Efficient phthalate-tethered ring-closing metathesis as a cross-coupling reaction

Article abstract of DOI:10.1016/S0040-4039(01)01649-5

An efficient method for cross-coupling using phthalate-tethered ring-closing metathesis was developed. Based on this method, the stereocontrolled syntheses of both (R,R)- and (S,R)-1-methoxypentadecane-2,9-diol (17, 20) were achieved from (R)-1-undecen-5-ol (4e) and (R)-1-methoxy-5-hexen-2-ol (13).

Full text of DOI:10.1016/S0040-4039(01)01649-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7633–7636
Efficient phthalate-tethered ring-closing metathesis as a
cross-coupling reaction
Yasuharu Sakamoto,* Masato Okazaki, Kazuyuki Miyamoto and Tadashi Nakata*
RIKEN (The Institute of Physical and Chemical Research), Wako, Saitama 351-0198, Japan
Received 10 August 2001; revised 30 August 2001; accepted 31 August 2001
Abstract—An efficient method for cross-coupling using phthalate-tethered ring-closing metathesis was developed. Based on this
method, the stereocontrolled syntheses of both (R,R)- and (S,R)-1-methoxypentadecane-2,9-diol (17, 20) were achieved from
(R)-1-undecen-5-ol (4e) and (R)-1-methoxy-5-hexen-2-ol (13). © 2001 Elsevier Science Ltd. All rights reserved.
Carbonꢀcarbon bond formation is indispensable in
organic synthesis. Particularly efficient cross-coupling
reactions are required for the convergent syntheses of
complex compounds. Recently, olefin metathesis, espe-
cially ring-closing metathesis, is often used for the
synthesis of various compounds as an efficient reaction
providing a CꢀC double bond under mild conditions.1
Although cross-coupling reactions using olefin metathe-
sis (cross metathesis) have been also reported,2 these
reactions essentially involve a concomitant competitive
homo-coupling reaction.3 We report here an alternative
method for the cross-coupling of alkenes, employing
ring-closing metathesis of the temporarily phthalate-
tethered compounds4,5 (Scheme 1).
alkenol with phthalic anhydride should exclusively give
a half-ester, which could easily connect with a second
alkenol to afford a phthalate linking two different
alkenes.
First, the cross-coupling reactions of primary alcohols
having a terminal olefin with a different methylene
carbon chain were demonstrated (Scheme 2, Table 1,
entry 1–3). Treatment of 4-pentenol (1) with phthalic
anhydride (2) provided a half-ester 3 in 98% yield,
which was esterified with allyl alcohol (4a), 3-butenol
(4b), and 5-hexenol (4c) by DCC and DMAP to give
diesters 5a, 5b, and 5c, respectively, in high yield.
Ring-closing metathesis reactions of 5a–c were per-
formed with Grubbs catalyst RuCl2(ꢁCHPh)(PCy3)2 6
in CH2Cl2 at room temperature to afford the cyclized
products 7a–c having 12-, 13-, and 15-membered rings,
respectively, in 85–99% yield as a mixture of cis- and
trans-isomers. Next, the cross-coupling reactions of sec-
ondary alcohols were examined (Table 1, entries 4 and
5). Diesters 5d and 5e were prepared from the half-ester
3 with (R)-1-decen-4-ol (4d)10 and (R)-1-undecen-5-ol
(4e),10 respectively, by the DCC/DMAP method. A
Some tethered ring-closing metathesis approaches using
1,2-benzenedimethanol,6 dichlorodiphenylsilane,7 or
dichlorodimethylsilane8 as a linking reagent to connect
two different alkenes have been reported.9 In these
cases, there is a possibility of formation of a by-product
having two similar alkenes on the linker, which can
afford a homo-coupling product in the ring-closing
metathesis. To avoid this occurrence, we chose phthalic
anhydride as a linking reagent.4 Thus, reaction of a first
O
R2
R2
R2
O
R2
O
O
O
Ring-Closing
Metathesis
OH
OH
n
O
O
O
O
O
OH
OH
n
m
n
m
n
m
m
R1
O
R1
R1
R1
Scheme 1.
Keywords: metathesis; coupling reaction; stereocontrol; remote chiral centers.
* Corresponding authors. E-mail: ysakamot@postman.riken.go.jp (Y.S.); nakata@postman.riken.go.jp (T.N.)
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01649-5

7634
Y. Sakamoto et al. / Tetrahedron Letters 42 (2001) 7633–7636
O
R
O
O
R
O
O
OH
n
O
2
HO
O
4a-e
O
O
n
OH
Py, DMAP
rt
DCC, DMAP
toluene, rt
1
O
3
5a-e
R = H, C6H13
98%
79-99%
n = 0,1,2,3
Scheme 2.
Table 1. Ring-closing metathesis reactions of phthalate-tethered dienes
Entry
Substrate
Products
Timea (h) Yield (%) cis/trans Ratiob
O
O
O
O
O
12
1
1.5
89
99
85
99
92
85
1.3 : 1
O
5a
7a
O
O
O
O
O
O
O
O
2c
3c
4
13
1 : 1.7
1.75
4.75
3.3
5b
7b
O
O
O
O
O
O
O
O
15
1.1 : 1
5c
7c
O
O
O
O
C6H13
C6H13
O
O
O
13
1 : 2.4
O
5d
7d
O
O
O
O
C6H13
C6H13
O
O
O
14
5
6.8 : 1
13 : 1
1.0
O
5e
7e
O
O
O
O
H
N
O
H
N
14
6
1.0
O
8
9
O
O
a All reactions were carried out with 2.5 mM of substrate and 10 mol% of 6 in CH2Cl2 at room temperature, unless
otherwise noted.
b Determined by 1H NMR spectroscopy.
c Performed with 20 mol% of 6.
cyclized product 7d was obtained by treatment of 5d with
Ru catalyst 6 in almost the same yield and stereoselectivity
as 7b. Interestingly, ring-closing metathesis of 5e provided
a 14-membered product 7e with modest cis selectivity.
These results showed that the ring-closing metathesis of
the phthalate-tethered dienes occurred in high yield and
that the stereoselectivity would depend on the ring size.
useful synthetic intermediate utilized in various reac-
tions. For example, the half-ester 3 was able to give amide
8 by reaction with 4-pentenyl amine in the presence of
EDC·HCl (Table 1, entry 6). Thus, the ring-closing
metathesis of 8 affording 9 has enabled the cross-cou-
pling between alkenol and alkenyl amine. The half-ester
3 can also be used as a nucleophile (Scheme 3). Reaction
of 3 with epoxide 1011 using Ti(Oi-Pr)4 effected the
regioselective epoxide-opening to give diol 11 with inver-
sion.12 Treatment of diol 11 with catalyst 6 gave a
An important characteristic of the phthalate-tethered
ring-closing metathesis is the fact that the half-ester is a

Y. Sakamoto et al. / Tetrahedron Letters 42 (2001) 7633–7636
7635
OH
OH
OH
HO
HO
O
O
O
O
20 mol% 6
CH2Cl2
10
HO
O
O
O
O
O
Ti(OiPr)4
r.t., 3.6 h
94%
CH2Cl2, r.t.
O
O
3
11
O
O
12
O
63%
C6H13
OH
cis : trans = 6.5 : 1
C6H13
C6H13
O
10 mol% 6
CH2Cl2
R
HO
O
S
S
O
O
O
O
4e
DEAD, PPh3
THF, r.t.
r.t., 1 h
99%
O
ent-5e
ent-7e
cis : trans = 6.1 : 1
O
O
3
79%
Scheme 3.
C6H13
C6H13
O
O
O
a
R
R
R
O
O
O
R
O
b
O
Method A
(DCC, DMAP)
MeO
MeO
cis : trans = 11 : 1
15
16
OH
R
C6H13
O
R
MeO
C6H13
R
OH
OH
17
20
R
O
+
OH
HO
14
MeO
13
S
R
MeO
C6H13
O
OH
Method B
(DEAD, PPh3)
C6H13
C6H13
O
O
O
O
b
R
R
a
O
O
S
S
O
O
MeO
MeO
cis : trans = 6.2 : 1
18
19
Scheme 4. Reagents and conditions: (a) 10 mol% 6, CH2Cl2, 1 h, 94% for 16, 99% for 19; (b) (i) NaOMe, MeOH, 40°C, (ii) H2,
Pd/C, EtOH, 82% for 17, 86% for 20 in two steps.
cyclized diol 12 in 94% yield. It is important that the amide
proton in 8 and the free hydroxyl group in 11 do not
interfere in the present cross-coupling. The Mitsunobu
reaction13 of the half-ester 3 and (R)-1-undecen-5-ol (4e)
by using DEAD and PPh3 provided a diester ent-5e, the
enantiomer of 5e, which gave a macrocycle ent-7e by
ring-closing metathesis. Thus, stereoisomeric cross-cou-
pling products can be produced independently from the
same segments by selection of the conditions in this
cross-coupling.
and hydrogenation afforded (R,R)- and (S,R)-1-meth-
oxypentadecane-2,9-diol (17, 20), respectively, in good
yield.
In summary, an efficient phthalate-tethered ring-closing
metathesisasacross-couplingreactionwasdevelopedand
the stereocontrolled synthesis of the diastereomers having
remote chiral centers was demonstrated. The present
methodology could be applied to syntheses and stereo-
chemical elucidations of natural products having
undefined stereochemistry.
Based on this concept, the diastereomers 17 and 20 having
two remote chiral centers were synthesized by the present
phthalate-tethered ring-closing metathesis (Scheme 4).
Diesters 15 and 18 were prepared from (R)-1-methoxy-5-
hexen-2-ol (13)14 and a half-ester 1415 by the DCC/DMAP
and DEAD/PPh3 methods, respectively. The ring-closing
metathesis of 15 and 18 followed by methanolysis
Acknowledgements
We thank Ms. K. Harata for the mass spectral
measurements.

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Y. Sakamoto et al. / Tetrahedron Letters 42 (2001) 7633–7636
37, 1105–1108; (d) Yamada, H.; Imamura, K.; Taka-
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