- Utility of the ammonia-free birch reduction of electron-deficient pyrroles: Total synthesis of the 20S proteasome inhibitor, clasto-lactacystin β-lactone
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A new synthesis of the 20S proteasome inhibitor clasto-lactacystin β-lactone is described. Our route to this important natural product involves the partial reduction of an electron deficient pyrrole as a key step. By judicious choice of enolate counterion, we were able to exert complete control over the stereoselectivity of the reduction/aldol reaction. Early attempts to complete the synthesis by using a C-4 methyl substituted pyrrole are described in full, together with our attempts to promote regioselective elimination of a tertiary alcohol. The lessons learnt from this first approach led us to develop another, and ultimately successful, route that introduced the C-4 methyl group at a late stage in the synthesis. Our successful route is then described and this contains several highly stereoselective steps including a cis-dihydroxylation and an enolate methylation. The final synthesis proceeds in just 13 steps and in 15% overall yield making it an extremely efficient route to this valuable compound.
- Donohoe, Timothy J.,Sintim, Herman O.,Sisangia, Leena,Ace, Karl W.,Guyo, Paul M.,Cowley, Andrew,Harling, John D.
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Read Online
- An efficient synthesis of lactacystin β-lactone
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A key step in the synthesis of lactacystin β-lactone (3), an inhibitor of the 20 S proteasome, was the ammonia-free reductive aldol reaction of pyrrole 1 to form 2 with complete anti selectivity. This route to 3 takes just 13 steps (14% overall yield) and allows the late-stage stereoselective introduction of a methyl group at C4, which is crucial for the production of analogues. Boc = tert-butoxycarbonyl.
- Donohoe, Timothy J.,Sintim, Herman O.,Sisangia, Leena,Harling, John D.
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Read Online
- Total Synthesis of Proteasome Inhibitor (-)-Omuralide through Asymmetric Ketene [2 + 2]-Cycloaddition
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The total synthesis of (-)-omuralide, a potent specific proteasome inhibitor, has been achieved through an unprecedented route. The C3 and C4 chiral centers of the natural product have been selectively installed by an asymmetric [2 + 2]-cycloaddition betw
- Rullière, Pauline,Cannillo, Alexandre,Grisel, Julien,Cividino, Pascale,Carret, Sébastien,Poisson, Jean-Fran?ois
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supporting information
p. 4558 - 4561
(2018/08/09)
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- Application of Two Direct C(sp3)-H Functionalizations for Total Synthesis of (+)-Lactacystin
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(Figure Presented). Herein, we report a new synthetic route from (S)-pyroglutaminol to (+)-lactacystin, a potent inhibitor of the 20S proteasome. The photoinduced intermolecular C(sp3)-H alkynylation and intramolecular C(sp3)-H acylation chemo- and stereoselectively constructed the tetra- and trisubstituted carbon centers, respectively. The obtained bicycle was transformed into the target compound in a concise manner. The present total synthesis demonstrates the power of the direct C(sp3)-H functionalizations for the assembly of multiple functionalized structures of natural products.
- Yoshioka, Shun,Nagatomo, Masanori,Inoue, Masayuki
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supporting information
p. 90 - 93
(2015/07/28)
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- Stereospecific total syntheses of proteasome inhibitors omuralide and lactacystin
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Omuralide, a transformation product of the microbial metabolite lactacystin, was the first molecule discovered as a specific inhibitor of the proteasome and is unique in that it specifically inhibits the proteolytic activity of the 20S subunit of the prot
- Gu, Wenxin,Silverman, Richard B.
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experimental part
p. 8287 - 8293
(2012/04/10)
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- Enantioselective total syntheses of omuralide, 7-epi-omuralide, and (+)-lactacystin
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(Chemical Equation Presented) An alkylidene carbene 1,5-CH insertion has been used as a key step in an enantioselective total syntheses of omuralide, its C7-epimer, and (+)-lactacystin. An additional noteworthy feature of the synthesis is the use of a nov
- Hayes, Christopher J.,Sherlock, Alexandra E.,Green, Martin P.,Wilson, Claire,Blake, Alexander J.,Selby, Matthew D.,Prodger, Jeremy C.
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p. 2041 - 2051
(2008/09/19)
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- Stereogenic evolution of clasto-lactacystin β-lactone from L-serine
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Reported herein is a novel synthesis of clasto-lactacystin β-lactone. The γ-lactam core was selectively prepared by an intramolecular C-H insertion to establish the stereocenter, C(6). The ensuing construction of the quaternary C(5) and carbinol C(9) cent
- Yoon, Cheol H.,Flanigan, David L.,Yoo, Kyung S.,Jung, Kyung W.
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- Enantioselective total syntheses of (-)-clasto-lactacystin β-lactone and 7-epi-(-)-clasto-lactacystin β-lactone
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An alkylidene carbene 1,5-CH insertion has been used as a key step in an efficient enantioselective total synthesis of (-)-clasto-lactacystin β-lactone, and its C7-epimer. An additional noteworthy feature of the synthesis is the use of a novel oxidative deprotection procedure, utilizing DMDO, for the conversion of a late-stage benzylidene acetal into a primary alcohol and a secondary benzoate ester. The Royal Society of Chemistry 2006.
- Hayes, Christopher J.,Sherlock, Alexandra E.,Selby, Matthew D.
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p. 193 - 195
(2007/10/03)
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- Catalytic asymmetric total synthesis of (+)-lactacystin
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Total synthesis of (+)-lactacystin, a potent and selective proteasome inhibitor, was accomplished using a catalytic enantioselective Strecker reaction of a ketoimine as the initial key step. An enone-derived N-phosphinoyl ketoimine 7 was selected as a sta
- Fukuda, Nobuhisa,Sasaki, Kazuki,Sastry,Kanai, Motomu,Shibasaki, Masakatsu
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p. 1220 - 1225
(2007/10/03)
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- SUBSTITUTED 2-PYRROLIDONE DERIVATIVES AS FUNGICIDES AND INSECTICIDES
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The use of a compound of formula (I) or a salt thereof, where the symbols have the meanings given in the description, for the control of phytopathogenic mircroorganisms of harmful animals.
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Page/Page column 109-110
(2010/02/15)
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- Simple enantiospecific syntheses of the C(2)-diastereomers of omuralide and 3-methylomuralide
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(Chemical Equation Presented) Syntheses of two novel omuralide derivatives are described.
- Reddy, Leleti Rajender,Saravanan,Fournier, Jean-Francois,Subba Reddy,Corey
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p. 2703 - 2705
(2007/10/03)
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- A concise route to (+)-lactacystin
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A facile chromatography-free route to Kang's intermediate for the synthesis of (+)-lactacystin, a potent proteasome inhibitor, has been developed starting with Brown's asymmetric crotylation of tert-butyl 5-formyl-2,2-dimethyl-1,3- dioxan-5-ylcarbamate, e
- Ooi, Hidenori,Ishibashi, Norihisa,Iwabuchi, Yoshiharu,Ishihara, Jun,Hatakeyama, Susumi
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p. 7765 - 7768
(2007/10/03)
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- The structural requirements for inhibition of proteasome function by the lactacystin-derived β-lactone and synthetic analogs
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The synthesis of analogs of the lactacystin-derived β-lactone (2) in which the substituents at C(5), C(7) and C(9) were systematically varied has led to a well defined structure-activity correlation for the highly selective inhibition of the mammalian 20 S proteasome.
- Corey,Li, Wei-Dong Z.,Nagamitsu, Tohru,Fenteany, Gabriel
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p. 3305 - 3316
(2007/10/03)
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- A novel and efficient synthesis of a highly active analogue of clasto-lactacystin β-lactone
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Herein, we describe a new convergent synthesis of a more potent analogue of clasto-lactacystin β-lactone (2), PS-519 compound 4, which is currently in preclinical development for the treatment of ischemia-reperfusion injury in stroke and myocardial infarction. The synthetic strategy relies on building two intermediates (an oxazoline and an aldehyde) which are joined through a doubly diastereoselective aldol reaction, setting up the requisite unichiral centers in the final product (4). The facial selectivity and ultimate stereocontrol are achieved by employing a trivalent aluminum Lewis acid, Me2AlCl, in a chelation-induced reaction which yields a single aldol adduct. The efficiency of the synthetic approach has allowed for the preparation of multigram quantities of clinical grade material, which will support Phase I studies.
- Soucy, Francois,Grenier, Louis,Behnke, Mark L.,Destree, Antonia T.,McCormack, Teresa A.,Adams, Julian,Plamondon, Louis
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p. 9967 - 9976
(2007/10/03)
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- Total synthesis of (+)-lactacystin
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A double stereodifferentiating crotylation between aldehyde 1 and silane (S)-2 to afford homoallylic alcohol 3 is the key diastereoselective step (anti:syn > 30:1) in an efficient asymmetric synthesis of (+)-lactacystin. This compound is a metabolite isol
- Panek, James S.,Masse, Craig E.
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p. 1093 - 1095
(2007/10/03)
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- Enantioselective synthesis of the (5S, 6R, 9R) and (5S, 6R, 9S) analogs of lactacystin β-lactone
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The synthesis of two diastereomers of lactacystin β-lactone (2), the β-lactones 3 and 4, is described.
- Corey,Li, Wei-Dong Z.
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p. 8043 - 8046
(2007/10/03)
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- An efficient and concise enantioselective total synthesis of lactacystin
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A selective, irreversible inhibitor of proteasome function, lactacystin (1) is an important experimental tool in cell biology. An efficient and direct enantioselective synthesis of lactacystin proceeds via the intermediates shown below. This process allow
- Corey,Li, Weidong,Nagamitsu, Tohru
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p. 1676 - 1679
(2007/10/03)
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- A new magnesium-catalyzed doubly diastereoselective anti-aldol reaction leads to a highly efficient process for the total synthesis of lactacystin in quantity
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A new process is described for metal-catalyzed doubly diastereoselective Mukaiyama aldol coupling of a chiral tertiary α-amino aldehyde and an achiral silyl enol ether to form selectively an anti-aldol product. The metal requirement is strict, since of se
- Corey,Li, Weidong,Reichard, Gregory A.
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p. 2330 - 2336
(2007/10/03)
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- Total synthesis of (+)-lactacystin
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A total synthesis of the novel neurotrophic agent (+)-lactacystin (1) has been achieved in 11 steps and 14% overall yield from (2R,3S)-3-hydroxyleucine [(+)-16]. The construction and bioassay of several active analogs are also described. A new asymmetric approach furnished the four stereoisomers of 3-hydroxyleucine, as required starting materials in high overall yield and enantiomeric purity.
- Nagamitsu, Tohru,Sunazuka, Toshiaki,Tanaka, Haruo,Omura, Satoshi,Sprengeler, Paul A.,Smith III, Amos B.
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p. 3584 - 3590
(2007/10/03)
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- STUDIES ON THE TOTAL SYNTHESIS OF LACTACYCLIN. AN IMPROVED ALDOL COUPLING REACTION AND A β-LACTONE INTERMEDIATE IN THIOL ESTER FORMATION
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The recently developed total synthesis of lactacystin (1) has been improved by using the zirconium enolate derived from (R)- or (S)-2-silyloxy-1,2,2-triphenylpropionate which lead stereospecifically to either (6S,7R) or (6R,7S) lactacystin, respectively.T
- Corey, E. J.,Reichard, Gregory, A.,Kania, Robert
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p. 6977 - 6980
(2007/10/02)
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