Despite this progress, an efficient catalyst for the addition
of MeMgBr to R,â-unsaturated esters is still lacking. This
impedes the introduction of one of the most common and
valuable structural motifs in biologically relevant compounds
like polydeoxypropionate chains.9
Table 1. CA of MeMgBr to Aromatic R,â-Unsaturated
Thioesters (1) with Josiphos (L1)/CuBr‚SMe2
a
To address this issue, we recently developed the Josiphos/
CuBr-catalyzed CA of Grignard reagents to R,â-unsaturated
thioesters,10 which are more reactive and synthetically very
versatile.11 The application of this methodology in an iterative
fashion has culminated in the construction of 1,3-oligomethyl
(deoxypropionate) arrays used in the synthesis of mycocer-
osic acid12 and phthioceranic acid,13 both isolated from
Mycobacterium tuberculosis. However, in spite of the wide
applicability, this methodology presents two limitations: (1)
addition of sterically hindered Grignard reagents proceeds
with poor enantioselectivity and (2) aromatic substrates with
substituents on the phenyl ring display low reactivity toward
the addition of MeMgBr.
entry
1
Ar
R′ convnb (%) yieldc (%) eed (%)
1
2
3
4
1a Ph
1b p-Cl-Ph
1d p-Me-Ph
Me
Me
Et
90
95
75
35
65 (2a)
60 (2d)
33 (2f)
24 (2g)
95 (S)e
>99 (S)e
>99 (+)
93 (+)
1e p-MeO-Ph Et
a Conditions: 1 (1 equiv), MeMgBr (1.2 equiv), CuBr‚SMe2 (5 mol %),
L1 (6 mol %) in t-BuOMe at -75 °C, 12 h. b Determined by 1H NMR.
c Isolated yield. d Determined by chiral HPLC. e Absolute configuration
determined by correlation with known compounds (see Supporting Informa-
tion).
Herein, we report an extension of the catalytic protocol
for the copper-catalyzed conjugate addition of MeMgBr to
aromatic R,â-unsaturated thioesters using Josiphos/CuBr‚
SMe2. We also report the high enantioselective copper
catalyzed conjugate addition of MeMgBr and sterically
demanding Grignard reagents to aromatic and aliphatic R,â-
unsaturated thioesters using a new catalytic system based
on Tol-BINAP/CuI.
Our initial efforts in broadening the substrate scope of the
CA of Grignard reagents were focused on the reactivity and
selectivity of the Josiphos/CuBr complex toward aromatic
R,â-unsaturated thioesters (Table 1). In general, aryl-
substituted substrates are less reactive toward the CA of
Grignard reagents (see, for example, entry 1, 90% conversion
overnight) compared to aliphatic substrates, which give full
conversion typically in 2-5 h.10 In order to increase the
reactivity of the substrate, the substituent at the para position
of the phenyl ring was varied. Reactions were typically
carried out with 6 mol % of Josiphos ligand (L1), 5 mol %
of CuBr‚SMe2, and 1.1 equiv of MeMgBr in t-BuOMe at
-75 °C. The reactivity of 1b, containing an electron-
withdrawing substituent at the para position of the aromatic
ring, did not increase significantly compared to unsubstituted
cinnamic thioester 1a (90% conversion, overnight). Surpris-
ingly, the enantioselectivity increased to >99% (entry 2).
Thioesters 1d and 1e, bearing electron-donating groups at
the para position of the aromatic ring, proved to be even
less reactive (75 and 35% conversion overnight) although
the ee’s remained at excellent levels.14
Since Josiphos/copper complexes are not active enough
in the addition of MeMgBr to aromatic R,â-unsaturated
thioesters, we screened several monodentate and bidentate
phosphorus-containing chiral ligands and copper sources.
Most catalysts employed gave low enantioselectivities, but
the in situ prepared complex from CuI (1 mol %) and (S)-
Tol-BINAP (1.1 mol %) catalyzed the 1,4-addition of
MeMgBr to 1a to reach, in 16 h at -70 °C in t-BuOMe,15
full conversion and excellent regio- and enantioselectivity
(88% yield, >99:1, 1,4-addition versus 1,2-addition
product, 94% ee; Table 2, entry 1). At higher temperature
(-50 °C), full conversion was achieved in 8 h albeit with
much lower enantioselectivity (40% ee). Increased ratios of
ligand to metal (1.5:1 and 2:1) had no detectable effect on
the ee of the reaction.16 As expected, this catalytic system
also showed to be effective in the addition of EtMgBr to
1a, affording 2b in good yield and enantioselectivity (Table
2, entry 2). Remarkably, addition of bulky i-BuMgBr gave
2c in good yield and enantioselectivity (Table 2, entry 3).
(3) For reviews, see: (a) Tomioka, K.; Nagaoka, Y. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: New York, 1999, Vol. 3, pp 1105-1120. (b) Krause, N.;
Hoffmann-Ro¨der, A. Synthesis 2001, 171-196. (c) Feringa, B. L.; Naasz,
R.; Imbos, R. Arnold, L. A. In Modern Organocopper Chemistry; Krause,
N., Ed.; VCH: Weinheim, Germany, 2002; pp 224-258. (d) Alexakis, A.;
Benhaim, C. Eur. J. Org. Chem. 2002, 3221-3236. (e) Hayashi, T.;
Yamasaki, K. Chem. ReV. 2003, 103, 2829-2844. (f) Woodward, S. Angew.
Chem., Int. Ed. 2005, 44, 5560-5562. (g) Lo´pez, F.; Minnaard, A. J.;
Feringa, B. L. Acc. Chem. Res. 2007, 40, 179-188.
(4) Feringa, B. L.; Badorrey, R.; Pen˜a, D.; Harutyunyan, S. R.; Minnaard,
A. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5834-5838.
(5) Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert, H.; Tijani,
A. J. Am. Chem. Soc. 1994, 116, 4062-4066.
(6) Lo´pez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J.
Am. Chem. Soc. 2004, 126, 12784-12785.
(7) Lo´pez, F.; Harutyunyan, S. R.; Meetsma, A.; Minnaard, A. J.; Feringa,
B. L. Angew. Chem., Int. Ed. 2005, 44, 2752-2756.
(8) Wang, S.-Y.; Ji, S.-J.; Loh, T.-P. J. Am. Chem. Soc. 2007, 129, 276-
277.
(9) For review, see: Hanessian, S.; Giroux, S.; Mascitti, V. Synthesis
2006, 7, 1057-1076.
(10) Des Mazery, R.; Pullez, M.; Lo´pez, F.; Harutyunyan, S. R.;
Minnaard, A. J.; Feringa, B. L J. Am. Chem. Soc. 2005, 127, 9966-
9967.
(11) For recent examples of the versatility of thioesters, see: (a) Lalic,
G.; Aloise, A. D.; Shair, M. D. J. Am. Chem. Soc. 2003, 125, 2852-
2853. (b) Wittenberg, R.; Srogl, J.; Egi, M.; Liebeskind, L. S. Org. Lett.
2003, 5, 3033-3035 and references therein. (c) Agapiou, K.; Krische, M.
J. Org. Lett. 2003, 5, 1737-1740. (d) Howell, G. P.; Fletcher, S. P.; Geurts,
K.; ter Horst, B.; Feringa, B. L. J. Am. Chem. Soc. 2006, 128, 14977-
14985.
(14) It is worth noting that, in all cases, the isolated yields are rather
low compared to the conversions; this may be due to partial decomposition
of the starting material during the reaction.
(12) ter Horst, B.; Feringa, B. L.; Minnaard, A. J. Chem. Commun. 2007,
489-491.
(13) ter Horst, B.; Feringa, B. L.; Minnaard, A. J. Org. Lett. 2007, 9,
3013-3015.
(15) Reagent-grade t-BuOMe was used without further purification.
(16) These findings are in contrast with those of Loh and co-workers
who reported an increase in ee when a 2:1 ratio of ligand/metal was used
instead of a 1:1 ratio; see ref 8.
5124
Org. Lett., Vol. 9, No. 24, 2007