Copper-catalyzed regio-and enantioselective synthesis of chiral enol acetates and β-substituted aldehydes

Article abstract of DOI:10.1021/ja105585y

The in situ transformation of α,β-unsaturated aldehydes into α-chloroallylic acetates and subsequent copper-catalyzed regio-and enantioselective (up to 94% ee) allylic alkylation with Grignard reagents provides chiral enol acetates and chiral β-substituted aldehydes in a one-pot protocol.

Full text of DOI:10.1021/ja105585y

Published on Web 09/07/2010
Copper-Catalyzed Regio- and Enantioselective Synthesis of Chiral Enol
Acetates and ꢀ-Substituted Aldehydes
Mart´ın Fan˜ana´s-Mastral and Ben L. Feringa*
Stratingh Institute for Chemistry, UniVersity of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
Received June 25, 2010; E-mail: B.L.Feringa@rug.nl
quenching the reaction with methanol, adding potassium carbonate,
and stirring the mixture for 1 h. Although different phosphoramidites
(Figure 1) were tested using these conditions, L1 was found to be
the most effective. The use of L2 led to a mismatch effect affording,
after hydrolysis, the same enantiomer of aldehyde 5a with 27% ee
(Table 1, entry 2). The 3,3′-disubstituted ligand L3 enhanced the
Z/E ratio of enol acetate 2a (14:1), but aldehyde 5a was obtained
Abstract: The in situ transformation of R,ꢀ-unsaturated aldehydes
into R-chloroallylic acetates and subsequent copper-catalyzed
regio- and enantioselective (up to 94% ee) allylic alkylation with
Grignard reagents provides chiral enol acetates and chiral
ꢀ-substituted aldehydes in a one-pot protocol.
with a moderate 40% ee (entry 3). The change of the amine group
In recent years, major breakthroughs in enantioselective copper-
catalyzed conjugate addition and allylic substitution with Grignard
reagents, two of the most powerful C-C bond-forming reactions,
have been achieved.1 However, these strategies have not been
applied to the synthesis of chiral enol acetates, which are versatile
intermediates in organic synthesis.2
for a pyrrolidine ring or the replacement of the binaphthol ring for
a biphenol or a Taddol group led to similar regioselectivities, but
lower enantioselectivities were obtained.7
Table 1. Screening of Phosphoramidite Ligands and Conditionsa
It has long been known that aldehydes can be transformed into
R-haloacetates by reacting them with an acid halide in the presence
of a catalytic amount of zinc chloride.3 In contrast to allylic geminal
diacetates, which have been applied in asymmetric Pd-catalyzed
allylic alkylation,4 to our knowledge allylic R-haloacetates have
not been used in any enantioselective transformation. We envisioned
the possibility of converting in situ an R,ꢀ-unsaturated aldehyde
into the corresponding allylic R-haloacetate and then carrying out
a copper-catalyzed enantioselective allylic alkylation.1 This reaction
would lead to a chiral enol acetate, which additionally could be
easily converted in a one-pot operation into the corresponding chiral
ꢀ-substituted aldehyde. This overall transformation can be consid-
ered as a catalytic asymmetric formal conjugate addition of a
Grignard reagent to an R,ꢀ-unsaturated aldehyde (Scheme 1). This
strategy would result in a synthetically useful alternative to the direct
catalytic enantioselective conjugate addition to enals, which is
particularly difficult to achieve because of their high reactivity
toward 1,2-addition and double-addition products.5,6
yield (%)b
ee (%)
entry
L
2a
3
4
Z/Ec
2ad
5ae
1
L1f
80
6
2
4:1
Z: 72
E: 91
Z: 27
E: 25
74
2
3
4
5
6
7
8
L2f
L3f
L1g
L1h
L4h
L5h
L6h
76
68
82
89
90
88
80
9
4
6
2
3:1
14:1
5:1
27
-40i
82
Z: -43
E: n.d.j
Z: 78
E: 95
Z: 91
E: 92
Z: 39
E: 55
Z: 65
E: 96
Z: 90
E: n.d.j
2
1
-
1
-
-
-
-
13:1
4:1
92
42
Scheme 1. Approach to Chiral Enol Acetates and ꢀ-Substituted
Aldehydes
-
8
3:1
84
17:1
90
a Reactions were run on a 0.5 mmol scale by adding 1.2 equiv of
EtMgBr diluted with CH2Cl2 (0.7 mL). b Isolated yield. c Determined by
1H NMR spectroscopy. d Determined by chiral HPLC. e Determined by
chiral GC. f EtMgBr was added over 1 h. g EtMgBr was added over 4 h.
h EtMgBr was added over 6 h. i The negative ee value indicates that the
opposite enantiomer was formed. j Not determined.
We started our investigation with the reaction between cinna-
maldehyde (1a) and ethylmagnesium bromide (Table 1). After some
preliminary experiments using different chiral ligands and copper
sources,7 we found that the use of a 1:1.1 ratio of copper(I)
thiophenecarboxylate (CuTC) to phosphoramidite L1 was an
optimal catalyst for this process.8 Thus, when ethylmagnesium
bromide was added to a solution of the in situ-formed chloroacetate
and a 5 mol % loading of this chiral Cu-catalyst, enol acetate 2a
was obtained as the major product as a mixture of Z and E isomers
in 80% yield. Subsequently, hydrolysis afforded aldehyde 5a, which
was obtained in quantitative yield and 74% ee (Table 1, entry 1).
It is important to note that enol acetate 2a can either be isolated
and then hydrolyzed or transformed in situ to aldehyde 5a by
As the addition rate is often crucial in C-C bond-forming
reactions with highly reactive Grignard reagents, we examined
different addition times while keeping L1 as the ligand. Slow
addition of the Grignard reagent over 4 h increased the regio- and
enantioselectivity (82% ee, entry 4). An addition time of 6 h allowed
us to obtain exclusively enol acetate 2a, almost exclusively as the
Z isomer (13:1 Z/E). The subsequent hydrolysis afforded aldehyde
9
13152 J. AM. CHEM. SOC. 2010, 132, 13152–13153
10.1021/ja105585y  2010 American Chemical Society

C O M M U N I C A T I O N S
5a with a high enantiomeric excess (92% ee; entry 5).9 Using the
optimal addition time of 6 h, we also checked ligands L4 and L5
(entries 6 and 7), which have been shown to work well in the
copper-catalyzed allylic alkylation of simple cinnamyl-type allylic
chlorides.1,10 In these cases, we observed a mismatch effect opposite
to the one observed for ligands L1 and L2, with (S,S,S)-L5 as the
most effective of the two ortho-substituted ligands. However, the
enantioselectivity was not higher than the one obtained for L1. It
is also important to note that in these cases, the Z/E ratio of enol
acetate 2a was significantly lower than the ratio observed for ligand
L1. Finally, we checked the very bulky ligand L6 (entry 8), which
led to 90% ee but lower regioselectivity.
reactions. Thus, the Pd-catalyzed coupling of enol acetate 2a with
2-bromonaphthalene in the presence of tributyltin methoxide12 led
to aryl ketone 6 in 71% yield with retention of the stereochemistry
(91% ee) (Scheme 2).
Scheme 2. Formation of Chiral ꢀ-Substituted Aryl Ketone 6
It should be pointed out that the enantioselective Cu-catalyzed
conjugate addition of Grignard reagents to aliphatic R,ꢀ-unsaturated
enones provides optically active ꢀ-substituted ketones with high
yields and enantioselectivities.13 However, carrying out this trans-
formation with aromatic enones has to date provided only modest
ee’s. Thus, the above-described enantioselective formation of enol
acetates combined with the coupling reaction shown in Scheme 2
provides an alternative to the conjugate addition of Grignard
reagents to aromatic R,ꢀ-unsaturated enones.
In summary, we have developed a catalytic asymmetric synthesis
of chiral enol acetates based on in situ conversion of an R,ꢀ-
unsaturated aldehyde into an R-chloroallylic acetate and subsequent
regio- and enantioselective allylic alkylation. This new methodology
can also be used to access highly desirable ꢀ-substituted aldehydes
or, alternatively, ꢀ-substituted ketones.
Figure 1. Chiral phosphoramidites used in the optimization experiments.
Having established the optimized conditions (Table 1, entry 5),
we examined the scope of this new method (Table 2). This new
Table 2. Scope of Substrates and Grignard Reagentsa
Acknowledgment. M.F.-M. thanks the Spanish Ministry of
Science and Innovation (MICINN) for a postdoctoral fellowship.
Supporting Information Available: Experimental procedures and
spectroscopic data for the reaction products. This material is available
free of charge via the Internet at http://pubs.acs.org.
yield of 2 (%)b
2/3c
Z/Ed yield of 5 (%)e ee of 5 (%)f
References
entry
1
R′
1
2
3
4
1a Et
1a n-Hex
1a Me
2a, 89
2b, 88
2c, 66
2d, 85
2e, 75
2f, 69
2g, 77
2h, 81
2i, 86
99:1
99:1
74:26
97:3
99:1
99:1
98:2
99:1
98:2
13:1
10:1
7:1
12:1
18:1
17:1
16:1
20:1
2:1
5a, 89
5b, 88
5c, 66
5d, 80
5e, 68
5f, 63
5g, 77
5h, 79
5i, 81
92
94
72
48
90
90
91
93
92
(1) (a) Harutyunyan, S.; den Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa,
B. L. Chem. ReV. 2008, 108, 2824. (b) Alexakis, A.; Ba¨ckvall, J. E.; Krause,
N.; Pa`mies, O.; Die´guez, M. Chem. ReV. 2008, 108, 2796. (c) Jerphagnon,
T.; Pizzuti, M. G.; Minnaard, A. J.; Feringa, B. L. Chem. Soc. ReV. 2009,
38, 1039.
1a i-Bu
5g 1b Et
(2) Hart, H.; Rappoport, Z.; Biali, S. E. In The Chemistry of Enols; Rappoport,
Z., Ed.; Wiley: Chichester, U.K., 1990.
6g 1b n-Hex
7g 1c Et
(3) (a) Ulich, L. H.; Adams, R. J. Am. Chem. Soc. 1921, 43, 660. (b) Bigler,
P.; Muhle, H.; Neuenschwander, M. Synthesis 1978, 593.
(4) Trost, B. M.; Lee, C. B. J. Am. Chem. Soc. 2001, 123, 3671.
(5) For an example of a catalytic enantioselective 1,4-addition of organozinc
compouds to enals, see: (a) Bra¨se, S.; Ho¨fener, S. Angew. Chem., Int. Ed.
2005, 44, 7879. For Rh-catalyzed asymmetric 1,4-additions, see: (b) Paquin,
J.-F.; Defieber, C.; Stephenson, C. R. J.; Carreira, E. M. J. Am. Chem.
Soc. 2005, 127, 10850. (c) Nishimura, T.; Sawano, T.; Hayashi, T. Angew.
Chem., Int. Ed. 2009, 48, 8057.
(6) Recently, a Cu-catalyzed asymmetric conjugate addition of Grignard
reagents to enals with modest selectivities and yields was described. See:
Palais, L.; Babel, L.; Quintard, A.; Belot, S.; Alexakis, A. Org. Lett. 2010,
12, 1988.
(7) See the Supporting Information.
(8) For a recent review of phosphoramidites, see: Teichert, J. F.; Feringa, B. L.
Angew. Chem., Int. Ed. 2010, 49, 2486.
(9) As the substrate is a racemic chloroacetate, it is probable that in situ
racemization of the starting material or isomerization of the copper
intermediate occurs during slow addition of the Grignard reagent. Because
of the high sensitivity of the in situ-formed chloroacetate, to date it has
not been possible to monitor the ee of the substrate during the reaction
(kinetic resolution).
(10) (a) Tissot-Croset, K.; Polet, D.; Alexakis, A. Angew. Chem., Int. Ed. 2004,
43, 2426. (b) Carosi, L.; Hall, D. Angew. Chem., Int. Ed. 2007, 46, 5913.
(11) It has been shown that the regioselectivity of the copper-catalyzed addition
of MeMgBr to cinnamyl-type allylic chlorides is lower than for other alkyl
Grignard reagents. See: Tissot-Crosset, K.; Alexakis, A. Tetrahedron Lett.
2004, 45, 7377.
(12) Jean, M.; Renault, J.; Uriac, P.; Capet, M.; van de Weghe, P. Org. Lett.
2007, 9, 3623.
(13) Lo´pez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem.
Soc. 2004, 126, 12784.
8g 1c n-Hex
9
1d n-Hex
a Reactions were run on a 0.5 mmol scale using 1.2 equiv of R′MgBr
diluted with CH2Cl2 (0.7 mL) and added over 6 h. b Isolated yield.
c Based on GC. d Determined by 1H NMR spectroscopy. e Isolated yield
for the one-pot process. f Determined by chiral HPLC or GC. g The
chloroacetate was formed at -78 °C.
one-pot procedure was found to be very efficient with primary alkyl
Grignard reagents, which gave excellent regioselectivity and very
high enantioselectivities ranging from 90 to 94% (entries 1, 2, and
5-9). Although the reaction still showed excellent regioselectivity,
a lower enantiomeric excess was observed when isobutylmagnesium
bromide was used (entry 4). A decrease in the regioselectivity was
observed when MeMgBr was used (entry 3).11 However, it is
important to note that the reaction can be successfully carried out
using crotonaldehyde as the starting material. With this reverse
approach, the corresponding ꢀ-methyl-substituted aldehyde was
obtained with excellent regio- and enantioselectivity (98:2, 92%
ee; entry 9). Excellent results were also obtained when heteroaro-
matic or substituted aryl aldehydes were used (entries 5-8).
An attractive feature of this new transformation is the fact that
chiral enol acetates are versatile intermediates for cross-coupling
JA105585Y
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