Helical primary structures of 1,2-spiroannelated five-membered rings: attempted synthesis of (±)-tetraspiro[4.0.0.0.4.3.3.3]heneicosane

Article abstract of DOI:10.1016/j.tet.2008.02.073

A β-hydroxy ketone with a helical carbon skeleton of five 1,2-spiroannelated cyclopentane rings is the main product of a Lewis acid catalyzed rearrangement of suitable sized α-hydroxy epoxides followed by an in situ equilibration via retro aldol reactions. Various attempts of a conversion to the title hydrocarbon failed.

Full text of DOI:10.1016/j.tet.2008.02.073

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4304e4312
www.elsevier.com/locate/tet
Helical primary structures of 1,2-spiroannelated five-membered rings:
attempted synthesis of (ꢀ)-tetraspiro[4.0.0.0.4.3.3.3]heneicosane*
b
b
Tien Widjaja a, Lutz Fitjer a, , Kathrin Meindl , Regine Herbst-Irmer
*
a Institut fu¨r Organische und Biomolekulare Chemie der Universita¨t Go¨ttingen, Tammannstrasse 2, D-37077 Go¨ttingen, Germany
b Institut fu¨r Anorganische Chemie der Universita¨t Go¨ttingen, Tammannstrasse 4, D-37077 Go¨ttingen, Germany
Received 23 November 2007; received in revised form 18 February 2008; accepted 25 February 2008
Available online 4 March 2008
Abstract
A b-hydroxy ketone with a helical carbon skeleton of five 1,2-spiroannelated cyclopentane rings is the main product of a Lewis acid cata-
lyzed rearrangement of suitable sized a-hydroxy epoxides followed by an in situ equilibration via retro aldol reactions. Various attempts of a con-
version to the title hydrocarbon failed.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Helicenes; Spiro compounds; a-Hydroxy epoxides; Rearrangements
1. Introduction
þ63.3 (c 1.09, CHCl3))4 and diminishes in (P)-5 ([a]2D0
þ26.0, (c 1.18, CHCl3)).5 Surprisingly, with (P)-3 ([a]2D0
ꢁ62.6 (c 1.10, CHCl3))8 the sign of rotation changes, and
the magnitude increases again. It is therefore tempting to
speculate that the specific rotation of (P)-6 could further
increase. However, quantum chemical computations predict
the contrary ([a]2D0 ꢁ36.2).8 To clarify the matter, a synthesis
of (P)-6 seems highly desirable. We hereby report on an
attempted synthesis of (ꢀ)-6.
During the past decade, helical primary structures of spi-
roannelated hydrocarbon rings have been the focus of consid-
erable interest.1e8 Representative examples are the trispiranes
1,2,3 2,4 and 3,8 and the tetraspiranes 43 and 55 (Fig. 1). With
regard to their specific rotations, interesting observations have
been made: the specific rotation of (P)-1 is high ([a]2D0 þ192.7
(c 1.20, CHCl3))2,3 and doubles in (P)-4 ([a]2D0 þ373.0 (c 1.0,
CHCl3)),3 while the specific rotation of (P)-2 is low ([a]2D0
2. Results
Our first approach to a synthesis of 6 was based on the suc-
cessful synthesis of 3 (Scheme 1).8 The key step of this synthesis
was a regio- and stereoselective brominative rearrangement9 of
the vinylcyclobutanol 9, itself obtained by a stereoselective
addition of 1-lithio-cyclopentene (8) to dispiroketone 7. Debro-
mination and deoxygenation of the b-bromo ketone 10 then
yielded 3.
1
2
3
4
5
6
For an analogous synthesis of 6 we needed 1-lithio-spiro-
[4.4]non-1-ene (14). This reagent was generated by treat-
ment of the tosylhydrazone 12 of spiroketone 13 with
n-butyllithium, but not used as such,10 but first brominated
to 1-bromo-spiro[4.4]non-1-ene (11) and then regenerated by
Figure 1.
*
Polyspiranes: Part 29. For Part 28, see Ref. 8.
* Corresponding author. Tel.: þ49 551 393278.
E-mail address: lfitjer@gwdg.de (L. Fitjer).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.073

T. Widjaja et al. / Tetrahedron 64 (2008) 4304e4312
4305
1. CeCl3/THF
Chloramin-T
OH
OH
2. Li
MCPB
quant.
ZnBr2
+
15
OH
O
8
CH3CN
(3:2)
O
O
O
82%
82%
Br
21
20
7
9
10
.
BF3 OEt2
1. Zn/AcOH (83%)
2. H2NNH2
NaO(CH2)2O(CH2)2OH (50%)
OH
O
OCOR
O
RCOCl
C5H5N
O
3
+
28%
(9:1)
Scheme 1.
OH
treatment with tert-butyllithium (Scheme 2).11 Catalyzed by
anhydrous cerium trichloride,12 14 added to dispiroketone 7,
yields a single vinylcyclobutanol, thought to be formed by an at-
tack of the reagent from the less hindered side of 7 and deduced
to be 15. Albeit we recognized that a regioselective ring enlarge-
ment of 15 could have led not only to the bromo ketone 16, but
also to a stereoisomer with an undesired non-helical carbon
skeleton, we were disappointed by the fact that no tetraspirane
was formed at all. Ring opened products and polymers were
observed instead. We therefore tried to modify 15 such that
the desired ring enlargement could take place.
23
24
22
R = 4-NO2C6H4
OH
+
+
OHC
25
OH
O
O
+
OH
26
27
Br
O
NNHTs
1. 2 n-BuLi
Scheme 4.
H2NNHTs
95%
2. Br(CH2)2Br
49%
11
12
13
Toward this end, we subjected the vinylcyclobutanol 15 first
to a buffered epoxidation and obtained a 3:2 mixture of two
epoxides (1H/13C NMR). Upon chromatography on silica gel
in pentane/ether 8:2, the minor epoxide (Rf¼0.42) proved unsta-
ble and rearranged, while the major epoxide (Rf¼0.55) persisted
and was obtained pure. Next, we subjected both the 3:2 mixture
of the two epoxides, and the major epoxide to a boron trifluoride
etherate catalyzed rearrangement in dichloromethane. To our
surprise, in both cases identical 9:1 mixtures of two b-hydroxy
ketones were formed (1H/13C NMR). This indicated that in both
cases the rearrangements were followed by an in situ equilibra-
tionvia retro aldol reactions, i.e., via 25 as the common interme-
diate (Scheme 4). Chromatography on silica gel in pentane/ether
8:2 delivered the major b-hydroxy ketone (Rf¼0.11) pure, while
the minor b-hydroxy ketone (Rf¼0.18) was isolated to a lower
degree of purity (85%).
Of the products formed, the major b-hydroxy ketone could
unequivocally be identified as 23 by a crystal structure analysis
of its 4-nitro benzoate 22. To identify the minor product, we
calculated the heats of formation of all four b-hydroxy ketones
(23, 24, 26, 27), which could have been formed and taken part in
the observed equilibration using our conformational search
routine HUNTER14 in connection with MM3.15 The result
was clear: it confirmed 23 (DHf¼ꢁ99.4 kcal/mol) as the most
thermodynamically stable b-hydroxy ketone, followed by 24
(DHf¼ꢁ98.7 kcal/mol). As 26 (DHf¼ꢁ95.1 kcal/mol) and 27
(DHf¼ꢁ95.5 kcal/mol) were calculated to be considerably
less stable, we deduced the minor b-hydroxy ketone to be 24.
1. CeCl3/THF
Li
2 t-BuLi
Chloramin-T
ZnBr2
2.
Br
O
CH3CN
OH
14
O
77%
7
15
16
6
Scheme 2.
It has been reported13 that a-hydroxy epoxides undergo
Lewis acid catalyzed rearrangements to b-hydroxy ketones,
including spirocyclic systems. An illustrative example is the
zinc bromide catalyzed rearrangement of the a-hydroxy epox-
ide 17 yielding a 57:43 mixture of the b-hydroxy ketones 18
and 19 (Scheme 3). Although the poor diastereoselectivity
pointed to a cationic intermediate that would eventually favor
ring openings in more complex systems, we set out to imple-
ment this approach for a synthesis of 6.
OH
O
OH
O
OH
O
ZnBr2/CH2Cl2
94%
+
(57:43)
17
18
19
Scheme 3.

4306
T. Widjaja et al. / Tetrahedron 64 (2008) 4304e4312
OH
of the chlorides proved difficult, and only one of them could
O
be obtained pure. Cyclization by treatment with potassium
hydride in toluene at 110 ꢂC proceeded smoothly, but much
to our disappointment the spectral data indicated that a bridged
ketone had been formed.19 To clarify its stereochemistry, we
reduced the ketone with lithium aluminum hydride, reacted
the resulting alcohol with 4-nitrobenzoic acid chloride in
pyridine, and subjected the 4-nitro benzoate formed to a crystal
structure analysis. This analysis disclosed its structure as 35,
and hence the structures of the corresponding alcohol, ketone,
and chloride as 34, 32, and 31, respectively.
23
LiAlH4
OH
OH
OH
O
O
H
+
+
H
Faced with the fact that arrival at 33 via 31 was barred, we
focused on 23 and investigated the possibility of an elimina-
tion followed by a hydrogenation (23e38e33) (Scheme 6).
We soon discovered that all reactions carried out for this
purpose were to no avail. Treatment of 23 with phosphoryl
chloride in pyridine20 or with methyltriphenoxyphosphonium
iodide in hexamethylphosphoramide21 afforded an a,b-unsatu-
rated ketone. A crystal structure analysis confirmed its struc-
ture as 36 and thus made clear that in both cases ionization
with a concomitant 1,2-acyl shift had taken place.22 An
attempted synthesis of a thiocarbonate ester as substrate for
a thermal syn-elimination23 failed as well. Upon treatment of
23 with 4-methylphenyl thiochloroformate in pyridine a pleth-
ora of products was formed, and the only one, which could be
obtained pure was once again 36.
30
28
29
OH
from 23 : 60%
from 20 : 95%
14%
14%
LiAlH4
TsCl/C5H5N 33%
Cl
H
O
OH
O
O
H
KH
H
44%
31
32
20
KH
LiAlH4
H
H
O
H
OR
In a last approach to a synthesis of 6 we explored the feasibil-
ity of an oxidation of 23 followed by a WolffeKishner reduction
(23e37e6). Toward this end, we reacted 23 with pyridinium
chlorochromate24 and heated the resulting dione 37 with a large
excess of neat hydrazine to reflux. However, even after
prolonged reaction times, no derivatization was observed.
In summary, boron trifluoride catalyzed rearrangements of
the a-hydroxy epoxides 20 and 21 yield a 9:1 mixture of the
b-hydroxy ketones 23 and 24. Of these, 23 exhibits the desired
helical carbon skeleton and has been obtained pure. However,
until now all attempts to remove its functionalities have failed.
Due to a pronounced tendency to ring openings and rearrange-
ments, 23 may be an unsuitable candidate for a conversion to
6. We therefore believe that new strategies must be developed
for a successful synthesis of 6.
RCl
C5H5N
R=H (80%)
33
34
R=4-NO2C6H4CO (53%)
35
Scheme 5.
The assignment of 20 as the major and 21 as the minor ep-
oxide was based on the results of a reduction of the b-hydroxy
ketone 23 in conjunction with the results of a reductive rear-
rangement16 of the major epoxide (Scheme 5). Upon treatment
with lithium aluminium hydride, both compounds yielded the
cis-cis-1,3-diol 28.17 This indicated that the reductive rear-
rangement of the major epoxide had been proceeded via 23
and that the sought structure was 20.
Unexpectedly, the reduction of 23 yielded not only the diol
28, but also an inseparable 1:1 mixture of the primary alcohols
29 and 30. Obviously, these alcohols resulted from a retro
aldol reaction to the lithium salt of 25 (Scheme 4) followed
by a reduction of the aldehyde and a non-stereoselective pro-
tonation of the enolate during the final hydrolysis. In any case,
their formation opened up the opportunity to explore the fea-
sibility of a spiroalkylation with an eventual formation of
ketone 33 as another potential precursor of 6. For the experi-
mental realization, we reacted the 1:1 mixture of 29 and 30
with an excess of p-toluenesulfonyl chloride in pyridine and
were pleased to learn that after 24 h, the alcohols had disap-
peared and that the intermediately formed p-toluenesulfonates
had largely been chlorinated.18 To accelerate the chlorination,
the remaining reagent was hydrolyzed with a stoichiometric
amount of water, and after an additional 36 h the reaction
was complete. Unfortunately, a chromatographic separation
(a) POCl3/C5H5N or
(b) (PhO)3PCH3+I–
HMPA or
O
O
(c) 4-CH3C6H4OC(S)Cl
C5H5N
OH
O
O
PCC
64%
(a) 40%
(b) 72%
(c) 11%
23
1. H2NNH2/
37
36
2. NaO(CH2)2O(CH2)2OH/
O
O
6
33
38
Scheme 6.

T. Widjaja et al. / Tetrahedron 64 (2008) 4304e4312
4307
3. Experimental
n-butyllithium in hexane (236 mL, 378 mmol) within 1.5 h at
ꢁ78 ꢂC. After an additional 30 min at ꢁ78 ꢂC the mixture was
allowed to warm up to 20 ꢂC and held at this temperature until
the nitrogen evolution had ceased (3 h). At this stage, a GC anal-
ysis [3 mꢃ1/400 all glass system. 15% FFAP on Chromosorb W
AW/DMCS, 60/80 mesh, 140 ꢂC; retention times (min): 1.55
(olefin), 8.49 (11)] of a hydrolyzed sample indicated complete
conversion to spiro[4.4]non-1-ene. The mixture was cooled to
ꢁ35 ꢂC and 1,2-dibromoethane (26.6 g, 142 mmol) was added
dropwise. After the addition was complete, the mixture was
stirred for 30 min at room temperature until it was poured into
water (1 L) and extracted with pentane (3ꢃ300 mL). The ex-
tracts were washed with water (2ꢃ300 mL) and dried
(MgSO4). The solvents were evaporated on a rotary evaporator
(bath temperature 40 ꢂC/15 Torr) and the residual brown liquid
was filtered through silica gel (0.05e0.20 mm) in pentane [col-
umn 25ꢃ4.5 cm; Rf¼0.72 (olefin), 0.61 (11)] to yield 14.4 g of
crude 11 as slightlyyellow liquid (purity76%, GC). The material
of three identical experiments (56.0 g, purity 70%, GC) was
combined and distilled over a 30 cm vigreux column to yield
40.3 g (49%) of 11 as a colorless liquid, bp 95e108 ꢂC/35 Torr
(purity 94%, GC). An analytically pure sample was obtained
3.1. General
IR spectra were obtained with a PerkineElmer 298 spec-
trometer. 1H and 13C NMR spectra were recorded on a Varian
VXR 500 or VXR 600 spectrometer. As standards the follow-
ing chemical shifts were used: dH (CHCl3)¼7.24, dH
(C6D5H)¼7.15, dH (CD3COCD2H)¼2.04, dC (CDCl3)¼77.00,
dC (C6D6)¼128.00, dC [(CD3)2CO]¼29.80. 13C multiplicities
were studied by HMQC measurements. Mass spectra were
obtained with a Finnegan MAT 95 spectrometer (EI and
HREI) operated at 70 eV. Analytical and preparative GC
were carried out on a Carlo Erba 6000 Vega 2 instrument using
a thermal conductivity detector and hydrogen as carrier gas. 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 subse-
quent warming. Melting points were observed on a Reichert
microhotstage. Boiling and melting points are not corrected.
Microanalytical determinations were done at the Microanalyt-
ical Laboratory of the Institute of Organic and Bioorganic
1
Chemistry, Gottingen. For the preparation of anhydrous
¨
by preparative GC. IR (neat): 1620 cmꢁ1 (C]C); H NMR
CeCl3, finely powdered CeCl3$7H2O was heated at 140 ꢂC/
0.1 Torr to constant weight.
(500 MHz, CDCl3, CHCl3 int): d¼1.35e1.42 (m, 2H), 1.53e
1.77 (m, 6H), 1.83 (t, J¼7 Hz, 2H), 2.24 (dt, J¼7, 2.5 Hz, 2H),
5.97 (t, J¼2.5 Hz); 13C NMR (125.7 MHz, CDCl3, CDCl3 int):
d¼24.81 (t), 30.02 (t), 36.90 (t), 37.83 (t), 58.12 (s), 129.51
(d), 131.90 (s); MS (EI): m/z¼200 (36, Mþ), 121 (100).
C9H13Br requires C, 53.75; H, 6.52. Found: C, 53.92; H, 6.51.
3.2. Spiro[4.4]nonan-1-one tosylhydrazone (12)
To a solution of 138 (30.0 g, 217 mmol) in absolute metha-
nol (375 mL) was added p-toluenesulfonyl hydrazine (43.5 g,
234 mmol) and the mixture was stirred under argon at room
temperature. According to TLC [pentane/ether 1:1; Rf¼0.67
(13), 0.32 (12)], after 94 h the reaction was complete. The
mixture was concentrated (bath temperature 35 ꢂC/15 Torr)
and the residue was washed with cold methanol (2ꢃ60 mL)
and dried to constant weight (4 h at 40 ꢂC/15 Torr, 24 h at
45 ꢂC/0.1 Torr). The combined yield of two identical experi-
ments amounted to 122 g (95%). Colorless solid, mp 145 ꢂC
(lit.19e 146e147 ꢂC). This material was used in the next
step. An analytically pure sample was obtained by crystalliza-
tion from methanol, mp 148 ꢂC. IR (KBr): 3230 (NeH),
1605 cmꢁ1 (C]N); 1H NMR (600 MHz, CD3COCD3,
CD3COCD2H int): d¼1.36e1.44 (m, 2H), 1.50e1.59 (m,
2H), 1.61 (t, J¼7 Hz, 2H), 1.61e1.70 (m, 4H), 1.70 (quint,
J¼7 Hz, 2H), 2.32 (t, J¼7 Hz, 2H), 2.39 (s, 3H), 2.85 (br s,
1H), 7.36 (AA0-part of an AA0BB0-system, 2H), 7.76 (BB0-
part of an AA0BB0-system, 2H), 8.61 (s, 1H); 13C NMR
(125.7 MHz, CD3COCD3, CD3COCD3 int): d¼21.38 (q),
22.11 (t), 25.55 (t), 28.48 (t), 38.29 (t), 39.82 (t), 54.80 (s),
128.74 (d), 129.89 (d), 137.68 (s), 144.10 (s), 172.64 (s);
MS (EI): m/z¼306 (32, Mþ), 121 (100). C16H22N2O2S re-
quires C, 62.72; H, 7.24. Found: C, 62.76; H, 6.95.
3.4. rel-(1R,4R)-1-(Spiro[4.4]non-1-enyl)-dispiro[3.0.4.3]-
dodecan-1-ol (15)
To a stirred solution of 11 (16.0 g, 75 mmol) in anhydrous
THF (250 mL) was added under argon a 1.5 M solution of tert-
butyllithium in pentane (100 mL, 150 mmol) within 1.75 h at
ꢁ78 ꢂC. After additional 45 min at ꢁ78 ꢂC the mixture was
allowed to warm up to 0 ꢂC. The resulting 0.21 M solution of
1-lithio-spiro[4.4]non-1-ene(14) wasusedinthenextstep. Asus-
pension of finely powdered dry CeCl3 (14.8 g, 60 mmol) in anhy-
drousTHF(220 mL)wasstirredatroomtemperatureunderargon
for 2 h. After additionof 7 (5.74 g, 30 mmol), stirring was contin-
uedfor2 huntilthemixturewascooledto0 ꢂCandthesolutionof
1-lithio-spiro[4.4]non-1-ene (14) was added dropwise. Accord-
ing to TLC [pentane/ether 95:5; Rf¼0.35 (15), 0.20 (7)], after
an additional 30 min at room temperature the reaction was com-
plete. The mixturewas diluted with pentane (300 mL) and hydro-
lyzed with saturated ammonium chloride (60 mL). The organic
phase was decanted, the residue was extracted with pentane
(2ꢃ150 mL), and the combined organic phases were washed
with water (2ꢃ300 mL), and dried (MgSO4). The solvents were
distilled off on a rotary evaporator (bath temperature 40 ꢂC/
15 Torr) and the residue (15.5 g) was chromatographed on silica
gel (0.05e0.20 mm) in pentane/ether 95:5 to yield 7.0 g (77%) of
pure 15 as a colorless viscous oil. IR (neat): 3650e3400 cmꢁ1
(OHass); 1H NMR (600 MHz, C6D6, C6D5H int): d¼1.34e1.76
(m, 19H), 1.78 (ddd, J¼12, 7, 2 Hz, 1H), 1.83e1.98 (m, 4H),
3.3. 1-Bromo-spiro[4.4]non-1-ene (11)
To a stirred solution of 12 (29.0 g, 94.5 mmol) in anhydrous
THF (280 ml) was added under argon a 1.6 M solution of

4308
T. Widjaja et al. / Tetrahedron 64 (2008) 4304e4312
2.00e2.06 (m, 1H), 2.09e2.15 (m, 2H), 2.25 (dddd, J¼16, 9, 7,
2 Hz, 1H), 2.34e2.40 (m, 2H), 5.52 (dd, J¼2.5, 2 Hz, 1H);
13C NMR (150.8 MHz, C6D6, C6D6 int): d¼19.19 (t), 24.82
(t), 25.01 (t), 25.40 (t), 25.69 (t), 27.46 (t), 29.43 (t), 34.13 (t),
35.28 (t), 35.99 (t), 36.99 (t), 37.40 (t), 37.42 (t), 38.84 (t),
42.33 (t), 55.19 (s), 58.23 (s), 60.00 (s), 81.60 (s), 125.97 (d),
153.69 (s); MS (EI): m/z¼300 (11, Mþ), 164 (100). C21H32O
requires C, 83.94; H, 10.73. Found: C, 83.62; H, 10.82.
dichloromethane (250 mL) and rearranged at 0 ꢂC by dropwise
addition of boron trifluoride etherate (90 mL). According to
TLC [pentane/ether 8:2; Rf¼0.55 (20), 0.42 (21), 0.18 (24),
0.11 (23)], after the last drop the rearrangement was complete.
The mixture was stirred with potassium carbonate (30 g) until
it was filtered and concentrated (bath temperature 40 ꢂC/
15 Torr) to yield 510 mg of a slightly impure 9:1 mixture of 23
and 24 (1H and 13C NMR). Chromatography on silica gel
(0.05e0.20 mm) in pentane/ether 8:2 yielded 12 mg (2%) of
24 as colorless liquid (purity 85%, 13C NMR) and 327 mg
(62%) of 23 as colorless solid, mp 142e145 ꢂC (purity 99%,
1H NMR). An analytically pure sample was obtained by crystal-
lization from acetone by diffusion of water, mp 146e147 ꢂC.
Compound 23: IR (KBr): 3600e3200 (OHass), 1725 cmꢁ1
(C]O); 1H NMR (600 MHz, C6D6, C6D5H int) d¼1.01e1.05
(m, 1H), 1.19e1.23 (m, 1H), 1.29e1.71 (m, 22H), 1.77e1.83
(m, 1H), 1.94e2.05 (m, 2H), 2.10e2.18 (m, 2H), 2.44e2.54 (m,
2H), 4.53 (symm m, 1H); 13C NMR (125.7 MHz, C6D6, C6D6
int): d¼20.13 (t), 23.53 (t), 23.70 (t), 24.67 (t), 24.71 (t),
31.16 (t), 32.80 (t), 33.50 (t), 35.58 (t), 35.93 (t), 37.34 (t),
37.47 (t), 38.02 (t), 39.43 (t), 40.21 (t), 57.13 (s), 57.94 (s),
58.56 (s), 70.58 (s), 76.49 (d), 221.84 (s); MS (EI): m/z¼316
(28, Mþ), 108 (100). C21H32O2 requires C, 79.70; H, 10.19.
Found: C, 79.46; H, 10.13. Compound 24: 1H NMR
(600 MHz, C6D6, C6D5H int) d¼1.10e1.15 (m, 1H),
1.17e1.90 (m, 26H), 2.07 (symm m, 1H), 2.20 (symm m, 1H),
2.26 (symm m, 1H), 2.32e2.41 (br s, 1H), 3.79 (dd, J¼7.5,
5.5 Hz, 1H); 13C NMR (125.7 MHz, C6D6, C6D6 int): d¼20.87
(t), 22.93 (t), 23.41 (t), 23.53 (t), 24.46 (t), 29.03 (t), 31.65 (t),
31.74 (t), 33.44 (t), 35.26 (t), 35.48 (t), 35.75 (t), 36.18 (t),
36.32 (t), 37.83 (t), 56.53 (s), 56.61 (s), 62.86 (s), 82.56 (d),
224.88 (s).
3.5. rel-(1R,10S,20R,4R)-1-(10,20-Epoxy-spiro[4.4]non-10-yl)-
dispiro[3.0.4.3]dodecan-1-ol (20) and rel-(1R,10R,20S,4R)-1-
(10,20-epoxy-spiro[4.4]non-10-yl)-dispiro[3.0.4.3]dodecan-1-
ol (21)
To a vigorously stirred solution of 15 (500 mg, 1.66 mmol) in
dichloromethane (10 mL) were added a solution of sodium bi-
carbonate (349 mg, 4.15 mmol) in water (6.6 mL) and a solution
of 3-chloro-perbenzoic acid (821 mg, 70% w/w, 3.32 mmol) in
dichloromethane (11 mL). According to TLC [pentane/ether
8:2; Rf¼0.68 (15), 0.55 (20), 0.42 (21)], after 10 min the reaction
was complete. The mixture was diluted with dichloromethane
(60 mL) and the organic phase was extracted with 1 M aqueous
KOH (2ꢃ60 mL), washed with water (2ꢃ60 mL), and dried
(MgSO4). The solvent was distilled off (bath temperature
40 ꢂC/15 Torr) to yield 530 mg of a 3:2 mixture of 20 and 21
(1H and 13C NMR). Attempted separation on silica gel (0.05e
0.20 mm) in pentane/ether 8:2 (column 45ꢃ2.5 cm) led to com-
plete conversion of 21 to a mixture of ketols (see below), while
145 mg (30%) 20 persisted and were obtained pure. Colorless
1
oil. Compound 20: IR (neat): 3650e3350 cmꢁ1 (OHass); H
NMR (600 MHz, C6D6, C6D5H int): d¼1.09e1.14 (m, 1H),
1.16e1.20 (m, 1H), 1.24e1.79 (m, 21H), 1.84e1.98 (m, 3H),
2.16e2.22 (m, 1H), 2.33e2.42 (m, 2H), 2.49e2.55 (m, 1H),
2.56 (s, 1H, OH), 3.31 (s, 1H); 13C NMR (125.7 MHz, C6D6,
C6D6 int): d¼19.98 (t), 25.17 (t,t) (coincidence of two lines),
25.54 (t), 26.02 (t), 28.65 (t), 32.69 (t), 33.90 (t), 34.61 (t),
34.83 (t), 35.90 (t), 36.05 (t), 37.43 (t), 38.94 (t), 53.33 (s),
55.47 (s), 60.01 (s), 63.09 (d), 71.56 (s), 81.32 (s); MS (EI):
m/z¼316 (2, Mþ), 121 (100). C21H32O2 requires C, 79.70; H,
3.6.2. From 20
A solution of analytically pure 20 (5.0 mg, 16 mmol) in
C6D6 (160 mL) was placed in a 3 mm o.d. NMR tube. Addition
of 10 mL (2.7 mmol) of a 0.27 M solution of boron trifluoride
etherate in C6D6 induced complete conversion to a 9:1 mixture
of 23 and 24 (1H and 13C NMR).
1
10.19. Found: C, 79.45; H, 9.97. Compound 21: the H and
13C NMR datawere extracted from the spectra of the 3:2 mixture
of 20 and 21. In the 1H NMR spectrum only the proton of the
epoxide ring could be assigned. In the 13C NMR spectrum all
3.7. 4-Nitrobenzoic acid rel-(6R,7R,15R)-16-oxo-
tetraspiro[4.0.0.0.4.3.3.3]heneicos-15-yl ester (22)
1
resonances could be identified. H NMR (600 MHz, C6D6,
A solution of 4-nitrobenzoic acid chloride (23 mg, 0.12 mol)
and 23 (30 mg, 0.10 mmol) in dry pyridine (200 mL) was stirred
under argon at 90 ꢂC. According to TLC [pentane/ether 8:2;
Rf¼0.31 (22), 0.11 (23)], after 1 h the reaction was complete.
The mixture was diluted with water (2 mL) and extracted with
dichloromethane (4 mL). The extract was washed with 1 N
aqueous HCl, water (2ꢃ3 mL) and dried (K2CO3). The solvent
was evaporated (bath temperature 40 ꢂC/15 Torr) and the
residue (48 mg) purified by thick layer chromatography in
pentane/ether 8:2 to yield 12.4 mg (28%) of 22 as a colorless
solid, mp 193 ꢂC (crystallized from ethanol). IR (KBr):
C6D5H int) d¼3.20 (s, 1H); 13C NMR (125.7 MHz, C6D6,
C6D6 int): d¼19.56 (t), 24.71 (t), 24.72 (t), 25.14 (t), 25.35 (t),
26.22 (t), 28.71 (t), 31.31 (t), 33.89 (t), 34.03 (t), 34.87 (t),
36.04 (t), 37.78 (t), 38.06 (t), 38.10 (t), 53.38 (s), 55.85 (s),
58.75 (s), 61.58 (d), 70.69 (s), 82.48 (s).
3.6. rel-(6R,7R,15R)-15-Hydroxy-tetraspiro[4.0.0.0.4.3.3.3]-
heneicosan-16-one (23) and rel-(6R,7S,15S)-15-hydroxy-
tetraspiro[4.0.0.0.4.3.3.3]heneicosan-16-one (24)
1
3.6.1. From 20 and 21
A 3:2 crude mixture of 20 and 21 (525 mg), obtained by
epoxidation of 15 (500 mg, 1.66 mmol), was dissolved in dry
1720 cmꢁ1 (C]O); H NMR (600 MHz, C6D6, C6D5H int)
d¼1.08 (symm m, 1H), 1.19e1.31 (m, 3H), 1.33e1.74 (m,
17H), 1.76e1.88 (m, 5H), 2.12 (symm m, 1H), 2.26 (dd,

T. Widjaja et al. / Tetrahedron 64 (2008) 4304e4312
4309
J¼18, 8 Hz, 1H), 2.45 (symm m, 1H), 2.71 (symm m, 1H), 5.72
(dd, J¼9, 4 Hz, 1H), 7.56 (AA0-part of an AA0BB0-system, 2H),
7.75 (BB0-part of an AA0BB0-system, 2H); 13C NMR
(125.7 MHz, C6D6, C6D6 int): d¼20.32 (t), 23.55 (t), 23.65
(t), 24.66 (t), 25.01 (t), 30.89 (t), 31.16 (t), 32.71 (t), 36.00 (t),
36.30 (t), 37.17 (t), 37.34 (t), 37.56 (t), 39.34 (t), 40.49 (t),
57.19 (s), 57.73 (s), 58.85 (s), 68.22 (s), 81.50 (s), 123.65 (d),
130.25 (d), 135.20 (s), 150.67 (s), 163.83 (s), 217.61 (s); MS
(EI): m/z¼465 (2, Mþ), 298 (100). C28H35NO5 requires C,
71.92; H, 7.98. Found: C, 72.29; H, 7.78.
41.80 (t), 48.45 (s), 50.16 (s), 55.44 (s), 56.04 (s), 58.69
(s), 58.71 (s), 59.88 (d), 63.58 (d,t) (coincidence of two
lines), 63.80 (t), 217.48 (s), 221.56 (s); MS (EI): m/z¼318
(3, Mþ), 192 (100); HRMS m/z (Mþ) calcd 318.2559, obsd
318.2553.
3.9. Reductive rearrangement of 20: rel-(6R,7R,15R,16R)-
tetraspiro[4.0.0.0.4.3.3.3]heneicosan-15,16-diol (28)
The reductive rearrangement of 20 (36.6 mg, 0.12 mmol)
with LiAlH4 (30.0 mg, 0.80 mmol) in anhydrous ether
(3.5 mL) was performed as described for the reduction of 23
(see Section 3.8). After 1.5 h of reflux, TLC [pentane/ether
1:1; Rf¼0.67 (20), 0.22 (28)] indicated that the reaction was
complete. Hydrolysis and work up yielded 36.8 mg (100%)
of 28 as a colorless solid (purity 95%). The 1H and 13C
NMR data were identical with those of the product given in
Section 3.8.
3.8. Reduction of 23: rel-(6R,7R,15R,16R)-tetraspiro-
[4.0.0.0.4.3.3.3]heneicosan-15,16-diol (28), rel-(1R,5S)-1-
[1-(3-hydroxy-propyl)-cyclopentyl]-dispiro[4.0.4.3]tridecan-
2-one (29), and rel-(1R,5R)-1-[1-(3-hydroxy-propyl)-
cyclopentyl]-dispiro[4.0.4.3]tridecan-2-one (30)
To a stirred suspension of LiAlH4 (600 mg, 15.8 mmol) in
anhydrous ether (30 mL) was added under argon a solution of
23 (1.00 g, 3.16 mmol) in anhydrous ether (40 mL) and the
mixture was heated to reflux. According to TLC [pentane/
ether 1:1; Rf¼0.42 (23), 0.22 (28), 0.13 (29, 30)], after 3 h
the reaction was complete. Water (0.6 mL), 15% aqueous
potassium hydroxide (0.6 mL), and water (1.8 mL) were
added, the liquid was decanted, and the residue was extracted
with ether (3ꢃ25 mL). The combined organic phases were
dried (MgSO4) and concentrated (bath temperature 40 ꢂC/
15 Torr), and the heterogeneous residue (960 mg) was chroma-
tographed on silica gel (0.05e0.20 mm) in ethyl acetate/hex-
ane 1:1 [column 90ꢃ4.5 cm; Rf¼0.52 (28), 0.41 (29, 30)] to
yield 605 mg (60%) of 28 as a colorless solid, mp 153 ꢂC,
and 276 mg (28%) of a 1:1 mixture of 29 and 30 as a colorless
oil. An analytically pure sample of 28 was obtained by crystal-
lization from ethanol by diffusion of water, mp 154e158 ꢂC.
Compound 28: IR (KBr): 3600e3200 cmꢁ1 (OHass); 1H
NMR (600 MHz, CDCl3, CHCl3 int): d¼1.22e1.69 (m,
20H), 1.70e1.77 (m, 3H), 1.83 (symm m, 2H), 1.94 (symm
m, 1H), 2.09e2.25 (m, 4H), 4.56 (dd, J¼9, 7 Hz, 1H), 4.61
(dd, J¼6.5, 6.5 Hz, 1H); 13C NMR (125.7 MHz, CDCl3,
CDCl3 int): d¼19.23 (t), 23.47 (t), 23.91 (t), 24.08 (t), 24.72
(t), 32.20 (t), 33.48 (t), 34.29 (t), 34.40 (t), 34.67 (t), 35.69
(t), 37.04 (t), 38.95 (t), 39.08 (t), 39.50 (t), 55.88 (s), 57.67
(s), 59.99 (s), 65.68 (s), 75.62 (d), 77.36 (d); MS (DCI):
m/z¼336 (63, [MþNH4]þ), 318 (52, [MꢁH2OþNH4]þ).
C21H34O2 requires C, 79.19; H, 10.76. Found: C, 78.93; H,
10.50. The data for 29 and 30 account for the 1:1 mixture:
3.10. rel-(1R,5S)-1-[1-(3-Chloro-propyl)-cyclopentyl]-
dispiro[4.0.4.3]tridecan-2-one (31)
To a stirred solution of a 1:1 mixture of 29 and 30 (240 mg,
0.76 mmol) in dry pyridine (6.0 mL) was added p-toluenesul-
fonic acid chloride (430 mg, 2.26 mmol) under argon at room
temperature. The reaction progress was monitored by TLC
[CH2Cl2; Rf¼0.69 (31), 0.50 (tosylates), 0.05 (29, 30)]. After
24 h the alcohols had been consumed and 70% of the initially
formed tosylate(s) had been chlorinated (1H NMR). To accel-
erate the chlorination, the remaining acid chloride was hydro-
lyzed with water (27 mg, 1.52 mmol), and after an additional
36 h the chlorination was complete (1H NMR). The mixture
was poured into water and extracted with dichloromethane
(4ꢃ40 mL). The combined organic phases were washed with
water (120 mL), dried (MgSO4), and concentrated (bath
temperature 40 ꢂC/15 Torr) to yield 390 mg of a pyridine-
containing liquid. Chromatography on silica gel (0.05e
0.20 mm) in dichloromethane (column 45ꢃ2.5 cm) yielded
83 mg (33%) of 31 as a colorless oil (purity 95%). This mate-
rial was cyclized without further purification. 1H NMR
(600 MHz, CDCl3, CHCl3 int): d¼1.10e1.16 (m, 1H),
1.19e1.26 (m, 2H), 1.30e1.37 (m, 1H), 1.42e1.78 (m,
21H), 1.93e2.00 (m, 1H), 2.02e2.30 (m, 5H), 3.43e3.51
(m, 2H); 13C NMR (125.7 MHz, CDCl3, CDCl3 int):
d¼19.44 (t), 22.99 (t), 24.22 (t), 24.54 (t), 25.27 (t), 28.29
(t), 31.74 (t), 33.77 (t), 33.96 (t), 34.93 (br t), 34.96 (t),
35.71 (t), 36.31 (br t), 37.88 (t), 38.13 (t), 45.96 (s), 49.46
(s), 55.49 (s), 58.04 (br d), 224.44 (s); MS (EI): m/z¼300
(5, MþꢁHCl), 96 (100).
1
IR (neat): 3600e3200 (OHass), 1725 cmꢁ1 (C]O); H NMR
(600 MHz, C6D6, C6D5H int): d¼0.92e0.97 (m, 1H),
0.98e1.04 (m, 1H), 1.04e1.10 (m, 1H), 1.17e1.93 (m,
55H), 2.01 (symm m, 2H), 2.03e2.13 (m, 3H), 2.14 (s, 1H),
3.30e3.34 (m, 2H), 3.36e3.40 (m, 2H); 13C NMR
(150.8 MHz, C6D6, C6D6 int, 70 ꢂC): d¼18.53 (t), 20.02 (t),
23.78 (t), 24.07 (t), 24.80 (t), 24.83 (t), 25.04 (t), 25.11 (t),
25.17 (t), 25.85 (t), 28.71 (t), 29.08 (t), 30.07 (t), 32.30
(t), 34.32 (t), 34.40 (t), 34.59 (t,t) (coincidence of two lines),
34.62 (t), 35.41 (t), 35.87 (t), 36.31 (t), 36.46 (t,t) (coincidence
of two lines), 36.92 (t), 37.02 (t), 38.35 (t), 38.44 (t), 40.09 (t),
3.11. rel-(6R,7S,16R)-7,16-Methano-trispiro[4.0.1.4.5.3]-
eicosan-21-one (32)
To a stirred suspension of potassium hydride (71 mg,
1.8 mmol) in dry toluene (4.0 mL) was added 31 (75 mg,
0.22 mmol) under argon. After the hydrogen evolution had
ceased, the mixture was heated to 110 ꢂC. According to GC

4310
T. Widjaja et al. / Tetrahedron 64 (2008) 4304e4312
[3 mꢃ1/400 all glass system, 15% OV 210 on Chromosorb W/
AW DMCS 60/80 mesh, 230 ꢂC; retention times (min): 13.1
(32), 24.3 (31)], after 2 h the reaction was complete. The mix-
ture was diluted with pentane (8 mL) and hydrolyzed with wa-
ter (4 mL). The phases were separated, the aqueous phase was
extracted with pentane (2ꢃ8 mL), and the combined organic
phases were washed with water (10 mL) and dried (MgSO4).
The solvent was evaporated (bath temperature 40 ꢂC/15 Torr)
and the residue (57 mg) purified by thick layer chromatogra-
phy in pentane/ether 9:1 [Rf¼0.36 (32)] to yield 29.4 mg
(44%) of pure 32 as a colorless oil. 1H NMR (600 MHz,
CDCl3, CHCl3 int): d¼1.12e1.25 (m, 3H), 1.26e1.39 (m,
2H), 1.40e1.73 (m, 21H), 1.78 (symm m, 1H), 1.88e1.98
(m, 2H), 2.02 (s, 1H), 2.40e2.48 (m, 2H); 13C NMR
(125.7 MHz, CDCl3, CDCl3 int): d¼19.21 (t), 20.99 (t),
23.12 (t), 23.92 (t), 24.65 (t,t) (coincidence of two lines),
29.65 (t), 33.41 (t), 33.47 (t), 34.04 (t), 35.90 (t), 36.48 (t),
40.46 (t), 42.62 (t), 44.95 (d), 46.43 (s), 52.73 (s), 57.56 (s),
62.93 (d), 224.44 (s); MS (EI): m/z¼300 (100, Mþ); HRMS
m/z (Mþ) calcd 300.2453, obsd 300.2453.
Compounds 35: 1H NMR (600 MHz, C6D6, C6D5H int):
d¼1.05 (dd, J¼13, 2 Hz, 1H), 1.17e1.80 (m, 24H), 1.83e
1.95 (m, 4H), 2.00 (symm m, 1H), 2.33 (d, J¼7 Hz, 1H),
2.37e2.43 (m, 1H), 5.67 (dd, J¼7.5, 7.5 Hz, 1H), 7.63 (AA0-
part of an AA0BB0-system, 2H), 7.88 (BB0-part of an AA0BB0-
system, 2H); 13C NMR (125.7 MHz, C6D6, C6D6 int):
d¼19.95 (t), 22.45 (t), 23.29 (t), 23.67 (t), 24.50 (t), 25.28 (t),
32.36 (t), 35.25 (t), 35.32 (t), 36.14 (t), 36.16 (t), 38.39 (d),
38.48 (t), 41.06 (t), 41.21 (t), 42.00 (t), 50.28 (s), 54.18 (d),
56.85 (s), 58.51 (s), 80.08 (d), 123.66 (d), 130.40 (d), 135.88
(s), 150.52 (s), 164.62 (s); MS (EI): m/z¼451 (2, Mþ), 284
(100); HRMS m/z (Mþ) calcd 451.2722, obsd 451.2722.
3.13. Trispiro[4.0.1.4.6.3]heneicos-7,15-en-16-one (36)
3.13.1. From 23 with phosphorous oxychloride
To a stirred solution of 23 (100 mg, 0.31 mmol) in dry pyri-
dine (2.2 mL) was added phosphorous oxychloride (121 mg,
0.79 mmol) at 0 ꢂC under argon. After 3 h the mixture was
allowed to warm up to room temperature, and after an additional
20 h, TLC [pentane/ether 7:3, Rf¼0.34 (36), 0.25 (23)] indicated
that the reaction was complete. The mixture was diluted with
water (8 mL) and extracted with ether (15 mL). The organic
phase was washed with 1 N aqueous HCl (2ꢃ6 mL), water
(3ꢃ10 mL), and dried (MgSO4). The solvent was distilled off
(bath temperature 40 ꢂC/15 Torr), and the residue (46 mg) was
purified by thick layer chromatography in pentane/ether 7:3 to
yield 37.4 mg (40%) of 36 as a colorless solid, mp 82e84 ꢂC.
This material was recrystallized from ethanol (2.5 mL) by
diffusion of water (2.5 mL) to yield 18.4 mg of pure 36,
mp 86e88 ꢂC. IR (KBr): 1655 cmꢁ1 (C]O); 1H NMR
(600 MHz, C6D6, C6D5H int): d¼1.05e1.12 (m, 1H), 1.13e
1.55 (m, 21H), 1.61 (dd, J¼12, 7.5 Hz, 1H), 1.82 (ddd, J¼14,
6.5, 1 Hz, 1H), 2.05e2.11 (m, 1H), 2.18e2.26 (m, 2H), 2.36
(ddd, J¼16.5, 10.5, 7.5 Hz, 1H), 2.54 (ddd, J¼19, 13, 6.5 Hz,
1H), 2.84 (dd, J¼16.5, 8.5 Hz, 1H); 13C NMR (125.7 MHz,
C6D6, C6D6 int): d¼21.09 (t), 21.91 (t), 22.94 (t), 23.72 (t),
25.94 (t), 26.96 (t), 35.09 (t), 35.70 (t), 35.96 (t), 36.09 (t),
36.11 (t), 36.34 (t), 37.26 (t), 38.16 (t), 38.75 (t), 49.94 (s),
60.47 (s), 62.15 (s), 139.47 (s), 169.12 (s), 196.60 (s); MS
(EI): m/z¼298 (100, Mþ). C21H30O requires C, 84.51; H,
10.13. Found: C, 84.36; H, 10.11.
3.12. rel-(6R,7S,16R,21R)-7,16-Methano-trispiro-
[4.0.1.4.5.3]eicosan-21-ol (34) and 4-nitrobenzoic acid rel-
(6R,7S,16R,21R)-7,16-methano-trispiro[4.0.1.4.5.3]eicos-21-
yl ester (35)
To a stirred suspension of LiAlH4 (20 mg, 0.51 mmol) in an-
hydrous ether (0.7 mL) was added under argon a solution of 32
(24 mg, 0.080 mmol) in anhydrous ether (1.0 mL) and the mix-
ture was heated to reflux. After 1.5 h, TLC [pentane/ether 8:2;
Rf¼0.56 (32), 0.40 (34)] indicated that the reaction was com-
plete. The mixturewas diluted with ether (4 mL) and hydrolyzed
by successive addition of water (20 mL), 15% potassium
hydroxide (20 mL), and water (60 mL). The liquid phase was
decanted and the residue extracted with ether (3ꢃ4 mL). The
combined organic phases were dried (MgSO4) and concentrated
(bath temperature 40 ꢂC/15 Torr) to yield 19.3 mg (80%) of 34
1
as a colorless oil (purity 95%). H NMR (600 MHz, CDCl3,
CHCl3 int): d¼1.08 (symm m, 1H), 1.20e1.71 (m, 25H), 1.78
(symm m, 1H), 1.86e1.91 (m, 2H), 1.91e2.13 (m, 3H), 2.28
(symm m, 1H), 4.40 (dd, J¼7.5, 7.5 Hz, 1H); 13C NMR
(125.7 MHz, CDCl3, CDCl3 int): d¼19.56 (t), 22.21 (t), 22.86
(t), 23.39 (t), 24.06 (t), 24.91 (t), 31.58 (t), 34.69 (t), 34.78 (t),
35.37 (t), 37.27 (t), 37.84 (t), 40.56 (t), 40.65 (t), 40.70 (t),
44.45 (d), 50.01 (s), 56.09 (d), 56.65 (s), 58.47 (s), 78.40 (d).
To a solution of the crude 34 in dry pyridine (500 mL) was added
4-nitrobenzoic acidchloride (15.4 mg, 0.083 mmol). The result-
ing solution was stirred at 90 ꢂC under argon. According to TLC
[pentane/ether 8:2; Rf¼0.65 (35), 0.40 (34)], after 9 h the
reaction was nearly complete. The mixture was diluted with
water (6 mL) and extracted with dichloromethane (4ꢃ4 mL).
The combined organic phases were washed with 1 N aqueous
HCl (8 mL), water (2ꢃ10 mL), and dried (MgSO4). The solvent
was evaporated (bath temperature 40 ꢂC/15 Torr) and the resi-
due (22 mg) purified by thick layer chromatography in pen-
tane/ether 8:2 to yield 15.4 mg (53%) of 35 as a colorless
solid, mp 164 ꢂC, and 2.4 mg (10%) of recovered 34.
3.13.2. From 23 with methyltriphenoxyphosphonium iodide
To a stirred solution of 23 (50.0 mg, 0.16 mmol) in hexame-
thylphosphoramide (530 mL) was added methyltriphenoxy-
phosphonium iodide (152 mg, 0.34 mmol) under argon and
the mixture was heated to 75 ꢂC. According to TLC [pentane/
ether 8:2, Rf¼0.18 (36), 0.12 (23)], after 16 h the reaction was
complete. Aqueous KOH (2 N, 4 mL) was added, the mixture
was extracted with ether (3ꢃ6 mL), and the combined extracts
were washed with water (2ꢃ8 mL), and dried (MgSO4). The
solvent was evaporated (bath temperature 40 ꢂC/15 Torr) to
yield 34.4 mg (72%) of slightly impure 36 as a highly viscous
1
oil (purity 95%). The H and 13C NMR data were identical
with those of the product given in Section 3.8.

T. Widjaja et al. / Tetrahedron 64 (2008) 4304e4312
4311
3.13.3. From 23 with 4-methylphenyl thiochloroformate
To a stirred solution of 23 (50 mg, 0.16 mmol) in dry pyridine
(580 mL) was added at room temperature under argon a solution
of 4-methylphenyl thiochloroformate (45 mg, 0.24 mmol) in
anhydrous THF (75 mL). After 72 h, TLC [pentane/ether 8:2,
Rf¼0.60, 0.53, 0.46, 0.40, 0.30, 0.35, 0.18 (36), 0.12 (23)] indi-
cated that at least seven products had been formed. The mixture
was worked up as described in Section 3.13.1, and the residue
(64 mg) was subjected to thick layer chromatography in
pentane/ether 8:2. Of the products formed, only 36 (5.2 mg,
twin domain was refined to 0.1346(19). The crystallographic
data (excluding structure factors) have been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC 668187 (36), 668188 (35), and 668189
(22). 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).
Supplementary data
1
11%) could be obtained pure. Its H and 13C NMR data were
1H and 13C NMR spectra of 11, 12, 15, 20e24, 28e32, and
34e37, and data of the X-ray analyses including ORTEP plots
of 22, 35, and 36. Supplementary data associated with this
article can be found in the online version, at doi:10.1016/
j.tet.2008.02.073.
identical with those of the product given in Section 3.8.
3.14. rel-(6R,7R)-Tetraspiro[4.0.0.0.4.3.3.3]heneicosan-
15,16-dione (37)
To a stirred suspension of pyridinium chlorochromate
(371 mg, 1.72 mmol) in dichloromethane (0.8 mL) was added
under argon a solution of 23 (223 mg, 0.71 mmol) in dichloro-
methane (1.5 mL) causing an exothermic effect and the separa-
tion of black grease. According to TLC [pentane/ether 7:3;
Rf¼0.57 (37), 0.25 (23)], after 1.5 h the reaction was complete.
The supernatant liquid was decanted and the residual grease ex-
tracted with ether (3ꢃ1 mL). The combined organic phases
were filtered through silica gel (0.05e0.20 mm, column
14ꢃ1 cm) and concentrated (bath temperature 40 ꢂC/15 Torr)
to yield 199 mg of crude 37 as a highly viscous yellow oil. Thick
layer chromatography in pentane/ether 7:3 yielded 143 mg
(64%) of pure 37 as a colorless solid, mp 116e119 ꢂC. IR
References and notes
1. Gaini-Rahimi, S.; Steeneck, C.; Meyer, I.; Fitjer, L.; Pauer, F.;
Noltemeyer, M. Tetrahedron 1999, 55, 3905e3916.
2. de Meijere, A.; Khlebnikov, A. F.; Kostikov, R. R.; Kozhushkov, S. I.;
Schreiner, P. R.; Wittkopp, A.; Yufit, D. S. Angew. Chem. 1999, 111,
3682e3685; Angew. Chem., Int. Ed. 1999, 38, 3474e3477.
3. 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, 828e842.
4. Fitjer, L.; Gerke, R.; Weiser, J.; Bunkoczi, G.; Debreczeni, J. E.
Tetrahedron 2003, 59, 4443e4449.
5. Fitjer, L.; Kanschik, A.; Gerke, R. Tetrahedron 2004, 60, 1205e1213.
6. 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, 6715e6719; Angew. Chem., Int. Ed. 2004, 43, 6553e
6557.
1
(KBr): 1738, 1705 cmꢁ1 (C]O); H NMR (600 MHz, C6D6,
C6D5H int): d¼1.10e1.15 (m, 1H), 1.15e1.20 (m, 1H), 1.22e
1.48 (m, 12H), 1.49e1.69 (m, 8H), 1.89 (symm m, 1H), 1.96
(ddd, J¼18, 13, 9.5 Hz, 1H), 2.03 (ddd, J¼18, 13, 9.5 Hz,
1H), 2.200 (dd, J¼18, 8.5 Hz, 1H), 2.202 (dd, J¼18,
8.5 Hz, 1H), 2.32 (symm m, 1H), 2.49 (dddd, J¼13, 13, 8.5,
2 Hz, 1H), 2.83 (dddd, J¼13, 13, 8.5, 2 Hz, 1H); 13C NMR
(125.7 MHz, C6D6, C6D6 int): d¼23.06 (t), 23.64 (t), 23.97
(t), 24.24 (t), 25.31 (t), 31.24 (t), 36.00 (t), 36.26 (t), 36.88
(t), 38.23 (t,t) (coincidence of two lines), 38.46 (t), 39.08
(t), 39.47 (t), 42.90 (t), 54.93 (s), 56.06 (s), 60.44 (s),
79.06 (s), 214.22 (s), 215.36 (s); MS (EI): m/z¼314 (100,
Mþ). C21H30O2 requires C, 80.21; H, 9.62. Found: C, 79.95;
H, 9.35.
7. 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.; Rinderspacher, B. C.; Fujisawa, M.; Yamamoto, C.;
Okamoto, Y. Chem.dEur. J. 2006, 5697e5721.
8. Widjaja, T.; Fitjer, L.; Pal, A.; Schmidt, H.-G.; Noltemeyer, M.; Diedrich,
C.; Grimme, S. J. Org. Chem. 2007, 72, 9264e9277.
9. Wang, B. M.; Song, Z. L.; Fan, C. A.; Tu, Y. Q.; Chen, W. M. Synlett 2003,
1497e1499.
10. For possible complications in addition reactions of vinyllithium reagents,
as generated from tosyl hydrazones, see: Chamberlin, A. R.; Bloom, S. H.
Org. React. 1990, 39, 1e83.
11. For reductive lithiations of vinyl bromides with tert-butyllithium, see:
Neumann, H.; Seebach, D. Chem. Ber. 1978, 111, 2785e2812.
12. Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamija, J. J. Am.
Chem. Soc. 1989, 111, 4392e4398.
3.15. X-ray analyses of rel-(6R,7R,15R)-22,
(6R,7S,16R,21R)-35 and 36
13. (a) Tu, Y. Q.; Fan, C. A.; Ren, S. K.; Chan, A. S. C. J. Chem. Soc., Perkin
Trans. 1 2000, 3791e3794; (b) For a review on recent advances in the
semi-pinacol rearrangement of a-hydroxy epoxides and related
compounds, see: Snape, T. J. Chem. Soc. Rev. 2007, 36, 1823e1842.
14. Weiser, J.; Holthausen, M. C.; Fitjer, L. J. Comput. Chem. 1997, 18,
1264e1281.
X-ray data were collected at 100 K on a Bruker three-circle
diffractometer with mirror-monochromated Cu Ka radiation
˚
(l¼1.54178 A) equipped with a SMART 6000 area detector.
15. Allinger, N. L.; Yuh, Y. H.; Lii, J.-H. J. Am. Chem. Soc. 1989, 111,
8551e8556.
The structures were solved by using direct methods with
SHELXS-97 and refined by full-matrix least-squares on F2
for all data with SHELXL-97.25 All non-hydrogen atoms
were refined anisotropically. A riding model with idealized
geometry was employed for all hydrogen atoms. Data for
(6R,7S,16R,21R)-35 were collected on a non-merohedrally
twinned crystal. The fractional contribution of the second
16. (a) Tu, Y. Q.; Yang, L. M.; Chen, Y. Z. Chem. Lett. 1998, 285e286; (b)
Tu, Y. Q.; Sun, L. D.; Wang, P. Z. J. Org. Chem. 1999, 64, 629e633.
17. The stereochemical assignment of 28 as cis-cis follows from a comparison
of the chemical shifts of the methine protons of 23 and 28 with those of
18, 38, 39, and 40. For the data of 18, see: Suemune, H.; Maeda, K.; Kato,
K.; Sakai, K. J. Chem. Soc., Perkin Trans. 1 1994, 3441e3447; For the
data of 38, 39, and 40, see: Chan, A. S.; Lin, C.-C.; Sun, J.; Hu, W.;

4312
T. Widjaja et al. / Tetrahedron 64 (2008) 4304e4312
Li, Z.; Pan, W.; Mi, A.; Jiang, Y.; Huang, T.-M.; Yang, T.-K.; Chen, J.-H.;
Wang, Y.; Lee, G.-H. Tetrahedron: Asymmetry 1995, 6, 2953e2959.
19. With the structurally related but sterically less demanding 2-(4-chloro-
butyl)-cyclopentanone and 2-(4-bromobutyl)-cyclopentanone exclusive
spiroalkylations have been observed: (a) Eilerman, R. G.; Willis,
B. J. J. Chem. Soc., Chem. Commun. 1981, 30e32; (b) Meyer, R.;
OH
H 4.53
OH
OH
H
4.56
(4.61)
Wenschuh, G.; Topelmann, W. Chem. Ber. 1958, 91, 1616e1620; (c)
¨
O
Christol, H.; Mousseron, M.; Plenat, F. Bull. Soc. Chim. Fr. 1959,
543e553; (d) Krapcho, A. P.; Benson, M. J. Am. Chem. Soc. 1962,
84, 1036e1040; (e) Krapcho, A. P.; Donn, R. J. Org. Chem. 1965,
30, 641e644.
H
4.61
(4.56)
20. For a successful elimination on a a-quaternary b-hydroxy ketone with
ˆ
phosphorous oxychloride, see: Tsunoda, T.; Kodama, M.; Ito, S. Tetrahe-
23
28
cis-cis
dron Lett. 1983, 24, 83e86.
21. Hutchins, R. O.; Hutchins, M. G.; Milewski, C. A. J. Org. Chem. 1972, 37,
4190e4192.
OH
H 3.82
OH
OH
O
OH
H 4.26
H 4.15
H 4.00
3.82
OH
3.91 H
OH
H
22. A similar rearrangement of the b-hydroxy ketone 18 has been described:
Carruthers, W.; Orridge, A. J. Chem. Soc., Perkin Trans. 1 1977, 2411e
2416.
OH
40
H
4.15
18
38
cis-cis
39
cis-trans
23. Gerlach, H.; Huong, T. T.; Muller, W. J. Chem. Soc., Chem. Commun.
¨
trans-trans
1972, 1215e1216; See also: Paquette, L. A.; Leone-Bay, A. J. Am.
Chem. Soc. 1983, 105, 7352e7358.
18. For an early report on a chlorination of a p-toluenesulfonate with pyridi-
nium chloride, see: Bensimon, Y.; Ucciani, E. C.R. Acad. Sci. Paris 1973,
276, 683e685.
24. Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 2647e2650.
25. Sheldrick, G. M. Acta Crystallogr., Sect. B 2008, 64, 112e122.