Development of tartaric acid derived chiral guanidines and their application to catalytic enantioselective α-hydroxylation of β-dicarbonyl compounds

Article abstract of DOI:10.1021/ol401306h

A novel library of chiral guanidines featuring a tartaric acid skeleton was developed from diethyl l-tartrate. These guanidines are easily accessed with tunable steric and electronic properties. The utilities of the guanidines were highlighted by their ability to catalyze the α-hydroxylation of β-ketoesters and β-diketones with remarkable efficiency and excellent enantioselectivity.

Full text of DOI:10.1021/ol401306h

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Development of Tartaric Acid Derived
Chiral Guanidines and Their Application
to Catalytic Enantioselective
r‑Hydroxylation of β‑Dicarbonyl
Compounds
Liwei Zou, Baomin Wang,* Hongfang Mu, Huanrui Zhang, Yuming Song, and Jingping Qu*
State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and
Technology, Dalian University of Technology, Dalian 116024, P. R. China
bmwang@dlut.edu.cn; qujp@dlut.edu.cn
Received May 10, 2013
ABSTRACT
A novel library of chiral guanidines featuring a tartaric acid skeleton was developed from diethyl L-tartrate. These guanidines are easily accessed
with tunable steric and electronic properties. The utilities of the guanidines were highlighted by their ability to catalyze the R-hydroxylation of
β-ketoesters and β-diketones with remarkable efficiency and excellent enantioselectivity.
Tartaric acid has played a prominent role in the devel-
opment of chiral auxiliaries and chiral catalysts for use in
asymmetric organic synthesis due to its rich abundance
and ready diversification.1 In the context of the flourishing
development of asymmetric organocatalysis with small
chiral organic molecules as catalysts over the past decade,2
a number of tartaric acid derivatives have been introduced
as organic catalysts including, for example, TADDOLs,3
TADDOL-based phosphoric acids,4 and TADDOL-
derived phase transfer catalysts.5 Despite these sporadic
reports, the potential of tartaric acid as a parent scaffold
for the development of chiral organic catalysts is far from
being fully exploited.
In the field of asymmetric organocatalysis, chiral guani-
dines represent a preeminent catalyst class, which have
enabled a broad spectrum of asymmetric organic reac-
tions.6 Although a wide array of structurally diverse chiral
guanidines have been developed, there still exists a paucity
in this field of more general guanidine catalysts capable of
catalyzing a broader scope of asymmetric transformations.
As a consequence, the development of chiral guanidines
(1) (a) Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem., Int. Ed.
2001, 40, 92. (b) Pellissier, H. Tetrahedron 2008, 64, 10279.
(2) (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138.
(b) Berkessel, A.; Grc-ger, H. Asymmetric Organocatalysis; Wiley-VCH:
New York, 2005. (c) Dalko, P. L. Enantioselective Organocatalysis; Wiley-
VCH: Weinheim, 2007. (d) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B.
Chem. Rev. 2007, 107, 5471. (e) Doyle, A. G.; Jacobsen, E. N. Chem. Rev.
2007, 107, 5713. (f) Pellissier, H. Tetrahedron 2007, 63, 9267. (g)
MacMillan, D. W. C. Nature 2008, 455, 304.
(5) (a) Belokon, Y. N.; Kochetkov, K. A.; Churkina, T. D.; Ikonnikov,
ꢀ
N. S.; Chesnokov, A. A.; Larionov, O. V.; Parmar, V. S.; Kumar, R.;
Kagan, H. B. Tetrahedron: Asymmetry 1998, 9, 851. (b) Belokon, Y. N.;
Kochetkov, K. A.; Churkina, T. D.; Ikonnikov, N. S.; Chesnokov, A. A.;
Larionov, O. V.; Singh, I.; Parmar, V. S.; Vyskocil, S.; Kagan, H. B. J. Org.
(3) (a) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature
2003, 424, 146. (b) McGilvra, J. D.; Unni, A. K.; Modi, K.; Rawal, V. H.
Angew. Chem., Int. Ed. 2006, 45, 6130. (c) Gondi, V. B.; Hagihara, K.;
Rawal, V. H. Angew. Chem., Int. Ed. 2009, 48, 776. (d) Seebach, D.;
€
Chem. 2000, 65, 7041. (c) Waser, M.; Gratzer, K.; Herchl, R.; Muller, N.
Org. Biomol. Chem. 2012, 10, 251. (d) Gratzerand, K.; Waser, M. Synthesis
2012, 3661.
€
Beck, A. K.; Bichsel, H. -U.; Pichota, A.; Sparr, C.; Wunsch, R.;
Schweizer, W. B. Helv. Chim. Acta 2012, 95, 1303.
(4) Akiyama, T.; Saitoh, Y.; Morita, H.; Fuchibe, K. Adv. Synth.
Catal. 2005, 347, 1523.
(6) (a) Ishikawa, T.; Kumamoto, T. Synthesis 2006, 737. (b) Leow,
D.; Tan, C. H. Chem.;Asian. J. 2009, 4, 488. (c) Leow, D.; Tan, C. H.
Synlett 2010, 1589.
r
10.1021/ol401306h
XXXX American Chemical Society

from simple precursors with readily tunable steric and
electronic factors for more asymmetric applications is
highly desirable. Since its first introduction by Seebach
and co-workers two decades ago, the TADDOL derived
diamine 1 and derivatives thereof have found very few
catalytic asymmetric applications.7 Given the readily tun-
able nature of the TADDOL backbone, we envisioned that
diamine 1 (Scheme 1) could serve as a promising precursor
for the construction of a library of guanidine catalysts.
oxygenating agents.10,11 In the case of asymmetric organo-
catalysis toward this goal, only the cinchona alkaloid11a,d,e
and chiral phosphoric acid11b have been reported as effi-
cient catalysts, while other organocatalysts include the
natural alkaloid lappaconitine11c and a synthetic analogue
of S-timolol,11f but with moderate results. To the best of
our knowledge, there is no literature precedent with gua-
nidine catalysis on this project. Herein, we report the
development of a novel library of chiral guanidines featur-
ing a tartaric acid skeleton and their efficient application to
the enantioselective R-hydroxylation of β-dicarbonyl com-
pounds.
Our studies commenced with the construction of the
library of guanidine catalysts starting from diethyl
L-tartrate. The key diamine intermediate was readily ob-
tained according to the literature procedure,7a which was
transformed into thiourea 2 almost quantitatively upon
treatment with carbon disulfide.12 The reaction of the
thiourea 2 with primary amines smoothly occurred under
the mediation of CuCl,13 affording the guanidines 3aÀj in
good to excellent yield.14 By varying R1, Ar, and R2, a
library of chiral guanidines with different steric and elec-
tronic properties was constructed (Scheme 1).
Scheme 1. Tartaric Acid Derived Chiral Guanidines and the
Known Catalysts Used in This Work
With the guanidine library established, we evaluated the
catalytic activity and enantioselectivity on the R-hydro-
xylation of β-dicarbonyl compounds. To this end, the
R-hydroxylation of indanone derived β-ketoester was se-
lected as a model reaction to identify the optimal reaction
conditions. With the hydroxylation of 6a in toluene under
the catalysis of 10 mol % 3b, the oxidants were first
screened. While the reactions with H2O2 and tert-butyl
hydroperoxide (TBHP) were very sluggish with low en-
antioselectivity, m-chloroperoxybenzoic acid (mCPBA)
reacted much faster but afforded a racemic product
(Table 1, entries 1À3). When oxaziridine 7a was used, to
our delight, the reaction was complete in 5 min with full
conversion and a promising enantioselectivity of 48% ee
(Table 1, entry 4). Further investigation on the use of
chloro substituted oxaziridine 7b and saccharin-based 7c
and 7d afforded inferior ee values (Table 1, entries 5À7).15
On the other hand, the R-hydroxy-β-dicarbonyl moiety
is an intriguing structural motif commonly found in a
variety of biologically active natural products, agrochem-
icals, pharmaceuticals, and advanced synthetic intermedi-
ates thereof.8 Consequently, much effort has been devoted
to the construction of this architecture over the past
decade, including the stoichiometric use of chiral oxazir-
idine initiated by Davis9 and asymmetric catalysis by chiral
metal or organic catalysts in conjunction with appropriate
~
(11) For organocatalysis, see: (a) Acocella, M. R.; Mancheno, O. G.;
Bella, M.; Jørgensen, K. A. J. Org. Chem. 2004, 69, 8165. (b) Lu, M.;
Zhu, D.; Lu, Y.; Zeng, X.; Tan, B.; Xu, Z.; Zhong, G. J. Am. Chem. Soc.
2009, 131, 4562. (c) Gong, B.; Meng, Q.; Su, T.; Lian, M.; Wang, Q.;
Gao, Z. Synlett 2009, 2659. (d) Lian, M.; Li, Z.; Du, J.; Meng, Q.; Gao,
Z. Eur. J. Org. Chem. 2010, 34, 6525. (e) Yao, H.; Lian, M.; Li, Z.; Wang,
Y.; Meng, Q. J. Org. Chem. 2012, 77, 9601. (f) Cai, Y.; Lian, M.; Li, Z.;
Meng, Q. Tetrahedron 2012, 68, 7973.
(7) (a) Seebach, D.; Hayakawa, M.; Sakaki, J.; Schweizer, W. B.
Tetrahedron 1993, 49, 1711. (b) Seebach, D.; Pichota, A.; Beck, A. K.;
Pinkerton, A. B.; Litz, T.; Karjalainen, J.; Gramlich, V. Org. Lett. 1999,
1, 55. (c) Kretzschmar, E. A.; Kipke, J.; Sundermeyer, J. Chem. Com-
€
mun. 1999, 2381. (d) Lauber, M. B.; Frohlich, R.; Paradies, J. Synthesis
2012, 3209.
(8) (a) Guanti, G.; Banfi, L.; Powles, K.; Rasparini, M.; Scolastico,
C.; Fossati, N. Tetrahedron: Asymmetry 2001, 12, 271. (b) Christoffers,
J.; Baro, A.; Werner, T. Adv. Synth. Catal. 2004, 346, 143.
(9) Davis, F.; Liu, H.; Chen, B. C.; Zhou, P. Tetrahedron 1998, 54,
10481.
(12) (a) Merrer, Y. L.; Gauzy, L.; Gravier-Pelletier, C.; Depezay
J.-C. Bioorg. Med. Chem. 2000, 8, 307. (b) Pichota, A.; Gramlich, V.;
€
€
Bichsel, H.-U.; Styner, T.; Knopfel, T.; Wunsch, R.; Hintermann, T.;
Schweizer, W. B.; Beck, A. K.; Seebach, D. Helv. Chim. Acta 2012, 95,
1273.
(10) For chiral metal complex catalysis, see: (a) Ishimaru, T.; Shibata,
N.; Nagai, J.; Nakamura, S.; Toru, T.; Kanemasa, S. J. Am. Chem. Soc.
2006, 128, 16488. (b) Reddy, D. S.; Shibata, N.; Nagai, J.; Nakamura, S.;
Toru, T. Angew. Chem., Int. Ed. 2009, 48, 803. (c) Smith, A. M. R.;
Billen, D.; Hii, K. K. Chem. Commun. 2009, 26, 3925. (d) Smith,
A. M. R.; Rzepa, H. S.; White, A. J. P.; Billen, D.; Hii, K. K.
J. Org. Chem. 2010, 75, 3085. (e) Jiang, J. J.; Huang, J.; Wang, D.;
Zhao, M. X.; Wang, F. J.; Shi, M. Tetrahedron: Asymmetry 2010, 21,
794. (f) Cao, S. H.; Shi, M. Tetrahedron: Asymmetry 2010, 21, 2675. (g)
Smith, A. M. R.; Hii, K. K. Chem. Rev. 2011, 111, 1637. (h) Li, J.; Chen,
G.; Wang, Z.; Zhang, R.; Zhang, X.; Ding, K. Chem. Sci. 2011, 2, 1141.
(i) Takechi, S.; Kumagai, N.; Shibasaki, M. Tetrahedron Lett. 2011, 52,
2140.
(13) Ube, H.; Uraguchi, D.; Terada, M. J. Organomet. Chem. 2007,
692, 545.
(14) The X-ray crystal structure of 3a hydrochloride was shown in the
Supporting Information. CCDC 934885 of this compound contains the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Center via www.ccdc.cam.ac.uk /data_request/cif.
(15) For the preparation of oxaziridines 7aÀd, see: (a) Davis, F. A.;
Towson, J. C.; Vashi, D. B.; ThimmaReddy, R.; McCauley, J. P., Jr.;
Harakal, M. E.; Gosciniak, D. J. J. Org. Chem. 1990, 55, 1254. (b)
ꢀ
Ruano, J. L. G.; Aleman, J.; Fajardo, C.; Parra, A. Org. Lett. 2005, 7,
5493.
B
Org. Lett., Vol. XX, No. XX, XXXX

With 7a as the oxidant and 3b as the catalyst other solvents
were surveyed, and the result indicated that toluene main-
tained the solvent of choice (see the Supporting Informa-
tion Table S-1).
Table 2. Optimization of the Reaction Conditionsa
Table 1. Survey of the Oxidanta
entry
cat.
temp (°C)
time (min)
yield (%)b
ee (%)c
1
3a
3b
3c
3d
3b
3b
3b
3b
3b
3b
3e
3f
rt
5
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
40
48
0
2
rt
5
3
rt
1
4
rt
10
10
10
40
120
120
120
50
40
30
60
120
60
150
1
2
5
À20
À20
À60
À78
À78
À78
À78
À78
À78
À78
À78
À78
À78
rt
67
69
81
84
84
85
87
83
90
82
86
93
92
26
À28
6d
7d
8d
9d,e
10dÀ
f
11dÀ
f
12dÀ
f
13dÀ
3g
3h
3i
f
14dÀ
f
15dÀ
f
16dÀ
3j
f
17dÀ
3j
g
18
4
19
5
rt
1
a Unless otherwise noted, reactions were conducted with β-ketoester
6a (0.2 mmol), catalyst (0.02 mmol, 10 mol %), and oxaziridine 7a
(0.26 mmol, 1.3 equiv) in toluene (1 mL). b Isolated yield. c Determined
by chiral HPLC analysis (Chiralcel OD-H). d Toluene (2 mL). e Oxazir-
idine 7a (0.24 mmol, 1.2 equiv). f Under a nitrogen atmosphere.
g Catalyst (5 mol %).
a Unless otherwise noted, reactions were conducted with β-ketoester
6a (0.2 mmol), catalyst 3b (0.02 mmol, 10 mol %), and oxidant (0.26
mmol, 1.3 equiv) in toluene (1 mL) at room temperature. b Isolated yield.
c Determined by chiral HPLC analysis (Chiralcel OD-H). d The conver-
sion was not complete.
to 87% ee at À78 °C (Table 2, entry 11), but the guanidine
with a 3,4,5-trimethoxybenzyl group gave a slightly lower
ee of 83% (Table 2, entry 12). Interestingly, the use of the
guanidine with a p-methylbenzyl group delivered the prod-
uct with 90% ee (Table 2, entry 13). Further variation of
the aryl groups at 1,4-position of the tartaric acid back-
bone with p-bisphenyl functionality finally gave rise to an
enantioselectivity of 93% ee (Table 2, entry 16). Notably,
the catalyst loading could be reduced to 5 mol % without
erosion of the yield and enantioselectivity, albeit at the
expense of an extended reaction time (Table 2, entry 17).
For comparison, some amino acid based guanidine cata-
lysts were tested. The result indicated that both L-tert-
leucine and L-proline based guanidines16 showed inferior
asymmetric induction at rt compared to 3b, affording 26%
and 28% ee, respectively (Table 2, entries 18 and 19).
With the optimized conditions established, we next
explored the substrate scope of the R-hydroxylation pro-
cess (Figure 1). Initially, esters of different steric bulk were
investigated (6aÀe). The substrate displaying a methyl
ester proved the most effective. As the steric bulk of the
ester group increased, the reactivity and enantioselectivity
With the optimal oxidant and solvent identified, other
reaction parameters were examined including the guanidine
catalyst, temperature, and concentration. Itwasfoundthat
the amine moiety, which was introduced at the final stage
as an integral component of the guanidine catalyst, has a
marked influence on the enantioselectivity of the hydro-
xylation reaction. While benzyl amine derived guanidine
3b exhibited promising enantioselectivity at rt, other alkyl
amine based guanidine catalysts generally showed poor
enantiocontrol except for the methylamine derived guani-
dine which afforded 40% ee (Table 2, entries 1À4). When
the reaction was run at À20 °C, to our delight, the en-
antioselectivity was improved to 67% ee (Table 2, entry 5).
Dilution of the reaction to 0.1 M resulted in a slight in-
crease of the enantioselectivityto69% ee (Table 2, entry 6).
Further lowering of the temperature to À60 and À78 °C
gave 81% and 85% ee values, respectively (Table 2, entries
7À10). To further improve the enantioselectivity, we then
focused our attention on the modification of the benzyl
moiety of the guanidine (Table 2, entries 11À15). Substitu-
tion with a p-methoxy group on the phenyl ring of the
benzyl unit led to a slight increase of the enantioselectivity
(16) (a) Ye, W.; Leow, D.; Goh, S. L. M.; Tan, C. T.; Chian, C. H.;
Tan, C. H. Tetrahedron Lett. 2006, 47, 1007. (b) Yu, Z.; Liu, X.; Zhou,
L.; Lin, L.; Feng, X. Angew. Chem., Int. Ed. 2009, 48, 5195.
Org. Lett., Vol. XX, No. XX, XXXX
C

decreased accordingly, albeit to a small extent in terms of
enantioselectivity. As exemplified in the case of the steri-
cally hindered tert-butyl ester, the reaction reached com-
pletion after 13 h giving 86% ee (8d). The benzyl ester
afforded a comparable result to ethyl ester with 88% and
89% ee, respectively, in 2 h (8b and 8e).
and 85% ee values (8j and 8k), respectively. The substrate
with a six-membered ring also underwent the hydroxyla-
tion reaction, but with lowered enantioselectivity (8l).
In sharp contrast to β-ketoesters as common hydroxylation
substrates, the asymmetric R-hydroxylation of β-diketone
compounds has been much less explored, although the
R-hydroxy-β-diketone moiety is of pharmaceutical and
synthetic relevance.17 To date, there is only one litera-
ture precedent that documented the R-hydroxylation of
β-diketone compounds which built upon the use of chiral
phosphoric acid catalysis in combination with nitroso
arene as the oxidant.11b To further highlight the utility of
our guanidine catalysts, the hydroxylation procedure was
extended to β-diketone compounds. Gratifyingly, a variety
of indanone based β-diketones were found to smoothly
undergo the R-hydroxylation with excellent yield and
synthetically useful enantioselectivity (Figure 1, 6mÀs).
The steric character of the exocyclic acyl group does not
exert an appreciable effect on the reactivity and enantio-
selectivity, as evidenced by the observation that diketones
displaying acetyl, propionyl, and butionyl groups gave the
same levels of yield and enantioselectivity (8mÀo). Sub-
stitution on the phenyl ring led to a slight erosion of the
enantioselectivity regardless of the electronic character of
the substituent, but synthetically useful ee values were still
maintained (8pÀs).
The absolute configurations of R-hydroxy β-ketoesters
8aÀe and 8g and R-hydroxy β-diketones 8l and 8p were
determined to be S and R, respectively, by comparison of
their optical rotations with literature data,11b and the ab-
solute stereochemistry of other products was assigned by
analogy.
In summary, we have developed a novel library of
guanidines starting from ethyl L-tartrate as the chiral
source. The guanidines are easily accessed with a tunable
steric environment and basicity. The utilities of the guani-
dines were highlighted by their ability to catalyze the
R-hydroxylation of β-ketoesters and β-diketones with
remarkable efficiency and excellent enantioselectivity. Stud-
ies toward extending the catalytic applications of this novel
chiral guanidine library for other asymmetric transforma-
tions are currently underway in our laboratory.
Figure 1. Substrate scope of the R-hydroxylation process.
The effect of the substituent identity and substitution
pattern on the phenyl ring was then studied. Substrates
halogenated at the 5-position all gave the desired prod-
ucts in quantitative yield with excellent enantioselectivity
(Figure 1). In particular, in the case of the brominated
substrate, the hydroxylation occurred very fast which was
completed in 30 min with 94% ee (8h). The presence of the
bromo atom provides a versatile handle for further ela-
boration of the product through, for example, coupling
reactions. The occurrence of a methoxy group at the
5-position also afforded an excellent result with 91% ee
and 99% yield (8i). Notably, the substitution at the 4- and
6-position was found to be deleterious to the asymmetric
induction. For example, the 4- and 6-methyl substituted
substrates afforded decreased enantioselectivities to 80%
Acknowledgment. We thank the National Natural
Science Foundation of China (Nos. 21076035, 20972022),
the Program for New Century Excellent Talents in Uni-
versity (NCET-11-0053), the Fundamental Research Funds
for the Central Universities (DUT13ZD202), and the
Science and Technology Department of Liaoning Province
(No. 20102032) for support of this work.
Supporting Information Available. Experimental proce-
dures, full characterization data for all new compounds, and
crystallographic data in cif format. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) (a) Olack, G.; Morrison, H. J. Org. Chem. 1991, 56, 4969. (b)
Komatsu, K.; Shigemori, H.; Mikami, Y.; Kobayashi, J. J. Nat. Prod.
2000, 63, 408. (c) Perpelescu, M.; Kobayashi, J.; Furuta, M.; Ito, Y.;
Izuta, S.; Takemura, M.; Suzuki, M.; Yoshida, S. Biochemistry 2002, 41,
7610.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX