Substrate encapsulation: An efficient strategy for the RCM synthesis of unsaturated ε-lactones

Article abstract of DOI:10.1021/ol8022227

(Chemical Equation Presented) A facile substrate-encapsulated RCM-based synthesis of 7-membered lactones is reported. Coordination of the α,ω-dienyl ester precursor to the bulky Lewis acid (LA) aluminum tris(2,6-diphenylphenoxide) (ATPH) provides a protective extended steric pocket to the olefin moieties, thereby favoring intramolecular RCM over intermolecular ADMET oligomerization. The LA-encapsulated esters undergo ring-closure in the presence of Ru-based olefin metathesis catalysts to give previously difficult-to-access 7-membered β,γ- and γ,δ-unsaturated lactones in good yields.

Full text of DOI:10.1021/ol8022227

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
ORGANIC
LETTERS
2008
Vol. 10, No. 24
5613-5615
Substrate Encapsulation: An Efficient
Strategy for the RCM Synthesis of
Unsaturated E-Lactones
Emily B. Pentzer, Tendai Gadzikwa, and SonBinh T. Nguyen*
Department of Chemistry and International Institute of Nanotechnology, Northwestern
UniVersity, 2145 Sheridan Road, EVanston, Illinois 60208-3113
stn@northwestern.edu
Received October 23, 2008
ABSTRACT
A facile substrate-encapsulated RCM-based synthesis of 7-membered lactones is reported. Coordination of the r,ω-dienyl ester precursor to
the bulky Lewis acid (LA) aluminum tris(2,6-diphenylphenoxide) (ATPH) provides a protective extended steric pocket to the olefin moieties,
thereby favoring intramolecular RCM over intermolecular ADMET oligomerization. The LA-encapsulated esters undergo ring-closure in the
presence of Ru-based olefin metathesis catalysts to give previously difficult-to-access 7-membered ꢀ,γ- and γ,δ-unsaturated lactones in good
yields.
Ring-closing metathesis (RCM) is rapidly evolving into a
major strategy in the synthesis of numerous cyclic natural
products and fine chemical intermediates. As a high-yielding
synthetic method with few side products, it is an ideal route
to otherwise difficult-to-make cyclic molecules.1-3 The
popularity of RCM as a synthetic tool can be attributed to
the wide availability of well-defined olefin metathesis
catalysts (Figure 1) and the emerging understanding of
conditions that favor intramolecular ring-closure.4 Unfortu-
nately, RCM must often be carried out under highly dilute
conditions to suppress undesirable acyclic diene metathesis
(ADMET) oligomerizations. Some RCM substrates are
further plagued by conformational biases that prevent ring
Figure 1. Commonly used Ru-based metathesis catalysts: first-
generation Grubbs (I), second-generation Grubbs (II), third-
generation Grubbs (III), second-generation Hoveyda-Grubbs (IV).
closure and therefore require covalent modification before
the desired reactivity can be realized.2,5 Herein, we present
a substrate-encapsulated methodology that enables, for the
first time, the ring-closure of RCM-unfavorable R,ω-dienyl
(1) Brenneman, J. B.; Martin, S. F. Curr. Org. Chem. 2005, 9, 1535–
1549
.
(2) Collins, S. K. J. Organomet. Chem. 2006, 691, 5122–5128
(3) Sieck, S. R.; Hanson, P. R. Chemtracts: Org. Chem. 2006, 19, 280–
.
294
.
(4) Han, S.-Y.; Chang, S. In Handbook of Metathesis; Grubbs, R. H.,
Ed.; Wiley-VCH: Weinheim, 2003; Vol. 2, pp 5-22.
(5) Kaul, R.; Surprenant, S.; Lubell, W. D. J. Org. Chem. 2005, 70,
3838–3844
.
10.1021/ol8022227 CCC: $40.75
Published on Web 11/17/2008
2008 American Chemical Society

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
esters to occur without covalent substrate modification and
demonstrate its use in the preparation of previously inac-
cessible 7-membered unsaturated lactones.
(ATPH, Figure 2, left) given that Yamamoto and co-workers
have elegantly employed it to selectively encapsulate con-
jugated carbonyl systems and control their regio-reactivi-
ties.18
Under conventional RCM concentrations (30-40 mM) the
metathesis of 1 by catalyst II yields exclusively cyclic dimer
D1; the desired ꢀ,γ-unsaturated ꢀ-lactone M1 can only be
obtained under extremely dilute conditions (0.5 mM, see the
Supporting Information). Thus, it is remarkable that in the
presence of ATPH, M1 can be readily obtained from 1 at
0.1 M (Table 1, entry 6), 200 times more concentrated. The
Although ꢀ,γ- and γ,δ-unsaturated 7-membered lactones
are important intermediates in medicinal, natural product,
and polymer chemistry, their syntheses are often low
yielding6 or cumbersome.7,8 We believe that RCM would
be an excellent modular route to these compounds, which
can serve as new synthons bearing orthogonal, noninteracting
olefin/ester functionalities. While RCM has been used to
synthesize conjugated 7-membered lactones,9-11 its use in
the synthesis of other unsaturated ꢀ-lactones has been met
with only limited success.12-15 This can be partially at-
tributed to an unfavorable geometry of the starting acyclic
esters, which are well-known to exist almost exclusively in
the Z conformation, opposite of the required E ester
geometry16,17 of the ꢀ-lactone product. This geometry places
the two olefins of the substrate far apart and intermolecular
ADMET is favored over intramolecular RCM.
Table 1. Optimization of RCM Conditions To Form
7-Membered Lactones
We hypothesize that the aforementioned RCM-unfavorable
conformational bias can be overcome by coordination of the
carbonyl functionality of R,ω-dienyl esters to a cone-like,
bulky LA. Such coordination could “encapsulate” the
substrate (Figure 2, right), prevent intermolecular reactivity,
catalyst
(loading)
LA additive
(equiv)
b
entrya
T (°C)
M1:D1
1
2
3
4
5
6c
7
II (10 mol %)
II (10 mol %)
II (10 mol %)
II (10 mol %)
II (10 mol %)
II (10 mol %)
II (10 mol %)
none
45
45
45
45
45
45
45
0:100
0:100
0:100
0:100
87:13
90:10
31:79
Ti(OiPr)4 (1.05)
ATMP (1.05)
ATIP (1.05)
ATPH (1.05)
ATPH (1.05)
ATPH (0.1)
a Reactions performed at 20 mM substrate concentration in refluxing
methylene chloride for 5 h. b Product distribution determined by GC(FID).
c Reaction performed at 0.1 M substrate concentration. ATMP ) aluminum
tris(2,6-dimethylphenoxide). ATIP ) aluminum tris(2,6-diisopropylphe-
noxide). ATPH ) aluminum tris(2,6-diphenylphenoxide).
Figure 2. Aluminum tris(2,6-diphenyl)phenoxide (left) and pro-
posed encapsulation of R,ω-dienyl ester (right).
1H NMR spectrum of a mixture of 1 and ATPH clearly
indicates a single complex, supporting our encapsulation
hypothesis. The extended steric pocket of ATPH is important
as the RCM of 1 yielded only D1 in the presence of the
less-shielding Ti(OiPr)4, aluminum tris(2,6-dimethyl)phe-
noxide, and aluminum tris(2,6-diisopropyl)phenoxide LAs
(Table 1, entries 2-4). Catalysts I-IV all afford the
ꢀ-lactone M1 in the presence of ATPH, though catalyst I is
the least efficient (Table S1, Supporting Information). While
ATPH can act catalytically (Table 1, entry 7), the best yields
are observed with a slight stoichiometric excess, consistent
with the observations of Yamamoto and co-workers.19
Our substrate-encapsulated RCM strategy can be readily
extended to synthesize several ꢀ,γ- and γ,δ-unsaturated ꢀ-lac-
tones in excellent yield, regardless of substitution pattern (Table
2). Although ATPH can be prepared and stored before use, it
is more conveniently made in situ and used directly for RCM
in a one-pot method (Table 2, entry 2). In addition, 2,6-
diphenylphenol can easily be recovered in over 80% yield and
and allow the desired RCM to occur, even at concentrations
much higher than those used in conventional RCM. We
selected the bulky LA aluminum tris(2,6-diphenyl)phenoxide
(6) Lou, X.; Detrembleur, C.; Lecomte, P.; Jerome, R. J. Polym. Sci.,
Part A: Polym. Chem. 2002, 40, 2286–2297.
(7) Oka, T.; Murai, A. Tetrahedron 1998, 54, 1–20
.
(8) Kido, F.; Kazi, A. B.; Yoshikoshi, A. Chem. Lett. 1990, 613–616
.
(9) Briggs, T. F.; Dudley, G. B. Tetrahedron Lett. 2005, 46, 7793–7796
.
(10) Choi, T.-L.; Grubbs, R. H. Chem. Commun. 2001, 2648–2649
.
(11) Nakashima, K.; Imoto, M.; Miki, T.; Miyake, T.; Fujisaki, N.;
Fukunaga, S.; Mizutani, R.; Sono, M.; Tori, M. Heterocycles 2002, 56,
85–89
.
(12) Agrawal, D.; Sriramurthy, V.; Yadav, V. K. Tetrahedron Lett. 2006,
47, 7615–7618
.
(13) Dirat, O.; Vidal, T.; Langlois, Y. Tetrahedron Lett. 1999, 40, 4801–
4802
.
(14) Christoffers, J.; Oertling, H.; Fischer, P.; Frey, W. Tetrahedron
2003, 59, 3769–3778
.
(15) Conrad, J. C.; Eelman, M. D.; Duarte Silva, J. A.; Monfette, S.;
Parnas, H. H.; Snelgrove, J. L.; Fogg, D. E. J. Am. Chem. Soc. 2007, 129,
1024–1025
.
(16) Jones, G. I. L.; Owen, N. L. J. Mol. Struct. 1973, 18, 1–32
.
(17) The rotational barrier (∼10 kcal/mol) between the E and Z isomers
of open-chain esters can easily be overcome at room temperature, but the
5 kcal/mol difference in ground-state energy between these two isomers is
heavily biased towards the RCM-unfavorable Z conformation See Eliel et
al. Stereochemistry of Organic Compounds; John Wiley & Sons: New York,
(18) Yamamoto, H.; Saito, S. Pure Appl. Chem. 1999, 71, 239–245.
(19) Saito, S.; Yamamoto, H. In Modern Carbonyl Chemistry; Otera,
J., Ed.; Wiley-VCH: Weinheim, 2000; pp 33-42.
1994; p 618
.
5614
Org. Lett., Vol. 10, No. 24, 2008

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
ATPH·4 does not deviate significantly from this structure,
coordination of the dienyl ester to ATPH would enhance its
intramolecular RCM reactivity due to steric confinement. The
ROESY spectrum of ATPH·4 complex (Figure S3, Supporting
Information) reveals an off-diagonal peak corresponding to a
proximal interaction between protons H1 and H2 (Figure 2, right)
that was not observed in the analogous spectrum of the free
ester 4 (Figure S2, Supporting Information). This data clearly
shows the presence of the ATPH-(E)-4 isomer in solution,21
and suggests that coordination may provide the added benefit
of an increased population/prolonged lifetime of the E ester
isomer necessary for intramolecular RCM.
Table 2. RCM Results for the Synthesis of Various
7-Membered Unsaturated Lactones
In conclusion, by exploiting steric interactions between
an encapsulating LA and an ester-containing substrate,
intramolecular ring-closure of RCM-unfavorable dienyl esters
can now be achieved in excellent conversions. In contrast
to the analogous R,ω-dienyl secondary amides, which must
be N-modified to be RCM-reactive,5 our strategy requires
no covalent modification of the substrate. We emphasize that
the results presented here demonstrate the first use of
encapsulation to alter substrate reactivity in RCM, in contrast
to the well-explored use of LA additives to prevent substrate
coordination to metathesis catalysts.22,23 Our results stress
the critical importance of substrate conformation,24 which
must be taken into account in the RCM of problematic
precursors. Efforts are currently underway to expand this
methodology to include other carbonyl-containing 7- and
8-membered rings (see the Supporting Information).
a All reactions performed at 10 mM substrate concentration in methylene
chloride with 10 mol% catalyst and solid ATPH (see the Supporting Information).
b Product distribution determined by GC(FID). c Catalyst II was used, 4 h. d ATPH
was prepared in situ from recycled 2,6-diphenylphenol. e Catalyst IV was used,
8 h. f Isolated yields can be found in the Supporting Information.
reused without detriment to reaction yield or selectivity (Table
2, entry 2). While catalyst II can be used in the synthesis of all
ꢀ,γ-unsaturated ꢀ-lactones, catalyst IV is preferred for the γ,δ-
unsaturated isomers to avoid their rearrangement to the more
thermodynamically stable γ-lactones (see the Supporting In-
formation). Presumably, this undesirable process is catalyzed
by a decomposition side product of II.20
The encapsulation effects of ATPH on R,ω-dienyl esters can
readily be seen in the crystal structure of the ATPH•4 complex
(Figure 3), where the binding pocket of ATPH extends over
Acknowledgment. Financial support was provided by the
NSF (Grant No. DMR-0094347), the AFOSR (MURI Grant
No. FA9550-07-1-0534), and the NIH CCNE program (Grant
No. NCI 1U54 CA119341-01). We thank Prof. Deryn Fogg
(U. Ottawa), Prof. Joseph B. Lambert (NU), and Dr. Yuyang
Wu (NU) for helpful discussions, Mr. Byungman Kang for
the calculated structure of 1, and the reviewers for excellent
suggestions that helped to improve the current manuscript.
We thank Dr. Richard Pedersen (Materia, Inc.) for his advice
and for the gifts of catalysts II and IV. E.B.P. is an NSF
Graduate Research Fellow.
Note Added after ASAP Publication. Due to a produc-
tion error, various galley corrections were not included in
the version published ASAP November 17, 2008; the correct
version was published on the Web December 11, 2008.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL8022227
(20) Hong, S. H.; Wenzel, A. G.; Salguero, T. T.; Day, M. W.; Grubbs,
R. H. J. Am. Chem. Soc. 2007, 129, 7961–7968.
Figure 3. Ball-and-stick depiction of the crystal structure of the
ATPH-(Z)-4 complex.
(21) Unfortunately, repeated attempts to obtain crystallographic structural
information for this isomer resulted only in the isolation of the ATPH-
(Z)-4 isomer (see Figure 3 and the Supporting Information), most likely
due to crystal packing forces.
(22) Yang, Q.; Xiao, W.-J.; Yu, Z. Org. Lett. 2005, 7, 871–874
.
(23) Fuerstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119, 9130–
the ester moiety and forces the two olefins closer together than
would be expected in the unbound state (Figure S5, Supporting
Information). Assuming that the solution conformation of
9136
.
(24) Paquette, L. A.; Basu, K.; Eppich, J. C.; Hofferberth, J. E. HelV.
Chim. Acta 2002, 85, 3033–3051.
Org. Lett., Vol. 10, No. 24, 2008
5615