An Evaluation of Biomimetic Synthesis: Common Traits and Identification Criteria

1. An Evaluation of Biomimetic Synthesis: Common Traits and Identification Criteria Taylor P.A. Hari March 17, 2011

2. The Field of Biomimicry • Relatively young field within science; rapidly emerging field • SciFinder locates 17, 407 citations containing “biomimetic” Images from Flickr.com

3. The Field of Biomimetic Synthesis • SciFinder locates 5045 citations containing “biomimetic + synthesis” • 5 Year Trend - Organocatalysis(3533):Biomimetic synthesis (2231) • SciFinder locates 5045 citations containing “biomimetic + synthesis” • 5 Year Trend - OrganocatalysisBiomimetic synthesis • To date, there does not exist general, fully definitive criteria outlining what constitutes biomimetic synthesis

4. What is “Biomimetic?” • The term itself holds ambiguous origins within chemical synthesis: • R. Robinson, A Synthesis of Tropinone, J. Chem. Soc.1917, 111, 762 – 768. • E. E. van Tamelen, Biogenetic-type Syntheses of Natural Products, Fortchr. Chem. Org. Naturst.1961, 4, 242 – 290. ... a specific reaction or sequence of reactions that mimic a proposed biological pathway. The process being imitated usually has solid biochemical background. • R. Breslow, Biomimetic chemistry, centenary lecture, Chem. Soc. Rev. 1972, 1, 553 – 580. Biomimetic chemistry is the branch of organic chemistry which attempts to imitate natural reactions and enzymatic processes as a way to improve the power of organic chemistry.

5. Presentation Outline • Superior examples of biomimetic syntheses in chemistry • Tropinone (Robinson) • Daphniphyllum Alkaloids (Heathcock) • Endiandric Acids A-G (Nicolaou) • Nitrophenyl-Substituted Polyene Metabolites (Baldwin, Trauner & Hertweck) • Establishment of criteria permitting use of biomimetic term • Evaluation of published articles against criteria • (+)-FR182877 (Sorensen) • (S)-(–)-Zearalenone (Barrett) • Summary

6. An Elegant Synthesis of Tropinone • Tropinone is a precursor to atropine • First synthesis (Willstätter) was 14 steps • WWI instrumental in Robinson’s synthetic optimization of Tropinone R Willstätter, Annalen, 1901, 317, 204; 1903, 326, 1. R Robinson, J. Chem. Soc.1917, 111, 762 – 768, 876 – 899.

7. A Comparison of Robinson and Nature • Synthetic Approach to Tropinone (i) • Biogenic Formation of Tropinone (i) P Dewick, Medicinal Natural Products, Pyrrolidine and Tropane Alkaloids, 2002, 292 – 293. R Robinson, J. Chem. Soc.1917, 111, 762 – 768, 876 – 899.

8. An Accidental Biomimetic Synthesis • Synthetic Approach to Tropinone (ii) • Biogenic Formation of Tropinone (ii) P Dewick, Medicinal Natural Products, Pyrrolidine and Tropane Alkaloids, 2002, 292 – 293. R Robinson, J. Chem. Soc.1917, 111, 762 – 768, 876 – 899.

9. A Retrospective Tropinone Summary • One-pot transformation in 42% yield • Robinson employs same key transformations as nature • Mild conditions (H2O solvent at room temperature until final decarboxylation step) • First occurrence of biomimetic synthesis [This synthesis] was quite ahead of its time both in terms of elegance and logic. With this synthesis Robinson introduced aesthetics into total synthesis … K.C. Nicolaou K C Nicolaou, et al., Angew. Chem. Int. Ed., 2000, 39, 44 – 122.

10. The Daphniphyllum Family of Alkaloids C Heathcock, et al, Pure & Appl. Chem., 1989, 61 (3), 289 – 292.

11. The Proposed Biosynthesis of the Daphniphyllum Alkaloid Family C Heathcock, et al, Pure & Appl. Chem., 1989, 61 (3), 289 – 292.

12. The Biomimetic Synthesis of Proto-daphniphylline Yields Great Insight • Mislabelled bottle of ammonia actually contained methylamine, which acts as a substitute until the final cyclization step C Heathcock, et al, Pure & Appl. Chem., 1990, 62 (10), 1911 – 1920.

13. True Biogenetic Precursor of the Daphniphyllum Alkaloid Family Discovered • Dihydro-proto-daphniphyllum suggests an alkylamine as the biosynthetic source of nitrogen C Heathcock, et al, Proc. Natl. Acad. Sci., 1996, 93, 14323 – 14327.

14. The Daphniphyllum Alkaloids Summary • One-pot transformation of linear precursor to a complex product containing 5 fused rings and 8 stereocenters in 65% yield • Fully diastereoselective without use of asymmetric catalyst • Initial hypothesis based on earlier precedence was synthetically supported • Biomimetic precursor modification still yields final product • Initial biogenic hypothesis improved by accident, but logically accounted for and supported by nature

15. The Endiandric Acids A-D: Electrocyclization Cascade Products? D Black et al, J. Chem. Soc. Chem. Commun., 1980, 902.

16. The Development of a Polyunsaturated Biomimetic Precursor . K C Nicolaou et al, J. Am. Chem. Soc., 1982, 104, 5555 – 5564.

17. Confirmation of Electrocyclization Cascade . K C Nicolaou et al, J. Am. Chem. Soc., 1982, 104, 5555 – 5564.

18. The Endiandric Acid Summary • Both E,E and Z,Z geometries of the outer olefins in the tetraene system yield product • Framework established in one-pot operation by creating four fused rings and eight stereocenters without the use of an asymmetric catalyst • Racemic nature of the endiandric acids strongly suggests a nonenzymatic pathway from Black’s achiralpolyene precursors • High-yielding process provided synthetic support for biogenic hypothesis

19. Unusual Nitrophenyl-Substituted Polyene Metabolites • SNF4435C/D show selective immunosuppression in vitro J Baldwin, et al, Org. Lett.,2002, 4, 3731 – 3734; ibid., 2005, 2473 – 2476; Tetrahedron, 2006, 62, 1675 – 1689. D Trauner, et al, Org. Lett., 2002, 4 (13), 2221 – 2224. C Hertweck, D Trauner, et al, Angew. Chem. Int. Ed., 2006, 45, 7835 – 7838; Phytochemistry, 2009, 70, 1833 – 1840.

20. SNF4435C & SNF4435D: Product of Spectinabilin Isomerization • J Baldwin et al Key Biomimetic Transformation • D Trauner et al Key Biomimetic Transformation J Baldwin, et al, Org. Lett.,2002, 4, 3731 – 3734; ibid., 2005, 2473 – 2476; Tetrahedron, 2006, 62, 1675 – 1689. D Trauner, et al, Org. Lett., 2002, 4 (13), 2221 – 2224; ibid., 2005, 7 (20), 4475 – 4477.

21. In vivo Confirmation of Biosynthetic Origin Yields Novel Discovery “Polyene Splicing” C Hertweck, D Trauner, et al, Angew. Chem. Int. Ed., 2006, 45, 7835 – 7838; Phytochemistry, 2009, 70, 1833 – 1840.

22. The Nitrophenyl-Substituted Metabolite Summary • Racemic nature of SNF4435C&D strongly suggests a nonenzymatic pathway in resemblance of the endiandric acids • Framework established in a single operation by installing the bicyclo [4.2.0] octadiene core via photoisomerization • Photoisomerization of spectinabilin confirmed as biogenic origin • Discovery of new metabolite, orinocin, and “polyene splicing”

23. Biomimetic Criteria Established from Synthetic Commonalities A biomimetic synthesis is an organic synthesis designed to follow, via key transformations, biosynthetic pathways proved, or presumed, to be used in the natural construction of the desired product An organic synthesis designed to follow, via key transformations, biosynthetic pathways proved, or presumed, to be used in the natural construction of the desired product • The biosynthetic pathway does not need to be experimentally proven, but when hypothetical, must be based on sound biochemical principles • Term is meant to refer to presumed intermediates and biosynthetic paths, and little emphasis is placed on reagents and conditions (“physiological synthesis”) E E van Tamelen, Fortschr. Chem. Org. Naturst., 1961, 19, 242 – 290.

24. Biomimetic Criteria Established from Synthetic Commonalities A biomimetic synthesis is an organic synthesis designed to follow, via key transformations, biosynthetic pathways proved, or presumed, to be used in the natural construction of the desired product An organic synthesis designed to follow, via key transformations, biosynthetic pathways proved, or presumed, to be used in the natural construction of the desired product • One key reaction (or cascade) in the synthesis should yield considerable progress in the assembly of the desired product • The intermediate required for the execution of the key reaction may possess the exact biogenic structure, or be a simple modification • Synthesis must provide isolatable quantity of the desired product and be moderately yielding from the proposed precursor E E van Tamelen, Fortschr. Chem. Org. Naturst., 1961, 19, 242 – 290.

25. Presentation Outline • Superior examples of biomimetic syntheses in chemistry • Tropinone (Robinson) • Daphniphyllum Alkaloids (Heathcock) • Endiandric Acids A-G (Nicolaou) • Nitrophenyl-Substituted Polyene Metabolites (Baldwin, Trauner & Hertweck) • Establishment of criteria permitting use of biomimetic term • Evaluation of published articles against criteria • (+)-FR182877 (Sorensen) • (S)-(–)-Zearalenone (Barrett) • Summary

26. Synthesis of FR182877 Based on Hexacyclinic Acid Biogenesis • Cytotoxic fungal metabolite with efficacy against several human cancer cell lines comparable to Taxol® A Zeeck, et al, Angew. Chem. Int. Ed., 2000, 39 (18), 3258 – 3261. E Sorensen, et al, J. Am. Chem. Soc., 2002, 124, 4552 – 4553.

27. Biosynthetic Origin of (+)-FR182877 Proposes Alternate Pathways The biosynthetic pathway does not need to be experimentally proven, but when hypothetical, must be based on sound biochemical principles Term is meant to refer to presumed intermediates and biosynthetic paths, and little emphasis is placed on reagents and conditions E Sorensen, et al, Org. Lett., 1999, 1 (4), 645 -648. E Sorensen, et al, J. Am. Chem. Soc., 2002, 124, 4552 – 4553.

28. An Approach Based on Tandem Diels-Alder Reactions Yields (+)-FR182877 One key reaction (or cascade) in the synthesis should yield considerable progress in the assembly of the desired product The intermediate required for the execution of the key reaction may possess the exact biogenic structure, or be a simple modification Synthesis must provide isolatable quantity of the desired product and be moderately yielding from the proposed precursor E Sorensen, et al, J. Am. Chem. Soc., 2002, 124, 4552 – 4553. E Sorensen, et al, J. Am. Chem. Soc., 2003, 125 (18), 5393 – 5407.

29. (+)-FR182877 Summary • Provides synthetic support for postulated biogenic origin based on unsound biochemical principle (i) • Based on flawed PKS biosynthetic pathway (ii) • Complex framework established via tandem Diels-Alder approach without the use of an asymmetric catalyst (iii) • Synthetic precursor possessed minor adjustments to proposed biosynthetic precursor (iv) • 18% yield from the proposed biomimetic precursor; 40% yield during key tandem Diels-Alder operation (v) • Determined that natural product is the enantiomer of originally published work as synthetic rotation was opposite sign • Verdict: Biosynthetically-Inspired Synthesis

30. Development of Resorcylate Natural Products One key reaction (or cascade) in the synthesis should yield considerable progress in the assembly of the desired product The intermediate required for the execution of the key reaction may possess the exact biogenic structure, or be a simple modification Synthesis must provide isolatable quantity of the desired product and be moderately yielding from the proposed precursor A Barrett & H Miyatake-Ondozabal, Tetrahedron, 2010, 66, 6331 – 6334.

31. Aromatization Precedes Cyclization in (S)-(–)-Zearalenone Biosynthesis The biosynthetic pathway does not need to be experimentally proven, but when hypothetical, must be based on sound biochemical principles Term is meant to refer to presumed intermediates and biosynthetic paths, and little emphasis is placed on reagents and conditions Iffa Gaffoor & Frances Trail, Appl. Environ. Microbiol., 2006, 72 (3), 1793 – 1799. M Wang, et al, Biochemistry, 2009, 48 (27), 6288 – 6290.

32. (S)-(–)-Zearalenone • Contradicts biosynthetic origin in order of sequences (i/ii) • Framework established via macrocyclization of a ketene-trapped linear precursor, followed by a late-stage aromatization step (iii) • Biomimetic precursor valid with PKS linear elongation products (iv) • 46% yield from the proposed biomimetic precursor without the use of asymmetric catalysts (v) • Verdict: Total Synthesis A Barrett & H Miyatake-Ondozabal, Tetrahedron, 2010, 66, 6331 – 6334. M Wang, et al, Biochemistry, 2009, 48 (27), 6288 – 6290.

33. Presentation Summary A biomimetic synthesis is an organic synthesis designed to follow, via key transformations, biosynthetic pathways proved, or presumed, to be used in the natural construction of the desired product • Term may be at risk for misuse and criteria should be met in order to avoid “buzzword” status • Provides advantages including relatively high yields and mild conditions to complex frameworks in few key transformations • Currently, most examples appear to be pericyclic reactions; as field expands, criteria can undergo appropriate growth as well • It should be noted, a successful biomimetic synthesis by itself does not definitively prove a proposed biogenic pathway

34. Acknowledgments Christopher Boddy, Christine Achampong, Kyle Conway, Mark Dornan, Wab Falsetto, Pat “In Gronigen” Hill, Mark Horsman, Kevin Lafayette, Sanjay Manhas, Nelson Pearce, Ata Pinto, Cole Stevens, Luis Villegas, Ramburk Wilke, Winnipeg Wirz

35. The biosynthetic pathway does not need to be experimentally proven, but when hypothetical, must be based on sound biochemical principles Term is meant to refer to presumed intermediates and biosynthetic paths, and little emphasis is placed on reagents and conditions One key reaction (or cascade) in the synthesis should yield considerable progress in the assembly of the desired product The intermediate required for the execution of the key reaction may possess the exact biogenic structure, or be a simple modification Synthesis must provide isolatable quantity of the desired product and be moderately yielding from the proposed precursor