Total synthesis of (±)-brazilin and formal synthesis of (±)-brazilein, (±)-brazilide A using m-CPBA

Total synthesis of (±)-brazilin has been accomplished. m-CPBA epoxidation of allyl alcohol 10 and epoxy opening reaction mediated by m-chlorobenzoic acid, formed in situ as a byproduct, gave advanced intermediate diol 14. O-alkylation and cyclization gave phenol 6 which enabled the formal synthesis of (±)-brazilein and (±)-brazilide A.     

Stereocontrolled total synthesis of (±)-pisiferol and (±)-pisiferal

The stereoselective total synthesis of (±)-pisiferol (1) and (±)-pisiferal (2) has been successfully accomplished using the trans-octahydrophenanthrene derivative 20 as a key intermediate. Intramolecular cyclisation of the diazoketone 15 followed by catalytic hydrogenation provided, stereoselectively, the keto-ester 17 which was converted into the acetate 20 through the intermediates 18 and 19.     

Total synthesis of (±)-luminacin D

A 15-step synthesis of (±)-luminacin D from ethyl pent-2-ynoate is reported. The pivotal step involves the formation of the central C-2′/C-3′ bond of the natural product by condensation of the titanium enolate derived from aromatic ketone 1 with aldehyde 2a. A remote asymmetric centre in aldehyde 2a exerts control over the stereochemical course of this reaction, with the major adduct (3a, 54% yield) possessing the required (2′S^∗,3′R^∗,5′R^∗)-stereochemistry. This assignment was unambiguously established by X-ray crystallography of late stage synthetic intermediate, 17. Further manipulation of 3a (six steps) yielded synthetic (±)-luminacin D spectroscopically identical to material isolated from Streptomyces sp. Mer-VD1207 by Naruse et al.     

Different recognitions of (E)- and (Z)-1,1′-binaphthyl ketoximes using lipase-catalyzed reactions

Lipase-catalyzed hydrolysis of (E)-2-[α-(acetoxyimino)benzyl]-1,1′-binaphthyl [(±)-1a] and (Z)-2-[α-(acetoxyimino)benzyl]-1,1′-binaphthyl [(±)-1b] yielded optically active (E)-2-[α-(hydroxyimino)benzyl]-1,1′-binaphthyl [(S)-2a] and (Z)-2-[α-(hydroxyimino)benzyl]-1,1′-binaphthyl [(R)-2b], respectively, with high enantiomeric excess. Selectivity for the opposite enantiomer of the axial binaphthyl skeleton was shown by (Z)-isomer 1b against (E)-isomer 1a.     

A stereocontrolled total synthesis of methyl (±)-O-methylpodocarpate

A stereocontrolled total synthesis of methyl (±)-O-methyl podocarpate (4) has been successfully accomplished using the trans-fused diester 21 as a key intermediate. Intramolecular Michael reaction of the enone-diester 18 afforded the cis-fused keto-diester 19 in high yield which was stereoselectively converted into 21 via the enone 20.     

Synthesis of (±)-phthalascidin 650 analogue: new synthetic route to (±)-phthalascidin 622

A synthesis of functionalized phenolic α-amino-alcohol (±)-13 as synthetic precursor of the catechol tetrahydroisoquinoline structure of phthalascidin 650 is disclosed. Starting from 3-methylcatechol 5, eight steps of synthesis give rise to the synthesis of phenolic α-amino-alcohol (±)-13 in 27% overall yield. This synthetic strategy involves the elaboration of fully functionalized aromatic aldehyde 8 and its transformation into a phenolic α-amino-alcohol (±)-13, through a Knoevenagel condensation, simultaneous reduction of nitroketene and ester functions and hydrogenolysis of the benzyl protecting group. The pentacycle (±)-18 was obtained after four additional steps. The Pictet-Spengler cyclisation between the phenolic α-amino-alcohol (±)-13 and N-protected α-amino-aldehyde 4 allowed to obtain (1,3′)-bis-tetrahydroisoquinoline 14 with N-methylated and N-Fmoc removed. The last step was a Swern oxidation for allowing an intramolecular condensation.     

Synthetic study of hetisine-type aconite alkaloids. Part 3: Total synthesis of (±)-nominine

Completion of the total synthesis of (±)-nominine (1) is described in detail. Based on the results of the preceding two papers, total synthesis of (±)-nominine was accomplished diverging from the intermediate 7. Thus, following pyrrolidine ring formation through transformation from 7 to 8, the C-ring was constructed by radical cyclization to form 10 from the enyne precursor 9. Subsequent elaboration of the C-ring, followed by formation of the azabicyclic ring system, completed a total synthesis of (±)-1. Single-crystal X-ray analysis of (±)-1 unambiguously confirmed its molecular structure and racemic crystal structure.     

The first total synthesis of (±)-zenkequinone B

The first total synthesis of tetrahydrobenzo[a]anthraquinone natural product (±)-zenkequinone B (1) is reported. The key step involves the TiCl₄-promoted intramolecular cyclization of 4-aryl-2-hydroxybutanal diethyl acetal 4 to give compound 3. The total synthesis of (±)-zenekequinone B (1) has been accomplished in five steps from readily available 2-(chloromethyl)-9,10-dimethoxyanthracene (5) in 40.3% overall yield.     

First synthesis of (±)-bis-homosarkomycin ethyl ester

A five step synthesis of (±)-bis-homosarkomycin ethyl ester 6 has been achieved starting from commercially available ethyl phosphonoacetate and ethyl 5-bromovalerate. The successful synthetic approach to 6 uses α-methylene pimelate 3 as a key intermediate.     

Stereocontrolled total syntheses of (±)-clovan-3-one and (±)-epi-clovan-3-one and a facile total synthesis of (±)-pseudoclovene-A

Stereocontrolled total syntheses of the bridged tricyclic ketones (±)-clovan-3-one (5) and (±)-epi-clovan-3-one (6) and a facile total synthesis of the tricyclic sesquiterpene (±)-pseudoclovene-A (3) have been successfully accomplished involving participation of an aryl intramolecular cyclisation of the bromophenol 11 as a key step.     

Total synthesis of (±)-debromoflustramine B and E and (±)-debromoflustramide B based on one-pot intramolecular Ullmann coupling and Claisen rearrangement

Total syntheses of (±)-debromoflustramine B and E and (±)-debromoflustramide B were accomplished using a common and versatile intermediate spirocyclic oxindole 14, which was concisely prepared through intramolecular Ullmann coupling and Claisen rearrangement from iodoindole 13 on a multigram scale.     

A new total synthesis of (±)-oestrone

A conceptually new total synthesis of oestrone, based on a novel cascade of radical cyclisations from the iodo aryl vinylcyclopropane 2, via 10, 15, 16 and 17, leading to the intermediate trans,anti,trans-oestradiol derivative 11 in one step, is described. Oxidation of 11, followed by demethylation of the resulting aryl methyl ether 18 then gives (±)-oestrone 1.     

A general approach to crinine-type Amaryllidaceae alkaloids: total syntheses of (±)-haemanthidine, (±)-pretazettine, (±)-tazettine, and (±)-crinamine

A general strategy for synthesizing the crinine-type Amaryllidaceae alkaloids was developed. And total syntheses of four representative crinine-type Amaryllidaceae alkaloids: (±)-haemanthidine, (±)-pretazettine, (±)-tazettine, and (±)-crinamine, were accomplished via a common intermediate 17. This crucial precursor was achieved on the basis of the NBS-promoted semipinacol rearrangement recently developed by our group and an intramolecular Michael addition, which efficiently constructed the sterically congested quaternary carbon center and the hydroindole skeleton of the crinine-type alkaloids, respectively.     

Chemistry of renieramycins. Part 11: Total synthesis of (±)-cribrostatin 4

A 19-step synthesis of (±)-cribrostatin 4 (1) from readily available piperazine-2,5-dione derivative 6 is described. The synthesis features the concise construction of a pentacyclic framework, followed by the base-catalyzed epimerization of the C-1 stereo center of aldehyde (11). The results of cytotoxicity studies are also presented.     

Total syntheses of (±)-lentiginosine and (±)-1-epi-lentiginosine from hexahydro-1H-indol-3-one

Total syntheses of (±)-lentiginosine 1 and (±)-1-epi-lentiginosine 2 were achieved efficiently from hexahydro-1H-indol-3-one 7.     

Total synthesis of (±)-pentenomycin

A concise stereoselective route to (±)-pentenomycin 1 in 33% overall yield starting from the readily accessible Diels-Alder adduct 4 is reported. The key reaction involves decarbonylation of β-methoxy-α,β-unsaturated aldehyde 8 obtained from β-hydroxy-dimethylketal 6.     

First synthesis of naturally occurring (±)-epi-conocarpan

(±)-epi-Conocarpan 1 was synthesized via the key intermediate 5-bromo-cis-2-(4-methoxyphenyl)-3-methyl-2,3-dihydrobenzofuran 6 which was synthesized by a ruthenium(II) porphyrin-catalyzed intramolecular C-H insertion reaction using aryl tosylhydrazone salt 5 as the carbene source, starting from the commercially available 5-bromo-2-hydroxyacetophenone.     

(±)-Diinsininone: made nature's way

We report the synthesis of diinsininone (33), the aglycone of (±)-diinsinin (2). Thereby, we complete the first construction of a proanthocyanidin (PA) type-A compound incorporating a [3.3.1]-bicyclic ketal as its characteristic core. Our strategy utilizes a coupling between a benzopyrilium salt and a flavanone that proves applicable to other PA type-A compounds. During this undertaking, treatment of naringenin (9) with 2-iodoxybenzoic acid (IBX) followed by reductive work-up affords eriodictyol (10). This reactivity mirrors that of catechol hydroxylase (F3H) found in the flavonoid pathway. Other interesting transformations include the formation of flavonoids through an ortho-quinone methide (o-QM) cycloaddition-oxidation sequence and regioselective β-glycosidations of several unprotected flavanones suggesting a likely synthesis of 2 from the aglycone 33.     

Total synthesis of (±)-xanthocidin using FeCl3-mediated Nazarov reaction

The total synthesis of the antibiotic, (±)-xanthocidin (1), is described. The FeCl₃-promoted fast Nazarov reaction of the β-alkoxy divinyl ketone in the presence of t-BuOH provided the α-exo-methylene cyclopentenone, which is the core skeleton of this natural product. After methoxymethyl (MOM) esterification and protection of the reactive exo-methylene unit with a phenylseleno group, dihydroxylation, followed by oxidation, gave xanthocidin MOM ester. Finally, this ester was converted into (±)-xanthocidin (1) under mild conditions.     

Phosphinyl analogues of hydroxybupropion: (±)-2-aryl-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinanes

Analogous structures in phosphinate series of hydroxybupropion 2, that is, (±)-2-aryl-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinanes 8, are prepared according to a two step sequence: addition-cyclization reaction from methyl hypophosphite and oxazolidine 6, followed by a pallado-catalyzed arylation of P-H bond from oxazaphosphinane 7.