Macrocyclic Ring Closure of OH‐assisted Prins Reaction. A new and efficient synthesis of (R,S)‐muscone

Abstract

SummaryA new strategy for the synthesis of muscone (1) using the OH-assisted Prim reaction for macrocyclic ring closure has been developed. The monoacetal 4 of (Z, E)-4,%dodecadienedial (3), easily obtainable from (Z, E, E)-1,5,9-cyclododecatriene (2), is treated with methallylmagnesium chloride, and the resulting C16-precursor 5 is subjected to acid-catalyzed cyclization in dilute ( 6 1%) solutions. This results in formation of the bicyclic dihydropyran derivatives 6 which directly yield muscone (1) on heating with a noble metal catalyst saturated with hydrogen. The five-step pathway proceeds with readily available starting materials in conventional steps and excellent overall yield (-40%). This new principle of macrocyclic ring formation has also been used successfully for the preparation of 3-methylcyclotridecanone (34) and should be generally applicable for other suitable ring systems.In the preceding communication Buchi & Wiiest describe a new method for the preparation of macrocyclic ketones by the direct coupling of a , o -C ,,-dialdehydes with 1,3-bis (dimethylphosphono)-2-propanone [ 11. In this way cyclopentadecanone (Exaltone@) is obtained in an elegant and novel manner.We now describe a new and direct pathway to muscone (1) from the same readily accessible C,,-dialdehydes [2], which is particularly efficient when (Z, E)-4,%dodecadienedial(3) (Scheme) is used. The key step is the acid-catalyzed cyclization of the (E, Z)-isomeric hydroxyacetals 5 to the bicyclic dihydropyran derivatives 6, in which the 16 C-and the 0-atoms are already positioned as in muscone (1).When carrying out the cyclization with p-toluenesulfonic acid in boiling toluene, the formation of 6 proceeds smoothly, attaining 75% yield, provided that the concentration of 5 is kept below -1%. substantial reductions in the yield due to an increase of higher molecular weight by-products is observed only if the concentration of 5 exceeds -1.5%.The final step is effected by heating the bicyclic ether 6 to 3 135" with H2-activated noble metal catalysts (Pd/C, Pt, etc.) in xylene in a N2/H2 mixture to give muscone (1) in ca. 75% yield. There is also formed ca. 15% of the saturated ether 18 which is stable under these conditions. A virtually complete conversion of the bicyclic ethers, including the saturated compound 18, into muscone (1) then

Stereochemistry of an Ene Reaction Involving 1,7‐Dienes; Bicyclo[3.3.1]nonanes from (3‐Cyclohexenyl)diallylcarbinols

“…Introduction. -One route for the preparation of the useful perfume substances 1-(1,3-dimethyl-3-cyclohexenyl)-2-buten-1-one (1) and 1-(1,4-dimethyl-3-cyclohexenylj-2-buten-1-one (2) involves the reaction of allylmagnesium chloride with the products 3, 4, of a Diels-Alder reaction between isoprene and methyl methacrylate [l] (Scheme I ) . The initial compounds formed are the diallyl compounds 5 and 6, and these can be transformed either by pyrolysis or with t-BuOK in THF to 1 and 2.…”

“…The initial compounds formed are the diallyl compounds 5 and 6, and these can be transformed either by pyrolysis or with t-BuOK in THF to 1 and 2. The latter transformations of homoallylic alkoxide fragmentations have been described in various synthetic applications, particularly in the preparation of the damascones from cyclogeraniates [2].…”

Pyranone Natural Products as Inspirations for Catalytic Reaction Discovery and Development

“…Importantly, when this work was initiated, the use of a Prins cyclization as a macrocyclization reaction had only been reported a single time. 28 As time would demonstrate, other groups were also independently pursuing this general strategy, for example, Wender with the bryostatins, and a full account of these activities have been summarized elsewhere. 13 We viewed this target as a means to expand the venerable Prins into a new type of enabling transformation while simultaneously highlighting the power of our dioxinone mediated cyclizations.…”

Flavours and Fragrances

“…[184] The starting point is cyclododecatriene, which is subjected to partial ozonolysis. With one aldehyde group protected, the other is reacted with isobutenylmagnesium chloride, and the protecting acetal group is hydrolysed off.…”