Enzymatic synthesis of (-)- and (+)-acetoxyhexamides and (-)- and (+)-hydroxyhexamides.

The enantioselective hydrolysis of (+/-)-4-(1-acetoxyethyl)-N-(cyclohexylcarbamoyl)-benzenesulfona mides 3 with lipase Amano P from Pseudomonas sp. in a water-saturated solvent gave (R)-4-(1-hydroxyethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide 2 (39%, > 99% ee) and unchanged (S)-3 (50%, 62% ee). On the other hand, enantioselective esterification of (+/-)-2 with lipase Amano P in the presence of vinyl acetate provided (R)-3 (41%, > 99% ee) and unchanged (S)-2 (46%, 78% ee).     

Mononitrosyl tris(thiolate) iron complex [Fe(NO)(SPh)3]- and dinitrosyl iron complex [(EtS)2Fe(NO)2]-: formation pathway of dinitrosyl iron complexes (DNICs) from nitrosylation of biomimetic rubredoxin [Fe(SR)4]2-/1- (R = Ph, Et)

Nitrosylation of the biomimetic reduced- and oxidized-form rubredoxin [Fe(SR)4]2-/1- (R = Ph, Et) in a 1:1 stoichiometry led to the formation of the extremely air- and light-sensitive mononitrosyl tris(thiolate) iron complexes (MNICs) [Fe(NO)(SR)3]- along with byproducts [SR]- or (RS)2. Transformation of [Fe(NO)(SR)3]- into dinitrosyl iron complexes (DNICs) [(RS)2Fe(NO)2]- and Roussin's red ester [Fe2(mu-SR)2(NO)4] occurs rapidly under addition of 1 equiv of NO(g) and [NO]+, respectively. Obviously, the mononitrosyl tris(thiolate) complex [Fe(NO)(SR)3]- acts as an intermediate when the biomimetic oxidized- and reduced-form rubredoxin [Fe(SR)4]2-/1- exposed to NO(g) were modified to form dinitrosyl iron complexes [(RS)2Fe(NO)2]-. Presumably, NO binding to the electron-deficient [Fe(III)(SR)4]- and [Fe(III)(NO)(SR)3]- complexes triggers reductive elimination of dialkyl/diphenyl disulfide, while binding of NO radical to the reduced-form [Fe(II)(SR)4]2- induces the thiolate-ligand elimination. Protonation of [Fe(NO)(SEt)3]- yielding [Fe(NO)(SPh)3]- by adding 3 equiv of thiophenol and transformation of [Fe(NO)(SPh)3]- to [Fe(NO)(SEt)3]- in the presence of 3 equiv of [SEt]-, respectively, demonstrated that complexes [Fe(NO)(SPh)3]- and [Fe(NO)(SEt)3]- are chemically interconvertible. Mononitrosyl tris(thiolate) iron complex [Fe(NO)(SPh)3]- and dinitrosyl iron complex [(EtS)2Fe(NO)2]- were isolated and characterized by X-ray diffraction. The mean NO bond distances of 1.181(7) A (or 1.191(7) A) in complex [(EtS)2Fe(NO)2]- are nearly at the upper end of the 1.178(3)-1.160(6) A for the anionic {Fe(NO)2}9 DNICs, while the mean FeN(O) distances of 1.674(6) A (or 1.679(6) A) exactly fall in the range of 1.695(3)-1.661(4) A for the anionic {Fe(NO)2}9 DNICs.     

Total synthesis of (S)-(+)-curcudiol, and (S)-(+)- and (R)-(-)-curcuphenol.

A highly enantioselective synthesis of the versatile chiral synthons possessing one stereogenic center, (S)- and (R)-4-aryl-5-hydroxy-(2E)-pentenoate (3) was achieved based on the enzymatic reaction of (+/-)-3 with commercially available lipases MY-30 or OF-360 from Candida rugosa. Application of (S)-3 and (R)-3 to the total syntheses of(S)-curcuphenol (1), (S)-curcudiol (2), and (R)-curcuphenol (1), respectively, is described.     

Highly efficient total synthesis of the marine natural products (+)-avarone, (+)-avarol, (-)-neoavarone, (-)-neoavarol and (+)-aureol

Biologically important and structurally unique marine natural products avarone (1), avarol (2), neoavarone (3), neoavarol (4) and aureol (5), were efficiently synthesized in a unified manner starting from (+)-5-methyl-Wieland-Miescher ketone 10. The synthesis involved the following crucial steps: i) Sequential BF(3)Et(2)O-induced rearrangement/cyclization reaction of 2 and 4 to produce 5 with complete stereoselectivity in high yield (2 --> 5 and 4 --> 5); ii) strategic salcomine oxidation of the phenolic compounds 6 and 8 to derive the corresponding quinones 1 and 3 (6 --> 1 and 8 --> 3); and iii) Birch reductive alkylation of 10 with bromide 11 to construct the requisite carbon framework 12 (10 + 11 --> 12). An in vitro cytotoxicity assay of compounds 1-5 against human histiocytic lymphoma cells U937 determined the order of cytotoxic potency (3 > 1 > 5 > 2 > 4) and some novel aspects of structure-activity relationships.     

Short asymmetric synthesis of (-)- and (+)-cis-lauthisan

The asymmetric synthesis of both enantiomers of cis-lauthisan (3) is achieved in only six steps from diethyl pimelate (4), the key steps being the diastereodivergent reduction of beta-ketosulfoxide 7 and the highly cis-stereoselective Et(3)SiH/TMSOTf-promoted reductive cyclization of enantiopure hydroxy sulfinyl ketones (S)-14 and (R)-14.     

Enantioselective Syntheses of (-)- and (+)-Homocitric Acid Lactones

Highly enantioselective syntheses of enantiomers of homocitric acid lactones (R)-5a and (S)-5b are described. Thermal Diels-Alder cycloadditions of 2a and 2b to 1,3-butadiene produced adducts 3a and 3b, respectively. Oxidative ozonolysis of latter adducts gave products 4a and 4b which after acid treatment afforded a mixture with 5a and 5b as major component. Acid lactones 5a and 5b were converted into their dimethyl esters 6a and 6b which were purified by chromatography. After saponification, the products obtained were crystallized to yield (-)- and (+)-homocitric acid lactones ((R)-5a and (S)-5b). Diastereomeric excess (de) of Diels-Alder adducts 3a and 3b was determined by means of Mosher esters of glycols 8a, 8b, and racemic 8. Diels-Alder cycloaddition products of lactones 2a and 2b to 1,3-butadiene showed a diastereoselectivity of 96%.     

Enantioselective total synthesis of (-)-triptolide, (-)-triptonide, (+)-triptophenolide, and (+)-triptoquinonide

The first enantioselective total synthesis of (-)-triptolide (1), (-)-triptonide (2), (+)-triptophenolide (3), and (+)-triptoquinonide (4) was completed. The key step involves lanthanide triflate-catalyzed oxidative radical cyclization of (+)-8-phenylmenthyl ester 30 mediated by Mn(OAc)3, providing intermediate 31 with good chemical yield (77%) and excellent diastereoselectivity (dr 38:1). (+)-Triptophenolide methyl ether (5) was then prepared in > 99% enantiomeric excess (> 99% ee), and readily converted to natural products 1-4. In addition, transition state models were proposed to explain the opposite chiral induction observed in the oxidative radical cyclization reactions of chiral beta-keto esters 17 (without an alpha-substituent) and 17a (with an alpha-chloro substituent).     

Synthesis of (−)- and (+)-8-fluoro-galanthamine

The synthesis of racemic 8-fluorogalanthamine and its separation into (−)- and (+)-8-fluorogalanthamine (= (4aS,6R,8aS)- and (4aR,6S,8aR)-1-fluoro-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol) is described.     

Syntheses of (+)- and (–)-Methyl 8-Epinonactate and (+)- and (–)-Methyl Nonactate

In four synthetic steps, (+)- and (–)-methyl 8-epinonactate ((+)- and (–)− 4 ) have been derived from (+)- and (–)-7-oxabicyclo[2.2.1]heptan-2-one ((+)- and (–)− 9 ), respectively. The (+)- and (–)-methyl nonactate ((+)- and (–)− 3 ) were obtained from (+)- and (–)− 4 , respectively, by Mitsunobu displacement reactions. Optical resolution of (±)− 9 via chromatographic separation of the corresponding N-methyl-S-alkyl-S-phenylsulfoximides 24 and 25 yielded the starting materials (+)- and (–)− 9 , respectively.     

Total synthesis of (-)- and ent-(+)-vindoline and related alkaloids

A concise 11-step total synthesis of (-)- and ent-(+)-vindoline (3) is detailed based on a unique tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole inspired by the natural product structure, in which three rings and four C-C bonds are formed central to the characteristic pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural product in a single step. As key elements of the scope and stereochemical features of the reaction were defined, a series of related natural products of increasing complexity were prepared by total synthesis including both enantiomers of minovine (4), 4-desacetoxy-6,7-dihydrovindorosine (5), 4-desacetoxyvindorosine (6), and vindorosine (7) as well as N-methylaspidospermidine (11). Subsequent extensions of the approach provided both enantiomers of 6,7-dihydrovindoline (8), 4-desacetoxyvindoline (9), and 4-desacetoxy-6,7-dihydrovindoline (10).     

Transformation of (+)-thiomicamine into the p-methylthio analogue of (+)-5-epi-cytoxazone

(2S,3S)-(+)-Thiomicamine 3, a commercially available aminodiol, was transformed into (4R,5S)-5-hydroxymethyl-4-(p-methylthiophenyl)-2-oxazolidinone 10, a compound related to cytoxazone-type biologically active natural products. The synthetic strategy of the highly regio- and stereoselective synthesis was based upon the reversal of the position of the hydroxyl and amine functionalities in 3, accomplished via azidolysis of the key intermediate, epoxide 6.     

Structural, electronic, optical, and chiroptical properties of small thiolated gold clusters: the case of Au6 and Au8 cores protected with dimer [Au2(SR)3] and trimer [Au3(SR)4)] motifs

We report results of a theoretical study, based on density functional theory (DFT), on the structural, electronic, optical, and chiroptical properties of small thiolated gold clusters, [Au(n)(SR)(m) (n = 12-15, 16-20; m = 9-12, 12-16)]. Some of these clusters correspond to those recently synthesized with the surfactant-free method. To study the cluster physical properties, we consider two cluster families with Au(6) and Au(8) cores, respectively, covered with dimer [Au(2)(SR)(3)] and trimer [Au(3)(SR)(4)] (CH(3) being the R group) motifs or their combinations. Our DFT calculations show, by comparing the relaxed structures of the [Au(6)[Au(2)(SR)(3)](3)](+), [Au(6)[Au(2)(SR)(3)](2)[Au(3)(SR)(4)]](+), [Au(6)[Au(2)(SR)(3)][Au(3)(SR)(4)](2)](+), and [Au(6)[Au(3)(SR)(4)](3)](+) cationic clusters, that there is an increasing distortion in the Au(6) core as each dimer is replaced by a longer trimer motif. For the clusters in the second family, Au(8)[Au(3)(SR)(4)](4), Au(8)[Au(2)(SR)(3)][Au(3)(SR)(4)](3), Au(8)[Au(2)(SR)(3)](2)[Au(3)(SR)(4)](2), Au(8)[Au(2)(SR)(3)](3)[Au(3)(SR)(4)], and Au(8)[Au(2)(SR)(3)](4), a smaller distortion of the Au(8) core is observed as dimer motifs are substituted by trimer ones. An interesting trend emerging from the present calculations shows that as the number of trimer motifs increases in the protecting layer of both Au(6) and Au(8) cores, the average of the interatomic Au(core)-S distances reduces. This shrinkage in the Au(core)-S distances is correlated with an increase of the cluster HOMO-LUMO (H-L) gap. From these results, it is predicted that a larger number of trimer motifs in the cluster protecting layer would induce larger H-L gaps. By analyzing the electronic transitions that characterize the optical absorption and circular dichroism spectra of the clusters under study, it is observed that the molecular orbitals involved are composed of comparable proportions of orbitals corresponding to atoms forming the cluster core and the protecting dimer and trimer motifs.     

Chemoenzymatic synthesis of (+)-totarol, (+)-podototarin, (+)-sempervirol, and (+)-jolkinolides E and D

The enzymatic resolution products [(1R,4aR,8aR)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aR)-7 (98% ee) and {acetate of (1S,4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal} (8aS)-9 (>99% ee)] obtained by the lipase-catalyzed enantioselective acetylation of (±)-7 in the presence of vinyl acetate as an acyl donor were converted to the ,β-unsaturated ketones (8aR)-6 and (8aS)-6, respectively. Concise syntheses of (+)-totarol 1, (+)-podototarin 2 and (+)-sempervirol 3 were achieved based on Michael reactions between (8aS)-6 and the appropriate β-keto ester followed by aldol condensation. The first chiral syntheses of (+)-jolkinolides E 4 and D 5 were achieved from (5R,10R,12R)-12-hydroxypodocarpa-8(14)-en-13-one 15 derived from (8aR)-6.     

Total syntheses of (+)-tedanolide and (+)-13-deoxytedanolide

Convergent total syntheses of the potent cytotoxins (+)-tedanolide (1) and (+)-13-deoxytedanolide (2) are described. The carbon framework of these compounds was assembled via a stereoselective aldol reaction that unifies the C(1)-C(12) ketone fragment 5 with a C(13)-C(23) aldehyde fragment 6 (for 13-deoxytedanolide) or 52 (for tedanolide). Multiple obstacles were encountered en route to (+)-1 and (+)-2 that required very careful selection and orchestration of the stereochemistry and functionality of key intermediates. Chief among these issues was the remarkable stability and lack of reactivity of hemiketals 33b and 34 that prevented the tedanolide synthesis from being completed from aldol 4. Key to the successful completion of the tedanolide synthesis was the observation that the 13-deoxy hemiketal 36 could be oxidized to C(11,15)-diketone 38 en route to 13-deoxytedanolide. This led to the decision to pursue the tedanolide synthesis via C(15)-(S)-epimers, since this stereochemical change would destabilize the hemiketal that plagued the attempted synthesis of tedanolide via C(15)-(R) intermediates. However, use of C(15)-(S)-configured intermediates required that the side-chain epoxide be introduced very late in the synthesis, owing to the ease with which the C(15)-(S)-OH cyclized onto the epoxide of intermediate 50.     

Triimidosulfonic acid and organometallic triimidosulfonates: S(+)-N(-) versus S=N bonding

Sulfonic acids RSO(2)OH and their metal salts MO(3)SR are versatile catalysts in large-scale industrial cyclization and polymerization processes. Isoelectronic replacement of the oxygen atoms by NR imido groups gives triimidosulfonic acid and triimidosulfonates. The salts form nonaggregated soluble molecules rather than infinite solid-state lattices such as their oxo analogues. In this paper, we present the synthesis and structure of the basic starting material MeS(N(t)Bu)(3)H (1), the metal complexes [Me(2)Al(N(t)Bu)(3)SMe] (2) and [Zn[(N(t)Bu)(3)SMe](2)] (3), and the mixed metal adduct [(thf)Li[(N(t)Bu)(3)SMe].ZnMe(2)] (4). The chelating coordination, rather than the tripodal coordination, cannot be attributed to steric effects of the S-bonded methyl group, as the less demanding Ph-C triple bond C-alkynyl substituent at sulfur in [(thf)(2)Li[(N(t)Bu)(3)SCCPh]] (5) causes the same conformation. S-N bond shortening to the pendant imido group has to be attributed to closed-shell electrostatic attraction rather than to S-N double bonding by valence expansion at the central sulfur atom. Coordination to an additional N-->Zn dative bond in 4 widens the bond length to values normally interpreted as S-N single bonds. We take this fact as experimental evidence that S-N bonding is predominantly governed by electrostatic interaction rather than by valence expansion employing d-orbitals. This was predicted by theoreticians more than a decade ago.     

Absolute configuration and conformational stability of (+)-2,5-dimethylthiolane and (-)-2,5-dimethylsulfolane

Enantiopure (+)-2,5-dimethylthiolane and (-)-2,5-dimethylsulfolane were prepared using literature procedures and investigated using vibrational circular dichroism (VCD). Experimental absorption and VCD spectra of (+)-2,5-dimethylthiolane and (-)-2,5-dimethylsulfolane in CCl(4) solution in the 2000-900 cm(-)(1) region were compared with the ab initio predictions of absorption and VCD spectra obtained with density functional theory using the B3LYP/6-311G(2d, 2p) basis set for different conformers of (2R,5R)-2,5-dimethylthiolane and (2R,5R)-2,5-dimethylsulfolane. This comparison indicates that (+)-2,5-dimethylthiolane is of the (2R,5R)-configuration and has two predominant conformations in CCl(4) solution. In addition, (-)-2,5-dimethylsulfolane is of (2R,5R)-configuration and has only one predominant conformation. The stereochemical assignment is in agreement with literature.     

Syntheses of (+)-alismoxide and (+)-4-epi-alismoxide

The first total syntheses of (+)-alismoxide and (+)-4-epi-alismoxide are reported. Formal chemo-, regio-, and stereoselective addition of water to 10alpha-acetoxy-1alphaH,5betaH-guaia-3,6-diene afforded the target compounds after reduction. The absolute stereochemistry of (+)-alismoxide has been established. The low [alpha](D) +8.6 value indicates that significant amounts of alismoxide result from biosynthetic processes. Furthermore, the structure of the natural guaienediol isolated from Silphium perfoliatum has been corrected to (-)-alismoxide.     

Synthetic studies on nogalamycin congeners [3]1,2 total syntheses of (+)-nogarene, (+)-7-deoxynogarol,and (+)-7-con-o-methylnogarol

According to the retrosynthetic perspective, the title total syntheses were accomplished by employing the regioselective Diels-Alder reactions of the (+)-naphthoquinone (5), the CDEF-ring system of nogalamycin congeners, with various structural types of dienes (8, 16, and 26). The highly functionalized dienes (16 and 26) incorporating all the functionalities present in the A-rings of (+)-7-deoxynogarol (3) and (+)-7-con-O-methylnogarol (2), were prepared efficiently by way of the 1 ,4-cyclohexadiene and 2-cyclohexanone derivatives (6 and 21), respectively. Reaction mechanism of the key Diels-Alder reaction was also discussed in terms of its stereoselectivity.     

The absolute configuration of (+)-(E)-4-phenylbut-3-ene-2-ol

A derivative of (+)-(E)-4-phenylbut-3-ene-2-ol is shown by X-ray crystallography to be of (R) configuration, confirming the assumption in the literature that the absolute configuration of (+)-(E)-4-phenylbut-3-ene-2-ol is (R).     

Synthesis and Anticancer Activity Evaluation of 5-[2-Chloro-3-(4-nitrophenyl)-2-propenylidene]-4-thiazolidinones

A series of novel 5-[(Z,2Z)-2-chloro-3-(4-nitrophenyl)-2-propenylidene]-thiazolidinones (Ciminalum–thiazolidinone hybrid molecules) have been synthesized. Anticancer activity screening toward the NCI60 cell lines panel, gastric cancer (AGS), human colon cancer (DLD-1), and breast cancer (MCF-7 and MDA-MB-231) cell lines allowed the identification of 3-{5-[(Z,2Z)-2-chloro-3-(4-nitrophenyl)-2-propenylidene]-4-oxo-2-thioxothiazolidin-3-yl}propanoic acid (2h) with the highest level of antimitotic activity with mean GI₅₀/TGI values of 1.57/13.3 μM and a certain sensitivity profile against leukemia (MOLT-4, SR), colon cancer (SW-620), CNS cancer (SF-539), melanoma (SK-MEL-5), gastric cancer (AGS), human colon cancer (DLD-1), and breast cancers (MCF-7 and MDA-MB-231) cell lines. The hit compounds 2f, 2i, 2j, and 2h have been found to have low toxicity toward normal human blood lymphocytes and a fairly wide therapeutic range. The significant role of the 2-chloro-3-(4-nitrophenyl)prop-2-enylidene (Ciminalum) substituent in the 5 position and the substituent’s nature in the position 3 of core heterocycle in the anticancer cytotoxicity levels of 4-thiazolidinone derivatives have been established