Organocatalytic highly enantioselective synthesis of β-Formyl-α- hydroxyphosphonates

Article abstract of DOI:10.1002/adsc.201000835

The cross-aldol reaction between enolizable aldehydes and α-ketophosphonates was achieved for the first time by using 9-amino-9-deoxy-epi-quinine as the catalyst. β-Formyl-α- hydroxyphosphonates were obtained in high to excellent enantioselectivities. The

Full text of DOI:10.1002/adsc.201000835

COMMUNICATIONS
DOI: 10.1002/adsc.201000835
Organocatalytic Highly Enantioselective Synthesis of b-Formyl-a-
hydroxyphosphonates
Sandun Perera,a Vijaya Kumar Naganaboina,a Long Wang,b Bin Zhang,b,*
Qunsheng Guo,a Laxmidhar Rout,a and Cong-Gui Zhaoa,*
a
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249, USA
Fax : (+1)-210-458-7428; phone: (+1)-210-458-5432; e-mail: cong.zhao@utsa.edu
Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio,
b
Texas 78229-3900, USA
Fax : (+1)-210-567-4654; phone: (+1)-210-562-5234; e-mail: zhangb3@uthscsa.edu
Received: November 9, 2010; Revised: April 9, 2011; Published online: June 30, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201000835.
Abstract: The cross-aldol reaction between enoliza-
ble aldehydes and a-ketophosphonates was ach-
ieved for the first time by using 9-amino-9-deoxy-
epi-quinine as the catalyst. b-Formyl-a-hydroxy-
phosphonates were obtained in high to excellent
enantioselectivities. The reaction works especially
well with acetaldehyde, which is a tough substrate
for organocatalyzed cross-aldol reactions. The prod-
ucts were demonstrated to have anticancer activi-
ties.
best of our knowledge, such a reaction has not been
realized so far. Herein we wish to report the first or-
ganocatalyzed cross-aldol reaction of enolizable alde-
hydes and a-ketophosphonates for the highly enantio-
selective synthesis of tertiary b-formyl-a-hydroxy-
phosphonates,[11,12] using a quinine-derived primary
amine as the catalyst and the preliminary biological
study of these compounds.
Although l-proline and l-prolinamide (compounds
1 and 2, Figure 2) are excellent catalysts for the cross-
aldol reaction of acetone and a-ketophosphonates,[8a,b]
they fail to catalyze the cross-aldol reaction between
propanal and a-ketophosphonates.[10] After carefully
comparing the proposed transition states[8b,e] of these
two similar reactions (Figure 1), we believe the reac-
tion failed in the case of propanal because of the un-
favorable interactions between the enamine methyl
Keywords: aldehydes; hydroxyphosphonates; keto-
phosphonates; organocatalysis; primary amines
a-Hydroxyphosphonate derivatives are highly biologi- group and the large phosphonate group in the transi-
cally active compounds.[1] Previous studies have dem- tion state (Figure 1, right structure). Thus, we hy-
onstrated that these compounds have anti-cancer,[2] pothesized that the reaction should proceed if such
anti-virus,[3] anti-bacterial[4] and anti-fungal[4] activi- unfavorable interactions are alleviated.
ties. They are also proven inhibitors of such important
One way to reduce the unfavorable interactions is
enzymes as renin[5] and HIV (human immunodeficien- to use acetaldehyde (9a) as the substrate,[13] since,
cy virus) protease and polymerase.[6] Due to their with 9a, the methyl group in the proposed transition
relevance to biomedical applications, there have been state (Figure 1) will be replaced with a much smaller
considerable interests in developing highly enantiose- hydrogen atom (as in the acetone case). Acetaldehyde
lective methods for the synthesis of these compounds (9a) and diethyl benzoylphosphonate (10a) were then
in recent years.[7–9] Our own interest[8] in this area led
to the development of an organocatalyzed asymmetric
synthesis of a-hydroxyphosphonates on the basis a
proline derivative-catalyzed cross-aldol reaction.[8a,b]
Nevertheless, although high enantioselectivities have
been achieved in the cross-aldol reaction of ketones
and a-ketophosphonates by others[9] and us,[8a,b] the
cross-aldol reaction of enolizable aldehydes and a-ke-
Figure 1. Proposed favoured transition states for the aldol
tophosphonates proves to be very difficult.[10] To the reactions of a-ketophosphonate with acetone and propanal.
Adv. Synth. Catal. 2011, 353, 1729 – 1734
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1729

Sandun Perera et al.
COMMUNICATIONS
Table 1. Catalyst screening and optimization of reaction con-
ditions.[a]
Entry Catalyst Additive
Solvent Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
8
8
8
8
8
8
8
8
8
8
8
none
none
CH2Cl2 50
CH2Cl2 59
9
13
3
10
–
6
17
PhCO2H[d] CH2Cl2 11
PhCO2H[d] CH2Cl2
9
0
none
CH2Cl2
PhCO2H[e] CH2Cl2 49
PhCO2H CH2Cl2 45
PhCO2H CH2Cl2 46
CH3CO2H CH2Cl2 30
57[f]
71[f]
74[f]
41[f]
–
Figure 2. Catalysts screened for the cross-aldol reaction.
9
10
11
12
13
14
15
16
17
18
19[g]
EtCO2H
CF3CO2H CH2Cl2 23
CH2Cl2 39
adopted as the substrates to test our hypothesis, using
proline (1) and prolinamide (2) as the catalysts
(Figure 2). As shown by the results collected in
Table 1, indeed, after reacting in CH2Cl2 at room tem-
perature for a week, the desired aldol product 11a
may be obtained in reasonable yields (50% and 59%
with l-proline and l-prolinamide, respectively, en-
tries 1 and 2). Diphenylprolinol catalysts 3 and 4 are
known to catalyze highly enantioselective cross-aldol
reactions of acetaldehydes;[13a,b,l] however, poorer re-
sults were obtained with these two catalysts (entries 3
and 4). Nevertheless, since acetaldehyde is a known
tough substrate for organocatalyzed cross-aldol reac-
tions,[13a,b,l] we were encouraged by these results even
though the enantioselectivities obtained were imprac-
tical.
p-TsOH
MBA[g]
MBA[g]
MBA[g]
MBA[g]
MBA[g]
MBA[g]
MBA[g]
CH2Cl2
CH2Cl2 46
THF 51
0
75[f]
86[f]
77[f]
84[f]
83[f]
91[f]
93[f]
CH3CN 38
hexane 45
benzene 53
toluene 53
toluene 75
[a]
Unless otherwise specified, all reactions were carried out
with 10a (0.30 mmol) and 9a (1.5 mmol) in the specified
solvent (2.0 mL) with the amine catalyst (10 mol%) and
the acid cocatalyst (30 mol%) at room temperature for
7 days.
Yield of isolated product after column chromatography.
Determined by HPLC analysis on a ChiralCel OJ-H
column.
The loading of the acid cocatalyst was 10 mol%.
The loading of the acid cocatalyst was 20 mol%.
The opposite enantiomer was obtained.
4-Methoxybenzoic acid.
[b]
[c]
[d]
[e]
[f]
Another way to solve the aforementioned problem
is to use a different catalyst, because the transition
state is known to be dependent on the catalyst struc-
ture and the catalysis mechanism. In this regard, we
were very interested in primary amine catalysts,[14]
since primary amines would lead to less crowded tran-
[g]
[h]
Carried out at 08C.
sition states.[14a] Thus, we screened several primary The ee value was improved to 57% ee when com-
amines as the catalyst for the cross-aldol reaction of pound 8 was applied (entry 6). Since catalyst 8 leads
9a and 10a (compounds 5–8, Figure 2). The results are to highest ee value of the product, it was selected for
also collected in Table 1. Among these catalysts, l- further optimizations. Firstly, several acid cocatalysts
phenylalanine (5) is not effective at all as no desired were screened, and it was found that aliphatic acids,
product could be obtained after the reaction such as acetic acid and propoinic acid, led to im-
(entry 5). Nonetheless, in the presence of benzoic acid proved ee values of the product (71% and 74%, re-
as the cocatalyst, (S,S)-1,2-diphenyl-1,2-ethanedia- spectively, entries 9 and 10); however, the yields of
mine (6) gave the expected product 11a in 49% yield the product were lower. In contrast, stronger acids,
and 6% ee (entry 6). Catalysts 7 and 8, derived from such as trifluoroacetic acid and toluenesulfonic acid,
quinidine, and quinine, respectively, have been used are not effective (entries 11 and 12). Additional
by List and co-workers as the catalyst in an intramo- screening identified 4-methoxybenzoic acid as the
lecular aldol reaction;[14a] however, to the best of our best cocatalyst, as the highest ee value of 75% was ob-
knowledge, they have never been used in an intermo- tained in a reasonable yield (46%, entry 13). Then the
lecular aldol reaction. When 7 was used as the cata- solvent effects were evaluated (entries 14–18), and
lyst with benzoic acid as the cocatalyst, the expected toluene was identified as the best solvent for this re-
11a was obtained in 45% yield and 17% ee (entry 5). action, because the product 11a could be obtained in
1730
asc.wiley-vch.de
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1729 – 1734

Organocatalytic Highly Enantioselective Synthesis of b-Formyl-a-hydroxyphosphonates
53% yield with a high ee value of 91% with this sol- of the substituents on the phenyl ring of the benzoyl-
vent (entry 16). Further optimization of the reaction phosphonates: Excellent ee values were obtained for
temperature revealed that an improved yield of 75% both electron-withdrawing and electron-donating sub-
of the desired product could be obtained at 08C, with stituents (entries 4–9).
also a slightly improved ee value of 93% (entry 17).
Benzoylphosphonate with an ortho-chloro substitu-
The improved product yield at this temperature was ent is less reactive and the yield obtained was much
probably due to reduced competing reactions. Further lower (entry 10), which is most probably due to steric
dropping the reaction temperature, however, leads to reasons. However, as shown in Table 2, the position of
inferior reaction yield without improvement in the ee the substituent on the phenyl ring has almost no influ-
value (data not shown). It should be pointed out that ence on the enantioselectivity (entries 5, 10–12).
the major enantiomer obtained with catalyst 8 is op- Propanal, which has failed with other catalysts, also
posite to that obtained with the rest of the catalysts.
participates in the reaction under these new condi-
Next the scope of this reaction was evaluated with tions, and the reaction yielded the desired product in
different a-ketophosphonate and aldehyde substrates. 44% yield as a diastereomeric mixture (dr 7:5), with
The results are presented in Table 2. As shown in ee values of 68% and 73% for the major and minor
Table 2, the size of the ester alkyl groups in the phos- diastereomers, respectively (entry 13). The methyl
phonate has almost no influence on the enantioselec- and hydroxy groups in the major diastereomer were
tivity of this reaction, as similar ee values were ob- determined to be anti by NOE experiments.
tained for the methyl, ethyl and isopropyl esters (en-
The fact that all the products obtained in this study
tries 1–3). The same is true with the electronic nature are liquid makes the direct determination of the abso-
lute configuration of major enantiomer obtained in
this reaction difficult. To determine the absolute con-
Table 2. Enantioselective synthesis of b-formyl-a-hydroxy-
figuration of the major enantiomer, compound 11f
was converted to its 2,4-dinitrophenylhydrazone de-
rivative 12 (Figure 3), and its stereochemistry at the
quaternary stereogenic center was successfully deter-
mined to be R by X-ray crystallography.[16] Thus, the
absolute configuration of compound 11f was assigned
as R. On the basis of these results, a tentative mecha-
nism is proposed to account for the formation of the
major enantiomer in this reaction (Figure 4). The
attack of the enamine on the si face of the hydrogen-
bound a-ketophosphonate gives the expected R-enan-
tiomer.
phosphonates.[a]
Entry R1
R2
R3
t
Product/
ee
[d] Yield [%][b] [%][c]
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
4-FC6H4
4-ClC6H4
4-BrC6H4
4-IC6H4
4-MeC6H4
Me
Et
i-Pr
Et
Et
Et
8
7
5
7
7
7
7
6
7
5
7
7
9
11b/67
11a/75
11c/67
11d/61
11e/62
11f/55
11g/54
11h/67
11i/66
11j/35
11k/67
11l/60
11m/44
96
93
96
99
94
>99
95[d]
96
Et
Et
9
4-MeOC6H4 Et
92[d]
96
10
11
12
13
2-ClC6H4
3-ClC6H4
3-ClC6H4
Et
Et
Me
Et
93[d]
97
Me Ph
68[e,f]
Figure 3. Synthesis of 2,4-dinitrophenylhydrazone derivative
12.
[a]
All reactions were carried out with a-ketophosphonate
10 (0.30 mmol) and aldehyde 9 (1.50 mmol) in dry tolu-
ene (2.0 mL) with catalyst 8 (0.03 mmol, 10 mol%) and
4-methoxybenzoic acid (0.09 mmol, 30 mol%) at 08C.
Yield of isolated product after column chromatography.
Unless otherwise specified, ee values were determined by
chiral HPLC analyses on a ChiralCel OJ-H column.
Determined by chiral HPLC analyses on a ChiralPak
AD-H column.
[b]
[c]
[d]
[e]
[f]
Value of the major diastereomer. The ee value of the
minor enantiomer was 73%.
The dr was 7:5 (1H NMR analysis of the crude product);
the Me and OH groups have the anti configuration in the
major diastereomer as determined by NOE experiments.
Figure 4. Proposed transition states for the formation of the
major enantiomer (AÀ =4-methoxybenzoate).
Adv. Synth. Catal. 2011, 353, 1729 – 1734
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1731

Sandun Perera et al.
COMMUNICATIONS
Figure 6. Structure of I-ZCG-1.
murine tumour cells (B16F10) were also observed
(data not shown).
In summary, we have developed the first cross-aldol
reaction of enolizable aldehydes and a-ketophospho-
nates for the highly enantioselective synthesis of terti-
ary b-formyl-a-hydroxyphosphonates. The reaction
utilizes a quinine-derived primary amine as the cata-
lyst, and excellent enantioselectivities were achieved
for the cross-aldol products of acetaldehyde, which is
unprecedented for such primary amine catalysts. A
preliminary screen of some of the b-formyl-a-hydrox-
yphosphonate products indicates the products can
suppress the proliferation of human and murine
tumour cells, while are mild against immortalized
cells (HFF).
Experimental Section
Figure 5. Inhibitory effect of the screened compounds on
cell proliferation. [The results are expressed as percentage
of the control (DMSO controls set at 100%). Data are given Typical Procedure for the Aldol Reaction
as meansÆSEM, * p<0.05 (Studentꢁs t-test)][15] (II-SP-72 is
To a stirred solution of p-methoxybenzoic acid (13.7 mg,
compound 11h; I-VKN-81 is compound 11a; I-VKN-97 is
0.09 mmol, 30 mol%) and quinine-derived amine 8 (9.7 mg,
compound 11f).
0.03 mmol, 10 mol%) in toluene (2.0 mL) were added the a-
ketophosphonate (0.30 mmol) and the aldehyde (1.5 mmol)
It is well known that a-hydroxyphosphonate deriva-
tives are biologically active molecules. However, the
biological activities of b-formyl-a-hydroxyphospho-
nates are still unknown. To assess their biological ac-
tivities, we conducted some preliminary biological
assays of these compounds. Thus, human immortal-
ized foreskin fibroblasts (HFF) and ovarian cancer
cells (ID8) were first incubated for 24 h, then the
screened compounds were added in the indicated
amounts and the cells were further incubated for an-
other 48 h. Cell proliferation was assessed by the
MTT assay as described previously and the results are
presented in Figure 5.[15]
As shown in Figure 5, b-formyl-a-hydroxyphospho-
nate derivatives, II-SP-72 (11h), I-VKN-81 (11a) and
I-VKN-97 (11f), significantly inhibited the prolifera-
tion of immortalized cell line HFF and ovarian cancer
cell line ID8 in a dose-dependent manner (from 1 to
100 mM). In contrast, a similar a-hydroxyphosphonate
derivative that does not contain an aldehyde group, I-
ZCG-1 (Figure 6), displays only minor antiprolifera-
tive activity at a high concentration (100 mM). Inter-
estingly, I-VKN-97 preferentially inhibited ID8 cancer
cells rather than HFF immortalized cells. Moreover,
antiproliferative effects of II-SP-72, I-VKN-81 and I-
VKN-97 on other human (SKOV3 and K562) and
at 08C. After completion of the reaction (monitored by
TLC), the reaction mixture was concentrated under reduced
pressure to yield the crude product, which was purified by
column chromatography over silica gel (7:3 ethyl acetate/
hexane) to furnish the desired b-formyl-a-hydroxyphospho-
nate as a pure compound.
Acknowledgements
The generous financial support of this project from the NIH-
NIGMS (Grant no. SC1GM082718) and the Welch Founda-
tion (Grant No. AX-1593) is gratefully acknowledged. The
authors also thank Dr. Sampak Samanta for performing
some initial experiments, Dr. William Haskins and the RCMI
Proteomics Core (NIH G12 RR013646) at UTSA for assis-
tance with HR-MS analysis, and Dr. Arman Hadi for per-
forming an X-ray analysis of compound 12.
References
[1] For reviews, see: a) O. I. Kolodiazhnyi, Tetrahedron:
Asymmetry 2005, 16, 3295–3340; b) J. Stawinski, A.
Kraszewski, Acc. Chem. Res. 2002, 35, 952 À960.
[2] a) M. L. Peters, M. Leonard, A. A. Licata, Clev. Clin. J.
Med. 2001, 68, 945–951; b) M. V. Lee, E. M. Fong,
1732
asc.wiley-vch.de
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1729 – 1734

Organocatalytic Highly Enantioselective Synthesis of b-Formyl-a-hydroxyphosphonates
F. R. Singere, R. S. Guenette, Cancer Res. 2001, 61,
2602–2608; c) B. Z. Leder, H. M. Kronenberg, Gastro-
enterology 2000, 119, 866–869.
[13] Acetaldehyde has been seldom used in organocatalyzed
cross-aldol reactions, for examples, see: a) Y. Hayashi,
T. Itoh, S. Aratake, H. Ishikawa, Angew. Chem. 2008,
120, 2112–2114; Angew. Chem. Int. Ed. 2008, 47, 2082–
2084; b) Y. Hayashi, S. Samanta, T. Itoh, H. Ishikawa,
Org. Lett. 2008, 10, 5581–5583. For examples of cross-
aldol reactions with isatins, see: c) W.-B. Chen, X.-L.
Du, L.-F. Cun, X.-M. Zhang, W.-C. Yuan, Tetrahedron
2010, 66, 1441–1446; d) T. Itoh, H. Ishikawa, Y. Haya-
shi, Org. Lett. 2009, 11, 3854–3857; e) N. Hara, S. Na-
kamura, N. Shibata, T. Toru, Chem. Eur. J. 2009, 15,
6790–6793. For application of acetaldehyde in other or-
ganocatalyzed reactions, see: f) J. W. Yang, C. Chan-
dler, M. Stadler, D. Kampen, B. List, Nature 2008, 452,
453–455; g) P. Garcꢃa-Garcꢃa, A. LadꢄpÞche, R.
Halder, B. List, Angew. Chem. 2008, 120, 4797–4799;
Angew. Chem. Int. Ed. 2008, 47, 4719–4721; h) Y. Hay-
ashi, T. Itoh, M. Ohkubo, H. Ishikawa, Angew. Chem.
2008, 120, 4800–4802; Angew. Chem. Int. Ed. 2008, 47,
4722–4724; i) Y. Hayashi, T. Okano, T. Itoh, T. Urushi-
ma, H. Ishikawa, T. Uchimaru, Angew. Chem. 2008,
120, 9193–9198; Angew. Chem. Int. Ed. 2008, 47, 9053–
9058; j) T. Kano, Y. Yamaguchi, K. Maruoka Angew.
Chem. 2009, 121, 1870–1872; Angew. Chem. Int. Ed.
2009, 48, 1838–1840; k) C. Chandler, P. Galzerano, A.
Michrowska, B. List, Angew. Chem. 2009, 121, 2012–
2014; Angew. Chem. Int. Ed. 2009, 48, 1978–1980. For
a review, see: l) B. Alcaide, P. Almendros, Angew.
Chem. 2008, 120, 4710–4712; Angew. Chem. Int. Ed.
2008, 47, 4632–4634.
[3] R. Snoeck, A. Holy, C. Dewolf-Peeters, J. Van Den
Oord, E. De Clercq, G. Andrei, Antimicrob. Agents
Chemother. 2002, 46, 3356–3361.
[4] A. H. Kategaonkara, R. U. Pokalwara, S. S. Sonara,
V. U. Gawalib, B. B. Shingatea, M. S. Shingare, Eur. J.
Med. Chem. 2010, 45, 1128–1132.
[5] a) M. Tao, R. Bihovsky, G. J. Wells, J. P. Mallamo, J.
Med. Chem. 1998, 41, 3912–3916; b) J. F. Dellaria Jr,
R. G. Maki, H. H. Stein, J. Cohen, D. Whittern, K.
Marsh, D. J. Hoffman, J. J. Plattner, T. J. Perun, J. Med.
Chem. 1990, 33, 534–542.
[6] B. Stowasser, K.-H. Budt, J.-Q. Li, A. Peyman, D. Rup-
pert, Tetrahedron Lett. 1992, 33, 6625–6628.
[7] a) K. Suyama, Y. Sakai, K. Matsumoto, B. Saito, T. Kat-
suki, Angew. Chem. 2010, 122, 809–811; Angew. Chem.
Int. Ed. 2010, 49, 797–799; b) V. B. Gondi, K. Hagi-
hara, V. H. Rawal, Angew. Chem. 2009, 121, 790–793;
Angew. Chem. Int. Ed. 2009, 48, 776–779; c) J. P. Abell,
H. Yamamoto, J. Am. Chem. Soc. 2008, 130, 10521–
10523; d) J. Huang, J. Wang, X. Chen, Y. Wen, X. Liu,
X. Feng, Adv. Synth. Catal. 2008, 350, 287–294; e) X.
Chen, J. Wang, Y. Zhu, D. Shang, B. Gao, X. Liu, X.
Feng, Z. Su, C. Hu, Chem. Eur. J. 2008, 14, 10896–
10899; f) V. D. Pawar, S. Bettigeri, S.-S. Weng, J.-Q.
Kao, C.-T. Chen, J. Am. Chem. Soc. 2006, 128, 6308–
6309; g) V. Nesterov, O. I. Kolodyazhnyi, Russ. J. Gen.
Chem. 2005, 75, 1161–1162; h) D. Skropeta, R. R.
Schmidt, Tetrahedron: Asymmetry 2003, 14, 265–723;
i) B. J. Rowe, C. D. Spilling, Tetrahedron: Asymmetry
2001, 12, 170–1708; j) D. M. Cermak, Y. Du, D. F.
Wiemer, J. Org. Chem. 1999, 64, 388–393; k) D. M. Po-
gatchnik, D. F. Wiemer, Tetrahedron Lett. 1997, 38,
3495–3498; l) C. Meier, W. H. G. Laux, Tetrahedron:
Asymmetry 1996, 7, 89–94; m) T. Arai, M. Bougauchi,
H. Sasai, M. Shibasaki, J. Org. Chem. 1996, 61, 2926–
2927.
[8] a) S. Samanta, C.-G. Zhao, J. Am. Chem. Soc. 2006,
128, 7442–7443; b) R. Dodda, C.-G. Zhao, Org. Lett.
2006, 8, 4911–4914; c) T. Mandal, S. Samanta, C.-G.
Zhao, Org. Lett. 2007, 9, 943–945; d) S. Samanta, S.
Perera, C.-G. Zhao, J. Org. Chem. 2010, 75, 1101–1106.
[9] For recent examples of asymmetric synthesis on the
basis of organocatalyzed cross-aldol reactions, see: a) J.
Jiang, X. Chen, J. Wang, Y. Hui, X. Liu, L. Lin, X.
Feng, Org. Biomol. Chem. 2009, 7, 4355–4357; b) J.
Liu, Z. G. Yang, Z. Wang, F. Wang, X. H. Chen, X. H.
Liu, X. M. Feng, Z. S. Su , C. W. Hu, J. Am. Chem. Soc.
2008, 130, 5654–5655.
[14] For selected examples of primary amine-catalyzed
enantioselective reactions involving an enamine or imi-
nium intermediate, see: a) J. Zhou, V. Wakchaure, P.
Kraft, B. List, Angew. Chem. 2008, 120, 7768–7771;
Angew. Chem. Int. Ed. 2008, 47, 7656–7658; b) N. J. A.
Martin, B. List, J. Am. Chem. Soc. 2006, 128, 13368–
13369; c) X. Lu, Y. Liu, B. Sun, B. Cindric, L. Deng, J.
Am. Chem. Soc. 2008, 130, 8134–8135; d) X. Wang,
C. M. Reisinger, B. List, J. Am. Chem. Soc. 2008, 130,
6070–6071; e) S. H. McCooey, S. J. Connon, Org. Lett.
2007, 9, 599–602; f) T.-Y. Liu, H.-L. Cui, Y. Zhang, K.
Jiang, W. Du, Z.-Q. He, Y.-C. Chen, Org. Lett. 2007, 9,
3671–3674; g) B.-L. Zheng, Q.-Z. Liu, C.-S. Guo, X.-L.
Wang, L. He, Org. Biomol. Chem. 2007, 5, 2913–2915;
h) C. M. Reisinger, X. Wang, B. List, Angew. Chem.
2008, 120, 8232–8235; Angew. Chem. Int. Ed. 2008, 47,
8112–8115; i) G. Bartoli, P. Melchiorre, Synlett 2008,
1759–1772; j) Y.-C. Chen, Synlett 2008, 1919–1930;
k) S. Gogoi, C.-G. Zhao, D. Ding, Org. Lett. 2009, 11,
2249–2252; l) T. Mandal, C.-G. Zhao, Angew. Chem.
2008, 120, 7828–7831; Angew. Chem. Int. Ed. 2008, 47,
7714–7717; m) J.-W. Xie, W. Chen, R. Li, M. Zeng, W.
Du, L. Yue, Y.-C. Chen, Y. Wu, J. Zhu, J.-G. Deng,
Angew. Chem. 2007, 119, 393–396; Angew. Chem. Int.
Ed. 2007, 46, 389–392; n) H. Huang, E. N. Jacobsen, J.
Am. Chem. Soc. 2006, 128, 7170–7171. For a review on
primary amine catalysis, see: o) F. Peng, Z. Shao, J.
Mol. Catal. A 2008, 285, 1–13. For a review on Cincho-
na alkaloid catalysis, see: p) C. E. Song, (Ed.), Cincho-
na Alkaloids in Synthesis and Catalysis, Wiley-VCH,
Weinheim, 2009.
[10] The attempted cross-aldol reaction of propanal and
benzoylphosphonate failed, see: S. Samanta, J. Krause,
T. Mandal, C.-G. Zhao, Org. Lett. 2007, 9, 2745–2748.
[11] The synthesis of racemic b-formyl-a-hydroxyphospho-
nates has not been systemically studied; for examples,
see: a) J.-P. Haeltersa, H. Couthon-Gourvꢂsa, A. Le
Goffa, G. Simona, B. Corbela P.-A. Jaffrꢂ, Tetrahedron
2008, 64, 6537–6543; b) G. Guanti, M. T. Zannetti, L.
Banfi, R. Riva, Adv. Synth. Catal. 2001, 343, 682–691.
[12] For an example of enzymatic resolution of secondary
b-formyl-a-hydroxyphosphonates, see ref.[11b]
Adv. Synth. Catal. 2011, 353, 1729 – 1734
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1733

Sandun Perera et al.
COMMUNICATIONS
[15] D. Jin, J. Fan, L. Wang, L. F. Thomson, A. Liu, B. J.
Daniel, T. Shin, T. J. Curiel, B. Zhang, Cancer Res.
2010, 70, 2245–2255.
charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif. For
the ORTEP drawing of compound 12, please see the
Supporting Information.
[16] CCDC 820954 contains the supplementary crystallo-
graphic data for 12. These data can be obtained free of
1734
asc.wiley-vch.de
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1729 – 1734