Hydroformylation homoallylic alcohols

A new chiral auxiliary based on a camphor-derived 8-lactol has been developed for the stereoselective alkylation of glycine enolate in order to give enantiomerically pure a-amino acid derivatives. As a key step for the synthesis of this useful auxiliary has served the rc-selective hydroformylation of a homoallylic alcohol employing the rhodium(I)/XANTPHOS catalyst (Scheme 11) [56]. 

Very recently the tandem hydroformylation/acetalization has been used for the synthesis of new synthetically valuable chiral auxiliary derived from camphor. Stereoselective allylation of camphor and subsequent terminal hydroformylation of the resulting homoallylic alcohol affords the 5-lactol auxiliary (camTHP OH) in multigram scale (Scheme 8) [41]. 

The approach to polyketide synthesis described in Scheme 5.2 requires the relatively nontrivial synthesis of acid-sensitive enol acetals 1. An alternative can be envisioned wherein hemiacetals derived from homoallylic alcohols and aldehydes undergo dia-stereoselective oxymercuration. Transmetallation to rhodium could then intercept the hydroformylation pathway and lead to formylation to produce aldehydes 2. This proposal has been reduced to practice as shown in Scheme 5.6. For example, Yb(OTf)3-cata-lyzed oxymercuration of the illustrated homoallyhc alcohol provided organomercurial 14 [6]. Rhodium(l)-catalyzed hydroformylation of 14 proved successful, giving aldehyde 15, but was highly dependent on the use of exactly 0.5 equiv of DABCO as an additive [7]. Several other amines and diamines were examined with variation of the stoichiometry and none proved nearly as effective in promoting the reaction. This remarkable effect has been ascribed to the facilitation of transmetallation by formation of a 2 1 R-HgCl DABCO complex and the unique properties of DABCO when both amines are complexed/protonated. 

The first total synthesis of the marine macrolide leucascandrolide A relied upon the use of two key hydroformylahon reactions [25]. Yb(OTf)3-catalyzed oxymercuration of homoallylic alcohol 46 provided organomercurial 47, which was hydroformylated to give... 

Hydroformylation of a secondary homoallylic alcohol such as 1 followed by PCC oxidation provides a useful route to the 8-lactone 2. The product was converted by known reactions into the Prelog-Djerassi lactone (3). ... 

When allylic and homoallylic alcohols are subjected to hydroformylation, the product was obtained as a lactol, e.g., 3-phenyl-2-hydroxytetrahydrofuran (Scheme 12) [96]. Due to the relative configuration between the C-2 and C-3 carbons, it was formed as a 1 1 diastereomeric mixture. The enantiomeric excesses were determined by oxidizing the lactols into the corresponding lactones. 

For example, hydroformylation of homoallylic alcohols gives isolable lactols 42, which can be oxidized to the corresponding lactones 43 (Eq. 20). The... 

The rhodium-catalyzed hydroformylation of unsaturated alcohols is useful for the synthesis of important intermediates in organic synthesisThe hydroformylation of homoallylic alcohols has been shown to give isolable lactols, which can be further oxidized to the corresponding lactonesJ ... 

Spiropyrans (55a and 55b) and other related systems bearing quaternary centers are important synthons in a large class of natural products with bodi biological and pharmaceutical importance. These natural products include several important antibiotics and pheromones. Eilbracht and co-workers developed a tandem hydroformylation/cyclization sequence under relatively mild conditions, which led selectively to several spiropyrans 55a and 55b (Table 2-2) from relatively easy to synthesize homoallylic alcohols 54. Furthermore, little or no purification was required for this tandem series of reactions. 

Table 2-2. Tandem hydroformylation cyclization of homoallyl alcohols.

The hydroformylation of allylic and homoallylic alcohols has been widely studied in this process because hydroxy-aldehydes can easily lead to hemiacetals with five- or six- member rings. Likewise, the hydroformylation of allyhc alcohol to give 4-hydroxybutanol and 1,4-dihydroxybutanoI is an important industrial process [63]. 

Seok and colleagues investigated the hydroformylation of allyl alcohol with paraformaldehyde in the presence of HRh(CO)(PPh3)3 (Scheme 3.4) [14]. Similar to that found in the reaction with syngas (see Section Allyl and homoallyl alcohols in Chapter 4), the functional group in the olefinic substrate directed the regiochemistry of the reaction and a cyclic transition state between catalyst and substrate was assumed. A maximum isomeric product ratio of lib = 21 was achieved. The addition of syngas to the reaction with paraformaldehyde or an excess of phosphine inhibited the formation of the linear aldehyde. 

Homoallyl alcohols, such as 3-methyl-3-buten-l-ol, under the condition of n-regioselective hydroformylation at 3 bar, subsequent hemi-acetal formation, and final dehydration give rise to 3,4-dihydro-4-methyl-2//-pyran (Scheme 4.34) [76]. 

Scheme 4.119 Regio- and diastereoselective hydroformylation of homoallyl alcohols with...

As a special case, the formation of hemiacetals 2 (lactolization) during the hydroformylation of hydroxy-functionalized olefins, such as allyl or homoallyl alcohols, has to be mentioned (1, Y= O, Scheme 5.70). With these substrates, the reaction occurs in an intramolecular manner. In the presence of an external alcohol, the cyclic hemiacetal can further react to give a nonsymmetric cyclic acetal 3. Hemiacetals can be subjected to hydrogenation to afford diols 4. Under reducing conditions and in the presence of amines, amino alcohols 5 are formed both are valuable building blocks in fine chemistry. Alternatively, oxidation gives lactones 6 [5]. By dehydration of hemiacetals, cychc vinyl ethers 7 are formed. The same transformation with allylamines (Y=NR) gives cyclic hemiaminals, A/ ,0-acetals, lactames, or vinyl amines. 

The hydroformylation of allylic or homoallyl alcohols represents a direct method for the synthesis of substituted tetrahydrofurans (THFs) or tetrahy-dropyrans since the primarily formed hydroxy aldehydes may undergo a... 

The successful completion of this domino reaction encouraged us to check some further hydroformylation-allylboration-hydroformylation sequences. For instance, the homoallylic alcohol 58 was converted to the ynol ether 59. To convert the latter to the alkenyl boronate (55%) 60 a zirconium catalyst (30) had to be chosen for the hydroboration. With rhodium catalysts chemoselectivity between the alkyne and the alkene moieties was... 

Epoxidation of oleic and linoleic acid was readily achieved by treatment with the acetonitrile complex of hypofluorous acid (55). Phase-transfer-catalyzed biphasic epoxidation of unsaturated triglycerides was accomplished with ethylmethyldioxirane in 2-butanone (56). The enantioselective formation of an a,P-epoxy alcohol by reaction of methyl 13()S)-hydroperoxy-18 2(9Z,llfi) with titanium isopropoxide has been reported (57). An immobilized form of Candida antartica on acrylic resin (Novozyme 435) was used to catalyze the perhydrolysis and the interesterification of esters. Unsaturated alcohols were converted with an ester in the presence of hydrogen peroxide to esters of epoxidized alcohols (e.g., epoxystearylbutyrate) directly (58). Homoallyl ethers were obtained from olefinic fatty esters by the ethylaluminium-in-duced reactions with dimethyl acetals of formaldehyde, acetaldehyde, isobutyralde-hyde, and pivaldehyde (59). Reaction of 18 2(9Z, 12Z) with 50% BF3-methanol gave monomethoxy and dimethoxy derivatives (60). A bulky phosphite-modified rhodium catalyst was developed for the hydroformylation of methyl 18 1 (9Z)and 18 1(9 ), which furnished mixtures of formylstearate and diformylstearate (61). 

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