Squalene oxide, cyclization

S. ferax and related sterol-producing Oomycetes synthesize lanosterol rather than cycloartenol (10) in Stage II. The mechanism of squalene-oxide cyclization to lanosterol involves a nonconcerted process in which a terminal intermediate,... 

We challenged the central dogma recently (72,52,55). Our hypothesis is that the enzymes that transform the tetracyclic products of squalene oxide cyclization possess a high degree of substrate specificity for sterol, and kinetically favored taxa-specific pathways operate in nature, so that only certain intermediates may ultimately be... 

Irrespective of whether the oxidative cyclization of pCA is a concerted reaction or involves two (or more) steps, the reaction requires a single enzyme molecule. This conversion, therefore, differs from squalene oxidative cyclization, which requires an enzyme for the oxidative step and another enzyme (2,3-oxidosqualene lanosterol cyclase) for the cyclization (Singer et aL, 1956). The possibility that the oxidative cyclization of pCA may be a true concerted (one step) process cannot be ruled out at this stage. It may explain the specificity (Steenkamp et aL, 1974) of the enzyme for pCA as substrate and the observation that in all reaction mixtures aCA was formed at approximately the same rate as the rate of dehydrogenation of the electron acceptor. 

The most important oxirane, from an anthropocentric viewpoint, is probably squalene oxide (72), a precursor of lanosterol (73) and thus of the maligned but essential cholesterol (74 Scheme 87) 78MI50501). The cyclization of (72) to (73) represents nucleophilic tr-attack on oxirane carbon cf. Section 5.05.3.4.3(t)()), and the process has also been extensively investigated in vitro (68ACR1). Oxiranes are even more ubiquitous in steroid biosynthesis than had been thought, for a cholesterol epoxide has been shown to be a product of mammalian steroid biosynthesis <81JA6974). 

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. 

Scheme 1, Enzyme-induced cyclizations of squalene oxide (2) (a) and the Stork-Eschenmoser hypothesis (b).

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. 

Until recently, the only marine example of cycloartenol (32) production was in the chrysophyte Ochromonas sp. [20], A survey, documenting the products of squalene oxide (37) cyclization (see Scheme 3) using crude enzyme preparations of various algal phyla has recently been reported [21]. Interestingly, while all... 

Sea cucumbers (Holothuroidea, Echinodermata) appear to be unique in their mode of squalene oxide (37) cyclization. Tritium-labeled lanosterol (33), cycloartenol (32) and parkeol (38) were individually administered to the sea cucumber Holothuria arenicola. While the former two triterpenes were not metabolized [22], parkeol was efficiently transformed into 14x-methyl-5a-cho-lest-9(l l)-en-3/ -ol (39) (Scheme 3). Other A1 sterols present in H. arenicola were not found to be radioactive and were thus assumed to be of dietary origin. The intermediacy of parkeol was confirmed by the feeding of labeled mevalonate (23) and squalene (26) to the sea cucumber Stichopus californicus [15]. Both precursors were transformed into parkeol, but not lanosterol nor cycloartenol, aqd to 4,14a-dimethyl-5a-cholest-9(ll)-en-3/J-ol (40) and 14a-methyl-5a-cholest-9(ll)-en-3/ -ol. Thus, while all other eukaryotes produce either cycloartenol or lanosterol, parkeol is the intermediate between triterpenes and the 14-methyl sterols in sea cucumbers. 

As described above, the cyclization of squalene oxide is a biosynthetic branching point not only for phytosterols and triterpenes but also for dammarane- and oleanane-type ginsenosides. In ginseng, the enzyme... 

Synthesis takes place in four stages, as shown in Figure 21-33 (D condensation of three acetate units to form a six-carbon intermediate, mevalonate (2) conversion of mevalonate to activated isoprene units (3) polymerization of six 5-carbon isoprene units to form the 30-carbon linear squalene and ( ) cyclization of squalene to form the four rings of the steroid nucleus, with a further series of changes (oxidations, removal or migration of methyl groups) to produce cholesterol. 

The epoxy alcohol 47 is a squalene oxide analog that has been used to examine substrate specificity in enzymatic cyclizations by baker s yeast [85], The epoxy alcohol 48 provided an optically active intermediate used in the synthesis of 3,6-epoxyauraptene and marmine [86], and epoxy alcohol 49 served as an intermediate in the synthesis of the antibiotic virantmycin [87], In the synthesis of the three stilbene oxides 50, 51, and 52, the presence of an o-chloro group in the 2-phenyl ring resulted in a lower enantiomeric purity (70% ee) when compared with the analogs without this chlorine substituent [88a]. The very efficient (80% yield, 96% ee) formation of 52a by asymmetric epoxidation of the allylic alcohol precursor offers a synthetic entry to optically active 11 -deoxyanthracyclinones [88b], whereas epoxy alcohol 52b is one of several examples of asymmetric epoxidation used in the synthesis of brevitoxin precursors [88c]. Diastereomeric epoxy alcohols 54 and 55 are obtained in combined 90% yield (>95% ee each) from epoxidation of the racemic alcohol 53 [89], Diastereomeric epoxy alcohols, 57 and 58, also are obtained with high enantiomeric purity in the epoxidation of 56 [44]. The epoxy alcohol obtained from substrate 59 undergoes further intramolecular cyclization with stereospecific formation of the cyclic ether 60 [90]. 

In the biogenesis of steroids, the enzyme-catalyzed polycyclization of squalene (225) produces the tetracyclic substance lanosterol (225) which is eventually converted into cholesterol (227) Eschenmoser, Stork, and their co-workers (80-82) have proposed that the squalene-1anosterol conversion can be rationalized on the basis of stereoelectronic effects. The stereochemical course of this biological cyclization (83, 84) can be illustrated by considering the transformation of squalene oxide (228) (an intermediate in the biosynthesis of cholesterol (83, 84)) into dammaradienol 229. This transfor-... 

Cyclization of squalene is via the intermediate squalene-2,3-oxide (Figure 5.55), produced in a reaction catalysed by a flavoprotein requiring O2 and NADPH cofactors. If squalene oxide is suitably positioned and folded on the enzyme surface, the polycyclic triterpene structures formed can be rationalized in terms of a series of cycliza-tions, followed by a sequence of concerted Wag-ner-Meerwein migrations of methyls and hydrides... 

The CYCLIZATION OF SQUALENE OXIDE TO LANOSTEROL. Test yourself on the concepts in this figure at OrganicChemistryNow. 

Cyclization of Squalene Oxide to Lanosterol Section 28.5 Figure 28.7... 

The following reaction resembles the acid-catalyzed cyclization of squalene oxide. Propose a mechanism for this reaction. 

The epoxy alcohol (47) is a squalene oxide analog which has been used to examine substrate specificity in enzymatic cyclizations by baker s yeast The epoxy alcohol (48) provided an optically active intermediate used in the synthesis of 3,6-epoxyauriq>tene and marmine, and epoxy alcdiol (49) served as an intermediate in the synthesis of the antibiotic virantmycin. In the synthesis of the three stilbene... 

The full details of the synthesis and resolution of presqualene and prephytoene alcohols and the stereochemistry of the non-oxidative cyclization of squalene to tetrahymanol by Tetrahymena pyriformis have appeared (see Vol. 9, p. 187). 

Cyclization of Squalene-like Substrates. Ultrasonically stimulated BY is a source of sterol cyclase, which catalyzes the cyclization of squalene oxide and squalenoid compounds to lanos-terol derivatives (eq 13). ... 

Cyclization of squalene oxide yields a carbocation, called the protosterol cation. This reaction results in the formation of four new C—C bonds and the tetracyclic ring system. 

In related work, a series of important studies have been devoted to enzymatic cyclization of unnatural lanosterol precursors. Thus both epoxides (23) and (29), despite being notably different in structure from squalene oxide (32), were transformed enzymatically into the pentanorlanosterol (33a) and dihydrolano-sterol (33b), respectively. These results lend support to the suggestion that the methyl-hydrogen migration sequence rests solidly on physico-chemical... 

Through a series of cyclizations, squalene oxide (C30) affords lanosterol in animals and fungi and cycloartenol in plants (Fig. 19). In both instances, the intermediate is a protosteryl cation that can also undergo a series of Wagner-Meerwein rearrangements to afford the cytotoxic cucurbitacins of melons and cucumbers. Squalene oxide in a chair-chair-chair-boat conformation yields the dammarenyl cation, a parent of numerous triterpene skeleta (e.g., lupane, oleanane, ursane, and taraxerane) contained in the saponins found in many foodstuffs, in soaps, and in several... 

---