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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: PMC2798906

Gold(I)-Catalyzed Enantioselective [4+2]-Cycloaddition of Allene-Dienes


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An enantioselective gold(I)-catalyzed intramolecular [4+2]-cycloaddition of allenes and dienes is reported. The reactions allows for the asymmetric synthesis of trans-hexahydroindenes and pyrrolidine products using C3-symmetric phosphitegold(I) and ortho-arylphosphoramiditegold(I) complexes as catalysts, respectively.

The nature of the ancillary ligand can have a dramatic impact on the course of gold(I)-catalyzed reactions.1 Gold(I) complexes of N-heterocyclic carbene,2 phosphites,3 bidentate,4 electron-deficient5 and bulky6 phosphines can display dramatically different reactivity and selectivity. We recently reported a striking example of ligand-controlled reactivity in which allene-dienes underwent a selective [4+2]- or [4+3]-cycloaddition catalyzed by gold complexes of phosphites and bulky phosphines, respectively.7 With few exceptions,8 enantioselective gold(I)-catalyzed transformations have largely relied on the use of bis(gold)-phosphine complexes.9 Herein we report that, in the course of developing an enantioselective variant of the gold-catalyzed [4+2]-cycloaddition, we have uncovered two new ligand platforms for asymmetric gold catalysis.9l

Given the success of bidentate phosphines in gold-catalyzed enantioselective reactions, our initial efforts towards an enantioselective [4+2]-cycloaddition focused on the use of chiral diphosphonites10 as ligands. Unfortunately, the L1 and L2Au(I)-catalyzed reaction of 1 failed to produce any of the desired cycloadduct (Table 1, entries 1 and 2). Moreover, racemic 3 was formed in the chiraphite(L3)Au(I)-catalyzed reaction of 1 (entry 3). As a result of the lack of success experienced with gold complexes of bidentate ligands, we then decided to examine the gold(I) complexes of chiral monodentate phosphite-like ligands as catalysts. While the gold(I) complex of phosphoramidite L411 did catalyze the desired transformation, it afforded cycloadducts 3 and 4 with low enantiomeric excess (entries 4 and 5).

Table 1
Ligand optimization for the enantioselective [4+2]-cycloaddition of allene-dienes.

During the course of our studies, Reetz reported the use of configurationally stable C3-symmetric monodentate phosphite ligand L5 in the Rh-catalyzed enantioselective hydrogenation of homoallylic alcohols.12 We were attracted to this type of ligand because the ester moiety appears to extend outward, potentially providing a chiral environment around the gold atom (Figure 1). We were pleased to find that, while only a low degree of enantioinduction was observed with L5Au(I)-catalyzed reaction of 1 (entry 6), this complex catalyzed the formation of cycloadduct 4 in an encouraging 66% ee;13 however, a small amount of the competing [4+3]-cycloaddition was observed (entry 7). The chemo- and enantioselectivity of this transformation could be improved by changing the solvent from dichloromethane to benzene (entry 8). Employing the H8-BINOL derived ligand L6 resulted in substantially improved enantioselectivity, yielding 4 in 82% ee in dichloromethane (entry 9). In this case, the use of benzene as solvent resulted in formation of substantial amounts of the [4+3]-cycloadduct (entry 10). The chemoselectivity was restored by replacing the SbF6-counterion with BF4-, allowing for the L6Au(I)-catalyzed formation of 4 in 92% ee with complete diastereo- and chemoselectivity (entry 11). Unfortunately, significant erosion in the enantiomeric excess was observed in the L6Au(I)-catalyzed reaction of 1, providing cycloadduct 3 with low enantioselectivity (entries 12 and 13).

Figure 1
X-ray structure of (S,S,S)-L5AuCl. Side view (top) and view along the C3 axis of the chiral complex (bottom).

Given the promising results and with optimized reaction conditions, we set out to examine the scope of the enantioselective gold(I)-catalyzed [4+2] cycloaddition reaction. Substitution on the diene component was well tolerated, efficiently providing 5 and 6 in 88% and 82% ee, respectively (Table 2, entries 2 and 3). Accordingly, a 1,1-disubstituted diene underwent the gold(I)-catalyzed cycloaddition to afford cycloadduct 6 containing a quaternary stereogenic center (entry 3). Variation in the allene provided 7 and 8 with little decrease in enantiomeric excess (entries 4 and 5). In all cases, the reactions were highly diastereoselective, affording exclusively the trans-fused bicyclo[4.3.0]nonane ring system.

Table 2
Asymmetric gold(I)-catalyzed cycloadditions of allenedienes with L6AuCl.

With the exception of the formation of 5, the reaction was also highly selective for the [4+2]-cycloadduct with no observable formation of the isomeric [4+3]-counterparts. Importantly, silica gel chromatography of the crude reaction allowed not only for the purification of the desired product, but also for the recovery of the L6AuCl complex in up to 84% yield (Scheme 1). The recovered catalyst could be reused with no observable erosion in the enantioselectivity of the product.

Scheme 1
Recovery of L6AuCl.

As a result of the low enantiomeric excess observed in the cycloaddition leading to pyrrolidine 3 (Table 1, entries 12 and 13) we returned to chiral phosphoramiditegold(I) complexes as catalysts. Our initial studies pointed to the fact that the latter catalyst could potentially be more selective in the cycloadditions of N-Tos tethered substrates (Table 1, entries 4 and 5). Thus, when the phosphoramidite dimethylamine moiety was changed to a bis(phenylethyl)amine ((S,S,S)-L7),14 the gold(I)-catalyzed reaction produced 3 with a modest improvement in enantioselectivity to 21% ee (89% yield). Examination of the X-ray crystal structure of L4AuCl (Figure 2) suggested that ortho-substitution on the phosphoramidite ligands15 might provide a steric environment similar to that found with phosphites L5 and L6. After a systematic study of various substituents, we were pleased to find that the gold(I)-complex of pyrenyl-substituted ligand L8 catalyzed the formation of 3 in 83% yield and with a markedly improved 99% ee (eq. 1).16 Similarly, varying the allene moiety also produced pyrrolidine 10 in 91% ee and an excellent 99% ee.17

Figure 2
X-ray structure of (S)-L4AuCl.

equation image

In conclusion, we have demonstrated that high enantioselectivity can be achieved for gold(I)-catalyzed intramolecular [4+2] cycloaddition reactions of dieneallenes. Two complementary catalyst systems have been developed: C3-symmetric phosphitegold(I) complexes are employed for the enantioselective synthesis of trans-hexahydroindenes and pyrrolidine products are prepared using ortho-arylphosphoramiditegold(I) complexes as catalysts. These studies demonstrate that, despite the linear geometry of gold(I) complexes, chiral monodentate phosphorous ligands can be employed in asymmetric gold(I) catalysis.8 Application of these phosphite and phosphoramiditegold(I) complexes in other enantioselective transformations are ongoing and will be reported in due course.

Figure 3
X-ray structure of (S,S,S)-L8AuCl.

Supplementary Material






We acknowledge funding from the National Institute of General Medical Services (GM073932), Bristol-Myers Squibb and Novartis. A. Z. González thanks the NIH for a postdoctoral fellowship. We thank R. M. Zeldin (UC, Berkeley) for preliminary experiments, Dr. B. K. Corkey (UC Berkeley) for obtaining the X-ray structure of L4AuCl and Johnson Matthey for a generous gift of AuCl3.


Supporting Information Available Experimental procedures and compound characterization data (PDF). This material is available free of charge via the Internet at


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13. All other derivatives in which the adamantyl ester was varied gave lower enantioselectivities (see Supporting Information)
14. The gold(I)-catalyzed reaction of 1 using (R,S,S)-L7 as the ligand afforded 3 in 92% yield and 0% ee.
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16. For additional ortho-substituted phosphoramiditegold(I) complexes that were examined see Supporting Information.
17. Chiral phosphoramiditegold(I)-catalyzed reactions of 2 gave 4 with only modest enantioselectivitity (up to 54% ee). L8AuCl/AgSbF6 catalyst system reacted sluggishly with 2.