The unexpected formation of bicyclo[2.2.1]heptane derivatives by Lewis acid-catalyzed transannular double cyclization

Article abstract of DOI:10.1039/b005727o

Attempted synthesis of the cyclooctanoid skeleton of taxane molecules, by an intramolecular Lewis acid catalyzed Hosomi-Sakurai cyclization of the allylsilane with the aldehyde moiety in 17, unexpectedly led to the formation of bicyclo[2.2.1]-heptane deri

Full text of DOI:10.1039/b005727o

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The unexpected formation of bicyclo[2.2.1]heptane derivatives by
Lewis acid-catalyzed transannular double cyclization
Vattoly J. Majo, Shuichi Suzuki, Masahiro Toyota and Masataka Ihara*
1
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku University, Aobayama, Sendai, 980-8578, Japan
Received (in Cambridge, UK) 17th July 2000, Accepted 21st August 2000
First published as an Advance Article on the web 2nd October 2000
Attempted synthesis of the cyclooctanoid skeleton of taxane molecules, by an intramolecular Lewis acid catalyzed
Hosomi–Sakurai cyclization of the allylsilane with the aldehyde moiety in 17, unexpectedly led to the formation
of bicyclo[2.2.1]heptane derivatives 18 and 19a. Since the formation of spiro compounds by allylsilane terminated
domino reaction has no precedent in literature, we extended the reaction conditions to unactivated olefins.
Spontaneous aromatization accompanied by bicyclic ring formation was observed in these cases. Bicyclo[2.2.1]-
heptane derivative 11 was also formed in high yield by an intramolecular SmI2 mediated ketyl–olefin coupling of
aldehyde in the hydroxysulfone 10.
To our delight, spontaneous aromatization accompanied by
Introduction
bicyclic ring formation was observed in these cases. A detailed
report of this useful synthetic methodology is disclosed in this
paper.11
Taxol 1 and its analogues have been the focus of organic
Results and discussion
The prerequisite allyl silane 17, which was anticipated to under-
go the key Lewis acid catalyzed transformation to give the
cyclooctanoid framework, was prepared by the following
sequence of reactions. The known compound 4 was prepared
by an alternative strategy from the reported procedure,12 using
Diels–Alder reaction as the key step (Scheme 1). Thus, acetate
213 on treatment with acrolein at Ϫ78 ЊC in the presence of a
stoichiometric amount of BF3ؒEt2O gave the carbaldehyde 3 in
82% yield. The aldehyde 3 was reduced using NaBH4 in meth-
anol and protected as the TBDMS ether using TBDMSCl and
Et3N in the presence of 4-dimethylaminopyridine (DMAP).
The acetate functionality was then reduced to the correspond-
ing hydroxy group by diisobutylaluminium hydride (DIBAL-H)
at 0 ЊC to yield the alcohol 4 in an overall yield of 89% for three
steps from 3. Sulfenylation of 4 was carried out by adopting
Hata’s protocol using (PhS)2 and Bu3P in pyridine.14 The select-
ive oxidation of the sulfide 5 to the corresponding sulfone,
without cleaving the TBDMS ether, could not be achieved by
Oxone in a reasonable yield, even under buffered conditions in
the presence of Na2HPO4.15 The best results were achieved by
carrying out the oxidation with Oxone followed by reintro-
ducing the TBDMS protection into the crude hydroxysulfone
using TBDMSCl and Et3N to furnish the sulfone 6 in 96%
overall yield for 2 steps.
After securing a high yield route to the A ring precursor
6, various conditions were examined to effectively carry out
coupling of the sulfone with 1-methylcyclohexa-2,5-diene-1-
carbaldehyde 7.16 BuLi failed to effect the desired reaction even
in the presence of HMPA or mild Lewis acids. However, the
sulfonyl carbanion generated using lithium diisopropylamide
(LDA) at 0 ЊC could be efficiently coupled with cyclohexadiene
carbaldehyde 7 at Ϫ78 ЊC to furnish the hydroxysulfone 8 in
80% yield as a mixture of two diastereoisomers in the ratio of
2.2:1. The reverse quenching of the reaction mixture by pour-
ing into a suspension of saturated NH4Cl in Et2O was critical to
achieve product formation in a reasonable yield, presumably,
due to the reversibility of the reaction. Based on the steric
research in the past decade owing to their unique structural
features and significant biological activities.1,2 After the iso-
lation of Taxol from the barks of the Pacific yew trees and its
structural elucidation,3 synthetic approaches toward the struc-
turally complex polycyclic diterpenoids of Taxus family have
provided a valuable forum for assessing the current state-of-the-
art of organic methodology.4 Although the efforts of six groups
have so far culminated in the total synthesis of Taxol,5
the fascinating array of contiguous stereocentres, functionality
embellished skeleton and the sterically encumbered eight mem-
bered ring of this molecule continue to cast its spell over syn-
thetic organic chemists.5 Undoubtedly, the emergence of Taxol
as a potent anticancer drug has served to spearhead a recent
spurt in synthetic activity directed towards cyclooctanoid sys-
tems.6 On our part, we have reported a quantitative construc-
tion of the BC ring system through a KHMDS mediated
intramolecular Michael addition of a sulfone stabilized carb-
anion to a dienone moeity.7 However, due to preliminary dif-
ficulties encountered in adopting this useful methodology for
the construction of a highly functionalized ABC skeleton from
a preformed AC ring system, we undertook studies on some
alternative convergent synthetic approaches in this direction.
These include an intramolecular Lewis acid catalyzed Hosomi–
Sakurai cyclization8 of the aldehyde with the allylsilane in
compound 17 and a SmI2 mediated intramolecular cycliz-
ation of the aldehyde with activated olefins.9 However, these
strategies, which were envisaged to bring about the tactical eight
membered ring closure of advanced AC ring precursor, led to
the exclusive formation of bicyclo[2.2.1]heptane rings. The
unique features of the allylsilane terminated domino reaction,10
which furnished spirocyclization resulting in the formation of
bicyclo[2.2.1]heptane derivative, prompted us to extend this
useful methodology for the reaction of unactivated olefins.
DOI: 10.1039/b005727o
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This journal is © The Royal Society of Chemistry 2000
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Scheme 2 Reagents and conditions: i, HF–Py, THF–Py, RT; ii, 5 mol%
TPAP, NMO, 4 Å MS, CH2Cl2, RT; iii, SmI2, HMPA, THF, 0 ЊC;
iv, 5 mol% TPAP, NMO, 4 Å MS, CH2Cl2, RT.
1776 cmϪ1. The geometry about the double bond of the ketone
was established by NOE measurements. Although sulfone ter-
minated ketyl–olefin couplings are documented in the liter-
ature,21 there is no precedent for the efficient construction
of bicyclo[2.2.1]heptanol derivatives under these conditions.22
Also, the exclusive ketyl–olefin reductive coupling using SmI2 in
the presence of HMPA to give a bicyclo[2.2.1]heptane system is
in marked contrast with the Julia–Lythgoe olefination of a
hydroxysulfone under similar conditions in the absence of
a carbonyl moiety (vide infra).23
Scheme 1 Reagents and conditions: i, acrolein, BF3ؒEt2O, CH2Cl2,
Ϫ78 ЊC; ii, NaBH4, MeOH, 0 ЊC; iii, TBDMSCl, DMAP, Et3N,
CH2Cl2, 0 ЊC–RT; iv, DIBAL-H, Et2O, 0 ЊC; v, (PhS)2, Bu3P, Py, RT; vi,
Oxone, THF–MeOH–H2O, 0 ЊC–RT; vii, TBDMSCl, DMAP, Et3N,
CH2Cl2, 0 ЊC–RT; viii, LDA, THF, Ϫ78 ЊC.
interactions in the Felkin–Ahn model, it could be presumed
that the major diastereoisomer would be 8a, in which the bulky
CH2OTBDMS group occupies an equatorial position in the
cyclohexene ring and the hydroxy and phenyl sulfonyl groups
are oriented syn to each other.
A closer examination of the molecular model of compound 8
revealed that the olefinic moiety of the cyclohexadiene and the
carbaldehyde on the A-ring are brought to close proximity by
the introduction of a cis-double bond between the A and C
ring. Accordingly, attempts were made to protect the secondary
hydroxy group of 8 as its acetate to carry out the Julia–Lythgoe
elimination (Scheme 3). However, the neopentyl environment
of the neighbourhood spoiled all the efforts in this direction
and the protection of the alcohol could not be achieved even
under drastic conditions. Using Birch conditions, the elimin-
ation of hydroxysulfone could be carried out to furnish the
trans-isomer 14, albeit, in low yield. SmI2 in THF also failed to
induce the elimination of hydroxy sulfone.24 Fortunately, under
modified conditions developed by us,25 Julia–Lythgoe elimin-
ation could be effected in high yield by SmI2 in the presence of
HMPA.26 The best results were obtained by the rapid addition
of a solution of the hydroxysulfone in THF to 0.1 M solution
of SmI2 in THF containing 6 equivalents of HMPA at RT.
The trans-double bond was then isomerized under photo-
chemical conditions. The isomerization was induced by irradiat-
ing a solution of the trans-isomer 13 in benzene in a Pyrex glass
apparatus, using 2-acetylnaphthalene as the sensitizer and
using a 450 W Hg lamp as the source of light, maintaining the
reaction temperature below 5 ЊC. Other sensitizers such as
benzophenone and 1-acetylnaphthalene did not give satisfac-
At this stage, we decided to explore the feasibility of ketyl–
olefin reductive coupling using Lewis acids to construct the B
ring, as represented in Scheme 2. For this purpose, attempts
were made to cleave the TBDMS ether of 8 using TBAF in
THF, which resulted in the cleavage of the hydroxysulfone
moiety in a retro-aldol fashion. Aqueous acetic acid also failed
to furnish the desired dihydroxy sulfone in good yield. However,
the TBDMS ether could be cleaved in excellent yield by using
70% HF in pyridine buffered with pyridine according to Trost’s
procedure.17 The selective oxidation of the primary alcohol in
compound 9 to give 10 was achieved in quantitative yield using
5 mol% of tetrapropylammonium perruthenate (TPAP)18 in the
presence of 4-methylmorpholine N-oxide as the reoxidant in
CH2Cl2 and quenching the reaction after 10 min. Interestingly,
when the reaction is carried out over a longer duration, allylic
oxidation of the cyclohexadiene moiety is observed in consider-
able yields.19
With the desired aldehyde 10 in hand, several attempts were
made to carry out the cyclization in the presence of Lewis acids.
However, all these efforts were thwarted by the presence of the
hydroxysulfone moiety and an inseparable mixture of products
was obtained under these conditions. Since, a Lewis acid
catalyzed reaction failed to induce the formation of the eight-
membered B ring, it was intriguing to check the reactivity of
this aldehyde towards SmI2.20 Interestingly, the reaction exclus-
ively furnished bicyclo[2.2.1]heptanol derivative 11 in 71%
yield. Oxidation of the alcohol using TPAP quantitatively
furnished the corresponding ketoenone 12, which exhibited a
characteristic carbonyl absorption of five-membered ketones at
1
tory results for the reaction. The H NMR spectrum of the
cis-isomer 14 revealed that the compound exists as two conform-
ational isomers as in the case of cis-β-ionol derivatives.27
After the successful installation of the desired cis-double
bond, we focussed our attention on introducing a suitable
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Scheme 3 Reagents and conditions: i, SmI2, HMPA, THF, RT;
ii, hν (450 W), 2-acetylnaphthalene, benzene, 0–5 ЊC; iii, TBAF, THF,
0 ЊC–RT; iv, BuLi, TMEDA, TMSCl, THF, 0 ЊC; then 0.5 M H2SO4–
THF; v, 3 mol% TPAP, NMO, 4 Å MS, CH2Cl2, RT.
functional group at the allylic position of the cyclohexadiene
moiety, which could facilitate an intramolecular ketyl–olefin
coupling to provide the eight membered ring. Initially, an
intramolecular SmI2 mediated coupling of the aldehyde with
the dienone moiety was attempted. After deprotection of the
silyl group, the alcohol 15 was subjected to a double oxidation
using TPAP in a mixed solvent system of CH3CN and CH2Cl2
to provide the corresponding keto–dienone precursor in 45%
yield which was treated without further purification with SmI2
in the presence of HMPA. Unfortunately, the reaction fur-
nished a complex mixture of products, which could not be
characterized by conventional techniques of analysis. Various
attempts made to introduce a leaving group such as a sulfone or
a chloride at the allylic position of the cyclohexadiene moiety
also met with failure.
We then planned to attempt a Hosomi–Sakurai coupling
of the allylsilane in the hope of forming the elusive eight-
membered ring. The allyl silane 17 was prepared by the follow-
ing sequence of reactions. The dianion derived from alcohol 15
by treatment with BuLi in the presence of tetramethylethylene-
diamine (TMEDA) was subjected to disilylation with TMSCl.
The silyl protection of the hydroxy group was then selectively
cleaved in a 1:1 mixture of 0.5 M H2SO4–THF to give 16 in 94%
overall yield as a complex mixture of two diastereoisomers and
the corresponding atropisomers. Oxidation of the resultant
diastereoisomeric mixture of alcohols using Ley’s method18
afforded 17 quantitatively.
Scheme 4 Lewis acid-catalysed cyclization yielding bicyclo[2.2.1]-
heptane derivatives.
phile should take place in an anti fashion; i.e. with a simple
1,3-transfer of chirality.28 Therefore, it could be expected that
only one of the diastereoisomers of 2 in which the silyl sub-
stituent is oriented trans to the angular methyl group could lead
to the observed product as represented in the transition state A
whereas the other isomer might undergo decomposition on
treatment with a Lewis acid. The formation of spiro compound
18 as a single isomer further indicates the concerted nature of
the cyclization via the transition state A. Unfortunately, various
efforts to separate the two diastereoisomers of 17 and investi-
gate the reactivity of aldehydes derived from the individual
isomers towards Lewis acid were not successful. To the best of
our knowledge, an allylsilane terminated domino reaction to
accomplish spirocyclization is unprecedented in the literature.
In addition, the reaction provides an expeditious assembly of
bicyclo[2.2.1]heptane derivatives combined with spirocycliz-
ation in a sterically encumbered environment.
This prompted us to explore further the generality of the
cyclization, in order to firmly establish the role played by the
silyl group. For this purpose, the olefinic aldehydes 20 and 21
carrying no silyl groups were treated with various Lewis acids
(Scheme 5). The aldehydes in turn were prepared by desilylation
followed by TPAP oxidation of the corresponding alcohols.
Treatment of 20 with SnCl4 in CH2Cl2 provided the aromatized
products 19a and 19b in 90% yield as a 1:1:6:6 mixture of four
isomers. On the other hand, similar treatment of the cis isomer
21 gave 19a and 19b in 50% yield, again as a mixture of four
stereoisomers. The mixtures were oxidized using Ley’s
method18 to quantitatively give a mixture of two stereoisomers
22 and 23. Geometry about the double bond of these ketones
was unequivocally established by NOE measurements.
Next, Lewis-acid catalyzed cyclization of 17 was investigated
under a variety of reaction conditions (Scheme 4). When 17 was
treated with TiCl4 (1.2 equiv) in CH2Cl2 at Ϫ40 ЊC, the spiro
compound 18 was obtained in 28% yield as a single stereo-
isomer along with 19a in 5% yield as a mixture of two isomers.
The structure and the relative stereochemistry of the compound
were established on the basis of its NOESY spectrum and the
long range coupling observed in the COLOC spectrum. Since
the SE2Ј reaction of allylsilanes is mechanism-controlled, loss
of the silyl group and the subsequent reaction with the electro-
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The resultant solution was vigorously stirred with 10% aq.
NaOH for 30 min. The phases were separated and the organic
layer was washed with water, brine, dried over MgSO4 and con-
centrated under vacuum. The crude product was column
chromatographed (hexane–AcOEt 50:1) to provide the sulfide
as a colourless liquid (22.4 g, 95%) (Found C, 70.8; H, 9.8; S,
8.0. C23H38OSSi requires C, 70.7; H, 9.8; S, 8.2%); νmax(neat)/
cmϪ1 1580, 1465, 1250; δH (300 MHz, CDCl3) 0.05 (6H, s,
t
2 × CH3Si), 0.90 (9H, s, Bu), 0.94 (3H, s, 6-CH3), 1.19 (3H, s,
6-CH3), 1.36–1.52 (2H, m, 4-H2), 1.77 (3H, s, 2-CH3), 1.78–1.87
(1H, m, 5-H), 1.95–2.05 (2H, m, 3-H2), 3.38 (1H, dd, J = 9.5, 8.4
Hz, CHHOTBDMS), 3.55–3.64 (2H, m, CH2SPh), 3.78 (1H,
dd, J = 9.5, 3.7 Hz, CHHOTBDMS), 7.11–7.18 (1H, m, ArH),
7.23–7.34 (4H, m, ArH); m/z 390 (Mϩ).
5-tert-Butyldimethylsiloxymethyl-1-phenylsulfonylmethyl-2,6,6-
trimethylcyclohex-1-ene 6
Oxone (4.0 g, 6.5 mmol) was added in portions to a solution of
the sulfide 5 (900 mg, 2.31 mmol) in THF–MeOH–H2O (3:1:1,
22.5 cm3) at 0 ЊC. After stirring for 4 h at RT, the reaction
mixture was concentrated under vacuum, the residue was dis-
solved in water, and repeatedly extracted with AcOEt. The
combined organic layer was washed with brine, dried (MgSO4),
and concentrated. The crude residue was dissolved in CH2Cl2
(20 cm3) and treated with TBDMSCl (491 mg, 3.26 mmol),
DMAP (27 mg, 0.22 mmol) followed by Et3N (910 mm3, 6.53
mmol) at 0 ЊC. The reaction mixture was allowed to warm to
RT and stirred further for 12 h. The reaction mixture was
diluted with Et2O, washed with water, brine, dried over MgSO4
and concentrated under vacuum. The crude product was puri-
fied by column chromatography (hexane–AcOEt 95:5) to give a
colourless solid (880 mg, 96%). Mp 77–78 ЊC (Found C, 65.2;
H, 8.8; S, 7.3. C23H38O3SSi requires C, 65.4; H, 9.1; S, 7.6%);
νmax(CHCl3)/cmϪ1 1305, 1155; δH (300 MHz, CDCl3) 0.05 (6H,
s, 2 × CH3Si), 0.89 (9H, s, tBu), 0.93 (3H, s, 6-CH3), 1.12 (3H, s,
6-CH3), 1.53–1.55 (2H, m, 4-H2), 1.68 (3H, s, 2-CH3), 1.79–1.88
(1H, m, 5-H), 2.04–2.12 (2H, m, 3-H2), 3.38 (1H, dd, J = 9.5, 8.8
Hz, CHHOTBDMS), 3.76 (1H, dd, J = 9.5, 3.7 Hz, CHHO-
TBDMS), 3.91–4.02 (2H, m, CH2SO2Ph), 7.50–7.65 (3H, m,
ArH), 7.88–7.95 (2H, m, ArH); δC (75 MHz, CDCl3) Ϫ5.3,
18.3, 20.9, 22.0, 23.3, 26.0, 28.3, 31.7, 36.7, 47.0, 57.8, 63.5,
126.0, 127.8, 129.1, 133.2, 139.5, 141.8; m/z 281 (Mϩ Ϫ SO2Ph).
Scheme 5 Reagents and conditions: i, SnCl4, CH2Cl2, Ϫ30 ЊC; ii, SnCl4,
CH2Cl2, Ϫ30 to Ϫ10 ЊC; iii, 3 mol% TPAP, NMO, 4 Å MS, CH2Cl2, RT.
In conclusion, in pursuit of a synthetic methodology for the
construction of the ABC skeleton of taxoid molecules, we have
unravelled some novel methods for the assembly of bicyclo-
[2.2.1]heptane derivatives. These methods include an intra-
molecular SmI2 mediated ketyl–olefin coupling and a Lewis
acid catalyzed Hosomi–Sakurai reaction of an olefin with an
aldehyde. Especially noteworthy is the domino reaction in
which an allylsilane terminated spirocyclization is triggered by
Lewis acid catalyzed ketyl–olefin coupling to yield a bicyclo-
[2.2.1]heptane derivative.
Experimental
General
All moisture and air sensitive reactions were carried out in
an atmosphere of argon. Diisopropylamine and triethylamine
were freshly distilled from calcium hydride prior to use.
TMEDA and HMPA were distilled from calcium hydride and
stored over 4 Å molecular sieves. All other reagents and sol-
vents were used as obtained from commercial suppliers. Melt-
ing points were measured on a Yanaco micro melting point
apparatus and are uncorrected. 1H NMR spectra were recorded
using a JEOL GX-500 at 500 MHz, a Hitachi R-3000 or
Varian Gemini-2000 at 300 MHz for samples in CDCl3 using
tetramethylsilane as the internal standard. 1H NMR data
are presented in the following order: chemical shift, multiplicity
[s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet),
br (broadened)], coupling constant(s) (J/Hz) and integration.
13C NMR spectra were recorded using a Varian Gemini-2000 at
75 MHz for samples in CDCl3. IR spectra were recorded with a
JASCO IR Report-100 or Shimadzu FT-IR 8300 spectro-
photometer. Mass spectra were taken on JEOL-DX-300 spec-
trometer. Flash column chromatography was carried out on
neutral silica gel (230–400 mesh).
5-tert-Butyldimethylsiloxymethyl-1-[2-(1-methylcyclohexa-2,5-
dien-1-yl)-2-hydroxy-1-phenylsulfonylethyl]-2,6,6-trimethyl-
cyclohex-1-ene 8
A solution of diisopropylamine (2.32 cm3, 16.6 mmol) in THF
(60 cm3) was treated with BuLi (1.56 M solution in hexane, 9.10
cm3, 14.2 mmol) and stirred for 30 min at 0 ЊC. A solution of
sulfone 6 (5.00 g, 11.8 mmol) in THF (25 cm3) was added drop-
wise at 0 ЊC and stirred for further 30 min. The reaction mixture
was cooled to Ϫ78 ЊC and a solution of the aldehyde 7 (1.88 g,
15.4 mmol) in THF (15 cm3) was added dropwise and stirred for
further 1 h. The reaction was quenched by pouring into a sus-
pension of saturated NH4Cl in Et2O. The aqueous layer was
extracted with Et2O, and the combined organic layer was
washed with brine, dried over MgSO4, and concentrated under
vacuum. The crude product was purified by flash column
chromatography (hexane–Et2O–CH2Cl2 10:1:1) to give a col-
ourless solid (5.13 g, 80%). Mp 109 ЊC (decomp.) (Found C,
68.4; H, 8.9; S, 5.8. C31H48O4SSi requires C, 68.3; H, 8.9; S,
5.9%); νmax(CHCl3)/cmϪ1 3400; δH (500 MHz, CDCl3) 0.03
(1.88H, s, CH3Si), 0.05 (2.06H, s, CH3Si), 0.06 (2.06H, s,
CH3Si), 0.88 (2.81H, s, tBu), 0.90 (6.19H, s, tBu), 0.98 (0.94H, s,
CH3), 1.02 (2.06H, s, CH3), 1.11 (2.06H, s, CH3), 1.14 (0.94H,
s, CH3), 1.16 (2.06H, s, CH3), 1.18 (0.94H, s, CH3), 1.43 (0.94H,
s, 2-CH3), 1.44–1.60 (1H, m, 4-HH), 1.62 (2.06H, s, 2-CH3),
1.64–1.81(2H, m, 4-HH and 5-H), 1.96–2.14 (2H, m, 3-H2),
2.60–2.67 (2H, m, 4Ј-H2), 3.24 (0.31H, dd, J = 9.7, 9.2 Hz,
5-tert-Butyldimethylsiloxymethyl-1-phenylthiomethyl-2,6,6-
trimethylcyclohex-1-ene 5
A solution of the alcohol 4 (18.0 g, 60.4 mmol) in pyridine (49
cm3) was treated with Bu3P (45 cm3, 181 mmol) followed by
(PhS)2 (39.5 g, 180 mmol) at RT. After stirring for 9 h at ambi-
ent temperature, the reaction mixture was diluted with Et2O.
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CHHOTBDMS), 3.44 (0.69H, dd, J = 9.8, 9.8 Hz, CHHOTB-
DMS), 3.67 (0.31H, dd, J = 9.7, 3.7 Hz, CHHOTBDMS), 3.72
(0.69H, dd, J = 9.8, 4.3 Hz, CHHOTBDMS), 3.96 (0.31H, d,
J = 4.9 Hz, CHOH), 4.05 (0.69H, d, J = 4.9 Hz, CHOH), 4.38–
4.43 (1H, m, CHSO2Ph), 5.39–5.79 (4H, m, olefinic H), 7.47–
7.51 (2H, m, ArH), 7.57–7.61 (1H, m, ArH), 7.90–7.92 (2H, m,
ArH); m/z 487 (Mϩ Ϫ tBu).
1,3,3-Trimethyl-2-[2-oxo-2-(1-methylcyclohexa-2,5-dien-1-yl)-
ethylidene]bicyclo[2.2.1]heptan-7-one 12
To a suspension of the alcohol 11 (20 mg, 0.069 mmol), 4-
methylmorpholine N-oxide (33 mg, 0.278 mmol) and 4 Å
molecular sieves (50 mg) in CH2Cl2 (3 cm3) was added TPAP
(2.4 mg, 10 mol%) and the reaction mixture was stirred at RT
for 15 min. The reaction mixture was loaded onto a short
column of silica gel, and washed down with Et2O (40 cm3). The
crude product was purified by column chromatography
(hexane–Et2O 8:2) to give a colourless solid (19 mg, 96%). Mp
81 ЊC (Found C, 80.6; H, 8.6. C19H24O2 requires C, 80.2; H,
8.5); νmax(neat)/cmϪ1 1776, 1689; δH (500 MHz, CDCl3) 1.00
(3H, s, 3-CH3), 1.06 (3H, s, 1-CH3), 1.18 (3H, s, 3-CH3), 1.19
(3H, s, 1Ј-CH3), 1.65–1.70 (1H, m, 6-HH), 1.77–1.72 (1H, m,
5-HH), 1.78–1.79 (1H, m, 5-HH), 1.80–1.83 (1H, m, 4-H),
1.88–1.93 (1H, m, 6-HH), 2.64–2.73 (2H, m, 4Ј-H2), 5.46–5.49
(1H, m, olefinic H), 5.53–5.56 (1H, m, olefinic H), 5.77–5.78
(1H, m, olefinic H), 5.79–5.90 (1H, m, olefinic H), 6.31 (1H, s,
5-Hydroxymethyl-1-[2-(1-methylcyclohexa-2,5-dien-1-yl)-2-
hydroxy-1-phenylsulfonylethyl]-2,6,6-trimethylcyclohex-1-ene 9
The TBDMS ether 8 (200 mg, 0.367 mmol) was dissolved in a
solution of HF–pyridine in THF–pyridine in a Teflon vial pre-
pared according to the method of Trost.17 After stirring for 5 h
at RT, the reaction mixture was diluted with Et2O, washed with
1 M HCl, water, brine, dried over MgSO4, and concentrated
under vacuum. The crude product was purified by column
chromatography (hexane–AcOEt 1:1) to give a colourless solid
(145 mg, 92%). Mp 87 ЊC (decomp.) (Found C, 69.9; H, 8.1; S,
7.7. C25H34O4S requires C, 69.7; H, 8.0, S, 7.45%); νmax(KBr)/
cmϪ1 3509, 1278, 1130; δH (300 MHz, CDCl3) 1.05–1.24 (9H, m,
3 × CH3), 1.46 (0.9H, s, 2-CH3), 1.48–1.59 (1H, m, 4-HH),
1.68–1.77 (1H, m, 4-HH), 1.78 (2.1H, s, 2-CH3), 1.89–2.00
(1.6H, m), 2.03–2.14 (0.7H, m), 2.19–2.35 (0.7H, m), 2.54–2.59
(1.3H, m, 4Ј-H2), 2.62–2.67 (0.7H, m, 4Ј-H2), 3.24–3.30 (0.3 H,
m, CHHOH), 3.65–3.72 (0.7H, m, CHHOH), 3.73–3.81 (1H,
m, CHHOH), 3.96–3.99 (0.3H, d, J = 5.4 Hz, CHOH), 4.11–
4.14 (0.7H, d, J = 5.7 Hz, CHOH), 4.38–4.43 (1H, d, J = 5.7 Hz,
CHSO2Ph), 5.32–5.45 (1.7H, m, olefinic H), 5.46–5.52 (0.7H,
m, olefinic H), 5.68–5.73 (1.3H, m, olefinic H), 5.75–5.80 (0.3H,
m, olefinic H), 7.46–7.53 (2H, m, ArH), 7.54–7.62 (1H, m,
ArH), 7.90–7.94 (2H, m, ArH); m/z 337.1475 (Mϩ Ϫ C ring).
᎐CHCO); δ (125 MHz, CDCl3) 12.14 (1-CH3), 17.72 (5-C),
᎐
C
22.62 (3-CH3), 24.31 (1Ј-CH3), 26.09 (4Ј-C), 28.96 (3-CH3),
30.25 (6-C), 41.98 (3-C), 50.63 (1Ј-C), 50.74 (4-C), 50.86 (1-C),
118.04 (᎐CHCO) [124.86, 125.14, 129.44, 130.08 (4 × olefinic
᎐
C)], 167.31 (2-C), 202.48 (1Ј-CO), 215.40 (7-C); m/z 191.1080
(Mϩ Ϫ C ring).
(E)-5-tert-Butyldimethylsiloxymethyl-1-[2-(1-methylcyclohexa-
2,5-dien-1-yl)ethenyl]-2,6,6-trimethylcyclohex-1-ene 13
A 0.1 M solution of SmI2 in THF (6.43cm3, 0.643 mmol) was
treated with HMPA (0.23 cm3) and stirred at RT for 10 min. A
solution of sulfone 8 (100 mg, 0.184 mmol) in THF (3 cm3) was
added rapidly and the reaction mixture was stirred for 30 min.
The reaction mixture was diluted with Et2O, washed with 1 M
HCl, satd. NaHCO3, water and brine, dried over MgSO4 and
concentrated under vacuum. The crude product was purified by
column chromatography (hexane–Et2O 500:1) to give a colour-
less liquid (58 mg, 82%) (Found C, 77.5; H, 11.0. C25H42OSi
requires C, 77.65; H, 10.95%); νmax(neat)/cmϪ1 1470, 1460, 1360;
δH (300 MHz, CDCl3) 0.04 (6H, s, 2 × CH3Si), 0.80 (3H, s,
1,3,3-Trimethyl-2-[2-hydroxy-2-(1-methylcyclohexa-2,5-dien-1-
yl)ethylidene]bicyclo[2.2.1]heptan-7-ol 11
To a suspension of the alcohol 9 (50 mg, 0.116 mmol),
4-methylmorpholine N-oxide (34 mg, 0.290 mmol) and 4 Å
molecular sieves (50 mg) in CH2Cl2 (3 cm3) was added TPAP
(2.2 mg, 5 mol%) and the reaction mixture was stirred at RT for
15 min. The reaction mixture was loaded onto a short column
of silica gel, and washed down with Et2O (40 cm3). The crude
aldehyde 10 was concentrated under vacuum and used for the
next step without further purification.
t
CH3), 0.89 (9H, s, Bu), 1.02 (3H, s, CH3), 1.17 (3H, s, CH3),
1.35–1.50 (2H, m, 4-H2), 1.63 (3H, s, 2-CH3), 1.78–1.85 (1H,
m, 5-H), 1.94–1.99 (2H, m, 3-H2), 2.59–2.64 (2H, m, 4Ј-H2),
3.36 (1H, dd, J = 9.9, 9.2 Hz, CHHOTBDMS), 3.76 (1H, dd,
J = 9.9, 4.0 Hz, CHHOTBDMS), 5.30 (1H, d, J = 16.1 Hz,
trans-olefinic H), 5.53–5.57 (2H, m, olefinic H), 5.65–5.75 (3H,
m, olefinic H); δC (75 MHz, CDCl3) Ϫ5.1, 18.4, 21.6, 22.6, 26.1,
27.9, 28.5, 31.4, 36.4, 38.9, 46.9, 64.0, 121.9, 125.0, 127.7, 133.2,
137.7, 142.4; m/z 386 (Mϩ).
A 0.1 M solution of SmI2 was prepared by the addition of a
solution of 1,2-diiodoethane (229 mg, 0.81 mmol) in THF
(5 cm3) to a stirred suspension of Sm (131 mg, 0.87 mmol) in
THF (4 cm3). After stirring the suspension for 1 h, deaerated
HMPA (1 cm3, 6 mmol) was added to the resultant dark blue
solution and stirred for a further 10 min. A solution of the
crude aldehyde 10 in THF (3 cm3) was added slowly to the
reaction mixture using a syringe pump at 0 ЊC. After stirring for
an additional 30 min, the reaction was quenched by the addi-
tion of satd. NH4Cl. The reaction mixture was then diluted
with Et2O, and treated with a saturated aqueous solution of
sodium potassium tartrate. After separating the phases, the
aqueous layer was extracted with Et2O. The combined organic
layer was washed with brine, dried (MgSO4) and concentrated.
The crude product was purified by flash chromatography
(hexane–AcOEt 7:3) to give pure diol 11 as a colourless solid
(23.4 mg, 71%). Mp 112–113 ЊC (Found (Mϩ Ϫ 18) 270.1949.
C19H26O requires m/z 270.1984); νmax(neat)/cmϪ1 3382, 1455;
δH (300 MHz, CDCl3) 1.04 (3H, s, CH3), 1.05 (3H, s, CH3), 1.06
(3H, s, CH3), 1.35 (3H, s, CH3), 1.56–1.63 (2H, m, 5-HH and
6-HH), 1.64–1.74 (1H, m, 5-HH), 1.77–1.79 (1H, m, 4-H),
1.80–1.86 (1H, m, 6-HH), 2.62–2.67 (2H, m, 4Ј-H2), 3.86 (1H, s,
7-H), 4.36 (1H, d, J = 10.2, CHOH), 5.10 (1H, d, J = 10.2,
(Z)-5-tert-Butyldimethylsiloxymethyl-1-[2-(1-methylcyclohexa-
2,5-dien-1-yl)ethenyl]-2,6,6-trimethylcyclohex-1-ene 14
A solution of trans-13 (535 mg, 1.39 mmol) and 2-acetyl-
naphthalene (470 mg, 2.76 mmol) in benzene (55 cm3) in a
Pyrex vessel was irradiated with a 450 W high pressure Hg lamp
for 3 h, maintaining the temperature of the reaction mixture
below 5 ЊC. The reaction mixture was concentrated under
vacuum and the cis–trans mixture was separated by flash
column chromatography (hexane) to give the cis-isomer 14 as a
colourless liquid [360 mg, 67% (98% based on recovered start-
ing material)] (Found C, 77.7; H, 10.9. C25H42OSi requires C,
77.65; H, 10.95%). νmax(neat)/cmϪ1 1472, 1465, 1360, 1260;
δH (300 MHz, CDCl3, RT) 0.05 (6H, s, 2 × CH3Si), 0.83 (1.5H,
t
s, CH3), 0.86 (1.5H, s, CH3), 0.90 (9H, s, Bu), 1.05 (1.5H, s,
CH3), 1.08 (1.5H, s, CH3), 1.11 (3H, s, CH3), 1.35–1.50 (2H, m,
4-H2), 1.54 (3H, br s, 2-CH3), 1.75–1.97 (3H, m, 3-H2 and 5-H),
2.45–2.69 (2H, m, 4Ј-H2), 3.30–3.43 (1H, m, CHHOTBDMS),
3.71–3.83 (1H, m, CHHOTBDMS), 5.25 (1H, br d, J = 12.5
Hz, cis-olefinic H), 5.45–5.72 (5H, m, olefinic H); δH (500 MHz,
DMSO-d6, 90 ЊC) 0.05 (6H, s, 2 × CH3Si), 0.87 (3H, s, CH3),
2-C᎐CH), 5.51–5.56 (2H, m, olefinic H), 5.82–5.92 (2H, m,
᎐
olefinic H); δC (75 MHz, CDCl3) 17.2, 22.1, 25.5, 26.6, 27.0,
29.4, 31.4, 40.5, 41.6, 51.3, 52.8, 72.9, 80.8, 117.9, 125.5, 125.9,
130.1, 131.6, 158.5.
J. Chem. Soc., Perkin Trans. 1, 2000, 3375–3381
3379

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0.90 (9H, s, tBu), 1.06 (3H, s, CH3), 1.10 (3H, s, CH3), 1.36–1.48
(2H, m, 4-CH2), 1.54 (3H, s, 2-CH3), 1.69–1.95 (3H, m, CH2
and CH), 2.46-2.71 (2H, m, 4Ј-CH2), 3.33–3.46 (1H, m,
CHHOTBDMS), 3.76 (1H, dd, J = 9.8, 3.7 Hz, CHHOTB-
DMS), 5.30 (1H, d, J = 12.8 Hz, cis-olefinic H), 5.46–5.68 (5H,
m, olefinic H); m/z 386 (Mϩ).
A solution of the aldehyde 17 in CH2Cl2 (1.7 cm3) was treated
with TiCl4 (12 mm3, 0.11 mmol) in CH2Cl2 (0.1 cm3) at Ϫ40 ЊC.
After stirring the reaction mixture for 2 h at the same temper-
ature, it was quenched by the addition of satd. NH4Cl. The
reaction mixture was then extracted with Et2O. The combined
organic layer was washed with water and brine, dried (MgSO4),
and concentrated. The residue was purified by column chrom-
atography on silica gel (hexane–AcOEt 9:1) to give a mixture
of 18 and 19a. The separation of the mixture was achieved by
HPLC (hexane–AcOEt 15:1) to give the alcohol 19a (1.2 mg,
5%) (Found Mϩ 270.1976. C19H26O requires m/z 270.1984);
νmax(neat)/cmϪ1 3380; δH (500 MHz, CDCl3) 1.01–1.06 (6H, m,
2 × CH3), 1.23–1.38 (6H, m, 2 × CH3), 1.54–1.62 (2H, m, 6-HH
and 5-HH), 1.63–1.74 (1H, m, 5-HH), 1.76–1.86 (2H, m, 6-HH
and 4-H), 3.84–3.92 (1H, m, CHAr), 3.96–4.04 (1H, m,
CHOH), 5.12 (1H, d, J = 9.8, olefinic H), 7.13–7.31 (5H, m,
ArH).
(Z)-5-Hydroxymethyl-1-[2-(1-methylcyclohexa-2,5-dien-1-yl)-
ethenyl]-2,6,6-trimethylcyclohex-1-ene 15
Bu4NF (1.0 M solution in THF, 0.78 cm3, 0.78 mmol) was
added to a solution of 14 (150 mg, 0.388 mmol) in THF (2.2
cm3) at 0 ЊC and the reaction mixture was stirred for 16 h at RT.
After addition of water, the reaction mixture was extracted with
AcOEt, the combined organic layer was washed with brine,
dried over MgSO4 and concentrated under vacuum. The crude
product was purified by column chromatography (hexane–
AcOEt 5:1) to give the corresponding alcohol 15 (100 mg, 95%)
(Found C, 83.4; H, 10.3. C19H28O requires C, 83.8; H, 10.4%).
νmax(neat)/cmϪ1 3300; δH (300 MHz, CDCl3) 0.85 (1.5H, s, CH3),
0.88 (1.5H, s, CH3), 1.07 (1.5H, s, CH3), 1.09 (1.5H, s, CH3), 1.12
(3H, s, CH3), 1.22–1.29 (1H, m, 4-HH), 1.41–1.52 (1H, m,
4-HH), 1.55 (1.5H, br s, 2-CH3), 1.57 (1.5H, br s, 2-CH3), 1.76–
2.05 (3H, m, 3-H2 and 5-H), 2.58–2.64 (2H, m, 4Ј-H2), 3.34–
3.52 (1H, m, CH2OH), 3.78–3.93 (1H, m, CH2OH), 5.23–5.34
(1H, m, olefinic H), 5.43–5.73 (5H, m, olefinic H); m/z
272.2141.
Further elution yielded the spiro compound 18 (7.0 mg, 28%)
(Found Mϩ 270.1995. C19H26O requires m/z 270.1984); νmax
-
(neat)/cmϪ1 3420; δH (400 MHz, CDCl3) 0.77 (3H, s, 1-CH3),
0.87 (3H, s, 3-CH3), 1.03 (3H, s, 3-CH3), 1.10 (3H, s, 3aЈ-CH3),
1.12–1.18 (1H, m, 6-HH), 1.65–1.78 (3H, m, 5-H2 and 4-H),
2.27–2.36 (1H, m, 6-HH), 2.51 (1H, dd, J = 5.9, 1.3 Hz, 7aЈ-H),
4.00 (1H, br s, 7-H), 5.48 (1H, br d, J = 9.3 Hz, olefinic H), 5.52
(1H, d, J = 6.1 Hz, olefinic H), 5.59 (1H, d, J = 6.1 Hz, olefinic
H), 5.68–5.73 (1H, m, olefinic H), 5.81–5.87 (1H, m, olefinic H),
5.93–5.99 (1H, m, olefinic H); δC (100 MHz, CDCl3) 16.0, 22.2,
25.3, 26.7, 28.3, 28.4, 39.8, 46.8, 48.9, 53.4, 53.8, 70.7, 79.4,
119.2, 122.0, 129.1, 132.8, 135.4, 137.1.
(Z)-5-Hydroxymethyl-1-[2-(1-methyl-4-trimethylsilylcyclohexa-
2,5-dien-1-yl)ethenyl]-2,6,6-trimethylcyclohex-1-ene 16
To a solution of the alcohol 15 (59 mg, 0.22 mmol) and
TMEDA (165 mm3, 1.09 mmol) in THF (2 cm3) at 0 ЊC was
added BuLi (1.56 M solution in hexane, 300 mm3, 0.468 mmol).
The reaction mixture was stirred for 1 h at the same temper-
ature and the resultant dianion was trapped by the addition of
TMSCl (140 cm3, 1.10 mmol). After stirring for 30 min at the
same temperature, the reaction mixture was diluted with Et2O,
washed with H2O, 0.5 M H2SO4, and brine, dried over MgSO4
and concentrated under vacuum. The crude disilyl derivative
was dissolved in THF (1.5 cm3) and treated with 0.5 M H2SO4
(1.5 cm3) at 0 ЊC. The mixture was stirred for 30 min at RT. The
reaction mixture was then diluted with Et2O, washed with H2O,
saturated NaHCO3, saturated NaCl, dried (MgSO4) and con-
centrated under vacuum. The crude product was purified by
column chromatography (hexane–AcOEt 15:1) to give the
allylsilane 16 (70 mg, 94%) (Found C, 76.2; H, 10.3. C22H36OSi
requires C, 76.7; H, 10.5); νmax(neat)/cmϪ1 3320; δH (300 MHz,
CDCl3) Ϫ0.01 (1.8H, s, CH3), 0.01 (4.2H, s, CH3), 0.03
(0.9H, s, CH3), 0.05 (2.1H, s, CH3), 0.81–0.92 (3H, m, CH3),
1.02–1.17 (6H, m, 2 × CH3), 1.17–1.26 (1H, m, 4-HH), 1.39–
1.48 (1H, m, 4-HH), 1.56 (0.6H, s, CH3), 1.57 (1.4H, s, CH3),
1.63 (0.3 H, s, CH3), 1.66 (0.7 H, s, CH3), 1.78–2.04 (3H, m,
3-H2 and 5-H), 2.13–2.21 (1H, m, 4Ј-H), 3.36–3.49 (1H, m,
CHOH), 3.79–3.92 (1H, m, CHOH), 5.22–5.41 (2H, m,
olefinic H), 5.42–5.47 (1H, m, olefinic H), 5.48–5.72 (3H, m,
olefinic H); m/z 344.2535.
1,3,3-Trimethyl-2-(2-methyl-2-phenylethylidene)bicyclo[2.2.1]-
heptan-7-ol 19a and 19b
Bu4NF (1.0 M solution in THF, 520 mm3, 0.520 mmol) was
added to a solution of the TBDMS ether 13 (100 mg, 0.259
mmol) in THF (1 cm3) at 0 ЊC and the reaction mixture was
stirred for 16 h at RT. After addition of water, the reaction
mixture was extracted with AcOEt. The combined organic layer
was washed with brine, dried over MgSO4 and concentrated
under vacuum. The crude product was purified by column
chromatography (hexane–AcOEt 5:1) to give the correspond-
ing alcohol (61 mg, 87%) (Found Mϩ 272.2123. C19H28O
requires m/z 272.2140); νmax(neat)/cmϪ1 3350; δH (300 MHz,
CDCl3) 0.82 (3H, s, CH3), 1.04 (3H, s, CH3), 1.17 (3H, s, CH3),
1.24–1.39 (1H, m, 4-HH), 1.41–1.54 (1H, m, 4-HH), 1.63 (3H,
s, 2-CH3), 1.80–1.93 (1H, m, 5-H), 1.95–2.07 (2H, m, 3-H2),
2.57–2.68 (2H, m, 4Ј-H2), 3.34–3.50 (1H, m, CHHOH), 3.78–
3.92 (1H, m, CHHOH), 5.32 (1H, d, J = 15.9 Hz, trans-olefinic
H), 5.49–5.79 (5H, m, olefinic H); δC (75 MHz; CDCl3) 21.4,
21.6, 22.5, 26.0, 27.6, 28.4, 31.1, 36.3, 38.3, 47.2, 64.0, 122.1,
124.9, 127.9, 133.2, 137.7, 142.7.
To a suspension of this alcohol (20 mg, 0.074 mmol), NMO
(17 mg, 0.15 mmol), 4 Å molecular sieves (30 mg) in CH2Cl2
(1 cm3), was added TPAP (1.3 mg, 0.0037 mmol) and the
reaction mixture was stirred at RT for 15 min. The reaction
mixture was then loaded onto a short column of silica gel and
washed down with Et2O and concentrated. A solution of the
crude aldehyde in CH2Cl2 (1.4 cm3) was treated with SnCl4
(10mm3, 0.085 mmol) in CH2Cl2 (0.1 cm3) at Ϫ30 ЊC. After
stirring the reaction mixture for 1.5 h at the same temperature,
it was quenched by the addition of satd. NH4Cl. The reaction
mixture was then extracted with Et2O. The combined organic
layer was washed with water and brine, dried (MgSO4), and
concentrated. The residue was purified by column chroma-
tography on silica gel (hexane–AcOEt 9:1) to give a 6:6:1:1
mixture of 19a and 19b (17.8 mg, 90%).
( )-(1R*,2S*,4S*,7S*,3aЈR*,7aЈR*)-1,3,3,3aЈ-Tetramethyl-
spiro[bicyclo[2.2.1] heptane-2,1Ј-(cis-3aЈ,7aЈ-dihydroinden)]-7-ol
18 and 1,3,3-trimethyl-2-(2-methyl-2-phenylethylidene)bicyclo-
[2.2.1]heptan-7-ol 19a
To a suspension of the alcohol 16 (32 mg, 0.93 mmol), NMO
(22 mg, 0.19 mmol), 4 Å molecular sieves (50 mg) in CH2Cl2
(1 cm3), was added TPAP (3.2 mg, 0.0091 mmol) and the
reaction mixture was stirred at RT for 15 min. The reaction
mixture was then loaded onto a short column of silica gel
and washed down with Et2O and concentrated. The crude alde-
hyde was used as such without further purification for the next
step.
Similarly, the crude aldehyde obtained by oxidation of the
alcohol 15 (21.5 mg, 0.0790 mmol) with TPAP (1.4 mg, 0.0040
mmol) and NMO (18.5 mg, 0.158 mmol), was dissolved in
CH2Cl2 (1.5 cm3), and treated with SnCl4 (11 mm3, 0.094
3380
J. Chem. Soc., Perkin Trans. 1, 2000, 3375–3381

View Article Online
mmol) in CH2Cl2 (0.1 cm3) at Ϫ30 ЊC. The reaction mixture
was allowed to warm to Ϫ10 ЊC over 4.5 h. The usual workup
furnished a 7.5:7.5:1:1 mixture of 19a and 19b (10.6 mg,
50%).
117, 653; (b) R. A. Holton, H.-B. Kim, C. Somoza, L. Liang, R. J.
Bieediger, P. D. Boatman, M. Shindo, C. C. Smith, S. Kim,
H. Nadizadeh, Y. Suzuki, C. Tao, P. Vu, S. Tang, P. Zhang, K. K.
Murthy, L. N. Gentile and J. H. Liu, J. Am. Chem. Soc., 1994, 116,
1599; (c) S. J. Danishefsky, J. J. Masters, W. B. Young, J. T. Link,
L. B. Snyder, T. V. Magee, D. K. Jung, R. C. A. Isaacs, W. G.
Bornmann, C. A. Alaimo, C. A. Coburn and M. J. Di Grandi,
J. Am. Chem. Soc., 1996, 118, 2843; (d) P. A. Wender, N. F. Badham,
S. P. Conway, P. E. Floreacig, T. E. Glass, J. B. Houze, N. E. Krauss,
D. Lee, D. G. Marquess, P. I. McGrane, W. Meng, M. G. Natchus,
A. J. Schuker, J. C. Sutton and R. E. Taylor, J. Am. Chem. Soc.,
1997, 119, 2757; (e) T. Mukaiyama, I. Shiina, H. Iwadare,
M. Saitoh, T. Nishimura, N. Ohkawa, H. Sakoh, K. Nishimura,
Y. Tani, M. Hasegawa, K. Yamada and K. Saitoh, Chem. Eur. J.,
1999, 5, 121; (f) K. Morihira, R. Hara, S. Kawahara, T. Nishimori,
N. Nakamura, H. Kusama and I. Kuwajima, J. Am. Chem. Soc.,
1998, 120, 12980.
1,3,3-Trimethyl-2-(2-methyl-2-phenylethylidene)bicyclo[2.2.1]-
heptan-7-one 22 and 23
A 7.5:7.5:1:1 mixture of the bicyclic alcohol 19a and 19b (10
mg, 0.037 mmol) in CH2Cl2 (300 mm3) was stirred with 4 Å
molecular sieves (30 mg), NMO (9.0 mg, 0.077 mmol) and
TPAP (1.3 mg, 0.0037 mmol) at RT for 30 min. The reaction
mixture was loaded onto a short column of silica gel and
washed down with Et2O. The residue was concentrated to fur-
nish a 7.5:7.5:1:1 mixture of the ketones 22 and 23 (9.6 mg,
97%). The separation of the isomers by HPLC (hexane–Et2O
20:1) gave the two Z-isomers 22.
6 G. Mehta and V. Singh, Chem. Rev., 1999, 99, 881.
7 M. Ihara, S. Suzuki, Y. Tokunaga, H. Takeshita and K. Fukumoto,
Chem. Commun., 1996, 1801.
8 (a) A. Hosomi and H. Sakurai, Tetrahedron Lett., 1976, 1295;
(b) G. Majitech, D. Lowey and V. Khetani, Tetrahedron Lett., 1990,
31, 51.
(1) (Found Mϩ 268.1846. C19H24O requires m/z 268.1827),
νmax(CHCl3)/cmϪ1 1765; δH (500 MHz, CDCl3) 1.04 (3H, s,
3-CH3), 1.20 (3H, s, 1-CH3), 1.30 (3H, d, J = 6.7 Hz, CH3CH),
1.35 (3H, s, 3-CH3), 1.54–1.63 (2H, m, CH2), 1.65–1.86 (3H, m,
CH2 and 4-H), 3.83–3.92 (1H, m, CHAr), 5.37 (1H, d, J = 9.8
Hz, olefinic H), 7.17–7.33 (5H, m, ArH).
9 (a) M. Kito, T. Sakai, H. Shirahama, M. Miyashita and F. Matsuda,
Synlett, 1997, 219; (b) G. A. Molander and J. A. McKie, J. Org.
Chem., 1994, 59, 3186.
(2) (Found Mϩ 268.1870. C19H24O requires m/z 268.1827);
νmax(CHCl3)/cmϪ1 1770; δH (500 MHz, CDCl3) 1.01 (3H, s,
3-CH3), 1.25 (3H, s, 1-CH3), 1.28 (3H, s, 3-CH3), 1.32 (3H, d,
J = 7.3 Hz, CH3CH), 1.52–1.62 (2H, m, CH2), 1.78–1.97 (3H,
m, CH2 and 4-H), 3.84–3.92 (1H, m, CHAr), 5.36 (1H, d,
J = 10.3Hz, olefinic H), 7.15–7.33 (5H, m, ArH).
10 L. Tietze, Chem. Ind. (London), 1995, 453.
11 For a preliminary report of this work: M. Ihara, S. Suzuki, Y.
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15 Facile cleavage of TBDMS ethers using Oxone has been recently
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Further elution with hexane–Et2O (80:1 v/v) gave the corre-
sponding two E-isomers 23.
(1) (Found Mϩ 268.1807. C19H24O requires m/z 268.1827);
νmax(CHCl3)/cmϪ1 1760; δH (500 MHz, CDCl3) 1.06 (3H, s,
3-CH3), 1.21 (3H, s, 1-CH3), 1.31 (3H, d, J = 6.7 Hz, CH3CH),
1.41 (3H, s, 3-CH3), 1.56–1.62 (1H, m, 6-HH), 1.66–1.79 (3H,
m, 5-H2 and 6-HH), 1.88–1.96 (1H, m, 4-H), 3.80–3.90 (1H, m,
CHAr), 5.19 (1H, d, J = 11.0 Hz, olefinic H), 7.19–7.34 (5H, m,
ArH).
(2) (Found Mϩ 268.1863. C19H24O requires m/z 268.1827);
νmax(CHCl3)/cmϪ1 1765; δH (500 MHz, CDCl3) 1.03 (3H, s,
3-CH3), 1.14 (3H, s, 1-CH3), 1.36 (3H, d, J = 6.7 Hz, CH3CH),
1.49 (3H, s, 3-CH3), 1.56–1.82 (4H, m, 5-H2 and 6-H2), 1.96–
2.04 (1H, m, 4-H), 3.82–3.90 (1H, m, CHAr), 5.20 (1H, d,
J = 10.4 Hz, olefinic H), 7.16–7.34 (5H, m, ArH).
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(c) G. A. Molander and C. R. Harris, Tetrahedron, 1998, 54, 3321;
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21 T. Kan, S. Nara, S. Ito, F. Matsuda and H. Shirahama, J. Org.
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22 For the synthesis of bicycloalkanols from cyclohexanones using
SmI2: (a) G. A. Molander and J. A. McKie, J. Org. Chem., 1991, 56,
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Acknowledgements
One of the authors (V. J. M.) is grateful to Japan Society for
the Promotion of Science (JSPS) for
Fellowship.
a Post-Doctoral
References and notes
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