Perillyl alcohol

Silica gel successfully catalyzed the stereoselective synthesis of several glucoside terpenoids. Treatment of 49a with propan-2-ol, geraniol, the tetrahydropyranyl (THP) ether of coniferyl alcohol, and (—)-perillyl alcohol gave glucosides 52a-d in good yields (Scheme 12). The acid-labile THP group was retained under these reaction... 

Stark MJ, Burke YD, McKinzie JH, Ayoubi AS and Crowell PL. 1995. Chemotherapy of pancreatic cancer with the monoterpene perillyl alcohol. Cancer Lett 96 15-21. 

Geraniol is an interesting substrate that presents a hindered terminal C = C bond and an allylic function. The carbonylation reaction gives, beside the acid, the six-membered lactone and not the butyrolactone that means that initially an isomerization step occurred as depicted in Scheme 13. The most adapted ligand to obtain good selectivity in this lactone is dppb [98]. In the case of perillyl alcohol such an isomerization does not occur and the C5-lactone is produced (Scheme 14) [99]. 

Further variations on the epoxyketone intermediate theme have been reported. In the first (Scheme 9A) [78], limonene oxide was prepared by Sharpless asymmetric epoxidation of commercial (S)-(-)- perillyl alcohol 65 followed by conversion of the alcohol 66 to the crystalline mesylate, recrystallization to remove stereoisomeric impurities, and reduction with LiAlH4 to give (-)-limonene oxide 59. This was converted to the key epoxyketone 60 by phase transfer catalyzed permanganate oxidation. Control of the trisubstituted alkene stereochemistry was achieved by reaction of the ketone with the anion from (4-methyl-3-pentenyl)diphenylphosphine oxide, yielding the isolable erythro adduct 67, and the trisubstituted E-alkene 52a from spontaneous elimination by the threo adduct. Treatment of the erythro adduct with NaH in DMF resulted... 

Mechanistic studies revealed that the effects of limonene on cell proliferation and cell cycle progression were preceded by a decrease in cyclin D1 messenger RNA levels [284] and inhibition of posttranslational isoprenylation, rather than through the suppression of cholesterol biosynthesis [271 279, 285-293]. Limonene and perillyl alcohol and their active serum metabolites inhibit protein isoprenylation [287, 289-291, 294]. 

Limonene and perillic acid remarkably reduced the lung metatastatic tumour nodule formation by 65 and 67%, respectively however, perillyl alcohol was considerably more potent than limonene against breast cancer [284, 302], rat mammary cancer and pancreatic tumours [288]. Phase 1 studies of d-limo-nene [303, 304] and phase I and phase II [305-311] studies of perillyl alcohol revealed dose-limiting toxicities nausea, vomiting, anorexia, unpleasant taste and eructation, and thus a maximum tolerated dose for perillyl alcohol was determined [305]. 

Perillyl alcohol induced apoptosis and was more effective than perillaldehyde at inhibiting the proliferation of human carcinoma cell lines cultured in vitro [319]. Perillyl alcohol treatments suppressed cell growth [313-315], reduced cyclin D1 RNA and protein levels and prevented the formation of active cyclin D1 associated with kinase complexes in synchronous cells during the exit of GO and entry into the cell cycle [284, 316, 317]. In addition, perillyl alcohol treatment induced an increased association of p21 [316-318] with cyclin E-Gdk2 complexes, inhibited the activating phosphorylation of Gdk2 [312, 316, 318-320], initiated apoptosis [321-324] and suppressed small G-protein isoprenylation... 

Perillyl alcohol represents a novel small molecule that might be effective for treating leukaemia by inducing growth arrest and apoptosis in transformed cells [313], Blends of isoprenoids suppressed growth of murine melanoma and human leukaemic cells [265, 271],... 

A phase I clinical trial with limonene indicated its toxic effects in humans thus, perillyl alcohol is more effective at lower doses [279],... 

If you would like a little more tantalizing cherry information, then here it is. Quite aside from the antioxidants, cherries contain another substance with interesting properties. Research has shown that perillyl alcohol produces antitumor effects in laboratory animals and that it has cancer-prevention properties. In preliminary human trials researchers have not yet seen a significant effect in terms of treatment, but perillyl alcohol does hold promise as a model for a new class of antitumor agents. 

The same group has also isolated a strain of Pseudomonas putida-arvilla (PL-strain) from limonene and (+)-a-pinene as the sole carbon source that was capable of growing on (+)-limonene, (+)-a-pinene, (-)-a-pinene, / -pinene, 1-p-menthene, 3-p-menthene and p-cymene as substrates [75]. Limonene was degraded to perillyl alcohol, perillaldehyde and perillic acid. 

The fungal bioconversion of limonene was further studied [82]. Penicillium sp. cultures were isolated from rotting orange rind that utilised limonene and converted it rapidly to a-terpineol. Bowen [83] isolated two common citrus moulds, Penicillium italicum and P. digitatum, responsible for the postharvest diseases of citrus fruits. Fermentation of P. italicum on limonene yielded cis- and frans-carveol (93) (26%) as main products, together with cis- and from-p-mentha-2,8-dien-l-ol (110) (18%), (+)-carvone (94) (6%), p-mentha-1,8-dien-4-ol (111) (4%), perillyl alcohol (100) (3%), p-menth-8-ene-1,2-diol (98) (3%), Fig. (17). Conversion by P. digitatum yielded the same products in lower yields. The two alcohols />-mentha-2,8-dien-1 -ol (110) and p-mentha-1,8-dien-4-ol (111) were not described in the transformation studies where soil Pseudomonads were used [69]. 

Cyclopropanation of unsaturated alcohols.1 The reaction of perillyl alcohol (1) with this reagent results in regioselective cyclopropanation of the isolated double bond and is therefore complementary to the regioselectivity of the Simmons-Smith reaction. The actual reagent is probably diisobutyl(iodomethyl)aluminum. 

Selective Cyclopropanation of Perillyl Alcohol 1-Hydroxymethyl-4-(1-methylcyclopropyl)-1-cyclohexene... 

Figure 8. Hydroxylation of L-limoneneto (-)-perillyl alcohol by cytochrome P450. Growing cells of P. putida GPol2 (pG Ec47AB) (pCom8-PFRl 500) containing the P450 alkane monooxygenase of Mycobacterium sp. strain HXN-1500 are used as catalyst.

---