Journal of the American Chemical Society
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77% yield and 17:1 dr. 12-epi-17 was smoothly advanced
four steps to complete the synthesis of 12-epi-1 15
1
2
3
4
5
6
7
8
.
1. (a) Kavanagh, F.; Hervey, A.; Robbins, W. J. Proc. Natl. Acad. Sci. U.S.A.
1951, 37, 570. (b) Birch, A. J.; Holzapfel, C. W.; Rickards, R. W. Tetra-
hedron 1966, Suppl. 8, Part II, 359.
2. Poulsen, S. M.; Karlsson, M.; Johansson, L. B.; Vester, B. Mol. Microbiol.
2001, 41, 1091-1099.
In contrast, attempts to cyclize aldehyde 22, prepared from
crotylation product 13b, revealed that the C11 stereochemis-
try exerts a pronounced effect on reactivity (Scheme 5, b).
Subjection of 22 to the SmI2-mediated cyclization conditions
3. (a) Rittenhouse, S.; Biswas, S.; Broskey, J.; McCloskey, L.; Moore, T.;
Vasey, S.; West, J.; Zalacain, M.; Zonis, R.; Payne, D. Antimicrob.
Agents. Chemother. 2006, 50, 3882. (b) Fazakerley, N. J.; Procter, D. J.
Tetrahedron, 2014, 70, 6911.
4. Thirring, K.; Heilmayer, W.; Riedl, R.; Kollmann, H.; Ivezic-Schoenfeld;
Wicha, W.; Paukner, S.; Strickmann, D. WO2015110481A1, 30 July
2015.
5. (a) Gibbons, E. G. J. Am. Chem. Soc. 1982, 104, 1767. (b) Boeckman Jr.,
R. K.; Springer, D. M.; Alessi, T. R. J. Am. Chem. Soc. 1989, 111, 8284.
(c) Helm, M. D.; Da Silva, M.; Sucunza, D.; Findley, T. J. K.; Procter, D.
J. Angew. Chem. Int. Ed. 2009, 48, 9315. (d) Fazakerley, N. J.; Helm, M.
D.; Procter, D. J. Chem. Eur. J. 2013, 19, 6718. (e)Murphy, S. K.; Zeng,
M.; Herzon, S. B. Science 2017, 356, 956. (f) Zeng, M.; Murphy, S. K.;
Herzon, S. B. J. Am. Chem. Soc. 2017, 139, 16377.
6. Synthetic studies toward pleuromutilin: (a) Paquette, L. A.; Wiedeman,
P. E.; Bulman-Page, P. C. J. Org. Chem. 1988, 53, 1441. (b) Bacque, E.;
Pautrat, F.; Zard, S. Org. Lett. 2003, 5, 325. (c) Loresta, S. D.; Liu, J.;
Yates, E. V.; Krieger, I.; Sacchettini, J. C.; Freundlich, J. S.; Sorensen, E.
22
provided tricycle 26 as the major product in 20% yield. It is
proposed that conformational gearing to minimize A1,2 strain
at C11 reverses the regioselectivity of the Sm-ketyl addition
to the enone, producing radical 23. Subsequent Dowd-
Beckwith rearrangement proceeding through cyclopropane
24 delivers the product bearing a bridgehead olefin.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In summary, the total syntheses of (+)-pleuromutilin and
(+)-12-epi-pleuromutilin were each completed in 18 steps
(longest linear sequence) from (+)-trans-dihydrocarvone.
These syntheses were enabled by a modular approach, which
employed a highly diastereoselective SmI2-mediated radical
cyclization to form the eight-membered ring. In addition, we
uncovered a transannular [1,5]-HAT that effects a stereospe-
cific redox relay to set the C10 stereocenter. The brevity and
modularity of the route will enable the design and synthesis
of new fully synthetic variants of mutilin antibiotics.
J. Chem. Sci.
2011
, 2, 1258.
7. For a review of the role of synthesis in antibacterial drug discovery:
Wright, P. M; Seiple, I. B.; Myers, A. G. Angew. Chem. Int. Ed. 2014, 53,
8840.
8. For examples of medium size ring construction using SmI2, see: (a) Mo-
lander, G. A.; McKie, J. J. Org. Chem. 1994, 59, 3186. (b) Enholm, E. J.;
Satici, H.; Trivellas, A. J. Org. Chem. 1989, 54, 5841. (c) Matsuda, F.;
Sakai, T.; Okada, N.; Miyashita, M. Tetrahedron Lett. 1998, 39, 863. (d)
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: xx.xxxx/jacs.xxxxxxxxx.
Molander, G. A.; George, K. M.; Monovich, L. G. J. Org. Chem. 2003
,
Crystallographic data for 16,
17, and 26 (CIF)
Experimental procedures and characterization and spectral
data for all compounds (PDF)
68, 9533. Blot, V.; Reibig, H.-U. Eur. J. Org. Chem. 2006, 4989. For a re-
view: (e) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev. 2004
104, 3371.
,
9. (a) Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2006, 128,
12660. (b) Alam, R.; Vollgraff, T.; Eriksson, L.; Szabó, K. L. J. Am.
Chem. Soc. 2015, 137, 11262.
10. White, J. D.; Grether, U. M.; Lee, C-S. Org. Synth. 2005, 82, 108.
Commercially available (+)-dihydrocarvone is supplied as 4:1 mixture of
trans and cis isomers, which can be chromatographically separated to
give pure trans.
11. Singh, D.; McPhee, D.; Paddon, C. J.; Cherry, J.; Maurya, G.; Mahale,
G.; Patel, Y. Kumar, N.; Singh, S.; Sharma, B.; Kushwaha, L.; Singh, S.;
Kumar, A. Org. Process Res. Dev. 2017, 21, 551.
12. Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45,
497.
AUTHOR INFORMATION
Corresponding Author
*reisman@caltech.edu
Author Contributions
†These authors contributed equally to this work.
ACKNOWLEDGMENT
We thank Dr. Michael Takase and Larry Henling for X-ray data
collection, Ms. Julie Hofstra for X-ray data refinement, Dr. Da-
vid VanderVelde for assistance with NMR structure determina-
tion, Dr. Scott Virgil for assistance with crystallization of 26, and
the Caltech 3CS for access to analytical equipment. Fellowship
support was provided by the NIH (E.P.F., Grant
1F32GM117764) and NSF (S.S.F., DGE-1144469). Financial
support from the Heritage Medical Research Institute is grate-
fully acknowledged.
13. Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682.
14. See the Supporting Information for the synthesis of Z-6 and E-6
.
15. See Supporting Information.
16. Steves, J. E.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 15742.
17. This type of oxidative ring scission has previously been observed:
Spring, D. M.; Bunker, A.; Luh, B. Y.; Sorenson, M. E.; Goodrich, J. T.;
Bronson, J. J.; DenBleyker, K.; Dougherty, T. J.; Fung-Tomc, J. Eur. J.
Med. Chem. 2007, 42, 109.
18. (a) Ma, X.; Herzon, S. Chem. Sci. 2015, 6, 6250. (b) Crossely, S. W. M.;
Obradors, C.; Martinez, R. M.; Shenvi, R. A. Chem. Rev. 2016, 116, 8912.
19. Conditions were adapted from: Iwasaki, K.; Wan, K. K.; Oppedisano,
A.; Crossley, S. W. M.; Shenvi, R. A. J. Am. Chem. Soc. 2014, 136, 1300.
REFERENCES
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