Удосконалений синтез ROCKYPhos та його застосування для асиметричного гідрування похідних дигідроізохіноліну
An optimized approach to the multigram synthesis of [(1R,2R,3S)-(+)-1,2-dimethyl-2,3-bis(diphenylphosphinomethyl)cyclopentyl]methanol (ROCKYPhos, CatASium I®), a camphor-derived chiral diphosphine ligand, has been developed. The key improvement in the synthetic scheme involved the oxidative cleavage...
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Journal of Organic and Pharmaceutical Chemistry| _version_ | 1874455190352953344 |
|---|---|
| author | Bilenko, Vitalii A. Gorichko, Marian V. |
| author_facet | Bilenko, Vitalii A. Gorichko, Marian V. |
| author_institution_txt_mv | [
{
"author": "Vitalii A. Bilenko",
"institution": "Enamine Ltd.; Taras Shevchenko National University of Kyiv",
"orcid": ""
},
{
"author": "Marian V. Gorichko",
"institution": "Taras Shevchenko National University of Kyiv",
"orcid": "0000-0002-5401-9597"
}
] |
| author_orcid_str_mv | 0000-0002-5401-9597 |
| author_sort | Bilenko, Vitalii A. |
| baseUrl_str | https://ophcj.nuph.edu.ua/oai |
| collection | OJS |
| container_end_page | 22 |
| container_issue | 1 |
| container_start_page | 13 |
| container_title | Журнал органічної та фармацевтичної хімії |
| container_volume | 24 |
| datestamp_date | 2026-08-24T19:33:19Z |
| description | An optimized approach to the multigram synthesis of [(1R,2R,3S)-(+)-1,2-dimethyl-2,3-bis(diphenylphosphinomethyl)cyclopentyl]methanol (ROCKYPhos, CatASium I®), a camphor-derived chiral diphosphine ligand, has been developed. The key improvement in the synthetic scheme involved the oxidative cleavage of 3,9-dibromocamphor with V2O5 – HNO3 or NH4VO3 – Cu(NO3)2 – HNO3 system, which gave the corresponding dicarboxylic acid in the yield of 28% and significantly reduced the reaction sequence. The NMR study of a diselenide derivative of ROCKYPhos showed that one of the PPh2 groups had strong donor properties comparable to those of trialkylphosphines. The asymmetric hydrogenation of N-acetyl-1,2-dihydroisoquinoline-4-carboxylates in the presence of ROCKYPhos provided target tetrahydroisoquinolines with up to 52% ee – an outstanding result for this substrate class. |
| doi_str_mv | 10.24959/ophcj.26.353838 |
| first_indexed | 2026-04-24T01:00:13Z |
| format | Article |
| fulltext |
ISSN 2308-8303 (Print) / 2518-1548 (Online) 13
Original Research
http://ophcj.nuph.edu.ua
UDC 547.241+544.47:547.831
V. A. Bilenko1,2, M. V. Gorichko2
1 Enamine Ltd., 78 Winston Churchill Street, Kyiv 02094, Ukraine
2 Taras Shevchenko National University of Kyiv, 60 Volodymyrska Str., Kyiv 01601, Ukraine
The improved synthesis of ROCKYPhos and its application
for the asymmetric hydrogenation of dihydroisoquinoline
derivatives
Abstract
An optimized approach to the multigram synthesis of [(1R,2R,3S)-(+)-1,2-dimethyl-2,3-bis(diphenylphosphinomethyl)cyclopen-
tyl]methanol (ROCKYPhos, CatASium I®), a camphor-derived chiral diphosphine ligand, has been developed. The key improvement
in the synthetic scheme involved the oxidative cleavage of 3,9-dibromocamphor with V2O5 – HNO3 or NH4VO3 – Cu(NO3)2 – HNO3
system, which gave the corresponding dicarboxylic acid in the yield of 28 % and significantly reduced the reaction sequence.
The NMR study of a diselenide derivative of ROCKYPhos showed that one of the PPh2 groups had strong donor properties com-
parable to those of trialkylphosphines. The asymmetric hydrogenation of N-acetyl-1,2-dihydroisoquinoline-4-carboxylates
in the presence of ROCKYPhos provided target tetrahydroisoquinolines with up to 52 % ee – an outstanding result for this
substrate class.
Keywords: asymmetric synthesis; phosphine ligands; nitrogen heterocycles; isoquinoline
В. А. Біленко1,2, М. В. Горічко2
1 ТОВ НВП «Єнамін», вул. Вінстона Черчилля, 78, м. Київ, 02094, Україна
2 Київський національний університет імені Тараса Шевченка,
вул. Володимирська, 60, Київ, 01601, Україна
Удосконалений синтез ROCKYPhos та його застосування для асиметричного гідрування
похідних дигідроізохіноліну
Анотація
Було розроблено оптимізований підхід до багатограмового синтезу [(1R,2R,3S)-(+)-1,2-диметил-2,3-біс(дифенілфосфіно-
метил)циклопентил]метанолу (ROCKYPhos, CatASium I®) – хірального дифосфінового ліганду, похідної камфори.
Ключове покращення синтетичної схеми полягало в окиснювальному розщепленні 3,9-дибромкамфори системою
V2O5 – HNO3 або NH4VO3 – Cu(NO3)2 – HNO3, що дало відповідну дикарбонову кислоту з виходом 28 % і суттєво скороти-
ло послідовність реакцій. Дослідження методом ЯМР диселенідного похідного ROCKYPhos показало, що одна з груп
PPh2 має сильні донорні властивості, близькі до відповідних значень для триалкілфосфінів. Асиметричне гідрування
N-ацетил-1,2-дигідроізохінолін-4-карбоксилатів у присутності ROCKYPhos забезпечило утворення цільових тетрагідроізохі-
нолінів з енантіомерним надлишком до 52 % ee, що є видатним результатом для цього класу субстратів.
Ключові слова: асиметричний синтез; фосфінові ліганди; азотовмісні гетероцикли; ізохінолін
Citation: Bilenko, V. A.; Gorichko, M. V. The improved synthesis of ROCKYPhos and its application for the asymmetric hydrogenation
of dihydroisoquinoline derivatives. Journal of Organic and Pharmaceutical Chemistry 2026, 24 (1), 13 – 22.
https://doi.org/10.24959/ophcj.26.353838
Received: 8 January 2026; Revised: 17 February 2026; Accepted: 25 February 2026
Copyright© 2026, V. A. Bilenko, M. V. Gorichko. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0).
Funding: The authors received no specific funding for this work.
Conflict of interests: The authors are employees or consulting scientists at Enamine Ltd., which offers title compounds
from the company’s catalog.
ISSN 2308-8303 (Print) / 2518-1548 (Online) 14
Журнал органічної та фармацевтичної хімії 2026, 24 (1)
■ Introduction
Chiral diphosphines are widely used in va-
rious areas of organic synthesis, but became most
famous for their Nobel prize-winning application
in the asymmetric hydrogenation [1]. Ligands like
BINAP, DIPAMP, or DuPhos (Figure 1) became
classical in this area, and many others were syn-
thesized and evaluated for the preparation of va-
rious enantioenriched products [2]. Nevertheless,
most of them demonstrated a narrow substrate
scope in the case of the asymmetric C=C bond hy-
drogenation, and despite numerous efforts and
considerable achievements for specific substrate
classes (e.g., α-dehydroamino acid derivatives),
there is still no general method. Therefore, any
new information on the possible extension of the
asymmetric olefin hydrogenation scope remains
valuable.
In 2001, Komarov, Börner, and co-authors re-
ported the synthesis of camphor-derived hydroxy-
diphosphine ligand 1 (later named ROCKYPhos
or CatASium I®) and illustrated its efficiency for
the asymmetric hydrogenation of several α- and
β-dehydroamino acid derivatives [3]. The origi-
nal synthetic approach to compound 1 proposed
by authors was lengthy and the involved Bayer-
Villiger oxidation of 9-bromocamphor (4) as one
of the key steps (Scheme 1). This reaction pro-
vided modest yield of target lactone 5 (33 %).
An alternative approach included even more steps,
i.e., the oxidation of ketone 4 with SeO2, the
Bayer-Villiger reaction, and the reduction of the
resulting anhydride 9 (Scheme 2).
In this work, we report our efforts on fur-
ther optimization of the synthesis of ligand 1.
In addition to that, we characterized its donor
properties and evaluated it in the asymmetric
O
P
P
Ph
O
Ph
(R,R)-DIPAMP
PPh2
PPh2
( )-BINAPR
P
P
R
R
R
R
( )-DuPhosR,R
R = Me, Et, Pri
Ph2P
PPh2
Me
MeHO
1, ROCKYPhos
(CatASium I® )
Figure 1. Diphosphine-based ligands used in the asymmetric hydrogenation
Ph2P
PPh2
HO
O O
Br
(+)-Camphor 2
AcOH
Br2
HSO3Cl
Br2
O
Br
3
Br
AcOH
Zn
O
4
Br
MCPBA
TsOH
33 %
O
5
Br
O
LiAlH4
78−100 %
OH
6
Br
OH
TsCl, py
97 %
OH
7
Br
OTs
100 %
O
TsOH
OTHP
8
Br
OTs
1. Ph2PLi
43 % OH
1
Ph2P
PPh2
≡
Scheme 1. The original synthetic approach to compound 1 proposed by Komarov, Börner, and co-authors in 2001
ISSN 2308-8303 (Print) / 2518-1548 (Online) 15
Journal of Organic and Pharmaceutical Chemistry 2026, 24 (1)
hydrogenation of N-acetyl-1,2-dihydroisoquino-
line-4-carboxylates. It should be noted that whi-
le examples of the asymmetric hydrogenation of
β-dehydroamino acid derivatives were reported
in the literature [4, 5], to the best of our knowl-
edge, the method was never applied to the syn-
thesis of enantioenriched tetrahydroisoquinoline
derivatives.
To further shorten the synthetic scheme used
for the preparation of ligand 1, we considered
a direct oxidative cleavage of 3,9-dibromocam-
phor (3) as a possible alternative. We found that
the reaction of compound 3 with 63 % aq. HNO3
at 130 °C, nitro derivative 11 was formed in an
isolated yield of 68 % (Table 1). The addition of
V2O5 led to a mixture of compound 11 (65 % yield)
and target dicarboxylic acid 12 (15 % yield).
Decreasing the HNO3 concentration to 53 % im-
proved the yield of 12 to 28 %. Further dilution
(to 30 % HNO3) was ineffective since the reaction
became too slow. One more variation included the
use of NH4VO3 – Cu(NO3)2 as additives (as re-
ported by Whittaker and co-authors for the oxi-
dation of cyclohexanol to adipic acid [6]). In this
case, the yield of compound 12 was also 28 %.
Unfortunately, a prolonged heating of com-
pound 11 under the reaction conditions did not re-
sult in its transformation to target compound 12.
The reduction of dicarboxylic acid 12 with
LiAlH4 proceeded smoothly and gave target diol 6
in the yield of 96 % (Scheme 3). Further trans-
formation of compound 6 into ligand 1 followed
the reaction sequence shown in Scheme 1.
To estimate the donor properties of diphos-
phine ligand 1, we applied the method based on
the analysis of 1J(31P–77Se) coupling constants in
the corresponding diselenides. The value of
this constant correlated with electron-donating
Me
Me
O
4
Br
Me
Me
O
10
Br
O
LiAlH4
78 100 %–
Me
Me OH
6
Br
OH
SeO2
AcOH
93 %
Me
Me
O
9
Br
O
H2O2
AcOH
92 %
O
Scheme 2. An alternative approach to 6
Table 1. The oxidative cleavage of 3,9-dibromocamphor (3) with HNO3
Me
Me
O
Br
3
Br aq HNO3
Me
Me
12
Br
OHadditive
125 130 °C–
Me
Me
O
BrBr
NO2
+
11
O
OH
O
No. Reaction time, h HNO3 concentration Additive
Yield, %
3 11 12
1 18 63 – – 40 –
2 78 63 – – 68 –
3 78 63 V2O5 – 65 15
4 78 53 V2O5 – 58 28
5 78 30 V2O5 35 12 13
6 78 30 NH4VO3 – Cu(NO3)2 traces 46 28
96 %
LiAlH4
Me
Me OH
6
Br
OH
Me
Me OH
1
Ph2P
PPh2
Me
Me
12
Br
OH
O
HO
O
4 steps
Scheme 1
Scheme 3. Further access to 1 from 12
ISSN 2308-8303 (Print) / 2518-1548 (Online) 16
Журнал органічної та фармацевтичної хімії 2026, 24 (1)
properties of the substituents attached to the
phosphorus atom [7]. The corresponding disele-
nide 13 was prepared by the reaction of com-
pound 1 with Se (Scheme 4).
It was found that the 1J(31P–77Se) values for
compound 13 were 702 Hz and 720 Hz, which was
comparable to those for a bis(dimethylphosphino)-
ethane derivative (1J(31P–77Se) = 706 Hz). This re-
sult suggests that ligand 1 is highly P-donating,
which can be used as a rationale for its high ef-
ficiency potential.
As a further illustration of the promising pro-
perties of ligand 1 in the asymmetric catalysis (in
addition to the previous work [3]), we evaluated
the hydrogenation of N-acetyl-1,2-dihydroisoqui-
noline-4-carboxylates 14a – d. Compounds 14a – d
were obtained from the corresponding esters
15a – d (Scheme 5). For the first step, we used
methoxycarbonylation of commercially available
bromides 16a – d, and the obtained esters 15a – d
were reduced with tributylstannane in the pres-
ence of acetyl chloride to form 14a – d. It was found
that the parent substrate underwent the hydro-
genation smoothly: the conversion was comple-
te after 18 h, and product 17a was obtained with
52 % ee (according to the chiral stationary phase
HPLC) (Table 2). Substituted derivatives 14b – d
reacted much slower. Derivative 14b with the
electron-donating OMe group reached a 90 % con-
version after a week; the corresponding product 17b
was formed with 45 % ee. The hydrogenation of
substrates with electron-withdrawing substitu-
ents (14c, R = Cl, or 14d, R = CF3) was virtually
inefficient.
To confirm the absolute configuration of the ma-
jor enantiomer in product 17a, it was transformed
Me
Me OH
1
Ph2P
PPh2
Me
Me
OH
13
P
P
Se
Se
Ph
Ph
Ph
Ph
CDCl3, 40 °C
18 h
Se
Scheme 4. The reaction of 1 with Se
N
O
O O
R
14a d–
N
O O
R
15a d–
N
Br
R
Bu3SnH, AcCl
CH2Cl2, -78 °C to rt
65 8 %–7
CO (20 atm)
Pd(dppf)Cl2
Et3N, MeOH
90 99 %–
16a d–
a: b: c: d:R = H; R = OMe; R = Cl; R = CF
3
Scheme 5. Obtaining substrates for the hydrogenation
Table 2. The asymmetric hydrogenation of isoquinoline derivatives 14a – d
N Me
O
O O
R
H2 (50 atm), ligand
Rh[COD]BF4
CF3CH2OH, rt
14a d–
N Me
O
O O
R
17a d–
*
Me
Me OH
1
PPh2
PPh2
P
P
Me
Me
Me
Me
18
No. Substrate R Ligand Time, d Conversion, % ee, %
1 14a H 1 0.75 100 52
2 14b OMe 1 7 90 45
3 14c Cl 1 7 67 7
4 14d CF3 1 7 6 –
5 14a H 18 0.75 21 –
6 14a H 18 3 100 0
ISSN 2308-8303 (Print) / 2518-1548 (Online) 17
Journal of Organic and Pharmaceutical Chemistry 2026, 24 (1)
into the known ester 20. The main challenge here
was to avoid racemization at the hydrolysis/
esterification steps. We achieved this by per-
forming the ester hydrolysis with Me3SnOH in
1,2-dichloroethane [8] and then, simultaneous-
ly, the amide hydrolysis and esterification of 19
with HCl in EtOH at 50 °C (Scheme 6). Product
20×HCl had [α]D = +19.7° (c 1.0, MeOH), which
corresponded to (S) enantiomer (according to
the literature data, [α]D = –42.3° (c 1.0, MeOH)
for (R) isomer [8]).
■ Conclusions
An improved and scalable route to the camphor-
derived chiral diphosphine ligand ROCKYPhos
has been developed and validated for the multi-
gram synthesis. The key advancement of the up-
dated strategy is an efficient oxidative cleavage
of 3,9-dibromocamphor upon action of V2O5 – HNO3
or NH4VO3–Cu(NO3)2–HNO3, providing the cor-
responding dicarboxylic acid in the yield of 28 %
while significantly shortening the overall synthe-
tic sequence.
The electronic properties of ROCKYPhos were
investigated by the thNMR analysis of its dise-
lenide derivative, revealing the pronounced do-
nor ability of one of the PPh2 fragment compara-
ble to that of trialkylphosphines.
Finally, ROCKYPhos was successfully applied
in the asymmetric hydrogenation of N-acetyl-
1,2-dihydroisoquinoline-4-carboxylates, giving the
corresponding tetrahydroisoquinolines with enan-
tioselectivities of up to 52 % ee. This level of stereo-
control represents a considerable advancement
for this challenging substrate class and demon-
strates the practical value of ROCKYPhos as a pro-
mising ligand for the asymmetric hydrogenation.
■ Experimental part
General part
The solvents were purified according to the
standard procedures [9]. [1,1’-Bis(diphenylphosphi-
no)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2),
(+)-3,9-dibromocamphor 3, and other starting
reagents were available commercially and ob-
tained from Enamine Ltd. All operations with
compounds 14a – d were performed under the ar-
gon atmosphere in a glove box. Melting points
were measured on the MPA100 OptiMelt auto-
mated melting point system. 1H, 13C{1H}, 19F{1H}
and 31P{1H} NMR spectra were recorded on a Bru-
ker 170 Avance 500 spectrometer (at 500 MHz
for 1H NMR and 126 MHz for 13C{1H} NMR) or
a Varian Unity Plus 400 spectrometer (at 400 MHz
for 1H NMR, 101 MHz for 13C{1H} NMR, and
376 MHz for 19F{1H} NMR), as well as using an
Agilent ProPulse 600 spectrometer (at 600 MHz
for 1H, 151 MHz for 13C{1H} and 243 MHz for
31P{1H}). NMR chemical shifts are reported in ppm
(δ scale) downfield from TMS or CFCl3 (19F) as
an internal standard, and are referenced using
residual NMR solvent peaks in CDCl3 at 7.26 ppm
for 1H and 77.16 ppm for 13C{1H} respectively, in
DMSO-d6 at 2.50 ppm for 1H and 39.52 ppm for
13C{1H}, 4.78 and 3.31 ppm for 1H or 49.15 ppm
for 13C{1H} in CD3OD. H3PO4 (85 % in H2O) used
as an external 31P{1H} standard. Coupling con-
stants (J) are given in Hz. Elemental analyses
were performed at the Laboratory of Organic Ana-
lysis, Department of Chemistry, Taras Shevchen-
ko National University of Kyiv. Mass spectra were
recorded on an Agilent 1100 LC/MSD SL instru-
ment (APCI atmospheric pressure chemical ioni-
zation). High-resolution mass spectra (HRMS)
were obtained on an Agilent 1260 Infinity UHPLC
instrument coupled with an Agilent 6224 Accu-
rate Mass TOF mass spectrometer. Enantiome-
ric excess determinations were obtained by high-
performance liquid chromatography (HPLC) with
chiral columns Chiralpak IA-U (for 17a), Chiral-
cel OJ-H (for 19) and Chiralpak IC (for 20·HCl).
ee Values for 17a, 19, and 20·HCl were not cor-
rected for the chromatogram baseline and may
include minor errors.
(1S,3R,4S,7R)-3-Bromo-7-(bromomethyl)-
1,7-dimethyl-3-nitrobicyclo[2.2.1]heptan-2-
one (11)
The mixture of 3,9-dibromocamphor 3 (0.76 g,
2.45 mmol) and the aq. nitric acid (13 M, 10 mL)
was heated to reflux, and then stirred at this
N Me
O
O O
(CH2Cl)2
94 %
17a
N Me
O
O OH
19
Me3SnOH
EtOH, H2O, 50 °C
99 %
HCl, 1,4-dioxane NH2
O OEt
20 HCl.
Cl* * *
Scheme 6. The confirmation of the absolute configuration of the major enantiomer in product 17a
ISSN 2308-8303 (Print) / 2518-1548 (Online) 18
Журнал органічної та фармацевтичної хімії 2026, 24 (1)
temperature under the argon atmosphere for 78 h.
The solvents were removed under reduced pres-
sure, and distilled water (50 mL) was added to
the residue. The mixture obtained was extracted
with toluene (3×20 mL). The combined organic
phases were dried over Na2SO4, and then concen-
trated under reduced pressure. The crude product
was purified by crystallization from 2-propanol.
A colorless solid. Yield – 0.590 g (68 %). M. p.
98 – 99 °C. [α]D
20 = +43.8 (c 0.5, MeOH). 1H NMR
(500 MHz, CD3OD), δ, ppm: 1.08 (3H, s, CH3),
1.31 – 1.40 (4H, m, CH3 and CH2), 1.64 – 1.74 (1H,
m, CH2), 1.90 – 2.00 (1H, m, CH2), 2.08 – 2.20 (1H,
m, CH2), 3.15 (1H, d, J = 4.3 Hz, CH), 3.38 (1H,
dd, J = 10.8, 1.5 Hz, CH2), 3.82 (1H, d, J = 10.8 Hz,
CH2). 13C{1H} NMR (126 MHz, CD3OD), δ, ppm:
10.3, 20.6, 24.8, 28.9, 39.7, 48.9, 55.8, 60.7, 92.3,
199.9. HRMS (ESI/QTOF), m/z: calculated for
C10H14Br2NO3
+ 353.9335 [M + H]+; found 353.9342.
1-(1S,2R,3S)-2-(Bromomethyl)-1,2-dimethyl-
cyclopentane-1,3-dicarboxylic acid (12)
The mixture of 3,9-dibromocamphor 3 (5.00 g,
16.1 mmol) and vanadium (V) oxide (0.292 g,
1.60 mmol) in the aq. nitric acid (11.3 M, 80 mL,
ca. 53 % in water) was heated to reflux, and then
stirred at the same temperature under the argon
atmosphere for 78 h. Nitric acid was removed
under reduced pressure, a fresh portion of dis-
tilled water (20 mL) was added to the residue,
and the resulting mixture was re-evaporated
under reduced pressure. The residue was mixed
with water (100 mL) and extracted with EtOAc
(3×200 mL). The combined organic phases were
dried over Na2SO4 and concentrated under reduced
pressure. The residue obtained was triturated
with benzene to give 1,3-dicarboxylic acid 12
(1.26 g, 4.5 mmol, 28 % yield).
A colorless solid. Yield – 1.26 g (28 %). M. p.
199 – 201 °C. 1H NMR (500 MHz, DMSO-d6), δ, ppm:
1.04 (3H, s, CH3), 1.22 (3H, s, CH3), 1.40 – 1.49
(1H, m, CH2), 1.80 – 1.99 (2H, m, CH2), 2.38 (1H,
td, J = 12.2, 7.6 Hz, CH2), 3.00 (1H, t, J = 9.3 Hz,
CH), 3.79 (1H, d, J = 10.5 Hz, CH2), 3.89 (1H, d, J
= 10.5 Hz, CH2), 12.34 (2H, s, OH). 13С{1H} NMR
(126 MHz, DMSO-d6), δ, ppm: 18.7, 21.3, 23.6,
33.7, 41.6, 48.7, 50.0, 55.8, 174.6, 176.3. HRMS
(ESI/QTOF), m/z: calculated for C10H15BrO4Na+
301.0046 [M + Na]+; found 301.0039.
((1S,2R,3S)-2-(Bromomethyl)-1,2-dimethyl-
cyclopentane-1,3-diyl)dimethanol (6)
To the stirred solution of dicarboxylic acid 12
(1.26 g, 4.52 mmol) in THF (50 mL), LiAlH4
(0.690 g, 18.1 mmol) was added in portions un-
der the gentle argon gas flow. The suspension
obtained was heated at reflux for 5 h. Upon the
completion, the mixture was cooled to 0 °C using an
ice/water bath and quenched by the addition of wa-
ter (1.5 mL) under vigorous stirring. Then EtOAc
(300 mL) was added, the cooling bath was remo-
ved, and the resulting suspension was stirred for
2 h at r.t., then dried over Na2SO4 (50.0 g), fil-
tered, and the filtrate was concentrated under
reduced pressure. The residual viscous oil was
dissolved in the CH2Cl2/MeOH mixture (300 mL,
9:1, v/v) and filtered through a small column
packed with SiO2 (approx. 100 g). The eluate con-
taining the product was collected and concentra-
ted under reduced pressure to give the title com-
pound 6, which was used further as obtained.
A colorless powder. Yield 1.08 g (96 %).
The spectral and physical data are consistent with
those previously reported [3].
{[(1R,2S,3S)-2-{[diphenyl(selanylidene)-λ5-
phosphanyl]methyl}-3-(hydroxymethyl)-2,3-
dimethylcyclopentyl]methyl}diphenyl-λ5-
phosphaneselone (13)
In an NMR vial, selenium (16.5 mg, 0.208 μmol)
was added to the solution of diphosphine 1 (65 mg,
0.095 μmol) in CDCl3 under the argon atmosphere.
The reaction mixture was heated to 40 °C and
shaken vigorously at that temperature overnight.
The compound was characterized directly by the
NMR analysis without further isolation or puri-
fication.
An orange solution. 1H NMR (400 MHz, CDCl3),
δ, ppm: 0.69 – 0.91 (1H, m), 1.07 (3H, s, CH3), 1.14
(3H, s, CH3), 1.17 – 1.36 (3H, m, CH2), 2.32 (1H,
dt, J = 14.2, 9.9 Hz), 2.56 – 2.73 (1H, m), 2.82
(1H, t, J = 14.8 Hz, CH), 3.11 – 3.23 (2H, m, CH2),
3.45 (1H, t, J = 15.6 Hz, CH2), 3.81 (1H, d, J =
11.9 Hz, CH2), 7.22 – 7.33 (2H, m, Ph), 7.32 – 7.53
(10H, m, Ph), 7.70 – 7.81 (2H, m, Ph), 7.79 – 7.93
(2H, m, Ph), 7.92 – 8.07 (4H, m, Ph). 13C{1H}
NMR (101 MHz, CDCl3), δ, ppm: 14.7 (d, JCP =
10.5 Hz), 33.9 (d, JCP = 46.2 Hz), 34.2, 35.4 (d, JCP
= 46.5 Hz), 44.9 (d, JCP = 6.2 Hz), 48.8 (dd, JCP
= 12.5, 4.5 Hz), 48.9 (d, JCP = 12.9 Hz), 49.9 (d,
JCP = 4.8 Hz), 67.6, 128.5 (d, JCP = 12.2 Hz), 128.7
(d, JCP = 12.0 Hz), 131.4 (dd, JCP = 9.2, 3.0 Hz),
131.6 (d, JCP = 14.3 Hz), 131.7 (d, JCP = 14.6 Hz),
132.5 (t, JCP = 11.4 Hz), 133.4 (dd, JCP = 74.2,
5.76 Hz). 31P{1H} NMR (243 MHz, CDCl3), δ, ppm:
28.0 (JPSe = 702.8 Hz), 36.6 (JPSe = 720.0 Hz).
The general procedure for the prepara-
tion of compounds 15a – d
In an autoclave, to the solution of the corre-
sponding 4-bromoisoquinoline 16 (10.0 mmol) in
MeOH (100 mL), Pd(dppf)Cl2 (0.220 g, 0.3 mmol)
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Journal of Organic and Pharmaceutical Chemistry 2026, 24 (1)
and Et3N (1.7 mL, 12.0 mmol, 1.22 g) were subse-
quently added at 25 °C. The reaction vessel was
purged with argon for 5 min, then filled with CO
from a gas cylinder. The reaction mixture was
vigorously stirred at the temperatures indicated
(80 °C for 15a,c; 120 °C for 15b; 110 °C for 15d)
under the CO atmosphere at 20 bar for 16 h (with
the conversion monitored by the LC-MS analysis
of the reaction aliquots). Upon the completion,
the reaction mixture was concentrated under re-
duced pressure, and the residue was triturated
with the anhydrous THF (10 mL) and filtered.
The filtrate was evaporated under reduced pres-
sure, and the residual crude product was used
in the next step without further purification.
Methyl isoquinoline-4-carboxylate (15a)
The compound was synthesized according to the
General Procedure from 16a (3.00 g, 14.4 mmol).
The reaction mixture was stirred at 80 °C for 16 h.
Beige crystals. Yield – 2.64 g (98 %). M. p.
81 – 82 °C. 1H NMR (400 MHz, DMSO-d6), δ, ppm:
3.97 (3H, s, CH3), 7.79 (1H, t, J = 7.6 Hz, Ar), 7.95
(1H, t, J = 7.7 Hz, Ar), 8.26 (1H, d, J = 8.2 Hz,
Ar), 8.76 (1H, d, J = 8.7 Hz, Ar), 9.05 (1H, s, Ar),
9.53 (1H, s, Ar). LC-MS, m/z (APCI): 188 [M+H]+.
The analytical data are consistent with those pre-
viously reported [10].
Methyl 6-methoxyisoquinoline-4-carboxylate (15b)
The compound was synthesized according to the
General Procedure from 16b (2.50 g, 10.5 mmol).
The reaction mixture was stirred at 120 °C over-
night.
A colorless powder. Yield – 2.04 g (90 %). M. p.
122 – 124 °C. Anal. Calcd. for C12H11NO3, %: C 66.35;
H 5.10; N 6.45. Found, %: C 66.07; H 5.47; N 6.38.
1H NMR (400 MHz, CDCl3), δ, ppm: 4.01 (3H, s,
CH3), 4.02 (3H, s, CH3), 7.29 (1H, dd, J = 9.0, 2.5 Hz,
Ar), 7.91 (1H, d, J = 9.0 Hz, Ar), 8.40 (1H, d, J =
2.5 Hz, Ar), 9.18 (1H, s, Ar), 9.22 (1H, s, Ar).
13С{1H} NMR (126 MHz, CDCl3), δ, ppm: 52.2, 55.7,
103.1, 119.0, 120.9, 124.5, 130.1, 136.5, 148.0, 156.0,
162.8, 167.3. LC-MS, m/z (APCI): 218 [M+H]+.
Methyl 6-chloroisoquinoline-4-carboxylate (15c)
The compound was synthesized according to the
General Procedure from 16c (2.44 g, 10.0 mmol).
The reaction mixture was stirred at 80 °C for 18 h.
A light-brown powder. Yield – 2.03 g (92 %).
M. p. 111 – 112 °C. Anal. Calcd. for C11H8ClNO2, %:
C 59.61; H 3.64; N 6.32; Cl 15.99. Found, %: C 59.93;
H 3.82; N 6.60; Cl 16.11. 1H NMR (400 MHz,
DMSO-d6), δ, ppm: 3.96 (3H, s, CH3), 7.83 (1H,
dt, J = 8.8, 2.0 Hz, Ar), 8.31 (1H, dd, J = 8.8,
1.8 Hz, Ar), 8.82 (1H, s, Ar), 9.10 (1H, s, Ar), 9.55
(1H, s, Ar). 13С{1H} NMR (101 MHz, DMSO-d6),
δ, ppm: 52.5, 118.8, 123.2, 126.4, 128.6, 130.9, 133.3,
137.7, 147.0, 157.1, 165.8. HRMS (ESI/QTOF), m/z:
calculated for C11H9ClNO2
+ 222.0316 [M+H]+;
found 222.0314.
Methyl 6-(trifluoromethyl)isoquinoline-4-carboxy-
late (15d)
The compound was synthesized according to the
General Procedure from 16d (2.80 g, 10.2 mmol).
The reaction mixture was stirred at 110 °C over-
night.
A brown powder. Yield – 2.57 g (99 %). M. p.
76 – 78 °C. 1H NMR (500 MHz, CDCl3), δ, ppm:
4.06 (3H, s, CH3), 7.87 (1H, dd, J = 8.5, 1.7 Hz,
Ar), 8.18 (1H, d, J = 8.5 Hz, Ar), 9.31 (1H, s, Ar),
9.37 (1H, s, Ar,), 9.47 (1H, s, Ar). 13С{1H} NMR
(126 MHz, CDCl3), δ, ppm: 52.7, 121.0, 123.4 (q,
3JCF = 4.7 Hz), 123.7 (q, 3JCF = 2.6 Hz), 123.8 (q,
1JCF = 272.9 Hz), 129.3, 129.5, 133.3, 133.8 (q,
2JCF = 32.5 Hz), 148.1, 157.1, 166.4. 19F{1H} NMR
(376 MHz, DMSO-d6), δ, ppm: −62.2. HRMS
(ESI/QTOF), m/z: calculated for C12H9F3NO2
+
256.0580 [M+H]+ ; found 256.0575.
The general procedure for the prepara-
tion of compounds 14a – d
To a pre-cooled to −78 °C solution of the corre-
sponding ester 15a – d (1 mmol) in CH2Cl2 (6 mL),
Bu3SnH (0.292 g, 1 mmol), and neat acetyl chlo-
ride (79.0 μL, 1.1 mmol, 87.0 mg) were sequen-
tially added with stirring under the argon atmo-
sphere. The reaction mixture was stirred, main-
taining the same temperature for 2 h. The cool-
ing bath was then removed, and the reaction
mixture gradually warmed to rt with stirring.
In case of the incomplete conversion (as deter-
mined by LC-MS of a small aliquot of the reac-
tion mixture), the reaction mixture was treated
with additional separate portions of Bu3SnH and
acetyl chloride at −40 °C, with stirring main-
tained at this temperature under the argon at-
mosphere for 2 h before warming to rt. Once the
reaction was complete, a sat. aq. NH4Cl solution
was added, and the mixture was stirred over-
night. The layers were separated, the organic
layer was then dried over Na2SO4 and concen-
trated under reduced pressure. The residual cru-
de product was purified by the trituration with
hexane/tBuOMe mixture (5 mL, 4:1, v/v).
Methyl 2-acetyl-1,2-dihydroisoquinoline-4-carboxy-
late (14a)
The compound was synthesized according to the
General Procedure from 15a (0.750 g, 4.00 mmol).
A beige powder. Yield – 0.668 g (72 %). M.p.
88 – 91 °C. 1H NMR (500 MHz, CDCl3), δ, ppm:
2.34 (3H, s, CH3), 3.86 (3H, s, CH3), 4.88 (2H,
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Журнал органічної та фармацевтичної хімії 2026, 24 (1)
s, CH2), 7.11 (1H, d, J = 7.5 Hz, Ar), 7.21 (1H,
t, J = 7.4 Hz, Ar), 7.28 (1H, t, J = 7.7 Hz, Ar),
7.86 (1H, s, CH), 8.16 (1H, d, J = 8.0 Hz, Ar).
13С{1H} NMR (151 MHz, CDCl3), δ, ppm: 21.5,
44.9, 51.8, 110.4, 125.1, 126.1, 127.8, 128.1, 128.2,
128.9, 136.7, 166.1, 169.3. HRMS (ESI/QTOF),
m/z: calculated for C13H14NO3
+ 232.0968 [M + H]+;
found 232.0971.
Methyl 2-acetyl-6-methoxy-1,2-dihydroisoquino-
line-4-carboxylate (14b)
The compound was synthesized according to the
General Procedure from 15b (0.560 g, 2.58 mmol).
A colorless powder. Yield – 0.522 g (78 %).
M.p. 86 – 87 °C. Anal. Calcd. for C14H15NO4, %:
C 64.36; H 5.79; N 5.36. Found, %: C 64.43; H 5.83;
N 5.06. 1H NMR (500 MHz, CDCl3), δ, ppm: 2.34
(3H, s, CH3), 3.83 (3H, s, CH3), 3.86 (3H, s), 4.83
(2H, s, CH2), 6.77 (1H, dd, J = 8.8, 2.3 Hz, Ar), 7.02
(1H, d, J = 8.5 Hz, Ar), 7.83 (1H, s, Ar), 7.89 (1H,
s, CH). 13С{1H} NMR (126 MHz, CDCl3), δ, ppm:
21.5, 44.5, 51.8, 55.5, 103.4, 110.6, 113.6, 121.0,
127.0, 129.3, 137.2, 159.5, 166.1, 169.3 (the com-
pound demonstrated a significant decomposi-
tion rate in the solution). LC-MS, m/z (APCI):
262 [M+H]+.
Methyl 2-acetyl-6-chloro-1,2-dihydroisoquino-
line-4-carboxylate (14c)
The compound was synthesized according to the
General Procedure from 15c (0.325 g, 1.50 mmol).
A yellowish solid. Yield 0.260 g (67 %). M.p.
112 – 114 °C. Anal. Calcd. for C13H12ClNO3, %:
C 58.77; H 4.55; N 5.27; Cl 13.34. Found, %:
C 58.81; H 4.68; N 5.40; Cl 13.22. 1H NMR
(400 MHz, CDCl3), δ, ppm: 2.35 (3H, s, CH3),
3.87 (3H, s, CH3), 4.85 (2H, s, CH2), 7.03 (1H, d,
J = 8.1 Hz, Ar), 7.18 (1H, dd, J = 8.1, 2.2 Hz, Ar),
7.91 (1H, s, CH), 8.23 (1H, s, Ar). 13С{1H} NMR
(101 MHz, CDCl3), δ, ppm: 21.5, 44.5, 52.0, 109.1,
125.2, 127.0, 127.3, 127.6, 129.8, 134.1, 137.7,
165.7, 169.3. LC-MS, m/z (APCI): 266 [M+H]+.
Methyl 2-acetyl-6-(trifluoromethyl)-1,2-dihy-
droisoquinoline-4-carboxylate (14d)
The compound was synthesized according to the
General Procedure from 15d (0.250 g, 1.00 mmol).
A beige powder. Yield – 0.192 g (65 %). M.p.
104 – 106 °C. Anal. Calcd. for C14H12F3NO3, %:
C 56.19; H 4.04; N 4.68. Found, %: C 56.42;
H 4.25; N 4.72. 1H NMR (400 MHz, CDCl3), δ, ppm:
δ 2.37 (3H, s, CH3), 3.89 (3H, s, CH3), 4.95 (2H,
s, CH2), 7.22 (1H, d, J = 8.0 Hz, Ar), 7.47 (1H, d,
J = 8.5 Hz, Ar), 7.96 (1H, s, CH), 8.54 (1H, s, Ar).
13С{1H} NMR, δ, ppm: the spectrum is uninforma-
tive due to the compound decomposition during
NMR processing. LC-MS, m/z (APCI): 300 [M+H]+.
Methyl 2-acetyl-1,2,3,4-tetrahydroisoquino-
line-4-carboxylate (17a)
The mixture of isoquinoline methyl carboxy-
late 14a (500.0 mg, 2.16 mmol), bis(1,5-cycloocta-
diene)rhodium(I) tetrafluoroborate (43.9 mg,
108.1 µmol) and [(1R,2R,3S)-2,3-bis[(diphenyl-
phosphanyl)methyl]-1,2-dimethylcyclopentyl]me-
thanol 1 (56.7 mg, 108.1 µmol) was dissolved in
degassed CF3CH2OH (5 mL). All operations with
reagents for the asymmetric hydrogenation were
performed in a glove box. The solution obtained
was transferred to the autoclave. Subsequently,
the autoclave was evacuated and backfilled with
H2 (50 bar) from a gas cylinder. The reaction
mixture was vigorously stirred at 20 °C for 18 h.
The solvent was evaporated under reduced pres-
sure, and the residue was purified by the flash
column chromatography (tBuOMe/MeOH = 1:0
to 5:1, v/v as an eluent) to give tetrahydroisoqui-
noline methyl carboxylate 17a.
A viscous oil. Yield – 451.0 mg (1.94 mmol, 89 %).
1H NMR (400 MHz, CDCl3), the compound exists
as a mixture of rotamers (ca. 2:1) δ, ppm: 2.18
(0.36×3H, s, CH3), 2.25 (0.64×3H, s, CH3), 3.57
(0.64×1H, dd, J = 13.4, 4.1 Hz, CH2), 3.64 – 3.69
(0.36×1H, m, CH2), 3.71 (3H, m, CH3), 3.87 (1H, dt,
J = 12.7, 4.3 Hz, CH), 4.34 (0.64×1H, dd, J = 13.4,
3.6 Hz, CH2), 4.42 (0.64×1H, d, J = 17.4 Hz, CH2
AB system), 4.47 (0.36×1H, dd, J = 13.3, 5.1 Hz,
CH2), 4.60 (0.36×1H, d, J = 16.2 Hz, CH2 AB sys-
tem), 4.74 (0.36×1H, d, J = 16.2 Hz, CH2 AB sys-
tem), 5.06 (0.64×1H, d, J = 17.6 Hz, CH2 AB sys-
tem), 7.12 – 7.25 (2H, m, Ph), 7.28 (2H, t, J = 6.6 Hz,
Ph). 13С{1H} NMR (101 MHz, CDCl3), the compound
exists as a mixture of rotamers (ca. 2:1) δ, ppm:
21.5 and 21.9, 41.6 and 44.2, 44.3 and 45.0,
45.5 and 48.1, 52.5 and 52.6, 126.5 and 126.7,
127.0 and 127.3, 127.8 and 128.0, 129.2 and
129.7, 129.9 and 130.6, 133.3 and 133.8, 169.9
and 170.3, 172.0 and 172.5. HRMS (ESI/QTOF),
m/z: calcd. for C13H15NO3Na+ 256.0944 [M + Na]+;
found 256.0951. ee = 52 % (determined by chiral
HPLC).
The general procedure for the synthesis
of tetrahydroisoquinoline-4-carboxylates
rac-17 (prepared for the ee determination)
In a high-pressure vessel to the solution of the
corresponding dihydroisoquinoline-4-carboxyla-
te 14a (0.50 mol) in MeOH (5 mL), Pd/C (10 %
w/w, 50.0 mg) was added in one portion. The re-
action vessel was evacuated and backfilled with
H2 from a gas cylinder (repeated twice), and the
suspension was kept at rt with intensive stir-
ring under the H2 atmosphere at 50 bar for 24 h.
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Journal of Organic and Pharmaceutical Chemistry 2026, 24 (1)
The catalyst was filtered off, the filter cake was
washed with MeOH (3×2 mL). The filtrate was
concentrated under reduced pressure, the re-
mained solid was dried under a high vacuum
(1 mmHg) to give the title product (±)-17a.
2-Acetyl-1,2,3,4-tetrahydroisoquinoline-
4-carboxylic acid (19)
To the solution of tetrahydroisoquinoline
methyl carboxylate (0.400 g, 1.72 mmol) in di-
chloroethane (50 mL), neat trimethylstannanol
(0.936 g, 5.17 mmol) was added. The reaction
mixture was heated to reflux and kept with stir-
ring at that temperature for 18 h. After cooling
to room temperature, the resulting solution was
diluted with CH2Cl2 (100 mL), washed with the
aq. 1 M solution of NaHSO4 (2×50 mL), then
a sat. aq. solution of NaCl (40 mL). The organic
layer was separated, dried over Na2SO4, and con-
centrated under reduced pressure to give the crude
title compound, which was used in the next step
without further purification. The analytical sample
was obtained after the purification by the reverse-
phase HPLC (performed on a puriFlash C18-HP
column using CH3CN–H2O–0.1 %HCOOH gradi-
ents).
A colorless powder. Yield – 0.353 g (94 %).
M. p. 155 – 157 °C. ee 53 % (determined by HPLC).
1H NMR (400 MHz, CD3OD), the compound ex-
ists as a mixture of rotamers (ca. 2:1) δ, ppm:
2.18 (0.34×3H, s, CH3), 2.24 (0.66×3H, s, CH3),
3.50 (0.34×1H, dd, J = 13.2, 4.6 Hz, CH2), 3.58
(0.64×1H, dd, J = 13.6, 4.1 Hz, CH2), 3.88
(0.34×1H, t, J = 4.4 Hz, CH), 3.91 (0.64×1H, t,
J = 3.6 Hz, CH), 4.34 (0.64×1H, d, J = 17.3 Hz,
CH2 AB system), 4.35 – 4.47 (0.66×1H, m, CH2),
4.56 (0.34×1H, dd, J = 13.2, 4.2 Hz, CH2), 4.65
(0.34×1H, d, J = 16.4 Hz, CH2 AB system), 4.79
(0.34×1H, d, J = 16.4 Hz, CH2 AB system), 5.01
(0.64×1H, d, J = 17.3 Hz, CH2 AB system),
7.15 – 7.36 (4H, m, Ph). 13С{1H} NMR (101 MHz,
CD3OD), the compound exists as a mixture of
rotamers (ca. 2:1) δ, ppm: 21.4 and 21.7, 42.8,
45.5 and 45.7, 45.1 and 46.7, 127.5 and 127.64,
127.60, 128.0 and 128.7, 130.1 and 130.8, 132.8
and 133.5, 134.0 and 134.1, 172.6 and 172.9,
175.1 and 175.6. HRMS (ESI/QTOF), m/z:
calculated for C12H14NO3
+ 220.0968 [M + H]+; found
220.0964.
Ethyl 1,2,3,4-tetrahydroisoquinoline-4-
carboxylate hydrochloride (20×HCl)
To the solution of tetrahydroisoquinoline
carboxylic acid 19 (100.0 mg, 0.456 mol) in
EtOH (5 mL), aq. HCl (0.2 mL, 10 M) was add-
ed. The resulting mixture was stirred at 50 °C
for 9 days. After the completion of the reaction
(by 1H NMR spectra of the small aliquots of the
reaction mixture) all volatiles were removed un-
der reduced pressure. The residue was dissolved
in a dry EtOH (4 mL), the solution was acidi-
fied with an anhydrous HCl (0.2 mL, ca. 3.6 M
in 1,4-dioxane) and then stirred at 50 °C for 36
h. The reaction mixture was concentrated under
reduced pressure to give tetrahydroisoquinoline
hydrochloride 20 with a sufficient purity.
A colorless powder. Yield 109.6 mg (99 %).
M. p. 124 – 126 °C. ee 57 % (determined by HPLC).
[α]D
20 = +19.7 (c 1.0, MeOH) (lit. [α]D = –42.3° (c 1.0,
MeOH) [8]). Anal. Calcd. for C12H16ClNO2: C 59.63;
H 6.67; N 5.79; Cl 14.67. Found: C 60.02; H 6.39;
N 5.62; Cl 14.59. 1H NMR (400 MHz, DMSO-d6),
δ, ppm: 1.23 (3H, t, J = 7.1 Hz, CH3), 3.54 (2H, d,
J = 6.2 Hz, CH2), 4.18 (2H, q, J = 7.1 Hz, CH2),
4.22 – 4.31 (3H, m, CH2 and CH), 7.25 – 7.30
(1H, m, Ph), 7.32 (2H, dt, J = 7.2, 3.6 Hz, Ph),
7.35 – 7.39 (1H, m, Ph). 13С{1H} NMR (101 MHz,
DMSO-d6), δ, ppm: 14.4, 40.9, 42.2, 43.8, 61.8,
127.6, 128.1, 128.2, 128.9, 129.6, 129.7, 171.2.
LC-MS, m/z (APCI): 206 [M+H]+. The spectral and
physical data were consistent with those previ-
ously reported [8].
■ Acknowledgements
The work was supported by Enamine Ltd.
The authors thank Prof. Dr. Igor V. Komarov and
Prof. Dr. Oleksandr O. Grygorenko for helpful dis-
cussions, Dr. Anastasiia Hurieva, Dr. Oleksandr
Liashuk, and Prof. Dr. Oleksandr O. Grygorenko
for their help in preparing the manuscript, Prof.
Dr. Andriy O. Tolmachov for his encouragement
and support, and all the brave defenders of
Ukraine for making this publication possible.
■ References
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Information about the authors:
Vitalii A. Bilenko (corresponding author), Ph.D. Student at the Educational and Scientific Institute of High Technologies,
Taras Shevchenko National University of Kyiv; Head of the Laboratory, Enamine Ltd; https://orcid.org/0009-0001-4428-4821;
e-mail for correspondence: v.bilenko@enamine.net.
Marian V. Gorichko, Ph. D. in Chemistry, Associate Professor of the Organic Chemistry Department, Chemical Faculty,
Taras Shevchenko National University of Kyiv; https://orcid.org/0000-0002-5401-9597.
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| id | oai:ojs.journals.uran.ua:article-353838 |
| institution | Journal of Organic and Pharmaceutical Chemistry |
| issn | 2518-1548 |
| keywords_txt_mv | |
| language | English |
| last_indexed | 2026-08-25T01:02:52Z |
| publishDate | 2026 |
| publisher | National University of Pharmacy |
| record_format | ojs |
| resource_txt_mv | ophcjnupheduua/10/d2e44ae6b0060d81212e666fa9e05510.pdf |
| spelling | oai:ojs.journals.uran.ua:article-3538382026-08-24T19:33:19Z The improved synthesis of ROCKYPhos and its application for the asymmetric hydrogenation of dihydroisoquinoline derivatives Удосконалений синтез ROCKYPhos та його застосування для асиметричного гідрування похідних дигідроізохіноліну Bilenko, Vitalii A. Gorichko, Marian V. асиметричний синтез фосфінові ліганди азотовмісні гетероцикли ізохінолін asymmetric synthesis phosphine ligands nitrogen heterocycles isoquinoline An optimized approach to the multigram synthesis of [(1R,2R,3S)-(+)-1,2-dimethyl-2,3-bis(diphenylphosphinomethyl)cyclopentyl]methanol (ROCKYPhos, CatASium I®), a camphor-derived chiral diphosphine ligand, has been developed. The key improvement in the synthetic scheme involved the oxidative cleavage of 3,9-dibromocamphor with V2O5 – HNO3 or NH4VO3 – Cu(NO3)2 – HNO3 system, which gave the corresponding dicarboxylic acid in the yield of 28% and significantly reduced the reaction sequence. The NMR study of a diselenide derivative of ROCKYPhos showed that one of the PPh2 groups had strong donor properties comparable to those of trialkylphosphines. The asymmetric hydrogenation of N-acetyl-1,2-dihydroisoquinoline-4-carboxylates in the presence of ROCKYPhos provided target tetrahydroisoquinolines with up to 52% ee – an outstanding result for this substrate class. Було розроблено оптимізований підхід до багатограмового синтезу [(1R,2R,3S)-(+)-1,2-диметил-2,3-біс(дифенілфосфінометил)циклопентил]метанолу (ROCKYPhos, CatASium I®) – хірального дифосфінового ліганду, похідної камфори. Ключове покращення синтетичної схеми полягало в окиснювальному розщепленні 3,9-дибромкамфори системою V2O5 – HNO3 або NH4VO3 – Cu(NO3)2 – HNO3, що дало відповідну дикарбонову кислоту з виходом 28% і суттєво скоротило послідовність реакцій. Дослідження методом ЯМР диселенідного похідного ROCKYPhos показало, що одна з груп PPh2 має сильні донорні властивості, близькі до відповідних значень для триалкілфосфінів. Асиметричне гідрування N-ацетил-1,2-дигідроізохінолін-4-карбоксилатів у присутності ROCKYPhos забезпечило утворення цільових тетрагідроізохінолінів з енантіомерним надлишком до 52% ee, що є видатним результатом для цього класу субстратів. National University of Pharmacy 2026-05-04 Article Article application/pdf application/pdf https://ophcj.nuph.edu.ua/article/view/353838 10.24959/ophcj.26.353838 Journal of Organic and Pharmaceutical Chemistry; Vol. 24 No. 1 (2026); 13-22 Журнал органической и фармацевтической химии; Том 24 № 1 (2026); 13-22 Журнал органічної та фармацевтичної хімії; Том 24 № 1 (2026); 13-22 2518-1548 2308-8303 en https://ophcj.nuph.edu.ua/article/view/353838/345461 https://ophcj.nuph.edu.ua/article/view/353838/344298 Copyright (c) 2026 Vitalii A. Bilenko, Marian V. Gorichko http://creativecommons.org/licenses/by/4.0 |
| spellingShingle | асиметричний синтез фосфінові ліганди азотовмісні гетероцикли ізохінолін Bilenko, Vitalii A. Gorichko, Marian V. Удосконалений синтез ROCKYPhos та його застосування для асиметричного гідрування похідних дигідроізохіноліну |
| title | Удосконалений синтез ROCKYPhos та його застосування для асиметричного гідрування похідних дигідроізохіноліну |
| title_alt | The improved synthesis of ROCKYPhos and its application for the asymmetric hydrogenation of dihydroisoquinoline derivatives |
| title_full | Удосконалений синтез ROCKYPhos та його застосування для асиметричного гідрування похідних дигідроізохіноліну |
| title_fullStr | Удосконалений синтез ROCKYPhos та його застосування для асиметричного гідрування похідних дигідроізохіноліну |
| title_full_unstemmed | Удосконалений синтез ROCKYPhos та його застосування для асиметричного гідрування похідних дигідроізохіноліну |
| title_short | Удосконалений синтез ROCKYPhos та його застосування для асиметричного гідрування похідних дигідроізохіноліну |
| title_sort | удосконалений синтез rockyphos та його застосування для асиметричного гідрування похідних дигідроізохіноліну |
| topic | асиметричний синтез фосфінові ліганди азотовмісні гетероцикли ізохінолін |
| topic_facet | асиметричний синтез фосфінові ліганди азотовмісні гетероцикли ізохінолін asymmetric synthesis phosphine ligands nitrogen heterocycles isoquinoline |
| url | https://ophcj.nuph.edu.ua/article/view/353838 |
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