- A Total Synthesis of Salinosporamide A
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Salinosporamide A is a β-lactone proteasome inhibitor currently in clinical trials for the treatment of multiple-myeloma. Herein we report a short synthesis of this small, highly functionalized, biologically important natural product that uses an oxidative radical cyclization as a key step and allows for the preparation of gram quantities of advanced synthetic intermediates.
- Marx, Léo B.,Burton, Jonathan W.
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- Stereoselective enzymatic reduction of keto-salinosporamide to (-)-salinosporamide A (NPI-0052)
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Salinosporamide A (NPI-0052, 1), a highly potent 20S proteasome inhibitor, has been prepared from its ketone precursor (2) by asymmetric enzymatic reduction. The yields are quantitative with complete stereoselective conversion to the desired product, with no evidence for the undesired diastereomer. This process should lead to new synthetic strategies for the total synthesis of 1.
- Manam, Rama Rao,Macherla, Venkat R.,Potts, Barbara C.M.
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- Preparation method and application of Marizomib key intermediate
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The invention belongs to the field of chemical synthesis, particularly relates to a preparation method and application of a Marizomib key intermediate, and particularly relates to a preparation methodof a Marizomib key intermediate. Natural L-serine is selected as an initial raw material, and an obtained serine fragment protected by a functional group is connected with a 1, 3-dicarbonyl cyclopropyl compound so that the Marizomib key intermediate (a skeleton structure) is prepared, and the preparation method is high in preparation efficiency and yield, safer and more environmentally friendly.Then, the prepared Marizomib key intermediate is used for producing Marizomib, and the Marizomib is obtained through intramolecular cyclization reaction and group modification, protective group removal and structural modification in sequence. Besides, the low-toxicity solvent is used in the whole synthesis process, reagents with high toxicity and difficult preparation are avoided, the solvent consumption is low, the target product recovery rate is high and the stability is good.
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- Total Synthesis of (?)-Salinosporamide A via a Late Stage C?H Insertion
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The synthesis of (?)-salinosporamide A, a proteasome inhibitor, is described. The synthesis highlights the assembly of a densely decorated pyrrolidinone core via an aza-Payne/hydroamination sequence. Central to the success of the synthesis is a late-stage C?H insertion reaction to functionalize a sterically encumbered secondary carbon. The latter functionalization leads to an enabling transformation where most of the prototypical strategies failed.
- Gholami, Hadi,Kulshrestha, Aman,Favor, Olivia K.,Staples, Richard J.,Borhan, Babak
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p. 10110 - 10113
(2019/04/25)
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- Total synthesis of (-)-salinosporamide A
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A detailed description of our second-generation total synthesis of salinosporamideA is presented. Three contiguous stereocenters in the γ-lactam structure seen in the natural product were established by stereoselective functionalization of a D-arabinose scaffold, including an Overman rearrangement to generate a highly congested tetrasubstituted carbon center. One of the definitive reactions in the synthesis was a Lewis acid mediated skeletal rearrangement of a pyranose structure, which enabled the practical conversion of the carbohydrate scaffold to the γ-lactam structure embedded in salinosporamideA. The use of a benzyl ester as a protective group for a sterically hindered carboxylic acid led to a one-pot global deprotection at the end of the synthesis. Rearrange your chemistry! The total synthesis of anticancer natural product salinosporamideA has been achieved through a unique skeletal rearrangement (see scheme). This reaction enabled the construction of the densely functionalized γ-lactam structure found in salinosporamideA through practical methodologies including an Overman rearrangement on a D-arabinose scaffold. Copyright
- Kaiya, Yuji,Hasegawa, Jun-Ichi,Momose, Takayuki,Sato, Takaaki,Chida, Noritaka
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p. 209 - 219
(2011/10/03)
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- Total synthesis of (-)-salinosporamide A
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A concise and stereoselective total synthesis of (-)-salinosporamide A (1), a potent inhibitor of the 20S proteasome that is in clinical development as an anticancer drug candidate, has been accomplished in 14 steps with 19% overall yield from 4-pentenoic acid. Our synthesis features a stereoselective alkylation utilizing a chiral auxiliary, formation of a pyrrolidine unit, and oxidation of the pyrrolidine to a γ-lactam. To demonstrate the scalability of our synthesis, (-)-salinosporamide A has been synthesized on a gram scale.
- Satoh, Nobuhiro,Yokoshima, Satoshi,Fukuyama, Tohru
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p. 3028 - 3031
(2011/08/06)
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- Bioinspired total synthesis and human proteasome inhibitory activity of (-)-salinosporamide A, (-)-homosalinosporamide A, and derivatives obtained via organonucleophile promoted bis-cyclizations
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A full account of concise, enantioselective syntheses of the anticancer agent (-)-salinosporamide A and derivatives, including (-)-homosalinosporamide, that was inspired by biosynthetic considerations is described. The brevity of the synthetic strategy stems from a key bis-cyclization of a β-keto tertiary amide, which retains optical purity enabled by A1,3-strain rendering slow epimerization relative to the rate of bis-cyclization. Optimization studies of the key bis-cyclization, enabled through byproduct isolation and characterization, are described that ultimately allowed for a gram scale synthesis of a versatile bicyclic core structure with a high degree of stereoretention. An optimized procedure for zincate generation by the method of Knochel, generally useful for the synthesis of salino A derivatives, led to dramatic improvements in side-chain attachment and a novel diastereomer of salino A. The versatility of the described strategy is demonstrated by the synthesis of designed derivatives including (-)-homosalinosporamide A. Inhibition of the human 20S and 26S proteasome by these derivatives using an enzymatic assay are also reported. The described total synthesis of salino A raises interesting questions regarding how biosynthetic enzymes leading to the salinosporamides proceeding via optically active β-keto secondary amides, are able to maintain the stereochemical integrity at the labile C2 stereocenter or if a dynamic kinetic resolution is operative.
- Nguyen, Henry,Ma, Gil,Gladysheva, Tatiana,Fremgen, Trisha,Romo, Daniel
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experimental part
p. 2 - 12
(2011/03/23)
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- An enantio-and diastereocontrolled synthesis of (-)-salinosporamide A
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The enantio-and diastereocontrolled total synthesis of (-)-salinosporamide A, a potent 20S proteasome inhibitor, was accomplished through organocatalytic aldolization, diastereoselective Claisen condensation, a Rh-catalyzed Reformatsky reaction, and an AZADO-catalyzed oxidative β-lactonization reaction as the key reactions. The Japan Institute of Heterocyclic Chemistry.
- Sato, Yosuke,Fukuda, Hayato,Tomizawa, Masaki,Masaki, Tomohito,Shibuya, Masatoshi,Kanoh, Naoki,Iwabuchi, Yoshiharu
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p. 2239 - 2246
(2011/04/15)
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- Total synthesis of salinosporamide A
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(Chemical Equation Presented) The total synthesis of salinosporamide A has been achieved through enzymatic desymmetrization, diastereoselective aldol reaction, intramolecular aldol reaction, and intermolecular Reformatsky-type reaction followed by 1,4-reduction as key reactions.
- Fukuda, Takeo,Sugiyama, Kouhei,Arima, Shiho,Harigaya, Yoshihiro,Nagamitsu, Tohru,Omura, Satoshi
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supporting information; experimental part
p. 4239 - 4242
(2009/06/06)
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- A METHOD OF USING PROTEASOME INHIBITORS IN COMBINATION WITH HISTONE DEACETYLASE INHIBITORS TO TREAT CANCER
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Disclosed are methods of treating cancer comprising administering to the animal, a therapeutically effective amount of proteasome inhibitors and one or more histone deacetylase inhibitor. The animal is a mammal, preferably a human or a rodent.
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Page/Page column 105
(2008/12/04)
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- Entry to heterocycles based on indium-catalyzed Conia-ene reactions: Asymmetric synthesis of (-)-salinosporamide A
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Conica can: The In(OTf)3-catalyzed cyclization of nitrogen- and oxygen-tethered acetylenic malonic esters gives five- to seven-membered heterocycles in moderate to excellent yields (see scheme; Tf = trifluoromethanesulfonyl). The asymmetric synthesis of (-)-salinosporamide A illustrates the synthetic utility of the method. (Chemical Equation Presented).
- Takahashi, Keisuske,Midori, Michiko,Kawano, Kei,Ishihara, Jun,Hatakeyama, Susumi
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supporting information; experimental part
p. 6244 - 6246
(2009/04/06)
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- Enantioselective total synthesis of (-)-salinosporamide A (NPI-0052)
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A novel enantioselective total synthesis of 20S proteasome inhibitor Salinosporamide A (NPI-0052; 1) is presented. Key features include intramolecular aldol cyclization of 6 to simultaneously generate the three chiral centers of advanced intermediate 5, cyclohexene ring addition using B-2-cyclohexen-1-yl-9-BBN, and inversion of the C-5 stereocenter by oxidation followed by enantioselective enzymatic reduction.
- Ling, Taotao,Macherla, Venkat R.,Manam, Rama Rao,McArthur, Katherine A.,Potts, Barbara C. M.
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p. 2289 - 2292
(2008/02/05)
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- TOTAL SYNTHESIS OF SALINOSPORAMIDE A AND ANALOGS THEREOF
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The present invention relates to certain compounds and to methods for the preparation of certain compounds that can be used in the fields of chemistry and medicine. Specifically, described herein are methods for the preparation of various compounds and intermediates, and the compounds and intermediates themselves. More specifically, described herein are methods for synthesizing Salinosporamide A and its analogs from a compound of formula (V).
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- SYNTHESIS OF SALINOSPORAMIDE A AND ANALOGUES THEREOF
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A novel synthesis of salinosporamide A is provided. Salinospoamide A as well as structurally related natural products, omuralide and lactacystin, have been shown to be proteasome inhibitors. Therefore, these compounds as well as analogues of these natural products may be useful in the treatment of proliferative diseases such as cancer, autoimmune diseases, diabetic retinopathy, etc. The invention provides for the synthesis of salinosporamide A as well as analogs thereof using a convenient point for derivatization of the bicyclic core. Pharmaceutical compositions and method of using the inventive compounds are also provided.
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Page/Page column 62; 86-87
(2010/11/25)
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- Simple stereocontrolled synthesis of salinosporamide A
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A simple and effective stereocontrolled synthesis of salinosporamide A (1) has been developed which follows the pathway outlined in the Figure. The process, the first total synthesis of salinosporamide A, is capable of providing the compound in substantial quantities for further biological studies. In addition to the method of Scheme I, the present invention also includes several novel synthetic intermediate compounds, several intermediate steps of the preferred synthetic process; and the uses of these compounds in the preparation of synthetic derivatives of the compound Salinosporamide A. Salinosporamide A is of special interest as a synthetic target because of its protein in vitro cytotoxic activity against many tumor cell lines (IC50 values of 10 nM or less).
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Page/Page column 10-11
(2010/02/14)
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- [3.2.0] Heterocyclic compounds and methods of using the same
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Compounds of Formulae I-VI and derivatives thereof having anti-cancer, anti-inflammatory, and anti-microbial properties and to compositions that include one or more of compounds and their derivatives or analogs having anti-cancer, anti-inflammatory and anti-microbial properties are disclosed. Pharmaceutical compositions comprising such compounds and methods of treating cancer, inflammatory conditions, and microbial infections with the disclosed compounds or the disclosed pharmaceutical compositions are also disclosed.
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Page/Page column 36
(2008/06/13)
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- Total synthesis of salinosporamide A
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Total synthesis of potent proteasome inhibitor salinosporamide A (1) has been accomplished, which features strictly substrate-controlled operations starting with the only chiral center of (R)-pyroglutamic acid. The consecutive quaternary carbons within 1 have been efficiently constructed by manipulation of two intramolecular reactions: (1) carbonate-mediated internal acylation of imidate ester (4 → 14) and (2) selenocyclization of aldehyde to exocyclic methylene group (5 → 18). Copyright
- Endo, Atsushi,Danishefsky, Samuel J.
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p. 8298 - 8299
(2007/10/03)
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- A simple stereocontrolled synthesis of salinosporamide A
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A simple and effective stereocontrolled synthesis of salinosporamide A has been developed. This process, the first synthesis of salinosporamide A, is capable of providing the compound in substantial quantities for further biological studies. Salinosporamide A was of special interest as a synthetic target because of its potent in vitro cytotoxic activity against many tumor cell lines (IC50 values of 10 nM or less). Copyright
- Reddy, Leleti Rajender,Saravanan,Corey
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p. 6230 - 6231
(2007/10/03)
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