Enantioselective radical conjugate addition to α′-phosphoric enones

Article abstract of DOI:10.1021/ol8017177

(Chemical Equation Presented) Catalytic enantioselective radical conjugate addition reactions using α′-phosphoric enone templates have been studied. The C₂-symmetric bisoxazoline-zinc(ll) complex proves to be effective for high enantioselectivi

Full text of DOI:10.1021/ol8017177

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4255-4258
Enantioselective Radical Conjugate
Addition to r′-Phosphoric Enones†
Sunggi Lee and Sunggak Kim*
Department of Chemistry, School of Molecular Science (BK-21), Korea AdVanced
Institute of Science and Technology (KAIST), Daejeon 305-701, Korea
skim@kaist.ac.kr
Received July 27, 2008
ABSTRACT
Catalytic enantioselective radical conjugate addition reactions using r′-phosphoric enone templates have been studied. The C2-symmetric
bisoxazoline-zinc(II) complex proves to be effective for high enantioselectivities and chemical yields. In addition, intermediate r-carbonyl
alkyl radicals could be trapped with allyltributylstannane to afford anti-isomers as major products with high enantioselectivities.
During the last several decades, enantioselective C-C bond-
forming reactions were intensively investigated. Among the
various methods to achieve highly efficient enantioselective
C-C bond formations, enantioselective radical conjugate
addition reactions have been studied with great interest to
take advantage of unique features of radical chemistry.1 Since
oxazolidinone templates were extensively studied for the 1,4-
addition of nucleophilic radicals to electrophilic double bonds
by Sibi,2 several additional bidentate templates including
imide,3 pyrazole,4 pyrazolidinone,5 and R′-hydroxyketone
groups6 have attracted recent attention. However, R,ꢀ-
unsaturated ketones have been rarely used for enantioselec-
tive radical conjugate addition reactions.6,7
We have been interested in utilizing R′-phosphoric enone
templates in asymmetric reactions and reported asymmetric
(2) (a) Sibi, M. P.; Zimmerman, J.; Rheault, T. Angew. Chem., Int. Ed.
2003, 42, 4521. (b) Sibi, M. P.; Manyem, S.; Subramaniam, R. Tetrahedron
2003, 59, 10575. (c) Sibi, M. P.; Chen, J. J. Am. Chem. Soc. 2001, 123,
9472. (d) Sibi, M. P.; Ji, J.; Wu, J. H.; Gurtler, S.; Porter, N. A. J. Am.
Chem. Soc. 1996, 118, 9200. (e) Wu, J. H.; Radinov, R.; Porter, N. A.
J. Am. Chem. Soc. 1995, 117, 11029. (f) Porter, N. A.; Feng, H.; Kavrakova,
I. K. Tetrahedron Lett. 1999, 40, 6713. (g) Porter, N. A.; Wu, J. H.; Zhang,
G.; Reed, A. D. J. Org. Chem. 1997, 62, 6702. (h) Wu, J. H.; Zhang, G.;
† Dedicated to Professor E. J. Corey on the occasion of his 80th birthday.
(1) For review: (a) Sibi, M. P.; Manyem, S.; Zimmerman, J. Chem. ReV.
2003, 103, 3263. (b) Bar, G.; Parsons, A. F. Chem. Soc. ReV. 2003, 32,
251. (c) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-
VCH: Weinheim, 2001; Vols. 1 and 2. (d) Curran, D. P.; Porter, N. A.;
Giese, B. Stereochemistry of Radical Reactions. Concepts, Guidelines and
Synthetic Applications; VCH: Weinheim, 1996. (e) Sibi, M. P.; Porter, N. A.
Acc. Chem. Res. 1999, 32, 163. (f) Sibi, M. P.; Manyem, S. Tetrahedron
2000, 56, 8033.
Porter, N. A. Tetrahedron Lett. 1997, 38, 2067.
(3) Sibi, M. P.; Petrovic, G.; Zimmerman, J. J. Am. Chem. Soc. 2005,
127, 2390
.
(4) Sibi, M. P.; Guerrero, M. A. Synthesis 2005, 9, 1528
(5) Sibi, M. P.; Prabagaran, N. Synlett 2004, 2421
(6) Lee, S.; Lim, C. J.; Kim, S.; Subramaniam, R.; Zimmerman, J.; Sibi,
M. P. Org. Lett. 2006, 8, 4311
(7) (a) Sibi, M. P.; Zimmerman, J. J. Am. Chem. Soc. 2006, 128, 13346.
(b) Sibi, M. P.; Nad, S. Angew. Chem., Int. Ed. 2007, 46, 9231
.
.
.
.
10.1021/ol8017177 CCC: $40.75
Published on Web 09/10/2008
2008 American Chemical Society

Friedel-Crafts alkylation,8 a Mukaiyama-Michael reaction,9
and a 1,3-dipolar cycloaddition reaction,10 in which the R′-
phosphoric enone template showed high chemical reactivities
and enantioselectivities with chiral Lewis acids derived from
chiral bisoxazoline (Box) derivatives and copper(II) triflate.
In addition, compared with previously reported templates,
R′-phosphoric enone templates have the unique application
scope beyond the territory of carboxylic acid derivatives.
To further extend the synthetic usefulness of R′-phosphoric
enone templates, we have studied enantioselective radical
conjugate addition reactions using R′-phosphoric enones.
We initially examined the effectiveness of several chiral
Lewis acids derived from chiral Box ligands and metal salts.
As shown in Table 1, several features are noteworthy. First,
indanyl, and monophenyl substituted Box ligands (entries
9-11). Among several bridges in 6, the dimethyl-substituted
Box ligand 6a was the most effective, yielding the highest
enantioselectivity (82% ee) (entry 9). Third, chiral ligands
7 and 4 were totally ineffective (entries 7 and 12). It is
noteworthy that the radical conjugate addition reaction was
very slow with sterically bulky Box 4 (entry 7). Finally, when
the counteranion was changed from triflate anion to bistri-
flimide anion, surprisingly, almost a racemic mixture was
obtained (entry 13).
Next, the solvent effect was examined with Zn(OTf)2 and
6a (Table 2). When the reaction was carried out in
Table 2. Effect of Solventa
Table 1. Effect of Lewis Acids and Ligandsa
entry
solvent
time (h)
yield (%)b
88
ee (%)c
1
2
3
4
5
6
CH2 Cl2
CHCl3
CH3CN
THF
toluene
Et2O
6
24
24
24
6
82
63
6
70
86
91
86(13)d e
,
57(35)d f
,
87
95
90
12
a Typical reaction conditions: 1.0 equiv of substrate, 0.3 equiv of chiral
Lewis acid, 10.0 equiv of alkyl iodide, 4.0 equiv of Bu3SnH, and 3.0 equiv
of Et3B were used. b Isolated yield. c ee’s were determined using chiral
HPLC. d Recovered starting material. e At -60 °C. f At -40 °C.
chloroform at -60 °C, the reaction slowed down to some
extent, and the enantioselectivity was dropped considerably
(entry 2). In acetonitrile, the inferior result was obtained in
terms of the chemical yield and the enantioselectivity (entry
3). Among the solvents tested in this study, toluene and
diethyl ether were better than dichloromethane. The reaction
was faster in toluene (entry 5), but the higher enantioselec-
tivity was realized in diethyl ether (entry 6). Apparently, the
reaction slowed down to some extent due to the strong
coordination ability of etheral solvents toward zinc triflate
(entries 4 and 6).
The effect of structural modifications on the phosphonate
was briefly studied and is shown in Table 3. Dimethyl
phosphonate 1 gave the best result. When the methyl group
was changed to sterically bulkier isopropyl and phenyl
groups, the enantioselectivities were dropped to 72% and
13%, respectively. Furthermore, cyclic phosphonate 8c was
totally ineffective. The reaction was very slow, and a racemic
mixture was isolated.
entry
Lewis acid
ligand
none
(R)-3
(S)-4
(S)-5
(S)-5
(R)-3
(S)-4
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
none
57(25)d
82
22
-
11
0
MgBr2 Et2O
MgBr2 Et2O
MgBr2 Et2O
Cu(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(NTf2)2
73
46
20
29
0
70
82
73
72
2
39(50)d
56(37)d
41(47)d
78
(S)-5
(4R,5S)-6a
(4R,5S)-6b
(4R,5S)-6c
(S)-7
88
83
95
81
(4R,5S)-6a
83
5
a Typical reaction conditions: 1.0 equiv of substrate, 0.3 equiv of chiral
Lewis acid, 10.0 equiv of alkyl iodide, 4.0 equiv of Bu3SnH, and 3.0 equiv
of Et3B were used. b Isolated yield. c ee’s were determined using chiral
HPLC. d Recovered starting material.
To determine the scope and limitation of the present
method, the reaction was carried out with several structurally
different R′-phosphoric enones using the chiral Lewis acid
(30 mol %) derived from Zn(OTf)2 and 6a in diethyl ether
at -78 °C, and the experimental results are summarized in
Table 4. In general, the reaction proceeded cleanly, yielding
the addition products in high yields. The enantioselectivities
among several metal salts tested in this study, zinc triflate
gave the best result. Second, bisphenyl-substituted Box
ligands 6 gave higher enantioselectivities than t-butyl,
(8) Yang, H.; Hong, Y.-T.; Kim, S. Org. Lett. 2007, 9, 2281.
(9) Yang, H.; Kim, S. Synlett 2008, 555.
(10) Lim, K.-C.; Hong, Y.-T.; Kim, S. AdV. Synth. Catal. 2008, 350,
380.
4256
Org. Lett., Vol. 10, No. 19, 2008

1 and 10, but the enantioselectivities remained as the same
level (entries 10-14).
The absolute stereochemistry was determined by convert-
ing phosphonate 12b to the previously known compound 14.
Treatment of 12b with NaH and LAH in THF at room
temperature in 1 h afforded 14 (-34.8 in CHCl3 at 23 °C)
(Scheme 1).11 On the basis of the previously reported value
Table 3. Modification of R′-Phosphoric Enonesa
Scheme 1. Absolute Configuration
a Typical reaction condition: 1.0 equiv of substrate, 0.3 equiv of chiral
Lewis acid, 10.0 equiv of alkyl iodide, 4.0 equiv of Bu3SnH, and 3.0 equiv
of Et3B were used. b Isolated yield. c ee’s were determined using chiral
HPLC. d CH2Cl2 was added to solve starting material. e Recovered starting
material.
of the optical rotation, the stereochemistry was assigned as
S.12 A tentative model which accommodates the observed
face selectivity is shown in Figure 1. In this model, Zn2+
of the products are generally high, ranging from 82% to 95%
ee, and the best enantioselectivity was as high as 95% ee
Table 4. Addition of Alkyl Radicals to R′-Phosphoric Enonesa
yield
ee
entry
R
R′
product (%)b (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1 CH2CH2Ph Et
2b
2a
2c
2d
76
85
61
77
69
68
93
79
98
90
84
90
93
96
89
91
84
91
83
82
90
84
95
88
86
88
92
83
Figure 1. Tetrahedral transition state.
1
1
i-Pr
c-Hexyl
1
t-Bu
1
(CH3)2C(CH2)3Cl
2e
that could have a tetrahedral geometry occupied the center
of the transition state.13 Two coordination sites would be
filled with nitrogen atoms of the Box ligand, and the
remaining two sites are for the oxygen atoms of the starting
phosphoric enone. A phenyl group of the 4-position in the
ligand shielded only the Re face of the reactive double bond,
and another phenyl group at the 5-position blocked the
rotation of the nearby 4-phenyl group to maintain an effective
face shielding. Furthermore, it is assumed that the control
of the conformation of R′-phosphoric enones could result
from a π-π stabilization of the transition state.14
10 Ph
10
10
10
10
11 Me
11
11
11
Et
i-Pr
c-Hexyl
t-Bu
(CH3)2C(CH2)3Cl
Et
i-Pr
t-Bu
12a
12b
12c
12d
12e
13a
13bd
13cd
13d
(CH3)2C(CH2)3Cl
a Typical reaction conditions: 1.0 equiv of substrate, 0.3 equiv of chiral
Lewis acid, 5.0 equiv of alkyl iodide, 3.0 equiv of Bu3SnH, and 2.0 equiv
of Et3B were used. b Isolated yield. c ee’s were determined using chiral
HPLC. d The reaction time was 6 h.
(11) Hong, J. E.; Shin, W. S.; Jang, W. B.; Oh, D. Y. J. Org. Chem.
1996, 61, 2199.
(12) Knazawa, Y.; Tsuchiya, Y.; Kobayashi, K.; Shiomi, T.; Itoh, J.;
Kikuchi, M.; Yamamoto, Y.; Nishiyama, H. Chem.-Eur. J. 2006, 12, 63.
(13) Evans, D. A.; Kozlowski, M. C.; Tedrow, J. S. Tetrahedron Lett.
1996, 37, 7481.
when unsaturated enone 10 was reacted with t-butyl iodide
(entry 9). The size of the alkyl radical did not have a large
impact on the chemical yields and enantioselectivities.
Furthermore, the method works equally well with three
phosphoric enone substrates. In the case of phosphoric enone
11, the reaction was somewhat faster than similar substrates
(14) (a) Hunter, C. A.; Sanders, J. K. M. J. Am. Chem. Soc. 1990, 112,
5525. (b) Evans, D. A.; Johnson, J. S.; Olhava, E. J. J. Am. Chem. Soc.
2000, 122, 1635. (c) Pandey, M. K.; Bisai, A.; Singh, V. K. Tetrahedron
Lett. 2006, 47, 897. (d) Zhao, J.-L.; Liu, L.; Sui, Y.; Liu, Y.-L.; Wang, D.;
Chen, Y.-J. Org. Lett. 2006, 8, 6127.
Org. Lett., Vol. 10, No. 19, 2008
4257

To achieve sequential conjugative addition and R-alkyla-
tion, an electrophilic radical intermediate was trapped using
allyltributylstannane (Scheme 2). When phosphoric ester 10
was reacted with isopropyl iodide in the presence of
reaction (Scheme 3). A phosphoric ester 10 was reacted with
tertiary iodide 16 and allyltributylstannane to produce 70%
Scheme 3. Relative Stereochemistry
Scheme 2
.
Trapping of the R-Carbonyl Alkyl Radical with
Allyltin
of addition/allylation product 17 in 24 h. This product was
further treated with K2CO3 in THF/H2O at room temperature
to provide the cyclic compound 18 in 73% yield (94% ee).
By NOE experiment, the relative stereochemistry of the R
and ꢀ center was defined as an anti-isomer that agrees with
a previous reported case.2c
In summary, R′-phosphoric enones are highly efficient
substrates for the enantioselective conjugate radical addition
reactions and work well with various alkyl iodides. When
allyltributylstannane was used as the radical trapping agent,
allylation products were formed with high diastereo- and
enantioselectivities. In addition, optically active cyclohep-
tenone derivatives can be prepared via intramolecular
Horner-Emmons reactions of conjugate radical addition
products.
allyltributylstannane, only one diastereoisomer bearing 91%
ee was obtained. The high diastereoselectivity was noted
previously.2c Interestingly, the change of isoproyl iodide to
bulkier t-butyl iodide caused a significant increase in the
enantioselectivity (99% ee). In addition, a small amount of
the reduced side product (10%) was obtained with a lowered
enantioselectivity (66% ee). A similar observation was
obtained with another bulky tertiary iodide (product 15c: 97%
ee).
The increase in selectivity could be explained by a kinetic
resolution between chiral Lewis acid and ꢀ-stereocenter. A
matched major enantiomer reacted much faster with allyl-
tributylstannane than a mismatched minor enantiomer. The
minor enantiomer mainly reacted with Et3B to afford the
reduced product.15 As a result, most of the allylation product
came from the major enantiomer, and the enantiomeric
excess could exceed the ee value of 100% catalyst loading
(97% ee for compound 12d).
Acknowledgment. We thank Korea Science and Engi-
neering Foundation (R01-2007-000-21315-0), KEPCO, and
BK21 for financial support.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
The relative stereochemistry was determined by making
a cyclic compound using an intramolecular Horner-Emmons
(15) Brown, H. C.; Kabalka, G. W. J. Am. Chem. Soc. 1970, 92, 714.
OL8017177
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Org. Lett., Vol. 10, No. 19, 2008