Tetrakis{1-[(4-dodecylphenyl)sulfonyl]-(2S)-prolinate} Dirhodium

[179162-32-4]  · C90H140N4O16Rh2S4  · (1866)

(chiral catalyst for asymmetric reactions of diazo compounds, especially aryldiazoacetates and vinyldiazoacetates1)

Physical Data: mp 195-200°C [a]22D -165 ° (c = 1, CHCl3); 1H NMR (200 MHz, CDCl3) d 7.74 (d, 8 H, J = 9.2 Hz), 7.53 (d, 8 H, J = 9.2 Hz), 4.32 (m, 4 H), 3.25 (m, 4 H), 3.05 (m, 4 H), 2.07 (m, 4 H), 1.85 (m, 4 H), 1.57 (m, 8 H), 1.25 (bs, 36 H), 0.85 (m, 10 H).

Solubility: very soluble in most organic solvents including hydrocarbons.

Form Supplied in: green solid; available from Aldrich Chemical Co. The linear alkylbenzene side chains consist of a mixture of 1% C10, 40% C11, 28% C12 and 31% C13.

Preparative Methods: from dirhodium tetraacetate by ligand exchange with N-[1-(dodecylphenyl)sulfonyl]-(2S)-prolinate.2

Purification: further purification is generally not necessary. May be dried by heating under vacuum at 100°C. May be purified by column chromatography on silica with ether/petroleum ether as solvent. If contaminated with the free ligand, can be purified by dissolving in diethyl ether and extracting the organic layer with aqueous sodium bicarbonate, followed by drying the organic layer over MgSO4, then filtering and evaporation of the solvent.

Handling, Storage, and Precautions: the catalyst is moisture, air, and thermally stable. It may be stored at room temperature for extended periods of time without any apparent decomposition. The toxicity of the title reagent, Rh2(S-DOSP)4, is unknown. Strong nucleophiles such as nitriles, phosphines, amines, pyridines, and sulfides will tend to coordinate to the axial site of the catalyst. This may cause partial poisoning of the catalyst or catalyst decomposition, depending on the coordinating ligand. Reactions carried out under non-anhydrous conditions tend to result in lower enantioselectivity.3


The title reagent Rh2(S-DOSP)4 and its R-enantiomer have been shown to be exceptional chiral catalysts for transformations of carbenes derived from aryldiazoacetates and vinyldiazoacetates. The related p-tert-butylphenyl prolinate derivative Rh2(TBSP)4 is also commercially available. All of these catalysts display higher levels of asymmetric induction in reactions that are carried out in hydrocarbon solvents and Rh2(DOSP)4 is generally favored over Rh2(TBSP)4 because it is soluble in hydrocarbon solvents even at -78°C. All of these catalysts are considered to be conformationally flexible but preferentially adopt a D2-symmetric arrangement in solution.1,2 This is a critical component for their effectiveness as chiral catalysts. Conformationally rigid analogs of Rh2(S-DOSP)4 have been reported4 and these are also promising chiral catalysts.

Asymmetric Cyclopropanations

Rh2(S-DOSP)4 has been shown to be an exceptional chiral catalyst for asymmetric cyclopropanations of vinyldiazoacetates,2,5 aryldiazoacetates,6 and alkynyldiazoacetates.7 Enantioselectivities of greater than 90% ee are very common with this catalyst. The decomposition of a vinyldiazoacetate by Rh2(S-DOSP)4 in the presence of styrene generates a vinylcyclopropane in 98% de and 98% ee (eq 1). This product has been applied to the asymmetric synthesis of (+)-sertraline8 and the cyclopropane analogs of phenylalanine.2

A special feature of Rh2(S-DOSP)4 is that it is designed for asymmetric transformations of donor/acceptor substituted carbenoids, unlike most of the chiral catalysts for diazo decomposition which are optimized for the cyclopropanation chemistry of unsubstituted diazoacetates.9 Indeed, the rhodium prolinates rarely induce good asymmetric induction in the reactions of other classes of carbenoids.2,10 The highest levels of enantioselectivity are obtained when the reactions are carried out in hydrocarbon solvents, and Rh2(S-DOSP)4 is ideally suited because it is soluble in hydrocarbon solvents even at -78°C.2 Typically, 1 mol% of catalyst is used and the reactions are virtually instantaneous at room temperature, while at -78°C, the reaction times are 12-48 h. Several comparison studies with various other chiral rhodium and copper catalysts have been reported in recent years,6b,c,11 but so far none have outperformed Rh2(S-DOSP)4 on a regular basis. Cyclopropanations with Rh2(S-TBSP)4 carried out under non-anhydrous reaction conditions result in considerable lowering of the enantioselectivity.3 Using trioctylphosphine oxide as an additive can minimize this effect.3 Asymmetric cyclopropanations have also been carried out with Rh2(S-TBSP)4 in supercritical fluids.3

Rh2(S-DOSP)4 catalyzed decomposition of vinyldiazoacetates in the presence of vinyl ethers leads to donor/acceptor substituted vinylcyclopropanes.12 On treatment with diethylaluminum chloride these vinylcyclopropanes undergo a stereoselective rearrangement to cyclopentanes. An illustrative example is shown in eq 2, whereby the tricyclic system is formed in 86% ee.12 The extent of retention of the asymmetric induction during the vinylcyclopropane rearrangement is very dependent on the cyclopropane substitution pattern.

Rhodium(II) carboxylate-catalyzed decomposition of vinyldiazoacetates in the presence of dienes is a very effective stereoselective method for the construction of highly functionalized cycloheptadienes.13 The [3+4] cycloaddition proceeds via a divinylcyclopropane, which undergoes a Cope rearrangement in a stereodefined manner, leading to cycloheptadienes with stereocontrol at up to three stereogenic centers. When these reactions are catalyzed by Rh2(S-DOSP)4 highly enantioselective reactions are obtained.14 The reactions with phenylbutadiene and cyclopentadiene illustrate the synthetic potential of this chemistry (eq 3 and 4).14 Asymmetric [3+4] cycloadditions are also possible between vinylcarbenoids and furans15 or N-BOC-pyrroles16 leading to the synthesis of 8-oxabicyclo[3.2.1]octadienes or tropanes.

Reasonably high asymmetric induction can be obtained in intramolecular cyclopropanations.17 Rh2(S-DOSP)4-catalyzed decomposition of a Z,E-diene generated a tricyclic system in 93% ee with full control of relative stereochemistry (eq 5). As this reaction initially forms a trans-divinylcyclopropane, heating to 140°C is required to induce equilibration to the cis-divinylcyclopropane followed by the Cope rearrangement. In general, the intramolecular cyclopropanations are not as highly enantioselective as the intermolecular cyclopropanations, and with certain substrates, other chiral catalysts can result in higher enantioselectivity than Rh2(S-DOSP)4.18

Aryldiazoacetates are capable of being used in solid-phase synthesis.19 The traditional diazoacetates do not react effectively with substrates on solid support because the carbenoid intermediates are highly reactive and prone to dimerization.20 The carbenoids derived from aryldiazoacetates are considerably more chemoselective,21 and when Rh2(S-DOSP)4 is used as catalyst, effective asymmeric cyclopropanation of an alkene on a solid support is possible (eq 6).19 This protocol can be used to achieve asymmetric cyclopropanation of elaborate alkenes because the alkene is used as the limiting reagent.

[3+2] Cycloaddition

The Rh2(S-DOSP)4 catalyzed reaction of certain vinyldiazoacetates with styryl ethers results in a very unusual transformation.22 As illustrated in eq 7, instead of the normal cyclopropanation, a [3+2] cycloaddition product is formed. Remarkably, this product is formed as the all cis diastereomer in 98% ee. Selective cuprate additions to these [3+2] cycloaddition products can generate, stereoselectively, cyclopentanes with five contiguous stereocenters.

Asymmetric C-H Insertion

A major advantage with the use of aryldiazoacetates is that effective intermolecular C-H insertions can be achieved.23 Rh2(S-DOSP)4-catalyzed decomposition of methyl phenyldiazoacetate in the presence of cyclohexane results in the formation of the C-H insertion product in 95% ee (eq 8).24 The reaction has been extended to a range of alkanes and the selectivity of competing insertions between secondary and tertiary C-H sites depends on a delicate balance between steric and electronic effects.24

Highly efficient C-H insertion into allylic C-H positions is possible as illustrated in the example with 1,4-cyclohexadiene shown in eq 9.25 Similar highly enantioselective C-H insertions are possible with cycloheptatriene,26 while the reaction with cyclohexene proceeded with moderate enantioselectivity but poor diastereoselectivity.27

The intermolecular C-H insertion is a very general method for C-H functionalization and represents a surrogate to many classic synthetic transformations. The allylic C-H insertion of trisubstituted vinyl silyl ethers shown in eq 10 represents the equivalent of an asymmetric Michael addition.28 Remarkably, the C-H insertion product in this case is formed with very high diastereoselectivity. In general, high diastereoselectivity is observed for C-H insertions at methylene sites in which there is considerable size differential between the two substituents.23

Another spectacular example of a highly diastereoselective intermolecular C-H insertions is the reaction between aryldiazoacetates and tetralkoxysilanes, which generate silyl-protected b-hydroxy esters,29 products that would be typically prepared by an aldol reaction. The utility of this reaction is illustrated in the example with tetraethoxysilane, in which the C-H insertion product is formed in 95% ee and >90% de (eq 11). Highly diastereoselective C-H insertions are also possible with allyl silyl ethers.30

C-H insertions adjacent to nitrogen results in the formation of products that would be typically formed by a Mannich reaction. N-BOC-pyrrolidine is another substrate that undergoes highly diastereoselective C-H insertions, as illustrated in eq 12.31 The related reaction with N-BOC-piperidine31,32 is also a very important transformation because it represents a very direct synthesis of ritalin.

The chemoselectivity of the C-H insertion is sufficiently great that these reactions can display very impressive levels of kinetic resolution.33 An illustrative example is the C-H insertion with the racemic 2-substituted pyrrolidine derivative shown in eq 13.33 The C-H insertion product is formed in 98% ee with excellent control of stereochemistry at three stereogenic centers. By appropriate control of reaction conditions, a double C-H insertion on N-BOC-pyrrolidine is possible, generating a 2,5-disubstituted pyrrolidine with excellent control of stereochemistry at four stereogenic centers.31

Highly asymmetric intramolecular C-H insertions are also possible in Rh2(S-DOSP)4-catalyzed reactions, as illustrated in eq 14.34 The level of asymmetric induction is very dependent on the substitution pattern at the C-H insertion site, with the highest level of C-H insertion obtained for reactions at tertiary C-H sites.34,35

Combined C-H Insertion Cope Rearrangement

The reaction of vinyldiazoacetates at allylic C-H sites does not result in the predominant formation of the products of a simple C-H insertion.25 Instead, combined C-H insertion/Cope rearrangement products with very high enantioselectivity are formed, as illustrated in the example shown in eq 15.25 This process has been applied to a very short asymmetric synthesis of (+)-sertraline.

Si-H Insertions

Vinyldiazoacetates and aryldiazoacetates are capable of undergoing effective asymmetric Si-H insertions when the reaction is catalyzed by Rh2(S-DOSP)4. An illustrative example is shown in the reaction of a vinyldiazoacetate that results in the formation of an allylsilane in 95% ee (eq 16).36

In summary, the Rh2(S-DOSP)4-catalyzed reactions of aryldiazoacetates and vinyldiazoacetates offer a wide range of applications in organic synthesis. The carbenoids derived from these diazo systems are highly chemoselective and the reactions catalyzed by Rh2(S-DOSP)4 are often highly enantioselective.

1. (a) Davies, H. M. L., Aldrichimica Acta 1997, 30, 105. (b) Davies, H. M. L., Eur. J. Org. Chem. 1999, 2459.
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Huw M. L. Davies

University at Buffalo, The State University of New York, Buffalo, NY, USA

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