An asymmetric Kharasch reaction mediated by D-xylose: Long range diastereocontrol

Article abstract of DOI:10.1016/S0040-4039(03)00756-1

An asymmetric Kharasch-type atom transfer reaction was studied under 13 different sets of reaction conditions in order to obtain the highest levels of diastereoselection. The highest ratio of 12.5:1 (71%) was observed at low temperatures (-78°C) using the Lewis acid Eu(OTf)₃. Because the new asymmetric center is so distant from the D-xylose, we propose a transition state involving two sugars. The conversion of the major product to a naturally occurring chiral γ-butyrolactone, under basic conditions, is described which also confirmed the diastereoselectivity and absolute stereochemistry of the Kharasch reaction.

Full text of DOI:10.1016/S0040-4039(03)00756-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3763–3765
An asymmetric Kharasch reaction mediated by
long range diastereocontrol
D-xylose:
Eric J. Enholm* and Ashwin Bhardawaj
Department of Chemistry, University of Florida, Gainesville, FL 32611, USA
Received 28 January 2003; revised 18 March 2003; accepted 21 March 2003
Abstract—An asymmetric Kharasch-type atom transfer reaction was studied under 13 different sets of reaction conditions in order
to obtain the highest levels of diastereoselection. The highest ratio of 12.5:1 (71%) was observed at low temperatures (−78°C) using
the Lewis acid Eu(OTf)3. Because the new asymmetric center is so distant from the
D-xylose, we propose a transition state
involving two sugars. The conversion of the major product to a naturally occurring chiral g-butyrolactone, under basic conditions,
is described which also confirmed the diastereoselectivity and absolute stereochemistry of the Kharasch reaction. © 2003 Elsevier
Science Ltd. All rights reserved.
Free radical reactions involving atom transfer were
studied by Kharasch many years ago as shown in
Scheme 1.1 Related efforts, particularly from Curran
and others, have expanded on this work and led to a
better understanding of atom transfer reactions in gen-
eral.2 Chiral versions of the Kharasch reaction are
particularly scarce, however, Porter and co-workers
have performed interesting experiments on these reac-
tions using a chiral oxazolidinone auxiliary.3 In this
letter, we will describe our results in this area using an
Particularly helpful in this newer Kharasch atom trans-
fer reaction is the ability to run the reaction at lower
temperatures. Thus, the potential for good diastereose-
lectivity in the introduction of the bromide was possible
with some reasonable experimental design.
In our design it was recognized that the ester function
represents a good functionality for the introduction of a
removable chiral auxiliary. In these transformations, we
wanted to study the asymmetric variation of this reac-
inexpensive
D-xylose carbohydrate as an auxiliary that
tion by using
D-xylose as a chiral auxiliary for the
produced ratios varying from a low diastereoselectivity
of 1.5:1 to a potentially synthetically useful 12.5:1.4 The
modern version of this radical transformation, shown
in Scheme 2, represents a more useful and successful
variation of the classic Kharasch reaction, in part due
to the use of an electrophilic a-bromo ester and a Lewis
acid.3
chiral R* as shown in Scheme 2. Particularly concern-
ing was the long-range distance of several atoms from
the controlling C-3 carbon on D-xylose not just in a free
radical reaction but any asymmetric induction over that
span. To the best of our knowledge, this is also the first
example of any sugar auxiliary used in a Kharasch
reaction.
Scheme 1.
Keywords: free radical; diastereoselective; atom transfer; Kharasch
reaction.
* Corresponding author.
Scheme 2.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00756-1

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E. J. Enholm, A. Bhardawaj / Tetrahedron Letters 44 (2003) 3763–3765
Table 1. Conditions for the Kharasch reaction
Lewis acid
Temp. (°C) Solvent
d.e.b
Yield (%)c
Eu(OTf)3
ZnCl2
Yb(OTf)3
Zn(OTf)2
Yb(OTf)3
ZnCl2
25
25
25
25
0
0
0
0
−78
−78
−78
−78
−78
CH2Cl2
1.7:1
56
67
63
57
62
56
62
65
70
52
56
65
71
CH2Cl2/THFa
CH2Cl2
1.6:1
1.7:1
1.5:1
2.2:1
2.5:1
1.5:1
2.8:1
7.3:1
3.3:1
3.0:1
4.1:1
12.5:1
CH2Cl2/THF
CH2Cl2
CH2Cl2/THF
CH2Cl2/THF
CH2Cl2
MgBr2
Eu(OTf)3
Eu(OTf)3
ZnCl2
MgBr2
Yb(OTf)3
Eu(OTf)3
Ether
CH2Cl2/THF
CH2Cl2/THF
CH2Cl2
CH2Cl2
a A mixture of solvents was used for solubility.
b d.e. measured by gas chromatography.
c Yields are for isolated materials.
in one case (7.3:1) to dichloromethane (12.5:1). The
diethylether oxygen (Lewis base) ties up the Eu(OTf)3
while access to the carbonyl is much better in CH2Cl2.
Reactions under Kharasch conditions with 1-hexene
and no Lewis acid did not produce any of the expected
product 8 and no reaction was observed. We concluded
that an external Lewis acid is critical to the outcome of
the reaction; subsequently all the examples worked well
when one was added. When one considers that the
bromide is several atoms removed from the nearest
asymmetric center, the 12.5:1 ratio with Eu(OTf)3 in
CH2Cl2 was very gratifying.7
Scheme 3.
Our synthesis of the xylose auxiliary, shown in Scheme
3, begins by treatment of 5 with acetone and 2,2-
dimethoxypropane to form the 1,2:3,5-diacetonide as a
crystalline solid in 90% yield, followed by selective
deprotection of the 3,5-acetonide with acetic acid (70%
aq.) constructing diol 6 in 70% yield. Selective protec-
tion of the primary C-5 hydroxyl as its benzyl ether
(60% yield) and esterification with bromoacetic acid
gave 7 (89% yield) as the key starting compound for the
asymmetric Kharasch reactions examined here.
To confirm the stereochemistry of the major
diastereomer 8, it was cleaved with base along with
concurrent cyclization of the acid to the naturally
occurring chiral S-g-butyrolactone 9.8 This lactone is
ubiquitous and found in a number of natural fruit
flavors such as apricots, peaches and strawberries.
Clean closure by SNi backside displacement of the
bromide from the reaction producing 8 in 12.5:1 ratio
constructed 9 in 74% e.e. in our best attempt (Scheme
4).
The Kharasch reaction we are investigating involves a
type of Lewis acid complexation that also appears to
accelerate many examples of other radical reactions.5
This occurs by weakening the CꢀBr bond or increasing
the electrophilic nature of the radical. Researchers have
found that a CꢀBr bond next to a carbonyl, as in 7, is
weakened by chelation with a Lewis acid.3 Others6 have
also studied this bond-weakening effect suggesting that
the carbonyl function destabilizes the CꢀBr bond dipole
in the parent compound. This effect makes the parent
species less stable than the radical formed from it.
Thus, a carbon bearing a bromine (CHBr) is a weaker
bond when placed adjacent to a metal-chelated car-
bonyl function.
Although we do not yet have a complete explanation
for the origin of the diastereoselection, the delivery of
the bromide from chiral bromoester 7 to 10, the radical
derived from 8, may resemble that depicted in Figure 1.
The possibility shows the two metal-coordinated sugar
species in delivery of the bromide to the radical. Lewis
acid M likely draws the bromide close to the intermedi-
ate radical species in an intramolecular-like internal
delivery.
In an attempt to improve the diastereoselectivity of the
reaction, more than 13 different sets of conditions were
examined for the Kharasch reaction of 7“8, as summa-
rized in Table 1. Temperatures at or above 0°C gave
ratios that were not over 3:1. The reactions at −78°C
were somewhat improved in d.e., while the best results
were observed using Eu(OTf)3 as a Lewis acid. The
solvent gave some variation in ratios comparing ether
Scheme 4.

E. J. Enholm, A. Bhardawaj / Tetrahedron Letters 44 (2003) 3763–3765
3765
3. (a) Mero, C. L.; Porter, N. A. J. Am. Chem. Soc. 1999,
121, 5155–5160; (b) Feng, H.; Kavrakova, I. K.; Pratt, D.
A.; Tellinghuisen, J.; Porter, N. A. J. Org. Chem. 2002, 67,
6050–6054.
4. See for example: (a) Enholm, E. J.; Cottone, J. S.; Allais,
F. Org. Lett. 2001, 3, 145–147; (b) Enholm, E. J.; Gal-
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5. (a) Guindon, Y.; Yoakim, C.; Lemieux, R.; Boisvert, L.;
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2845; (b) Guindon, Y.; Lavallee, J.-F.; Llinas-Brunet, M.;
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Org. Chem. 1996, 61, 6090; (h) Sibi, M. P.; Ji, J. Angew.
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Figure 1. Transition state for 7“8.
With non-bonded conformational preferences becoming
important now. It should be noted that M probably has
several other unknown sites of lone-pair polydentate
interactions with both molecules. Molecular models
indicate that the two sugars easily sandwich the reac-
tion with one directly on top of the other. Because both
sugars must be involved in this bromine atom transfer,
the long distance from the controlling asymmetric cen-
ter in 10, may be just part of the picture in addition to
how the two xylose sugars have nonbonded interactions
and fit together.9
6. Clark, K. B.; Wayner, D. D. M. J. Am. Chem. Soc. 1991,
113, 9363–9365.
In conclusion, an asymmetric Kharasch-type atom
transfer reaction was studied to obtain the highest
levels of diastereoselection. The highest ratio of 12.5:1
(71%) was observed at low temperatures (−78°C) using
the Lewis acid Eu(OTf)3. Because the new asymmetric
7. For longer range acyclic diastereoselective radical reac-
tions, see: (a) Sibi, M. P.; Johnson, M. D.; Punniya-
murthy, T. Can. J. Chem. 2001, 79, 1546–1555; (b) Sibi,
M. P.; Manyem, S. Tetrahedron 2000, 56, 8033–8061; (c)
Sibi, M. P.; Ji, J.; Sausker, J. B.; Jasperse, C. P. J. Am.
Chem. Soc. 1999, 121, 7517–7526; (d) Sibi, M. P.; Porter,
N. A. Acc. Chem. Res. 1999, 32, 163–171; (e) Renaud, P.;
Gerster, M. Angew. Chem., Int. Ed. Engl. 1998, 37, 2562–
2579; (f) Porter, N. A.; Feng, H.; Kavrakova, I. K.
Tetrahedron Lett. 1999, 40, 6713–6716; (g) Wu, J. H.;
Radinov, R.; Porter, N. A. J. Am. Chem. Soc. 1995, 117,
11029–11030.
center is six atoms away from the
D-xylose, we pro-
posed a transition state involving two sugars. The
conversion of the major product to a naturally occur-
ring chiral S-g-butyrolactone, confirmed the absolute
stereochemistry of the Kharasch reaction.
Acknowledgements
8. (a) Yadav, J.; Manivan, P. P. Synth. Commun. 1993, 23,
2731–2741; (b) Ravid, U.; Silverstein, R. M.; Smith, L. R.
Tetrahedron 1978, 34, 1449–1452.
We gratefully acknowledge support by the National
Science Foundation (grant CHE-0111210) for this
work.
9. Selected spectral data. Bromoester 7: 1H NMR 7.30 (m,
5H), 6.00 (d, 1H, J=3.5), 4.71 (d, 1H, J=11.9), 4.60 (d,
1H, J=3.5), 4.45 (d, 1H, J=11.9), 4.43–4.34 (m, 3H), 3.81
(s, 2H), 3.69 (m, 1H), 1.45 (s, 3H), 1.31 (s, 3H); 13C NMR
l 167.3, 137.3, 128.8, 128.4, 128.1, 112.2, 105.5, 82.3, 81.7,
References
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76.9, 72.1, 64.1, 41.0, 27.0, 26.5. Bromoester 8: H NMR
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(CDCl3, 300 MHz) l 7.30 (m, 5H), 5.98 (d, 1H, J=3.8),
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82.3, 81.8, 78.3, 72.1, 62.6, 57.3, 39.2, 34.1, 32.4, 29.9, 27.0,
26.5, 22.3, 14.1.