Alcohols are ubiquitous compounds in nature that offer modular building blocks for synthetic chemistry. Here we discuss the most recent development of different classes of alcohols and their coupling chemistry with carbon dioxide as to afford linear and cyclic carbonates, the challenges associated with their formation, and the potential of this chemistry to revive a waste carbon feed stock.
Substituted homoallylic alcohols 4c,d have then been synthesised via a [2,3]-Wittig rearrangement reaction of the unsymmetrical bis allyl ethers under an argon atmosphere and at –75 oC in high yields according to literature methods [,,].
Different from the C2-anti pathway, the stereoselective C2-syn epoxidation of cis- or trans-2-methyl-1-homoallylic alcohols has been more challenging and fewer practical methods have been reported. Yamagushi and coworkers obtained 1,2-syn-selectivity for cis homoallylic alkenols after protecting the secondary alcohol with a bulky non-coordinating TIPS group using a tungsten-based epoxidizing complex. Guanti and coworkers reported the C2-syn epoxidation of chemoenzymatically generated ⌠-symmetric chiral cis homoallylic diols using m-CPBA or VO(acac)2/TBHP., Since both hydroxy groups were primary, the application of a 3–4 steps protecting group manipulation protocol was required prior to the epoxidation reaction. In both studies, trans alkenols showed to be poor substrates. To circumvent this limitation, Sato and collaborators introduced a removable TMS group at the C3 epoxide carbon to generate a trisubstituted Z-alkene substrate. This modification provided high 1,2-syn selectivity in the VO(acac)2/TBHP epoxidation, that after the removal of the TMS group gave rise to the elusive trans epoxy alcohols.
The vanadium-catalyzed epoxidation reaction (VO(acac)2/t-butyl hydroperoxide) has become a very popular procedure for the stereoselective epoxidation of acyclic homoallylic alcohols. This reaction works well for cis and terminal homoallylic alcohols, favoring the C2-anti epoxide 3 (1,2-relative asymmetric induction), whereas poor stereoselectivities are observed with trans alkenols. The improved diastereoselectivity obtained for cis homoallylic alcohols is rationalized by the vanadium “chair-like” cyclic transition state model proposed by Mihelich that minimizes the syn-pentane repulsion between the C2 and allylic methyl groups. The poor selectivity observed for the trans systems is due to the formation of a competing boat-like transition state.,
Recently, in studies related to the development of an epoxide-based methodology for polypropionate synthesis, we applied the VO(acac)2 catalyzed epoxidation reaction to a series of hindered cis- and trans-2-methyl-3-alkenols using a microwave assisted procedure (MW). In this study the reaction time for the epoxidation was dramatically reduced compared to the use of conventional heating (CH). Similar to the standard conditions, under MW irradiation, the cis homoallylic alkenols provided excellent C2-anti selectivities, while the trans systems showed a small C2-syn preference. This approach provided a series of diastereomeric 2-methyl-3,4-epoxy alcohols, where the C2-anti,cis-epoxides 3a-anti and 3c-anti were obtained as the only diastereomer, while both trans homoallylic alcohols produced the C2-syn epoxide 2d-syn and C2-anti epoxide 3b-anti with moderate diastereoselectivity (). 2-Methyl-3,4-epoxy alcohols are useful precursors for polypropionate synthesis as their regioselective cleavage produces configurationally defined stereotetrads.,, In fact, this methodology was successfully used in the synthesis of the all-anti C5–C10 fragment of streptovaricin U, starting from 3a-anti. Unfortunately, this approach is not suitable for the stereoselective preparation of the complementary C2-syn epoxides 2a–c-syn and the anti epoxide 3d-anti.
Having prepared the free epoxy diols 5a–d, it gave us the opportunity to also explore the reaction of these second-generation homoallylic alkene diol with mCPBA. Although this epoxidation reagent usually gives poor to moderate anti diastereoselectivities on aliphatic epoxy alcohols, it has shown excellent C2-anti selectivity in some sterically hindered systems.,, Thus, the epoxidation of 5a and 5c with mCPBA provided an approximately 2:1 C2-anti:C2-syn selectivity (entries 2 and 4). Interestingly, a 63:37 C2-syn selectivity was observed for epoxy alcohol 5b (entry 6).
Having the cis- and trans-homoallylic bis-diols 5a–d on hand, a study on their epoxidation was undertaken. Although it is known that trans alkenols do not provide good diastereoselectivity for this reaction, being the trans diols 5b and 5d atypical substrates, they were also included in the study. To assess the best conditions in terms of reaction time, yield and diastereoselectivity, diols 5a–d were submitted to the VO(acac)2 catalyzed epoxidation reaction at rt, with conventional heating (CH) and the microwave (MW) assisted conditions. While it was expected that the reaction would proceed faster with heating, we were also interested in exploring differences in diastereoselectivity under the rt conditions. In general, the diastereoselectivities were not affected by the conditions, even though the reaction at rt required longer reaction times (36 h–7 d) and produced lower yields. Under the CH and MW conditions, the reaction time was significantly reduced to less than 30 min in most cases. The MW assisted conditions gave the shortest reaction completion times, thus these were the conditions of choice. The epoxidation of the anti,cis-alkenediol 5a gave moderate diastereoselectivity favoring the C2-syn epoxide 10a-syn (, entry 1). Epoxidation of the syn,cis-diol 5c provided the syn,syn,cis-epoxide 10c-syn with the best C2-syn selectivity (84:16), although in a disappointingly low yield (entry 3). Whereas, the anti,trans-alkenediol 5b showed no selectivity (entry 5), the syn,trans-diol 5d showed a moderate 65:35 C2-syn selectivity favoring epoxide 10d-syn in 10 minutes (entry 7). This result is comparable to the first generation-methodology, which provided the structurally related epoxy alcohols 2d-syn in 3 h with a similar stereoselectivity. Even though the VO(acac)2 catalyzed epoxidation of the free diols 5a–d provided variable diastereoselectivities, it is remarkable that the C2-syn selectivity was favored in all cases, regardless of the alkene geometry or the relative configuration of the C1 and C2 carbons. In these exploratory studies, epoxides 10a-syn, 10c-syn and 10d-syn were obtained as the mayor products. These 3,4-epoxy alcohols cannot be prepared diastereoselectively by the standard first-generation homoallylic alcohol substrates.
The application of the copper-catalyzed Grignard conditions on 4-trans produced the syn,cis homoallylic alcohol 5c in 88% yield. Propynyl alane cleavage of 4-trans, followed by trans reduction produced the syn,trans homoallylic alcohol 5d in 70% yield (). The TBS diprotection-deprotection sequence on 5c and 5d produced the free primary homoallylic alcohols 8c and 8d in 73% and 90% yield, respectively. The selective TBS protection of the primary alcohol in 5c and 5d produced alkenols 9c and 9d in 74% and 66% yield, correspondingly.
To gain insight into the discrimination of the vanadium catalyst between the primary and secondary homoallylic alcohols in the relatively hindered diols 5a–d, we performed a semi-empirical calculation on the exchange reaction between the epoxy alcohols and the vanadium catalyst (). The formation of a vanadate ester is well precedented and represents the first step in the mechanism of the vanadium epoxidation proposed by Sharpless. For the four systems, the vanadium complex formed from the primary homoallylic alcohol is energetically favored over the secondary hydroxy, ranging from 4.5 kcal/mol for system 5c to 20.8 kcal/mol in 5b. These energy differences confirm that the initial vanadate ester complex is formed with the primary alcohol, discarding competition from the secondary alcohols. These results imply that the free primary alcohol solely controls the diastereoselectivity of the epoxidation reaction producing the inverted C2-syn selectivity.
The anti,cis diol 5a was obtained in 66% yield from the regioselective cleavage of epoxy alcohol 4-cis using a copper-catalyzed cis-propenyl Grignard reaction, previously developed by our group. The corresponding anti,trans homoallylic diol 5b was prepared in 77% yield by the regioselective epoxide ring opening of 4-cis using the diethylpropynylalanate conditions developed by Miyashita followed by the sodium/ammonia reduction of the resulting alkynol (). The synthesis of the free primary homoallylic alcohols 8a and 8b was achieved by the diprotection of 5a and 5b as the TBS ethers, followed by selective deprotection of the primary TBS group. The selective TBS protection of the primary hydroxyl group in 5a and 5b produced 9a and 9b, correspondingly.