Enol Ethers as Substrates for Efficient Z- and Enantioselective Ring-Opening/Cross-Metathesis Reactions Promoted by Stereogenic-at-Mo Complexes. Utility in Chemical Synthesis and Mechanistic Attributes
The first examples of catalytic enantioselective ring-opening/cross-metathesis (EROCM) reactions that involve enol ethers are reported. Specifically, we demonstrate that catalytic EROCM of several oxa- and azabicycles, cyclobutenes and a cyclopropene with an alkyl- or aryl-substituted enol ether proceed readily in the presence of a stereogenic-at-Mo monopyrrolide-monoaryloxide. In some instances, as little as 0.15 mol % of the catalytically active alkylidene is sufficient to promote complete conversion within 10 minutes. The desired products are formed in up to 90% yield and >99:1 enantiomeric ratio (er) with the disubstituted enol ether generated in >90% Z selectivity. The enol ether of the enantiomerically enriched products can be easily differentiated from the terminal alkene through a number of functionalization procedures that lead to the formation of useful intermediates for chemical synthesis (e.g., efficient acid hydrolysis to afford the enantiomerically enriched carboxaldehyde). In certain cases, enantioselectivity is strongly dependent on enol ether concentration: larger equivalents of the cross partner leads to the formation of products of high enantiomeric purity (versus near racemic products with one equivalent). The length of reaction time can be critical to product enantiomeric purity; high enantioselectivity in reactions that proceed to >98% conversion in as brief a reaction time as 30 seconds can be nearly entirely eroded within 30 minutes. Mechanistic rationale that accounts for the above characteristics of the catalytic process is provided.
Introduction<!>1. Preliminary studies with commonly used Ru- and Mo based complexes<!>i. Initial examination of various Mo-based monopyrrolides<!>ii. Mo-catalyzed EROCM with oxabicyclic alkenes<!>iii. Mo-catalyzed EROCM with an azabicyclic alkene, two cyclobutenes and a cyclopropene<!>iv. Utility in Chemical Synthesis; representative functionalization of the enantiomerically enriche Z enol ethers<!>i. Influence of post-EROCM ring closure on product enantiopurity; rationale for the effect of larger equivalents of enol ether cross partner<!>ii. Mo alkylidene isomerization through degenerate olefin metathesis and variations in enantioselectivity; rationale for enhanced enantioselectivity due to increased enol ether concentration<!><!>Conclusions
<p>Advances in catalytic olefin metathesis during the last two decades have transformed the way in which a great number of organic molecules can be prepared.1 Cyclic structures of nearly any size and/or variety as well as a considerable number of unsaturated acyclic molecules are rendered easily accessible through this remarkable class of transformations.2 Nonetheless, major advances remain to be achieved if catalytic olefin metathesis is to reach its true potential.3 Discovery and development of catalysts that promote olefin metathesis efficiently and can control stereoselectivity – that is, furnish high Z or E selectivity and/or enantioselectivity – stands as a critical and challenging objective.</p><p>Since the first efficient cases of catalytic enantioselective olefin metathesis were reported in 1998 (ring-closing),4,5 ring-opening/cross-metathesis (ROCM) processes have received significant attention.6,7 Chiral Mo alkylidenes and Ru-based carbenes have been developed for desymmetrization of cyclic alkenes, generating carbo- or heterocyclic dienes enantioselectively. In 2007, we reported the first application of catalytic enantioselective ring-opening/cross-metathesis (EROCM) to the total synthesis of natural product baconipyrone C.8 In spite of the above advances, a number of shortcomings remain unaddressed. One deficiency concerns the limited range of cross partners utilized: nearly all reactions have been with aryl-substituted alkenes. Furthermore, several problems relating to stereochemical control stand unresolved. High enantiomeric ratios are observed in a number of EROCM reactions; in most instances, however, either E alkenes are formed predominantly or exclusively6a–d,7a–c,e or a mixture of olefin isomers is generated with little or no stereochemical control.7d,f Another problem concerns the extensive reaction times (up to 120 hours)7e–f that might be required for achieving high conversion; a more facile transformation is achievable but only at the expense of higher catalyst loadings. The issue of catalyst efficiency is a growing concern with transformations that are promoted by complexes derived from ruthenium, which is a relatively rare and increasingly precious metal.</p><p>Enol ethers are easily accessible cross partners that might be used in catalytic EROCM reactions9 to afford versatile enantiomerically enriched products; there are, nonetheless, only a small number of cases where such O-substituted alkenes have been utilized as cross partners in intermolecular olefin metathesis reactions; all reported processes have been catalyzed by an achiral complex.10 A disclosure by Ozawa in 2000 outlines a Ru-catalyzed transformation involving norbornene and phenylvinyl ether; the desired product was obtained in only 17% yield and, notably, with 85% Z selectivity.11 Subsequent studies by Rainier offer five additional examples of transformations of ethylvinyl ether or enol acetate with 7-oxa- or 7-azanorbornenes, promoted by achiral Ru-based carbenes; nearly equal mixtures of Z and E alkenes were uniformly generated.12 Thus, to the best of our knowledge, catalytic ROCM or EROCM reactions that involve an enol ether and which proceed with effective control of alkene stereoselectivity and/or enantioselectivity have not been disclosed.</p><p>We have developed stereogenic-at-Mo and W complexes that display the unique ability to catalyze a range of olefin metathesis reactions with unique levels of efficiency and stereoselectively.13 We have demonstrated that the Mo- or W-based monopyrrolidemonoaryloxides promote ring-closing metathesis of dienes14 or enynes15 in high yield and with exceptional enantioselectivity. Subsequent investigations led us to establish that Z-selective EROCM16 and homocoupling of terminal alkenes17 as well as ethenolysis of Z-1,2-disubstituted olefins18 can be performed. We have put forth the first examples of Z-selective cross-metathesis processes with enol ethers serving as one set of cross partners.19 Most recently we have shown that the corresponding tungsten complexes can be used to promote Z-selective macrocyclic ringclosing metathesis.20 In the case of catalytic EROCM, highly enantio- and Z-selective, reactions proved to be largely restricted to aryl olefins (i.e., styrenyl derivatives). Such a drawback diminishes utility, since the resulting aryl-substituted alkenes offer a limited range of possibilities for functionalization.21</p><p>Here, we report a protocol for efficient, enantio- and Z-selective ROCM involving an alkyl- or aryl-substituted enol ether in combination with oxa- or azabicyclic alkenes, cyclobutenes or a cyclopropene. Transformations are promoted by 0.15–3.0 mol % of a stereogenic-at-Mo monopyrrolide-monoaryloxide and proceed to completion, typically at 22 °C, within 30 minutes. The desired cyclic or acyclic dienes, containing an easily differentiable terminal alkene and a vinyl ether in addition to one or more tertiary or quaternary carbon stereogenic centers, are generated in 61–90% yield, 85:15–99:1 enantiomeric ratio (er) and 84:16 to >98:2 Z:E selectivity. We show that, depending on the structure of the cyclic alkene, the amount of the terminal olefin present and the reaction time can have a significant influence on the enantioselectivity and efficiency of the EROCM (but not enol ether stereochemistry). As will be detailed below, such attributes are mechanistically important, offering valuable insights regarding the inner workings of this emerging class of olefin metathesis catalysts.13–20</p><!><p>We began by probing the ability of widely used Ru- and Mo-based complexes to catalyze a representative ROCM reaction with an enol ether. We selected silyl-protected oxabicycle 4 as the substrate and examined processes involving commercially and/or easily accessible n-butylvinyl ether 5a or p-methoxyphenylvinyl ether 5b (1.1 equiv vs 4). As the data in entry 1 of Table 1 illustrate, with Ru carbene 1, 69% disappearance of the cyclic alkene is observed after 30 minutes but only 32% of the desired product (6a) is isolated; the remainder of the substrate is likely consumed through oligomerization. Furthermore, the resulting disubstituted enol ether moiety of the 2,4,6-trisubstituted pyran is generated as a 3:1 mixture of E and Z isomers. With the sterically more congested enol ether 5b as the cross partner (entry 2, Table 1), 95% of 4a disappears within 30 minutes but oligomerization of the cyclic alkene represents the predominant pathway. In a similar fashion, with Mo-based diolate 2, the relatively strained alkene is consumed rapidly but the desired ROCM product is isolated in 10–14% yield (entries 3–4, Table 1), and the product enol ether is generated either non-selectively (1:1 Z:E; entry 3) or with moderate preference for the Z isomer (80% Z, entry 4). Finally, when chiral Mo diolate 3 is used, disappearance of the starting materials is not detected even after 12 hours.</p><!><p>Next, we investigated whether stereogenic-at-Mo monopyrrolide-monoalkoxide or aryloxides might not only promote EROCM reactions efficiently and with high enantioselectivity, but deliver the resulting disubstituted enol ether with a high degree of Z selectivity as well. We thus discovered that reactions with Mo-based monopyrrolide monoalkoxide 7 and enol ethers 5a or 5b proceed with significantly higher efficiency than observed with the complexes shown in Table 1. As illustrated in entries 1–2 of Table 2, with 1.0 mol % catalyst in the presence of 1.1 equiv of either cross partner, there is complete consumption of oxabicycle 4a within 30 minutes at 22 °C and 6a–b are obtained in 48% and 75% yield, respectively, and with ~80:20 Z:E selectivity (er is not applicable since 7 is racemic). Based on the formerly proposed models to account for Z selectivity observed in transformations promoted by stereogenic-at-Mo complexes,16,19 we surmised that reactions catalyzed by a related alkylidene that carries a larger aryloxide ligand might deliver improved stereoselectivity. Indeed, as the findings in entries 3–4 of Table 2 indicate, when dimethylarylamido aryloxide 8a is employed, 6a–b are generated exclusively as Z enol ethers (>98%) with exceptional enantioselectivity (99:1 er, respectively); however, efficiency is less than desirable, as the discrepancy between percent conversion and values of isolated products (cf. entries 3–4, Table 2) indicates incomplete transformation and significant oligomer formation. When the sterically more demanding di(i-propyl)arylimido complex 8b is used (entries 5–6, Table 2), none of the desired EROCM products are generated within 30 minutes. After 12 hours, under otherwise identical conditions, reactions with 5a and 5b result in 48% and 31% conversion, 34% and 27% yield and 96.5:3.5 and 97.5:2.5 er, respectively (>98% Z in both cases).</p><p>It is when Mo complex 9a, bearing 3,3'-difluoroaryloxide and a relatively small adamantylimido (vs 2,6-dialkylarylimido), is used (entry 7, Table 2) that EROCM with n-butylvinyl ether 5a proceeds with high efficiency (>98% conv, 87% yield), affording the desired pyran in high Z- and enantioselectivity (>98% Z and 97:3 er). The corresponding reaction with p-methoxyphenylenol ether (5b; entry 8, Table 2) proceeds to 60% conversion, affording 6b in 41% yield, >98% Z selectivity but a lower 88.5:11.5 er (vs 97:3 with 5a). The less efficient reaction could be the result of the larger size of the aryl substituent in 5b (vs n-Bu in 5a), exacerbated by the lower concentration of the catalytically active complex (0.07 mol % monopyrrolide-monoaryloxide generated in situ upon reaction of 1.0 mol % bispyrrolide and aryl alcohol;22 45–50% of the much less active bis-aryloxide14 formed as the major component of the mixture). It follows that in the presence of the corresponding dichloroaryloxide 9b (entries 9–10, Table 2), in situ formation of which is more efficient (0.5 mol % of the desired alkylidene generated), the EROCM products are isolated in higher yields (6a in 87% and 6b in 80%), with enantioselectivity remaining high (98:2 and 92:8 er, respectively) and Z selectivity complete (>98%) in both instances. When the derived dibromide 9c is employed (0.6 mol % generated from combination of 1.0 mol % each of the bispyrrolide and aryl alcohol; entries 11–12), further improvement in enantioselectivity is achieved and 6a–b are generated in 99:1 and 98.5:1.5 er, respectively, without diminution in efficiency (89% and 90% yield, respectively) or control of enol ether stereochemistry (>98% Z). There is a nearly identical outcome when diiodoaryloxide 9d is used (entries 13–14, Table 2). Since preparation of the requisite diiodoaryl alcohol for 9d involves a relatively lengthy procedure,23 we decided on dibromoaryloxide 9c as the complex of choice for the follow-up investigations.</p><!><p>Next, we turned to examining transformations of oxabicyclic alkenes of varying stereochemical identities that contain different protecting groups at their carbinol site. The results of this phase of our investigations are summarized in Table 3. When exo oxabicycle 10a is subjected to 1.1 equivalents of n-butylvinyl ether 5a (entry 1, Table 3) or p-methoxyphenylvinyl ether 5b (entry 3, Table 3), EROCM proceeds readily to ≥97% conversion with >98% Z selectivity, but unexpectedly and in stark contrast to the reactions with the corresponding endo isomer 6a (cf. Table 2), enantioselectivity is minimal (52:48 and 56.5:43.5 er for 11a and 11b, respectively). Subsequent studies, further discussed below, allowed us to establish that when larger amounts of enol ethers 5a–b are utilized, as the data in entries 2 and 4 of Table 3 illustrate, the desired pyrans are formed in high enantioselectivity as a single enol ether isomer (>98% Z) and in 87–88% yield. The findings in entries 5–10 of Table 3, involving EROCM reactions of oxabicyclic benzyl ethers indicate that the requirement for excess cross partner for attaining high enantioselectivity is particular to exo oxabicyclic substrates (compare to entries 9–14 of Table 2). It should be noted that 12a–b (entries 5–6, Table 3) as well as 13a–b (entries 7–10) are generated with >98% Z selectivity regardless of the conditions used.</p><!><p>Z-Selective Mo-catalyzed EROCM with enol ethers is not limited to reactions with oxabicyclic alkenes. As shown in entries 1–3 of Table 4, reaction with endo azabicycle 14 delivers 2,6-disubstituted piperidene. Although the process is significantly less efficient when lower amounts of the enol ether cross partner are employed (compare entries 1–2, Table 4), EROCM in the presence of 20 equivalents of 5b (entry 3) generates the desired product with 92% Z selectivity, in 91:9 er and 90% yield. The relatively diminished Z selectivity compared to the transformations involving oxabicyclic alkenes (cf. Tables 2–3) might be partly because to achieve high conversion with the less reactive azabicycle, elevated temperatures are needed (60 °C vs 22 °C); the reactivity differential is likely the reason for the necessity of a higher catalyst loading (3.0 vs 0.6 mol %) as well as the need for excess cross partner (20 equiv 5b). Another attribute of the reactions with azabicycle 14, one that is unlike the EROCM of oxabicycles (cf. Table 3), relates to lower Z:E ratios when less equivalents of 5a or 5b are employed. It is likely that such a difference arises to a degree from alkene isomerization at elevated temperatures: when the reaction in entry 1 of Table 4 is analyzed after 30 minutes (2.0 equiv 5b, 60 °C), an 85:15 mixture Z- and E-15 is observed (vs 75:25 after 3.0 h). Mechanistic factors that account for dependence of stereo- and enantioselectivity on enol ether concentration will be addressed below.</p><p>When bis-silylether cyclobutene 16 is used (entries 4–7, Table 4), similar to endo oxabicycles (Table 3), lower amounts of the catalyst (0.6 mol %) are sufficient for achieving >98% conversion; however, the need for excess enol ether for achieving higher enantioselectivity (cf. entries 4 vs 5 and 6 vs 7, Table 4) is reminiscent of the exo oxabicyclic alkenes (Table 3; see below for mechanistic rationale). With bis-benzyl ether cyclobutene 18 as the cyclic alkene (entries 8–9, Table 4), reactions are significantly more sluggish, in spite of the smaller size of the alkoxy groups (vs OTBS in 16, entries 4–7 of Table 4). Such a difference in rate might be the result of internal chelation between the Mo center and the sterically accessible and Lewis basic benzyloxy, leading to lowering of reaction rate.24 Accordingly, as shown in entries 8–9 of Table 4, elevated temperatures (60 vs 22 °C in reaction of 16) are required for achieving complete conversion to bis-benzyloxy dienes 19a–b, which are formed in 85:15 er and isolated in 61 and 73% yield, respectively. It is noteworthy that the Z:E value for synthesis of 19a is lower than all other examples; this might partly arise from the elevated temperatures required for efficient EROCM, which could cause Mo-catalyzed isomerization of the kinetically preferred Z enol ether. Isomerization of the sterically more hindered 1,2-disubstituted alkene in 19b likely occurs less readily (98% Z; entry 9, Table 4). Catalytic EROCM of cyclopropene 20 (entries 10–11, Table 4) proceeds to >98% conversion in 30 minutes, affording 1,4-dienes 21a–b, bearing a quaternary carbon stereogenic center, with complete Z selectivity, in 79 and 71% yield and 94.5:5.5 and 96.5:3.5 er, respectively. The lower enantioselectivities observed with cyclobutenes 16 and 18 (entries 4–9, Table 4 vs cyclopropene 20) is likely due to the lower degree of steric differentiation between the two faces of the cyclic alkene (i.e., the oxygen atom of the substituent reduces the effective size of the silyl and benzyl ether units).</p><!><p>A hallmark of the present class of catalytic reactions is the degree of efficiency with which these highly Z- and enantioselective processes proceed. As further demonstration of the exceptional facility of the Mo-catalyzed transformations and as the representative cases in Scheme 1 illustrate, we have been able to establish that reactions can be performed in minimal solvent25 in the presence of only 0.15 mol % of the monopyrrolide-monoaryloxide, leading to complete consumption of starting materials within 10 minutes to afford the desired heterocyclic Z enol ethers in >70% yield and with exceptional stereoselectivity.</p><p>The enantiomerically enriched dienes available through Mo-catalyzed EROCM can be functionalized in a variety of manners; several preliminary examples are provided in Scheme 2. A noteworthy aspect of the present approach, in contrast to the related previously reported protocols involving styrenyl cross partners, is that the two alkenes of the products are electronically distinct and can be readily differentiated. Thus, as the formation of 22 and 23 illustrates, the enol ether moiety can be efficiently hydrolyzed to afford the desired aldehyde in 87% yield. Aldehydes such as 22 and 23 are versatile intermediates, allowing access to a range of additional enantiomerically enriched molecules. γ-δ-Unsaturated aldehyde 23, bearing an all-carbon quaternary stereogenic center26 at its β carbon constitutes the product of a conjugate addition, which does not have a catalytic enantioselective variant available.27</p><p>The Z enol ether of the EROCM products can participate in stereoselective transformations; two examples are shown in Scheme 2. Preliminary studies indicate that diastereoselective epoxidation/hydrolysis of 6a affords 24, which upon treatment with diisobutylaluminum hydride is converted to diol 25 as a 3:1 mixture of diastereomers in 43% overall yield.28 Equally noteworthy is the Cu-catalyzed diastereoselective cycloaddition29 that converts 10a to bispyran 27 in 5:1 diastereoselectivity and 68% yield. Future development of more efficient strategies, reagents and catalysts for functionalization of enol ethers is expected to enhance the utility of the enantiomerically enriched Z enol ethers accessed through catalytic EROCM.</p><!><p>As described above, in the case of certain cyclic alkene substrates, larger equivalents of the enol ether cross partner lead to higher enantioselectivity (cf. Tables 3 and 4). Specifically, EROCM reactions with oxabicyclic alkenes that contain an exo siloxy or benzyloxy group (entries 1–4 and 7–10 in Table 3) otherwise furnish 2,4,6-trisubstituted pyrans with relatively low enantiomeric purity (52:48–82:18 er vs 92:8–96.5:3.5 er with excess enol ether); this is in contrast to the corresponding endo derivatives (cf. Table 2 and entries 5–6, Table 3). Another set of transformations where enantioselectivity improves with excess enol ether, albeit to a lesser degree, relates to reactions with cyclobutenes 16 and 18 (cf. entries 4–9, Table 4). A systematic investigation with different amounts of 5a or 5b, summarized in Table 5, further underlines the strong dependence of enantioselectivity in Mocatalyzed EROCM of the aforementioned selected cyclic alkenes. The level of Z selectivity, however, is unaltered by enol ether concentration in the above cases.</p><p>One likely reason for the dependence of enantioselectivity in EROCM of exo (but not endo) oxabicyclic substrates is related to the higher tendency of the corresponding products or the derived alkylidenes to undergo ring closure; reformation of the cyclic substrates leads to sequences of ring-opening/ring-closing reactions that can result in diminution of kinetically derived er values.30 As illustrated in Scheme 3, the pyran ring within Mo alkylidene II is able to undergo ring-closing metathesis (RCM) to regenerate 10a; although II can be converted to the conformational isomer III, the energetic difference is not such that the latter exists in solution exclusively. Such a chain of events allows the overall transformation to occur under more thermodynamically controlled (reversible) conditions, leading to diminution of enantioselectivity. In contrast, the alkylidene that is formed through reaction of the endo oxabicycle (IV, Scheme 3) is unlikely to participate in a similarly facile RCM to regenerate the relatively more strained 4a (vs exo isomer 10a), since the relatively high-energy all-axial pyran likely isomerizes rapidly to all-equatorial V, which cannot undergo RCM (Scheme 3). In the presence of excess amounts of enol ether, reaction with intermediate complexes II or III takes place more readily, minimizing the degree to which enantioselectivity-reducing equilibration takes place; therefore, higher er values are obtained with an increase in enol ether concentration.</p><p>The validity of the above scenario is supported by the substantial variations in enantiomeric purity of EROCM products as a function of reaction time; representative observations are presented in Table 6. Whereas within 30 seconds, pyrans 11a and 11b are obtained in 95:5 and 90:10 er (entries 1 and 2, Table 6), after only three minutes, enantioselectivity is decreased (84.5:14.5 and 86:14, respectively; entries 3 and 7); particularly in the case of 11a, diminution of enantioselectivity continues after 30 minutes (entries 4 and 8, Table 6). Facile rates of RCM/ROM can therefore lead to highly efficient erosion of er values.</p><p>To substantiate further the proposed mechanistic scenario, we re-subjected several enantiomerically enriched pyrans to the reaction conditions to confirm that the aforementioned equilibration through RCM of pyran products is indeed detrimental. As the findings summarized in Table 7 indicate, loss of enantioselectivity by post-EROCM isomerization afflicts the reactions of exo bicyclic substrates (entries 3–4, Table 7) but, as predicted by the model illustrated in Scheme 3, significantly less erosion is observed with products derived from reactions of the endo diastereomers (entries 1–2).</p><!><p>Another key factor to be considered is the identity of the alkylidene diastereomer (i.e., S or R at the Mo center) that reacts with the cyclic alkene. As outlined in Scheme 4, such principles can dictate which pyran-containing alkylidene stereoisomer is involved (V vs X, Scheme 4) and how critical is the facility with which the two oxygen-substituted alkylidene diastereomers isomerize (i.e., S-I vs R-I leading to VII vs IX, respectively, in Scheme 4).</p><p>Previous investigations performed in these laboratories involving examination of various kinetic parameters, labeling studies as well as X-ray structures corresponding to the two diastereomeric forms of the stereogenic-at-Mo complexes,31 point to one isomer as substantially more reactive (i.e., the S isomer of complexes shown in Schemes 3–4 is more active). The primary reason for such a difference appears to be the blocking of the approach of the incoming alkene, which likely occurs anti to the pyrrolide, by the large aryloxide ligand. As shown in Figure 1, the X-ray structure of the related R neophylidene isomer shows that the oxygen-based ligand is held in a particularly unfavorable orientation for alkene substrate approach, partly due to association of one of its halides with the Lewis acidic metal center.</p><!><p>The rate with which the two diastereomeric oxygen-substituted alkylidenes (S-I and R-I) isomerize influences the overall reaction rate and enantioselectivity. At higher enol ether concentration, alkylidene diastereomers interconvert more readily as a result of an increasingly facile non-productive ("degenerate") olefin metathesis, as illustrated in Scheme 5. When alkylidene isomerization proceeds rapidly, the more reactive isomer remains more available, allowing EROCM to proceed rapidly and enantioselectively through the intermediacy of S-I. Both isomeric forms likely promote highly Z-selective processes, since the size differential between the adamantylimido and aryloxide ligands, the purported roots of high alkene stereoselectivity, remains unaltered. The R alkylidene (R-I) diastereomer can promote EROCM via VIII, IX, and X (Scheme 4) to cause diminution of enantioselectivity, unless it is rapidly isomerized to the S isomer. Rapid conversion of R-I to S-I ensures a faster rate of formation and yield of the desired EROCM product as well as higher enantioselectivity. This proposal is in line with previous mechanistic investigations31 and is further supported by the deuterium scrambling observed when a mixture of 5b and d3-5b are subjected to 1.2 mol % 9c (C6D6, 22 °C; Scheme 5); facile scrambling of the atomic labels takes place within 30 minutes, generating significant amounts of d1-5b and d2-5b (detected through high resolution mass spectrometry). Similarly, when an equal mixture of 5a and d3-5b is treated with 1.2 mol % 9c, after 30 minutes all the volatiles (including 5a and d2-5a) are removed and the remaining residue is analyzed by 400 MHz 1H NMR spectroscopy, a 45:55 mixture of d1-5b and d2-5b is detected (Scheme 5).32 Such exchange of deuterium likely proceeds through a non-productive olefin metathesis process via the symmetric metallacyclobutane XI (Scheme 5).</p><p>The significance of the rate of isomerization of alkylidene diastereomers is especially relevant to EROCM reactions with cyclobutene substrates, where substantially higher ring strain renders post-metathesis RCM unlikely (in contrast to oxabicycles). The higher enantioselectivity observed with increasing concentration of enol ether, as shown in entries 11–14 of Table 5, is probably due to an increase in the rate of degenerate olefin metathesis of the enol ether cross partner, leading to a steady concentration of the more active and stereochemically discriminating S-I. Similar principles can be used to explain why in reactions of exo oxabicyclic alkenes (e.g., entries 1 vs 2, Table 3), lower enol ether concentration leads to formation of significant amounts of achiral bis-cross products. Such a complication concerns EROCM with exo isomers only, because, as detailed above (Scheme 3), unlike endo variants (cf. Table 2 and entries 5–6, Table 3), they can undergo facile ring closure, allowing increasing amounts of initially generated chiral pyran to be converted to the achiral bis-cross product through the pathway shown below (via XIII in Scheme 6). The above considerations suggest that the less reactive31R-III (Scheme 6), derived from S-I, reacts preferably through the sterically less congested, symmetrically substituted metallacyclobutane XII to produce the corresponding chiral pyran in high enantioselectivity. In contrast, alkylidene X, a more reactive and less discriminating S-Mo complex, can give rise to the formation of the meso bis-enol ether through metallacyclobutane XIII, while generation of the alternative product enantiomer occurs through XV (Scheme 6). High yields and enantioselectivities might thus depend on the fast rate of alkylidene isomerization not only because the appropriate alkylidene isomer can then efficiently participate in the ring-opening process, but also since the latter pathway delivers a diastereomer (XII, Scheme 6) that reacts more readily with an enol ether in such a way that leads to the chiral product (vs meso). The improved enantioselectivity in reactions of azabicycle 14 (entries 1–3, Table 4) can be accounted for through similar reasoning. Moreover, the effect of enol ether concentration on Z:E selectivity is probably due to minimization of RCM of the piperidene product to regenerate the starting azabicycle, which undergoes ring closure faster than the more strained oxabicycles.6c</p><p>The predominant involvement of S-I as the initiating alkylidene suggests the intermediacy of III (Scheme 3), which possesses an R stereogenic Mo center – an isomeric form that, as was described above, is relatively hesitant to react intermolecularly with another alkene substrate. Accordingly, higher concentrations of enol ether could be required to enhance the rate of intermolecular transformation with the cross partner, minimizing the potentially more facile intramolecular RCM that leads to loss of enantiomeric purity.</p><!><p>Examples of efficient and highly stereoselective olefin metatesis reactions that involve enol ethers are highly uncommon; the first cases of cross metathesis reactions with this electronically distinct class of alkenes were developed in these laboratories only recently.19 In this disclosure, we put forward the first instances of catalytic EROCM processes that proceed readily and with exceptional Z selectivity, delivering the desired products in high enantiomeric purity. The products obtained from reactions of oxa- or azabicycles, cyclobutenes or cyclopropenes cannot be readily accessed by alternative protocols and are amenable to site selective functionalization of the enol ether moiety and should thus prove to be of value in chemical synthesis. As detailed above, enantioselectivity levels can vary, dictated by various mechanistic aspects of the process. Additionally, an aspect that is particular to the class of stereogenic-at-metal catalysts used in these studies is the facility with which the complex diastereomers interconvert, strongly impacting the stereochemical outcome of the reaction. That is, conditions that accelerate the rate of isomerization between the diastereomeric forms of such complexes (e.g., excess cross partner) by non-productive olefin metathesis pathways can be used to impact the reaction outcome.</p><p>The catalytic transformations described in this report bear further testimony to the unique ability of monopyrrolide stereogenic-at-metal complexes to promote highly efficient and stereoselective olefin metathesis reactions. Design and development of additional catalysts and methods for stereo- and enantioselective olefin metathesis reactions involving enol ethers, as well as application of catalytic EROCM processes described herein to efficient preparation of biologically active complex molecules19–20 are in progress.</p>