Cation cyclizations

The following acid-catalyzed cyclizations leading to steroid hormone precursors exemplify some important facts an acetylenic bond is less nucleophilic than an olelinic bond acetylenic bonds tend to form cyclopentane rather than cyclohexane derivatives, if there is a choice in proton-catalyzed olefin cyclizations the thermodynamically most stable Irons connection of cyclohexane rings is obtained selectively electroneutral nucleophilic agents such as ethylene carbonate can be used to terminate the cationic cyclization process forming stable enol derivatives which can be hydrolyzed to carbonyl compounds without this nucleophile and with trifluoroacetic acid the corresponding enol ester may be obtained (M.B. Gravestock, 1978, A,B P.E. Peterson, 1969). 

Ring closures based upon electrophilic processes are uncommon. The cationic cyclization in Scheme 29a proceeds via transformation of the commencing oxime into a nitrilium ion (81CC568). Schemes 29b (82CB706) and 29c (82CB714) exemplify the application of intramolecular acylation. 

In general, fluorinated sulfonic acids can be used as eatalysts for various cationic cyclizations Typical examples are the triflic acid catalysis in the double cyclization of A,VV-dibenzylpropynylamine [82] (equation 30) and the fluorosulfonic acid catalyzed condensation of phenylacetaldehyde [<5J] (equation 31)... 

Figure 27.14 MECHANISM Mechanism of the conversion of 2,3-oxidosquaJene to lanosterol. Four cationic cyclizations are followed by four rearrangements and a final loss of H+ from C9. The steroid numbering system is used for referring to specific positions in the intermediates (Section 27.6). Individual steps are explained in the text.

Step 3 of Figure 27.14 Third Cyclization The third cationic cyclization is somewhat unusual because it occurs with non-Markovnikov regiochemistry and gives a secondary cation at C13 rather than the alternative tertiary cation at C14. There is growing evidence, however, that the tertiary carbocation may in fact be formed initially and that the secondary cation arises by subsequent rearrangement. The secondary cation is probably stabilized in the enzyme pocket by the proximity of an electron-rich aromatic ring. 

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. 

Utilization of a similar [Sc(OTf)3-promoted)] approach by Overman on the ger-anylgeraniol-derived cyclization substrate 98 provided the desired tetracyclization product 99, in which the terminator of the cationic cyclization is an arene group. Compound 99 is then transformed into the kinesin motor protein inhibitor adocia-sulfate 1 (Scheme 8.27) [47]. 

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. 

A retrosynthetic analysis corresponding to the synthesis in Scheme 13.28 is given in Scheme 13.27. The striking feature of this synthesis is the structural simplicity of the key intermediate 27-IV. A synthesis according to this scheme generates the tricyclic skeleton in a single step from a monocyclic intermediate. The disconnection 27-III-27-IV corresponds to a cationic cyclization of the highly symmetric allylic cation 27-IVa. 

No issues of stereochemistry arise until the carbon skeleton is formed, at which point all of the stereocenters are in the proper relative relationship. The structures of the successive intermediates, assuming a stepwise mechanism for the cationic cyclization, are shown below. 

Evidently, these or closely related intermediates are accessible and reactive, since the synthesis was successfully achieved as outlined in Scheme 13.28. In addition to the key cationic cyclization in Step D, interesting transformations were carried out in Step E, where a bridgehead tertiary alcohol was reductively removed, and in Step F, where a methylene group, which was eventually reintroduced, had to be removed. The endocyclic double bond, which is strained because of its bridgehead location, was isomerized to the exocyclic position and then cleaved with Ru04/I04. The enolate of the ketone was then used to introduce the C(12) methyl group in Steps F-3 and F-4. 

Scheme 1.30. Cationic cyclization/aziridinium ion formation/nucleophilic ring-opening procedure for the synthesis of pyrrolidines.

Scheme 3.5. Rare example of a domino radical ring expansion/cationic cyclization procedure.

PET reactions [2] can be considered as versatile methods for generating radical cations from electron-rich olefins and aromatic compounds [3], which then can undergo an intramolecular cationic cyclization. Niwa and coworkers [4] reported on a photochemical reaction of l,l-diphenyl-l, -alkadienes in the presence of phenanthrene (Phen) and 1,4-dicyanobenzene (DCNB) as sensitizer and electron acceptor to construct 5/6/6- and 6/6/6-fused ring systems with high stereoselectivity. 

The second example was reported by Baldwin, Bulger and coworkers, and features the oxidation of a phenol initiating a cationic cyclization sequence to afford the natural product ( )-aculeatin D (7-12) [5], Thus, when the dihydroxyketone 7-8 is treated with PhI(02CCF3)2, a formal two-electron oxidation of the phenol moiety takes place, triggering a twofold cationic-based cyclization to furnish the desired ( )-aculeatin D [( )-7-12] in 19% yield, together with 43% of the isomer ( )-7-ll and the side product ( )-7-10 via the cation 7-9 (Scheme 7.3). 

The present method is successful with a wide variety of ketones (see Table). Cyclic ketones (entries 1-4, 8) produce benzoannelated products in excellent overall yields. There is no need to purify the intermediate both the nucleophilic addition of methallylmagnesium chloride and the aromatic cyclization take place cleanly. Acyclic ketones (entries 5-7) also provide high yields of benzoannelated product. Aromatic ketones are particularly interesting substrates for this reaction since they provide substituted biphenyls, which are potentially useful materials for liquid crystal synthesis and whose preparation through classical methodology is often not straightforward. The conditions for the cationic cyclization step can be modified to accommodate acid-sensitive functionality. For example, cyclization of 3 to 4, the latter a precursor for 3-methyl-8,14-dehydromorphinan, was accomplished in 77% yield by treatment of 3 at... 

The formation of a number of spiro compounds by cationic cyclization has been reported. Formic acid transforms the ketal 132 into 133 in 40% yield (equation 67)77 and the alcohol 134 into the formate 135 (35%) (equation 68)78. The alcohols 136 and 138 yield the spiro compounds 137 (45-50%) (equation 69)79 and 139 (25%) (equation 70)80, respectively. Pallescensin A (141) is produced in 84% yield by the twofold cyclization of the furan derivative 140, induced by boron trifluoride (equation 71)81. 

Anodic oxidation reactions have been utilized to reverse the polarity of enol ethers and to initiate radical cation cyclizations. As shown below, the ketene acetal 97 is oxidized on a... 

Fig. 18 Crossings of in-plane and out-of-plane frontier MOs in radical-anionic Bergman and C1C5 cyclizations (crossings for photochemical, dianionic and radical-cationic cyclizations involve the same MOs but differ in the number of electrons).

Cationic cyclization. A key step in the synthesis of the diterpenes cafestol5 and atractyligenin4 involves a novel cation cyclization of bicyclic cyclopropanes to the tetracyclic systems of the diterpenes (equations I and II). Thus treatment of 1 with a slight excess of triflic anhydride and 2,6-lutidine effects cyclization to the rather unstable pentacycle 2 with the kaurene system. The related conversion of 3 to 4 can be effected with triflic anhydride and 2,6-di-r-butyl-4-methylpyridine in 1-nitropropane. 

Alternative, also stereoselective, routes to allenic steroids take advantage of cationic cyclization reactions [108] or [2,3]-sigmatropic rearrangements [109]. For example, the allenic Michael acceptor 112 was prepared with 57% chemical yield by reaction of mestranol (111) with diethyl chlorophosphite and was found to inhibit the sterol biosynthesis of the pathogen responsible for Pneumocystis carinii pneumonia (PCP), the most abundant AIDS-related disease (Scheme 18.36) [110]. 

Further examples of catalytic antibodies that are presumed to control rotational entropy are AZ-28, which catalyses an oxy-Cope [3.3]-sigmatropic rearrangement (Appendix entry 13.1) (Braisted and Schultz, 1994 Ulrich et al, 1996) and 2E4, which catalyses a peptide bond isomerization (Appendix entry 13.3) (Gibbs et al., 1992b Liotta et al., 1995). Perhaps the area for the greatest opportunity for abzymes to achieve control of rotational entropy is in the area of cationic cyclization reactions (Li et al., 1997). The achievements of the Lerner group in this area (Appendix entries 15.1-15.4) will be discussed later in this article (Section 6). 

The cationic cyclization of polyenes to give multi-ring carbocyclic compounds with many sterically defined centres is one of the more remarkable examples... 

While cyclopentanes have also been produced by antibody-catalysed cyclization (Appendix entry 15.2) (Li et al., 1996), much the most striking example of cationic cyclization by antibodies is the formation of the decalins [79], [80] and [81] (Fig. 29). The rra/w-decalin epoxide [82] (tu2 100 h at 37°C) was employed as a mixture of two enantiomeric pairs of diastereoisomers as a TSA to raise antibodies, among which HA5-19A4 emerged as the best catalyst for cyclization of substrate [83] (Appendix entry 15.4) (Hasserodt et al., 1997). 

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