As in the reactions of crotyl derivative 1a, performing the
reactions of 1b and 1c at -78 °C significantly improved
the diastereoselectivity. Furthermore, acceptable levels of
selectivity were obtainable even at 0 °C using our fluorous
oxazolidinone, in contrast to the Evans auxiliary with which
cryogenic conditions were necessary.16
The diastereomers of the conjugate addition products 2a-c
were separated using HPLC. In each case, the new stereo-
center in the major diastereomer had the R configuration.
This was determined by hydrolysis of the addition products
2a-c to give the known carboxylic acids 4a-c17 (Scheme
1). The observed stereochemistry represents radical addition
nonfluorous chiral auxiliaries. The oxazolidinone derived
from norephedrine18 was selected as the nonfluorous candi-
date, as a result of its similar syn-4,5 substitution pattern.
The N-cinnamoyl and N-monoethyl fumarate derivatives 6a
and 6b were synthesized and alkylated at 0 °C under the
same conditions employed for the fluorous oxazolidinones
1a-c (Table 3).
Table 3. Radical Conjugate Addition Using Norephedrine
Derivativesa
Scheme 1
entry
compound
yield (%)b
ratioc
1
2
7a
7b
82
87
1.7:1
1.3:1
a Lewis acid (2 equiv), i-PrI (10 equiv), Bu3SnH (5 equiv), Et3B (10
equiv), O2, THF/CH2Cl2 (1:4), 0 °C, 2 h. b Isolated yield. c Diastereomer
1
ratios were determined by H NMR at 500 MHz.
from the less hindered face of the alkene, which is consistent
with the behavior of other oxazolididone chiral auxiliaries
under similar conditions. 3a,12
Both fluorous and norephedrine compounds were purified
using the combination of silica and fluorous solid phase
extractions described above. The total tin content was
measured after each stage using atomic absorption spectros-
copy (Table 4).
Following FSPE cleanup of the products, no further
purification was necessary, even when a large excess (5
equiv) of tributyltin hydride was present. This was encourag-
ing, as alkyltin species are typically very difficult to remove
from reaction products. Curran et al. have shown that
fluorous alkyltin compounds are effectively removed from
organic materials by fluorous liquid-liquid extraction.8a This
method provides a complementary technique to the work
previously reported by Curran, allowing the selective extrac-
tion of reaction products, as opposed to capture of undesirable
reagents.
Table 4. Residual Tin in Samplesa
silica pad
(% w/w)
FSPE
(% w/w)
flash column
(% w/w)
entry
compound
1
2
3
4
2a
2b
7a
7b
3.7
6.4
6.6
4.5
0.054
0.070
6.6b
The effectiveness of the FSPE technique was evaluated
quantitatively by measuring the residual tin content of the
crude reaction products obtained from both fluorous and
0.013
0.023
4.5b
a Determined by atomic absorption spectroscopy. b Material was not
retained on FSPE cartridge and isolated in 7:3 MeOH/H2O wash.
(8) (a) Curran, D. P.; Hadida, S.; Kim, S.-Y.; Luo, Z. J. Am. Chem. Soc.
1999, 121, 6607. (b) Curran, D. P.; Hadida, S. J. Am. Chem. Soc. 1996,
118, 2531. (c) Crombie, A.; Kim, S.-Y.; Hadida, S.; Curran, D. P. Org.
Synth. 2003, 79, 1.
(9) Hein, J. E.; Hultin, P. G. Synlett 2003, 635.
(10) Soloshonok, V. A.; Ueki, H.; Jiang, C.; Cai, C.; Hruby, V. J. HelV.
Chim. Acta 2002, 85, 3616.
(11) Fluorous oxazolidinone 5 was synthesised from L-phenylalanine
using a modification of a procedure previously reported. See ref 9 for details.
(12) Sibi, M. P.; Ji, J.; Sausker, J. B.; Jasperse, C. P. J. Am. Chem. Soc.
1999, 121, 7517.
(13) FluoroFlash silica gel was obtained from Fluorous Technologies,
Inc. and has a perfluorooctylethylsilyl (C8F17CH2CH2Si) bonded phase.
(14) For details, see Supporting Information.
The first stage using standard silica gel gave similar results
for all compounds, leaving behind between 3.7% and 6.6%
tin by weight. The products of this process were then
subjected to FSPE. Table 4 shows that FSPE is very effective
at removing alkyltin species from fluorous materials, while
nonfluorous substances coeluted with the alkyltin com-
pounds. It is also evident that the fluorous solid phase is not
sequestering alkyltin species (entries 1, 2 vs 3, 4). To remove
the excess tin from the norephedrine derivatives, a third flash
chromatography step was required. The FSPE purification
(15) Sibi, M. P.; Manyem, S. Org. Lett. 2002, 4, 2929.
(16) Isopropyl radical addition to crotonate derived from 4-benzyl-
oxazolidin-2-one using ytterbium triflate as a Lewis acid proceeds with
2:1 diastereoselectivity. See ref 12 for details.
(17) Absolute configuration determined by chemical correlation to
literature results. 4a, (R)-3,4-Dimethylpentanoic acid: Enders, D.; Ren-
denbach, B. E. M. Tetrahedron 1986, 42, 2235. 4b, (R)-3-Phenyl-4-
methylpentanoic acid: Sibi, M. P.; Ji, J.; Wu, J. H.; Gu¨rtler, S.; Porter, N.
A. J. Am. Chem. Soc. 1996, 118, 9200. 4c, (R)-2-isopropylsuccinic acid:
Lawston, I. W.; Inch, T. D. J. Chem. Soc., Perkin Trans. 1 1983, 2629.
(18) The oxazolidinone was synthesized from (-)-(1R,2S)-norephedrine
using triphosgene by adapting the reported procedure by Sibi et al. See:
Sibi, M. P.; Rutherford, D.; Renhowe, P. A.; Li, B. J. Am. Chem. Soc.
1999, 121, 7509. See Supporting Information section for details.
Org. Lett., Vol. 7, No. 13, 2005
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