Aldehyde-alkene cyclizations via O-stannyl ketyl radicals using sugars as chiral auxiliaries

Article abstract of DOI:10.1016/j.tetasy.2003.07.006

This investigation illustrates the utility of two inexpensive carbohydrate derivatives as sources of asymmetry for aldehyde-alkene radical cyclizations. Diastereomeric ratios as high as 9:1 were achieved with an ester-appended (+)-isosorbide and 100:1 for

Full text of DOI:10.1016/j.tetasy.2003.07.006

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2871–2874
Aldehyde–alkene cyclizations via O-stannyl ketyl radicals using
sugars as chiral auxiliaries
Eric J. Enholm,* Florent Allais and Sebastian Bareyt
Department of Chemistry, University of Florida, Gainesville, FL 32611, USA
Received 13 June 2003; accepted 25 July 2003
Abstract—This investigation illustrates the utility of two inexpensive carbohydrate derivatives as sources of asymmetry for
aldehyde–alkene radical cyclizations. Diastereomeric ratios as high as 9:1 were achieved with an ester-appended (+)-isosorbide and
100:1 for (+)-isomannide. Temperature dependence, Lewis acids and solvents were all examined.
© 2003 Elsevier Ltd. All rights reserved.
For more than 20 years tributyltin hydride (nBu3SnH)
has been used in a wide diversity of free radical cycliza-
tion reactions.1 Almost all free radical reactions use
nBu3SnH with halides and other precursors to obtain a
carbon-centered radical, which, upon cyclization with
an alkene, result in a net loss of both functions in the
end. We have actively reported on studies directed
towards the use of O-stannyl ketyls in synthesis.2 This
interest began with simple carbonyl-alkene coupling
reactions3a and tandem cyclizations3c using these poten-
tially useful intermediates. Although there is still much
to be learned, O-stannyl ketyl radical anions differs
markedly from other radicals because (1) they have an
inherent nucleophilic/anionic component to their prop-
erties, (2) they are more stable and less reactive due to
resonance, and (3) they produce a useful alcohol func-
tion after the reaction.3e
Recently, the diastereoselectivity of free radical reac-
tions has been greatly enhanced due to the use of a
combination of Lewis acids and appended chiral auxil-
iaries, scaffolds, and templates.4a Similar O-stannyl
ketyl-mediated reactions have not been studied.3 This
investigation examined, for the first time, two carbohy-
drate derivatives as chiral auxiliaries for aldehyde–
alkene radical cyclizations with a Lewis acid at low
temperatures (−78°C) with tributyltin hydride, as
shown in Scheme 1.
racemic stereogenic centers are formed in this reaction,
raising the possibility for four different stereoisomers to
result in 2. Thus, product mixtures have the potential to
be complex. Second, the controlling asymmetric center
in either (+)-isosorbide 3 or (+)-isomannide 4 is a
distance of 5–6 atoms away from the newly formed
stereogenic centers in 2. Asymmetric synthesis over this
span of atoms clearly has the potential to reduce
diastereoselectivity. On the other hand, it is beneficial
that both carbohydrate precursors are highly oxy-
genated and provide multiple sites for metal chelation.
This oxophilicity for Lewis acids was a key and desir-
able trait in selecting these auxiliaries. We were pleased
to obtain diastereomeric ratios as high as 9:1 for 1“2
with ester-appended (+)-isosorbide 3 and 100:1 for (+)-
isommanide 4.
A preliminary study of the diastereoselectivity of the
cyclization without any chiral appendage was first
Note that there are two challenging problems to over-
come in this transformation. First, two new non-
* Corresponding author. E-mail: enholm@chem.ufl.edu
Scheme 1.
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.07.006

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E. J. Enholm et al. / Tetrahedron: Asymmetry 14 (2003) 2871–2874
Table 1. Ratios of 6:7
Entry
Lewis acid
Solvent
Temp. (°C)
% Yieldb
6:7c
1.1:1
1.8:1
3:1
1a
2
3
4
5
None
None
None
None
MgBr2–OEt2
CuOTf
ZnCl2
Benzene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2–ether
CH2Cl2
CH2Cl2–ether
80
20
0
−78
−78
−78
−78
97
70
58
30
83
98
90
7:1
>100:1
>100:1
>100:1
6
7
a AIBN was used as an initiator in entry 1; all other entries used BEt3 and O2.
b Isolated yields for material judged to be pure.
c Ratios determined by capillary GC.
examined. Previous studies had indicated that 6 should
be favored in the reaction at 80°C, where the
appendages avoid each other in the transition state.3a
The studies are summarized in Table 1.
trans-Alcohol 6 was the major product in every reac-
tion and, unlike 7, it cannot spontaneously close to a
Scheme 2.
bicyclic lactone due to high strain.5 Without the use of
Lewis acids in entries 1–4, the ratios gradually
improved as the temperature was lowered to −78°C. In
entry 4, we obtained a 7:1 ratio as the best attempt.
Yields and ratios favoring
6 were dramatically
improved with the addition of Lewis acids in entries
5–7. The minor cis-lactone 7 could only be observed in
trace quantities here. The use of Lewis acid-mediated
reactions gave ratios up to >100:1 in all cases (Scheme
2).
We next decided to prepare chiral auxiliaries of 1 with
either ester-appended sugar 3 or 4. Chiral cyclization
precursors 12 and 13 (Scheme 4) were to be constructed
via a Wittig reaction and the remaining framework was
to be assembled via an unsaturated chiral ester and an
aliphatic aldehyde. Starting monobenzyl ethers 8 and
10 prepared from 3 and 4 by standard treatment with
benzyl bromide (1 equiv.), were used in Scheme 3. The
remaining hydroxyl in each sugar was converted to a
stabilized ylide by treatment with chloroacetic anhy-
dride and pyridine, followed by triphenylphosphine and
aqueous base. The Wittig reagents 9 and 11 were then
coupled with freshly distilled glutaraldehyde to con-
struct the chiral precursors 12 and 13, respectively, as
shown in Scheme 4.
Scheme 3.
Once the a,b-unsaturated ester of each carbohydrate
derivative had been synthesized, various reaction condi-
tions for radical cyclizations were explored. The four
different aldehyde–alkene products that can result from
the cyclization of 12 are shown in Scheme 5. The
conditions for the cyclizations we studied are summa-
rized in Table 2. At 80°C, AIBN was used as a radical
initiator; however, triethylborane and oxygen were uti-
lized for the lower temperature studies. The lactones
15a and 15b were usually formed in smaller amounts, a
trend we noticed in the cyclization of less complex
compound 5. Without a Lewis acid, the diastereomer
ratios for 14a:14b were very low, ranging from 1:1 to
1.1:1. When certain Lewis acids were employed,
Scheme 4.
diastereomeric ratios increased. Among the most suc-
cessful of the Lewis acids studied, zinc chloride proved
to be the most effective for isosorbide chiral scaffold 12
with diastereomeric values of 9:1 in entry 6 in Table 2.6
The radical cyclization of isomannide adduct 13 proved
to be even more successful and differed from 12 only by
the stereochemistry of a single hydroxyl. The four
different products that can result from the cyclization
of 13 are shown in Scheme 6. The conditions for the

E. J. Enholm et al. / Tetrahedron: Asymmetry 14 (2003) 2871–2874
2873
Scheme 5.
Scheme 6.
cyclizations we studied are summarized in Table 3.
Similar to Table 1, much improvement in
diastereomeric ratios with Lewis acids were observed
for these cyclizations too. In general, the ratios were
much higher in the case of 13 versus 12. Isomannide
gave a very high diastereomeric ratio of 100:1 for
16a:16b with three different Lewis acids, including,
ZnCl2, MgBr2–OEt2, and CuOTf.
Once the diastereomeric ratios of each reaction set had
been determined, elucidation of the absolute stereo-
chemistry of the major diastereomer was achieved by
chemical correlation as shown in Scheme 7. Major
isomer 16a8 from the radical cyclization of isomannide
derivative 13 in presence of ZnCl2 (entry 4, Table 3)
was saponified and esterified, affording chiral methyl
ester 17 with a specific rotation of +43.1. The specific
rotation of 17 is known (+43.1).9 The same process was
done with 14a,6 the major isomer from the cyclization
of the isosorbide adduct (entry 6, Table 2). A similar
specific rotation +43.0 was obtained after careful chro-
matographic isolation.
For both sugars, lanthanide-based Lewis acids such as
Eu(III) and Yb(III) were uniformly ineffective in
enhancing the diastereoselectivity of the cyclization. In
some cases the lanthanide Lewis acids gave ratios that
were similar to those reactions lacking any added Lewis
acids. This was expected because lanthanide Lewis
acids have demonstrated poor results in a previous
study involving those sugars.7
A proposed working model of the transformation of 13
to 16a using ZnCl2 as a Lewis acid is shown in Scheme
8. The a-disposed benzyloxy function clearly plays a
Table 2. Product ratios from the cyclization of 12
Entry
Lewis acid
Solvent
% Yieldb
14a/14b:15a/15bc
14a:14bc
1a
2
3
4
5
None
None
Eu(OTf)3
MgBr2–OEt2
CuOTf
Benzened
84
40
65
71
70
73
68
2:1
3.3:1
6:1
48:1
48:1
48:1
48:1
1:1
1:1
1.7:1
1.1:1
2.3:1
9:1
e
CH2Cl2
CH2Cl2
CH2Cl2
e
f
f
CH2Cl2
6
7
ZnCl2
Yb(OTf)3
CH2Cl2–THFf
f
CH2Cl2
1.4:1
a AIBN was used as an initiator in entry 1; all other entries used BEt3 and O2.
b Isolated yields for material judged to be pure by 1H NMR.
c Ratios determined by HPLC.
d Run at 80°C.
e Run at 0°C.
f Run at −78°C.
Table 3. Product ratios from the cyclization of 13
Entry
Lewis acid
Solvent
% Yieldb
16a/16b:15a/15bc
16a:16bc
1a
2
3
4
5
None
MgBr2–OEt2
CuOTf
ZnCl2
Yb(OTf)3
Benzened
96
91
89
93
68
100:1
100:1
100:1
100:1
100:1
1:1
100:1
100:1
100:1
2:1
e
CH2Cl2
e
CH2Cl2
CH2Cl2–THFe
e
CH2Cl2
a AIBN was used as an initiator in entry 1; all other entries used BEt3 and O2.
b Isolated yields for material judged to be pure by 1H NMR.
c Ratios determined by HPLC.
d Run at 80°C.
e Run at −78°C.

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E. J. Enholm et al. / Tetrahedron: Asymmetry 14 (2003) 2871–2874
3. For examples of O-stannyl ketyls, see: (a) Enholm, E. J.;
Burroff, J. A. Tetrahedron 1997, 53, 13583–13602; (b)
Enholm, E. J.; Jia, Z. J. Tetrahedron Lett. 1996, 37,
1177–1178; (c) Enholm, E. J.; Jia, Z. J. Journal of Organic
Chemistry 1997, 62, 9159–9164; (d) Enholm, E. J.; Jia, Z.
J. J. Org. Chem. 1997, 62, 5248–5249; (e) Enholm, E. J.;
Moran, K. M. Tetrahedron Lett. 1998, 971–974; (f) Hays,
D. S.; Fu, G. C. J. Org. Chem. 1996, 61, 4–5.
Scheme 7.
4. (a) Murakata, M.; Jono, T.; Mizuno, Y.; Hoshino, O. J.
Am. Chem. Soc. 1997, 119, 11713; (b) Porter, N. A.;
Giese, B.; Curran, D. P. Acc. Chem. Res. 1991, 24, 296
and references cited therein; (c) Renaud, P.; Gerster, M.
Angew. Chem., Int. Ed. 1998, 37, 2562.
5. (a) Kigoshi, H.; Imamura, Y.; Niwa, H.; Yamada, K. J.
Am. Chem. Soc. 1989, 111, 2302; (b) Enholm, E. J.;
Trivellas, A. J. Am. Chem. Soc. 1989, 111, 6463.
Scheme 8.
6. Partial spectroscopic data for 14a: [h]2D5=+125.4 (c 0.1,
1
MeOH); H NMR l 1.21 (m, 1H), 1.58 (m, 2H), 1.71 (m,
role in the reaction because the b-benzyloxy in 12 leads
to decreased diastereoselectivity. The polydentate zinc
metal likely chelates the readily available oxygens with
the isomannide forming a ‘clamshell’ to cup the metal
in place in 18. Using 16b, the aldehyde oxygen points
down and is not readily accessible to the Lewis acid and
cannot partake in the metal chelate.
1H), 1.94 (m, 2H), 2.11 (m, 1H), 2.38 (dd, J=16.5, 7.8
Hz, 1H), 2.41 (ddd, J=16.5, 6.3, 1.0 Hz, 1H), 2.60 (br s,
1H), 3.82 (m, 8H), 4.23 (q, J=6.3 Hz, 1H), 4.81 (t, J=6.3
Hz, 1H), 5.12 (q, J=6.6 Hz, 1H), 7.23 (m, 5H); 13C
NMR (CDCl3) 172.8, 137.2, 128.4, 127.6, 83.3, 79.0, 76.8,
75.5, 74.1, 72.2, 64.9, 64.2, 36.5, 32.0, 30.7, 23.7, 17.2.
7. Enholm, E. J.; Cottone, J. S.; Allais, F. Org. Lett. 2001,
3, 145–147.
In conclusion, O-stannyl ketyl promoted aldehyde-
alkene cyclizations with two appended carbohydrate
derivatives. Diastereomeric ratios as high as 9:1 were
achieved with an ester-appended (+)-isosorbide and
100:1 for (+)-isommanide were observed over a remote
distance from the nearest asymmetric center.10 Temper-
ature dependence, Lewis acids and solvents were all
examined.
8. Partial spectroscopic data for 16a: [h]2D5=+137.6 (c 0.1,
MeOH); 1H NMR l 1.16–1.36 (m, 1H), 1.54–164 (m,
2H), 1.67–1.77 (m, 1H), 1.91–1.99 (m, 2H), 2.03–2.13 (m,
1H), 2.39 (dd, J=16.3, 8.0 Hz, 1H), 2.45 (ddd, J=16.3,
6.1, 1.0 Hz, 1H), 2.51 (br s, 1H), 3.40–4.08 (m, 7H), 3.85
(m, 1H), 4.20 (q, J=6.5 Hz, 1H), 4.85 (t, J=6.4 Hz, 1H),
5.15 (q, J=6.4 Hz, 1H), 7.14 (m, 5H); 13C NMR (CDCl3)
172.0, 137.2, 128.4, 127.6, 82.9, 79.2, 76.4, 75.6, 73.8,
72.2, 65.4, 64.6, 36.1, 31.8, 30.7, 23.5, 16.9 HRMS calcd
for C20H26O6 362.1729, found 362.1747.
Acknowledgements
9. Hashimoto, S.; Miyazaki, Y.; Ikegami, S. Synth. Com-
mun. 1992, 2717–2722.
10. For a review of asymmetric synthesis using remote atom
centers in stereo-communications, see: Mikami, M.;
Shimizu, M.; Zhang, H.-C.; Maryanoff, B. E. Tetra-
hedron 2001, 57, 2917–2951; For longer range acyclic
diastereoselective radical reactions, see: (a) Sibi, M. P.;
Johnson, M. D.; Punniyamurthy, 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.
We gratefully acknowledge support by the National
Science Foundation (grant CHE-0111210) for this
work.
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