C-H insertion approach to the synthesis of endo,exo-furofuranones: Synthesis of (±)-asarinin, (±)-epimagnolin A, and (±)-fargesin

Article abstract of DOI:10.1021/jo015829q

A series of novel 5-aryl-4-aryloxymethyl-3-diazotetrahydrofuran-2-ones (12, 24, and 35a/b) have been prepared and found to undergo regio- and stereoselective C-H insertion reactions to afford 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane-8-ones (18, 26, and 36a/b) with endo,exo stereochemistry. Subsequent reduction of the lactone ring and cyclization of the resulting diols 27 and 37a/b permitted the synthesis of three endo, exo-furofuran lignans: asarinin (2), fargesin (3), and epimagnolin A (4). En route to the key diazo compounds 24 and 35a/b, a modified procedure for the Ghosez keteniminium-olefin cyclization was developed, which was required to minimize the decomposition of acid-sensitive functional groups such as electron-rich benzylic ethers that were present in the target compounds 2-4.

Full text of DOI:10.1021/jo015829q

J . Org. Chem. 2001, 66, 6719-6728
6719
C-H In ser tion Ap p r oa ch to th e Syn th esis of
en d o,exo-F u r ofu r a n on es: Syn th esis of (()-Asa r in in ,
(()-Ep im a gn olin A, a n d (()-F a r gesin
Richard C. D. Brown,*,† Carole J . R. Bataille,† Gordon Bruton,‡ J eremy D. Hinks,† and
Nigel A. Swain†
Department of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ , UK, and
GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Harlow, Essex CM19 5AW, UK
rcb1@soton.ac.uk
Received J une 8, 2001
A series of novel 5-aryl-4-aryloxymethyl-3-diazotetrahydrofuran-2-ones (12, 24, and 35a /b) have
been prepared and found to undergo regio- and stereoselective C-H insertion reactions to afford
2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane-8-ones (18, 26, and 36a /b) with endo,exo stereochemistry.
Subsequent reduction of the lactone ring and cyclization of the resulting diols 27 and 37a /b permitted
the synthesis of three endo,exo-furofuran lignans: asarinin (2), fargesin (3), and epimagnolin A
(4). En route to the key diazo compounds 24 and 35a /b, a modified procedure for the Ghosez
keteniminium-olefin cyclization was developed, which was required to minimize the decomposition
of acid-sensitive functional groups such as electron-rich benzylic ethers that were present in the
target compounds 2-4.
In tr od u ction
The furofurans are one of the largest subclass of
lignans, and their isolation, characterization, biological
activity,1 biosynthesis, and synthesis have been exten-
sively reviewed.2,3 The majority of furofuran lignans have
their 2,6-diaryl substituents on the exo face of the bicyclic
core (e.g., 1), although many compounds with endo,exo-
aryl substitution (e.g., 2-4) and some compounds with
endo,endo substitution are known (Figure 1). A variety
of biological activities have been described within the
endo,exo-furofuran series, with certain compounds having
been isolated during the bioassay-guided fractionation of
traditional Asian medicines.4-8 Asarinin (2) has been
shown to have several significant biological activities,
including the following: anti-tumor promotion,4 anti-
allergic activity,9 and enhancement of the toxicity of
certain insecticides.10,11 Bioassay-guided fractionation of
F igu r e 1. Structures of exo,exo- and endo,exo-furofuran
lignans.
the Chinese crude drugs shin-i and xinyi, used to treat
nasal congestion and headache, has unveiled the Ca2+
and PAF antagonist activity of fargesin (3)6,8 and led to
the isolation of a new insecticidal furofuran epimagnolin
A (4).7
† University of Southampton.
Given the varied biological activities displayed by the
furofuran lignans, and interesting structural features
there has been substantial interest in their syn-
thesis.2,3,12-15 The aim of our work was to develop a new
strategy for the synthesis of furofuran lignans, which
involved the use of an intramolecular C-H insertion
reaction to close the C1-C2 σ-bond (Scheme 1).13,16 Using
this approach, we hoped to introduce different aryl
groups at the 2- and 6-positions and control the relative
‡ GlaxoSmithKline Pharmaceuticals.
(1) MacRae, W. D.; Towers, G. H. N. Phytochemistry 1984, 23, 1207.
(2) For the latest in a series of lignan reviews, see: Ward, R. S. Nat.
Prod. Rep. 1999, 16, 75.
(3) Whiting, D. A. Nat. Prod. Rep. 1990, 7, 349.
(4) Takasaki, M.; Konoshima, T.; Yasuda, I.; Hamano, T.; Tokuda,
H. Biol. Pharm. Bull. 1997, 20, 776.
(5) Hashimoto, K.; Yanagisawa, T.; Okui, Y.; Ikeya, Y.; Maruno, M.;
Fujita, T. Planta Med. 1994, 60, 124.
(6) Chen, C. C.; Huang, Y. L.; Chen, H. T.; Chen, Y. P.; Hsu, H. Y.
Planta Med. 1988, 438.
(7) Miyazawa, M.; Ishikawa, Y.; Kasahara, H.; Yamanaka, J .;
Kameoka, H. Phytochemistry 1994, 35, 611.
(8) Pan, J . X.; Hensens, O. D.; Zink, D. L.; Chang, M. N.; Hwang, S.
B. Phytochemistry 1987, 26, 1377.
(9) Hashimoto, K.; Yanagisawa, T.; Okui, Y.; Ikeya, Y.; Maruno, M.;
Fujita, T. Planta Med. 1994, 60, 124.
(10) Haller, H. L.; McGovran, E. R.; Goodhue, L. D.; Sulivan, W. N.
J . Org. Chem. 1942, 7, 183.
(11) Haller, H. L.; LaForge, F. B.; Sulivan, W. N. J . Org. Chem. 1942,
7, 185.
(12) Aldous, D. J .; Dutton, W. M.; Steel, P. G. Synlett 1999, 474.
(13) A part of the work described here has been reported in
communications: (a) Brown, R. C. D.; Hinks, J . D. Chem. Commun.
1998, 1895. (b) Brown, R. C. D.; Bataille, C. J . R.; Hinks, J . D.
Tetrahedron Lett. 2001, 42, 473.
(14) Hull, H. M.; J ones, R. G.; Knight, D. W. J . Chem. Soc., Perkin
Trans. 1 1998, 1779.
(15) Ohmizu, H.; Ogiku, T.; Iwasaki, T. Heterocycles 2000, 52, 1399.
10.1021/jo015829q CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/05/2001

6720 J . Org. Chem., Vol. 66, No. 20, 2001
Brown et al.
Sch em e 1
Sch em e 3. P r eviou sly Rep or ted Syn th esis of a n
r-d ia zo-γ-bu tyr ola cton e by Sch m itz et a l.19 a
a
Reagents and conditions: (a) NaOMe, MeO2CH, Et2O; (b)
TsN3, CH3CN.
Sch em e 2a
Sch em e 4a
a
Reagents and conditions: (a) Tf2O, CH2Cl2, 2,6-di-tert-butylpy-
ridine, allylbenzyl ether; (b) H2O2, AcOH; (c) LDA, 4-nitroben-
zenesulfonyl azide then pH 7 buffer.
a
stereochemistry such that either C2-epimer could be
produced selectively. At the outset, several issues relating
to the key insertion reaction were unclear, not least of
all being other potential decomposition pathways of a
formal carbene intermediate 6. Additional uncertainties
included the stereoselectivity of the proposed C-H inser-
tion and the synthesis of the pivotal R-diazo-γ-butyro-
lactone 5.
To investigate the proposed C-H insertion reaction,
we required diazolactone 5, which would be derived from
a diazo-transfer reaction on the corresponding lactone.
The desired trans relationship of the lactone substituents
would be established in an earlier [2 + 2] keteniminium-
olefin cycloaddition reaction.17,18
Reagents and conditions: (a) LiHMDS, THF, -78 °C, 4-ni-
trobenzene-sulfonyl azide; (b) AcOH, -78 °C; (c) warm to room
temperature; (d) AcCl; (e) DMAP, THF.
epimerisation so separation of the isomers was left until
after the next step. Baeyer-Villiger oxidation of 9 to the
corresponding lactone 10 was accomplished either with
m-CPBA or peracetic acid generated in situ, with the
latter method returning the lactone in a marginally
higher yield. Any of the remaining minor diastereoisomer
was removed by column chromatography at this point.
With reasonable quantities of the lactone 10 in hand,
we then turned our attention to the diazo-transfer re-
action.16b Prior to our work, we only knew of one example
of an R-diazo-γ-butyrolactone 14, which had been pre-
pared from γ-butyrolactone (13) in low yield using a
deformylative method (Scheme 3).19 Using our substrate
10, the deformylative diazo-transfer faired no better and
gave a mixture of azide 11 and the desired diazo com-
pound 12 in low yield, leading us to consider direct diazo
transfer. Results from Evans et al. using imide enolates
indicated that it might be possible to prepare the diazo-
lactone 12 by direct diazo transfer to the enolate of 10
using an appropriate sulfonyl azide.20 However, numer-
ous attempts to effect the diazo-transfer using various
metal counterions and workup procedures afforded the
azide 11 as the major isolated product (Scheme 2).
Resu lts a n d Discu ssion
Mod el Stu d ies. Our investigation began with the
synthesis of 3-benzyloxymethyl-2-phenylcyclobutanone
(9) using the Ghosez [2 + 2] keteniminium-olefin cy-
cloaddition procedure (Scheme 2).17 The desired cyclic
ketone 9 was obtained as a 9:1 mixture of diastereoiso-
mers, which could be separated by preparative normal-
phase HPLC (Phenomenex Luna silica column, eluting
with ether/hexane 1:9). However, it subsequently became
apparent that the benzylic position underwent facile
In their work, Evans et al. had shown that the inter-
mediate triazine anion, generated upon reaction of a
carboximide enolate with a sulfonyl azide, could be pro-
tonated at low temperature leading to isolable triazines.20
Treatment of these triazines with KOAc then led to an
azide whereas treatment with pyridine favored the for-
mation of the corresponding diazo compound. Although
direct translation of this chemistry to our system failed
as the triazine 16 was too unstable to be isolated (Scheme
4), decomposing predominantly to azide 11 upon warming
(16) For a selection of reviews containing examples of cyclisation
by metal-catalysed C-H insertion of R-diazocarbonyls: (a) Doyle, M.
P. Chem. Rev. 1986, 86, 919. (b) Ye, T.; McKervey, M. A. Chem. Rev.
1994, 94, 1091. (c) Doyle, M. P.; McKervey, M. A. J . Chem. Soc., Chem.
Commun. 1997, 983. (d) Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998,
98, 911. (e) Padwa, A.; Krumpe, K. E. Tetrahedron 1992, 48, 5385. (f)
Sulikowski, G. A.; Cha, K. L.; Sulikowski, M. M. Tetrahedron: Asym-
metry 1998, 9, 3145. (g) Taber, D. F. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 3, 1045. (h) Taber, D. F. In Stereoselective Synthesis, 4th
ed.; Helmchen, G., Hoffmann, R. W., Mulzer, J ., Schaumann, E., Eds.;
Georg Thieme Verlag: Stuttgart, 1995; Vol. E21a, p 1127. (i) Taber,
D. F.; Stiriba, S. E. Chem. Eur. J . 1998, 4, 990.
(17) Falmagne, J . B.; Schmit, C.; Escudero, J .; Vanlierde, H.; Ghosez,
L. Org. Synth. 1990, 69, 199.
(18) Ghosez, L.; Marchand-Brynaert, J . In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 5, p 85.
(19) Schmitz, A.; Kraatz, U.; Korte, F. Chem. Ber. 1975, 108, 1010.
(20) Evans, D. A.; Britton, T. C.; Ellman, J . A.; Dorow, R. L. J . Am.
Chem. Soc. 1990, 112, 4011.

Synthesis of endo,exo-Furofuranones
J . Org. Chem., Vol. 66, No. 20, 2001 6721
Sch em e 5a
Sch em e 6a
a
Reagents and conditions: (a) Rh2(OAc)4, CH2Cl2, rt.
to room temperature, a modification of the method proved
more rewarding. It was discovered that the intermediate
triazine anion could be trapped by acylation at -78 °C
to afford a mixture of isomeric acyl triazines 17. A study
on the decomposition of acyl triazine 17 then revealed
that addition of 1 equiv of DMAP in CH2Cl2 produced a
moderate yield of the desired diazolactone 12, along with
a similar amount of azide 11, thus permitting further
progress toward the furofuranone system. It is worthy
to note that the diazolactone 12 was quite robust,
surviving chromatography on silica to allow separation
of the close-running azide 11 and some 4-nitrophenyl-
sulfonamide byproduct.
a
Reagents and conditions: (a) (i) Tf2O, CH2Cl2, -25 °C, 2,6-
di-tert-butylpyridine, CH2)CHCH2OCH2Ar (22); (ii) NaHCO3 (aq).
Sch em e 7a
The key C-H insertion reaction was then attempted
using a catalytic quantity of rhodium(II) acetate dimer,
and we were delighted to observe rapid and highly
diastereoselective conversion of diazolactone 12 to furo-
furanone 18 bearing phenyl substituents with the endo,-
exo configuration (Scheme 5). The stereochemistry was
supported by NOE experiments (see Scheme 5) and by
comparison of the spectral data with that reported for
analogous furofuranones.21 More recently, an X-ray struc-
ture was obtained for 18, confirming the proposed relative
stereochemistry.22 The C-H insertion reaction of diazo-
lactone 12 could also be achieved by refluxing 12 in 1,2-
dichloroethane (82%), although thermal insertion did not
proceed as cleanly as the rhodium-catalyzed reaction and
the presence of other minor components was evident from
a
Reagents and conditions: (a) (i) Tf2O, CH2Cl2, -25 °C then
K2CO3, 2,6-di-tert-butylpyridine, 22; (ii) NaHCO3 (aq); (b) H2O2,
AcOH; (c) (i) LiHMDS, THF; (ii) 4-nitrobenzenesulfonyl azide,
-78 °C; (iii) AcCl; (d) DMAP, THF; (e) Rh2(OAc)4, CH2Cl2; (f)
LiAlH4, THF; (g) MsCl, pyr.
1
the crude H NMR spectrum.
Syn th esis of (()-Asa r in in . With the successful syn-
thesis of a model furofuranone 18 having been completed,
we embarked upon the synthesis of the endo,exo-furofu-
ran lignan (()-asarinin (2) with the expectation that
application of the route described above would be fairly
straightforward. However, we had underestimated the
sensitivity of the electron-rich benzylic ethers to the
conditions of the keteniminium-olefin cycloaddition.
Attempted formation of the cyclobutanone 21 led to a
relatively complex mixture of products, from which the
debenzylated cyclobutanone 20 and Friedel-Crafts alky-
lation products were isolated in modest yield, along with
traces of the desired product 21 (Scheme 6). Reasoning
that debenzylation might be occurring due to the pres-
ence of di-tert-butylpyridinium triflate, powdered anhy-
drous K2CO3 was added to the reaction mixture prior to
the olefin 22 (Scheme 7). The buffering effect of the
K2CO3 allowed the desired cycloadduct 21 to be isolated
in 56% yield, and this modification may find use in other
keteniminium-olefin cycloaddition reactions where acid-
sensitive functionalities are present.
by column chromatography, and subsequent diazo-trans-
fer produced the diazolactone 24 in moderate yield. As
experienced in the model study, purification of the di-
azolactone involved a rather tricky chromatographic
separation from some recovered parent lactone 23, azide
25, and sulfonamide byproducts. C-H insertion of 24
cleanly produced a furofuranone 26 with spectroscopic
data in accord with the proposed structure, although the
observed melting point (142-143 °C, EtOAc/hexane) was
significantly lower than that reported (158-159 °C,
EtOAc/hexane).21 Subsequently, the endo,exo stereo-
chemistry was confirmed by X-ray crystallography.23
Various methods for the final transformation of furo-
furanones to furofurans have been described.21,24 Reduc-
tion of 26 with LiAlH4 followed by acid-promoted cycliza-
tion of the resulting diol 27 led to a mixture of dia-
stereoisomeric furofurans and some recovered diol (20%).
Asarinin (2) was isolated from the mixture in 65% yield,
with the major byproduct tentatively assigned as the
endo,endo isomer (5%). The diastereoselective conversion
of 27 to (()-asarinin (2) was ultimately achieved by
exposure of diol 27 to excess methanesulfonyl chloride
in pyridine for 17 h.
Cyclobutanone 21 was then oxidized to afford the
lactone 23, after removal of the minor diastereoisomer
(21) Stevens, D. R.; Till, C. P.; Whiting, D. A. J . Chem. Soc., Perkin
Trans. 1 1992, 185.
(23) Coles, S. J .; Hursthouse, M. B. Acta Crystallogr. 2001, E57,
o544.
(22) Gelbrich, T.; Hursthouse, M. B. Acta Crystallogr. 2001, E57,
o566.
(24) Yoshida, S.-i.; Ogiku, T.; Ohmizu, H.; Iwasaki, T. J . Org. Chem.
1997, 62, 1310.

6722 J . Org. Chem., Vol. 66, No. 20, 2001
Brown et al.
Sch em e 8a
Sch em e 9a
a
a
Reagents and conditions: (a) LiHMDS (2 equiv), F3CCH2O2-
Reagents and conditions: (a) NaH, F3CCH2O2CCF3, DME,
CCF3, THF; (b) NaH (4 equiv), PhCO2Me, DME, MeOH cat.; (c)
4-nitrobenzenesulfonyl azide, Et3N, CH2Cl2.
MeOH cat.; (b) NaH (4 equiv), PhCO2Me, DME, MeOH cat.; (c)
4-nitrobenzenesulfonyl azide, Et3N, CH2Cl2; (d) 4-nitrobenzene-
sulfonyl azide, DBU, CH2Cl2.
Sch em e 10a
Deca r bon yla tive Dia zo-Tr a n sfer Str a tegy. The
poor efficiency of the diazo-transfer reactions described
above imposed a considerable limitation on the overall
approach to furofuran lignans, not just in terms of yield
but also introducing a tricky purification of the diazolac-
tones 12 and 24. To improve the diazo-transfer process,
we decided to conduct a survey of more recently intro-
duced decarbonylative diazo-transfer methods using
5-phenyl-γ-butyrolactone (28) as a model substrate
(Scheme 8).25,26 Acylation of 28 with either trifluoroacetyl
or benzoyl groups was achieved using NaH as the base.
The acyl derivatives 29a /b were then treated with
4-nitrobenzenesulfonyl azide in the presence of base to
afford 3-diazo-5-phenylfuran-2-one (30) in quite good
yields. On the basis of these unoptimized experiments,
we settled on the use of Et3N as base and CH2Cl2 as the
solvent. The use of excess base, particularly when DBU
was employed, was detrimental to the yield of 30. Control
experiments indicated that the base caused decomposi-
tion of 4-nitrobenzenesulfonyl azide.
We also examined the use of a supported diazo-transfer
reagent to facilitate reaction workup and purification.27,28
However, sulfonyl azide resin prepared from 20% cross-
linked polystyrene following a reported method failed to
effect diazo-transfer to the trifluoroacylated lactone 29a
or even to ethyl acetoacetate in our hands.27 Fortunately
sulfonyl azide resin prepared from commercial polysty-
renesulfonyl chloride (Argonaut, 1% cross-linked) did
function as a diazo-transfer reagent to afford 30 from 29a
in 64% yield, although relatively large amounts of the
expensive resin were required and reaction was signifi-
cantly slower than its homogeneous counterpart. The
development of other readily accessible supported diazo-
transfer reagents is under investigation in our laboratory
and will be reported in due course.29
After having established an efficient diazo-transfer
protocol for the model lactone 28, we returned our
attention to the 4-benzyloxymethyl substituted lactone
10 (Scheme 9). The acylated lactone 31a was prepared
with quantitative crude mass recovery using NaH or
LiHMDS as the base. The trifluoroacyl lactone 31a was
unstable to column chromatography and decomposed
fairly rapidly on standing, requiring it to be used directly
in diazo-transfer reactions for optimum results. The more
stable 3-benzoyl-5-phenylfuran-2-one (31b), obtained in
modest yield, did not react with the 4-nitrobenzenesulfo-
nyl azide under the conditions developed for the model
a
Reagents and conditions: (a) Tf2O, CH2Cl2, -25 °C, 2,6-di-
tert-butylpyridine, K2CO3, CH2dCHCH2OCH2Ar2 (38); (b) H2O2,
AcOH; (c) LiHMDS (2 equiv), CF3CH2OCOCF3, THF; (d) Et3N,
4-nitrobenzenesulfonyl azide, CH2Cl2; (e) Rh2(OAc)4, CH2Cl2; (f)
LiAlH4, THF; (g) MsCl, pyr, CH2Cl2; (h) MsCl, Et3N, DMAP,
CH2Cl2.
system, and diazo-transfer reactions with this substrate
were not investigated further. The less stable trifluoro-
acyl derivative 31a did undergo the desired diazo-transfer
efficiently, almost doubling the yield for the conversion
of lactone 10 to 12 obtained using our original method.
Reaction of 31a with the sulfonyl azide resin was much
slower and was not practically useful for these substrates.
Syn th esis of Ep im a gn olin A a n d F a r gesin . To
demonstrate the more general utility of the C-H inser-
tion reaction in the synthesis of endo,exo-furofuran
lignans, the syntheses of two unsymmetrically substi-
tuted compounds, fargesin (3) and epimagnolin A (4),
were investigated (Scheme 10). The initial [2 + 2]
cycloaddition proved to be more problematic for the
compounds with the dimethoxyphenyl and trimethoxy-
phenyl substituents. However, enough of the cyclobu-
tanones 33a /b were produced to continue with the
synthesis. The ring expansion and diazo-transfer pro-
ceeded in good yields to provide the C-H insertion
precursors 35a /b, which underwent efficient cyclization
upon exposure to 2 mol % of the rhodium(II) catalyst.
(25) Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J .
Org. Chem. 1990, 55, 1959.
(26) Taber, D. F.; You, K.; Song, Y. J . Org. Chem. 1995, 60, 1093.
(27) Roush, W. R.; Feitler, D.; Rebek, J . Tetrahedron Lett. 1974,
1391.
(28) Durr, H.; Hauck, G.; Bruck, W.; Kober, H. Z. Naturforsch., B:
Chem. Sci. 1981, 36, 1149.
(29) During the course of this work, a paper appeared describing
the synthesis and use of an immobilised diazo-transfer reagent,
prepared from a commercial sulfonyl chloride resin: Green, G. M.; Peet,
N. P.; Metz, W. A. J . Org. Chem. 2001, 66, 2509.

Synthesis of endo,exo-Furofuranones
J . Org. Chem., Vol. 66, No. 20, 2001 6723
1H NMR (400 MHz) δ 2.98 (s, 3H), 3.00 (s, 3H), 3.73 (s, 2H),
7.22-7.36 (m, 5H).
Confirmation of stereochemistry for 36b was achieved
by X-ray crystallography.30
(2S*, 3S*)-3-[(Ben zyloxy)m eth yl]-2-p h en ylcyclobu ta -
n on e (9). To a solution of N,N-dimethyl-2-phenylacetamide
(8) (1.63 g, 10.0 mmol) in CH2Cl2 (20 mL) at -25 °C (internal,
CO2(s)/acetone) was added freshly distilled Tf2O (2.0 mL, 12
mmol) at such a rate that the temperature did not rise above
-20 °C. The colorless homogeneous reaction mixture was
stirred at -20 °C for 10 min before addition of a mixture of
2,6-di-tert-butylpyridine (2.7 mL, 12 mmol) and allylbenzyl
ether36 (2.3 mL, 15 mmol) in CH2Cl2 (15 mL) over a period of
10 min. The reaction was then allowed to warm to room
temperature and stirred for 13 h (the formation of the cyclic
iminium species was monitored by IR; υmax 1734 cm-1). The
mixture was diluted with CH2Cl2 (10 mL) and treated with
sat. NaHCO3 (aq) (20 mL) with vigorous stirring for 1 h. The
organic layer was separated and the aqueous extracted with
CH2Cl2 (3 × 20 mL), and the combined extracts were washed
with water (30 mL) and brine (30 mL), dried with MgSO4, and
concentrated in vacuo to yield a orange oil (6.2 g). Purification
was accomplished by flash chromatography on silica gel (5 ×
10) eluting with Et2O/hexane (1:9 then 1:4) to give the title
compound 9 (1.73 g, 6.5 mmol, 65%) as a colorless oil (9:1
mixture of diastereoisomers). NMR data are given for the
major diastereoisomer: IR νmax (neat) 1779 cm-1; 1H NMR (400
MHz) δ 2.81-2.94 (m, 1H), 3.01-3.13 (m, 2H), 3.78 (d, J )
9.0 Hz, 2H), 4.39 (d, J ) 7.4 Hz, 1H), 4.62 (s, 2H), 7.21-7.48
(m, 10H); 13C NMR (100 MHz) δ 206.2, 138.2, 136.1, 128.8,
128.7, 128.0, 127.8, 127.3, 127.2, 73.4, 72.1, 66.6, 47.4, 32.5;
LRMS (CI, ammonia) m/z (relative intensity) 284 (10) [M +
NH4]+, 91 (100) [PhCH2]+, 175 (15) [M - PhCH2]+; HRMS (EI)
calcd for C18H18O2 266.1307, found 266.1303.
Careful reduction of the lactones 36a /b afforded the
ring-opened diols 37a /b in excellent yields, prior to
reclosure of the lower tetrahydrofuran ring by treatment
with excess methanesulfonyl chloride. The syntheses of
fargesin (3) and epimagnolin A (4) were thus completed
in 10% and 6% overall yield, respectively.
Su m m a r y. A number of novel diazolactones have been
prepared and shown to undergo highly efficient and
diastereoselective C-H insertion reactions to give
endo,exo-furofuranones. The scope of the methodology in
the context of furofuran lignan synthesis was demon-
strated by the synthesis of three lignans: (()-asarinin,
(()-epimagnolin A, and (()-fargesin. During the course
of this work, we have developed modified conditions for
the [2 + 2] keteniminium-olefin cycloaddition to allow
the use of acid-sensitive substrates (3,4-methylenedioxy-
benzyl ethers), although for certain compounds (di- and
trimethoxybenzyl ethers) the yields of cycloadducts are
still modest. Our future work in this area will focus on
the development of an asymmetric synthesis of γ-buty-
rolactones, and further investigation of the synthesis and
reactions of R-diazolactones and lactams.
Exp er im en ta l Section
1
Gen er a l Meth od s. H NMR and 13C NMR were recorded
on 300, 360, or 400 MHz spectrometers (300, 360, or 400 MHz,
1H NMR respectively and 75, 90, or 100 MHz, 13C NMR,
respectively) in deuteriochloroform (CDCl3) with chloroform
(4R*,5S*)-5-P h en yl-4-[(ben zyloxy)m eth yl]tetr a h yd r o-
2-fu r a n on e (10). To a solution of cyclobutanone 9 (1.50 g of
an approximately 9:1 mixture of diastereoisomers, 5.6 mmol)
in glacial acetic acid (15 mL) at 0 °C (ice bath) was added a
30% aqueous solution of hydrogen peroxide (1.9 mL, 17.2
mmol) dropwise over 5 min and the reaction maintained at 4
°C for 18 h. The reaction mixture was then diluted with Et2O
(40 mL) and quenched with a saturated aqueous solution of
sodium bicarbonate (40 mL). The two phases were separated
and the organic layer washed with saturated NaHCO3 (aq) (3
× 30 mL) before the combined base washes were extracted
with Et2O (3 × 40 mL). The combined organic layers were then
washed with water (50 mL) and brine (50 mL), dried with
MgSO4, and concentrated in vacuo to yield a crude yellow oil
(1.2 g). Purification and separation from the minor diastere-
oisomer was accomplished on silica gel (4.5 × 5.5) eluting with
Et2O/hexane (3:7) to yield the title compound 10 (1.08 g, 4.1
1
(δ 7.26 ppm H, δ 77.5 ppm 13C) as the internal standard unless
stated otherwise. Infrared (IR) spectra are reported in wave-
numbers (cm-1). Melting points were obtained in open capillary
tubes and are uncorrected. All nonaqueous reactions were
carried out under an inert atmosphere, in oven-dried glass-
ware. The following solvents were distilled before use: THF
(from Na/benzophenone) and CH2Cl2 (from CaH2) and where
appropriate, other reagents and solvents were purified by
standard techniques.31 p-nitrobenezenesulfonyl azide was
prepared according to literature procedures.32,33 TLC was
performed on glass-backed plates coated with silica gel 60 with
an F254 indicator; the chromatograms were visualized under
UV light and/or by staining with phosphomolybdic acid (20%
solution in ethanol) or KMnO4. Flash column chromatography
was performed with 40-63 µm silica gel (Merck) and column
dimensions are quoted in cm (width × height).
mmol, 72%) as a colorless oil: IR νmax (neat) 1779 cm-1 1H
;
NMR (400 MHz) δ 2.62-2.78 (m, 3H), 3.45-3.61 (m, 2H), 4.53
(d, J ) 12.0 Hz, 1H), 4.64 (d, J ) 12.0 Hz, 1H), 5.39 (d, J )
5.5 Hz, 1H), 7.12-7.45 (m, 10H); 13C NMR (100 MHz) δ 176.5,
138.9, 137.8, 128.9, 128.7, 128.0, 127.8, 125.8, 82.7, 73.4, 68.3,
44.7, 31.7; LRMS (CI, ammonia) m/z (relative intensity) 300
(3) [M + NH4]+, 91 (100) [PhCH2]+, 191 (25) [M - PhCH2]+;
HRMS (EI) calcd for C18H18O3 282.1256, found 282.1259.
N,N-Dim eth yl-2-p h en yla ceta m id e (8). To a solution of
phenylacetyl chloride (4.0 mL, 30 mmol) in CH2Cl2 (40 mL) at
0 °C (ice/salt bath) was added a solution of dimethylamine
hydrochloride (5.87 g, 72 mmol) in aqueous sodium hydroxide
solution (3.2 g NaOH in 18 mL of water) by dropwise addition.
The reaction mixture was allowed to warm to room temper-
ature and stirred overnight. After dilution with CH2Cl2 (40
mL), the reaction mixture was washed sequentially with 2 N
HCl (40 mL), saturated NaHCO3 (aq) (40 mL), water (40 mL),
and brine (40 mL), dried with MgSO4, and concentrated in
vacuo to give the title compound 8 (4.81 g, 29 mmol, 98%) as
a viscous colorless oil that solidified on standing to a white
solid; spectroscopic details are consistent with those ob-
served in the literature:34 bp 170-173 °C (0.2 mmHg); mp
(4R*,5S*) 3-Dia zo-5-p h en yl-4-[(ben zyloxy)m eth yl]tet-
r a h yd r o-2-fu r a n on e (12) F ollow in g th e Or igin a l P r oce-
d u r e. LiHMDS (400 µL of a 0.93M solution in THF, 0.37
mmol) was dissolved in dry THF (2 mL) and cooled to -78 °C
under nitrogen. A precooled solution of lactone 10 (100 mg,
0.35 mmol) in THF (2 mL) was added via a cannula and the
reaction mixture stirred at -78 °C. After 45 min, a precooled
solution of the p-nitrobenzenesulfonyl azide (84 mg, 0.37 mmol)
in THF (2 mL) was added via cannula and the resulting deep
red solution stirred for 10 min. Acetyl chloride (110 mg, 100
mL, 1.4 mmol) was added, and the reaction was allowed to
warm slowly to room temperature. The red coloration dis-
sipated within 5 min of adding the acetyl chloride. The reaction
mixture was diluted with Et2O (30 mL) and washed with water
and brine (30 mL) each before drying (MgSO4). Removal of
37-39 °C (lit.35 mp 38-40 °C); IR νmax (neat) 1652 cm-1
;
(30) Light, M. E.; Hursthouse, M. B. Acta Crystallogr. 2001, E57,
o514.
(31) Perin, D. D.; Armarego, W. L. F. Purification of laboratory
chemicals, 3rd ed.; Butterworth-Heinemann Ltd.: Oxford, 1994.
(32) Baum, J . S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D. Synth.
Commun. 1987, 17, 1709.
(33) Rector, D. L.; Harman, R. E. J . Org. Chem. 1966, 31, 2837.
(34) Mårtensson, O.; Nilsson, E. Acta Chem. Scand. 1960, 1129.
(35) Bordwell, F. G.; Fried, H. E. J . Org. Chem. 1981, 46, 4327.
(36) Arndt, H. C.; Carroll, S. A. Synthesis 1979, 202.

6724 J . Org. Chem., Vol. 66, No. 20, 2001
Brown et al.
solvent in vacuo afforded (4R*,5S*)-3-[(E)-3-Acetyl-3-[(4-
n it r op h e n yl)su lfon yl]-1-t r ia ze n yl]-5-p h e n yl-4-[(b e n -
zyloxy)m eth yl]tetr a h yd r o-2-fu r a n on e (17), apparently un-
stable to silica gel, was isolated as a foam (200 mg, quant.).
The compounds inherent instability required its immediate use
in the next reaction. Thus, a sample of the material (25 mg,
0.05 mmol) was dissolved in THF (2 mL) and treated with
DMAP (7 mg, 0.06 mmol) and the reaction stood at 4°C
overnight. The solvent was removed and the crude mixture
purified by radial chromatography on silica gel plate (2 mm)
eluting with EtOAc/hexane (1:4). The title compound 12 was
isolated as a pale yellow solid (8 mg, 0.026 mmol, 51%) along
with the azide byproduct 11, which was also isolated as an oil
(8 mg, 0.024 mmol, 48%). Data for diazolactone 12: mp 57-
59 °C (Et2O/hexane); IR νmax (neat) 2103, 1707 cm-1; 1H NMR
(400 MHz) δ 3.72-3.85 (m, 3H), 4.60 (s, 2H), 5.18 (d, J ) 4.0
Hz, 1H), 7.30-7.43 (m, 10H); 13C NMR (100 MHz) δ 169.6,
139.3, 137.6, 129.4, 129.3, 129.0, 128.5, 128.1, 125.8, 80.8, 74.1,
71.1, 45.8. Anal. Calcd for C18H16N2O3: C, 70.09; H, 5.23.
Found: C, 70.01; H, 5.36. Data for (3R,4R,5S)-3-Azid o-5-
p h e n yl-4-[(b e n zyloxy)m e t h yl]t e t r a h yd r o-2-fu r a n on e
(11): IR νmax (CH2Cl2) 2116, 1788 cm-1; 1H NMR (300 MHz) δ
2.36 (ddt, J ) 11.2, 10.3, 2.6 Hz, 1H), 3.48 (dd, J ) 10.3, 2.6
Hz, 1H), 3.63 (dd, J ) 10.3, 2.9 Hz, 1H), 4.54 (d, J ) 11.8 Hz,
1H), 4.64 (d J ) 12.1 Hz, 1H) superimposed on (d, J ) 11.0
Hz, 1H), 5.34 (d, J ) 11.9 Hz, 1H), 7.15-7.55 (m, 10H); 13C
NMR (75 MHz) δ 172.6, 137.4, 136.5, 129.2, 128.9, 128.7, 128.1,
126.3, 79.6, 73.4, 63.0, 58.8, 51.8; LRMS (EI) m/z (relative
poured onto water (10 mL), the organic layer separated, and
the aqueous extracted with CH2Cl2 (3 × 10 mL). The combined
organic layers were washed with saturated NaHCO3 (aq) (10
mL) and brine (10 mL), dried with MgSO4, and concentrated
in vacuo to yield a white solid (105 mg). Purification was
accomplished on silica gel (1.5 × 7) eluting with Et2O/hexane
(2:3) to yield the title compound 18 (80 mg, 0.29 mmol, 91%)
as a white crystalline solid: mp 121-123 °C (Et2O/hexane);
IR νmax (neat) 1773 cm-1; 1H NMR (400 MHz) δ 3.27 (ddd, J )
9.4, 6.5, 5.5 Hz, 1H), 3.61 (t, J ) 8.9 Hz, 1H), 3.96 (dd, J )
9.9, 5.0 Hz, 1H), 4.38 (d, J ) 9.4 Hz, 1H), 5.12 (d, J ) 8.9 Hz,
1H), 5.33 (d, J ) 6.5 Hz, 1H), 7.32-7.45 (m, 10H); 13C NMR
(100 MHz) δ 174.7, 140.0, 136.5, 129.4, 129.2, 129.0, 126.7,
125.8, 85.8, 84.4, 72.4, 51.9, 51.6; LRMS (CI, ammonia) m/z
(relative intensity) 281 (65) [M + H]+, 298 (100) [M + NH4]+,
263 (20) [M - H2O]H+. Anal. Calcd for C18H16O3: C, 77.12; H,
5.75. Found: C, 77.27; H, 5.79.
N ,N -D im e t h y l-2-(3,4-m e t h y le n e d io x y p h e n y l)a c e t -
a m id e (19). 3,4-Methylenedioxyphenylacetic acid (4.83 g, 26.7
mmol) was suspended in dry CH2Cl2 (25 mL) and treated with
oxalyl chloride (3.72 g, 2.57 mL, 29.4 mmol) followed by DMF
(1 drop). The reaction was stirred until gaseous evolution
ceased and the starting acid was fully dissolved. The crude
acid chloride (IR νmax 1790 cm-1) was cooled on ice before
adding dimethylamine (25% aqueous solution, 10.8 g, 11.5 mL,
60 mmol) by dropwise addition over a period of 20 min. The
solution was stirred overnight at room temperature before the
reaction mixture was washed with saturated NaHCO3 (aq) (50
mL). Extraction of the aqueous phase with CH2Cl2 (3 × 30
mL) was followed by washing of the combined organic layers
with brine (20 mL) and drying with MgSO4. The crude product
was purified by bulb-to-bulb distillation (2 mmHg, oven
temperature >250 °C) to give the title compound 19 as a
viscous oil that solidified on standing (4.90 g, 23.7 mmol,
88%): mp 49-52 °C; IR νmax (CH2Cl2) 1641 cm-1; 1H NMR (300
MHz) δ 2.97 (s, 3H), 3.01 (s, 3H), 3.62 (s, 2H), 5.94 (s, 2H),
6.68 (dd, J ) 7.7, 1.0 Hz, 1H), 6.75 (d, J ) 8.4 Hz, 1H), 6.77
(bs, 1H); 13C NMR (75 MHz) δ 171.3, 147.9, 146.5, 128.8, 121.9,
109.4, 108.5, 101.1, 40.7, 37.8, 35.8; LRMS (ES +ve) m/z
(relative intensity) 208 (100) [M + H]+, 415 (20) [2M + H]+.
(2S*,3S*)-2-(3,4-Meth ylen ed ioxy)p h en yl-3-[[(3,4-m eth -
ylen ed ioxyben zyl)oxy]m eth yl]cyclobu ta n on e (21). N,N-
Dimethyl-2-(3,4-methylenedioxyphenyl)acetamide (19) (517
mg, 2.5 mmol) was dissolved in CH2Cl2 (10 mL) under nitrogen.
The solution was cooled to -20 °C (internal) and treated with
trifluoromethanesulfonic anhydride (0.47 mL, 2.8 mmol) at
such a rate that the reaction temperature did not rise above
-15 °C. The yellow homogeneous mixture was stirred at -20
°C for 10 min before the addition of anhydrous K2CO3 (386
mg, 2.8 mmol) in one portion followed by a mixture of 2,6-di-
tert-butylpyridine (0.75 mL, 3.3 mmol) and 4-[(allyloxy)-
methyl]-1,2-methylenedioxybenzene (22) (0.576 g, 3.0 mmol)
in CH2Cl2 (10 mL) over a period of 10 min. The reaction was
stirred at -20 °C for 10 min and allowed to warm to 10 °C.
After 1 h at 10 °C, the solution was treated with saturated
NaHCO3 (aq) (20 mL) and stirred for a further 1 h at room
temperature. The reaction was diluted with CH2Cl2 (20 mL)
and sequentially washed with water and brine (30 mL each)
before drying with MgSO4. After removal of solvent, the crude
product was purified by chromatography on silica gel (3 × 6)
eluting with EtOAc/hexane (1:4). The title compound 21 was
isolated as a colored oil and as a mixture of diastereomers in
the ratio of 12 (trans)/1 (cis) (0.497 g, 1.40 mmol, 56%): IR
intensity) 323 (10) [M]•+, 91 (100) [PhCH2]•+
.
(4R*,5S*)-5-P h en yl-3-d ia zo-4-[(b en zyloxy)m et h yl]t et -
r a h yd r o-2-fu r a n on e (12) by a Detr iflu or oa cyla tive Ap -
p r oa ch . To a solution of hexamethyldisilylazane (1.1 mL, 5.02
mmol) in THF (15 mL) at 0 °C (ice/salt bath) was added n-BuLi
(3.2 mL of a 1.6 M solution in hexanes, 5.16 mmol) dropwise
over 5 min. The colorless solution was stirred at 0 °C for 10
min before cooling to -78 °C (CO2(s)/acetone bath) and adding
a solution of lactone 10 (710 mg, 2.51 mmol) in THF (25 mL)
dropwise over 10 min. The pale yellow reaction mixture was
allowed to stir at -78 °C for 45 min, 2,2,2-trifluoroethyltri-
fluoroacetate (0.37 mL, 2.76 mmol) was added dropwise over
2 min, and the reaction mixture was warmed to room tem-
perature over 100 min. The reaction mixture was acidified to
pH ) 4 with an aqueous solution of 1 N HCl and diluted with
Et2O (20 mL) before the organic layer was separated and the
aqueous extracted with Et2O (3 × 30 mL). The combined
organic layers were washed with brine (30 mL), dried with
MgSO4, and concentrated in vacuo to yield (4R*, 5S*)-5-
p h en yl-4-[(ben zyloxy)m eth yl]-3-(tr iflu or oa cetyl)tetr a h y-
d r o-2-fu r a n on e (31a ) (950 mg, quantitative) as a crude cream
solid - this crude material was used directly in the subsequent
diazo-transfer reaction: IR νmax (neat) 1784, 1747 cm-1 1H
;
NMR (300 MHz) δ 3.38-3.67 (m, 3H), 4.47-4.66 (m, 3H), 5.38
(d, J ) 8.4 Hz, 1H), 7.18-7.45 (m, 10H); 13C NMR (75 MHz) δ
177.5, 137.9, 137.4, 129.4, 129.0, 128.9, 128.8, 128.3, 128.2,
126.9, 125.8, 83.1, 73.6, 65.3, 46.2, 45.5. Thus, to a solution of
crude trifluoroacylated lactone 31a (2.20 mmol thereoretical)
in bench grade CH2Cl2 (30 mL) at room temperature was
added 4-nitrobenzenesulfonyl azide (0.65 g, 2.86 mmol) fol-
lowed by NEt3 (0.40 mL, 2.86 mmol) and the yellow reaction
mixture was left to stir for 18 h. The mixture was poured
onto water (30 mL) and diluted with CH2Cl2 (10 mL), the
organic layer was separated and the aqueous extracted with
CH2Cl2 (3 × 30 mL). The combined organic layers were washed
with brine (30 mL), dried with MgSO4 and concentrated in
vacuo to yield a crude yellow oil (3.2 g). Purification was
accomplished by flash chromatography on silica gel (5.5 × 6)
eluting with Et2O/hexane (2:3) to yield the title compound 12
(550 mg, 1.78 mmol, 81% - from lactone 10) as a pale yellow
solid. Spectroscopic data reported above.
1
νmax (CH2Cl2) 1779 cm-1; H NMR (300 MHz, C6D6) δ 2.68-
2.84 (m, 1H), 3.04 (d, J ) 8.4 Hz, 2H), 3.73 (d, J ) 5.5 Hz,
2H), 4.26 (d, J ) 7.8 Hz, 1H), 4.51 (s, 2H), 5.86 (s, 2H), 5.88
(s, 2H), 6.67-6.83 (m, 5H), 6.85 (s, 1H); 13C NMR (75 MHz,
C6D6) δ 206.0, 147.9, 147.2, 147.2, 146.6, 131.9, 129.7, 121.3,
120.3, 108.4, 108.1, 107.8, 101.1, 101.0, 73.1, 71.6, 66.2, 47.0,
32.8; HRMS (EI) calcd for C20H18O6 354.1103, found 354.1099.
4-[(Allyloxy)m eth yl]-1,2-m eth ylen ed ioxyben zen e (22).
Sodium hydride (60% dispersion in mineral oil, 5.04 g, 87.5
mmol) was washed with dry pentane in oven dried apparatus
while under nitrogen. Dry DMF (55 mL) was added to the
resulting solid. To this suspension was added 3,4-methylene-
(1S*,2R*,5R*,6S*)-2,6-Dip h en yl-3,7-d ioxa bicyclo[3.3.0]-
octa n -8-on e (18). To a solution of diazo lactone 12 (100 mg,
0.32 mmol) in CH2Cl2 (4 mL) at room temperature was added
Rh2(OAc)4 (3 mg, 0.006 mmol), and the resulting pale green,
effervescing (N2) reaction mixture was stirred under nitrogen
for 3 h. The mixture was diluted with CH2Cl2 (10 mL) and

Synthesis of endo,exo-Furofuranones
J . Org. Chem., Vol. 66, No. 20, 2001 6725
dioxybenzyl alcohol (10.65 g, 70 mmol) by dropwise addition
and the mixture stirred at room temperature for 45 min. KI
(2.32 g, 14 mmol) was added prior to the addition of a solution
of allyl bromide (9.46 g, 6.76 mL, 78 mmol) in DMF (25 mL),
which was added over a period of 10 min. The resulting
mixture was left to stir for 16 h at room temperature before
pouring into an aqueous solution of NaCl (20 g in 250 mL)
and extracting with Et2O (3 × 100 mL). The combined extracts
were washed with water and brine (100 mL each) and dried
with MgSO4. Purification was effected by vacuum distillation
to provide the title compound 22 (12.1 g, 63 mmol, 90%) as a
colorless oil: bp 84-88 °C (0.4 mmHg); IR νmax (CH2Cl2) 1503,
6.80 (m, 6H); 13C NMR (75 MHz) δ 169.2, 148.5, 148.3, 148.1,
147.7, 132.6, 131.1, 121.7, 119.6, 108.5, 108.4, 106.1, 101.6,
101.3, 80.6, 73.6, 70.3, 53.0, 45.4; LRMS (EI) m/z (relative
intensity) 368 (40) [M - N2]+; (ES +ve) 414 (80) [M + NH4]+;
810 (100), [2M + NH4]+. Data for (4R*,5S*)-5-(3,4-m eth -
ylen ed ioxy)p h en yl-3-a zid o-4-[[(3,4-m eth ylen ed ioxyben -
zyl)oxy]m eth yl]tetr a h yd r o-2-fu r a n on e (25). Isolated from
the reaction mixture as a 5:1 mixture of diastereoisomers: IR
ν
max (CH2Cl2) 2113, 1784 cm-1; 1H NMR (300 MHz) δ 2.31 (dt,
J ) 10.7, 2.9 Hz, 1H), 3.41 (dd, J ) 10.3, 2.6 Hz, 1H), 3.57
(dd, J ) 10.3, 2.9 Hz, 1H), 4.41 (d, J ) 11.8 Hz, 1H), 4.50 (d,
J ) 11.8 Hz, 1H), 4.56 (d, J ) 11.4 Hz, 1H), 5.19 (d, J ) 9.9
Hz, 1H), 5.95 (s, 4H), 6.65-6.85 (m, 6H); 13C NMR (75 MHz)
172.4, 148.6, 148.4, 148.2, 147.8, 131.1, 130.0, 122.0, 120.8,
108.8, 108.4, 106.7, 101.6, 101.4, 79.8, 73.4, 62.9, 59.0, 51.6;
LRMS (ES +ve) m/z (relative intensity) 429 (100) [M + NH4]+,
840 (95) [2M + NH4]+.
1490 cm-1 1H NMR (300 MHz) δ 4.01 (dt, J ) 5.9, 1.1 Hz,
;
2H), 4.43 (s, 2H), 5.22 (dq, J ) 10.3, 1.1 Hz, 1H), 5.31 (dq, J
) 16.9, 1.5 Hz, 1H), 5.96 (s, 2H) superimposed on 5.89-6.02
(m, 1H), 6.77-6.83 (m, 2H), 6.87 (bs, 1H); 13C NMR (75 MHz)
δ 147.9, 147.2, 134.9, 132.3, 121.5, 117.3, 108.7, 108.2, 101.1,
72.1, 71.0.
(1S*,2R*,5R*,6S*)-2-(3,4-Meth ylen ed ioxy)p h en yl-6-(3,4-
m et h ylen ed ioxy)p h en yl-3,7-d ioxa b icyclo[3.3.0]oct a n -8-
on e (26). The diazo compound 24 (160 mg, 0.404 mmol) was
dissolved in CH2Cl2 (3 mL) and the solution treated with Rh2-
(OAc)4 (5 mg, 0.01 mmol) with stirring at room temperature.
After 1 h, the reaction was evaporated to dryness and the
resultant residue purified by chromatography on silica gel (3
× 6) eluting with EtOAc/hexane (3:7). The product, initially
isolated as a foam, was crystallized from EtOAc/hexane to give
the title compound 26 as a white solid (91 mg, 0.247 mmol,
61%): mp 140-141 °C (EtOAc/hexane) (lit.21 mp 158-159 °C,
(4R*,5S*)-5-(3,4-Meth ylen ed ioxy)p h en yl-4-[[(3,4-m eth -
ylen edioxyben zyl)oxy]m eth yl]tetr ah ydr o-2-fu r an on e (23).
The cyclobutanone 21 (2.06 g of an approximately 12:1 mixture
of diastereoisomers, 5.81 mmol) was dissolved in glacial acetic
acid (20 mL) and cooled over an ice bath during the addition
of 30% hydrogen peroxide solution (1.64 mL, 14 mmol). The
reaction was stirred at 0 °C for 4 h before partitioning between
2 M sodium hydroxide (aq) (150 mL) and EtOAc (100 mL).
After separation, the aqueous phase was re-extracted with
EtOAc (50 mL), and the combined organic phases were washed
with sodium metabisulfite (aq), water, and brine (50 mL each)
and finally dried with MgSO4. The crude material was purified
and separated from the minor diastereoisomer by chromatog-
raphy on silica gel (6 × 4.5) eluting with EtOAc/hexane (1:4)
to provide the title compound 23 (1.76 g, 4.76 mmol, 82%) as
a colorless oil: IR νmax (CH2Cl2) 1778 cm-1; 1H NMR (300 MHz)
δ 2.56-2.76 (m, 3H), 3.45 (dd, J ) 9.6, 4.0 Hz, 1H), 3.51 (dd,
J ) 9.6, 4.4 Hz, 1H), 4.40 (d, J ) 11.8 Hz, 1H), 4.46 (d, J )
11.8 Hz, 1H), 5.23 (d, J ) 6.3 Hz, 1H), 5.95 (s, 4H), 6.70-6.82
(m, 6H); 13C NMR (75 MHz) δ 176.1, 148.3, 148.1, 148.0, 147.5,
132.5, 131.6, 121.6, 119.8, 108.6, 108.4, 108.3, 106.4, 101.5,
101.3, 83.2, 73.3, 68.0, 44.8, 32.0; LRMS (EI) m/z (relative
intensity) 370 (40) [M]•+, 135 (100) [ArCH2]•+; HRMS (EI) calcd
EtOAc/hexane); IR νmax (CH2Cl2) 1774 cm-1 1H NMR (300
;
MHz) δ 3.21 (ddd, J ) 9.0, 6.7, 4.5 Hz, 1H), 3.54 (app. t, J )
6.9 Hz, 1H), 3.90 (dd, J ) 9.8, 4.6 Hz, 1H), 4.28 (d, J ) 9.7 Hz,
1H), 5.02 (d, J ) 8.8 Hz, 1H), 5.19 (d, J ) 6.6 Hz, 1H), 5.99 (s,
4H), 6.81-6.88 (m, 6H); 13C NMR (75 MHz) δ 174.4, 148.5,
148.2, 148.0, 147.8, 133.3, 130.0, 120.0, 119.6, 108.6, 108.4,
106.8, 106.1,101.5, 101.3, 85.7, 83.9, 71.8, 51.7, 51.3; LRMS
(EI) m/z (relative intensity) 368 (100) [M]•+; HRMS (EI) calcd
for C20H16O7 368.0896, found 368.0886.
(2R *,3R *,4S *)-2[(3,4-Me t h yle n e d ioxy)p h e n yl]-3-h y-
d r oxym eth yl-4-[[(3,4-m eth ylen ed ioxy)p h en yl]h yd r oxy]-
m eth yltetr a h yd r ofu r a n (27). LiAlH4 (57 mg, 1.5 mmol) was
suspended in THF (2 mL) under nitrogen. A solution of the
furofuranone derivative 26 (56 mg, 0.15 mmol) in dry THF (3
mL) was added and the reaction warmed to reflux for 1 h. After
cooling, the reaction mixture was treated with wet THF/MeOH
followed by 2.0 M HCl (30 mL) before extraction with EtOAc
(2 × 30 mL). The combined extracts were washed with brine
(30 mL) and dried with MgSO4. The crude material was
filtered through silica prior to purification by radial chroma-
tography eluting with EtOAc/hexane (4:6). The title compound
27 was isolated as a white solid (47 mg, 1.26 mmol, 83%): mp
153-155 °C (EtOAc/hexane); IR νmax (CH2Cl2) 3604, 3459, 1504
cm-1; 1H NMR (300 MHz) δ 2.65 (tt, J ) 5.9, 2.9 Hz, 1H), 2.97
(qd, J ) 9.6, 6.2 Hz, 1H), 3.29 (dd, J ) 11.1, 2.9 Hz, 1H), 3.50-
3.65 (m, 3H), 4.68 (d, J ) 10.3 Hz, 1H), 5.01 (d, J ) 5.5 Hz,
1H), 5.96 (s, 2H) 5.97 (s, 2H), 6.70-6.89 (m, 6H); 13C NMR
(75 MHz) δ 148.1, 147.9, 147.5, 146.8, 136.6, 132.8, 120.0,
118.7, 108.2, 106.6, 106.2, 101.1, 101.0, 83.5, 73.5, 68.9, 59.4,
for
C20H18O7 370.1053, found 370.1035. Anal. Calcd for
C
20H18O7: C, 64.87; H, 4.89. Found: C, 64.73; H, 4.84.
(4R*,5S*)-5-(3,4-Meth ylen edioxy)ph en yl-3-diazo-4-[[(3,4-
m et h ylen ed ioxyb en zyl)oxy]m et h yl]t et r a h yd r o-2-fu r a -
n on e (24). LiHMDS (0.8 mL of a 0.74 M solution in THF, 0.59
mmol) was dissolved in dry THF (3 mL) while under an
atmosphere of nitrogen and the solution cooled to -78 °C. To
this was added a precooled solution of the lactone 23 (200 mg,
0.54 mmol) in dry THF (3 mL) via a cannula. The yellow
solution was stirred at -78 °C for 45 min before treating with
a solution of p-nitrobenzenesulfonyl azide (135 mg, 0.59 mmol)
in dry THF (3 mL) and stirring for a further 10 min. Acetyl
chloride (0.153 mL, 2.2 mmol) was added and the reaction
allowed to warm to room temperature. The mixture was
diluted with Et2O (25 mL) and water (25 mL) and the organic
phase separated and washed with brine (25 mL) before drying
with MgSO4. The crude material was partially purified by
rapid filtration through silica gel, eluting with EtOAc/hexane
(1:1) to give (4R*,5S*)-3-[(E)-3-a cet yl-3-[(4-n it r op h en yl)-
su lfon yl]-1-t r ia zen yl]-5-(3,4-m et h ylen ed ioxy)p h en yl-4-
[[(3,4-m et h ylen ed ioxyben zyl)oxy]m et h yl]t et r a h yd r o-2-
fu r a n on e (303 mg, 0.473 mmol, 88%) as a yellow oil: IR νmax
(CH2Cl2) 1783, 1733, 1609, 1372 cm-1; LRMS (ES +ve) m/z
(relative intensity) 658 (100) [M + NH4]+. A portion of the oil
(251 mg, 0.39 mmol) was dissolved in THF (5 mL) and treated
with DMAP (53 mg, 0.43 mmol) and the reaction stirred at
room temperature for 16 h. The solvent was removed, and the
crude material was purified by chromatography on silica gel
(4.5 × 3) eluting with EtOAc/hexane (1:4) providing the title
compound 24 as a colored oil (71 mg, 0.179 mmol, 46% from
the triazine) along with the azide 25 (50 mg, 0.122 mmol, 31%
from the triazine). Data for diazolactone 24: IR νmax (CH2Cl2)
51.5, 47.4; LRMS (EI) m/z (relative intensity) 372 (40) [M]•+
,
354 (40) [M - H2O]•+; HRMS (EI) calcd for C20H20O7 372.1209,
found 372.1203.
5-P h en yl-3-(2,2,2,-t r iflu or oa cet yl)t et r a h yd r o-2-fu r a -
n on e (29a ). The title compound was prepared according to
the method outlined for 29b, whereby reaction of γ-phenyl-γ-
butyrolactone (0.28 mL, 2.0 mmol) with 2,2,2-trifluoroethyl
trifluoroacetate (0.40 mL, 3.0 mmol) and workup under the
conditions described gave a yellow oil (1.48 g). Purification was
accomplished by flash chromatography on silica (3 × 7.5)
eluting with Et2O/hexane (3:7) to yield the product 29a as a
white solid (0.44 g, 1.7 mmol, 84%): mp 72-75 °C (Et2O/
hexane); IR νmax (neat) 1737 cm-1; 1H NMR (300 MHz) - both
diastereoisomers reported δ [2.57 (q, J ) 11.4 Hz, 1H) and
2.98-3.13 (m, 1H)] and 2.75-2.87 (m, 2H), 3.23 (dd, J ) 12.4,
8.4 Hz, 1H) and 3.51-3.65 (m, 1H), 5.44 (dd, J ) 10.9, 6.0 Hz,
1H) and 5.65-5.78 (m, 1H), 7.28-7.48 (m, 2 × 5H); 13C
NMR (75 MHz) δ 177.2 and 174.0, 137.5, 129.4, 129.2, 129.1,
2102, 1736 cm-1
4.47 (s, 2H), 5.03-5.07 (m, 1H), 5.98 (s, 2H), 5.99 (s, 2H), 6.60-
;
1H NMR (300 MHz) δ 3.62-3.73 (m, 3H),

6726 J . Org. Chem., Vol. 66, No. 20, 2001
Brown et al.
128.9, 126.2, 125.6, 124.9, 81.1 and 80.1, 44.2 and 41.6, 33.6
and 32.6.
(7.92 g, 35 mmol) in CH2Cl2 (35 mL), at room temperature,
was added oxalyl chloride (3.4 mL, 38.5 mmol) followed by two
drops of DMF. The reaction was stirred for 6 h where upon
gaseous evolution had ceased and full conversion of acid
was observed (monitoring by IR -CdO(COOH) 1699 cm-1 and
-CdO(COCl) 1793 cm-1). The crude acid chloride was im-
mediately converted to the amide according to the method
outlined for 19. Purification was accomplished by distillation
under reduced pressure to give the title compound 32b (8.45
g, 33 mmol, 95%) as a viscous colorless oil that solidified on
standing to a white solid: bp 136-139 °C (0.5 mbar); mp
53-55 °C; IR νmax (neat) 1652 cm-1; 1H NMR (400 MHz) δ 3.01
(s, 3H), 3.05 (s, 3H), 3.68 (s, 2H), 3.85 (s, 3H), 3.87 (s, 6H),
6.51 (s, 2H); 13C NMR (100 MHz) δ 171.3, 153.7, 137.3, 131.1,
106.3, 61.2, 56.5, 41.5, 38.1, 36.1. Anal. Calcd for C13H19NO4:
C, 61.64; H, 7.56; N, 5.53. Found: C, 61.58; H, 7.65; N, 5.45.
3-Ben zoyl-5-p h en yltetr a h yd r o-2-fu r a n on e (29b). The
title compound was prepared according to the general proce-
dure described by Taber et al.26 NaH (1.53 g of a 60%
dispersion in mineral oil, 40.0 mmol) was washed twice with
dry hexanes (2 × 10 mL) and then suspended in DME (freshly
distilled over CaH2, 25 mL). To this suspension at 0 °C (ice/
salt) was added γ-phenyl-γ-butyrolactone (1.40 mL, 10.0 mmol)
in DME (8 mL). After 10 min at 0 °C, methyl benzoate (1.87
mL, 15.0 mmol) in DME (8 mL) was added dropwise. After
four drops of methanol were added, the mixture was allowed
to warm to room temperature and allowed to stir for 4 h. The
reaction mixture was acidified to pH ) 4 with an aqueous
solution of 1 N HCl and diluted with Et2O (20 mL). The yellow
organic layer was separated and the aqueous extracted with
Et2O (3 × 40 mL), dried with MgSO4, and concentrated in
vacuo to give a yellow oil that crystallized on standing. This
crude product was treated with ice-cold Et2O and filtered to
yield the product as a white solid (0.87 g, 3.3 mmol, 33%). The
filtrate was concentrated in vacuo and purified by flash
chromatography on silica (3 × 9) eluting with Et2O/hexane
(3:2) to provide the title compound (0.53 g, 2.1 mmol, 21%) as
an off-white solid (1:1 mixture of diastereoisomers) - overall
yield of 29b (1.40 g, 5.3 mmol, 53%): mp 95-97 °C (Et2O/
(2S *,3S *)-2-(3,4-Me t h y le n e d io x y )p h e n y l-3-[[(3,4-
d im eth oxyben zyl)oxy]m eth yl]cyclobu ta n on e (33a ). To a
solution of N,N-dimethyl(3,4-methylenedioxy)phenylacetamide
(19) (207 mg, 1.0 mmol) in CH2Cl2 (3.5 mL) at -25 °C (internal,
CO2(s)/acetone) was added Tf2O (0.18 mL, 1.05 mmol) at such
a rate that the temperature did not rise above -20 °C. The
colorless homogeneous reaction mixture was stirred at -25
°C for 2 min before addition of anhydrous potassium carbonate
(152 mg, 1.1 mmol) followed by a mixture of 2,6-di-tert-
butylpyridine (0.25 mL, 1.1 mmol) and 4-[(allyloxy)methyl]-
1,2-dimethoxybenzene (38)37 (310 mg, 1.5 mmol) in CH2Cl2 (0.5
mL) over a period of 2 min. The reaction was then allowed to
warm to room temperature and stirred for 18 h (the formation
of the cyclic iminium species was monitored by IR; υmax 1733
cm-1). The mixture was diluted with CH2Cl2 (10 mL) and
treated with saturated NaHCO3 (aq) (10 mL) with vigorous
stirring for 1 h. The organic layer was separated and the
aqueous layer extracted with CH2Cl2 (3 × 20 mL), and the
combined extracts were washed with water (20 mL) and brine
(20 mL), dried with MgSO4, and concentrated in vacuo to yield
a yellow oil (740 mg). Purification was accomplished by flash
chromatography on silica gel (3 × 8.5) eluting with EtOAc/
hexane (3:7) to give the title compound 33a as a 12:1 mixture
of diastereoisomers (158 mg, 0.43 mmol, 43%) as a colorless
oil. NMR data is reported for the major diastereoisomer: IR
1
hexane); IR νmax (neat) 1765, 1686 cm-1; H NMR (300 MHz)
- both distereoisomers reported δ 2.48 (dt, J ) 12.9, 8.4 Hz,
1H) and 3.03 (dt, J ) 13.4, 8.0 Hz, 1H), 2.82 (ddd, J ) 13.4,
8.9, 6.5 Hz, 1H) and 3.21 (ddd, J ) 10.4, 6.9, 3.5 Hz, 1H), 4.75
(dd, J ) 8.9, 3.0 Hz, 1H) and 4.83 (dd, J ) 10.9, 8.9 Hz, 1H),
5.57 (dd, J ) 10.4, 6.5 Hz, 1H) and 5.80 (dd, J ) 8.5, 7.0 Hz,
1H), 7.32-7.45 (m, 2 × 5H), 7.48 - 7.57 (m, 2 × 2H), 7.59-
7.70 (m, 2 × 1H), 8.08 (dd, J ) 7.4, 1.5 Hz, 2H) and 8.15 (dd,
J ) 7.4, 1.5 Hz, 2H); 13C NMR (75 MHz) δ 193.0 and 192.9,
172.3 and 172.2, 139.1 and 138.5, 136.0 and 135.1, 134.4 and
134.2, 129.8 and 129.6, 129.0 and 128.8, 126.1 and 125.6, 81.2
and 80.3, 49.9 and 49.4, 35.0 and 34.2; LRMS (AP +ve) m/z
(relative intensity) 267 (100) [M + H]+. Anal. Calcd for
C
17H14O3: C, 76.68; H, 5.30. Found: C, 76.67; H, 5.29.
3-Dia zo-5-p h en yltetr a h yd r o-2-fu r a n on e (30). To a solu-
tion of trifluoroacylated lactone 29a (30 mg, 0.11 mmol) in
bench-grade CH2Cl2 (2 mL) was added NEt3 (20 µL, 0.14 mmol)
and the mixture stirred at room temperature for 10 min before
p-nitrobenzenesulfonyl azide (33 mg, 0.14 mmol) was added
in one portion. The reaction mixture was stirred at room
temperature for 13 h, diluted with CH2Cl2 (5 mL), and
quenched with water (5 mL). The organic phase was separated
and the aqueous extracted with CH2Cl2 (3 × 8 mL), washed
with brine (10 mL), dried with MgSO4 and concentrated in
vacuo to yield a yellow oil (25 mg). Purification was ac-
complished by column chromatography on silica (3 × 3) eluting
with Et2O/hexane (3:2) to yield the title compound 30 (15 mg,
0.08 mmol, 72%) as a yellow oil: IR νmax (neat) 2095, 1729
νmax (neat) 1778 cm-1 1H NMR (400 MHz) δ 2.70-2.79 (m,
;
1H), 3.02 (d, J ) 9.0 Hz, 2H), 3.69-3.77 (m, 2H), 3.84 (s, 3H),
3.87 (s, 3H), 4.24 (d, J ) 8.0 Hz, 1H), 4.52 (s, 2H), 5.91 (s,
2H), 6.69-6.76 (m, 3H), 6.81-6.87 (m, 3H); 13C NMR (100
MHz) δ 206.3, 149.6, 149.2, 148.3, 147.0, 131.0, 130.1, 120.6,
111.4, 108.8, 108.2, 101.4, 73.5, 72.2, 66.8, 56.4, 56.2, 47.5, 33.1;
LRMS (CI, ammonia) m/z (relative intensity) 388 (10) [M +
NH4]+, 235 (70) [M - ArCH2]•+, 151 (100) [ArCH2]+; HRMS
(EI) calcd for C21H22O6 370.1416, found 370.1426.
(2S*,3S*)-3-[[3,4-Dim eth oxyben zyl)oxy]m eth yl]-2-(3,4,5-
tr im eth oxyp h en yl)cyclobu ta n on e (33b). The title com-
pound was prepared according to the method outlined for 33a ,
whereby N,N-dimethyl(3,4,5-trimethoxy)phenylacetamide 32b
(2.78 g, 11.0 mmol) and 4-[(allyloxy)methyl]-1,2-dimethoxy-
benzene (38)37 (3.44 g, 16.5 mmol) were reacted under the
conditions described (except reaction quenched at +5 °C after
150 min). Purification was accomplished by flash chromatog-
raphy on silica gel (5 × 10) eluting with EtOAc/hexane (1:9)
followed by EtOAc/hexane (1:1) to yield the title compound 33b
as a 12:1 mixture of diastereoisomers (720 mg, 1.73 mmol,
16%) as a very pale yellow oil. NMR data is reported for the
major diastereoisomer: IR νmax (neat) 1777 cm-1; 1H NMR (400
MHz) δ 2.77-2.86 (m, 1H), 3.04 (dd, J ) 4.5, 1.5 Hz, 1H), 3.05
(dd, J ) 5.5, 1.5 Hz, 1H), 3.71-3.78 (m, 2H), 3.79 (s, 6H), 3.80
(s, 3H), 3.84 (s, 3H), 3.87 (s, 3H), 4.28 (d, J ) 8.0 Hz, 1H),
4.54 (s, 2H), 6.52 (s, 2H), 6.81-6.85 (m, 1H), 6.84-6.89 (m,
2H); 13C NMR (100 MHz) δ 206.2, 153.7, 149.3, 149.2, 137.5,
132.0, 131.0, 120.8, 111.6, 111.4, 104.6, 73.6, 72.5, 67.3, 61.2,
56.5, 56.4, 56.3, 47.4, 33.0; LRMS (EI) m/z (relative intensity)
1
cm-1; H NMR (300 MHz) δ 3.28 (dd, J ) 12.9, 6.9 Hz, 1H),
3.75 (dd, J ) 12.9, 8.9 Hz, 1H), 5.56 (dd, J ) 8.4, 6.9 Hz, 1H),
7.33-7.46 (m, 5H); 13C NMR (75 MHz) δ 173.9, 139.4, 129.1,
129.0, 125.5, 78.1, 31.7.
(4R*,5S*)-3-Ben zoyl-4-[(ben zyloxy)m eth yl]-5-ph en yltet-
r a h yd r o-2-fu r a n on e (31b). The title compound was prepared
according to the method outlined for 29b, whereby reaction of
lactone 10 (0.29 g, 1.0 mmol) with methyl benzoate (0.19 mL,
1.5 mmol) and workup under the conditions described gave a
colorless oil (0.68 g). Purification was accomplished by column
chromatography on silica (3 × 6.5) eluting with Et2O/hexane
(3:7) to yield the title compound 31b (3 mg, 0.19 mmol, 19%)
as a colorless oil: IR νmax (neat) 1770, 1681 cm-1 1H NMR
;
(300 MHz) - major diastereoisomer reported δ 3.32-3.43 (m,
1H), 3.44-3.57 (m, 2H), 4.47 (d, J ) 12.4 Hz, 1H), 4.56 (d, J
) 12.4 Hz, 1H), 5.00 (d, J ) 10.9 Hz, 1H), 5.44 (d, J ) 9.4 Hz,
1H), 7.18-7.47 (m, 10H), 7.54 (dd, J ) 7.9, 7.4 Hz, 2H), 7.64
(dd, J ) 7.4, 1.5 Hz, 1H), 8.08 (d, J ) 7.4 Hz, 2H); 13C NMR
(75 MHz) δ 193.1, 171.7, 137.4, 136.3, 134.2, 129.7, 129.2,
128.9, 128.7, 128.2, 128.1, 126.7, 81.5, 73.4, 65.0, 51.0, 48.6.
N,N-Dim et h yl-2-(3,4,5-t r im et h oxyp h en yl)a cet a m id e
(32b). To a suspension of 3,4,5-trimethoxyphenyl acetic acid
416 (20) [M]•+, 265 (15) [M - ArCH2]•+, 151 (100) [ArCH2]•+
HRMS (EI) calcd for C23H28O7 416.1835, found 416.1837.
;
(37) Denmark, S. E.; Herbert, B. J . Org. Chem. 2000, 65, 2887.

Synthesis of endo,exo-Furofuranones
J . Org. Chem., Vol. 66, No. 20, 2001 6727
(4R *,5S *)-5-(3,4-Me t h yle n e d ioxy)p h e n yl-4-[[(3,4-d i-
m eth oxyben zyl)oxy]m eth yl]tetr ah ydr o-2-fu r an on e (34a).
The title compound was prepared according to the method
outlined for 23, whereby reaction of cyclobutanone 33a (1.50
g, 4.05 mmol) with hydrogen peroxide and workup under the
conditions described led to a crude yellow oil (1.9 g). Purifica-
tion and separation from the minor diastereoisomer was
accomplished on silica gel (5 × 7) eluting with EtOAc/hexane
(2:3) to yield the title compound 34a (1.11 g, 2.87 mmol, 71%)
as a colorless oil: IR νmax (neat) 1777 cm-1; 1H NMR (400 MHz)
δ 2.57-2.75 (m, 3H), 3.45-3.53 (m, 2H), 3.88 (s, 6H), 4.44 (d,
J ) 11.5 Hz, 1H), 4.49 (d, J ) 11.5 Hz, 1H), 5.23 (d, J ) 6.5
Hz, 1H), 5.95 (s, 2H), 6.69-6.77 (m, 3H), 6.84 (s, 3H); 13C NMR
(100 MHz) δ 176.4, 149.6, 149.3, 148.6, 148.3, 132.9, 130.6,
120.8, 119.9, 111.5, 111.4, 108.7, 106.6, 101.7, 83.4, 73.6, 68.6,
56.4, 56.3, 45.0, 32.2; LRMS (EI) m/z (relative intensity) 386
(30) [M]•+, 235 (70) [M - ArCH2]•+, 151 (100) [ArCH2]•+; HRMS
(EI) calcd for C21H22O7 386.1366, found 386.1372.
outlined for 35a , whereby reaction of lactone 34b (450 mg, 1.04
mmol) with lithium hexamethyldisilyl azide and 2,2,2-trifluo-
roethyltrifluoroacetate (0.15 mL, 1.14 mmol) under the
conditions described gave crude (4R*,5S*)-4-[[(3,4-dim eth oxy-
ben zyl)oxy]m eth yl]-3-(tr iflu or oa cetyl)-5-(3,4,5-tr im eth -
oxyp h en yl)tetr a h yd r o-2-fu r a n on e (600 mg, quantitative)
as a foam. This crude material was used directly in the
subsequent diazo-transfer reaction, which was conducted
following the procedure described for 12, whereby reaction of
crude the trifluoroacylated lactone (1.04 mmol theoretical) with
4-nitrobenzenesulfonyl azide (310 mg, 1.35 mmol) and workup
under the conditions described gave a crude yellow oil (1.2 g).
Trituration with Et2O/EtOAc and filtration gave the title
compound 35b (294 mg, 0.64 mmol, 62%) as a pale yellow solid.
Further purification of the filtrate was accomplished by flash
chromatography on silica gel (3 × 7) eluting with EtOAc/
hexane (3:2) to yield 35b (66 mg, 0.14 mmol, 14%) as a pale
yellow powdery solidsoverall yield of 35b (360 mg, 0.79 mmol,
76%sfrom lactone 34b): mp 131-132 °C; IR νmax (neat) 2110,
(4R*,5S*)-4-[[(3,4-Dim eth oxyben zyl)oxy]m eth yl]-5-(3,4,5-
tr im eth oxyp h en yl)tetr a h yd r o-2-fu r a n on e (34b). The title
compound was prepared according to the method outlined for
23, whereby reaction of cyclobutanone 33b (650 mg, 1.56
mmol) with hydrogen peroxide and workup under the condi-
tions described led to a crude yellow oil (3.5 g). Purification
and separation from the minor diastereoisomer was ac-
complished by flash chromatography on silica gel (4 × 8)
eluting with EtOAc/hexane (3:2) to yield the title compound
34b (535 mg, 1.24 mmol, 79%) as a colorless oil: IR νmax (neat)
1
1730 cm-1; H NMR (400 MHz) δ 3.71-3.81 (m, 3H), 3.82 (s,
6H), 3.83 (s, 3H), 3.88 (s, 3H), 3.88 (s, 3H), 4.51 (d, J ) 11.5
Hz, 1H), 4.54 (d, J ) 11.5 Hz, 1H), 5.09 (d, J ) 4.0 Hz, 1H),
6.49 (s, 2H), 6.84 (s, 3H); 13C NMR (100 MHz) δ 169.5, 154.1,
149.7, 149.5, 138.8, 134.8, 130.1, 120.9, 111.5, 111.4, 102.8,
81.0, 74.0, 70.7, 61.3, 56.7, 56.4, 56.3, 53.2, 45.7. Anal. Calcd
for C23H26N2O8: C, 60.26; H, 5.72; N, 6.11. Found: C, 60.21;
H, 5.78; N, 6.21.
(1S *,2R *,5R *,6S *)-2-(3,4-Dim e t h oxy)p h e n yl-6-(3,4-
m et h ylen ed ioxy)p h en yl-3,7-d ioxa bicyclo[3.3.0]oct a n -8-
on e (36a ). The title compound was prepared according to the
method outlined for 26, whereby reaction of diazo-lactone 35a
(0.48 g, 1.16 mmol) with dirhodium(II) tetraacetate (10 mg,
0.02 mmol) and workup under the conditions described gave
crude furofuranone as a yellow oil (0.48 g). Purification was
accomplished on silica gel (4.5 × 10) eluting with EtOAc/
hexane (2:3) to yield the title compound 36a (0.36 g, 0.94 mmol,
81%) as a white crystalline solid: mp 125-127 °C; IR νmax
1
1778 cm-1; H NMR (400 MHz) δ 2.59-2.77 (m, 3H), 3.52 (d,
J ) 4.5 Hz, 2H), 3.79 (s, 6H), 3.82 (s, 3H), 3.87 (s, 3H), 3.87 (s,
3H), 4.44 (d, J ) 11.5 Hz, 1H), 4.53 (d, J ) 11.5 Hz, 1H), 5.27
(d, J ) 6.0 Hz, 1H), 6.45 (s, 2H), 6.81-6.87 (m, 3H); 13C NMR
(100 MHz) δ 176.3, 153.8, 149.4, 149.2, 138.3, 134.8, 130.4,
120.7, 111.4, 111.2, 102.8, 83.3, 73.5, 68.6, 61.1, 56.4, 56.2, 44.8,
31.9; LRMS (EI) m/z (relative intensity) 432 (30) [M]•+, 281
(35) [M - ArCH2]•+; 151 (100) [ArCH2]•+; HRMS (EI) calcd for
C
23H28O8 432.1784, found 432.1790.
(4R *,5S *)-5-(3,4-Me t h yle n e d ioxy)p h e n yl-3-d ia zo-4-
(neat) 1761 cm-1 1H NMR (400 MHz) δ 3.21 (ddd, J ) 9.0,
;
[[(3,4-d im et h oxyb en zyl)oxy]m et h yl]t et r a h yd r o-2-fu r a -
n on e (35a ). To a solution of hexamethyldisilylazane (1.1 mL,
5.2 mmol) in THF (15 mL) at 0 °C (ice/salt bath) was added
n-butyllithium (3.8 mL, 5.3 mmol) dropwise over 5 min. The
colorless solution was stirred at 0 °C for 10 min before cooling
to -78 °C (CO2(s)/acetone) and adding a solution of lactone
34a (1.0 g, 2.6 mmol) in THF (20 mL) dropwise over 10 min.
The pale yellow reaction mixture was left stirring at -78 °C
for 60 min and 2,2,2-trifluoroethyltrifluoroacetate (0.38 mL,
2.86 mmol) was added dropwise over 2 min. and the reaction
was warmed to room temperature over 100 min. The reaction
mixture was acidified to pH ) 4 with an aqueous solution of
1 N HCl and diluted with Et2O (20 mL) before the organic
layer was separated and the aqueous extracted with Et2O (3
× 30 mL). The combined organic layers were washed with
brine (30 mL), dried with MgSO4 and concentrated in vacuo
to afford crude (4R*,5S*)-5-(3,4-m et h ylen ed ioxy)p h en yl-
4-[[(3,4-dim eth oxyben zyl)oxy]m eth yl]-3-(tr iflu or oacetyl)-
tetr a h yd r o-2-fu r a n on e (1.39 g, quantitative) as a pale
orange foam. This crude material was used directly in the
subsequent diazo-transfer reaction, which was conducted
following the procedure described for 12, whereby reaction of
crude trifluoroacylated lactone (2.6 mmol theoretical) with
4-nitrobenzenesulfonyl azide (0.77 g, 3.4 mmol) and workup
under the conditions described gave a crude yellow oil (3.2 g).
Purification was accomplished by flash chromatography on
silica gel (5 × 7) eluting with EtOAc/hexane (2:3) to yield the
title compound 35a (730 mg, 1.77 mmol, 68% - from lactone
34a ) as a bright yellow oil: IR νmax (neat) 2101, 1733 cm-1; 1H
NMR (400 MHz) δ 3.65-3.76 (m, 3H), 3.87 (s, 3H), 3.87 (s,
3H), 4.49 (s, 2H), 5.02 (d, J ) 5.0 Hz, 1H), 5.96 (s, 2H), 6.72-
6.79 (m, 3H), 6.80-6.85 (m, 3H); 13C NMR (100 MHz) δ 171.9,
152.1, 151.8, 151.2, 151.0, 135.4, 132.6, 123.3, 122.3, 113.9,
113.9, 111.3, 108.8, 104.3, 83.4, 76.2, 73.2, 58.9, 58.8, 55.7, 48.2.
(4R*,5S*)-3-Diazo-4-[[(3,4-dim eth oxyben zyl)oxy]m eth yl]-
5-(3,4,5-tr im eth oxyp h en yl)tetr a h yd r o-2-fu r a n on e (35b).
The title compound was prepared according to the method
6.5, 4.5 Hz, 1H), 3.54 (t, J ) 8.5 Hz, 1H), 3.87 (s, 3H), 3.89 (s,
3H), 3.90 (dd, J ) 10.0, 5.0 Hz, 1H), 4.29 (d, J ) 9.5 Hz, 1H),
5.03 (d, J ) 8.5 Hz, 1H), 5.20 (d, J ) 6.5 Hz, 1H), 5.97 (s, 2H),
6.81 (s, 3H), 6.86-6.89 (m, 2H), 6.95 (dd, J ) 8.0, 2.0 Hz, 1H);
13C NMR (100 MHz) δ 174.7, 149.5, 149.4, 148.8, 148.5, 133.7,
128.9, 119.8, 119.3, 111.5, 109.9, 108.9, 106.3, 101.8, 85.9, 84.3,
72.1, 56.3, 56.2, 51.9, 51.7. Anal. Calcd for C21H20O7: C, 65.62;
H, 5.24. Found: C, 65.23; H, 5.02.
(1S*,2R*,5R*,6S*)-2-(3,4-Dim eth oxy)p h en yl-6-(3,4,5-tr i-
m eth oxy)ph en yl-3,7-dioxabicyclo[3.3.0]octan -8-on e (36b).
The title compound was prepared according to the method
outlined for 26, whereby reaction of diazo lactone 35b (320
mg, 0.70 mmol) with Rh2(OAc)4 (6 mg, 0.01 mmol) and workup
under the conditions described gave the crude furofuranone
as an off-white powdery solid (285 mg). Purification was
accomplished on silica gel (2.5 × 4) eluting with EtOAc/hexane
(3:2) to give the title compound 36b (261 mg, 0.60 mmol, 87%)
as a white powdery solid: mp 175-176 °C; IR νmax (neat) 1763
1
cm-1; H NMR (400 MHz) δ 3.24 (ddd, J ) 9.0, 6.5, 4.5 Hz,
1H), 3.55 (t, J ) 9.0 Hz, 1H), 3.85 (s, 3H), 3.88 (s, 6H), 3.88 (s,
3H), 3.90 (s, 3H), 3.94 (dd, J ) 9.5, 4.5 Hz, 1H), 4.34 (d, J )
9.5 Hz, 1H), 5.05 (d, J ) 8.5 Hz, 1H), 5.24 (d, J ) 6.5 Hz, 1H),
6.54 (s, 2H), 6.87-7.00 (m, 3H); 13C NMR (100 MHz) δ 174.8,
154.2, 149.6, 149.5, 138.8, 135.5, 128.8, 119.3, 111.5, 110.0,
102.8, 85.9, 84.3, 72.2, 56.7, 56.3, 56.2, 51.9, 51.8. Anal. Calcd
for C23H26O8: C, 64.18; H, 6.09. Found: C, 63.87; H, 5.89.
(2R*,3R*,4S*)-2[(3,4-Dim et h oxy)p h en yl]-3-h yd r oxy-
m e t h y l-4-[[(3,4-m e t h y le n e d i o x y )p h e n y l]h y d r o x y ]-
m eth yltetr a h yd r ofu r a n (37a ). To a suspension of LiAlH4
(35 mg, 0.93 mmol) in THF (5 mL) at 0 °C (ice/salt) was added
furofuranone 36a (120 mg, 0.31 mmol) in THF (10 mL), and
the gray suspension warmed to room temperature over 20 min.
Water (0.04 mL), 15% NaOH (aq) (0.04 mL) and water (0.12
mL) were sequentially added dropwise, producing a pale gray/
white granular precipitate that was filtered and washed with
THF (5 mL) and Et2O (10 mL). The filtrate was poured onto
brine (15 mL), the organic phase separated, and the aqueous

6728 J . Org. Chem., Vol. 66, No. 20, 2001
Brown et al.
extracted with Et2O (3 × 20 mL). The combined organic phases
were washed with brine (20 mL), dried with MgSO4, and
concentrated in vacuo to yield crude diol as a white solid (125
mg). Purification was accomplished on silica gel (3 × 2.5)
eluting with EtOAc/hexane (1:1) to yield the title compound
37a (118 mg, 0.30 mmol, 98%) as a white powdery solid: mp
66-68 °C; IR νmax (neat) 1254, 1237 cm-1; 1H NMR (400 MHz)
δ 2.30 (br s, 1H), 2.70-2.77 (m, 1H), 3.04 (dq, J ) 6.0, 9.5 Hz,
1H), 3.41 (dd, J ) 11.0, 2.5 Hz, 1H), 3.49 (br s, 1H), 3.60-3.70
(m, 3H), 3.88 (s, 3H), 3.88 (s, 3H), 4.78 (d, J ) 10.5 Hz, 1H),
5.09 (d, J ) 5.0 Hz, 1H), 5.97 (s, 2H), 6.77-6.87 (m, 5H), 6.93
(d, J ) 1.5 Hz, 1H); 13C NMR (100 MHz) δ 149.4, 148.6, 148.5,
147.8, 137.0, 131.8, 120.2, 118.2, 111.6, 109.2, 108.7, 107.0,
101.5, 83.7, 74.0, 74.0, 69.2, 60.2, 56.4, 56.3, 51.9, 47.8; LRMS
(EI) m/z (relative intensity) 388 (75) [M]•+, 370 (100) [M -
H2O]•+; HRMS (EI) calcd for C21H24O7 388.1522, found 388.1518.
(2R*,3R*,4S*)-2[(3,4-Dim et h oxy)p h en yl]-3-h yd r oxy-
m e t h yl-4-[[(3,4,5-t r im e t h oxy)p h e n yl]h yd r oxy]m e t h -
yltetr a h yd r ofu r a n (37b). The title compound was prepared
according to the method outlined for 37a , whereby reaction of
furofuranone 36b (165 mg, 0.38 mmol) with LiAlH4 (43 mg,
1.14 mmol) and workup under the conditions described gave
crude diol as a white solid (166 mg). Purification was ac-
complished on silica gel (10 × 2.3) eluting with EtOAc/hexane
(7:3) to yield the title compound 37b (149 mg, 0.34 mmol, 90%)
as a powdery white solid: mp 141-143 °C; IR νmax (neat) 1241
cm-1; 1H NMR (400 MHz) δ 2.55 (br s, 1H), 2.69-2.76 (m, 1H),
3.05 (dq, J ) 6.5, 9.5 Hz, 1H), 3.39 (d, J ) 11.0 Hz, 1H), 3.61-
3.69 (m, 2H), 3.72 (q, J ) 9.0 Hz, 1H), 3.84 (s, 3H), 3.87 (s,
6H), 3.87 (s, 6H), 4.76 (d, J ) 10.5 Hz, 1H), 5.08 (d, J ) 5.0
Hz, 1H), 6.61 (s, 2H), 6.79-6.86 (m, 3H); 13C NMR (100 MHz)
δ 153.8, 149.4, 148.6, 138.7, 138.1, 131.8, 118.2, 111.6, 109.2,
103.6, 83.7, 74.3, 69.2, 61.2, 60.1, 56.6, 56.4, 56.3, 51.9, 47.8.
Anal. Calcd for C23H30O8: C, 63.58; H, 6.96. Found: C, 63.31;
H, 6.99.
(1R *,2R *,5R *,6S *)-2-(3,4-Dim e t h oxy)p h e n yl-6-(3,4-
m eth ylen edioxy)ph en yl-3,7-dioxabicyclo[3.3.0]octan e ((()-
F a r gesin ) (3). To a solution of diol 37a (40 mg, 0.103 mmol)
in CH2Cl2 (0.4 mL) and pyridine (0.1 mL) at 0 °C (ice/salt) was
added MsCl (40 µL, 0.515 mmol) and the reaction warmed to
room temperature and stirred for 4 days. The mixture was
pipetted onto 1 N HCl (aq) (5 mL) and diluted with CH2Cl2 (8
mL). The organic layer was separated and the aqueous layer
extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were washed with 1 N HCl (aq) (10 mL) and brine (15
mL), dried with MgSO4, and concentrated in vacuo to yield a
crude orange oil (51 mg). Purification was accomplished on
silica gel (2.3 × 2.5) eluting with EtOAc/hexane (2:3) to yield
(()-fargesin (3) (23 mg, 0.062 mmol, 60%) as a white solid:
spectroscopic data were consistent with those reported previ-
ously;24,38,39 mp 138-141 °C (lit.24 mp 138-141 °C, lit.39 mp
145 °C, lit.40 mp 138-139 °C); IR νmax (neat) 1239, 1033 cm-1
;
1H NMR (400 MHz) δ 2.84-2.91 (m, 1H), 3.28-3.37 (m, 2H),
3.81-3.88 (m, 2H), 3.88 (s, 3H), 3.91 (s, 3H), 4.12 (d, J ) 9.5
Hz, 1H), 4.42 (d, J ) 7.0 Hz, 1H), 4.87 (d, J ) 5.0 Hz, 1H),
5.95 (s, 2H), 6.76-6.87 (m, 5H), 6.93 (s, 1H); 13C NMR (100
MHz) δ 149.3, 148.5, 148.4, 147.6, 135.6, 131.4, 119.9, 118.1,
111.5, 109.4, 108.6, 106.9, 101.4, 88.1, 82.4, 71.4, 70.2, 56.3,
56.3, 55.0, 50.6; MS (EI) m/z (relative intensity) 370 (45) [M]•+,
339 (6) [M - OMe]•+, 149 (100), 165 (50) [ArCO]•+
.
(1R*,2R*,5R*,6S*)-2-(3,4-Dim eth oxy)p h en yl-6-(3,4,5-tr i-
m eth oxy)p h en yl-3,7-d ioxa bicyclo[3.3.0]octa n e ((()-Ep i-
m a gn olin A) (4). To a solution of diol 37b (40 mg, 0.092 mmol)
in CH2Cl2 (1 mL) at 0 °C (ice/salt) was added Et3N (38 µL,
0.276 mmol) and DMAP (1 mg, cat.) followed by MsCl (9 µL,
0.11 mmol). The reaction mixture was allowed to warm to room
temperature and stirred for 6 h before additional MsCl (4 µL,
0.046 mmol) was added and the reaction stirred for a further
12 h. TLC analysis still showed starting diol 37b so NEt3 (38
µL, 0.276 mmol) and MsCl (18 µL, 0.221 mmol) were again
added and the reaction stirred for 15 min before pipetting onto
water (5 mL) and diluting with CH2Cl2 (8 mL). The organic
layer was separated and the aqueous extr acted with CH2Cl2
(3 × 10 mL). The combined organic layers were washed with
1N HCl (aq) (15 mL) and brine (15 mL), dried with MgSO4
and concentrated in vacuo to yield an orange oil (58 mg).
Purification was accomplished on silica gel (2.3 × 2) eluting
with EtOAc/hexane (3:2) to yield epimagnolin A (4) (29 mg,
0.070 mmol, 76%) as a glassy solid/viscous oil: spectroscopic
data were consistent with those reported previously;7 IR νmax
(1R*,2R*,5R*,6S*)-2,6-Di[(3,4-m eth ylen ed ioxy)p h en yl]-
3,7-d ioxa bicyclo[3.3.0]octa n e ((()-Asa r in in ) (2). The diol
27 (42 mg, 0.11 mmol) was dissolved in THF (5 mL) and
treated with 2.0 M HCl (5 mL). The reaction was stirred at
room temperature for 3 days. Although still not complete, the
reaction mixture was diluted with Et2O (10 mL) and washed
with saturated NaHCO3 (aq), water, and brine (10 mL of each)
before drying with MgSO4. The crude material was subjected
to radial chromatography eluting with EtOAc/hexane (1:4). (()-
Asarinin (2) was isolated as a crystalline solid (27 mg, 0.07
mmol, 65%) along with recovered starting material 27 (8 mg,
20%): mp 130-131°C (CH2Cl2/hexane) (lit.21 mp 132-133 °C);
spectroscopic data were in accord with those described in the
1
(neat) 1234, 1127 cm-1; H NMR (400 MHz) δ 2.90-2.97 (m,
1H), 3.31-3.39 (m, 2H), 3.84 (s, 3H), 3.86-3.91 (m, 2H), 3.88
(s, 6H), 3.89 (s, 3H), 3.92 (s, 3H), 4.17 (d, J ) 9.0 Hz, 1H),
4.45 (d, J ) 7.0 Hz, 1H), 4.89 (d, J ) 5.5 Hz, 1H), 6.60 (s, 2H),
6.87 (s, 2H), 6.95 (s, 1H); 13C NMR (100 MHz) δ 153.8, 149.3,
148.5, 138.0, 137.3, 131.3, 118.1, 111.5, 109.4, 103.4, 88.2, 82.4,
71.5, 70.2, 61.2, 56.6, 56.4, 56.3, 55.0, 50.5; MS (EI) m/z
1
literature;38 IR νmax (CH2Cl2) 1504, 1490 cm-1; H NMR (360
MHz) δ 2.85 (q with fine coupling, J ) 7.3, 0.9 Hz, 1H), 3.27-
3.33 (m, 2H), 3.83 (dd, J ) 9.4, 6.2 Hz, 1H) superimposed on
3.83-3.87 (m, 1H), 4.10 (d, J ) 9.2 Hz, 1H), 4.39 (d, J ) 7.2
Hz, 1H), 4.83 (d, J ) 5.4 Hz, 1H), 5.95 (s, 2H), 5.97 (s, 2H),
6.77-6.87 (m, 6H); 13C NMR (90 MHz) δ 148.1, 147.8, 147.3,
146.7, 135.2, 132.3, 119.7, 118.8, 108.2, 106.6, 106.5, 101.2,
101.1, 87.8, 82.1, 71.0, 69.8, 54.8, 50.3.
(relative intensity) 416 (100) [M]•+, 385 (10) [M - OMe]•+
.
Ack n ow led gm en t . We thank GlaxoSmithKline
(N.A.S.) for a CASE studentship and The Royal Society
for a University Research Fellowship (R.C.D.B.). R.C.D.B.
also thanks AstraZeneca and Merck Sharp and Dohme
for unrestricted grants. We wish to acknowledge the use
of the EPSRC’s Chemical Database Service at Dares-
bury.41
Im p r oved P r oced u r e for th e P r ep a r a tion of (()-Asa r i-
n in (2) fr om Diol 27. The diol 27 (80 mg, 0.22 mmol) was
dissolved in dry CH2Cl2, and the solution was cooled on ice.
Pyridine (180 µL, 2.2 mmol) was added rapidly followed by
freshly distilled MsCl (25 µL, 0.33 mmol). The reaction was
allowed to warm to room temperature and stirred for 5 h. A
further aliquot of MsCl (50 µL, 0.06 mmol) was added and
stirring continued for an additional 12 h. The reaction mixture
was diluted with CH2Cl2 (30 mL) and washed sequentially with
1.0M HCl (aq), sat. NaHCO3 (aq) then brine (20 mL of each)
before drying (MgSO4) and removal of solvent in vacuo. The
crude product was purified by chromatography on silica gel
(3 × 3) loading in CH2Cl2 and eluting with EtOAc/hexane (1:
1) to afford the title compound 2 as a white solid (60 mg, 0.17
mmol, 77%).
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H or 13C
NMR spectra for compounds 2-4, 9, 10, 19, 21, 22, 24-27,
29a , 30, 31a , 33a /b, 34a /b, 35a , and 37a . This material is
available free of charge via the Internet at http://pubs.acs.org.
J O015829Q
(39) Kakisawa, H.; Chen, Y. P.; Hsu¨, H. Y. Phytochem. 1972, 11,
2289.
(40) Ogiku, T.; Yoshida, S. I.; Ohmizu, H.; Iwasaki, T. J . Org. Chem.
1995, 60, 1148.
(41) The United Kingdom Database Service. Fletcher, D. A.; Mc-
Meeking, R. F.; Parkin, D. J . Chem. Inf. Comput. Sci. 1996, 36, 746.
(38) Pelter, A.; Ward, R. S. Tetrahedron 1976, 32, 2783.