Synthesis of a model bicyclic core related to Microscleroderma spirophora steroids

Article abstract of DOI:10.1016/S0040-4039(03)00378-2

An approach to the strained B,C-bicyclic nucleus of a heterocyclic class of steroids is described. The approach relies on a sigmatropic shift for installation of the strained bridge.

Full text of DOI:10.1016/S0040-4039(03)00378-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2633–2636
Synthesis of a model bicyclic core
related to Microscleroderma spirophora steroids
Anand Mayasundari, Ulf Peters and David G. J. Young*
Department of Chemistry, University of Tennessee, Knoxville, TN 37996, USA
Received 31 January 2003; revised 5 February 2003; accepted 7 February 2003
Abstract—An approach to the strained B,C-bicyclic nucleus of a heterocyclic class of steroids is described. The approach relies on
a sigmatropic shift for installation of the strained bridge. © 2003 Elsevier Science Ltd. All rights reserved.
In connection with our program aimed at the synthe-
sis of strained bridgehead olefins, we undertook the
stereocontrolled synthesis of structures related to the
bicyclic nucleus of steroids isolated from Microsclero-
derma spirophora (Fig. 1).1 As shown in Scheme 1
retrosynthetic analysis involved assembly of the
bicyclic core using a sigmatropic shift where epoxide
ring strain was used as a driving force for rearrange-
ment to the bridgehead diene.2
Synthesis of the bicyclic core was completed by
directed stereoselective introduction of the bridging
oxygen using tert-butyl hydroperoxide and vanadium
to afford 10 (Scheme 3).7 As anticipated, heating 10
in the presence of triethylamine led to smooth Cope
conversion to the target oxabicyclic 11.8,9
Structural proof for 11 was obtained through prepa-
ration of the derived benzoate which yielded X-ray
quality crystals. The ORTEP of 12 is shown in Fig-
ure 2 where the ester oxygen and bridging oxygen are
poised on the same face of the ring system.
As outlined in Scheme 2, addition of vinyl Grignard
to iodocyclohexenone 5 followed by PCC oxidation
afforded the rearranged product 7.3 The resulting
ketone was reduced with sodium borohydride and
cerium trichloride in methanol to yield alcohol 8.4
Directed Grignard cross coupling afforded the hexa-
triene 9 in 44% overall yield for four steps.5,6
Turning to the synthesis of the second analog
(Scheme 4), 11 was acylated with acetic anhydride
and 4-DMAP. The resulting material was deproto-
nated with lithium diisopropylamide, silylated with
Figure 1.
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00378-2

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A. Mayasundari et al. / Tetrahedron Letters 44 (2003) 2633–2636
tert-butyldimethylsilyl chloride and DMPU, and then
warmed to room temperature to afford the rearranged
diene 13 via Ireland–Claisen rearrangement.10
In summary two strained analogs of steroidal systems
have been synthesized using a Cope rearrangement
strategy. The synthesis of analog 11 required six steps
and proceeded in 13% yield while the synthesis of
analog 13 included two additional steps for 10% overall
yield.11 Further transformations of these structures are
being investigated and will be reported in due course.
Scheme 1. Retrosynthetic analysis of 3.
Scheme 2. Preparation of hexatriene.
Scheme 3. Preparation of model compound 11.
Scheme 4. Rearrangement of acetate 12.

A. Mayasundari et al. / Tetrahedron Letters 44 (2003) 2633–2636
2635
reaction was warmed to 80°C and stirred 10 h, then
cooled to room temperature and concentrated in vacuo.
The residue was chromatographed over 5 g of silica gel
eluted with hexanes–ether, 1:1) to yield 66 mg (66%) of 11
as a yellow oil.
9. Ireland, R. E.; Wipf, P.; Xiang, J. N. J. Org. Chem. 1991,
56, 3572.
10. Procedure for 12 to 13: To a solution of 0.73 mL of
diisopropylamine in 6 mL of THF at 0°C was added 3.6
mL of a 1.5 M solution of n-BuLi in hexanes over 5 min.
After stirring at 0°C for 10 min, the solution was cooled
to −78°C and acetate 12 was added over 10 min as a
solution of 5 mL of THF. The reaction stirred for 40 min
at −78°C, then 887 mg (5.9 mmol) of TBDMSCl in 4.5
mL of THF was added over 5 min, followed 4 min later
by 4.3 mL of DMPU. The reaction stirred 15 min at
−78°C, warmed to room temperature, and was heated
under reflux for 18 h. After cooling to room temperature,
the solution was extracted with two 25-mL portions of
2N aqueous NaOH, and the aqueous phase was then
acidified with 6N aqueous HCl. The resulting solution
was extracted with three 40-mL portions of diethyl ether
and the combined organic layers were washed with 30 mL
of brine, dried (MgSO4) and concentrated in vacuo. The
residue was chromatographed over 65 g of SiO2 (eluted
with hexanes–ethyl acetate 1:1) to afford 768 mg (3.69
mmol, 69%) of 13 as a pale yellow solid.
Figure 2. ORTEP of 12.
11. Selected data for new compounds:
Compound 6: 1H NMR (CDCl3): l 6.57–6.52 (m, 1H),
5.79 (ddd, 1H), 5.33–5.18 (m, 2H), 2.19–1.89 (m, 5H),
1.81–1.60 (m, 2H); 13C NMR (CDCl3): l 142.99, 141.37,
114.85, 109.33, 74.75, 36.17, 29.42, 18.83. HRMS (EI)
calcd for C8H11IO: m/z 249.9855. Found: m/z 249.9848.
Compound 7: 1HNMR (CDCl3): l 7.02 (dd, 1H), 5.78 (d,
1H), 5.58 (d, 1H), 2.68–2.59 (m, 4H), 2.25–1.96 (m, 2H);
13C NMR (CDCl3): l 192.96, 158.68, 142.65, 124.07,
110.40, 37.23, 28.07, 21.81. HRMS (EI) calcd for
C8H9IO: m/z 247.9698. Found: m/z 247.9693.
References
1. Costantino, V.; Fattorusso, E.; Mangoni, A.; Aknin, M.;
Gaydou, E. M. Steroids 1994, 59, 181.
2. Von Zezschwitz, P.; Voigt, K.; Lansky, A.; Noltemeyer,
M.; de Meijere, A. J. Org. Chem. 1999, 64, 3806.
3. (a) Babler, J. H.; Coghlan, M. J. Synth. Commun. 1976, 6,
469; (b) Dauben, W. G.; Michno, D. M. J. Org. Chem.
1977, 42, 682; (c) Sundararaman, P.; Herz, W. J. Org.
Chem. 1977, 42, 806.
4. Germal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103,
5454.
5. Mayasundari, A.; Young, D. G. J. Tetrahedron Lett.
2001, 42, 203.
Compound 8: 1H NMR (CDCl3): l 6.64 (dd, 1H), 5.36
(dd, 1H), 5.21 (d, 1H), 4.36 (q, 1H), 2.43–2.30 (m, 2H),
2.27–2.16 (m, 1H), 2.01–1.63 (m, 4H); 13C NMR
(CDCl3): l 142.14, 140.24, 117.93, 110.57, 74.41, 32.10,
27.77, 17.95. HRMS (EI) calcd for C8H11IO: m/z
249.9855. Found: m/z 249.9864.
6. Procedure for 8 to 9: To a solution of 8.97 g (35.9 mmol)
of 8 in 90 mL of THF was added 117.4 mg (102 mmol) of
Pd(PPh3)4. The reaction stirred 10 min, was cooled to
−78°C, and 89.7 mL (89.7 mmol) of CH2ꢀCHMgBr was
added over 30 min. The reaction was warmed to room
temperature stirred for 12 h and quenched with saturated
aqueous ammonium chloride. The layers were separated,
and the aqueous phase was extracted with three 100-mL
portions of ether. The combined organic layers were
washed with 100 mL of brine, dried (MgSO4) and con-
centrated in vacuo. The residue was chromatographed
over 175 g of silica gel (eluted with dichloromethane) to
afford 4.99 g (33.18 mmol, 93%) of 9.
Compound 9: 1H NMR (CDCl3): l 6.98–6.80 (m, 2H),
5.46 (d, 1H), 2.18–2.05 (m, 1H), 1.97–1.88 (m, 1H),
1.82–1.55 (m, 4H); 13C NMR (CDCl3): l 135.28, 133.90,
133.85, 132.56, 115.42, 114.66, 63.87, 30.58, 25.77, 16.60.
HRMS (EI) calcd for C10H14O: m/z 150.1045. Found:
m/z 150.1047.
1
Compound 10: H NMR (CDCl3): l 5.84–5.68 (m, 2H),
5.42–5.21 (m, 4H), 4.12–4.06 (m, 1H), 2.16 (d, 1H),
1.95–1.90 (m, 2H), 1.65–1.54 (m, 3H), 1.39–1.32 (m, 1H);
13C NMR (CDCl3): l 135.94, 134.01, 119.16, 117.88,
68.64, 68.46, 67.59, 29.63, 26.76, 16.61. HRMS (EI) calcd
for C10H14O2: m/z 166.0994. Found: m/z 166.0991.
1
Compound 11: H NMR (CDCl3): l 5.00–4.97 (m, 1H),
7. Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc.
4.91–4.87 (m, 1H), 4.18 (dd, 1H), 2.87–2.76 (m, 1H); 13C
NMR (CDCl3): l 163.37, 159.81, 114.74, 110.51, 72.36,
34.28, 32.81, 24.08, 22.04, 21.74. HRMS (EI) calcd for
C10H14O2: m/z 166.0994. Found: m/z 166.0994.
1973, 95, 6136.
8. Procedure for 10 to 11: To 99.3 mg (0.60 mmol) of
epoxide 10 in 15 mL of 1,4-dioxane at room temperature
was added 0.17 mL (1.2 mmol) of triethylamine. The

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A. Mayasundari et al. / Tetrahedron Letters 44 (2003) 2633–2636
1
1
Compound 12: H NMR (CDCl3): l 5.28 (dd, 1H), 5.14
(dd, 1H), 4.93 (t, 1H), 2.92–2.80 (m, 1H), 2.56–2.46 (m,
1H), 2.24 (t, 2H), 2.02 (s, 3H), 1.99–1.70 (m, 5H), 1.43–
11.30 (m, 1H); 13C NMR (CDCl3): l 170.55, 164.17,
155.76, 118.52, 110.40, 74.58, 33.14, 30.80, 24.59, 22.91,
21.51, 21.37. HRMS (EI) calcd for C12H16O3: m/z
208.1099. Found: m/z 208.1097.
Compound 13: H NMR (CDCl3): l 11.40 (s, 1H), 5.11
(dd, 1H), 5.01–4.97 (m, 1H), 3.00–2.97 (m, 1H), 2.83 (dd,
1H), 2.69–2.51 (m, 3H), 2.45–2.25 (m, 2H), 1.94–1.67 (m,
4H), 1.59–1.49 (m, 1H), 1.35–1.23 (m, 1H); 13C NMR
(CDCl3): l 178.90, 161.26, 159.68, 112.71, 110.92, 39.43,
35.12, 34.70, 32.34, 28.12, 24.31, 20.13. HRMS (EI) calcd
for C12H16O3: m/z 208.1099. Found: m/z 208.1098.