Terpene synthesis

The last group of reactions uses ring opening of carbonyl or 1-hydroxyalkyl substituted cyclopropanes, which operate as a -synthons. d -Synthons, e.g. hydroxide or halides, yield 1,4-disubstituted products (E. Wenkert, 1970 A). (1-Hydroxyalkyl)- and (1-haloalkyl)-cyclopropanes are rearranged to homoallylic halides, e.g. in Julia s method of terpene synthesis (M. Julia, 1961, 1974 S.F. Brady, I968 J.P. McCormick, 1975). 

Bromomethyl)- or (hydroxymethyl)cycIopropane derivatives undergo acid-catalyzed homoallyiic rearrangements to yield trans-olefins (J.P. McCormick, 1975 S.F. Brady, 1968 M. Julia, 1974). This rearrangement is the basis of Julia s terpene synthesis (see. p. 70). 

Since GAs as diterpenes share many intermediates in the biosynthetic steps leading to other terpenoids, eg, cytokinins, ABA, sterols, and carotenoids, inhibitors of the mevalonate (MVA) pathway of terpene synthesis also inhibit GA synthesis (57). Biosynthesis of GAs progresses in three stages, ie, formation of / Akaurene from MVA, oxidation of /-kaurene to GA 2" hyde, and further oxidation of the GA22-aldehyde to form the different GAs more than 70 different GAs have been identified. 

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. 

Microbial reduction of prochiral cyclopentane- and cyclohexane-1,3-diones was extensively studied during the 1960 s in connection with steroid total synthesis. Kieslich, Djerassi, and their coworkers reported the reduction of 2,2-dimethylcyclohexane-l,3-dione with Kloeokera magna ATCC 20109, and obtained (S)-3-hydroxy-2,2-dimethylcyclohexanone. We found that the reduction of the 1,3-diketone can also be effected with conventional baker s yeast, and secured the hydroxy ketone of 98-99% ee as determined by an HPLC analysis of the corresponding (S)-a-methoxy-a-trifluoromethylphenylacetate (MTPA ester).(S)-3-Hydroxy-2,2-dimethy1cyc1ohexanone has been proved to be a versatile chiral non-racemic building block in terpene synthesis as shown in Figure 1. 

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... 

As is indicated in Fig. 22-3, the same intermediate cation can yield a variety of end products. For example, pure geranyl diphosphate pinene cyclase catalyzes formation of several other terpenes in addition to a-pinene.89 Another aspect of terpene synthesis is that insects may convert a plant terpene into new compounds for their own use. For example, myrcene, which is present in pine trees, is converted by bark beetles to ipsenol (Fig. 22-3), a compound that acts as an aggregation pheromone.90... 

Dimerization of isoprene, if carried out regioselectively to give the head-to-tail dimer 97, would be useful for terpene synthesis. So far few reports on successful regioselective dimerization of isoprene have been given, and this remains an unsolved problem. 2,6-Dimethyl-1,3,6-octatriene (97), the head-to-tail dimer, can be prepared with high selectivity using Zr [36], Ni [37,38] and Pd [39] catalysts. However, selective functionalization of this dimer to the terpene alcohol 98 is not easy. 

As an example of carbometallation, the 1,4-carbosilylation product 218 is obtained by the reaction of dienes, disilanes and acid chlorides of aromatic and a,/i-unsaturatcd acids at 80 °C. The phenylpalladium 216 is formed by the oxidative addition of benzoyl chloride, followed by facile decarbonylation at 80 °C, and reacts with butadiene to generate the benzyl-7i-allylic complex 217. Then, transmetallation with the disilane and reductive elimination afford 4-silyl-2-butenylbenzene 218 [92], Regioselective carbomagnesation of isoprene with allylic magnesium bromide 219 catalysed by Cp2TiCl2 gives 220, which is useful for terpene synthesis [93,94],... 

Soft corals have been shown to release terpene chemicals into the water column.210 Their interactions with other invertebrates,211 or with algae122-212-213 have been monitored. Some algal species cause localized tissue necrosis, or reduce terpene levels, in adjacent soft corals 122 213 however, stressing soft corals by transplanting them to new sites stimulates terpene synthesis.199 Some species of algae, notably the chemically protected Halimeda spp., grow in abundance at the base of soft coral colonies, but the soft coral chemical defense does not play a role in maintaining this association.214... 

A student was studying terpene synthesis, and she wanted to make the compound shown here. First she converted... 

S)-3-Hydroxy-2,2-dimethylcyclohexanone as a Building Block. Reduction of 2,2-dimethylcyclohexane-l,3-dione (24) with baker s yeast gives (S)-3-hydroxy-2,2-dimethylcyclohexanone (25) of 98-99% e.e. 21). This hydroxy ketone 25 was proved to be a versatile chiral building block in terpene synthesis (3). 

A broad array of organic reactions displays bifnrcating PESs. An extensive review of examples was authored by Houk. Tantillo has shown examples of bifurcations in terpene synthesis, and a few examples have been found in substitution chemistry. The importance of dynamics cannot be overstated for reactions on bifurcating surfaces and clearly additional research needs to be done, especially to aid in creating more robust predictive models. 

A relevant extension of the ring opening of epoxides with a titanium salt can be seen in the concomitant scission of the C-C bond of cyclobutane illustrated in Eqs (285) and (286) [648]. Choice of each diastereoisomer enables highly selective construction of the trisubstituted double bond which finds application in terpene synthesis. The tandem cleavage of the C-O and C-C bonds was similarly feasible in the combination of oxetane and cyclobutane as illustrated in the stereoselective synthesis of a homoallyl alcohol (Eq. 287) [648]. 

Whereas the thio-2,3-Wittig reaction is well recognized and used, particularly in terpene synthesis e.g. Scheme 49), the amino counterpart is less studied. 

A similar rearrangement occurs with phenylhalocarbene adducts of alkylsilyl ketene acetals 16/ and with siloxycyclopropanes obtained by addition of other carbenoids. ° The method is useful in terpene synthesis. ° ° ... 

There are three reviews of the use of isoprene in terpene synthesis, one of which is in Japanese. There is also an excellent review of the industrial synthesis of isoprene from isobutylene and formaldehyde which also mentions other isoprene syntheses. ... 

The petrochemical building blocks used for terpene synthesis are all readily available bulk feedstocks and are therefore free from concerns regarding availability and security of supply. 

Figure 2.47 shows our retrosynthetic analysis of O-methyl pisiferic acid (57).126 The starting material is the same (.S )-3-hydroxy ketone A as employed by us for the synthesis of glycinoeclepin A (see Figure 2.36). The ready availability of A by reduction of 2,2-dimethyl-1,3-cyclohexanedione with baker s yeast makes A a versatile starting material in terpene synthesis.104 Conversion of A to two diastereomeric compounds B and C enables the synthesis of both (+)-57 and (—)-57. ...

Tse-Lok Ho, Carbocycle Construction in Terpene Synthesis, VCH, Weinheim, 1988, ISBN 0-89573-279-3. 

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