Julia Reaction Research Articles

Cobalt versus Osmium: Control of Both trans and cis Selectivity in Construction of the EFG Rings of Pectenotoxin 4.

Catalytic oxidative cyclisation reactions have been employed for the synthesis of the E and F rings of the complex natural product target pectenotoxin 4. The choice of metal catalyst (cobalt- or osmium-based) allowed for the formation of THF rings with either trans or cis stereoselectivity. Fragment union using a modified Julia reaction then enabled the synthesis of an advanced synthetic intermediate containing the EF and G rings of the target.

Cobalt versus Osmium: Control of Both trans and cis Selectivity in Construction of the EFG Rings of Pectenotoxin 4

AbstractCatalytic oxidative cyclisation reactions have been employed for the synthesis of the E and F rings of the complex natural product target pectenotoxin 4. The choice of metal catalyst (cobalt‐ or osmium‐based) allowed for the formation of THF rings with either trans or cis stereoselectivity. Fragment union using a modified Julia reaction then enabled the synthesis of an advanced synthetic intermediate containing the EF and G rings of the target.

Total synthesis of 7-des-O-pivaloyl-7-O-benzylbryostatin 10.

The first total synthesis of a derivative of a 20-deoxybryostatin, namely 7-des-O-pivaloyl-7-O-benzylbryostatin 10 is described. Preliminary studies demonstrated that the modified Julia reactions of 2-benzothiazolylsulfones corresponding to the C17-C27 fragment with aldehydes corresponding to the C1-C16 fragment, provided an efficient and stereoselective assembly of advanced intermediates with the (E)-16,17-double-bond. The synthesis of the C1-C16 fragment was then modified so that the C1 acid was present as its allyl ester before the Julia coupling. A more efficient synthesis of the C17-C27 sulfone was developed in which a key step was the bismuth mediated coupling of an allylic bromide with an aldehyde in the presence of an acrylate moiety in the allylic bromide. A scalable synthesis of an advanced macrolide was completed using the modified Julia reaction followed by selective deprotection and macrolactonisation. The final stages of the synthesis required selective hydroxyl deprotection and the introduction of the sensitive C19-C21 unsaturated keto-ester functionality. Unexpected selectivities were observed during studies of the hydroxyl group deprotections. In particular, cleavage of tri-isopropylsilyl ethers of the exocyclic primary allylic alcohols was observed in the presence of the triethylsilyl ether of the secondary alcohol at C19. Model studies helped in the design of the methods used to introduce the C19-C21 keto-ester functionality and led to the completion of a total synthesis of a close analogue of bryostatin 10 in which a benzyloxy group rather than the pivaloyloxy group was present at C7.

Synthesis of Chiral, Enantiopure Allylic Amines by the Julia Olefination of α-Amino Esters.

The four-step conversion of a series of N-Boc-protected l-amino acid methyl esters into enantiopure N-Boc allylamines by a modified Julia olefination is described. Key steps include the reaction of a lithiated phenylalkylsulfone with amino esters, giving chiral β-ketosulfones, and the reductive elimination of related α-acetoxysulfones. The overall transformation takes place under mild conditions, with good yields, and without loss of stereochemical integrity, being in this respect superior to the conventional Julia reaction of α-amino aldehydes.

Modified Julia Olefination on Sugar‐Derived Lactones: Synthesis of Difluoro‐exo‐glycals

AbstractWe report the preparation of difluoro‐exo‐glycals by gem‐difluoroolefination of benzylated sugar‐derived lactones using a modified Julia reaction. The addition is highly stereoselective, and the Smiles‐rearrangement–elimination sequence can be carried out under microwave irradiation.

Gold nanoparticles decorated with mannose-6-phosphate analogues.

Herein, the preparation of neoglycoconjugates bearing mannose-6-phosphate analogues is described by: (a) synthesis of a cyclic sulfate precursor to access the carbohydrate head-group by nucleophilic displacement with an appropriate nucleophile; (b) introduction of spacers on the mannose-6-phosphate analogues via Huisgen’s cycloaddition, the Julia reaction, or the thiol-ene reaction under ultrasound activation. With the resulting compounds in hand, gold nanoparticles could be functionalized with various carbohydrate derivatives (glycoconjugates) and then tested for angiogenic activity. It was observed that the length and flexibility of the spacer separating the sugar analogue from the nanoparticle have little influence on the biological response. One particular nanoparticle system substantially inhibits blood vessel growth in contrast to activation by the corresponding monomeric glycoconjugate, thereby demonstrating the importance of multivalency in angiogenic activity.

ChemInform Abstract: Aza‐Michael Access to Fluoroalkylidene Analogues of Biomolecules.

AbstractA direct access for the preparation of fluoroallylamines via an aza‐Michael reaction followed by a modified Julia reaction is presented.

Aza-Michael Access to Fluoroalkylidene Analogues of Biomolecules

The synthesis of fluoroaminosulfones derived from piperidine and nucleic bases followed by the study of their chemical behavior in the modified Julia reaction are described. The resulting aminosulfones open a straightforward access to a series of new fluorinated biomolecules including a potent DPP-II inhibitor and acyclonucleoside analogues as potential enzyme inhibitors.

Approaches to the total synthesis of biologically active natural products: studies directed towards bryostatins

Progress on a total synthesis of the marine natural products, the bryostatins, is reviewed. Following studies aimed at the synthesis of the 1,16- and 17,27-fragments, procedures for the assembly of the macrocyclic ring of the bryostatins were investigated. Although ring-closing metathesis was not found to be useful for the synthesis of bryostatins with geminal dimethyl groups at C18, the modified Julia reaction was found to be useful for the stereoselective formation of the 16,17-double-bond and led to a synthesis of an advanced macrocyclic intermediate. Several novel synthetic procedures feature in this work.

Synthesis of macrocyclic precursors of lankacidins using Stille reactions of 4-(2-iodo-alkenyl)azetidinones and related compounds for ring closure

In the context of a proposed total synthesis of lankacidins, the synthesis of 4-(2-iodo-alkenyl)azetidinones and their participation in Stille coupling reactions have been investigated. 1- tert-Butyldimethylsilyl-4-(2-iodoethenyl)azetidinone was found to undergo a Stille coupling reaction with a 3-hydroxy-1-tributylstannylhepta-1,5-diene to give an acceptable yield of the corresponding conjugated diene but the analogous reaction with a 3- tert-butyldimethylsilyloxy-1-tributylstannylhepta-1,5-diene was unsuccessful. A series of 4-[( E)-2-iodoprop-1-enyl]azetidinones, a ring-opened ester and a lactone were also found to undergo Stille reactions with 3-tributylstannylprop-2-enol albeit with variable yields. Asymmetric syntheses of methyl (2 R,3 R,5 S)-3- tert-butyldimethylsilyloxy-2-methyl-5-(2-trimethylsilylethoxy)methoxy-6-oxohexanoate, (3 R,4 S)-1- tert-butyldimethylsilyl-4-[( E)-2-iodoprop-1-enyl]-3-methylazetidin-2-one, and (5 S,2 E,6 E)-5- tert-butyldimethylsilyloxy-2-methyl-1-phenylsulfonyl-7-tributylstannylhepta-2,6-diene and their incorporation into macrocyclic precursors of the lankacidins were then investigated. Key reactions were a Julia reaction between the aldehyde and the sulfone to form the 12,13-double-bond, a stereoselective acylation of the azetidinone, and formation of macrocycles using intramolecular Stille reactions in the presence of a free hydroxyl group at C(8) (lankacidin numbering).

Optically Active γ‐Hydroxy Sulfone Julia Reagents for the Synthesis of Peptidyl Olefin Peptidomimetics

AbstractPeptidyl olefin peptidomimetics serve as biologically active compounds or as intermediates for other peptidyl isosteres. We developed a chemoenzymatic stereoselective approach to optically active γ‐hydroxy sulfones to be assembled into peptidyl olefins by the Julia reaction. Key enzymatic hydrolysis of prochiral diesters to the corresponding hydroxy esters introduces optical activity. The sequence of the subsequent chemical reactions, either protection–hydrolysis–functionalization or functionalization–hydrolysis–protection, determines the absolute stereochemistry of the final sulfone building block.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Total Synthesis of Peridinin and Related C37‐Norcarotenoid Butenolides

As an extension of our synthesis of symmetrical carotenoids, the preparation of the highly functionalized C37-norcarotenoid butenolide peridinin (1), its 6'-epi- and 11'Z stereoisomers has been completed. Featuring a central dihalogenated C8 linchpin unit 6, two synthetic routes, differing in the ordering of the last three steps were explored by using the C3,C3'-bisdehydroxylated target as the model system. The first route uses the combination of a modified Z-selective Julia reaction and two sequential Stille couplings, the last one producing the isomerisation of the polyene Z double bond. The second route inverts these steps and makes the isolation of the 11'Z stereoisomers as major products possible. An efficient Z to E isomerisation of the final carotenoid skeleton simply uses the Stille reaction conditions at ambient temperature. As the reaction of bromoallene 12 with alkenylstannane 11 occurs with inversion of configuration, 6'-epi-peridinin could also be prepared by route A. The advantages and limitations of the sequential Stille cross-coupling approach to carotenoids are highlighted.

Total Synthesis of a 28-Member Stereoisomer Library of Murisolins

Total syntheses of two 16-member libraries of murisolin isomers are reported. In the first library, fluorous PMB (p-methoxybenzyl) groups encode configurations, and four mixtures of four dihydroxy-tetrahydrofurans are prepared by Shi epoxidation followed (optionally) by Mitsunobu reaction. The mixtures are coupled by Kocienski-Julia reaction with a single hydroxybutenolide followed by hydrogenation. Demixing and detagging provide the 16 pure stereoisomers. In the second synthesis, a single mixture of four fluorous-tagged dihydroxy-tetrahydrofurans is coupled with a four-compound mixture of hydroxybutenolides that bear derivatives of DMB (dimethoxybenzyl) groups with oligoethylene glycol (OEG) units that encode the configurations at C4 and C34. The 16-compound mixture is subjected to hydrogenation, double demixing, and detagging to provide the 16 isomerically pure murisolins. Twelve of these isomers are new, while four match samples from the first library.

Synthetic studies of the HIV-1 protease inhibitive didemnaketals: precise and stereocontrolled synthesis of the key mother spiroketal

The precise and stereocontrolled synthesis of the C 9–C 23 portion, the key mother spiroketal of the HIV-1 protease inhibitive didemnaketals from the ascidian Didemnum sp., has been carried out through multisteps starting from ( R)-pulegone as the chiral template. This approach involved the distereoselective construction of eight chiral centers by intramolecular chiral inducement and the coupling of two fragments by Julia reaction.

An expedient approach to E, Z-dienes using the Julia olefination

New reaction conditions were developed for the synthesis of E, Z-dienes from α,β-unsaturated aldehydes and heteroarylsulfones using the Julia reaction. In most cases under optimal conditions, the selectivity of the olefination reaction is better than 88:12 when a pyridylsulfone was used as the precursor. In addition, novel reaction conditions for the chemoselective oxidation of heteroarylthioethers that are compatible with alkenes and dienes are also reported.

Synthesis of 5-(mercaptomethyl)-3( E)-undecene-1,11-dioic acid, a non-peptide glutathione analog

The key step in the synthesis of the title compound is a Julia reaction to create the E-double bond by introducing a functionalized C3 carbon chain.

Stereoselective Synthesis of Polyhydroxylated Indolizidines from γ-Hydroxy α,β-Unsaturated Sulfones

The polyhydroxylated indolizidines castanospermine and swainsonine as well as some of their stereoisomers are powerful glycosidase inhibitors. An efficient and stereochemically flexible synthesis of racemic 1,7,8-trihydroxylated and 1,6,7,8-tetrahydroxylated indolizidines (castanospermine stereoisomers) from readily available N-substituted γ-oxygenated α,β-unsaturated sulfones 3 and 4 has been developed. The construction of the bicyclic skeleton of 1-hydroxyindolizidine has been accomplished by intramolecular conjugate addition of the nitrogen moiety of 3 and 4 to the α,β-unsaturated sulfone unit to give the pyrrolidine intermediates 5 and 6, followed by formation of the C(7)−C(8) bond by intramolecular acylation (or alkylation) of the α-sulfonyl carbanion. The stereoselectivity of the pyrrolidine synthesis was highly dependent on the bulkiness of the γ-oxygenated function; thus, the free alcohols gave predominantly cis-pyrrolidines while the OTIPS derivatives led to the trans isomers. After straightforward functional group transformations, the removal of the sulfonyl group at C(8) either by Julia reaction or by basic elimination (depending on the substrate used) afforded the key C(7)C(8) unsaturated indolizidines 10, 22, 30, and 31, whose stereoselective dihydroxylations with OsO4 gave a variety of cis C(1)C(8a) and trans C(1)C(8a) trihydroxylated and tetrahydroxylated indolizidines, among which (±)-1,7-di-epi-castanospermine and (±)-1,8-di-epi-castanospermine have been reported for the first time.

ChemInform Abstract: Synthesis of 2,7‐Diazabicyclo(3.3.0)octane and 2,7‐Diazabicyclo(3.3.0) oct‐4‐ene Derivatives via Cyclization Reaction and Julia Reaction.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of 2,7-Diazabicyclo[3.3.0]octane and 2,7-Diazabicyclo[3.3.0]oct-4-ene Derivatives via Cyclization Reaction and Julia Reaction

Abstract 2,7-Diazabicyclo[3.3.0]octan-4-ol (1) and 2,7-diazabicyclo[3.3.0]oct-4-ene (2) are synthesized by the desulfonylation using Mg-HgCl2(cat.) of β-hydroxy sulfone derivatives which have been prepared via cyclization of sulfone ester derivative.

Novel Concurrent Synthesis of Side-Chain Analogues of Vitamins D2 and D3: 24,24-Dihomo-25-hydroxycholecalciferol and (22E)-22-Dehydro-24,24-dihomo-25-hydroxycholecalciferol

A novel method for the preparation of side-chain extended analogues of vitamins D is described. Both 24,24-dihomo- and (22E)-22-dehydro-24,24-dihomo-25-hydroxycholecalciferols were efficiently prepared from the same intermediates, i.e., the phenyltriazolinedione adduct of previtamin D with a C-22 aldehyde group and a side-chain alkyl sulfone. The key steps in this synthesis involve the Julia coupling of the vitamin D synthon with the side-chain sulfone followed by Barton radical deoxygenation of the C-22 alcohol or dehydroxydesulfonylation of the respective β-hydroxysulfone. All four β-hydroxysulfones of the Julia reaction were separated and characterized for the first time. The absolute configurations at C-22 and C-23 in these compounds were tentatively assigned by high-field proton magnetic resonance. The synthetic method allows a highly efficient concurrent preparation of analogues with a modified side chain attached to the vitamin D nucleus via both single and double bonds.