Synthesis of Glycaro‐1,5‐lactams and Tetrahydrotetrazolopyridine‐5‐carboxylates: Inhibitors of β‐D‐Glucuronidase and α‐L‐Iduronidase

The known glucaro‐1,5‐lactam 8 , its diastereoisomers 9 – 11 , and the tetrahydrotetrazolopyridine‐5‐carboxylates 12 – 14 were synthesised as potential inhibitors of β‐D ‐glucuronidases and α‐L ‐iduronidases. The known 2,3‐di‐O‐benzyl‐4,6‐O‐benzylidene‐D ‐galactose ( 16 ) was transformed into the D ‐galactaro‐ and L ‐altraro‐1,5‐lactams 9 and 11 via the galactono‐1,5‐lactam 21 in twelve steps and in an overall yield of 13 and 2%, respectively. A divergent strategy, starting from the known tartaric anhydride 41 , led to the D ‐glucaro‐1,5‐lactam 8 , D ‐galactaro‐1,5‐lactam 9 , L ‐idaro‐1,5‐lactam 10 , and L ‐altraro‐1,5‐lactam 11 in ten steps and in an overall yield of 4–20%. The anhydride 41 was transformed into the L ‐threuronate 46 . Olefination of 46 to the (E)‐ or (Z)‐alkene 47 or 48 followed by reagent‐ or substrate‐controlled dihydroxylation, lactonisation, azidation, reduction, and deprotection led to the lactams 8 – 11 . The tetrazoles 12 – 14 were prepared in an overall yield of 61–81% from the lactams 54, 28 , and 67 , respectively, by treatment with Tf₂O and NaN₃, followed by saponification, esterification, and hydrogenolysis. The lactams 8 – 11 and 40 and the tetrazoles 12 – 14 are medium‐to‐strong inhibitors of β‐D ‐glucuronidase from bovine liver. Only the L ‐ido‐configured lactam 10 (K_i = 94 μM ) and the tetrazole 14 (K_i = 1.3 mM ) inhibit human α‐L ‐iduronidase.     

Controlled helical orientation of carbazole in amino acid derived poly(N‐propargylamide)s

Novel L ‐alanine and L ‐glutamic acid derivatized, carbazole‐containing N‐propargylamides [N‐(9‐carbazolyl)ethyloxycarbonyl‐L ‐alanine N′‐propargylamide and N‐(9‐carbazolyl)ethyloxycarbonyl‐L ‐glutamic acid‐γ‐benzyl ester N′‐propargylamide] were synthesized and polymerized with (nbd)Rh⁺[η⁶‐C₆H₅B^?(C₆H₅)₃] (nbd = norbornadiene) as a catalyst to obtain the corresponding polymers with moderate molecular weights in high yields. Polarimetry, circular dichroism, and ultraviolet–visible spectroscopy studies revealed that both poly[N‐(9‐carbazolyl)ethyloxycarbonyl‐L ‐alanine N′‐propargylamide] and poly[N‐(9‐carbazolyl)ethyloxycarbonyl‐L ‐glutamic acid‐γ‐benzyl ester N′‐propargylamide] took a helical structure with a predominantly one‐handed screw sense in tetrahydrofuran, CHCl₃, and CH₂Cl₂. The helix content of poly[N‐(9‐carbazolyl)ethyloxycarbonyl‐L ‐alanine N′‐propargylamide] could be tuned by heat or the addition of a protic solvent, and the helical sense of poly[N‐(9‐carbazolyl) ethyloxycarbonyl‐L ‐glutamic acid‐γ‐benzyl ester N′‐propargylamide] was inverted by heat in CHCl₃ or in mixtures of tetrahydrofuran and CH₂Cl₂. Poly[N‐(9‐carbazolyl) ethyloxycarbonyl‐L ‐alanine N′‐propargylamide] and poly[N‐(9‐carbazolyl)ethyloxycarbonyl‐L ‐glutamic acid‐γ‐benzyl ester N′‐propargylamide] also took a helical structure in film states. They showed small fluorescence in comparison with the monomers and redox activity based on carbazole. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 253–261, 2007     

Methyl 2‐acetamido‐2‐deoxy‐β‐d‐glucopyranoside dihydrate and methyl 2‐formamido‐2‐deoxy‐β‐d‐glucopyranoside

Methyl 2‐acetamido‐2‐deoxy‐β‐d ‐glucopyranoside (β‐GlcNAcOCH₃), (I), crystallizes from water as a dihydrate, C₉H₁₇NO₆·H₂O, containing two independent molecules [denoted (IA) and (IB)] in the asymmetric unit, whereas the crystal structure of methyl 2‐formamido‐2‐deoxy‐β‐d ‐glucopyranoside (β‐GlcNFmOCH₃), (II), C₈H₁₅NO₆, also obtained from water, is devoid of solvent water molecules. The two molecules of (I) assume distorted ⁴C₁ chair conformations. Values of ϕ for (IA) and (IB) indicate ring distortions towards B_C2,C5 and ^C3,O5B, respectively. By comparison, (II) shows considerably more ring distortion than molecules (IA) and (IB), despite the less bulky N‐acyl side chain. Distortion towards B_C2,C5 was observed for (II), similar to the findings for (IA). The amide bond conformation in each of (IA), (IB) and (II) is trans, and the conformation about the C—N bond is anti (C—H is approximately anti to N—H), although the conformation about the latter bond within this group varies by ∼16°. The conformation of the exocyclic hydroxymethyl group was found to be gt in each of (IA), (IB) and (II). Comparison of the X‐ray structures of (I) and (II) with those of other GlcNAc mono‐ and disaccharides shows that GlcNAc aldohexopyranosyl rings can be distorted over a wide range of geometries in the solid state.     

Efficient Synthesis of 1,2,3,4,6‐Penta‐O‐acetyl‐L‐idopyranose

An efficient synthesis of 1,2,3,4,6‐penta‐O‐acetyl‐L ‐idopyranose 2 from 3,5‐O‐benzylidene‐1,2‐O‐isopropylidene‐α‐D ‐glucofuranose in five steps in 45% overall yield via hydroboration of enol ether, hydrolysis of L ‐idofuranosyl sugar and acetolysis of 1,6‐anhydro‐β‐L ‐idopyranose as key steps is described here.     

Synthesis and Evaluation as Glycosidase Inhibitors of Isoquinuclidines Mimicking a Distorted β‐Mannopyranoside

Racemic and enantiomerically pure manno‐configured isoquinuclidines were synthesized and tested as glycosidase inhibitors. The racemic key isoquinuclidine intermediate was prepared in high yield by a cycloaddition (tandem Michael addition/aldolisation) of the 3‐hydroxy‐1‐tosyl‐pyridone 10 to methyl acrylate, and transformed to the racemic N‐benzyl manno‐isoquinuclidine 2 and the N‐unsubstituted manno‐isoquinuclidine 3 (twelve steps; ca. 11% from 10 ). Catalysis by quinine of the analogous cycloaddition of 10 to (?)‐8‐phenylmenthyl acrylate provided a single diastereoisomer in high yield, which was transformed to the desired enantiomerically pure D ‐manno‐isoquinuclidines (+)‐ 2 and (+)‐ 3 (twelve steps; 23% from 10 ). The enantiomers (?)‐ 2 and (?)‐ 3 were prepared by using a quinidine‐promoted cycloaddition of 10 to the enantiomeric (+)‐8‐phenylmenthyl acrylate. The N‐benzyl D ‐manno‐isoquinuclidine (+)‐ 2 is a selective and slow inhibitor of snail β‐mannosidase. Its inhibition strength and type depends on the pH (at pH 4.5: K_i=1.0 μM , mixed type, α=1.9; at pH 5.5: K_i=0.63 μM , mixed type, α=17). The N‐unsubstituted D ‐manno‐isoquinuclidine (+)‐ 3 is a poor inhibitor. Its inhibition strength and type also depend on the pH (at pH 4.5: K_i=1.2?10³ μM , mixed type, α=1.1; at pH 5.5: K_i=0.25?10³ μM , mixed type, α=11). The enantiomeric N‐benzyl L ‐manno‐isoquinuclidine (?)‐ 2 is a good inhibitor of snail β‐mannosidase, albeit noncompetitive (at pH 4.5: K_i=69 μM ). The N‐unsubstituted isoquinuclidine (?)‐ 2 is a poor inhibitor (at pH 4.5: IC₅₀=7.3?10³ μM ). A comparison of the inhibition by the pure manno‐isoquinuclidines (+)‐ 2 and (+)‐ 3 , (+)‐ 2 /(?)‐ 2 1 : 1, and (+)‐ 3 /(?)‐ 3 1 : 1 with the published data for racemic 2 and 3 led to a rectification of the published data. The inhibition of snail β‐mannosidase by the isoquinuclidines 2 and 3 suggests that the hydrolysis of β‐D ‐mannopyranosides by snail β‐mannosidase proceeds via a distorted conformer, in agreement with the principle of stereoelectronic control.     

Synthesis and chiral recognition properties of poly(N‐propargylamide) gels derived from ornithine and lysine

Copolymerization of ornithine‐ and lysine‐derived N‐propargylamides, N‐α‐tert‐butoxycarbonyl‐N‐δ‐fluorenylmethoxycarbonyl‐L ‐ornithine N′‐propargylamide ( 1 ), N‐α‐tert‐butoxycarbonyl‐N‐ε‐fluorenylmethoxycarbonyl‐L ‐lysine N′‐propargylamide ( 2 ), N‐α‐fluorenylmethoxycarbonyl‐N‐δ‐tert‐butoxycarbonyl‐L ‐ornithine N′‐propargylamide ( 3 ), and N‐α‐fluorenylmethoxycarbonyl‐N‐ε‐tert‐butoxycarbonyl‐L ‐lysine N′‐propargylamide (4) with dipropargyl adipate was carried out using (nbd)Rh⁺[η⁶‐C₆H₅B^?(C₆H₅)₃] as a catalyst in THF to obtain polymer gels in 80–93% yields. The gels adsorbed N‐benzyloxycarbonyl L ‐alanine, N‐benzyloxycarbonyl L ‐alanine methyl ester, and (S)‐(+)‐1‐phenyl‐1,2‐ethanediol preferably than the corresponding optical isomers. The order of chiral discrimination was poly( 1 ) > poly( 4 ) > poly( 2 ), poly( 3 ) gels. The fluorenylmethoxycarbonyl groups of the gels could be partly removed by piperidine treatment, leading to increase of adsorptivity but decrease of chiral recognition ability. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 4175–4182, 2008     

15N Chemically Induced Dynamic Nuclear Polarization (15N‐CIDNP) Investigations of the Peroxynitrite Decay and Nitration of N‐Acetyl‐L‐tyrosine

During the decay of (¹⁵N)peroxynitrite (O?¹⁵NOO ^? ) in the presence of N‐acetyl‐L ‐tyrosine (Tyrac) in neutral solution and at 268 K, the ¹⁵N‐NMR signals of ¹⁵NO and ¹⁵NO show emission (E) and enhanced absorption (A) as it has already been observed by Butler and co‐workers in the presence of L ‐tyrosine (Tyr). The effects are built up in radical pairs [CO , ¹⁵NO ]^S formed by O? O bond scission of the (¹⁵N)peroxynitrite? CO₂ adduct (O?¹⁵NO? OCO ). In the absence of Tyrac and Tyr, the peroxynitrite decay rate is enhanced, and ¹⁵N‐CIDNP does not occur. This is explained by a chain reaction during the peroxynitrite decay involving N₂O₃ and radicals NO ^. and NO . The interpretation is supported by ¹⁵N‐CIDNP observed with (¹⁵N)peroxynitrite generated in situ during reaction of H₂O₂ with N‐acetyl‐N‐(¹⁵N)nitroso‐dl ‐tryptophan ((¹⁵N)NANT) at 298 K and pH 7.5. In the presence of Na¹⁵NO₂ at pH 7.5 and in acidic solution, ¹⁵N‐CIDNP appears in the nitration products of Tyrac, 1‐(¹⁵N)nitro‐N‐acetyl‐L ‐tyrosine (1‐¹⁵NO₂‐Tyrac) and 3‐(¹⁵N)nitro‐N‐acetyl‐L ‐tyrosine (3‐¹⁵NO₂‐Tyrac). The effects are built up in radical pairs [Tyrac ^. , ¹⁵NO ]^F formed by encounters of independently generated radicals Tyrac ^. and ¹⁵NO . Quantitative ¹⁵N‐CIDNP studies show that nitrogen dioxide dependent reactions are the main if not the only pathways for yielding both nitrate and nitrated products.     

Stereoselective Synthesis of [5‐[4,4,4,4′,4′,4′‐Hexafluoro‐N‐(2‐hydroxyethoxy)‐D‐valine]]‐ and [5‐[4,4,4,4′,4′,4′‐Hexafluoro‐N‐(2‐hydroxyethoxy)‐L‐valine]cyclosporin A

Addition of various amines to the 3,3‐bis(trifluoromethyl)acrylamides 10a and 10b gave the tripeptides 11a – 11f , mostly as mixtures of epimers (Scheme 3). The crystalline tripeptide 11f ₂ was found to be the N‐terminal (2‐hydroxyethoxy)‐substituted (R,S,S)‐ester HOCH₂CH₂O‐D ‐Val(F₆)‐MeLeu‐Ala‐O^tBu by X‐ray crystallography. The C‐terminal‐protected tripeptide 11f ₂ was condensed with the N‐terminus octapeptide 2b to the depsipeptide 12a which was thermally rearranged to the undecapeptide 13a (Scheme 4). The condensation of the epimeric tripeptide 11f ₁ with the octapeptide 2b gave the undecapeptide 13b directly. The undecapeptides 13a and 13b were fully deprotected and cyclized to the [5‐[4,4,4,4′,4′,4′‐hexafluoro‐N‐(2‐hydroxyethoxy)‐D ‐valine]]‐ and [5‐[4,4,4,4′,4′,4′‐hexafluoro‐N‐(2‐hydroxyethoxy)‐L ‐valine]]cyclosporins 14a and 14b , respectively (Scheme 5). Rate differences observed for the thermal rearrangements of 12a to 13a and of 12b to 13b are discussed.     

New saponins from Sechium mexicanum

The chemical study of Sechium mexicanum roots led to the isolation of the two new saponins {3‐O‐β‐D ‐glucopyranosyl (1 → 3)‐β‐D ‐glucopyranosyl‐2β,3β,16α,23‐tetrahydroxyolean‐12‐en‐28‐oic acid 28‐O‐α‐L ‐rhamnopyranosyl‐(1 → 3)‐β‐D ‐xylopyranosyl‐(1 → 4)‐α‐L ‐rhamnopyranosyl‐(1 → 2)‐α‐L ‐arabinopyranoside} (1) and {3‐O‐β‐D ‐glucopyranosyl (1 → 3)‐β‐D ‐glucopyranosyl‐2β,3β,16α,23‐tetrahydroxyolean‐12‐en‐28‐oic acid 28‐O‐α‐L ‐rhamnopyranosyl‐(1 → 3)‐β‐D ‐xylopyranosyl‐(1 → 4)‐[β‐D ‐apiosyl‐(1 → 3)]‐α‐L ‐rhamnopyranosyl‐(1 → 2)‐α‐L ‐arabinopyranoside} (2), together with the known compounds {3‐O‐β‐D ‐glucopyranosyl‐(1 → 3)‐β‐D ‐glucopyranosyl‐2β,3β,6β,16α,23‐pentahydroxyolean‐12‐en‐28‐oic acid 28‐O‐α‐L ‐rhamnopyranosyl‐(1 → 3)‐β‐D ‐xylopyranosyl‐(1 → 4)‐α‐L ‐rhamnopyranosyl‐(1 → 2)‐α‐L ‐arabinopyranoside} (3), tacacosides A₁ (4) and B₃ (5). The structures of saponins 1 and 2 were elucidated using a combination of ¹H and ¹³C 1D‐NMR, COSY, TOCSY, gHMBC and gHSQC 2D‐NMR, and FABMS of the natural compounds and their peracetylated derivates, as well as by chemical degradation. Compounds 1–3 are the first examples of saponins containing polygalacic and 16‐hydroxyprotobasic acids found in the genus Sechium, while 4 and 5, which had been characterized partially by NMR, are now characterized in detail. Copyright © 2009 John Wiley & Sons, Ltd.     

An Efficient Synthesis of 3′‐Amino‐3′‐deoxyguanosine from Guanosine

3′‐Amino‐3′‐deoxyguanosine was synthesized from guanosine in eight steps and 58% overall yield. The 2′,3′‐diol of 5′‐O‐[(tert‐butyl)diphenylsilyl]‐2‐N‐[(dimethylamino)methylidene]guanosine was reacted with α‐acetoxyisobutyryl bromide and treated with 0.5n NH₃ in MeOH to yield 9‐{2′‐O‐acetyl‐3′‐bromo‐5′‐O‐[(tert‐butyl)diphenylsilyl]‐3′‐deoxy‐β‐D ‐xylofuranosyl]‐2‐N‐[(dimethylamino)methylidene]guanine, which was reacted with benzyl isocyanate, NaH, and then 3.0n NaOH, and finally with Pd/C (10%) and HCO₂NH₄ in EtOH/AcOH to afford 3′‐amino‐3′‐deoxyguanosine.     

Simple Synthesis of Ruthenium π Complexes of Aromatic Amino Acids and Small Peptides

The interaction of [Ru(η⁶‐C₁₀H₈)(Cp)]⁺ (Cp=C₅H₅) with aromatic amino acids (L ‐phenylalanine, L ‐tyrosine, L ‐tryptophane, D ‐phenylglycine, and L ‐threo‐3‐phenylserine) under visible‐light irradiation gives the corresponding [Ru(η⁶‐amino acid)(Cp)]⁺ complexes in near‐quantitative yield. The reaction proceeds in air at room temperature in water and tolerates the presence of non‐aromatic amino acids (except those which are sulfur containing), monosaccharides, and nucleotides. The complex [Ru(η⁶‐C₁₀H₈)(Cp)]⁺ was also used for selective labeling of Tyr and Phe residues of small peptides, namely, angiotensin I and II derivatives.     

Acylated Triterpene Saponins from Atroxima liberica Stapf

The four new acylated triterpene saponins 1 – 4 , isolated as two pairs of isomers and named libericosides A₁/A₂ and B₁/B₂, one pair of isomers 5 / 6 , the (Z)‐isomer libericoside C₂ ( 5 ) being new, one new sucrose ester, atroximoside ( 7 ), and eight known compounds were isolated from the roots of Atroxima liberica by repeated MPLC and VLC on normal and reversed‐phase silica gel. Their structures were elucidated on the basis of extensive 1D‐ and 2D‐NMR studies (¹H‐ and ¹³C‐NMR, DEPT, COSY, TOCSY, NOESY, HSQC, and HMBC) and mass spectrometry as 3‐O‐β‐D ‐glucopyranosylpresenegenin 28‐{O‐α‐L ‐arabinopyranosyl‐(1→3)‐O‐β‐D ‐xylopyranosyl‐(1→4)‐O‐α‐L ‐rhamnopyranosyl‐(1→2)‐4‐O‐[(E)‐3,4‐dimethoxycinnamoyl]‐β‐D ‐fucopyranosyl} ester ( 1 ) and its (Z)‐isomer 2 , 3‐O‐β‐D ‐glucopyranosylpresenegenin 28‐{O‐α‐L ‐arabinopyranosyl‐(1→4)‐O‐β‐D ‐xylopyranosyl‐(1→4)‐O‐α‐L ‐rhamnopyranosyl‐(1→2)‐O‐[O‐β‐D ‐xylopyranosyl‐(1→3)‐β‐D ‐glucopyranosyl‐(1→3)]‐4‐O‐[(E)‐3,4‐dimethoxycinnamoyl]‐β‐D ‐fucopyranosyl} ester ( 3 ) and its (Z)‐isomer 4 , 3‐O‐β‐D ‐glucopyranosylpresenegenin 28‐{O‐β‐D ‐xylopyranosyl‐(1→4)‐O‐α‐L ‐rhamnopyranosyl‐(1→2)‐O‐[6‐O‐acetyl‐β‐D ‐glucopyranosyl‐(1→3)]‐4‐O‐[(Z)‐3,4‐dimethoxycinnamoyl]‐β‐D ‐fucopyranosyl} ester ( 5 ), and 3‐O‐[(Z)‐feruloyl]‐β‐D ‐fructofuranosyl α‐D ‐glucopyranoside ( 7 ). Compounds 1 – 6 and the known saponins 8 / 9 were evaluated against the human colon cancer cells HCT 116 and HT‐29 and showed moderate to weak cytotoxicity.     

New Acylated Saponins from Polygala myrtifolia

The ten new acylated presenegenin (=(2β,3β,4α)‐2,3,27‐trihydroxyolean‐12‐ene‐23,28‐dioic acid) glycosides 1 – 10 have been isolated by successive MPLC from the roots of Polygala myrtifolia L. as five inseparable mixtures of the trans‐ and cis‐4‐methoxycinnamoyl derivatives, i.e., myrtifoliosides A₁/A₂ ( 1 / 2 ), B₁/B₂ ( 3 / 4 ), C₁/C₂ ( 5 / 6 ), D₁/D₂ ( 7 / 8 ), and E₁/E₂ ( 9 / 10 ). Their structures were elucidated mainly by extensive spectroscopic experiments, including 2D NMR techniques, as 3‐O‐(β‐D ‐glucopyranosyl)presenegenin 28‐{O‐β‐D ‐galactopyranosyl‐(1→3)‐O‐β‐D ‐xylopyranosyl‐(1→4)‐O‐[D ‐apio‐β‐D ‐furanosyl‐(1→3)]‐O‐α‐L ‐rhamnopyranosyl‐(1→2)‐O‐[α‐L ‐arabinopyranosyl‐(1→3)]‐4‐O‐(trans‐4‐methoxycinnamoyl)‐β‐D ‐fucopyranosyl} ester ( 1 ) and its cis‐isomer 2 , 3‐O‐(β‐D ‐glucopyranosyl)presenegenin 28‐{O‐β‐D ‐galactopyranosyl‐(1→3)‐O‐β‐D ‐xylopyranosyl‐(1→4)‐O‐[D ‐apio‐β‐D ‐furanosyl‐(1→3)]‐α‐L ‐rhamnopyranosyl‐(1→2)‐4‐O‐(trans‐4‐methoxycinnamoyl)‐β‐D ‐fucopyranosyl} ester ( 3 ) and its cis‐isomer 4 , 3‐O‐(β‐D ‐glucopyranosyl)presenegenin 28‐{O‐β‐D ‐galactopyranosyl‐(1→3)‐O‐β‐D ‐xylopyranosyl‐(1→4)‐O‐α‐L ‐rhamnopyranosyl‐(1→2)‐4‐O‐(trans‐4‐methoxycinnamoyl)‐β‐D ‐fucopyranosyl} ester ( 5 ) and its cis‐isomer 6 , 3‐O‐(β‐D ‐glucopyranosyl)presenegenin 28‐{O‐D ‐apio‐β‐D ‐furanosyl‐(1→3)‐O‐[β‐D ‐xylopyranosyl‐(1→4)]‐O‐α‐L ‐rhamnopyranosyl‐(1→2)‐4‐O‐(trans‐4‐methoxycinnamoyl)‐β‐D ‐fucopyranosyl} ester ( 7 ) and its cis‐isomer 8 , and 3‐O‐(β‐D ‐glucopyranosyl)presenegenin 28‐{O‐α‐L ‐arabinopyranosyl‐(1→3)‐O‐[β‐D ‐xylopyranosyl‐(1→4)]‐O‐α‐L ‐rhamnopyranosyl‐(1→2)‐4‐O‐(trans‐4‐ methoxycinnamoyl)‐β‐D ‐fucopyranosyl} ester ( 9 ) and its cis‐isomer 10 .     

2‐[2‐(Pyrrolidin‐2‐yl)propan‐2‐yl]‐1H‐pyrrole and its amide derivative 1‐{2‐[2‐(1H‐pyrrol‐2‐yl)propan‐2‐yl]pyrrolidin‐1‐yl}ethanone

In the title compounds, C₁₁H₁₈N₂, (II), and C₁₃H₂₀N₂O, (III), the pyrrolidine rings have twist conformations. Compound (II) crystallizes with two independent molecules (A and B) in the asymmetric unit. The mean planes of the pyrrole and pyrrolidine rings are inclined to one another by 89.99 (11) and 89.35 (10)° in molecules A and B, respectively. In (III), the amide derivative of (II), the same dihedral angle is much smaller, at only 13.42 (10)°. In the crystal structure of (II), the individual molecules are linked via N—H...N hydrogen bonds to form inversion dimers, each with an R²₂(12) graph‐set motif. In the crystal structure of (III), the molecules are linked via N—H...O hydrogen bonds to form inversion dimers with an R²₂(16) graph‐set motif.     

1,1′‐Dimethylvanadocene α‐amino acid complexes: synthesis,characterization and antimicrobial behavior toward Escherichia coli B

Eight water‐soluble 1,1′‐dimethylvanadocene amino acid complexes have been prepared via the reaction of (MeCp)₂VCl₂ ( 2 ) with one equivalent of amino acid (aa) in water affording [(MeCp)₂V( aa )]Cl, where aa is glycine ( 3 ), L ‐alanine ( 4 ), L ‐valine ( 5 ), L ‐leucine ( 6 ), L ‐isoleucine ( 7 ), L ‐phenylalanine ( 8 ), L ‐histidine ( 9 ) and L ‐tryptophane ( 10 ). All prepared complexes have been characterized by EPR, IR and Raman spectroscopy, elemental analysis and mass spectrometry. Molecular structures of [(MeCp)₂V(ala)]BPh₄·CH₃OH ( 11 ), [(MeCp)₂V(leu)]PF₆ ( 12 ) and [(MeCp)₂V(ile)]PF₆ ( 13 ) were determined by X‐ray diffraction analysis. Cytotoxic properties of complexes 2–10 were investigated toward Escherichia coli B and compared with analogical unsubstituted vanadocene compounds ( 1, 14–21 ). The results showed that 1,1′‐dimethylvanadocene amino acid complexes have identical or slightly higher antiproliferative activity then their unsubstituted analogs. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis and Conformational Analysis of 1′‐ and 3′‐Substituted 2‐Deoxy‐2‐fluoro‐D‐ribofuranosyl Nucleosides

Convergent syntheses of the 9‐(3‐X‐2,3‐dideoxy‐2‐fluoro‐β‐D ‐ribofuranosyl)adenines 5 (X=N₃) and 7 (X=NH₂), as well as of their respective α‐anomers 6 and 8 , are described, using methyl 2‐azido‐5‐O‐benzoyl‐2,3‐dideoxy‐2‐fluoro‐β‐D ‐ribofuranoside ( 4 ) as glycosylating agent. Methyl 5‐O‐benzoyl‐2,3‐dideoxy‐2,3‐difluoro‐β‐D ‐ribofuranoside ( 12 ) was prepared starting from two precursors, and coupled with silylated N⁶‐benzoyladenine to afford, after deprotection, 2′,3′‐dideoxy‐2′,3′‐difluoroadenosine ( 13 ). Condensation of 1‐O‐acetyl‐3,5‐di‐O‐benzoyl‐2‐deoxy‐2‐fluoro‐β‐D ‐ribofuranose ( 14 ) with silylated N²‐palmitoylguanine gave, after chromatographic separation and deacylation, the N⁷‐β‐anomer 17 as the main product, along with 2′‐deoxy‐2′‐fluoroguanosine ( 15 ) and its N⁹‐α‐anomer 16 in a ratio of ca. 42 : 24 : 10. An in‐depth conformational analysis of a number of 2,3‐dideoxy‐2‐fluoro‐3‐X‐D ‐ribofuranosides (X=F, N₃, NH₂, H) as well as of purine and pyrimidine 2‐deoxy‐2‐fluoro‐D ‐ribofuranosyl nucleosides was performed using the PSEUROT (version 6.3) software in combination with NMR studies.     

Heterospirocyclic N‐(2H‐Azirin‐3‐yl)‐L‐prolinates: New Dipeptide Synthons

The synthesis of methyl N‐(1‐aza‐6‐oxaspiro[2.5]oct‐1‐en‐2‐yl)‐L ‐prolinate ( 1e ) has been performed by consecutive treatment of methyl N‐[(tetrahydro‐2H‐pyran‐4‐yl)thiocarbonyl]‐L ‐prolinate ( 5 ) with COCl₂, 1,4‐diazabicyclo[2.2.2]octane (DABCO), and NaN₃ (Scheme 1). As the first example of a novel class of dipeptide synthons, 1e has been shown to undergo the expected reactions with carboxylic acids and thioacids (Scheme 2). The successful preparation of the nonapeptide 16 , which is an analogue of the C‐terminal nonapeptide of the antibiotic Trichovirin I 1B, proved that 1e can be used in peptide synthesis as a dipeptide building block (Scheme 3). The structure of 7 has been established by X‐ray crystal‐structure analysis (Figs. 1 and 2).     

Mechanistic Investigation of Phenylalanine Ammonia Lyase by Using N‐Methylated Phenylalanines

N‐Methyl‐L ‐phenylalanine ( 5 ), N‐methyl‐4‐nitro‐L ‐phenylalanine ( 6 ), and N,N‐dimethyl‐4‐nitro‐L ‐phenylalanine ( 7 ?H⁺) were investigated as substrates or inhibitors of phenylalanine ammonia lyase from Petroselinum crispum. Whereas the former was a reluctant substrate (K_m =6.6 mM , k_cat =0.22 s^?1), no reverse reaction could be detected by using methylamine and (E)‐cinnamate ( 2 ). The K_m value for ammonia in the reverse reaction by using (E)‐cinnamate ( 2 ) was determined to be 4.4 and 2.6M at pH 8.8 and 10, respectively. The N‐methylated 4‐nitro‐L ‐phenylalanines 6 and 7 showed only strong inhibitory effects (K_i =130 nM and 8 nM , resp.). These and former results are discussed in terms of the mechanism of action of phenyalalanine and histidine ammonia lyases.     

Synthesis and ring‐opening (co)polymerization of L‐lysine N‐carboxyanhydrides containing labile side‐chain protective groups

This contribution describes the synthesis and ring‐opening (co)polymerization of several L ‐lysine N‐carboxyanhydrides (NCAs) that contain labile protective groups at the ?‐NH₂ position. Four of the following L ‐lysine NCAs were investigated: N^?‐trifluoroacetyl‐L ‐lysine N‐carboxyanhydride, N^?‐(tert‐butoxycarbonyl)‐L ‐lysine N‐carboxyanhydride, N^?‐(9‐fluorenylmethoxycarbonyl)‐L ‐lysine N‐carboxyanhydride, and N^?‐(6‐nitroveratryloxycarbonyl)‐L ‐lysine N‐carboxyanhydride. In contrast to the harsh conditions that are required for acidolysis of benzyl carbamate moieties, which are usually used to protect the ?‐NH₂ position of L ‐lysine during NCA polymerization, the protective groups of the L ‐lysine NCAs presented here can be removed under mildly acidic or basic conditions or by photolysis. As a consequence, these monomers may allow access to novel peptide hybrid materials that cannot be prepared from ?‐benzyloxycarbonyl‐L ‐lysine N‐carboxyanhydride (Z‐Lys NCA) because of side reactions that accompany the removal of the Z groups. By copolymerization of these L ‐lysine NCAs with labile protective groups, either with each other or with γ‐benzyl‐L ‐glutamate N‐carboxyanhydride or Z‐Lys NCA, orthogonally side‐chain‐protected copolypeptides with number‐average degrees of polymerization ≤20 were obtained. Such copolypeptides, which contain different side‐chain protective groups that can be removed independently, are interesting for the synthesis of complex polypeptide architectures or can be used as scaffolds for the preparation of synthetic antigens or protein mimetics. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 1167–1187, 2003     

Total Synthesis and Absolute Configuration of Epicoccamide D,a Naturally Occurring Mannosylated 3‐Acyltetramic Acid

The endofungal metabolite epicoccamide D was synthesised in eighteen steps and 17 % yield as the first member of the family of natural glycotetramic acids. The modular character of the synthesis opens access also to analogues featuring different sugars and spacers. It comprises several high‐yielding key steps. The β‐D ‐mannosyl group was introduced by using an α‐D ‐glucosyl imidate donor with subsequent oxidative‐reductive epimerisation at C‐2′. The pyrrolidine ring was closed quantitatively by a Lacey‐Dieckmann condensation of an N‐(β‐ketoacyl)‐N‐methyl alaninate. The resulting 3‐[ω‐(β‐D ‐mannosyl)octadec‐2‐enoyl]tetramic acid was hydrogenated in the presence of the rhodium catalyst (R,R)‐[Rh(Et‐DUPHOS)][BF₄] to establish the (7S)‐stereocentre. This was possible only after blocking the acyltetramic acid as a BF₂‐chelate to prevent capture of the metal catalyst. We also assigned the hitherto unknown configuration of the natural product as being 5S,7S by comparison of its ¹³C NMR spectroscopic and optical rotation data with those of our two synthetic 5S,7R/S‐diasteromers.