Helical primary structures of 1,3-spiroannelated five-membered rings: (±)-trispiro[4.1.1.4.2.2]heptadecane and (±)-tetraspiro[4.1.1.1.4.2.2.2]heneicosane

Article abstract of DOI:10.1016/j.tet.2008.12.025

A combination of three spiroannelation methods forms the basis for a synthesis of the first two helical hydrocarbons of 1,3-spiroannelated five-membered rings.

Full text of DOI:10.1016/j.tet.2008.12.025

Tetrahedron 65 (2009) 1689–1696
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Helical primary structures of 1,3-spiroannelated five-membered rings: (ꢀ)-
trispiro[4.1.1.4.2.2]heptadecane and (ꢀ)-tetraspiro[4.1.1.1.4.2.2.2]heneicosaneq
Imelda Meyer-Wilmes, Ralf Gerke, Lutz Fitjer *
Institut fu¨r Organische und Biomolekulare Chemie der Universita¨t Go¨ttingen, Tammannstrasse 2, D-37077 Go¨ttingen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 October 2008
Received in revised form 5 December 2008
Accepted 8 December 2008
Available online 13 December 2008
A combination of three spiroannelation methods forms the basis for a synthesis of the first two helical
hydrocarbons of 1,3-spiroannelated five-membered rings.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Helicenes
Spiroannelations
Rearrangements
1. Introduction
a rule, the rotatory power of the rigid systems (1, 2)3,4 is high and
increases with the length of the helix, while the rotatory power of
Since the first report in 1996,1 helical primary structures of 1,2-
spiroannelated hydrocarbon rings have been the subject of an in-
tense research.2–10 Illustrative examples are the rigid helices 13,4
and 2,4 and the flexible helices 3,5 4,6 5,9 and 6 (Fig. 1). With the
exception of 6,10 all systems cited have been synthesized both in
racemic and in enantiomerically pure form, and striking differ-
ences concerning their rotatory power have been observed. As
the flexible systems (3–5)5,6,9 is low and decreases with the length
of the helix.
Interestingly, it was already in 1991 that Trost and Shi11 rec-
ognized that with five-membered rings 1,3-spiroannelation may
lead to helical structures as well. Upon palladium catalyzed
polycyclization of suitable sized polyenynes they obtained the 1,1-
bis-sulfones 7 and 8 with a helical (7) and a potentially helical
carbon skeleton (8), respectively. However, inseparable mixtures
of diastereoisomers were formed in both cases and no proof of
a helical structure of 8 could be given. We now report on the
synthesis of (ꢀ)-9 and (ꢀ)-10, the first helical hydrocarbons of
1,3-spiroannelated cyclopentane rings that bear no functionalities
(Fig. 2).
2
1
4
3
CH3O
CH3O
PhSO2
PhSO2
PhSO2
PhSO2
7
8
6
5
Figure 1.
q
Polyspiranes, Part 31. For Part 30, see Ref. 10.
9
10
* Corresponding author. Tel.: þ49 551 393278.
E-mail address: lfitjer@gwdg.de (L. Fitjer).
Figure 2.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.025

1690
I. Meyer-Wilmes et al. / Tetrahedron 65 (2009) 1689–1696
2. Results
Our approach to the desired carbon frameworks relied on three
11
1. Cl2C=C=O
methods for the construction of spiranes12 (Scheme 1): (i) a cyclo-
addition of dichloroketene to methylenecyclopentane (11)
with subsequent dehalogenation and ring enlargement to yield
42%
2. Zn/HOAc
the
butylidenation of 13 with subsequent epoxidation and
oxaspiropentane to cyclopentanone rearrangement to yield the
quaternary cyclopentanone 15 (13–15), and (iii) two cyclo-
alkylations of 15 to yield the
0-diquaternary cyclopentanones 16
and 17, respectively [15–16(17)]. The hitherto unknown 1,4-diio-
dobutane 14, needed for the synthesis of 17, was thought to be
accessible by standard operations from 12, and the final de-
oxygenations of 16 and 17 to 9 and 10, respectively, seemed diffi-
cult, but feasible.
b-quaternary cyclopentanone 13 (11–12–13), (ii) a cyclo-
O
MCPB
87%
O
O
a
-
12
18
a,a
LiAlH4
CH2N2 60%
X
X
O
19 X = OH (99%)
20 X = OTs (79%)
14 X = I
TsCl/C5H5N
LiI/CH3CN
13
Experimentally, the addition of dichloroketene to methyl-
enecyclopentane (11) proceeded regioselectively and yielded, after
(78%)
PPh3
83%
dehalogenation, the
ment with diazomethane, this compound ring enlarged to give the
-quaternary cyclopentanone 13.14 The cyclobutylidenation of 13 to
b
-quaternary cyclobutanone 12.13 Upon treat-
O
1. MCPB
b
.
2. BF3 OEt2
21 proceeded smoothly, and subsequent epoxidation and boron
trifluoride etherate catalyzed rearrangement of the resulting
oxaspirohexane yielded the desired a-quaternary cyclopentanone
93%
21
15
15 (Scheme 2).
Scheme 2.
For the synthesis of 1,4-diiodobutane 14 we subjected 12 to
a Bayer–Villiger oxidation, transformed the resulting spirolactone
1815 via diol 19 to ditosylate 20, and replaced the tosyloxy groups by
iodine through reaction with anhydrous lithium iodide in the
presence of 12-crown-416 (Scheme 2).
24.30 (t), 39.14 (t), 40.80 (t), 40.81 (t), 40.88 (t), 50.34 (s), 50.43 (s),
54.24 (t)].
Tetraspirane 10 was more difficult to obtain: the cycloalkylation
of 15 with 1,4-diiodobutane 14 at reflux in benzene over 48 h went
to completion but afforded a 1:1 mixture of the desired trans-
configurated a,a
0-diquaternary cyclopentanone 17 and its cis-con-
The last two steps from 15 to trispirane 9 were straightforward:
cycloalkylation with 1,4-diiodobutane in the presence of potassium
hydride in ether at room temperature yielded the
a,a
0-diquater-
nary cyclopentanone 16,17 and subsequent Wolff–Kishner re-
duction using a high temperature modification developed by
Barton et al.18 yielded the desired trispirane 9 (Scheme 3). This
compound (symmetry C2) was easily recognized by the appearance
figurated counterpart 22. Unfortunately, the components of this
mixture could not be separated, and the same was found true for
of only nine resonance lines in the 13C NMR spectrum [
d¼24.25 (t),
KH
O
O
I
14
I
9
7
76%
11
15
rel-(7R,9S)-22
1. Cl2C=C=O
2. Zn/HOAc
+
KH/I(CH2)4I 73%
(1:1)
CH2N2
O
O
O
O
9
7
12
13
1. MCPB
2. LiAlH4
3. TsCl/C5H5N
4. LiI/CH3CN
16
rel-(7R,9R)-17
1. Ph3P
2. MCPB
.
3. BF3 OEt2
H2NNH2
NaO(CH2)2O(CH2)2OH
H2NNH2
NaO(CH2)2O(CH2)2OH
65%
61%
O
I
I
14
15
( )-9
meso-23
2KH/I(CH2)4I
2KH/14
+
(1:1)
O
O
( )-10
16
17
Scheme 3.
Scheme 1.

I. Meyer-Wilmes et al. / Tetrahedron 65 (2009) 1689–1696
1691
the 1:1 mixture of tetraspiranes 10 and 23 obtained therefrom
(Scheme 3). Therefore, a possibility for the separation via de-
rivatives was searched for.
Having established productive procedures for the synthesis of
-quaternary cyclo-
pentanone 15, we shortly investigated whether the methods
(ꢀ)-9 and (ꢀ)-10 via cycloalkylations of the
a
Toward this end, the 1:1 mixture of 17 and 22 was reduced with
lithium aluminum hydride. Fortunately, the resulting alcohols 24–
26 could be separated by chromatography on silica gel in pentane/
ether (97:3) and identified by NMR and by the outcome of separate
oxidations (Scheme 4).
employed could also be used for the synthesis of higher analogues.
Toward this end, we first tried to synthesize the
cyclopentanone 33 as higher analogue of 15 (Scheme 5).
For the experimental realization, we subjected the -quaternary
a-quaternary
b
cyclopentanone 13 first to a methylenation, and then to an addition
As could have been expected, the 13C NMR data of 24 (sym-
metry Cs, 11 resonances), 25 (symmetry Cs, 11 resonances), and 26
(symmetry C1, 21 resonances) allowed only the identification of
26, but no distinction between 24 and 25. Fortunately, the 1H
NMR data were more instructive. Distinct differences in the
chemical shifts and the multiplicity of the four protons of the
methylene groups neighboring the hydroxyl group were ob-
of dichloroketene, a reductive dehalogenation, and a ring enlarge-
ment with diazomethane (13–27–29–28). The resulting b-quater-
nary cyclopentanone 28 was then cyclobutylidenated and
subsequently epoxidized and rearranged to yield a 1:1 mixture of
the desired
a-quaternary cyclopentanone rel-(5R,7S)-33 and its
undesired counterpart rel-(5R,7R)-31 [28–30–33(31)]. Un-
fortunately, all efforts for the separation of 31 and 33 failed.
Therefore, the envisioned spiroalkylation with 14, which probably
would have led to four stereoisomeric a,a
0-diquaternary cyclo-
pentanones with (7R,9R,11R)-32 as the only one with a helical
carbon skeleton, was abandoned.
In summary, we have developed productive syntheses of the
helical hydrocarbons (ꢀ)-9 and (ꢀ)-10 via spiroalkylations of the
hitherto unknown dispiroketone 15. This means that a resolution of
15 will open the way to enantiopure specimen. Due to lack of
stereoselectivity in the synthesis of 33, experiments directed to-
ward the synthesis of a higher analogue of (ꢀ)-10 were cut off.
0
served: those nearest to the hydroxyl group (Ha, Ha ) appeared
0
downfield (
upfield (
d
w2.0 ppm) and those farer away (Hb, Hb ) appeared
d
w1.2 ppm). Moreover, those being part of a one-carbon
bridge appeared as doublet, and those being part of a two-carbon
bridge appeared as doublet of doublets of doublets. Thus, the data
for the first eluted alcohol [yield 17%,
(d, J¼13 Hz, 2H)] were conclusive for 24, those of the second
eluted alcohol [yield 32%,
d¼1.23 (d, J¼13 Hz, 2H), 2.06
d
¼1.21 (d, J¼13 Hz, 1H), 1.26 (ddd, J¼12,
6, 6 Hz, 1H), 1.97 (ddd, J¼12, 8, 8 Hz, 1H), 2.04 (d, J¼13 Hz, 1H)]
were conclusive for 26, and those of the last eluted alcohol [yield
20%,
d
¼1.23 (ddd, J¼12, 6, 6 Hz, 2H), 1.96 (ddd, J¼12, 8, 8 Hz, 2H)]
were conclusive for 25.
3. Experimental
3.1. General
A chemical proof resulted from separate oxidations with pyr-
idinium chlorochromate:19 both 24 and 25 delivered one and the
same ketone, and hence 22 (symmetry Cs), while 26 delivered
a stereoisomer and hence 17 (symmetry C2). Of these, 22 was de-
oxygenated to 23 (symmetry Cs) and 17 to the desired helical 10
(symmetry C2) (Scheme 4).
IR spectra were obtained with a Perkin–Elmer 298 spectrometer.
1H and 13C NMR spectra were recorded on a Bruker AMX 300,
a Varian VXR 500, or a Varian VXR 600 spectrometer. As standards
the following chemical shifts were used: dH (CHCl3)¼7.24, dH
(C6D5H)¼7.15, dC (CDCl3)¼77.00, dC (C6D6)¼128.00. 13C multiplici-
ties were studied by HMQC measurements. Mass spectra were
obtained with a Finnegan MAT 95 spectrometer (EI and HREI)
rel-(7R,9R)-17 + rel-(7R,9S)-22
(1:1)
LiAlH4
OH
Ph3P=CH2
Ha
Ha
O
8
85%
9
7
Hb
Hb
13
27
rel-(7R,8R,9S)-24(17%)
meso-23
1. CH2=C=CCl2
2. Zn/CH3COOH
72%
H2NNH2
NaO(CH2)2O(CH2)2OH
+
42%
OH
H
H
O
89%
CH2N2
Ha Ha
O
8
42%
PCC
93%
O
9
7
H
H
Hb
Hb
28
85%
29
rel-(7R,8S,9S)-25 (20%)
rel-(7R,9S)-22
PPh3
+
1. MCPB
OH
H
O
2. BF3.OEt2
Ha’
Ha
7
5
PCC
97%
38%
9
7
9
7
H
O
O
Hb’
Hb
30
rel-(5R,7R)-31
rel-(7R,9R)-26 (32%)
rel-(7R,9R)17
+
(1:1)
H2NNH2
NaO(CH2)2O(CH2)2OH
50%
O
2 KH
14
11
7
5
7
9
rel-(7R,9R,11R)-32
rel-(5R,7S)-33
( )-10
Scheme 5.
Scheme 4.

1692
I. Meyer-Wilmes et al. / Tetrahedron 65 (2009) 1689–1696
operated at 70 eV. Analytical and preparative GC was carried out on
a Carlo Erba 6000 Vega 2 instrument using a thermal conductivity
detector and hydrogen as carrier gas. The following columns were
used: (A): 3 mxꢁ1/400 all-glass system, 15% OV 210 on Chromosorb
W AW/DMCS 60/80 mesh; (B): 3 mꢁ1/400 all-glass system, 15% FFAP
on Chromosorb W AW/DMCS 60/80 mesh. Product ratios were not
corrected for relative response. Rf values are quoted for Macherey
and Nagel Polygram SIL G/UV254 plates. Colorless substances were
detected by oxidation with 3.5% alcoholic 12-molybdophosphoric
acid and subsequent warming. Melting points were observed on
a Reichert microhotstage. Boiling and melting points are not cor-
rected. Microanalytical determinations were done at the Microan-
alytical Laboratory of the Institute of Organic and Bioorganic
Chemistry, Go¨ttingen.
preparative GC [column B, 190 ꢂC; retention time (min): 3.80 (13)].
The 1H NMR data were in accord with the literature data.14b 13
NMR (50 MHz, CDCl3, CDCl3 int):
C
d
¼24.01 (t), 34.83 (t), 37.74 (t),
38.00 (t), 47.40 (s), 51.17 (t), 219.50 (s).
3.4. 2-Cyclobutyliden-spiro[4.4]nonane (21)
To a suspension of 4-bromobutyltriphenylphosphonium bro-
mide21 (96 g, 0.20 mol) in dry benzene (250 mL) was added under
argon with stirring potassium-tert-butoxide (3ꢁ14.9 g, 0.40 mol)
and the mixture heated for 3 h to 50 ꢂC. Compound 13 (17.7 g,
0.13 mol) was added and after 1 h at 60 ꢂC the reaction was com-
plete according to GC [column B,190 ꢂC; retention times (min): 3.23
(21), 3.80 (13)]. The mixture was hydrolyzed with water (20 mL),
the organic layer was decanted, and the residue was extracted with
pentane (3ꢁ100 mL). The combined organic phases were concen-
trated (bath temperature up to 120 ꢂC) and the residue diluted with
pentane (300 mL). Precipitated triphenylphosphine oxide was fil-
tered off and the filtrate was concentrated and distilled to yield
18.8 g (83%) of 21 as colorless liquid, bp 126–135 ꢂC/20 Torr (purity
94% GC). An analytically pure sample was obtained by preparative
3.2. Spiro[3.4]octan-2-one (12)
To
a
boiling mixture of methylenecyclopentane20 (12.3 g,
150 mmol) and zinc dust (19.6 g, 300 mmol) in ether (200 mL) was
added within 1 h under argon with stirring a solution of tri-
chloroacetyl chloride (41.0 g, 225 mmol) in ether (200 mL); 15–
30 min after the addition was complete, a vigorous reaction
occurred making occasional cooling necessary. Afterward the
mixture was heated for additional 1.5 h to reflux. The mixture was
filtered over Celite, the residue was washed with ether (100 mL),
and the combined filtrates were washed with water (5ꢁ100 mL),
saturated sodium bicarbonate (5ꢁ100 mL), and brine (5ꢁ100 mL),
and dried (MgSO4). The solvent was distilled off (bath temperature
50 ꢂC/15 Torr), and the remaining crude dichloroketone resulting
from four identical experiments (137 g, purity 65% GC) [column A,
2 min, 60 ꢂC, 10 ꢂC/min to 200 ꢂC; retention time (min): 13.45] was
directly used in the next step. To a suspension of zinc dust (231 g,
3.55 mol) in acetic acid (300 mL) was added within 30 min under
argon with stirring a solution of the crude dichloroketone (68.5 g,
purity 65%) in acetic acid (150 mL) (exothermic effect) until the
mixture was heated for 1.5 h to 60 ꢂC. After cooling, the mixture
was filtered over Celite and the residue was washed with pentane
(2ꢁ200 mL). Water (400 mL) was added, the organic phase was
separated, the aqueous phase was extracted with pentane
(5ꢁ100 mL), and the combined organic phases were washed with
1 N sodium hydroxide (2ꢁ100 mL) and brine (2ꢁ100 mL), and dried
(MgSO4). The solvent was distilled off (bath temperature 40 ꢂC/
20 Torr) and the remaining crude 12 resulting from two identical
experiments (65 g, purity 71% GC) [column A, 80 ꢂC, 10 ꢂC/min to
220 ꢂC; retention time (min): 6.57 (12)] was fractionated first over
a 20 cm vigreux column and then over a 55 cm vigreux column
yielding 31.4 g (42%) of 12 as colorless liquid, bp 78 ꢂC/20 Torr
(purity 95% GC). The 1H and 13C NMR data were in accord with the
literature data.13
GC. 1H NMR (600 MHz, CDCl3, CHCl3 int):
d
¼1.37–1.45 (m, 4H),
1.50–1.54 (m, 2H), 1.55–1.63 (m, 4H), 1.89–1.96 (m, 4H), 2.06–2.12
(m, 2H), 2.51–2.57 (m, 4H); 13C NMR (150.8 MHz, CDCl3, CDCl3 int):
d
¼17.13 (t), 24.69 (t, 2C), 28.12 (t), 29.85 (t), 30.04 (t), 38.09 (t, 2C),
38.65 (t), 42.21 (t), 50.67 (s), 129.61 (s), 132.47 (s); MS (EI): m/z¼176
(32, Mþ), 147 (100). C13H20 requires: C, 88.57; H, 11.43. Found: C,
88.12; H, 11.30.
3.5. Dispiro[4.1.4.2]tridecan-1-one (15)
To a stirred solution of 21 (17.6 g,100 mmol) in dichloromethane
(100 mL) was added within 2 h a solution of 3-chloroperoxybenzoic
acid (49.4 g, 70% w/w, 200 mmol) in dichloromethane (400 mL).
After 1 h, the reaction was complete according to GC [column B,
190 ꢂC; retention times (min): 3.21 (21), 6.12 (epoxide), 10.79 (15)].
NaOH (1 N, 200 mL) was added with stirring, the phases were
separated, and the organic phase was washed with water
(2ꢁ200 mL), dried (MgSO4), and concentrated to approximately
300 mL by distillation over a 40 cm vigreux column. Solid potas-
sium carbonate (1.0 g) was added to the remaining solution until it
was cooled to 5 ꢂC and boron trifluoride etherate (260 mg,
1.8 mmol) was added drop by drop, causing an exothermic reaction,
which with the last drops subsided. After the addition was com-
plete, the mixture was stirred for 30 min at room temperature, until
it was washed with 1 N NaOH (50 mL), water (2ꢁ150 mL), and dried
(MgSO4). The solvent was distilled off over a 40 cm vigreux column
and the residue fractionated to yield 17.7 g (93%) of 15 as colorless
liquid, bp 108–110 ꢂC/1 Torr (purity 97% GC). An analytically pure
sample was obtained by preparative GC. IR (neat): 1740 cmꢃ1
3.3. Spiro[4.4]nonan-2-one (13)
(C]O); 1H NMR (600 MHz, CDCl3, CHCl3 int):
1H), 1.39–1.63 (m, 11H), 1.76–1.90 (m, 6H), 2.11–2.25 (m, 2H); 13C
NMR (150.8 MHz, CDCl3, CDCl3 int):
d¼1.34 (d, J¼13 Hz,
The reaction was performed in fire-polished glassware in
a well ventilated hood. To a solution of potassium hydroxide (74 g,
1.32 mol) in methanol (170 mL) and water (30 mL) was added
dropwise at 0 ꢂC with stirring 12 (13.6 g, 110 mmol), and, within
3 h, a solution of N-methyl-N-nitroso-p-toluenesulfonic acid am-
ide (30.0 g, 140 mmol) in methanol (360 mL). After additional
0.5 h, the mixture was hydrolyzed with acetic acid (60 mL), di-
luted with water (400 mL), and extracted with pentane
(4ꢁ150 mL). The combined extracts were washed with water
(2ꢁ150 mL), dried (MgSO4), and concentrated (bath temperature
40 ꢂC/15 Torr) to yield 13.4 g of crude 13. The material of two
experiments (27.3 g) was fractionated over a 20 cm vigreux
column to yield 18.0 g (60%) of 13 as colorless liquid, bp
93–95 ꢂC/16 Torr (purity 94% GC). A pure sample was obtained by
d¼19.47 (t), 24.31 (t), 24.59 (t),
36.33 (t), 36.92 (t), 38.94 (t), 39.02 (t), 39.35 (t), 39.44 (t), 48.60 (t),
51.47 (s), 56.11 (s), 223.74 (s); MS (EI): m/z¼192 (26, Mþ), 97 (100).
C13H20O requires: C, 81.20; H, 10.48. Found: C, 81.21; H, 10.42.
3.6. Trispiro[4.1.1.4.2.2]heptadecan-6-one (16)
To a suspension of potassium hydride (240 mg, 6.0 mmol) in
ether (15 mL) were added under argon with stirring 15 (384 mg,
2.0 mmol) and 1,4-diiodobutane (775 mg, 2.5 mmol). According to
GC [column B, 230 ꢂC; retention times (min): 4.29 (15), 9.61 (16)],
after 20 h at room temperature the reaction was complete. The
mixture was diluted with pentane (15 mL) and hydrolyzed with
saturated ammonium chloride (1 mL). The organic phase was

I. Meyer-Wilmes et al. / Tetrahedron 65 (2009) 1689–1696
1693
decanted, the residue was extracted with pentane (5 mL), and the
combined organic phases were washed with water (2ꢁ15 mL) and
dried (MgSO4). The solvents were distilled off (bath temperature
50 ꢂC/15 Torr), and the residue (458 mg) was chromatographed on
silica gel (0.05–0.20 mm) in pentane/ether (95:5, column
50ꢁ2.5 cm, control by GC) to yield 350 mg (73%) of 16 as colorless
oil (purity 98% GC). An analytically pure sample was obtained by
preparative GC. IR (neat): 1735 cmꢃ1 (C]O); 1H NMR (600 MHz,
temperature 60 ꢂC/15 Torr) to yield 9.3 g (99%) of 19 as colorless oil
(purity 96% GC). This material was used for the synthesis of 20.
Analytically pure 19 was obtained by preparative GC. 1H NMR
(600 MHz, CDCl3, CHCl3 int):
2H),1.54–1.61 (m, 4H),1.64 (mc, 2H), 3.37 (s, 2H), 3.68 (mc, 2H), 4.08
(br s, 2H); 13C NMR (150.8 MHz, CDCl3, CDCl3 int):
d¼1.26–1.33 (m, 2H), 1.45–1.52 (m,
d
¼24.51 (t, 2C),
35.02 (t, 2C), 41.92 (t), 47.06 (s), 59.89 (t), 69.03 (t); MS (CI):
m/z¼289 (5, [2MþH]þ), 162 (100, [MþNH4]þ), 145 (14, [MþH]þ).
C8H16O2 requires: C, 66.63; H, 11.18. Found: C, 66.90; H, 10.93.
C6D6, C6D5H int):
d
¼1.23–1.31 (m, 2H), 1.25 (d, J¼13 Hz, 1H), 1.32–
1.41 (m, 3H), 1.42–1.73 (m, 16H), 1.71–1.84 (m, 1H), 1.88–1.96 (m,
2H), 1.99 (d, J¼13 Hz, 1H); 13C NMR (150.8 MHz, C6D6, C6D6 int):
3.10. 1-Tosyloxymethyl-1-(2-tosyloxyethyl)-cyclopentane (20)
d
¼24.68 (t), 24.96 (t), 26.08 (t), 26.18 (t), 35.65 (t), 37.12 (t), 37.59 (t),
37.64 (t), 37.81 (t), 39.31 (t), 39.48 (t), 39.86 (t), 50.08 (t), 51.79 (s),
55.65 (s), 56.02 (s), 225.50 (s); MS (EI): m/z¼246 (14, Mþ),151 (100).
C17H26O requires: C, 82.87; H, 10.64. Found: C, 83.07; H, 10.43.
To a solution of p-toluenesulfonic acid chloride (48.8 g,
256 mmol) in pyridine (100 mL) was added under argon with stir-
ring a solution of 19 (9.2 g, 64 mmol) in pyridine (60 mL) such that
the internal temperature did not exceed 3 ꢂC (2 h). After having
been stirred at 0 ꢂC overnight, the mixture was poured into ice-cold
water (1 L) and the separating oil extracted with dichloromethane
(400 mL). The extract was washed with water (200 mL), 5% H2SO4
(200 mL), and water (200 mL), and dried (MgSO4). The solvent was
distilled off on a rotary evaporator (bath temperature up to 60 ꢂC/
15 Torr) to yield 22.8 g (79%) of 20 as slightly yellow sticky gum
(purity 94% 1H NMR). An analytically pure sample was obtained by
thick layer chromatography on silica gel in pentane/ether [1:1,
Rf¼0.32 (20)], colorless sticky gum. 1H NMR (600 MHz, CDCl3, CHCl3
3.7. ( )-Trispiro[4.1.1.4.2.2]hexadecane [( )-9]
Sodium metal (140 mg, 6.0 mmol) was dissolved in diethyl-
eneglycol (8.0 mL). Anhydrous hydrazine (1.30 g, 40 mmol) and 16
(119 mg, 0.50 mmol) were added under argon with stirring, and the
resulting mixture was heated to 140 ꢂC. According to GC [column A,
200 ꢂC; retention times (min): 1.75 (9), 4.52 (16), 6.28 (hydrazone)],
after 24 h the mixture contained >90% hydrazone. The temperature
was raised to 200 ꢂC and after additional 48 h the mixture
contained >90% 9. The mixture was diluted with water (50 mL),
extracted with pentane (2ꢁ50 mL), and the extracts were washed
with water (2ꢁ50 mL) and dried (MgSO4). The solvent was distilled
off (bath temperature 30 ꢂC/15 Torr) and the residue (100 mg)
was chromatographed on silica gel (0.05–0.20 mm) in pentane
(column 10ꢁ1 cm) to yield 69 mg (61%) of 9 as colorless liquid
(purity 96% GC). An analytically pure sample was obtained by
int):
d
¼1.27–1.33 (m, 2H), 1.34–1.40 (m, 2H), 1.40–1.54 (m, 4H), 1.71
(pseudo t, J¼7 Hz, 2H), 2.42 (s, 6H), 3.65 (s, 2H), 3.95 (pseudo t,
J¼7 Hz, 2H), 7.30–7.33 (m, 4H), 7.69–7.73 (m, 4H); 13C NMR
(150.8 MHz, CDCl3, CDCl3 int):
d¼21.55 (q), 21.56 (q), 24.32 (t, 2C),
34.52 (t, 2C), 35.66 (t), 44.39 (s), 67.48 (t), 74.10 (t), 127.72 (d, 2C),
127.73 (d, 2C), 129.81 (d, 2C), 129.87 (d, 2C), 132.49 (s), 132.79 (s),
144.79 (s), 144.88 (s); MS (EI): m/z¼452 (<1, Mþ), 109 (100); (CI):
m/z¼922 (7, [2MþNH4]þ), 470 (100, [MþNH4]þ). C22H28O6S2
requires: C, 58.38; H, 6.24. Found: C, 58.55; H, 6.31.
preparative GC. 1H NMR (600 MHz, CDCl3, CHCl3 int):
(m, 12H), 1.51–1.58 (m, 16H); 13C NMR (150.8 MHz, CDCl3, CDCl3
int):
d¼1.40–1.49
d
¼24.25 (t, 2C), 24.30 (t, 2C), 39.14 (t, 2C), 40.80 (t, 2C), 40.81 (t,
2C), 40.88 (t, 2C), 50.34 (s, 2C), 50.43 (s), 54.24 (t, 2C); MS (EI):
m/z¼232 (58, Mþ), 175 (100). C17H28 requires: C, 87.86; H, 12.14.
Found: C, 88.00; H, 11.89.
3.11. 1-Iodomethyl-1-(2-iodoethyl)-cyclopentane (14)
A mixture of 20 (22.6 g, 50 mmol), anhydrous lithium iodide
(26.8 g, 200 mmol), and 12-crown-4 (1.76 g,10 mmol) in anhydrous
acetonitrile (300 mL) was heated to reflux. According to TLC in
pentane/ether [1:1; Rf¼0.32 (20), 0.58, 0.75 (14)] after 20 h the
reaction was complete. Most of the solvent was distilled off on
a rotary evaporator (bath temperature 40 ꢂC/30 Torr) and the res-
idue was extracted with ether (3ꢁ200 mL). The combined extracts
were washed with water (300 mL), Na2S2O3 solution (10%, 350 mL),
and water (300 mL), and dried (MgSO4). The solvent was distilled
off and the residue fractionated to yield 14.2 g (78%) of pure 14 as
slightly yellow liquid, bp 108–109 ꢂC/0.1 Torr. 1H NMR (600 MHz,
3.8. 2-Oxa-spiro[4.4]nonan-3-one (18)
To a vigorously stirred solution of 12 (9.3 g, 75 mmol) in
dichloromethane (100 mL) was added a 0.7 M aqueous solution of
sodium bicarbonate (150 mL), and, within 2 h at 20–25 ꢂC, a solu-
tion of 3-chloroperoxybenzoic acid (24.7 g, 70% w/w, 100 mmol) in
dichloromethane (300 mL). According to GC [column B, 190 ꢂC;
retention times (min): 2.16 (12), 12.05 (18)], after additional 0.5 h
the reaction was complete. The organic phase was washed with 1 N
NaOH (150 mL), water (150 mL), and dried (MgSO4). The solvent
was distilled off and the residue fractionated to yield 9.1 g (87%) of
18 as colorless liquid, bp 86 ꢂC/0.4 Torr (purity 99% GC) (lit.15a 120–
121 ꢂC/11 Torr). The 1H and 13C NMR data were in accord with the
literature data.15b
CDCl3, CHCl3 int):
d
¼1.52–1.58 (m, 4H), 1.61–1.67 (m, 4H), 2.12 (AA0
part of an AA0BB0 system, 2H), 3.07 (BB0 part of an AA0BB0 system,
2H), 3.16 (s, 2H); 13C NMR (150.8 MHz, CDCl3, CDCl3 int):
d
¼ꢃ0.53
(t), 19.52 (t), 24.84 (t, 2C), 37.01 (t, 2C), 45.19 (t), 48.26 (s); MS (EI):
m/z¼364 (<1, Mþ), 237 (66, MþꢃI), 109 (100, MþꢃIꢃHI). C8H14 2
I
requires: C, 26.40; H, 3.88. Found: C, 26.69; H, 3.68.
3.9. 1-Hydroxymethyl-1-(2-hydroxyethyl)-cyclopentane (19)
3.12. rel-(7R,9R)-Tetraspiro[4.1.1.1.4.2.2.2]heneicosan-8-one
[rel-(7R,9R)-17] and rel-(7R,9S)-tetraspiro[4.1.1.1.4.2.2.2]-
heneicosan-8-one [rel-(7R,9S)-22]
To a suspension of lithium aluminum hydride (3.8 g, 100 mmol)
in anhydrous ether (110 mL) was added at room temperature under
argon with stirring 18 (9.1 g, 65 mmol) causing an exothermic ef-
fect. Afterward the mixture was heated to reflux. According to GC
[column A, 180 ꢂC; retention times (min): 4.51 (18), 11.21 (19)], after
2 h the reduction was complete. Water (3.8 mL), 15% aqueous po-
tassium hydroxide (3.8 mL), and water (11.4 mL) were added, the
liquid phase was decanted, and the residue was extracted with
ether (3ꢁ100 mL). The combined organic phases were dried
To a suspension of potassium hydride (1.20 g, 30 mmol) in
benzene (75 mL) were added under argon with stirring 15 (0.96 g,
5.0 mmol) and 14 (2.73 g, 7.5 mmol). Afterward, the mixture was
heated to reflux. The reaction progress was monitored by GC [col-
umn A, 200 ꢂC; retention times (min): 3.08 (15), 3.53 (14),18.85 (17/
22)], and, after 24 and 30 h, more 14 (2ꢁ0.91 g, 2ꢁ2.5 mmol) was
added. After 48 h, the reaction was complete. The mixture was
(MgSO4) and concentrated on
a rotary evaporator (bath

1694
I. Meyer-Wilmes et al. / Tetrahedron 65 (2009) 1689–1696
diluted with pentane (75 mL), hydrolyzed with saturated ammo-
nium chloride (50 mL), and the organic phase was washed with
water (2ꢁ50 mL) and dried (MgSO4). The solvents were distilled off
(bath temperature 50 ꢂC/15 Torr), and the residue (3.86 g yellow
oil) was chromatographed on silica gel (0.05–0.20 mm) in pentane/
ether (95:5, column 70ꢁ4.5 cm, control by GC) to yield 1.14 g (76%)
of a 1:1 mixture of 17 and 22 as colorless solid, mp 34–36 ꢂC. The
data refer to the mixture. 1H NMR (600 MHz, C6D6, C6D5H int):
2C), 52.75 (s, 2C), 52.92 (t, 2C), 85.66 (d); MS (EI): m/z¼302 (22,
Mþ), 284 (21, MþꢃH2O), 67 (100); HRMS m/z (Mþ) calcd 302.2620,
obsd 302.2610. Compound 26: 1H NMR (600 MHz, C6D6, C6D5H int):
d
¼1.14 (br s, 1H), 1.21 (d, J¼13 Hz, 1H), 1.26 (ddd, J¼12, 6, 6 Hz, 1H),
1.43 (d, J¼13 Hz, 1H), 1.46–1.58 (m, 14H), 1.58–1.73 (m, 13H), 1.97
(ddd, J¼12, 8, 8 Hz, 1H), 2.04 (d, J¼13 Hz, 1H), 3.34 (s, 1H); 13C NMR
(150.8 MHz, C6D6, C6D6 int):
d¼24.52 (t), 24.60 (t), 24.90 (t), 24.93
(t), 33.58 (t), 38.37 (t), 38.40 (t), 38.96 (t), 39.45 (t), 39.73 (t), 40.59
(t), 40.62 (t), 40.66 (t), 40.97 (t), 46.36 (t), 50.19 (s), 50.87 (s), 52.87
(t), 52.96 (s), 53.27 (s), 85.94 (d); MS (EI): m/z¼302 (23, Mþ), 284
(15, MþꢃH2O), 67 (100); HRMS m/z (Mþ) calcd 302.2620, obsd
302.2610.
d
¼1.265 (d, J¼12.5 Hz, 1H), 1.275 (d, J¼13 Hz, 1H), 1.33–1.70 (m,
26H), 1.90 (ddd, J¼12.5, 7.5, 7.5 Hz, 1H), 1.96 (d, J¼13 Hz, 1H), 2.00
(ddd, J¼13, 7.5, 7.5 Hz, 1H), 2.05 (d, J¼12.5 Hz, 1H); 13C NMR
(150.8 MHz, C6D6, C6D6 int):
d¼24.67 (t), 24.71 (t), 24.96 (t), 24.97
(t), 37.09 (t), 37.14 (t), 37.66 (t), 37.82 (t), 39.33 (t), 39.36 (t), 39.44
(t), 39.60 (t), 39.90 (t), 39.90 (t), 50.17 (t), 50.42 (t), 51.80 (s), 51.84
(s), 55.57 (s), 55.60 (s), 225.33 (s), 225.49 (s). C21H32O requires: C,
83.94; H, 10.73. Found: C, 84.11; H, 10.66.
3.15. rel-(7R,9R)-Tetraspiro[4.1.1.1.4.2.2.2]heneicosan-8-one
[rel-(7R,9R)-17]
To pyridinium chlorochromate (173 mg, 0.80 mmol) was added
under argon with stirring a solution of 26 (121 mg, 0.40 mmol) in
dichloromethane (2.0 mL). After 1 h at room temperature, the re-
action was complete according to GC [column A, 230 ꢂC; retention
times (min): 5.33 (26), 5.88 (17)]. The mixture was diluted with
ether (5 mL), the liquid phase was decanted, the residual black tar
was extracted with ether (2ꢁ2 mL), and the combined organic
phases were first filtrated over a short pad of silica gel (0.05–
0.20 mm; column 7ꢁ2 cm) and then concentrated (bath tempera-
ture 60 ꢂC/15 Torr) to yield 117 mg (97%) of 17 as colorless solid, mp
56–58 ꢂC (purity >99%, GC). IR (KBr): 1720 cmꢃ1 (C]O); 1H NMR
3.13. ( )-Tetraspiro[4.1.1.1.4.2.2.2]heneicosane [( )-10] and
meso-tetraspiro[4.1.1.1.4.2.2.2]heneicosane (meso-23)
The 1:1 mixture of 17 and 22 (140 mg, 0.50 mmol) was reduced
as described for 16 (see Section 3.7). According to GC [column A,
230 ꢂC; retention times (min): 2.60 (10/23), 5.89 (17/22), 7.72
(hydrazones)], after 24 h at 140 ꢂC the mixture contained >90%
hydrazones, and after additional 48 h at 200 ꢂC >90% 10 and 23.
Work up and chromatography yielded 93 mg (65%) of a 1:1 mixture
of 10 and 23 as colorless liquid (purity 95% GC). The data refer to the
mixture. 1H NMR (600 MHz, CDCl3, CHCl3 int):
12H), 1.52–1.60 (m, 22H); 13C NMR (150.8 MHz, CDCl3, CDCl3 int):
d¼1.40–1.48 (m,
(600 MHz, C6D6, C6D5H int):
(m, 26H), 1.90 (ddd, J¼12.5, 7.5, 7.5 Hz, 2H), 2.06 (d, J¼12.5 Hz, 2H);
13C NMR (150.8 MHz, C6D6, C6D6 int):
d
¼1.27 (d, J¼12.5 Hz, 2H), 1.33–1.69
d
¼24.23 (t) (coincidence of two lines), 24.29 (t) (coincidence of two
d¼24.70 (t, 2C), 24.97 (t, 2C),
lines), 39.12 (t), 39.18 (t), 40.86 (t), 40.88 (t) (coincidence of two
lines), 40.89 (t), 40.90 (t), 40.91 (t), 41.12 (t), 41.14 (t), 50.29 (s)
(coincidence of two lines), 50.31 (s), 50.32 (s), 54.46 (t), 54.49 (t),
55.95 (t), 56.05 (t).
37.13 (t, 2C), 37.83 (t, 2C), 39.34 (t, 2C), 39.44 (t, 2C), 39.90 (t, 2C),
50.18 (t, 2C), 51.80 (s, 2C), 55.59 (s, 2C), 225.41 (s); MS (EI): m/z¼300
(23, Mþ), 205 (100); HRMS m/z (Mþ) calcd 300.2453, obsd
300.2453.
3.14. rel-(7R,8R,9S)-Tetraspiro[4.1.1.1.4.2.2.2]heneicosane-8-ol
[rel-(7R,8R,9S)-24], rel-(7R,8S,9S)-tetraspiro[4.1.1.1.4.2.2.2]-
heneicosane-8-ol [rel-(7R,8S,9S)-25], and rel-(7R,9R)-
tetraspiro[4.1.1.1.4.2.2.2]heneicosane-8-ol [rel-(7R,9R)-26]
3.16. rel-(7R,9S)-Tetraspiro[4.1.1.1.4.2.2.2]heneicosan-8-one
[rel-(7R,9S)-22]
3.16.1. From 24
Compound 24 (75 mg, 0.25 mmol) was oxidized as described for
26 (see Section 3.15) yielding 67 mg (89%) of 22 as colorless solid,
mp 50–52 ꢂC (purity >98%, GC) [column A, 230 ꢂC, retention times
(min): 5.11 (24), 5.89 (22)]. IR (KBr): 1720 cmꢃ1 (C]O); 1H NMR
To
a suspension of lithium aluminum hydride (285 mg,
7.5 mmol) in ether (30 mL) was added under argon with stirring
a solution of a 1:1 mixture of 17 and 22 (450 mg, 1.5 mmol) in ether
(5 mL). After 1 h of reflux, the reaction was complete according to
GC [column A, 230 ꢂC; retention times (min): 5.45 (24/25/26), 5.89
(17/22)]. The mixture was treated with water (300
KOH (300 L), and water (900 L), the organic phase was decanted,
and the residue was extracted with ether (3ꢁ20 mL). The combined
organic phases were concentrated (bath temperature 60 ꢂC/
15 Torr) and the solid residue (438 mg) was chromatographed on
silica gel (0.040–0.063 mm) in pentane/ether [97:3, column
100ꢁ2.5 cm, Rf¼0.18 (24), 0.15 (26), 0.13 (25)] to yield 78 mg (17%)
24, mp 92–94 ꢂC, 89 mg (20%) 25, mp 170–172 ꢂC, and 147 mg (32%)
26, mp 82–84 ꢂC, as colorless solids. Compound 24: 1H NMR
(600 MHz, C6D6, C6D5H int):
1.46–1.56 (m,14H),1.56–1.72 (m,14H), 2.06 (d, J¼13 Hz, 2H), 3.32 (s,
1H); 13C NMR (150.8 MHz, C6D6, C6D6 int):
(600 MHz, C6D6, C6D5H int):
d
¼1.27 (d, J¼13 Hz, 2H), 1.34–1.70 (m,
26H), 1.96 (d, J¼13 Hz, 2H), 2.01 (ddd, J¼13, 7.5, 7.5 Hz, 2H); 13C
mL), 15% aqueous
NMR (150.8 MHz, C6D6, C6D6 int):
d
¼24.67 (t, 2C), 24.96 (t, 2C),
m
m
37.08 (t, 2C), 37.67 (t, 2C), 39.36 (t, 2C), 39.60 (t, 2C), 39.91 (t, 2C),
50.43 (t, 2C), 51.84 (s, 2C), 55.61 (s, 2C), 225.55 (s); MS (EI):
m/z¼300 (27, Mþ), 205 (100); HRMS m/z (Mþ) calcd 300.2453, obsd
300.2453.
3.16.2. From 25
Compound 25 (75 mg, 0.25 mmol) was oxidized as described for
26 (see Section 3.15) yielding 70 mg (93%) of 22 as colorless solid,
mp 50–52 ꢂC (purity >98%, GC) [column A, 230 ꢂC; retention times
(min): 5.63 (25), 5.89 (22)]. The 1H and 13NMR data were identical
with those of authentic material.
d¼1.07 (br s, 1H), 1.23 (d, J¼13 Hz, 2H),
d¼24.53 (t, 2C), 24.90 (t,
2C), 38.42 (t, 2C), 39.06 (t, 2C), 39.70 (t, 2C), 40.60 (t, 2C), 40.95 (t,
2C), 46.43 (t, 2C), 50.79 (s, 2C), 53.43 (s, 2C), 86.15 (d); MS (EI):
m/z¼302 (11, Mþ), 284 (10, MþꢃH2O), 67 (100); HRMS m/z (Mþ)
calcd 302.2620, obsd 302.2610. Compound 25: 1H NMR (600 MHz,
3.17. ( )-Tetraspiro[4.1.1.1.4.2.2.2]heneicosane [( )-10]
Compound 17 (90 mg, 0.30 mmol) was reduced as described for
16 (see Section 3.7) and the mixture of 10 and 23 (see Section 3.13)
yielding 43 mg (52%) of (ꢀ)-10 as colorless liquid (purity >98% GC)
[column A, 230 ꢂC; retention times (min): 2.41 (10), 5.45 (17), 7.17
C6D6, C6D5H int):
d¼1.03 (br s, 1H), 1.23 (ddd, J¼12, 6, 6 Hz, 2H), 1.41
(d, J¼13 Hz, 2H), 1.45–1.54 (m, 14H), 1.57–1.64 (m, 10H), 1.66 (d,
J¼13 Hz, 2H), 1.96 (ddd, J¼12, 8, 8 Hz, 2H), 3.33 (br s, 1H); 13C NMR
(150.8 MHz, C6D6, C6D6 int):
d¼24.61 (t, 2C), 24.94 (t, 2C), 33.46 (t,
(hydrazone)]. 1H NMR (600 MHz, CDCl3, CHCl3 int):
d
¼1.40–1.48
2C), 38.45 (t, 2C), 39.54 (t, 2C), 40.53 (t, 2C), 40.60 (t, 2C), 50.09 (s,
(m, 12H), 1.50–1.57 (m, 22H); 13C NMR (150.8 MHz, CDCl3, CDCl3

I. Meyer-Wilmes et al. / Tetrahedron 65 (2009) 1689–1696
1695
int):
d
¼24.22 (t), 24.28 (t), 39.11 (t), 40.85 (t), 40.87 (t), 40.90 (t),
51.84 (t), 52.91 (t), 220.07 (s); MS (EI): m/z¼192 (100, Mþ); C13H20
O
41.13 (t), 50.29 (s), 50.32 (s), 54.45 (t), 56.04 (t); MS (EI): m/z¼286
requires: C, 81.19; H, 10.48. Found: C, 81.52; H, 10.28.
(82, Mþ), 95 (100); HRMS m/z (Mþ) calcd 286.2661, obsd 286.2661.
3.22. 2-Cyclobutyliden-dispiro[4.1.4.2]tridecan-2-one (30)
3.18. meso-Tetraspiro[4.1.1.1.4.2.2.2]heneicosane (meso-23)
Compound 30 was prepared as described for 21 (see Section
3.4); 3.60 g (18.7 mmol) 28 yielded 3.67 g (85%) crude 30 as col-
orless liquid (purity 90% GC) [column B, 220 ꢂC; retention times
(min): 4.34 (30), 5.53 (28)]. This material was directly used in the
Compound 22 (90 mg, 0.30 mmol) was reduced as described
for 16 (see Section 3.7) and the mixture of 10 and 23 (see Section
3.13) yielding 36 mg (42%) of meso-23 as colorless liquid (purity
>98% GC) [column A, 230 ꢂC; retention times (min): 2.41 (23),
5.38 (22), 7.06 (hydrazone)]. 1H NMR (600 MHz, CDCl3, CHCl3 int):
next step. 1H NMR (300 MHz, CDCl3, CHCl3 int):
d
¼1.40–1.62 (m,
16H), 1.94 (mc, 2H), 2.00 (mc, 2H), 2.07 (mc, 2H), 2.54 (mc, 4H); 13
NMR (125.7 MHz, CDCl3, CDCl3 int):
C
d
¼1.40–1.48 (m, 12H), 1.50–1.57 (m, 22H); 13C NMR (150.8 MHz,
d¼17.13 (t), 24.32 (t), 24.37 (t),
28.02 (t), 29.85 (t), 30.06 (t), 38.30 (t), 39.03 (t), 40.24 (t), 40.53 (t),
40.61 (t), 43.83 (t), 50.29 (s), 50.61 (s), 51.72 (t), 129.62 (s), 132.47
(s); MS (EI): m/z¼230 (69, Mþ), 201 (100). HRMS m/z (Mþ) calcd
230.2035, obsd 230.2035.
CDCl3, CDCl3 int):
d
¼24.22 (t, 2C), 24.28 (t, 2C), 39.18 (t, 2C), 40.86
(t, 2C), 40.89 (t, 2ꢁ2C) (coincidence of two lines), 41.11 (t, 2C),
50.29 (s, 2C), 50.30 (s, 2C), 54.49 (t, 2C), 55.95 (t); MS (EI):
m/z¼286 (52, Mþ), 81 (100); HRMS m/z (Mþ) calcd 286.2661, obsd
286.2661.
3.23. rel-(5R,7R)-Trispiro[4.1.1.4.2.2]heptadecan-1-one [rel-
(5R,7R)-31] and rel-(5R,7S)-Trispiro[4.1.1.4.2.2]heptadecan-1-
one [rel-(5R,7S)-33]
3.19. 2-Methylene-spiro[4.4]nonane (27)
To
a suspension of methyltriphenylphosphonium bromide
Compound 30 (3.80 g, 16.5 mmol) was epoxidized and rear-
ranged as described for 15 (see Section 3.5). The reactions were
monitored by GC [column B, 220 ꢂC; retention times (min): 4.35
(30), 13.45 (31/33), 14.82 (epoxide), 16.10 (epoxide)] and the ke-
tones formed chromatographed on silica gel (0.05–0.20 mm) in
pentane/ether [8:2, column 3.5ꢁ80 cm, Rf¼0.54 (31/33)] to yield
1.53 g (38%) of a 1:1 mixture of 31 and 33 as colorless oil. The data
account for the mixture. IR (neat): 1735 cmꢃ1 (C]O); 1H NMR
(69.1 g, 193 mmol) in ether (200 mL) was added under argon with
stirring potassium-tert-butoxide (21.7 g, 193 mmol) and the mix-
ture heated to reflux. After 1 h,13 (17.9 g,129 mmol) was added and
after additional 30 min, the reaction was complete. The mixture
was hydrolyzed with water (50 mL), the organic phase was dec-
anted, the residue was extracted with ether (3ꢁ100 mL), and the
combined organic phases were washed with water (2ꢁ200 mL) and
dried (MgSO4). The solution was concentrated and the residue
fractionated to yield 15.2 g (86%) of 27 as colorless liquid, bp 105 ꢂC/
80 Torr. IR (neat): 3080 (]C–H), 1660 cmꢃ1 (C]C); 1H NMR
(300 MHz, CDCl3, CHCl3 int):
d
¼1.35–1.70 (m, 36H), 1.70–1.90 (m,
12H), 2.05–2.30 (m, 4H); 13C NMR (125.7 MHz, CDCl3, CDCl3 int):
d
¼19.48 (t), 19.50 (t), 24.25 (t), 24.27 (t), 24.31 (t), 24.34 (t), 36.35
(300 MHz, CDCl3, CHCl3 int):
d
¼1.38–1.48 (m, 4H), 1.52–1.64 (m,
6H), 2.15 (mc, 2H), 2.33 (mc, 2H), 4.80 (mc, 2H); 13C NMR (75.5 MHz,
(t), 36.44 (t), 36.83 (t), 36.93 (t), 38.92 (t), 39.16 (t), 39.22 (t), 39.49
(t), 39.57 (t), 39.68 (t), 40.46 (t), 40.47 (t), 40.64 (t) 40.65 (t) (co-
incidence of two lines), 40.69 (t), 50.10 (t), 50.12 (s), 50.33 (t), 50.66
(s), 51.30 (s), 51.34 (s), 52.36 (t), 53.19 (t), 55.98 (s), 56.09 (s), 223.77
(s), 223.81 (s); MS (EI): m/z¼246 (26, Mþ), 150 (100). HRMS m/z
(Mþ) calcd 246.1984, obsd 246.1984.
CDCl3, CDCl3 int):
d¼24.63 (t, 2C), 31.66 (t), 37.93 (t, 2C), 38.57 (t),
46.30 (t), 50.49 (s), 105.12 (t), 153.00 (s); MS (EI): m/z¼136 (61, Mþ),
121 (100). C10H16 requires: C, 88.16; H, 11.83. Found: C, 88.44; H,
11.61.
3.20. Dispiro[3.1.4.2]dodecan-2-one (29)
Supplementary data
Compound 29 was prepared as described for 12 (see Section
3.2); 18.8 g (138 mmol) of 27 yielded 26.0 g of crude dichloro-
ketone (purity 92% GC) [column B, 220 ꢂC; retention time (min):
8.79], and, after dechlorination, 17.6 g (72%) of 29 as colorless liq-
uid, bp 131 ꢂC/17 Torr (purity 96% GC) [column B, 210 ꢂC; retention
time (min): 4.05]. An analytically pure sample was obtained by
preparative GC. IR (neat): 1780 cmꢃ1 (C]O); 1H NMR (300 MHz,
1H and 13C NMR spectra of 9, 10, 14–17, 19–30, and 31/33. Sup-
plementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2008.12.025.
References and notes
1. Kakiuchi, K.; Okada, H.; Kanehisa, N.; Kai, Y.; Kurosawa, H. J. Org. Chem. 1996, 61,
2972–2979.
2. Gaini-Rahimi, S.; Steeneck, C.; Meyer, I.; Fitjer, L.; Pauer, F.; Noltemeyer, M.
Tetrahedron 1999, 55, 3905–3916.
3. de Meijere, A.; Khlebnikov, A. F.; Kostikov, R. R.; Kozhushkov, S. I.; Schreiner, P.
R.; Wittkopp, A.; Yufit, D. S. Angew. Chem. 1999, 111, 3682–3685; Angew. Chem.,
Int. Ed. 1999, 38, 3474–3477.
4. de Meijere, A.; Khlebnikov, A. F.; Kozhushkov, S. I.; Kostikov, R. R.; Schreiner, P.
R.; Wittkopp, A.; Rinderspacher, C.; Menzel, H.; Yufit, D. S.; Howard, J. A. K.
Chem.dEur. J. 2002, 828–842.
CDCl3, CHCl3 int):
d
¼1.40–1.50 (m, 4H), 1.50–1.62 (m, 6H), 1.80 (s,
2H), 1.85 (t, J¼7.5 Hz, 2H), 2.92 (mc, 4H); 13C NMR (50.3 MHz,
CDCl3, CDCl3 int):
d
¼24.03 (t, 2C), 36.25 (s), 38.92 (t), 39.60 (t),
40.29 (t, 2C), 50.85 (s), 52.28 (t), 58.71 (t, 2C), 208.88 (s); MS (EI):
m/z¼178 (10, Mþ), 121 (100); C12H18O requires: C, 80.85; H, 10.18.
Found: C, 81.10; H, 9.92.
3.21. Dispiro[4.1.4.2]tridecan-2-one (28)
5. Fitjer, L.; Gerke, R.; Weiser, J.; Bunkoczi, G.; Debreczeni, J. E. Tetrahedron 2003,
59, 4443–4449.
6. Fitjer, L.; Kanschik, A.; Gerke, R. Tetrahedron 2004, 60, 1205–1213.
7. de Meijere, A.; Khlebnikov, A. F.; Kozhushkov, S. I.; Miyazawa, K.; Frank, D.;
Schreiner, P. R.; Rinderspacher, C.; Yufit, D. S.; Howard, J. A. K. Angew. Chem.
2004, 116, 6715–6719; Angew. Chem., Int. Ed. 2004, 43, 6553–6557.
8. de Meijere, A.; Khlebnikov, A. F.; Kozhushkov, S. I.; Yufit, D. S.; Chetina, O. V.;
Howard, J. A. K.; Kurahashi, T.; Mijazawa, K.; Frank, D.; Schreiner, P. R.; Rin-
derspacher, B. C.; Fujisawa, M.; Yamamoto, C.; Okamoto, Y. Chem.dEur. J. 2006,
5697–5721.
9. Widjaja, T.; Fitjer, L.; Pal, A.; Schmidt, H.-G.; Noltemeyer, M.; Diedrich, C.;
Grimme, S. J. Org. Chem. 2007, 72, 9264–9277.
10. For an attempted synthesis of 6, see: Widjaja, T.; Fitjer, L.; Meindl, K.; Herbst-
Irmer, R. Tetrahedron 2008, 64, 4304–4312.
Compound 28 was prepared as described for 13 (see Section
3.3); 10.8 g (60 mmol) 29 yielded 7.8 g (67%) 28 as colorless liquid,
bp 165 ꢂC/18 Torr (purity 90% GC) [column B, 210 ꢂC; retention
times (min): 4.05 (29), 6.82 (28)]. An analytically pure sample was
obtained by preparative GC. IR (neat): 1780 cmꢃ1 (C]O); 1H NMR
(300 MHz, CDCl3, CHCl3 int):
d
¼1.40–1.50 (m, 4H), 1.50–1.66 (m,
10H), 1.88 (t, J¼7.5 Hz, 2H), 2.16 (s, 2H), 2.22 (t, J¼7.5 Hz, 2H); 13C
NMR (75.5 MHz, CDCl3, CDCl3 int):
d¼24.19 (t), 24.24 (t), 36.72 (t),
37.99 (t), 38.44 (t), 38.67 (t), 40.47 (t), 40.66 (t), 47.32 (s), 50.52 (s),

1696
I. Meyer-Wilmes et al. / Tetrahedron 65 (2009) 1689–1696
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J. Am. Chem. Soc. 1993, 115, 9421–9438.
15. (a) Sircar, S. S. G. J. Chem. Soc. 1928, 898–903; (b) Doyle, M. P.; Dyatkin, A. B.
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12. For early reviews on methods for the construction of carbocyclic spiro com-
pounds, see: (a) Krapcho, A. P. Synthesis 1974, 383–419; (b) Krapcho, A. P.
Synthesis 1976, 425–444; (c) Krapcho, A. P. Synthesis 1978, 77–126.
13. Compound 12 has first been prepared by Baldwin, et al.: Baldwin, J. E.; Keene,
M. E.; Shukla, R. Tetrahedron Lett. 2000, 41, 9441–9443; However, no experi-
mental details were given. We therefore followed the general procedures given
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14. For an alternative approach, see: (a) Wender, P. A.; Eck, S. L. Tetrahedron Lett.
1977, 1245–1248; (b) Wender, P. A.; White, A. W. J. Am. Chem. Soc. 1988, 110,
2218–2223.
16. Fitjer, L.; Gerke, R.; Anger, T. Synthesis 1994, 893–894.
17. For cycloalkylations of
a-quaternary cyclopentanones using potassium tri-
ethylcarbinolate and 1,4-dibromobutane, see: Brugidou, J.; Christol, H. Bull. Soc.
Chim. Fr. 1968, 1141–1144.
18. Barton, D. H. R.; Ives, D. A. J.; Thomas, B. R. J. Chem. Soc. (London) 1955, 2056.
19. Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 2647–2650.
20. Methylenecyclopentane (bp 75–76 ꢂC, yield 70%, purity 98% GC) was prepared
as described for methylenecyclohexane: Fitjer, L.; Quabeck, U. Synth. Commun.
1985, 15, 855–864.
21. Fitjer, L.; Quabeck, U. Synthesis 1987, 299–300.