A Linear Triquinanes

Reductive cyclization.1 Reduction of the unsaturated aldehyde 1 with Sml2 in THF/HMPT (20 1) at 0° effects a tandem radical cyclization of the fram-3,5-disubstituted cyclopentene system to a linear triquinane unit (2) with surprisingly high cw-ann-di-stereoselectivity. 

Transmetalation of the allyllithium intermediates allowed access to the cuprate manifold of reactivity. The rapid construction of a linear triquinane, 229, using this methodology demonstrates the potential for synthetic application (Scheme 70). 

Oxidation of 4-methoxycarbonyl-2-methoxyphenol (421) with PhI(OAc)2 in MeOH was carried out in the presence of cyclopentadiene (CPD) to afford in 87% yield a Diels-Alder adduct 434, which was subjected to photochemical reaction followed by Ac20-BF3-Et20 treatment to give a linear triquinane 435 (47.6% in 2 steps). ... 

A linear triquinane synthesis is started from a bicyclo[6.3.0]precursor initiated by chemoselee-tive Lewis acid attack on the least hindered olefin. Reaction of precapnelladiene (10) to capnellene (11) can be carried out in refluxing benzene in the presence of boron trifluoride-diethyl ether complex22 giving a yield of greater than 50%. 

Scheme 14. Synthesis of a linear triquinane via 0-stannyl ketyls...

Generation of non-stabilized alkyl radicals. Malacria has developed several new cascade reactions taking advantage of selective hydrogen atom abstractions by alkenyl radicals [145]. Recently, he achieved the preparation of a linear triquinane from an acyclic precursor. The last steps of the reaction sequence are a hydrogen abstraction by a vinyl radical at the /i-position of the sulfone followed by the elimination of a sulfonyl radical, affording the final product in 50% yield (Scheme 44)... 

Although Wender s synthesis was completed prior to Hudlicky s, it was published later [65]. It utilized the technique of mefa-photocycloaddition of arenes that Wender developed into a general method of synthesis for both angular and linear triquinanes. The overall strategy was centered around an intramolecular Diels-Alder cycloaddition for construction of the internal six-membered ring of the target. 

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. 

An elegant application of this photocycloaddition in the field of triquinane synthesis has been reported by Reddy and Rawal [160]. The initially formed oxetane 163, formed from the Diels-Alder adduct 162, is easily cleaved reductively (by use of LiDBB = lithium di-/er -butyl-biphenylide) to give 164. This approach was also used for the construction of structurally diverse di- and (propellane-type as well as linear or angular anellated) triquinanes [161]. The classic linear triquinane hirsutene is also available via this route [162]. Star-like molecules like the tiene 167 are available via a sequence of intramolecular photocycloaddition (from the 1,3-cyclohexadiene/acylallene adduct 165) and oxetane (166) ring-opening (Sch. 58) [163]. Further examples of intramolecular... 

Very likely the ammonium fluorides are the proton sources and therefore the reason for incomplete conversions, since potassium fluoride in acetonitrile gives high yields in a very elegant [3 + 2]-annuIation process 87). It combines a Michael addition to a vinyl phosphonium salt with an intramolecular Wittig reaction and proceeds only in the presence of 18-crown-6 with satisfying yield. This cyclopentene synthesis has been executed in a repetitive manner to prepare linear triquinanes as illustrated in Scheme 6. Unfortunately, the sequence is non-stereoselective with regard to the ethoxycarbonyl functions. 

Asymmetric hydroboration using IpC2BH was also applied in the stereocontrolled synthesis of a linearly fused triquinane, (+)-hirsutic acid (eq 1) ... 

The pentalenene precursor (141) can be derived firom a TMM cycloadduct (142) (equation 147). This synthetic approach is expedited by the facile conversion of the methylene unit of (142) to a gem-di-methyl function found in (141). This is normally accomplished by a simple cyclopropanation-hydro-genolysis sequence. The two reported TMM-based syntheses of the linear triquinane (l)-hirsutene (143) also utilize this particular strategy for the gem-dimethyl formation (equation 148). ""... 

Isomerizations. A synthetically useful transformation is the rearrangement of linear triquinanes to the angular isomers. For the conversion of propargyl ethers to allenyl ethers microwave promotion is advantageous. ... 

In conclusion, it is now possible to assemble highly functionalized linear triquinanes from acyclic precursors with high diastereocontrol. The sequence mixing intramolecular cyclizations and a [3-f2] radical annulation appears as the strategy of choice. To probe its versatility, this strategy will have to materialize into total syntheses of natural products. 

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