+
+
+
(
3
100) [M + H ], 410.3 (16) [M – H
2
O], 368.3 (16) [M – C
2
H
4
O
2
],
(1 ml) and refluxed for 4 h. The solvent was removed under
+
40.4 (12) [M – C
2
H
4
O
2
– CO], 227.2 (62).
vacuum and the residue dissolved in sat. NaHCO
aqueous phase was extracted (three times) with CH
and the combined organic phases were dried over Na
filtered and evaporated. The residue was purified by column
3
solution. The
Cl (15 ml),
SO
2
2
ꢀ
ꢀ
(
2R,3R,6R)-N-Formyl-2-methyl-6-[10 -(2 -methyl-[1,3]-dioxolan-
-yl)-2 -phenoxythiocarbonyloxy-decyl]-3-piperidinyl-acetate (22).
2
4
,
ꢀ
2
To a solution of compound 21 (50 mg, 121 lmol) in CH
15 ml) phenylchlorothioformiate (23 mg, 133 lmol; 1.1 equiv.),
DMAP (16 mg, 133 lmol; 1.1 equiv.) and triethylamine (24 mg,
42 lmol; 2 equiv.) were added with stirring. The reaction was
monitored by TLC. After 2 days at room temp. the mixture was
extracted with 1 M HCl, washed with H O (10 ml) and the organic
phase was dried over Na SO . The solvent was removed under
vacuum and the residue was purified by column chromatography
2
Cl
2
chromatography (CH
Yield: 14 mg (47 lmol; 79%). mp: 58 C; ref.: 57–58 C. R
2
Cl
2
/MeOH/NH
4
OH 25% 88 : 10 : 2).
◦
◦
19
(
f
: 0.25
−
1
(CH
2
Cl
2
/MeOH/NH
4
OH 25% 88 : 10 : 2). IR (KBr): m (cm ) =
1
2
3700–3050 (s, NH, OH), 2900, 2840 (s, CH), 1675 (s, C=O). H
3
ꢀ
NMR (CDCl
3
): d = 1.04 (d, JCH3,6ꢀ = 6.56 Hz, 3H, 6 -CH
3
),
2
1.17–1.25 (m, 16H, 5-H, 6-H, 7-H, 8-H, 9-H, 10-H, 11-H, 12-H),
ꢀ
ꢀ
ꢀ
2
4
1.27 (m, 1H, 3 -H), 1.39 (m, 1H, 3 -H), 1.42 (m, 1H, 4 -Hax), 1.49
ꢀ
(m, 2H, 4-H), 1.83 (m, 1H, 4 -Heq), 2.06 (s, 3H, 1-H), 2.34 (t,
−
1
3
ꢀ
ꢀ
(
2
Et
2
O). Yield: 62 mg (91%). R
f
: 0.22 (Et
2
O). IR (film): m (cm ) =
J
3,4 = 7.56 Hz, 2H, 3-H), 2.47 (m, 1H, 2 -H), 2.70 (m, 1H, 6 -H),
1
ꢀ
13
ꢀ
940, 2860 (s, CH), 1735, 1665 (2 × s, C=O), 1200. H NMR
3.48 (m, 1H, 5 -H). C NMR (CDCl
), 29.3 (C
), 43.8 (C
): d = 18.6 (6 -CH
), 23.9,
3
3
3
(CDCl
3
): d = 1.24 (d, J2,Me = 7.08 Hz, 3H, 2-Me), 1.27–1.39
), 1.61–2.04
25.8, 26.0, 29.2 (4 × CH
2
1
), 29.4, 29.4, 29.5, 29.5, 29.7,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀꢀ
(
m, 15H, 4 -H, 5 -H, 6 -H, 7 -H, 8 -H, 9 -H, 2 -CH
3
32.0, 36.9 (7 × CH
2
3
), 55.8 (C2ꢀ ), 57.3 (C6ꢀ ), 68.0 (C5ꢀ ),
ꢀ
ꢀ
ꢀ
20
D
(
O
m, 10H, 4-H, 5-H, 1 -H, 3 -H, 10 -H), 2.06/2.07 (2 × s, 3H,
209.4 (C
2
). [a] = −6.5 (c = 0.6, CHCl
3
). MS (70 eV, CI): calc.
ꢀꢀ
ꢀꢀ
+
2
CCH
3
), 3.77/4.09 (2 × m, 1H, 6-H), 3.93 (m, 4H, 4 -H, 5 -H),
298.27406 for [C18
H
36NO
2
] , found 298.27416.
4
2
.66/4.83 (2 × m, 1H, 2-H), 4.83 (m, 1H, 3-H), 5.44 (m, 1H,
ꢀ
-H), 7.11 (m, 2H, Ar–H), 7.29 (m, 1H, Ar–H), 7.42 (m, 2H,
1
3
Acknowledgements
Ar–H), 8.08/8.11 (2 × s, 1H, CHO). C NMR (CDCl
3
): d =
), 21.0, 24.0, 24.0, 25.0, 25.0,
6.8, 27.0, 29.3, 29.4, 29.5, 29.5, 29.8, 29.8, 33.5, 34.1, 38.2, 39.2,
9.7 (18 × CH ), 43.2/44.9 (C ), 50.2/51.4 (C
0.4/71.5 (C
), 83.1/83.4 (C2ꢀ ), 110.1/110.2 (C2ꢀꢀ ), 121.9/122.0
1
2
3
7
4.7/16.8 (CH
3
), 20.8/23.7 (CH
3
We thank TauroPharm GmbH and the Fonds der Chemischen
Industrie for their financial support and express our gratitude to
Mrs. A. Betz for the preparation of starting materials.
), 64.6 (C4ꢀꢀ ,C5ꢀꢀ ),
2
2
6
3
(
(
(
(
Ar–C), 126.4/126.7 (Ar–C), 129.5/129.6 (Ar–C), 153.3/153.4
Ar–C), 162.2/162.4 (CHO), 169.8/170.1 (O CCH ), 194.8/194.9
S (563.76). MS
References
2
3
2
D
0
OCSO). [a] = −8.1 (c = 1.6, CHCl
3
+
). C30
H
47NO
7
1 (a) L. F. Tietze and N. Rackelmann, Pure Appl. Chem., 2004, 76, 1967;
(b) A. Padwa, Pure Appl. Chem., 2004, 76, 1933; (c) A. Padwa, Pure
Appl. Chem., 2003, 75, 47; (d) L. F. Tietze, Chem. Rev., 1996, 96,
+
70 eV, CI): m/z (%) = 410.3 (78) [M – C
7
H
6
O
2
S], 350.3 (54) [M
S].
–
C
7
H
6
O
2
S – C
2
H
4
O
2
], 243.2 (100), 154.2 (13) [C
7
H
6
O
2
1
1
15; (e) L. F. Tietze and U. Beifuss, Angew. Chem., Int. Ed. Engl.,
993, 32, 131; (f) T. L. Ho, Tandem Reactions in Organic Synthesis
ꢀ
ꢀ
(
2R,3R,6S)-N-Formyl-2-methyl-6-[10 -(2 -methyl-[1,3]-dioxolan-
Highlight II, ed. H. Waldmann, 1995, VCH, Weinheim, pp. 193–202; (g)
H. Waldmann, Domino Reactions in Organic Synthesis Highlight II, ed.
H. Waldmann, 1995, VCH, Weinheim, pp. 193–202; (h) M. Rejzek,
R. A. Stockman, J. H. van Maarseveen and D. L. Hughes, Chem.
Commun., 2005, 4661.
2
-yl)-decyl]-3-piperidinyl-acetate (23). To solution of
a
compound 22 (40 mg, 71 lmol) in oxygen free acetone was
added tributyltin hydride (207 mg, 710 lmol; 10 equiv.) under N
2
atmosphere. Di-t-butylperoxyoxalate (4 mg, 14 lmol; 0.2 equiv.)
was added in three portions over 12 h with stirring. The reaction
progress was monitored by TLC. After 30 h the solvent was
removed under vacuum and the residue was purified by column
2 (a) Review: P. M. Weintraub, J. S. Sabol, J. M. Kane and D. R.
Borcherding, Tetrahedron, 2003, 59, 2953; (b) T. A. Johnson, D. O.
Jang, B. W. Slafer, M. D. Curtis and P. Beak, J. Am. Chem. Soc., 2002,
1
24, 11689; A. Deyine, J.-M. Delcroix and N. Langlois, Heterocycles,
004, 64, 207; M. Amat, M. Perez, N. Llor and J. Bosch, Org. Lett.,
2
chromatography (Et
2
O). Yield: 24 mg (83%). R
f
: 0.19 (Et
2
O). IR
2002, 4, 2787; C. Shu, A. Alcudia, J. Yin and L. S. Liebeskind, J. Am.
Chem. Soc., 2001, 123, 12477; M. Amat, Org. Lett., 2001, 3, 611; Perez,
N. Llor, J. Bosch, E. Lago, E. Molins, S. Hanessian, W. A. van Otterlo,
I. Nilsson and U. Bauer, Tetrahedron Lett., 2002, 43, 1995.
3 Y.-S. Lee, Y.-H. Shin, Y.-H. Kim, K.-Y. Lee, C.-Y. Oh, S.-J. Pyun, H.-J.
Park, J.-H. Jeong and W.-H. Ham, Tetrahedron: Asymmetry, 2003, 14,
87; S. D. Koulocheri, E. N. Pitsinos and S. A. Haroutounian, Synthesis,
−
1
(
film): m (cm ) = 2940, 2860 (s, CH), 1740, 1660 (2 × s, C=O),
1
3
1
1
7
3
230. H NMR (CDCl
3
): d = 1.13 (d, J2,Me = 6.84 Hz, 3H, 2-Me),
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
.17–1.88 (m, 27H, 4-H, 5-H, 1 -H, 2 -H, 3 -H, 4 -H, 5 -H, 6 -H,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀꢀ
-H, 8 -H, 9 -H, 10 -H, 2 -CH
3
), 1.99/2.00 (2 × s, 3H, O
2
CCH ),
3
ꢀꢀ
ꢀꢀ
.42/3.99 (2 × m, 1H, 6-H), 3.88 (m, 4H, 4 -H, 5 -H), 4.33/4.72
2
002, 111.
(
2 × m, 1H, 2-H), 4.72 (m, 1H, 3-H), 7.97/8.00 (2 × s, 2H, CHO).
C NMR (CDCl ), 20.8 (CH ), 29.8 (CH ),
): d = 14.5/16.8 (CH
3.7, 24.1, 26.2, 26.8, 26.9, 27.2, 27.7, 29.4, 29.4, 29.5, 29.6, 29.9,
0.3, 34.4, 35.2, 39.2 (16 × CH ), 44.9/46.9 (C ), 51.6/53.7 (C ),
4.6 (C4ꢀꢀ ,C5ꢀꢀ ), 70.8/71.8 (C
), 162.4/162.6 (CHO), 169.9/170.2
4
(a) Reviews: C. Sears and C. H. Wong, Angew. Chem., Int. Ed., 1999,
38, 2300; M. Bols, Acc. Chem. Res., 1998, 31, 1; B. Ganem, Acc. Chem.
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and Beyond, ed. A. E. Stutz, Wiley-VCH: Weinheim, Germany, 1999;
U. Kazmeier, Recent Res. Dev. Org. Chem., 1998, 2(2), 351; (b) J. Pabba
and A. Vasella, Tetrahedron Lett., 2005, 46, 3619; M. Achmatowitz
and L. S. Hegedus, J. Org. Chem., 2004, 69, 2229; N. T. Patil,
J. N. Tilekar and D. D. Dhavale, J. Org. Chem., 2001, 66, 1065; Y.
Banba, C. Abe, H. Nemoto, A. Kato, I. Adachi and H. Takahata,
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Tetrahedron: Asymmetry, 1998, 9, 4157.
1
3
3
3
3
3
2
3
6
2
2
6
3
2
D
0
(
O
2
CCH
3
). [a] = +7.9 (c = 1.1, CHCl
3
). C23
H
41NO (411.59),
5
+
+
MS (70 eV, CI): m/z (%) = 428.3 (6) [M + CH
5
], 411.4 (3) [M ],
+
+
+
3
83.1 (2) [M – CO], 351.4 (26) [M – C
2
H
4
2
O ], 323.4 (22) [M –
C
2
H
4
O
2
– CO] 291.1 (100).
(
2S,5R,6R)-12-(5-Hydroxy-6-methyl-piperidin-2-yl)-dodecan-
-one, (−)-Cassine (5). Compound 23 (24 mg, 59 lmol) was
dissolved in a mixture of methanol (4 ml) and 2 M H SO
2
2
4
5
28 | Org. Biomol. Chem., 2006, 4, 524–529
This journal is © The Royal Society of Chemistry 2006