Total synthesis of (+)-galanthamine starting from d-glucose

The stereoselective total synthesis of (+)-galanthamine (+)-1 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 based on the Claisen rearrangement of a cyclohexenol. The dibenzofuran skeleton was effectively constructed by the bromonium ion-mediated intramolecular cyclization of a cyclohexene possessing a phenolic ether function. After the introduction of a carbon-carbon double bond, the Pictet-Spengler type cyclization, followed by the reduction of the amide function completed the chiral synthesis of (+)-1.     

New synthesis of (−)- and (+)-actinobolin from d-glucose

The total synthesis of (−)-actinobolin 2, an antipode of the natural product starting from d-glucose is described. A three-component coupling reaction of a functionalized cyclohexenone (+)-6, derived from d-glucose by way of Ferrier's carbocyclization, with vinyl cuprate and an aldehyde (R)-5 effectively constructed the carbon framework of 2 in a highly stereoselective manner. The formal synthesis of the natural enantiomer 1 from d-glucose was also achieved.     

Total synthesis of (+)-epiepoformin, (+)-epiepoxydon and (+)-bromoxone employing a useful chiral building block, ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclohexanecarboxylate

Enantioselective total synthesis of (+)-epiepoformin 1, (+)-epiepoxydon 2 and (+)-bromoxone 3 using a chiral building block, ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclo- hexanecarboxylate 6, is described. Since the synthesis afforded intermediates 18, 2 and 25, it accomplished a formal synthesis of (−)-theobroxide 19, (−)-phyllostine 22, (+)-herveynone 27 and (−)-asperpentyn 28. The usefulness of 6 for the synthesis of natural epoxycyclohexene derivatives was demonstrated.     

Total synthesis of (+)-Z-deoxypukalide, a furanobutenolide-based cembranoid isolated from the pacific octocoral Leptogorgia spp.

A total synthesis of (+)-Z-deoxypukalide 3 using a combination of Stille and Nozaki-Hiyama-Kishi(NHK) coupling reactions as key steps, is described. During this study a new practical synthesis of the substituted butenolide intermediate 10, based on a combination of RCM and CM reactions from the cyclobutene ester 21 in the presence of 2-methylpropenol was also developed. Attempts to apply the intramolecular NHK reaction to the substrates 8a and 8b containing an ester group adjacent to the reacting aldehyde functionality gave disappointing low yields (<6%) of the corresponding coupled products 9. The synthetic (+)-Z-deoxypukalide 3 was correlated with naturally derived material, and also with pukalide 1, the first member of the furanobutenolide-based cembranoids to be isolated from corals.     

Synthesis of C1- and C8a-epimers of (+)-castanospermine from d-glucose derived γ,δ-epoxyazide: intramolecular 5-endo epoxide opening approach

A concise synthesis of two diastereomers of (+)-castanospermine namely 1- and 8a-epi-castanospermine 1b and 1c, respectively, is reported from d-glucose. The methodology involves stereoselective cross metathesis of d-glucose derived alkene 2 with 4-bromo-1-butene followed by azide displacement and m-CPBA oxidation to afford diastereomeric γ,δ-epoxyazides 5a/5b. The Staudinger reaction of epoxyazide 5a followed by reaction with benzylchloroformate (CbzCl) unexpectedly furnished 1,3-oxazinan-2-one derivative 7 whose stereochemistry was establish by single crystal X-ray. This helps to assign the stereochemistry in the epoxidation reaction. The reduction of 5a/5b was then carried out by transfer hydrogenation to provide γ,δ-epoxyamine that concomitantly undergoes intramolecular 5-endo-tet cyclization to afford hydroxypyrrolidine ring skeleton with sugar framework-a precursor to castanospermine analogues 1b/1c.     

Synthesis and reactions of sulfur-substituted indolizidinones

An aza-Diels-Alder reaction product 2 was readily converted to a tetrahydropyridine derivative 6, but its N-benzyl group was unexpectedly difficult to cleave under various conditions. On the other hand, the N-tosyl α,β-unsaturated ester 14 was transformed in one step by Mg/MeOH/Et₃N to a thio-substituted indolizidinone 3. This method was also extended to a methyl-substituted diene 16, which stereoselectively provided the cis-2,6-disubstitutedproduct 17. Further synthetic transformations yielded indolizidinones 20-24, including a formal synthesis of the natural product monomorine I.     

Total synthesis of actinobolin from d-glucose by way of the stereoselective three-component coupling reaction

The total synthesis of (−)-actinobolin 3, an antipode of the natural product, starting from d-glucose is described. A three-component coupling reaction of functionalized cyclohexenone (+)-6 derived from d-glucose by way of Ferrier's carbocyclization reaction, with vinyl cuprate and 2-alkoxypropanal 7 effectively constructed the carbon framework of 3 in a highly stereoselective manner. In an aldol process of the three-component coupling reaction, stereochemical control (chelation and Felkin-Anh conditions) was achieved by the choice of the protecting groups of a hydroxy function in 2-hydroxypropanal and the reaction solvents. The formal synthesis of the natural enantiomer, (+)-actinobolin 1, starting from d-glucose was also accomplished.     

Total synthesis of the mushroom metabolite (+)-calopin

A synthesis of (+)-calopin (1a) was achieved employing a highly stereoselective ene reaction between 8-phenylmenthyl glyoxylate (3) and the β,β-dimethylstyrene 4c. Transesterification of the resulting homoallylic alcohol 5c, followed by allylic oxidation and hydrogenation yielded the δ-lactone 13 which was deprotected to the natural product 1a.     

Stereoselective synthesis of tetrahydroisoquinoline alkaloids: (−)-trolline, (+)-crispin A, (+)-oleracein E

Tetrahydroisoquinoline alkaloids, (S)-(−)-trolline, (R)-(+)-crispin A, and (R)-(+)-oleracein E, have been synthesized stereoselectively from the both enantiomers of common intermediate (S)-4 and (R)-4. The key step in the synthesis include a stereoselective Bi(OTf)₃-catalyzed intramolecular 1,3-chirality transfer reaction of chiral non-racemic amino allylic alcohols (S)-6 and (R)-6 to construct both enantiomers of (E)-1-propenyl tetrahydroisoquinoline 4.     

Synthesis of (−)-lentiginosine, its 8a-epimer and dihydroxylated pyrrolizidine alkaloid from d-glucose

The d-glucose derived α,β-unsaturated ester 5 on 1,2-acetonide deprotection, oxidative diol cleavage followed by treatment with N-benzylamine in the presence of NaBH₃CN undergoes reductive amination and a concomitant intramolecular conjugate addition reaction leading to the formation of dihydroxypyrrolidine-ester 6a and monohydroxypyrrolidine-γ-lactone 6b. Intermediates 6a and 6b were efficiently converted to (−)-lentiginosine 3a, its 8a-epimer 3b, and pyrrolizidine azasugar 4 in good overall yield.     

Synthesis of five and six membered aminocyclitols: stereoselective Michael and Henry reaction approach with d-glucose derived α,β-unsaturated ester

The stereoselective intermolecular Michael addition of nitromethane to d-glucose derived α,β-unsaturated ester 7 afforded l-ido-configurated nitroester 8 as the only product that on reduction of the ester functionality, cleavage of 1,2-acetonide and the intramolecular Henry reaction afforded exclusively muco-nitroinositol 9. While reduction of the ester functionality in 8, deprotection of 1,2-acetonide, oxidative cleavage with NaIO₄ and the intramolecular Henry reaction afforded nitrocyclopentitol 13. Nitrocyclitols 9 and 13 were converted to the hydroxyethyl substituted aminocyclohexitol 5 and aminocyclopentitol 6, respectively.     

Domino intramolecular enyne metathesis/cross metathesis approach to the xanthanolides. Enantioselective synthesis of (+)-8-epi-xanthatin

The first total synthesis of (+)-8-epi-xanthatin (1) has been achieved in 14 steps starting from the commercially available ester 24, which was converted into aldehyde 23 in six steps. An enantioselective aldol reaction of 23 gave 30, which was transformed into triflate 22 in four steps, setting the stage for a palladium-catalyzed carbonylation reaction to form acrylate 34. Compound 34 was then subjected to a deprotection/lactonization sequence to furnish enyne 21, which underwent a domino enyne ring-closing metathesis/cross metathesis process to form a seven-membered carbocycle and (E)-conjugated dienone, thereby completing the synthesis of 1. This domino ruthenium-catalyzed metathesis reaction thus serves as an efficient method to construct the core of xanthanolide and other sesquiterpene lactones.     

Asymmetric synthesis of (+)-1-deoxynojirimycin and (+)-castanospermine

Asymmetric total syntheses of (+)-1-deoxynojirimycin (1) and (+)-castanospermine (2) are described. Starting from diene 3, the required absolute stereochemistry is introduced by an asymmetric hydroxylation followed by epoxidation. An intramolecular cyclization of amine 17 gives access to the corresponding tetrasubstituted piperidine 18, which is a precursor to compounds 1 and 2. (+)-Deoxynojirimicyn (1) was obtained in 36% yield over 11 steps from diene 3, while (+)-castanospermine (2) was achieved in 13% after 19 steps from the same starting material.     

The second generation synthesis of (+)-pseudodeflectusin

The second generation synthesis of (+)-pseudodeflectusin (1), a potential antitumor agent, has been achieved. The key synthetic step is the cascade reaction involving Diels-Alder reaction, lactonization, and decarboxylation to give cycloadduct 6 with complete regioselectivity in good yield. We found that NaH is the best base to facilitate the Diels-Alder reaction of hydroxypyrone 7 with alkyne 8. The present synthetic route enables the total synthesis of (+)-1 in only five-steps from the known compounds 7 and 8.     

The synthesis of compounds related to the indole-indoline core of the vinca alkaloids (+)-vinblastine and (+)-vincristine

A series of α′-aryl-α′-carbomethoxycycloalk-2-en-1-ones, 16, has been prepared using the Pinhey arylation methodology for introducing the aromatic residue. Subjection of these compounds to Johnson iodination and Pd[0]-catalyzed Ullmann cross-coupling of the resulting α-iodocycloalkenones 11 with 2-iodonitrobenzene (5, X = I) then affords α,α′-diaryl-α′-carbomethoxycycloalk-2-en-1-ones of the general form 10. Reductive cyclization of this last type of compound gives the corresponding indoles 9a-f (n = 1-3), some of which resemble the indole-indoline cores of the clinically important alkaloids (+)-vinblastine (1) and (+)-vincristine (2).     

Stereoselective construction of the pyrrolizidine bridgehead stereochemistry by the adjacent hydroxyl group in the synthesis of (+)-heliotridine and (−)-retronecine

Formal total synthesis of (+)-heliotridine (4) and total synthesis of (−)-retronecine (5) were accomplished by using (S)-3-acetoxysuccinimide (6) as the common starting material. The stereogenic center of 6 ended up as C-1 in both alkaloids. The chiral centers at C-7a of the alkaloids were stereoselectively constructed through the help of the adjacent functionality at C-1. The B-rings of the alkaloids were formed through α-sulfonyl radical cyclizations.     

Temporary thio-derivatization in the synthesis of (+)-4-acetylbromoxone

A stereocontrolled synthesis of the marine natural products (+)-bromoxone (1) and (+)-4-acetylbromoxone (2) is reported. The sequence features the enzymatic kinetic resolution of 4-hydroxycyclohexenone (6) via its S-benzyl adduct. Thereafter, a base-mediated elimination-silylation generated an optically active (−)-4S-4-tert-butyldimethylsilyoxycyclohexenone (5), which then underwent diastereoselective epoxidation. Saegusa-Ito oxidation enabled formation of the corresponding α,β-unsaturated ketone 13. Bromination-elimination and subsequent removal of the silicon protecting group afforded (+)-bromoxone (1) which was converted into (+)-(4S,5R,6R)-4-acetoxy-2-bromo-5,6-epoxycyclohex-2-enone (2) [(+)-4-acetylbromoxone]. Using a luciferase gene reporter assay ED₅₀ for NFκB inhibition of 9 μM was determined.     

Total syntheses of the sesquiterpenoids (+)-trans-dracunculifoliol and (+)-4-hydroxyoppositan-7-one

Sesquiterpenoids (+)-trans-dracuncuflifoliol (1) and (+)-4-hydroxyoppositan-7-one (2) were prepared stereoselectively from enantiomerically pure (7aR)-7a-methyl-1,2,5,6,7,7a-hexahydro-4H-inden-4-one ((−)-6), whose synthesis was described herein. Conjugate addition of the organocopper (I) reagent 10 to (−)-6, followed by epimerization of the ring junction, generated 3 of the 4 contiguous chiral centers of both natural products.     

[3+2] Cycloaddition reactions: a simple entry to the 1-aza-2-oxo-3,4,5,6-tetrahydroxybicyclo[3.3.0]octane ring system

The [3+2] intramolecular nitrone cycloaddition (INC) reaction on appropriately designed olefinic nitrones derived from d-glucose, having the nitrone at C-1 and α,β-unsaturated ester functionalities at C-5 of the sugar backbone, afforded the isoxazolidine fused carbocycles 11-13, which were subsequently transformed into the chiral, tetrahydroxylated cis-azabicyclo[3.3.0]octanones 14-18 in good yields.     

Enantioselective synthesis of (+)-anatoxin-a via enyne metathesis

A concise synthesis of the potent nAChR agonist (+)-anatoxin-a (1) has been completed by a series of nine chemical operations and in 27% overall yield from commercially available d-methyl pyroglutamate (12). The strategy featured the application of a new protocol for the diastereoselective synthesis of cis-2,5-disubstituted pyrrolidines bearing unsaturated side chains and an intramolecular enyne metathesis to provide the bridged bicyclic framework of 1. Thus, d-methyl pyroglutamate (12) was converted in five steps to 32, which underwent facile enyne metathesis to deliver the bicyclic diene 33. Selective oxidative cleavage of the less substituted carbon-carbon double bond in 33 followed by deprotection furnished (+)-anatoxin-a (1).