Modification of D-ring moiety of steroids - A novel palladium catalyzed baeyer-villiger type rearrangement of cyclic silylenol ether derivatives

Article abstract of DOI:10.3987/COM-10-S(E)83

A novel Baeyer-Villiger type rearrangement reaction of cyclic silylenol ether derived from dehydroepiandrosterone via oxygen and catalytic amount of palladium acetate in the presence of DMSO has been developed. The reaction proceeded at low temperature an

Full text of DOI:10.3987/COM-10-S(E)83

HETEROCYCLES, Vol. 82, No. 2, 2011
1119
HETEROCYCLES, Vol. 82, No. 2, 2011, pp. 1119 - 1125. © The Japan Institute of Heterocyclic Chemistry
Received, 30th June, 2010, Accepted, 10th August, 2010, Published online, 12th August, 2010
DOI: 10.3987/COM-10-S(E)83
MODIFICATION OF D-RING MOIETY OF STEROIDS – A NOVEL
PALLADIUM
CATALYZED
BAEYER–VILLIGER
TYPE
REARRANGEMENT OF CYCLIC SILYLENOL ETHER DERIVATIVES
Minoru Tamiya,a* Futa Takada,a Nobuhisa Isaka,a Nahoko Iimura,b and
Masaji Ishiguroa*
Department of Applied Life Sciencea and Pharmacyb, Niigata University of
Pharmacy and Applied Life Sciences, 265-1 Higashijima Akiha-ku Niigata City,
956-8603, Japan; emails: ishiguro@nupals.ac.jp, tamiya@nupals.ac.jp
This paper is dedicated with respect and admiration to Prof. Albert Eschenmoser
on the occasion of his 85th birthday.
Abstract – A novel Baeyer–Villiger type rearrangement reaction of cyclic
silylenol ether derived from dehydroepiandrosterone via oxygen and catalytic
amount of palladium acetate in the presence of DMSO has been developed. The
reaction proceeded at low temperature and high pressure of oxygen to afford
corresponding -unsaturated lactones in moderate yields.
Steroids are ubiquitous in many biologically important compounds including natural products, clinical
medicines, and hormones.1 Because of these reasons, many methods and unique reactions for the
modification of steroidal skeletons2 have been developed. Due to the rigidity of the skeleton and the
stereochemical property of steroid, the steroidal reactions sometime make themselves very unique. Here
we report the unexpected and unique side-reaction, which may demand steroidal backbone of the reactant,
found during the course of an oxidative conversion of steroid. Thus, the treatment of cyclic silylenol
ether derivative (1)3 under the Larock protocol of Saegusa oxidation,4 using catalytic amount of Pd(OAc)2
(0.1 equiv.)5 and O2 as re-oxidant of palladium(0) in DMSO at 60 °C, gave desired -enone 2 in 75%
yield along with a side-product in 6% (Scheme 1; Table 1, entry 1). However, the side-product was not
obtained when p-benzoquinone was used as a re-oxidant of palladium(0). This result suggested that O2
1
13
probably plays a critical role in the formation of the side-product. According to H and C NMR, IR,
and Mass spectra, the side-product was anticipated as -unsaturated lactone 3.6 To confirm this

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HETEROCYCLES, Vol. 82, No. 2, 2011
prospect, the side-product was treated with catalytic amount of Pd/C under hydrogen gas. The product
of the hydrogenation showed spectroscopic properties identical to lactone 4 derived from ketone 5. Two
possible reaction pathways could be envisioned from these results: 1) Baeyer–Villiger rearrangement
proceeded after the formation of the corresponding enone; 2) Baeyer–Villiger type rearrangement
occurred before unsaturation of the -position. For the determination of the reaction pathway, enone 2
was subjected to catalytic amount of Pd(OAc)2 and O2 at atmosphere, which resulted in no reaction
(Scheme 1). According to these results mentioned above, lactone 4 was probably produced by
Baeyer–Villiger type rearrangement of corresponding ketone followed by the unsaturation of -position
of carbonyl via -hydride elimination of palladium in one pod. Because the conversion of cyclic ketone
to the corresponding -unsaturated lactone by using catalytic amount of bivalent palladium and O2 is
completely a novel transformation to our knowledge, we investigated to gain a further insight into this
reaction.
O
OSiMe3
O
O
Pd(OAc)2
oxidant
+
H
H
H
DMSO
60 °C
OMe
OMe
OMe
2
1
side-product (3)
oxidant
6%
0%
O2
75%
77%
p-benzoquinone
H2, Pd/C
MeOH
Pd(OAc)2, O2
DMSO
68%
O
O
O
mCPBA
H
H
CH2Cl2
32%
OMe
OMe
5
4
Scheme 1. Characterization of Side-Product in Saegusa Oxidation of Silylenol Ether 1
We investigated the reaction conditions for producing lactone 3 as a major product. Concerning the
reaction temperature, the silylenol ether (1) was treated with Pd(OAc)2 (0.1 equiv.) and O2 (1 atm) in
DMSO (0.06 M) at room temperature to afford lactone 3 in 35% yield along with enone 2 in 45% yield
(Table 1, entry 2). These results indicated that low temperature would be necessary for the formation of
lactone 3. Because it is impossible to perform the reaction at lower temperature due to high freezing
point of DMSO (16~19 °C), other solvent should be applied for the investigation. For the alternative

HETEROCYCLES, Vol. 82, No. 2, 2011
1121
solvent, we examined DMF, DMA, and CH2Cl2 that, unfortunately, gave low yields of lactone 3 (entries
3–5). We next examined CH2Cl2 as a co-solvent of DMSO, which could stand from freezing at low
temperature (DMSO/CH2Cl2=1/1, fp. ~–20 °C). To make a comparison between DMSO and
DMSO/CH2Cl2 co-solvent system, the reaction was performed at room temperature to afford lactone 3 in
37% yield along with enone 2 in 42% yield (entry 6). With the ideal solvents in hand, we next examined
the reaction at 0 °C and –15 °C (entries 7, 8). In these conditions, lactone 3 (ca. 43%) was major
product to enone 2 (ca. 35%). Further enhancement of the yield of lactone 3 (ca. 50%) was observed in
more diluted conditions (0.06 M to 0.03 M) (entries 9, 10).
Table 1. Optimization of Reaction Conditions
O
OSiMe3
Pd(OAc)2
O
O
O
(0.1 equiv.)
O2 (1 atm)
LDA
TMSCl
H
H
H
+
H
THF
solvent
temp.
OMe
OMe
OMe
OMe
5
1
2
3
yield/%
solvent
entry
conc./M
temp.
60 °C
2
3
5
1
2
DMSO
DMSO
DMF
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.03
0.03
75
45
34
42
3
6
4
—
9
35
7
rt
rt
3
10
—
37
43
45
50
51
4
DMA
rt
8
73
—
—
—
—
—
5
CH2Cl2
rt
42
35
36
33
31
6
DMSO/CH2Cl2 (3/2)
DMSO/CH2Cl2 (3/2)
DMSO/CH2Cl2 (1/1)
DMSO/CH2Cl2 (3/2)
DMSO/CH2Cl2 (1/1)
rt
7
0 °C
–15 °C
0 °C
–15 °C
8
9
10
The other trimethylsilylenol ethers 6 and 7 possessing tri-substituted double bond at C5–C6 position (5)
were also converted to lactone (B) in 54% and 56% yield, respectively, along with enone (A) in 38% and
30% yield without any touch of 5 (Scheme 2). Since compound 10 formed single crystals suitable for
X-ray analysis, the structure of 10 was unambiguously established by the single-crystal X-ray analysis.7
The triethylsilylenol ether 8 and the trans-fused bicyclic compound 138 were also converted to enone (9:
46% and 14: 47%) and lactone (10: 44% and 15: 19%) at 0 °C, while the cis-fused compound 16 was
quickly converted solely to enone 17 in 85% yield without any trace of lactone 18. This suggests that
the trans junction of CD ring moiety of steroid is suitable for the rearrangement.

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HETEROCYCLES, Vol. 82, No. 2, 2011
Pd(OAc)2
(0.1 equiv.)
O2 (1 atm)
DMSO/CH2Cl2
(1/1)
OR
O
O
O
+
A
B
0 °C
OTMS
OR
TBDPSO
H
13
A (14): 47%, B (15): 19%
H
R'O
OTMS
6: R = TMS, R' = Me; A (9): 38%, B (10): 54%
7: R = TMS, R' = TBDPS; A (11): 30%, B (12): 56%
8: R = TES, R' = Me; A (9): 46%, B (10): 44%
TBDPSO
H
16
A (17): 85%, B (18): 0%
Scheme 2. Other Substrates and X-Ray Analysis of 10
In an attempt to increase the yield of lactone, we then examined a variety of Pd catalysts (Table 2),
comparing with Pd(OAc)2 (entry 1). The Pd(II) catalysts such as PdCl2 and Pd(COCF3)2 were not
effective to afford the lactone (entries 2 and 3), whereas Pd(0) catalysts such as Pd(PPh3)4 and Pd(dba)2
were able to give the lactone (entries 4–7). These results indicate that Pd(II) species resulted from the
oxidation of Pd(0) by O2 are possibly important intermediates for the formation of the lactone. Among
the catalysts examined, Pd(OAc)2 was the most suitable reagent for this reaction.
Table 2. Effect of the Pd catalysts
OSiMe3
O
O
O
Pd
(0.1 equiv.)
O2 (1 atm)
H
H
+
H
DMSO/CH2Cl2
(3/2, 0.06 M)
rt
MeO
MeO
MeO
9
6
10
yield/%
10
entry
Pd
9
17-keto
1
2
3
4
5
6
7
Pd(OAc)2
PdCl2
46
—
39
—
—
88
93
18
7
trace
44
trace
22
Pd(OCOCF3)2
Pd(PPh3)4
33
36
Pd(dba)2
52
22
Pd2(dba)3CHCl3
Pd2(dba)3
3
52
33
3

HETEROCYCLES, Vol. 82, No. 2, 2011
1123
All the results described above indicate that O2 is important in this rearrangement reaction. Thus, we
next examined the effects of O2 pressure (Table 3). Although 8 atm O2 atmosphere showed no
significant difference in a yield of lactone 10 at room temperature and/or 0 °C (entry 1), the treatment of
silylenol ether 6 at lower temperature (0 °C and –15 °C) gave lactone 10 in a yield of 53% and 61%
respectively exceeding the yield of enone 9 (entries 2 and 3). Furthermore, the reaction at 28 atm gave
the best result, affording lactone 10 in 70% yield (entry 5) although the reaction at 20 atm gave only a
little improvement of a yield of lactone 10 (63%, entry 4). It is noted that this reaction also proceeded
with 5 mol% of Pd(OAc)2 (entry 6).
Table 3. Effect of the O2 Pressure
OSiMe3
Pd(OAc)2 (0.1 equiv.)
O
O
O
O2 (Pressure)
H
H
+
H
DMSO/CH2Cl2
(1/1, 0.04 M)
temp.
MeO
MeO
MeO
6
9
10
yield/%
entry
Pressure/atm
temp.
rt
9
10
1
42
8
8
48
39
32
53
61
63
70
73
2
0
3
8
–15 °C
–15 °C
–15 °C
–15 °C
4
20
28
28
29
25
25
5
6*
* 0.05 equiv. of Pd(OAc)2 was employed.
Based on the above results, we anticipate that formation of palladium(II) complex I-b by the reaction of
silylenol ether and three-membered palladium peroxide,9 resulting from palladium catalytic cycle,
followed by cyclization of I-b, rearrangement of III, and -hydride elimination of alkylpalladium
complex IV gave lactone B as outlined in Scheme 3. The high pressure of O2 probably accelerated the
formation of palladium peroxide and low temperature may avoid the -hydride elimination pathway from
I-b to II. The conformation of the trans-fused CD-ring may allow the formation of the intermediate III
(see, 13,14-trans-I-b) whereas cis-fused CD-ring system (see, 13,14-cis-I-b) would disturb the formation
of the intermediate III due to the steric hindrance at the -face of the 5-membered ring. However, the
other possible reaction mechanism cannot be ruled out.
In summary, we have developed Baeyer–Villiger type rearrangement reaction of silylenol ether
derivatives promoted by 5 mol% of Pd (OAc)2 at high pressure of O2 and low temperature. At this point,

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HETEROCYCLES, Vol. 82, No. 2, 2011
the substrates of this rearrangement reaction were limited to the 17-oxosteroid derivatives; however, more
scopes of this reaction are now under investigation.
O
O
Pd(OAc)2
OTMS
PdOAc
O
H
A
I-a
-hydride
elimination
OR
H
Pd
R
H
H
II
O
O
O
O
O
O
O
Pd
Pd
13
14
PdOR
RO
O
H
H
IV
O
O
O
13,14-trans-I-b
Pd
-hydride
elimination
rearrangement
H
H
III
B
H3C
HO
H
Palladium Catalytic Cycle
H3C
13
O
O
AcOTMS
AcOH
13
O2
O
H
O
O
Pd
Pd(0)
H
Pd
Pd(OAc)2
RO Pd H
14
HO
14
Pd
H
O
ROH
13,14-trans-I-b
13,14-cis-I-b
Scheme 3. Proposed Mechanism
ACKNOWLEDGEMENTS
Generous financial support by the Grant-in-Aid for Young Scientists (B) from JSPS (to M.T.) is
gratefully acknowledged.
REFERENCES AND NOTES
1. D. A. Williams and T. L. Lemke, 'Foye’s Principals of Medicinal Chemistry (fifth edition)',
Lippincott Williams & Wilkins, Philadelphia, 2002, pp. 653–717; D. A. Williams and T. L. Lemke,
'Comprehensive Natural Products Chemistry', Vol. 2, ed. by D. E. Cane, Elsevier, Amsterdam, 1999,
pp. 267–318.
2. D. N. Kirk and M. P. Hartshorn, 'Steroid Reaction Mechanisms', Elsevier, Amsterdam, 1968, pp.
24–438.
3. Compound 1, 2, and 3 are all contaminated with 3-OMe derivatives 6, 9, and 10 respectively in the
ratio of 9:1. For the synthesis of compound 5, see: H. Suginome, Y. Nakayama, and H. Senboku, J.
Chem. Soc., Perkin Trans. 1, 1992, 1837.
4. R. C. Larock and N. H. Lee, Tetrahedron Lett., 1991, 31, 5911; R. C. Larock, T. R. Hightower, G. A.

HETEROCYCLES, Vol. 82, No. 2, 2011
1125
Kraus, P. Hahn, and D. Zheng, Tetrahedron Lett., 1995, 36, 2423.
5. Contaminated by-products were removed by filtration. Thus, after dissolution of Pd(OAc)2 in hot
benzene and its filtration, the filtrate was concentrated in vacuo to give pure Pd(OAc)2.
1
6. Chemical data of 3: H NMR (500 MHz, CDCl3): = 6.86 (dd, J = 2.1, 9.9 Hz, 1H), 6.04 (dd, J =
2.9, 9.9 Hz, 1H), 3.37 (s, 3H), 2.89 (t, J = 2.9 Hz, 1H), 2.38–2.30 (m, 1H), 2.23 (td, J = 2.9, 13.2 Hz,
1H), 2.01 (td, J = 3.4, 12.0 Hz, 1H), 1.90–1.70 (m, 4H), 1.63–1.51 (m, 2H), 1.44–1.32 (m, 1H), 1.38
(s, 3H), 1.25–1.18 (m, 1H), 1.12–1.05 (m, 1H), 1.02 (s, 3H), 0.98–0.89 (m, 2H), 0.74–0.71 (m, 1H),
0.54 (dd, J = 5.1, 8.0 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3): =164.0, 145.5, 121.5, 83.6, 81.4,
56.7, 48.1, 47.6, 43.5, 38.2, 34.6, 34.0, 33.2, 30.6, 24.7, 23.2, 21.1, 19.1, 18.5, 13.2 ppm; IR (NaCl):
v = 2946, 2869, 1722, 1457, 1381, 1097, 816 cm–1; MS (EI): m/z (%): 316 (14)[M+], 301 (45), 284
(37), 261 (100), 243 (11), 226 (5), 211 (8), 159 (20), 123 (15), 105 (22), 91 (31), 79 (25), 55 (16).
7. The structure of lactone 10 was determined by X-ray crystallographic analysis. CCDC-788111
contains the supplementary crystallographic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre request/cif.
8. A. R. Daniewski and J. Kiegiel, Synthetic Commun., 1988, 18, 115; W. Peng, P. Tang, X. Hu, J. O.
Liu, and B. Yu, Bioorg. Med. Chem. Lett., 2007, 17, 5506.
9. J. E. Lyons, 'Oxygen Complexes and Oxygen Activation by Transition Metals', A. E. Martell, D. T.
Sawyer, Eds., Plenum Press, New York, 1988, pp. 233; G. Wilke, H. Schott, P. Heimbach, Angew.
Chem. Int., Ed. Engl., 1967, 6, 92; for a review of palladium catalytic cycle, see: J. Muzart, Chem.
Asian J., 2006, 1, 508.
10. General Procedure: The reactions were carried out in an HPG-10-1 (Taiatsu Techno®) autoclave.
To a solution of silylenol ether 6 (99.2 mg, 0.265 mmol) in CH2Cl2/DMSO (1/1, 12 mL) was added
Pd(OAc)2 (2.8 mg, 0.012 mmol) at –15 °C. After O2 was pumped into the autoclave to reach 28
atm, the reaction mixture was stirred for 141 h at –15 °C. After venting O2, the reaction was
stopped by adding brine and the mixture was extracted with EtOAc (×3). The combined organic
extracts were washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and concentrated
in vacuo. The residue was purified by column chromatography (hexane/EtOAc = 8/2) to afford 9
(19.9 mg, 25%) as a white solid and 10 (59.5 mg, 73%) as a white solid.