Synthesis of a highly functionalized γ-lactone as a precursor of 9-pentyl anthracyclines

The synthesis of non racemic chiral γ-lactone 7 from α-D-isosaccharino-1,4-lactone (+)-8, as a precursor of the A-ring of the targeted 3′-morpholinyl-9-pentyl anthracycline 6, is described.     

Preparation of an A-ring building block for the total synthesis of 1α,25-dihydroxy vitamin D3 and structurally related congeners: lipase-catalyzed stereoselective esterification of a suitable epoxyalcohol

An useful A-ring building block for the total synthesis of vitamin D₃ congeners, compound 7, has been prepared starting from vitamin D₂ by a chemo-enzymatic approach that relies on lipase-catalyzed acylation in an organic solvent for the stereoselective step.     

Synthesis and anticancer activity of conformationally constrained Smac mimetics containing pseudo β turns

Herein, we report synthesis and in vitro anticancer activity of conformationally constrained Smac mimetics containing reverse turn inducing motifs “Ant-Pro” and “^sAnt-Pro”. The synthesis of Smac analogs with diverse hydrophobic groups at the C-terminus was carried out using solution phase peptide synthesis. The synthesis of Ant-Pro containing analogs 3a–j was carried out by ring opening of benzoxazinones 7a–c, whereas, their sulfonamide counterparts 4a–h were synthesized by using routine acid-amine coupling reaction. In vitro anticancer studies against breast cancer cell line MDA-MB-231 revealed that some of the new analogs had better anticancer activity than the standard AVPI Smac tetrapeptide.     

An efficient method for preparing the sphingosine-1-phosphate receptor agonist, KRP203-phosphate

An efficient method for mono-phosphorylation of 2(KRP203)using cbz-protection,dibenzylphosphoryl chloride and TMSI affording 2-P(KRP203-P)was developed.We applied the present method to the synthesis of KRP203 phosphate analogs which were difficult to produce through tradition procedures.     

Synthesis of 1,7-dimethoxy-2-hydroxyxanthone,a natural product with potential activity on erectile dysfunction

The natural product,1,7-dimethoxy-2-hydroxyxanthone(1),isolated from Securidaca inappendiculate Hassk,has a potential in the treatment of erectile dysfunction due to its significant relaxation activity on rabbit Corpus cavernosum.However,the isolation of compound 1 is problematic because of its high similarity in structure to its analogs.In this paper,the first synthesis of 1 was reported featuring two key reactions:a copper-catalyzed coupling reaction and an intramolecular cyclization.     

Furan approach to the synthesis of the A-ring of Vitamin D analogues

The efficient transformation of 2,3-disubstituted furan (3) into (Z)-dienol (2) illustrates a useful strategy for the synthesis of the A-ring of Vitamin D analogues.     

The synthesis of 13-hydroxylated ent-kaur-16-ene derivatives using an acyloin-like cyclization of keto esters

The synthesis of steviol (27) and two A-ring modified analogues (9 and 15) is described. The synthetic sequences involve the preparation of suitably constituted 17-nor-13,16-seco-ent-kauranoid keto esters (22, 7 and 13) which are then cyclized to 13,16-dooxygenated-17-nor-ent-kauranes (23, 8 and 14).     

Synthetic approach to condensed heterocyclic analogues from etoposide revisited. Synthesis of A-ring pyridazine etoposide

The synthetic approach to condensed heterocyclic analogues from etoposide was revisited. The described procedure allows the synthesis of A-ring pyridazine etoposide 13, featuring the use of tetrakis(triphenylphosphine)palladium as catalyst under optimized conditions in the key Stille cross coupling between bistriflate 14 and the vinylstannane without epimerization at C-2. The TBDMS-protecting group was critical to cleanly obtain the pivotal intermediate 19.     

The C4-functionalized 9,10-seco-5,7,10(19)-cholestatriene derivatives: Concise synthesis and characterization of novel vitamin D analogues with a four-membered heterocyclic ether

Two novel stereoisomeric 9,10-seco-steroids (3a,b) bearing a spiro-oxetane at the C2 position of the A-ring with an unconventional C4-hydroxy group have been designed and synthesized by a convergent manner. The requisite A-ring enyne precursors (±)-9 were prepared in excellent yield from our reported aldehyde 4 according to a five-step procedure. The absolute configurations at the C4-hydroxy groups of the targeted compounds (3a,b) were determined by the circular dichroism (CD) exciton chirality method using the corresponding benzoates of the C4-allylic alcohol. Preliminary biological characterization using the bovine thymus VDR suggested that the incorporation of a spiro-oxetane at the C2 position, in combination with a hydroxy group at the C4 position, had negative effects on the VDR affinity.     

A novel approach to the Taxol A-ring synthetic equivalents

A novel short approach to the A-ring synthetic equivalents of Taxol was described. Oxabicyclic ketone 3 served as a versatile template for selective functionalization leading to oxabicyclic vinylic ether 6 in two steps, which was hydrolyzed under mild acidic conditions to afford the hydroxy aldehyde derivative 7. Synthetic equivalents 2 of Taxol A-ring were thus, accessible from hydroxy aldehyde 7.     

Efficient synthesis of analogs of safflower yellow B, carthamin, and its precursor: two yellow and one red dimeric pigments in safflower petals

The synthesis of analogs (8, 12, 14) of two yellow pigments, safflower yellow B and the precursor of carthamin, and carthamin itself, a red pigment, which are produced in safflower (Carthamus tinctrious L.) petals and, which have a common dimeric quinochalcone structure, is reported. The key compound for the synthesis of these analogs, (p-hydroxycinnamoyl)filicinic acid (7) was synthesized in six steps from phloroglucinol in a total yield of 39%, which was reacted with 2,3,4,5,6-penta-O-acetyl-aldehydo-d-glucose, glyoxylic acid, and ethyl orthoformate in the presence of base to afford the corresponding analog, 8, 12, 14, in good yields, respectively. Precursor analog 12 was then converted to carthamin analog 14 by oxidative decarboxylation by treatment with potassium permanganate as well as the natural specimen.     

Enantioselective synthesis of phyllanthurinolactone, a leaf-closing substance of Phyllanthus urinaria L., and its analogs toward the development of molecular probes

We report enantioselective synthesis of phyllanthurinolactone (1), a leaf-closing substance of Phyllanthus urinaria L., and its analogs with sugars other than d-glucose. Structure-activity relationship study using them revealed that the structure of the sugar moiety did not affect their bioactivity at all. This result is very important for the development of molecular probes based on the structure of 1.     

Synthetic studies toward (+)-cortistatin A

We describe herein the synthesis of a late-stage intermediate en route to cortistatin A. Key transformations included a Snieckus-like cascade sequence culminating in a 6π-electrocyclization, an alkylative dearomatization, and the stereoselective functionalization of the cortistatin A-ring. While the total synthesis we sought was not accomplished, the work sets the stage for several approaches to the preparation of novel analogs via diverted total synthesis.     

Preparation of penta-azole containing cyclopeptides: challenges in macrocyclization

Herein is described the synthesis of several analogs of the natural product IB-01211 from concatenated azoles, via a biomimetic pathway based on cyclization-oxidation of serine containing peptides combined with the Hantzsch synthesis. The macrocyclization of rigid peptide compounds 1 and 2 to give IB-01211 and its epimer 12b was explored, and the results are compared here to those previously obtained for the macrocyclization of more flexible structures in the syntheses of YM-216391, telomestatin, and IB-01211. Lastly, the preliminary results of anti-tumor activity screening of the synthesized analogs are discussed.     

A total synthesis of distamycin a,an antiviral antibiotic

A new total synthesis of distamycin A (1) is described. The route followed passes through an intermediate acid (2a) which can serve as a convenient starting material for the synthesis of distamycin analogs.     

A solid phase approach to PDMP analogs：A general strategy for combinatorial library

The present work reports the first solid phase synthesis of biologically interesting D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol(D-threo-PDMP)derivatives.This synthetic strategy includes facile preparation of versatile azido intermediate(5) in a relatively short sequence and the subsequent derivatization of 5,which led to a series of sulfonamide,urea and heterocycle substituted PDMP analogs(10 and 10’).With this method,a 5280-member compound library has been successfully built by IRORI Nanokan? system.     

Synthesis of aromatic stigmastanes: application to the synthesis of aromatic analogs of brassinosteroids

In this paper, we report the first synthesis of aromatic analogs of brassinosteroids. In order to accomplish this task, we explored two different synthetic approaches, which involved demethylation of the C-19 of stigmasterol to yield A-ring aromatic 3-hydroxystigmastanes. One of the new aromatic analogs showed a reduced but significant bioactivity when compared to the natural hormones.     

Systematic solution-phase parallel synthesis of active vitamin D3 analogs with elongated side chains and their cell differentiation activities

Side-chain elongation of active vitamin D3 is acknowledged as a structural modification to enhance its cell differentiation activity; however, the comprehensive structure-activity relationship (SAR) as a result of this modification has not been reported. To clarify the SAR, we synthesized six analogs systematically elongated at the 24-position, 26,27-position, or both by methylene (normal A-ring series 1a-f) in a facile parallel solution-phase synthesis. Using parallel synthesis, we expanded the side chain-elongation study into two 19-exomethylene analog series: 19-nor-A-ring (4a-f) and 2-methylene-19-nor-A-ring (5a-f). In the 19-nor-A-ring analog series, the SAR induced by side-chain elongation was similar to the normal A-ring analog series, but in the 2-methylene-19-nor-A-ring series, the SAR was unique.     

An enantiospecific synthesis of a taxol A-ring building unit.

The optically active Taxol A-ring segment 2 was synthesized from L-arabinose via ring closure of epoxy-allylsilane 3 with BF₃.OEt₂.     

Function Oriented Synthesis: Preparation and Initial Biological Evaluation of New A-Ring-Modified Bryologs

The synthesis and biological evaluation of the first members of a new series of designed bryostatin A-ring analogues (bryologs) are described. An advanced intermediate is produced that allows for step economical access to diverse analogs. The first of these analogues, bearing side chains of completely different polarities from alkyl to hydroxyl and carboxyl functionalities, were evaluated. All exhibit potent protein kinase C binding (54.7-2.4 nM) with affinities increasing with decreasing side chain polarity. This series of bryostatin analogues demonstrates that A-ring surrogates can indeed be used for tuning pharmacophore and ADME characteristics as needed to improve bryolog function.