Scheme 1. Retrosynthetic Analysis of Lignans 1, 2, 8, and 9
Scheme 2. Lithium Alkoxide Conjugate Addition to
Nitroalkene 4
The retrosynthetic analyses of Galgravin 1, Veraguensin
2, Ganschisandrin 8, and Galbelgin 9 lead to nitrotetrahy-
drofurans 3 as central cyclic precursors. The nitro group
serves as a removable activating functionality to facilitate
the synthesis of 3 (Scheme 1). Further disconnection gives
rise to nitroalkene 4 and allylic alcohol 5, which can be easily
synthesized from the common precursor 3,4-dimethoxyben-
zaldehyde 6. An attractive feature of this strategy is that the
lignans are also accessible from 4 and 5 by reductive radical
cyclizations of the â-nitro ether 7 mediated by tributyltin
hydride.8 This allows a direct comparison of the radical
cyclization methods and establishes their potential for the
synthesis of 1, 2, 8, and 9.
During studies toward the design of new oxidative tandem
processes involving carbanions, radicals, and carbocations,
we developed tandem reactions consisting of alkoxide
conjugate addition to nitroalkenes/oxidative radical cycliza-
tion/ligand transfer to highly functionalized nitrotetrahydro-
furans.7a Given the interest in lignans, we decided to apply
this methodology to their synthesis. We present here initial
results on short three- to four-step total syntheses of
Galgravin 1, Veraguensin 2, Ganschisandrin 8, and Galbelgin
9 (Scheme 1).
Starting materials 4 and 5 were synthesized in good yield
according to the literature (Supporting Information). Al-
though racemic 5 was used in this study, asymmetric
approaches to 5 will be applied in the future.9
(2) Zhang, S.; Liu, X.; Zhang, L.; Wan, D. Tianran Chanwu Yanjiu Yu
Kaifa 1992, 4, 1-4; Chem. Abstr. 1993, 118, 109472.
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Med. Chem. 1986, 29, 1917-1921. (c) Wang, B.-G.; Hong, X.; Li, L.; Zhou,
J.; Hao, X.-J. Planta Med. 2000, 66, 511-515. (d) Hossain, C. F.; Kim,
Y.-P.; Baerson, S. R.; Zhang, L.; Bruick, R. K.; Mohammed, K. A.; Agarwal,
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As a prerequisite to the projected tandem reactions, the
efficiency of the alkoxide conjugate addition had to be tested.
Addition of 4 to a solution of 2 equiv of the lithium alkoxide
of 5 at -78 to 0 °C in THF or DME for 5 h afforded â-nitro
ether 7 in good yield as a mixture of four diastereomers
(Scheme 2). The diastereomers syn- and anti-7 at the ether
positions were separable by chromatography. A further
separation of the diastereomers differing in the configuration
at the nitro group was not possible. The configuration of
syn- and anti-7 was assigned on the basis of the cyclization
results (vide infra).
The tandem alkoxide conjugate addition/radical 5-exo
cyclization/ligand transfer reactions were performed as
described above for the addition step until 4 was consumed
followed by immediate addition of the oxidant at the given
temperature (Scheme 3, Table 1).
The results revealed the following features of the tandem
process: Both CuCl2 and CuBr2 are convenient SET oxidants
and ligand transfer agents in these sequences (entries 1-6).
On the other hand, bromine reacted presumably as an
electrophile toward the nitronate 7-, providing exclusively
â-bromo-â-nitro ether 12b as a mixture of diastereomers
(entry 7). The outcome of the sequences is dependent on
the solvent and the temperature of oxidant addition. Com-
pounds 3a,b were formed as predominantly single diaster-
eomers in reasonable yields, based on the diastereomeric
composition of 7, in THF at 0 °C (entries 1 and 5). This
means that radical syn-10 cyclized efficiently under the
reaction conditions, whereas anti-10 was trapped predomi-
nantly as the acyclic â-halo-â-nitro ether anti-12. In contrast,
both syn- and anti-10 are reactive enough to cyclize to 3
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