Dane diene

Case Study (+)-Estrone 24. The Dane-style estrone synthesis provides a classic example of stereoselective access to an envisaged target molecule. The Diels-Alder reactions between 14 and 15a or 19a are chirogenic71 reaction steps or, put another way, the enantioselective access to the Diels-Alder adducts can already be set at this stage. This requires, for example, the participation of a nonracemic Lewis acid with the right sense of chirality. In the presence of a Ti-TADDOLate [42], cycloadduct 20a was thus obtained from the Dane diene 14 and the bidentate dienophile 19a and was further transformed via 23 into (+)-estrone 248) [33d]. 

A positive sign for reaction acceleration and regioselection in the right direction was provided by Valenta et al. [134], who treated the Dane diene 139 with the unsymmetrically substituted dienophile 2,6-dimethyl-l,4-benzoquinone to furnish the racemic mixture analogous to rac-141a and rac-142a. 

D were cis-fused. In point of fact, the Dane diene 4 and cyclopentenone 5 (R = Me or Et) on reaction are expected to lead to rac-3. Since this [4+21-cycloaddition would comfortably construct the steroid skeleton, one might accept additional effort required to correct the configuration at C(14). 

Fig 12. According to Dane et al. Diels/Alder reaction of the Dane diene 4 with 5 does not take place. 

Z. Valenta et al. [20] in 1979 reported on the reaction of the Dane diene 1 (Fig. 13) and 2,6-dimethyl-1,4-benzoquinone (2) in boiling benzene, affording after 24 h adduct 4 in 82% yield, which has obviously got the wrong constitution as far as the construction of the steroid skeleton is concerned. After 30 min at -15°C in ether, however, the adduct components 3 and 4 in a ratio of 86 14 were produced, provided BF3 OEt2 had been present. The major adduct can easily be isolated in 69% yield. Undoubtedly, the dramatic change in stereoselection promises to be of synthetic value. 

The question comes up, of course, of whether adduct formation between the Dane diene 1 and dienophile 2 (Fig. 14) might be brought about by Lewis acid. The answer is yes . Depending on the nature of the Lewis acid, the primary adduct rac-3 or the secondary isomerization product rac-4 can be isolated [21]. 

Fig. 13. Intermolecular Diels/Alder reaction of the Dane diene 1 with 2,6-dimethyl-1,4-benzo-quinone (2) direction of stereoselection is inverted in the presence of Lewis acid.

Methylcyclopent-3-en-l,2-dione (2) (Fig. 18) had already been chosen as a dienophile to react with Dane diene 1 by the Munich group [28]. The isolated product was sent to Schering AG then for an estrogenic activity test. No positive result has ever been reported. 

With TiCl4 or SnC, acenaphthenquinone, bSnzil and camphorquinone function as bidentate ligands, while the last compound on complexation with MAD acts as a monodentate ligand. On reaction of the Dane diene 1 and 3-ethylcy-clopent-3-en-l,2-dione (2) it was shown by W. Daring [31] (Fig. 22) that the type of Lewis acid used determines adduct composition. 

In one case (R = phenanthren-9-yl R2 = R3 = ethyl) compound 3 was isolated in 65% chemical yield and an enantiomeric excess of 93%. When the Dane diene 1 reacted with the ethyl substituted diketone 2 (Fig. 25) under the above mentioned conditions (20 mol% of the chiral-nonracemic ligand) 3 was accessible in 77% chemical yield and an enantiomeric excess of 88% [31]. 

To sum up, (+)-estrone is accessible as outlined (Fig. 27) after seven synthetic steps in an overall yield of 9.6%, using the intermolecular Diels/Alder reaction of the Dane diene AB and dienophile D in the presence of TiCl2(OiPr)2 and the auxiliary A. 

Fig. 25. Enantioselective verification of the chirogenic Diels/Alder reaction of the Dane diene 1 and 3-ethyl-3-cyclopenten-l,2-dione 2 in the presence of a chiral-nonracemic Ti-complex.

The asymmetric Diels-Alder cycloadditions of enantiopure (5)-5-(/ -tolylsulfinyl)-1,4-benzoquinones with Dane s diene under thermal and Lewis acid conditions produce tetracyclic quinones after spontaneous elimination of the sulfinyl group.The Diels-Alder reaction of barrelene with o-benzoquinone produces tetracyclo[6.2.2.2 .0 ]tetradeca-9,ll,13-triene-4,5-dione. Under kinetic control, the Diels-Alder cycloaddition of 2,3-dicyano-p-benzoquinone (98) with cyclopentadiene in MeOH produces the single cycloadduct (99) (Scheme 38). ... 

A domino reaction,in this case consisting of an inter- and an intramolecular Diels-Alder reaction, is a key step in the synthesis of the hydrocarbon pago-dane 30, reported by Prinzbach et al When the bA-diene 27 is treated with maleic anhydride 4, an initial intermolecular reaction leads to the intermediate product 28, which cannot be isolated, but rather reacts intramolecularly to give the pagodane precursor 29 ... 

Scheme 1-7 Analysis of the relative orientation of Dane s diene 14 and the complementary dienophile following Robinson s way.

Alkylation of the metallated enol derived from 52 with m-methoxy-phenylethyl-iodide to afford the tricyclic jj-keto ester 53, followed by cationic cydization of this to furnish the steroid derivative 54, warrants particular attention. Corey and colleagues have recently published another total synthesis of 40 [82], beginning with an enantioselective Diels-Alder reaction between Dane s diene 14 and dienophile 61. An oxazaborolidinium salt (see Section 1.3.2.3) was used as an efficient catalyst (Scheme 1-14). 

Scheme 1-14 Collection of formulae relevant to a synthesis of (—)-desogestrel 40 opened by an asymmetric Diels-Alder reaction of Dane s diene 14 and dienophile 61.

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