Total synthesis of (S)-(+)-citreofuran by ring closing alkyne metathesis

Article abstract of DOI:10.1021/jo026686q

A concise total synthesis of citreofuran 4 is described, a structurally unique octaketide derivative belonging to the curvularin family. Key steps involve the elaboration of orsellinic acid methyl ester 5 to acid 14, which converts, on attempted formation of the corresponding acid chloride, to the 3-alkoxyisocoumarin derivative 20. This heterocycle can be used as an activated ester to give ketone 21 on treatment with 3-pentynylmagnesium bromide in the presence of TMSCl as the activating agent. Ring-closing alkyne metathesis (RCAM) of diyne 21 catalyzed by (tBuO)₃W≡CCMe₃ affords the strained cycloalkyne 22. Treatment with acid renders its triple bond susceptible to nucleophilic attack by the adjacent carbonyl group, thus leading to a transannular cycloaromatization with formation of the intact skeleton of citreofuran. An X-ray crystallographic study reveals conformational details about this natural product. Finally, it is shown that 4 as well as its protected precursor 23 are able to cleave double-stranded DNA under oxidative conditions.

Full text of DOI:10.1021/jo026686q

Tota l Syn th esis of (S)-(+)-Citr eofu r a n by Rin g Closin g Alk yn e
Meta th esis
Alois Fu¨rstner,* Anne-Sophie Castanet, Karin Radkowski, and Christian W. Lehmann
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim/ Ruhr, Germany
fuerstner@mpi-muelheim.mpg.de
Received November 11, 2002
A concise total synthesis of citreofuran 4 is described, a structurally unique octaketide derivative
belonging to the curvularin family. Key steps involve the elaboration of orsellinic acid methyl ester
5 to acid 14, which converts, on attempted formation of the corresponding acid chloride, to the
3-alkoxyisocoumarin derivative 20. This heterocycle can be used as an activated ester to give ketone
21 on treatment with 3-pentynylmagnesium bromide in the presence of TMSCl as the activating
agent. Ring- closing alkyne metathesis (RCAM) of diyne 21 catalyzed by (tBuO)3WtCCMe3 affords
the strained cycloalkyne 22. Treatment with acid renders its triple bond susceptible to nucleophilic
attack by the adjacent carbonyl group, thus leading to a transannular cycloaromatization with
formation of the intact skeleton of citreofuran. An X-ray crystallographic study reveals conforma-
tional details about this natural product. Finally, it is shown that 4 as well as its protected precursor
23 are able to cleave double-stranded DNA under oxidative conditions.
In tr od u ction
the subject of many preparative6 and biosynthetic stud-
ies.7 Moreover, it has been found that some of the
producing strains lend themselves to biotechnological
modification by the cell fusion technique. The resulting
hybrid strains not only produce a host of novel curvularin
type compounds with different oxidation states along the
backbone, but also turned out to be surprisingly rich
sources of secondary metabolites of totally different and
rather diverse structures.8
Curvularin 1 and related polyketide metabolites such
as 2 and 3 isolated from various Curvularia, Penicillium,
Alternaria, and Cochliobolus species are known to elicit
diverse biological effects ranging from phytotoxicity
to antibacterial and antifungal activity.1 Most notice-
able, however, is their ability to arrest cell division at
low concentrations by disrupting microtubulin assembly
via a mechanism similar to that of colchicin or the
combretastatins.2-4 This ability is likely to originate from
the conformation of their macrocyclic ring, which mimics
the M-helicity of the colchicin skeleton,5 a stereochemical
feature known to be important for tubulin binding of
these agents.3 Consequently, the curvularins have been
(1) (a) Musgrave, O. C. J . Chem. Soc. 1956, 4301. (b) Fennell, D.;
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J . C. J . Am. Chem. Soc. 1989, 111, 3391.
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see: (a) Andreu, J . M.; Timasheff, S. N. Proc. Natl. Acad. Sci. U.S.A.
1982, 79, 6753. (b) Hamel, E. In Microtubule Proteins; Avila de Grado,
J ., Ed.; CRC: Boca Raton, FL, 1989.
Citreofuran 4 is a new member of the curvularin family
produced by the hydrid strain Penicillium citreo-viride
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literature cited therein.
10.1021/jo026686q CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/23/2003
J . Org. Chem. 2003, 68, 1521-1528
1521

Fu¨rstner et al.
SCHEME 1. Retr osyn th etic An a lysis of
Citr eofu r a n
borne scrutiny in target-oriented synthesis, it was invari-
ably applied so far in combination with Lindlar- or Birch-
type reductions as post metathesis transformations.17-23
Therefore the projected synthesis of citreofuran bears a
chance to illustrate that RCAM has a significantly
broader scope than just the preparation of stereodefined
olefins and may prove relevant for heterocycle synthesis
as well.
The required diyne precursor itself appears to be
readily available from rather simple building blocks,
notably from well-accessible orsellinic acid. Proper choice
of the protecting groups during the assembly stages
should result in a convenient and high-yielding access
to this key synthon.
Tota l Syn th esis. Our synthesis of 4 starts from
orsellinic acid methyl ester 5, which is readily available
on a multigram scale by base-induced cyclodimerization
of methyl acetoacetate. Alkylation of the phenolic -OH
groups24 followed by saponification of the methyl ester
affords acid 6 in excellent overall yield.
ME 0005.9 While its biosynthesis has been studied in
detail and its activity has been claimed to be promising,
the only previous total synthesis of this particular
metabolite suffered from the poor yield (15%) obtained
in the intramolecular Friedel-Crafts acylation reaction
forming the macrocyclic skeleton.10 Therefore we targeted
4 by an entirely different route as part of an ongoing
project dealing with bioactive furan,11 resorcinol,12 and
orsellinic acid derivatives.13,14 Described below is a concise
total synthesis of this natural product together with a
preliminary evaluation of its previously unknown DNA-
damaging capacity.
Dianions derived from o-methylbenzoic acid by depro-
tonation with strong bases can be trapped at the benzylic
position with various electrophiles including methyl
chloroformate.25 Therefore several attempts were made
to adopt this methodology to the present series. Unfor-
tunately, however, only complex mixtures were obtained
upon quenching the dilithio derivative formed from 6 and
LDA (g3 equiv) at -78 °C with 2-hexyl chloroformate 7
as the model compound. A closer inspection showed the
diacylation product 9 and unreacted starting material 6
to be the major components. This distribution is best
explained by the fact that the product of the first
acylation, i.e., compound 8, is more acidic than the
starting material, therefore being preferentially depro-
tonated by the residual dilithio derivative, and can hardly
Resu lts a n d Discu ssion
Str a tegy a n d Retr osyn th etic An a lysis. Rather than
taking recourse to established retrosynthetic logic that
suggests strategic disconnections at the biaryl axis (cross
coupling) and the ester bond (macrolactonization), we
were prompted to use citreofuran as a testing ground for
some of the methodology recently developed in our
laboratory (Scheme 1).
Specifically, it was envisaged to encode the furan ring
of 4 as a macrocyclic yne-one derivative,15 which should
derive from ring-closing alkyne metathesis (RCAM) of a
suitable diyne precursor.16 Although RCAM has already
(15) (a) Cook, S.; Henderson, D.; Richardson, K. A.; Taylor, R. J .
K.; Saunders, J .; Strange, P. G. J . Chem. Soc., Perkin Trans. 1 1987,
1825. (b) Brown, C. D.; Chong, J . M.; Shen, L. Tetrahedron 1999, 55,
14233. (c) Marshall, J . A.; van Devender, E. A. J . Org. Chem. 2001,
66, 8037 and literature cited therein. (d) For a recent review see: Hou,
X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.;
Wong, H. N. C. Tetrahedron 1998, 54, 1955.
(16) (a) Fu¨rstner, A.; Seidel, G. Angew. Chem., Int. Ed. Engl. 1998,
37, 1734. (b) Fu¨rstner, A.; Mathes, C.; Lehmann, C. W. J . Am. Chem.
Soc. 1999, 121, 9453. (c) Fu¨rstner, A.; Guth, O.; Rumbo, A.; Seidel, G.
J . Am. Chem. Soc. 1999, 121, 11108. (d) Fu¨rstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3012.
(17) (a) Fu¨rstner, A.; Mathes, C.; Lehmann, C. W. Chem. Eur. J .
2001, 7, 5299. (b) Fu¨rstner, A.; Mathes, C.; Grela, K. Chem. Commun.
2001, 1057.
(18) (a) Fu¨rstner, A.; Grela, K.; Mathes, C.; Lehmann, C. W. J . Am.
Chem. Soc. 2000, 122, 11799. (b) Fu¨rstner, A.; Grela, K. Angew. Chem.,
Int. Ed. 2000, 39, 1234.
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Lai, S.; Shizuri, Y.; Yamamura, S.; Kawai, K.; Terada, Y.; Furukawa,
H. Chem. Lett. 1990, 589. (c) Lai, S.; Shizuri, Y.; Yamamura, S.; Kawai,
K.; Furukawa, H. Bull. Chem. Soc. J pn. 1991, 64, 1048.
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Furukawa, H. Tetrahedron Lett. 1989, 30, 2241. (b) Lai, S.; Shizuri,
Y.; Yamamura, S.; Kawai, K.; Niwa, M.; Furukawa, H. Heterocycles
1991, 32, 307.
(19) Fu¨rstner, A.; Radkowski, K.; Grabowski, J .; Wirtz, C.; Mynott,
R. J . Org. Chem. 2000, 65, 8758.
(20) Fu¨rstner, A.; Dierkes, T. Org. Lett. 2000, 2, 2463.
(21) (a) Fu¨rstner, A.; Rumbo, A. J . Org. Chem. 2000, 65, 2608. (b)
Fu¨rstner, A.; Seidel, G. J . Organomet. Chem. 2000, 606, 75.
(22) Aguilera, B.; Wolf, L. B.; Nieczypor, P.; Rutjes, F. P. J . T.;
Overkleeft, H. S.; van Hest, J . C. M.; Schoemaker, H. E.; Wang, B.;
Mol, J . C.; Fu¨rstner, A.; Overhand, M.; van der Marel, G. A.; van Boom,
J . H. J . Org. Chem. 2001, 66, 3584.
(23) Fu¨rstner, A.; Radkowski, K. Chem. Commun. 2002, 2182.
(24) Basak, A.; Nayak, M. K.; Chakraborti, A. K. Tetrahedron Lett.
1998, 39, 4883.
(25) (a) Bunce, R. A.; J ohnson, L. B. Org. Prep. Proc. Int. 1999, 31,
407. (b) Carpenter, T. A.; Evans, G. E.; Leeper, F. J .; Staunton, J .;
Wilkinson, M. R. J . Chem. Soc., Perkin Trans. 1 1984, 1043. (c)
Deshpande, V. H.; Rai, B.; Khan, R. A. Tetrahedron 1996, 52, 7159.
(d) Braun, M.; Mahler, U.; Houben, S. Liebigs Ann. Chem. 1990, 513.
(e) Myers, A. G.; Horiguchi, Y. Tetrahedron Lett. 1997, 38, 4363. (f)
Xu, X.-Y.; Qin, G.-W.; Xu, R.-S.; Zhu, X.-Z. Tetrahedron 1998, 54, 14179.
(10) Lai, S.; Gao, X.; Shizuri, Y.; Yamamura, S. Chin. Chem. Lett.
1994, 5, 481-484.
(11) (a) Fu¨rstner, A.; Weintritt, H. J . Am. Chem. Soc. 1998, 120,
2817. (b) Fu¨rstner, A.; Gastner, T.; Rust, J . Synlett 1999, 29. (c)
Fu¨rstner, A.; Gastner, T. Org. Lett. 2000, 2, 2467.
(12) (a) Fu¨rstner, A.; Seidel, G. J . Org. Chem. 1997, 62, 2332. (b)
Fu¨rstner, A.; Stelzer, F.; Rumbo, A.; Krause, H. Chem. Eur. J . 2002,
8, 1856.
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(b) Fu¨rstner, A.; Seidel, G.; Kindler, N. Tetrahedron 1999, 55, 8215.
(c) Fu¨rstner, A.; Thiel, O. R.; Kindler, N.; Bartkowska, B. J . Org. Chem.
2000, 65, 7990.
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3731. (b) Fu¨rstner, A.; Dierkes, T.; Thiel, O. R.; Blanda, G. Chem. Eur.
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3072.
1522 J . Org. Chem., Vol. 68, No. 4, 2003

Total Synthesis of (S)-(+)-Citreofuran
SCHEME 2
SCHEME 3
THF results in selective saponification of the â-trimeth-
ylsilylethyl ester6b and sets the stage for the introduction
of the second alkyne group.
Although many procedures are known for the conver-
sion of carboxylic acid derivatives to the corresponding
ketones,27 this step initially turned out to be delicate.
Attempted acyl-Negishi coupling reactions28 of the puta-
tive acid chloride derived from 14 and the chloroenamine
reagent 1529 with 3-pentynylzinc iodide invariably led to
rather complex mixtures. Quenching of the transient acid
chloride with MeOH also leads to erratic results, giving
rise to a mixture of compound 16 and the unexpected
dimethylester 17 in somewhat variable yields and ratios
(Scheme 3). This outcome might be explained by a
neighboring group participation of the residual ester in
14, thus leading to an equilibrium between the desired
acid chloride 18 and the cyclic chloroacetal derivative 19
(or the corresponding oxocarbenium cation derived
thereof)30 (Scheme 4) which compete with one another
for the added nucleophile. This interpretation is cor-
roborated by the fact that treatment of the reaction
mixture with NEt3 leads to the clean and virtually
quantitative formation of alkoxyisocoumarin 20 as judged
by NMR, although the isolated product rapidly degrades
upon storage.
It was anticipated that this isocoumarin behaves as
an activated ester able to replace the capricious acid
chloride in the envisaged ketone formation step. Because
of its instability, however, it seemed necessary to avoid
isolation of this intermediate but to react the crude
product with an appropriate nucleophile.31 Although
initial attempts to attack the isocoumarin ring of 20 with
3-pentynylmagnesium bromide32 were unsuccessful, a
smooth conversion to the desired diyne 21 takes place if
survive under the reaction conditions (Scheme 2). On the
basis of this analysis, we did not pursue the envisaged
C-acylation route any further despite the seemingly
encouraging literature precedence.25a,b,26
(27) Review: Dieter, R. K. Tetrahedron 1999, 55, 4177.
(28) (a) Negishi, E.; Bagheri, V.; Chatterjee, S.; Luo, F.-T.; Miller,
J . A.; Stoll, A. T. Tetrahedron Lett. 1983, 24, 5181. (b) Negishi, E.;
Liu, F. In Metal-catalyzed Cross-coupling Reactions; Diederich, F.,
Stang, P. J ., Eds.; Wiley-VCH: Weinheim, Germany, 1998; p 1. (c)
Tamaru, Y.; Ochiai, H.; Sanda, F.; Yoshida, Z. Tetrahedron Lett. 1985,
26, 5529.
(29) (a) Devos, A.; Remion, J .; Frisque-Hesbain, A.-M.; Colens, A.;
Ghosez, L. J . Chem. Soc., Chem. Commun. 1979, 1180. (b) Haveaux,
B.; Dekoker, A.; Rens, M.; Sidani, A. R.; Toye, J .; Ghosez, L. Org. Synth.
1980, 59, 26.
(30) The available information at this point does not allow us to draw
an unambiguous conclusion as to the actual constitution of this
intermediate.
(31) For the opening of isocoumarins with stabilized C-nucleophiles
see: Watanabe, M.; Date, M.; Furukawa, S. Chem. Pharm. Bull. 1989,
37, 292.
A much more convenient preparation of the desired
alkyne metathesis precursor commences with a Mit-
sunobu-type esterification of acid 6 and 2-trimethylsilyl
ethanol to give compound 10, which can be deprotonated
at the benzylic site with LDA at low temperature;
quenching of the reaction mixture with CO2 furnishes
acid 11 in 85% yield after acidic workup. Subsequent
esterification with the enantiomerically pure alcohol 12,
derived from a ring-opening reaction of (S)-propene oxide
with propynyllithium in THF/DMPU, gives compound 13
in high yield (Scheme 2). Its treatment with TBAF in
(26) It has previously been reported that the C-silylation (stanny-
lation) of orsellinic acid esters can also lead to substantial amounts of
disilylated (stannylated) products, cf. ref 25b.
(32) It is important to keep the temperature below 40 °C during
the formation of this Grignard reagent to minimize undesirable side
reactions.
J . Org. Chem, Vol. 68, No. 4, 2003 1523

Fu¨rstner et al.
SCHEME 4
SCHEME 5
the reaction is carried out at low temperature in the
presence of TMSCl as a mild activating agent.33 Under
these conditions, product 21 is obtained by a three-step/
one-pot operation in 75% yield starting from acid 14
(Scheme 5).
Gratifyingly, the RCAM reaction proceeds in excellent
yield on exposure of diyne 21 to Schrock’s tungsten
alkylidyne complex (tBuO)3WtCCMe334 in toluene at 85
°C. It was noticed, however, that the substrate must be
devoid of any trace impurities to avoid catalyst poison-
ing.35 The fact that the yield is highly dependent on the
chosen dilution is deemed to reflect the strain in the
benzo-annellated oxacyclododecyne ring of compound 22,
with best results being obtained at c ) 0.0085 M (78-
81% isolated yield).
The subsequent formation of the furan ring from the
γ-alkynyl ketone substructure in 22 essentially follows
literature procedures describing similar transforma-
tions.15 Thereby, the use of p-toluenesulfonic acid (1
equiv) in toluene at 85 °C turned out to be optimal in
terms of yield and reaction rates. In contrast to the ease
of this cyclization reaction, however, the final deprotec-
tion of compound 23 thus formed was far from trivial.
Specifically, the use of BBr3 entailed considerable de-
composition, although it was possible to identify the
desired citreofuran in the NMR spectrum of the crude
mixture. Therefore, we reasoned that 9-iodo-9-BBN, a
more moderate congener that has previously proven
highly successful in the deprotection of different resor-
cinol derivatives,12a might lead to a more favorable
outcome. This is indeed the case. Thus, treatment of 23
with 9-iodo-9-BBN in CH2Cl2 at -10 °C effects the
consecutive cleavage of the two methyl ether groups, with
side reactions coming into play only on prolonged stir-
ring.36 Although the crude mixture is quite clean, it
turned out to be very difficult to remove traces of different
boron impurities due to their very similar retention
times. Therefore, analytically pure samples of citreofuran
4 had to be prepared by preparative HPLC (27%). Its
physical and spectroscopic properties are in excellent
agreement with those reported in the literature.9
(33) This experiment shows that the TMSCl-promoted addition of
RMgX to the activated ester is faster than the interception of the
Grignard reagent as R-SiMe3. While the use of TMSCl as activating
agent in 1,2-additions of RMgX to carbonyl compounds seems to be
largely unexplored, its accelerating effect on 1,4-additions under
“Kharasch conditions” (RMgX + Cu(I) cat.) or with preformed orga-
nocuprates as the reagents is well precedented. See the following for
leading references and literature cited therein: (a) Corey, E. J .; Boaz,
N. W. Tetrahedron Lett. 1985, 26, 6015-6018. (b) Nakamura, E.;
Matsuzawa, S.; Horiguchi, Y.; Kuwajima, I. Tetrahedron Lett. 1986,
27, 4029-4032. (c) Linderman, R. J .; Godfrey, A. Tetrahedron Lett.
1986, 27, 4553-4556. (d) Alexakis, A.; Berlan, J .; Besace, Y. Tetrahe-
dron Lett. 1986, 27, 1047-1050. (e) Lipshutz, B. H.; Aue, D. H.; J ames,
B. Tetrahedron Lett. 1996, 37, 8471-8474. (f) Reetz, M. T.; Kindler,
A. J . Organomet. Chem. 1995, 502, C5-C7. (g) Yamazaki, T.; Umetani,
H.; Kitazume, T. Tetrahedron Lett. 1997, 38, 6705-6708. (h) Bertz, S.
H.; Miao, G.; Rossiter, B. E.; Snyder, J . P. J . Am. Chem. Soc. 1995,
117, 11023-11024.
(34) (a) Schrock, R. R.; Clark, D. N.; Sancho, J .; Wengrovius, J . H.;
Rocklage, S. M.; Pedersen, S. F. Organometallics 1982, 1, 1645. (b)
Freudenberger, J . H.; Schrock, R. R.; Churchill, M. R.; Rheingold, A.
L.; Ziller, J . W. Organometallics 1984, 3, 1563. (c) Listemann, M. L.;
Schrock, R. R. Organometallics 1985, 4, 74. (d) Schrock, R. R.
Polyhedron 1995, 14, 3177.
(35) The catalyst is known to be poisoned by amines or thioethers,
cf. ref 16c. Therefore it is particularly important that the substrate is
devoid of any trace of Et3N used in the previous step.
Str u ctu r a l Asp ects. As mentioned in the Introduc-
tion, the ability of curvularin derivatives to bind to
tubulin and hence to disrupt the assembly of the micro-
tubules during mitosis has been ascribed to the confor-
mational peculiarities of their macrocyclic ring. There-
fore, it seemed appropriate to study the structure of
citreofuran in more detail and to compare it with the
structure of the other members of this family.
Single crystals of 4 suitable for X-ray analysis have
been grown from CH2Cl2. As can be seen from the
structure depicted in Figure 1, the macrocycle of 4 adopts
(36) Due to the formation of unidentified byproducts toward the end
of the reaction, the mixture was quenched before the deprotection was
complete. This affords a mixture of the monoprotected and the fully
deprotected compounds in an ca. 1:6.4 ratio.
1524 J . Org. Chem., Vol. 68, No. 4, 2003

Total Synthesis of (S)-(+)-Citreofuran
F IGURE 1. Molecular structure of citreofuran 4 obtained
from single-crystal structure determination. Anisotropic dis-
placement parameters are shown at the 50% probability
level. Dashed bonds indicate hydrogen bonds to atoms of
neighboring molecules. O5i‚‚‚H7 ) O5‚‚‚H7ii 1.963(1) Å, O1iii‚
1
‚‚H5 ) O1‚‚‚H5iv 1.877(1) Å (iv ) 1 - x, y - /2, 1 - z).
a double-chair conformation. The benzo ring is found in
the equatorial position while the furan is rotated in such
a manner as to point the ring oxygen toward the inner
perimeter of the macrocycle directly opposite the carbonyl
oxygen, which is axially oriented. The distance between
the furan ring oxygen atom and the carbonyl carbon atom
is only 2.551(2) Å (which is at least 0.7 Å shorter than
the sum of the VDW radii). The dihedral angle between
the benzo ring and the furan is 41.28(6)°. The hydrogen
bonding of 4 consists of a cooperative hydrogen bond
network based on molecules related to each other via the
21-screw axis. A chain running parallel to the b-axis at
[0, y, 1/2] is formed by the hydroxyl groups O5i‚‚‚H7-C7-
F IGURE 2. Top: Superposition of the X-ray structures of 4
(green) and 1 (blue)5b shown in an orthographic projection.
Bottom: Superposition of the X-ray structures of 4 (green) and
2 (blue)5a based on atoms C13 to O16 plus C1 and the methyl
carbon atom. All hydrogen atoms have been omitted for clarity.
1
C6-C5-O5‚‚‚H7ii (i ) -x, y - /2, 1 - z; ii ) -x, y +1/2,
1 - z) and is supplemented by an additional hydrogen
1
bond between O1iii and H5 (iii ) 1 - x, y + /2, 1 - z).
specific mode of action.12b,38,39 Therefore, we expected
citreofuran to exert similar functions due to its resorcinol
substructure.
As is evident from Figure 2, the ring conformations of
citreofuran 4 and curvularin 1 are remarkably similar.
The rms based on all ring atoms excluding C9 to C13 is
0.21 Å. In contrast, dehydrocurvularin 2 adopts a com-
pletely different conformation of the macrocycle,5 which
is characterized by the anticlinal arrangement of C12 and
C15 and the boatlike conformation of that half of the
macrocycle annellated to the benzo ring (Figure 2,
bottom).
Assessm en t of th e DNA-Clea vin g P r op er ties. It is
well-established in the literature that phenols are regio-
selectively oxygenated by O2 in the presence of copper-
amine complexes as catalysts. The resulting catechols are
further oxidized to o-quinones and derivatives thereof by
a mechanism that leads to the concomitant formation of
H2O2.37 Its subsequent cleavage by the metal cation then
produces diffusible oxygen radicals which entail massive
DNA damage. The catalytic action of copper in this
overall process is remarkably specific, as this metal cation
can hardly be replaced by other ones known to effect the
catalytic decomposition of H2O2.
In fact, 4 readily relaxes the supercoiled plasmid DNA
of the bacteriophage ΦX174 (form I) to the nicked form
II and even to the linear form III in the presence of Cu-
(OAc)2 and n-BuNH2 (Figure 3). Surprisingly, however,
this ability to cause single- and even double-strand
cleavage is not directly linked to the presence of the free
-OH groups in the resorcinol ring as evident by com-
parison with lane 5 of the agarose gel, which shows that
the di-O-methyl derivative 23 leads to similar effects.
This observation is in striking contrast to the behavior
of other resorcinol derivatives which are completely inert
as long as their hydroxyl groups are protected as the
corresponding methyl ethers.12b,38 Therefore, a second
mode of action must be operative, at least in part, which
is likely related to the presence of the furan moiety. It
has previously been shown that certain heteroaromatic
systems engender DNA cleavage in the presence of Cu-
(II) by a mechanism that is triggered by oxidation to the
corresponding radical cations.40,41 Because the rather
electron-rich biaryl system in 23 is susceptible to such
oxidation, it is thought to be responsible for the DNA-
It has previously been shown that many natural
products bearing hydroxylated aromatic or heteroaro-
matic rings, though rather diverse in structure, are able
to effect DNA cleavage under oxidative conditions by this
(38) Fu¨rstner, A.; Krause, H.; Thiel, O. R. Tetrahedron 2002, 58,
6373.
(39) (a) Lytollis, W.; Scannell, R. T.; An, H.; Murty, V. S.; Reddy, K.
S.; Barr, J . R.; Hecht, S. M. J . Am. Chem. Soc. 1995, 117, 12683. (b)
Singh, U. S.; Scannell, R. T.; An, H.; Carter, B. J .; Hecht, S. M. J . Am.
Chem. Soc. 1995, 117, 12691.
(37) (a) Brackman, W.; Havinga, E. Recl. Trav. Chim. Pays-Bas
1955, 74, 937-956. (b) Brackman, W.; Havinga, E. Recl. Trav. Chim.
Pays-Bas 1955, 74, 1100-1106. (c) Brackman, W.; Havinga, E. Recl.
Trav. Chim. Pays-Bas 1955, 74, 1107-1118.
(40) Fu¨rstner, A.; Grabowski, E. J . ChemBioChem 2001, 2, 706.
J . Org. Chem, Vol. 68, No. 4, 2003 1525

Fu¨rstner et al.
quenched with water, the aqueous phase was extracted with
EtOAc, and the combined organic layers were successively
washed with aq ammonia solution (10% w/w) and brine, dried
(Na2SO4), and evaporated. Flash chromatography of the crude
product (hexane/EtOAc, 4:1) afforded 2,4-dimethoxy-6-meth-
ylbenzoic acid methyl ester as a colorless solid (5.058 g, 86%)
that shows the following spectroscopic properties: 1H NMR
(400 MHz, CDCl3): δ 2.28 (s, 3H), 3.785 (s, 3H), 3.79 (s, 3H),
3.87 (s, 3H), 6.31 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 20.0,
52.1, 55.5, 56.0, 96.4, 106.9, 116.6, 138.4, 158.4, 161.5, 168.8.
A solution of this compound (0.667 g, 3.17 mmol) in aq NaOH
(4 M, 12 mL) and MeOH (15 mL) was heated for 24 h at 60
°C. After cooling to ambient temperature, the mixture was
acidified with aq HCl (2 M) until a pH of ca. 2 was reached. A
standard extractive workup afforded acid 6, which was used
in the next step without further purification (0.601 g, 97%).
Its analytical and spectroscopic data are in agreement with
those previously reported.43 1H NMR (300 MHz, acetone-d6):
δ 2.3 (s, 3H), 3.81 (s, 3H), 3.82 (s, 3H), 6.42 (d, 1H, J ) 2.2
Hz), 6.46 (d, 1H, J ) 2.2 Hz). 13C NMR (75 MHz, acetone-d6):
δ 20.2, 55.7, 56.3, 96.9, 108.0, 117.8, 139.0, 159.2, 162.4, 168.7.
F IGURE 3. Result of an agarose gel electrophoresis showing
the extent of DNA cleavage produced by compounds 4 and 23
(200 µM) in the presence of Cu(OAc)2 and n-BuNH2 after an
incubation time of 1.5 h at 37 °C. Lane 1: DNA marker (500
base pairs molecular weight difference). Lane 2: DNA alone.
Lane 3: DNA enriched in linear form III (partial cleavage of
parent DNA by restriction endonuclease Xho I). Lane 4: DNA
+ compound 4 + CuII + n-BuNH2. Lane 5: DNA + compound
23 + CuII + n-BuNH2.
2,4-Dim eth oxy-6-m eth ylben zoic Acid 2-Tr im eth ylsila -
n yleth yl Ester (10). To a solution of carboxylic acid 6 (0.798
g, 4.07 mmol), PPh3 (2.736 g, 10.43 mmol), and trimethylsi-
lylethanol (0.9 mL, 6.28 mmol) in THF (22 mL) at 0 °C was
added diisopropylazodicarboxylate (DIAD, 1.85 mL, 9.41 mmol)
and the resulting mixture was stirred for 3 h at 0 °C and then
for 40 min at ambient temperature. The solution was parti-
tioned between Et2O and sat aq NaHCO3, the aqueous phase
was extracted with Et2O, and the combined organic extracts
were dried over Na2SO4, filtered, and concentrated. Purifica-
tion of the crude product by flash chromatography afforded
ester 15 (1.027 g, 85% yield) as a colorless solid. Mp 37-39
cleaving properties of this molecule. A more detailed
investigation of this and related aspects together with
other biological evaluations of citreofuran are subject to
further studies in this laboratory.
Exp er im en ta l Section
Gen er a l. All reactions were carried out under Ar. The
solvents were purified by distillation over the drying agents
indicated and were transferred under Ar: THF, Et2O, DME
(Mg-anthracene), CH2Cl2 (P4O10), MeCN, Et3N, pyridine, DMF
(CaH2), MeOH (Mg), hexane, toluene (Na/K). Flash chroma-
tography: Merck silica gel 60 (230-400 mesh). NMR: chemi-
cal shifts (δ) are given in ppm relative to TMS, coupling
constants (J ) in Hz. Melting points are uncorrected. All
commercially available compounds were used as received.
Meth yl 2,4-Dih yd r oxy-6-m eth ylben zoa te (5). Methyl
acetoacetate (22.4 mL, 207 mmol) was slowly added to a stirred
suspension of NaH (6.50 g, 271 mmol) in THF (100 mL) at 0
°C. After the evolution of gas had ceased, the reaction mixture
was cooled to -78 °C and n-BuLi (1.6 M in hexane, 108 mL,
173 mmol) was added dropwise. The mixture was allowed to
warm to ambient temperature overnight and was then refluxed
for 24 h. The resulting dark red suspension was treated at 0
°C with aq HCl (2 M) until a pH of ca. 2 was reached and
stirring was continued at ambient temperature for 2 h. A
standard extractive workup with EtOAc followed by flash
chromatography of the crude product (hexane/EtOAc, 10/1 f
4/1) provided ester 5 as a colorless solid (12.73 g, 67%). Mp
1
°C. H NMR (400 MHz, CDCl3): δ 0.06 (s, 9H), 1.08-1.13 (m,
2H), 2.29 (s, 3H), 3.78 (s, 3H), 3.79 (s, 3H), 4.36-4.40 (m, 2H),
6.30 (s, 2H). 13C NMR (100 MHz, CDCl3): δ -1.4, 17.5, 20.0,
55.4, 55.9, 63.3, 96.3, 106.7, 117.1, 138.0, 158.2, 161.3, 168.6.
MS, m/z (rel intensity): 296 ([M+], 21), 253 (25), 196 (11), 179
(100), 178 (24), 152 (4), 136 (5), 121 (3), 93 (2), 73 (19). IR
(KBr): 3026, 3024, 2956, 2896, 2839, 1717, 1606, 1585, 1467,
1458, 1267, 839 cm-1
.
2-Ca r b oxym et h yl-4,6-d im et h oxyb en zoic Acid 2-t r i-
m eth ylsila n yleth yl Ester (11). n-BuLi (1.6 M in hexane, 8.2
mL, 13.12 mmol) was added to a solution of diisopropylamine
(2 mL, 14.27 mmol) in THF (20 mL) at 0 °C. After 15 min, the
resulting solution of LDA was cooled to -78 °C and a solution
of compound 10 (2.014 g, 6.90 mmol) in THF (30 mL) was
added dropwise. The reaction mixture was stirred for 25 min
at that temperature prior to the addition of dry ice, which leads
to an immediate disappearance of the deep red color. The
reaction mixture was stirred at -78 °C for 15 min before it
was hydrolyzed with aq HCl (2 M). After reaching ambient
temperature, it was acidified until a pH of 2 was reached and
extracted with EtOAc. The organic extract was washed with
brine, dried over Na2SO4, filtrated, and evaporated. Flash
chromatography of the residue (hexane/EtOAc/CH3COOH, 1:1:
0.01) afforded acid 11 (1.985 g, 85%) as a colorless solid. Mp
1
134-136 °C (lit.42 136-138 °C). H NMR (400 MHz, acetone-
d6): δ 2.45 (s, 3H), 3.91 (s, 3H), 6.22-6.29 (m, 2H), 9.03 (br s,
OH), 11.6 (br s, OH). 13C NMR (100 MHz, acetone-d6): δ 24.4,
52.3, 101.8, 112.4, 114.5, 163.4, 166.5, 173.2. MS: m/z (rel
intensity): 182 ([M+], 45), 151 (24), 150 (100), 122 (39), 94 (11).
IR (film): 3369, 3312, 3044, 2984, 2958, 1640, 1582, 1503,
1446, 1391, 1380, 1313, 1267, 1201, 1160, 1112, 1062, 1033,
1
62-63 °C. H NMR (300 MHz, acetone-d6): 0.08 (s, 9H), 1.10
(t, 2H, J ) 8.5 Hz), 3.66 (s, 2H), 3.81 (s, 3H), 3.83 (s, 3H), 4.32
(t, 2H, J ) 8.5 Hz), 6.54 (s, 2H). 13C NMR (75 MHz, acetone-
d6): δ -1.4, 17.8, 39.4, 55.8, 56.3, 63.4, 98.1, 108.8, 117.9,
136.1, 159.6, 162.4, 168.0, 171.8. MS, m/z (rel intensity): 340
([M+], 47), 297 (44), 269 (31), 253 (37), 223 (77), 205 (38), 194
(64), 178 (84), 149 (14), 73 (100). IR (KBr): 3087, 3001, 2951,
2897, 2843, 1718, 1707, 1606, 1491, 1425, 1241, 1165, 835
cm-1. HRMS (C16H24O6Si): calcd 340.1342, found 340.1343.
995, 953, 854, 838, 800, 753, 703, 642, 624, 576, 524 cm-1
.
2,4-Dim eth oxy-6-m eth ylben zoic Acid (6). A solution of
ester 5 (5.086 g, 27.95 mmol) in THF (60 mL) was treated with
LiOH‚H2O (3.696 g, 88.1 mmol) at ambient temperature for
10 min. Dimethyl sulfate (7.8 mL, 82.5 mmol) was added and
the mixture was stirred for 3 h at 50 °C. The reaction was
(S)-Hex-4-yn -2-ol (12). DMPU (15 mL) was added to a
suspension of propynyllithium (1.614 g, 39.4 mmol) in THF
(10 mL). After the mixture was stirred for 30 min at -20 °C,
(41) (a) Borah, S.; Melvin, M. S.; Lindquist, N.; Manderville, R. A.
J . Am. Chem. Soc. 1998, 120, 4557. (b) Melvin, M. S.; Tomlinson, J .
T.; Saluta, G. R.; Kucera, G. L.; Lindquist, N.; Manderville, R. A. J .
Am. Chem. Soc. 2000, 122, 6333.
(42) Barrett, A. G. M.; Morris, T. M.; Barton, D. H. R. J . Chem. Soc.,
Perkin Trans. 1 1980, 2272.
(43) Solladie´, G.; Rubio, A.; Carren˜o, M. C.; Garc´ıa Ruano, J . L.
Tetrahedron: Asymmetry 1990, 1, 187.
1526 J . Org. Chem., Vol. 68, No. 4, 2003

Total Synthesis of (S)-(+)-Citreofuran
a solution of (S)-methyloxirane in DMPU (5 mL) was slowly
added and the resulting mixture was stirred overnight at -20
°C before it was allowed to reach ambient temperature. After
being stirred for another 6 h, the reaction mixture was
quenched with sat aq NH4Cl, the aqueous layer was extracted
with Et2O, and the combined organic phases were dried over
Na2SO4, filtrated, and evaporated. Purification of the residue
by filtration through a pad of silica (pentane/Et2O, 4:1) afforded
alcohol 12 as a colorless syrup (0.726 g, 52%). Its spectral and
analytical data are in agreement with those reported in the
through a short pad of silica (hexane/EtOAc, 1:1) to give
isocoumarin 20, which was immediately used in the next step.
Characteristic data for compound 20: 1H NMR (300 MHz,
CDCl3): δ 1.43 (d, 3H, J ) 6.3 Hz), 1.77 (t, 3H, J ) 2.6 Hz),
2.39-2.616 (m, 2H), 3.86 (s, 3H), 3.93 (s, 3H), 4.68-4.75 (m,
1H), 5.50 (s, 1H), 6.25 (d, 1H, J ) 2.1 Hz), 6.27 (d, 1H, J ) 2.1
Hz). 13C NMR (75 MHz, CDCl3): δ 3.6, 13.3, 26.2, 55.7, 56.3,
74.1, 74.6, 78.5, 82.8, 96.5, 99.0, 100.7, 145.2, 157.7, 158.0,
163.7, 165.7. To a solution of isocoumarin 20 prepared as
described above in THF (5 mL) was successively added a
solution of pent-3-ynylmagnesium bromide (0.7 mL, 0.54 M
in THF)32,45 and TMSCl (33 µL, 0.26 mmol), and the resulting
mixture was stirred for 30 min at -78 °C before it was allowed
to warm to ambient temperature. After being stirred for 3 h,
the reaction mixture was hydrolyzed at 0 °C with sat aq NH4-
Cl. A standard extractive workup followed by flash chroma-
tography (hexane/EtOAc, 4:1) provided ketone 21 as a colorless
solid (72.5 mg, 75%). Mp 67-68 °C. [R]2D0 -18.4 ° (c 1.005,
CHCl3). 1H NMR (300 MHz, CDCl3): δ 1.29 (d, 3H, J ) 4.8
Hz), 1.76 (t, 3H, J ) 2.3 Hz), 2.34-2.50 (m, 4H), 3.03-3.09
(m, 2H), 3.63 (s, 2H), 3.81 (s, 3H), 3.82 (s, 3H), 4.90-4.97 (m,
1H), 6.37 (d, 1H, J ) 2.2 Hz), 6.39 (d, 1H, J ) 2.2 Hz). 13C
NMR (75 MHz, CDCl3): δ 3.6, 3.65, 14.0, 19.2, 26.0, 39.2, 43.9,
55.6, 55.8, 70.0, 74.6, 75.7, 77.9, 78.6, 97.6, 108.1, 123.7, 135.0,
159.1, 161.7, 170.8, 204.7. MS, m/z (rel intensity): 370 ([M+],
5), 290 (32), 273 (33), 231 (11), 223 (100), 203 (10), 197 (6),
195 (42), 81 (16), 79 (13), 53 (12). IR (KBr): 3098, 2980, 2919,
literature.44 [R]D20 +19.2° (c 1.19, CHCl3). H NMR (300 MHz,
1
CDCl3): δ 1.18 (d, 3H, J ) 6.2 Hz), 1.75 (t, 3H, J ) 2.6 Hz),
2.04 (s, 1H), 2.15-2.34 (m, 2H, CH2), 3.81-3.88 (m, 1H). 13C
NMR (75 MHz, CDCl3): δ 3.6, 22.3, 29.5, 66.7, 75.5, 78.5. MS,
m/z (rel intensity): 98 (0.16), 83 (15), 79 (7), 54 (100), 51 (11),
45 (62), 43 (25), 39 (36), 27 (22). IR (KBr): 3362, 2972, 2921,
2217, 1713, 1375, 1116, 1085 cm-1
.
2,4-Dim et h oxy-6-(1-m et h ylp en t -3-yn yloxyca r b on yl-
m eth yl)ben zoic Acid 2-Tr im eth ylsila n yleth yl Ester (13).
To a stirred solution of acid 11 (1.033 g, 3.13 mmol), alcohol
12 (0.409 g, 4.17 mmol), and DMAP (0.318 g, 2.6 mmol) in
CH2Cl2 (30 mL) was added DCC (0.715 g, 3.5 mmol) and the
resulting mixture was stirred overnight. The white precipitate
was filtered off through a short pad of silica and the filtrate
was partitioned between H2O and EtOAc. The combined
organic phases were dried over Na2SO4, filtrated, and evapo-
rated, and the residue was purified by flash chromatography
(hexane/EtOAc, 4:1) to furnish ester 13 as a colorless oil (1.238
g, 94%). [R]2D0 -13.6° (c 1.145, CHCl3). 1H NMR (300 MHz,
CDCl3): δ 0.06 (s, 9H), 1.07-1.14 (m, 2H), 1.30 (d, 3H, J )
6.3 Hz), 1.76 (t, 3H, J ) 2.6 Hz), 2.30-2.44 (m, 2H), 3.65 (s,
2H), 3.80 (s, 3H), 3.81 (s, 3H), 4.32-4.39 (m, 2H), 4.88-5.01
(m, 1H), 6.39 (d, 1H, J ) 2.25 Hz), 6.41 (d, 1H, J ) 2.25 Hz).
13C NMR (100 MHz, CDCl3): δ -1.4, 3.6, 17.5, 19.2, 25.9, 39.7,
55.5, 56.1, 63.4, 70.0, 74.5, 77.9, 98.0, 107.3, 116.9, 134.9, 158.9,
161.6, 167.6, 170.3. MS, m/z (rel intensity): 420 ([M+], 58),
303 (20), 295 (57), 267 (22), 223 (100), 205 (59), 194 (48), 178
(35), 81 (27), 73 (95), 53 (14). IR (KBr): 2953, 2901, 2841,
1734, 1606, 1588, 1458, 1426, 1272, 1162, 839 cm-1. HRMS
(C22H32O6Si): calcd 420.1968, found 420.1966.
2843, 1728, 1660, 1602, 1577, 1457, 1426, 1167 cm-1
.
Cycloa lk yn e 22. To a solution of ketone 21 (93.5 mg, 0.253
mmol) in toluene (20 mL) was added a solution of (tBuO)3Wt
CCMe3 (11.9 mg, 0.025 mmol)34 in toluene (10 mL) and the
mixture was stirred at 85 °C for 1 h. For workup, the solvent
was evaporated and the residue was purified by flash chro-
matography (hexane/EtOAc, 3:1) to give product 22 as a
colorless solid (62.7 mg, 78%). Mp 163-166 °C. [R]2D0 +83.5° (c
1
1.02, CHCl3). H NMR (400 MHz, CDCl3): δ 1.21 (d, 3H, J )
6.35 Hz), 2.10-2.36 (m, 3H), 2.70-2.78 (m, 1H), 3.05-3.27 (m,
2H), 3.29 (d, 1H, J ) 17.6 Hz), 3.78 (s, 3H), 3.81 (s, 3H), 4.30
(d, 1H, J ) 17.6 Hz), 5.33 (m, 1H), 6.33 (d, 2H, J ) 2.1 Hz),
6.40 (d, 2H, J ) 2.1 Hz). 13C NMR (100 MHz, CDCl3): δ 13.3,
20.2, 27.6, 38.8, 42.3, 55.5, 55.7, 68.9, 76.4, 82.2, 97.4, 109.1,
124.6, 134.4, 158.2, 161.3, 171.4, 205.0. IR (KBr): 3015, 2962,
2929, 2840, 1738, 1693, 1603, 1586, 1458, 1425, 1409, 1167,
1157, 837 cm-1. MS, m/z (rel intensity): 316 ([M+], 71), 288
(25), 272 (37), 257 (51), 244 (24), 223 (63), 205 (23), 195 (100),
178 (30), 135 (16), 92 (13), 79 (84), 77 (44). HRMS (C18H20O5):
calcd 316.13107, found 316.13112.
2,4-Dim et h oxy-6-(1-m et h ylp en t -3-yn yloxyca r b on yl-
m eth yl)ben zoic Acid (14). To a solution of ester 13 (1.109
g, 2.64 mmol) in THF (40 mL) was added TBAF (1 M in THF,
4.6 mL, 4.6 mmol). The resulting mixture was stirred overnight
before it was hydrolyzed with saturated aqueous NH4Cl and
repeatedly extracted with EtOAc. The combined organic
phases were dried over Na2SO4, filtered, and evaporated, and
the residue was purified by flash chromatography (hexane/
EtOAc/HOAc, 1:1:0.01) to give acid 14 as a colorless solid
Di-O-m eth ylcitr eofu r a n (23). To a solution of compound
22 (63.5 mg, 0.201 mmol) in toluene (5 mL) was added
p-toluenesulfonic acid (47.1 mg, 0.248 mmol) and the reaction
mixture was stirred at 85 °C for 5.5 h. Quenching of the
reaction at 0 °C with aq sat NaHCO3 followed by a standard
extractive workup and flash chromatography of the crude
product (hexane/EtOAc, 4:1) afforded compound 23 as a
colorless solid (54.0 mg, 85%). Mp 138-140 °C. [R]2D0 +94.4° (c
0.465, CHCl3). 1H NMR (300 MHz, CDCl3): δ 1.26 (d, 3H, J )
6.5 Hz), 1.75-1.87 (m, 1H), 2.01-2.09 (m, 1H), 2.66-2.87 (m,
2H), 3.19-3.31 (m, 2H), 3.76 (s, 3H), 3.85 (s, 3H), 5.20-5.27
(m, 1H), 6.10 (d, 1H, J ) 3 Hz), 6.27 (d, 1H, J ) 3 Hz), 6.46 (d,
1H, J ) 2.25 Hz), 6.54 (d, 1H, J ) 2.25 Hz). 13C NMR (100
MHz, CDCl3): δ 21.2, 25.7, 36.1, 42.2, 55.6, 56.0, 72.4, 97.8,
106.8, 109.0, 110.3, 113.7, 138.9, 147.2, 155.0, 158.7, 161.0,
171.7. MS, m/z (rel intensity): 316 ([M+], 100), 229 (8), 202
(17), 187 (12), 115 (8). IR (KBr): 3007, 2980, 2909, 2840, 1739,
(0.806 g, 95%). Mp 84-85 °C. [R]2D0 -23.8° (c 1.02, CHCl3). H
1
NMR (400 MHz, acetone-d6): δ 1.26 (d, 3H, J ) 6.3 Hz), 1.73
(t, 3H, J ) 2.6 Hz), 2.26-2.46 (m, 2H), 3.76 (s, 2H), 3.85 (s,
3H), 3.89 (s, 3H), 4.85-4.90 (m, 1H), 6.54 (d, 1H, J ) 2.3 Hz),
6.60 (d, 1H, J ) 2.3 Hz). 13C NMR (75 MHz, acetone-d6): δ
3.3, 19.4, 26.3, 40.5, 56.0, 56.7, 70.3, 75.4, 78.3, 98.2, 109.8,
116.6, 137.6, 160.1, 162.8, 167.9, 170.7. MS, m/z (rel inten-
sity): 320 ([M+], 25), 240 (13), 223 (100), 195 (58), 178 (21),
79 (13), 53 (11). IR (KBr): 3100, 3068, 2983, 2940, 2920, 2852,
2056, 1727, 1676, 1604, 1574, 1462, 1433, 1277, 1172 cm-1
HRMS (C17H20O6): calcd 320.1260, found 320.1258.
.
2-Hex-4-yn oyl-3,5-d im eth oxyp h en yla cetic Acid 1-Me-
th ylp en t-3-yn yl Ester (21). To a solution of acid 14 (83.1 mg,
0.26 mmol) in THF (3 mL) was added chloroenamine 15 (43
µL, 0.32 mmol)29 and the resulting mixture was stirred for 2.5
h prior to the additon of Et3N (73 µL, 0.52 mmol). After being
stirred for another 10 min, the reaction mixture was quenched
with water, the aqueous layer was repeatedly extracted with
EtOAc, the combined organic phases were dried over Na2SO4,
filtered, and evaporated, and the residue was rapidly passed
1617, 1601, 1578, 1479, 1460, 1438, 1200, 1157, 788 cm-1
HRMS (C18H20O5): calcd 316.13107, found 316.13098.
.
Citr eofu r a n (4). A solution of 9-iodo-9-BBN (57.8 mg, 0.233
mmol) in CH2Cl2 (0.2 mL) was added to a solution of compound
(45) The concentration of the Grignard solution was determined as
described in: Bergbreiter, D. E.; Pendergrass, E. J . Org. Chem. 1981,
46, 219.
(44) Adam, W.; Saha-Mo¨ller, C. R.; Schmid, K. S. J . Org. Chem.
2001, 66, 7365.
J . Org. Chem, Vol. 68, No. 4, 2003 1527

Fu¨rstner et al.
23 (19.0 mg, 0.060 mmol) in CH2Cl2 (1.25 mL) at -10 °C and
the resulting mixture was stirred for 4 h at that temperature.
During this time, the course of the reaction was followed by
HPLC/MS, which indicated consecutive cleavage of the methyl
ether groups. After 4 h the formation of byproducts becomes
significant; therefore the reaction was quenched with sat aq
Na2S2O3 (4 mL) and aq sat NaHCO3 (1.5 mL), the aqueous
layer was repeatedly extracted with CH2Cl2, and the combined
organic layers were consecutively washed with aq sat NaHCO3
and brine, dried over Na2SO4, and evaporated to give crude
citreofuran (10.4 mg, 60%). An analytically pure sample was
obtained by preparative HPLC (Nucleosil-100-7-C18/A column,
125 mm, L 20 mm; MeOH:H2O 60:40; 6.8 MPa, 10.0 mL/min)
(4.5 mg, 27%). Pale brown solid, Mp 202-205 °C (lit.9 brownish
needles, mp 203-205 °C). [R]2D7 +104.9 (c 0.185, EtOH) [lit.9
107.6, 111.1, 112.0, 112.3, 139.8, 148.8, 156.2, 157.5, 159.7,
174.2. MS, m/z (rel intensity): 289 (18), 288 ([M+], 100), 273
(10), 205 (14), 174 (27). IR (KBr): 3419, 2976, 2932, 1707, 1627,
1590, 1560, 1459, 1322, 1261, 1243, 1160, 1123, 1051, 1026,
1011, 845, 784 cm-1
.
Ack n ow led gm en t. Generous financial support by
the Deutsche Forschungsgemeinschaft (Leibniz award
to A.F.) and the Fonds der Chemischen Industrie is
gratefully acknowledged. We thank Mrs. Helga Krause
for performing the gel electrophoresis experiment and
Mr. A. Deege and his crew for performing the HPLC
separation.
[R]2D7 +112 (c 0.18, EtOH)]. H NMR (600 MHz, MeOH-d4): δ
1
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of all
new compounds and crystal structure data for product 4
including atomic positions, bond length, and bond and dihedral
angles, as well as hydrogen bonds. This material is available
free of charge via the Internet at http://pubs.acs.org.
1.23 (d, 3H, J ) 6.5 Hz), 1.77 (m, 1H), 2.04 (m, 1H), 2.66 (ddd,
1H, J ) 2.9, 11.4, 14.7 Hz), 2.84 (ddd, 1H, J ) 2.8, 6.1, 15.3
Hz), 3.10 (d, 1H, J ) 14.3 Hz), 3.20 (d, 1H, J ) 14.6 Hz), 5.16
(m, 1H), 6.09 (d, 1H, J ) 3.0 Hz), 6.21 (d, 1H, J ) 3.0 Hz),
6.30 (d, 1H, J ) 2.3 Hz), 6.33 (d, 1H, J ) 2.3 Hz). 13C NMR
(150 MHz, MeOH-d4): δ 21.2, 26.6, 37.3, 42.6, 74.0, 102.6,
J O026686Q
1528 J . Org. Chem., Vol. 68, No. 4, 2003