A chiral primary amine thiourea catalyst for the highly enantioselective direct conjugate addition of α,α-disubstituted aldehydes to nitroalkenes

Article abstract of DOI:10.1002/anie.200602221

(Chemical Equation Presented) Dual activation: The bifunctional primary amine thiourea catalyst 1 promotes the highly enantioselective direct conjugate addition of α-branched aldehydes to nitroalkenes (see scheme). Cooperative activation of both the nucleophile and electrophile allows the use of mild reaction conditions and provides access to a wide variety of adducts with vicinal quaternary and tertiary stereogenic centers (>90% ee).

Full text of DOI:10.1002/anie.200602221

Communications
Organocatalysis
group] as a possible attractive solution to the challenging
problem of generating chiral building blocks with contiguous
quaternary and tertiary stereogenic centers.[10] We describe
here the identification of primary amine thiourea derivatives
as effective and general catalysts for the enantio- and
diastereoselective conjugate addition of a,a-disubstituted
aldehydes to nitroalkenes.
Despite extensive studies on secondary amine catalyzed
conjugate additions of carbonyl compounds to nitroal-
kenes,[11,12] only two reports by Barbas and co-workers have
addressed a,a-disubstituted aldehydes as potential nucleo-
philic partners.[13] We selected the challenging combination of
1-nitrohex-1-ene, a b-alkyl-substituted nitroalkene, and 2-
phenylpropionaldehyde as model substrates for initial opti-
mization studies,[14] with the hope that broad reaction scope
would ensue. Among the primary amine thiourea catalysts
examined, derivatives 1 and 3 were found to induce partic-
ularly high diastereo- and enantioselectivities (Table 1,
DOI: 10.1002/anie.200602221
AChiral Primary Amine Thiourea Catalyst for the
Highly Enantioselective Direct Conjugate
Addition of a,a-Disubstituted Aldehydes to
Nitroalkenes**
Mathieu P. Lalonde, Yonggang Chen, and
Eric N. Jacobsen*
The remarkable advances in the application of secondary
amines as enantioselective catalysts are tied to the accessi-
bility of divergent carbonyl activation pathways, either via
nucleophilic enamines or electrophilic imminium ions, and to
the highly effective stereoinduction that is achievable in
reactions of such covalent intermediates.[1] By comparison,
little progress has been made in the development of small-
molecule chiral primary amine catalysts,[2] a fact that is
attributable, at least in part, to unfavorable imine–secondary
enamine equilibria.[3] Nevertheless, primary amine catalysis is
effectively exploited by enzymes such as type I aldolases,
decarboxylases, and dehydratases, each of which contain
catalytically active lysine residues.[4] We became interested in
the possible use of chiral primary amine thiourea derivatives
in enamine catalysis motivated partly by their straightforward
accessibility from chiral 1,2-diamines and partly by recent
successes in the application of related tertiary amine thiourea
frameworks as bifunctional catalysts in a wide variety of
enantioselective catalytic reactions.[5–7] In this vein, Tsogoeva
and Wei, as well as our own group, reported recently the
successful application of primary amine thiourea catalysts to
the addition of ketones to nitroalkenes.[8] The proven ability
of secondary enamines to participate in conjugate addition
reactions between sterically demanding partners[9] prompted
us to examine the primary amine thiourea catalyzed addition
of racemic a,a-disubstituted aldehydes to b-substituted
Michael acceptors [Eq. (1); EWG = electron-withdrawing
Table 1: Optimization studies.
[a]
Entry Catalyst H2O [equiv]Yield [%]
d.r. (syn/anti)[a] ee [%][b]
1
2
3
4
5
6
7
8
1
3
1
1
1
2
4
3
0
0
2.0
5.0
10
5.0
5.0
5.0
34
93
56
64
54
31
<5
100
>10:1
>10:1
>10:1
>10:1
>10:1
>10:1
–
96
99
96
96
96
96
–
>10:1
99
[a]Product yields determined by 1H NMR spectroscopic analysis of the
crude reaction mixture using trimethoxybenzene as an internal standard.
[b]Determined by chiral HPLC analysis compared with authentic racemic
material.
entries 1 and 2). The best results were obtained using only a
twofold excess of aldehyde relative to nitroalkene.[15,16]
Diaminocyclohexane-derived catalyst 1 proved more broadly
applicable and was selected for further optimization as
catalyst 3, derived from diphenylethylene diamine, was
found subsequently to afford optimal results only in reactions
involving 2-phenylpropionaldehyde.[17] Variation of standard
reaction parameters (solvent, temperature, reagent ratios,
concentration, catalyst loading) failed to improve the product
yield, however, inclusion of controlled amounts of water led
to significant improvements (Table 1, entry 1 vs 3–5, 2 vs 8).[18]
Catalysts bearing a secondary amide (1 and 3) afforded higher
levels of substrate conversion and product yields than their
tertiary amide counterparts (e.g. 2), while derivatives lacking
an amide, as in 4, were virtually inactive (Table 1, entry 7).
[*]M. P. Lalonde, Dr. Y. Chen, Prof. Dr. E. N. Jacobsen
Department of Chemistry and Chemical Biology
Harvard University
Cambridge, MA 02138 (USA)
Fax: (+1)617-496-1880
E-mail: jacobsen@chemistry.harvard.edu
[**]This work was supported by the NIH (GM-43214 and P50
GM069721). M.P.L. gratefully acknowledges the NSERC and La
Fondation Baxter et Alma Ricard for graduate scholarships. Dr.
Richard Staples is acknowledged for the determination of the crystal
structure of 22.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
A wide range of a,a-disubstituted aldehyde/nitroalkene
combinations were surveyed to determine the scope and
limitations of the methodology. Excellent enantioselectivity
and useful levels of diastereoselectivity were obtained with a
variety of substrates by using catalyst 1 (Table 2). The highest
levels of diastereoselectivity (> 10:1 d.r.) were observed for
aldehydes bearing phenyl or ethereal (R1 = OPh and p-
MeOC6H4CH2O) a-substituents. At the other extreme, only
modest diastereoselectivities (2.1–4.7:1 d.r.) were obtained
for adducts 9, 10, and 19–22, results that were deemed
Table 2: Asymmetric addition of a,a-disubstituted aldehydes to nitroalkenes catalyzed by 1.[26]
Product
Yield [%]d.r. (
54
syn/anti)
ee [%]Product
96 (syn)
Yield [%d.]r. (
91
syn/anti)
ee [%]
28:1
23:1
99 (syn)
34
61
>50:1
97 (syn)
87
82
>50:1
99 (syn)
99 (syn)
99 (anti)
99 (syn)
99 (anti)
3.3:1
3.9:1
99 (syn)
98 (anti)
99 (syn)
94 (anti)
87
6.3:1
86
6.6:1
99 (syn)
95 (anti)
99 (syn)
97 (anti)
85
79
78
7.1:1
5.4:1
85
94
78
6.6:1
5.6:1
13:1
99 (syn)
95 (anti)
99 (syn)
96 (anti)
94 (syn)
92 (anti)
10.4:1
96 (syn)
99 (syn)
97 (anti)
99 (syn)
99 (anti)
98
63
2.1:1
4.7:1
82
81
3.1:1
3.8:1
98 (syn)
92 (anti)
99 (syn)
99 (anti)
TBS=tert-butyldimethylsilyl.
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Table 3: Diphenylethylene diamine derived catalysts in the addition of 2-
phenylpropionaldehyde to trans-b-nitrostyrene.
satisfactory nonetheless given the minimal degree of steric
differentiation between the aldehyde a-substituents. A vari-
ety of b-aryl-, b-heteroaryl-, and b-alkyl-substituted nitro-
alkenes underwent conjugate addition in good yields regard-
less of their electronic properties. The highly electrophilic
3,3,3-trifluoro-1-nitroprop-1-ene afforded adduct 7 in high ee
and d.r. but only modest yield, a result ascribable to its
susceptibility to effect alkylation of the primary amine group
of 1.[19,20]
As noted above, diphenylethylene diamine derivative 3
proved a more effective catalyst than 1 in conjugate additions
involving 2-phenylpropionaldehyde as the nucleophilic part-
ner. The effect was especially pronounced in additions to
trans-b-nitrostyrene, which proceeded in substantially higher
enantioselectivity and diastereoselectivity with catalyst 3
compared to 1 (Table 3, entries 1–2). Further modifications
to the catalyst structure led to the observation that valine-
derived catalyst 23 afforded almost identical results to tert-
leucine-derived 3, a significant outcome given the substan-
tially lower cost of the precursor amino acid and also because
this equivalence has not been observed in any other tert-
leucine-derived thiourea-catalyzed reactions. The signifi-
cantly diminished yield and ee values obtained with mis-
matched catalyst 24 point to the cooperative role of the
stereochemistry of both the amino acid and the diamine in
simultaneously defining conjugate addition selectivity and
catalyst activity.
A catalytic cycle consistent with our experimental obser-
vations is depicted in Scheme 1. Tautomerization of imine A,
resulting from the condensation of aldehyde and catalyst 1,
leads to the formation of an E or Z enamine. Preferred
reaction via the thermodynamically favorable E enamine B is
proposed to account for the observed diastereoselectivities.[21]
Binding of the nitroalkene through only one oxygen atom
allows the enamine to attain sufficiently close proximity for
carbon–carbon bond for-
Entry
Catalyst
Yield [%][a]
d.r.
ee [%]
(syn/anti)[a]
(syn/anti)[b]
1
2
3
4
1
3
23
24
100
86
84
1.2:1
8.6:1
11.9:1
6.9:1
67:3
97:24
97:32
71:40[c]
35
[a]Product yields were determined by 1H NMR spectroscopic analysis of
the crude reaction mixture using trimethoxybenzene as an internal
standard. [b]Determined by chiral HPLC analysis compared with
authentic racemic material. [c]Products are of opposite absolute
configuration to those in entries 1–3.
analogous to G requires strong aqueous acid.[23i,l] The
beneficial role of water may lie in increasing turnover by
eliminating a potential catalyst sink (formation of F) and
accelerating imine (E) hydrolysis. However, cyclobutane G is
unlikely to undergo hydrolysis under the catalytic conditions,
and its irreversible formation may be responsible for catalyst
deactivation.[24]
We have shown that chiral primary amine thiourea
catalysts are highly effective in the addition of a,a-disubsti-
tuted aldehydes to nitroalkenes, generating synthetically
versatile nitroaldehyde adducts. Simultaneous activation of
both nucleophile and electrophile through a combination of
effects typically associated with enzymes (approximation,
mation to occur (intermedi-
ate C).[22] Proton transfer
(D to E) followed by imine
hydrolysis yields the prod-
uct and regenerates the cat-
alyst. Zwitterionic species
analogous to D have been
invoked in numerous stud-
ies concerning the mecha-
nism of conjugate addition
of enamines to nitroal-
kenes.[23] These intermedi-
ates may undergo hydroly-
sis to the nitroaldehyde
product or collapse to 1,2-
oxazine-N-oxide and cyclo-
butane intermediates F and
G, respectively. Although
1,2-oxazine-N-oxides such
as
F undergo hydrolysis
readily in the presence of
atmospheric moisture,[23l]
Scheme 1. Proposed mechanism for the asymmetric addition of a,a-disubstituted aldehydes to nitroalkenes
hydrolysis of cyclobutanes catalyzed by 1. Bn=benzyl.
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Angewandte
Chemie
hydrogen bonding, and covalent nucleophilic catalysis) allows
this challenging transformation to take place under mild
reaction conditions and with broad substrate scope. Interest-
ingly, and in contrast to many enzymes, these bifunctional
catalysts function by sequestering substrates from hydro-
phobic organic solvents into hydrophilic active sites. This
study adds to a growing body of evidence suggesting that
dual-activation catalysis with simple bifunctional organic
frameworks holds substantial promise for asymmetric syn-
thesis.[25] Our current efforts are focused on further develop-
ment of conjugate addition reactions promoted by thiourea
amine derivatives, as well as on the design of new bifunctional
frameworks for use in asymmetric catalysis.
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pressure of nitrogen at room temperature, thiourea catalyst 1
(75.3 mg, 0.20 mmol, 20 mol%) was loaded into an oven-dried 25-
mL round-bottomed flask equipped with a magnetic stir bar, rubber
septum, and nitrogen inlet. The catalyst was dissolved in dichloro-
methane (6.7 mL). Water (90.1 mL, 5.0 mmol, 5.0 equiv) and 2-
phenylpropionaldehyde (265.4 mL, 2.0 mmol, 2.0 equiv) were subse-
quently added by syringe. The resulting clear colorless solution was
stirred for approximately 2 min. Addition of 1-nitropropene (87.1 mg,
1.0 mmol, 1.0 equiv) by syringe produced a light yellow solution. The
rubber septum was quickly replaced with a yellow polyethylene
stopper (to avoid absorption of dichloromethane by the septum), and
the reaction mixture was stirred for 24 h at room temperature.
Aqueous hydrochloric acid solution (1m, 7 mL) was added to the
reaction flask, and the resulting biphasic mixture was stirred
vigorously for 5 min at room temperature. The biphasic mixture
was transferred to a separating funnel, and additional portions of
dichloromethane (30 mL) and 1m HCl (30 mL) were added. The
phases were separated, and the aqueous layer was washed with
dichloromethane (30 mL). The organic layers were combined and
washed with saturated aqueous sodium bicarbonate solution (30 mL),
saturated aqueous sodium chloride solution (30 mL), dried over
anhydrous sodium sulfate, filtered, and concentrated under reduced
pressure. The resulting yellow residue was purified by chromatog-
raphy on silica (8% diethyl ether/hexanes), providing the title
compound as a colorless/light yellow liquid in 91% yield (201.1 mg)
in 23:1 diastereomeric ratio and with 99% ee (major diastereomer) as
determined by HPLC (Chiralpak AD-H, 2.0% propan-2-ol/hexanes,
1.0 mLminÀ1, 230 nm; tr(minor enantiomer, minor diastereomer) =
11.83 min, tr(major enantiomer, minor diastereomer) = 12.87 min,
tr(minor enantiomer, major diastereomer) = 13.82 min, tr(major en-
antiomer, major diastereomer) = 15.48 min). [a]2D5 = + 88.68 (c =
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1
0.0200 g/2.0 mL, chloroform); H NMR (400 MHz, CDCl3): d = 9.47
(1H, s), 7.42 (2H, t, J = 7.3 Hz), 7.34 (1H, t, J = 7.3 Hz), 7.24 (2H, d,
J = 7.3 Hz), 4.57 (1H, dd, J = 3.3, 12.0 Hz), 4.19 (1H, dd, J = 10.6,
12.0 Hz), 3.17 (1H, m), 1.48 (3H, s), 0.81 ppm (3H, d, J = 7.0 Hz);
13C NMR (100 MHz, CDCl3): d = 200.6, 137.4, 129.4, 128.2, 127.4,
78.8, 55.9, 37.1, 14.6, 13.2 ppm; IR (neat): n˜ = 3060 (w), 2981 (m), 2819
(w), 2719 (w), 1722 (s), 1533 (s), 1496 (m), 1446 (m), 1377 (s), 763 (m),
702 (m); HRMS (ESI): calcd for [C12H15NO3+NH4]+: 239.1396;
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Received: June 2, 2006
Published online: August 28, 2006
Keywords: amines · asymmetric catalysis · conjugate addition ·
.
organocatalysis
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Communications
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[24] See Supporting Information for experimental evidence for the
formation of G.
[25] For a discussion of dual activation within the context of
asymmetric catalysis by chiral hydrogen-bond donors, see
Ref. [6b].
[26] Yields are of isolated products after column chromatography.
Diastereomeric ratios and enantiomeric excesses were deter-
mined by SFC or HPLC analysis compared with authentic
racemic material. The absolute configuration of 22 was deter-
mined by X-ray crystallography, whereas those of 6–21 were
inferred.
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[12] For a review of asymmetric conjugate additions to nitroalkenes,
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[14] Secondary enamines conjugated to aromatic systems are known
to display low reactivity (see Ref. [9]). Relative to nitrostyrene
derivatives, inferior product yields have been reported in
additions of aldehydes to b-alkyl-substituted nitroalkenes (see
Refs. [11a,c–e]).
[15] Direct Michael additions to nitroalkenes promoted by secondary
amine catalysts typically require large (e.g. tenfold) excess of
aldehyde due to competing aldol pathways (see Ref. [11]).
[16] 2-Phenylpropionaldehyde was recovered in 2.5% ee, thus
indicating that a simple kinetic resolution mechanism is not
operative.
[17] The addition of 2-methylvaleraldehyde to trans-b-nitrostyrene
catalyzed by 20 mol%
conversion.
3 proceeded with less than 10%
[18] The benefit of added water has been observed in other primary
amine catalyzed transformations (see references [2c–j, 8a]).
[19] For the conjugate addition of a-amino acid esters to trans-3,3,3-
trifluoro-1-nitropropene, see: M. Molteni, A. Volonterio, M.
Zanda, Org. Lett. 2003, 5, 3887 –3890.
[20] The addition of amines to nitroalkenes has been extensively
studied with very few stable adducts isolated. Anilines and
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