An efficient new process is described for the synthesis of ecteinascidin ET-743 (1) and phthalascidin (2), starting from readily available cyanosafracin B (3).

The intramolecular reductive coupling of a series of simple or polyoxygenated oxime ethers δ-or -functionalized with bromide, R, -unsaturated ester, aldehyde, or ketone groups is reported. The cyclization of a nitrile-tethered aldehyde is also studied. These reductive couplings are promoted by tributyltin hydride or samarium diiodide. The reactions proceed under mild conditions, in good chemical yield, and with high stereoselectivity. When applied to highly functionalized substrates derived from carbohydrates, this approach provides a selective entry to enantiomerically pure aminocyclitols of varying regio-and stereochemistry. In particular, the reductive coupling reaction of carbonyl-tethered oxime ethers promoted by samarium diiodide can be performed in a one-pot sequence, following a Swern oxidation step, allowing the direct transformation of hydroxyl-tethered oxime ethers into the corresponding aminocyclitols. Moreover, the resultant O-benzylhydroxylamine products of these cyclizations can be further reduced in situ with excess samarium diiodide, in the presence of water, to the corresponding amino alcohols in excellent yields. Some transformations of these compounds are discussed.

The semisynthetic process initially described for the synthesis of 1 (ET-743) has been extended to the preparation of other natural ecteinascidins. For the synthesis of 2 (ET-729) a demethylation of a N-Me intermediate was carried out by a selective oxidation with MCPBA. Other natural ecteinascidins (ET-745, ET-759B, ET-736, ET-637, ET-594) were accessible from key intermediate 25. The described methodologies allow for the preparation of a wide variety of ecteinascidins by procedures that can be easily scaled up.

In our current work on the tributyltin hydride 1 -mediated cycloisomerizations of conveniently functionalized O-alkyl oxime ethers derived from carbohydrates, we were usually confronted with the necessary transformation of the resulting O-alkylhydroxylamines into the corresponding free amino derivatives. A detailed survey of the methods currently available for effecting this N-O bond cleavage 2 in our polyfunctionalized substrates proved in some cases inappropriate and, in practice, resulted in low yielding processes. 3,4 Obviously, a new and milder method was desired in order to overcome these unexpected difficulties.Although samarium diiodide is known to promote some N-O reductive cleavage reactions, 5 to our knowledge this reagent has never been exploited for the chemoselective reduction of O-alkylhydroxylamines to amines. We have recently shown 6 that samarium diiodide is a convenient and efficient reagent for effecting this particular transformation in densely functionalized aminocyclopentitols such as 3 6a and 5. 6b A recent report from Keck's laboratory describing a similar process using samarium diiodide 7 prompted us to report here in full our experimental conditions for the synthesis of amines from O-alkylhydroxylamines. Additional examples (compounds 1, 8 2, 6a and 4 8 ) have been included in order to test the scope and extent of the new methodology. For the sake of simplicity, only the corresponding free or N-acetylated Obenzylhydroxylamines have been studied, but in principle these conditions can be easily applied to other Oalkylhydroxylamines or O-alkylhydroxamic acids. 7 General and reliable conditions (see Experimental Section) were found for the successful implementation of the desired transformation. The results are shown in Table 1. These results deserve some comments. All reductions have been performed at room temperature either by adding the substrate to samarium diiodide in THF or by reverse addition, with no significant change in chemical yield. The reductive cleavage is strongly accelerated in the presence of a proton source. Water (20-25 equiv with respect to substrate) has proven to be most effective. 9,10 Compounds with free hydroxyl groups (e.g., 4 and 5) are reduced reasonably fast in the absence of added water, except if the hydroxyl group is tertiary (as in 1) or hindered (as in 4 11 ). The reduced products derived from 3-5 have been transformed in situ into the corresponding acetamides to ease isolation and characterization. Due to the highly functionalized nature of our precursors, we had the opportunity to test the stability of different functional groups to the reaction conditions: esters, acetals, silyl 12 or benzyl ethers, double bonds, and vinylstannylidene functions remain unaltered and the hydroxyl groups do not need to be protected. Finally, it is also important to emphasize the very simple workup manipulation required for the isolation of the final products. Tetrahedron Lett. 1995, 36, 7419. (8) The synthesis of these compounds will be reported elsewhere.(9) For pr...

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