A. V. Tymtsunik et al. / Tetrahedron Letters 53 (2012) 3847–3849
3849
Reinhold, U.; Saulnier, M.; Claridge, S. Bioorg. Med. Chem. Lett. 1998, 8, 2123–
2128; (f) Mori, M.; Kubo, Y.; Ban, Y. Tetrahedron 1988, 44, 4321–4330.
3. For some recent reviews on conformationally restricted molecules, see: (a)
Cativiela, C.; Ordóñez, M. Tetrahedron: Asymmetry 2009, 20, 1–63; (b)
Trabocchi, A.; Scarpi, D.; Guarna, A. Amino Acids 2008, 34, 1–24; (c)
Grygorenko, O. O.; Radchenko, D. S.; Volochnyuk, D. M.; Tolmachev, A. A.;
Komarov, I. V. Chem. Rev. 2011, 111, 5506–5568; (d) Soloshonok, V. A. Curr. Org.
Chem. 2002, 6, 341–364.
4. The proline analogue 11 was described in the literature as an antibiotic isolated
from the culture filtrate of Streptomyces zaomiceticus: (a) Shimura, M.; Iwata,
M.; Omoto, S.; Sekizawa, Y. Agric. Biol. Chem. 1979, 43, 2271–2279; (b) Kodama,
Y.; Ito, T. Agric. Biol. Chem. 1980, 44, 73–76. Its synthesis, to the best of our
knowledge, is still not reported..
4.38 (dd, J = 9.1 Hz and 2.5 Hz, 0.5H), 4.08 (br s, 1H), 4.04 (br s, 1H), 3.71 (s, 3H),
2.88–3.01 (s, 1H), 2.65 (br s, 0.5H), 2.59 (br s, 0.5H), 1.46 (s, 4.5H), 1.41 (s,
4.5H). 13C NMR (125 MHz, CDCl3, d): 173.1 and 172.8 (C), 154.4 and 153.7 (C),
143.5 and 142.4 (C), 107.9 and 107.7 (CH2), 80.1 (C), 59.1 and 58.6 (CH), 52.1
and 52.0 (CH3), 50.8 and 50.6 (CH2), 36.8 and 36.0 (CH2), 28.4 and 28.3 (CH3).
12. Yang, Z.; Lorenz, J. C.; Shi, Y. Tetrahedron Lett. 1998, 8621–8624.
13. (6S)-5-tert-Butyl-6-methyl-5-azaspiro[2.4]heptane-5,6-dicarboxylate (17): 1H
NMR (500 MHz, CDCl3, d): 4.46 (dd, J = 3.0 and 8.5 Hz, 0.5H), 4.36 (dd, J = 3.0
and 8.5 Hz, 0.5H), 3.72 (s, 3H), 3.37 (m, 1H), 3.30 (m, 1H), 2.22 (m, 1H), 1.75 (m,
1H), 1.45 (s, 4.5H), 1.41 (s, 4.5H), 0.3–0.6 (m, 4H). 13C NMR (125 MHz, CDCl3, d):
174.2 and 173.1, 79.9, 59.6 and 59.2, 54.1 and 53.7, 52.0 and 51.8, 39.1 and
38.3, 28.4, 21.4, 20.7, 20.1, 12.4, 11.6, 9.6, 8.9, 1.0.
14. Procedure
for
the
preparation
of
(6S)-5-(tert-butoxycarbonyl)-5-
5. Tandon, M.; Wu, M.; Begley, T. P. Bioorg. Med. Chem. Lett. 1998, 8, 1139–1144.
6. Petter, R. C. Tetrahedron Lett. 1989, 30, 399–402.
azaspiro[2.4]heptane-6-carboxylic acid [(S)-19]: Et2Zn (48 mL, 15% in hexane,
41 mmol) was added to dry CH2Cl2 (40 mL) under an argon atmosphere. The
solution was cooled to ꢁ5 °C, and TFA (3.03 mL, 41 mmol) was added dropwise
slowly and carefully. The resulting mixture was stirred at this temperature for
30 min. A solution of CH2I2 (3.28 mL, 41 mmol) in dry CH2Cl2 was added
dropwise at ꢁ5 °C, and the mixture stirred at this temperature for 1 h. Next, a
solution of (S)-15 (0.82 g, 3.4 mmol) in absolute CH2Cl2 (30 mL) was added
dropwise at ꢁ5 °C. The resulting mixture was stirred at 30 °C for 3 d, and then
cooled to 0 °C. Saturated aq NH4Cl (50 mL) was added dropwise at this
temperature, and the resulting mixture stirred for 1 h. The organic phase was
separated, and the aqueous phase washed with CH2Cl2 (4 ꢀ 20 mL). The
combined organic extracts were dried over Na2SO4 and evaporated to dryness
to give a crude mixture (1.58 g) containing (S)-17 and (S)-18 which was
dissolved in EtOAc (30 mL). Et3N (1.6 mL) and Boc2O (1.6 g) were added, and
the mixture stirred at rt for 1 d, then filtered and acidified with 0.3 M aq
NaHSO4 to pH = 1–2. The organic phase was separated, and the product
extracted from the aqueous phase with EtOAc (4 ꢀ 20 mL). The combined
organic extracts were dried over Na2SO4 and evaporated to dryness to give
crude (S)-17 (1.85 g).13 Attempts to purify the residue by column
chromatography led to a considerable loss of the product. Therefore crude
(S)-17 was dissolved in EtOH (20 mL), and a solution of NaOH (1 g) in H2O
(20 mL) was added. The resulting mixture was stirred for 1 d and then
evaporated to dryness. The residue was triturated with Et2O (40 mL) and
filtered. The precipitate was washed with Et2O (25 mL), and then dissolved in
H2O (50 mL). The solution was acidified with 1 M aq KHSO4 to pH = 2, extracted
with CH2Cl2 (4 ꢀ 30 mL), dried over Na2SO4 and evaporated in vacuo to give
7. (a) Cheng, M.; De, B.; Almstead, N. G.; Pikul, S.; Dowty, M. E.; Dietsch, C. R.;
Dunaway, C. M.; Gu, F.; Hsieh, L. C.; Janusz, M. J.; Taiwo, Y. O.; Natchus, M. G. J.
Med. Chem. 1999, 42, 5426–5436; (b) Qiu, X.-l.; Qing, F.-l. J. Org. Chem. 2002, 67,
7162–7164; (c) Schumacher, K. K.; Jiang, J.; Joullié, M. M. Tetrahedron:
Asymmetry 1998, 17, 47–53; (d) Grygorenko, O. O.; Komarov, I. V.; Cativiela,
C. Tetrahedron: Asymmetry 2009, 20, 1433–1436.
8. (a) Manfré, F.; Kern, J.-M.; Biellmann, J.-F. J. Org. Chem. 1992, 57, 2060–2065; (b)
Cheng, M.; De, B.; Pikul, S.; Almstead, N. G.; Natchus, M. G.; Anastasio, M. V.;
McPhail, S. J.; Snider, C. E.; Taiwo, Y. O.; Chen, L.; Dunaway, C. M.; Gu, F.; Dowty,
M. E.; Mieling, G. E.; Janusz, M. J.; Wang-Weigand, S. J. Med. Chem. 1999, 42,
5426–5436; (c) Shi, W.; Ma, H.; Duan, Y.; Yang, L.; Hu, W.; Aubart, K.; Fang, Y.;
Zonis, R. Bioorg. Med. Chem. Lett. 2011, 21, 1060–1063; (d) Arakawa, Y.; Yagi, N.;
Arakawa, Y.; Tanaka, K.-I.; Yoshifuji, S. Chem. Pharm. Bull. 2009, 57, 167–176;
(e) Herdewijn, P.; Claes, P. J.; Vanderhaeghe, H. Can. J. Chem. 1982, 60, 2903–
2907.
9. The enantiomeric excess of 15 was determined by HPLC analysis which was
carried out by injection of
2
lL
of
a
1 g/L solution into
a
4.6 ꢀ 250 mm
ChiralPack IAÒ column using hexane-2-propanol (95:5) as eluent (flow rate:
0.6 mL/min) with UV monitoring performed at 215 nm. Resolution parameters:
Rt [(R)-15] = 9.3 min, Rt [(S)-15] = 10.8 min.
10. Murphy, A. C.; Mitova, M. I.; Blunt, J. W.; Munro, M. H. G. J. Nat. Prod. 2008, 71,
806–809.
11. Procedure
for
the
preparation
of
1-tert-butyl-2-methyl-(2S)-4-me-
suspension of Cp2TiCl2
thylenepyrrolidine-1,2-dicarboxylate [(S)-15]: To
a
(10.5 g, 42 mmol) in dry toluene (10 mL), Me3Al (46.4 mL, 2 M in toluene,
93 mmol) was added at rt. The mixture was stirred for 3 d at rt under an argon
atmosphere, and then an additional portion of Me3Al (17 mL, 2 M in toluene,
34 mmol) was added. The resulting mixture was stirred overnight at rt and
evaporated to dryness in vacuo without external heating. The residue was
dissolved in toluene (120 mL). The resulting solution of Tebbe’s reagent18 was
added dropwise to a solution of (S)-14 (13.2 g, 54 mmol) in dry THF (150 mL)
under an argon atmosphere at ꢁ78 °C. The resulting mixture was stirred at
ꢁ78 °C for 2 h and at rt for 1 d. Next, dry THF (50 mL) was added, and the
resulting mixture was stirred vigorously for 15 min, and then cooled to ꢁ10 °C.
A 10% aq K2CO3 solution (150 mL) was added with vigorous stirring. The
resulting mixture was filtered through a silica gel pad and washed with THF
(3 ꢀ 50 mL). The filtrate was evaporated in vacuo, and the residue diluted with
Et2O (250 mL). The resulting suspension was dried over Na2SO4 overnight,
filtered, and evaporated in vacuo. The residue was purified by column
chromatography (hexanes-EtOAc, 5:1) as eluent, Rf = 0.56) to give (S)-15
(S)-19 (0.28 g, 34% from (S)-15, >95% by NMR). Anal. Calcd for C12H19NO4 C
59.73, H 7.94, N 5.80. Found C 60.02, H 8.36, N 5.63. 1H NMR (500 MHz, CDCl3,
d): 9.76 (br s, 1H), 4.48 (br s, 0.5H), 4.39 (br s, 0.5H), 3.44 (d, J = 9.2 Hz, 0.5H),
3.39 (br s, 1H), 3.16 (d, J = 9.2 Hz, 0.5H), 2.25–2.31 (m, 1H), 2.00 (d, J = 12.2 Hz,
0.5H), 1.93 (d, J = 12.2 Hz, 0.5H), 1.47 (s, 4.5H), 1.43 (s, 4.5H), 0.55–0.67 (m,
4H). 13C NMR (125 MHz, CDCl3, d): 178.4 and 174.8, 156.2 and 153.8, 81.4 and
80.4, 59.6 and 59.4, 54.4 and 53.6, 38.9 and 36.5, 28.39 and 28.32, 20.6 and
20.1, 13.1 and 11.7, 9.3 and 7.7.
15. Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd; John
Wiley & Sons Inc: New York, 1991. p. 779.
16. The enantiomeric excess of 20 was determined by HPLC analysis which was
carried out by injection of
3
lL
of
a
1 g/L solution into
a
4.6 ꢀ 250 mm
ChiralPack IBÒ column using hexane-2-propanol (80:20) as eluent (flow rate:
0.5 mL/min) with UV monitoring performed at 225 nm. Resolution parameters:
Rt [(R)-20] = 24.4 min, Rt [(S)-20] = 10.7 min.
17. (a)Modern carbonyl olefination: methods and applications; Takeda, T., Ed.; Wiley-
VCH: Weinheim, 2004. p. 365; (b) Korotchenko, V. N.; Nenajdenko, V. G.;
Balenkova, E. S.; Shastin, A. V. Russ. Chem. Rev. 2004, 73, 957–989.
18. Cannizzo, L. F.; Grubbs, R. H. J. Org. Chem. 1985, 50, 2386–2387.
(2.56 g, 25% from Cp2TiCl2; 19% from (S)-14). ½a D20
= ꢁ29.4 (c 1.0, MeOH). Anal.
ꢂ
Calcd for C12H19NO4 C 59.73, H 7.94, N 5.80. Found C 59.38, H 8.25, N 5.94. 1H
NMR (500 MHz, CDCl3, d): 5.01 (s, 0.5H), 4.98 (s, 1.5H), 4.49 (d, J = 9.1 Hz, 0.5H),