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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Org Lett. Author manuscript; available in PMC 2011 January 1.
Published in final edited form as:
PMCID: PMC2814301

Catalytic Enantioselective Formation of Chiral Bridged Dienes Which Are Themselves Ligands for Enantioselective Catalysis


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This paper reports a method for highly enantioselective Diels-Alder reaction with an acetylene equivalent to produce chiral bridged dienes. These dienes, by coordination to Rh(I), can serve as catalysts for the enantioselective addition of vinyl or aryl groups to α,β-unsaturated ketones.

Reaction sequences in which a catalytic enantioselective process produces a catalyst for another enantioselective transformation are synthetically advantageous. In addition, along with template-directed molecular reproduction, such catalytic cascades are fundamental to life.

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The N-protonated oxazaborolidine I and its N+-AlBr3 and N+-CH3 coordinated analogs represent a new class of chiral and strong Lewis acids that have proved to be remarkably useful for the synthesis of chiral organic molecules from simple, achiral precursors.1 These catalysts offer numerous advantages in enantioselective Diels-Alder reactions, including: (1) broad applicability, even with less reactive substrates, (2) 20:1 or better enantioselectivity and (3) predictable absolute configuration of product. Their use has enabled the conversion of some of the most important multi-step syntheses of racemic natural products to catalytic enantioselective versions. This note describes the use of I toward two objectives: first, the development of a method for the enantioselective synthesis of Diels-Alder adducts of acetylenic dieneophiles;2 and second, the development of methodology for the catalytic enantioselective synthesis of catalysts (e.g., [M]-II), which can function enantioselectively. The advent of cascades of processes for the generation of enantioselective catalysts would allow significant improvement in the power of chemical synthesis. One can envisage that there will be a large collection of molecules produced by enantioselective catalysts that constitutes a “catalytic pool” analogous to the “chiral pool” of naturally produced organic molecules.

Chiral, non-racemic, bridged dienes have proven to be exceptionally useful ligands for several classes of catalytic enantioselective C-C bond forming reactions.3 Nearly all of the known bicyclic diene ligands are prepared in enantiomerically pure form from either chiral pool starting materials or by the use of resolution techniques (fractional crystallization or HPLC with a chiral column).

As illustrated in Scheme 1, we have established a catalytic enantioselective route to norbornadiene-based ligands (4-6).4,6a The route hinges on the use of a catalytic enantioselective Diels-Alder cycloaddition of β-chloroacrylate 1 (a relatively unreactive dieneophile) with cyclopentadiene promoted by protonated oxazaborolidine 2, which proceeds with high enantioselectivity and in good yield. From there, the dienes are prepared in enantiomerically pure form in two to three straightforward, high-yielding transformations (Scheme 1).

Scheme 1
Preparation of Norbornadiene-Based Ligands

The utility of dienes 4-6 as chiral ligands was examined in the context of Rh-catalyzed enantioselective conjugate additions of ArB(OH)2 to α,β-unsaturated ketones (Table 1).3,5,6 Initial studies established that while use of ligands 4-6 all lead to highly enantioselective reactions (96-98% ee), the BOM-ether 6 gives the highest conversion of starting material (Table 1, entry 3).

Table 1
Initial Survey of Norbornadiene-Based Chiral Ligands

As illustrated in Table 2, highly enantioselective (86-96% ee) conjugate additions of PhB(OH)2 to various α,β-unsaturated carbonyls promoted by Rh-6 can be carried out. With five- and six-membered ring α,β-unsaturated ketones (Table 2, entries 1 and 2), only 0.5 mol% catalyst is adequate, but somewhat more (3 mol %) is appropriate for less reactive substrates, such as cycloheptenone (Table 2, entry 3) or an acyclic enone (Table 2, entry 4).7

Table 2
Rh-Catalyzed Enantioselective Conjugate Addition of PhB(OH)2 to Various Enones Promoted by Rh-6a

During the course of our studies, we discovered that the efficiency of the reaction depends on the order of addition of reagents as outlined in Figure 1. One explanation for this observation is that the ligand (6) is transformed into a catalytically incompetent product under the conditions of the conjugate addition. This possibility was tested by allowing the diene 6 to react with stoichiometric amounts of PhB(OH)2 and [RhCl(CH2CH2)2]2 in dioxane-KOH-H2O for 10 min at 24 °C. Under these standard reaction conditions, rapid phenylation of the disubstituted olefinic linkage of 6 occurred to form the product shown in Scheme 2 (stereochemistry assumed). Catalytic arylation of norbornenes has been observed previously.8

Figure 1
Investigations into Order of Addition
Scheme 2
Arylation of Diene 6

To overcome the issues associated with such strained ligands, we turned to the less strained bicyclooctadiene systems. As illustrated in Scheme 3, bicyclooctadienes 11 and 12 are prepared efficiently in three steps. Diels-Alder reaction of trifluoroethylacrylate (7) and 1,3-cyclohexadiene gives 8 in 90% yield and 99% ee using 2 as catalyst.9 Oxidation of 8 with the Mukiyama reagent 910 followed by reaction with an alkyllithium reagent provides the diene ligands 11 and 12.11 While it is not necessary to prepare and isolate Rh-12 for efficient conjugate addition, we have established its structure by X-ray crystallography (Scheme 2).

Scheme 3
Preparation of Bicyclooctadiene-Based Ligands

The hydroxy bicyclooctadienes 11 and 12 are excellent ligands for the Rh-catalyzed enantioselective conjugate addition of PhB(OH)2 to cyclohexenone (Table 3) and Rh-12 is especially effective with only 0.25 mol % catalyst. (Table 4, entry 2).12

Table 3
Initial Survey of Bicyclooctadiene-Based Chiral Ligands
Table 4
Rh-Catalyzed Enantioselective Conjugate Addition of PhB(OH)2 to Various Enones Promoted by Rh-12a

Several points regarding reactions promoted by Rh-12 merit mention:13 (1) lower catalyst loading of Rh-12 can be employed as compared to Rh-6 (0.5 mol % vs. 3.0 mol %, Table 4). (2) Addition of a vinylboronic acid or a sterically hindered arylboronic acid to cyclohexenone (1 mol % Rh-12, dioxane, 50 °C, 2 h) provides 14 or 15 (respectively) in high yield and enantiomeric excess. (3) Rhodium-catalyzed conjugate addition of boronic acid 17 to α,β-unsaturated ketone 16 provides 18, a key intermediate for the enantioselective synthesis of 9-isocyanopupukeanane via the bicyclic ketone 20 (Scheme 4).14

Scheme 4
Enantioselective Synthesis of 9-Isocyanopupukeanane Intermediate 20

The results above effectively address the longstanding problem of catalytic enantioselective synthesis of adducts of 1,3-dienes and acetylenic dieneophiles. The application of this advance leads to a useful catalytic cascade in which a catalyst is used for the enantioselective synthesis of another chiral catalyst.

Supplementary Material





We thank the National Institutes of Health for a Postdoctoral Fellowship to M.K.B., the Jacobsen lab (Harvard University) for assistance in acquiring HPLC and IR data and Dr. Shao-Liang Zheng (Harvard University) for X-ray diffraction analysis.


Supporting Information Available Experimental procedures, spectral and analytical data for all compounds. This material is available free of charge via the Internet at


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