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.     

Phosphine-catalyzed allylic substitution of Morita-Baylis-Hillman acetates: synthesis of N-protected beta-aminophosphonic acid esters

A series of N-protected beta-amino phosphonic acid esters have been prepared by phosphine-catalyzed allylic substitution of 2-(diethylphosphonyl)-substituted allylic acetates employing 4,5-dichlorophthalimide as nucleophilic partner. These organocatalytic allylic substitutions exhibit exceptionally high levels of regiospecificity by virtue of a tandem S(N)2'-S(N)2' mechanism.     

Regio- and stereoselectivity in the reactions of organometallic reagents with an electron-deficient and an electron-rich vinyloxirane: applications for sequential bis-allylic substitution reactions in the generation of vicinal stereogenic centers

Vinyloxiranes provide opportunities for bis-allylic substitution reactions and the generation of new vicinal stereogenic centers if regio- and stereocontrol can be achieved. Ethyl (E)-4,5-epoxy-2-hexenoate affords excellent S(N)2':S(N)2 regioselectivity and anti:syn product diastereoselectivity with dialkyzinc reagents in the presence of CuCN, and conversion of the resultant allylic alcohol to the acetate affords good syn:anti product diastereoselectivity in S(N)2'-selective allylic substitutions with alkylcyanocuprates in THF. (E)-1-(tert-Butyldimethylsilyloxy)-2,3-epoxy-4-hexenonate gives excellent S(N)2':S(N)2 regioselectivity and anti:syn product diastereoselectivity with dialkyzinc reagents in THF or DMF or Grignard reagents in Et(2)O/THF (10/1) in the presence of CuCN. Conversion of the product allylic alcohol into the allylic phosphate affords excellent S(N)2' regioselectivity and syn:anti product diastereoselectivity with lithium alkylcyanocuprates for primary and secondary alkyl transferable ligands, while S(N)2 regioselectivity is observed for the tert-butyl ligand. Reaction conditions have been developed for regio- and stereocontrolled bis-allylic substitution reactions on both electron-rich and electron-deficient alkenyloxiranes, providing a methodology for the generation of vicinal alkane stereogenic centers.     

High diversity on simple substrates: 1,4-dihalo-2-butenes and other difunctionalized allylic halides for copper-catalyzed S(N)2' reactions

Enantioselective allylic alkylation with an organomagnesium reagent catalyzed by copper thiophene carboxylate (CuTC) was carried out on difunctionalized substrates, such as commercially available 1,4-dichloro-2-butene and 1,4-dibromo-2-butene, and on similar compounds of higher substitution pattern of the olefin for the formation of all-carbon chiral quaternary centers. The high regioselectivity obtained throughout the reactions favored good regiocontrol for the addition of phenyl Grignard reagents. Other difunctionalized substrates (allylic ethers and allylic alcohols) also underwent asymmetric S(N)2' substitution.     

Chirality transfer in Au-catalyzed cyclization reactions of monoallylic diols: selective access to specific enantiomers based on olefin geometry

The gold(I)-catalyzed cyclization of monoallylic diols to form tetrahydropyrans is shown to be highly stereoselective when chiral allylic alcohols are employed. Substrates that differ only in olefin geometry provide enantiomeric products from formal S(N)2' reactions in high yields with excellent chirality transfer. The allylic alcohol stereochemistry also efficiently controls the facial selectivity when the substrates include additional stereocenters.     

Stereoselective S N 2-substitutions using polyfunctional lithium arylcuprates prepared by an iodine-copper exchange

[reaction: see text] Polyfunctional mixed lithium arylcuprates of the type (FG-Ar)(PhMe(2)CCH(2))CuLi obtained via iodine- or bromine-copper exchange with (PhMe(2)CCH(2))(2)CuLi react with cyclic 2-iodoallylic acetates with high S(N)2 selectivity. The addition of ZnBr(2) changes this selectivity and allows the performance of highly regioselective and enantioselective anti S(N)2' substitutions using open-chain allylic pentafluorobenzoates.     

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.     

Regio- and enantioselective control in the reactions of alpha-(N-carbamoyl)alkylcuprates with allylic phosphates

Alpha-(N-carbamoyl)alkylcuprates (RCuCNLi or R2CuLi) react with allylic phosphates to afford homoallylic amines in good chemical yields. Regioselectivity is governed by steric factors in both the cuprate reagent and phosphate substrate and systems can be designed to give either the S(N)2' or S(N)2 substitution product cleanly. Excellent enantioselectivities can be achieved with either a scalemic alpha-di[(N-carbamoyl)alkyl]cuprate and an achiral phosphate or with a scalemic allylic phosphate and an achiral cuprate reagent. [reaction: see text]     

Asymmetric synthesis of novel thioiso dideoxynucleosides with exocyclic methylene as potential antiviral agents

Novel thioiso pyrimidine and purine nucleosides substituted with exocyclic methylene have been synthesized, starting from D-xylose. The glycosyl donor 14 was synthesized from D-xylose, using cyclization of dimesylate 10 with sodium sulfide as a key step. Cyclization proceeded in pure S(N)2 reaction without going through S(N)1 reaction in the presence of an allylic functional group at low reaction temperature (0 degrees C) in polar solvent (DMF), affording compound 12 as a major product. At higher temperatures, S(N)2' product 11 was almost exclusively obtained as a major product. On the other hand, glycosylation of 14 with 6-chloropurine under Mitsunobu conditions afforded the desired S(N)2 product 26, while palladium-catalyzed glycosylation resulted in the sole formation of S(N)2' product 34.     

Allylic substitution on cyclopentene and -hexene rings with alkynylcopper reagents

Substitution of cyclic allylic picolinates with a reagent derived from TMS-C≡CMgBr and a copper salt was investigated. Although the previous type of reagent (TMSC≡CMgBr and CuBr·Me(2)S) developed for linear allylic picolinates was less product selective and regioselective, the Cu(acac)(2)-derived reagent was highly selective (94-95%) to afford the S(N)2' product in good yields. As an application, several C-C bond formations at the acetylenic carbon and the synthesis of the PG intermediate were studied with success.     

Photoredox catalysed allylic trifluoromethylation via ring opening of vinyl cyclopropanes using Langlois reagent

Trifluoromethylation of vinylcyclopropanes (VCPs) has been developed under mild reaction conditions to synthesize allylic trifluoromethylated derivatives with high yield and E/Z selectivity using visible light photo-redox catalysis and Langlois reagent (CF₃SO₂Na) as a trifluoromethylation source. Further, we demonstrate a gram scale synthesis procedure for a trifluoromethylation of vinylcyclopropane.     

Enantioselective synthesis of alpha-ionone derivatives using an anti S(N)2' substitution of functionalized zinc organometallics

[reaction: see text] The allylic substitution of sterically hindered (2-iodocycloalkyl)phosphates proceeds with complete anti S(N)2' stereoselectivity with mixed diorganozincs of the type RZnCH(2)SiMe(3) in the presence of CuCN.2LiCl. Only the group R of the copper-zinc reagent is transferred in the allylic substitution. This method was used to prepare odoriferous substances such as (R)-alpha-ionone in 97% ee and (R)-dihydro-alpha-ionone in 98% ee.     

S(N)/S(N)' competition: selective access to new 10-fluoro artemisinins

In this paper, we report a simple route to accede to a new family of C-10 fluorinated derivatives of artemisinin 7. We demonstrated that nucleophilic substitution of the allylic bromide 6 with alcohols can occur at carbon 10 (compounds 7) under solvolytic conditions (S(N)'/S(N) ratio, 87:13). Furthermore, using the particular properties of hexafluoroisopropanol (HFIP), we are able to increase the selectivity of the substitution. Primary alcohols are completely selective for allylic substitution. With amines as nucleophiles, selectivity of substitution is dependent on their nucleophilicity, but attack at carbon 16 was always favored. However, the S(N)'/S(N) ratio could be slightly increased by adding HFIP, which is able to modulate their nucleophilicity through hydrogen bonding. In preliminary in vitro assessments, these new compounds, 7, exhibited a satisfying activity against malaria.     

Phosphine-catalyzed regiospecific allylic amination and dynamic kinetic resolution of Morita-Baylis-Hillman acetates

Exposure of Morita-Baylis-Hillman (MBH) acetates to tertiary phosphine catalysts in the presence of 4,5-dichlorophthalimide enables regiospecific allylic substitution through a tandem S(N)2'-S(N)2' mechanism. Through the use of the chiral phosphine catalyst (R)-Cl-MeO-BIPHEP, chiral racemic MBH acetate 4 is converted to the corresponding allylic amination product in 80% yield and 56% enantiomeric excess, thus establishing the feasibility of dynamic kinetic resolution. [reaction: see text]     

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.     

Practical approach to alpha- or gamma-heterosubstituted enoic acids

The reaction of alkenyl trichloromethyl carbinols with various nucleophiles under protic basic conditions reveals that mercaptans participate by alpha-substitution (S(N)2) of the intermediate alkenyl gem-dichloroepoxides. Conversely, hydroxide results in preferential gamma-substitution with stereoselective allylic transposition (S(N)2'). Regioselectivity with alkoxides depends upon the level of alkene substitution. [reaction: see text]     

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]     

Catalytic asymmetric synthesis of chiral allylic esters

A broadly useful catalytic enantioselective synthesis of branched allylic esters from prochiral (Z)-2-alkene-1-ols has been developed. The starting allylic alcohol is converted to its trichloroacetimidate intermediate by reaction with trichloroacetonitrile, either in situ or in a separate step, and this intermediate undergoes clean enantioselective S(N)2' substitution with a variety of carboxylic acids in the presence of the palladium(II) catalyst (R(p),S)-di-μ-acetatobis[(η(5)-2-(2'-(4'-methylethyl)oxazolinyl)cyclopentadienyl-1-C,3'-N)(η(4)-tetraphenylcyclobutadiene)cobalt]dipalladium, (R(p),S)-[COP-OAc](2), or its enantiomer. The scope and limitations of this useful catalytic asymmetric allylic esterification are defined.     

Copper-catalyzed regioselective allylic substitution reactions with indium organometallics

The first nucleophilic allylic substitution reactions of triorganoindium compounds with allylic halides and phosphates are reported. The reactions of trialkyl- and triarylindium reagents with cinnamyl and geranyl halides and phosphates, with the aid of copper catalysis [Cu(OTf)(2)/P(OEt)(3)], are described. In general, the reaction proceeds efficiently to give good yields and regioselectively to afford the S(N)2' product.     

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.