Protoilludane sesquiterpenes: synthesis of (±)-cerapicol, formal synthesis of (±)-sterpurene, and synthesis and absolute configuration of (+)-cerapicol

Article abstract of DOI:10.1016/j.tet.2008.11.066

New approaches to the protoilludane sesquiterpenes (±)-cerapicol and (±)-sterpurene via rearrangement routes are described. The absolute configuration of (+)-cerapicol has been determined and found in accord with a biosynthesis of the natural product via

Full text of DOI:10.1016/j.tet.2008.11.066

Tetrahedron 65 (2009) 1040–1047
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Protoilludane sesquiterpenes: synthesis of (ꢀ)-cerapicol, formal synthesis of
(ꢀ)-sterpurene, and synthesis and absolute configuration of (þ)-cerapicolq
,
Nizar El-Hachach a, Ralf Gerke a, Mathias Noltemeyer b, Lutz Fitjer a
*
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
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 October 2008
Received in revised form 12 November 2008
Accepted 20 November 2008
Available online 27 November 2008
New approaches to the protoilludane sesquiterpenes (ꢀ)-cerapicol and (ꢀ)-sterpurene via rearrange-
ment routes are described. The absolute configuration of (þ)-cerapicol has been determined and found in
accord with a biosynthesis of the natural product via cyclization of humulene to the so-called proto-
illudyl cation and a subsequent 1,2-alkyl shift.
Ó 2008 Elsevier Ltd. All rights reserved.
Dedicated to Professor Erik Jayme on the
occasion of his 75th birthday
Keywords:
Protoilludanes
Cerapicol
Sterpurene
Rearrangements
1. Introduction
contrast, sesquiterpenes with the skeleton of 5 are abound and not
restricted to (ꢁ)-
D
6-protoilludene (ꢁ)-11. Significantly, in all de-
Protoilludane sesquiterpenes arise from cyclization of humu-
lene 1 to the so-called protoilludyl cation 5 and subsequent
transformations, in particular 1,2-alkyl shifts.2 A central part of the
resulting ‘protoilludane tree’ comprises the cations 3–6 and the
rivatives examined,10 the absolute configuration proved in accord
with a biosynthesis via 5. Assuming the same to be true for (ꢁ)-11,
we thought it would be most valuable to determine the absolute
configuration of (þ)-10, and to check its compatibility with a bio-
synthesis of (þ)-10 via 4.
sesquiterpenes (þ)-sterpurene 9,3 (þ)-cerapicol 10,4 (ꢁ)-
D
6-pro-
toilludene 11,5 and (þ)-ceratopicanol 126 derived there from
(Scheme 1). Of these, 104a and 126a were detected last and taken
as evidence that two long-sought links (4, 6) within the bio-
syntheses of (þ)-sterpurene 9 (1-5-4-3-9)3b–d and (þ)-hirsutene 27
(1-5-6-7-8-2) had been identified.8 However, an examination of the
absolute configurations known so far reveals that (þ)-sterpurene
[(þ)-(2aS,3aS,7aS)-9]3e,f and (þ)-ceratopicanol [(þ)-(1R,3aR,3b-
S,6aS,7aS)-12]6b may well be formed via 5, but not (þ)-hirsutene
[(þ)-(3aR,3bR,6aR,7aS)-2].7b–e Indeed, convincing evidence exists
that the biosynthesis of (þ)-2 begins with a cyclization of humu-
lene 1 to ent-6 and proceeds via ent-7 and ent-8 to (þ)-2.9 There-
fore, in the strict sense, hirsutanes are not protoilludanes.
Toward this end, and under the condition of a resolution of
ketone 13, we could have used our previous synthesis of (ꢀ)-10 [13-
14-10(15,16)]4c directly (Scheme 2). However, this synthesis is
hampered by the fact that the trifluoroacetic acid induced rear-
rangement of the vinylcyclobutane 14 proceeds with preferential
protonation at C-3 leading to the undesired norbornanes 15 and 16
as main products. Therefore, two alternatives for a hopefully more
selective conversion of 14 to 10 were examined.
The first alternative was to transform the vinylcyclobutane 14 to
the epoxide 17 prior to a rearrangement. With 17, a ring enlargement
of the 3,3-dimethyl-cyclobutyl ring seemed not to be inhibited, and
even in case that the 1,3-bridge would form first, we expected the
olefin 18 as stabilomer of seven isomers4c and as a potential pre-
cursor of (ꢀ)-10 (14-17-18-10) as the final product (Scheme 2). The
second alternative was to transform the epoxide 17 to the
Of the sesquiterpenes with unknown absolute configuration,
(þ)-cerapicol 10 is the only compound with the skeleton of 4. In
a
-hydroxyketone 19 as a promising candidate for a rearrangement to
the enone 2011 as a potential precursor of the ketone 21. Given the
fact that 21 hadpreviously been transformed to (ꢀ)-sterpurene9,3i,k,l
and the latter to (ꢀ)-cerapicol 10,4b a synthesis of 21 (17-19-20-21)
q
Cascade Rearrangements: Part 25. For part 24, see Ref. 1.
* 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.2008.11.066

N. El-Hachach et al. / Tetrahedron 65 (2009) 1040–1047
1041
H
H
3a
7a
-H+
3b
6a
ent-7
ent-8
H+
+
H
H
H
1
ent-6
(+)-(3aR,3bR,6aR,7aS)-2
(+)-Hirsutene
Humulene
-H+
H
H
H
H
H
+
H
+
H
H
+
+
+
H
+
H
H
H
H
H
H
H
H
3
4
5
6
7
8
+H2O/-H+ +H+/-H2O
H
+H2O/-H+ +H+/-H2O
H
-H+ +H+
-H+ +H+
H
3b
3a
3a
8a
4
7
7a
7b
3a
7a
1
4a
6a 7a
9
OH
2a
OH
H
H
H
H
10
(+)-Cerapicol
11
(+)-(2aS,3aS,7aS)-9
(+)-Sterpurene
(+)-(1R,3aR,3bS,6aS,7aS)-12
(+)-Ceratopicanol
(-)-Δ6-Protoilludene
Scheme 1.
a buffered epoxidation and obtained a single epoxide thought to be
formed by an attack of the reagent from the less hindered side of 14
and formulated as 17 (Scheme 3). On treatment with trifluoroacetic
acid in pentane,17 rearranged to yield a mixture of trifluoroacetates
containing 48% of 22 and 16% of 23. Pure samples were obtained by
a combination of thick layer and gas chromatography, and their
structures were established by NMR. However, the configuration of
22 is tentative and implies that 17 rearranges with inversion of
configuration at the migration origins and termini. In any case, the
preferred formation of 22 indicates that the cyclopentyl cation
formed by enlargement of the 3,3-dimethyl-cyclobutyl ring is
effectively trapped.
H
O
13
1.
MgBr
2. p-TsOH
1. CF3COOH
2. LiAlH4
H
H
OH
OH
2
3
+
H
10
14
15 (41%) (2S*)
16 (25%) (2R*)
(12%)
MCPB
H2
1. HCOOH
2. K2CO3
CF3COO
H
OCOCF3
+
OCOCF3
O
CF3COOH
1. CF3COOH
2. LiAlH4
H
H
OH
O
17
22 (48%)
LiAlH4
23 (16%)
H
9
MCPB 90%
17
18
1. CH3Li
2. SOCl2
C5H5N
1. LDA
HO
H
2. O3
OH
+
OH
O
O
O
H
H
H
H
H
HO
H+
H2
18 (14%)
(57%) 44%
14
24 (44%)
H2SO4/SiO2
(a) H2/PtO2 or
(b) Na/HMPA
19
20
Scheme 2.
21
H
H
H
H
OH
+
OH
+
OH
would not only have constituted a formal synthesis of (ꢀ)-9, but
would also have opened another possibility for a determination of
the absolute configuration of (þ)-10 (21-9-10). The necessary reso-
lution at the stage of ketone 13 seemed feasible.
H
H
(a)
(b)
25 (36%)
26 (30%)
10 (14%)
(100%) 77%
2. Results
Scheme 3.
2.1. Synthesis of ( )-cerapicol [( )-10]
As could have been expected, the reduction of the mixture of
trifluoroacetates with lithium aluminum hydride delivered a mix-
ture of alcohols containing 44% of 24 and 14% of 18. Once again,
To explore the possibility of a synthesis of (ꢀ)-cerapicol [(ꢀ)-10]
via the olefin 18 we subjected the vinylcyclobutane 14 first to

1042
N. El-Hachach et al. / Tetrahedron 65 (2009) 1040–1047
pure samples were obtained by a combination of thick layer and gas
chromatography, and once again their structures resulted from an
analysis of their NMR data. At this stage, a rearrangement of 24 to
18 seemed feasible. Toward this end, we treated a solution of the
mixture of alcohols in hexane with 5% (w/w) sulfuric acid on silica
gel. After 42 h at 50 ꢂC 24 had disappeared and the content of 18
had risen to 57%. Upon chromatography on silica gel in pentane/
ether 7:3, 44% of 18, as referred to 17, were obtained pure.
To our disappointment, the hydrogenation of 18 did not proceed
as desired. A hydrogenation over Pd/C in methanol failed, a hydro-
genation over platinum dioxide in acetic acid yielded the undesired
diastereoisomers 25 (36%) and 26 (30%) instead of 10 (14%) as main
products, and a hydrogenation with sodium in hexamethylphos-
phoramide (HMPA) containing tert-butyl alcohol12 delivered 25
exclusively. Of the products formed, 25 was identified by an anal-
ysis of its 1H NMR, 13C NMR, HETCOR, COSY, and NOESY spectra, 26
by means of an X-ray analysis, and 10 via its known 1H and 13C NMR
data.4c Clearly, the low yield in the hydrogenation step made the
synthesis of 10 via 18 much less attractive than the direct synthesis
from 14. Therefore, the second alternative of a synthesis via ster-
purene 9 was examined.
an analysis of its 1H NMR, 13C NMR, HETCOR, COSY, and NOESY spectra
revealed that this product was the undesired cis-syn-cis configured
ketone 29. Fortunately, switching to lithium in liquid ammonia as the
reducing system15 reversed the stereochemistry. The desired cis-anti-cis
configured ketone 213m (53%) was now the main product, followed by
29 (19%) and 303i,n (13%) (Scheme 4). Interestingly, 21 proved to be
unstable in CDCl3 and slowly epimerized to yield, at equilibrium, a 7:3
mixture with 30. This equilibrium could almost instantaneously be
established by use of Nafion NR 50 in benzene. Of the products formed,
21 was isolated by chromatography on silica gel in pentane/ether 9:1
(Rf¼0.27; yield 34%). Under these conditions, 29 and 30 (Rf¼0.33) were
eluted as mixture. However, pure 30 could be obtained after epimeri-
zation of 21 by gas chromatography.
From a preparative point of view, the overall yield of 21 from 17
(8%) was too low as to allow an economic synthesis of (ꢀ)-cerapicol
10 via (ꢀ)-sterpurene 9 (21-9-10) (Scheme 2). Therefore, for the
determination of the absolute configuration of (þ)-cerapicol
(þ)-10, we turned to our original synthesis of (ꢀ)-10.4c
2.3. Synthesis and absolute configuration of (D)-cerapicol
[( )-10]
The synthesis of enantiopure cerapicol 10 via the vinylcy-
clobutane 14 required a resolution of the racemic ketone (ꢀ)-13.
According to a general method of Johnson et al.16a,b we treated
(ꢀ)-13 with lithiated (þ)-(S)-N,S-dimethyl-S-phenylsulfoximine16c–e
2.2. Formal synthesis of ( )-sterpurene [( )-9]
For the synthesis of the
a-hydroxyketone 19 as a potential
precursor of the enone 20, and hence of the ketone 21, we treated
the epoxide 17 with lithium diisopropyl amide (LDA) and subjected
the resulting allylic alcohol 2713 to an ozonolysis. The reaction
progress was monitored by GC and stopped after 27 had been
consumed. At this time, the reaction mixture contained 70% of the
and obtained four diastereoisomeric b
-hydroxy-sulfoximines (1H
NMR). Upon chromatography on silica gel in pentane/ether 7:3, the
first eluted diastereoisomer (mp 150–152 ꢂC) was obtained pure
and an X-ray analysis disclosed its identity as (SS,1S,3R,4S,5R)-31
20
(>99% ee, [
a]
þ88.3 (c 1.22, CHCl3)). The subsequent fragmenta-
D
desired
a-hydroxyketone 19 and 14% of the d-keto-acid 28 as
product of an ‘anomalous’ ozonolysis.14 Chromatography on silica
gel in pentane/ether 7:3 yielded 60% of pure 19 (mp 59 ꢂC) and 13%
of pure 28 (mp 50–52 ꢂC). The structure and configuration of 19
followed from an X-ray analysis, which indicated that the structure
and configuration of 17 and 27 were also correct. The rearrange-
ment of 19 was induced by treatment with 4 equiv of a 0.15 molar
solution of anhydrous p-toluenesulfonic acid in benzene. After 7 h
at 80 ꢂC, the concentration of 20 had reached its maximum (73%),
and work up and chromatography on silica gel in pentane/ether 7:3
then yielded 20 in 42% isolated yield (Scheme 4).
tion proceeded smoothly and delivered the enantiomerically pure
ketone (1S,4S,5R)-13 (purity 99% GC, >99% ee, [
acetone)) (Scheme 5).
20
a
]
þ78.7 (c 1.41,
D
H
HO
H
H3CN
4
5
3
1
(SS)-C6H5S(O)(NCH3)CH2Li
O
S
76%
O
( )-13
(+)-(SS,1S,3R,4S,5R)-31
In contrast to 18, the hydrogenation of 20 over Pd/C proceeded
smoothlyand yielded a single product. However, to ourdisappointment,
89%
Δ
1. CeCl3/THF
H
H
H
H
HO
4
2.
MgBr
HO
4
O
5
1
5
1
LDA
94%
3
O
78%
17
27
O3
(+)-(1S,3S,4S,5R)-32
(+)-(1S,4S,5R)-13
1. CF3COOH
2. LiAlH4
O
H
O
HOOC
O
H
H
H
OH
OH
OH
HO
1
1
4
p-TsOH
9
7
+
3a
8a
7
7
+
+
2
2
4
4
H
(12%)
28 (14%) 13%
19 (70%) 60%
20 (73%) 42%
(40%)
(20%)
(a) H2/Pd/C/CH3OH or
(b) Li/NH3
(-)-(1R,2S,4S,7R)-15 (+)-(1R,2R,4S,7R)-16 (+)-(3aS,4R,7S,8aS,9R)-10
Scheme 5.
O
O
O
H
H
H
H
H
H
H
The remaining steps were performed as described for the syn-
thesis of (ꢀ)-10.4c Addition of 3,3-dimethyl-cyclobutylmagnesium
+
+
bromide to (1S,4S,5R)-13 yielded the alcohol (1S,3S,4S,5R)-32 (pu-
20
H
30
H
21
rity 99% GC, >99% ee, [
a
]
D
þ22.9 (c 1.39, acetone)), and subsequent
(a) 29 (100%) 80%
(b)
(19%)
treatment with trifluoroacetic acid followed by reduction with
lithium aluminum hydride delivered, with the transient formation
of 14, the norbornane (ꢁ)-(1R,2S,4S,7R)-15 (purity 99% GC, >99%
(13%)
Scheme 4.
(53%) 34%

N. El-Hachach et al. / Tetrahedron 65 (2009) 1040–1047
1043
20
ee, [
16 (purity 99% GC, >99% ee, [
(þ)-cerapicol [(þ)-(3aS,4R,7S,8aS,9R)-10] (purity 99% GC, >99% ee,
a
]
ꢁ33.8 (c 1.35, acetone)), the norbornane (þ)-(1R,2R,4S,7R)-
1H); 13C NMR (125.7 MHz, C6D6, C6D6 int):
d
¼12.64 (q), 18.22 (t),
D
20
a]
þ75.5 (c 1.36, acetone)), and
28.22 (q), 28.87 (q), 29.65 (d), 30.62 (q), 32.12 (s), 32.96 (t), 36.70
(t), 37.58 (t), 42.01 (s), 44.45 (t), 52.01 (d), 72.56 (s), 75.05 (s); MS
(EI): m/z¼220 (3, Mþ), 205 (100), 191 (30), 164 (30), 149 (85), 135
(57), 121 (60), 95 (23), 94 (40), 93 (22), 55 (23), 43 (26). Anal. Calcd
for C15H24O: C, 81.75; H, 10.98. Found: C, 82.04; H, 10.69.
D
20
[
a]
(nm) þ25.2 (589), þ26.3 (578), þ30.0 (546), þ49.9 (436),
þ73.9 (365) (c 1.00, CHCl3)). In the case of (þ)-10, the optical
20
rotations perfectly matched those of the natural product ([a]
(nm) þ24.7 (589), þ26.0 (578), þ29.3 (546), þ48.8 (436), þ73.9
(365) (c 1.00, CHCl3)). This means that the absolute configuration of
the natural product is undoubtedly (3aS,4R,7S,8aS,9R), which is in
accord with a biosynthesis of (þ)-10 via 4 (Scheme 1).
3.3. rel-(1R,2R,20S,4S,7R)-Trifluoroacetic acid 20-trifluoro-
acetoxy-1,4,40,40-tetramethyl-spiro{bicyclo[2.2.1]-
heptan-2,10-cyclopentan}-7-yl ester (22) and trifluoroacetic
acid rel-(4R,7S,9R)-2,2,4,7-tetramethyl-1,2,3,4,5,6,7,8-
octahydro-4,7-methanoazulen-9-yl ester (23)
In summary, we have developed a new synthesis of racemic
cerapicol [(ꢀ)-10] and a new formal synthesis of racemic sterpur-
ene [(ꢀ)-9]. Moreover, we have determined the absolute configu-
ration of natural (þ)-cerapicol [(þ)-10] as (3aS,4R,7S,8aS,9R). This
configuration is in accord with a biosynthesis of (þ)-10 via 4. Of the
methods employed, the rearrangement of 19 to 20 should also have
potential for a synthesis of other systems with a 1,2,3,5,6,7-hexa-
hydro-inden-4-one substructure.
To a stirred solution of 17 (3.20 g, 14.5 mmol) in pentane (45 mL)
was added within 5 min trifluoroacetic acid (15 mL) causing an
exothermic effect. The mixture was stirred at room temperature
and the reaction progress was monitored by GC [column B, 160 ꢂC;
retention times (min): 1.52, 2.53 (23), 3.38, 3.78, 4.42, 5.70, 8.58
(22), 10.76]. After 3 h, the mixture did not change further and
contained 48% 22, 16% 23, and a total of 36% of six unidentified
compounds. Water (250 mL) was added, the layers were separated,
and the aqueous phase was extracted with pentane (2ꢄ50 mL). The
combined organic layers were washed with water (2ꢄ50 mL), dried
(K2CO3), and concentrated (bath temperature 35 ꢂC/15 Torr) to
3. Experimental
3.1. General
IR spectra were obtained with a Perkin–Elmer 298 spectrometer.
1H and 13C NMR spectra were recorded on a Varian VXR 500, VXR
600 or a Bruker AMX 300 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 multiplicities were studied by
ATP and/or DEPT and/or HMQC measurements. Mass spectra were
obtained with a Finnegan MAT 95 spectrometer (EI and HREI) op-
erated at 70 eV. Only fragment ions with a relative intensity of
ꢃ20% are given. Optical rotations were measured on a Perkin–
Elmer 241 digital polarimeter in a 1 dm cell. Analytical and pre-
parative 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 mꢄ1/400 all-glass system,
15% FFAP on Chromosorb W AW/DMCS 60/80 mesh; (B): 3 mꢄ1/400
all-glass system, 15% OV 210 on Chromosorb W AW/DMCS 60/80
mesh. Product ratios were not corrected for relative response. Rf
values are quoted for Machery 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 corrected. Microanalytical de-
terminations were done at the Microanalytical laboratory of the
Institute of Organic and Bioorganic Chemistry, Go¨ttingen.
yield 4.60 g of
a slightly yellow liquid containing the tri-
fluoroacetates. 4.40 g were reduced with LiAlH4 (see Section 3.4)
and 0.20 g were purified by thick layer chromatography in pentane
[SIL G-100 UV254, 20ꢄ20ꢄ0.1 cm; Rf¼0.1–0.2 (22), 0.2–0.3 (23)]
followed by preparative GC on column B [160 ꢂC; retention time
(min): 8.55 (22)] and column A [160 ꢂC; retention time (min): 2.87
(23)], respectively. Colorless liquids. Compound 22: 1H NMR
(600 MHz, CDCl3, CHCl3 int):
d¼0.975 (s, 6H), 0.984 (s, 3H), 1.08 (s,
3H), 1.36–1.50 (m, 5H), 1.57–1.64 (m, 2H), 1.81 (d, J¼14 Hz, 1H), 2.07
(dd, J¼12, 7.5 Hz, 1H), 2.21 (dd, J¼13, 1 Hz, 1H), 4.65 (d, J¼1 Hz, 1H),
5.08 (dd, J¼8, 7.5 Hz, 1H); 13C NMR (125.7 MHz, CDCl3, CDCl3 int):
d
¼14.92 (q), 18.15 (q), 29.63 (t), 30.98 (t), 31.08 (q), 31.24 (q), 34.32
(s), 45.24 (t), 45.88 (s), 46.57 (t), 50.75 (s), 52.48 (t), 53.51 (s), 81.18
1
1
(d), 91.29 (d), 114.51 (q, JCF¼286 Hz), 114.60 (q, JCF¼286 Hz),
2
2
156.68 (q, JCF¼42 Hz), 157.32 (q, JCF¼42 Hz); MS (EI): m/z¼430
(10, Mþ), 316 (38), 289 (40), 208 (26), 207 (59), 206 (100), 107 (23),
95 (69), 94 (22), 93 (24). Anal. Calcd for C19H24F6O4: C, 53.00; H,
5.62. Found: C, 53.04; H, 5.92. Compound 23: 1H NMR (600 MHz,
CDCl3, CHCl3 int):
d¼0.98 (s, 3H), 1.02 (s, 3H), 1.03 (s, 3H), 1.05 (s,
3H), 1.47–1.54 (m, 1H), 1.55–1.56 (m, 2H), 1.63–1.69 (m, 1H), 1.71–
1.77 (m, 1H), 1.95–2.11 (m, 5H), 4.79 (s, 1H); 13C NMR (125.7 MHz,
CDCl3, CDCl3 int):
d¼19.39 (q), 25.12 (q), 29.74 (q), 29.85 (q), 34.53
(t), 36.27 (t), 38.05 (s), 40.02 (t), 40.68 (s), 43.71 (s), 46.43 (t), 50.23
(t), 87.79 (d), 114.71 (q, 1JCF¼286 Hz), 131.28 (s), 136.87 (s), 157.90 (q,
2JCF¼42 Hz); MS (EI): m/z¼316 (100, Mþ), 301 (23), 187 (33), 175
(34), 174 (95), 159 (44); HRMS m/z (Mþ) calcd 316.1650, obsd
316.1650.
3.2. rel-(1S,2R,4R,6S)-4-(3,3-Dimethyl-cyclobutyl)-2,6-
dimethyl-3-oxa-tricyclo[4.2.0.02,4]octane (17)
To a vigorously stirred mixture of 144c (7.6 g, 37 mmol) in
dichloromethane (225 mL) and 0.5 M aqueous sodium bicarbonate
(225 mL) was added within 1 h at 0–5 ꢂC a solution of 3-chloro-
peroxybenzoic acid (19.4 g, 70% w/w, 80 mmol) in dichloromethane
(225 mL). According to TLC [pentane/ether 9:1, Rf¼0.74 (14), 0.58,
0.50 (17)], after additional 0.5 h the reaction was complete. The
phases were separated, the aqueous layer was extracted with
dichloromethane (2ꢄ100 mL), the combined organic layers were
washed with 1 N NaOH (2ꢄ125 mL), brine (125 mL), and dried
(MgSO4). The solvent was distilled off (bath temperature 35 ꢂC/
15 Torr) and the residue (8.1 g) chromatographed on silica gel
(0.05–0.20 mm) in pentane/ether 9:1 (column 90ꢄ6 cm) yielding
7.3 g (90%) of 17 as colorless liquid. 1H NMR (600 MHz, C6D6, C6D5H
3.4. rel-(1R,2R,20S,4S,7R)-20,7-Dihydroxy-1,4,4040-tetramethyl-
spiro{bicyclo[2.2.1]heptan-2,10-cyclopentan} (24) and rel-
(4R,7S,9R)-2,2,4,7-tetramethyl-1,2,3,4,5,6,7,8-octahydro-
4,7-methanoazulen-9-ol (18)
The mixture of trifluoroacetates (4.40 g) obtained as described
in Section 3.3 was dissolved in ether (20 mL) and added under
argon with stirring to a suspension of LiAlH4 (975 mg, 25 mmol) in
ether (100 mL). After 2 h of reflux, TLC in pentane/ether 7:3
[Rf¼0.21, 0.30 (24), 0.42 (18)] indicated that the reaction was
complete. The mixture was hydrolyzed by successive addition of
water (1.0 mL), 15% NaOH (1.0 mL), and water (3.0 mL). The organic
layer was decanted and the residue was extracted with ether
(3ꢄ50 mL). The combined organic layers were dried (MgSO4) and
int):
d
¼1.03 (s, 3H), 1.10 (s, 3H), 1.14 (d, J¼1.5 Hz, 3H), 1.15 (d,
J¼1.2 Hz, 3H), 1.47 (symm m, 1H), 1.58–1.83 (m, 8H), 1.84 (pseudo s,
2H), 1.96 (pseudo t, 1H), 2.27 (pseudo t, 1H), 2.46 (pseudo quint,

1044
N. El-Hachach et al. / Tetrahedron 65 (2009) 1040–1047
concentrated on a rotary evaporator (bath temperature 35 ꢂC/
15 Torr) to yield 4.30 g of a slightly yellow liquid containing 44% of
24 and 14% of 18. 4.00 g were subjected to an acid catalyzed
isomerization (see Section 3.5), and 0.30 g were used for the iso-
lation of 18 and 24 by thick layer chromatography in pentane/ether
7:3 [SIL G-100 UV254, 20ꢄ20ꢄ0.1 cm; Rf¼0.30 (24), 0.42 (18)] fol-
lowed by preparative GC [column B, 160 ꢂC; retention times (min):
3.53 (18), 10.37 (24)]. Compound 18: colorless liquid (purity 99%
to yield 295 mg colorless, partly crystallizing oil. According to GC
[column B, 160 ꢂC; retention times (min): 3.78 (18), 4.81 (25)], this
material contained 70 mg (23%) of unreacted 18 and 225 mg (72%)
of 25. Analytically pure 25 was obtained by preparative GC. Color-
less solid, mp 71 ꢂC. 1H NMR (600 MHz, C6D6, C6D5H int):
d¼0.85 (s,
3H), 0.93 (s, 3H), 0.96 (s, 3H), 0.955 (dddd, J¼14, 13, 5, 1.5 Hz, 1H),
0.985 (d, J¼5 Hz, 1H), 1.08 (s, 3H), 1.13 (d, J¼14 Hz, 1H), 1.25 (ddd,
J¼13, 7, 1.5 Hz, 1H), 1.26 (dddd, J¼13, 13, 5, 2 Hz, 1H), 1.31 (dd, J¼14,
6 Hz, 1H), 1.34 (dd, J¼14, 13 Hz, 1H), 1.41 (ddd, J¼13, 11, 5 Hz, 1H),
1.52 (ddd, J¼14, 10, 1.5 Hz, 1H), 1.58 (ddd, J¼14, 11, 5 Hz, 1H), 1.88
(ddd, J¼14, 10, 2 Hz, 1H), 2.19 (dddd, J¼10, 10, 6, 1.5 Hz, 1H), 2.28
(dddd, J¼14, 10, 10, 7 Hz, 1H), 2.89 (d, J¼5 Hz, 1H); 13C NMR
GC). 1H NMR (600 MHz, CDCl3, CHCl3 int):
d
¼1.009 (s, 3H), 1.017 (s,
3H), 1.023 (s, 3H), 1.04 (s, 3H), 1.32–1.38 (m, 1H), 1.41–1.46 (m, 2H),
1.51–1.54 (m, 1H), 1.56–1.67 (m, 2H), 1.91–1.95 (m, 1H), 1.97–2.05
(m, 3H), 2.07–2.12 (m, 1H), 3.15 (s, 1H); 13C NMR (125.7 MHz, CDCl3,
CDCl3 int):
d
¼19.63 (q), 25.36 (q), 30.04 (q), 30.15 (q), 34.51 (t),
(125.7 MHz, C6D6, C6D6 int):
d
¼25.12 (q), 26.44 (q), 27.57 (t), 29.49
36.37 (t), 37.76 (s), 39.08 (t), 40.43 (s), 44.40 (s), 46.85 (t), 50.48 (t),
84.03 (d), 131.80 (s), 138.43 (s); MS (EI): m/z¼220 (98, Mþ), 205
(46), 191 (39), 190 (36), 189 (86), 187 (24), 175 (42), 174 (100), 163
(24), 159 (59), 150 (22), 135 (46), 121 (30), 119 (34), 107 (40), 105
(35), 95 (73), 93 (28), 91 (43), 77 (27), 55 (30), 43 (34), 41 (54). Anal.
Calcd for C15H24O: C, 81.75; H. 10.98. Found: C, 81.57; H, 11.05.
Compound 24: colorless solid, mp 99 ꢂC (purity 99% GC). 1H NMR
(q), 29.94 (q), 32.67 (t), 34.58 (d), 35.15 (t), 37.52 (s), 40.62 (s), 41.04
(d), 42.69 (t), 44.95 (s), 49.18 (t), 83.65 (d); MS (EI): m/z¼222 (6,
Mþ), 191 (39), 176 (46), 95 (100). Anal. Calcd for C15H26O: C, 81.02;
H, 11.79. Found: C, 81.08; H, 11.55.
3.6.2. Through catalytic hydrogenation: rel-(3aR,4R,7S,8aR,9R)-
2,2,4,7-tetramethyl-decahydro-4,7-methanoazulen-9-ol (25), rel-
(3aR,4R,7S,8aS,9R)-2,2,4,7-tetramethyl-decahydro-4,7-methano-
azulen-9-ol (26), and rel-(3aS,4R,7S,8aS,9R)-2,2,4,7-tetramethyl-
decahydro-4,7-methanoazulen-9-ol (10)
(600 MHz, CDCl3, CHCl3 int):
d
¼0.90 (s, 3H), 0.97 (s, 3H), 0.98 (s,
3H), 1.01 (s, 3H), 1.14 (ddd, J¼12.5, 12, 6 Hz, 1H), 1.26–1.37 (m, 3H),
1.39 (dd, J¼12.5, 3.5 Hz, 1H), 1.46 (br s, 2H), 1.52 (d, J¼14 Hz, 1H),
1.77 (dd, J¼12, 7 Hz, 1H), 1.83 (d, J¼14 Hz, 1H), 1.89 (d, J¼12.5 Hz,
1H), 3.17 (s, 1H), 4.02 (dd, J¼10, 7 Hz, 1H); 13C NMR (125.7 MHz,
Compound 18 (48 mg, 0.22 mmol) was dissolved in acetic acid
(10 mL) and hydrogenated at room temperature at 1.1 atm H2 over
PtO2 (1.0 g) in a shaking gear. After 48 and 72 h, additional PtO2
(2ꢄ0.50 g) was added and after 96 h the hydrogenation was
stopped. According to capillary GC [30 mꢄ0.32 mm i.d. deactivated
CDCl3, CDCl3 int):
d
¼15.32 (q), 18.64 (q), 29.73 (t), 31.37 (q), 31.98
(q), 32.08 (t), 33.17 (s), 45.30 (t), 45.79 (s), 49.99 (t), 50.55 (s), 53.87
(s), 53.99 (t), 74.91 (d), 88.03 (d); MS (EI): m/z¼238 (6, Mþ), 220
(23), 189 (24), 152 (23), 137 (29), 123 (30), 112 (61), 111 (41), 109
(42), 107 (33), 97 (34), 95 (100), 94 (97), 85 (34), 81 (25), 71 (22), 69
(31), 55 (28), 43 (34), 41 (27). Anal. Calcd for C15H26O2: C, 75.57; H,
11.00. Found: C, 75.40; H, 10.82.
fused-silica capillary column coated with 0.25 mm DB FFAP; 5 min
100 ꢂC, 10 ꢂC/min to 220 ꢂC; 0.6 bar of H2; retention times (min):
10.09 (18), 12.71 (26), 13.09 (10), 13.72 (25)], at this time the re-
action mixture contained 20% 18, 36% 25, 30% 26, and 14% 10. The
mixture was filtered, the filtrate was diluted with water (20 mL),
and extracted with pentane (4ꢄ20 mL). The combined extracts
were dried (MgSO4) and concentrated (bath temperature 30 ꢂC/
15 Torr), and the residual oil (52 mg) was chromatographed on
silica gel (0.015–0.035 mm) in pentane/ether 7:3 [column
60ꢄ2 cm; Rf¼0.53 (10), 0.44 (18), 0.39 (25), 0.35 (26)] to yield pure
samples of 10 (colorless liquid), 25 (colorless solid, mp 71 ꢂC), and
26 (colorless solid, mp 79 ꢂC). The 1H and 13C NMR data of 10 were
identical with the literature data,4c and those of 25 with the data
given in Section 3.6.1. Compound 26: 1H NMR (500 MHz, C6D6,
3.5. Acid catalyzed isomerization of 24: rel-(4R,7S,9R)-2,2,4,7-
tetramethyl-1,2,3,4,5,6,7,8-octahydro-4,7-methano-
azulen-9-ol (18)
The crude mixture of alcohols described in Section 3.4 (4.00 g)
was dissolved in hexane (100 mL) and treated with 5% (w/w) H2SO4
on silica gel (0.05–0.20 mm) (4.70 g). The mixture was heated to
50 ꢂC. After 24 and 27 h, more catalyst (2ꢄ2.3 g) was added, and
after 46 h, the reaction was stopped. According to GC [column B,
160 ꢂC; retention times (min): .25, 1.89, 2.46, 3.53 (18), 5.51, 6.09,
7.21, 8.36, 9.13, 10.37 (24)], at this time 24 was consumed and the
content of 18 amounted to 57%. The mixture was filtered, the filtrate
was washed with ether (3ꢄ50 mL), the combined organic layers
were washed with saturated aqueous sodium bicarbonate (100 mL),
water (2ꢄ100 mL), and dried (MgSO4).The solvent was distilled
off (bath temperature 35 ꢂC/15 Torr) and the residue (2.60 g)
chromatographed on silica gel (0.05–0.20 mm) in pentane/ether
7:3 (column 70ꢄ4 cm; control by GC) to yield 1.36 g (44% from 17)
of 18 as colorless liquid (purity 98%, GC). The 1H and 13C NMR data
were identical with those given for the product in Section 3.4.
C6D5H int):
d
¼0.90 (s, 3H), 0.95 (s, 3H), 0.96–1.11 (m, 5H), 1.04 (s,
3H), 1.05 (s, 3H), 1.16–1.24 (m, 1H), 1.29 (dd. J¼12, 6.5 Hz, 1H), 1.31–
1.37 (m, 1H), 1.38–1.50 (m, 4H), 1.83 (ddd, J¼12, 12, 6.5 Hz, 1H), 2.87
(br s, 1H); 13C NMR (75.5 MHz, C6D6, C6D6 int):
d
¼22.73 (q), 25.44
(q), 28.19 (t), 32.34 (q), 32.36 (q), 33.38 (t), 36.55 (s), 36.70 (t), 39.93
(d), 41.23 (t), 42.22 (s), 43.22 (s), 45.63 (d), 47.13 (t), 84.22 (d); MS
(EI): m/z¼222 (8, Mþ), 176 (60), 175 (42), 95 (100), 81 (22), 73 (23),
61 (43), 55 (27), 45 (69), 43 (59), 41 (42); HRMS m/z (Mþ) calcd
222.1984, obsd 222.1984.
3.7. rel-(1S,3R,5S)-3-(3,3-Dimethyl-cyclobutyl)-1-methyl-4-
methylene-bicyclo[3.2.0]heptan-3-ol (27)
3.6. Reduction of 18
To a 1.0 M solution of lithium diisopropyl amide in hexane
(120 mL, 120 mmol) was added at room temperature under argon
with stirring a solution of 17 (7.3 g, 33 mmol) in THF (30 mL). The
mixture was heated to 50 ꢂC and after 1 h the reaction was com-
plete according to TLC [pentane/ether 7:3, Rf¼0.67 (17), 0.52 (27)].
The mixture was hydrolyzed with saturated aqueous ammonium
chloride (40 mL), the organic layer was washed with water
(3ꢄ100 mL), and dried (MgSO4). The solvent was distilled off (bath
temperature 35 ꢂC/15 Torr) and the residue (7.3 g) chromato-
graphed on silica gel (0.05–0.20 mm) in pentane/ether 7:3 (column
90ꢄ6 cm) to yield 6.9 g (94%) of 27 as colorless liquid. According to
3.6.1. With sodium in HMPA: rel-(3aR,4R,7S,8aR,9R)-2,2,4,7-
tetramethyl-decahydro-4,7-methanoazulen-9-ol (25)
To a solution of 18 (308 mg, 1.40 mmol) in dry HMPA (18 mL)
were added at room temperature under argon with stirring small
pieces of sodium (161 mg, 7.00 mmol) causing the mixture to turn
blue. After 0.5, 2.0, and 3.5 h, tert-butanol (3ꢄ0.30 mL) was added.
Afterwards the mixture was stirred overnight. The now colorless
mixture was poured into water (100 mL) and extracted with pen-
tane (3ꢄ50 mL). The extracts were washed with water (2ꢄ50 mL),
dried (MgSO4), and concentrated (bath temperature 30 ꢂC/15 Torr)

N. El-Hachach et al. / Tetrahedron 65 (2009) 1040–1047
1045
GC [column A, 160 ꢂC, retention time (min): 9.65], the material was
99% pure. 1H NMR (600 MHz, C6D6, C6D5H int):
(s, 3H), 1.10 (s, 3H), 1.16 (s, 3H), 1.57–1.64 (m, 1H), 1.61 (d, J¼14 Hz,
1H), 1.65–1.77 (m, 4H), 1.81 (d, J¼14 Hz, 1H), 1.94 (symm m, 2H),
2.18–2.28 (m, 1H), 2.58 (pseudo quint, 1H), 2.77–2.82 (m, 1H), 4.71
(br s, 1H), 4.85 (br s, 1H); 13C NMR (125.7 MHz, C6D6, C6D6 int):
(7 h, 73%). The mixture was washed with saturated sodium bi-
carbonate (60 mL), water (2ꢄ60 mL) and dried (MgSO4). The solvent
was distilled off (bath temperature 30 ꢂC/15 Torr) and the residual
slightly yellow liquid (1.50 g) was chromatographed on silica gel
(0.05–0.20 mm) in pentane/ether 7:3 (column 70ꢄ4 cm; control by
GC) to yield 510 mg (42%) of 20 as colorless liquid (purity 97% GC).
The 1H and 13C NMR data were in accord with the literature data.11
d¼0.96 (s, 1H), 1.05
d
¼23.45 (t), 28.01 (q), 28.93 (q), 30.30 (q), 30.33 (s), 33.21 (t), 35.50
(t), 36.11 (t), 36.36 (d), 42.52 (s), 49.77 (d), 51.47 (t), 83.97 (s), 105.76
(t),163.43 (s); MS (EI): m/z¼220 (2, Mþ),192 (34),177 (45), 165 (50),
164 (80), 159 (27), 149 (43),146 (29),137 (85), 136 (83), 131 (30), 121
(81), 118 (39), 109 (100), 108 (30), 107 (34), 106 (49). Anal. Calcd for
C15H24O: C, 81.75; H, 10.98. Found: C, 81.93; H, 11.00.
3.10. Reduction of 20
3.10.1. Through catalytic hydrogenation: rel-(2aS,3aR,6aR,7aS)-
5,5,7a-trimethyl-decahydro-cyclobuta[f]inden-3-one (29)
A solution of 20 (51 mg, 0.25 mmol) in methanol (8 mL) was
hydrogenated at room temperature and 1.1 atm H2 over 10% Pd/C
(200 mg) in a shaking gear until GC analysis [column B, 180 ꢂC;
retention times (min): 4.26 (29), 6.66 (20)] indicated that the
reaction was complete (1.5 h). The mixture was filtered, the filtrate
was diluted with water (20 mL), and extracted with pentane
(4ꢄ5 mL). The combined extracts were dried (MgSO4) and con-
centrated (bath temperature 20 ꢂC/15 Torr) to yield 41 mg (80%) of
29 as colorless liquid (purity 95% GC). An analytically pure sample
was obtained by preparative GC. IR (neat): 1710 cmꢁ1 (C]O); 1H
3.8. rel-(1S,3R,5S)-3-(3,3-Dimethyl-cyclobutyl)-3-hydroxy-5-
methyl-bicyclo[3.2.0]heptan-2-one (19) and rel-(1S,2S)-2-
[2-(3,3-dimethyl-cyclobutyl)-2-oxo-ethyl]-2-methyl-
cyclobutanecarboxylic acid (28)
An ozone–oxygen mixture (1.5% w/w O3 in O2) was bubbled
through
a solution of 27 (1.50 g, 6.8 mmol) in anhydrous
dichloromethane (10 mL) at ꢁ78 ꢂC. Every 5 min the ozone–oxy-
gen stream was stopped and the reaction progress monitored by
GC [column B, 200 ꢂC; retention times (min): 1.27 (27), 2.45 (19),
3.25, 4.05, 5.01 (28), 6.77]. After 20 min, 27 was consumed and the
mixture contained 70% 19, 14% 28, and a total of 16% of three un-
identified compounds. The still cold mixture was transferred to
a suspension of thiourea (0.52 g, 6.8 mmol) in dichloromethane
(5 mL) cooled to 0 ꢂC and stirred for 40 min at this temperature.
The mixture was filtered, the filtrate was washed with saturated
aqueous sodium bicarbonate (10 mL), water (10 mL), and dried
(MgSO4). The solvent was distilled off (bath temperature 40 ꢂC/
15 Torr) and the residue (1.6 g) chromatographed on silica gel
(0.05–0.20 mm) in pentane/ether 7:3 [column 50ꢄ2.5 cm; Rf¼0.30
(19), 0.12 (28)] to yield 920 mg (60%) of 19, mp 59 ꢂC, and 220 mg
(13%) of 28, mp 50–52 ꢂC, as colorless solids. According to GC, both
compounds were 99% pure. Compound 19: IR (KBr): 1729 cmꢁ1
NMR (600 MHz, CDCl3, CHCl3 int):
d
¼0.90 (s, 3H), 1.02 (dd, J¼11,
11 Hz, 1H), 1.04 (s, 3H), 1.18 (dd, J¼13, 13 Hz, 1H), 1.30 (s, 3H), 1.43
(ddd, J¼13, 8, 2 Hz, 1H), 1.62 (dddd, J¼12, 10, 5, 1 Hz, 1H), 1.62
(ddd, J¼11, 7, 2 Hz, 1H), 1.63 (dd, J¼13, 5 Hz, 1H), 1.78 (ddd, J¼12,
10, 8 Hz, 1H), 1.82 (dd, J¼13, 9 Hz, 1H), 2.11 (dddd, J¼12.5, 10, 10,
5 Hz, 1H), 2.17 (dddd, J¼12.5, 10, 8, 7 Hz, 1H), 2.58 (ddd, J¼10, 7,
1 Hz, 1H), 2.77 (ddd, J¼12, 9, 8 Hz, 1H), 2.89 (ddddd, J¼13, 12, 11, 7,
5 Hz, 1H); 13C NMR (125.7 MHz, CDCl3, CDCl3 int):
d¼17.62 (t),
26.76 (q), 27.29 (q), 28.76 (q), 32.59 (t), 38.29 (s), 39.05 (t), 40.14
(d), 41.16 (t), 43.84 (s), 48.29 (d), 48.52 (t), 50.60 (d), 218.24 (s);
MS (EI): m/z¼206 (37, Mþ), 191 (54), 178 (68), 163 (22), 122 (30),
109 (20), 82 (100), 81 (25), 67 (22), 55 (26); HRMS m/z (Mþ) calcd
206.1671, obsd 206.1671.
(C]O); 1H NMR (600 MHz, CDCl3, CHCl3 int):
d¼1.03 (s, 3H), 1.14 (s,
3.10.2. With lithium in liquid ammonia: rel-(2aS,3aR,6aR,7aS)-
5,5,7a-trimethyl-decahydro-cyclobuta[f]inden-3-one (29), rel-
(2aS,3aR,6aS,7aS)-5,5,7a-trimethyl-decahydro-cyclobuta[f]inden-3-
one (30), and rel-(2aS,3aS,6aS,7aS)-5,5,7a-trimethyl-decahydro-
cyclobuta[f]inden-3-one (21)
3H), 1.25 (s, 3H), 1.62 (symm m, 1H), 1.69–1.76 (m, 2H), 1.76 (d,
J¼14 Hz, 1H), 1.81 (symm m, 1H), 1.88 (pseudo t, 1H), 1.95–2.06 (m,
2H), 2.05 (d, J¼14 Hz, 1H), 2.34 (br s, 1H), 2.35 (symm m, 1H), 2.59
(dd, J¼11, 5.5 Hz, 1H), 2.71 (pseudo quint, 1H); 13C NMR
(125.7 MHz, CDCl3, CDCl3 int):
d
¼18.19 (t), 28.17 (q), 28.52 (q),
To a solution of lithium (42 mg, 6.0 mmol) in liquid ammonia
(60 mL) was added at ꢁ78 ꢂC under argon with stirring a solution of
20 (409 mg, 2.0 mmol) in anhydrous ether (20 mL). After 30 min at
ꢁ78 ꢂC the ammonia was allowed to evaporate. The residue was
diluted with ether (40 mL) and hydrolyzed by careful addition of
saturated aqueous ammonium chloride (10 mL). The layers were
separated, the aqueous layer was extracted with pentane (40 mL),
and the combined organic layers were washed with water
(3ꢄ40 mL) and dried (MgSO4). Most of the solvents were distilled
off over a 20 cm vigreux column and last traces were eliminated in
vacuo (bath temperature 30 ꢂC/15 Torr). According to GC [column
A,180 ꢂC; retention times (min): 7.67 (30), 8.31 (29), 9.73 (21),12.58
(20); column B, 180 ꢂC; retention times (min): 4.42 (29, 30), 5.48
(21), 6.94 (20)], the residue (410 mg) contained still 40% of 20.
Therefore, a second reduction with lithium (69 mg, 10 mmol) in
liquid ammonia (100 mL) under the same conditions was per-
formed. The material thus obtained (408 mg) contained 15% 20, 19%
29, 13% 30, and 53% 21 and was chromatographed on silica gel
(0.05–0.20 mm) in pentane/ether 9:1 [column 50ꢄ2.5 cm; Rf¼0.33
(29, 30), 0.27 (21), 0.10 (20); control by GC] to yield 46 mg (11%) of
a mixture of 29 and 30 as colorless liquid, and 144 mg (34%) of pure
21 as colorless solid, mp 155–157 ꢂC. Pure 30 was obtained by acid
catalyzed epimerization of 21 to give a separable 7:3 mixture of 21
and 30 (see Section 3.11). We observed this epimerization even in
CDCl3. Therefore all spectra were taken in C6D6. Compound 21:
30.11 (q), 30.58 (s), 33.15 (t), 34.39 (d), 34.50 (t), 34.88 (t), 37.83 (s),
47.23 (t), 49.92 (d), 82.05 (s), 221.37 (s); MS (EI): m/z¼222 (17, Mþ),
166 (20), 112 (22), 111 (80), 83 (66), 70 (75), 55 (100), 41 (37). Anal.
Calcd for C14H22O2: C, 75.63; H, 9.97. Found: C, 75.89; H, 9.88.
Compound 28: IR (KBr): 1697 cmꢁ1 (C]O); 1H NMR (600 MHz,
C6D6, C6D5H int):
d
¼0.93 (d, J¼1.8 Hz, 3H), 0.96 (s, 3H), 1.26 (s, 3H),
1.56–1.67 (m, 3H), 1.70–1.78 (m, 1H), 1.94–2.02 (m, 3H), 2.17–2.25
(m, 1H), 2.47 (d, J¼17 Hz, 1H), 2.57 (d, J¼17 Hz, 1H), 2.67 (pseudo
quint, 1H), 2.74 (pseudo t, 1H); 13C NMR (125.7 MHz, C6D6, C6D6
int):
d
¼18.33 (t), 27.44 (q), 28.39 (q), 29.64 (q), 30.74 (t), 31.23 (s),
36.16 (t), 36.45 (t), 39.06 (d), 40.80 (s), 45.25 (t), 48.17 (d), 179.93
(s), 209.00 (s); MS (EI): m/z¼238 (2, Mþ), 111 (70), 83 (94), 70 (21),
56 (62), 55 (100), 41 (60). Anal. Calcd for C14H22O3: C, 70.56; H,
9.30. Found: C, 70.50; H, 9.08.
3.9. rel-(2aS,7aS)-5,5,7a-Trimethyl-1,2,2a,4,5,6,7,7a-octahydro-
cyclobuta[f]inden-3-one (20)
Compound 19 (1.33 g, 6.0 mmol) was added to a 0.15 M solution
of anhydrous p-toluenesulfonic acid in benzene (160 mL,
24.0 mmol) under argon with stirring. Afterwards the mixture was
heated to 80 ꢂC. The rearrangement was monitored by GC [column
B, 200 ꢂC; retention times (min): 1.70, 2.40 (19), 3.33, 3.94 (20)] and
stopped, after the concentration of 20 had reached its maximum

1046
N. El-Hachach et al. / Tetrahedron 65 (2009) 1040–1047
1H NMR (600 MHz, C6D6, C6D5H int):
d
¼0.70 (dd, J¼13, 13 Hz, 1H),
3.13. (D)-(1S,4S,5R)-1,4-Dimethyl-bicyclo[3.2.0]heptan-3-one
[(D)-(1S,4S,5R)-(13)]
0.925 (dd, J¼13, 8 Hz, 1H), 0.93 (s, 3H), 1.27 (dd, J¼13, 5 Hz,
1H), 1.50–1.57 (m, 1H), 1.60 (ddd, J¼13, 8, 2 Hz, 1H), 1.64–1.70 (m,
2H), 1.80–1.92 (m, 3H), 2.66 (dd, J¼10, 6.5 Hz, 1H), 2.68–2.76 (m,
1H), 2.99 (ddd, J¼11, 11, 8 Hz, 1H); 13C NMR (125.7 MHz, C6D6, C6D6
Compound (þ)-31 (2.16 g, 7.0 mmol) was heated under argon to
140 ꢂC. According to TLC [pentane/ether 7:3; Rf¼0.53 ((þ)-13), 0.24
(31)], after 4 h the reaction was complete. The resulting mixture
was chromatographed on silica gel (0.05–0.20 mm) in pentane/
ether 7:3 (column 70ꢄ4 cm) yielding 770 mg (89%) of (þ)-13 as
colorless liquid (purity 99%). The chemical purity was determined
by GC [column B, 160 ꢂC; retention time (min): 1.69 ((þ)-13)]. As
derived from (þ)-31 (>99% ee), (þ)-13 was enantiomerically pure
int):
d
¼16.80 (t), 27.36 (q), 28.17 (t), 28.92 (q), 29.94 (q), 36.99 (d),
37.68 (s), 40.86 (t), 41.55 (s), 42.24 (t), 47.38 (d), 48.99 (t), 52.36 (d),
214.43 (s). For data in CDCl3, see Ref. 3m.
3.11. Acid catalyzed equilibration of 21: rel-(2aS,3aR,6aS,7aS)-
5,5,7a-trimethyl-decahydro-cyclobuta[f]inden-3-one (30)
(>99% ee). [
a]
20 (nm) þ78.7 (589), þ82.7 (578), þ95.0 (546), þ177.3
(436), þ318.9 (365) (c 1.41, acetone). The 1H and 13C NMR data were
identical with those of (ꢀ)-13.4c
To a solution of pure 21 (85 mg, 0.41 mmol) in benzene
(3.0 mL) was added Nafion NR 50 (beads, 10–35 mesh, 200 mg)
and the mixture stirred at room temperature. According to GC
[column B; 180 ꢂC; retention times (min): 4.50 (30), 5.49 (21)],
after 1 h the equilibration to a 7:3 mixture of 21 and 30 was
complete. Pure 30 was obtained by preparative GC. Colorless liq-
3.14. (D)-(1S,3S,4S,5R)-3-(3,3-Dimethyl-cyclobutyl)-1,4-
dimethyl-bicyclo[3.2.0]heptan-3-ol [(D)-(1S,3S,4S,5R)-(32)]
The addition of 3,3-dimethyl-cyclobutylmagnesium bromide to
(þ)-13 (690 mg, 5.0 mmol) was performed as described for (ꢀ)-134c
and yielded 1.75 g (78%) of (þ)-32 as colorless oil (purity 99%). The
chemical purity was determined by GC [column A, 200 ꢂC; re-
tention time (min): 3.91 ((þ)-32)]. As derived from (þ)-13 (>99%
uid. 1H NMR (600 MHz, C6D6, C6D5H int):
d¼0.83 (dd, J¼13, 12 Hz,
1H), 0.92 (dd, J¼12, 11 Hz, 1H), 0.95 (s, 3H), 0.96 (s, 3H), 1.08 (s,
3H), 1.19–1.24 (m, 1H), 1.32 (dd, J¼13, 3.5 Hz, 1H), 1.46 (dd, J¼12,
6.5 Hz, 1H), 1.485 (dd, J¼13, 7.5 Hz, 1H), 1.76–1.83 (m, 2H), 1.84–
1.96 (m, 1H), 1.98 (dd, J¼13, 10 Hz, 1H), 2.03–2.13 (m, 2H), 2.28–
ee), (þ)-32 was enantiomerically pure (>99% ee). [
a
]
20 (nm) þ22.9
2.32 (m, 1H); 13C NMR (125.7 MHz, C6D6, C6D6 int):
d
¼20.28 (t),
(589), þ23.7 (578), þ26.8 (546), þ43.0 (436), þ62.8 (365) (c 1.39,
acetone). The 1H and 13C NMR data were identical with those of
(ꢀ)-32.4c
29.34 (q), 30.54 (t), 31.64 (q), 32.06 (q), 37.03 (s), 38.88 (t), 42.90
(t), 43.39 (d), 44.32 (s), 48.94 (t), 52.08 (d), 56.73 (d), 211.90 (s). For
data in CDCl3, see Refs. 3i,n.
3.15. (L)-(1R,2S,4S,7R)-2-(3,3-Dimethyl-cyclobutyl)-1,4-
dimethyl-bicyclo[2.2.1]heptan-7-ol [(L)-(1R,2S,4S,7R)-(15)],
(D)-(1R,2R,4S,7R)-2-(3,3-dimethyl-cyclobutyl)-1,4-dimethyl-
bicyclo[2.2.1]heptan-7-ol [(D)-(1R,2R,4S,7R)-(16)], and (D)-
(3aS,4R,7S,8aS,9R)-2,2,4,7-tetramethyl-decahydro-4,7-
methanoazulen-9-ol [(D)-(3aS,4R,7S,8aS,9R)-(10)]
3.12. (D)-(SS,1S,3R,4S,5R)-3-(N-Methyl-S-phenyl-
sulfonimidoylmethyl)-1,4-dimethyl-bicyclo-
[3.2.0]heptan-3-ol [(D)-(SS,1S,3R,4S,5R)-(31)]
To a solution of (S)-(þ)-N,S-dimethyl-S-phenylsulfoximine16c–e
20
(1.28 g, 7.5 mmol, [
a]
þ183 (c 1.64, acetone), >99% ee17) in an-
D
hydrous THF (22.5 mL) was added at 0 ꢂC under argon with stir-
The rearrangement of (þ)-32 (667 mg, 3.00 mmol) with tri-
fluoroacetic acid, the subsequent reduction with lithium aluminum
hydride, and the purification of the resulting alcohols (614 mg)
were performed as described for (ꢀ)-324c and yielded (ꢁ)-15 (pu-
rity 99%), (þ)-16 (purity 99%), and (þ)-10 (purity 99%). The chem-
ical purities were determined by GC {column A, 180 ꢂC; retention
times (min): 10.83 [(þ)-16], 11.43 [(ꢁ)-15], 15.01 [(þ)-10]}. As de-
rived from (þ)-32 (>99% ee), all compounds were enantiomerically
ring
a 1.6 M solution of n-butyllithium in hexane (4.7 mL,
7.5 mmol). Afterwards the mixture was stirred for 15 min at room
temperature until it was cooled to ꢁ78 ꢂC. A solution of (ꢀ)-134c
(690 mg, 5.0 mmol) in anhydrous THF (2.5 mL) was added and the
reaction progress monitored by TLC [pentane/ether 7:3; Rf¼0.53
(13), 0.24 (31), 0.14 (3 diastereoisomers)]. After 1.5 h at ꢁ78 ꢂC no
further change was observed. The mixture was hydrolyzed with
saturated aqueous ammonium chloride (2.0 mL), the aqueous
layer was discarded, and the organic layer was dried (MgSO4) and
concentrated (bath temperature 35 ꢂC/15 Torr). The residue (2.0 g)
was chromatographed on silica gel (0.05–0.20 mm) in pentane/
ether 7:3 (column 65ꢄ3.5 cm) to yield 590 mg (76%) of pure
(þ)-31 as colorless solid, mp 150–152 ꢂC (purity 99% 1H/13C). As
derived from (S)-(þ)-N,S-dimethyl-S-phenylsulfoximine (>99%
ee), (þ)-31 was enantiomerically pure (>99% ee). A second eluted
crop of 500 mg (64%) contained 20% (þ)-31 and 80% of a 7:2:1
mixture of three diastereoisomers (13C NMR) and was discarded.
pure (>99% ee). The optical rotations were as follows: compound
20
(ꢁ)-15: [
a]
(nm) ꢁ33.8 (589), ꢁ35.3 (578), ꢁ40.2 (546), ꢁ69.9
(436), ꢁ112.8 (365) (c 1.35, acetone); compound (þ)-16: [
a]
20 (nm)
þ75.5 (589), þ78.8 (578), þ89.6 (546), þ152.2 (436), þ238.2 (365)
(c 1.36, acetone); compound (þ)-10: [
a
]
20 (nm) þ25.2 (589), þ26.3
(578), þ30.0 (546), þ49.9 (436), þ73.9 (365) (c 1.00, CHCl3). The 1H
and 13C NMR data were identical with those previously reported.4c
3.16. X-ray analyses of rel-(1S,3R,5S)-19, rel-
(3aR,4R,7S,8aS,9R)-26, and (D)-(SS,1S,3R,4S,5R)-31
Compound (þ)-31: 1H NMR (600 MHz, C6D6, C6D5H int):
¼1.00
d
(d, J¼7 Hz, 3H), 1.20 (s, 3H), 1.39 (dq, J¼7, 7 Hz, 1H), 1.86–1.94 (m,
2H), 2.08 (d, J¼14 Hz, 1H), 2.15–2.20 (m, 1H), 2.35 (d, J¼13 Hz, 1H),
2.49–2.54 (m, 1H), 2.53 (s, 3H), 2.56–2.61 (m, 1H), 2.86 (d, J¼14 Hz,
1H), 3.32 (d, J¼13 Hz, 1H), 6.70 (s, 1H), 6.95–7.01 (m, 3H), 7.64–
X-ray data were collected on a Stoe IPDSII diffractometer at
200 K (19, 26) and on a Stoe four-circle diffractometer equipped
with a Bruker CCD camera at 273 K (31), respectively, using
graphite-monochromated Mo K
a
radiation (l¼0.71073 Å). The
7.67 (m, 2H); 13C NMR (125.7 MHz, C6D6, C6D6 int):
d
¼8.40 (q),
structures were solved by using direct methods with SHELX-97 and
refined by full-matrix least-squares on F2 for all data with SHELX-
97.18 All non-hydrogen atoms were refined anisotropically. A riding
model with idealized geometry was employed for all hydrogen
atoms. The crystallographic data (excluding structure factors) have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC 705776 (19), 705777 (26),
and 705778 (31). Copies of the data can be obtained, free of charge,
15.23 (t), 28.62 (q), 28.92 (q), 31.54 (t), 43.60 (s), 48.65 (d), 48.72
(d), 53.53 (t), 64.97 (t), 83.01 (s), 129.26 (d), 129.46 (d), 132.64 (d),
139.84 (s); MS (EI): m/z¼308 (2, [MþH]þ), 252 (45), 156 (100), 125
(98), 107 (66); MS (DCI): m/z¼308 (100, [MþH]þ). [
a]
(nm)
20
þ88.3 (589), þ92.2 (578), þ105.7 (546), þ187.7 (436), þ313.9 (365)
(c 1.22, CHCl3). Anal. Calcd for C17H25NO2S: C, 66.41; H, 8.20.
Found: C, 66.54; H, 7.94.

N. El-Hachach et al. / Tetrahedron 65 (2009) 1040–1047
1047
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7. (þ)-Hirsutene. Systematic name (Chemical Abstracts): (þ)-(3aR,3bR,6aR,7aS)-
2,2,3b-trimethyl-4-methylen-decahydro-cyclopenta[a]pentalen. Isolation: (a)
Nozoe, S.; Furukawa, J.; Sankawa, U.; Shibata, S. Tetrahedron Lett. 1976, 17, 195–
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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
1H and 13C NMR spectra of 17–19, 21–31, and data of the X-ray
analyses including ORTEP plots of 19, 26, and 31 are provided.
Supplementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2008.11.066.
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D
6-Protoilludene. Systematic name (Chemical Abstracts): (ꢁ)-(4aR
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* *
7bR
*
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20
17. Optically pure (S)-(þ)-N,S-dimethyl-S-phenylsulfoximine exhibits [
a
]
þ184
6. (þ)-Ceratopicanol. Systematic name (Chemical Abstracts): (þ)-(1R,3aR,3bS,6a-
S,7aS)-3a,5,5,7a-tetramethyl-decahydro-cyclopenta[a]pentalen-1-ol. Isolation
and biosynthesis: (a) See Ref. 4a; Enantioselective syntheses: (b) Mehta, G.;
D
(c 3, acetone) (Ref. 16e).
18. Sheldrick, G. M. Acta Crystallogr., Sect. B 2008, 64, 112–122.