An efficient protocol for the cross-metathesis of sterically demanding olefins

Article abstract of DOI:10.1021/ol401194h

Cross-metathesis of a wide range of previously unreactive, sterically demanding alkenes can be achieved in fair to excellent yield using a commercially available catalyst by a facile strategy involving reversal of steric preference.

Full text of DOI:10.1021/ol401194h

ORGANIC
LETTERS
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Vol. XX, No. XX
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An Efficient Protocol for the
Cross-Metathesis of Sterically
Demanding Olefins
Zhen J. Wang, W. Roy Jackson, and Andrea J. Robinson*
School of Chemistry, Monash University, Clayton 3800, Victoria, Australia
Andrea.Robinson@monash.edu
Received April 28, 2013
ABSTRACT
Cross-metathesis of a wide range of previously unreactive, sterically demanding alkenes can be achieved in fair to excellent yield using a
commercially available catalyst by a facile strategy involving reversal of steric preference.
Ruthenium alkylidene catalyzed cross-metathesis (CM)
has been used as an efficient CdC bond forming reaction
in many syntheses.1 To date, however, CM of sterically
demanding substrates remains a challenge. In particular,
one class of alkenes that possesses 1,1-disubstitution and
allylic branching, generically depicted by structure 1, per-
forms poorly in CM reactions (Figure 1a). A literature
survey of CM reactions involving this olefin subclass2
reveals that only a few ring strained examples lead to
viable reaction yields using Ru-alkylidene catalysts 2À4
(Figure 1b).2d,3 Hence, this olefin class regularly falls into
the type IV classification, namely as spectators to CM,4
and appear to be beyond the scope of existing, commer-
cially available catalysts such as 2À4. In order to address
this deficiency, catalysts designed with decreased steric
crowding around the Ru-center, such as 4, have been in-
vestigated but success to date has been limited (Figure 1b).2b,5
Herein, we report a facile methodology to perform effi-
cient CM reactions involving sterically challenging cross
(1) (a) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751–
1753. (b) Blackwell, H. E.; O’Leary, D. J.; Chatterjee, A. K.; Washenfelder,
R. A.; Bussmann, D. A.; Grubbs, R. H. J. Am. Chem. Soc. 2000,
122, 58–71. (c) Sanford, M. S.; Ulman, M.; Grubbs, R. H. J. Am. Chem.
Soc. 2001, 123, 749–750. For a review, see: (d) Connon, S. J.; Blechert, S.
Angew. Chem., Int. Ed. 2003, 42, 1900–1923. (e) Handbook of Metath-
esis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003. (f)
Vougloukalakis, G. C.; Grubbs, R. H. Chem. Rev. 2010, 110, 1746–1787.
(g) Prunet, J.; Grimaud, L. Cross-metathesis in Natural Products
Synthesis. In Metathesis in Natural Product Synthesis: Strategies, Sub-
strates and Catalysts; Cossy, J., Arseniyadis, S., Meyer, C., Eds.;
Wiley-VCH: Weinheim, Germany, 2010; pp 287À312.
(2) (a) Lee, M. J.; Lee, K. Y.; Lee, J. Y.; Kim, J. N. Org. Lett. 2004, 6,
3313–3316. (b) Stewart, I. C.; Douglas, C. J.; Grubbs, R. H. Org. Lett.
2008, 10, 441–444. (c) Barile, F.; Bassetti, B.; D’Annibale, A.; Gerometta,
R.; Palazzi, M. Eur. J. Org. Chem. 2011, 6519–6526. (d) Plummer, C. W.;
Soheili, A.; Leighton, J. L. Org. Lett. 2012, 14, 2462–2464.
Figure 1. Difficult CM reactions. (a) Generic structure of un-
reactive CM substrates. (b) Example of poor yields observed for
CM reactions involving olefins with general structure 1.
(3) Raju, R.; Howell, A. R. Org. Lett. 2006, 8, 2139–2141.
(4) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 11360–11370.
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10.1021/ol401194h
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hindered olefinic substrate 6 disfavors the formation of
the 1,2-metallocyclobutane 9 and, therefore, results in a
poor yield of 8.10,11 The reason for the poor reactivity was
initially unclear to us. The sterically hindered olefin 6 could
be acting predominantly as a spectator, or the reaction
could be preferentially cycling through the nonproductive
intermediate 10. Both of these explanations would result in
low conversion of the starting materials. Furthermore, a
secondary catalytic cycle involving the self-metathesis of
allylglycine 5 to give byproduct 7 also competes with the
process of the desired CM reaction (Scheme 1). As a result,
despite catalyst turnover, only small quantities of the
desired cross product 8 are generated.
Scheme 1. Catalytic Pathways for the CM Reaction between
5 and 66
In order to acertain whether the metathesis reaction was
cycling through the nonproductive intermediate 10, a
deuterium-labeled crossover experiment was conducted
(Scheme 2). CM between allylglycine derivative 5 and the
Scheme 2. Deuterium Crossover Experiment for CM Reaction
between 5 and 11
partners conforming to the general structure 1 using com-
mercially available catalyst 3. Our study began with an in-
depth analysis of a representative reaction between 5 and 6
(Scheme 1). The reaction gave starting material 5 as a
mixture of regioisomers (38% combined yield),7,8 the
dimer 7 (55%), and the desired cross product 8 in only
7% isolated yield. A possible explanation for the observed
product distribution can be provided by examining the
productive and nonproductive metathesis pathways within
the catalytic cycle (Scheme 1). These pathways are char-
acterized by the intermediate metallocyclobutanes 9 and
10.9 The 1,2-metallocyclobutane 9 can ring open in a
productive fashion to give the desired cross product 8,
whereas the 1,3-metallocyclobutane 10 can only un-
dergo nonproductive Ru-alkylidene exchange reactions.
We hypothesized that the steric bulk imposed by the
dideutero-cross partner 11 was performed under identical
reaction conditions to those depicted in Scheme 1. This
resulted in a mixture of dideutero-crossover product 12,
isomerized analogues 13 and 14, and isomerized starting
material 5b.12 Subsequent hydrogenation of the mixture
gave the expected deuterium-labeled compound 15 and
15b in a 46% combined yield as a 1:1 mixture. Exclusive
deuterium incorporation was observed at the C5 position,
and the label did not scramble despite the isomerization
process. This crossover experiment therefore supports the
formation of the nonproductive 1,3-metallocyclobutane
intermediate 10 during the CM reaction between 5 and
6.13 More importantly, these results show that the catalyst
3 is reactive toward sterically hindered olefins such as 6 but
almost exclusively in a nonproductive fashion. This result
(5) (a) Bieniek, M.; Bujok, R.; Cabaj, M.; Lugan, N.; Lavigne, G.;
Arit, D.; Grela, K. J. Am. Chem. Soc. 2006, 128, 13652–13653. (b)
Chung, C. K.; Grubbs, R. H. Org. Lett. 2008, 10, 2693–2696. (c) Kuhn,
K. M.; Bourg, J. B.; Chung, C. K.; Virgil, S. C.; Grubbs, R. H. J. Am.
€
Chem. Soc. 2009, 131, 5313–5320. (d) Vorfalt, T.; Leuthauβer, S.; Plenio,
H. Angew. Chem. 2009, 121, 5293–5296.
(6) It should be noted that an alternative pathway to product 8 exists
via reaction of intermediate 16 with 5.
(7) During CM, concomitent isomerization of 5, but not 6, is
observed. The resultant internal C2 and C3 olefins do not undergo
CM under the reaction conditions employed.
~
(8) (a) McNaughton, B. R.; Bucholtz, K. M.; Camaano-Moure, A.;
Miller, B. L. Org. Lett. 2005, 7, 733–736. (b) Hong, S. H.; Sanders, D. P.;
Lee, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2005, 127, 17160–17161.
(9) (a) Crowe, W. E.; Zhang, Z. J. J. Am. Chem. Soc. 1993, 115,
10998–10999. (b) Stewart, I. C.; Keitz, B. K.; Kuhn, K. M.; Thomas,
R. M.; Grubbs, R. H. J. Am. Chem. Soc. 2010, 132, 8534–8535. (c)
Wenzel, A. G.; Blake, G.; VanderVelde, D. G.; Grubbs, R. H. J. Am.
Chem. Soc. 2011, 133, 6429–6439.
(10) To further support this steric argument, the nor-methyl analo-
gue of 6, methylenecyclohexane, can undergo CM with 5 in 98% isolated
yield. The dramatic difference in yield arising from CM of methylene-
cyclohexane and 6 under identical experimental conditions can only be
attributed to the steric crowding imposed by the methyl group in the
allylic position of 6.
(11) Up to eight possible diastereoisomers of 9 (and 10) could be
formed during the CM reaction. The reaction equilibrium, however,
would favor the formation of diastereoisomers of 10 over diastereo-
isomers of 9 to avoid adverse steric interaction.
(12) The dimer 7 and trace amounts of cross product 8 (<5%) were
also isolated.
(13) Whilst it is possible to also obtain 15 via the productive pathway,
the observed level of deuterium incorporation (46%) exceeds the
theoretical yield via this pathway (5%).
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also supports the formation of the intermediate 16 in a
system where more reactive olefins such as 5 and 7 are
present (Scheme 1).
Scheme 3. Catalytic Pathways for the CM Reaction between 17
and 6
Following from this experiment we hypothesized that
strategies which promoted cycling through the productive
1,2-metallocycle, rather than increasing catalyst reactivity,
would be more successful in achieving efficient CM. To-
ward this end, we investigated the effect of adding addi-
tional substitution to the reactive type I cross partner. The
addition of two terminal methyl groups to olefin 5 gen-
erates the trisubstituted olefin 17 and causes steric reversal
within the molecule; that is, the terminus of the olefin
becomes more sterically encumbered (Figure 2).14,15 We
postulated that this key structural alteration would reorient
olefin binding at the ruthenium center and promote formation
of a productive metallocyclobutane over a nonproductive
metallocyclobutane. Importantly, the same product would
be generated from the terminal alkene (e.g., 5) and its
prenylated derivative (e.g., 17) following the CM reaction.
The scope of this approach was explored via the CM of
the geminal dimethyl analogues 17 and 20 with hindered
exocyclic and aliphatic olefins of the generic structure 1
bearing increasing steric bulk in the vicinity of the reacting
olefin (Figure 3). Each of these reactions was first per-
formed with the corresponding unsubstituted, terminal
equivalents of 17 and 20 (i.e., 5 and pent-4-en-1-yl acetate
respectively), and in every case, nonviable yields of the desired
cross product were obtained (Figure 3, entries in parentheses
(0À17% yield)). Similarly, the crotylglycine derivative 21
also failed to react with 6 to generate the target product 8
(Scheme 4). In conclusion, trisubstituted olefins are required
to facilitate the steric reversal, and prenylation of terminal
olefins readily accomplishes this end.
Gratifyingly, the geminal dimethyl analogue 20 reacted
with a hindered exocyclic and functionalized aliphatic
olefin to provide cross products 22 and 23 in excellent
yield (90and 87% respectively). A direct comparison of the
yield obtained for compound 22 with previous results
summarized in Figure 1b shows the significant improve-
ment in the CM efficiency. A regioselective CM was also
achieved between R-benzyl methylenecyclohexane and
geranyl acetate to give 24 in 53% yield (Figure 3).17
The use of the prenylglycine analogue 17 also led to
synthetically viable CM yields with various hindered ole-
finic cross partners (compounds 8 and 25À32, Figure 3).
Unavoidably, in all cases except compounds 28 and 29, an
inseparable mixture of E- and Z-isomers was obtained.
Additionally, in the cases where racemic cross partners
were used (compounds 8, 25, 26, and 32), a mixture of
epimers was obtained. Compounds 28 and 29, on the other
hand, were obtained as single stereoisomers possessing the
Figure 2. Comparison of relative steric demand in 5 and 17
showing steric reversal across the alkene bond.
To examine this hypothesis, the CM of the prenylglycine
derivative 17 with 6 was performed under identical reac-
tion conditions to those previously described (Scheme 3).
This time, however, the elusivecross product8 was isolated
in 55% yield. Notably, the previously observed isomeriza-
tion was eliminated when using the prenylated analogue
17. Furthermore, the required product 8 was not accom-
panied by the dimer 7. This result is consistent with
previous work by us showing that under analogous me-
tathesis conditions prenylglycine does not self-dimerize.16
Hence, the steric reversal modification promotes cycling
through the previously disfavored productive pathway
(that is, cycling through 18 is now favored over 19). In
conclusion, with this simple structural modification, the
synthesis of 8 could finally be achieved using an unmodified,
commercially available catalyst 3 at a 5 mol % loading.
(14) Chatterjee, A. K.; Sanders, D. P.; Grubbs, R. H. Org. Lett. 2002,
4, 1939–1942.
(15) Transformation of terminal olefins into trisubstituted analogues
is readily achieved via CM with isobutylene or 2-methyl-2-butene.
(16) Robinson, A. J.; Elaridi, J.; Patel, J.; Jackson, W. R. Chem.
Commun. 2005, 5544–5545.
(17) (a) BouzBouz, S.; Simmons, R.; Cossy, J. Org. Lett. 2004, 6,
3465–3467. (b) Bilel, H.; Hamdi, N.; Zagrouba, F.; Fischmeister, C.;
Bruneau, C. Green Chem. 2011, 13, 1448–1452.
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Scheme 4. Attempted Screening for an Alternative Cross Partner
E-configuration (determined by NOESY experiments) in
71% and 43% yield respectively.
Pleasingly, several highly hindered terpenes, such as
β-pinene, camphene, and methylenecamphor, also partici-
pated in productive catalyst turnovers, albeit in lower
yield, to generate olefins 30À32 respectively.17,18 The limit
of this steric reversal strategy was finally reached when a
highly hindered cross-coupling partner, a tetra-allylic sub-
stituted methylenefenchone derivative, was employed
(compound 33, Figure 3).
In all cases, the desired cross product was the only olefin
generated in each of these reactions; the presence of tetra-
substituted olefins was undetected under the new reaction
conditions suggesting that the active metathesis catalyst was
unable to cycle via the nonproductive intermediate (such
as 19). In each of the reactions, excess starting material was
recovered unchanged and in high yield (90À95%) upon
completion of the reaction for recycling in subsequent reac-
tions. Attempts were made to lower the equivalents of the
excess cross partner; however a decline in yield was observed.
In conclusion, previous work by others has shown that
CM of sterically demanding 1,1-disubstituted, allylic
branched olefins under Ru-alkylidene catalysis is challen-
ging. Close examination of the catalytic cycle of these
substrates has enabled us to achieve viable CM yields with
these olefins using second generation HoveydaÀGrubbs
catalyst (3) via a steric-reversal strategy driven by minor
modification of the starting type I olefin. This work there-
fore extends the scope of this already remarkable catalyst
and facilitates the expedient synthesis of highly substituted
and functionalized olefins. This CM approach is currently
being exploited for the synthesis of tricyclic marine alkaloids.
Figure 3. Scope of CM reaction involving hindered olefins.
Acknowledgment. The authors wishtoacknowledgethe
financial support of the Australian Research Council
and the award of a postgraduate research award to Z.J.W.
The authors acknowledge Nicolas D. Spiccia (Monash
University) for prior contributions and discussions.
Supporting Information Available. Experimental pro-
cedures, characterization, and spectral data. This materi-
al is available free of charge via the Internet at http://
pubs.acs.org.
(18) The cross partners used to synthesize 31 and 32 were generated
from camphor and fenchone, respectively, using forcing Wittig olefina-
tion reaction conditions.
The authors declare no competing financial interest.
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