ARCM

An area in which catalytic olefin metathesis could have a significant impact on future natural product-directed work would be the desymmetrization of achiral molecules through asymmetric RCM (ARCM) or asymmetric ROM... 

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. 

Asymmetric microbial acyloin condensation, 16 402 Asymmetric oxidation, 23 735 Asymmetric ring-closing metathesis (ARCM), 26 922... 

The new catalyst is developed from commercially available starting materials and can be used in situ without isolation, to effect enantioselective olehn metathesis [Eq. (6.69)]. An active catalyst solution can be accessed by premixing of readily available (7 )-102, and a commercially available Mo-triflate 103 and can be used directly without further purification. This catalyst solution promotes ARCM reactions with equal or higher levels of efficiency and selectivity than does 75a. Desymmetrization of 80c with THE solution of 77 gave furan derivative 81c with 88% ee. Use of 75a gave 81c with 93% ee [Eq. (6.70)] similarly, AROM-CM of norbomene 82e gave cyclopentane derivative (R)-83e with 98% ee ... 

Catalytic Kinetic Resolution Through Mo-Catalyzed ARCM.210... 

Catalytic Asymmetric Synthesis Through Mo-Catalyzed ARCM. . . 214... 

With the above considerations in mind, we prepared and examined a myriad of chiral Mo-based catalysts for both asymmetric RCM (ARCM) and ROM (AROM) transformations [5]. In this article, several efficient and enantioselec-tive reactions that are catalyzed by these chiral complexes are discussed [6]. The structural modularity inherent to the Mo-based systems allows screening of catalyst pools, so that optimal reactivity and selectivity levels are identified expeditiously. 

The catalytic kinetic resolution of various dienes through ARCM can be carried out in an efficient manner at 22 °C in the presence of 5 mol %4a [10]. As the data in Scheme 1 illustrate, 1,6-dienes 5-7 are resolved with excellent levels of enan-tiocontrol (krei>20) [11]. Chiral complex 4a readily promotes the resolution of allylic ethers 8-10 as well [12]. 

Scheme 1. Mo-catalyzed kinetic resolution of 1,6-dienes through ARCM...

Catalyst Modularity and Optimization of Mo-Catalyzed ARCM Efficiency and Selectivity... 

In spite of the high asymmetric induction observed in the Mo-catalyzed ARCM of 1,6-dienes, when complexes 4a and 4b are used in reactions involving 1,7-dienes, inferior asymmetric induction is obtained. For example, as illustrated... 

The data in Scheme 3 illustrate that a wide range of 1,7-dienes can be resolved with high selectivity and efficiency. These findings provide further evidence regarding the importance of the availability of a diverse set of chiral catalysts. Although BINOL-based complexes (e.g., 11a) typically promote ARCM... 

Scheme 4. Mo-catalyzed ARCM of achiral trienes can be effected efficiently, enantioselectively, and in the absence of solvent...

The Mo-catalyzed ARCM technology summarized above has been utilized in a brief and enantioselective total synthesis of exo-brevicomin (30) by Burke. The key step, as illustrated in Scheme 7, is the desymmetrization of achiral triene 28 [17]. 

Mo-catalyzed ARCM may be used in the enantioselective synthesis of medium ring carbo- and heterocycles [18]. As shown in Scheme 8,medium ring tertiary siloxanes (e.g., 35), are prepared with high levels of enantioselectivity. These processes can be effected efficiently in preparative scale and at low catalyst loading (e.g., 33—>35). Such attributes render the catalytic enantioselective method attractive from the practical point of view. 

The representative transformation in Scheme 9 illustrates that the optically enriched siloxanes obtained by Mo-catalyzed ARCM can be further functionalized to afford tertiary alcohols (e.g., 39) with excellent enantio- and diastereo-meric purity. Conversion of 38 to 39 in Scheme 9 is carried out without solvent, at 1 mol % catalyst loading and on 1-g scale (only 30 mg of catalyst 4a is needed) [18]. 

Most recent studies indicate that ARCM can be used to synthesize small and medium ring N-containing unsaturated heterocycles in high yield and with excellent ee through catalytic kinetic resolution and asymmetric synthesis [19]. As the representative data in Scheme 10 illustrate, levels of enantioselectivity can vary depending on the nature of the arylamine (compare 44 to 46). As the synthesis of 48 indicates (cf. Scheme 10), the facility and selectivity with which medium ring unsaturated amines are obtained by the Mo-catalyzed protocol is particularly noteworthy. 

Scheme 8. Mo-catalyzed tandem ARCM can be used to synthesize seven-membered carbo-and heterocyclic structures efficiently and in optically enriched form...

Unlike carbocyclic and oxygen-containing heterocyclic systems, catalytic enantioselective synthesis of eight-membered ring amines proceeds efficiently and with excellent enantioselectivity. These catalytic ARCM reactions can be carried out in the absence of solvent as well. Representative data regarding cat-... 

Scheme 10. Enantioselective synthesis of amines through Mo-catalyzed ARCM...

The appreciable levels of asymmetric induction observed in the catalytic ARCM reactions mentioned above suggest a high degree of enantiodifferentiation in the association of olefinic substrates and chiral complexes. This stereochemical induction may also be exploited in asymmetric ring-opening metathesis (AROM). Catalytic ROM transformations [20] offer unique and powerful methods for the preparation of complex molecules [2d, 2g]. The chiral Mo-alkyli-denes that are products of AROM reactions can be trapped either intramolecu-larly (RCM) or intermolecularly (cross metathesis, CM) to afford a range of optically enriched adducts. 

In contrast to 52 (Scheme 12), diastereomer 55 (Scheme 13), because of its more exposed and highly reactive strained olefin, undergoes rapid polymerization in the presence of 4a. The less reactive Ru complex 56 [23] can however be used under an atmosphere of ethylene to effect a tandem ROM/CM to generate 57. The resulting triene can be induced to undergo Mo-catalyzed ARCM (5 mol % 4a) to afford optically pure 58, the AROM/RCM product that would be obtained from 55. 

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... 

The non-racemic pyrans shown in Scheme 14 can be accessed by Mo-catalyzed ARCM of the corresponding trienes. The example shown in Eq. (1) is illustrative. Interestingly, elevated temperatures are required for high levels of enan-tioselectivity under conditions shown in Scheme 15, trienes such as 65 afford the desired pyrans in significantly lower ee (e.g., 66 is obtained in 30% ee at 50 °C). Clearly, detailed mechanistic studies must be carried out before the origin of such variations in selectivity is understood. 

More recently, we have synthesized and studied the activity of 89, the first supported chiral catalyst for olefin metathesis (Scheme 20) [28]. Catalyst 89 efficiently promotes a range of ARCM and AROM processes a representative example is shown in Scheme 20. Rates of reaction are lower than observed with the corresponding monomeric complex, but similar levels of enantioselectivity are observed. Although 89 must be kept under rigorously dry and oxygen-free conditions, it can be recycled. Catalyst activity, however, is notably diminished by the third cycle. As the data and the figure in Scheme 20 show, the product solution obtained by filtration contains significantly lower levels of metal impu-... 

---