2
22 J ournal of Natural Products, 1999, Vol. 62, No. 2
Gabetta et al.
-44° (c
N-Deben zoyl-N-(2-m eth ylbu tyr yl)p a clita xel (1b): white
mg 1d as a colorless powder: mp 232 °C (dec); [R]25
D
2
5
-1
1
powder, mp 226 °C; [R]
3
1
D
-48° (c 0.10, MeOH); IR (KBr) νmax
0.70, MeOH); IR (KBr) νmax 3439, 1731, 1717, 1647 cm ; H
-
1
1
13
438, 2961, 1730, 1714, 1638 cm ; H NMR data, see Table
NMR data, see Table 1; C NMR data, see Table 2; CIMS
1
3
+
+
+
;
C NMR data, see Table 2; CIMS (NH
3
) m/z 851 [M + NH
4
]
(NH
3
) m/z 849 [M + NH
4
] (3), 832 [M + H] (1), 564 [m/z 849
+
+
+
+
(
3), 729 [M - PhCOOH] (2), 586 [M - ScH] (10), 568 [M -
- ScOH] (16), 547 [m/z 832 - ScOH] (9), 504 [m/z 564 -
+
+
+
+
ScOH] (7), 464 [m/z 586 - PhCOOH] (100), 446 [m/z 464 -
H
AcOH] (15), 487 [m/z 547 - AcOH] (9), 464 [m/z 564 -
+
+
+
+
+
2
O] (41), 283 [ScOH + NH
4
]
(93), 266 [ScOH + H] (86),
TiglOH] (29), 447 [m/z 547 - TiglOH] (65), 387 [m/z 447 -
+
+
+
+
+
2
48 [m/z 266 - H
2
O] (44); HREIMS m/z 833.3619 [M] (0.5)
55NO14, 833.3622).
AcOH] (13), 303 [ScOH + NH
4
] (100), 286 [ScOH + H] (51),
+
+
(calcd for C45
H
268 [m/z 286 - H
2
+
O] (10), 240 [268 - CO] (59); HREIMS
m/z 831.3471 [M] (1) (calcd for C45H53NO14, 831.3466).
Syn th esis of N-Deben zoyl-N-cin n a m oylp a clita xel (1c).
a) Synthesis of (2S,3R)-N-cinnamoylphenylisoserine 2,4-
(
dimethoxybenzal derivative 2: A solution of of N-BOC-2R,3S-
2
1
Ack n ow led gm en t. We are grateful to Prof. Richard H.
Himes (Department of Biochemistry, University of Kansas) for
the biological data.
phenylisoserine methyl ester (2.0 g, 6.8 mmol) in MeOH (30
mL) was treated with concentrated HCl (2 mL). The mixture
was heated while being stirred in an oil bath for 8 h. The
solvent was then removed under vacuum and the residue
2 2 3
diluted with CH Cl (25 mL) and saturated with NaHCO (25
Refer en ces a n d Notes
mL). After stirring for 10 min at room temperature, cinnamoyl
chloride (1.35 g, 8.1 mmol, 1.19 mol equivalents) was added.
Stirring was continued for 3 h at room temperature, and the
(
1) For relevant reviews, see: (a) Chen, S.-H.; Farina, V. In The
Chemistry and Pharmacology of Taxol and Its Derivatives; Farina,
V., Ed.; Elsevier: 1995; pp 165-253. (b) Georg, G. I.; Boge, T. C.;
Cheruvallath, Z. S.; Clowers, J . S.; Harriman, G. C. B.; Hepperle,
M.; Park, H. In Taxol: Science and Applications; Suffness, M., Ed.;
CRC, Boca Raton, FL, 1995; pp 317-375.
reaction was then worked up by dilution with H
extraction with CH Cl . The residue obtained after drying
) and removal of the solvent was dissolved in dry THF
50 mL) and treated with pyridinium-p-toluenesulfonate (90
2
O and
2
2
(MgSO
4
(
(2) Gu e´ nard, D.; Gu e´ ritte-Voegelein, F.; Potier, P. Acc. Chem. Res. 1993,
mg) and with an excess 2,4-dimethoxybenzaldehyde dimethyl-
acetal (10 g). After distillation at ambient pressure to remove
ca. half of the solvent, the solution was evaporated, and the
residue was dissolved in MeOH (60 mL) and treated with a
2
6, 160-167.
(3) Rao, R.; Orr, G. A.; Chaudhary, A. G.; Kingston, D. G. I.; Horwitz, S.
B. J . Biol. Chem. 1995, 270, 20235-20238, and references therein.
4) Xiao, X.-Y.; Parandoosh, Z.; Nova, M. P. J . Org. Chem. 1997, 62,
(
6
029-6033.
solution of K
overnight at room temperature, the solvent was evaporated,
and the residue partitioned between H O and EtOAc. The H
phase was then acidified (5% KHSO ) and extracted with
2
CO
3
(1.4 g) in H
2
O (3.0 mL). After being stirred
(5) Powell, R. G.; Miller, R. W.; Smith, C. R., J r. J . Chem. Soc., Chem.
Commun. 1979, 102-104.
6) S e´ nilh, V.; Blechert, S.; Colin, M.; Gu e´ nard, D.; Picot, F.; Potier, P.;
Varenne, P. J . Nat. Prod. 1984, 47, 131-137.
(
2
2
O
4
(
7) (a) Polycystic kidney disease: Woo, D. D. L.; Miao, S. Y. P.; Pelayo,
J . C.; Woolf, A. S. Nature 1994, 368, 750-755. (b) Restenosis: Pallot,
S. J .; Cheng, L.; Pauly, R. R.; J enkins, G. M.; Monticone, R. E.;
Kuzuya, M.; Froehlich, J . P.; Crow, M. T.; Lakatta, E. G. J . Clin.
Invest. 1995, 95, 1969-1979. (c) Alzheimer’s disease: Michaelis, M.
L.; Ranciat, N.; Chen, Y.; Bechtle, M.; Ragan, R.; Hepperle, M.; Liu,
Y.; Georg, G. J . Neurochem. 1998, 70, 1623-1627. (d) Rheumatoid
arthritis: Arsenault, A. L.; Lhotak, S.; Hunter, W. L.; Banquerigo,
M. L.; Brahn, E. Clin. Immunol. Immunopathol. 1998, 86, 280-
EtOAc to afford crude 2. The latter was used for the next step
without further purification.
(b) Synthesis of 1c from 2 and 7-TES-baccatin III: To a
solution of 2 in toluene (60 mL), DCC (1 g), and DMAP (200
mg) were added. After being stirred for 10 min at room
temperature, 7-TES-baccatin III (750 mg) was added. The
solution was stirred at 70 °C for 2 h, filtered, and evaporated.
The residue was dissolved in 0.2 N MeOH hydrochloric acid
2
89.
(8) For reviews on the occurrence of taxoids in yew species, see: (a)
Kingston, D. G. I.; Molinero, A. A.; Rimoldi, J . M. In Progress in the
Chemistry of Organic Natural Products; Herz, W., Kirby, G. W.,
Moore, R. E., Steglich, W., Tamm, C., Eds.; Springer: New York, 1993;
Vol. 61, pp 1-206. (b) Appendino, G. Nat. Prod. Rep. 1995, 12, 349-
360.
(
30 mL) and stirred for 1 h. After evaporation of the solvent,
the residue was taken up in CH Cl and washed with satu-
rated NaHCO and brine. After drying (Na SO ) and evapora-
tion of the solvent, the residue was purified by column
chromatography (Si gel, CH Cl -EtOH, 98:2 as eluent) to
afford 750 mg 1c as a white powder: mp 180 °C (dec); [R]
16.6° (c 0.90, MeOH); IR (KBr) νmax 3412, 2936, 1724, 1661,
2
2
3
2
4
(
9) Ho, T.-Y.; Lin, Y.-C.; Lee, G.-H.; Peng, S.-M.; Yeh, M.-K.; Chen, F.-C.
2
2
2
5
Acta Cryst. 1987, C43, 1380-1383.
D
(
10) (a) Ma, W.; Park, G. L.; Gomez, G. A.; Nieder, M. H.; Adams, T. L.;
Ansley, J . S.; Sahai, O. P.; Smith, R. J .; Stahlhut, R. W.; Hylands, P.
J . J . Nat. Prod. 1994, 57, 116-122. (b) Appendino, G.; Cravotto, G.;
Enri u` , R.; Gariboldi, P.; Barboni, L.; Torregiani, E.; Gabetta, B.; Zini,
G.; Bombardelli, E. J . Nat. Prod. 1994, 57, 607-613.
-
1
2
-1
1
13
626 cm ; H NMR data, see Table 1; C NMR data, see Table
+
+
; CIMS (NH
3
) m/z 897 [M + NH ] (3), 880 [M + H] (4), 862
4
+
+
+
[
m/z 880 - H
2
O] (1), 586 [M - ScH] (100), 568 [M - ScOH]
(
11) Manitto, P. Biosynthesis of Natural Products; Ellis Horwood: Chi-
chester, UK, 1981; p 237.
(12) 10-Deacetyl-2-debenzoyl-2-tigloylbacctin III has been reported from
T. baccata L. (Gabetta, B.; De Bellis, P.; Pace, R.; Appendino, G.;
Barboni, L.; Torregiani, E.; Gariboldi, P.; Viterbo, D. J . Nat. Prod.
+
+
(17), 551 [m/z 862 - ScOH] (15), 526 [m/z 586 - AcOH] (36),
+
+
5
3
8
09 [m/z 551 - CH
3
CO] (37), 387 [m/z 509 - BzOH] (26),
+
+
29 [ScOH + NH
4
] (19), 312 [ScOH + H] (20); HREIMS m/z
79.3470 [M] (1) (calcd for C49 53NO14, 879.3466).
Syn th esis of 2-Deben zoyl-2-tigloylp a clita xel (Isocep h -
a lom a n n in e, 1d ). To a solution of 2′-TBS-7-TES-2-deben-
+
H
1
995, 58, 1508-1514). One 11(15f1)abeotaxane with a tigloyl group
bound to the 10-hydroxyl was isolated from T. cuspidata Sieb. et Zucc.
Wang, X.-X.; Shigemori, H.; Kobayashi, J . Tetrahedron 1996, 52,
(
1
2159-12164).
1
6
2 2
zoylpaclitaxel (1.5 g, 1.5 mMol) in CH Cl -toluene (1:2), tiglic
(
13) Gabetta, B.; Orsini, P.; Peterlongo, F.; Appendino, G. Phytochemistry
acid (3.0 g, 30 mMol, 20 mol equivalents), DMAP (1.8 g, 15
mMol, 10 mol equivalents), and DCC (8.2 g, 40 mmol, 26 mol
equivalents) were added, and the solution was refluxed (100
1998, 47, 1325-1329.
(14) For a general review on the various syntheses of the side chain of
antitumor taxoids, see: Kant, J . In The Chemistry and Pharmacology
of Taxol and Its Derivatives; Farina, V., Ed.; Elsevier: 1995; pp 255-
°
C) for 16 h. After cooling to room temperature, the reaction
3
00.
was worked up by dilution with toluene and filtration. The
filtrate was washed sequentially with 3% HCl, saturated
NaHCO , and brine. After drying (Na SO ) and evaporation,
3 2 4
the residue was filtered through a short Si gel column to
remove the excess tiglic acid (hexane-EtOAc, 7:3 as eluent).
The residue was then dissolved in pyridine (7 mL), and the
solution was cooled to 0 °C and pyridinium hydrogen fluoride
(15) For the debenzoylation of baccatin III and paclitaxel derivatives,
see: (a) Chaudhary, A. G.; Gharpure, M. M.; Rimoldi, J . M.; Chordia,
M. D.; Gunatilaka, A. A. L.; Kingston, D. G. I. J . Am. Chem. Soc.
1
994, 116, 4097-4098. (b) Chen, S.-H.; Farina, V.; Wei, J .-M.; Long,
B.; Fairchild, C.; Mamber, S. W.; Dkadow, J . F.; Vyas, D.; Doyle, T.
W. Bioorg. Med. Chem. Lett. 1994, 4, 479-482. (c) Georg, G. I.; Ali,
S. M.; Boge, T. C.; Datta, A.; Flaborg, L. Tetrahedron Lett. 1994, 35,
8
930-8934.
(
16) Ojima, I.; Kuduk, S. D.; Pera, P.; Veith, J . M.; Bernacki, R. J . J . Med.
(
1.4 mL) was added. After stirring at 0 °C for 3 h and then at
room temperature for 12 h, the reaction was worked up by
the addition of saturated NaHCO and extraction with Et O.
The organic phase was washed with 3% HCl and brine, dried
Na SO ), and evaporated. The residue was purified by column
chromatography (hexane-EtOAc, 1:1 as eluent) to give 180
Chem. 1997, 40, 279-285.
(17) Park, H.; Hepperle, M.; Boge, T. C.; Himes, R. H.; Georg, G. I. J .
Med. Chem. 1996, 39, 2705-2709.
18) Vander Velde, D. G.; Georg, G.; Grunewald, G. L.; Gunn, C. W.;
Mitscher, L. A. J . Am. Chem. Soc. 1993, 115, 11650-11651.
19) Cocciancich, E.; Pace, R. European Patent EP 0553780, J an. 27,
1993.
3
2
(
(
2
4
(