Thiophostone-derived Bronsted acids in the organocatalyzed transfer hydrogenation of quinolines: Influence of the P-stereogenicity

Article abstract of DOI:10.1002/ejoc.201301253

A new approach to Bronsted acid organocatalysis is described and is based on the use of thiophosphonic acids possessing both a chiral backbone and a chiral phosphorus function. The influence of the phosphorus stereochemistry on the enantioselectivity prov

Full text of DOI:10.1002/ejoc.201301253

FULL PAPER
DOI: 10.1002/ejoc.201301253
Thiophostone-Derived Brønsted Acids in the Organocatalyzed Transfer
Hydrogenation of Quinolines: Influence of the P-Stereogenicity
Angélique Ferry,[a][‡] Jérémy Stemper,[a][‡] Angela Marinetti,[a] Arnaud Voituriez,*[a] and
Xavier Guinchard*[a]
Keywords: Chirality / Phosphorus / Organocatalysis / Heterocycles / Brønsted acids
A new approach to Brønsted acid organocatalysis is de-
scribed and is based on the use of thiophosphonic acids pos-
sessing both a chiral backbone and a chiral phosphorus func-
tion. The influence of the phosphorus stereochemistry on the
enantioselectivity proved to be crucial in the hydrogen trans-
fer hydrogenation of 2-phenylquinoline with Hantzsch es-
ters.
Introduction
Over the past few years, catalysis by chiral Brønsted
acids has been the subject of much interest.[1] Among this
class of organocatalysts, the most used are cyclic phos-
phoric acids[2] derived from chiral diols such as 1,1Ј-bi-
naphthol (BINOL),[3] 2,2Ј-diphenyl-(3,3Ј-biphenanthrene)-
4,4Ј-diol (VAPOL),[4] tetraaryl-1,3-dioxolane-4,5-dimeth-
anol (TADDOL),[5] 1,1Ј-spirobiindane-7,7Ј-diol (SPINOL),[6]
and others.[7] Alternatively, acid derivatives with other PV
functions have also been used, such as dithiophosphoric
acid or N-triflylphosphoramide derivatives (Figure 1a).[8]
Although all these catalysts have demonstrated their effi-
ciency in many organocatalytic reactions, to the best of our
knowledge, neither phosphonic or thiophosphonic acids
nor P-chiral derivatives[9] have been used in Brønsted acid
catalysis. This work intends to afford a first insight into this
field.
In the course of the synthesis of new glycomimetics, we
recently described the synthesis of various PV phostone[10]
derivatives from tri-O-benzyl-d-glucal. They display either
a phosphonate or thiophosphonate function and a stereo-
genic phosphorus atom at the pseudoanomeric position.[11]
We envisioned that these thiophostone scaffolds might be
good precursors for the synthesis of P-chiral, acidic organ-
ocatalysts with C1 symmetry (Figure 1b). In this paper, we
Figure 1. Classical approach (left) and our approach (right) to chi-
ral Brønsted acid catalysts.
2-phenylquinoline, and the influence of the stereochemistry
of the phosphorus atom on these reactions.
Results and Discussion
The synthesis of various stereoisomers of P-chiral thio-
phosphonic acids with a phostone scaffold is shown in
Scheme 1. Four α- or β-configured[12] thiophostones 1a–4
in both gluco and manno series were prepared as previously
reported[11] and then converted into the corresponding thio-
phosphonic acids 5a–8. Initially, classical conditions for the
removal of a methyl group from PV derivatives were ap-
plied. These conditions involve the use of bromotrimethyl-
silane (TMSBr)[10g,10f] or sodium iodide in acetonitrile at
reflux[10c,10f] and either left the starting material unchanged
or led to degradation. The use of diisopropylamine or, pref-
erably, trimethylamine[13] led to the targeted thio-
phosphonic acids in excellent yields. Such species can exist
in two tautomeric forms, namely, the thiono and thiolo
forms; however, this equilibrium usually lies far on the
thiono side.[14] In the case of 5a–8, the NMR spectroscopic
data are diagnostic of their structures: the 31P NMR shifts
in the δ = 69–81 ppm range and the absence of 31P NMR
signals in the δ = 45–55 ppm region, characteristic of the
thiolo form,[15] confirm the prevalence of the thiono form
wish
to
report
on
the
synthesis
of
thio-
phostone-derived P-chiral thiophosphonic acids, the reac-
tivity of these new species in the transfer hydrogenation of
[a] Centre de Recherche de Gif, Institut de Chimie des Substances
Naturelles, CNRS,
1 Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
E-mail: arnaud.voituriez@cnrs.fr
xavier.guinchard@cnrs.fr
http://www.icsn.cnrs-gif.fr/
[‡] These authors contributed equally.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301253.
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Organocatalyzed Transfer Hydrogenation of Quinolines
and thereby the presence of an OH function. The chemical glucose- and mannose-derived catalysts 7a and 8, which
shift for the β diastereoisomers is higher than for the corre- possess α configuration at the phosphorus atom, did not
sponding α isomers, in accordance with previous observa- induce any stereoselectivity (0 and 2% ee, respectively). On
tions.[10f,11] From the above NMR spectroscopic data, the the other hand, both β-configured catalysts 5a and 6 in-
methyl removal was demonstrated to be stereoretentive.
duced significant stereoselectivities and gave (R)-2-phenyl-
tetrahydroquinoline in 40 and 24% ee, respectively. The
gluco-like diastereoisomer 5a proved superior to the manno-
like diastereoisomer 6.
To afford additional evidence for the crucial effect of the
P-stereogenicity on the stereochemical outcome of the reac-
tion, we compared the enantioselectivities obtained with
thioacids 5–8 with those of the two phosphonic acids 12
and 14a. The gluco- and manno-type phosphonic acids 12
and 14a were both obtained in 92% yield from the known
phostones 11 and 13a,[21] respectively, by reaction with
bromotrimethylsilane (Scheme 3).[22,10g]
Scheme 1. Preparation of 2-OAc thiophosphonic acids derived
from thiophostones.
With these new acids in hand, we selected the Brønsted
acid catalyzed transfer hydrogenation of quinolines as a
benchmark reaction for the evaluation of their reactivity. Scheme 3. Preparation of phosphonic acids from phostones.
The reduction of quinolines is a very efficient way to syn-
The H-transfer reduction in Scheme 2 was attempted
thesize 1,2,3,4-tetrahydroquinoline derivatives, which are
with phosphonic acids 12 and 14a as catalysts,[23] and the
important synthetic intermediates[16] and building blocks
reactions proceeded in high yields but with low enantio-
for biologically active compounds.[17] For this transforma-
selectivity levels, irrespective of the stereochemistry of the
tion, the enantioselective metal-catalyzed hydrogenation of
2-substituted quinoline derivatives was initially envi-
chiral scaffold (gluco or manno; 12: 14% ee, 14a: 7% ee, see
Supporting Information for full experimental data). These
sioned.[18] An alternative strategy was then developed in
preliminary results suggest a key role of the P configura-
2006 by Rueping.[19] This strategy is based on the combined
tion, that is, the relative configuration of the phosphorus
use of a chiral Brønsted acid catalyst and Hantzsch esters
centre with respect to the chiral scaffold, in the stereochemi-
as the reducing agents.[20] In our work, the reduction of 2-
cal control of these reactions.
phenylquinoline (9) has been undertaken under the condi-
As the β-gluco scaffold produced the highest ee values,
tions developed by Rueping with thiophosphonic acids 5a–
thiophosphonic acids 5 were selected as the best candidates
8 as the catalysts (Scheme 2).
for further studies. Their acetyl function was replaced by
various protecting groups to determine the possible influ-
ence of the protecting group as well as to optimize the
enantioselectivity levels.
Thiophostone 1a was deacetylated in 64% yield by
MeOH in the presence of K2CO3,[25] and the resulting
alcohol 1b was protected with various protecting groups in
usually good yields (Scheme 4).[26] The methyl groups of
thioesters 1b–f were removed with trimethylamine[13] to
provide the requisite β-gluco-configured thiophosphonic ac-
ids 5b–f in excellent yields. Once again, thioacids 5 were
obtained as single diastereomers in their thiono tautomeric
forms. These catalysts were evaluated in the test reaction of
transfer hydrogenation of 9 (selected results are displayed
in Table 1, see Supporting Information for full data).
Scheme 2. Preliminary catalytic tests: H-transfer reduction of 2-
As mentioned before, thiophosphonic acid 5a afforded
phenylquinoline.
40% ee (Table 1, Entry 1). The reduction of 2-phenylquinol-
We were pleased to find that the conversion rates to the ine at 60 °C with the ethyl Hantzsch ester in the presence
desired hydrogenated product 10 were good to excellent, of the unprotected acid 5b (R1 = H) proceeded efficiently
which proves that the thiophosphonic acid function is but without any enantioselectivity (Table 1, Entry 2). The
acidic enough to catalyze the reaction efficiently. Both the replacement of the acetate group by a 3-methylbutanoate
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189

A. Ferry, J. Stemper, A. Marinetti, A. Voituriez, X. Guinchard
FULL PAPER
vent at room temperature with 2.0 equiv. of Hantzsch ester.
An 82% yield and a 68% ee were obtained (Table 1, En-
try 14).[28] Decreasing the temperature to –4 °C did not im-
prove the enantioselectivity (Table 1, Entry 13). Finally, for
comparison purposes, the optimized conditions were as-
sayed with catalyst 7f, which possesses an axial OH func-
tion.[29] This experiment resulted in a very low 5% ee
(Table 1, Entry 15). This last result clearly demonstrates the
strong influence of the phosphorus stereochemistry on the
enantioselectivity of these reactions.
The (R) stereochemistry of the final product 10 suggests
the transition state shown in Scheme 5 for these reactions.
The stereogenic (S)-configured phosphorus atom imposes a
syn relationship between the P=S bond and the OPiv group.
From this arrangement, both the P=S and C=O function
might interact with the Hantzsch ester through H bond-
ing.[30] The approach and positioning of 2-phenylquinoline
would then be directed by a H bond between the acidic
proton and the basic nitrogen centre, which would allow
asymmetric hydride transfer from the Si face and finally
lead to (R)-2-phenyltetrahydroquinoline (10).
Scheme 4. Preparation of various O-protected thiophosphonic
acids in the gluco series. Conditions: [a] ClC(O)iBu, 4-(dimeth-
ylamino)pyridine (DMAP), dichloromethane (DCM), room temp.,
3 h. [b] Sodium hexamethyldisilazide (NaHMDS), THF, room
temp., then CS2, MeI, room temp., 1 h.[24a] [c] tBuNCO, trimethyl-
silyl chloride (TMSCl), DCM, room temp., 16 h.[24b] [d] Pivalic an-
hydride (Piv2O), Sc(OTf)3 (0.5 mol-%), MeCN, room temp.,
2.5 h.[24c]
Table 1. Transfer hydrogenation of 2-phenylquinoline.[a]
Entry Catalyst
R2
Solvent T [°C] Yield [%] ee [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14[b]
15
5a
5b
5c
5d
5e
5f
5f
5f
5f
5f
5f
5f
5f
5f
7f
Et
Et
Et
Et
Et
Et
Me
tBu
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
60
60
60
60
60
60
60
60
60
22
60
22
–4
22
22
80
83
62
73
67
86
90
89
89
99
97
97
80
82
98
40
1
38
40
41
52
45
59
65
66
55
67
62
68
5
Scheme 5. Proposed transition state.
Conclusions
tBu cC6H12
tBu
tBu
tBu
tBu
tBu
tBu
Et2O
We have described the stereoselective synthesis of P-
chiral thiophosphonic acids with a sugarlike scaffold. We
have shown that these acids are good catalysts for the trans-
fer hydrogenation of 2-phenylquinoline. The influence of
the P-stereochemistry on the stereochemical outcome of
this reaction has been demonstrated. These results open the
way to new approaches in the field of organocatalysis with
P-chiral Brønsted acids.
CPME
CPME
CPME
CPME
CPME
[a] General reaction conditions: 2.4 equiv. Hantzsch ester, 10 mol-
% catalyst, 0.05 m. CPME = cyclopentyl methyl ether. [b] 2.0 equiv.
Hantzsch ester.
(catalyst 5c), xanthate (catalyst 5d), or carbamate group
(catalyst 5e) did not improve the enantioinduction (Table 1,
Entries 3–5). However, the pivaloyl (Piv) protecting group
(Table 1, Entry 6) resulted in an increase in the ee to 52%.
In a second series of experiments, the influence of the
ester groups of the Hantzsch reductant[27] was demon-
strated by comparing the ee values obtained with methyl
and tert-butyl esters with 5f as the catalyst (Table 1, En-
tries 7–8). The product was obtained in 45 and 59% ee,
respectively.
Experimental Section
General: Reactions were performed by using oven-dried glassware
under argon. All separations were performed under flash-chroma-
tographic conditions on silica gel (Redi Sep prepacked column,
230–400 mesh) at medium pressure (20 psi) with the use of a Com-
biFlash Companion chromatography system. Reactions were moni-
tored by thin-layer chromatography on Merck silica gel plates
(60 F254 aluminum sheets), which were rendered visible by ultravio-
let light and/or spraying with vanillin (15%) and sulfuric acid
(2.5%) in EtOH followed by heating. Tetrahydrofuran (THF),
CH2Cl2, N,N-dimethylformamide (DMF), MeOH, and methyl tert-
butyl ether (MTBE) were purchased from Acros Organics at the
highest commercial quality and used without further purification.
The effect of the solvent was also evaluated, and cyclo-
hexane and diethyl ether furnish comparable, improved ee
values of 65–66% (Table 1, Entries 9–10). The best result
was then obtained with cyclopentyl methyl ether as the sol- Reagent-grade chemicals were obtained from diverse commercial
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Organocatalyzed Transfer Hydrogenation of Quinolines
suppliers (Sigma–Aldrich, Acros Organics, TCI, and Alfa-Aesar)
and were used as received. 1H (500 or 300 MHz), 13C (125 or
75 MHz), and 31P NMR Spectra (122 or 202 MHz) were recorded
with Bruker Avance spectrometers at 298 K. Chemical shifts (δ) are
given in ppm and are referenced to the internal solvent signal or
to tetramethylsilane (TMS) used as an internal standard. Multi-
plicities are declared as follow: s (singlet), br. s (broad singlet), d
(doublet), t (triplet), q (quadruplet), dd (doublet of doublets), ddd
(doublet of doublet of doublets), dt (doublet of triplets), m (mul-
tiplet). Coupling constants J are given in Hz. Carbon multiplicities
were determined by DEPT-135 experiments. Diagnostic corre-
lations were obtained by two-dimensional COSY and heteronuclear
single quantum coherence (HSQC) experiments. Infrared spectra
(IR) were recorded with a Perkin–Elmer FTIR system with a dia-
mond window Dura SamplIR II attenuated total reflectance (ATR)
accessory, and the data are reported in reciprocal centimeters
(cm–1). Optical rotations were measured with an Anton Paar MCP
300 polarimeter at 589 nm. [α]TD°C is expressed in °cm3 g–1 dm–1,
and c is expressed in g/100 cm3. Melting points were determined in
open capillary tubes with a Büchi B-540 apparatus. High-resolution
mass spectra (HRMS) were recorded with a Micromass LCT Prem-
ier XE instrument (Waters) and were determined by electrospray
ionization (ESI).
(300 MHz, CDCl3): δ = 7.36–7.23 (m, 13 H, Har), 7.16–7.10 (m, 2
H, Har), 4.87 (s, 2 H, CH2Ph), 4.85 (d, J = 10.7 Hz, 1 H, CH2Ph),
4.61 (d, J = 11.9 Hz, 1 H, CH2Ph), 4.57 (d, J = 10.5 Hz, 1 H,
CH2Ph), 4.52 (d, J = 11.9 Hz, 1 H, CH2Ph), 4.18–4.10 (m, 1 H, 5-
H), 4.01 (d, J = 9.6 Hz, 1 H, 2-H), 3.90 (dd, J = 9.2 and 2.3 Hz, 1
H, 3-H), 3.88–3.70 (m, 3 H, 4-H and 6-H), 3.82 (d, J = 13.0 Hz, 3
H, OMe) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.3 (Cq, Car),
137.9 (Cq, Car), 137.8 (Cq, Car), 128.8 (2 CH, Car), 128.7 (2 CH,
Car), 128.6 (3 CH, Car), 128.2 (CH, Car), 128.1 (CH, Car), 128.1 (4
CH, Car), 128.1 (CH, Car), 128.0 (CH, Car), 83.8 (d, J = 4.4 Hz,
CH, C3), 77.9 (d, J = 8.2 Hz, CH, C5), 77.6 (CH, C-4), 76.4
(CH2Ph), 75.8 (CH2Ph), 75.5 (d, J = 111.4 Hz, CH, C-2),73.9
(CH2Ph), 68.9 (d, J = 9.9 Hz, CH2, C-6), 54.0 (d, J = 7.7 Hz, CH3,
OMe) ppm. 31P{1H} NMR (122 MHz, CDCl3): δ = 85.7 ppm.
HRMS (ESI-TOF): calcd. for C27H32O6PS [M + H]+ 515.1657;
found 515.1649.
(2S,3S,4S,5S,6R)-4,5-Bis(benzyloxy)-6-[(benzyloxy)methyl]-2-meth-
oxy-2-sulfido-1,2-oxaphosphinan-3-yl Pivalate (1f): To a solution of
1b (830 mg, 0.16 mmol) in acetonitrile (20 mL) were added pivalic
anhydride (1.96 mL, 0.8 mmol, 5 equiv.) and scandium trifluoro-
methanesulfonate (40 mg, 0.008 mmol, 0.5 mol-%) dissolved in ace-
tonitrile (2 mL). The resulting mixture was stirred at room temp.
for 2.5 h. The reaction was then quenched with a saturated solution
of NaHCO3. The two layers were separated, and the aqueous layer
was reextracted twice with dichloromethane. The combined organic
(2S,3S,4S,5S,6R)-4,5-Bis(benzyloxy)-6-[(benzyloxy)methyl]-3-
hydroxy-2-methoxy-1,2-oxaphosphinane 2-Sulfide (1b): To a solu-
tion of 1a (800 mg, 1.44 mmol) in MeOH (20 mL) was added layers were dried, filtered, and concentrated. The crude product
K2CO3 (476 mg, 1.73 mmol, 1.2 equiv.). The resulting mixture was
stirred at room temp. for 2 h and then quenched with a saturated
solution of NH4Cl. The two layers were separated, and the aqueous
layer was reextracted twice with MTBE. The combined organic lay-
ers were dried with MgSO4, filtered, and concentrated. The crude
product was purified on silica gel (eluent: EtOAc/heptane, 1:3) to
yield 1b as a colorless oil (470 mg, 0.91 mmol, 64%). [α]2D2 = +61.8
was purified on silica gel (eluent: EtOAc/heptane, 1:5) to yield 1f
as a colorless oil (634.5 mg, 0.106 mmol, 66%). Rf = 0.53 (EtOAc/
heptane, 1:4). [α]2D0 = +79.9 (c = 1.5, CHCl ). IR (neat): ν
=
˜
3
max
3030, 2955, 2930, 2870, 1738, 1454, 1130, 1089, 1043, 1028, 970,
850, 815, 736, 698 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.29–
7.10 (m, 13 H, Har), 7.07–6.98 (m, 2 H, Har), 5.24 (dd, J = 10.0
and 9.4 Hz, 1 H, 2-H), 4.74 (d, J = 11.1 Hz, 1 H, CH2Ph), 4.70 (d,
(c = 0.8, CHCl ). IR (neat): ν
= 3443, 3062, 3031, 2916, 2868, J = 10.9 Hz, 1 H, CH2Ph), 4.68 (d, J = 10.9 Hz, 1 H, CH2Ph), 4.55
˜
3
max
1497, 1454, 1360, 1136, 1107, 1038, 1026, 965, 840, 808, 734, (d, J = 12.1 Hz, 1 H, CH2Ph), 4.48 (d, J = 10.7 Hz, 1 H, CH2Ph),
696 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.38–7.22 (m, 13 H,
Har), 7.19–7.09 (m, 2 H, Har), 4.92 (d, J = 11.1 Hz, 1 H, CH2Ph),
4.84 (d, J = 10.7 Hz, 1 H, CH2Ph), 4.83 (d, J = 10.9 Hz, 1 H,
4.44 (d, J = 12.1 Hz, 1 H, CH2Ph), 4.31–4.20 (m, 1 H, 5-H), 4.02
(td, J = 9.4 and 3.2 Hz, 1 H, 3-H), 3.86 (t, J = 9.4 Hz, 1 H, 4-H),
3.80 (td, J = 11.0 and 3.0 Hz, 1 H, 6-H), 3.72 (d, J = 13.9 Hz, 3
CH2Ph), 4.61 (d, J = 12.1 Hz, 1 H, CH2Ph), 4.56 (d, J = 10.7 Hz, H, OMe), 3.66 (dd, J = 11.3 and 2.1 Hz, 1 H, 6-H), 1.15 (s, 9 H,
1 H, CH2Ph), 4.51 (d, J = 12.1 Hz, 1 H, CH2Ph), 4.34–4.24 (m, 1
Piv) ppm. 13C NMR (75 MHz, CDCl3): δ = 177.3 (Cq, C=O), 138.1
H, 5-H), 4.02–3.92 (m, 1 H, 2-H), 3.91–3.78 (m, 3 H, 3-H, 4-H, (Cq, Car), 137.9 (Cq, Car), 137.9 (Cq, Car), 128.6 (2 CH, Car), 128.6
and 6-H), 3.85 (d, J = 13.9 Hz, 3 H, OMe), 3.73 (dd, J = 11.1 and
(2 CH, Car), 128.6 (2 CH, Car), 128.0 (4 CH, Car), 128.0 (2 CH,
Car), 127.9 (CH, Car), 127.4 (2 CH, Car), 82.4 (d, J = 13.2 Hz, CH,
2.1 Hz, 1 H, 6-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.3
(Cq, Car), 137.9 (Cq, Car), 137.8 (Cq, Car), 128.7 (2 CH, Car), 128.6 C-3), 77.9 (CH, C-4), 76.2 (CH2Ph), 75.7 (CH, C-5), 75.6 (CH2Ph),
(2 CH, Car), 128.6 (2 CH, Car), 128.2 (2 CH, Car), 128.1 (CH, Car),
73.7 (CH2Ph), 72.5 (d, J = 109.2 Hz, CH, C-2), 68.4 (d, J =
11.0 Hz, CH2, C-6), 54.2 (d, J = 6.0 Hz, CH3, OMe), 39.0 (Cq, Piv),
128.0 (4 CH, Car), 128.0 (2 CH, Car), 85.4 (d, J = 17.0 Hz, CH, C-
3), 77.3 (CH, C-4), 76.4 (CH2Ph), 75.9 (d, J = 2.2 Hz, CH, C-5), 27.3 (3 CH3, Piv) ppm. 31P{1H} NMR (122 MHz, CDCl3): δ =
75.6 (CH2Ph), 73.7 (CH2Ph), 72.8 (d, J = 103.2 Hz, CH, C-2), 68.4
(d, J = 11.0 Hz, CH2, C-6), 54.2 (d, J = 6.6 Hz, CH3, OMe) ppm.
31P{1H} NMR (122 MHz, CDCl3): δ = 96.2 ppm. HRMS (ESI-
TOF): calcd. for C27H32O6PS [M + H]+ 515.1657; found 515.1685.
88.9 ppm. HRMS (ESI-TOF): calcd. for C32H40O7PS [M + H]+
599.2232; found 599.2239.
(2R,3S,4S,5S,6R)-4,5-Bis(benzyloxy)-6-[(benzyloxy)methyl]-2-meth-
oxy-2-sulfido-1,2-oxaphosphinan-3-yl Pivalate (3f): To a solution of
(2R,3S,4S,5S,6R)-4,5-Bis(benzyloxy)-6-[(benzyloxy)methyl]-3- 3b (141 mg, 0.275 mmol) in acetonitrile (2.4 mL) were added pivalic
hydroxy-2-methoxy-1,2-oxaphosphinane 2-Sulfide (3b): To a solu- anhydride (0.33 mL, 1.38 mmol, 5 equiv.) and a solution of scan-
tion of 3a (60 mg, 0.11 mmol) in MeOH (1 mL) was added K2CO3 dium trifluoromethanesulfonate (6.8 mg, 0.014 mmol, 5 mol-%) in
(60 mg, 0.43 mmol, 4 equiv.). The resulting mixture was stirred at
room temp. for 1 h and then quenched with a solution of HCl (2 n
in H2O). The two layers were separated, and the aqueous layer was
reextracted twice with EtOAc. The combined organic layers were
dried with MgSO4, filtered, and concentrated. The crude mixture
was purified on silica gel (eluent: EtOAc/heptane, 1:3) to yield 3b
as a colorless oil (48 mg, 0.093 mmol, 85%). [α]2D2 = +55.1 (c = 0.9,
acetonitrile (1 mL). The resulting mixture was stirred at room temp.
for 1 h. The reaction was quenched with a saturated solution of
NaHCO3. The aqueous layer was reextracted twice with CH2Cl2.
The combined organic layers were dried, filtered, and concentrated.
The crude product was purified on silica gel (eluent: EtOAc/hept-
ane, 20:80) to yield 3f as a colorless oil (93.5 mg, 0.157 mmol,
57%). Rf = 0.43 (EtOAc/heptane, 1:1). [α]2D3 = +59.1 (c = 0.8,
CHCl ). IR (neat): νmax = 3418, 3063, 3031, 2924, 2868, 1497, 1454, CHCl ). IR (neat): νmax = 3031, 2972, 2933, 2870, 1746, 1455, 1363,
˜
˜
3
3
1361, 1136, 1137, 1041, 1026, 967, 796, 736, 697 cm–1. 1H NMR
1147, 1124, 1096, 1045, 1028, 987, 973, 806, 737, 698 cm–1
.
1H
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A. Ferry, J. Stemper, A. Marinetti, A. Voituriez, X. Guinchard
FULL PAPER
NMR (300 MHz, CDCl3): δ = 7.38–7.19 (m, 13 H, Har), 7.13–7.05 J = 11.1 Hz, 1 H, CH2Ph), 4.63 (d, J = 12.8 Hz, 1 H, CH2Ph), 4.53
(m, 2 H, Har), 5.61 (dd, J = 10.0 and 2.8 Hz, 1 H, 2-H), 4.80 (d, J (d, J = 12.4 Hz, 1 H, CH2Ph), 4.40 (d, J = 10.5 Hz, 1 H, CH2Ph),
= 11.1 Hz, 1 H, CH2Ph), 4.77 (d, J = 10.5 Hz, 1 H, CH2Ph), 4.70 4.30–4.20 (m, 1 H, 5-H), 3.96 (td, J = 10.0 and 2.4 Hz, 1 H, 3-H),
(d, J = 11.1 Hz, 1 H, CH2Ph), 4.64 (d, J = 12.1 Hz, 1 H, CH2Ph), 3.76–3.65 (m, 2 H, 4-H and 6-H), 3.64–3.55 (m, 1 H, 6-H), 1.14 (s,
4.55 (d, J = 10.5 Hz, 1 H, CH2Ph), 4.54 (d, J = 12.1 Hz, 1 H,
CH2Ph), 4.24–4.16 (m, 1 H, 5-H), 4.04–3.90 (m, 2 H, 3-H and 4-
H), 3.87–3.80 (m, 1 H, 6-H), 3.85 (d, J = 13.4 Hz, 3 H, OMe), 3.76
(dd, J = 11.1 and 1.3 Hz, 1 H, 6-H), 1.22 (s, 9 H, Piv) ppm. 13C
9 H, Piv) ppm. 13C NMR (75 MHz, CDCl3): δ = 177.0 (d, J =
3.3 Hz, Cq, C=O Piv), 137.9 (Cq, Car), 137.3 (Cq, Car), 137.0 (Cq,
Car), 128.7 (2 CH, Car), 128.7 (2 CH, Car), 128.6 (2 CH, Car), 128.4
(2 CH, Car), 128.4 (2 CH, Car), 128.3 (CH, Car), 128.3 (CH, Car),
NMR (75 MHz, CDCl3): δ = 176.5 (d, J = 3.8 Hz, Cq, C=O Piv), 127.9 (CH, Car), 127.4 (2 CH, Car), 82.2 (d, J = 4.9 Hz, CH, C-3),
137.9 (Cq, Car), 137.8 (Cq, Car), 137.7 (Cq, Car), 128.6 (3 CH, Car), 78.2 (CH, C-4), 77.4 (d, J = 8.8 Hz, CH, C-5), 76.0 (CH2Ph), 75.9
128.6 (2 CH, Car), 128.1 (4 CH, Car), 128.1 (2 CH, Car), 128.0 (CH, (CH2Ph), 73.8 (CH2Ph), 73.0 (d, J = 112.5 Hz, CH, C-2), 69.1 (d,
Car), 127.9 (CH, Car), 127.3 (2 CH, Car), 82.2 (d, J = 4.9 Hz, CH, J = 9.9 Hz, CH2, C-6), 39.1 (Cq, Piv), 27.3 (3 CH3, Piv) ppm.
C-3), 78.0 (d, J = 8.8 Hz, CH, C-5), 77.9 (CH, C-4), 76.0 (CH2Ph),
75.8 (CH2Ph), 73.8 (CH2Ph), 73.3 (d, J = 113.6 Hz, CH, C-2), 68.8
31P{1H} NMR (122 MHz, CDCl3): δ = 74.3 ppm. HRMS (ESI-
TOF): calcd. for C31H41NO7PS [M + NH4]+ 602.2341; found
(d, J = 9.9 Hz, CH2, C-6), 53.9 (d, J = 6.6 Hz, CH3, OMe), 39.1 602.2324.
(Cq, Piv), 27.3 (3 CH3, Piv) ppm. 31P{1H} NMR (122 MHz,
General Procedure for the Asymmetric Hydrogenation of 2-Phenyl-
CDCl3): δ = 80.7 ppm. HRMS (ESI-TOF): calcd. for C32H40O7PS
quinoline: A solution of 2-phenylquinoline (20.5 mg, 0.1 mmol),
Hantzsch ester (0.24 mmol, 2.4 equiv.), and the catalyst
(0.01 mmol, 10 mol-%) in toluene (2 mL) was stirred at room temp.
for 90 min. The solvent was evaporated in vacuo, and the residue
was purified on silica gel (eluent: toluene). 2-Phenyl-1,2,3,4-tetra-
[M + H]+ 599.2232; found 599.2261.
General Procedure for the Demethylation of Thiophosphonate Esters
to Thiophosphonic Acids: To a solution of thiophostone in toluene
was added Me3N at –78 °C. The resulting mixture was stirred at
50 °C for 3 h. The mixture was cooled to room temp. and the reac-
tion quenched with 1 n aqueous HCl. The two layers were sepa-
rated, and the aqueous layer was reextracted twice with EtOAc.
The combined organic layers were dried with MgSO4, filtered, and
concentrated to yield the pure thiophosphonic acid.
hydroquinoline was obtained as
a
colorless oil. 1H NMR
(500 MHz, CDCl3): δ = 7.45–7.34 (m, 4 H), 7.31 (t, J = 7.5 Hz, 1
H), 7.07–6.98 (m, 2 H), 6.68 (t, J = 7.5 Hz, 1 H), 6.57 (d, J =
8.0 Hz, 1 H), 4.46 (dd, J = 9.5, 3.3 Hz, 1 H), 4.10 (br. s, 1 H), 3.00–
2.88 (m, 1 H), 2.80–2.70 (m, 1 H), 2.21–2.10 (m, 1 H), 2.08–1.95
(m, 1 H) ppm. Chiral HPLC analysis: [CHIRALPAK® IB, 30 °C,
5% iPrOH/n-heptane, 1 mL/min, 250 nm, retention times: 6.8 min
(minor) and 8.6 min (major)]. [α]2D0 = +23 (c = 1.8, CHCl3; 68%
ee) {lit.: [α]2D0 = –37.7 (c = 1.1, CHCl3) for (S)-2-phenyl-1,2,3,4-
tetrahydroquinoline (97% ee),[19b] [α]2D0 = –34.8 (c = 1.1, CHCl3)
for (S)-2-phenyl-1,2,3,4-tetrahydroquinoline (96% ee)]}.[7a]
(2S,3S,4S,5S,6R)-4,5-Bis(benzyloxy)-6-[(benzyloxy)methyl]-2-
hydroxy-2-sulfido-1,2-oxaphosphinan-3-yl Pivalate (5f): Compound
5f was synthesized according to the general procedure by reaction
of 1f (25 mg, 0.042 mmol) in toluene (0.5 mL) and trimethylamine
(0.5 mL). Compound 5f was obtained as a colorless oil (22 mg,
0.038 mmol, 90%). [α]2D3 = +70.2 (c = 0.7, CHCl ). IR (neat): ν
˜
3
max
Supporting Information (see footnote on the first page of this arti-
= 2969, 2922, 2873, 1736, 1497, 1480, 1455, 1363, 1277, 1142, 1058,
989, 829, 742, 699 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.28–
7.15 (m, 13 H, Har), 7.07–7.00 (m, 2 H, Har), 4.91 (dd, J = 9.8 and
7.6 Hz, 1 H, 2-H), 4.75 (s, 2 H, CH2Ph), 4.72 (d, J = 11.0 Hz, 1 H,
CH2Ph), 4.56 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.48 (d, J = 11.0 Hz,
1 H, CH2Ph), 4.43 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.32–4.16 (br. s,
1 H, OH), 4.29–4.22 (m, 1 H, 5-H), 4.02 (td, J = 9.8 and 2.5 Hz,
1 H, 3-H), 3.85 (t, J = 9.8 Hz, 1 H, 4-H), 3.79 (dt, J = 11.0 and
2.5 Hz, 1 H, 6-H), 3.70 (dd, J = 11.0 and 1.3 Hz, 1 H, 6-H), 1.18
(s, 9 H, Piv) ppm. 13C NMR (125 MHz, CDCl3): δ = 179.8 (d, J =
1.8 Hz, Cq, Piv), 138.1 (Cq, Car), 137.9 (Cq, Car), 137.6 (Cq, Car),
128.7 (2 CH, Car), 128.6 (2 CH, Car), 128.6 (2 CH, Car), 128.2 (2
CH, Car), 128.2 (CH, Car), 128.1 (CH, Car), 128.0 (CH, Car), 127.9
(2 CH, Car), 127.6 (2 CH, Car), 82.3 (d, J = 10.1 Hz, CH, C-3),
77.6 (CH, C-4), 76.4 (CH2Ph), 76.1 (d, J = 98.1 Hz, CH, C-2), 75.6
(CH2Ph), 75.4 (d, J = 1.8 Hz, CH, C-5), 73.8 (CH2Ph), 68.4 (d, J
= 11.0 Hz, CH2, C-6), 39.1 (Cq, Piv), 27.4 (3 CH3, Piv) ppm.
31P{1H} NMR (202 MHz, CDCl3): δ = 82.7 ppm. HRMS (ESI-
TOF): calcd. for C31H36O7PS [M – H]– 583.1919; found 583.1926.
cle): Full experimental details and copies of 1H and 13C NMR spec-
tra.
Acknowledgments
A. F. thanks the Institut de Chimie des Substances Naturelles
(ICSN) for a fellowship; J. S. thanks the Ministère de l’Enseigne-
ment Supérieur et de la Recherche (MESR) and the Paris-Sud Uni-
versity for a fellowship. This work was also support by the Agence
Nationale de la Recherche (ANR Blanc, “Chiracid”) and the
COST ORCA action CM0905.
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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[29] This catalyst was prepared by a procedure analogous to that
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Received: August 20, 2013
Published Online: October 24, 2013
Eur. J. Org. Chem. 2014, 188–193
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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