Hirsutene, synthesis

While reaction 119bhas been used for a (+/—) hirsutene synthesis, the annelation according 119c was elaborated for a (+/—) pentalene preparation 2Z9b). 

The general process is illustrated by the classic hirsutene synthesis developed by Curran (Scheme 25.2). In the 1980s, Stork and Curran contributed to a rapid expansion of synthetic applications involving radical processes, which was preceded by the work of Barton, Giese and Hart, who had begun a new era for radical chemistry by introducing novel radical-featuring synthetic methods. Subsequent... 

On the basis of the examples addressed thus far, it is clear that radical reactions can accomplish manifold transformations in organic synthesis. One of the outstanding achievements of synthetic radical chemistry is the development of synthetic strategies based on controlled, tandem radical cyclizations. The efficiency of such strategies is exemplified in the substantial and elegant synthetic work of D. P. Curran and his group.54 The remainder of this chapter will address the concise total syntheses of ( )-hirsutene [( )-1]55 and ( )-A9(12)-capnellene [( )-2]56 by the Curran group. 

Schemes 28 and 29 illustrate Curran s synthesis of ( )-hirsutene [( )-1]. Luche reduction58 of 2-methylcyclopentenone (137), followed by acetylation of the resulting allylic alcohol, furnishes allylic acetate 138. Although only one allylic acetate stereoisomer is illustrated in Scheme 28, compound 138 is, of course, produced in racemic form. By way of the powerful Ireland ester enolate Clai-sen rearrangement,59 compound 138 can be transformed to y,S-unsaturated tm-butyldimethylsilyl ester 140 via the silyl ketene acetal intermediate 139. In 140, the silyl ester function and the methyl-substituted ring double bond occupy neighboring regions of space, a circumstance that favors a phenylselenolactonization reac-...

Scheme 28. Curran s synthesis of ( )-hirsutene [( )-1] construction of intermediate 134.

This type of asymmetric conjugate addition of allylic sulfinyl carbanions to cyclopen-tenones has been applied successfully to total synthesis of some natural products. For example, enantiomerically pure (+ )-hirsutene (29) is prepared (via 28) using as a key step conjugate addition of an allylic sulfinyl carbanion to 2-methyl-2-cyclopentenone (equation 28)65, and (+ )-pentalene (31) is prepared using as a key step kinetically controlled conjugate addition of racemic crotyl sulfinyl carbanion to enantiomerically pure cyclopentenone 30 (equation 29) this kinetic resolution of the crotyl sulfoxide is followed by several chemical transformations leading to (+ )-pentalene (31)68. 

In their elegant synthesis of (-i-)-hirsutene 6/1-261, Oppolzer and coworkers [126] combined an intramolecular Pd-catalyzed nucleophilic substitution of the allylcar-bonate 6/1-259 with carbonylation this is followed by an insertion of the formed carbonyl Pd-species into the double bond, obtained in the former reaction. The last step is a second carbonylation to give 6/1-260 after methylation of the formed acid moiety (Scheme 6/1.68). 

The synthesis of other angularly fused triquinanes as well as linearly fused sesquiterpenes such as hirsutene and capnellene quickly followed. Many general methods for the synthesis of cyclopentanoid natural products emerged as a result of the target-oriented effort [6]. These accomplishments have been reviewed extensively on numerous occasions [7]. This chapter reviews the history of retigeranic acid from its isolation and structure determination to published approaches to its synthesis and the four total syntheses accomplished to date. 

An enantioselective intramolecular Pauson-Khand reaction based on chiral auxiliary-directed 7t-face discrimination in acetylenic 0-alkyl enol ether-dicobalt hexacarbonyl complexes, which proceeds with good yields and high facial diastereoselectivity, has recently been developed by M.A. Pericas, A. Moyano, A.E. Greene and their associates. The method has been applied to an enantioselective formal synthesis of hirsutene. Moreover, the process is stereodivergent and the chiral auxiliary -rran5-2-phenylcyclohexanol- is recovered in a yield as high as 92% [18]. 

In practice, it was found that whereas the synthesis of hirsutene according to the dual strategy met with success under thermal conditions, but at temperatures as high as 580 °C, under photochemical conditions it afforded the unnatural cis, syn, cis configuration of some intermediates which then need further elaboration. Although the transformations 44 — 43a and 45. — 43a by a [2 + 2] -cycloaddition and a vinylcyclopropane rearrangement, respectively, may involve intermediates with a more or less biradical character, they are not typical radical reactions such as the ones we are considering here. 

This strategy has been successfully employed for the construction of [5,5,5,5]-fenestranes (Equation (36)), as well as for the synthesis of complex natural products such as terpenoids, for example, hirsutene (Equation (37)). ... 

Dehydroxylation Deoxygenation of the mesylate or tosylate of the alcohol 1, an intermediate in a synthesis of ( + )-hirsutene (2), with Li(C2H5)3BH results... 

The isoxazolidines (47) and (48) were obtained by cyclization of the corresponding ketone-derived exocyclic nitrones (Scheme 11).22 Such reactions have been used for natural product sysnthesis, as in the conversion of isoxazolidine (49) to ( )-hirsutene. Methylation and catalytic hydrogenolysis provided a y-dimethylamino alcohol, which underwent Cope elimination to provide an alkenyl alcohol in a key step. A related synthesis of ( )-7,12-sechoishwaran-12-ol is also reported. 

A key step in the total synthesis of ( )-hirsutene was the acid catalysed (p-TsOH/CH 2CI2/RT) cyclisation of 1 to 2, which proceeded in 95% yield and gave a 10 1 mixture of epimers at C4 (the major epimer was 2). 

Hirsutene (A).2 A short synthesis of hirsutene is formulated in equation (II). 

Cyclopentenone annelation (cf. 10,444). The reagent undergoes a Nazarov-type cyclization with an a,/S-unsaturated acid chloride to give an annelated 3-phenylthio-cyclopentenone. This reaction was used to prepare the bicyclic cyclopentenone 3, a useful intermediate in synthesis of cyclopentenoid natural products, such as hirsutene (4).3... 

These intramolecular meta-addition processes were utilized in the key steps for the total synthesis of a-cedrene [245], isocomene [246], hirsutene [247], coriolin [248], silphinene [249], rudmollin [250], laurenene [251], and fenestranes [252-254], which were synthesized by Wender s and Keese s groups (Scheme 58). 

A chemoenzymatic synthesis of the linear triquinane (-)-hirsutene and identification of possible precursors to the naturally occurring (+ (-enantiomer. Tetrahedron, 60 (3), 535-547 (b) Banwell, M.G., Edwards, A.J., Harfoot, G.J., and Jolliffe, K.A. (2002) A chemoenzymatic synthesis of (—)-hirsutene from toluene. Journal of the Chemical Society, Perkin Transactions 1, 2439-2441. 

The efficiency of this protocol has been adequately demonstrated by applying it to the total synthesis of ( )-Hirsutene (224), as depicted in Scheme 8.61 [100]. 

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