Synthesis of Squalamine Utilizing a Readily Accessible Spermidine Equivalent

Zhang, Xuehai; Rao, M. Narasimha; Jones, Stephen R.; Shao, Bin; Feibush, Penina; McGuigan, Melissa; Tzodikov, Nathan; Feibush, Binyamin; Sharkansky, Ilya; Snyder, Brad; Mallis, Larry M.; Sarkahian, Ani; Wilder, Susan Z.; Turse, Joshua E.; Kinney, William A.; Kjærsgaard, Hans Jørgen; Michalak, Ronald S.

doi:10.1021/jo981344z

Cited by 51 publications

(39 citation statements)

References 11 publications

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“…17) We were offered a sample of the (24R)-compound 3 (diastereomeric ratio, 24R : 24Sϭ96 : 4, as revealed by the signal intensity of 0.66 (24R) and 0.62 (24S) ppm of compound 4 in 1 H-NMR analysis [19][20][21] ) from the company and started the synthesis from the compound to obtain the key intemediate (13) via nine steps. Compound 13 was further converted into squalamine 1 in high yield by modified procedures of Kinney's method 9) via two further steps. The route of synthesis is shown in Chart 1.…”

Section: Resultsmentioning

confidence: 99%

“…[8][9][10] However, since the 3-O-acetyl group was partially hydrolyzed during the reaction, the crude product was reacetylated before purification. Hydrogenation of compound 7 using Adams catalyst under an atmospheric pressure of hydrogen resulted in the formation of 7-keto compound 9 in 66% yield together with 7b-alcohol 8 in 23% yield under the influence of steric hindrance of the C-19 methyl group.…”

Section: Resultsmentioning

confidence: 99%

“…[3][4][5][6][7] A practical way was found by Kinney and coworkers to prepare it from stigmasterol in 15 steps. [8][9][10] Very recently, a dramatically shortened synthetic route (10 steps) via microbial 7a-hydroxylation of 22-hydroxy-23,24-bisnorchol-4-en-3-one was reported. 11) Other groups also developed their own synthetic route of squalamine.…”

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confidence: 99%

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Formal Synthesis of Squalamine from Desmosterol

Okumura

Nakamura

Takeuchi

et al. 2003

CHEMICAL & PHARMACEUTICAL BULLETIN

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Formal Synthesis of Squalamine from Desmosterol

Okumura

Nakamura

Takeuchi

et al. 2003

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…The reaction was stirred at reflux for 20 h. Then, solvent was removed at reduced pressure and the residue obtained was poured into water and extracted with CH 2 Cl 2 (3 X 10 mL). The combined organic layer was dried over anhydrous Na 2 …”

Section: Synthesis Of 13-dimethyl-5-{[(3-{[(2-nitrophenyl) Sulfonyl]mentioning

confidence: 99%

“…1 Additionally, a wide range of biological activities have been attributed to polyamines conjugates and derivatives, such as antianigogenic, anticancer, and neurotoxins, to name a few. 2 The metabolism of polyamines in prokaryotes has also gained increased importance. 3 In fact, the inhibition of enzymes involved in the metabolism of parasitic protozoa has been recognized as a promising strategy for the chemotherapy of tropical diseases.…”

Section: Introductionmentioning

confidence: 99%

The use of Fukuyama's sulfonamide in the synthesis of selectively protected spermidines

Silva

Fona

Lima

2004

J. Braz. Chem. Soc.

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A diferenciação dos grupos amino terminais de poliaminas freqüentemente envolve uma série de etapas de proteção e desproteção, resultando em rotas sintéticas longas e de baixo rendimento global. Tendo em vista o relevante papel biológico atribuído a estas substâncias, torna-se necessário o desenvolvimento de sínteses mais eficientes para poliaminas. Neste artigo descrevemos uma síntese de duas espermidinas seletivamente protegidas, empregando a sulfonamida de Fukuyama. As duas sínteses foram executadas em três etapas a partir da 1,3-propanodiamina, com um rendimento global superior a 40%.The differentiation of terminal amino groups in polyamines usually involves a series of protection and deprotection steps, leading to long reaction sequences with low overall yields. Given the relevance of the biological activities displayed by polyamines, the development of more efficent synthetic routes for these compounds is highly desired. Herein we report the synthesis of two selectively protected spermidines, using Fukuyama's sulfonamide. Both syntheses were performed in three steps, starting from 1,3-diaminopropane, with an overall yield higher than 40%. Keywords: polyamines, spermidine, Fukuyama's sulfonamide IntroductionIn the past decades a great deal of attention has been given to polyamines, especially because of their involvement in the regulation of cellular functions, such as cell proliferation and differentiation.1 Additionally, a wide range of biological activities have been attributed to polyamines conjugates and derivatives, such as antianigogenic, anticancer, and neurotoxins, to name a few. 2The metabolism of polyamines in prokaryotes has also gained increased importance.3 In fact, the inhibition of enzymes involved in the metabolism of parasitic protozoa has been recognized as a promising strategy for the chemotherapy of tropical diseases. 4 For instance, the inhibition of ornithine descaboxylase by a-difluoromethylornithine, a drug candidate against African sleeping sickness and malaria, 4,5 blocks the first step of polyamine biosynthetic pathway.6 Trypanothione, structurally characterized as N 1 ,N 8 -bis(glutathionyl)spermidine, is a polyamine derivative used by trypanosomatids as a defense against reactive oxygen species during their infective cycle. 7 The metabolism of trypanothione is another target for drug development against trypanosomiases and leishmanioses. 8As part of a research program aiming the synthesis of peptide-polyamine conjugates, we became interested in the preparation of selectively protected spermidines. 9 However, the synthesis of unsymmetrical polyamines usually requires several protection and deprotection steps, making such approaches unnatractive due to the long reaction sequences involved. 10 More straighforward alternatives to acess polyamine backbones are needed.The dual role of Fukuyama's sulfonamide, 11 which not only masks the amino group, but also activates it to grow the polyamine chain, meet the requirements to solve those issues.12 Herein, we wish to describe a versatile...

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Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents

2002

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Reductive amination is an important tool for synthetic organic chemists in the construction of carbon‐nitrogen bonds. This reaction, also termed reductive alkylation, involves condensation of an aldehyde or ketone with an amine in the presence of a reducing agent. A wide variety of substrates can be used including aliphatic and aromatic aldehydes and ketones, and even benzophenones. A range of amines from ammonia to aromatic amines, including those with electron‐withdrawing substituents, can be employed. For particularly sluggish reactions, such as those involving weakly electrophilic carbonyl groups, poorly nucleophilic amines, or sterically congested reactive centers, additives such as molecular sieves or Lewis acids are often useful. This chapter focuses on those conditions in which the carbonyl component, amine, and reducing reagent react in the same vessel. This review is restricted to reductive aminations using borohydride and borane reducing agents. This chapter concentrates on reductive amination chemistry mediated by borohydride and other boron‐containing reducing agents from 1971, the year when sodium cyanoborohydride was introduced, through the middle of 1999. In addition to reductive aminations of aldehyde and ketone substrates, reactions of related structures including acetals, aminals, ketals, carboxylic acids, nitriles, and dicarbonyls that form a nitrogen‐containing ring are reviewed. Intramolecular processes in which the substrate contains both the carbonyl and amine moieties are described. The intramolecular variant is a useful method for preparing cyclic amines. All of the various boron‐containing hydride sources in reductive aminations, including labeled metal hydrides, are reviewed. Instances of reductive aminations that failed are described. Applications of this method to a solid support in parallel synthesis in combinatorial chemistry as well as reductive aminations that proceed in tandem with a second reaction such as reductive lactamizations are discussed.

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Synthesis of Squalamine Utilizing a Readily Accessible Spermidine Equivalent

Cited by 51 publications

References 11 publications

Formal Synthesis of Squalamine from Desmosterol

Formal Synthesis of Squalamine from Desmosterol

The use of Fukuyama's sulfonamide in the synthesis of selectively protected spermidines

Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents

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