Highly enantioselective co-catalytic direct aldol reactions by combination of hydrogen-bond donating and acyclic amino acid catalysts

Article abstract of DOI:10.1002/adsc.201100408

Highly enantioselective co-catalytic direct aldol reactions by a combination of simple hydrophobic acyclic amino acid and hydrogen-bond donating catalysts are presented. The corresponding aldol products are formed in high yields with high regio-, diastere

Full text of DOI:10.1002/adsc.201100408

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DOI: 10.1002/adsc.201100408
Highly Enantioselective Co-Catalytic Direct Aldol Reactions by
Combination of Hydrogen-Bond Donating and Acyclic Amino
Acid Catalysts
Guangning Ma,a Agnieszka Bartoszewicz,b,c Ismail Ibrahem,a,*
and Armando Cꢀrdovaa,b,c,
*
a
Department of Natural Sciences, Engineering and Mathematics, Mid Sweden University, SE-851 70 Sundsvall, Sweden
Fax : (+46)-8-154908; e-mail: ismail.ibrahem@miun.se
b
c
Department of Organic Chemistry, The Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
E-mail: armando.cordova@miun.se or acordova@organ.su.se
The Berzelii Center EXSELENT, Stockholm University, SE-106 91 Stockholm, Sweden
Received: May 19, 2011; Revised: July 25, 2011; Published online: November 16, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100408.
Abstract: Highly enantioselective co-catalytic direct
aldol reactions by a combination of simple hydro-
phobic acyclic amino acid and hydrogen-bond do-
nating catalysts are presented. The corresponding
aldol products are formed in high yields with high
regio-, diastereo- (anti or syn) and enantioselectivi-
ty (up to 99.5:0.5 er). The catalyst loadings can be
decreased to as little as 2 mol%.
tions.[5,8] However, proline itself may present some
drawbacks such as poor solubility in non-polar organ-
ic solvents, low reactivity and high catalyst loadings
(20–40 mol%). Recently, we disclosed that primary
amino acids, chiral amines and small peptides with a
primary amine functionality can catalyze highly enan-
tioselective reactions by enamine activation.[9,10] Tso-
goeva and Wei showed that histidine based di-pep-
tides can catalyze the direct aldol reaction with ace-
tone as donor with good enantioselectivity.[11a] In sev-
eral of the cases we investigated, it was necessary to
employ water or a Brønsted acid as a co-catalyst. If
not, only trace amounts of products were formed.[9]
Thus, acyclic amino acids without a co-catalyst gener-
ally exhibit lower reactivity as compared to proline
and bring the same disadvantages (e.g., low reactivity,
Keywords: aldol reaction; amino acids; asymmetric
catalysis; co-catalysis; hydrogen-bond donating
À
The direct asymmetric aldol reaction is a powerful C
C bond-forming transformation in nature and synthet- high catalyst loadings and low solubility in polar
ic chemistry.[1] In nature, it is catalyzed by enzymes aprotic solvents). Hence, there is a need to address
with excellent stereoselectivity using either a metal as these issues. With respect to the direct asymmetric
a co-factor (class II) or a primary amine functionality aldol reaction catalyzed by primary amino acids and
(class I) for the activation of the carbonyl donors.[2] primary amines, to date the most common way to im-
Thus, researchers have also utilized enzymes as cata- prove the enantioselectivity and reactivity is to add a
lysts in organic synthesis.[2,3] Inspired by the high se- co-catalyst (e.g., water, Brønsted acid or base).[9,11,12]
lectivity of the aldolases, chemists have developed
The employment of supramolecular interactions
biomimetic direct catalytic aldol reactions using small such as hydrogen bonding is a fundamental activation
organometallic or organic molecules as catalysts.[4–6] mode for controlling reaction pathways both in syn-
In this context, the proline-catalyzed enantioselective thetic chemistry and life.[13] It is also a powerful acti-
aldol reaction was discovered in the beginning of the vation mode in small molecule asymmetric cataly-
1970s by Hajos and Parrish.[6,7] Starting with the sis.[14–16] In this context, hydrogen bonding is very im-
works from List, Barbas and Lerner, the use of pro- portant for the reactivity and enantioselectivity of in-
line catalysis has had a renaissance during the last termolecular aldol reactions catalyzed by small pepti-
decade.[8] In fact, it was generally considered that a des.[11c,15] In 2005, Gellman introduced a co-catalytic
five-membered cyclic secondary amine structural system based on the combination of hydrogen-bond
motif of the amine catalyst was essential for being donation and chiral secondary amine catalysts for
À
À
able to perform asymmetric C C bond-forming reac- achieving highly enantioselective C C bond-formatio-
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Highly Enantioselective Co-Catalytic Direct Aldol Reactions
n.[16a,b] Shan and co-workers employed hydrogen-bond solvent screen using 5a and 4a as co-catalysts. The re-
donors as additives for improving proline-catalyzed action rate was highest in n-hexane and 3a was isolat-
direct asymmetric aldol reactions.[16d] However, the ed in 90% yield with 95.5:5.5 dr and 99.5:0.5 er
catalyst loadings were still high. Zhao et al. disclosed (entry 19). Significant rate acceleration was also ob-
a thiourea and proline co-catalyzed Michael addition served in neat cyclohexanone 1a (entry 24). The cata-
of ketones to nitrostyrenes.[16e] Recently, Demir lyst loadings could also be decreased to 10 mol%
et al.[16f] and shortly after Moyano, Rios et al.[16g] re- without decreasing the stereoselectivity (entries 23
ported that proline in combination with thiourea de- and 24). With these results in hand, we began to
rivatives such as Schreinerꢂs thiourea 4a[14e] can co- probe the direct intermolecular aldol reaction be-
catalyze highly stereoselective aldol reactions be- tween cyclic ketones 1a–1c and different acceptor al-
tween cyclohexanones 1 and benzaldehydes 2. We re- dehydes 2 using thiourea 4a (10 mol%) and 5 a
cently, found that oxime 4b can act as a hydrogen- (10 mol%) as the co-catalysts and n-hexane as the sol-
bond donating co-catalyst for chiral amine-catalyzed vent (Table 2).
dynamic one-pot three-component enantioselective
To our delight, the 4a and 5a co-catalyzed aldol re-
[2+3] cycloadditions.[16i] Based on our research inter- actions gave the corresponding aldol products 3 gen-
ests in amino acid catalysis and co-catalytic system- erally in high yields, drs and ers. For example, the
s,[16i,17,18] we became interested in whether the power- transformations with cyclohexanone 1a gave the cor-
ful activation mode of hydrogen-bond activation responding aldol products 3b–3n with ers ranging
could be used to improve acyclic amino acid-catalyzed from 92:8 to >99.5:0.5 (entries 1–14). In comparison,
À
direct enantioselective C C bond-forming reactions. the co-catalytic aldol transformation with cyclopenta-
Here we disclose highly regio- and enantioselective none 1b or cycloheptanone 1c as the donor gave the
direct asymmetric aldol reactions catalyzed by combi- corresponding aldol products 3 with high er but slight-
nation of a simple hydrophobic amino acid (e.g., O- ly lower dr (entries 15–17). It is noteworthy that the
protected threonine derivatives) and hydrogen-bond transformation became syn-selective when cyclopen-
donating catalysts. The co-catalyst loadings could be tanone 1b was used as the donor. In fact, this behav-
decreased to as little as 2 mol%.
ior has recently been observed in primary amino acid
In initial experiments, we investigated the direct in- catalysis.[12t] With these results in hand, we decided to
termolecular aldol reaction between cyclohexanone probe the 5a and 4a-co-catalyzed reactions using
1a and 4-nitrobenzaldehyde 2a in the presence of dif- linear and oxygen-functionalized ketones 3 as donors
ferent primary amino acids 5 and hydrogen-bond do- (Table 3).
nating catalysts 4a[14e] or 4b.[16i] Toluene was chosen as
We found that the enantioselectivity was high to ex-
the solvent since we wanted to avoid the use of polar cellent (95:5 to >99.5:0.5 er) for the investigated re-
aprotic solvents (e.g., DMSO and DMF). Key results actions with cyclic and branched ketones 1e–1i. In
are shown in Table 1.
comparison, the reaction with acetone 1d as the
We found that the hydrophobic amino acids 5a, 5c, donor gave the corresponding product 3s in 71%
5d, 5e, 5g, 5h and 5i were able to catalyze the reaction yield and 85:15 dr (entry 1). This result is in accord-
in toluene. The highest stereoselectivity was observed ance with our previous experiments and DFT calcula-
when the protected threonine derivatives 5a[11a,12f] and tions,[19] which showed that the stereoselectivity of the
5d[12y] were used as the co-catalysts. Significant rate acyclic primary amino acid-catalyzed aldol reaction
acceleration was observed when the reactions were increases when branched or cyclic ketones 1 are used
performed in the presence of hydrogen-bond donating as donors.[9] The reactions with linear non-symmetric
À
catalysts 4a and 4b, respectively (entries 4–6). The use ketones 1g and 1h was regiospecific and the C C
of 4b as the co-catalyst gave the fastest reaction but bond formation occurred at the most substituted
the diastereoselectivity was lower as compared to em- carbon (entries 5–9). The reactions with acyclic ke-
ployment of 4a (entries 4 and 6). The reactions were tones 1 were also syn-selective and can therefore be
also accelerated by the addition of Brønsted acids and considered complementary to the reactions with the
water (entries 9 and 10). In addition, other hydrogen- cyclic six-membered ketones 1. For example, the reac-
bond donating catalysts 4 did accelerate the reaction tion with protected dihydroxy acetone 1e[20] is anti-se-
(entries 25–27). However, all these reactions were lective while the reaction with protected dihydroxy-
slower as compared to the reactions performed with
ACHTUNGTRENaNGNU cetone 1i is syn-selective (entries 2 and 10). In addi-
hydrogen-bond donating co-catalyst 4a or 4b. For ex- tion, it is also complimentary to the proline-catalyzed
ample, the reaction with 4a as the co-catalyst gave the aldol reactions with linear ketones 1 that is anti-selec-
corresponding aldol product 3a in 82% yield with tive.[8] We also investigated if it was possible to de-
96:4 dr and 99.5:0.5 er after 7 h (entry 7). Thus, out of crease the catalyst loadings of 5a and 4. To our de-
the investigated co-catalytic systems, catalyst 5a in light, using 2 mol% of 5a in combination with 2 mol%
combination with co-catalyst 4a exhibited the highest of 4a or 4b gave the corresponding aldol product 3a
rate as well as stereoselectivity. We next performed a in high yield and up to 99:1 er, respectively (Eq. [1]).
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Table 1. Co-catalyst and condition screening.[a]
[a]
Reaction conditions: 1a (1.25 mmol), 2a (0.125 mmol),
5 (0.025 mmol) and 4
(0.025 mmol) were mixed in toluene (0.5 mL).
[b]
[c]
1
Determined by H NMR of the crude reaction mixture.
[d]
1
Yield of isolated pure product 3a.
Determined by H NMR analysis of the crude
reaction mixture.
[e]
[g]
Determined by chiral-phase HPLC analysis.
10 equiv. of water were added.
methylsilyl, TBDPS=tert-butyldiphenylsilyl.
[f] 5 equiv. of water were added.
[h] 5a (10 mol%) and 4a (10 mol%). TBS=tert-butyldi-
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Highly Enantioselective Co-Catalytic Direct Aldol Reactions
Table 2. The scope of the co-catalyzed aldol reactions between ketones 1 and aldehydes
2.[a]
[a]
Reaction conditions:
1 (2.5 mmol), 2 (0.25 mmol), 5a (0.025 mmol) and 4a
(0.025 mmol) were mixed in n-hexane (1.0 mL).
[b]
[c]
[d]
[e]
[f]
Yield of isolated pure product 3.
1
Determined by H NMR of the crude reaction mixture.
Determined by chiral-phase HPLC analysis.
Neat reaction.
20 mol% 5a and 4a.
The er of the syn-3p.
Determined by chiral GC analysis.
[g]
[i]
The relative and absolute configuration of the aldol catalyst 4 (Table 1). Thus, the enantioselectivity did
products were determined by comparison with the not significantly increase by the addition of the hydro-
previously reported literature data of aldol products gen-bond donating co-catalysts 4. However, as men-
3a,[9c,d] 3t,[9c,d] and 3y[9d] (see the Supporting Informa- tioned above a dramatic rate acceleration occurred.
tion). Moreover, the er of products 3 was nearly the In fact, it was significantly higher as compared to the
same when comparing the 5a-catalyzed reactions with rate acceleration achieved by addition of water or a
or without the presence of a hydrogen-bond donating Brønsted acid as the co-catalyst (Table 1). It is also
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Table 3. The scope of the co-catalyzed aldol reactions of 1 with aldehyde 2.[a]
[a]
Reaction conditions: 1 (2.5 mmol), 2 (0.25 mmol), 5a (0.025 mmol) and 4a (0.025 mmol) were
mixed in n-hexane (1.0 mL).
[b]
[c]
[d]
[e]
[f]
Yield of isolated pure product 3.
1
Determined by H NMR of the crude reaction mixture.
The er of the major diastereoisomer was determined by chiral-phase HPLC analysis.
T= +48C.
Neat reaction.
5d (20 mol%) and 4a (20 mol%) were used as co-catalysts.
The er of the anti-diastereoisomer.
1.0 mmol 1i was used; TBS=tert-butyldimethylsilyl.
[g]
[h]
[i]
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Highly Enantioselective Co-Catalytic Direct Aldol Reactions
Scheme 1. The proposed catalytic mechanism.
À
noteworthy that the reactions with protected threo- other C C bond-forming reactions and mechanistic
nine derivatives 5 were always homogeneous. Taken studies are ongoing in our laboratories.[23]
as a whole these experimental results suggest that the
hydrogen-bond donating catalyst 4 did not play a sig-
nificant role in the transition state of the aldol reac- Experimental Section
tion. It is rather involved in the catalytic cycle of the
co-catalyzed aldol reactions where it possibly acceler- Typical Procedure for the Co-Catalytic Asymmetric
ates the iminium and enamine formation between the Aldol Reactions
amino acid 5 and the donor ketones (Scheme 1).[21]
To
a solution of (S)-Thr-(OTBS)-OH (5a) (5.83 mg,
Thus, we propose that the reaction proceeds via the
carboxylic acid-catalyzed enamine mechanism involv-
ing a six-membered transition state I.[19] In the case of
the amino acid-catalyzed syn-selective aldol reactions,
we propose transition states II–IV to account for the
observed stereochemistry.[9,12,19] This is contrary to the
proline- and thiourea-cocatalyzed aldol reaction
where the thiourea 4a is suggested to be involved in
the transition state by increasing the acidity of the
amino acid.[16f,g,22] However, in this case, a significant
improvement of the stereoselectivity was observed.
In summary, we have disclosed a highly enantiose-
lective (up to 99.5:0.5 er), direct aldol reaction by a
combination of acyclic primary amino acid (e.g., pro-
tected threonine) and hydrogen-bond donating small
molecule catalysts. The co-catalytic reactions were
either highly anti- or syn-selective depending on the
ketone donor. The efficiency of this co-catalyst
system enabled the decrease of the catalyst loading to
as little as 2 mol%. Further applications of amino
0.025 mmol, 10 mol%, 0.1 equiv.) in n-hexane (1.0 mL, C=
0.25M) was sequentially added thiourea (4a) (12.5 mg,
0.025 mmol, 10 mol%, 0.1 equiv.) and ketone 1 (2.5 mmol,
10 equiv). After stirring for 15 min, aldehyde 2a (0.25 mmol,
1.0 equiv.) was added. The reaction mixture was vigorously
stirred at room temperature (228C) until the completion of
the reaction (crude NMR monitoring). Diastereoselectivity
1
and conversion were determined by H NMR analysis of the
crude product. The crude product was purified by silica gel
column chromatography (pentane/EtOAc mixtures) to give
the pure aldol product 3.
Acknowledgements
Financial support was provided by Mid Sweden University
and The Swedish National Research Council (VR). G. M. is
grateful for funding from the City of Sundsvall, I. I. is grate-
ful for repatriation funding from VR. We are also grateful to
Hꢀkan Norberg for help in setting up the lab and Dr.
acid and hydrogen-bond donating co-catalysis to Shuangzheng Lin for running the HR-MS analysis. The Ber-
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the Swedish Governmental Agency for Innovation Systems
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