Synthesis of hydroazulene

A stereoselective convergent synthesis of hydroazulenes 538 was also based on a tandem intermolecular cyclopropanation-Cope rearrangement sequence with predictable stereocontrol (equation 211)262. 

Removal of the 0-substituted Fp group can be achieved by conversion into the cationic alkene-Fp complex using Ph3CPF6 and subsequent treatment with iodide, bromide or acetonitrile. Oxidative cleavage with ceric ammonium nitrate in methanol provides the methyl esters via carbon monoxide insertion followed by demetallation. The [3 + 2]-cydoaddition has been successfully applied to the synthesis of hydroazulenes (Scheme 1.11) [34]. This remarkable reaction takes advantage of the specific nucleophilic and electrophilic properties of V-allyl-, cationic t 5-dienyl-, cationic ri2-alkene- and ti4-diene-iron complexes, respectively. 

As previously described, RCM is a powerful tool for the preparation of useful carbo- and heterocyclic intermediates. Almost all of the recent RCM reactions have been performed homogeneously with well-defined metal carbene complexes as catalysts. An example of the use of a heterogeneous catalyst in RCM is the synthesis of hydroazulenes such as 6 via RCM of highly functionalized diolefins (Eq. 17) catalyzed by CH3Re03/Si0i-Al703 and with heating under reflux at 80 °C [41]. 

A review has recently appeared describing the synthesis of hydroazulene sesquiterpenes through rearrangement of substituted hydronaphthalene precursors, including some syntheses of guaianolides from santonin (1)... 

Uses Solvent for lacquers, resins, emulsionbonding adhesives fragrance in cosmetics building block for synthesis of hydroazulenes prep, of dilongifolylborane (a chiral hydroborating agent)... 

Methylnaphthalene isomerises to 1-methylnaphthalene, with very little dimethylnaphthalene being formed, over various zeolites [93]. Silica gel has been used in the synthesis of hydroazulenes with good yields and selectivity [94]. 

Hydroazulenes. Startg. l,2-epoxy-2-methyl-3-methylenebicyclo[4.4.0]decane distilled slowly at 380-385°/4.5 mm under Ng through a column of sand cis-l-methyl-10-methylenebicyclo[5.3.0]decan-2-one. Y 75%. R. A. Kretdimer and W. J. Frazee, J. Org. Chem. 36, 2855 (1971) synthesis of hydroazulenes, review, s. J. A. Marshall, Synthesis 1972, 517. 

Another example, which takes place in weakly basic conditions, is provided by the key step of the synthesis of aromadendrene (111 accomplished by Biichi and coworkers [4], in which a cw-decalin system (9) rearranges to a hydroazulene system (10) through a process induced by activated AI2O3 (Scheme 7.3). 

The first total synthesis of a racemic dolastane (rac-llO) was apparently published by Pattenden as a short communication 1986 followed in 1988 by a full paper [77, 78]. Pattenden s strategy is based on an intramolecular [2+2]-photocycloaddition/cyclobutane fragmentation to transform the diene 133 into the hydroazulene 136 (Scheme 20). In between the cycloaddition... 

The total synthesis of the natural ( )-l(15),7,9-dolastatrien-14-ol (( )-122) was reported in 1986 by Piers and Friesen (Scheme 21) [80]. The hydroazulene 143 served as key intermediate and the C-ring was annulated by an intramolecular Grignard reaction of the vinyl magnesium ketone 144 to provide the desired dolastane (+)-122 in moderate yield as a single... 

The enantioselective ex-chiral-pool synthesis of the enantiomer of the natural (-i-)-dolasta-l(15),7,9-trien-14-ol (ent-122) was achieved by Mehta and coworkers in 1987 (Scheme 24) [85, 86]. From the hydroazulene 136, the synthesis proceeded analogous to the synthesis of Pattenden (Scheme 20) and provided the dolastane ent-122 as a mixture with the non-natural dolas-tanes 153 and 154. However, in contrast to Pattenden s work, Mehta and... 

The formal total synthesis of racemic guanacastepene (rac-187) from Snider and co-workers (Fig. 20) was submitted six months later than the completed synthesis of Danishefsky s group [116-118]. The shortest sequence developed by the Snider group utilized the sequential cuprate addition/enolate alkylation of 2-methylcyclopent-2-enone 90 previously exploited by Piers, Williams and Danishefsky (Schemes 15 and 31). As outlined in Figs. 19 and 20, the strategies of Danishefsky and Snider are closely related. Both rely on stepwise annulations to build up the tricyclic ring system. They differ only in respect to the particular reactions that converted the monocyclic starting material (90) via bicyclic hydroazulenes (207 vs 227) into the desired tricyclic 5-7-6-system (224). 

Ether cleavage and further functionalization afforded the intermediate 268. The [5+2]-cycloaddition provided the hydroazulene 267 with the correct relative configuration at and C. Tracing back the synthesis of the pyryli-um ylide 266 leads to the astonishing realization that 2-methyl cyclopent-2-enone (90) was the original cyclic starting material and that the methyl as well as the isopropyl group were introduced by a sequence of cuprate addition and enolate alkylation (see Schemes 15, 31 and 36 for comparison). 

The synthesis of some hydroazulenes such as 51a by reaction 35a, catalysed by CH3Re03/Si02-Al2C>3236, or better still by 19237, has been reported. Such ring systems occur in many natural products of pharmacological interest. 

Pyrovellerolactone (169) has been synthesized77" by a synthetic route in which the hydroazulene intermediate (168)776 is constructed (Scheme 23) by a procedure similar to that used in a previous synthesis of bulnesol.78 A novel feature of the... 

In woric related to natural product synthesis the efficacy of silver carbonate on Celite was compared with a platinum-catalyzed oxidation using an oxygen atmosphere for the oxidation of (23 equation 26). In some cases the Pt/Oz system was superior, but in others the situation was reversed, with no obvious rationale. The Pt/02 reagent has been used in the total synthesis of the hydroazulene natural products damsin (24 Scheme 7), aromatin (25) and aromaticin (26 Scheme 8). ... 

Fragmentation of appropriate bicyclic sulfonyloxy alcohols or ketones is a general route towards cy-cloalkene ketones or carboxylic acids. Thus, the hydroazulene alcohol (59 Scheme 22), precursor for the synthesis of daucene (60), jaeschkeana diol and others, has been synthesized by a one-pot reaction (fragmentation and isopropylation) of the hydroxy tosylate (57) with Pr Li. The fragmentation of (57) to give the ketone (58) as the primary product can be achieved by treatment with pyridine. 

A fragmentation of a similar tricyclus has been used by Oppolzer for the synthesis of the hydroazulene ketone (74 Scheme 25), precursor of the bulnesenes (75). The tricyclic ketone (71), obtained by intramolecular photoaddition, is converted to the diol (72). Fragmentation is accomplished in one... 

S.J. Danishefsky and co-workers identified an exo-methylene hydroazulenone as a versatile intermediate in efforts directed toward the total synthesis of guanacastepene. The exo-methylene group was introduced on the hydroazulene by the two-step Eschenmoser methenylation procedure. The substrate was deprotonated with LiHMDS followed by the addition of 3 equivalents of Eschenmoser s salt. The resulting a-(dimethylamino)methyl ketone was treated with mCPBA to form the A/-oxide, which spontaneously underwent a Cope elimination to afford the desired exo-methylene hydroazulenone. 

The thio-Prins-pinacol rearrangement was the key transformation in L.E. Overman s enantioselective total synthesis of (+)-shahamin K. Treatment of the dithioacetal substrate with DMTSF brought about the rearrangement, which gave rise to the c/s-hydroazulene core of the natural product. 

The reaction was used in the first step of a synthesis of the hydroazulenic alcohol bulnesol (4). ... 

In connection with a synthesis of the hydroazulenic sesquiterpene kessanol (304), Knoevenagel condensation of photocitral-A (302) with ethyl cyanoacetate was found to give (303) as a single isomer. The following sequence includes an intramolecular Prins reaction initiated with SnCU. In Isobe s synthesis of vemolepin (307) the two carbons of the -y-iactone are introduced by a Knoevenagei condensation. Reaction of ketone (305) with di-f-butyl maionate followed by treatment with DBU affords (306), which is transformed to the a,a -dihydroxy compound (308). Hydrolysis of the esters foliowed by decarboxy-iation, formation of the y-lactone, Mannich reaction and elimination yields vemolepin (307 Scheme 58).3"... 

Another example is the synthesis of the central hydroazulene unit 10 of dictyols (isolated from various marine algae, some of which exhibit antimicrobial activities), which has the correct configuration at C-l and C-7 and allows independent manipulation of functionalities for further transformations617. 

Among the many isolated sesquiterpene lactones, the nonisoprenoid hydroazulenic pseudogua-ianolides are the largest family51. Most of these tricyclic compounds contain a c -fused /3-lactone subunit, as well as a trans-fused hydroazulene. In a synthesis of damsin. a./i-unsatu-rated lactone 5 was hydrogenated over platinum on carbon to yield an 85 15 mixture of the C-6-isomeric products 6 with a <7s-fused lactone subunit49. 

Similar results are obtained in the synthesis of precursors (8 and 10) of naturally occurring confertin. Thus, hydrogenation of dienone 7 results in the formation of the thermodynamically more stable traw.r-fused hydroazulene 8 with a high degree of diastereoselectivity52. 

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