Enantioselective RCM

For a recent report on Mo-catalyzed enantioselective RCM, see Alexander JB, La DS, Cefalo DR, Hoveyda AH, Schrock RR (1998) J Am Chem Soc 120 4041 and references cited therein... 

Enantioselective RCM is achieved using the chiral Mo complex 79 [30]. Kinetic resolution occurred in the reaction of the racemic diene 80 catalysed by 79, and the cyclized product 81 with 93% ee was obtained, and the unreacted diene 80 (19%) of 99% ee was recovered. Also the optically active dihydrofuran 83 with 93% ee was obtained in 85% yield by enantioselective desymmetrization through RCM of triene 82 using the Mo complex 79 [30a]. 

Analogs of (97a), (97b), (97f), and (97g), with 2,6-dichlorophenylimido instead of 2,6-diisopropylphenylimido (97h), (97i), (97j), and (97k), respectively (Scheme 16) were also synthesized. These complexes were found to have similar activity and scope to the parent complexes, giving enantioselective RCM of unprotected tertiary amines with good yields and enantioselectivities exceeding 90%. ... 

The effect of ethylene on the enantioselective RCM of triene 12 was probed by the addition of diallyl ether, which rapidly undergoes RCM to generate dihydrofuran and ethylene. Both the initial rate and initial enantioselectiv-ity for the formation of 13 were increased in the presence of diallyl ether (Scheme 10.24). Ethylene apparently allows the catalyst to enter a true Curtin-Hammett regime, wherein the catalyst diastereomer that leads to the minor enantiomer of the product can be epimerized by a degenerate metathesis reaction, leading to an increase in both rates and selectivity for the desired RCM process. 

Scheme 10.25 Processes involved in enantioselective RCM with a stereogenic metal catalyst.

Alternatively, monoaryloxide-pyrrolide (MAP) complexes of Mo and W have been developed. It was found that the methyUdene species of these complexes were quite stable toward bimolecular decomposition, yet very reactive [20]. As such, MAP catalysts are very efficient in reactions, including the ethenolysis of methyl oleate [21], enantioselective RCM [22], and Z-selective homocouplings and cross metatheses [23, 24]. MAP catalysts are further discussed in detail in Chapters 1, 6, and see Grubbs, Handbook of Metathesis, 2nd Edition, Volume 2, Chapter 7. 

Enantioselective RCM of planar-chiral ferrocenes was accomplished with a Mo-chiral catalyst (Scheme 12.10) [17]. 

Recent developments in the area of the W and Mo catalysts concern the incorporation of enantiomerically pure bidentate alkoxide ligands as well as of a series of different imido ligands. The resulting complexes have proved to be excellent catalysts for enantioselective RCM, ROM, and CM reactions. 

Ru-catalyzed AROM/CM sequences served as a key step in the total synthesis of baconipyrone C (163, Scheme 24.42), a marine polyketide isolated from Siphonaria baconi The employed Ru carbene [Ru]-VI is generated in situ by treatment of the achiral Ru-PCya complex with Ag-based V-heterocyclic carbene (NHC) and Nal. And then, the [Ru]-VI-catalyzed AROM/RCM of oxabicycle 161 with styrene (8 equiv) afforded the fully substituted pyran 162 in 62% yield and in 88% ee. The additional transformations led to 163 in good overall yield. Although this application of AROM/CM process to 161 was the first and rare example of Ru-catalyzed enantioselective olefin metathesis process, very recently, an application of enantioselective RCM reaction catalyzed by [Ru]-VII to the synthesis of (—)-5-e/>/-citreoviral has been reported by Funk. ... 

Total Synthesis of Coniine through Enantioselective RCM with Substrates Bearing a Tertiary Amine... 

Scheme 12.4 A stereogenic-at-Mo complex as chiral catalyst for enantioselective RCM in a stereoselective synthesis of...

We will focus on the development of ruthenium-based metathesis precatalysts with enhanced activity and applications to the metathesis of alkenes with nonstandard electronic properties. In the class of molybdenum complexes [7a,g,h] recent research was mainly directed to the development of homochi-ral precatalysts for enantioselective olefin metathesis. This aspect has recently been covered by Schrock and Hoveyda in a short review and will not be discussed here [8h]. In addition, several important special topics have recently been addressed by excellent reviews, e.g., the synthesis of medium-sized rings by RCM [8a], applications of olefin metathesis to carbohydrate chemistry [8b], cross metathesis [8c,d],enyne metathesis [8e,f], ring-rearrangement metathesis [8g], enantioselective metathesis [8h], and applications of metathesis in polymer chemistry (ADMET,ROMP) [8i,j]. Application of olefin metathesis to the total synthesis of complex natural products is covered in the contribution by Mulzer et al. in this volume. 

Further detailed investigations towards new chiral ruthenium catalysts that could enhance enantioselectivity and expand the substrate scope in asymmetric RCM were reported by Grubbs and co-workers in 2006 [70] (Fig. 3.24). Catalysts 59 and 61, which are close derivatives of 56 incorporating additional substituents on the aryl ring para to the ort/to-isopropyl group, maintained similar enantioselectivity than 56b. However, incorporation of an isopropyl group on the side chain ortho to the ortho-isopropyl group 60 led to an increase in enantioselectivity for a number of substrates. 

In 2008, Grisi et al. reported three ruthenium complexes 65-67 bearing chiral, symmetrical monodentate NHC ligands with two iV-(S)-phenylethyl side chains [74] (Fig. 3.26). Three different types of backbones were incorporated into the AT-heterocyclic moiety of the ligands. When achiral triene 57 was treated with catalysts 65-67 under identical reaction conditions, a dramatic difference was observed. As expected, the absence of backbone chirality in complex 65 makes it completely inefficient for inducing enantioselectivity in the formation of 58. Similarly, the mismatched chiral backbone framework of complex 66 was not able to promote asymmetric RCM of 57. In contrast, appreciable albeit low selectivity (33% ee) was observed when the backbone possessed anti stereochemistry. 

Molybdenum catalysts that contain enantiomerically pure diolates are prime targets for asymmetric RCM (ARCM). Enantiomerically pure molybdenum catalysts have been prepared that contain a tartrate-based diolate [86], a binaph-tholate [87], or a diolate derived from a traris-1,2-disubstituted cyclopentane [89, 90], as mentioned in an earlier section. A catalyst that contains the diolate derived from a traris-1,2-disubstituted cyclopentane has been employed in an attempt to form cyclic alkenes asymmetrically via kinetic resolution (inter alia) of substrates A and B (Eqs. 45,46) where OR is acetate or a siloxide [89,90]. Reactions taken to -50% consumption yielded unreacted substrate that had an ee between 20% and 40%. When A (OR=acetate) was taken to 90% conversion, the ee of residual A was 84%. The relatively low enantioselectivity might be ascribed to the slow interconversion of syn and anti rotamers of the intermediates or to the relatively floppy nature of the diolate that forms a pseudo nine-membered ring containing the metal. 

In 1993, we began to incorporate catalytic RCM into a select number of our programs in reaction development and enantioselective organic synthesis. In... 

Catalytic RCM and Zr-Catalyzed Enantioselective Alkylation of Unsaturated Heterocycles... 

Enantioselective Synthesis by Tandem Catalytic RCM and Catalytic Alkylation... 

Scheme 2. Ru-catalyzed RCM efficiently provides substrates required for the Zr-catalyzed enantioselective alkylation...

Enantioselective Synthesis of Unsaturated Heterocycles by Tandem Catalytic RCM-Catalytic Kinetic Resolution... 

The catalytic RCM with 31 as substrate (Scheme 7) is significantly more facile when the reaction is carried out under an atmosphere of ethylene, presumably due to the formation of the more active Mo=CH2 system (see below for further details). Thus, after catalytic removal of the directing unit, the chiral unsaturated alcohol (S)-32,the formal product of an enantioselective addition of the Grignard reagent to unfunctionalized heterocycle 33, is obtained. An additional in-... 

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. 

The oxypalladation method mentioned above was introduced as a crucial step in the synthesis of several natural products. As shown in Scheme 8.51, Metz and coworkers used this strategy in an enantioselective synthesis of ricciocarpin A [122], Other impressive applications including the acetalization-RCM sequence have been employed in the synthesis of the AB ring of ciguatoxin [123] and of the Q-C fragment of laulimalide [124] (Scheme 8.52). 

Scheme 7.27. Catalytic enantioselective annulations using RCM (ring-closing metathesis).

Furstner succeeded in the synthesis of dactylol using ring-closing metathesis of 9d. Crimmins synthesized enantioselectively diene 9e, and RCM of 9e gave eight-membered ring compound lOe, which is an intermediate for the synthesis of laurencin [Eq. (6.12)] ... 

Last year, a short enantioselective total synthesis of herbarumin III (42) in 11% overall yield was published the approach applied uses Keck s asymmetric allylation and Sharpless epoxidation to build the key fragment. Esterification with 5-hexenoic acid and a RCM was used to yield 42. Finally, another asymmetric synthesis of herbarumin III (42) was carried out using (R)-cyclohexylidene glyceraldehyde as the chiral template. The key steps of the synthesis were the enantioselective preparation of the... 

The Mo-catalyzed transformations shown in Scheme 14 may also be viewed as AROM/RCM processes [24], Furthermore, it is possible that initiation occurs at the terminal olefin, followed by an ARCM involving the cyclic alkene. Regardless of these mechanistic possibilities, the enantioselective rearrangements... 

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