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Iterative assembly line synthesis of polypropionates with full stereocontrol

Nature Chemistry volume 9, pages 896–902 (2017)Cite this article

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Abstract

The polypropionate motif is ubiquitous, being characteristic of the most important family of natural products for human health, the polyketides. Numerous strategies have been devised to construct these molecules with high stereocontrol, but certain stereoisomers remain challenging to prepare. We now describe the development of an iterative assembly line strategy for the construction of polypropionates. An assembly line strategy for the synthesis of deoxypolypropionates has already been described. However, the introduction of carbinol units required the development of new building blocks and new reaction conditions. This has been achieved by the use of enantioenriched lithiated α-chlorosilanes [1-((2′-lithiochloromethyldimethylsilyl)-methyl)-2-(methoxymethyl)-pyrrolidine], thus enabling the programmed synthesis of polypropionates in a fully stereocontrolled manner, including the stereochemically challenging anti–anti isomers. The versatility of the approach is exemplified in its extension to the synthesis of 1,3-related polyols. The methodology now allows access to a much wider family of polyketide natural products with stereochemistry being dialled in at will.

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Figure 1: Iterative assembly line strategy for polyketide synthesis.
Figure 2: Issues associated with homologation of β-alkoxy boronic esters and possible solutions using a silyl group as a masked-oxygen functionality for iterative homologations.
Figure 3: Development of assembly line synthesis protocol for the construction of polypropionates.
Figure 4: Proposed catalytic cycle for photoredox cleavage of aminosilane 8a.

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References

  1. Rohr, J. A new role for polyketides. Angew. Chem. Int. Ed. 39, 2847–2849 (2000).

    Article  CAS  Google Scholar 

  2. Koskinen, A. M. P. & Karisalmi, K. Polyketide stereotetrads in natural products. Chem. Soc. Rev. 34, 677–690 (2005).

    Article  CAS  Google Scholar 

  3. Hertweck, C. The biosynthetic logic of polyketide diversity. Angew. Chem. Int. Ed. 48, 4688–4716 (2009).

    Article  CAS  Google Scholar 

  4. Rimando, A. M. & Baerson, S. R. (eds) Polyketides: Biosynthesis, Biological Activity, and Genetic Engineering (American Chemical Society, 2006).

    Google Scholar 

  5. Weissman, K. J. & Leadlay, P. F. Combinatorial biosynthesis of reduced polyketides. Nat. Rev. Microbiol. 3, 925–936 (2005).

    Article  CAS  Google Scholar 

  6. Koehn, F. E. & Carter, G. T. The evolving role of natural products in drug discovery. Nat. Rev. Drug Discov. 4, 206–220 (2005).

    Article  CAS  Google Scholar 

  7. Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs over the last 25 years. J. Nat. Prod. 70, 461–477 (2007).

    Article  CAS  Google Scholar 

  8. Butler, M. S., Robertson, A. A. B. & Cooper, M. A. Natural product and natural product derived drugs in clinical trials. Nat. Prod. Rep. 31, 1612–1661 (2014).

    Article  CAS  Google Scholar 

  9. Omura, S. (ed.) Macrolide Antibiotics. Chemistry, Biology, and Practice (Academic, 2002).

    Google Scholar 

  10. Paterson, I. & Findlay, A. D. Recent advances in the total synthesis of polyketide natural products as promising anticancer agents. Aust. J. Chem. 62, 624–638 (2009).

    Article  CAS  Google Scholar 

  11. Hoffmann, R. W. Stereoselective syntheses of building blocks with three consecutive stereogenic centers: important precursors of polyketide natural products. Angew. Chem. Int. Ed. 26, 489–503 (1987).

    Article  Google Scholar 

  12. Li, J. & Menche, D. Direct methods for stereoselective polypropionate synthesis: a survey. Synthesis 2293–2315 (2009).

  13. Schetter, B. & Mahrwald, R. Modern aldol methods for the total synthesis of polyketides. Angew. Chem. Int. Ed. 45, 7506–7525 (2006).

    Article  CAS  Google Scholar 

  14. Evans, D. A. et al. Chiral enolate design. Pure Appl. Chem. 53, 1109–1127 (1981).

    Article  CAS  Google Scholar 

  15. Dechert-Schmitt, A.-M. R., Schmitt, D. C., Gao, X., Itoh, T. & Krische, M. J. Polyketide construction via hydroxyalkylation and related alcohol C–H functionalizations: reinventing the chemistry of carbonyl addition. Nat. Prod. Rep. 31, 504–513 (2014).

    Article  CAS  Google Scholar 

  16. Feng, J., Kasun, Z. A. & Krische, M. J. Enantioselective alcohol C–H functionalization for polyketide construction: unlocking redox-economy and site-selectivity for ideal chemical synthesis. J. Am. Chem. Soc. 138, 5467–5478 (2016).

    Article  CAS  Google Scholar 

  17. Chen, M. & Roush, W. R . Highly stereoselective synthesis of anti,anti-dipropionate stereotriads: a solution to the long-standing problem of challenging mismatched double asymmetric crotylboration reactions. J. Am. Chem. Soc. 134, 3925–3931 (2012).

    Article  CAS  Google Scholar 

  18. Cheng, B. & Trauner, D. A highly convergent and biomimetic total synthesis of portentol. J. Am. Chem. Soc. 137, 13800–13803 (2015).

    Article  CAS  Google Scholar 

  19. Burns, M. et al. Assembly-line synthesis of organic molecules with tailored shapes. Nature 513, 183–188 (2014).

    Article  CAS  Google Scholar 

  20. Balieu, S. et al. Toward ideality: the synthesis of (+)-kalkitoxin and (+)-hydroxyphthioceranic acid by assembly-line synthesis. J. Am. Chem. Soc. 137, 4398–4403 (2015).

    Article  CAS  Google Scholar 

  21. Sadhu, K. M. & Matteson, D. S. (Chloromethyl)lithium: efficient generation and capture by boronic esters and a simple preparation of diisopropyl (chloromethyl)boronate. Organometallics 4, 1687–1689 (1985).

    Article  CAS  Google Scholar 

  22. Xu, S., Li, H., Komiyama, M., Oda, A. & Negishi, E.-i. One-step homologation for the catalytic asymmetric synthesis of deoxypropionates. Chem. Eur. J. 23, 149–156 (2017).

    Article  CAS  Google Scholar 

  23. Xu, S. & Negishi, E.-i. Zirconium-catalyzed asymmetric carboalumination of unactivated terminal alkenes. Acc. Chem. Res. 49, 2158–2168 (2016).

    Article  CAS  Google Scholar 

  24. Gati, W. & Yamamoto, H. Second generation of aldol reaction. Acc. Chem. Res. 49, 1757–1768 (2016).

    Article  CAS  Google Scholar 

  25. Lin, L. et al. Catalytic asymmetric iterative/domino aldehyde cross-aldol reactions for the rapid and flexible synthesis of 1,3-polyols. J. Am. Chem. Soc. 137, 15418–15421 (2015).

    Article  CAS  Google Scholar 

  26. Zheng, K., Xie, C. & Hong, R. Bioinspired iterative synthesis of polyketides. Front. Chem. 3, 1–17 (2015).

    Google Scholar 

  27. Matteson, D. S. Functional group compatibilities in boronic ester chemistry. J. Organomet. Chem. 581, 51–65 (1999).

    Article  CAS  Google Scholar 

  28. Vedrenne, E., Wallner, O. A., Vitale, M., Schmidt, F. & Aggarwal, V. K. Homologation of boronic esters with lithiated epoxides for the stereocontrolled synthesis of 1,2- and 1,3-diols and 1,2,4-triols. Org. Lett. 11, 165–168 (2009).

    Article  CAS  Google Scholar 

  29. Jones, G. R. & Landais, Y. The oxidation of the carbon–silicon bond. Tetrahedron 52, 7599–7662 (1996).

    Article  CAS  Google Scholar 

  30. Basu, A. & Thayumanavan, S . Configurational stability and transfer of stereochemical information in the reactions of enantioenriched organolithium reagents. Angew. Chem. Int. Ed. 41, 716–738 (2002).

    Article  CAS  Google Scholar 

  31. Hoffmann, R. W., Rühl, T. & Harbach, J. On the configurational stability of α-hetero-substituted benzyllithium compounds. Liebigs Ann. Chem. 1992, 725–730 (1992).

  32. Schweifer, A. & Hammerschmidt, F. Formal and improved synthesis of enantiopure chiral methanol. Tetrahedron 64, 7605–7610 (2008).

    Article  CAS  Google Scholar 

  33. Aggarwal, V. K. et al. Asymmetric synthesis of tertiary and quaternary allyl- and crotylsilanes via the borylation of lithiated carbamates. Org. Lett. 13, 1490–1493 (2011).

    Article  CAS  Google Scholar 

  34. Barsamian, A. L., Wu, Z. & Blakemore, P. R. Enantioselective synthesis of α-phenyl- and α-(dimethylphenylsilyl)alkylboronic esters by ligand mediated stereoinductive reagent-controlled homologation using configurationally labile carbenoids. Org. Biomol. Chem. 13, 3781–3786 (2015).

    Article  CAS  Google Scholar 

  35. Nakamura, S. & Nakagawa, R. Watanabe, Y . & Toru, T. Highly enantioselective reactions of configurationally labile α-thioorganolithiums using chiral bis(oxazoline)s via two different enantiodetermining steps. J. Am. Chem. Soc. 122, 11340–11347 (2000).

    Article  CAS  Google Scholar 

  36. Lange, H., Huenerbein, R., Fröhlich, R., Grimme, S. & Hoppe, D . Configurationally labile lithiated O-benzyl carbamates: application in asymmetric synthesis and quantum chemical investigations on the equilibrium of diastereomers. Chem. Asian J. 3, 78–87 (2008).

    Article  CAS  Google Scholar 

  37. Chan, T. H. & Pellon, P. Chiral organosilicon compounds in synthesis. Highly enantioselective synthesis of arylcarbinols. J. Am. Chem. Soc. 111, 8737–8738 (1989).

    Article  CAS  Google Scholar 

  38. Strohmann, C., Lehmen, K., Wild, K. & Schildbach, D. A highly diastereomerically enriched benzyllithium compound: the molecular structure and the stereochemical course of its transformations. Organometallics 21, 3079–3081 (2002).

    Article  CAS  Google Scholar 

  39. Strohmann, C., Buchold, D. H. M., Seibel, T. Wild, K. & Schildbach, D. Syntheses and crystal structures of highly diastereomerically enriched lithiated benzylsilanes in the presence of external donor molecules: experiment and theory. Eur. J. Inorg. Chem. 2003, 3453–3463 (2003).

    Article  Google Scholar 

  40. Bagutski, V., French, R. M. & Aggarwal, V. K. Full chirality transfer in the conversion of secondary alcohols into tertiary boronic esters and alcohols using lithiation–borylation reactions. Angew. Chem. Int. Ed. 49, 5142–5145 (2010).

    Article  CAS  Google Scholar 

  41. Evans, D. A., Crawford, T. C., Thomas, R. C. & Walker, J. A. Studies directed toward the synthesis of prostaglandins. Useful boron-mediated olefin syntheses. J. Org. Chem. 41, 3947–3953 (1976).

    Article  CAS  Google Scholar 

  42. Tamao, K., Ishida, N., Tanaka, T. & Kumada, M. Hydrogen peroxide oxidation of the silicon–carbon bond in organoalkoxysilanes. Organometallics 2, 1694–1696 (1983).

    Article  CAS  Google Scholar 

  43. Stymiest, J. L., Bagutski, V., French, R. M. & Aggarwal, V. K. Enantiodivergent conversion of chiral secondary alcohols into tertiary alcohols. Nature 456, 778–782 (2008).

    Article  CAS  Google Scholar 

  44. Leonori, D. & Aggarwal, V. K. Lithiation–borylation methodology and its application in synthesis. Acc. Chem. Res. 47, 3174–3183 (2014).

    Article  CAS  Google Scholar 

  45. Bonet, A., Odachowski, M., Leonori, D., Essafi, S. & Aggarwal, V. K. Enantiospecific sp2–sp3 coupling of secondary and tertiary boronic esters. Nat. Chem. 6, 584–589 (2014).

    Article  CAS  Google Scholar 

  46. Wang, Y., Noble, A., Myers, E. L. & Aggarwal, V. K. Enantiospecific alkynylation of alkylboronic esters. Angew. Chem. Int. Ed. 55, 4270–4274 (2016).

    Article  CAS  Google Scholar 

  47. Hoppe, D . & Hense, T. Enantioselective synthesis with lithium/(−)-sparteine carbanion pairs. Angew. Chem. Int. Ed. 36, 2282–2316 (1997).

    Google Scholar 

  48. Beak, P., Baillargeon, M. & Carter, L. G. Lithiation of ethyl 2,4,6-triisopropylbenzoate adjacent to oxygen: the α-lithioalkyl alcohol synthon. J. Org. Chem. 43, 4255–4256 (1978).

    Article  CAS  Google Scholar 

  49. Hoppe, D., Marr, F. & Brüggemann, M. Organolithiums in Enantioselective Synthesis (ed. Hodgson, D. M.) 61–137 (Springer, 2003).

    Book  Google Scholar 

  50. Miyake, Y., Ashida, Y., Nakajima, K. & Nishibayashi, Y. Visible-light-mediated addition of α-aminoalkyl radicals generated from α-silylamines to α,β-unsaturated carbonyl compounds. Chem. Commun. 48, 6966–6968 (2012).

    Article  CAS  Google Scholar 

  51. Espelt, L. R., McPherson, I. S., Wiensch, E. M. & Yoon, T. P. Enantioselective conjugate additions of α-amino radicals via cooperative photoredox and Lewis acid catalysis. J. Am. Chem. Soc. 137, 2452–2455 (2015).

    Article  Google Scholar 

  52. Bode, S. E., Wolberg, M. & Müller, M . Stereoselective synthesis of 1,3-diols. Synthesis 557–588 (2006).

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Acknowledgements

Thge authors thank the European Research Council (FP7, ERC grant no. 670668), the EPSRC (EP/I038071/1) and Bristol University for financial support. T.B. acknowledges support from the Marie Curie Fellowship programme (EC FP7, no. 626828). The authors thank P.J. Unsworth for discussions and preliminary work.

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  1. School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK

    Teerawut Bootwicha, Julian M. Feilner, Eddie L. Myers & Varinder K. Aggarwal

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  1. Teerawut Bootwicha
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  2. Julian M. Feilner
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V.K.A. and E.L.M. conceived and directed the project. T.B. and J.M.F. conducted and designed the experiments and analysed the data. V.K.A., E.L.M. and T.B. co-wrote the paper.

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Correspondence to Varinder K. Aggarwal.

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Bootwicha, T., Feilner, J., Myers, E. et al. Iterative assembly line synthesis of polypropionates with full stereocontrol. Nature Chem 9, 896–902 (2017). https://doi.org/10.1038/nchem.2757

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