OH
10b. Instead the major isolated product was the alcohol 15
arising from acid-catalysed cleavage of the benzylic ether bond
which was assisted by the electron donating methylenedioxy
group. The problem was almost certainly due to the formation of
di-tert-butylpyridinium triflate under the reaction conditions.
Fortunately this problem was easily resolved by the addition of
anhydrous K2CO3 to the reaction mixture, allowing the desired
cycloadduct 10b to be obtained in good yield.
Baeyer–Villager oxidation of 10b followed by diazo transfer
to the resulting lactone 11b afforded the cyclisation precursor
5b in a yield of 37% from ketone 4b. As was the case for the
model diazo lactone 5a, the C–H insertion reaction of 5b
proceeded cleanly to give the known furofuranone (±)-epi-
aptosimon 12b in good yield.
Ph
O
N2
N3
O
O
O
O
O
O
O
13
14
15
pursue other methods of decarbonylative diazo transfer,9,10 and
the existence of encouraging reports of direct diazo transfer to
ester and imide enolates, we focused our efforts on the later
approach.11,12
In summary, we have achieved a concise and diaster-
eoselective synthesis of the 2,6-diaryl-3,7-dioxabicy-
clo[3.3.0]octane ring system. Significant contributions include:
the development of conditions for conducting the ketenimin-
ium–olefin [2+2] cycloaddition reaction with alkenes bearing
acid-sensitive functionality; and a method for effecting diazo
transfer on g-butyrolactones to provide the a-diazo-
g-butyrolactones 5 in acceptable yield. Finally, (±)-epi-aptosi-
mon 12b has been synthesised using this approach, representing
a formal synthesis of the natural product (±)-asarinin 1.
We thank the Royal Society for a University Research
Fellowship (R. C. D. B.). We would also like to acknowledge
the use of the EPSRC funded Chemical Database Service at
Daresbury.21
The conditions reported for direct diazo transfer to ester
enolates failed to give satisfactory yields of the diazo lactone 5a,
with azide 14 isolated as the major product. Although
disappointing, the isolation of substantial amounts of azide 14
strongly implied that the intermediate triazine anion 17 was
being formed efficiently (Scheme 3). An earlier study of the
decomposition of triazines had shown that the relative propor-
tions of diazo transfer and azide transfer were influenced by the
reaction conditions.12 In our case the triazine 18 proved to be
too unstable to isolate,§ however, treatment of the reaction
mixture with AcCl provided
a mixture of isomeric
N-acetyltriazines 19.13¶ When the acetyl triazines 19 were
treated with an equivalent of DMAP smooth conversion to a 1:1
mixture of azide 14 and the desired diazo lactone 5a was
observed. The reason for the increased proportion of diazo
lactone 5a are not clear at present although it is tempting to
suggest that generation of a metal-free triazine anion, by the
nucleophilic deacylation of 19 with DMAP, is important.
Notes and References
† E-mail: rcb1@soton.ac.uk
‡ Due to the difficult chromatographic separation of the cis- and trans-
diastereoisomers, g-lactone 11a was contaminated with a trace of the cis-
isomer.
§ Protonation of the triazine anion (ref. 17) (AcOH or pH 7 phosphate
buffer) followed by warming to ambient temperature afforded predom-
Y
OBn
BnO
N
SO2Ar
N
N
inantly azide 14 along with a small amount of diazo transfer product 5a.
i
13
¶ The N-acetyltriazines 19 exhibited very complex 1H and
C NMR
Ph
OM
Ph
O
spectra, probably due to the presence of regio- and diastereo-isomers.
O
O
16 M = Li or Na
17 Y = Li
18 Y = H
19 Y = Ac
1 R. S. Ward, Nat. Prod. Rep., 1995, 12, 183.
2 R. S. Ward, Nat. Prod. Rep., 1997, 14, 43.
ii
3 R. S. Ward, Chem. Soc. Rev., 1982, 75.
4 C. Schmit, J. B. Falmangne, J. Escudero, H. Vanlierde and L. Ghosez,
Org. Synth., 1990, 69, 199.
Scheme 3 Reagents and conditions: i, p-NO2C6H4SO2N3, THF, 278 °C; ii,
AcCl, 278 °C to room temp.
5 O. Mårtensson and E. Nilsson, Acta Chem. Scand., 1960, 1129.
6 H. C. Arndt and S. A. Carroll, Synthesis, 1979, 202.
7 E. J. Corey, Z. Arnold and J. Hutton, Tetrahedron Lett., 1970, 307.
8 A. Schmitz, U. Kraatz and F. Korte, Chem. Ber., 1975, 108, 1010.
9 M. D. Weingarten and A. Padwa, Synlett, 1997, 189.
10 D. F. Taber, K. You and Y. Song, J. Org. Chem., 1995, 60, 1093.
11 L. Lombardo and L. N. Mander, Synthesis, 1980, 368.
12 D. A. Evans, T. C. Britton, J. A. Ellman and R. L. Dorow, J. Am. Chem.
Soc., 1990, 112, 4011.
Gratifyingly, the key C–H insertion reaction required to set
up the furofuranone framework proceeded extremely cleanly
when diazo lactone 5a was treated with a catalytic amount of
Rh2(OAc)4, providing a single diastereoisomeric product 12a.
The relative stereochemistry of the furofuranone 12a was
assigned as endo,exo on the basis of NOE experiments. We
were intrigued by the possibility of conducting the same
intramolecular C–H insertion reaction under thermal condi-
tions, which might provide altered stereoselectivity. In fact,
heating the diazo lactone 5a in 1,2-dichloroethane cleanly
afforded the same cyclised product 12a, again in excellent yield
and stereoselectivity.
Relatively few of the published approaches to the synthesis of
furofuranoid lignans have addressed the stereoselective synthe-
sis of the less common endo,exo structures.14–19 To demonstrate
the scope of our approach to the synthesis of furofuranoid
containing natural products the synthesis of epi-aptosimon 12b
was investigated. The conversion of epi-aptosimon 12b to the
furofuran lignan asarinin 1 has been reported previously.17
Initial attempts to carry out the [2+2] cycloaddition reaction of
allyl ether 7b6 (Ar = 3,4-methylenedioxyphenyl) with the
keteniminium salt derived from amide 9b20 failed to provide
13 S. E. Denmark, N. Chatani and S. V. Pansare, Tetrahedron, 1992, 48,
2191.
14 S. Takano, K. Samizu and K. Ogasawara, Synlett, 1993, 785.
15 K. Samizu and K. Ogasawara, Chem. Lett., 1995, 543.
16 D. R. Stevens and D. A. Whiting, Tetrahedron Lett., 1986, 27, 4629.
17 D. R. Stevens, C. P. Till and D. A. Whiting, J. Chem. Soc., Perkin Trans.
1, 1992, 185.
18 C. P. Till and D. A. Whiting, J. Chem. Soc., Chem. Commun., 1984,
590.
19 A. Pelter, R. S. Ward, P. Collins, R. Venkateswarlu and I. T. Kay,
J. Chem. Soc., Perkin Trans. 1, 1985, 587.
20 J. S. Buck and W. H. J. Perkin, J. Chem. Soc., 1924, 125, 1680.
21 D. A. Fletcher, R. F. McMeeking and D. Parkin, J. Chem. Inf. Comput.
Sci., 1996, 36, 746.
Received in Cambridge, UK, 8th July 1998; 8/05296D
1896
Chem. Commun., 1998