Syntheses of terpenoids

Several syntheses of terpenoids are outlined in retrosynthetic form. Suggest a reagent or short reaction sequence that could accomplish each lettered transformation in the synthetic direction. The structures refer to racemic material. 

Angular alkylations of fused-ring ketones are an important step in syntheses of terpenoids, steroids and related natural products. The steric course of these alkylations has therefore been the subject of several systematic investigations and has been reviewedl 3 71. Alkylation of the lithium enolate 38 (R = H) derived from octahydro-1 (2//)-naphthalenone (1 -decalone) primarily yields the civ-fused octahydro-8a-methyl-l(2F/)-naphthalenone (39, R = H)35,62,79. Due to steric reasons, the lithium enolate 38 (R = CH3), with an angular methyl group, provides the irans-fused product 39 (R = CH3). 

The cyclopropylimine ynoline rearrangement (equation 68) has been exploited by Stevens in alkaloid syntheses. - Wenkert s cyclopropylcarbinyl rearrangement (equation 69) served extremely well in the design of 1,4-dicarbonyl synthons or 3,-y-unsaturated carbonyl compounds which then were expressed in numerous syntheses of terpenoid and alkaloid natural products. Donor-acceptor concepts continue to be express in the applicability of these rearrangements to organic synthesis. 

The asymmetric intramolecular Heck reaction in total syntheses of terpenoids and alkaloids 03CRV2945. 

From the viewpoint of organic synthesis, nature provides us with a number of target molecules, which have novel structures and a variety of biological activities. As already shown in Section II.A, electrochemical oxidation of phenols has been applied successfully to natural products synthesis. Hypervalent (diacyloxyiodo)benzenes have also been proved to be effective for natural products synthesis. Generally, oxidation of o- and p-methoxyphenols in MeOH provides the corresponding o- and p-quinone monoketals, respectively. They are utilized as promising synthons for natural products and related bioactive compounds, as demonstrated by Swenton . Recently, these quinone monoketals have been utilized for syntheses of terpenoids, neolignans, anthraquinones, alkaloids and related compounds. 

Still another application of carbon monoxide consists of a palladium-ene process followed by carbonylationf f (Scheme 59). Applications to synthesis have been described by Oppolzer and co-woikers in the preparation of alkaloid (+)-3-isorauniticine.f Cases of triple bonds reacting intramolecularly are also reported by Oppolzer and coworkers in the syntheses of terpenoid pentalenolactone E methyl estert" and of tricyclic terpenoid hirsutene.t ... 

Despite generally moderate product yields, these reactions have been applied to a number of noteworthy syntheses of natural and unnatural organic compounds of considerable complexity. The synthesis of tetracychc[5.5.5.5]fenestranes by Keese and co-workerst - (Scheme 29) is particularly noteworthy, and it persuasively demonstrates the synthetic utility of the cyclic acylpalladation methodology. A series of elegant syntheses of terpenoids by Oppolzer and co-woikersf f" are discussed later in this section. 

H. Frauenrath Lewis Acid Promoted Rearrangements of Vinyl Actals - Basics and Applications H. Hagiwara, A. Okano, T. Akama and H. Uda Lewis Acid Promoted Sequential Multifold Michael Reactions and Application to Syntheses of Terpenoids ... 

Several papers have concerned syntheses of terpenoids. The skeleton of sesquiterpenes such as eremophilane has been constructed by Naf etal. from the dienone (45), and Taber and Gunn have described a synthesis of ( )-torreyol (47) as outlined from the enone (46). Wilson and Mao have provided a further paper on their use of the intramolecular Diels-Alder reaction in the synthesis of diterpenes. 

Thus (Z)-(trimethylsilyloxy)vinyllithium (1) is an excellent reagent for the preparation of building blocks such as (4), (5a), and (5b) (eq 3), which are useful for short convergent syntheses of terpenoid compounds (eqs 4 and 5). ... 

Aside from Coreys phenylmenthyl propanoate 424, several chiral enolates have been utilized for Michael additions with substantial degrees of diastereoselectiv-ity. Yamaguchi s group developed a series of chiral amide enolates 436 and studied the conjugate addition to crotonates [210]. Another remarkable early contribution came from Oppolzer and coworkers who used dienolate 437 for diastereoselec-tive consecutive additions to cyclopentenone and allylation [211]. The auxiliaries 436 and 437 served for total syntheses of terpenoid natural products. Diastereos-elective Michael additions were also achieved by means of imidazolidinone-based lithium enolate 438 [212] - another showcase of the efficiency of imidazolidinone 118 [54] (Scheme 4.94). 

Labeled phosphonoacetates have found wide application in the carbon-13 and carbon-14 syntheses of terpenoids such as [2- C]geranylgeraniol ° , (13 )-[ C] and [ CJretinoic acid ° ° [ CJinsect juvenile hormone and [ CJpseudomonic acid as... 

Uses ndReactions. a-Pinene (8) is useful for synthesizing a wide variety of terpenoids. Hydration to pine oil, acid-catalyzed isomerization to camphene, thermal isomerization to ocimene and aHoocimene, and polymerization to terpene resins are some of its direct uses. Manufacture of linalool, nerol, and geraniol has become an economically important use of a-pinene. 

By combining the benefits of Pd(II) and Ti(III) chemistry, syntheses of y-dioxygenated terpenoids, such as rostratone could be readily accessed (Scheme 27) [113]. 

Epoxides (oxirans) and 1,2-diols can also be looked upon as disguised ketones capable of being unmasked by acids. Since its development by Spencer et al49 the idea has been utilized by several other groups who used protic acids in work aimed at syntheses of methyl lambertianate,50 a rare furanoid fatty acid from an Exocarpus species,51 and a terpenoid furan,... 

Terpenoid Synthesis from Isoprene.—Syntheses of the useful synthons (33) and (34) have been reported. The vinyl-oxygen bond of diketen is selectively cleaved by Me3SiCH2MgCl-NiCl2 to yield the synthon (35) which is readily converted into the dicopper dienolate (Vol. 7, p. 14) and prenylated to yield (36 X = C02H) after hydrolytic work-up and desilylation (36 X = C02H) yields... 

The format of these Reports has remained relatively constant from year to year to facilitate the location of subject matter. However, this year two changes have occurred. Firstly, as an experiment, the information on biosynthesis is contained within the chapters dealing with the individual group of terpenoids rather than as a separate chapter. Secondly, the steroid section has been recast to minimize overlap. A report of the application of physical methods to steroids forms one chapter whilst steroid reactions and partial syntheses are reported in the second. Total synthesis will be reviewed biennially. 

The alkylation of cyclopentanoid enolate groups, which are part of polycyclic systems, is a common step in natural product syntheses, particularly in the synthesis of terpenoids and steroids. A high degree of stereoselectivity is usually encountered in such reactions, for example, in the preparation of the bicyclic compounds 17-2054 59. Steric, rather than electronic, control elements determine the diastereoselectivity. 

Dienolate alkylations have been applied successfully in syntheses of steroids and terpenoids. A highly diastereoselective application81 is the preparation of the phenanthrene derivative 35. 

Methyl-l,3-cyclohexanedione has been used as starting material for the syntheses of several polycyclic compounds for projected syntheses of steroids and terpenoids.11-13 It has also been used to prepare l -diketo-Sa-methyl-l a-octahydro-naphthalene.3 4- 16... 

S. Akutagawa, Practical Asymmetric Syntheses of (—)-Menthol and Related Terpenoids, in R. Noyori, T. Hiraoka, K. Mori, S. Murahashi, T. Onoda, K. Suzuki, and O. Yonemitsu, eds., Organic Synthesis in Japan Past, Present, and Future, p. 75, Tokyo Kagaku Dozin, Tokyo, 1992. 

Studies of terpenoid chemistry have also in volved syntheses. Several of the complex sesquiterpenoid structures have been confirmed or. in some cases, correctly established through synthesis. Many elegant new general synthetic methods have been developed asaresult of attempts to synthesize terpenoids. The chemistry of terpenoids present a continually growing area of chemical research, perhaps the equal of any in complexity, subtlety, and variety. 

Warzecha, K.-D., Xing, X. and Demufh, M. (1997) Cydization of terpenoid polyalkenes via photo-induced electron transfer — versatile single-step syntheses of mono- and polycycles. Pure Applied Chemistry, 69, 109-112. 

The work is based on the idea of W. Reppe of applying the acetylene chemistry developed by him to the synthesis of terpenes. The 2-methylbutyn-2-ol (40, see page 14) formed by the addition of acetylene to acetone (39) was intended, as the C5 building block, as the starting point for terpene syntheses. A C5 building block appeared to be small enough to ensure the required flexibility for terpenoid vitamins and carotenoids and the extensive area of terpenoid flavors and fragrances. 

A further set of terpenoid lactones of the carane type were synthesized starting from (+)-3-carene (87). Three of the semisynthetic lactones 88-90 were active as antifeedants, although full data are not yet published.55... 

Terpenoid Synthesis from Isoprene.—Interest continues in new syntheses of iso-prene and its derivatives the dioxan (37) is obtained108 in good yield by the Prins reaction of methylallyl chloride with formaldehyde (cf. Vol. 5, p. 8) free-radical addition of isopropyl alcohol to vinyl acetate yields compound (38) which gives isoprene by acid-catalysed reaction over alumina.109 (Z)-2-Methylbut-2-en-l-ol and dimethylallyl alcohol are readily available from frans-crotyl alcohol.110... 

The following syntheses of natural products were based on the use of substo-ichiometric quantities of Cp2TiCl to catalyze different cyclization processes initiated by homolytic epoxide opening. They have been classified according to the type of cyclization process employed. Section 4.4 has been reserved for the Cp2TiCl-catalyzed radical cyclization of 2,3-oxidosqualene due to the biological importance of this terpenoid and steroid precursor. 

This is a mild, simple and practical procedure for 1,4-addition of an aldehyde to methyl vinyl ketone, without converting the aldehyde into an enamine or a silyl enol ether. The products, substituted 5-ketoaldehydes, are important compounds, especially for the preparation of substituted 2-cyclohexen-1-one derivatives, which have been versatile starting materials for syntheses of natural products such as terpenoids. These 5-ketoaldehydes have been prepared previously by the 1,4-addition of modified aldehydes, i.e., morpholinoenamines of aldehydes,trimethylsilyl enol ethers of aldehydes in the presence of a Lewis acid, or diethylallylamine in the presence of a catalytic amount of a Ru complex, to methyl vinyl ketones. 

The use of anisoles (22) as synthetic equivalents to cyclohex-2-enones (Scheme 3) has been widespread since the original observations of Birch, and the literature is replete with examples over the past five decades, e.g. in the syntheses of steroids, terpenoids and alkaloids. The most thorough studies have been carried out within the context of the conversion of estrone derivatives to 19-norandrostane and pregnane derivatives and are instructive for the selection of reagents and reaction parameters for reductions of this general type. ... 

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