Recent topics of the natural product synthesis by Horner–Wadsworth–Emmons reaction

The Horner–Wadsworth–Emmons (HWE) reaction has become well established among existing methodologies for the highly stereoselective olefination of carbonyl compounds. The reliability of this reaction in terms of its robustness, high stereoselectivity, and broad substrate scope permit retrosynthetic disconnection of the olefin bond in α,β-unsaturated carbonyl intermediates in natural product synthesis. This review discusses recent applications of the HWE reaction in natural product synthesis, highlighting its use for carbon chain elongation, coupling reactions of synthetic segments, ring-closing reactions, tandem reactions including HWE olefination, and asymmetric reactions.     

Highly enantioselective synthesis of tetrahydroquinolines via cobalt(II)-catalyzed tandem 1,5-hydride transfer/cyclization

A chiral catalyst prepared from N,N'-dioxide and Co(BF(4))(2)·6H(2)O was applied in the asymmetric hydride transfer initiated cyclization reaction, giving optically active tetrahydroquinolines in good yields with high enantioselectivities under mild reaction conditions. Meanwhile, in light of the absolute configuration of the product, a possible working model was proposed to explain the origin of the activation and asymmetric induction.     

Studies directed towards the total synthesis of koshikalide: stereoselective synthesis of the macrocyclic core

The stereoselective synthesis of the macrolactone core of the natural product koshikalide is described. Starting with readily available 1,4-butanediol and malic acid as synthons, our synthetic strategy involved the reiterative application of Gilman’s reaction, Swern oxidation and Sharpless asymmetric epoxidation to establish the required stereocentres. Other key steps in the synthesis include Negishi cross coupling and Horner–Wadsworth–Emmons (HWE) reactions for construction of the main fragments. The 14-membered lactone ring was prepared by a selective Mitsunobu macrolactonization approach.     

Total Synthesis of Panaginsene

The total synthesis of panaginsene has been accomplished in 11 linear steps starting from methyl 3,3-dimethyl-5-oxocyclopent-1-ene-1-carboxylate. The key steps are a Sharpless asymmetric epoxidation and Ti(III)-mediated reductive epoxide opening-radical cyclization to construct the chiral quaternary carbon stereocenter followed by a very challenging HWE olefination reaction on an 1,3-keto aldehyde and a late stage McMurry olefination using low valent titanium to construct the highly constrained angular tetrasubstituted olefin in a five-membered ring.     

Catalytic asymmetric reactions in alkaloid and terpenoid syntheses

Catalytic asymmetric induction is one of the most important methods in current synthetic organic chemistry for designing efficient and attractive synthetic routes. The efficient total synthesis of a natural product can be achieved through the identification of appropriate method and strategy. This Letter introduces the catalytic asymmetric syntheses of alkaloids and terpenoids based on an overview of four recently reported types of asymmetric reaction: (1) asymmetric decarboxylative allylation, (2) organocatalytic cascade reaction, (3) polyene cyclization, and (4) asymmetric [2+2]-photocycloaddition catalyzed by a chiral Lewis acid.     

Synthesis of the C(18)-C(34) fragment of amphidinolide C and the C(18)-C(29) fragment of amphidinolide F

A convergent synthesis of the C(18)-C(34) fragment of amphidinolide C and the C(18)-C(29) fragment of amphidinolide F is reported. The approach involves the synthesis of the common intermediate tetrahydrofuranyl-β-ketophosphonate via cross metathesis, Pd(0)-catalyzed cyclization, and hydroboration-oxidation. The β-ketophosphonate was coupled to three side chain aldehydes using a Horner-Wadsworth-Emmons (HWE) olefination reaction to give dienones, which were reduced with l-selectride to give the fragments of amphidinolide C and F.     

Biocatalytic organic synthesis of optically pure (S)-scoulerine and berbine and benzylisoquinoline alkaloids

A chemoenzymatic approach for the asymmetric total synthesis of the title compounds is described that employs an enantioselective oxidative C-C bond formation catalyzed by berberine bridge enzyme (BBE) in the asymmetric key step. This unique reaction yielded enantiomerically pure (R)-benzylisoquinoline derivatives and (S)-berbines such as the natural product (S)-scoulerine, a sedative and muscle relaxing agent. The racemic substrates rac-1 required for the biotransformation were prepared in 4-8 linear steps using either a Bischler-Napieralski cyclization or a C1-Cα alkylation approach. The chemoenzymatic synthesis was applied to the preparation of fourteen enantiomerically pure alkaloids, including the natural products (S)-scoulerine and (R)-reticuline, and gave overall yields of up to 20% over 5-9 linear steps.     

Asymmetric cyclization of omega-formyl-1,3-dienes catalyzed by a zerovalent nickel complex in the presence of silanes

A nickel(0)-catalyzed asymmetric cyclization of omega-formyl-1,3-diene in the presence of silanes in which five- or six-membered carbocycles or pyrrolidine derivatives were afforded up to 86% ee by the use of (2R,5R)-2,5-dimethyl-1-phenylphospholane as a monodentate chiral ligand was investigated. The reaction course of this asymmetric cyclization can be explained for by two possible mechanisms: one in which the cyclization proceeds via a pi-allylnickel intermediate to produce a cyclized product having an internal olefin in the side chain, and one in which the cyclization proceeds via a sigma bond metathesis of silane and the nickel-oxygen bond of oxanickelacycle to produce a cyclized compound having a terminal olefin and/or an internal olefin in the side chain. It was speculated that both of these mechanisms operate in this asymmetric cyclization depending upon the nature of silanes and the reaction conditions.     

Enantioconvergent synthesis by sequential asymmetric Horner-Wadsworth-Emmons and palladium-catalyzed allylic substitution reactions

A new method for enantioconvergent synthesis has been developed. The strategy relies on the combination of an asymmetric Horner-Wadsworth-Emmons (HWE) reaction and a palladium-catalyzed allylic substitution. Different alpha-oxygen-substituted, racemic aldehydes were initially transformed by asymmetric HWE reactions into mixtures of two major alpha,beta-unsaturated esters, possessing opposite configurations at their allylic stereocenters as well as opposite alkene geometry. Subsequently, these isomeric mixtures of alkenes could be subjected to palladium-catalyzed allylic substitution reactions with carbon, nitrogen, and oxygen nucleophiles. In this latter step, the respective (E) and (Z) alkene substrate isomers were observed to react with opposite stereospecificity: the (E) alkene reacted with retention and the (Z) alkene with inversion of stereochemistry with respect to both the allylic stereocenter and the alkene geometry. Thus, a single gamma-substituted ester was obtained as the overall product, in high isomeric purity. The method was applied to a synthesis of a subunit of the iejimalides, a group of cytotoxic macrolides.     

Stereoselective total synthesis of (−)-pyrenophorol

An efficient stereoselective total synthesis of (−)-pyrenophorol 1 is described. The key steps involved in this synthesis are hydrolytic kinetic resolution (HKR), MacMillan α-hydroxylation, Horner-Wadsworth-Emmons (HWE) reaction, and Mitsunobu cyclization.     

Total synthesis of pyranicin

[Reaction: see text] A stereocontrolled convergent synthesis of the annonaceous acetogenin pyranicin (1) is presented. Asymmetric Horner-Wadsworth-Emmons (HWE) reactions were used to access key intermediates. The tetrahydropyran derivative 2 was obtained via an asymmetric desymmetrization of the meso-dialdehyde 6, and the butenolide fragment was constructed using a stereoconvergent reaction sequence involving a parallel kinetic HWE resolution followed by a Pd-catalyzed allylic substitution. The C10/C15 1,6-diol motif was installed using Carreira's asymmetric acetylide addition methodology.     

Easy and Stereoselective One-Step Incorporation of Two Asymmetric Carbons in Pyranose Derivatives to Acyclic Epoxyamides: New, Potentially Useful Acyclic Chiral Templates

We reacted N,N-diethyl-2-(dimethylsulfuranylidene)acetamide with 4,6-O-alkylidene-glycopyranoses under several experimental conditions and obtained, stereoselectively, derivatives of acyclic 3-(polyhydroxyalkyl)-alpha,beta-epoxyamides. In this way, and in one stage, we introduced, highly stereoselectively, two new chiral carbons with a substituted asymmetric epoxide group that could then be regioselectively transformed and, in addition, obtained highly functionalized acyclic structures starting from easily obtained cyclohemiacetalic monosaccharides. The configuration of the new chiral carbons of the resulting trans-epoxyamides was determined by comparing the IR, NMR, and polarimetric data with another epoxyamide of known configuration. We attempted to explain the stereochemistry of the major products by proposing a preferential conformation for the different starting aldehyde sugars in the basic reaction medium that took into account, at first, the principal electrical interactions between the carbonyl group and those unprotected hydroxyl groups with partial hydroxylate character and, secondarily, the preferred equatorial approach (exo) of the nucleophile. Finally, we studied the cyclization of the reaction products by an initial Payne transposition of the gamma-hydroxy-alpha,beta-epoxide to alpha-hydroxy-beta,gamma-epoxide, followed by its cyclization to a C-glycofuranoside.     

Synthesis of Chiral 2-OXO- and 2-THIO-1,3,2-Oxazaphospholidines via the Asymmetric Cyclization of L-Serinoates with (Thio)Phosphoryl Dichlorides

In this paper is described the asymmetric cyclization of L-serine derivatives with phosphoro(no-)dichloridates or their thio-analogues, and investigated the asymmetric induction effect of chiral carbon centre on the forming chiral phosphorus centre. Some cyclization products have been separated as a pure diastereomer and their configuration is preliminarily discussed.     

Control of surface functionality in poly(phenylenevinylene) dendritic architectures

The efficient synthesis of new asymmetric poly(phenylenevinylene) dendritic macromolecules using a stepwise convergent-growth approach is described. By an iterative methodology that made use of the Horner-Wadsworth-Emmons (HWE) reaction, dendrons and dendrimers up to the third generation, with eight different functional groups located at the periphery, were prepared in good yields. Both the number and placement of functionalities can be accurately controlled to afford a large variety of dendritic architectures.     

Tandem conjugate addition-aldol cyclization of 2-formylbenzylidenemalonate with ether radicals by the mediation of dimethylzinc

The chemoselective radical conjugate addition reaction of THF or 4,4,5,5-tetramethyl-1,3-dioxolane with 2-formylbenzylidenemalonate gave tandem conjugate addition-aldol cyclization product in one pot. The radical tandem reaction was extended to the asymmetric reaction using bis(8-phenylmenthyl) 2-formylbenzylidenemalonate as a chiral Michael acceptor to provide an enantioenriched indane derivative.     

Asymmetric synthesis of cis-1,2-dialkenyl-substituted cyclopentanes via (-)-sparteine-mediated lithiation and cycloalkylation of a 9-chloro-2,7-nonadienyl carbamate

Herein we report our comprehensive results in enantioselective cyclopentane synthesis via stereogenic allyllithium compounds. The described cycloalkylation reaction starts with a (-)-sparteine-mediated asymmetric deprotonation of the 2,7-alkadienyl carbamate 7e and leads to the enantioenriched (80% ee) and diastereomerically pure (dr = 99:1) cis-1,2-divinyl-cyclopentane 8, by a subsequent cyclization and elimination of lithium chloride. The reaction mechanism has been investigated by silylation and lithiodestannylation experiments and was found to represent a completely regioselective anti-S(N)'S(E)'-reaction. Trapping of the vinyllithium intermediate 12 with various electrophiles under retention of the configuration at the double bond extends the field of application for this cyclization. We also applied this reaction as the key step in the enantioselective synthesis of (+)-dihydromultifidene (17).     

Absolute asymmetric photocyclization of isopropylbenzophenone derivatives using a cocrystal approach involving single-crystal-to-single-crystal transformation

Absolute asymmetric photocyclization of isopropylbenzophenone derivatives was achieved by means of a cocrystal approach. Three chiral salt crystals formed by carboxylic acid derivatives with achiral amines could be prepared by spontaneous crystallization. In the M-crystal of 4-(2,5-diisopropylbenzoyl)benzoic acid with 2,4-dichlorobenzylamine, a twofold helical arrangement occurs in a counterclockwise direction to generate the crystal chirality. Conversely, the clockwise helix exists alone in the P-crystal. Irradiation of the M-crystal at >290 nm caused highly enantioselective Norrish type II cyclization to give the (R,R)-cyclopentenol, (R)-cyclobutenol, and (R)-hydrol in a 6:3:1 molar ratio, resulting in successful absolute asymmetric synthesis, while irradiation at around 350 nm afforded the (R,R)-cyclopentenol as the sole product. The reaction proceeded via single-crystal-to-single-crystal transformation, and therefore the reaction path producing the (R,R)-cyclopentenol could be traced by X-ray crystallographic analysis before and after irradiation.     

Stereochemistry of the asymmetric carbopalladation of allenes followed by nucleophilic substitution reactions with carbo- and aminonucleophiles

The stereochemistry of the asymmetric palladium-catalyzed reaction of allenes with iodobenzene followed by nucleophilic substitution reaction with sodium malonate and N-methylbenzylamine is described. On the basis of the absolute configuration of the product and the stereochemical result of a similar reaction of a chiral allene, the mechanism of the above asymmetric reactions is discussed.     

Exceptional stereoselectivity in the synthesis of 1,3,4-trisubstituted 4-carboxy beta-lactam derivatives from amino acids

[reaction: see text] The base-promoted cyclization of optically pure N-(p-methoxybenzyl)-N-(2-chloro)propionyl amino acid derivatives resulted in a diastereo- and enantioselective approach to valuable 1,3,4,4-tetrasubstituted beta-lactams. The stereochemical outcome of the reaction is exclusively governed by the configuration of the N-(2-chloro)propionyl moiety.     

Asymmetric synthesis of the carbocyclic nucleoside building block (R)-(+)-4-aminocyclopentenone using delta-amino beta-ketophosphonates and ring-closing metathesis (RCM)

Amino keto-2,7-dienes undergo ring-closing metathesis (RCM) to give 4-aminocyclopentenones, valuable intermediates in the asymmetric construction of carbocyclic nucleosides. The key amino ketodienes were prepared using delta-amino beta-ketophophonates, a new sulfinimine-derived chiral building block, and HWE chemistry. [reaction: see text]