The mild and selective N-debenzylation of tertiary alkylamines using β-trimethylsilylethyl chloroformate.

Campbell, Arthur L.; Pilipauskas, Daniel; Khanna, Ish; Rhodes, R. A.

doi:10.1016/s0040-4039(00)96116-1

Cited by 37 publications

(7 citation statements)

References 5 publications

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“…Initial attempts to directly demethylate the N8-position of 16 and 18 using β-(trimethylsilyl)ethyl chloroformate were unsuccessful. [22] We therefore adopted a benzyl protecting group strategy for N8. Benzylated 7-amino-1-benzylpyrimido[4,5- c ]pyridazine-4,5(1 H ,6 H )-diones 12–15 were synthesized from 6 with benzylhydrazine using a similar approach as described for 9–11 .…”

Section: Chemistrymentioning

confidence: 99%

Structure‐Based Design of Novel Pyrimido[4,5‐c]pyridazine Derivatives as Dihydropteroate Synthase Inhibitors with Increased Affinity

et al. 2012

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Dihydropteroate synthase (DHPS) is the validated drug target for sulfonamide antimicrobial therapy. However, due to widespread drug resistance and poor tolerance, the use of the sulfonamide antibiotics is now limited. The pterin binding pocket in DHPS has a high degree of conservation and is distinct from the sulfonamide binding site, and therefore represents an attractive alternative target for the design of novel antibacterial agents. Previously, we have structurally characterized a known pyridazine inhibitor in the Bacillus anthracis DHPS pterin site and identified a number of unfavorable interactions that appear to compromise the binding. Using this structural information, a series of 4,5-dioxo-1,4,5,6-tetrahydropyrimido[4,5-c]pyridazines was designed to improve binding affinity. Most importantly, the N-methyl ring substitution was removed to improve binding within the pterin pocket and the length of the side chain carboxylic acid was optimized to fully engage the pyrophosphate binding site. These inhibitors were synthesized and evaluated by an enzyme activity assay, X-ray crystallography, isothermal calorimetry, and surface plasmon resonance to obtain a comprehensive understanding of the binding interactions from structural, kinetic and thermodynamic perspectives. This study clearly demonstrates that compounds lacking the N-methyl substitution exhibit increased inhibition of DHPS, but the beneficial effects of optimizing the side chain length were less apparent.

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Section: Chemistrymentioning

confidence: 99%

Structure‐Based Design of Novel Pyrimido[4,5‐c]pyridazine Derivatives as Dihydropteroate Synthase Inhibitors with Increased Affinity

et al. 2012

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“…Indeed, when heating a suspension of cis-7 and 9 molar equivalents of LAH in THF at 60 °C for 5 hours, 3-piperidinol 18 was formed in 74% yield. Unfortunately, after several attempts, we were unable to realize the key one-pot debenzylative-carbamoylation 20 (CbzCl, THF, reflux) 11g for the conversion of 17 to 19. At this stage, the change of N-protective group from benzyl (in 7 and 9) to 4-methoxybenzyl (in 8 and 10) appeared to be an attractive solution to our approach, because PMB is a wellknown complementary protective group to benzyl 21 in the sense that the former is removable under mild oxidative conditions.…”

Section: Methodsmentioning

confidence: 99%

Asymmetric Synthesis of AntimalarialAlkaloids (+)-Febrifugine and (+)-Isofebrifugine

Huang¹,

Wei²,

Ruan³

2003

Synlett

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“…The successive O-allylation, reduction, 7) and replacement 8) of the benzyloxycarbonyl (Cbz) group from 3 afforded benzyl 1-(3-allyloxy-1,2,5,6-tetrahydropyridine)carboxylate (4) in 47% yield. The Claisen rearrangement of 4 by heating at 140°C in xylene proceeded smoothly to give benzyl 4-allyl-3-oxo-1-piperidinecarboxylate (5) in 99% yield.…”

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confidence: 99%

Synthesis and Antimalarial Activity of Febrifugine Derivatives.

Takeuchi

Koike

Azuma

et al. 2001

CHEMICAL & PHARMACEUTICAL BULLETIN

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Febrifugine (1a) is an antimalarial agent which was isolated from Dichroa febrifuga or Hydrangea umbellata with isofebrifugine (1b). 1) Recently Kobayashi et al. corrected the error in the absolute structures of 1a,b, as shown in Fig. 1, by achieving the asymmetric syntheses of all the stereoisomers. 2) We have developed a new synthetic method for 1a,b, 3) and our interest next focused on the structure-activity relationship (SAR) of 1a,b. The difficulty in the purification or antimalarial screening of 1a,b is isomerization 4) between 1a and 1b, which occurs via a reversible Michael reaction. We thought that a derivative in which isomerization did not occur might be a more potent compound. Although much is reported on the SAR of substituents 5) on the 4(3H)-quinazolinone ring, the only known modification of the piperidine ring involves regioisomers of the hydroxy group. 6) In this report, we describe the synthesis and antimalarial activity of derivatives (2a,b) that are regioisomers of the nitrogen atom on the piperidine ring of 1a,b.We prepared 2a,b from 1-benzyl-3-hydroxypyridinium chloride (3) in seven isolated steps by modifying our method for synthesizing 1a,b (Chart 1). The successive O-allylation, reduction, 7) and replacement 8) of the benzyloxycarbonyl (Cbz) group from 3 afforded benzyl 1-(3-allyloxy-1,2,5,6-tetrahydropyridine)carboxylate (4) in 47% yield. The Claisen rearrangement of 4 by heating at 140°C in xylene proceeded smoothly to give benzyl 4-allyl-3-oxo-1-piperidinecarboxylate (5) in 99% yield. Reduction of 5 with sodium borohydride (NaBH 4 ) afforded trans (6a) and cis (6b) benzyl 4-allyl-3-hydroxy-1-piperidinecarboxylate as an inseparable mixture.Purification and structural determination of the inseparable mixture of 6a and 6b were achieved as shown in Chart 2. Although trans (12a) and cis (12b) benzoate produced from 6a,b were separated by column chromatography, the existence of rotomers 9) in the 1 H-NMR spectrum made the structural analysis of 12a,b difficult. Hydrogenolysis of 12a,b produced trans (13a) or cis (13b) 4-propyl-3-piperidinyl benzoate, respectively. In the 1 H-NMR spectrum, the proton at the 3 position on the piperidine ring of 13a was observed at 4.73 ppm with a coupling constant of 4.0 and 9.5 Hz. The proton on 13b, on the other hand, was observed at 5.10 ppm as a single broad peak. Pure 6a and 6b were prepared by hydrolysis of 12a and 12b and led to 7a and 7b, respectively.We previously found that reduction of benzyl 2-allyl-3-oxo-1-piperidinecarboxylate (14) with NaBH 4 at room tem- The regioisomers (2a,b) of the piperidine ring of febrifugine (1a) and isofebrifugine (1b) were synthesized from 4-allyl-3-piperidone (5). Reduction of 5 afforded a mixture of the trans and cis alcohols (6a,b) without diastereoselectivity; this result differentiated it from the reduction of 2-allyl-3-piperidone (14). The antimalarial activity of 2a,b and related compounds was tested.

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The mild and selective N-debenzylation of tertiary alkylamines using β-trimethylsilylethyl chloroformate.

Cited by 37 publications

References 5 publications

Structure‐Based Design of Novel Pyrimido[4,5‐c]pyridazine Derivatives as Dihydropteroate Synthase Inhibitors with Increased Affinity

Structure‐Based Design of Novel Pyrimido[4,5‐c]pyridazine Derivatives as Dihydropteroate Synthase Inhibitors with Increased Affinity

Asymmetric Synthesis of AntimalarialAlkaloids (+)-Febrifugine and (+)-Isofebrifugine

Synthesis and Antimalarial Activity of Febrifugine Derivatives.

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