Alkoxypalladation, intramolecular

The basic principle of this chemistry is that rf-alkene-Pd(II) complexes, usually generated in situ, are easily attacked by nucleophiles to form (T-alkyl-Pd species, which in turn are able to react further in a variety of ways. In general, several kinds of nucleophiles (e.g. alcohols, amines and enolethers) are able to attack the alkene complex intermediates in an intra- or intermolecular fashion. This article, however, focusses exclusively on intramolecular alkoxypalladations, i.e. transformations of the type 2 3, which are of particular synthetic relevance. 

After James and Stille had shown the general possibility to link (intermolecular) alkoxypalladation and carbonylation processes 4], Semmelhack et al. were the first to achieve Pd-catalyzed intramolecular alkoxycarbonylation reactions and to apply them in the synthesis of specific target molecules [5]. In a typical reaction, the substrate is stirred at room temperature in methanol under an atmosphere of CO (I. I atm) in the presence of 5-10 mol% of PdCl2 and an excess (3 eq.) of CuClj. As the conversion of the simple model compound 4 to the products 5 and 6 implies, such reactions often proceed in good yields but not necessariliy with high diastereoselectivies (5 6 = 3 I). 

The presumed reaction mechanism is shown in Scheme 1. First, the in situ generated rf-d kcne-Pd(II) complex 2 is intramolecularly attacked by the nucleophile to form an alkoxypalladated species 3. In the presence of carbon monoxide this intermediate rapidly undergoes migratory inser-... 

In a synthesis of tetronomycin (45) published in 1994 [14], Semmelhack et al. probe the scope of intramolecular alkoxypalladations. The retro-synthetic analysis (Scheme 4) shows that the chosen strategy exploits such Pd-catalyzed transformations even twice. The pre-target structure 46 is formally derived from 47 by Pd-mediated cy-clization. Compound 47 can be traced back via 48 to the tetrahydrofuran derivative 49, which in turn should be available by alkoxycarbonyla-tion from a precursor of type 50. 

Although diastereoselective intramolecular al-koxypalladations have been investigated intensively and have found application in synthesis (see above), there are few examples of enantioselective alkoxypalladations [2bJ. For instance, Hosokawa et al. were able to cyclize unsaturated phenol derivatives of type 62 in the presence of chiral (// -allyl-PdOAc complexes, i.e. 63), but only with modest enantioselectivities. Under the same conditions the conversion of the phenol 65 to chroman 66 (a compound related to vitamin E) proceeded in acceptable yields, but with only low asymmetric induction. Newer results by Uozumi et al., for instance the Pd-catalyzed cyclization of 67 to 68 in the presence of a chiral bis-oxazolin ligand [15], show that much higher enantioselectivities can be achieved, at least for certain substrates. 

The intramolecular alkoxypalladation has been developed into a remarkable (catalytic) methodology which exhibits a great synthetic potential, especially in combination with carbonyla-tion. This is reflected by convincing applications in natural product syntheses. This chemistry opens reliable and highly diastereoselective approaches to several hydropyran and hydrofuran systems. The development of efficient enantioselective protocols for the various chirogenic transformations is still a challenging goal for the future. 

This intramolecular alkoxypalladation/carbonylation has been used to synthesize the ester (2) of optically pure civet cat acid from 1. 

Semmelhack, M.F. and Bodurow, C. (1984) Intramolecular alkoxypalladation/ carbonylation of alkenes. Journal of the American Chemical Society, 106,1496-1498. 

Geis O, Schmalz HG. Intramolecular alkoxypalladation. In Schmalz HG, editor. Organic synthesis highlights IV. Weinheim Wiley VCH 2000. p 83-90. 

McCormick M, Monohan IIIR, Soria J, Goldsmith D, Liotta D. Effects of substitution on intramolecular alkoxypalladation carbonylation reactions. J. Org. Chem. 1989 54 4485 87. 

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