Ruthenium-catalyzed cyclotrimerization of α-amino-α-propargyl carboxylates and phosphonates with 1,6-diynes: Synthesis of α-CF3-containing phenylalanine derivatives and their P-analogs

Article abstract of DOI:10.1007/s11172-014-0762-9

Ruthenium-catalyzed cocyclotrimerization of α-amino-α-propargyl-α-trifluoromethyl carboxylates and phosphonates with functional 1,6-diynes gives the corresponding CF₃-containing phenylalanine derivatives and their phosphorus analogs.

Full text of DOI:10.1007/s11172-014-0762-9

Russian Chemical Bulletin, International Edition, Vol. 63, No. 11, pp. 2455—2460, November, 2014
2455
Rutheniumꢀcatalyzed cyclotrimerization of -aminoꢀꢀpropargyl carboxylates
and phosphonates with 1,6ꢀdiynes: synthesis
of ꢀCF3ꢀcontaining phenylalanine derivatives and their Pꢀanalogs*
M. A. Zotova, T. P. Vasilyeva, and S. N. Osipov
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5085. Eꢀmail: osipov@ineos.ac.ru
Rutheniumꢀcatalyzed cocyclotrimerization of ꢀaminoꢀꢀpropargylꢀꢀtrifluoromethyl
carboxylates and phosphonates with functional 1,6ꢀdiynes gives the corresponding CF3ꢀconꢀ
taining phenylalanine derivatives and their phosphorus analogs.
Key words: 1,6ꢀdiynes, acetyleneꢀcontaining ꢀamino acids, ꢀamino phosphonates,
cyclotrimerization, trifluoromethylphenylalanine, ruthenium complexes, organofluorine
compounds.
Over last two decades, transition metal complexꢀcataꢀ
lyzed intraꢀ and intermolecular cyclotrimerization reacꢀ
tions of acetylenes became of a wide use as a versatile
synthesis of substituted aromatic and heteroaromatic comꢀ
pounds.1 Catalysts based on transition metal complexes,
most often those of cobalt and rhodium, were successfully
used in cyclotrimerization of alkynes as a key step in the
preparation of a series of biological important structures,
including natural compounds.2
lineꢀ3ꢀcarboxylic acid derivatives and their phosphorus
analogs (Scheme 1).6 In continuation of these studies, in
the present work we report the synthesis of new derivatives
of CF3ꢀphenylalanine and their P analogs.
Scheme 1
At the same time, the introduction of ꢀtrifluoromethylꢀ
containing ꢀamino acids at the strategically important
positions of bioactive peptides can considerably improve
their metabolic stability, lipophilicity, and selectivity of
binding with bioreceptors due to the electronꢀwithdrawꢀ
ing nature, a large hydrophobic size of the CF3 group, as
well as to the ability of fluorine atoms to form hydrogen
bonds.3 Therefore, development of efficient methods for
the synthesis of new representatives of ꢀCF3ꢀꢀamino
acids and their phosphorus analogs4 is an actual problem
for both the fundamental and applied studies.
R1 = Ph; R2 = C4H9, C6H13, Ph; Y = Co2Me, P(O)(OEt)2;
PG = Boc, Cbz
Despite the fact that cyclotrimerization of alkynes is
actively used in the synthesis of functionally substituted
benzenes, only several examples of the preparation of
ꢀamino acid derivatives are known5 using this strategy.
Earlier, we have shown that ꢀCF3ꢀꢀamino carboxylꢀ
ates and ꢀCF3ꢀꢀamino phosphonates of a 1,7ꢀdiyne seꢀ
ries underwent cyclotrimerization with terminal alkynes
with the formation of the corresponding tetrahydroquinoꢀ
Results and Discussion
The synthesis of ꢀCF3ꢀcontaining phenylalanine deꢀ
rivatives was carried out using a rutheniumꢀcatalyzed
cyclotrimerization of functional 1,6ꢀdiynes with terminal
alkynes. The alkynes were represented by the propargylꢀ
containing ꢀCF3ꢀꢀamino carboxylates 1a,b (see Ref. 7)
and ꢀCF3ꢀꢀamino phosphonate 2 (see Ref. 8).
As the starting 1,6ꢀdiynes, we used commercially availꢀ
able dipropargyl ether and synthesized NꢀtosylꢀN,Nꢀdiproꢀ
pargylamine,9 diethyl dipropargylmalonate,10 and Nꢀtosylꢀ
N,Nꢀdi(butꢀ2ꢀynꢀ1ꢀyl)amine.11
* Dedicated to Academician of the Russian Academy of Sciences
Yu. N. Bubnov on the occasion of his 80th birthday and to the
60th anniversary of A. N. Nesmeyanov Institute of Organoꢀ
element Compounds of the Russian Academy of Sciences.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2455—2460, November, 2014.
1066ꢀ5285/14/6311ꢀ2455 © 2014 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 63, No. 11, November, 2014
Zotova et al.
Scheme 2
A model reaction of ꢀCF3ꢀꢀamino carboxylate 1a
with dipropargyl ether was used to select the optimal conꢀ
ditions (Scheme 2).
The analysis of the 19F NMR spectra of the reaction mixꢀ
ture showed that the conversion 1a3a was 42%. The
target product 3a was isolated by column chromatography
in a low yield (20%). We also isolated and characterꢀ
ized the side products 4 (15%) and 5 (10%). The use of
rhodium catalyst (Wilkinson´s catalyst RhCl(PPh3)3) inꢀ
stead of ruthenium one did not essentially improve yield of
the desired product and the conversion of the starting CF3ꢀ
containing acetylene component.
Initially, we found that the mixing of compound 1a
with two equivalents of dipropargyl ether at ~20 C
in dichloroethane in the presence of 5 mol.% of
Cp*RuCl(COD) causes a fast completion of the reaction
with the formation of a fourꢀcomponent mixture (TLC
data), consisting of the product 3a, the unreacted starting
acetylene 1a, as well as of the products of selfꢀcyclotriꢀ
merization of dipropargyl ether of dimeric 4 and trimeric
structure 5 (Scheme 3, Table 1).
As a result of a thorough selection of the reaction conꢀ
ditions (amount of catalyst, ratio of reactants, temperaꢀ
ture, reaction time, and order of mixing of components),
Scheme 3
1: Y = Co2Me (a, b), PG = Boc (a), Cbz (b);
2: Y = P(O)(OEt)2, PG = Cbz
Table 1. Yield of products 3a—d,f and 6a—d
Entry
X
Y
R
PG
Conversion
of alkynea (%)
Product
Yieldb
(%)
1
2
3
4
5
6
7
8
9
O
N—Ts
N—Ts
N—Ts
C(CO2Et)2
O
N—Ts
C(CO2Et)2
N—Ts
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
H
H
H
Me
H
H
H
H
Me
Boc
Boc
Cbz
Boc
Cbz
Cbz
Cbz
Cbz
Cbz
70
80
90
85
90
75
88
86
80
3a
3b
3c
3d
3f
6a
6b
6c
6d
50
65
62
54
68c
45
55
58
56
a Determined by 19F NMR spectroscopy.
b The yield after column chromatography.
c Contained ~20% of the type 5 trimerization product of the starting diyne.

CF3ꢀContaining phenylalanines
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 11, November, 2014 2457
Scheme 4
we increased the conversion of compound 1a to 76% and
minimized the formation of the side products 4 and 5.
This was achieved by a slow addition (over 1 h) of two
equivalents of dipropargyl ether to a mixture of compounds
1a and 3 mol.% of Cp*RuCl(COD) in dichloroethane at
40 C. The target product 3a was isolated by column chroꢀ
matography in 50% yield.
ing group from the amino function, thus making the
difference between the Rf values of these compounds
large enough for the separation of the products on a colꢀ
umn. Thus, the corresponding cyclotrimerization prodꢀ
uct was isolated as a free amino ester 7 in 52% yield
(Scheme 5).
These conditions were used in the series of reactions of
amino carboxylates 1a and 1b and amino phosphonate 2
with 1,6ꢀdiynes (see Scheme 3, Table 1). The highest conꢀ
version of the starting acetylenes was 75—90%, insignifiꢀ
cant amounts of side products of selfꢀcyclotrimerization
of the starting 1,6ꢀdiynes similar to compounds 4 and 5
were also identified in the reaction mixtures. The target
products 3 and 6 were isolated in the pure form by column
chromatography on silica gel in yields from moderate to good.
However, in the reactions of alkynes 1 and 2 with
Nꢀtosylꢀcontaining diynes (see Scheme 3, Table 1, entries 3,
7, and 9), column chromatography has proved inefficient
because of the close Rf values of the product and the correꢀ
sponding dimeric impurity with a triple bond of type 4.
Therefore, to purify the product from this impurity, we
used a technique based on the CuIꢀcatalyzed 1,3ꢀdipolar
acetyleneꢀazide cycloaddition ("click" reaction). The reꢀ
action mixture obtained after cyclotrimerization was treatꢀ
ed with benzyl azide in the presence of copper sulfate and
sodium ascorbate in a mixture of water—tertꢀbutanol and
stirred for 8 h at ~20 C (Scheme 4). The triazole formed
from the side acetylene derivative was filtered off, the tarꢀ
get product was isolated by column chromatography.
In the case of the reaction of compound 1b with diproꢀ
pargylmalonate (see Scheme 3, Table 1, entry 5), a similar
purification problem was caused by the close Rf values
for the target product and the selfꢀcyclotrimerization prodꢀ
uct without triple bond of type 5. Therefore, the reacꢀ
tion mixture containing 80% of compound 3f was subjectꢀ
ed to catalytic hydrogenolysis to remove the Cbz protectꢀ
Scheme 5
To illustrate a possibility of further modification of
new compounds, in particular, in the peptide synthesis at
the Cꢀterminal position, we carried out the saponification
reaction of the ester group in product 3b, which gave acid
8 in 91% yield (Scheme 6).
In conclusion, based on the Ruꢀcatalyzed cocyclotriꢀ
merization of ꢀaminoꢀꢀpropargylꢀꢀtrifluoromethyl
carboxylates and amino phosphonates with symmetric
1,6ꢀdiynes we have developed a convenient method for
the synthesis of new functionally substituted ꢀCF3ꢀpheꢀ
nylalanine derivatives and their phosphorus analogs, whose
aromatic ring is fused to the fiveꢀmembered heteroꢀ or
carbocycles.

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Zotova et al.
Scheme 6
Methyl Nꢀtertꢀbutoxycarbonylꢀ3ꢀ{2ꢀ[(4ꢀmethylphenyl)sulfꢀ
onyl]ꢀ2,3ꢀdihydroꢀ1Hꢀisoindolꢀ5ꢀyl}ꢀ2ꢀ(trifluoromethyl)alaninate
(3b). The yield was 65%, oil. 1H NMR (300 MHz, CDCl3), :
1.51 (s, 9 H, (CH3)3); 2.47 (s, 3 H, CH3); 3.41 (d, CH2, J = 13.9 Hz);
3.90 (s, 3 H, OCH3); 4.15—4.19 (m, 1 H, CH2); 4.61 (d, 4 H,
NCH2, J = 5.6 Hz); 5.53 (br.s, 1 H, NH); 7.07—7.11 (m, 3 H,
Ar); 7.38 (d, 1 H, Ar, J = 7.8 Hz); 7.81 (d, Ar, J = 8.2 Hz). 19F NMR
(282 MHz, CDCl3), : 4.65 (s, 3 F, CF3). 13C NMR (101 MHz,
CDCl3), : 21.5, 28.2, 53.5, 53.5, 53.8, 66.9 (q, J = 28.4 Hz),
80.7, 122.5, 123.9 (q, J = 289.0 Hz), 124.4, 127.6, 129.5, 129.8,
133.4, 133.9, 135.6, 136.5, 143.7. Found (%): C, 55.36; H, 5.40;
N, 5.14. C25H29F3N2O6S. Calculated (%): C, 55.34; H, 5.39;
N, 5.16.
Methyl Nꢀbenzyloxycarbonylꢀ3ꢀ{2ꢀ[(4ꢀmethylphenyl)sulfꢀ
onyl]ꢀ2,3ꢀdihydroꢀ1Hꢀisoindolꢀ5ꢀyl}ꢀ2ꢀ(trifluoromethyl)alaninate
(3c). The yield was 62%, oil. 1H NMR (300 MHz, CDCl3),
: 2.47 (s, 3 H, CH3); 3.40 (d, 1 H, CH2, J = 13.9 Hz); 3.88
(s, 3 H, OCH3); 4.21 (d, 1 H, CH2, J = 14.0 Hz); 4.44 (q, 2 H,
CH2, J = 13.1 Hz); 4.58 (s, 2 H, CH2); 5.08 (d, 1 H, CH2,
J = 12.2 Hz); 5.30 (d, 1 H, CH2, J = 12.1 Hz); 5.83 (s, 1 H, NH);
6.88—7.03 (m, 3 H, Ar); 7.36—7.47 (m, 7 H, Ar); 7.80 (d, 2 H,
Ar, J = 8.2 Hz). 19F NMR (282 MHz, CDCl3), : 4.64 (s, 3 F,
CF3). 13C NMR (101 MHz, CDCl3), : 21.5, 54.0, 53.6, 53.4,
67.1 (q, J = 28.4 Hz), 67.2, 122.6, 123.8 (q, J = 289.0 Hz), 124.2,
127.6, 128.7, 128.6, 128.7, 129.5, 129.8, 133.0, 134.0, 135.6,
136.0, 136.7, 143.7, 154.1, 166.5. Found (%): C, 58.35; H, 4.71;
N, 4.88. C28H27F3N2O6S. Calculated (%): C, 58.33; H, 4.72;
N, 4.86.
Methyl Nꢀtertꢀbutoxycarbonylꢀ3ꢀ{4,7ꢀdimethylꢀ2ꢀ[(4ꢀmethꢀ
ylphenyl)sulfonyl]ꢀ2,3ꢀdihydroꢀ1Hꢀisoindolꢀ5ꢀyl}ꢀ2ꢀ(trifluoroꢀ
methyl)alaninate (3d). The yield was 54%, oil. 1H NMR (300 MHz,
CDCl3), : 1.47 (s, 9 H, (CH3)3); 2.17 (br.s., 6 H, CH3); 2.46
(s, 3 H, CH3); 3.46 (d, 1 H, CH2, J = 14.9 Hz); 3.82 (s, 3 H,
OCH3); 3.88 (br.s., 1 H, CH2); 4.59 (s, 4 H, NCH2); 5.39 (br.s.,
1 H, NH); 6.87 (s, 1 H, Ar); 7.38 (d, 2 H, Ar, J = 8.0 Hz); 7.84
(d, 2 H, Ar, J = 8.2 Hz). 19F NMR (282 MHz, CDCl3), : 4.51
(s, 3 F, CF3). 13C NMR (101 MHz, CDCl3), : 15.3, 18.3, 21.5,
28.2, 53.4, 53.9, 65.5 (q, J = 27.8 Hz), 81.0 (m), 124.1 (q,
J = 288.1 Hz), 127.6, 129.4, 129.5, 129.9, 130.9, 131.6, 134.1,
134.2, 136.0, 143.7, 153.5, 167.0. Found (%): C, 56.80; H, 5.85;
N, 4.89. C27H33F3N2O6S. Calculated (%): C, 56.83; H, 5.83;
N, 4.91.
5ꢀ[(Propꢀ2ꢀynyloxy)methyl]ꢀ1,3ꢀdihydroisobenzofuran (4).
1H NMR (300 MHz, CDCl3), : 2.21 (t, 1 H, CH, J = 3.0 Hz);
4.46 (d, 2 H, CH2, J = 2.9 Hz); 4.65 (s, 2 H, CH2); 4.76 (s, 2 H,
OCH2); 4.77 (s, 2 H, OCH2); 7.14—7.25 (m, 3 H, Ar).
Found (%): C, 76.65; H, 6.37. C12H12O2. Calculated (%):
C, 76.57; H, 6.43.
5,5´ꢀOxybis(methylene)bis(1,3ꢀdihydroisobenzofuran) (5).
1H NMR (300 MHz, CDCl3), : 4.63 (s, 4 H, CH2); 4.75 (s, 4 H,
OCH2); 4.78 (s, 4 H, OCH2); 7.15—7.27 (m, 6 H, Ar).
Found (%): C, 76.67; H, 6.36. C18H18O3. Calculated (%):
C, 76.57; H, 6.43.
Diethyl 1ꢀbenzyloxycarbonylaminoꢀ1ꢀ(1,3ꢀdihydroꢀ2ꢀbenzoꢀ
furanꢀ5ꢀylmethyl)ꢀ2,2,2ꢀtrifluoroethyl]phosphonate (6a). The
yield was 45%, oil. 1H NMR (300 MHz, CDCl3), : 1.18 (t, 3 H,
CH3, J = 7.1 Hz); 1.28 (t, 3 H, CH3, J = 7.1 Hz); 3.66—3.76 (m,
2 H, CH2); 3.89—4.26 (m, 4 H, OCH2); 4.92 (s, 2 H, CH2); 4.98
(s, 2 H, CH2); 5.18 (q, 2 H, CH2, J = 12.4 Hz); 6.57 (d, 1 H,
NH, J = 8.0 Hz); 7.14 (d, 1 H Ar, J = 8.3 Hz); 7.20 (d, 2 H, Ar,
J = 6.7 Hz); 7.35—7.48 (m, 5 H, Ar). 19F NMR (282 MHz,
Experimental
NMR spectra were recorded on Bruker Avanceꢀ300, ꢀ400,
and ꢀ600 spectrometers (300, 400, and 600 MHz for 1H NMR
(TMS), respectively; 101 or 151 MHz for 13C NMR; 282 or 376
MHz for 19F NMR (CF3CO2H); 121 or 161 MHz for 31P NMR
(H3PO4)). Elemental analysis for all the compounds obtained
was carried out in the Laboratory of Microanalysis of the A. N.
Nesmeyanov Institute of Organoelement Compounds of the Rusꢀ
sian Academy of Sciences. Solvents used in the work were puriꢀ
fied according to the standard procedures. Merck Kieselgel 60
silica gel was used for column chromatography.
Rutheniumꢀcatalyzed cyclotrimerization (general procedure).
A solution of alkyne (1 equiv.) and Cp*Ru(Cod)Cl (3 mol.%) in
anhydrous dichloroethane (10 mL) was thrice degassed upon coolꢀ
ing. The solution obtained was heated to 40 C, followed by
a dropwise addition of a solution of 1,6ꢀdiyne (2 equiv.) in anhyꢀ
drous dichloroethane over 1 h. The reaction mixture was stirred
at 40 C until the reaction reached completion (TLC monitorꢀ
ing). The solvent was evaporated at reduced pressure, the crude
product was purified by column chromatography on silica gel
(eluent dichloromethane—EtOAc or light petroleum—EtOAc).
Removal of acetylene side products by 1,3ꢀdipolar cycloaddiꢀ
tion. A reaction mixture obtained after cyclotrimerization was
concentrated dry. The content of the acetylene impurity was
determined by 1H NMR spectroscopy. The dry residue was disꢀ
solved in a mixture of ButOH—H2O (1 : 1), followed by the adꢀ
dition of a solution of benzyl azide (1.1 equiv.) in the same
solvents, sodium ascorbate (30 mol.%), and CuSO4•5H2O
(5 mol.%) (all the components were calculated on the acetylene
impurity). The reaction mixture was stirred for 12 h at 20 C,
then treated with 1N HCl, and extracted with ethyl acetate. The
combined organic layer was dried with MgSO4. The solvent was
evaporated at reduced pressure, the crude product was purified
by column chromatography on silica gel (eluent dichloroꢀ
methane—EtOAc or light petroleum—EtOAc).
Methyl Nꢀtertꢀbutoxycarbonylꢀ3ꢀ(1,3ꢀdihydroꢀ2ꢀbenzofuranꢀ
5ꢀyl)ꢀ2ꢀ(trifluoromethyl)alaninate (3a). The yield was 50%, oil.
1H NMR (300 MHz, CDCl3), : 1.52 (s, 9 H, (CH3)3); 3.47
(d, 1 H, CH2, J = 13.7 Hz); 3.93 (s, 3 H, OCH3); 4.20 (d, 1 H,
CH2, J = 13.5 Hz); 5.12 (d, 4 H, OCH2, J = 6.2 Hz); 5.59 (br.s,
1 H, NH); 7.09—7.21 (m, 3 H, Ar). 19F NMR (282 MHz,
CDCl3), : 4.76 (s, 3 F, CF3). 13C NMR (101 MHz, CDCl3), :
28.2, 33.7 (m), 53.8, 67.0 (q, J = 27.9 Hz), 73.4, 73.4, 80.7 (m),
120.9, 122.8, 125.4, 132.8, 138.6, 139.6, 153.5, 166.9. Found (%):
C, 55.50; H, 5.71; N, 3.58. C18H22F3NO5. Calculated (%):
C, 55.52; H, 5.70; N, 3.60.

CF3ꢀContaining phenylalanines
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 11, November, 2014 2459
CDCl3), : 10.27 (d, 3 F, CF3, J = 3.6 Hz). 31P NMR (161 MHz,
CDCl3), : 16.79 (d, J = 3.7 Hz). 13C NMR (101 MHz, CDCl3),
: 15.6 (dd, J = 18.0 Hz, J = 5.8 Hz); 63.2 (d, J = 7.2 Hz); 63.4
(d, J = 7.0 Hz); 63.9 (dq, J = 27.0 Hz, J = 151.2 Hz); 66.3, 72.6,
72.7, 120.3, 123.4, 124.8 (q, J = 285.2 Hz), 128.1, 128.1, 128.4,
130.1, 133.5 (d, J = 7.4 Hz), 136.9, 138.2, 139.1, 154.7 (d,
J = 7.8 Hz). Found (%): C, 55.07; H, 5.44; N, 2.80. C23H27F3NO6P.
Calculated (%): C, 55.09; H, 5.43; N, 2.79.
methanol (10 mL), followed by the addition of 10% Pd/C
(0.016 mmol). A suspension obtained was degassed twice and
stirred for 3 h in the hydrogen atmosphere at 20 C. The catalyst
was filtered off, the solvent was evaporated in vacuo to obtain
a pure product 7.
Diethyl 5ꢀ[2ꢀaminoꢀ3,3,3ꢀtrifluoroꢀ2ꢀ(methoxycarbonyl)ꢀ
propyl]ꢀ1,3ꢀdihydroꢀ2Hꢀindeneꢀ2,2ꢀdicarboxylate (7). The yield
was 52%, oil. 1H NMR (600 MHz, CDCl3), : 1.24 (td, 6 H,
CH3, J = 7.1 Hz, J = 1.8 Hz); 1.35—2.20 (m, 2 H, NH2); 2.97
(d, 1 H, CH2, J = 13.4 Hz); 3.39 (d, 1 H, CH2, J = 13.4 Hz);
3.55 (d, 4 H, CH2, J = 3.6 Hz); 3.78 (s, 3 H, OCH3); 4.19 (qd, 4 H,
OCH2, J = 7.1 Hz, J = 2.5 Hz), 7.08 (d, 1 H, Ar, J = 7.7 Hz);
7.13—7.19 (m, 2 H, Ar). 19F NMR (282.4 MHz, acetoneꢀd6),
: 0.92 (s, 3 F, CF3). 13C NMR (151 MHz, acetoneꢀd60, : 13.4,
38.5, 39.8, 40.0, 52.5, 60.0, 61.3, 65.7 (q, J = 25.9 Hz); 124.0,
125.3 (q, J = 284.5 Hz); 126.2, 129.0, 132.6, 139.3, 140.4, 168.8,
171.1. Found (%): C, 55.66; H, 5.60; N, 3.27. C20H24F3NO6.
Calculated (%): C, 55.68; H, 5.61; N, 3.25.
2ꢀtertꢀButoxycarbonylaminoꢀ2ꢀ({2ꢀ[(4ꢀmethylphenyl)sulfonꢀ
yl]ꢀ2,3ꢀdihydroꢀ1Hꢀisoindolꢀ5ꢀyl}methyl)ꢀ3,3,3ꢀtrifluoroproꢀ
panoic acid (8). Amino ester 3b (0.4 mmol) was dissolved in 5%
solution of KOH in methanol (6 mL). The mixture obtained was
stirred for 12 h at 20 C. The solvent was evaporated in vacuo,
the residue was diluted with water and acidified with 1N HCl to
neutrality. The solution obtained was extracted with ethyl acetate.
The combined organic layers were dried with MgSO4. After reꢀ
moval of the solvent in vacuo, product 8 was obtained in the
analytically pure form. The yield was 91%, oil. 1H NMR
(400 MHz, CDCl3), : 1.33 (s, 9 H, (CH3)3); 2.36 (s, 3 H, CH3);
2.89 (br.s., 1 H, OH); 3.43 (d, 1 H, CH2, J = 12.8 Hz); 3.78 (d, 2 H,
CH2, J = 12.8 Hz); 4.35—4.49 (m, 4 H, NCH2); 6.30 (s, 1 H,
NH); 6.93 (d, 1 H, Ar, J = 7.8 Hz); 7.15—7.21 (m, 2 H, Ar); 7.35
(d, 2 H, Ar, J = 8.1 Hz); 7.70 (d, 2 H, Ar, J = 8.2 Hz). 19F NMR
(282 MHz, CDCl3), : 4.00 (s, 3 F, CF3). 13C NMR (101 MHz,
CDCl3), : 21.5, 28.6, 33.7, 54.5 (d, J = 2.8 Hz); 67.0 (q, J =
= 25.1 Hz); 79.4, 118.3, 120.3 (qd, J = 8.6 Hz, J = 244.9 Hz);
123.0, 125.8, 128.5, 130.9, 131.1, 134.5, 135.2, 136.5, 136.8,
145.0, 154.6, 169.3. Found (%): C, 54.49; H, 5.12; N, 5.36.
C24H27F3N2O6S. Calculated (%): C, 54.54; H, 5.15; N, 5.30.
Diethyl [1ꢀbenzyloxycarbonylaminoꢀ1ꢀ({2ꢀ[(4ꢀmethylphenꢀ
yl)sulfonyl]ꢀ2,3ꢀdihydroꢀ1Hꢀisoindolꢀ5ꢀyl}methyl)ꢀ2,2,2ꢀtriꢀ
1
fluoroethyl]phosphonate (6b). The yield was 55%, oil. H NMR
(300 MHz, CDCl3), : 1.19 (t, 3 H, CH3, J = 7.1 Hz); 1.34 (t, 3 H,
CH3, J = 7.1 Hz); 2.46 (s, 3 H, CH3); 3.54—4.25 (m, 6 H, CH2);
4.48 (s, 2 H, NCH2); 4.60 (s, 2 H, NCH2); 5.21 (dd, 2 H, CH2,
J = 29.1 Hz, J = 12.1 Hz); 5.34 (d, 1 H, NH, J = 9.8 Hz);
7.03—7.14 (m, 3 H, Ar); 7.36 (d, 2 H, Ar, J = 8.0 Hz); 7.46 (m, 5 H,
Ar); 7.80 (d, Ar, J = 8.2 Hz). 19F NMR (282 MHz, CDCl3),
: 10.19 (d, 3 F, CF3, J = 3.8 Hz). 31P NMR (161 MHz, CDCl3),
: 15.64 (d, J = 3.5 Hz). 13C NMR (101 MHz, CDCl3), : 16.0
(d, J = 5.5 Hz); 16.26 (d, J = 5.9 Hz); 21.5, 33.3, 53.5, 53.6, 63.8
(q, J = 7.2 Hz), 63.8 (dq, J = 27.1, 150.6 Hz); 64.1 (q, J = 7.2 Hz);
67.4, 122.1, 124.4 (q, J = 287.8 Hz); 125.1, 127.6, 128.6, 128.7,
129.8, 130.7, 133.6, 133.7, 133.9, 135.1, 135.9, 136.0, 143.7,
154.5 (d, J = 10.1 Hz). Found (%): C, 55.08; H, 5.21; N, 4.30.
C30H43F3N2O7PS. Calculated (%): C, 55.04; H, 5.23; N, 4.28.
Diethyl 5ꢀ(2ꢀbenzyloxycarbonylaminoꢀ2ꢀdiethoxyphosphorylꢀ
3,3,3ꢀtrifluoropropyl)ꢀ1,3ꢀdihydroꢀ2Hꢀindeneꢀ2,2ꢀdicarboxylate
(6c). The yield was 58%, oil. 1H NMR (300 MHz, CDCl3),
: 1.18 (t, 3 H, CH3, J = 7.0 Hz); 1.27—1.35 (m, 9 H, CH3); 3.52
(s, 2 H, NCH2); 3.57 (s, 2 H, NCH2); 3.80—4.27 (m, 10 H,
CH2); 5.22 (dd, 2 H, CH2, J = 24.7 Hz, J = 12.1 Hz); 5.38 (d, 1 H,
NH, J = 10.5 Hz); 7.03—7.13 (m, 3 H, Ar); 7.38—7.46 (m, 5 H,
Ar). 19F NMR (282 MHz, CDCl3), : 10.25 (d, 3 F, CF3,
J = 4.1 Hz). 31P NMR (161 MHz, CDCl3), : 15.65 (d, J = 4.2 Hz).
13C NMR (101 MHz, CDCl3), : 14.1, 16.2 (dd, J = 14.5 Hz,
J = 5.8 Hz); 33.7, 40.3, 40.5, 60.6, 61.7, 63.8 (d, J = 6.7 Hz);
64.0 (d, J = 7.2 Hz); 64.0 (dq, J = 27.5 Hz, J = 151.1 Hz); 67.4,
123.8, 124.7 (q, J = 287.1 Hz); 127.0, 128.5, 128.5, 128.7, 130.0,
132.6 (d, J = 5.9 Hz); 136.2, 139.2, 140.0, 154.6 (d, J = 10.6 Hz);
171.7 (d, J = 2.9 Hz). Found (%): C, 56.01; H, 5.78; N, 2.17.
C30H37F3NO9P. Calculated (%): C, 55.99; H, 5.79; N, 2.18.
Diethyl [1ꢀbenzyloxycarbonylaminoꢀ1ꢀ({4,7ꢀdimethylꢀ2ꢀ[(4ꢀ
methylphenyl)sulfonyl]ꢀ2,3ꢀdihydroꢀ1Hꢀisoindolꢀ5ꢀyl}methyl)ꢀ
2,2,2ꢀtrifluoroethyl]phosphonate (6d). The yield was 56%, oil.
1H NMR (300 MHz, CDCl3), : 1.26 (t, 3 H, CH3, J = 7.1 Hz);
1.34 (t, 3 H, CH3, J = 7.2 Hz); 2.09 (s, 3 H, CH3); 2.18 (s, 3 H,
CH3); 2.46 (s, 3 H, CH3); 3.53—3.71 (m, 2 H, CH2); 3.97—4.31
(m, 4 H, OCH2); 4.58—4.59 (m, 4 H, NCH2); 5.17 (q, 2 H,
CH2, J = 12.1 Hz); 5.28 (d, 1 H, NH, J = 12.0 Hz); 6.99 (s, 1 H,
Ar); 7.34—7.47 (m, 7 H, Ar); 7.83 (d, 2 H, Ar, J = 8.3 Hz).
19F NMR (282 MHz, CDCl3), : 9.23 (d, 3 F, CF3, J = 4.1 Hz).
31P NMR (161 MHz, CDCl3), : 16.25 (d, J = 4.1 Hz). 13C NMR
(101 MHz, CDCl3), : 15.5, 16.2 (dd, J = 7.7 Hz, J = 6.1 Hz);
18.2, 21.5, 30.5, 53.4, 53.9, 62.6 (dq, J = 27.3 Hz, J = 151.9 Hz);
64.0 (dd, J = 24.1 Hz, J = 7.3 Hz); 67.3, 124.7 (qd, J = 3.4 Hz,
J = 287.3 Hz); 127.5, 128.3, 128.4, 128.6, 129.2, 129.8, 130.0,
131.8 (d, J = 6.8 Hz); 132.1, 134.0, 134.0, 135.8, 135.9, 143.6,
154.2 (d, J = 7.9 Hz). Found (%): C, 56.28; H, 5.60; N, 4.13.
C32H38F3N2O7PS. Calculated (%): C, 56.30; H, 5.61; N, 4.10.
Removal of the Cbz protecting group. A crude alkynylꢀconꢀ
taining amino ester 3f (0.26 mmol) was dissolved in anhydrous
This work was financially supported by the Russian
Foundation for Basic Research (Project Nos 12ꢀ03ꢀ00557
and 12ꢀ03ꢀ93111).
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Received July 22, 2014