The development of new enantioselective methods for the formation of cyclopentane rings containing multiple stereocenters is of importance both in organic and medicinal chemistry.[1] A powerful approach would be a metal catalyzed asymmetric formal [3+2]-cycloaddition between a 1,3-dipole and an olefin; it would allow for the construction of the cyclopentane and form multiple stereocenters in a single synthetic step. Additionally development of this methodology would identify new “three-carbon-atom” precursors for asymmetric cycloadditions, beyond the relatively small number that currently exist in the literature.[2]
Vinyl epoxides, aziridines, and cyclopropanes bearing electron withdrawing groups are known to open into 1,3-dipoles in the presence of palladium(0) catalysts. The resulting Pd(II) complexes add across olefins,[3] isocyanates,[4,5] carbodiimides,[6] and aldehydes[7] to afford five-membered rings. We hypothesized that we could use 1,3-dipoles generated from vinyl cyclopropanes as a novel three carbon fragment to generate cyclopentanes in an asymmetric fashion via palladium catalysis.
Tsuji has reported that vinylcyclopropane 1a adds across methyl vinyl ketone in the presence of Pd2dba3 and bis(diphenylphosphino)ethane to afford vinylcyclopentane 3 (Scheme 1).[3] Later, Johnson demonstrated the Pd-catalyzed additions of the vinyl cyclopropane 1a to aldehydes.[7] However, he needed to employ an alternative strategy using chiral Lewis acid catalysts to achieve asymmetric induction, a process that has not been expanded to electron poor olefins.[8,9]
Scheme 1.
Palladium-catalyzed addition of vinyl cyclopropanes 1 to electron poor olefins.
Previously, the class of chiral ligands, developed in our laboratory (L1-L4) for the Pd-catalyzed asymmetric allylic alkylation, have been employed to induce asymmetry at both the prochiral nucleophile and/or at the carbon of the π-allyl which is being attacked.[10a,b,c] However, it has not been demonstrated for these ligands to be able to control stereochemistry in a bond forming event distal to the π-allyl Pd-complex. Our proposed Pd-catalyzed formal [3+2]-cycloaddition is a new challenge for these chiral ligands, in that it is requisite for them to control the stereochemistry of the Michael addition by the malonate carbanion, in addition to the stereochemistry at the nucleophile and the allyl center.
To explore the prospect of this new class of asymmetric 1,3-dipole donors, we chose alkylidene azlactones as acceptors since these olefins should represent a reactive and useful class that would generate an interesting family of conformationally constrained α-amino acids.[11] Promisingly, when 1a and 4a were combined with Pd2(dba)3·CHCl3 (3 mol %) and L1 (9 mol %) in toluene at room temperature, the desired [3+2]-cycloadduct was observed, albeit in only a 16% yield with a 10:1 dr and 60% ee.
Attributing the low reactivity of the dipole 2 derived from precursor 1a to its low lifetime, we speculated that the trifluoroester 1b might possess sufficiently greater stability to increase its lifetime, while at the same time maintaining reactivity.[12] Indeed, by combining our more reactive vinyl cyclopropane 1b and Michael acceptor 4a, we were able to observe the desired product in 64% yield, 19:1 dr and 96% ee (Table 1, entry 1). Notably, only two of four possible diastereomers were observed, one of which was heavily favored. Furthermore, the reactions proceeded well at room temperature.
Table 1. Selected optimization results.
| Entry | Ligand | Solvent | Yield[a] | dr[b] | ee[c] |
|---|---|---|---|---|---|
| 1 | L1 | Toluene | 64% | 19:1 | 96% |
| 2 | L2 | Toluene | 61% | 19:1 | 92% |
| 3 | L3 | Toluene | 66% | 15:1 | -87% |
| 4 | L4 | Toluene | 21% | 4:1 | 23% |
| 5 | L1 | α,α,α-Trifluorotoluene | 69% | 4:1 | 83% |
| 6 | L1 | THF | 14% | 15:1 | 89% |
| 7 | L1 | CH2Cl2 | 77% | 8:1 | 91% |
| 8 | L1 | Dioxane | 82% | 14:1 | 94% |
Isolated yields.
Diastereomeric ratios determined by 1H NMR spectroscopy.
Determined by chiral HPLC.
Further ligand (Table 1, entries 2-4) and solvent (Table 1, entries 5-8) optimization confirmed that ligand L1 was differential, and the highest selectivities were observed with toluene. Dioxane provided higher yields at only a modest decrease in stereoselectivity (Table 1, entry 8). We also found the catalyst loading could be reduced from 6% to 4%.
We then sought to evaluate the scope of the reaction with a variety of aryl-substituted azlactones, using the conditions for optimal diastereoselectivity (Table 2). Moderately election-withdrawing substituents in the meta- and para- positions (entries 1-3) were well tolerated, maintaining high levels of enantioselectivity and diastereoselectivity. However, when a substituent was introduced in the ortho-position (entry 4), no product was obtained, presumably due to the additional steric bulk. The moderately electron rich 2-naphthyl system was also well tolerated (entry 5). A substrate bearing a highly electron withdrawing substituent (entry 6) proved slightly detrimental to the enantioselectivity and diastereoselectivity, while electron rich furan (entry 7) gave excellent diastereoselectivity, enantioselectivity and yield.
Table 2.
Cycloaddition of vinyl cyclopropanes with aryl alkylidene azlactones.
| |||||
|---|---|---|---|---|---|
|
| |||||
| Entry | Substrate | Product | Yield[a] | dr[b] | ee[c] |
| 1 |
|
|
78% | 19:1 | 98% |
| 2 |
|
|
70% | >19:1 | 93% |
| 3 |
|
|
83% | 19:1 | 94% |
| 4 |
|
|
0% | n.d. | n.d. |
| 5 |
|
|
84% | >19:1 | 94% |
| 6 |
|
|
72% | 8:1 | 85% |
| 7 |
|
|
87% | >19:1 | 95% |
Isolated yields.
Diastereomeric ratios determined by 1H NMR spectroscopy.
Determined by chiral HPLC.
Next, we examined non-aromatic substituents on the azlactone electrophile (Table 3). The cinnamyl derivative (entry 1) gave excellent selectivities, albeit in a slightly reduced yield. Notably, only 1,4-addition was observed. The n-hexyl derivative (entry 2) reacted well, affording a 63% yield of the desired product, with somewhat reduced diastereo- and enantioselectivity. Increasing the steric bulk to cyclohexyl led to no product formation (entry 3), suggesting sensitivity to steric effects on the electrophile, similar to the ortho-methoxyphenyl group (Table 2, entry 4). Finally, both a protected alcohol in the alkyl chain (entry 4) and a heteroatom were well tolerated, with no elimination products observed in the latter case (entry 5). Those azlactones which are more reactive for steric (6b) or electronic reasons (4g), gave reduced diastereo- and enantioselectivities, while those with increased steric bulk (6c) or with electron donating (6a) substituents appeared gave good selectivity but reduced (or no) yield.
Table 3.
Cycloaddition of vinyl cyclopropanes with non-aryl alkylidene azlactones.
| |||||
|---|---|---|---|---|---|
|
| |||||
| Entry | Substrate | Product | Yield[a] | dr[b] | ee[c] |
| 1 |
|
|
51% | >19:1 | 94% |
| 2 |
|
|
63% | 8:1 | 74% |
| 3 |
|
|
0% | n.d. | n.d. |
| 4 |
|
|
64% | 3:1[d] | 77%[e] |
| 5 |
|
|
73% | 10:1 | 63% |
Isolated yields.
Diastereomeric ratios determined by 1H NMR spectroscopy.
Determined by chiral HPLC.
A 3:1 mixture of the E/Z isomers of 6d was used.
Determined on a derivative of this compound.
To rationalize the observed stereoselectivity, we propose a modification of our previously reported “wall and flap” model (Scheme 2). [10b,13] Both the matched and mismatched ionization of the starting vinyl cyclopropane ((R)-1b, (S)-1b)) occur to give complexes 8 and 9. By π-σ-π equilibration, 8 and 9 can interconvert to the thermodynamically-favored 8, where the malonate sits under the “flap,” in order to avoid the steric bulk of the “wall” in 9. The malonate anion attacks the alkylidene azlactone, when the aryl group on the alkylidene is oriented away from the back “wall” of the ligand (10). Finally, attack of the azlactone anion onto the π-allyl-palladium (11) provides the observed major diastereomer 5a.
Scheme 2. Mechanistic rationale.
In order to determine the stereochemistry of 5b, it was treated with sodium methoxide in methanol (Scheme 3) to afford trimethyl ester 12 in quantitative yield as a crystalline solid. Single crystal X-ray diffraction analysis secured the relative and absolute stereochemistry of 12.[14] Interestingly, our method provides a trans relationship between the vinyl and aryl groups, rather than the thermodynamically more favored cis diastereomer.[15]
Scheme 3.
Functionalization of cycloadduct for crystallographic analysis.
The juxtaposition of functionality allows for ready structural modification (Scheme 4). For example, treatment of 5f with dicyclohexyl borane in THF, followed by m-CPBA oxidation of the trialkylborane gives the primary alcohol in situ, which cyclizes onto the azlactone to give lactone 13.
Scheme 4.
One step functionalization to bicyclic system.
In conclusion, we have developed a new palladium-catalyzed enantioselective formal [3+2] cycloaddition between vinyl cyclopropanes and prochiral Michael acceptors. The use of the bis(2,2,2-trifluoroethyl)malonate vinylcyclopropanes allows for much higher yields and selectivities. Using alkylidene azalactones as the acceptor for this reaction provides access to highly functionalized chiral amino acid derivatives, a method which simultaneously sets three stereogenic centers in excellent enantio- and diastereoselectivies. This represents the first time this class of chiral ligands has been used to induce asymmetry in conjugate addition reactions, as well as the first time racemic vinyl cyclopropanes have been utilized in a formal [3+2] cycloaddition to form carbocycles in an asymmetric fashion. Work continues in our laboratory towards expanding the scope of this reaction towards a range of other acceptors.
Figure 1. Trost asymmetric allylic alkylation ligands.
Footnotes
This work has been supported by the National Science Foundation and the National Institutes of Health (GM033049). The authors thank Johnson Matthey for the gift of palladium salts, Dr. Allen Oliver of Notre Dame for X-ray crystallography, and Dr.Kami Hull for editorial assistance.
References
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