Total Synthesis of (+)-Lactacystin

Nagamitsu, Tohru; Sunazuka, Toshiaki; Tanaka, Haruo; Ōmura, Satoshi; Sprengeler, Paul A.; Smith, Amos B.

doi:10.1021/ja9541544

Cited by 151 publications

(50 citation statements)

References 48 publications

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“…Selective oxidation of the primary hydroxyl group of 34 to the acid using the CoreyϪMyers protocol, [29] followed by an acid-catalyzed methylene transfer to 1,3-propanedithiol gives the dihydroxyacid 26. Dihydroxyacid 26 undergoes esterification by treatment with BOP-Cl, triethylamine (Et 3 N), and N-acetyl--cysteine allyl ester to form the allyl ester of (ϩ)-lactacystin (35). Deallylation of 35 under transfer hydrogenation conditions affords 1.…”

Section: Corey Synthesesmentioning

confidence: 99%

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Syntheses and Biological Evaluation of (+)-Lactacystin and Analogs

et al. 2000

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Since its isolation in 1991, (+)-lactacystin (1) has attracted considerable attention among leading synthesis laboratories due to its highly selective and potent inhibition of the 20S proteasome. The syntheses of this molecule described herein demonstrate several important strategies in the area of acyclic stereocontrol including the use of chiral metal enolate and chiral allylmetal-based bond construction methods. Figure 1) is a secondary metabolite derived from a streptomyces bacterial strain (OM-6519) [a] with the area of organic synthesis. His research group is engaged in the development of new reaction methodology concerned with acyclic stereocontrol as well as the application of these methods to the asymmetric synthesis of natural products and complex organic molecules. Biological Activity of Lactacystin Adam J. Morgan was born in 1978 in Phoenix, AZ. He is currently a senior at Boston University working toward a B. A. degree in chemistrywhere he is engaged in undergraduate research in the laboratories of Professor James S. Panek. For the past two summers, he has been the recipient of a Pfizer PREPARE fellowship. His research efforts include the asymmetric syntheses of natural products containing α-amino-β-hydroxyacid functionalities. Upon graduation, he plans on pursuing a career in the pharmaceutical industry.MICROREVIEWS: This feature introduces the readers to the authors' research through a concise overview of the selected topic. Reference to important work from others in the field is included.

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Section: Corey Synthesesmentioning

confidence: 99%

“…[35] In this work, the hydroxyleucine derivative 8 was prepared by a Sharpless asymmetric epoxidation of (E)-4-methyl-2-penten-1-ol (59) to give the chiral epoxide which was elaborated in a nine-step sequence to furnish amino ester 8. The hydroxyleucine synthon was subsequently cyclized as in Scheme 4 to oxazoline 7.…”

Section: Omura؊smith Synthesismentioning

confidence: 99%

Syntheses and Biological Evaluation of (+)-Lactacystin and Analogs

et al. 2000

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“…The biosynthetic origin of carbon atoms of lactacystin was studied by the feeding experiment of 13 C-labeled precursors to the culture medium of the producing microorganism. From 13 C-NMR analysis, lactacystin was found to be synthesized from acetate, L-cysteine, L-leucine and isobutyrate [9,10]. Total synthesis of lactacystin has been accomplished by many research groups.…”

Section: Biosynthesis and Chemical Synthesismentioning

confidence: 99%

“…The second synthesis was done by our group as shown in Fig. 3 [12,13]. Lactacystin was synthesized from (2R,3S )-3-hydroxyleucine by 10 steps with overall yield of 14%.…”

Section: Biosynthesis and Chemical Synthesismentioning

confidence: 99%

Recent progress of the research on novel microbial metabolites

Ōmura¹,

Hayashi²,

Tomoda³

1999

Pure and Applied Chemistry

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Three kinds of microbial metabolites with unique structures and activities were discovered in cell-based screening systems. Lactacystin with a peptide-like structure, isolated as an inducer of neurite outgrowth of Neuro 2a cells (a mouse neuroblastoma cell line), was found to inhibit proteasome functions speci®cally by binding to the active site N-terminal threonine of the catalytic subunit. Macrospelides with a 16-membered-ring structure embodying three lactone likages were isolated as inhibitors of the adhesion of HL-60 cells to the monolayer of LPS-activated human umbilical vein endothelial cells. They blocked the cell±cell adhesion by inhibiting the endothelial cell-leukocyte adhesion molecule-1/sialyl-Lewis x recognition system. Macrosphelides proved effective in in vivo models of the lung metastasis and ®brosis. Madindolines with an indoline-diketocyclopenetene connecting structure, isolated as inhibitors of the growth of IL-6 dependent cells, were found to inhibit IL-6 and IL-11 functions selectively. LACTACYSTIN Background

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“…[3][4][5][6][7] As reported preliminarily by Õmura et al, ( ＋ )-lactacystin (I) (Scheme 1), an NTF-like substance, was isolated from a culture broth of Streptomyces sp. OM-6519 in 1991 [8][9][10] and elucidated as the novel γ-lactam thiolester structure through spectral data and X-ray analysis. [11][12][13][14][15] Lactacystin was thought to be a small molecular mimic of nerve growth factor.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Neurotrophic Activities of N‐p‐Tolyl/phenylsulfonyl L‐Amino Acid Thiolester Derivatives

et al. 2008

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Various N-p-tolyl/phenylsulfonyl L-amino acid thiolester derivatives were designed and synthesized according to combination of functional groups. The synthesized compounds were identified by spectral methods ( 1 H NMR, 13 C NMR, MS and HRMS). Preliminary bioassays indicated that the compounds 4a, 4b, 4d, 5c, 5d, 5g, 6b and 6dshowed remarkable activities and the compounds 4c, 5b and 6c showed moderate activities to inhibit anoxic damage of PC12 cells at 10 µg/mL, but the compounds 4d and 6d only showed moderate protective activities against PC12 cells at 5 µg/mL. Preliminary bioassays also indicated that the compounds 4c, 5a, 5c, 5d, 5e and 6b showed moderate activities to induce PC12-differentiation at 10 µg/mL.

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Total Synthesis of (+)-Lactacystin

Cited by 151 publications

References 48 publications

Syntheses and Biological Evaluation of (+)-Lactacystin and Analogs

Syntheses and Biological Evaluation of (+)-Lactacystin and Analogs

Recent progress of the research on novel microbial metabolites

Synthesis and Neurotrophic Activities of N‐p‐Tolyl/phenylsulfonyl L‐Amino Acid Thiolester Derivatives

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