Regioselective 1,4-Conjugate Addition of Grignard Reagents to α,ß-γ,δ-Dienones and α,ß-γ,δ-Dienyl Thiol Esters.

Alkyl Grignard reagents (Et, nBu, iPr, cyclohexyl), with the exception of tBuMgCl, undergo exclusive or exceptionally highly regioselective 1,4-addition reactions to α,ß-γ,δ-unsaturated ketones, while aryl and heteroaryl Grignard reagents give mixed results ranging from exclusive 1,4-addition (1-naphthyl, 2-N-methylpyrrolyl) to regioselective 1,2-addition (2-furyl, 2:1). All alkyl, aryl, and heteroaryl Grignard reagents examined gave exclusive 1,4-addition reactions with α,ß-γ,δ-unsaturated thiol esters, with the exception of tBuMgCl, which gave an 80:20 mixture of 1,4:1,6-addition products. The high chemo- and regioselectivity observed for these reactions is attributed to a radical or radical-like pathway for the alkyl Grignard reagents and possibly a carbanion pathway for aryl Grignard reagents. The α,γ-dienyl thiol esters provide for a one-pot tandem 1,4-addition-nucleophilic acyl substitution reaction sequence to afford 3-substituted 4-enone moieties.

A Serendipitous Synthesis of Bis-Heterocyclic Spiro 3(2H)-Furanones.

(Z) Enol triflates 6, 11b-d, (E) enol triflate 11e, and phenol triflate 11a, derived from ß-keto esters or 2-carboalkoxy phenols, respectively, react with N-Boc 2-lithiopyrrolidine (5a), N-Boc N-methylaminomethyllithium (5b), or 2-lithio-1,3-dithiane (14) to afford 3(2H)-furanones in modest to good yields (38-81%). Product and carbanion reagent studies suggest that the 3(2H)-furanone is formed in a cascade of reactions involving nucleophilic acyl substitution, enolate formation, trifluoromethyl transfer, iminium or sulfenium ion formation, and subsequent ring closure to form the 3(2H)-furanone. The use of 2-lithio-1,3-dithiane affords a cyclic α-keto-S,S,O-orthoester in which the functionality can be selectively manipulated for synthetic applications.

Regio- and stereocontrol in the reactions of α-halo-ß,γ-enoates and α-O-phosphono-ß,γ-enenitriles with organocuprates.

The reactions of (Z)- and (E)-ethyl 2-chloro-3-octenoate (4a and 17) and (E)- and (Z)-diethyl (1-cyano-2-heptenyl)phosphate (21a and 21b) with organocuprates were investigated as potential substrates for preparing γ-substituted α,ß-enoates and enenitriles. In these copper-mediated allylic substitution reactions, the Z-isomer 4a displayed complete regio- and stereoselectivity (i.e., E:Z), while the regio- and stereoselectivity for E-isomer 17 varied as a function of solvent, cuprate reagent, transferable ligand, and cuprate counterion (e.g., Li(+) vs MgX(+)). Excellent selectivities could be achieved with 17 and (n)BuCuCNLi in Et2O. Conditions for improved selectivities in the reactions of allylic cyanophosphates over those previously reported were found. A series of relative rate and competition experiments was performed, and the degree of regio- and stereoselectivity for each system was rationalized in the light of the current mechanistic understanding of cuprate-mediated allylic substitution reactions.

Regio- and stereocontrol in the Michael-initiated ring-closure reactions of γ,δ-epoxy-α,ß-unsaturated esters, ketones, sulfones, and amides.

Organozincates or Grignard reagents in the presence of zinc catalysts undergo Michael initiated ring closure (MIRC) reactions with γ,δ-epoxy-α,ß-enoates, enones, enesulfones, and enamides to afford 1,2,3-trisubstituted cyclopropanes. The direction of diastereoselectivity is solvent dependent for alkyl Grignard reagents reacting with epoxy enoates, ensulfones, and enamides but solvent independent for the enones. Excellent diastereoselectivity can be achieved for the epoxy enoates, enones, and ensulfones, while the enamides afford modest diastereoselectivity under optimal conditions. The MIRC reaction can be achieved with phenylmagnesium chloride and these substrates under reaction conditions designed to minimize biphenyl formation.

Conjugate addition reactions of N-carbamoyl-4-pyridones and 2,3-dihydropyridones with Grignard reagents in the absence of Cu(I) salts.

N-Boc- and N-ethoxycarbonyl-4-pyridones and the resulting 2,3-dihydropyridones undergo 1,4-addition reactions with Grignard reagents in the presence of chlorotrimethylsilane (TMSCl) or BF3·Et2O in excellent yields. Copper catalysis is not required, and mechanistic considerations suggest that the reaction is proceeding by a conjugate addition pathway rather than by a pathway involving 1,2-addition to an intermediate pyridinium ion. TMSCl-mediated conjugate addition of Grignard reagents to 2-substituted-2,3-dihydropyridones gives the trans-2,6-disubstitued piperidinones stereoselectively, while cuprate reagents give either the trans or cis diastereomers or mixtures.

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.

Conjugate addition reactions of N-carbamoyl-4-pyridones with organometallic reagents.

N-carbamoyl-4-pyridones undergo conjugate addition reactions with organocuprates and organozincates to afford 2-substituted-2,3-dihydro-4-pyridones providing a direct synthetic approach to substituted piperidines and piperidones. Good to excellent yields of conjugate adducts are achieved with lithium dialkylcuprates, alkylcyanocuprates, RLi/CuCN (0.3 equiv), and trialkylzincates with copper catalysis. Copper catalysis in the conjugate addition of Grignard reagents affords modest yields of conjugate adducts. An enantioenriched phosphoramidite ligand promotes the copper catalyzed conjugate addition of Et(2)Zn to a N-carbamoyl-4-pyridone with an er of 91.5:8.5.

Tandem regio- and stereoselective organocuprate-mediated bis-allylic substitutions.

anti-5-Acetoxy-4-halo-alpha,beta-enoates undergo sequential or tandem reactions with two different magnesium cuprate reagents to afford anti-2,3-dialkyl-4,5-enoates in high chemical yield and with excellent diastereoselectivity. The one-pot tandem procedure can be achieved with 30 mol % of CuCN and affords a rapid stereoselective combinatorial approach to vicinal disubstituted gamma,delta-enoates containing functionality at either end of the carbon chain for subsequent functional group elaboration. The methodology should provide a powerful practical strategy for acyclic stereoselection.

A rapid divergent synthesis of highly substituted delta-lactones.

[reaction: see text] Nucleophilic 1,2-addition of (Z)-gamma-silyloxyvinylzinc reagents to ethyl glyoxylate followed by desilylation and cyclization affords 3,6-dihydro-3-hydroxypyran-2-ones in good chemical yields. In situ formation of allylic phosphates followed by reaction with RCu(CN)Li reagents affords substituted 5,6-dihydropyran-2-ones. The parent compound, 3,6-dihydro-3-hydroxypyran-2-one, undergoes allylic phosphate formation, cuprate-mediated allylic substitution, and 1,4-conjugate addition to afford trans-4,5-disubstituted tetrahydropyran-2-ones in a one-pot process.

Enantioselective reactions of scalemic acyclic alpha-(alkoxy)alkyl- and alpha-(N-carbamoyl)alkylcuprates.

[reaction: see text] Scalemic acyclic alpha-(alkoxy)alkyl- and alpha-(N-carbamoyl)alkylcuprates prepared from organostannanes via organolithium reagents react with vinyl iodides, propargyl mesylates, and alpha,beta-enones to afford coupled products with enantioselectivities ranging from 0 to 99% ee depending upon cuprate reagent, substrate structure, solvent, and temperature. In general, lithium cuprates give higher chemical yields and lower enantioselectivities, while the trends are reversed for the corresponding zinc cuprate reagents.

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]

Regioselective 1,4-conjugate addition of Grignard reagents to nitrodienes in the presence of catalytic amounts of Zn(II) salts.

Grignard reagents undergo facile regioselective 1,4-conjugate addition to nitrodienes in the presence of catalytic amounts of Zn(II) salts with excellent yields. A wide range of ligands such as alkyl, aryl, heteroaryl, allyl, vinyl, 1-alkynyl, and alkoxy ligands were transferred, while a thiolate ligand afforded 1,6-regioselectivity. The reactions were successfully carried out on δ-alkyl- or aryl-substituted α,ß,γ,δ-diunsaturated nitrodiene substrates. Regioselectivity is minimally influenced by temperature or choice of solvent.

Asymmetric synthesis of enantioenriched (+)-elaeokanine A.

The key transformation in the total synthesis of (+)-elaeokanine A was accomplished by asymmetric deprotonation of N-Boc pyrrolidine, followed by the reaction of the in situ generated enantioenriched stereogenic cuprate reagent with (E)-4-bromo-1-iodo-1-trimethylsilyl-1-butene with retention of configuration. N-Boc deprotection, followed by a one-pot olefin isomerization and intramolecular amine alkylation afforded a bicyclic vinyl bromide that was converted into (+)-elaeokanine A by sequential halogen metal exchange and reaction of the organolithium reagent with N-butanoylmorpholine.

Reaction of alpha-(N-carbamoyl)alkylcuprates with enantioenriched propargyl electrophiles: synthesis of enantioenriched 3-pyrrolines.

Enantioenriched propargyl mesylates or perfluorobenzoates react with alpha-(N-carbamoyl)alkylcuprates to afford scalemic alpha-(N-carbamoyl) allenes which undergo N-Boc deprotection and AgNO3-promoted cyclization to afford N-alkyl-3-pyrrolines. The synthetic sequence proceeds under optimal conditions with no loss of enantiopurity relative to the starting propargyl alcohols prepared by asymmetric addition of terminal alkynes to aldehydes.

Reaction of alpha-(N-carbamoyl)alkylcuprates with propargyl substrates: synthetic route to alpha-amino allenes and delta3-pyrrolines.

[reaction: see text] Carbamate deprotonation followed by treatment with CuCN.2LiCl affords alpha-(N-carbamoyl)alkylcuprates which react with propargyl halides, mesylates, tosylates, phosphates, acetates, and epoxides to give alpha-(N-carbamoyl) allenes via an anti-S(N)2' substitution process. Propargyl halides, sulfonates, and phosphates give good yields of carbamoyl allenes, while the acetates afford low yields. Propargyl substrates undergo regiospecific S(N)2' substitution in the absence of severe steric hindrance. The alpha-(N-carbamoyl) allenes can be cyclized to 2-oxazolidinones or deprotected to afford the free amines which can be cyclized to Delta(3)-pyrrolines with either AgNO(3) or Ru(3)(CO)(12).

Coupling reactions of alpha-(N-carbamoyl)alkylcuprates with enol triflates derived from cyclic beta-keto esters: A facile approach to gamma-carbamoyl-alpha,beta-enoates.

alpha-(N-Carbamoylalkyl)cuprates couple with enol triflates derived from carbocyclic and heterocyclic (i.e., piperidinones) beta-keto esters. Product yields are higher with the alkyl(cyano)cuprates [i.e., RCu(CN)Li, 56-93%] than with the dialkylcuprate reagents (i.e., R(2)CuLi.LiCN). An enol nonaflate works as well as the corresponding enol triflate. A facile synthetic route to gamma-amino alpha,beta-enoates not readily prepared from gamma-keto-alpha,beta-enoates is thus established. The gamma-amino-alpha,beta-enoates, available via N-Boc deprotection, can be cyclized to annulated pyrrolin-2-ones.

Alpha-(N-carbamoyl)alkylcuprate chemistry in the synthesis of nitrogen heterocycles.

The conjugate adducts obtained via coupling of alpha-(N-carbamoyl)alkylcuprates with alpha,beta-ynoates, alpha-allenyl esters, or alpha.beta-enoates or enimides undergo N-Boc deprotection and cyclization onto the ester functionality upon treatment with PhOH/TMSCl, catecholboron bromide, or trimethylsilyl triflate. This two-pot sequence provides synthetic routes to 4-alkylidinepyrrolidine-2-ones, 4-alkylidinepyrrolizidin-2-ones, and 4-alkylidineindolizidin-2-ones via allenyl esters; pyrrolin-2-ones, tetrahydropyrrolizin-2-ones, and tetrahydroindolizin-2-ones via alpha/beta-ynoates; pyrrolidin-2-ones, pyrrolizidin-2-ones, and indolizidin-2-ones via alpha,beta-enoates or alpha.beta-enimides. The reluctance of gamma-carbamoyl-alpha,beta-enoates to undergo E/Z isomerization requires the use of (Z)-beta-iodo-alpha,beta-enoates readily prepared by the addition of HI to the alkynyl esters for the efficient preparation of pyrrolinones, tetrahydropyrrolizinones, and tetrahydroindolizinones. Utilization of omega-functionalized alpha,eta-ynoates or beta-iodo-alpha,beta-enoates allows for cyclization onto the omega-functionality providing for a synthetic route to quinolizidines.

Halogen- and N-haloimide-promoted homo- and heterocoupling of alpha-(N-carbamoyl)alkylcuprates and alpha-(alkoxy)alkylcuprates.

Both homo- and mixed lithium di-alpha-(heteroatom)alkylcuprates readily dimerize upon addition of halogens (e.g., I(2), Br(2)) or N-halosuccinimides to afford the coupled products in excellent yields. Higher yields result when the requisite alpha-(heteroatom)alkyllithium reagents are generated via deprotonation rather than by transmetalation of the corresponding stannanes. Mixed lithium dialkyl- or alkyl(aryl)cuprate reagents containing one alpha-(heteroatom)alkyl ligand and one simple alkyl or aryl ligand give significantly lower yields of coupled product. Low enantioselectivity has been achieved in the oxidative coupling of lithium (n-Bu)(2-pyrrolidinyl)cuprate.