Cyclization of terpenes

Carter-Franklin JN, Parrish JD, Tschirret-Guth RA, Little RD, Butler A (2003) Vanadium Haloperoxidase-Catalyzed Bromination and Cyclization of Terpenes. J Am Chem Soc 125 3688... 

Cyclization of terpene derivatives. Japanese chemists have devised a method for biomimetic conversion of acyclic terpene allylic phosphates into cyclic compounds based on organoaluminum compounds. Of several reagents tested of this type, tetraisobutyidialuminoxane (1) proved to be most selective. Two of the cyclizations realized with 1 are formulated in equations (I) and,(II). 

The diastereosclectivity in this particular cyclization was exploited in a number of direct syntheses of terpenes from the eudesmane type (see Table 2). By this technique tricyclic compounds can be synthesized generating three new asymmetric centers55. 

Phosphonate-based cyclization has been increasingly used in macrocyclic terpene synthesis. In a synthesis of the marine cembranoid (+)-desepoxyasperidiol the cyclization of the phosphonate (192) was attempted under a variety of conditions without success. 

The cyclization of epoxyolefins has been the subject of intense study ever since the discovery that these reactions are involved in the biosynthesis of many terpenes, including cholesterol. An early example is the cyclization of geraniolene oxide 25 using BF3Et20 to give a mixture of acyclic and cyclic products (Scheme 6) [57,58]. 

Polyene cyclization in terpene and steroid synthesis is critically dependent on the terminator in order to generate useful functionalities for further modification of the products. Allyl- and propargylsilanes have proven their value in facilitation of the cyclization and generation of an exocyclic methylene and allene, respectively. Thus, a concise approach to albicanyl acetate [126] and the rapid construction of a tetracyclic precursor of steroids [127] are sufficient to demonstrate the concept. Again, a comparison of the substrates with a silyl group with those having a simple alkyl moiety is very enlightening. 

The biomimetic-type cyclization of polyisoprenoids is an important industrial process for terpene synthesis. In most cases, a large excess of coned. H SO and SnCl. has been employed For example, ionone, a precursor of vitamin A, is prepared by coned. H2SO4 catalyzed cyclization of pseudoionone. The disadvantage of this process is undoubtedly the requirement of bases to neutralize the large excess of acid. The EGA method offers a promising alternative for this purpose. Thus, Electrolysis of 15 and 17 in a ClCHjCH Cl—LiClO —Et NClO — (Pt) system provides 16 and 18, respectively in reasonable yields and the neutralization of the reaction solution can be performed simply by addition of a small amount of pyridine... 

Products from such reactions have been employed in the synthesis of terpenes via intramolecular Diels-Alder cyclizations (94-96). If the bulk of the carbonyl reagent is increased by inclusion of a large adjacent protecting group, much improved regioselectivity toward terminal attack is acheived (97,98). A complementary approach has been adopted by Oppolzer who... 

Catalytic transformations of terpenes are well documented [213-215], comprising a wide variety of reactions hydrogenation, dehydrogenation, oxidation, hy-droformylation, carbonylation, hydration, isomerization and rearrangement, and cyclization. 

This reaction was used for a synthesis of the seven-membered cyclic terpene karahan-aenol (3) from the methyl ether (2) of geranioi by an electrophilic cyclization of an allylsilane. ... 

Terpene synthases, also known as terpene cyclases because most of their products are cyclic, utilize a carbocationic reaction mechanism very similar to that employed by the prenyltransferases. Numerous experiments with inhibitors, substrate analogues and chemical model systems (Croteau, 1987 Cane, 1990, 1998) have revealed that the reaction usually begins with the divalent metal ion-assisted cleavage of the diphosphate moiety (Fig. 5.6). The resulting allylic carbocation may then cyclize by addition of the resonance-stabilized cationic centre to one of the other carbon-carbon double bonds in the substrate. The cyclization is followed by a series of rearrangements that may include hydride shifts, alkyl shifts, deprotonation, reprotonation and additional cyclizations, all mediated through enzyme-bound carbocationic intermed iates. The reaction cascade terminates by deprotonation of the cation to an olefin or capture by a nucleophile, such as water. Since the native substrates of terpene synthases are all configured with trans (E) double bonds, they are unable to cyclize directly to many of the carbon skeletons found in nature. In such cases, the cyclization process is preceded by isomerization of the initial carbocation to an intermediate capable of cyclization. 

Figure 5.6 Proposed mechanism for the cyclization of geranyl diphosphate to sabinene and sabinene hydrate under catalysis by monoterpene synthases the reaction begins with the hydrolysis of the diphosphate moiety to generate a resonance-stabilized carbocation (1) the carbocation then isomerizes to an intermediate capable of cyclization by return of the diphosphate (2) and rotation around a single bond (3) after a second diphosphate hydrolysis (4) the resulting carbocation undergoes a cyclization (5) a hydride shift (6) and a second cyclization (7) before the reaction terminates by deprotonation (8) or capture of the cation by water (9). Cyclizations, hydride shifts and a variety of other rearrangements of carbocationic intermediates are a characteristic of the mechanisms of terpene synthases. No known terpene synthase actually produces both sabinene and sabinene hydrate these are shown to indicate the possibilities for reaction termination. PP indicates a diphosphate moiety.

Figure 5.7 Proposed mechanism for the cyclization of geranylgeranyl diphosphate (GGPP) to the diterpene copalyl diphosphate, an example of terpene synthase-catalysed cyclization initiated by double-bond protonation, rather than by hydrolysis of the diphosphate ester. PP indicates a diphosphate moiety.

Booker-Milburn et al. used the oxidative ring-expansion/cycHzation strategy they previously developed as an efficient way to stereoselectively build the bicyclo [5.3.0] framework of terpene-based natural products. For example, reaction of substrate 258 with iron (in) nitrate in DMF led to the formation of keto-alcohol 260 in fair yield as a single diastereomer (Scheme 76) [214]. Reduction of the final radical coming from the cyclization of 259 by 1,4-cyclohexadiene was smooth and the overall reaction proceeded without protection of the tertiary alcohol, opening the way to the total synthesis of pogostol and kessane. 

The one-pot epoxidation/cyclization of unsaturated terpene alcohols, for example linalool and a-terpineol, to mono- and bicyclic derivatives also required the catalysis of large-pore Ti,Al-P (Scheme 18.10) [93, 107]. 

Tetracyclic terpene from Eocene Messel shale (Germany) can be also synthesized by using the LBA-induced enantioselective cyclization of 3-homofarnesyltoluene as a key step (eq 16). 

The terpene menthol is widely used in organic synthesis, and serves as a chiral auxiliary for several asymmetric reactions [39]. (-)-Menthol 53 could be produced in one step from isopulegol 55 by hydrogenation of the carbon-carbon double bond, and the latter compound could be prepared by a Lewis acid-induced carbonyl-ene reaction [40] of f-(y )-citronellal 54. Nakatani and Kawashima examined that the ene cyclization of citronellal to isopulegol with several Lewis acids in benzene (Sch. 22) [41]. The zinc reagents were far superior to other Lewis acids for obtaining... 

An intramolecular cyclization of -hydroxysulfoxides effected by At-chloro-succinimide, A bromosuccinimide, or sulfuryl chloride gives 1,2-oxathietane 2-oxides, for example, 496, via a sulfoxonium salt. These cyclic sulfoxonium intermediates have been suggested in the conversion of /3-hydroxy-sulfoxides to /3-chlorosulfones, and to a,j3-unsaturated sulfones, in the conversion of /3-ethoxycarbonylsulfoxides to alkenes and of /3-hydroxysulfides to /3-hydroxysulfoxides, and in the conversion of 3-hydroxy- 3-vinylsulfoxides (e.g., 497) to useful terpene building blocks. The yields of the products from 497 vary somewhat depending on the stereochemistry about the two chiral centers. The more highly substituted 1,2-oxathietane 2-oxides are the most stable, because of... 

A variety of natural products have been synthesized via application of reductive pinacolic couplings. An early example is the cyclization of the keto aldehyde (51) to the alkene (52 equation 89) a precursor to the terpene, cuparene (18).A modified McMurry procedure provides a novel route to steroids such as estrone methyl ether, via chemoselective cyclization of the keto aldehyde (53 equation 90). The... 

The cyclization of polyolefin terpenes occurs readily once they have been converted into terminal epoxides. The tetracyclic diterpenes 3a- and 3/S-kaurene have been prepared enzymically from chemically synthesized (/ ,5)-14,15-oxidogeranylgeranyl pyrophosphate (42), providing another example of this cyclization. Trimethyl-aluminium can promote the non-enzymic cyclization of the diethyl ester of neryl phosphate (43), presumably a carbonium ion, to 4-t-butyI-l-methylcyclohexene. ... 

Cationic cyclizations of polyolefins to oligocyclic terpenes such as that catalyzed by squalene-cyclases in the biosynthesis of steroids have long fascinated chem-... 

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