Both reaction mechanisms proposed in Scheme 1.2.1 assume that CM reactions involving α,β-unsaturated carbonyl compounds are essentially irreversible. The most important message to be taken from the results presented in Table 1.2.5, however, is that each step in these ROCM reactions is reversible, and thus neither of the two proposed mechanisms given in Scheme 1.2.1 is completely correctly.
Substituted Cycloolefins
We also investigated the use of other acrylates as cross-linking partners in the ROCM of these seven-membered rings of cycloolefins bearing allylic substituents. Finally, we investigated the use of non-acrylate cross-linking partners in the ROCM of these seven-membered ring cycloolefins.
Experimental Section
Purified via silica gel chromatography (8:2 hexanes:ethyl acetate) to afford 20 mg of 4 as an oil (44% yield). Purified via silica gel chromatography (19:1 hexanes:ether) to afford 441 mg of 68 as an almost colorless oil (48% yield).
For the synthesis of chromenes via ROM/RCM, see: (a) Harrity, J. d) For a review on telechelic polymers, see: Goethals, E.
Cross-Metathesis of Vinyl Boronates
Background
Vinylboronic acids and esters serve as versatile synthetic intermediates for organic chemists.1 As illustrated in Scheme 2.1.1, the boronate portion of these. This hydroboration protocol can provide high yields of the vinyl boronate products under mild reaction conditions, yet efficient and selective. Therefore, CM offers an attractive alternative to alkyne hydroboration for vinyl boronate synthesis, as illustrated in Scheme 2.1.3.
This synthetic strategy is advantageous compared to alkyne hydroboration because alkenes are easier to prepare than alkynes. In addition, various synthetic strategies had to be explored to find reactions that would not. If vinyl boronate CM had been used in this synthesis instead, the transformation from B to A would have been accomplished in a single step under very mild reaction conditions.
Vinyl Boronates Lacking α-Substitution
In these cases, the relative amount of E-isomer present in the isolated product mixture, which is the value given in all the tables herein, was somewhat enriched. For the most part, the cross-partners listed in Table 2.2.3 that led to ≥ 50% yield of the desired product are Type I alkenes, and those resulting in < 50% yield are either Type II or Type III alkenes . The results of these one-pot reactions are listed in Table 2.2.6.15 Consistent with Brown's observations 3b, the alkene stereochemistry of the vinyl boronate intermediate was always inverted upon bromination, resulting in the formation of predominantly Z-vinyl bromides.
Some substrates, such as allylsilanes (Table 2.2.6, entries 4-5), unsubstituted styrene (entry 8), and gemically disubstituted alkenes (entry 17) were unsuccessful in these reactions, but all other substrates tested were successful. at least somewhat successful. Unfortunately, we were unable to obtain high yields of the vinyl iodide product using one-pot CM/iodination procedures. For Catalyst 2, these substrates are most likely on the less reactive side of the Type II group.
In these reactions, CM boronate 48, which had an α-methyl substituent, gave moderate yields of the desired α,α',β-trisubstituted vinyl. The most challenging aspect of this project proved to be the synthesis of various α-substituted vinyl boronates. A more promising synthetic route to these α-substituted vinyl boronates involved the formation of the corresponding vinyllithium species from vinyl iodides rather than vinyl bromides.
The procedure shown at the top of Table 2.3.3 was used to synthesize the necessary vinyl iodides. Iodination of this alkyne led to the isolation of the desired product (60) in 81% yield, with no appreciable formation of the methyl ketone (entry 4). These side products resulted from the migration of the α-substituent on the vinyl boronate to the β-position.
Experimental Section
Purified via silica gel chromatography (7:3 hexanes:ethyl acetate) to give 28 mg of 5 as a yellow oil (58% yield). Purified via silica gel chromatography (9:1 hexanes:ethyl acetate) to obtain 22 mg of 32 as an orange oil (23% yield). Purified via silica gel chromatography (8:2 hexanes:ethyl acetate) to give 32 mg of 72 as an oil (41% yield).
Purify by chromatography on silica gel (9:1 hexanes:ethyl acetate) to give 32 mg of 73 as an oil (35% yield). Purify by chromatography on silica gel (9:1 hexanes:ethyl acetate) to give 16 mg of 74 as an oil (17% yield). Purify by chromatography on silica gel (19:1 hexanes:ethyl acetate) to give 317 mg of 75 as a pale yellow oil (23% yield).
Rhenium-Catalyzed 1,3-Isomerization of Allylic Alcohols
Background
Allyl alcohols and their derivatives serve as useful precursors for numerous synthetic transformations, including Claisen1 and Cope2 rearrangements, directed epoxidations3 and cyclopropanations,4 carbonyl formation,5 and palladium-catalyzed electrophilic substitutions.6. Scheme 3.1.1, is a reaction that allows the two regioisomers of an allylic alcohol to be interchanged. This mechanism has been proposed for a number of known catalysts for this reaction, 7,8,10,11 including catalyst 1.14. Theoretical studies support the proposal that this mechanism is operative in isomerization reactions involving catalyst 1.15 These studies also show that the transition state of the six-membered ring contains an anionic perrhenate moiety and a cationic allyl moiety (Scheme 3.1.2), suggesting that the superior catalytic activity of 1 arises from the stabilizing effect of its additional oxo spectator ligands.
The alternative mechanism proposed for this reaction is shown on the right-hand side of Scheme 3.1.2. As shown in Scheme 3.1.2, regardless of which mechanism is operative, each step in this reaction is reversible. As shown in the reaction given in Scheme 3.1.3, which was taken from Osborne's initial report of catalyst 1,14 the product ratio of regioisomers was often close to 1:1, severely limiting the utility of this reaction.i The high catalyst activity of 1 still created the potential for this isomerization reaction to be of use to the synthetic chemist, but only if its product selectivity could be improved.
Formation of Conjugated Allylic Alcohols
Eg. CH2Cl2 favored the formation of the dehydration product (Table 3.2.1, entry 2), while acetonitrile favored the formation of allylic ether (C) (item 7). Therefore, the more favorable transition state in each case leads to the formation of the E product, alcohol 3, which is consistent with our observations (Table 3.2.2, entries 1-2). To test this hypothesis, we investigated the reaction of the para analog of 7c, substrate 9b, with catalyst 1.
The reactions of the electron-deficient substrates shown in Table 3.2.4 (entries 8–11) were also consistent with our substrate effect hypothesis. Second, the 1,3-isomerization of 2-phenylbut-3-en-2-ol is much less E-selective than that of 5a, which proceeded with E:Z > 20:1, regardless of the reaction conditions. As observed in the isomerization reactions of secondary alcohol substrates in Section 3.2.1, lowering the temperature of reactions involving 2-phenylbut-3-en-2-ol favored product formation over side reactions (Table 3.2.5, entries 7- 14).
Use of Protecting Group Additives
It is possible that protonation is needed in order for the OSiPh3 anionic moiety to dissociate from 1 at the beginning of the reaction, thus. As shown in Table 3.3.1, the addition of BSA (1.2 equiv) promoted the selective 1,3-isomerization of various tertiaries. The use of BSA as a reaction additive also promoted the isomerization of tertiary allylic alcohols to form secondary alcohols (Table 3.3.1, entries 5–7).
We do not know why BSA deactivated catalyst 1 in reactions of secondary alcohols but not in reactions of tertiary alcohols. We have shown that the addition of BSA greatly improves certain isomerization reactions of 1,3-allyl alcohol. The use of the BSA additive was moderately successful in promoting the selective 1,3-isomerization of tertiary allylic alcohols having disubstituted alkene components, but was unsuccessful in
Chirality Transfer
The most interesting observation made during these studies was that the absolute configuration of the products shown in Table 3.4.1 was determined by the alkene geometry of the respective starting materials. This observation can be rationalized by considering the chair-like transition states proposed for each of these reactions, which are illustrated in Scheme 3.4.2. Only a few examples are known of using enantioselective catalysis to form these substrates.
However, it was surprising that a single methyl group made the significant difference as the isomerization of the analogous enantioenriched disubstituted substrate (alcohol 43) proceeded with ca. 80% ee (table 3.4.1, entry 4). Addition of 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 analogue substrate possesses a disubstituted alkene (alcohol 49, see Table 3.4.1, entry 7). We also demonstrated that the absolute stereochemistry of the products of these reactions depended on the alkene geometry of the starting material and could be predicted from the structure of the chair-like transition state that has been proposed for this reaction.
General Summary and Conclusions
With respect to chirality transfer, these reactions currently only proceed in high enantiomeric excess when highly electron-deficient substrates are used. It is likely that the development of a new catalyst, one that less readily transforms the alcohol moiety into a leaving group, will be necessary to improve this aspect of the reaction. The fundamental properties of the reaction that we have observed during these studies, namely (a) the lower reactivity and higher stereoselectivity exhibited by electron-deficient substrates, (b) the dependence of E selectivity on the steric bulk surrounding the tertiary alcohols, and ( c ) the correlation between alkene geometry and absolute configuration of enantioenriched allylic alcohols are all consistent with the proposed chair transition state containing a partially cationic allylic moiety.
However, the side product formation and imperfect chirality transfer that we observed also indicate that competing reaction pathways, which may involve the formation of allylic cations, are also operative. The actual mechanism lies somewhere between that of the transition state of the six-membered ring and that of the discrete allylic cation, and will more closely resemble one or the other, depending on the reaction conditions and the electronic properties of the allylic alcohol. substrate.
Experimental Section
Dissolved in a small amount of dry ether and placed in the freezer (in the glove box) overnight. A second crystallization from the remaining ether solution resulted in the isolation of 720 mg 1, again as white crystals (overall 73% yield). 1 was stored in the freezer in the glove box for an extended period of time (many months).
The product was purified by silica gel chromatography (8:2 .pentane:ether) to obtain 636 mg of 2 as an orange oil (58% yield).
