Organocatalytic enantioselective synthesis of both diastereomers of α-hydroxyphosphinates

Article abstract of DOI:10.1021/jo9022099

(Chemical Equation Presented) Racemic α-acylphosphinates and formylphosphinate hydrate were used directly as the substrates in a proline derivative-catalyzed cross aldol reaction with ketones. Because of the preexisting phosphorus stereogenic center, a mixture of two diastereomers of the corresponding α-hydroxyphosphinates was obtained in this reaction. Good to high enantioselectivities (up to 99% ee) were obtained simultaneously for the two diastereomers in good yields. Good diastereoselectivities were also obtained when the reaction generates an additional carbon stereogenic center.

Full text of DOI:10.1021/jo9022099

pubs.acs.org/joc
Organocatalytic Enantioselective Synthesis of Both Diastereomers of
r-Hydroxyphosphinates
Sampak Samanta,† Sandun Perera, and Cong-Gui Zhao*
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio,
Texas 78249-0698. †Current address: Ranbaxy Laboratory Ltd., India.
cong.zhao@utsa.edu
Received October 14, 2009
Racemic R-acylphosphinates and formylphosphinate hydrate were used directly as the substrates in a
proline derivative-catalyzed cross aldol reaction with ketones. Because of the preexisting phosphorus
stereogenic center, a mixture of two diastereomers of the corresponding R-hydroxyphosphinates was
obtained in this reaction. Good to high enantioselectivities (up to 99% ee) were obtained simulta-
neously for the two diastereomers in good yields. Good diastereoselectivities were also obtained when
the reaction generates an additional carbon stereogenic center.
Introduction
activities: One enantiomer was found significantly more
herbicidal than the other enantiomer or the racemic mix-
ture.6 This finding evinces the importance of the phosphorus
chirality in the biological activity of the phosphinate compounds.
Thus, developing an asymmetric synthesis for R-hydroxy-
phoshinates that can fix both the stereochemistry of the
R-hydroxy-substituted carbon and the phosphorus stereo-
genic centers during the synthesis is very important. Such a
method is expected to have the potential of lowering produc-
tion costs and use rates, reducing the side effects, and
lessening the environmental burden during the manufacture
and application of these materials.
Besides the enzymatic resolution of racemic R-hydroxy-
phosphinates7 and the synthesis starting with optically active
R-hydroxyphosphonates8 or R-hydroxy-H-phosphinates,7
only a handful of chemical methods are available for the
synthesis of optically active R-hydroxyphosphinates.8 Shi-
buya and co-workers have reported a synthesis via the
diastereoselective reaction of chiral aldehydes and achiral
phosphites (a phosphoaldol reaction).9a Alternatively, the
R-Hydroxyphosphinic acid derivatives, such as R-hydro-
xyphosphinates, have been shown to be very important
enzyme inhibitors.1 For example, R-hydroxyphosphinate-
derived peptides have been used as the inhibitors of human
immunodeficiency virus (HIV) protease2 and renin.3 Also
these compounds have found use as GABA antagonists4 or
herbicides.5,6 With the exception of phosphinic acids, the
phosphoryl groups in other phosphinic acid derivatives, such
as phosphinates, generally are chiral because the pentavalent
phosphorus atom has a tetrahedral structure. Recent study6
also revealed that phosphinate enantiomers due to such
phosphorus chirality may have totally different biological
(1) For reviews, see: (a) Aminophosphonic and Aminophosphinic Acids;
Kuhkar, V. P., Hudson, H. R., Eds.; John Wiley: Chichester, UK, 2000.
(b) Kafarski, P.; Lejczak, B. Curr. Med. Chem.: Anti-Cancer Agents 2001, 1,
301–312. (c) Berlicki, L.; Kafarski, P. Curr. Org. Chem. 2005, 9, 1829–1850.
(d) Redmore, D. In Topics in Phosphorus Chemistry; Griffith, E. J., Grayson, M.,
Eds.; John Wiley: New York, 1976; Vol. 8, pp 515-585.
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Tetrahedron Lett. 1992, 33, 6625–6628.
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W. L.; Smith, S. A.; DeForrest, J. M.; Oehl, R. S.; Petrillo, E. W., Jr.
J. Med. Chem. 1995, 38, 4557–4569.
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Lett. 2004, 45, 6713–6716.
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38, 3297–3312. (b) Froestl, W.; Mickel, S. J.; von Sprecher, G.; et al. J. Med.
Chem. 1995, 38, 3313–3331.
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hedron Lett. 2001, 42, 5033–5036. (b) Cai, J.; Zhou, Z.; Zhao, G.; Tang, C.
Heteroatom Chem. 2003, 14, 312–315. (c) Yamagishi, T.; Yokomatsu, T.;
Suemune, K.; Shibuya, S. Tetrahedron 1999, 55, 12125–12136. For a review,
see: (d) Shibuya, S. Yakugaku Zasshi 2004, 124, 725–749.
ꢀ
(6) Spangler, L. A.; Mikozajczyk, M.; Burdge, E. L.; Kiezbasinski, P.;
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DOI: 10.1021/jo9022099
r
Published on Web 01/19/2010
J. Org. Chem. 2010, 75, 1101–1106 1101
2010 American Chemical Society

Samanta et al.
JOCArticle
phosphoaldol reaction may be carried out with achiral
aldehydes and chiral phosphites.9b An enantioselective
method based on the phosphoaldol reaction was as also
reported;9c however, due to the intrinsic chirality of the
phosphinate group, this method actually generates a mixture
of diastereomers, which has not been analyzed for its ee
values.9c While the above chemical methods produce useful
degrees of stereocontrol at the hydroxy-substituted R-carbon
center, none of them has addressed the stereochemistry of the
phosphinate group. Simultaneously fixing the stereochemis-
try of both the R-carbon and phosphorus stereogenic centers
during the synthesis of R-hydroxyphosphonates is still a
great challenge for organic chemists.
SCHEME 1. Catalytic Enantioselective Reaction with a Race-
mic Substrate
SCHEME 2. Proposed Transition States for the Cross Aldol
Reaction of R-Ketophosphonates
Recently we reported the first organocatalytic cross aldol
reaction10 of R-ketophosphonates and ketones for the synthesis
of R-hydroxyphosphonates (eq 1).11a,b In principle, this
reaction may be used for the preparation of R-hydroxypho-
sphinates, since the structures of R-ketophosphinates and
individual enantiomeric substrates and lead to a kinetic
resolution.13 If the reaction rates k and k- are equal, a
þ
kinetic resolution is avoidable, and the reaction may be
carried out with 100% conversion of the racemic substrate,
which is the major advantage of this approach as compared
with the normal kinetic resolution where the maximum
conversion of the substrate is only 50%. Because it is
difficult to meet both requirements at the same time, it is
not surprising that only a few such chemical reactions are
known in the literature.14 Gotor and co-workers have
classified this type of reaction into the stereodivergent
parallel kinetic resolution.15 Nevertheless, it should be
pointed out that this type of reaction does not always fulfill
one of the guidelines laid down for parallel kinetic resolu-
tion by Eames:16 the reactions must afford distinct and
easily separable products. While the diastereomers obtained
in this type of reaction are distinct, they are not always easy
to separate, as with our R-hydroxyphosphinate products
(see below).
R-ketophosphonates are very similar. Nonetheless, unlike
R-ketophosphonates, R-ketophosphinates are chiral due to
the chirality of the phosphorus atom. To use a racemic
starting material (A) in a catalytic enantioselective synthesis
(Scheme 1) to obtain both diastereomeric products (B and
C) in high ee values is highly challenging because (1) the
preexisting stereogenic center in substrate A may interfere
with the enantiofacial selectivity of the catalyst so that
matched reactants generate diastereomers with higher en-
antiomeric excesses12 and (2) the preexisting stereogenic
center in substrate A may affect the reaction rates of the
It is our contention that the enantiofacial selectivity of the
aldol reaction of R-ketophosphonates is mainly determined
by the size difference between the phosphonate and the alkyl
group of the R-ketophosphonate,11b while the actual stereo-
chemistry of the phosphorus atom should have minimum
influence on the enantiofacial selectivity (Scheme 2).
Furthermore, the phosphonate group is pointing away from
the reaction center in the favored transition state11 and,
therefore, its stereochemistry should not have a major influ-
ence on the reaction rate. Thus, we hypothesized that such a
cross aldol reaction may be used for the high enantioselective
synthesis of both diastereomers of the R-hydroxyphosphi-
nates from racemic R-ketophosphinates. Herein, we wish to
report a catalytic and highly enantioselective synthesis of
both diastereomers of R-hydroxyphosphinates with simulta-
neous fixing of both the hydroxy-substituted R-carbon and
the phosphorus stereogenic centers in the products through a
proline derivative-catalyzed cross aldol reaction of racemic
acylphosphinates and ketones.
(10) For reviews on organocatalyzed cross aldol reactions, see: (a) List, B.
Synlett 2001, 1675–1686. (b) List, B. Tetrahedron 2002, 58, 5573–5590.
(c) List, B. Acc. Chem. Res. 2004, 37, 548–557. (d) Notz, W.; Tanaka, F.;
Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580–597. For examples on the
cross aldol of activated ketone substrates, see: (e) Enders, D.; Grondal, C.
Angew. Chem., Int. Ed. 2005, 44, 1210–1212. (f) Luppi, G.; Cozzi, P. G.;
Monari, M.; Kaptein, B.; Broxterman, Q. B.; Tomasini, C. J. Org. Chem.
2005, 70, 7418–7421. (g) Shen, Z.; Li, B.; Wang, L.; Zhang, Y. Tetrahedron
Lett. 2005, 46, 8785–8788. (h) Tokuda, O.; Kano, T.; Gao, W.-G.; Ikemoto,
T.; Maruoka, K. Org. Lett. 2005, 7, 5103–5105. (i) Tang, Z.; Cun, L.-F.; Cui,
X.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Org. Lett. 2006, 8, 1263–1266.
(j) Samanta, S.; Zhao, C.-G. Tetrahedron Lett. 2006, 47, 3383–3386.
(k) Bøgevig, A.; Kumaragurubaran, N.; Jørgensen, K. A. Chem. Commun.
2002, 620–621. (l) References 11a-c.
(11) For some recent examples of asymmetric synthesis of R-hydroxypho-
sphonates, see: (a) Samanta, S.; Zhao, C.-G. J. Am. Chem. Soc. 2006, 128,
7442–7443. (b) Dodda, R.; Zhao, C.-G. Org. Lett. 2006, 8, 4911–4914.
(c) Liu, J.; Yang, Z.; Wang, Z.; Wang, F.; Chen, X.; Liu, X.; Feng, X.; Su,
Z.; Hu, C. J. Am. Chem. Soc. 2008, 130, 5654–5655. (d) Pawar, V. D.;
Bettigeri, S.; Weng, S.-S.; Kao, J.-Q.; Chen, C.-T. J. Am. Chem. Soc. 2006,
128, 6308–6309. (e) Gondi, V. B.; Hagihara, K.; Rawal, V. H. Angew. Chem.,
Int. Ed. 2009, 48, 776–779. (f) Abell, J. P.; Yamamoto, H. J. Am. Chem. Soc.
2008, 130, 10521–10523. (g) Pogatchnik, D. M.; Wiemer, D. F. Tetrahedron
Lett. 1997, 38, 3495–3498. (h) Cermak, D. M.; Du, Y.; Wiemer, D. F. J. Org.
Chem. 1999, 64, 388–393. (i) Skropeta, D.; Schmidt, R. R. Tetrahedron:
Asymmetry 2003, 14, 265–273. (j) Wroblewski, A. E.; Balcerzak, K. B.
Tetrahedron: Asymmetry 2001, 12, 427–431. (k) Yokomatsu, T.; Yamagishi,
T.; Shibuya, S. Tetrahedron: Asymmetry 1993, 4, 1401–1404. (l) Rowe, B. J.;
Spilling, C. D. Tetrahedron: Asymmetry 2001, 12, 1701–1708. (m) Arai, T.;
Bougauchi, M.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1996, 61, 2926–2927.
(n) Sasai, H.; Bougauchi, M.; Arai, T.; Shibasaki, M. Tetrahedron Lett. 1997,
38, 2717–2720. (o) Saito, B.; Katsuki, T. Angew. Chem., Int. Ed. 2005, 44,
4600–4602. (p) Groaning, M. D.; Rowe, B. J.; Spilling, C. D. Tetrahedron
Lett. 1998, 39, 5485–5488.
(13) For reviews, see: (a) Hoveyda, A. H.; Didiuk, Mary T. Curr. Org.
Chem. 1998, 2, 489–526. (b) Robinson, D. E. J. E.; Bull, St. D. Tetrahedron:
Asymmetry 2003, 14, 1407–1446.
(14) (a) Reynolds, N. T.; Rovis, T. Tetrahedron 2005, 61, 6368–6378.
(b) Bocknack, B. M.; Wang, L.-C.; Krische, M. J. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5421–5424. For a review on enzymatic reactions, see ref 15.
(15) For review, see: Dehli, J. R.; Gotor, V. Chem. Soc. Rev. 2002, 31,
365–370.
€
(12) Adam, W.; Humpf, H.-U.; Roschmann, K. J.; Saha-Moller, C. R.
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TABLE 1. Cross Aldol Reaction of Ethyl (Benzoylphenyl)phosphinate
(5a) and Acetone (6a) Catalyzed by L-Proline Derivativesa
FIGURE 1. Catalysts screened for the cross aldol reaction.
Results and Discussion
ee (%)d
Ethyl benzoylphenylphosphinate (5a) and acetone (6a)
were used as the model compounds to study the reaction
conditions. We screened several readily available proline
derivatives as the catalyst (Figure 1). The results are summarized
in Table 1. The cross aldol reaction went smoothly at room
temperature with all these catalysts and excellent yields of the
aldol product were obtained. Although L-prolinamide (1),
(S)-N-tosylprolinamide (2), and L-proline tetrazole (3) are
very reactive catalysts, only moderate enantioselectivities
were obtained for the two diastereomeric products 7a and
8a (entries 1-3). Nevertheless, the results of L-proline (4)
were promising: By using a 20 mol % loading of 4 and
acetone as the solvent at room temperature, 7a and 8a were
obtained in a total yield of 89% in a ratio of 53:47. The ee
values of these two diastereomeric products were determined
to be 95% and 74%, respectively (entry 4). Other solvents,
such as THF, CH2Cl2, DMF, DMSO, and an ionic liquid,
proved to be inferior to acetone (entries 5-9). To our
pleasure, by lowering the reaction temperature to -30 °C,
the enantioselectivities of these two products were further
improved to 99% and 91% ee, respectively, although the
reaction was slower at this temperature and the total yield
was lower (entry 10). It should be pointed out that, under all
these conditions, diastereomeric products 7a and 8a were
obtained in a ratio of roughly 50:50 with different degrees of
conversions of the substrate (from around 60% to over
90%), which hints that the reaction rates of both enantio-
meric substrates of 5a are almost equal.
The scope of this reaction was then evaluated, and the
results are collected in Table 2. It was found that, besides
ethyl benzoylphenylphosphinate (entry 1), substituted ben-
zoylphosphinates were also good substrates for this reaction.
For example, 98% and 91% ee were obtained for the two
diastereomeric products of 4-fluorobenzoylphosphinate (5b)
in 67% total yield under the optimized reaction conditions
(entry 2). Also good ee values (98% and 80% ee, respectively)
were obtained for the product of 3-fluorobenzoylphosphi-
nate (5c, entry 3). Similarly, 4-bromo- (5d), 4-chloro- (5e),
and 3-chloro- (5f) substituted derivatives also produce ex-
cellent results (entries 4-6). Substrates substituted with
electron-donating groups (i.e., Me, OMe, 5g and 5h) react
more slowly, but the enantioselectivities obtained for the
products are very good (entries 7 and 8). A heteroarene-
substituted (thiophen-2-yl) R-ketophosphinate (5i) also leads
to good enantioselectivity for one of the diastereomers (84%
ee), whereas the enantioselectivity for the other diastereomer
is slightly lower (62% ee, entry 9). Alkyl-substituted R-
ketophosphinates react in a similar manner. For example,
ethyl acetylphenylphosphinate (5j) gives 95% and 87% ee of
the two diastereomeric products, respectively (entry 10).
Similar results were also obtained for ethyl phenylpropio-
nylphosphinate (5k, entry 11). From the results in Table 2, it
is evident that the stereochemistry of the phosphinate group
entry catalyst loadingb solvent yield (%)c 7a
8a 7a/8ae
1f
2 f
3 f
4 f
5
1
2
3
4
4
4
4
4
4
4
10
10
10
20
20
20
20
20
20
20
acetone
acetone
acetone
acetone
THF
CH2Cl2
DMSO
DMF
93
63
83
89
90
79
81
81
87
58
72
45
82
95
95
94
52
69
91
99
47
28
62
74
67
65
32
39
59
91
55:45
58:42
54:46
53:47
52:48
50:50
48:52
58:42
59:41
52:48
6
7
8
9g
acetone
acetone
10 f,h
aUnless otherwise indicated, all reactions were carried out with the
ketophosphinate 5a (0.50 mmol), acetone (0.5 mL), and the catalyst in
the specified solvent (1.0 mL) at rt for 24 h. bIn mol %. cTotal yield of the
inseparable diastereomers (7a and 8a) isolated after column chroma-
d
e
tography. Determined by HPLC analyses. The ratio of 7a/8a; deter-
mined by 1H NMR analyses. f2.0 mL of acetone was used. gIonic liquid
1-butyl-3-methylimidazolium terafluoroborate (300 mg) was added.
hCarried out at -30 °C for 96 h.
does have some influence on the enantioselectivity of this
reaction: The ee value of one of the two diastereomers is
always slightly higher than the other. Nevertheless, the
reactivity of the two enantiomers of the racemic starting
acylphosphinates is almost the same since the ratio of the two
diastereomeric products 7 and 8 was maintained around
50:50 in all cases.
Methyl R-ketophosphinates also participate in this reac-
tion. However, determining the enantiomeric excess values
of the products is highly challenging, as the enantiomers
cannot be separated by the columns we have (data not
shown).
To determine the absolute configuration of the major
enantiomers formed in this reaction, the two diastereomeric
products 7 and 8 have to be separated. While compounds
7 and 8 obtained in this reaction cannot be separated by
column chromatography, we did achieve separation through
recrystallization in a few cases, and suitable crystals for the
X-ray crystallographic analysis were obtained for the enan-
tiomer of products 7d (ent-7d) with D-proline as the catalyst.
As shown in Scheme 3, ethyl (4-bromobenzoyl)phenyl-
phosphinate (5d) was allowed to react with acetone with
D-proline as the catalyst under the optimized conditions
identified for L-proline. The diastereomeric mixture of ent-
7d and ent-8d obtained this way was separated by careful
recrystallization from a mixture solvent of EtOAc and
hexane. (The diastereomeric products were dissolved in a
minimum amount of EtOAc and then diluted with hexane.
The solution was kept in an open system in such a way that
the solvents evaporated very slowly. After 24 h at rt, about
70% of compound ent-7d crystallized out.) The crystalline
compound obtained was identified to be ent-7d, whereas the
mother liquor contains mainly the remaining ent-8d. The
absolute configuration of ent-7d was determined to be S for
both the R-carbon and the phosphorus stereogenic centers
J. Org. Chem. Vol. 75, No. 4, 2010 1103

Samanta et al.
JOCArticle
TABLE 2. L-Proline-Catalyzed Aldol Reaction of Racemic R-Keto-
SCHEME 3. Determination of the Absolute Configuration of
the Reaction Products
phosphinates and Acetonea
because most of the R-configured phosphinate group already
has been fixed in compound 7d (retention time 111.2 min).
Thus, the peak at 27.2 min must be SCRP. On the basis of the
above analysis, compound 8d should have a stereochemistry
of RC,SP (retention time 117.1 min, see page S-60 in the
Supporting Information), which is also consistent with the
reaction mechanism.
On the basis of the aforementioned results, a mechanism is
proposed to account for the enantioselectivity outcome
(Scheme 4). Just as we expected, it does not matter whether
the stereochemistry of the phosphorus atom in acylpho-
sphinate 5a is R (TS-I and II) or S (TS-III and IV), the
attack of the enamine onto the si-face of this substrate is
always favored (TS-I and TS-III in Scheme 4), because the
unfavorable steric interactions between the large axial phos-
phinate group and the axial enamine methyl group (see TS-II
and TS-IV) are avoided in these two transition states. These
favored transition states lead to the formation of RCRP-7a
and RCSP-8a diastereomers as the major products, as ob-
served in the experiment. These results are also in accord with
those of the aldol reaction of acylphosphonate derivatives
catalyzed by similar catalysts (Scheme 2).11
Next the aldol reaction of the hydrate of ethyl formylpho-
sphinate (9) was studied. This reaction is expected to gen-
erate secondary R-hydroxyphosphinates, which are closer
analogues of proteinogenic R-amino acids. The results of this
reaction are summarized in Table 3. When acetone was used
as the substrate at room temperature, L-proline (4) failed to
generate any desired product (entry 1), probably because
compound 9 is not compatible with the acidity of 4. These
results are not surprising, since previously we obtained
similar results with formylphosphonate hydrate.11b When
less acidic L-prolinamide (1) was used as the catalyst under
the above conditions (entry 2), the desired product was
obtained in 89% yield with ee values of 90% and 79% for
SCRP (10a) and SCSP (11a) products, respectively, in a ratio
of 50:50. (The absolute configuration of products was
assigned on the basis of the proposed mechanism in
Scheme 4.) When the reaction was carried out at 0 °C, the
ee values of these two products were further improved to
93% and 87%, respectively (entry 3). Cyclopentanone may
also be used in this reaction (entry 4). Although this reaction
potentially can generate 8 diastereomers, it was found that
only the syn diastereomers (referring to the newly formed
aUnless otherwise indicated, all reactions were carried out with the
racemic ketophosphinate (0.50 mmol) in dry acetone (2.0 mL), with
L-proline (0.10 mmol, 20 mol %) as the catalyst for the specified reaction
time and temperature. bTotal yield of the inseparable diastereomers
(7 and 8) isolated after column chromatography. cEnantioselectivity was
determined by HPLC analyses, due to the overlap of some of the peaks,
the error limits may be is considerably larger than normal in those cases.
dThe ratio of 7:8 or vice versa; determined by 1H NMR analyses.
(SC,SP) by X-ray crystallography.17 To determine the abso-
lute configuration of the other diastereomers, separate
HPLC analyses of the racemic product, the product obtained
from L-proline (Table 2, entry 1) and DL-proline (Scheme 3),
and pure ent-7d were undertaken.18 From the results of the
racemic sample, it is clear that the stereoisomers with reten-
tion times of 48.1 and 113.8 min are a pair of enantiomers,
and those with retention times of 27.2 and 117.1 min are the
other pair of enantiomers (please see page S-61 of the
Supporting Information).18 Pure ent-7d, which has been
determined to be SCSP by X-ray crystallography, shows a
retention time of 48.1 min (page S-62). Thus, the stereoiso-
mer with the retention time of 113.8 min should have the
stereochemistry of RCRP since it is the enantiomer of ent-7d
(that is, it is 7d). With these results at hand, it is relatively easy
to determine the stereochemistry of the other two enantio-
mers by using the HPLC analysis of the compounds 7d/8d
obtained in Table 2, entry 1. In this HPLC spectrum (page
S-64 in the Supporting Information), one major peak is at
111.2 min, which was assigned to RCRP as described above.
The other major peak is at 115.1 min, which must be RCSP,
(17) For the ORTEP drawing of compound ent-7d, please see the
Supporting Information.
(18) For details, please see the Supporting Information.
1104 J. Org. Chem. Vol. 75, No. 4, 2010

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JOCArticle
TABLE 3. Aldol Reaction of Racemic Formylphosphinate Hydrate and Ketonesa
6
ee (%)e
entry
R1
R2
catalyst
10 and 11
time (h)
yield (%)b
10/11c
syn/antid
syn-10
syn-11
anti-10
anti-11
1f
2f
3
H
H
H
H
H
H
4
1
1
1
1
1
1
a
a
a
b
b
c
24
1.5
7
24
30
32
30
0
89
91
79
83
88
91
50:50
50:50
50:50
50:50
50:50
50:50
90g
93g
97
79g
87g
62
4f
5
-(CH2)2-
>99:1
99:1
35:65
40:60
-(CH2)2-
-(CH2)3-
96
87
6
7
98h
99h
95h
94h
89h
26h
93h
99h
-(CH2OCH2)-
d
aUnless otherwise indicated, all reactions were carried out with the racemic formylphosphinate hydrate (0.50 mmol) in dry ketone (0.5 mL) with the
catalyst (0.10 mmol, 5 mol %) for the specified reaction time at 0 °C. bTotal yield of the inseparable diastereomers (10 and 11) isolated after column
chromatography. cDetermined by 1H NMR analyses; the value refers to the ratio of the products containing RP and SP stereochemistry. dDetermined by
1H NMR analyses; syn and anti refer to the stereochemistry of the two newly generated carbon stereogenic centers. eEnantioselectivity was determined by
HPLC analyses. fThe reaction was carried out at room temperature. gThis compound does not have syn or anti stereochemistry. hThe assignments of the
ee values to the structures are arbitrary in these cases. Due to partial overlaps of some of the peaks, the error limit of the ee values is considerably larger
than normal.
SCHEME 4. Proposed Mechanism for the Cross Aldol Reaction of Acylphosphinates
carbon stereogenic centers)19 were formed during the re-
action (>99:1 dr), and the ee value of the two diastereomers
syn-10b (configuration: SC,SC,RP) and syn-11b (configurat-
ion: SC,SC,SP) obtained at room temperature is 97% and
62%, respectively. When the reaction was carried out at
0 °C, the ee value of syn-11b was further improved to 87%
(entry 5). Cyclohexanone and 4-oxacyclohexanone are also
suitable substrates for this reaction; nevertheless, the reac-
tions are less diastereoselective (entries 6 and 7). For cyclo-
hexanone an anti/syn ratio of 65:35 was obtained, and the
four diastereomers 10c and 11c were obtained in 98%, 95%,
89%, and 93% ee, respectively (entry 6). Similarly, 4-oxacy-
clohexanone yielded an anti/syn ratio of 60:40, and the ee
values for the four diastereomers 10d and 11d are 99%, 94%,
26%, and 99% ee, respectively (entry 7). The low diastereos-
electivities observed for six-membered cyclic ketones versus
cyclopentanone are in-line with our previous report on cross
aldol reaction of the R-formylphosphonate hydrate deriva-
tive11b and are probably due to steric reasons, although the
exact reason is not clear at this moment. Since these products
are inseparable liquid compounds by column chromatogra-
phy, it is impossible to assign the ee values to the correspond-
ing structures without ambiguity. Nevertheless, it is clear
from Table 3 that the ratio of 50:50 was achieved in each
entry for compounds containing RP and SP stereogenic
centers, which indicates that both enantiomers of the race-
mic substrate 9 react efficiently under the reaction condi-
tions.
Conclusions
In summary, a novel method for the highly enantioselec-
tive synthesis of the biologically significant R-hydroxypho-
sphinates was developed on the basis of a proline derivative-
catalyzed asymmetric aldol reaction of ketones and R-keto-
phosphinates or R-formyphosphinate hydrate. Both the
newly formed carbon stereogenic centers and the phos-
phorus stereogenic center were fixed during the aldol reac-
tion.
(19) The syn/anti stereochemistry was determined by the NOE experi-
ments on the products syn-10b/syn-11b and anti-10c/anti-11c (for details,
please see pages S-59 and S-60 of the Supporting Information). The results
are also in-line with those of the corresponding R-hydroxyphosphonates
(please see ref 11b).
J. Org. Chem. Vol. 75, No. 4, 2010 1105

Samanta et al.
JOCArticle
Experimental Section
The reaction mixture was stirred at this temperature for 24-32 h
(depending on the substrate). The solvent was evaporated under
vacuum and the residue was purified by flash chromatography
(EtOAc) over silica gel to furnish the desired secondary R-hydro-
xyphosphinate as a pure compound (a mixture of inseparable
diastereomers).
Ethyl (1-hydroxy-3-oxobutyl)(phenyl)phosphinate (10a/11a):
colorless oil; H NMR (500 MHz, CDCl3) δ (mixture of two
diastereomers) 1.28 (2 t, J = 7.0 Hz, 3 H), 2.14 (s, 3H),
2.68-2.84 (m, 2 H), 3.91-3.99 (m, 1 H), 4.07-4.14 (m, 1 H),
4.47-4.58 (m, 1 H); 13C NMR (125 MHz, CDCl3) δ (mixture of
two diastereomers) 16.7(q), 30.9 (d), 44.1 (q), 61.9 (q), 65.8 and
General Experimental Procedure for the Synthesis of Tertiary
r-Hydroxyphosphinate via Aldol Reaction of Racemic r-Keto-
phosphinate. To a stirred solution of the R-ketophosphinate
(0.5 mmol) and dry acetone (2.0 mL) was added L-proline
(0.10 mmol, 20 mol %) at -30 °C. The reaction mixture was
stirred at this temperature for the time specified in Table 1
(monitored by TLC) and then quenched by a few drops of water.
The mixture was extracted with ethyl acetate (3 ꢀ 10 mL), and
the combined extracts were washed with brine solution (2 mL),
dried over MgSO4, and then evaporated to give the crude
product, which was purified by column chromatography over
silica gel (4:1 ethyl acetate/hexane) to furnish the desired
R-hydroxyphosphinate as a pure compound (a mixture of two
inseparable diastereomers).
Ethyl (1-hydroxy-3-oxo-1-phenylbutyl)(phenyl)phosphinate
(7a/8a): white solid, mp 91-92 °C; 1H NMR (500 MHz, CDCl3)
δ (mixture of two diastereomers) 1.13 and 1.36 (t, J = 7.0 Hz, 3
H), 2.05 and 2.17 (s, 3 H), 3.05 and 3.08 (d, J = 8.0 Hz, 0.5 H),
3.75-4.15 (m, 2 H), 4.88 and 5.06 (br s, 1 H), 7.15-7.66 (m, 10 H);
13C NMR (125 MHz, CDCl3) δ (mixture of two diastereomers)
16.6 (q), 32.5 (q), 46.7 (q), 62.2 (q), 76.2 and 76.4 (d), 126.2 and
126.6 (d), 126.8 (q), 127.6 and 127.8 (d), 127.9 and 128.0 (d),
128.1 (q), 132.6 and 132.7 (d), 133.4 and 133.7 (d), 139.2 (q),
210.1 (q); 31P NMR (CDCl3) δ (mixture of two diastereomers)
36.3, 37.4; νmax (neat, cm-1) 3212, 1710, 1598, 1510, 1475, 1439,
1411. Anal. Calcd for C18H21O4P: C, 65.05; H, 6.37. Found:
C, 64.75; H, 6.45.
1
66.5 (d, JCP = 121.6 and 120.1 Hz), 127.4 and 128.4 (d, JCP
=
P
25.8 and 25.3 Hz), 128.8 (q), 132.8 (q), 133.0 (d), 207.2 (q); 31
NMR (CDCl3) δ (mixture of two diastereomers) 39.6, 40.1; νmax
(neat, cm-1) 3251, 1715, 1592, 1479, 1439, 1394 1362. Anal.
Calcd for C12H17O4P: C, 56.25; H, 6.69. Found: C, 56.11; H,
6.88.
Acknowledgment. The authors thank the NIH-NIGMS
(Grant No. 1SC1GM082718-01A1) for the generous finan-
cial support of this research and the Welch Foundation
(Grant No. AX-1593) for the financial support in getting
the preliminary data of this research. The authors also thank
Dr. Derong Ding for help with the synthesis of some of the
R-ketophosphonate starting materials and Dr. Edward R. T.
Tiekink for help with the X-ray analysis of compound ent-7d.
General Procedure for the Synthesis of Secondary r-Hydro-
xyphosphinate via Aldol Reaction of Racemic r-Formylphosphi-
nate Hydrate. To a stirred solution of the formylphosphinate
hydrate (108 mg, 0.5 mmol) in the ketone (0.5 mL) in dry CH2Cl2
at 0 °C was added L-prolinamide (2.9 mg, 0.025 mmol, 5 mol %).
Supporting Information Available: Full citation of refs 4a
and 4b, HPLC conditions, characterization data and NMR
spectra for all new compounds, HPLC analysis spectra, and
CIF data for compound ent-7d. This material is available free of
charge via the Internet at http://pubs.acs.org.
1106 J. Org. Chem. Vol. 75, No. 4, 2010