- Copper-Catalyzed Enantioconvergent Cross-Coupling of Racemic Alkyl Bromides with Azole C(sp2)?H Bonds
-
The development of enantioconvergent cross-coupling of racemic alkyl halides directly with heteroarene C(sp2)?H bonds has been impeded by the use of a base at elevated temperature that leads to racemization. We herein report a copper(I)/cinchona-alkaloid-derived N,N,P-ligand catalytic system that enables oxidative addition with racemic alkyl bromides under mild conditions. Thus, coupling with azole C(sp2)?H bonds has been achieved in high enantioselectivity, affording a number of potentially useful α-chiral alkylated azoles, such as 1,3,4-oxadiazoles, oxazoles, and benzo[d]oxazoles as well as 1,3,4-triazoles, for drug discovery. Mechanistic experiments indicated facile deprotonation of an azole C(sp2)?H bond and the involvement of alkyl radical species under the reaction conditions.
- Chang, Xiao-Yong,Chen, Ji-Jun,Gu, Qiang-Shuai,Jiang, Sheng-Peng,Li, Zhong-Liang,Liu, Lin,Liu, Xiao-Dong,Liu, Xin-Yuan,Su, Xiao-Long,Wang, Fu-Li,Yang, Chang-Jiang,Ye, Liu
-
supporting information
p. 380 - 384
(2020/10/30)
-
- Transition-metal-free oxidative iodination of 1,3,4-oxadiazoles
-
Transition-metal-free oxidative iodination of 2-substituted 1,3,4-oxadiazoles was achieved by using sodium iodide as the halide source and Selectfluor as the oxidant. Variously substituted products were obtained in moderate to good yields under operationa
- Dannenberg, Carl Albrecht,Bizet, Vincent,Zou, Liang-Hua,Bolm, Carsten
-
supporting information
p. 77 - 80
(2015/02/02)
-
- Tri-peptide Inhibitors of Serine Elastases
-
The present invention provides compounds of formula (I): where X is R1—(CR3R4)nOC(O)—; R1—(CR3R4)nC(O)—; R1—C(O)NH(CR3R4)nOC(O)—; R1—C(O)NH(CR3R4)nC(O)—; R1—C(O)(CR3R4)nOC(O)—; or R1—C(O)(CR3R4)nC(O)—; where R1 is optionally substituted C5-10 aryl or heteroaryl; OH or NH2; where R3 and R4 are independently H or methyl; and n is 0 to 6; and Y is —CF3 or one of: where R2 is C1-8 alkyl optionally substituted with halo or —OH; —(CR6R7)p—C5-6 aryl optionally substituted with halo, —OH, C1-8 alkyl, C1-8 haloalkyl, —(CH2)mC(O)NH2 or —(CH2)mOCH3; where R6 and R7 are independently H or methyl; m is 0 to 4, and p is 0 or 1 or a pharmaceutically acceptable salt, ester, metabolite or prodrug thereof
- -
-
-
- Development of a kilogram-scale synthesis of cis-LC15-0133 tartrate, a potent dipeptidyl peptidase IV inhibitor
-
(45)-N-Boc-4-fluoro-L-proline methyl ester (4) was prepared from the following sequence of reactions: esterification of trans-4-hydroxy-L-proline (2), Boc protection, and fluorination by DAST. Reaction of 4 with lithiated oxadiazole provided oxadiazolyl ketone 7. Deprotection of the Boc group of 7 and subsequent coupling with bromoacetyl bromide gave bromide 9. Coupling reaction of 9 with excess oxazolidine 16 provided coupled product 17. Unexpectedly, the stereogenic center of 17 was completely epimerized to a virtually 1:1 mixture of cis- and trans-17 at this stage. After the deprotection of the N,O-methylene acetal group of 17 using aqueous ammonium chloride, crystallization induced dynamic resolution (CIDR) of cis- and Awns-mixture of LC15-0133 (1) in the course of tartrate salt formation provided cis-LC15-0133 (1a) tartrate salt in 83% yield (>98% de).
- Kim, Bong Chan,Kim, Kyu-Young,Lee, Hee Bong,Shin, Hyunik
-
p. 626 - 631
(2013/01/03)
-
- Keto-1,3,4-oxadiazoles as cathepsin K inhibitors
-
We have prepared a series of cathepsin K inhibitors bearing the keto-1,3,4-oxadiazole warhead capable of forming a hemithioketal complex with the target enzyme. By modifying binding moieties at the P1, P2, and prime side positions of the inhibitors, we have achieved selectivity over cathepsins B, L, and S, and have achieved sub-nanomolar potency against cathepsin K. This series thus represents a promising chemotype that could be used in diseases implicated by imbalances in cathepsin K activity such as osteoporosis.
- Palmer, James T.,Hirschbein, Bernard L.,Cheung, Harry,McCarter, John,Janc, James W.,Yu, Z. Walter,Wesolowski, Gregg
-
p. 2909 - 2914
(2008/09/21)
-
- 1,3,4-oxadiazole derivatives and process for producing the same
-
Oxadiazole derivatives represented by formula (I): (wherein R1represents a hydrogen atom or an amino-protective group; R2, R3, and R4each independently represents an alkyl group, a cycloalkyl group, a phenyl gro
- -
-
-
- Peptoid and nonpeptoid containing alpha-keto oxadiazoles as serine protease inhibitors
-
The present invention relates to certain substituted oxadiazole peptoids and nonpeptoids useful as inhibitors of serine proteases, especially human neutophil elastase (HNE). Compounds of the present invention are useful for the treatment or amelioration of symptoms of adult respiratory distress syndrome, septic shock, and multiple organ failure. Processes mediated by HNE are also implicated in conditions such as arthritis, periodontal disease, glomerulonephritis, and cystic fibrosis.
- -
-
-
- Development of orally active nonpeptidic inhibitors of human neutrophil elastase
-
5-Amino-2-phenylpyrimidin-6-ones, some of their desamino derivatives, and miscellaneous derivatives were synthesized and biologically evaluated on both in vitro activity and oral activity in an acute hemorrhagic assay. These compounds contained an α-keto-1,3,4-oxadiazole moiety to bind covalently to the Ser-195 hydroxy group of human neutrophil elastase (HNE). Among those tested, compounds 11a-c,e,i-l(F), 11d,e,k(H), 21d,e,k(F), and 21d,e(H) showed a good oral profile. RS-Mixture 3(H) was selected for clinical evaluation based on its oral potency, duration of action, enzyme selectivity, safety profile, and ease of synthesis. Structure -activity relationships (SARs) are discussed.
- Ohmoto,Yamamoto,Okuma,Horiuchi,Imanishi,Odagaki,Kawabata,Sekioka,Hirota,Matsuoka,Nakai,Toda,Cheronis,Spruce,Gyorkos,Wieczorek
-
p. 1268 - 1285
(2007/10/03)
-
- Indole and tetrahydroisoquinoline containing Alpha-keto oxadiazoles as serine protease inhibitors
-
The present invention relates to certain substituted oxadiazole nonpeptides, which are useful as inhibitors of human neutrophil elastase (HNE) for the treatment of HNE-mediated processes implicated in conditions such as adult respiratory distress syndrome, septic shock and multiple organ failure. A series of studies also have indicated the involvement HNE in myocardial ischemia-reperfusion injury, emphysema. HNE-mediated processes are implicated in other conditions such as arthritis, periodontal disease, glomerulonephritis, dermatitis, psoriasis, cystic fibrosis, chronic bronchitis, atherosclerosis, Alzheimer's disease, organ transplantation, corneal ulcers, and invasion behavior of malignant tumors.
- -
-
-
- VAL-PRO CONTAINING ALPHA-KETO OXADIAZOLES AS SERINE PROTEASE INHIBITORS
-
The present invention relates to certain substituted oxadiazole tripeptides, which are useful as inhibitors of human neutrophil elastase (HNE) for the treatment of HNE-mediated processes implicated in conditions such as adult respiratory distress syndrome, septic shock and multiple organ failure. A series of studies also have indicated the involvement HNE in myocardial ischemia-reperfusion injury, emphysema. HNE-mediated processes are implicated in other conditions such as arthritis, periodontal disease, glomerulonephritis, dermatitis, psoriasis, cystic fibrosis, chronic bronchitis, atherosclerosis, Alzheimer's disease, organ transplantation, corneal ulcers, and invasion behavior of malignant tumors.
- -
-
-
- SERINE PROTEASE INHIBITORS
-
The present invention relates to certain substituted oxadiazole nonpeptides, which are useful as inhibitors of human neutrophil elastase (HNE) for the treatment of HNE-mediated processes implicated in conditions such as adult respiratory distress syndrome, septic shock and multiple organ failure. A series of studies also have indicated the involvement HNE in myocardial ischemia-reperfusion injury, emphysema. HNE-mediated processes are implicated in other conditions such as arthritis, periodontal disease, glomerulonephritis, dermatitis, psoriasis, cystic fibrosis, chronic bronchitis, atherosclerosis, Alzheimer's disease, organ transplantation, corneal ulcers, and invasion behavior of malignant tumors.
- -
-
-