Ethers diastereocontrol

An efficient two-step annelation of functionalized orthoesters with trimethyl-silyloxyfuran derivatives has been reported that produces bicyclo[3. .0]lactones. ° The reaction in Scheme 7 shows an example in which the initial condensation between silyl enol ether and orthoester is followed by the radical cyclization reaction under standard conditions. It is worth underlining the complete diastereocontrol in which three contiguous stereocenters are generated in one step with >95% stereoselectivity. 

The etherification between alcohol 10 and imidate 67 was one of the key transformations in the successful preparation of compound 1. The use of HBF4 as the catalyst for the etherification was crucial for obtaining high levels of diastereose-lectivity and relatively high conversion to the desired product 18. The fact that sec-sec ethers have rarely, if ever, been obtained with high levels of diastereocontrol in Sn2 fashion under typical SN1 reaction conditions prompted us to investigate the complex mechanistic details of this exceptional reaction. 

The zirconocene catalysts described above are very oxophilic, which provides several synthetically useful transformations. Oxygen substitution at the al-lylic or homoallylic position of an olefin substrate allows for excellent regio-and diastereocontrol in the ethyl magnesiation reactions of a-olefins and dienes [21]. When 29 is substituted with a hydroxyl group (29a), syn 30a is favored over anti in a 95 5 ratio, while substitution with OCH3 (29b) reversed the diastereoselectivity to 11 89 (Eq. 6). Use of THF in place of diethyl ether as the reaction solvent for the reaction of 29a lowered the overall diastereo-... 

Ketone and ester enolates have historically proven problematic as nucleophiles for the transition metal-catalyzed allylic alkylation reaction, which can be attributed, at least in part, to their less stabilized and more basic nature. In Hght of these limitations, Tsuji demonstrated the first rhodium-catalyzed allylic alkylation reaction using the trimethly-silyl enol ether derived from cyclohexanone, albeit in modest yield (Eq. 4) [9]. Matsuda and co-workers also examined rhodium-catalyzed allylic alkylation, using trimethylsilyl enol ethers with a wide range of aUyhc carbonates [22]. However, this study was problematic as exemplified by the poor regio- and diastereocontrol, which clearly delineates the limitations in terms of the synthetic utihty of this particular reaction. 

There have been two main approaches to the development of dipolarophile facial selectivity (1) the use of chiral substrates, templates, and auxiharies and (2) the use of chiral rhodium catalysts [35]. In one of the earhest examples of chiral substrate selectivity, Pirmng and Lee reported a selective hydroxy-directed cycloaddition with chiral hydroxy-substituted vinyl ethers [95]. This effort was followed by a number of chiral template approaches to diastereocontrol, including the use of (R)- or (S)-phenylglycinol to form a cycHc phenyloxazinone for the facially selective cycloaddition of isomtinchnones [96, 97]. Padwa and Prein demonstrated acycHc diastereofacial control in the cycloaddi-... 

Hoveyda and coworkers have further demonstrated that allylic alcohols and ethers are good substrates exhibiting notable diastereocontrol (Scheme 79) . The ethylmagnesiation of allylic alcohol 129 affords the syn diol with 95 5 diastereoselectivity (70% yield). On the other hand, the reaction of the corresponding methyl ether 130 affords the monoprotected alcohol with opposite sense of diastereoselectivity (syrr.anti = 11 89). The corresponding f-butyldimethylsUyl ether 131 is recovered unchanged, and oxygen-free substrate 132 provides an equal mixffire of diastereomers. The chelation between the... 

A modification to the original gem-dizinc protocol to improve the scope of the reaction was also reported. Ethylzinc iodide was used as the carbenoid precursor, and the reaction was run in the presence of zinc iodide. Under these conditions, simple aUylic ethers could be converted into iodo-cyclopropanes in high yields and diastereocontrol (equation 35). 

Chiral acetals have also been used as chiral auxiliaries for the enantioselective cyclopropanation of a,/3-unsaturated carbonyl derivatives (Figure 7). Yamamoto s tartrate derived auxiliaries (15) based on the ether-directed cyclopropanation allowed the efficient preparation of cyclopropylcarboxaldehyde derivatives The reaction proceeded with high diastereocontrol, and the auxiliary could be cleaved under mild acidic conditions (equation 73). 

A very useful class of chiral auxiliaries has been developed for alkenes substituted with a heteroatom. These auxiliaries, attached to the heteroatom, allow for the preparation of enantiomerically enriched cyclopropanols, cyclopropylamines and cyclopropylboronic acids. Tai and coworkers have developed a method to efficiently generate substituted cyclopropanol derivatives using the cyclopropanation of a chiral enol ether (equation 78) . The reaction proceeds with very high diastereocontrol with five- to eight-membered ring sizes as well as with acyclic enol ethers. The potential problem with the latter is the control of the double bond geometry upon enol ether formation. A detailed mechanistic study involving two zinc centers in the transition structure has been reported. ... 

Often, ethers are constructed by alkoxide displacement of a stereodefined leaving group. Hirakazu Arimoto of Nagoya University has found (Chem. Commun. 2004, 1220) that it is possible to effect diastereocontrolled construction of cyclic benzylic ethers such as 2 by oxidation of 1 to the o-quinone methide. The more stable equatorial C-glycoside product 2 is formed in near quantitative yield. 

Cyclic enol ethers such as 8 are also easily epoxidized. R. Daniel Little of the University of California, Santa Barbara has found (J. Org. Chem. 2005, 70, 5249) that such an epoxide is reduced with Tifffl) regioselectively to the radical, that adds with remarkable diastereocontrol to enones such as 7 to give the adduct 9. Reductive cyclization converted 9 to the tricyclic ether 10. The C-Br bond of 10 was stable both to the Et,SiH conditions, and to the free radical removal of the xanthate derived from the alcohol. 

Another approach towards diastereo- and enantio-enriched homoalyllic ethers was used by Panek et al. during their synthesis of kabiramide C [18]. In this case, optically pure allylsilane 35 was allowed to react with acetal 36, forming the expected syn ether 37 with moderate diastereocontrol (Scheme 13.14). 

Since 1995, Tietze et al. [26-32] have studied the use of norpseudoephedrin derivative 61 as a chiral auxiliary in order to perform a diastereocontrolled SMS reaction. Further cleavage of the benzylic ether bond of 62 by Na/NH3 led to optically active homoallylic alcohol 26 with good yields and selectivity (Scheme 13.25). 

An aluminium-promoted, cobalt-mediated O C rearrangement reaction of cyclic enol ethers has been reported to give functionalized cyclohexanones with good diastereocontrol (Scheme 81).123 The product stereochemistry has been shown to be ( ) dependent on the 7Z-stereochemistry of the starting enol ether. 

Solvents which are poor donors are commonly used in glycoside synthesis, for instance dichlorometh-ane, cyclohexane or petroleum ether. These solvents favor SN2-type reactions. Solvents which are better donors, for instance ethers (diethyl ether, THF, etc.), acetonitrile, pyridine, nitromethane etc., each result in a typical change in the reaction course due to their different participation in the stabilization of the reaction intermediates. With ethers, acetonitrile and pyridine participation leads to onium-type intermediates (Scheme 5 8 and 9), which eventually provide, via fast equilibration, mainly the -anomer (8), due to their higher thermodynamic stability, based on the inverse anomeric effect .Thus a-product formation is often favored in these solvents (see Section 1.2.3.2.5). Solvents with even higher dielectric constants commonly result in lower diastereocontrol in glycoside synthesis. 

The use of C2-symmetric 1,2- and 1,3-diols as chiral auxiliaries is a reliable method for asymmetric allylation of acetals [382]. Acyclic acetals derived from homochiral 1-phenylethanol undergo the Hosomi-Sakurai allylation with high diastereoselectivity [383]. Tietze et al. have, on the other hand, reported that the TMSOTf-catalyzed successive acetalization-allylation reaction of aliphatic aldehydes with homochiral silyl ethers 123 and allyltrimethylsilane gives the corresponding homoallyl ethers with complete diastereocontrol these ethers can be readily converted into enantiomerically pure homoallyl alcohols without epimerization (Scheme 10.135) [384]. This method is applicable to asymmetric allylation of methyl ketones [385]. 

As a result of the excellent diastereocontrol observed in these reactions, it was envisaged that the use of chiral ether linkages might impart a degree of absolute stereocontrol on the IMDA reaction [19b], Preliminary results were encouraging. For example, the menthone-derived triene 47 provided a 10 1 mixture of two (out of a possible four) dia-stereoisomers with proposed structures 48 and 49 in 94% yield (Scheme 10-17). 

An early report by Thornton and co-workers indicates low levels of diastereocontrol in the reaction of pyrone 61 with ethyl vinyl ether. ... 

To improve stereoselectivity, pyrone lactate methyl and ethyl esters 62 and 63 were synthesized. Early experiments with a variety of achiral Lewis acids produced modest levels of diastereocontrol (33-60%). Reaction of methyl lactate ester 63 with benzyl vinyl ether in the presence of zinc bromide at -50 °C that yields the bicylic lactone adduct in 80% diastereomeric excess encouraged us to pursue the possibility of double asymmetric induction. 

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