(R,R)-1,2-Bis(aminocarbonylphenyl-2-diphenylphosphino)cyclohexane

[138517-61-0]  · C44H40N2O2P2  · (690.76)

(chiral phosphine ligand used in asymmetric Pd0-catalyzed allylic substitution reactions)1

Physical Data: mp 134-136°C.2

Solubility: soluble in chlorinated solvents, ethers, alcohols, toluene and most organic solvents. Partially soluble in acetonitrile.

Form Supplied in: white to off-white crystalline solid. Major impurity is the corresponding monophosphine oxide (<1%).

Analysis of Reagent Purity: NMR and IR details are available.3,4 Optical rotation [a]D25 +46.7 (c 2.4, CH2Cl2).3 [a]D25 +88 (c 7.0, CH2Cl2);2 crystalline material. Chiral HPLC: Chiracel OD-R, UV 210 nm, 0.8 mL min-1, 100% MeOH. Retention time (R,R)=6.3 min, retention time (S,S)=9.4 min. Achiral HPLC: Hypersil BDS C8, UV 254 nm, 1.0 mL min-1, 85% MeOH, 15% H2O. Retention time ligand=9.5 min, retention time monophosphine oxide=5.2 min, retention time bisphosphine oxide=3.6 min.

Preparative Methods: commercially available. The ligand can be prepared by the coupling of (1R,2R)-(-)-1,2-diaminocyclohexane [20439-47-8] with 2-(diphenylphosphino)benzoic acid [17261-28-8],5 using reagents such as DCC.3 An alternative procedure has been developed whereby (1R,2R)-(+)-1,2-diaminocyclohexane L-tartrate salt [39961-95-0]6 is coupled to a mixed anhydride of 2-(diphenylphosphino)benzoic acid and diphenylchlorophosphate.2 The procedure is reproduced below 2-(Diphenylphosphino)benzoic acid (20 g, 65.3 mmol, 2 equiv) is suspended in dichloromethane (150 mL) and cooled in an ice-water bath to 0°C (internal temperature). Triethylamine (10.1 mL, 71.8 mmol, 2.2 equiv) is added dropwise and a clear solution is obtained. This process is exothermic and a rise in temperature to 5°C is observed. The solution is re-cooled to 0°C and diphenylchlorophosphate (13.4 mL, 64.7 mmol, 1.98 equiv) is added slowly, maintaining the internal temperature between 0-5°C. The yellow solution is stirred for 1 h at 0°C. (1R,2R)-(+)-1,2-Diaminocyclohexane-L-tartrate salt (8.63 g, 32.65 mmol, 1 equiv) is suspended in water (50 mL, 5.8 vol) and potassium carbonate (15 g, 107.8 mmol, 3.3 equiv) is added. This process is exothermic and a clear solution is obtained after approximately 10 min. After 30 min, the clear aqueous solution of diamine is added to the mixed anhydride solution at 0°C, and the resulting yellow two-phase mixture is stirred for 2 h at 0°C, then allowed to warm to room temperature. After 14 h, the mixture is poured into a separating funnel and 200 mL of dichloromethane and 100 mL of water are added. The organic phase is separated, washed with 2 N HCl (100 mL) and saturated aqueous NaHCO3 solution (100 mL), then dried over magnesium sulfate. The dried organic phase is filtered through a silica pad and the pad is washed with dichloromethane (50 mL). The combined filtrates are evaporated to dryness under reduced pressure, producing a yellow foam (22.3 g, 99% crude). The foam is crystallized from boiling acetonitrile (390 mL, 17.5 vol) to afford a white crystalline solid. The solid is dried under vacuum to provide the phosphine ligand (15 g, 67%).

Purification: column chromatography on silica gel, eluting with 15-30% ethyl acetate/hexanes.3,4 Recrystallization from hot acetonitrile.2,7

Handling, Storage, and Precautions: store under nitrogen at room temperature. Oxidation to phosphine oxides may occur upon prolonged exposure to air. No known toxicology data.

Chiral Diphosphine Ligands

In 1992, Professor Barry Trost introduced a family of chiral diphosphine ligands for palladium(0)-catalyzed asymmetric allylic substitution reactions. The first ligands were based on 2-(diphenylphosphino)benzoic acid with a variety of chiral backbones.3 The most useful of these backbones are trans-1,2-diaminocyclohexane, trans-1,2-diphenylethanediamine, and trans-11,12-diamino-9,10-dihydro-9,10-ethanoanthracene. The ligand based on the diaminocyclohexane backbone has proved to be the most generically useful ligand, with the most reported applications. Throughout this text the term ‘ligand’ refers to (R,R)-1,2-bis(aminocarbonylphenyl-2-diphenylphosphino)cyclohexane.

Catalyst Preparation

Two palladium sources are generally used to form the active precatalysts (1) and (2) in situ, the allylpalladium chloride dimer [12012095-2] and the tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct [52522-40-4]. For the palladium dibenzylideneacetone complex (1), NMR data to support the proposition that the bis-phosphine acts as a bidentate ligand has been reported.8 A triflate salt of the p-allyl palladium complex has been isolated and is stable in the solid state. However, no crystals suitable for X-ray analysis were obtained.7 An X-ray crystal structure of the ligand and a bis-palladium complex has been reported.7 The palladium complexes are generated just before use under an inert atmosphere; exposure to air affords a catalytically inactive tetra-coordinated palladium(II) species.8

Reactions with Carbon Nucleophiles

A wide range of carbon nucleophiles have been used in asymmetric allylic alkylation reactions (AAA). The first reported reactions involved the use of the sodium salt of malonates as the nucleophile. Five-, six-, and seven-membered ring allylic acetates and carbonates (in general, the carbonates are more reactive substrates) are ionized by the catalyst, prepared from the ligand and a palladium source, to provide a single palladium(0) intermediate (eq 1). Reaction of the intermediate with the sodium malonate in the presence of tetra-n-hexylammonium bromide gives the malonate product in high yield (n=1, 81%) and enantiomeric excess (n=1, 98%).9 The use of microwave radiation has been reported to accelerate the rate of this reaction with carbon, oxygen and nitrogen nucleophiles.10

In addition to cyclic allylic substrates, malonate nucleophiles have been used in reactions with both symmetrical11 and unsymmetrical12 acyclic systems, and with geminal dicarboxylates.13 Malonates and Meldrum's acid have also been used as nucleophiles in the desymmetrization of meso diesters.14

Azlactones have been used as nucleophiles to provide access to a variety of a-alkylated amino acid derivatives. This has been demonstrated with 3-acetoxycyclohexene and with geminal dicarboxylates (eq 2).15 The enantiomeric and diastereoisomeric excess of the products increase with more bulky R groups.

This method has also been applied to unsymmetrical acyclic allyl esters.16 The reaction of an azlactone with a geminal diacetate substrate gave access to an advanced intermediate for the synthesis of sphingofungin F.17

This methodology has been used to provide efficient protocols for the asymmetric allylic alkylation of b-keto esters,18 ketone enolates,19 barbituric acid derivatives,20 and nitroalkanes.21

Several natural products and analogs have been accessed using asymmetric desymmetrization of substrates with carbon nucleophiles. The palladium-catalyzed reaction of a dibenzoate with a sulfonylsuccinimide gave an advanced intermediate in the synthesis of L-showdomycin (eq 3).22

The alkylation of a dibenzoate with (phenylsulfonyl)nitromethane gave an intermediate for the synthesis of (+)-valienamine.23

The reaction of azlactones or a Meldrum's acid derivative with 2-phenylbut-3-ene-2-yl acetate, in the presence of the racemic ligand and a palladium source has provided a new method for controlling alkene geometry. By varying the reaction conditions excellent selectivities for either E or Z geometry could be obtained.24

Reactions with Nitrogen Nucleophiles

The palladium(0)-catalyzed asymmetric desymmetrization of cis-3,5-dibenzoyloxy-1-cyclopentene, with 6-chloropurine and 2-amino-6-chloropurine as nucleophiles, has been utilized in the synthesis of (-)-carbovir25 and (-)-neplanocin.26 In these examples, the diphenylethanediamine3 and the anthracenyldiamine3 based ligands were found to be superior to the standard ligand.

Phthalimide has been used as a nucleophile with cyclic (as depicted for carbon nucleophiles in eq 1)9 and acyclic allylic carbonates.27 In addition, phthalimide has been used for the amination of 3,4-epoxybut-1-ene and, in this case, the 1,2-bis(aminocarbonyl-1'-naphthyl-2-diphenylphosphino)cyclohexane ligand was found to provide the catalyst of choice.28

Azide has been used as a nucleophile in the desymmetrization of a dicarbonate derivative (eq 4).29 In this example, a key intermediate in the synthesis of (+)-pancratistatin was produced.

Basic hydrolysis of the allylic azide affords the rearranged 1,2-isomer, which was an intermediate in the synthesis of (+)-conduramine E.30 Following a similar strategy, but starting with cis-3,6-dibenzoyloxycyclohex-1-ene, a total synthesis of the non-opioid analgesic (-)-epibatidine was developed.31

Trost has reported enhanced enantioselectivity in the desymmetrization of meso-biscarbamates in the presence of triethylamine.32 Under these conditions, high yields (>80%) and enantiomeric excesses (93-99% ee) are obtained. This methodology has been applied to the synthesis of (-)-swainsonine.33

a-Amino esters have been used as nucleophiles in the reaction with acyclic allylic esters and isoprene monoepoxide, providing access to diastereoselective N-alkylated a-amino esters.34 By employing the feature ligand, asymmetric palladium(0)-catalyzed cyclization of 2-(tosylamino)phenol with (Z)-1,4-bis[(methoxycarbonyl)oxy]but-2-ene provides 2-vinylbenzomorpholine in 79% ee.35 A number of alternative diphosphine ligands were studied and found to be inferior.

The asymmetric synthesis of indolizidine alkaloids is described utilizing a palladium-catalyzed amination process. Ionization of an allylic carbonate provides a symmetrical p-allyl palladium complex, subsequent reaction with a protected homoallylamine gave the product in 93% yield and >99.5% ee (eq 5).36

The product of the allylic amination process is set up for a ring-closing-ring-opening metathesis process, and subsequent elaboration to alkaloid derivatives.

Reactions with Oxygen Nucleophiles

The first report of the reaction of oxygen nucleophiles was for the deracemization of cyclic allylic ethers, for example, the palladium(0)-catalyzed reaction of 2-cyclohexenyl-1-methyl carbonate with sodium pivalate afforded the pivalate ester in 94% yield and 92% ee.37 This reaction was extended to other cyclic allylic carbonates.

Racemic conduritol B acetates and carbonates provide very versatile substrates for asymmetric allylic substitution reactions. Reaction of conduritol B tetraacetate with sodium pivalate in the presence of a palladium catalyst, generated from the ligand and allylpalladium chloride dimer, resulted in a kinetic resolution to give the monosubstituted product in 44% yield (>99% ee) and the recovered tetraacetate in 50% yield (83% ee) (eq 6). This method provided a key intermediate for the synthesis of (+)-cyclophellitol.38

Later work has shown that a dynamic kinetic asymmetric transformation could be obtained if the acetates were converted into carbonate groups. With the tetra(2,2,2-trichloroethyl) carbonate derivative, reactions with carbon and nitrogen nucleophiles gave exclusively the monosubstituted products in high yield (61-95%) and excellent enantiomeric excesses (95-99%).39 However, carboxylate nucleophiles afforded the disubstituted products in high yield and enantiomeric excess (eq 7).39 This allowed an efficient synthesis of D-myo-inositol-1,4,5-trisphosphate to be devised.

The reaction of isoprene monoxide with a range of alcohol pronucleophiles in the presence of the ligand (3 mol%), Pd2dba3.CHCl3 (1 mol%) and triethylboron (1 mol%) gave the glycol monoethers in excellent yield and enantiomeric excess.40 The use of p-methoxybenzyl alcohol and 3-nonyl-3,4-epoxybut-1-ene afforded an intermediate that was converted into (-)-malyngolide (eq 8).41

Extending this methodology to 3,4-epoxybut-1-ene was not successful with the featured ligand and the more sterically encumbered 1,2-bis(aminocarbonyl-1-naphthyl-2-diphenylphosphino)cyclohexane ligand was required.40 The use of inorganic carbonates for the asymmetric synthesis of vinylglycidols has also been reported.42 Reaction of isoprene monoxide with sodium bicarbonate, or sodium carbonate in the presence of the ligand, Pd2dba3.CHCl3 and triethylboron afforded the diol in 91% yield and 97% ee. In the absence of triethylboron a cyclic carbonate was formed. Again, the 2-naphthyl ligand was required to provide optimum selectivity with 3,4-epoxybut-1-ene.42

The palladium(0)-catalyzed asymmetric O-allylation of phenols has been described using five-, six- and seven-membered ring allylic carbonates and acyclic allylic carbonates (eq 9).43 The products from these reactions were subjected to a Claisen rearrangement to provide C-alkylated phenols. A study of various ligands for the reaction of phenol with 2-cyclohexenyl-1-methyl carbonate clearly showed that the Trost ligand is superior.44

This methodology has been expanded to geranyl methyl carbonate for the synthesis of the vitamin E nucleus, and to tiglyl methyl carbonate for the synthesis of (-)-calanolide A and B.45 In the latter example, the anthracenyldiamine3-based ligand was required for optimum selectivity. The synthesis of (-)-aflatoxin B lactone utilizes a dynamic kinetic asymmetric transformation, whereby a suitably functionalized phenol reacts with a racemic 5-acyloxy-2-(5H)-furanone to provide a single product in 89% yield.46 One final example of phenol as a nucleophile is for the deracemization of Baylis-Hillman adducts.47

Cyclic 1,2-diketones, such as 3-methylcyclopentane-1,2-dione, act as oxygen nucleophiles in palladium(0)-catalyzed reactions with a range of cyclic and acyclic allylic esters.48 The products of these reactions were subjected to a lanthanide-catalyzed Claisen rearrangement to access the C-alkylated products.

Reactions with Sulfur Nucleophiles

The use of sulfur nucleophiles in palladium-catalyzed allylic substitution reactions is less well documented than that of carbon, nitrogen and oxygen nucleophiles. The asymmetric synthesis of allylic sulfones utilizing a catalytic phase transfer system has been used to produce (3S)-(phenylsulfonyl)cyclohex-1-ene on a 45 g scale (eq 10).49 In many cases, it has been reported that allylic carbonates are more reactive than allylic acetates in asymmetric allylic substitution reactions.49,50

A range of cyclic allylic carbonates was found to be useful in this process and a myriad of useful functionalized building blocks were accessed via dihydroxylation and epoxidation reactions.49 The reaction of lithium tert-butylsulfinate with acyclic allylic acetates in the presence of the ligand, Pd2(dba)3.CHCl3 and tetrahexylammonium bromide under phase-transfer conditions (CH2Cl2/H2O) led to a kinetic resolution whereby the starting material was isolated in 96% ee and the tert-butyl sulfone in 95% ee.50 With cyclic allylic carbonates, a single tert-butyl sulfone is obtained in 76-92% yield and 89-93% ee.50 However, stopping the reaction at 54% conversion gave the sulfone (49% yield, 98% ee) and the carbonate (34% yield, 99% ee), this kinetic resolution protocol was later extended to thiols with cyclic and acyclic allylic carbonates.51 In general, the synthesis of allylic sulfides requires higher catalyst loading and was found to be unsuccessful for tert-butyl thiol and thiophenol.52 However, cyclic and acyclic allylic S-p-chlorophenyl, S-2-pyridyl and S-2-pyrimidyl sulfides could be obtained in high yield and enantiomeric excess, in the presence of the ligand and Pd2(dba)3.CHCl3 in organic solvent.52

A more efficient method to access single enantiomer thiols and sulfides has been developed using a palladium(0)-catalyzed rearrangement of O-allylic thiocarbamates (eq 11).53

This reaction was carried out on cyclic and acyclic allylic carbonates. The S-allylic thiocarbamate products were hydrolyzed to the corresponding thiol or reacted with 2-chloropyrimidine in the presence of potassium hydroxide to provide the sulfide without any loss in stereochemical purity for either example.53

a-Acetoxysulfones can be regarded as acid-stable, but base-labile, chiral aldehyde equivalents. These can be accessed through the palladium(0)-catalyzed reaction of geminal esters with sodium benzenesulfinate under phase-transfer conditions (eq 12).54

Osmium tetroxide-catalyzed dihydroxylation of the chiral a-acetoxysulfones and acetonide formation affords versatile chemical intermediates. Reduction with DIBAL-H provides primary alcohols, and addition of Grignard reagents provides secondary alcohols with excellent stereochemical control of the newly formed chiral center.54


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2. Lennon, I. C.; Berens, U.,WO 99/51614 (October 1999).
3. Trost, B. M.; Van Vranken, D. L.; Bingel, C., J. Am. Chem. Soc. 1992, 114, 9327.
4. Trost, B. M.; Van Vranken, D. L.; Bunt, R. C., US Patent 5,739,396 (April 1998).
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6. Larrow, J. F.; Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.; Zepp, C. M., J. Org. Chem. 1994, 59, 1939.
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9. Trost, B. M.; Bunt, R. C., J. Am. Chem. Soc. 1994, 116, 4089.
10. Bremberg, U.; Lutsenko, S.; Kaiser, N.-F.; Larhed, M.; Hallberg, A.; Moberg, C., Synthesis 2000, 1004.
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Ian C. Lennon

Chirotech Technology Limited, Cambridge, UK



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