Asymmetric allylic alkylation of isatin-derived morita-baylis-hillman carbonates with nitroalkanes

A stereoselective allylic alkylation of isatin-derived Morita-Baylis-Hillman (MBH) carbonates with nitroalkanes has been developed. In the presence of 10 mol % β-isocupreidine (β-ICD), 3,3'-disubstituted oxindoles were prepared with moderate diastereoselectivities and excellent enantioselectivities.     

Organocatalytic asymmetric allylic alkylation of sulfonylimidates with Morita-Baylis-Hillman carbonates

The asymmetric allylic alkylation reaction of sulfonylimidates with various Morita-Baylis-Hillman (MBH) carbonates was accomplished by the catalysis of commercially available cinchona alkaloids catalyst (DHQD)2AQN.The corresponding allylic alkylation products were obtained in good yields with high stereoselectivities (up to 99% ee,89:11 dr).     

Room temperature asymmetric allylic trifluoromethylation of Morita-Baylis-Hillman carbonates

(DHQD)(2)PHAL-catalyzed asymmetric allylic trifluoromethylation of Morita-Baylis-Hillman adducts using a Rupert-Prakash reagent is reported. This transformation provided the S(N)2' trifluoromethylated products with good yields and excellent enantioselectivities at room temperature. It was also found that the reaction could be accelerated using acetonitrile as cosolvent.     

Aromatic spiroketal bisphosphine ligands: palladium-catalyzed asymmetric allylic amination of racemic morita-baylis-hillman adducts

Showing a backbone: The spiroketal backbone of the bis(phosphine) ligand 1 led to good regio- and enantioselectivity in the palladium-catalyzed asymmetric allylic amination of racemic Morita-Baylis-Hillman adducts with aromatic amines. The methodology provides a facile and efficient synthesis of precursors for optically active β-lactam derivatives, including the cholesterol drug Ezetimibe.     

Palladium-catalyzed allylic alkenylation of allylic alcohols with n-butyl acrylate

Various allylic alcohols reacted with n-butyl acrylate in the presence of p-toluenesulfonic anhydride and palladium catalysts to yield the corresponding n-butyl 2,5-dienoates with high regioselectivity.     

Ruthenium complex-catalyzed allylic alkylation of carbonucleophiles with allylic carbonates

Allylic carbonates except for allyl methyl carbonate reacted with carbonucleophiles such as ethyl acetoacetate in the presence of a catalytic amount of Ru(cod)(cot) [cod = cycloocta-1,5-diene, COT = cycloocta-1,3,5-triene] in N-methylpiperidine at 80°C to give the corresponding monoallylated carbonucleophiles in high yields with high regioselectivity. The regioselectivity was quite different from that in the palladium-catalyzed reactions. The allylation of carbonucleophiles using allyl methyl carbonate selectively gave the diallylated carbonucleophiles in high yields.     

Direct catalytic asymmetric addition of allylic cyanides to ketoimines

Direct catalytic asymmetric addition of allylic cyanides to N-diphenylphosphinoyl ketoimines with a bimetallic catalytic system comprising Ph-BPE/[Cu(CH3CN)4]ClO4/LiOAr is described. Intermediary alpha-adducts readily isomerized to afford synthetically useful alpha,beta-unsaturated nitriles bearing an optically active tetrasubstituted carbon. Applicability to aromatic, heteroaromatic, and aliphatic ketoimines exemplifies wide substrate generality. Transformation of the product into densely functionalized material showcases the utility of the present protocol.     

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 asymmetric synthesis of allylic alcohols from unsymmetrical and symmetrical racemic allylic carbonates featuring C-O-bond formation and dynamic kinetic resolution

Described is the asymmetric synthesis of the allylic alcohols 11 (85% ee), 15 (99% ee), 17 (93% ee), 19 (61% ee), and 21 (69% ee) through a Pd-catalyzed reaction of the unsymmetrical carbonates rac-10, rac-12, rac-14, rac-16, rac-18, and rac-20, respectively, with KHCO₃ and H₂O in the presence of bisphosphane 6. Similarly the allylic alcohols 23 (99% ee) and 25 (97% ee) have been obtained from the symmetrical carbonates rac-22 and rac-24, respectively. Reaction of the meso-biscarbonate 26 with H₂O and Pd(0)/6 afforded alcohol 27 (96% ee), which was converted to the PG building block 32. The unsaturated bisphosphane 33 showed in the synthesis of alcohols 36, 37, and 39 a similar high selectivity as 6. The formation of alcohols 11, 15, and 17 involves an efficient dynamic kinetic resolution.     

Regio- and enantioselective iridium-catalyzed intermolecular allylic etherification of achiral allylic carbonates with phenoxides

An enantioselective and regioselective iridium-catalyzed allylic etherification is described. The reaction of sodium and lithium aryloxides with achiral (E)-cinnamyl and terminal aliphatic allylic electrophiles in the presence of 2 mol % of an iridium-phosphoramidite complex provides chiral allylic aryl ethers in high yields and excellent levels of regio- and enantioselectivity. Lithium aryloxides containing a single substituent at an ortho, meta, or para position as well as sterically hindered phenoxides were tolerated. Reactions in THF displayed the most suitable balance of rate, regio-, and enantioselectivity. High ee's were also observed for the products from the reaction of alkyl (E)-allylic carbonates.     

Iridium-catalyzed allylic vinylation and asymmetric allylic amination reactions with o-aminostyrenes

An Ir-catalyzed allylic vinylation reaction of allyl carbonates with o-aminostyrene derivatives has been realized, providing skipped (Z,E)-diene derivatives. With (E)-but-2-ene-1,4-diyl dimethyl dicarbonate as the substrate, an efficient enantioselective synthesis of 1-benzazepine derivatives via an Ir-catalyzed domino allylic vinylation/intramolecular allylic amination reaction has been developed. Mechanistic studies of the allylic vinylation reaction have been carried out, and the results suggest that the leaving group of the allylic precursor plays a key role in directing the reaction pathway. Screening of various allylic precursors showed that Ir-catalyzed reactions of allyl diethyl phosphates with o-aminostyrene derivatives proceed via an allylic amination pathway. A subsequent ring-closing metathesis (RCM) reaction of the amination products led to a series of enantiomerically enriched 1,2-dihydroquinoline derivatives. Their utility is indicated by an asymmetric total synthesis of (-)-angustureine.     

Enantioselective organocatalytic asymmetric allylic alkylation. Bis(phenylsulfonyl)methane addition to MBH carbonates

The highly enantioselective asymmetric allylic alkylation of Morita-Baylis-Hillman carbonates with bis(phenylsulfonyl)methane is presented. The reaction is simply catalyzed by cinchona alkaloid derivatives affording the final alkylated products in good yields and enantioselectivities.     

Ni-catalyzed reductive allylation of unactivated alkyl halides with allylic carbonates

Game of two electrophiles: Two partially positively charged sp(3) carbon atoms can be connected by using a catalytic Ni species in the presence of an environmentally benign Zn reductant, delivering allylated alkanes. This unprecedented approach allowed a variety of unactivated alkyl halides and substituted allylic carbonates to regioselectively afford E-alkenes in good to excellent yields.     

Highly enantioselective regiodivergent allylic alkylations of MBH carbonates with phthalides

Phthalides were used for the first time in the allylic alkylation reactions with MBH carbonates for the creation of chiral 3,3-disubstituted phthalides. Highly enantioselective regiodivergent synthesis of γ-selective or β-selective allylic alkylation products was achieved by employing bifunctional chiral phosphines or multifunctional tertiary amine-thioureas as the catalyst, respectively. It was demonstrated that proper selection of catalysts and reaction conditions would differentiate an S(N)2'-S(N)2' pathway and an addition-elimination process, yielding different regioisomers of the allylic alkylation products in a highly enantiomerically pure form.     

Chiral phosphine-catalyzed asymmetric allylic alkylation of 3-substituted benzofuran-2(3H)-ones or oxindoles with Morita-Baylis-Hillman carbonates

An efficient chiral phosphine-catalyzed asymmetric substitution reaction of MBH carbonates with 3-substituted benzofuran-2(3H)-ones or 3-substituted oxindoles has been described in this context, giving the corresponding allylic alkylation products bearing adjacent quaternary and tertiary stereogenic centers in high yields, moderate diastereoselectivities and high enantioselectivities under mild conditions.     

Iridium-catalysed asymmetric allylic substitutions

Ir-catalysed allylic substitution is supplementing the traditional Pd-catalysed variant. With simple, easily available monosubstituted allylic acetates and carbonates as substrates, Ir catalysts generally favour chiral, branched products, while Pd catalysts typically give rise to linear, achiral products. With phosphorus amidites as ligands, regioselectivities >10 : 1 and enantiomeric excess in the range 95-99 %ee are currently routinely achieved. A broad range of nucleophiles can be employed: for example stabilised carbanions, amines including their sulfonyl- and diacyl-derivatives, phenolates and alkoxides. A few applications, based on combinations of the allylic substitution and ring closing metathesis, indicate considerable potential of the method for the synthesis of biologically active compounds.     

Chiral biscinchona alkaloid promoted asymmetric allylic alkylation of 3-substituted benzofuran-2(3H)-ones with Morita-Baylis-Hillman carbonates

A highly diastereo- and enantioselective asymmetric allylic alkylation reaction with respect to prochiral 3-substituted benzofuran-2(3H)-ones and MBH carbonate by a chiral biscinchona alkaloid catalyst was investigated. The corresponding adducts, containing a quaternary center at the C3-position of the benzofuran-2(3H)-one as well as a vicinal tertiary center, were generally obtained in high yields (up to 97%) with very good diastereo- (up to 98:2 dr) and enantioselectivities (up to 95% ee).     

Lewis base catalyzed enantioselective allylic hydroxylation of Morita-Baylis-Hillman carbonates with water

A Lewis base catalyzed allylic hydroxylation of Morita-Baylis-Hillman (MBH) carbonates has been developed. Various chiral MBH alcohols can be synthesized in high yields (up to 99%) and excellent enantioselectivities (up to 94% ee). This is the first report using water as a nucleophile in asymmetric organocatalysis. The nucleophilic role of water has been verified using (18)O-labeling experiments.     

Rhodium-catalyzed asymmetric allylic substitution with boronic acid nucleophiles

An enantio-, regio-, and diastereoselective rhodium(I)-catalyzed desymmetrization of a meso-cyclic allylic dicarbonate with organoboronic acid nucleophiles is described. The rhodium(I) catalyst formed in situ from [Rh(cod)OH]2 and Xyl-P-PHOS allowed the S(N)2' allylic substitution product to be obtained with a range of arylboronic acids in enantiomeric excesses of up to 92% with regioselectivities of up to >20:1.