1. Field of the Invention
This invention relates to a new process for the carbonylation of substituted allylic alcohols, and to an efficient synthesis of an ambergris fragrance compound, comprising: carbonylation of the allylic alcohols nerolidol, farnesol, or their monocyclic analogues described herein; 2) reduction of the resulting carboxylic acid or ester thereof to the corresponding alcohols; and 3) cyclization of the obtained alcohols to the ambergris fragrance compound.
2. Discussion of Related Art
Allylic carbonylation is a useful synthetic route for the preparation of .beta.,.gamma.-unsaturated acids and esters. The carbonylation of readily available allylic compounds, such as allylic halides and alcohols, typically requires carbon monoxide pressures in excess of 100 bar. For example, U.S. Pat. No. 4,585,594 discloses the carbonylation of tertiary allylic alcohols with the aid of a palladium halide catalyst and a phosphine promoter at a temperature of 50-150.degree. C. and under a pressure of 200-700 bar. The carbonylation of allyl alcohol and/or its derivatives in the presence of a carboxylic acid solvent has been previously reported by Fenton in U.S. Pat. No. 3,655,745 and by Kurkov in U.S. Pat. No. 4,189,608. The two processes described therein are reported to give dissimilar products, methacrylic acid derivatives in the former case, and 3-butenoic acid in the latter case. These processes have not been extended to more substituted, higher molecular weight allylic substrates. The use of halide promoters in catalyst systems developed for the carbonylation of allylic compounds has been disclosed in a number of patents, for example, U.S. Pat. No. 3,980,671, U.S. Pat. No. 4,025,547, U.S. Pat. No. 4,140,865 and GB 1,080,867. These patents cite improvements in the carbonylation process for the production of vinyl acetic acid and its esters derived from the addition of organic and Group IVA metal halide compounds to the reaction system. Alkali metal halides may be present but are not specifically included in lists of effective promoters.
Recent advances in the carbonylation of allylic compounds under conditions of low temperature and pressure have been reported by J. Tsuji, et al. in J. Org. Chem. 49, 1341 (1984) and S. I. Mirahashi, et al. in Tetrahedron Lett. 29, 4945 (1988). Tsuji describes the carbonylation of allylic carbonates at 50.degree. C under a pressure of 1-20 bar of carbon monoxide. Murahashi describes the carbonylation of allylic phosphates and acetates at the same temperature under a pressure of 29-59 bar of carbon monoxide. The carbonylation of allylic acetates under these conditions is enhanced by the addition of quaternary and alkali metal halides, but lithium chloride is stated as being ineffective. The disadvantage of these mild carbonylation processes for the preparation of .beta.,.gamma.-unsaturated acids and esters via allylic alcohol derivatives is that they require one or more additional synthesis steps to convert the allylic alcohol to a more reactive derivative, and are of limited applicability for sterically hindered (e.g. tertiary) alcohols, which are difficult to quantitatively derivatize. In cases where the desired product is the .beta.,.gamma.-unsaturated carboxylic acid, carbonylation of these alcohol derivatives has the further disadvantage of necessitating a hydrolysis step, since the carbonylation product is an anhydride or ester. The carbonylation of allylic alcohols under low pressure, phase transfer conditions has been reported by H. Alper et al. in J. Mol. Catal. 54, L33 (1989) and EP Appl. 89 303688. This methodology, incorporating Ni(CN).sub.2 complex catalysts, has not been demonstrated to be applicable to the carbonylation of higher molecular weight allylic alcohols such as nerolidol, farnesol, monocyclonerolidol or monocyclofarnesol. Using this method, the yield of .beta.,.gamma.-unsaturated acid decreases from 53% to 36% upon changing the allylic alcohol substrate from the C.sub.5 alcohol 2-methyl-3-buten-2-ol (compound A1; CH.sub.2 .dbd.CH-CR.sup.1 R.sup.2 -OH; R.sup.1 .dbd.CH.sub.3, R.sup.2 =CH.sub.3) to the C.sub.6 alcohol 3-methyl 1-penten-3-ol (compound A2; HO--CH.sub.2 --CH.dbd.CR.sup.1 R.sup.2 ; R.sup.1 .dbd.CH.sub.2 CH.sub.3, R.sup.2 .dbd.CH.sub.3).
The enzyme-catalyzed cyclization of trans, trans-homofarnesol (I) to 3a,6,6,9a-tetramethyldodecahydronaphtho-[2,1-b]-furan (B) has been reported by S. Neumann and H. Simon in Biol. Chem. Hoppe-Sevler 367, 723 (1986), but is impractical as a means of producing this material on a commercial scale. Russian patent 1,498,767 reports the reduction of (E,E)-homofarnesic acid (H; R=H) to (E,E)-homofarnesol (I) using lithium aluminum hydride, followed by cyclization of 33 mg of this alcohol with fluorosulfonic acid in 2-nitropropane at -80.degree. to -90.degree. C. to give (.+-.)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan (B). These conditions are not practical for commercial use, since they make use of extremely low temperatures, the suspected carcinogen 2-nitropropane, and a very large excess (10-15 fold) of fluorosulfonic acid, which is an extremely expensive and hazardous material. Furthermore, no evidence was given that this approach can be used on a realistic scale for the production of a commercial product.
Mixtures of 3a, 6,6,9a-tetramethyldodecahydronaphtho-[2,1-b]furan diastereomers (B) have been prepared from homofarnesic acid (G; R=H) and from its monocyclic analogue (H; R=H) by Staiger and Macri in U.S. Pat. No. 4,503,240 (1985) and by Kawanobe, et al., in Agric. Biol. Chem. 50, 1475 (1986), respectively. In these approaches, carboxylic acid G or H (R=H), respectively, is cyclized in the presence of acid to afford a mixture of diastereomers of tricyclic lactone K having the following structure. ##STR1## This lactone mixture is then reduced to a mixture of the corresponding diols, which is then cyclodehydrated to give a mixture of diastereomers of ambergris fragrance compound B having the structure shown herein in the following disclosure. This cyclodehydration reaction is difficult to control, and often gives large amounts of undesired side products. To avoid this, a number of approaches have been devised which give improved yields but involve the use of expensive and/or hazardous reagents. In contrast, the synthetic approach of this invention for the preparation of said compound B avoids this troublesome diol cyclodehydration step. While Russian patent 1,498,767 reports the cyclization of (E,E)-homofarnesol (I) under commercially impractical conditions, the combination of carbonylation, reduction and cyclization steps of this invention is believed to be new, and gives good yields of ambergris fragrance compound B under commercially practical conditions.
USPTO Backgrounds
USPTO Backgrounds