A Convenient Two-Step Procedure for the Synthesis of Substituted Allylic Amines from Allylic Alcohols

Sen, Stephanie E.; Roach, Steven L.

doi:10.1055/s-1995-4012

Cited by 111 publications

(77 citation statements)

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“…By comparison of their spectroscopic data with values available in the literature, the known alkaloids were identified as: (+)-pachysandrine B (10) [10], epipachysandrine-A (11) [11], 3β-methylamino 16-oxo 5,17 (20) cis-pregnadiene (12) [12], Z-salignone (13) [13], terminamine H (14) [8], 3β-methylamino 16-oxo 5,17 (20) trans-pregnadiene (15) [12], E-salignone (16) [13], and (+)-spiropachysine (17) [14] (Figure 1). Structures of 1-9 were determined based on the 1D-and 2D-NMR, and mass spectrometric analytical results.…”

Section: Purification and Characterizationmentioning

confidence: 99%

“…However, there was no further chemical or spectral evidence for the identification of the relative configuration for C-3, except for the 1D-NMR data [8,13]. A series of 3-isomers of pregnane alkaloid derivatives were synthesized using the stereoselective Mitsunobu reaction [16] by this group [17][18][19]. The results suggested that the C-3 signal of 3β-dimethylamino derivatives appeared more downfield.…”

Section: Positionmentioning

confidence: 99%

“…Previous pharmacological research has shown that these compounds produce a wide range of pharmacological effects, such as antiulcer [4], cytotoxic [3], anti-leishmanial [5], anti-cancer [6], anti-breast cancer metastatic activities [7,8], as well as estrogen biosynthesis-promoting effects [9]. As part of an ongoing research program to identify bioactive steroidal alkaloids with anti-metastatic effects nine new (1)(2)(3)(4)(5)(6)(7)(8)(9) and eight known (10)(11)(12)(13)(14)(15)(16)(17) pregnane alkaloids were isolated from the whole herb of Pachysandra terminalis. The isolation, structure elucidation, and anti-metastatic effects of these compounds are described, and their structure-activity relationships is discussed.…”

Section: Introductionmentioning

confidence: 99%

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Terminamines K–S, Antimetastatic Pregnane Alkaloids from the Whole Herb of Pachysandra terminalis

Xiang-yu

Jia

et al. 2016

Molecules

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Abstract:Nine new pregnane alkaloids (1-9), together with eight known alkaloids (10-17), were isolated from the whole herb of Pachysandra terminalis. Their structures were elucidated on the basis of spectroscopic analyses. In addition, the isolates were examined for their ability to inhibit the migration of MDA-MB-231 cells induced by the chemokine epidermal growth factor (EGF). Alkaloids 1, 5, 7, 9, 12, and 17 presented significant anti-metastasis activities compared with the positive reagent, LY294002.

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Section: Purification and Characterizationmentioning

confidence: 99%

Section: Positionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Terminamines K–S, Antimetastatic Pregnane Alkaloids from the Whole Herb of Pachysandra terminalis

Xiang-yu

Jia

et al. 2016

Molecules

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“…A Mitsunobu reaction with phthalimide followed by deprotection with hydrazine gave a primary amine. 8 Addition of benzoyl isothiocyanate to the amine followed by hydrolysis produced thiourea 15. Heating thiourea 15 with ethyl 2-bromo-isovalerate in a microwave reactor delivered 5-isopropylthiazolone.…”

mentioning

confidence: 99%

Synthesis and Evaluation of the Metabolites of AMG 221, a Clinical Candidate for the Treatment of Type 2 Diabetes

Yuan

Chow

et al. 2011

ACS Med. Chem. Lett.

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1 there has been a renewed focus on studying the metabolites of clinical candidates during the drug development process throughout the pharmaceutical industry.2 While the FDA MIST guidelines recommend that certain metabolites be subjected to additional safety studies, metabolites of clinical candidates are also needed for pharmacokinetic and pharmacological studies. In fact, there are examples where a metabolite, after being profiled further, replaced the parent compound as the drug candidate.3,4 Therefore, the development of synthetic routes to supply sufficient amounts of metabolites for their complete characterization has become an important objective for many drug discovery and development programs.Recently, we reported on the discovery of AMG 221 (1), an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that has entered clinical trials for the treatment of type 2 diabetes. 5,6 During our development efforts, we discovered that 1 was metabolized into eight common oxidation products among rat, mice, dog, monkey, and human (2À9) (Chart 1). The norbornyl and isopropyl groups of 1 underwent metabolic oxidation to give hydroxylation products 2, 3, 5À8, ketone 4, and alkene 9. For structure elucidation (see the Supporting Information for more details), these metabolites were isolated from in vitro dog/human liver microsomal incubations supplemented with NADPH or isolated from rat urine obtained following a single dose administration of AMG 221 (1). However, the bioactivity and pharmacokinetics of these metabolites could not be determined with the small amount of material generated from microsomes. Therefore, we set out to prepare these metabolites by synthetic methods so that we might more fully characterize these compounds and further confirm their structures.Turning first to the synthesis of the metabolites formed on the norbornyl ring (2À5), we devised a route (Scheme 1) that allowed us to prepare three of these from a common intermediate 16. We envisioned using chiral norbornyl diol 10, 7 as an intermediate for the preparation of analogs 2À4. Preparation of norbornyl diol 10 by Hiyashi's method 7 followed by monobenzylation delivered compound 11. Compound 11 was treated with tert-butylchlorodiphenylsilane in DMF to give compound 12, which was then debenzylated by hydrogenation to give compound 13. The chirality of the hydroxyl group was inverted through a two step sequence by oxidation to the ketone, followed by reduction with L-selectride to give compound 14. A Mitsunobu reaction with phthalimide followed by deprotection with hydrazine gave a primary amine.8 Addition of benzoyl isothiocyanate to the amine followed by hydrolysis produced thiourea 15. Heating thiourea 15 with ethyl 2-bromo-isovalerate in a microwave reactor delivered 5-isopropylthiazolone. Alkylation at the 5-position of the thiazolone was achieved with LDA and methyl iodide, and after removal of the TBDPS protecting group, the desired thiazolone 16 was obtained as a mixture of two diastereomers. The metabolite 2 was obtained thro...

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“…The phthalimide was reacted with alcohol under Mitsunobu conditions, 10 followed by oxidative cleavage of double-bond afforded 7 in 88% yield.…”

mentioning

confidence: 99%

Synthesis of Porphyrins Bearing Multiple meso-Aminoalkyl Groups

Hong¹,

Jeong²,

Lee

2008

Bulletin of the Korean Chemical Society

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meso-Substituted porphyrins have been widely used as key components in constructing porphyrin-based model systems as well as molecular materials.1,2 The design and synthesis of basic porphyrin building blocks for the construction of highly ordered systems often require incorporation of different peripheral substituents. The synthesis of porphyrins bearing specific patterns of functionality is still challenging task in spite of the ample presence of reported procedure.1 The difficulties also arise from the separation and limited availablilty of suitable precursors. Although many sophisticated synthetic routes for designed porphyrins have been reported recently, 3,4 some of the porphyrin building blocks bearing specific peripheral substituents are not available yet. The molecular weight of the porphyrins lacking of any peripheral substituents has considerably lower molecular weight than the porphyrins bearing substituents at meso-or β-pyrrolic positions. Keeping the low molecular weight of porphyrins is sometimes important in medical application.5 It has been demonstrated that lower molecular weight of porphyrins permits high charge density when electro-active surface is constructed for molecular information storage applications.6 Most of the reported methods generally adopted acid-catalyzed condensation of dipyrromethanes with appropriate aldehydes for the construction of porphyrins. Generally, porphyrins bearing one carbon unit directly attached to the meso-positions have been synthesized by selective formylation followed by conversion to other functional groups.7 Although selective Vilsmeier formylation resulted in high yields in some cases, the method is not applicable when the starting porphyrins have unsymmetrical multiple reaction sites. On the other hand, porphyrins bearing aminoalkyl group at meso-positions such as 1 or 2 are rare and only handful examples have been reported. 8,9 Directly attachment of basic functional groups at the meso-position with proper dimension would enable the construction of porphyrin-based supramolecular architectures more conveniently. With these regards, we here report a new synthetic method of porphyrins bearing aminoalkyl equivalents at multiple meso-positions. Also is reported the synthesis of amine-protected aldehydes which can be used as building blocks for the synthesis of meso-amine substituted porphyrins. The aldehydes and corresponding dipyrromethanes would provide the starting point for the desired porphyrin synthesis.As shown in Scheme 1, phthalimido-aldehyde 4 was prepared from phthalimidoacetaldehyde diethyl acetal and compound 7 was synthesized by two steps starting from phthalimide and 3-buten-1-ol. The phthalimide was reacted with alcohol under Mitsunobu conditions, 10 followed by oxidative cleavage of double-bond afforded 7 in 88% yield.11 Since the starting aldehydes 4 and 7 are in hand, the desired dipyrromethane derivatives then were prepared by condensation of 4 or 7 with pyrrole in neat excess pyrrole presence as shown in Scheme 2. Corresponding dipyrrom...

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A Convenient Two-Step Procedure for the Synthesis of Substituted Allylic Amines from Allylic Alcohols

Cited by 111 publications

References 0 publications

Terminamines K–S, Antimetastatic Pregnane Alkaloids from the Whole Herb of Pachysandra terminalis

Terminamines K–S, Antimetastatic Pregnane Alkaloids from the Whole Herb of Pachysandra terminalis

Synthesis and Evaluation of the Metabolites of AMG 221, a Clinical Candidate for the Treatment of Type 2 Diabetes

Synthesis of Porphyrins Bearing Multiple meso-Aminoalkyl Groups

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