Blocking fluorine substitution in biotransformation of nortricyclanyl N-phenylcarbamates with Beauveria bassiana

Article abstract of DOI:10.1002/ejoc.200200647

The biotransformation of tricyclo[2,2,1,0^2,6]hept-3-yl N-phenylcarbamate (8) by a standard procedure using Beauveria bassiana gave a 7:1 mixture of optically active exo,exo- and exo,endo-5-hydroxytricyclo[2.2.1.0^2,6]hept-3-yl N-phenylcarbamates 15 and 16 in 19% isolated yield. No ring opening of the three-membered ring was observed. Substitution with a fluorine atom at the 5-endo- or 5-exo-position prevented hydroxylation of any alicyclic position of the molecules, p-hydroxylation of the aromatic ring occurring to a small extent instead. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200200647

FULL PAPER
Blocking Fluorine Substitution in Biotransformation of Nortricyclanyl
N-Phenylcarbamates with Beauveria bassiana
Günter Haufe*[a] and Dörthe Wölker[a]
Keywords: Biotransformations / Epoxides / Fluorine / Hydroxylation / Fungi
The biotransformation of tricyclo[2.2.1.02,6]hept-3-yl N-
phenylcarbamate (8) by standard procedure using
Beauveria bassiana gave a 7:1 mixture of optically active
exo,exo- and exo,endo-5-hydroxytricyclo[2.2.1.02,6]hept-3-yl
N-phenylcarbamates 15 and 16 in 19% isolated yield. No
ring opening of the three-membered ring was observed. Sub-
stitution with a fluorine atom at the 5-endo- or 5-exo-position
prevented hydroxylation of any alicyclic position of the mole-
cules, p-hydroxylation of the aromatic ring occurring to a
small extent instead.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
a
Introduction
˚
varied from 3.3 to 6.2 A, so the previously described dis-
Selective oxygenation of chemically non-activated hydro-
carbon positions still remains a problem in synthesis. Mic-
robiological hydroxylation involving monooxygenases is
one way to overcome this drawback,[1] one of the most fre-
quently used microorganisms for this purpose being Beau-
veria bassiana. The biocatalytic reactions of this fungus
have been reviewed recently.[2] As early as at the end of the
1960s, Fonken et al. proposed an enzyme-substrate model
to account for the preferential hydroxylation by that micro-
organism of certain positions in cyclic alcohols or alicyclic
carboxamides.[3] For the latter substrates, the model sug-
gests that in a first step an electron-rich center, such as the
carbonyl oxygen, becomes attached to the enzyme’s active
site. Hydroxylation then occurs selectively at a carbon atom
tance criterion was no longer useful as a general predictive
tool.[11] Later on, other authors added more examples of
hydroxylation of the above classes of compounds.[12] Even
saturated carbocycles, including steroids or terpenes, a
tetrahydrofuran derivative, and alkyl side chains of aro-
matic compounds not possessing any electron-rich func-
tional binding group may be hydroxylated.[7,13] Moreover,
the ability of this fungus to p-hydroxylate aromatic rings of
N-benzoylamines, N-phenylcarbamates, or substituted het-
eroaromatics is also well known.[8,10,14] In addition, olefins
are epoxidized,[3a,15] sulfoxides are produced from thioe-
thers,[16] and even a BaeyerϪVilliger oxidation of a ketone
has been facilitated by this microorganism.[17] Holland et
al. suggested[2] that no fewer than four distinct types of hy-
droxylases are responsible for the hydroxylation activity of
B. bassiana: one monooxygenase for the hydroxylation of
hydrocarbon positions in amides and related polar sub-
strates, one for the hydroxylation of non-activated hydro-
carbons lacking any directing influence from existing sub-
strate functionality, another for the hydroxylation of
benzylic positions, and the fourth for the p-hydroxylation
of aromatic positions.
˚
approximately 5.5 A distant from this oxygen atom. Suc-
ceeding investigations established an optimum distance of
4.5 to 6.2 A for regioselective hydroxylation,[4] and this rule
˚
became the first predictive tool for the selectivity of hydrox-
ylation of non-activated hydrocarbon positions by B. bassi-
ana. Different hydroxylation models have been reviewed by
Holland,[5] and a new concept of docking/protecting groups
in biohydroxylation was recently published by Griengl et
al.[6]
This microorganism was used by Furstoss et al. for bio-
In 1997 we modified the original distance models of
hydroxylation of various other substrates, and the original Fonken et al.[3] and Furstoss et al.[7] for hydroxylation, with
model was extended.[7] Mostly alicyclic amides,[8] lac- B. bassiana, of non-activated hydrocarbon positions in N-
tams,[8b,9] and carbamates[10] have been transformed. For phenylcarbamates of rigid and flexible mono- and bicyclic
these substrates the authors found that the distance between alcohols,[12d] taking regio- and stereoselectivity into ac-
the carbonyl oxygen and the hydroxylated carbon atom count. After an induced fit of the substrate into the en-
zyme’s active site, a hydrogen of a chemically non-activated
[a]
methylene or methine group is replaced by an OH group by
a radical ‘‘oxygen rebound’’ mechanism[1c,18] or a carbo-
cationic[19] mechanism at an optimum distance of about 5.5
Organisch-Chemisches Institut, Westfälische Wilhelms-
Universität Münster,
Corrensstr. 40, 48149 Münster, Germany
Fax: (internat.) ϩ49-251-8339772
˚
E-mail: haufe@uni-muenster.de
A from the oxygen atom directly attached to the alicyclic
Eur. J. Org. Chem. 2003, 2159Ϫ2165
DOI: 10.1002/ejoc.200200647
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2159

G. Haufe, D. Wölker
FULL PAPER
stereochemistry of biohydroxylation, depending on the
absolute configuration of the substrate and the ring
size.[12,20] Continuing our ongoing research on the regio-
and stereoselectivity of microbiological hydroxylation and
the influence of a single fluorine substituent in strategic po-
sitions on the selectivity of such reactions, here we present
the results of synthesis and biohydroxylation of 3-nortri-
cyclanyl N-phenylcarbamate (8) and the stereoisomeric
monofluorinated analogues 13 and 14, each bearing a
fluorine atom in either the exo-5- or the endo-5-position.
Scheme 1
Results and Discussion
part of the substrate.[12d] This is illustrated in Scheme 1 for
the N-phenylcarbamates of two diastereomeric bicyclo-
[3.2.1]octan-7-ols 1 and 4.
Synthesis of the Carbamates
Tricyclo[2.2.1.02,6]heptan-3-ol (7) was synthesized from
norbornene (6) by a known sequence,[22] and subsequently
heated at reflux with phenyl isocyanate in petroleum ether
(110Ϫ140 °C) to give the corresponding carbamate 8 in
85% yield (Scheme 2).
In the anti isomer 1, the equatorial hydrogen in position
˚
3, at a distance of 5.2 A (AM1 calculation) from the oxy-
gen, is selectively replaced by a hydroxy group. This pro-
duces the alcohol 2, which is partially dehydrogenated to
afford the ketone 3. In contrast, the syn isomer 4, lacking
˚
any oxygenϪhydrogen distance close to 5 A in an alicyclic
˚
˚
position (4.3 A for 3-Hax and 4.5 A for 3-Heq), was not
hydroxylated in this part of the molecule at all, although
traces of the phenol 5 were found as the sole oxygenated
product (Scheme 1). Most of this substrate was reco-
vered.[12d] In agreement with this model, cyclopentyl N-phe-
nylcarbamate was also not hydroxylated at all,[10c] while all
˚
substrates containing such a distance of about 5 A were
Scheme 2
hydroxylated in the corresponding positions.[10,12c,12d,20]
This model takes into account that the binding mode of
the substrate to the enzyme’s active site is dictated mainly
by intrinsic steric and electronic properties of the involved
The 5-fluoro derivatives of 8 should be available through
electron-rich docking group.[7,11,21] Similarly, the regio- and epoxide ring-opening of exo-2,3-epoxynorbornene (10) with
stereochemistry of hydroxylation is determined mainly by an acidic fluorinating agent through transannular π-partici-
the structure of the hydrocarbon: namely by a specific dis- pation of the double bond in an intermediary carbocation,
tance from the anchoring group to potentially replacable similarly to the mechanism of bromofluorination of nor-
hydrogens. For the definition of the distance of potentially bornadiene (9).[23] However, synthesis of the desired epox-
substituted hydrogen atoms to the oxygen atom attached ide in pure form was difficult, because of rearrangement of
directly at the alicyclic ring, distance variations caused by 10 to endo-bicyclo[3.1.0]hex-2-ene-6-carbaldehyde (11).[24]
the mobility of the phenylcarbamate function are excluded.
Thus, a CH2Cl2 solution containing 63Ϫ68% of 10 was
This oxygen can move only together with the ring carbons. prepared from 9 by treatment with buffered peracetic acid
Movement of the docking group indeed influences the in- at Ϫ15 °C according to a method reported by Meinwald
duced fit of the substrate, but does not influence the dis- et al.[25] The solvent was evaporated, and the mixture was
tance of the catalytically active center that activates molecu- dropped into neat trimethylamineϪtrihydrofluoride
lar oxygen, and the potential hydroxylation position. This (Me3N·3HF)[26] at 45 °C over 45 min and stirred for an-
distance is therefore independent of the specific confor- other 5 min. After workup, the fluorohydrins 12 (30%) and
mational requirements for the induced fit of the docking 13 (10%) were separated from the aldehyde 11 and from
group, and is also independent of the distance between the one another by column chromatography. The dia-
binding site and the catalytic center of the enzyme.
stereomeric fluorohydrins were then heated at reflux with
Recently, we have shown that the presence of a fluorine phenyl isocyanate in petroleum ether (80Ϫ120 °C) for 4 h
substituent in the trans-2-position of a carbamoyl group did to give the corresponding carbamates 14 and 15 in 73% or
not change the regioselectivity but rather influences the 83% isolated yield (Scheme 3).
2160
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Microbiological Hydroxylation with Beauveria bassiana
FULL PAPER
The biotransformation of compound 8 by this procedure
gave a 7:1 mixture of the diastereomers 16 and 17 in 19%
isolated yield (Scheme 4), no other hydroxylated products
being found, and with 22% of the starting material being
recovered. Separation of 16 from 17 was not successful. The
structures of compounds 16 and 17 were assigned from
spectroscopic data extracted from the spectra of the product
mixture. The data for 16 agree with those observed for the
major product of biotransformation of compound 8 with
Rhizopus arrhizus.[28]
Scheme 3
The assignment of the structures of the fluorohydrins 12
and 13 is demonstrated by some indicative signals. The 19F
NMR spectrum of the exo,exo compound 12 shows a signal
at Ϫ192.0 ppm with a geminal H,F coupling constant of
59.1 Hz. This coupling constant is also found in the mul-
Scheme 4
1
tiplet at δ ϭ 4.57 ppm for 5-H in the H NMR spectrum.
1
The doublet of C-5 is found at δ ϭ 93.6 ppm with JC,F
ϭ
Thus, the exo hydroxylation is strongly preferred over the
endo hydroxylation. This might be an indication of a pre-
ferred abstraction of the 5-Hexo, which lies at a distance
190.7 Hz in the proton-decoupled 13C NMR spectrum. For
C-3, a doublet is found at δ ϭ 71.2 ppm (3JC,F ϭ 5.1 Hz).
The fluorine signal of the exo,endo compound 13 is located
at Ϫ197.6 ppm. (2JF,H ϭ 61.0 Hz). This coupling constant
is also found in the signal of 5-H at δ ϭ 4.77 ppm in the
proton NMR spectrum. The doublet corresponding to C-5
is found at δ ϭ 98.6 ppm (2JC,F ϭ 188.2 Hz), while the sig-
nal for C-3 is found at δ ϭ 74.9 ppm, not showing any
coupling to the fluorine atom because of the gauche ar-
rangement (cf. discussion in ref.[23]).
˚
of 4.6 A from the oxygen attached directly to the tricyclic
hydrocarbon skeleton (AM1 calculation), rather than the 5-
˚
Hendo (distance 4.1 A), provided that the hydroxylation oc-
curs with retention of configuration. Surprisingly, no ring-
opening of the cyclopropane ring was observed, so no hint
of the nature of the intermediary species[18,19] could be ob-
tained from the structures of the products.
Furthermore, the optical rotation of the 7:1 mixture of
16 and 17 was determined to be [α]2D0 ϭ ϩ2.1. Provided that
the specific rotation of the endo compound 17 is not signifi-
cantly larger than the rotation of 16, the enantiospecificity
of B. bassiana is thus the opposite of that of Rhizopus
arrhizus. The specific rotation (same solvent) of the isolated
Similar signals were also found in the corresponding
NMR spectra of compounds 14 and 15. Moreover, the as-
signment of configuration was confirmed by X-ray analy-
sis[27] of
a
single crystal of 5-exo-fluorotricyclo-
[2.2.1.02,6]hept-3-exo-yl N-phenylcarbamate (14, Figure 1).
pure exo,exo-16 in that case was determined to be [α]D20
ϭ
Ϫ1.1.[28] The absolute configurations of the products were
not assigned.
We were also interested in the influence of a fluorine sub-
stituent attached to the carbon atom to be hydroxylated.
Fluorine is known to change the electronic properties of
compounds dramatically without strong alterations to the
steric demand.[29] The formation of additional hydrogen
bonds to the enzyme might be responsible for different se-
lectivities occasionally observed for fluorinated substrates
relative to their non-fluorinated parent compounds.[30] Such
observations have been applied to change the position of
hydroxylation in steroids, for instance. Thus, substitution of
Figure 1. Crystal structure of compound 14
Biotransformation by use of Beauveria bassiane
All biotransformations of compounds 8, 14, and 15 were the 6α-position in 21-hydroxy-16α-methyl-4-pregnene-3,20-
performed by a standard procedure through the use of a dione by fluorine blocks the unwanted 7β-hydroxylation by
2 L fermenter with 200 mg substrate per liter of a growing Curvularia lunata, redirecting hydroxylation to the 11α- or
culture of B. bassiana ATCC 7159.[20] In a standard me- the 9α-position.[31] Several more monofluoro- and gem-di-
dium,[12d] the culture with the substrate was aerated with fluoro-5a-androstanones and the parent ketones have been
1.5 L air per minute at 30 °C for 72 h.
transformed with different fungi such as Aspergillus ochra-
Eur. J. Org. Chem. 2003, 2159Ϫ2165
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2161

G. Haufe, D. Wölker
FULL PAPER
ceus. With few exceptions, hydroxylation is diverted to an peaks at m/z ϭ 263 are found for both compounds. Most
alternative position neither at nor adjacent to the carbon indicatively, a fragment peak at m/z ϭ 135 is found, rep-
atom to which a fluorine atom is attached, even though one resenting the cation of 4-hydroxyphenyl isocyanate. For the
of these centers in the parent compound is a favored site. starting materials, corresponding phenyl isocyanate ions are
Fluorine acts merely as a blocking group.[31,32] Where the identified at m/z ϭ 119.
favored site is more remote from the fluorine substituent(s),
the behavior of a fluoro compound resembles that of its
parent.[32] Holland et al. observed different enantioselec-
Conclusion
tivity for the monohydroxylation of o-, m-, or p-fluorinated
ethylbenzenes by Mortierella isabellina.[33]
The presence of the fluorine atom at C-5, either in the
Substitution of the natural hydroxylation position at C-5
by a geminal difluoro moiety resulted in hydroxylation of
one of the geminal methyl groups of 5,5-difluorocamphor
by Pseudomonas putida cytochrome P450.[34] On the other
hand, a single fluorine substituent in the trans-2-position
close to the anchoring group of cycloalkyl N-phenylcarba-
mates did not change the regioselectivity, but rather influ-
enced the diastereoselectivity of hydroxylation with B. bas-
siana, depending on the absolute configuration of the sub-
strate and ring size.[12c,12d,20]
endo- or in the exo-position, thus prevents hydroxylation in
any position of the nortricyclane skeleton, the only oxygen-
ation observed in biotransformation of compounds 14 and
15 being p-hydroxylation of the aromatic ring. In contrast,
the non-fluorinated parent N-phenylcarbamate of nortricy-
clanol 8 was preferentially hydroxylated in the 5-exo posi-
tion under identical conditions, though the calculated dis-
˚
tance of 4.6 A between the oxygen atom attached to the
skeleton and the hydrogen to be displaced is slightly shorter
[12d]
˚
than the approximately 5 A suggested by the model.
Biotransformation of the fluorinated derivatives 14 and
15 under standard conditions resulted in very low levels of
conversion of the substrates (Scheme 5).
Experimental Section
1
General Remarks: H NMR (300.1 MHz), 13C NMR (75.5 MHz),
and 19F NMR spectra (282.3 MHz) were recorded in CDCl3 with
a Bruker WM 300 spectrometer. Chemical shifts are reported as δ
values [ppm] relative to TMS (1H and 13C) or CFCl3 (19F), respec-
tively, as internal standards. The multiplicities of 13C signals were
determined by the DEPT operation. Mass spectra (electron impact
ionization, 70 eV) were recorded by GC/MS coupling, Varian GC
3400/MAT and Finnigan/MAT data system. The product ratios of
microbial transformations were determined on the crude product
mixtures by 19F NMR spectroscopy or by gas chromatography. The
products were separated by column chromatography (silica gel,
Scheme 5
No products of hydroxylation of any alicyclic position
were found. In both cases only p-hydroxylation of the sub- Merck 60, 70Ϫ230 mesh, diethyl ether/pentane 1:1). Optical ro-
tations were determined with a PerkinϪElmer 241 polarimeter
(NaD line, λ ϭ 589 nm). Elemental analyses were carried out by
the Microanalytical Laboratory, Organic Chemistry Institute, Uni-
versity of Münster, on a Foss Heraeus CHN-O analyzer.
strates was observed, giving compound 18 in 3% yield or
compound 19 in 1% isolated yield. The structures of the
products were determined by NMR spectroscopy and mass
spectrometry; the following signals are indicative for the
structures. The proton spectrum of 18 shows the doublet
Nortricyclanol (7) was synthesized in two steps from norbornene
(6) by a procedure reported by Roberts et al.[22] This compound
was then heated at reflux with phenyl isocyanate (10% excess) in
petroleum ether (110Ϫ140 °C) for 24 h to give 85% of compound
8 after recrystallization from the same solvent. M.p. 148 °C (ref.[22]
146Ϫ147.5 °C). All spectroscopic data agree with those published
recently.[28]
for 3-H at δ ϭ 4.66 ppm (4JH,H ϭ 1.4 Hz) and a doublet of
4
triplets for 5-H at δ ϭ 4.69 ppm (2JH,F ϭ 58, JH,H
ϭ
1.9 Hz). The corresponding signal for 3-H of 19 is shifted
significantly downfield to δ ϭ 5.31 ppm (4JH,H ϭ 1.7 Hz)
because of the through-space effect of the fluorine atom in
the endo position at C-5. The doublet of triplets for 5-H is
4
located at δ ϭ 4.80 ppm (2JH,F ϭ 59, JH,H ϭ 2.2 Hz). The
2,3-exo-Epoxynorborn-5-ene (10): Norbornadiene (9, 18.4 g, 0.2
meta- and ortho-protons of the aromatic ring are found at mol) and NaOAc (24.0 g, 0.29 mol) in CH2Cl2 (100 mL) were
cooled to Ϫ20 °C in a 500-mL two-necked round-bottomed flask
fitted with a thermometer, a dropping funnel, and an efficient
stirrer bar. Peracetic acid (40%, 44 mL, 0.23 mol) was dropped into
the mixture with vigorous stirring over a period of 2 h, with the
temperature being maintained below Ϫ15 °C. After complete ad-
dition of the peracid, stirring at Ϫ15 °C was continued for another
15 min. The mixture was warmed slowly to ϩ5 °C and was then
poured into ice-cold aqueous Na2S2O7 solution (0.1 , 150 mL).
This mixture was transferred into a separation funnel and shaken,
and the phases were separated. The organic layer was shaken again
δ ϭ 6.75 ppm and 7.17 ppm for 18, or at δ ϭ 6.67 ppm and
7.21 ppm for 19. In the 13C NMR spectra of 18 and 19, the
signals for C-3 are found at δ ϭ 74.4 ppm or 78.4 ppm and
the signals for C-5 at δ ϭ 93.1 ppm (1JC,F ϭ 193 Hz) or
97.7 ppm (1JC,F ϭ 189 Hz), respectively. In relation to the
starting materials 14 and 15, the p-carbons of the aromatic
rings of 18 and 19 are shifted downfield from δ ϭ
123.5 ppm to δ ϭ 152.2 ppm or from δ ϭ 123.4 ppm to δ ϭ
152.0 ppm, respectively. The p-hydroxylation of the prod-
ucts is also evident from the mass spectra. Molecular ion with another portion of the thiosulfate solution mentioned
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Eur. J. Org. Chem. 2003, 2159Ϫ2165

Microbiological Hydroxylation with Beauveria bassiana
FULL PAPER
3
(150 mL) and subsequently twice with a saturated aq. solution of
NaOAc. The organic layer was dried with MgSO4, the solvent was
evaporated at about 10 °C, and the yellowish liquid (8.7 g) solidi-
4JH,H ϭ 1.2 Hz, 1 H, p-H), 7.29 (t, JH,H ϭ 8.0 Hz, 2 H, m-H),
7.35 (br. d, JH,H ϭ 11.9 Hz, 2 H, o-H) ppm. 13C NMR: δ ϭ 13.0
3
2
3
(d, C-1), 18.6 (dd, JC,F ϭ 25.4 Hz, C-6), 19.4 (dd, JC,F ϭ 5.1 Hz,
2
fied at Ϫ18 °C. The content of epoxide 10 was gas chromatograph- C-2), 27.4 (t, C-7), 38.5 (dd, JC,F ϭ 17.8 Hz, C-4), 74.3 (dd,
1
ically determined to be 63Ϫ68%. In addition, 10Ϫ15% of norbor-
nadiene (9) and 15Ϫ20% of the aldehyde 11 were found. The spec-
troscopic data determined for 10 from the spectra of the mixture
containing 68% of 10 agree with those published in ref.[24]
3JC,F ϭ 5.1 Hz, C-3), 93.0 (dd, JC,F ϭ 193.3 Hz, C-5), 118.7 (2d,
o-C), 123.5 (d, p-C), 129.0 (2d, m-C), 137.6 (s, ipso-C), 152.8 (s,
CϭO) ppm. 19F NMR: δ ϭ Ϫ193.2 (d, 2JF,H ϭ 59.1 Hz, 5-F) ppm.
MS (GC/MS): m/z (%) ϭ 248 (9) [Mϩ ϩ 1), 247 (54) [Mϩ], 204
(1), 203 (5), 183 (5), 182 (6), 137 (5) [C6H5NHCO2Hϩ], 120 (5),
119 (25) [137 Ϫ H2O], 111 (100) [C7H8Fϩ], 109 (38), 104 (7), 93
(24) [C6H5NH2ϩ], 91 (45) [C7H7ϩ], 83 (5), 77 (14) [C6H5ϩ], 66 (4),
65 (11), 59 (4), 51 (6), 39 (8). C14H14FNO2 (247.3): calcd. C 68.01,
H 5.71, N 5.67; found C 67.86, H 5.74, N 5.56.
Epoxide Ring-Opening with Trimethylamine؊Trihydrofluoride
TrimethylamineϪtrihydrofluoride (595 mg, 5 mmol) was placed in
a 10 mL two-necked flask, fitted with a gas pipe and a septum, and
heated at 45 °C. At this temperature, a sample of the mixture as
prepared above, containing 63% of the epoxide 10 (422 mg,
2.5 mmol), was added dropwise by syringe, with stirring, over
45 min. Stirring was then continued for an additional 5 min. After
cooling to room temperature, the mixture was dissolved in CH2Cl2
(10 mL). Water (15 mL) was added and the mixture was neutralized
with concentrated ammonia solution. The phases were separated,
and the aqueous layer was extracted with CH2Cl2 (2 ϫ 10 mL).
The combined organic layer was washed with concentrated NaCl
solution (15 mL) and dried over MgSO4. Besides some quantities
of norbornadiene (9) and the aldehyde 11, the mixture contained a
3:1 mixture (GC) of the fluorohydrins 12 and 13. These products
were separated from one another and from the impurities by col-
umn chromatography on silica gel (15 g) by use of pentane/diethyl
ether (1:1) as eluent.
3-exo,5-endo-Fluorotricyclo[2.2.1.02,6]hept-3-yl N-Phenylcarbamate
(15): The carbamate 15 was synthesized from the fluorohydrin 13
as described above for compound 14. Yield: 820 mg (83%). M.p.
1
127Ϫ129 °C (petroleum ether). H NMR: δ ϭ 1.43Ϫ1.65 (m, 3 H,
3
ϪCH, ϪCH2), 1.75 (tm, JH,H ϭ 5.0 Hz, 1 H, ϪCH) 1.86 (dd,
2JH,H ϭ 11.0, JH,H ϭ 1.4 Hz, 1 H, 7-H2a), 2.28 (br. s, 1 H, 4-H),
4
4.81 (dt, 2JH,F ϭ 58.7, 4JH,H ϭ 2.2 Hz, 1 H, 5-H), 5.33 (q, 4JH,H ϭ
3
1.7 Hz, 1 H, 3-H), 6.59 (br. s, 1 H, NH), 7.04 (tt, JH,H ϭ 7.3,
3
4
4JH,H ϭ 1.3 Hz, 1 H, p-H), 7.29 (tt, JH,H ϭ 8.0, JH,H ϭ 1.9 Hz,
2 H, m-H), 7.36 (br. d, 3JH,H ϭ 7.4 Hz, 2 H, o-H) ppm. 13C NMR:
3
2
δ ϭ 15.3(dd, JC,F ϭ 7.6 Hz, C-6), 16.0 (d, C-1), 17.3 (dd, JC,F
ϭ
ϭ
3
2
22.9 Hz, C-2), 27.0 (dt, JC,F ϭ 5.1 Hz, C-7), 38.0 (dd, JC,F
15.3 Hz, C-4), 78.5 (d, C-3), 97.7 (dd, 1JC,F ϭ 188.2 Hz, C-5), 118.7
(2d, o-C), 123.4 (d, p-C), 129.0 (2d, m-C), 137.8 (s, ipso-C), 153.1
3-exo,5-exo-Fluorotricyclo[2.2.1.02,6]heptan-3-ol (12): Yield: 96 mg
(30%). M.p. 82Ϫ86 °C (pentane/diethyl ether). 1H NMR: δ ϭ
1.36Ϫ1.63 (m, 3 H, 1-H, 2-H, 6-H), 1.79Ϫ1.95 (m, 2 H, 7-H2),
(s, CϭO) ppm. 19F NMR: δ ϭ Ϫ196.7 (d, JF,H ϭ 59.1 Hz, 5-F)
2
ppm. MS (GC/MS): m/z (%) ϭ 250 (2), 248 (15) [Mϩ ϩ 1), 247
(81) [Mϩ], 203 (4), 182 (16), 137 (25) [C6H5NHCO2Hϩ], 119 (36)
[137 Ϫ H2O], 111 (81) [C7H8Fϩ], 91 (100) [C7H7ϩ], 77 (29) [C6H5ϩ],
65 (11), 39 (8). C14H14FNO2 (247.3): calcd. C 68.01, H 5.71, N
5.67; found C 68.15, H 5.78, N 5.79.
4
2.11Ϫ2.19 (br. s, 1 H, 4-H), 3.82 (q, JH,H ϭ 1.8 Hz, 1 H, 3-H),
4.57 (dt, 2JH,F ϭ 58.9, 4JH,H ϭ 1.9 Hz, 1 H, 5-H) ppm. 13C NMR:
δ ϭ 12.4 (d, C-1), 19.0 (dd, 2JC,F ϭ 25.4 Hz, C-6), 21.5 (dd, 3JC,F ϭ
2
5.1 Hz, C-2), 26.4 (t, C-7), 40.5 (dd, JC,F ϭ 12.7 Hz, C-4), 71.2
3
1
Biotransformation with Beauveria bassiana ATCC 7159: The N-phe-
nylcarbamates 8, 14, or 15 (300 mg each) were transformed through
the use of a growing culture of B. bassiana ATCC 7159 as described
in ref.[12c,20]
(dd, JC,F ϭ 5.1 Hz, C-3), 93.6 (dd, JC,F ϭ 190.7 Hz, C-5) ppm.
19F NMR: δ ϭ Ϫ192.0 (d, JF,H ϭ 59.1 Hz, 5-F) ppm. MS (GC/
2
MS, ion trap): m/z (%) ϭ 127 (5) [Mϩ Ϫ 1], 109 (48), 99 (9), 91
(42), 84 (18), 79 (100), 72 (9), 66 (63), 51 (13), 43 (8), 39 (51).
C7H9FO (128.1): calcd. C 65.61, H 7.08; found C 65.43, H 7.22.
3-exo,5-exo-Hydroxytricyclo[2.2.1.02,6]hept-3-yl N-Phenylcarbamate
(16) and 3-exo,5-endo-Hydroxytricyclo[2.2.1.02,6]hept-3-yl N-Phe-
nylcarbamate (17): Together with the starting material 8 (66 mg,
22%), a 7:1 mixture of compounds 16 and 17 (62 mg, 19%) was
isolated. M.p. 128 °C (cyclohexane/ethyl acetate, 1:1). [α]2D2 ϭ ϩ2.1
(c ϭ 1, CHCl3). The spectroscopic data for 16 agree with those
reported recently.[28] For the isomer 17 the following data were ex-
tracted from the spectra of the 7:1 mixture: 1H NMR: δ ϭ
1.35Ϫ1.99 (m, 1-H, 2-H, 5-H2, 6-H, 7-H2, ϪOH), 2.05 (s, 1 H, 4-
H), 4.47 (m, 1 H, 5-H), 4.78 (m, 1 H, 3-H), 6.74 (br. s, 1 H, NH),
3-exo,5-endo-Fluorotricyclo[2.2.1.02,6]heptan-3-ol (13): Yield: 32 mg
(10%). M.p. 59Ϫ63 °C (pentane/diethyl ether). 1H NMR: δ ϭ
1.38Ϫ1.62 (m, 4 H, 1-H, 2-H, 6-H, 7-H2b), 1.79Ϫ1.95 (dd, 2JH,H ϭ
4
11.0, JH,H ϭ 1.4 Hz, 1 H, 7-H2a), 2.01 (br. d, 1 H, 4-H), 4.54 (q,
2
4
4JH,H ϭ 1.7 Hz, 1 H, 3-H), 4.77 (dt, JH,F ϭ 59.4, JH,H ϭ 2.1 Hz,
1 H, 5-H) ppm. 13C NMR: δ ϭ 15.1 (dd, JC,F ϭ 7.6 Hz, C-2),
17.8 (dd, JC,F ϭ 25.4 Hz, C-6), 18.2 (d, C-1), 26.2 (t, C-7), 40.0
(dd, JC,F ϭ 15.3 Hz, C-4), 74.9 (d, C-3), 98.6 (dd, JC,F
3
2
2
1
ϭ
188.2 Hz, C-5) ppm. 19F NMR: δ ϭ Ϫ197.6 (d, JF,H ϭ 61.0 Hz,
5-F) ppm. MS (GC/MS, ion trap): m/z (%) ϭ 127 (5) [Mϩ Ϫ 1],
109 (83), 99 (12), 91 (85), 85 (22), 79 (100), 72 (7), 66 (92), 53 (15),
43 (4), 39 (65). C7H9FO (128.1): calcd. C 65.61, H 7.08; found C
65.81, H 7.10.
2
3
3
7.03 (t, JH,H ϭ 7.3 Hz, 1 H, p-H), 7.28 (t, JH,H ϭ 7.3 Hz, 2 H,
m-H), 7.34 (br. d, 3JH,H ϭ 7.9 Hz, 2 H, o-H) ppm. 13C NMR: δ ϭ
14.1(d, C-1), 17.8 (d, C-2), 20.7 (d, C-6), 27.1 (t, C-7), 39.5 (d, C-
4), 75.2 (d, C-5), 80.7 (d, C-3), 118.7 (d, o-C), 123.2 (d, p-C), 128.9
(d, m-C), 137.9 (s, ipso-C), 153.4 (s, CϭO) ppm. MS (GC-MS,
70 eV, ion trap): m/z (%) ϭ 245 (4) [Mϩ], 207 (2), 119 (26)
[C6H5NCOϩ], 109 (18) [C7H9Oϩ] 93 (57) [C6H5NH2ϩ], 79 (100)
[C6H7ϩ], 77 (53) [C6H5ϩ], 65 (34), 51 (23), 39 (53) [C3H3ϩ].
3-exo,5-exo-Fluorotricyclo[2.2.1.02,6]hept-3-yl N-Phenylcarbamate
(14): The fluorohydrin 12 (512 mg, 4 mmol) was heated at reflux
with phenyl isocyanate (524 mg, 4.4 mmol) in petroleum ether
(110Ϫ140 °C) for 24 h by the procedure given in ref.[12c], and the
mixture was worked up to give 14. Yield: 721 mg (73%). M.p.
3-exo,5-exo-Fluorotricyclo[2.2.1.02,6]hept-3-yl N-(4-Hydroxyphenyl)-
1
116Ϫ120 °C (petroleum ether). H NMR: δ ϭ 1.54Ϫ1.70 (m, 3 H, carbamate (18): Compound 18 (8 mg, 3%) was isolated together
2
1
1-H, 2-H, 6-H), 1.88 (d, JH,H ϭ 10.7 Hz, 1 H, 7-H2), 1.97 (dd,
with starting material 14 (109 mg, 36%). H NMR: δ ϭ 1.55Ϫ1.68
4
2
2JH,H ϭ 10.7, JH,H ϭ 1.0 Hz, 1 H, 7-H2), 2.41 (br. s, 1 H, 4-H), (m, 3 H, 1-H, 2-H, 6-H), 1.81Ϫ2.00 (d, JH,H ϭ 10.7 Hz, 1 H, 7-
4.68 (d, 4JH,H ϭ 1.7 Hz, 1 H, 3-H), 4.70 (dt, 2JH,F ϭ 58.2, 4JH,H ϭ H2), 1.96 (dd, JH,H ϭ 10.7, JH,H ϭ 1.0 Hz, 1 H, 7-H2), 2.39 (br.
4
4
3
4
2
1.9 Hz, 1 H, 5-H), 6.72 (br. s, 1 H, NH), 7.05 (tt, JH,H ϭ 7.2, s, 1 H, 4-H), 4.66 (d, JH,H ϭ 1.4 Hz, 1 H, 3-H), 4.69 (dt, JH,F
ϭ
Eur. J. Org. Chem. 2003, 2159Ϫ2165
www.eurjoc.org  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2163

G. Haufe, D. Wölker
FULL PAPER
[1f]
4
K. Faber, Biotransformations in Organic Chemistry, 4th ed.,
58.4, JH,H ϭ 1.9 Hz, 1 H, 5-H), 6.41 (br. s, 1 H, NH), 6.75 (dt,
4
3
3JH,H ϭ 10.0, JH,H ϭ 2.9 Hz, 2 H, m-H), 7.17 (br. d, JH,H
ϭ
Springer, Berlin, 2000, p. 225Ϫ236.
[2] [2a]
8.6 Hz, 2 H, o-H) ppm. 13C NMR: δ ϭ 13.1 (d, C-1), 18.7 (dd,
2JC,F ϭ 24.6 Hz, C-6), 19.5 (d, C-2), 27.5 (t, C-7), 38.6 (dd, 2JC,F ϭ
16.0 Hz, C-4), 74.4 (d, C-3), 93.1 (dd, 1JC,F ϭ 193.4 Hz, C-5), 115.8
(2d, o-C), 121.5 (2d, m-C), 130.5 (s, ipso-C), 152.2 (s, p-C), 153.4
H. L. Holland, T. A. Morris, P. J. Nava, M. Zabic, Tetra-
[2b]
hedron 1999, 55, 7441Ϫ7460.
G. J. Grogan, H. L. Holland,
J. Mol. Catal. B, Enzym. 2000, 9, 1Ϫ32.
[3] [3a]
G. S. Fonken, M. E. Herr, H. C. Murray, L. M. Reineke, J.
R. A. Johnson, M. E.
Herr, H. C. Murray, G. S. Fonken, J. Org. Chem. 1968, 33,
[3b]
Am. Chem. Soc. 1967, 89, 672Ϫ675.
(s, CϭO) ppm. 19F NMR: δ ϭ Ϫ193.3 (d, JF,H ϭ 57.2 Hz, 5-F)
2
ppm. MS (GC/MS): m/z (%) ϭ 263 (36) [Mϩ], 219 (11), 198 (8),
172 (7), 153 (9), 135 (31) [C6H4NHCO2ϩ], 120 (10), 111 (90)
[C7H8Fϩ], 91 (100) [C6H4NHϩ], 81 (11) [C6H9ϩ], 65 (16) [C5H5ϩ],
39 (15) [C3H3ϩ].
3217Ϫ3221.
[4] [4a]
R. A. Johnson, M. E. Herr, H. C. Murray, G. S. Fonken, J.
[4b]
Org. Chem. 1970, 35, 622Ϫ626.
M. E. Herr, H. C. Murray,
G. S. Fonken, J. Med. Chem. 1971, 14, 842Ϫ845.
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[5]
[6] [6a]
3-exo,5-endo-Fluorotricyclo[2.2.1.02,6]hept-3-yl N-(4-Hydroxyphe-
nyl)carbamate (19): Compound 19 (3 mg, 1%) was isolated together
G. Braunegg, A. de Raadt, S. Feichenhofer, H. Griengl,
I. Kopper, A. Lehmann, H. Weber, Angew. Chem. 1999, 111,
1
[6b]
with starting material 15 (157 mg, 52%). H NMR: δ ϭ 1.43Ϫ1.67
2946Ϫ2949; Angew. Chem. Int. Ed. 1999, 38, 2763Ϫ2766.
(m, 3 H, ϪCH, ϪCH2), 1.73 (tm, 3JH,H ϭ 4.4 Hz, 1 H, ϪCH) 1.86
A. de Raadt, B. Fetz, H. Griengl, M. F. Klingler, I. Kopper, B.
Krenn, D. F. Münzer, R. G. Ott, P. Plachota, H. J. Weber, G.
Braunegg, W. Mosler, R. Saf, Eur. J. Org. Chem. 2000,
2
(d, JH,H ϭ 10.0 Hz, 1 H, 7-H2a), 2.27 (br. s, 1 H, 4-H), 4.80 (dt,
4
4
2JH,F ϭ 58.7, JH,H ϭ 2.2 Hz, 1 H, 5-H), 5.31 (d, JH,H ϭ 1.7 Hz,
3835Ϫ3847. [6c] A. de Raadt, H. Griengl, H. Weber, Chem. Eur.
3
4
1 H, 3-H), 6.39 (br. s, 1 H, NH), 6.76 (dt, JH,H ϭ 8.8, JH,H
ϭ
[6d]
J. 2001, 7, 27Ϫ31.
A. de Raadt, B. Fetz, H. Griengl, M. F.
3
2.8 Hz, 2 H, m-H), 7.21 (br. d, JH,H ϭ 8.6 Hz, 2 H, o-H) ppm.
Klingler, B. Krenn, K. Mereiter, D. F. Münzer, P. Plachota, H.
J. Weber, R. Saf, Tetrahedron 2001, 57, 8151Ϫ8157.
13C NMR: δ ϭ 15.4 (d, C-1), 16.0 (d, C-2), 17.3 (dd, JC,F
ϭ
2
2
[7a] A. Archelas, R. Furstoss, B. Waegell, J. Le Petit, L. Deveza,
[7]
23.1 Hz, C-6), 27.1 (t, C-7), 38.1 (dd, JC,F ϭ 15.9 Hz, C-4), 78.4
1
[7b]
(d, C-3), 97.7 (dd, JC,F ϭ 188.8 Hz, C-5), 115.8 (2d, o-C), 121.0
Tetrahedron 1984, 40, 355Ϫ367.
R. Furstoss, A. Archelas,
(2d, m-C), 129.1 (s, ipso-C) 152.0 (s, p-C), 153.5 (s, CϭO) ppm. 19
F
J.-D. Fourneron, B. Vigne, in Organic Synthesis an Interdisci-
plinary Challenge (Eds.: J. Streith, H. Prinzbach, G. Schill),
Blackwell, Oxford 1985, p. 215Ϫ226.
NMR: δ ϭ Ϫ196.7 (d, 2JF,H ϭ 61.0 Hz, 5-HF) ppm. MS (GC/MS):
m/z (%) ϭ 263 (22) [Mϩ], 243 (2) [Mϩ Ϫ HF], 219 (5), 198 (4), 172
(7), 153 (13), 135 (18) [C6H4NHCO2ϩ], 111 (40) [C7H8Fϩ], 91 (100)
[111 Ϫ HF], 79 (21) [C6H7ϩ], 65 (13) [C5H5ϩ], 52 (15), 39 (11)
[C3H3ϩ].
[8] [8a]
J.-D. Fourneron, A. Archelas, B. Vigne, R. Furstoss, Tetra-
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R. Furstoss, J. Org. Chem. 1988, 53, 1797Ϫ1799.
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2478Ϫ2483.
X-ray Crystallographic Study
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A. Archelas, R. Furstoss, B. Vigne, G. Manry, Bull. Soc. Chim.
Fr. 1986, 234Ϫ238.
3-exo,5-exo-Fluorotricyclo[2.2.1.02,6]hept-3-yl N-Phenylcarbamate
(14): Formula C14H14FNO2, M ϭ 247.26, colorless crystal 0.25 ϫ
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[10b]
˚
hedron 1986, 42, 2451Ϫ2456.
B. Vigne, A. Archelas, J.-D.
0.15 ϫ 0.10 mm, a ϭ 10.974(3), b ϭ 9.812(4), c ϭ 22.542(12) A,
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3
V ϭ 2427.3(18) A , ρcalcd. ϭ 1.353 g cmϪ3, µ ϭ 8.39 cmϪ1, empiri-
˚
[10c]
B. Vigne, A. Archelas, R. Furstoss, Tetrahedron 1991, 47,
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[10d]
1447Ϫ1458, and references cited therein.
S. J. Aitken, G.
˚
Grogan, C. S. Y. Chow, N. J. Turner, S. L. Flitsch, J. Chem.
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˚
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residual electron density 0.30 (Ϫ0.28) e·AϪ3, hydrogen at N9 from
˚
difference Fourier calculation, others calculated and all refined as
riding atoms, poorly diffracting crystal, positional disorder of the
group C1 to C7 including F1 refined with split positions to a ratio
of 0.64(1):0.36, due to the small amount of observed data the minor
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This work was supported by the Fonds der Chemischen Industrie.
We wish to thank Dr. R. Fröhlich for X-ray analysis. The generous
gift by Hoechst AG, Frankfurt/Main, of trimethylamine trihydro-
fluoride is gratefully acknowledged.
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CCDC-197806 contains the supplementary crystallographic
data (excluding structure factors) for compound 14. These data
can be obtained free of charge at www.ccdc.cam.ac.uk/conts/
Received November 22, 2002
Eur. J. Org. Chem. 2003, 2159Ϫ2165
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2165