Highly enantioselective aza Morita-Baylis-Hillman reaction catalyzed by bifunctional β-isocupreidine derivatives

Article abstract of DOI:10.1021/ja805122j

The aza-MBH reaction of imines 1 and β-naphthyl acrylate 2 in the presence of C-6′ modified β-isocupreidine derivative 1c (0.1 equiv) and β-naphthol 5 (0.1 equiv) afforded the corresponding (3S)-aza-MBH adducts 4 in high yield and excellent enantiomeric excess. These catalytic conditions allowed the aliphatic imines to be employed for the first time as electrophilic partners of the aza-MBH reaction. The coexistence of two H-bond donors with different acidic strengths was found to be crucial for the observed high enantioselectivity. Copyright

Full text of DOI:10.1021/ja805122j

Published on Web 08/26/2008
Highly Enantioselective Aza Morita-Baylis-Hillman Reaction Catalyzed by
Bifunctional ꢀ-Isocupreidine Derivatives
Nacim Abermil, Ge´raldine Masson,* and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-YVette Cedex, France
Received July 3, 2008; E-mail: zhu@icsn.cnrs-gif.fr; masson@icsn.cnrs-gif.fr
Table 1. Aza-MBH Reaction: Survey of Catalysis
The Morita-Baylis-Hillman (MBH) reaction and its aza
counterpart (aza-MBH) have attracted considerable attention among
synthetic chemists because of the utility of these adducts in organic
synthesis.1 Since one chiral center is created during these reactions,
the search for enantioselective variants has been the main focus of
the recent decades. However, the complexity of the reaction
mechanism made the development of the asymmetric version
particularly challenging, and only a few efficient catalyses have so
far been developed.2 For the aza-MBH reaction, the ꢀ-isocupreidine
(ꢀ-ICD),3,4 phosphinyl BINOLs,5 and 3-(N-3′-pyridinylaminom-
ethyl) BINOL6 developed by Hatakeyama, Shi, and Sasai, respec-
tively, stood out as the most efficient bifunctional catalysts. On
entry
catalyst
temperature (°C)
yield (%)b
ee (%)c
the other hand, Jacobsen documented that a combined use of a chiral
urea and DABCO can afford the aza-MBH adducts in excellent
ee, albeit with moderate yields.7 Despite these notable achievements,
two problems persisted with the enantioselective aza-MBH:8 (a)
acrylates including the activated HFIP and naphthol acrylates were
poor substrates providing the adduct in only moderate ee;3b,9 (b)
aliphatic imine failed to participate in this reaction.9 We report
herein a solution to these two issues by developing a novel catalysis
that was applicable to the reaction of acrylate with both aromatic
and aliphatic imines.
1a
2a
3a
4a
5
6
7
8
9
1b
1c
1d
1e
1c
1a
1f
1g
1c
1c
room temp
room temp
room temp
room temp
-30
81
99
88
64
87
39
75
57
80
95
30d
76d
69d
55d
91d
77d
78d
86d
79e
92f,g
-30
-30
-30
-30
10
-30
a Use of 20 mol % of catalyst 1. b Isolated yield after column chro-
matography. c Determined by chiral HPLC analysis. d Use of commercially
available ꢀ-naphtyl acrylate (2.0 equiv). e Use of freshly prepared ꢀ-naphtyl
acrylate (2.0 equiv). f The reaction was carried out in presence of 1c (10
mol %), ꢀ-naphtol 5 (10 mol %) and of freshly prepared ꢀ-naphtyl acrylate
(2.0 equiv). g The absolute configuration of 4a was determined to be
(S)-enriched. For details see Supporting Information.
The 6′-OH group in ꢀ-ICD 1a provided a handle for the
introduction of other H-bond donors that were modulable both
sterically and electronically. Consequently, a series of amides and
thioureas were synthesized from 1a and screened as catalysts using
N-(p-methoxybenzenesulfonyl)imine 2a and ꢀ-naphtyl acrylate 3
as model substrates.10 As summarized in Table 1, the previously
unknown 6′-N-Boc-glycine ꢀ-ICD (1c) gave much better results
than 6′-N-thiourea ꢀ-ICD 1b11 in terms of yield and ee (entries 2
vs 1). Catalysts 1d and 1e incorporating a N-trifluorosulfonyl and
N-thiourea glycinamide, respectively, afforded adduct 4a with
diminished ee (entries 3, 4). After a survey of reaction conditions
by varying the solvents, the temperatures, the stoichiometries, and
the additives, the optimal conditions consisted of performing the
reaction in CH2Cl2 at -30 °C in the presence of 0.1 equiv of catalyst
(cf. Supporting Information for details). Under these conditions,
catalyst 1c afforded the adduct 4a in 87% yield with 91% ee,
whereas the ꢀ-ICD 1a provided 4a in only 39% yield with 77% ee
(entries 5 and 6). The superiority of 1c over ꢀ-ICD 1a is thus clearly
demonstrated. Encouraged by these results, catalysts 1f and 1g
incorporating the N-Boc D- and L-phenylalanine unit, respectively,
were prepared. However, neither of them was as efficient as 1c as
catalyst (entries 7 and 8 vs 5). Serendipitously, when freshly
prepared acrylate 3 instead of the commercial one was used, 4a
was isolated with significantly reduced enantiomeric excess (entries
9 vs 5) under otherwise identical conditions. Noticing that com-
mercial acrylate 3 contained nearly 10% of ꢀ-naphthol, the influence
of the additives with different acidic strength was next investigated.
Analysis of these results (Supporting Information) showed that the
acidity of the additives affected significantly the yield and the ee
of 4a, with ꢀ-naphtol 5 being optimal (pKaH2O ) 9.5, pKaDMSO
)
17.2). When 1c along with ꢀ-naphthol (10 mol % each) were
employed as a dual catalysts, 4a was isolated in 95% yield with
92% ee. Too strong acids (PhCOOH) either reduced the yield of
4a or completely inhibited the reaction (PhSO3H) probably due to
the acid-base quench of active catalyst.12
The scope of this enantioselective aza-MBH reaction was next
examined (Table 2). For aromatic imines, the yield and the ee of
adducts 4 were not sensitive to the electronic properties of the aromatic
ring and the presence of strong electron withdrawing (NO2, entry 3)
or donating group (MeO, entry 4) were well tolerated. The ortho-
substituted aromatic imines, known to be challenging substrates for
the aza-MBH reaction, worked well. Indeed, 4h derived from 2,6-
dichlorobenzaldehyde was obtained in high yield and enantioselectivity
(entry 7). 2-Naphthylimine, 2-furylimine, and 2-cinnnamyl imine
(entries 8-10) were suitable substrates providing aza-MBH products
with excellent enantioselectivities (up to 98% ee).
All previous efforts to include aliphatic imines as electrophilic
partner in the MBH reaction have met with failure.13 It is thus
remarkable to find that, under our catalytic conditions, aliphatic
imines including R-unbranched imines readily participated in the
aza-MBH reaction to yield adducts 4l-p in moderate yields and
9
12596 J. AM. CHEM. SOC. 2008, 130, 12596–12597
10.1021/ja805122j CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective aza-MBH Reaction of Aromatic and
Aliphatic Iminesa
entry
R
time (h)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
p-MeC6H4 (4b)
p-ClC6H4 (4c)
p-NO2C6H4 (4d)
p-MeOC6H4 (4e)
m-BrC6H4 (4f)
m-MeC6H4 (4g)
2,6-dichloro-C6H3 (4h)
3-furyl (4i)
2-naphthyl (4j)
PhCHdCH (4k)
Ph(CH2)2 (4l)
n-pentyl (4m)
n-butyl (4n)
67
47
47
80
72
68
60
60
47
72
24
24
24
24
24
90
81
67
84
84
95
86
80
81
52
39
38
91
94
97
93
92
92
85
98
92
90
86
85
Figure 1
9
In summary, ꢀ-ICD derived bifunctional catalyst 1c in combina-
tion with ꢀ-naphtol served as a highly effective dual catalyst for
the asymmetric aza-MBH reactions. High yield and enantioselec-
tivity were uniformly observed in the case of aromatic imines. In
addition, the aliphatic N-sulfinyl imines have been successfully
employed in the aza-MBH reaction for the first time leading to the
corresponding adduct in over 85% ee. The pairing of cooperative
H-bonds was thought to be important in developing the present
catalysis and we assumed that such approach could be of general
implication in devising the novel catalytic systems.
10
11
12
13
14
15
41
85
i-PrCH2 (4o)
c-hexylCH2 (4p)
57(43)d
45
87(82)d
84
a Reaction conditions: imine (1 mmol), ꢀ-naphtyl acrylate (2 mmol),
ꢀ-naphtol (0.1 mmol), 1c (0.1 mmol) in CH2Cl2 (0.35 mL) at -30 °C or
aromatic imines and at 0 °C for aliphatic imines. b Isolated yield after
column chromatography. c Determined by chiral HPLC analysis. d Use
of ꢀ-naphtyl acrylate (2.0 equiv) freshly prepared without ꢀ-naphtol.
Acknowledgment. Financial support from CNRS is gratefully
acknowledged. N.A. thanks ICSN for a doctoral fellowship.
good enantioselectivities (Table 2, entries 11-15). In this case, the
reaction was best carried out at 0 °C in CH2Cl2. Naphthol had a
lesser impact on the enantioselectivity in this case; however, higher
yield was obtained in its presence (Table 2, entry 14).
Supporting Information Available: Catalysis optimization, spec-
troscopic data, ee measurement, and absolute configuration determi-
nation for 4a and 4o. This material is available free of charge via the
Internet at http://pubs.acs.org.
Selective and rapid proton transfer of one of the diastereomers of
the aldol adduct was thought to be crucial in determining the ee of the
MBH process based on the reversibility of the aldol reaction.14 This
guideline has been considered as a key element in designing the catalyst
for enantioselective MBH as well as aza-MBH reactions and the
capability of selectively promoting intramolecular proton transfer has
frequently been advanced to account for the success of bifunctional
catalyst. Indeed, the Hatakeyama’s and Sasai’s catalysts gave much
reduced enantioslectivity when the reaction was performed in the
presence of an external proton source.3,6,9 The positive effect of
ꢀ-naphthol in the present catalytic system is thus intriguing. Consider-
ing the low reversibility of the Mannich reaction,15 the coexistence of
two H-bond acceptors (enoate oxygen, imine nitrogen) and two H-bond
donors (naphthol, amide NH), we proposed following H-bond pairings
to explain the observed enantioselectivity. Thus, the E-enolate formed
upon addition of 1c to acrylate, being more Lewis basic, would form
a H-bond with the ꢀ-naphthol, which could in turn be stabilized by
π-π interaction between two naphthyl groups. The less basic neutral
imine would H-bonded to the less acidic amide NH.16 These
H-bonding pairs would be stronger and sterically less constrained than
the alternative intramolecular H-bond. Among two possible transition
states (only one was shown), that of 6 was less crowded and should
lead, after the C-C bond formation, to the adduct 7. The ꢀ-naphthol
mediated proton transfer followed by ꢀ-elimination would afford then
the observed (S)-adduct. It is interesting to note that enantioselectivity
dropped significantly when MeOH having similar pKa as amide NH
was used as cosolvent, probably due to the break down of the H-bond
pairs shown in 6.
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donor capacity, as found in the Sasai’s catalyst. The important role
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to C-6′ position was synthesized. Reaction of 2a and 3 in the
presence of 1h under otherwise identical conditions afforded the
adduct (S)-4a in comparable yield and ee as in the case of 1c. This
experiment indicated that the NHBoc in 1c might not be involved
in H-bonding in accord with the transition state models 6 and 7.
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J. AM. CHEM. SOC. VOL. 130, NO. 38, 2008 12597