Natural hydroazulenes

Deliberate dehydrogenation of natural hydroazulenes and other sesquiterpene derivatives, sometimes after preceding dehydration, hydrogenation, and reduction, has been the first synthetic path to azulenes (55FCF(3)334, p. 355 59MI2, p. 301). Similar reactions yielded... 

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 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. 

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). ... 

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. 

Marshall and Huffman have employed a neat combination of the aforementioned principles to access the hydroazulene system (109) by solvolysis of (107) in the presence of aqueous dioxane the reaction (107) —> (109 equation 42) proceeds via the incipient allylic carbonium ion intermediate (lOS). Indeed, subsequent to this woric, a wide range of cyclodecenols (many naturally occurring) have been used to... 

Formic acid catalyzed transannulation of the 8,9-epoxide (163), derived from natural zerumbone, has been shown to lead to a mixture of the bicyclo[6.3.0]undecane (164) and the hydroazulene (165 equation 72). 

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. 

A third skeletal system which occurs widely in natural products is the hydroazulene skeleton. The /rans-annulated form seems to be somewhat more stable than the corresponding nix-form41- 48. Thus, isomerization of compounds such as 1 can be easily achieved in alkaline media and the equilibrium is largely in favor of the trans-fused product49. 

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. 

The [3+4] annulation approach to the hydroazulenes is achieved with high asymmetric induction (greater than 90% de) by using (/ )-pantolactone as a chiral auxiliary (Table 7). The nature of the catalyst has a considerable effect on the level of asymmetric induction. A sterically crowded catalyst, such as rhodium pivalate, results in much lower diastereoselectivity than rhodium(II) acetate or rho-dium(II) hexanoate. Consequently, even though the enantiomers of rhodium(II) mandelate exhibit double stereodifferentiation with the (/ )-pantolactone auxiliary (entries 5,6), both catalysts are bulky and result iinferior asynunetric induction compared to that obtained with an uncrowded achiral catalyst (entries 1-3). 

The first azulenes were obtained by dehydrogenation of naturally occurring hydroazulenes. The first intentional synthesis was carriec out in 1936 starting from an octalin [4]. The method, together witl later modifications [8.9] is shown in the following chart ... 

In some cases the XtOi system was superior, but in others the situation was reversed, with no obvious rationale. The Pi/Oz reagent has been used in the total synthesis of the hydroazulene natural products... 

The oxabicyclo[3.2.1]octan-2-one ring systems form a core skeleton of many naturally existing molecules. In an approach towards guaianolide sesquiterpenes, their hydroazulenic framework has been constructed through a rhodium(II)-catalyzed reaction [82] of the a-diazo ketone 106 with DMAD to afford the oxatricyclic system 107, which forms the skeleton of ambrosic acid 108 (Scheme 33). 

Domino metathesis reactions of the dienynes 97 and 99 catalyzed by the phosphine-free ruthenium catalyst 4 in the presence of ethylene allowed a rapid access to the naturally occurring marine trisnorsesquiterpenes (—)-clavukerin A (98) and (—)-isoclavukerin A (100), respectively, by preferential initiation at the disubstituted alkene (Scheme 2.36) [18i]. As the dienyne substrates 97 and 99 were easily available from (S)- and (J )-citronellal, respectively, in only three high yielding operations, the 1,3-dienes 98 and 100 now offer themselves as enantiopure building blocks for the preparation of structurally more complex hydroazulene targets. 

The Robinson-Schdpf condensation has been employed to construct structures other than the familiar tricyclic core. In addition, there are cases where once obtained, the triyclic core is fragmented into natural or synthetic scaffolds. Contexts for use of the Robinson-Schopf in these ways include hydroazulenes," betalains, ( )-coniine, pyrrolidine synthons, " and substituted piperidones. ... 

Proazulenes, azulenogens, hydroazulenes a group of natural cyclic sesquiterpenes, which can be terminally dehydrogenated or dehydrated to Azulenes (see). P. are chiefly compounds of the guaiane type, e.g. guaiol. 

The complex structure along with the potential medicinal properties of the naturally occuring hydroazulenic lactones have stimula-ted an intensive synthetic activity in the field. 

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