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A cationic palladium-complex-catalyzed addition of arylboronic acids to N-tert-butanesulfinyl iminoacetates to yield the optically active arylglycine derivatives with moderate to good yield and high diastereoselectivity was developed. This reaction provides a convenient and efficient method for the synthesis of arylglycine derivatives.

Lipozyme TL IM immobilized on silica catalyses the deacylation of 4-C-acyloxymethyl-3,5-di-O-acyl-1,2-O-(1-methylethylidene)-beta-L-threo-pentofuranose to form 3,5-di-O-acyl-4-C-hydroxymethyl-1,2-O-(1-methylethylidene)-alpha-d-xylo-pentofuranose in a highly selective and efficient manner.

[reaction: see text] In the presence of ruthenium-based olefin metathesis catalysts and triphenylphosphine, alpha,beta-unsaturated aldehydes can be olefinated with diazoacetates. This ruthenium-catalyzed transformation has been employed in tandem with olefin cross-metathesis to convert terminal olefins into 1,3-dienoic esters in a single operation.

[reaction: see text] The novel three-component reaction of aromatic aldehydes, ethylenediamine, and beta-keto esters is described. In this reaction, beta-keto esters react at the gamma-position which is generally unreactive to produce the seven-membered ring compounds. Products have secondary amines and beta-enamino esters, which can serve in further functionalizations to produce molecular diversity.

[reaction: see text] The 2-O-[3-(2'-benzyloxyphenyl)-3,3-dimethylpropanoate] and 2-O-[3-(2'-benzyloxy-4',6'-dimethylphenyl)-3,3-dimethylpropanoate] esters enable the synthesis of a range of beta-glucosides and alpha-mannosides through neighboring participation in excellent yield, and are removed by hydrogenolysis in concert with the cleavage of benzyl esters in the presence of other esters making them particularly well suited to the stereocontrolled synthesis of glycosyl esters.

A new steroid with an uncommon 21-oic acid methyl ester moiety designated methyl spongoate (1) which exhibited potent cytotoxicity against BEL-7402 tumor cells in vitro has been isolated from the Sanya soft coral Spongodes sp. Its structure was determined by detailed interpretation of spectroscopic data and by comparison with related compounds.

Enantioselective copper-catalyzed allylic alkylations were performed on allylic bromides with a protected hydroxyl or amine functional group using several Grignard reagents and Taniaphos L1 as a ligand. The terminal olefin moiety in the products was transformed into various functional groups without racemization, providing facile access to a variety of versatile bifunctional chiral building blocks.

We report herein an intermolecular ene reaction using oxazolones with enol ethers which results in the formation of novel quaternary amino esters in near quantitative yields. The overall reaction transformation closely resembles an intermolecular version of the Conia-ene reaction. The reactions are uncatalyzed and occur under very mild conditions.

[reaction: see text] Condensation between N-alkyl, N'-aryl carbodiimides and malonic acid monoesters leads to a high-yield formation of N-acyl urea derivatives that could be cyclized to C-monosubstituted barbiturates by addition of a suitable base in a one-pot sequential fashion. In the presence of an electrophile, the last step gives rise to a one-pot, three-component sequential synthesis of fully substituted barbiturates.

A new ursane-type triterpene, named as cheiranthic acid (1), was isolated from the MeOH extract of whole plants of Oenothera cheiranthifolia (Onagraceae) along with an isomeric pair of known oleanane- and ursane-type triterpenes (arjunolic acid and asiatic acid) and three flavonol glucuronide analogues (quercetin 3-O-glucuronide, its n-butyl ester, and myricetin 3-O-glucuronide). Their structures were elucidated based on spectroscopic evidence.

Many challenges of chemoselectivity arise from the requirement to manipulate incompatible functional groups. Synthetic methods that do not rely on protecting groups are of strategic significance to chemical synthesis. Particularly valuable are molecules with reactive functionalities that are kinetically stabilized against inter- or intramolecular reactions with each other. We have developed a simple access to molecules that contain both ketone and N-H aziridine functionalities. These compounds were found to undergo highly selective reduction and carbonyl addition reactions, making them versatile precursors to complex amines.

We report the first hydrogen-mediated C−C bond formations catalyzed by iridium. Hydrogenation of commercially available alkyl-substituted alkynes, 3-hexyne 1a and 1-phenylpropyne 1b, in the presence of α-ketoesters 2a−2g using cationic iridium precatalysts results in reductive C−C coupling to afford β,γ-unsaturated α-hydroxyesters 3a−3f and 4a−4e and 4g, which are formed in excellent yield, with complete control of olefin geometry and, in most cases, with excellent regiocontrol. Similar levels of selectivity are observed across a range of alkynes 1c−1h. Reductive coupling of 3-hexyne 1a and α-ketoester 2a under an atmosphere of elemental deuterium provides the monodeuterated product deuterio-3a, consistent with a catalytic mechanism involving alkyne−carbonyl oxidative coupling followed by hydrogenolysis of the resulting oxametallacycle.

Re(2)O(7), which is known primarily as a strong oxidant, was found to be a highly selective Lewis acid catalyst that affects the heteroacylative dimerization of THF at room temperature. This multicomponent reaction, which involves THF, trifluoroacetic anhydride (TFAA), and a carboxylic acid, produces a nonsymmetrical diester, RCO(2)(CH(2))(4)O(CH(2))(4)OCOCF(3), in high yields. The reaction is quite general with respect to the carboxylic acid but is highly selective for unsubstituted THF in preference to other cyclic ethers. It is also highly selective for TFAA in preference to other anhydrides. Isotope labeling experiments indicate that two of the five oxygen atoms in the product originate from THF; one comes from rhenium oxide, and the two carbonyl oxygens originate from the carboxylic acid and from TFAA. The catalytic cycle, which is proposed on the basis of these experiments, involves a multistep sequence of nucleophilic attacks, starting with an attack of a rhenium oxo ligand on a coordinated THF, then attack of the resultant alkoxide ligand on a second coordinated THF, nucleophilic addition of the resultant alkoxide ligand to the coordinated carboxylic acid (an intramolecular metal-oxygen bond metathesis), and, finally, electrophilic cleavage of the other coordinated alkoxide by TFAA to produce the nonsymmetrical diester. This synthetically useful reaction highlights the unique, frequently avoided Lewis acidity of transition-metal oxides.

The full details of the asymmetric epoxidation of alpha,beta-unsaturated esters catalyzed by yttrium complexes with biaryldiol ligands are described. An yttrium-biphenyldiol catalyst, generated from Y(OiPr)3-biphenyldiol ligand-triphenylarsine oxide (1:1:1), is suitable for the epoxidation of various alpha,beta-unsaturated esters. With this catalyst, beta-aryl alpha,beta-unsaturated esters gave high enantioselectivities and good yields (< or = 99% ee). The reactivity of this catalyst is good, and the catalyst loading could be decreased to as little as 0.5-2 mol % (the turnover number was up to 116), while high enantiomeric excesses were maintained. For beta-alkyl alpha,beta-unsaturated esters, an yttrium-binol catalyst, generated from Y(OiPr)3-binol ligand-triphenylphosphine oxide (1:1:2), gave the best enantioselectivities (< or = 97% ee). The utility of the epoxidation reaction was demonstrated in an efficient synthesis of (-)-ragaglitazar, a potential antidiabetes agent.

The 1,3-dipolar cycloaddition of trimethylsilyldiazomethane with alpha,beta-unsaturated esters was examined. The resulting 1-pyrazolines isomerize to regioisomeric 2-pyrazolines (a or b) or undergo desilylation (c). Acrylates yield only b or c. beta-Substituted dipolarophiles may yield all three types of products. This work demonstrates that the distribution of 2-pyrazoline products is highly dependent on the relative configuration of the substituents on the 1-pyrazoline intermediate.

N-heterocyclic carbenes catalyze the oxidation of allylic, propargylic, and benzylic alcohols to esters with manganese(IV) oxide in excellent yields. A variety of ester derivatives can be synthesized, including protected carboxylates. This one-pot tandem oxidation represents the first organocatalytic oxidation of alcohols to esters. Saturated esters can also be accessed from aldehydes using this method. Through the utilization of a chiral catalyst, the acyl-heteroazolium intermediate becomes a chiral acylating agent, which can desymmetrize meso-1,2-diols. [reaction: see text].

Carnitine-esters (1-8) including, a compound (R)-3-hydroxybutanoyl-(R)-carnitine (5), were isolated from the mushroom Suillus laricinus. Their structures were determined by spectroscopic analyses and by total synthesis. One of these, (R)-3-hydroxy-2-methylpropanoyl-(R)-carnitine (4), promoted hyaluronan-degradation by human skin fibroblasts.

Direct activation of alkylmagnesium halides with a chiral bidentate N-hetrocyclic carbene (NHC), formed in situ from the imidazolinium chloride precursor, is reported. The Cu-free catalytic asymmetric allylic alkylation (AAA) of alpha-alkyl-gamma-chloro-alpha,beta-unsaturated esters with alkyl-based Grignard reagents is promoted in the presence of 5-10 mol % of the chiral imidazolinium salt to afford synthetically versatile beta,gamma-unsaturated esters. Products bear all-carbon quaternary sterogenic centers generated in 3.5-13.3:1 regioselectivity, 63-98% ee, and in up to 80% isolated yield of the SN2' product. The in-situ-generated chiral NHC promotes enantioselectivity while altering the reactivity of the Grignard reagents: there is only approximately 30% conversion and

Iron complexes of porphyrins (and corroles to a lesser extent) are the first catalysts to utilize ammonia for the synthesis of N-free amino acid esters.

A Pd(II)-catalyzed intramolecular cyclization of o-(1-alkynyl)phenylphosphonamide monoethyl esters was examined, and a new class of six-membered phosphorus heterocycles (phosphaisoquinolin-1-ones) were formed with high regioselectivity and good yields. The present reaction is the first example of intramolecular addition of P-NH to substituted alkynes, which provides a valuable way to synthesize novel phosphorus heterocycles with potential bioactivities.

Desymmetrization of a readily derived pseudo-C(2)-symmetric monocyclic phosphate via highly diastereoselective anti-S(N)2' allylic displacement reactions is reported. This method utilizes of a wide variety of zinc-derived organocuprates to afford E-1,2-syn-configured phosphate acid building blocks. Extension of this protocol to unsymmetric monocyclic phosphates exclusively yields 1,2-anti-configured products. Within this study, stereoelectronic factors, coupled with allylic strain, ultimately govern regio- and diastereoselective cuprate reactions, further substantiating the Corey mechanism for organocuprate additions into allylic esters. [reaction: see text]

A gram scale synthesis of the glucuronide metabolite of ABT-724 is reported. Glycosidic coupling between a trichloroacetimidate glucuronyl donor and a Cbz-protected hydroxypyridylpiperazine glycosyl acceptor is the key step in the synthesis, since attempts to directly glucuronidate the aglycon, aglycon derivatives, and other truncated glycosyl acceptors were unsuccessful. The route was used to produce 2.1 g of metabolite in eight steps from 2-chloro-5-hydroxypyridine in 21% overall yield.

As part of our continuing program focused on the de novo asymmetric synthesis of polyketide based natural products,1 we developed a sequential hydration approach (enantioselective hydration 1 to 2 and a diastereoselective hydration 2 to 3) that converts achiral conjugated dienoates into enantiomerically enriched benzylidine protected syn-3,5-dihydroxyesters.2 The transformation relies upon a Sharpless asymmetric dihydroxylation followed by a Pd-π-allyl catalyzed allylic reduction to control both the regio-and enantioselectivity of the first hydration, and an Evans hemiacetal addition to achieve diastereoselectivity in the second hydration.3 With the successful application of this approach to various 1,3-polyol natural products, we targeted the structurally more complex polyene-polyol macrolides (e.g., mycoticin A4, Figure 1). Thus we required a strategy that would address two structural motifs of mycoticin A. That is to say, we required access to both 2-methyl-1,3-diol (C-11 to C-17),3,4 and δ-hydroxy-γ-methyl enoate (C-27 to C-31) subunits. Other approaches to δ-hydroxy-γ-methyl enoate synthons usually involve crotylation/metathesis, aldol/Wittig, or vinylogous aldol sequences; a few other more diverse strategies have been employed in recent years, as well.5 Unfortunately, our initial studies on a new catalytic asymmetric approach using various carbon nucleophiles to install an alkyl group at C-4 was met with little success (i.e., replacing the palladium hydride with a palladium alkyl in the Pd-π-allyl intermediate 5). Scheme 1 Asymmetric iterative hydration of C4-methyl dienoates Alternatively, we envisioned that these two structural features could be prepared from C-4 substituted achiral dienoates by an iterative hydration approach (Scheme 1). This, of course, required that the initial asymmetric hydration reaction be stereospecific, which was demonstrated by substituting DCO2H for HCO2H (Scheme 1, R3 = H; see supporting information). Then, we embarked on an effort to expand the asymmetric hydration methodology to include substituted dienoates (1) for the preparation of the 4-methyl-5-hydroxyenoates (2) and the benzylidine protected 4-methyl-3,5-dihydroxy esters (3) via the substitution of cyclic carbonates 4 and Pd-π-allyl intermediates 5.6 Herein, we describe the successful development of a de novo asymmetric synthesis of these two structural motifs (2 and 3) from simple achiral dienoates (1). While we were initially concerned about the problems associated with enantio- and regioselectivity in both the osmium and palladium steps, the initial dienoates (6a/b) we chose to study proved to be very promising (Scheme 2).7 Thus, exposure of dienoates 6a and 6b to Sharpless dihydroxylation conditions proceeded uneventfully (Table 1), providing diols 7a and 7b in good yields and excellent enantioselectivity. Similarly, the resulting diols were diastereoselectively converted to homo-allylic alcohols 8a and 8b by conversion to a cyclic carbonate and reduction with Et3N•HCO2H (Table 2).8 Finally, both homo allylic alcohols 8a and 8b were readily converted into the benzylidine protected syn-3,5-dihydroxyester 9a and 9b by exposure to the Evans conditions (PhCHO, cat. KOt-Bu, Table 3). Scheme 2 Asymmetric double hydration of (E,E)-dienoate Table 1 Asymmetric dihydroxylation of (E,E)-dienoates Table 2 Diastereoselective carbonate reduction Table 3 Diastereoselective hydration of δ-hydroxyenoates Unfortunately, when we investigated the scope of this reaction sequence we uncovered complications with the dihydroxylation step (Table 1). The simplest dienoate substrate (Table 1, entry d, R = Me)9 underwent dihydroxylation using (DHQ)2PHAL and (DHQD)2PHAL with excellent enantio- and regioselectivity; however, the regioselectivities were diminished for branched-alkyl and aryl substituents (Table 1, entries a-c).10 For instance, when dienoate 10c (R = Ph) was dihydroxylated with the PHAL-linked dimeric ligands the α,β-olefin 12c was preferentially formed (2.5:1). To our delight, switching to a “first-generation” dihydroxylation ligand, DHQ-4-Me-2-Quinolyl ether (DHQ-MEQ), eliminated this problem and gave the desired diol with excellent selectivity in all three cases (entries a-c, Table 1) with greatly improved regio- (> 16:1) and enantioselectivity (73−90 %ee) for the diols 11a-c. The palladium catalyzed reduction proved to be very tolerant to a variety of functionalities, giving excellent yields and selectivities in all cases. As with the diols 7a/b, the diastereomerically pure diols 11a-e were converted into the corresponding cyclic carbonates 13a-e (Table 2) in excellent yields using triphosgene and pyridine in CH2Cl2. We next examined the Pd-catalyzed reduction of the (E,E)-allylic carbonates 13a-e. After some experimentation it was found that the optimal conditions were 1% Pd2(dba)3•CHCl3/PPh3 in THF with 5 equiv. of Et3N•HCO2H.11 In all case the carbonates were cleanly converted into homoallylic alcohols in excellent yields (> 95%). It is worth noting that we have been able to use this procedure for the preparation of multigram quantities of 14b (i.e., several 10 g batches). To demonstrate both the synthetic utility of this oxidation/reduction sequence as well as to assign the stereochemistry of the asymmetric hydration reaction the homoallylic alcohols 14a-d were converted into the 1,3-syn diols 15a-d. Thus exposure of alcohols 14a-d to the Evans 1,3-syn diol protocol provided the benzylidine protected syn-3,5-dihydroxyesters 15a-d. With the exception of the phenyl substituted substrate 14c the benzylidine acetals were formed in good yields (57 to 75%, Table 3).12 We next set out to test the stereospecificity of the overall transformation (6/10 to 9/15). To do so we chose the (Z,E)-methyl substituted dienoate 16 (c.f., Table 4 and Scheme 3). Once again the initial dihydroxylation proved to be problematic. While no regioisomers were detected, the enantioselectivities were unsatisfactory using the PHAL-linked dimeric ligands (Table 4 entries 1−2). Scheme 3 Shi epoxidation of (E,Z)-dienoates Table 4 Asymmetric dihydroxylation of (E,Z)-dienoates We again turned to the DHQ-MEQ ligand but this time we were met with lower ee (entry 3, Table 4). A screening of commercially-available AD ligands was conducted in which the optimum ligand was determined to be (DHQD)2PYR (entry 4, Table 4).13 In an effort to further increase the enantioselectivity, a Shi epoxidation14 was attempted on 16 (Scheme 3). Indeed, epoxide 19 was formed in greater enantioexcess and was subjected to identical Pd-reduction conditions as the carbonate 18. Both 18 and 19 behaved similarly in the reaction giving excellent dr with the epoxide opening having higher yield (98% vs 86%). Finally, the conversion of 20 to the anti-methyl diastereomer 21 occurred in 80% yield and diastereoselectivity (> 95:5) via the Evans protocol.15 In summary we have demonstrated the utility of our asymmetric bis-hydration methodology for the stereospecific conversion of both (E,E)- and (E,Z)-dienoates into either C-4 diastereomer of benzylidine protected syn-3,5-dihydroxy esters (9, 15 and 21).9 Key to this development was the control of regioselectivity in both the osmium-catalyzed asymmetric dihydroxylation and palladium-catalyzed reduction reactions. Further development to improve the enantioselectivity of the oxidation of the (E,Z)-dienoates and its application toward natural product synthesis is ongoing.

About 12 glycosides prepared through amyloglucosidase catalysis and 23 amino acyl esters of carbohydrates prepared through lipase catalysis in organic solvents showed angiotensin converting enzyme (ACE) inhibition activity. Both amino acyl esters of carbohydrates and glycosides exhibited IC50 values for ACE inhibition in the 0.5 mM to 15.7 mM range. Eugenyl-D-glucoside (IC50: 0.5+/-0.04 mM), L-isoleucyl-D-glucose (IC50: 0.7+/-0.067 mM), vanillyl-D-sorbitol (IC50: 0.8+/-0.09 mM), L-histidyl-D-fructose (IC50: 0.9+/-0.087 mM), L-tryptophanyl-D-fructose (IC50: 0.9+/-0.092 mM), octyl-D-glucoside (IC50: 1.0+/-0.093 mM), vanillyl-D-mannoside (IC50: 1.0+/-0.089 mM), L-valyl-D-mannitol (IC50: 1.0+/-0.092 mM) and L-phenylalanyl-D-glucose (IC50: 1.0+/-0.089 mM) were the compounds, which showed the best ACE inhibitory activities.

The chemical constituents of some species of Euphorbia, which grow mostly in semi-desert areas in Iran and on the Alborz Mountains in the north of Tehran, have been found to include chemotaxonomically important myrsinane diterpenoids and cycloartane triterpenoids. The Euphorbia plants collected in province of Azarbaijan in the northwestern part of Iran contained mostly derivatives of skin-irritating ingenol esters. Some of the diterpenoids with myrsinane carbon skeleton inhibited enzymes such as alpha-glycosidase, urease, HIV-1 reverse transcriptase, and prolyl endopeptidase. They also showed analgesic and DNA-damaging activities. The present review describes the chemistry and biological activity of several compounds isolated from different species of Iranian Euphorbia: diterpenoids with myrsinane skeletons, flavonoids, tannins, alkanes, sterols, mono-, sesqui- and triterpenoids, skin-irritating and tumor-promoting latexes and their active ingenol diterpenoids.

[reaction: see text] 1,4-Diazepinones 5 and pyrrolodiazepinones 8 and 9 were synthesized from common homoallylic ketone precursors 4 prepared by copper-catalyzed cascade addition of a vinyl Grignard reagent to alpha-aminoacyl beta-amino esters 3. Nitrogen deprotection and intramolecular reductive amination yielded 1,4-diazepinones 5. Olefin oxidation, Boc removal, and intramolecular Paal-Knorr condensation gave pyrrolodiazepinones 8 and 9. X-ray structures of diazepinones 5c and 5d depicted dihedral angles about the alpha-amino acid moiety similar to those of the central residue in an ideal reverse gamma-turn.

The selective reduction of one of the three carboxyl groups of two chiral citric acid derivatives to the corresponding aldehydes, under Rosenmund conditions, are reported together with the application of these aldehydes to the syntheses of the ester side chains of some potently antileukemic Cephalotaxus alkaloids e.g. anhydroharringtonine.

Beta-amino esters are readily formed from the rhodium(II) prolinate-catalyzed intermolecular C-H insertion between methyl aryldiazoacetates and a bis-silyl protected methylamine.

[reaction: see text] The first example of the Lewis acid-catalyzed three-component direct-type Mannich reaction of simple aromatic and enolizable aliphatic aldehydes, secondary amines, and glycine derivatives is described. The procedure is highly atom economical and can be performed in a simple one-pot operation under mild conditions to afford a wide variety of synthetically important anti-alpha,beta-diamino ester derivatives in high yields with high diastereoselectivities.

[reaction: see text] The reaction of alpha-sulfonyl acetamide 1 with various cyclic unsaturated esters 2 to fused bicyclic glutarimides is reported. Syntheses of (+/-)-alloyohimbane (4) and louisianin D (5) have been accomplished.

A synthetic method for multifunctionalized oligoarenes using rapid Suzuki-Miyaura coupling of pinacol esters of hydroxyphenylboronic acids and subsequent triflation of the hydroxy group was developed.

A Pt-catalyzed pentannulation of propargylic esters containing an epoxide moiety has been developed. The present transformation achieves the formation of cyclopentenone products as single diastereomers in good yields. The observed products likely form from pyran intermediates that undergo an oxa-6pi electrocyclic ring opening to a functionalized dienone, followed by ring closure with an accompanying acyl shift.