Ti(III)-catalyzed radical cyclization of 6,7-epoxygeranyl acetate

Article abstract of DOI:10.1016/j.tetlet.2003.12.138

The reductive cyclization of epoxygeranyl acetate (1) was investigated using a catalytic amount of Cp₂TiCl with various additives. The newly developed Cp₂TiCl-Mn-lutidine·HCl-BEt₃ system was found to be as effective as the reported stoichiometric system to afford the cyclized dehydro products 4 and 5 with 72% selectivity.

Full text of DOI:10.1016/j.tetlet.2003.12.138

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1961–1963
Ti(III)-catalyzed radical cyclization of 6,7-epoxygeranyl acetate
Shinichiro Fuse, Malcoln Hanochi, Takayuki Doi and Takashi Takahashi*
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology, 2-12-1, Ookayama,
Meguro, Tokyo 152-8552, Japan
Received 15 October 2003; revised 5 December 2003; accepted 22 December 2003
Abstract—The reductive cyclization of epoxygeranyl acetate (1) was investigated using a catalytic amount of Cp2TiCl with various
additives. The newly developed Cp2TiCl–Mn–lutidine Æ HCl–BEt3 system was found to be as effective as the reported stoichiometric
system to afford the cyclized dehydro products 4 and 5 with 72% selectivity.
Ó 2004 Elsevier Ltd. All rights reserved.
Stereo- and regio-selective cyclization of epoxy-alkenes
can generate cycloalkanols.1 Barrero reported the
Ti(III)-mediated cyclization of various geraniol deriva-
tives.2 We have also reported that the Ti(III)-mediated
radical cyclization of 6,7-epoxygeranyl acetate deriva-
tives provided important synthetic intermediates for
both the A and C ring synthons in the synthesis of
paclitaxel.3 In the synthesis, a stoichiometric amount of
Cp2TiCl was used; therefore, the work-up process was
very tedious due to a large amount precipitated Ti-salts.
A catalytic cycle, however, had only been reported for
product 4 and 5 and concomitantly produce a similar
species to Cp2Ti(IV)HCl. In order to accomplish a cata-
lytic cycle of Ti(IV) to Ti(III), another transformation of
this Ti(IV) species to Cp2TiCl is necessary. This process
may be possible by addition of Et3B because that would
reduce the Cp2ZrHCl into Cp2ZrCl.6 It will be very
important whether these systems are compatible in the
same reaction flask.
We initially investigated the effect of the additives, Et3B,
2,6-lutidine Æ HCl, 2,4,6-collidine Æ HCl (Table 1, entries
2, 3 and 5) using 10 mol % of Cp2TiCl and 4 equiv of
Mn. The results are shown in Table 1. In the absence of
additives, only 10% conversion of 1 was observed. A
catalytic process was achieved when 2,6-lutidine Æ HCl
(99%) and 2,4,6-collidine Æ HCl (71%) were added,
respectively (entries 3 and 5). Addition of only Et3B was
not effective (entry 2). However, addition of Et3B and
2,6-lutidine Æ HCl gave better selectivities than that of
2,6-lutidine itself to afford the desired 4 and 5 (entry 4).
Addition of Et3B was slightly more effective with the use
of 2,4,6-collidine Æ HCl (entry 6 vs entry 5). Presumably,
Et3B promotes a smooth catalytic cycle to result in
efficient supply of Cp2TiCl for disproportionation rather
than the protonated termination by HCl salt.7 To avoid
the protonated termination, addition of TMSCl was
attempted instead of lutidine salt.8 However, unwanted
chlorohydrin 8 was mostly formed (entry 7). The re-
cently reported Cp2TiCl–Mn–lutidine Æ TMSCl system5
was not effective in this cyclization yielding at most 55%
conversion (entry 8). The best result was obtained using
Cp2TiCl–Mn–lutidine Æ HCl–BEt3 (entry 4). This is as
good as the results obtained using the stoichiometric
system reported previously (entry 9).2;3
the reductive opening of epoxides using a novel
4
€
Cp2TiCl–Mn–collidine Æ HCl system by Gansauer, until
Barrero recently demonstrated the Ti(III)-catalyzed
transannular cyclization of an epoxy-alkene in a ger-
macrane skeleton using Cp2TiCl–Mn–collidine Æ
TMSCl.5 We wish to report that the catalytic cyclization
of 6,7-epoxygeranyl acetate was efficiently achieved by
using Cp2TiCl–Mn–lutidine Æ HCl–BEt3.
A plausible mechanism for the Ti(III)-catalyzed radical
cyclization of 6,7-epoxygeranyl acetate (1) is shown in
Scheme 1. Reductive opening of the epoxide with
Cp2Ti(III)Cl, followed by endo-trig cyclization via a
chair-like transition state would form 2. According to
€
Gansauerꢀs method, transformation of the Ti(IV) of
Cp2Ti(OR)Cl 2 can be carried out by a Cp2TiCl–Mn–
collidine Æ HCl system to afford Cp2Ti(III)Cl and 3.
Then, disproportionation of the radical of 3 with
Cp2Ti(III)Cl would provide a double bond in the
* Corresponding author. Tel.: +81-3-5734-2120; fax: +81-3-5734-2884;
e-mail: ttak@apc.tiitech.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.138

1962
S. Fuse et al. / Tetrahedron Letters 45 (2004) 1961–1963
Mn
Cp2TiIIICl
Cp2TiIVCl2
R
N
H
OAc
OAc
OAc
R
OH
O
OTiIVCp2Cl
3
1
2
Cp2TiIIICl
Et-H
N
HCl
Cp2TiIVHCl
OAc
Et
OAc
OAc
OAc
Et3B
Cl
OH
OH
OH
OH
OH
4
5
6
7
8
Scheme 1. Plausible mechanism of Ti(III)-catalyzed reductive cyclization of epoxygeranyl acetate (1).
Table 1. The Cp2TiCl-catalyzed radical cyclization of 1 using various additivesa
4 (RTb/min) 5 (RTb/min) 6 (RTb/min) 7 (RTb/min) 8 (RTb/min)
Entry Cp2TiCl/ Additives
mol %
Time/h
Conversion/%
(1.5 equiv)
(57 for cis
and 87 for
trans)
(51 for cis
and 82 for
trans)
(47, 70, and (21 and 24) (41)
78)c
1
10
10
None
BEt3
9
9
10
30
99
99
71
86
89
55
99
5
1
4
2
6
2
12 (5:1)
16 (7:1)
3
17
12
18
19
8
1
7
3
10
10
2,6-Lutidine Æ HCl
BEt3, 2,6-lutidine Æ HCl
2,4,6-Collidine Æ HCl
BEt3, 2,4,6-collidine Æ HCl
TMSCl
2,4,6-Collidine Æ TMSCle
None
9
43 (3:1)
56 (3:1)
30 (3:1)
35 (3:1)
20 (3:1)
25 (5:1)
64 (3:1)
4
4
5
10
10
9
5
9
6
5
2
11
5
6
9
6
2
7
10
20
4
41
8d
9f
24
2
6
300
15
9
a The reaction was carried out in THF with 4 equiv of Mn at room temperature. The conversion and ratio of the products were determined by HPLC
analysis with RI intensities (Silica-3301-N 8/ꢀ300 mm, 13% ethyl acetate in hexane, 2.0 mL/min).
b RT ¼ retention time.
c Three of four possible diastereomers were observed.
d Ref. 5.
e 4 equiv.
f Refs. 2 and 3.
We have demonstrated that the reductive cyclization of
6,7-epoxygeranyl acetate was accomplished using a
catalytic amount of Cp2TiCl with Mn, lutidine Æ HCl,
and BEt3 as additives. A larger scale reaction is under-
way in our laboratory toward a key synthetic interme-
diate of paclitaxel.
6,7-epoxygeranyl acetate (1) (1.80 g, 8.48 mmol) in
40 mL of dry THF. Then, the mixture was treated with a
0.1 M THF solution of BEt3 (12.7 mL, 12.7 mmol) and
was stirred at room temperature under argon. After 4 h,
1 M HCl was added at 0 °C. Usual work-up and flash
column chromatography on silica gel afforded the
alcohols 4–6 (1.77 g) as a colorless oil.
Experimental procedure of the Ti(III)-catalyzed cycli-
zation of (1).
A mixture of Cp2TiCl2 (211 mg,
0.848 mmol) and manganese (62 mg, 1.1 mmol), and
10 mL of THF was stirred under argon. The supernatant
of Cp2TiCl was transferred via a cannular to a mixture
of 2,6-lutidine Æ HCl (1.84 g, 12.8 mmol, pre-dried at
60 °C under 600 Pa), manganese (1.80 g, 33.9 mmol), and
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