Ring systems domino reactions

This reaction also represents an example of the intramolecular Heck reaction, a variant that has gained some importance in recent years. Another instructive example of the potential of this reaction for the construction of ring systems has been reported by de Meijere and coworkers, taking advantage of a sequence of four consecutive intramolecular Heck reactions. The bromodiene-yne 18 reacts in a sequence of domino reactions within 3 d at 80 °C under Heck conditions to give the tetracyclic product 19 in 74% yield ... 

Scheme 8.50 Construction of the ABCD ring system of stachyflin by an acid-induced domino reaction.

In an approach towards a total synthesis of the marine ascidian metabolite pero-phoramidine (6/1-96) [55], Weinreb and coworkers developed a domino Heck/car-bonylation process [56]. This allowed construction of the C,E,F-ring system of 6/1-96, together with the C-20 quaternary center and the introduction of a functionality at C-4 (Scheme 6/1.25). Thus, reaction of 6/1-97 in the presence of catalytic amounts of Pd(OAc)2 and P(oTol)3 under a CO atmosphere in DMA/MeOH led to 6/1-98 in 77% yield. 

Grubbs and coworkers [238] used the ROM/RCM to prepare novel oxa- and aza-heterocyclic compounds, using their catalyst 6/3-15 (Scheme 6/3.9 see also Table 6/3.1). As an example, 6/3-35 gave 6/3-36, by which the more reactive terminal alkene moiety reacts first and the resulting alkylidene opens the five-membered ring. In a similar reaction, namely a domino enyne process, fused bicyclic ring systems were formed. In this case the catalyst also reacts preferentially with the terminal alkene moiety. 

Another example of an efficient domino RCM is the synthesis of the highly functionalized tricyclic ring system 6/3-72 by Hanna and coworkers [252], which is the core structure of the diterpene guanacastepene A (6/3-73) (Scheme 6/3.21) [253]. Reaction of 6/3-71 in the presence of 10 mol% of Grubbs II catalyst 6/3-15 led to 6/3-372 in 93 % yield. Interestingly, the first-generation Ru-catalyst 6/3-13 did not allow any transformation. 

Moreover, compounds of type 7-127, which were obtained from 7-125 by reaction with Pb(OAc)4, can undergo a further domino process when treated with potassium carbonate in a mixture of water and methanol [57]. This includes saponification of the acetate moieties in 7-127 to provide 7-129 via the unstable cyclic hemiacetal 7-128 (Scheme 7.35). Retro-Claisen reaction and ring closure with the proposed intermediates 7-130 and 7-131 led to the bridged ring-system 7-132 as a mixture of di-astereomers with preference of the (3-isomer. 

Both natural and non-natural compounds with a 2ff,5ff-pyrano[4,3-fc]pyran-5-one skeleton are of interest in medicinal chemistry. Several natural products, such as the pyripyropenes, incorporate this bicyclic ring system. The group of Beifuss has described an efficient microwave-promoted domino synthesis of the 2ff,5H-pyr-ano[4,3-fo]pyran-5-one skeleton by condensation of a,/3-unsaturated aldehydes with 4-hydroxy-6-methyl-2]-f-pyran-2-one (Scheme 6.244) [428]. It is assumed that in the presence of an amino acid catalyst a Knoevenagel condensation occurs first, which is then followed by a 6jr-electron electrocyclization to the pyran ring. While the conventional thermal protocol required a reaction time of up to 25 h (refluxing ethyl... 

In general, the homo radical domino reaction is a powerful tool for the construction of complex molecules. Further examples are the synthesis of the BCD-Ring system of progesterone by Takahashi et al.,[521 the construction of bicyclic octanol derivatives by Sonoda et al.[531 and the total synthesis of (+)-claantholide and (-)-estafiatin by Lee et al.[541... 

A broad variety of special aldehydes and ketones are easily accessible by Heck-type reactions with allylic alcohols and their homologs [3]. The potential for the synthesis of carbocydic structures is illustrated by the macrocyde 11 [4] which obviously is the product of a fourfold Heck reaction (Scheme 3). A domino process consisting of a double Heck reaction followed by an intramolecular Aldol condensation leads to the annulated ring system 15 [5]. 

As for the biaryl ether containing macrocycles, an array of bioactive macrocycles with an endo aryl-aryl bond exist in nature. A new palladium catalyzed reaction has been recently developed in which bis(pinacolato)diborane(4) mediated the process to reach such a structural motif. The reaction consists of a domino process involving a Miyaura s arylboronic ester synthesis and an intramolecular Suzuki-coupling. Synthesis of a bicyclic A-B-O-C ring system of RP-66453 273, a neurotensine receptor antagonist, with an endo aryl-aryl and an endo aryl-aryl ether bond was described (Scheme 53).141... 

It should be noted that several domino reactions exist where the Michael/SN-type processes are reversed. For instance, bicylo[3.3.1]nonane ring systems, applicable as synthons for the construction of various natural products [96], have been synthesized by Srikrishna and coworkers using a domino SN/Michael process [97]. This type of domino reaction was also used by the group of Bunce to synthesize N-pro-tected pyrrolidines and piperidines bearing functionalized side chains at C-2 [98], For a domino alkylation/spiroannulation process to give homoerythrina alkaloids 2-177 [99], Desmaele/dAngelo and coworkers have treated the 2-tetralones 2-179 with 2-180 in the presence of Cs2C03 as base (Scheme 2.42) [100],... 

In 2003 Uemura reported on a domino reaction, including a Type M rearrangement and a Diels-Alder reaction, which efficiently generates complex polycyclic ring systems (Scheme 86) [200]. Enynal 349 was transformed to 2-furyl carbenoid species 350 [201-203], which formed ylide 351 after treatment with diallyl sulfide 281. After [2,3]-sigmatropic rearrangement of the latter, furan 352 was formed which readily underwent an intramolecular Diels-Alder reaction furnishing adducts 353 that were epimeric at the... 

If the biosynthesis proceeds via a domino-cyclization, it would require a novel transformation, because the known reactions are not able to create such unfavored ring systems as that of 1. A possible substrate for a thermodynamically favorable reductive polycyclization with addition of 2 H atoms would be the allenic C2o-fatty acid 9,10,12,16,18,19-docosahexanoic acid (32). ... 

Cyclic azoalkanes continue to be of active interest because they serve as precursors to interesting diradicals and as synthons for the preparation of highly strained ring systems and sterically crowded structures. One of the most important syntheses of the azoalkanes involves the cycloaddition of TADs to a suitable substrate to give urazoles by a method mentioned in preceding parts of this review. These methods include Diels-Alder, homo Diels-Alder, and domino Diels-Alder addition, as well as the ene reaction, 1,2-cycloaddition, or other types of cycloaddition reactions. These adducts are transformed into cyclic azoalkanes by hydrolysis an oxidation. The azoalkanes are very often used for thermal or photochemical decomposition to cyclic compounds. This sequence is outlined in Scheme 79. 

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