Terpenoids lanosterol

Open-chain 1,5-polyenes (e.g. squalene) and some oxygenated derivatives are the biochemical precursors of cyclic terpenoids (e.g. steroids, carotenoids). The enzymic cyclization of squalene 2,3-oxide, which has one chiral carbon atom, to produce lanosterol introduces seven chiral centres in one totally stereoselective reaction. As a result, organic chemists have tried to ascertain, whether squalene or related olefinic systems could be induced to undergo similar stereoselective cyclizations in the absence of enzymes (W.S. Johnson, 1968, 1976). 

Terpenes (and terpenoids) are further classified according to the number of 5-carbon units they contain. Thus, monoterpenes are 10-carbon substances biosynthesized from two isoprene units, sesquiterpenes are 15-carbon molecules from three isoprene units, diterpenes are 20-carbon substances from four isoprene units, and so on. Monoterpenes and sesquiterpenes are found primarily in plants, but the higher terpenoids occur in both plants and animals, and many have important biological roles. The triterpenoid lanosterol, for example, is the precursor from which all steroid hormones are made. 

Isoprene itself is not the true biological precursor of terpenoids. As we ll see in Chapter 27, nature instead uses two "isoprene equivalents"—isopentenvl diphosphate and dimethylallyl diphosphate—which are themselves made by two different routes depending on the organism. Lanosterol, in particular, is biosynthesized from acetic acid by a complex pathway that has been worked out in great detail. 

Steroids are plant and animal lipids with a characteristic tetracyclic carbon skeleton. Like the eicosanoids, steroids occur widely in body tissues and have a large variety of physiological activities. Steroids are closely related to terpenoids and arise biosynthetically from the triterpene lanosterol. Lanosterol, in turn, arises from cationic cyclization of the acyclic hydrocarbon squalene. 

Polyene cyclizations have been of substantial value in the synthesis of polycyclic natural products of the terpene type. These syntheses resemble the processes by which terpenoid and steroidal compounds are assembled in nature. The most dramatic example of biological synthesis of a polycyclic skeleton from a polyene intermediate is the conversion of squalene oxide to the steroid lanosterol. In the biological reaction, the enzyme presumably functions not only to induce the cationic cyclization but also to bind the substrate in a conformation corresponding to the stereochemistry of the polycyclic product.21... 

Further studies of the steric requirements of this enzyme by van Tamelen and Corey and their co-workers show that the enzyme is relatively insensitive to the nature of the oxygen-free end and does not need to rearrange the biological equivalent of the carbonium ion (72) to produce a free terpenoid. However, the environment of the epoxide group is important. Although these two enzymes can be purified and are both active individually, the possibility of an enzyme complex linking the various steps between famesyl pyrophosphate (6 = 2) and lanosterol was examined. In the presence of [4S- H]NADPH the lanosterol contained... 

The present state of knowledge of terpenoid biosynthesis does not allow many detailed conclusions to be reached on its taxonomic importance. However, some gross differences at the phyla level are apparent. This review has already commented on differences observed in the formation of steroidal A - and A -double bonds, 24-alkyl groups, and whether lanosterol or cycloartenol is formed from squalene epoxide. 

You might recall from Chapter 8 that terpenoids are classified according to the number of five-carbon multiples they contain. Monoterpenoids contain 10 carbons and are derived from two isopentenyl diphosphates, sesquiterpenoids contain 15 carbons and are derived from three isopentenyl diphosphates, diterpenoids contain 20 carbons and are derived from four isopentenyl diphosphates, and so on, up to triterpenoids (C30) and tetraterpenoids (C40). Lanosterol, for example, is a triterpenoid from which steroid hormones are made, and )3-carotene is a tetraterpenoid that serves as a dietary source of vitamin A (Figure 27.6). 

According to the Stork-Eschenmoser hypothesis [lb, c], many polycyclic terpenoids such as hopene and lanosterol are biosynthesized via the site- and enantioselective protonation or epoxidation of a terminal olefin followed by diastereoselective x-cation cyclization [16]. Corey s group performed pioneering work on the cation-induced diastereoselective polycyclization of enantiopure epoxides [17]. For example, a very direct enantioselective total synthesis of members of the p-amyrin family of pentacyclic triterpenes has been developed by diastereoselective x-cation tricycli-zation reaction as a key step (Scheme 9.9) [17g]. 

Roller, P., Tursch, B., and Djerassi, C. (1970) Terpenoids. LXVII. Chemical studies of marine invertebrates. Vll. Interrelation of seychellogenin and lanosterol through lanostane-3 3,ll 3,18-triol. J. Org. Chem., 35, 2585-2593. 

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