Synthesis of the CD ring system of paclitaxel by atom-transfer radical annulation reaction

Article abstract of DOI:10.1016/S0040-4039(02)02058-0

Atom-transfer radical annulation of diene derived from D-glucose under Kharasch conditions provided access to the fully functionalized CD ring system of paclitaxel.

Full text of DOI:10.1016/S0040-4039(02)02058-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8587–8590
Synthesis of the CD ring system of paclitaxel by atom-transfer
radical annulation reaction
Takehiko Yoshimitsu,* Hideyuki Nakajima and Hiroto Nagaoka*
Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
Received 19 July 2002; revised 2 September 2002; accepted 13 September 2002
Abstract—Atom-transfer radical annulation of diene derived from
D-glucose under Kharasch conditions provided access to the
fully functionalized CD ring system of paclitaxel. © 2002 Elsevier Science Ltd. All rights reserved.
The atom-transfer radical reaction has been found quite
useful for functionalizing unsaturated organic
molecules.1 The Kharasch reaction, which involves the
addition of various halocarbons to olefins in the pres-
ence of radical initiators, is particularly effective for this
purpose (Scheme 1).2–4 Poly-halogenated compounds
obtained by this reaction have been used as versatile
intermediates for organic synthesis owing to their com-
patibility with numerous transformations.5
vided an aldehyde. Addition of isopropenylmagnesium
bromide to the aldehyde gave the desired b-alcohol 8b
(54%) together with a-isomer 8a (27%) in two steps
from 7. The minor a-alcohol 8a was converted to 8b in
74% overall yield via the Mitsunobu reaction followed
by methanolysis. Acetylation of the b-alcohol 8b pro-
ceeded to afford b-acetate 1 quantitatively. Using this
acetate 1, the atom-transfer radical annulation reaction
under Kharasch conditions was carried out (Scheme 4).
In the present study, synthesis of the CD ring system of
paclitaxel through a peroxide-initiated carbon–halogen
transfer reaction was accomplished, thereby demon-
strating the usefulness of radical annulation strategy
(Scheme 2).6 This synthesis provides a novel route to
chiral 3-epi-CD ring system,† which would be utilized
as a key intermediate for the synthesis of paclitaxel.7
Scheme 1.
The conversion of readily available carbohydrates into
functionalized carbocycles via radical reactions has
been extensively studied.8 In consideration of the intrin-
sic ability of
D-glucose to produce the oxetane ring (D
ring) of paclitaxel with the requisite absolute configura-
tion, the synthesis was initiated with
tive 1 (Scheme 3).
D-glucose deriva-
9–11
Alcohol 5 prepared by a known procedure12 was sub-
jected to deoxygenation of the secondary hydroxy
group to afford 6 in 62% overall yield. The trityl group
of 6 was removed by sodium in liq. NH3 to give diol 7
whose oxidation with Dess–Martin periodinane pro-
Keywords: radicals and radical reactions; annulation; taxoids.
* Corresponding authors. Tel./fax: +81-424-95-8849; e-mail:
takey@my-pharm.ac.jp
† Paclitaxel numbering.
Scheme 2.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02058-0

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T. Yoshimitsu et al. / Tetrahedron Letters 43 (2002) 8587–8590
quantitatively. Hydrolysis of the isopropylidene acetal
of 12 gave hemiacetals whose oxidative cleavage fol-
lowed by the reduction with LiAlH4 afforded diol 13 in
78% overall yield. Selective mesylation of diol 13 fol-
lowed by the treatment with NaH in refluxing ether
furnished the CD ring system of paclitaxel in quantita-
tive yield.17
In conclusion, we have succeeded in synthesizing the
CD ring system of paclitaxel via the atom-transfer
radical annulation of diene 1 derived from diacetone-D-
glucose. This synthesis features the concise construction
of highly functionalized carbocycles through the intro-
duction of multifunctional groups. The transformation
clearly demonstrates the usefulness of the atom-transfer
radical annulation reaction in increasing molecular
complexity in only a few synthetic steps. Studies toward
the total synthesis of paclitaxel based on this radical
annulation strategy are presently under investigation.
Scheme 3. Reagents and conditions: (i) thiocarbonyl diimida-
zole, DMAP, CH2Cl2, rt, 83%; (ii) Bu3SnH, AIBN, toluene,
reflux, 75%; (iii) Na, liq. NH3, THF, −78°C, 70%; (iv) Dess–
Martin periodinane, CH2Cl2, rt; (v) isopropenylMgBr, THF,
0°C, b-alcohol 8b (54%), a-alcohol 8a (27%), two steps; (vi)
4-nitrobenzoic acid, DEAD, PPh3, toluene, −10°C; (vii)
K2CO3, MeOH, rt, 74%, 2 steps; (viii) Ac2O, Et3N, CH2Cl2,
rt, quant.
A solution of 1 and catalytic amount of benzoyl perox-
ide in carbon tetrachloride was heated to reflux for 3 h
to provide cyclized products 2 and its C8-epimer in a
ratio of 3:1 in ca. 80% yield,13 along with a trace of
unidentified by-product. Compound 2, having the pacli-
taxel CD substructure, was found to possess halogen
functionalities that would allow the multiple transfor-
mations in one step. Thus, on treating 2 with an excess
of cesium acetate14 in DMSO at 120°C for 45 min,
chloroalkenyl ethers 9 was obtained in 72% yield along
with diene 10 (16%).15 This transformation established
the stereochemistry of a quaternary carbon at C8 whose
trichloroethyl substituent was found situated syn to the
hydroxy group at C4. Other configurations of 9 were
confirmed by NOE correlations.16 Ozonization of
chloroalkenyl ether 9 afforded lactone 3 in 65% yield.
Reduction of 3 with LiAlH4 and subsequent benzyla-
tion of the hydroxy groups in tetraol 11 provided 12
Acknowledgements
We thank Ms. T. Koseki and Ms. A. Ohmae for
conducting mass and NOE measurements.
References
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Scheme 4. Reagents and conditions: (i) cat. benzoyl peroxide, CCl4, reflux, 2 (58%), C8-epimer (19%); (ii) 5 equiv. CsOAc, DMSO,
120°C, 9 (72%), 10 (16%); (iii) O3, NaHCO3, CH2Cl2, −78°C, then Me2S, −78°C to rt, 65%; (iv) LiAlH4, THF, 0–50°C; (v) NaH,
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THF, 0°C, 78%, three steps; (ix) MsCl, Et3N, CH2Cl2, rt; (x) NaH, Et2O, reflux, quant., two steps.

T. Yoshimitsu et al. / Tetrahedron Letters 43 (2002) 8587–8590
8589
Figure 1.
Figure 2.
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9. Utilization of
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Jenkins, P. R.; Lawrence, N. J. J. Chem. Soc., Chem.
Commun. 1993, 151.
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ring systems: (a) Nakai, K.; Miyamoto, S.; Sasuga, D.;
Doi, T.; Takahashi, T. Tetrahedron Lett. 2001, 42, 7859;
(b) Shing, T. K. M.; Lee, C. M.; Lo, H. Y. Tetrahedron
Lett. 2001, 42, 8361; (c) Uttaro, J.-P.; Audran, G.;
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Lett. 1998, 39, 313.
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7. The C3 stereocenter of 3-epi-C ring derivatives has been
shown to be amenable to epimerization at a later stage of
the paclitaxel synthesis: (a) Morihira, K.; Hara, R.;
Kawahara, S.; Nishimori, T.; Nakamura, N.; Kusama,
H.; Kuwajima, I. J. Am. Chem. Soc. 1998, 120, 12980.
Another instance of the construction of the natural C3
configuration through epimerization: (b) Holton, R. A.;
Somoza, C.; Kim, H.-B.; Liang, F.; Biediger, R. J.;
Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.;
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Zhang, P.; Murthi, K. K.; Gentile, L. N.; Liu, J. H. J.
Am. Chem. Soc. 1994, 116, 1597. Various 3-epi-C or -CD
12. Nielsen, P.; Petersen, M.; Jacobsen, J. P. J. Chem. Soc.,
Perkin Trans. 1 2000, 3706.
13. In contrast to the present case, a related cyclization of
germacrene has been shown to selectively provide trans-
decalin derivatives (Ref. 6b). The preferred formation of
2, possessing the C8b-methyl group and the C3b-hydro-
gen, may be attributed to the conformationally flexible
1,7-diene system in 1 leading to the transition state (I)
that alleviates steric interaction between the C8 methyl
and C4 axial substituents (Fig. 1).

8590
T. Yoshimitsu et al. / Tetrahedron Letters 43 (2002) 8587–8590
HRMS calcd for C16H21Cl4O6 449.0094 (M+−Me), found
449.0091.; 9: [h]D23 +80.5 (c 0.365, CHCl3); IR (neat) wmax
1
1744 cm−1; H NMR (300 MHz, CDCl3) l 5.77 (d, 1H,
J=3.5 Hz), 5.15 (s, 1H), 4.86 (d, 1H, J=3.5 Hz), 4.79
(dd, 1H, J=7.2, 2.2 Hz), 4.43 (dd, 1H, J=12.1, 3.5 Hz),
4.27 (dd, 1H, J=7.8, 1.8 Hz), 4.11 (dd, 1H, J=12.1, 7.5
Hz), 2.65 (dd, 1H, J=7.5, 3.5 Hz), 2.38 (ddd, 1H, J=
17.2, 7.8, 7.2 Hz), 2.09 (s, 3H), 2.08 (s, 3H), 1.88 (ddd,
1H, J=17.2, 2.2, 1.8 Hz), 1.61 (s, 3H), 1.38 (s, 3H), 1.21
(s, 3H); MS(EI) m/z: 416 (M+), 401, 358; HRMS calcd
for C19H25ClO8 416.1238 (M+), found 416.1217.; 3: [h]2D3
Figure 3.
+117 (c 0.078, CHCl3); IR (neat) wmax 1794, 1742 cm−1
;
1H NMR (300 MHz, CDCl3) l 5.83 (d, 1H, J=3.5 Hz),
5.01 (dd, 1H, J=7.7, 4.0 Hz), 4.82 (d, 1H, J=3.5 Hz),
4.57 (dd, 1H, J=12.5, 2.7 Hz), 4.32 (dd, 1H, J=8.1, 3.5
Hz), 4.15 (dd, 1H, J=12.5, 5.1 Hz), 2.75 (dd, 1H, J=5.1,
2.7 Hz), 2.60 (ddd, 1H, J=16.6, 8.1, 7.7 Hz), 2.10 (s, 3H),
2.09 (s, 3H), 1.89 (ddd, 1H, J=16.6, 4.0, 3.5 Hz), 1.60 (s,
3H), 1.38 (s, 3H), 1.29 (s, 3H); MS(EI) m/z: 369 (M+−15)
(100%), 326; HRMS calcd for C17H21O9 369.1185 (M+−
14. (a) Huffman, J. W.; Desai, R. C. Synth. Commun. 1983,
13, 553; (b) Kruizinga, W. H.; Strijtveen, B.; Kellogg, R.
M. J. Org. Chem. 1981, 46, 4321; (c) Hawryluk, N. A.;
Snider, B. B. J. Org. Chem. 2000, 65, 8379.
15. This alkenyl ether formation may proceed via the
intramolecular cyclization of dichloro olefin 15 with a
hydroxy group, followed by the elimination of hydrogen
chloride (Fig. 2).
1
Me), found 369.1184.; 4: [h]2D3 +58.0 (c 0.148, CHCl3); H
16. NOE interactions in 9 (Fig. 3).
NMR (300 MHz, CDCl3) l 7.31–7.11 (m, 20H), 5.11 (dd,
1H, J=6.1, 3.1 Hz), 4.88 (d, 1H, J=6.4 Hz), 4.67 (d, 1H,
J=11.8 Hz), 4.62 (d, 1H, J=11.8 Hz), 4.61 (d, 1H,
J=12.1 Hz), 4.40–4.30 (m, 5H), 4.21 (d, 1H, J=12.1 Hz),
3.82 (dd, 1H, J=10.5, 9.0 Hz), 3.70 (dd, 1H, J=9.0, 4.7
Hz), 3.36 (dd, 1H, J=4.5, 4.0 Hz), 3.22 (s, 2H), 3.04 (dd,
1H, J=10.5, 4.7 Hz), 1.99 (ddd, 1H, J=15.6, 4.5, 3.1
Hz), 1.62 (ddd, 1H, J=15.6, 6.1, 4.0 Hz), 1.15 (s, 3H);
MS(EI) m/z: 578 (M+), 91 (100%); HRMS calcd for
C38H42O5 578.3034 (M+), found 578.3026.
17. Selected data: 2: [h]D23 +83.9 (c 0.329, CHCl3); IR (neat)
wmax 3506, 1738 cm−1 1H NMR (300 MHz, CDCl3) l
;
5.83 (d, 1H, J=4.0 Hz), 5.65 (t, 1H, J=3.0 Hz), 4.63 (d,
1H, J=4.0 Hz), 3.95 (dd, 1H, J=12.7, 3.5 Hz), 3.94 (m,
1H), 3.69 (dd, 1H, J=12.7, 3.1 Hz), 3.41 (d, 1H, J=16.7
Hz), 2.86 (d, 1H, J=1.7 Hz), 2.85 (d, 1H, J=16.7 Hz),
2.33 (m, 1H), 2.24 (ddd, 1H, J=16.9, 3.9, 3.0 Hz), 2.14
(m, 1H), 2.05 (s, 3H), 1.55 (s, 3H), 1.50 (s, 3H), 1.39 (s,
3H); MS(EI) m/z: 449 (M+−15), 406, 290, 100 (100%);