A new reagent system for installation of an aryl group onto the monoacetate of 4-cyclopentene-1,3-diol

Article abstract of DOI:10.1016/S0040-4039(03)00777-9

Among the three types of reagents from PhMgX (X=Br, Cl) and CuCN for phenylation of 4-cyclopentene-1,3-diol monoacetate, PhMgCl/CuCN (cat.) and Ph₂Cu(CN)(MgCl)₂ in THF afforded the trans-1,4-isomer efficiently (82-87% yields, 91-93% regioselectivity). Similarly, o- and p-RC₆H₄MgCl (R=Me, OMe, CH₂=CH) in combination with CuCN furnished good to excellent reactivity and regioselectivity. As an application, a three-step synthesis of dihydromultifidene was accomplished successfully.

Full text of DOI:10.1016/S0040-4039(03)00777-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3983–3986
A new reagent system for installation of an aryl group onto the
monoacetate of 4-cyclopentene-1,3-diol
Takayuki Ainai, Michiko Ito and Yuichi Kobayashi*
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501,
Japan
Received 30 January 2003; revised 13 March 2003; accepted 14 March 2003
Abstract—Among the three types of reagents from PhMgX (X=Br, Cl) and CuCN for phenylation of 4-cyclopentene-1,3-diol
monoacetate, PhMgCl/CuCN (cat.) and Ph2Cu(CN)(MgCl)2 in THF afforded the trans-1,4-isomer efficiently (82–87% yields,
91–93% regioselectivity). Similarly, o- and p-RC6H4MgCl (R=Me, OMe, CH2ꢀCH) in combination with CuCN furnished good
to excellent reactivity and regioselectivity. As an application, a three-step synthesis of dihydromultifidene was accomplished
successfully. © 2003 Elsevier Science Ltd. All rights reserved.
Although the preparation of monoacetate 1 (shown in
Eq. (1) is (1S,3R)-isomer) has been established,1 it is
quite recent that installation of aryl and alkenyl groups
onto the ring of 1 was accomplished successfully with a
reagent system consisting of lithium borate 4, a nickel
catalyst, NaI, and t-BuCN, which affords the trans-1,4-
isomer 2 regioselectively (Eq. (1)).2 Afterwards, the
reaction was applied2b–d,3 to synthesis of the primary
prostaglandin (PG) intermediates, D7-PGA1 methyl,
and aristeromycin. These syntheses clearly demonstrate
the efficiency of the reaction with borates for synthesis
of the cyclopentanoids.4,5 However, further investiga-
tion revealed that the reactivity of the reagent is
impeded by the ortho substitution2d and that the prepa-
ration of small boronate ester precursors such as that
corresponding to the borate 4 with the CH2ꢀCH group
as R results in low yields, probably due to inclination
of the corresponding boronic acids to polymerize6 and/
or due to the volatile nature of such boronate esters.7
In order to circumvent these limitations, we turned our
attention to reagents based on aryl magnesium halides
and CuCN (Fig. 1)8 since we were aware that alkylation
of 1 proceeds with the reagents derived from alkyl
magnesium halides and CuCN with high regio- and
stereoselectivities.9
Figure 1. Previous and present reagents for the installation of
aryl and alkenyl groups to monoacetate 1.
(1)
The fact that the regioselectivity in the alkylation is
controlled by the halide anion in RMgX, the ratio of
RMgX/CuCN, and the solvent (THF or Et2O) led us to
examine first the reagents derived from PhMgBr and
CuCN because PhMgBr is easily prepared in either
THF or Et2O. The results obtained with three (3) equiv.
of the reagents, i.e. PhMgBr with catalytic CuCN
Keywords: coupling reaction; 4-cyclopentene-1,3-diol monoacetate;
Grignard reagent; copper catalyst; dihydromultifidene.
* Corresponding author. Tel.: +81-45-924-5789; fax: +81-45-924-5789;
e-mail: ykobayas@bio.titech.ac.jp
(PhMgBr/CuCN=10:1),
Ph2Cu(CN)(MgBr)2,
and
PhCu(CN)(MgBr), are listed in entries 1–6 of Table 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00777-9

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T. Ainai et al. / Tetrahedron Letters 44 (2003) 3983–3986
Table 1. Phenylation with the reagents derived from PhMgX and CuCN
Entry
Reagent
Solvent
Temp. (°C)
Time (h)
Ratio of 2a:3aa
Yield of 2a (%)b,c
1
2
3
4
5
6
7
8
9
PhMgBr,d CuCN (cat.)e
PhMgBr,d CuCN (cat.)e
THF
Et2O
THF
Et2O
THF
Et2O
THF
THF
THF
−18
−18
−18
−18
0
3
2
3
4
3
1
1
1
10
70:30
73:27
71:29
61:39
28:72
59:41
93:7
63
11f
d
Ph2Cu(CN)(MgBr)2
60
d
Ph2Cu(CN)(MgBr)2
56
PhCu(CN)(MgBr)d
23f,g
–
PhCu(CN)(MgBr)d
rt
PhMgCl (5a),d CuCN (cat.)e
Ph2Cu(CN)(MgCl)2 (6a)d
PhCu(CN)(MgCl) (7a)d
−18
−18
0
90 (87)
84 (82)
18f
91:9
35:65
a Determined by 1H NMR spectroscopy.
b Determined by 1H NMR spectroscopy with pyridine.
c Isolated yields are given in parentheses.
d Three (3) equiv.
e 30 mol%.
f Monoacetate 1 was recovered.
g Yield of 1,2-isomer 3a was 58%.
Although these reagents showed excellent stereoselectiv-
ity producing the trans isomers, the regioselectivity and
reactivity were found to be quite low as compared to
those of the alkylation reagents derived from alkyl
magnesium bromides and CuCN. These results are
probably not surprising since it has been reported that
there is difference in the selectivities and/or the reactiv-
ity between arylation and alkylation of allylic esters
with reagents involving the copper species.10 The differ-
ence has unfortunately been left unsolved.
yields of 2a after chromatography were 87 and 82%,
respectively. On the other hand, PhCu(CN)(MgCl) (7a)
afforded a mixture of 2a and 3a (entry 9) with low
efficiency (yield and regioselectivity), which is in sharp
contrast to that obtained with BuCu(CN)(MgCl) in
THF producing the 1,2-isomer 3 (R=Bu) efficiently
(entry 1 of Table 1 in Ref. 9).
Substituted-phenylmagnesium chlorides were also sub-
jected to the reaction with monoacetate 1 to gain
insight into the inclination of the reagents with respect
to reactivity and selectivity. As shown in Table 2,
p-MeC6H4 and p-MeOC6H4 groups were installed
efficiently on the ring with two types of reagents,
RMgCl/CuCN (cat.) and R2Cu(CN)(MgCl)2, to furnish
the corresponding 1,4-isomers (2b and 2d) in good
yields (entries 1, 2, 7, and 8), whereas the reagents of
the RCu(CN)MgCl type were less productive (entries 3
Next, we examined the reagents derived from PhMgCl
and CuCN. The solvent we could use in this case was
THF because the preparation of PhMgCl in Et2O by
the usual manner was found to be quite difficult. As
shown in entries 7 and 8, PhMgCl (5a)/CuCN (cat.)
and Ph2Cu(CN)(MgCl)2 (6a) furnished 1,4-isomer 2a
(R=Ph) with high regioselectivity, and the isolated
Table 2. Arylation of monoacetate 1a
Entry
R
Reagentb
Products
Ratioc
Yield of 2 (%)d
1
2
3
4
5
6
7
8
p-MeC6H4
p-MeC6H4
p-MeC6H4
o-MeC6H4
o-MeC6H4
o-MeC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
o-MeOC6H4
o-MeOC6H4
o-MeOC6H4
5b
6b
7b
5c
6c
7c
5d
6d
7d
5e
6e
7e
2b/3b
2b/3b
2b/3b
2c/3c
2c/3c
2c/3c
2d/3d
2d/3d
2d/3d
2e/3e
2e/3e
2e/3e
94:4
98:2
38:62
91:9
91:9
19:81
95:5
93:7
63:37
94:6
90:10
39:61
94 (86)
91 (91)
25e
83 (81)
92 (80)
10e
96 (87)
94 (80)
34e
66 (74)
59 (60)
15e
9
10
11
12
a Reactions were carried out at −18°C for 1–4 h except for entries 3 and 6 at 0°C for 7–22 h, and 9 and 12 at rt for 20–21 h.
b CuCN (30 mol%) was used with 5.
c Determined by 1H NMR spectroscopy.
d Calculated yields by 1H NMR; isolated yields are shown in parentheses.
e Monoacetate 1 was recovered in 5–62% yields.

T. Ainai et al. / Tetrahedron Letters 44 (2003) 3983–3986
3985
and 9). These results are consistent with those obtained
above for the phenylation (Table 1). The o-substituted
phenyl groups such as o-MeC6H4 and o-MeOC6H4
were installed similarly (entries 4–6 and 10–12). It is
noteworthy that the efficiency (yield and regioselectiv-
ity) is retained even for the reagents possessing a sub-
stituent at the ortho position (entries 4, 5, 10, and 11).
Scheme 2. Synthesis of the diastereoisomer of dihydromulti-
fidene.
The observed efficiency of the reaction with the two
types of the reagents (5/CuCN and 6) is comparable to
or higher than that obtained by the reaction with the
borates 4.2d,11 Thus, it is no longer necessary to rely on
the previous borates 4 for installation of aryl groups
onto the ring of monoacetate 1.
purification, the crude product was converted to acetate
8 in 60% isolated yield from 1 (two steps). The final
step of the synthesis is butylation of 8, which was
accomplished by using the procedure developed by us19
to furnish the target molecule 9 in 66% yield. No regio-
1
and diastereoisomers were detected by H NMR spec-
The p-styryl group was also added to the ring to
produce 2f in good yield (Eq. (2)). As expected from the
above results, (styryl)Cu(CN)(MgCl)—a reagent of the
type 7—at rt for 18 h afforded a mixture of 2f, 3f, and
1 in a ratio of 28:57:15. Although the products are
prone to polymerize, chromatography on silica gel
allowed isolation of the product. Product 2f will serve
as a new monomer in material science.
1
troscopy. The H and 13C NMR spectra of synthetic 9
were in good agreement with those reported for di-
hydromultifidene.14d,e It is emphasized that the synthe-
sis was achieved with the shortest steps among the
methods published so far.14
The diastereoisomer of 9 (i.e. 11), a minor constitute in
Macrocystis pyrifera,13c was also synthesized selectively
from 1,4-isomer 2g through the Mitsunobu inversion
with AcOH as an acid partner and the subsequent
butylation of the resulting acetate 10 (Scheme 2).19 The
1H NMR spectra of the diastereomer 11 were quite
different from that of dihydromultifidene obtained
above.
(2)
In summary, we have developed a new reagent system
for the installation of aryl groups onto the ring of
monoacetate 1, and achieved a shortest-synthesis of di-
hydromultifidene. We think that synthesis of the
multifidene family as well as compounds with similar
structures such as brefeldin C would be feasible by
using the present method.
It is quite reasonable that the above reagents and
conditions for the productive arylation would be
extended to alkenylation on the basis of the same
orbital character at the reacting center (sp2–carbon) of
the reagent. With this expectation in mind, we envi-
sioned a synthesis of dihydromultifidene,12–14 which is
presented in Scheme 1. The first step is vinylation of 115
with (CH2ꢀCH)MgCl/CuCN (cat.), which afforded 1,4-
Acknowledgements
1
isomer 2g (77% yield by H NMR) with >93% regio-
selectivity.16 It should be noted that 2g has been
synthesized by the reaction of cyclopentadiene mono-
epoxide with CH2ꢀCHSnPh3/Pd (cat.)17 and with
CH2ꢀCHCu(CN)Li in Et2O,18 but only with the low
regioselectivities of 1.2:1 and 1:1, respectively. Without
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Science,
Sports, and Culture, Japan. We thank Dr. K. Uedan of
Hokko Chemical for providing CH2ꢀCHMgCl.
References
1. (1R,3S)-1: (a) Sugai, T.; Mori, K. Synthesis 1988, 19–22;
(b) Laumen, K.; Schneider, M. P. J. Chem. Soc., Chem.
Commun. 1986, 1298–1299. (1S,3R)-1: (c) Laumen, K.;
Schneider, M. Tetrahedron Lett. 1984, 25, 5875–5878; (d)
Wang, Y.-F.; Chen, C.-S.; Girdaukas, G.; Sih, C. J. J.
Am. Chem. Soc. 1984, 106, 3695–3696. rac-1: (e) Dear-
dorff, D. R.; Myles, D. C.; MacFerrin, K. D. Tetrahedron
Lett. 1985, 26, 5615–5618; (f) Deardorff, D. R.; Myles,
D. C. In Organic Syntheses; Freeman, J. P., Ed.; Wiley:
New York, 1993; Collect. Vol. 8, pp. 13–16.
2. (a) Kobayashi, Y.; Takahisa, E.; Usmani, S. B. Tetra-
hedron Lett. 1998, 39, 579–600; (b) Usmani, S. B.;
Scheme 1. Synthesis of dihydromultifidene (9).

3986
T. Ainai et al. / Tetrahedron Letters 44 (2003) 3983–3986
Takahisa, E.; Kobayashi, Y. Tetrahedron Lett. 1998, 39,
12. A review: Jaenicke, L.; Boland, W. Angew. Chem., Int.
Ed. Engl. 1982, 21, 643–653.
601–604; (c) Kobayashi, Y.; Murugesh, M. G.; Nakano,
M. Tetrahedron Lett. 2001, 42, 1703–1707; (d)
Kobayashi, Y.; Murugesh, M. G.; Nakano, M.;
Takahisa, E.; Usmani, S. B. J. Org. Chem. 2002, 67,
7110–7123.
13. Isolation: (a) Boland, W.; Jaenicke, L.; Mu¨ller, D. G.;
Peters, A. Eur. J. Biochem. 1984, 144, 169–176; (b)
Boland, W.; Mu¨ller, D. G. Tetrahedron Lett. 1987, 28,
307–310; (c) Maier, I.; Mu¨ller, D. G. Z. Naturforsch.
1987, 42c, 948–954; (d) Kajiwara, T.; Hatanaka, A.;
Tanaka, Y.; Kawai, T.; Ishihara, M.; Tsuneya, T.;
Fujimura, T. Phytochem. 1989, 28, 636–639; (e)
Fujimura, T.; Kawai, T.; Kajiwara, T.; Ishida, Y. Plant
Tissue Culture Lett. 1994, 11, 34–39; (f) Yamamoto, Y.;
Akakabe, Y.; Matsui, K.; Shimizu, H.; Kajiwara, T. Z.
Naturforsch. 2000, 56c, 6–12.
3. Tokoro, Y.; Kobayashi, Y. Chem. Commun. 1999, 807–
809.
4. Kobayashi, Y. Curr. Org. Chem. 2003, 7, 133–147.
5. (a) Crimmins, M. T. Tetrahedron 1998, 54, 9229–9272; (b)
Collins, P. W.; Djuric, S. W. Chem. Rev. 1993, 1533–
1564; (c) Noyori, R.; Suzuki, M. Chemtracts–Org. Chem.
1990, 3, 173–197.
14. Synthesis: (a) Boland, W.; Mertes, K. Helv. Chim. Acta
1984, 67, 616–624; (b) Wirth, D.; Fischer-Lui, I.; Boland,
W.; Icheln, D.; Runge, T.; Ko¨nig, W. A.; Phillips, J.;
Clayton, M. Helv. Chim. Acta 1992, 75, 734–744; (c)
Kramp, P.; Helmchen, G.; Holmes, A. B. J. Chem. Soc.,
Chem. Commun. 1993, 551–552; (d) Lebreton, J.;
Alphand, V.; Furstoss, R. Tetrahedron 1997, 53, 145–160;
(e) Kajiwara, T.; Akakabe, Y.; Matsui, K.; Kodama, K.;
Koga, H.; Nagakura, T. Phytochem. 1997, 45, 529–532.
15. Racemic 1 was used for the study. For synthesis, see
Refs. 1e and 1f.
6. Kerins, F.; O’Shea, D. F. J. Org. Chem. 2002, 67, 4968–
4971.
7. Unpublished results in this laboratory.
8. Although the precise structures are not established, we
use (R)nCu(CN)(MgX)n (n=2 or 1) to show 2:1 or 1:1
ratios of RMgX and CuCN.
9. Ito, M.; Matsuumi, M.; Murugesh, M. G.; Kobayashi, Y.
J. Org. Chem. 2001, 66, 5881–5889.
10. For example: (a) Tseng, C. C.; Paisley, S. D.; Goering, H.
L. J. Org. Chem. 1986, 51, 2884–2891; (b) Underiner, T.
L.; Paisley, S. D.; Schmitter, J.; Lesheski, L.; Goering, H.
L. J. Org. Chem. 1989, 54, 2369–2374; (c) Underiner, T.
L.; Goering, H. L. J. Org. Chem. 1990, 55, 2757–2361; (d)
Ba¨ckvall, J.-E.; Persson, E. S. M.; Bombrun, A. J. Org.
Chem. 1994, 59, 4126–4130.
11. Yields and ratios of the 1,4- and 1,2-isomers recalculated
from the original publication2d are as follows: 2a, 84%
yield with a 93:7 ratio; 2b, 82% yield with a 92:8 ratio; 2c,
52% yield with a 88:12 ratio; and 2d, 81% yield with a
90:10 ratio.
16. Reaction of 1 with CH2ꢀCHCu(CN)(MgCl) in THF even
1
at rt afforded a 57:25 mixture of 2g and 3g in <20% H
NMR yield and recovered 1 in ca. 40%.
17. Tueting, D. R.; Echavarren, A. M.; Stille, J. K. Tetra-
hedron 1989, 45, 979–992.
18. Marino, J. P.; Ferna´ndez de la Pradilla, R.; Laborde, E.
J. Org. Chem. 1987, 52, 4898–4913.
19. Kobayashi, Y.; Ito, M.; Igarashi, J. Tetrahedron Lett.
2002, 43, 4829–4832.