Stereoisomeric sugar-derived indolizines as versatile building blocks: synthesis of enantiopure di- and tetrahydroxyindolizidines.

The synthesis of the sugar-derived (1S,2R,8aR)-1,2-di-O-isopropylidene-1,2,3,5,6,8a-hexahydro-5-oxoindolizine (8) and by analogy of the corresponding stereoisomers ent-8 and ent-7, an epimer at C2 of ent-8, has been accomplished in a straightforward manner. The carbon-carbon double bond and the carbonyl functionalities on the six-membered ring make these nitrogen-containing heterocycles useful building blocks for the efficient preparation of a variety of enantiopure polyhydroxylated indolizidines of interest for their glycosidase inhibitory activity. We report here the synthesis of 2,8a-diepilentiginosine 12 from 8 and the preparation of stereoisomeric 1,2,7,8-tetrahydroxyindolizidines 9-11 performed by OsO4-catalyzed double bond syn dihydroxylation of 7 and 8, followed by deoxygenation of the amide group.     

A chiral synthesis of four stereoisomers of 1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline, an inducer of Parkinson-like syndrome

Four stereoisomers of 1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline, an inducer of Parkinson-like syndrome, were synthesized by applying a new method of 1,2,3,4-tetrahydroisoquinoline (TIQ) synthesis utilizing the Pummerer reaction as a key step. The chiral centers at C-1 and C-3 were constructed by two routes starting from alaninol (3) and 1-phenylethylamine (4) as a chiral source. Enantiomerically pure 1,3-dimethyl-TIQs (1R,3S)-(2) [corrected], (1S,3R)-(ent-2) [corrected], (1S,3S)-(1) [corrected], and (1R,3R)-(ent-1) [corrected] were prepared in a stereochemically unambiguous manner from 3 in 11 steps (route I) and from 4 in 6 steps (route II). The conformations of tetrahydroisoquinoline ring in 1-methyl, 3-methyl, and 1,3-dimethyl-TIQs were discussed on the basis of their CD, 1H-NMR spectra, and steric energies.     

Total synthesis of the originally proposed and revised structures of palmerolide A and isomers thereof

Palmerolide A is a recently disclosed marine natural product possessing striking biological properties, including potent and selective activity against the melanoma cancer cell line UACC-62. The total syntheses of five palmerolide A stereoisomers, including the originally proposed (1) and the revised [ent-(19-epi-20-epi-1)] structures, have been accomplished. The highly convergent and flexible strategy developed for these syntheses involved the construction of key building blocks 2, 19-epi-2, 20-epi-2, ent-2, 3, ent-3, 4, and ent-4, and their assembly and elaboration to the target compounds. For the union of the building blocks, the Stille coupling reaction, Yamaguchi esterification, Horner-Wadsworth-Emmons olefination, and ring-closing metathesis reaction were employed, the latter being crucial for the stereoselective formation of the macrocycle of the palmerolide structure. The Horner-Wadsworth-Emmons olefination and the Yamaguchi lactonization were also investigated and found successful as a means to construct the palmerolide macrocycle. The syntheses were completed by attachment of the enamide moiety through a copper-catalyzed coupling process.     

New building block for polyhydroxylated piperidine: total synthesis of 1,6-dideoxynojirimycin

(3R,4S)-3-Hydroxy-4-N-allyl-N-Boc-amino-1-pentene 10, an important precursor for the synthesis of polyhydroxylated piperidines, has been achieved as a single diastereomer without racemization via vinyl Grignard addition to N-Boc-N-allyl aminoaldehyde 9, which was derived from an enantiopure natural amino acid. Having forged a tetrahydropyridine ring scaffold 13 from 10 in 85% yield via RCM using Grubbs II catalyst, we were able to effect its stereodivergent dihydroxylation, via a common epoxide intermediate to yield a range of interesting hydroxylated piperidines, including ent-1,6-dideoxynojirimycin (ent-1,6-dDNJ) 1 (28% overall yield) and 5-amino-1,5,6-trideoxyaltrose 2 (29% over all yield) in excellent dr. To the best of our knowledge, our synthesis of ent-1,6-dDNJ 1 is the most expeditious to date.     

Stereoselective synthesis of 7,11-guaien-8,12-olides from santonin. Synthesis of podoandin and (+)-zedolactone A

Photochemical rearrangement of hydroxy ester 2, easily obtained from santonin (1), afforded butenolide 4, a good starting material for the synthesis of 7,11-guaien-8,12-olides. Compound 4 has been transformed into compound 10, which has been used for the synthesis of podoandin (5) and (+)-zedolactone A (ent-6). Regioselective elimination of the acetyl group on C10 afforded directly podoandin (5). For the synthesis of ent-6, a hydroxyl group has been regio- and stereoselectively introduced at the 4alpha-position through the 3alpha,4alpha-epoxide 15. The basic hydrolysis of the 10-acetyl group in compound 18 took place with concomitant intramolecular conjugated addition of the alkoxide to the butenolide moiety to give ether 19. Cleavage of the 7,10-oxido bridge via the lactone enolate afforded (+)-zedolactone A (ent-6). This synthesis has allowed for the establishment of the absolute stereochemistry of natural zedolactone A as the enantiomer of our synthetic product.     

Photochemical deconjugation of chiral 3-methyl-2-butenoates derived from carbohydrate-based alcohols: the influence of the sugar backbone on the facial diastereoselectivity

The photodeconjugation of the alpha-(4-trimethylsilyl-3-butynyl)-substituted senecio acid esters 7 was studied. Chiral alcohols ROH (9) were employed as auxiliaries to control the facial diastereoselectivity of the protonation step. The conversion of the four sugar alcohols diacetone-D-glucofuranose, diacetone-D-allofuranose, diacetone-D-gulofuranose, and diacetone-D-fructopyranose (9a-d) to the esters 7 was achieved in four steps employing 4-iodo-1-trimethylsilylbut-1-yne (3) as the alkylating agent (27-45% yield overall). Their photodeconjugation gave the corresponding beta,gamma-unsaturated (R)-esters 14a-d with moderate to excellent diastereomeric excess. The best results were achieved with diacetone-D-glucofuranose and diacetone-D-fructopyranose as the auxiliary (>95% de). To achieve the synthesis of the target compound 1 which has the (S)-configuration, the deconjugation was conducted with the diacetone-L-fructopyranose (ent-9d) derived ester ent-7d. L-Fructose (20) was prepared from L-sorbose (15) in a modified procedure that allowed for the isolation of intermediates. The 2-fold inversion of configuration worked nicely, and the fructofuranose 19 was obtained in 19% yield from L-sorbose. The conversion of L-fructose to the ester ent-7d was conducted in full analogy to the synthesis of its enantiomer 7d. Deconjugation of ester ent-7d yielded the product 2d (70% yield), which was reduced to the alcohol 1 (85% yield).     

Catalytic Enantioselective Desymmetrisation as a Tool for the Synthesis of Hodgkinsine and Hodgkinsine B

Two palladium‐catalysed amination protocols are deployed in the desymmetrisation of the complex dimeric alkaloid meso‐chimonanthine. The power of these transformations is showcased in an efficient formal and total synthesis of the natural products hodgkinsine and hodgkinsine B, respectively.     

Super acid-induced Pummerer-type cyclization reaction: improvement in the synthesis of chiral 1,3-dimethyl-1,2,3,4-tetrahydroisoquinolines

Improved synthesis of four stereoisomeric chiral 1,3-dimethyl-1,2,3,4-tetrahydroisoquinolines (1a, b, ent-1a, b) was achieved via the super acid-induced cyclization of chiral N-[1-methyl-2-(phenylsulfinyl)ethyl]-N-(1-phenylethyl)formamides (4a, b, ent-4a, b) using the Pummerer-type cyclization reaction as a key step. The cyclization leading to the isoquinoline ring proceeded in a quantitative manner when trifluoromethane sulfonic acid (TFSA) was used as the super acid, although Friedel-Crafts-type alkylation of 4-phenylsulfanyl TIQ derivatives (5) with benzene used as the solvent accompanied cyclization to yield the 4-phenyl-TIQs (7). The byproduct (7) was exclusively formed when a large excess amount of TFSA was used.     

Variable strategy toward carbasugars and relatives. 5.(1) Focus on preparation of chiral nonracemic medium-sized carbocycles

The feasibility of sequential vinylogous aldol (intermolecular)/silylative aldol (intramolecular) addition reactions involving furan- and pyrrole-based dienoxysilanes, 6 and 12, in the synthesis of carbasugar frameworks is illustrated by the preparation of the scantily investigated carbaseptanose and carbaoctanose representatives of this class of compounds. The target compounds, 1, 2, 3, ent-2, ent-3, and 4, were obtained from readily available carbohydrate precursors (5 and 19) in yields of 21-30% over 8-12 steps. The irreversible silylative ring-closing aldolisation of gamma-substituted dihydro-5H-furan-2-one and pyrrolidin-2-one aldehydes (9, 16, ent-16, and 22) driven by the TBSOTf/Pr(i)(2)EtN Lewis acid-Lewis base couple was shown to be a practical, diastereoselective maneuver to forge the densely functionalized, medium-sized core carbocycles.     

Total synthesis and preliminary biological evaluation of cis-solamin isomers

An efficient total synthesis of cis-solamin (1) has been achieved in 21% overall yield and with a longest linear sequence of just 11 steps from aldehyde 8. A key feature of the approach was the use of asymmetric permanganate-promoted oxidative cyclization to introduce four of the five required stereocenters in a single step. The use of robust and chemoselective methodology meant that the use of protecting groups could be avoided during the assembly of cis-solamin (1) from the three fragments 23, 6, and 4. The methodology was also applied to the synthesis of three further cis-solamin isomers 2, ent-1, and ent-2. Cytotoxicity and hemolytic properties of cis-solamin isomers and synthetic intermediates are reported.     

Enantioselective [6pi]-photocyclization reaction of an acrylanilide mediated by a chiral host. Interplay between enantioselective ring closure and enantioselective protonation

The [6pi]-photocyclization of the anilides 1a and 5 was studied in the absence and in the presence of the enantiomerically pure chiral lactam 4. The relative configuration of the products was unambiguously established by single-crystal X-ray crystallography and by NMR spectroscopy. A significant enantiomeric excess was observed upon reaction of compound 1a to its photocyclization products at -55 degrees C employing lactam 4 as a chiral complexing agent in toluene as the solvent (66% yield). The trans product ent-3a was obtained in 57% ee, and the minor diastereoisomer (trans/cis = 73/27), cis product ent-2a, was obtained in 30% ee. DFT calculations were conducted modeling the complexation of intermediates 8 and ent-8 to host 4. In agreement with steric arguments concerning the conrotatory ring closure of 1a, the formation of ent-8 is favored leading to the more stable complex 4.ent-8 as compared to 4.8. Whereas the enantioselectivity in the photocyclization to trans compound ent-3a increased upon reduction in the reaction temperature, the enantiomeric excess in the formation of cis compound ent-2a went through a maximum at -15 degrees C (45% ee) and decreased at lower temperatures. Deuteration experiments conducted with the pentadeuterated analogue of 1a, d(5)-1a, revealed that the protonation of the intermediates 8 and ent-8 is influenced by chiral amide 4. In the formation of ent-3a/3a, both the enantioselective ring closure and the enantioselective protonation by amide 4 favor the observed (6aS,10aS)-configuration of the major enantiomer ent-3a. In the formation of ent-2a/2a, the enantioselective ring closure (and the subsequent diastereoselective protonation) favors the (6aR,10aS)-configuration that is found in compound 2a. Contrary to that, the enantioselective protonation by amide 4 shows a preference for ent-2a with the (6aS,10aR)-configuration.     

Development of versatile cis- and trans-dicarbon-substituted chiral cyclopropane units: synthesis of (1S,2R)- and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes and their enantiomers as conformationally restricted analogues of histamine

The cyclopropane ring can be used effectively in restricting the conformation of biologically active compounds to improve activity and also to investigate bioactive conformations. We designed (1S,2R)- and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes (1 and 2, respectively) and their enantiomers (ent-1 and ent-2) as conformationally restricted analogues of histamine. The four types of chiral cyclopropanes bearing two differentially functionalized carbon substituents in a cis or trans relationship on a cyclopropane ring, (1S,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (7) and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (8) and their enantiomers (ent-7 and ent-8), were developed as the key intermediates for synthesizing 1, 2, ent-1, and ent-2. The reaction between (R)-epichlorohydrin [(R)-12] and phenylsulfonylacetonitrile (13a) in the presence of NaOEt in EtOH followed by treatment with acid gave the chiral cyclopropane lactone 11a with 98% ee in 82% yield. Compound 11a was converted into both the cis- and trans-chiral cyclopropane units 7 and 8, respectively, via reductive desulfonylation with Mg/MeOH as the key step. The corresponding enantiomers, the cis-substituted ent-7 and the trans-substituted ent-8, were also prepared starting from (S)-epichlorohydrin [(S)-12]. The four conformationally restricted target histamine analogues 1, 2, ent-1, and ent-2 were successfully synthesized from 7, 8, ent-7, and ent-8, respectively. The chiral cyclopropane units 7, 8, ent-7, and ent-8 should be useful as versatile intermediates for synthesizing various compounds having an asymmetric cyclopropane structure.     

A short enantioselective pathway for the synthesis of the anti-influenza neuramidase inhibitor oseltamivir from 1,3-butadiene and acrylic acid

A short synthetic pathway has been developed for the synthesis of oseltamivir (1) or the enantiomer (ent-1). The intermediates and conditions for this process are summarized in Scheme 1. The synthesis provides a number of advantages: (1) use of inexpensive and abundant starting materials; (2) complete enantio-, regio-, and diastereocontrol; (3) avoidance of explosive, azide-type intermediates; (4) good overall yield (ca. 30%, still not completely optimized); and (5) scalability.     

A chemoenzymatic total synthesis of (+)-clividine

The title compound, ent-1, the non-natural enantiomeric form of the lycorenine-type alkaloid (-)-clividine (1), has been prepared using the enantiomerically pure (ee >99.8%) cis-1,2-dihydrocatechol 3 as starting material. A key feature associated with the closing stages of the synthesis involved the diastereoselective addition of a nitrogen-centered radical onto a pendant cyclohexene to establish the cis-fused D-ring and the required stereochemistry at C11b in the final product ent-1.     

Synthesis of the C(29)-C(45) bis-pyran subunit (E-F) of spongistatin 1 (Altohyrtin A)

A synthesis of the C(29)-C(45) bis-pyran subunit 2 of spongistatin 1 (1a) is described. The synthesis proceeds in 19 steps from the chiral aldehyde ent-7, and features highly diastereoselective alpha-alkoxyallylation reactions using the gamma-alkoxy substituted allylstannanes 17 and 19, as well as a thermodynamically controlled intramolecular Michael addition to close the F-ring pyran. The E ring was assembled via the Mukaiyama aldol reaction of F-ring methyl ketone 3 and the 2,3-syn aldehyde 4.     

Cytotoxic diterpenoids from Vietnamese medicinal plant Croton tonkinensis GAGNEP

Six new ent-kaurane-type diterpenoids were isolated from the leaves of the endemic Vietnamese medicinal plant Croton tonkinensis GAGNEP. (Euphorbiaceae) together with three known ent-11alpha-acetoxy-7beta,14alpha-dihydroxykaur-16-en-15-one (1), ent-kaur-16-en-15-one 18-oic acid (5) and ent-18-hydroxykaur-16-ene (7). Their structures were determined by spectroscopic analyses to be ent-7beta-acetoxy-11alpha-hydroxykaur-16-en-15-one (2), ent-18-acetoxy-11alpha-hydroxykaur-16-en-15-one (3), ent-11alpha-acetoxykaur-16-en-18-oic acid (4), ent-15alpha,18-dihydroxykaur-16-ene (6), ent-11alpha,18-diacetoxy-7beta-hydroxykaur-16-en-15-one (8), and ent-(16S)-1alpha,14alpha-diacetoxy-7beta-hydroxy-17-methoxykauran-15-one (14). ent-Kaurane-type diterpenoids from Croton tonkinensis 2-4, 6, and 9-13, were tested for toxicity in the brine shrimp lethality assay. Compounds 9, 10, and 12 demonstrated significant activity, compounds 2, 3, 6, and 11 showed weak activity, and compounds 4 and 13 were inactive.     

Synthesis of the enantiomer of the structure assigned to the natural product nobilisitine A

The synthesis of the enantiomer of the structure, 1, assigned to the natural product nobilisitine A has been accomplished using the enantiomerically pure cis-1,2-dihydrocatechol 4 as starting material. The (1)H and (13)C NMR spectral data derived from compound ent-1 do not match those reported for the natural product, thus suggesting its structure has been incorrectly assigned.     

New diterpenoid glucosides from Siegesbeckia pubescens

Plants of the genus Siegesbeckia are annual herbs widely distributed in tropical and temperate zones and they are used as a traditional medicine to treat rheumatic arthritis, hypertension, malaria, neurasthenia and snake-bite in China. In previous papers, we reported on five new ent-kaurane and ent-pimarane diterpenoids, siegesbeckioside, siegesbeckiol and siegesbeckic acid1, orientalin A and B, and eight know compounds2,3. The present paper describes the isolation and structural elucidation …     

Four ent-kaurane-type diterpenoids from Croton tonkinensis Gagnep

From the leaves of the endemic Vietnamese medicinal plant Croton tonkinensis GAGNEP. (Euphorbiaceae) the four new ent-kaurane-type diterpenoids ent-1alpha,14alpha-diacetoxy-7beta-hydroxykaur-16-en-15-one (1), ent-1alpha,7beta-diacetoxy-14alpha-hydroxykaur-16-en-15-one (2), ent-18-acetoxy-14alpha-hydroxykaur-16-en-15-one (3), and ent-(16S)-18-acetoxy-7beta-hydroxykauran-15-one (4) were isolated. Their structures were elucidated by spectroscopic analyses.     

Cyclic sulfonimidates by dynamic diastereomer-differentiating cyclisation: large-scale synthesis and mechanistic studies

A dynamic diastereomer differentiating cyclisation is the key step in a new large-scale synthesis of both enantiomers of the cyclic sulfonimidates 1 (Aldrich no. 54099-4) and ent-1 (Aldrich no. 54412-4). These are valuable starting materials in the asymmetric synthesis of chiral oxa- and azaheterocyclic compounds. NMR spectroscopic studies on the reacting system reveal N-chloro sulfinamides to be reactive intermediates in the oxidative chlorination of sulfinamides with tert-butyl hypochlorite and allow for the inspection of the configurational behaviour of the involved sulfonimidoyl chlorides and sulfonimidoyl bromides.