Stereochemical investigation on the construction of poly-functionalized bicyclo[3.3.1]nonenones by successive Michael reactions of 2-cyclohexenones

Article abstract of DOI:10.1039/b615702e

A method for the practical construction of poly-functionalized bicyclo[3.3.1]nonenones by successive Michael reactions of cyclohexenones 1 with acrylates 2 using K₂CO₃ and TBAB (n-Bu₄N ⁺Br^-) was devel

Full text of DOI:10.1039/b615702e

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Stereochemical investigation on the construction of poly-functionalized
bicyclo[3.3.1]nonenones by successive Michael reactions of 2-cyclohexenones†
Ryukichi Takagi,* Yukiko Miwa, Takashi Nerio, Yuta Inoue, Shuji Matsumura and Katsuo Ohkata
Received 30th October 2006, Accepted 17th November 2006
First published as an Advance Article on the web 8th December 2006
DOI: 10.1039/b615702e
A method for the practical construction of poly-functionalized bicyclo[3.3.1]nonenones by successive
+
−
Michael reactions of cyclohexenones 1 with acrylates 2 using K
2
CO
3
and TBAB (n-Bu N Br ) was
4
developed. The construction could be carried out in both stepwise and one-pot reactions with similar
tendencies in regioselectivity. The a-regioselectivity in the intramolecular Michael reaction agreed with
that stereoelectronically expected in intermolecular reactions based upon consideration of the HOMO
orbital profile of the enolate I, the precursor to ring-closure, although the reaction site was trisubstituted
and prone to steric hindrance in most of the examples presented. For the acetoxymethylacrylates
substituted at either the a or c position, steric hindrance of the substituents (R
2
and R ) served as a
3
controlling factor to induce high regiocontrol. Facial selection in the protonation of enolate II, formed
upon ring-closure, was also affected by these substituents. In both the intramolecular Michael reaction
and the protonation of enolate II, the ammonium counter cation played an important role.
Introduction
of double Michael acceptors for the construction of various ring
systems, as far as we are aware, they have been overlooked over
the years, and have not been exploited for bicyclic systems by oth-
ers. We have found that cyclohexenones could be applied directly,
not necessitating enamines, and that a regioselectivity issue which
is unique to our system and has not been exploited in this type of
Many natural products bearing the bicyclo[3.3.1]nonane skeleton,
suchas garsubellin A, huperzine A, plukenetioneA, lycopodine
1
2
3
4
and so forth, have been shown to exhibit promising biologically
activity and also have unique complex structures. Therefore, they
have attracted attention as targets for organic synthesis. The key
step towards the synthetic goals would be the construction of the
bicyclo[3.3.1]nonane core and many types of synthetic methods
for this purpose have been reported. Bicyclo[3.3.1]nonanes have
also found use as synthetic intermediates for other ring systems.
In relation to research on bicyclic natural product synthesis carried
out in our group, we also have been interested in this ring system.
[
3 + 3] reaction previously, could be controlled for the amphiphilic
Michael donors. In this paper, in addition to providing details
of these previous results, we report on the extended scope of the
reaction by utilizing additionally-functionalized double Michael
acceptors en route to more advanced and complex synthetic
intermediates, and on the stereocontrol in the annulation step (the
second step) for the newly examined substrates. Also provided
is a rationale on the regio- and stereo-selectivity based upon
theoretical calculations.
5
,6
7
8
To preparation of a densely functionalized bicyclo[3.3.1]nonane
core, such as that seen in garsubellin A, we envisioned that the
[3 + 3] annulation reaction between a-acetoxymethylacrylates
(
which could function as double Michael acceptors) and cyclo-
Results and discussion
hexenones with substituents a to the carbonyl group would meet
our objective. As presented in a preliminary report, we have found
that this could be realized in either a two-step or one-pot procedure
using K
(
compounds with high regioselectivity. Quite a while ago, two
groups independently and ingeniously utilized bromomethyl acry-
lates as double Michael acceptors in conjunction with enamines
derived from cyclohexanones as double Michael donors; Lawton
in preparing bicyclo[3.3.1]nonanes and Stetter in providing
adamantane derivatives in a cascade of reactions, including two
The stepwise Michael reactions of 2 or 6-mono- or 2,6-
12
disubstituted-cyclohexenones 1 with acrylate 2a were examined
2
CO
3
in conjunction with tetrabutylammonium bromide
9a
first. Annulation precursor 3a was obtained by the intermolec-
TBAB) as a phase transfer catalyst to furnish the desired bicyclic
ular Michael reaction of 1a with acrylates 2a, by the use of
LDA where deprotonation a to the keto-carbonyl group of the
thermodynamically less acidic site was required (Scheme 1). Upon
treating the annulation precursor 3a with K
the intramolecular Michael reaction proceeded to give a-endo-4a,
9
2
CO and TBAB,
3
10
which was a kinetically protonated product, (90%) and a-exo-4a
13,14
(
3%).
The relative stereochemistry of a-endo-4a was confirmed
11
initial Michael reactions. Despite the high potential of this group
15
by X-ray structural analysis (Fig. 1). ‡
Furthermore, treatment of the annulation precursor 3a in the
Department of Chemistry, Graduate School of Science, Hiroshima Uni-
versity, 1-3-1 Kagamiyama, Higashi-Hiroshima, 739-8526, Japan. E-mail:
rtakagi@hiroshima-u.ac.jp; Fax: +81 (0)82 424 0724; Tel: +81
presence of acrylate 2a (2.0 eq) with K
2
CO and TBAB gave the
3
13
annulation product 5 in 51% yield (Scheme 2). Thus, not only
(
0)82 424 7434
†
Electronic supplementary information (ESI) available: Data for deter-
mination of relative stereochemistry and detail of theoretical calculations.
See DOI: 10.1039/b615702e
‡ CCDC reference numbers 600955–600957. For crystallographic data in
CIF format see DOI: 10.1039/b615702e
2
86 | Org. Biomol. Chem., 2007, 5, 286–300
This journal is © The Royal Society of Chemistry 2007

View Article Online
Scheme 1
Fig. 2 ORTEP drawing of a-7-endo,8-exo-4b showing the thermal
ellipsoids at the 30% probability level.
Michael reaction of acrylate 2c, Z-3c was obtained as a minor
product along with E-3c (Table 1, entry 2). The isomers could be
separated by preparative TLC and only E-3c was used for the in-
tramolecular Michael reaction. Treatment of annulation precursor
E-3c with K
2
CO and TBAB gave the bicyclo[3.3.1]nonenones a-
3
and c-4c along with the bicyclo[3.2.1]octane 6, generated by bond
ꢀ
formation between the c-carbon of the enolate and the C2 -carbon
of the tether. The stereochemistry of the annulation products
a- and c-4c was characteristically and specifically “exo,exo” in
contrast to results involving the t-Bu ester.
Table 2 summarizes the results of the stepwise Michael reactions
Fig. 1 ORTEP drawing of a-endo-4a showing the thermal ellipsoids at
the 30% probability level.
16c,d
of cyclohexenones 1a–c with 1-substituted acrylates 2d and e,
which have a stereogenic carbon center for the first Michael
13,18
reaction.
The annulation precursors 3d–g were obtained as
mixtures of diastereomers by the intermolecular Michael reactions
of cyclohexenones 1a–c with acrylates 2d and e, respectively (dr =
1.2–4.5 : 1.0), and were used for the sequential intramolecular
Michael reaction without separation. The intramolecular Michael
reaction of 3d, generated from cyclohexenone 1a with acrylate
2d, gave a-6-exo,7-endo-4d as the major product, along with a
small amount of c-6-exo,7-endo-4d, both of which have the methyl
group on the convex face of the compounds and are products
of exo-face protonation (Table 2, entry 1). Judging from the
relative stereochemistry of the first junction in the products, the
major product can be looked upon as that exclusively from the
major R*,R* isomer of 3d, whereas the minor product can be
viewed as that from the minor R*,S* isomer of 3d. Thus, it
is suggested that the annulation reaction of each isomer of 3d
was completely stereospecific, with one diastereomer giving the
a-annulation product and the other giving the c-product. Under
likewise conditions, annulation precursors 3e–g gave mixtures of
products with a- and c-6-exo,7-exo-4e–g as the main products
Scheme 2 Intramolecular Michael reaction of 3a in the presence of
acrylate 2a.
protonation, but also alkylation of the intermediate enolate was
preferred from the exo-side.
The stepwise Michael reactions of 2-cyclohexenone 1a with
16a,b
acrylates 2b and c,
bearing a stereocenter that would serve
as a stereogenic center for the second Michael reaction, were also
investigated, in order to construct more densely-functionalized
13
bicyclic compounds (Table 1). Regardless of the fact that the
Michael donor was greatly hindered and led to the formation
of the quaternary center b from the enolate double bond, the
stereoelectronically favored E-3b was formed as the exclusive
isomer in the intermolecular Michael reaction of cyclohexenone
19
(Table 2, entries 2–4).
In order to investigate the stereochemical outcome of the
annulation process in more detail, the diastereomeric mixture of 3f
was separated with high-performance liquid chromatography and
the two diastereomers were subjected separately to the annulation
conditions (Scheme 3). The annulation product a-6-exo,7-exo-4f
was obtained as the exclusive product in the reaction of one of the
diastereomers, and this indicated that the relative stereochemistry
1
7,18
1
a with acrylate 2b (Table 1, entry 1).
The major product
ꢀ
from the intramolecular reaction of E-3b was the a,a annulation
product with an exo methyl group and an endo t-Bu ester group,
and it was accompanied by a small amount of the c-7-endo,8-exo
product. The stereochemistry of a-7-endo,8-exo-4b was confirmed
by X-ray structural analysis (Fig. 2). ‡ Despite the formation of
regioisomers, the stereoselectivity regarding the newly generated
stereocenters was completely controlled. In the intermolecular
15
20
of the reactant was “anti” in regards with the first juncture.
Thus, as for the reaction of anti-3f, annulation can be regarded as
This journal is © The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 286–300 | 287

View Article Online
Table 1 Stepwise Michael reactions of 2-cyclohexenone 1a with acrylates 2b,c
a
a,b
Entry
1
Acrylate
3
Conditions
Products
◦
90 C, 67 h
◦
2
110 C,
2
7 h
a
b
c
Isolated yield. The numbering is based on the bicyclo[3.3.1]non-2-ene core. A mixture of E-and Z-3c was obtained in the intermolecular Michael
reaction of 1a and 2c (E : Z = 10 : 1). The mixture was separated into E-and Z-3c by preparative TLC. Only E-3c was used for the intramolecular Michael
reaction.
stereospecific and protonation as stereoselective. The reaction of
the other diastereomer, logically syn-3f, was not as clean giving rise
to two c and three a annulation products, among which the major
product was c-6-exo,7-exo-4f. The reaction of syn-3f was not as
selective as that of anti-3f. Thus, as a whole, for the reaction of 2e
as the double Michael acceptor, the anti-series of diastereomers
underwent stereospecific reaction to give thea-annulation product,
whereas the syn-series gave rise to both the a and c-products.
Since the stepwise Michael reactions of cyclohexenones 1 with
acrylates 2 proceeded sufficiently, one-pot Michael reactions were
of 1d afforded c-endo-4h as the major product (Table 3, entry 4).
The relative stereochemistry of c-endo-4h was confirmed by X-ray
structural analysis (Fig. 3). ‡
In order to examine the effect of the counter cation in the
intramolecular Michael reaction, t-BuOK was used as the base
15
instead of the combination of TBAB and K
2
CO (Scheme 4).
3
Treatment of the annulation precursor 3a with t-BuOK (3.0 eq)
◦
(toluene, rt, 7 h then 90 C, 24 h) gave c-exo-4a in 40% yield.
On the other hand, the reaction of 3a with t-BuOK (3.0 eq)
in the presence of 18-crown-6 (3.0 eq) (toluene, rt, 2 h) gave
carboxylic acids 7, generated from hydrolysis of the annulation
products a-exo-4a and c-exo-4a (a-exo-7: 8%, c-exo-7: 16%).
Since the regioselectivity changed dramatically with the obvious
intervention of the potassium ion, favoring the c product, it
was suggested that under phase transfer conditions, not the free
potassium ion but the ammonium ion was what interacted with the
enolate. Since the region of charge in the ammonium is sterically
shielded by the alkyl groups, its interaction with the enolate oxygen
13
subsequently examined (Table 3). The reaction of 1a with 2a in
9a
the two operation method gave annulation products with a higher
ratio of the thermodynamically more stable a-exo-4a compared
with the stepwise protocol (Table 3, entry 1). In the case of entry
2
, the ratios were similar to those of the stepwise reactions. The
one-pot Michael reactions of cyclohexenones 1c and d bearing
the active methylene could be performed by the one-operation
method (Table 3, entries 3 and 4). The one-pot Michael reaction
2
88 | Org. Biomol. Chem., 2007, 5, 286–300
This journal is © The Royal Society of Chemistry 2007

View Article Online
This journal is © The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 286–300 | 289

View Article Online
Fig. 3 ORTEP drawing of c-endo-4h showing the thermal ellipsoids at
the 30% probability level.
ꢀ
were performed at the HF/6–31G* level with compounds 3 as
21
models of the annulation precursors. Since the counter cation
experiments suggested the presence of loose interaction of the
ammonium ion with the enolate oxygen, and not by metals, we
decided to ignore the counter cation as an approximation to
simplify the theoretical calculations. Both chair-like and boat-like
transition states leading to both a and c products were calculated.
Scheme 3 Intramolecular Michael reaction of anti- and syn-3f.
atom must be weaker than that of metals in metal enolates, and
this difference in interaction could be the reason for the observed
difference in regioselectivity, according to the base used.
To elucidate the factors controlling the observed selectivity,
ab initio calculations on the intramolecular Michael reactions
ꢀ
ꢀ
ꢀ
The relative energies of the transition states for 3a –c and h are
22
summarized in Table 4. For transition states leading to both the
a- and c-products, the chair forms were more stable than the boat
forms, and the chair form (leading to the a-product) was the most
Table 3 One-pot Michael reactions of 2-cyclohexenones 1a, c and d with acrylates 2a, b and e
a
Entry
1
1
Acrylate
Conditions
Products
◦
(i) LDA, −78 C, THF,
◦
6
h; (ii) 90 C, 18 h
b
◦
2
(i) LDA, −78 C, THF,
◦
3
h; (ii) 110 C, 18 h
b,c
3
K
2
CO
3
, TBAB, toluene,
◦
rt, 24 h; then 110 C, 8 h
c
4
K
2
CO
3
, TBAB, toluene,
◦
◦
4
2
0 C, 18 h; then 80 C,
5 h
a
b
c
Isolated yield. The numbering is based on the bicyclo[3.3.1]non-2-ene core.
K
2
CO
3
(3.0 eq) and TBAB (1.0 eq) were used.
2
90 | Org. Biomol. Chem., 2007, 5, 286–300
This journal is © The Royal Society of Chemistry 2007

View Article Online
sterically favored TSa-chair transition state, since the two oxygen
functions are in an anti relationship, although it could be in force
for TSa-boat
.
Tables 5 and 6 indicate relative transition state energies in the
ꢀ
ꢀ
intramolecular Michael reaction for anti- and syn-3d –g at the
22
HF/6–31G* level, respectively. For the intramolecular Michael
ꢀ
ꢀ
reaction of anti-3d –g , the TSa-chair transition state was more
stable than the transition state, leading to the c-product by 5.9–
−
1
1
0.3 kcal mol (Table 5), which is larger than the differences in
Table 4. Experimentally, these diastereomers could be regarded as
species giving rise to only the a-product. Thus, it can be considered
that the TSc-chair transition states in the intramolecular Michael
ꢀ
ꢀ
reaction of anti-3d –g were destabilized by the R
3
substituents.
The relative difference in energy between the a and c-series for
ꢀ
ꢀ
syn-3d –g was rather small and in good accordance with the
higher proportion of the c-product compared with the anti-series
(Table 6). In the syn-series, whichever the product (a or c), the
chair-like transition state was much more stable.
Scheme 4 Effect of the counter cation in the intramolecular Michael
reaction.
The HOMOs and HOMO potential maps of the enolates
−
1
stable of the four. The TSa-chair transition state was ca. 4 kcal mol
ꢀ
ꢀ
24
generated from 3a and h are illustrated in Fig. 4. The HOMO
potential maps showed higher electron density at the C2-carbon
than at the C4-carbon, as would be expected from precedence
in similar conjugated systems. The 3-OMe substituent did not
affect the relative electron density. Thus, although we are dealing
with an intramolecular reaction and a-annulation gives rise to the
sterically hindered quaternary carbon in most of the examples, the
primary factor controlling regioselectivity here could be said to be
the profile of the HOMO.
23
ꢀ
more stable than the TSc-chair transition state, except for 3c and
h where the differences were much smaller. These calculations
ꢀ
3
nicely correspond with the experimental data from a relative point
of view. As a general trend, the experimental ratio of the cproduct
was higher than expected from calculation, thus it can be said that
our approximations in not considering the ammonium ion in the
calculations slightly underestimated the stability of the transition
state leading to the c product. In light of this good correlation
between experiment and calculation, it could be assumed that, in
the reaction involving t-BuOK, the potassium ion stabilizes the
TSc-chair transition state by electrostatic interaction with the ester
moiety of the acceptor. Similar interaction is not possible for the
Table 4 Relative energies of the transition state in the intramolecular
ꢀ
ꢀ
ꢀ
Michael reactions of 3a –c and h at the HF/6–31G* level
−
1
Relative energy/kcal mol
Entry
1
TSa-chair
TSa-boat
TScchair
TSc-boat
0
+8.80
+4.77
+9.72
2
3
4
0
0
0
+7.54
+8.91
+9.63
+0.06
+4.06
+1.76
+6.20
+8.98
+10.19
Fig. 4 HOMOs and HOMO potential maps of the enolates of 3aꢀ and hꢀ
by B3LYP/6–31G* calculations.
The significant difference in regioselectivity observed between
diastereomers of the anti series and the syn series can be attributed
to steric effects in the transition state (Fig. 5). For the anti series,
1
,2
ꢀ
there is an A strain between the 2 -carboxylate of the tether and
ꢀ
the 1 -R
3
group in the TSc-chair transition state. This strain should
Org. Biomol. Chem., 2007, 5, 286–300 | 291
This journal is © The Royal Society of Chemistry 2007

View Article Online
ꢀ
ꢀ
Table 5 Relative energies of the transition state in the intramolecular Michael reactions of anti-3d –g at the HF/6–31G* level
−
1
Relative energy/kcal mol
Entry
1
TSa-chair
TSa-boat
TSc-chair
TScboat
a
a
a
a
0 (−765.695)
+9.97
+5.91 (−765.686)
+7.75
a
2
3
4
0 (−914.326)
0 (−953.295)
+9.41
+10.53 (−914.309)
+7.29
+7.29
+8.54
a
+10.07
+10.00
+9.42 (−953.280)
a
a
0 (−1140.889)
+7.19 (−1140.876)
a
The absolute energy (au) calculaated at the HF/6–31G* level in parentheses.
ꢀ
ꢀ
Table 6 Relative energies of the transition state in the intramolecular Michael reactions of syn-3d –g at the HF/6–31G* level
−
1
Relative energy/kcal mol
Entry
1
TSa-chair
TSa-boat
TSc-chairt
TSc-boat
a
a
a
a
a
a
0 (−765.692)
+8.27
+1.48 (−765.689)
+3.93 (−914.321)
+1.85 (−953.292)
+8.83
2
3
4
0 (−914.626)
0 (−953.295)
+11.03
+9.57
+9.23
+14.13
+19.28
a
a
0 (−1140.896)
+13.71
+2.53 (−1140.892)
a
The absolute energy (au) calculated at the HF/6–31G* level in parentheses.
2
92 | Org. Biomol. Chem., 2007, 5, 286–300
This journal is © The Royal Society of Chemistry 2007

View Article Online
Fig. 5 Newman projection of the transition state in the intramolecular
Michael reaction of anti- and syn-3d–g.
disfavour the TSc-chair transition state, and increase the energy
difference between the TSa-chair and TSc-chair transition states, with
the difference calculated between the two chair-type transition
Scheme 5 Stereoselectivity in the intramolecular Michael reactions of
3a–c.
ꢀ
states for the corresponding 1 -unsubstituted substrates (Table 5).
In some cases, this steric hindrance seemed to be so significant,
that the TSc-chair transition state was calculated to be higher in
energy (Table 5, entries 2 and 3). Conversely, for the syn series,
the absolute energy of the TSc-chair transition state was uniformly
lower than that of the corresponding anti TSc-chair transition state,
2
which function as double Michael acceptors. The construction
could be carried out in both a stepwise and a one-pot reaction
with similar tendencies in regioselectivity. The generally high a-
regioselectivity in the intramolecular Michael reaction was in good
correlation with the profile of the HOMO orbital of enolate I, as
usually observed for similar conjugated enolates in intermolecular
reactions. However, the regioselectivity was somewhat dependent
1
,2
most likely due to release of the A strain. As for the syn TSa-chair
1
,2
transition state, the A strain becomes operative and serves as an
destabilizing factor. However, there is also stabilization gained by
relief of the repulsive electrostatic interaction present in the anti
on the substitution pattern of the reactants (R
2
or R ). Consequent
3
protonation was also selective, but the preferred face differed
with the substitution pattern. In both the intramolecular Michael
reaction and the protonation of enolate II, the ammonium counter
cation played an important role. Synthetic studies towards natural
products using the developed methodology are now in progress.
TSa-chair transition state between the R
3
or R ester and the keto-
4
carbonyl groups. Thus, the relative stability between the anti and
syn TSa-chair transition states seems to depend upon which of these
offsetting factors contributes more. Nonetheless, the overall effect
is a narrowing down in the energy gap between the TSa-chair and the
TSc-chair transition states (Table 6).
Schemes 5 and 6 summarize the major pathways for the
reactions of 3a–h. The observed selectivity in the protonation of
enolate II for 3a, b and d can be rationalized to be due to reaction
from the less crowded convex side, i.e., the exo side, giving the endo
Experimental
All reactions involving air- and moisture-sensitive reagent were
products as the exclusive or the major products (R
As for the opposite propensity observed when R
3c and e–g), the reason is less obvious and we can only make a
guess. It could be that since these Et esters are less prone to steric
hindrance than their t-Bu counterparts, electrostatic interaction
2
or R
or R
3
= H, Me).
carried out under N . Tetrahydrofuran (THF) was distilled after
2
2
3
is CO Et
2
refluxing over Na–benzophenone before use. Merck silica gel
60F254 TLC aluminum sheets was used for routine monitoring
of reaction. Column chromatography was performed on Merck
silica gel 60 (70–230 mesh, ASTM). Merck silica gel 60F254 was
used for preparative thin-layer chromatography.
(
between the R
2
or R ester and the ammonium ion, which can
3
be assumed to preside near the enolate oxygen on the convex
side of the molecule in enolate II, is at play, thereby making the
convex face more hindered than the concave face. This would direct
protonation to occur upon the endo face.
Melting points were taken on a Yanagimoto melting-point
apparatus. NMR spectra were recorded on JEOL JNM-LA500
1
instruments. Internal references for H NMR spectra were Me
4
Si
(TMS; 0.0 ppm) for CDCl
ppm), and C CD (2.09 ppm). Chemical shifts for C NMR
spectra were referenced to CDCl (77.0 ppm), CD OD (49.0 ppm),
N (135.5 ppm), and C CD (20.4 ppm). MS were recorded
3
, CD
3
OD (3.30 ppm), C
5
D
5
N (7.55
1
3
6
D
5
3
3
3
Conclusions
C
5
D
5
6
D
5
3
In summary, we have developed a practical method for the
construction of poly-functionalized bicyclo[3.3.1]nonenones by
successive Michael reactions of cyclohexenones 1 with acrylates
on a JEOL JMS-SX102A instrument under electron ionization
(EI) conditions (70 eV). Elemental analyses were carried out on a
Perkin-Elmer 2400II analyzer.
This journal is © The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 286–300 | 293

View Article Online
Scheme 6 Stereoselectivity in the intramolecular Michael reactions of anti- and syn-3d–h.
Typical procedure for preparation of the annulation
precursor using LDA
was added a solution of cyclohexenone 1a (50.2 mg, 0.40 mmol)
◦
in THF (0.5 mL) at −78 C. The reaction mixture was stirred at
◦
−
78 C for 30 min. Then, a solution of acrylate 2a (81.2 mg,
To a stirred solution of LDA, prepared from i-Pr
2
NH (0.30 mL,
0
.48 mmol) in THF (0.5 mL) was added to the mixture at
2
.32 mmol) and n-BuLi (1.56 M in THF, 1.20 mL, 1.93 mmol),
◦
−
78 C. After the reaction mixture was allowed to warm to rt
was added a solution of cyclohexenone 1a (201.1 mg, 1.62 mmol)
over 6 h, to the reaction mixture was added K
2
CO (167.7 mg,
3
◦
in THF (0.5 mL) at −78 C. After 0.5 h, a solution of acrylate 2a
1
.21 mmol) and TBAB (130.9 mg, 0.41 mmol). The mixture was
(
322.4 mg, 1.61 mmol) in THF (0.5 mL) was added and the mixture
◦
stirred at 90 C for 18 h. After complete consumption of 3a, by
◦
was stirred at −78 C for 6.5 h. The mixture was quenched with sat.
GC monitoring, the mixture was cooled to rt and quenched with
NH
4
Cl and extracted with Et
2
O. The combined organic layer was
SO , and evaporated. The
sat. NH
combined organic layer was washed with H
over MgSO , filtered and evaporated. The resulting residue was
4
Cl. The resulting mixture was extracted with Et
2
O. The
washed with water, brine, dried over Na
2
4
2
O and brine, dried
resulting residue was purified by column chromatography (silica
gel, hexane–EtOAc 10 : 1) to give 3a (355.3 mg, 83%).
4
purified by preparative TLC (silica gel, hexane–EtOAc 10 : 1)
to give a-endo-4a (36.1 mg, 34%), a-exo-4a (33.5 mg, 32%), and
c-endo-4a (4.0 mg, 4%).
Typical procedure for the intramolecular Michael reaction
To a solution of 3a (203.3 mg, 0.77 mmol) in toluene (1.0 mL)
were added K
2
CO
3
(319.3 mg, 2.31 mmol) and TBAB (248.3 mg,
Typical procedure for the one-pot Michael reactions
by one operation
◦
0
.77 mmol). The mixture was stirred at 90 C for 15.5 h. After
complete consumption of 3a by GC monitoring, the mixture
was cooled to rt and quenched with sat. NH Cl. The resulting
mixture was extracted with ether. The combined organic layer
was washed with H O, brine, dried over MgSO , filtered and
evaporated. The resulting residue was purified by preparative TLC
silica gel, hexane–EtOAc 10 : 1) to give annulation products a-
To a solution of cyclohexenone 1d (100.7 mg, 0.48 mmol) in THF
4
(
(
1.5 mL) were added acrylate 2a (94.5 mg, 0.48 mmol), K
2
CO
3
203.6 mg, 1.47 mmol) and TBAB (152.6 mg, 0.47 mmol). The
2
4
◦
resulting mixture was warmed to 45 C and stirred for 18 h.
After complete consumption of 1d by GC monitoring, the reaction
(
◦
mixture was heated to 80 C and stirred. After 25 h, the mixture
endo-4a (183.0 mg, 90%) and c-endo-4a (6.7 mg, 3%).
was quenched with sat. NH
combined organic layer was washed with H
over MgSO , filtered and evaporated. The resulting residue was
4
Cl and extracted with Et
2
O. The
2
O and brine, dried
Typical procedure for the one-pot Michael reactions
by two operations
4
purified by preparative TLC (silica gel, EtOAc–hexane 1 : 10) to
give a-endo-4h (35.5 mg, 25%), a-exo-4h (8.5 mg, 6%), and c-endo-
4h (49.1 mg, 35%).
To a solution of LDA, prepared from i-Pr
2
NH (0.080 mL,
0
.58 mmol) and n-BuLi (1.56 M in THF, 0.31 mL, 0.48 mmol),
2
94 | Org. Biomol. Chem., 2007, 5, 286–300
This journal is © The Royal Society of Chemistry 2007

View Article Online
1
3
6
-Ethoxycarbonyl-2-methyl-2-cyclohexenone (1c). Yellow oil;
3 H), 1.03 (s, 3 H); C NMR (125 MHz, CDCl
3
) d 202.4, 167.4,
1
H NMR (500 MHz, CDCl ) d 6.76–6.72 (m, 1 H), 4.24 (dq,
3
165.7, 145.3, 142.8, 134.2, 128.0, 61.5, 60.5, 45.5, 36.0, 32.6, 22.7,
+
J = 10.7, 7.0 Hz, 1 H), 4.19 (dq, J = 10.7, 7.0 Hz, 1 H), 3.37–3.41
21.5, 16.5, 14.1, 14.0; HR-EIMS: m/z calcd for C17
H
24
O
5
[M ]:
(
m, 1 H), 2.48–2.32 (m, 3 H), 2.22–2.16 (m, 1 H), 1.80 (dt, J =
308.1624. Found: 308.1630; anal. calcd for C17
7.84. Found: C, 66.13; H, 8.10.
H
24
O
5
: C, 66.21; H,
1
3
1
.8, 1.5 Hz, 3 H), 1.28 (t, J = 7.0 Hz, 3 H); C NMR (125 MHz,
) d 194.5, 170.3, 145.3, 135.2, 61.0, 53.6, 26.1, 24.4, 15.9,
4.1; anal. calcd for C10 : C, 65.91; H, 7.74. Found: C, 65.71;
H, 7.61.
CDCl
1
3
ꢀ
ꢀ
ꢀ
ꢀ
6
-(2 Z-2 -Ethoxylcarbonyl-3 -ethoxylcarbonyl-2 -propenyl)-2,6-
H
14
O
3
1
dimethyl-2-cyclohexenone (Z-3c). Yellow oil;
H
NMR
(
500 MHz, CDCl
3
) d 6.66–6.62 (m, 1 H), 5.83 (t, J = 1.0 Hz,
3
-Acetoxy-2-methylenebutylic acid tert-butyl ester (2a). Yellow
1 H), 4.24 (dq, J = 10.7, 7.0 Hz, 1 H), 4.19 (dq, J = 10.7, 7.0 Hz,
1 H), 4.16 (q, J = 7.0 Hz, 2 H), 2.95 (dd, J = 13.7, 1.2 Hz, 1 H),
2.42–2.30 (m, 2 H), 2.37 (dd, J = 13.7, 0.9 Hz, 1 H), 2.08 (ddd,
J = 13.4, 9.4, 5.5 Hz, 1 H), 1.76 (q, J = 1.6 Hz, 3 H), 1.71 (dt, J =
13.4, 4.9 Hz, 1 H), 1.31 (t, J = 7.0 Hz, 3 H), 1.26 (t, J = 7.0 Hz,
1
oil; H NMR (500 MHz, CDCl
(
(
8
8
3
) d 6.26 (q, J = 1.2 Hz, 1 H), 5.74
q, J = 1.2 Hz, 1 H), 4.77 (t, J = 1.2 Hz, 2 H), 2.10 (s, 3 H), 1.50
s, 9 H); C NMR (125 MHz, CDCl ) d 170.4, 164.4, 136.9, 126.1,
1.3, 62.6, 28.0 (×3), 20.8; anal. calcd for C10 : C, 59,98; H,
.05. Found: C, 59.81; H, 7.90.
1
3
3
H
16
O
4
1
3
3 H), 1.12 (s, 3 H); C NMR (125 MHz, CDCl
3
) d 201.9, 168.6,
1
2
3
7
64.5, 146.5, 143.5, 133.9, 123.9, 61.3, 60.7, 45.0, 42.0, 32.8, 22.7,
1
6a
3
-Acetoxy-2-methylenebutylic acid tert-butyl ester (2b)
.
Col-
) d 6.19 (t, J = 1.2 Hz, 1 H),
.71 (t, J = 1.2 Hz, 1 H), 5.68 (qt, J = 6.7, 1.2 Hz, 1 H), 2.07 (s,
+
2.5, 16.4, 14.0, 13.8; HR-EIMS: m/z calcd for C17
H
24
O
5
[M ]:
1
orless oil; H NMR (500 MHz, CDCl
3
08.1624. Found: 308.1631; anal. calcd for C17
.84. Found: C, 66.49; H, 7.84.
H
24
O
5
: C, 66.21; H,
5
3
1
3
H), 1.50 (s, 9 H), 1.39 (d, J = 6.7 Hz, 3 H); C NMR (125 MHz,
ꢀ
ꢀ
ꢀ
CDCl
3
) d 169.7, 164.5, 142.6, 123.4, 81.2, 68.2, 28.0 (×3), 21.1,
6-(2 -tert-Butoxycarbonyl-1 -methyl-2 -propenyl)-2,6-dimethyl-
2-cyclohexenone (3d). A mixture of diastereomers: dr 3.6 : 1.0;
yellow oil; major-3d: H NMR (500 MHz, CDCl ) d 6.65–6.62
+
2
2
6
0.0; EI-HRMS: m/z calcd for C11
14.1202. Anal. calcd for C11
1.63; H, 8.56.
H
18
O
4
[M ]: 214.1205. Found:
1
H
18
O
4
: C, 61.66; H, 8.47. Found: C,
3
(m, 1 H), 6.25 (d, J = 1.2 Hz, 1 H), 5.45 (bs, 1 H), 3.55 (d, J =
7
1
0
1
1
1
.3 Hz, 1 H), 2.45–2.36 (m, 1 H), 2.28–2.19 (m, 1 H), 2.03–1.95 (m,
3
-Acetoxy-3-ethoxycarbonyl-2-methylenepropionic acid ethyl es-
H), 1.79–1.70 (m, 4 H), 1.54 (s, 9 H), 1.06 (d, J = 7.3 Hz, 3 H),
16b
1
ter (2c)
.
Colorless oil; H NMR (500 MHz, CDCl ) d 6.49 (s,
3
1
3
.93 (s, 3 H). C NMR (125 MHz, CDCl ) d 203.3, 166.8, 142.4,
34.8, 125.0, 124.6, 80.3, 47.0, 34.6, 31.4, 28.0 (×3), 22.3, 18.6,
3
1
H), 5.98 (s, 1 H), 5.98 (s, 1 H), 4.26 (q, J = 7.0 Hz, 2 H), 4.22 (q,
J = 7.0 Hz, 2 H), 2.17 (s, 3 H), 1.31 (t, J = 7.0 Hz, 3 H), 1.26 (t,
1
6.6, 15.3; minor-3d: H NMR (500 MHz, CDCl
3
) d 6.62–6.59 (m,
J = 7.0 Hz, 3 H).
6
H), 6.13 (d, J = 1.2 Hz, 1 H), 5.50 (bs, 1 H), 3.33 (d, J = 7.3 Hz,
ꢀ
ꢀ
-(2 -tert-Butoxycarbonyl-2 -propenyl)-2,6-dimethyl-2-cyclohexe-
1 H), 2.73–2.55 (m, 1 H), 2.17–2.10 (m, 1 H), 2.03–1.95 (m, 1 H),
1
none (3a). Yellow oil; H NMR (500 MHz, CDCl
3
) d 6.64–6.61
1.79–1.70 (m, 4 H), 1.50 (s, 9 H), 1.00 (d, J = 7.3 Hz, 3 H), 0.98 (s,
+
(
m, 1 H), 6.12 (d, J = 1.8 Hz, 1 H), 5.44 (dt, J = 1.8, 0.9 Hz,
3 H); HR-EIMS m/z calcd for C17
H
26
O
3
[M ]: 278.1882. Found:
1
1
1
H), 2.70 (dd, J = 13.4, 0.9 Hz, 1 H), 2.47 (dd, J = 13.4, 0.9 Hz,
278.1876; anal. calcd for C17
73.46; H, 9.63.
H
26
3
O : C, 73.34; H, 9.41. Found: C,
H), 2.46–2.38 (m, 1 H), 2.32–2.24 (m, 1 H), 1.87–1.77 (m, 2 H),
1
3
.76 (q, J = 1.8 Hz, 3 H), 1.48 (s, 9 H), 1.04 (s, 3 H); C NMR
ꢀ
ꢀ
ꢀ
6
-(1 ,2 -Diethoxycarbonyl-2 -propenyl)-2-methyl-2-cyclohexen-
(
125 MHz, CDCl
3
) d 203.1, 166.9, 143.1, 138.6, 134.2, 127.3,
one (3e). a mixture of diastereomers: dr 2.1 : 1; yellow oil; major-
8
0.4, 44.9, 37.2, 33.9, 27.9 (×3), 22.7, 22.0, 16.5; HR-EIMS:
1
3e: H NMR (500 MHz, CDCl ) d 6.72–6.68 (m, 1 H), 6.41 (s, 1 H),
3
+
m/z calcd for C16
calcd for C16
.08.
H
24
O
3
[M ]: 264.1725. Found: 264.1736; anal.
5
.69 (s, 1 H), 4.32 (d, J = 6.1 Hz, 1 H), 4.26–4.11 (m, 4 H), 2.83
H
24
O
3
: C, 72.69; H, 9.15. Found: C, 72.66; H,
(
(
ddd, J = 12.8, 6.1, 4.6 Hz, 1 H), 2.45–2.27 (m, 2 H), 2.20–2.10
9
m, 1 H), 1.99–1.91 (m, 1 H), 1.77 (s, 3 H), 1.31 (t, J = 7.0 Hz,
ꢀ
ꢀ
13
6
-(2 -tert-Butoxycarbonyl-2 -Z-butenyl)-2,6-dimethyl-2-cyclo-
hexenone (3b). Yellow oil; H NMR (500 MHz, CDCl
3 H), 1.23 (t, J = 7.0 Hz, 3 H); C NMR (125 MHz, CDCl
3
)
1
3
) d 6.82
d 199.0, 172.0, 166.1, 144.5, 137.2, 135.4, 127.2, 61.1, 60.7, 48.8,
1
(
q, J = 7.3 Hz, 1 H), 6.65–6.61 (m, 1 H), 2.85 (d, J = 13.7 Hz,
45.5, 26.4, 25.4, 16.0, 14.1, 14.0; minor-3e: H NMR (500 MHz,
CDCl ) d 6.69–6.66 (m, 1 H), 6.41 (s, 1 H), 5.89 (s, 1 H), 4.26–4.11
1
2
1
H), 2.54–2.45 (m, 1 H), 2.43 (d, J = 13.7 Hz, 1 H), 2.29–
3
.20 (m, 1 H), 1.90–1.79 (m, 2 H), 1.76 (q, J = 1.7 Hz, 3 H),
(m, 4 H), 3.95 (d, J = 9.1 Hz, 1 H), 3.09 (ddd, J = 14.3, 9.1,
4.3 Hz, 1 H), 2.45–2.27 (m, 2 H), 1.99–1.91 (m, 1 H), 1.76 (s, 3 H),
1.72–1.61 (m, 1 H), 1.30 (t, J = 7.0 Hz, 3 H), 1.26 (t, J = 7.0 Hz,
1
3
.74 (d, J = 7.3 Hz, 3 H), 1.46 (s, 9 H), 1.01 (s, 3 H);
C
NMR (125 MHz, CDCl
3
) d 203.3, 167.9, 143.0, 138.4, 134.2,
1
3
1
31.5, 80.0, 45.7, 35.3, 31.8, 28.1 (×3), 22.8, 21.9, 16.6, 15.2; HR-
3 H); C NMR (125 MHz, CDCl ) d 199.9, 172.8, 166.1, 144.4,
3
+
EIMS: m/z calcd for C17
anal. calcd for C17
.50.
H
26
O
3
[M ] 278.1882. Found: 278.1893;
137.2, 135.2, 128.1, 61.1, 60.9, 49.8, 45.6, 26.1, 25.7, 15.9, 14.1,
+
H
26
O
3
: C, 73.34; H, 9.41. Found: C, 73.06; H,
14.0; HR-EIMS: m/z calcd for C17
294.1475; anal. calcd for C17 : C, 65.29; H, 7.53. Found: C,
5.06; H, 7.53.
H
22
O [M ]: 294.1467. Found:
5
9
H
22
O
5
6
ꢀ
ꢀ
ꢀ
ꢀ
6
-(2 E-2 -Ethoxylcarbonyl-3 -ethoxylcarbonyl-2 -propenyl)-2,6-
1
ꢀ
ꢀ
ꢀ
dimethyl-2-cyclohexenone (E-3c). Yellow oil;
500 MHz, CDCl ) d 6.74 (s, 1 H), 6.65–6.61 (m, 1 H),
.26–4.14 (m, 4 H), 3.30 (d, J = 12.5 Hz, 1 H), 3.17 (d, J =
2.5 Hz, 1 H), 2.54–2.44 (m, 1 H), 2.30–2.20 (m, 1 H), 1.94 (dt,
H
NMR
6-(1 ,2 -Diethoxycarbonyl-2 -propenyl)-2,6-dimethyl-2-cyclohexen-
one (3f). A mixture of diastereomers: dr 1 : 1.2; yellow oil;
major-3f: H NMR (500 MHz, CDCl ) d 6.64–6.60 (m, 1 H),
6.49 (s, 1 H), 6.10 (s, 1 H), 4.23 (q, J = 7.1 Hz, 2 H), 4.15 (dq,
J = 10.8, 7.1 Hz, 1 H), 4.12 (s, 1 H), 4.10 (dq, J = 10.8, 7.1 Hz,
1 H), 2.40–2.30 (m, 2 H), 1.96 (ddd, J = 13.5, 8.5, 6.4 Hz, 1 H),
(
3
1
4
1
3
J = 13.4, 5.2 Hz, 1 H), 1.87 (ddd, J = 13.4, 8.5, 5.5 Hz, 1 H), 1.74
(
q, J = 1.8 Hz, 3 H), 1.31 (t, J = 7.3 Hz, 3 H), 1.30 (t, J = 7.3 Hz,
This journal is © The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 286–300 | 295

View Article Online
1
.77 (q, J = 1.6 Hz, 3 H), 1.71 (dt, J = 13.5, 4.8 Hz, 1 H), 1.31
1 H), 2.27 (dddd, J = 17.7, 2.7, 2.4, 1.8 Hz, 1 H), 2.21 (dt, J = 7.6,
1.5 Hz, 1 H), 1.86 (ddd, J = 14.6, 7.6, 1.8 Hz, 1 H), 1.48 (s, 9 H),
1
3
(
t, J = 7.1 Hz, 3 H), 1.30 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H);
C
1
3
NMR (125 MHz, CDCl
3
) d 201.8, 171.5, 166.8, 143.1, 135.2,
1.06 (s, 3 H), 1.06 (s, 3 H), 0.93 (d, J = 7.3 Hz, 3 H); C NMR
3
1
1
1
2
1
1
3
1
2
3
7
33.7, 129.6, 61.1, 60.4, 48.4, 47.7, 32.5, 22.4, 17.6, 16.3, 14.0,
3.9; minor-3f: H NMR (500 MHz, CDCl
H), 6.48 (s, 1 H), 5.74 (s, 1 H), 4.37 (s, 1 H), 4.20 (q, J = 7.1 Hz,
H), 4.08 (q, J = 7.1 Hz, 2 H), 2.55 (ddd, J = 13.3, 10.1, 6.1 Hz,
H), 2.40–2.25 (m, 2 H), 1.79 (q, J = 1.6 Hz, 3 H), 1.56 (dt, J =
3.3, 3.9 Hz, 1 H), 1.30 (t, J = 7.1 Hz, 3 H), 1.19 (t, J = 7.1 Hz,
(125 MHz, CDCl ) d 216.4, 172.9, 134.9, 127.6, 80.5, 50.2, 46.2,
1
3
) d 6.67–6.63 (m,
45.3, 44.3, 43.7, 38.2, 28.0 (×3), 23.9, 19.4, 16.3; HR-EIMS: m/z
+
calcd for C17
H
26
O
3
[M ]: 278.1882. Found: 278.1881; anal. calcd
for C17
H
26
3
O : C, 73.34; H, 9.41. Found: C, 73.10; H, 9.37.
7
-endo-tert-Butoxycarbonyl-1,2,6-exo-trimethylbicyclo[3.3.1]non-
1
1
3
3-en-2-one (c-7-endo,8-exo-4b). Yellow oil; H NMR (500 MHz,
H), 1.05 (s, 3 H); C NMR (125 MHz, CDCl ) d 201.9, 171.9,
3
CDCl ) d 6.63–6.60 (m, 1 H), 2.64–2.57 (m, 1 H), 2.28–2.23 (m,
3
66.2, 142.8, 135.6, 133.9, 129.9, 61.0, 60.4, 51.1, 46.1, 29.8, 22.3,
0.4, 16.4, 13.9, 13.8; HR-EIMS: m/z calcd for C17
08.1624. Found: 308.1630; anal. calcd for C17
.84. Found: C, 66.08; H, 7.72.
+
2 H), 2.22–2.17 (m, 1 H), 1.90–1.85 (m, 1 H), 1.80 (ddd, J = 12.8,
H
24
O
5
[M ]:
2
1
.7, 2.1 Hz, 1 H), 1.65 (bs, 3 H), 1.54 (dd, J = 14.0, 7.3 Hz, 1 H),
.37 (s, 9 H), 1.24 (d, J = 7.3 Hz, 3 H), 1.09 (s, 3 H); C NMR
) d 203.3, 173.3, 147.7, 136.1, 80.2, 43.9, 41.2,
H
24
O
5
: C, 66.21; H,
1
3
(125 MHz, CDCl
3
ꢀ
ꢀ
ꢀ
3
7.1, 35.4, 31.6, 28.9, 28.1 (×3), 25.5, 20.1, 16.4; HR-EIMS: m/z
6
-(1 ,2 -Diethoxycarbonyl-2 -propenyl)-6-ethoxycarbonyl-2-methyl-
+
calcd for C17
for C17
H
26
O
3
[M ]: 278.1882. Found: 278.1891; anal. calcd
2
-cyclohexenone (3g). A mixture of diastereomers: dr 4.5 : 1;
yellow oil; major-3g: H NMR (500 MHz, CDCl
1
H
26
O
3
: C, 73.34; H, 9.41. Found: C, 73.57; H, 9.45.
3
) d 6.63–6.60
(
6
2
m, 1 H), 6.48 (s, 1 H), 5.73 (s, 1 H), 4.69 (s, 1 H), 4.25–4.05 (m,
7
-exo,8-exo-Diethoxycarbonyl-1,5-dimethylbicyclo[3.3.1]non-2-
H), 2.66 (ddd, J = 13.1, 11.3, 5.5 Hz, 1 H), 2.46–2.35 (m, 1 H),
1
en-9-one (a-7-exo,8-exo-4c). Yellow oil; H NMR (500 MHz,
CDCl
) d 5.88 (ddd, J = 9.4, 4.0, 3.1 Hz, 1 H), 5.34 (ddd, J =
.4, 2.4, 1.2 Hz, 1 H), 4.18–4.06 (m, 2 H), 4.18–4.06 (m, 2 H), 3.51
.35–2.25 (m, 1 H), 2.30–2.25 (m, 1 H), 1.82–1.80 (m, 3 H), 1.30
3
(
t, J = 7.0 Hz, 3 H), 1.22 (t, J = 7.0 Hz, 3 H), 1.21 (t, J = 7.0 Hz,
9
(
(
2
5
3
1
3
3
1
1
H). C NMR (125 MHz, CDCl
3
) d 194.7, 171.1, 169.6, 166.0,
dt, J = 13.7, 5.2 Hz, 1 H), 3.01 (dd, J = 5.2, 1.8 Hz, 1 H), 2.59
44.0, 135.3, 135.1, 129.7, 61.6, 61.3, 60.9, 59.1, 47.6, 27.1, 23.5,
ddd, J = 18.6, 4.0, 1.2 Hz, 1 H), 2.52 (td, J = 13.7, 1.8 Hz, 1 H),
1
6.4, 14.1, 13.9, 13.8; minor-3g: H NMR (500 MHz, CDCl )
3
.45 (dddd, J = 18.6, 3.1, 2.4, 1.8 Hz, 1 H), 2.03 (ddd, J = 13.7,
.2, 1.8 Hz, 1 H), 1.24 (t, J = 7.0 Hz, 3 H), 1.24 (t, J = 7.0 Hz,
H), 1.14 (s, 3 H), 1.12 (s, 3 H).
d 6.63–6.60 (m, 1 H), 6.52 (s, 1 H), 5.97 (s, 1 H), 4.39 (s, 1 H),
4
2
1
.25–4.05 (m, 6 H), 2.46–2.35 (m, 1 H), 2.35–2.23 (m, 2 H),
.22–2.14 (m, 1 H), 1.82–1.80 (m, 3 H), 1.31 (t, J = 7.0 Hz, 3 H),
1
3
.24 (t, J = 7.0 Hz, 3 H), 1.21 (t, J = 7.0 Hz, 3 H); C NMR
6-exo,7exo-Diethoxycarbonyl-1,3-dimethylbicyclo[3.3.1]non-3-
en-2-one (c-7-exo,8-exo-4c). Yellow oil; H NMR (500 MHz,
C D N) d 6.70–6.64 (m, 1 H), 4.22–4.08 (m, 4 H), 3.30–3.27 (m,
1
(125 MHz, CDCl
3
) d 195.5, 171.3, 170.2, 166.7, 143.7, 135.2,
1
1
34.7, 129.0, 61.5, 61.2, 61.0, 59.1, 48.9, 30.5, 23.6, 16.4, 14.1,
6
5
+
3.9, 13.8; HR-EIMS: m/z calcd for C19
H
26
O
7
[M ]: 366.1679.
1 H), 3.08–3.04 (m, 1 H), 2.83 (dt, J = 13.4, 5.2 Hz, 1 H), 2.20
(t, J = 13.4 Hz, 1 H), 2.14 (ddd, J = 13.4, 5.2, 1.8 Hz, 1 H),
1.92–1.86 (m, 1 H), 1.82 (bs, 3 H), 1.64 (ddd, J = 13.1, 2.1, 2.1 Hz,
Found: 366.1662; anal. calcd for C19
Found: C, 61.98; H, 7.45.
H
26
O
7
: C, 62.28; H, 7.15.
1
3
1
1
3
H), 1.15 (t, J = 7.0 Hz, 3 H), 1.14 (s, 3 H), 1.11 (t, J = 7.0 Hz,
7
-endo-tert-Butoxycarbonyl-1,5-dimethylbicyclo[3.3.1]non-2-en-
13
H); C NMR (125 MHz, C
6
5
D N) d 202.7, 173.5, 172.7, 145.8,
◦
1
9
-one (a-endo-4a). yellow solid; mp 75 C; H NMR (500 MHz,
CDCl
) d 5.55 (ddd, J = 9.7, 4.3, 2.4 Hz, 1 H), 5.30 (ddd, J = 9.7,
.7, 1.2 Hz, 1 H), 2.81 (ddd, J = 18.3, 4.3, 0.9 Hz, 1 H), 2.73 (ddd,
J = 14.3, 3.4, 1.8 Hz, 1 H), 2.59 (ddd, J = 14.0, 3.7, 1.8 Hz, 1 H),
.43 (ddt, J = 7.3, 6.4, 1.8 Hz, 1 H), 2.31–2.25 (m, 1 H), 1.80 (dd,
J = 14.0, 6.4 Hz, 1 H), 1.72 (ddd, J = 14.3, 7.3, 1.8 Hz, 1 H), 1.47
s, 9 H), 1.09 (s, 3 H), 1.07 (s, 3 H); C NMR (500 MHz, CDCl
d 216.5, 172.9, 133.4, 128.3, 80.5, 46.5, 45.5, 43.7, 42.5, 41.4, 38.1,
38.8, 61.0, 60.6, 42.6, 41.8, 37.4, 36.7, 35.0, 34.4, 25.1, 16.0, 14.2,
4.2; HR-EIMS: m/z calcd for C17
08.1633.
3
+
H
24
O [M ]: 308.1624. Found:
5
2
2
7-endo-tert-Butoxycarbonyl-1,5,6-exo-trimethylbicyclo[3.3.1]non-
2-en-9-one (a-6-exo,7-endo-4d). Yellow oil; H NMR (500 MHz,
CDCl
1
1
3
(
3
)
3
) d 5.52 (ddd, J = 9.4, 4.0, 2.7 Hz, 1 H), 5.30 (ddd, J = 9.4,
2.7, 0.9 Hz, 1 H), 2.99 (ddd, J = 18.3, 4.0, 0.9 Hz, 1 H), 2.92 (qt,
J = 7.3, 2.1 Hz, 1 H), 2.48 (dt, J = 14.0, 2.1 Hz, 1 H), 2.27 (dt,
J = 18.3, 2.7 Hz, 1 H), 2.22 (dt, J = 6.4, 2.1 Hz, 1 H), 1.87 (dd,
J = 14.0, 6.4 Hz, 1 H), 1.47 (s, 9 H), 1.08 (s, 3 H), 1.05 (s, 3 H),
+
2
2
9
7.9 (×3), 24.0, 21.6; HR-EIMS: m/z calcd for C16
H
24
O
3
[M ]:
64.1725. Found: 264.1734; anal. calcd for C16
.15. Found: C, 72.79; H, 9.23.
H
24
O
3
: C, 72.69; H,
1
3
0
1
(
2
.92 (d, J = 7.3 Hz, 3 H). C NMR (125 MHz, CDCl
3
) d 216.0,
7
-endo-tert-Butoxycarbonyl-1,3-dimethylbicyclo[3.3.1]non-3-en-
72.9, 133.6, 128.2, 80.5, 48.7, 46.3, 45.9, 45.2, 44.1, 37.8, 27.9
1
+
2
-one (c-endo-4a). Yellow oil; H NMR (500 MHz, CDCl )
3
×3), 21.7, 21.6, 18.7; HR-EIMS: m/z calcd for C17
H
26
O
3
[M ]:
d: 6.60–6.56 (m, 1 H), 2.59–2.54 (m, 1 H), 2.57–2.53 (m, 1 H),
.40–2.35 (m, 1 H), 2.37–2.32 (m, 1 H), 2.14–2.09 (m, 1 H), 1.80
ddd, J = 14.0, 7.3, 4.0 Hz, 1 H), 1.66 (bs, 3 H), 1.57–1.53 (m,
H), 1.40 (dd, J = 14.0, 7.6 Hz, 1 H), 1.37 (s, 9 H), 1.09 (s, 3 H).
78.1882. Found: 278.1871; anal. calcd for C17
.41. Found: C, 73.64; H, 9.19.
H
26
O
3
: C, 73.34; H,
2
(
1
9
7-endo-tert-Butoxycarbonyl-1,3,8-exo-trimethylbicyclo[3.3.1]non-
◦
1
3
-en-2-one (c-6-exo,7-endo-4d). Yellow solid; mp 59 C;
H
7
-endo-tert-Butoxycarbonyl-1,5,8-exo-trimethylbicyclo[3.3.1]-
NMR (500 MHz, CDCl
3
) d 6.60–6.57 (m, 1 H), 2.52–2.47 (m,
◦
1
non-2-en-9-one (a-7-endo,8-exo-4b). Yellow solid; mp 77 C; H
NMR (500 MHz, CDCl
1 H), 2.45 (q, J = 7.3 Hz, 1 H), 2.29–2.23 (m, 2 H), 1.92 (ddd,
3
) d 5.50 (ddd, J = 9.4, 4.3, 2.4 Hz, 1 H),
J = 14.0, 6.7, 4.0 Hz, 1 H), 1.80–1.78 (m, 2 H), 1.66 (bs, 3 H),
1
3
5
2
.31 (ddd, J = 9.4, 2.7, 0.9 Hz, 1 H), 2.84 (qt, J = 7.3, 1.5 Hz, 1 H),
1.37 (s, 9 H), 1.08 (d, J = 7.3 Hz, 3 H), 1.02 (s, 3 H); C NMR
3
.78 (ddd, J = 17.7, 4.3, 0.9 Hz, 1 H), 2.66 (dt, J = 14.6, 1.5 Hz,
96 | Org. Biomol. Chem., 2007, 5, 286–300
(125 MHz, CDCl
) d 204.3, 173.2, 146.7, 136.6, 80.0, 45.3, 43.9,
2
This journal is © The Royal Society of Chemistry 2007

View Article Online
3
6.1, 33.7, 31.0, 28.1 (×3), 23.5, 23.4, 16.6, 15.9; HR-EIMS: m/z
6-endo,7-exo-Diethoxycarbonyl-1,5-dimethylbicyclo[3.3.1]non-
2-en-9-one (a-6-endo,7-exo-4f). Yellow oil; H NMR (500 MHz,
+
1
calcd for C17
for C17
H
26
O
3
[M ]: 278.1882. Found: 278.1887; anal. calcd
H
26
O
3
: C, 73.34; H, 9.41. Found: C, 73.14; H, 9.58.
CDCl
3
) d 5.85 (ddd, J = 9.4, 4.0, 3.1 Hz, 1 H), 5.39 (ddd, J = 9.4,
2
1
1
2
1
.4, 1.2 Hz, 1 H), 4.22–4.07 (m, 4 H), 3.56 (td, J = 12.7, 4.6 Hz,
6
-exo,7exo-Diethoxycarbonyl-1-methylbicyclo[3.3.1]non-2-en-9-
H), 3.03 (ddd, J = 18.9, 4.0, 1.2 Hz, 1 H), 2.77 (d, J = 12.7 Hz,
H), 2.14 (dd, J = 12.7, 4.6 Hz, 1 H), 2.08 (ddd, J = 18.9, 3.1,
.4 Hz, 1 H), 1.67 (t, J = 12.7 Hz, 1 H), 1.28 (t, J = 7.0 Hz, 3 H),
1
one (a-6-exo,7-exo-4e). Yellow oil; H NMR (500 MHz, CDCl
d 5.88–5.83 (m, 1 H), 5.42–5.38 (m, 1 H), 4.19–4.07 (m, 4 H),
3
)
3
1
1
3
.35–3.31 (m, 1 H), 3.29 (dt, J = 13.0, 4.9 Hz, 1 H), 2.92–2.89 (m,
H), 2.93–2.85 (m, 1 H), 2.60–2.52 (m, 1 H), 2.41 (t, J = 13.0 Hz,
H), 2.07 (ddd, J = 13.0, 4.9, 2.1 Hz, 1 H), 1.24 (t, J = 7.0 Hz,
13
.23 (t, J = 7.0 Hz, 3 H), 1.14 (s, 3 H), 1.13 (s, 3 H); C NMR
(
5
125 MHz, CDCl ) d 213.3, 173.8, 171.5, 132.6, 128.9, 61.0, 60.8,
3
6.0, 46.4, 46.1, 42.5, 40.1, 38.8, 22.2, 21.4, 14.2, 14.1; HR-EIMS:
1
3
H), 1.23 (t, J = 7.0 Hz, 3 H), 1.13 (s, 3 H); C NMR (125 MHz,
+
m/z calcd for C17
calcd for C17
H
24
O
5
[M ]: 308.1624. Found: 308.1635; anal.
CDCl
3
) d 212.8, 172.9, 171.9, 134.3, 127.7, 61.0, 60.9, 52.6, 46.6,
H
24
O
5
: C, 66.21; H, 7.84. Found: C, 66.01; H, 7.92.
4
5.9, 38.8, 37.9, 37.1, 21.1, 14.1, 14.0; HR-EIMS: m/z calcd for
+
C
16
H
22
O
5
[M ]: 294.1467. Found: 294.1471.
7-exo,8-exo-Diethoxycarbonyl-1,3-dimethylbicyclo[3.3.1]non-3-
1
en-2-one (c-6-exo,7-exo-4f). Yellow oil; H NMR (500 MHz,
6
-exo,7-endo-Diethoxycarbonyl-1-methylbicyclo[3.3.1]non-2-en-
CDCl
3
) d 6.82–6.78 (m, 1 H), 4.21–4.04 (m, 4 H), 2.88 (d, J =
.2 Hz, 1 H), 2.79–2.74 (m, 1 H), 2.65 (dt, J = 13.0, 5.2 Hz, 1 H),
.49 (td, J = 13.0, 4.6 Hz, 1 H), 2.21–2.15 (m, 1 H), 1.87–1.83
1
9
-one (a-6-exo,7-endo-4e). Yellow oil; H NMR (500 MHz,
5
2
(
CDCl
3
) d 5.56 (ddd, J = 9.5, 4.0, 2.5 Hz, 1 H), 5.30 (ddd, J = 9.5,
2
1
6
1
3
.5, 0.8 Hz, 1 H), 4.21–4.12 (m, 4 H), 3.90 (dd, J = 4.0, 2.2 Hz,
m, 1 H), 1.84–1.80 (m, 1 H), 1.81 (s, 3 H), 1.28 (t, J = 7.0 Hz,
H), 3.04–3.00 (m, 2 H), 2.84–2.79 (m, 1 H), 2.72 (ddt, J = 18.3,
.7, 2.5 Hz, 1 H), 2.58 (dt, J = 14.1, 2.2 Hz, 1 H), 2.09 (dd, J =
4.1, 6.6 Hz, 1 H), 1.30 (t, J = 7.0 Hz, 3 H), 1.26 (t, J = 7.0 Hz,
H), 1.09 (s, 3 H).
13
3
H), 1.20 (t, J = 7.0 Hz, 3 H), 1.10 (s, 3 H); C NMR (125 MHz,
CDCl ) d 202.0, 173.4, 172.2, 148.2, 137.4, 60.7, 60.2, 47.3, 44.2,
3
3
7.8, 35.4, 30.5, 23.8, 23.0, 15.8, 14.1, 14.0; HR-EIMS: m/z calcd
+
for C17
H
24
O
5
[M ]: 308.1624. Found: 308.1634; anal. calcd for
C
17
H
24
O
5
: C, 66.21; H, 7.84. Found: C, 66.38; H, 7.86.
6
-endo,7-exo-Diethoxycarbonyl-1-methylbicyclo[3.3.1]non-2-en-
1
9
-one (a-6-endo,7-exo-4e). Yellow oil; H NMR (500 MHz,
) d 5.87 (ddd, J = 9.4, 4.0, 3.4 Hz, 1 H), 5.39 (ddd, J = 9.4,
1
-Methyl-5,6-exo,7-exo-triethoxycarbonylbicyclo[3.3.1]non-2-
CDCl
3
1
en-9-one (a-6-exo,7-exo-4g). Yellow oil; H NMR (500 MHz,
CD
2
1
1
(
7
.4, 1.2 Hz, 1 H), 4.21–4.11 (m, 4 H), 3.36 (td, J = 13.0, 4.9 Hz,
C
6
D
5
3
) d 5.25 (dt, J = 9.4, 3.4 Hz, 1 H), 4.98 (ddd, J = 9.4, 2.4,
H), 3.19 (dd, J = 13.0, 4.3 Hz, 1 H), 3.03 (dd, J = 7.0, 4.3 Hz,
H), 2.62–2.53 (m, 1 H), 2.43 (dd, J = 18.9, 4.0 Hz, 1 H), 2.10
1
3
1
1
.5 Hz, 1 H), 4.10–3.88 (m, 6 H), 3.40 (dd, J = 4.5, 1.8 Hz, 1 H),
.24 (dt, J = 13.1, 4.5 Hz, 1 H), 3.20 (ddd, J = 19.2, 3.4, 2.4 Hz,
H), 2.54 (t, J = 13.1 Hz, 1 H), 2.02 (ddd, J = 19.2, 3.4, 1.5 Hz,
H), 1.57 (ddd, J = 13.1, 4.5, 1.8 Hz, 1 H), 1.11 (s, 3 H), 1.08 (t,
dd, J = 13.0, 4.9 Hz, 1 H), 1.65 (t, J = 13.0 Hz, 1 H), 1.25 (t, J =
1
3
.0 Hz, 3 H), 1.24 (t, J = 7.0 Hz, 3 H), 1.12 (s, 3 H). C NMR
(
5
125 MHz, CDCl
3
) d 212.4, 174.1, 171.5, 132.9, 128.9, 61.1, 60.9,
J = 7.0 Hz, 3 H), 1.05 (t, J = 7.0 Hz, 3 H), 0.98 (t, J = 7.0 Hz,
0.7, 46.0, 45.7, 42.2, 38.6, 32.3, 20.7, 14.1 (×2); HR-EIMS: m/z
13
3
1
2
H); C NMR (125 MHz, C
6
D
5
CD ) d 203.8, 171.6, 170.5, 170.5,
3
+
calcd for C16
H
22
O
5
[M ]: 294.1467. Found: 294.1459.
35.2, 127.1, 61.6, 60.8, 60.7, 59.1, 55.2, 45.6, 40.4, 39.5, 37.9,
1.6, 14.2, 14.1, 14.0; HR-EIMS: m/z calcd for C19
+
H
26
O [M ]:
7
7
-exo,8-exo-Diethoxycarbonyl-3-methylbicyclo[3.3.1]non-3-en-
1
366.1679. Found: 366.1676; anal. calcd for C19
.15. Found: C, 62.15; H, 7.19.
H
26
O
7
: C, 62.28; H,
2
-one (c-6-exo,7-exo-4e). Yellow oil; H NMR (500 MHz,
CDCl
7
3
) d 6.83–6.78 (m, 1 H), 4.16 (q, J = 7.0 Hz, 2 H), 4.12
(
q, J = 7.0 Hz, 2 H), 3.28–3.24 (m, 1 H), 3.01–2.97 (m, 1 H), 2.77–
1-Methyl-5,6-endo,7-endo-triethoxycarbonylbicyclo[3.3.1]non-2-
1
2
4
1
1
1
2
2
.71 (m, 1 H), 2.56 (dt, J = 12.8, 4.9 Hz, 1 H), 2.29 (td, J = 12.8,
.3 Hz, 1 H), 2.11–2.05 (m, 1 H), 1.96–1.90 (m, 1 H), 1.83 (s, 3 H),
.77 (ddd, J = 12.8, 4.9, 2.3 Hz, 1 H), 1.26 (t, J = 7.0 Hz, 3 H),
en-9-one (a-6-endo,7-endo-4g). Yellow oil; H NMR (500 MHz,
CDCl ) d 5.62 (ddd, J = 9.4, 4.6, 2.4 Hz, 1 H), 5.48 (dd, J = 9.4,
3
2.4 Hz, 1 H), 4.28–4.12 (m, 4 H), 4.10 (q, J = 7.0 Hz, 2 H), 3.91
1
3
.20 (t, J = 7.0 Hz, 3 H); C NMR (125 MHz, CDCl
3
) d 199.9,
(d, J = 8.2 Hz, 1 H), 3.18 (dt, J = 18.3, 2.4 Hz, 1 H), 3.03 (dd, J =
18.3, 4.6 Hz, 1 H), 2.84 (td, J = 8.2, 7.3 Hz, 1 H), 2.28 (dd, J =
13.4, 8.2 Hz, 1 H), 2.10 (dd, J = 13.4, 7.3 Hz, 1 H), 1.29 (t, J =
7.0 Hz, 3 H), 1.27 (t, J = 7.0 Hz, 3 H), 1.22 (t, J = 7.0 Hz, 3 H),
73.4, 172.1, 148.3, 137.5, 60.9, 60.6, 44.7, 43.4, 36.0, 30.3, 29.8,
+
4.5, 15.6, 14.1, 14.0; HR-EIMS: m/z calcd for C16
94.1467. Found: 294.1455.
H
22
O [M ]:
5
1
3
1
1
3
.14 (s, 3 H); C NMR (125 MHz, CDCl ) d 208.2, 173.6, 171.9,
3
6
-exo,7-exo-Diethoxycarbonyl-1,5-dimethylbicyclo[3.3.1]non-2-
70.2, 136.2, 124.6, 61.6, 61.1 (×2), 59.4, 51.0, 45.1, 40.0, 39.6,
1
en-9-one (a-6-exo,7-exo-4f). Yellow oil; H NMR (500 MHz,
CDCl
9.5, 21.6, 14.1, 14.0, 13.9; HR-EIMS: m/z calcd for C19
H
26
O
O : C,
7
3
) d 5.79 (dt, J = 9.4, 3.4, 3.4 Hz, 1 H), 5.42 (ddd, J =
+
[
M ]: 366.1679. Found: 366.1694; anal. calcd for C19
H
26
7
9
4
3
3
.4, 2.4, 1.5 Hz, 1 H), 4.18–4.04 (m, 4 H), 3.44 (dt, J = 13.0,
6
2.28; H, 7.15. Found: C, 62.07; H, 7.31.
.9 Hz, 1 H), 3.09 (dd, J = 4.9, 1.8 Hz, 1 H), 2.66 (ddd, J = 18.9,
.4, 1.5 Hz, 1 H), 2.52 (t, J = 13.0 Hz, 1 H), 2.45 (ddd, J = 18.9,
.4, 2.4 Hz, 1 H), 1.92 (ddd, J = 13.0, 4.9, 1.8 Hz, 1 H), 1.25 (t,
1-Methyl-5,6-endo,7-exo-triethoxycarbonylbicyclo[3.3.1]non-2-
1
en-9-one (a-6-endo,7-exo-4g). Yellow oil; H NMR (500 MHz,
CDCl
J = 7.0 Hz, 3 H), 1.23 (t, J = 7.0 Hz, 3 H), 1.18 (s, 3 H), 1.09 (s,
3
) d 5.87 (ddd, J = 9.4, 4.3, 2.7 Hz, 1 H), 5.35 (ddd, J = 9.4,
1
3
3
1
1
3
6
H); C NMR (125 MHz, CDCl
3
) d 212.6, 172.8, 171.7, 134.9,
2.7, 1.2 Hz, 1 H), 4.31 (dq, J = 10.7, 7.0 Hz, 1 H), 4.27 (dq, J =
10.7, 7.0 Hz, 1 H), 4.17 (q, J = 7.0 Hz, 2 H), 4.14 (dq, J = 10.7,
7.0 Hz, 1 H), 4.09 (dq, J = 10.7, 7.0 Hz, 1 H), 4.03 (dd, J = 13.1,
1.2 Hz, 1 H), 3.43 (td, J = 13.1, 4.6 Hz, 1 H), 3.39–3.32 (m, 1 H),
2.53 (ddd, J = 19.5, 4.3, 1.2 Hz, 1 H), 2.09 (dd, J = 13.1, 4.6 Hz,
27.7, 60.9, 60.6, 58.4, 46.2, 46.0, 45.9, 39.4, 38.5, 21.7, 21.3, 14.1,
4.0; HR-EIMS: m/z calcd for C17
08.1639; anal. calcd for C17
6.01; H, 7.92.
+
H
24
O
5
[M ]: 308.1624. Found:
H
24
O
5
: C, 66.21; H, 7.84. Found: C,
This journal is © The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 286–300 | 297

View Article Online
1
H), 1.79 (t, J = 13.1 Hz, 1 H), 1.34 (t, J = 7.0 Hz, 3 H), 1.27
(d, J = 13.1 Hz, 1 H), 2.23–2.16 (m, 1 H), 1.68 (d, J = 13.9 Hz,
1 H), 1.66 (d, J = 13.9 Hz, 1 H), 1.48 (s, 9 H), 1.47 (s, 9 H), 1.16 (s,
1
3
(
t, J = 7.0 Hz, 3 H), 1.20 (t, J = 7.0 Hz, 3 H), 1.14 (s, 3 H);
C
1
3
NMR (125 MHz, CDCl
3
) d 207.9, 173.9, 170.6, 170.1, 132.0, 128.0,
3 H), 1.12 (s, 3 H); C NMR (125 MHz, C
6
5
D N) d 215.9, 173.7,
6
1
3
6
1.7, 61.5, 61.1, 59.0, 51.8, 46.4, 40.6, 39.3, 35.4, 20.7, 14.1, 14.0,
166.8, 138.5, 134.2, 128.7, 128.1, 81.0, 80.7, 48.8, 48.3, 47.1, 46.3,
+
3.9; HR-EIMS: m/z calcd for C19
H
26
O
7
[M ]: 366.1679. Found:
45.4, 43.9, 43.7, 28.1 (×3), 27.9 (×3), 24.9, 22.2; HR-EIMS: m/z
+
66.1668; anal. calcd for C19
2.01; H, 7.43.
H
26
O
7
: C, 62.28; H, 7.15. Found: C,
calcd for C24
H
36
O
5
[M ]: 404.2563. Found: 404.2577; anal. calcd
for C24
H
36
5
O : C, 71.26; H, 8.97. Found: C, 71.09; H, 8.88.
3
-Methyl-1,7-exo,8-exo-triethoxycarbonylbicyclo[3.3.1]non-3-en-
6-Ethoxycarbonyl-6-ethoxycarbonylmethyl-1,3-dimethylbicyclo-
1
2
-one (c-6-exo,7-exo-4g). Yellow oil; H NMR (500 MHz,
) d 6.86–6.83 (m, 1 H), 4.27–4.04 (m, 6 H), 3.50 (d, J =
[3.2.1]oct-3-en-2-one (6). Major : minor ca. 3 : 2; major-6: yellow
1
CDCl
3
oil; H NMR (500 MHz, CDCl ) d 6.79–6.76 (m, 1 H), 4.15–4.06
3
5
1
2
1
7
.4 Hz, 1 H), 2.87–2.83 (m, 1 H), 2.76 (ddd, J = 13.2, 3.5, 1.8 Hz,
(m, 4 H), 3.14 (d, J = 15.5 Hz, 1 H), 2.80 (dd, J = 7.0, 4.3 Hz,
1 H), 2.66 (d, J = 15.5 Hz, 1 H), 2.57 (d, J = 14.6 Hz, 1 H),
1.96–1.92 (m, 1 H), 1.86 (ddd, J = 11.9, 4.3, 1.8 Hz, 1 H), 1.72 (d,
J = 1.5 Hz, 3 H), 1.58 (d, J = 14.6 Hz, 1 H), 1.26 (s, 3 H), 1.23 (t,
H), 2.73 (ddd, J = 13.2, 5.4, 3.5 Hz, 1 H), 2.58–2.53 (m, 1 H),
.03 (td, J = 13.2, 4.0 Hz, 1 H), 1.84 (bs, 3 H), 1.70–1.64 (m, 1 H),
.26 (t, J = 7.0 Hz, 3 H), 1.25 (t, J = 7.0 Hz, 3 H), 1.23 (t, J =
.0 Hz, 3 H).
1
3
J = 7.0 Hz, 3 H), 1.22 (t, J = 7.0 Hz, 3 H); C NMR (125 MHz,
CDCl
3
) d 203.1, 173.6, 170.7, 146.2, 135.8, 60.9, 60.8, 56.5, 53.7,
7
-endo-tert-Butoxycarbonyl-2-ethoxy-5-ethoxycarbonylbicyclo-
4
7.1, 45.7, 45.3, 41.4, 20.7, 15.1, 14.1, 14.1; HR-EIMS: m/z calcd
1
[
(
(
2
4
7
3.3.1]non-2-en-9-one (a-endo-4h). Yellow oil;
500 MHz, CDCl
H
NMR
+
for C17
H
24
O
5
[M ]: 308.1624. Found: 308.1612; anal. calcd for
3
) d 4.56 (dd, J = 4.6, 2.7 Hz, 1 H), 4.27–4.20
C
17
H
24
O
5
: C, 66.21; H, 7.84. Found: C, 66.49; H, 7.76; minor-6:
m, 2 H), 3.74–3.68 (m, 2 H), 3.11 (dd, J = 16.8, 2.7 Hz, 1 H),
1
yellow oil; H NMR (500 MHz, CDCl ) d 6.92–6.88 (m, 1 H),
3
.84 (tt, J = 5.3, 2.4 Hz, 1 H), 2.82–2.76 (m, 1 H), 2.72–2.57 (m,
4
4
1
1
(
1
.25–4.14 (m, 2 H), 4.10 (q, J = 7.0 Hz, 2 H), 3.08 (dd, J = 7.3,
H), 2.17 (dt, J = 13.7, 5.3 Hz, 1 H), 1.46 (s, 9 H), 1.31 (t, J =
.0 Hz, 1 H), 2.82 (d, J = 16.1 Hz, 1 H), 2.59 (d, J = 14.6 Hz,
H), 2.53 (d, J = 16.1 Hz, 1 H), 1.95 (ddd, J = 11.6, 4.0, 1.5 Hz,
H), 1.85 (d, J = 11.6 Hz, 1 H), 1.80 (d, J = 1.5 Hz, 3 H), 1.46
1
3
.0 Hz, 3 H), 1.30 (t, J = 7.0 Hz, 3 H); C NMR (500 MHz,
CDCl
9.1, 37.1, 36.8, 32.8, 32.2, 28.0 (×3), 14.5, 14.1; HR-EIMS: m/z
calcd for C19 [M ]: 352.1886. Found: 352.1879; anal calcd
for C19 : C, 64.75; H, 8.01. Found: C, 64.61; H, 8.05.
3
) d 207.6, 172.2, 171.7, 151.6, 93.2, 80.7, 62.8, 61.4, 56.9,
4
dd, J = 14.6, 1.5 Hz, 1 H), 1.28 (t, J = 7.0 Hz, 3 H), 1.27 (s, 3 H),
+
H
28
O
6
1
3
.23 (t, J = 7.0 Hz, 3 H); C NMR (125 MHz, CDCl
3
) d 204.1,
H
28
O
6
1
75.6, 171.1, 147.0, 136.0, 61.4, 60.7, 56.0, 52.7 (×2), 45.7, 42.5,
7
-exo-tert-Butoxycarbonyl-2-ethoxy-5-ethoxycarbonylbicyclo-
42.0, 19.9, 15.3, 14.1, 14.1; HR-EIMS: m/z calcd for C17
H
24
O
5
1
+
[
(
(
3
3.3.1]non-2-en-9-one (a-exo-4h). Yellow oil;
H
NMR
) d 4.81 (t, J = 3.7 Hz, 1 H), 4.27–4.20
m, 2 H), 3.78–3.72 (m, 2 H), 3.30 (dd, J = 17.4, 1.2 Hz, 1 H),
[M ]: 308.1624. Found: 308.1610.
500 MHz, CDCl
3
1
,5-Dimethyl-7-endo-hydroxycarbonylbicyclo[3.3.1]non-2-en-9-
1
one (a-endo-7). Yellow oil; H NMR (500 MHz, CDCl
3
) d 5.66
dt, J = 9.5, 3.9 Hz, 1 H), 5.21 (ddd, J = 9.5, 2.4, 1.5 Hz, 1 H), 3.15
tt, J = 12.8, 4.4 Hz, 1 H), 2.37 (ddd, J = 18.7, 3.9, 1.3 Hz, 1H),
.18 (ddd, J = 18.7, 3.9, 2.4 Hz, 1 H), 2.10–1.99 (m, 2 H), 1.79 (dt,
J = 12.8, 1.3 Hz, 1 H), 1.76 (t, J = 12.8 Hz, 1 H), 1.11 (s, 3 H),
.04 (s, 3 H); C NMR (125 MHz, CDCl ) d 215.0, 176.6, 133.1,
128.6, 46.5, 46.2, 45.0, 44.3, 43.5, 37.7, 23.8, 21.6; EI-HRMS: m/z
.01 (tt, J = 12.8, 4.3 Hz, 1 H), 2.91 (t, J = 3.4 Hz, 1 H), 2.52 (td,
(
(
2
J = 12.8, 1.2 Hz, 1 H), 2.44 (dd, J = 17.4, 4.0 Hz, 1 H), 2.33 (ddt,
J = 12.8, 4.3, 3.4 Hz, 1 H), 2.21 (dt, J = 12.8, 4.3, 3.4 Hz, 1 H),
2
.02 (td, J = 12.8, 3.4 Hz, 1 H), 1.45 (s, 9 H), 1.32–1.27 (m, 6 H);
3
1
3
C NMR (500 MHz, CDCl ) d 206.4, 173.1, 171.3, 150.5, 94.2,
1
3
1
3
8
1
3
1.0, 63.0, 61.6, 56.9, 50.1, 40.6, 37.0, 34.0, 33.4, 28.0 (×3), 14.4,
+
4.1; HR-EIMS: m/z calcd for C19
H
28
O
3
[M ]: 352.1886. Found:
+
calcd for C12
H
16
O
3
[M ]: 208.1099. Found: 208.1101.
52.1888.
1
,3-Dimethyl-7-endo-hydroxycarbonylbicyclo[3.3.1]non-3-en-2-
7
-endo-tert-Butoxycarbonyl-4-ethoxy-1-methylbicyclo[3.3.1]non-
1
1
one (c-exo-7). Yellow oil; H NMR (500 MHz, CDCl ) d 6.74–
3
-en-2-one (c-endo-4h). Yellow oil; H NMR (500 MHz, CDCl
3
)
3
6
2
1
.71 (m, 1 H), 2.76–2.71 (m, 1 H), 2.56 (tt, J = 13.0, 4.4 Hz, 1 H),
.12–2.06 (m, 1 H), 1.93–1.87 (m, 2 H), 1.81 (s, 3 H), 1.69 (td, J =
3.0, 3.9 Hz, 1 H), 1.56 (ddd, J = 12.7, 2.5, 1.9 Hz, 1 H), 1.42 (t,
d 5.22 (s, 1 H), 4.24–4.15 (m, 2 H), 3.90 (dq, J = 9.4, 7.0 Hz,
1
1
7
1
H), 3.80 (dq, J = 9.4, 7.0 Hz, 1 H), 2.84 (dd, J = 14.6, 1.5 Hz,
H), 2.70–2.65 (m, 2 H), 2.65–2.59 (m, 2 H), 1.92 (dd, J = 14.6,
.6 Hz, 1 H), 1.72 (dd, J = 12.5, 2.4 Hz, 1 H), 1.70–1.64 (m, 1 H),
.40 (t, J = 7.0 Hz, 3 H), 1.38 (s, 9 H), 1.24 (t, J = 7.3 Hz, 3 H);
J = 13.0 Hz, 1 H), 1.12 (s, 3 H).
1
3
C NMR (125 MHz, CDCl
3
) d 196.0, 179.3, 172.8, 172.5, 103.6,
X-Ray structure determination‡
8
1
3
6
0.9, 64.6, 60.8, 52.3, 36.5, 36.1, 34.2, 29.2, 27.5 (×3), 25.8, 14.2,
+
A crystal suitable for X-ray structure determination was mount
on a Mac science DIP2030 imaging plate equipped with graphite-
4.0; HR-EIMS: m/z calcd for C19
H
28
O
6
[M ]: 352.1886. Found:
52.1884; anal calcd for C19
4.58; H, 7.95.
H
28
6
O : C, 64.75; H, 8.01. Found: C,
˚
monochromated Mo Ka radiation (k = 0.71073 A). Unit-cell
parameters were determined by autoindexing several images in
ꢀ
ꢀ
25
7
-endo-tert-Butoxycarbonyl-7-exo-(2 -tert-butoxycarbonyl-2 -pro-
penyl)-2-ethoxy-1,5-dimethylbicyclo[3.3.1]non-2-en-9-one (5).
N) d 6.16 (bs, 1 H), 5.53
each data set separately with the DENZO program. For each
◦
data set, rotation images were collected in 3 increments with a
1
◦
Yellow oil; H NMR (500 MHz, C
6
D
5
total rotation of 180 about u (60 frames). Data were processed by
2
(
2
2
ddd, J = 9.4, 4.3, 2.4 Hz, 1 H), 5.47 (bs, 1H), 5.37–5.33 (m, 1 H),
using the SCALEPACK program. The structure were solved by
.88 (dd, J = 18.0, 4.3 Hz, 1 H), 2.78 (dd, J = 13.9, 3.7 Hz, 1 H),
.71 (dd, J = 13.9, 3.7 Hz, 1 H), 2.59 (d, J = 13.1 Hz, 1 H), 2.55
a direct method and refined by full-matrix least-squares methods
26
with the TeXsan (Rigaku) program.
2
98 | Org. Biomol. Chem., 2007, 5, 286–300
This journal is © The Royal Society of Chemistry 2007

View Article Online
Acknowledgements
122, 12874; (b) C.-H. Byeon, D. J. Hart, C.-S. Lai and J. Unch,
SYNLETT, 2000, 119; (c) P. Camps, A. Gonzlez, D. Mu n˜ oz-Torrero,
M. Simon, A. Z u´ n˜ iga, M. A. Martins, M. Font-Bardia and X. Solans,
Tetrahedron, 2000, 56, 8141; (d) J.-D. Yang, M.-S. Kim, M. Lee, W.
Baik and S. Koo, Synthesis, 2000, 801; (e) L. Klai c´ , J. Veljkovi c´ and K.
Mlinari c´ -Majerski, Synth. Commun., 2002, 32, 89; (f) C. Simon, J.-F.
Peyronel, F. Clerc and J. Rodriguez, Eur. J. Org. Chem., 2002, 3359;
This work was supported by a Grant-in-Aid for Scientific Research
on Priority Areas (No. 17035055) from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT). NMR, MS,
and elemental analysis measurements were made using JEOL
JMN-LA500, JEOL SX-102A, and Perkin-Elmer 2400 CHN
instruments, respectively, at the Natural Science Center for Basic
Research and Development (N-BARD), Hiroshima University.
We thank Dr Yoshikazu Hiraga for NMR measurements (JEOL
JMNLA500) at the Hiroshima Prefectural Institute of Science and
Technology. We thank Dr Satoshi Kojima for the crystallographic
analysis and for pre-reading the manuscript.
(
g) J. Barluenga, A. Ballesteros, R. B. de la R u´ a, J. Santamar ´ı a, E.
Rubio and M. Toms, J. Am. Chem. Soc., 2003, 125, 1834; (h) J. K. F.
Geirsson, S. Jonsson and J. Valgeirsson, Bioorg. Med. Chem., 2004, 12,
5563.
7
8
(a) M. Miesch, G. Mislin and M. Franck-Neumann, SYNLETT, 1996,
3
85; (b) T. Momose, M. Toshima, S. Seki, Y. Koike, N. Toyooka and Y.
Hirai, J. Chem. Soc., Perkin Trans. 1, 1997, 1315; (c) J. K. F. Geirsson
and E. G. Eiriksdottir, SYNLETT, 2001, 664; (d) A. Gambacorta,
D. Tofani, P. Lupattelli and A. Tafi, Tetrahedron Lett., 2002, 43,
2
195.
(a) N. Ohmori, M. Yoshimura and K. Ohkata, Heterocycles, 1997, 45,
097; (b) N. Ohmori, T. Miyazaki, S. Kojima and K. Ohkata, Chem.
2
Lett., 2001, 906; (c) N. Ohmori, Chem. Commun., 2001, 1552; (d) N.
Ohmori, J. Chem. Soc., Perkin Trans. 1, 2002, 755.
References
1
Isolation: (a) Y. Fukuyama, A. Kuwayama and H. Minami, Chem.
Pharm. Bull., 1997, 45, 947. Synthetic studies: (b) K. C. Nicolaou,
J. A. Pfefferkorn, S. Kim and H. X. Wei, J. Am. Chem. Soc., 1999,
9 (a) R. Takagi, T. Nerio, Y. Miwa, S. Matsumura and K. Ohkata,
Tetrahedron Lett., 2004, 45, 7401; (b) R. Takagi, Y. Miwa, S. Matsumura
and K. Ohkata, J. Org. Chem., 2005, 70, 8587.
10 (a) R. P. Nelson and R. G. Lawton, J. Am. Chem. Soc., 1966, 88, 3884;
(b) R. P. Nelson, J. M. McEuen and R. G. Lawton, J. Org. Chem., 1969,
34, 1225; (c) J. M. McEuen, R. P. Nelson and R. G. Lawton, J. Org.
Chem., 1970, 35, 690.
11 (a) H. Stetter and H. G. Thomas, Angew. Chem., Int. Ed. Engl., 1967,
6, 554; (b) H. Stetter and H. G. Thomas, Chem. Ber., 1968, 101, 1115;
(c) H. Stetter, H. G. Thomas and K. Meyer, Chem. Ber., 1970, 103,
863.
1
21, 4724; (c) K. C. Nicolaou, J. A. Pfefferkorn, G.-Q. Cao, S. Kim
and J. Kessabi, Org. Lett., 1999, 1, 807; (d) H. Usuda, M. Kanai and
M. Shibasaki, Org. Lett., 2002, 4, 859; (e) H. Usuda, M. Kanai and
M. Shibasaki, Tetrahedron Lett., 2002, 43, 3621; (f) S. J. Spessard
and B. M. Stoltz, Org. Lett., 2002, 4, 1943; (g) D. G. J. Young and
D. Zeng, J. Org. Chem., 2002, 67, 3134; (h) R. Ciochina and R. B.
Grossman, Org. Lett., 2003, 5, 4619; (i) G. A. Kraus, T. H. Nguyen
and I. Jeon, Tetrahedron Lett., 2003, 44, 659; (j) G. A. Kraus, E.
Dneprovskaia, T. H. Nguyen and I. Jeon, Tetrahedron, 2003, 59, 8975;
12 J. Villi e´ ras and M. Rambaud, Synthesis, 1982, 924.
(
(
k) G. Mehta and M. K. Bera, Tetrahedron Lett., 2004, 45, 1113;
l) K. C. Nicolaou, G. E. A. Carenzi and V. Jeso, Angew. Chem., Int.
13 The relative stereochemistry of the annulation products 4 was deter-
1
mined by coupling constants and/or H dif-NOE experiments. The
Ed., 2005, 44, 3895. Total synthesis: (m) A. Kuramochi, H. Usuda, K.
Yamatsugu, M. Kanai and M. Shibasaki, J. Am. Chem. Soc., 2005, 127,
1
1
coupling constants are summarized in the ESI† (Table S1). Figure S1
1
indicates the H dif-NOE experiments.
ꢀ
−1
4200; (n) D. R. Siegel and S. J. Danishefsky, J. Am. Chem. Soc., 2006,
28, 1048.
14 According to HF/6–31G* calculations, a-exo-4a was 1.6 kcal mol
ꢀ
more stable than a-endo-4a . The details of the HF/6–31G* calculations
2
Isolation: (a) J.-S. Liu, Y.-L. Zhu, C.-M. Yu, Y.-Z. Zhou, Y.-Y. Hann,
F.-W. Wu and B.-F. Qi, Can. J. Chem., 1986, 64, 837. Synthetic studies:
are described in the ESI† (Table S2).
¯
15 Crystal data: For a-endo-4a: triclinic system, space group P1 (#2), a =
8.5780(9) A
˚
, b = 9.4770(9) A˚ , c = 9.818(1) A˚ , V = 763.6(1) A˚
, Z =
3
(
4
b) K. H o¨ genauer, K. Baumann and J. Mulzer, Tetrahedron Lett., 2000,
1, 9229; (c) A. Haudrechy, C. Chassaing, C. Riche and Y. Langlois,
−
3
2, qcalc = 1.150 g cm , F(000) = 288, R = 0.212 (R = 0.432) for
w
Tetrahedron, 2000, 56, 3181; (d) Y. Foricher and J. Mann, Tetrahedron
Lett., 2000, 41, 2007; (e) X.-C. He, B. Wang, G. Yu and D. Bai,
Tetrahedron: Asymmetry, 2001, 12, 3213; (f) S. A. Kelly, Y. Foricher,
J. Mann and J. M. Bentley, Org. Biomol. Chem., 2003, 1, 2865 and
references therein. Total synthesis: (g) F. Yamada, A. P. Kozikowski,
E. R. Reddy, Y.-P. Pang, J. H. Miller and M. McKinney, J. Am. Chem.
Soc., 1991, 113, 4695; (h) A. P. Kozikowski, G. Campiani, P. Aagaard
and M. McKinney, J. Chem. Soc., Chem. Commun., 1993, 860; (i) G.
Campiani, L.-Q. Sun, A.-P. Kozikowski, P. Aagaard and M. McKinney,
J. Org. Chem., 1993, 58, 7660; (j) S. Kaneko, T. Yoshino, T. Katoh and
S. Terashima, Tetrahedron, 1998, 54, 5471; (k) P. Camps, J. Contreras,
R. El Achab, J. Morral, D. Mu n˜ oz-Torrero, M. Font-Bardia, X. Solans,
A. Badia and N. M. Vivas, Tetrahedron, 2000, 56, 4541 and references
therein.
1994 reflections out of 2520 collected (172 parameters) with I > 3
(I). Goodness of fit = 1.94. For a-7-endo,8-exo-4b: monoclinic system,
space group P2
1
/a (#14), a = 12.3010(4) A
, b = 11.0530(3) A˚ , c =
3
calc
˚
, Z = 4, q = 1.117 g cm−3, F(000) =
13.2020(4) A
˚
, V = 1655.76(9) A˚
608, R = 0.122 (R = 0.292) for 2684 reflections out of 3449 collected
w
(181 parameters) with I > 3 (I). Goodness of fit = 1.47. For c-endo-4h:
¯
˚
˚
triclinic system, space group P1 (#2), a = 9.8930(3) A, b = 11.1740(2) A,
3
, Z = 4, q = 1.219 g cm−3
c = 19.1870(7) A
˚
, V = 1920.77(10) A˚
calc
,
F(000) = 760, R = 0.225 (R = 0.449) for 6944 reflections out of
w
7906 collected (451 parameters) with I > 3 (I). Goodness of fit =
2.13.
16 (a) H. M. R. Hoffmann and J. Rabe, Helv. Chim. Acta, 1984, 67, 413;
(b) Y. Guindon, M. Bencheqroun and A. Bouzide, J. Am. Chem. Soc.,
2005, 127, 554; (c) R. Csuk, C. Schr o¨ der, S. Hutter and K. Mohr,
Tetrahedron: Asymmetry, 1997, 8, 1411; (d) A. Kar and N. P. Argade,
J. Org. Chem., 2002, 67, 7131.
17 (a) T. B. Ayed, H. Amri and M. E. L. Gaied, Tetrahedron, 1991, 47,
9621; (b) B. Das, J. Banerjee and N. Ravindranath, Tetrahedron, 2004,
60, 8357; (c) S. Chandrasekhar, G. Chandrashekar, K. Vijeender and
M. S. Reddy, Tetrahedron Lett., 2006, 47, 3475.
3
4
Isolation: G. E. Henry, H. Jacobs, C. M. S. Carrington, S. McLean and
W. F. Reynolds, Tetrahedron Lett., 1996, 37, 8663.
Isolation: (a) R. H. Manske and L. Marion, Can. J. Res. Sect. B, 1943,
2
1, 92. Synthetic studies: (b) G. Stork, R. A. Kretchmer and R. H.
Schlessinger, J. Am. Chem. Soc., 1968, 90, 1647; (c) W. A. Ayer, W. R.
Bowman, T. C. Joseph and P. Smith, J. Am. Chem. Soc., 1968, 90,
1
648; (d) C. H. Heathcock, E. F. Kleinman and E. S. Binkley, J. Am.
18 The numbering is based on the bicylo[3.3.1]non-2-ene core.
19 When a diastereomer mixture of 4g (a-6-exo,7-exo-4g: a-6-endo,7-endo-
4g: a-6-endo,7-exo-4g: c-4g = 1:1.7:1.3:2.2) was treated with DBU
Chem. Soc., 1982, 104, 1054; (e) D. Schumann, H.-J. Mueller and A.
Naumann, Liebigs Ann. Chem., 1982, 1700; (f) E. Wenkert and C. A.
Broka, J. Chem. Soc., Chem. Commun., 1984, 714; (g) G. A. Kraus and
Y.-S. Hon, J. Am. Chem. Soc., 1985, 107, 4341; (h) A. Padwa, M. A.
Brodney, J. P. Marino, Jr. and S. M. Sheehan, J. Org. Chem., 1997, 62,
◦
in toluene at 80 C for 13 h, the relative ratio of a-6-endo,7-exo-4g
increased (a-6-exo,7-exo-4g: a-6-exo,7-exo-4g: c-4g = 1 : 4.2 : 0.7).
This suggested that a-6-endo,7-exo-products were thermodynamically
favored (see also the ESI (Table S2))‡.
7
1
8. Total synthesis: (i) P. A. Grieco and Y. Dai, J. Am. Chem. Soc.,
998, 120, 5128.
20 The relative stereochemical relationship between the two newly formed
stereocenters was arbitrarily designated anti–syn according to the
structures depicted in Scheme 3.
21 The calculations were performed with PC Spartan Pro, Wavefunction,
Inc., Irvine, CA 92715.
5
6
For reviews: (a) J. A. Peter, Synthesis, 1979, 321; (b) E. Butkus,
SYNLETT, 2001, 1827.
For some recent reports: (a) J. Barluenga, A. Ballesteros, J. Santamar ´ı a,
R. B. de la R u´ a, E. Rubio and M. Toms, J. Am. Chem. Soc., 2000,
This journal is © The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 286–300 | 299

View Article Online
2
2
2 All the results of the HF/6–31G* calculations on the intramolecular
Michael reaction are provided in the ESI (Table S2)‡.
25 DENZO and SCALEPACK: Processing of X-ray Diffraction Data
Collected in Oscillation Mode; Z. Otwinowsky and W. Minor,
Methods Enzymol., 1997, 276. The program is available from Mac
Science Co.
26 TeXsan: Single-Crystal Analysis Software, version 1.9, Molecular
Structure Corporation, The Woodlands, Texas 77381, USA, 1998. The
program is available from Mac Science Co.
3 Calculations on the non-substituted model compound (R
= R = R = H) also exhibited the same tendency (see the ESI
Table S2)‡.
1
= Me, R =
2
R
3
5
6
(
2
4 HOMO orbitals and HOMO potential maps of enolates generated from
other cyclization precursors are summarized in the ESI (Fig. S2)‡.
3
00 | Org. Biomol. Chem., 2007, 5, 286–300
This journal is © The Royal Society of Chemistry 2007