titanium complex of glucose diacetonide with 88% ee.[101 Quite... 

Yamamoto and coworkers described a highly enantioselective asymmetric domino 0-nitroso aldol-conjugate addition seqnence using cyclic enones 221 and aromatic nitroso compounds 222 as depicted in Scheme 36 [346]. A related reaction with imines was also reported by Cdrdova and coworkers (Scheme 37) [228]. 

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