Ring opening and rearrangement reactions of tricyclo [4.2.1.0 2,5]nonan-9-one

Article abstract of DOI:10.1055/s-2007-990937

A general concept is introduced to synthesize bicyclo[4.2.0]octanes by a sequence of intramolecular coppers-catalyzed [2+2] photocycloaddition and subsequent fragmentation reactions. The concept was tested by subjecting the photochemically accessible tric

Full text of DOI:10.1055/s-2007-990937

3896
PAPER
Ring Opening and Rearrangement Reactions of
Tricyclo[4.2.1.02,5]nonan-9-one
R
eaction
n
s
of Tricyclo
g
[4.2.1.02,5]nobnan-9-one ert Braun,a Florian Rudroff,b Marko D. Mihovilovic,b Thorsten Bach*a
a
Lehrstuhl für Organische Chemie I, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
Fax +49(89)28913315; E-mail: thorsten.bach@ch.tum.de
b
Institut für Angewandte Synthesechemie, Technische Universität Wien, Getreidemarkt 9/163-OC, 1060 Vienna, Austria
Received 26 September 2007
clo[4.2.0]octanes.5 Apparently, copper association to
these dienes is disfavored, and the catalytic effect of the
metal, which is due to a long-wavelength (l ≅ 250 nm)
charge-transfer excitation of the corresponding complex,
Abstract: A general concept is introduced to synthesize bicyc-
lo[4.2.0]octanes by a sequence of intramolecular copper(I)-cata-
lyzed [2+2] photocycloaddition and subsequent fragmentation
reactions. The concept was tested by subjecting the photochemical-
ly accessible tricyclo[4.2.1.02,5]nonan-9-one to four different ring- does not operate. A possible detour to access bicyc-
opening or rearrangement reactions, which allowed for the forma-
lo[4.2.0]octanes by an intramolecular copper(I)-catalyzed
tion of functionalized bicyclo[4.2.0]octanes by cleavage of the car-
[2+2] photocycloaddition is depicted in Scheme 1. With a
bonyl bridge. All four methods investigated, Haller–Bauer
bridging substituent Z present in 1,7-diene A, intramolec-
cleavage, the Schmidt reaction, Baeyer–Villiger oxidation, and
ular cycloaddition to provide B should be possible, and,
rhodium(II)-catalyzed rearrangement were applicable to tricyc-
lo[4.2.1.02,5]nonan-9-one, but they differed with regard to enan-
tioselectivity. Enzymatic Baeyer–Villiger oxidation was the most
successful of these methods, also more successful than metal-cata-
lyzed Baeyer–Villiger oxidation, providing access to enantiomeri-
cally enriched lactones, for example in 72% yield and 95% ee. The
second-most successful method was with a commercially available
rhodium catalyst, which effected ring enlargement of tricyc-
lo[4.2.1.02,5]nonan-9-one to its homologue in good overall yield and
modest enantioselectivity (up to 24% ee).
upon cleavage of the bridge, products of type C could be
obtained.
X
Z
R
Z
R
R
Y
A
B
C
Key words: cycloadditions, ketones, lactones, photochemistry,
ring opening, stereoselective synthesis
R = H
O
OTBDMS
Bicyclo[4.2.0]octanes can be prepared by annulation of a
four-membered ring to a six-membered ring, the annula-
tion method of choice being a [2+2] cycloaddition. Most
often, [2+2] cycloaddition is conducted photochemically,
and requires an appropriate six-membered-ring enone as
the starting material.1 Thermal cycloaddition reactions
have been reported less frequently, and among these,
ketene cycloaddition has been shown to be the most reli-
able,2 producing a cyclobutanone. Examples of intramo-
lecular [2+2]-photocycloaddition reactions3 as entry to
the bicyclo[4.2.0]octane ring skeleton are scarce. In con-
trast, bicyclo[3.2.0]heptanes have often been prepared by
the versatile intramolecular copper(I)-catalyzed [2+2]
photocycloaddition of 1,6-dienes.4 The latter reaction
nicely complements intermolecular enone photocycload-
dition, giving access to different substitution patterns and
being compatible with several functional groups. Given
these benefits, it is unfortunate that the copper(I)-cata-
lyzed [2+2] photocycloaddition cannot be applied to 1,7-
dienes and other 1,w-dienes. Irradiation experiments with
several 1,7-dienes did not result in the formation of bicy-
1
2
Scheme 1 General access to bicyclo[4.2.0]octanes C from 1,3-divi-
nyl-substituted cyclopentanes or their heteroanalogues A, and more
specific access via tricyclo[4.2.1.02,5]nonan-9-one (2), which is
available from precursor 1
In this paper, we describe our attempts to achieve the se-
quence depicted in Scheme 1 to produce a parent com-
pound (R = H) of class B, i.e. tricyclo[4.2.1.02,5]nonan-9-
one (2).6 Compound 2 represents B in which a carbonyl
group has been employed as the bridging group Z; the car-
bonyl bridge was incorporated in protected form from si-
lyl ether 1 as starting material, and is accessible to various
cleavage and rearrangement reactions. Since substrate 2 is
a meso compound, any reaction leading to ring-opened
products with X ≠ Y will offer the possibility of enantioto-
pos differentiation. There are fewer precedences for the
ring-opening reactions of norbornan-7-ones7 than for
those of norbornan-2-ones. Examples will be discussed
for the individual compounds below. On the basis of a lit-
erature survey, we decided to have a closer look at the
Haller–Bauer cleavage, the Schmidt reaction, Baeyer–
Villiger oxidation, and a rhodium-catalyzed ring-expan-
sion reaction.
SYNTHESIS 2007, No. 24, pp 3896–3906
x
x.
x
x
.
2
0
0
7
Advanced online publication: 28.11.2007
DOI: 10.1055/s-2007-990937; Art ID: Z22907SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Reactions of Tricyclo[4.2.1.02,5]nonan-9-one
3897
Firstly, tricyclo[4.2.1.02,5]nonan-9-one (2) had to be pre- Yields given in the subsequent schemes (see below) are
pared. Mimicking a general access to compounds of type not corrected for loss of exo-isomer, but were calculated
B (Scheme 1), we planned to synthesize the tricyclic sub- on the basis of the mole equivalents of endo/exo-mixture,
strate 2 by an intramolecular copper(I)-catalyzed [2+2] thus allowing for a theoretical maximum of 88% yield of
photocycloaddition. The synthesis commenced with the endo-derived product. The configuration of the major
known alcohol 3 (Scheme 2), which was prepared in three endo-diastereomer was proved by characteristic NOE
steps from commercially available norbornadiene.8 Ring- contacts (H-3/4, d = 2.18 to H-7/8, d = 1.85).
opening metathesis9 was problematic because of the insta-
bility of the product under the reaction conditions. We
Haller–Bauer cleavage of compound 2 was investigated.
Non-enolizable ketones can be cleaved into the corre-
therefore used the corresponding silyl ether, which was
sponding acids or amides by treatment with hydroxide or
obtained by protection with tert-butyldimethylsilyl chlo-
amide as base (Haller–Bauer reaction or Haller–Bauer
ride and imidazole (im) in N,N-dimethylformamide (99%
cleavage).12 The cleavage of norbornan-7-ones was inten-
yield). The subsequent ring-opening metathesis was facile
sively studied and beautifully incorporated into several
in the presence of the Grubbs first generation catalyst,10
natural product syntheses by Mehta.13 The regioselectivi-
and proceeded quantitatively within 18 hours under an at-
ty of the Haller–Bauer cleavage has been extensively
mosphere of ethene (90% yield) (Scheme 2). The [2+2]
studied14 and there are cases in which enantiomerically
photocycloaddition was attempted with silyl ether 1 and,
pure chiral ketones can lead to enantiomerically pure
after deprotection, with the volatile free alcohol 4. The
former reaction gave higher yields and selectivities than
the latter, with the endo-product, endo-5, prevailing over
exo-5 with a diastereomeric ratio of 88:12 (Scheme 2).
The selectivity decrease for the reaction of alcohol 4 is
presumably due to coordination of copper to the hydroxy
group. The coordination also explains the lower reaction
rate for this reaction. While the conversion of 1 into 5 was
complete within five hours, the reaction of alcohol 4 re-
quired 20 hours for full conversion of starting material.
products via configurationally stable carbanions.15 The re-
action attracted our interest because Ishihara and Yano
had reported in 2004 a kinetic resolution of 2-phenylcy-
clohexanone with chiral lithium bases.16
In a first set of experiments, we checked whether the title
compound 2 underwent Haller–Bauer cleavage reactions
under standard conditions. Indeed, reactions with potassi-
um tert-butoxide (benzene, r.t., 62%)17 and with sodium
amide (benzene, reflux, 89%) proceeded cleanly and in
good chemical yields. The application of a primary amide
such as lithium hexylamide, as previously used by Ishiha-
ra and Yano, was successful, but resulted in lower yields
(46%) than those obtained from the sodium amide reac-
tion (Scheme 3). Best results were obtained when 2.2
equivalents of the amide were used in refluxing benzene.
In refluxing tetrahydrofuran the yield amounted to only
14%. Attempts to use catalytic amounts (0.1 equiv) of
lithium diisopropylamide to promote the cleavage in tet-
rahydrofuran at room temperature were not efficient (10%
yield).
Silyl ether 5 could be deprotected quantitatively (TBAF,
THF) to yield the corresponding alcohol 6 in a diastereo-
meric ratio of 88:12. Separation of the diastereomers at ei-
ther stage was impossible on a preparatively useful scale.
We consequently continued to work with the endo/exo-
mixture, which was oxidized to ketone 2 by use of o-io-
doxybenzoic acid (IBX)11 in dimethyl sulfoxide as oxi-
dant (89% yield). The ketone was used in this form, i.e. as
an endo/exo-mixture (dr = 88:12) for all subsequent reac-
tions. It has been noted, however, that after most ring-
opening or rearrangement reactions the purified product
was exclusively derived from the endo-starting material.
The secondary amide rac-7 was isolated as a pure diaste-
reomer with the relative configuration shown in
Scheme 3. The yield decreased when RNH– was used in-
1. TBDMSCl, im, DMF, r.t.
2. C2H4, CH2Cl2, r.t.
[RuCl2(PCy3)2CHPh]
–
HO
H
stead of NH2 ; this indicates that the reaction, which likely
proceeds by a rate-determining attack of the amide at the
carbonyl carbon atom,18 is highly sensitive towards the
steric bulk of the base. In this respect, it did not come as a
big surprise – but still was disappointing to note – that the
chiral amine anions 8 and 9 (Scheme 3) were not suited to
promote the desired cleavage under a variety of condi-
OR
89%
3
1: R = TBDMS
TBAF (THF)
65%
4: R = H
O
NHC6H11
H
Ph
Ph
NHLi
H
H
LiNHC6H11
benzene, 80 °C
hν, Cu(OTf)2
Et2O, r.t.
LiHN
+
RO
RO
O
8
46%
H
H
H
Ph
NHLi
2 (dr = 88:12)
rac-7
exo-5
exo-6
dr = 88:12
dr = 80:20
endo-5
endo-6
72%
57%
R = TBDMS
R = H
9
Scheme 3 Haller–Bauer cleavage of title compound 2 with lithium
hexylamide to yield racemic bicyclo[4.2.0]octanone rac-7; structures
of chiral amide bases 8 and 9
Scheme 2 Synthesis of silyl ethers 5 and alcohols 6 from known
norbornenol 38 by ring-opening metathesis and intramolecular cop-
per(I)-catalyzed [2+2] photocycloaddition (im = imidazole)
Synthesis 2007, No. 24, 3896–3906 © Thieme Stuttgart · New York

3898
I. Braun et al.
PAPER
tions. Starting material was recovered unchanged. Further reaction mixture at room temperature for different time
experiments were not conducted.
periods prior to reflux was also examined (Table 1, entries
2 and 3). The latter reaction (Table 1, entry 3), in which
the mixture was stirred for 12 hours, gave a low, but mea-
surable diastereoselectivity. The key to complete reaction
was the switch of the solvent to carbon tetrachloride
(Table 1, entries 4 and 5). The reaction was completed at
room temperature after 12 hours (Table 1, entry 4). In an
optimized run (Table 1, entry 5), a yield of 83% could be
achieved.
The Schmidt reaction was investigated next. The classical
Schmidt reaction19 employs hydrogen azide as the reagent
to convert a ketone into the corresponding secondary
amide. The reaction has been previously applied to nor-
bornan-7-ones, e.g. to nortricyclanone.7e Searching for a
method which would possibly allow differentiation of the
enantiotopic positions of ketone 2, we found the use of
chiral enantiomerically pure azides attractive. Aubé et al.
have developed an elegant method, which relies on the use
of chiral azido alcohols and which has been employed to
desymmetrize prochiral ketones, e.g. 4-tert-butylcyclo-
hexanone.20 A typical chiral alcohol used by Aubé et al. in
their studies is (R)-3-azido-1-phenylpropan-1-ol (10,
Scheme 4). With this alcohol the desymmetrization of 4-
tert-butylcyclohexanone was conducted in remarkable dia-
stereoselectivity (dr = 95:5). It was also noted, however,
that bicyclic meso-ketones were less susceptible to de-
symmetrization. Our plan was to employ alcohol 10 for a
first screening, and if significant yields and diastereose-
lectivities were obtained, we would further test other azi-
do alcohols.
Table 1 Optimization of the Diastereoselective Schmidt Reaction
of Compounds 2 and 10 To Yield Compounds 11 and 12a
Entry Lewis acid Solvent Reaction conditions Yieldb (%) drc
1
2
BF3·OEt2
BF3·OEt2
CH2Cl2 20 °C, 10 h
–
–
CH2Cl2 0 °C to r.t., 1 h,
then reflux, 12 h
22
50:50
3
BF3·OEt2
CH2Cl2 0 °C to r.t., 12 h,
then reflux, 5 h
22
64
56:44
d
4
5
BF3·OEt2
BF3·OEt2
CCl4
CCl4
r.t., 12 h
–
–20 °C to r.t., 36 h 83
58:42
a See Scheme 4.
Ph
b Yield of isolated products (11 and 12 combined).
see Table 1
O
+
c The dr of 11 and 12 was determined by NMR analysis of the product
mixture.
N3
OH
d Appropriate signals could not be separated in the 1H NMR spectrum,
but the 13C NMR spectrum showed signals of both diastereomers with
equal height (i.e., dr = ~50:50).
2 (dr = 88:12)
10
Ph
H
H
H
H
Ph
HO
O
HO
N
+
N
It was disappointing that the diastereomeric ratio for the
reaction of 2 with 10 to give 11 and 12 never exceeded
60:40 (Scheme 4, Table 1). Although the reaction can be
used for the synthesis of pure amide enantiomers after
separation of the diastereomers and cleavage of the auxil-
iary, the low selectivity made this route unattractive. An
optimization beyond the variation of reaction conditions
was not indicated, because the low selectivity achieved
with the standard alcohol established that the tricyclic
starting material 2 was not an optimal substrate for the
diastereoselective Schmidt reaction.
O
11
12
Scheme 4 Schmidt reaction of title compound 2 with chiral alcohol
10 to give the diastereomeric tertiary amides 11 and 12
The reaction of compound 2 with chiral alcohol 10 should
lead to the two diastereomeric tertiary amides 11 and 12
(Scheme 4). The reaction is acid-catalyzed and proceeds
via the O,O-hemiacetal of the ketone and the alcohol. Af-
ter protonation and dehydration, the resulting onium ion is
attacked intramolecularly by the azide nucleophile, which
induces the dediazotation/migration sequence.19 Gratify-
ingly, product formation was observed by gas–liquid
chromatography (GLC) when the boron trifluoride–dieth-
yl ether complex was used as the Lewis acid. The purifi-
cation and product isolation was difficult and tedious,
however. The reaction of ketone 2 in dichloromethane
was much slower than the reaction described for cyclo-
hexanones.19,21 At –20 °C there was no conversion
(Table 1, entry 1). The reaction started at room tempera-
ture but did not go to completion. It was necessary to heat
the mixture to reflux to drive the reaction to completion.
The high reaction temperature, in turn, was problematic,
due to instability of the starting material under thermal
conditions and required the tedious removal of byproducts
in subsequent purification steps. The effect of stirring the
Baeyer–Villiger oxidation, examined next, is generally
applicable to ketones, and it was readily shown that ke-
tone 2 could be oxidized to the corresponding lactone rac-
13 (Scheme 5) by m-chloroperbenzoic acid in dichlo-
romethane (79% yield). There were two obvious alterna-
tives for a possible enantioselective route to lactone 13
and its enantiomer ent-13: the use of a chiral transition-
metal complex as catalyst22 or the application of an enzy-
matic process.23 Both options were checked in parallel.
The success of the chiral copper(II) complex 14
(Scheme 5) in enantiotopos-differentiating Baeyer–Vil-
liger oxidations of bicyclic and tricyclic ketones24 made
this catalyst our first choice for the transition-metal-cata-
lyzed route. The use of benzene as the solvent and the ex-
clusion of light to avoid any uncatalyzed background
reactions were crucial for the success of the reaction. Un-
Synthesis 2007, No. 24, 3896–3906 © Thieme Stuttgart · New York

PAPER
Reactions of Tricyclo[4.2.1.02,5]nonan-9-one
3899
O2
der these conditions, the endo-diastereomer of ketone 2
was converted into the enantioenriched (32% ee) lactone
13 (Scheme 5). The exo-diastereomer did not react and
was recovered unchanged. Interestingly, the use of benz-
aldehyde instead of pivalaldehyde as oxygen carrier did
result in oxidation of both endo- and exo-isomers of ke-
tone 2, but neither this, nor other modifications resulted in
improved enantioselectivities.
H
CHMOBrevi1
O
LBAmp, 24 °C
72%
O
O
H
ent-13 (95% ee)
2 (dr = 88:12)
Scheme 6 Enantioselective enzymatic Baeyer–Villiger oxidation of
the ketone endo-2 (exo-2 did not react) to give lactone 13 (LBAmp
=
Luria–Bertami medium supplemented with ampicillin)
H
O2, t-BuCHO
14 (3 mol%)
benzene, r.t., dark
O
enantiomerically enriched with lactone 13, but also con-
tained its enantiomer ent-13, so that we could obtain a dia-
stereomeric mixture of acylation products 16 and 17. As
there is a change in priority according to the Cahn–In-
gold–Prelog nomenclature, the stereogenic center of the
(methoxy)(phenyl)(trifluoromethyl)acetyl group is for-
mally (S)-configured. As expected, the diastereomeric ex-
cess corresponded to the enantiomeric excess of the
starting lactone, and the major diastereomer was separated
from the minor diastereomer by semiprepreparative
HPLC (ZR-Carbon, MeCN–H2O, 1:1) (Scheme 7). Be-
cause of the preferred conformation of the (meth-
oxy)(phenyl)(trifluoromethyl)acetyl ester, in which its
methoxy group is antiperiplanar to the carbonyl group,
and the hydrogen atom at C-5 is synperiplanar to the O–
CO bond, the phenyl group exerts a shielding effect at the
protons adjacent to the stereogenic center C-5. According-
ly, a downfield shift at H-6 is expected for the (5R)-con-
figuration, and a downfield shift at H-4 is expected for the
(5S)-configuration. Indeed, in the major diastereomer 16,
to which the (5R)-configuration was assigned (Scheme 7),
the proton H-6 resonated at d = 2.62 and the H-4 protons
at d = 1.83 and 1.77. The 1H–1H COSY NMR spectrum re-
vealed signals for the minor diastereomer 17 at d = 2.50
for H-6 and at d = 1.87 and 1.80 for the H-4 protons.
O
O
72%
H
2 (dr = 88:12)
14:
13 (32% ee)
tBu
tBu
O
N
O
O2N
O
N
Cu
NO2
O
tBu
tBu
Scheme 5 Enantioselective Baeyer–Villiger oxidation, catalyzed
by the chiral copper(II) complex 14, of the ketone endo-2 (exo-2 did
not react) to give lactone 13
Enzymatic oxidation reactions were conducted with
whole-cell systems. Previous work had shown that nor-
bornan-7-ones25 and norbornen-7-ones26 can be oxidized
enantioselectively. Our own experiments were conducted
in a standardized setup, which allowed for rapid screening
of recombinant Escherichia coli whole-cell-expression
systems overexpressing Baeyer–Villiger monooxygenas-
es (BVMO). In 12- or 24-well plates, 0.5 mg ketone per
mL media was used, and the cultures were incubated for
24 hours at 24 °C. After that, the samples were extracted
and analyzed by gas–liquid chromatography. Perhaps the
most important result is that the flavin-dependent cyclo-
hexanone monooxygenase, CHMOBrevi2, and the cyclo-
pentanone monooxygenase, CPMOComa, produced lactone
13 (75% and 86% ee, respectively), while CHMOBrevi1 and
CHMOBrachy gave predominantly the enantiomeric prod-
uct ent-13 (96% and 92% ee, respectively). As previously
observed in the metal-catalyzed reaction, the exo-diaste-
reomer of ketone 2 was not oxidized. The reaction of 2 to
provide ent-13, catalyzed by CHMOBrevi1, was conducted
on preparative scale (0.1 g ketone) and yielded the product
in 72% yield with an enantiomeric excess of 95% ee
(Scheme 6).
O
F3C
Ph
OH
Cl
K2CO3
MeOH
r.t.
H
OMe
py, r.t.
16/17
(33% de)
13
(32% ee)
quant.
53%
H
COOMe
15 (32% ee)
O
O
F3C
Ph
F3C
Ph
S
S
O
O
H
H
HPLC
separation
OMe
4
OMe
+
5R
4
5S
6
6
H
H
COOMe
COOMe
The well-established Mosher method27 was employed to
prove the absolute configuration of lactones 13 and ent-13
(Scheme 7). Lactone 13 was quantitatively ring-opened
by treatment with potassium carbonate in methanol, and
the resulting d-hydroxy ester 15 was O-acylated with the
16
17
Scheme 7 Proof of absolute configuration of ketone 13 on the basis
of the Mosher method
corresponding
(R)-(methoxy)(phenyl)(trifluorometh-
To the best of our knowledge, this is the first proof of the
configuration of a product obtained by Baeyer–Villiger
oxidation of a norbornan-7-one. Previous experiments for
yl)acetyl chloride (Scheme 7). It was shown that the lac-
tone opening proceeds without racemization. We
intentionally worked with a mixture, which was only
Synthesis 2007, No. 24, 3896–3906 © Thieme Stuttgart · New York

3900
I. Braun et al.
PAPER
norbornen-7-ones26 conducted with cyclohexanone mo- Since the ring expansion of achiral ketone 2 to the chiral
nooxygenase (E.C. 1.14.13.22) are difficult to compare.
ketone 21 proceeded in an overall yield of 69%, and since
the regioselective ring opening of ketone 21 is straightfor-
ward,33 studies towards an enantioselective rearrangement
were warranted. A matter of concern was that a complete
separation of alcohols 18 and 19 could be achieved neither
by column chromatography nor by HPLC. Provided that
an enantiotopos-differentiating catalyst was found, it was
clear that alcohols 18 and 19 should lead preferentially to
different enantiomers with the very same catalyst. This
disadvantage in mind we undertook experiments with the
commercially available catalysts 22 and 23 (Scheme 9).
With the mixture 18/19 (dr 63:37) as obtained from the
addition reaction (Scheme 8) used on a preparative scale,
catalyst 22 delivered ketone 21 in 71% yield and in a small
but detectable 10% ee (Scheme 9).
Rhodium(II)-catalyzed rearrangement was next exam-
ined. The rearrangement of b-diazo alcohols to the corre-
sponding ketones28 is an alternative to the long-
established Tiffeneau–Demjanov rearrangement.29 Like
the latter, it can be used for the ring enlargement of cyclic
ketones. Most frequently, the diazo group is introduced by
addition of a-diazocarboxylates to ketones30 and the rear-
rangement of the a-diazo-b-hydroxycarboxylates so ob-
tained results primarily in b-oxocarboxylates, which are
easily decarboxylated. In the presence of Lewis acids the
two-step sequence of carbonyl addition/rearrangement
can be conducted in one pot.31 The rhodium-catalyzed de-
diazotization/rearrangement was studied by Pellicciari
and Nagao.32 In unsymmetrically substituted ketones the
less substituted group usually migrates, while a phenyl
group has a higher migration aptitude than an alkyl sub-
stituent. To the best of our knowledge, a rhodium-cata-
lyzed rearrangement of a-diazo-b-hydroxycarboxylates
has not yet been used for the differentiation of enan-
tiotopic positions.
1. 22 (1 mol%)
CH2Cl2, r.t.
2. KOH, H2O, r.t.
3. HCl, acetone, reflux
H
H
H
H
O
18/19
(dr = 63:37)
+
71%, 10% ee
O
In preliminary experiments, we investigated the feasibili-
ty of the addition/rearrangement sequence in the racemic
series. A smooth reaction between ketone 2 and lithiated
ethyl a-diazoacetate resulted in a mixture of the two
achiral, diastereomeric alcohols 18 and 19 (Scheme 8).
The relative configuration was proved for the minor dia-
stereomer 19 by a weak NOE signal between the hydroxy
proton and H-2/5 of the ring. Treatment of the mixture 18/
19 with catalytic amounts of the rhodium(II) acetate dimer
(1 mol%) resulted in a smooth rearrangement to the race-
mic b-keto ester rac-20 (Scheme 8). The decarboxylation
of this product, to give the ketone rac-21, was induced by
saponification and subsequent acidification of the result-
ing carboxylate (Scheme 8). Smooth decarboxylation to
the ketone rac-21 was also observed during GLC analysis
of rac-20.
21
ent-21
Rh2L4
22: L = R-DOSP
23: L = 5S-MEPY
O
H
C12H25
S
N
CO2Me
O
N
H
O
O
O
Scheme 9 Enantioselective rhodium-catalyzed rearrangement of
diazo alcohols 18/19 to ketones 21 and ent-21
The rhodium catalyst 23 (Scheme 9) showed no activity in
the desired reaction (Table 2, entry 9). Further studies
were undertaken to elucidate the influence of the diaste-
reomeric composition of the substrate on the enantiomeric
excess (Table 2). As anticipated (see above), one alcohol
(19) was preferentially converted into one enantiomeric
product 21 while – with the same catalyst 22 – its diaste-
reomer 18 produced more of the isomer ent-21 (cf.
Table 2, entries 2 and 6).
N2
N2
N2
Li
COOEt
OH
OH
COOEt
EtOOC
THF, –78 °C
+
2
5
Interestingly, minor diastereomer 19 seems to be more
susceptible to an asymmetric induction by the catalyst.
The use of a 15:85 mixture of 18/19 resulted in a 21/ent-
21 enantiomeric ratio of 62:38 (23% ee, Table 2, entry 1),
while the use of an 81:19 mixture of 18/19 gave product
ent-21 in only 10% ee (Table 2, entry 6). Even with al-
most pure diastereomer 18, the enantiomeric ratio rose
only to 58:42 (15% ee, Table 2, entry 8). Since the tem-
perature could not be varied extensively (Table 2, entries
3–5) its influence remained low, although from this series
it appears as if there was a slight increase of selectivity
with a decrease in temperature. But when entries 6 and 7
of Table 2 are compared, no such effect is observed. It is
unfortunate that compound 19 was not obtained diaste-
82%
2
18
dr = 63:37
19
H
H
H
[Rh(OAc)2]2
CH2Cl2, r.t.
1. KOH, H2O, r.t.
2. HCl, acetone, reflux
O
O
84%
quant.
COOEt
H
rac-20
rac-21
Scheme 8 Preparation of diazo alcohols 18 and 19 by carbonyl ad-
dition to ketone 2 and their consecutive reactions, i.e. rhodium-cata-
lyzed rearrangement to b-keto ester rac-20, whose decarboxylation
gave the ketone rac-21
Synthesis 2007, No. 24, 3896–3906 © Thieme Stuttgart · New York

PAPER
Reactions of Tricyclo[4.2.1.02,5]nonan-9-one
3901
Table 2 Influence of Diastereomeric Composition and Conditions
in the Reaction of 18/19 on the Enantiomeric Ratio of the Chiral Ke-
tones 21/ent-21a
All reactions involving water-sensitive chemicals were carried out
in flame-dried glassware with magnetic stirring under argon. Anhyd
CH2Cl2 was distilled from CaH2, and anhyd THF and Et2O were dis-
tilled from Na prior to use. Anhyd EtOH and MeOH were distilled
from Na. Anhyd Et3N and DIPEA were distilled from CaH2. Com-
mon solvents (Et2O, pentane, EtOAc, CH2Cl2, MeOH) were dis-
tilled prior to use. All other solvents and reagents were used as
Entry dr
(18/19)
Conditionsb
erc
eed
(21/ent-21) (%)
1
2
3
4
5
15:85
22:78
63:37
63:37
63:37
cat. 22, CH2Cl2, r.t., 6 h
cat. 22, CH2Cl2, 5 °C, 12 h
cat. 22, CH2Cl2, r.t., 8 h
cat. 22, CH2Cl2, 0 °C, 12 h
62:38
56:44
45:55
46:54
46:54
23
12
10
8
received. TLC was performed on glass plates (silica gel 60, F254
,
0.25 mm) by coloration with ceric ammonium molybdate (CAM) or
phosphomolybdic acid (PMA). Column chromatography was per-
formed on silica gel 60 (230–400 mesh) (ca. 50 g per 1 g of material
to be separated) with the eluent mixture indicated. 1H and 13C NMR
spectra were recorded at 303 K on Bruker DMX-360 and AV-500
spectrometers. Chemical shifts are reported relative to TMS as in-
ternal standard. Apparent multiplets, which occur as a result of co-
incidental equality of coupling constants to those of magnetically
nonequivalent protons, are marked as virtual (virt). The multiplici-
ties of the 13C NMR signals were determined by DEPT experiments
and standard two-dimensional NMR experiments. anti-Bicyc-
lo[2.2.1]hept-2-en-7-ol (3) was synthesized by a reported proce-
dure.8
cat. 22, CH2Cl2, –20 °C,
8
then 0 °C, 12 h
6
7
8
9
81:19
81:19
99:1
cat. 22, CH2Cl2, r.t., 12 h
cat. 22, CH2Cl2, 5 °C, 12 h
cat. 22, CH2Cl2, 5 °C, 12 h
cat. 23, CH2Cl2, r.t., 4 d
45:55
44:56
42:58
–
10
11
15
–
63:37
tert-Butyl(anti-2,5-divinylcyclopentyloxy)dimethylsilane (1)
Protection of 3
a Reaction depicted in Scheme 9.
b Decarboxylation occurred thermally on GLC injection. The er ob-
tained by this method was identical to the er determined after saponi-
fication and decarboxylation (Scheme 9).
anti-Bicyclo[2.2.1]-hept-2-en-7-ol (3; 1.10 g, 10.0 mmol) and imi-
dazole (1.36 g, 20.0 mmol) were dissolved in anhyd DMF (25 mL).
A soln of 50% TBDMSCl in toluene (5.20 mL, 4.52 g, 15 mmol)
was added slowly to the mixture at r.t., and the soln was stirred over-
night. H2O (250 mL) was added, and the aqueous layer was extract-
ed with Et2O (3 × 150 mL). The combined organic layers were
washed with brine (150 mL), dried (Na2SO4), filtered, and concen-
trated. The residue was subjected to column chromatography (silica
gel, pentane); this gave protected 3 as anti-(bicyclo[2.2.1]hept-2-
en-7-yloxy)-tert-butyldimethylsilane.
c The er was determined by GLC on a chiral stationary phase.
d The ee was calculated from the er.
reomerically pure, as with catalyst 22, >30% ee would be
predicted.
The configuration assignment of ketones 21 and ent-21
was tentatively based on their CD spectra. The spectrum
of ketone 21 shows a negative Cotton effect at 300 nm.
The octant rule34 for ketones predicts a negative Cotton ef-
fect for enantiomer 21: six atoms lie on a nodal plane and
have only low contributions to the optical rotation. For ke-
tone 21, three atoms (C-3, C-4, C-5) are located in a neg-
ative and one (C-10) in a positive octant, which should
result in an overall negative Cotton effect.
Yield: 4.24 g (99%); colorless liquid; Rf = 0.60 (pentane).
IR (film): 2955 (s), 2857 (s), 1361 (m), 1256 (s), 1129 (s), 1112 (s),
897 (s), 836 (s) cm–1.
1H NMR (360 MHz, CDCl3):d = 5.94 (t, J = 2.2 Hz, 2 H), 3.44 (s,
1 H), 2.43–2.40 (m, 2 H), 1.83–1.78 (m, 2 H), 0.93–0.87 (m, 2 H),
0.87 (s, 9 H), 0.03 (s, 6 H).
13C NMR (90.6 MHz, CDCl3): d = –4.7 (CH3), 18.1 (C), 21.9 (CH3),
25.9 (CH2), 46.4 (CH), 82.9 (CH), 134.3 (CH).
In summary, four different ring-opening or ring-expan-
sion reactions could be successfully applied to tricyc-
MS (EI, 70 keV): m/z (%) = 224 (60) [M+], 209 (5) [M+ – CH3], 167
(100) [M+ – C4H9], 139 (30) [M+ – C6H13], 75 (90) [C2H7SiO+].
lo[4.2.1.02,5]nonan-9-one
(2).
With
regard
to
Anal. Calcd for C13H24OSi (224.41): C, 69.58; H, 10.78. Found: C,
69.85; H, 10.79.
enantioselectivity, the enzymatic Baeyer–Villiger oxida-
tion proved to be most successful, generating ketone 13 or
its enantiomer ent-13 in high enantiomeric excesses (86%
ee and 96% ee). The second notable enantiotopos-differ-
entiating reaction was achieved with the chiral commer-
cially available rhodium catalyst 22, which resulted in the
homologation of 2 to provide 21 in up to 23% ee. While
the stereospecific conversion of this homologation prod-
uct into a ring-opened product (e.g., by Baeyer–Villiger
oxidation)32 is straightforward, the catalyst needs to be
optimized. The Haller–Bauer cleavage and the Schmidt
reaction were applicable to ketone 2, but efficient enan-
tiotopos differentiation could not be achieved. Further re-
search will be devoted to optimizing the rhodium-
catalyzed reaction and to applying this method and the en-
zymatic Baeyer–Villiger oxidation to other photochemi-
cally generated bicyclic ketones.
Ring-Opening Metathesis of Protected 3
anti-(Bicyclo[2.2.1]hept-2-en-7-yloxy)-tert-butyldimethylsilane
(637 mg, 3.0 mmol) was dissolved in anhyd CH2Cl2 (30 mL) under
an atmosphere of ethene (balloon). The Grubbs catalyst
[Ru(=CHPh)Cl2(PCy3)2] (74.0 mg, 90 mmol, 3 mol%) was added.
The soln was stirred vigorously under an atmosphere of ethene at r.t.
for 3 h. Silica gel (2 g) was added, the solvent was removed under
reduced pressure, and the resulting brown powder was directly sub-
jected to purification by column chromatography (silica gel, pen-
tane); this gave 1.
Yield: 703 mg (93%); colorless liquid; Rf = 0.28 (pentane).
IR (film): 2956–2857 (s, br, C-H), 1370 (m), 1256 (s), 1123 (s), 912
(s), 868 (s), 836 (s), 776 (s) cm–1.
1H NMR (360 MHz, CDCl3): d = 5.74 (ddd, J = 17.1, 10.2, 8.3 Hz,
2 H), 5.04 (ddd, J = 17.1, 2.0, 1.1 Hz, 2 H), 4.99 (ddd,
J = 10.2, 2.0, 0.9 Hz, 2 H), 3.53 (t, J = 7.9 Hz, 1 H), 2.49–2.39 (m,
Synthesis 2007, No. 24, 3896–3906 © Thieme Stuttgart · New York

3902
I. Braun et al.
PAPER
2 H), 1.94–1.84 (m, 2 H), 1.52–1.42 (m, 2 H), 0.88 (s, 9 H), 0.02 (s,
6 H).
13C NMR (90.6 MHz, CDCl3): d = –4.7 (CH3), 18.2 (C), 19.9 (CH2),
21.2 (CH2), 25.9 (CH3), 35.8 (CH), 44.9 (CH), 81.7 (CH).
13C NMR (90.6 MHz, CDCl3): d = –3.6 (CH3), 18.2 (C), 26.1 (CH3),
MS (EI, 70 keV): m/z (%) = 252 (10) [M+], 237 (2) [M+ – CH3], 224
27.8 (CH2), 52.5 (CH), 83.9 (CH), 114.9 (CH2), 141.4 (CH).
(1) [M+ – C2H4], 195 (100) [M+ – C4H9], 119 (20) [M+ – C6H16OSi],
+
91 (15) [C7H7 ], 75 (70) [C2H7SiO+], 59 (10).
MS (EI, 70 keV): m/z (%) = 252 (10) [M+], 237 (2) [M+ – CH3], 195
(100) [M+ – C4H9], 119 (15) [M+ – C6H17OSi], 91 (10), 75
[C2H7SiO+] (50).
HRMS (EI): m/z calcd for C15H28OSi: 252.1909; found: 252.1906.
Anal. Calcd for C15H28OSi (252.47): C, 71.36; H, 11.18; Si, 11.12.
Found: C, 71.31; H, 11.30; Si, 11.13.
Anal. Calcd for C15H28OSi (252.47): C, 71.36; H, 11.18. Found: C,
71.18; H, 11.18.
Tricyclo[4.2.1.02,5]nonan-9-ol (6)
anti-2,5-Divinylcyclopentanol (4)
Method A (from 4): According to the general procedure, alcohol 4
(28.0 mg, 200 mmol) and Cu(OTf)2 (6 mg, 20.0 mmol, 10 mol%)
were dissolved in anhyd Et2O (15 mL) and irradiated at 254 nm for
20 h. Workup and column chromatography (silica gel, pentane–
Et2O, 1:1) gave alcohol 6.
Compound 1 (314 mg, 1.20 mmol) was dissolved in anhyd THF
(6 mL) and 1 M TBAF in THF (2.40 mL, 2.40 mmol) was added.
After the mixture had stirred at r.t. for 1 h, silica gel (0.5 g) was add-
ed. The solvent was removed under reduced pressure, and the dry
powder was placed on top of a chromatographic column for purifi-
cation (silica gel, pentane–Et2O, 1:1); this gave 4.
Yield: 16.0 mg (120 mmol, 57%); endo/exo = 80:20; colorless crys-
tals.
Yield: 111 mg (65%); volatile, colorless liquid; Rf = 0.47 (pentane–
Et2O, 1:1).
IR (KBr): 3362 (s, br), 2955 (s), 2872 (s), 1640 (s), 1089 (s) cm–1.
1H NMR (360 MHz, CDCl3): d = 5.78 (ddd, J = 17.1, 10.2, 8.0 Hz,
2 H), 5.12 (ddd, J = 17.1, 1.8, 1.0 Hz, 2 H), 5.05 (ddd,
J = 10.2, 1.8, 0.8 Hz, 2 H), 3.46 (t, J = 9.1 Hz, 1 H), 2.46–2.34 (m,
2 H), 1.98–1.87 (m, 2 H), 1.64 (br s, 1 H), 1.54–1.45 (m, 2 H).
13C NMR (90.6 MHz, CDCl3): d = 27.4 (CH2), 51.6 (CH), 81.8
(CH), 115.5 (CH2), 140.6 (CH).
Method B (from 5): Photoproduct 5 (1.24 g, 4.90 mmol) was dis-
solved in anhyd THF (10 mL) and 1 M TBAF in THF (ca. 5% H2O
content; 12.0 mL, 12.0 mmol) was added. After the mixture had
stirred at r.t. for 12 h, most of the THF was removed under reduced
pressure, H2O (100 mL) was added, and the soln was extracted with
Et2O (2 × 100 mL). The aqueous layer was saturated with NaCl and
again extracted with Et2O (2 × 50 mL). The combined organic lay-
ers were washed with brine (80 mL), dried (Na2SO4), and filtered,
and the solvent was removed under reduced pressure. Column chro-
matography (silica gel, pentane–Et2O, 1:1) gave alcohol 6.
MS (EI, 70 keV): m/z (%) = 138 (1) [M+], 120 (5) [M+ – H2O], 94
(15) [M+ – C2H4O], 91 [M+ – C2H7O]; 83 (45) [M+ – C3H3O], 79
(50) [M+ – C4H11], 70 (85) [C4H6O+], 67 (65) [M+ – C4H7O], 55
Yield: 678 mg (100%); colorless crystals
endo-6
+
(100) [C4H7 ].
Rf = 0.33 (pentane–Et2O, 1:1).
IR (KBr): 3362 (s, br), 2968 (s), 2939 (s), 2879 (s), 1110 (s), 1048
(s) cm–1.
1H NMR (360 MHz, CDCl3): d = 3.88 (s, 1 H), 2.55–2.52 (m, 2 H),
2.00–1.95 (m, 6 H), 1.94–1.91 (m, 2 H), 1.81–1.77 (m, 3 H).
13C NMR (90.6 MHz, CDCl3): d = 19.8 (CH2), 20.9 (CH2), 36.2
(CH), 44.5 (CH), 81.8 (CH).
Copper-Catalyzed [2+2] Photocycloaddition; General Proce-
dure
A 15-mL quartz tube with a rubber seal was charged with Cu(OTf)2
(10 mol%) under argon, and the copper salt was dissolved in anhyd,
degassed Et2O (10 mL). The appropriate substrate was added, and
the tube was filled with additional Et2O (final diene concentration
ca. 50 mmol/L). The mixture was shaken or treated with ultrasound
until the Cu(OTf)2 was mostly dissolved. The tube was irradiated at
r.t. (254 nm, Rayonet RPR-2537 Å) until conversion was complete
(by GLC and TLC analysis). The Et2O soln was then added to a
mixture of 25% aq NH3 (15 mL) and ice (15 g). After the ice had
melted, the layers were separated. The aqueous layer was saturated
with NaCl and extracted with Et2O (3 × 10 mL). The combined or-
ganic layers were washed with brine (20 mL), dried (Na2SO4), fil-
tered, and concentrated.
MS (EI, 70 keV): m/z (%) = 138 (1) [M+], 120 (10) [M+ – H2O], 110
+
+
(10) [M+ – C2H4], 91 (90) [C7H7 ], 79 (100) [C6H7 ], 77 (50)
[C6H5 ], 67 (45) [C4H3O+], 55 (30) [C3H3O+], 53 (30) [C4H5 ], 51
+
+
+
(30) [C4H3 ].
Anal. Calcd for C9H14O (138.21): C, 78.21; H, 10.21. Found: C,
77.76; H, 10.23.
Tricyclo[4.2.1.02,5]nonan-9-one (2)
Alcohol 6 (566 mg, 4.09 mmol) was dissolved in DMSO (30 mL),
and IBX (2.80 g, 10.2 mmol) was added. After stirring for 48 h at
r.t., the reaction mixture was hydrolyzed by the addition of H2O
(250 mL), and the mixture was extracted with Et2O (3 × 100 mL).
The combined organic layers were washed with brine (100 mL),
dried (Na2SO4), and filtered, and the solvent was removed under re-
duced pressure. Purification of the residue by column chromatogra-
phy (silica gel, pentane–Et2O, 1:1) gave ketone 2.
tert-Butyldimethyl(tricyclo[4.2.1.02,5]non-9-yloxy)silane (5)
According to the general procedure, compound 1 (126 mg,
560 mmol) and Cu(OTf)2 (18.0 mg, 50.0 mmol, 10 mol%) were dis-
solved in anhyd Et2O (15 mL) and irradiated at 254 nm for 5 h.
Workup and column chromatography (silica gel, pentane) gave 5.
Yield: 91.0 mg (72%); endo/exo = 88:12; colorless oil.
endo-5
Rf = 0.55 (pentane).
Yield: 495 mg (89%); easily melting and volatile solid; mp 32 °C;
Rf = 0.34 (pentane–Et2O, 1:1).
IR (KBr): 2959 (s), 1764 (vs), 1453 (m) cm–1.
IR (film): 2953 (s), 2856 (s), 1375 (m), 1256 (s), 1125 (s), 1060 (s),
907 (s), 863 (s), 835 (s) cm–1.
1H NMR (360 MHz, CDCl3): d = 3.76 (s, 1 H), 2.53–2.47 (m, 2 H),
1.99–1.95 (m, 4 H), 1.87–1.83 (m, 2 H), 1.83–1.78 (m, 4 H), 0.87
(s, 9 H), 0.03 (s, 6 H).
endo-2
1H NMR (360 MHz, CDCl3): d = 2.85–2.78 (m, 2 H), 2.28–2.22 (m,
4 H), 2.20–2.14 (m, 2 H), 1.90–1.80 (m, 4 H).
13C NMR (90.6 MHz, CDCl3): d = 18.2 (CH2), 20.6 (CH2), 31.3
(CH), 42.0 (CH), 214.3 (C).
Synthesis 2007, No. 24, 3896–3906 © Thieme Stuttgart · New York

PAPER
Reactions of Tricyclo[4.2.1.02,5]nonan-9-one
3903
MS (EI, 70 keV): m/z (%) = 136 (20) [M+], 108 (20) [M+ – CO], 93
13C NMR (90.6 MHz, CDCl3, 300 K): d = 17.3 (CH2), 18.5 (CH2),
18.6 (CH2), 18.8 (CH2), 19.4 (CH2), 21.8 (CH2), 22.7 (CH2), 33.0
(CH), 33.9 (CH), 36.4 (CH), 37.4 (CH), 38.6 (CH2), 38.7 (CH2),
41.4 (CH), 41.4 (CH), 41.9 (CH2), 42.0 (CH2), 57.5 (CH), 57.7
(CH), 69.8 (CH), 70.0 (CH), 125.5 (CH), 125.6 (CH), 127.0 (CH),
127.0 (CH), 128.2 (CH), 128.2 (CH), 144.1 (C), 144.1 (C), 176.7
(C). [Note that the 13C NMR signals are separated for the two dia-
stereomers 11 and 12, except for CO (d = 176.7) and C-2¢ (d = 17.3)].
(20) [M+ – C3H7], 91 (15) [C7H7 ], 79 (100) [C6H7 ], 77 (20)
+
+
[C6H5 ], 67 (50) [C4H3O+].
+
Anal. Calcd for C9H12O (136.19): C, 79.37; H, 8.88. Found: C,
79.49; H, 8.60.
N-Hexylbicyclo[4.2.0]octane-2-carboxamide (7)
To a soln of n-hexylamine (108 mL, 82.0 mg, 808 mmol) in anhyd
benzene (5 mL), 2.5 M n-BuLi in hexane (351 mL, 239 mg,
808 mmol) was added at 0 °C. After 15 min, ketone 2 (50.0 mg,
367 mmol) was added and the soln was refluxed for 12 h. After
cooling to r.t., the soln was hydrolyzed by the addition of H2O
(5 mL) and extracted with Et2O (5 × 10 mL). The combined organic
layers were washed with brine (10 mL), dried (Na2SO4), and fil-
tered, and the solvent was removed under reduced pressure. Purifi-
cation by column chromatography (silica gel, pentane–Et2O, 8:2)
gave 7 as a single diastereomer.
MS (EI, 70 eV): m/z (%) = 285 (18) [M+], 267 (11) [M+ – H2O], 238
(1) [M+ – CH3OH2], 238 (1) [C16H16NO+], 231 (1) [M+ – C4H2], 212
+
(2) [M+ – C4H9O], 207 (1) [M+ – C6H6], 179 (77) [C11H17NO2 ], 165
(100) [C10H15NO2 ], 109 (18) [C8H13+], 97 (8) [C6H9O+], 91 (15)
+
[C7H7 ], 79 (62) [C6H7 ], 67 (15) [C4H3O+], 55 (15) [C3H3O+], 50
+
+
+
(1) [C4H2 ].
HRMS (EI): m/z calcd for C18H24NO2 [M + H+]: 286.1807; found:
286.1799.
Yield: 40.0 mg (46%); colorless crystals; Rf = 0.12 (pentane–Et2O,
7-Oxatricyclo[4.2.2.02,5]decan-8-one (13/ent-13)
8:2).
Method A (Cu-catalyzed): A mixture of (S)-2-tert-butyl-6-(4-tert-
butyl-4,5-dihydrooxazol-2-yl)-4-nitrophenol35 (9.0 mg, 27.0 mmol,
2.6 mol%) and Cu(OAc)2·H2O (2.40 mg, 12.0 mmol, 1.1 mol%) in
H2O-saturated benzene (5 mL) was stirred under an atmosphere of
O2 (balloon) for 15 min. The reaction flask was then covered with
Al foil to exclude any light, and ketone 2 (145 mg, 1.07 mmol) and
98% t-BuCHO (120 mL, 92.0 mg, 1.07 mmol) were added. The soln
was stirred vigorously under an atmosphere of O2 (balloon). Every
24 h another 1 equiv t-BuCHO (120 mL, 92.0 mg, 1.07 mmol) was
added until a total amount of 3 equiv had been added. After 4 d,
Et2O (10 mL) was added and the soln was washed with sat. aq
NaHCO3 (5 mL) and brine (5 mL). After drying (Na2SO4) and fil-
tration of the mixture, the solvent was removed under reduced pres-
sure. Purification by column chromatography (silica gel, pentane–
H2O, 8:2) gave lactone 13.
IR (KBr): 3287 (m), 2960 (s), 2927 (s), 2858 (s), 1642 (s), 1549 (s),
1240 (m), 1207 (m) cm–1.
1H NMR (360 MHz, CDCl3, 300 K): d = 5.39 (br s, 1 H), 3.22 (dt,
J = 7.1, 5.9 Hz, 2 H), 2.53–2.64 (m, 1 H), 2.30–2.40 (m, 1 H), 2.23
(ddd, J = 11.6, 9.3, 3.6 Hz, 1 H), 2.03–2.15 (m, 1 H), 1.93 (virt quin,
J ≅ 9.3 Hz, 1 H), 1.72–1.87 (m, 2 H), 1.61–1.66 (m, 1 H), 1.38–1.57
(m, 6 H), 1.22–1.35 (m, 7 H), 0.88 (t, J = 6.8 Hz, 3 H).
13C NMR (90.6 MHz, CDCl3, 300 K): d = 14.0 (CH3), 21.2 (CH2),
22.5 (CH2), 23.6 (CH2), 25.7 (CH2), 26.3 (CH2), 26.5 (CH2), 26.7
(CH2), 29.7 (CH2), 31.5 (CH2), 33.4 (CH), 36.6 (CH), 39.4 (CH),
47.5 (CH), 176.0 (C).
MS (EI, 70 eV): m/z (%) = 237 (49) [M+], 222 (15) [M+ – CH3], 209
(85) [M+ – C2H4], 194 (38) [M+ – CONH], 180 (18) [M+ – C4H9],
169 (100) [M+ – C5H8], 67 (62) [C5H5 ], 55 (23) [C4H7 ].
+
+
Yield: 118 mg (72%); 32% ee; colorless crystals.
Method B (enzymatic): A baffled Erlenmeyer flask was charged
with fresh LBAmp media (250 mL), inoculated with a preculture of a
recombinant E. coli strain (CHMOBrevi1) (2.5 mL, 1%), and the cul-
ture was incubated at 37 °C and 120 rpm in an orbital shaker for 2
h. Afterwards an IPTG stock soln (50 mL) was added to a final con-
centration of 0.004 wt/v, and addition of ketone 2 (97 mg,
0.712 mmol) and b-cyclodextrin (808 mg, 0.712 mmol) followed.
The culture was incubated for 24 h at 24 °C and 120 rpm in an or-
bital shaker. The biomass was removed by centrifugation (15 min,
4000 rpm) and the aqueous layer was extracted with Et2O
(3 × 250 mL). The combined organic layers were dried (Na2SO4)
and filtered, and the solvent was removed under reduced pressure.
After column chromatography (silica gel, pentane–Et2O, 7:3) lac-
tone ent-13 was isolated.
HRMS (EI): m/z calcd for C15H27NO: 237.2093; found: 237.2092.
7-(3-Hydroxy-3-phenylpropyl)-7-azatricyclo[4.2.2.02,5]decan-8-
one (11, 12)
Lactone 2 (50.0 mg, 367 mmol) and alcohol 10 (98.0 mg, 551 mmol)
were dissolved in CCl4 (3 mL) and the mixture was cooled to
–20 °C. At that temperature, BF3·OEt2 (140 mL, 156 mg, 110 mmol)
was added dropwise (gas evolution) and the same temperature was
maintained for another 4 h. Afterwards the temperature was raised
to –10 °C (12 h) and then to r.t. (24 h). The solvent was then re-
moved under reduced pressure and the yellow residue was hydro-
lyzed by the addition of 15% aq KOH (2 mL). After 15 min, H2O
(5 mL) was added and the soln was extracted with CH2Cl2 (5 × 10
mL). The combined organic layers were washed with brine (10
mL), dried (Na2SO4), and filtered, and the solvent was removed un-
der reduced pressure. Purification of the residue by column chroma-
tography (silica gel, pentane–EtOAc, 1:1) gave an inseparable
mixture of diastereomers 11 and 12.
Yield: 78 mg (72%); 95% ee; colorless crystals; [a]D20 –41.5 (c 10.0
g·L–1, CH2Cl2).
rac-13
Mp 107 °C; Rf = 0.10 (pentane–Et2O, 7:3).
Yield: 87.0 mg (83%); colorless liquid; Rf = 0.15 (pentane–EtOAc,
IR (KBr): 2959 (s), 1752 (s), 1006 (m, C–O) cm–1.
1:1).
1H NMR (360 MHz, CDCl3): d = 4.65–4.61 (m, 1 H), 2.87–2.69 (m,
2 H), 2.59–2.53 (m, 1 H), 2.40 (dddd, J = 13.5, 10.7, 4.9, 2.3 Hz,
1 H), 2.28–2.09 (m, 4 H), 2.00–1.74 (m, 3 H).
13C NMR (90.6 MHz, CDCl3): d = 17.3 (CH2), 17.9 (CH2), 19.1
(CH2), 21.3 (CH2), 32.2 (CH), 34.5 (CH), 38.5 (CH), 78.9 (CH),
176.6 (C).
IR (film): 3364 (m, br), 2954 (s), 2930 (s), 2860 (s), 1640 (s), 1455
(s), 1284 (s), 1068 (m), 745 (m), 693 (m) cm–1.
1H NMR (360 MHz, CDCl3, 300 K): d = 7.20–7.39 (m, 5 H), 5.28
(s, 1 H), 4.49–4.62 (dd, J = 10.2, 3.2 Hz, 1 H), 4.03–4.16 (m, 1 H),
3.49–3.55 (m, 1 H), 3.02–3.14 (m, 1 H), 2.53–2.80 (m, 3 H), 1.62–
2.41 (m, 10 H). [Note that the 1H NMR signals of the two diastere-
omers 11 and 12 overlap, except for H-3¢: d = 4.56 (dd, J = 10.3, 3.3
Hz) and d = 4.52 (dd, J = 10.1, 3.1 Hz), which were used for the de-
termination of the dr. The other signals are therefore reported for the
50:50 mixture of 11 and 12.]
MS (EI, 70 keV): m/z (%) = 152 (10) [M+], 123 (2) [M+ – HCO], 97
(5) [M+ – C4H7], 70 (10) [M+ – C5H9O].
HRMS (EI): m/z calcd for C9H12O2: 152.0837; found: 152.0835.
Synthesis 2007, No. 24, 3896–3906 © Thieme Stuttgart · New York

3904
I. Braun et al.
PAPER
Anal. Calcd for C9H12O2 (152.19): C, 71.03; H, 7.95. Found: C,
70.91; H, 8.00.
Ethyl Diazo(9-hydroxytricyclo[4.2.1.02,5]non-9-yl)acetate (18,
19)
A soln of LDA [441 mmol; prepared from i-Pr2NH (62.0 mL, 45 mg,
441 mmol) and 2.6 M n-BuLi in hexane (192 mL, 130 mg, 441 mmol)
in anhyd THF (1 mL)] was added dropwise over 15 min to a cooled
soln (–78 °C) of 2 (50.0 mg, 367 mmol) and ethyl diazoacetate
(39.0 mL, 42.0 mg, 367 mmol) in THF (5 mL). After stirring at
–78 °C for 1.5 h, the reaction mixture was hydrolyzed by fast addi-
tion of sat. aq NH4Cl (2 mL) and warmed to r.t. Then H2O (10 mL)
was added, and the mixture was extracted with Et2O (3 × 15 mL).
The combined organic layers were washed with sat. aq NaHCO3 (10
mL) and brine (10 mL), dried (Na2SO4), and filtered, and the solvent
was removed under reduced pressure. After column chromatogra-
phy (silica gel, pentane–Et2O, 8:2) diazo esters 18 and 19 were iso-
lated as a mixture of diastereomers.
Methyl 5-Hydroxybicyclo[4.2.0]octane-2-carboxylate (15)
K2CO3 (118 mg, 854 mmol) was added to a soln of lactone 13 (33%
ee; 52.0 mg, 342 mmol) in anhyd MeOH (2 mL). After stirring at
r.t. for 1 h, the soln was neutralized by the addition of dilute AcOH
and extracted with EtOAc (3 × 20 mL). The combined organic lay-
ers were washed with brine (10 mL), dried (Na2SO4), and filtered,
and the solvent was removed under reduced pressure. After column
chromatography (silica gel, pentane–Et2O, 1:1), ester 15 was ob-
tained.
Yield: 62.0 mg (99%); colorless liquid; Rf = 0.17 (pentane–Et2O,
1:1).
IR (film): 3416 (s, br), 2949 (s), 2868 (s), 1773 (vs), 1435 (s), 1274
(s), 1196 (s), 1064 (m) cm–1.
1H NMR (500 MHz, CDCl3, 300 K): d = 3.73–3.79 (m, 1 H), 3.68
(s, 3 H), 2.63 (dd virt q, J ≅ 7.4, 4.6, 2.6 Hz, 1 H), 2.43–2.48 (m, 1
H), 2.34–2.41 (m, 1 H), 2.03–2.10 (m, 1 H), 1.95–2.03 (m, 1 H),
1.66–1.86 (m, 5 H), 1.57–1.66 (m, 1 H), 1.49 (br s, 1 H).
13C NMR (90.6 MHz, CDCl3, 300 K): d = 21.3 (CH2), 23.6 (CH2),
25.4 (CH2), 29.5 (CH2), 35.2 (CH), 41.2 (CH), 43.7 (CH), 51.6 (q,
CH3), 69.4 (d, CH), 176.2 (s, CO).
Yield: 75 mg (82%); dr 67:33; yellow liquid; Rf = 0.09 (pentane–
Et2O, 8:2).
IR (KBr): 3566–3325 (br), 2943 (s), 2361 (s), 2067 (s), 1691 (vs),
1301 (s), 1171 (s), 1038 (s) cm–1.
1H NMR (360 MHz, CDCl3, 300 K): d = 4.23 (q, J = 7.1 Hz, 2 H),
2.83–2.92 (m, 1 H), 2.50–2.64 (m, 2 H), 2.18–2.28 (m, 2 H), 1.88–
2.13 (m, 6 H), 1.46–1.61 (m, 2 H) 1.29 (t, J = 7.1 Hz, 3 H).
13C NMR (90.6 MHz, CDCl3, 300 K): d = 14.5 (CH3), 19.1 (CH2),
22.1 (CH2), 36.9 (CH), 46.4 (CH), 60.8 (CH2), 86.8 (C), 133.1 (C),
166.9 (C).
MS (EI, 70 eV): m/z (%) = 184 (2) [M+], 166 (3) [M+ – H2O], 155
(6) [M+ – C2H5], 152 (31) [M+ – CH3OH], 124 (23) [M+ – C2H4O2],
107 (54) [M+ – C6H5], 96 (77) [M+ – C4H8O2], 91 (31), 79 (100)
MS (EI, 70 eV): m/z (%) = 250 (3) [M+], 222 (53) [M+ – N2], 204
[C6H7 ], 67 (62) [C4H3O+], 59 (100) [C3H7O+], 55 (69) [C4H7 ], 51
(13) [M+ – C2H6O], 176 (65) [M+ – C3H6O2], 169 (42) [M+ – C6H9],
+
+
+
+
+
(23) [C4H3 ].
131 (22) [M+ – C3H6O2], 120 (60) [C7H4O2 ], 115 (46) [C6H11O2 ],
93 (43) [C6H5O+], 80 (100) [C6H8 ], 67 (64) [C5H7 ], 55 (49)
+
+
Anal. Calcd for C10H16O3 (184.232): C, 65.19; H, 8.75%. Found: C,
65.58; H, 8.65%.
+
+
[C4H7 ], 41 (46) [C3H5 ].
HRMS (EI): m/z calcd for C13H18N2O3: 250.1317; found: 250.1318.
Methyl (2R,5S)- and (2S,5R)-5-{[(R)-3,3,3-trifluoro-2-methoxy-
2-phenylpropanoyl]oxy}bicyclo[4.2.0]octane-2-carboxylate (16
and 17)
Ethyl 8-Oxotricyclo[4.2.2.02,5]decane-7-carboxylate (20)
A soln of 18 and 19 (dr 67:33; 72.0 mg, 288 mmol) in anhyd CH2Cl2
(1 mL) was added to a soln of [Rh(OAc)2]2 (1.27 mg, 2.87 mmol,
1 mol%) in anhyd CH2Cl2 (4 mL), and the soln was stirred for 12 h
at r.t. The catalyst was then removed by filtration, and the solvent
was removed under reduced pressure. After column chromatogra-
phy (silica gel, pentane–Et2O, 8:2), rac-20 was obtained as a mix-
ture of diastereomers.
Ester 15 (41.0 mg, 223 mmol) was dissolved in anhyd py (8.20 mL),
and (R)-(–)-(methoxy)(phenyl)(trifluoromethyl)acetyl chloride
(41.6 mL, 56.2 mg, 223 mmol) was added by syringe. After the mix-
ture had stirred at r.t. for 2.5 h, the solvent was removed under re-
duced pressure and the residue was purified by column
chromatography (silica gel, pentane–H2O, 2:8); this gave the Mosh-
er esters 16 (RS) and 17 (SS) as a mixture of diastereomers; yield:
47 mg (53%); dr = 2:1, 33% de. Separation of the diastereomers
was possible by semi-preparative HPLC (Sigma-Aldrich ZR-Car-
bon, 150 × 4.6 mm, MeCN–H2O, 1:1, 30 mL/min, 215 nm), which
gave pure main diastereomer 16 (dr >95:5). HPLC: tR = 18.40 min
(16), 19.82 min (17). Where possible, chemical shifts in the NMR
spectra are reported separately below.
1H NMR (500 MHz, CDCl3): d = 7.53–7.48 (m, 2 H), 7.41–7.38 (m,
3 H), 5.08 (virt q, J ≅ 3.5 Hz, 1 H), 3.65 (s, 3 H), 3.54 (q, 5JHF = 1.0
Hz, 3H) (16), 3.53 (q, 5JHF = 1.0 Hz, 3 H) (17), 2.65–2.54 (m, 2 H)
(16), 2.65–2.54 (m, 1 H) (17), 2.50 (ddd, J = 10.8, 8.1, 3.5 Hz, 1H)
(16), 2.54–2.46 (m, 2 H) (17), 2.15–1.52 (m, 8 H).
Yield: 54.0 mg (84%); dr 67:33; colorless liquid; Rf = 0.26 (pen-
tane–Et2O, 8:2) (PMA).
IR (KBr): 2935 (s), 1743 (s), 1715 (s), 1257 (s), 1147 (s), 1031 (s)
cm–1.
1H NMR (360 MHz, CDCl3, 300 K): d = 4.09–4.29 (m, 2 H), 3.22
(d, J = 2.4 Hz, 1 H) (minor diastereomer), 2.99 (virt t, J ≅ 2.1 Hz, 1
H) (major diastereomer), 2.48–2.88 (m, 2 H), 2.10–2.44 (m, 8 H),
1.66–1.97 (m, 2 H), 1.17–1.34 (m, 3 H).
13C NMR (90.6 MHz, CDCl3, 300 K): d = 14.1 (CH3), 16.2 (CH2),
17.7 (CH2), 18.7 (CH2), 20.6 (CH2), 31.6 (CH), 35.2 (CH), 35.8
(CH), 45.0 (CH), 58.3 (CH), 61.1 (CH2), 169.5 (C), 209.7 (C).
13C NMR (90.6 MHz, CDCl3): d = 175.6 (CO), 165.9 (CO), 132.4
(C), 129.5 (CH), 128.4 (CH), 127.3 (CH), 124.9, 121.7 (CF3), 74.3
(CH) (16), 74.2 (CH) (17), 55.3 (CH3), 51.7 (CH3), 43.8 (CH) (16),
43.7 (CH) (17), 37.4 (CH), 35.1 (CH), 26.6 (CH2) (17), 26.4 (CH2)
(16), 25.5 (CH2) (16), 25.4 (CH2) (17), 23.2 (CH2) (17), 23.2 (CH2)
(16), 21.3 (CH2) (17), 21.2 (CH2) (16).
MS (EI, 70 eV): m/z (%) = 222 (100) [M+], 194 (35) [M+ – CO], 176
(80) [M+ – C2H5OH], 168 (42) [M+ – C4H6], 148 (38) [M+
–
+
+
C3H6O2], 115 (60) [C6H11O2 ], 91 (55) [C7H7 ], 80 (95) [C5H5O+],
+
+
+
+
67 (65) [C5H7 ], 55 (30) [C4H7 ], 53 (28) [C4H4 ], 41 (42) [C3H5 ].
HRMS (EI): m/z calcd for C13H18O3: 222.1256; found: 222.1251.
19F NMR (235.4 MHz, CDCl3): d = –72.12 (CF3) (16), –72.15 (CF3)
(17).
Screening of Catalysts and Conditions in the Reaction of Esters
18 and 19 To Give Ketones 21 and ent-21; General Procedure
To preform the catalyst, the ligand (4 equiv) and [Rh(OAc)2]2 were
stirred for 5 min in CH2Cl2. Then the soln was brought to the appro-
priate temperature (cf. Table 2) and the diazo esters 18 and 19 were
slowly added. After the appropriate time an aliquot was taken, and
MS (EI, 70 eV): m/z (%) = 369 (1) [M+ – CH3O], 189 (78)
+
+
[C9H8OF3 ], 167 (63) [C10H15O2 ], 135 (50) [C9H11O+], 107 (100)
[C8H8 ], 79 (50) [C6H7 ], 59 (6) [C3H7O+], 41 (6) [C3H5 ].
+
+
+
Synthesis 2007, No. 24, 3896–3906 © Thieme Stuttgart · New York

PAPER
Reactions of Tricyclo[4.2.1.02,5]nonan-9-one
3905
filtered through a pad of silica gel (EtOAc), and the ee was deter-
mined by GC. Decarboxylation to ketones 21 was achieved ther-
mally in the injection block heated at 230 °C. The ee determined
this way was the same as that determined by previous decarboxyla-
tion.
(5) For examples, see: (a) Salomon, R. G.; Coughlin, D. J.;
Ghosh, S.; Zagorski, M. G. J. Am. Chem. Soc. 1982, 104,
998. (b) Avasthi, K.; Raychaudhuri, S. R.; Salomon, R. G.
J. Org. Chem. 1984, 49, 4322. (c) Ghosh, S.; Raychaudhuri,
S. R.; Salomon, R. G. J. Org. Chem. 1987, 52, 83.
(6) For a preliminary communication, see: Braun, I.; Rudroff,
F.; Mihovilovic, M. D.; Bach, T. Angew. Chem. Int. Ed.
2006, 45, 5541.
(7) For examples, see: (a) Lumb, J. T.; Whitham, G. H.
Tetrahedron 1965, 21, 499. (b) Mehta, G.; Khan, F. A.;
Ganguly, B.; Chandrasekhar, J. J. Chem. Soc., Chem.
Commun. 1992, 1711. (c) Müller-Bötticher, H.; Fessner,
W.-D.; Melder, J.-P.; Prinzbach, H.; Gries, S.; Irngartinger,
H. Chem. Ber. 1993, 126, 2275. (d) Suri, S. C. Tetrahedron
Lett. 1996, 37, 2335. (e) Rosenberg, M. G.; Haslinger, U.;
Brinker, U. H. J. Org. Chem. 2002, 67, 450.
Tricyclo[4.2.2.02,5]decan-7-one (21)
Ester 20 (31.0 mg, 139 mmol) was dissolved in dilute aq KOH
(2 mL) and the soln was stirred at r.t. for 1 h. Then the soln was acid-
ified with diluted HCl, and acetone (3 mL) was added. The soln was
refluxed until no starting material was detectable (TLC, ca. 30 min).
H2O (3 mL) was added and the soln was extracted with Et2O (3 × 15
mL). The combined organic layers were washed with brine (10
mL), dried (Na2SO4), and filtered, and the solvent was removed un-
der reduced pressure. After column chromatography (silica gel,
pentane–Et2O, 9:1) ketone 21 was obtained.
(8) Story, P. R. J. Org. Chem. 1961, 26, 287.
(9) For a review, see: Grubbs, R. H. Tetrahedron 2004, 60,
7117.
(10) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc.
1996, 118, 100.
(11) (a) Hartmann, C.; Meyer, V. Chem. Ber. 1893, 26, 1727.
(b) Frigerio, M.; Santagostino, M.; Suptore, S.; Palmisano,
G. J. Org. Chem. 1995, 60, 7272. (c) Frigerio, M.;
Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537.
(12) (a) Haller, A.; Bauer, E. C. R. Hebd. Seances Acad. Sci.
1908, 147, 824. (b) Hamlin, K. E.; Weston, W. A. Org.
React. 1957, 9, 1.
(13) (a) Mehta, G.; Praveen, M. J. Org. Chem. 1995, 60, 279.
(b) Mehta, G.; Reddy, D. S. Synlett 1996, 229. (c) Mehta,
G.; Reddy, D. S. J. Chem. Soc., Perkin Trans. 1 2001, 1153.
(14) For a review, see: Mehta, G.; Venkateswaran, R. V.
Tetrahedron 2000, 56, 1399.
Yield: 21 mg (100%); colorless liquid; Rf = 0.23 (pentane–Et2O,
9:1).
IR (film): 2917 (s), 1713 (vs), 1482 (m), 1404 (m) cm–1.
1H NMR (360 MHz, CDCl3, 300 K): d = 2.43–2.70 (m, 2 H), 1.99–
2.38 (m, 10 H), 1.51–1.77 (m, 2 H).
13C NMR (90.6 MHz, CDCl3, 300 K): d = 18.3 (CH2), 18.5 (CH2),
20.0 (CH2), 20.9 (CH2), 31.6 (CH), 31.9 (CH), 35.0 (CH), 44.4
(CH2), 45.5 (CH), 216.8 (C).
MS (EI, 70 eV): m/z (%) = 150 (98) [M+], 122 (22) [M+ – CO], 108
+
(63) [C8H14+], 93 (75) [C6H5O+], 79 (100) [C6H7 ], 67 (67)
+
+
[C4H3O+], 54 (31) [C4H6 ], 41 (31) [C3H5 ].
HRMS (EI): m/z calcd for C10H14O: 150.1045; found: 150.1045.
Acknowledgment
(15) Impastato, F. J.; Walborsky, H. M. J. Am. Chem. Soc. 1962,
84, 4838.
(16) Ishihara, K.; Yano, T. Org. Lett. 2004, 6, 1983.
(17) Paquette, L. A.; Maynard, G. D. J. Org. Chem. 1989, 54,
5054.
This project was supported by the Deutsche Forschungsgemein-
schaft (Ba 1372/11), by the Fonds der Chemischen Industrie, and
by the Austrian Science Fund (FWF, P-I19-B10).
(18) Gassman, P. G.; Lumb, J. T.; Zalar, F. V. J. Am. Chem. Soc.
1967, 89, 946.
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Synthesis 2007, No. 24, 3896–3906 © Thieme Stuttgart · New York

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Synthesis 2007, No. 24, 3896–3906 © Thieme Stuttgart · New York