issues.4 Similarly, there are a number of examples where
readily available myo-inositol has been transformed by this
approach into 2-deoxy-2,2-difluoro5 and 5-deoxy-5,5-difluoro
species,6 some of which show some interesting enzymology.7
However, there are no obvious starting materials for such a
route to (()-3a-5b where R ) Me or CH2OPG and
definitely no one strategy which can deliver all three classes
of analogue from a common class of starting material. We
planned a flexible route, which would deliver three classes
of precursors (()-3a-5b to carba-sugars by a common
strategy from trifluoroethanol. The retrosynthetic analysis is
presented in Scheme 1.
first two could be set in the [3,3]-Claisen rearrangement, if
efficient transcription of alkene configuration could be
achieved. The rearrangement would of course be facilitated
by the rehybridization from sp2 to sp3 of the CF2 center. The
key step would then involve a dehydrofluorination/metalation
of a trifluoroethyl ether 6-8 and the addition of the
alkenylmetal reagent 9 to an enal electrophile to deliver
allylic alcohol (()-10. The route would avoid purification
wherever possible and would be carried out on a multigram
scale, prioritising rapid deliVery of the target compounds
from inexpensiVe and commercial starting materials. Mini-
mal use of protecting group chemistry would also be a feature
of the route and we would be happy to synthesize mixtures
of diastereoisomeric products at this stage, provided separa-
tion could be achieved, because small libraries of sugar
analogues would then become available. We therefore sought
the execution of syntheses illustrative of each class of
proposed analogue.
Scheme 1. Retrosynthetic Analysis
We previously10 used phase-transfer-catalyzed allylation
or Falck’s Mitsunobu procedure11 to prepare the ethers, but
allyl ethers 6-8 were synthesized in water by a simple and
scaleable procedure (Scheme 2).
Scheme 2. Synthesis of Allyl Ethers 6-8
Cyclohexene diols (()-3a-5b would be versatile sub-
strates for various stereoselective alkene transformations and
we knew that RCM reactions using the commercial second
generation Grubbs’ catalyst8 14 were likely to tolerate the
two hydroxyl groups in 15-17.9 Reduction of hydroxyketone
11-13 would introduce a third stereogenic center, while the
(3) (a) Singh, R. P.; Shreeve, J. M. Synthesis 2002, 2561. (b) Dax, K.;
Albert, M.; Ortner, J.; Paul, B. J. Carbohydr. Res. 2000, 327, 47. (c) Dax,
K.; Albert, M.; Ortner, J.; Paul, B. J. Curr. Org. Chem. 1999, 3, 287.
(4) (a) Ellaghdach, A.; Echarri, R.; Matheu, M. I.; Barrena, M. I.;
Castillon, S.; Garcia, J. J. Org. Chem. 1991, 56, 4556. (b) Barrena, M. I.;
Matheu, M. I.; Castillon, S. J. Org. Chem. 1998, 63, 2184. (c) Aghmiz, M.
L.; Diaz, Y.; Jana, G. H.; Matheu, M. I.; Echarri, R.; Castillon, S.; Jimeno,
M. L. Tetrahedron 2001, 57, 6733.
(5) For synthesis of 2-deoxy-2,2-difluoro species, see: (a) Boehm, M.
F.; Prestwich, G. D. Tetrahedron Lett. 1988, 29, 5217. (b) Sawyer, D. A.;
Potter, B. V. L. Bioorg. Med. Chem. Lett. 1991, 1, 705. (c) Sawyer, D. A.;
Potter, B. V. L. J. Chem. Soc., Perkin Trans. 1 1992, 923. (d) Zhai, H. X.;
Ping-Sheng, L.; Morris, J. C.; Mensa-Wilmot, K.; Shen, T. Y. Tetrahedron
Lett. 1995, 36, 7403.
We were able to prepare 1 mol batches of the volatile
ethers 6 (99%) and 7 (87%), which were won from the
reaction mixture in a separating funnel and redistilled directly
from calcium hydride to ensure dryness. Less volatile ether
8 was prepared in the same way (81%), but on a smaller
scale, from a known chloride, and isolated following an
extractive workup.12
Ether 6 underwent dehydrofluorination/metalation at low
temperature (n-butyllithium at -100 °C) to deliver the crude
acrolein adducts (on the basis of 19F NMR evidence), which
proved volatile and extremely difficult to handle. Also, there
was significant contamination of the products with hept-1-
en-3-ol, formed by the direct addition of n-butyllithium to
acrolein. This side reaction highlights the problems involved
(6) For synthesis of 5-deoxy-5,5-difluoro species, see: Jiang, C.;
Schedler, D. J. A.; Morris, P. E.; Zayed, A. H. A.; Baker, D. C. Carbohydr.
Res. 1990, 207, 277.
(7) (a) Morris, J. C.; Ping-Sheng, L.; Zhai, H. X.; Shen, T. Y.; Mensa-
Wilmot, K. J. Biol. Chem. 1996, 271, 15468. (b) Morris, J. C.; Ping-Sheng,
L.; Zhai, H. X.; Shen, T. Y.; Mensa-Wilmot, K. Biochem. Biophys. Res.
Commun. 1998, 244, 873. For related species, see (c) Lampe, D.; Liu, C.;
Mahon, M. F.; Potter, B. V. L. J. Chem. Soc., Perkin Trans. 1 1996, 1717.
(d) Kozikowski, A. P.; Fauq, A. H.; Wilcox, R. A.; Nahorski, S. R. Bioorg.
Med. Chem. Lett. 1995, 5, 1295. (e) Rich, R. H.; Lawrence, B. M.; Bartlett,
P. A. J. Org. Chem. 1994, 59, 693. (f) Jiang, S.; Singh, G.; Boam, D. J.;
Coggins, J. R. Tetrahedron: Asymmetry. 1999, 10, 4087. (g) Eguchi, T.;
Sasaki, S.; Huang, Z.; Kakinuma, K. J. Org. Chem. 2002, 67, 3979. For a
recent review fluorinated cyclitol analogues as probes, see: (h) Schedler,
D. J. A.; Baker, D. C. Carbohydr. Res. 2004, 339, 1585.
(8) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron
Lett. 1999, 40, 2247.
(9) For strong direct precedents, see: (a) Ackermann, L.; El Tom, D.;
Furstner, A. Tetrahedron 2000, 56, 2195. (b) Hyldtoft, L.; Madsen, R. J.
Am. Chem. Soc. 2000, 122, 8444. (c) Conrad, R. M.; Grogan, M. J.; Bertozzi,
C. R. Org. Lett. 2002, 4, 1359. (d) Heo, J. N.; Holson, E. B.; Roush, W. R.
Org. Lett. 2003, 5, 1697.
(10) (a) Garayt, M. R.; Percy, J. M. Tetrahedron Lett. 2001, 42, 6377.
For other examples of the dehydrofluorination/metalation approach, see:
(b) Nakai, T.; Tanaka, K.; Ishihawa, N. Chem. Lett. 1976, 1263. (c)
Ichikawa, J.; Sonoda, T.; Kobayashi, H. Tetrahedron Lett. 1989, 30, 6379.
(d) Patel, S. T.; Percy, J. M.; Wilkes, R. D. Tetrahedron 1995, 51, 9201.
(e) Howarth, J. A.; Owton, W. M.; Percy, J. M.; Rock, M. H. Tetrahedron
1995, 51, 10289. (f) Harrington, P. E.; Tius, M. A. J. Org. Chem. 1999,
64, 4025. (g) See Cox, L. R.; DeBoos, G. A.; Fullbrook, J. J.; Percy, J. M.;
Spencer, N. S.; Tolley, M. Org. Lett. 2003, 5, 337 for applications of
dehydrofluorination/metalation methodology in asymmetric synthesis.
(11) Falck, J. R.; Yu, J.; Cho, H.-S. Tetrahedron Lett. 1994, 35, 5997.
(12) (a) Audouard, C.; Garayt, M. R.; Ke´roure´dan, E.; Percy, J. M.; Yang,
H. submitted to J. Fluorine Chem. (b) The study was based on the seminal
preliminary publication by Metcalf and co-workers: Metcalf, B. W.; Jarvi,
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