Remote C-H bond functionalization of androstane C-ring: C12-amination

Article abstract of DOI:10.1016/j.tetlet.2012.12.103

A new functionalization method for the C-ring of the androstane framework has been established. The key feature is a remote C-H amination, which enables the preparation of the C12-amino, oxo, hydoxy, and C11,12-dehydro derivatives of epiandrosterone.

Full text of DOI:10.1016/j.tetlet.2012.12.103

Tetrahedron Letters 54 (2013) 1307–1308
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Remote C–H bond functionalization of androstane C-ring: C12-amination
Shuji Yamashita a, , Masafumi Himuro a, Yujiro Hayashi a, Masahiro Hirama a,b
⇑
a Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
b Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new functionalization method for the C-ring of the androstane framework has been established. The
key feature is a remote C–H amination, which enables the preparation of the C12-amino, oxo, hydoxy,
and C11,12-dehydro derivatives of epiandrosterone.
Received 6 December 2012
Revised 21 December 2012
Accepted 26 December 2012
Available online 3 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
C–H bond functionalization
Steroid
Androstane
Amination
Chemical derivatization of steroids is an effective tool for natu-
ral product synthesis1 and can provide important bioactive
agents.2,3 However, only a few functionalizations of the non-
activated C-ring of the androstanes have been reported. In 2003,
Shönecker and co-workers developed a copper-mediated remote
hydroxylation of the C12 position.4–6 This method enabled Giannis
and Shair to accomplish the elegant total syntheses of cyclop-
amine7 and cephalostatin,8 respectively. We describe here a new
method to functionalize the androstane C-ring through a remote
C–H amination.
Functionalization of the C-ring was investigated using epian-
drosterone (1, Scheme 1). Protection of the secondary alcohol of
1, stereoselective reduction of the ketone, and subsequent treat-
ment with chlorosulfonyl isocyanate and formic acid9 afforded sul-
famate 2 in 80% overall yield. Rhodium-catalyzed C–H bond
amination of 2 according to the Du Bois method10 successfully pro-
vided the C12,17-oxathiazinane 3 in 86% yield. It is noteworthy
that the C16- and C18-aminated products were not detected. This
exclusive chemoselectivity is attributed to the long S–O and S–N
bonds and the obtuse N–S–O angle of the sulfamate, as well as
the difference in reactivity between the primary and secondary
C–H bonds.10 The structure of 3 was unambiguously confirmed
by X-ray crystallographic analysis of the corresponding alcohol 4
(Fig. 1).11
LiAlH4 reduction in toluene followed by Boc-protection furnished
carbamate 5 in 39% yield (entry 3). After careful screening of re-
agents and conditions, we found that refluxing with AlH3 in tolu-
ene afforded amino alcohol 6 in 90% yield (entry 5).
Selective oxidation of the amino group was achieved by treat-
ment of 6 with 3,5-di-t-butyl-1,2-benzoquinone 7 to give ketone
8 in 95% yield (Scheme 2).14 Stereoselective reduction of ketone
8 was realized by treatment with sodium metal in the presence
of isopropanol to give the C12b-hydroxy product 9 (77%). The
C11,12-dehydro derivative 10 was also prepared under Shapiro’s
conditions in 63% overall yield.
In summary, we established a versatile method to install
functionality to the non-activated C-ring of epiandrosterone.
1. TIPSOTf, 2,6-lutidine
CH2Cl2, 0 °C
2. NaBH4, MeOH, 0 °C
O
OSO2NH2
Me
H
Me
H
Me
H
Me
H
3. ClSO2NCO, HCO2H
H
H
DMA, RT
HO
TIPSO
H
H
80% (3 steps)
epiandrosterone (1)
2
Rh2(OAc)4
PhI(OAc)2, MgO
CH2Cl2, RT
86%
O
O
O
O
S
S
18
HN
HN
O
O
17
We next examined the cleavage of the S–O and/or S–N bonds of
oxathiazinane 3 (Table 1).12 Birch reduction resulted in no reaction
and the starting material was recovered (entry 1). Treatment of 3
with LiAlH4 in THF afforded no products (entry 2),13 whereas
Me
Me
aq HCl, THF
RT
12
16
Me
H
Me
H
68%
H
H
H
H
HO
TIPSO
H
H
4
3
⇑
Corresponding author.
E-mail address: s-yamashita@m.tohoku.ac.jp (S. Yamashita).
Scheme 1. Remote amination of epiandrosterone C-ring.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.103

1308
S. Yamashita et al. / Tetrahedron Letters 54 (2013) 1307–1308
Foundation for Life Sciences. A fellowship to M. Himuro from JSPS
is gratefully acknowledged. We are grateful to Dr. S. Ishida at the
Graduate School of Science, Tohoku University for his assistance
with X-ray crystallographic analysis and helpful discussions.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
12.103.
References and notes
Figure 1. ORTEP drawing of 4.
1. For selected examples of natural product synthesis from commercially
available steroids, see: (a) cortistatin: Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li,
C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241; (b) Shi, J.; Manolikakes, G.;
Yeh, C.-H.; Guerrero, C. A.; Shenvi, R. A.; Shigehisa, H.; Baran, P. S. J. Am. Chem.
Soc. 2011, 133, 8014; (c) sominone: Matsuya, Y.; Yamakawa, Y.; Tohda, C.;
Teshigawara, K.; Yamada, M.; Nemoto, H. Org. Lett. 2009, 11, 3970; (d)
pavoninin-4: Williams, J. R.; Gong, H.; Hoff, N.; Olubodun, O. I. J. Org. Chem.
2005, 70, 10732.
Table 1
Cleavage of oxathiazinane moiety
O
O
S
HN
H
O
XHN
OH
Me
Me
H
12
2. Currently, many steroid-based medicines are provided by pharmaceutical
companies via semi-synthesis, see: McGrath, N. A.; Brichacek, M.; Njardarson, J.
T. J. Chem. Educ. 2010, 87, 1348.
Me
conditions
H
H
H
H
TIPSO
3. (a) Hamiton, N. M.; Dawson, M.; Fairweather, E. E.; Hamilton, N. S.; Hitchin, J.
R.; James, D. I.; Jones, S. D.; Jordan, A. M.; Lyons, A. J.; Small, H. F.; Thomson, G.
J.; Waddell, I. D.; Ogilvie, D. J. J. Med. Chem. 2012, 55, 4431; (b) Kranz, D. P.;
Chiha, S.; zu Greffen, A. M.; Neudörfl, J.-M.; Schmalz, H.-G. Org. Lett. 2012, 14,
3692; (c) Pettit, G. R.; Moser, B. R.; Mendonça, R. F.; Knight, J. C.; Hogan, F. J. Nat.
Prod. 2012, 75, 1063; (d) Farhane, S.; Fournier, M.-A.; Maltais, R.; Poirier, D.
Tetrahedron 2011, 67, 2434; (e) Ravindar, K.; Reddy, M. S.; Lindqvist, L.;
Pelletier, J.; Deslongchamps, P. J. Org. Chem. 2011, 76, 1269; (f) Li, Y.; Huang, J.;
Liu, J.; Yan, P.; Liu, H.; Sun, Q.; Wang, X.; Wang, C. Steroids 2011, 76, 1615; For a
recent review, see: (g) Hanson, J. R. Nat. Prod. Rep. 2010, 27, 887.
4. (a) Schönecker, B.; Zheldakova, T.; Liu, Y.; Kötteritzsch, M.; Günther, W.; Görls,
H. Angew. Chem. 2003, 115, 3361. Angew. Chem., Int. Ed. 2003, 42, 3240; (b)
Schönecker, B.; Zheldakova, T.; Lange, C.; Günther, W.; Görls, H.; Bohl, M. Chem.
Eur. J. 2004, 10, 6029; (c) Schönecker, B.; Lange, C.; Zheldakova, T.; Günther, W.;
Görls, H.; Vaughan, G. Tetrahedron 2005, 61, 103.
H
3
5: X = Boc
6: X = H
Entry
1
Conditions
Na, EtOH, NH3
Results
No reaction
À78 to À33 °C, 2 h
2
3
LiAlH4, THF, reflux, 12 h
LiAlH4, toluene, reflux, 24 h;
(Boc)2O, rt, 1 h
No reaction
5: 39%
3: 25%
4
5
Red-Al, toluene, reflux, 24 h;
(Boc)2O, rt, 1 h
AlH3, toluene, reflux, 5 h
5: 53%
6: 90%
5. For pioneering studies on remote hydroxylation of steroids, see: (a) Groves, J.
T.; Neumann, R. J. Org. Chem. 1988, 53, 3891; (b) Groves, J. T.; Neumann, R. J.
Am. Chem. Soc. 1989, 111, 2900; (c) Grieco, P. A.; Stuk, T. L. J. Am. Chem. Soc.
1990, 112, 7799; (d) Stuk, T. L.; Grieco, P. A.; Marsh, M. M. J. Org. Chem. 1991, 56,
2957; (e) Kaufman, M. D.; Grieco, P. A.; Bougie, D. W. J. Am. Chem. Soc. 1993,
115, 11648; (f) Breslow, R.; Huang, Y.; Zhang, X.; Yang, J. Proc. Natl. Acad. Sci.
U.S.A. 1997, 94, 11156; (g) Breslow, R.; Gabriele, B.; Yang, J. Tetrahedron Lett.
1998, 39, 2887; (h) Yang, J.; Breslow, R. Angew. Chem. 2000, 112, 2804. Angew.
Chem., Int. Ed. 2000, 39, 2692; (i) Yang, J.; Gabriele, B.; Belvedere, S.; Huang, Y.;
Breslow, R. J. Org. Chem. 2002, 67, 5057.
6. For recent reviews on C–H functionalization in natural product synthesis, see:
(a) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40, 1885; (b)
Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976; (c) Yamaguchi, J.;
Yamaguchi, A. D.; Itami, K. Angew. Chem. 2012, 124, 9092. Angew. Chem., Int. Ed.
2012, 51, 8960..
t-Bu
O
H2N
O
OH
OH
Me
7
O
(CO2H)2·2H2O
MeOH, THF
Me
H
t-Bu
12
12
H
Me
H
Me
H
H
H
95%
TIPSO
TIPSO
H
H
6
8
Na, i-PrOH
toluene, RT
1. TsNHNH2
MeOH, reflux
2. n-BuLi, THF
RT
63%
7. Giannis, A.; Heretsch, P.; Sarli, V.; Stößel, A. Angew. Chem. 2009, 121, 8052.
Angew. Chem., Int. Ed. 2009, 48, 7911.
(2 steps)
77%
8. Fortner, K. C.; Kato, D.; Tanaka, Y.; Shair, M. D. J. Am. Chem. Soc. 2010, 132, 275.
9. Okada, M.; Iwashita, S.; Koizumi, N. Tetrahedron Lett. 2000, 41, 7047.
10. (a) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123,
6935; (b) Fiori, K. W.; Espino, C. G.; Brodsky, B. H.; Du Bois, J. Tetrahedron 2009,
65, 3042.
HO
OH
OH
Me
H
Me
H
12
11
12
Me
H
Me
H
H
H
11. Crystallographic data of
4 have been deposited with the Cambridge
TIPSO
TIPSO
Crystallographic Data Centre as supplementary publication no. CCDC-
912944. Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 (0) 1223 336033 or e-
mail: deposit@ccdc.cam.ac.uk).
H
H
9
10
Scheme 2. Functionalization of the C-ring.
12. Cleavage of the oxathiazinane-ring under the reported conditions was
unsuccessful. For representative conditions, see: (a) Vargas, L. M.; Rozo, W.;
Kouznetsov, V. Heterocycles 2000, 53, 785; (b) Wehn, P. M.; Du Bois, J. J. Am.
Chem. Soc. 2002, 124, 12950; (c) Posakony, J. J.; Tewson, T. J. Synthesis 2002,
859; (d) Fleming, J. J.; Fiori, K. W.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 2028;
(e) Liu, Y.; Xiao, W.; Wong, M.-K.; Che, C.-M. Org. Lett. 2007, 9, 4107; (f) Airiau,
E.; Girard, N.; Pizzeti, M.; Salvadori, J.; Taddei, M.; Mann, A. J. Org. Chem. 2010,
75, 8670. and Ref. 10. Treatment with oxidants [e.g., KMnO7, CrO3, IBX, (COCl)2/
DMSO, TPAP/NMO, silver picolinate, and Mukaiyama reagent] did not realize
the ring-opening of oxathiazinane.
Rhodium-catalyzed remote C–H amination efficiently furnished
the oxathiazinane, which was converted into the C12-amino, oxo,
hydoxy, and C11,12-dehydro androstanes. Natural product synthe-
ses using this strategy will be reported in due course.
Acknowledgments
13. Wang, Y.-Q.; Yu, C.-B.; Wang, D.-W.; Wang, X.-B.; Zhou, Y.-G. Org. Lett. 2008, 10,
2071.
14. (a) Corey, E. J.; Achiwa, K. J. Am. Chem. Soc. 1969, 91, 1429; (b) Klein, R. F. X.;
Bargas, L. M.; Horak, V. J. Org. Chem. 1988, 53, 5994.
This work was supported financially by a Grant-in-Aid for Sci-
entific Research (B) and (C) from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan and the Suntory