Naturally Occurring Coumarins

Coumarin occurs in lavender, woodruff [Asperula), tonka beans, and sweet clover (Melilotus). Coumarin can be extracted from sweet clover with hot water. Reference (Sethna 1945) 

Umbelliferone (7-Hydroxycoumarin) can be obtained from the distillation of the resin from umbelliferae species of plants. 

Scopoletin (7-Hydroxy-6-methoxycoumarin) occurs in Solanaceac, Convolvulacea and various other species of plants. It can also be mad( synthetically. 

Esculetin (6,7-Dihydroxycoumarin) can be obtained by the hydrolysis of esculin. Esculin occurs in the leaves and bark of the horse chestnut tree Hippocastanacea). 

Fraxetin (7,8-Dihydroxy-6-methoxycoumarin) is obtained be heating fraxin with sulfuric acid. Fraxin occurs in the bark of the Com mon Ash tree (Fraxinus excelsior). 

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Two possible structures, A and B, were initially considered for a naturally occurring coumarin isolated from Murraya paniculata. Its nOe difference and H-NMR spectra are presented. The relevant H chemical shift values are given around structure A. On the basis of the nOe data, identify the correct structure of the coumarin. 

Scheme 2.206. Synthesis of naturally occurring coumarins and analogs.

Cairns N, Harwood LM, Astles DP (1994) Tandem thermal claisen-cope rearrangements of coumarate derivatives. Total syntheses of the naturally occurring coumarins suberosin, demethylsuberosin, ostruthin, balsamiferone and gravelliferone. J Chem Soc Perkin Trans... 

Decursinol (18) is a naturally occurring coumarin compound isolated from Angelica gigas (Umbelliferae). In recent studies, two important properties of this compound have been discovered, affecting neuropathology in AD. In one study, mice pretreated with decursinol were able to... 

In coumarins which bear large alkyl side chains, such as osthol (122), the primary fragmentation does not involve carbon monoxide loss. The dominant processes are side chain cleavage, methyl radical elimination from the side chain, and loss of a methoxyl radical. The mass spectra of this and related naturally occurring coumarins have been intensively studied and reviewed (75RCR603). 

Elaboration of the side-chain of the salicylaldehyde (376) coupled with a Knoevenagel condensation enabled a number of naturally occurring coumarins such as xanthyletin (377) to be prepared (71CJC2297). The use of C-labelled malonic acid leading to coumarins labelled at C-3 enhances the potential of this route. 

Insecticidal activity is shown by a number of oxygen heterocycles. Xanthone is an ovicide for the codling moth and the naturally occurring coumarin mammein (713) shows insecticidal properties. 

A review detailing the structures and isolation of naturally occurring coumarins is available <1997NPR465>. 

Cai Y, Baer-Dubowska W, Ashwood-Smith MJ, et al. Mechanism-based inactivation of hepatic ethoxyresorufm O-dealkylation activity by naturally occurring coumarins. Chem Res Toxicol 1996 9(4) 729-736. 

Coumarins constitute a major class of widely distributed O-heterocyclic natural products isolated from citrus fruits and vegetables [52]. Naturally occurring coumarins possess a variety of biological activities, including antitumor activity [53]. 7-Hydroxycoumarin and 8-nitro-7-hydroxycoumarin were shown to be potent cytotoxic agents against the human renal cell carcinoma cell line. 

Coumarin constituents (black cohosh, chamomile, fenugreek, horse chestnut, sweet melilot, tonka beans, sweet woodruff). Naturally occurring coumarins are only weakly anticoagulant, but improper storage causes the production of dicoumarol by microbial transformation. Woodruff may contain constituents of warfarin... 

Cai, Y.N., Baerdubowska, W., Ashwoodsmith, M. and Digovanni, J. (1997) Inhibitory effects of naturally occurring coumarins on the metabolic activation of benzo[A]pyrene and 7,12-dimethylbenz[A]anthracene in cultured mouse keratinocytes. Carcinogenesis. 18, 215. 

Coumarin is one of the earliest ring systems to be studied. In view of the interesting physiological activities exhibited by the synthetic and the naturally occurring coumarins, there is still continued interest in this field... 

Synthesis of coumarins with 3,4-fused ring systems and their physiological activity , Darbarwar, M. and Sundaramurthy, V., Synthesis, 1982, 337 Naturally occurring coumarins . Dean, F. M., Fortschr. Chem. Org. Naturst, 1952, 9, 225 Naturally occurring plant coumarins , Murray, R. D. H., Fortschr. Chem. Org. Naturst, 1978, 35, 199 The natural coumarins occurrence, chemistry and biochemistry , Murray, R. D. H., Mendez, J. and Brown, S. A., Chichester, Wiley, 1982. 

Kleiner, H.E., Reed, M.J., and DiGiovanni, J. (2003) Naturally occurring coumarins inhibit human cytochrome P450 and block benzoja] pyrene and 7,12-dimethylbenz[a] anthracene DNA adduct formation in MCF-7 cells. Chem. Res. Toxicol., 16, 415-422. 

M.J. Ashwood-Smith, and J. DiGiovanni (1993). Inhibition and inactivation of murine hepatic ethoxy- and pentoxyresorufin O-dealkylase by naturally occurring coumarins. Chem. Res. Toxicol. 6, 872-879. 

However, a screening of red clover for 17 naturally occurring coumarins identified 5 coumarin compounds in red clover, 1 with anticoagulant activity, 1 with procoagulant activity, and 3 with no activity reported (Booth et al. 2004). No changes in bleeding or blood clotting were observed in women after 30 days of red clover supplementation (Booth et al. 2004). 

Synthesis of coumarins with 3,4-fused ring systems and their physiological activity , Darbarwar, M. and Sundaramurthy, V., Synthesis, 1982, 337 Naturally occurring coumarins . Dean, F. M., Fortschr. Chem. Org. Naturst., 1952, 9, 225 Naturally... 

Simple coumarins (lactones of phenylpropanoic acids with a 2//-l-benzopyran-2-one nucleus) are widespread in plants the four most widely distributed coumarins are coumarin (1), umbelliferone (2), esculetin (aesculetin) (3), and scopo-letin (4) (Fig. 9.1) (Brown, 1979). Coumarins have not been reported from algae or mosses, although umbelliferone has been reported from a liverwort (Berenbaum, 1991). Coumarin is both the name of a specific compound and the name of a group of structurally related compounds. Variations of these basic coumarin structures are encountered commonly (especially in the Apiaceae) and at least 300 simple coumarins and a total of at least 1000 naturally occurring coumarins are known (Berenbaum, 1991 Brown, 1986, personal communication). Many coumarins, such as xanthyletin (5) and seselin (6), are prenylated. 

In plants, however, almost all naturally occurring coumarins are 7-hydroxy derivatives, marking the possible site of the initiation of coumarin biotransformation. It seems that the electron charge theory is not congruent with any relationship between the wide occurrence of the 7-hydroxylated plant coumarins and their metabolism. It is, therefore, likely that the hydroxy group is formed before the ring closure [51,52] and the hydroxylated products do not originate from the parent compound. 

Table 49. Naturally occurring coumarins and their cinnamic acid precursors...

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