Asymmetric desymmetrization of pseudo-meso 5-hydroxy-endo-tricyclo[5.2.1.02,6]deca-4,8-dien-3-ones

Article abstract of DOI:10.1016/S0040-4020(01)01007-9

A novel route to the enantiopure endo-tricyclodecadienone system has been accomplished starting from readily accessible pseudo-meso-5-hydroxy-endo-tricyclo[5.2.1.0^2,6]deca-4,8-dien-3- one. Desymmetrization using (S)-prolinol or its methyl ether leads to the corresponding enaminones in high yields and with a de of 50%. Complete separation of the diastereomers has been conveniently achieved via their acetates. The absolute stereochemistry of the major diastereomer was determined by single-crystal X-ray diffraction analysis. Reductive elimination of the chiral auxiliary with lithium aluminum hydride affords optically pure parent tricyclodecadienone in good overall yield.

Full text of DOI:10.1016/S0040-4020(01)01007-9

TETRAHEDRON
Pergamon
Tetrahedron 57 92001) 9877±9887
Asymmetric desymmetrization of pseudo-meso
5-hydroxy-endo-tricyclo[5.2.1.02,6]deca-4,8-dien-3-ones
²
Namakkal G. Ramesh, Frank J. A. D. Bakkeren, Debby de Groot, Umberto Passamonti,
Antonius J. H. Klunder and Binne Zwanenburgp
Department of Organic Chemistry, NSR Center for Molecular Structure, Design and Synthesis, University of Nijmegen,
Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Received 9 July 2001; revised 12 September 2001; accepted 4 October 2001
AbstractÐA novel route to the enantiopure endo-tricyclodecadienone system has been accomplished starting from readily accessible
pseudo-meso-5-hydroxy-endo-tricyclo[5.2.1.02,6]deca-4,8-dien-3-one. Desymmetrization using 9S)-prolinol or its methyl ether leads to the
corresponding enaminones in high yields and with a de of 50%. Complete separation of the diastereomers has been conveniently achieved via
their acetates. The absolute stereochemistry of the major diastereomer was determined by single-crystal X-ray diffraction analysis. Reductive
elimination of the chiral auxiliary with lithium aluminum hydride affords optically pure parent tricyclodecadienone in good overall yield.
q 2001 Published by Elsevier Science Ltd.
1. Introduction
routes to the tricyclodecadienone system based on either
asymmetric synthesis or asymmetric transformation are
much in demand. Our earlier reports on the synthesis of
tricyclodecadienone 13 relied on the asymmetric Diels±
Alder approach of enantiopure 4-substituted cyclo-
pentenones 11 with cyclopentadiene 9Scheme 1).9 The key
step in the preparation of the starting cyclopentenones was
the enantioselective hydrolysis of the meso-diacetate 9. As a
result of low p-facial selectivity during the Diels±Alder
addition with cyclopentadiene, the ees of the tricyclic
compounds 12 and 13 were only moderate 961%).9
The endo-tricyclodecadienone system 1 has been the pivotal
intermediate in the synthesis of a large variety of naturally
occurring cyclopentanoids1,2 and other compounds of
pharmacological interest.3 In addition, this system is an
indispensable precursor for cubane-type polycyclic
compounds.4,5 The practical synthesis of enantiopure tri-
cyclodecadienones 1 so far relied mostly on the enzymatic
hydrolysis of carboxylic esters 26 and 46,7 or esteri®cation of
the allylic alcohol 37 9Fig. 1).
Ogasawara et al.10 described a kinetic desymmetrization of
the meso-diol 5 for the enantioselective preparation of the
endo-tricyclodecadienone 13. This methodology is closely
related to the approach depicted in Scheme 1. Feringa and
coworkers have reported the synthesis of enantiopure 13
starting from the Diels±Alder adduct 6 of cyclopentadiene
and enantiopure 5R-9l-menthyloxy)-295H)furanone.11
Although these enzyme mediated kinetic resolutions can be
accomplished with good optical ef®ciency, chemical yields
are obviously limited to 50% of one enantiomer. Inter-
conversion of both enantiomers of 1 9RˆH) can be achieved
using Wharton's methodology to effect a 1,3-ketone trans-
position, but the overall yield of this conversion is generally
moderate.8 For this reason alternative enantioselective
Figure 1.
Keywords: dynamic kinetic resolution; pseudo-meso; asymmetric desymmetrization; tricyclodecadienone.
Corresponding author. Tel.: 131-24-3653159; fax: 131-24-3653393; e-mail: zwanenb@sci.kun.nl
Present address. Department of Chemistry, Indian Institute of Technology-Delhi, Hauz Khas, New Delhi-110 016, India.
p
²
0040±4020/01/$ - see front matter q 2001 Published by Elsevier Science Ltd.
PII: S0040-4020901)01007-9

9878
N. G. Ramesh et al. / Tetrahedron 57 +2001) 9877±9887
is expressed by the equation KkR/kS, wherein kR and kS are
the respective rate constants of the reaction of R and S
enantiomers. For an enantioselective reaction with, e.g. an
enzyme, one of the enantiomers will predominate or be
obtained exclusively in an ideal case. A chiral reagent will
lead to a mixture of diastereomeric products, of which one
may be formed preferentially depending on the ratio of kR/kS
9Scheme 3). For 16 such a process can also be denoted as an
asymmetric desymmetrization of a pseudo-meso compound.
The objective of this study is to utilize the enolic nature of
compound 16 and perform a desymmetrization either
enzymatically or chemically in order to obtain optically
pure tricyclodecadienone system 1.
Scheme 1.
Scheme 3.
Scheme 2.
We have recently communicated a novel and non enzymatic
route for the synthesis of optically active tricyclodecadie-
none12 via an asymmetric desymmetrization of b-hydroxy-
a,b-unsaturated ketone 16 using chiral amines. In this
article we report a full account of our ®ndings including
our attempted enzymatic approach to achieve the target.
2.1. Enzymatic resolution
Preliminary attempts were made to carry out the asymmetric
desymmetrization of the tricyclic alcohol 16 in an
enzymatic fashion with a lipase under non aqueous condi-
tions using vinyl acetate as acyl donor under a variety of
conditions 9Scheme 4). Disappointingly, under the condi-
tions applied no esteri®cation was observed, not even after
stirring the reaction mixture for several weeks. In all the
cases, the starting material was recovered quantitatively.
This result is rather unexpected as a closely related
compound 7 is known to give excellent results.11,16 Further
efforts to transesterify compound 16 using different
enzymes such as porcine pancreatic lipase 9PPL), candida
cylindracea lipase 9CCL)) and other acyl donors 9i.e. methyl
acetate, trichloroethyl ester of butanoic acid) also met with
little success.
2. Results and discussion
The Diels±Alder reaction of cyclopentadiene with cyclo-
penten-1,4-dione 1413 offers a convenient and direct route
to substituted endo-3-oxo-dicyclopentadiene system 1
9Scheme 2). Interestingly, cycloadduct 15 does not exist
in its meso-symmetric form but is completely enolized as
1
is evident from its H NMR spectrum. The adduct actually
consists of a racemic and rapidly equilibrating mixture of
antipodes 16 and ent-16. These adducts 16 have no
Cs-symmetry but as a result of the very fast tautomeric
equilibrium they behave like meso-compounds. For this
reason the term pseudo-meso has been assigned to the
equilibrating compounds.14
The fast enantiomerization of tricyclic enols 16 in principle
allows a dynamic kinetic resolution,15 with the possible
formation of a single enantiomer or diastereomer. Assuming
a fast interconversion of both enantiomers, the product ratio
Scheme 4.

N. G. Ramesh et al. / Tetrahedron 57 +2001) 9877±9887
Table 1. Reaction conditions for enzymatic hydrolysis of 17 9RˆCH3)
9879
excellent yields except in one case 9Table 2). Azeotropic
removal of water was not necessary. Attempts to perform
this reaction in lower boiling solvents, such as benzene,
n-hexane or THF resulted in incomplete conversions and
formation of a substantial amount of the corresponding
ammonium salt. Such salt formation is a well known
phenomenon for this type of reaction.18 Hence, it has been
inferred that after the initial salt formation, the elimination
of water leads to the desired enaminone only when the
reaction is carried out for a suf®ciently long time and at a
high temperature of at least 1118C in the present case.
Attempts to accomplish the amination of enol 16 at lower
temperatures either by acid- or base-catalysis or at high
pressure were not successful. Reaction of the tosylate of
16 with ammonia led to a quantitative reformation of 16
Entry
Enzyme
R0 ±OHa
Time 9h) [a]D20b 98) ee 9%)
1
2
3
4
Lipase PS
Lipase AY
Lipase R
n-BuOH
n-BuOH
n-BuOH
3
4
2.5
5
15.8
14.2
12.0
0
,3±4
,2
,1
Lipase N conc n-BuOH
5
Lipase PS
Lipase PS
Lipase R
Lipase PS
n-OctOH
n-BuOH
n-BuOH
n-BuOH
5.5
2.2
2
0
0
6c
7c
8d
0
11.2
4
,1
All reactions were terminated at 50% conversion.
a
A 25% solution of the alcohol R0 ±OH in n-hexane was applied.
9cˆ0.5, MeOH).
b
c
d
4 equiv. of triethylamine was added.
0.5 equiv. of pyridine was added.
Scheme 5.
As the 5-hydroxytricyclodecadienone 16 can be considered
as a vinylogous acid, reaction with an alcohol could, in
principle, lead to vinylogous ester 9i.e. an enol ether).
However attempts to perform such an esteri®cation
9etheri®cation) in presence of lipase and various alcohols
9methanol, 1-butanol, 1-octanol) was not successful.
and p-toluenesulfonamide. Mitsunobu condition or use of
dicyclohexylcarbodiimide 9DCC) as a coupling reagent for
the amination of 16 resulted only in the formation of the
corresponding ammonium salts.
2.2.2. Dynamic kinetic resolution utilizing chiral amines.
Next the synthesis of enaminones using optically active
amines was investigated in order to perform an asymmetric
desymmetrization of 16. First, 9R)-91)-a-phenylethylamine
was used as the chiral amine. The corresponding enaminone
25 was obtained in an excellent yield of 91%, but no dia-
stereoselectivity was observed 9Scheme 7, Table 3, entry 1).
Fortunately, both diastereomers 25a and 25b could be
readily separated by crystallization from ethyl acetate and
subsequent column chromatography on silica gel. Thus, the
An alternative approach to obtain an enantiopure 5-substi-
tuted tricyclodecadienone involves the enzymatic resolution
of 5-alkylcarbonyloxy compounds 17. Initial attempts using
PLE in an aqueous phosphate buffer did not lead the desired
result, instead a spontaneous non enzymatic hydrolysis of 17
9RˆCH3, n-C3H7, i-C3H7, n-C7H15) was observed. Such a
hydrolysis even took place in demineralized water without
any addenda. Enzymatic alcoholysis of 17 was considered
next. No optically enriched product was obtained using
butyrate 17 9RˆC3H7) or acetate 17 9RˆCH3) and ethanol
in the presence of PPL, in fact no reaction took place at all.
Transesteri®cation of acetoxy derivative 17 9RˆCH3) using
Amano lipases and n-butanol led to some enrichment with
1
an estimated ee of 3±4% 9measured with H NMR using
Eu9hfc)3 as the chiral shift reagent) 9Table 1). The lack of
enantioselectivity may be attributable to the ¯at nature of
the enone unit and the remote position of the stereogenic
center in the substrate 9Scheme 5).
Scheme 6.
In view of the disappointing results with enzymatic
resolutions, attention was focused on chemical approaches.
Table 2. Synthesis of tricyclic enaminones 18±24
Entry
HNR1R2
Product
Time 9h)
Yield 9%)
2.2. Chemical resolution
1
2
3
4
5
6
7
Cyclohexylamine
n-Pentylamine
Benzylamine
Pyrrolidine
Piperidine
Morpholine
Di-n-butylamine
18
19
20
21
22
23
24
24
48
23
23
24
24
120
95
89
94
93
92
94
9
2.2.1. Preparation of tricyclic enaminones. An important
lead to a chemical desymmetrization of 16 was that these
enols can be ef®ciently aminated to the corresponding
enaminones 18±24 using the common method17 of heating
16 to re¯ux in toluene in the presence of a small excess of
amine 9Scheme 6). The enaminones were obtained in
All reactions were performed in re¯uxing toluene.

9880
N. G. Ramesh et al. / Tetrahedron 57 +2001) 9877±9887
amine the reaction rate for the formation of the dia-
stereomeric enaminone was practically the same 9see
Scheme 3).
When S-91)-prolinol20 was used as the chiral amine,
enaminone 26 was obtained in an overall yield of 91%
and with a de of 50% as established by H NMR analysis
1
20
9Table 3, entry 2). The major diastereomer 9[a]D ˆ220.8
Scheme 7.
9cˆ1.14, CHCl3), mp 1828C) was separated by repeated
crystallization from ethyl acetate and its absolute con®gura-
tion was established to be as shown in 26a by single-crystal
X-ray diffraction analysis 9Fig. 2).21 Complete separation of
the diastereomers of 26 was not possible directly, but could
be accomplished via their acetates. Under standard
acylating conditions the respective acetates 29a and 29b
were obtained in almost quantitative yield from 26 which
could then be easily separated by column chromatography
9Scheme 8).
Table 3. Asymmetric desymmetrization of 16 using chiral amines
Entry
1
HNR1R2
Product Time 9h) Yield 9%) Ratio 9a/b)
25
26
60
48
91
91
1:1
3:1
2
The NMR analyses of the prolinol-derived enaminones were
not quite as trivial as may be anticipated. This is due to the
appearance of an extra set of signals because of the occur-
rence of rotamers as was clearly evident from the 1H NMR
spectrum wherein the signal due to H4, the enaminone
3
4
27
28
42
24
79
94
3:1
1.8:1
1
a-proton, appeared as two singlets. Both the H and 13C
NMR spectra indicated that at room temperature both dia-
stereomeric products 26 exist as two rotamers in a ratio of
about 4:1. These rotamers are the result of hindered rotation
around the C5±N bond which is nicely supported by the
crystallographic analysis, revealing a signi®cantly shorter
®rst optical resolution of 5-hydroxy-3-oxo-dicyclopenta-
diene 16 was accomplished. The absolute con®guration of
20
one of the two diastereomers 9[a]D ˆ1178 9cˆ1, CHCl3),
Ê
mp 222±2248C) was established to be 25a by single-crystal
X-ray diffraction 9Fig. 2).19 In this case of a-phenylethyl-
C5±N bond 91.33 A) as compared to a regular, non
Ê
conjugated C±N bond 91.40 A).
Figure 2.
Scheme 8.

N. G. Ramesh et al. / Tetrahedron 57 +2001) 9877±9887
9881
Scheme 9.
Rotamers were also observed for the acetates 29. The minor
acetate 29b has a rotamer ratio of 3:1 at room temperature,
as was indicated by its 1H NMR 9400 MHz). Variable
temperature NMR studies using a 90 MHz NMR instrument
reveal that H4 signal starts to coalesce at 300 K. At 315 K a
single sharp signal was obtained. Similar results were
obtained for the acetate 29a with the signals starting to
coalesce at 317 K 990 MHz) and ®nally merge to give a
sharp signal at 330 K.
be determined precisely due to the presence of rotamers.
However a rough estimate indicates a ratio of ca. 10:1.
Coalescence could not be achieved as the temperature
necessary to enforce coalescence at 400 MHz could not be
reached.
This prolinol mediated desymmetrization reaction was also
successful for the hydroxytricycloundecadienone 30 derived
from cyclohexadiene and cyclopentendione 9Scheme 9).
Compound 30 was prepared under high pressure,23 and
heated at re¯ux with prolinol in toluene to obtain the opti-
cally active tricyclic enaminone 31 in 51% yield with a de of
50%. However, the diastereomers could not be separated
directly but only through their acetates 32a and 32b. The
obsolute con®guration was assigned to the diastereomers of
31 by analogy. Interestingly, the major diastereomer 32a
exists as a single rotomer at room temperature whereas
the minor diastereomer 32b had a rotomer ratio of 85:15.
The same optical yield was obtained for the desymmetriza-
tion process using 9S)-91)-prolinol methyl ether20 instead of
prolinol 9Table 3, entry 3). GC-analysis of the mixture of
diastereomers 27 showed a 3:1 ratio. This mixture itself
could not be separated as crystallization failed and no
difference in Rf on TLC was observed. The absolute con-
®guration of the major enaminone 27a was the same as that
of 26a. Simple methylation of 26a yielded 27a which,
according to GC analysis, was identical to the most
abundant diastereomer in the mixture of 26a and 26b.
Tricyclic enaminone 27a also consisted of two rotamers in
a ratio of 5:2 at room temperature.
The diastereoselectivity in the reaction of the proline
derivatives with the pseudo-meso tricyclic enol can be
explained in analogy with that of Albers et al.22 for the
desymmetrization of norbornene derived anhydrides where
steric effects between the anhydride and the proline
reactants are held responsible. Hence it is assumed that
the proline reacts exclusively with the keto±enol moiety
from the less hindered exo-face of the tricyclic system
An ef®cient desymmetrization of meso-anhydrides derived
from norbornene using 9S)-92)-methyl prolinate, reported
by Albers et al.22 prompted the investigation of proline
methyl ester in the present case. However, contrary to the
expectation, the use of methyl prolinate instead of prolinol
rather resulted in a considerable reduction of the diastereo-
selectivity. The diastereomers were obtained in a ratio of
1.8:1 as was determined by GC analysis 9Table 3, entry 4).
In analogy with the results described earlier it is assumed
that the major diastereomer has absolute con®guration 28a.
Proline itself showed a deviating behavior. For the comple-
tion of its reaction with the tricyclic enol 9^)-16 4 days of
heating at re¯ux was necessary. This resulted in a consider-
able decomposition of the starting material and/or product
and hence a moderate yield of product 9ca. 60%) was
1
obtained. According to the H NMR 9400 MHz) spectrum
a mixture of diastereomers was obtained. The ratio could not
Figure 3.

9882
N. G. Ramesh et al. / Tetrahedron 57 +2001) 9877±9887
thereby approaching the ¯at keto±enol system along a
trajectory of 1098 as shown in Fig. 3, and whereby the
CH2OH-group will be positioned as remote as possible.
The steric hindrance exerted by the methylene bridge
hydrogen H10a on the incoming proline-derivative, there-
fore, determines the stereochemistry of the product. This
steric approach control results in a preference for pathway
A in which the hindrance between the methylene bridge and
prolinol is the least. The observed stereochemistry is in
agreement with this explanation.
The reaction conditions for the reduction in order to achieve
selective formation of parent tricyclodecadienone 13 are
critical. The best result was obtained when only 0.7 equiv.
of LiAlH4, was added as a 1.0 M solution in THF to the neat
substrate.
3. Conclusions
It was established that pseudo-meso 5-hydroxytricyclo-
decadienone 16 undergoes an asymmetric desymmetriza-
tion to enaminones applying prolinol or its methyl ether as
chiral mediator. The diastereoselectivity of this asymmetric
desymmetrization amounts to a de of 50%. Both diastereo-
mers derived from prolinol could conveniently be separated
via their acetates. When a-phenylethylamine is used as a
chiral amine the diastereomeric enaminones were obtained
in equal amounts, but separation by crystallization and
subsequent chromatography could be readily achieved.
Attempts to accomplish an enzymatic desymmetrization
were not successful, which underlines the importance of
chemical methods via chiral enaminones. Reduction of the
enaminone 26a with LiAlH4 under carefully chosen con-
ditions allows the preparation of enantiopure parent
tricyclodecadienone 13 in good yield.
A series of other chiral amines, namely l-20-diphenyl-
prolinol, 92S)-hydroxymethylpiperidine, 91R,2S)-92)-ephe-
drine, 91S,2S)-91)-2-amino-1-phenyl-1,3-propandiol, 91)-
dehydroabiethylamine,
94R,5S)-4-methyl-5-phenyl-1,3-
oxazolidine-2-thione, were also tried in this desymmetriza-
tion reaction. None of them was effective. Thus, prolinol is a
unique chiral auxiliary for this desymmetrization.
2.2.3. Reduction of tricyclic enaminones. In order to
obtain optically pure tricyclodecadienone 13, it is essential
to remove the chiral auxiliary in an ef®cient and convenient
way. This was achieved by the reduction of tricyclic
enaminone 26a with LiAlH4 whereby parent tricyclo-
decadienone 91)-13 was obtained in 71% yield with an
enantiomeric purity of more than 98% 9Scheme 10).
Two different mechanistic pathways can be envisaged for
the reduction of 26a, as depicted in Scheme 11. As the
absolute con®guration of the obtained tricyclodecadienone
91)-13 is the same as that of 26a, reduction proceeds
exclusively by a 1,4-addition process 9pathway A). Initial
1,2-hydride reduction followed by hydrolysis would
have caused an inversion of the absolute con®guration
9pathway B).
4. Experimental
4.1. General
Melting points were measured with a Reichert Thermopan
microscope and are uncorrected. IR spectra were recorded
on a Perkin Elmer 298 infrared spectrophotometer. FT-IR
spectra were taken on a Biorad WIN-IR FTS-25 spectro-
1
photometer. H and 13C NMR spectra were recorded on a
Bruker AM-400, a Bruker AC-300 and a Bruker AC-100 at
rt unless stated otherwise. Chemical shifts are reported in
ppm relative to TMS. For mass spectra a double focussing
VG 7070E mass spectrometer was used. GC±MS spectra
were run on a Varian Saturn 2 benchtop GC±MS ion-trap
system. Elemental analyses were performed on a Carlo Erba
Instruments CHNS-O 1108 Elemental Analyzer. Optical
rotations were measured with a Perkin Elmer 241 Polari-
meter. GC analyses were conducted with a Hewlett±
Packard HP5890II instrument. Flash chromatography was
carried out using Merck Kieselgel 60H and column chro-
matography at atmospheric pressure was performed using
Merck Kieselgel 60. Thin layer chromatography 9TLC) was
carried out on Merck precoated silicagel 60 F254 plates
90.25 mm) and spots were visualized with UV, iodine or a
molybdate spray. Solvents used were of analytical grade
and wherever necessary, were dried using the standard
methods.
Scheme 10.
4.1.1. 5-Hydroxy-endo-tricyclo[5.2.1.02,6]deca-4,8-dien-
3-one 216). The Diels±Alder reaction of cyclopentadiene
and cyclopenten-1,4-dione 1413c using the procedure of
DePuy et al.13a gave 16 in 96% yield. Recrystallization
from 2-propanol gave analytically pure samples. Mp
1
1708C; H NMR 9400 MHz, DMSO-d6) d 11.80 9brs, 1H,
exchangeable with D2O), 5.87 9s, 2H), 4.82 9s, 1H), 2.96 9s,
4H), 1.57 9d, Jˆ8.2 Hz, 1H), 1.47 9d, Jˆ8.2 Hz, 1H); 13C
Scheme 11.

N. G. Ramesh et al. / Tetrahedron 57 +2001) 9877±9887
9883
NMR 9100 MHz, DMSO-d6) d 200.6, 133.6, 108.6, 52.8,
49.2, 43.9; IR 9KBr, cm21) n 3055, 1615 and 1495; MS
9EI, m/z): 162 9M1), 134, 97, 91, 66.
4.1.6. 5-n-Pentylamino-endo-tricyclo[5.2.1.02,6]deca-4,8-
dien-3-one 219). Enaminone 19 was obtained in 89%
yield 93.22 g) as white crystals by re¯uxing n-pentylamine
91.49 g, 17.1 mmol) with 16 92.52 g, 15.6 mmol) in toluene
950 mL) for 48 h. Mp 1198C; 1H NMR 9400 MHz, CDCl3) d
6.09 9dd, Jˆ5.4, 2.9 Hz, 1H), 5.82 9dd, Jˆ5.4, 2.7 Hz, 1H),
5.22 9brs, 1H), 4.81 9s, 1H), 3.15 9brs, 1H), 3.14 9t,
Jˆ5.9 Hz, 1H), 3.05 9q, Jˆ6.5 Hz, 2H), 3.00 9brs, 1H),
2.91 9t, Jˆ5.5 Hz, 1H), 1.74 9d, Jˆ8.3 Hz, 1H), 1.56 9t,
Jˆ7.0 Hz, 2H), 1.51 9d, Jˆ8.3 Hz, 1H), 1.32 9m, 4H),
0.91 9t, Jˆ6.7 Hz, 3H); 13C NMR 9100 MHz, CDCl3) d
204.4, 176.0, 134.7, 131.1, 101.6, 51.7, 50.8, 46.1, 44.8,
43.6, 43.3, 29.0, 28.4, 22.3, 13.9; IR 9KBr, cm21) n 3210,
1640, 1550 9broad), 1475; MS9EI, m/z): 231 9M1), 216,
203,188, 174, 165, 160, 150, 146, 137, 122, 109, 66, 43,
28; HRMS/EI: m/z calcd for C15H21NO: 231.1623 9M1)
Found: 231.16233 9M1); Anal. calcd for C15H21NO: C,
77.88; H, 9.15; N, 6.05 9%). Found: C, 77.82; H, 9.16; N,
6.10 9%).
4.1.2. General procedure for the attempted lipase-cata-
lyzed acylation of 5-hydroxy-endo-tricyclo[5.2.1.02,6]-
deca-4,8-dien-3-one 216). Following the procedure of
Klunder et al.,4e the lipase 9200 mg) and powdered molecu-
Ê
lar sieves 94 A, 100 mg) were added under argon to a stirred
suspension of 16 9100 mg, 0.62 mmol) and vinyl acetate
96 mL, 65 mmol) in 3 mL of the solvent. The reaction
was monitored by GC and TLC 9eluentˆchloroform/
methanolˆ7:1).
4.1.3. General procedure for the attempted lipase-cata-
lyzed
transesteri®cation
of
5-acetoxy-endo-tri-
cyclo[5.2.1.02,6]deca-4,8-dien-3-one 217) 2RˆCH3). The
lipase 9100 mg) was added to a stirred solution of 17
9RˆCH3) 9200 mg, 1.0 mmol) and biphenyl 960 mg) in a
3:1 mixture of n-hexane and the alcohol mentioned in
Table 1 932 mL). The suspension was stirred at room
temperature for the time indicated in Table 1. The reaction
was monitored by GC-analysis. At 50% conversion the
reaction was terminated by ®ltering the suspension over a
celite pad. The mixture was then concentrated in vacuo; the
alcohol used was removed azeotropically by adding cyclo-
hexane. Pure 17 9RˆCH3) was obtained by ¯ash chromato-
graphy 9diethyl ether/n-hexaneˆ3:1) in yield varying
between 35 and 45%.
4.1.7. 5-Benzylamino-endo-tricyclo[5.2.1.02,6]deca-4,8-
dien-3-one 220). Enaminone 20 was obtained in 94%
yield 93.66 g) as white crystals by re¯uxing benzylamine
91.88 g, 17.6 mmol) with 16 92.52 g, 15.6 mmol) in toluene
1
950 mL) for 23 h. Mp 1578C; H NMR 9400 MHz, CDCl3,
Tˆ310 K) d 7.30 9m, 5H), 6.12 9brs, 1H), 6.03 9dd, Jˆ5.5,
2.8 Hz, 1H), 5.82 9dd, Jˆ5.5, 2.8 Hz, 1H), 4.82 9s, 1H), 4.19
9d, Jˆ3.3 Hz, 2H), 3.18 9t, Jˆ5.2 Hz, 1H), 3.10 9brs, 1H),
3.03 9brs, 1H), 2.85 9t, Jˆ5.6 Hz, 1H), 1.71 9d, Jˆ8.3 Hz,
1H), 1.48 9d, Jˆ8.3 Hz, 1H); 13C NMR 9100 MHz, CDCl3,
Tˆ310 K) d 204.5, 176.3, 137.0, 134.5, 131.3, 128.7, 127.8,
127.5, 102.1, 51.8, 50.9, 46.1, 43.7, 43.3, 48.9; IR 9KBr,
cm21) n 3184, 3060, 1638, 1572±1533 9broad), 1454; MS
9EI, m/z): 251 9M1), 223, 185, 160, 146,132, 104, 91, 77, 66,
28; Anal. calcd for C17H17NO: C, 81.24; H, 6.82; N, 5.57
9%). Found: C, 81.23; 6.82; N, 5.58 9%).
4.1.4. General procedure for the reaction of 5-hydroxy-
endo-tricyclo[5.2.1.02,6]deca-4,8-dien-3-one 216) with
amines. Synthesis of enaminones. To a suspension of the
compound 16 in toluene was added the desired amine and
the reaction mixture was heated at re¯ux. During this
treatment the reaction mixture became clear and then
turned yellow. In some cases, within a few hours the
product started to precipitate. After re¯uxing for the
required time, the reaction mixture was cooled to rt and
the product was obtained by ®ltration followed by extensive
washing with diethyl ether. In some cases, yellow oil was
obtained. Recrystallization of the crude product from
2-propanol and/or puri®cation by column chromatography
provided analytically pure enaminones as white or yellow
crystals.
4.1.8. 5-Pyrrolidino-endo-tricyclo[5.2.1.02,6]deca-4,8-dien-
3-one 221). Enaminone 21 was obtained in 93% yield
90.242 g) as yellow crystals by re¯uxing pyrrolidine
90.097 g, 1.37 mmol)) with 16 90.196 g, 1.21 mmol) in
toluene 930 mL) for 23 h. Mp 165±1678C; 1H NMR
9400 MHz, CDCl3) d 6.10 9dd, Jˆ5.6, 2.9 Hz, 1H), 5.81
9dd, Jˆ5.6, 2.9 Hz, 1H), 4.70 9s, 1H), 3.65 9m, 1H), 3.53
9m, 1H), 3.26 9dd, Jˆ6.1, 4.3 Hz, 1H), 3.20 9m, 1H), 3.18 9s,
2H), 3.07 9brs, 1H), 2.96 9dd, Jˆ6.1, 4.6 Hz, 1H), 2.00 9m,
4H), 1.75 9d, Jˆ8.4 Hz, 1H), 1.55 9d, Jˆ8.4 Hz, 1H); 13C
NMR 9100 MHz, CDCl3) d 203.0, 174.3, 134.6, 130.6,
102.8, 51.8, 51.4, 49.1, 48.2, 45.9, 44.1, 43.8, 25.6, 24.7;
IR 9KBr, cm21) n 1643, 1576 9broad); MS9EI, m/z): 215
9M1), 187, 149, 121, 70, 66, 28. Anal. calcd for
C14H17NO: C, 78.11; H, 7.95; N, 6.51 9%). Found: C,
77.26; H, 7.92; N, 6.52 9%).
4.1.5. 5-Cyclohexylamino-endo-tricyclo[5.2.1.02,6]deca-
4,8-dien-3-one 218). Enaminone 18 was obtained in 95%
yield 97.27 g) as white crystals by re¯uxing cyclohexyl-
amine 93.45 g, 34.8 mmol) with 16 95.11 g, 31.5 mmol) in
toluene 9100 mL) for 24 h. Mp 2498C; 1H NMR 9400 MHz,
CDCl3) d 6.09 9dd, Jˆ5.4, 2.8 Hz, 1H), 5.81 9dd, Jˆ5.4,
2.6 Hz, 1H), 4.82 9s, 2H), 3.17 9brs, 1H), 3.13 9m, 2H), 2.97
9brs, 1H), 2.90 9t, Jˆ5.4 Hz, 1H), 1.94 9brt, 2H), 1.78 9brt,
4H), 1.73 9d, Jˆ8.3 Hz, 1H), 1.50 9d, Jˆ8.3 Hz, 1H), 1.40±
1.10 9m, 4H); 13C NMR 9100 MHz, CDCl3) d 204.3, 174.5,
134.8, 130.9, 101.9, 53.5, 51.6, 50.6, 46.3, 43.6, 43.3, 32.4,
25.4, 24.6 24.5; IR 9KBr, cm21) n 3220, 3190, 1640, 1590±
1520, 1450; MS 9EI, m/z): 243 9M1), 215, 177, 161, 146,
133, 118, 96, 82, 66, 28; HRMS/EI: m/z calcd for
C16H21NO: 243.1623 9M1) Found: 243.1625; Anal. calcd
for C16H21NO: C, 78.97; H, 8.70; N, 5.76 9%). Found: C,
78.72, H, 8.81, N, 5.76 9%).
4.1.9. 5-Piperidino-endo-tricyclo[5.2.1.02,6]deca-4,8-dien-
3-one 222). Enaminone 22 was obtained in 92% yield
92.59 g) as yellow crystals by re¯uxing piperidine 91.15 g,
13.6 mmol) with 16 92.00 g, 12.3 mmol) in toluene 930 mL)
1
for 24 h. Mp 135±1378C; H NMR 9400 MHz, CDCl3) d
6.12 9dd, Jˆ5.6, 2.9 Hz, 1H), 5.83 9dd, Jˆ5.6, 2.9 Hz, 1H),
4.85 9s, 1H), 3.60 9brs, 1H), 3.40 9brs, 1H), 3.30 9brs, 1H),
3.25 9dd, Jˆ6.3, 4.0 Hz, 1H), 3.20 9brs, 1H), 3.19 9brs, 1H),
3.02 9brs, 1H), 2.95 9dd, Jˆ6.3, 4.6 Hz, 1H), 1.65 9m, 6H),

9884
N. G. Ramesh et al. / Tetrahedron 57 +2001) 9877±9887
1.73 9d, Jˆ8.4 Hz, 1H), 1.54 9d, Jˆ8.4 Hz, 1H); 13C NMR
9100 MHz, CDCl3, Tˆ260 K) d 203.6, 175.6, 134.9, 130.8,
101.7, 51.6, 51.1, 49.0, 48.7, 45.1, 44.6, 43.5, 26.3, 25.1,
23.9; IR 9KBr, cm21) n 1643, 1560 9broad); MS 9EI, m/z):
229 9M1), 201, 163, 135, 117, 84, 79, 66, 28. Anal. calcd for
C15H19NO: C, 78.56; H, 8.35; N, 6.11 9%). Found: C, 78.45;
H, 8.32; N, 6.18 9%).
+1R,2S,6R,7S,10R)-5-+10-Phenylethylamino)-endo-tricyclo-
[5.2.1.02,6]deca-4,8-dien-3-one 925a). Mp 222±2248C;
20
1
[a]D ˆ1178 9cˆ1, CHCl3); H NMR 9400 MHz, CDCl3)
d 7.30 9m, 5H), 6.09 9dd, Jˆ4.8, 2.6 Hz, 1H), 5.89 9brs, 1H),
5.47 9brd, Jˆ5.0 Hz, 1H), 4.73 9s, 1H), 4.35 9quin,
Jˆ6.6 Hz, 1H), 3.14 9brs, 2H), 3.03 9brs, 1H), 2.84 9t,
Jˆ5.4 Hz, 1H), 1.74 9d, Jˆ8.3 Hz, 1H), 1.49 9m, 4H); 13C
NMR 9100 MHz, CDCl3): d 204.5, 174.6, 142.2, 134.7,
131.1, 128.8, 127.7, 125.9, 103.4, 54.6, 51.8, 50.7, 46.3,
43.6, 43.3, 22.5; IR 9KBr, cm21) n 3199, 1640, 1550
9broad), 1493, 1447; MS 9EI, m/z): 265 9M1), 237, 222,
199, 184, 171, 160, 132, 105, 77, 66, 28; Anal. calcd for
C18H19NO: C, 81.48; H, 7.22; N, 5.28 9%). Found: C, 81.49;
H, 7.19; N, 5.39 9%).
4.1.10. 5-Morpholino-endo-tricyclo[5.2.1.02,6]deca-4,8-
dien-3-one 223). Enaminone 23 was obtained in 94%
yield 91.34 g) as yellow crystals by re¯uxing morpholine
90.59 g, 6.78 mmol) with 91.00 g, 6.17 mmol) in toluene
1
930 mL) for 24 h. Mp 1138C; H NMR 9400 MHz, CDCl3,
Tˆ330 K, ppm) d 6.11 9dd, Jˆ5.5, 2.8 Hz, 1H), 5.82 9dd,
Jˆ5.5, 2.8 Hz, 1H), 4.86 9s, 1H), 3.73 9t, Jˆ5.0 Hz, 4H),
3.36 9m, 4H), 3.25 9dd, Jˆ6.4, 4.0 Hz, 1H), 3.20 9brs, 1H),
2.97 9brs, 1H), 2.95 9dd, Jˆ6.4, 4.5 Hz, 1H), 1.75 9d,
Jˆ8.4 Hz, 1H), 1.64 9brs, H2O), 1.55 9d, Jˆ8.4 Hz, 1H);
13C NMR 9100 MHz, CDCl3, ppm) d 203.8, 176.0, 135.1,
130.5, 103.5, 66.4, 51.8, 51.4, 47.6, 45.1, 44.8, 43.8; IR
9KBr, cm21) n 3470, 1630, 1550 9broad), 1455; MS 9EI,
m/z): 231 9M1), 203, 165, 145, 137, 117, 79, 66, 51, 28;
HRMS/EI: m/z calcd for C14H17NO2: 231.1259 9M1).
+1S,2R,6S,7R,10R)-5-+10-Phenylethylamino)-endo-tricyclo-
[5.2.1.02,6]deca-4,8-dien-3-one 925b). Mp 208±2098C;
20
[a]D ˆ1117 9cˆ0.51, CHCl3); 1H NMR 9400 MHz,
CDCl3, Tˆ320 K, ppm) d 7.3 9m, 5H), 5.96 9dd, Jˆ5.5,
2.9 Hz, 1H), 5.68 9brs, 1H), 5.21 9brs, 1H), 4.72 9s, 1H),
4.37 9brs, 1H), 3.13 9t, Jˆ6.5 Hz, 1H), 3.12 9brs, 1H),
2.99 9brs, 1H), 2.86 9dd, Jˆ6.3, 4.6 Hz, 1H), 1.71 9d,
Jˆ8.4 Hz, 1H), 1.48 9d, Jˆ8.4 Hz, 1H), 1.51 9d,
Jˆ6.8 Hz, 3H); 13C NMR 9100 MHz, CDCl3, Tˆ320 K,
ppm) d 204.3, 174.5, 142.6, 134.7, 130.9, 128.8, 127.7,
125.8, 103.6, 54.7, 51.8, 50.8, 46.4, 43.9, 43.4, 22.8; IR
9KBr, cm21) n 3202, 1638, 1550 9broad), 1493, 1448; MS
9EI, m/z): 265 9M1), 237, 222, 199, 184, 171, 160, 132, 105,
77, 66; Anal. calcd for C18H19NO: C, 81.48; H, 7.22; N, 5.28
9%). Found: C, 81.40; H, 7.19; N, 5.36 9%).
Found:
231.12584
9M1);
Anal.
calcd
for
C14H17NO2´0.5H2O: C, 69.98; H, 7.55; N, 5.83 9%).
Found: C, 69.94; H, 7.56; N, 5.87 9%).
4.1.11. 5-Di-n-butylamino-endo-tricyclo[5.2.1.02,6]deca-
4,8-dien-3-one 224). Di-n-butylamine 90.878 g, 6.79
mmol) was added to a suspension of 16 91.00 g,
6.17 mmol) in toluene 930 mL). The reaction mixture was
heated at re¯ux for 120 h. During this treatment the reaction
mixture turned into a yellow suspension. After cooling, the
precipitated salt was ®ltered off and the ®ltrate was concen-
trated in vacuo. The residue was dissolved in dichloro-
methane, extracted with 1 M HCl 9aq.), 1 M KOH 9aq.)
and brine and subsequently dried over MgSO4. Puri®cation
by ¯ash chromatograpy 9ethyl acetate/methanolˆ10:1)
4.1.13. 5-22S)-20-Hydroxymethylpyrrolidin-10-yl)-endo-
tricyclo[5.2.1.02,6]deca-4,8-dien-3-one 226). 9S)-91)-pro-
linol20 90.97 g, 9.6 mmol) was added to a suspension of 16
91.30 g, 8.0 mmol) in toluene 930 mL). The reaction mixture
was heated at re¯ux for 48 h after which it was cooled and
concentrated in vacuo. Puri®cation by column chromato-
graphy 9ethyl acetate/methanolˆ6:1) afforded a 3:1 dia-
stereomeric mixture of 26 in 91% 91.79 g) yield. When
the reaction was performed on larger scale 940 mmol) 26a
was obtained in pure form in 42% yield 94.13 g) as colorless
crystals from the diastereomeric mixture by repeated
crystallization from ethyl acetate.
1
yielded pure 24 90.15 g, 9%) as a colorless oil. H NMR
9400 MHz, CDCl3) d 6.12 9dd, Jˆ5.6, 2.9 Hz, 1H), 5.77 9dd,
Jˆ5.6, 2.8 Hz, 1H), 4.78 9s, 1H), 3.38 9m, 2H), 3.25 9m,
1H), 3.19 9brs, 1H), 3.07 9m, 2H), 3.00 9brs, 1H), 2.95 9m,
1H), 1.75±1.25 9m, 10H), 0.99 9t, Jˆ7.3 Hz, 3H), 0.92 9t,
Jˆ7.3 Hz, 3H); 13C NMR 9100 MHz, CDCl3) d 203.2,
175.8, 135.0, 130.5, 102.9, 51.6, 51.4, 50.5, 50.2, 45.4,
45.0, 43.7, 31.1, 28.1, 20.1, 20.0, 13.8, 13.7; IR 9CH2Cl2,
cm21) n 1640, 1555 9broad), 1460; MS 9EI, m/z): 273 9M1),
245, 230, 216, 188, 164, 150, 137, 123, 109; HRMS/EI: m/z
calcd for C18H27NO: 273.20926 9M1). Found: 273.20923
9M1).
+1R,2S,6R,7S,20R)-5-+20-Hydroxymethylpyrrolidin-10-yl)-
endo-tricyclo[5.2.1.02,6]deca-4,8-dien-3-one 926a). Mp
20
1828C; [a]D ˆ220.8 9cˆ1.14, CHCl3); The NMR spectral
data of the major rotomer of 26a are given below. 1H NMR
9400 MHz, CDCl3, ppm) d 6.01 9dd, Jˆ5.5, 2.8 Hz, 1H);
5.83 9dd, Jˆ5.5, 2.8 Hz, 1H); 4.84 9s, 1H), 3.63 9m, 4H),
3.42 9m, 1H), 3.26 9m, 1H), 3.15 9m, 2H), 3.07 9brs, 1H),
2.92 9m, 1H), 2.04 9m, 4H), 1.73 9d, Jˆ8.3 Hz, 1H), 1.54 9d,
Jˆ8.3 Hz, 1H); 13C NMR 9100 MHz, CDCl3, ppm) d 203.7,
175.3, 134.3, 130.9, 102.6, 62.0, 60.5, 51.6, 50.9, 49.0, 46.2,
44.0, 43.9, 27.4, 23.5; IR 9CHCl3, cm21) n 3300, 1635,
1545; MS 9EI, m/z): 245 9M1), 217, 180, 148; HRMS/EI:
m/z calcd for C15H19NO2: 245.1416 9M1). Found 245.14164
9M1).
4.1.12.
5-22R)-10-Phenylethylamino)-endo-tricyclo-
[5.2.1.02,6]deca-4,8-dien-3-one 225). 9R)-91)-a-phenyl-
ethylamine 92.11 g, 17.4 mmol) was added to a suspension
of 16 92.55 g, 15.7 mmol) in toluene 950 mL). The reaction
mixture was heated at re¯ux for 60 h after which it was
cooled and concentrated in vacuo. The diastereomers were
separated by ¯ash chromatography 9ethyl acetate/
methanolˆ10:1), affording 25a 91.89 g) and 25b 91.89 g)
in an overall yield of 91%. Analytically pure samples of
25a and 25b were obtained as white crystals by
crystallization from 2-propanol and ethyl acetate,
respectively.
4.1.14. 5-22S)-20-Methoxymethylpyrrolidin-10-yl)-endo-
tricyclo[5.2.1.02,6]deca-4,8-dien-3-one 227). 9S)-91)-pro-
linol methyl ether20 90.28 g, 2.4 mmol) was added to a
suspension of 16 90.32 g, 2.0 mmol) in toluene 920 mL).

N. G. Ramesh et al. / Tetrahedron 57 +2001) 9877±9887
9885
The reaction mixture was heated at re¯ux for 42 h. During
this treatment the reaction mixture became clear and then
turned yellow. After cooling, the reaction mixture was
concentrated in vacuo. The 3:1 diastereomeric mixture of
27a and 27b was puri®ed by column chromatography 9ethyl
acetate/methanolˆ4:1) but the isomers could not be
separated. The overall yield of the reaction was 79%
90.49 g).
+1R,2S,6R,7S,20S)-5-+-20-Acetoxymethylpyrrolidin-10-yl)-
endo-tricyclo[5.2.1.02,6]deca-4,8-dien-3-one 929a). The
NMR spectral data of the major rotomer of 29a are given
below. 1H NMR 9400 MHz, CDCl3, ppm) d 6.08 9dd, Jˆ5.4,
2.9 Hz, 1H), 5.78 9dd, Jˆ5.4, 2.8 Hz, 1H), 4.86 9s, 1H), 4.10
9dd, Jˆ11.1, 5.1 Hz, 1H), 3.93 9dd, Jˆ11.1, 6.3 Hz, 1H),
3.83 9m, 1H), 3.65 9m, 2H), 3.28 9dd, Jˆ6.0, 4.2 Hz, 1H),
3.19 9brs, 1H), 3.06 9brs, 1H), 2.92 9dd, Jˆ5.8, 4.8 Hz, 1H),
2.04 9m, 4H), 2.00 9s, 3H), 1.74 9d, Jˆ8.3 Hz, 1H), 1.55 9d,
Jˆ8.3 Hz, 1H); 13C NMR 9100 MHz, CDCl3) d 203.3,
174.5, 134.4, 130.5, 103.5, 62.8, 58.6, 51.5, 50.9, 48.4,
46.1, 43.9, 43.8, 27.5, 23.4, 20.7; IR 9CHCl3, cm21) n
1735 9CvO, acetate), 1640, 1545 9broad); MS 9EI, m/z):
287 9M1), 259, 222, 162, 148; HRMS/EI; m/z calcd for
C17H21NO3: 287.1521 9M1). Found: 287.1522 9M1).
+1R,2S,6R,7S,20R)-5-+20-Methoxymethylpyrrolidin-10-yl)-
endo-tricyclo[5.2.1.02,6]deca-4,8-dien-3-one 927a). The
major diastereomer 27a could be obtained in pure form by
alkylating 26a. Sodium hydride 90.36 g of a 50% suspension
in mineral oil, 7.5 mmol) was added to a solution of 26a
91.23 g, 5.0 mmol) in DMF 912 mL), under argon at room
temperature. After 15 min of stirring, methyl iodide 91.07 g,
7.5 mmol) was added through a syringe. The reaction
mixture was stirred for 1 h at room temperature. After
quenching with water the reaction mixture was extracted
with dichloromethane. The combined organic layers were
washed with brine, dried over Na2SO4 and concentrated in
vacuo. The crude reaction product was puri®ed by ¯ash
chromatography 9ethyl acetate/methanolˆ6:1), yielding
27a as a yellowish oil 91.18 g, 91%). The NMR spectral
+1S,2R,6S,7R,20S)-5-+-20-Acetoxymethylpyrrolidin-10-yl)-
endo-tricyclo[5.2.1.02,6]deca-4,8-dien-3-one 929b). The
NMR spectral data of the major rotomer of 29b are given
1
below H NMR 9400 MHz, CDCl3) d 6.11 9brs, 1H), 5.82
9brs, 1H), 4.88 9s, 1H), 4.15 9dd, Jˆ11.1, 3.7 Hz, 1H), 3.94
9dd, Jˆ11.1, 7.8 Hz, 1H), 3.80 9brs, 1H), 3.70 9m, 1H), 3.56
9m, 1H), 3.28 9dd, Jˆ5.8, 4.3 Hz, 1H), 3.20 9brs, 1H), 3.09
9brs, 1H), 2.97 9m, 1H), 2.15±1.85 9m, 4H), 2.05 9s, 3H),
1.75 9d, Jˆ8.3 Hz, 1H), 1.56 9d, Jˆ8.3 Hz, 1H); 13C NMR
9100 MHz, CDCl3) d 203.3, 173.9, 134.8, 130.3, 104.5,
62.1, 58.6, 52.0, 51.4, 48.6, 46.4, 44.2, 44.1, 28.2, 23.2,
20.7; IR 9CHCl3, cm21) n 1730, 1640, 1545 9broad); MS
9EI, m/z): 287 9M1), 259, 222, 162, 148; HRMS/EI: m/z
calcd for C17H21NO3: 287.1521 9M1). Found: 287.1522
9M1).
1
data of the major rotomer of 27a are given below. H
NMR 9300 MHz, CDCl3) d 6.11 9dd, Jˆ5.4, 2.8 Hz, 1H);
5.77 9dd, Jˆ5.4, 2.8 Hz, 1H); 4.77 9s, 1H), 3.73±2.91 9m,
6H), 3.32 9s, 3H), 3.21 9brs, 1H), 3.05 9brs, 1H), 2.93 9m,
1H), 2.03 9m, 4H), 1.74 9d, Jˆ8.3 Hz, 1H), 1.55 9d,
Jˆ8.3 Hz, 1H); 13C NMR 975 MHz, CDCl3) d 203.3,
174.2, 134.5, 130.6, 102.8, 70.8, 59.6, 58.9, 51.5, 50.9,
48.9, 46.3, 44.0, 43.9, 27.8, 23.7; IR 9CHCl3, cm21) n
1640, 1550 9broad); MS 9EI, m/z): 259 9M1), 231, 214,
193, 186, 148; HRMS/EI: m/z calcd for C16H21NO2:
259.1572 9M1). Found: 259.15705 9M1).
4.1.17. Synthesis of endo-tricyclo[5.2.2.02,6]undeca-4,8-
dien-3-one 230). Compound 30 was prepared as per litera-
ture procedure.23 A solution containing cyclopentadienone
91.55 g, 16.2 mmol), cyclohexadiene 93.37 g, 42.1 mmol)
and few crystals of hydroquinone in benzene/toluene 91:9)
solvent mixture taken in a Te¯on tube ®tted with a metal
screw cap, was subjected to 12 kbar pressure at room
temperature overnight after which the precipitate formed
was ®ltered, washed with acetone followed by hexane and
dried to afford the enol 30 in 87% yield 92.40 g) as a white
solid. The 1H NMR spectrum of this compound was found to
be identical with that of the literature reported one.23 1H
NMR 9100 MHz, DMSO-d6,) d 6.03 9t, Jˆ4.2 Hz, 2H),
5.05 9s, 1H), 3.50 9broad, OH), 2.85 9bs, 2H), 2.57 9m,
2H), 1.57 9m, 2H), 1.30 9m, 2H).
4.1.15. 5-22S)-20-Carbomethoxypyrrolidin-10-yl)-endo-
tricyclo[5.2.1.02,6]deca-4,8-dien-3-one 228). l-proline
methyl ester 90.39 g, 3.0 mmol) was added to a suspension
of 16 90.32 g, 2.0 mmol) in toluene 920 mL). The reaction
mixture was heated at re¯ux for 24 h after which it was
cooled and concentrated in vacuo. The 1.8:1 diastereomeric
mixture of 28a and 28b was puri®ed by column chromato-
graphy 9ethyl acetate/methanolˆ6:1) but the isomers could
not be separated. The overall yield is 94% 90.55 g). IR
9CHCl3, cm21) n 1735, 1655, 1555; MS 9EI, m/z): 273
9M1), 245, 214, 207, 186, 148, 70; HRMS/EI: m/z calcd
for C16H19NO3: 273.1365 9M1). Found: 273.1365 9M1).
The NMR spectra were very complex due to the mixture
of both the diastereomers and the presence of rotamers for
each diastereomer.
4.1.18. 5-22S)-20-Hydroxymethylpyrrolidin-10-yl)-endo-
tricyclo[5.2.2.02,6]undeca-4,8-dien-3-one 231). 9S)-91)-
Prolinol 9303 mg, 3 mmol) was added to a suspension of
the enol 30 9372 mg, 2 mmol) in toluene 910 mL). The reac-
tion mixture was heated under re¯ux for 48 h after which it
was cooled, concentrated and puri®ed by column chromato-
graphy 9EtOAc/MeOH 6:1) to afford an inseparable dia-
stereomeric mixture of the enaminones 31 in 51% yield.
The diastereomeric ratio was found to be 3:1.
4.1.16. Acetylation of enaminone 226). A 3:1 mixture of
26a and 26b 9261 mg, 1.07 mmol) was dissolved in
dichloromethane 95 mL) together with triethylamine
9222 mg, 2.2 mmol) and DMAP 912 mg, 0.1 mmol). After
the addition of acetic anhydride 9123 mg, 1.2 mmol) the
reaction mixture was stirred for 25 min at room temperature.
The reaction was terminated by concentration in vacuo. The
crude reaction mixture was puri®ed by ¯ash chromato-
graphy 9ethyl acetate/methanolˆ4:1). Both the diastereo-
mers 29a 9212 mg) and 29b 973 mg) were obtained
separately as yellowish oil in an overall yield of 96%.
+1R,2S,6R,7S,20R)-5-+20-Hydroxymethylpyrrolidin-10-yl)-
endo-tricyclo[5.2.2.02,6]undeca-4,8-dien-3-one 931a). Spec-
tral data for the major diastereomer 31a from the mixture of
31a and 31b: 1H NMR 9400 MHz, CDCl3) d 6.13 9m, 1H),
5.91 9m, 1H), 5.03 9s, 1H), 3.85±3.30 9m, 5H), 3.00±2.85

9886
N. G. Ramesh et al. / Tetrahedron 57 +2001) 9877±9887
9m, 3H), 2.49 9dd, Jˆ6.4, 3.2 Hz, 1H), 2.30±1.80 9m, 5H),
1.70±1.30 9m, 4H); 13C NMR 975 MHz, CDCl3) d 213.2,
204.6, 176.7, 132.8, 128.9, 103.2, 62.1, 61.2, 50.0, 49.6,
45.3, 32.5, 27.6, 25.1, 24.2, 23.5; MS 9EI, m/z): 259 9M1),
228, 200, 148; HRMS/EI: m/z calcd for C16H21NO2:
259.15723 9M1). Found: 259.15730 9M1).
ethyl acetateˆ2:1), to give colorless crystalline optically
MeOH) [lit. [a]D ˆ1139 9cˆ0.95, MeOH)].1j,6a
20
24
pure 91)-13 9104 mg, 71%). [a]D ˆ1137 9cˆ1.05,
Acknowledgements
4.1.19. Acetylation of enaminone 231). A 3:1 mixture of
the prolinol enaminone 31 9207 mg, 0.8 mmol) was
dissolved in 10 mL of CH2Cl2 and cooled to 08C. 0.22 mL
of Et3N 91.6 mmol) was added followed by 5 mg of DMAP.
The reaction mixture was stirred for 10 min and 0.11 mL
91 mmol) of Ac2O was added. After stirring the reaction
mixture for 0.5 h at 08C, when TLC indicated the absence
of starting material the reaction was stopped and CH2Cl2
was concentrated. Separation of the two diastereomers
was achieved by column chromatography 9EtOAc/MeOH
6:1) to afford 32a 9155 mg) and 32b 950 mg) as colorless
oil in an overall yield of 85% 9205 mg).
This investigation was supported by the Netherlands
Foundation of Chemical Research 9SON) with ®nancial
aid from the Netherlands Organization for Scienti®c
Research 9NWO). We thank Amano Enzyme Europe Ltd
for a generous gift of a selection of their lipases.
References
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