Intramolecular addition of acyl radicals to α-substituted vinylogous carbonates: Demonstrating the effect of ring size on acyclic stereocontrol

Article abstract of DOI:10.1039/b106766b

The level of stereocontrol obtained in the reduction of the free radical derived from the intramolecular addition of an acyl radical to an α-branched vinylogous carbonate is dependent upon the ring-size of the cyclic ether.

Full text of DOI:10.1039/b106766b

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Intramolecular addition of acyl radicals to a-substituted vinylogous
carbonates: demonstrating the effect of ring size on acyclic
stereocontrol†
a
b
a
P. Andrew Evans,* ‡ Sushil Raina and Khalid Ahsan
a
Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
E-mail: paevans@indiana.edu; Fax: +1(812) 855-8300
Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA
b
Received (in Corvallis, USA) 14th July 2001, Accepted 18th September 2001
First published as an Advance Article on the web 9th November 2001
The level of stereocontrol obtained in the reduction of the
free radical derived from the intramolecular addition of an
acyl radical to an a-branched vinylogous carbonate is
dependent upon the ring-size of the cyclic ether.
radical reduction in tetrahydrofuran derivatives.5–7 Conversely,
the tetrahydropyran-3-ones 2b/3b were afforded with excellent
diastereoselectivity, favoring the syn-isomer 2b (Entry 3).
Furthermore, the diastereoselectivity could be further improved
by lowering the reaction temperature (220 °C), which is in
sharp contrast to the tetrahydrofuran-3-one 2a/3a and tetra-
hydrooxepin-3-one 2c/3c derivatives (Entry 4 vs 2/6).§ The
origin of the stereoselectivity may be rationalized using the
static model for allylic strain,7 in which the ketone is
responsible for promoting re-face reduction of the radical (Fig.
1). The difference in selectivity between the various ring sizes
may be attributed to conformation, which presumably alters the
relative orientation of the carbonyl relative to the incipient
radical. This observation is likely to provide a useful guide in
understanding the factors that influence stereocontrol in acyclic
radical reductions involving the intramolecular addition of acyl
radicals.
The stereoselective construction of cyclic ethers remains an
important area of interest due to the ubiquity of this structural
motif in biologically significant natural and unnatural mole-
cules.1 In the course of our studies focused on the intra-
2
3,4
molecular addition of acyl radicals to vinylogous carbonates
and sulfonates,5 we anticipated that we could expand the
synthetic utility of the former through the examination of a-
branched derivatives, which should provide access to an
additional stereogenic center.6 The ability to control the
relative and absolute configuration of acyclic stereogenic
centers in free radical addition reactions represents an important
,7
8
method in asymmetric synthesis. Herein, we report that the
level of stereocontrol in the intramolecular addition of acyl
radicals, derived from the selenoesters 1a–c (n = 0–2), to a-
substituted vinylogous carbonates, is directly dependent upon
the ring size of the resulting cyclic ether 2/3a–c (eqn. 1).
(
1)
Fig. 1
Table 1 outlines the results for the preliminary study.
9
Treatment of 1a–c with tris(trimethylsilyl)silane and tri-
The ability to undertake the stereoselective synthesis of
tetrahydropyran-3-ones in this manner prompted the extension
of this study as outlined in Scheme 2. The benzylidene acetal 8
was expected to promote the formation of cis-2,6-disubstituted
tetrahydropyran-3-one 9a in accord with previous studies and
thus determine whether the more conformationally rigid system
would deviate from the excellent stereoselectivity obtained in
the simple acyclic radical reduction in eqn. 1.
ethylborane in the presence of air, furnished the cyclic ethers
2
3
/3a–c in excellent yield. Interestingly, the tetrahydrofuran-
-one 2a/3a and tetrahydrooxepin-3-one 2c/3c were furnished
with only modest diastereocontrol irrespective of reaction
temperature (Entries 1/2 and 5/6). This trend in selectivity was
somewhat surprising given the precedent for this type of free
Table 1 Intramolecular additions of acyl radical to a-substituted vinylogous
carbonates†
The acyl selenide 8 required for this study was prepared from
the secondary alcohol 4 derived from deoxy- -ribose (Scheme
D
10
1
). Ozonolysis of the a,b-unsaturated ester 4 followed by in
Acyl
selenide 1
Ratio of Yield
situ reductive work-up furnished the diol, which was selectively
a
n = Temp./°C Conc./M 2 + 3b
c
Entry
(%)
1
2
a
B
0
B
22
220
0.02
B
3 + 1
4 + 1
84
76
3
4
b
B
1
B
22
220
0.01
B
21 + 1
46 + 1
80
82
5
6
a
c
2
B
22
220
0.005
B
7 + 1
8 + 1
81
37
B
All reactions carried out in hexane on a 0.5 mmol reaction scale. b Ratios
c
of diastereoisomers determined by capilliary GLC. Isolated yields.
†
Electronic supplementary information (ESI) available: spectral data (IR,
1
13
H and C NMR) and high resolution MS for 1/2a-c, 7–10. See http://www/
rsc.org/suppdata/cc/b1/b106766b/
‡
Current Address: Indiana University.
Scheme 1
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Chem. Commun., 2001, 2504–2505
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b106766b

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protected as the primary tert-butyldimethylsilyl ether 5 in
5–75% overall yield from 4. Treatment of 5 with potassium
Eli Lilly for a Young Faculty Grantee Award, GlaxoWellcome
for a Chemistry Scholar Award and Novartis Pharmaceuticals
for an Academic Achievement Award. The Camille and Henry
Dreyfus Foundation is also thanked for a Camille Dreyfus
Teacher-Scholar Award (PAE).
6
hexamethyldisilazide followed by the b-bromomethacrylate 6,
furnished the vinylogous carbonate 7 in 83–86% yield.
Oxidation of the primary tert-butyldimethylsilyl ether 7 with
Jones reagent afforded the carboxylic acid,11 which was then
converted to the acyl selenide 8, using the Crich protocol in 77%
Notes and references
12
yield from 7. The chemoselectivity of the oxidation is
pertinent given that the benzylidene acetal and vinylogous
carbonate are susceptible to acid-catalyzed hydrolysis.
§
The relative configuration of the major diastereoisomer 2a–c was
confirmed by NMR after conversion to the corresponding cis-lactone in an
analogous manner to that described in eqn. 2.
¶
Correspondence regarding the X-ray crystallography should be addressed
to: Arnold L. Rheingold, Department of Chemistry and Biochemistry,
University of Delaware, Newark, DE 19716, USA.
∑
8
2
Crystal structure data for 10, (C16
18 5 1
H O ): monoclinic, P2 , a =
.4891(2), b = 17.5380(3), c = 14.1931(2) Å, b = 93.9331(7), V =
2
1
108.09(6), Z = 6, ZA = 3, T = 198(2) K, Dcalc = 1.372 g cm , colorless
plate, GOF = 0.904, R(F) = 0.058 for 6032 observed independent
reflections (2.9° @ 2q @ 56.9°). CCDC 172435. See http://www.rsc.org/
suppdata/cc/b1/b10676b/ for crystallographic data in .cif or other electronic
format.
1
For reviews on cyclic ether syntheses, see: (a) C. J. Moody and M.
Davies, in Studies in Natural Product Chemistry, ed. Atta-ur-Rahman,
Elsevier, Amsterdam, 1992, vol. 10, pp. 201–239; (b) J.-C. Harmange
and B. Figadère, Tetrahedron: Asymmetry, 1993, 4, 1711; (c) E.
Alvarez, M.-L. Candenas, R. Perez, J. L. Ravelo and J. D. Martin, Chem.
Rev., 1995, 95, 1953; (d) J. O. Hoberg, Tetrahedron, 1998, 54, 12631
and pertinent refereces cited therein.
Scheme 2
The acyl selenide 8 was then subjected to the optimized
cyclization conditions, as outlined in Scheme 2. Treatment of
the acyl selenide 8 in an analogous manner to 1b, at 220 °C,
furnished the cyclic ethers 9a/b in 90–96% yield, with 33+1
diastereoselectivity (by HPLC) at C-3A favoring 9a. The
stereochemical outcome is consistent with the model outlined in
Fig. 1.
The relative configuration of the radical cyclization–reduc-
tion was proven unequivocally through X-ray crystallography
of the tricyclic lactone 10 (Fig. 2).¶ Reduction of the cyclic
ketone 9a with K-Selectride at 278 °C resulted in an in situ
lactonization, to afford 10 in 90% yield with !19 + 1
diastereoselectivity for the cis-lactone (eqn. 2).
2 For recent reviews on acyl radicals, see: (a) I. Ryu, N. Sonoda and D. P.
Curran, Chem. Rev., 1996, 96, 177; (b) C. Chatgilialoglu, D. Crich, M.
Komatsu and I. Ryu, Chem. Rev., 1999, 99, 1991 and pertinent
references cited therein.
3
(a) P. A. Evans and J. D. Roseman, Tetrahedron Lett., 1995, 36, 31; (b)
P. A. Evans and J. D. Roseman, J. Org. Chem., 1996, 61, 2252; (c) P. A.
Evans, J. D. Roseman and L. T. Garber, J. Org. Chem., 1996, 61, 4880.
;
For an example of an acyl radical cyclization in the total synthesis of
(
2)-kumausallene, see: P. A. Evans, V. S. Murthy, J. D. Roseman and
A. L. Rheingold, Angew. Chem., Int. Ed., 1999, 38, 3175 and pertinent
references within these articles.
4 For related examples of radical additions to b-alkoxyacrylates, see: (a)
alkyl radicals: E. Lee, S.-K. Yoo, H. Choo and H. Y. Song, Tetrahedron
Lett., 1998, 39, 317; (b) Lewis acid catalyzed addition of alkyl radicals:
Y. Yuasa, W. Sato and S. Shibuya, Synth. Commun., 1997, 27, 573; (c)
photosensitized electron-transfer addition of aldehydes: G. Pandey, S.
Hajra, M. K. Ghorai and R. Kumar, J. Org. Chem., 1997, 62, 5966; (d)
(
2)
2
SmI reduction of aldehydes: N. Hori, H. Matsukura, G. Matsuo and T.
Nakata, Tetrahedron Lett., 1999, 40, 2811; (e) alkyl radicals from
selenoacetals: M. Sasaki, T. Noguchi and K. Tachibana, Tetrahedron
Lett., 1999, 40, 1337.
In conclusion, we have demonstrated that the level of
stereocontrol in the reduction of the insipient radical derived
from the intramolecular addition of an acyl radical to a a-
substituted vinylogous carbonate is dependent on the relative
ring-size of the cyclic ether. The ability to achieve excellent
acyclic stereocontrol in 6-exo acyl radical addition reactions is
likely to have considerable synthetic utility, particularly for the
construction of C-glycosides.
5
6
(a) P. A. Evans and J. D. Roseman, Tetrahedron Lett., 1997, 38, 5249;
(
b) P. A. Evans and T. Manangan, Tetrahedron Lett., 1997, 38, 8165; (c)
P. A. Evans and T. Manangan, J. Org. Chem., 2000, 65, 4523.
For a closely related rationale for the reduction of b-alkoxy-a-
halomethacrylates, see: Y. Guindon, J.-F. Lavallée, L. Boisvert, C.
Chabot, D. Delorme, C. Yoakim, D. Hall, R. Lemieux and B. Simoneau,
Tetrahedron Lett., 1991, 32, 27; for semiempirical calculations on this
type of radical reduction reaction, see: K. Durkin, D. Liotta, J. Rancourt,
J.-F. Lavallée, L. Boisvert and Y. Guindon, J. Am. Chem. Soc., 1992,
1
14, 4912.
7
8
For a related example of an alkyl radical addition to a b-alkoxy-
methacrylate, see: E. Lee and S. J. Choi, Org. Lett., 1999, 1, 1127.
D. P. Curran, N. D. Porter and B. Giese, in Stereochemistry of Radical
Reactions: Concepts, Guidelines and Synthetic Applications, VCH
Publishers, New York, 1995, pp. 147–177.
9
(a) C. Chatgilialoglu, Acc. Chem. Res., 1992, 25, 188; (b) C.
Chatgilialoglu, C. Ferreri and T. Gimisis, in The Chemistry of Organic
Silicon Compounds, ed. S. Rappoport and Y. Apeloig, Wiley, London,
1
998, vol. 2, chapter 25, pp. 1539.
1
0 K. C. Nicolaou, C. A. Veale, C.-K. Hwang, J. Hutchinson, C. V. C.
Prasad and W. W. Ogilvie, Angew. Chem., Int. Ed. Engl., 1991, 30,
299.
Fig. 2 Thermal ellipsoid plot of 10 (50% probability thermal ellipsoids).∑
1
1 P. A. Evans, J. D. Roseman and L. T. Garber, Synth. Commun., 1996, 26,
We sincerely thank the National Institutes of Health
4
685.
(
GM58877) for generous financial support. We also thank
12 The acyl selenides were prepared from carboxylic acids, see D. Batty
Zeneca Pharmaceuticals for an Excellence in Chemistry Award,
and D. Crich, Synthesis, 1990, 273.
Chem. Commun., 2001, 2504–2505
2505