Lanosterol synthesis

Other, removable cation-stabilizing auxiliaries have been investigated for polyene cyclizations. For example, a sdyl-assisted carbocation cyclization has been used in an efficient total synthesis of lanosterol. The key step, treatment of (257) with methyl aluminum chloride in methylene chloride at —78° C, followed by acylation and chromatographic separation, affords (258) in 55% yield (two steps). When this cyclization was attempted on similar compounds that did not contain the C7P-silicon substituent, no tetracycHc products were observed. Steroid (258) is converted to lanosterol (77) in three additional chemical steps (225). 

The biomimetic approach to total synthesis draws inspiration from the enzyme-catalyzed conversion of squalene oxide (2) to lanosterol (3) (through polyolefinic cyclization and subsequent rearrangement), a biosynthetic precursor of cholesterol, and the related conversion of squalene oxide (2) to the plant triterpenoid dammaradienol (4) (see Scheme la).3 The dramatic productivity of these enzyme-mediated transformations is obvious in one impressive step, squalene oxide (2), a molecule harboring only a single asymmetric carbon atom, is converted into a stereochemically complex polycyclic framework in a manner that is stereospecific. In both cases, four carbocyclic rings are created at the expense of a single oxirane ring. 

Polyene cyclizations are of substantial value in the synthesis of polycyclic terpene natural products. These syntheses resemble the processes by which the polycyclic compounds are assembled in nature. The most dramatic example of biosynthesis of a polycyclic skeleton from a polyene intermediate is the conversion of squalene oxide to the steroid lanosterol. In the biological reaction, an enzyme not only to induces the cationic cyclization but also holds the substrate in a conformation corresponding to stereochemistry of the polycyclic product.17 In this case, the cyclization is terminated by a series of rearrangements. 

Synthesis of endogenic cholesterol is also controlled by exogenous cholesterol supplied in food the more dietary cholesterol is digested, the less endogenic cho-lesterol is produced in the liveV. Exogenous cholesterol inhibits the activity of hydroxymethylglutaryl-CoA reductase and the cyclization of squalene to lanosterol. 

Analysis of the details of the pathway was helped by the discovery by Nancy Bucher (1953) that cholesterol synthesis took place in cell-free post-mitochondrial supernatants. ATP, Mg2+ and NAD+ were required. Tchen and Bloch extended these findings to show that squalene could be formed anaerobically but the conversion of squalene to cholesterol was oxygen dependent, the oxygen of the intermediate lanosterol being derived from 8C>2 not H2180. It therefore became possible to focus either on the conversion of acetate to squalene or on the latter s cyclization to the sterol. 

The first committed step in the synthesis of triterpenoid saponins involves the cyclisation of 2,3-oxidosqualene to give one of a number of different potential products [9]. Most plant triterpenoid saponins are derived from oleanane or dammarane skeletons, although lupanes are also common [9]. This cycHsation event forms a branchpoint with the sterol biosynthetic pathway, in which 2,3-oxidosqualene is cyclised to lanosterol (in animals and fungi) or to cycloartenol (in plants) (Fig. 2). Sterols are important membrane constituents and also serve as precursors for hormone biosynthesis. 

Point mutations that give altered sterol profiles have been generated in A. thaliana and S. cerevisiae LSs. Matsuda and co-workers used a yeast expression system to select for spontaneous mutations in A. thaliana CS that restored sterol-independent growth to an LS-deficient mutant of yeast [67]. In this way they were able to identify a mutation from isoleucine to valine (at Ile481) that allowed synthesis of the sterols lanosterol and parkeol. Further studies have identified a number of other amino acid residues in A. thaliana CS and... 

The synthesis of all isoprenoids starts with acetyl-CoA, which in a series of six different enzyme reactions is converted into isopentenyl-diphosphate (-PP), the basic C-5 isoprene unit that is used for the synthesis of all subsequent isoprenoids (Fig. 5.1.1). At the level of farnesyl-PP the pathway divides into several branches that are involved in the production of the various isoprenoid end products. One of the major branches involves the cholesterol biosynthetic part of the pathway, of which squalene is the first committed intermediate in the production of sterols. Following cycliza-tion of squalene, lanosterol is produced. To eventually produce cholesterol from la-... 

Stereospecific 2,3-epoxidation of squalene. followed by a non-concerted carbocationic cyclization and a seiies of carbocationic rearrangements, forms lanosterol (26) in the first steps dedicated solely toward steroid synthesis. Cholesterol is the principal starting material for steroid hormone biosynthesis ill animals. The cholesterol biosynthetic pathway is composed of at least 30 enzymatic reactions. Lanosterol and squalene appear to he normal constituents, in trace amounis. in tissues that are actively synthesizing cholesterol,... 

The Rate of Mevalonate Synthesis Determines the Rate of Cholesterol Biosynthesis Six Mevalonates and 10 Steps Are Required to Make Lanosterol, the First Tetracyclic Intermediate... 

In the next segment of the pathway, mevalonate is converted to squalene, which is cyclized to form lanosterol. The first stage in this sequence of reactions is the synthesis of the five-carbon isoprenoid intermediates, isopentenyl pyro-... 

Recent syntheses of steroids apply efficient strategies in which open-chain or monocyclic educts with appropiate side-chains are stereosclectively cyclized in one step to a tri- or tetracyclic steroid precursor. These procedures mimic the biochemical synthesis scheme where acyclic, achiral squalene is first oxidized to a 2,3-epoxide containing one chiral carbon atom and then enzymatically cyclized to lanosterol with no less than seven asymmetric centres (W.S. Johnson, 1968, 1976 E.E. van Tamelen, 1968). 

It is also possible that vitamin E can nullify some of the main adverse effects of oestrogen on blood platelets. Administration of ethynyloestradiol to female rats increased lipid synthesis, mainly lanosterol, and thrombin-induced platelet aggregation. Treatment of the rats with a-tocopheryl acetate depressed the enhanced lipid synthesis and aggregation induced by the oestrogen. In vitro, too, platelet aggregation was enhanced by the addition of lanosterol, and this response was almost completely antagonised by preincubation with a-tocopheryl acetate [145]. 

The first pathogen-specific reaction is the S-adenosylmethio-nine-dependent side chain aklylation of lanosterol. This is pathogen specific since in cholesterol synthesis, a side chain alkylation does not take place. Secondly, the demethylation reactions at C - and C -positions of 24-methylene-dihydrolanosterol are pathogen-specific as well. In mammals demethylation reactions take place, but the substrate is not side chain alkylated, so the corresponding enzyme should possess different binding sites for the different substrates. 

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