Metathesis, diastereoselective

Allylboronates are attractive reagents for the highly diastereoselective ally-lation of carbonyl compounds. A sequential cross-metathesis-allylation reaction has recently been developed by Grubbs et al. [88c] and by Miyaura et al. [103]. The sequence is illustrated in Scheme 23 for the formation of homoallylic alcohol 114 from allylboronate 112, acetal 113, and benzaldehyde [88c]. 

Negishi E, Tan Z (2005) Diastereoselective, Enantioselective, and Regioselective Carbo-alumination Reactions Catalyzed by Zirconocene Derivatives. 8 139-176 Netherton M, Fu GC (2005)Pa]ladium-catalyzed Cross-Coupling Reactions of Unactivated Alkyl Electrophiles with Organometallic Compounds. 14 85-108 Nicolaou KC, King NP, He Y (1998) Ring-Closing Metathesis in the Synthesis of EpothUones and Polyether Natmal Products. 1 73-104 Nishiyama H (2004) Cyclopropanation with Ruthenium Catalysts. 11 81-92 Noels A, Demonceau A, Delaude L (2004) Ruthenium Promoted Catalysed Radical Processes toward Fine Chemistry. 11 155-171... 

Despite those challenges, both Johnson [161] and Grela [162] performed several cross metathesis reactions with vinylhalides using phosphine free catalysts. Turnover numbers (TON) above 20 were very few, while in many cases the TON stayed below ten. The diastereoselectivity of CMs with vinylhalides is shghtly in favour of the Z product which is similar to their acrolein-counterparts. 

An interesting way to control the stereoselectivity of metathesis-reactions is by intramolecular H-bonding between the chlorine ligands at the Ru-centre and an OH-moiety in the substrate [167]. With this concept and enantiomerically enriched allylic alcohols as substrates, the use of an achiral Ru-NHC complex can result in high diastereoselectivities like in the ROCM of 111-112 (Scheme 3.18). If non-H-bonding substrates are used, the selectivity not only decreases but proceeds in the opposite sense (product 113 and 114). 

The use of stoichiometric ruthenium-NHC complexes generated in situ from [Ruljd-COCKp-cymene)], an imidazohnm salt [4] or an imidizol(idin)ium-2-carboxylate [4] has been applied in the cyclopropanation of styrene 5 with ethyl diazoacetate (EDA) 6 (Scheme 5.2). No base was necessary when imidazolium-2 carboxylate were employed. The diastereoselectivity was low and the cis/trans ratio was around 50/50 (Table 5.1). Although the diastereoselectivity was moderate, the reaction was highly chemoselectivity as possible side reactions (homologation, dimerisation and metathesis) were totally or partially suppressed. 

Representatives of the bridged sulfone system 70 have been subjected to ruthenium catalysed ring-closing metathesis reactions (Grubbs catalyst) and shown to afford, in low yields, a few selected cyclic dimers and trimers, of all the possibilities available. The diastereoselectivities observed were rationalised in terms of kinetic control involved with internal ruthenium/sulfonyl oxygen coordination . 

More recently, the bis-cyclopropanation of dienyne 325 has also been investigated by Fensterbank, Malacria, and Marco-Contelles to construct highly strained cyclopropyl-substituted diquinane frameworks 327 in a completely diastereoselective manner (Scheme 84). 3 It is noteworthy that the formal metathesis product was also observed in these reactions, albeit as a minor product, and that a simple introduction of a methyl group to one of the two ene moieties substantially affects the reaction. 

The aryl radical cyclization has been successfully used for the preparation of substituted dihydrobenzo[Z)]indoline derivatives [59], An example is shown in Reaction (7.49). The diene 42 was preliminarly subjected to ring-closure metathesis using Grubbs catalyst and then treated with (TMS)3SiH and EtsB at -20 °C, in the presence of air, to provide the compound 43 with an excellent diastereoselectivity. 

This approach sets the stage for an enantiotopos-differentiating olefin metathesis which would allow the enantioselective synthesis of 258. However, the realization of such an approach has not yet been successful [132]. The second building block (259) containing the A ring was synthesized diastereoselectively by a diastereoface-differentiating intramolecular Heck-Mizoroki reaction of the enantiomerically enriched furan 260 [120]. 

Titanium-catalyzed cyclization/hydrosilylation of 6-hepten-2-one was proposed to occur via / -migratory insertion of the G=G bond into the titanium-carbon bond of the 77 -ketone olefin complex c/iatr-lj to form titanacycle cis-ll] (Scheme 16). cr-Bond metathesis of the Ti-O bond of cis- iij with the Si-H bond of the silane followed by G-H reductive elimination would release the silylated cyclopentanol and regenerate the Ti(0) catalyst. Under stoichiometric conditions, each of the steps that converts the enone to the titanacycle is reversible, leading to selective formation of the more stable m-fused metallacycle." For this reason, the diastereoselective cyclization of 6-hepten-2-one under catalytic conditions was proposed to occur via non-selective, reversible formation of 77 -ketotitanium olefin complexes chair-1) and boat-1), followed by preferential cyclization of chair-1) to form cis-11) (Scheme 16). 

A new concept of diastereoselective ring-rearrangement metathesis has been developed for the synthesis of various carbo- and hetero-cycles (134) and (135) (Scheme 35).107 A strong influence of the substitution pattern of the directing stereocentre on ... 

Despite the unrivaled easy access to 1,4-dicarbonyl compounds, only a few examples of the application of Stetter reactions in the synthesis of natural products have been reported to date [55]. Tius et al. have employed a diastereoselective in-termolecular Stetter reaction and a ring-closing metathesis reaction as the key steps in their elegant synthesis of roseophilin (58 Scheme 9.16) [56]. The 1,4-... 

In a beautifully choreographed sequence of events, Judd and co-workers installed the C3 to C4 bridged bicyclic lactam moiety of 129 with diastereoselective control via an Ugi 4-component coupling, ring-closing metathesis, and Heck reaction <07OL5119>. 

Overall, the new possibilities of RCM were impressively demonstrated on the epothilones. Unfortunately it is too early to address substantial problems with RCM in a satisfactory way. The relatively large amounts of catalyst (15-50 mol%) and the low diastereoselectivity make the syntheses very expensive, because half of the advanced material lost in one of the last steps of the syntheses in form of the wrong double-bond isomer. With the current efforts and the excitement about the truely unique possibilities of metathesis, it is predictable that these drawbacks will be overcome in the future, especially regarding catalyst quantity. 

Scheme 9. Diastereoselective ring-closing metathesis and C8 methylation according to Kalesse et al. to synthesize C7-C2I (fragment A-B) (PMB = /i-methoxybenzyl).

Schmidt B, Westhus M (2000) Diastereoselectivity in a ring closing metathesis reaction with a remote stereogenic centre leading to quaternary dihydropyrans. Tetrahedron 56 2421-2426... 

Tandem alkene metathesis-intramolecular Michael addition of (R)-amine 276 proceeds diastereoselectively, providing pyrrolidines 278 and 279. These pyrrolidines can be... 

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