Organic Letters
Letter
Scheme 3. Total Synthesis of the Revised Structure of
Mangrolide D (2)
AUTHOR INFORMATION
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a
Corresponding Author
ORCID
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This work is dedicated to the memory of Prof. Dr. Kenji Mori.
We gratefully acknowledge financial support from the Swiss
National Science Foundation (182043) and thank Simon Jurt
(University of Zurich) for assistance with NMR spectroscopy.
REFERENCES
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(1) Luepke, K. H.; Suda, K. J.; Boucher, H.; Russo, R. L.; Bonney,
M. W.; Hunt, T. D.; Mohr, J. F. Pharmacotherapy 2017, 37, 71.
(2) (a) Simpkin, V. L.; Renwick, M. J.; Kelly, R.; Mossialos, E. J.
Antibiot. 2017, 70, 1087. (b) Fischbach, M. A.; Walsh, C. T. Science
2009, 325, 1089. (c) Cooper, M. A.; Shlaes, D. Nature 2011, 472, 32.
(3) Liu, F.; Myers, A. G. Curr. Opin. Chem. Biol. 2016, 32, 48.
(4) Totally synthetic mangrolide A: (a) Hattori, H.; Roesslein, J.;
Caspers, P.; Zerbe, K.; Miyatake-Ondozabal, H.; Ritz, D.; Rueedi, G.;
Gademann, K. Angew. Chem., Int. Ed. 2018, 130, 11020. Totally
synthetic fidaxomicin: (b) Kaufmann, E.; Hattori, H.; Miyatake-
Ondozabal, H.; Gademann, K. Org. Lett. 2015, 17, 3514. (c) Hattori,
H.; Kaufmann, E.; Miyatake-Ondozabal, H.; Berg, R.; Gademann, K. J.
Org. Chem. 2018, 83, 7180. Syntheses of the fidaxomicin aglycon :
(d) Jeanne-Julien, L.; Masson, G.; Astier, E.; Genta-Jouve, G.;
Servajean, V.; Beau, J. M.; Norsikian, S.; Roulland, E. Org. Lett. 2017,
19, 4006. (e) Glaus, F.; Altmann, K. H. Angew. Chem., Int. Ed. 2015,
54, 1937. (f) Erb, W.; Grassot, J. M.; Linder, D.; Neuville, L.; Zhu, J.
Angew. Chem., Int. Ed. 2015, 54, 1929. (g) Miyatake-Ondozabal, H.;
Kaufmann, E.; Gademann, K. Angew. Chem., Int. Ed. 2015, 54, 1933−
1936.
a
TCBC = 2,4,6-trichlorobenzoyl chloride, 2,6-t-BuPy = 2,6-di-tert-
butylpyridine.
obtained the α-isomer α-17, we attempted the final trans-
formations to the revised structure 2 of mangrolide D .
Deprotections of the silyl protecting groups were achieved
using 3HF·NEt3 to give diol 18. At this point, we were
surprised to find that the (E)-18 could be separated from the
undesired (Z)-isomer.22 The pure azide (E)-18 was finally
reduced under Staudinger conditions, and the subsequent
purification by reversed-phase HPLC furnished the targeted
product 2. Analysis of H and 13C NMR spectra revealed that
1
the chemical shift and coupling constants of the revised
compound 2 completely match those reported for natural
sample as well as the recently reported data for revised
mangrolide D.9 Other spectroscopic data, including 2D NMR
results, also supported the identity between the synthetic 2 and
the natural 2.5
(5) Jamison, M. T. Mangrolide A, A Novel Marine Derived
Polyketide with Selective Antibiotic Activity. Ph.D. thesis, The
University of Texas Southwestern Medical Center (US), May 2013.
(6) (a) Bylsma, M.; Bennett, C. S. Org. Lett. 2018, 20, 4695.
(b) Parker, K. A.; Chang, W. Org. Lett. 2003, 5, 3891 and references
therein .
In conclusion, the total synthesis of the revised structure 2 of
mangrolide D is presented. The synthesis of the carbohydrate
segment is enabled by an enantioselective LLB catalyzed
epoxidation, Lewis acid promoted intramolecular aza-Michael
addition, and careful selection of leaving groups and the
respective activation conditions for the key glycosylation. The
differences in 1H NMR spectra of the key sugar segment 4 led
us to revise the structure to its epimer 13 as an intermediate.
Finally, the successful glycosylation with the sterically
demanding macrocyclic alcohol provided the revised structure
2 after a series of deprotections.
(7) For the few successful applications, see: (a) Nicolaou, K. C.;
Mitchell, H. J.; Jain, N. F.; Bando, T.; Hughes, R.; Winssinger, N.;
Natarajan, S.; Koumbis, A. E. Chem. - Eur. J. 1999, 5, 2648.
(b) Kitamura, K.; Maezawa, Y.; Ando, Y.; Kusumi, T.; Matsumoto, T.;
Suzuki, K. Angew. Chem., Int. Ed. 2014, 53, 1262.
(8) Review for glycosylation of 2-deoxy sugars: Bennett, C. S.;
Galan, M. C. Chem. Rev. 2018, 118, 7931.
(9) Gong, J.; Li, W.; Fu, P.; MacMillan, J.; De Brabander, J. K. Org.
Lett. 2019, 21, 2957.
(10) Chen, H.; Thomas, M. G.; Hubbard, B. K.; Losey, H. C.;
Walsh, C. T.; Burkart, M. D. Proc. Natl. Acad. Sci. U. S. A. 2000, 97,
11942.
(11) (a) Yu, B. Acc. Chem. Res. 2018, 51, 507. (b) Li, W.; Yu, B.
Chem. Soc. Rev. 2018, 47, 7954.
(12) Nemoto, T.; Ohshima, T.; Yamaguchi, K.; Shibasaki, M. J. Am.
Chem. Soc. 2001, 123, 2725.
ASSOCIATED CONTENT
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S
* Supporting Information
(13) (a) Yu, X.-Q.; Yoshimura, F.; Ito, F.; Sasaki, M.; Hirai, A.;
Tanino, K.; Miyashita, M. Angew. Chem., Int. Ed. 2008, 47, 750.
(b) Yu, X. Q.; Yoshimura, F.; Tanino, K.; Miyashita, M. Tetrahedron
Lett. 2008, 49, 7442.
The Supporting Information is available free of charge on the
(14) A mixture of (E)- and (Z)-isomers was used for the
lactonization. We found that separation of the isomers was
unnecessary as both could be converted to the desired lactone 8
under the given conditions. We assume the reduction in yield is
Experimental procedures, characterization data, and
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copies of H, 13C, and 2D NMR spectra for all new
C
Org. Lett. XXXX, XXX, XXX−XXX