Stereoselective total synthesis of the (Z)-isomer of a novel phytotoxic nonenolide from Phomopsis sp. HCCB03520 and its C-6 epimer

The (Z)-isomer of a phytotoxic nonenolide, (6S,7R,9R)-6,7-dihydroxy-9-propylnon-4-eno-9-lactone isolated from Phomopsis sp. HCCB03520 and its C-6 epimer have been synthesized through a common route starting from butyraldehyde. The synthesis involves enantioselective Maruoka allylation, Sharpless asymmetric epoxidation and intramolecular ring closing metathesis as the important steps.     

Formal enantioselective synthesis of (+)-vincamine. The first enantioselective route to (+)-3,14-epivincamine and its enantiomer

A formal synthesis of (+)-vincamine (1) from (S)-(+)-2-ethyl-2-(2-methoxycarbonylethyl) cyclopentanone (6a) is described. This intermediate had previously been obtained by our research group in 90% ee through d'Angelo's deracemizing alkylation of the chiral imine 7, easily prepared from (R)-(+)-α-methylbenzylamine and 2-ethyl cyclopentanone with methyl acrylate. A potencial advanced intermediate for the synthesis of (+)-4, an epimer of (+)-1 at positions C-3 and C-14, has also been prepared from 6a.     

5′-Noraristeromycin possessing a C-1′ cyclopentyl double bond: a new carbanucleoside structural prototype

Prior to this work only two examples of carbanucleosides possessing a C-1′/C-6′ double bond had been reported and they were minor derivatized side products arising during other targeted syntheses. To develop this structural feature into a new class of potential antiviral agents, the 5′-nor derivative of aristeromycin with such an olefinic structure (6) represents the first example. In this regard, treatment of (1′S,2′S,3′S,4′R,5′S)-6-chloro-9-(2′,3′-isopropylidenedioxy-6′-oxabicyclo[3.1.0]hex-4′-yl)purine (7) with sodium methoxide yielded 6 via an E′₂-like elimination pathway. A convenient way to the C-4′ epimer of 6 (that is, 17) also arose during these studies and is described. Antiviral analysis of 6 and 17 failed to produce any significant activity.     

Synthese et configuration de l'alnincanone

Alnincanone 1, and its three diastereoisomers at C-20 and C-24, have been synthesized from dipterocarpol. The configuration of the four isomers has been defined by several independent methods; the naturally occurring alnincanone is 20S,24R.     

Synthesis and biological evaluation of oxoapratoxin E and its C30 epimer

30R- and 30S-oxazoline analogues of apratoxin E have been prepared with late-stage formation of an oxazoline ring. These two compounds have a potent inhibitory effect on HCT-116 cell proliferation with IC₅₀ values of 345 and 638 nM, respectively. These results suggest that apratoxin E oxazoline bioisosteres are approximately 6-fold less potent than their thiazoline parent compounds. A positive impact of the 30R conformation on antiproliferative activity was also observed, with approximately 2-fold enhancement when compared to the 30S epimer.     

Ring opening of chiral 2-(1-aminoalkyl)epoxides by aliphatic thiols with total selectivity: synthesis of enantiopure 3-amino-1-(alkylthio)alkan-2-ols

We have studied the thiolysis of (2R,1′S)- or (2S,1′S)-2-(1-aminoalkyl)epoxides 1 or 2 in the presence of BF₃·OEt₂. The ring opening took place at C-3 with complete regioselectivity, affording the corresponding enantiopure (2R,3S)- or (2S,3S)-3-amino-1-(alkylthio)alkan-2-ols 3 or 4 in good or high yield. The structures of compounds 3 and 4 have been proposed based on HMBC NMR experiments.     

Enhancement of saccharothriolide production and discovery of a new metabolite,saccharothriolide C2, by combined-culture of Saccharothrix sp. and Tsukamurella pulmonis

A combined-culture method was applied to saccharothriolide-producing strain Saccharothrix sp. A1506 with the mycolic acid-containing bacterium (MACB) Tsukamurella pulmonis TP-B0596. The combined-culture not only enhanced saccharothriolide production, but also produced saccharothriolide C₂, a new C-2 epimer of saccharothriolide C, thereby indicating its potential for increasing the chemical diversity of microbial metabolites.     

A short approach to the synthesis of the ritonavir and lopinavir core and its C-3 epimer via cross metathesis

A short synthesis of hydroxyethylene dipeptide isostere, a core unit of the HIV-protease inhibitors ritonavir and lopinavir, its C-3 epimer and C₂ symmetric diamino diol is described. The crucial aspects of the synthesis are self-cross metathesis and exploitation of C₂-symmetric of the metathesis product 8 to obtain the required skeleton.     

Hydrogen atom transfer methodology for the synthesis of C-22, C-23, and C-25 stereoisomers of cephalostatin north 1 side chain from spirostan sapogenins

A simple synthesis of all eight C-22, C-23, and C-25 diastereoisomers of the cephalostatin north 1 side chain has been accomplished from (25R)-5α-spirostan-3β-ol (tigogenin). The synthesis involves selective hydroxylations at C-23 and C-25 and reductive opening of the 1,6-dioxaspiro[4.5]decane spirostan system to give a conveniently protected 5α-furostan-3β,23,25,26-tetrol. The construction of the required 1,6-dioxaspiro[4.4]nonane system entailed an intramolecular hydrogen abstraction reaction promoted by the C-25 alkoxyl radical as the key step. Acid-catalyzed isomerization of the spiroketal unit suggested that 22R isomers are the thermodynamic products while the 22S isomers are the result of kinetic control. The acid-catalyzed equilibrium between 1,6-dioxaspiro[4.4]nonane and 1,6-dioxaspiro[4.5]decane systems was also studied. In the 1,6-dioxaspiro[4.4]nonane units, the observed ³J_23,24 coupling constants suggest that the five-membered puckered ring-F undergoes substantial conformational changes on going from 22S to 22R isomers.     

Total Synthesis of 6-Deoxydihydrokalafungin,a Key Biosynthetic Precursor of Actinorhodin,and Its Epimer

In this article, we report the total synthesis of 6-deoxydihydrokalafungin (DDHK), a key biosynthetic intermediate of a dimeric benzoisochromanequinone antibiotic, actinorhodin (ACT), and its epimer, epi-DDHK. Tricyclic hemiacetal with 3-siloxyethyl group was subjected to Et₃SiH reduction to establish the 1,3-cis stereochemistry in the benzoisochromane, and a subsequent oxidation/deprotection sequence then afforded epi-DDHK. A bicyclic acetal was subjected to AlH₃ reduction to deliver the desired 1,3-trans isomer in an approximately 3:1 ratio, which was subjected to a similar sequence to that used for the 1,3-cis isomer that successfully afforded DDHK. A semisynthetic approach from (S)-DNPA, an isolable biosynthetic precursor of ACT, was also examined to afford DDHK and its epimer, which are identical to the synthetic products.     

Synthesis of 4-(thien-2-yl)-substituted coumarins through Lewis acid catalyzed Michael addition of thiophenes to 3-benzoylcoumarins followed by oxidation

3-Benzoyl-4-(thien-2-yl)coumarins have been obtained in good yields according to the S_N^H addition–oxidation protocol, involving the diastereoselective addition of thiophenes at C-4 of 3-benzoylcoumarins under BBr₃ catalysis, followed by oxidation of the intermediate 3,4-trans-3-benzoyl-4-(thien-2-yl)-3,4-dihydrocoumarins with DDQ. This two-step procedure can be regarded as nucleophilic substitution of hydrogen (S_N^H) on the heterocyclic ring of coumarins.     

Samarium diiodide-mediated reductive couplings of chiral nitrones with aldehydes/ketones and acyl chlorides

The SmI₂-mediated and H₂O-promoted reductive cross-coupling reactions of the l-tartaric acid derived nitrone (3S,4S)-8 with aldehydes/ketones, and the l-malic acid derived nitrone (S)-6 with aliphatic acyl chlorides have been investigated, respectively. (2R,3S,4S)-1,3,4-Trihydroxyprolinol derivatives 9a-f were obtained with high C-2/C-3 trans-selectivities, and 72:28-85:15 diastereoselectivities at the carbinol center from aromatic ketones/aldehydes, while low diastereoselectivities for aliphatic aldehydes. Conditions have been established for the syntheses of (2R,3S,4S)-3,4-dihydroxyprolinol derivatives such as 18, by N-O bond cleavage of the corresponding N-hydroxyprolinol derivatives 9b-f, or more conveniently by a one-pot reductive coupling of nitrone 8 and in situ N-O bond cleavage of the resultant coupling product. The 2-acyl-3-benzyloxy-1-hydroxypyrrolidines 10a-f were formed in 48-82% yields, and in 74:26-78:22 diastereoselectivities. It was revealed that the amount of water required for the reaction is substrate-depending.     

Palladium complexes of a chiral P,C-chelating phosphino-(sulfinylmethyl)phosphonium ylide ligand

A new type of phosphino-phosphonium ylide ligand bearing a chiral sulfinyl center affords a P,C-chelated palladium(II) complex with a resolved asymmetric ylidic carbon atom. According to ³¹P NMR analysis of the crude material, the diastereoselectivity of the complexation at room temperature is ca. 7:1. In the crystal state, an X-ray diffraction analysis of one epimer reveals a quasi C₂-symmetric chloro-bridged dinuclear structure, where the (S) configuration of the sulfur atom induces a (S) configuration of the ylidic carbon atom. A in situ Pd(0) catalyst generated from the phosphino-ylide and Pd(PPh₃)₄ promotes allylic substitution of 3-acetoxy-1,3-diphenylpropene by sodium malonate in 70% yield and 5% e.e.     

New phenolic triterpenes from Maytenus blepharodes. Semisynthesis of 6-deoxoblepharodol from pristimerin

Four new phenolic triterpenes with a 24-nor-D:A-friedoleane skeleton, isoblepharodol, 7-oxoblepharodol, blepharotriol and 6-deoxoblepharodol, were isolated from Maytenus blepharodes. Their structures were elucidated on the basis of spectroscopic analysis, including homo and heteronuclear correlation NMR experiments (COSY, ROESY, HSQC, and HMBC). The semisynthesis of 6-deoxoblepharodol and its epimer at C-8 was achieved by catalytic reduction of pristimerin, a quinone-methide triterpene present in the plant. The biosynthetic formation of the phenolic triterpenes isolated from this species is also discussed. The compounds were assayed for antimicrobial and cytotoxic activities.     

5-epi-Deoxyrhamnojirimycin is a potent inhibitor of an α-l-rhamnosidase: 5-epi-deoxymannojirimycin is not a potent inhibitor of an α-d-mannosidase

Whereas deoxyrhamnojirimycin (LRJ) 1 shows no significant inhibition of naringinase (an α-l-rhamnosidase), its C-5 epimer 2 is a potent and specific inhibitor of the enzyme and demonstrates the value of unambiguous chemical synthesis of such materials in the evaluation of their biological properties. In contrast, moderately weak inhibition towards an α-d-mannosidase is shown by both deoxymannojirimycin (DMJ) 5 and its C-5 epimer 6. Mimics of l-rhamnose which are recognised by enzymes that synthesise or process l-rhamnose may inhibit either the biosynthesis of the sugar or its incorporation into mycobacterial cell walls, providing new strategies for the treatment of diseases such as tuberculosis and leprosy. Molecular modelling studies provide a rationale for the surprisingly potent activity of the C-5 epimer 2 compared with LRJ 1 and support a general hypothesis that potent piperidine glycosidase inhibitors mimic the ⁴H₃ conformation of the relevant glycopyranosyl cation intermediate.     

Synthetic Studies on the Incorporation of N-Acetylallosamine in Hyaluronic Acid-Inspired Thiodisaccharides

Two approaches for the synthesis of the thiodisaccharide β-S-GlcA(1→3)β-S-AllNAc are described here. The target disaccharide was a C-3 epimer and thio-analogue of the hyaluronic acid repetitive unit, tuned with a thiopropargyl anomeric group for further click conjugation. Thus, we analysed and tested two convenient sequences, combining the two key steps required to introduce the thioglycosidic bonds and consequently reach the target molecule: the S_N2 substitution of a good leaving group (triflate) present at C-3 of a GlcNAc derivative and the introduction of the anomeric thiopropargyl substituent. The use of a 2-azido precursor showed to be a convenient substrate for the S_N2 step. Nevertheless, further protecting group manipulation and the introduction of the thiopropargyl anomeric residue were then required. This approach showed to provide access to a variety of thiodisaccharide derivatives as interesting building blocks for the construction of neoglycoconjugates.     

Isolation and partial synthesis of 3(R)- and 3(S)-deoxypumiloside; structural revision of the key metabolite from the camptothecin producing plant,Ophiorrhiza pumila

Both the C-3 epimeric pair of 3(R)- and 3(S)-deoxypumiloside were found in Ophiorrhiza pumila (Rubiaceae), a source plant of camptothecinoid metabolites. These structures were confirmed by spectroscopic analysis and partial stereoselective syntheses. The configuration at C-3 of the previously reported “deoxypumiloside” is revised to 3(R) from 3(S).     

Synthesis and regioselective substitution of C-6 alkoxy derivatives of (S)-nicotine

Enantiopure (S)-6-alkoxynicotine derivatives have been synthesized in two steps from (S)-nicotine via (S)-6-iodonicotine. Deprotonation and substitution at the C-5 position of the pyridine ring of (S)-6-methoxynicotine were achieved using mesityllithium as the base at 0 °C. Conditions for the C-4 lithiation/substitution of (S)-6-isopropoxynicotine and (S)-5-chloro-6-methoxynicotine were also developed.     

Isolation and structure of koshikalide,a 14-membered macrolide from the marine cyanobacterium Lyngbya sp.

A 14-membered macrolide, koshikalide (1), was isolated from the marine cyanobacterium Lyngbya sp., and its planar structure was elucidated by spectroscopic analysis. The relative stereochemistry of C-11 and C-13 was elucidated by NOESY experiments and by an analysis of ¹H–¹H coupling constants. Koshikalide (1) exhibited weak cytotoxicity against HeLa S₃ cells.     

Asymmetric synthesis of allylic sulfides via palladium-mediated allylation of thiols

Cyclic and acyclic allylic S-p-chlorophenyl, S-2-pyridyl and S-2-pyrimidyl sulfides of 50–96% ee have been obtained in 24–87% yield through reaction of the corresponding racemic carbonates with p-chlorothiophenol, 2-mercaptopyridine and 2-mercaptopyrimidine, respectively, mediated by a complex generated in situ from Pd₂(dba)₃·CHCl₃ and the Trost ligand.