Posted by Natural cyclodextrins (CDs) have waited for about 130 years until they could see their mirror image when looking into the mirror. During the 130-year-old life of CDs, many significant discoveries have occurred, but a recent report on the very first synthesis of the mirror image, The recent seminal publication on the synthesis of L-CDs, (Fig.1) reported in Nature Synthesis (1) will certainly open a new chapter in the CDs-related supramolecular chemistry. The synthesis of L-CDs starting from the unnatural monosaccharide, L-glucose reported by a research group under the leadership of Nobel laurate Sir Fraser Stoddart, resulted in the creation of about 500 mg each of the L-optical antipodes of most widely used parent CDs: L-alpha-, L-beta- and L- gamma CDs. This discovery represents a fundamental addition to the CDs toolbox. However, it may take time for CD technologists to see some really unique, practical application of L-CDs.
Figure 1. Looking into the mirror: pictures of L-alpha CD „born” in 2024 and D-alpha CD „born” in 1891 (from Ref. Wu et al Nature Synt., 2024)
The syntheses of each of the three L-CDs took at most eight steps starting from two readily available monosaccharide building blocks with combinations of commonly used protecting and leaving groups. The elegant synthtic route to L-CDs includes the highly diastereoselective installations of multiple contiguous 1,2-cis L-glucopyranosidic linkages, the rapid assembly of linear oligosaccharides employing one-pot glycosylation strategies and three efficient diastereoselective cyclizations. Authors chose the most commonly used protecting groups in carbohydrate chemistry, benzoyl- and benzyl-groups to protect the primary (O-6) and secondary (O-2,3) hydroxyls. The chemical structures and inherent NEW chiralities of all three synthetic L-CDs have been established by single-crystal X-ray diffraction and induced electronic circular dichroism spectroscopy. These unique characteristics of L-CDs will render them useful in the development of host–guest systems capable of performing chiral recognition, and chemical reactions which will differ in their enantio-selectivities from the current ones, based on the widely applied natural D-CDs.
Since the mirror image CDs have unnatural stereochemistry, they most probably, will be more resitant to the attack of amylolytic enzymes, and their fate/metabolism in living organisms will be a great challenge for biologists. The fact that L-CDs will not be susceptible to enzymatic degradation could be a critical issue for their biomedical applications wherein CDs act as delivery agents, functional excipients.
However, these L-CDs – just because of their resistance to enzymatic degradation – might have a role in biomedical research and applications.
The authors of this great study should feel comfortably and encouraged by a recent publication that describes the occurrence of α-L-glucosidase, thus indicating the possible existence of α-L-glucosides in nature. (2) So, authors foresee a future in which enzymatic synthesis of L-CDs – by using synthetic mirror-image CD-glucosyl-transferase acting on α-L-glucosides – might become a possibility.
Read also the review from S.R. Beeren (3).
References:
1. Yong Wu, Saba Aslani, Han Han, Chun Tang, Guangcheng Wu, Xuesong Li, Huang Wu, Charlotte L. Stern, Qing-Hui Guo, Yunyan Qiu, Aspen X.-Y.Chen, Yang Jiao, Ruihua Zhang, Arthur H. G. David, Daniel W. Armstrong* & J. Fraser Stoddart (2024) Mirror-Image Cyclodextrins. Nature Synthesis https://doi.org/10.1038/s44160-024-00495-8
2. Rikako Shishiuchi, Hyejin Kang, Takayoshi Tagami, Yoshitaka Ueda, Weeranuch Lang, Atsuo Kimura, Masayuki Okuyama (2022) Discovery of α-l-Glucosidase Raises the Possibility of α-l-Glucosides in Nature ACS Omega 7, 47411–47423. https://doi.org/10.1021/acsomega.2c06991
3. S. R. Beeren (2024) Synthesis of L-cyclodextrins. Nature Synthesis (2024) https://doi.org/10.1038/s44160-024-00512-w
*A personal remark: Author of this blog is pleased to read among the authors of this seminal paper the name of Prof. Daniel W. Armstrong, the great pioneer of CD-based enantioseparations.