Asymmetric aldol reaction of thiazole-carbaldehydes: Regio- And stereoselective synthesis of tubuvalin analogues

Article abstract of DOI:10.1002/adsc.201400640

The first organocatalytic enantioselective approach to precursors of tubuvaline (pre-Tuv) is presented employing a prolinamide-catalyzed aldol reaction of easily accessible thiazole-carbaldehyde with methyl isopropyl ketone "on water" in excellent yield as well as regio- and enantioselectivities. The analogues of pre-Tuv were achieved using an l-proline-catalyzed direct asymmetric aldol reaction of substituted thiazole-carbaldehydes with acetone. A direct and flexible approach to the tubavaline (Tuv) core of tubusylins has been established employing the reductive amination of the pre-Tuv species. The key aldol reaction should greatly expand the potential of this strategy to the synthesis of natural product tubulysins and a range of analogues.

Full text of DOI:10.1002/adsc.201400640

COMMUNICATIONS
DOI: 10.1002/adsc.201400640
Asymmetric Aldol Reaction of Thiazole-Carbaldehydes:
Regio- and Stereoselective Synthesis of Tubuvalin Analogues
Sushovan Paladhi,a,b Joydeb Das,a Mousumi Samanta,b and Jyotirmayee Dasha,b,*
a
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata – 700032, India
E-mail: ocjd@iacs.res.in
b
Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, West Bengal
741252, India
Received: July 2, 2014; Published online: September 26, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400640.
Abstract: The first organocatalytic enantioselective
approach to precursors of tubuvaline (pre-Tuv) is
presented employing a prolinamide-catalyzed aldol
reaction of easily accessible thiazole-carbaldehyde
with methyl isopropyl ketone “on water” in excel-
lent yield as well as regio- and enantioselectivities.
The analogues of pre-Tuv were achieved using an l-
proline-catalyzed direct asymmetric aldol reaction
of substituted thiazole-carbaldehydes with acetone.
A direct and flexible approach to the tubavaline
(Tuv) core of tubusylins has been established em-
ploying the reductive amination of the pre-Tuv spe-
cies. The key aldol reaction should greatly expand
the potential of this strategy to the synthesis of nat-
ural product tubulysins and a range of analogues.
Figure 1. Structures of tubulysins, a family of tetrapeptides,
most potent anti-cancer agents so far reported.
Keywords: asymmetric catalysis; green chemistry;
reductive amination; regioselectivity; tubulysins
The most important part of the tubulysins is the
synthesis of the thiazole-containing unusual amino
acid central core tubuvaline (Tuv) 2. Among the pre-
vious approaches, Ellmanꢀs method employs thiazole-
Development of novel and sustainable synthetic carbaldehyde 1 as the starting material to access the
methods for the asymmetric synthesis of potent bio- Tuv central core.[8,9] This method utilizes the reaction
logically active molecules is one of the key paradigms of N-sulfinyl metalloenamine, derived from an enan-
of organic chemistry. Thiazole derivatives are one of tiopure ketimine 3 with the aldehyde 1 followed by
the most widely investigated heterocycles for their a stereoselective reduction (Scheme 1).
significant biological activities.[1] Among these, tubu-
There is a need for the development of new and ef-
lysins constitute a novel group of tetrapeptides that ficient approaches for the synthesis of tubuvaline
exhibit cytotoxicity toward a number of cancer cell using catalytic enantioselective and atom economic
lines, including multidrug-resistant cell lines, with IC50 reactions. As a part of our ongoing research programs
values between 0.01 and 10 nM (Figure 1).[1–3] Sasse et aimed at the development of efficient green synthetic
al. first reported tubulysins as cytostatic peptides, methodologies,[10] we herein devise a rapid, highly
which were isolated from the myxobacteria and inhib- regio- and stereoselective synthesis of the unusual tu-
it tubulin polymerization, ultimately leading to cell buvaline core via a simple organocatalytic aldol reac-
death by apoptosis.[2,4] Due to their powerful anti- tion of the aldehyde 2-formylthiazole-4-carboxylate
cancer activities, tubulysins have attracted broad at- 1 with methyl isopropyl ketone “on water” followed
tention from the synthetic community in recent years by reductive amination (Scheme 1).
and a number of impressive total syntheses, fragment
Initially, 4-bromothiazole-2-carboxaldehyde (5a)
preparations and their analogues have been accom- was chosen as the model substrate in the direct asym-
plished.[5–9]
metric aldol reaction with acetone (6) in the presence
3370
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 3370 – 3376

COMMUNICATIONS
Asymmetric Aldol Reaction of Thiazole-Carbaldehydes
Table 1. Optimization of reaction conditions for aldol reac-
tion of 4-bromothiazole-2-carboxaldehyde (5a) with acetone
(6).[a]
Entry Solvent
Additive
Conv. Ratio
ee of
Scheme 1. Comparision of the previously reported method
with our method.
[%][b] 7a:8[b] 7a [%][c]
1
2
3
4
5
6
7
DMSO
DMF
DCM
dioxane
THF
MeCN
–
–
–
–
–
–
–
>99
50
36
73
57
70:30
65:35
92:8
80:20
82:18
85:15
85:15
50
52
50
56
54
48
<5
of 10 mol% l-proline (Figure 2, Table 1). It is impor-
tant to point out that an enantioselective aldol reac-
tion[11–14] of thiazole carbaldehydes with ketones has
not yet been devised. We monitored the outcome of
the reaction in various solvents. In our preliminary
studies, the reaction of 5a with acetone 6 gave unsatis-
factory results because of the formation of a mixture
of expected product 7a along with the side product 8,
which is derived from the reaction of aldehyde 5a and
catalyst l-proline (entries 1–7, Table 1).[15] Using
DMSO as the solvent, the product 7a was obtained
with 50% ee as a 70:30 mixture of 7a and 8 (Table 1,
entry 1). Poor results were obtained using DMF, di-
chloromethane, dioxane, THF, acetonitrile as solvents
(entries 2–6). A moderate yield of the product 7a
without any enantiomeric excess (ee) was obtained
using a protic solvent like MeOH (entry 7). The reac-
tion using excess acetone (100 equiv.) proceeded es-
sentially to completion giving high selectivity for the
formation of the product 7a (ee up to 65%) with 7a/8
ratio of >99:1 (entry 8). With this initial outcome in
hand, subsequently we investigated the effect of addi-
tives, catalyst loading and temperature on the enan-
22
55
MeOH
8
9
acetone[d]
acetone[d]
acetone[d]
acetone[d]
acetone[d]
acetone[d]
acetone[d]
–
80
>99:1 65
>99:1 34
>99:1 56
>99:1 50
>99:1 58
>99:1 60
>99:1 69
>99:1 51
>99:1 50
>99:1 55
>99:1 68
LiCl
TFA
A
AcOH
imidazole
>99
>99
>99
>99
>99
10
11
12
13
14
15
16
17
18
R-BINOL >99
acetone[d,e] R-BINOL 70
acetone[d,f] R-BINOL 80
acetone[d,g] R-BINOL >99
acetone[d,h] R-BINOL >99
[a]
Unless otherwise stated, all the reactions were carried
out using 1 equiv. of 5a and 50 equiv. of 6.
The conversion and ratios of 7a/8 were determined by
1H NMR analysis of the crude mixture.
The ee values were determined by chiral HPLC analysis.
Using 100 equiv. of 6.
Using 5 mol% of l-proline.
Using 20 mol% of l-proline.
Using 30 mol% of l-proline.
For 48 h at À208C.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
tioselectivity of this reaction (entries 9–18). Some of
the representative results are summarized in Table 1.
When the reaction was conducted in the presence
of LiCl as an additive (entry 9), the conversion and
the selectivity of 7a were increased with a significant
decrease in enantioselectivity. The enantioselectivity
of the reaction was not substantially improved using
either TFA (entry 10), benzoic acid (A, Figure 2,
entry 11) or acetic acid (entry 12) compared to the re-
action in the absence of an additive (entry 8). Using
Figure 2. Catalysts and additives used for the aldol reaction. 10 mol% of R-BINOL, the aldol reaction proceeded
Adv. Synth. Catal. 2014, 356, 3370 – 3376
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3371

COMMUNICATIONS
Sushovan Paladhi et al.
Table 2. l-Proline-catalyzed aldol reaction thiazole-carbalde-
efficiently at room temperature with >99% conver-
sion of the aldehyde 5a, >99:1 ratio of 7a:8 and up to
69% ee of 7a (entry 14). Reducing or increasing the
loading of l-proline lowered the reactivity and the
enantioselectivity of the reaction (entries 15–17). Sim-
ilarly, by lowering the reaction temperature to À208C,
a longer reaction time (48 h) was required for comple-
tion with no appreciable change in enantioselectivity
(entry 18).
hydes with acetone.[a]
Next we examined the asymmetric aldol reaction of
a variety of thiazole-aldehydes 5 with acetone under
the optimal conditions using 10 mol% l-proline and
10 mol% R-BINOL (Table 2). Thiazole-2-carbalde-
hyde 5b reacted smoothly to give the corresponding
aldol product 7b in high yield (85%) and moderate
enantioselectivity (ee 61%) within 24 h (Table 2,
entry 2). The reaction of 5c containing the aldehyde
group at the C-5 position of the thiazole ring pro-
duced the aldol product 7c in excellent yield (90%)
and enantioselectivity (ee 80%, Table 2, entry 3). Al-
dehyde 5d reacted smoothly to afford the correspond-
ing aldol product 7d in excellent yield and enantiose-
lectivity (entry 4).
Entry Aldehyde
Product
Conv. Yield ee
[%][b] of 7
[%]
[%] (7)[c]
1
2
3
>99 91
>99 85
>99 90
69
61
80
A decrease in enantioselectivity (71% ee) was ob-
served when employing 4-chlorothiazole-5-carboxal-
dehyde (5e), although the reactivity (91% yield) was
high (entry 5). The product 7e was obtained in 62%
yield with 63% ee (entry 6). The reaction of ethyl 2-
formylthiazole-4-carboxylate (1) with acetone needed
longer reaction time (120 h) too. The reaction of ethyl
2-formylthiazole-4-carboxylate (1) with acetone took
also needed a longer reaction time (120 h) to yield
the desired product 7f (entry 7) in moderate yield
(62%) and enantioselectivity (ee 63%). These results
showed that the position of the aldehyde and the
nature of the substituents have dramatic effects on
the reactivity and selectivity of the aldol reaction.
The utility of the l-proline-catalyzed aldol reaction
was next explored with the unsymmetrical methyl iso-
propyl ketone (4) for the synthesis of aldol precursor
9 of tubuvaline (Table 3), where there is a possibility
for formation of two different regioisomers (linear 9
4
5
>99 92
>99 91
84
71
63
6
70[d]
62
[a]
Unless otherwise stated, all the reactions were carried
out using 100 equiv. of 6 and 1 equiv. of 5.
The conversion was determined by H NMR analysis of
[b]
1
the crude mixture.
[c]
[d]
The ee values were determined by chiral HPLC analysis.
Reaction was continued for 120 h.
When the aldol reaction between 2-formylthiazole-
and the branched 10).[16] However, the result was very 4-carboxylate (1) and methyl isopropyl ketone (4)
disappointing. Under the optimal conditions, only was carried out using 20 mol% Pro-1 in the presence
moderate conversion of the aldehyde 1 was obtained of water, a moderate conversion of 1 was observed
leading to a 50:50 mixture of linear 9 and branched with the formation of an 85:15 mixture (linear/
10 aldol products without any enantioselectivity of 9 branched) of aldol products 9 and 10 with a low ee for
(entry 1). The reaction was sluggish using TFA as an the desired linear isomer 9 (entry 3, Table 3). This
additive (entry 2). These poor results for the forma- result indicates that Pro-1 shows a preference for the
tion of pre-Tuv 9 prompted us to screen our recently linear aldol product 9. Next we screened the aldol re-
developed triazole-prolinamide Pro-1, which catalyzes action with a series of additives in order to improve
the direct asymmetric aldol reaction of aromatic alde- the activity and selectivity of Pro-1. In the presence
hydes with cyclic ketones in the presence of water.[10c] of two additives such as benzoic acid and formic acid,
The prolinamide Pro-1 was easily prepared using the reaction occurred preferentially at the methyl
using Cu(I)-catalyzed 1,3-dipolar azide-alkyne cyclo- carbon favouring the linear aldol product 9 with ex-
addition[17] of an azido-prolinamide with phenylacety- cellent regioselectivity (>99:1) and high enantioselec-
lene.
tivity (entry 4). This result shows that additives have
3372
asc.wiley-vch.de
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 3370 – 3376

COMMUNICATIONS
Asymmetric Aldol Reaction of Thiazole-Carbaldehydes
Table 3. Aldol reaction of 2-formylthiazole-4-carboxylate (1) with methyl isopropyl ketone (4).[a]
Entry
Cat.[b]
Solvent
Additive
Conv.[c]/yield [%]
ratio 9:10[c]
ee 9 [%][d]
1
2
3
4
5
6
7
8
l-proline
l-proline
Pro-1
Pro-1
Pro-1
Pro-1
Pro-1
Pro-1
Pro-1
Pro-1
Pro-1
Pro-1
Pro-1
Pro-1
Pro-1
Pro-1
4[e]
R-BINOL
TFA
–
A+HCO2H
A + HCO2H
A+HCO2H
A+HCO2H
A
A+CH3CO2H
A+TFA
B+HCO2H
C+HCO2H
D+HCO2H
D+TFA
D+HCO2H
A+HCO2H
–
50/44
>5/n.d.
50/43
95/89
70/61
50/43
60/54
85/79
90/73
89/68
95/90
95/91
96/91
90/74
96/93
91/84
<5/nd
70/62
no product
50:50
–
0
–
4[e]
H2O (0.1)
H2O (0.1)
DMSO (0.1)
CHCl3 (0.1)
THF (0.1)
H2O (0.1)
H2O (0.1)
H2O (0.1)
H2O (0.1)
H2O (0.1)
H2O (0.1)
H2O (0.2)
H2O (0.2)
4[e]
85:15
> 99:1
70:30
60:40
60:40
90:10
90:10
85:15
95:5
32
70
30
<5
<5
55
65
76
82
87
88
89
92
40
–
9
10
11
12
13
14
15
16
17
18
19
99:1
99:1
99:1
> 99:1
50:50
–
l-proline
l-proline
4-hydroxyproline
H2O (0.2)
H2O (0.2)
H2O (0.2)
A+HCO2H
D+HCO2H
50[f]:50
<5
[a]
Unless otherwise stated, all the reactions were carried out using 50 equiv. of 4 and 1 equiv. of 1.
[b]
[c]
[d]
[e]
[f]
Using 10 mol% of l-proline and 20 mol% of Pro-1.
1
The product and side product ratios and conversion were determined by H NMR analysis of the crude mixture.
The ee values were determined by chiral HPLC analysis.
Using 100 equiv. of 4.
20% isolated yield of 9, n.d.=not determined.
a dramatic effect on the conversion and selectivity of without any additive (entry 17). However, in the pres-
the aldol reaction. Solvents also play a role on the ence of benzoic acid and formic acid, l-proline pro-
conversion and selectivity of the aldol reaction. vided a moderate level of reaction efficiency (70%
Lower regioselectivity of the reaction without any conversion) with the formation of a 50:50 mixture of
enantioselectvity was observed in chloform and THF both aldol products 9 and 10 with virtually no enan-
(entries 6 and 7). In DMSO, 70% conversion of 1 was tioselectivity (entries 17 and 18). Similarly, no reac-
observed within 120 h leading to the formation of tion was obtained using 4-hydroxyproline (entry 19).
70:30 mixtures of both the aldol products 9 and 10 The branched aldol product 10 may also be regarded
with poor enantioselectivity of 9. The reaction in the as a regioisomeric analogue of preTuv.
presence of excess methyl isopropyl ketone
4
Based on our experimental results and recent stud-
(100 equiv.) afforded a 50:50 mixture of the desired ies on Pro-1-catalyzed aldol reactions in the presence
pre-Tuv 9 with its branched isomer 10 with poor ee of water, we proposed a plausible reaction pathway to
(40%) of 9 (entry 16). Further optimization of the re- explain the high selectivity of this reaction. The regio-
action revealed that a combination of 2,4,6-trifluoro- and enantioselectivity can be explained based on the
benzoic acid (D), formic acid in the presence of 0.2M enamine intermediates shown in Figure 3. With the
concentration of water with respect to the aldehyde unsymmetrical ketone 4, two enamine interemediates
1 provides the most effective conditions (entry 15) for 11a and 11b are possible. The facial linear selectivity
Pro-1 catalysis with respect to the yield (93%), regio- over the branched product may be explained by the
selectivity (>99:1) and enantioselectivity (92%). In predominant formation of the thermodynamically
this reaction both the reactants 1 and 4 and the prod- more favourable 11a over the more substituted enam-
uct 9 are insoluble in water.[18] l-Proline showed no ine 11b. The steric hindrance in 11b forces the facile
catalytic activity for this reaction in water medium reaction of the intermediate 11a with 2-formylthia-
Adv. Synth. Catal. 2014, 356, 3370 – 3376
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3373

COMMUNICATIONS
Sushovan Paladhi et al.
Figure 3. Proposed mechanism.
zole-4-carboxylate (1) with high enantioselectivity. l- a rapid, flexible and convergent entry to tubvaline
Proline may stabilize both the enamines 11c and 11d and the analogues of the most potent anti-cancer drug
and this equilibrium would have led to a 1:1 mixture tubulysin.
of the regioisomers 9 and 10 with no enantioselectivity.
Surprisingly, Pro-1 provided a good level of catalytic
activity (>80% conversion) for the aldol reaction of Experimental Section
thiazole aldehydes 1 and 5a with water-miscible ace-
tone but failed to induce any enantioselectivity.
Pro-1-Catalyzed Aldol Reaction
This can be explained based on the biphasic nature
of Pro-1, which acts as a phase-transfer catalyst, and
effectively shows better selectivity in aqueous
medium with water-immiscible ketones. This reaction
provides a unique example of the substrate selectivity
of Pro-1, where the substrate simply fits into the
active site to perform the reaction.
In
a small vial, catalyst Pro-1 (17.9 mg, 0.054 mmol,
0.2 equiv.), methyl isopropyl ketone 4 (1.5 mL, 13.5 mmol,
50 equiv.), 2,4,6-trifluorobenzoic acid (9.5 mg, 0.054 mmol,
0.2 equiv.) and water (0.5 mL, 0.2M) were charged. Then,
formic acid (2 mL, 0.054 mmol, 0.2 equiv.) was added to the
reaction mixture and stirred at room temperature. After
30 min, aldehyde 1 (50 mg, 0.27 mmol, 1.0 equiv.) was added
to the reaction vial and the stirring was continued at room
temperature until the disappearance of the aldehyde by
TLC analysis. Then ethyl acetate was added to the reaction
mixture which was then extracted with ethyl acetate (3ꢃ
5 mL), dried over Na2SO4, filtered and concentrated under
vacuum. The product was then purified by flash chromatog-
raphy on 100–200 mesh silica gel using hexane-ethyl acetate
(80:20 to 70:30) as eluent to provide the corresponding
aldol product 9. The conversion was determined by
1H NMR and the enantioselectivity (ee) was determined by
chiral HPLC of the crude reaction mixture.
We next performed the reductive amination[19] of
pre-Tuv analogue 7f and pre-Tuv 9 with benzylamine
(12) and NaBH3CN in the presence of AcOH and
4ꢂ molecular sieves. The reaction yielded the
corresponding 1,3-amino alcohols 13 and 14 in high
yields, diastereoselectivities and enantioselectivities
(Scheme 2 and the Supporting Information). The de-
sired N-Bn protected tubuvalines 14 were obtained in
65% yields as a 90:10 (syn/anti) mixture of diastereo-
mers with high enantioselectivity (83% ee) for the
major isomer. The syn configuration was confirmed
by an NMR analysis (NOE assignments) of the cyclic
derivative15. The cyclic compound 15 was prepared
from the tubuvaline analogue syn-13 in 98% yield
(Scheme 2 and the Supporting Information).
Supporting Information
Experimental procedures, characterization data of com-
pounds, copies of the H NMR, 13C NMR and HPLC analy-
1
sis spectra are available in the Supporting Information.
In summary, we have presented the first l-proline-
catalyzed enantioselective aldol reaction of thiazole-
carbaldehydes with acetone, which enables a direct
access to the analogues of pre-tubuvaline. Significant-
ly, we identified the prolinamide-catalyzed aldol reac-
tion of 2-formylthiazole-4-carboxylate with methyl
isopropyl ketone “on water” to afford pre-Tuv in ex-
cellent yield, regio- and enantioselectivities. The re-
Acknowledgements
We thank Professor Subrata Ghosh for helpful discussions
and DST-Green Chemistry India for research funding. SP
and JD thank CSIR and MS thanks UGC for research fel-
ductive amination of pre-Tuv analogues constitutes lowships.
3374
asc.wiley-vch.de
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 3370 – 3376

COMMUNICATIONS
Asymmetric Aldol Reaction of Thiazole-Carbaldehydes
Scheme 2. Synthesis of tubuvaline analogues.
References
Pando, S. Dçrner, R. Preusentanz, A. Denkert, A.
Porzel, W. Richter, L. Wessjohann, Org. Lett. 2009, 11,
5567–5569; e) R. Balasubramanian, B. Raghavan, A.
Begaye, D. L. Sackett, R. A. Fecik, J. Med. Chem. 2009,
52, 238–240; f) T. Shibue, T. Hirai, I. Okamoto, N.
Morita, H. Masu, I. Azumaya, O. Tamura, Chem. Eur.
J. 2010, 16, 11678–11688; g) O. Pando, S. Stark, A. Den-
kert, A. Porzel, R. Preusentanz, L. A. Wessjohann, J.
Am. Chem. Soc. 2011, 133, 7692–7695.
[1] a) A. Dçmling, W. Richter, Mol. Diversity 2005, 9, 141–
147; b) Z. Jin, Nat. Prod. Rep. 2006, 23, 464–496.
[2] F. Sasse, H. Steinmetz, J. Heil, G. Hçfle, H. Reichen-
bach, J. Antibiot. 2000, 53, 879–885.
[3] a) G. Hçfle, N. Glaser, T. Leibold, U. Karama, F. Sasse,
H. Steinmentz, Pure Appl. Chem. 2003, 75, 167–178;
b) A. Sandmann, F. Sasse, R. Mꢄller, Chem. Biol. 2004,
11, 1071–1079; c) G. Kaur, M. Hollingshead, S. Hol-
[6] a) G. K. Friestad, J.-C. Mariꢅ, A. M. Deveau, Org. Lett.
2004, 6, 3249–3252; b) P. Wipf, T. Takada, M. J. Rishel,
Org. Lett. 2004, 6, 4057–4060; c) R. Balasubramanian,
B. Raghavan, J. C. Steele, D. L. Sackett, R. A. Fecik,
Bioorg. Med. Chem. Lett. 2008, 18, 2996–2999; d) S.
Chandrasekhar, B. Mahipal, M. Kavitha, J. Org. Chem.
2009, 74, 9531–9534; e) D. Becker, U. Kazmaier, J. Org.
Chem. 2013, 78, 59–65.
[7] a) A. W. Patterson, H. M. Peltier, F. Sasse, J. A.
Ellman, Chem. Eur. J. 2007, 13, 9534–9541; b) B. Ra-
ghavan, R. Balasubramanian, J. C. Steele, D. L. Sackett,
R. A. Fecik, J. Med. Chem. 2008, 51, 1530–1533; c) A.
Ullrich, Y. Chai, D. Pistorius, Y. A. Elnakady, J. E.
Herrmann, K. J. Weissman, U. Kazmaier, R. Mꢄeller,
Angew. Chem. 2009, 121, 4486–4489; Angew. Chem.
Int. Ed. 2009, 48, 4422–4425; d) A. Ullrich, J. Herr-
mann, R. Mꢄeller, U. Kazmaier, Eur. J. Org. Chem.
2009, 6367–6378; e) W. C. Floyd III, G. K. Datta, S. Im-
amura, H. M. Kieler-Ferguson, K. Jerger, A. W. Patter-
son, M. E. Fox, F. C. Szoka, J. M. J. Frꢅchet, J. A.
´
beck, V. Schauer-Vukasinovic, R. F. Camalier, A. Dçm-
ling, S. Agarwal, Biochem. J. 2006, 396, 235–242;
d) M. W. Khalil, F. Sasse, H. Lꢄnsdorf, Y. A. Elnakady,
H. Reichenbach, ChemBioChem 2006, 7, 678–683; e) T.
Schluep, P. Gunawan, L. Ma, G. S. Jensen, J. Duringer,
S. Hinton, W. Richter, J. Hwang, Clin. Cancer Res.
2009, 15, 181–189; f) Y. Chai, D. Pistorius, A. Ullrich,
K. J. Weissman, U. Kazmaier, R. Mꢄller, Chem. Biol.
2010, 17, 296–309.
[4] H. Steinmetz, N. Glaser, E. Herdtweck, F. Sasse, H.
Reichenbach, G. Hçfle, Angew. Chem. 2004, 116, 4996–
5000; Angew. Chem. Int. Ed. 2004, 43, 4888–4892.
[5] a) A. Dçmling, B. Beck, U. Eichelberger, S. Sakamuri,
S. Menon, Q.-Z. Chen, Y. Lu, L. A. Wessjohann,
Angew. Chem. 2006, 118, 7393–7397; Angew. Chem. Int.
Ed. 2006, 45, 7235–7239; b) M. Sani, G. Fossati, F. Hu-
guenot, M. Zanda, Angew. Chem. 2007, 119, 3596–
3599; Angew. Chem. Int. Ed. 2007, 46, 3526–3529; c) P.
Wipf, Z. Wang, Org. Lett. 2007, 9, 1605–1607; d) O.
Adv. Synth. Catal. 2014, 356, 3370 – 3376
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3375

COMMUNICATIONS
Sushovan Paladhi et al.
Ellman, ChemMedChem 2011, 6, 49–53; f) J. L. Bur-
khart, R. Mꢄeller, U. Kazmaier, Eur. J. Org. Chem.
2011, 3050–3059; g) X. Yang, C. Dong, J. Chen, Q. Liu,
B. Han, Q. Zhang, Y. Chen, Tetrahedron Lett. 2013, 54,
2986–2988.
Barbas III, Org. Lett. 2004, 6, 3541- -3544; e) N. Mase,
Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F. Tanaka,
C. F. Barbas III, J. Am. Chem. Soc. 2006, 128, 734–735;
f) Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Ur-
ushima, M. Shoji, Angew. Chem. 2006, 118, 972–975;
Angew. Chem. Int. Ed. 2006, 45, 958–961; g) A. P.
Brogan, T. J. Dickerson, K. D. Janda, Angew. Chem.
2006, 118, 8278–8280; Angew. Chem. Int. Ed. 2006, 45,
8100–8102; h) T. Kano, Y. Yamaguchi, Y. Tanaka, K.
Maruoka, Angew. Chem. 2007, 119, 1768–1770; Angew.
Chem. Int. Ed. 2007, 46, 1738–1740; i) M. Rueping, A.
Kuenkel, F. Tato, J. W. Bats, Angew. Chem. 2009, 121,
3754–3757; Angew. Chem. Int. Ed. 2009, 48, 3699–3702;
j) D. G. Blackmond, A. Moran, M. Hughes, A. Arm-
strong, J. Am. Chem. Soc. 2010, 132, 7598–7599; k) T.
Kano, H. Sugimoto, K. Maruoka, J. Am. Chem. Soc.
2011, 133, 18130–18133.
[8] H. M. Peltier, J. P. McMahon, A. W. Patterson, J. A.
Ellman, J. Am. Chem. Soc. 2006, 128, 16018–16019.
[9] A. W. Patterson, H. M. Peltier, J. A. Ellman, J. Org.
Chem. 2008, 73, 4362–4369.
[10] a) G. C. Midya, S. Paladhi, K. Dhara, J. Dash, Chem.
Commun. 2011, 47, 6698–6700; b) S. Paladhi, A. Chau-
han, K. Dhara, A. K. Tiwari, J. Dash, Green Chem.
2012, 14, 2990–2995; c) S. Paladhi, J. Das, P. K. Mishra,
J. Dash, Adv. Synth. Catal. 2013, 355, 274–280; d) S.
Pagoti, S. Surana, A. Chauhan, B. Parasar, J. Dash,
Catal. Sci. Technol. 2013, 3, 584–588; e) S. Pagoti, D.
Dutta, J. Dash, Adv. Synth. Catal. 2013, 355, 3532–
3538; f) S. Paladhi, M. Bhati, D. Panda, J. Dash, J. Org.
Chem. 2014, 79, 1473–1480; g) G. C. Midya, B. Parasar,
K. Dhara, J. Dash, Org. Biomol. Chem. 2014, 12, 1812–
1822.
[15] a) T. Kano, O. Tokuda, J. Takai, K. Maruoka, Chem.
Asian J. 2006, 1, 210–215; b) N. Zotova, A. Franzke, A.
Armstrong, D. G. Blackmond, J. Am. Chem. Soc. 2007,
129, 15100–15101.
[11] a) Modern Aldol Reactions, (Ed.: R. Mahrwald),
Wiley-VCH, Weinheim, 2004; b) B. Schetter, R. Mahr-
wald, Angew. Chem. 2006, 118, 7668–7687; Angew.
Chem. Int. Ed. 2006, 45, 7506–7525.
[12] For the first proline-catalysed aldol reaction, see: B.
List, R. A. Lerner, C. F. Barbas III, J. Am. Chem. Soc.
2000, 122, 2395–2396.
[16] For organocatalytic aldol reaction of unsymmetrical ke-
tones, see: a) Z. Tang, Z.-H. Yang, X.-H. Chen, L.-F.
Cun, A.-Q. Mi, Y.-Z. Jiang, L.-Z. Gong, J. Am. Chem.
Soc. 2005, 127, 9285–9289; b) S. Guizzetti, M. Benaglia,
L. Raimondi, G. Celentano, Org. Lett. 2007, 9, 1247–
1250; c) X.-Y. Xu, Y.-Z. Wang, L.-Z. Gong, Org. Lett.
2007, 9, 4247–4249.
[13] Asymmetric Organocatalysis: From Biomimetic Con-
cepts to Applications in Asymmetric Synthesis, (Eds.: A.
Berkessel, H. Grçger), Wiley-VCH, Weinheim, 2005.
[14] For a review see, a) B. M. Trost, C. S. Brindle, Chem.
Soc. Rev. 2010, 39, 1600–1632. For leading references,
see: b) S. Kandasamy, W. Notz, T. Bui, C. F. Barbas III,
J. Am. Chem. Soc. 2001, 123, 5260–5267; c) A. B.
Northrup, D. W. C. MacMillan, J. Am. Chem. Soc. 2002,
124, 6798–6799; d) R. Thayumanavan, F. Tanaka, C. F.
[17] V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharp-
less, Angew. Chem. 2002, 114, 2708–2711; Angew.
Chem. Int. Ed. 2002, 41, 2596–2599.
[18] For the ꢆon-waterꢀ concept, see: S. Narayan, J. Mul-
doon, M. G. Finn, V. V. Fokin, H. C. Kolb, K. B. Sharp-
less, Angew. Chem. 2005, 117, 3339–3343; Angew.
Chem. Int. Ed. 2005, 44, 3275–3279.
[19] M. Haddad, J. Dorbais, M. LarchevÞque, Tetrahedron
Lett. 1997, 38, 5981–5984.
3376
asc.wiley-vch.de
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 3370 – 3376