Synthesis of Conjugated γ- and δ-Lactones from Aldehydes and Ketones via a Vinylation/Allylation-Ring Closing Metathesis-Oxidation Sequence

Abstract

Nucleophilic C-vinylation or C-allylation of aldehydes and ketones followed by O-allylation of the obtained carbinols gave the corresponding allyl ethers. Ring-closing metathesis of the latter afforded cyclic ethers (dihydrofurans and dihydropyrans, respectively) which were then subjected to allylic oxidation to yield conjugated g-and d-lactones. Among the different types of structures that have attracted our attention are (-)-malyngolide 1, 2 (Z)-topostines (e.g. 2) 3 and other saturated and unsaturated d-lactones with potential pharmacological application.As a method to construct the lactone ring, we initially considered a ring closing metathesis (RCM) 4 in the ester of an allyl carbinol with an acrylic-type acid using the well established catalysts 3 or 4 (see scheme below). This would yield a conjugated d-lactone which, if desired, should provide a saturated lactone by subsequent hydrogenation, Michael addition or similar functional manipulations. The overall reaction sequence would represent a synthetic equivalent of the general d 4 synthon depicted below. The feasibility of this sequence has been very recently established for allyl and homoallyl acrylates to yield conjugated g-and d-lactones, respectively, with a disubstituted C=C bond. 5 In view of our ongoing synthetic projects mentioned above, our purpose was to test the generality of this procedure for the preparation of conjugated lactones with a higher degree of substitution at the C=C bond.A number of aldehydes and ketones 5a-f was thus allowed to react with allyl bromide or methallyl chloride and zinc in an aqueous medium. 6 The expected allyl carbinols 6 (R 3 = H or Me) were obtained in all cases with good yields. 7 We then acylated the alcohol group of the allylation products 6 with acryloyl or methacryloyl chloride to yield the corresponding esters 7. However, and in contrast with that observed with acrylates 7 (R 3 , R 4 = H), 5 compounds 7 (R 3 or R 4 π H) did not undergo RCM with catalyst 3, neither after a prolonged reaction time nor after addition of Lewis acids. 5,8 In view of the failure to obtain lactones 8 (R 3 or R 4 π H) by this procedure, 9 we considered an alternative method based on O-allylation of allyl carbinols 6 and RCM of the resulting ethers 9 (R 3 , R 4 = H or Me) to dihydropyrans 10, 10 followed by allylic oxidation of the latter compounds (Scheme 1). Scheme 1As a matter of fact, O-allylation of carbinols 6 to allyl ethers 9 transcurred uneventfully. RCM of the latter compounds using 3 afforded cyclic ethers 10 in very good yields. Trisubstituted C=C bonds (10, R 3 or R 4 = Me) were also formed under these conditions. 11,12 Unfortunately, however, tetrasubstituted olefins (10, R 3 = R 4 = Me) were not obtained, even when using the more reactive Schrock molybdenum catalyst 4. 4c Finally, oxidation of the allylic methylene next to the oxygen atom in cyclic ethers 10 was achieved using the chromium trioxide complexes with pyridine 13 or 3,5-dimethylpyrazole. 14 While both reagents gave similar yields, CrO 3 /3,5-dimethylpy...

Ruthenium Carbene Complexes with N,N‘-Bis(mesityl)imidazol-2-ylidene Ligands: RCM Catalysts of Extended Scope

“…Electron-deficient alkenes are known to be rather poor substrates for metathesis reactions catalyzed by this complex. Although scattered reports on RCM of acrylates can be found in the literature, such transformations are far from being general and often require assistance by Lewis acidic additives such as Ti(OiPr) 4 to reach a preparatively useful level. , To the best of our knowledge, direct formations of tri- or tetrasubstituted acrylic acid derivatives via olefin metathesis have previously not yet been accomplished . As can be seen from the results compiled in Table , the use of the “second-generation” carbene complex 3a allows for the first time to access di-, tri-, and even tetrasubstituted α,β-unsaturated lactones of ring size 5−7 in good to excellent yields.…”

Alternative and Expedient Asymmetric Syntheses of l-(+)-Noviose

“…Application of the recently reported isomerization of terminal double bonds to the 2-propenyl equivalent in the presence of 10 mol % of the second generation Grubbs' catalyst C and equimolar Et 3 N in refluxing methanol gave 11 as a cis / trans mixture in excellent yield even on a gram scale . After reaction of 11 with MeMgBr, the resulting gem -dimethyl tertiary alcohol was O-allylated to the diene 12 by treatment with allyl iodide and NaH in THF/DMPU in excellent yield for the two steps . A ring closing metathesis reaction in the presence of 5 mol % of Grubbs' second generation catalyst gave the α,β-unsaturated dihydropyran 13 in good yield.…”

Efficient Synthesis of 4-(2‘-Alkenyl)-2,5-dihydrofurans and 5,6-Dihydro-2H-pyrans via the Pd-Catalyzed Cyclizative Coupling Reaction of 2,3- or 3,4-Allenols with Allylic Halides

“…2,5-Dihydrofurans and 5,6-dihydro-2 H -pyrans, important classes of heterocyclic compounds, are useful intermediates for organic synthesis and common structural units in many natural products . These compounds are usually prepared via a RCM reaction, Ag(I)-catalyzed rearrangement−cyclization of 4-hydroxypropargyl esters, dehydration of cis -2-alkene-1,4-diols, palladium-catalyzed reaction of cyclic alkynyl carbonates with electron-deficient alkenes, Prins reaction of terminal alkene and formaldehyde, reaction of oxazirconacyclopentenes with propynoates, cyclization of allenols upon the addition of electrophiles, and Ag(I)- or Hg(II)-catalyzed cyclization reaction of allenols …”