Formation of isomerized E,Z-configured 1,3-dienes in construction of macrocyclic trienes by diene-ene RCM

Article abstract of DOI:10.1246/bcsj.20140250

Construction of macrocyclic trienes by diene-ene RCM of tetraenes was examined. In the reactions, macrocyclic trienes were obtained as a mixture of two isomers with E,Z-configured 1,3-diene moiety. The formation of two isomers can be understandable by the

Full text of DOI:10.1246/bcsj.20140250

Short Articles
Formation of Isomerized
RCM
TDAD
E,Z-Configured 1,3-Dienes in
Construction of Macrocyclic
Trienes by Diene-Ene RCM
Scheme 1. Hypothesized tandem RCM/TADA protocol.
PCy3
Cl
Ru
Ph
Cl
Ryukichi Takagi,* Kenji Tanaka,
Koumei Yamamoto, Yoshikazu Hiraga,
Satoshi Kojima, and Manabu Abe
PCy3
Grubbs 1st
CO2Et
(10 mol%)
CH2Cl2, reflux
E,Z-1a
CO2Et
Department of Chemistry, Graduate School of Science,
Hiroshima University, 1-3-1 Kagamiyama,
Higashi-Hiroshima, Hiroshima 739-8526
CO2Et
E-mail: rtakagi@hiroshima-u.ac.jp
Received: August 25, 2014; Accepted: September 11, 2014;
Web Released: September 19, 2014
3a
2a
Scheme 2. Reaction of tetraenes E- or Z-1a with Grubbs 1st
catalyst.
Construction of macrocyclic trienes by diene-ene RCM
of tetraenes was examined. In the reactions, macrocyclic
trienes were obtained as a mixture of two isomers with E,Z-
configured 1,3-diene moiety. The formation of two isomers
can be understandable by the E-Z isomerization of the
initially generated ruthenium-alkenyl carbene intermediate.
First, we examined the reaction of tetraenes E- and Z-1a with
Grubbs 1st catalyst to construct a 5-6-6 ring system via the
tandem RCM/TADA protocol (Scheme 2). Although several
reaction conditions were attempted, the formation of the com-
plex mixture by self cross-metathesis and/or the recover of
tetraenes E- or Z-1a with low isolated yield was observed.
Next, the reaction of tetraenes E- and Z-1b, which was
expected to construct a 7-6-6 ring system via the tandem RCM/
TADA protocol, was examined (Table 1). In these reactions,
the first step of the tandem protocol, RCM of tetraenes E- and
Z-1b, proceeded to afford macrocyclic trienes E- and Z-2b,
respectively, although the TADA product, 7-6-6 ring system
3b, was not obtained. Interestingly, macrocyclic trienes E- and
Naturally occurring macrocyclic compounds exhibit a wide
range of biological activities and are attractive molecules as
synthetic targets.1 Various types of reactions, such as macro-
lactonization, Horner-Wadsworth-Emmons reaction, alkyl-
ation of β-ketoesters, Stille coupling, ring-closing metathesis
(RCM), and amidation, have been used to construct the
macrocyclic ring. Among them, RCM is a most attractive
strategy due to the accessibility to the RCM-precursor and the
tolerance to various functional groups.2 However, the geometry
of the double bond formed by RCM is difficult to control.3
Moreover, in the case of diene-ene RCM, the formation of ring
contracted macrocyclic compounds via ethanolysis of the diene
moiety may also interfuse.3a
Grubbs ruthenium-carbene complexes have both powerful
metathetic ability and versatile nonmetathetic applications.4,5
On the basis of their properties, several tandem processes
involving the ruthenium-catalyzed olefin metathesis reaction
were developed over the past decade.6 In the course of our
studies on development of a novel tandem reaction involving
RCM,7 we designed a combination of macrocyclization by
diene-ene RCM and transannular Diels-Alder reaction (TADA)
for constructing tricyclic frameworks (Scheme 1). However,
satisfactory results for the tandem RCM/TADA protocol were
not obtained. On behalf of the tandem RCM/TADA product,
the RCM products, i.e. macrocyclic trienes, were obtained as an
unpredicted mixture of two isomers with E,Z-configured 1,3-
diene moiety. In this paper, the details of the macrocyclization
by diene-ene RCM of teraenes are reported.
1
Z-2b were observed by H NMR as a mixture of two isomers.
According to the coupling constants of the two isomers in
1H NMR measurement, the newly formed 1,3-diene moieties by
diene-ene RCM were assigned as a E,Z-configuration, respec-
tively (Figure 1).8 However, the two-dimensional structure of
the two isomers was not clearly determined due to the overlap
1
of the methylene-proton signals in H NMR. At this moment,
the possibility of regio-isomerization via [1,5]-sigmatropic
migration of hydrogen cannot be dismissed.9
The effects of additives (p-benzoquinone10 and Ti(Oi-Pr)4
11
)
on the reaction of tetraenes E- or Z-1b with Grubbs 1st cata-
lyst were also examined (Table 1, Entries 2, 3, 5, and 6).
The reaction was accelerated by the addition of Ti(Oi-Pr)4
and proceeded at room temperature. However, the additives
affected neither the ratio of the two isomers nor the reaction
yield.
With macrocyclic trienes E- and Z-2b in hand, the con-
struction of a 7-6-6 ring system by TADA was also attempted
under various conditions. However, tricyclic product 3b was
not obtained. Therefore, tetraene E-1c, which was expected
to afford an electronically more reactive macrocyclic triene
toward TADA reaction, was used for the reaction with Grubbs
1st catalyst (Scheme 3). The treatment of tetraene E-1c with
146 | Bull. Chem. Soc. Jpn. 2015, 88, 146–148 | doi:10.1246/bcsj.20140250
© 2014 The Chemical Society of Japan

Table 1. Reaction of Tetraenes E- or Z-1b with Grubbs
1st Catalyst
Grubbs 1st
CO2Et
(10 mol%)
CH2Cl2 (1 mM)
E,Z-1b
CO2Et
CO2Et
3b
Figure 2. 1H NMR spectra (CDCl3, 500 MHz) of E-2c.
two isomer
E,Z-2b
O
Entry
1
Tetraene
Conditions
reflux, 18 h
Producta),b)
O
E-1b
E-2b:48%
(1.4:1)
E-2b:36%
(1.7:1)
Ha
Hb
Ha
Hd
Hc
Hd
2
p-benzoquinone
(20 mol %),
reflux, 1.5 h
Hc
major isomer of E-2c
Hb
minor isomer of E-2c
3
4
5
Ti(Oi-Pr)4 (1.0 equiv),
rt, 19 h
reflux, 17 h
E-2b:43%
(1.8:1)
Z-2b:57%
(10:1)
Z-2b:65%
(7:1)
1H-1H COSY
TOCSY
Figure 3. Two isomers of E-2c based on the key 1H-1H
COSY and TOCSY correlations.
Z-1b
p-benzoquinine
(20 mol %),
R
R, X = Me, O
or
reflux, 1.5 h
Ti(Oi-Pr)4 (1.0 equiv),
rt, 19 h
R,X = CO2Et, H,H
X
6
Z-2b:51%
(10:1)
1
R
Grubbs 1st
R
X
PCy3
Ru
a) Isolated yield. b) The ratio of two isomers are in paren-
theses. The ratio was determined by H NMR analysis of the
Cl
Cl
RCM
1
I
X
crude product.
major isomer
of macrocyclic triene 2
E-Z isomerization
PCy3
R
Cl
Cl
Ru
R
X
RCM
II
X
minor isomer
of macrocyclic triene 2
Scheme 4. Proposed mechanism for the reaction of tetraene
1 with Grubbs 1st catalyst.
1
moderately separated. On the basis of the key H-1H COSY
and TOCSY correlations, the two isomers of macrocyclic triene
E-2c were assigned to the predicted E,Z-configured 1,3-diene
as a major isomer and the isomer of E,Z-1,3-diene moiety
(Figure 3). The formation of the isomerized E,Z-configured
1,3-diene can be understood by considering the E-Z isomer-
ization from ruthenium-alkenyl carbene complex I to II
(Scheme 4).12 At the end, heating triene E-2c at 250 °C gave
the 7-6-6 ring system as a single isomer, although the reaction
yield (18%) was low.
Figure 1. 1H NMR spectra (CDCl3, 500 MHz) of E- and
Z-2b.
Grubbs 1st
(10 mol%)
O
CH2Cl2 (1 mM)
reflux, 1h
O
E-1c
two isomer
(5.6 : 1)
In conclusion, the diene-ene RCM of tetraenes 1 with
Grubbs 1st catalyst was examined and macrocyclic trienes 2
were obtained as a mixture of two isomers with E,Z-configured
1,3-diene moiety. The formation of two isomers can be under-
standable by the E-Z isomerization of the initially generated
ruthenium-alkenyl carbene intermediate I. The results may
be in accordance with the formation of three isomers in the
RCM-macrocyclization of trienes, which was briefly reported
E-2c: 59%
Scheme 3. Reaction of tetraene E-1c with Grubbs 1st catalyst.
Grubbs 1st catalyst afforded macrocyclic triene E-2c as a
mixture of two isomers with similar selectivity to the reac-
tion of tetraene Z-1b (Figure 2).8 In the H NMR spectra of
1
macrocyclic triene E-2c, the methylene-proton signals were
Bull. Chem. Soc. Jpn. 2015, 88, 146–148 | doi:10.1246/bcsj.20140250
© 2014 The Chemical Society of Japan | 147

by Fürstner et al.3a To the best of our knowledge, this paper is a
first distinct report of the E-Z isomerization of the ruthenium-
alkenyl carbene intermediate in diene RCM. The E-Z isomer-
ization should be also considered in the design of diene RCM.
NMR and MS measurements were made using JEOL JMN-
LA500 and JEOL SX-102A instruments, respectively, at the
Natural Science Center for Basic Research and Development
(N-BARD), Hiroshima University. We appreciate the reviewers
of the manuscript for valuable comments.
Experimental
Supporting Information
General Procedure for the Reaction of Tetraene 1 with
Grubbs 1st Catalyst. To a solution of tetraene 1 in CH2Cl2
(1.0 or 10 mM) was added Grubbs 1st catalyst (10 mol %). The
reaction mixture was refluxed. After the reaction was complete,
the reaction mixture was cooled to room temperature and treated
with DMSO (50 equiv relative to Grubbs 1st catalyst).13 After
3 h, the solvent was evaporated under reduced pressure. The
residue was purified by column chromatography on silica gel.
E-2b: pale yellow oil; IR (thin film): 3016, 2978, 2927, 2858,
Experimental procedures and spectroscopic data. This mate-
rial is available free of charge on J-STAGE.
References
1
For some recent reviews: a) H. Hussain, I. R. Green, K. Krohn, I.
Ahmed, Nat. Prod. Rep. 2013, 30, 640. b) A. Lorente, J. Lamariano-
Merketegi, F. Albericio, M. Álvarez, Chem. Rev. 2013, 113, 4567. c) B.
Chatterjee, S. Bera, D. Mondal, Tetrahedron: Asymmetry 2014, 25, 1.
1
1709, 1643, 1457, 1365 cm¹1; H NMR (500 MHz, CDCl3): ¤
2
For some recent reports: a) J. Xie, Y. Ma, D. A. Horne, Tetrahedron
6.72 (t, J = 8.3 Hz, 1H, He), 6.31 (dd, J = 10.5, 5.1 Hz, minor-
Hb), 6.25 (dd, J = 15.2, 10.5 Hz, major-Hb), 6.06 (t, J =
10.5 Hz, major-Hc), 6.04 (t, J = 10.5 Hz, minor-Hc), 5.64 (dt,
J = 15.2, 7.5 Hz, major-Ha), 5.53 (dt, J = 15.1, 7.5 Hz, minor-
Ha), 5.39 (dt, J = 10.5, 8.7 Hz, minor-Hd), 5.29 (dt, J = 10.5,
8.5 Hz, major-Hd), 4.18 (q, J = 7.1 Hz, 2H), 2.27-2.22 (m, 2H),
2.20-2.05 (m, 6H), 1.49-1.35 (m, 10H), 1.29 (t, J = 7.1 Hz,
3H); 13C NMR (125 MHz, CDCl3): ¤ 168.4, 168.3, 142.6,
142.4, 132.9 (©3), 132.5, 129.7 (©2), 129.3, 128.0, 127.8, 60.3,
31.1, 30.8, 29.8, 29.5, 29.3, 29.1, 28.3 (©2), 28.0, 27.8, 27.7
(©2), 26.9, 26.8, 26.7, 26.2, 26.1, 26.0, 14.3; HR-EIMS m/z
[M+] calcd for C18H28O2 276.2089, found: 276.2100.
2011, 67, 7485. b) M. S. Kwon, S. H. Sim, Y. K. Chung, E. Lee,
Tetrahedron 2011, 67, 10179. c) A. D. Wadsworth, D. P. Furkert, J. Sperry,
M. A. Brimble, Org. Lett. 2012, 14, 5374. d) L. N. Aldrich, C. B. Berry,
B. S. Bates, L. C. Konkol, M. So, C. W. Lindsley, Eur. J. Org. Chem. 2013,
4215.
3
a) D. Gallenkamp, A. Fürstner, J. Am. Chem. Soc. 2011, 133, 9232.
b) Y. Wang, M. Jimenez, A. S. Hansen, E.-A. Raiber, S. L. Schreiber, D. W.
Young, J. Am. Chem. Soc. 2011, 133, 9196. c) C. Wang, F. Haeffner, R. R.
Schrock, A. H. Hoveyda, Angew. Chem., Int. Ed. 2013, 52, 1939. d) V. M.
Marx, M. B. Herbert, B. K. Keitz, R. H. Grubbs, J. Am. Chem. Soc. 2013,
135, 94. e) L. E. Rosebrugh, M. B. Herbert, V. M. Marx, B. K. Keitz, R. H.
Grubbs, J. Am. Chem. Soc. 2013, 135, 1276. f) C. Wang, M. Yu, A. F. Kyle,
P. Jakubec, D. J. Dixon, R. R. Schrock, A. H. Hoveyda, Chem.®Eur. J.
2013, 19, 2726.
Z-2b: pale yellow oil; IR (thin film): 3016, 2978, 2927,
4
For a recent review on Grubbs ruthenium-carbene complexes:
G. C. Vougioukalakis, R. H. Grubbs, Chem. Rev. 2010, 110, 1746.
For some recent reviews of nonmetathetic reactions catalyzed
¹1
2858, 1712, 1639, 1446, 1377 cm
,
1H NMR (500 MHz,
CDCl3): ¤ 6.30 (dd, J = 15.1, 10.7 Hz, minor-Hb), 6.22 (dd,
J = 15.1, 10.6 Hz, major-Hb), 6.03 (t, J = 10.7 Hz, minor-Hc),
5.99 (t, J = 10.6 Hz, major-Hc), 5.90 (t, J = 6.6 Hz, minor-He),
5.81 (t, J = 6.7 Hz, major-He), 5.66 (dt, J = 15.1, 7.4 Hz,
minor-Ha), 5.56 (dt, J = 15.1, 7.4 Hz, major-Ha), 5.47 (dt, J =
10.6, 8.4 Hz, major-Hd), 5.32 (dt, J = 10.7, 8.5 Hz, minor-Hd),
4.20 (q, J = 7.1 Hz, 2H), 2.46 (q, J = 6.7 Hz, 2H), 2.28 (t, J =
6.4 Hz, 2H), 2.23 (t, J = 6.7 Hz, 2H), 2.14-2.06 (m, 4H), 1.49-
1.44 (m, 4H), 1.42-1.33 (m, 4H), 1.30 (t, J = 7.1 Hz, 3H);
13C NMR (125 MHz, CDCl3): ¤ 168.4, 142.5, 133.1, 132.3,
129.5, 129.3, 127.4, 60.0, 33.3, 30.4, 29.0, 28.4 (©2), 27.6,
27.4, 27.2, 25.5, 14.3; HR-EIMS m/z [M+] calcd for C18H28O2
276.2089, found 276.2095.
5
by Grubbs ruthenium-carbene complexes: a) V. Dragutan, I. Dragutan,
J. Organomet. Chem. 2006, 691, 5129. b) B. Schmidt, Pure Appl. Chem.
2006, 78, 469. c) V. Dragutan, I. Dragutan, L. Delaude, A. Demonceau,
Coord. Chem. Rev. 2007, 251, 765. d) B. Alcaide, P. Almendros, A. Luna,
Chem. Rev. 2009, 109, 3817.
6
For some recent representative reports: a) H. Fuwa, T. Noguchi, K.
Noto, M. Sasaki, Org. Biomol. Chem. 2012, 10, 8108. b) S. Fustero, P.
Bello, J. Miró, A. Simón, C. del Pozo, Chem.®Eur. J. 2012, 18, 10991.
c) M. Arisawa, Y. Fujii, H. Kato, H. Fukuda, T. Matsumoto, M. Ito, H. Abe,
Y. Ito, S. Shuto, Angew. Chem., Int. Ed. 2013, 52, 1003.
7
a) K. Tanabe, A. Fujie, N. Ohmori, Y. Hiraga, S. Kojima, K.
Ohkata, Bull. Chem. Soc. Jpn. 2007, 80, 1597. b) R. Takagi, K. Yamamoto,
Y. Hiraga, S. Kojima, M. Abe, J. Organomet. Chem. 2013, 723, 171.
8
a) The isomer ratios of E-, Z-2b and E-2c were not changed by
1
E-2c: pale yellow oil; H NMR (500 MHz, CDCl3): ¤ 6.72
heating in the attempt of TADA to construct a tricyclic ring system.
Moreover, The coalescence between the two isomers in the VT-1H NMR
measurement (r.t. to 100 °C) of E-2c was not observed. b) The key 1H NMR
data of triene 2 for the determination of the relative setereochemistry is
summarized in Supporting Information.
(tq, J = 7.6, 1.3 Hz, minor-He), 6.64 (tq, J = 7.5, 1.3 Hz, major-
He), 6.16 (dd, J = 14.9, 11.0 Hz, minor-Hb), 6.11-6.00 (m,
major-Hb, Hc), 5.53 (dt, J = 14.9, 7.4 Hz, minor-Ha), 5.52 (dt,
J = 14.5. 7.2 Hz, major-Ha), 5.32 (dt, J = 10.1, 8.5 Hz, major-
Hd), 5.25 (dt, J = 10.4, 8.3 Hz, minor-Hd), 2.62 (t, J = 6.6 Hz,
major-2H), 2.57 (t, J = 6.1 Hz, minor-2H), 2.29-2.22 (m, 2H),
2.14-2.06 (m, 2H, major-2H), 2.06-2.03 (m, minor-2H), 1.91-
1.84 (m, minor-2H), 1.82-1.72 (m, major-2H), 1.78 (d, J =
1.3 Hz, 3H), 1.54-1.45 (m, 2H), 1.44-1.39 (m, 2H), 1.34-1.26
(m, 2H); 13C NMR (125 MHz, CDCl3): ¤ 202.7, 143.4, 137.5,
134.1, 130.1, 129.0, 126.9, 35.8, 30.6, 28.1, 27.4, 26.9, 26.6,
25.3, 24.7, 11.5; HR-EIMS m/z [M+] calcd for C16H24O
232.1827; found 232.1829.
9
a) A. Ndibwami, S. Lamothe, P. Soucy, S. Goldstein, P.
Deslongchamps, Can. J. Chem. 1993, 71, 714. b) Y.-C. Xu, A. L.
Roughton, R. Plante, S. Goldstein, P. Deslongchamps, Can. J. Chem. 1993,
71, 1152. c) Y.-C. Xu, A. L. Roughton, P. Soucy, S. Goldstein, P.
Deslongchamps, Can. J. Chem. 1993, 71, 1169.
10 S. H. Hong, D. P. Sanders, C. W. Lee, R. H. Grubbs, J. Am. Chem.
Soc. 2005, 127, 17160.
11 a) Q. Yang, W.-J. Xiao, Z. Yu, Org. Lett. 2005, 7, 871. b) E. B.
Pentzer, T. Gadzikwa, S. T. Nguyen, Org. Lett. 2008, 10, 5613.
12 S. T. Diver, Coord. Chem. Rev. 2007, 251, 671.
13 Y. M. Ahn, K. Yang, G. I. George, Org. Lett. 2001, 3, 1411.
148 | Bull. Chem. Soc. Jpn. 2015, 88, 146–148 | doi:10.1246/bcsj.20140250
© 2014 The Chemical Society of Japan