Homoallyl alcohols 7-lactone synthesis

An (E)-selective CM reaction with an acrylate (Scheme 61) was applied by Smith and O Doherty in the enantioselective synthesis of three natural products with cyclooxygenase inhibitory activity (cryptocarya triacetate (312), cryptocaryolone (313), and cryptocaryolone diacetate (314)) [142]. CM reaction of homoallylic alcohol 309 with ethyl acrylate mediated by catalyst C led (E)-selectively to d-hydroxy enoate 310 in near quantitative yield. Subsequent Evans acetal-forming reaction of 310, which required the trans double bond in 310 to prevent lactonization, led to key intermediate 311 that was converted to 312-314. 

A novel lactone and lactol synthesis was achieved by Cossy and coworkers [268], usinga CM followedby ahydrogenationandaringclosure. Ina typical procedure, aso-lution of acrylic acid or acrolein and an allylic or homoallyhc alcohol is stirred at room temperature under 1 atm of H2 in the presence of the ruthenium catalyst 6/3-16a and Pt02. Under these conditions, the homoallylic alcohols 6/3-101 (n= 1) and acrylic acid 6/3-102 led to the lactones 6/3-103 and the reduced alcohol 6/3-104 with acrolein, the corresponding lactols were obtained, together with 6/3-104 (Scheme 6/3.30). 

The grem-dibromocyclopropanes 152 bearing a hydroxyalkyl group, prepared by the addition of dibromocarbene to allylic or homoallylic alcohols, undergo an intramolecular reductive carbonylation to the bicyclic lactones 153. bicyclic lactone derived from prenyl alcohol is an important precursor for the synthesis of ris-chrysanthemic acid. (Scheme 54)... 

Iodocyclization.1 This reagent converts various unsaturated alcohols into ethers and unsaturated carboxylic acids into lactones. It is particularly useful for synthesis of 2-(l-iodomethyl)oxiranes from allylic alcohols and of 2-(l-iodomethyl)oxetanes from homoallylic alcohols. 

Lactone synthesis. This Ti(II) complex can serve as catalyst for hydro-magnesiation of allylic or homoallylic alcohols, prepared by addition of vinyl- or allyl-Grignard reagents to ketones. Ethylmagnesium bromide is used as the source of magnesium hydride. The carbonylation of the organomagnesium intermediate results in a -y- or a 5-lactone (equation I). 

Zinc-mediated Barbier-t) e addition of 238, followed by Luche s procedure obtained a mixture of the homoallylic alcohol diastereomers 239 and 240. Alcohol 239 was carried through benzoylation, deketalization, silylation, and ozonolysis, to produce C-branched y-lactone 241. Benzoylation of 240 followed by hydroboration, PCC oxidation, debenzoylation, and alkaline-promoted cyclization directly formed C3-branching 2-deoxyfuranose 242 [87] (O Scheme 63). A novel method for stereoselective synthesis of 4 -a-carbon-substituted nucleosides, through epoxidation of 4, 5 -unsaturated nucleosides and SnCU-promoted epoxy ring opening, was... 

Compared with the synthesis of five-membered rings relatively little has been done on the synthesis of 8-lactones. Homoallylic alcohols can be converted into 8-lactones by rhodium-catalyzed hydroformyla-tion followed by oxidation (equation 48). The thallation and subsequent palladium-catalyzed carbonylation described earlier can also be used for the synthesis of six-membered rings (equation 49). ... 

The first total synthesis of ( )-lycoridine margetine (33), a member of the non-basic alkaloids which possess antimitotic activity has been achieved (Scheme 3). The homoallylic alcohol (26) served as a latent diene in a Diels-Alder reaction with ethyl acrylate to give a diastereomeric mixture of adducts which upon base equilibration and hydrolysis provided the tmns-acid (27). Modified Curtius reaction on (27) afforded the corresponding isocyanate which was cyclized to the lactam (28) in 89% yield by a new method using boron trifluoride etherate. Compound (28) was converted into an N-acetyl derivative which upon basic hydrolysis gave the acid (29). Treatment of (29) with NBS followed by reflux in pyridine solution gave the lactone... 

Homoallylic alcohols are also suitable for controlling the introduction of an alkyl chain, as shown by the synthesis of the diterpenoid atractyligenin61, The starting tricyclic alcohol is converted to the selenocarbonate, a suitable radical precursor. Treatment with tributyltin hydride initiates the stereoselective cyclization which affords the bridged lactone system, an intermediate in the diterpenoid synthesis. Due to the low cyclization rate, tributyltin hydride is added slowly to suppress the formation of noncyclized reduction products. 

The synthesis of the C1-C7 fragment, which corresponds to the lactone, starts with the homoallylic alcohol 2 which was prepared from 1. The existing stereocenter and the conjugate addition method of Evans [21] allow the control of the C5 stereocenter. The homoallylic alcohol 2 was oxidatively cleaved and homologated to the trans enoate 3 by a Wittig olefination. Treatment of 3 with benzaldehyde and a catalytic amount of KHMDS provided acetal 4. The internal Michael addition of the hemiacetal intermediate proceeds with complete stereoselectivity [22]. After deprotection and oxidation, the corresponding aldehyde was treated with Amberlyst-15 and then with camphor sulfonic acid (CSA), to yield pyrane 5 as a mixture of (3- and a-anomers (1.8/1). This compound was converted to the thiophenyl acetal 6 (4 steps) as this compound can be hydrolyzed later under mild conditions (Hg +) with subsequent oxidation of the lactol to the desired lactone. Compound 6 represents the C1-C7 fragment of discodermolide (Scheme 1). 

Many other allylborating agents (12-21) utilizing chiral auxiliaries derived from carenes, camphor, tartaric acid, stein, etc. are also known (Figure 2) (2i-33). Recently Villieras described an ester-containing chiral allylborating agent which could be used directly for the synthesis of a-methylene-y-butyrolactones (32). In this review, we have restricted our discussions to the synthesis of lactones via homoallylic alcohols derived from B-allyldiisopinocampheyl-borane, 1. 

Our first synthesis of lactones via allylboration involved the protection of homoallylic alcohols as a p-nitrobenzoate ester, followed by hydroboration with chloroborane and oxidation of the intermediate with CrOa in acetic acid. Deprotection under basic conditions provided the lactones in very high yields with the same enantiomeric excesses as the starting homoallyl alcohols (Scheme 3) (6). 

A modified Peterson reaction has been used to generate silenes which have then been converted to diols and lactones. The reaction involves the formation of the sila-Grignard reagents under standard conditions, followed by treatment with isobutyraldehyde to give the silene precursor 76. Silacyclohexene 76 was then produced by reaction with 1,3-pentadiene. High diastereoselectivity was observed and confirmed by 2D NMR experiments on the subsequent reduction and oxidation products. Thus, standard conditions converted silane 78 into diol 79 which was then oxidised to give lactone 80. The protocol can be expanded to achieve further functionalisation, for example in the synthesis of homoallylic alcohol 82. 

A further application of the carbonylation strategy for construction of 2,3-cis substituted tetrahydrofuran derivatives is shown in Scheme 15.23. Nesbitt and McErlean reported on the synthesis of C19 lipid diols, the enantiomers of the anthelmintic marine natural products. Key steps in the divergent synthesis include a syn selective epoxidation of a homoallylic alcohol, a one-pot alkoxypalladation-lactonization reaction sequence, and diethyl azodicarboxy-late promoted Mitsunobu inversion. 

Numerous substrate variations can be explored as a com-plemoit to the ether transfer. Therefore, 1,1-disubstitution in the homoallylic alcohol starting material was envisioned as an avenue to access tertiary ethers. The synthesis of such fimctionahty from stereoselective C—O bond formation is rare. To access the issue of the stereoselective synthesis of calcitriol lactone, a major metabolite of vitamin D3 developed by Hoffmann-La Roche U.C. Riverside, Jonhson and Chan synthesized tertiary ethers in high stereocontrol through iodocyclization of the coiresponding tert-butyl carbonate 161 using Barlett s procedure (Scheme 37.32). ... 

This method can he used for a variety of alkenes. The siliranes can he efficiently applied for thermal di-terf-butylsilylene transfer reactions to form other di-terf-hutylsiliranes (8), other thermal and photochemical ring expansion reactions, eg, to diastereoselectively form seven- (6,11), eight- (7), or nine-memhered heterocycles (12). Furthermore the siliranes may he applied to synthesize y-lactones (13), selective synthesis of tiiols, and homoallylic alcohols (14) or stereoselective formation of chiral allylic silanes (15) have also been reported. The following experimental procedure of isonitrile insertions exemplifies the silirane s high reactivity and facile formation of 1,1-di-terf-butyl-iminosilacyclobutanes (1,1-di-tert-butyl-iminosiletans or silacyclobutanimines) (4,5). 

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