A concise synthesis of honokiol

A simple synthesis of the natural product honokiol 1 has been developed which proceeds in four steps and provides a 32% overall yield. Suzuki coupling of 4-allyl-2-bromoanisole 3 with 4-hydroxyphenyl boronic acid, followed by allylation, gave 5-allyl-4′-allyloxy-2-methoxy-biphenyl 5. This compound 5 underwent Lewis acid-catalyzed Claisen rearrangement and demethylation in a one-pot reaction which yielded honokiol.     

A stereoselective total synthesis of (+)-α-herbertenol

A stereoselective total synthesis of (+)-α-herbertenol starting from the allyl alcohol 12, readily available in three steps from the monoterpene (R)-limonene, is described. Claisen rearrangement of the aryl allyl ether 10 and concomitant cyclisation furnished a 5:3 mixture of the tricyclic compounds 13 and 14. Degradation of the isopropenyl group followed by cleavage of the central ring and functional group manipulation transformed 13 into (+)-α-herbertenol (1b).     

Synthesis of vinylcyclopropanes by allylation/ring-closing metathesis/Claisen rearrangement

A facile double allylation/ring-closing metathesis/Claisen rearrangement route for preparing vinylcyclopropanes 6 is developed. The efficient synthesis includes O-allylation of α-allyl-α-sulfonylketones 8 with allylic bromides, ring-closing metathesis of diallyl compounds 9 and sequential Claisen rearrangement of the resulting oxepines.     

Efficient synthesis of neurotrophic honokiol using Suzuki–Miyaura reactions

Efficient synthesis of honokiol (1) was accomplished using two kinds of Suzuki–Miyaura reactions. The first Suzuki–Miyaura reaction was employed to couple 2-bromophenol (6) with 4-hydroxyphenylboronic acid (5), giving rise to biphenol 4, and the second coupling was used to introduce allyl groups at 5- and 3′-positions of honokiol. The total synthesis of 1 was completed in 74% yield over five steps from 6, or in 83% yield over four steps from biphenol 4.     

Total synthesis of (−)-funebrine via Au-catalyzed regio- and stereoselective γ-butyrolactonization of allenylsilane

The stereoselective total synthesis of (−)-funebrine from 2-butyn-1-ol was described. The crucial steps in the synthesis involved the stereoselective enolate Claisen rearrangement of the (S)-α-acyloxy-α-alkynylsilane 8, the Au-catalyzed regio- and stereoselective lactonization of the allenylsilane 7, and the Paal-Knorr pyrrole condensation using an unsymmetrical 1,4-diketone 4b.     

Total synthesis of (−)-amathaspiramide F

The stereoselective total synthesis of the marine alkaloid, (−)-amathaspiramide F (1), was achieved from the α-hydroxy-α-ethynylsilane 2. The key steps involved in the synthesis were (1) the enolate Claisen rearrangement of the α-acyloxy-α-alkenylsilane for the stereoselective construction of the consecutive C5 and C9 chiral centers of 1 (erythro configuration), (2) the construction of aza-spirohemiaminal 28, and (3) dibromination during the final stage of the total synthesis. The reaction of the (Z)-α-acyloxy-α-alkenylsilane 22 possessing the Boc-homoallylglycine ester as the acyloxy group underwent stereoselective enolate Claisen rearrangement to give the desired erythro product 23. On the other hand, the reaction of the α-acyloxy-α-alkenylsilane (Z)-5 having Boc-proline gave the unexpected threo product 6. Oxidative cleavage of the vinylsilane group of 23 followed by treatment with heptamethyldisilazane as the methylamine equivalent gave aza-spirohemiaminal 28. The problematic regioselective dibromination to 28 was achieved using n-Bu₄NBrCl₂.     

Synthesis of γ-fluoro-α-amino acids by Claisen rearrangement

A series of N-protected glycine and alanine esters 4-7 of different fluorinated allylic alcohols 1 was prepared using the dicyclohexylcarbodiimide/dimethylaminopyridine method. All fluorinated esters of this type failed to react in an esterenolate Claisen rearrangement under the general conditions of the Kazmaier variant of this rearrangement. Change of the solvent from tetrahydrofuran to the less coordinating diethyl ether enabled the rearrangement of N-Boc-protected glycine esters 4a-c of 2-fluoroalken-3-ols 1a-c to form N-Boc-2-amino-4-fluoroalk-4-enecarboxylic acids 8a-c, while the rearrangement failed with N-Boc-alanine esters and all amino acid esters of 2-fluoroallylic alcohol (1e). This might be due to competing deprotonation of the position β to fluorine. Similarly to the esters 4a-c, the TFA-protected glycine esters 5a-c of 2-fluoroalken-3-ols 1a-c were rearranged. Deprotection of the Boc or the TFA group under salt-free conditions yielded the free amino acids 11a-c, which might be seen as mimics for N-alkylasparagines a group of lipoproteins.     

Synthesis of poinsettifolin A

A synthesis of poinsettifolin A (1), a prenylated flavonol isolated from Dorstenia poinsettifolia, is described. Two routes starting from quercetin were explored, and 1 could be prepared if a prenyl group first was incorporated at C-6 of the protected quercetin followed by a condensation with citral at C-8. The key synthetic steps are a Mitsunobu reaction, an europium (III)-catalysed Claisen rearrangement coupled with cross-metathesis, and a benzopyran-forming geranylation. The two geranylated 3,5,3′,4′-tetrahydroxyflavonols prepared, 1 and 3, were assayed for antileishmanial activity against Leishmania amazonensis and Leishmania braziliensis, and found to be active. Compound 3 showed cytotoxic activity against leukaemia and lung cancer cells while 1 lacked cytotoxicity.     

The synthesis of heliannuol C, an allelochemical from Helianthus annuus

The synthesis of the allelochemical heliannuol C 1 is described by employing a Bargellini condensation and a Claisen rearrangement to install the gem-dimethyl and vinyl functionalities, respectively. A Dieckmann cyclisation of diester 11 enabled the generation of the benzoxepane ring system enshrined in 1.     

Total synthesis of atroviridin

A total synthesis of atroviridin (1) based on biosynthetic principles is presented. The tetracyclic xanthone structure of the natural product was constructed by coupling aryl bromide 8 with aldehyde 7 and subsequent intramolecular conjugate addition on a quinone precursor. Bromide 8 was produced from aldehyde 9 via a sequence of steps involving Baeyer-Villiger oxidation and Claisen cyclization.     

Concise total synthesis of honokiol via Kumada cross coupling

A concise four-step efficient synthesis of honokiol 1 in 68% overall yield is described here. The present method involves tetrakis(triphenylphosphine)palladium [Pd(Ph₃)₄] catalyzed Kumada coupling in two key steps. First coupling generates biaryl backbone intermediate 5 and second generates 2,4′-O-dimethylhonokiol 3. Final demethylation under AlCl₃/DMS condition affords honokiol in quantitative yield.     

Total synthesis of Amaryllidaceae alkaloids, (+)-vittatine and (+)-haemanthamine, starting from d-glucose

The stereoselective total synthesis of (+)-vittatine 1 and (+)-haemanthamine 2 starting from d-glucose is described. The cyclohexene ring in 1 was prepared in an optically active form from d-glucose using Ferrier's carbocyclization reaction, and the critical quaternary carbon was stereoselectively generated via chirality transfer by the Claisen rearrangement of cyclohexenol 6. The hexahydroindole skeleton was effectively constructed by the intramolecular aminomercuration-demercuration of 14, followed by Chugaev reaction to provide 16. Finally, Pictet-Spengler reaction completed the first chiral synthesis of (+)-vittatine 1. On the other hand, the α-hydroxylation of the ester 5 stereoselectively proceeded to give α-hydroxy ester 19, to which was introduced an amino function to provide 4. A similar transformation of 4, as employed in the synthesis of vittatine, furnished (+)-haemanthamine 2.     

Ester-enolate Claisen rearrangement of proline-containing α-acyloxy-α-vinylsilane. Synthesis of pyrrolidine-fused glutamate analogs

The stereoselective syntheses of pyrrolidine-fused aspartate and glutamate analogs, (S)-α-carboxymethyl-proline 3 and (S)-α-2-carboxyethyl-proline 4, using a chirality-transferring ester-enolate Claisen rearrangement of α-vinyl-α-acyloxysilane having a Boc-Pro as an acyloxy group, are described. The stereochemical outcome of the proline ester-derived ester-enolate Claisen rearrangement is also disclosed.     

A convenient and efficient route for the synthesis of amidecrownophanes via 1:1 macrocyclization of di(acid chloride) with diamine derivatives

Four amidecrownophanes 3a-d, including three new compounds 3a, 3c and 3d, were readily prepared through amidation of dicarbonyl dichloride with diamine derivatives without using high-dilution or template conditions and then the tandem Claisen rearrangement. At the macrocyclization step the intramolecular hydrogen bonding of the intermediate might play an important role to give high yields of 1:1 macrocycles.     

A rapid access to chiral alkylidene cyclopentenone prostaglandins involving ring-closing metathesis reaction

A synthesis of the alkylidene cyclopentenone prostaglandin TEI 9826 has been realized. The synthesis involved the preparation of the chiral 1,5-diene 8 using a stereoselective Claisen rearrangement from the allylic alcohol 6 giving the ester 7 after vinylation. Then a key RCM reaction allowed the preparation of the cyclopentenol 9 which, after oxidation, gave the cyclopentenone 10, precursor of the prostaglandin.     

Annulated butanolides by ring closing metathesis of diallyltetronic acid derivatives

3,3-Diallyldihydrofuran-2,4-diones 5 with two identical allyl residues were obtained by Tsuji-Trost-type Pd-catalysed allylation of either 4-O-allyltetronates or 3-allyltetronic acids. Allylation of sodium 3-allyltetronate with a second allyl acetate gave mixed derivatives 5 as did the Claisen rearrangement of 4-O-allyl 3-allyltetronates 6 under microwave conditions. Compounds 5 and 6 were converted to butanolides with 3,3-spirocyclopentenyl or 3,4-cycloalkanyl annulation by ring closing metathesis with Grubbs catalysts.     

Concise synthesis of prenylated and geranylated chalcone natural products by regiospecific iodination and Suzuki coupling reactions

Four natural chalcones bearing prenyl or geranyl groups, i.e., isobavachalcone (1), bavachalcone (2), xanthoangelol (3), and 2′,4′,4-trihydroxy-5′-geranylchalcone (isoxanthoangelol, 4) were synthesized by using a regio-selective iodination and the Suzuki coupling reaction as key steps. Among them, the first total synthesis of 2′,4′,4-trihydroxy-5′-geranylchalcone was achieved in 36% overall yield. Comparing with the reported methods based on C-alkylation or O-alkylation followed by Claisen rearrangement to introduce the side chain, this new strategy capitalizes on a precious regiochemical control during iodination. The overall yields for the synthesis of the first three chalcones were improved from 17% to 53%, 12% to 35%, and 28% to 50%, respectively.     

Enantioselective total synthesis of (−)-pseudophrynaminol through tandem olefination, isomerization and asymmetric Claisen rearrangement

A new and efficient total synthesis of (−)-pseudophrynaminol, the pyrrolo[2,3-b]indole alkaloid bearing the allylic moiety at the 3a-position, has been achieved by a sequence involving 3-allylindol-2-one 8 as a key intermediate. The enantioselective construction of the quaternary carbon in 8 was performed through a tandem cascade reaction of 2-allyloxyindolin-3-one 4, olefination, isomerization, and asymmetric Claisen rearrangement.     

Synthesis of the alkaloid tyroscherin by an aldol/Curtius strategy

The alkaloid tyroscherin (2), which contains a vicinal anti-amino alcohol subunit was prepared from 4-hydroxyphenylpropionic acid (5) and meso-diol 9. After desymmetrization of diol 9 and suitable protecting group manipulations, one terminus was extended via a Claisen rearrangement giving rise to enoate ent-15. The missing carbon on the other end could be incorporated using MeMgCl/CuBr·SMe₂ leading eventually to aldehyde ent-22. The acylated oxazolidinone 32 derived from acid 5 and aldehyde ent-22 were combined in an aldol reaction. A subsequent Curtius rearrangement on the carboxylic group furnished the amino function of tyroscherin (2). In a proof of concept study the same strategy was used to prepare tyroscherin analog 28.     

Stereoselective synthesis of morphine fragments trans- and cis-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinolines

A stereoselective synthesis of the ACNO partial structures of morphine has been developed. Palladium-catalyzed cyclization of carbamate 2 provided the tetracyclic (ACNO) 3-ethoxycarbonyl-9-methoxy-2,3,5,6,7,7a-hexahydro-1H-benzofuro[3,2-e]isoquinoline (14); while treatment of 5-(2-bromo-6-methoxyphenoxy)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (8) under the same reaction condition gave 8a-(2-hydroxy-3-methoxyphenyl)-1,2,3,4,6,7,8,8a-octahydroisoquinoline (11) via an unusual Claisen rearrangement. 9-Methoxy-3-methyl-2,3,5,6,7,7a-hexahydro-1H-benzofuro[3,2-e]isoquinoline (7) was successfully transformed to trans-octahydroisoquinoline 3 and cis-octahydroisoquinoline 4 via catalytical hydrogenation over PtO₂ and chemical reduction with acidic NaBH₄, respectively.