Desymmetrizations forming tetrasubstituted olefins using enantioselective olefin metathesis

Article abstract of DOI:10.1021/ol100511d

Figure presented Highly reactive chiral Ru-based catalysts possessing C₁-symmetric N-heterocyclic carbene ligands adorned with one N-alkyl group and one N-aryl group were evaluated in asymmetric desymmetrizations to form cyclic products possess

Full text of DOI:10.1021/ol100511d

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2032-2035
Desymmetrizations Forming
Tetrasubstituted Olefins Using
Enantioselective Olefin Metathesis
Brice Stenne,† Justin Timperio,‡ Jolaine Savoie,† Travis Dudding,*,† and Shawn
K. Collins*,‡
Department of Chemistry, UniVersite´ de Montre´al, C.P. 6128 Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7, and Department of Chemistry, Brock UniVersity,
St. Catharines, Ontario, Canada LS2 3A1
shawn.collins@umontreal.ca; tdudding@brocku.ca
Received March 1, 2010
ABSTRACT
Highly reactive chiral Ru-based catalysts possessing C1-symmetric N-heterocyclic carbene ligands adorned with one N-alkyl group and one
N-aryl group were evaluated in asymmetric desymmetrizations to form cyclic products possessing a tetrasubstituted olefin.
Among the current challenges in the field of olefin metath-
esis, both the synthesis of tetrasubstituted olefins, and the
development of asymmetric processes have recently received
increasing attention.1 Although Herrmann and co-workers
reported the use of catalyst 1c to promote cyclizations to
form tetrasubstituted olefins almost 10 years ago,2 the
challenges associated with this transformation have recently
led to new catalyst developments.3 Some of the recent
developments include the phosphine-containing catalyst 1a3b
in which a modified NHC ligand (compared to parent
catalysts 1b and 1c4) has been exploited to improve reac-
tivities (Figure 1, top). Different Hoveyda-type catalysts
bearing modified benzylidenes and NHC ligands (including
2a,2 2b, 2c,5 and 2d2) have also shown the propensity to
effect the ring-closing metathesis of methallyl-substituted
dienes to afford tetrasubstituted olefins to some degree
(Figure 1, top).6,7 Recently, our group reported the synthesis
of new chiral Ru-based catalysts bearing C1-symmetric NHC
ligands (Figure 1, bottom).8 The corresponding catalysts were
(4) (a) Huang, J.; Schanz, H.-J.; Stevens, E. D.; Nolan, S. P. Organo-
metallics 1999, 18, 2370–2375. (b) Clavier, H.; Nolan, S. P. Chem.sEur.
J. 2007, 13, 8029–8036. (c) Clavier, H.; Blanco, C. A.; Nolan, S. P.
Organometallics 2009, 28, 2848–2854.
† Universite´ de Montre´al.
‡ Brock University.
(1) For recent reviews on asymmetric olefin metathesis, see: (a) Hoveyda,
A. H. In Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, Germany, 2003; Vol. 2,Chapter 2.3. (b) Schrock, R. R.; Hoveyda,
A. H. Angew. Chem., Int. Ed. 2003, 42, 4592–4633. (c) Hoveyda, A. H.;
Schrock, R. R. Chem.sEur. J. 2001, 7, 945–950. See also: (d) Hoveyda,
A. H.; Zhugralin, A. R. Nature 2007, 450, 243–251.
(5) Chung, C. K.; Grubbs, R. H. Org. Lett. 2008, 10, 2693–2696.
(6) (a) Gatti, M.; Vieille-Petit, L.; Luan, X.; Mariz, R.; Drinkel, E.;
Linden, A.; Dorta, R. J. Am. Chem. Soc. 2009, 131, 9498–9499. For a
stucturally similar catalyst as 6a, see: (b) Rost, D.; Porta, M.; Gessler, S.;
Blechert, S. Tetrahedron Lett. 2008, 49, 5968–5971. (c) Vorfalt, T.;
(2) Ackermann, L.; Furstner, A.; Weskamp, T.; Kohl, F. J.; Herrmann,
W. A. Tetrahedron Lett. 1999, 40, 4787–4790.
Leutha¨uꢀer, S.; Plenio, H. Angew. Chem., Int. Ed. 2009, 48, 5191–5194.
(7) Backbone substitution of the NHC has also been studied with regard
to tetrasubstituted olefin synthesis, see: Kuhn, K. M.; Bourg, J.-B.; Chung,
C. K.; Virgil, S. C.; Grubbs, R. H. J. Am. Chem. Soc. 2009, 131, 5313–
(3) (a) Vougioukalakis, G. C.; Grubbs, R. H. Chem. ReV. 2010, 110,
1746–1787. (b) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs,
R. H.; Schrodi, Y. Org. Lett. 2007, 9, 1589–1592.
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10.1021/ol100511d  2010 American Chemical Society
Published on Web 03/25/2010

isolated as mixtures of syn/anti isomers,9,10 were highly
reactive, and produced high enantioselectivities in the
desymmetrization of meso-trienes without the need for halide
additives.11a Herein, we report on the first asymmetric
desymmetrizations via ring closing metathesis that form
tetrasubstituted olefins using catalysts bearing chiral C1-
symmetric NHC ligands.
10a was conducted (Table 1).13 When diene 10 was subjected
to catalyst 3 and 5 at 30 °C in CH2Cl2 for 12 h, only 34%
and 55% conversion, respectively, to 10a were observed.
Table 1. RCM To Form Tetrasubstituted Olefin 10a
entry catalyst convna (%) entry catalyst convna (%)
1
2
3
3b
5b
6b
34
55
84
4
5
6
7
8
9
0
63
38
a Determined by 1H NMR of crude reaction mixture. b Reaction
concentration ) [0.055].
Catalysts 8 and 9 afforded 63% and 38% conversions of
10 after 12 h. Catalyst 7 showed only a negligible cyclization
of 10 and was clearly inferior to the analogous catalyst 5
(55% conversion after 12 h). Gratifyingly, catalyst 6 showed
an improved conversion of 10 (84%) when compared with
3 (34%) after 12 h. To put the above results in context,
catalysts 3-9 can effectively promote ring-closing metathesis
cyclizations to form 10a and various other tetrasubstituted
olefins.14 With these results in hand, we decided to proceed
to investigate the asymmetric desymmetrization to form
tetrasubstituted olefins using the Ru-based catalysts 3-9.
The evaluation of catalysts bearing C1-symmetric NHC
ligands (3-9) in promoting the enantioselective cyclization
of a series of meso-trienes is summarized in Table 2. The
series of meso-trienes were chosen to study various aspects
of substrate scope including olefin geometry, cyclizations
onto 1,1-disubstituted olefins versus 1,1,2-trisubstituted ole-
fins, olefin substitution patterns, and ring size (five- or six-
membered rings). It should be noted that all the catalysts
bearing C1-symmetric ligands were isolated as mixtures of
syn and anti isomers. Catalyst 9 was the only catalyst isolated
in which a slight separation of the syn and anti isomers was
possible by silica gel chromatography. As such, the cycliza-
tion of the various meso-trienes were also studied using a
sample of catalyst 9 in which the syn isomer was the major
isomer (1:0.7 syn:anti) and a sample in which the anti isomer
is the major isomer (9anti, 1:8 syn:anti).15
Figure 1. (Top) Olefin metathesis catalysts. (Bottom) Chiral Olefin
Metathesis Catalysts Bearing C1-symmetric NHC ligands.
At the outset of our study, it was reasoned that desym-
metrization via asymmetric ring-closing metathesis,11,12 to
form tetrasubstituted olefins would be more challenging than
desymmetrizations to form trisubstituted olefins in terms of
conversion and enantioselectivity. When considering the
former, the meso-trienes used for the desymmetrizations
possess a prochiral carbon adjacent to a reacting olefin and
thus are significantly more sterically demanding than the
typical dienes previously studied in the ring-closing metath-
esis to form tetrasubstituted olefins. Thus, a preliminary study
of the ring closing of 10 to form the tetrasubstituted olefin
(8) (a) Fournier, P.-A.; Collins, S. K. Organometallics 2007, 26, 2945–
2949. (b) Fournier, P.-A.; Savoie, J.; Be´dard, M.; Stenne, B.; Grandbois,
A.; Collins, S. K. Chem.sEur. J. 2008, 14, 8690–8695
.
(9) Throughout this paper, syn refers the N-alkyl group of the NHC
ligand being on the same side as the Ru carbene. Isomer mixtures for
catalysts 4, 5, and 7-9 were inseparable by silica gel chromatography. After
repeated attempts, partial separation of the syn/anti isomers of catalyst 9
was possible.
When the meso-triene 11 was treated with catalyst 3 or 5,
excellent conversions were obtained (>95%); however, low
enantiomeric excesses (ee’s) were observed (8% and 38%,
(10) For a discussion of carbene lifetimes, see: Ulman, M.; Grubbs, R. H.
J. Org. Chem. 1999, 64, 72037207.
.
(13) For a full comparison of the ring closing of 10 with other Ru-
based catalysts, see the Supporting Information.
(14) See the Supporting Information for a list of other five- and six-
membered rings containing tetrasubstituted olefins that were cyclized using
catalysts 3-9.
(15) Catalysts 3-9 were all heated in an NMR tube in toluene-d8 to
60 °C. Catalysts 3-5 rapidly decompose, while catalysts 6-9 are stable
for up to 4 h before the solution slowly darkened and the benzylidene peaks
in the 1H NMR slowly began to decrease in intensity. In addition, 2D EXSY
experiments of catalysts 6-9 conducted in NMR tubes in toluene-d8 at 40
or 50 °C revealed no rotation of the NHC in the precatalyst.
(11) For examples of desymmetrizations : (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. (c) Berlin,
J. M.; Goldberg, S. D.; Grubbs, R. H. Angew. Chem., Int. Ed. 2006, 45,
7591–7595
.
(12) For examples in tandem ring-opening/cross-metathesis processes:
(a) 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. (b) Van Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.;
Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 6877–6882
.
Org. Lett., Vol. 12, No. 9, 2010
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than with catalyst 9. When the triene 12 was cyclized with
9, the conversion was low (33%), but a 61% ee of the product
was obtained. When the cyclization of triene 12 was
attempted with catalyst 9anti a low ee (26%) was observed,
although a higher conversion (76%, 52% yield) to the
corresponding tetrasubstituted olefin 12a was observed in
comparison with catalyst 9.
Table 2. ARCM Desymmetrization Reactions Forming
Tetrasubstituted Olefins
In light of these results, we investigated whether high
conversions and enantioselectivities could be obtained using
triene 13, in which the geometry of the double bonds is
changed with respect to triene 11. When triene 13 was treated
with catalyst 9anti, the product was again obtained in good
ee (71%) and in moderate conversion (50%). These results
are similar to what was observed in the desymmetrization
of trienes 11 and 12. Ring closing of triene 13 with catalyst
5 gave excellent conversion (>95%, 84% yield) but poor ee
(31%). Catalyst 8 provided the five-membered ring product
13a in 56% ee and in excellent conversion (>95%, 67%
isolated yield). The above results demonstrate that the
terminal Me group in trienes 11-13 affect both the conver-
sion and the observed enantioselectivity in the cyclizations.
We then attempted to cyclize the more challenging
substrates, trienes 14 and 15, to afford the corresponding
products 14a and 15a. Almost all cyclizations to form
tetrasubstituted olefins to date have formed an olefin with
two Me groups as substituents,17 and no cyclizations to form
tetrasubstituted olefins bearing both a Me and Et group have
been reported. While 8 afforded only traces of the desired
product 14a in low ee (6%), 9anti gave a 46% conversion
of 14, albeit in low ee (12%). Given that the cyclization onto
the Et-substituted olefins of 14 was difficult to achieve, we
next investigated the cyclizations of triene 15 in which the
Et-substituted olefin is expected to react first with the catalyst.
Cyclization using the standard conditions provided only
traces of the desired product. However, rapid heating using
microwave irradiation proved helpful.18 Treating 15 with
catalyst 9anti in C6D6 at 100 °C afforded the desired product
15a in 49% conversion and 49% ee after 15 min. The best
ee for a desymmetrization forming a tetrasubstituted olefin
was observed in the cyclizations of a six-membered ring
using the 9anti catalyst. The cyclization of meso-triene 16
afforded the tetrasubstituted olefin 16a in 47% conversion
and 78% ee with catalyst 9anti.
a The absolute configuration of 11a and 12a has been determined (see
the Supporting Information). The configuration of the remaining products
is assumed on the basis of 11a and previous desymmetrizations of
meso-trienes. b Conversion determined by 1H NMR spectrum of crude
reaction mixture. Yields are following purification via silica gel chroma-
tography. The products are volatile and yields can sometimes vary greatly.
c The ee is an estimate, due to a irremovable impurity. See the Supporting
Information. d A second portion of catalyst (2.5 mol %) was added after 10
min. MW ) microwave irradiation.
The results obtained with catalyst 9 and 9anti in the
desymmetrizations demonstrate the importance of under-
standing the origin of enantioselectivity in catalysts possess-
ing C1-symmetric NHC ligands. As such, we performed
preliminary DFT calculations using Gaussian 03 in order to
(16) The influence of perfluorinated solvents on challenging RCM
reactions has been documented. Samojlowicz, C.; Bieniek, M.; Zarecki,
A.; Kadyrov, R.; Grela, K. Chem. Commun. 2008, 47, 6282–6284.
Curiously, when 11 was treated with 5 in C6F6, identical conversions were
obtained but the ee decreased from 38% to 0%.
(17) For traditional tetrasubstituted olefins bearing two Me groups, see:
Berlin, J. M.; Campbell, K.; Ritter, T.; Funk, T. W.; Chlenov, A.; Grubbs,
R. H. Org. Lett. 2007, 9, 1339–1342. (b) For an example of a tetrasubstituted
olefin formed with a Cl and a Me substituent, see: White, D. E.; Stewart,
I. C.; Grubbs, R. H.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 810–811.
(18) Microwave heating was not used for the other substrates. For an
example of microwave-assisted RCM, see :Collins, S. K.; Grandbois, A.;
Vachon, M. P.; Coˆte´, J. Angew. Chem., Int. Ed. 2006, 45, 2923–2926.
respectively). Catalysts 6 and 7 afforded mediocre ee’s (43
and 54%, respectively), although catalyst 7 (60% conv, 42%
yield) was again less reactive than 6 (95% conv, 82% yield).
Catalysts 8 and 9 also afforded similar results, (52 and 50%
ee, respectively).16
Interestingly, the best ee for cyclizations of 11 was
observed using the catalyst 9anti (59% ee), although the
conversion to heterocycle 11a (46%) was significantly less
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Org. Lett., Vol. 12, No. 9, 2010

gain a deeper insight into the enantiodescriminating transi-
tion-state structures responsible for asymmetric ring closure
of meso-triene 11 with catalyst 9. In this vein, the ONIOM19
(Our Own N-Layered Integrated Molecular Orbital + Mo-
lecular Mechanics Method) theoretical approach at the HF20/
LANL2MB:21UFF22 level was employed for initial optimi-
zation of transition state structures, followed by the
implementation of single-point B3LYP23/LANL2DZ calcula-
tions to gain more accurate final energies (i.e., B3LYP/
LANL2DZ//HF/LANL2MB:UFF) (Figure 2). Gratifyingly,
these calculations lead to the location of enantiodetermining
TS-9-S and TS-9-R, corresponding to the respective transition
states responsible for the formation of the major S- and minor
R-enantiomeric products observed experimentally.24 The
predicted energetic difference between these two first order
saddle points was computed to be 0.91 kcal/mol, which
corresponds to a predicted ee of 65%. It is worth noting that
this computed energetic difference, comparatively speaking,
is a value well in line with the experimentally observed ee
of 50%.
Perhaps the most interesting geometrical difference be-
tween the two transition states is where the alkylidene is
placed with respect to the substituents on the NHC ligand.
In TS-9-S, the ring closing event takes place “underneath”
the N-Bn substituent of the NHC ligand. Consequently, the
alkylidene resides underneath the N-Bn group and the pro-S
olefin of the substrate beneath the aryl group. Inspection of
TS-9-S and TS-9-R suggests that a predominant factor
contributing to enantioselectivity is the position of the
alkylidene with respect to the NHC ligand. In the former,
the alkylidene resides “beneath” the aryl group, placing a
methyl hydrogen on the prochiral olefin within 2.49 Å of
the tert-butyl moiety. In the latter, the alkylidene is beneath
the N-Bn group and thus brings the t-Bu group within 2.29
Å of the furan methylene hydrogens; this creates van der
Waals repulsions that raise the energy of the TS enough for
the reaction to favor one stereochemical outcome over the
other. It is possible then that the observed differences
between 9 and 9anti are due to the rotational barrier of the
Figure 2. Transition states (TS) for the ring-closing of meso-triene
11 with catalyst 9. (Top) TS calculated for the major enantiomer.
(Bottom) TS calculated for the minor enantiomer. (S)-TS is 0.91
kcal/mol less in energy than (R)-TS.
NHC ligand at various points of the catalytic cycle, and
computational investigations are being continued in hopes
of unveiling such mechanistic nuances.
In summary, the cyclization to produce tetrasubstituted
olefins is possible using Ru-based olefin metathesis catalysts
bearing chiral C1-symmetric NHC ligands with small N-alkyl
groups such as n-Pr or Bn. In addition, the desymmetrization
of meso-trienes to afford tetrasubstituted olefins afforded five-
membered rings with up to 71% ee and six-membered rings
with up to 78% ee. Computational studies suggest a new
model for the origin enantioinduction in the formation of
the major enantiomer via desymmetrization. We continue
to study new enantioselective processes through the use of
these catalysts; we aim to gain a better understanding of the
importance of ligand dynamics through molecular modeling.
(19) Dapprich, S.; Komiromi, I.; Byun, K. S.; Morokuma, K.; Frisch,
M. J. THEOCHEM 1999, 461-462, 1–21.
Acknowledgment. We thank the NSERC (Canada),
FQRNT (Que´bec), CFI (Canada), Boehringer Ingelheim
(Canada) Ltd., Merck Frosst Centre for Therapeutic Re-
search, and the Universite´ de Montre´al for generous financial
support. We thank Prof. R. H. Grubbs and Dr. I. C. Stewart
(Caltech) for a sample of 2a.
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Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(24) It should be noted that although only the two lowest energy
transition states are shown here, a total of 96 geometrically distinct transition
structures were considered, including the enantiomorphic TSs of those shown
in Figure 2. See Table S1 in the Supporting Information for the energetic
data for all TSs examined.
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