Biomimetic synthesis

Biomimetic synthesis is an area of organic chemical synthesis that is specifically biologically inspired. The term encompasses both the testing of a "biogenetic hypothesis" (conjectured course of a biosynthesis in nature) through execution of a series of reactions designed to parallel the proposed biosynthesis, as well as programs of study where a synthetic reaction or reactions aimed at a desired synthetic goal are designed to mimic one or more known enzymic transformations of an established biosynthetic pathway.^[1][2] The earliest generally cited example of a biomimetic synthesis is Sir Robert Robinson's organic synthesis of the alkaloid tropinone.^[3]

A more recent example is E.J. Corey's carbenium-mediated cyclization of an engineered linear polyene to provide a tetracyclic steroid ring system,^[4] which built upon studies of cationic cyclizations of linear polyenes by the Albert Eschenmoser and Gilbert Stork,^[5][6] and the extensive studies of the W.S. Johnson to define the requirements to initiate and terminate the cyclization, and to stabilize the cationic carbenium group during the cyclization (as nature accomplishes via enzymes during biosynthesis of steroids such as cholesterol).^[7] In relation to the second definition, synthetic organic or inorganic catalysts applied to accomplish a chemical transformation accomplished in nature by a biocatalyst (e.g., a purely proteinaceous catalyst, a metal or other cofactor bound to an enzyme, or a ribozyme) can be said to be accomplishing a biomimetic synthesis, where design and characterization of such catalytic systems has been termed biomimetic chemistry.^[8][9][10]

Synthesis of proto-daphniphylline

Proto-Daphniphylline is biosynthesized from squalene

(a) Key precursors A and B for the synthesis of proto-daphniphylline. (b) Mechanisms for converting dialdehyde A to proto-daphniphylline.

Proto-daphniphylline is a precursor in the biosynthesis of a family of alkaloids found in Daphniphyllum macropodum. It is of interest due to its complex molecular structure making it a challenging target for conventional organic synthesis methods due to the fused ring structure and the spiro carbon centre. Based on a proposed biosynthesis pathway of proto-daphniphylline from squalene, Clayton Heathcock and co-workers developed a remarkably elegant and short total synthesis of proto-daphniphylline from simple starting materials.^[11] This is an example of how biomimetic synthesis can simplify the total synthesis of a complex natural product.

The key step in Heathcock's synthetic route involves a cyclization of acyclic dialdehydes A or B to form proto-daphniphylline. Both dialdehydes (A or B) have carbon skeletons analogous to squalene and can be synthesized from simple starting materials. Treating A or B with a sequence of simple reagents containing potassium hydroxide, ammonia, and acetic acid led to the formation of proto-daphniphylline. Six σ-bonds and five rings were formed in this remarkable step. It was proposed in the original report that hydroxyldihydropyran intermediate C was first formed when the dialdehyde starting material (A) was treated with potassium hydroxide. A 2-aza-1, 3-diene intermediate (D) was generated from the reaction of intermediate C with ammonia. An acid-catalyzed Diels-Alder reaction formed intermediate E which was further converted to the final product under the reaction conditions.

Examples of biomimetic syntheses in Wikipedia

• carpanone, via the Chapman approach
• spirotryprostatin B, via the Ganesan approach
• endiandric acid, see Biomimetic Total synthesis, via Nicolaou approach

Further literature examples of biomimetic syntheses

• Merck synthesis of nakiterpiosin-type C-nor-D-homosteroids, e.g., Structural: Cleaved, contracted, and expanded rings (seco-, nor-, and homosteroids), via C-13 atom migration^[12]
• Heathcock synthesis of squalene-derived daphniphylline-type alkaloids, via tetracyclization or pentacyclization cascades^[13][14]

References

1. de la Torre MC, Sierra MA (January 2004). "Comments on recent achievements in biomimetic organic synthesis". Angew. Chem. Int. Ed. Engl. 43 (2): 160–81. doi:10.1002/anie.200200545. PMID 14695603.
2. van Tamelen EE (1961). "Biogenetic-type Syntheses of Natural Products". Fortschritte der Chemie Organischer Naturstoffe / Progress in the Chemistry of Organic Natural Products / Progrès dans la Chimie des Substances Organiques Naturelles. Vol. 19. pp. 242–290. doi:10.1007/978-3-7091-7156-1_5. ISBN 978-3-7091-7158-5. PMID 13924635.
3. Robinson R (1917). "LXIII. A Synthesis of Tropinone". Journal of the Chemical Society, Transactions. 111: 762–768. doi:10.1039/CT9171100762.
4. Corey EJ, Luo G, Lin LS (1997). "A simple enantioselective synthesis of the biologically active tetracyclic marine sesterterpene scalarenedial". J. Am. Chem. Soc. 119 (41): 9927–28. doi:10.1021/ja972690l.
5. Eschenmoser A, Felix D, Gut M, Meier J, Stadler P (1959). "Some aspects of acid-catalysed cyclizations of terpenoid polyenes". In Wolstenholme GE, O'Conner M (eds.). Ciba Foundation Symposium on the Biosynthesiis of Terpenes and Steroids. Novartis Foundation Symposia. London: J. & A. Churchill. pp. 217–230. doi:10.1002/9780470719121.ch14. ISBN 9780470719121.
6. Stork G, Burgstrahler AW (1955). "The stereochemistry of polyene cyclization". J. Am. Chem. Soc. 77 (19): 5068–77. doi:10.1021/ja01624a038.
7. Johnson WS, Marshall JA, Keana JF, Franck RW, Martin DG, Bauer JV (1966). "Steroid total synthesis—hydrochrysene approach—XVI: Racemic conessine, progesterone, cholesterol, and some related natural products". Tetrahedron. 22: 541–601. doi:10.1016/S0040-4020(01)90961-5.
8. Breslow R (January 2009). "Biomimetic chemistry: biology as an inspiration". The Journal of Biological Chemistry. 284 (3): 1337–42. doi:10.1074/jbc.X800011200. PMID 18784073.
9. Lee SC, Holm RH (April 2003). "Speculative synthetic chemistry and the nitrogenase problem". Proceedings of the National Academy of Sciences of the United States of America. 100 (7): 3595–600. doi:10.1073/pnas.0630028100. PMC 152967. PMID 12642670.
10. Breslow R (1995). "Biomimetic chemistry and artificial enzymes: Catalysis by design". Accounts of Chemical Research. 28 (3): 146–153. doi:10.1021/ar00051a008.
11. Piettre S, Heathcock CH (June 1990). "Biomimetic total synthesis of proto-daphniphylline". Science. 248 (4962): 1532–4. Bibcode:1990Sci...248.1532P. doi:10.1126/science.248.4962.1532. PMID 17818314. S2CID 37777797.
12. Gao S, Chen C (2012). "Nakiterpiosin". In Li JJ, Corey EJ (eds.). Total Synthesis of Natural Products: At the Frontiers of Organic Chemistry. Berlin: Springer. pp. 25–38. ISBN 978-3-642-34065-9.
13. Heathcock CH, Hansen MM, Ruggeri RB, Kath JC (1992). "Daphniphyllum alkaloids. 11. Biomimetic total synthesis of methyl homosecodaphniphyllate. Development of the tetracyclization reaction". Journal of Organic Chemistry. 57 (9): 2544–53. doi:10.1021/jo00035a008.
14. Heathcock CH, Piettre S, Ruggeri RB, Ragan JA, Kath JC (1992). "Daphniphyllum alkaloids. 12. A proposed biosynthesis of the pentacyclic skeleton. proto-Daphniphylline". Journal of Organic Chemistry. 57 (9): 2554–66. doi:10.1021/jo00035a009.

Further reading

• Poupon E, Nay B, eds. (2011). Biomimetic Organic Synthesis. Alkaloids. Vol. 1. Wiley-VCH Verlag GmbH & Co. KGaA. doi:10.1002/9783527634606. ISBN 978-3-527-32580-1.
• Ashely E (January 5, 2004). "Biomimetic Synthesis of Natural Products" (PDF). Literature Seminar, Stoltz Research Group. California Institute of Technology. Archived from the original (PDF) on June 23, 2010. Retrieved November 24, 2013.