Stereo- and regio-selective Ti-mediated radical cyclization of epoxy-alkenes: Synthesis of the A and C ring synthons of paclitaxel

Article abstract of DOI:10.1016/S0040-4039(01)01655-0

We have developed a practical synthetic route for the A and C rings of paclitaxel. The key reaction is a Ti-mediated radical cyclization of an epoxyalkene.

Full text of DOI:10.1016/S0040-4039(01)01655-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7855–7857
Stereo- and regio-selective Ti-mediated radical cyclization of
epoxy-alkenes: synthesis of the A and C ring synthons of
paclitaxel
Kazuoki Nakai, Miyuki Kamoshita, Takayuki Doi, Haruo Yamada† and Takashi Takahashi*
Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro, Tokyo 152-8552, Japan
Received 16 July 2001; revised 20 August 2001; accepted 31 August 2001
Abstract—We have developed a practical synthetic route for the A and C rings of paclitaxel. The key reaction is a Ti-mediated
radical cyclization of an epoxyalkene. © 2001 Elsevier Science Ltd. All rights reserved.
Paclitaxel (1) is a potent antitumor agent that consists
of fully functionalized ABCD ring system including a
highly strained 8-membered B ring.1 Our synthetic
strategy is to close the B ring at a late stage of the
synthesis by intramolecular cyanohydrin alkylation of 2
as we previously reported in the model ABC ring
system (Scheme 1).2 We wish to report3 a Ti-mediated
radical cyclization of epoxyalkenes 4 and 6 to synthe-
size an A ring moiety 3 and a C ring synthon 5, both of
which were prepared from geraniol (7).4
We first describe the synthesis of the A ring moiety 3
(Scheme 2). Epoxyalkene 4 (R=Ac) readily prepared
from geraniol was treated with 2.5 equiv. of Cp2TiCl5
(prepared in situ from Cp2TiCl2 and Zn-dust in THF)
at room temperature. Ring opening of the epoxide,
followed by concomitant radical cyclization provided
exo- and endo-olefin mixture 8 in 72% combined yield.6
Interestingly, termination of this radical cyclization is
not reductive as reported by RajanBabu,5 rather it
involves b-hydrogen elimination, providing an alkene
OR
CN
X
OR
OR
RO
O
O
O
H
OR
A-ring 3
4
OR
RO
2
Intramolecular
Alkylation
OR
OR
OH
O
OR
O
AcO
OH
Geraniol (7)
BzHN
Ph
O
B
C
A
O
O
O
OR
H
OAc
HO
OBz
OH
C-ring 5
6
Paclitaxel (1)
Scheme 1. Synthetic strategy for the A and C rings of paclitaxel from geraniol.
Keywords: cyclisation; epoxides; stereocontrol; taxoids; titanium and compounds.
* Corresponding author. E-mail: ttakashi@o.cc.titech.ac.jp
† Present address: Department of Chemistry, Okayama University of Science, 1-1 Ridaicho, Okayama 700-0005, Japan.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01655-0

7856
K. Nakai et al. / Tetrahedron Letters 42 (2001) 7855–7857
function. This observation is consistent with the recent
report of Barrero et al.7 Protection of the secondary
alcohol with TBS, hydrolysis of the acetoxy group, and
Swern oxidation of the resulting alcohol afforded an
aldehyde whose double bond isomerized to the a,b-
unsaturated 9 upon DBU treatment.8 Reduction of enal
9, deprotection of the TBS, followed by selective pro-
tection of the primary alcohol provided alcohol 10.
Swern oxidation of 10 gave desired ketone 3, which was
converted to tosylhydrazone 11 according to the
reported procedure.9
diastereomer ratio increased with the ethereal protec-
tion of the epoxy alcohol and a benzyloxymethyl group
afforded the best results (15a:16a=4.5:1) when the
reaction was carried out at 0 °C (Entry 3).12 Pre-
sumably, a 6-membered chelation A is important to
produce the desired stereochemistry at the C8 position.
The stereochemistry of 15 was established from nOe
determinations on the bicyclic compound 18.13
4.1%
4.5%
We next investigated the stereochemistry of the Ti-
mediated radical cyclization of 6 (Scheme 1). The allylic
alcohol 1210 and its protected derivatives 13a–d were
subjected to this reaction (Scheme 3). The results are
depicted in Table 1. The protection of the epoxy alco-
hol is necessary to achieve the cyclization, as the free
alcohol 12 exclusively gave reduced product 17.11 How
ever, the reactions of 13a–d afforded the desired
cyclized products 14a–d as mixtures of diastereomers of
endo- and exo-olefins. We subjected these mixtures to
an additional four steps, to investigate the stereoselec-
tion at the cyclization stage. Protection of the sec-
ondary alcohol of 14 with TBS and hydrolysis of the
acetate afforded the alcohol. The primary alcohol was
oxidized to the aldehyde and the mixture of alkene
moieties isomerized to the a,b-unsaturated aldehyde
upon DBU treatment. The products obtained, 15 and
16, are diastereomers at the C7 and C8 positions.8 The
Hb
Me
Me
Ha
nOe
O
O
H
Hb
(Jab = 11.9, 4.6 Hz)
Me
10%
AcO
8%
H
21%
4.7%
18
We have demonstrated that the Ti-mediated radical
cyclization of epoxy alkenes prepared from geraniol
provides the important synthetic intermediates for both
A ring and C ring synthons for the synthesis of pacli-
taxel. Further synthetic study is presented in the follow-
ing paper.
OAc
O
OTBS
OTBS
a
b, c, d, e
f, g, h
i
4
OH
OTBS
OH
Y
8
10
9
3 Y = O
11 Y = NNHTs
j
Scheme 2. The synthesis of A ring 3 by way of Ti-mediated cyclization (a) 2.5 equiv. Cp2TiCl2, Zn, THF, 78%; (b) TBSOTf,
2,6-Lutidine, CH2Cl2; (c) K2CO3, MeOH; (d) Swern Oxid.; (e) DBU, CH2Cl2 60% (4 steps); (f) NaBH4, MeOH; (g) TBAF, THF;
(h) TBSCl, NEt3, CH2Cl2; (i) Swern Oxid. 71% (4 steps); (j) NH2NHTs, THF.
RO
9
O
O
RO
OH
O
R
Ti
a
ref 11
7
O
O
OAc
12 R = H
13a - 13d
OAc
A
14
RO
OTBS
OH
RO
OTBS
b, c, d, e
8
+
a R = BOM
b R = Bn
c R = MEM
d R = Piv
O
OAc
O
17
15
16
Scheme 3. (a) Cp2TiCl2, Zn, THF (see Table 1); (b) TBSOTf, 2,6-lutidine, CH2Cl2; (c) LiAlH4, ether; (d) SO3·Py, NEt3, DMSO;
(e) DBU, CH2Cl2, 38% (4 steps).

K. Nakai et al. / Tetrahedron Letters 42 (2001) 7855–7857
7857
Table 1. Stereoselectivity of radical cyclization of 12 and
13a–d
Barrero, A. F.; Cuerva, J. M.; Herrador, M. M.; Valdi-
via, M. V. J. Org. Chem. 2001, 66, 4074–4078.
8. All new compounds reported here were characterized on
the basis of their spectral data (1H and 13C NMR, IR).
Selected spectral data for compound 9: 1H NMR (270
MHz, CDCl3) l 0.06 (s, 6H), 0.89 (s, 9H), 1.16 (s, 3H),
1.19 (s, 3H), 1.64–1.80 (m, 2H), 2.08 (s, 3H), 2.08–2.42
(m, 2H), 3.44 (dd, 1H, J=7.6, 3.4 Hz), 10.09 (s, 1H); 13C
NMR (67.8 MHz, CDCl3), l −4.8, −4.1, 18.2, 19.2, 21.8,
26.0, 26.4, 32.7, 38.5, 76.3, 139.3, 154.5, 192.6; IR (neat)
Entry
Substrate
Temperature Yielda (%)
(°C)
Ratiob
(15:16)
1
2
3
4
5
6
12
20
20
0
(27c)
85
80
–
13a
13a
13b
13c
13d
2.7: 1
4.5: 1
2.5: 1
2.7: 1
1.8: 1
20
20
20
79
51(13c)
89
2948, 1673, 1460, 1380, 1253, 1085, 885, 837, 774 cm−1
;
1
15a: H NMR (270 MHz, CDCl3), l 0.06 (s, 3H), 0.08 (s,
3H), 0.89 (s, 9H), 1.08 (s, 3H), 1.61–1.81 (m, 2H), 2.10 (s,
3H), 2.26–2.44 (m, 2H), 3.57 (d, 1H, J=8.9 Hz), 3.95 (dd,
1H, J=6.6, 7.9 Hz), 4.13 (d, 1H, J=8.9 Hz), 4.45 (d, 1H,
J=11.9 Hz), 4.55 (d, 1H, J=11.9 Hz), 4.64 (d, 1H,
J=6.6 Hz), 4.68 (d, 1H, J=6.6 Hz), 7.20–7.44 (m, 5H),
10.12 (s, 1H); 13C NMR (67.8 MHz, CDCl3), l −4.9(q),
−3.8(q), 16.9(q), 18.1(s), 19.2(q), 25.9(q), 26.4(t), 33.6(t),
43.1(s), 69.4(t), 69.88(t), 69.95(d), 95.1(t), 127.6(d),
127.9(d), 128.4(d), 136.6(s), 138.0(s), 156.2(s), 192.1(d);
IR (neat) 2946, 1675, 1459, 1381, 1253, 1113, 1047, 837,
a Yields in cyclization reaction.
b This ratio was determined by 1H NMR (270 MHz).
c The formation of 17 was found at the cyclization stage.
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1
777, 699 cm−1; 16a: H NMR (270 MHz, CDCl3), l 0.06
(s, 3H), 0.08 (s, 3H), 0.89 (s, 9H), 1.21 (s, 3H), 1.62–1.81
(m, 2H), 2.13 (s, 3H), 2.20–2.44 (m, 2H), 3.63 (dd, 1H,
J=3.3, 9.9 Hz), 3.70 (d, 1H, J=8.9 Hz), 4.04 (d, 1H,
J=8.9 Hz), 4.50 (d, 1H, J=11.9 Hz), 4.57 (d, 1H,
J=11.9 Hz), 4.63 (d, 1H, J=6.3 Hz), 4.69 (d, 1H, J=6.3
Hz), 7.25–7.40 (m, 5H), 10.10 (s, 1H); 13C NMR (67.8
MHz, CDCl3),
l −4.9(q), −3.9(q), 18.2(s), 19.7(q),
22.0(q), 26.0(q), 26.9(t), 33.3(t), 42.5(s), 69.1(t), 69.9(t),
74.6(d), 94.8(t), 128.0(d), 128.4(d), 128.5(d), 136.0(s),
138.2(s), 156.4(s), 192.6(d); IR (neat) 2948, 1677, 1468,
1381, 1253, 1106, 1050, 836, 777, 698 cm−1
.
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12. Five-exo cyclization was also observed by the formation
of 2-(benzyloxymethyloxy)-2,3-dimethyl-3-vinylcyclopen-
tan-1-ol (14%).
13. Preparation of 18 from 15a (i) NaBH4, MeOH; (ii)
TBAF, THF; (iii) TBSCl, NEt3, CH2Cl2; (iv) Na, NH3;
(v) 2,2-dimethoxypropane, CSA, CH2Cl2; (vi) TBAF,
THF; (vii) Ac2O, DMAP, CH2Cl2.
6. exo-Olefin 46% (77:23 diastereomer mixture), endo-olefin
(26%, 60:40 diastereomer mixture), and non-olefin (6%)
were isolated. Five-exo cyclization was also observed by
the formation of 2,2,3-trimethyl-3-vinylcyclopentan-1-ol
(12%, 51:49 diastereomer mixture).
7. A report performed on various geraniol derivatives
appeared during the preparation of this manuscript, see: