Highly selective palladium catalyzed kinetic resolution and enantioselective substitution of racemic allylic carbonates with sulfur nucleophiles: asymmetric synthesis of allylic sulfides,allylic sulfones,and allylic alcohols

We describe the highly selective palladium catalyzed kinetic resolutions of the racemic cyclic allylic carbonates rac-1 a-c and racemic acyclic allylic carbonates rac-3 aa and rac-3 ba through reaction with tert-butylsulfinate, tolylsulfinate, phenylsulfinate anions and 2-pyrimidinethiol by using N,N'-(1R,2R)-1,2-cyclohexanediylbis[2-(diphenylphosphino)-benzamide] (BPA) as ligand. Selectivities are expressed in yields and ee values of recovered substrate and product and in selectivity factors S. The reaction of the cyclohexenyl carbonate 1 a (>/=99 % ee) with 2-pyrimidinethiol in the presence of BPA was shown to exhibit, under the conditions used, an overall pseudo-zero order kinetics in regard to the allylic substrate. Also described are the highly selective palladium catalyzed asymmetric syntheses of the cyclic and acyclic allylic tert-butylsulfones 2 aa, 2 b, 2 c, 2 d and 4 a-c, respectively, and of the cyclic and acyclic allylic 2-pyrimidyl-, 2-pyridyl-, and 4-chlorophenylsulfides 5 aa, 5 b, 5 ab, 6 aa-ac, 6 ba and 6 bb, respectively, from the corresponding racemic carbonates and sulfinate anions and thiols, respectively, in the presence of BPA. Synthesis of the E-configured allylic sulfides 6 aa, 6 ab, 6 ac and 6 bb was accompanied by the formation of minor amounts of the corresponding Z isomers. The analogous synthesis of allylic tert-butylsulfides from allylic carbonates and tert-butylthiol by using BPA could not be achieved. Reaction of the cyclopentenyl esters rac-1 da and rac-1 db with 2-pyrimidinethiol gave the allylic sulfide 5 c having only a low ee value. Similar results were obtained in the case of the reaction of the cyclohexenyl carbonate rac-1 a and of the acyclic carbonates rac-3 aa and rac-3 ba with 2-pyridinethiol and lead to the formation of the sulfides 5 ab, 6 ab, and 6 bb, respectively. The low ee values may be ascribed to the operating of a "memory effect", that is, both enantiomers of the substrate give the substitution product with different enantioselectivities. However, in the reaction of the racemic carbonate rac-1 a as well as of the highly enriched enantiomers 1 a (>/=99 % ee) and ent-1 a (>/=99 % ee) with 2-pyrimidinethiol the ee values of the substrates and the substitution product remained constant until complete conversion. Similar results were obtained in the reaction of the cyclic carbonates rac-1 a, ent-1 a (>/=99 % ee) and ent-1 c (>/=99 % ee) with lithium tert-butylsulfinate. Thus, in the case of rac-1 a and 2-pyrimidinthiol and tert-butylsulfinate anion as nucleophiles the enantioselectivity of the substitution step is, under the conditions used, independent of the chirality of the substrate; this shows that no "memory effect" is operating in this case. Hydrolysis of the carbonates ent-1 a-c, ent-3 aa and ent-3 ba, which were obtained through kinetic resolution, afforded the enantiomerically highly enriched cyclic allylic alcohols 9 a-c (>/=99 % ee) and acyclic allylic alcohols 10 a (>/=99 % ee) and 10 b (99 % ee), respectively.     

Palladium-catalyzed enantioselective 1,3-rearrangement of racemic allylic sulfinates: asymmetric synthesis of allylic sulfones and kinetic resolution of an allylic sulfinate

Described is an asymmetric synthesis of cyclic and acyclic allylic S-aryl and S-alkyl sulfones through a highly selective palladium(0)-catalyzed 1,3-rearrangement of racemic allylic sulfinates. Treatment of racemic cyclic and acyclic allylic S-tolyl- and S-tert-butylsulfinates with Pd(2)(dba)(3).CHCl(3) as precatalyst and N,N'-(1R,2R)-1,2-cyclohexanediylbis[2-(diphenylphosphino)benzamide] as ligand for the palladium atom afforded the corresponding isomeric allylic S-tolyl and S-tert-butyl sulfones of 93-99% ee in 82-96% yield. The rearrangement of the allylic sulfinates most likely proceeds in an intermolecular fashion via formation of a cationic pi-allylpalladium complex and the sulfinate ion. The racemic allylic sulfinates were obtained from the corresponding racemic alcohols and racemic tolylsulfinyl chloride and racemic tert-butylsulfinyl chloride, respectively, in high yields. Rearrangement of the racemic tert-butylsulfinic acid 2-cyclooct-1-enyl ester with Pd(2)(dba)(3).CHCl(3) and the bisphosphane was accompanied by a highly selective kinetic resolution of the substrate and gave at 50% conversion the (R)-configured sulfinate as mixture of the S(S) and R(S) diastereomers of 92% ee and 85% ee and the (S)-configured 3-tert-butylsulfonyl cyclooctene sulfone 15a with 98% ee in almost quantitative yields.     

Features and applications of [Rh(CO)(2)Cl](2)-catalyzed alkylations of unsymmetrical allylic substrates

A novel regio- and stereoselective [Rh(CO)2Cl]2-catalyzed allylic alkylation of unsymmetrical allylic carbonates was discovered. The regioselectivity of the reaction favors product ratios in which substitution occurs at the carbon bearing the leaving group. When an enantiomerically enriched carbonate (> or = 99% ee) was examined, the Rh(I)-catalyzed allylic alkylation proceeded stereoselectively to provide the alkylation product with retention of absolute stereochemistry (98% ee). To establish the scope of the [Rh(CO)2Cl]2-catalyzed allylic alkylation, a variety of carbon and heteroatom nucleophiles were examined and the results described. As an application of the Rh(I)-catalyzed allylic alkylation, a series of novel domino reactions have been developed that couple the unique regio- and stereoselective [Rh(CO)2Cl]2-catalyzed alkylation of allylic trifluoroacetates with an intramolecular Pauson-Khand annulation, a cycloisomerization, or a [5+2] cycloaddition. A unique aspect of the method described is the use of a single catalyst to effect sequential transformations in which the catalytic activity is moderated simply by controlling the reaction temperature. Implementation of such processes provides a rapid and efficient entry to a variety of bicyclic carbon skeletons from simple precursors.     

A new class of chiral P,N-ligands and their application in palladium-catalyzed asymmetric allylic substitution reactions

An efficient and modular synthesis of a series of chiral nonracemic P,N-ligands is reported. The P,N-ligands were prepared from 2-chloro-4-methyl-6,7-dihydro-5H-[1]pyrindine-7-one and a series of substituted chiral C(2)-symmetric 1,2-ethanediols (R = Me, i-Pr, and Ph). The ligands were evaluated for use in catalytic asymmetric synthesis in the palladium-catalyzed allylic substitution reactions of a racemic allylic acetate and dimethyl malonate. In the case of the P,N-ligand (R = Ph), the reaction was found to be highly stereoselective (90% ee).     

Highly anti-selective SN2' substitutions of chiral cyclic 2-iodo-allylic alcohol derivatives with mixed zinc-copper reagents

[reaction: see text] Functionalized allylic electrophilic reagents such as chiral 2-iodo-1-cyclohexenyl and -cyclopentenyl phosphates undergo highly stereoselective anti-S(N)2'-allylic substitution reactions with a wide range of organozinc reagents (R(2)Zn and RZnI) leading to chiral products with a transfer of the chiral information >95%. The use of functionalized organozinc iodides allows preparation of the bicyclic enones 8 and 9 in >or=93% ee.     

Application of pyranoside phosphite-pyridine ligands to enantioselective metal-catalyzed allylic substitutions and conjugate 1,4-additions

A series of glucopyranoside phosphite–pyridine ligands have been applied in the metal-catalyzed allylic substitution and conjugate 1,4-addition reactions of several substrate types. We have been able to identify ligands that provided promising enantioselectivities in the Pd-catalyzed intermolecular allylic substitution of cyclic substrates (ee’s up to 86%) and desymmetrization (ee’s up to 94%) and in the Cu-catalyzed conjugate addition of challenging aliphatic enones (ee’s up to 90%).     

Enantioselective synthesis of alpha-alkyl-beta,gamma-unsaturated esters through efficient cu-catalyzed allylic alkylations

A method for enantioselective Cu-catalyzed allylic substitution between various alkylzincs and alpha,beta-unsaturated carboxylic esters that bear a gamma-phosphate is reported. These transformations afford alpha-alkyl-beta,gamma-unsaturated carbonyls with regioselectivities of 7:1 to >20:1 (S(N)2':S(N)2) and in 87-97% ee. The utility of the method is illustrated by a convergent total synthesis of topoisomerse II inhibitor (R)-elenic acid.     

Chiral lithium amide base-mediated rearrangement of meso-cyclohexene oxides: asymmetric synthesis of amino- and aziridinocyclohexenols

Two different chiral lithium amide base routes for the synthesis of amino- and aziridino-containing cyclohexenols have been explored. The first strategy involved the diastereoselective preparation of novel meso-aziridinocyclohexene oxides and their subsequent enantioselective rearrangement using chiral bases. In this approach, the diphenylphosphinoyl nitrogen protecting group proved optimal and aziridinocyclohexenols of 47-68% ee were obtained. Of particular note was the smooth rearrangement of the epoxide to an allylic alcohol in the presence of an aziridine: under optimised chiral base conditions, the aziridine remained essentially unaffected. A second more straightforward strategy for introduction of an amino functionality was also investigated: (1S,4R,5S)- and (1R,4R,5S)-4,5-bis(tert-butyldimethylsilyloxy)cyclohex-2-enols, readily prepared in > 95% ee using a chiral base approach, were subjected to Mitsunobu substitution using a sulfonamide and Overman rearrangement.     

Highly enantioselective synthesis of (E)-allylic alcohols

The asymmetric addition of alkenylzincs to aromatic and alpha-branched aliphatic aldehydes catalyzed by 1 generated the corresponding (E)-allylic alcohols with >95% ee and good to excellent chemical yields, especially >99.5% ee was observed in the case of 4-CF3-benzaldehyde. Notably, 1 is an effective ligand to catalyze the addition of disubstituted (R2 = R3 = ethyl) and bulky substituted (R2 = H, R3 = tert-butyl) alkenylzincs to benzaldehyde, affording the corresponding allylic alcohols both with 96% ee.     

A new type of C2-symmetric bisphospine ligands with a cyclobutane backbone: practical synthesis and application

[reaction: see text] A highly efficient and practical optical resolution of anti-head-to-head racemic coumarin dimer, (+/-)-5, by molecular complexation with TADDOL (6) through hydrogen bonding and a convenient transformation of enantiopure 5 to a new type of C(2)-symmetric bisphosphine ligand (3) have been achieved. The asymmetric induction efficiency of these chiral bisphosphine ligands was evaluated in Pd-catalyzed asymmetric allylic substitution, affording the allylic substitution products in excellent yield (up to 99%) and enantioselectivity (up to 98.9% ee).     

Synthesis of beta-substituted alpha-amino acids with use of iridium-catalyzed asymmetric allylic substitution

The asymmetric synthesis of beta-substituted alpha-amino acids with use of iridium-catalyzed allylic substitution was described. The Ir-catalyzed allylic substitution of diphenylimino glycinate with allylic phosphates proceeded smoothly even at 0 degrees C and gave branch products with high enantioselectivity (up to 97% ee), when chiral bidentate phosphite bearing the 2-ethylthioethyl group was employed. In addition, both diastereomers of the branch products were synthesized stereoselectively by simply switching the base employed. These methods were also applied to the asymmetric synthesis of quaternary alpha-amino acids.     

t-Bu-QuinoxP* ligand: applications in asymmetric Pd-catalyzed allylic substitution and Ru-catalyzed hydrogenation

The potential of the t-Bu-QuinoxP* ligand (1) as a chiral ligand in asymmetric synthesis was examined. The ligand exhibited good to excellent asymmetric induction in Pd-catalyzed asymmetric allylic substitution of 1,3-diphenyl-2-propenyl acetate (up to 98.7% ee) and in Ru-catalyzed asymmetric hydrogenation of ketones (up to 99.9% ee).     

Copper catalyzed enantioselective allylic substitution by MeMgX

Methyl Grignard undergoes highly regio (>90/10) and enantioselective (ee 91-96%) copper catalyzed allylic substitution on cinnamyl-type chlorides. CuBr (3%) and 3.3% of a chiral phosphoramidite ligand are sufficient for a complete reaction. The synthesis of a precursor of (+)-Naproxen is described. The reaction can be extended to alkyl substituted allylic chlorides (ee 72%).     

Asymmetric allylic substitutions on symmetrical and non-symmetrical substrates using [5]ferrocenophane ligands

A series of [5]ferrocenophane diphosphane ligands were used in Pd-catalyzed allylic substitution reactions. With a symmetrical substrate, 1,3-diphenylpropenyl acetate, enantioselectivities between 70% and 94% ee were observed. Several non-symmetrically substituted allylic substrates were also used. Depending on the substituents of the non-symmetrical allylic substrates, various degrees of regioselectivity (from 1:1 to 100:0) and enantioselectivity (from 0% to 96% ee) were observed. Tentative catalytically active complexes were studied by DFT computational methods.     

Chiral phosphine-catalyzed regio- and enantioselective allylic amination of Morita–Baylis–Hillman acetates

Enantioselective allylic substitution of Morita–Baylis–Hillman (MBH) acetates with phthalimide was realized in the presence of a novel l-proline-derived chiral trifunctional phosphine amide ligand to give the corresponding allylic amination adducts in good yields (70–95%) and in modest to good enantioselectivities (34–78% ee’s).     

New types of soluble polymer-supported bisphosphine ligands with a cyclobutane backbone for Pd-catalyzed enantioselective allylic substitution reactions

A highly efficient and practical optical resolution of anti head-to-head racemic coumarin dimer 7 has been achieved by molecular complexation with TADDOL, (-)-8, through a hydrogen bonding interaction to afford the corresponding two enantiomers, (-)- and (+)-7, in 70 and 75 % yields, respectively, with >99 % ee. Starting from enantiopure (-)-7, a new type of C2-symmetric bisphosphine ligand (S,S,S,S)-3 with a cyclobutane backbone has been synthesized in good yield by facile transformations. The asymmetric induction efficiency of these chiral bisphosphine ligands in Pd-catalyzed asymmetric allylic substitution reactions was evaluated. Under the experimental conditions, the allylic substitution products could be obtained in excellent yields (up to 99 %) and enantioselectivities (up to 98.9 % ee). By taking advantage of the high enantioselectivity of this catalytic reaction and the easily derivable carboxylate groups on the cyclobutane backbone of ligand (S,S,S,S)-3, a new type of analogous ligand (S,S,S,S)-4 as well as the MeO-PEG-supported soluble ligand (S,S,S,S)-5 (PEG=polyethylene glycol) have also been synthesized and utilized in asymmetric allylic substitution reactions. In particular, the MeO-PEG supported (S,S,S,S)-5 b had a synergistic effect on the enantioselectivity of the reaction compared with its nonsupported precursor (S,S,S,S)-4 c, affording the corresponding allylation products 14 a and 14 b with excellent enantioselectivities (94.6 and 97.2 % ee, respectively). Moreover, the Pd complex of (S,S,S,S)-5 b could easily be recovered and recycled several times without significant loss of enantioselectivity and activity in the allylic substitution reactions.     

An asymmetric synthesis of (+)-grandisol, a constituent of the aggregation pheromone of the cotton boll weevil, via a kinetic resolution

A novel approach to the asymmetric synthesis of (+)-grandisol, (1R, 2S)-isopropenyl-1-methylcyclobutaneethanol, involves the use of catalytic kinetic resolution of a primary allylic alcohol, [(1RS, 5SR)-5-methylbicyclo[3.2.0]hept-2-en-2-yl] methanol. The allylic alcohol is prepared in four steps from simple achiral materials involving the use of a modified Shapiro reaction. The resolved alcohol (95% ee) is then reduced in two steps to the corresponding methyl alkene, (1S,5R)-2,5-dimethylbicyclo[3.2.0]hept-2-ene. This alkene is converted to (+)-grandisol (95% ee), in three steps, by modified literature procedures.     

Palladium-catalyzed enantioselective allylic alkylation of thiocarboxylate ions: asymmetric synthesis of allylic thioesters and memory effect/dynamic kinetic resolution of allylic esters

The palladium-catalyzed allylic alkylation of KSAc and KSBz with racemic cyclic and acyclic allylic esters by using N,N'-(1R,2R)-1,2-cyclohexandiylbis[2-(diphenylphosphino)-benzamide] as ligand frequently gave the corresponding allylic thioesters with high ee values and yields. The reaction of the cyclic allylic carbonates with KSAc in the presence of H(2)O was accompanied by a partial palladium-catalyzed enantioselective "hydrolysis" of the substrates with formation of the corresponding enantioenriched allylic alcohols. The degree of the "hydrolysis" was strongly dependent on the solvent and the thiocarboxylate ion. Highly selective kinetic resolutions (KRs) were observed in the palladium-catalyzed reaction of the racemic cyclohexenyl and cycloheptenyl acetates with KSAc. While the KR of the cyclohexenyl acetate is characterized by a selectivity factor S = 72 +/- 19, that of the cycloheptenyl acetate afforded (R)-cycloheptenyl acetate of >or=99% ee in 48% yield and (S)-cycloheptenyl thioacetate of 98% ee in 50% yield. The palladium-catalyzed reaction of the racemic cyclopentenyl acetate with KSAc showed a strong "memory effect" (ME), that is, both enantiomers reacted with different enantioselectivities. The ME was probed by studying the palladium-catalyzed reactions of both the matched acetate of >or=99% ee and the mismatched acetate of >or=99% ee with KSAc. The acetates not only reacted with different enantioselectivities and rates but also suffered an unexpected and concomitant palladium-catalyzed racemization in the presence of the chiral ligand. This led in the case of the mismatched acetate to a temporary dynamic kinetic resolution (DKR) that featured a racemization of the mismatched acetate by the chiral catalyst. Studies of the palladium-catalyzed reaction of the racemic cyclopentenyl acetate, carbonate, and naphthoate with KSAc in the presence of the chiral ligand also showed the ME to be strongly dependent on the nucleofuge. This also allowed the synthesis of (S)-cyclopentenyl thioacetate of 92% ee in high yield from the racemic cyclopentenyl naphthoate.     

Sequential catalytic isomerization and allylic substitution. Conversion of racemic branched allylic carbonates to enantioenriched allylic substitution products

A catalytic protocol for the conversion of readily accessible racemic, branched aromatic allylic esters to branched allylic amines, ethers, and alkyls has been developed. Palladium-catalyzed isomerization of branched allylic esters to terminal allylic esters, followed by sequential iridium-catalyzed allylic substitution, gave the branched allylic products in good yield with high regioisomeric and enantiomeric selectivity. Both electron-rich and electron-poor branched allylic esters gave products in >90% ee. High enantiomeric excesses were also observed for the products from the reactions of 2-thienyl acetates and dienyl carbonates.     

Tandem copper-catalyzed enantioselective allylation-metathesis

Grignard reagents undergo enantioselective (up to 86% ee) copper-catalyzed S(N)2' substitution on achiral allylic chlorides. The reaction is wide in scope for both the Grignard reagent and the allylic substrate. The resulting terminal alkene could be submitted to intra- or intermolecular metathesis to afford new chiral synthons. The experimental conditions are compatible with a one-pot overall substitution-metathesis procedure without loss of enantioselectivity. [reaction: see text]