Acetylphosphonate as a surrogate of acetate or acetamide in organocatalyzed enantioselective aldol reactions

Article abstract of DOI:10.1021/ol301270w

Highly enantioselective aldol reactions of acetylphosphonates and activated carbonyl compounds was realized with cinchona alkaloid derived catalysts, in which the acetylphosphonate was directly used as an enolate precursor for the first time. The aldol product obtained was converted in situ to its corresponding ester or amide through methanolysis or aminolysis. The overall process may be viewed as formal highly enantioselective acetate or acetamide aldol reactions, which are very difficult to achieve directly with organocatalytic methods.

Full text of DOI:10.1021/ol301270w

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3174–3177
Acetylphosphonate as a Surrogate of
Acetate or Acetamide in Organocatalyzed
Enantioselective Aldol Reactions
Jie Guang, Qunsheng Guo, and John Cong-Gui Zhao*
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle,
San Antonio, Texas 78249-0698, United States
cong.zhao@utsa.edu
Received May 8, 2012
ABSTRACT
Highly enantioselective aldol reactions of acetylphosphonates and activated carbonyl compounds was realized with cinchona alkaloid derived
catalysts, in which the acetylphosphonate was directly used as an enolate precursor for the first time. The aldol product obtained was converted in
situ to its corresponding ester or amide through methanolysis or aminolysis. The overall process may be viewed as formal highly enantioselective
acetate or acetamide aldol reactions, which are very difficult to achieve directly with organocatalytic methods.
The aldol reaction1 is arguably one of the most impor-
tant reactions in organic synthesis because this reaction
forms a β-hydroxycarbonyl moiety that may be found in
many natural products.1b,2 Because a new carbonÀcarbon
bond is formed with the concurrent creation of a stereo-
genic center in the aldol product, many asymmetric var-
iants of this reaction have been developed in the past few
decades.1,2 In recent years, significant advances have also
been made for the organocatalytic direct aldol reactions.3
Despite this great progress, the direct enantioselective ace-
tate aldol reaction1b,4 still remains a very challenging task.
Most of the reported asymmetric acetate aldol reactions
have been achieved through diastereoselective reactions
controlled by chiral auxiliaries or ligands involving the use
of metal acetate enolates, such as those of tin,5 lithium,6
boron,7 or titanium.8 These are not catalytic methods, and
the reagents used in these reactions are often expensive
and/or difficult to handle. Moreover, many of these methods
also suffer from narrow substrate scopes and low stereo-
selectivities. Catalytic highly enantioselective acetate aldol
reactions have been reported by Carreira,9 Denmark,10
Shibasaki,11 and List12 using Mukaiyama aldol reactions;
however, preformed silyl ketene acetals have to be used in
these reactions. On the other hand, to form an enolate or
(6) (a) Braun, M.; Devant, R. Tetrahedron Lett. 1984, 25, 5031.
(b) Saito, S.; Hatanaka, K.; Kano, T.; Yamamoto, H. Angew. Chem.,
Int. Ed. 1998, 37, 3378. (c) Song, J. J.; Xu, J.; Tan, Z.; Reeves, J. T.;
Grinberg, N.; Lee, H.; Kuzmich, K.; Feng, X.; Yee, N. K.; Senanayake,
C. H. Org. Process Res. Dev. 2007, 11, 534.
(7) (a) Yan, T. H.; Hung, A. W.; Lee, H. C.; Chang, C. S. J. Org.
Chem. 1994, 59, 8187. (b) Zhang, Y. C.; Sammakia, T. Org. Lett. 2004, 6,
23. (c) Zhang, Y. C.; Phillips, A. J.; Sammakia, T. Org. Lett. 2004, 6, 3139.
(8) (a) Yan, T. H.; Hung, A. W.; Lee, H. C.; Chang, C. S.; Liu, W. H.
J. Org. Chem. 1995, 60, 3301. (b) Gonzalez, A.; Aiguade, J.; Urpi, F.;
Vilarrasa, J. Tetrahedron Lett. 1996, 37, 8949. (c) Guz, N. R.; Phillips,
A. J. Org. Lett. 2002, 4, 2253. (d) Crimmins, M.l T.; Shamszad, M. Org.
Lett. 2007, 9, 149.
(9) Carreira, E. M.; Singer, R. A.; Lee, W. J. Am. Chem. Soc. 1994,
116, 8837.
(10) (a)Denmark,S.E.;Wynn,T.;Buetner,G.L.J. Am. Chem. Soc. 2002,
124, 13405. (b) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2002, 124, 4233.
(11) Oisaki, K.; Zhao, D.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2006, 128, 7164.
(1) For reviews, see: (a) Mukaiyama, T. Org. React. 1982, 28, 203.
(b) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004.
(2) For a review, see: Norcross, R. D.; Paterson, I. Chem. Rev. 1995,
95, 2041.
(3) For reviews, see: (a) List, B. Acc. Chem. Res. 2004, 37, 548.
(b) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37,
580. (c) List, B. Tetrahedron 2002, 58, 5573. (d) Pellissier, H. Tetrahedron
2007, 63, 9267.
(4) For reviews, see: (a) Braun, M. Angew. Chem., Int. Ed. 1987, 26,
24. (b) Palomo, C.; Oiarbide, M.; Garcıa, J. M. Chem.;Eur. J. 2002, 8,
36. (c) Ariza, X.; Garcia, J.; Romea, P.; Urpı, F. Synthesis 2011, 2175.
(5) For selected examples, see: (a) Nagao, Y.; Yamada, S.; Kumagai,
T.; Ochiai, M.; Inoue, T.; Fujita, E. J. Chem. Soc., Chem. Commun. 1985,
1418. (b) Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiai, M.; Inoue, T.;
Hashimoto, K.; Fujita, E. J. Org. Chem. 1986, 51, 2391.
(12) Garcıa-Garcıa, P.; Lay, F.; Garcıa-Garcıa, P.; Rabalakos, C.;
List, B. Angew. Chem., Int. Ed. 2009, 48, 4363.
r
10.1021/ol301270w
Published on Web 05/31/2012
2012 American Chemical Society

enamine from acetate directly with organocatalysts is very
difficult. To our knowledge, there has been no report on an
organocatalyzed direct acetate aldol reaction.
phosphonates is a good leaving group,17 the original aldol
product was directly converted to the corresponding
methyl ester 3a in 68% yield via a nucleophilic acyl sub-
stitution reaction using MeOH in the presence of DBU
(Table 1, entry 1).19 The ee value of this product was
determined to be 53% (entry 1). The overall reaction may
be regarded as a formal enantioselective acetate aldol reac-
tion, which is difficult to achieve otherwise.
Previously, we demonstrated that R-keto phosphonates
are excellent electrophiles in organocatalyzed asymmetric
direct aldol reactions.13 Nevertheless, using enolizable
R-keto phosphonates as nucleophiles in chiral amine deri-
vative-catalyzed asymmetric direct aldol reactions has never
been reported because the labile and bulky phosphonate
group in these compounds prevents the formation of the
desired enamine intermediates. Most recently, we realized a
base-catalyzed stereoselective aldol14 reaction of unacti-
vated ketones.15 These reactions only involve the formation
of the ketone enolate as the nucleophile in a complete
noncovalent catalysis.14,15 Because no enamine formation
is involved in the mechanisms, we envisioned that substrates
with a labile and/or poor electrophilic ketone group may
still be used in this reaction as nucleophiles. Since the
R-hydrogen in acetylphosphonates (1) should be more
acidic than that of an unactivated ketone, we hypothesized
that a base-catalyzed enantioselective aldol reaction of
acetylphosphonates should be feasible. Herein, we report
the first successful application of the enolizable acetyl-
phosphonates (1) as a nucleophile in an organocata-
lyzed aldol reaction. More importantly, taking advantage
of the lability of the R-keto phosphonate group,16 com-
pound 1 was successfully employed as a surrogate of acetate
or acetamide17 to achieve a convenient, one-pot, highly
enantioselective formal acetate/acetamide aldol reaction.
Isatin (2a, R1 = H) was chosen as the model substrate
to test our hypothesis. On the basis of the results of our
previous study,14 cinchona alkaloid derivatives18 were
chosen as the catalysts (Figure 1). The results of the
catalystscreening are summarizedin Table1. Asthe results
show (Table 1), with the quinidine thiourea catalyst 4a, the
desired aldol product was obtained when diethyl acetyl-
phosphonate 1a and 2a were reacted in THF at rt for 4 h
(Table 1, entry 1). Since the phosphonate group in R-keto
The effects of the ester group (R2) of the acetylpho-
sphonate were then investigated. It was found that,
although dimethyl acetylphosphonate 1b led to a slightly
higher ee value of the product (62% ee, entry 2), the yield
was much poorer (39%). In contrast, diisopropyl acetyl-
phosphonate 1c led to an excellent yield (91%) of the
expected product 3a with the same ee value (entry 3) as that
of diethyl acetylphosphonate (entry 1). Therefore, 1c was
adopted as the model substrate for catalyst screening. As
the results in Table 1 show, except for catalysts 4g and 4h,
all the other cinchona alkaloid catalysts led to the forma-
tion of 3a in good to high yields (entries 4À12). High ee
values wereachieved for the quinidine thiourea catalysts4b
(75% ee, entry 4) and 4c (72% ee, entry 5), and 9-O-
(1-naphthylmethyl)cupreidine (4j, 73% ee, entry 12). In
contrast, proline-based catalysts 4k and 4l failed to gen-
erate the desired product from acetylphosphonate 1c
(entries 13 and 14). These results clearly demonstrate the
advantages of the enolate mechanism over the enamine
mechanism for such bulky and labile ketone substrates. A
solvent study with catalyst 4b revealed that THF is the best
solvent for this reaction.20 A lower reaction temperature
was found to be beneficial for improving the enantioselec-
tivity of this reaction (entries 15 and 16), and the ee value of
(13) (a) Samanta, S.; Zhao, C.-G. J. Am. Chem. Soc. 2006, 128, 7442.
(b) Dodda, R.; Zhao, C.-G. Org. Lett. 2006, 8, 4911. (c) Mandal, T.;
Samanta, S.; Zhao, C.-G. Org. Lett. 2007, 9 (943), 16. (d) Samanta, S.;
Perera, S.; Zhao, C.-G. J. Org. Chem. 2010, 75, 1101. (e) Perera, S.;
Naganaboina, V. K.; Wang, L.; Zhang, B.; Guo., Q.; Rout., L.; Zhao,
C.-G. Adv. Synth. Catal. 2011, 353, 1729.
(14) Guo, Q.; Bhanushali, M.; Zhao, C.-G. Angew. Chem., Int. Ed.
2010, 49, 9460. See also ref 15b for a similar study.
(15) For related examples, see: (a) Paradowska, J.; Rogozinnska, M.;
ꢀ
Mlynarski, J. Tetrahedron Lett. 2009, 50, 1639. (b) Allu, S.; Molleti, N.;
Panem, R.; Singh, V. K. Tetrahedron Lett. 2011, 52, 4080. (c) Li, L.;
Klauber, E. G.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 12248.
(d) Misaki, T.; Takimoto, G.; Sugimura, T. J. Am. Chem. Soc. 2010,
132, 6286. (e) Liu, G.-G.; Zhao, H.; Lan, Y.-B.; Wu, B.; Huang, X.-F.;
Chen, J.; Tao, J.-C.; Wang, X.-W. Tetrahedron 2012, 68, 3843.
(16) For examples, see: (a) Maeda, H.; Takahashi, K.; Ohmori, H.
Tetrahedron 1998, 54, 12233. (b) Afarinkia, K.; Twist, A. J.; Yu, H.-w.
J. Organomet. Chem. 2005, 690, 2688. (c) Afarinkia, K.; Twist, A. J.; Yu,
H.-w. J. Org. Chem. 2004, 69, 6500.
(17) For an example of using acylphosphonate as a surrogate of esters
and amides in an enantioselective Michael addition reaction, see: Jiang,
H.; Paixao, M. W.; Monge, D.; Jorgensen, K. A. J. Am. Chem. Soc. 2010,
132, 2775.
(18) These catalysts were prepared according to the reported proce-
ꢀ
ꢀ
dures, see: (a) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett.
2005, 7, 1967. (b) Wu, W.; Min, L.; Zhu, L.; Lee, C.-S. Adv. Synth. Catal.
2011, 353, 1135. (c) Amere, M.; Lasne, M.-C.; Rouden J. Org. Chem.
2007, 9, 2621. (d) Wang, H.-F.; Cui, H.-F.; Chai, Z.; Li, P.; Zheng,
C.-W.; Yang, Y.-Q.; Zhao, G. Chem.;Eur. J. 2009, 15, 13299–13303.
(e) Denis, J.-B.; Masson, G.; Retailleau, P.; Zhu, J. Angew. Chem., Int.
Ed. 2011, 50, 5356.
(19) This also facilitates the isolation and purification of the reaction
product.
(20) The product was obtained in 74% ee in dioxane, while lower ee
values were obtained in DME, ether, CH2Cl2, EtOAC, and MeCN. Only
a trace amount of the product was obtained when MeOH was used.
Figure 1. Catalysts screened in the aldol reaction (Nap = naphthyl).
Org. Lett., Vol. 14, No. 12, 2012
3175

data, high yields and good to excellent ee values of the
expected formal acetate aldol products were obtained for a
variety of substituted N-tritylisatinsusing either catalyst4b
or 4j. Interestingly, these two catalysts were found to be
complementary in terms of enantioselectivity for substi-
tuted isatins. For example, catalyst 4b is very sensitive
toward the substituent at the 4-position of isatin and leads
to the formation of the opposite enantiomers as the major
products in very poor ee values (Table 2, entries 2 and 3).
The exact reason for this inversion is not clear at the
moment, but most likely it is due to steric effects.21 In
contrast, substituents on any other locations of the ring do
not show much effect (entries 1, 4À14). On the other hand,
catalyst 4j is much less sensitive toward the substituents on
the isatin ring and high ee values of products were obtained
for the 4-substituted isatins (data in parentheses, entries 2
and 3). Nevertheless, it normally produces slightly lower ee
values of the products than catalyst 4b does when there is a
substituent on the 5-, 6-, or 7-position (entries 4À14). It
should be pointed out that when isatin has a substituent at
the 7-position, it is impossible to protect it with the large
trityl group, and therefore, N-benzyl-protected substrates
were used instead (entries 12À14), and very good results
were obtained as well. The absolute configuration of the
major enantiomer formed in this reaction was assigned as
R by X-ray crystallographic analysis of a crystal of com-
pound 3o. On the basis of this result, transition-state
models are proposed to account for the stereochemical
outcome of this reaction.21
Table 1. Catalyst Screen and Reaction Condition Optimizationa
entry
4
R1
R2
Et
solvent time (h) yieldb (%) eec (%)
1
2
4a
4a
4a
4b
4c
4d
4e
4f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
4
4
4
2
2
4
2
2
2
2
2
2
4
4
2
4
6
4
4
6
4
4
6
68
39
53
62
53
75
72
50d
23d
53
nde
47
65
73
nde
nde
79
81
86
85
87
94
84
86
95
Me
3
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
91
4
87
5
84
6
88
7
63
8
83
9
4g
4h
4i
trace
44
10
11
12
13
14
15f
16g
17g
18g
19g
20g
21g
22g
23g
90
4j
91
4k
4l
trace
trace
88
4b
4b
4j
90
88
4b Me i-Pr
4b Bn i-Pr
88
88
4b Tr
i-Pr
80
4j
4j
4j
Me i-Pr
Bn i-Pr
85
84
When diisopropyl propionylphosphonate (1d) was used
as the substrate, the corresponding aldol product 3r was
obtained with a dr of 80:20 and a 94% ee for the major
diastereomer (Scheme 1, equation A). The absolute stereo-
chemistry of compound 3r was determined on the basis of
the X-ray crystallographic analysis of its crystals.21
Tr
i-Pr
83
a Unless otherwise specified, all aldol reactions were conducted with
acetylphosphonate (1, 0.50 mmol), isatin (2, 0.10 mmol), and catalyst 4
(0.0050 mmol, 5 mol %) in the indicated solvent (1.0 mL) at rt under a
nitrogen atmosphere. After the aldol reaction was complete, the reaction
mixture was treated with DBU (0.10 mmol) and MeOH (1.0 mL) at rt for
15 min to convert the original reaction product to compound 3 in situ.
b Yield of isolated compound 3 after column chromatography. c Deter-
mined by HPLC analysis using a ChiralCel OD-H column. For the
assignment of the absolute configuration of the major enantiomer, see
the text. d The S-enantiomer was obtained as the major product. e Not
determined. f The aldol reaction was carried out at 0 °C. g The aldol
reaction was carried out at À15 °C.
Besides isatins, phenylglyoxal hydrates (5) may
also be used as the substrates in this reaction, and
the corresponding β-hydroxy esters 6 were obtained
in good ee values (87% and 84% for the 4-H- and 4-MeO-
subsituted 6, respectively) after converting the original aldol
products through methanolysis (Scheme 1, equation B).
Since the phosphonate group may be easily replaced by
nucleophiles, we also attempted the in situ aminolysis of the
original aldol product (Scheme 1, equation C), and the
corresponding β-hydroxyamide 7 was obtained in 90% yield
and 96% ee. Similarly, a β,γ-alkynyl-R-keto ester 8 gave
directly the cyclized product 9 in 76% ee after the al-
dolÀaminolysis sequence. This reaction provides a one-pot
synthesis of optically enriched 3-hydroxy-2,5-pyrrolidine-
diones (Scheme 1, equation D). These results may be regarded
as formal acetamide aldol reactions, which again are very
difficult to achieve directly.
the product 3a was improved to 81% when the reaction
was conducted at À15 °C (entry 16). Under these opti-
mized conditions, catalyst 4j yielded 3a in 88% yield and
86% ee in 6 h (entry 17). Intrigued by our previous finding
that the substituent on the isatin nitrogen atom (R1) has a
dramatic effect on the enantioselectivity,14 we also studied
N-substituted isatins in this aldol reaction. It is interesting
to find that higher ee values of the products were obtained
when the size of the N-substituent was increased. For
examples, with catalyst 4b, N-methyl (2b), N-benzyl (2c),
and N-trityl (2d) isatins lead to the corresponding products
3b, 3c, and3d in 85%, 87%, and 94% ee, respectively (entries
18À20). A similar trend was also observed for catalyst 4j
(entries 21À23).
The N-trityl protecting group that is necessary for
achieving high enantioselectivity in this reaction may be
easily removed by using a reported procedure22 to give the
Once the reaction conditions were optimized, the scope
of this reaction was then established using N-tritylisatins.
The results are collected in Table 2. As is evident from the
(21) For details, see the Supporting Information.
(22) Vedejs, E.; Klapars, A.; Warner, D. L.; Weiss, A. H. J. Org.
Chem. 2001, 66, 7542.
3176
Org. Lett., Vol. 14, No. 12, 2012

Table 2. Substrate Scope of the Direct Aldol Reactiona
Scheme 2. Deprotection of the Trityl Group
entry
X
R
3
time (h)
yieldb (%)
eec (%)
1
2
H
Tr
Tr
Tr
Tr
Tr
Tr
Tr
Tr
Tr
Tr
Tr
Bn
Bn
Bn
3d
3e
3f
6.0 (6.0)
5.5 (4.0)
5.0 (4.5)
4.0 (4.5)
4.0 (4.0)
3.0 (4.0)
4.0 (3.5)
4.0 (3.0)
3.0 (2.0)
4.5 (4.5)
4.0 (3.0)
3.0 (3.0)
1.0 (1.5)
5.0 (5.0)
80 (83)
81 (87)
70 (92)
92 (94)
90 (88)
88 (93)
84 (86)
89 (92)
91 (93)
88 (85)
92 (94)
91 (92)
85 (88)
82 (80)
94 (95)
8d(96)
4-Cl
3
4-Br
21d(96)
98 (95)
94 (94)
95 (90)
95 (90)
93 (89)
94 (89)
84 (72)
97 (94)
93 (88)
93 (82)
94 (92)
4
5-Me
5-MeO
5-F
3g
3h
3i
Scheme 3. Synthesis of the Half Fragment of Madindoline A
and B
5
6
7
5-Cl
3j
8
5-Br
3k
3l
9
5-I
10
11
12
13
14
5-NO2
6-Br
3m
3ne
3oe
3pe
3qe
7-Br
5,7-Br2
5,7-Me2
synthesis of natural products madindolines A and B,23 was
obtained in 53% overall yield and 94% ee.
a Unless otherwise specified, all aldol reactions were conducted with
diisopropyl acetylphosphonate (1c, 0.50 mmol), isatin (2, 0.1 mmol), and
catalyst 4b or4j(0.0050 mmol, 5 mol %) inTHF (1.0mL) atÀ15 °C under
a nitrogen atmosphere. After the aldol reaction was completed, the
reaction mixture was treated with DBU (0.10 mmol) and MeOH (1.0
mL) at rt for 15 min to convert the original reaction product to compound
3 in situ. Data in parentheses are those of catalyst 4j. b Yield of
isolated compound 3 after column chromatography. c Unless otherwise
noted, ee values were determined by HPLC analyses using a ChiralCel
OD-H column. The absolute configuration of the major enantiomer of
compound 3o was assigned by X-ray crystallographic analysis. The
configuration of the rest compounds was assigned on the basis of the
reaction mechanism. d The S-enantiomer was obtained as the major
product. e Determined by HPLC analysis using a ChiralPak AD-H column.
In conclusion, we have developed the first highly en-
antioselective aldol reaction of acetylphosphonates and
activated carbonyl compounds, such as isatins, phenyl-
glyoxals, and R-keto esters, using cinchona alkaloid de-
rived catalysts, in which acetylphosphonate was used as a
nucleophile. Through an in situ methanolysis or aminoly-
sis of the phosphonate group of the original aldol products
obtainedinthisreaction, thecorrespondingestersoramide
were obtained. The overall reaction may be viewed as
formal highly enantioselective acetate or acetamide aldol
reactions, which are very difficult to achieve directly with
organocatalytic methods.
Scheme 1. Additional Substrate Scope Studies of the Base-
Catalyzed Aldol Reactions
Acknowledgment. The generous financial support of
this research from the National Science Foundation
(Grant No. CHE 0909954), the NIH-NIGMS (Grant
No. SC1GM082718), and the Welch Foundation (Grant
No. AX-1593) is gratefully acknowledged. We also thank
Dr. Hadi Arman (UTSA) for his assistance in the X-ray
crystallographic analyses of the reaction products.
Supporting Information Available. Full experimen-
tal procedures, transition-state models, compound
characterization data, ORTEP drawings and X-ray data
(CIF) of compounds 3o and 3r, and copies of NMR
spectra and HPLC chromatograms. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(23) For examples, see: (a) Itoh, T.; Ishikawa, H.; Hayashi, Y. Org.
Lett. 2009, 11, 3854. (b) Hirose, T.; Sunazuka, T.; Shirahata, T.;
Yamamoto, D.; Harigaya, Y.; Kuwajima, I.; Omura, S. Org. Lett.
2002, 4, 501. (c) Wan, L.; Tius, M. A. Org. Lett. 2007, 9, 647.
(d) Sunazuka, T.; Hirose, T.; Shirahata, T.; Harigaya, Y.; Hayashi,
M.; Komiyama, K.; Omura, S.; Smith, A. B., III. J. Am. Chem. Soc.
2000, 122, 2122.
deprotected product in high yield with complete retention
of the stereochemistry (Scheme 2).22
To further demonstrate the utility of our method, we
also developed an efficient two-step synthesis of com-
pound 11 from the aldol product 3d (Scheme 3). Com-
pound 11, which is the half fragment used in the total
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
3177