Homoallylic alcohols synthetic function

In reactions of chiral aldehydes, TiIV compounds work well as both activators and chelation control agents, a- or A-oxygcnated chiral aldehydes react with allylsilanes to afford chiral homoallylic alcohols with high selectivity (Scheme 22).85 These chiral alcohols are useful synthetic units for the synthesis of highly functionalized chiral compounds. Cyclic chiral 0,0- and A/O-acetals react with allylsilanes in the same way.86,87 Allenylsilanes have also been reported as allylation agents. 

In order to apply tartrate ester-modified allyl- and crotylboronates to synthetic problems,23 Roush and Palkowitz undertook the stereoselective synthesis of the C19-C29 fragment 48 of rifamycin S, a well-known member of the ansamycin antibiotic group24 (Scheme 3.1u). The synthesis started with the reaction of (S,S)-43E and the chiral aldehyde (S)-49. This crotylboration provided the homoallylic alcohol 50 as the major component of an 88 11 1 mixture. Compound 50 was transformed smoothly into the aldehyde 51, which served as the substrate for the second crotylboration reaction. The alcohol 52 was obtained in 71% yield and with 98% diastereoselectivity. After a series of standard functional group manipulations, the alcohol 53 was oxidized to the corresponding aldehyde and underwent the third crotylboronate addition, which resulted in a 95 5 mixture... 

In the thirty-some years since Konig and Neumann reported that allyl triethyltin adds thermally to aldehydes to yield homoallylic alcohols, extensive studies on the mechanism and synthetic applications of numerous variants of this reaction have been reported by research groups around the world [1,2], In the thermal version of these additions the EtsSn moiety functions as a weak Lewis acid to afford the adduct via a cyclic transition state (Eq. 1). 

Since its original publication,94 the Julia olefination has become a very important tool in organic synthesis for the site- and stereoselective synthesis of alkenes. The synthetic importance of the process is reflected by its numerous applications in the synthesis of a diverse range of functionalized alkenes such as allylic alcohols,198 allylic amines,199-201 homoallylic alcohols,202 homoallylic amines,203 and allylsilanes.204,129 The reaction has also been used as a key step in many... 

Since many other functional groups are tolerated in this reaction, a great variety of useful synthetic intermediates have been assembled 4-styryl-2-azetidinones, 4,5-diphenyl-3-styryloxazolin-2-ones, jS-alkoxystyrenes, allylic and homoallylic alcohols. " The coupling between vinylic iodides and tertiary allylic alcohols to construct isoprenoid segments has also been demonstrated."... 

These methodological studies served to demonstrate that reactions of an a-oxygenated crotyltitanium reagent and aldehyde lead to anft-homoallylic alcohol with a Z-O-enecarbamate group in a one-step sequence. We could take advantage of this functionality to give access either to the natural product or to synthetic analogues. 

The conversion of a ketonic carbonyl into a functionalized epoxide presents much more of a synthetic challenge, and a useful method for doing just that has been published by Cookson and Crurabie. Thus, addition of allyl Grignard reagents to the ketones (9) affords the homoallylic alcohols (10), which are converted into the epoxides (11) by treatment with NBS followed by cyclization with NaH. ... 

Aldehydes have been converted to functionalized homoallylic alcohols in high de, using 1-alkenylboronates, acting as synthetic equivalents of y-substituted allyl-boronates. The 1-alkenylboronates are readily prepared by hydroboration of terminal alkynes. ... 

Zirconocene-catalyzed carbomagnesation of internal allylic ethers proceeds by a different pathway. The carbometallation of allylic ethers with the internal double bond gives formally the S 2 substitution product 15 with the loss of the ether moiety (Scheme 7). A few examples are given in Table 4. Especially interesting, from the synthetic point of view, is ethylmagnesation of cyclic ethers (the last entry in Table 4), because it opens a pathway to the synthesis of functionalized homoallylic alcohols [14]. An asymmetric variant of this reaction gives products with ees>90% [15]. 

The Lewis-acid-catalyzed carbonyl-ene reaction represents an important alternative method for the addition of an allyl group to a carbonyl group (Equation 23). The resulting secondary homoallylic alcohols are amenable to a number of structural modifications and constitute useful synthetic building blocks. Because the olefin of the products can be a surrogate for a carbonyl functionality, these homoallylic alcohol are formally the synthetic equivalent of aldol addition products. Powerful asymmetric versions of the carbonyl-ene reaction [196, 197] provide an important alternative to the more traditional allylation methods, which primarily employ silanes, boranes, or stannanes (see Chapter 5). 

In numerous synthetic studies it has been demonstrated that DMP can be used for a selective oxidation of alcohols containing sensitive functional groups, such as unsaturated alcohols [297,1215-1218], carbohydrates and polyhydroxy derivatives [1216, 1219-1221], silyl ethers [1222,1223], amines and amides [1224-1227], various nucleoside derivatives [1228-1231], selenides [1232], tellurides [1233], phosphine oxides [1234], homoallylic and homopropargylic alcohols [1235], fluoroalcohols [1236-1239] and boronate esters [1240]. Several representative examples of these oxidations are shown below in Schemes 3.349-3.354. Specifically, the functionalized allylic alcohols 870, the Baylis-Hillman adducts of aryl aldehydes and alkyl acrylates, are efficiently oxidized with DMP to the corresponding a-methylene-p-keto esters 871 (Scheme 3.349) [1217]. The attempted Swern oxidation of the same adducts 870 resulted in substitution of the allylic hydroxyl group by chloride. 

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. 

Carreira has demonstrated that the hydroxy-directed nitrile oxide cycloaddition reaction is a general synthetic approach to polyketide fragments, with the intermediate isoxazolines functioning as latent, masked aldol adducts [65], The 1,3-dipolar cycloadditions have been shown to tolerate a large variety of alcohol substrates, including aliphatic allylic, homoallylic, and cyclic allylic alcohols [65-67], A demonstration of the versatility of the approach was reported in the synthesis of erythronolide A (58, Scheme 18.12) [67], This synthetic effort took advantage of two sequential hydroxy-directed nitrile oxide cycloadditions to provide fragments 55 and 57, both of which were obtained with excellent yields and diastereoselectivity (dr2 98 2). 

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