Organocatalytic enantioselective hydrophosphonylation of aldehydes

Article abstract of DOI:10.1039/c3ob42403k

We report our results concerning the first squaramide-catalysed hydrophosphonylation of aldehydes. In all cases, the reactions proceeded smoothly and cleanly under mild reaction conditions rendering final α-hydroxy phosphonates in very good yields and hig

Full text of DOI:10.1039/c3ob42403k

Organic &
Biomolecular Chemistry
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Organocatalytic enantioselective
hydrophosphonylation of aldehydes†
Cite this: Org. Biomol. Chem., 2014,
12, 1258
Juan V. Alegre-Requena,a Eugenia Marqués-López,a Pablo J. Sanz Miguelb and
Raquel P. Herrera*a
We report our results concerning the first squaramide-catalysed hydrophosphonylation of aldehydes. In
all cases, the reactions proceeded smoothly and cleanly under mild reaction conditions rendering final
α-hydroxy phosphonates in very good yields and high enantioselectivities. It is one of the few organocata-
lytic examples of this reaction using aldehydes. It is the first time that diphenylphosphite (1e) has been
successfully employed in a chiral Pudovik reaction with aldehydes, in contrast to the dialkylphosphites
used in previously published procedures, extending the generality of this asymmetric methodology.
Received 2nd December 2013,
Accepted 18th December 2013
DOI: 10.1039/c3ob42403k
www.rsc.org/obc
Introduction
The addition of dialkyl- and diphenylphosphites to carbonyl
compounds (Pudovik reaction)1 is a powerful and widely
applied strategy for the construction of C–P bonds, and a
straightforward tool for providing efficient access to chiral
α-hydroxy phosphonates and their corresponding phosphonic
acids.2 Interestingly, compounds bearing this motif have
shown remarkable biological activities and are currently
employed in the pharmaceutical industry (Scheme 1).3 The
absolute configuration of these phosphonyl compounds could
strongly influence their biological activities,4 and a growing
interest in their asymmetric synthesis has been promoted
during the last two decades. Several efficient enantioselective
catalytic methods of hydrophosphonylation of aldehydes have
been reported in the presence of a chiral metal complex giving
access to α-hydroxy phosphonates with good outcomes.5,6
In addition to the extensive spectrum of biological pro-
Scheme 1 Direct approach to appealing phosphonate derivatives.
Although the Pudovik reaction with aldehydes has been the
perties exhibited by this kind of compound (antibacterial, anti- focus of intensive studies using chiral metal catalysts,2,5,6 the
virus, antibiotic and pesticidal activities, as well as being a organocatalytic version of this appealing strategy has been
potent antitumor agent),7 α-hydroxy phosphonates have also overlooked in the literature. After the pioneering chiral organo-
attracted attention as synthetic intermediates for preparing catalytic example appeared in 1983,10 in which a limited
further α-8 and γ-functionalised9 phosphonates (Scheme 1).
number of aldehydes (only two) was disclosed, requiring suc-
cessive recrystallizations to improve the enantioselectivities,
only a pivotal example of an organocatalysed approach has
been published in 2009 by Ooi’s group.11 Our experience in
the organocatalysed Pudovik reaction with imines12,13 and
hydrazones,14 and the lack of background information on alde-
hydes encouraged us to explore the feasibility of catalysing this
process with hydrogen bonding based catalysts, due to their
well-known capacity to activate carbonyl groups.15,16 In this
communication, we report our appealing results concerning
the first asymmetric squaramide-organocatalysed Pudovik
reaction using aldehydes.
aLaboratorio de Síntesis Asimétrica, Departamento de Química Orgánica, Instituto
de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC-Universidad de Zaragoza,
E-50009 Zaragoza, Spain. E-mail: raquelph@unizar.es; Fax: +34 976762075;
Tel: +34 976762281
bDepartamento de Química Inorgánica, Instituto de Síntesis Química y Catálisis
Homogénea (ISQCH), CSIC-Universidad de Zaragoza, E-50009 Zaragoza, Spain
†Electronic supplementary information (ESI) available: General experimental
information, 1H and 13C NMR spectra and HPLC chromatograms for all final
products 4ea–ek. CCDC 953498 and 953499. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c3ob42403k
1258 | Org. Biomol. Chem., 2014, 12, 1258–1264
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with some of the phosphites investigated while using catalyst
3c (entries 6 and 7), we found that diphenylphosphite (1e) led
Results and discussion
We started our investigation examining the viability of the to the best results in terms of enantioselectivity and reactivity
addition of dibenzylphosphite (1a) to aldehyde 2a catalysed by (entry 8). Subsequent to this exploration, we continued the
chiral catalysts 3a–3c acting through hydrogen bonding study with squaramide 3c as the catalyst of choice and phos-
(Scheme 2). Based on our own experience in the hydrophos- phite 1e for testing different key parameters such as type of
phonylation reaction,12,14 we foresaw the importance of com- solvent, temperature and concentration (Table 2).
prising a basic functionality in the catalyst structure, favouring
Among all the studied solvents, we found CH3CN to be the
a plausible bifunctional catalysis, since only model catalysts best choice for this procedure in terms of enantioselectivity
3a–c afforded promising results, compared with simple (entry 5), whereas no reaction was observed with some ethereal
thioureas.17
solvents such as 1,4-dioxane (entry 6) or Et2O (entry 7), having
To our delight, the initial screening of catalysts revealed a negative influence on the activity of the catalyst. Further-
squaramide 3c to be the best compromise in terms of both more, we were pleased to find that cooling the reaction
enantioselectivity and reactivity. However, before discarding mixture to −38 °C had a remarkable positive effect on the
thioureas 3a and 3b, we continued exploring these catalysts to enantioselectivity of the process, without impairing the levels
verify if they worked better with other phosphites 1b–1e of reactivity (entry 14). We did not decrease the temperature of
(Table 1).
the reaction any further since we were close to the m.p. of the
After examining the influence of diverse phosphites 1b–e in solvent (−44 °C). The dilution of the reaction also had a posi-
our reaction model, and although we did not observe reactivity tive effect at −27 °C on the enantioselectivity of the products
(entry 11). Lowering the catalyst loading did not afford better
results (entries 13 and 17) and although better yields are
attained with a higher catalytic charge as expected (entry 16),
we continued with a reasonable 20 mol%. Surprisingly, we
observed that performing the reaction at −38 °C in the
absence of stirring afforded the best results in terms of
enantioselectivity and reactivity (compare entries 14 and 15).
Table 2 Screening of the reaction conditionsa
Scheme 2 Model hydrophosphonylation reaction tested.
Cat.
(%)
T
(°C)
Time
(h)
Yieldb
(%)
eec
(%)
Entry
Solvent (mL)
Table 1 Screening of different phosphites 1b–e with catalysts 3a–ca
1
2
3
4
5
6
7
8
Xylene (0.5)
CH2Cl2 (0.5)
CH3Cl (0.5)
THF (0.5)
CH3CN (0.5)
1,4-Dioxane (0.5)
Et2O (0.5)
CH2Cl2 (0.5)
CH2Cl2 (0.5)
CH3CN (0.5)
CH3CN (1)
CH3CN (1)
CH3CN (1)
CH3CN (0.5)
CH3CN (0.5)
CH3CN (0.5)
CH3CN (0.5)
20
20
20
20
20
20
20
20
20
20
20
20
10
20
20
30
10
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
5
−27
−27
−27
−27
−27
−38
−38
−38
−38
24
24
24
24
24
24
24
19
19
72
96
83
95
52
96
52
99
92
97
81
94
50
62
60
62
70
70
n.r.d
n.r.d
83
n.r.d
n.r.d
68
Entry
R
Cat.
Time (h)
Yieldb (%)
eec (%)
9
75
80
98
71
85
85
88
97
72
79
82
82
80
87
76
86
10
11
12e
13
14f
15
16f
17
1d
2d
3d
4d
5
6
7
8
9
Me
Et
iPr
Ph
Me
Et
iPr
Ph
Ph
3a
3a
3a
3a
3c
3c
3c
3c
3b
20
18
48
72
20
24
24
20
48
83
90
83
30
8
14
14
18
86
38
n.d.e
n.d.e
83
n.d.e
n.d.e
46
62
52
a Experimental conditions: to a mixture of catalyst 3c (0.02 mmol) and
aldehyde 2a (0.1 mmol) in the corresponding solvent, phosphite 1e
(0.2 mmol) was further added in a test tube at the temperature
indicated. After the reaction time, adduct 4ea was isolated by flash
chromatography. b Isolated yield. c Determined by chiral HPLC analysis
(Chiralpak IA, flow hexane–AcOEt 70 : 30, 1 mL min−1). d No reaction.
57
25
a Experimental conditions: to a mixture of catalyst 3a–c (0.02 mmol)
and aldehyde 2a (0.1 mmol) in toluene (0.5 mL), phosphite 1b–e
(0.2 mmol) was further added in a test tube at room temperature. After
the reaction time, adducts 4 were isolated by flash chromatography.
b Isolated yield. c Determined by chiral HPLC analysis. d Reaction
performed using 0.2 mmol of aldehyde. e Not determined.
e Reaction performed with
1
equiv. of phosphite 1e. f Reaction
performed in the absence of stirring.
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It seems that the insolubility of the product at this temperature configuration of our products, single crystals were grown from
is the driving force of the reaction, since in the absence of stir- adducts 4ee and 4eg. The stereochemical outcome was deter-
ring a big precipitate is observed at the bottom of the reaction mined to be R for both final products (Fig. 1).18 The same
tube. This fact resulted in better yields when compared with absolute configuration was assumed for all products 4.
the same reaction performed at higher temperatures and it
Having demonstrated the capacity of squaramide 3c to
also had a clear positive effect on the enantioselectivity. With efficiently catalyse the addition of diphenylphosphite 1e to
the optimised reaction conditions in hand, we extended our aldehydes 2a–k, we propose the following reasonable tran-
methodology to a broad range of different substituted alde- sition state to explain the role of the catalyst based on previous
hydes as shown in Table 3.
modes of activation by this kind of structure (Fig. 2).19 On the
The addition reaction took place smoothly giving rise to the basis of the experimental results, we envisioned that the chiral
desired α-hydroxy phosphonates 4 in excellent yields (up to
98%) and high enantioselectivities (up to 88%). The efficiency
of the developed methodology is well accounted since it was
successfully applied to all the aldehydes examined 2a–k. We
could reach 88% and 85% of ee using aldehydes 2a and 2h,
respectively, simply through slight modifications of the reac-
tion conditions, using 1 mL of solvent instead of 0.5 mL
(entries 1 and 8). The electronic effects on the enantio-
selectivity and reactivity were explored using different meta-
and para-substituted benzaldehydes (entries 1–8). Neither the
reactivity nor the enantioselectivity suggested a dependence on
the electronic environment in the aromatic ring, as excellent
results were accomplished with all of them. On the other
hand, when using aliphatic aldehydes, a clear dependence on
steric hindrance could be observed (compare entries 9, 10 and
11), since better enantioselectivities were achieved with bulkier
groups, that is from primary < secondary < tertiary carbon,
although no correlation with the yield was revealed. In the
case of aldehyde 2k, it was necessary to cool the aldehyde
before its addition in order to avoid its evaporation. Its vola-
tility could justify the yield reached with this substrate
(entry 11).
Since these final adducts have not been previously reported
in the chiral version, in order to determine the absolute
Fig. 1 X-ray crystal structures of (R)-4ee and (R)-4eg.
Table 3 Scope of the squaramide-catalysed hydrophosphonylation
reaction
Entry
R
Product
Time (h)
Yielda (%)
eeb (%)
1c
2
3
4
5
4-NO2Ph, 2a
4-MePh, 2b
1-Naphthyl, 2c
Ph, 2d
4-BrPh, 2e
4-ClPh, 2f
3-ClPh, 2g
4-CNPh, 2h
PhCH2CH2, 2i
Cy, 2j
4ea
4eb
4ec
4ed
4ee
4ef
4eg
4eh
4ei
95
96
92
92
92
88
88
90
90
92
94
98
81
92
82
72
80
98
98
77
98
73
88
80
80
81
84
82
80
85
68
75
85
6
7
8c
9
10
11
4ej
4ek
tBu, 2k
a Isolated yield. b Determined by chiral HPLC. c Reaction performed in
1 mL of solvent.
Fig. 2 Proposed mechanistic hypothesis.
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squaramide 3c could act in a bifunctional fashion.20 On one solvent. Chemical shifts were reported in the δ scale relative to
1
hand, the aldehyde could be activated by the squaramide residual CHCl3 (7.26 ppm) for H NMR and to the central line
moiety through double hydrogen bonding with the NH groups. of CDCl3 (77 ppm) for 13C NMR.
Simultaneously, the basic nitrogen atom on the piperidine
Materials
ring would activate the phosphonate form in the tautomeric
equilibrium,21 driving the attack of the active phosphite form All commercially available solvents and reagents were used as
over the Re-face of the fixed aldehyde. This would afford the R received. The H and 13C NMR spectra for compounds 4eb,24
1
absolute configuration in all final products, which is consist- 4ed,25 and 4ef25 are consistent with values previously reported
ent with the observed results in our products.
in the literature.
Our developed methodology, if compared with the pioneer-
ing protocol described by Wynberg and co-workers,10,22 has
broader applicability. It is evident by the fact that our strategy
Representative procedure for squaramide-organocatalysed
hydrophosphonylation reaction of aldehydes
is tolerant towards various functional groups including To a mixture of catalyst 3c (0.02 mmol) and aldehyde 2a–k
halides, nitro, cyano, naphthyl and alkyl groups. Additionally, (0.1 mmol) in CH3CN (0.5 mL), phosphite 1e (0.2 mmol) was
the herein described method is a more straightforward proto- further added in a test tube at −38 °C. After the reaction time
col achieving the final goal in a simpler manner, without the (see Table 3), adducts 4 were isolated by flash chromatography
necessity of subsequent derivatization or recrystallization in (SiO2, hexane–EtOAc 7 : 3). Yields and enantioselectivities are
order to obtain high enantioselectivities. Furthermore, our reported in Table 3.
most accessible catalyst 3c compared with that used by Ooi
(R)-Diphenyl
hydroxy(4-nitrophenyl)methylphosphonate
and co-workers and the development of the reaction at −38 °C (4ea). Following the general procedure, compound 4ea was
instead of at −98 °C makes our procedure an attractive obtained after 95 h of reaction at −38 °C as a white solid in
alternative.11a
98% yield (37.7 mg). The ee of the product was determined to
be 88% by HPLC using a Daicel Chiralpak IA column (n-
hexane–AcOEt = 70 : 30, flow rate 1 mL min−1, λ = 268.3 nm):
τmajor = 23.7 min; τminor = 20.7 min. M.p. 137–140 °C. [α]D26
=
Conclusions
1
+47 (c 0.40, CHCl3, 80% ee). H NMR (400 MHz, CDCl3) δ 8.24
In conclusion, we have demonstrated the ability of the chiral (d, J = 8.1 Hz, 2H), 7.76 (dd, J = 2.4, 8.4 Hz, 2H), 7.27–7.31 (m,
squaramide 3c to accomplish the addition of diphenyl- 4H), 7.16–7.20 (m, 2H), 7.03–7.08 (m, 4H), 5.44 (dd, J = 4.8,
phosphite 1e to a variety of aromatic 2a–h and aliphatic alde- 11.0 Hz, 1H), 4.02 (dd, J = 5.3, 7.8 Hz, 1H). 13C NMR (75 MHz,
hydes 2i–k through a simple and general approach, with very CDCl3) δ 150.0 (d, J = 10.1 Hz, 1C), 149.9 (d, J = 10.6 Hz, 1C),
good results in terms of enantioselectivity and reactivity. This 147.7 (d, J = 4.0 Hz, 1C), 143.0 (d, J = 1.8 Hz, 1C), 129.9 (d, J =
protocol represents an additional extended organocatalytic 6.6 Hz, 4C), 128.0 (d, J = 1.8 Hz, 2C), 125.7 (d, J = 7.6 Hz, 2C),
procedure of hydrophosphonylation of aldehydes, with all 123.4 (d, J = 2.8 Hz, 2C), 120.5 (d, J = 9.3 Hz, 2C), 120.4 (d, J =
reagents and catalysts being commercially available. Moreover, 9.3 Hz, 2C), 69.8 (d, J = 160.3 Hz, 1C). IR (KBr film) (cm−1) ν
tedious or hazardous conditions, anhydrous solvents or 3306, 2923, 2853, 1588, 1513, 1488, 1377, 1215, 1182, 945, 761,
reagents and inert atmosphere are not required as they are in 690. HRMS (ESI+) calcd C19H16NNaO6P 408.0613; found
the organometallic version. The potential of this methodology 408.0607 [M + Na].
is demonstrated by its simplicity and generality which could
(R)-Diphenyl hydroxy(p-tolyl)methylphosphonate (4eb).24
become a key work in this area of research. Moreover, it is the Following the general procedure, compound 4eb was obtained
first time, to the best of our knowledge that diphenylphosphite after 96 h of reaction at −38 °C as a white solid in 81% yield
1e has been successfully employed in a chiral Pudovik reaction (28.7 mg). The ee of the product was determined to be 80% by
of aldehydes in contrast to the other dialkylphosphites used in HPLC using a Daicel Chiralpak IC column (n-hexane–i-PrOH =
previously published procedures,2 extending the generality of 90 : 10, flow rate 1 mL min−1, λ = 262 nm): τmajor = 18.9 min;
this asymmetric methodology.23
τminor = 16.8 min. [α]2D8 = +27 (c 0.87, CHCl3, 74% ee). IR (KBr
film) (cm−1) ν 3337, 2924, 2854, 1590, 1489, 1456, 1377, 1260,
1241, 1212, 1190, 1163, 1071, 1022, 1040, 940, 800, 764, 689.
HRMS (ESI+) calcd C20H19NaO4P 377.0919; found 377.0913
[M + Na].
Experimental section
General experimental methods
(R)-Diphenyl hydroxy(naphthalen-1-yl)methylphosphonate
Purification of reaction products was carried out by flash (4ec). Following the general procedure, compound 4ec was
chromatography using silica-gel (0.063–0.200 mm). Analytical obtained after 92 h of reaction at −38 °C as a white solid in
thin layer chromatography was performed on 0.25 mm silica 92% yield (35.9 mg). The ee of the product was determined
gel 60-F plates. ESI ionization method and mass analyser type to be 80% by HPLC using a Daicel Chiralpak IC column
1
MicroTof-Q were used for the HRMS measurements. H NMR (n-hexane–i-PrOH = 90 : 10, flow rate 1 mL min−1, λ = 283.7 nm):
spectra were recorded at 300 MHz and 400 MHz; 13C NMR τmajor = 21.5 min; τminor = 17.3 min. M.p. 110–112 °C. [α]D26
spectra were recorded at 75 MHz and 100 MHz; CDCl3 as the +98 (c 0.61, CHCl3, 80% ee). H NMR (400 MHz, CDCl3) δ 8.16
=
1
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(d, J = 8.5 Hz, 1H), 7.97 (dd, J = 3.4, 7.2 Hz, 1H), 7.85–7.90 (m, +26 (c 0.33, CHCl3, 77% ee). 1H NMR (400 MHz, CDCl3) δ
2H), 7.49–7.56 (m, 3H), 7.04–7.27 (m, 8H), 6.88–6.90 (m, 2H), 7.60–7.61 (m, 1H), 7.46–7.51 (m, 1H), 7.26–7.35 (m, 6H),
6.20 (dd, J = 3.8, 10.5 Hz, 1H), 3.56 (br s, 1H). 13C NMR 7.15–7.21 (m, 2H), 7.04–7.11 (m, 4H), 5.35 (dd, J = 5.0, 9.6 Hz,
(100 MHz, CDCl3) δ 150.3 (d, J = 10.3 Hz, 1C), 150.3 (d, J = 9.9 1H), 3.46 (dd, J = 5.1, 10.0 Hz, 1H). 13C NMR (75 MHz, CDCl3)
Hz, 1C), 133.7 (d, J = 1.7 Hz, 1C), 131.5 (d, J = 1.8 Hz, 1C), δ 150.2 (d, J = 10.0 Hz, 1C), 150.1 (d, J = 10.2 Hz, 1C), 137.4 (d,
130.9 (d, J = 6.8 Hz, 1C), 129.6 (d, J = 14.5 Hz, 4C), 129.4 (d, J = J = 2.2 Hz, 1C), 134.4 (d, J = 3.0 Hz, 1C), 129.7 (d, J = 4.4 Hz,
3.5 Hz, 1C), 128.8 (d, J = 0.7 Hz, 1C), 126.5 (1C), 126.1 (d, J = 4C), 129.7 (1C), 128.7 (d, J = 3.4 Hz, 1C), 127.5 (d, J = 6.3 Hz,
6.4 Hz, 1C), 125.8 (1C), 125.4 (d, J = 3.5 Hz, 1C), 125.2 (d, J = 1C), 125.5 (d, J = 5.8 Hz, 1C), 125.4 (d, J = 5.3 Hz, 2C), 120.5 (d,
14.9 Hz, 2C), 123.4 (1C), 120.4 (d, J = 22.4 Hz, 2C), 120.3 (d, J = J = 6.6 Hz, 2C), 120.5 (d, J = 6.6 Hz, 2C), 70.1 (d, J = 160.8 Hz,
22.4 Hz, 2C), 67.2 (d, J = 163.7 Hz, 1C). IR (KBr film) (cm−1) ν 1C). IR (KBr film) (cm−1) ν 3343, 2924, 2853, 1723, 1589, 1490,
3252, 2924, 2854, 1590, 1513, 1488, 1463, 1377, 1250, 1186, 1456, 1377, 1252, 1240, 1208, 1196, 1184, 1166, 1099, 1071,
1161, 942, 804, 767, 688. HRMS (ESI+) calcd C23H19NaO4P 1010, 960, 938, 808, 769, 759, 690. HRMS (ESI+) calcd
413.0919; found 413.0913 [M + Na].
C19H16ClNaO4P 397.0372; found 397.0367 [M + Na].
(R)-Diphenyl (4-cyanophenyl)(hydroxy)methylphosphonate
(R)-Diphenyl hydroxy(phenyl)methylphosphonate (4ed).25
Following the general procedure, compound 4ed was obtained (4eh). Following the general procedure, compound 4eh was
after 92 h of reaction at −38 °C in 82% yield (27.9 mg). The ee obtained after 90 h of reaction at −38 °C as a white solid in
of the product was determined to be 81% by HPLC using a 98% yield (35.8 mg). The ee of the product was determined
Daicel Chiralpak IC column (n-hexane–i-PrOH = 90 : 10, flow to be 85% by HPLC using a Daicel Chiralpak IA column
rate 1 mL min−1, λ = 261.2 nm): τmajor = 16.9 min; τminor
14.4 min. [α]2D8 = +21 (c 0.35, CHCl3, 79% ee).
=
(n-hexane–i-PrOH = 90 : 10, flow rate 1 mL min−1, λ = 236.4 nm):
τmajor = 31.7 min; τminor = 27.8 min. M.p. 124–126 °C. [α]D30
=
(R)-Diphenyl (4-bromophenyl)(hydroxy)methylphosphonate +51 (c 1.31, CHCl3, 82% ee). 1H NMR (400 MHz, CDCl3) δ
(4ee). Following the general procedure, compound 4ee was 7.64–7.70 (m, 4H), 7.26–7.31 (m, 4H), 7.15–7.20 (m, 2H),
obtained after 92 h of reaction at −38 °C as a white solid in 7.01–7.06 (m, 4H), 5.34 (dd, J = 5.1, 10.7 Hz, 1H), 4.52 (t, J = 6.4
72% yield (30.2 mg). The ee of the product was determined Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 150.0 (d, J = 13.4 Hz,
to be 84% by HPLC using a Daicel Chiralpak IA column 1C), 149.9 (d, J = 13.9 Hz, 1C), 140.8 (d, J = 2.4 Hz, 1C), 132.1
(n-hexane–i-PrOH = 90 : 10, flow rate 1 mL min−1, λ = 260.7 nm): (d, J = 2.9 Hz, 2C), 129.8 (d, J = 7.2 Hz, 4C), 127.9 (d, J = 5.7 Hz,
τmajor = 21.1 min; τminor = 19.3 min. M.p. 128–130 °C. [α]D23
=
2C), 125.6 (d, J = 9.8 Hz, 2C), 120.4 (d, J = 4.2 Hz, 2C), 120.4 (d,
+29 (c 0.47, CHCl3, 83% ee). 1H NMR (400 MHz, CDCl3) δ J = 4.1 Hz, 2C), 118.5 (d, J = 2.2 Hz, 1C), 112.2 (d, J = 3.8 Hz,
7.49–7.51 (m, 2H), 7.42–7.46 (m, 2H), 7.25–7.30 (m, 4H), 1C), 70.0 (d, J = 159.8 Hz, 1C). IR (KBr film) (cm−1) ν 3319,
7.13–7.19 (m, 2H), 7.06–7.08 (m, 2H), 7.01–7.03 (m, 2H), 5.25 2924, 2854, 2225, 1641, 1529, 1491, 1462, 1377, 1245, 1208,
(d, J = 9.3 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 150.2 (d, J = 1184, 1069, 940, 757, 685. HRMS (ESI+) calcd C20H16NNaO4P
10.4 Hz, 1C), 150.1 (d, J = 11.1 Hz, 1C), 134.8 (1C), 131.5 (d, J = 388.0715; found 388.0709 [M + Na].
2.6 Hz, 2C), 129.7 (d, J = 8.3 Hz, 4C), 129.0 (d, J = 6.1 Hz, 2C),
(R)-Diphenyl-1-hydroxy-3-phenylpropylphosphonate
(4ei).
125.3 (d, J = 10.4 Hz, 2C), 122.5 (d, J = 4.3 Hz, 2C), 120.5 (d, J = Following the general procedure, compound 4ei was obtained
4.6 Hz, 2C), 120.5 (d, J = 4.8 Hz, 2C), 69.9 (d, J = 161.9 Hz, 1C). after 90 h of reaction at −38 °C as a white solid in 77% yield
IR (KBr film) (cm−1) ν 3319, 2924, 2854, 1730, 1589, 1511, (28.4 mg). The ee of the product was determined to be 68% by
1487, 1462, 1403, 1377, 1242, 1212, 1189, 1163, 1101, 1070, HPLC using a Daicel Chiralpak IA column (n-hexane–i-PrOH =
1043, 1025, 1010, 942, 823, 766, 730, 689, 616, 581, 442. HRMS 90 : 10, flow rate 1 mL min−1, λ = 261.2 nm): τmajor = 13.1 min;
(ESI+) calcd C19H16BrNaO4P 440.9867; found 440.9862 τminor = 14.7 min. M.p. 108–110 °C. [α]2D5 = −6.8 (c 1.02, CHCl3,
[M + Na].
67% ee). 1H NMR (400 MHz, CDCl3) δ 7.12–7.32 (m, 15H),
(R)-Diphenyl (4-chlorophenyl)(hydroxy)methylphosphonate 4.15–4.19 (m, 1H), 3.16 (br s, 1H), 2.98–3.04 (m, 1H), 2.77–2.85
(4ef).25 Following the general procedure, compound 4ef was (m, 1H), 2.17–2.32 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 150.3
obtained after 88 h of reaction at −38 °C as a white solid in (d, J = 9.1 Hz, 1C), 150.2 (d, J = 10.0 Hz, 1C), 140.9 (1C), 129.8
80% yield (30 mg). The ee of the product was determined to be (4C), 128.6 (d, J = 13.0 Hz, 4C), 126.2 (1C), 125.3 (d, J = 5.0 Hz,
82% by HPLC using a Daicel Chiralpak IC column (n-hexane–i- 1C), 125.3 (d, J = 4.9 Hz, 1C), 120.7 (d, J = 5.9 Hz, 2C), 120.7 (d,
PrOH = 98 : 2, flow rate 1 mL min−1, λ = 261.3 nm): τmajor
=
J = 5.9 Hz, 2C), 66.8 (d, J = 160.6 Hz, 1C), 33.0 (d, J = 2.0 Hz,
12.2 min; τminor = 10.3 min. [α]2D8 = +18 (c 0.32, CHCl3, 78% ee). 1C), 31.6 (d, J = 15.0 Hz, 1C). IR (KBr film) (cm−1) ν 3338, 3062,
IR (KBr film) (cm−1) ν 3313, 2924, 2853, 1589, 1489, 1457, 3026, 2926, 2856, 2225, 1591, 1490, 1454, 1188, 1162, 1070,
1377, 1185, 1162, 1014, 759, 687.
1025, 1008, 941, 762, 689. HRMS (ESI+) calcd C21H21NaO4P
(R)-Diphenyl (3-chlorophenyl)(hydroxy)methylphosphonate 391.1075; found 391.1070 [M + Na].
(4eg). Following the general procedure, compound 4eg was
(R)-Diphenyl cyclohexyl(hydroxy)methylphosphonate (4ej).
obtained after 88 h of reaction at −38 °C as a white solid in Following the general procedure, compound 4ej was obtained
98% yield (36.7 mg). The ee of the product was determined to after 92 h of reaction at −38 °C as a white solid in 98% yield
be 80% by HPLC using a Daicel Chiralpak IC column (n- (33.9 mg). The ee of the product was determined to be 75% by
hexane–i-PrOH = 95 : 5, flow rate 1 mL min−1, λ = 272.6 nm): HPLC using a Daicel Chiralpak IA column (n-hexane–i-PrOH =
τmajor = 21.7 min; τminor = 16.5 min. M.p. 154–156 °C. [α]D28
=
95 : 5, flow rate 1 mL min−1, λ = 262.4 nm): τmajor = 22.1 min;
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τminor = 26.2 min. M.p. 100–102 °C. [α]2D6 = –3 (c 0.96, CHCl3,
69% ee). 1H NMR (400 MHz, CDCl3) δ 7.29–7.34 (m, 4H),
7.15–7.21 (m, 6H), 4.02 (q, J = 5.7, 12.8 Hz, 1H), 2.47 (dd, J =
6.5, 7.2 Hz, 1H), 2.10–2.13 (m, 1H), 1.95–2.06 (m, 1H),
1.88–1.91 (m, 1H), 1.79–1.81 (m, 2H), 1.66–1.70 (m, 1H),
1.13–1.46 (m, 5H). 13C NMR (100 MHz, CDCl3) δ 150.3 (d, J =
10.1 Hz, 1C), 150.2 (d, J = 9.8 Hz, 1C), 129.7 (d, J = 5.7 Hz, 4C),
125.2 (m, 2C), 120.6 (d, J = 4.0 Hz, 2C), 120.6 (d, J = 4.0 Hz,
2C), 72.6 (d, J = 155.1 Hz, 1C), 39.8 (d, J = 2.4 Hz, 1C), 29.9 (d,
J = 9.5 Hz, 1C), 27.9 (d, J = 7.6 Hz, 1C), 26.1 (1C), 25.9 (d, J =
17.6 Hz, 2C). IR (KBr film) (cm−1) ν 3325, 2932, 2852, 1591,
1487, 1448, 1408, 1193, 1161, 1106, 1070, 1003, 972, 935, 802,
774, 690, 661, 475. HRMS (ESI+) calcd C19H23NaO4P 369.1232;
found 369.1226 [M + Na].
3 For selected examples, see: (a) D. V. Patel, K. Rielly-Gauvin
and D. E. Ryono, Tetrahedron Lett., 1990, 31, 5587;
(b) D. V. Patel, K. Rielly-Gauvin and D. E. Ryono, Tetra-
hedron Lett., 1990, 31, 5591; (c) B. Stowasser, K.-H. Budt,
L. Jian-Qi, A. Peyman and D. Ruppert, Tetrahedron Lett.,
1992, 33, 6625; (d) J. A. Sikorski, M. J. Miller,
D. S. Braccolino, D. G. Cleary, S. D. Corey, J. L. Font,
K. J. Gruys, C. Y. Han, K. C. Lin, P. D. Pansegrau,
J. E. Ream, D. Schnur, A. Shah and M. C. Walker, Phos-
phorus, Sulfur Silicon Relat. Elem., 1993, 76, 375; (e) P. Page,
C. Blonski and J. Périé, Bioorg. Med. Chem., 1999, 7, 1403;
(f) Y. Kobayashi, A. D. William and Y. Tokoro, J. Org. Chem.,
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W. Zhong, Z. Hong and J.-L. Girardet, J. Med. Chem., 2005,
48, 2867.
(R)-Diphenyl-1-hydroxy-2,2-dimethylpropylphosphonate (4ek).
Following the general procedure, compound 4ek was obtained
after 94 h of reaction at −38 °C as a white solid in 73% yield
(23.4 mg). The ee of the product was determined to be 85% by
HPLC using a Daicel Chiralpak IA column (n-hexane–i-PrOH =
98 : 2, flow rate 1 mL min−1, λ = 262.4 nm): τmajor = 28.2 min;
τminor = 32.6 min. M.p. 116–120 °C. [α]2D5 = +7 (c 0.47, acetone,
84% ee). 1H NMR (400 MHz, CDCl3) δ 7.28–7.34 (m, 4H),
7.14–7.20 (m, 6H), 3.92 (dd, J = 6.4, 7.2 Hz, 1H), 2.59 (dd, J =
6.8, 7.8 Hz, 1H), 1.22 (s, 9H). 13C NMR (100 MHz, CDCl3) δ
150.3 (d, J = 22.2 Hz, 1C), 150.2 (d, J = 21.9 Hz, 1C), 129.7 (d,
J = 7.6 Hz, 4C), 125.2 (d, J = 3.5 Hz, 1C), 125.1 (d, J = 3.5 Hz,
1C), 120.6 (d, J = 4.0 Hz, 2C), 120.6 (d, J = 4.1 Hz, 2C), 76.3 (d,
J = 152.5 Hz, 1C), 35.0 (d, J = 3.6 Hz, 1C), 26.7 (d, J = 6.7 Hz,
3C). IR (KBr film) (cm−1) ν 3357, 2924, 2854, 1590, 1490, 1462,
1377, 1246, 1205, 1189, 1161, 1064, 945, 903, 802, 766, 690.
HRMS (ESI+) calcd C17H21NaO4P 343.1075; found 343.1070
[M + Na].
4 For selected examples, see: (a) J. G. Allen, F. R. Atherton,
M. J. Hall, C. H. Hassall, S. W. Holmes, R. W. Lambert,
L. J. Nisbet and P. S. Ringrose, Antimicrob. Agents Che-
mother., 1979, 15, 684; (b) F. R. Atherton, M. J. Hall,
C. H. Hassall, R. W. Lambert, W. J. Lloyd and
P. S. Ringrose, Antimicrob. Agents Chemother., 1979, 15, 696;
(c) D. V. Patel, K. Rielly-Gauvin, D. E. Ryono, C. A. Free,
W. L. Rogers, S. A. Smith, J. M. DeForrest, R. S. Oehl and
E. W. Petrillo Jr., J. Med. Chem., 1995, 38, 4557;
(d) Aminophosponic and aminophosphinic acids: Chemistry
and Biological Activity, ed. V. P. Kukhar and H. R. Hudson,
Wiley, Chichester, 2000; (e) J. Huang and R. Chen, Heteroat.
Chem., 2000, 11, 480.
5 For the pioneering enantioselective hydrophosphonylation
of aldehydes using metal catalysts, see: (a) T. Arai,
M. Bougauchi, H. Sasai and M. Shibasaki, J. Org. Chem.,
1996, 61, 2926; (b) H. Sasai, M. Bougauchi, T. Arai and
M. Shibasaki, Tetrahedron Lett., 1997, 38, 2717.
6 For additional remarkable examples of metal catalysed-
hydrophosphonylation reaction of aldehydes, see also:
(a) D. M. Cermak, Y. Du and D. F. Weimer, J. Org. Chem.,
1999, 64, 388; (b) J. P. Duxbury, J. N. D. Warne, R. Mushtaq,
C. Ward, M. Thornton-Pett, M. Jiang, R. Greatrex and
T. P. Kee, Organometallics, 2000, 19, 4445; (c) B. Saito and
T. Katsuki, Angew. Chem., Int. Ed., 2005, 44, 4600;
(d) B. Saito, H. Egami and T. Katsuki, J. Am. Chem. Soc.,
2007, 129, 1978; (e) X. Zhou, X. Liu, X. Yang, D. Shang,
J. Xin and X. Feng, Angew. Chem., Int. Ed., 2008, 47, 392;
(f) J. P. Abell and H. Yamamoto, J. Am. Chem. Soc., 2008,
130, 10521; (g) F. Yang, D. Zhao, J. Lan, P. Xi, L. Yang,
S. Xiang and J. You, Angew. Chem., Int. Ed., 2008, 47, 5646;
(h) K. Suyama, Y. Sakai, K. Matsumoto, B. Saito and
T. Katsuki, Angew. Chem., Int. Ed., 2010, 49, 797;
(i) P. Muthupandi and G. Sekar, Org. Biomol. Chem., 2012,
10, 5347.
Acknowledgements
We thank the Spanish Ministry of Economía y Competitividad
(MEC CTQ2010-19606 and CTQ2011-27593) and the Govern-
ment of Aragón (Zaragoza, Spain Research Group E-10) for
financial support of our research. P. J. S. M. acknowledges
funding through the “Ramón y Cajal” program (MEC).
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