Selective formation of dihydropyran derivatives by a tandem domino ring-closing metathesis/cross-metathesis

Article abstract of DOI:10.1016/j.tetlet.2006.12.092

A ring-closing metathesis (RCM)/cross-metathesis (CM) domino reaction has been applied to esters and unsymmetrical ether prepared from 1,5-hexadien-3-ol. For the first time, dihydropyran derivatives have been obtained via a regioselective cyclization. Thi

Full text of DOI:10.1016/j.tetlet.2006.12.092

Tetrahedron Letters 48 (2007) 1417–1420
Selective formation of dihydropyran derivatives by a
tandem domino ring-closing metathesis/cross-metathesis
Marie-Alice Virolleaud and Olivier Piva*
Universite´ de Lyon 1, F-69003 Lyon, France
`
´
CNRS UMR 5181 Me´thodologies de synthese et molecules bioactives, Equipe CheOPS, Bat. Raulin/4, F-69622 Villeurbanne, France
Received 23 November 2006; revised 12 December 2006; accepted 15 December 2006
Available online 20 December 2006
Abstract—A ring-closing metathesis (RCM)/cross-metathesis (CM) domino reaction has been applied to esters and unsymmetrical
ether prepared from 1,5-hexadien-3-ol. For the first time, dihydropyran derivatives have been obtained via a regioselective cycliza-
tion. This reaction was performed in high yield and E stereoselectivity.
Ó 2006 Elsevier Ltd. All rights reserved.
With the discovery of well-defined catalysts 1a and 1b
(Fig. 1), which can react with highly functionalized sub-
strates, metathesis1,2 is more and more applied even for
the total synthesis of natural products.3,4 Due to the
mildness of the experimental conditions, tandem
metathesis processes have been also obviously consid-
ered: the catalyst used for a first metathesis coupling is
able to promote a second reaction from the intermediate
generated during the first step.5
and easily complex structures, a major challenge is still
to investigate the regioselectivity issue when different
competitive cyclizations are possible.
Therefore, we previously studied a similar process start-
ing from 3-O-1,5-hexadienyl esters (Scheme 1).7 In that
case, the diene which should interact with the ester part
is not symmetrical and two competitive ring-closing
metatheses could be expected leading to the formation
of two regioisomers. The reaction showed a moderate
ring-size selectivity while both five- and six-membered
ring lactones were obtained with a noticeable preference
for the c-lactone (6/5 = 2/1).
In this context, we already reported two different tan-
dem ring-closing/cross-metathesis reactions from b,c-
or a,b-unsaturated 3-O-1,4-pentadienyl esters leading,
respectively, to d-lactones6 and c-lactones.7 In the latter
case, the reaction proceeded via an efficient alkylidene
transfer. Although tandem metathesis reactions are
nowadays well recognized methods to reach rapidly
We have subsequently performed a tandem RCM/CM
process with acrylate 7 in the presence of 1-hexene
(Scheme 2). The reaction delivered unsaturated lactones
in higher chemical yields and with a better selectivity still
in favour of the c-lactone (9/8 = 3/1).8 These results are
closed to those observed by Quinn et al. who observed
the exclusive formation of butenolides from the related
acrylates of C2-symmetric alcohols.9
MesN
Cl
NMes
Ph
PCy3
Ru
Cl
Cl
Ru
Cl
Ph
The difference in the chemical yields between the two
processes described above can be correlated with the ste-
ric hindrance generated by the alkyl substituent on 4,
which could prevent the formation of the metallacyclo-
butane. Furthermore, the intermediate for the five-mem-
bered ring formation in the case of 4 should be more
sterically encumbered than the six-membered one. These
reasons could explain the lower yields for the butenolide
isolated from ester 4.
PCy3
PCy3
1a
1b
Figure 1.
Keywords: Ring-closing metathesis; Cross-coupling metathesis; Allyl
ethers; Cyclization.
*
Corresponding author. Tel./fax: +33 472 448 136; e-mail: piva@
univ-lyon1.fr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.092

1418
M.-A. Virolleaud, O. Piva / Tetrahedron Letters 48 (2007) 1417–1420
O
O
O
1b (7.5 mol%)
O
O
O
C6H13
C6H13
C6H13
-2
CH Cl (10 M)
2
2
5 (17%)
6 (34%)
4
50 ºC,18 h
5/6 = 1/2
Scheme 1. Formation of d-lactones (5) and c-lactones (6) by a RCM/CM process from 2-nonenoate 4.
O
O
C4H9
(5 eq.)
O
1b (5 mol%)
O
O
O
C4H9
C4H9
-2
CH Cl (10 M)
2
2
7
8 (17%)
9 (52%)
50 ºC,8 h
8/9 = 1/3
Scheme 2. Formation of d-lactones (8) and c-lactones (9) by a RCM/CM process from acrylic ester 7.
We next examined the regioselectivity issue of the RCM/
CM domino process applied to ether derivatives. We
envisaged that an important modification of our sub-
strate could modify the regioselectivity of the reaction.
Moreover, starting from a hexadienyl ether, and in the
case of a regioselective pathway, we could apply this
strategy to a direct synthesis of the isolated pyran of lau-
limalide as depicted in Figure 2. It should be noted that
the heterocyclic subunit has been already obtained by
RCM while the exocyclic chain was functionalized by
a Stille coupling.10
formation of dihydrofurans versus dihydropyrans by
modifying the nature of alkoxy group. For this ether ser-
ies, the formation of the five-membered ring was again
preferred.
All these recent published data urged us to disclose
herein our preliminary investigations performed on
allylether 10 prepared from 1,5-hexadien-3-ol.15 The
expected RCM/CM reaction was first tested with
5-bromopentene 15a as the alkene partner (R =
–(CH2)3Br) for the second coupling (Scheme 3).
Performed in the presence of catalytic amounts of
Grubbs catalyst 1a, the only compound isolated in a
low yield was dihydropyran 11 functionalized by a
5-bromopentenyl lateral chain (Table 1, entry 1).
The access to five- or six-membered cyclic ethers has
been widely investigated by RCM and applied in total
synthesis. In the context of the synthesis of (À)-muco-
cin,11 Crimmins et al. used a tandem relay strategy12
from a triene derivative to circumvent the lack of regio-
selectivity and to obtain an efficient access to a
dihydrofuran. Furthermore, Basu and Waldmann stud-
ied the regioselectivity during the ring-closure of allyl
and conjugated pentadienyl ethers.13 In a recent arti-
cle,14 Schmidt and Nave described the reactivity of hexa-
dienyl ethers derived from D-mannitol and the selective
With the more active catalyst 1b (entry 2), the reaction
again delivered six-membered ring 11 in far better yield.
Another compound was isolated from the reaction mix-
ture and identified as dimeric dihydropyran 13 and
present according to the 13C NMR spectrum as a nearly
1:1 mixture of diastereomers (Fig. 3).
To ascertain that the formation of the six-membered
ring was preferred, the process was generalized with
other alkenes 15b–e by using the same experimental con-
ditions, and results are summarized in Table 1.16 Only
traces of 13 were detected by TLC control on the crude
reaction mixture, while the E configuration of the new
C@C bond was determined by analysis of the 1H
NMR spectra for all isolated compounds 11. With ter-
minal alkenes, the reaction occurred in yields up to
78% and with a total E selectivity for 11b, c and e, which
laulimalide
OH
H
O
O
O
O
OH
H
Me
H
Me
O
CM
(5 eq.)
R
O
O
R'
O
catalyst (5 mol%)
Me
R
-2
CH Cl (10 M)
2
2
10
11 (major)
50 °C, 8 h
RCM
Figure 2. RCM/CM approach for a subunit of laulimalide.
Scheme 3. Regioselective formation of dihydropyran 11 from ether 10.

M.-A. Virolleaud, O. Piva / Tetrahedron Letters 48 (2007) 1417–1420
Table 1. Tandem RCM/CM of ether 10 with alkenes 15a–e
1419
Entry
Alkene
Catalysta
Product
Yieldb (%)
O
O
Br
1
15a
1a
11a
9
Br
3
3
3
3
Br
2
3
15a
15b
1b
1b
11a
11b
78
69
Br
O
TBSO
TBSO
3
3
O
4
5
6
7
15c
15d
15e
1b
1b
1b
1b
11c
11d
11e
73
40
61
10
10
O
Br
Br
Br
O
Ph
Ph
O
No alkene
13
14
24
23
O
O
O
aReaction performed in the presence of 5 mol % of catalyst.
b Isolated yields.
O
any alkene, a preferred formation of the pyran ring is
observed.
Ph
12e
In conclusion, we have developed a short access to
2-alkylidene dihydropyrans by using a RCM/CM start-
ing from 1,5-hexadien-3-ol allyl ether. The reaction
occurred in yields up to 78% with always high regio
and E stereo selectivities. To the best of our knowledge,
this is the first example of a regioselective RCM per-
formed on trienic ether bearing three terminal double
bonds. We currently investigate the synthesis of the
laulimalide subunit using this strategy.
O
O
O
O
13
14
Figure 3.
reflects the thermodynamic conditions of this tandem
metathesis process. Similarly, a E configuration was
attributed both to compounds 11a and 11d. Even
styrene, which is not an efficient partner in RCM/CM
of esters,6 gave the functionalized 2-styryl dihydropyran
11e in 61%. In this case, the dihydrofuran 12e was also
isolated in a 12% yield (Fig. 3) maybe due to a deactivat-
ing effect of the phenyl group which could disturb the
equilibrium of the process.
Experimental procedure: A nitrogen stream was bubbled
through a dichloromethane solution of ether 10 (69 mg,
0.5 mmol) containing the chosen alkene 15 (5 equiv).
Grubbs type II catalyst (5 mol %) was added at once
and the resulting solution was heated for 8 h at 50 °C.
After cooling, the solvent was removed by concentration
and the mixture was purified by flash-chromatography
(SiO2—eluent: EtOAc/PE = 10/90).
In the absence of alkene (entry 7), two compounds 13
and 14 were isolated. Compound 13 corresponds to
the self-coupling of 2-vinyldihydropyran while 14
results from the cross-coupling of the same intermediate
with a 2-allyldihydrofuran obtained by the competitive
pathway. Even when the reaction is performed without
Acknowledgments
`
M.A.V. is grateful to the ‘Ministere de la Recherche et
´
de l’Enseignement Superieur’ for a Ph.D. grant.

1420
M.-A. Virolleaud, O. Piva / Tetrahedron Letters 48 (2007) 1417–1420
13. Basu, S.; Waldmann, H. J. Org. Chem. 2006, 71, 3977–
References and notes
3979.
14. Schmidt, B.; Nave, S. Chem. Commun. 2006, 2489–
2491.
1. (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–
4450; (b) Furstner, A. Angew. Chem., Int. Ed. 2000, 39,
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Chem. 1987, 52, 83–90.
3012–3043; (c) Schrock, R. R.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2003, 42, 4592–4633.
2. Nobel lecture 2005: (a) Chauvin, Y. Angew. Chem., Int.
Ed. 2006, 45, 3740–3747; (b) Schrock, R. R. Angew.
Chem., Int. Ed. 2006, 45, 3748–3759; (c) Grubbs, R. H.
Angew. Chem., Int. Ed. 2006, 45, 3760–3765.
16. Compound 11a: 78%. 1H NMR (300 MHz, CDCl3):
d = 1.93 (quin, J = 7.1 Hz, 2H), 2.12–2.30 (m, 4H), 3.39
(t, J = 6.9 Hz, 2H), 3.98 (quin, J = 4.7 Hz, 1H), 4.20 (sl,
2H), 5.58–5.93 (m, 4H). 13C NMR (75 MHz, CDCl3):
d = 30.9, 31.4, 32.2, 33.4, 65.9, 73.9, 124.1, 126.5, 130.2,
132.2. HRMS (CI) calcd for C10H15BrO–H+ = 229.0228,
found 229.0221.
3. Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.,
Int. Ed. 2005, 44, 4490–4527.
4. Recent applications in total synthesis: (a) Pfeiffer, M. W.
B.; Phillips, A. J. J. Am. Chem. Soc. 2005, 127, 5334–5335;
(b) Kim, S.; Ko, H.; Lee, T.; Kim, D. J. Org. Chem. 2005,
70, 5756–5759; (c) Mehta, G.; Shinde, H. M. Chem.
Commun. 2005, 3703–3705; (d) Nicolaou, K. C.; Harisson,
S. T. Angew. Chem., Int. Ed. 2006, 45, 3256–3260; (e)
Barluenga, S.; Dakas, P.-Y.; Ferandin, Y.; Meijer, L.;
Winssinger, N. Angew. Chem., Int. Ed. 2006, 45, 3951–
3954; (f) Virolleaud, M.-A.; Menant, C.; Fenet, B.; Piva,
O. Tetrahedron Lett. 2006, 47, 5127–5130.
5. (a) Randl, S.; Blechert, S. Tandem Ring-closing Meta-
thesis. In Handbook of Metathesis; Grubbs, R. H., Ed.;
Wiley, VCH: Weiheim, 2003; Vol. 2, pp 151–175; (b)
Aitken, S. G.; Abell, A. D. Aust. J. Chem. 2005, 58, 3–13;
(c) Fukumoto, H.; Takahashi, K.; Ishihara, J.; Hatake-
yama, S. Angew. Chem., Int. Ed. 2006, 45, 2731–2734; (d)
Kummer, D. A.; Brenneman, J. B.; Martin, S. F. Org.
Lett. 2005, 7, 4621–4623; (e) Royer, F.; Vilain, C.; Elka¨ım,
L.; Grimaud, L. Org. Lett. 2003, 5, 2007–2009.
Compound 11b: 69%. 1H NMR (300 MHz, CDCl3):
d = 0.04 (s, 6H), 0.90 (s, 9H), 1.50–1.80 (m, 2H), 1.94–
2.37 (m, 4H), 3.62 (t, J = 6.4 Hz, 2H), 3.98 (dt, J = 6.2–
3.7 Hz, 1H), 4.20 (sl, 2H), 5.55 (dd, J = 15.4(E)-6.2 Hz,
1H), 5.68–5.87 (m, 3H). 13C NMR (75 MHz, CDCl3):
d = À5.0, 18.6, 26.2, 28.9, 31.4, 32.5, 62.8, 65.9, 74.2,
124.3, 126.5, 131.0, 132.3. HRMS (CI) calcd for
C16H30O2Si–H+ = 281.1937, found 281.1936.
Compound 11c: 73%. 1H NMR (300 MHz, CDCl3):
d = 0.89 (t, J = 7.1 Hz, 3H), 1.17–1.46 (m, 18H), 1.93–
2.18 (m, 4H), 3.98 (dt, J = 6.2–3.7 Hz, 1H), 4.24 (sl, 2H),
5.52 (dd, J = 15.4(E)-6.2 Hz, 1H), 5.14–5.96 (m, 3H). 13C
NMR (75 MHz, CDCl3): d = 14.4, 23.0, 29.4, 29.5, 29.7,
29.8, 29.9, 30.0, 30.1, 31.4, 32.2, 32.7, 66.0, 74.3, 124.3,
126.5, 130.6, 133.0. HRMS (EI) calcd for C18H32O =
264.2453, found 264.2450.
Compound 11d: 40%. 1H NMR (300 MHz, CDCl3):
d = 2.05–2.16 (m, 2H), 3.96 (d, J = 7.2 Hz, 2H), 4.03–
4.12 (m, 1H), 4.23 (sl, 2H), 5.70–5.89 (m, 3H), 5.90–6.03
(m, 1H). 13C NMR (75 MHz, CDCl3): d = 30.9, 32.5, 66.0,
72.9, 123.9, 126.6, 127.3, 135.6. HRMS (CI) calcd for
C8H11BrO–H+ = 200.9915, found 200.9917.
6. Virolleaud, M.-A.; Bressy, C.; Piva, O. Tetrahedron Lett.
2003, 44, 8081–8084.
7. Virolleaud, M.-A.; Piva, O. Synlett 2004, 2087–2090.
8. Compound 8: 1H NMR (300 MHz, CDCl3): d = 0.80–0.96
(m, 3H), 1.11–1.43 (m, 4H), 1.96–2.14 (m, 2H), 2.34–2.57
(m, 2H), 4.87 (q, J = 7.3 Hz, 1H), 5.53–5.65 (m, 1H), 5.83
(dt, J = 15.3(E)-6.8 Hz, 1H), 6.04 (dt, J = 9.8–1.7 Hz,
1H), 6.88 (dt, J = 9.8–4.2 Hz, 1H). 13C NMR (75 MHz,
CDCl3): d = 14.1, 22.5, 30.1, 31.1, 32.0, 78.6, 121.7, 126.9,
136.0, 145.1, 164.5.
Compound 11e: 61%. 1H NMR (300 MHz, CDCl3):
d = 2.06–2.30 (m, 2H), 4.18 (quin, J = 4.8 Hz, 1H), 4.27
(s, 2H), 5.75 (dm, J = 10.3–1.2 Hz, 1H), 5.85 (dm,
J = 10.3–2.5 Hz, 1H), 6.24 (dd, J = 16.0(E)-5.8 Hz, 1H),
6.62 (d, J = 16.0 Hz, 1H), 7.17–7.40 (m, 5H). 13C NMR
(75 MHz, CDCl3): d = 31.4, 66.0, 74.1, 124.2, 126.6, 126.8,
127.9, 128.8, 130.2, 130.8, 137.1. HRMS (CI) calcd for
C13H14O–H+ = 185.0966, found 185.0960.
Compound 9: 1H NMR (300 MHz, CDCl3): d = 0.80–0.96
(m, 3H), 1.11–1.43 (m, 4H), 1.96–2.14 (m, 2H), 2.34–2.57
(m, 2H), 5.03 (t, J = 6.4 Hz, 1H), 5.35 (dt, J = 15.3(E)-
7.3 Hz, 1H), 5.60 (dt, J = 15.3(E)-6.8 Hz, 1H), 6.13 (dd,
J = 5.7–2.0 Hz, 1H), 7.44 (dd, J = 5.7–1.4 Hz, 1H). 13C
NMR (75 MHz, CDCl3): d = 14.1, 22.3, 31.5, 32.4, 36.4,
83.2, 122.0, 122.2, 136.3, 156.4, 173.3.
Compound 12e: 12%. 1H NMR (300 MHz, CDCl3):
d = 2.51 (t, J = 6.5 Hz, 2H), 4.58–4.76 (m, 2H), 4.98 (m,
1H), 5.85 (dd, J = 6.2–1.3 Hz, 1H), 5.93 (dd, J = 6.4–
1.6 Hz, 1H), 6.24 (dt, J = 15.8(E)-7.2 Hz, 1H), 6.48 (d,
J = 15.8 Hz, 1H), 7.17–7.40 (m, 5H).
Compound 13: 24%. 1H NMR (300 MHz, CDCl3):
d = 1.98–2.23 (m, 4H), 4.00–4.10 (m, 2H), 4.23 (sl, 4H),
5.72 (dm, J = 10.3 Hz, 2H), 5.78–5.87 (m, 4H). 13C NMR
9. (a) Quinn, K. J.; Isaacs, A. K.; Arvary, R. A. Org. Lett.
2004, 6, 4143–4145; (b) Quinn, K. J.; Isaacs, A. K.;
DeChristopher, B. A.; Szklarz, S. C.; Arvary, R. A. Org.
Lett. 2005, 7, 1243–1245.
(75 MHz, CDCl3):
2
diastereomers: d = 31.2 and
31.3, 66.0 and 66.1, 73.4 and 73.7, 124.2, 126.6, 131.6
and 131.9.
10. Nelson, S. G.; Cheung, W. S.; Kassick, A. J.; Hilfiker, M.
A. J. Am. Chem. Soc. 2002, 124, 13654–13655.
11. Crimmins, M. T.; Zhang, Y.; Diaz, F. A. Org. Lett. 2006,
8, 2369–2372.
12. (a) Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang,
J.; Zhao, H. J. Am. Chem. Soc. 2004, 126, 10210–10211;
(b) Wallace, D. J. Angew. Chem., Int. Ed. 2005, 44, 1912–
1915.
Compound 14: 23%. 1H NMR (300 MHz, CDCl3):
d = 1.96–2.20 (m, 2H), 2.23–2.40 (m, 2H), 4.00 (quin,
J = 4.8 Hz, 1H), 4.20 (sl, 2H), 4.53–4.70 (m, 2H), 4.85 (sl,
1H), 5.47–5.96 (m, 6H). 13C NMR (75 MHz, CDCl3):
d = 30.1, 31.4, 66.0, 74.1, 75.6, 85.9, 124.3, 126.7, 127.2,
127.9, 139.7, 133.6.