Chemical synthesis of 12-HHT and related metabolites derived from polyunsaturated fatty acids
协作的有机化学和生物学successfully developed a new area of research. Science of metabolites derived from polyunsaturated fatty acids by COX or LOX is one of successful examples. These metabolites are chemical mediators that promote initiation or resolution of inflammation and wound healing. Among the mediators 12-hydroxyheptadecatrienoic acid (12-HHT,1) derived from arachidonic acid (ARA) has a somewhat unique history (Fig. 1).
Fig. 1. Polyunsaturated fatty acids and targeted metabolites.
This metabolite has been isolated as a byproduct in the cascade producing thromboxane A2in 1970s. Later in 1997 and 2000, Yokomizo and Shimizu have isolated receptors BLT1 and BLT2 for leukotriene B4 (LTB4), which is an inflammatory mediator derived from ARA. Affinity is high and low, respectively. After a while Yokomizo and Okuno discovered high affinity of 12-HHT for BLT2. BLT2 is ubiquitously distributed in humans. In the colon epithelium, mucosal integrity is maintained by 12-HHT/BLT2, which also responsible for skin wound healing. Similar metabolites HHTE (2) and HHD (3从二十碳五烯酸(EPA)的起源) and dihomo-γ-linolenic acid (DGLA) have also been isolated (Fig. 1). However, supply of these metabolites is limited leaving biological study behind.
With the above background in mind, organic synthesis of 12-HHT and the metabolites derived from EPA and DGLA in optically active forms was undertaken using the two key transformations based on Sharpless asymmetric epoxidation and the Suzuki-Miyaura coupling reaction. Thus, the former reaction of trimethylsilyl (TMS)-substituted allylic alcohol in racemic form (rac–4) afforded epoxide5and allylic alcohol (R)-4(Fig. 2, eq 1) The TMS group was responsible for attaining high enantiomeric excesses for both (98% ee). Furthermore, the TMS group in epoxide5directed reaction with Bu3SnLi and the resulting vinylstannane was converted to iodide6with trans iodo-olefin selectively. Allylic alcohol (R)-4was also converted to6via epoxidation and the Mitsunobu inversion. The borane reagent7for the Suzuki-Miyaura coupling was derived from the corresponding acetylene by hydroboration with HB(Sia)2(eq 2). This reagent was mixed with iodoalcohol6in the presence of Pd(PPh3)4as a catalyst and aqueous NaOH to furnish methyl ester of2, which upon hydrolysis afforded2. Similarly, racemic (E)-1-iodooct-1-en-3-ol was converted to optically active 12-HHT (1) and HHD (3). The synthesis was scaled up to more than 100 mg of1. With 12-HHT in hand, the authors found that 12-HHT was decomposed to some extent in a halogenated solvent such as CH2Cl2and CHCl3at room temperature overnight, whereas EtOH was a safe solvent.
Fig. 2. Synthesis of HHTE and the two key transformation. Sia: -CHMeCHMe2
In addition, Suzuke-Miyaura coupling is a strong and convenient method for construction of conjugated olefins and compatible with hydroxyl and ester groups. We have utilized this coupling for synthesis of 12-HHT analogues, resolvin E1, protectin D1, and maresin 1.
Yuichi Kobayashi
Department of Biotechnology, Tokyo Institute of Technology
Yokohama, Japan
Publication
Asymmetric synthesis of 12-hydroxyheptadecatrienoic acid and its 5,6-dihydro- and 14,15-dehydro-derivatives.
Kobayashi Y, Morita M, Ogawa N, Kondo D, Tojo T
Org Biomol Chem. 2016 Dec 7
Related Articles:
|
The roles of mesenchymal stem cells secretome in diabetic…There has been a fourfold rise in the number of diabetics from 108 million in 1980 to 422 million in 2014 and by 2040 the number will reach to 642… |
|
The efficacy of L-Mesitran Medical Grade Honey for wound…South Africa is home to some of the world's most endangered wildlife, with the White rhinoceros (Cerathotherium simum) among its most threatened species due to its highly sought-after horn. The… |
|
Essential fatty acids in the vegan/total vegetarian dietPeople choose vegetarian/vegan diets and for many reasons, however, these diets require careful dietary planning. The essential polyunsaturated n-6 (omega-6) and n-3 (omega-3) fatty acids are required for synthesis of… |
|
Medical grade honey facilitates the healing of minor…Children are at risk to injuries and wounds as it is their nature to play and explore in adventurous environments. At the same time, they are less experienced in calculating… |
|
3D-bioengineered human amniotic membrane scaffold for…In the tissue engineering context, attention to the biological scaffolds due to the safety, efficacy, and bio-mimicity was discussed. Among the natural scaffolds, human amniotic membrane (HAM) has shown to… |
|
L-Mesitran Medical Grade Honey works better for treating…In a recent clinical study, it was shown that L-Mesitran improves the healing time of cold sores in relation to conventional treatments. In addition, pain and itching were decreased. Cold… |
Leave a Reply
You must belogged into post a comment.