Homoallylic Ether Substrates

In order to explain why in 33 the bond from zirconium to C-l is selectively cleaved rather than the zirconium-C-4 bond it is necessary to take note that this reaction involves allylic and homoallylic ethers and alkoxides. With such species the magnesium cation also coordinates with an oxygen atom from the substrate, as in model system 36. It can further be shown that in the transition from 33 to 34 zirconium generally remains with the statically least hindered residue even if there is no heteroatom present12... 

The first asymmetric total synthesis of (+)-astrophylline was accomplished in the laboratory of S. Blechert. The Still variant of the [2,3]-Wittig rearrangement was used to generate the 1,2-trans relationship between the substituents of the key cyclopentene intermediate. The tributylstannylmethyl ether substrate was transmetalated with n-BuLi, which initiated the desired [2,3]-sigmatropic shift to afford the expected homoallylic alcohol as a single enantiomer. 

In the cyclization reactions of homoallylic ethers and higher homologs, alkoxymethyl radicals play a prominent role [26]. Substrates like 28 supply more useful carbon-centered radicals enjoying captodative stabilization, and trany-2,3-disubstituted tet-rahydropyrans were prepared stereoselectively with judicious modification of the double bond in the substrate [27] (Scheme 12). The same radical species from the substrate 30 was reported to give the oxocane 31 via the xanthate transfer %-endo cyclization, from which lauthisan (32) was obtained [28] (Scheme 13). 

Gold(lII) chloride and silver hexafluoroantimonate can also be used as catalyst for addition reactions of electron-rich arenes and heteroarenes to olefins. In a similar fashion, the intramolecular hydroarylation of aryl homoallyl ethers and related substrates takes place upon heating with AuCb and AgOTf in dichloroethane to 80 °C and affords dihydrobenzopyrans, tetrahydroquinolines, and tetralins with good yield (Scheme 4-18). ... 

Finally, Chen s work on the direct allylation of carbonyl compounds using benzyl alcohol in the multicomponent Sakurai reaction catalyzed by selective and green solid acids, such as sihcomolybdic acid (SMA-SiO ) [92] or perchloric acid (HClO -SiOj) [93], both supported on silica gel, should be mentioned. In some cases, the use of preformed acetals as substrates provided better results. These methods allowed the synthesis of a broad number of homoallylic ethers in moderate to high yields in a short reaction time. Significantly, catalyst loading of HClO -SiOj is only 2mol%. 

There are two main classes of RCM reactions that are important in the synthesis of THP rings (Scheme 54). Class 1 involves the ring closure of ether 199 bearing allylic and homoallylic functionalities to afford 3,4-dihydropyrans 198, which upon simple reduction leads to THP 202. Class 2 involves an RCM of homoallylic acrylate substrate 203 to provide unsaturated lactone 204, which can be further functionalized to THP 202. All of the RCM metathesis examples in this survey utilize either the first-generation Grubbs catalyst (G-I) or the second-generation Grubbs catalyst (G-II), shown in Fig. 2. 

A general synthetic strategy for the synthesis of Class 1 RCM substrates is shown in Scheme 55. Easily accessible chiral allylic alcohols, such as 205, can be alkylated with haloacetic acids and derivatized to the oxazolidinone 206. The chiral auxiliary can undergo standard enolate alkylation to provide the homoallylic ether 207 in high diastereoselectivity. The major advantage to this approach is that either 2,6-cis or 2,6-trans stereochemistry can be accessed from the allylic alcohol [103]. Unfortunately, this approach requires extra synthetic operations to append and remove the stoichiometric chiral auxiliary, as well as further functionalization in order to access the RCM substrate 199. 

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-... 

Pioneering studies of Trost and his co-workers have explored all the parameters of this reaction. An interesting piece of work has, for instance, shown that the presence of an ether or a silyl ether in a substrate also exerts a profound effect on the regioselectivity of the cyclization. Thus, a silyl ether group at the allylic position (202) furnishes the corresponding 1,3-diene 203, whereas an ether group at the homoallylic position gives exclusively the 1,4-diene 205 (Scheme 50).210... 

Substrate-induced diastereoselection has also been achieved in the case of alkenyllithium reagents derived from (Z)-5-iodo homoallylic ethers152,153. Thus, the allylzincation of the alkenyllithium derived from 230 proceeded efficiently in ether at — 20 °C and led after hydrolysis to 231 as a single diastereomer (equation 112). 

Aryl homoallyl ketones and 4-methoxy phenyl ethers are also good substrates for the AD [8], whereas the structurally related allyl amides and thioesters give products with insufficient enantioselectivity. Homoallylic 4-methoxy benzoates perform relatively poor, which is consistent with Corey s proposed mechanistic model [9],... 

The basic Markovnikov selectivity pattern is partially or fully overrun in the presence of neighboring coordinating groups within the olefin substrate (Section 2.2.2). Known functionalities where inversed selectivity can occur include 3-alke-noylamides (e.g. 17 reacts to give a mixture of 18 and 19, Table 3) [43], homoallyl esters and alcohols, allyl ethers (but not necessarily allyl alcohols) [44], allyl amines, allyl amides, or carbamates (cf. 20 to 21) [45], allyl sulfides [46] or 1,5-dienes [47]. As a matter of fact, aldehyde by-products are quite normal in Wacker reactions, but tend to be overlooked. 

Carbonyl Allylation and Propargylation. Boron complex (8), derived from the bis(tosylamide) compound (3), transmeta-lates allylstannanes to form allylboranes (eq 12). The allylboranes can be combined without isolation with aldehydes at —78°C to afford homoallylic alcohols with high enantioselectivity (eq 13). On the basis of a single reported example, reagent control might be expected to overcome substrate control in additions to aldehydes containing an adjacent asymmetric center. The sulfonamide can be recovered by precipitation with diethyl ether during aqueous workup. Ease of preparation and recovery of the chiral controller makes this method one of the more useful available for allylation reactions. 

A considerable success has been realized for asymmetric hydrogenation of functionalized alkenes since the discovery of BINAP-Ru complexes in the mid-1980s [5]. The details are described in each of the following substrates, enamides, alkenyl esters and ethers, a,/3- and /3,y-unsaturated carboxylic acids, a,/3-unsaturated esters and ketones, and allylic and homoallylic alcohols. 

This intramolecular bis-silylation has been extended to terminal and 2,2-disubstituted alkenes. 1,2-Disubstituted alkenes do not undergo this reaction. The substrates, unsat-urated disilanyl ethers, arc prepared by silylation of allylic and homoallylic alcohols. 

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