C.-X. Huang et al. / Tetrahedron Letters 52 (2011) 4123–4125
4125
between the newly formed C20-ketone and C16
a
-OMgII altered
OR
OH
the conformation of C20-ketone, and the resulting conformational
immobility of transition state enabled the stereochemical control
of ketone addition reaction, in which the C20-ketone was attacked
by the organometallic reagent from the less hindered face to yield
the corresponding product.
In conclusion, a tandem semipinacol rearrangement/ketone
addition process has been discovered and investigated. This pro-
cess offers unique opportunities to access steroids with an unusual
O
H
a
H
H
OH
H
H
H
H
RO
Et3SiO
10a R = Me 10b R = MOM
H
H
11 (from 10c)
10c R = SiEt3
b
OR
OH
OH
O
C17a side chain which are not accessible by other synthetic meth-
ods. Efforts to expand the scope of this process and apply it in syn-
thesis are in progress.
H
H
H
H
H
H
RO
AcO
H
Acknowledgment
H
12a R = Me
12b R = MOM
13
The authors are grateful to Science and Technology Commission
of Shanghai Municipality for financial support (09DZ1905602).
Scheme 4. Reagents and conditions: (a) MeLi/MeMgCl (1:1), DME, reflux, 3–5 h,
60%; (b) CuBrÁMe2S, MeMgCl, DME, 80 °C, 3 h, 91% for 12a, 78% for 12b.
Supplementary data
18
Me
H
Me
Supplementary data (experimental procedures and analytic
data and copies of NMR spectra for all new compounds) associated
with this article can be found, in the online version, at doi:10.1016/
O
Mg
4
17
XMgO
[1.2]-H shift
Me
16
X
O
A
B
Me
PhMgX
H
References and notes
17
16
O
XMgO
O
1. Coveney, D. J. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 3,. p 777.
2. Snape, T. J. Chem. Soc. Rev. 2007, 36, 1823–1842.
Mg
X
3. Jung, M. E.; van den Heuvel, A. Org. Lett. 2003, 5, 4705–4707.
4. (a) Fan, C.-A.; Wang, B.-M.; Tu, Y.-Q.; Song, Z.-L. Angew. Chem., Int. Ed. 2001, 40,
3877–3880; (b) Tu, Y. Q.; Sun, L. D.; Wang, P. Z. J. Org. Chem. 1990, 64, 629–633;
(c) Hu, X.-D.; Fan, C.-A.; Zhang, F.-M.; Tu, Y. Q. Angew. Chem., Int. Ed. 2004, 43,
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Eur. J. 2003, 9, 4301–4310.
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Pizza, C.; Piacente, S. Steroids 2005, 70, 594–603.
6. (a) Cabeza, M.; Gutiérrez, E.; Miranda, R.; Heuze, I.; Bratoeff, E.; Flores, G.;
Ramírez, E. Steroids 1999, 64, 413–421; (b) Kongkathip, N.; Kongkathip, B.;
Noimai, N. Synth. Commun. 2006, 36, 865–874.
7. Shapiro, E. L.; Steinberg, M.; Gould, D.; Gentles, M. J.; Herzog, H. L.; Gilmore, M.;
Charney, W.; Hershberg, E. B.; Mandell, L. J. Am. Chem. Soc. 1959, 81, 6483–
6486.
8. Angeles, A. R.; Waters, S. P.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130,
13765–13770.
9. (a) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1993, 115, 12208–12209; (b)
Jung, M. E.; Lee, W. S.; Sun, D. Org. Lett. 1999, 1, 307–310; (c) Jung, M. E.; van
den Heuvel, A. Tetrahedron Lett. 2002, 43, 8169–8172.
10. Compound 13 was prepared through a Luche reduction and epoxidation from
pregnane-16,17-en-20-one.
18
Me
H
Me
H
17
16
O
XMgO
MgX
O
MgX
workup
6b
Scheme 5. A plausible mechanism for the formation of 6b. (A) Semipinacol
rearrangement. (B) Chelation-controlled ketone addition.
On the basis of these experimental observations, a plausible
pathway of this tandem process is proposed as shown in Scheme 5.
First, the acetyls were cleaved by Grignard reagent, and the
resulting a-hydroxy epoxide underwent a semipinacol rearrange-
ment in the presence of MgII at elevated temperature. Due to the
chelation effect between C20–OMgII and epoxide, the C20–H and
epoxide were placed on a privileged anti-periplanar conformation
to promote the [1.2]-hydride shift. Then, a similar chelation
11. Zheng, Z.-J.; Shu, X.-Z.; Ji, K.-G.; Zhao, S.-C.; Liang, Y.-M. Org. Lett. 2009, 11,
3214–3217.