Pentacyclic compounds by samarium diiodide-induced cascade cyclizations of naphthyl-substituted 1,3-diones

Article abstract of DOI:10.1002/adsc.200700283

Treatment of naphthyl-substituted cyclopentane-1,3-diones with the samarium diiodidehexamethylphosphoramide (HMPA) complex in the presence of tert-butyl alcohol provided the expected tetracyclic diols with steroid-like structures. Surprisingly, reactions

Full text of DOI:10.1002/adsc.200700283

COMMUNICATIONS
DOI: 10.1002/adsc.200700283
Pentacyclic Compounds by Samarium Diiodide-Induced Cascade
Cyclizations of Naphthyl-Substituted 1,3-Diones
Ulrike K. Wefelscheida and Hans-Ulrich Reissiga,*
a
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax : (+49)-30-838-55367; e-mail: hans.reissig@chemie.fu-berlin.de
Received: June 8, 2007; Published online: December 20, 2007
Abstract: Treatment of naphthyl-substituted cyclo-
pentane-1,3-diones with the samarium diiodide-
hexamethylphosphoramide (HMPA) complex in the
presence of tert-butyl alcohol provided the expected
tetracyclic diols with steroid-like structures. Surpris-
ingly, reactions without the proton source led to the
efficient formation of a new pentacyclic diol. In this
case the toxic additive HMPA could be substituted
by a combination of lithium bromide (in situ gener-
ation of samarium dibromide) and N,N-dimethyl-
imidazolidone. The styrene-like alkene moiety of
this product was used to prepare an ensemble of
highly substituted pentacyclic steroid-like com-
pounds.
Scheme 1.
Keywords: electron transfer; ketyl-aryl coupling;
polycycles; radical reactions; samarium diiodide;
steroids
35% overall yield. Analogously, 6 and 13 were pre-
pared from the corresponding precursors.
Cyclopentane-1,3-dione derivative 5 was treated
with an excess of samarium diiodide in the presence
of HMPA[6] and tert-butyl alcohol and provided the
expected diols 7a/7b in yields varying between 67–
In earlier communications we have reported that g- 74%. The ratio of diastereomers 7a/7b strongly de-
aryl ketones undergo novel samarium diiodide-in- pends on the amount of the proton source (Table 1,
duced cyclizations leading to synthetically useful hexa- entries 1–4). Standard conditions (8 equivs.) led to an
hydronaphthalene derivatives.[1] The closely related unselective reaction (entry 1), whilst use of only
reaction of simple cyclic g-naphthyl-substituted ke- 1 equiv. of tert-butyl alcohol (entry 4) induced a
tones furnished tetracyclic compounds with steroid- highly diastereoselective formation of tetracyclic diol
like constitution, but “unnatural” cis/cis annulation of 7a.[7] The relative configurations of 7a and 7b were
rings B/C/D.[2] Here we describe our experiments with unequivocally proven by X-ray analyses.[8] The con-
cyclic 1,3-diones as precursors for the crucial samari- version of cyclohexane-1,3-dione derivative 6 into tet-
um ketyls,[3] which were performed to generate ste- racyclic diol 8 is rather slow and even after a reaction
roid analogous products with additional functionality time of two days 25% of 6 was recovered (entry 5).
in ring D.
We assume a mechanism for these cyclizations as pro-
The required naphthyl-substituted 1,3-diketones posed before,[2] but here a subsequent stereoselective
were prepared by a straightforward four-step synthe- reduction of the remaining cycloalkanone carbonyl
sis following the Torgovapproach to steroids as exem-
group by the excess of samarium diiodide generates
plified for compound 5 (Scheme 1).[4] Dione 3 was ob- the second hydroxy group. This step affords products
tained by addition of vinylmagnesium bromide to tet- 7 and 8 with trans-arranged hydroxy groups. However,
ralone 1 followed by a Pd-catalyzed allylic alkyla- the protonation at the carbon adjacent to the benzene
tion.[4d] Oxidation of 3 with DDQ[4e] and subsequent ring proceeds with varying stereoselectivity, being
reduction[5] of the alkene moiety furnished dione 5 in strongly dependent on the amount of tert-butyl alco-
hol in the case of 5!7.[9]
Adv. Synth. Catal. 2008, 350, 65 – 69
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65

Ulrike K. Wefelscheid and Hans-Ulrich Reissig
COMMUNICATIONS
Table 1. Cyclizations of 1,3-diones 5 and 6 with samarium
diiodide.
ion). However, in the absence of tert-butyl alcohol, 12
is not rapidly protonated to provide the precursor of
7, but undergoes the second cyclization involving the
carbanionic centre and the remaining carbonyl group
of the cyclopentane ring (Scheme 2).[10] This conver-
sion could also be performed replacing HMPA by
DMI (1,3-dimethyl-2-imidazolidinone, 36 equivs.) and
lithium bromide (22 equivs.). The desired cyclization
product 9 was obtained in ca. 50% yield under these
conditions even in the presence of tert-butyl alco-
hol![11] Unfortunately, a similar reaction cascade was
not successful with 6 as a homologue precursor, which
was entirely unreactive under these conditions and re-
isolated.
To obtain products with an even closer similarity to
steroids we introduced the 3-methoxy group into the
precursor. Compound 13 underwent analogous, but
less efficient cyclizations giving tetracyclic diol 14a/
14b in the presence of tert-butyl alcohol or pentacyclic
diol 15 in 23% yield, if no proton source was added
(Scheme 3). In the last transformation we could again
work with the HMPA substitute DMI. Starting mate-
rial 13 was completely consumed in both cases, but
the reduction of the carbonyl moieties was the major
process. Due to the electron-donating methoxy group
the cyclizations to the naphthalene unit were consid-
erably less efficient as already observed for other g-
aryl ketones.[1b,2b]
[a]
Determined by NMR spectroscopy of the crude product.
Ratio of purified isomers 8a (33%) and 8b (20%).
Yield refers to isolated material of purified mixtures of
7a/7b.
[b]
[c]
[d]
Combined yield of separated isomers 8a/8b; 25% of 6
was recovered.
Most surprisingly, reaction of precursor 5 with an
excess of samarium diiodide-HMPA without proton
source furnished the novel pentacyclic diol 9 in good
yield (Scheme 2). The constitution and configuration
of compound 9 was also determined by X-ray analy-
sis.[8]
As mechanism for this unexpected cascade cycliza-
tion we suggest a sequence with intermediates 10 (sa-
marium ketyl), 11 (benzylic radical), and 12 (carban-
Scheme 3.
Having established a fast route to the rigid, and yet
steroid-related pentacyclic scaffold we prepared an
ensemble of highly substituted derivatives exploiting
the reactive styrene-type alkene moiety of compound
9 (Table 2). The resulting products should be of inter-
est because of potential biological activity. Many
transformations proceeded nicely to furnish reduced
compounds such as 16 (entry 1) or oxidized products
like 17, 18, 19, and 20 (entries 2–4) by stereoselective
epoxidation, dihydroxylation and hydroboration. The
latter transformation was only moderately regioselec-
tive; alternative borane derivatives did not react with
9. Conversion of 9 into amide 21 could be achieved
Scheme 2.
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Cascade Cyclizations of Naphthyl-Substituted 1,3-Diones
COMMUNICATIONS
via epoxide 17 as intermediate.[13] Similarly, opening
of this epoxide in methanol with a catalytic amount of
indium trichloride[14] provided the diastereomeric me-
thoxy-substituted compounds 23a/b (entry 7). The two
bromohydrins 24a and 24b were also formed unselec-
tively (entry 8).[14]
Table 2. Addition reactions of pentacyclic compound 9.
Finally, we converted 1,3-dione 5 into mesylate 25
by selective reduction of one carbonyl group followed
by sulfonylation.[15] Treatment of this compound with
the samarium diiodide-HMPA complex and tert-butyl
alcohol furnished pentacyclic alcohol 26 in 45% yield
(Scheme 4). The yield of this reaction was not im-
Scheme 4.
proved when no tert-butyl alcohol was present. This
product is related to 9, but it bears only one bridge-
head hydroxy group. We assume that the first cycliza-
tion occurs analogously to the process described in
Scheme 2. The second cyclization should involve a nu-
cleophilic displacement of the mesylate by the inter-
mediate carbanion. According to NOE measurements
the depicted configuration of precursor 25 is very
likely, which excludes an SN2 process for the second
cyclization step. An SN1-type reaction [triggered by
the Lewis acidic samarium(III) and samarium(II) spe-
G
cies present] seems to be more likely.[16]
In conclusion, we found that samarium diiodide
also promotes the reductive cyclizations of naphthyl-
substituted cycloalkane-1,3-diones, stereoselectively
leading to tetracyclic diols or in the absence of proton
sources to novel pentacyclic steroid-like compounds.
These products are suitable scaffolds for installing ad-
ditional substituents and functional groups. Mechanis-
tic details of the reported cascade cyclizations and fur-
ther functionalizations of the products in order to in-
crease their steroid similarity will be reported in due
time.
[a]
Cat Pd/C, H2, EtOAc, r.t., 5 h.
m-CPBA, CH2Cl2, r.t., 22 h.
Cat K2OsO2(OH)4, cat quinuclidine, K3Fe(CN)6, K2CO3,
methylsulfonamide, t-BuOH/H2O 1:1, r.t., 45 h.
[b]
[c]
[d]
BH3·THF, THF, 08C, 2.5 h, r.t., 2 h; NaOH, 30% H2O2,
r.t., 2 h.
[e]
CH3C(=O)NHBr, BF3·OEt2, H2O, CH3CN, 08C, 2 h.
a) m-CPBA, CH2Cl2, r.t., 22 h; b) NaN3, NH4Cl, acetone/
Experimental Section
[f]
H2O 4:1, 548C, 3 d.
a) m-CPBA, CH2Cl2, r.t., 22 h; b) Cat InCl3, MeOH,
[g]
General Methods
08C, 2.5 h, r.t., 15 h.
NBS, H2O, THF, 0 8C, 4.5 h, r.t., 15.5 h.
Reactions were generally performed under argon in flame-
dried flasks. Solvents and reagents were added by syringes.
Solvents were dried using standard procedures. Tetrahydro-
furan (THF) was freshly distilled from sodium/benzophe-
none under argon. Hexamethylphosphoramide was distilled
from calcium hydride, 1,2-diiodoethane was dried at 508C
[h]
by a recently published method[12] (entry 5). Its con-
figuration was proven by an X-ray analysis.[8] Azide
22 (entry 6) was prepared regio- and stereoselectively for 3 h under vacuum. SmI2 was either freshly prepared (see
Adv. Synth. Catal. 2008, 350, 65 – 69
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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67

Ulrike K. Wefelscheid and Hans-Ulrich Reissig
COMMUNICATIONS
typical procedure) or taken from a previously prepared
0.1M stock solution. Other reagents were purchased and
were used as received without further purification unless
otherwise stated. Unless otherwise stated, products were pu-
rified by flash chromatography on silica gel (230–400 mesh,
Merck or Fluka) or HPLC (Nucleosil 50–5). Unless other-
wise stated, yields refer to analytical pure samples. NMR
spectra were recorded on Bruker (AC 250, AM 270, AC
500) and JOEL (Eclipse 500) instruments. Chemical shifts
are reported relative to TMS (1H: d=0.00 ppm), CDCl3
(13C: d=77.0 ppm), or CD3OD (1H: d=3.31 ppm, 13C: d=
49.0 ppm). Integrals are in accordance with assignments;
coupling constants are given in Hz. All 13C spectra are
proton-decoupled. For detailed peak assignments 2D spectra
were measured (COSY and HMQC for all steroid-like com-
pounds, NOESY and NOE if necessary). IR spectra were
measured with an FT-IRD spectrometer Nicolet 5 SXC. MS
and HR-MS analyses were performed with Finnigan MAT
711 (EI, 80 eV, 8 kV), MAT CH7A (EI, 80 eV, 3 kV),
CH5DF (FAB, 3 kV) and Varian Ionspec QFT-7 (ESI-FT
ICRMS) instruments. Elemental analyses were carried out
with a CHN-Analyzer 2400 (Perkin–Elmer), Vario EL or
Vario EL III (Elementar). Melting points were measured
with a Reichert apparatus Thermovar and are uncorrected.
1H, 1-H), (*overlapping signals); 13C NMR (126 MHz,
CDCl3): d=16.5 (q, CH3), 19.9 (t, C-11), 24.6 (t, C-12) 28.3
(t, C-16), 31.4 (t, C-15), 36.3 (d, C-9), 41.5 (d, C-8), 47.2 (s,
C-13), 80.9 (d, C-17), 83.8 (s, C-14), 123.5 (d, C-1), 126.1 (d,
C-3), 126.5 (d, C-4), 127.7 (d, C-2), 129.1 (d, C-7), 129.8 (d,
ꢁ
C-6), 134.1, 136.3 (2 s, C-5, C-10); IR (KBr): n=3325 (O
H), 3060–2830 (=CH, C H), 1655–1570 (C=C) cmꢁ1; MS
ꢁ
(EI, 80 eV, 908C): m/z (%)=270 (82) [M]+, 156 (31), 154
(72), 142 (40), 141 (55), 129 (59), 128 (100), 28 (51); HR-
MS: m/z=270.16256, calcd. for C18H22O2: 270.16199.
1
7b: mp 176–1788C; H NMR (500 MHz, CDCl3): d=1.07
(s, 3H, CH3), 1.41 (dt, J=3.8, 13.6 Hz, 1H, 12-H1), 1.56–1.72
(m, 6H, 11-H1, 12-H2, 15-H1, 15-H2, 16-H1, OH), 2.16–2.34
(m, 4H, 8-H, 11-H2, 16-H2, OH), 2.63 (ddd, J=3.7, 11.9,
15.4 Hz, 1H, 9-H), 4.32 (t, J=8.6 Hz, 1H, 17-H), 6.17 (dd,
J=2.0, 9.7 Hz, 1H, 7-H), 6.57 (dd, J=2.9, 9.7 Hz, 1H, 6-H),
7.08 (dd, J=1.6, 7.1 Hz, 1H, 4-H), 7.17–7.21 (m, 1H, 3-H),
7.22 (dt, J=1.6, 6.9 Hz, 1H, 2-H), 7.25–7.29 (m, 1H, 1-H);
13C NMR (126 MHz, CDCl3): d=16.6 (q, CH3), 23.2 (t, C-
11), 28.4 (t, C-12), 28.8 (t, C-15), 30.0 (t, C-16), 39.3 (d, C-
9), 44.9 (d, C-8), 47.7 (s, C-13), 80.9 (d, C-17), 83.1 (s, C-14),
123.5 (d, C-1), 126.0 (d, C-4), 126.4 (d, C-3), 127.3 (d, C-2),
129.0 (d, C-6), 129.4 (d, C-7), 134.1, 138.4 (2 s, C-5, C-10);
ꢁ
ꢁ
IR (KBr): n=3315 (O H), 3060–2830 (=CH, C H), 1660–
1600 (C=C) cmꢁ1; MS (EI, 80 eV, 1508C): m/z (%)=270
(81) [M]+, 157 (73), 155 (75), 142 (87), 141 (100), 129 (59),
128 (95), 115 (30), 97 (60), 43 (41), 41 (32), 28 (69); HR-
MS: m/z=270.16114, calcd. for C18H22O2: 270.16199.
Typical Procedure for the Preparation of Steroid
Analogues
(8S*,9S*,13R*,14R*,17S*)-3-Methoxy-9,17-cycloestra-1(10),
2,4,6-tetraene-14,17-diol (15): LiBr (774 mg, 8.91 mmol,
22 equivs.) was dissolved in THF (5 mL), 1,3-dimethyl-2-imi-
dazolidinone (1.6 mL, 1.7 g, 15 mmol, 36 equivs.) was added
and argon was bubbled through the solution for 20 min. The
solution was added to a solution of SmI2 in THF (0.1M,
23 mL, 2.3 mmol, 5.7 equivs.). Dione 13 (120 mg,
0.405 mmol) was dissolved in THF (5 mL), argon was bub-
bled through the solution for 25 min, and the solution was
added to the SmBr2 solution and stirred at room tempera-
ture for 1 day. Saturated aqueous NaHCO3 solution (30 mL)
was added, the organic layer was separated and the aqueous
layer was extracted with Et2O (3”30 mL). The combined or-
ganic layers were washed with brine (6”3 mL) and dried
with Na2SO4. The solvent was removed under reduced pres-
sure. Column chromatography on silica gel (hexane/EtOAc,
2:1) afforded 15 as a colorless solid; yield: 28 mg (23%);
mp 1448C; 1H NMR (500 MHz, CDCl3): d=1.01 (s, 3H,
13-CH3), 1.26 (dt, J=2.6, 12.3 Hz, 1H, 16-H1), 1.45–1.52 (m,
3H, 16-H2, 11-H1, OH), 1.54 (ddd, J=2.2, 11.1, 13.4 Hz, 1H,
12-H1), 1.65 (br. s, 1H, OH), 1.72 (ddt, J=2.8, 6.4, 12.3 Hz,
1H, 15-H1), 1.85–1.92 (m, 2H, 12-H2, 15-H2), 2.40 (q,
Jꢀ2.5 Hz, 1H, 8-H), 2.51 (dt, J=7.0, 11.1 Hz, 1H, 11-H2),
3.78 (s, 3H, OCH3), 5.91 (dd, J=3.0, 9.9 Hz, 1H, 7-H), 6.31
(dd, J=2.3, 9.9 Hz, 1H, 6-H), 6.63 (d, J=2.7 Hz, 1H, 4-H),
6.71 (dd, J=2.7, 8.4 Hz, 1H, 2-H), 7.25 (d, J=8.4 Hz, 1H,
1-H); 13C NMR (126 MHz, CDCl3): d=11.0 (q, CH3), 26.0,
26.1 (2 t, C-12, C-16), 31.1 (t, C-15), 37.4 (t, C-11), 50.9 (d,
C-8), 51.2, 52.1 (2 s, C-9, C-13), 55.2 (q, OCH3), 83.0, 86.4
(2 s, C-14, C-17), 112.1 (d, C-2), 113.1 (d, C-4), 124.9 (s, Ar),
127.0 (d, C-6), 127.1 (d, C-1), 127.8 (d, C-7), 134.6, 158.6
(8S*,9S*,13S*,14R*,17S*)-Estra-1(10),2,4,6-tetraene-14,17-
diol (7a) and (8S*,9R*,13S*,14R*,17S*)-Estra-1(10),2,4,6-
tetraene-14,17-diol (7b): Sm (325 mg, 2.16 mmol, 6.0 equivs.)
and ICH2CH2I (503 mg, 1.98 mmol, 5.5 equivs.) were sus-
pended in THF (30 mL) at room temperature and vigorous-
ly stirred until the deep blue color of SmI2 appeared (1–
4 h); then HMPA (2.3 mL, 2.3 g, 13 mmol, 36 equivs.) was
added. Dione 5 (95 mg, 0.36 mmol) and t-BuOH (0.26 mL,
0.21 g, 2.9 mmol, 8.0 equivs.) were dissolved in THF (10 mL)
and argon was bubbled through the solution for 30 min. This
solution of 5 was added via syringe to the SmI2-HMPA solu-
tion. The mixture was stirred at room temperature over-
night. Saturated aqueous NaHCO3 solution (50 mL) was
added, the organic layer was separated and the aqueous
layer was extracted with Et2O (3”50 mL). The combined or-
ganic layers were washed with water (2”10 mL) and brine
(1”5 mL) and dried with Na2SO4. The solvents were re-
moved under reduced pressure. Column chromatography on
silica gel (hexane/EtOAc 2:1) afforded a 56:44 mixture of
isomers 7a and 7b as a colorless solid; yield: 72 mg (74%).
Analytically pure samples of 7a and 7b were obtained by
HPLC.
1
7a: mp 167–1698C; H NMR (500 MHz, CDCl3): d=1.12–
1.21 (m, 2H, 16-H1, OH), 1.16 (s, 3H, CH3), 1.26* (ddd, J=
4.5, 10.1, 14.7 Hz, 1H, 15-H1), 1.26* (s, 1H, OH), AB-signal
(dA =1.38, dB =1.42, JA,B =13.8 Hz, additional couplings of
A, J=3.1, 13.8 Hz, and of B J=3.6, 3.6 Hz, 1 H each, 12-
H2), 1.53 (ddd, J=5.9, 12.5, 14.7 Hz, 1H, 15-H2), 1.87–2.01
(m, 2H, 16-H2, 11-H1), 2.43 (qd, J ꢀ 3, 14.6 Hz, 1H, 11-H2),
2.52 (dd, J=6.1, 6.9 Hz, 1H, 8-H), 3.34 (br. dd, J=6.0,
6.9 Hz, 1H, 9-H), 4.17 (t, J=8.5 Hz, 1H, 17-H), 6.14 (dd,
J=6.1, 9.8 Hz, 1H, 7-H), 6.59 (d, J=9.8 Hz, 1H, 6-H), 7.02
(dd, J=1.2, 7.4 Hz, 1H, 4-H), 7.14 (br. t, J=7.4 Hz, 1H, 3-
H), 7.19 (dt, J=1.2, 7.4 Hz, 1H, 2-H), 7.26 (br. d, J=7.4 Hz,
ꢁ
(2 s, Ar); IR (KBr): n=3460, 3410 (O H), 3025–2830 (=CH,
C H, OCH3), 1600, 1500 (C=C) cmꢁ1; anal. calcd. for
ꢁ
C19H22O3 (298.4): C 76.48, H 7.43; found: C 76.58, H 7.48.
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Cascade Cyclizations of Naphthyl-Substituted 1,3-Diones
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[5] The outcome of the reduction strongly depends on the
amount and the reactivity of the Pd-catalyst as well as
on the reaction time. Too much Pd/C or excess reaction
times led to partial reduction of the naphthyl moiety.
[6] The use of HMPA raises the reducing potential of sa-
marium diiodide and is required for many ketyl cou-
pling reactions, see: a) K. Otsubo, J. Inanaga, M. Yama-
guchi, Tetrahedron Lett. 1986, 27, 5763–5764; b) J. Ina-
naga, M. Ishikawa, M. Yamaguchi, Chem. Lett. 1987,
1485–1486; c) M. Shabangi, R. A. Flowers II, Tetrahe-
dron Lett. 1997, 38, 1137–1140; d) J. B. Shotwell, J. M.
Sealy, R. A. Flowers II, J. Org. Chem. 1999, 64, 5251–
5255; e) R. S. Miller, J. M. Sealy, M. Shabangi, M. L.
Kuhlman, J. Fuchs, R. A. Flowers II, J. Am. Chem. Soc.
2000, 122, 7718–7722; f) E. Prasad, R. A. Flowers II, J.
Am. Chem. Soc. 2002, 124, 6895–6899; g) R. A. Flow-
ers II, X. Xu, C. Timmons, G. Li, Eur. J. Org. Chem.
2004, 2988–2990; h) A. DahlØn, G. Hilmersson, Eur. J.
Inorg. Chem. 2004, 3393–3404; there has been no gen-
eral success by replacing HMPA with less toxic cosol-
vents.
[7] For entries 3 and 4 (Table 1) it is important to add tert-
butyl alcohol to the SmI2-HMPA complex before addi-
tion of precursor 5; when the standard sequence was
applied the yields were lower.
[8] Crystallographic data for 7a: U. K. Wefelscheid, I.
Brüdgam, H. Hartl, H.-U. Reissig, Z. Kristallogr. NCS
2007, 222, in press; for 7b: CCDC 659637; for 9: U. K.
Wefelscheid, I. Brüdgam, H.-U. Reissig, Z. Kristallogr.
NCSZ. 2007, 222, in press; for 21: CCDC 659638; the
data for 7b and 21 can be obtained free of charge from
the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
Generous support ofthis work by the Deutsche Forschungs-
gemeinschaft and the Fonds der Chemischen Industrie is
gratefully acknowledged. We also thank the Schering AG for
general support, Dr. M. Berndt for preliminary experiments
and Dr. R. Zimmer and Dr. S. Yekta for help during prepara-
tion ofthis manuscript.
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[9] This dependency was not observed in cyclizations of
monoketones (ref.[2]) and requires further investiga-
tions.
[10] The detailed mechanistic features of these cyclization
reactions are still unclear and have to be investigated.
Actually, 2 equivs. of samarium diiodide should be suf-
ficient for conversion of compound 5 into 9, however,
if 2.75 equivs. of SmI2 were used only reduction of one
of the two carbonyl groups of 5 was observed.
[11] Monocyclization product 7 was not detected under
these conditions.
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