Stereoselective synthesis of novel 4,5-epoxy-1,2-oxazin-6-ones and alpha,beta-epoxy-gamma-amino acids from beta-lithiated oxazolinyloxiranes and nitrones

[reaction: see text] A stereoselective synthesis of 9,10-epoxy-1,6-dioxa-4,7-diazaspiro[4,5]decanes has been developed on the basis of the addition of beta-lithiated oxazolinyloxiranes to nitrones. Conversion of these spirocyclic derivatives into 4,5-epoxy-1,2-oxazin-6-ones and successively into alpha,beta-epoxy-gamma-amino acids, alpha-hydroxy-gamma-amino acids, and gamma-butyrolactams is described.     

Enantiomerically pure synthesis of beta-substituted gamma-butyrolactones: a key intermediate to concise synthesis of pregabalin

Chiral beta-substituted gamma-butyrolactones are known to be important intermediates for many biologically active compounds such as gamma-aminobutyric acid (GABA) derivatives and lignans. We have developed a general, convenient, and scalable synthetic method for enantiomerically pure beta-substituted gamma-butyrolactones, with either configuration, via nucleophilic cyclopropane ring opening of (1S,5R)- or (1R,5S)-bicyclic lactone followed by decarbethoxylation. The utility of our method was demonstrated by streamlined synthesis of pregabalin ((S)-3-isobutyl-gamma-aminobutyric acid), an anticonvulsant drug for the treatment of peripheral neuropathic pain.     

Development of a solid-phase 'asymmetric resin-capture-release' process: application of an ephedrine chiral resin in an approach to gamma-butyrolactones

The potential of a solid-phase asymmetric resin-capture-release strategy for high-throughput synthesis has been evaluated. Fukuzawa's Sm(ii)-mediated, asymmetric approach to gamma-butyrolactones was selected to illustrate the feasibility of such a process. Alpha,beta-unsaturated esters immobilised on an ephedrine chiral resin have been applied in an asymmetric approach to gamma-butyrolactones. Lactone products are obtained in moderate isolated yields with selectivities up to 96% ee. In addition, we have shown that the ephedrine resin can be conveniently recovered and recycled although in some cases lower yields were obtained on reuse of the chiral resin. A short synthesis of a moderate DNA-binding microbial metabolite using asymmetric resin-capture-release is also described.     

Development of a new reaction system for the synthesis of highly optically active alpha,gamma-substituted gamma-butyrolactones

A highly useful method for the synthesis of optically active alpha,gamma-substituted gamma-butyrolactones has been developed. The SmI(2)-induced reductive coupling of chiral 2-alkyl acrylates derived from isosorbide with ketones in the presence of (1S)-(-)-2,10-camphorsultam as a proton source give the chiral alpha,gamma-substituted gamma-butyrolactones in good yields and high enantiomeric purities (up to >99% ee for trans and 75% ee for cis). The reaction system has been investigated with various ketones, and it is demonstrated that this system is very effective for trans-alpha,gamma-substituted gamma-butyrolactones. Both the chiral auxiliary and the hindered proton source in this system are necessary for the observed excellent ee values of the products. The absolute configuration of the trans products is assigned on the basis of the X-ray crystal structure.     

N-heterocyclic carbene-catalyzed generation of homoenolates: gamma-butyrolactones by direct annulations of enals and aldehydes

N-Heterocyclic carbenes, prepared in situ from diarylimidazolium salts, serve as highly effective catalysts for the generation of reactive homoenolates from alpha,beta-unsaturated aldehydes. The catalyst-bound homoenolate reacts with electrophilic aldehydes leading, via the key intermediacy of an activated carboxylate, to gamma-butyrolactones in good yields and stereoselectivities. Importantly, this process demonstrates an unprecedented reaction mode for the generation of nucleophilic carbanions with a multifunctional organocatalyst under exceptionally mild and convenient reaction conditions.     

Diastereoselective conjugate additions to pi-allylmolybdenum complexes: a stereocontrolled route to 3,4,5-trisubstituted gamma-butyrolactones

[reaction: see text] pi-Allylmolybdenum complex 6b is obtained as a single isomer by Knoevenagel condensation of aldehyde 1 with Meldrum's acid. Conjugate additions of Grignard reagents to Meldrum's acid alkylidene derivative 6b are shown to be completely diastereoselective. Further functional group transformation of the 1,4-adducts, followed by demetalation, leads to trisubstituted tetrahydrofurans and gamma-butyrolactones. Whereas the synthesis of tetrahydrofurans (X = 2H) is not completely stereoselective, the gamma-butyrolactones (X = O) are obtained with good to excellent diastereoselectivities.     

Comparison of solid-phase and solution-phase chiral auxiliaries in the alkylation/iodolactonization sequence to gamma-butyrolactones

Five prolinol-based chiral auxilaries have been compared for the stereoselective synthesis of gamma-butyrolactones via the sequence of N-acylation, C(alpha)()-allylation, and iodolactonization under both solution-phase and solid-phase conditions. Comparisons of stereoselectivity of both the C(alpha)()-allylation and iodolactonization processes indicate that incorporation of a non-C(2)-symmetric auxiliary as a polymer cross-link gives results superior to those obtained either in solution or with other non-C(2)-symmetric auxiliaries and comparable to those observed using a polymer-supported pseudo-C(2)-symmetric auxiliary.     

Facile synthesis of optically active gamma-lactones via lipase-catalyzed reaction of 4-substituted 4-hydroxybutyramides

Lipase-catalyzed transesterification of racemic 4-substituted 4-hydroxybutyramides with succinic anhydride proceeded enantioselectively to afford (S)-succinic acid monoester and unreacted (R)-4-hydroxybutyramide derivative, which were separated easily by treatment with an alkaline solution. Both enantiomers were converted easily to optically active gamma-substituted gamma-butyrolactones.     

Novel fragmentation reaction of 2-alkyl- and 2,4-dialkyl-3-iodo-1-oxocyclohexan-2,4-carbolactones

2-Alkyl- and 2,4-dialkyl-3-iodo-1-oxocyclohexan-2,4-carbolactones undergo lithium hydroxide- and lithium alkoxide-induced fragmentation reactions to provide butenolides, gamma-hydroxycyclohexenones, and/or gamma-butyrolactones. In general, product distribution is governed by two factors: (1) the nature of nucleophiles and (2) the steric bulkiness of the substituents at C-2 and C-4 of the cyclohexanones. Lithium hydroxide-induced fragmentation provides butenolides and gamma-hydroxycyclohexenones. In contrast, lithium alkoxide-promoted fragmentation results in predominantly 5-substituted gamma-butyrolactones along with a small amount of butenolides in limited cases. Fragmentation products induced by lithium hydroxide are largely influenced by the steric bulkiness of the substituents at C-2 and C-4 of the cyclohexanone ring. The bulky substituents render the exclusive formation of butenolides.     

Heteroatom-guided torquoselective olefination of alpha-oxy and alpha-amino ketones via ynolates

Ynolates were found to react with alpha-alkoxy-, alpha-siloxy-, and alpha-aryloxyketones at room temperature to afford tetrasubstituted olefins with high Z selectivity. Since the geometrical selectivity was determined in the ring opening of the beta-lactone enolate intermediates, the torquoselectivity was controlled by the ethereal oxygen atoms. From experimental and theoretical studies, the high Z selectivity is induced by orbital and steric interactions rather than by chelation. In a similar manner, alpha-dialkylamino ketones provided olefins with excellent Z selectivity. These products can be easily converted into multisubstituted butenolides and gamma-butyrolactams in good yield.     

A highly efficient asymmetric synthesis of optically active alpha, gamma-substituted gamma-butyrolactones using a chiral auxiliary derived from isosorbide

Using an easily accessible and inexpensive chiral auxiliary derived from isosorbide, optically active alpha,gamma-substituted gamma-butyrolactones were obtained in high enantiomeric purity (up to >99% ee for trans) by the SmI(2)-induced reductive coupling of chiral methacrylate 7 with ketones in the presence of (-)-sultam as a proton source.     

Study of hydrolysis of amido-substituted gamma-butyrolactones by pH-stat titration and ultraviolet spectroscopic analyses

pH-Stat titration and ultraviolet absorption spectroscopy have been used to study the rates of ring-opening in a series of gamma-butyrolactones and their analogues. The half-lives for the lactones can be related to Hammett inductive and steric parameters.     

Application of an ephedrine chiral linker in a solid-phase, 'asymmetric catch-release' approach to gamma-butyrolactones

A Sm(II)-mediated, asymmetric, intermolecular ketyl-olefin addition employing alpha,beta-unsaturated esters linked to resin through an ephedrine 'chiral link' has been applied in a direct 'asymmetric catch-release' approach to gamma-butyrolactones.     

Synthesis of different chiral amino gamma-butyrolactones and amino gamma-butenolides

Different transformations of chiral epoxy esters 1 afford two different amino gamma-butyrolactones 2 and 6, and amino gamma-butenolides 8, by different nucleophilic opening-closing processes. [reaction: see text]     

Stereoselective conjugate addition of benzyl phenylsulfonyl carbanions to enoates derived from d-mannitol

The conjugate addition of benzylic phenylsulfonyl carbanions (2a'-d') to enoates derived from d-(+)-mannitol (E- or Z-1a-c) was studied using THF and THF/HMPA as solvent. Under kinetic conditions (-78 degrees C), enoate E-1a,b led to a mixture of syn-(R,S) and anti-(S,S) adducts (55/45), and syn-(R,S) adducts were the main product obtained ( approximately 90/10) from enoate Z-1a. Under thermodynamic conditions (-78 degrees C to room temperature) syn-(R,S) adducts were also preferentially formed ( approximately 90/10), despite the geometry at the double bond in the acceptor. Enoate 1c (E/Z = 57/43), bearing an additional benzyl group at the alpha-position, also reacted with carbanions 2'a,b, under thermodynamic conditions, leading to syn-adducts in excellent de (control at the three newly generated stereogenic centers). The adducts were quantitatively transformed into the corresponding beta-gamma-disubstituted gamma-butyrolactones and alpha,beta,gamma-trisubstituted gamma-butyrolactones. (1)H NMR studies (NOE and J-coupling) of these lactones allowed us to determine their configuration at the newly generated chiral centers. The reduction of the C-S bond in adducts syn-(R,S) with Na/Hg, followed by treatment of the resulting products in aqueous acid media, led to enantioenriched beta-benzyl-gamma-hydroxymethyl-gamma-butyrolactones. The conformational equilibrium of enoates E- and Z-1b was evaluated by theoretical calculations (ab initio, MP2/6-31G), and a mechanistic rationale was proposed to explain the observed stereoselectivities.     

Stereocontrolled construction of tetrahydrofurans and gamma-butyrolactones using organomolybdenum chemistry

[reaction: see text]. Diastereoselective conversion of pi-allylmolybdenum complex aldehyde 1 to organometallic triol 4 and diols 5, 10, and 13 is described. Stereocontrolled demetalation of 4, 5, and 13 was accomplished, leading to hydroxylated tetrahydrofurans and gamma-butyrolactones, as single diastereoisomers.     

Novel rhodium-catalyzed cycloisomerization of 1,6-enynes with an intramolecular halogen shift

A new Rh-catalyzed 1,6-enyne cycloisomerization process with a pi-allyl rhodium species as the key intermediate is investigated. A halogen shift happened in this novel process. The synthesis of stereodefined alpha-halomethylene gamma-butyrolactones has been achieved using the readily accessible Rh catalysts.     

Facile asymmetric synthesis of the core nuclei of xanthanolides,guaianolides, and eudesmanolides

[reaction: see text] Bicyclic and tricyclic gamma-butyrolactones with 5,7-, 5,6,5-, 5,6,6-, or 5,7,5-fused ring systems, being found in xanthanolides, eudesmanolides, and guaianolides, were readily synthesized from methyl furan-2-carboxylic acid. Key steps were a copper(I)-catalyzed asymmetric cyclopropanation, Sakurai allylations, intramolecular ene reactions, and ring-closing metathesis reactions.     

One-step assembly of functionalized gamma-butyrolactones from benzoins or benzaldehydes via an N-heterocyclic carbene-mediated tandem reaction

We describe here a direct, efficient, one-step construction of gamma,gamma-difunctionalized gamma-butyrolactones from benzoins or benzaldehydes via a tandem reaction promoted by 1,3-dimethyl imidazolin-2-ylidene, an N-heterocyclic carbene (NHC). [reaction: see text]     

Asymmetric synthesis of carboxylic acid derivatives having an all-carbon alpha-quaternary center through Cu-catalyzed 1,4-addition of dialkylzinc reagents to 2-aryl acetate derivatives

The asymmetric synthesis of carboxylic acid derivatives having an all-carbon alpha-quaternary center has been achieved via copper-catalyzed 1,4-addition of dialkylzinc reagents to aryl acetate derivatives in the presence of phosphoramidite ligand. High isolated yields and enantioselectivities were obtained. It was demonstrated that the Meldrum's acid and ester moieties present on the all-carbon quaternary center allow for a wide variety of subsequent transformations, leading to the expedient preparation of succinimides, succinate esters and succinic acids, gamma-butyrolactones, and beta-amino acid derivatives.