Sn(OTf)2 as an effective lewis acid in reactions of cyclopropyl ketones with acetic anhydride: Application in the synthesis of a 19-Nor-B-homo steroid

Article abstract of DOI:10.1002/ejoc.201100020

Attempts to convert 3β-acetoxy-5,19-cyclo-pregna-6,20-dione (8) into a cyclocitrinol-related steroid with a bicyclo[4.4.1]-undecane AB-ring substructure through a Lewis acid-assisted fragmentation failed. Instead, treating 8 with an excess of Ac₂

Full text of DOI:10.1002/ejoc.201100020

FULL PAPER
DOI: 10.1002/ejoc.201100020
Sn(OTf)2 as an Effective Lewis Acid in Reactions of Cyclopropyl Ketones with
Acetic Anhydride: Application in the Synthesis of a 19-Nor-B-homo Steroid
Darius Paul Kranz,[a] Aike Meier zu Greffen,[a] Sherif El Sheikh,[b] Jörg Martin Neudörfl,[a]
and Hans-Günther Schmalz*[a]
Keywords: Rearrangement / Cations / Steroids / Fused-ring systems / Lewis acids
Attempts to convert 3β-acetoxy-5,19-cyclo-pregna-6,20-di-
as a model substrate, did not react under the same condi-
one (8) into a cyclocitrinol-related steroid with a bicy- tions. However, by screening various Lewis acids, stannous
clo[4.4.1]-undecane AB-ring substructure through a Lewis
acid-assisted fragmentation failed. Instead, treating 8 with an
excess of Ac2O and BF3·Et2O afforded B-homo steroid 9 in
90% yield. This unexpected rearrangement is assumed to
proceed via an intermediate bicyclobutonium cation. Re-
markably, tricyclo[4.4.1.0]undecane-1-one (rac-13), prepared
triflate was identified as a particularly efficient reagent for
this and related Lewis acid-assisted ring-opening reactions
of cyclopropyl ketones in the presence of Ac2O, and even
catalytic amounts of Sn(OTf)2 (5 mol-%) proved to be effec-
tive.
Inspired by the possible biosynthetic formation of the
bicyclo[4.4.1]undecane substructure, the AB-ring core of
1,[2c] we asked ourselves whether 5,19-cyclo-6-oxo steroid 3
could possibly be converted into the ring-fragmented prod-
uct 4 under the assistance of a Lewis acid (Scheme 1).
Introduction
Due to their unsurpassed biological importance and
structural diversity, steroids continue to play a major role
in natural products research and medicinal chemistry.[1] In
recent years, some unusual steroids displaying a rearranged
AB-ring system (Figure 1), such as isocyclocitrinol (1)[2]
and cortistatin A (2),[3] have also received much attention
by synthetic chemists. This is not only because of the prom-
ising biological properties of such compounds, but also be-
cause the construction of the functionalized AB-ring sub-
structure with at least one seven-membered ring represents
a nontrivial challenge.
Scheme 1. A key question is whether a cyclopropyl ketone 3 will
undergo a “biomimetic” fragmentation to give cyclocitrinol-type
product 4 under Lewis acid (LA) assistance.
Results and Discussion
To probe the possibility of synthesizing compound 4
through a cyclopropane fragmentation, we first had to pre-
pare precursor 3. This was achieved by the semisynthesis of
5,19-cyclo steroid 8 starting from pregnenolone acetate (5)
as shown in Scheme 2. To prepare for the cyclopropane for-
mation, we first had to functionalize the C-19 methyl
group.[4] This was achieved by treating 5 with N-bromoacet-
amide (NBA) in the presence of HClO4 to produce the bro-
mohydrin intermediate which then underwent a hypoiodite
reaction [Pb(OAc)4, I2].[5] After reductive cleavage (Zn,
AcOH, iPrOH)[6] of the initially formed cyclic ether, 19-
hydroxy pregnenolone acetate 6 was obtained in 42% over-
all yield. The conversion of 6 into cyclopropane derivative
Figure 1. Structure of isocyclocitrinol (1) and cortistatin A (2).
[a] Department für Chemie, Universität zu Köln,
Greinstr. 4, 50939 Köln, Germany
Fax: +49-221-470-3064
E-mail: schmalz@uni-koeln.de
[b] Bayer Healthcare AG,
Gebäude 460, 42096 Wuppertal, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100020.
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Reactions of Cyclopropyl Ketones
7 was initiated by mesylation of the hydroxy group followed flux; (3) Me2AlCl, CH2Cl2, 0 °C; (4) Me2AlCl, Ac2O,
by solvolysis in a buffered solution of HOAc and KOAc CH2Cl2, 0 °C; (5) LiCl, 1,8-diazabicyclo[5.4.0]undec-7-ene
in aqueous acetone.[7] The resulting cyclopropylcarbinol 7, (DBU), acetonitrile, reflux; and (6) pyridinium p-toluene-
obtained in 52% yield, was then carefully oxidized under sulfonate (PPTS), CH2Cl2, reflux. However, the expected
Dess–Martin conditions[8] to give compound 8 in 88% product 4 was not observed. Interestingly, treating 8 with
yield.
an excess amount of BF3·Et2O and Ac2O in CH2Cl2
(–20 °C, 16 h) resulted in a surprisingly clean transforma-
tion to give a single new product in 90% isolated yield. This
product turned out to be B-homo steroid 9 as unambigu-
ously proven by X-ray crystal structure analysis (Fig-
ure 2).[9]
Scheme 2. Synthesis of the 5,19-cyclo steroid 8 from pregnenolone
acetate (5). Reagents and conditions: (a) NBA, catalytic HClO4,
1,4-dioxane, room temp., 1 h; (b) Pb(OAc)4, I2, benzene, reflux, Hg
lamp (150 W), 1.5 h; (c) Zn, AcOH, iPrOH, reflux, 30 min;
(d) MsCl, pyridine, 0 °C, 2 h; (e) KOAc, acetone/H2O, reflux, 16 h;
(f) Dess-Martin periodinane (DMP), CH2Cl2, room temp.
Figure 2. Structure of the B-homo steroid 9 in the crystalline state.
We assume the reaction of 8 to rearranged product 9 was
Using 8 as a substrate, we tested the proposed rearrange- initiated by O-acetylation, that is, by the formation of cat-
ment (Scheme 3) under different conditions such as: ionic intermediate 10a. As a cyclopropylcarbinyl cation,
(1) BF3·Et2O, CH2Cl2, –20 °C; (2) LiCl, HCl, ethanol, re- this species can rearrange via bicylobutonium-type[10] inter-
Scheme 3. Conversion of 8 into B-homo steroid 9 and a mechanistic rationalization for this unexpected transformation.
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mediate 10b to give isomeric cyclopropylcarbinyl cation product was formed when only Ac2O, Sn(OTf)2, or TfOH
10c, which readily undergoes oxygen-assisted fragmentation was utilized. Using less than 50 mol-% of Sn(OTf)2 in the
to give the less strained cycloheptenyl cation 11. Finally, presence of 8 equiv. of Ac2O resulted in incomplete conver-
oxy-stabilized carbenium cation 11 delivers dienyl acetate 9 sion of the starting material.
by proton elimination. The fact that no conversion of 8 was
Having identified Sn(OTf)2 as a particularly effective
observed under similar conditions in the absence of acetic Lewis acid, we probed the developed protocol in the related,
anhydride suggests that the initial activation of Ac2O by the albeit non-rearranging, ring-opening followed by acety-
Lewis acid, that is, formation of an acetyl cation equivalent, lation of the simple substrate rac-15.[16] This reaction sys-
plays an important role in this reaction.
tem had previously been investigated by Rigby et al. who
We then wondered whether the interesting rearrangement treated rac-15 with an excess amount of BF3·Et2O and
and cyclopropane ring-opening (i.e., 8 to 9) proceeded only Ac2O in CH2Cl2 to obtain a 3:1 mixture of the isomeric
in the specific structural context of the steroidal system, or enol acetates rac-16 and rac-17 resulting from homoconju-
if this type of transformation would also be observed with gate addition of the acetate (Scheme 5).[17] We were pleased
less complex substrates. Therefore we decided to investigate to find that under our conditions, that is, in the presence of
tricyclo[4.4.1.0]undecane-1-one (rac-13) as a simplified 50 mol-% of Sn(OTf)2 and 8 equiv. of Ac2O, this transfor-
model substrate (Scheme 4). The synthesis of rac-13 began mation proceeded with a greatly improved 10:1 regioselec-
with enone 12[11] which was reduced to the corresponding tivity. When the amount of Sn(OTf)2 was lowered to 5 mol-
allylic alcohol under Luche conditions (NaBH4/CeCl3 in %, but still using 8 to 10 equiv. of Ac2O, no significant con-
MeOH)[12] before the cyclopropane ring was introduced, version of rac-15 was observed after 12 h. However, when
syn to the OH group, in a Simmons–Smith-type reaction.[13] the excess amount of Ac2O was reduced to 2.5 equiv., full
The crude cyclopropanation product was finally oxidized conversion of rac-15 was observed with only 5 mol-% of
with Jones reagent[14] to afford pure cyclopropyl ketone rac- Sn(OTf)2, and the products rac-16 and rac-17 were isolated
13 in 70% yield from 12, after chromatography.
in at least a 37% combined yield after chromatography.
With less than 2.5 equiv. of Ac2O in the presence of 5 mol-
% of Sn(OTf)2, however, incomplete conversion of the start-
ing material was observed. In a similar fashion, the cy-
clopropyl ketone rac-18 afforded enol acetate rac-19
(Scheme 5).
Scheme 4. Synthesis of the model substrate rac-13 and its conver-
sion to 14. Reagents and conditions: (a) NaBH4, CeCl3, MeOH,
0 °C, 1 h; (b) ZnEt2, ClCH2I, ClCH2CH2Cl/THF (tetra-
hydrofuran), 0 °C, 6 h; (c) CrO3, aqueous H2SO4, acetone, 15 min;
(d) Ac2O (8 equiv.), Sn(OTf)2 (50 mol-%), CH2Cl2, 0 °C, 3 h;
(e) Ac2O (2.5 equiv.), Sn(OTf)2 (5 mol-%), CH2Cl2, 0 °C, 22 h.
To our surprise, treatment of rac-13 with Ac2O and
BF3·Et2O under the proven conditions (Scheme 4) did not
result in the formation of 14 to any significant extent. With
this reagent combination, the expected ring-opening re-
arrangement also did not occur at higher temperatures, up
to 25 °C, or concentrations. We then replaced BF3 with
other Lewis acids, such as SnCl2, CoCl2, TiCl4, ZnCl2,
FeCl3, Fe(acac)3, FeI3, LiCl, or SnCl4, however, the ex-
pected product 14 could not be detected by GC–MS. In-
stead in most cases, complex mixtures were obtained. In a
next series of experiments, we tested different metal triflates,
that is, Fe(OTf)3, Yb(OTf)3, LiOTf, Mg(OTf)2, Sm(OTf)3,
Scheme 5. Stannous triflate-promoted fragmentation of rac-15 and
rac-18. Reagents and conditions: (a) Ac2O (8 equiv.), Sn(OTf)2
(50 mol-%), CH2Cl2, 0 °C to room temp., 12 h; (b) Ac2O
(2.5 equiv.), Sn(OTf)2 (5 mol-%), CH2Cl2, 0 °C to room temp., 24 h.
Eu(OTf)3, Ga(OTf)3, Bi(OTf)2, Sn(OTf)2, and Sc(OTf)3.
To probe the possible stereospecificity[18] for the ring-
[15]
Remarkably, only Sn(OTf)2 gave rise to significant levels opening reaction of 15, we prepared a non-racemic sample
of conversion forming a product with the expected mass of of 15 (78% ee) by an asymmetric cyclopropanation
14 in a surprisingly clean reaction as indicated by GC–MS procedure according to the protocol of Mash et al.
analysis. When the reaction was repeated on a preparative (Scheme 6).[19] When this material was treated with acetic
scale, 100 mg, using 50 mol-% of Sn(OTf)2 in the presence anhydride under the optimized stannous triflate-mediated
of 8 equiv. of Ac2O (3 h reaction time), the desired bicy- conditions, the main product (i.e., rac-16) was formed in
clo[5.4.0]undecane derivative 14 was obtained in 55% iso- almost racemic form (Յ 5% ee) as determined by chiral GC
lated yield after purification by flash chromatography analysis. This suggests the presence of an achiral carbenium
(Scheme 4). In control experiments it was shown that no cation intermediate, such as 20, in the reaction course.
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Reactions of Cyclopropyl Ketones
and 75 MHz (for 13C NMR) at 25 °C with a Bruker DPX 300 spec-
trometer. CDCl3 was used as the NMR solvent unless otherwise
indicated. Proton shifts are reported in ppm (δ) downfield from
TMS (tetramethylsilane) and were determined by reference to the
residual solvent signals (CDCl3, 7.24 ppm). Data are reported as
follows: chemical shift, multiplicity [singlet (s), doublet (d), triplet
(t), quartet (q), quintet (quint), or multiplet (m)], coupling con-
stants (Hz), integration, assignment. 13C NMR spectra were re-
corded using the APT (Attached Proton Test) sequence with com-
plete proton decoupling. Multiplicities [C (s), CH2 (t) or CH (d),
CH3 (q)] were deduced from these spectra. 13C NMR chemical
shifts are reported in ppm (δ) relative to solvent signals as the in-
ternal standard (CDCl3, 77.00 ppm). Melting points were measured
with a Büchi B-454. IR spectra were measured at 25 °C as ATR
(attenuated total reflectance) with a Perkin–Elmer FTIR Paragon
Scheme 6. Loss of absolute stereochemical information in the
stannous triflate-promoted ring-opening acetylation of 15.
Finally, we were curious whether stannous triflate would
also be effective as a Lewis acid in our original reaction
system, that is, the ring-opening and rearrangement of
steroid derivative 8 to give 9. Much to our satisfaction, the
desired product 9 was obtained in 95% yield after treatment
of 8 with an excess amount of Ac2O in the presence of
50 mol-% of Sn(OTf)2 for 16 h (Scheme 7). The particular
ease of this transformation is reflected by the fact that prod-
uct 9 was also obtained in high yield (81% yield) when only
5 mol-% of Sn(OTf)2 and 2.5 equiv. of Ac2O were em-
ployed.
1000. Data are reported in cm–1 as follows: absorption (ν values),
˜
weak (w), middle (m), strong (s), or broad (br.). Mass spectra were
recorded with a Finnigan MAT Incos 50 Galaxy system and a Fin-
nigan MAT 900. Energy and the method of ionization are noted
for each measurement, and the intensities are given proportionally
to the basic peak (100%). Flash chromatography was done with
Merck silica gel 60 (230–400 mesh). Mass spectra (MS) and high
resolution mass spectra (HRMS) were measured with a Varian
MAT 711, Finnigan Incos 500, or Finnigan MAT 95 ST. The spec-
tra were measured under electron impact (EI) with an ionization
potential of 70 eV. Gas chromatography with mass selective detec-
tion (GC–MS) was carried out using an Agilent instrument with a
5973 N detector on 30 mϫ0.25 mm capillary columns (Optima-1-
MS from Macherey–Nagel) with H2 as the carrier gas (1.7 mL/min,
1.2 bar). Routinely, the following temperature program was used:
50 °C for 2 min, then heating with 25 °C/min to 300 °C for 5 min,
and finally 320 °C for 5 min. Optical rotations were measured with
a Perkin–Elmer 343 polarimeter at 20 °C using a 10 cm cell. The
solvents and concentrations in g/100 mL are indicated.
Scheme 7. Stannous triflate-promoted fragmentation of 8. Rea-
gents and conditions: (a) Ac2O (8 equiv.), Sn(OTf)2 (50 mol-%),
CH2Cl2, 0 °C to room temp., 16 h; (b) Ac2O (2.5 equiv.), Sn(OTf)2
(5 mol-%), CH2Cl2, 0 °C to room temp., 16 h.
3β-Acetoxy-19-hydroxy-Δ5-pregnen-20-one (6): To a solution of pre-
gnenolone acetate (5) (10 g, 27.9 mmol) in dioxane (75 mL) was
added HClO4 (0.5 n, 18 mL) and N-bromoacetamide (5.3 g,
38.4 mmol) at room temp. The mixture was stirred in the dark until
the TLC indicated complete consumption of the starting material
(1 h). Then, the mixture was decolorized by the addition of satu-
rated aqueous Na2SO3, diluted with H2O (500 mL), and extracted
with methyl tert-butyl ether (MTBE, 3ϫ750 mL). The organic
Conclusions
By probing a postulated “biomimetic” transformation in
the steroid series, we accidently discovered the high-yielding
conversion of 8 to B-homo steroid 9 by a Lewis-acid-medi- phase was washed with brine, dried with MgSO4, and evaporated
under reduced pressure (water bath Ͻ 35 °C). The crude product
(13.5 g), a colorless solid, was dissolved in benzene (750 mL),
treated with Pb(OAc)4 (47 g, 106 mmol) and iodine (12.1 g,
47.7 mmol), and heated at reflux under irradiation with a sun lamp
until the reaction mixture was decolorized. The mixture was
cooled, and the Pb(OAc)2 precipitate was removed by filtration and
washed with MTBE (500 mL). The combined organic phases were
washed with saturated Na2SO3 (3ϫ300 mL) and brine (200 mL)
and then dried with MgSO4. The solvent was evaporated under
reduced pressure. The residue was taken up in iPrOH (500 mL),
ated reaction with acetic anhydride. After extensive optimi-
zation, the same ring-opening rearrangement was also
achieved using the parent tricyclo[4.4.1.0]undecane-1-one
(rac-13) as a substrate. In this context, we found that the
combination of Ac2O and Sn(OTf)2 represents a particu-
larly powerful reagent[20] which was also successfully used
in the ring-opening O-acetylation of other less reactive cy-
clopropyl ketones. While the reason for the superior behav-
ior of the reagent remains unknown, we are optimistic that
the stannous triflate-mediated (or catalyzed) reaction of cy- treated with zinc dust (10 g, 153 mmol) and AcOH (16 mL), and
the mixture was heated at reflux for 30 min. After filtration and
evaporation under reduced pressure, the residue was taken up in
MTBE (500 mL) and washed with H2O (100 mL) and brine
(100 mL). The organic solution was dried with MgSO4, and the
solvent was evaporated under reduced pressure. The residue was
purified by flash chromatography to yield 6 as a colorless solid
(4.4 g, 11.75 mmol, 42%). Rf = 0.1 [cyclohexane (CyH)/EtOAc,
2:1]; m.p. 164–165 °C (MTBE, see ref.[21] 163–167 °C). [α]D = 24.1
(c = 0.78, CHCl3), [α]546 = 33.5, [α]405 = 153.3, [α]365 = 320.7,
clopropyl ketones with carboxylic acid anhydrides will find
future applications in organic synthesis.
Experimental Section
General: All reactions were conducted in flame-dried glassware un-
der an argon atmosphere using freshly distilled anhydrous solvents.
1
NMR spectra were routinely recorded at 300 MHz (for H NMR)
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1
[α]334 = 806.0. H NMR (300 MHz, CDCl3): δ = 5.70–5.68 (m, 1 H, 3-H), 2.97–2.90 (m, 1 H), 2.50 (t, J = 9.0 Hz, 1 H), 2.31 (dd, J1
H, 6-H), 4.62–4.51 (m, 1 H, 3-H), 3.77 (d, J = 11.5 Hz, 1 H, 19a-
H), 3.53 (d, J = 11.5 Hz, 1 H, 19b-H), 2.48–2.08 (m, 4 H), 2.04 (s,
3 H, 21-H), 1.95 (s, 3 H, OAc), 1.88–0.80 (m, 16 H), 0.60 (s, 3 H,
= 18.2 Hz, J2 = 3.9 Hz, 1 H), 2.23–2.09 (m, 2 H), 2.07 (s, 3 H, 21-
H), 2.03–2.02 (m, 1 H), 1.96 (s, 3 H, OAc), 1.76–1.10 (m, 15 H),
0.88 (d, J = 5.7 Hz, 1 H, 19a-H), 0.59 (s, 3 H, 18-H) ppm. 13C
18-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 209.5 (s, C-20), 170.5 NMR (75 MHz, CDCl3): δ = 208.9 (s, C-6), 207.7 (s, C-20), 170.3
(s, OAc), 134.6 (d, C-6), 127.8 (s, C-5), 73.3 (d, C-3), 63.5 (d, C-
17), 62.6 (t, C-19), 57.6 (d), 50.1 (d), 44.1 (s), 41.5 (s), 39.0 (t), 38.1
(t), 33.2 (t), 33.1 (d), 31.4 (q, C-21), 31.1 (t), 28.0 (t), 24.2 (t), 22.7
(s, OAc), 70.0 (d, C-3), 63.2 (d, C-17), 55.5 (d), 45.5 (t), 44.2 (s),
41.8 (t), 38.6 (t), 33.9 (s), 31.8 (q, C-21), 31.4 (d), 30.6 (s), 30.5 (t),
27.6 (t), 25.6 (t), 24.8 (t), 23.6 (t), 22.7 (t), 21.3 (t), 21.2 (q, OAc),
(t), 21.6 (t), 21.3 (q, OAc), 13.5 (q, C-18) ppm. IR (ATR): ν = 3462
13.5 (q, C-18) ppm. IR (ATR): ν = 2939 (s), 2869 (m), 1729 (s),
˜
˜
(br. m), 2940 (s), 1728 (vs), 1699 (vs), 1471 (w), 1440 (w), 1357 (m), 1699 (s), 1679 (s), 1472 (m), 1447 (m), 1361 (s), 1245 (s), 1190 (w),
1241 (vs), 1189 (m), 1029 (s), 907 (w), 884 (w), 838 (w), 796 (w),
733 (s), 701 (w) cm–1. MS (EI, 70 eV): m/z (%) = 314 (15) [M –
AcOH]+, 298 (3), 283 (95), 265 (20), 241 (13), 227 (4), 213 (8), 199
(15), 183 (10), 159 (12), 145 (31), 131 (25), 105 (24), 91 (34), 67
(15), 43 (100).
1169 (w), 1126 (w), 1028 (s), 982 (m), 911 (w), 869 (w), 751 (s), 666
(m) cm–1. MS (EI, 70 eV): m/z (%) = 312 (42) [M – AcOH]+, 298
(2), 284 (5), 268 (5), 251 (3), 225 (15), 198 (7), 173 (5), 147 (14),
121 (18), 105 (16), 91 (30), 77 (21), 60 (8), 43 (100). HRMS (EI):
12
calcd. for C21H2816O2 312.2089; found 312.209.
3β-Acetoxy-5,19-cyclo-pregnan-6β-ol-20-one (7):
A solution of
3b,7-Diacetoxy-B-homo-pregna-5(10),6-dien-2-one
(9).
Using
alcohol 6 (4.4 g, 11.75 mmol) in pyridine (50 mL) was cooled to
0 °C before MsCl (4.4 mL) was added over 10 min. The solution
was stirred at 0 °C for 2 h and then poured into iced water
(500 mL). After 30 min, the mixture was extracted with MTBE/
EtOAc (1:1, 3ϫ750 mL). The combined organic phases were
washed with brine, dried with MgSO4, and evaporated under re-
duced pressure to give the mesylate as a slightly yellow solid (4.9 g,
65.5 mmol). The crude mesylate was dissolved in acetone (150 mL)
and treated with a solution of KOAc (6.7 g, 65.6 mmol) in H2O
(50 mL). The mixture was heated at reflux for 16 h, concentrated
under reduced pressure to approximately 70 mL, and extracted
with MTBE (3ϫ600 mL). The combined organic layers were
washed with brine (100 mL) and dried with MgSO4, and the sol-
vents were evaporated under reduced pressure. The residue was
purified by flash chromatography to yield 7 as a colorless solid
(2.1 g, 5.61 mmol, 52%). Rf = 0.1 (CyH/EtOAc, 1:1); m.p. 114–
116 °C (MTBE). [α]D = 4.5 (c = 0.347, CHCl3), [α]546 = 8.6, [α]405
= 59.8, [α]365 = 129.4, [α]334 = 308.6. 1H NMR (300 MHz, CDCl3):
δ = 4.68–4.58 (m, 1 H, 3-H), 4.05–4.03 (m, 1 H, 6-H), 2.47 (t, J =
9.0 Hz, 1 H), 2.14–2.07 (m, 2 H), 2.04 (s, 3 H, 21-H), 2.02–1.97 (m,
1 H), 1.94 (s, 3 H, OAc), 1.83–1.76 (m, 3 H), 1.69–0.96 (m, 14 H),
0.84 (d, J = 5.1 Hz, 1 H, 19b-H), 0.54 (s, 3 H, 18-H), 0.23 (d, J =
5.1 Hz, 1 H, 19a-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 209.3
(s, C-20), 170.5 (s, OAc), 73.6 (d, C-3), 70.5 (d, C-6), 63.7 (d, C-
17), 54.9 (d, C-9), 48.1 (d), 44.5 (s, C-13), 40.2 (t), 38.8 (t), 37.1 (t),
31.4 (d), 29.4 (q, C-21), 28.1 (t), 27.2 (s), 26.6 (s), 26.1 (t), 25.0 (t),
24.0 (t), 22.8 (t), 21.3 (q, OAc), 15.7 (t, C-19), 13.6 (q, C-18) ppm.
BF3·Et2O: Compound 8 (35 mg, 0.095 mmol) was dissolved in dry
CH2Cl2 (0.5 mL) and dry Ac2O (0.5 mL, 5.28 mmol). Then BF3
etherate (0.1 mL) was added at –20 °C, and the mixture was stirred
for 16 h. Saturated aqueous NaHCO3 (10 mL) was added, and the
mixture was extracted with EtOAc (3ϫ90 mL). The combined or-
ganic phases were washed with brine, dried with MgSO4, and con-
centrated under reduced pressure. The residue was purified by flash
chromatography to yield 9 as a colorless solid (35 mg, 0.085 mmol,
90%).
Using Sn(OTf)2: Compound 8 (30 mg, 0.081 mmol) was dissolved
in dry CH2Cl2 (1 mL), cooled to 0 °C, and Sn(OTf)2 (16.7 mg,
0.04 mmol) was added. The reaction mixture was stirred for 5 min,
and dry Ac2O (0.06 mL, 0.65 mmol) was added. Stirring was con-
tinued for 16 h, and the conversion was monitored by TLC. Then
the reaction was quenched by the addition of saturated NaHCO3
(10 mL) and extracted with EtOAc (3ϫ30 mL). The combined or-
ganic phases were washed with brine (5 mL), dried with MgSO4,
and evaporated to yield
9 as a colorless residue (32 mg,
0.076 mmol, 95%). In a similar experiment, Sn(OTf)2 (1.7 mg,
0.004 mmol) and Ac2O (0.38 mL, 0.04 mmol) were used to give 9
(27 mg, 0.065 mmol, 81%) after 16–24 h. Rf = 0.45 (PhMe/EtOAc,
4:1); m.p. 155–156 °C. [α]D = –308.9 (c = 0.5, CHCl3), [α]546
=
–372.1, [α]405 = –820.2, [α]365 = –1102.1, [α]334 = –1357.3. 1H NMR
(300 MHz, CDCl3): δ = 5.43 (s, 1 H, 6-H), 4.88–4.79 (m, 1 H, 3-
H), 2.57 (t, J = 9.0 Hz, 1 H), 2.45–2.15 (m, 6 H), 2.11 (s, 3 H, 21-
H), 2.07 (s, 3 H, OAc), 2.0 (s, 3 H, OAc), 1.96–1.09 (m, 13 H), 0.56
(s, 3 H, 18-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 209.4 (s, C-
20), 170.7 (s, OAc), 169.2 (s, OAc), 152.50 (s, C-7), 139.2 (s, C-10),
126.3 (s, C-5), 118.6 (d, C-6), 70.2 (d, C-3), 63.7 (d, C-17), 54.1 (d),
53.5 (d), 46.7 (d), 44.4 (s), 38.4 (t), 34.9 (t), 33.2 (t), 31.5 (q, C-21),
28.3 (t), 25.2 (t), 24.8 (t), 24.4 (t), 22.5 (t), 21.3 (q, OAc), 21.0 (q,
IR (ATR): ν = 3462 (br. m), 2940 (s), 1728 (s), 1699 (vs), 1471 (w),
˜
1440 (w), 1357 (m), 1241 (vs), 1189 (m), 1029 (s), 907 (w), 884 (w),
838 (w), 796 (w), 733 (s), 701 (w) cm–1. MS (EI, 70 eV): m/z (%) =
356 (2) [M – H2O]+, 314 (18), 296 (40), 281 (28), 253 (27), 239 (5),
225 (5), 211 (30), 197 (10), 183 (9), 159 (28), 143 (29), 129 (28), 105
(28), 91 (35), 67 (20), 43 (100). HRMS (EI): calcd. for 12C23H3416O4
374.2457; found 374.246.
OAc), 13.1 (q, C-18) ppm. IR (ATR): ν = 2940 (s), 1750 (s), 1729
˜
(s), 1699 (s), 1651 (w), 1428 (w), 1362 (m), 1241 (vs), 1207 (vs),
1126 (w), 1090 (w), 1032 (m), 733 (w) cm–1. MS (EI, 70 eV): m/z
(%) = 354 (2) [M – AcOH]+, 294 (96), 279 (13), 265 (5), 251 (20),
236 (8), 223 (18), 209 (25), 195 (15), 181 (15), 156 (73), 141 (43),
128 (30), 115 (25), 91 (25), 77 (16), 60 (18), 43 (100). HRMS (EI):
3β-Acetoxy-5,19-cyclo-pregna-6,20-dione (8): To a stirred solution
of 7 (548 mg, 1.47 mmol) in CH2Cl2 (15 mL) was added Dess–Mar-
tin reagent (730 mg, 1.76 mmol) followed by the slow addition of
H2O (32 µL, 1.76 mmol). After 15 min, MTBE (100 mL) was
added, and the cloudy solution was washed with a 1:1 mixture of
saturated NaHCO3 and Na2S2O3 (10% solution) until the organic
phase was completely clear. The organic phase was dried with
MgSO4, and the solvents were evaporated. The crude product was
dissolved in EtOAc and filtered through SiO2. Evaporation of all
the volatiles afforded 8 as a crystalline solid (480 mg, 1.29 mmol,
calcd. for C23H3016O3 354.2195; found 354.220 (MTBE).
12
(4aS,8aR)-3,4,5,6,7,8-Hexahydro-4a,8a-methanonaphthalen-1(2H)-
one (rac-13): To a stirring solution of enone 12 (1.56 g, 10.4 mmol)
and CeCl3 (4.65 g, 12.5 mmol) in methanol (100 mL), sodium
borohydride (0.98 g, 26 mmol) was added portionwise at 0 °C over
a period of 15 min. The reaction mixture was stirred continuously
88%). Rf = 0.22 (PhMe/EtOAc, 4:1); m.p. 150–153 °C. [α]D = 90.7 at 0 °C for 1 h. Then, the excess reagent was destroyed by the ad-
(c = 0.56, CHCl3), [α]546 = 111.1, [α]405 = 299.7, [α]365 = 494.2, dition of water (100 mL), and the mixture was extracted with
[α]334 = 894.0. H NMR (300 MHz, CDCl3): δ = 4.57–4.47 (m, 1 EtOAc (4ϫ240 mL). The combined organic layers were washed
1
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Reactions of Cyclopropyl Ketones
with brine (50 mL), dried with Na2SO4, filtered, and concentrated
under reduced pressure to give 1.47 g of the crude alcohol. A 250-
mL Schlenk flask was charged with 1,2-dichloroethane (80 mL),
and a solution of Et2Zn (1 m in hexane, 38.62 mL, 38.62 mmol) was
and GC–MS. Then, brine (5 mL) was added, and after 1 min the
mixture was extracted with portions of pentane and ethyl acetate
(60 mL). The combined organic phases were dried with anhydrous
Na2SO4, and the solvent was removed under reduced pressure to
added at 0 °C. Then, ICH2Cl (6.3 mL, 15.3 mmol) was added over yield the crude product, which was purified by flash chromatog-
a period of 5 min, and the resulting cloudy solution was stirred
for an additional 5 min. A solution of the crude alcohol (1.47 g,
9.6 mmol) in dry THF (20 mL) was added at once, before the cool-
ing bath was removed, and the reaction mixture was stirred for 6 h.
The conversion was monitored by GC–MS and TLC. The mixture
was quenched by the addition of brine (10 mL), and the organic
phase was separated, washed with water and brine, dried with
Na2SO4, and concentrated under reduced pressure to give 1.41 g of
the crude cyclopropylcarbinol. A solution of the crude cyclopro-
pylcarbinol (500 mg, 3 mmol) in acetone (40 mL) was cooled to
0 °C and treated with Jones Reagent until the orange color per-
sisted. After stirring the mixture for an additional 8 min, iPrOH
(15 mL) was added, and the reaction mixture was evaporated to a
volume of 10 mL under reduced pressure. Water (150 mL) was then
added, and the solution was extracted several times with MTBE.
The combined organic phases were washed with brine and dried
with MgSO4, and the solvents were evaporated. The residue was
purified by flash chromatography to yield rac-13 as a colorless li-
quid (393 mg, 2.39 mmol, 70% for 3 steps). Compound rac-13 was
essentially pure according to GC, TLC, and NMR analysis. Fur-
ther purification was achieved by column chromatography (SiO2),
albeit with substantial loss of material due to decomposition on
the column. The spectroscopic data were in accordance to those
reported in the literature.[22] Rf = 0.26 (CyH/EtOAc, 3:1). 1H NMR
(300 MHz, CDCl3): δ = 2.52–2.44 (m, 1 H), 2.38–2.29 (m, 1 H),
2.14–1.98 (m, 1 H), 1.93–1.86 (m, 2 H), 1.75–1.50 (m, 5 H), 1.51–
1.52 (d, J = 5.2 Hz, 1 H, cyclopropyl-H), 1.49–1.32 (m, 2 H), 1.22–
1.08 (m, 2 H), 0.84–0.86 (d, J = 5.2 Hz, 1 H, cyclopropyl-H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 18.2 (t), 20.6 (t, cyclopropyl-
CH2), 21.1 (t), 22.2 (t), 23.8 (t), 29.1 (s), 30.0 (t), 30.9 (t) 35.2 (s),
raphy (CyH/EtOAc, 18:1) to give the corresponding acetoxy-enol
acetate.
Bicyclo[5.4.0]undeca-2,7(1)-dien-3-yl Acetate (14): Following Gene-
ral Procedure A, reaction with cyclopropyl ketone rac-13 for 3.5 h
gave 14 as a colorless oil after flash chromatography (143 mg,
0.55 mmoL, 55%). The conversion was monitored by TLC and
GC–MS. Applying General Procedure B, cyclopropyl ketone rac-
13 (90 mg, 0.54 mmol) was treated with Sn(OTf)2 (0.012 g,
0.028 mmol) and dry Ac2O (0.13 mL, 1.37 mmol) for 22 h to yield
14 (85 mg, 0.41 mmol, 77%). Rf = 0.34 (CyH/EtOAc, 10:1). 1H
NMR (300 MHz, CDCl3): δ = 5.36 (s, 1 H, CH=C), 2.37 (t, J =
6.6 Hz, 2 H), 2.16–2.13 (m, 2 H), 2.09 (s, 3 H, OAc), 2.04 (m, 2
H), 1.97–1.99 (m, 2 H), 1.79–1.87 (m, 2 H), 1.52–1.54 (m, 4
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.7 (s, OAc), 21.1 (q,
OAc), 150.6 (s, OAc), 137.3 (s), 120.3 (d, CH=C), 123.3 (s), 35.0
(t), 33.2 (t), 32.7 (t), 31.3 (t), 25.2 (t), 22.9 (t), 22.8 (t) ppm. IR
(ATR): ν = 2929 (m), 2860 (m), 2825 (w), 1749 (s), 1666 (m), 1449
˜
(w), 1432 (w), 1367 (m), 1238 (m), 1214 (s), 1115 (m), 1000 (m),
922 (w) cm–1. MS (EI, 70 eV): m/z (%) = 206 (15) [M]+, 164 (100),
149 (5), 135 (37), 122 (18), 108 (12), 91 (26), 79 (16), 67 (6), 55
12
(5), 43 (47). HRMS (EI): calcd. for C13H1816O2 206.1307; found
206.130.
1,4-Diacetoxycycloheptene (rac-16) and 1-Acetoxy-3-(acetoxymeth-
yl)cyclohexane (rac-17): Following General Procedure A (12 h of
reaction time), the reaction of rac-15 afforded a 10:1 mixture (by
NMR) of rac-16 and rac-17 as a colorless oil (156 mg, 0.60 mmol,
60%) after purification by flash chromatography. Following Gene-
ral Procedure B, (24 h of reaction time), the yield dropped to 78 mg
(0.37 mmol, 37%). Rf
=
0.25 (CyH/EtOAc, 5:1). 1H NMR
36.4 (t), 210.1 (s, C=O) ppm. IR (ATR): ν = 2985 (w), 2921 (s),
˜
(300 MHz, CDCl3): δ = 5.28–5.22 (m, 1 H, CH=C-OAc), 5.24 (m,
1 H, CH=C-OAcЈ), 4.67–4.75 (m, 1 H, CH-OAc), 3.99–3.80 (m, 2
H, CH2-OAcЈ), 2.51 (m, 1 H, CHЈ), 2.31–2.38 (m, 1 H), 2.25–2.30
(m, 2 H), 2.08–2.16 (m, 2 H), 2.07 (s, 3 H, OAc), 2.04 (s, 3 H,
OAcЈ), 1.98 (s, 3 H, OAcЈ), 1.95 (s, 3 H, OAc), 1.59–1.79 (m, 4
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.0 (s, OAcЈ), 170.0
(s, OAc), 169.3 (s, OAc), 169.0 (s, OAcЈ), 154.2 (s, C-OAc), 150.1
(s, C-OAcЈ), 114.1 (d, CHC-OAcЈ), 111.4 (d, CHC-OAc), 71.5 (d,
CH-OAc), 67.4 (t, CHCH2-OAcЈ), 36.2 (t), 34.2 (dЈ), 32.4 (t,
CHCH2-OAc), 30.2 (t, C=CHCH2), 26.7 (tЈ), 24.7 (tЈ), 22.3 (t), 21.2
2843 (s), 1751 (w), 1666 (s), 1443 (m), 1375 (m), 1351 (w), 1322
(w), 1244 (m), 1184 (w), 1138 (w), 1053 (w), 1035 (w), 939 (w), 890
(w), 851 (w), 822 (w) cm–1. MS (EI, 70 eV): m/z (%) = 164 (40)
[M]+, 146 (41), 131 (37), 121 (27), 108 (69), 93 (100), 79 (77), 65
(26), 39 (35).
General Procedure A. Reaction of Cyclopropyl Ketones with Ac2O
in the Presence of 50 mol-% Sn(OTf)2: A two-neck flask containing
dry CH2Cl2 (1 mL) was charged with a cyclopropyl ketone
(1 mmol) and cooled to 0 °C. Dry Ac2O (0.756 mL, 8 mmol) and
Sn(OTf)2 (0.208 g, 0.5 mmol) were added at the indicated tempera-
ture, and the reaction was stirred continuously for the appropriate
reaction time. The conversion was monitored by TLC and GC–
MS. Then brine (5 mL) was poured into the reaction mixture, and
stirring continued for 1 min. The mixture was extracted (4ϫ) with
portions of pentane and ethyl acetate (60 mL), and the combined
organic phases were dried with anhydrous Na2SO4. The solution
was concentrated under reduced pressure to yield the crude prod-
uct, which was purified by flash chromatography (CyH/EtOAc,
18:1) to give the corresponding acetoxyenol acetate.
(q), 20.9 (qЈ), 20.8 (q), 20.8 (qЈ), 20.6 (tЈ) ppm. IR (ATR): ν = 2933
˜
(w), 2860 (w), 2353 (m), 2333 (m), 1729 (s), 1646 (w), 1433 (w),
1366 (m), 1235 (s), 1216 (s), 1173 (m), 1096 (m), 1023 (s), 983 (w),
963 (w) cm–1. MS (EI, 70 eV): m/z (%) = 152 (5) [M – AcOH]+,
127 (2), 110 (100), 95 (28), 81 (16), 67 (19), 57 (21), 43 (82).
Enantiomeric analysis using GC: BGB-176SE capillary column
(30 mϫ0.25 mm, 0.25 μm film), 50 °C to 150 °C (3 °C/min); H2 as
the carrier gas; Rt for 16/ent-16, 31.47 and 32.43 min, respectively.
1,4-Diacetoxycyclohexene (rac-19): Following General Procedure A,
(6 h of reaction time), ketone rac-19 was obtained as a pure isomer
General Procedure B. Reaction of Cyclopropyl Ketones with Ac2O (128 mg, 0.62 mmol, 62% yield). Purification by flash chromatog-
in the Presence of 5 mol-% Sn(OTf)2: A two-neck flask containing
dry CH2Cl2 (1 to 2 mL) was charged with cyclopropyl ketone
(1 mmol) and cooled to 0 °C. Then, Sn(OTf)2 (0.021 g, 0.05 mmol)
was added, and the mixture was stirred for 5 min. Afterwards, dry
Ac2O (0.23 to 0.47 mL, 2.5 to 5 mmol) was added slowly (within
5 min), and the mixture was stirred continuously at 0 °C for the
appropriate reaction time. The conversion was monitored by TLC
raphy was not necessary using Procedure A. Following General
Procedure B, (12 h of reaction time), ketone rac-19 was obtained
1
(57 mg, 0.29 mmol, 29%). Rf = 0.27 (CyH/EtOAc, 5:1). H NMR
(300 MHz, CDCl3): δ = 5.25–5.24 (m, 1 H, CHC-OAc), 5.04–4.97
(m, 1 H, CH-OAc), 2.45 (m, 1 H, CCHCHH), 2.23 (m, 1 H,
CCHCHH), 2.26–2.19 (m, 2 H, CCH2CH2), 2.08 (s, 3 H, acetoxy-
CH3), 2.01 (s,
3
H, acetoxy-CH3), 1.92–1.86 (m,
2
H,
Eur. J. Org. Chem. 2011, 2860–2866
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H.-G. Schmalz et al.
FULL PAPER
CCH2CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.6 (s, OAc),
169.2 (s, OAc), 147.5 (s, C-OAc), 110.6 (d, CH=C-OAc), 68.1 (d,
CH-OAc), 28.9 (t, C=CHCH2), 26.9 (t), 24.1 (t), 21.3 (q, OAc),
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20.9 (q, OAc) ppm. IR (ATR): ν = 2920 (w), 2846 (w), 1733 (s),
˜
1690 (w), 1646 (w), 1440 (w), 1433 (w), 1363 (m), 1220 (s), 1120
(m), 1036 (m), 1016 (w), 1016 (w), 973 (w), 950 (w), 903 (w) cm–1.
MS (EI, 70 eV): m/z (%) = 158 (1) [M – AcOH]+, 138 (8), 113 (2),
96 (100), 68 (7), 55 (9), 43 (73).
CCDC-805058 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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Acknowledgments
This work was supported by the Universität zu Köln.
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Received: January 7, 2011
Published Online: April 8, 2011
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Eur. J. Org. Chem. 2011, 2860–2866