Stereocontrolled total synthesis of (-)-callipeltoside A

[structure: see text] A highly stereocontrolled total synthesis of the cytotoxic macrolide (-)-callipeltoside A has been achieved in 23 steps (4.8% overall). Notable features include a novel asymmetric vinylogous aldol reaction to install the C13 stereocenter and (E)-trisubstituted alkene, an anti-selective aldol addition, a Sonogashira coupling, and, last, a Schmidt-type glycosylation to attach the sugar unit.     

Towards Stereoselective Synthesis of the C(31)–C(39) and C(20)–C(27) Fragments of Phorboxazole A

The stereoselective synthesis of the C(31)–C(39) and C(20)–C(27) fragments of phorboxazole A ( 1 ) was achieved from commercially available and inexpensive D ‐mannitol. Crimmins aldol reaction and a decarboxylative Claisen‐type reaction are the key steps for the C(31)–C(39) fragment, and L ‐proline‐catalyzed aldol reaction, Sharpless asymmetric epoxidation, and epoxide ring opening reaction with Gilman's reagent are the key steps for the C(20)–C(27) fragment of phorboxazole.     

A ribozyme for the aldol reaction

Directed in vitro evolution can create RNA catalysts for a variety of organic reactions, supporting the "RNA world" hypothesis, which proposes that metabolic transformations in early life were catalyzed by RNA molecules rather than proteins. Among the most fundamental carbon-carbon bond-forming reactions in nature is the aldol reaction, mainly catalyzed by aldolases that utilize either an enamine mechanism (class I) or a Zn(2+) cofactor (class II). We report on isolation of a Zn(2+)-dependent ribozyme that catalyzes an aldol reaction at its own modified 5' end with a 4300-fold rate enhancement over the uncatalyzed background reaction. The ribozyme can also act as an intermolecular catalyst that transfers a biotinylated benzaldehyde derivative to the aldol donor substrate, coupled to an external hexameric RNA oligonucleotide, supporting the existence of RNA-originated biosynthetic pathways for metabolic sugar precursors and other biomolecules.     

Measurement of five dipolar couplings from a single 3D NMR multiplet applied to the study of RNA dynamics

A new three-dimensional NMR experiment is described that yields five scalar or dipolar couplings from a single cross-peak between three spins. The method is based on the E.COSY principle and is demonstrated for the H1'-C1'-C2' fragment of ribose sugars in a uniformly 13C-enriched 24-nucleotide RNA stem-loop structure, for which a complete set of couplings was obtained for all nonmodified nucleotides. The values of the isotropic J couplings and the 13C1' and 13C2' chemical shifts define the sugar pucker. Once the sugar pucker is known, the five dipolar couplings between C1'-H1', C2'-H2', H1'-H2', C1'-H2', and C2'-H1', together with C1'-C2', C3'-H3', and C4'-H4' available from standard experiments, can be used to derive the five unknowns that define the local alignment tensor, thereby simultaneously providing information on relative orientation and dynamics of the ribose units. Data indicate rather uniform alignment for all stem nucleotides in the 24-nt stem-loop structure, with only a modest reduction in order for the terminal basepair, but significantly increased mobility in part of the loop region. The method is applicable to proteins, nucleic acids, and carbohydrates, provided 13C enrichment is available.     

Isotope Probing of the UDP‐Apiose/UDP‐Xylose Synthase Reaction: Evidence of a Mechanism via a Coupled Oxidation and Aldol Cleavage

The C‐branched sugar d ‐apiose (Api) is essential for plant cell‐wall development. An enzyme‐catalyzed decarboxylation/pyranoside ring‐contraction reaction leads from UDP‐α‐d ‐glucuronic acid (UDP‐GlcA) to the Api precursor UDP‐α‐d ‐apiose (UDP‐Api). We examined the mechanism of UDP‐Api/UDP‐α‐d ‐xylose synthase (UAXS) with site‐selectively ²H‐labeled and deoxygenated substrates. The analogue UDP‐2‐deoxy‐GlcA, which prevents C‐2/C‐3 aldol cleavage as the plausible initiating step of pyranoside‐to‐furanoside conversion, did not give the corresponding Api product. Kinetic isotope effects (KIEs) support an UAXS mechanism in which substrate oxidation by enzyme‐NAD⁺ and retro‐aldol sugar ring‐opening occur coupled in a single rate‐limiting step leading to decarboxylation. Rearrangement and ring‐contracting aldol addition in an open‐chain intermediate then give the UDP‐Api aldehyde, which is intercepted via reduction by enzyme‐NADH.     

Synthesis of the C15-C35 northern hemisphere subunit of the chivosazoles

An advanced C15-C35 subunit of the chivosazole polyene macrolides was prepared in a convergent manner, exploiting boron-mediated aldol reactions for the stereocontrolled construction of the C15-C26 and C27-C35 segments, followed by their Pd/Cu-promoted Stille coupling to configure the signature (23E,25E,27Z)-triene motif. Correlation with a known C28-C35 degradation fragment of chivosazole A was also achieved.     

Synthesis of C3' modified nucleosides for selective generation of the C3'-deoxy-3'-thymidinyl radical: a proposed intermediate in LEE induced DNA damage

DNA damage pathways induced by low-energy electrons (LEEs) are believed to involve the formation of 2-deoxyribose radicals. These radicals, formed at the C3' and C5' positions of nucleotides, are the result of cleavage of the C-O phosphodiester bond through transfer of LEEs to the phosphate group of DNA oligomers from the nucleobases. A considerable amount of information has been obtained to illuminate the identity of the unmodified oligonucleotide products formed through this process. There exists, however, a paucity of information as to the nature of the modified lesions formed from degradation of these sugar radicals. To determine the identity of the damage products formed via the 2',3'-dideoxy-C3'-thymidinyl radical (C3'(dephos) sugar radical), phenyl selenide and acyl modified sugar and nucleoside derivatives have been synthesized, and their suitability as photochemical precursors of the radical of interest has been evaluated. Upon photochemical activation of C3'-derivatized nucleosides in the presence of the hydrogen atom donor tributyltin hydride, 2',3'-dideoxythymidine is formed indicating the selective generation of the C3'(dephos) sugar radical. These precursors will make the identification and quantification of products of DNA damage derived from radicals generated by LEEs possible.     

Studies directed towards the synthesis of antascomicin A: stereoselective synthesis of the C22-C34 fragment of the molecule

A stereoselective synthesis of the C22-C34 fragment of the non-immunosuppressive immunophilin-binding natural product, antascomicin A was achieved using d-quinic acid as the starting material and highly stereoselective aldol reactions were employed, as key steps, to build the remaining stereocentres at C23, C26 and C27.     

Synthesis of the C1-C21 (C1'-C21') fragment of the dimeric polyketide natural product SCH 351448

[structure: see text] A convergent, stereoselective assembly of the C1-C21 (C1'-C21') fragment of SCH 351448, a 28-membered bis-lactone natural product, has been developed. A highly efficient approach to this fragment assembles 75% of the carbon skeleton and all the stereochemical elements present in the natural product. In addition, an interesting boron ligand effect on the diastereoselectivity of a key aldol reaction with methyl ketone-derived enolborinates is reported.     

Synthesis and confirmation of the absolute stereochemistry of the (-)-aflastatin A C9-C27 degradation polyol

[reaction: see text]. The C(8)-C(18) ethyl ketone and C(19)-C(28) aldehyde aflastatin A fragments were synthesized and coupled using a diastereoselective anti aldol reaction. This adduct was successfully converted into the C(9)-C(27) polyol degradation product of (-)-aflastatin A to confirm the relative and absolute stereochemistry of this region of the natural product.     

A highly stereoselective samarium diiodide-promoted aldol reaction with 1'-phenylseleno-2'-keto nucleosides. Synthesis of 1'alpha-branched uridine derivatives

Since 1'-branched nucleosides are biologically important targets in medicinal chemistry, more efficient methods for preparing them are required. The 1'alpha-branched uridine derivatives were successfully synthesized via a samarium diiodide (SmI(2))-promoted aldol reaction. Treatment of the 1'alpha-phenylseleno-2'-ketouridine derivative 6, readily prepared from uridine, with SmI(2) at -78 degrees C in THF reductively cleaved the anomeric Se-C bond to generate the corresponding samarium enolate, which was highly stereoselectively condensed with aldehydes, such as PhCHO, MeCHO, i-PrCHO, or (CH(2)O)(n)(), to give the corresponding 1'alpha-1' 'S-branched products 12a-d. This is the first time an enolate has been generated by reductively cleaving a C-Se bond. The highly selective stereochemical results suggest that the aldol reaction proceeds via a chelation-controlled transition state. When an excess of aldehyde was used and the reaction mixture was gradually warmed, the tandem aldol-Tishchenko reaction proceeded to give the "arabino-type" nucleosides 14a-c, having a 2'-"up" hydroxyl and 1'alpha-1' 'S-branched chain. 1'alpha-Hydroxymethyluridine (21), which is the uracil version of the antitumor antibiotic angustmycin C, was synthesized from the aldol reaction product 10.     

Development of a Simple Adjustable Zinc Acid/Base Hybrid Catalyst for C−C and C−O Bond‐Forming and C−C Bond‐Cleavage Reactions

A newly designed zinc Lewis acid/base hybrid catalyst was developed. By adjusting the Lewis acidity of the zinc center, aldol‐type additions of 2‐picolylamine Schiff base to aldehydes proceeded smoothly to afford syn‐aldol adduct equivalents, trans‐N,O‐acetal adducts, in high yields with high selectivities. NMR experiments, including microchanneled cell for synthesis monitoring (MICCS) NMR analysis, revealed that anti‐aldol adducts were formed at the initial stage of the reactions under kinetic control, but the final products were the trans‐(syn)‐N,O‐acetal adducts that were produced through a retro‐aldol process under thermodynamic control. In the whole reaction process, the zinc catalyst played three important roles: i) promotion of the aldol process (C?C bond formation), ii) cyclization process to the N,O‐acetal product (C?O bond formation), and iii) retro‐aldol process from the anti‐aldol adduct to the syn‐aldol adduct (C?C bond cleavage and C?C bond formation).     

Formation of sugar radicals in RNA model systems and oligomers via excitation of guanine cation radical

In previous work, we have shown that photoexcitation of guanine cation radical (G*+) in frozen aqueous solutions of DNA and its model compounds at 143 K results in the formation of neutral sugar radicals with substantial yield. In this report, we present electron spin resonance (ESR) and theoretical (DFT) evidence regarding the formation of sugar radicals after photoexcitation of guanine cation radical (G*+) in frozen aqueous solutions of one-electron-oxidized RNA model compounds (nucleosides, nucleotides and oligomers) at 143 K. Specific sugar radicals C5'*, C3'* and C1'* were identified employing derivatives of Guo deuterated at specific sites in the sugar moiety, namely, C1'-, C2'-, C3'- and C5'-. These results suggest C2'* is not formed upon photoexcitation of G*+ in one-electron-oxidized Guo and deuterated Guo derivatives. Phosphate substitution at C5'- (i.e., in 5-GMP) hinders formation of C5'* via photoexcitation at 143 K but not at 77 K. For the RNA-oligomers studied, we observe on photoexcitation of oligomer-G*+ the formation of mainly C1'* and an unidentified radical with a ca. 28 G doublet. The hyperfine coupling constants of each of the possible sugar radicals were calculated employing the DFT B3LYP/6-31G* approach for comparison to experiment. This work shows that formation of specific neutral sugar radicals occurs via photoexcitation of guanine cation radical (G*+) in RNA systems but not by photoexcitation of its N1 deprotonated species (G(-H)*). Thus, our mechanism regarding neutral sugar formation via photoexcitation of base cation radicals in DNA appears to be valid for RNA systems as well.     

Syntheses of cystothiazole A and its stereoisomers: importance of stereochemistry for antifungal activity

The enantiocontrolled total syntheses of all the stereoisomers of a myxobacterial antibiotic, cystothiazole A, are described. The natural syn stereochemistry at the C4-C5 position was controlled by the asymmetric Evans aldol process, whereas the anti relationship was introduced by a modified Evans aldol methodology. Starting with a known aldehyde, the common substrate of the aldol reactions, cystothiazole A and its three stereoisomers were synthesized in 9 steps. All three stereoisomers did not show antifungal activity even at a dosage 2500-fold that of cystothiazole A.     

Synthesis of a pladienolide B analogue with the fully functionalized core structure

Starting from (R)-(-)-linalool (6), terminus differentiation and chain extension via aldol type reactions led to ketophosphonate 16 (C1-C8 building block). In a Horner-Wadsworth-Emmons reaction, 16 reacted with aldehyde 22, which contained the vicinal anti-Me-OH pattern and a vinyl iodide function, to provide the C1-C13 part of pladienolide B. After Shiina macrolactonization, reduction of the enone 26 gave the core structure 27. A Stille cross-coupling of vinyl iodide 27 with tributylphenylstannane eventually furnished analogue 30.     

Total synthesis of (+)-cystothiazole A

[structure: see text]. The total synthesis of cystothiazole A is described. Key steps of the synthesis include an Evans asymmetric catalytic aldol reaction, which established the required C4-C5 stereochemistry. The [2,4']-bis(thiazole) was obtained applying our methodology of electrophilic activation of amide. Semistabilized Wittig reaction between the phosphonium salt 3 and the aldehyde 2 afforded 1 in nine linear steps and 38% overall yield.     

Synthesis of bridged sugar amino acids: a new entry into conformationally locked δ- and ε-amino acids

The synthesis of three methylene bridged sugar amino acids is described. Key transformations in the synthetic strategy are a CO-insertion on fully protected ribose, an aldol condensation with formaldehyde and an oxetane forming cyclisation step. A novel Leu-enkephalin analogue containing the δ-SAA 1 was prepared using standard solution phase peptide chemistry.     

Sugar radicals formed by photoexcitation of guanine cation radical in oligonucleotides

This work presents evidence that photoexcitation of guanine cation radical (G+*) in dGpdG and DNA-oligonucleotides TGT, TGGT, TGGGT, TTGTT, TTGGTT, TTGGTTGGTT, AGA, and AGGGA in frozen glassy aqueous solutions at low temperatures leads to hole transfer to the sugar phosphate backbone and results in high yields of deoxyribose radicals. In this series of oligonucleotides, we find that G+* on photoexcitation at 143 K leads to the formation of predominantly C5'* and C1'* with small amounts of C3'*. Photoconversion yields of G+* to sugar radicals in oligonucleotides decreased as the overall chain length increased. However, for high molecular weight dsDNA (salmon testes) in frozen aqueous solutions, substantial conversion of G+* to C1'* (only) sugar radical is still found (ca. 50%). Within the cohort of sugar radicals formed, we find a relative increase in the formation of C1'* with length of the oligonucleotide, along with decreases in C3'* and C5'*. For dsDNA in frozen solutions, only the formation of C1'* is found via photoexcitation of G+*, without a significant temperature dependence (77-180 K). Long wavelength visible light (>540 nm) is observed to be about as effective as light under 540 nm for photoconversion of G+* to sugar radicals for short oligonucleotides but gradually loses effectiveness with chain length. This wavelength dependence is attributed to base-to-base hole transfer for wavelengths >540 nm. Base-to-sugar hole transfer is suggested to dominate under 540 nm. These results may have implications for a number of investigations of hole transfer through DNA in which DNA holes are subjected to continuous visible illumination.     

Role of chirality of the sugar ring in the ribosomal peptide synthesis

We present a theoretical analysis of the role of the natural chirality of the sugar ring ( D-enantiomeric form) in the peptide synthesis reaction in ribosome. The study is based on a model from the crystal structure of the ribosomal subunit of Haloarcula marismortui using hybrid quantum mechanical-molecular mechanical method. The result indicates that the natural heterochiral sugar-amino acid combination ( D: L) is most favorable for the formation of the peptide bond within the structure of peptidyl transferase center (PTC). Other possible combinations of unnatural chiral form of the sugar-amino acid pair are unfavorable to perform the reaction within the PTC. The presence of the sugar ring has favorable influence on the rotatory path. The chirality of the 2' carbon of the sugar ring is vital for the peptide synthesis. Alteration of the stereochemistry or removal of chirality at the 2' center makes the rate as several orders slower in magnitude. This is in agreement with the recent experimental result that the replacement of the 2' OH by H or F reduces the rate by several orders of magnitude. Two different mechanisms for the catalytic effect of the stereochemistry of 2' OH are investigated. In one mechanism, the 2' OH is involved in proton shuttle, and in the second mechanism, the OH group acts as an anchoring group. The transition state barriers of both mechanisms are found to be comparable. The natural chirality of the 2' center helps lowering the transition state barrier height of the reaction substantially compared with the cases where the 2' center is made achiral or with altered chirality. Thus, the stereochemistry of the 2' center has a major role in synthesis. Few surrounding residues like U2620, A2486, G2618, and C2487 have favorable influence on rotatory path, while the residues like U2541, C2104, C2105, A2485, C2542, C2608, U2619, and A2637 have little influence. The present study shows that the natural chirality of the sugar ring and amino acid makes a perfect heteropair within the PTC to carry out peptide synthesis with high efficiency.     

Total Syntheses of Daphenylline,Daphnipaxianine A,and Himalenine D

We report the total syntheses of daphenylline ( 1 ), daphnipaxianine A ( 5 ), and himalenine D ( 6 ), three Daphniphyllum alkaloids from the calyciphylline A subfamily. A pentacyclic triketone was prepared by using atom‐transfer radical cyclization and the Lu [3+2] cycloaddition as key steps. Inspired by the proposed biosynthetic relationship between 1 and another calyciphylline A type alkaloid, we developed a ring‐expansion/aromatization/aldol cascade to construct the tetrasubstituted benzene moiety of 1 . The versatile triketone intermediate was also elaborated into 5 and 6 through a C=C bond migration/aldol cyclization approach.