Total synthesis of (–)-carbovir

Jones, Martin; Myers, Peter L.; Robertson, C. A.; Storer, Richard; Williamson, Christopher

doi:10.1039/p19910002479

Cited by 31 publications

(19 citation statements)

References 14 publications

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“…Alternative synthetic strategies in solution have used 3-keto-acid esters or O,O-isopropylidene protected 3-keto-acid esters. 3 These acylating agents, however, required more drastic reaction conditions in our solid phase synthesis and gave less satisfactory results as compared to acylated Meldrum's acids.…”

Section: Methodsmentioning

confidence: 97%

“…Racemisation of 3-acyltetramic acids in a corresponding liquid phase synthesis has been already described to depend on the cyclization reaction time. 3,10 Our solid phase synthesis procedure gave a 65/35 ratio of the corresponding enantiomers of 6a. 11 Work is currently in progress that should allow for the synthesis of enantiomerically pure 3-acyltetramic acids.…”

Section: Methodsmentioning

confidence: 99%

“…Similarly, using reaction conditions as described 5 with aldehyde, trimethyl orthoformate, acetic acid and NaCNBH 3 gave only a reaction yield of 46% for 3a. Other reducing reagents, like NaBH 4 or Na(OAc) 3 BH that were claimed 6 to be especially useful for the reduction of azomethines in solution phase, were found to be inferior.…”

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confidence: 97%

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Solid Phase Synthesis of 3-Acyltetramic Acids

Weber¹,

Iaiza²,

Biringer³

et al. 1998

Synlett

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We report a solid-phase synthesis of 3-acyltetramic acids that are components of naturally occurring antibiotics. The products were obtained in satisfactory purity by a novel cyclization-cleavage strategy via a Dieckmann condensation.Combinatorial chemistry started with the sequential synthesis of peptide libraries on solid support and is now being applied towards the synthesis of catalysts, polymers, drug-like molecules and very recently towards more complex natural products like epothilones. 1 The elaboration of combinatorial synthesis methods for various classes of interesting organic backbone structures as e.g. natural products represents a challenge for modern organic chemistry in the pharmaceutical industry. Whereas natural product chemistry has typically concentrated on the most efficient synthesis of one particular compound in the past, combinatorial chemistry aims rather at the simultaneous synthesis of structurally related compounds -compound libraries. Ideally, such new combinatorial synthetic procedures should be amenable towards parallel or split-mix automated robotics synthesis. We present here a facile, solid-phase synthesis that illustrates the above mentioned approach for the synthesis of 3-acyltetramic acids.3-Acyltetramic acids are substructures observed in several natural products that exhibit antibiotic activities. 2 A range of solution phase synthetic strategies have been reported. 2,3 A novel synthesis and purification method for tetramic acid derivatives has been published recently that takes advantage of the acidic nature of tetramic acids by using cationic ion exchanger resins to adsorb and release the final products selectively. 4 Our synthetic strategy is an extension of the published results and allows to generate combinatorial libraries of 3-acyltetramic acid derivatives using a solid phase support. The compounds are obtained in high purity and tedious purification of reaction intermediates or end products that may occur in several tautomeric forms and tend to form complexes or salts with metals and bases, respectively, is not necessary.The synthesis starts with Fmoc-protected amino acids that are linked via an ester bond to a high-loading hydroxymethyl polystyrene resin. After standard deprotection, the free amine 1 is reacted with aldehydes to give the corresponding azomethines 2. The progress of the reaction is easily monitored on beads by ATR-IR following the disappearance of free NH 2 groups. To achieve complete conversion for a broad range of aliphatic and aromatic aldehydes this condensation step had to be repeated. Subsequent acid catalyzed reduction with sodium cyanoborohydride in DMF gave the reductive alkylation products 3. This reduction step had to be carried out twice in order to achieve almost quantitative conversion as revealed by attenuated total reflection infrared spectroscopy of single resin beads (ATR-IR) by the disappearance of the C=N absorption at 1640 cm -1 . Attempts to perform the reductive N-alkylation in a single step using e.g. NaCNBH 3 , aldehyde and Mg...

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Section: Methodsmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

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Solid Phase Synthesis of 3-Acyltetramic Acids

Weber¹,

Iaiza²,

Biringer³

et al. 1998

Synlett

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show abstract

“…1 Naturally occurring CNs-aristeromycin (1) 2 and neplanocin A (2) 3 served as an inspiration for the design and synthesis of many unnatural analogs. 4 Some of these, entecavir (3), 5 carbovir (4), 6 abacavir (5), 7 and ticagrelor (6), 8 have found application as drugs (Fig. 1).…”

Section: Introductionmentioning

confidence: 98%

Synthesis of an all-cis intermediate of ticagrelor

Włodarczyk¹,

Wolan

Rakowiecki³

et al. 2015

Tetrahedron Letters

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“…Compound 4 was prepared by epoxide-opened reaction with Obenzylguanine. [6] After acetylating hydroxyl and amino groups, 5 was obtained. Compound 6 was synthesized by removal of the p-methoxybenzyl group of 5 with DDQ.…”

Section: Introductionmentioning

confidence: 99%