Biomimetic synthesis is an area of
organicchemical 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 knownenzymic 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
inorganiccatalysts 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 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.
Heathcock synthesis of
squalene-derived daphniphylline-type alkaloids, via tetracyclization or pentacyclization cascades[13][14]
References
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PMID14695603.
^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.
ISBN978-3-7091-7158-5.
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cite book}}: |journal= ignored (
help)
^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.
^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.
ISBN9780470719121.
^Stork G, Burgstrahler AW (1955). "The stereochemistry of polyene cyclization". J. Am. Chem. Soc. 77 (19): 5068–77.
doi:
10.1021/ja01624a038.
^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.
^Breslow R (1995). "Biomimetic chemistry and artificial enzymes: Catalysis by design". Accounts of Chemical Research. 28 (3): 146–153.
doi:
10.1021/ar00051a008.
^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.
ISBN978-3-642-34065-9.
^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.
^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.
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.