Rhenium-Catalyzed 1,3-Isomerization of Allylic Alcohols
3.4. Chirality Transfer
silylation of allylic alcohols and the addition of allylic alcohols to 3,4-dihydro-2H-pyran.
Though further studies are greatly needed before conclusive statements can be made to explain these results, our current observations suggest that (a) either catalyst 1 or one of its decomposition products (e.g., HOSiPh3 or perrhenic acid) can operate as an efficient general acid catalyst, and (b) this acidic quality of 1 may be essential to its catalytic activity in the 1,3-isomerization of allylic alcohols.
3.4.1. Formation of enantioenriched secondary allylic alcohols
Table 3.4.1 lists the results of the isomerization of enantioenriched 1-phenyl allylic alcohols bearing various substituents.19 Substrates 43 and 45, which possessed an unsubstituted 1-phenyl substituent, underwent this isomerization reaction with only a small loss (ca. 10%) of enantiopurity (entries 3-5). Higher retention of enantiopurity was
observed when the reaction was performed at –78 °C, rather than at –50 °C (compare entries 1-2 and entries 3-4). Because side product formation in this reaction was completely suppressed at –50 °C (see Table 3.2.1, entry 22), the fact that an even lower reaction temperature was needed to minimize racemization strongly suggested that a competing reaction pathway other than that involving discrete allylic cation formation
(which has been assumed to be responsible for the formation of side products) was responsible for the observed partial loss of enantiopurity in these reactions. Subsequent loss of enantiopurity did not appear to occur to a significant extent over time (compare entries 1-2 and entries 3-4).xviii
The most interesting observation that was made during these studies was that the absolute configuration of the products shown in Table 3.4.1 was controlled by the alkene geometry of the respective starting materials. For example, the isomerization of alcohol 43, which possessed E-stereochemistry, led to the formation of (R)-product 44, while the isomerization of the Z-analog of 43 (alcohol 45) led to the formation of the (S)-
enantiomer of 44 (product 46). This observation can be rationalized by consideration of the chair-like transition states that have been proposed for each of these reactions, which are illustrated in Scheme 3.4.2. Because the absolute stereochemistry of the products
xviii Differences of up to ca. 5% in ee were observed for a given reaction under the same conditions. For
example, we performed the reaction shown in Table 3.4.1, entry 4 on a separate occasion and observed a 98% yield with an 84% ee (notebook page: cm5-263). It appeared that the observed ee in these reactions was extremely sensitive to the reaction conditions, and variables such as catalyst loading and concentration were not reproduced with a high level of rigor from reaction to reaction. Therefore the small difference between entries 1 and 2, and between entries 3 and 4, are likely within reasonable error.
predicted by this model matched that of the observed products of this reaction, the results presented in entries 1-5 of Table 3.4.1 provided strong experimental evidence to support this proposed reaction mechanism.
As a first approximation, we hypothesized that the minor loss of enantiopurity that was exhibited in the isomerization reactions shown in entries 3-5 of Table 3.4.1 was the result of a competing reaction pathway that involved an allylic cation (see Scheme 3.1.2). To test this hypothesis, we evaluated the extent of chirality transfer present in the isomerization of both electron-rich and electron-deficient analogs of substrate 43. The electron-rich analog, methoxy-substituted substrate 47 underwent the isomerization reaction with essentially no transfer of chirality (Table 3.4.1, entry 6). The electron- deficient analog, trifluoromethyl-substituted substrate 49, on the other hand, exhibited nearly quantitative chirality transfer in this reaction (entry 7). In fact, substrate 49 isomerized with a high transfer of chirality even at –50 °C. These results were completely consistent with our hypothesis regarding the involvement of a competing allylic cation pathway, as substrate 47 should favor this pathway, while 49 should not.
3.4.2. Formation ofenantioenriched tertiary allylic alcohols
Another potentially useful application of this methodology involves the formation of enantioenriched tertiary allylic alcohols. These substrates are quite difficult to
synthesize in enantiopure form. Only a few examples of the use of enantioselective catalysis to form these substrates are known. These examples involve the asymmetric addition of vinyl groups to ketones, which is illustrated in Scheme 3.4.3.23 This reaction only works efficiently if the two substituents on the ketone differ greatly in steric bulk, and thus its substrate scope is limited. We envisioned that the 1,3-isomerization of chiral,
nonracemic secondary allylic alcohols possessing trisubstituted alkene components could be employed to generate enantioenriched tertiary allylic alcohols, as illustrated in Scheme 3.4.4. Enantioenriched secondary allylic alcohols are much easier to synthesize than are enantioenriched tertiary ones.24 The advantage of the reaction strategy presented in Scheme 3.4.4, relative to the asymmetric vinylation of ketones, lies in the fact that, for the former, the two substituents on the tertiary alcohol product (R1 and R2) can
theoretically be anything, since the absolute stereochemistry of the product is set by the alkene geometry of the starting material.
Because we had not yet investigated the reactivity of substrates of the form shown in Scheme 3.4.4 with catalyst 1, we first looked at the reactivity of a racemic model substrate, (E)-3-methyl-1-phenylnon-2-en-1-ol. Table 3.4.2 lists the results of these studies. As expected, the isomerization of this substrate was more prone to side product formation than was that of its disubstituted analog, substrate 7a (see section 3.2), because
the allyl moiety of (E)-3-methyl-1-phenylnon-2-en-1-ol was more electron-rich than that of 7a. Again, the use of low reaction temperatures was necessary to prevent the
occurrence of extensive side reactions. Surprisingly, ether proved to be a poor solvent for the isomerization of this substrate (Table 3.4.2, entries 2-4), with THF and CH2Cl2 giving much more desirable results (entries 5-8). Only THF permitted selective product
formation at –78 °C (entry 6). This solvent trend was notably different from that
observed with the analogous secondary alcohol substrate 7a (see Table 3.2.1). As before, the isomerization of (E)-3-methyl-1-phenylnon-2-en-1-ol proceeded with high E-
stereoselectivity.
Table 3.4.3 lists the results of the isomerization reactions of the enantioenriched secondary allylic alcohols with trisubstituted alkene components. The isomerization of (R,E)-3-methyl-1-phenylnon-2-en-1-ol (51) resulted in almost no chirality transfer, even at –78 °C (entries 1-2). We suspected that enantiopurity loss might be problematic for
substrate 51, due to the extra substituent on its allyl moiety, which rendered the substrate more electron-rich. It was surprising, however, that a single methyl group made that significant of a difference, as the isomerization of the analogous enantioenriched disubstituted substrate (alcohol 43) proceeded with approximately 80% ee (Table 3.4.1, entry 4). Adding an electron-withdrawing trifluoromethyl substituent to 51 (alcohol 53) allowed this isomerization reaction to proceed with significantly higher selectivity, resulting in a product with 58% ee (entry 3), although this ee was again much smaller than that of the analogous substrate possessing a disubstituted alkene (alcohol 49, see Table 3.4.1, entry 7).
It was tempting to attribute the lack of efficient chirality transfer in the
isomerization of these chiral, nonracemic allylic alcohols bearing trisubstituted alkene components to their partial reaction through the competing allylic cation pathway (see Scheme 3.1.2). However, as aforementioned, the lack of side product formation, which would be indicative of such a reaction pathway, in these reactions questioned the
likelihood of such a scenario. An alternative explanation was that the chair-like structure
of the transition state underwent a ring flip, which would form a boat-like structure and thus invert the stereocenter. Further analysis of this proposal revealed that this boat-like transition state would generate the Z-isomer of the product, as illustrated for substrate 43 in Scheme 3.4.5. We never observed the Z-product in any of these reactions, and thus the
possibility that competing boat-like transitions states were responsible for the partial racemization of these substrates was eliminated. A third possible explanation suggests that, in the presence of catalyst 1, these allylic alcohols undergo a series of intermolecular SN2/SN2'-type reactions. As shown with substrate 51 in Scheme 3.4.6, this reaction pathway would result in the racemization of both the product and the starting material, without ever forming a discrete allylic cation. Because this reaction pathway involves the interaction of two substrate molecules, it should be discouraged by carrying out the isomerization reaction at a lower concentration.
Table 3.4.4 illustrates our investigation of the isomerization of selected chiral, nonracemic allylic alcohols under dilute reaction conditions. These conditions did not have a significant effect on the reaction of methoxy-substituted substrate 47 (entry 1), but they did significantly increase the selectivity of the isomerization of substrates 43 and 53, increasing the ee of the product by 12% and 33%, respectively (entries 2-3).
Unfortunately these dilute reaction conditions also severely decreased the rate of these two isomerization reactions, resulting in very low conversions to product (11% and 18%, respectively). While these results do suggest that the racemization mechanism shown in Scheme 3.4.6 may be operative in these reactions, more quantitative studies need to be performed in order to confirm this hypothesis.
3.4.3. Summary and conclusions
We have observed that chirality can be transferred during the 1,3-isomerization of chiral, nonracemic secondary allylic alcohols at low reaction temperatures. The extent of chirality transfer was highly dependent upon both the reaction conditions and the
electronic nature of the substrate. Electron-deficient substrates transferred chirality to a far greater extent than did electron-rich substrates. Isomerization reactions that formed tertiary alcohols transferred chirality much less efficiently than those that formed
secondary ones, presumably because the former possessed more electron-rich allyl systems. To date, only one substrate, alcohol 49, has undergone this isomerization reaction with > 90% ee. We also demonstrated that the absolute stereochemistry of the products of these reactions depended upon the alkene geometry of the starting material and could be predicted from the structure of the chair-like transition state that has been suggested for this reaction. This observation provided our strongest piece of
experimental evidence to support this proposed reaction mechanism.