DTDA reactions

Schreiber and coworkers reported a branching diversity-oriented synthesis applying DTDA methodology that yielded 29 400 discrete compounds comprising 10 distinct polycyclic skeletons [31]. Scheme 2.20 shows only two DTHDA products in the DTDA reactions in which 40 aromatic hydroxyaldehydes, 41 disubstituted dienophiles, and 22 tri- or tetrasubstituted dienophiles were employed as building blocks. 

We begin by considering the most conceptually simple case intermolecular DTDA reactions of acyclic [3]dendralenes. To date, the majority of studies have been conducted on 3-substituted systems as a consequence of their accessibility [4], and the control they offer over DA site selectivity. In the generalized example illustrated in Scheme 12.3, the [3]dendralene conformation 26 is disfavored due to the steric interaction between the terminal Z-hydrogen atom shown, and the inside substituent R. Thus, assuming the activation barrier for each DA reaction is approximately equal, the reaction should preferably occur at the s-cis diene site depicted in 25 as a result of its increased population. 

Scheme 12.4 DTDA reaction sequence of 3-substituted [3]dendraiene 27 by Fallis et al.

Only one study detailing DTDA reactions of the pseudo-acyclic 1,1- or 3,3-cyclo[3]dendralenes has been reported, most likely owing to the difficulties associated with DA reactions of such highly substituted dienes. The prototypical, and not yet reahzed, DTDA cascade of l,l-cyclo[3]dendralene 17 is presented in Scheme 12.12. If the first DA reaction occurs at the more sterically demanding exocyclic diene site, spiro-bicycle 65 is produced, which could react further to generate the... 

Owing to their availability through cyclo-isomerization reactions, a number of studies describing DTDA reactions of 2,3-cyclo[3]dendralenes have been disclosed [20-22]. One example that perhaps best demonstrates the high levels of stereo- and chemoselectivity possible in such reaction sequences was published by Brummond and coworkers in 2006 (Scheme 12.16) [23]. In this... 

The first successful natural product synthesis incorporating a DTDA reaction sequence was published by Sherburn and coworkers in 2008, and constitutes a formal synthesis of triptolide (165) (Scheme 12.34) [46]. The carbon framework of this natural product was rapidly assembled from silyl protected [3]dendralene 161, beginning with a DA reaction between the free alcohol and methyl acrylate. In situ lactonization provided semicyclic diene 162, which was subjected to a high-pressure DA reaction with quinone 163. Tetracycle 164 was functionalized further to intercept an intermediate from Berchtold s 1982 total synthesis of triptolide [47]. 

Tsuge and co-workers - building on work by Bailey and Blomquist [5] - have already made extensive use of the preparative potential of these so-called diene transmissive Diels-Alder additions (DTDA additions) [8]. Clearly, the dienophile does not have to be identical in the two stages of the reaction, which increases the preparative potential of these double cycloadditions considerably. The adducts of type 22 can be further processed in various ways, for example by dehydrogenation to give 1,2,6,7-tetrasubstituted naphthalene derivatives as will be discussed below. Consecutive reactions of this type with their excellent atom economy are of considerable interest particularly in view of the current efforts to increase the efficiency of organic transformations. 

The DTHDA reaction is a special case of the DTDA (diene-transmissive Diels-Alder) reaction in which one or more heteroatoms are contained within a cross-conjugated triene/polyene (heterodendralene) it-system, a dienophile it-system, or both. The DTHDA protocol is an efficient and attractive method for the stereoselective synthesis of a variety of heterocyclic systems. 

The DTDA cycloaddition strategy for the synthesis of oxygenated norsteroid and triterpenoid skeletons has been disclosed by Fallis et al. [28]. Scheme 2.17 illustrates the representative DTHDA cycloaddition strategy involving the initial intramolecular DA and the second HDA reaction with Ph-TAD. l-Arabinose-derived allylic alcohol 112 was oxidized to form 113 in situ, which spontaneously cyclized (first DA) at rt or 0 °C to afford a s-fused, eu fo-adduct 114 (R = H, 78% ... 

This DTDA sequence begins with a completely diastereoselective double DA reaction between [3]dendralene 27 and / -benzoquinone, yielding tetracycle 29 (Scheme 12.4) [5].This compound was not isolated, and the subsequent addition of cyclopentadiene to the same reaction vessel allowed for two more DA reactions, generating the octacyclic skeleton 30 as a mixture of diastereomers. 

We conclude our section on cyclic [3]dendralenes with Meier and coworkers DTDA cascade of 1,5-dihydropentalene (109) [34] (Scheme 12.24). The sequence began with the addition of tetracyanoethylene (TCNE) to triene 109, providing the bridging tricycle 110. This was followed by a second in situ) DA reaction, to the less sterically encumbered bottom face of the diene, yielding 111 in excellent yield. To the best of our knowledge this is the only report of a bicyclic [3]dendralene undergoing multiple DA reactions. 

The first (and only) detailed DTDA study of parent [4] dendralene (14) was reported by the Sherburn group in 2005 [35]. Upon addition of an excess of NMM, at ambient pressure and temperature, a mixture of five products was obtained in excellent overall yield (Scheme 12.26). The first DA reaction occurred primarily at the terminal diene site to provide l,2-monocyclic[3]dendralene 119, as well as 21% of the internal adduct 120. Triene 119 could not be isolated, and a second cycloaddition, predominately at the internal site, afforded the two endo-DA adducts 121 and 122. The major diastereomer arises via approach of the dienophile anti with respect to the succinimide ring in compound 119. The tris-adducts 123 and 124 originate from reaction at the acyclic diene site of 119, and from the less hindered top face (as drawn). The two intermediates generated... 

While the selectivity of this DTDA cascade is relatively poor, preliminary studies under Lewis acid conditions exhibit essentially complete control over site selectivity [35]. These reactions were conducted by pre-complexing NMM with stoichiometric amounts of MeAlCl2 at low temperature. When a 1 1M ratio of NMM MeAlCl2 was employed, a 77% yield of internal DA adduct 120 was obtained. Interestingly, with a 1 2 ratio, exclusive formation of the tris-DA adducts 123 and 124 was observed. At present, the origin of this selectivity remains unclear. 

At present, the higher dendralenes remain comparatively unexplored, owing partly to the complexity of their DTDA chemistry. However, recent promising results suggest that control over their DTDA chemistry is possible. In particular, the organocatalyzed DA reactions of [4]dendralene (11), and the remarkable increase in DA selectivity (with respect to [4] dendralene) observed for the exhaustive addition of NMM to DVC (139), both reported by Sherburn et cd. (Scheme 12.45). 

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