Pyranophane transannular diels-alder approach to (+)-chatancin: a biomimetic asymmetric total synthesis

An asymmetric total synthesis of (+)-chatancin was achieved via a transannular Diels-Alder (TADA) reaction of an in situ generated macrocyclic pyranophane pseudobase. The presented route constitutes the second of two proposed biosynthetic pathways that involves a TADA reaction. It links this diterpene biogenetically to the cembranoids. A set of TADA selection rules that rationalize the formation of (+)-chatancin from a dynamic equilibrium of four 2-hydroxy-2H-pyrane bicycles and their 16 potential TADA transition states are also outlined. Beyond the TADA reaction, highlights of the synthetic work include the assembly of a chiral acyclic macrocyclization substrate from (S)-citronellol and an efficient macrocyclization via a beta-ketosulfoxyde/enone Michael addition.     

Orthogonally protected lanthionines: synthesis and use for the solid-phase synthesis of an analogue of nisin ring C

[structure: see text] Lanthionine, a thioether analogue of cystine, is a key component of the lantibiotics, a family of modified peptides bearing multiple thioether bridges resulting from posttranslational modifications between side chains. It is also used as a conformational constraint in medicinally active peptides. We have explored two synthetic routes to give lanthionine, orthogonally protected with Alloc/allyl and Fmoc groups. One route utilized a carbamate-protected iodoalanine that yielded a mixture of diastereoisomers, and one utilized a trityl-protected iodoalanine, formed via a Mitsunobu reaction, that gave the single desired lanthionine, in complete regio- and diastereoselectivity. We then used this orthogonally protected lanthionine in the solid-phase synthesis of an analogue of a fragment of nisin containing its ring C. The chemoselective deprotection of the allyl and Alloc groups of the incorporated lanthionine unit was followed by regio- and stereoselective cyclization on resin to give the desired lanthionine-bridged peptide.     

A New Route for Synthesis of Entecavir

2-Amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopen tyl]-6H-purin-6-one (entecavir, Scheme 1) is a novel carbocyclic 2-deoxyguanosine analog drug which has potent and selective anti hepatitis B virus (HBV) activity1-3. Entecavir is also effective against lamivudine-resistant YMDD mutants4. The US Food and Drug Administration (FDA) approved entecavir as a new preferred drug for the treatment of HBV after lamivudine in March, 2005. Scheme 1 The structure o…     

Synthesis of Entecavir (BMS-200475)

A synthesis of Entecavir (BMS-200475) was achieved starting from 1,3-propanediol in 15 steps and 23.4% overall yield. A unique feature of the synthetic route is that the five-membered carbocyclic core is installed by an intramolecular nitrile oxide cycloaddition (INOC) reaction and the guanine moiety is introduced by a Mitsunobu reaction. The route is characteristic of low cost, high yield and easy operation.     

(salen)MnIII compounds as nonpeptidyl mimics of catalase. Mechanism-based tuning of catalase activity: a theoretical study

We present the results of the first theoretical investigation of salen-manganese complexes as synthetic catalytic scavengers of hydrogen peroxide molecules that mimic catalase enzymes. Catalase mimics can be used as therapeutic agents against oxidative stress in treatment of many diseases, including Alzheimer's disease, stroke, heart disease, aging, and cancer. A ping-pong mechanism approach has been considered to describe the H2O2 dismutation reaction. The real compounds reacting with a peroxide molecule were utilized in our BP density functional calculations to avoid uncertainties connected with using incomplete models. Part I of the dismutation reaction-converting a peroxide molecule into a water molecule with simultaneous oxidation of the metal atom of the catalyst-can be done quite effectively at the Mn catalytic center. To act as catalytic scavengers of hydrogen peroxide, the oxomanganese salen complexes have to be deoxidized during part II of the dismutation reaction. It has been shown that there are two possible reaction routes for the second part of the dismutation reaction: the top and the side substrate approach routes. Our results suggest that the catalyst could be at least temporarily deactivated (poisoned) in the side approach reaction route due to the formation of a kinetically stable intermediate. Overall, the side approach reaction route for the catalyst recovery is the bottleneck for the whole dismutation process. On the basis of the detailed knowledge of the mode of action of the (salen)MnIII catalase mimics, we suggest and rationalize structural changes of the catalyst that should lead to better therapeutic properties. The available experimental data support our conclusions. Our findings on the reaction dismutation mechanism could be the starting point for further improvement of salen-manganese complexes as synthetic catalytic scavengers of reactive oxygen species.     

Synthesis of (S)-3-amino-benzo[b][1,4]oxazepin-4-one via Mitsunobu and SNAr reaction for a first-in-class RIP1 kinase inhibitor GSK2982772 in clinical trials

Two new synthetic routes were developed to prepare the RIP1 kinase inhibitor clinical candidate GSK2982772 involving a key (S)-3-amino-benzo[b][1,4]oxazepin-4-one intermediate prepared via Mitsunobu and S_NAr cyclization reactions. Both routes are practical and cost effective compared to the initial medicinal chemistry route and are also applicable to kilogram scale-up to support on-going clinical studies.     

Synthesis of orthogonally protected lanthionines

Synthetic approaches to the lantibiotics, a family of thioether-bridged antimicrobial peptides, require flexible synthetic routes to a variety of orthogonally protected derivatives of lanthionine 1. The most direct approaches to lanthionine involve the reaction of cysteine with an alanyl beta-cation equivalent. Several possibilities exist for the alanyl beta-cation equivalent, including direct activation of serine under Mitsunobu conditions: however, the low reactivity of sulfur nucleophiles in the Mitsunobu reaction has previously precluded its use in the synthesis of the lantibiotics. We report here a new approach to the synthesis of protected lanthionine, using a novel variant of the Mitsunobu reaction in which catalytic zinc tartrate is used to enhance the nucleophilicity of the thiol. In the course of these studies, we have also demonstrated that the synthesis of lanthionine from trityl-protected beta-iodoalanines is prone to rearrangement, via an aziridine, to give predominantly trityl-protected alpha-iodo-beta-alanines, and hence norlanthionines, as the major products.     

(-)-(1R,2S)-肉豆蔻木脂素的不对称合成

报道了天然产物(-)-肉豆蔻木脂素的全合成. 以香草醛为起始原料, 经Wittig反应、LiAlH₄还原和Sharplass不对称双羟化等反应构建了苏式结构的中间体; 以焦性没食子酸为原料, 经Claisen重排反应制得另一种苯丙素片段; 2个中间体通过Mitsunobu反应, 缩合并使构型翻转, 得到赤式-(-)-肉豆蔻木脂素. 为赤式8-O-4′新木脂素的合成提供了一种新方法.     

Predicting experimental yields as an index to rank synthesis routes: application for Diels-Alder reactions

It is possible to create novel synthetic routes for compounds using synthesis route design systems (SRDS). We have been investigating an in silico screening protocol, which makes it possible to reduce the number of SRDS experiments in developing new synthesis routes. However, there still remains the problem of how to rank synthesis routes for experiments. The experimental yield is considered to be one of the most important factors in determining which synthesis route is better. The present study describes an attempt toward predicting the trends of experimental yields for organic synthesis by fusing computational chemistry and chemoinformatics. We examined whether the prediction of experimental yields for Diels-Alder reactions is feasible using activation energies obtained from Density Functional Theory (DFT) calculations together with the experimental conditions. A partial least squares analysis using these values gave correlation equations for the experimental yields. If it is possible to construct similar correlation equations for other reactions, then SRDS synthetic routes could be ranked on the basis of their predicted yields, and an order can be determined before beginning the experiments.     

Probing the Mechanism of Allylic Substitution of Morita–Baylis–Hillman Acetates (MBHAs) by using the Silyl Phosphonite Paradigm: Scope and Applications of a Versatile Transformation

A P?C bond‐forming reaction between silyl phosphonites and Morita–Baylis–Hillman acetates (MBHAs) is explored as a general alternative towards medicinally relevant β‐carboxyphosphinic structural motifs. Conversion rates of diversely substituted MBHAs to phosphinic acids 9 or 14 that were recorded by using ³¹P NMR spectroscopy revealed unexpected reactivity differences between ester and nitrile derivatives. These kinetic profiles and DFT calculations support a mechanistic scenario in which observed differences can be explained from the “lateness” of transition states. In addition, we provide experimental evidence suggesting that enolates due to initial P‐Michael addition are not formed. Based on the proposed mechanistic scenario in conjunction with DFT calculations, an interpretation of the E/Z stereoselectivity differences between ester and nitriles is proposed. Synthetic opportunities stemming from this transformation are presented, which deal with the preparation of several synthetically capricious phosphinic building blocks, whose access through the classical P‐Michael synthetic route is not straightforward.     

Noise reduction method for molecular interaction energy: application to in silico drug screening and in silico target protein screening

We developed a new method to improve the accuracy of molecular interaction data using a molecular interaction matrix. This method was applied to enhance the database enrichment of in silico drug screening and in silico target protein screening using a protein-compound affinity matrix calculated by a protein-compound docking software. Our assumption was that the protein-compound binding free energy of a compound could be improved by a linear combination of its docking scores with many different proteins. We proposed two approaches to determine the coefficients of the linear combination. The first approach is based on similarity among the proteins, and the second is a machine-learning approach based on the known active compounds. These methods were applied to in silico screening of the active compounds of several target proteins and in silico target protein screening.     

Stereoselective Access to Fluorinated and Non‐fluorinated Quaternary Piperidines: Synthesis of Pipecolic Acid and Iminosugar Derivatives

The preparation of optically pure quaternary piperidines, both fluorinated and non‐fluorinated, has been achieved from a chiral imino lactone derived from (R)‐phenylglycinol. In the case of the fluorinated derivatives, the addition of (trifluoromethyl)trimethylsilane (TMSCF₃) followed by iodoamination and migration of the CF₃ group allowed access to four derivatives of α‐(trifluoromethyl)pipecolic acid. A theoretical study of the CF₃‐group rearrangement has been carried out to help establish the reaction mechanism of this uncommon transformation. Moreover, a route to trifluoromethyl‐substituted iminosugars was also developed through the diastereoselective dihydroxylation of suitable synthetic intermediates. Conversely, alkylation of the starting substrate and subsequent cross‐metathesis and aza‐Michael reactions led to α‐alkyl derivatives of the target compounds.     

Negishi's Reagent Versus Rosenthal's Reagent in the Formation of Zirconacyclopentadienes

Zirconacyclopentadienes are versatile precursors for a large number of heteroles, which are accessible by Zr-element exchange reactions. The vast majority of reports describe their preparation by the use of Negishi′s reagent, which is a species that is formed in situ. The zirconacyclopentadiene is then formed by the addition of one equivalent of a diyne or two equivalents of a monoyne moiety to this Negishi species. Another route involves Rosenthal′s reagent (Cp₂Zr(py)Me₃SiC≡CSiMe₃), which then reacts with a diyne or monoyne moiety. In this work, the efficiency of both routes was compared in terms of reaction time, stability of the product in the reaction mixture, and yield. The synthetic implications of using both routes are evaluated. Novel zirconacyclopentadienes were synthesized, characterized directly from the reaction mixture, and crystal structures could be obtained in most cases.     

间叔丁基苯乙醚的合成研究

通过两条路线合成了生产新型农药乙螨唑的关键中间体间叔丁基苯乙醚。其一以叔丁基苯为原料,通过溴代、硝化、还原(脱卤素)、重氮化和乙醚化反应得到目标化合物;另一采用对氨基叔丁基苯为原料,通过乙酰化、溴代、脱乙酰化、重氮化去氨基和乙醚化反应得到目标化合物。两条路线的总收率都较高,分别为45%和63%。所得产品中未检测到异构体对叔丁基苯乙醚,质量好,纯度高。其中路线一原料便宜,操作简单,更适合进一步工业化放大生产。合成路线中的有机中间体和目标化合物的化学结构通过MS和NMR进行确证。     

Total synthesis of salicylihalamides A and B

The paper illustrates two efficient routes to macrolactone 19 containing a 3-(para-methoxybenzyloxy)propyl side chain at C-15. The chiral center at C-15 was introduced by a Noyori reduction of keto ester 5. The intermediate common to both routes, aldehyde 8, was prepared from keto ester 5. The subsequent chain extension utilized Evans aldol reactions. The first route leads to the alkene 14, which was used, after hydroboration, for a Suzuki cross-coupling reaction with vinyl iodide 15. The derived seco acid 18 was converted into the macrolactone 19 by a Mitsunobu lactonization by using immobilized triphenylphosphine. Alternatively, an aldol reaction of 8 with the 4-pentenoyl derivative 20 was used to prepare alkene 26. This building block led to ester 28, which could also be converted into macrolactone 19 by the classical ring-closing metathesis. After conversion of the C-15 side chain to the corresponding aldehyde, the enamide was introduced through hemiaminal formation and formal elimination of water. Separation of the double-bond isomers and removal of the silyl protecting groups provided salicylihalamides A (E)-1 and B (Z)-1.     

A Concise Synthesis of the HCV Protease Inhibitor BILN 2061 and Its P3 Modified Analogs

A concise synthesis of BILN 2061 was achieved through more efficient installation of P2 4‐quinoline moiety via S_N2 displacement of the β‐OBs group located on the 4‐hydroxyl proline intermediate, which was prepared from 4‐α‐hydroxyl proline analog via Mitsunobu reaction with inversion of stereochemistry. In addition, a short and practical synthesis for P3 unit is also described herein. Final assembly of four fragments for BILN 2061 was achieved with an overall yield of 58% in 4 steps from P1 to 15a . Furthermore several analogs of BILN 2061 ( WX‐1 – WX ‐ 5 ) containing modifications on P3 unit were synthesized successfully using the same synthetic route as described for the parent inhibitor BILN 2061 .     

Toward the development of a cephalosporin-based dual-release prodrug for use in ADEPT

In previous work we have shown that a cephalosporin structure bearing an S-aminosulfenimine at the 7-position behaved as a beta-lactamase-dependent dual-release prodrug. Scission of the beta-lactam ring of such a structure led to the rapid loss of the sulfur-attached side chain moiety via an intramolecular displacement, while the 3'-group was lost via the well-established elimination process at that position. In the present work we report on an evaluation of the scope and limitations of exploiting the S-aminosulfenimine functionality to generate a cephalosporin-based prodrug incorporating two biologically active components. Starting from 7-ACA, a viable synthetic cycle was put in place that avoided formation of the Delta(2) isomer throughout and that allowed incorporation of aminoglutethimide at the 3'-position and of a tosyl S-aminosulfenimine at the 7-position. The direct incorporation of a biologically active sulfonamide (ethoxzolamide) or a sulfamate (coumate) at this latter position was not achieved as a result of the difficulty of generating the corresponding sulfur diimides. An indirect route for the formation of an S-aminosulfenimine was put in place, as was a general method of alkylation (Mitsunobu reaction) of the tosyl S-aminosulfenimine following its incorporation.     

Enantioselective Total Synthesis of Four Styrylpyrone Derivatives

The first enantioselective total synthesis of 5-acetoxygoniothalamin 1 and 5-acetoxyisogoniothalamin oxide 2 was achieved through the Sharpless kinetic resolution of recemic secondary 2-furylmethanol 5 and the Mitsunobu reaction. At the same time we developed a short synthetic route for 6R-( )-goniothalamin 3 and (6R,7R,8R)-( )-goniothalamin oxide 4. And according to this route the configuration of 5-acetoxygoniothalamin 1 was confirmed as (5S,6S).     

Total Syntheses of (−)‐Minovincine and (−)‐Aspidofractinine through a Sequence of Cascade Reactions

We report 8‐step syntheses of (?)‐minovincine and (?)‐aspidofractinine using easily available and inexpensive reagents and catalyst. A key element of the strategy was the utilization of a sequence of cascade reactions to rapidly construct the penta‐ and hexacyclic frameworks. These cascade transformations included organocatalytic Michael‐aldol condensation, a multistep anionic Michael‐S_N2 cascade reaction, and Mannich reaction interrupted Fischer indolization. To streamline the synthetic routes, we also investigated the deliberate use of steric effect to secure various chemo‐ and regioselective transformations.     

Correlation between the rate order and the number of molecules in the reaction of trimethyl phosphite with water in acetonitrile solvent

Density functional theory calculations of the title reaction, P(OCH?)? + (H?O)(n) in CH?CN, were conducted, where n is the number of water molecules. Two routes, the routes suggested by (A) Aksnes and (B) Arbuzov, were traced with various n values. Both routes consist of two transition states (TSs) and one intermediate. Route B was found to be more likely than route A. In the former, the activation free energy (ΔG(?)) of n = 3 is slightly smaller than that of n = 2. The n = 3 TS geometry is composed of a nucleophile H?O, a proton donor H?O, and an auxiliary one. Indeed, the geometry appears to be plausible for ready proton relays along hydrogen bonds, but it is inconsistent with the observed third-order rate constant. Catalytic water molecules were added to the n = 2 and 3 bond-interchange circuits. Then route B with n = 2 + 2 was found to be best. By n = 2 + 10 and n = 3 + 12 models, the n = 2 based route B was confirmed to be likely.