Highly diastereoselective 7-endo radical cyclization of ethyl α-methylene-γ-(bromomethyl)dimethylsiloxycarboxylates

Article abstract of DOI:10.1016/j.tetlet.2004.03.188

The 7-endo radical cyclization of (bromomethyl)dimethylsilyl ethers derived from ethyl γ-hydroxy-α-methylenecarboxylates bearing a bulky γ-substituent such as isopropyl, cyclohexyl, and tert-butyl groups in tetrahydrofuran gave preferentially cyclic silyl ethers bearing the ethoxycarbonyl group anti to the γ-substituents in high yields. Treatment of the cyclic silyl ethers with silica gel gave acyclic ethyl γ-hydroxy-α-[2-(hydroxydimethylsilyl)ethyl]carboxylates. The reduction of the cyclization products with DIBAL followed by Tamao oxidation gave the corresponding acyclic triols.

Full text of DOI:10.1016/j.tetlet.2004.03.188

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4329–4332
Highly diastereoselective 7-endo radical cyclization of ethyl
a-methylene-c-(bromomethyl)dimethylsiloxycarboxylates
Hajime Nagano* and Saori Hara
Department of Chemistry, Faculty of Science, Ochanomizu University, Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan
Received 11 March 2004; revised 25 March 2004; accepted 31 March 2004
Abstract—The 7-endo radical cyclization of (bromomethyl)dimethylsilyl ethers derived from ethyl c-hydroxy-a-methylenecarb-
oxylates bearing a bulky c-substituent such as isopropyl, cyclohexyl, and tert-butyl groups in tetrahydrofuran gave preferentially
cyclic silyl ethers bearing the ethoxycarbonyl group anti to the c-substituents in high yields. Treatment of the cyclic silyl ethers with
silica gel gave acyclic ethyl c-hydroxy-a-[2-(hydroxydimethylsilyl)ethyl]carboxylates. The reduction of the cyclization products with
DIBAL followed by Tamao oxidation gave the corresponding acyclic triols.
Ó 2004 Elsevier Ltd. All rights reserved.
Chelation provides a powerful means of controlling the
stereochemistry in acyclic radical reactions.1;2 Recently,
we reported the chelation-controlled 1,3-asymmetric
induction in the radical reactions of c-benzyloxy-a-
methylenecarboxylic acid esters 2 with alkyl iodides
yielding syn-4 with high diastereoselectivity (Scheme
1).3;4 The high syn-selectivitiy is referred to the H-atom
transfer to the outside face of radical center in the
sharply folded seven-membered chelate intermediates
yielding 3.4d;e;5
Br
Mg O
Bn
R2I, n-Bu3SnH
Et3B / O2
Br
Bn
R2
O
O
OEt
Bn
O
R1
CO2Et
R1
CO2Et
MgBr2•OEt2
CH2Cl2, 0 ˚C
R1
2
syn-4
R2
3
OH
R1
CO2Et
γ
α
1
Br
OH
Si
Si
n-Bu3SnH
Et3B / O2
Tamao
oxidation
O
O
R1
OH
R1
CO2Et
R1
CO2Et
CO2Et
7-endo cyclization
anti-7
5
anti-6
Scheme 1.
Keywords: Radical reaction; a-Silyl radical; Solvent effect; 1,3-Asymmetric induction.
* Corresponding author. Tel.: +81-3-5978-5348; fax: +81-3-5978-5715; e-mail: nagano@cc.ocha.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.188

4330
H. Nagano, S. Hara / Tetrahedron Letters 45 (2004) 4329–4332
Si
O
R1
CO2Et
R2
Br
Si
anti-6a–anti-6g
OH
R2
O
i
ii
R1
CO2Et
R1
CO2Et
+
R2
1a–1g
5a–5g
Si
O
R1 = Ph, R2 = H
1a, 5a,
1b, 5b,
1c, 5c,
1d, 5d,
1e, 5e,
1f, 5f,
1g, 5g,
6a
6b
6c
6d
6e
6f
R1
CO2Et
R2 = CH3, R2 = H
R2
R2 = n-C7H15 , R2 = H
R2 = i-Pr, R2 = H
R1 = c-C6H11, R2 = H
R2 = t-Bu, R2 = H
R1 = Ph, R2 = Me
syn-6a–syn-6g
6g
Scheme 2. Reagents and conditions: (i) BrCH2Si(Me)2Cl (1.3 equiv), DMAP (0.1 equiv), Et3N (1.1 equiv), CH2Cl2, 0 °C; (ii) n-Bu3SnH (2 equiv),
Et3B (0.4 equiv), 0 °C.
On the other hand, the 7-endo radical cyclization of
bromomethylsilyl ethers 56 derived from ethyl c-hydroxy-
a-methylenecarboxylates 1 is expected to give cyclic
silyl ethers 6 bearing the ethoxycarbonyl group anti to
the c-substituent via the seven-membered radical inter-
mediates (Scheme 1).7 In contrast to the chelate ring
where the carbonyl group is part of the ring, the cyclic
radical intermediate possessing an exocyclic ethoxycar-
bonyl group at the radical center would give rise to the
H-atom transfer with anti mode. The subsequent
cleavage of C–Si bond using Tamao oxidation is there-
fore expected to give the acyclic dihydroxy esters 7 with
anti configuration. We report herein the diastereoselec-
tivity in the 7-endo radical cyclization of 5 yielding 6 and
the subsequent ring cleavage.
Initially, we examined the radical cyclization of 5a with
n-Bu3SnH (2 equiv) and Et3B (0.4 equiv) at 0 °C in
dichloromethane and obtained 6a in 85% yield with a
8
diastereomer ratio syn/anti ¼ 1:12 (entry 1). The anti-
selectivity was not ameliorated at lower temperatures.
The use of Ph3SnH instead of n-Bu3SnH lowered the
anti-selectivity.5a In the reaction of 5a with tris(tri-
methylsilyl)silane, a complex mixture was yielded. In
diethyl ether, 1,4-dioxane, tetrahydrofuran, or ethyl
acetate, 6a was obtained in high yield and with higher
anti-selectivity (entries 2–5). However, in nonpolar
hexane (entry 6) and in a polar solvent such as acetone,
acetonitrile, and methanol (entries 7–9), the anti-selec-
tivities were lower.
A series of (bromomethyl)dimethylsilyl ethers 5b–g were
cyclized in order to probe the effects of substituents R1
and R2 on syn–anti-selectivity (Table 1). The reactions
of 5b and 5c bearing a primary alkyl group at the
c-position gave lower anti-selectivities (entries 10 and
11). The reaction of 5c in THF gave a complex mixture.
Entries 12–14 show that the cyclization of 5d–f bearing a
bulky secondary or tertiary alkyl group at the c-position
gave exclusively anti-products 6d–f, respectively. The
reaction of 5g bearing two substituents at the c-position,
however, showed poor diastereoselectivity.
The substrates 5a–g were prepared from ethyl c-hydroxy-
a-methylenecarboxylates4
1a–g
with
(bromo-
methyl)dimethylchlorosilane, respectively (Scheme 2).6
A summary of the radical cyclizations of 5a–g is shown
in Table 1.
Table 1. Radical-mediated 7-endo cyclization of bromides 5a
Entry
Substrate Solvent
Product Yield (%) syn/anti
1
5a
CH2Cl2
Et2O
6a
85
86
97
97
96
96
91
92
93
95
74
90
99
95
88
1:12
1:17
1:18
1:18
1:18
1:12
1:10
1:9
2
The NOE difference spectra and conformational analy-
sis using CONFLEX calculations9 of 6a suggested that
the phenyl and ethoxycarbonyl groups are in anti rela-
tion. Furthermore, the stereochemistry of 6a was con-
firmed as follows. Treatment of 6a with p-TsOH in
benzene at room temperature gave c-lactone 8a in 48%
yield together with a mixture containing 9a (Scheme 3).
The NOE experiment of 8a was not achieved due to the
overlapping of signals. The Tamao oxidation of 8a with
hydrogen peroxide gave 10a in 14% yield. The NOE
difference spectra of 10a showed the phenyl and hy-
droxyethyl groups are in syn relation. Thus, the anti
stereochemistry of 6a was established without ambigu-
ity. The configurations of the other products 6b–f were
determined by comparing their chemical shift values
3
1,4-Dioxane
THF
4
5
AcOEt
Hexane
Acetone
MeCN
MeOH
THF
6
7
8
9
1:10
1:12
1:6.6
1:34
1:39
1:47
1:2.5
10
11
12
13
14
15
5b
5c
5d
5e
5f
6b
6c
6d
6e
6f
CH2Cl2
THF
THF
THF
THF
5g
6g
a Reactions performed with n-Bu3SnH (2 equiv), Et3B (0.4 equiv) at
0 °C.

H. Nagano, S. Hara / Tetrahedron Letters 45 (2004) 4329–4332
4331
OH
OH
Si
O
ii
OH
OH
R
R
anti-12a
anti-13a
anti-13d–anti-13f
(major isomers)
anti-12d–anti-12f
(major isomers)
OH
Si
iv
OH
iii
6a–6f
R
CO2Et
11a–11f
(major isomers)
i
HO
Ph
Si
O
O
Ph
O
O
9a
X
8a X = Si(Me)2OH
10a X = OH
ii
a
R = Ph
b R = CH3
R = n-C7H15
d
e
f
R = i-Pr
R =c-C6H11
R = t-Bu
Figure 1. Global minimum energy conformers A-1 and A-2.
c
Scheme 3. Reagents and conditions: (i) p-TsOH, benzene, rt; (ii) 30%
H2O2, KF, KHCO3, MeOH–THF (1:1), rt; (iii) silica gel; (iv) DIBAL,
CH2Cl2, ꢀ50 °C.
of 6a are ascribable to the relative populations of the
low energy conformers, each of them exhibiting a dif-
ferent diastereoselectivity. The addition of magnesium
dibromide lowered the anti-selectivity in the reaction 5a.
The coordination of the Lewis acid to the oxygen atom
of ester carbonyl may shield the H-atom transfer.
with those of 6a. The stereochemistry of 6g was assigned
by comparing the chemical shift values of CH3–Si with
those of 6a.
Finally, the cyclization products 6a–f were allowed to
stand on a silica gel column to give the acyclic dihydroxy
esters 11a–f in high yields, respectively (Scheme 3).11 The
Tamao oxidation of ester 6a with hydrogen peroxide
gave a complex mixture and the expected product 7a
was not isolated. We, therefore, initially reduced 6a and
6d–f with diisobutylaluminum hydride (DIBAL) at
ꢀ50 °C and then oxidized the resulting silyl ethers 12a
and 12d–f with hydrogen peroxide to give triols 13a and
13d–f in good yields, respectively.12 The reactions pro-
ceeded without epimerization.
Ph
O
O
H
7%
11%
H
H
4%
OH
5%
NOE
10a
The diastereoselectivity in the radical cyclizations was
rationalized based on the conformational analysis of
radical intermediate model A using CONFLEX and
subsequent PM3 calculations.4d;e The calculations gave
two global minimum energy conformers A-1 and A-2
(Fig. 1) and four low energy conformers A-3–A-6 within
1.0 kcal molꢀ1 of the global minimum energy structures.
The structures of A-3–A-6 differ from the structure A-1
or A-2 only in the geometry of ethoxy group. The H-
atom transfer reactions to A-1–A-6 occur on the exposed
lower face of radical center to afford the anti-selectivity.
In summary we have reported the 7-endo cyclization of
(bromomethyl)dimethylsilyl ethers 5 yielding preferen-
tially anti-6 and the subsequent ring cleavage yielding
dihydroxy esters 11 and triols 13. The reactions
affording anti-13 and the previously reported chelation-
controlled radical reaction of c-benzyloxy-a-methylene-
carboxylic acid esters 2 with alkyl iodides yielding syn-44
are complementary to each other with respect to dia-
stereoselectivity.
To our knowledge, the solvent effect on the conforma-
tions associated to the rotation of the polar ethoxycar-
bonyl group at the prochiral radical center has not been
studied.10 The solvent effects on the diastereomer ratios
References and notes
1. For reviews and books, see: (a) Smadja, W. Synlett 1994,
1–26; (b) Porter, N. A.; Giese, B.; Curran, D. P. Acc.

4332
H. Nagano, S. Hara / Tetrahedron Letters 45 (2004) 4329–4332
Chem. Res. 1991, 24, 296–304; (c) RajanBabu, T. V. Acc.
see: (d) Mayon, P.; Chapleur, Y. Tetrahedron Lett. 1994,
35, 3703–3706; (e) Koreeda, M.; George, I. A. J. Am.
Chem. Soc. 1986, 108, 8098–8100.
Chem. Res. 1991, 24, 139–145; (d) Renaud, P.; Sibi, M. P.
In: Radicals in Organic Synthesis; VCH: Weinheim, 2001;
Vols. 1–2; (e) Curran, D. P.; Porter, N. A.; Giese, B.
Stereochemistry of Radical Reactions; VCH: Weinheim,
1996.
7. For a review on intramolecular free radical conjugate
additions, see: Zhang, W. Tetrahedron 2001, 57, 7237–
7262.
2. For reviews see: (a) Sibi, M. P.; Porter, N. A. Acc. Chem.
Res. 1999, 32, 163–171; (b) Renaud, P.; Gerster, M.
Angew. Chem., Int. Ed. 1998, 37, 2562–2579; (c) Guindon,
8. Typical procedure: To a solution of 5a (96 mg, 0.26 mmol)
in dry THF (2.6 mL) was added n-Bu3SnH (140 lL,
0.52 mmol) and Et3B (105 lL, 0.11 mmol) at 0 °C. The
mixture was stirred at this temperature for 2 h. KF and
water were added and the mixture was stirred at room
temperature for 3 h. After filtration through a pad of
Florisil, the filtrate was concentrated under reduced
pressure. The residue was chromatographed on Florisil
(eluent: hexane and then hexane–ethyl acetate (40:1)) to
give 6a (74 mg, 0.25 mmol, 97% yield).
ꢀ
Y.; Guerin, B.; Rancourt, J.; Chabot, C.; Makintosh, N.;
Ogilvie, W. W. Pure Appl. Chem. 1996, 68, 89–96.
3. For a review on 1,3-asymmetric induction, see: (a) Mengel,
A.; Reiser, O. Chem. Rev. 1999, 99, 1191–1224; (b) For
radical mediated 1,3-asymmetric inductions via eight-
membered chelate rings, see: Hayen, A.; Koch, R.;
Metzger, J. O. Angew. Chem., Int. Ed. 2000, 39, 2758–
2761; (c) Hayen, A.; Koch, R.; Saak, W.; Haase, D.;
Metzger, J. O. J. Am. Chem. Soc. 2000, 122, 12458–12468;
(d) For recent radical mediated 1,3-asymmetric inductions,
see also: Bertrand, M. P.; Feray, L.; Nouguier, R.; Stella,
L. Synlett 1998, 780–782.
4. (a) Nagano, H.; Toi, S.; Yajima, T. Synlett 1999, 53–54;
(b) Nagano, H.; Hirasawa, T.; Yajima, T. Synlett 2000,
1073–1075; (c) Nagano, H.; Matsuda, M.; Yajima, T. J.
Chem. Soc., Perkin Trans. 2001, 1, 174–182; (d) Nagano,
H.; Toi, S.; Matsuda, M.; Hirasawa, T.; Hirasawa, S.;
Yajima, T. J. Chem. Soc., Perkin Trans. 1 2002, 2525–
2538; (e) Nagano, H.; Ohkouchi, H.; Yajima, T. Tetrahe-
dron 2003, 59, 3649–3663.
9. (a) Goto, H.; Osawa, E. J. Am. Chem. Soc. 1989, 111,
8950–8953; (b) Goto, H.; Osawa, E. J. Chem. Soc., Perkin
Trans. 2 1993, 187–198.
10. For the solvent effects on the stereocontrol of radical
reactions, see: (a) Ishihara, T.; Mima, K.; Konno, T.;
Yamanaka, H. Tetrahedron Lett. 2002, 43, 3493–3497; (b)
Braslau, R.; Naik, N.; Zipse, H. J. Am. Chem. Soc. 2000,
122, 8421–8434; (c) Yorimitsu, H.; Nakamura, T.; Shin-
okubo, H.; Oshima, K.; Omoto, K.; Fujimoto, H. J. Am.
Chem. Soc. 2000, 122, 11041–11047; (d) Yorimitsu, H.;
Wakabayashi, K.; Shinokubo, H.; Oshima, K. Tetrahe-
dron Lett. 1999, 40, 519–522; (e) Yorimitsu, H.; Nakam-
ura, T.; Shinokubo, H.; Oshima, K. J. Org. Chem. 1998,
63, 8604–8605; (f) Hanessian, S.; Yang, H.; Schaum, R. J.
Am. Chem. Soc. 1996, 118, 2507–2508; (g) Curran, D. P.;
Abraham, A. C. Tetrahedron 1993, 49, 4821–4840; (h)
Hart, D. J.; Krishnamurthy, R. J. Org. Chem. 1992, 57,
4457–4470.
11. Typical procedure: A solution of the crude cyclization
product 6d prepared from 5d (88 mg, 0.26 mmol) in hexane
was put on a silica gel column and allowed to stand at
room temperature for 1 h. Elution with hexane and then
with hexane–ethyl acetate (1:1) gave 11d (60 mg, 83%
yield). Yields: 11a (94%); 11b (92%); 11c (conversion yield
91%); 11e (95%); 11f (90%).
5. (a) Little is known about the conformations of seven-
membered cyclic radicals, see Nagano, H.; Mikami, A.;
Yajima, T. Tetrahedron Lett. 2003, 44, 6867–6870; (b) Sibi,
M. P.; Asano, Y.; Sausker, J. B. Angew. Chem., Int. Ed.
2001, 40, 1293–1296; (c) For examples, of five-and six-
membered cyclic radicals, see Giese, B. Angew. Chem., Int.
Ed. Engl. 1989, 28, 969–980; (d) Damm, W.; Giese, B.;
€
Hartung, J.; Hasskerl, T.; Houk, K. N.; Huter, O.; Zipse,
H. J. Am. Chem. Soc. 1992, 114, 4067–4079; (e) Cai, Y.;
Roberts, B. P. J. Chem. Soc., Perkin Trans. 1 1998, 467–
476.
6. (a) Koreeda, M.; Hamann, L. G. J. Am. Chem. Soc. 1990,
112, 8175–8177; (b) Koreeda, M.; George, I. A. Chem.
Lett. 1990, 83–86; (c) Koreeda, M.; Wu, J. Synlett 1995,
850–852; For 6-endo radical cyclization of a-silyl radical,
12. Yields: 12a (85%); 12d (95%); 12e (87%); 12f (95%);
13a (80%); 13d (80%); 13e (81%); 13f (conversion yield
87%).