Comparison of Ru- and Mo-based chiral olefin metathesis catalysts. Complementarity in asymmetric ring-opening/cross-metathesis reactions of oxa- and azabicycles

Article abstract of DOI:10.1021/ol071008h

A comparative study of chiral Mo- and Ru-based catalysts to promote enantioselective synthesis of 2,6-disubstituted pyrans and piperidines through asymmetric ring-opening/cross-metathesis (AROM/CM) reactions is presented. These studies demonstrate the cri

Full text of DOI:10.1021/ol071008h

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2871-2874
Comparison of Ru- and Mo-Based Chiral
Olefin Metathesis Catalysts.
Complementarity in Asymmetric
Ring-Opening/Cross-Metathesis
Reactions of Oxa- and Azabicycles
G. Alex Cortez,† Carl A. Baxter,† Richard R. Schrock,# and Amir H. Hoveyda*,†
Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467, and Department of Chemistry,
Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
amir.hoVeyda@bc.edu
Received May 8, 2007
ABSTRACT
A comparative study of chiral Mo- and Ru-based catalysts to promote enantioselective synthesis of 2,6-disubstituted pyrans and piperidines
through asymmetric ring-opening/cross-metathesis (AROM/CM) reactions is presented. These studies demonstrate the critical complementarity
that exists between the two classes of chiral catalysts.
Ru- and Mo-based catalysts are central to the emergence of
olefin metathesis as an indispensable method in chemical
synthesis.1 Detailed studies that compare these catalyst
classes are, nonetheless, uncommon, and the limited infor-
mation available relates to reactivity, not selectivity (par-
ticularly enantioselectivity).2 Herein, we describe the results
of our investigations on Ru- and Mo-catalyzed asymmetric
ring-opening/cross-metathesis (AROM/CM) reactions of oxa-
and azabicycles with aromatic alkenes; these processes afford
functionalized pyrans and piperidines in up to >98% ee.3
We show that, depending on the substrate, one particular
catalyst system (Mo- or Ru-based) may provide superior
reactivity and/or enantioselectivity.
Chiral Ru (1-2) and Mo (3-7) complexes utilized are
depicted in Figure 1. The first-generation binaphthyl-based
carbenes 1a,b,4 as well as the more recently developed
biphenyl-based complexes 2a,b,5 were probed. Ru-iodides
1b6 and 2b,5 although typically less active,5 have been shown
in previous investigations to provide enhanced enantiose-
lectivities (vs chlorides 1a and 2a). Chiral Mo alkylidenes,
such as biphenolates 3a-c7 (arylimido) and 68 (adamantyl-
imido), binaphtholates 4a-c9 (arylimido) and 710 (adaman-
tylimido), as well as partially hydrogenated complexes 5a,b,11
were examined.
† Boston College.
# Massachusetts Institute of Technology.
(1) For reviews on catalytic olefin metathesis, see: Handbook of
Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003.
(2) For example, see: (a) Schneider, M. F.; Lucas, N.; Velder, J.;
Blechert, S. Angew. Chem., Int. Ed. 1997, 36, 257-259. (b) Chatterjee, A.
K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360-11370. (c) Michrowska, A.; Bieniek, M.; Kim, M.; Klajn, R.;
Grela, K. Tetrahedron 2003, 59, 4525-4531. (d) Schrock, R. R.; Hoveyda,
A. H. Angew. Chem., Int. Ed. 2003, 42, 4592-4633.
(4) (a) Van Veldhuizen, J. J.; Garber, S. B.; Kingsbury, J. S.; Hoveyda,
A. H. J. Am. Chem. Soc. 2002, 124, 4954-4955. (b) Van Veldhuizen, J.
J.; Gillingham, D. G.; Garber, S. B.; Kataoka, O.; Hoveyda, A. H. J. Am.
Chem. Soc. 2003, 125, 12502-12508. For a brief overview, see: 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.
(5) Van Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.; Hoveyda, A.
H. J. Am. Chem. Soc. 2005, 127, 6877-6882.
(3) For a review on catalytic olefin metathesis methods used in the
synthesis of heterocycles, see: Deiters, A.; Martin, S. F. Chem. ReV. 2004,
104, 2199-2238.
(6) Gillingham, D. G.; Kataoka, O.; Garber, S. B.; Hoveyda, A. H. J.
Am. Chem. Soc. 2004, 126, 12288-12290.
10.1021/ol071008h CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/22/2007

the previous data, catalyst 2b is more effective than 1b
(>98% vs 70% conversion) in furnishing 9.
To probe the feasibility of Mo-catalyzed AROM/CM of
oxabicycles, we examined various chiral alkylidenes illu-
strated in Figure 1. As the data summarized in Table 1
Table 1. Screening of Chiral Mo Catalysts for AROM/CM of
8 with Styrenea
entry
Mo catalyst
conv (%)b
E:Z
ndd
ee (%)c
ndd
1
2
3
4
5
6
7
8
9
3a
3b
3c
4a
4b
4c
5a
5b
6
>98
<5
50
<5
<5
<5
<5
<5
>98
<5
ndd
ndd
>98:<2
94
10
7
a Reactions performed under N2; all conversions are >98%. b Determined
by 400 MHz 1H NMR analysis. c Determined by chiral HPLC analysis
(chiralcel OD). d Unidentifiable oligomeric products formed, nd ) not
determined.
indicate, with the exception of adamantyl biphenolate 6 (entry
9), which emerges as a highly effective catalyst, other chiral
Mo alkylidenes either do not promote reaction (<5% conv)
or, as in the case of 3a (entry 1) and 3c (entry 3), generate
oligomeric products. Thus, with 5 mol % chiral alkylidene
6, unsaturated pyran 9 is obtained as a single olefin isomer
(>98% E) and in 94% ee.
As summarized in entry 3 of Table 2, with C6H6 as the
solvent, Mo-catalyzed AROM/CM of oxabicycle 8 and
styrene generates pyran 9 in 97% ee and ∼55% isolated
yield12 (>98% E). Comparison of the data shown in entries
Figure 1. Chiral Ru- and Mo-Based Catalysts for Enantioselective
Olefin Metathesis.
We began our investigations with catalytic AROM/CM
of meso oxabicycles. We have previously demonstrated that
chiral Ru complexes 1a and 1b promote this class of
enantioselective transformations to afford the desired pyrans
as a single alkene isomer (>98% E), in up to 98% ee and
91% isolated yield.6 As illustrated in the representative
AROM/CM process in eq 1, reactions can be performed in
the absence of solvent, a condition required for transforma-
tions with relatively less reactive substrates such as 8;
otherwise, <20% conversion is observed. Consistent with
(9) (a) 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. (b) Alexander, J. B.; Schrock, R. R.; Davis, W. M.; Hultzsch, K. C.;
Hoveyda, A. H.; Houser, J. H. Organometallics 2000, 19, 3700-3715. (c)
Schrock, R. R.; Jamieson, J. Y.; Dolman, S. J.; Miller, S. A.; Bonitatebus,
P. J., Jr.; Hoveyda, A. H. Organometallics 2002, 21, 409-417.
(10) Pilyugina, T. S.; Schrock, R. R.; Mu¨ller, P.; Hoveyda, A. H.
Organometallics 2007, 26, 831-837.
(7) (a) Alexander, J. B.; La, D. S.; Cefalo, D. R.; Hoveyda, A. H.;
Schrock, R. R. J. Am. Chem. Soc. 1998, 120, 4041-4042. (b) Weatherhead,
G. S.; Houser, J. H.; Ford, J. G.; Jamieson, J. Y.; Hoveyda, A. H.; Schrock,
R. R. Tetrahedron Lett. 2000, 41, 9553-9559.
(8) Tsang, W. C. P.; Jernelius, J. A.; Cortez, G. A.; Weatherhead, G. S.;
Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 2591-2596.
(11) Aeilts, S. L.; Cefalo, D. R.; Bonitatebus, P. J., Jr.; Houser, J. H.;
Hoveyda, A. H.; Schrock, R. R. Angew. Chem., Int. Ed. 2001, 40, 1452-
1456.
2872
Org. Lett., Vol. 9, No. 15, 2007

(82% ee; entry 13).13 Finally, as illustrated in entries
15-18 (Table 2), formation of a fully functionalized pyran,
an intermediate utilized in a recently disclosed enantioslective
total synthesis of baconipyrone C,14 proceeds less readily
but more enantioselectively with chiral Ru carbenes than Mo
catalyst 6.
Table 2. Ru- and Mo-Catalyzed AROM/CM of Oxabicycles
and Styrenea
The above study demonstrates that chiral Ru and Mo
catalysts promote highly selective AROM/CM of oxabicyclic
substrates with styrene. Which catalyst class engenders higher
enantioselectivity, however, depends on the identity of the
particular substrate (e.g., compare entries 12-14 for superior
Mo performance and 15-18 for examples of more selective
Ru-catalyzed AROM/CM). Although Mo catalysts initiate
faster transformations, in cases where the cyclic olefin is
highly reactive and competitive oligomerization is a possible
complication, Ru carbenes are preferable (e.g., entries 4-7,
Table 2). With these results in hand, we carried out a
comparative study of the two catalyst systems in AROM/
CM of azabicyclic substrates to obtain enantiomerically
enriched piperidines.
We recently demonstrated that chiral Mo catalyst 6 readily
(>98% conversion in 1 h) promotes AROM/CM of azabi-
cycles bearing an NMe unit (e.g., 18, Table 3) and a range
a Reactions at 22 °C under N2. Ru-catalyzed reactions run in the absence
of solvent; Mo-catalyzed reactions carried out in C6H6. All conversions
are >98%, judged by analysis of 400 MHz 1H NMR spectra of unpurified
mixtures. >98% E:Z in all cases. b Isolated yields. c See Table 1. d Oligo-
meric products formed. nd ) not determined.
Table 3. Comparison of Ru- and Mo-Based Catalysts in
AROM/CM of NMe- and NBn-Azabicyclesa
1-3 of Table 2 suggests that the reaction promoted by Mo
complex 6 is more efficient, even though those with Ru
carbenes are performed without solvent. The higher activity
of 6 proves detrimental in the transformation of the more
reactive endocyclic benzyl ether 10 (see entries 4-7,6 Table
2); only oligomeric products are generated when the Mo
complex is used to promote AROM/CM of oxabicycle 10
(entry 7). The less potent Ru carbenes, however, initiate
efficient desymmetrizations to deliver 11 in 96% and 88%
ee with 1a and 2b, respectively (entries 4 and 5, Table 2).
With 2b, the reaction can be carried out at -15 °C to afford
11 in 87% isolated yield and 91% ee (entry 6). Chiral catalyst
6 can be used for AROM/CM of the less reactive exocyclic
benzyl ether 12: reaction proceeds readily, without oligo-
merization, to afford 13 in 90% ee and 81% isolated yield
(entry 11, Table 2). Although more sluggish than Mo-
catalyzed processes, transformations promoted by Ru cata-
lysts, shown in entries 8-10, deliver products of higher
enantiopurity; as depicted in entry 10 of Table 2, at -15
°C, carbene 2b gives rise to pyran 13 in 84% isolated yield
and as a single olefin isomer (>98% E) and enantiomer
(>98% ee). Comparison of the data in entries 12 and 14,
involving secondary iodide 14 as the substrate, shows that
this catalytic AROM/CM can be highly enantioselective with
Ru carbene 1b as well as the more reactive Mo complex 6
(93% and 97% ee, respectively). In contrast, the second-
generation Ru iodide 2b furnishes lower enantioslectivity
a Reactions at 22 °C performed under N2. Ru-catalyzed reactions were
preformed neat; Mo-catalyzed reactions were carried out in C6H6. b Deter-
mined by analysis of 400 MHz 1H NMR spectra of unpurified mixtures.
c ,dSee Table 2. nd ) not determined.
of aromatic olefin cross partners in up to 98% ee (>98%
E).15 In contrast, Ru carbenes 1a and 2a,b are ineffective;
the data in entries 1-3 of Table 3 are illustrative. Similar
general trends were observed for less reactive substrates that
carry a carbamate group (e.g., NCbz or NCO2Et derivative
of 18).
As the data in entries 5-8 of Table 3 illustrate, catalytic
AROM/CM of benzyl-protected azabicycles, represented by
20, follow an entirely different trend compared to methyl-
amines, such as 18. In stark contrast to unsaturated methyl-
(12) Varying values for isolated yield is due to the volatility of pyran 9.
(13) Enantioselectivity does not improve when this reaction is carried
out at -15 °C.
(14) Gillingham, D. G.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2007,
46, 3860-3864.
(15) Cortez, G. A.; Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int.
Ed. 2007, 46, 4534-4538.
Org. Lett., Vol. 9, No. 15, 2007
2873

amine 18, with benzylamine 20 as the substrate (entry 5,
Table 3), first-generation Ru catalyst 1a (5 mol %) promotes
AROM/CM with styrene (>98% conversion, 80% isolated
yield), affording 21 in >98% ee (>98% E). As shown in
entry 6 of Table 3, unlike a number of previously reported
observations,5 the second-generation chiral carbene 2a proves
to be less efficient in this case, giving rise to 70% conversion
under identical conditions (vs >98% conversion with 1a);
the less reactive second-generation Ru-iodide (2b) is entirely
ineffective (entry 7, Table 3). Moreover, unlike reactions of
methylamine 18, chiral Mo alkylidene 6, optimal for AROM/
CM of 18 (94% ee), delivers benzylpiperidine 21 in only
21% ee. These observations underline the versatile comple-
mentary nature of chiral Ru and Mo catalysts; seemingly
minor variations in substrate structure can render Ru carbenes
superior to Mo alkylidenes and vice versa.
asymmetric olefin metathesis reactions. Our investigations
provide evidence for the significance of catalyst diversity
on different levels. In certain cases involving AROM/CM
of oxabicycles, it is the Ru catalysts that perform more
effectively. In other instances, Mo complexes generate more
attractive results. Strikingly, in reactions of azabicycles, when
the amine unit carries a methyl or a carbonyl group, Mo
alkylidenes deliver high activity and selectivity, whereas with
benzyl-protected azabicycles, Ru catalysts are superior.
In spite of the advances rendered possible by the avail-
ability of chiral catalysts,16 such as those illustrated in Figure
1, notable issues of reactivity and selectivity remain unad-
dressed in asymmetric olefin metathesis. For example, the
reaction shown in eq 2 cannot be promoted by any of the
complexes depicted in Figure 1.
The results of studies on catalytic AROM/CM of azabi-
cycle 22 with styrenyl cross partners are summarized in Table
4. In addition to the low selectivities that would be expected
Table 4. Ru-Catalyzed AROM/CM of NBn-Azabicyclesa
Another critical point is that catalytic AROM/CM pro-
cesses are largely limited to aromatic alkenes as cross part-
ners. Aliphatic olefins readily undergo homocoupling, caus-
ing formation of highly reactive methylidenes that compete
with alkyl-substituted Ru carbenes or Mo alkylidenes, leading
to diminution of enantioselectivities.17 One solution may arise
through the recently reported strategy involving cross partners
that carry metal-coordinating groups (enoates and ynoates),
which stabilize the resulting carbenes and can exist pre-
dominantly as one carbene stereoisomer.18
Ru
catalyst
conv (%)b;
yield (%)c
ee
entry
Ar
C6H5
product
(%)d
1
2
3
4
5
6
7
8
23a
23a
23b
23b
23c
23c
23d
23e
23e
23f
1a
2a
1a
2a
1a
2a
1a
1a
2a
1a
>98; 82
80; 65
63; 55
27; nd
>98; 81
95; 60
87; 70
87; 67
50; 38
>98; 78
>98
94
97
nd
98
C6H5
Investigations directed toward development of new cata-
lysts, strategies, and methods that address such unresolved
problems are in progress.
o-BrC6H4
o-BrC6H4
o-MeC6H4
o-MeC6H4
o-FC6H4
p-OMeC6H4
p-OMeC6H4
p-CF3C6H4
98
Acknowledgment. Financial support was provided by the
NSF (CHE-0213009 to A.H.H.) and the NIH (GM-59426
to R.R.S. and A.H.H.). G.A.C. was an NIH predoctoral
fellow (F31 GM-73556) and C.A.B. a Fulbright Scholar. We
thank D. G. Gillingham (Boston College) for performing the
reactions in entries 15-17 of Table 2 and for many helpful
discussions.
>98
>98
96
9
10e
97
a Reactions at 22 °C performed under N2 in the absence of solvent.
b-d See Table 3. e Reaction performed with 5 equiv of the cross partner,
and catalyst was added in two batches (see the Supporting Information for
details). nd ) not determined
Supporting Information Available: Experimental pro-
cedures and spectral data for products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(see Table 3), such transformations cannot be performed with
Mo alkylidenes due to the free hydroxyl group. As the
observations in Table 4 indicate, Ru-catalyzed AROM/CM
reactions with electron-deficient (entries 3-4, 7, and 10) as
well as electron-rich (entries 8 and 9) substituents proceed
readily and with high enantioselectivity (96% to >98% ee).
The facile reactions shown in entries 5 and 6, involving
sterically hindered o-methylstyrene, are noteworthy. Com-
parison of data in entries 1-2, 3-4, 5-6, and 8-9 further
indicates that first-generation Ru catalyst 1a is superior to
complex 2a in promoting such processes.
OL071008H
(16) For another class of chiral Ru catalysts (monodentate NHC), see:
(a) Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org. Lett. 2001, 3, 3225-
3228. (b) Funk, T. W.; Berlin, J. M.; Grubbs, R. H. J. Am. Chem. Soc.
2006, 128, 1840-1846. These catalysts have thus far proven to be less
effective in promoting AROM/CM (1.4-1:1 E:Z, 33-80% ee); see: (c)
Berlin, J. M.; Goldberg, S. D.; Grubbs, R. H. Angew. Chem., Int. Ed. 2006,
45, 7591-7595.
(17) For a discussion regarding the effect of competing methylidene
complexes on catalytic AROM/CM reactions, see: La, D. S.; Sattely, E.
S.; Ford, J. G.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2001,
123, 7767-7778.
(18) Giudici, R. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2007, 129, 3824-
3825.
This study furnishes the first comparative study of chiral
Ru- and Mo-based catalysts in promoting a useful class of
2874
Org. Lett., Vol. 9, No. 15, 2007