Organocatalytic enantioselective decarboxylative aldol reaction of malonic acid half thioesters with aldehydes

Article abstract of DOI:10.1002/anie.201306297

Copycat: A highly enantioselective biomimetic aldol reaction of malonic acid half thioesters with a variety of aldehydes affords optically active β-hydroxy thioesters by employing the cinchona-derived sulfonamide organocatalyst 1. The synthetic utility of this protocol was demonstrated by performing formal syntheses of the antidepressants (R)-fluoxetine, (R)-tomoxetine, (-)-paroxetine, and (R)-duloxetine. Copyright

Full text of DOI:10.1002/anie.201306297

Angewandte
Chemie
DOI: 10.1002/anie.201306297
Organocatalysis
Organocatalytic Enantioselective Decarboxylative Aldol Reaction of
Malonic Acid Half Thioesters with Aldehydes**
Han Yong Bae, Jae Hun Sim, Ji-Woong Lee, Benjamin List,* and Choong Eui Song*
The direct asymmetric aldol reaction is one of the most
powerful and fundamental tools for forming new carbon–
carbon bonds and chiral hydroxy functional groups simulta-
neously.[1] Inspired by nature, the development of prefunc-
tionalized metal enolates and metal Lewis acids to mimic
type II aldolases have provided a general solution to accessing
enantioenriched b-hydroxy carbonyl compounds in coopera-
tion with chiral auxiliaries and metal complexes.[2] Specifi-
cally, the Mukaiyama aldol reaction[3] is general in scope and
is practical for controlling chemo-, stereo-, and enantioselec-
tivity with a pregenerated silyl enol ether. However, to gain
access to a variety of aldol products with defined stereo-
chemistry, it is necessary to develop a reaction with a distinct
catalytic reaction mode. Since 2000, primary and secondary
amine organocatalysts have shown excellent performance,
compared to chiral metal Lewis acids, for direct aldol
reactions and Mukaiyama-type reactions by forming an
enamine intermediate with a carbonyl compound.[4]
were shown to be poor substrates.[9b] Herein, we report the
first organocatalytic asymmetric aldol reaction of methyl-
substituted and unsubstituted MAHTs (2) with a variety of
aromatic and aliphatic aldehydes to afford enantioenriched b-
hydroxythioesters (3) by employing a sulfonamide-based
organocatalyst [Eq. (2)]. To the best of our knowledge, this
is the first example of metal-free enantioselective organo-
catalytic aldol reaction of MAHTs (2) with aldehydes (1), as
a polyketide synthase mimic,[12] to provide b-hydroxy thio-
esters (3).
Recent studies by us[6c] and others[5–10] using malonic acid
half thioesters (2, MAHTs) as ester enolate equivalents with
various electrophiles were compelling for the application of
organocatalytic aldol reactions to mimic polyketide synthases.
Moreover, the desired b-hydroxy thioesters 3 could readily be
transformed into various functional groups.[11] In addition,
such a reaction generates only CO2 as a sole by-product.
Recently, Shair et al. investigated the aldol reaction with
methyl-substituted MAHT (MeMAHT) using a chiral CuII/
bis(oxazoline) catalyst. Aliphatic aldehydes underwent the
aldol reaction to afford the a-methyl substituted aldol
products with excellent diatereo- and enantioselectivity
[Eq. (1)]. However, aromatic and a,b-unsaturated aldehydes
Polyketide synthases (PKSs) use the catalytic triad to
organize and stabilize the reaction intermediates by hydro-
gen-bonding interactions.[13] Thus, we presumed that Brønsted
acid/base bifunctional moieties in an organocatalyst might be
crucial for the deprotonation/stabilization of MAHTs and
orientation of the aldehyde for high facial selectivity
(Scheme 1). The model reaction was conducted by using the
MAHT 2a and benzaldehyde (1a) in MTBE/THF at room
temperature with different types of cinchona-based bifunc-
tional catalysts. As shown in Scheme 2, this preliminary
[*] J.-W. Lee, Prof. Dr. B. List
Max-Planck-Institut fꢀr Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mꢀlheim an der Ruhr (Germany)
E-mail: list@mpi-muelheim.mpg.de
H. Y. Bae, J. H. Sim, Prof. Dr. C. E. Song
Department of Chemistry, Sungkyunkwan University
300, Cheoncheon, Jangan, Suwon, 440-746 (Korea)
E-mail: s1673@skku.edu
[**] We gratefully acknowledge the financial support provided by the
Max Planck Society, the European Research Council (Advanced
grant “High Performance Lewis Acid Organocatalysis, HIPOCAT” to
B.L.), and the Ministry of Education, Science and Technology (the
Basic Science Research Programme (NRF-20090085824, MEST),
Priority Research Centres Programme (NRF-2012-R1A6A1040282,
MEST), SRC programme (2012-0000647, MEST), and the WCU
programme (R31-2008-10029, MEST). H.Y.B. acknowledges Global
Ph. D. Fellowship.
Scheme 1. Reaction mechanism of the polyketide synthase[13a] and
plausible working hypothesis for the organocatalytic aldol reaction of
the malonic acid half thioester 2 with a chiral hydrogen-bonding
donor/acceptor catalyst.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306297.
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Table 1: Screening of sulfonamide-based catalyst for the aldol reaction of
2a with benzaldehyde (1a).[a]
Entry
Catalyst
Solvent
t
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
C3
C4
C5
C6
C7
C8
C9
C10
C9
C9
C9
C9
C9
C9
MTBE/THF[d]
MTBE/THF
MTBE/THF
MTBE/THF
MTBE/THF
MTBE/THF
MTBE/THF
MTBE/THF
CH2Cl2
THF
1,4-dioxane
EVE
EtOAc
acetone
5 days
5 days
5 days
5 days
5 days
5 days
48 h
80
91
67
73
78
79
99
93
7
91
81
47
67
56
70
79
55
76
85
63
94
94
61
91
93
94
94
94
48 h
9
7 days
3 days
7 days
7 days
7 days
7 days
10
11
12
13
14
Scheme 2. Preliminary catalyst screening for the decarboxylative aldol
reaction of the MAHT 2a with benzaldehyde (1a). MTBE=tert-butyl
methyl ether, Tf=trifluoromethanesulfonyl.
[a] Reaction conditions: 1a (0.5 mmol), 2a (3.0 equiv), and catalyst
(30 mol%) in 2.5 mL of solvent at 208C. [b] Yields of products isolated
after purification by column chromatography. [c] Determined by HPLC
analysis on a chiral stationary phase (see the Supporting Information).
[d] MTBE/THF (9:1, v/v). EVE=ethyl vinyl ether, THF=tetrahydrofuran.
catalyst screening revealed that the cinchona-based thiourea
C1[14a,b] and squaramide C2[14c] led to low turnover numbers
and poor enantioselectivities. Gratifyingly, the sulfonamide-
based catalyst C3, which was developed previously in our
laboratory,[15] showed distingushed catalytic activity and
enantioselectivity (80% yield, 70% ee[16]) compared to C1
and C2. It should be noted here that a-unsubstituted MAHTs
such as 2a were not tolerated under the copper(II)-catalyzed
aldol reaction conditions, thus conversion into the desired
aldol product was not observed with either aromatic or
aliphatic aldehydes (see the Supporting Information).[9b]
These results prompted us to investigate the unique activity
and enantioselectivity of the sulfonamide-based catalyst C3 in
detail.
Since the hydrogen-bonding property of C3 could be
easily modulated by changing the substitution of the aromatic
functional group, we modified the aromatic moiety in the
catalyst to induce higher activity and facial selectivity
(Table 1). Sterically bulky substituents and strong p-electron
donors showed no significant improvement (entries 3–5).
Surprisingly, we could obtain remarkable catalytic activity
(99% yield) and enantioselectivity (94% ee) with a 1-
naphthyl substituent (entry 7). The highly fluorescent dansyl
sulfonamide catalyst C10, which also bears a 1-naphthyl
moiety together with an electron-donating group, showed
excellent catalytic performance (entry 8). However, the 2-
naphthyl substituent showed only modest activity and enan-
tioselectivity, and might imply a subtle effect from hydrogen
bonding and steric interactions (entry 6). In addition, the
solvent has an important effect on reactivity and enantiose-
lectivity. Although a range of aprotic nonpolar and polar
solvents afforded high enantioselectivity (entries 9–14),
MTBE/THF (entry 7) proved best with respect to both
chemical yield and enantioselectivity.
By using C9 as the optimal catalyst and 2a as the optimal
reaction partner (for effects of the substituents on various
MAHTs on the reaction outcome, see the Supporting
Information), we explored the scope of the organocatalytic
decarboxylative aldol reaction with a variety of aromatic and
aliphatic aldehydes. As summarized in Scheme 3, regardless
of the electronic nature of the aromatic substituent, high
enantioselectivity (up to 96% ee) was achieved with electron-
donating and electron-withdrawing substituents under the
standard reaction conditions.[17] Heteroaromatic aldehydes
were also smoothly converted into the desired products 3m
and 3n with high enantioselectivity. Nonaromatic aldehydes,
such as 1o and 1p were tolerated and afforded the desired
aldol products 3o and 3p, respectively, in good to excellent
enantioselectivity, although a significant amount of by-
products was observed.[18] Fortunately, enantiomerically
pure aldol products (3; > 99% ee) were easily isolated by
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Scheme 4. Facile conversion of the thioesters (R)-4 into the corre-
sponding aldehydes (R)-5 under the Fukuyama reduction conditions.[21]
M.S.=molecular sieves, TBS=tert-butyldimethylsilyl.
Scheme 5. Utility of the aldol products 3a, 3i, and 3m in the
asymmetric syntheses of valuable drug intermediates.
afford the products in an enantioenriched form in good yield.
Amide formation using 3a, 3i, and 3m provided the chiral
synthons 6, 7 and 8, respectively, as precursors for antide-
pressant drugs such as (R)-fluoxetine, (R)-tomoxetine, (À)-
paroxetine, and (R)-duloxetine.[22] The amides were obtained,
without any silica gel chromatography and tedious purifica-
tion, in high yields as a single enantiomer after a single
recrystallization (for detailed experimental results, see the
Supporting Information). Although our protocol requires
high catalyst loading (30 mol%) to facilitate the reaction, C9
could be easily recovered from the reaction mixture after
a simple acid/base workup to afford the pure catalyst C9 in
greater than 95% yield. The recovered catalyst was success-
fully reused for the subsequent runs and showed identical
activity and enantioselectivity, and can be ascribed to the
robustness of the catalyst (for details of catalyst recycling
experiments, see the Supporting Information).
To gain insight into the reaction mechanism as well as the
observed catalytic activity of C9, we conducted in situ
electrospray ionization mass spectroscopy analysis of the
reaction mixture (see the Supporting Information). In the
presence of C9 under the standard reaction conditions, we
observed signals at m/z 732.1 and m/z 838.2, which correspond
to the complex A + Na+ (catalyst/2a) and the complex B +
Na+ (catalyst/3a’; Scheme 6), respectively.[23] The observation
of the complex B indicated that the reaction operates by the
aldol addition of 2 to the aldehyde and subsequent decar-
boxylation to complete the catalytic cycle by releasing 3a.
Other types of catalytic reactions using MAHTs have been
Scheme 3. Substrate scope. General reaction conditions: 1 (0.5 mmol),
2 (3.0 equiv), and C9 (30 mol%) in 2.5 mL of MTBE/THF (9:1) at
208C. [a] Using HQN-1-Np-SA (C11) as a catalyst. [b] After single
recrystallization. [c] The reactions were performed at 108C.
a simple recrystallization because of the crystalline property
of the b-hydroxy thioesters 3. Notably, the present reaction
conditions were also compatible with the methyl-substituted
MAHT 2b and afforded anti-3q selectively with excellent
enantioselectivity (97% ee), although the chemical yield still
requires further optimization.
To demonstrate synthetic utility of our methodology with
enantioenriched b-hydroxy thioesters, the aldol product (R)-4
was subjected to Fukuyama reduction conditions. The desired
aldehyde (R)-5 was isolated without erosion of enantiopurity
(Scheme 4). Acetaldehyde has long been considered as
a problematic nucleophile for aldol reactions because of the
severe polymerization and self-aldol reactions of acetalde-
hyde, and the unstable nature of the aldol products.[19] No
successful suppression of the over-reaction of the product has
been reported to date in spite of extensive research.[20] Thus,
a-unsubstituted MAHTs can be used as feasible surrogates
for an acetaldehyde nucleophile in the aldol reaction.
Additional synthetic applications of the b-hydroxy thio-
esters 3 began with preparation of the aldol products 3a, 3i,
and 3m on a multigram scale. As summarized in Scheme 5,
the aldol reactions were performed on a 10 mmol scale to
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Scheme 6. A proposed reaction mechanism and observation of com-
plex A (C9/2a) and complex B (C9/3a’).
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known to proceed by a similar reaction sequence.[7b,8b,24]
When C1 and C2 were used as catalysts instead of C9, the
corresponding complex of the catalyst and 3a was addition-
ally observed. The formation of a strong complex of either C1
or C2 with the aldol product can be ascribed to their efficient
bifurcated hydrogen-bonding donor character which might
have higher binding affinity than the sulfonamide-based
catalysts. Formation of such a stable catalyst–product com-
plex can deplete the effective catalyst concentration during
the reaction course, thus resulting in low turnover numbers
(Scheme 2). A fine-tuning of the hydrogen-bond donor
property of sulfonamide catalysts might be key to the
successful enantioselective catalysis by avoiding the catalyst
poisoning by the product.
In summary, we disclosed the first successful metal-free
biomimetic enantioselective decarboxylative aldol reaction of
MAHTs with various aldehydes using sulfonamide-based
organocatalysts to afford enantioenriched b-hydroxy thioest-
ers. A range of aromatic and nonaromatic aldehydes were
converted into the corresponding aldol products in good to
excellent yields and enantioselectivities. The obtained enan-
tioenriched aldol products were easily converted into val-
uable synthetic intermediates without loss of enantiopurity.
In situ ESI-MS analysis provided insight into the origin of the
unique catalytic activity of C9 as well as the reaction
sequence. The ready accessibility of the organocatalysts and
enantioenriched b-hydroxy thioesters will lead to various
applications in the field of natural product synthesis, such as
catalytic asymmetric polyketide synthesis.
[10] For the catalytic enantioselective decarboxylative amination
reactions of MAHTs, see Ref. [7b].
[11] T. Miyazaki, X. Han-ja, H. Tokuyama, T. Fukuyama, Synlett
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[12] For reviews, see a) J. Staunton, K. J. Weissman, Nat. Prod. Rep.
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Hurlbert, S. W. White, C. O. Rock, J. Biol. Chem. 2006, 281,
Received: July 19, 2013
Published online: && &&, &&&&
Keywords: aldehydes · aldol reaction · organocatalysis ·
.
reaction mechanisms · synthetic methods
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V. H. Rawal, J. Am. Chem. Soc. 2008, 130, 14416 – 14417.
[15] a) S. H. Oh, H. S. Rho, J. W. Lee, J. E. Lee, S. H. Youk, J. Chin,
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2010, 352, 2211 – 2217.
[16] The absolute configuration of 3a was established to be R by
conversion into the corresponding (R)-b-hydroxymethylester.
See the Supporting Information.
[17] The enantiomer can be obtained using the quinidine-derived
catalyst QD-1-Np-SA (C12). However, the enantioselectivity
was lower than that obtained with the quinine analogue (e.g.,
78% ee with 2a). However, fortunately, the crystalline property
of most of the aldol products 3 enabled facile recrystallization of
3 to improve the enantiopurity of the products.
[19] Y. Hayashi, T. Itoh, S. Aratake, H. Ishikawa, Angew. Chem. 2008,
120, 2112 – 2114; Angew. Chem. Int. Ed. 2008, 47, 2082 – 2084.
[20] For recent selected examples, see: a) S. S. V. Ramasastry, H.
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Soc. 2007, 129, 3074 – 3075. For the Mannich-type reaction with
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[21] For a review of Fukuyama reduction, see: T. Fukuyama, H.
Tokuyama, Aldrichimica Acta 2004, 37, 87 – 96.
[22] For selected references concerning the asymmetric syntheses of
Fluoxetine, (À)-Paroxetine, and Duloxetine, see the Supporting
Information page 116.
[23] MS (ESI +): calcd for (A+Na+): m/z 732.2 (100.0%), 733.2
(42.2%); observed: 732.1 (100%), 733.2 (40%); calcd for
(B+Na+): m/z 838.3 (100.0%), 839.3 (49.8%); observed: 838.2
(100%), 839.2 (48%). See the Supporting Information.
[24] J. Baudoux, P. Lefebvre, R. Legay, M. Lasne, J. Rouden, Green
Chem. 2010, 12, 252 – 259.
[18] The low yields of 3o and 3p could be ascribed to the formation
of side products such as 9o and 9p, respectively (see the
Supporting Information). In all cases, S-phenyl thioacetate was
also formed during the reaction. However, the use of S-phenyl
thioacetate as a substrate resulted in almost no reaction leading
to the desired aldol product in the presence of the catalyst C9.
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Communications
Organocatalysis
H. Y. Bae, J. H. Sim, J.-W. Lee, B. List,*
C. E. Song*
&&&& — &&&&
Organocatalytic Enantioselective
Decarboxylative Aldol Reaction of
Malonic Acid Half Thioesters with
Aldehydes
Copycat: A highly enantioselective bio-
mimetic aldol reaction of malonic acid
half thioesters with a variety of aldehydes
affords optically active b-hydroxy thioest-
ers by employing the cinchona-derived
sulfonamide organocatalyst 1. The syn-
thetic utility of this protocol was demon-
strated by performing formal syntheses of
the antidepressants (R)-fluoxetine, (R)-
tomoxetine, (À)-paroxetine, and (R)-
duloxetine.
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