Enantioselective radical addition/trapping reactions with α,β-disubstituted unsaturated imides. Synthesis of anti-propionate aldols

Article abstract of DOI:10.1021/ja043371e

This manuscript describes a highly diastereo- and enantioselective intermolecular radical addition/hydrogen atom transfer to α,β-disubstituted enoates. Additionally, we show that anti-propionate aldol-like products can be easily prepared from α-methyl-β-acyloxyenoates in good yields and high diastereo- and enantioselectivities. Copyright

Full text of DOI:10.1021/ja043371e

Published on Web 02/03/2005
Enantioselective Radical Addition/Trapping Reactions with r,â-Disubstituted
Unsaturated Imides. Synthesis of anti-Propionate Aldols
Mukund P. Sibi,* Goran Petrovic, and Jake Zimmerman
Department of Chemistry, North Dakota State UniVersity, Fargo, North Dakota 58105.
Received November 2, 2004; E-mail: mukund.sibi@ndsu.edu
Table 1. Evaluation of Imides in Addition/Trapping Experimentsa
Enantioselective Lewis acid-mediated free radical reactions
continue to attract interest.1 We have recently shown that inter-
molecular free radical addition to â-substituted R,â-unsaturated
carbonyl compounds followed by trapping with allyl stannanes can
lead to two new stereocenters with high diastereo- and enantio-
selectivity.2 There are few addition reactions to R,â-disubstituted
enoyl systems 1 that proceed in good yield and are able to control
the absolute and relative stereochemistry of both new stereocenters.
This is a consequence of problematic A1,3 interactions in either
rotamer when traditional templates such as oxazolidinone are used;
to relieve A1,3 strain, the C-C bond of the enoyl group twists,
breaking conjugation, which results in diminished reactivity and
selectivity.3,4 We recently reported that N-H imides5 are excellent
templates that relieve such A1,3 problems in substrates 1, improve
reactivity for R,â-disubstituted substrates 1, and under Lewis-acid
catalysis react via the s-cis rotamer.6 In this manuscript we
demonstrate for the first time that intermolecular radical addition
to R,â-disubstituted substrates followed by hydrogen atom transfer
proceeds with high diastereo- and enantioselectivity (1 f 2 or 3,
eq 1). The method is applied to the enantioselective and highly
diastereoselective (99:1 dr) synthesis of anti-aldol-type adducts.
yield
(%)b
drc
ee
(%)d
entry
R
Lewis acid
ligand
anti/syn
1
2
3
4
5
6
7
i-Pr 4a
i-Pr 4a
Mg(NTf2)2
Mg(NTf2)2
Mg(NTf2)2
Mg(NTf2)2
Mg(NTf2)2
Mg(ClO4)2
MgI2
74
69
67
78
58
72
83
98:2
97:3
98:2
98:2
96:4
97:3
99:1
7
7
7
7
7
7
69
65
74
83
92
94
cyc-hexyl 4b
Ph 4c
t-Bu 4d
t-Bu 4d
t-Bu 4d
a For reaction conditions, see Supporting Information. b Isolated yield.
c Diastereomeric ratio determined by 1H NMR (500 MHz). d Determined
by chiral HPLC.
Table 2. Radical Additions to R,â-Disubstituted Imide Substrates
We began our experiments with the addition of tert-butyl radical
to imides 4 under standard radical reductive alkylation conditions
(Table 1). Racemic addition to isopropyl imide 4a using magnesium
triflimide in the absence of a chiral ligand proceeded via anti
addition to give the anti product7 5a in good yield and excellent
diastereoselectivity (entry 1). A chiral reaction using 7 as a ligand
gave the anti product with moderate enantioselectivity (entry 2).
Screening of the R group on the N-H imide (entries 2-5) showed
the tert-butyl imide template (4d) to give the highest enantio-
selectivity (entry 5) with Mg(NTf2)2-7 as a Lewis acid. Further
evaluation of several magnesium Lewis acids (entries 5-7) showed
MgI2-7 to be optimal, giving product 5d in good yield with excellent
enantioselectivity and diastereoselectivity (entry 7). These results
clearly demonstrate that addition/trapping experiments using R,â-
disubstituted enoyls as substrates can proceed with a high degree
of both diastereo- and enantiocontrol. Furthermore, they also
underscore the ease with which one can vary the template leading
to improved selectivity. Under the same reaction conditions, the
chemical yield was <10% using oxazolidinone rather than an N-H
imide as a template.
ee
yield
(%)a
anti
(%)c
entry
R1
R2
R3
SM
product
dr 5/6b
1
2
3
4
5
6
7
8
Et
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Et
4d
4d
4d
4d
4d
4e
4f
63
59
79
62
83
37
71
50
5e/6e
5f/6f
5g/6g
5h/6h
5d/6d
5i/6i
87:13
3:1
92
56
92
79
94
80
93
74
MeOCH2
i-Pr
c-Hex
t-But
i-Pr
99:1
98:2
99:1
95:5
99:1
87:13
i-Pr
i-Pr
Ph
Me
5j/6j
5k/6k
4g
a Isolated yield. b Diastereomeric ratio determined by 1H NMR (500
MHz). c Determined by chiral HPLC.
product was excellent (entry 1). In contrast, reaction with the small
and highly reactive methoxymethyl radical was not chemically
efficient and the diastereo- and enantioselectivity were not high
(entry 2). Addition/trapping with the secondary isopropyl radical
gave excellent yield of the anti product in high enantioselectivity
(entry 3). Similar results were also obtained using cyclohexyl radical
We next investigated the addition of various radicals R1 to
substrate 4d under the optimized conditions (Table 2). Addition of
a primary ethyl radical gave a moderate yield and reduced
diastereoselectivity, but the enantioselectivity for the major anti
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10.1021/ja043371e CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Preparation of anti-Propionate Aldol-like Products
formed â-stereocenter, with the radical R1 group shielding the top
face.2 The diastereoselectivity is insensitive to the nature of the
â-substituent R2: addition of isopropyl radical occurs with 99:1 dr
whether R2 is methyl, phenyl, or benzoyloxy.2 The insensitivity to
the size or electronic character of R2 suggests that rotameric
equilibrium is minimal prior to hydrogen addition.12,2 The dia-
stereoselectivity does correlate the size of the radical R1 group
(Table 2).2 Work is underway to expand the scope of this addition/
trapping methodology.
mol %
CLA
yield
(%)a
ee
entry
R1
product
drb
(%)c
1
2
3
4
i-propyl
i-propyl
tert-butyl
c-hexyl
<5
79
60
64
30
30
30
9a
9b
9c
99:1
99:1
99:1
82
90
70
Acknowledgment. This work was supported by the National
Institutes of Health (NIH-GM-54656).
a Isolated yield. b Diastereomeric ratio determined by 1H NMR (500
MHz). c Determined by chiral HPLC.
Supporting Information Available: Characterization data for
compounds 4-9 and experimental procedures (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Sibi, M. P.; Manyem, S.; Zimmerman, J. Chem. ReV. 2003, 103, 3263.
(b) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 33, 163. Sibi, M. P.;
Manyem, S. Tetrahedron 2000, 56, 8033.
(2) Sibi, M. P.; Chen. J. J. Am. Chem. Soc. 2001, 123, 9472.
(3) Enantioselective tandem C-C bond formation using ionic intermediates.
(a) Yamada, K.-i.; Arai, T.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1998,
63, 3666. (b) Arai, T.; Sasai, H.; Aoe, K.; Okamura, K.; Date, T.;
Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 104. (c) Naasz, R.;
Arnold, L. A.; Pineschi, M.; Keller, E.; Feringa, B. L. J. Am. Chem. Soc.
1999, 121, 1104. (d) Alexakis, A.; Trevitt, G. P.; Bernardinelli, G. J. Am.
Chem. Soc. 2001, 123, 4358. (e) Arnold, L. A.; Naasz, R.; Minnaard, A.
J.; Feringa, B. L. J. Am. Chem. Soc. 2001, 123, 5841. (f) Doi, H.; Sakai,
T.; Iguchi, M.; Yamada, K.-i.; Tomioka, K. J. Am. Chem. Soc. 2003, 125,
2886. (g) Nishimura, K.; Tomioka, K, J. Org. Chem. 2002, 67, 431.
(4) For examples of radical reactions where stereocenter R- to a carbonyl is
established, see: (a) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry
of Radical Reactions; VCH: Weinheim, 1995. (b) Durkin, K.; Liotta, D.;
Rancourt, J.; Lavalle´e, J.-F.; Boisvert, L.; Guindon, Y. J. Am. Chem. Soc.
1992, 114, 4912. (c) Guindon, Y.; Houde, K.; Prevost, M.; Cardinal-David,
B.; Landry, S. R.; Daoust, B.; Bencheqroun, M.; Guerin, B. J. Am. Chem.
Soc. 2001, 123, 8496. (d) Curran, D. P.; Abraham, A. C. Tetrahedron
1993, 49, 4821. (e) Curran, D. P.; Ramamoorthy, P. S. Tetrahedron 1993,
49, 4841. (f) Curran, D. P.; Geib, S.; De Mello, N. Tetrahedron 1999,
55, 5681. For a reaction with tiglates, see: Kopping. B.; Chatgilialoglu,
C.; Zehnder, M.; Giese, B. J. Org. Chem. 1992, 57, 3994.
Figure 1. Model to explain enantioselectivity and diastereoselectivity.
(entry 4). As illustrated earlier, tert-butyl radical gave the anti isomer
with outstanding selectivity (entry 5).
The impact of changing the R- and â-substituents on the substrate
is shown in entries 6-8. A decrease in yield and diastereo- and
enantioselectivity was observed on changing the â-substituent R2
from a methyl group to an ethyl group (compare entry 3 with 6).
However, changing the â-substituent to a phenyl group gave the
addition/trapping product with very high selectivity (entry 7). A
larger R-ethyl substituent was less well tolerated, leading to reduced
selectivity (entry 8).
While many ionic routes are available for the synthesis of aldol
products,8 the neutral conditions associated with radical reactions
have some appeal in terms of functional group compatibility. In
addition, despite the array of solutions for the synthesis of syn-
aldols, the number of highly selective methods for preparing anti-
aldols is limited.9 We have recently shown that acetate aldols are
accessible through enantioselective conjugate radical additions to
â-acyloxyenoyl oxazolidinones.10 Initial attempts to add radicals
to R-methyl-â-acyloxy oxazolidinones, however, gave negligible
reactivity (<10%). However, greatly improved reactivity results
were achieved when an N-H imide template lacking A1,3 strain
was used, making possible a highly diastereo- and enantioselective
method for the preparation of anti-propionate aldol-like products
(Table 3). These reactions have not been optimized, and the
benzimide 8 rather than a tert-butyl imide was used because of its
ease of preparation and product analysis. Mg(ClO4)2-7 was used
as the chiral Lewis acid rather than MgI2-7. With all three radicals
screened, yields are good, enantioselectivity is high, and the anti
diastereoselectivity is outstanding (entries 2-4).
(5) For the use of imide templates in conjugate additions to R-unsubstituted
substrates, see: (a) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999,
121, 8959-8960 and (b) Sammis, G. M.; Jacobsen, E. N. J. Am. Chem.
Soc. 2003, 125, 4442 and references therein. Reaction via an s-trans
rotamer was proposed in ref 5a.
(6) Sibi, M. P.; Prabagaran, N.; Ghorpade, S. G.; Jasperse, C. P. J. Am. Chem.
Soc. 2003, 125, 11796-11797. Additional references to the cis-octahedral
model are included.
(7) For the synthesis of starting materials, reaction conditions for radical
reactions, ee determination, and product stereochemical analysis, see
Supporting Information.
(8) For selected recent reviews, see: (a) Palomo, C.; Oiarbide, M.; Garcia, J.
M. Chem. Soc. ReV. 2004, 33, 65. (b) Abiko, A. Acc. Chem. Res. 2004,
37, 387. (c) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357.
(9) For leading references on anti-propionate aldols, see: (a) Evans, D. A.;
Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2002, 124,
392. (b) Denmark, S. E.; Wynn, T.; Beutner, G. L. J. Am. Chem. Soc.
2002, 124, 13405. (c) Ghosh, A. K.; Kim, J.-H. Org. Lett. 2003, 5, 1063.
(d) Kiyooka, S. Tetrahedron: Asymmetry 2003, 14, 2897. (e) Walker,
M. A.; Heathcock, C. H.; J. Org. Chem. 1991, 56, 5747. (f) Corey, E. J.;
Kim, S. S. J. Am. Chem. Soc. 1990, 112, 4976. (g) Evans, D. A.; Downey,
C. W.; Shaw, J. T.; Tedrow, J. S. Org. Lett. 2002, 4, 1127.
(10) Sibi, M. P.; Zimmerman, J.; Rheault, T. Angew. Chem., Int. Ed. 2003,
42, 4521.
(11) Absolute and relative configurations of 5e and 9a were established by
conversion to (5e) and synthesis from (9a) known compounds. The relative
configuration of 5d was established by conversion to a known compound.
See Supporting Information for details.
The absolute and relative stereochemistry11 in these reactions
are analogous to those observed for tandem alkylation-allylation
addition to oxazolidinone cinnamate using MgI2-72 and consistent
with a model6,2 in which initial addition to the â-carbon occurs
from the top face opposite the aryl group of the ligand (see Figure
1). Subsequent hydrogen transfer to the R-carbon is apparently
controlled not by the chiral ligand (which might be expected to
block the bottom face resulting in syn addition) but by the newly
(12) The observed 99:1 diastereoselectivity when R1 ) isopropyl and R2
)
phenyl (Table 2, entry 7) seems unlikely on the basis of size, given
complete rotameric equilibration prior to hydrogen transfer. This model
is consistent with the related observations and proposed model for
alkylation-allylation additions; see ref 2. That rotameric equilibration
might erode diastereoselectivity is consistent with the somewhat lower
diastereoselectivities observed in ref 2 using the less reactive allyltributyltin
as a radical trap.
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