An efficient synthesis of the protected carbohydrate moiety of Brasilicardin A

A synthesis of the protected carbohydrate moiety 2 of Brasilicardin A starting from l-rhamnose and d-glucosamine is described. The disaccharide was synthesized using a TMSOTf-mediated glycosylation of the 2-phthalimido-2-deoxyglucose donor 5 and the 3-hydroxyl group of the protected L-rhamnose derivative 4, which already bears the 3-hydroxybenzoate unit. The imidate 2 was coupled via TMSOTf-mediated glycosidation with cholesterol as a model aglycone followed by the selective cleavage of all the acetate groups to give the Brasilicardin A analogue 16.     

Catalytic asymmetric synthesis of a nitrogen analogue of dialkyl tartrate by direct mannich reaction under phase-transfer conditions

[reaction: see text] Phase-transfer-catalyzed direct Mannich reaction of glycinate Schiff base 3 with alpha-imino ester 4 has been accomplished with high enantioselectivity by the utilization of N-spiro C(2)-symmetric chiral quaternary ammonium bromide 2 as a catalyst. This methodology enables the catalytic asymmetric synthesis of differentially protected 3-aminoaspartate, a nitrogen analogue of dialkyl tartrate. The product (syn-5) was converted into a precursor (6) of streptolidine lactam.     

Synthesis of 2′-O-α-d-ribofuranosyladenosine, monomeric unit of poly(ADP-ribose)

The first chemical synthesis of 2′-O-α-d-ribofuranosyladenosine, monomeric unit of poly(ADP-ribose), has been achieved starting from 3′,5′-O-bis protected 9-(2-O-α-d-arabinofuranosyl-β-d-ribofuranosyl)-adenine. Configurational inversion of 2′-hydroxyl group of arabinose moiety was performed by oxidation-reduction sequence.     

Enzymatic synthesis of carnosine derivatives catalysed by Burkholderia cepacia lipase

A new enzymatic synthesis of α,β-dipeptides has been developed with particular focus on the preparation of carnosine (β-alanyl-α-histidine) and analogues. The lipase PS-D from Burkholderia cepacia has been used as a catalyst for the formation of the peptide bond starting from a β-lactam and a protected α-amino acid.     

Peptides—XXXXII: Synthesis of the 76–93 fragment of a lysozyme analogue

The synthesis of the (76–93) fragment of a lysozyme analogue was achieved using a fragment condensation approach employing the protected subfragments (76–79), (80–86), and (87–93). The utility of Bates' reagent in conjunction with N-hydroxysuccinimidc was examined for the linking of fragments. The resulting protected peptide (76–93) was found to be one of the most insoluble encountered in this whole programme directed towards the synthesis of a lysozyme analogue.     

Synthesis of phosphatidyl-β-glucosyl glycerol containing a dioleoyl diglyceride moiety : Application of the tetraisopropyldisiloxane-1,3-diyl (tips) protecting group in sugar chemistry. part IV

The preparation of phosphatidyl-β-glucosyl diglyceride $\text{12c}$ is described. The synthesis of glycophospholipid $\text{12c}$ was accomplished by using: (a) the levulinoyl group for the temporary protection of the glucose hydroxyl functions of $\text{6b}$, which could then be converted into the dioleoyl substituted derivative $\text{7c}$; (b) the tetraisopropyldisiloxane-1,3-diyl (TIPS) group to protect the 3'- and 4'-hydroxyl groups of $\text{7c}$, in a two step procedure, to afford compound $\text{8}$; (c) a 2,4-dichlorophenyl protected phosphatidic acid derivative $\text{11}$. Compound $\text{11}$ could be selectively coupled to the primary hydroxyl function of $\text{8}$ to afford the fully protected glycophospholipid $\text{12a}$. Finally, removal of the 2,4-dichlorophenyl and TIPS protecting groups from $\text{12a}$ was performed with syn-4-nitrobenzaldoximate and fluoride ions, respectively, to afford glycophospholipid $\text{12c}$.     

Synthesis of conformationally constrained lysine analogues

The synthesis of two conformationally constrained lysine analogues is reported. The synthesis of the novel analogue 1 based on the 3-aza-bicyclo[3.1.0]hexane system is accomplished from the known tricycle 3 in eight steps. The synthesis of the analogue 2 is accomplished in eight steps from 4-hydroxy proline. Both analogues are synthesized appropriately protected for Fmoc/Boc solid-phase peptide synthesis.     

Studies of nucleosides and nucleotides—LXXIV: Purine cyclonucleosides—34 a new method for the synthesis of 2'-substituted 2'-deoxyadenosines

8,2'-O-Cycloadenosine was protected at 3' and 5'-OHs with acetyl groups and cleaved using liq. H₂S. Subsequent dethiolation and mesylation gave 2'-O-mesyl-3',5'-di-O-acetyl-arabinosyladenine (6). When 6 or its deacetylated parent compound (7) was heated with sodium azide in DMF, 3'-azido-3'-deoxyxylofuranosyladenine (9) was the only product. The cyclonucleoside was then protected with tetrahydropyranyl groups and subjected to a similar series of reactions as above to give 2'-O-mesyl-3',5'-di-O-tetrahydropyranylarabinosyladenine (14). The compound 14 was heated with sodium azide after which acidic deprotection afforded 2'-azido-2'-deoxyadenosine (16). Hydrogenation of 16 gave 2'-amino-2'-deoxyadenosine (18). 2'-Chloro-2'-deoxyadenosine (19) was also obtained by treatment of 14 with lithium chloride and subsequent deprotection. UV, IR and NMR spectral data of these compounds are described.     

Synthesis of (+)-patulolide C via an asymmetric hydroformylation/macrocyclization cascade

A highly atom-economical total synthesis of (+)-patulolide C has been accomplished in three steps from the known (2R)-8-nonyn-2-ol in 49% overall yield and 93% de. A Rh(I)-catalyzed asymmetric hydroformylation (AHF)/ intramolecular Wittig olefination cascade was utilized to set the C4-hydroxyl stereochemistry and E-olefin geometry as well as form the macrolactone.     

Early introduction of the amino group to the C27–C35 building block of Eribulin

A new synthetic strategy towards the C27–C35 subunit of Eribulin (1) has been devised to include a protected 1,2-amino alcohol at C34–C35. Early introduction of the C35 amino group in the synthesis of 1 increases the efficiency of the route. This new approach can be accomplished on a multi-gram scale and allows for the successful synthesis of Eribulin.     

2-O-Benzylation in D-Gluconamide Derivative Under Basic Conditions with Complete Retention of Stereo-Integrity: Convenient Access to 2-O-benzyl-3,4:5,6- di-O-isopropylidene-D-glucitol and other Differently Protected D-glucitol Derivatives

A new and convenient synthesis of 2-O-benzyl-3, 4: 5, 6-di-O-isopropylidene-D-glucitol has been accomplished and has been generalized with the syntheses of differently protected D-glucitols at C-2 position. In the course of our new route to the differently protected D-glucitols at C-2 position, a new D-gluco configured building block, 1-morpholino-(3, 4: 5, 6-di-O-isopropylidene)-D-gluconamide has been achieved.     

Stereoselective Synthesis of β-Glycinamide Ribonucleotide

A diastereoselective synthesis of the β-anomer of glycinamide ribonucleotide (β-GAR) has been developed. The synthesis was accomplished in nine steps from D-ribose and occurred in 5% overall yield. The route provided material on the multi-milligram scale. The synthetic β-GAR formed was remarkably resistant to anomerization both in solution and as a solid.     

First enantiospecific total synthesis of the antitubercular marine natural product pseudopteroxazole. Revision of assigned stereochemistry

A concise, enantiospecific synthesis of pseudopteroxazole (3), which had originally been assigned structure 1, has been accomplished starting from S-(-)-limonene. The known cyclohexanone 5 was converted in five steps to the alpha,beta-enone 8 by a modified Robinson annulation. Transformation of 8 to the orthogonally protected amino phenol 11 was accomplished by a new modification of the Wolff-Semmler rearrangement. The synthesis was completed by cationic cyclization to form 14 diastereoselectively and subsequent introduction of the terminal oxazole subunit.     

Peptides-XXXIV: Synthesis of the 1–16 fragment of a lysozyme analogue

The synthesis of the 1–16 fragment of a lysozyme analogue is described. Three protected subfragments 1-4, 5-10 and 11-16 were combined using the N, N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide method. The fully protected hexadecapeptide was purified by gel filtration on Sephadex LH-60 eluting with N-methylpyrrolidone.     

An efficient synthesis of the taxane-derived anticancer agent ABT-271

ABT-271, 1, has been identified as a promising anticancer agent. ABT-271 is a novel taxane possessing a C9-(R)-hydroxyl group as opposed to a C9-ketone which is present in Taxol and Taxotere. To further evaluate ABT-271 as a potential anticancer agent, an efficient synthesis was developed which allows the large scale synthesis of ABT-271. Ketalization of the 7,9-diol of 9-DHAB-III, 2, allows selective removal of the C13-acetate with phenyllithium. The resulting C13-hydroxyl group is then acylated using LiHMDS and beta-lactam 22 to give ABT-271 in protected form. The protecting groups were removed first by acidic hydrolysis followed by basic hydrolysis to provide ABT-271. Application of this synthetic sequence provided over 600 g of ABT-271, 1.     

New access to the synthetic building block -aspartic acid β-semialdehyde via Grignard reaction

A new, efficient, and inexpensive synthesis of protected -aspartic acid β-semialdehyde has been developed starting from -glutamic acid via a substituted -allylglycine derivative as intermediate. The key step of the reaction sequence was a strongly solvent-dependent Grignard reaction of an -glutamic acid semiester. The desired regioselective addition to the C-5 ester group was achieved in 1,2-dimethoxyethane while reactions in diethyl ether gave products resulting from additional attack at the carboxylic acid functionality.     

Synthesis of oligoribonucleotides by use of S,S-diphenyl n-monomethoxytrityl ribonucleoside 3'-phosphorodithioates

The fully protected ribonucleotide units (6a–d) have been synthesized in 42–62% overall yields by the 5- or 6-step reactions. The dimethoxtrityl, monomethoxytrityl, tetrahydropyran-2-yl, and phenylthio groups were introduced onto the 5'-OH, exo-amino, 2'-OH, and 3'-phosphoryl functions, respectively. The units were converted to the OH or phosphodiester components by treatment with trifluoroacetic acid or with phosphinic acid-triethylamine. Both the components were appropriately coupled by means of mesitylenedisulphonyl chloride 3-nitro-1,2,4-triazole to give dimers in high yields. This method was successfully applied to the synthesis of GpUpApUpUpApApUpAp, i.e. the 5'-terminal base sequence of brome mosaic virus m RNA No. 4 filament.     

Regioselective synthesis of 3-deazacarbovir and its 3-deaza-adenosine analogues

We herein report the hitherto unknown synthesis of 3-deazacarbovir and its adenosine analogue. The major highlight in the synthesis of adenosine analogs is to use 6-N,N-diboc protected 3-deazapurines 9 and 11 for regioselective Mitsunobu coupling as well as unexplored palladium catalyzed coupling with these substrates. Synthesis of 3-deazacarbovir 1 has been accomplished by the regioselective palladium catalyzed coupling of 6-N,N-diphenylcarbamoyl protected 3-deazaguanine base 18 with dicarbonate 14. All the target nucleosides were screened for anti-HIV-1 activity and none of them have significant activity as well as toxicity up to 100 μM.     

Synthesis of 2-β-D-ara- and 2-β-D-xylofuranosylthiazole-4-carboxamide

The syntheses of the heretofore unknown 2-β-D-ara and 2-β-D-xylofuranosyl isomers of the antitumor agent tiazofurin have been accomplished. In both cases the stereospecific inversion of the required 2′ or 3′-hydroxyl group in the protected parent compound afforded the desired products.     

Synthesis of the polycyclic ring systems of artocarpol A and D

The first synthesis of the polycyclic ring systems of artocarpol A and D has been accomplished. These natural products were isolated recently from the root bark of Artocarpus rigida, and artocarpol A has been shown to have potent antiinflammatory properties. The synthesis of an artocarpol D analogue was achieved on condensation of 11H-dibenzo[b,f]oxepin-10-one with senecialdehyde. The reaction of this oxepinone with citral afforded a 2H-pyran that on subsequent irradiation afforded an analogue of artocarpol A. [reaction: see text]