Carbomagnesation

A concise total synthesis of the indole alkaloid dihydrocorynantheol (101) (Scheme 19), that features two RCM steps and a zirconocene-catalyzed carbo-magnesation [68], is a further example of Martin s interest in applying RCM as a key reaction for the construction of alkaloid frameworks [69]. The first RCM step was applied to bis-allyl amide 96. The resulting intermediate 97 was directly subjected to carbomagnesation and subsequent elimination to deliver 98 in 71% yield from 96. Amide 98 was then transformed into acrylamide 99 in... 

Scheme 19 Construction of key lactam 100 via two RCM steps and a zirconocene-mediated carbomagnesation in Martin s total synthesis of dihydrocorynantheol (101) [68]...

All of the reactions discussed in the preceding section are stoichiometric in Mn. Over the past decade, however, Mn-catalyzed carbomagnesation reactions of potential synthetic utility have been developed by Oshima, as summarized in Scheme 63.271-275 Attempts to use PdCl2(MeCN)2, NiCl(PPh3)2, CrCI (, and PuOI ( were unsuccessful, and... 

Keywords Catalytic metathesis, Enantioselective synthesis, Catalytic kinetic resolution, Catalytic carbomagnesation, Catalytic rearrangement, 2-Substituted chromenes, Catalytic m aero cyclization... 

As was mentioned previously, certain disubstituted styrene ethers can be efficiently resolved through the Zr-catalyzed kinetic resolution. As illustrated in Eq. 7, optically pure cycloheptenyl ether 64c is obtained by the Zr-catalyzed process. The successful catalytic resolution makes the parent alcohol and the derived benzyl ether derivatives 64a and 64b accessible in the optically pure form as well. However, this approach cannot be successfully applied to all the substrates shown in Table 1. Lor example, under identical conditions, cyclopentenyl susbstrate 60b is recovered in only 52% ee after 60% conversion. Cycloheptenyl substrates shown in entry 4 undergo significant decomposition under the Zr-catalyzed carbomagnesation conditions. These observations indicate that future work should perhaps be directed towards the development of a chiral metathesis catalyst that effects the chromene formation and resolves the two styrene ether enantiomers simultaneously. 

The chemistry described in this review article demonstrates the impressive positive influence that catalytic RCM has had on our research in connection to the development of other catalytic and enantioselective C-C bond forming reactions. There is no doubt that in the absence of pioneering work by Schrock and Grubbs, the Zr-catalyzed alkylation and kinetic resolution would be of less utility in synthesis. The number of unsaturated heterocyclic and carbocyclic substrates available for Zr-catalyzed asymmetric carbomagnesation would be far more limited without catalytic RCM. 

An important aspect of the carbomagnesation of six-membered and larger heterocycles is the exclusive intermediacy of metallacyclopentanes, in which the C—Zr bond is formed a to the heterocycle C—X bond (Scheme 6.2). Whether the regioselectivity in the zircona-... 

The aforementioned observations have significant mechanistic implications. As illustrated in Eqs. 6.2—6.4, in the chemistry of zirconocene—alkene complexes derived from longer chain alkylmagnesium halides, several additional selectivity issues present themselves. (1) The derived transition metal—alkene complex can exist in two diastereomeric forms, exemplified in Eqs. 6.2 and 6.3 by (R)-8 anti and syn reaction through these stereoisomeric complexes can lead to the formation of different product diastereomers (compare Eqs. 6.2 and 6.3, or Eqs. 6.3 and 6.4). The data in Table 6.2 indicate that the mode of addition shown in Eq. 6.2 is preferred. (2) As illustrated in Eqs. 6.3 and 6.4, the carbomagnesation process can afford either the n-alkyl or the branched product. Alkene substrate insertion from the more substituted front of the zirconocene—alkene system affords the branched isomer (Eq. 6.3), whereas reaction from the less substituted end of the (ebthi)Zr—alkene system leads to the formation of the straight-chain product (Eq. 6.4). The results shown in Table 6.2 indicate that, depending on the reaction conditions, products derived from the two isomeric metallacyclopentane formations can be formed competitively. 

Detailed studies in these laboratories have shed light on the mechanistic intricacies of asymmetric catalytic carbomagnesations, allowing for an understanding of the above trends in regio- and stereoselectivity [9]. Importantly, these mechanistic studies have indicated that there is no preference for the formation of either the anti or the syn (ebthi)Zr—alkene isomers (e. g. 8 anti vs. 8 syn) it is only that one metallocene—alkene... 

As depicted in Eqs. 6.5—6.7, kinetic resolution of a variety of cyclic allylic ethers is effected by asymmetric Zr-catalyzed carbomagnesation. Importantly, besides six-membered ethers, seven- and eight-membered ring systems can readily be resolved by the Zr-catalyzed protocol. 

In 1997, Whitby reported that treatment of 2,5-dihydrofuran with Et3Al in the presence of 5 mol% 31 leads to the enantioselective formation of 39 (Scheme 6.13), rather than the product obtained from catalytic carbomagnesations (40) [34]. This outcome can be rationalized on the basis of Dzhemilev s pioneering report that with Et3Al, in contrast to the mechanism that ensues with EtMgCl (see Scheme 6.2), the intermediate alumina-cyclopentane (i) is converted to the corresponding aluminaoxacyclopentane ii. To ensure the predominant formation of 39, catalytic alkylations must be carried out in absence of solvent. 

A concise total synthesis of the indole alkaloid dihydrocorynantheol 148 (Scheme 27) that features two RCM steps and a zirconocene-catalyzed carbomagnesation is a further example of Martin s interest in applying RCM as a key... 

Addition of the Grignard reagent to the carbon-carbon double bond requires severe reaction conditions.508 513 Zirconium-based compounds, in contrast, catalyze carbomagnesation of 1-alkenes to occur selectively under mild conditions. [NiCl2(PPh3)2] is the best catalyst to promote syn addition to disubstituted acetylenes, although usually in low yields 514... 

Since the early 1990s catalytic carbomagnesation of alkenes has become an established method for the synthesis of special Grignard reagents useful for preparing functionalized organic molecules.637 Detailed studies with respect to reactivates, and regio- and stereoselectivities allowed the identification of a... 

Zirconium-Catalyzed Enantioselective Carbomagnesation-Elimination Tandem Reaction of Allylic Derivatives... 

In view of the Zr-catalyzed enantioslective carbomagnesation-elimination tandem reaction of allylic derivatives discussed earlier, a similar process with EtjAl might be expected and has indeed been developed recently [29]. As a representative example, the reaction of 2,5-dihydro-furan with 3 equiv. of Et3Al in the presence of (i )-(EBTHI)Zr[B[NOL-(5)] (8) and (NMTHI)ZrCpCl2 (9) produced, after hydrolysis, (S)-2-ethyl-3-buten-1 -ol in 90 and 67% yields, respectively. The enantioselectivity observed with 8 was >99% ee, whereas that observed with 9 was 85-90% ee. Upon deuterolysis of the organoaluminum products, a mixture of monodeuterated and nondeuterated products was obtained and the extent of D incorporation increased to 94% with neat Et3Al without any solvent. The results indicate that the reaction must produce two organoaluminum products, 10 and 11 (Scheme 4.18). On oxidation with 02 only... 

Zirconium-Catalyzed Enantioselective Cyclic Carbomagnesation of Diallylamines... 

As an example of carbometallation, the 1,4-carbosilylation product 218 is obtained by the reaction of dienes, disilanes and acid chlorides of aromatic and a,/i-unsaturatcd acids at 80 °C. The phenylpalladium 216 is formed by the oxidative addition of benzoyl chloride, followed by facile decarbonylation at 80 °C, and reacts with butadiene to generate the benzyl-7i-allylic complex 217. Then, transmetallation with the disilane and reductive elimination afford 4-silyl-2-butenylbenzene 218 [92], Regioselective carbomagnesation of isoprene with allylic magnesium bromide 219 catalysed by Cp2TiCl2 gives 220, which is useful for terpene synthesis [93,94],... 

The regioselective carbomagnesation of alkenes is catalysed by Cp2ZrCl2 (449) [173], In this reaction, the zirconocenc ethylene complex (450) is generated and reacts... 

Fig. 19 Radical carbomagnesation reactions and cyclization/addition sequences...

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