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).     

Absolute stereochemistry of TT-1 (rasfonin), an α-pyrone-containing natural product from a fungus, Trichurus terrophilus

The absolute stereochemistry of TT-1 (1=rasfonin), an α-pyrone-containing natural product from a Fungi Imperfecti, Trichurus terrophilus, was determined as 5R,6R,7S,9R, and 6′S on the basis of synthesis of diastereomers of two fragments of 1 in optically active forms, and comparison of their spectral and optical data with those of natural specimens.     

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.     

First synthesis and absolute configuration of (−)-pyriculariol, a phytotoxin isolated from rice blast fungus, Magnaporthe grisea. Use of microwave irradiation to control Stille coupling reaction products

First total synthesis of (−)-pyriculariol, a phytotoxin isolated from rice blast fungus, Magnaporthe grisea, was achieved to determine the absolute configuration of the natural product to be 5′R,6′S. The key step was Stille coupling reaction using microwave irradiation from −78 °C to control the reaction.     

Cyclization versus oligomerization of SP- and RP-5′-OH-N-benzoyl-2′-deoxycytidine-3′-O-(2-thio-4,4-pentamethylene-1,3,2-oxathiaphospholane)s

The S_P-isomer of 5′-OH-N⁴-benzoyl-2′-deoxycytidine-3′-O-(2-thio-4,4-pentamethylene-1,3,2-oxathiaphospholane) undergoes DBU-promoted intramolecular cyclization providing as a sole product S_P-deoxycytidine cyclic 3′,5′-O,O-phosphorothioate. Unexpectedly, the R_P-counterpart yields a mixture of products consisting of R_P-deoxycytidine cyclic 3′,5′-O,O-phosphorothioate and macrocyclic oligo(deoxycytidine phosphorothioate)s. The results of molecular modeling indicate that the dychotomy observed for the R_P substrate may result from remarkably higher energy of the corresponding transition states, caused by the presence of bulky ‘spiro’ pentamethylene substituent at the position C4 in the oxathiaphospholane ring.     

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.     

Enantioselective total synthesis of (2R,3R,6R)-N-methyl-6-(deca-1′,3′,5′-trienyl)-3-methoxy-2-methylpiperidine, an insecticidal alkaloid

An insecticidal piperidine alkaloid, (2R,3R,6R)-N-methyl-6-(deca-1′,3′,5′-trienyl)-3-methoxy-2-methylpiperidine, was efficiently synthesized in a stereoselective manner starting from d-alanine. Chiral center at C-6 was controlled by hydrogenation of imine and side chain was introduced by Julia olefination. The absolute configuration of natural product was determined to be 2R, 3R, 6R.     

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.     

Isolation and total synthesis of gymnastatin N, a POLO-like kinase 1 active constituent from the fungus Arachniotus punctatus

A high throughput screen against POLO-like kinase 1 (Plk1), an anti-cancer target, identified an active extract from the fungus Arachniotus punctatus. Bioassay guided fractionation led to the isolation of the new natural product, gymnastatin N (1) and the known compound aranorosinol A (2) with IC₅₀ values of 13 and 118 μM, respectively. A 12′-hydroxy analog of gymnastatin N, 3, was also isolated as a minor component. Gymnastatin N (1) was found to be a 52:48 mixture of (1S,6′R) and (1R,6′R) diastereomers, by synthesis of the four possible diastereomers and comparison of the optical rotation and chiral HPLC profile of each diastereoisomer with the natural product. Analogues of 1 were synthesized and evaluated against the Plk1 assay and these SAR studies suggested that the diene and free carboxylic acid moieties might be responsible for its bioactivity.     

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.     

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.     

Model dipeptides incorporating the trans cyclohexane analogues of phenylalanine: further evidence of the relationship between side-chain orientation and β-turn type

In order to study the influence of the side-chain orientation on the peptide backbone conformation we have synthesised the model dipeptides t-BuCO-l-Pro-(1S,2R)-c₆Phe-NHMe and t-BuCO-l-Pro-(1R,2S)-c₆Phe-NHMe, incorporating each enantiomer of the trans cyclohexane analogue of phenylalanine (trans-1-amino-2-phenylcyclohexanecarboxylic acid). The orientation of the aromatic side-chain determines the β-turn type accommodated by these peptides to the point that the (1S,2R)-c₆Phe derivative retains the type I β-turn in the crystalline state, in contrast to the behaviour exhibited by the natural counterpart t-BuCO-l-Pro-l-Phe-NHMe.     

4-Ketoantheraxanthin, a novel carotenoid produced by the combination of the bacterial enzyme β-carotene ketolase CrtW and endogenous carotenoid biosynthetic enzymes in higher plants

Higher plants do not ordinarily possess ketocarotenoids due to the absence of a carotenoid ketolase enzyme. We expressed genes coding for marine-bacterial enzymes β-carotene ketolase (CrtW) and β-carotene hydroxylase (CrtZ) in tobacco plants (Nicotiana tabacum) by transplastomic engineering. A novel carotenoid, 4-ketoantheraxanthin, was isolated from the leaves of the tobacco transformants. The structure of 4-ketoantheraxanthin was determined to be (3S,3′S,5′R,6′S)-5′,6′-epoxy-3,3′-dihydroxy-β,β-caroten-4-one by analysis of the MS, NMR, and CD data. This carotenoid was considered to be synthesized by a 4-ketolation reaction by CrtW of antheraxanthin that had been synthesized by the endogenous carotenoid biosynthetic enzymes present in higher plants and CrtZ. 4-Ketoantheraxanthin was also shown to have potent antioxidative activity against a ¹O₂ suppression model.     

Synthesis of enantiopure, axially chiral, C-tetrasubstituted α-amino acids with binaphthyl-based crowned side chains and 3D-structural analysis of their peptides

The syntheses of the terminally protected, crowned, C^α-tetrasubstituted α-amino acids with only axial chirality, the two diastereomers Boc-(S)-Bip[(R)-Binol-22-C-6]-OMe and Boc-(R)-Bip[(R)-Binol-22-C-6]-OMe, and their respective enantiomers Boc-(R)-Bip[(S)-Binol-22-C-6]-OMe and Boc-(S)-Bip[(S)-Binol-22-C-6]-OMe, all derived from 2′,1′:1,2; 1″,2″:3,4-dibenzcyclohepta-1,3-diene-6-amino-6-carboxylic acid (Bip), were performed by bis-alkylation with cyclization of racemic (R+S)-Boc-[HO]₂-Bip-OMe, possessing two phenolic OH groups at the 6,6′-positions of the biphenyl frame of Bip, using (+)-(R)- and (−)-(S)-Binol[(OCH₂CH₂)₂OTs]₂ (2,2′-bis[5-tosyloxy-3-oxa-1-pentyloxy]-1,1′-binaphthyl), respectively, as the alkylating agent followed by chromatographic separation. Two series of terminally protected model peptides to the hexamer level, containing the (R)-Bip[(S)-Binol-22-C-6] residue at i and i+3 positions of the sequence, combined with either l-Ala or l-Ala/Aib, were synthesized by solution methods. Their 3D-structural analyses by FTIR absorption and NMR suggest that these peptides preferentially adopt folded secondary structures.     

δ-Lactone formation from δ-hydroxy-trans-α,β-unsaturated carboxylic acids accompanied by trans-cis isomerization: synthesis of (−)-tetra-O-acetylosmundalin

(±)-(4,5-anti)-4-Benzyloxy-5-hydroxy-(2E)-hexenoic acid 6 was subjected to δ-lactonization in the presence of 2,4,6-trichlorobenzoyl chloride and pyridine to give the α,β-unsaturated-δ-lactone congener (±)-7 (87% yield) accompanied by trans-cis isomerization. This δ-lactonization procedure was applied to the chiral synthesis of (+)-(4S,5R)-7 or (−)-(4R,5S)-7 from the chiral starting material (+)-(4S,5R)-6 or (−)-(4R,5S)-6. Deprotection of the benzyl group in (+)-(4S,5R)-7 or (−)-(4R,5S)-7 by the AlCl₃/m-xylene system gave the natural osmundalactone (+)-(4S,5R)-5 or (−)-(4R,5S)-5 in good yield, respectively. Condensation of (−)-(4R,5S)-5 and tetraacetyl-β-d-glucosyltrichloroimidate 22 in the presence of BF₃·Et₂O afforded the condensation product (−)-8 (97% yield), which was identical to tetra-O-acetylosmundalin (−)-8 derived from natural osmundalin 9.     

Chemo-enzymatic short-step total synthesis of symbioramide

A concise synthesis of symbioramide, a marine-origin ceramide from a common starting material, methyl (±)-trans-2,3-epoxyoctadecanoate, in a convergent manner was achieved. The key step is the direct lipase-catalyzed coupling reaction between methyl (2R,3E)-2-hydroxy-3-octadecenoate and non-protected (±)-erythro-dihydrosphingosine, giving natural (2S,3R,2′R)-symbioramide and its (2R,3S,2′R)-isomer in 38% and 37% yield, respectively. The optically active β,γ-unsaturated α-hydroxyester was prepared by Mg(ClO₄)₂-mediated isomerization of epoxide and the subsequent lipase PS-catalyzed kinetic resolution.     

Synthesis and evaluation of new chiral diols based on the dicyclopentadiene skeleton

The resolution by Lipase PS of rac-5 (from reduction of ketone 6, obtained from dicyclopentadiene with a new environment-friendly synthesis) gives (2S)-5, which was further reduced to the endo(2R)-1a alcohol. The endo(2S)-1b alcohol was obtained from camphor with a multistep synthesis. Pinacol couplings of 3a,b, carried out with Mg/Hg or Corey's general procedure respectively, afforded with high diastereoselectivity the C₂ symmetry diols (2R,2′R)-2a and (2S,2′S)-2b, with endo oriented OH functions. The enantiogenic power of the endo alcohol (2R)-1a and (2S)-1b and of the diols (2R,2′R)-2a and (2S,2′S)-2b was tested towards the LiAlH₄ reduction of acetophenone. The C₂ symmetry appears to play a fundamental role.     

First synthesis of (+)-myxothiazol A

First convergent synthesis of (+)-myxothiazol A (1) was achieved based on modified (one-pot) Julia olefination between (3,5R)-dimethoxy-(4R)-methyl 6-oxo-(2E)-hexenamide (2), corresponding to left-side of the final molecule, and E-4-2′-(1S,6-dimethylheptadiene)-(2,4′-bis-thiazole)-4-methybenzothiazole sulfone (4) corresponding to right-side.