Achiral co-catalyst induced switches in catalytic asymmetric reactions on racemic mixtures (RRM): From stereodivergent RRM to stereoconvergent deracemization by combination of hydrogen bond donating and chiral amine catalysts

Article abstract of DOI:10.1002/adsc.201200357

A stereochemical divergent approach for the highly enantioselective synthesis of distinct bicyclic products with multiple stereocenters from a racemate using a single chiral catalyst is disclosed. It is based on switches of the overall reaction pathways i

Full text of DOI:10.1002/adsc.201200357

UPDATES
DOI: 10.1002/adsc.201200357
Achiral Co-Catalyst Induced Switches in Catalytic Asymmetric
Reactions on Racemic Mixtures (RRM): From Stereodivergent
RRM to Stereoconvergent Deracemization by Combination of
Hydrogen Bond Donating and Chiral Amine Catalysts
Guangning Ma,a Shuangzheng Lin,b Ismail Ibrahem,a Grzegorz Kubik,b
Leifeng Liu,c,d Junliang Sun,c,d 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: acordova@organ.su.se or armando.cordova@miun.se
Department of Organic Chemistry, The Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
Berzelii Center EXSELENT on Porous Materials, The Arrhenius Laboratory, Stockholm University, 106 91 Stockholm,
Sweden
b
c
d
Department of Materials and Environmental Chemistry, The Arrhenius Laboratory, Stockholm University, 106 91
Stockholm, Sweden
Received: April 25, 2012; Revised: July 31, 2012; Published online: October 5, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200357.
Abstract: A stereochemical divergent approach for
the highly enantioselective synthesis of distinct bicy-
clic products with multiple stereocenters from
a racemate using a single chiral catalyst is disclosed.
It is based on switches of the overall reaction path-
ways in the chiral amine-catalyzed cascade reac-
tions between racemic g-nitro ketones and a,b-un-
saturated aldehydes using different achiral co-cata-
lysts. The utility of the method is exemplified by
the highly diasteroselective switch and stereocon-
vergent deracemization process by combination of
chiral amine and achiral hydrogen-bond-donating
catalysts.
one growing area is the development of catalytic
asymmetric multi-component and cascade reactions
that include advantages of reducing synthetic steps
and other green chemistry parameters.[4–7] Despite
these and other advances in asymmetric catalysis,[7]
during the last 50 years industrial processes often
have to deal with stereomeric mixtures. Consequently,
enzymatic or chemical resolution is applied where
50% (racemate) or more (diastereomeric mixtures) of
the starting material is disposed.[8] In order to im-
prove kinetic resolutions (KR), the less reactive enan-
tiomer can be removed by a parallel reaction to yield
a different product that can be readily separated.[8c,9]
If this process is carried out by a single chiral reagent
it is called “divergent reactions on a racemic mixture”
(divergent RRM)[9] where a variation is the parallel
kinetic resolution (PKR) in which two complementa-
ry chiral reagents are employed to afford distinct
products (Scheme 1, a).[8c] Thus, a diastereo- and
enantio-(stereo)divergent RRM or PKR can give four
possible products (the four enantiomers of the two
products) but in 50% theoretical yield. To overcome
Keywords: cascade reactions; deracemization; dy-
namic asymmetric catalysis; hydrogen-bond donor;
organocatalysis; reactions on racemic mixtures;
stereodivergence
Chiral small molecules with multiple stereocenters the limitations of KR and allow for deracemization
are essential for life on earth and the betterment of (the complete transformation of a racemate into
human health. A striking aspect of nature is that a single stereoisomeric product) different protocols
chiral molecules (e.g., sugars) with several stereocen- have been developed. Among the most popular are
ters are made as single enantiomers (e.g., d-glu- dynamic kinetic resolution (DKR) and dynamic kinet-
cose).[1–3] In contrast, to achieve similar levels of selec- ic asymmetric transformation (DYKAT, Scheme 1, b)
tivity in one-pot by chemical synthesis is a very chal- that allow for the synthesis of two possible products
lenging task since a molecule containing n number of (the two enantiomers of the product) in 100% theo-
chiral centers can form 2n possible stereoisomers. retical yield.[10,11]
Chemical research is addressing this challenge and
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Guangning Ma et al.
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Scheme 1. a) RRM. R=R-enantiomer. S=S-enantiomer. b) Simplified DYKAT type IV. ESR and ERS are the two enantio-
mers of the starting racemate.[10a]
From a stereochemical divergent strategy perspec- also a powerful activation mode in asymmetric cataly-
tive,[12,13] it would be highly appealing to be able to sis.[17,18] In this context, we recently found that the
switch between the above described systems since it generation of an achiral hydrogen bond-donating net-
could allow for the synthesis of distinct products from work could switch the chemoselectivity of a chiral
a racemate using a single chiral catalyst. For example, amine-catalyzed one-pot three-component reac-
if the overall process and diastereoselectivity of a ster- tion.[18j] Thus, we believed that the kinetics of the cas-
eodivergent RRM were switched to a stereoconver- cade transfromation depicted in Scheme 2 should be
gent deracemization, six diffrent products (the six different in the presence of a suitable achiral hydro-
enantiomers of the three products) would be ob- gen bond-donating co-catalyst. In addition, we envi-
tained. Herein, we disclose that this systems strategy sioned that the achiral non-covalent hydrogen bond
is indeed possible by the synergistic action of an achi- interactions could induce a diastereoselective switch
ral catalyst.
in the transition state of the cascade transformation.
We initially began our studies of finding a suitable For example, redirecting the equatorial g-nitro group
model system. In this context, the catalytic asymmet- of 1 in transisition state I to an axial position as in
ric cascade transformation on racemic g-nitro ketone transition state II by the hydrogen bond-donating cat-
1a with cinnamic aldehyde 2a could in theory deliver alyst (Figure 1).
polyfunctionalized [4.4.0] bicyclic compounds 3 with 6
At the onset of our catalyst and conditions screen-
chiral centers as a mixture of 64 different possible ste- ing (Supporting Information), we discovered that the
reoisomers 3 and dehydrated products 4 (Scheme 2). reaction between racemic 1a and 2a in the presence
As a consequence, this type of reaction has to date of a chiral amine catalyst 5 delivered bicyclic com-
only been performed on enantiopure (S,R)-1a with pounds 3a and ent-4aII as the major diastereoisomers
a chiral amine as the catalyst to give the bicyclic com- (Table 1). Thus, this transformation is a formal stereo-
pound 3a together with a minor unidentified diaste- divergent RRM. We also found that the reaction was
reoisomer.[14,15] The use of supramolecular interactions accelerated by the co-catalysis of an achiral acid and
(e.g., hydrogen bonding) is very important for con- amine (entry 1 vs. entry 2; the reaction with only
trolling the reaction outcome and selectivity of dy- chiral amine 5a as the catalyst gave less than 50%
namic processes.[16] These types of interactions are conversion after 24 h so the products were not isolat-
Scheme 2. Some of the possible pathways of the for catalytic asymmetric transformations on racemic syn-1a. The possible
pathways of the anti-1a are not shown.
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Achiral Co-Catalyst Induced Switches in Catalytic Asymmetric Reactions on Racemic Mixtures
DIPEA as the co-catalysts in toluene at room temper-
ature (Table 1).
Compounds 3a–3g and ent-4aII-ent-4gII were ob-
tained with good to high drs and high ers, respectively
(entries 2–10). Furthermore, bicyclic compounds 3
were readily separated from bicyclic compounds ent-
4II by silica-gel column chromatography. The ratio of
3 to ent-4II was slightly higher than 50:50 demonstrat-
ing that g-nitro ketone enantiomers (S,R)-1 reacted
faster than enantiomers (R,S)-1 under these reaction
conditions. The use of (R)-5a as the catalyst gave the
opposite enantiomers ent-3 and 4II, respectively
(entry 11). The reactions on racemic g-nitro ketones
1 showed that it should be possible to synthesize pre-
dominantly ent-4II when starting with enantioenriched
(R,S)-1. Indeed performing the reaction with (R,S)-1a
as the starting material (96.5:3.5 er) gave nearly enan-
tiomerically pure ent-4aII in 61% yield (entry 12).
Figure 1. Possible transition states I and II.
ed). The optimal conditions to perform the stereodi- Having discovered this chiral amine-catalyzed stereo-
vergent RRMs were use of the combination of chiral divergent RRM process, we began to investigate
protected diarylprolinols 5,[19] 4-nitrobenzoic acid and whether we could convert it to a stereoconvergent de-
Table 1. Examples of catalytic RRM of rac-1.[a]
[a]
A mixture of 1 (0.2 mmol), enal 2 (0.4 mmol), 5 (20 mol%) 4-NO2C6H4CO2H (20 mol%) and DIPEA (25 mol%) in tolu-
ene (0.4 mL) was stirred at room temperature for the time shown.
[b]
The isolated yields of pure 3 and ent-4II after silica-gel column chromatography.
[c]
[d]
[e]
[f]
1
Determined by H NMR analysis of the crude reaction mixture.
Determined by chiral-phase HPLC analysis (see Supporting Information).
No acid and base additive.
The reaction was performed with (R,S)-1a (96.5:3.5 er) as the starting material. DIPEA=N,N-diisopropylethylamine.
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Guangning Ma et al.
UPDATES
[b]
[c]
[d]
[e]
[f]
[g]
[h]
Scheme 3. [a] 5b, 6 h; 5a, 16 h; 5b, 4 h; 5b, 5 h; 5a, 10 h; 5b, 13 h; 5a, 2 h; 5a, 60 h, 1f [>95:5 dr, 71:29 er (S,S-
1f major enantiomer)]; 5a, 4 h, 1e [>95:5 dr, 70.5:29.5 er (S,R-1e major enantiomer)]; [j] ent-5b, 8 h.
[i]
racemization using a hydrogen bond-donating co-cata- 3I (Scheme 4, TS IV). The reaction was also readily
lyst. We found that achiral hydrogen bond-donating performed on a gram-scale on racemic 1a to give the
co-catalysts 6 accelerated the chiral amine 5-catalyzed corresponding 3aI with 84:16 dr and 96:4 er. We also
cascade transformation on racemic 1a. To our delight, investigated the co-catalyzed stereoselective reaction
the overall system converted from a RRM to a dynam- on scalemic mixtures of (S,S)-1f (71:29 er) and (S,R)-
ic deracemization process when thiourea derivatives 1e (70.5:29.5 er) and the corresponding products 3nI
were used as the co-catalysts (Supporting Information and 3oI were isolated in high yields, drs and ers, re-
and Scheme 3). In particular, the use of Schreinerꢂs spectively. The co-catalytic stereoconvergent dera-
thiourea derivative 6a[17c] in combination with diary- cemizations with ent-5a or ent-5b as the chiral amine
lprolinols 5a or 5b induced a diastereoselective switch catalysts gave as expected the opposite enantiomer
in the cascade transformation to form 3aI instead of ent-3I. In attempts to fill the other quadrants of ste-
3a as the major diastereoisomer (Scheme 3). Thus, we reochemical space, the co-catalytic asymmetric cas-
decided to probe the scope of this deracemization cade transformation on racemic mixtures of the anti-
process for a set of g-nitro ketones 1 with enals 2 isomer 1a was investigated (Eq. [1]).
using 5a or 5b as the chiral amine catalyst and 6a as
the hydrogen bond-donating catalyst in toluene at corresponding bicyclic ent-3IV were obtained in high
room temperature (Scheme 3). yields with >95:5 dr and 95:5 er, respectively. Thus,
The reactions were highly stereoselective and the
The synergistic co-catalysis was highly stereoselec- we were able to synthesize different stereoisomers
tive and enabled the isolation of bicyclic compounds and products (e.g., 3, 3I, ent-4II and ent-3IV) with high
3aI–3mI in high yields. Thus, the thiourea 6a was es- ers by chiral amine 5-catalyzed asymmetric cascade
sential in assisting the dynamic conversion of enantio- recations on racemic syn- or anti-1, respectively. The
mer (R,S)-1 to the fast reacting enantiomer (S,R)-1 as relative stereochemistries of 3, 3I, ent-4II, ent-4III and
well as inducing the diastereomeric switch from 3 to ent-3IV were determined by NOE experiments and X-
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Achiral Co-Catalyst Induced Switches in Catalytic Asymmetric Reactions on Racemic Mixtures
Scheme 4. Proposed reaction pathway for the formation of 3I.
ray analyses. The absolute stereochemistry of com- could catalyze these processes alone (see the Support-
pounds 3, 3I and 4II were confirmed by the X-ray ing Information). However, in combination a signifi-
analysis
of
3b
(1R,2S,3S,4R,4aS,8aS),
3bI cant loss of both the dr and the er of both (S,R)-1a
(1R,2S,3R,4R,4aS,8aS) and ent-4bII (2R,3R,4S,4aR), and (R,S)-1a was observed with the latter epimerizing
respectively.[20] The analyses revealed that the stereo- and racemizing at a higher rate. Thus, the slow react-
chemistry was the same for all compounds at the C- ing enantiomer of the cascade reaction (R,S)-1a was
1 and C-2 positions which was controlled by the (S)-5 converted to the fast reacting enantiomer (S,R)-1a by
catalyst. The absolute stereochemistries of compounds the essential synergistic non-covalent self-assembled
ent-3IV were confirmed by these experiments and the bifunctional catalysis (Scheme 4). However, product
X-ray analysis of ent-3bIV (1R,2S,3R,4R,4aR,8aS).[20] 1a was not formed when 2-(nitrovinyl)benzene was
The ability of chiral amine 5a or Schreiner thiourea reacted with cyclohexanone in the presence of co-cat-
1
6a to epimerize and racemize (S,R)-1a or (R,S)-1a, re- alysts 5a and thiourea 6a. HR-MS and H NMR anal-
spectively, was examined next. None of these catalysts ysis established that no detectable covalent intermedi-
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UPDATES
ates between 6a and 1a were formed during this pro- the combination of chiral amine and achiral hydrogen
1
cess. Based on our experimental results, H NMR, X- bond-donating catalysts. The racemization and the
ray analyses, and HR-MS analyses, we propose the iminium-enamine-activated asymmetric cascade trans-
following mechanistic reasoning to account for the formation processes were both accelerated by the
stereoconvergent deracemization of racemic syn-1 to non-covalent hydrogen-bond activation. In fact, en-
stereoisomer 3I (Scheme 4). The catalytic cascade zymes use the same type of activation modes (hydro-
cycle starts with hydrogen bond-donating 6a-acceler- gen bond-donation, iminium and enamine actvation)
ated iminium intermediate III formation between as the disclosed primitive small molecule cooperative
chiral amine 5 and enals 2. The bulky chiral group ef- catalysis system to bring stereochemical “order” in
ficiently shields the Re-face of III. Next, of all the their biosynthesis of complex molecules essential for
possible stereoisomers of 1 the fast reacting enantio- life. Beyond nature, the presented approach accom-
mer (S,R)-1 will perform a nucleophilic Si-facial con- plished stereochemical diversification with a single
jugate attack on III to form enamine intermediate IV chiral catalyst by achiral co-catalyst-induced switches
via transition state II, which involves hydrogen bond in the overall reaction system. Further mechanistic in-
activation by co-catalyst 6a.
vestigations to understand, control and eventually
The subsequent cascade intramolecular 6-exo-trig design other such processes are ongoing in our labora-
aldol reaction at the Re-face of the keto moiety of IV tories.
results in intermediate V. Subsequent hydrolysis re-
generates the chiral catalyst 5 and delivers 3I. In par-
allel to this catalytic proposed cycle, the achiral hy-
Experimental Section
drogen bond-donating catalyst 6a together with chiral
amine 5 co-catalyze the dynamic conversion of enan-
tiomer (R,S)-1 to (S,R)-1 so that all of the starting
racemic mixture is converted to 3I (deracemization).
The presence of intermediates III, IV and V was ex-
perimentally confirmed by HR-MS analysis[21] on the
crude reaction mixture. With respect to the formation
of stereoisomers ent-4II and ent-3IV, we propose transi-
tion states VI and VII to account for the enantioselec-
tive conjugate attack of (R,S)-1 and (R,R)-1 to imini-
um intermediate III, respectively (Figure 2).
In summary, we have disclosed a stereochemical di-
vergent approach to distinct products with multiple
stereocenters from a racemate using a single chiral
catalyst. It is based on switches of the overall system
in catalytic asymmetric reactions on racemic mixtures
using achiral co-catalysts. As demonstrated by the
highly diastereoselective switch in a catalytic asym-
metric RRM to a stereoconvergent deracemization by
General Procedure for the Co-Catalytic
Deracemization Reaction (Scheme 3)
To an 8-mL vial equipped with a magnetic stir bar was
added organocatalyst 5a or 5b (0.02 mmol, 20 mol%), enal 2
(0.2 mmol, 2.0 equiv.), Schreinerꢂs thiourea 6a (10.0 mg,
0.02 mmol, 20 mol%) and toluene (0.2 mL). After stirring at
room temperature for 10 min, the racemic g-nitro ketone
rac-1 (0.1 mmol, 1.0 equiv.) was added and the mixture was
vigorously stirred. The reaction progress was monitored by
1H NMR analysis. After complete consumption (>95%) of
g-nitro ketone 1, CH2Cl2 (5.0 mL) was added to the vial.
Next, 400~500 mL of this solution were added to a vial fol-
lowed by removal of the solvent under reduced pressure.
The resulting pale yellow solid was dissolved in 400 mL
CDCl3. The ratio of 3:3I was determined by H NMR analy-
1
sis. Next, all of this solution was combined with the remain-
ing CH2Cl2 solution and the pure compounds 3I were ob-
tained by silica-gel column chromatography (pentane/ethyl
acetate=8/1–3/1).
General Procedure for the Gram-Scale Reaction
To a 16-mL vial equipped with a magnetic stir bar were
added organocatalyst 5b (298 mg, 0.8 mmol, 20 mol%), enal
2a (1.02 mL, 8.1 mmol, 2.0 equiv.), Schreinerꢂs thiourea 6a
(400 mg, 0.8 mmol, 20 mol%) and toluene (8.0 mL). After
stirring at room temperature for 10 min, the racemic g-nitro
ketone rac-1a (1.0 g, 4.05 mmol, 1.0 equiv.) was added to the
vial in one portion and the resulting mixture was allowed to
stir at room temperature for 12 h. The ratio of 3aI/3a=84:16
1
was determined by H NMR analysis of the crude reaction
mixture. The pure compounds 3aI and 3a were obtained by
flash column chromatography on silica gel (pentane/ethyl
acetate=8:1~3:1), to afford 3aI (yield: 940 mg, 61%, >95:5
dr, 95:5 er) and 3a (yield: 170 mg, 11%, >95:5 dr, 96:4 er)
as white solids.
Figure 2. Possible transition states VI and VII.
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Achiral Co-Catalyst Induced Switches in Catalytic Asymmetric Reactions on Racemic Mixtures
[8] For non-enzymatic reactions, see: a) H. B. Kagan, J. C.
Acknowledgements
Fiaud, Top. Stereochem. 1988, 18, 249; b) M. Breuer, K.
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er, T. Zelinski, Angew. Chem. 2004, 116, 806; Angew.
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Angew. Chem. 2005, 117, 4040; Angew. Chem. Int. Ed.
2005, 44, 3974; d) H. Pellissier, Adv. Synth. Catal. 2011,
353, 1613. For enzymatic reactions, see: e) C. J. Sih, S.-
H. Wu, Top. Stereochem. 1989, 19, 63; f) A. M. Kliba-
nov, Acc. Chem. Res. 1990, 23, 114; g) A. Steinreiber,
K. Faber, Curr. Opin. Chem. Biol. 2001, 5, 552.
We gratefully acknowledge the European Union, Sunsvall
Municipality and Swedish National Research Council for fi-
nancial support. The Berzelii Center EXSELENT is finan-
cially supported by VR and the Swedish Governmental
Agency for Innovation Systems (VINNOVA).
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