Pd-catalyzed asymmetric synthesis of allylic tert-butyl sulfones and sulfides: Kinetic resolution of the allylic substrate by a chiral Pd-complex

The acyclic and cyclic allylic tert-butyl sulfones 3, ent-3, 11a, 11b and 15a–c of 89–98% ee were synthesized in 40–92% yield by a Pd-catalyzed reaction of the respective allylic acetates and carbonates rac-1a, rac-1b, rac-10a, rac-10b and rac-14a–c with LiO₂St-Bu in the presence of the chiral ligands 2a, ent-2b and 12. Formation of the n-butyl sulfones 13a and 13b of 95% ee was observed. Reactions of rac-1a and 1b/ent-1b with LiO₂St-Bu in the presence of 2a and ent-2b, respectively, in THF under heterogeneous conditions were accompanied by a kinetic resolution of the allylic substrates. The faster reacting allylic substrate and the preferentially formed sulfone had the same absolute configuration. The allylic tert-butyl sulfide 17 of 92% ee was obtained in 63% yield by the Pd-catalyzed reaction of rac-1b with Me₃SiSt-Bu in the presence of ent-2b.     

Enantioselective synthesis of chiral sulfones by Rh-catalyzed asymmetric addition of boronic acids to alpha,beta-unsaturated 2-pyridyl sulfones

A general and efficient method for the rhodium-catalyzed enantioselective catalytic conjugate addition of organoboronic acids to alpha,beta-unsaturated sulfones is described. The success of the process relies on the use of alpha,beta-unsaturated 2-pyridyl sulfones as key metal-coordinating substrates; typical sulfones such as vinyl phenyl sulfones are inert under the reaction conditions. Among a variety of chiral ligands, Chiraphos provided the best asymmetric induction. This rhodium [Rh(acac)(C2H4)2]/Chiraphos catalyst system has a broad scope, being applicable to the addition of both aryl and alkenyl boronic acids to cis and trans alpha,beta-unsaturated 2-pyridyl sulfones. In most cases, especially in the addition of aryl boronic acids, the reactions take place cleanly and with high enantioselectivity, affording chiral beta-substituted 2-pyridyl sulfones in good yields and enantioselectivities (70-92% ee). The sense and magnitude of this enantioselectivity have been studied by DFT theoretical calculations of the aryl-rhodium insertion step. These calculations strongly support the formation of a five-membered pyridyl-rhodium chelated species as the most stable complex after the insertion into the C=C bond. These highly enantioenriched chiral sulfones are very appealing building blocks in enantioselective synthesis. For instance, the straightforward elimination of the 2-pyridylsulfonyl group by either Julia-Kociensky olefination or alkylation/desulfonylation sequences provides a variety of functionalized chiral compounds, such as allylic substituted alkenes or beta-substituted ketones and esters.     

Stereoselective synthesis of allylic sulfones via the oxonia-Cope rearrangement of homoallylic alcohols containing a homoallylic sulfone moiety

The homoallylic alcohols 3 that can be prepared by the indium-mediated addition of haloallylic sulfones 1 to aldehydes 2 undergo the oxonia-Cope rearrangement with aldehydes 2 to give rise to the allylic sulfones 4 containing a conjugated diene moiety in a highly stereoselective manner. Electron-rich aldehydes preferentially participate in this oxonia-Cope rearrangement with the homoallylic alcohols 3. Excellent correlations of the stereochemistry (anti-3 to trans-allylic sulfone 4 and syn-3 to cis-allylic sulfone 4) have been observed in the oxonia-Cope rearrangement.     

Enantioselective synthesis of a chiral fluoropiperidine via asymmetric hydrogenation of a vinyl fluoride

Asymmetric hydrogenation of a vinyl fluoride derivative gives efficient access to enantioenriched 1,3,4-trisubstituted piperidine 1 with a stereogenic alkyl fluoride center. Extensive catalyst screening across transition metals and chiral ligands identified only one catalyst, a Rh/Walphos complex, that gives high conversion, enantioselectivity and chemoselectivity for olefin reduction over defluorination. The presence of acid additives in the hydrogenation exerts a profound effect on reaction outcome. The results of deuterium labeling studies demonstrate that significant olefin isomerization accompanies the undesired defluorination side-reaction.     

Novel approach for asymmetric synthesis of fluorinated beta-amino sulfones and allylic amines

[reaction: see text] Enantiomerically pure gamma-fluoroalkyl beta-amino sulfones are readily synthesized in three steps starting from fluorinated imidoyl chlorides and arylmethyl sulfones. A complementary two-step sequence starting from chiral fluorinated beta-amino sulfoxides has also been developed. To illustrate the application of this procedure, a new method for the synthesis of alpha-fluoroalkyl allylic amines in optically pure form involving a Julia methylenation-desulfonylation reaction is presented.     

From allylic alcohols to chiral tertiary homoallylic alcohol: palladium-catalyzed asymmetric allylation of isatins

A palladium-catalyzed asymmetric allylation of isatins with allylic alcohols as an allyl donor was developed by using chiral spiro phosphoramidite ligands. A variety of chiral tertiary homoallylic alcohols 3-allyl-3-hydroxy-2-oxindoles were prepared directly from allylic alcohols in one step with excellent yields and moderate enantioselectivities. This represents the first catalytic asymmetric allylation of ketones with allylic alcohol as the allylating agent.     

Regioselective synthesis of allylic sulfones by palladium-catalyzed denitro-sulfonylation of allylic nitro compounds

Allylic nitro compounds undergo denitro-sulfonylation catalyzed by Pd(PPh₃)₄ or Pd(PPh₃)₄ +NaNO₂ with PhSO₂Na·2H₂O to afford allylic sulfones regioselectively.     

Enantioselective Pd-catalyzed hydrogenation of fluorinated imines: facile access to chiral fluorinated amines

An enantioselective hydrogenation of simple fluorinated imines has been developed using Pd(OCOCF(3))(2)/(R)-Cl-MeO-BIPHEP as a catalyst, and up to 94% ee was achieved. This method provides an efficient route to enantioenriched fluorinated amines.     

Catalytic asymmetric synthesis of chiral allylic esters

Trichloroacetimidate derivatives of prochiral (Z)-2-alken-1-ols react at room temperature with carboxylic acids to give chiral 3-acyloxy-1-alkenes in high enantiopurity in the presence of di-mu-acetatobis[(eta5-(S)-(pR)-2-(2'-(4'-methylethyl)oxazolinyl)cyclopentadienyl,1-C,3'-N)(eta4-tetraphenylcyclobutadiene)cobalt]dipalladium (COP-OAc) or its enantiomer. This reaction has broad scope, proceeds with predictable high stereoinduction, is accomplished at room temperature using high substrate concentrations and low catalyst loadings, and likely proceeds by a novel mechanism.     

Efficient synthesis of chiral phenethylamines: preparation, asymmetric hydrogenation, and mild deprotection of ene-trifluoroacetamides

A mild and efficient route to enantioenriched aryl alkyl amines from ketones has been developed. The first successful synthesis and asymmetric hydrogenation of ene-trifluoroamides from oximes gave highly enantioenriched trifluoroacetamides (94-98% ee). The corresponding phenethyl amides are liberated under mild conditions (K₂CO₃, MeOH/H₂O). In addition, a new application of Josiphos ligands toward the asymmetric hydrogenation of both ene-acetamides and ene-trifluoroacetamides was discovered.     

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.     

A mixed anhydride approach to the preparation of sulfinate esters and allylic sulfones: Trimethylacetic p-toluenesulfinic anhydride

A reagent combination of toluenesulfinic acid and trimethylacetyl chloride affords a putative trimethylacetic p-toluenesulfinic anhydride. This reagent has been used to prepare a series of sulfinate esters from primary and secondary alcohols. In addition, the reagent was used to convert Baylis-Hillman substrates into allylic sulfones. Attempts to use the reagent to convert amines to sulfinamides were unsuccessful. In contrast, the use of 2-pyrrolidinone afforded N-p-toluenesulfinyl pyrrolidinone in 64% yield. The use of a chiral 4-benzyl-1,3-oxazolidinone or 4-benzyl-1,3-oxazolidine-2-thione led to the isolation of S-p-tolyl p-toluenethiosulfonate.     

Enantioselective synthesis of homoallylic alcohols via a chiral In(III)-PYBOX complex

In the presence of 20 mol% of a chiral catalytic complex prepared from In(OTf)(3) and chiral PYBOX, allyltributylstannane reacted with aldehydes to afford the corresponding homoallylic alcohols in moderate to high enantioselectivities (60-93% ee).     

Expedient approach to chiral cyclobutanones: asymmetric synthesis of cyclobut-G

An efficient one-pot asymmetric synthesis of cyclobutanones from chiral enol ethers is described. The approach is illustrated with alkyl- and functionalized alkyl-substituted enol ethers (nine examples). A new enantioselective synthesis of cyclobut-G (Lobucavir) could thus be achieved.     

Unusual effects in the pd-catalyzed asymmetric allylic alkylations: synthesis of chiral chromans

An examination of earlier reports of poor-to-modest results using Pd-catalyzed asymmetric allylic alkylations (AAA) to effect cyclization to form tetrasubstituted carbons reveals several novel factors that can influence this class of reactions. Thus, carboxylate has a major effect on such cyclizations wherein the ee increases from 14% ee favoring the S with no carboxylate to 84% ee favoring the R enantiomer in the presence of 1 equiv of carboxylate. Changing the double bond geometry from E to Z further increases the ee to 97%. Furthermore, the chiral catalyst that forms the R enantiomer with the E-alkene forms the S enantiomer with the Z alkene. In contrast to trisubstituted alkene substrates, disubstituted ones show a decrease in ee in going from the E to Z alkenes. The role of carboxylate appears to be a ligand to Pd during the catalytic cycle, a previously unsuspected phenomenon since such reactions are generally believed to involve pi-allylpalladium cationic complexes. The dependence upon alkene geometry helps define the nature of the chiral pocket which better accommodates a Z alkene compared to an E alkene. The results are compatible with the enantiodiscriminating step being ionization which occurs by coordination of the palladium to one of the two prochiral faces of the double bond. A synthesis of (+)-clusifoliol, a constituent of a folk medicine for treatment of malignant tumors, which also assigns the absolute configuration, illustrates the utility of the method.     

Aqueous-phase asymmetric transfer hydrogenation of ketones--a greener approach to chiral alcohols

Asymmetric transfer hydrogenation (ATH) has emerged as a practical, powerful alternative to asymmetric hydrogenation for the production of chiral alcohols, one of the most valuable intermediates in chemical synthesis. In the last a few years, ATH in neat water has proved to be viable, affording chiral alcohols in fast rates, high productivity and high enantioselectivity. The reduction can be carried out with unmodified or tailor-made catalysts by using mild, readily available formate salt as reductant with no organic solvents required, thus providing a simple, economic and green pathway for alcohol production. This Feature Article attempts to present an account of the progress made on aqueous-phase transfer hydrogenation (TH) reactions, with a focus on ATH. The coverage includes a brief background of the chemistry, TH and ATH reactions in water, and the mechanistic aspects of the aqueous-phase reduction.     

A facile approach to the synthesis of chiral 2-substituted benzofurans

An effective route to chiral optically active 2-substituted benzofurans directly from carboxylic acids is reported. This procedure, which allows the preparation of alpha-alkyl-2-benzofuranmethanamines from N-protected alpha-amino acids without sensible racemization phenomena, proceeds in good yields under mild conditions with the help of microwave irradiation.