Biomimetic olefin cyclization

Epoxides can also serve as effective carbocyclization promotors, either through a polyene cyclization, as in the biomimetic epoxy-olefin cyclization of 100 in the presence of boron trifluoride etherate <99CC325>, or by a Friedel-Crafts approach, as exemplified by the cycli-alkylation of arylalkyl epoxides 102 under the influence of solid acid catalysts <99EJOC837>. 

Stereospecific 2,3-epoxidation of squalene, followed by a nonconcerted carbocationic cyclization and a series of carbocationic rearrangements, forms lanosterol [79-65-0] (77) in the first steps dedicated solely toward steroid synthesis (109,110). Several biomimetic, cationic cydizations to form steroids or steroidlike nuclei have been observed in the laboratory (111), and the total synthesis of lanosterol has been accomplished by a carbocation—olefin cyclization route (112). Through a complex series of enzyme-catalyzed reactions, lanosterol is converted to cholesterol (2). Cholesterol is the principal starting material for steroid hormone biosynthesis in animals. The cholesterol biosynthetic pathway is composed of at least 30 enzymatic reactions. Lanosterol and squalene appear to be normal constituents, in trace amounts, in tissues that are actively synthesizing cholesterol. 

As part of his extensive program on steroid synthesis based on biomimetic olefin cyclization processes, W. S. Johnson has developed a stereospecific synthesis of ( )-estrone (Scheme 23). ... 

Baiyunoside (1) is the sweet principle of a Chinese drug Phlontis hetonicoides (Labiatae).2 Through mercury (11) triflate induced biomimetic olefin cyclization followed by... 

Electrophilic Addition Reactions. Further work by Johnson on the biomimetic polyene olefin cyclization reactions has shown that asymmetric induction by a chiral centre remote from the initiating cationic centre is possible. This was shown by the preparation of 11 a-methylprogesterone and a stereospecific total synthesis of racemic 11 a-hydroxyprogesterone via this route (Scheme 48). > ... 

Natural product structures often elicit biomimetic reasoning that leads to mechanistic hypotheses for new reaction processes. Two notable examples of syntheses that capitalized on snch thinking are the progesterone 128) and homosecodaphniphyllate 129) syntheses highlighted in Figure 22. The cation-olefin cyclization used by William S. Johnson drew its inspiration from the Stork-Eschemnoser hypothesis 130,131,132) for enzymatic squalene... 

The chemical simulation of this biosynthetic process has been developed as an important methodology in organic synthesis. Van Tamelen reported the add-catalyzed cyclization of chiral terminal epoxides of polyprenoids [11]. In contrast, Johnson adopted the acid-catalyzed cyclization of poly-prenic acetals derived from chiral diols [12]. In addition to these pioneering studies, the biomimetic polyene cycliza-tions of polyprenoids, which are induced by a variety of electrophiles such as proton, oxonium ion, halonium ion [13], or metal ion [14], have also been developed. Despite extensive studies on these diastereoselective olefin cyclizations, enantioselective processes using synthetic chiral catalysts had not been developed for a long time. In 1999, Yamamoto s... 

Closely related to the polyepoxide cascade procedure for the synthesis of polycyclic systems is Corey s biomimetic-type, nonenzymatic, oxirane-initiated (Lewis acid-promoted) cation-olefin polyannulation. By this strategy, compound 96, containing the tetracyclic core of scalarenedial, was constructed by exposure of the acyclic epoxy triene precursor 95 to MeAlCl2-promoted cyclization reaction conditions (Scheme 8.25) [45]. 

The biomimetic cationic domino cyclization of an acyclic unsaturated substrate to give the tetracyclic scaffold of triterpenes and steroids is intensively described in the literature.1121 The concept has recently been used by Corey et al. to prepare enanti-opure (+)-dammarenediol II 18 in an exceptional short way.1131 The synthesis demonstrates the power of the combination of cation-olefin polyannulation with the aldol cyclization for tetraannulation (scheme 4). Successive treatment of the acylsilane 13 with 2-propenyllithium 14 and the iodoalkane 15 efficiently yidds the epoxytriene 16. The Lewis acid... 

In this approach, the cis-disubstituted tetrahydrofuranone 75 [accessible with high diastereoselectivity via radical cyclization of the acylselenide 74 with tris(tri-methylsilyl) silane and triethylborane] was transformed into the corresponding enyne 76 by reduction and Wittig olefination. The subsequent electrophilic cyclization was carried out in analogy with the biomimetic synthesis of panacene (Scheme... 

Another example is the cyclization of the racemic allylic alcohol 232 at -80°C which furnished the racemic tetracyclic bis-olefin 233 in 70% yield (89, 90). Ozonolysis of 233 gave the bicyclic triketone aldehyde 234 which underwent under acidic conditions a double intramolecular aldol cyclodehydration to produce racemic 16,17-dehydroprogesterone 235. This represents the first synthesis of a steroid via the now so-called "biomimetic" polyene cyclization method. 

The isomeric cis-internal olefinic precursor yielded only a cis-decalin derivative, in accordance with the predictions of orbital orientation and overlap. It is important to note that the products of all these biomimetic cyclizations are racemic. However, it is interesting to observe that when an optically active dienic acetal is used, a very high degree of asymmetric induction is realized ... 

As mentioned in the Introduction, the group 3 biomimetic approach (see Scheme 1) has been the most popular route to the trichothecene skeleton. Two different moieties have served as the electrophilic site for biomimetic cyclization. When the cyclization proceeds via an allylic carbonium ion (127) (Path A, Scheme 9), the desired trisubstituted olefin (126) is obtained directly. On the other hand, the Michael acceptor (128) (PathB) yields, upon cyclization, a ketone (129) which must then be transformed into the olefin (126), a process which shows good but not complete regioselectivity. Hence, Path A, which can also be entered from the enone (128), is the superior route. Further analysis of Scheme 9 reveals that the primary stereochemical challenge of the biomimetic approach is to control the relative stereochemistry at the two quaternary centers C-5 and C-6. Within the context of trichothecene synthesis, a number of useful protocols have been devised for this purpose and include photocyclization (99), selective ring contraction (134), Diels-Alder cycloaddition (117,125) conjugate addition (27,120), and interconversion of dienyl iron complexes (114). 

Suppose you made the following observation [Schoemaker, H. E. Dijkink, J. Speckamp, W. N. Biomimetic a-acylimmonium cyclizations of unactivated olefins Tetrahedron 1978, 34,163-172. How might you develop this into an approach to the pyrrolizidine alkaloids ... 

Shair and co-workers turned their attention to the regiochemical outcome of enyne-metathesis macrocyclizations, and they completed the biomimetic synthesis of a cytotoxic marine natural product (—)-longithorone A (204, Scheme 24.51). Biosynthetically, the natural product has been proposed originating from two [12]-paracyclophanes 205 and 206 by two Diels-Alder reactions, and thus, the authors applied enyne metathesis macrocyclization to the preparations of paracyclophanes 205 and 206. Both metathesis precmsors 208 and 210 were prepared from the common intermediate 207. The cyclization of enyne 208 in the presence of [Ru]-Ia (50mol%) in refluxing CH2CI2 under ethylene atmosphere proceeded with excellent atropdiastereoselectivity and -stereoselectivity. On the other hand, the macrocyclization of enyne 210 was less atropdiastereoselective (selective formation of the endocy-clic olefin ( /Z= 3.9 1). Nevertheless, the desired product 211 was obtained in 31% yield. In the absence of ethylene, neither macrocyclization of 208 nor 210 occurred. 

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