Synthesis of orthogonally protected cyclic homooligomers from sugar amino acids

Two new families of orthogonally protected cyclic homooligomers with two to four sugar units were synthesized from pyranoid sugar amino acids. Cyclic oligomers composed of amide-linked sugar amino acids (1-3) were prepared by cyclization of linear oligomers of the novel orthogonally protected pyranoid sugar amino acid 12 using a solution-phase coupling method. These orthogonally protected cyclic molecules can be selectively or fully deprotected, affording the macrocycles ready to further functionalization. The straightforward reduction of the amide bonds in the cyclic oligomers 1-3 gave the corresponding amine-linked macrocycles 4-6. This kind of amine-linked carbohydrate-based cyclic oligomer has never been reported before. These flexible molecular receptors could be studied as molecular hosts for molecular, cationic, and anionic recognition. Conformational analysis by molecular modeling (AM1) showed that all of the deprotected cyclic trimers and tetramers preferred a (4)C(1) chair conformation with oxygen atoms of the sugar ring located on the interior of the cavity and the secondary hydroxyl groups outward. In the amide-linked macrocycles, all of the amide bonds are in s-trans conformation. The estimated size of the internal cavity is about 4.5 A for the cyclic trimer and 6.9 A for the cyclic tetramer. The amine-linked macrocycles displayed similar conformational behavior with a slight decrease in internal cavity.     

Synthesis and structural studies of peptides containing a mannose-derived furanoid sugar amino acid

A mannose-derived furanoid sugar amino acid (Maa) induced helical turns in peptides having repeat units of Maa(Bn(2))-Phe-Leu, which aggregated into head-to-tail duplexes in the longer oligomers.     

Conformational studies of peptides containing cis-3-hydroxy-D-proline

Conformational analysis of peptides containing cis-3-hydroxy-d-proline (d-cis-3-Hyp) by NMR studies revealed that the 3-hydroxyl group in this amino acid plays a significant role in the overall three-dimensional structures of the peptides. When the d-cis-3-Hyp had its 3-hydroxyl group protected as the benzyl (Bn) ether, the peptide displayed a beta-hairpin structure in both CDCl(3) and DMSO-d(6). Even after the removal of the Bn group, the resulting deprotected compound retained the same structure as in the protected version in CDCl(3). However, in polar solvent DMSO-d(6), the C-terminal strand of the hydroxyl-deprotected peptide flipped to the side of the hydroxyl group, breaking the hairpin to form a pseudo beta-turn-like nine-membered ring structure involving an intramolecular hydrogen bond between LeuNH --> HypC3-OH.     

Synthesis and conformational studies of amide-linked cyclic homooligomers of a thymidine-based nucleoside amino acid

Cyclic homooligomers of a thymidine-based nucleoside amino acid were synthesized from the linear dimer using BOP reagent in the presence of DIPEA under dilute conditions. Conformational analysis by NMR and constrained MD studies revealed that all the cyclic products had symmetrical structures. The NH and CO groups in these molecules point in opposite directions with near perpendicular orientation with respect to the plane of the macrocyclic ring having CO on the same side as the base.     

Synthesis and conformational studies of peptidomimetics containing furanoid sugar amino acids and a sugar diacid

Furanoid sugar amino acids (1) were synthesized and used as dipeptide isosteres to induce interesting turn structures in small linear peptides. They belong to a new variety of designed hybrid structures that carry both amino and carboxyl groups on rigid furanose sugar rings. Four such molecules, 6-amino-2,5-anhydro-6-deoxy-D-gluconic acid (3, Gaa) and its mannonic (4, Maa), idonic (5, Iaa), and a 3,4-dideoxyidonic (6, ddIaa) congeners were synthesized. The synthesis followed a novel reaction path in which an intramolecular 5-exo S(N)2 opening of the hexose-derived terminal aziridine ring in 2 by the gamma-benzyloxy oxygen with concomitant debenzylation occurred during pyridinium dichromate oxidation of the primary delta-hydroxyl group to carboxyl function, leading to the formation of furanoid sugar amino acid frameworks in a single step. Incorporation of these furanoid sugar amino acids into Leu-enkephalin replacing its Gly-Gly portion gave analogues 8-11. Detailed structural analysis of these molecules by circular dichroism (CD) and various NMR techniques in combination with constrained molecular dynamics (MD) simulations revealed that two of these analogues, 8a and 10a, have folded conformations composed of an unusual nine-membered pseudo beta-turn-like structure with a strong intramolecular H-bond between LeuNH --> sugarC3-OH. This, in turn, brings the two aromatic rings of Tyr and Phe in close proximity, a prerequisite for biological activities of opioid peptides. The analgesic activities of 8a,b determined by mouse hot-plate and tail-clip methods were similar to that of Leu-enkephalin methyl ester. The syn disposition of the beta-hydroxycarboxyl motif on the sugar rings appears to be the driving force to nucleate the observed turn structures in some of these molecules (8 and 10). Repetition of the motif on both sides of a furanose ring resulted in a novel molecular design of sugar diacid, 2,5-anhydro-D-idaric acid (7, Idac). Bidirectional elongation of the diacid moieties of 7 with identical peptide strands led to the formation of a C2-symmetric reverse-turn mimetic 12 which displayed a very ordered structure consisting of identical intramolecular H-bonds at two ends between LeuNH --> sugar-OH, the same as in 8 and 10.     

Synthesis and Conformational Analysis of Cyclic Homooligomers from Pyranoid ε‐Sugar Amino Acids

New pyranoid ε‐sugar amino acids were designed as building blocks, in which the carboxylic acid and the amine groups were placed in positions C2 and C3 with respect to the tetrahydropyran oxygen atom. By using standard solution‐phase coupling procedures, cyclic homooligomers containing pyranoid ε‐sugar amino acids were synthesized. Conformation analysis was performed by using NMR spectroscopic experiments, FTIR spectroscopic studies, X‐ray analysis, and a theoretical conformation search. These studies reveal that the presence of a methoxy group in the position C4 of the pyran ring produces an important structural change in the cyclodipeptides. When the methoxy groups are present, the structure collapses through interresidue hydrogen bonds between the oxygen atoms of the pyran ring and the amide protons. However, when the cyclodipeptide lacks the methoxy groups, a U‐shape structure is adopted, in which there is a hydrophilic concave face with four oxygen atoms and two amide protons directed toward the center of the cavity. Additionally, we found important evidence of the key role played by weak electrostatic interactions, such as the five‐membered hydrogen‐bonded pseudocycles (C₅) between the amide protons and the ether oxygen atoms, in the conformation equilibrium of the macrocycles and in the cyclization step of the cyclic tetrapeptides.     

Anodic Amide Oxidation/Olefin Metathesis Strategies: Developing a Unified Approach to the Synthesis of Bicyclic Lactam Peptidomimetics

In connection with efforts to build constrained peptidomimetics for the endocrine hormone TRH, a general strategy for the construction of bicyclic lactam peptide building blocks has been developed. This strategy used an anodic amide oxidation to selectively functionalize proline and then an olefin metathesis to build the desired lactam constraint. The route described provides a single approach for synthesizing both fully functionalized TRH analogs having seven- and eight-membered ring lactam constraints, as well as six- and seven-membered ring lactam analogs without the sidechain on the central amino acid.     

Structure investigation of Maltacine C1a, C1b, C2a and C2b-cyclic peptide lactones of the Maltacine complex from Bacillus subtilis

A new complex of cyclic peptide lactone antibiotics from Bacillus subtilis, which we named Maltacines, has recently been described. The structure elucidation of four of them is reported in this paper. The amino acid sequences and structures of the peptides were found by MS(n) of the ring-opened linear peptides, which gave uninterrupted sequences of Bn and Y'n ions. The identities of three unknown residues in the sequences were solved by a combination of derivatisation with phenylisothiocyanate (PITC), high-resolution mass spectrometry and H/D exchange. The nature and position of the cyclic structure was disclosed by a chemo-selective ring opening with Na18OH and was found to be a lactone formed between a hydroxyl of residue number 4 and the C-terminal amino acid number 12. For verification of the structure of the B2+ ion, peptides with different combinations of P/Q and P/K at the N-terminus were synthesised. The structure of the four peptides were found to be: C1a and C2a: cyclo-4,12(P-Q-Y-Adip-V-E-T-Y-Orn-103-Y-I-OH) and C1b/C2b: cyclo-4,12(P-Q-Y-Adip-V-E-T-Y-K-103-Y-I-OH). Adip = aminodihydroxy pentanoic acid.     

P[N(i-Bu)CH(2)CH(2)](3)N: nonionic Lewis base for promoting the room-temperature synthesis of α,β-unsaturated esters, fluorides, ketones, and nitriles using Wadsworth-Emmons phosphonates

The bicyclic triaminophosphine P(RNCH(2)CH(2))(3)N (R = i-Bu, 1c) serves as an effective promoter for the room-temperature stereoselective synthesis of α,β-unsaturated esters, fluorides, and nitriles from a wide array of aromatic, aliphatic, heterocyclic, and cyclic aldehydes and ketones, using a range of Wadsworth-Emmons (WE) phosphonates. Among the analogues of 1c [R = Me (1a), i-Pr (1b), Bn (1d)], 1a and 1b performed well, although longer reaction times were involved, and 1d led to poorer yields than 1c. Functionalities such as cyano, chloro, bromo, methoxy, amino, ester, and nitro were well tolerated. We were able to isolate and characterize (by X-ray means; see above) the reactive WE intermediate species formed from 2b and 1c.     

Influence of "alternative" C-terminal amino acids on the formation of [b3 + 17 + Cat]+ products from metal cationized synthetic tetrapeptides

The aim of this study was to investigate the dissociation patterns, and in particular the relative abundance of [b(3) + 17 + Cat](+), for peptides with C-termini designed to allow transfer of the -OH required to generate the product ion, but not necessarily as the most favored pathway. Working with the hypothesis that formation of a five-membered ring intermediate, including intramolecular nucleophilic attack by a carbonyl oxygen atom, is an important mechanistic step, several model peptides with general sequence AcFGGX were synthesized, metal cationized by electrospray ionization and subjected to collision-induced dissociation (CID). The amino acid at position X was one that either required a larger ring intermediate (beta-alanine, gamma-aminobutyric acid and epsilon-amino-n-caproic acid to generate six-, seven- or nine- membered rings, respectively) to transfer -OH, lacked a structural element required for nucleophilic attack (aminoethanol) or prohibited cyclization because of the inclusion of a rigid ring (p- and m-aminobenzoic acid). For Ag(+), Li(+) and Na(+) cationized peptides, our results show that amino acids requiring the adoption of larger ring intermediates suppressed the formation of [b(3) + 17 + Cat](+), while amino acids that prohibit cyclization eliminated the reaction pathway completely. Formation of [b(3) - 1 + Cat](+) from the alkali metal cationized versions was not a favorable process upon suppression or elimination of the [b(3) + 17 + Cat](+) pathway: the loss of H(2)O to form [M - H(2)O + Cat](+) was instead the dominant dissociation reaction observed. Multiple-stage dissociation experiments suggest that [M - H(2)O + Cat](+) is not [b(4) - 1 + Cat](+) arising from the loss of H(2)O from the C-terminus, but may instead be a species that forms via a mechanism involving the elimination of an oxygen atom from an amide group.     

C-Glykoside der N-Acetylneuraminsäure. Synthese und Untersuchung ihrer Wirkung auf die Vibrio cholerae Sialidase

C-Glycosides of N-Acetylneuraminic Acid The synthesis of the C-glycosides 8 , 15 , and 9 of N-acetylneuraminic acid is described. Hydroxymethylation of the Li-ester enolate, derived from 5 , yielded the protected C-glycosides 7 and 10 (46%; 3:1), which were deprotected to yield 8 (54%) and 15 (51%; Scheme 2). The mesylate 16 was obtained from 7 (73%) and transformed via the azide 17 (75%) into the acid 18 (66%) and the amino acid 9 (Scheme 3). The configuration at C(2) of 17 was proved by transforming 17 into the bicyclic lactam 19 . Both 8 and 15 are very weak inhibitors of Vibrio cholerae sialidase; 9 appears to stimulate this enzyme.     

Synthetic approaches to the polycyclic alkaloid stemofoline

Preliminary studies of a synthetic approach to the alkaloid stemofoline 1 are reported. Stereoselective cyclisation of the ketoester 14 gave the 1-butyl-2,8-bis(methoxycarbonyl)-8-azabicyclo[3.2.1]octane 21 in which the 2-methoxycarbonyl group is in the axial position. The analogous ketones 15, 18, and 19 were also cyclised to give the 8-azabicyclo[3.2.1]octanes 22-24 with axial electron-withdrawing 2-substituents. The structure of the bicyclic ketosulfone 22 was confirmed by X-ray diffraction. Conversion of ester 21 into the tricyclic lactams 31 and 39, in which the amide fragments are significantly distorted from planarity, was achieved by treatment of the iodides 29 and 38 with tert-butyllithium. The structure of the deprotected tricyclic hydroxylactam 40 was confirmed by X-ray diffraction, which showed the non-planar geometry of the lactam fragment and the distortion induced into the bicyclo[3.2.1]octane by the additional two-carbon bridge. This meant that the endo hydrogen at C9 was significantly closer to the 5-hydroxyl group than the endo hydrogen at C8. This structural feature was utilised to direct a regioselective remote oxidation of the hydroxylactam 40 using lead tetraacetate, which was accompanied by selective insertion into the closer endo C-H bond to give the tetracyclic ether 41. Lactam 39 was converted into the tricyclic aminoketone 49 by reduction to the aminol 44 using lithium aluminium hydride and reduction of the intermediate, possibly the chloride 46, formed from aminol 44 using thionyl chloride, with more lithium aluminium hydride, followed by O-deprotection and oxidation. The bicyclic ketoester 21 was also protected as its ketal 50, which was taken through via the tricyclic lactam 54 into the ketoamine 49. Finally, allylation of the tricyclic lactam 42 and amine 49 gave the axial allylated products 60 and 58, but further elaboration for incorporation of C10 and C11 (of stemofoline) was not straightforward. Alkylation of the protected hydroxyketone 64, which was prepared from the bicyclic ketoester 21, gave the axial alkylated products 65 and 69, and the ketoester 69 was converted into the tricyclic hydroxylactone 73. However, the formation of a tetracyclic lactam by treatment of the iodide 75 with tert-butyllithium was not successful.     

A double alkylation—ring closing metathesis approach to spiroimines

As part of a programme directed towards the synthesis of the marine toxins, the spirolides and gymnodimine, a convenient synthesis of the key bicyclic spiroimine ring systems has been developed. The method involves double alkylation of a simple lactam, Grubbs ring closing metathesis of the resultant dialkylated lactam then reduction of the lactam to an imine.     

Structure investigation of maltacine B1a, B1b, B2a and B2b: cyclic peptide lactones of the maltacine complex from Bacillus subtilis

A new complex of cyclic peptide lactone antibiotics from Bacillus subtilis, which we named maltacines, has recently been described. The structure elucidation of four of them is reported in this paper. The amino acid sequences and structures of the peptides were found by MSn of the ring-opened linear peptides that gave uninterrupted sequences of Bn and Y'n ions. The identities of three unknown residues in the sequences were solved by a combination of derivatization with phenyl isothiocyanate (PITC), high-resolution mass spectrometry and H/D exchange. The nature and position of the cyclic structure were revealed by a chemoselective ring opening with Na18OH and was found to be a lactone formed between a hydroxyl of residue number 4 and the C-terminal amino acid number 12. For verification of the structure of the B2+ ion, peptides with different combinations of P/Q and P/K at the N-terminus were synthesized. The structures of the four peptides were found to be as follows: B1a/B2a, cyclo-4,12(P-Q-Y-HNLeu-A-E-T-Y-Orn-103-Y-I-OH); and B1b/B2b, cyclo-4,12(P-Q-Y-HNLeu-A-E-T-Y-K-103-Y-I-OH).     

Construction of an advanced tetracyclic intermediate for total synthesis of the marine alkaloid sarain A

In work directed toward a total synthesis of the marine alkaloid sarain A (1), the advanced intermediate 54, containing all the key elements and the seven stereogenic centers of sarain A, has been successfully synthesized from bicyclic lactam 4, previously prepared via an intramolecular stereospecific [3 + 2]-azomethine ylide dipolar cycloaddition. Intermediate lactam 4 could be efficiently converted to N-Boc derivative 12. Introduction of a two-carbon fragment into lactam 12 which eventually becomes the C-7',8' syn diol of the "eastern" ring was then achieved by C-acylation of the corresponding enolate with methoxyacetyl chloride followed by a highly stereoselective ketone reduction with Zn(BH4)2 to afford alcohol 16. Intermediate 16 has the incorrect C-7' relative stereochemistry for sarain A, but this problem was conveniently remedied by inverting the C-7' center via an intramolecular Ohfune-type cyclization of the silyl carbamate derived from Boc mesylate 27 to produce the key cyclic carbamate 28. It was then possible to convert acetal 28 to allylsilane 32 followed by cyclization to the alkaloid tricyclic core 33 via an allylsilane/N-sulfonyliminium ion cyclization. Formation of the "western" macrocyclic ring has been successfully addressed using functional group handles at C-3' and N-1' on the tricyclic core via a ring-closing olefin metathesis (RCM) strategy with the second-generation Grubbs ruthenium catalyst to produce intermediate macrolactam 47. A chelation-controlled addition of ethynylmagnesium bromide to advanced aldehyde 51 afforded a single diastereomeric adduct 53 which is tentatively assigned to have the correct C-7',8' syn-diol stereochemistry. This adduct could be rearranged to the conveniently protected amino carbonate 54 which is set up for construction of the remainder of the eastern ring of sarain A.     

Synthesis of an external beta-turn based on the GLDV motif of cell adhesion proteins

The (3S,6S,10S)-7/5 bicyclic lactam 8, designed as an external turn constraint, was synthesised by a new stereoselective route involving Eschenmoser condensation. The cyclic peptide 35 containing the integrin recognition motif GLDV added across the amino and carboxyl groups of the lactam external constraint 8 was prepared.     

Synthesis and NMR studies of cyclopeptides containing a sugar amino Acid

[structure: see text] Cyclopeptides containing Glucuronic acid methylamine (Gum) alternating with Gly, L-Ala, D-Ala, L-Phe, D-Phe, L-Lys, or D-Lys were synthesized by a combination of solid-phase synthesis and solution chemistry. A more effective pathway to synthesize the sugar amino acid Gum in higher yields and in a shorter period of time was developed. Gum is employed in the benzylated and deprotected form. The cyclopeptides were characterized by NMR and the structure of one deprotected cyclic peptide solved.     

Mass spectrometric investigation of Maltacines E1a and E1b--two members of the Maltacine family of peptide antibiotics

We have recently described the discovery of the Maltacines--a new family of cyclic peptide antibiotics from Bacillus subtilis. In this paper the mass spectrometric characterisation of two of the members is reported. A chemoselective ring opening with base to give the linear peptides was necessary before mass spectrometric characterisation could be performed. MS(n) of the singly and doubly charged protonated molecules gave uninterrupted series of Bn and Y'n ions that allowed determination of the amino acid sequence. By using a combination of derivatisation with phenylisothiocyanate (PITC), high-resolution mass spectrometry and H/D exchange, the identities of three unknown residues were determined. The nature and position of the cyclic structure were disclosed by a chemoselective ring opening with Na 18OH and it was found to be a lactone formed between a hydroxyl of residue number 4 and the C-terminal amino acid number 12. Peptides with different combinations of P/Q and P/K at the N-terminus were synthesised to verify the sequence of the N-terminal B2 ion. The structure of the two peptides is proposed to be: E1a: cyclo-4,12(P-Q-Y-Adip-V-E-T-Y-Orn-S-Y-I-OH) and E1b: cyclo-4,12(P-Q-Y-Adip-V-E-T-Y-K-S-Y-I-OH). Adip = (2-amino-4,5-dihydroxypentanoic acid).     

Enantioselective total synthesis and structure revision of spirodihydrobenzofuranlactam 1. Total synthesis of stachybotrylactam

[reaction: see text] The enantioselective total synthesis and structure revision of spirodihydrobenzofuranlactam 1 and of its regioisomer 25 are presented. Optically pure (+)-Wieland-Miescher ketone was utilized to construct the AB bicyclic core in 10 steps. Introduction of the resorcylate D-ring unit was achieved by use of our tert-butyl ester metalation sequence. Subsequent stereoselective spirocyclization to form the C-ring was followed by regioselective ring cyanation and lactam formation to produce the pentacyclic structure 1 and its regioisomer 25.     

Etude dans la série des pyrrolidinones: Dérivés de l'acide N-méthylol pyroglutamique; synthèse d'un nouveau système bicyclique,la dioxo-(1,5) pyrrolidino[2,1-c]oxazolidine

1-Hydroxymethyl-5-oxopyrrolidine-2-carboxylic acid and its methyl ester have been synthesized and the reactivity of their N CH₂ O H group has been studied. Depending upon the reactant, they react by breaking their N C or C O or O H bond. A new simple bicyclic system, an azlactone fused to a lactam ring, has been obtained. Some of these new molecules display antifungal properites.