Tricyclic challenges: Synthetic approaches toward dodecahydrocyclopenta[a] indenes

Article abstract of DOI:10.1016/j.tet.2013.06.070

Tetrahydrospiro[1,3-dioxolane-2,1′-pentalen]-4′-ones were stereoselectively converted to either (cis,anti,cis)- or (cis,syn)-linear dodecahydrocyclopenta[a]indene isomers employing a 1,4- or 1,2-conjugate addition of organometallic reagents and an intramolecular aldol reaction as the key steps. The relative configuration of the products was determined by X-ray crystal structure analysis and 1D NOE spectroscopy.

Full text of DOI:10.1016/j.tet.2013.06.070

Tetrahedron 69 (2013) 7373e7380
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tricyclic challenges: synthetic approaches toward
dodecahydrocyclopenta[a]indenes
a
a
a
a
€
Michael Krebs , Matthaus Kalinowski , Wolfgang Frey , Birgit Claasen ,
Angelika Baro a, Rainer Schobert b, Sabine Laschat a
Institut fur Organische Chemie, Universitat Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
,
*
a
€
€
b
€
€
€
Lehrstuhl fur Organische Chemie, Universitat Bayreuth, Universitatsstr. 30, D-95447 Bayreuth, Germany
a r t i c l e i n f o
a b s t r a c t
Tetrahydrospiro[1,3-dioxolane-2,10-pentalen]-40-ones were stereoselectively converted to either (cis,-
anti,cis)- or (cis,syn)-linear dodecahydrocyclopenta[a]indene isomers employing a 1,4- or 1,2-conjugate
addition of organometallic reagents and an intramolecular aldol reaction as the key steps. The relative
configuration of the products was determined by X-ray crystal structure analysis and 1D NOE
spectroscopy.
Article history:
Received 24 April 2013
Accepted 19 June 2013
Available online 26 June 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Intramolecular aldol reaction
Pentalene functionalization
Linear cyclohexano diquinanes
Conjugate addition
1. Introduction
While the decahydro-1H-cyclopenta[a]pentalene skeleton (1) is
quite common in natural products and derivatives thereof,1 the
corresponding six-membered homologous dodecahydrocyclopenta
[a]indene (5) is very rare (Fig. 1). Typical examples for 1 are (ꢀ)
D
9(12)-capnellene (2) from the soft coral Capnella imbricata2 or the
sesquiterpenes hirsutene (3)3 and coriolin (4)4 from a Japanese
mushroom, Coriolus consors.5
Natural products with cyclopenta[a]indene core 5 are tetramic
acid macrolactams discodermide (6), which was isolated from the
Caribbean marine sponge Discodermia dissoluta6 and maltophilin
(7) obtained from strains of Stenotrophomonas maltophilia R3089.7
While discodermide (6) was found to inhibit in vitro proliferation
of P388 murine leukemia cells and to inhibit growth of the yeast
Candida albicans,6 maltophilin (7) is an antifungal compound,
which is active against various human-pathogenic and phyto-
pathogenic fungi.7 In contrast to tricyclic system 1 for which a va-
riety of synthetic methods,8 in particular radical reactions,8b,9 were
established, synthetic access toward tricyclic system 5 has only
been poorly explored.10
Fig. 1. Linear triquinane natural products 2e4 and cyclopenta[a]indene core con-
taining 6, 7.
We were therefore interested to prepare stereoisomers of the
dodecahydrocyclopenta[a]indene core and focussed on a linear
approach via 1,4-addition followed by an intramolecular aldol re-
action as the key step starting from the known diketone 1211,12
(Scheme 1). Our results in exploring the access to tricyclic com-
ponents are reported below.
* Corresponding author. E-mail address: sabine.laschat@oc.uni-stuttgart.de
(S. Laschat).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.070

7374
M. Krebs et al. / Tetrahedron 69 (2013) 7373e7380
Scheme 1. Retrosynthetic route to dodecahydrocyclopenta[a]indene derivatives. Ste-
reochemical nomenclature of compounds 8 was used in analogy to the literature.1a
2. Results and discussion
As previously described, racemic diketone 12 was converted to
bicyclo[3.3.0]octenone 10a by TsOH mediated ketalization with
ethylene glycol followed by oxidation of the intermediate ketone
according to Nicolaou’s methodology.11a,b Derivative 10a was sub-
mitted to a Grignard reaction with 3-butenylmagnesiumbromide
(11)/CuCN in the presence of chlorotrimethylsilane (TMSCl) and
tetramethylethylenediamine (TMEDA) (Scheme 2).13
Scheme 3. Grignard reaction of (3aR,6aR)-10a and characterization of product 13.
(Scheme 3). To confirm this assignment, the 47:53 mixture of 13a,b
was treated with ethylene glycol giving indeed the corresponding
diketal 14 quantitatively, while treatment of 13a,b with TsOH in
acetone led to the diketone 15 in quantitative yield. Consequently,
the Cu-catalyzed Grignard reaction proceeded diastereoselectively
with >99% de albeit with competing ketal migration.
The planned synthesis was then continued using compound 14
(Scheme 4). Hydroboration of 14 yielded alcohol 16 in 45%, which
was deprotected to give derivative 17. The latter was submitted to
Swern oxidation to afford aldehyde 18 in 95% yield. In the crude
reaction mixture of subsequent aldol reactions in the presence of
LDA two products were detected, however, after workup, only
product 18 was recovered. Presumably, ring closure competed with
a retro aldol reaction.
Scheme 2. Conjugate addition of Grignard reagent 11 to pentalenone 10a.
After hydrolytic workup, the GCeMS analysis of the crude
product showed as the major product a mixture of two compounds
(ratio 99.7:0.3) each with a molpeak at m/z¼236, corresponding to
the diastereomers of 13. Additionally, a compound with m/z¼280,
indicative of the diketal 14 and a compound with m/z¼192, i.e.,
hexahydropentalene-1,4-dione 15 were detected. After chromato-
graphic purification on SiO2, keto ketal 13 was isolated in 42%,
however, in a decreased ratio of 72:28. As we surmised a diaster-
Scheme 4. First attempt to synthesize a cyclopenta[a]indene derivative.
To circumvent the described problems, the brominated penta-
lenone 10b was prepared from dibromo derivative 1911a,b,14 by
treatment with NaOMe and selective ketal cleavage in the mono
elimination product 20 with pyridinium p-toluenesulfonate (PPTS)
in acetone (Scheme 5).
Conjugate addition of 11/CuCN to 10b and hydroboration of the
resulting addition product 21 provided a mixture of the diols 22a,b
and monoalcohol 23, which could be separated by flash chroma-
tography for full characterization. It should be emphasized that
compound 21 did not undergo ketal migration and the sequence
from 19 to 22/23 did not require any chromatographic separation.
The mixture of 22/23 was oxidized under Swern conditions,
resulting in three compounds, i.e., the bicyclic ketoaldehyde 9b, the
eoselective reaction but an epimerization of the
a-stereogenic
center relative to the ketone moiety under the slightly acidic con-
ditions during chromatography, the addition reaction was per-
formed using chiral (3aR,6aR)-10a11a,b (Scheme 3). Based on our
assumption, only one diastereomer should be formed. But again,
the two MS peaks at m/z¼236 (ratio 47:53) were detected together
with those of 14 and 15. From 1H NMR spectra an epimerization
could be excluded, and NOESY spectra of 13 derived from
(3aR,6aR)-10a clearly revealed the cis-configuration of 3a-H and
6a-H for both ketals (Figs. S1 and S2, Supplementary data). Careful
analysis of the NMR spectra finally indicated that ketal migration
had taken place and 13a,b were present in the mixture of 13

M. Krebs et al. / Tetrahedron 69 (2013) 7373e7380
7375
Fig. 2. Structure of tricyclic
b-hydroxy ketone 8b and tricyclic enone 24 in the solid
state.
Scheme 5. Alternative preparation of trans-fused cyclopenta[a]indene derivatives.
tricyclic aldol product 8b, and the tricyclic enone 24. Ketoaldehyde
9b and tricyclic -hydroxy ketone 8b were found to display an odd
b
behavior. In CDCl3 solution or upon storage in the freezer aldol
product 8b underwent a retro aldol reaction. Conversely, treatment
of 9b with KOt-Bu, KHMDS or LDA or even silica gel afforded the
ketol 8b. During column chromatography 9b and 8b behaved like
a ‘chromatographic azeotrope’, that means, first 59% of a (1:1)
mixture of 9b and 8b was isolated [Rf 0.5 (hexanes/EtOAc¼1:1)] and
in a later fraction [Rf 0.2 (hexanes/EtOAc¼1:1)] pure compound 8b
was obtained in 15% yield.
X-ray single-crystal structure analysis of 8b and 24 reveals the
cis,trans-configuration for both tricyclic derivatives (Fig. 2). Linear
(cis,anti,cis)-isomer 8b crystallized in the monoclinic, acentric
space group Cc with two independent conformers, which have the
same configuration, whereas compound 24 crystallized as pure
enantiomer in an acentric space group. The absolute configuration
could be determined directly by anomalous dispersion.
Scheme 6. Preparation of (cis,syn)-cyclopenta[a]indene derivative 31.
The crude mixture of 26 and 27 was reacted with pyridinium
chlorochromate (PCC) according to a literature procedure19 to yield
the rearranged enone 28 after chromatographic separation of 27 in
46% over both steps. Hydrogenolytic removal of the benzyl group in
28 and subsequent Swern oxidation of the resulting alcohol 29
provided the ketoaldehyde 30 in 91% overall yield. Upon reaction of
30 with KOt-Bu, an aldol condensation gave the tricyclic enone 31
as the main product. Although GCeMS of the crude product dis-
played only one major peak at m/z¼234 resulting from 31 together
with some minor impurities (Fig. S3, Supplementary data), purifi-
cation by chromatography provided 31 in only 18% yield pre-
sumably due to decomposition on SiO2. The relative configuration
of 31 could be determined by 1D NOE experiments to be cis,syn (for
details see Supplementary data).
The access to (cis,syn,cis)-dodecahydrocyclopenta[a]indene de-
rivatives required a modified synthetic route. Mehta15 and Piers16
demonstrated in the synthesis of kelsoene that both heteroge-
nous and homogenous catalytic hydrogenation of a bicyclo[3.3.0]
octenone with exocyclic double bond proceeded with good dia-
stereoselectivity. The incoming hydrogen atoms were located on
the same side as the angular hydrogen atoms thus favoring an all-
cis-configuration. This literature precedence motivated us to de-
velop a stereoselective synthetic strategy to a (cis,syn,cis)-cyclo-
hexano diquinane by using a hydrogenation to generate the first
stereocenter followed by aldol reaction for ring closure. The re-
action sequence commenced with a 1,2-addition reaction of
Grignard reagent 25 derived from benzyl 4-bromobutyl ether17 to
pentalenone 10a to give an inseparable mixture of the 1,2-addition
product 26 and 4-benzyloxy-1-butanol 2718 besides the 1,4-
addition product, 60-[4-(benyzloxy)butyl]hexahydro-40H-spiro
[1,3-dioxolane-2,10-pentalen]-40-one, which could be separated by
flash chromatography (Scheme 6).
3. Conclusion
Two synthetic strategies towards dodecahydrocyclopenta[a]
indene isomers 8b, 24, and 31 are presented. The first route

7376
M. Krebs et al. / Tetrahedron 69 (2013) 7373e7380
involving
a
Cu-catalyzed Grignard reaction of 3-butenyl-
EtOAc¼3:1) to give 14 (15 mg, 0.05 mmol, 3%), a mixture of 13
(160 mg, 0.68 mmol, 42%) and 15 (80 mg, 0.42 mmol, 25%) as col-
orless oils. The mixture of 13 was re-chromatographed on SiO2
(hexanes/EtOAc¼5:1) to give analytically pure 13a and 13b.
magnesiumbromide 11 and 2-bromopentalenone 10b to give the
1,4-addition product 21 and final ring closure by aldol reaction led
to the linearly fused tricyclic (cis,anti,cis)-isomer 8b and (cis,anti)-
isomer 24. However, in the case of pentalenone 10a, a ketal mi-
gration was observed during the conjugate addition of 11.
The second synthetic route, which utilized a hydrogenation to
create the first stereocenter, provided the tricyclic (cis,syn)-isomer
31. In this case, the addition of Grignard reagent 25 derived from
benzyl 4-bromobutyl ether to 10a yielded the 1,2-addition product
26, which was converted to derivative 31 by hydrogenolytic
debenzylation, Swern oxidation, and final aldol reaction. The con-
figurations of 8b and 24 were unambiguously verified by X-ray
single-crystal structure analysis, while the structure of 31 was de-
termined by 1D NOE spectroscopy. Previous reports15,16 suggested
that hydrogenation of enone 31 should lead to (cis,syn,cis)-linear
cyclohexano diquinanes, which are conceivable precursors in the
synthesis of discodermide (6).
4.2.1. 30-But-3-enylhexahydrodispiro[1,3-dioxolane-2,10-pentalene-
20
40,200-[1,3]dioxolane] (14). Rf 0.6 (hexanes/EtOAc¼2:1); [
a
]
þ21.9
D
(c 1.0, CH2Cl2); 1H NMR (500 MHz, CDCl3)
d 1.27e1.43 (m, 2H, 2-Ha,
7-Ha), 1.58e1.74 (m, 4H, 5-Ha, 6-H, 7-Hb), 1.81e1.89 (m, 1H, 5-Hb),
1.91e2.08 (m, 5H, 2-Hb, 3-H, 3a-H, 8-H), 2.89 (td, J¼10.0, 3.9 Hz, 1H,
6a-H), 3.84e3.95 (m, 8H, OCH2CH2O), 4.91e5.03 (m, 2H, 10-H), 5.79
(ddt, J¼16.6,10.2, 6.7 Hz,1H, 9-H); 13C NMR (125 MHz, CDCl3)
d 22.7
(C-6), 32.9 (C-8), 35.1 (C-5), 35.8 (C-7), 38.3 (C-3), 42.0 (C-2), 48.6
(C-6a), 54.7 (C-3a), 64.0, 64.4, 65.0, 65.2 (OCH2CH2O), 114.3 (C-10),
~
n
117.9, 119.1 (C-1, C-4), 139.2 (C-9); FTIR (ATR)
2934 (m), 2881 (m),
1437 (w), 1337 (w), 1264 (s), 1120 (m), 1036 (m), 947 (w), 908
(w) cmꢀ1; MS (ESI) m/z 303.2 [MþNa]þ, 281.2 [MþH]þ, 237.2, 219.1,
þ
193.1, 175.1, 133.1. HRMS (ESI) calculated for
303.1572, found 303.1575.
C16H24NaO4
4. Experimental section
4.1. General methods
4.2.2. (3a0R,60S,6a0R)-60-But-3-enylhexahydro-40H-spiro[1,3-
dioxolane-2,10-pentalen]-40-one (13a). Yield: 0.80 g, 21%; Rf 0.5
(hexanes/EtOAc¼2:1);
[
a
]
þ50.9 (c 0.44, CH2Cl2); 1H NMR
20
D
€
Melting points were measured on a Buchi SMP 20 and are un-
(500 MHz, CDCl3) d 1.35e1.43 (m, 1H, 7-Ha), 1.65e1.85 (m, 4H, 2-H,
corrected. NMR spectra were recorded on a Bruker Avance 300 or
3-Ha, 7-Hb), 1.91e2.19 (m, 5H, 5-Ha, 6-H, 3-Hb, 8-H), 2.38 (ddd,
J¼9.8, 5.4, 0.6 Hz, 1H, 6a-H), 2.49 (ddt, J¼17.7, 7.9, 0.7 Hz, 1H, 5-Hb),
2.73e2.80 (m, 1H, 3a-H), 3.91e3.99 (m, 4H, OCH2CH2O), 4.96e5.06
(m, 2H, 10-H), 5.81 (ddt, J¼17.1, 10.4, 6.7 Hz, 1H, 9-H); 13C NMR
500 spectrometer with TMS (
d¼0.00) as internal standard. Nuclear
Overhauser effect (NOESY), homonuclear (1H/1H) correlation
spectroscopy (COSY), and inverse gradient heteronuclear (1H/13C)
correlation spectroscopy (HSQC and HMBC) were obtained using
the standard Bruker pulse sequence for structural assignment of
(125 MHz, CDCl3) d 24.9 (C-6), 32.2 (C-8), 34.6 (C-5), 35.2 (C-3), 36.2
(C-7), 45.1 (C-2), 49.4 (C-6a), 53.1 (C-3a), 64.5, 65.3 (OCH2CH2O),
~
n
NMR spectra. IR spectra were recorded on
a
Bruker FT-IR-
115.3 (C-10), 118.8 (C-4), 138.5 (C-9), 221.6 (C-1); FTIR (ATR):
2964
spectrometer Vector 22 with MKII golden gate single reflection
Diamant ATR-system. Mass spectra were recorded on a Finnigan
MAT 95 spectrometer (CI) with methane as carrier gas, a Varian
MAT 711 (EI, 70 eV), and a Bruker Daltonics micrOTOF_Q (ESI).
Optical rotations were measured with a PerkineElmer 241 polar-
imeter at 20 ꢁC. Flash chromatography was performed on silica gel,
(m), 2930 (m), 2883 (m), 1736 (vs), 1640 (w), 1440 (w), 1338 (w),
1214 (w), 1176 (w), 1147 (m), 1117 (m), 1021 (m), 949 (m), 914
(m) cmꢀ1; MS (ESI) m/z 259.1 [MþNa]þ, 237.2 [MþH]þ, 193.1, 175.1,
þ
147.2, 133.1; HRMS (ESI) calculated for C14H20NaO3 259.1310,
found 259.1310.
grain size 40e63
mm (Fluka). X-ray single-crystal structure analysis
4.2.3. (30S,3a0R,6a0R)-30-But-3-enylhexahydro-40H-spiro[1,3-dioxolane-
was performed on
a
Bruker APEX II Duo diffractometer
k
2,10-pentalen]-40-one (13b). Yield: 0.78 g, 20%; Rf 0.5 (hexanes/
(l¼0.71073 A) at 100 K. All reactions were performed in oven-dried
EtOAc¼2:1); [
a]
20 þ75.0 (c 0.44, CH2Cl2); 1H NMR (500 MHz, CDCl3)
ꢀ
D
glassware. All reagents were used as purchased unless otherwise
noted. Hexanes, EtOAc, and acetone were distilled prior to use. THF
and Et2O were distilled from sodium/benzophenone, CH2Cl2 from
CaH2, MeOH from magnesium. The reactions were monitored by
TLC (Merck 60 F254 plates) and visualized with an ethanolic solution
of p-anisaldehyde and sulfuric acid.
d 1.44e1.53 (m, 2H, 5-Ha, 7-Ha),1.66e1.75 (m,1H, 7-Hb),1.86e2.13 (m,
6H, 5-Hb, 3-H, 6-H, 8-H), 2.19 (dddd, J¼18.1, 9.5, 5.2, 2.0 Hz, 1H, 2-Ha),
2.31 (ddd, J¼10.0, 5.0, 1.6 Hz, 1H, 3a-H), 2.39 (dd, J¼18.1, 9.1 Hz, 1H, 2-
Hb), 2.83e2.90 (m, 1H, 6a-H), 3.89e3.99 (m, 4H, OCH2CH2O),
4.92e5.04 (m, 2H, 10-H), 5.81 (ddt, J¼17.1, 10.4, 6.6 Hz, 1H, 9-H); 13
C
NMR (125 MHz, CDCl3)
d 20.5 (C-6), 32.1 (C-8), 35.9 (C-7), 37.8 (C-2),
38.9 (C-3), 42.0 (C-5), 47.4 (C-6a), 55.7 (C-3a), 64.8, 64.9 (OCH2CH2O),
4.2. Grignard reaction of (3a0R,6a0R)-20,30,3a0,6a0-tetrahydro-
40H-spiro[1,3-dioxolane-2,10-pentalen]-40-one (3aR,6aR)-10a
114.8 (C-10), 117.8 (C-1), 138.5 (C-9), 221.9 (C-4); FTIR (ATR)
2956
~
n
(m), 2923 (m), 2877 (m), 1734 (vs), 1639 (w), 1453 (w), 1336 (w), 1306
(w), 1264 (m), 1162 (s), 1126 (s), 1034 (s), 948 (m), 911 (m) cmꢀ1; MS
(ESI) m/z 259.1 [MþNa]þ, 237.2 [MþH]þ, 193.1, 181.1 [MꢀC4H7]þ,
To a suspension of CuCN (0.20 mg, 2.33 mmol) in freshly dis-
tilled THF was added TMEDA (0.25 mL, 0.20 g, 1.67 mmol) and the
reaction mixture cooled to ꢀ78 ꢁC. A solution of Grignard reagent
11, freshly prepared from Mg (0.16 g, 6.67 mmol) and 4-bromo-1-
butene (0.34 mL, 0.45 g, 3.37 mmol), was added dropwise and
the resulting mixture stirred at ꢀ78 ꢁC for 20 min. Then TMSCl
(0.26 mL, 0.22 g, 2.00 mmol) was added followed by a cooled so-
lution of (3aR,6aR)-10a11a,b (1 mL, 0.30 g, 1.67 mmol) in THF (5 mL).
After stirring for 30 min, the reaction mixture was hydrolyzed with
a mixture of a satd NH4Cl solution/25%ic NH3 solution (10:1, 15 mL).
The layers were separated and the aqueous layer was extracted
with Et2O (3ꢂ20 mL). A 1 N HCl solution (50 mL) was added to the
combined organic layers, and the mixture stirred for 30 min to
hydrolyze the formed silyl enol ether. The layers were separated
and the organic layer was dried (MgSO4) and concentrated. The
residue was purified by flash chromatography on SiO2 (hexanes/
þ
175.1, 147.2, 133.1; HRMS (ESI) calculated for C14H20NaO3 259.1310,
found 259.1308.
4.2.4. 3-But-3-enylhexahydropentalene-1,4-dione (15). Rf 0.3 (hex-
20
anes/EtOAc¼2:1); [
a
]
þ150.3 (c 1.0, CH2Cl2); 1H NMR (500 MHz,
D
CDCl3)
d
1.41e1.50 (m, 1H, 7-Ha), 1.71e1.80 (m, 1H, 7-Hb), 2.03e2.23
(m, 6H, 2-Ha, 5-Ha, 6-H, 8-H), 2.27e2.40 (m, 3H, 2-Hb, 3-H, 5-Hb),
2.62 (dd, J¼9.1, 4.3 Hz, 1H, 3a-H), 2.97 (td, J¼9.1, 4.9 Hz, 1H, 6a-H),
4.94e5.03 (m, 2H,10-H), 5.76 (ddt, J¼16.8,10.2, 6.6 Hz,1H, 9-H); 13
C
NMR (125 MHz, CDCl3) d 23.0 (C-6), 31.9 (C-8), 35.1 (C-7), 36.8 (C-3),
37.6 (C-5), 44.5 (C-2), 49.2 (C-6a), 55.3 (C-3a), 115.5 (C-10), 137.6 (C-
~
n
9), 218.9, 219.1 (C-1, C-4); FTIR (ATR)
2927 (m), 2183 (w), 1972 (w),
1728 (vs), 1640 (m), 1455 (m), 1408 (m), 1167 (m), 1132 (s), 936 (m),
913 (m) cmꢀ1; MS (EI, 70 eV) m/z (%) 192.1 (63) [M]þ, 181.1 (8), 164.1
(40), 149.1 (18), 137.0 (20) [MꢀC4H7]þ, 122.0 (18), 110.1 (55), 95.0

M. Krebs et al. / Tetrahedron 69 (2013) 7373e7380
7377
(20), 83.0 (100), 81.0 (25), 67.0 (18), 55.0 (17), 41.0 (16); HRMS (ESI)
calculated for C12H16NaO2 215.1048, found 215.1051.
(w), 1357 (w), 1263 (m), 1175 (m), 1134 (m), 1058 (m) cmꢀ1; MS (EI,
70 eV) m/z (%) 210.1 (20) [M]þ, 199.1 (10), 182.1 (18), 164.1 (14),
155.0 (38), 150.1 (8), 137.1 (23) [MꢀC4H9O]þ, 122.1 (13), 110.1 (21),
95.1 (18), 91.0 (60), 83.0 (100), 6þ7.1 (18), 55.0 (38), 45.0 (22); HRMS
(ESI) calculated for C12H18NaO3 233.1154, found 233.1155.
þ
4.3. 20-Bromo-60-but-3-enylhexahydro-40H-spiro[1,3-
dioxolane-2,10-pentalen]-40-one (21)
As described above for 10a, from 10b (1.57 g, 6.09 mmol), Mg
(0.87 g, 37.0 mmol), 11 (1.83 mL, 2.43 g, 18.0 mmol), TMEDA
(0.92 mL, 0.71 g, 6.09 mmol), TMSCl (0.93 mL, 0.79 g, 7.30 mmol),
and CuCN (0.73 g, 8.52 mmol), crude yield: 1.90 g (6.03 mmol, 99%),
brown oil; Rf 0.7 (hexanes/EtOAc¼2:1); 1H NMR (500 MHz, CDCl3)
4.6. General procedure for the Swern oxidation
To a solution of oxalyl chloride (1.1e2.5 equiv) in dry CH2Cl2 at
ꢀ78 ꢁC was slowly added a solution of DMSO (2.2e5 equiv) in
CH2Cl2 whereby the temperature did not exceed ꢀ60 ꢁC. Then
a solution of the appropriate alcohol (1 equiv) in CH2Cl2 (1.5 mL)
was slowly added and the reaction mixture stirred at ꢀ78 ꢁC for
20 min. After addition of NEt3 (5e12 equiv) (temperature did not
exceed ꢀ60 ꢁC), the reaction mixture was stirred at ꢀ78 ꢁC for
a further 15 min and then allowed to warm to room temperature.
The mixture was hydrolyzed with H2O, the layers were separated
and the aqueous layer was extracted with CH2Cl2 (3ꢂ10 mL). The
combined organic layers were dried (MgSO4) and the solvent was
removed under reduced pressure. The product was used without
further purification unless otherwise noted.
d
1.38e1.47 (m, 1H, 7-Ha), 1.65e1.73 (m, 1H, 7-Hb), 2.00e2.17 (m,
4H, 2-Ha, 3-H, 8-H), 2.30e2.40 (m, 2H, 6-H), 2.54 (dd, J¼17.8, 8.1 Hz,
1H, 2-Hb), 2.78 (dd, J¼10.8, 4.5 Hz, 1H, 3a-H), 2.89 (td, J¼10.2,
4.5 Hz,1H, 6a-H), 3.92e4.12 (m, 5H, OCH2CH2O, 5-H), 4.95e5.05 (m,
2H, 10-H), 5.79 (ddt, J¼17.0, 10.2, 6.6 Hz, 1H, 9-H); 13C NMR
(125 MHz, CDCl3) d 32.6 (C-8), 34.0 (C-3), 35.1 (C-6), 36.3 (C-7), 45.0
(C-2), 46.8 (C-6a), 49.8 (C-3a), 53.2 (C-5), 65.8, 66.0 (OCH2CH2O),
~
n
115.4 (C-10), 116.8 (C-4), 138.2 (C-9), 220.0 (C-1); FTIR (ATR)
2962
(w), 2853 (w), 1699 (vs), 1586 (w), 1453 (m), 1344 (w), 1298 (w),
1260 (m), 1166 (s), 1130 (m), 1038 (m), 1011 (m), 847 (w) cmꢀ1; MS
(EI, 70 eV) m/z (%) 316.0 (5), 314.0 (5) [M]þ, 235.1 (25) [MꢀBr]þ,
178.9 (20), 176.9 (20) [C5H7BrO2], 165.9 (45), 163.9 (45), 125.0 (10),
99.0 (100) [C5H8O2], 81.0 (5), 55.0 (9); HRMS (EI) calculated for
4.6.1. 4-(3,6-Dioxooctahydropentalen-1-yl)butanal (18). From
(COCl)2 (0.07 mL, 99.2 mg, 0.79 mmol), DMSO (0.11 mL, 0.12 g,
1.57 mmol), 17 (150 mg, 0.71 mmol) and Et3N (0.50 mL, 0.37 g,
3.57 mmol). Yellow oil, 140 mg, yield: 95%; 1H NMR (500 MHz,
C
14H19BrO3 [M]þ 314.0518, found 314.0513.
4.4. 4-Hexahydrodispiro[1,3-dioxolane-2,10-pentalene-40,200-
[1,3]dioxolan]-30-ylbutan-1-ol (16)
CDCl3) d 1.36e1.49 (m, 1H, 7-Ha), 1.60e1.73 (m, 3H, 7-Hb, 8-H),
2.06e2.53 (m, 9H, 2-H, 3-H, 5-H, 6-H, 9-H), 2.63 (dd, J¼9.1, 4.7 Hz,
1H, 3a-H), 2.94e3.04 (m, 1H, 6a-H), 9.76 (t, J¼1.3 Hz, 1H, 10-H); 13
C
To a solution of 14 (370 mg, 1.32 mmol) in dry THF (15 mL) at
NMR (125 MHz, CDCl3) d 20.1 (C-8), 23.0 (C-7), 35.4 (C-6), 37.1 (C-3),
0
ꢁC was slowly added a 1 M solution of BH3$THF in THF (1.3 mL,
37.6 (C-5), 43.5 (C-2), 44.4 (C-9), 49.1 (C-6a), 55.0 (C-3a), 201.7 (C-
10), 218.5, 219.0 (C-1, C-4); MS (EI, 70 eV) m/z (%) 208.1 (20) [M]þ,
190.2 (40) [MꢀH2O]þ, 180.2 (22), 162.2 (65), 155.2 (22), 137.2 (78)
[MꢀC4H7O]þ, 123.1 (30), 109.1 (57), 98.1 (39), 83.1 (100), 79.1 (55),
77.1 (20), 67.1 (20), 55.1 (38).
1.32 mmol), the reaction mixture warmed to room temperature and
stirred for 3 h. Then a 3 M NaOH solution (0.6 mL) and a 30%ic H2O2
solution (0.3 mL) were added and the reaction mixture stirred for
a further 2 h at 45 ꢁC. After addition of Et2O (5 mL), the layers were
separated and the aqueous layer was extracted with Et2O (3ꢂ5 mL).
The combined organic layers were dried (MgSO4) and concentrated.
The residue was purified by flash chromatography on SiO2 (hex-
anes/EtOAc¼1:7) to give 16 (150 mg, 0.50 mmol, 45%) as a yellow
4.6.2. Products 8b, 9b, and 24. From (COCl)2 (1.50 mL, 2.18 g,
17.2 mmol) in dry CH2Cl2 (20 mL), DMSO (2.44 mL, 2.66 g,
34.0 mmol) in CH2Cl2 (15 mL), 22/23 (2.30 g, 6.89 mmol), and Et3N
(11.5 mL, 8.40 g, 83.0 mmol); chromatographed on SiO2 (hexanes/
EtOAc¼3:1). 2-Bromo-1,2,3a,3b,4,5,6,8a-octahydro-8H-spiro[cyclo-
penta[a]indene-3,20-[1,3]dioxalan]-8-one (24). Colorless solid,
430 mg, yield: 20%; Rf 0.7 (hexanes/EtOAc¼1:1); mp 175 ꢁC; 1H
oil; Rf 0.6 (EtOAc); 1H NMR (500 MHz, CDCl3)
d 1.15e1.37 (m, 4H, 2-
Ha, 5-Ha, 7-H), 1.45e1.59 (m, 5H, 5-Hb, 6-Ha, 8-Ha, 9-H), 1.60e1.68
(m, 1H, 6-Hb), 1.74e1.99 (m, 4H, 3-H, 2-Hb, 3a-H, 8-Hb), 2.57 (td,
J¼9.6, 3.1 Hz, 1H, 6a-H), 3.56 (t, J¼6.8 Hz, 2H, 10-H), 3.76e3.87 (m,
8H, OCH2CH2O); 13C NMR (125 MHz, CDCl3)
d
22.4 (C-6), 24.5 (C-7),
NMR (300 MHz, CDCl3) d 1.03e1.20 (m, 1H, 4-Ha), 1.50e1.69 (m, 1H,
32.9 (C-9), 34.7 (C-8), 35.8 (C-5), 38.4 (C-3), 41.8 (C-2), 48.4 (C-6a),
54.4 (C-3a), 63.0 (C-10), 63.9, 64.3, 64.9, 65.1 (OCH2CH2O), 117.8,
5-Ha),1.83e1.94 (m,1H, 5-Hb), 2.15e2.51 (m, 7H,1-H, 3a-H, 3b-H, 4-
Hb, 6-H), 2.85e2.95 (m, 1H, 8a-H), 3.95e4.27 (m, 5H, OCH2CH2O, 2-
119.0 (C-1, C-4); FTIR (ATR)
n
3454 (w), 2934 (m), 2882 (m), 1965
H), 6.63 (q, J¼3.5 Hz, 1H, 7-H); 13C NMR (75 MHz, CDCl3)
d 22.3 (C-
~
(m), 1436 (w), 1337 (w), 1264 (s), 1121 (m), 1033 (m), 947 (w) cmꢀ1
;
5), 25.2 (C-6), 29.5 (C-4), 35.0 (C-1), 39.2 (C-3b), 47.5 (C-8a), 49.2 (C-
3a), 51.7 (C-2), 66.0, 66.5 (OCH2CH2O), 116.9 (C-3), 134.0 (C-7), 141.7
MS (ESI) m/z 321.2 [MþNa]þ, 299.2 [MþH]þ, 283.1, 255.2, 237.1;
þ
~
n
HRMS (ESI) calculated for C16H26NaO5 321.1678, found 321.1672.
(C-7a), 207.6 (C-8); FTIR (ATR)
2938 (w), 2253 (w), 1714 (m), 1649
(m), 1421 (w), 1264 (s), 1171 (w), 1041 (w), 951 (w), 704 (s), 650
(w) cmꢀ1; MS (ESI) m/z 315.0, 313.0 [MþH]þ, 271.0, 269.0, 253.0,
251.0, 233.1 [MꢀBr]þ, 189.1, 179.0, 177.0, 171.1, 161.1, 143.1; HRMS
(ESI) calculated for C14H17BrO3 [MþH]þ 313.0439, found 313.0434.
4.5. 3-(4-Hydroxybutyl)hexahydropentalene-1,4-dione (17)
A solution of 16 (120 mg, 0.40 mmol) and p-TsOH (30.0 mg,
0.16 mmol) in acetone (10 mL) was stirred at room temperature for
10 h. After addition of a satd NaHCO3 solution (10 mL), the layers
were separated and the aqueous layer was extracted with CH2Cl2
(3ꢂ5 mL). The combined organic layers were dried (MgSO4) and
concentrated in vacuo to give 17 (55 mg, 0.156 mmol, 98%, >97% GC
4.6.2.1. 4-(20-Bromo-40-oxohexahydro-20H-spiro[1,3-dioxolane-
2,10-pentalen]-60-yl)butanal (9b). Colorless oil, 1.34 g, yield: 59%
(1:1 mixture of 9b and 8b); Rf 0.5 (hexanes/EtOAc¼1:1); 1H NMR
(500 MHz, CDCl3) d 1.35e1.47 (m,1H, 7-Ha),1.55e1.63 (m,1H, 7-Hb),
purity) as a yellow oil; 1H NMR (500 MHz, CDCl3)
d
1.30e1.42 (m,
1.63e1.71 (m, 2H, 8-H), 2.06 (ddd, J¼17.5, 6.9, 1.8 Hz, 1H, 2-Ha),
2.09e2.17 (m, 1H, 3-H), 2.29e2.43 (m, 2H, 6-H), 2.47 (td, J¼7.1,
1.4 Hz, 2H, 9-H), 2.56 (dd, J¼17.5, 8.0 Hz, 1H, 2-Hb), 2.78 (dd, J¼10.7,
4.5 Hz, 1H, 3a-H), 2.91 (td, J¼10.0, 4.5 Hz 1H, 6a-H), 3.93e4.10 (m,
5H, OCH2CH2O, 5-H), 9.77 (t, J¼1.6 Hz, 1H, 10-H); 13C NMR
3H, 5-Ha, 7-H), 1.47e1.56 (m, 2H, 5-Hb, 6-Ha), 2.00e2.40 (m, 8H, 2-
H, 3-H, 6-Hb, 8-H, 9-H), 2.58 (dd, J¼9.2, 4.7 Hz, 1H, 3a-H), 2.90e2.97
(m, 1H, 6a-H), 3.58 (t, J¼6.5 Hz, 2H, 10-H); 13C NMR (125 MHz,
CDCl3) d 22.0 (C-6), 22.9 (C-7), 31.5 (C-9), 34.7 (C-8), 36.3 (C-3), 36.7
(C-5), 43.5 (C-2), 48.1 (C-6a), 54.2 (C-3a), 61.5 (C-10), 218.0, 218.4
(125 MHz, CDCl3) d 20.3 (C-8), 34.4 (C-3), 35.2 (C-6), 36.6 (C-7), 43.9
~
n
(C-1, C-4); FTIR (ATR)
3449 (m), 2932 (s), 1732 (s), 1458 (w), 1407
(C-9), 45.0 (C-2), 46.8 (C-6a), 49.9 (C-3a), 53.2 (C-5), 65.8, 66.0

7378
M. Krebs et al. / Tetrahedron 69 (2013) 7373e7380
~
(OCH2CH2O), 116.9 (C-4), 202.1 (C-10), 219.5 (C-1); FTIR (ATR)
n
4.8. 20-Bromo-20,30,3a0,6a0-tetrahydro-40H-spiro[1,3-
2935 (w), 2253 (w), 1736 (m), 1714 (m), 1414 (w), 1359 (w), 1264
(m), 1165 (w), 1034 (w), 949 (w), 649 (m) cmꢀ1; MS (EI, 70 eV) m/z
(%) 332.1 (1), 330.1 (1) [M]þ, 304.2 (5), 302.2 (5), 263.1 (10), 261.1
(10), 251.1 (20) [MꢀBr]þ, 233.2 (12), 223.2 (12), 179.0 (15), 177.0
(15), 166.0 (11), 164.0 (11), 153.0 (10), 125.1 (18), 99.1 (100)
[C5H7O2], 55.1 (16); HRMS (EI) calculated for C14H19BrO4 [M]þ
330.0467, found 330.0468.
dioxolane-2,10-pentalen]-40-one (10b)
A solution of 20 (1.66 g, 5.50 mmol) and PPTS (400 mg,
3.18 mmol) in acetone/3% H2O (100 mL) was heated at reflux for 3 h.
Then the solvent was removed under vacuum, the residue was
taken up in Et2O (40 mL) and washed with brine. The organic layer
was dried (MgSO4) and evaporated to give 10b (1.41 g, 99%) as
a colorless solid; mp 118 ꢁC; Rf 0.2 (hexanes/EtOAc¼2:1); 1H NMR
4.6.2.2. 2-Bromo-7-hydroxydecahydro-8H-spiro[cyclopenta[a]in-
dene-3,20-[1,3]dioxolan]-8-one (8b). Colorless solid, 330 mg, yield:
15%; Rf 0.2 (hexanes/EtOAc¼1:1); mp 240 ꢁC; 1H NMR (500 MHz,
(500 MHz, CDCl3) d 2.23e2.34 (m, 2H, 6-H), 2.79e2.84 (m, 1H, 6a-
H), 3.30e3.33 (m, 1H, 3a-H), 3.86e3.91 (m, 1H, 5-H), 4.01e4.25 (m,
4H, OCH2CH2O), 6.24 (dd, J¼5.7, 2.0 Hz, 1H, 2-H), 7.60 (dd, J¼5.7,
CDCl3)
d
1.17e1.28 (m, 1H, 4-Ha), 1.43e1.57 (m, 3H, 5-Ha, 6-H),
3.0 Hz,1H, 3-H); 13C NMR (125 MHz, CDCl3)
d 34.1 (C-6), 45.4 (C-6a),
1.61e1.75 (m, 2H, 4-Hb, 5-Hb), 2.21e2.29 (m, 1H, 1-Ha), 2.30e2.38
(m, 1H, 1-Hb), 2.38e2.44 (m, 1H, 3b-H), 2.57 (dd, J¼6.8, 5.6 Hz, 1H,
7a-H), 2.70 (dd, J¼10.4, 4.6 Hz, 1H, 3a-H), 2.98 (td, J¼10.4, 5.4 Hz,
1H, 8a-H), 3.95e4.10 (m, 6H, OCH2CH2O, 2-H, 7-H); 13C NMR
50.9 (C-5), 51.8 (C-3a), 65.9, 66.6 (OCH2CH2O), 113.5 (C-4), 136.2 (C-
~
n
2), 163.1 (C-3), 210.5 (C-1); FTIR (ATR)
2957 (w), 2849 (w), 1704
(vs), 1585 (w), 1450 (w), 1341 (w), 1302 (w), 1266 (m), 1166 (s),
1144(m),1037 (m),1006 (m),1017 (w), 948 (m) cmꢀ1; MS (EI, 70 eV)
m/z (%) 260.0 (27), 258.0 (28) [M]þ, 179.0 (100) [MꢀBr]þ, 177.0 (98),
165.9 (14), 163.9 (15), 151.1 (7), 135.0 (12), 107.1 (7), 99.1 (41)
[C5H7O2], 79.1 (15), 55.1 (15); HRMS (EI) calculated for C10H11BrO3
[M]þ 257.9892, found 257.9893.
(125 MHz, CDCl3)
d 19.5 (C-5), 29.2 (C-4), 32.0 (C-6), 34.0 (C-3b),
35.9 (C-1), 46.4 (C-8a), 47.7 (C-3a), 54.1 (C-2), 56.9 (C-7a), 66.0, 66.6
~
n
3447
(OCH2CH2O), 66.5 (C-7), 116.9 (C-3), 218.7 (C-8); FTIR (ATR)
(w), 2933 (m), 1730 (m), 1447 (w), 1264 (s), 1173 (w), 1118 (w), 1033
(m), 1014 (w), 947 (w) cmꢀ1; MS (ESI) m/z 355.0, 353.0 [MþNa]þ,
333.1, 331.1 [MþH]þ, 315.0, 313.0 [MꢀH2OþH]; HRMS (ESI) calcu-
lated for C14H19BrO4 [MþH]þ 331.0545, found 331.0539.
4.9. Hydroboration of 21 to alcohols 22, 23
To a solution of 21 (150 mg, 0.48 mmol) in dry THF (10 mL) at 0 ꢁC
was slowly added a 1 M solution of BH3$THF in THF (1.05 mL,
1.05 mmol), and the reaction mixture was warmed to room temper-
ature and stirred for a further 3 h. After addition of a 3 M NaOH so-
lution (2 mL) and H2O2 (30%ic, 2 mL), the reaction mixture was stirred
for a further 2 h at 45 ꢁC. Then Et2O (10 mL) was added and the layers
were separated. The aqueous layer was extracted with Et2O (3ꢂ5 mL).
The combined organic layers were dried (MgSO4) and concentrated to
give a mixture of alcohols 22a,b, 23 (147 mg, 92%), which were sep-
arated by flash chromatography (hexanes/EtOAc¼1:2). Further re-
actions were performed with a mixture of 22/23.
4.6.3. 4-(60-Oxohexahydro-20H-spiro[1,3-dioxolane-2,10-pentalen]-
40-yl)butanal (30). From (COCl)2 (0.014 mL, 20.7 mg, 0.16 mmol) in
dry CH2Cl2 (2 mL), DMSO (0.024 mL, 26.4 mg, 0.34 mmol) in CH2Cl2
(2 mL), 29 (35 mg, 0.14 mmol), and Et3N (0.11 mL, 80.3 mg,
0.83 mmol). Colorless oil, 34 mg, yield: 96%; 1H NMR (300 MHz,
CDCl3) d 1.41e1.87 (m, 8H, 5-H, 6-H, 7-H, 8-H), 2.03e2.15 (m, 3H, 1-
H, 2-H), 2.45 (td, J¼7.2, 1.6 Hz, 2H, 9-H), 2.64 (dd, J¼9.6, 4.5 Hz, 1H,
3a-H), 2.78e2.95 (m, 1H, 6a-H), 3.69e4.04 (m, 4H, OCH2CH2O), 9.74
(t, J¼1.6 Hz, 1H, 10-H); 13C NMR (75 MHz, CDCl3)
d 20.6 (C-8), 24.0
(C-6), 30.7 (C-7), 36.1 (C-1), 38.9 (C-5), 42.9 (C-2), 43.4 (C-6a), 44.0
(C-9), 61.8 (C-3a), 65.3, 65.4 (OCH2CH2O), 117.5 (C-4), 202.7 (C-10),
214.8 (C-3); FTIR (ATR)
n
2944 (w), 2253 (w), 1733 (m), 1460 (w),
4.9.1. (40S)-20-Bromo-60-(4-hydroxybutyl)hexahydro-20H-spiro[1,3-
dioxolane-2,10-pentalen]-40-ol (22a). Colorless solid, 32 mg, yield:
20%; mp 128 ꢁC; Rf 0.35 (EtOAc); 1H NMR (500 MHz, CDCl3)
~
1077 (w), 1009 (w), 649 (s) cmꢀ1; MS (EI, 70 eV) m/z (%) 252.3 (3)
[M]þ, 208.2 (18), 191.2 (16), 164.2 (5), 137.2 (12), 127.1 (12), 109.1
(10), 99.1 (100) [C5H7O2], 86.1 (17), 67.1 (12), 55.2 (20); HRMS (ESI)
calculated for C14H20O4 [M]þ 252.1362, found 252.2363.
d
1.30e1.49 (m, 4H, 2-Ha, 7-H, 9-Ha), 1.49e1.63 (m, 3H, 8-H, 9-Hb),
2.00e2.15 (m, 3H, 2-Hb, 3-H, 6-Ha), 2.44e2.52 (m, 1H, 6-Hb), 2.55
(dd, J¼11.3, 7.3 Hz, 1H, 3a-H), 2.75e2.85 (m, 1H, 6a-H), 3.65 (t,
J¼6.5 Hz, 2H, 10-H), 3.92e4.15 (m, 5H, OCH2CH2O, 1-H), 4.31 (t,
4.7. 20-Bromo-20,30,3a0,6a0-tetrahydrodispiro[1,3-dioxolane-
2,10-pentalene-4’,200-[1,3]dioxolane (20)
J¼5.6 Hz, 1H, 5-H); 13C NMR (125 MHz, CDCl3)
d 24.8 (C-7), 31.9 (C-
6), 32.9 (C-8), 36.2 (C-9), 36.3 (C-3), 44.5 (C-2), 44.6 (C-6a), 52.1 (C-
NaOMe (588 mg, 10.9 mmol), which was freshly prepared by
dissolving sodium (250 mg, 10.9 mmol) in methanol (15 mL) fol-
lowed by removal of excess solvent, was solved in DMSO (20 mL)
and slowly added to a solution of 1911a,b (2.85 g, 7.42 mmol) in
DMSO (10 mL), and the reaction mixture was then heated to 70 ꢁC
for 2 h. After addition of H2O (40 mL), the reaction mixture was
extracted with Et2O (3ꢂ40 mL). The combined organic layers were
washed with brine, dried (MgSO4), and concentrated to give crude
20 (1.66 g, 5.5 mmol, 75%) as a colorless oil; Rf 0.6 (hexanes/
3a), 56.8 (C-5), 63.5 (C-10), 65.7, 65.9 (OCH2CH2O), 73.3 (C-1), 116.1
~
n
(C-4); FTIR (ATR)
3351 (w), 2932 (w), 2252 (w),1299 (w),1165 (w),
1114 (w), 1034 (m), 949 (w), 804 (w), 648 (w) cmꢀ1; MS (EI, 70 eV)
m/z (%) 336.1 (17), 334.1 (16) [M]þ, 263.0 (29), 261.0 (30)
[MꢀC4H9O]þ, 255.1 (28) [MꢀBr]þ, 237.0 (10), 207.0 (8), 205.0 (8),
193.1 (21), 171.1 (18), 125.0 (8) [C7H9O2], 99.0 (100) [C5H7O2], 55.0
(16); HRMS (EI) calculated for C14H23BrO4 [M]þ 334.0780, found
334.0778. Elemental Anal. Calcd for C14H23BrO4: C, 50.16; H, 6.92;
Br, 23.84. Found: C, 50.04; H, 6.91; Br, 23.87.
EtOAc¼2:1); 1H NMR (500 MHz, CDCl3)
d 2.01e2.14 (m, 1H, 6-Ha),
2.41 (ddd, J¼13.0, 6.6, 2.3 Hz, 1H, 6-Hb), 2.72 (td, J¼8.8, 2.4 Hz, 1H,
4.9.2. (40R)-20-Bromo-60-(4-hydroxybutyl)hexahydro-20H-spiro[1,3-
dioxolane-2,10-pentalen]-40-ol (22b). Colorless solid, 51 mg, yield:
32%; mp 130 ꢁC; Rf 0.45 (EtOAc); 1H NMR (500 MHz, CDCl3)
6a-H), 3.19 (dt, J¼7.8, 2.4 Hz, 1H, 3a-H), 3.87e4.22 (m, 9H, OCH2
-
CH2O, 5-H), 5.59 (dd, J¼5.7, 1.9 Hz, 1H, 2-H), 6.07 (dd, J¼5.7, 2.6 Hz,
1H, 3-H); 13C NMR (125 MHz, CDCl3)
d
32.6 (C-6), 45.6 (C-6a), 52.8
d 1.30e1.43 (m, 4H, 2-Ha, 7-H, 9-Ha), 1.52e1.64 (m, 3H, 8-H, 9-Hb),
(C-5), 53.8 (C-3a), 64.4, 65.5, 65.6, 66.2 (OCH2CH2O), 114.7, 119.2 (C-
1.85e1.94 (m, 1H, 3-H), 2.02e2.09 (m, 1H, 6-Ha), 2.09e2.16 (m, 1H,
2-Hb), 2.20e2.29 (m, 1H, 6-Hb), 2.35 (dd, J¼11.0, 7.4 Hz, 1H, 3a-H),
2.47e2.54 (m, 1H, 6a-H), 3.64 (t, J¼6.6 Hz, 2H, 10-H), 3.86e4.17 (m,
~
n
1, C-4), 133.0 (C-3), 135.6 (C-2); FTIR (ATR)
2890 (w), 2253 (w),
1362 (w), 1306 (w), 1157 (m), 1087 (w), 1042 (w), 1017 (w), 948 (w),
649 (m) cmꢀ1; MS (EI, 70 eV) m/z (%) 304.0 (3), 302.0 (3) [M]þ, 223.1
(100) [MꢀBr]þ, 179.0 (23), 177.0 (23) [C5H7BrO2], 151.1 (10), 138.1
(7), 99.1 (40) [C5H7O2], 79.1 (3), 55.1 (7). HRMS (EI) calculated for
6H, OCH2CH2O, 1-H, 5-H); 13C NMR (125 MHz, CDCl3)
d 24.8 (C-7),
32.6 (C-8), 36.2 (C-9), 36.6 (C-6), 38.1 (C-3), 42.2 (C-2), 48.1 (C-6a),
52.2 (C-3a), 54.2 (C-5), 63.0 (C-10), 65.4, 66.2 (OCH2CH2O), 79.6 (C-
12H15BrO4 [M]þ 302.0154, found 302.0152.
1), 116.5 (C-4); FTIR (ATR)
3351 (w), 2932 (w), 2252 (w), 1299 (w),
~
n
C

M. Krebs et al. / Tetrahedron 69 (2013) 7373e7380
7379
1165 (w), 1114 (w), 1034 (m), 949 (w), 804 (w), 648 (w) cmꢀ1; MS
(EI, 70 eV) m/z (%) 336.1 (9), 334.1 (9) [M]þ, 255.1 (7) [MꢀBr]þ, 237.0
(8), 207.0 (5), 205.0 (5), 193.1 (8), 175.1 (9), 133.0 (8), 99.0 (100)
[C5H7O2], 55.0 (10); HRMS (ESI) calculated for C14H23BrO4 [MþNa]þ
357.0677, found 357.0672.
J¼5.7, 1.7 Hz, 1H, 2-H), 7.24e7.38 (m, 5H, Ph); 13C NMR (75 MHz,
CDCl3) d 20.8 (C-8), 21.0 (C-6), 30.2 (C-9), 36.4 (C-5), 41.1 (C-7), 47.8
(C-6a), 57.3 (C-3a), 64.6, 64.7 (OCH2CH2O), 70.3 (C-10), 72.9
(CH2Ph), 84.6 (C-1), 117.0 (C-4), 130.2 (C-3), 139.4 (C-2), 127.5, 127.6,
~
n
128.3, 138.6 (Ph); FTIR (ATR)
3426 (w), 3054 (w), 2939 (m), 2863
(m), 2361 (w), 2252 (w), 2007 (w), 1453 (m), 1362 (m), 1264 (s),
1100 (m), 1027 (w), 906 (vs), 728 (vs) cmꢀ1; MS (EI, 70 eV) m/z (%)
326.2 (65) [MꢀH2O]þ, 258.1 (7), 253.2 (18), 220.2 (4), 191.1 (12),
180.2 (7), 173.1 (12), 163.1 (7) [MꢀC10H13O3]þ, 149.1 (28), 131.1 (21),
121.1 (8), 105.1 (16), 99.1 (100) [C5H8O2], 91.1 (98), 71.1 (17), 55.0
(18); HRMS (ESI) calculated for C21H28O4 [MþNa]þ 367.1885, found
367.1882. The spectroscopic data of 27 were in accordance with
those in the literature.18
4.9.3. 20-Bromo-60-(4-hydroxybutyl)hexahydro-40H-spiro[1,3-
dioxolane-2,10-pentalen]-40-one (23). Colorless oil, 64 mg, yield:
40%; Rf 0.5 (EtOAc); 1H NMR (300 MHz, CDCl3)
d 1.28e1.42 (m, 3H,
7-H, 8-Ha), 1.46e1.59 (m, 3H, 8-Hb, 9-H), 1.93e2.12 (m, 2H, 2-Ha, 3-
H), 2.25e2.36 (m, 2H, 6-H), 2.44e2.56 (m, 1H, 2-Hb), 2.74 (dd,
J¼10.7, 3.9 Hz, 1H, 3a-H), 2.79e2.88 (m, 1H, 6a-H), 3.64 (t, J¼6.5 Hz,
2H, 10-H), 3.91e4.10 (m, 5H, OCH2CH2O, 5-H); 13C NMR (125 MHz,
CDCl3) d 23.9 (C-7), 32.6 (C-9), 34.3 (C-3), 35.0 (C-6), 35.7 (C-8), 44.9
(C-2), 46.6 (C-6a), 49.5 (C-3a), 53.0 (C-5), 62.7 (C-10), 65.7, 65.9
4.11. 40-[4-(Benzyloxy)butyl]-20,30,3a0,6a0-tetrahydro-60H-spiro
(OCH2CH2O), 116.9 (C-4), 220.2 (C-1); FTIR (ATR)
3387 (w), 2932
[1,3-dioxolane-2,10-pentalen]-60-one (28)
~
n
(m), 1735 (s), 1442 (w), 1298 (w), 1264 (m), 1168 (w), 1138 (m), 1036
(m), 949 (m) cmꢀ1; MS (EI, 70 eV) m/z (%) 334.1 (6), 332.1 (6) [M]þ,
253.1 (25) [MꢀBr]þ, 179.0 (7), 177.0 (7), 165.9 (6), 163.9 (6), 125.1 (5)
[C7H9O2], 99.0 (100) [C5H7O2], 55.0 (7); HRMS (EI) calculated for
To a solution of 26/27 (270 mg) in CH2Cl2 (10 mL) was added PCC
(500 mg, 2.30 mmol) and the reaction mixture stirred at room
temperature for 14 h. The residue was filtered off through Celite
and washed with CH2Cl2 (3ꢂ20 mL). The filtrate was concentrated
under reduced pressure and the crude product chromatographed
on SiO2 (hexanes/EtOAc¼2:1) to give 28 (148 mg, 0.43 mmol, 46%
referred to 10a) as a yellow oil; Rf 0.5 (hexanes/EtOAc¼1:1); 1H
C
14H21BrO4 [M]þ 332.0623, found 332.0621.
4.10. Grignard reaction of 25 and enone 10a
A Grignard solution of 25, freshly prepared from Mg (450 mg,
18.8 mmol), covered with dry THF (10 mL), under N2 atmosphere by
addition of a mixture of benzyl 4-bromobutyl ether17 (1.80 mL,
2.30 g, 9.40 mmol) and THF (10 mL) and heating at reflux for 30 min,
was added to a solution of 10a (170 mg, 0.94 mmol) in THF (5 mL) at
NMR (300 MHz, CDCl3) d 1.59e1.76 (m, 5H, 6-Ha, 7-H, 9-H),
1.77e1.88 (m, 2H, 5-H), 1.91e2.04 (m, 1H, 6-Hb), 2.22e2.38 (m, 1H,
8-Ha), 2.39e2.54 (m, 1H, 8-Hb), 2.78 (d, J¼6.6 Hz, 1H, 3a-H),
3.26e3.36 (m, 1H, 6a-H), 3.49 (t, J¼5.8 Hz, 2H, 10-H), 3.83e4.18 (m,
4H, OCH2CH2O), 4.51 (s, 2H, CH2Ph), 5.84e5.86 (m, 1H, 2-H),
0
ꢁC and the reaction mixture was stirred for 30 min at 0 ꢁC. The
7.27e7.39 (m, 5H, Ph); 13C NMR (75 MHz, CDCl3)
d 23.9 (C-9), 25.3
excess Grignard reagent was hydrolyzed by addition of H2O (15 mL)
followed by addition of Et2O (10 mL). The layers were separated and
the aqueous layer was extracted with Et2O (3ꢂ10 mL). The combined
organic layers were dried (MgSO4) and concentrated. The residue
was purified by flash chromatography (hexanes/EtOAc¼2:1) to give
the 1,4-addition product 60-[4-(benyzloxy)butyl]hexahydro-40H-
spiro[1,3-dioxolane-2,10-pentalen]-40-one (65.0 mg, 20%) and an
inseparable mixture of 26 and 27 (270 mg).
(C-6), 29.6 (C-7), 31.1 (C-8), 35.6 (C-5), 47.7 (C-6a), 57.7 (C-3a), 64.3,
65.4 (OCH2CH2O), 69.7 (C-10), 73.0 (CH2Ph), 115.0 (C-4), 129.4 (C-2),
127.62, 127.64, 128.4, 138.5 (Ph), 183.0 (C-1), 205.8 (C-3); FTIR (ATR)
~
(s), 1098 (w) cmꢀ1; MS (EI, 70 eV) m/z (%) 342.2 (18) [M]þ, 299.2
(24), 251.2 (5) [MꢀCH2Ph]þ, 207.1 (3), 163.1 (2), 127.1 (3), 99.1 (100)
[C5H8O2], 91.1 (44) [CH2Ph]þ, 65.0 (3), 55.0 (7); HRMS (ESI) calcu-
lated for C21H26O4 [MþNa]þ 365.1729, found 365.1725.
n
3053 (w), 2253 (w), 2183 (w), 1695 (m), 1612 (w), 1422 (w), 1264
4.10.1. 60-[4-(Benyzloxy)butyl]hexahydro-40H-spiro[1,3-dioxolane-
4.12. 40-(4-Hydroxybutyl)hexahydro-60H-spiro[1,3-dioxolane-
2,10-pentalen]-40-one. Rf 0.6 (hexanes/EtOAc¼1:1); 1H NMR
2,10-pentalen]-60-one (29)
(500 MHz, CDCl3) d 1.17e1.28 (m, 1H, 7-Ha), 1.28e1.39 (m, 2H, 8-H),
1.50e1.65 (m, 5H, 5-H, 7-Hb, 9-H), 1.70e1.77 (m, 1H, 6-Ha),
1.83e1.90 (m, 1H, 6-Hb), 1.92 (ddd, J¼17.6, 8.2, 1.7 Hz, 1H, 2-Ha),
2.00e2.08 (m, 1H, 3-H), 2.28 (dd, J¼9.8, 5.4 Hz, 1H, 3a-H), 2.39 (dd,
J¼17.6, 8.1 Hz, 1H, 2-Hb), 2.64e2.70 (m, 1H, 6a-H), 3.40 (t, J¼6.5 Hz,
2H, 10-H), 3.79e3.89 (m, 4H, OCH2CH2O), 4.43 (s, 2H, CH2Ph),
To 28 (75 mg, 0.22 mmol) and Pd/C (20 mg) under a satd H2
atmosphere (balloon technique) was added EtOAc (2 mL), and the
mixture was then stirred at room temperature for 2 h under
a continuous stream of H2. The black solid was filtered off through
Celite and washed with EtOAc (3ꢂ5 mL). The filtrate was concen-
trated under reduced pressure to give 29 (52.9 mg, 95%) as a col-
7.17e7.31 (m, 5H, Ph); 13C NMR (125 MHz, CDCl3)
d 24.6 (C-8), 24.7
(C-6), 29.8 (C-9), 34.5 (C-5), 35.6 (C-3), 36.7 (C-7), 45.1 (C-2), 49.3
(C-6a), 52.9 (C-3a), 64.3, 65.1 (OCH2CH2O), 70.3 (C-10), 73.0
(CH2Ph), 118.8 (C-4), 127.0, 127.6, 127.7, 128.4, 128.6, 138.6 (Ph),
~
orless oil; 1H NMR (500 MHz, C6D6)
d 1.12e1.22 (m, 4H, 7-H, 8-H),
1.34e1.43 (m, 2H, 9-H), 1.48e1.55 (m, 1H, 6-Ha), 1.55e1.63 (m, 1H,
6-Hb), 1.65e1.77 (m, 1H, 1-H), 1.87e1.99 (m, 2H, 5-H), 2.09 (d,
J¼11.7 Hz, 2H, 2-H), 2.44e2.52 (m, 1H, 6a-H), 2.75 (d, J¼10.0 Hz, 1H,
3a-H), 3.44 (t, J¼6.4 Hz, 2H, 10-H), 3.74e4.11 (m, 4H, OCH2CH2O);
221.5 (C-1); FTIR (ATR)
n
3053 (w), 2986 (w), 2254 (w), 1732 (m),
1421 (w), 1264 (s), 1097 (m), 1022 (w) cmꢀ1; MS (EI, 70 eV) m/z (%)
344.2 (22) [M]þ, 253.2 (28) [MꢀCH2Ph], 238.2 (4), 220.1 (4), 181.1
(14) [MꢀC11H15O]þ, 134.1 (12), 107.0 (15), 99.0 (100) [C5H8O2], 91.1
(53) [CH2Ph], 86.0 (29), 79.0 (13), 77.0 (6), 55.0 (12); HRMS (ESI)
calculated for C21H28O4 [MþNa]þ 367.1885, found 367.1882.
13C NMR (125 MHz, C6D6)
d 24.1 (C-6), 24.4 (C-8), 31.0 (C-7), 32.9 (C-
9), 36.2 (C-1), 39.4 (C-5), 43.0 (C-2), 43.6 (C-6a), 61.5 (C-3a), 62.8 (C-
~
n
10), 65.0, 65.1 (OCH2CH2O), 117.2 (C-4), 215.3 (C-3); FTIR (ATR)
3460 (w), 2932 (m), 1734 (s), 1411 (w), 1264 (s), 1218 (m), 1075 (m),
1008 (m), 948 (w), 649 (m) cmꢀ1; MS (EI, 70 eV) m/z (%) 254.1 (18)
[M]þ, 127.1 (7), 99.0 (100) [C5H7O2], 86.0 (15), 67.0 (3), 55.0 (6);
HRMS (EI) calculated for C14H22O4 [M]þ 254.1518, found 254.1518.
4.10.2. 40-[4-(Benzyloxy)butyl]-30,3a0,40,6a0-tetrahydro-20H-spiro
[1,3-dioxolane-2,10-pentalen]-40-ol (26). Rf 0.5 (hexanes/EtOAc¼
1:1); 1H NMR (300 MHz, CDCl3)
d 1.38e1.48 (m, 2H, 6-Ha, 8-Ha),
1.50e1.58 (m, 1H, 7-Ha), 1.58e1.64 (m, 1H, 7-Hb), 1.65e1.76 (m, 3H,
6-Hb, 9-H), 1.82 (t, J¼7.6 Hz, 2H, 5-H), 1.90e1.98 (m, 1H, 8-Hb), 2.21
(br, 1H, OH), 2.57 (td, J¼8.6, 4.6 Hz, 1H, 6a-H), 3.03 (dt, J¼8.6, 1.9 Hz,
4.13. 2,3,3a,3b,4,5,6,8a-Octahydro-8H-spiro[cyclopenta[a]in-
dene-1,20-[1,3]dioxolan]-8-one (31)
1H, 3a-H), 3.47 (t, J¼6.6 Hz, 2H, 10-H), 3.84e3.98 (m, 4H, OCH2
To a solution of 30 (30 mg, 0.12 mmol) in freshly distilled THF
(3 mL) at 0 ꢁC was added KOt-Bu (16 mg, 0.14 mmol) and the
-
CH2O), 4.49 (s, 2H, CH2Ph), 5.72 (dd, J¼5.7, 2.5 Hz,1H, 3-H), 5.75 (dd,

7380
M. Krebs et al. / Tetrahedron 69 (2013) 7373e7380
reaction mixture stirred for 30 min. The reaction mixture was then
hydrolyzed with a satd NH4Cl solution (10 mL). The layers were
separated and the aqueous layer was extracted with Et2O
(3ꢂ10 mL). The combined organic layers were washed with brine,
dried (MgSO4), and concentrated. The residue was purified by flash
chromatography on SiO2 (hexanes/EtOAc¼3:1) to give 31 (5 mg,
0.02 mmol, 18%) as a colorless oil; Rf 0.8 (hexanes/EtOAc¼1:1); 1H
References and notes
1. Reviews: (a) Singh, V.; Thomas, B. Tetrahedron 1998, 54, 3647e3692; (b) Mehta,
G.; Srikrishna, A. Chem. Rev. 1997, 97, 671e719; (c) Nozoe, S.; Furukawa, J.;
Sankawa, U.; Shibata, S. Tetrahedron Lett. 1976, 195e198.
2. (a) Ayanoglu, E.; Gebreyesus, T.; Beechan, C. M.; Djerassi, C.; Kaisin, M. Tetra-
hedron Lett. 1978, 1671e1674; (b) Sheikh, Y. M.; Singy, G.; Kaisin, M.; Eggert, H.;
Djerassi, C.; Tursch, B.; Daloze, D.; Braekman, J. C. Tetrahedron 1976, 32,
1171e1178; (c) Kaisin, M.; Sheikh, Y. M.; Durham, L. J.; Djerassi, C.; Tursch, B.;
Daloze, D.; Braekman, J. C.; Losman, D.; Karlsson, R. Tetrahedron Lett. 1974,
2239e2242.
3. (a) Chandler, C. L.; List, B. J. Am. Chem. Soc. 2008, 130, 6737e6739; (b)
Vandewalle, M.; De Clercq, P. Tetrahedron 1985, 41, 1767e1831.
4. Takahashi, S.; Naganawa, H.; Iinuma, H.; Takita, T.; Maeda, K.; Umezawa, H.
Tetrahedron Lett. 1971, 1955e1958.
5. Takeuchi, T.; Iinuma, H.; Iwanaga, J.; Takahashi, S.; Takita, T.; Umezawa, H. J.
Antibiot. 1969, 22, 215e217.
6. Gunasekera, S. P.; Gunasekera, M.; McCarthy, P. J. Org. Chem. 1991, 56,
4830e4833.
7. (a) Jakobi, M.; Winkelmann, G.; Kaiser, D.; Kempter, C.; Jung, G.; Berg, G.;
Bahl, H. J. Antibiot. 1996, 49, 1101e1104; (b) Graupner, P. R.; Thornburgh, S.;
Mathieson, J. T.; Chapin, E. L.; Kemmitt, G. M.; Brown, J. M.; Snipes, C. E. J.
Antibiot. 1997, 50, 1014e1019.
8. (a) Trost, B. M. Chem. Soc. Rev. 1982, 11, 141e170; (b) Hudlicky, T.; Price, J. D.
Chem. Rev. 1989, 89, 1467e1486; some recent examples: (c) Srikrishna, A.;
Neetu, G. Tetrahedron: Asymmetry 2010, 21, 2067e2071; (d) Srikrishna, A.;
Gowri, V.; Neetu, G. Tetrahedron: Asymmetry 2010, 21, 202e207; (e) Rieder,
C. J.; Fradette, R. J.; West, F. G. Chem. Commun. 2008, 1572e1574; (f) Austin,
K. A. B.; Banwell, M. G.; Harfoot, G. J.; Willis, A. C. Tetrahedron Lett. 2006, 47,
7381e7384.
NMR (500 MHz, CDCl3) d 1.22e1.33 (m, 1H, 4-Ha), 1.35e1.46 (m, 1H,
3-Ha), 1.51e1.60 (m, 1H, 5-Ha), 1.71e1.79 (m, 1H, 3-Hb), 1.83e1.96
(m, 4H, 5-Hb, 4-Hb, 2-H), 2.13e2.31 (m, 2H, 6-H), 2.63e2.73 (m, 1H,
3b-H), 2.77 (d, J¼9.6 Hz, 1H, 8a-H), 2.85e2.94 (m, 1H, 3a-H),
3.78e4.12 (m, 4H, OCH2CH2O), 6.60e6.70 (m, 1H, 7-H); 13C NMR
(125 MHz, CDCl3) d 22.3 (C-5), 24.6 (C-4), 25.5 (C-6), 26.0 (C-3), 37.8
(C-3b), 39.4 (C-2), 42.9 (C-3a), 61.2 (C-8a), 65.2, 65.8 (OCH2CH2O),
~
117.5 (C-1), 132.4 (C-7), 141.3 (C-7a), 202.0 (C-8); IR (ATR)
n
2984
(w), 1735 (s), 1446 (m), 1372 (m), 1235 (s), 1043 (s) cmꢀ1; MS (EI,
70 eV) m/z (%) 234.2 (5) [M]þ, 191.1 (55), 173.1 (3), 144.1 (5), 125.1
(7), 99.1 (100) [C5H7O2], 91.1 (12), 79.1 (18), 65.0 (6), 55.1 (10);
HRMS (EI) calculated for C14H18O3 [M]þ 234.1256, found 234.1256.
4.14. X-ray crystallographic analysis
Crystals of 8b suitable for X-ray diffraction were obtained by
slow evaporation of the solvent CDCl3. Formula C14H19BrO4, FW
331.20, crystal dimension 0.32ꢂ0.06ꢂ0.05 mm, monoclinic, space
€
9. For examples see: (a) Giese, B.; Kopping, B.; Gobel, T.; Dickhaut, J.; Thoma, G.;
Kulicke, K. J.; Trach, F. Org. React. 1996, 48, 301e361; (b) Winkler, J. D.; Sridar, V.
J. Am. Chem. Soc. 1986, 108, 1708e1709; (c) Curran, D. P.; Sun, S. Aust. J. Chem.
1995, 48, 261e267; (d) Jung, M. E.; Rayle, H. L. J. Org. Chem. 1997, 62,
4601e4609.
ꢀ
ꢀ
ꢀ
group Cc, Z¼8, a¼5.9552(13) A, b¼23.968(5) A, c¼19.200(4) A,
V¼2737.3(10) A , Dcalcd¼1.607 g cmꢀ3, R1¼0.0418, wR2¼0.0600 (all
reflections) for 4817 reflections and 345 parameters, GOF¼0.873.
Crystals of 24 were obtained by slow evaporation of the solvent
CDCl3. Formula C14H17BrO3, FW 313.19, crystal dimension
3
ꢀ
10. For examples see: (a) Kirmse, W.; Ritzer, J. Chem. Ber. 1985, 118, 4987e4996;
(b) Beckwith, A. L. J.; Roberts, D. H.; Schiesser, C. H.; Wallner, A. Tetrahedron
Lett. 1985, 26, 3349e3352; (c) Ihara, M.; Suzuki, T.; Katogi, M.; Taniguchi, N.;
Fukumoto, K. J. Chem. Soc., Chem. Commun. 1991, 646e647; (d) Ihara, M.;
Suzuki, T.; Katogi, M.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc., Perkin Trans. 1
1992, 865e873; (e) Arseniyadis, S.; Wang, Q.; Yashunsky, D. V.; Kaoudi, T.;
Bondi Alves, R.; Potier, P. Tetrahedron Lett. 1995, 36, 1633e1636; (f) Piers, E.;
Kaller, A. M. Tetrahedron Lett. 1996, 37, 5857e5860; (g) Hamon, S.; del Rosario
Rico Ferreira, M.; Quílez del Moral, J.; Hernando, J. I. M.; Candela Lena, J. I.;
Birlirakis, N.; Toupet, L.; Arseniyadis, S. Tetrahedron: Asymmetry 2005, 16,
3241e3255; (h) Tzvetkov, N. T.; Waske, P. A.; Neumann, B.; Stammler, H.-G.;
Mattay, J. Tetrahedron Lett. 2008, 49, 1710e1713; (i) Pan, G.; Williams, R. M. J.
Org. Chem. 2012, 77, 4801e4811.
0.29ꢂ0.14ꢂ0.07 mm, orthorhombic, space group P2(1)2(1)2(1), Z¼4,
3
ꢀ
ꢀ
ꢀ
ꢀ
a¼6.2781(6) A, b¼10.2482(9) A, c¼19.8601(19) A, V¼1277.8(2) A ,
Dcalcd¼1.628 g cmꢀ3, R1¼0.0369, wR2¼0.0554 (all reflections) for
2608 reflections and 163 parameters, GOF¼0.955.
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos.
CCDC-926793 (8b) and CCDC-926792 (24). Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: þ44 (0)1223 336033 or e-mail:
deposit@ccdc.cam.ac.UK).
11. (a) Cramer, N.; Buchweitz, M.; Laschat, S.; Frey, W.; Baro, A.; Mathieu, D.;
Richter, C.; Schwalbe, H. Chem.dEur. J. 2006, 12, 2488e2503; (b) Cramer, N.;
Laschat, S.; Baro, A.; Schwalbe, H.; Richter, C. Angew. Chem. 2005, 117, 831e833;
Angew. Chem., Int. Ed. 2005, 44, 820e822; (c) Zhong, Y.-W.; Tian, P.; Lin, G.-Q.
Tetrahedron: Asymmetry 2004, 15, 771e776; (d) Mehta, G.; Srinivas, K. Tetrahe-
ꢁ
dron Lett. 2001, 42, 2855e2857; (e) Perard-Viret, J.; Rassat, A. Tetrahedron:
Asymmetry 1994, 5, 1e4; (f) Moriarty, R. M.; Duncan, M. P.; Vaid, R. K.; Prakash,
O. M. Org. Synth. 1990, 68, 175e178.
12. (a) Helbig, S.; Axenov, K. V.; Tussetschlager, S.; Frey, W.; Laschat, S. Tetrahedron
Acknowledgements
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Lett. 2012, 53, 3506e3509; (b) Helbig, S.; Sauer, S.; Cramer, N.; Laschat, S.; Baro,
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13. (a) Molander, G. A.; McKie, J. A. J. Org. Chem. 1991, 56, 4112e4120; (b) Johnson,
C. R.; Marren, T. J. Tetrahedron Lett. 1987, 28, 27e30; (c) Barber, H. J. J. Chem. Soc.
1943, 79.
Generous financial support by the Deutsche Forschungsge
€
meinschaft, the Ministerium fur Wissenschaft, Forschung und
€
Kunst des Landes Baden-Wurttemberg and the Fonds der Chemi-
schen Industrie is gratefully acknowledged.
14. Hagedorn, A. A., III; Farnum, D. G. J. Org. Chem. 1977, 42, 3765e3767.
15. Mehta, G.; Srinivas, K. Synlett 1999, 555e556.
Supplementary data
16. Piers, E.; Orellana, A. Synthesis 2001, 2138e2142.
17. Versteegen, R. M.; van Beek, D. J. M.; Sijbesma, R. P.; Vlassopoulos, D.; Fytas, G.;
Meijer, E. W. J. Am. Chem. Soc. 2005, 127, 13862e13868.
18. Kiddle, J. J.; Green, D. L. C.; Thompson, C. M. Tetrahedron 1995, 51, 2851e2864.
19. (a) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 16, 2647e2650; (b) Dauben,
W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682e685.
Further experimental results and determination of structures and
relative configurations of isomers 13 and 31 by spectroscopic methods.
Supplementary data associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2013.06.070.