First Synthesis of (R)- and (S)-1,2,3,4-Tetrahydroisoquinoline-3-phosphonic Acid (TicP) Using a Pictet-Spengler Reaction

Article abstract of DOI:10.1002/ejoc.201600313

We report here a practical and efficient synthesis of diethyl 1,2,3,4-tetrahydroisoquinoline-3-phosphonate derivatives. The target compounds were prepared in good yield using a Pictet-Spengler reaction involving α-amino phosphonates that were easily obtai

Full text of DOI:10.1002/ejoc.201600313

DOI: 10.1002/ejoc.201600313
Full Paper
Phosphoisoquinolines
First Synthesis of (R)- and (S)-1,2,3,4-Tetrahydroisoquinoline-3-
phosphonic Acid (TicP) Using a Pictet–Spengler Reaction
José Luis Viveros-Ceballos,[a] Mario Ordóñez,*[b] Francisco J. Sayago,[c] Ana I. Jiménez,[c] and
Carlos Cativiela*[c]
Abstract: We report here a practical and efficient synthesis of phonic acid (TicP) 2a, a conformationally constrained analogue
of phosphophenylalanine PheP. The procedure is based on the
preparation of racemic phosphophenylalanine (PheP) diethyl es-
ter followed by chiral chromatographic separation and subse-
quent Pictet–Spengler chemistry.
diethyl 1,2,3,4-tetrahydroisoquinoline-3-phosphonate deriva-
tives. The target compounds were prepared in good yield using
a Pictet–Spengler reaction involving α-amino phosphonates
that were easily obtained. We have paid special attention to the
synthesis of (R)- and (S)-1,2,3,4-tetrahydroisoquinoline-3-phos-
Introduction
Due to the important properties exhibited by Tic 1 and related
derivatives, much effort has been dedicated to the preparation
of these compounds, mainly through the use of Pictet–Spengler
reactions.[13,14] However, the synthesis of the 1 analogue 1,2,3,4-
tetrahydroisoquinoline-3-phosphonic acid (TicP) 2a from race-
mic or enantiomerically pure phosphophenylalanine PheP di-
ethyl ester using Pictet–Spengler chemistry has not, to the best
of our knowledge, been described in the literature. This is
somewhat surprising due to the great promise this compound
likely has in medicinal chemistry and organic synthesis as is
demonstrated by the well-established significance of α-amino
phosphonic acids and their derivatives.[15,16] Consequently,
there is great interest and importance in developing new meth-
ods for the preparation of compound 2a and related agents.[17]
The 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) 1, con-
sidered a conformationally constrained analogue of phenyl-
alanine (Phe) with a fused phenyl ring, is an important non-
natural α-amino acid often used as a key intermediate in or-
ganic synthesis for the preparation of biologically active com-
pounds. Possibly one of the most successful examples of such
applications of 1 has involved its use as a proline replacement
in the drug enalapril. This modification led to quinapril, a newly
approved angiotensin converting enzyme (ACE) inhibitor.[1] This
discovery led to the preparation of several pharmacologically
relevant compounds that have been evaluated as anti-throm-
botic agents,[2] inhibitors of P-glycoprotein,[3] matrix-metallo-
proteinase inhibitors,[4] hepatitis C virus NS3 protease inhibi-
tors,[5] and as Rev-ErbA agonists.[6] Such agents have also been
tested as inhibitors of aminopeptidase N (APN/CD13) and MMP-
2,[7] as analogues of the antimicrobial gramicidin S,[8] as opioid
pharmacophores,[9] and as potent Rho Kinase inhibitors. Agents
containing 1 and related congeners are thus considered prom-
ising drug leads in the development of treatments for many
diseases including hypertension, multiple sclerosis, cancer and
glaucoma.[10] Furthermore, Tic 1 has been used as a precursor
in the synthesis of several catalysts[11] and chiral hydrides.[12]
[a] Secretaría Académica, Universidad Autónoma del Estado de Morelos.
Av. Universidad 1001, 62209 Cuernavaca, Morelos, Mexico
[b] Centro de Investigaciones Químicas-IICBA, Universidad Autónoma del
Estado de Morelos
Av. Universidad 1001, 62209 Cuernavaca, Morelos, Mexico
E-mail: palacios@uaem.mx
http://www.ciq.uaem.mx/nosotros/jose-mario-ordonez-palacios/
[c] Departamento de Química Orgánica, ISQCH, Universidad de
Zaragoza-CSIC,
Considering the high value of these non-coded compounds
in connection with our current research interest in the synthesis
of novel conformationally restricted α-amino phosphonic ac-
ids,[18] we report herein the first convenient synthesis of enan-
tiomerically pure (R)- and (S)-1,2,3,4-tetrahydroisoquinoline-3-
phosphonic acid (TicP) 2a. The procedure is based on the prepa-
ration of racemic phosphophenylalanine PheP diethyl ester fol-
lowed by chiral chromatography and subsequent Pictet–Spen-
gler chemistry.
50009 Zaragoza, Spain
E-mail: cativiela@unizar.es
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600313.
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Results and Discussion
For the synthesis of target compound 2a, our synthetic se-
quence begins with the preparation of diethyl phosphophenyl-
alaninate ( )-5a. For this aim, we explored the application of
methods already described in the literature.[19] Thus, commer-
cially available phenylacetyl chloride was treated with triethyl
phosphite at 70 °C to afford α-keto phosphonate 3, which with-
out additional purification was treated with hydroxylamine
hydrochloride and pyridine in ethanol, to render the corre-
sponding oxime 4. Reduction of oxime 4 with zinc in formic
acid at room temperature, provided diethyl phosphophenylala-
ninate ( )-5a in 51 % overall yield (Scheme 1).
Scheme 2. Synthesis of compound ( )-7a.
formaldehyde source. We envisioned that catalysis by BF3·OEt2,
would mediate the formation of formaldehyde from dimeth-
oxymethane, thus facilitating the desired Pictet–Spengler cycli-
zation.[22] Therefore, diethyl phosphophenylalaninate ( )-5a
was treated with benzyloxycarbonyl chloride and N,N-diisopro-
pylethylamine (DIPEA) in dichloromethane to afford N-Cbz-pro-
tected α-amino phosphonate ( )-8a in 98 % yield. Reaction of
( )-8a with dimethoxymethane at 35 °C in the presence of cata-
lytic BF3·OEt2, gave N-Cbz-protected diethyl 1,2,3,4-tetrahydro-
isoquinoline-3-phosphonate ( )-10a in 84 % yield, through the
Scheme 1. Preparation of diethyl phosphophenylalaninate ( )-5a.
With diethyl phosphophenylalaninate ( )-5a in hand, and ap- agency of N-acyliminium species ( )-9a. When the reaction was
plying the well-established protocol for the synthesis of 1,2,3,4- carried out at room temperature, low yields were observed, and
tetrahydroisoquinoline-3-carboxylic acids (Tic) 1 under Pictet– at temperatures higher than 35 °C, several unidentified prod-
Spengler conditions,[14] we carried out the reaction of ( )-5a ucts were formed, indicating that the temperature was a critical
with formaldehyde in the presence of 37 % HCl. However, after factor in this reaction. Cleavage of the N-Cbz group in com-
several attempts, only a complex mixture of unidentified prod- pound ( )-10a was accomplished by hydrogenolysis in the
ucts was obtained, possible due to hydrolysis of the phosphon- presence of Pd/C as catalyst in ethyl acetate to render diethyl
ate group. On the other hand, it has also been reported that 1,2,3,4-tetrahydroisoquinoline-3-phosphonate ( )-7a in 99 %
Tic 1 can be obtained using a benzotriazole-assisted methodol- yield. Importantly, this procedure enabled the preparation of
ogy. With this background, and applying a procedure described ( )-7a in large quantities (Scheme 3).
by Katritzky and co-workers,[20] diethyl phosphophenylalaninate
With these results, the next step was to explore the scope of
( )-5a, benzotriazole (BtH) and formaldehyde were allowed to
react at room temperature, rendering N-[(benzotriazolyl)methyl]
intermediate 6. Compound 6, without additional purification,
was treated with aluminum chloride in dichloromethane under
refluxing conditions in efforts to generate the desired product
( )-7a. However, under these conditions, only decomposition
products were obtained. Alternatively, the reaction of interme-
diate 6 with ZnBr2 in the presence of 4 Å molecular sieves in
dichloromethane at reflux, provided the desired compound ( )-
7a in 70 % yield (Scheme 2).
the Pictet–Spengler reaction using enantiomerically pure (R)-
and (S)-phosphophenylalanine diethyl ester 8a in order to ob-
tain the (R)- and (S)-1,2,3,4-tetrahydroisoquinoline-3-phos-
phonic acid (TicP) 2a in optically pure form. Moreover, this
would enable us to test the configurational stability of enantio-
merically pure α-amino phosphonates 8a and 10a in this reac-
tion. To achieve this goal, we prepared enantiomerically pure
compounds (R)- and (S)-8a. Although these compounds have
been obtained by asymmetric synthesis methods,[17b,17e] and
using chemical and biocatalytic resolutions,[23] to the best of
With this procedure, the synthesis of our target molecule ( )- our knowledge, preparative chiral HPLC resolution of racemic
7a was achieved. However, this approach was deemed impracti- phosphophenylalanine derivatives has not been explored.[24]
cal for larger-scale reactions since several by-products were ob- Based on our previous experience in the preparative-scale chiral
tained and purification proved difficult. To resolve this problem HPLC resolution of protected amino acids and α-amino phos-
in a general way, an electron-withdrawing group, specifically phonates,[25] we addressed the chromatographic resolution of
benzyloxycarbonyl (Cbz), was incorporated by way of N-protec- racemate 8a using commercially available preparative columns
tion to produce the N-acyliminium ion, anticipated to be Chiralpak® IA,[26a] IB[26b] and IC.[26c] These columns contain sta-
amenable to Pictet–Spengler cyclization.[21] Additionally, we tionary phases based on polysaccharide chiral supports cova-
changed the formaldehyde source to that of more reactive di- lently bonded to a silica gel matrix, which provide excellent
methoxymethane, which served both as solvent as well as the chiral recognition, high loading capacity and are very stable in
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Scheme 3. Synthesis of ( )-7a through the agency of intermediate N-
acyliminium species ( )-9a.
Scheme 4. HPLC resolution of racemic phosphophenylalanine derivative 8a.
we carried out the reaction of (R)-8a with dimethoxymethane
at 37 °C in the presence of catalytic BF3·OEt2, to produce diethyl
(R)-1,2,3,4-tetrahydroisoquinoline-3-phosphonate (R)-10a in
84 % yield. Treatment of (R)-10a with a 33 % solution of HBr in
acetic acid at room temperature produced (R)-1,2,3,4-tetra-
hydroisoquinoline-3-phosphonic acid (TicP) (R)-2a in 93 % yield.
Under identical conditions (S)-8a was converted into (S)-1,2,3,4-
tetrahydroisoquinoline-3-phosphonic acid (S)-2a in excellent
yield (Scheme 5).
the presence of a wide range of organic solvents.[26–28] In order
to establish the appropriate conditions for the preparative reso-
lution of compound ( )-8a, we first tested the separation at the
analytical level using 250 × 4.6 mm ID Chiralpak® IA, IB and IC
columns. No resolution was observed using the Chiralpak® IB
column, and with the Chiralpak® IC column only very poor en-
antiodiscrimination was obtained. However, assays performed
on the Chiralpak® IA column showed suitable separation of
both enantiomers. The best separation conditions were found
using n-hexane/iPrOH (85:15) as the mobile phase at a flow rate
of 1 mL/min. The addition of a third solvent to the mobile phase
(acetone, chloroform and tert-butyl methyl ether) did not im-
prove the enantioseparation. The analytical conditions were
used working in overload mode and then scaled-up for the
preparative resolution of ( )-8a using a 250 × 20 mm ID Chiral-
pak® IA column. The resolution was achieved by successive in-
jections of a solution of ( )-8a in chloroform (0.80 g per mL of
solvent) to obtain about 1.0 g of each enantiomer in a single
passage of the racemate through the column. The enantiomeric
purities of the resolved materials were evaluated on an analyti-
cal scale. The absolute configurations of (R)- and (S)-8a were
assigned on the basis of optical rotation data and comparisons
with previously reported data (Scheme 4).[29] Additionally, treat-
ment of compound (R)-8a with a 33 % solution of HBr in acetic
acid followed by purification using an ion-exchange column,
afforded (R)-phosphophenylalanine 11 in almost quantitative
yield. Comparison of the specific optical rotation of (R)-11 with
established data in the literature confirmed the absolute config-
uration assignments.[30]
With (R)- and (S)-phosphophenylalanine diethyl esters 8a in
enantiomerically pure form in hand, the next step was the syn-
thesis of our target molecules. For this purpose, and based on
Scheme 5. Synthesis of the target compounds (R)-2a and (S)-2a.
Finally, analyses of racemate ( )-10a and both enantiomers
our research on the Pictet–Spengler reaction with racemic 8a, (R)- and (S)-10a using a 150 × 4.6 mm ID Chiralpak® IB column
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and n-hexane/iPrOH (90:10) as the mobile phase at a flow rate
of 1 mL/min, revealed that the Pictet–Spengler reaction pro-
ceeded without racemization, establishing the configurational
stability of 8a and 10a under these reaction conditions.
To explore the scope of this method for the synthesis of
diethyl 1,2,3,4-tetrahydroisoquinoline-3-phosphonates, several
ꢀ-aryl-substituted α-amino phosphonates were examined in de-
tail. ꢀ-Aryl-substituted α-amino phosphonates ( )-5b–d and N-
Cbz-protected derivatives ( )-8b–d were prepared in moderate
to excellent yields from the corresponding arylacetic acids 12
via their acyl chlorides 13 according to the procedure described
above (Scheme 6).
Scheme 7. Synthesis of the N-methoxymethyl derivatives ( )-14b and 14c.
methylation of the aromatic ring, thus enabling the formation
of bis(aryl)methylenes, trimers and cyclotetramers;[21b] these
observations effectively support the legitimacy of our observa-
tions with this reaction and set of reactants.
Scheme 6. Synthesis of ( )-5b–d and their protected derivatives ( )-8b–d.
With the α-amino phosphonates ( )-8b–d in hand, we
started with the reaction of N-Cbz-protected diethyl (4-bromo-
phenyl)phosphoalaninate ( )-8b and dimethoxymethane in the
presence of catalytic BF3·OEt2 at 35 °C; under these conditions,
the desired 1,2,3,4-tetrahydroisoquinoline-3-phosphonate was
not isolated. Instead, this reaction produced N-methoxymethyl
derivative ( )-14b in 88 % yield. Similar results were obtained
when the N-Cbz-protected diethyl [4-(trifluoromethyl)phen-
yl]phosphoalaninate ( )-8c was allowed to react under the
same conditions to render ( )-14c in 89 %. Compounds ( )-14b
and ( )-14c were fully characterized by NMR spectroscopy and
mass spectrometry and, partly on this basis, we propose that
iminium ions 9b and 9c were formed. However, it is likely that
the insufficient reactivity of the aromatic ring with electron-
withdrawing substituents, enables these species (9b,c) to react
with methanol, thus leading to the formation of ( )-14b and
( )-14c (Scheme 7).[31]
Scheme 8. Synthesis of ( )-10d and dimeric product 15.
In order to equilibrate the reactivity of the aromatic ring and
the nitrogen atom, we next performed the Pictet–Spengler re-
action of diethyl (3,4-dimethoxyphenyl)phosphoalaninate ( )-
5d with excess of formaldehyde in the presence of 2
(1 equiv.) at room temperature for 32 h. These conditions af-
N HCl
With these results, we next turned our attention to the Pic- forded diethyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-
tet–Spengler reaction of N-Cbz-protected diethyl (3,4-di- phosphonate ( )-7d in quantitative yield. Compound ( )-7d
methoxyphenyl)phosphoalaninate ( )-8d with dimethoxymeth- was also obtained in quantitative yield by reaction of ( )-5d
ane and catalytic BF3·OEt2 at 35 °C. These reaction conditions with formaldehyde and excess of trifluoroacetic acid (TFA) in
generated the expected product ( )-10d in 64 % yield and a dichloromethane at room temperature for 5 h.[32] Hydrolysis of
dimeric product 15 in 15 % yield (Scheme 8). On the basis of the phosphonate moiety with simultaneous O–Me bond cleav-
these data, it is clear that the cyclization event in the Pictet– age in compound ( )-7d was carried out in refluxing concd. HBr
Spengler reaction proceeds optimally when the ring-closure po- to furnish 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-phos-
sition is activated by an electron-donating substituent. It is also phonic acid ( )-2d in 81 % yield, a conformationally constrained
known that activation in such reactions may confer hydroxy-
L
-DOPAP analogue (Scheme 9).
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ing with n-hexane/iPrOH (85:15) at a flow rate of 18 mL/min. The
process was monitored by UV absorption at 220 nm.
General Procedure for the Synthesis of α-Amino Phosphonates
5a–d: Thionyl chloride (8.3 g, 5.1 mL, 69.1 mmol) was added drop-
wise to a solution of (4-bromophenyl)acetic acid (5.0 g, 23.3 mmol),
dichloromethane (5 mL) and N,N-dimethylformamide (0.15 mL). The
resulting solution was stirred at room temperature in a well-venti-
lated hood overnight. The reaction mixture was concentrated in
vacuo to give the crude (4-bromophenyl)acetyl chloride as a yellow
liquid. The crude acyl chloride was dissolved in tetrahydrofuran
(13 mL), cooled to 0 °C, and triethyl phosphite (3.86 g, 4.1 mL,
23.3 mmol) was added dropwise under anhydrous conditions. When
the addition was complete, the solution was warmed at 70 °C and
stirred for additional 15 min. The volatile compounds were evapo-
rated in vacuo to obtain the α-keto phosphonate, which was added
to a solution of hydroxylamine hydrochloride (1.94 g, 28 mmol) in
dry pyridine (4.2 mL) and ethanol (7 mL). The reaction mixture was
stirred at room temperature for 12 h and then concentrated in
vacuo. The crude product was dissolved in dichloromethane
Scheme 9. Synthesis of the cyclic DOPAP analogue ( )-2d.
Conclusions
We have developed, for the first time, a practical and efficient
synthesis of diethyl 1,2,3,4-tetrahydroisoquinoline-3-phosphon-
ates from α-amino phosphonates using the Pictet–Spengler re-
action. This report highlights the use of α-amino phosphonates
as key intermediates in the Pictet–Spengler reaction. One appli-
cation of this procedure involves the synthesis of enantiomeri-
cally pure (R)- and (S)-1,2,3,4-tetrahydroisoquinoline-3-phos-
phonic acid (TicP) 2a from diethyl phenylphosphoalaninate 8a
which is readily obtained (on a large scale) by chiral HPLC sepa-
rations. Additionally, the configurational stabilities of starting
materials and products were evaluated.
(40 mL), washed with 3
N HCl (2 × 10 mL) and water (10 mL). The
organic layer was dried with anhydrous MgSO4, filtered and concen-
trated in vacuo to obtain the crude oxime. Finally, the crude oxime
under argon was added to a suspension of zinc (6.1 g, 93.3 mmol)
in formic acid (23.2 mL), and the mixture was stirred at room tem-
perature overnight. The suspension was filtered, and the filtrate was
concentrated in vacuo to provide the crude product, which was
purified by flash chromatography using AcOEt/MeOH (95:5) to give
compound 5b (2.86 g, 37 %) as a yellow oil. Spectroscopic data for
5a[33] and 5b[34] were identical to those reported in the literature.
Diethyl [1-Amino-2-(4-trifluoromethylphenyl)ethyl]phosphon-
ate (5c): According to the general procedure, compound 5c was
obtained (1.49 g, 47 % yield) from [4-(trifluoromethyl)phenyl]acetic
acid (2.0 g, 9.8 mmol) as a yellow oil. IR (neat): ν = 3378, 3300, 1239,
˜
1
1066, 1027 cm–1. H NMR (400 MHz, CDCl3): δ = 1.31 (t, J = 7.1 Hz,
Experimental Section
3 H, CH3CH2O), 1.32 (t, J = 7.1 Hz, 3 H, CH3CH2O), 1.38 (br. s, 2 H,
NH2), 2.69–2.77 (m, 1 H, CH2CH), 3.18–3.27 (m, 2 H, CH2CH, CHP),
4.10–4.18 (m, 4 H, OCH2CH3), 7.34 (d, J = 8.0 Hz, 2 H, Harom), 7.54
(d, J = 8.0 Hz, 2 H, Harom) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.6
(d, J = 5.6 Hz, CH3CH2O), 37.7 (CH2CH), 50.2 (d, J = 152.9 Hz, CHP),
62.4 (d, J = 7.5 Hz, OCH2CH3), 62.5 (d, J = 7.5 Hz, OCH2CH3), 124.3
(q, J = 271.8 Hz, CF3), 125.5 (q, J = 3.8 Hz), 129.1 (q, J = 32.5 Hz),
129.7, 142.3 (d, J = 15.4 Hz) ppm. 31P NMR (162 MHz, CDCl3): δ =
27.48 ppm. 19F NMR (377 MHz, CDCl3): δ = –62.47 ppm. HRMS (ESI):
calcd. for C13H20F3NO3P [M + H]+ 326.1133; found 326.1135.
General: All reagents were used as received from commercial sup-
pliers without further purification. Thin-layer chromatography (TLC)
was performed on Macherey–Nagel Polygram® SIL G/UV254 pre-
coated silica gel polyester plates. The products were visualized by
exposure to UV light (254 nm), iodine vapors or submersion in a
solution of phosphomolybdic acid in ethanol. Flash chromatogra-
phy was performed using Silica 60
M (0.04–0.063 mm, 230–
400 mesh) from Macherey–Nagel. Melting points were determined
with a Gallenkamp apparatus and are uncorrected. IR spectra were
registered using a Nicolet Avatar 360 FTIR spectrophotometer; νmax
˜
is given for the main absorption bands. 1H, 13C and 31P NMR spectra
were recorded with Bruker AV-400 or AV-300 instruments at room
temperature except when another temperature is specified; the re-
sidual solvent signal was used as the internal standard (1H and 13C)
Diethyl [1-Amino-2-(3,4-dimethoxyphenyl)ethyl]phosphonate
(5d): According to the general procedure, compound 5d was ob-
tained (10.35 g, 53 % yield) from (3,4-dimethoxyphenyl)acetic acid
(12.0 g, 61.2 mmol) as a white solid. M.p. 58–59 °C. IR (neat): ν =
˜
or H3PO4 (
31P, internal); chemical shifts (δ) are expressed in parts
1
3378, 3297, 1231, 1057, 1025 cm–1. H NMR (400 MHz, CDCl3): δ =
per million (ppm) and coupling constants (J) in Hertz. High Resolu-
tion Mass Spectra (HRMS) were obtained with a Bruker Microtof-Q
spectrometer.
1.33 (t, J = 7.1 Hz, 6 H, CH3CH2O), 1.48 (br. s, 2 H, NH2), 2.58 (ddd,
J = 13.9, 11.0, 8.8 Hz, 1 H, CH2CH), 3.15 (ddd, J = 13.8, 6.9, 3.3 Hz,
1 H, CH2CH), 3.19–3.26 (m, 1 H, CHP), 3.83 (s, 3 H, CH3O), 3.84 (s, 3
H, CH3O), 4.20–4.11 (m, 4 H, OCH2CH3), 6.81–6.71 (m, 3 H, Harom
)
High-Performance Liquid Chromatography: HPLC was carried out
with a Waters 600 HPLC system equipped with a 2996 photodiode
array detector or a Hewlett–Packard 1100 system equipped with
a VIS-UV detector (used at the analytical level) and a 2487 dual-
wavelength absorbance detector (used for the preparative-scale
resolution). Analytical assays were performed using 250 × 4.6 mm
Chiralpak® IA, IB, and IC columns (Daicel Chemical Industries Ltd.,
Japan), eluting with different binary and ternary mixtures at flow
rates ranging from 0.8 to 1.0 mL/min. The preparative resolution
was carried out using 250 × 20 mm Chiralpak® IA columns and elut-
ppm. 13C NMR (100 MHz, CDCl3): δ = 16.6 (d, J = 5.5 Hz, CH3CH2O),
37.4 (CH2CH), 50.4 (d, J = 153.9 Hz, CHP), 55.9 (CH3O), 55.9 (CH3O),
62.3 (d, J = 6.8 Hz, OCH2CH3), 62.4 (d, J = 7.0 Hz, OCH2CH3), 111.3,
112.2, 121.3, 130.3 (d, J = 16.4 Hz), 147.9, 149.1 ppm. 31P NMR
(162 MHz, CDCl3): δ = 28.12 ppm. HRMS (ESI): calcd. for C14H25NO5P
[M + H]+ 318.1470; found 318.1445.
General Procedure for the Synthesis of N-Cbz-α-Amino Phos-
phonates 8a–d: Benzyloxycarbonyl chloride (2.52 g, 2.2 mL,
14.8 mmol) was added dropwise under argon to a solution of com-
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pound 5a (1.9 g, 7.4 mmol) and N,N-diisopropylethylamine (3.82 g,
6 (100 mg, 0.26 mmol) in dry dichloromethane (5 mL) in the pres-
5.2 mL, 29.6 mmol) in dichloromethane (37 mL) at 0 °C. The result- ence of 4 Å molecular sieves (50 mg), and the resulting mixture
ing solution was stirred at room temperature for 24 h. The reaction
mixture was diluted with dichloromethane (30 mL), washed with
was refluxed for 6 h. The reaction mixture was cooled to room
temperature, filtered, diluted with dichloromethane (30 mL),
1
N
HCl (30 mL), water (30 mL) and brine (30 mL). The organic
washed with 2 M NaOH (20 mL) and brine (10 mL) and dried with
layer was dried with anhydrous MgSO4, filtered and concentrated in anhydrous MgSO4. The solvent was evaporated in vacuo, and the
vacuo, and the crude product was purified by flash chromatography
using AcOEt/hexane (70:30) to afford compound 8a (2.83 g, 98 %
yield) as a white solid. 8a and 8b were identical to those reported
in the literature.[29]
crude product was purified by flash chromatography using AcOEt/
MeOH (90:10) to give compound 7a (48 mg, 70 % yield) as a color-
less oil. IR (neat): ν = 3294, 1240, 1054, 1024 cm–1 1H NMR
.
˜
(400 MHz, CDCl3): δ = 1.34 (t, J = 7.1 Hz, 3 H, CH3CH2O), 1.35 (t, J =
7.1 Hz, 3 H, CH3CH2O), 1.92 (br. s, 1 H, NH), 2.88–3.08 (m, 2 H), 3.24–
3.33 (m, 1 H), 3.99–4.10 (br. s, 2 H), 4.15–4.24 (m, 4 H, OCH2CH3),
6.96–7.03 (m, 1 H, Harom), 7.06–7.17 (m, 3 H, Harom) ppm. 13C NMR
(100 MHz, CDCl3): δ = 16.6 (d, J = 5.6 Hz, CH3CH2O), 28.9, 48.4 (d,
J = 16.6 Hz), 51.2 (d, J = 161.8 Hz), 62.5 (d, J = 6.7 Hz, OCH2CH3),
62.6 (d, J = 6.9 Hz, OCH2CH3), 126.2, 126.4, 129.2, 129.2, 133.2 (d,
J = 14.7 Hz), 135.1 (d, J = 1.9 Hz) ppm. 31P NMR (162 MHz, CDCl3):
δ = 26.16 ppm. HRMS (ESI): calcd. for C13H21NO3P [M + H]+
270.1259; found 270.1235. Method B: 10 % Pd/C (20 mg) was
added to a solution of compound 10a (100 mg, 0.25 mmol) in ethyl
acetate (2.5 mL). The reaction mixture was vigorously stirred under
hydrogen for 24 h, filtered, concentrated under reduced pressure,
and the crude product was purified by flash chromatography using
AcOEt/MeOH (90:10) to afford compound 7a (66 mg, 99 % yield) as
a colorless oil.
Diethyl {1-[(Benzyloxycarbonyl)amino]-2-[4-(trifluoromethyl)-
phenyl)]ethyl}phosphonate (8c): According to the general proce-
dure, a mixture of compound 5c (1.0 g, 3.07 mmol), dichloro-
methane (15.5 mL), N,N-diisopropylethylamine (1.59 g, 2.2 mL,
12.3 mmol) and benzyloxycarbonyl chloride (1.05 g, 0.88 mL,
6.15 mmol) was allowed to react to give 8c (1.31 g, 93 % yield) as
a white solid. M.p. 82–84 °C. IR (neat): ν = 3259, 1712, 1264, 1057,
˜
1
1032 cm–1. H NMR (400 MHz, CDCl3): δ = 1.22 (t, J = 7.0 Hz, 3 H,
CH3CH2O), 1.28 (t, J = 7.0 Hz, 3 H, CH3CH2O), 2.88–3.00 (m, 1 H,
CH2CH), 3.20–3.29 (m, 1 H, CH2CH), 3.99–4.17 (m, 4 H, OCH2CH3),
4.32–4.47 (m, 1 H, CHP), 5.00 (s, 2 H, OCH2Ph), 5.46 (d, J = 9.9 Hz, 1
H, NH), 7.18–7.25 (m, 2 H, Harom), 7.26–7.32 (m, 3 H, Harom), 7.34 (d,
J = 7.8 Hz, 2 H, Harom), 7.50 (d, J = 7.8 Hz, 2 H, Harom) ppm. 13C NMR
(100 MHz, CDCl3): δ = 16.4 (d, J = 5.7 Hz, CH3CH2O), 35.9 (d, J =
3.8 Hz, CH2CH), 48.5 (d, J = 157.4 Hz, CHP), 62.8 (d, J = 6.7 Hz,
OCH2CH3), 63.1 (d, J = 7.1 Hz, OCH2CH3), 67.2 (OCH2Ph), 124.3 (q,
J = 272.1 Hz, CF3), 125.4 (q, J = 3.7 Hz), 128.1, 128.3, 128.6, 129.2
(q, J = 32.3 Hz), 129.7, 136.3, 141.0 (d, J = 13.3 Hz), 155.9 (d, J =
7.1 Hz, C=O) ppm. 31P NMR (162 MHz, CDCl3, asterisk denotes minor
rotamer): δ = 23.00*, 23.55 ppm. 19F NMR (377 MHz, CDCl3): δ =
–62.37 ppm. HRMS (ESI): calcd. for C21H26F3NO5P [M + H]+ 460.1501;
found 460.1469.
Diethyl [2-(Benzyloxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-3-
yl]phosphonate (10a): BF3·OEt2 (4.35 g, 3.9 mL, 30.7 mmol) was
added under argon to a mixture of compound 8a (4.0 g, 10.2 mmol)
and dimethoxymethane (20 mL). The resulting solution was stirred
at 35 °C for 12 h. The reaction mixture was diluted with ethyl acet-
ate (40 mL) and water (40 mL). The organic layer was separated and
washed with saturated aqueous NaHCO3 (2 × 20 mL), dried with
anhydrous MgSO4, filtered, and concentrated under reduced pres-
Diethyl
{1-[(N-Benzyloxycarbonyl)amino]-2-(3,4-dimethoxy-
sure to give compound 10a (3.5 g, 84 % yield) as a yellow oil. IR
1
(neat): ν = 1701, 1244, 1052, 1026 cm–1. H NMR (400 MHz, CDCl3,
phenyl)ethyl}phosphonate (8d): According to the general proce-
dure, a mixture of compound 5d (1.0 g, 3.15 mmol), dichloro-
methane (16 mL), N,N-diisopropylethylamine (1.63 g, 2.2 mL,
12.6 mmol) and benzyloxycarbonyl chloride (1.08 g, 0.9 mL,
6.33 mmol) was allowed to react to give compound 8d (1.33 g,
˜
asterisk denotes minor rotamer): δ = 0.91* (t, J = 7.0 Hz, 3 H,
CH3CH2O), 0.96 (t, J = 7.1 Hz, 3 H, CH3CH2O), 1.12* (t, J = 7.0 Hz, 3
H, CH3CH2O), 1.18 (t, J = 7.0 Hz, 3 H, CH3CH2O), 3.13–3.33 (m, 2 H),
3.41–3.53* (m, 1 H, OCH2CH3), 3.57–3.70 (m, 1 H, OCH2CH3), 3.76–
4.08 (m, 3 H, OCH2CH3), 4.46* (d, J = 16.9 Hz, 1 H), 4.53 (d, J =
16.7 Hz, 1 H), 4.86–5.08 (m, 2 H), 5.14–5.26 (m, 2 H, OCH2Ph), 7.01–
7.19 (m, 4 H, Harom), 7.28–7.42 (m, 5 H, Harom) ppm. 13C NMR
(100 MHz, CDCl3, asterisk denotes minor rotamer): δ = 16.1 (d, J =
6.0 Hz, CH3CH2O), 16.3 (d, J = 6.1 Hz, CH3CH2O), 28.3 (d, J = 2.3 Hz),
28.5* (d, J = 2.2 Hz), 44.4, 46.5 (d, J = 154.2 Hz), 47.3* (d, J =
154.3 Hz), 61.9* (d, J = 6.9 Hz, OCH2CH3), 62.1 (d, J = 6.9 Hz,
OCH2CH3), 62.3 (d, J = 6.3 Hz, OCH2CH3), 67.8 (OCH2Ph), 67.8*
(OCH2Ph), 125.8, 126.0*, 126.5, 126.5*, 126.6, 128.0, 128.2*, 128.2,
128.5*, 128.6, 128.7, 131.1*, 131.6, 132.6, 132.7*, 136.2*, 136.5,
155.2* (C=O), 155.8 (d, J = 2.7 Hz, C=O) ppm. 31P NMR (162 MHz,
CDCl3, asterisk denotes minor rotamer): δ = 24.33*, 24.75 ppm.
HRMS (ESI): calcd. for C21H27NO5P [M + H]+ 404.1627; found
404.1608.
93 % yield) as a white solid. M.p. 89–91 °C. IR (neat): ν = 3244, 1715,
˜
1
1256, 1025 cm–1. H NMR (400 MHz, CDCl3): δ = 1.22 (t, J = 7.0 Hz,
3 H, CH3CH2O), 1.28 (t, J = 7.1 Hz, 3 H, CH3CH2O), 2.74–2.87 (m, 1
H, CH2CH), 3.11–3.22 (m, 1 H, CH2CH), 3.79 (s, 3 H, OCH3), 3.83 (s, 3
H, CH3O), 3.98–4.15 (m, 4 H, OCH2CH3), 4.30–4.44 (m, 1 H, CHP),
4.99 (s, 2 H, OCH2Ph), 5.20 (d, J = 10.2 Hz, 1 H, NH), 6.68–6.78 (m, 3
H, Harom), 7.16–7.22 (m, 2 H, Harom), 7.26–7.32 (m, 3 H, Harom) ppm.
13C NMR (100 MHz, CDCl3): δ = 16.4 (d, J = 5.8 Hz, CH3CH2O), 35.4
(d, J = 4.0 Hz, CH2CH), 48.6 (d, J = 156.5 Hz, CHP), 55.8 (CH3O), 55.9
(CH3O), 62.6 (d, J = 6.7 Hz, OCH2CH3), 62.8 (d, J = 7.1 Hz, OCH2CH3),
66.9 (OCH2Ph), 111.1, 112.2, 121.4, 127.9, 128.1, 128.5, 129.1 (d, J =
13.7 Hz), 136.4, 147.9, 148.8, 155.9 (d, J = 6.2 Hz, C=O) ppm. 31P
NMR (162 MHz, CDCl3, asterisk denotes minor rotamer): δ = 23.59*,
24.21 ppm. HRMS (ESI): calcd. for C22H31NO7P [M + H]+ 452.1838;
found 452.1824.
Diethyl {(R)- and (S)-1-[(Benzyloxycarbonyl)amino]-2-phenyl-
ethyl}phosphonate (8a): HPLC resolution of racemic rac-8a was
performed using a 250 × 20 mm Chiralpak® IA column and a mix-
ture of n-hexane/iPrOH (85:15) as eluent at a flow rate of 18 mL/
min. The process was monitored by UV absorption at 220 nm. The
racemic amino phosphonate 8a (2.15 g) was dissolved in chloro-
form (2.7 mL), and 80 μL aliquots of this solution were injected
consecutively every 9 min. Each injection was collected into three
separate fractions, with equivalent fractions of successive injections
being combined. Concentration of the first and third fractions pro-
3-Diethyl (1,2,3,4-tetrahydroisoquinolin-3-yl)phosphonate (7a).
Method A: A mixture of compound 5a (100 mg, 0.39 mmol) in
MeOH/H2O (2.6:1.3 mL), benzotriazole (46.3 mg, 0.39 mmol) and
formaldehyde as 37 % aqueous solution (31.5 mg, 30 μL,
0.39 mmol) was stirred at room temperature for 5 h. The clear solu-
tion was concentrated, extracted with CH2Cl2, dried with anhydrous
MgSO4 and concentrated under reduced pressure to obtain com-
pound 6 as a colorless oil that was used with no further purification.
ZnBr2 (232 mg, 1.03 mmol) was added to a solution of compound
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vided the enantiomerically pure (R)-8a (1.049 g) and (S)-8a (1.029 g),
62.9* (OCH2CH3), 65.4 (d, J = 154.4 Hz, CHP), 67.9 (OCH2Ph), 68.1
both of them as white solids. The second fraction (25 mg) was
(CH2N), 120.5, 128.1, 128.3, 128.4*, 128.6, 130.9, 131.5, 136.2, 136.7
found to contain a 19:81 mixture of (R)-8a/(S)-8a, which was dis- (d, J = 14.9 Hz), 156.4 (C=O) ppm. 31P NMR (asterisk denotes minor
carded. (R)-8a: M.p. 63–65 °C, [α]D = –42.9 (c = 1.04, CH2Cl2). (S)-8a:
M.p. 63–65 °C. [α]D = +43.1 (c = 1.04, CH2Cl2); ref.[29] [α]D = +42.3
(c = 1.05, CH2Cl2). Spectroscopic data were identical to those de-
scribed in the literature.[29]
rotamer, 162 MHz, CDCl3): δ = 23.51*, 24.03 ppm. HRMS (ESI): calcd.
for C22H30BrNO6P [M + H]+ 514.0994; found 514.0968.
Diethyl {1-[(Benzyloxycarbonyl)(methoxymethyl)amino]-2-[4-
(trifluoromethyl)phenyl]ethyl}phosphonate
(14c):
BF3·OEt2
[(R)-1-Amino-2-phenylethyl]phosphonic Acid [(R)-11]: Com-
pound (R)-8a (250 mg, 0.64 mmol) was dissolved in a 33 % solution
of HBr in acetic acid (5 mL) and stirred at room temperature for
24 h. The volatiles were evaporated under reduced pressure, and
the crude material was purified by ion exchange chromatography
on Dowex 50WX8 H+ form and eluted with water to afford com-
pound (R)-11 (120 mg, 93 %) as a white solid. M.p. 271–272 °C.
(190 mg, 0.17 mL, 1.34 mmol) was added under argon to a mixture
of compound 8c (200 mg, 0.43 mmol) and dimethoxymethane
(1 mL). The resulting solution was stirred at 35 °C for 12 h. The
reaction mixture was diluted with ethyl acetate (20 mL) and water
(20 mL). The organic layer was separated and washed with satu-
rated aqueous NaHCO3 (2 × 20 mL), dried with anhydrous MgSO4,
filtered, and concentrated under reduced pressure to give com-
[α]278 = –49.3 (c = 0.53, 1
NaOH). Spectroscopic data were identical to those described in
the literature.[35]
M
NaOH); ref.[30] [α]278 = –49.9 (c = 1.98,
pound 14c (195 mg, 89 % yield) as a yellow oil. IR (neat): ν = 1711,
˜
1257, 1055, 1020 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.21–1.30 (m,
6 H, CH3CH2O), 2.79–3.43 (m, 5 H, CH3O, CH2CH), 3.93–4.25 (m, 5 H,
OCH2CH3, CHP), 4.65–5.27 (m, 4 H, CH2N, OCH2Ph), 7.11–7.54 (m, 9
H, Harom) ppm. 13C NMR (asterisk denotes minor rotamer, 100 MHz,
CDCl3): δ = 16.4 (d, J = 5.8 Hz, CH3CH2O), 16.5* (d, J = 5.7 Hz,
CH3CH2O), 33.9 (CH2CH), 34.3* (CH2CH), 55.7 (CH3O), 56.4* (CH3O),
62.6 (OCH2CH3), 62.9* (OCH2CH3), 65.4 (d, J = 153.8 Hz, CHP), 67.9
(OCH2Ph), 68.1 (CH2N), 124.3 (q, J = 271.9 Hz, CF3), 125.2 (q, J =
3.7 Hz), 128.1, 128.3, 128.5*, 128.6, 128.6*, 128.9 (q, J = 32.2 Hz),
129.5, 135.8*, 136.1, 141.9 (d, J = 15.1 Hz), 156.3 (C=O) ppm. 31P
NMR (asterisk denotes minor rotamer, 162 MHz, CDCl3): δ = 23.36*,
23.87 ppm. 19F NMR (377 MHz, CDCl3): δ = –62.37 ppm. HRMS (ESI):
calcd. for C23H30F3NO6P [M + H]+ 504.1763; found 504.1722.
1
M
Diethyl [(R)-2-(Benzyloxycarbonyl)-1,2,3,4-tetrahydroisoquin-
olin-3-yl]phosphonate [(R)-10a]: Compound (R)-10a was obtained
from (R)-8a in a way similar to that for rac-10a as a colorless oil.
[α]D = –4.4 (c = 0.50, CHCl3). Spectroscopic data were identical to
those described for rac-10a.
Diethyl [(S)-2-(Benzyloxycarbonyl)-1,2,3,4-tetrahydroisoquinol-
in-3-yl]phosphonate [(S)-10a]: Compound (S)-10a was obtained
from (S)-8a in a way similar to that for rac-10a as a colorless oil.
[α]D = +4.5 (c = 0.47, CHCl3). Spectroscopic data were identical to
those described for rac-10a.
[(R)-1,2,3,4-Tetrahydroisoquinolin-3-yl]phosphonic Acid [(R)-
2a]: Compound (R)-10a (150 mg, 0.37 mmol) was dissolved in a
33 % solution of HBr in acetic acid (2 mL) and stirred at room tem-
perature for 24 h. The volatiles were evaporated under reduced
pressure, and the crude material was purified by ion exchange chro-
matography on Dowex 50WX8 H+ form and eluted with water to
afford compound (R)-2a (74 mg, 93 %) as a white solid. M.p. 278–
Diethyl
[2-(Benzyloxycarbonyl)-6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline-3-yl]phosphonate (10d): BF3·OEt2 (190 mg,
0.17 mL, 1.34 mmol) was added under argon to a mixture of com-
pound 8d (200 mg, 0.44 mmol) and dimethoxymethane (5 mL). The
resulting solution was stirred at 35 °C for 12 h. The reaction mixture
was diluted with ethyl acetate (20 mL) and water (20 mL). The or-
ganic layer was separated and washed with saturated aqueous NaH-
CO3 (2 × 20 mL), dried with anhydrous MgSO4, filtered, and concen-
trated under reduced pressure. The crude product was purified by
flash chromatography using AcOEt/MeOH (95:5) to provide com-
pound 10d (128 mg, 64 % yield) as a yellow oil, and the dimeric
280 °C. [α]D = –103.0 (c = 0.42, 1
M NaOH). IR (KBr): ν = 1215, 1056,
˜
957 cm–1 1H NMR (400 MHz, D2O, K2CO3): δ = 3.10–3.25 (m, 3 H),
.
4.30 (s, 2 H), 7.19–7.32 (m, 4 H, Harom) ppm. 13C NMR (100 MHz,
D2O, K2CO3): δ = 28.2, 46.5 (d, J = 8.5 Hz), 53.2 (d, J = 135.4 Hz),
126.5, 126.6, 127.5, 129.0, 129.8, 133.3 (d, J = 11.5 Hz) ppm. 31P
NMR (162 MHz, D2O, K2CO3): δ = 12.07 ppm. HRMS (ESI): calcd. for
C9H13NO3P [M + H]+ 214.0633; found 214.0631.
product 15 (30 mg, 15 % yield) as a yellow oil. 10d: IR (neat): ν =
˜
1700, 1259, 1095, 1025 cm–1. H NMR (asterisk denotes minor rota-
1
mer, 400 MHz, CDCl3): δ = 0.97* (d, J = 7.0 Hz, 3 H, CH3CH2O), 1.01
(t, J = 6.9 Hz, 3 H, CH3CH2O), 1.14* (t, J = 7.0 Hz, 3 H, CH3CH2O),
1.19 (t, J = 7.0 Hz, 3 H, CH3CH2O), 3.01–3.27 (m, 2 H), 3.43–3.57* (m,
1 H, OCH2CH3), 3.59–3.73 (m, 1 H, OCH2CH3), 3.75–4.09 (m, 3 H,
OCH2CH3), 3.80 (s, 3 H, CH3O), 3.83 (s, 3 H, CH3O), 4.39* (d, J =
16.4 Hz, 1 H), 4.46 (d, J = 16.3 Hz, 1 H), 4.78–5.08 (m, 2 H), 5.12–
5.25 (m, 2 H, OCH2Ph), 6.52 (s, 1 H, Harom), 6.57* (s, 1 H, Harom), 6.62
(s, 1 H, Harom), 7.27–7.41 (m, 5 H, Harom) ppm. 13C NMR (asterisk
denotes minor rotamer, 100 MHz, CDCl3): δ = 16.3 (d, J = 5.5 Hz,
CH3CH2O), 16.4 (d, J = 5.6 Hz, CH3CH2O), 27.8 (d, J = 2.6 Hz), 28.0*
(d, J = 2.4 Hz), 44.0, 46.5 (d, J = 153.9 Hz), 47.2* (d, J = 154.1 Hz),
55.9 (CH3O), 56.0 (CH3O), 61.9* (d, J = 6.9 Hz, OCH2CH3), 62.2 (d, J =
6.8 Hz, OCH2CH3), 62.3 (d, J = 6.3 Hz, OCH2CH3), 62.4* (d, J = 7.2 Hz,
OCH2CH3), 67.8 (OCH2Ph), 108.6, 108.8*, 111.1*, 111.3, 122.9*, 123.4,
124.2, 124.5*, 128.1, 128.2, 128.3*, 128.6, 136.2*, 136.5, 147.8, 147.9,
148.0*, 155.2* (C=O), 155.8 (d, J = 2.7 Hz, C=O) ppm. 31P NMR (aster-
isk denotes minor rotamer, 162 MHz, CDCl3): δ = 24.50*, 24.87 ppm.
HRMS (ESI): calcd. for C23H31NO7P [M + H]+ 464.1838; found
464.1814.
[(S)-1,2,3,4-Tetrahydroisoquinoline-3-yl]phosphonic Acid [(S)-
2a]: Compound (S)-2a was obtained in a way similar to that for (R)-
2a in 92 % yield as a white solid. M.p. 278–280 °C. [α]D = +102.5
(c = 0.40, 1
M NaOH). Spectroscopic data were identical to those
described for (R)-2a.
Diethyl {1-[(Benzyloxycarbonyl)(methoxymethyl)amino]-2-(4-
bromophenyl)ethyl}phosphonate (14b): BF3·OEt2 (182 mg,
0.17 mL, 1.28 mmol) was added under argon to a mixture of com-
pound 8b (200 mg, 0.42 mmol) and dimethoxymethane (1 mL). The
resulting solution was stirred at 35 °C for 36 h. The reaction mixture
was diluted with ethyl acetate (20 mL) and water (20 mL). The or-
ganic layer was separated and washed with saturated aqueous NaH-
CO3 (2 × 20 mL), dried with anhydrous MgSO4, filtered and concen-
trated under reduced pressure to afford compound 14b (193 mg,
88 % yield) as a yellow oil. IR (neat): ν = 1710, 1256, 1091, 1026 cm–1
.
˜
1H NMR (400 MHz, CDCl3): δ = 1.22–1.31 (m, 6 H, CH3CH2O), 2.95–
3.27 (m, 5 H, CH3O, CH2CH), 3.99–4.17 (m, 5 H), 4.66–5.16 (m, 4 H,
CH2N, OCH2Ph), 6.96–7.40 (m, 9 H, Harom) ppm. 13C NMR (asterisk
denotes minor rotamer, 100 MHz, CDCl3): δ = 16.5 (d, J = 5.8 Hz,
CH3CH2O), 33.6 (CH2CH), 55.8 (CH3O), 56.5* (CH3O), 62.6 (OCH2CH3),
Bis(2-{2′-[(benzyloxycarbonyl)amino]-2′-(diethoxyphosphinyl)-
ethyl}-4,5-dimethoxyphenyl)methane (15): IR (neat): ν = 3243,
˜
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1718, 1276, 1028 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.15–1.27 (m,
12 H, CH3CH2O), 2.75–2.88 (m, 2 H, CHCH2), 3.05–3.13 (m, 2 H,
CH2CH), 3.69 (s, 6 H, CH3O), 3.78 (s, 6 H, CH3O), 3.93–4.15 (m, 10 H),
4.31–4.44 (m, 2 H, CHP), 4.88 (AB system, J = 12.3 Hz, 2 H, OCH2Ph),
4.99 (AB system, J = 12.3 Hz, 2 H, OCH2Ph), 5.67 (d, J = 10.1 Hz, 2
H, NH), 6.44 (s, 2 H, Harom), 6.73 (s, 2 H, Harom), 7.13–7.31 (m, 10 H,
Harom) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.4 (d, J = 5.9 Hz,
CH3CH2O), 16.5 (d, J = 5.6 Hz, CH3CH2O), 32.2 (d, J = 4.3 Hz, CH2CH),
35.2 (CH2), 47.9 (d, J = 155.6 Hz, CHP), 55.9 (CH3O), 56.0 (CH3O), 62.6
(d, J = 6.4 Hz, OCH2CH3), 62.8 (d, J = 7.2 Hz, OCH2CH3), 66.9
(OCH2Ph), 112.9, 113.3, 127.2 (d, J = 13.8 Hz), 128.0, 128.2, 128.5,
131.2, 136.5, 147.3, 147.7, 156.1 (d, J = 6.0 Hz, C=O) ppm. 31P NMR
(162 MHz, CDCl3): δ = 24.60 ppm. HRMS (ESI): calcd. for
C45H61N2O14P2 [M + H]+ 915.3598; found 915.3577.
CTQ2010-17436), and the Gobierno de Aragón-FSE (research
group E40).
Keywords: Phosphoisoquinolines · Pictet–Spengler reaction ·
Chiral HPLC separation · Cyclization · Aldehydes · Chiral
resolution · Phosphorylation
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Diethyl (6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-
yl)phosphonate (7d). Method A: Formaldehyde (77 mg, 71 μL,
0.95 mmol, 37 % aqueous solution) was added dropwise to a solu-
tion of compound 5d (200 mg, 0.63 mmol) and 2
N HCl (0.32 mL,
0.64 mmol) in EtOH/water (1:0.1 mL). The solution was stirred at
room temperature for 32 h. The reaction mixture was concentrated
under reduced pressure, diluted with dichloromethane (20 mL), and
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layer was separated, dried with anhydrous MgSO4, filtered, and con-
centrated in vacuo. The residue was purified by column chromatog-
raphy with CH2Cl2/iPrOH (90:10) to give 7d (207 mg, 100 %) as a
yellow oil. IR (neat): ν = 3297, 1244, 1226, 965 cm–1 1H NMR
.
˜
(400 MHz, CDCl3): δ = 1.34 (t, J = 7.1 Hz, 3 H, OCH2CH3), 1.34 (t, J =
7.1 Hz, 3 H, OCH2CH3), 1.89 (br. s, 1 H, NH), 2.76–3.00 (m, 2 H), 3.24
(ddd, J = 15.8, 11.5, 4.5 Hz, 1 H), 3.81 (s, 3 H, OCH3), 3.82 (s, 3 H,
OCH3), 3.96 (s, 2 H), 4.14–4.23 (m, 4 H, OCH2CH3), 6.49 (s, 1 H, Harom),
6.57 (s, 1 H, Harom) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.6 (d, J =
5.6 Hz, OCH2CH3), 28.4, 48.1 (d, J = 16.8 Hz), 51.2 (d, J = 161.8 Hz),
55.9 (OCH3), 56.0 (OCH3), 62.5 (d, J = 6.9 Hz, OCH2CH3), 62.6 (d, J =
7.0 Hz, OCH2CH3), 109.0, 111.8 (d, J = 1.8 Hz), 125.0 (d, J = 15.2 Hz),
127.0 (d, J = 2.0 Hz), 147.6, 147.7 (d, J = 1.3 Hz) ppm. 31P NMR
(162 MHz, CDCl3): δ = 26.27 ppm. HRMS (ESI): calcd. for C15H25NO5P
[M + H]+ 330.1470; found 330.1460. Method B: Trifluoroacetic acid
(1.44 g, 1 mL, 12.63 mmol) was added dropwise to a solution of
compound 5d (200 mg, 0.63 mmol) in dichloromethane (3.2 mL)
and formaldehyde (77 mg, 71 μL, 0.95 mmol, 37 % aqueous solu-
tion) at room temperature. The solution was stirred at room temper-
ature for 5 h. Then, the workup was identically to that before to
obtain 7d in quantitative yield as a yellow oil.
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(6,7-Dihydroxy-1,2,3,4-tetrahydroisoquinolin-3-yl)phosphonic
Acid (2d): Compound 7d (400 mg, 1.2 mmol) was dissolved in 48 %
HBr (5 mL) and refluxed for 3 h. The volatiles were evaporated under
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afford 2d (242 mg, 81 %) as a white solid. M.p. 275–277 °C. IR (neat):
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.
˜
2.97–3.10 (m, 2 H), 3.18–3.28 (m, 1 H), 4.22 (s, 2 H), 6.64 (s, 1 H,
Harom), 6.73 (s, 1 H, Harom) ppm. 13C NMR (100 MHz, D2O, K2CO3):
δ = 26.8, 45.4 (d, J = 6.7 Hz), 53.2 (d, J = 132.0 Hz), 113.4, 115.6,
119.2, 124.1 (d, J = 11.1 Hz), 143.4, 144.4 ppm. 31P NMR (162 MHz,
D2O, K2CO3): δ = 9.99 ppm. HRMS (ESI): calcd. for C9H13NO5P [M +
H]+ 246.0531; found 246.0527.
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Eur. J. Org. Chem. 2016, 2711–2719
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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