Total synthesis of a novel 2-thiabicyclo[3.2.0]heptan-6-one analogue of penicillin N

A route has been developed which allows synthesis of novel cyclobutanone analogues of penicillin. This is illustrated by the synthesis of (1R,4R,5R,5′R,7S)-(1b) and (1S,4S,5S,5′R,7R)-7-[5′-amino-5′-carboxy]pentanamido]-2-thiabicyclo[3.2.0]heptan-6-one-4-carboxylate (1a), an analogue of penicillin N. The key steps in the synthesis were the formation of the bicyclic structure via a [2+2] cycloaddition and the introduction of nitrogen at C7 via an intramolecular nitrene insertion.     

Determination of the absolute configuration of the male aggregation pheromone, 2-methyl-6-(4′-methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol, of the stink bug Erysarcoris lewisi (Distant) as 2Z,6R,1′S,5′S by its synthesis

Lipase-catalyzed asymmetric acetylation of a mixture of (6R,1′S,4′S,5′R)- and (6R,1′R,4′R,5′S)-7′-norsesquisabinen-4′-ol (3) afforded a separable mixture of the recovered former and the acetate of the latter. The recovered alcohol was oxidized to (6R,1′S,5′R)-sesquisabina ketone (2), whose absolute configuration could be assigned by its CD comparison with (1R,5S)-sabina ketone (4). Conversion of (6R,1′S,5′R)-sesquisabina ketone (2) to the bioactive pheromone revealed the stereostructure of the male aggregation pheromone of the stink bug Erysarcoris lewisi (Distant) to be (2Z,6R,1′S,5′S)-2-methyl-6-(4′-methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol (sesquisabinen-1-ol, 1).     

A novel titanium tetrachloride-induced rearrangement of an enantiopure 4-naphthyldioxolane. The possible role of titanium in the umpolung of tosyloxy and chlorine

The rearrangement of (2′S,4′R,5′S)-2-(2′,5′-dimethyl-1′,3′-dioxolan-4′-yl)-4,5,7-trimethoxynaphthalen-1-yl 4″-methylbenzenesulfonate with titanium(IV) chloride affords (1R,3S,4R)-10-chloro-6,7,9-trimethoxy-1,3-dimethyl-3,4-dihydro-4-hydroxynaphtho[1,2-c]pyran in good yield. This transformation is characterized by two unusual aromatic substitution reactions in that, in one, tosyloxy is lost and, in the other, aromatic chlorination occurs with titanium(IV) chloride as the source of chlorine.     

Stereoselective synthesis of fluorine-containing analogues of anti-bacterial sanfetrinem and LK-157

The synthesis of (1′S,3R,4R)-4-acetoxy-3-(1′-trimethylsilyloxy-2′,2′,2′-trifluoroethyl)-2-azetidinone (10) precursor of modified carbapenems is described relying upon [Ru(C₆Me₆)(S,S)-(CH₂)₅NSO₂DPEN]-catalyzed asymmetric transfer hydrogenation under dynamic kinetic resolution using HCO₂H-Et₃N. This fluorine-containing precursor yielded the targeted trinems 1 and 2 via a stereoselective key step condensation with lithium (S)-6-methoxy-cyclohexenolate.     

Synthesis of the constrained glutamate analogues (2S,1′R,2′R)- and (2S,1′S,2′S)-2-(2′-carboxycyclobutyl)glycines L-CBG-II and L-CBG-I by enzymatic transamination

Optically pure trans-cyclobutane analogues of glutamic acid are prepared by highly selective enzymatic transamination of a single racemic trans-cyclobutane α-ketoglutaric acid derivative 5, which is synthesized in five steps from maleic anhydride. (2S,1′R,2′R)- and (2S,1′S,2′S)-2-(2′-carboxycyclobutyl)glycines L-CBG-II and L-CBG-I are obtained using aspartate aminotransferase (AAT) and branched chain aminotransferase (BCAT), respectively.     

Oxidative cleavage of ribofuranose 5-(α-hydroxyphosphonates): a route to erythrofuranose-based nucleoside phosphonic acids

We report here an oxidative cleavage of (5R)- and (5S)-ribofuranosyl-5-C-phosphonate derivatives with periodate anion under both strong acidic and neutral conditions. In both cases, only (5R)-configured compound underwent the expected oxidation reaction and afforded the desired (4R)-erythrofuranosylphosphonate, whereas the second epimer, (5S)-ribofuranosyl-5-C-phosphonate did not provide the corresponding (4S)-erythrofuranosylphosphonate derivative. This different behavior of epimers toward oxidative cleavage is an important phenomenon. The obtained (4R)-erythrofuranosylphosphonate was used for the preparation of phosphonate mimic of adenosine 5′-phosphate via classical nucleosidation reaction. Condensation of the protected shortened AMP analogue with adenosine derivatives, however, provided only the 2′,5′-linked ApA analogue. Study on hybridization of the modified 2′-5′ ApA with polyU revealed its ability to form stable triplex-like complex, similar to natural 2′-5′ r(ApA) and 3′-5′ r(ApA). NMR spectroscopy study showed that the erythrofuranose part of the phosphonate nucleotide unit of modified 2′-5′ ApA was predominantly in the C2′-endo conformation, which is characteristic for B-DNA.     

Synthesis of enantiomeric 9-(2′,3′,4′-trihydroxybutyl)adenine derivatives from l-ascorbic and d-isoascorbic acids

l-Ascorbic and d-isoascorbic acids were employed in syntheses of 9-(2′,3′,4′-trihydroxybutyl)adenines protected at 3′ and 4′ oxygens (all four enantiomers) and at 2′ oxygen (2′S,3′R and 2′S,3′S enantiomers).     

Stereoselective synthesis of (1′S,3R,4R)-4-acetoxy-3-(2′-fluoro-1′-trimethylsilyloxyethyl)-2-azetidinone

A stereoselective synthesis of (1′S,3R,4R)-4-acetoxy-3-(2′-fluoro-1′-trimethylsilyloxyethyl)-2-azetidinone as a new fluorine-containing intermediate towards β-lactams, is described. The synthetic key step relies upon the dynamic kinetic resolution (DKR) of ethyl 2-benzamidomethyl-4-fluoro-3-oxo-butanoate via asymmetric transfer hydrogenation catalyzed by [Ru(η⁶-arene)(S,S)-R₂NSO₂DPEN].     

DNA-, RNA- and self-pairing properties of a pyrrolidinyl peptide nucleic acid with a (2′R,4′S)-prolyl-(1S,2S)-2-aminocyclopentanecarboxylic acid backbone

A new pyrrolidinyl peptide nucleic acid (PNA) comprising of an alternate sequence of 4′-nucleobase-modified proline with (2′R,4′S) configuration and a (1S,2S)-2-aminocyclopentanecarboxylic acid [(2′R,4′S)-acpcPNA] backbone was synthesized and its DNA-, RNA- and self-pairing properties studied. T_m and CD studies suggested that the (2′R,4′S)-acpcPNA forms antiparallel hybrids to DNA and RNA with high sequence and direction specificity. The stability of these hybrids is comparable to those of the (2′R,4′R)-acpcPNA hybrids previously reported by our group. On the other hand, experiments with a self-complementary sequence indicated that the new (2′R,4′S)-acpcPNA forms a more stable antiparallel self-hybrid than (2′R,4′R)-acpcPNA.     

Efficient synthesis of the cyclopentanone fragrances (Z)-3-(2-oxopropyl)-2-(pent-2-en-1-yl)cyclopentanone and Magnolione

This paper describes the selective syntheses of two cis-isomer-enriched cyclopentanone fragrances: (Z)-3-(2-oxopropyl)-2-(pent-2-en-1-yl)cyclopentanone (four steps, 62% overall yield, 67% cis) and Magnolione^® (five steps, 60% overall yield, 55% cis). In addition, the asymmetric synthesis of (3aR,7aS)-5-methyl-2,3,3a,4,7,7a-hexahydro-1H-inden-1-one as well as (3a′R,7a′S)-5′-methyl-2′,3′,3a′,4′,7′,7a′-hexahydrospiro[[1,3]dioxolane-2,1′-indene] has been realized by an efficient kinetic resolution, which enables the selective synthesis of the 2S,3R-isomer-enriched 3 and 4.     

Polyhydroxylated macrolide isolated from the endophytic fungus Pestalotiopsis mangiferae

A new polyhydroxylated macrolide, named mangiferaelactone (1) was isolated from a solid culture of the endophytic fungus Pestalotiopsis manguiferae, together with ten known compounds [(6S,1′S)-LL-P880α; (6S,1′S,2′R)-LL-P880β; (1′S,2′R)-LL-880γ; (1′R)-dehydropestalotin; (−)-5-carboxylmellein; (−)-5-methylmellein; (−)-5-hydroxylmethylmellein; arabenoic acid; 5,6-dihydro-4-methoxy-2H-pyran-2-one; and the (−)-2-hexylidene-3-methylsuccinic acid]. P. manguiferae was isolated from Hyptis dilatata, a small shrub common in the central region of Panama. The structure of compound 1 was elucidated by a combination of spectroscopic methods (IR, MS, optical rotation, 1D and 2D NMR spectroscopy). The absolute configuration of 1 was established as 4R,7R,8R,9S by application of vibrational circular dichroism (VCD). Compound 1 showed a minimum inhibitory concentration (MIC) of 1.6863 mg/mL against Listeria monocytogenes, and 0.5529 mg/mL against Bacillus cereus. No activity was observed for compound 1 against Plasmodium falciparum or Trypanosoma cruzi; likewise, no cytotoxic activity was observed against A2058 and H522-T1 cells.     

Asymmetric syntheses of dihydroxyhomoprolines via doubly diastereoselective lithium amide conjugate addition reactions

The asymmetric syntheses of novel dihydroxyhomoprolines have been achieved using the doubly diastereoselective conjugate additions of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide to a set of four chiral α,β-unsaturated esters (derived from d-pentoses) as one of the key steps. A full account of the diastereoselectivity observed in these conjugate additions is presented and the stereochemical outcomes of these reactions have been established unambiguously via a combination of hydrogenolytic chemical correlation and single crystal X-ray diffraction analyses. A tandem hydrogenolysis/intramolecular reductive amination reaction was then used to create the corresponding enantiopure pyrrolidines, providing access to (2′S,3′S,4′R)-dihydroxyhomoproline and (2′S,3′R,4′S)-dihydroxyhomoproline after deprotection.     

Synthetic routes for naturally-occurring arsenic-containing ribosides

The synthesis of (R)-2′,3′-dihydroxypropyl 5-deoxy-5-dimethylarsinoyl-β-d-riboside, (S)-2′-hydroxy-3′-sulfonylpropyl 5-deoxy-5-dimethylarsinoyl-β-d-riboside and (S)-2′-hydroxy-3′-sulfooxypropyl 5-deoxy-5-dimethylarsinoyl-β-d-riboside, common naturally-occurring arsenicals in algae and molluscs, is reported.     

Acid-catalyzed rearrangement of α-hydroxytrialkylsilanes

Cationic rearrangement of several α-hydroxysilanes is described. Treatment of both (1R,1′R,2′S)-α-hydroxycyclopropylsilane syn-9 and (1S,1′R,2′S)-anti-9 under aqueous H₂SO₄ underwent rearrangement via a common α-silyl cation intermediate A to give a mixture of the ring-opened (R)-vinylsilane 13, the tandem [1,2]-CC bond migration product (1R,2S,1′R)-14, and its 1′S isomer 15. On the other hand, the acidic treatment of (R,E)-α-hydroxyalkenylsilane 8 or (R,Z)-8 was each accompanied with partial racemization to give an enantiomeric isomer of allylic alcohol 23 via a preferential syn-facial S_N2′ reaction, respectively. Both α-hydroxyalkynylsilane 6 and α-hydroxyalkylsilane 12 were inert to the acidic conditions; however, treatment of (R)-α-mesyloxyalkynylsilane 26 under aqueous H₂SO₄ gave a mixture of the optically active rearranged allene 27, α,β-unsaturated ketone 28, and (S)-α-hydroxyalkynylsilane 6 with partial racemization. Comparisons of the reactivities of these α-hydroxysilanes under acidic conditions are also disclosed.     

Latoxanthin, a minor carotenoid isolated from the fruits of yellow paprika (Capsicum annuum var. lycopersiciforme flavum)

Latoxanthin was isolated as a minor carotenoid from the ripe fruits of yellow tomato shaped paprika (Capsicum annuum var. lycopersiciforme flavum) and identified as (all-E,3S,5R,6R,3′S,5′R,6′S)-5′,6′-epoxy-5,6,5′,6′-tetrahydro-β,β-carotene-3,5,6,3′-tetrol based on spectral data.     

Dimerization of a lattice-framework silanone into the corresponding 1,3-dioxa-2,4-disiletanes

A lattice-framework silanone, a racemate of (4R,6R)- and (4S,6S)-2,3,4,6,7,8-hexa-tert-butyl-1,5-disilatricyclo[4.2.0.0^1,4]octa-2,7-dien-5-one (4), was generated by the photoreaction of the corresponding lattice-framework disilene, a racemate of (4R,6R,4′R,6′R)- and (4S,6S,4′S,6′S)-2,3,4,6,7,8,2′,3′,4′,6′,7′,8′-dodeca-tert-butyl-[5,5′]bi{1,5-disilatricyclo[4.2.0.0^1,4]octylidene}-2,7,2′,7′-tetraene (dl-1), with mesitonitrile oxide. The silanone 4 was dimerized to produce a mixture of the corresponding dl- and meso-1,3-dioxa-2,4-disiletane derivatives 2. DFT calculations suggested that the non-selective dimerization of 4 to 2 is attributed to the irreversibility of the reaction.     

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.     

Pheromone synthesis. Part 243: Synthesis and biological evaluation of (3R,13R,1′S)-1′-ethyl-2′-methylpropyl 3,13-dimethylpentadecanoate, the major component of the sex pheromone of Paulownia bagworm, Clania variegata, and its stereoisomers

All of the four stereoisomers of (1′S)-1′-ethyl-2′-methylpropyl 3,13-dimethylpentadecanoate, the major component of the female sex pheromone of Clania variegata, were synthesized by employing olefin cross metathesis as the key reaction and starting from (R)- or (S)-2-methyl-1-butanol, (R)- or (S)-citronellal, and (S)-2-methyl-3-pentanol. Their bioassay revealed the (3R,13R,1′S)-isomer as the bioactive one, whose more efficient synthesis was achieved in two different ways by employing Wittig reaction as the key step.     

Further monoterpene chromane esters from Peperomia obtusifolia: VCD determination of the absolute configuration of a new diastereomeric mixture

A reinvestigation of the monoterpene chromane ester enriched fraction from Peperomia obtusifolia using chiral chromatography led to the identification of a minor peak, which was elucidated by NMR and HRMS as fenchyl-3,4-dihydro-5-hydroxy-2,7-dimethyl-8-(3″-methyl-2″-butenyl)-2-(4′-methyl-1′,3′-pentadienyl)-2H-1-benzopyran-6-carboxylate, the same structure assigned to two other fenchyl esters described previously, pointing out a stereoisomeric relationship among them. Further NMR analysis revealed that it was actually a mixture of two compounds, whose absolute configurations were determined by VCD measurements. Although, almost no vibrational transitions could be assigned to the chiral chromane, the experimental VCD spectrum was largely opposite to that obtained for the average experimental VCD [(2S,1?R,2?R,4?S + 2R,1?R,2?R,4?S)/2] for fenchol derivatives. These results allowed us to assign the putative compounds as a racemic mixture of the chiral chromane esterified with the monoterpene (1S,2S,4R)-fenchol, which had not been identified in our early work.     

Synthesis of ‘thianthrene dimer’ by the coupling reaction of stannylthianthrenes in the presence of copper catalysts

The coupling reaction of 1-tributylstannylthianthrene (5) and 2-tributylstannylthianthrene (7) in the presence of copper catalysts at rt afforded the thianthrene dimer 1,1′-bithianthrene (3), 2,2′-bithianthrene (8), and 1,2′-dithianthrene (9) in high yields. Also we obtained thianthrene oxide dimer (R,R) (S,S)-1-(10-S-monoxythianthrene-1-yl)thianthrene-10-S-monoxide (12) and (R,S) (S,R)-1-(10-S-monoxythianthrene-1-yl)thianthrene-10-S-monoxide (13) from 1-tributylstannyl-10-S-monoxythianthrene (10) under the same reaction condition. The final structural conformation of 3, 8, 9, and 12 was performed by X-ray crystallographic analysis. Further, the solvent effects in the coupling reactions were also examined.