MgI2-accelerated enantioselective Morita-Baylis-Hillman reactions of cyclopentenone utilizing a chiral DMAP catalyst

Article abstract of DOI:10.1039/c001977a

Fu's planar chiral DMAP catalyst efficiently promotes the asymmetric Morita-Baylis-Hillman reactions of cyclopentenone with a variety of aldehydes in the presence of MgI₂ as a cocatalyst.

Full text of DOI:10.1039/c001977a

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MgI2-accelerated enantioselective Morita–Baylis–Hillman reactions
of cyclopentenone utilizing a chiral DMAP catalystw
Alejandro Bugarin and Brian T. Connell*
Received (in College Park, MD, USA) 29th January 2010, Accepted 25th February 2010
First published as an Advance Article on the web 12th March 2010
DOI: 10.1039/c001977a
Fu’s planar chiral DMAP catalyst efficiently promotes the
asymmetric Morita–Baylis–Hillman reactions of cyclopentenone
with a variety of aldehydes in the presence of MgI2 as a cocatalyst.
The Morita–Baylis–Hillman (MBH) reaction, first reported in
1968, is an important carbon–carbon bond-forming reaction
between electron-deficient alkenes, such as a,b-unsaturated
ketones, and aldehydes or activated ketones.1 It is usually
catalyzed by suitable nucleophilic tertiary amines or
phosphines.2 This transformation has attracted attention because
it can be a selective (chemo-, regio-, diastereo-, and enantio-)
and atom economical method for converting simple starting
materials into more densely functionalized products.3 Because
Fig. 1 Amine catalysts examined as nucleophiles.
of the easy accessibility of starting materials and the potential
MgI2 (Table 1). TMEDA and several chiral TMEDA-equivalent
of the poly-functionalized adducts, the development of a
ligands13 were also screened, but they resulted in low enantio-
suitable asymmetric version of this reaction has attracted
selectivity due to a reasonably high background reaction rate.
considerable interest in recent years.
Lewis acids other than MgI2, including NiCl2, SnCl4, LiCl,
Various attempts to accelerate this reaction through the use
LiClO4, Cu(OTf)2, and Zn(OTf)2, showed poor or no reactivity
of chiral catalysts, cocatalysts, and a chiral medium have been
studied.4 Hatakeyama et al. reported a chiral quinidine-
under these conditions.
Table 1 depicts the catalytic activity of several enantio-
derived catalyst for the reaction of a highly activated acrylate
selective nucleophiles (I–VI)14 towards the asymmetric MBH
with aldehydes, providing the adducts with ee values up to
99%.5 Maher and Connon were the first to use thioureas to
coupling of trans-cinnamaldehyde with cyclopentenone in the
accelerate the DABCO-promoted MBH reaction.6 Recently,
presence of 50 mol% MgI2. The reaction mediated by the most
several other thiourea-derived7 and BINOL-derived8 systems
nucleophilic catalyst (Fu’s chiral PPY I) occurred with the
highest yield (98%) but lower ee (81%) (Table 1, entry 1) than
have been reported. Each of these methods has been limited in
Fu’s less nucleophilic II, which delivered the product in a 96%
substrate scope to varying extents.
yield and 94% ee (Table 1, entry 2). Other catalytic nucleo-
The mechanism of the MBH reaction allows the use of a
Lewis acid cocatalyst to increase reaction rates.9 For example,
philes showed lower enantioselectivity and reactivity (Table 1,
entries 3–6). The chiral thiourea derived [(À)-HBTM V and
we recently reported a mild reaction system employing a 1 : 1 : 1
(À)-tetramisole VI] were also notably less reactive (Table 1,
ratio of catalytic amounts (10 mol%) of MgI2, TMEDA
entries 5 and 6) than the DMAP derivatives I and II.
and DMAP to accelerate the rates of the MBH reaction
between cyclic enones and enoates with aldehydes in methanol.10
Table 1 Enantioselective MBH reaction between cyclopenten-2-one
and trans-cinnamaldehyde
We were interested in an enantioselective process based on this
protocol utilizing cyclopentenone as
a substrate. MBH
adducts of cyclopentenone have potential utility towards the
total synthesis of natural products containing cyclopentenone
or cyclopent(en)yl moieties, including Lathyranoic acid A and
Euphorbia factor L11,11 as well as Acutaxyline A and B.12
Our initial studies identified chiral nucleophiles (Fig. 1),
which were capable of catalyzing the reaction of trans-
cinnamaldehyde with cyclopentenone in the presence of catalytic
Entry
Catalyst
Yielda (%)
eeb (%)
1
2
3
4
5
6
I
II
III
IV
V
98
96
45
89
5
81
94
54
45
63
48
Department of Chemistry, Texas A&M University, PO Box 30012,
College Station, TX 77842-3012, USA.
E-mail: connell@chem.tamu.edu; Tel: +1 979-845-5746
w Electronic supplementary information (ESI) available: Experimental
procedures for the preparation of Morita–Baylis–Hillman adducts;
copies of 1H and 13C NMR spectra of all compounds. See DOI:
10.1039/c001977a
VI
19
a
Isolated yield after purification by silica gel chromatography.
Enantiomeric excess determined by chiral HPLC (see the ESIw).
b
ꢀc
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With these data in hand, optimization of the reaction
conditions utilizing catalyst II was carried out (Table 2). At
À20 1C, no reaction was observed between trans-cinnam-
aldehyde and cyclopentenone in the absence of MgI2 (Table 2,
entry 1). However, increasing the amount of MgI2 from
10 mol% to 50 mol% increased the yield of the reaction from
45% to 96% yield without having a dramatic effect on the ee
(92% vs. 94%) (entries 2 and 5). Intermediate quantities of
MgI2 provided intermediate yields (entries 3 and 4). i-PrOH
proved to be the best solvent, delivering the product in
excellent yield while maintaining a high level of enantio-
selectivity compared to MeOH and EtOH (entries 6 and 7).
The use of less catalyst II (5 mol%) afforded a slower reaction
but no loss of ee (entry 8), while 20 mol% of catalyst II was no
better than 10 mol% (entry 5 vs. 9). Higher reaction concen-
tration had a negligible effect on the reaction (entry 10) while
higher temperatures eroded the observed ee (entries 11 and 12).
Lower temperature slowed the reaction with no marked
increase in enantioselectivity (entry 13).
Table 3 Enantioselective MBH reaction with various aldehydes
Entry Product
Time/h Yielda (%) eeb (%)
1
24
24
94
73
98
95
2
3
4c
24
24
96
93
94 (S)
94 (R)
We investigated the scope of this MBH reaction by examining
a variety of electrophiles (Table 3). For aromatic aldehydes,
the system is very efficient. The MBH reaction of 1-naphth-
aldehyde and cyclopentenone delivers the product in 94% yield
and 98% ee (Table 3, entry 1). The adduct of electron-rich
p-methoxybenzaldehyde is obtained in 73% yield and 95% ee
(Table 3, entry 2). The electron-poor p-nitrobenzaldehyde
afforded a lower yield (75%), likely due to solubility of the
aldehyde in i-PrOH (Table 3, entry 8).15 Additionally, this
chiral DMAP/MgI2 mixture afforded reasonable yields and
moderate ees for the aliphatic aldehydes. The lower yields
obtained in these cases are the result of incomplete reaction,
and extended reaction times will likely provide increased
yields.
5
6
24
24
87
81
94
92
7
8
24
24
92
75
89
89
To further examine the scope and utility of these reaction
conditions, a variety of cyclic and acyclic a,b-unsaturated
Table 2 Optimization of the MBH reaction
9
48
48
48
59
54
68
63
58
53
10
Entry MgI2 (mol%) II (mol%) Solvent Yielda (%) eeb (%)
11
1
2
3
4
5
6
7
8
0
5
10
10
10
10
10
10
10
5
20
20
10
10
10
i-PrOH NR
i-PrOH 21
i-PrOH 45
i-PrOH 57
i-PrOH 96
NA
80
92
93
94
77
53
94
94
94
70
91
95
10
20
50
50
50
50
50
50
50
50
50
a
Isolated yield after purification by silica gel chromatography.
c
Determined by chiral HPLC (see the ESIw). The (À)-enantiomer
b
of catalyst II was used.
EtOH
89
MeOH 98
i-PrOH 60
i-PrOH 93
i-PrOH 92
i-PrOH 97
i-PrOH 94
i-PrOH 39
9
ketones and esters were treated with benzaldehyde, but no
significant reaction occurred. Similar to other reported MBH
catalytic systems (vide supra), the present system demonstrates
a limited scope with respect to the nucleophilic component, so
a careful analysis of substrates is necessary when evaluating
various MBH reaction catalysts.
10c
11d
12e
13f
a
Isolated yield after purification by silica gel chromatography.
c
b
Determined by chiral HPLC (see ESIw). [c] = 0.1 M instead of
d
e
0.05 M. Reaction performed at 20 1C. Reaction performed at
0 1C. Reaction performed at À50 1C.
In summary, we have developed an effective asymmetric
MBH reaction involving the addition of cyclopentenone to
f
ꢀc
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aromatic and aliphatic aldehydes catalyzed by Fu’s planar
chiral DMAP derivative II in conjunction with readily
available MgI2 as a cocatalyst. The products are obtained in
good to excellent yields and moderate to excellent enantio-
meric excesses. Perhaps more importantly, the work described
here shows that the scope of reactions catalyzed by Fu’s planar
chiral DMAP catalysts can be increased by employing a simple
cocatalyst, a concept which, to our knowledge, has not been
documented previously. Efforts are underway to further
elucidate the mechanistic details of this reaction system
which should in turn allow for future advances in scope and
selectivity.
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The Norman Hackerman Advanced Research Program and
the Robert A. Welch Foundation (A-1623) are gratefully
acknowledged for support of this research.
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ꢀc
This journal is The Royal Society of Chemistry 2010
2646 | Chem. Commun., 2010, 46, 2644–2646