Stereoselective synthesis of Sch 642305, an inhibitor of bacterial DNA primase

Sch 642305 is a fungal nonanolide, which inhibits bacterial DNA primase and HIV-1 Tat transactivation. The enantioselective synthesis of Sch 642305 was succeeded starting from useful chiral building block via stereoselective dianion alkylation of β-ketosulfoxide and lactonization.     

Stereoselective synthesis of the bacterial DNA primase inhibitor Sch 642305 and its C-4 epimer

A convergent stereoselective synthesis of the bacterial DNA primase inhibitor Sch 642305 and its non-natural epimer at C-4 is described. A key aspect was the construction of a trans-2,3-disubstituted cyclohexanone system by means of a stereoselective Michael addition/α-alkylation sequence. The macrolactone ring of either stereoisomer was created using the Mitsunobu and Yamaguchi procedures, respectively.     

New perspective for natural products synthesis: concise synthesis of (+)-sch 642305 by chiral auxiliary multiuse methodology

The synthesis of (+)-Sch 642305 is an example of chiral auxiliary multiuse methodology, which shows a new perspective for the synthesis of compounds with multiple asymmetric centers. Thus, (+)-Sch 642305 was concisely synthesized from the known compound. Every reaction is stereoselective, and the chiral nonracemic hydrobenzoin worked as chiral auxiliary for desymmetrization of diene, as a template for attaining regio- and stereoselective reactions, as an oxygen source at the C4-position, and as a protecting group of hydroxyl functions. Namely, the chiral auxiliary played a role in every step throughout the synthesis. Furthermore, the synthesis contains a new protocol for obtaining alpha'-alkylated enone compounds.     

A radical mediated approach to the stereoselective formal total synthesis of (+)-Sch 642305

A formal total synthesis of (+)-Sch-642305 is described. The synthesis, which commenced from a simple chiral synthon (5S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one, employed, as a key step, a radical mediated opening of a chiral epoxy alcohol intermediate with Cp₂Ti(III)Cl following an efficient method developed by us earlier. The resultant intermediate radical was intramolecularly trapped by the electron deficient double bond present in the molecule to give rise to its highly functionalized six-membered carbocyclic ring in stereoselective manner.     

Synthesis of (+)-sch 642305 by a biomimetic transannular Michael reaction

[reaction: see text] The synthesis of (+)-Sch 642305 (1) has been completed in 17 steps in 1.6% overall yield. Transannular Michael reaction of 2b with NaH in THF provided cyclohexenone 23 stereospecifically. Heating 23 in TFA/CDCl(3) provided a 3:1 equilibrium mixture of 23 and 25, which was hydrolyzed to give (+)-6-epi-Sch 642305 (24) and (+)-Sch 642305 (1), respectively.     

Enantioselective total synthesis of bioactive natural product (+)-Sch 642305: a structurally novel inhibitor of bacterial DNA primase and HIV-1 Tat transactivation

The total synthesis of the bioactive natural product (+)-Sch 642305 has been achieved from a readily available chiral building block using an RCM protocol to construct the key decalactone moiety; our approach is notable for its built-in flexibility and is diversity oriented.     

Total Synthesis of Sch 725674

A concise total synthesis of the macrolactone natural product Sch 725674 is accomplished starting from commercially available 2-deoxy-d-ribose. Pivotal reactions employed in the synthesis include the addition of 4-pentenylmagnesium bromide to the lactol derived from 2-deoxy-d-ribose, olefin cross metathesis and Yamaguchi macrolactonization.     

Concise synthesis of the bacterial DNA primase inhibitor (+) -Sch 642305

[structure: see text]. A highly convergent, enantioselective synthesis of (+) -Sch 642305 is presented, which features a Mukaiyama-Michael addition followed by allylation to establish the syn-anti relationship of the three contiguous stereocenters. The 10-membered macrolactone was formed through ring-closing metathesis.     

An asymmetric synthesis of the novel H3 agonist (+)-(3R,4R)-3-(4-imidazolyl)-4-methylpyrrolidine dihydrochloride (Sch 50971)

A short, high yielding, enantioselective synthesis of the novel H₃ agonist Sch 50971 1 is described. The key enantiodifferentiating step is the 1,4-addition of a chiral N-propionyloxazolidinone to a nitroolefin.     

Quality control of Schizonepeta tenuifolia Briq by solid-phase microextraction gas chromatography/mass spectrometry and principal component analysis

The chemical composition of Schizonepeta tenuifolia Briq. (Sch.t.Briq.) is mainly composed of several volatile substances that affect multiple pharmacological targets and provide clinical efficacy. In this work, a headspace/solid-phase microextraction gas chromatography/mass spectrometry (HS-SPME-GC/MS) method was developed to evaluate the profiles of volatile compounds in Sch.t.Briq. The optimization of SPME conditions was carried out using four kinds of fiber, extraction time and temperature, desorption temperature and time, and sample amount. The GC/MS analysis allowed the tentative identification of 21 compounds, with similarities higher than 85%, in accordance with the NIST/Wiley mass spectral library. Major components such as (+)-menthone (14.32%), (−)-pulegone (47.73%), 2-hydroxy-2-isopropenyl-5-methylcyclohexane (5.97%), cis-pulegone oxide (4.12%), and schizonal (5.36%) were identified by comparison of retention time and mass spectral data of standards isolated from Sch.t.Briq. The contents of these compounds were about above 78% against total amounts of volatile compounds extracted from Sch.t.Briq. Based on optimized SPME method, 19 different Sch.t.Briq. samples collected from markets in Korea and China were analyzed to obtain the profiling data of volatile compounds. In addition, principal component analysis (PCA) was performed on the profiling data in order to classify the samples collected from the different regions. PCA could possibly visualize the grouping tendencies of the studied varieties of herbal samples, as well as the identification of the volatiles responsible for discriminating the groups.     

Efficient asymmetric synthesis of biologically important tryptophan analogues via a palladium-mediated heteroannulation reaction.

A novel and concise synthesis of optically active tryptophan derivatives was developed via a palladium-catalyzed heteroannulation reaction of substituted o-iodoanilines with an internal alkyne. The required internal alkyne 14a or 25 was prepared in greater than 96% de via alkylation of the Sch?llkopf chiral auxiliary 19 employing diphenyl phosphate as the leaving group. The Sch?llkopf chiral auxiliary was chosen here for the preparation of L-tryptophans would be available from D-valine while the D-isomers required for natural product total synthesis would originate from the inexpensive L-valine (300-g scale). Applications of the palladium-catalyzed heteroannulation reaction were extended to the first asymmetric synthesis of L-isotryptophan 38 and L-benz[f]tryptophan 39. More importantly, the optically pure 6-methoxy-D-tryptophan 62 was prepared by this protocol on a large scale (>300 g). This should permit entry into many ring-A oxygenated indole alkaloids when coupled with the asymmetric Pictet-Spengler reaction. In addition, an improved total synthesis of tryprostatin A (9a) was accomplished in 43% overall yield employing this palladium-mediated process.     

Electrochemical bromination of late stage intermediates and drug molecules

Aromatic CH bromination is one of the applications of late stage functionalization that provides precursors for generation of radio-labelled compounds to support drug metabolism and pharmacokinetic (DMPK) studies or provide a “handle” for further functionalization to expand SAR studies without having to resort to de novo synthesis. Electrochemical aromatic bromination was attempted on late stage intermediates and drug molecules such as cytidine, uridine, Tenofovir, MK-4618, Sch48973 and MK-8457. The reactions were conducted under mild galvanostatic electrolysis condition in aqueous NaBr solution. The brominated products were obtained and converted to the corresponding tritium labelled products. Electrochemical methodology provides an alternative way to quickly generate aryl bromides of late stage intermediates or drug molecules that are very useful in drug discovery.     

Progress toward synthesis of diazonamide A. Preparation of a 3-(oxazol-5-yl)-4-trifluoromethyl-sulfonyloxyindole and its use in biaryl coupling reactions

[formula: see text] The synthesis of a 3-oxazol-5-yl-indole-4-triflate is described, featuring a Sch?lkopf reaction to prepare the oxazole. In addition, the participation of this intermediate in biaryl coupling reactions toward the total synthesis of the natural product diazonamide A is presented.     

Studies towards the total synthesis of Sch 56036; isoquinolinone synthesis and the synthesis of phenanthrenes

The isoquinolinone hemisphere of Sch 56036 has been prepared using a modified Pomeranz-Fritsch reaction and the synthesis of the phenanthrene core has been modelled via a Suzuki coupling and subsequent ring closing metathesis.     

Enantioselective synthesis of macrolactone core of the natural product Sch725674

An enantioselective synthesis of the macrolactone core of natural product Sch725674 was accomplished from furfural. Key reactions in assembly of the macrolactone are the use of furan as a but-2-ene-dione equivalent and ring closing metathesis.     

Iterative benzyne-furan cycloaddition reactions: studies toward the total synthesis of ent-Sch 47554 and ent-Sch 47555

[reaction: see text] 7-Fluoro-5,8-dimethoxy-1-naphthol, prepared from the lithiation and benzyne formation from 1,4-difluoro-2,5-dimethoxybenzene and Diels-Alder cycloaddition with furan, was sequentially C-glycosidated under Suzuki conditions and O-glycosidated using di-O-acetyl-L-rhamnal to provide the corresponding beta-naphthyl C,O-disaccharide. Further lithiation, benzyne formation, and cycloaddition with furan gave an oxa-bridged 1,4-dihydroanthracenyl C,O-disaccharide, a model compound relevant to the total synthesis of Sch 47555.     

Regiospecific, enantiospecific total synthesis of the 12-alkoxy-substituted indole alkaloids, (+)-12-methoxy-Na-methylvellosimine, (+)-12-methoxyaffinisine, and (-)-fuchsiaefoline

[reaction: see text] The enantiospecific synthesis of 7-methoxy-d-tryptophan was completed by combination of the Larock heteroannulation process with a Sch?llkopf-based chiral auxiliary in good yield. This ester was then employed in the first total synthesis of (+)-12-methoxy-Na-methylvellosimine, (+)-12-methoxyaffinisine, and (-)-fuchsiaefoline in regiospecific, stereospecific fashion in excellent overall yield. The asymmetric Pictet-Spengler reaction and enolate-driven palladium-catalyzed cross coupling processes served as key steps.     

Total synthesis of (+/-)-phomactin G, a platelet activating factor antagonist from the marine fungus Phoma sp

A total synthesis of phomactin G (), which is a central intermediate in the biosynthesis of phomactin A () in Phoma sp. is described. The synthesis is based on a Cr(ii)/Ni(ii) macrocyclisation from the aldehyde vinyl iodide, leading to, followed by sequential conversion of into the [small beta]-epoxide and the ketone which, on deprotection, led to (+/-)-phomactin G. Phomactin G () shares an interesting structural homology with phomactin D (), the most potent PAF-antagonist metabolite in Phoma sp. It is most likely converted into phomactin A (), by initial allylic oxidation to the transient [small alpha]-alcohol 'phomactin' structure, known as Sch 49028, followed by spontaneous pyran ring formation.     

High-Yielding Enantioselective Synthesis of the Macrolactam Aglycon of Sch 38516 from Two Units of (2R)-2-Ethyl-4-penten-1-ol

The same precursor —namely, (2R)-2-ethyl-4-penten-1-ol—was used to obtain fragments C9–C13 and C1–C8 of 1 , the aglycon of Sch 38516 (which is active against Candida sp.) and fluvirucin B₁ (which is active against influenza A virus). The key steps of the synthesis were the aldol-like reaction between the two fragments and the macrolactamization of a 13-azidotridecanoic acid derivative (see scheme). MOM=methoxymethyl, Py=2-pyridyl.     

Peptides constrained by an aliphatic linkage between two C(alpha) sites: design, synthesis, and unexpected conformational properties of an i,(i + 4)-linked peptide.

A novel route for the synthesis of cyclic peptides constrained by an aliphatic bridge between two C(alpha)sites, using a triply orthogonal protecting group strategy, is described. The synthesis of the orthogonally protected bis-amino acid 1, via an enantioselective route utilizing the Sch?llkopf and Evans methodologies, is first described. This is then incorporated into a short, alanine-rich peptide 13, using a novel triply orthogonal protecting group strategy to couple first one, then the other, amino acid moiety in such a way that an aliphatic bridge is formed between the i and i + 4 positions. Unexpectedly, the resulting constrained peptide does not adopt a helical conformation: instead, it is shown by CD at low temperature to adopt a left-handed type II beta-turn conformation in aqueous media and a right-handed type I beta-turn conformation in TFE.