Synthesis and applications of C2-symmetric guanidine bases

Allingham, Matthew T.; Howard-Jones, Andrew; Murphy, P. J.; Thomas, Dafydd A.; Caulkett, Peter W. R.

doi:10.1016/j.tetlet.2003.09.162

Cited by 135 publications

(34 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Phosphonate 3 [35] was prepared by the Arbuzov reaction of the known iodide [36] 2 with triethyl phosphite followed by removal of the acetonide with para-toluenesulfonic acid (p-TsOH) in methanol. Monoacylation of the intermediate diol 3 was carried out in the presence of 2,4,6-collidine at low temperature.…”

Section: Chemical Synthesismentioning

confidence: 99%

“…A solution of iodide 2 [36] (600 mg, 2.34 mmol) in triethyl phosphite (6 mL) was heated at 130°C under nitrogen for 2 h. Excess triethylphosphite was evaporated and thoroughly dried under vacuum overnight. The crude mixture was then dissolved in 3 mL CH 3 OH containing p-TsOH monohydrate (7.7 mg, 0.042 mmol).…”

Section: Diethyl [3(s)-4-dihydroxybutyl]phosphonate (3)mentioning

confidence: 99%

See 1 more Smart Citation

α‐Substituted Phosphonate Analogues of Lysophosphatidic Acid (LPA) Selectively Inhibit Production and Action of LPA

Jiang

Fujiwara

et al. 2007

ChemMedChem

View full text Add to dashboard Cite

Isoform-selective agonists and antagonists of the lysophosphatidic acid (LPA) G-protein-coupled receptors (GPCRs) have important potential applications in cell biology and therapy. LPA GPCRs regulate cancer cell proliferation, invasion, angiogenesis, and biochemical resistance to chemotherapy-and radiotherapy-induced apoptosis. LPA and its analogues are also feedback inhibitors of the enzyme lysophospholipase D (lysoPLD, also known as autotaxin), a central regulator of invasion and metastasis. For cancer therapy, the ideal therapeutic profile would be a metabolically stabilized pan-LPA receptor antagonist that also inhibits lysoPLD. Herein we describe the synthesis of a series of novel α-substituted methylene phosphonate analogues of LPA. Each of these analogues contains a hydrolysis-resistant phosphonate mimic of the labile monophosphate of natural LPA. The pharmacological properties of these phosphono-LPA analogues were characterized in terms of LPA receptor subtype-specific agonist and antagonist activity using Ca 2+ mobilization assays in RH7777 and CHO cells expressing the individual LPA GPCRs. In particular, the methylene phosphonate LPA analogue is a selective LPA 2 agonist, whereas the corresponding α-hydroxymethylene phosphonate is a selective LPA 3 agonist. Most importantly, the α-bromomethylene and α-chloromethylene phosphonates show pan-LPA receptor subtype antagonist activity. The α-bromomethylene phosphonates are the first reported antagonists for the LPA 4 GPCR. Each of the α-substituted methylene phosphonates inhibits lysoPLD, with the unsubstituted methylene phosphonate showing the most potent inhibition. Finally, unlike many LPA analogues, none of these compounds activate the intracellular LPA receptor PPARγ.

show abstract

Section: Chemical Synthesismentioning

confidence: 99%

Section: Diethyl [3(s)-4-dihydroxybutyl]phosphonate (3)mentioning

confidence: 99%

α‐Substituted Phosphonate Analogues of Lysophosphatidic Acid (LPA) Selectively Inhibit Production and Action of LPA

Jiang

Fujiwara

et al. 2007

ChemMedChem

View full text Add to dashboard Cite

show abstract

“…These reactions were performed under Mendoza's conditions, [23][24][25][26] i.e., the ratio of 2, 3 and catalyst was 1 : 1 : 0.1, and the concentrations of the substrate 2 and 3 were set at 0.3 M in CDCl 3 . The accelerating activities of the catalysts for this hetero-Michael reaction were determined by measuring the t 1/2 (monitored by 1 H-NMR), and the results are summarized in Table 1.…”

Section: Resultsmentioning

confidence: 99%

“…[15][16][17][18][19][20][21][22] At the outset of our studies for developing new chiral urea and/or thiourea catalyst of the hetero-Micahel reaction, we investigated the reaction of pyrrolidine (2) with g-crotonolactone (3) in the presence of the simple ureas 5 and 7, 17) thioureas 6 and 8, 17) and guanidine 9 as catalysts (Fig. 2).These reactions were performed under Mendoza's conditions, [23][24][25][26] i.e., the ratio of 2, 3 and catalyst was 1 : 1 : 0.1, and the concentrations of the substrate 2 and 3 were set at 0.3 M in CDCl 3 . The accelerating activities of the catalysts for this hetero-Michael reaction were determined by measuring the t 1/2 (monitored by 1 H-NMR), and the results are summarized in Table 1.…”

mentioning

confidence: 99%

Development of Novel Chiral Urea Catalysts for the Hetero-Michael Reaction

Sohtome

Tanatani

Hashimoto

et al. 2004

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

Michael addition to a,b-unsaturated carbonyl compounds is one of the fundamental bond-forming processes and offers an extremely powerful tool for the synthesis of highly functionalized organic molecules.1) Thus, development of efficient chiral catalysts for this reaction is still an exciting topic in synthetic organic chemistry.2,3) Various types of catalysts have been developed so far. Among them, organocatalysts are especially attractive since they do not require strictly controlled reaction conditions, and are not considered to have much unfavorable environment effect compared to the metalcontaining catalysts. 4,5) We have recently developed the novel C 2 -symmetrical chiral cyclic guanidine compounds 1 as new organocatalysts, 6-9) whose structure was inspired by the marine guanidine alkaloid ptilomycalin A 10-12) and its analogs (Fig. 1). 13,14) These catalysts were found to accelerate the heteroMichael reaction depending upon their cavity size. 7) One of the catalyst 1b works as phase-transfer catalyst for the alkylation of Schiff base imine with high enantioselectivity.8) Although 1 possesses wide possibility to be developed as superior organocatalyst, it also have some deficiencies, i.e., requirement for relatively long steps preparation, and no asymmetric induction at the hetero-Michael reaction.7) To overcome these issues, we focused our attention on urea and/or thiourea compounds, which can be grasped as core structure of 1, as prototype of new efficient and practical organocatalysts. Herein we wish to report the preliminary/basic results of a novel urea-type catalyst 10 for the hetero-Michael reaction, including results on an asymmetric version of this conjugate addition reaction. Results and DiscussionUrea and thiourea groups are known to coordinate to a carbonyl group as guanidine group, and to activate it by lowering the LUMO energy via partial protonation. Thus, various carbonyl group reactions catalyzed by urea or thiourea compounds have been developed. [15][16][17][18][19][20][21][22] At the outset of our studies for developing new chiral urea and/or thiourea catalyst of the hetero-Micahel reaction, we investigated the reaction of pyrrolidine (2) with g-crotonolactone (3) in the presence of the simple ureas 5 and 7, 17) thioureas 6 and 8, 17) and guanidine 9 as catalysts (Fig. 2).These reactions were performed under Mendoza's conditions, [23][24][25][26] i.e., the ratio of 2, 3 and catalyst was 1 : 1 : 0.1, and the concentrations of the substrate 2 and 3 were set at 0.3 M in CDCl 3 . The accelerating activities of the catalysts for this hetero-Michael reaction were determined by measuring the t 1/2 (monitored by 1 H-NMR), and the results are summarized in Table 1.The urea 5 and thiourea 6 accelerated this conjugate addition reaction 3.0 and 2.6-fold, respectively, over the uncatalyzed reaction as expected. From the consideration of the reaction mechanism (vide infra), introduction of EWGs on the aromatic rings of 5 and/or 6 was expected to increase their catalytic activity. In fact, catalysts 7 ...

show abstract

“…Following this report, many efforts have been initiated and different kinds of organocatalysts have been designed in order to improve those pioneering results (Figure 1). In this context, further chiral guanidines were developed, such as guanidinium salt 3 synthesized by Murphy et al [29], however lower enantiomeric excesses were obtained in comparison with those previously reported and catalyst 4 used in a diastereoselective Henry reaction [30]. Moreover, in 2005, Nawasaga et al [31][32][33][34] developed the novel bifunctional catalyst 5 bearing guanidine and thiourea moieties in the same skeleton.…”

Section: Enantioselective Henry Reaction With Aldehydesmentioning

confidence: 99%

Organocatalytic Enantioselective Henry Reactions

2011

View full text Add to dashboard Cite

A large number of interesting organocatalytic enantioselective protocols have been explored and successfully applied in the last decade. Among them, the Henry (nitroaldol) reaction represents a powerful carbon-carbon bond-forming procedure for the preparation of valuable synthetic intermediates, such as enantioenriched nitro alcohols, which can be further transformed in a number of important nitrogen and oxygen-containing compounds. This area of research is still in expansion and a more complex version of this useful process has recently emerged, the domino Michael/Henry protocol, affording highly functionalized cycles with multiple stereogenic centers.

show abstract

Synthesis and applications of C2-symmetric guanidine bases

Cited by 135 publications

References 15 publications

α‐Substituted Phosphonate Analogues of Lysophosphatidic Acid (LPA) Selectively Inhibit Production and Action of LPA

α‐Substituted Phosphonate Analogues of Lysophosphatidic Acid (LPA) Selectively Inhibit Production and Action of LPA

Development of Novel Chiral Urea Catalysts for the Hetero-Michael Reaction

Organocatalytic Enantioselective Henry Reactions

Contact Info

Product

Resources

About