Organic & Biomolecular Chemistry Blog

“In biomimetic chemistry, we take what we have observed in nature and apply its principles to the invention of novel synthetic compounds that can achieve the same goals….”¹

– Ronald Breslow

Biomimetic chemistry is broadly defined as the area of chemistry which aims to imitate the biosynthetic pathways (or parts of the biosynthetic pathways) used by Nature to create chemical bonds.

Just as the fundamental principles of chemistry help us to understand how biological systems work, we can also use biology as an inspiration for developing new chemistry.

Biomimetic chemistry is often used as a method for attempting to prove or disprove proposed biosynthetic pathways; however it can also be used to design laboratory procedures for making synthetic compounds, resulting in reactions which imitate a natural chemical process. For example, elaborate natural products can be more efficiently synthesized in the laboratory by looking at how Nature handles the chemical complexity of such an operation; reaction selectivity can be greatly enhanced by taking tips from how Nature uses enzymes to hold substrates in position while reactions occur.²

α-Amino acids are a fundamental building block in Nature, as the precursors to many biological molecules. In biological systems, amino acids are synthesized from α-ketoacids in a transamination reaction catalysed by the enzyme aminotransferase, with glutamate as the nitrogen source (Scheme 1).³

In this paper, Shi and co-workers seek to mimic this reaction with an enantioselective transamination of α-ketoesters (which can be readily transformed into amino acids) using a substituted benzylamine as the nitrogen source (Scheme 2). The enantioselectivity is induced using chiral base (1, Scheme 2) derived from quinine, a naturally occurring alkaloid which is isolated from the bark of the cinchona tree. This new, biomimetic methodology is highly complementary to the current literature methods for making enantioenriched α-amino acids.

To read more, see;

Organocatalytic Synthesis of Optically Active β-Branched α-Amino Ester via Asymmetric Biomimetic Transamination

Cunxiang Su, Ying Xie, Hongjie Pan, Mao Liu, Hua Tian, Yian Shi, Org. Biomol. Chem., 2014, DOI:10.1039/c4ob00684d.

References

¹ R. Breslow, J. Bio. Chem., 2009, 284, 1337.

² S. France, D. Guerin, S. Miller, T. Lectka, Chem. Rev., 2003, 103, 2985.

³ E. J. Parker, A. J. Pratt, 2010, “Amino Acid Biosynthesis, in Amino Acids, Peptides and Proteins in Organic Chemistry: Building Blocks, Catalysis and Coupling Chemistry”, Volume 3 (ed A. B. Hughes), Wiley-VCH Verlag GmbH & Co.

Dr C. Liana Allen is currently a post-doctoral research associate in the group of Professor Scott Miller at Yale University, where she works on controlling the enantio- or regioselectivity of reactions using small peptide catalysts. Liana received her Ph.D. in organic chemistry at Bath University with Professor Jonathan Williams, where she worked on developing novel, efficient syntheses of amide bonds.

Vinigrol is a diterpenoid natural product, first isolated from the fungal strain Virgaria nigra F-5408 in 1987 by Ando and co-workers. It has been found to display biological activity against hypertension, platelet aggregation, HIV and inflammation. Despite these broad potential medicinal uses of vinigrol prompting great interest in its chemical synthesis, the first total synthesis of this molecule was not achieved until 2009, when Baran and co-workers published their outstanding stereocontrolled and fully scalable twenty three step route.¹

Figure 1. Vinigrol

The over two decade gap between isolation and the first published total synthesis can be attributed to the great synthetic challenges posed by the structure of vinigrol. The molecular structure of vinigrol (elucidated by X-ray crystallography) contains an unusual cis-decalin ring system, bridged by an eight membered ring, in addition to eight contiguous stereocentres. Due to this rare molecular structure, retrosynthetic analyses of vinigrol have been highly varied. A total synthesis attempt in 2003 by Paquette involved an anionic oxy-Cope rearrangement to create a decorated decalin ring system, however final closure of the eight membered ring was unsuccessful. In 2005, the same group found a ring closing metathesis strategy using Grubbs catalyst also failed to deliver the eight membered ring (Figure 2).² Separate attempts at a vinigrol total synthesis by Fallis, Njardarson and Hanna also did not result in complete synthesis of the natural product.³ The 2009 synthesis by Baran utilized two challenging Diels-Alder reactions to create much of the cyclic  core of vinigrol (Figure 2). A subsequent Grob fragmentation was the key step towards furnishing the tricyclic vinigrol core, with minimal further elaboration giving the completed natural product in 3% overall yield.

Figure 2. Precursors for the eight membered ring formation

In this paper, Sun and co-workers take on this long standing challenge from a new perspective. Instead of attempting to install the troublesome eight membered ring in a late-stage transformation, they begin with an eight membered ring as a starting material, and rely on its inherent conformational bias to control the selectivity of further functionalisations. This cleverly circumvents the necessity for the ring-closing step which caused so many problems in earlier synthesis attempts. Their strategy proved successful, with two Michael additions (which indeed proved to be stereoselective, based on the natural conformation of the eight membered ring) providing three of the eight stereocentres in just two steps. Further elaboration of the ring system followed by an intramolecular Tsuji-Trost allylation reaction gave 1 (Figure 3), which, despite bearing the wrong stereochemistry at one of its six stereocentres, can be regarded as a potential late-stage precursor to the natural product vinigrol.

Figure 3. Sun and coworkers approach to the synthesis of vinigrol

To read more, see;

“A novel synthetic approach to the bicyclo[5.3.1]-undecan-11-one framework of vinigrol”
Xian-Lei Wang, Yun-Yu Lu, Jie Wang, Xuan Wang, He-Quan Yao, Guo-Qiang Lin and Bing-Feng Sun,
Org. Biomol. Chem., 2014, DOI:10.1039/c4ob00046c. Free to access until 26 May

References

¹ T. J. Maimone, J. Shi, S. Ashida, P. S. Baran, J. Am. Chem. Soc., 2009, 131, 17066.

² L. A. Paquette, R. Guevel, S. Sakaoto, I. H. Kim, J. Crawford, J. Org. Chem., 2003, 68, 6096; L. A. Paquette, I. Efremov, Z. Liu, J. Org. Chem., 2005, 70, 505.

³ J. Lu, D. G. Hall, Angew. Chem. Int. Ed., 2010, 49, 2286.

Dr C. Liana Allen is currently a post-doctoral research associate in the group of Professor Scott Miller at Yale University, where she works on controlling the enantio- or regioselectivity of reactions using small peptide catalysts. Liana received her Ph.D. in organic chemistry at Bath University with Professor Jonathan Williams, where she worked on developing novel, efficient syntheses of amide bonds.

Deoxyribonucleic acid (DNA) is one of the most famous molecules in the world. First isolated and identified by Freidrich Miescher in 1871,¹ DNA is responsible for coding ‘genetic instructions’ in all known living organisms and viruses. DNA molecules consist of two long helical biopolymer chains wrapped around a common axis and held tightly together by intermolecular forces called hydrogen bonds and base-stacking interactions. Each biopolymer chain is made up of small units called nucleotides, which themselves consist of a sugar, a phosphate group, and one of four different nucleobases (guanine, adenine, thymine or cytosine, abbreviated to G, A, T and C respectively). The specific orders in which the nucleotides appear in a DNA strand is what allows for the storage of genetic information.

Figure 1. Modified deoxycytosine and deoxyguanosine forming four hydrogen bonds

Shorter, single strands of nucleotide residues bonded together are called oligonucleotides. They are capable of binding to another oligonucleotide strand (via the same intermolecular forces as found in full length DNA helices) if the other strand has the ‘complimentary’ order of nucleotides (cytosine and guanine exclusively bind with each other; as do adenine and thymine). Due to this property, they are used in areas such as genetic testing, gene therapy, DNA probes and forensics.

The binding of one strand to its complimentary strand can be strengthened by modifying the nucleobase, as long as the  modifications do not disrupt duplex formation. In particular, the nucleobase cytosine has several reported modifications² which allow for additional hydrogen bonding (thus strengthening the binding of two strands). Unfortunately, a lot of the previously reported cytosine modifications have the drawback of long synthetic sequences necessary to make them.

In this paper, Sekine and co-workers report their modifications of cytosine nucleotides, and measure these new molecule’s binding affinities with guanine (the ‘complimentary’ base which cytosine hydrogen bonds with, Figure 1). As well as demonstrating an efficient synthetic route to their new cytosine derivatives, the authours prove that oligonucleotides which incorporate their modified cytosine residue show an increased binding affinity to the complimentary strands when compared with the unmodified, parent oligonucleotide. These promising results could lead to the design and synthesis of even better cytosine nucleotides inspired by the scaffold reported in this work, in turn leading to oligonucleotides which can perform better in DNA-recognition based tests.

To read more, see;

A new modified cytosine base capable of base pairing with guanidine using four hydrogen bonds
K. Yamada, Y. Masaki, H. Tsunoda, A. Ohkubo, K. Seio and M. Sekine,
Org. Biomol. Chem., 2014, DOI:10.1039/c3ob42420k. Download PDF

Free to access until 10th April

References

¹ R. Dahm, “Discovering DNA: Friedrich Miescher and the early years of nucleic acid research” Human Genetics, 2008, 122, 565–81.
² A. S. Wahba, A. Esmaeili, M. J. Damha, R. H. E. Hudson, Nucleic Acids Res., 2010, 38, 1048; S. Preus, K. Kilsa, L. M. Wilhelmsson, B. Albinsson, Phys. Chem. Chem. Phys., 2010, 12, 8881; A. Ohkubo, T. Sakaue, H. Tsunoda, K. Seio, M. Sekine, Chem. Lett., 2010, 39, 726.

Dr C. Liana Allen is currently a post-doctoral research associate in the group of Professor Scott Miller at Yale University, where she works on controlling the enantio- or regioselectivity of reactions using small peptide catalysts. Liana received her Ph.D. in organic chemistry at Bath University with Professor Jonathan Williams, where she worked on developing novel, efficient syntheses of amide bonds.