Unusual E-selective ring-closing metathesis to form eight-membered rings

Article abstract of DOI:10.1002/anie.201004746

Tied back: The title reaction was observed when a silicon-tethered diene was treated with the Hoveyda-Grubbs second-generation catalyst. The structural requirements for the E-olefin-forming ring-closing metathesis, and the transition state leading to E olefin are discussed. This methodology will be useful in the synthesis of polyketides containing a pent-2-ene-1,5-diol unit. Copyright

Full text of DOI:10.1002/anie.201004746

Communications
DOI: 10.1002/anie.201004746
Synthetic Methods
Unusual E-Selective Ring-Closing Metathesis To Form
Eight-Membered Rings**
Ryosuke Matsui, Kentaro Seto, Kazuhiro Fujita, Takahiro Suzuki, Atsuo Nakazaki,
and Susumu Kobayashi*
Angewandte
Chemie
10068
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Chemie
Olefin metathesis has recently emerged as one of the most
powerful and convenient methodologies in natural prod-
uct synthesis. These reactions are particularly attractive
because they utilize nonfunctionalized olefins as sub-
strates and thus enable highly convergent strategies.[1]
Among the several types of olefin metathesis, ring-closing
metathesis (RCM) is considered to be the most useful
because of its efficiency and the use of equimolar amounts
of the two reacting olefins.
During the course of our synthetic efforts towards
polyketide antibiotics, we became interested in the
possibility of a novel RCM approach for the construction
of a pent-2-ene-1,5-diol unit that is a common motif in
many naturally occurring polyketides[2] such as TMC-
151C[2a] and migrastatin.[2c] We expected that the requisite
pent-2-ene-1,5-diol unit E could be constructed from
homoallylic alcohol A and allylic alcohol B, by introducing
Scheme 2. Unusual E-selective RCM to form the eight-membered-ring compound 2a.
Reagents and conditions: a) HG-II (20 mol%), para-benzoquinone (1.5 equiv)/
xylene, reflux, 24 h. The diastereomeric ratio was determined by 1H NMR analysis.
HG-II=Hoveyda–Grubbs second-generation catalyst.
a
silicon tether, RCM, and subsequent desilylation
(Scheme 1). Silicon-tethered intramolecular reactions,
including Diels–Alder and RCM, have already been
utilized in natural product synthesis.[3] In particular,
Herein we report an unusual E-selective RCM to form an
eight-membered ring from a silicon-tethered diene, wherein
we identified several factors that dictate the preferred
formation of the E olefin.
When silicon-tethered diene 1a, prepared from the
corresponding homoallylic alcohol and allylic alcohol, was
treated with the Hoveyda–Grubbs second-generation cata-
lyst[6] (HG-II) in the presence of para-benzoquinone[7] in
refluxing xylene for 24 hours, an eight-membered ring
containing an E olefin (2a; E/Z > 20:1) was obtained in
93% yield almost as a single isomer (Scheme 2).
The stereochemistry of the newly formed carbon–carbon
double bond in 2a was assigned E by using NOE experiments.
This result was surprising because we had expected the
exclusive formation of the Z olefin by analogy to the results of
Evans[4] and Harvey.[5] To the best of our knowledge, there is
only one reported example of a RCM giving an eight-
membered ring that selectively generates an E olefin (Prunet
et al.).[8]
(E)-Dioxasilacyclooctene 2a was obtained as a single
atrope isomer, and NOE analysis of 2a also indicated a
crownlike conformation wherein all substituents except one
phenyl group of the diphenylsilyl group occupied pseudoe-
quatorial positions.[9] We reasoned that the present selective
E-olefin formation could be attributed to these conforma-
tional characteristics.
Scheme 1. Strategy for pent-2-ene-1,5-diol unit by silicon-tethered ring-
closing metathesis.
Evans et al. reported a diastereomer-discriminating RCM to
form Z olefins containing eight-membered rings using silicon-
tethered substrates.[4] Harvey et al. also recently applied a
similar RCM to the study of natural product synthesis.[5]
[*] R. Matsui, K. Seto, K. Fujita, Dr. T. Suzuki, Dr. A. Nakazaki,
Prof. Dr. S. Kobayashi
To clarify the structural requirements of this unusual E-
olefin-forming reaction, in addition to its scope and limita-
tions, we examined the RCM in detail using a series of
systematically designed silylene acetals.
Prior to RCM experiments, we tried to develop an
efficient method for preparing the silylene acetal (RCM
precursor) from two different alcohols (Scheme 3). Generally,
silicon tethering is not always high-yielding because of the
competitive formation of symmetrical silylene acetals.
Ph2SiCl2, a well-known silylating reagent, was first employed
for preparing 1a. Although a relatively high chemical yield
(74%) of 1a was achieved, use of excess homoallylic alcohol 3
Faculty of Pharmaceutical Sciences, Tokyo University of Science
2641 Yamazaki, Noda-shi, Chiba 278-8510 (Japan)
Fax: (+81)4-7121-3671
E-mail: kobayash@rs.noda.tus.ac.jp
Homepage: http://www.rs.noda.tus.ac.jp/kobalab/index.html
[**] This research was supported in part by a Grant-in-Aid for Scientific
Research (B) (KAKENHI No.18390010) from the Japan Society for
the Promotion of Science. We sincerely thank Prof. Kazuo Miyamura
and Dr. Kazuaki Tomono (Department of Chemistry, Faculty of
Science, Tokyo University of Science) for assistance with the X-ray
analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004746.
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Communications
ized in Table 1. The stereochemistry of the newly formed
carbon–carbon double bonds was determined by NOE
experiments of either the RCM products or the products
obtained after desilylation.[13] The conformation of the RCM
products are also indicated in Table 1. Because we had
already observed the selective Z-olefin formation with the syn
isomer 1b and demethyl derivative 1c, the relative stereo-
chemistry of the homoallylic alcohol moiety was fixed as anti.
The silylene acetals 6a and 6b, which are closely related to 1a,
afforded the E olefins 7a and 7b, respectively (entries 1 and
2). Replacement of a relatively bulky side chain at C3’ with
isopropyl was next examined. The silylene acetal 6c, which
has the same stereochemistry as 1a, afforded the E olefin 7c
selectively, whereas the Z olefin 7d was selectively formed
from the C3’-epimer 6d (entries 3 and 4). The RCM product
7d was found to possess the chairlike conformation by NOE
experiments. The silylene acetal 6e lacking an isopropyl
group also completely reversed the stereochemistry, thereby
affording the Z olefin 7e exclusively (entry 5). It was also
found that the RCM of the silylene acetal 6 f, which has a less
bulky n-butyl substituent, was nonselective and afforded the
E olefin 7 f and Z olefin 8 f in a low combined yield
(entry 6).[14] In contrast, its epimer 6g afforded the Z olefin
7g as a single isomer. These results indicate that a sterically
demanding substituent at the allylic C3’ position with an
appropriate relative stereochemistry is necessary for selective
E-olefin formation. Moreover, the formation of the Z olefin
7h with the C2’-demethyl derivative 6h revealed an addi-
tional structural requirement for E-olefin formation.
Scheme 3. The development of silicon-tethering by using the
Et2NPh2SiCl/Et3N/DMAP method. DMAP=N,N-4-dimethylaminopyri-
dine.
(3.2 equiv) was necessary to realize a high yield. After
extensive experiments, we were able to develop the
Et2NPh2SiCl/Et3N/DMAP method. The improved method
consists of the initial treatment of 3 (1.5 equiv) with
Et2NPh2SiCl[10] (1.5 equiv) in the presence of Et3N and a
catalytic amount of DMAP to form intermediate 4, and
subsequent addition of alcohol 5 and DMAP to obtain
heterodimer 1a in 85% yield.[11]
With the efficient methodology established, we next
prepared the C3-epimer 1b and the C3-demethyl derivative
1c. These compounds were then subjected to a RCM using
HG-II (Scheme 4). In both cases, RCM products were
obtained in high yields. The stereochemistry of the C2–C2’
double bond was determined to be Z for the two products.
Furthermore, NOE experiments revealed that the C3-epimer
2b had a boatlike conformation wherein the C3-methyl group
occupied a pseudoequatorial position, and the C3-demethyl
derivative adopted a chairlike conformation as depicted in
Scheme 4.[12]
The para-bromophenyl derivative 7i, obtained by the
RCM of 6i, was a crystalline compound. The stereochemistry
of 7i was unambiguously confirmed by X-ray crystallographic
analysis (Figure 1).[15] For the cyclization product 7i, all
substituents, except one of the phenyl groups, occupied
pseudoequatorial positions in its crownlike conformation as
expected. Moreover, a torsion angle of 144.68 for C3-C2-C2’-
C3’ bonds in the solid-state structure indicates a significant
loss of p character in the newly formed double bond.
We then prepared several related silicon-tethered sub-
strates and subjected them to RCM. The results are summar-
From these results, we can conclude that the E olefin is
produced selectively when the substrate satisfies the following
requirements: 1) anti stereochemistry for homoallylic part A,
Scheme 4. RCM of the syn isomer 1b and C3-demethyl derivative 1c.
Reagents and conditions: a) HG-II (10 mol%), para-benzoquinone
(1.5 equiv)/xylene, reflux, 24 h. Diastereomeric ratio was determined by
1H NMR analysis.
Figure 1. An X-ray derived ORTEP drawing of E eight-membered ring
7i. Ellipsoids are drawn at 50% probability.
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Table 1: RCM of various silylene acetals.[a]
Entry
Substrate
Product
Yield [%]
75
E/Z[c]
Conformation
crownlike
1
6a
6b
6c
6d
7a
7b
7c
7d
>20:1
2
61
65
84
>20:1
>20:1
<1:20
crownlike
crownlike
chairlike
3
4[b]
5[b]
6e
7e
82
<1:20
chairlike
7 f
8 f
23
13
crownlike
chairlike
6
6 f
1.8:1
7
6g
6h
7g
7h
92
83
<1:20
<1:20
chairlike
chairlike
8[b]
57
9
6i
7i
>20:1
crownlike
(brsm 68%)
[a] Reagents and conditions: HG-II (20 mol%), para-benzoquinone (1.5 equiv)/xylene, reflux, 24 h. [b] Reagents and conditions: HG-II (10 mol%),
para-benzoquinone (1.5 equiv)/xylene, reflux, 24 h. [c] Diastereomeric ratio was determined by 1H NMR analysis. brsm=based on recovered starting
material.
2) a cis relationship between R1 and R2 in the eight-
membered dioxasilacyclooctene D in Scheme 1,
3) the presence of C2’–Me, and 4) the presence of
a sterically demanding substituent at the C4’-posi-
tion.
We also carried out the RCM of 9 which has two
prochiral isopropenyl groups (Scheme 5). The sily-
lene acetal 9 satisfies the structural requirement for
E-olefin formation, and this experiment was con-
Scheme 5. E-olefin formation versus Z olefin formation. Reagents and conditions:
ducted to establish the feasibility of E-olefin for-
mation. RCM of 9 gave the Z olefin 10 in 83% yield
a) HG-II (20 mol%), para-benzoquinone (1.5 equiv)/xylene, reflux, 24 h. The
diastereomeric ratio was determined by 1H NMR analysis.
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Scheme 6. Proposed transition state for the RCM of 1a.
and the E olefin 11 was isolated in only a trace amount. This
result shows that the RCM strongly favors Z-olefin formation,
and thus the present E-olefin-forming RCM is quite unusual.
With these results, we propose a plausible transition state
(TS) for the cyclization of 1a, 6a, 6b, 6c, and 6i to give the
corresponding E olefins. As an example, the transition state
for the cyclization of 1a into 2a is shown in Scheme 6. Thus,
on the basis of conformational analysis of 2a, its formation
may proceed via a crownlike TS wherein all substituents
occupy pseudoequatorial positions. Other possible chair- or
boatlike transition states leading to a Z olefin might be less
stable either because of the transannular strain between C3-H
and C3’-R or a steric repulsion between C3-Me and C3’-H. In
the case of other isomers, either the chairlike or boatlike
transition states might be free from a nonbonding interaction
to produce Z olefins, given the conformational analyses of 2b
and 2c.
In conclusion, we have observed a unique RCM of silylene
acetals that generate an E olefin in an eight-membered ring.
We propose a plausible transition state for this reaction as
well as clarify the structural requirements for E-olefin-
forming RCM. Although the E olefin was produced only in
a limited number of cases, our methodology will be useful for
the construction of a pent-2-ene-1,5-diol unit, which is
common to many naturally occurring polyketide antibiotics.
Applications along these lines are underway and will be
reported in due course.
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Received: July 31, 2010
Published online: October 4, 2010
Keywords: cyclization · metathesis · polyketides · silicon ·
.
stereoselectivity
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10072 www.angewandte.org
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Angewandte
Chemie
[10] K. Tamao, A. Kawachi, Y. Tanaka, H. Ohtani, Y. Ito, Tetrahe-
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[11] Silylation of 3 was initiated by the addition of DMAP, although
this reagent also accelerated the formation of symmetrical
silylene acetal. Therefore, only a catalytic amount of DMAP was
added in the first silylation step to reduce the formation of
symmetrical silylene acetals. However, in some cases, the
Et2NPh2SiCl/Et3N/DMAP method gave the corresponding hete-
rodimer in moderate yield upon isolation, because of the
difficulty in separating it from symmetrical silylene acetals. For
details, see the Supporting information.
[12] G. Favini, G. Buemi, M. Raimondi, J. Mol. Struct. 1968, 2, 137 –
148.
[13] For details, see the Supporting Information.
[14] We also observed the formation of the six-membered silylene
acetal 12, which was probably derived from 7 f through
rearrangement. The structure of 12 was confirmed by correlating
to the diol 14 (14% yield from 6 f). For details, see the
Supporting Information.
[15] CCDC 784810 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
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