organometallic species might be protonated by intramolecular
attack at the benzylic hydrogen via a five-membered ring
transition state.
achieved by chemoselective halogen–metal exchange using the
iodoketone 3. Current efforts are devoted to an enantioselective
modification of this novel route.
References and notes
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Scheme 5. Cyclization to ( )-variabilin (1).
In the 1990s, Mori used stannyl anions generated from
Me3SiSnBu3 to achieve a halogen–metal exchange in the
presence of a carbonyl group.27–29 Unfortunately, these conditions
only resulted in decomposition of the starting material. Another
6.
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promising methodology,
a palladium-catalyzed cyclization
developed by Yamamoto,30 was not successful either, probably
due to the thermal lability of the substrates 2 and 3. On the
assumption that in all cases replacement of the halogen atom is
too slow in competition to the side reactions mentioned above,
we looked for appropriate reactions at lower temperature. In 1970
Corey described the utilization of di-n-butylcopperlithium to
achieve an intramolecular addition of a vinyl iodide to a keto
group in high yield – a methodology, which was successfully
adapted by Posner some years later.31,32 However, brominated
substrate 2 was not dehalogenated under these conditions, and
substrate 3 led to complete decomposition.
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Inspired by the work of Chavan, we tested n- and t-BuLi
under several conditions to perform the desired transformation
(Table 1).33 No halogen–metal exchange was observed using
substrate 2 (entry 1), but iodoketone 3 was cyclized successfully
at temperatures below −100ꢀ°C. Using 1.0 ꢀequiv. of n-BuLi at
−108ꢀ°C gave rise to ( )-variabilin (1) in a good yield of 65ꢀ%
(entry 2), whereas t-BuLi resulted in a low yield of only 25ꢀ%
(entry 3). Application of the radical anion salt lithium di-tert-
butylbiphenyl was another potential alternative, as lithiation may
take place under less basic conditions. Indeed, the aryl anion was
formed successfully, since phenol 10 was isolated in about 76ꢀ%
yield. Unfortunately, no cyclization product was formed,
probably due to the competing homolytic cleavage of the
benzylic C–O bond.34
19. Castanet, A.-S.; Colobert, F.; Broutin, P.-E. Tetrahedron Lett. 2002,
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21. Diastereomeric ratios were determined by 1H NMR integration.
22. Separation of the diastereomers by flash chromatography is possible
but difficult.
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Table 1. Selected conditions for cyclization to ( )-variabilin (1)
Entry
Substrate
Conditions
Yield
[%]
1
2
3
2
3
3
1.1 ꢀequiv. n-BuLi, THF,
−78ꢀ°C → RT, 26.5ꢀ h
0ꢀa
1.0 ꢀequiv. n-BuLi, THF,
−108ꢀ°C → −2ꢀ°C, 6.25 ꢀh
65
25
30. Quan, L. G.; Lamrani, M.; Yamamoto, Y. J. Am. Chem. Soc. 2000,
122, 4827–4828.
31. Corey, E. J.; Kuwajima, I. J. Am. Chem. Soc. 1970, 92, 395–396.
32. Posner, G. H.; Asirvatham, E.; Webb, K. S.; Jew, S. Tetrahedron Lett.
1987, 28, 5071–5074.
2.2 ꢀequiv. t-BuLi, THF,
−108ꢀ°C → 1ꢀ°C, 6.33 ꢀh
aOnly 6 was isolated.
33. Chavan, S. P.; Chavan, S. P.; Sonawane, H. R.; Kalkote, U. R.; Sudrik,
S. G.; Gonnade, R. G.; Bhadbhade, M. M. Eur. J. Org. Chem. 2007,
2007, 3277–3280.
3. Summary and conclusion
34. Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924–1930.
In summary, we have developed a short total synthesis of ( )-
variabilin (1), which provides an entirely new access to the 6a-
Supplementary Material
hydroxypterocarpan skeleton. The natural product
1 was
constructed in only three steps from the known 7-
methoxychromene (4) in 40ꢀ% overall yield and over six steps
(35ꢀ% overall yield) from the commercially available 2-hydroxy-
4-methoxybenzaldehyde (8). The challenging key intramolecular
nucleophilic addition to give the target molecule 1 was eventually
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/XXXXXXXXXX.
These data include experimental procedures and analytical data
of all compounds described in this article.