Hydroazulenes, synthesis

Scheme 36 Hydroazulene synthesis by transition metal catalysed C/C-bond forming reactions...

A rather different approach to the hydroazulenic synthesis has been adopted by Hendrickson and Boeckman. Treatment of 1-cyclopentenylcarboxalde-hyde (411) with the pyrrolidine enamine of cyclopentanone (412) yielded the thermodynamically most stable adduct (413) which, on quaternization and base-induced fragmentation, gave the acid (414) in 25% yield. Furthermore, the acid (414) has been converted into the epoxide (415) and the (5-lactone (416), both of which are potential synthetic precursors of guaiane-type sesquiterpenoids, e.g. pseudoguaianolides. 

Scheme 3.52 Internal delivery of organocuprate addition in hydroazulene synthesis.

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

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 product of this synthesis is an especially useful, highly functionalized hydroazulene that is not available commercially. We have used it as a synthetic precursor to homoazulene,5 and to a variety of homoazulene derivatives,6 bridged homotropylium cations,7 and azulene quinones.8 It could undoubtedly serve as a precursor to numerous natural products. The cyclization reaction tolerates electron-donating substituents3 9 but not halogens10 on the aromatic ring. 

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. 

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. 

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... 

Because of the excellent performance of the new catalysts, many research groups use ringclosing metathesis as the key step in natural product synthesis [12]-[18]. Scheme 6 shows some examples. Via ring-closing metathesis of the olefin 37 to the hydroazulene 38, Blechert et al. [12] succeeded in synthesizing a cyclic system which is part of many sesquiterpenes. Cyclooctane derivatives, whose synthesis is the main problem in taxol synthesis, can be obtained in good yields (39 40), as demonstrated by Grubbs et al. [ 13]. 

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. 

From the viewpoint of natural products synthesis, retro-aldol condensation of the elec-trosynthesized tricyclic compounds 181 and 182 provided the selective formation of trans-hydroazulene 183 and triquinane 184 in good yields, respectively (Scheme 37). Herein, the selective attack of a methoxy anion to the /3-diketone is due to the stereochemistry of the aryl group introduced to the C6-position. 

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"... 

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