Synthesis of methyl (E)-2-[(3S,4S)-4-hydroxy-3-(pent-3-yloxy)-pyrrolidin-2- ylidene]propanoate and its unusual recyclization

Article abstract of DOI:10.1007/s11172-013-0168-0

Methyl (2E,4S,5S)-5-hydroxy-6-mesyloxy-2-methyl-4-(pent-3-yloxy)hex-2- enoate was synthesized from l-tartaric acid. Attempted substitution of the mesyloxy group by the reaction with NaN₃ directly led to methyl (E)-2-[(3S,4S)-4-hydroxy-3-(pent-3

Full text of DOI:10.1007/s11172-013-0168-0

Russian Chemical Bulletin, International Edition, Vol. 62, No. 5, pp. 1227—1231, May, 2013
1227
Synthesis of methyl (E)ꢀ2ꢀ[(3S,4S)ꢀ4ꢀhydroxyꢀ3ꢀ(pentꢀ3ꢀyloxy)ꢀ
pyrrolidinꢀ2ꢀylidene]propanoate and its unusual recyclization
F. A. Gimalova,a G. M. Khalikova,b V. A. Egorov,a A. G. Mustafin,b and M. S. Miftakhova
aInstitute of Organic Chemistry, Ufa Research Center of the Russian Academy of Sciences,
71 prosp. Oktyabrya, 450054 Ufa, Russian Federation.
Eꢀmail: bioreg@anrb.ru
bBashkir State University, Department of Chemistry,
32 ul. Z. Validi, 450074 Ufa, Russian Federation
Methyl (2E,4S,5S)ꢀ5ꢀhydroxyꢀ6ꢀmesyloxyꢀ2ꢀmethylꢀ4ꢀ(pentꢀ3ꢀyloxy)hexꢀ2ꢀenoate was
synthesized from Lꢀtartaric acid. Attempted substitution of the mesyloxy group by the reaction
with NaN3 directly led to methyl (E)ꢀ2ꢀ[(3S,4S)ꢀ4ꢀhydroxyꢀ3ꢀ(pentꢀ3ꢀyloxy)pyrrolidinꢀ2ꢀ
ylidene]propanoate. The latter on treatment with CF3COOH and then NaOH gave methyl
(2E)ꢀ2ꢀmethylꢀ4ꢀ[(S)ꢀoxiranꢀ2ꢀyl]ꢀ4ꢀ(pentꢀ3ꢀyloxy)butꢀ2ꢀenoate.
Key words: Lꢀtartaric acid, mesylates, azides, heterocyclization, pyrrolidines, recyclization.
Scheme 1
Heterocyclic secondary enamines bearing electronꢀ
withdrawing groups at the double bond are important interꢀ
mediates in the synthesis of natural and heterocyclic comꢀ
pounds.1—5 The latter can be conveniently synthesized by
the intramolecular 1,3ꢀdipolar azide—olefin cyclization
reactions.6—10
During development of a procedure for the synthesis of
seco analog of known antiviral agent Tamiflu, i.e., comꢀ
pound 1 (see Refs 11—14), based on Lꢀtartaric acid, the
standard step of the replacement of the OMs group in
compound 2 with the N3 group led, instead of the expectꢀ
ed azide 3, to the pyrrolidine derivative 4 (Scheme 1).
The synthesis of the starting mesylate 2 is shown in
Scheme 2. Ketal 5 obtained from Lꢀtartaric acid15 was
reduced with LiAlH4 to diol 6. Its oxidation with pyridinꢀ
ium dichromate was fairly selective and stopped at the
formation of hemiacetal 7. The latter reacted with phosꢀ
phorane 8 stereoselectively giving rise to (E)ꢀ,ꢀunsaturꢀ
ated ester 9. The reductive opening of the ketal function in
compound 9 with the system Et3SiH—TiCl4 (see Ref. 16)
led to diols 10 and 11 in the ratio ~3 : 2. The selectivity
of this step was somewhat improved by the use of Si
derivative 12, in this case alcohols 13 and 14 were
formed in the ratio 2 : 1. The mesylation of diol 10 was
also selective, leading to the primary mesylate 2 in high
yield. The more efficient pathway for the synthesis of
compound 2 was accomplished by the dioxolane ring openꢀ
ing in mesylate 15 with Et3SiH—TiCl4, which led to
the regioselective formation of single compound 2 in
high yield.
as well as on the results of the TEMPOꢀcatalyzed oxidaꢀ
tion of compound 14 with PhI(OAc)2 (see Ref. 17) to the
unambiguously spectroscopically identifiable enone 16
(Scheme 3).
Then, mesylate 2 was subjected to the azide substituꢀ
tion, however, no expected azide 3 was obtained. Instead,
pyrrolidine derivative 4 was isolated in good yield (Scheme 4).
The indicated geometry of the double bond in pyrrolidine 4
was confirmed by the NOE experiment: the nuclear Overꢀ
hauser effect (2.0%) was observed for the proton C(3´)—H
The structures of diols 10 and 11 and silyl derivatives
13 and 14 were assigned based on the spectroscopic data,
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1227—1231, May, 2013.
1066ꢀ5285/13/6205ꢀ1227 © 2013 Springer Science+Business Media, Inc.

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Gimalova et al.
Scheme 2
Scheme 4
upon irradiation of the protons of the CH3—C=C group.
Unlike compound 2, mesylate 15 in the reaction with
NaN3 gave the expected azide 17, which seems more
promising building block on the way to seco analog 1 (see
Scheme 4).
Pyrrolidine derivatives 4 cannot be used in the syntheꢀ
sis of compound 1. However, the unusual recyclization of
this compound in CF3COOH—THF discovered herein is
of undoubted interest (Scheme 5). The TLC monitoring
showed that the dropwise addition of a solution of comꢀ
pound 4 in THF to the mixture of CF3COOH—THF (1 : 10)
at 0 C rapidly led to a new product, which in the course of
neutralization with aqueous NaOH (pH > 8) was convertꢀ
ed to the low polar epoxide 18. Its spectroscopic characꢀ
teristics and the Rf values agree with those for the authenꢀ
tic sample 18 obtained by treatment of mesylate 2 with
NaHCO3 in aqueous ethanol. Additional studies are reꢀ
quired to establish the mechanism of the formation of
compound 18.
Scheme 5
Scheme 3
In conclusion, optically active methyl (E)ꢀ2ꢀ[(3S,4S)ꢀ
4ꢀhydroxyꢀ3ꢀ(pentꢀ3ꢀyloxy)pyrrolidinꢀ2ꢀylidene]propꢀ
anoate (4) was synthesized from Lꢀtartaric acid in nine
steps and its unusual recyclization to epoxide 18 was disꢀ
covered.

Pyrrolidine recyclization
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 5, May, 2013
1229
M = 257.1622. MS, m/z (Irel (%)): 257 [M]+ (3), 239 [M – H2O]+
(0.5), 228 [M – C2H5]+ (0.5), 186 [M – C5H11 + (18), 171 (19),
Experimental
]
154 (100), 138 (45), 126 (14), 110 (31), 94 (27), 82 (19), 74 (40),
56 (13), 43 (27). IR, /cm–1: 3360, 2960, 2880, 1695, 1655,
1603, 1460, 1319, 1278, 1232, 1190, 1132, 1070, 957, 760.
1H NMR (CDCl3), : 0.89 (t, 3 H, CH3, J = 7.3 Hz); 0.91 (t, 3 H,
CH3, J = 7.3 Hz); 1.49—1.66 (m, 4 H, CH2); 1.84 (s, 3 H, CH3);
3.39 (m, 2 H, NCH2, H(3)); 3.68 (s, 3 H, OCH3); 3.84 (dd, 1 H,
NCH2, J = 3.7 Hz, J = 11.1 Hz); 4.24 (d, H(4´), J = 3.9 Hz);
4.40 (s, H(3´)); 7.87 (br.s, 1 H, NH). 13C NMR (CDCl3),
: 9.17, 10.08 (CH3); 12.69 (CH3); 25.45, 26.15 (CH2); 50.80
(OCH3); 53.85 (NCH2); 72.29, 81.44 (C(3´), C(4´)); 82.85
(C(3)); 88.24 (=CMe); 158.84 (C(2´)); 171.47 (CO2).
IR spectra were obtained on a Prestigeꢀ21 Shimadzu IR specꢀ
trometer for neat samples. 1H and 13C NMR spectra were reꢀ
corded on Bruker AMꢀ300 (300.13 and 75.47 MHz, respectively)
and Bruker AVANCEꢀ500 spectrometers (500.13 and 125.77 MHz,
respectively), using Me4Si as an internal standard. Angles of
optical rotation were measured on a Perkin—Elmerꢀ341 instruꢀ
ment. Mass spectra were obtained on a Thermo Finnigan MAT
95XP instrument (70 eV). Reaction progress was monitored by
TLC on Sorbfil plates (Russia), with visualization by the moisꢀ
turizing the plates with a solution of anisaldehyde and sulfuric
acid in ethanol with subsequent heating at 120—150 C. Reacꢀ
tion products were isolated by column chromatography on silica
gel (30—60 g of the adsorbent per 1 g of compound), using freshly
distilled solvents as eluents. LꢀTartaric acid used in the work was
purchased from Aldrich.
(4S,5S)ꢀ2,2ꢀDiethylꢀ4,5ꢀbis(hydroxymethyl)ꢀ1,3ꢀdioxolane
(6). The ketalized dimethyl tartrate 5 (1.0 g, 3.87 mmol) was
added dropwise to a suspension of LiAlH4 (0.3 g, 7.75 mmol) in
anhydrous diethyl ether (15 mL) under argon at room temperaꢀ
ture. The reaction mixture was stirred for 4 h, then saturated
aqueous Na2SO4 was added, the organic layer was separated,
Et2O was evaporated, and the residue was extracted with CHCl3
(5×10 mL). The combined organic exstracts were washed with
brine, dried with MgSO4, and concentrated to obtain diol 6
(0.63 g, 85%). []D20 –1.4 (c 1.202, CHCl3). MS, m/z (Irel (%)):
161 [M – C2H5]+ (100), 99 (4), 87 (41), 75 (16), 69 (29), 57 (58).
IR, /cm–1: 3458, 3439, 3419, 3400, 3361, 3014, 2974, 2941,
2884, 1792, 1749, 1464, 1445, 1379, 1356, 1339, 1273, 1217,
1204, 1173, 1139, 1084, 1055, 1042, 979, 934, 891, 756, 667.
1H NMR (CDCl3), : 0.85 (t, 6 H, J = 7.4 Hz); 1.60 (q, 4 H,
CH2, J = 7.3 Hz); 3.33 (br.s, 2 H, OH); 3.68 (br.s, 4 H, OCH2);
3.86 (s, 2 H, H(4´), H(5´)). 13C NMR (CDCl3), : 8.02 (CH3);
30.34 (CH2); 62.60 (OCH2); 79.03 (C(4´), C(5´)); 113.03 (C(2´)).
Methyl (E)ꢀ3ꢀ[(4S,5S)ꢀ2,2ꢀdiethylꢀ5ꢀhydroxymethylꢀ1,3ꢀdiꢀ
oxolanꢀ4ꢀyl]ꢀ2ꢀmethylacrylate (9). Pyridinium dichromate (PDC)
(1.52 g, 4.05 mmol) was added in one portion to a solution of diol 6
(0.6 g, 3.11 mmol) in anhydrous CH2Cl2 (10 mL) at room temꢀ
perature with stirring. The reaction mixture was stirred for 3 h,
then filtered through a short layer of SiO2, the solvent was evapꢀ
orated. The crude lactol 7 (0.56 g) was dissolved in CH2Cl2
(10 mL), followed by the addition of phosphorane 8 (2.12 g,
5.60 mmol). The reaction mixture was stirred for 5 h at room
temperature (TLC monitoring) and concentrated, the resiꢀ
due was purified by column chromatography on SiO2 (eluent
AcOEt—light petroleum, 1 : 2) to obtain compound 9 (0.37 g, 45%).
Methyl (2E,4S,5S)ꢀ5ꢀhydroxyꢀ6ꢀmesyloxyꢀ2ꢀmethylꢀ4ꢀ(pentꢀ
3ꢀyloxy)hexꢀ2ꢀenoate (2). Triethylsilane (55 mg, 0.47 mmol) was
added to a solution of compound 15 (0.109 g, 0.32 mmol) in
anhydrous CH2Cl2 (5 mL) cooled to –30—–40 C with stirring,
followed by a dropwise addition of a solution of TiCl4 (74 mg,
0.39 mmol) in CH2Cl2 (1 mL) at such a rate that to keep the
temperature below –30 C. The reaction mixture was stirred at
this temperature until the starting compound was consumed
(TLC), then, an iceꢀcold water was rapidly added and the temꢀ
perature was raised to –5 C. The organic layer was separated, the
aqueous layer was extracted with CH2Cl2 (3×10 mL). The comꢀ
bined organic layers were washed with brine and dried with MgSO4.
The solvent was evaporated and the residue was subjected to
column chromatography with SiO2 (eluent AcOEt—light petroꢀ
20
leum, 1 : 5) to obtain compound 2 (0.105 g, 95%). []D +7.0
(c 0.252, CHCl3). MS, m/z (Irel (%)): 467 [M – C2H5]+ (14), 353
(100), 323 (12), 269 (10), 213 (61), 199 (50), 135 (25), 112 (16),
69 (37). IR, /cm–1: 3520, 2964, 2936, 2883, 1716, 1645, 1460,
1437, 1358, 1248, 1176, 1136, 1101, 1061, 1034, 964, 935, 831,
796, 528. 1H NMR (CDCl3), : 0.83 (t, 3 H, CH3, J = 7.3 Hz);
0.85 (t, 3 H, CH3, J = 7.3 Hz); 1.41 (m, 2 H, CH2, J = 7.4 Hz);
1.48 (m, 2 H, CH2, J = 7.4 Hz); 1.90 (d, 3 H, CH3, J = 1.3 Hz);
2.98 (d, 1 H, OH, J = 4.4 Hz); 3.07 (s, 3 H, CH3SO2); 3.19 (m, 1 H,
H(3´), J = 5.3 Hz, J = 5.9 Hz); 3.77 (s, 3 H, OCH3); 3.84 (m, 1 H,
OCH2); 4.17 (dd, 1 H, OCH2, J = 5.0 Hz, J = 11.4 Hz); 4.33
(m, 2 H, H(4), H(5)); 6.58 (dq, 1 H, =CH, J = 1.3 Hz, J = 9.6 Hz).
13C NMR (CDCl3), : 9.14, 9.87 (CH3); 13.33 (CH3); 25.28,
26.45 (CH2); 37.55 (CH3SO2); 52.19 (OCH3); 69.80 (OCH2);
71.78, 73.05 (C(5), C(4)); 80.09 (C(3´)); 132.42 (C(2)); 137.75
(C(3)); 167.62 (CO2). Found (%): C, 50.02; H, 7.56; S, 9.82.
C14H26O7S. Calculated (%): C, 49.69; H, 7.74; S, 9.48.
20
[]D –32.0 (c 0.881, CHCl3). HRMS, found: m/z 257.1
[M – H]+. C13H22O5. Calculated: [M – H]+ = 257.139. MS, m/z
(Irel (%)): 257 [M – H]+ (6), 229 [M – C2H5]+ (65), 198 (9), 167
(10), 155 (34), 141 (35), 123 (28), 112 (40), 97 (15), 87 (19), 58
(100). IR, /cm–1: 3440, 2974, 2941, 1721, 1690, 1462, 1439,
1379, 1336, 1317, 1265, 1225, 1198, 1173, 1138, 1115, 1082,
1057, 970, 941, 746. 1H NMR (CDCl3), : 0.95 (t, 6 H, CH3,
J = 7.4 Hz); 1.71 (q, 4 H, CH2, J = 7.4 Hz); 1.94 (d, 3 H, CH3,
J = 1.3 Hz); 2.00 (m, 1 H, OH); 3.55 (m, 1 H, OCH2); 3.76
(s, 3 H, OCH3); 3.85 (m, 1 H, OCH2, J = 3.7 Hz); 3.90 (m, 1 H,
H(5´)); 4.77 (d, 1 H, H(4´), J = 8.5 Hz); 6.66 (dq, 1 H, =CH,
J = 1.3 Hz, J = 8.4 Hz). 13C NMR (CDCl3), : 8.19 (CH3);
13.28 (CH3); 30.44 (CH2); 52.17 (OCH3); 60.49 (OCH2); 73.31
(C(5´)); 81.22 (C(4´)); 113.79 (C(2´)); 132.14 (C(2)); 137.10
(C(3)); 167.85 (CO2).
Methyl (E)ꢀ2ꢀ[(3S,4S)ꢀ4ꢀhydroxyꢀ3ꢀ(pentꢀ3ꢀyloxy)pyrrolꢀ
idinꢀ2ꢀylidene]propanoate (4). Sodium azide (10 mg, 0.16 mmol)
was added to a solution of mesylate 2 (26 mg, 0.08 mmol) in
a mixture of EtOH—H2O (5 : 1) (8 mL), and the reaction mixture
was refluxed for 4 h (TLC monitoring), then it was treated with
water and ethyl acetate (10 mL). The organic layer was separated,
the aqueous layer was extracted with AcOEt (3×10 mL). The
combined organic layers were washed with brine and dried with
MgSO4. The solvent was evaporated, the residue was subjected
to column chromatography on SiO2 (AcOEt—light petroleum, 1 : 5)
to obtain product 4 (19 mg, 95%). []D20 +39.3 (c 1.921, CHCl3).
HRMS, found: m/z 257.1618 [M]+. C13H22NO4. Calculated:
Methyl (2E,4S,5S)ꢀ5,6ꢀdihydroxyꢀ2ꢀmethylꢀ4ꢀ(pentꢀ3ꢀylꢀ
oxy)hexꢀ2ꢀenoate (10) and methyl (2E,4S,5S)ꢀ4,6ꢀdihydroxyꢀ2ꢀ
methylꢀ5ꢀ(pentꢀ3ꢀyloxy)hexꢀ2ꢀenoate (11) were obtained simiꢀ

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Russ.Chem.Bull., Int.Ed., Vol. 62, No. 5, May, 2013
Gimalova et al.
larly to compound 2 from alcohol 9 (0.30 g, 1.15 mmol), Et3SiH
(0.18 g, 1.55 mmol), and TiCl4 (0.24 g, 1.29 mmol). Chromatoꢀ
graphic purification on a column with SiO2 (eluent AcOEt—light
petroleum, 1 : 2) gave compound 10 (97 mg) and compound 11
(63 mg) (54% total yield). Compound 10. []D20 –32.4 (c 2.785,
CHCl3). MS, m/z (Irel (%)): 243 [M – OH]+ (0.3), 231 [M – C2H5]+
(0.4), 213 [M – C2H5 – H2O]+ (6), 183 (6), 155 [M – C5H11O –
– H2O]+ (7), 141 (9), 130 (100), 123 (28), 111 (10), 97 (30), 71
(22), 61 (8). IR, /cm–1: 3441, 3426, 2965, 2936, 2876, 1719,
1715, 1697, 1651, 1470, 1435, 1384, 1246, 1132, 1089, 1043,
937, 750. 1H NMR (CDCl3), : 0.83 (t, 3 H, CH3, J = 7.3 Hz);
0.85 (t, 3 H, CH3, J = 7.3 Hz); 1.38—1.52 (m, 4 H, CH2); 1.89
(d, 3 H, CH3, J = 1.3 Hz); 2.74 (m, 1 H, OH); 3.13 (m, 1 H,
H(3´)); 3.19 (br.s, 1 H, OH); 3.45 (m, 1 H, OCH2); 3.54—3.64
(m, 2 H, H(5), OCH2); 3.72 (s, 3 H, OCH3); 4.28 (dd, 1 H,
H(4), J = 7.0 Hz, J = 9.5 Hz); 6.54 (dq, 1 H, =CH, J = 1.3 Hz,
J = 9.6 Hz). 13C NMR (CDCl3), : 9.50, 9.90 (CH3); 13.24 (CH3);
25.33, 26.55 (CH2); 52.11 (OCH3); 62.60 (OCH2); 73.61, 74.18
(C(4), C(5)); 80.00 (C(3´)); 131.77 (C(2)); 138.94 (C(3)); 167.87
(CO2). Found (%): C, 60.23; H, 9.38. C13H24O5. Calculated (%):
diols 10 and 11 from compound 12 (0.11 g, 0.22 mmol), Et3SiH
(40 mg, 0.3 mmol), and TiCl4 (50 mg, 0.25 mmol). The products
were isolated by column chromatography on SiO2 (eluent
AcOEt—light petroleum, 1 : 5) to obtain compound 13 (50 mg)
and compound 14 (20 mg) (60% total yield). Compound 13.
[]D20 +32.4 (c 2.554, CHCl3). MS, m/z (Irel (%)): 454 (3), 431
(0.5), 441 [M – C4H9]+ (0.5), 353 (56), 277 (17), 241 (9), 213
(36), 199 (100), 169 (18), 119 (15), 77 (7). IR, /cm–1: 3520,
2961, 2932, 2876, 1719, 1645, 1462, 1427, 1389, 1362, 1317,
1248, 1219, 1134, 1113, 1063, 1009, 937, 824, 743, 702, 505.
1H NMR (CDCl3), : 0.87 (t, 3 H, CH3, J = 7.4 Hz); 0.88 (t, 3 H,
CH3, J = 7.4 Hz); 1.08 (s, 9 H, CMe3); 1.44—1.56 (m, 4 H,
CH2); 1.93 (d, 3 H, CH3, J = 1.3 Hz); 2.67 (d, 1 H, OH, J = 7.4 Hz);
3.20 (quint, 1 H, H(3´), J = 5.3 Hz, J = 6.0 Hz); 3.64 (m, 1 H,
H(5)); 3.69 (m, 2 H, OCH2); 3.76 (s, 3 H, OCH3); 4.52 (dd, 1 H,
H(4), J = 4.3 Hz, J = 9.3 Hz); 6.74 (dq, 1 H, =CH, J = 1.3 Hz,
J = 9.3 Hz); 7.41 (m, 6 H, Ph); 7.68 (m, 4 H, Ph). 13C NMR
(CDCl3), : 9.21, 9.96 (CH3); 13.25 (CH3); 25.47, 26.54 (CH2);
26.86 (3 CH3); 52.02 (OCH3); 63.79 (OCH2); 72.76, 74.20 (C(4),
C(5)); 79.99 (C(3´)); 127.74, 127.79, 129.69, 129.81, 133.18,
133.32, 135.57, 135.71 (Ph); 130.28 (C(2)); 140.03 (C(3)); 168.03
(CO2). Compound 14. 1H NMR (CDCl3), : 0.74 (t, 3 H, CH3,
J = 7.4 Hz); 0.85 (t, 3 H, CH3, J = 7.4 Hz); 1.07 (s, 9 H, CMe3);
1.27—1.45 (m, 4 H, CH2); 1.91 (d, 3 H, CH3, J = 1.3 Hz); 2.66
(d, 1 H, OH, J = 7.0 Hz); 3.14 (quint, 1 H, H(3´), J = 5.6 Hz,
J = 6.0 Hz); 3.36 (m, 1 H, H(5), J = 4.3 Hz, J = 3.6 Hz); 3.62 (dd,
1 H, OCH2, J = 4.3 Hz, J = 10.6 Hz); 3.76 (s, 3 H, OCH3); 3.79
(m, 1 H, OCH2); 4.64 (ddd, 1 H, H(4), J = 3.6 Hz, J = 5.0 Hz,
J = 8.6 Hz); 6.82 (dq, 1 H, =CH, J = 1.3 Hz, J = 8.6 Hz); 7.42
(m, 6 H, Ph); 7.68 (dt, 4 H, Ph, J = 1.7 Hz, J = 7.6 Hz).
20
C, 59.98; H, 9.29. Compound 11. []D –25.85 (c 0.928,
1
CHCl3). H NMR (CDCl3), : 0.86 (t, 3 H, CH3, J = 7.3 Hz);
0.87 (t, 3 H, CH3, J = 7.6 Hz); 1.46 (m, 4 H, CH2, J = 7.3); 1.89
(d, 3 H, CH3, J = 1.3 Hz); 2.96 (d, 1 H, OH, J = 5.9 Hz); 3.14—3.17
(m, 2 H, OH, H(3´)); 3.46 (dd, OCH2, 1 H, J = 5.0 Hz, J = 9.6 Hz);
3.53 (dd, 1 H, OCH2, J = 4.0 Hz, J = 9.7 Hz); 3.65 (m, 1 H,
H(5), J = 5.0 Hz, J = 5.3 Hz); 3.73 (s, 3 H, OCH3); 4.49 (m, 1 H,
H(4)); 6.69 (dq, 1 H, =CH, J = 1.3 Hz, J = 9.0 Hz). 13C NMR
(CDCl3), : 9.47 (CH3); 13.28 (CH3); 25.64 (CH2); 52.06
(OCH3); 69.77 (OCH2); 69.53, 72.89 (C(4), C(5)); 82.92 (C(3´));
130.73 (C(2)); 139.18 (C(3)); 168.18 (CO2).
(4S,5S)ꢀ2,2ꢀDiethylꢀ4ꢀmesyloxymethylꢀ5ꢀ(3ꢀmethoxyꢀ2ꢀ
methylꢀ3ꢀoxopropꢀ1Eꢀenyl)ꢀ1,3ꢀdioxolane (15). Triethylamine
(0.41 mL, 2.93 mmol) and methanesulfonyl chloride (0.335 g,
2.93 mmol) were added to a solution of compound 9 (0.377 g,
1.46 mmol) in CH2Cl2 (10 mL) at 0 C, and the reaction mixture
was stirred for 3 h at room temperature. Then, saturated aqueous
NH4Cl was added, the organic layer was separated, the aqueous
layer was extracted with CH2Cl2 (3×5 mL). The combined orꢀ
ganic layers were washed with brine and dried with MgSO4. The
solvent was evaporated, the residue was subjected to column
chromatography on SiO2 (eluent AcOEt—light petroleum, 1 : 5)
Methyl (E)ꢀ3ꢀ[(4S,5S)ꢀ2,2ꢀdiethylꢀ5ꢀ(tertꢀbutyldiphenylsilylꢀ
oxymethyl)ꢀ1,3ꢀdioxolanꢀ4ꢀyl]ꢀ2ꢀmethylacrylate (12). Imidazole
(50 mg, 0.77 mmol) and ButPh2SiCl (0.17 g, 0.60 mmol) were
added to a solution of compound 9 (0.14 g, 0.55 mmol) in anhyꢀ
drous CH2Cl2 (10 mL). The reaction mixture was stirred until
the starting alcohol was consumed (TLC monitoring), then diꢀ
luted with CH2Cl2 (10 mL) and saturated aqueous NH4Cl
(5 mL), the organic layer was separated, washed with brine, and
dried with MgSO4, the solvent was evaporated. The residue was subꢀ
jected to column chromatography on SiO2 (eluent AcOEt—light
20
20
petroleum, 1 : 5) to obtain silyl ether 12 (0.27 g, 98%). []D
to obtain compound 15 (0.40 g, 82%). []D –32.6 (c 1.819,
–6.5 (c 2.114, CHCl3). MS, m/z (Irel (%)): 467 [M – C2H5]+ (14),
353 (100), 323 (12), 269 (10), 213 (61), 199 (50), 135 (25), 112
(16), 69 (37). IR, /cm–1: 3440, 2957, 2930, 2887, 1720, 1710,
1470, 1420, 1390, 1330, 1230, 1113, 1040, 1001, 960, 822, 741,
702, 505, 489. 1H NMR (CDCl3), : 0.97 (t, 3 H, CH3, J = 7.3 Hz);
0.98 (t, 3 H, CH3, J = 7.3 Hz); 1.10 (s, 9 H, CMe3); 1.75 (m, 4 H,
CH2); 1.92 (d, 3 H, CH3, J = 1.3 Hz); 3.69 (dd, 1 H, OCH2,
J = 3.3 Hz, J = 11.3 Hz); 3.77 (s, 3 H, OCH3); 3.87 (m, 2 H, OCH2,
H(5´)); 4.89 (t, 1 H, H(4´), J = 8.4 Hz); 6.70 (dq, 1 H, =CH,
J = 1.3 Hz, J = 8.4 Hz); 7.42 (m, 6 H, Ph); 7.75 (m, 4 H, Ph).
13C NMR (CDCl3), : 8.06, 8.24 (CH3); 13.20 (CH3); 19.10
(CMe3); 26.78 (3 CH3); 30.23, 30.50 (CH2); 52.03 (OCH3);
62.19 (OCH2); 73.91 (C(5´)); 81.55 (C(4´)); 113.67 (C(2´));
127.72, 129.65, 134.81, 135.18 (Ph); 133.00 (C(2)); 137.59 (C(3));
168.10 (CO2).
CHCl3). MS, m/z (Irel (%)): 307 [M – C2H5]+ (100), 267 (14),
219 (18), 155 (54), 112 (40), 95 (12). IR, /cm–1: 2974, 2943,
2884, 1763, 1717, 1661, 1456, 1437, 1359, 1263, 1236, 1198,
1177, 1144, 1109, 1057, 1016, 966, 941, 831, 752, 528. 1H NMR
(CDCl3), : 0.83 (t, 3 H, CH3, J = 7.4 Hz); 0.85 (t, 3 H, CH3,
J = 7.3 Hz); 1.61 (q, 4 H, CH2, J = 7.3 Hz); 1.83 (d, 3 H, CH3,
J = 1.3 Hz); 2.99 (s, 3 H, SO2CH3); 3.68 (s, 3 H, OCH3); 3.89
(m, 1 H, OCH2, J = 4.4 Hz); 4.14 (dd, 1 H, OCH2, J = 4.6 Hz,
J = 11.4 Hz); 4.28 (m, 1 H, H(5´), J = 3.0 Hz, J = 7.2 Hz); 4.59
(t, 1 H, H(4´), J = 8.8 Hz); 6.58 (dq, 1 H, =CH, J = 1.3 Hz,
J = 8.8 Hz). 13C NMR (CDCl3), : 7.96, 8.09 (CH3); 13.30 (CH3);
30.28, 30.37 (CH2); 37.67 (SO2CH3); 52.21 (OCH3); 67.11
(OCH2); 73.72 (C(4´)); 78.48 (C(5´)); 114.69 (C(2´)); 133.04
(C(2)); 135.61 (C(1)); 167.53 (CO2). Found (%): C, 50.31; H, 7.24;
S, 9.35. C14H24O7S. Calculated (%): C, 49.98; H, 7.19; S, 9.53.
Methyl (2E,5S)ꢀ6ꢀ(tertꢀbutyldiphenylsilyloxy)ꢀ2ꢀmethylꢀ4ꢀ
oxoꢀ5ꢀ(pentꢀ3ꢀyloxy)hexꢀ2ꢀenoate (16). The reagents PhI(OAc)2
(54 mg, 0.17 mmol) and TEMPO (1 mg, 0.006 mmol) were
added to a solution of silyl ether 14 (20 mg, 0.04 mmol) in
Methyl (2E,4S,5S)ꢀ6ꢀ(tertꢀbutyldiphenylsilyloxy)ꢀ5ꢀhydroxyꢀ
2ꢀmethylꢀ4ꢀ(pentꢀ3ꢀyloxy)hexꢀ2ꢀenoate (13) and methyl
(2E,4S,5S)ꢀ6ꢀ(tertꢀbutyldiphenylsilyloxy)ꢀ4ꢀhydroxyꢀ2ꢀmethylꢀ
5ꢀ(pentꢀ3ꢀyloxy)hexꢀ2ꢀenoate (14) were obtained similarly to

Pyrrolidine recyclization
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 5, May, 2013
1231
CH2Cl2 (5 mL) under argon, and the reaction mixture was stirred
for 3 h at room temperature (TLC monitoring). Then the solvent
was evaporated, the residue was purified by column chromatoꢀ
graphy on SiO2 (eluent AcOEt—light petroleum, 1 : 5) to obtain
J = 6.0 Hz, J = 9.2 Hz); 6.65 (dq, 1 H, =CH, J = 1.3 Hz,
J = 9.2 Hz). 13C NMR (CDCl3), : 9.42, 9.76 (CH3); 13.30
(CH3); 26.05, 26.37 (CH2); 43.64 (OCH2); 52.09 (OCH3); 53.80
(C(5)); 75.34 (C(4)); 80.54 (C(3´)); 130.58 (C(2)); 137.37 (C(3));
167.96 (CO2). Found (%): C, 64.80; H, 9.08. C13H22O4. Calcuꢀ
lated (%): C, 64.44; H, 9.15.
B. A solution of pyrrolidine derivative 4 (83.4 mg, 0.32 mmol)
in THF (2 mL) was added dropwise to a solution of CF3COOH
(0.12 mL, 1.62 mmol) in THF (3 mL) at 0 C. The mixture was
stirred for 30 min at this temperature, followed by the addition of
10% aqueous NaOH to pH ~8. Then, THF was evaporated on
a rotary evaporator, the residue was extracted with CHCl3
(3×5 mL), The combined organic exstracts were washed with
brine, dried with MgSO4, and the solvent was evaporated.
Column chromatography of the product on silica gel (eluent
AcOEt—light petroleum, 1 : 2) gave compound 18 (30 mg, 38%),
whose spectroscopic characteristics agreed with those obtained
for compound 18 synthesized by the preceding procedure.
20
compound 16 (10 mg, 66%). []D –29.6 (c 0.7191, CHCl3).
MS, m/z (Irel (%)): 439 [M – C4H9]+ (0.2), 337 (9), 291 (100),
261 (22), 199 (43), 163 (21), 91 (6). IR, /cm–1: 2974, 2941,
2880, 2106, 1718, 1655, 1464, 1437, 1377, 1354, 1315, 1265,
1245, 1225, 1198, 1173, 1140, 1086, 1057, 1030, 970, 941, 850,
758, 680. 1H NMR (CDCl3), : 0.83 (t, 3 H, CH3, J = 7.4 Hz);
0.89 (t, 3 H, CH3, J = 7.4 Hz); 1.02 (s, 9 H, CMe3); 1.49 (q, 4 H,
CH2, J = 6.6 Hz, J = 7.6 Hz); 2.28 (d, 3 H, CH3, J = 1.7 Hz);
3.19 (t, 1 H, H(3´), J = 5.6 Hz); 3.81 (s, 3 H, OCH3); 3.87 (t, 2 H,
OCH2, J = 4.3 Hz, J = 5.3 Hz); 3.94 (dd, 1 H, H(5), J = 4.6 Hz,
J = 5.3 Hz); 7.54 (dq, 1 H, =CH, J = 1.3 Hz, J = 1.7 Hz); 7.42
(m, 6 H, Ph); 7.66 (dd, 2 H, Ph, J = 1.3 Hz, J = 7.6 Hz); 7.69
(dd, 2 H, Ph, J = 1.3 Hz, J = 7.6 Hz). 13C NMR (CDCl3),
: 9.05, 9.69 (CH3); 14.64 (CH3); 19.19 (CMe3); 25.10, 26.19
(CH2); 26.64 (3 CH3); 52.52 (OCH3); 65.05 (OCH2); 82.07,
84.15 (C(5), C(3´)); 127.71, 127.75, 129.77 (2 C), 132.93, 133.09,
135.65, 135.76 (Ph); 130.81 (C(2)); 141.56 (C(3)); 168.24 (CO2);
203.38 (C(4)). Found (%): C, 70.55; H, 7.98; Si, 5.97. C29H40O5Si.
Calculated (%): C, 70.12; H, 8.12; Si, 5.65.
This work was financially supported by the Russian
Foundation for Basic Research (Program Povolzh´e,
Project No. 11ꢀ03ꢀ97013 r_a).
Methyl (E)ꢀ3ꢀ[(4S,5S)ꢀ5ꢀazidomethylꢀ2,2ꢀdiethylꢀ1,3ꢀdiꢀ
oxolanꢀ4ꢀyl]ꢀ2ꢀmethylacrylate (17) was obtained similarly to the
preparation of compound 4 from mesylate 15 (0.2 g, 0.60 mmol)
and NaN3 (0.15 g, 2.38 mmol). The yield was 0.16 g (95%).
[]D20 –97.3 (c 2.731, CHCl3). MS, m/z (Irel (%)): 268 [M – CH3]+
(0.2), 254 [M – Et]+ (100), 198 (8), 155 (12), 112 (35), 97 (11).
IR, /cm–1: 2974, 2941, 2880, 2106, 1718, 1655, 1464, 1437,
1377, 1354, 1315, 1265, 1245, 1225, 1198, 1173, 1140, 1086,
1057, 1030, 970, 941, 850, 758, 680. 1H NMR (CDCl3), : 0.91
(t, 3 H, CH3, J = 7.4 Hz); 0.93 (t, 3 H, CH3, J = 7.4 Hz); 1.63—1.74
(m, 4 H, CH2); 1.88 (d, 3 H, CH3, J = 1.3 Hz); 3.15 (dd, 1 H,
NCH2, J = 4.3 Hz, J = 13.6 Hz); 3.56 (dd, 1 H, NCH2, J = 3.5 Hz,
J = 13.6 Hz); 3.85 (s, 3 H, OCH3); 3.87 (m, 1 H, H(5´)); 4.67
(t, 1 H, H(4´), J = 8.6 Hz); 6.58 (dq, 1 H, =CH, J = 1.3 Hz,
J = 8.6 Hz). 13C NMR (CDCl3), : 7.77, 7.86 (CH3); 13.01
(CH3); 30.09, 30.20 (CH2); 50.19 (NCH2); 51.84 (OCH3); 74.21
(C(4´)); 79.55 (C(5´)); 114.12 (C(2´)); 132.24 (C(2)); 136.15
(C(3)); 167.38 (CO2).
References
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Methyl (2E,4S,5S)ꢀ5,6ꢀepoxyꢀ2ꢀmethylꢀ4ꢀ(pentꢀ3ꢀyloxy)ꢀ
hexꢀ2ꢀenoate (18). A. Sodium hydrogen carbonate (60 mg,
0.69 mmol) was added to a solution of mesylate 2 (0.15 g,
0.43 mmol) in a mixture of EtOH—H2O (2 : 1) (10 mL), and the
mixture was heated for 1 h at 55—60 C. Then ethanol was
evaporated, the reaction mixture was diluted with water and
extracted with AcOEt (3×10 mL). The combined organic exꢀ
stracts were washed with water and dried with MgSO4, the solꢀ
vent was evaporated. Column chromatography of the product on
silica gel (eluent AcOEt—light petroleum, 1 : 2) gave epoxide 18
20
(90 mg, 90%). []D –27.17 (c 3.746, CHCl3). MS, m/z
+
(Irel (%)): 242 [M]+ (1), 213 [M – C2H5]+ (5), 199 [M – C5H11
]
(22), 155 (48), 129 (100), 110 (17), 95 (34), 82 (13), 43 (24). IR,
/cm–1: 2963, 2930, 2880, 1718, 1653, 1456, 1437, 1385, 1298,
1273, 1238, 1192, 1157, 1136, 1111, 1059, 1032, 959, 914, 852,
813, 744. 1H NMR (CDCl3), : 0.88 (t, 3 H, CH3, J = 7.4 Hz);
0.94 (t, 3 H, CH3, J = 7.4 Hz); 1.48 (dq, 2 H, CH2, J = 7.4 Hz,
J = 1.4 Hz); 1.52—1.56 (m, 2 H, CH2); 1.89 (d, 3 H, CH3,
J = 1.3 Hz); 2.57 (dd, 1 H, OCH2, J = 2.8 Hz, J = 4.8 Hz); 2.75
(t, 1 H, OCH2, J = 4.5 Hz); 3.12 (m, 1 H, H(5)); 3.31 (q, 1 H,
H(3´), J = 5.7 Hz); 3.76 (s, 3 H, OCH3); 4.04 (dd, 1 H, H(4),
17. E. A. Mash, K. A. Nelson, S. V. Densen, S. B. Hemperly,
Org. Synth. Coll., 1993, 8, 155.
Received February 20, 2012;
in revised form December 25, 2012