Enantioselective organocatalytic mannich reactions with autocatalysts and their mimics

Article abstract of DOI:10.1021/jo902500b

(Figure Presented) The Mannich reactions previously extensively investigated with organocatalysis of L-proline and other related small molecules were reinvestigated with detailed stereochemical analysis of their autocatalysis pathways, through employment

Full text of DOI:10.1021/jo902500b

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SCHEME 1. Remarkable Chiral Catalyst-Product Structural
Resemblance in the Soai Organometallic Autocatalysis Reaction
Enantioselective Organocatalytic Mannich Reactions
with Autocatalysts and Their Mimics
Xinbo Wang,† Yongbo Zhang,†,‡ Haibo Tan,†
Yanchao Wang,† Peng Han,† and David Zhigang Wang*,†
†School of Chemical Biology and Biotechnology, Shenzhen
Graduate School of Peking University, Shenzhen University
Town, Shenzhen 518055, China, and ‡School of Chemistry and
Chemical Engineering, South China University of Science and
Technology, Wushan Road 381, Guangzhou 510641, China
predominance.2 But experiments supporting this scenario did
not arrive until 1995, when Soai and his co-workers described
autocatalytic additions of dialkylzincs to pyrimidine carbalde-
hydes3 (Scheme 1). Due to the operation of strong positive
nonlinear effect, the chirality replication efficiency observed in
these reactions is enormously high,4 and a tiny initial chirality
imbalance created by even random chance5 or carbon isotopes6
can autocatalytically lead to very high levels of enantiomeric
excess. While it is not readily conceivable if such air-sensitive
organometallics could possibly function comparably well under
prebiotic environment, this landmark accomplishment has in-
spired us to embark on a search of small organic molecule-based
autocatalysis systems that are capable of delivering high en-
antioselections under more biologically relevant conditions. On
a more general perspective, although such organoautocatalytic
processes developed at this early stage may not benefit from the
nonlinear effect for enantioselective amplification, we believe
they would serve as structurally well-defined small-molecule
models that should aid our understanding of the stereochemical
control modes involved in biological replication events.7
The field of organocatalysis has recorded tremendous pro-
gress during the past few years, as witnessed by the discovery
and development of an unusually diverse range of small mole-
cules capable of promoting impressive reactivity and stereo-
selectivity.8 In spite of these marvelous advancements, surpris-
ingly, enantioselective organoautocatalysis,9 a process in which
a small organic molecule product enantioselectively catalyzes
its own formation, has for long represented a completely un-
explored area until the pioneering work of Mauksch, Tsogoeva,
and co-workers, who reported in 2007 the product catalysis in
the reaction of acetone with an imine. Such fully organoauto-
catalytic reactions, when efficiently developed, not only have
dzw@szpku.edu.cn
Received December 8, 2009
The Mannich reactions previously extensively investigated
with organocatalysis of L-proline and other related small
molecules were reinvestigated with detailed stereochemical
analysis of their autocatalysis pathways, through employ-
ment of both the products themselves and their close
structural mimics as the catalysts. These organo-autocata-
lytic processes function as meaningful molecular models
toward understanding the origin and maintenance of homo-
chirality under biologically relevant conditions.
Many molecules naturally occurring in the biological world,
such as L-amino acids and D-sugars, are chiral, meaning they
exist in only one form of the two possible mirror images. But
exactly how did one mirror image form start out and come to
dominate the other, i.e., the problem of the origin and main-
tenance of homochirality, remains to be a fundamental chal-
lenge yet to be solved. However, several inspirational hypo-
theses have been advanced,1 the most appealing one being the
autocatalysis concept proposed by Frank in 1953, in which he
suggested that reactions whose products themselves act as the
catalysts in their formations could in principle amplify a slight
enantiomeric excess of one enantiomer into its overwhelming
(3) Soai, K.; Shibata, T.; Morioka, H.; Choji, K. Nature 1995, 378, 767–
768.
(4) (a) Shibata, T.; Yamamoto, J.; Matsumuto, N.; Yonekubo, S.;
Osanai, S.; Soai, K. J. Am. Chem. Soc. 1998, 120, 12157–12158. (b) Soai,
K.; Shibata, T.; Sato, I. Acc. Chem. Res. 2000, 33, 382–390. (c) Soai, K.;
Kawasaki, T. Chirality 2006, 18, 469–478. (d) Todd, M. Chem. Soc. Rev.
2002, 31, 211–222.
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(b) Singleton, D.; Vo, L. Org. Lett. 2003, 5, 4337–4339.
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Soai, K. Science 2009, 324, 492–495.
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Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–5175.
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DOI: 10.1021/jo902500b
r
Published on Web 03/02/2010
J. Org. Chem. 2010, 75, 2403–2406 2403
2010 American Chemical Society

Wang et al.
JOCNote
significant practical value, as they eliminate the often trouble-
some problem of catalyst recovery and product purification,
but also possess considerable theoretical merits, as they offer
conceptually new models for enantioselective molecular repli-
cation, a scenario that should pave the way to the discovery of
broadly useful systems for efficient chirality amplification for
which the Soai organometallic autocatalysis processes appear
up to now to be the only successful examples (Scheme 1).6
In a new helix electronic theory of molecular chirality and
chiral interactions published recently by one of us,10 it was
reasoned that high enantioselectivity would most likely
arise from a type of autocatalytic system in which the product
not only catalyzes its own formation, but also does so through
a corresponding enantioselection-determining step in which
the forming product and its catalyst share an identical or
closely resembling structure, thereby ensuring a maximum
level of stereochemical matching and enantioselection.10b,d
In this context, the Soai organometallic autocatalytic
addition of ZniPr2 to pyrimidine-5-carbaldehyde reaction
(Scheme 1) represents an outstanding example in which the
forming product (highlighted in blue) structurally fully
mirrors the chiral catalyst (in red) in the transition state
elucidated through various mechanistic studies.11 This un-
ique feature was not yet examined in those limited few
systems9,12 in which the catalysis stereochemical courses
were reported to be significantly influenced by their reaction
products, and this feature, in conjunction with the strong
positive nonlinear effect13 involved in aminoalcohol-Zn-
catalyzed asymmetric alkylation of aldehydes, are responsi-
ble for the extremely efficient chirality amplification ob-
served in the Soai systems. Guided by this new conceptual
framework, we became interested in exploring the possibility
of autocatalysis pathways in the Mannich-type condensation
of protected imines and carbonyl compounds (Scheme 2).
The reactions were widely studied with L-proline14 and
related catalysts,15 yielding often syn- or anti-products in
SCHEME 2. Proline Catalysis and Autocatalysis Mechanistic
Scenarios in the Organocatalytic Mannich Reactions between
Protected Imines and Carbonyl Compounds
high enantioselectivities. A transition state assembly A in-
volving concomitant enamine activation of the carbonyl
precursor and hydrogen bonding to electrophilic imine has
been elegantly derived from experimental16 as well as com-
putational17 investigations.
We envisioned that the amine and carbonyl moieties in the
Mannich product may well mimic the roles of the bifunc-
tional proline thus leading to enantioselective autocatalysis.
This hypothesis was illustrated through the intermediacy of
B, it was a remarkable observation that in B the catalyst
portion (in red) and the forming product (in blue) are likely
to share exactly the same structural characters. The feasi-
bility of such an enamine-type carbonyl substrate activation
by its Mannich product is supported by the observation of
vinyl proton resonance at 5.64 ppm when mixing an aldehyde
2e (see entry 5, Table 1) with its product mimic catalyst 3e in
d6-DMSO. Mauksch, Tsogoeva, and their co-workers had
reported autocatalysis in the reaction of acetone with imine 1
(Table 1) under various catalyst loadings inducing 29-96%
9
ee; Cordova and his co-workers had communicated that the
ꢀ
(10) For a full account of the theory see: (a) Wang, D. Z. Tetrahedron
2005, 61, 7125–7133. and its online Supporting Material. (b) Wang, D. Z.
Tetrahedron 2005, 61, 7134–7143. For a concise summary of the major points
see: (c) Wang, D. Z. Mendeleev Commun. 2004, 6, 244–247. For a theoretical
treatment see: (d) Wang, D. Z. Chirality 2005, 17, S177–S182.
(11) (a) Buono, F. G.; Blackmond, D. G. J. Am. Chem. Soc. 2003, 125,
8978–8979. (b) Blackmond, D. G.; MacMillian, C. R.; Ramdeehul, S.;
Schorm, A.; Brown, J. M. J. Am. Chem. Soc. 2001, 103, 10103–10104. (c)
Buono, F. G.; Iwamura, H.; Blackmond, D. G. Angew. Chem., Int. Ed. 2004,
43, 2099–2103. (d) Gridnev, I. D.; Brown, J. M. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5727–5731. (e) Gridnev, I. D.; Serafimov, J. M.; Brown, J. M.
Angew. Chem., Int. Ed. 2004, 43, 4884–4887. (f) Gridnev, I. D.; Serafimov, J.
M.; Quiney, H.; Brown, J. M. Org. Biomol. Chem. 2003, 1, 3811–3819.
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6740–6741. (b) Sievers, D.; von Kiedrowski, G. Nature 1994, 369, 221–224.
reaction of propionaldehyde and 1 gave product in merely
1% yield and 40% ee when 30% mol of the product was
employed as the catalyst.18 Due to the indistinguishable
catalyst-product structures, in these reports the character-
izations on the yields, enantio- and diastereoselectivities of
the newly formed autocatalysis products, were indirectly
derived on the premise that the catalyst initially added into
the reaction mixture remained intact. This, however, was not
necessarily the case as the instability of the Mannich
products had already been noted by several authors.14,15 In
the present study, we therefore desired to employ the catalyst
3 as an excellent product structure mimic, which was found
to differentiate itself from its product in both NMR and
chiral HPLC analysis thus ensuring an accurate account
of both the reaction reactivity and stereoselectivity in
autocatalytic processes. The alkyne moiety in 3 may offer
additional benefits in catalyst-product isolation through
click chemistry technology.19 3 itself could be readily
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(c) Szlosek, M.; Figadere, F. Angew. Chem., Int. Ed. 2000, 39, 1799–1901. (d)
Bolm, C.; Bienewald, F.; Seger, A. Angew. Chem., Int. Ed. 1996, 35, 1657–
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III. J. Am. Chem. Soc. 2002, 124, 1866–1867. (b) Cordova, A.; Notz, W.;
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1842–1843. (c) Notz, W.; Tanaka, F.; Watanabe, S.; Chowdari, N. S.;
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Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 1040–1041. (e)
Zhang, H.; Mifsud, M.; Tanaka, F.; Barbars, C. F., III. J. Am. Chem. Soc.
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TABLE 1. Enantioselective Aldehyde Mannich Reactions Promoted by Autocatalyst Mimic 3d
catalyst 3 before reactionb
catalyst 3 after reaction
autocatalysis product 4
eesyn, % eeanti, % yield, %
entrya
R
cat., % AcOH
dr
eesyn, %
eeanti, %
dr
eesyn, %
eeanti, %
dr
1
2
3
4
5
6
7
8
9
Me
nPr
nPent
Decc
iPr
15
15
15
15
15
5
10
30
15
15
15
15
0
0
0
0
0
0
0
0
15
30
50
100
3:1
11:1
11:1
20:1
99
99
95
99
99
99
99
99
99
99
99
99
20
99
99
93
99
99
99
99
99
99
99
99
3:1
6:1
6:1
2:3
16:1
4:3
4:3
3:2
2:3
1:2
3:2
1:4
98
99
93
4
99
96
95
98
78
89
99
45
44
75
99
91
99
90
87
96
96
93
70
88
1:1.4
1:9
1.3:1
1:2.2
1:1
1:10
1:10
1:8
1:11
1:8
5:1
1:6
99
55
52
77
99
64
3
77
26
33
99
47
26
15
99
91
90
99
99
99
99
99
99
99
15
27
37
87
31
29
41
45
43
37
65
33
20:1
iPr
2.3:1
2.3:1
2.3:1
2.3:1
2.3:1
2.3:1
2.3:1
iPr
iPr
iPr
10
11
12
iPr
iPr
iPr
aIn all entries, enantiomeric excesses were determined by HPLC analysis on a Daicel ChiralPak AS-H column, and diastereomeric ratios (dr = syn/
anti) were measured by 1H NMR integrations of the formyl hydrogen signals of the crude reaction mixture. b3 was prepared following published
procedure.14 cThe substrate is 4-decenal. dReaction conditions: Imine 1, 0.5 mmol; aldehyde 2, 0.75 mmol; autocatalyst mimic 3, 0.15 equiv; anhydrous
dioxane, 5 mL; room temperature, 48 h.
SCHEME 3. Enantioselective Organoautocatalytic Mannich
Reaction of Imine 1 and Isovaleraldehyde
prepared through L-proline-catalyzed Mannich reactions,
generally in high enantio- and diastereoselectivities (up to
99% ee for both syn- and anti-isomers).14 3 is labile for
isomerization at its R-aldehyde position, even at neat storage
or on brief exposure to silica gel, thus its inseparable
diastereomers were purified via silica gel flash chromatogra-
phy and used directly as the catalyst. Prior to each use, the
mixture was analyzed by NMR (via integration of the formyl
hydrogen signals) to ascertain its current diastereomeric
ratio. The results on 3-catalyzed Mannich reactions of 1
and various aldehydes 2 at room temperature were compiled
in Table 1. The reaction diastereomeric ratios were deter-
mined by NMR analysis of the original crude mixture, and
the enantiopurities of the autocatalysis product and the
recovered catalyst were determined by chiral HPLC analysis
of their chromatographically purified mixture.
As is evident from the data in Table 1, the enantiomeric
and diastereomeric purities of the catalysts could undergo
fairly significant changes during the reaction courses, for
example, in entry 4, while the catalyst initially had 99% ee in
syn-isomer, 93% ee in anti-isomer, and a high diastereomeric
ratio of 20:1, after the reaction these numbers degraded to
4% ee, 91% ee, and 2:3, respectively. The reactions generally
went to completion within 48 h of stirring at rt, the yields of
the autocatalysis products showed a high level of substrate
dependence and were comparable to those found in proline-
catalyzed processes. In all of the cases except entries 3 and 11,
while the catalysts are mainly syn-enantiomers, in their
corresponding products anti-enantiomers predominated
with various ratios (1:1.4 to 1:11). This observation may be
accommodated by isomerization and/or by the possibility
that the formation of anti-products via Z/E enamine geo-
metry equilibrium may characterize a relatively faster cata-
lysis channel. Also in all of the cases except entry 2, syn-
or anti-products 4 were formed in high enantiopurities
(>90% ee), demonstrating a high level of chirality induc-
tion. Particularly notable is the autocatalytic reaction invol-
ving isovaleraldehyde (entry 11), in which both isomers were
obtained in 99% ee and 65% yield. The use of acetic acid as a
potential imine-activating additive at various loadings was
also examined with the isovaleraldehyde substrate, and was
found to lead to higher product yields via suppressing the
Aldol reactions of 2 but impose limited effect on reaction
stereoselectivities.
It should be emphasized that without employing these
close structural mimics 3 as the autocatalysts, it is simply
impossible to probe the stereochemical changes that might
have been associated with these labile species during the
reactions. Equally significant is that autocatalysis with the
products themselves reproduced the results in Table 1. For
example, stirring isovaleraldehyde and imine 1 with 15% mol
of the autocatalyst (99% ee in both syn- and anti-isomers,
20:1 syn/anti diastereomeric ratio) and 50% mol of AcOH in
dioxane for 2 days at rt gave the product in 76%, i.e., a net
61% yield and 3.2:1 syn/anti diastereomeric ratio, and the
enantiomeric excess of both isomers was 99% ee (Scheme 3).
The three-component Mannich reactions20 involving ketone
5, aldehyde 6, and amine 7 were next investigated (Table 2).
Regardless of the loading of the autocatalyst mimic 8, the
product 9 was consistently obtained in >99% ee in both its
syn- and anti-enantiomers. Importantly, while in the aldehyde
(19) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004–2021.
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Wang et al.
JOCNote
TABLE 2. Enantioselective Ketone Mannich Reactions Promoted by Autocatalyst Mimic 8c
catalyst 8 before reactionb
catalyst 8 after reaction
autocatalysis product 9
entrya
cat., %
AcOH
dr
eesyn, %
eeanti, %
dr
eesyn, %
eeanti, %
dr
eesyn, %
eeanti, %
yield, %
1
2
3
10
20
30
0
0
0
24:1
24:1
24:1
97
97
97
-
-
-
>30:1
>30:1
>30:1
>99
>99
99
-
-
-
3.6:1
4.3:1
3.7:1
>99
>99
>99
>99
>99
>99
28
30
36
aIn all entries enantiomeric excesses and diastereomeric ratios (dr = syn/anti) were both determined by HPCL analysis on a Daicel ChiralPak AD-H
column. b8 was prepared following a published procedure.14 cReaction conditions: Ketone 5, 1 mL (in excess); aldehyde 6, 0.5 mmol; aniline 7, 0.55
mmol; autocatalyst mimic 8, 0.1-0.3 equiv based on the amount of 6; DMSO solvent, 5 mL; room temperature, 50 h.
SCHEME 4. Enantioselective Ketone anti-Mannich Reaction
Promoted by Autocatalyst Mimic 10
Mannich systems (Table 1) both the diastereomeric ratios and
enantiopurities of the autocatalyst 3 were generally eroded in
the reactions, those of 8 in the three-component Mannich
reactions were, however, found to be improved, and the
products were predominantly syn-enantiomers.
Employment of an anti-autocatalyst mimic 10 prepared via
L-tryptophan catalysis (85% ee in anti-isomer, 24:1 anti/syn
diastereomeric ratio)21 was also found to yield both syn- and
anti-product 9 in >99% ee, but again with syn-9 as the major
isomer (Scheme 4). These inherent syn-stereochemical prefer-
ences uncovered with both 8 and 10 should have an origin in
the E-enamine geometry generated from 5.
In summary, with detailed stereochemical analysis of both
the catalysts and the products, we presented herein an
accurate account of the autocatalytic Mannich reactions
previously extensively investigated with L-proline and other
chiral organocatalysts. These organoautocatalytic processes
offer striking advantages in such critical issues as new
enantiocontrol strategy and catalyst-product isolation, thus
representing an exciting new area of endeavors. In addition
to these practical merits, organoautocatalysis also provides
conceptually novel and structurally well-defined small-mo-
lecule models in which chirality can be replicated with useful
efficiency and under biologically relevant conditions. Our
results on the design and development of other highly
enantioselective organoautocatalysis reactions will be com-
municated in due course.
NMR to determine the diastereomeric ratios of both the auto-
catalyst mimic and the reaction product. The residue was then
purified via silica gel flash column chromatography (note that
silica gel exposure here may cause partial compound isomeriza-
tion, but this generally will not affect the subsequent enantio-
purity measurement), and the enantiomeric excesses of the
autocatalyst and the reaction product were determined through
chiral HPLC analysis.
General Procedure for the Enantioselective Ketone Three-
Component Mannich Reaction. To a solution of 4-nitrobenzal-
dehyde(6, 75mg, 0.5mmol), 4-(prop-2-ynyloxy)aniline(7, 81 mg,
0.55 mmol), and 1-hydroxypropan-2-one (5, 1 mL, in large excess)
in DMSO (5 mL) was added (3S,4R)-3-hydroxy-4-(4-methoxy-
phenylamino)-4-(4-nitrophenyl)butan-2-one (8, 10 mmol %,
20 mmol %, or 30 mmol % as noted in the text and based on
the aldehyde). The mixture was stirred for 50 h at room tem-
perature. The reaction was worked up by addition of phosphate-
buffered saline (PBS) solution (pH 7.4) and extraction with ethyl
acetate. The organic layer was dried with Na2SO4, and concen-
trated in vacuum to give the crude Mannich product, which was
used directly for HPLC analysis. Characterization data for
Experimental Section
1
compound 9: H NMR (500 MHz, CDCl3) 8.17 (d, 2H, J =
General Procedure for the Enantioselective Mannich-Reaction
between N-PMP-Protected Imine 1 and Aldehyde Donors 2. In a
typical experiment, N-PMP-protected imine 1 (0.5 mmol) was
dissolved in anhydrous dioxane (5 mL) and then to the solution
was added the corresponding aldehyde donor 2 (0.75 mmol),
followed by addition of the autocatalyst mimic 3 (15 mol %) that
was separately prepared following literature procedure. After
being stirred for 48 h at room temperature in a closed system, the
reaction mixture was worked up by addition of half-saturated
NH4Cl solution and extraction with ethyl acetate. The com-
bined organic layers were dried over MgSO4, filtered, and
8.6 Hz), 7.56 (d, 2H, J = 8.6 Hz), 6.69 (d, 2H, J = 8.8 Hz), 6.47
(d, 2H, J = 8.8 Hz), 5.03 (s, 1H), 4.45 (d, 1H, J = 1.9 Hz), 3.94
(b, 1H), 3.68 (s, 3H), 2.37 (s, 3H); 13C NMR (125 MHz, CDCl3)
206.4, 152.9, 147.4, 139.3, 128.1, 123.7, 115.2, 115.0, 79.9, 60.3,
58.8, 55.6, 24.9, 14.1. Anal. Calcd for C19H19N2O5: 355.1296.
Found: 355.1301.
Acknowledgment. This work was funded by the National
Science Foundation of China (grant 20872004), Shenzhen
municipal “Shuang Bai Project”, and Shenzhen Bureau of
Science and Technology.
1
concentrated in vacuum, then the residue was analyzed by H
Supporting Information Available: Experimental proce-
dures, compound characterizations, and chiral HPLC analysis.
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This material is available free of charge via the Internet at http://
pubs.acs.org.
2406 J. Org. Chem. Vol. 75, No. 7, 2010