Tetracyclic intermediates

Pentacyclosqualene, the symmetrical hydropicene corresponding to squalene, has not been made by acid-induced cation-olefin cyclization of squalene, despite considerable experimental study. A simple, convergent synthesis of pentacyclosqualene using cation-olefin cyclization to generate ring C was developed. The Cjo-framework was constructed by radical coupling to a tetracyclic intermediate that was also used for the synthesis of onoceradiene. 

In the synthesis of the tetracyclic intermediates for the synthesis of isoarborinol and its CDE-antipode femenol, the stereochemistry of the Diels-Alder reaction can be varied using various Lewis-acid catalysts in aqueous media (Eq. 12.36).97 Their results show that the hydrophobic effects play an important role in enhancing reaction rates and can control product distribution. Novel 2,4-dialkyl-1-alkylideneamino-3-(methoxycarbonylmethyl)azetidines were obtained from aldazines and... 

Reaction of the heterocycle with 2-methylcyclopentane-1,3-dione in the presence of pyridine leads directly to tetracyclic intermediate 20. 5 The first step in this transformation probably consists in formation of the olefin 18 by elimination of dimethylamine. 

Reactions with dialdehydes allow the introduction of two additional rings in one step. Thus, condensation of 1 -(2-aminoethyl)pyrrole with glutaraldehyde and benzotriazole gives tricyclic intermediate 627 in which the benzotriazolyl moiety can be readily substituted with nucleophiles to give products 628 (Scheme 97) <2002JOC8220>. Condensation of ethyl ester of L-tryptophan with 2,5-dimethoxytetrahydrofuran and benzotriazole in acetic acid gives tetracyclic intermediate 629 which upon treatment with nucleophiles (silyl derivatives) is converted to products 630 <1999T3489>. 

Several factors and observations support the route proposed in Scheme 10 (1) Due to steric factors, the styrenyl alkene is expected to react preferentially (versus the neighboring disubstituted cyclic olefin see below for further discussion). (2) Involvement of tetracyclic intermediates such as 43 provides a plausible rationale for the reluctance of six-membered ring ethers [46 in Eq. 4] to participate in the catalytic rearrangement and for the lack of reactivity of cyclopen-tenyl substrates [48 in Eq. 5] because of the attendant angle strain, the generation of the tetracyclic intermediate is not favored. (3) Reactions under ethylene atmosphere inhibit dimer formation, since 44 is intercepted with H2CCH2, rather than 41 [19]. 

More recently, Szdntay and co-workers (232) succeeded in performing the enantioselective total synthesis of both natural and unnatural antipodes of yohimbine and -yohimbine. Utilizing second-order asymmetric induction, either the levorotatory or dextrorotatory antipode of key tetracyclic intermediate 400 could be obtained by the use of (—)- or (+)-tartaric acid, respectively. 

The enedione (15), a tetracyclic intermediate on a synthetic route to fusidic acid, has been synthesized from the a-methylene-ketone (16) (Scheme 2). The first step, involving a Diels-Alder reaction with a substituted acrylate (17), provides a new versatile annelation procedure. Further modification of (15) by a route worked out on model systems (see Vol. 4, p. 318) afforded the tetracyclic enone (24) with the desired trans-syn-trans geometry (Scheme 3). This compound (24) has also been prepared by degradation of fusidic acid. Attempts to introduce the C-11 oxygen function necessary for the synthesis of fusidic acid have not been very... 

Fukuyama and Yang (49) developed a highly efficient synthesis of the tetracyclic intermediate 241, used in a total synthesis of mitomycin A (Scheme 9.49). The required azide 240 was produced from 239 in several steps. Upon heating in refluxing toluene, the azide 240 underwent smooth intramolecular cycloaddition with the unsaturated lactone followed by extrusion of nitrogen to give aziridine 241 in 85% yield. 

In the synthesis of the marine neurotoxin hemibrevetoxin B 121, dienetriol 119 was used as an RCM substrate for elaboration of the seven-membered A ring in 121 (Scheme 21). While catalyst B was ineffective in this case, the ring closure occurred smoothly with catalyst G providing the tetracyclic intermediate 120 in high yield. 

A similar procedure has been applied to the preparation of tetracyclic intermediates having the Bruceantin tetrahydrofuran ring . The enolic -ketoesters are isolated with excellent yields (85-95%) (equation 76). 

Acetals are acid sensitive but alkaline stable because their hydrolysis requires activation of the oxygen atom by protonation or coordination with a Lewis acid. An ingenious way of differentiating two 2-methoxytetrahydroluran moieties during a synthesis of bilobalide [91] is to treat the tetracyclic intermediate with potassium hydroxide. Expulsion of a methoxide ion is triggered by attack of the y-lactone ring five carbons away. 

An even more complex series of bond formation and cleavage attends the construction of a secodine precursor for tabersonine [95], The initial tetracyclic intermediate provides two 3-carbon links between the two nitrogen atoms and therefore reaction pathways for skeletal reorganization. 

The first total synthesis of morphine [115] involves hydration of a tetracyclic intermediate. The attack of water from the more hindered face of the double bond could hardly have been predicted. However, the donor nitrogen atom of the molecule may have been responsible for the protonation at C-7 in favor of C-6 via a polarity alternation mechanism. 

The tandem Michad-Mannich reactions serve to assemble a tetracyclic intermediate with the aspidosperma alkaloid skeleton from 3-indoleacetyl chloride in one step [138]. 

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... 

Another approach for effecting the construction of the crinane ring system involved the photocyclization of bromophenolic compounds. For example, irradiation of 418 in 50% aqueous ethanol in the presence of sodium hydroxide followed by O-acetylation produced directly the tetracyclic intermediate 417, albeit in less than 4% yield 195). Saponification of the acetate function afforded an intermediate in a previous synthesis 176) of ( )-oxomaritidine (416). 

In the first attempt the tetracyclic intermediate (33) was prepared from 3,4-methylenedioxy-ta-nitrostyrene upon Diels-Alder addition of butadiene followed by zinc and hydrochloric acid reduction to an amine eventually converted into 33 by formaldehyde and hydrochloric acid. All other experiments, designed to anticipate the addition of a C6 diene (in order to introduce at once also the C2 carbon unit for ring D formation) or of a four-carbon diene with different functionality, failed. The structure of 33 is based on spectroscopic data, on considerations on the accepted stereochemical courses of this type of... 

The synthesis of the tetracyclic intermediate 49 was therefore studied in the hope that it might further cyclize to the desired lycorine skeleton. Birch reduction of o,p-dimethoxyphenethylamine led to the amine 50 which was converted into 51, giving rise in turn upon hydrolysis to 49. Its structure rests on physical data. Ordinary methods for nitro group reduction seemed to also destroy the 289-nm chromophore, but hydrogen transfer (a-phellandrene and Pd/C) gave a product which analyzed for the product of nitro reduction to amine in 49, the mass spectrometric data also being in agreement. The product was, however, not affected by diazotization, and, on the basis of spectral data, was... 

The development of sophisticated methods for tritium labeling made possible experiments which allow a rather precise description of the operations of the biosynthetic process leading (a) from the above-mentioned amino acids to the C1B intermediate O-methylnorbelladine (343) (b) from the latter to the tetracyclic intermediates norpluviine (10), noroxomaritidine (275), and narwedine (149) and (c) from the three latter alkaloids to the products of their metabolism. 

Decomplexation of the lA3,3A3-diphosphete n-ligand of iron complex 41 by C2CI6 results in a 1,3—> 1,2-isomerization, most probably via a tetracyclic intermediate and the formation of the P-dichloro-l -dihydro-l A3,2A3-diphos-phete derivative lb (Scheme 11) <1996S265>. 

Various intramolecular aryl radical reactions of pyridine derivatives have been developed <2004COR757, 2001J(P 1 )2885>. An early example of this type is found in a short synthesis of camptothecin 195. The tetracyclic intermediate 197 was cyclized by a free radical reaction to afford the natural product (Equation 106) <1994TL5331>. 

The photo-cycloaddition of ethylene to 3-alkoxy chromones such as 315 has been applied to the synthesis of marine sesquiterpene filiformin and congeners (Scheme 43) <1996JOC4391>. Tandem [2+2] 7i-photo-cycloaddi-tion and y-hydrogen abstraction provided tetracyclic intermediate 316 which was converted to terpene 317 by subsequent oxetane ring reduction and acid-catalyzed rearrangement. 

In the total synthesis of (-)-morphine, the pivotal tetracyclic intermediate was generated as depicted below. Thus, this core structure was synthesized by reduction of the enone to afford an allylic alcohol, which was then briefly exposed to BBr, to give the desired skeleton in 64% yield <02JA12416>. 

Finally, a thia Diels-Alder reaction representing a less common cycloaddition type in natural product synthesis shall be discussed. Thus, Vedejs et al. have included such a cycloaddition into an elegant strategy aimed at the synthesis of macrocyclic [ll]-cytochalasans such as zygosporin E 7-76 [536-538]. Thus, release of the thioaldehyde 7-73 from its phenacyl sulfide precursor in the presence of the silyloxydiene 7-74 yielded 7-75 as 2 1 mixture with its C20 epimer. Fortunately, equilibration of this mixture raised the ratio up to 10 1. Several subsequent steps yielded the tetracyclic intermediate 7-77 cleavage of its thioether moiety then liberated the 11-membered macrocycle present e.g. in zygosporin E 7-76 (Fig. 7-16). 

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