The Structure Elucidation of Haprolid

Dedicated to Professor Cesare Gennari on the occasion of his 65^th birthday

Abstract

The assignment of two stereocenters of the natural product haprolid through the application of a profile hidden Markov model (HMM) and its confirmation through total synthesis of the natural product and of two of its diastereomers are reported. The structure elucidation of this polyketide-peptide hybrid natural product is a telling showcase of how difficult it can be to determine the absolute configuration of isolated stereocenters and the benefits of a gene cluster analysis for structure determination. The key steps of the synthesis are a selective epoxidation of a terminal olefin and the stereodivergent macrolactonization strategy. Furthermore, the biological evaluation of all products showed that all diastereomers are potent inhibitors of hepatocellular carcinoma cell lines.

Key words

hidden Markov model - structure elucidation - natural products - stereoselective synthesis - biological evaluation

• References

• 1 New address: Sandoz GmbH, Biochemiestraße 10, 6336 Langkampfen, Austria.
• 2 Herrmann J. Fayad AA. Müller R. Nat. Prod. Rep. 2017; 34: 135
• 3a Jahns C. Hoffmann T. Müller S. Gerth K. Washausen P. Höfle G. Reichenbach H. Kalesse M. Müller R. Angew. Chem. Int. Ed. 2012; 51: 5239 ; Angew. Chem. 2012, 124, 5330
• 3b Rentsch A. Kalesse M. Angew. Chem. Int. Ed. 2012; 51: 11381 ; Angew. Chem. 2012, 124, 11543
• 3c Hartmann O. Kalesse M. Angew. Chem. Int. Ed. 2014; 53: 7335 ; Angew. Chem. 2014, 126, 7463
• 3d Gieseler MT. Kalesse M. Org. Lett. 2014; 16: 548
• 3e Tautz T. Hoffmann J. Hoffmann T. Steinmetz H. Washausen P. Kunze B. Huch V. Kitsche A. Reichenbach H. Höfle G. Müller R. Kalesse M. Org. Lett. 2016; 18: 2560
• 3f Gerstmann L. Kalesse M. Chem. Eur. J. 2016; 32: 11210
• 3g Poock C. Kalesse M. Org. Lett. 2017; 19: 4536
• 4 Steinmetz H. Li J. Fu C. Zaburannyi N. Kunze B. Harmrolfs K. Schmitt V. Herrmann J. Reichenbach H. Höfle G. Kalesse M. Müller R. Angew. Chem. Int. Ed. 2016; 55: 10113 ; Angew. Chem. 2016, 128, 10267
• 5a Symkenberg G. Kalesse M. Angew. Chem. Int. Ed. 2014; 53: 1795 ; Angew. Chem. 2014, 126, 1825
• 5b Xiao Q. Young K. Zakarian A. J. Am. Chem. Soc. 2015; 137: 5907
• 5c Wang J. Chen S.-G. Sun B.-F. Lin G.-Q. Shang Y.-J. Chem. Eur. J. 2013; 19: 2539
• 5d Wang Y. O’Doherty G. J. Am. Chem. Soc. 2013; 135: 9334
• 5e Kong K. Enquist JA. Jr. McCallum ME. Smith GM. Matsumaru T. Menhaji-Klotz E. Wood JL. J. Am. Chem. Soc. 2013; 135: 10890
• 5f Holmes MT. Britton R. Chem. Eur. J. 2013; 19: 12649
• 5g Vadhadiya PM. Puranik VG. Ramana CV. J. Org. Chem. 2012; 77: 2169
• 5h Florence GJ. Wlochal J. Chem. Eur. J. 2012; 18: 14250
• 6 Janssen D. Abert D. Jansen R. Müller R. Kalesse M. Angew. Chem. Int. Ed. 2007; 46: 4898 ; Angew. Chem. 2007, 119, 4985
• 7 Brodmann T. Janssen D. Kalesse M. J. Am. Chem. Soc. 2010; 132: 13610
• 8 Reid R. Piagentini M. Rodriguez E. Ashley G. Viswanathan N. Carney J. Santi DV. Hutchinson CR. McDaniel R. Biochemistry 2003; 42: 72
• 9 Caffrey P. ChemBioChem 2003; 4: 654
• 10 Kitsche A. Kalesse M. ChemBioChem 2013; 14: 851
• 11a Lu H.-H. Raja A. Franke R. Landsberg D. Sasse F. Kalesse M. Angew. Chem. Int. Ed. 2013; 52: 1354 ; Angew. Chem. 2013, 125, 13791
• 11b Lu H.-H. Hinkelmann T. Tautz T. Li J. Sasse F. Franke R. Kalesse M. Org. Biomol. Chem. 2015; 13: 8029
• 12 Appel R. Angew. Chem., Int. Ed. Engl. 1975; 14: 801 ; Angew. Chem. 1975, 87, 863
• 13 Grignard V. C. R. Hebd. Seances Acad. Sci. 1900; 130: 1322

For the use of terpenes in polyketide synthesis, see:
• 14a Swatschek J. Grothues L. Bauer JO. Strohmann C. Christmann M. J. Org. Chem. 2014; 79: 976
• 14b Winter P. Swatschek J. Willot M. Radtke L. Olbrisch T. Schäfer A. Christmann M. Chem. Commun. 2011; 47: 12200
• 15 Winter P. Vaxelaire C. Heinz C. Christmann M. Chem. Commun. 2011; 47: 394
• 16 Colladon M. Scarso A. Sgarbossa P. Michelin RA. Strukul G. J. Am. Chem. Soc. 2006; 128: 14006
• 17 Bal BS. Childers WE. Pinnick HW. Tetrahedron 1981; 37: 2091
• 18 Shiina I. Kubota M. Oshiumi H. Hashizume M. J. Org. Chem. 2004; 69: 1822
• 19 Mitsunobu O. Synthesis 1981; 1