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Relay Ring-Closing MetathesisЧA Strategy for Achieving Reactivity and Selectivity in Metathesis Chemistry.

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Highlights
Synthetic Methods
Relay Ring-Closing Metathesis—A Strategy for
Achieving Reactivity and Selectivity in Metathesis
Chemistry
Debra J. Wallace*
Keywords:
alkenes · cyclization · dienynes · metathesis ·
ruthenium
The power of metathesis chemistry in
organic synthesis is undeniable. Over
the past ten years technology has developed to promote ring-closing, ringopening, and cross metathesis reactions.[1] In particular, ring-closing reactions using the air-stable, commercially
available ruthenium alkylidene catalysts
such as 1,[2] 2,[3] and 3[4] have achieved
widespread use to promote a range of
cyclizations (Scheme 1). Alkenes, al-
of methods to overcome these shortcomings is ongoing in many laboratories,
and relay RCM is one such recent
development.
Historically, products that proved
difficult to access via RCM using the
first generation catalyst 1 were tetrasubstituted alkenes such as 4 (Scheme 2).
Scheme 2. A well-known difficult process: the
sythesis of tetrasubstituted alkenes by RCM.
Scheme 1. Commercially available ruthenium
alkylidene catalysts. Cy = cyclohexyl,
Mes = 2,4,6-trimethylphenyl.
kynes, and enynes have been used as
substrates and the selective formation of
one or even multiple rings has been
reported in numerous papers. Despite
the many successful applications, in
some instances reactions can still be less
than satisfactory, due to low reactivity
and/or low selectivity. To elevate ringclosing metathesis (RCM) to a universally applicable procedure, development
[*] Dr. D. J. Wallace
Department of Process Research
Merck Sharp and Dohme Research Laboratories
Hertford Road, Hoddesdon, Hertfordshire,
EN11 9BU (UK)
Fax: (+ 44) 199-247-0437
E-mail: debra wallace@merck.com
1912
reaction could proceed.[8] The relay
approach involves incorporation of a
temporary tether containing a sterically
unencumbered olefin for initiation of
the catalytic cycle. The olefin is positioned such that a kinetically favorable
formation of a five-membered ring is
used to deliver the ruthenium onto the
sterically hindered position with concomitant extrusion of the ring. The use
of this method to address such a problem was demonstrated by Hoye et al.,
and is exemplified in Scheme 3.[9] Diene
6 does not undergo cyclization promoted by catalyst 1; however when armed
with the relay moiety, as in compound 7,
the unencumbered terminal alkene became the site for initial reaction with the
catalyst,[10] leading to intramolecular
delivery of the ruthenium onto the
traditionally less accessible position.
The desired ring-closing reaction then
proceeded to give 8.
The application of this principle to
other substrates, many of which would
be unreactive to standard RCM conditions, at least with the originally employed first generation catalyst, has
been carried out by the same research
group.[9] For example, the butenolide 9
can be prepared from either of the
This was largely due to the difficulty of
initiating the catalytic process on either
of the sterically hindered acyclic alkenes
in diene 5.[5] Even with the development
of second-generation catalysts,[6] the formation of some tetrasubstituted olefins
remained elusive,[7] and this provided
one impetus for development of the
relay RCM method.
The rational behind this strategy
rests on the fact that although initiation
of the catalytic cycle between two sterically demanding alkenes as in 5 is a
challenge, the intramolecular reaction
of a ruthenium alkylidene onto such an alkene is attainable, as is
the subsequent reaction of the previously
inaccessible
alkylidene. As such, if a
method was available
to generate the initial
alkylidene in an intramolecular fashion the Scheme 3. Relay RCM to give tetrasubstituted olefins.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200462753
Angew. Chem. Int. Ed. 2005, 44, 1912 –1915
Angewandte
Chemie
starting materials 10 or 11 using catalyst
1 via initial reaction with the terminal
olefins incorporated into the tethers
(Scheme 4). In this instance, the relay
procedure overcame both a steric and an
electronic deactivation, as the intermolecular reaction of catalyst 1 with electron-deficient double bonds cannot usually be achieved, even when they are
unsubstituted.[11]
In some cases, formation of unsubstituted cyclic alkenes can also be challenging if the starting alkenes are substituted. In an interesting approach to a
diastereoselective RCM reaction, Robinson et al. installed a trigger in 12 to
promote initiation of the ring-closing
event via delivery of the ruthenium onto
the desired double bond.[12] This also
ensured that the stereodifferentiating
step was the intramolecular cyclization,
rather than an intermolecular differentiation between two diastereotopic
groups and the catalyst (Scheme 5).
The reaction did not proceed with the
truncated derivative 13, although it is
likely that substrate 14 would have been
a suitable starting material for this
transformation using second-generation
catalysts 2 or 3.
A different reactivity issue may be
encountered when the ruthenium catalyst reacts with an alkene to afford a
particularly stabilized alkylidene, which
then does not react in the subsequent
ring-closing reaction. Such a problem
could be overcome by blocking of the
non-productive site, or by relay activation of the alternate more reactive
position. In a recent synthesis of oximidine II Porco et al. attempted the RCM
of substrates such as 15 (Scheme 6).[13]
In 15, preferential reaction of either
catalyst 1 or 2 with the trans-diene
component afforded a stabilized alkylidene 16 that was unreactive to further
reaction. Blocking of this position by
introduction of substitution, as in 17,
allowed the catalytic cycle to initiate at
the cis-diene and the desired macrocycle
was formed, albeit in modest yield.
However, when this approach was applied to the closely related synthesis of
oximidine III, compound 18 did not give
the desired ring-closed product even
with second-generation catalysts.[14] This
was again attributed to the formation of
the stabilized alkylidene 19, which did
not undergo significant further reaction,
Angew. Chem. Int. Ed. 2005, 44, 1912 –1915
Scheme 4. Use of relay RCM by Hoye et al. to overcome both steric and electronic deactivation.
Scheme 5. Intramolecular differentiation of diastereotopic groups is achieved by using a relay
procedure.
Scheme 6. Synthesis of oximidine III by Porco et al. illustrates the use of relay RCM to avoid
generation of the unproductive alkylidene 19. MOM = methoxymethyl, TBS = tert-butyldimethylsilyl.
suggesting that the vinyl epoxide moiety
was too hindered for satisfactory catalyst interaction even when compared
with a trisubstituted olefin. The problem
was overcome by introduction of a relay
moiety onto the vinyl epoxide side in
compound 20, which allowed delivery of
www.angewandte.org
the ruthenium onto the aforementioned
vinyl epoxide position. The subsequent
ring-closing reaction proceeded smoothly and was more efficient than the
corresponding cyclization in the oximidine II route.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1913
Highlights
A similar strategy has also been used
by Lee et al. to increase reactivity and
yields in cross metathesis reactions
(Scheme 7).[15] The reaction of enyne
21 with alkene 22 afforded the cross
metathesis product 23 in good Z-selectivity but suffered from low yield and
reactivity, (18 h, 34 %). The authors
propose that the initiation site is the
alkene and low reactivity of the conjugated enyne towards the propagating
alkylidene is detrimental to the reaction
progress. To bias the system towards
generation of the conjugated enyne
alkylidene, the tethered substrate 24
was prepared, allowing relay generation
of the previously unattainable alkylidene 25, which was expected to react
more readily with the alkene. Indeed, a
more efficient reaction was now observed (6 h, 64 %). A reduced Z-selectivity was obtained for all substrates
examined when using the relay method,
supporting the proposal that different
reacting species were responsible for the
outcomes.
This work highlights one limitation
of the relay procedure which can arise
when the intramolecular formation of
the five-membered ring to generate the
“difficult” alkylidene is not sufficiently
favorable to take preference over an
alternate intra- or intermolecular reaction. As shown in Scheme 8 reaction of
alkene 26 with 22 afforded 27 rather
than the expected 28, indicating that
cyclization onto the electron-deficient
olefin to give alkylidene 29 was slower
than the competing intermolecular cross
metathesis process.[16]
Selectivity issues can arise in metathesis chemistry when more than one
ring is formed during a ring-closing
process. For example, a key factor in
determining the outcome of dienyne
RCM is the site of initiation of the
catalyst. Controlling this position can
aid in achieving the desired product.[17]
In Scheme 9, substrate 30 afforded a 1:1
mixture of products 31 and 32 on treatment with 2, due to non-discriminatory
interaction of the catalyst with either of
the unhindered terminal olefins.[18] In
many cases this lack of selectivity can be
addressed by biasing the initial reaction
by introduction of either steric hindrance or electronic deactivation on
one olefin. In the above example, compound 33 afforded a 6:1 mixture of
1914
Scheme 7. Different propagating species lead to differing reactivities and selectivities in a cross
metathesis reaction. Bn = benzyl.
Scheme 8. Cross metathesis with alkene 22 takes place in preference to the intramolecular ringclosing reaction.
Scheme 9. The outcome of a dienyne metathesis can be influenced by biasing the site of catalyst interaction.
31:32; other examples of controlling
dienyne metathesis in this way
abound.[19]
An alternative strategy for controlling the outcome of dienyne metathesis
is the introduction of a relay moiety to
direct the initial reaction of the catalyst.[9] As shown in Scheme 10, the
dienyne 34 gave a 1:2 ratio of 35:36
when treated with catalyst 2. However,
the relay substrates 37 or 38 gave ratios
of 1:7 and 5:1, respectively, when using
the same catalyst and near total selectivity with the less reactive first-gener-
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
ation catalyst 1. Given that the olefins in
this substrate are substituted the alternate strategy of introducing a blocking
group to either of the alkenes, such as in
39, would probably have led to low
reactivity, although some directionality
might have been achieved.
In conclusion, relay RCM has recently been developed as a method to
overcome both reactivity and selectivity
issues in metathesis chemistry. The installation of a “tether” containing a
reactive alkene has provided a mechanism to replace challenging intermolecAngew. Chem. Int. Ed. 2005, 44, 1912 –1915
Angewandte
Chemie
[9]
[10]
[11]
Scheme 10. Use of the relay procedure to control dienyne metathesis.
ular reactions between commonly used
alkylidene catalysts and electronically
or sterically deactivated alkenes, with
favorable intramolecular variants. This
has allowed previously unattainable
transformations to be realized, and also
provided a mechanism for controlling
the outcome of dienyne cyclizations.
Given the relative ease of synthesis of
the relay substrates it seems likely that
further examples of this strategy will
continue to emerge in this field.
Published online: February 2, 2005
[2]
[3]
[4]
[5]
[6]
[1] For recent reviews on metathesis reactions see: a) Tetrahedron, 1999, 55, 8141
(Symposium in Print; Eds.: M. L. Snapper, A. H. Hoveyda); b) “Alkene Metathesis in Organic Synthesis”: Top. Organomet. Chem. 1998, 1; c) S. Blechert,
Pure Appl. Chem. 1999, 71, 1393; d) A.
Frstner, Angew. Chem. 2000, 112, 3140;
Angew. Chem. Int. Ed. 2000, 39, 3012;
e) T. M. Trnka, R. H. Grubbs, Acc.
Chem. Res. 2001, 34, 18; f) S. J. Connon,
S. Blechert, Angew. Chem. 2003, 115,
1944; Angew. Chem. Int. Ed. 2003, 42,
1900; g) R. E. Schrock, A. H. Hoveyda,
Angew. Chem. 2003, 115, 4740; Angew.
Chem. Int. Ed. 2003, 42, 4592; h) A.
Angew. Chem. Int. Ed. 2005, 44, 1912 –1915
[7]
[8]
Deiters, S. F. Martin, Chem. Rev. 2004,
104, 2199.
a) P. Schwab, M. B. France, J. W. Ziller,
R. H. Grubbs, Angew. Chem. 1995, 107,
2179; Angew. Chem. Int. Ed. Eng. 1995,
34, 2039; b) P. Schwab, R. H. Grubbs,
J. W. Ziller, J. Am. Chem. Soc. 1996, 118,
100.
M. Scholl, S. Ding, C. W. Lee, R. H.
Grubbs, Org. Lett. 1999, 1, 953.
a) S. B. Garber, J. S. Kingsbury, B. L.
Gray, A. H. Hoveyda, J. Am. Chem.
Soc. 2000, 122, 8168; b) S. Gessler, S.
Randl, S. Blechert, Tetrahedron Lett.
2000, 41, 9973.
T. A. Kirkland, R. H. Grubbs, J. Org.
Chem. 1997, 62, 7310.
a) See references [3–5]; b) M. Scholl,
T. M. Trnka, J. P. Morgan, R. H. Grubbs,
Tetrahedron Lett. 1999, 40, 2247; c) A.
Briot, M. Bujard, V. Gouverneur, S. P.
Nolan, C. Mioskowski, Org. Lett. 2000,
2, 1517; d) H. Wakamatsu, S. Blechert,
Angew. Chem. 2002, 114, 2509; Angew.
Chem. Int. Ed. 2002, 41, 2403; e) A.
Michrowska, R. Bujok, S. Harutyunyan,
V. Sashuk, G. Dolgonos, K. Grela, J. Am.
Chem. Soc. 2004, 126, 9318.
In some cases use of molybedum catalyst can be used to overcome these
issues, for example: S. E. Denmark, S.M. Yang, Tetrahedron 2004, 60, 9695.
Geminal-disubstituted ruthenium alkylidenes are generated and react in dien-
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[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
yne RCM reactions: S.-H. Kim, W. J.
Zuercher, N. B. Bowden, R. H. Grubbs,
J. Org. Chem. 1996, 61, 1073.
T. R. Hoye, C. S. Jeffrey, M. A. Tennakoon, J. Wang, H. Zhao, J. Am. Chem.
Soc. 2004, 126, 10 210.
a) M. Ulman, R. H. Grubbs, Organometallics 1998, 17, 2484; b) T. R. Hoye,
H. Zhao, Org. Lett. 1999, 1, 1123.
a) M. Ulman, T. R. Belderrain, R. H.
Grubbs, Tetrahedron Lett. 2000, 41,
4689; b) T.-L. Choi, C. W. Lee, A. K.
Chatterjee, R. H. Grubbs, J. Am. Chem.
Soc. 2001, 123, 10 417; c) K. Basu, J. A.
Cabral, L. A. Paquette, Tetrahedron
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J. Robinson, A. D. Piscopio, L. Zhu,
Abstracts of Papers, 226th National
Meeting of the American Chemical
Society, New York, American Chemical
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X. Wang, J. A. Porco, Jr., J. Am. Chem.
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X. Wang, E. J. Bowman, B. J. Bowman,
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2035.
In contrast, the cyclization of 11 in
Scheme 4 does achieve a cyclization
onto an electron-deficient olefin in preference to competing reactions.
For reviews of enyne metathesis see:
a) C. S. Poulsen, R. Madsen, Synthesis
2003, 1; b) S. T. Diver, A. J. Giessert,
Chem. Rev. 2004, 104, 1317.
J. Huang, H. Xiong, R. P. Hsung, C.
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2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1915
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