Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Patent
2000-01-06
2000-12-12
Trinh, Ba K.
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
568379, 568819, 568823, C07C 49633, C07C 3523
Patent
active
061601845
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Natural products from plants and microorganisms have proven to be a major source of active anticancer agents and lead compounds for cancer chemotherapy. Mushrooms of the class Basidiomycetes are an exception. Although they occur widely and some are well known to contain a variety of highly poisonous substances, only Omphalotus illudens (jack o'lantern mushroom) is known to produce promising anticancer compounds. These are the sesquiterpenes illudin S and illudin M. The illudins are extremely cytotoxic compounds but have a low therapeutic index particularly in solid tumor systems. However, modification of their structures has yielded several analogs. which possess a greatly improved therapeutic index. Remarkable efficacy has been observed in tests on mouse xenografts of leukemias and various solid tumors.
First and second generation analogs. for example, dehydroilludin M and acylfulvene, have been described (WO 91/04754). A promising compound is a third generation analog hydroxymethylacylfulvene (HMAF). In tests with MV 522 metastatic lung carcinoma xenografts in nude mice, complete tumor regression was observed in all animals. HMAF also exhibited outstanding activity against breast (MX-1), colon (HT-29) and skin cancers.
The structures of illudin S and illudin M were first published in 1963 (McMorris et al., J. Am. Chem. Soc. 85:831 (1963)). Until recently only one total synthesis of these compounds had been reported (Matsumoto et al., Tetrahedron Lett. 1171 (1970)). This synthesis involved Michael addition of a cycylopropane intermediate to an appropriately substituted cyclopentenone. The resulting product was then transformed into an intermediate which could undergo aldol condensation to form illudin's six-membered ring. A number of further reactions were required to complete the synthesis.
Padwa et al., (J. Am. Chem. Soc. 116: 2667 (1994)), have published a synthetic approach to the illudin skeleton using a dipolar cycloaddition reaction of a cyclic carbonyl ylide dipole with cyclopentenone to construct the six-membered ring. Kinder and Bair (J. Org. Chem. 59:6955 (1994)), have also employed the Padwa methodology to synthesize illudin M. However, these syntheses are long and not well suited for making acylfulvenes on a large scale.
Thus, a continuing need exists for improved methods for synthesizing acylfulvenes.
SUMMARY OF THE INVENTION
The present invention provides a method of synthesizing compounds of formula (I): ##STR2## wherein R and R' are independently (C.sub.1 -C.sub.4)alkyl, preferably methyl. According to the invention, a method is provided of synthesizing a compound of formula (V), a preferred intermediate in the synthesis of compounds of formula (I),: ##STR3## comprising the steps of coupling a cyclopentanone of formula (II): ##STR4## wherein R.sub.4 is --O--C(R.sub.9).sub.2 O(R.sub.9), wherein R.sub.9 is (C.sub.1 -C.sub.4)alkyl, preferably methyl; with a cyclic carbonyl ylide dipole of formula (III): ##STR5## to form a compound of formula (IV): ##STR6## and treating compound (IV) with base to form a ketone of formula (V).
The present method further may further comprise the steps of dihydroxylating the ketone to yield a compound of formula (VI): ##STR7## and treating the compound of formula (VI) with a removable 1,2-diol protecting reagent to yield an intermediate of formula (VII): ##STR8## wherein X is a removable 1,2-diol protecting group. Protecting groups may be introduced by forming a cyclic acetal by treatment with an aldehyde or ketone such as acetone, formaldehyde, acetaldehyde or benzaldehyde. For example, an isopropylidene derivative (acetonide) may be introduced by reaction with acetone. Preferably, the isopropylidene group is introduced by acid-catalyzed exchange with 2,2-dimethoxypropane.
The method further comprises the steps of treating compound (VII) with RMgCl, where R is (C.sub.1 -C.sub.4)alkyl, to yield a Grignard product of formula VIII: ##STR9## and cleaving the oxybridge to yield a diol of formula (IX): ##STR10##
The method further comp
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Trinh Ba K.
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