Diastereoselective synthesis of all stereoisomers of beta-methoxytyrosine,a component of papuamides

beta-Methoxytyrosine (beta-OMeTyr) is a stereoundefined component of papuamides A and B, novel cyclodepsipeptides, with anti-HIV and cytotoxic activities. For structural determination and total synthesis of papuamides, all stereoisomers of beta-OMeTyr were stereoselectively prepared from (S)- and (R)-serine, respectively.     

Synthesis and Analysis of the Sterically Constrained L-Glutamine Analogues (3S,4R)-3,4-Dimethyl-l-glutamine and (3S,4R)-3,4-Dimethyl-l-Pyroglutamic Acid

The nonproteinogenic amino acids (3S,4R)-3,4-Dimethyl-l-pyroglutamic acid and (3S,4R)-3,4-dimethyl-l-glutamine -- found in the cyclic depsipeptides callipeltin B, callipeltin A, and papuamide A -- were synthesized from a common intermediate derived from l-pyroglutamic acid. The diastereoselective introduction of the methyl groups was accomplished by cuprate addition and enolate alkylation, followed by a kinetic epimerization of the C-4 methyl substituent. (3S,4R)-3,4-dimethyl-l-glutamine shows a conformational restriction of its side chain which may be related to its biological function in the natural products where it is found.     

Solid-phase total synthesis and structure proof of callipeltin B

The cytotoxic, cyclic heptadepsipeptide, natural product callipeltin B was synthesized on a solid-phase support in 15% overall yield. Comparison of the 1H NMR spectra of three synthetic isomers with those of callipeltin B confirmed the configurational reassignment of its threonine residues as d-allothreonine and the assignment of the configuration of its beta-methoxytyrosine residue as (2R,3R).     

Progress toward the total synthesis of callipeltin A (I): asymmetric synthesis of (3S,4R)-3,4-dimethylglutamine

[reaction:see text] During the total synthesis of the novel cyclic depsipeptide callipeltin A (1), the unit (3S,4R)-3,4-dimethylglutamine, was successfully synthesized by asymmetric Michael addition and subsequent electrophilic azidation. The key feature of this approach is the generation of three adjacent stereogenic centers using the same camphorsultam chiral auxiliary.     

Asymmetric synthesis of four diastereomers of 3-hydroxy-2,4,6-trimethylheptanoic acid: proof of configurational assignment

Four unique diastereomers of 3-hydroxy-2,4,6-trimethylheptanoic acid--(2R,3R,4R), (2S,3R,4R), (2S,3R,4S), and (2R,3R,4S)--the fatty acid component of callipeltin A and D, have been synthesized from commercially available (+)- and (-)-pseudoephedrine propionamide in 6 steps and 59% average overall yield. Comparison of the 1H and 13C NMR and optical rotation data of the resulting isomers with the natural fragment unambiguously verifies the configurational assignment of the natural isomer as (2R,3R,4R).     

Solid-phase synthesis of callipeltin D. Stereochemical confirmation of the unnatural amino acid AGDHE

[structure: see text] The lipopeptide callipeltin D (1) was synthesized using an Fmoc-based solid-phase strategy in seven steps and 35% overall yield. The 1H NMR of synthetic 1 correlated closely with that of the natural product, confirming the configurational assignment of the novel amino acid constituent (2R,3R,4S)-4-amino-7-guanidino-2,3-dihydroxyheptanoic acid.     

Stereoselective synthesis of (3S,4R)-3,4-dimethyl-(S)-glutamine and the absolute stereochemistry of the natural product from papuamides and callipeltin

(3S,4R)-3,4-Dimethyl-(S)-glutamine, a common component of cyclodepsipeptides, papuamide A and callipeltin A, was stereoselectively prepared from (S)-pyroglutamic acid. The stereostructure of natural dimethylglutamine was unambiguously confirmed to be (2S,3S,4R) by comparison of the CD and NMR spectra of the synthetic 3,4-dimethylpyroglutamic acid with the hydrolysate of callipeltin A.     

Solid-phase synthesis and configurational reassigment of callipeltin E. Implications for the structures of callipeltins A and B

Two possible isomers of the natural product callipeltin E (1, 5) were synthesized by using an Fmoc-based solid-phase strategy in 7 steps, in 20% and 26% overall yields, respectively. The (1)H NMR spectrum of synthetic 5 correlated closely with that of the natural product, whereas that of 1 did not, providing confirmation of the configurational reassignment of the N-terminal residue of callipeltin E as D-allothreonine. This result strongly implies that the corresponding residue in the closely related cyclic depsipeptides callipeltins A and B should also be considered a D-allothreonine residue.     

Solid phase total synthesis of callipeltin E isolated from marine sponge Latrunculia sp.

Solid phase total synthesis of callipeltin E (1), truncated linear peptide isolated from marine sponge, Latrunculia sp. was achieved. Our strategy based on traditional Fmoc-SPPS was in common use TFA-treatment final deprotection to reach callipeltin E (1) contained acid-sensitive βMeOTyr.     

Synthesis of fully protected (2R,3R,4S)-4-amino-7-guanidino-2,3-dihydroxy heptanoic acid

(2R,3R,4S)-4-Amino-7-guanidino-2,3-dihydroxyheptanoic acid (AGDHE), a common constituent of biologically active marine peptides, callipeltin A (1) and neamphamide A, was synthesized as its orthogonally protected derivative from l-glutamic acid in 15 steps. Guanidination by the Mitsunobu condition and osmium-catalyzed dihydroxylation of the corresponding Z-olefin were employed as the key steps.     

Chiron approach to callipeltin A: first synthesis of fully protected (2R,3R,4S)-4,7-diamino-2,3-dihydroxy heptanoic acid

Stereoselective synthesis of protected (2R,3R,4S)-4,7-diamino-2,3-dihydroxy heptanoic acid, which is present as a side chain attached to the main macrocyclic depsidecapeptide backbone of callipeltin A (a potent, cytotoxic, anti-HIV and anti-fungal agent) starting from a carbohydrate, is described.     

Preparation of (2R, 3R, 4R)-3-hydroxy-2,4,6-trimethylheptanoic acid via enzymatic desymmertization

Synthesis of a unique fatty acyl unit to build the N-terminus of callipeltin A and homophymine B is described. Our approach to access (2R, 3R, 4R)-3-hydroxy-2,4,6-trimethylheptanoic acid uses enzymatic hydrolysis for the desymmetrization of achiral acetate, followed by diastereoselective Roush crotylboration and Wittig olefination for the backbone construction.     

Stellatolide H,a cytotoxic peptide lactone from a deep-sea sponge Discodermia sp.

Stellatolide H (1) was isolated from a deep-sea sponge Discodermia sp. as the cytotoxic constituent. The planar structure of 1 was elucidated on the basis of the NMR spectroscopic and mass spectrometric data. The absolute configurations of the constituent amino acid residues were determined by the Marfey’s method. Stellatolide H (1) is a peptide lactone of the callipeltin class with its N-terminus blocked by 3-hydroxy-6,8-dimethyldeca-(4Z,6E)-dienoic acid (Hdda).     

罗汉松科植物中化学成分的研究:I.竹柏中的抗肿瘤成分

从罗汉松科植物竹柏(Podocarpus nagi(thunb.)Zoll.ct Mor.ex Zoll.)种子中分得七种成分。根据理化性质、波谱数据及化学反应鉴定为竹柏内酯A(1)、1-去氧-2α-羟基竹柏内酯A(3)、竹柏内酯苷A(4)、柳杉酚(5)、β-谷甾醇及蔗糖, 其中4是新化合物, 5是首次从该植物中分得。生物试验表明, 二萜双内酯化合物1-3具有较强的细胞毒作用, 4 无效。对2及3进行了结构改造, 提示了它们的构效关系。     

Pulsed ELDOR spectroscopy measures the distance between the two tyrosyl dadicals in the R2 subunit of the E. coli ribonucleotide reductase

Escherichia coli ribonucleotide reductase (RNR) catalyzes the conversion of nucleoside diphosphates (NDPs) to deoxynucleoside diphosphates (dNDPs). This RNR is composed of two homodimeric subunits: R1 and R2. R1 binds the NDPs in the active site, and R2 harbors the essential di-iron tyrosyl radical (Y*) cofactor. In this paper, we used PELDOR, a method that detects weak electron-electron dipolar coupling, to make the first direct measurement of the distance between the two Y*'s on each monomer of R2. In the crystal structure of R2, the Y*'s are reduced to tyrosines, and consequently R2 is inactive. In R2, where the Y*'s assume a well-defined geometry with respect to the protein backbone, the PELDOR method allows measurement of a distance of 33.1 +/- 0.2 A that compares favorably to the distance (32.4 A) between the center of mass of the spin density distribution of each Y* on each R2 monomer from the structure. The experiments provide the first direct experimental evidence for two Y*'s in a single R2 in solution.     

An Efficient Bidirectional Approach to the C(2)-Symmetric Stereoisomers of the Bistetrahydrofuran Core of the Acetogenins

A bidirectional route to nonracemic C(2)-symmetric bistetrahydrofuran units related to acetogenin natural products was developed starting from the (S,S)-tartrate-derived dialdehyde 3.3. Bis-homologation with the (R)-alpha-OMOM crotylstannane (R)-4.1 in the presence of InCl(3) afforded the anti adduct, diol 4.3. The derived tosylate 4.4, upon treatment with TBAF in THF, underwent sequential TBS cleavage and cyclization to the (R,R,R,R,R,R)-bis-OMOM bistetrahydrofuran 4.7. The epimeric (S,R,R,R,R,S)-bis-OMOM bistetrahydrofuran 4.10 was prepared along similar lines, except that the (R)-alpha-OMOM crotylstannane (R)-4.1 was first converted to the (R)-gamma-isomer (R)-4.2 with BF(3).OEt(2). Subsequent addition of dialdehyde 3.3 led to the diol adduct 4.5, which after tosylation and treatment with TBAF, yielded the bistetrahydrofuran 4.10. By repeating the aforementioned sequences, but starting with the (S)-alpha-OMOM-crotylstannane (S)-4.1, the (S,S,R,R,S,S)- and the (R,S,R,R,S,R)-bistetrahydrofurans 5.5 and 5.8 were prepared. A variation on the foregoing sequence in which the OTBS grouping of the adduct was converted to a mesylate and the OH group was used to effect intramolecular displacement was also examined. Accordingly, adduct ent-5.3 from BF(3)-promoted addition of stannane (R)-4.2 and ent-3.3, the enantiomer of aldehyde 3.3, was acetylated. Cleavage of the TBS ether followed by mesylate formation and then concommitant acetate hydrolysis and cyclization with methanolic Triton B yielded the bis-OMOM bistetrahydrofuran 5.5. An analogous sequence was used to convert adduct 4.3 to ent-4.10. In this case, acetate saponification was effected with methanolic K(2)CO(3), and the resulting diol, 7.4, was cyclized with NaH in THF.     

A serendipitous synthesis of (+)-gregatin B, second structure revisions of the aspertetronins, gregatins, and graminin A, structure revision of the penicilliols

A (DHQN)(2)AQN-promoted asymmetric dihydroxylation (92% ee) of the allyl chloride derived from enynol (E)-13 and an 8-step sequence provided access to the hydroxyethylated furanone (R)-21. Oxidation with MnO(2) furnished 50% furanone (+)-(R)-2a and 2.7% isomeric furanone (+)-(R)-3a. (R)-2a possesses the accepted constitution of (+)-gregatin B but its spectra are different. Surprisingly, (+)-(R)-3a equals the natural product. Analogous structure reassignments are due for the gregatins A and C-E, the aspertetronins A-B, graminin A, and the penicilliols A and B.     

Arg-72 of pharaonis phoborhodopsin (sensory rhodopsin II) is important for the maintenance of the protein structure in the solubilized states

In bacteriorhodopsin (bR), Arg-82bR has been proven to be a very important residue for functional role of this light-driven proton pump. The arginine residue at this position is a super-conserved residue among archaeal rhodopsins. pharaonis phoborhodopsin (ppR; or called as "pharaonis sensory rhodopsin II") has its absorption maximum at 498 nm and acts as a sensor in the membrane of Natronobacterium pharaonis, mediating the negative phototaxis from the light of wavelength shorter than 520 nm. To investigate the role of the arginine residue (Arg-72ppR) of ppR corresponding to Arg-82bR, mutants whose Arg-72ppR was replaced by alanine (R72A), lysine (R72K), glutamine (R72Q) and serine (R72S) were prepared. These mutants were unstable in low concentrations of NaCl and lost their color gradually when the proteins were solubilized with 0.1% n-dodecyl-beta-D-maltoside. The order of instability was R72S > R72A > R72K > R72Q > the wild type. The rates of denaturation were reduced in a solution of high concentrations of monovalent anions.     

Highly potent chiral labeling reagents for the discrimination of chiral alcohols.

Highly sensitive chiral labeling reagents, (1R,2R)- and (1S,2S)-2-(2,3-anthracenedicarboximido)cyclohexanecarboxylic acids [(1R,2R)- and (1S,2S)-A] and (1R,2R)- and (1S,2S)-2-(2,3-naphthalenedicarboximido)cyclohexanecarboxylic acids [(1R,2R)- and (1S,2S)-A'], were prepared. Reagent A has enabled us to discriminate the enantiomers of anteiso fatty alcohols up to C9 methyl branching by 1H NMR, and both reagents A and A' have allowed up to C16 methyl branching at the 10(-15) molar level by fluorescence detected reversed-phase HPLC.     

Interconversion of the cis-5R,6S- and trans-5R,6R-thymine glycol lesions in duplex DNA

Thymine glycol (Tg), 5,6-dihydroxy-5,6-dihydrothymine, is formed in DNA by the reaction of thymine with reactive oxygen species. The 5R Tg lesion was incorporated site-specifically into 5'-d(G(1)T(2)G(3)C(4)G(5)Tg(6)G(7)T(8)T(9)T(10)G(11)T(12))-3'; Tg = 5R Tg. The Tg-modified oligodeoxynucleotide was annealed with either 5'-d(A(13)C(14)A(15)A(16)A(17)C(18)A(19)C(20)G(21)C(22)A(23)C(24))-3', forming the Tg(6) x A(19) base pair, corresponding to the oxidative damage of thymine in DNA, or 5'-d(A(13)C(14)A(15)A(16)A(17)C(18)G(19)C(20)G(21)C(22)A(23)C(24))-3', forming the mismatched Tg(6) x G(19) base pair, corresponding to the formation of Tg following oxidative damage and deamination of 5-methylcytosine in DNA. At 30 degrees C, the equilibrium ratio of cis-5R,6S:trans-5R,6R epimers was 7:3 for the duplex containing the Tg(6) x A (19) base pair. In contrast, for the duplex containing the Tg(6) x G(19) base pair, the cis-5R,6S:trans-5R,6R equilibrium favored the cis-5R,6S epimer; the level of the trans-5R,6R epimer remained below the level of detection by NMR. The data suggested that Tg disrupted hydrogen bonding interactions, either when placed opposite to A(19) or G(19). Thermodynamic measurements indicated a 13 degrees C reduction of T(m) regardless of whether Tg was placed opposite dG or dA in the complementary strand. Although both pairings increased the free energy of melting by 3 kcal/mol, the melting of the Tg x G pair was more enthalpically favored than was the melting of the Tg x A pair. The observation that the position of the equilibrium between the cis-5R,6S and trans-5R,6R thymine glycol epimers in duplex DNA was affected by the identity of the complementary base extends upon observations that this equilibrium modulates the base excision repair of Tg [Ocampo-Hafalla, M. T.; Altamirano, A.; Basu, A. K.; Chan, M. K.; Ocampo, J. E.; Cummings, A., Jr.; Boorstein, R. J.; Cunningham, R. P.; Teebor, G. W. DNA Repair (Amst) 2006, 5, 444-454].