408348-31-2Relevant academic research and scientific papers
MACROCYCLIC INHIBITORS OF PEPTIDYLARGININE DEIMINASES
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, (2021/11/06)
The present disclosure relates to novel compounds for use in therapeutic treatement of a disease associated with peptidylarginine deiminases (PADs), such as peptidylarginine deiminase type 4 (PAD4). The present disclosure also relates to processes and intermediates for the preparation of such compounds, methods of using such compounds and pharmaceutical compositions comprising the compounds described herein.
Enantioselective total synthesis of (-)-Clavosolide A and B
Son, Jung Beom,Kim, Si Nae,Kim, Na Yeong,Hwang, Min-Ho,Lee, Wonsun,Lee, Duck Hyung
scheme or table, p. 653 - 663 (2010/08/19)
Enantioselective total synthesis of (-)-clavosolide A and B was reported in full including the synthesis of proposed structure of (-)-clavosoldie A (1), revised structure of (-)-clavosoldie A (5), and revised structure of (-)-clavosoldie B (6). The relative and absolute stereochemistries of the natural products were confirmed unambiguously by comparing the optical rotation values and 1H and 13C NMR spectra of them.
A systematic study of the hydride reduction of cyclopropyl ketones with structurally simplified substrates. Highly stereoselective reductions of trans-substituted cyclopropyl ketones via the bisected s-cis conformation
Kazuta, Yuji,Abe, Hiroshi,Yamamoto, Tamotsu,Matsuda, Akira,Shuto, Satoshi
, p. 3511 - 3521 (2007/10/03)
The stereoselective hydride reduction of the cis- and trans-substituted cyclopropyl ketones was systematically investigated using a series of structurally simplified substrates, trans-[tertbutyldiphenylsilyloxymethyl]cyclopropyl ketones 1a-e and trans-(benzyloxymethyl)cyclopropyl methyl ketone (2), and the corresponding cis congeners 3a,b,e and 4. The results showed that, not only in the reduction of the cis-substituted cyclopropyl ketones but also in that of the trans-substituted ketones, high stereoselectivity can be realized when the substrate has a bulky substituent on the cyclopropane ring, even though it is attached to the position trans to the acyl moiety. Ab initio calculations based on the density functional theory (DFT) of cyclopropyl ketones showed that (1) the bisected s-cis and s-trans conformers were the only two minimum energy conformers, while the s-cis conformer was more stable than the s-trans and (2) a bulky alkyl group in the acyl moiety and a cis substituent on the cyclopropane ring made the bisected s-cis conformer much more stable. On the basis of these calculations and experimental results, it is likely that the more stable the bisected s-cis conformer of the substrate, the more stereoselective the hydride reduction. Thus, the stereochemistry can be explained by hydride attack on the bisected s-cis conformation of the substrate from the less-hindered face. The predictability of the stereochemical results is predicated on the bisected s-cis transition-state model, which is very important from the viewpoint of synthetic organic chemistry.
Development of versatile cis- and trans-dicarbon-substituted chiral cyclopropane units: Synthesis of (1S,2R)- and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes and their enantiomers as conformationally restricted analogues of histamine
Kazuta, Yuji,Matsuda, Akira,Shuto, Satoshi
, p. 1669 - 1677 (2007/10/03)
The cyclopropane ring can be used effectively in restricting the conformation of biologically active compounds to improve activity and also to investigate bioactive conformations. We designed (1S,2R)- and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes (1 and 2, respectively) and their enantiomers (ent-1 and ent-2) as conformationally restricted analogues of histamine. The four types of chiral cyclopropanes bearing two differentially functionalized carbon substituents in a cis or trans relationship on a cyclopropane ring, (1S,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formyl-cyclopropane (7) and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (8) and their enantiomers (ent-7 and ent-8), were developed as the key intermediates for synthesizing 1, 2, ent-1, and ent-2. The reaction between (R)-epichlorohydrin [(R)-12] and phenylsulfonylacetonitrile (13a) in the presence of NaOEt in EtOH followed by treatment with acid gave the chiral cyclopropane lactone 11a with 98% ee in 82% yield. Compound 11a was converted into both the cis- and transchiral cyclopropane units 7 and 8, respectively, via reductive desulfonylation with Mg/MeOH as the key step. The corresponding enantiomers, the cis-substituted ent-7 and the trans-substituted ent-8, were also prepared starting from (S)-epichlorohydrin [(S)-12]. The four conformationally restricted target histamine analogues 1, 2, ent-1, and ent-2 were successfully synthesized from 7, 8, ent-7, and ent-8, respectively. The chiral cyclopropane units 7, 8, ent-7, and ent-8 should be useful as versatile intermediates for synthesizing various compounds having an asymmetric cyclopropane structure.
Synthesis of Optically Active cis- and trans-1,2-Disubstituted Cyclopropane Derivatives by the Simmons-Smith Reaction of Allyl Alcohol Derivatives Derived from (R)-2,3-O-Isopropylideneglyceraldehyde
Morikawa, Tsutomu,Sasaki, Hirofumi,Hanai, Ryo,Shibuya, Akira,Taguchi, Takeo
, p. 97 - 103 (2007/10/02)
The Simmons-Smith reactions of Z- and E-allyl alcohol derivatives 6 derived from (R)-2,3-O-isopropylideneglyceraldehyde (5) were used for the synthesis of optically active cis- and trans-1,2-disubstituted cyclopropane derivatives.Reaction of 6 with diethyl zinc and diiodomethane gave cyclopropane derivatives 7 in 84percent to quantitative yields with 35 to ca. 100percent des.Identical facial selectivities toward the double bonds, 1re-2si for Z-6 and 1re-2re for E-6, were observed in the cyclopropanations.The diastereoselectivity was dependent on the protecting group on the terminal allylic oxygen (R of 6, TBDPS > MOM > Bn) and on the stereochemistry of the double bond (Z > E).For TBDPS ethers Z- and E-6c, cis- and trans-7c were obtained as single diastereomers, respectively.It was clearly demonstrated that the stereoselectivity of the cyclopropanation is controlled by the directing effect of the allylic oxygen (O-1) of the dioxolane ring, which coordinates to the reagent.The terminal allylic oxygen (O-2) lowered the diastereoselectivity.This reaction was applied to the synthesis of optically active cyclopropane analogs of γ-aminobutyric acid (GABA) 18, 22, and ent-22.
