Hydrogen atom transfer methodology for the synthesis of C-22, C-23, and C-25 stereoisomers of cephalostatin north 1 side chain from spirostan sapogenins

A simple synthesis of all eight C-22, C-23, and C-25 diastereoisomers of the cephalostatin north 1 side chain has been accomplished from (25R)-5α-spirostan-3β-ol (tigogenin). The synthesis involves selective hydroxylations at C-23 and C-25 and reductive opening of the 1,6-dioxaspiro[4.5]decane spirostan system to give a conveniently protected 5α-furostan-3β,23,25,26-tetrol. The construction of the required 1,6-dioxaspiro[4.4]nonane system entailed an intramolecular hydrogen abstraction reaction promoted by the C-25 alkoxyl radical as the key step. Acid-catalyzed isomerization of the spiroketal unit suggested that 22R isomers are the thermodynamic products while the 22S isomers are the result of kinetic control. The acid-catalyzed equilibrium between 1,6-dioxaspiro[4.4]nonane and 1,6-dioxaspiro[4.5]decane systems was also studied. In the 1,6-dioxaspiro[4.4]nonane units, the observed ³J_23,24 coupling constants suggest that the five-membered puckered ring-F undergoes substantial conformational changes on going from 22S to 22R isomers.     

An efficient synthesis of the C-23 deoxy, 17 alpha-hydroxy South 1 hemisphere and its cephalostatin 1 analog

[reaction: see text] Methods for functionalization of the D ring of diene 1 were investigated. This study led to efficient syntheses of 3 and the subsequent 23'-deoxy,17'alpha-hydroxy cephalostatin 1 analog (4). The bioactivity data of 2 and 4 are in the low nanomolar range for a 10-cell-line minipanel.     

Regioselective C-2 and C-6 substitution of (S)-nicotine and nicotine derivatives

[reaction: see text] Regioselective deprotonations of (S)-nicotine and derivatives at the C-2 and C-6 positions of the pyridine ring were performed in good to excellent yields. These methodologies allow the direct introduction of a plethora of functional groups onto the pyridine ring of nicotine.     

Chemical transformation of prostaglandin-A2: a novel series of C-10 halogenated, C-12 hydroxylated prostaglandin-A2 analogues

[reaction: see text] Synthesis of a novel class of C-10 halogenated and C-12 oxygenated prostaglandin-A(2) derivatives (6a-6c) has been accomplished. (15S)-Prostaglandin-A(2) (1), from the gorgonian Plexaura homomalla, served as the starting material for the synthesis. The absolute configuration was determined using NMR.     

Synthesis of the bicyclo[7.3.0]dodecatrienediyne core of the C-1027 chromophore

[reaction: see text] C-1027, an extremely potent antitumor agent, is composed of chromophore 1 and an apoprotein. Here we report a general and efficient route to the exceedingly reactive bicyclo[7.3.0]dodecatrienediyne core of 1, utilizing selenoxide elimination and epoxide deoxygenation to build the cyclopentadiene and enediyne structures, respectively.     

1,3-Diphenylbenzo[e][1,2,4]triazin-7(1H)-one: selected chemistry at the C-6, C-7 and C-8 positions

1,3-Diphenylbenzo[e][1,2,4]triazin-7(1H)-one (6) reacts with tetracyanoethylene (TCNE) or tetracyanoethylene oxide (TCNEO) to give the deep green 2-[1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-ylidene]propanedinitrile (11) in 17 and 15% yields, respectively. Nucleophiles such as amines, alkoxides, thiols and Grignard reagents all reacted with the 1,3-diphenylbenzotriazinone 6 regioselectively at C-6, while halogenating agents reacted exclusively at C-8. Furthermore, 8-iodo-1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one (32) undergoes palladium-catalysed Suzuki-Miyaura and Stille coupling reactions to give 8-aryl- or heteroaryl-substituted benzotriazinones. By combining both the C-6 and C-8 chemistries 1,3,6,8-tetraphenylbenzo[e][1,2,4]triazin-7(1H)-one (42) and 1,3-diphenyl-6,8-di(thien-2-yl)-benzo[e][1,2,4]triazin-7(1H)-one (43) can be prepared. All new compounds are fully characterized.     

Introduction of vinyl and hydroxymethyl functionalities at C-4 of glucose-derived substrates: synthesis of spirocyclic, bicyclic, and tricyclic nucleosides

Installing hydroxymethyl and hydroxyethyl substitutions at C-4 through vinylation and hydroboration-oxidation reactions of the C-4 bis-hydroxymethyl derivative of d-glucose based substrate, and inserting heteroatoms thereafter permitted formation of N-, O-, or S-heterocycles leading to [4,5]- or [5,5]-spirocycles and a bicyclo[3.3.0]octane product. Some of the spirocycles were converted to spironucleosides under Vorbruggen glycosidation reaction conditions. Similarly, the bicyclic product was elaborated to the corresponding bicyclic nucleoside as well as an unexpected tricyclic nucleoside.     

A convenient oxazole C-2 protecting group: the synthesis of 4- and 5-substituted oxazoles via metalation of 2-triisopropylsilyloxazoles

[reaction: see text] Metalation of oxazoles at the 4 and 5 position was achieved after regioselective C-2 silyl protection. Removal of the protecting group was then accomplished under mild conditions allowing for a straightforward preparation of C-5 monosubstituted and C-4,5 disubstituted oxazoles. The first practical C-2 protecting group of oxazoles has been demonstrated.     

Generation of a C-3'-thymidinyl radical in single-stranded oligonucleotides under anaerobic conditions

[reaction: see text] A C-3'-thymidinyl radical has been photochemically generated site-specifically in DNA oligonucleotides. A nucleoside H-phosphonate bearing a C-3' acetyl group was incorporated into DNA oligomers using a hand-coupling technique. When nucleotides containing the modified monomer were photolyzed (> or =320 nm) in the presence of a hydrogen atom donor, reduction products were detected by RP-HPLC and MALDI-ToF MS analysis.     

Novel synthesis of C-3-(hetero)aryl [1,2,3]triazolo[1,5-a]pyridines using the Stille reaction

Herein, we report a novel and high yielding approach for the preparation of the first C-3-organometallic substituted [1,2,3]triazolo[1,5-a]pyridine and its application to the Stille reaction using MAOS.     

An unusual occurrence on attempted purine C-8 electrophilic fluorination of 5'-noraristeromycin

Reaction of the in situ generated purine C-8 carbanion of a protected 5'-noraristeromycin derivative with N-fluorobenzenesulfonimide gave 8-phenylsulfonyl-5'-noraristeromycin rather than the expected 8-fluoro derivative. A single electron transfer (SET) mechanism is proposed for this occurrence. The phenylsulfonyl product offers a structural feature common to some anti-HIV agents. [reaction: see text]     

Directed ortho metalation approach to C-7-substituted indoles. Suzuki-Miyaura cross coupling and the synthesis of pyrrolophenanthridone alkaloids

[reaction: see text] Although the indole N-phosphinoyl derivative 4 undergoes n-BuLi deprotonation/electrophile quench to afford C-7-substituted products, its deprotection requires harsh conditions. On the other hand, the N-amide 12, upon sequential or one-pot C-2 metalation, silylation, C-7 metalation, and electrophile treatment, furnishes indoles 7 in good overall yields. In combination with the Suzuki-Miyaura protocol, C-7 aryl (heteroaryl)-substituted indoles 14 and 16 are obtained, including hippadine and pratosine, members of the pyrrolophenanthridone alkaloid family.     

Synthesis of the C-1-C-28 ABCD unit of spongistatin 1

The synthesis of the C-1-C-28 ABCD fragment of spongistatin is described. Anti-selective boron-mediated aldol coupling of a CD spiroketal ketone fragment to an AB spiroketal aldehyde unit forms the desired C1-C28 advanced intermediate. Other features include the double conjugate addition of a dithiol to an ynone to generate the key beta-keto-dithiane unit required for the synthesis of the AB spiroketal fragment. [reaction: see text]     

Intramolecular Mannich reaction in the asymmetric synthesis of polysubstituted piperidines: concise synthesis of the dendrobate alkaloid (+)-241D and its C-4 epimer

[reaction: see text] The intramolecular Mannich reaction of delta-amino beta-keto esters with aldehydes and ketones is a new methodology for the synthesis of polysubstituted piperidines and is illustrated by the concise asymmetric synthesis of the dendrobate alkaloid (+)-241D and its C-4 epimer.     

Design and synthesis of C-2 substituted chiral imidazolium ionic liquids from amino acid derivatives

[reaction: see text] A series of novel chiral ionic liquids (CILs) has been synthesized and fully characterized. The reaction of 1-methyl-2-imidazolecarboxaldehyde and chiral amino alcohols followed by reduction is key to the design of these new CILs. This is the first time that CILs have been synthesized by introducing chiral scaffolds on the C-2 position of the imidazolium cation of ILs. The simple and straightforward procedure resulted in CILs as colorless oils at room temperature in good yields.     

Synthesis of C-2 Unsubstituted Furanonaphthoquinones

Four C-2 unsubstituted naphtho[2,3-b]furan-4,9-quinones were prepared via the corresponding phthalides obtained by directed ortho-metalation-based route.     

Alpha-hydroxylation at C-15 and C-16 in cholesterol: synthesis of (25R)-5alpha-cholesta-3beta,15alpha,26-triol and (25R)-5alpha-cholesta-3beta,16alpha,26-triol from diosgenin

[reaction: see text] (25R)-5alpha-cholesta-3beta,16alpha,26-triol 7b and (25R)-5alpha-cholesta-3beta,15alpha,26-triol 10b were synthesized, via (25R)-5alpha-cholesta-3beta,16beta,26-triol 5a, from diosgenin 3 in 52% yield over six steps and 47% yield over eight steps, respectively. An efficient method for inversion of a C-16beta hydroxyl to the C-16alpha position and a short method for transposition of a C-16beta hydroxyl to the C-15alpha position via the unexpected beta-reduction of a C-15 ketone in a steroid are reported.     

Mechanism of C-2 hydroxylation during the biosynthesis of 20-hydroxyecdysone in Ajuga hairy roots

Feeding synthetic [2beta-2H]- and [2alpha-2H]-cholesterols to the hairy roots of Ajuga reptans var. atropurpurea and 2H-NMR analysis of the biosynthesized 20-hydroxyecdysone revealed that hydroxylation at C-2 proceeds with retention of configuration. Feeding [2alpha,3alpha-2H2]cholesterol followed by 2H-NMR analysis of the 2,3,22-triacetate of the resulting 20-hydroxyecdysone ruled out a mechanism which involves a partial loss of the 2alpha-hydrogen. The steric course of C-2 hydroxylation in Ajuga hairy roots is identical with that reported in the insect, Schistocerca gregaria.     

1H and 13C NMR spectra of C-6 and C-9 substituted 3-azabicyclco[3.3.1]nonanes

The 1H and 13C NMR data for 3-azabicyclo[3.3.1]nonanes with OH and OMe substituents at C-6 and C-9 were measured using 1D (DEPT) and 2D (COSY, HSQC, HMBC, NOESY) experiments. Comparison of this NMR data illustrates the effects of stereochemistry and substitution at these positions.     

Ring-closing alkyne metathesis approach toward the synthesis of alkyne mimics of thioether A-, B-, C-, and DE-ring systems of the lantibiotic nisin Z

[reaction: see text] Ring-closing alkyne metathesis toward the synthesis of the alkyne-brigded A-, B-, C-, and (D)E-ring mimics of the peptide antibiotic nisin Z is described. We have successfully synthesized alkyne-bridged cyclic peptides containing 4-7 amino acid residues in yields ranging from 18 to 82%.