Organic Letters
Letter
data reported by Rezanka for the molecule named
lytophilippine A (Figure 2). From this comparison, it is
available NMR data basis, a global rather than regional
configurational misassignment of the marine macrolide named
lytopilippine A must be concluded.
ASSOCIATED CONTENT
* Supporting Information
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S
The Supporting Information is available free of charge on the
Experimental procedures, configurational assignment,
and comparison of NMR data for 1a and 1b (PDF)
Elemental analyses, MS spectra, and IR spectra (PDF)
AUTHOR INFORMATION
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Corresponding Author
ORCID
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support by the DFG (HI628/12-2) and the TU
Dortmund is gratefully acknowledged.
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REFERENCES
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(1) Rezanka, T.; Hanus, L. O.; Dembitsky, V. M. Tetrahedron 2004,
60, 12191. The C27 palmitic acid and the C27 oleic acid esters were
also isolated and named lytophilippines B and C. Weak antibacterial
activity against Escherichia coli and Agrobacterium tumefaciens was
reported for the molecule named lytophilippine A.
̈
(2) Cinar, M. E.; Bilecenoglu, M.; Ozturk, B.; Can, A. Aquat.
Invasions 2006, 1, 84.
̈
Figure 2. Comparison of 13C NMR data.
(3) (a) Zlotkowski, K.; Hewitt, W. M.; Yan, P.; Bokesch, H. R.;
Peach, M. L.; Nicklaus, M. C.; O’Keefe, B. R.; McMahon, J. B.;
Gustafson, K. R.; Schneekloth, J. S. Org. Lett. 2017, 19, 1726. (b) Yan,
P.; Ritt, D. A.; Zlotkowski, K.; Bokesch, H. R.; Reinhold, W. C.;
Schneekloth, J. S.; Morrison, D. K.; Gustafson, K. R. J. Nat. Prod.
2018, 81, 1666.
(4) For a review on tetrahydrofuran-containing macrolides from
marine producers, see: Lorente, A.; Lamariano-Merketegi, J.;
Albericio, F.; Alvarez, M. Chem. Rev. 2013, 113, 4567.
(5) For selected recent synthetic work on constitutionally related
marine [14]macrolides, see: (a) Gil, A.; Lamariano-Merketegi, J.;
Lorente, A.; Albericio, F.; Alvarez, M. Org. Lett. 2016, 18, 4485.
(b) Lorente, A.; Gil, A.; Fernandez, R.; Cuevas, C.; Albericio, F.;
Alvarez, M. Chem. - Eur. J. 2015, 21, 150. (c) Schomaker, J. M.;
Borhan, B. J. Am. Chem. Soc. 2008, 130, 12228. (d) Ueda, M.;
Yamaura, M.; Ikeda, Y.; Suzuki, Y.; Yoshizato, K.; Hayakawa, I.;
Kigoshi, H. J. Org. Chem. 2009, 74, 3370.
(6) For examples of polyketides featuring chlorine-substituted
stereogenic sp3 carbon atoms, see: (a) Wyche, T. P.; Piotrowski, J.
S.; Hou, Y.; Braun, D.; Deshpande, R.; McIlwain, S.; Ong, I. M.;
Myers, C. L.; Guzei, I. A.; Westler, W. M.; Andes, D. R.; Bugni, T. S.
Angew. Chem., Int. Ed. 2014, 53, 11583. (b) Du, L.; King, J. B.;
Cichewicz, R. H. J. Nat. Prod. 2014, 77, 2454.
(7) Gille, A.; Hiersemann, M. Org. Lett. 2010, 12, 5258.
(8) Hodgson, D. M.; Salik, S. Org. Lett. 2012, 14, 4402.
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2476 For a modified synthetic procedure to 3, see the Supporting
immediately evident that extensive global and solvent-
1
independent deviations between the measured H and 13C
chemical shifts of synthetic 1b and those reported for the
molecule named lytophilippine A by Rezanka exist. Further-
more, our extensive NMR studies reveal that Δδ(solvent) is
generally far less pronounced than Δδ(1aRezanka−1b). Hence,
the already reported chemical shift differences for synthetic
and natural 1a Δδ(Rezanka−Lee) are probably not caused by
NMR solvent effects. Consequently, a deep-seated global
configurational misassignment of lytophilippine A by Rezanka
et al. must be concluded. Hence, future attempts to assign the
configuration of lytophilippine A by total synthesis have
probably no prospect of success, and we refrained from
converting 16 to a 11,14-trans-configured tetrahydrofuran
diastereomer of the natural product.35
In conclusion, the total synthesis (11R,13S,14R,15R)-
lytophilippine A (1b), a diastereomer of a [14]macrolide
originally isolated from a sample of the marine animal M.
philippina (alias L. philippinus), was accomplished. A longest
linear sequence consisting of 22 steps from known aldehyde 3
was established. Efforts were made to formulate a robust and
reliable total synthesis, and the sequence consisting of cross-
metathesis−aldol addition−diasteroface-differentiating β-hy-
droxy ketone reduction nicely embodies the agenda. We
provide extensive NMR data for 1b in different solvents and a
transparent chemical shift assignment. According to the thus-
(10) Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997, 119,
2586.
D
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