Highly efficient copper(I) iodide-tolyl-BINAP-catalyzed asymmetric conjugate addition of methylmagnesium bromide to α,β-unsaturated esters

Article abstract of DOI:10.1002/adsc.200700567

A highly efficient asymmetric conjugate addition of methylmagnesium bromide (MeMgBr) to α,β-unsaturated esters catalyzed by copper(I) iodide-tolyl-BNIP (CuI-Tol-BINAP) is described.

Full text of DOI:10.1002/adsc.200700567

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DOI: 10.1002/adsc.200700567
Highly Efficient Copper(I) Iodide-Tolyl-BINAP-Catalyzed
Asymmetric Conjugate Addition of Methylmagnesium Bromide
to a,b-Unsaturated Esters
Shun-Yi Wang,a,b Tze-Keong Lum,a Shun-Jun Ji,b,* and Teck-Peng Loha,*
a
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University, Singapore 639798
Fax : (+65)-6791-1961; e-mail: teckpeng@ntu.edu.sg
Key Lab. of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Suzhou (Soochow)
b
University, Jiangsu 215123, Peopleꢀs Republic of China
Received: December4, 2007; Published online: March 17, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A highly efficient asymmetric conjugate
addition of methylmagnesium bromide (MeMgBr)
to a,b-unsaturated esters catalyzed by copper(I)
iodide-tolyl-BNIP (CuI-Tol-BINAP) is described.
Scheme 1. Asymmetric CA of Grignard reagents to a,b-un-
saturated esters.
À
Keywords: C C bond formation; conjugate addi-
tion; copper(I) iodide; methylmagnesium bromide;
tolyl-BINAP
pose a challenge for organic chemists. In this paper,
we report a highly efficient cooper(I) iodide-toyl-
BINAP (CuI-Tol-BINAP)-catalyzed asymmetric CA
of MeMgBrto a,b-unsaturated esters.
The enantiopure b-methyl substituted unit is a
Preliminary studies have shown that CuI-Tol-
common recurring motif in many deoxygenated poly- BINAP catalyzed CA of MeMgBrto a,b-unsaturated
ketide-type natural products.[1] Therefore many meth- esterat À408C afforded the desired b-methyl substi-
ods have been developed forthe synthesis of such
tuted methyl esterin low yield (20%), albeit excellent
compounds. Currently, most of the reported proce- enanatioselectivity (99% ee).[11] The low yield was due
dures are based on the use of chiral auxiliaries (eno- to the formation of a substantial amount of the unde-
late alkylations,[2] conjugate additions[3]), allylic substi- sired b-methyl substituted methyl ketone. Therefore a
tutions[4] or substrate control methods.[5] Catalytic systematic study was carried out by varying the reac-
asymmetric methods include Negishiꢀs Zr-catalyzed tion temperature to suppress the formation of the b-
carboalumination,[6] Cu-catalyzed conjugate reduc- methyl substituted methyl ketone by-product and im-
tion,[7] Lipshutzꢀs Cu-catalyzed hydrosilylation,[8] Ir- prove the yield of the b-methyl substituted methyl
catalyzed hydrogenation[9] and Feringaꢀs Josiphos-cat- ester. In this investigation, the reaction was per-
alyzed conjugate addition.[10] Conjugate addition formed using 2 mol% CuI and 3 mol% (S)-Tol-
(CA) of MeMgBrto simple and commecrially avail-
BINAP as the chiral catalyst for the reaction of
able a,b-unsaturated esters is one of the most direct MeMgBrwith ( E)-methyl 5-phenylpent-2-enoate 2 in
entries into these structural elements. In addition, not t-BuOMe at different temperatures (Table 1).
only are a,b-unsaturated esters easier to handle, a
Our investigation shows that the desired product
larger scope of useful chemical transformations can was obtained in excellent enantioselectivity (98% ee)
also be applied. Unfortunately, unsatisfactory results and good yield (74%) when the reaction was carried
were obtained in the asymmetric CA of the MeMgBr out at À208C in tBuOMe (Table 1, entry 4). Note that
to various a,b-unsaturated esters under previous con- when the reaction temperature was increased beyond
ditions (Scheme 1).[11] Despite these important advan- À208C, lower enantioselectivities were observed (en-
ces, the development of enantioselective methods for tries 5 and 6). When toluene, diethyl ether, or CH2Cl2
the asymmetric CA of MeMgBr to simple and com- were used as the solvent, yields were practically un-
mercially available a,b-unsaturated esters continue to changed but the enantioselectivities were reduced to
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Shun-Yi Wang et al.
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Table 1. CuI-Tol-BINAP-catalyzed CA of MeMgBrto a,b-unsaturated esters 2.[a]
[a]
All reactions were performed with 2 (0.25 mmol) and MeMgBr(1.25 mmol, 3M in ether) in t-BuOMe (1 mL).
Isolated yield. From NMR of crude reaction mixtures <5% yields of 1,2-addition products were obtained determined.
The ee value was determined by HPLC analysis employing a Daicel Chiracel OD-H column. Absolute configuration as-
signed by analogy (Table 2, entry 1).
[b]
[c]
94%, 90% and 89% respectively. There was no reac- ing the chiral ligands. When either (S)-BINAP or( S)-
tion when THF was used as the solvent. Xylyl-BINAP was employed, 3a was obtained in good
We further investigated this asymmetric CA reaction yields (82% and 84%) but with slightly lowerenantiose-
under the same catalytic conditions in entry 4 by vary- lectivities (90% and 81% ee), respectively (Scheme 2).
Scheme 2. Cu with different chiral ligands catalyzed of 2 with MeMgBr.
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Asymmetric Conjugate Addition of Methylmagnesium Bromide to a,b-Unsaturated Esters
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Analytical thin layer chromatography (TLC) was per-
formed using Merck 60 F254 precoated silica gel plates
(0.2 mm thickness). Subsequent to elution, plates were vi-
sualized using UV radiation (254 nm) on a Spectroline
Model ENF-24061/F 254 nm. Further visualization was pos-
sible by staining with a basic solution of potassium perman-
ganate oran acidic solution of ceric molybdate.
Flash chromatography was performed using Merck silica
gel 60 with freshly distilled solvents. Columns were typically
packed as a slurry and equilibrated with the appropriate sol-
vent system prior to use.
With the optimized conditions, we analyzed the
scope of this asymmetric CA reaction with various
a,b-unsaturated esters. As shown in Table 2, these re-
actions proceeded smoothly either by using different
enantiomers of the ligand or different geometrical iso-
mers of the enoate. For example, when (S)-Tol-
BINAP was used with the trans-enoate 2a (Table 2,
entry 6), enantiomer (À)-3a could be obtained in
good yield and excellent ee. Alternatively, when (R)-
Tol-BINAP was used with the cis-enoate 2b (Table 2,
entry 8), the same enantiomer (À)-3a could be ob-
tained (Figure 1).
In summary, we have developed a highly efficient
and enantioselective CuI-Tol-BINAP-catalyzed asym-
metric CA of MeMgBr to a,b-unsaturated esters
using simple reaction procedures. Further investiga-
tions will be directed toward understanding the mech-
anism, broadening the reaction scope and applying
the catalytic system in the total synthesis of natural
products. When we were preparing this manuscript,
Prof. Feringaꢀs group reported the asymmetric conju-
gate addition of Grignard reagents to a,b-unsaturated
thioesters catalyzed by Tol-BINAP/CuI.[13]
General Procedure for the Enantioselective
Conjugate Addition
In a round-bottom flask equipped with septum and stirring
bar, (S)-Tol-BINAP (5.1 mg, 0.0075 mmol) and CuI
(0.95 mg, 0.005 mmol) were dissolved in t-BuOMe (1.0 mL)
and stirred under nitrogen at room temperature until a
bright yellow suspension was observed. Alternatively, (S)-
Tol-BINAP and CuI were stirred in CH2Cl2 (1.0 mL) for
15 min, concentrated under vacuum and then stirred in t-
BuOMe (1.0 mL) until the same bright yellow suspension
was observed. The mixture was then cooled to À208C and
MeMgBr(Aldirch, 3.0M solution in Et 2O, 1.25 mmol) was
added carefully into the reaction mixture. After stirring for
15 min, a solution of unsaturated ester (0.25 mmol) in t-
BuOMe (0.30 mL) was added dropwise over 1 hour via a sy-
ringe pump. After vigorous stirring at À208C foranother
1.5 h, MeOH (0.5 mL) and saturated NH4Cl solution (2 mL)
were sequentially added at À208C, and the mixture was
warmed to room temperature. The aqueous layer was ex-
tracted with diethyl ether (5 mL”3) and the combined or-
ganic extracts were dried over anhydrous magnesium sul-
fate, filtered and carefully concentrated under vacuum. The
residual crude product was purified by flash chromatogra-
phy (1:99 Et2O/pentane) to afford the desired product as
colorless oil.
Experimental Section
General Methods
Experiments involving moisture- and/or air-sensitive compo-
nents were performed in oven-dried glassware under a posi-
tive pressure of nitrogen using freshly distilled solvents.
Commercial grade solvents and reagents were used without
further purification with the following exceptions: t-BuOMe
was distilled from calcium hydride, dichloromethane was
distilled from calcium hydride, diethyl ether was distilled
from sodium, hexane and ethyl acetate were fractionally dis-
tilled.
Copper(I) iodide, enoates 4a and 4b were purchased from
Aldrich or Acros. (R or S)-BINAP (L1), (R or S)-Tol-
BINAP (L2) and (R)-xylyl-BINAP (L3) were purchased
from Strem. Unsaturated esters (E)-2, (Z)-2, and 4c–f were
prepared from the corresponding aldehydes, using the
Horner–Emmons or Wittig–Horner reaction.[1] The grignard
reagent (MeMgBr, 3M in diethyl ether) was purchased from
Aldrich.
Racemic 1,4-addition products were obtained by reaction
of the enoates with MeMgBr(5.0 equiv., 3M in diethyl
ether) and CuI (0.05 mol%) at À208C in diethyl ether.
Supporting Information
Additional experimental procedures and spectral data for
reaction products (PDF) are available as Supporting Infor-
mation free of charge via the Internet.
Figure 1. The configuration relationship.
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Shun-Yi Wang et al.
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Table 2. Variation of the a,b-unsaturated ester.[a]
[a]
Reactions were performed with 2 or 4 (0.25 mmol), MeMgBr(1.25 mmol, 3M in diethyl ether), CuI (2.0 mol%), ( S)-Tol-
BINAP (3.0 mol%) in t-BuOMe (1 mL) at À208C unless otherwise described.
[b]
[c]
Isolated yield and in all cases <10% yields 1,2 and 1,4 addition products (b-methyl ketone products) were obtained deter-
1
mined by H NMR of crude reaction mixtures.
The ee value was determined by Chiral HPLC or chiral GC analysis. Absolute configurations were assigned by analogy
(entry 1).
[d]
[e]
[f]
Absolute configuration assigned by comparison with known compounds.[9c]
CuI (5 mol%), (S)-Tol-BINAP (7.5 mol%).
1
(R)-Tol-BINAP was used and <10% yields 1,2- and 1,4-addition products were obtained as determined by H NMR of
the crude reaction mixture.
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Asymmetric Conjugate Addition of Methylmagnesium Bromide to a,b-Unsaturated Esters
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Chem. Soc. 2006, 128, 2770–2771; g) G. Zhu, E. Ne-
gishi, Org. Lett. 2007, 9, 2771–2774.
Acknowledgements
[7] a) D. H. Appella, Y. Moritani, R. Shintani, E. M. Ferre-
ira, S. L. Buchwald, J. Am. Chem. Soc. 1999, 121, 9473–
9474; b) M. P. Rainka, J. E. Milne, S. L. Buchwald,
Angew. Chem. 2005, 117, 6333–6336; Angew. Chem.
Int. Ed. 2005, 44, 6177–6180.
We gratefully acknowledge the Nanyang Technological Uni-
versity, Ministry of Education, the National Natural Science
Foundation of China (No. 20472062, 20672079) and Biomed-
ical Research Council (A*STAR grant M47110003) for the
funding of this research.
[8] B. H. Lipshutz, J. M. Servesko, B. R. Taft, J. Am. Chem.
Soc. 2004, 126, 8352–8353.
[9] a) J. Zhou, K. Burgess, Angew. Chem. 2007, 119, 1147–
1149; Angew. Chem. Int. Ed. 2007, 46, 1129–1131; b) J.
Zhou, J. W. Ogle, Y. Fan, V. Banphavichit, Y. Zhu, K.
Burgess, Chem. Eur. J. 2007, 13, 7162–7170.
References
[1] S. Hanessian, S. Giroux, V. Mascitti, Synthesis 2006,
1057–1076.
[10] a) B. L. Feringa, R. Badorrey, D. PeÇa, S. R. Harutyun-
yan, A. J. Minnaard, Proc. Natl. Acad. Sci. USA 2004,
101, 5834–5838; b) F. Lꢂpez, S. R. Harutyunyan, A. J.
Minnaard, B. L. Feringa, J. Am. Chem. Soc. 2004, 126,
12784–12785; c) F. Lꢂpez, S. R. Harutyunyan, A. J.
Minnaard, B. L. Feringa, Angew. Chem. 2005, 117,
2812–2816; Angew. Chem. Int. Ed. 2005, 44, 2752–
2756; d) R. Des Mazery, M. Pullez, F. Lꢂpez, S. R. Har-
utyunyan, A. J. Minnaard, B. L. Feringa, J. Am. Chem.
Soc. 2005, 127, 9966–9967; e) R. P. Van Summeren,
D. B. Moody, B. L. Feringa, A. J. Minnaard, J. Am.
Chem. Soc. 2006, 128, 4546–4547; f) S. R. Harutyunyan,
F. Lopez, W. R. Browne, A. Correa, D. Pena, R. Bador-
rey, A. Meetsma, A. J. Minnaard, B. L. Feringa, J. Am.
Chem. Soc. 2006, 128, 9103–9118; g) B. terHorst, A. J.
Minnaard, B. L. Feringa, Chem. Commun. 2007, 5,
489–491; h) B. ter Horst, A. J. Minnaard, B. L. Feringa,
Org. Lett. 2007, 9, 3013–3015.
[11] S.-Y. Wang, S.-J. Ji, T.-P. Loh, J. Am. Chem. Soc. 2007,
129, 276–277.
[12] The CA reaction of MeMgBr with esters 4 (R=Ph,
furyl, cyclohexyl) provided 1,4- and 1,2-addition prod-
ucts with very poor enantioselectivities.
[13] B. M. Ruiz, K. Geurts, M. ꢃ. Fernµndez-lbµÇez, B. ter
Horst, A. J. Minnaard, B. L. Feringa, Org. Lett. 2007, 9,
5123–5126.
[2] a) A. Abiko, O. Moriya, S. A. Filla, S. Masamune,
Angew. Chem. 1995, 107, 869–871; Angew. Chem. Int.
Ed. Engl. 1995, 34, 793–795; b) D. Stoermer, S. Caron,
C. H. Heathcock, J. Org. Chem. 1996, 61, 9115–9125;
c) A. G. Myers, B. H. Yang, H. Chen, D. J. Kopecky,
Synlett 1997, 457–459.
[3] a) E. Nicolµs, K. C. Russel, V. J. Hruby, J. Org. Chem.
1993, 58, 766–770; b) D. R. Williams, A. L. Nold, R. J.
Mullins, J. Org. Chem. 2004, 69, 5374–5382.
[4] a) C. Spino, C. Beaulieu, J. Lafreniere, J. Org. Chem.
2000, 65, 7091–7097; b) B. Breit, C. Herber, Angew.
Chem. 2004, 116, 3878–3880; Angew. Chem. Int. Ed.
2004, 43, 3790–3792.
[5] a) B. Breit, P. Demel, Tetrahedron 2000, 56, 2833–2846;
b) S. Hanessian, N. Chahal, S. Giroux, J. Org. Chem.
2006, 71, 7403–7411.
[6] a) D. Y. Kondakov, E. Negishi, J. Am. Chem. Soc. 1995,
117, 10771–10772; b) E. Negishi, Z. Tan, B. Liang, T.
Novak, Proc. Natl. Acad. Sci. USA 2004, 101, 5782–
5787; c) Z. Tan, E. Negishi, Angew. Chem. 2004, 116,
2971–2974; Angew. Chem. Int. Ed. 2004, 43, 2911–
2914; d) M. Magnin-Lachaux, Z. Tan, B. Liang, E. Ne-
gishi, Org. Lett. 2004, 6, 1425; e) T. Novak, Z. Tan, B.
Liang, E. Negishi, J. Am. Chem. Soc. 2005, 127, 2838–
2839; f) B. Liang, T. Novak, Z. Tan, E. Negishi, J. Am.
Adv. Synth. Catal. 2008, 350, 673 – 677
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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