Endo-selective enyne ring-closing metathesis promoted by stereogenic-at-Mo monoalkoxide and monoaryloxide complexes. Efficient synthesis of cyclic dienes not accessible through reactions with Ru carbenes

Article abstract of DOI:10.1021/ja904098h

Stereogenic-at-Mo monoalkoxide and monoaryloxide complexes promote enyne ring-closing metathesis (RCM) reactions, affording the corresponding endo products with high selectivity (typically >98: <2 endo:exo). All catalysts can be prepared and used in situ.

Full text of DOI:10.1021/ja904098h

Published on Web 07/06/2009
Endo-Selective Enyne Ring-Closing Metathesis Promoted by
Stereogenic-at-Mo Monoalkoxide and Monoaryloxide
Complexes. Efficient Synthesis of Cyclic Dienes Not
Accessible through Reactions with Ru Carbenes
Yeon-Ju Lee,†,§ Richard R. Schrock,‡ and Amir H. Hoveyda*,†
Departments of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill,
Massachusetts 02467, and Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
Received May 20, 2009; E-mail: amir.hoveyda@bc.edu
Abstract: Stereogenic-at-Mo monoalkoxide and monoaryloxide complexes promote enyne ring-closing
metathesis (RCM) reactions, affording the corresponding endo products with high selectivity (typically >98:
<2 endo:exo). All catalysts can be prepared and used in situ. Five-, six-, and seven-membered rings are
obtained through reactions with enyne substrates that bear all-carbon tethers as well as those that contain
heteroatom substituents. The newly developed catalytic protocols complement the related exo-selective
Ru-catalyzed processes. In cases where Ru-based complexes deliver exo and endo products nondiscrimi-
nately, such as when tetrasubstituted cyclic alkenes are generated, Mo-catalyzed reactions afford the endo
product exclusively. The efficiency of synthesis of N- and O-containing endo diene heterocycles can be
improved significantly through structural modification of Mo catalysts. The modularity of Mo-based
monopyrrolides is thus exploited in the identification of the most effective catalyst variants. Through alteration
of O-based monodentate ligands, catalysts have been identified that promote enyne RCM with improved
efficiency. The structural attributes of three Mo complexes are elucidated through X-ray crystallography.
The first examples of catalytic enantioselective enyne RCM reactions are reported (up to 98:2 enantiomer
ratio and >98% endo).
Introduction
Herein, we detail our studies regarding the development of Mo-
catalyzed enyne RCM reactions,5 which in contrast to Ru-,1 W-,6
Catalytic enyne ring-closing metathesis (RCM) is an effective
method for preparation of cyclic dienes.1 Various mechanistic
aspects of this class of transformations, nearly all reported cases
of which are promoted by Ru-based carbenes, have been
elucidated;2 the utility of this important branch of catalytic olefin
metathesis has been demonstrated on several occasions in the
context of natural product total synthesis.3 Nonetheless, solutions
to a number of unresolved problems in reactivity and selectivity4
would substantially enhance the utility of metal-catalyzed enyne
RCM.
and Cr-catalyzed7 processes deliver cyclic endo diene isomers.
(3) For examples of application of exo-selective catalytic enyne RCM to
natural product synthesis, see: (a) Kinoshita, A.; Mori, M. J. Org.
Chem. 1996, 61, 8356–8357. (b) Boyer, F.-D.; Hanna, I.; Ricard, L.
Org. Lett. 2004, 6, 1817–1820. (c) Aggarwal, V. K.; Astle, C. J.;
Rogers-Evans, M. Org. Lett. 2004, 6, 1469–1471. (d) Kitamura, T.;
Sato, Y.; Mori, M. Tetrahedron 2004, 60, 9649–9657. (e) Cesati, R. R.,
III; de Armas, J.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 96–
101. (f) Brenneman, J. B.; Martin, S. F. Org. Lett. 2004, 6, 1329–
1331. (g) Orain, D.; Mattes, H. Synlett 2005, 3008–3010. (h)
Movassaghi, M.; Piizzi, G.; Siegel, D. S.; Piersanti, G. Angew. Chem.,
Int. Ed. 2006, 45, 5859–5863. (i) Satcharoen, V.; McLean, N. J.; Kemp,
S. C.; Camp, N. P.; Brown, R. C. D. Org. Lett. 2007, 9, 1867–1869.
(j) Hu, F.; Zhang, Y.-H.; Yao, Z.-J. Tetrahedron Lett. 2007, 48, 3511–
3515. (k) Boyer, F. D.; Hanna, I. Org. Lett. 2007, 9, 715–718. (l)
Paquette, L. A.; Lai, K. W. Org. Lett. 2008, 10, 2111–2113. (m) Yang,
X.; Zhai, H.; Li, Z. Org. Lett. 2008, 10, 2457–2460. (n) Ramharter,
J.; Mulzer, J. Org. Lett. 2009, 11, 1151–1153. (o) Li, J.; Park, S.;
Miller, R. L.; Lee, D. Org. Lett. 2009, 11, 571–574. For examples of
application of endo-selective catalytic enyne RCM to natural product
synthesis, see: (p) Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am.
Chem. Soc. 2002, 124, 773–775.
† Boston College.
‡ Massachusetts Institute of Technology.
§ Present address: Marine Biotechnology Research Department, Korea
Ocean Research & Development Institute, P.O. Box 29, Ansan 425-600,
Korea.
(1) For reviews on metal-catalyzed enyne metathesis, see: (a) Poulsen,
C. S.; Madsen, R. Synthesis 2003, 1–18. (b) Mori, M. In Handbook
of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim: 2003; Vol.
2, pp 176-204. (c) Diver, S. T.; Giessert, A. J. Chem. ReV. 2004,
104, 1317–1382. (d) Mori, M. J. Mol. Catal. A 2004, 213, 73–79. (e)
Villar, H.; Frings, M.; Bolm, C. Chem. Soc. ReV. 2007, 36, 55–66. (f)
Maifield, S. V.; Lee, D. Chem. Eur. J. 2005, 11, 6118–6126.
(2) For studies on mechanistic aspects of Ru-catalyzed enyne RCM
reactions, see: (a) Hansen, E. C.; Lee, D. J. Am. Chem. Soc. 2004,
126, 15074–15080. (b) Lippstreu, J. J.; Straub, B. F. J. Am. Chem.
Soc. 2005, 127, 7444–7457. (c) Lloyd-Jones, G. C.; Margue, R. G.;
de Vries, J. G. Angew. Chem., Int. Ed. 2005, 44, 7442–7447. (d)
Hansen, E. C.; Lee, D. Acc. Chem. Res. 2006, 39, 509–519. (e)
Dieltiens, N.; Moonen, K.; Stevens, C. V. Chem. Eur. J. 2007, 13,
203–214.
(4) Hoveyda, A. H.; Zhugralin, A. R. Nature 2007, 450, 243–251.
(5) For a preliminary account of this work, see: Singh, R.; Schrock, R. R.;
Mu¨ller, P.; Hoveyda, A. H. J. Am. Chem. Soc. 2007, 129, 12654–
12655.
(6) (a) Katz, T. J.; Sivavec, T. M. J. Am. Chem. Soc. 1985, 107, 737–
738. (b) Katz, T. J. In Handbook of Metathesis; Grubbs, R. H., Ed.;
Wiley-VCH: Weinheim: 2003; Vol. 1, pp 47-60.
(7) Watanuki, S.; Ochifuji, N.; Mori, M. Organometallics 1994, 13, 4129–
4130.
9
10652 J. AM. CHEM. SOC. 2009, 131, 10652–10661
10.1021/ja904098h CCC: $40.75  2009 American Chemical Society

Endo-Selective Enyne Ring-Closing Metathesis
A R T I C L E S
Scheme 1. Various Modes of Reaction in Metal-Catalyzed Enyne
RCM
formation through complex ii gives rise to ꢀ-substituted
metallacyclobutene iii, where the metal center forms a bond
with the terminal carbon of the alkyne; conversion of iii to
conjugated terminal alkylidene iW would then be followed by
RCM to afford cyclic diene W (endo product). A metal alkylidene
might alternatively coordinate to the alkyne in such a manner
that, as depicted in pathway 2 in Scheme 1, generation of
R-substituted metallacyclobutene Wii is preferred; cycloreversion
to disubstituted alkylidene Wiii culminates in the formation of
the exo product ix. Pathway 3 (Scheme 1) commences by initial
interaction of the catalyst with the alkene unit x, affording
terminal carbene xi, which through an intramolecular cycload-
dition is converted to R,ꢀ-metallacyclobutene xii. Subsequent
transformation gives rise to cyclopentene-substituted terminal
carbene xiii, which through a cross-metathesis process with
another enyne substrate (i) affords exo product ix and regenerates
terminal carbene xi.
Extensive previous research has established that when Ru-
based carbene complexes are used to promote enyne RCM, the
formation of exo products, represented by ix (Scheme 1), is
strongly favored.1 Our interest in examining the ability of
stereogenic-at-Mo complexes, recently developed in these
laboratories to address a number of unresolved issues in selective
catalytic olefin metathesis, arose from the principle that high
oxidation state complexes should favor reaction through a
pathway that commences with association with the alkyne site
of an enyne substrate.11 The above considerations, together with
the preference of the sterically demanding Mo center to form a
bond with the terminal carbon of an alkyne, led us to surmise
that ꢀ-metallacyclobutenes should prove to be favored inter-
mediates, leading to selective formation of endo RCM products
(pathway 1, Scheme 1). We were also aware, however, that the
strong preference for formation of Mo-alkyne complex could
lead to competitive oligomerization processes, involving reaction
of intermediate alkylidenes (e.g., iW or Wiii, Scheme 1) with an
alkyne of another substrate molecule. We will demonstrate that
such complications can be addressed through modification of
the catalyst structure so that intramolecular processes that lead
to RCM products are preferred over intermolecular reactions
that result in formation of oligomers.
None of the previously reported olefin metathesis-based methods
allow selective access to endo products.8 Five-, six-, and seven-
membered-ring endo dienes (vs exo dienes generated predomi-
nantly by Ru-based carbenes) bearing di-, tri-, and tetrasubsti-
tuted alkenes are obtained in 41-90% yield. Reactions generally
proceed with exceptional endo selectivity (typically >98:<2
endo:exo). Ring-forming processes are promoted by readily
prepared stereogenic-at-Mo complexes, which bear only mono-
dentate ligands.9 Such attributes allow for modification of Mo
complexes so that reactivity and selectivity of enyne RCM
reactions are enhanced. We introduce several structurally
modified stereogenic-at-Mo complexes that initiate enyne RCM
with degrees of efficiency and selectivity not achievable through
the use of previously reported catalysts. We conclude by
presenting the first examples of efficient metal-catalyzed enan-
tioselective enyne RCM reactions.10
The key challenge facing us in the course of investigations
detailed herein originates from the availability of various
pathways2 through which a catalyst might promote an enyne
RCM reaction: a metal-based alkylidene may first either
associate with the alkyne (pathways 1 and 2, Scheme 1) or the
alkene (pathway 3, Scheme 1) unit of the substrate i. Trans-
Results and Discussion
(8) It is noteworthy that other, non-metathesis-based catalytic protocols,
such as various cycloisomerization processes that are catalyzed by
different metal-based complexes and involve enyne substrates, pre-
dominantly generate the corresponding exo products. For selected
examples, see the following: (a) Pd-catalyzed: Trost, B. M.; Tanoury,
G. J. J. Am. Chem. Soc. 1988, 110, 11863–11869. (b) Ru-catalyzed:
Chatani, N.; Morimoto, T.; Muto, T.; Murai, S. J. Am. Chem. Soc.
1994, 116, 6049–6050. (c) Pt-catalyzed: Fu¨rstner, A.; Szillat, H.;
Stelzer, F. J. Am. Chem. Soc. 2001, 123, 6785–6786. (d) Ir-catalyzed:
Chatani, N.; Inoue, H.; Morimoto, T.; Muto, T.; Murai, S. J. Org.
Chem. 2001, 66, 4433–4436. (e) Ag-catalyzed: Porcel, S.; Echavarren,
A. M. Angew. Chem., Int. Ed. 2007, 46, 2672–2676. (f) Au-catalyzed:
Cabello, N.; Jime´nez-Nu´n˜ez, E.; Bunuel, E.; Cardenas, D. J.; Echa-
varren, A. M. Eur. J. Org. Chem. 2007, 4217–4223. (g) In-catalyzed:
Miyanohana, Y.; Chatani, N. Org. Lett. 2006, 8, 2155–2158. (h) Rh-
catalyzed: Ota, K.; Chatani, N. Chem. Commun. 2008, 2906–2907.
(9) For previous reports regarding stereogenic-at-Mo complexes, see: (a)
Malcolmson, S. J.; Meek, S. J.; Sattely, E. S.; Schrock, R. R.; Hoveyda,
A. H. Nature 2008, 456, 933–937. (b) Sattely, E. S.; Meek, S. J.;
Malcolmson, S. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem.
Soc. 2009, 131, 943–953. (c) Ibrahem, I.; Yu, M.; Schrock, R. R.;
Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3844–3845.
1. Selective Synthesis of endo-1,3-Carbocyclic Dienes through
Mo-Catalyzed Enyne RCM. 1.1. Initial Evaluation of Mo- and
Ru-Based Complexes. We began by examining the ability of
representative Mo-based complexes to catalyze RCM of enyne
1 (Scheme 2). Use of Mo alkylidene 410b (5 mol %) does not
lead to formation of either the endo or the exo cyclic diene
isomer (2 and 3, respectively; 22 °C, 30 min). In contrast, under
identical conditions, monopyrrolide-monoalkoxide 55 delivers
endo RCM product 2 in 72% yield (<2% exo isomer 3, detected
1
by 400 MHz H NMR spectroscopy). As has been described
previously, stereogenic-at-Mo complexes, represented by 5, are
(11) Based on previous theoretical studies (e.g., ref 2b), it is plausible that
Ru-based complexes as well as high-oxidation-state Mo-based alky-
lidenes prefer initial association with an alkyne site of an enyne, unless
the olefin presents a significantly less hindered alternative. It is,
however, the more reactive Mo complexes that can readily proceed
through the higher energy metallacycobutenes (vs metallacyclobu-
tanes). That is, in Ru-catalyzed processes, it is the rate of metallacy-
clobutane or metallacyclobutene formation that is critical (vs the site
of initial metal carbene binding). See also: Sohn, J.-H.; Kim, K. H.;
Lee, H.-Y.; No, Z. S.; Ihee, H. J. Am. Chem. Soc. 2008, 130, 16506–
16507.
(10) For reviews on metal-catalyzed enantioselective olefin metathesis
reactions, see: (a) Hoveyda, A. H. In Handbook of Metathesis; Grubbs,
R. H., Ed.; Wiley-VCH: Weinheim: 2003; Vol. 2, pp 128-150. (b)
Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42,
4592–4633.
9
J. AM. CHEM. SOC. VOL. 131, NO. 30, 2009 10653

A R T I C L E S
Lee et al.
Scheme 2. Mo and Ru Complexes as Enyne RCM Catalystsa
Table 1. Selective Synthesis of endo-Carbocyclic Dienes by
Mo-Catalyzed Enyne RCM (Diester Tether)a
a Reactions were performed under N2 atmosphere with 5 mol % 5 for
30 min in C6H6 at 22 °C. b Ratios were determined by analysis of 400
MHz 1H NMR spectra of unpurified mixtures prior to purification.
c Yield of isolated products after purification. d Combined yields of the
product mixture. e Reaction performed with 20 mol % 5.
as 1,1-disubstituted alkenes (e.g., entry 3, Table 1). The RCM
process in entry 4 of Table 1, involving enyne 11, which
contains an internal alkyne and a disubstituted olefin, leads to
the formation of a tetrasubstituted cyclic alkene; as a result,
unlike cases where di- or trisubstituted olefins are generated (5
mol % 5), higher catalyst loading (20 mol %) is required for
achieving complete substrate consumption. When 5 mol % 5 is
used, there is only 23% conversion, and with 10 mol % Mo-
alkylidene, 42% of the desired endo product is obtained after
30 min [70% conversion after 24 h; the remainder of the enyne
remains unreacted (i.e., <2% oligomerization)]. Additional points
regarding the RCM processes in Table 1 are worthy of note:
Although most reactions described above are performed with 5
mol % 5, in at least some cases, efficient transformation can be
achieved with lower catalyst loading. For example, RCM of 1
(Scheme 2) carried out in the presence of 1 mol % 5 proceeds
to >98% conversion within 30 min at 22 °C to afford endocyclic
diene 2 (Scheme 2) in 74% yield.
High endo selectivity is observed in most instances (entries
1 and 3-4), except for the reaction of internal alkyne 9 (entry
2), where a mixture of endo and exo dienes is formed (75:25).
It is plausible that the presence of the methyl substituent and
the attendant steric repulsion that entails Mo alkylidene-alkyne
association, represented by ii (Scheme 1, pathway 1), leads to
partial reaction through pathway 3, involving initiation at the
olefin site; some of the exo product could also result from
reaction via Wi and the corresponding R-metallacyclobutene Wii
(Scheme 1, pathway 2).15 The complete endo selectivity (<2%
exo) observed in RCM of enyne 11 (entry 4, Table 1), which
bears an internal alkyne in addition to a 1,1-disubstituted alkene
(vs a terminal olefin in 9), is noteworthy; with the more
substituted olefin, the Mo alkylidene likely initiates exclusively
at the site of the internal alkyne. When Ru-based carbenes are
used to promote RCM reactions of enynes bearing a terminal
alkyne and a disubstituted alkene (e.g., 11), nearly equal
mixtures of exo and endo isomers are generated.14g
prepared and often used in situ9a,b through reaction of a
bispyrrolide (e.g., 6) with an alcohol.12 As also shown in Scheme
2, the latter precursor complex does not exhibit any catalytic
activity in this case (<2% conversion). Ru-based carbene 713
initiates enyne RCM, albeit less effectively than 5 (2 h vs 30
min of reaction time). It is only the exo isomer 3 that is isolated
in the Ru-catalyzed process (Scheme 2).14 When the RCM
promoted by carbene 7 is performed under an atmosphere of
ethylene,14c after 1 h there is only 24% conversion to 3, which
is obtained along with a byproduct that is derived from homo-
cross-metathesis of the product (3, 26%; ∼50% recovered
substrate).
1.2. Enyne RCM Promoted by Monoalkoxide Mo Complex 5.
The findings summarized in Table 1 demonstrate that, through
the use of Mo complex 5, a range of cyclic dienes can be
accessed. Thus, five-, six-, and seven-membered ring products
are isolated in 70-82% yield after purification; reactions
proceed readily and selectively with terminal alkynes as well
(12) (a) Hock, A. S.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc.
2006, 128, 16373–16375. (b) Singh, R.; Czekelius, C.; Schrock, R. R.;
Mu¨ller, P.; Hoveyda, A. H. Organometallics 2007, 26, 2528–2539.
(13) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168–8179. For an overview of Ru-based
carbenes bearing bidentate styrene ether ligands, see: (b) Hoveyda,
A. H.; Gillingham, D. G.; Van Veldhuizen, J. J.; Kataoka, O.; Garber,
S. B.; Kingsbury, J. S.; Harrity, J. P. A. Org. Biomol. Chem. 2004, 2,
8–23.
(14) For Ru-catalyzed RCM reactions of enynes with all-carbon tethers,
see: (a) Kim, S.-H.; Bowden, N.; Grubbs, R. H. J. Am. Chem. Soc.
1994, 116, 10801–10802. (b) Kim, S.-H.; Zuercher, W. J.; Bowden,
N. B.; Grubbs, R. H. J. Org. Chem. 1996, 61, 1073–1081. (c) Mori,
M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63, 6082–
6083. (d) Renaud, J.; Graf, C.-D.; Oberer, L. Angew. Chem., Int. Ed.
2000, 39, 3101–3104. (e) Ackermann, L.; Bruneau, C.; Dixneuf, P. H.
Synlett 2001, 397–399. (f) Schramm, M. P.; Srinivasa Reddy, D.;
Kozmin, S. A. Angew. Chem., Int. Ed. 2001, 40, 4274–4277. (g)
Kitamura, T.; Sato, Y.; Mori, M. Chem. Commun. 2001, 1258–1259.
(h) Kitamura, T.; Sato, Y.; Mori, M. AdV. Synth. Catal. 2002, 344,
678–693. (i) Sashuk, V.; Grela, K. J. Mol. Cat. A 2006, 257, 59–66.
See ref 3 for additional examples and applications to natural product
synthesis.
(15) For a catalytic RCM reaction involving allenynes as substrates,
promoted by Mo-based complex 4, that delivers exo products
selectively, see: Murakami, M.; Kadowaki, S.; Matsuda, T. Org. Lett.
2005, 7, 3953–3956.
9
10654 J. AM. CHEM. SOC. VOL. 131, NO. 30, 2009

Endo-Selective Enyne Ring-Closing Metathesis
A R T I C L E S
Table 2. Selective Synthesis of endo-Carbocyclic Dienes by
Scheme 3. Initial Examination of Mo-Catalyzed RCM of Various
N-Containing Enynes
Mo-Catalyzed Enyne RCM (Acetonide Tether)a-d
sponding heterocyclic structures.16 Accordingly, we investigated
the effect of the presence of a heteroatom within the tether
separating the alkyne and alkene units on the efficiency and
selectivity of the catalytic RCM processes.
2.1. Mo-Catalyzed RCM of N-Containing Enynes. 2.1.1. Cata-
lytic RCM of Enynes Bearing Different N-Substituents. We
began by investigating the RCM of a small set of enynes with
various N-substituents. As the data summarized in Scheme 3
illustrate, in the presence of 5 mol % of Mo-based alkylidene
5, tosylamide 16a readily undergoes RCM to afford 17a in
>98% endo selectivity and 92% yield after purification. Catalytic
ring closure of 16b, carrying the more easily removable
o-nosylamide, is equally efficient: the desired N-containing
cyclic endo-1,3-diene 17b is isolated in 85% yield with only
slightly diminished product selectivity (97:3 endo:exo). When
Boc-amide 16c serves as the starting enyne (Scheme 3),
oligomer formation is competitive with the desired RCM, which
furnishes 17c in 48% yield and >98% endo selectivity. Adventi-
tious oligomerization competes with formation of 17c, likely
because the adjacent Boc unit renders the alkyne sterically more
accessible (vs Ts or o-Ns), causing the intermolecular reaction
to be favored. As the data below will demonstrate (see eq 5), it
is less likely that the reduced conformational constraint imposed
by the Boc-amide plays a significant role in the lower yield in
which 17c is isolated.
2.1.2. Selective Mo-Catalyzed RCM of Enynes Bearing an
N-Tosylamide Tether. A range of N-containing enynes readily
undergo RCM reactions to afford the derived cyclic diene
products with high endo selectivity (Table 3). Similar to previous
cases, even when a tetrasubstituted olefin is generated (entry 4,
Table 3), the endo isomer is generated exclusively. As illustrated
in entry 2 of Table 3, in only one case is a small amount of the
exo product formed (endo:exo ) 84:16). The arguments
discussed above, regarding reactions of substrates bearing an
internal alkyne and a terminal olefin, are likely valid here as
well.
a-d See Table 1.
To probe further the effect of steric factors on endo vs exo
selectivity, we prepared several acetonide-containing enynes
(Table 2) and examined the corresponding RCM reactions (vs
diesters in Table 1). Catalytic cyclizations of enynes 12 (entry
1, Table 2) and 15 (entry 4, Table 2) proceed to afford the endo
products exclusively (>98:<2). Unlike the reaction of diester 8
(entry 1, Table 1), however, RCM of acetonide-enyne 13 (entry
2, Table 2) gives rise to a 75:25 mixture of endo and exo
isomers. Similar to catalytic RCM of internal alkyne 9,
illustrated in entry 3 of Table 1, acetonide 14 undergoes
transformation readily to generate a mixture of endo and exo
dienes (66:33 endo:exo). We suggest that, in the case of 13,
exo isomer formation is competitive since generation of the
R-metallacyclobutene intermediate (pathway 2, Scheme 1) is
rendered more favorable as a result of reduced steric repulsion
between the metal complex and the less sterically cumbersome
and geometrically constrained acetonide moiety (vs the diester
units of 8). The latter scenario does not lead to diminution of
product selectivity in RCM of the structurally related acetonide-
enyne 12 (entry 1, Table 2), likely because of the sterically
accessible terminal alkyne and because the endo product is a
readily generated six-membered-ring diene. In contrast, endo
selectivity in RCM of acetonide-enyne 13 results in the
generation of a less readily formed seven-membered-ring
product (exo isomer is a six-membered ring). It merits mention
that the validity of some of the scenarios mentioned depends
on reversibility of some of the steps within the catalytic cycle
(Scheme 1); a more sophisticated appreciation regarding any
mechanistic preferences must await the outcome of more
detailed studies.
In cases where a medium ring is generated (entry 1, Table 3)
or when the rate of ring closure is retarded due to increased
substitution at the alkyne and/or the alkene site (entries 2-4,
Table 3), the reaction must be performed under conditions that
are designed to minimize oligomerization. That is, whereas the
transformations in Schemes 2 and 3 and Tables 1 and 2 were
performed in 0.16 M solutions, RCM processes in entries 1, 3,
and 4 of Table 3 were carried out under more dilute conditions
(1.3 × 10-3, 2 × 10-3, and 2 × 10-3 M, respectively).17 It is
The above observations illustrate that the degree of endo:exo
selectivity in Mo-catalyzed RCM of enynes can depend on whether
the typically favored mode of reaction (via Mo-alkyne complex ii
and ꢀ-metallacyclobutene iii in Scheme 1) engenders unfavorable
steric repulsion between any of the substrate substituents and the
relatively sizable ligands of the Mo center. Furthermore, diminished
selectivity may arise if the endo product represents a ring size (e.g.,
a cycloheptadiene) that is typically formed more slowly than that
which corresponds to the exo isomer (e.g., a cyclohexadiene).
2. Selective Synthesis of endo-1,3-Heterocyclic Dienes through
Mo-Catalyzed Enyne RCM. A significant consequence of the
ability of Mo-based monoaryloxide-monopyrrolides to promote
selective formation of endo-1,3-cyclic dienes is the possibility
of applying such protocols toward preparation of the corre-
(16) For recent reviews regarding the use of catalytic olefin metathesis for
preparation of heterocyclic structures in the context of natural product
syntheses, see: (a) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104,
2199–2238. (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew.
Chem., Int. Ed. 2005, 44, 4490–4527. (c) Mori, M. AdV. Synth Catal.
2007, 349, 121–135.
(17) See the Supporting Information for more details.
9
J. AM. CHEM. SOC. VOL. 131, NO. 30, 2009 10655

A R T I C L E S
Lee et al.
Table 3. Mo-Catalyzed RCM of N-Containing Enynesa-d
Scheme 4
a-d See Table 1.
noteworthy, however, that even when substrate concentration
is decreased significantly, the stereogenic-at-Mo complex
remains highly effective as an olefin metathesis catalyst.
As the example illustrated in eq 1 demonstrates, Mo-catalyzed
RCM reactions involving terminal alkynes and alkenes readily
proceed to >98% conversion with only 1 mol % 5, delivering
the corresponding endo products efficiently and with outstanding
selectivity (>98:<2 endo:exo). In cases where the alkyne or the
olefin unit is more sterically hindered, 5 mol % catalyst loading
is required for complete conversion; for example, with 1,6-enyne
20 (entry 2, Table 3) as the substrate, RCM in the presence of
2.5 mol % 5 leads to 68% conversion after 90 min. It should
also be noted that the Mo catalyst can be readily generated and
used in situ without any diminution in reaction efficiency or
product selectivity; the example illustrated in eq 2, regarding
the preparation of endo diene 23, is representative.
enyne 24 is converted within 30 min to seven-membered endo
diene 25 in >98% selectivity (<2% exo product 26) and 68%
yield. When Ru-based complex 7 is used, exo diene 26 is formed
as the sole product (<2% endo product, 25) in 70% yield
(Scheme 4). In contrast, when 1,7-enyne 27, bearing a less
sterically congested alkyne unit (vs the benzylic alkyne in 24),
is treated with the same conditions as mentioned above, only
rapid oligomerization ensues.
To address the aforementioned complication, we turned to
the modified stereogenic-at-Mo monopyrrolide complex 28,9a
where the hexafluoro-tert-butoxide ligand of 5 has been replaced
by a bulkier 2,6-di(isopropyl)phenoxide. We surmised that the
presence of the more sizable aryloxide would discourage the
competing intermolecular processes, leading to oligomeric
products (vs the desired RCM). As illustrated in Scheme 4, in
the presence of Mo monoaryloxide-monopyrrolide 28, the
efficiency of the RCM is increased significantly: a mixture of
endo-29 and exo-30 is obtained in 41% yield; the remainder of
the substrate is consumed toward side reactions. The low endo:
exo selectivity is likely due to favorable formation of the derived
Mo-arylidene complex (derived from the styrenyl alkene) that
gives rise to the competing mode of transformation (pathway
3, Scheme 1) involving initiation of the catalytic cycle at the
styrenyl site of enyne 27. Ru-catalyzed RCM with 27,18 as
indicated in Scheme 4, leads to formation of unidentified product
mixtures when carried out under N2; when ethylene atmosphere
is used at 22 °C, low efficiency is observed. It has, however,
been previously reported that, with 5 mol % Ru carbene 7, RCM
of the acetamide derivative of 27 proceeds readily at 80 °C
(toluene, under N2 atm, reaction time not specified) to deliver
the corresponding exo isomer in 65% yield.18d
The transformations illustrated in Scheme 4 involve RCM
reactions of N-substituted 1,7-enyne substrates (vs 1,6-enynes
examined above). We find that, with 5 mol % 5, aryl-substituted
2.2. Mo-Catalyzed RCM of O-Containing Enynes. 2.2.1. Ini-
tial Studies. We began our studies by treatment of 31 with 5
9
10656 J. AM. CHEM. SOC. VOL. 131, NO. 30, 2009

Endo-Selective Enyne Ring-Closing Metathesis
A R T I C L E S
Scheme 5. Initial Study of Mo-Catalyzed RCM of O-Containing
Table 4. Solvent Effect in Mo-Catalyzed RCM of O-Containing
Enynesa
Enynes Promoted by Mo-Monoalkoxide Complex 5a,b
a,b See Table 1. c Yields of purified endo products; >98% substrate
consumption in all cases (400 MHz 1H NMR analysis). nd ) not
determined.
a All reactions performed under N2 atmosphere, unless otherwise noted.
mol % 5, which resulted in the formation of pyran 32 in 46%
yield and >98% endo selectivity; a significant amount of
oligomer generation accounts for complete consumption of the
substrate. With the more sterically hindered monoaryloxide 28,
there is little or no competing oligomerization, but there is only
20% conversion to the desired product (>98% endo), and 32 is
obtained in 15% yield. When enyne 34 is used, a similar trend
in selectivity is observed (Scheme 5). The lower yield of the
endo diene 35 versus that of 32 is likely because the sterically
less hindered alkyne unit of 34 is more prone to undergo the
intermolecular cross-metathesis reactions that deliver oligomeric
products. As indicated in Scheme 5, when performed under an
atmosphere of ethylene, RCM with Ru complex 7 affords the
exo products with high efficiency; otherwise, only a complex
mixture of products is obtained.19
Table 5. Effect of Aryloxide on Efficiency of Catalytic RCM of
31a-c
2.2.2. Improved Mo-Catalyzed RCM Efficiency and Minimiza-
tion of Competitive Oligomerization through the Use of Coordi-
nating Solvents. To enhance the efficiency of RCM reactions of
O-containing enynes, we first turned our attention to investigat-
ing the effect of the reaction medium in diminishing the rate of
competitive oligomerization. We reasoned that, in the presence
of a coordinating solvent, which might associate with the metal
center, the steric requirements of the substrate coordination site
as well as the Lewis acidity of the Mo might be altered, such
that oligomerization reactions, for reasons delineated above
regarding the preparation and examination of monoaryloxide
28 (Scheme 4), would be rendered relatively sluggish. We have
successfully used the above strategy in enhancing the enanti-
oselectivity of RCM reactions of dienes promoted by chiral Mo
diolates.20
a-c See Table 1.
Whereas reactions performed in Et2O proceed in a similar
fashion as in benzene (Table 4, entries 1 and 5), when THF is
used the desired RCM pathway becomes significantly more
competitive: 32 and 35 constitute 76% and 46% of the mixture
(entries 2 and 6, Table 4; vs 46% and 22%, respectively) and
are isolated in 75% and 44% yield. The suggestion that the
positive effect of THF is, at least partly, due to its coordinating
ability is supported by the findings that, when 2-methyl-THF
(entries 3 and 7, Table 4) and the more sizable 2,5-dimethyl-
THF (entries 4 and 8) serve as solvent, reaction efficiency is
improved.
2.2.3. Enhancement of RCM Efficiency and Minimization of
Competitive Oligomerization through Catalyst Modification. We
next turned our attention to altering the structure of the Mo
catalyst. We reasoned that, although with alkylidene 28, bearing
a 2,6-di(isopropyl)phenoxide, formation of unsaturated pyran
32 is less efficient than when complex 5 is used (see Scheme
5), other modified catalyst structures might furnish superior
selectivity based on the aforementioned rationales (see Scheme
4 and related discussion). Several monoaryloxides were thus
prepared in situ through treatment of bispyrrolide 6 with the
appropriate phenol (Table 5), and their ability to promote RCM
9
J. AM. CHEM. SOC. VOL. 131, NO. 30, 2009 10657

A R T I C L E S
Lee et al.
of enyne 31 was investigated. In two cases (entries 1 and 4,
Table 5), a substantial amount of unreacted enyne is recovered;
with the catalyst derived from 2,3,5,6-tetraphenylphenol (entry
4, Table 5), the desired heterocycle 32 constitutes a substantial
portion of the product mixture (55% conversion of the substrate,
32% yield of 32). Furthermore, the Mo complex derived from
2,6-diphenylphenoxide (entry 3, Table 5) delivers the desired
monomeric product 32 in 62% yield after purification (>98%
endo; complete consumption of enyne 31).
whether the diphenylphenoxide 38a (e.g., in the case of 31 and
41 in entries 1-2 and 7-8) or the more sterically hindered
tetraphenylphenoxide 38b promotes a more efficient reaction
(e.g., with enynes 34 and 39 in entries 3-6). A significantly
improved ability to predict the outcome of RCM reactions
requires a more detailed understanding of the mechanistic
nuances of the catalytic process, including the relationship
between the structure of a Mo complex and the level of endo:
exo selectivity.
In light of the promising activity and selectivity levels
furnished by the two modified stereogenic-at-Mo alkylidenes,
we isolated and characterized complexes 38a,b which, as
illustrated in eq 3, are generated in 80% and 76% yield,
respectively. The ability of 38a,b, prepared and used in situ, to
promote RCM reactions of a select number of O-containing
enynes was then probed.
Several additional points regarding the data in Table 6 merit
mention: (a) The reaction performed in the presence of 38a
(entry 1, Table 6), although superior to that involving Mo
complex 5 (62% vs 46% yield of 32), remains less efficient
than when 5 is utilized in THF (see entry 2, Table 4: 75% yield
of 32). In the RCM involving enyne 34, however, it is the
tetraphenylphenoxide 38b that delivers 35 with the highest
degree of efficiency (entry 4, Table 6: 67% yield vs 22% and
44% yield with alkylidene 5 in C6H6 and THF, respectively).
(b) The amount of catalyst required depends on the structure of
the substrate. Thus, 5 mol % loading is sufficient for achieving
>98% conversion with enyne 34, which bears the less sterically
congested alkyne (vs 10 mol % for 31). The same amount of
38a,b engenders complete conversion in reactions of vinylsilanes
39 and 41 (entries 5-8, Table 6). The higher degree of efficiency
observed for RCM of 39 (vs 31) is likely due to the favorable
entropic (Thorpe-Ingold) effects due to the tetrasubstituted Si-
based tether within such substrates. Finally, it should be noted
that use of complexes 38a,b in THF (see Table 4) does not
give rise to any additional increase in RCM efficiency. It is
plausible that association of the Lewis basic solvent with the
metal center is less favorable with the more sterically demanding
aryloxide ligands.
Table 6. Mo-Catalyzed RCM of O-Containing Enynesa-c
3. Structural Attributes of Stereogenic-at-Mo Monopyrrolide
Complexes. Several stereogenic-at-Mo complexes, bearing dif-
ferent O-based ligands, have played a critical role in the
development of enyne RCM reactions described above. A brief
analysis of some of the structural features of these alkylidenes
is thus warranted. The X-ray structures of monopyrrolide
monoalkoxide complex 5 as well as monoaryloxides 38a,b are
illustrated in Scheme 6. The structural details of complex 28
(Scheme 4) have been previously disclosed.8a
Selected bond lengths and angles are depicted in Scheme 6.
Noteworthy is the relatively long Mo-O bond in 2,6-diphe-
nylphenoxide 38a and 2,3,5,6-tetraphenyphenoxide 38b, a
characteristic that is likely the result of minimization of
unfavorable steric interactions between the sizable aryloxides
and the other ligands. Similar considerations can be used to
offer a rationale for the unusually large C-Mo-O angle in 38b
(115.03° vs ∼109° for 5 and 28). The above attributes can give
rise to a more spacious binding pocket, allowing for facile RCM
a-c See Table 1. d Mixture of diastereomers (∼60:40; stereogenic at
(18) For Ru-catalyzed RCM reactions of enyne substrates with N-containing
tethers, see: (a) Reference 3c. (b) References 14c-i. (c) Castarlenas,
R.; Eckert, M.; Dixneuf, P. H. Angew. Chem., Int. Ed. 2005, 44, 2576–
2579. (d) Rosillo, M.; Dom´ınguez, G.; Cassarubios, L.; Amador, U.;
Pe´rez-Castells, J. J. Org. Chem. 2004, 69, 2084–2093. See ref 3 for
additional examples and applications to natural product synthesis.
(19) For Ru-catalyzed RCM reactions of enyne substrates withO-containing
tethers, see: (a) Reference 14. (b) Picquet, M.; Bruneau, C.; Dixneuf,
P. H. Chem. Commun. 1998, 2249–2250. (c) Hoye, T. R.; Donaldson,
S. M.; Vos, T. J. Org. Lett. 1999, 1, 277–280. (d) Clark, J. S.;
Elustondo, F.; Trevitt, G. P.; Boyall, D.; Robertson, J.; Blake, A. J.;
Wilson, C.; Stammen, B. Tetrahedron 2002, 58, 1973–1982. See ref
3 for additional examples and applications to natural product synthesis.
(20) Teng, X.; Cefalo, D. R.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem.
Soc. 2002, 124, 10779–10784.
Si).
As the data in Table 6 indicate, the two modified monoary-
loxides allow access to the desired O-substituted cyclic endo
dienes in useful levels of efficiency; none of the corresponding
exo product isomers are detected (as judged by analysis of 400
1
MHz H NMR spectra). It is noteworthy that Mo-catalyzed
RCM reactions of sterically congested vinylsilanes 39 and 41
(entries 5-8) proceed readily to afford the desired cyclic
unsaturated siloxanes in up to 85% yield. A notable feature of
the findings in Table 6 is the difficulty of gauging a priori
9
10658 J. AM. CHEM. SOC. VOL. 131, NO. 30, 2009

Endo-Selective Enyne Ring-Closing Metathesis
A R T I C L E S
Scheme 6. X-ray Structures and Select Physical Properties of Mo-Based Monopyrrolidesa
a See the Supporting Information for details regarding the X-ray structures of complexes 5, 38a, and 38b.
1
reactions of sterically demanding enyne substrates. Two note-
worthy examples within this context are the reactions of
vinylsilanes 39 and 41, shown in entries 5-8 of Table 6. In
contrast to RCM promoted by monopyrrolides 38a and 38b
(>98% conversion, 61-85% yields), <2% consumption of the
substrates is observed with Mo-based complexes 5 and 28 (as
well as the Ru-based carbene 7).
The H NMR spectrum of 38b (in C6D6), however, exhibits a
signal at δ 11.67 ppm, which is closely related to the chemical
shifts detected for the alkylidene proton in 38a (δ 11.70 ppm).
4. Enantioselective Mo-Catalyzed Enyne RCM Reactions.
Varying degrees of progress have been achieved in connection
with enantioselective versions of several types of olefin me-
tathesis reactions.22-24 One subset of transformations that has
not yet yielded to enantioselective catalysis is the RCM reactions
of enynes. Based on the outcome of the investigations sum-
marized above, and encouraged by the recent discoveries
regarding the exceptional ability of stereogenic-at-Mo complexes
to promote enantioselective RCM9a-b and ring-opening/cross-
metathesis reactions of olefinic substrates,9c we set out to
Somewhat surprisingly, Mo complex 38a (138.51°) has the
smallest Mo-O-C and C-Mo-O angles of the four com-
plexes. This unusual attribute may be due to π-stacking
associations21 between the phenyl unit of the neophylidene
substituent and the aryloxide group, as suggested by the distance
between these two aromatic planes (see X-ray of 38a, Scheme
6). Such an interaction would be less favored with the sterically
more demanding tetraphenylphenoxide of 38b. It is important
to note that, upon initiation and loss of the neophylidene group,
the Mo-O-C angle of the complexes derived from 38a would
likely resemble that of 38b. Thus, in general, whereas the bond
length values shown in Scheme 6 may prove to be relevant to
the properties of the catalytically active complex in solution,
the corresponding bond angles might be largely influenced by
crystal packing forces and steric interactions that arise from the
presence of the neophylidene unit. One set of observations
supports the validity of such a caveat: The alkylidene proton in
38b resides only ∼28 Å above the π surface of an aryl unit of
the aryloxide ligand, as observed in the X-ray structure of this
complex (Scheme 6), and would thus be expected to appear
more upfield as a result of well-established anisotropic effects.
(22) For Mo-catalyzed enantioselective RCM processes that deliver N-
containing heterocycles, see: (a) Dolman, S. J.; Sattely, E. S.; Hoveyda,
A. H.; Schrock, R. R. J. Am. Chem. Soc. 2002, 124, 6991–6997. (b)
Dolman, S. J.; Schrock, R. R.; Hoveyda, A. H. Org. Lett. 2003, 5,
4899–4902. (c) Sattely, E. S.; Cortez, G. A.; Moebius, D. C.; Schrock,
R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 8526–8533. For
Mo-catalyzed enantioselective RCM reactions that afford other types
of ring structures, see: (d) Alexander, J. B.; La, D. S.; Cefalo, D. R.;
Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 1998, 120, 4041–
4042. (e) La, D. S.; Alexander, J. B.; Cefalo, D. R.; Graf, D. D.;
Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 1998, 120, 9720–
9721. (f) Zhu, S. S.; Cefalo, D. R.; La, D. S.; Jamieson, J. Y.; Davis,
W. M.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 1999,
121, 8251–8259. (g) Cefalo, D. R.; Kiely, A. F.; Wuchrer, M.;
Jamieson, J. Y.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc.
2001, 123, 3139–3140. (h) Kiely, A. F.; Jernelius, J. A.; Schrock, R. R.;
Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 2868–2869. (i) Jernelius,
J. A.; Schrock, R. R.; Hoveyda, A. H. Tetrahedron 2004, 60, 7345–
7351. (j) Lee, A.-L.; Malcolmson, S. J.; Puglisi, A.; Schrock, R. R.;
Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 5153–5157. (k) For
applications of catalytic enantioselective RCM to natural product total
synthesis, see refs 8b and c.
(21) Suezawa, H.; Yoshida, T.; Umezawa, Y.; Tsuboyama, S.; Nishio, M.
Eur. J. Inorg. Chem. 2002, 3148–3155.
9
J. AM. CHEM. SOC. VOL. 131, NO. 30, 2009 10659

A R T I C L E S
Lee et al.
Scheme 7. Mo-Catalyzed Enantioselective RCM of a Dienyne
Scheme 8. Effect of Ethylene on Catalytic Cross-Metathesis/
Enantioselective RCM of a Dienyne
establish whether the same class of chiral alkylidenes can
promote the formation of enantiomerically enriched cyclic endo
dienes.
complex 44b: the endo product is obtained in 85:15 er. Although
unreacted substrate is recovered when 44b is used (69%
conversion), there is minimal oligomerization: endo product 45
is formed in 63% yield after purification (Scheme 7). It should
be noted that, despite repeated attempts, we did not detect the
purported diene intermediate 46 (see below for an additional
related observation).
Treatment of dienyne 43 with 10 mol % of 44a, prepared
and used in situ, leads to complete consumption of the substrate
(Scheme 7). The product from enantioselective RCM affords
the endo cycloadduct 45 in 79:21 enantiomer ratio (er) and 30%
yield after purification; a significant portion of the product
mixture consists of oligomeric materials. We then surmised that
if the RCM process is performed under an atmosphere of
ethylene (vs N2), the efficiency with which the monomeric
heterocycle is generated might be improved. This strategy,
previously utilized in relation to Ru-catalyzed enyne metathesis
reactions,14c is based on the principle that initial cross-metathesis
of the alkyne unit with ethylene might deliver tetraene 46
(Scheme 7), which would undergo RCM to generate endocyclic
product 45. Increased RCM efficiency would arise from the
more expeditious removal of the terminal alkyne, largely
responsible for the formation of oligomeric side products. When
RCM of 43 is carried out under an atmosphere of ethylene
(Scheme 7), unsaturated tosylpiperidine 45 is isolated in 60%
yield (vs 30% under N2) in the same degree of enantiomeric
purity (79:21 er). Enantioselectivity is improved with di-iodo
Next, we evaluated the corresponding transformation of
dienyne 47, which bears two 1,1-disubstituted alkenes (vs
terminal olefins in 43, Scheme 7). As shown in Scheme 8,
treatment of 47 with 10 mol % 44a under an atmosphere of
ethylene gives rise to >98% conversion within 2 h at 22 °C.
Tetraene 48 is isolated in 70% yield, and none of the expected
RCM product is detected (49, as judged by analysis of the 400
MHz 1H NMR spectrum of the unpurified mixture). Resubjec-
tion of 48 to 5 mol % 44a, this time under an atmosphere of
N2, gives rise to formation of 49 in >98% endo selectivity, 92%
yield, and 98:2 er. Minimal oligomerization is observed in the
transformations depicted in Scheme 8. It should be noted that
there is <10% conversion when 47 is subjected to 10 mol %
44a at 22 °C under an atmosphere of N2; longer reaction times
do not lead to additional transformation. The origin of the
aforementioned lack of reactivity is not clear at the present time;
it is feasible, however, that initial oligomerization leads to
formation of an unreactive Mo alkylidene, resulting in seques-
tration of all catalytically competent complexes. The two-step
procedure shown in Scheme 8 can be carried out in a single
vessel: treatment of 47 with 10 mol % 44a in benzene under
ethylene atmosphere for 10 min, followed by removing the
balloon and allowing the mixture to stir for 12 h, delivers 49 in
62% yield and 95:5 er.
(23) For Mo-catalyzed enantioselective ring-opening/cross-metathesis and/
or ring-opening/ring-closing reactions, see: (a) Weatherhead, G. S.;
Ford, J. G.; Alexanian, E. J.; Schrock, R. R.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 1828–1829. (b) La, D. S.; Sattely, E. S.; Ford,
J. G.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123,
7767–7778. (c) Cortez, G. A.; Schrock, R. R.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2007, 46, 4534–4538. (d) Reference 8d. For Ru-
catalyzed enantioselective ring-opening/cross-metathesis reactions, see:
(e) Gillingham, D. G.; Kataoka, O.; Garber, S. B.; Hoveyda, A. H.
J. Am. Chem. Soc. 2004, 126, 12288–12290. For a comparison of Mo-
and Ru-based enantioselective ring-opening/cross-metathesis processes,
see: (f) Cortez, G. A.; Baxter, C. A.; Schrock, R. R.; Hoveyda, A. H.
Org. Lett. 2007, 9, 2871–2874. For applications of catalytic enanti-
oselective ring-opening reactions to natural product total synthesis,
see: (g) Weatherhead, G. S.; Cortez, G. A.; Schrock, R. R.; Hoveyda,
A. H. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5805–5809. (h)
Gillingham, D. G.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46,
3860–3864.
Initial investigations indicate that use of an ethylene atmo-
sphere as the means to improve the efficiency of an enyne RCM
process does not apply to all substrate classes. As an example,
when O-containing enyne 34 (Table 6) is subjected to 10 mol
% Mo-based monopyrrolide complex 38b (prepared and used
in situ, as with 44a,b) under an ethylene atmosphere, after 2 h
at 22 °C, there is >98% substrate consumption but endo product
35 is obtained in 42% yield (vs 67% yield under N2; see entry
4, Table 6). It is plausible that sterically less congested alkynes
(24) For Ru-catalyzed enantioselective ring-opening/cross-metathesis and
cross-metathesis reactions developed in other laboratories, see: Berlin,
J. M.; Goldberg, S. D.; Grubbs, R. H. Angew. Chem., Int. Ed. 2006,
45, 7591–7595.
9
10660 J. AM. CHEM. SOC. VOL. 131, NO. 30, 2009

Endo-Selective Enyne Ring-Closing Metathesis
A R T I C L E S
(e.g., those bearing an allylic ether vs an NTs unit) undergo
oligomerization at a rate with which ethylene cross-metathesis
cannot effectively compete.
Attempts to promote Mo-catalyzed enantioselective RCM
reactions of the related enyne substrates bearing all-carbon or
O-containing tethers proved significantly less selective (<65:
35 er). Clearly, development of chiral catalyst variants that
exhibit a wider range of substrate generality is required; studies
along these lines are in progress.
Scheme 2). The catalysts bearing substituted phenoxide ligands,
however, promote formation of 51 with substantially higher
efficiency; complex 38a furnishes the desired product in 80%
yield with a similarly exceptional degree of endo selectivity.
Conclusions
We report the first endo-selective set of protocols for catalytic
RCM of enynes, including those that bear an N- or an O-based
tether. Cyclization reactions typically proceed with high endo:
exo selectivity and in yields that render the method of utility,
particularly since, in most instances, the Ru-catalyzed reactions
deliver the corresponding exo products. The endo cyclic dienes,
as illustrated by the highly site-selective oxidation25 in eq 4,
can be functionalized to allow access to a range of useful
heterocyclic small organic molecules (e.g., through alkylations
or substitution reactions of the allylic epoxide).26
The first examples of enantioselective enyne RCM reactions
are presented as well. Products are obtained in up to 98:2 er
and >98:<2 endo:exo selectivity through desymmetrization
reactions of N-containing dienynes in transformations promoted
by enantiomerically pure stereogenic-at-Mo complexes, which
have been shown to be exceptionally effective for RCM of
various diene substrates. Many shortcomings remain to be
addressed, including identification of catalysts that promote
enantioselective reactions of enynes with O-containing tethers,
a class of substrates particularly prone toward oligimerization.
It is important to note that not only will discovery and
development of new chiral catalysts be beneficial to enantiose-
lective variants of endo-selective enyne RCM reactions, but such
chiral complexes may prove to be superior catalysts in general
and highly effective in cases where the desired product is achiral.
Every Mo complex used in the present investigation is chiral;
this class of chiral catalysts, used in the racemic form, promotes
efficient endo-selective reactions. As has been described previ-
ously, the stereogenic Mo center and the attendant stereoelec-
tronic attributes of such chiral catalysts render the complexes
examined here effective RCM catalysts.9b,c These investigations
provide a clear example of the principle that chiral catalysts
should not be considered as potentially viable solutions only in
cases where control of enantioselectivity is desired.
Reactions are promoted by stereogenic-at-metal monoalkox-
ide- or monoaryloxide-monopyrrolide Mo complexes, pre-
pared from the corresponding bispyrrolide (6 in Scheme 2) and
the appropriate alkyl or aryl alcohols. Isolation and purification
of the metal complexes is not required, as they can be
synthesized and used in situ. The above characteristic, together
with the fact that the Mo-based catalysts bear only monodentate
ligands, lends itself to facile modification of the catalyst
structure. The latter attribute has been used in this study to alter
the catalyst structure in order to maximize the efficiency of
certain enyne RCM reactions (e.g., Tables 5and 6). The present
investigations have therefore led to identification of several new
catalyst variants that enhance the utility of this class of
transformations. An additional example is provided in eq 5.
Catalytic RCM of enyne 50 with Mo complex 5 affords diene
51 in only 45% yield as a result of a significant oligomerization,
likely due to the absence of the quaternary carbon, which
facilitates intramolecular cyclization (compare to RCM of 1 in
Future studies will be directed toward the design of more
efficient catalysts for enyne RCM reactions, further development
of the enantioselective variants, and applications to the synthesis
of biologically active molecules.
Acknowledgment. The NIH (GM-59426) provided financial
support. We are grateful to Dr. Bo Li (Boston College) for obtaining
the X-ray crystal structures. We thank S. J. Malcolmson and S. J.
Meek (Boston College) for valuable discussions. Mass spectrometry
facilities at Boston College are supported by the NSF (DBI-
0619576).
(25) For site-selective epoxidation reactions of endocyclic dienes, see: (a)
Evarts, J. B., Jr.; Fuchs, P. L. Tetrahedron Lett. 2001, 42, 3673–3675.
(b) Yang, D.; Wong, M.-K.; Yip, Y. C. J. Org. Chem. 1995, 60, 3887–
3889.
Supporting Information Available: Experimental procedures
and spectral data for substrates and products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(26) For representative procedures regarding functionalization of allylic
epoxides, see: (a) Cahiez, C.; Alexakis, A.; Normant, J. F. Synthesis
1978, 528–530. (b) Yang, D.; Xu, M. Org. Lett. 2001, 3, 1785–1788.
JA904098H
9
J. AM. CHEM. SOC. VOL. 131, NO. 30, 2009 10661