Asymmetric Induction via an Intramolecular Haloetherification Reaction of Chiral Ene Acetals: A Novel Approach to Optically Active 1,4- and 1,5-Diols

An asymmetric synthesis of chiral 1,4- and 1,5-diols has been developed from the ene acetals 1a and 1c, prepared from the corresponding aldehydes and chiral C(2)-symmetric diols, involving remote asymmetric induction as a key step. In the first step, treatment of 1 with I(coll)(2)ClO(4) in the presence of an alcohol afforded the macrocyclic acetals (3-5 and 7) in a highly stereoselective manner. Subsequent nucleophilic substitution of iodide followed by a Grignard reaction with complete retention of stereochemistry and a final deprotection of the diphenylethylene or diphenylpropylene unit successfully gave optically active 1,4- and 1,5-diols in good yields.     

Synthesis and stereochemistry of some bicyclic gamma-lactones from parasitic wasps (Hymenoptera: Braconidae). Utility of hydrolytic kinetic resolution of epoxides and palladium(II)-catalyzed hydroxycyclization-carbonylation-lactonization of ene-diols.

A palladium(II)-catalyzed hydroxycyclization-carbonylation-lactonization sequence with appropriate pent-4-ene-1,3-diols provides efficient access to the bicyclic gamma-lactones, 5-n-butyl- and 5-n-hexyltetrahydrofuro-[3,2-b]furan-2(3H)-ones (3) and (4), respectively, in both racemic and enantiomeric forms. Some of the substrate pent-4-ene-1,3-diols of high enantiomeric excess (ee) have been derived from racemic terminal epoxides by hydrolytic kinetic resolution (HKR) using cobalt (III)-salen complexes. (9Z,12R)-(+)-Ricinoleic acid also serves as a "chiral pool" source of other pent-4-ene-1,3-diols. These syntheses and enantioselective gas chromatography confirm the structures and absolute stereochemistry of the lactones in some species of parasitic wasps (Hymenoptera: Braconidae). The highly abundant 5-n-hexyltetrahydrofuro-[3,2-b]furan-2(3H)-one (4) in Diachasmimorpha kraussii and D. longicaudata is of high ee (>99%) with (3aR,5R,6aR) stereochemistry.     

C(2)-Symmetric bis-sulfoxide: A novel chiral auxiliary for asymmetric desymmetrization of cyclic meso-1,2-diols

A new heterocyclic compound, C(2)-symmetric bis-sulfoxide 1, has been found to be an efficient chiral auxiliary for asymmetric desymmetrization of cyclic meso-1,2-diols via diastereoselective acetal fission. Both (R,R)- and (S,S)-1 are readily synthesized with high optical purity via asymmetric oxidation of 1, 5-benzodithiepan-3-one (2). After acetalization of meso-1,2-diols 6a-e and a mono-TMS ether 6f with this chiral auxiliary 1, the resulting acetals 7a-f were subjected to base-promoted acetal fission upon treatment with potassium hexamethyldisilazide (KHMDS) followed by acetylation or benzylation to give the desymmetrized diol derivatives 8a-f with high diastereoselectivity. The chiral auxiliary 1 is readily removed by acid-promoted hydrolysis and can be recovered without a loss in enantiomeric excess.     

Enantioselective cyclization of chiral butane-1,4-diols to chiral tetrahydrofurans: synthesis of chiral trans-2-(3-methoxy-5-methylsulfonyl-4-propoxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (L-659,989), a potent PAF-receptor antagonist

Acid catalyzed cyclization of (1R,4RS)- and (1S,4RS)-1-(3-methoxy-5-methylsulfonyl-4-propoxyphenyl)-4-(3,4,5-trimethoxyphenyl)butane-1,4-diols to the corresponding chiral cis- and trans-tetrahydrofurans proceeds with retention of configuration at C-1. Using this stereo- and regioselective reaction, the two optically active enantiomers of L-659,989, a potent PAF-receptor antagonist, were prepared.     

Asymmetric tandem Michael-aldol reactions between 3-cinnamoyloxazolidine-2-thiones and aldehydes

Reactions between chiral 3-cinnamoyl-4-methyl-5-phenyl-1,3-oxazolidine-2-thiones and aromatic aldehydes in the presence of BF3Et2O diastereoselectively produced tricyclic compounds incorporating a bridgehead carbon bound to four heteroatoms in high yields. Four stereocenters were induced during the reaction. The tricyclic products were transformed into propane-1,3-diols bearing three consecutive stereocenters by acid hydrolysis, S-methylation, and reductive removal of the chiral auxiliary.     

Regio- and stereoselective microwave-assisted synthesis of 5-alkyl-4-alkenyl-4-phenyl-1,3-oxazolidin-2-ones

Chiral symmetrical alk-2-yne-1,4-diols have been stereoselectively transformed into 5-alkyl-4-alkenyl-4-phenyl-1,3-oxazolidin-2-ones, which are precursors of quaternary α-amino β-hydroxy acids. The key step was the cyclization of the bis(tosylcarbamates) of 2-phenylalk-2-yne-1,4-diols, easily obtained from the starting chiral diols. These cyclizations were accomplished with complete regioselectivity and up to 92:8 dr in the presence of catalytic amounts of Ni(0) or Pd (II) derivatives under microwave heating.     

Palladium-catalyzed stereospecific synthesis of 2,6-disubstituted tetrahydropyrans: 1,3-chirality transfer by an intramolecular oxypalladation reaction

PdCl2(CH3CN)2 (10 mol %) catalyzed reactions of non-3-ene-2,8-diols 1 and 2 gave 2,6-disubstituted tetrahydropyrans 3 and 4 in excellent yields with high diastereoselectivities (>20:1). Intramolecular cyclizations of the hydroxy nucleophile to the chiral allylic alcohol take place efficiently under mild conditions. A new stereogenic center is generated on the tetrahydropyran ring by 1,3-chirality transfer from the chiral allylic alcohol via a syn-SN2' type process. Cis tetrahydropyran 3E was formed from syn-2,8-diols 1a and 2a, and trans tetrahydropyran 4E was formed from anti-2,8-diol 1b, stereospecifically. Cis tetrahydropyran bearing a cis alkene 3Z was obtained from 2b at -40 degrees C, while 4E was formed from 2b in the presence of catalytic amount of water at -40 degrees C. The face selectivity of these cyclizations can be rationalized by taking a favorable conformation of the intermediary Pd pi-complex with allylic alcohols, escaping the allylic strain and 1,3-diaxial interactions. A stereocontrolled synthesis of optically pure 2-alkenyl-6-methyltetrahydropyran 17 was achieved efficiently in four steps from 6-silyloxy-1-heptyne 13 with an aldehyde and included asymmetric alkynylation, partial reduction of alkyne, deprotection of the silyl group, and the stereospecific cyclization.     

Enantioselective preparation of C2-symmetrical 1,4-diols

The catalytic enantioselective addition of functionalized dialkylzincs to the γ-alkoxyaldehydes 5, 6 and 7 provides 1,4-diols 1–3 with 73–99 %ee. After a simple reaction sequence, these diols are converted to chiral γ-alkoxyaldehydes which undergo a second catalytic enantioselective addition of the same diorganozinc providing C₂-symmetrical 1,4-diols 10a–f with excellent diastereoselectivity (up to 97 : 3).     

Asymmetric desymmetrization based on an intramolecular haloetherification: a highly effective and recyclable chiral nonracemic auxiliary, 2-exo-methyl-3-endo-phenyl-5-norbornene-2-carboxaldehyde, for meso-1,3- and meso-1,4-diols

A new chiral auxiliary, a 3-endo-phenyl norbornene aldehyde derivative, which is a crystalline, very stable, and easily handled, was developed for the desymmetrization of meso-1,3- and meso-1,4-diols. The key step of the method, an intramolecular bromoetherification, proceeded in a highly diastereoselective manner. A four-step sequence, 1) acetalization, 2) intramolecular bromoetherification followed by acid hydrolysis, 3) protection of the alcohol, and 4) retrobromoetherification, transformed the meso-diols into optically active derivatives. The 3-endo-phenyl norbornene aldehyde derivative was simultaneously reformed and could be used repeatedly. This is the first chemical example of a single auxiliary that is applicable for highly enantioselective desymmetrization of meso-1,3- and meso-1,4-diols; to the best of our knowledge, this is the best chemical method available for the desymmetrization of meso-1,4-diols.     

Stereoselective hydrocoupling of [(1R)-exo]-3-exo-(diphenylmethyl)bornyl cinnamates by electroreduction

[reaction: see text]. The chiral auxiliary [(1R)-exo]-3-exo-(diphenylmethyl)borneol, synthesized from (1R)-(+)-camphor in three steps, was highly effective for the stereoselective hydrocoupling of its cinnamates by electroreduction. From the resulting hydrodimers, (3R,4R)-3,4-diaryladipic acid esters and (3R,4R)-3,4-diarylhexane-1,6-diols were synthesized in 87-95% ee.     

(S)-(+)-N-acetylphenylglycineboronic acid: a chiral derivatizing agent for Ee determination of 1,2-diols

A new chiral derivatizing agent for ee determination of 1,2-diols via (1)H NMR is described. (S)-(+)-N-acetylphenylglycineboronic acid (1) is synthesized in enantiomerically pure form; its reaction with chiral diols quantitatively yields cyclic boronic esters 5a-g. The latter show a remarkably high diastereodifferentiation of proton NMR signals useful for de determination. [reaction: see text]     

Preparation of bicyclo[3.2.0]heptane-2-endo,7-endo-diols: 1,3-diols with a chiral rigid backbone

The easily available bicyclo[3.2.0]hept-3-en-6-ones (1a-f) have been converted into the corresponding bicyclo[3.2.0]heptane-2-endo,7-endo-diols (4a-f) in an efficient and stereoselective fashion. This preparation opens a route to a family of 1,3-diols with a chiral rigid backbone, potentially suitable as nonracemic precursors for bidentate ligands in asymmetric synthesis.     

Convenient access to sterically hindered C2 chiral 2,2,5,5-tetraphenyltetrahydrofuran-3,4-diols: intramolecular selective 1,4-cyclocondensation of (2R,3R)- and (2S,3S)-1,1,4,4-tetraphenylbutanetetraols

Sterically hindered C₂ chiral (3R,4R)- and (3S,4S)-2,2,5,5-tetraphenyltetrahydrofuran-3,4-diols have been conveniently prepared in a very high yield via heterogeneous intramolecular selective 1,4-cyclocondensation of (2R,3R)- and (2S,3S)-1,1,4,4-tetraphenylbutanetetraol in concentrated hydrohalic acids, respectively. Preliminary examination of additives for the Barbas–List reaction showed that in certain cases, the hindered C₂ chiral tetrahydrofuran-3,4-diols were better chiral auxiliaries than enantiopure (R)- and (S)-1,1′-bi-2-naphthols.     

Stereoselective synthesis of styrene oxides via a Mitsunobu cyclodehydration

[reaction: see text] The Mitsunobu cyclodehydration of chiral phenethane-1,2-diols (4), readily accessed from the styrene derivative (5), has been demonstrated to provide the corresponding styrene oxides (2) with high levels of stereoretention (up to 99%). Optimized reaction conditions are described, from which the combination of tricyclohexylphosphine (Chx(3)P) and diisopropylazodicarboxylate (DIAD) in THF and R = EWG provides the best results.     

Chromium-catalyzed asymmetric synthesis of 1, 3-diols

An efficient,chromium-catalyzed highly enantioselective preparation of protected 1,3-diols has been achieved.In the presence of a chiral chromium catalyst using the carbazole-based bisoxazoline as the chiral ligand,a variety of optically pure 1,3-diols were synthesized in 34%-87%yields with up to 98%ee.The benzyl as well as silyl ethers were suitable substitutions for the hydroxyl group.Meanwhile,aromatic,aliphatic and α,β-unsaturated aldehydes are well tolerated under the mild reaction conditions.     

Epoxide hydrolase-catalyzed enantioselective synthesis of chiral 1,2-diols via desymmetrization of meso-epoxides. lzhao@diversa.com

The discovery, from nature, of a diverse set of microbial epoxide hydrolases is reported. The utility of a library of epoxide hydrolases in the synthesis of chiral 1,2-diols via desymmetrization of a wide range of meso-epoxides, including cyclic as well as acyclic alkyl- and aryl-substituted substrates, is demonstrated. The chiral (R,R)-diols were furnished with high ee's and yields. The discovery of the first microbial epoxide hydrolases providing access to complementary (S,S)-diols is also described.     

Totally selective reaction of CO2 with enantiopure amino epoxides under mild reaction conditions. synthesis and synthetic applications of enantiopure (4R,1'S)- or (4S,1'S)-4-(1-Aminoalkyl)-2-oxo-1,3-dioxolanes

The reaction of chiral (2R,1'S)- or (2S,1'S)-2-(1-aminoalkyl)epoxides 1 or 2 with CO2, generated from acidic treatment of an aqueous solution of NaHCO3 at room temperature, efficiently afforded enantiopure cyclic carbonates 3 or 4, respectively, with total selectivity. Compounds 3 and 4 were readily transformed into the corresponding diols 7 and 8 by reaction with LiAlH4 or by basic hydrolysis. When compounds 3 or 4 were allowed to react with methyllithium at -78 degrees C, O1-acetylalkane-1,2-diols 9 and 10 were obtained with total or high selectivity.     

Diisopropyl tartrate (E)-γ-(dimethylphenylsilyl)allylboronate, a chiral allylic alcohol β-carbanion equivalent for the enantioselective synthesis of 2-butene-1,4-diols from aldehydes

An enantioselective synthesis of 4-substituted (E)-2-buten-1,4-diols is described. The method involves the reaction of aldehydes with the chiral PhMe₂Si- substituted allylboronate3 followed by epoxidation (dimethyl dioxirane) and acid catalyzed Petersen rearrangement of the intermediate epoxysilanols.     

Synthesis and properties of optically active 1,3-diols and their derivatives as chiral dopants for ferroelectric liquid crystals

New chiral dopants β-hydroxy ketones 1, 1,3-diols 2, 1,3-dioxanes 3 and 1,3-dioxan-2-ones 4 were designed and synthesized. Reaction of (R)-1,2-epoxyoctane with carbanions derived from 2-(4-substituted phenyl)-1,3-dithianes followed by hydrolysis of the resulting hydroxy dithianes afforded 1. Reduction of 1 gave the diols 2, which yielded 3 upon acetalization and 4 upon carbonation. The syn isomers of 2, 3, and 4 exhibited larger spontaneous polarizations, when applied as chiral dopants, than the anti isomers or hydroxy ketones 1.     

Enzymatic approach to enantiomerically pure 5-alken-2,4-diols and 4-hydroxy-5-alken-2-ones: application to the synthesis of chiral synthons

Enantiomerically pure 1,3-diols 1-3 were obtained by a chemoenzymatic approach (lipase PS from Burkholderia cepacia). These diols were converted into useful chiral synthons, which could be considered homologues of glyceraldehyde and glyceric acid acetonides. Applications of these synthons to the de novo synthesis of sugars and preparation of conagenin carboxylic moiety were shown. Hydroxy ketone 4 was chosen as a model system for another synthetic evolution: it was obtained in enantiomerically pure form by enzymatic resolution and converted into chiral tetrahydropyranes, such as the stereoisomers of the commercial fragrance Gyrane.