Exploiting domino enyne metathesis mechanisms for skeletal diversity generation

Article abstract of DOI:10.1039/b807278g

In the context of diversity-oriented synthesis, the exploration and optimization of the domino metathesis of decorated norbornenes allowed complex polycyclic architectures to be generated in a highly efficient and atom-economical process. The Royal Society of Chemistry.

Full text of DOI:10.1039/b807278g

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Exploiting domino enyne metathesis mechanisms for skeletal diversity
generationwz
Richard J. Spandl, Helene Rudyk and David R. Spring*
a
b
a
´
Received (in Cambridge, UK) 29th April 2008, Accepted 9th May 2008
First published as an Advance Article on the web 3rd June 2008
DOI: 10.1039/b807278g
In the context of diversity-oriented synthesis, the exploration
and optimization of the domino metathesis of decorated norbor-
nenes allowed complex polycyclic architectures to be generated
in a highly efficient and atom-economical process.
Structurally complex and skeletally diverse small molecule
collections synthesized using diversity-oriented synthesis
(DOS)1 have been used to discover novel bioactive molecules.2
With the most challenging facet of DOS being to efficiently
access distinct molecular scaffolds, a number of approaches
have been reported.3 To this end we envisaged a strategy
whereby, in the presence of Grubbs’ catalyst 1 or 2, a ‘tandem’
metathesis–Diels–Alder sequence reaction would convert de-
corated norbornenes 3, via 1,3-diene intermediates 4, into
complex and distinct polycyclic scaffolds 5. The key step (i.e.
3 to 4) requires a ‘domino’ ring closing metathesis (RCM)–ring
opening metathesis (ROM)–ring closing enyne metathesis
(RCEYM) reaction sequence to occur (Scheme 1).4 Although
domino metathesis reactions of oxa- and aza-norbornene-
enyne scaffolds5 and unstrained cylcoalkene-enynes6 have
been investigated, few examples of this transformation using
norbornene substrates have been reported.7 In these systems
reaction initiation can occur with either norbornene ring
opening or enyne metathesis (Scheme 2); herein this mechan-
istic distinction was found to be controlled by the choice of
catalyst i.e. Grubbs’ first (1) or second (2) generation catalyst.
The RCEYM reaction can be used to efficiently produce
1,3-diene containing ring systems.8 Although these reactions have
been exploited in the synthesis of natural products and related
compounds,9 selectivity issues may arise. The product distribu-
tion can be highly dependent on the nature of the substrate and
the catalyst used and, as a result, both exo and endo ring isomers
are sometimes produced.10 Combined with the complication of
two possible sites for reaction initiation, the domino metathesis
of the test substrate A(n) (n = 1 or 2) was investigated initially.
From these studies, designed to probe the product distribution
and reaction mechanism, five products were identified: the exo
isomer B(n) (the desired product); the endo isomer C(n); the ring-
opened enyne D(n); the tetra-ene E(n); and, the cross-metathesized
norbornene F(n). Two major pathways were proposed (Scheme 2);
these initiated with either ROM of the norbornene (Path 1) or
Scheme 1 Tandem reaction overview. RCM = ring closing meta-
thesis; ROM = ring opening metathesis; RCEYM = ring closing
enyne metathesis.
ruthenium carbene insertion into the alkyne (Path 2). A series of
metathesis reactions could then give the products A(n) to F(n).
In the presence of 1, the norbornene A(1) was converted to the
exo ring isomer B(1) (Scheme 3). As the endo ring isomer C(1) was
not observed, this suggested that the RCEYM reaction to form
B(n) proceeded via an ene-then-yne mechanism.11 A further
insight into the reaction mechanism came from the isolation of
a small amount of the ring opened enyne D(1). This suggested
that ROM of the norbornene A(1) occurred prior to RCEYM
(i.e. Path 1 with n = 1). Using the alternative substrate A(2), the
situation is somewhat different. Interestingly, catalyst 1 facil-
itates ROM to give D(2) but the subsequent RCEYM does not
occur and the exo ring isomer B(2) was not formed. The
sequential use of Grubbs’ more active catalyst 2 did, however,
facilitate the formation of B(2) from the enyne D(2). Again an
ene-then-yne mechanism was proposed. The stepwise use of
catalysts 1 and 2 has previously been reported.7a As a side
product of the metathesis reaction of D(2), the tetra-ene E(2) was
also formed as a result of CM of the alkyne moiety with
ethylene. This CM process is competitive since the RCEYM
reaction, which yields the exo ring isomer B(2), is slower.
In an effort to increase reaction efficiency, the metathesis
reactions of A(1) and A(2) were performed using catalyst 2
(Scheme 4). As a result of the competing ring opening meta-
thesis polymerization (ROMP) process,12 reaction yields were
low. Furthermore, mixtures of products resulted.13 In addition
to both the exo B(n) and the endo C(n) ring isomers being
produced, the tetra-ene compound E(n) was also isolated. In
both cases, the ring-opened enyne D(n) was not observed. More
significant was the formation of the cross-metathesized norbor-
nene F(n). These results suggest that different reaction pathways
were in operation in the presence of catalyst 1 compared to 2.14
The reaction of A(n) with 1 appears to initiate with the
primary ROM of the norbornene to give either MC-1a or
a Department of Chemistry, University of Cambridge, Lensfield Road,
Cambridge, UK CB2 1EW. E-mail: drspring@ch.cam.ac.uk;
Tel: +44 (0)1223 336498
b Lilly UK, Erl Wood Manor, Windlesham, Surrey, UK GU20 6PH
w Dedicated to Professor Sir Jack Baldwin in celebration of his 70th
birthday.
z Electronic supplementary information (ESI) available: Full experi-
mental details and spectra. See DOI: 10.1039/b807278g
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Scheme 3 Observed products with test substrates.
Scheme 4 Products identified using Grubbs’ catalyst 2.
endo-11 (an inseparable mixture). In addition to confirming
the hypothesis that tetra-ene compounds can be converted to
both ring isomers (Scheme 2), a Diels–Alder reaction could be
used to further diversify the exo compound 9, yielding 12, and
also to isolate the endo isomer 11 (Scheme 6).
Scheme 2 An overview of the primary reaction pathways illustrating
the products (black) and intermediates (grey). Norbornene ROM and
alkyne insertion are shown as irreversible.16a Polymerization (not
shown) is a possible alternative in many of the steps. Pathways 1
and 2 may occur concomitantly.16b RCM = ring closing metathesis;
ROM = ring opening metathesis; RCEYM = ring closing enyne
The exo-1,3-diene compounds A(1), A(2), 7 and 9 were
converted to the corresponding polycyclic adducts 12–15 in
excellent yield under microwave irradiation (Scheme 7).
Excellent facial selectivity was observed in all cases and the
products proposed resulted exclusively from endo-/top face
attack of N-ethylmaleimide on the 1,3-diene.
metathesis; MC = metallocarbene intermediate n = 1 or 2. For X(n)
where X is A–F, X(1) = n = 1 and X(2) = n = 2.
,
To realize our initial aim, and to more efficiently access the
polycyclic scaffolds required, a more efficient protocol was
developed whereby the cis-norbornene scaffold 6 could be
MC-1b (i.e. Path 1, Scheme 2). The subsequent steps and final
products, i.e. the exo isomer B(n) or the ring-opened enyne
D(n), are dictated by the value of n in the starting material (see
Scheme 3). Tentatively we propose that in the reaction of A(n)
with 2, initial alkyne insertion to give MC-2a or MC-2b
(i.e. Path 2, Scheme 2) is prevalent.
After extensive optimization, and considering the above
results, a novel metathesis protocol, which merged and modified
the approaches of the North,7a Porco,15c Lee15a and Diver15b
research groups was identified for the amide substrates 3
(Scheme 1). This protocol, which required the reaction to be
performed in ethylene saturated solvent and with microwave
irradiation, allowed the conversion of 6 to 7 and 8 to 9 and 10
(Scheme 5). To prevent product decomposition a polar isocya-
nate was used to quench the reaction mixture before work-up.15b
The diversity-oriented synthetic utility of the reaction of 8 to
form two distinct scaffolds (9 and 10) was further demon-
strated by the conversion of the tetra-ene 10 to both exo-9 and
Scheme 5 Optimized domino metathesis conditions. MW = micro-
wave heating.
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ROM of the norbornene before the RCM reactions (both
olefin and enyne) occurred. The tandem domino meta-
thesis–Diels–Alder strategy is currently being used in the
preparation of skeletally diverse small molecule collections.
We acknowledge the EPSRC, BBSRC and Augustus and
Harry Newman Foundation and Lilly for generous support.
We also acknowledge the EPSRC National Mass Spectro-
metry Service Centre, Swansea, for providing mass
spectrometric data.
Scheme 6 Ring closing metathesis gave both exo and endo cyclized
products (9 and 11, respectively), but only the exo isomer was able to
react with the dienophile to give 12.
Notes and references
1. For recent reviews on DOS see: (a) T. E. Nielsen and S. L. Schreiber,
Angew. Chem., Int. Ed., 2008, 47, 48–56; (b) D. S. Tan, Nat. Chem.
Biol., 2005, 1, 74–84; (c) R. J. Spandl, D. R. Spring and A. Bender,
Org. Biomol. Chem., 2008, 6, 1149–1158; (d) G. L. Thomas,
E. E. Wyatt and D. R. Spring, Curr. Opin. Drug Discovery Dev.,
2006, 9, 700–712 and references therein.
2. Selected recent examples: (a) S. K. Ko, H. J. Jang, E. Kim and
S. B. Park, Chem. Commun., 2006, 2962–2964; (b) E. E. Wyatt,
S. Fergus, W. R. J. D. Galloway, A. Bender, D. J. Fox,
A. T. Plowright, A. S. Jessiman, M. Welch and D. R. Spring,
Chem. Commun., 2006, 3296–3298; (c) G. L. Thomas,
R. J. Spandl, F. G. Glansdorp, M. Welch, A. Bender,
J. Cockfield, J. A. Lindsay, C. Bryant, D. F. J. Brown,
O. Loiseleur, H. Rudyk, M. Ladlow and D. R. Spring, Angew.
Chem., Int. Ed., 2008, 47, 2808–2812.
3. For a recent review see: R. J. Spandl, G. L. Thomas, M. Diaz-
Gavilan, K. M. G. O’Connell and D. R. Spring, Chem. Rec., 2008,
DOI: 10.1002/tcr.20144, and references therein.
4. For recent reviews see: (a) S. G. Aitken and A. D. Abell, Aust.
J. Chem., 2005, 58, 3–13; (b) S. J. Connon and S. Blechert,
Angew. Chem., Int. Ed., 2003, 42, 1900–1923. For
example see: (c) C. K. Malik and S. Ghosh, Org. Lett., 2007, 9,
2537–2540.
a recent
Scheme 7 Optimized Diels–Alder conditions.
converted directly to the adduct 15 in ‘one-pot’ (Scheme 8). An
alternative substrate, with trans-norbornene architecture, was
also investigated. Although 16 performed well in the initial
metathesis process, the selectivity in the Diels–Alder reaction
step was reduced; both 17 and 18 (which resulted from endo-/
top and endo-/bottom face attack, respectively) were formed.
In conclusion, we have developed an efficient process to
convert decorated norbornenes into complex polycyclic sys-
tems. It is notable that the choice of Grubbs’ metathesis
catalyst affected the reaction pathway, the product distribu-
tion, and the yield. Optimum results were obtained when
catalysts 1 and 2 were used in a stepwise fashion, to facilitate
5. (a) O. Arjona, A. G. Csaky, M. C. Murcia and J. Plumet,
Tetrahedron Lett., 2000, 41, 9777–9779; (b) M. Mori,
H. Wakamatsu, Y. Sato and R. Fujita, J. Mol. Catal. A: Chem.,
2006, 254, 64–67.
6. (a) T. Kitamura, Y. Kuzuba, Y. Sato, H. Wakamatsu, R. Fujita
and M. Mori, Tetrahedron, 2004, 60, 7375–7389; (b) S. Randl,
N. Lucas, S. J. Connon and S. Blechert, Adv. Synth. Catal., 2002,
344, 631–633.
7. For selected examples see: (a) D. Banti, E. Groaz and M. North,
Tetrahedron, 2004, 60, 8043–8052; (b) E. Groaz, D. Banti and
M. North, Eur. J. Org. Chem., 2007, 3727–3745 and references therein.
8. For recent reviews on enyne metathesis see: (a) H. Villar, M. Frings
and C. Bolm, Chem. Soc. Rev., 2007, 36, 55–66; (b) S. T. Diver and
A. J. Giessert, Chem. Rev., 2004, 104, 1317–1382.
9. M. Mori, Adv. Synth. Catal., 2007, 349, 121–135.
10. The selectivity problem in enyne metathesis has been reported/ad-
dressed previously: (a) T. Kitamura, Y. Sato and M. Mori, Adv. Synth.
Catal., 2002, 344, 678–693; (b) E. C. Hansen and D. S. Lee, Acc. Chem.
Res., 2006, 39, 509–519; (c) T. Kitamura, Y. Sato and M. Mori, Chem.
Commun., 2001, 1258–1259; (d) E. C. Hansen and D. S. Lee, J. Am.
Chem. Soc., 2004, 126, 15074-15080, 2004, 126, 15074–15080.
11. In the formation of 6- and 7-membered rings the ene-then-yne
pathway yields the smaller exo ring isomer B(n).
10a This pathway is
supported by: (a) G. C. Lloyd-Jones, R. G. Margue and J. G. de
Vries, Angew. Chem., Int. Ed., 2005, 44, 7442–7447. For a recent
review see: (b) S. T. Diver, Coord. Chem. Rev., 2007, 251, 671–701.
12. T. L. Choi and R. H. Grubbs, Angew. Chem., Int. Ed., 2003, 42,
1743–1746.
13. Full details including reaction yields and spectral data can be
found in the ESIz.
14. Observed previously: O. Arjona, A. G. Csaky, V. Leon, R. Medel
and J. Plumet, Tetrahedron Lett., 2004, 45, 565–567.
15. (a) D. S. Lee, J. K. Sello and S. L. Schreiber, Org. Lett., 2000, 2,
709–712; (b) B. R. Galan, K. P. Kalbarczyk, S. Szczepankiewicz,
J. B. Keister and S. T. Diver, Org. Lett., 2007, 9, 1203–1206;
(c) E. Comer, E. Rohan, L. Deng and J. A. Porco, E. Comer, E.
Rohan, L. Deng, J. A. Porco, Org. Lett., 2007, 9, 2123–2126.
16. (a) J. J. Lippstreu and B. F. Straub, J. Am. Chem. Soc., 2005, 127,
7444–7457; (b) a more detailed discussion can be found in section
3 of the ESIz.
Scheme
reactions.
8 ‘One-pot’, tandem domino metathesis–Diels–Alder
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