Linear triquinane synthesis

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%. 

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... 

H-silphiperfol-5-ene 93 (R = 11, R2 = Me) [70], subergorgic acid 94 [71], crinipellin B 95 (formal synthesis) [72], (—)-retigeranic acid 96 (formal asymmetric synthesis) [73] were synthesized via intramolecular meta cycloaddition as key step (Sch. 18). In the same way, linear triquinane... 

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. 

V. K. Singh and B. Thomas, Recent developments in general methodologies for the synthesis of linear triquinanes, Tetrahedron 1998, 54, 3647-3692. 

Hudlicky developed a general method of triquinane synthesis based on a cyclopropanation- arrange-ment sequence of dienic diazo ketones (Scheme 52). Topological selectivity of linear versus angular triquinane synthesis has been achieved. ... 

Singh, V., Alam, S. Q., Intramolecular Diels Alder Reaction in 1 Oxaspiro[2.5]octa 5,7 dien 4 one and Sigmatropic Shifts in Excited States Novel Route to Sterpuranes and Linear Triquinanes Formal Total Synthesis of ( ) Coriolin, Chem. Commun. 1999, 2519 2520. 

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

The extention of radical cyclization of (bromomethyl)dimethylsilyl allyl ethers to propargyl analogs 17 has been studied by Malacria and coworkers. The intermediate exocyclic vinyl radical 18 can be either trapped by the hydrogen atom to give, after simple chemical transformations, the trisubstituted alkene 19 (equation 25) or can be added intramolecularly to give cyclic products when suitably located double bonds are present (equations 26 and 27). An attempt to apply this methodology to the stereoselective synthesis of angular and linear triquinane has also been performed. When = t rt-butyl,... 

Interception of the alkylpalladium intermediate in a Mizoroki-Heck cyclization can be parlayed to introduce an additional stereocentre and increase molecular complexity. Shibasaki and coworkers insightfully recognized that the linear triquinanes represent a prime opportunity for exploring the feasibility of cascade Mizoroki-Heck processes in the context of natural product synthesis, with their studies leading to the first reported asymmetric Mizoroki-Heck cyclization- ) -allyl nucleophilic trapping sequence. 

Since their discovery in 1966 [116], linear triquinanes such as hirsutene (288) remained a popular synthetic target for organic chemists, and many research groups have developed efficient and short syntheses [117]. In 2008, the Rh-catalyzed [(5 -)- 2) - -1] cycloaddition of Yu and coworkers [118] proved useful for the synthesis of the tricychc skeleton of linear triquinanes. In detail, vinylcyclopropane... 

Scheme 9.1 S Synthesis and ODPM rearrangement reaction of a cyclopentannulated bicyc]nr2.2.21octenone leading to a cyclopropannulated linear triquinane.

The second case in which 1,4-addition of an allylsilane to a conjugate dienone produces a cycloperitane ring was discovered during an attempted synthesis of the linear triquinane hirsutene QQ) (Eq. 8). S Our approach featured the construction of the central cyclopentane ring of hirsutene via an intramolecular allylsilane addition of two functional-... 

Scheme 640 Synthesis of cyclopropane-fused linear triquinane.

A palladium-catalyzed cyclization sequence involving a mal-onate anion-based termination step and leading to linear triquinanes has been reported and employed in the synthesis of the sesquiterpene-type natural product ( )-A ( -capnellene (eq 114). i ... 

Winkler and Sridar investigated the transannular radical reaction cascade of 1,5-cyclooctadienes (i.e., 103 and 110) for synthesis of linear triquinanes (Schemes 20.29 and 20.30). The substituents were found to exert subtle... 

The transannular cationic cyclization was the key transformation for biomimetic synthesis of the linear triquinane A -capneUene by Birch and Pattenden. It involved treating the cycloocta-1,5-diene or its exo-methylene isomer (i.e., 154) with BF3-Et20 to initiate the transannular cycH-zations to give A -capnellene and the two isomers 157 and 158 (Scheme 20.38). These products were derived from the same carbocation intermediate 156 of the transannular cationic cyclization and the major product A -capnellene was also formed by the isomerization of the bridgehead capnellene 158. 

Dhimane AL, Ai ssa C, Malacria M. Transannular radical cascade as an approach to the diastereoselective synthesis of linear triquinane. Angew. Chem. Int. Ed. 2002 41 3284-3287. 

Hsu, D.-S., Chou, Y.-Y., Tung, Y.-S., and Liao, C.-C. (2010) Photochemistry of tricydo[5.2.2.0 ]-imdeca-4,10-dien-8-ones An effident general route to substituted linear triquinanes from 2-mefhoxyphenols. Total synthesis of ( )-A9,12-capnellene. Chem. Eur. ]., 16, 3121-3131. 

Singh, V. and Thomas, B., Aromatics to triquinanes synthesis and photoreaction of tricy-clo[5.2.2.0 > ] undecanes having an a-methoxy-P,y-unsaturated carbonyl chromophore a novel ef cient and general route to linearly fused cisiantixis tricyclopentanoids, /. Org. Chem., 62,5310, 1997. 

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. 

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