or F-TEDA-BF4) to give a 2:1 mixture of chromatographi-
cally inseparable trans- and cis-2-fluoro-5-tert-butylcyclo-
pentanones (5/6).7 The ratio of 5 to 6 can be increased to
4:1 by equilibrium using 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU). The 2:1 mixture of fluoroketones was exposed to
buffered m-chloroperbenzoic acid (m-CPBA) to give the
chromatographically separable trans- and cis-6-tert-butyl-
3-fluorotetrahydrapyran-2-ones (7) and (8) in 42 and 22%
yield, respectively. The stereochemical assignments for 7 and
8 are based on both proton NMR data (H-3 of 7 appears as
a ddd with J ) 47.1, 10.6, and 6.3 Hz, whereas in 8 it is a
dt with J ) 47.5 and 5.8 Hz) and fluorine NMR data (F of
7 appears as a dt with J ) 47.4 and 11.0 Hz, while in 8 it
is a ddd with J ) 47.6, 20.3, and 11.3 Hz).
Figure 2. Structures of 6-tert-butyltetrahydropyranosyl)oxyethyl
radicals.
At this point, the fluorinated chiral auxiliaries were ready
to be attached to our standard radical precursor, (S)-methyl
lactate (Scheme 2). The sequence began with the low-
we originally used to form the mixed acetal radical precursor
(dehydrative condensation of a hydroxyester with the lactol)
required heating in the presence of a large excess of alcohol.
Furthermore, the tBu-THP ether was somewhat prone to acid-
catalyzed hydrolytic degradation. Neither of these problems
would be amenable to our envisioned polymer-supported
strategy. This led us to consider the use of milder glycosy-
lation conditions as well as the introduction of an electrone-
gative fluorine atom at C-3, a well-known tactic that had
been used to stabilize analogous 2-deoxyglycosides.3 We now
report the synthesis and use of two new fluorinated “chiral
auxiliary donors” for hydroxyalkyl radicals (see 2b and 2c
in Figure 1).4
Scheme 2. Attachment of Chiral Auxiliaries to the Radical
Precursor
Our synthesis of the racemic5 auxiliaries began (Scheme
1) by converting the known 2-tert-butylcyclopentanone6 to
Scheme 1. Synthesis and Separation of Fluorinated Lactones
temperature DIBAL reduction of the lactones 7 and 8 to give
the lactols 9 and 13 in quantitative yield. Lactols 9 and 13
were then transformed into the trichloroacetamidates 10 and
14, respectively, by application of the standard Schmidt
conditions (Cl3CCN + DBU).8
These fluorinated “chiral auxiliary donors” were coupled
to (S)-methyl lactate (1.1 equiv) in the presence of TMSOTf
-20 °C to give good yields of the R-lactates 11 and 15.9
None of the corresponding â-lactates were detected in these
reactions. It should be noted that Schmidt glycosylation has
been performed using polymer supported alcohol acceptors.10
Therefore, this methodology will be applicable to our
projected polymer-supported radical homologations. Saponi-
fication of these esters proceeded uneventfully to give the
corresponding carboxylic acids 12 and 16 quantitatively.
These carboxylic acids were relatively stable compounds (no
decomposition after 3 months storage in refrigerator) as a
consequence of the fluorine substituent’s effect on acetal
stability.
the less substituted trimethylsilyl enol ether 4 (TMSOTf +
Et3N) followed by exposure to Selectfluor (1-chloromethyl-
4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate)
(3) (a) Withers, S. G.; MacLennan, D. J.; Street, I. P. Carbohydr. Res.
1986, 154, 127. We thank Prof. David Crich (UIC) for bringing this work
to our attention. (b) We were originally inspired by Fried’s use of fluorine
substitution to stabilize the very labile thromboxane A2 nucleus. See: Fried,
J.; Hallinan, E. A.; Szwedo, M. J. J. Am. Chem. Soc. 1984, 106, 3871.
(4) We recently reported a camphor-derived chiral auxiliary for hydroxy-
alkyl radicals that also incorporated an analogous fluorinated THP unit into
its structure. However, the diastereofacial selectivity observed with this
auxiliary was only modest (ds e 4.5:1 at -78 °C) due to geometrically
induced distortion of the THP ring from an ideal chair conformation. See:
Garner, P.; Sesenoglu, O.; Burgoon, H. Tetrahedron: Asymmetry 2003,
14, 2883.
(5) Racemic 2-tert-butylcyclopentanone was used in this preliminary
feasibility study. The individual enantiomers are available via kinetic
resolution: Mori, A.: Yamamoto, H. J. Org. Chem. 1985, 50, 5446.
(6) (a) Chan, T. H.; Paterson, I.; Pinsonnault, J. Tetrahedron Lett. 1977,
4183. (b) Reetz, M. T.; Maier, W. F. Angew. Chem., Int. Ed. Engl. 1978,
17, 48.
(7) Lal, G. S. J. Org. Chem. 1993, 53, 2791.
(8) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212.
(9) Albert, M.; Paul, B. J.; Dax, K. Synlett 1999, 1483.
(10) Seeberger, P. H.; Haase, W.-C. Chem. ReV. 2000, 100, 4349.
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Org. Lett., Vol. 6, No. 8, 2004