Efficient synthesis of bicyclo[6.3.0]undecadienones by Nazarov cyclization/regioselective elimination

Article abstract of DOI:10.1139/cjc-2013-0456

Easily accessible cyclooctadienyl vinyl ketones can generate fused bicyclic 8-5 (bicyclo[6.3.0]undecadienone) ring systems via the Nazarov cyclization when treated with Lewis acid. The resultant products contain three new stereocenters as well as olefins suitably situated to allow further structural elaboration. This concise sequence allows for the rapid preparation of intermediates that should be applicable to a variety of natural product targets containing this bicyclic core.

Full text of DOI:10.1139/cjc-2013-0456

58
ARTICLE
Efficient synthesis of bicyclo[6.3.0]undecadienones by Nazarov
cyclization/regioselective elimination
Carson D. Matier, Yonghoon Kwon, and F.G. West
Abstract: Easily accessible cyclooctadienyl vinyl ketones can generate fused bicyclic 8-5 (bicyclo[6.3.0]undecadienone) ring
systems via the Nazarov cyclization when treated with Lewis acid. The resultant products contain three new stereocenters as well
as olefins suitably situated to allow further structural elaboration. This concise sequence allows for the rapid preparation of
intermediates that should be applicable to a variety of natural product targets containing this bicyclic core.
Key words: divinyl ketone, medium rings, Nazarov cyclization, electrocyclization.
Résumé : Les cyclooctadiényl vinyl cétones, faciles a` obtenir, peuvent générer des systèmes a` noyau 8-5 (bicyclo[6.3.0]undecadiénone)
bicyclique fusionné par cyclisation de Nazarov lorsqu’elles sont traitées par des acides de Lewis. Les produits résultants contiennent
trois nouveaux stéréocentres, ainsi que des oléfines bien situées pour permettre une élaboration structurale plus poussée. Cette
séquence concise permet de préparer rapidement des produits qui devraient s’appliquer a` toute une gamme de substances naturelles
cibles contenant ce noyau bicyclique. [Traduit par la Rédaction]
Mots-clés : divinyl cétone, électrocyclisation, cyclisation de Nazarov, noyaux de taille moyenne.
Introduction
Results and discussion
The many diverse modalities in which the Nazarov cyclization
can by employed to form complex cyclopentanoids products have
rendered it a powerful synthetic tool, with many new variations
There are only a few examples of Nazarov cyclization to annulate a
new cyclopentenyl cation onto a preexisting cyclooctene ring. These
have typically involved unconventional precursors rather than the
usual cross-conjugated dienones, including dichlorohomoallyl alco-
1
appearing in recent years. The cyclization is typically performed
9
10
11
hols, propargyl alcohols, vinylcyclobutanones, organomanga-
by treating a cross-conjugated dienone (divinyl ketone) with a
Lewis or Brønsted acid, generating a pentadienyl cation, which
after cyclization yields an oxyallyl cation that undergoes elimina-
tion to furnish a conjugated enone. Since its discovery in 1949, the
Nazarov reaction has been extensively studied and modified. There is
an array of methods to access the pentadienyl cation intermedi-
nese intermediates, or pyran-4-ones.13 Thus, at the outset, we could
not be sure that the dienone precursors envisioned would be suitable
Nazarov substrates. Moreover, we required a straightforward route
to such substrates.
12
A succinct synthesis of the target trienones was possible via
a simple, two-step protocol (Table 1). Using well-established chem-
istry by Grunewald and Meier, 1,5-cyclooctadiene and 1-cyclooctene
2
ates with various substrates and acid promotors. Asymmetric
versions of the Nazarov cyclization have also been investigated,
allowing torquoselective conrotary ring closure.3
1
4
were dibromoinated using pyridinium hydrobromide perbro-
1
5
mide and eliminated with potassium tert-butoxide to give bro-
mides 1 and 5, respectively. Bromides 1 and 5 then underwent a
lithium−halogen exchange using tert-butyllithium. To these lithi-
ated species was added an array of 2-propenal analogues, which
coupled by a 1,2-addition to give trienols 2a−2e and dienol 6.
These doubly allylic alcohols were then oxidized with manganese
dioxide to give their corresponding ketones (3a−3e and 7) in mod-
erate to high yields.
Development of the interrupted Nazarov cyclization, where the
oxyallyl cation is trapped with a nucleophile, has provided meth-
ods to furnish new rings and stereocenters, resulting in substan-
tial increases in molecular complexity. Both intermolecular and
intramolecular trapping with hydrides, electron-rich arenes, ole-
fins, heteronucleophiles, halides, and [3+2] and [3+4] cycloadditions
4
have been shown. In the late 1990s, the first examples of intra-
molecular trapping of the oxyallyl cation with pendent olefins
were reported.5 On the other hand, transannular trapping
of an oxyallyl cation intermediate has not been described to
date. For example, transannulation by the distal olefin of a 1,5-
cyclooctadiene-derived Nazarov intermediate would rapidly as-
semble a triquinane skeleton, in analogy to the pioneering studies
Initial experiments using 3a in the presence of BF ·OEt at low
3
2
,6
temperature gave rapid consumption of the dienone substrate,
but the product proved to be bicyclic dienone 4a rather than the
desired triquinane (Table 2, entry 1). Thus, it appeared that follow-
ing electrocyclization, elimination of a cyclooctenyl proton was
preferred over transannular olefin trapping. On the assumption
that other activating reagents might modulate the electrophilic-
ity of the intermediate cyclopentenyl cation or affect the rate of
elimination, we then examined a number of other Lewis and
Brønsted acids (Table 2, entries 2–7).
7
8
of Wender and Mehta (Scheme 1). Here, we describe our efforts
to apply this approach, resulting in a short and effective route to
8
-5 bicyclic ring systems via Nazarov cyclization followed by a
highly regioselective elimination step.
Received 4 October 2013. Accepted 5 November 2013.
C.D. Matier, Y. Kwon, and F.G. West. Department of Chemistry, University of Alberta, E3-43 Gunning/Lemieux Chemistry Centre, Edmonton, AB T6G
G2, Canada.
2
Corresponding author: F.G. West (e-mail: frederick.west@ualberta.ca).
Can. J. Chem. 92: 58–61 (2014) dx.doi.org/10.1139/cjc-2013-0456
Published at www.nrcresearchpress.com/cjc on 11 November 2013.

Matier et al.
59
Scheme 1. Angular triquinane approach via interrupted Nazarov reaction.
Table 1. Preparation of dienone substrates.
Entry
R1
R2
Product
Yield (%)a
1
Me
Me
H
Ph
Me
Ph
H
3a
3b
3c
3d
3e
7
39
39
81
50
51
2
3
4
5
6
Me
−(CH ) −
2
4
Me
Ph
84
aIsolated yield over two steps.
Table 2. Effect of acid activator on Nazarov cyclization of 3a.
Temperature
(°C)
Entry Acid
Equivalents Solvent
Time
20 min 4a (72)
3 h 4a (trace) + intractable mixture
Product (% yield)a
1
BF ·OEt
1.1
1.1
CH Cl2
85% HCO H
−78
0
3
2
2
2
3
4
5
6
7
BF ·OEt
3
2
2
Sc(OTf)3 0.2
TiCl4
CH Cl2
rt
20 min 4a (53)
2
1.1
1.1
400
CH Cl2
−78
−78
Reflux
Reflux
20 min 4a (33)
20 min 4a (28) + mixture
2
Et AlCl
CH Cl2
2
2
HCO H
neat
THF
2 h
2 h
Intractable mixture
3a only
2
CF CO H 1.1
3
2
aYields are for isolated product after chromatographic purification.
Use of BF ·OEt at higher temperatures in 85% formic acid to
ination product 4a could be isolated. Other Lewis acids such as
scandium(III) triflate and titanium tetrachloride also effected
conversion to 4a in CH Cl at −78 °C (Table 2, entries 3 and 4),
3
2
nucleophilically assist the cation−olefin cyclization was exam-
ined (Table 2, entry 2); however, these conditions furnished an
intractable mixture from which only traces of the simple elim-
2
2
albeit in lower yields than was obtained with the original
Published by NRC Research Press

60
Can. J. Chem. Vol. 92, 2014
Scheme 2. Intermediates en route to transannular cyclization.
BF ·OEt conditions. However, it is notable that effective con-
Table 3. Nazarov cyclization and exo-elimination of trienones 3 and
dienone 7.
3
2
version of 3a to 4a could be accomplished with only catalytic
quantities of Sc(OTf)3.16 Diethylaluminum chloride also fur-
nished 4a (Table 2, entry 5), but with diminished yields and
the formation of multiple side-products. Finally, two Brønsted
acids, formic acid and trifluoroacetic acid, were examined
(Table 2, entries 6 and 7) but gave either intractable mixtures or
unconsumed starting material.
Failure to observe any triquinane formation from 3a under all
conditions surveyed indicates that the transannulation step is
difficult. We envision two possible explanations (Scheme 2). First,
the cyclooctene ring fused to the initially formed cyclopentenyl
cation A must assume a tub-like conformation (A=) to bring C-1
and C-5 within bonding distance, which may be disfavored in the
conformational equilibrium. Furthermore, cyclization of A= to
triquinane B would afford a relatively high-energy secondary car-
bocation at C-4, which is likely to raise the barrier for trans-
annulation. Notably, previous successful intramolecular trapping
reactions of the Nazarov intermediate by olefins proceeded
1
2
a
Entry
Substrate
R
R
Product (% yield)
1
3a
3b
3c
3d
3e
7
Me
Me
H
Ph
Me
Ph
H
4a (72)
5
,6
through tertiary carbocations. Moreover, Mehta and Rao found
that it was necessary to use a trisubstituted alkene to see efficient
b
2
3
4
5
6
a
4b (61)
c
4c (64)
8
transannulation in their triquinane strategy. With this in mind,
d
Me
O
it is unlikely that the desired process can be effected without
substantial redesign of the substrates. However, clean formation
of 4a under several conditions with no regio- or stereoisomers
offers a valuable synthetic tool. The bicyclo[6.3.0]undecane skele-
ton is found in a variety of diverse terpenoid natural products,
e
−(CH ) −
4e (80)
2
4
Me
Ph
8 (80)
Yields are for isolated product after chromatographic purification.
A 4:1 mixture of anti:syn diastereomers at R was obtained.
b
c
1
Reaction done at 0 °C.
1
7
18
19
including precapnelladiene, dactylol, pleuromutilin, and
d
Reaction formed a complex mixture of products.
R and R (cyclohexano ring methylene carbons) are syn in the case of 4e.
variecolin.2 With this in mind, we examined all of the substrates
0
e
1
2
(3a−3e and 7) under the optimal conditions to evaluate the gener-
ality of this useful transformation (Table 3).
whether a cyclooctene conformation favoring rapid elimination to-
Like 3a, substrates 3b and 3c also underwent conversion to the
corresponding bicyclo[6.3.0]undecadienones 4b and 4c (Table 3,
entries 2 and 3). However, dimethyl product 4b was not formed
with complete diastereoselectivity, furnishing a 4:1 mixture of
anti and syn isomers at C-9/C-10. Substrate 3c, lacking an ␣-
substituent on the dienone moiety, reacted cleanly but required
higher temperature (0 °C) compared with the other cases. Re-
moval of the ␤-substituent, as in the case of 3d, was far more
damaging to the success of the transformation (Table 3, entry 4).
In this case, a complex mixture from which no characterizable
product could be isolated was obtained. Cyclohexenyl ketone 3e
cyclized to the tricyclic product 4e in very good yield (Table 3,
entry 5), although in contrast with the other examples, it provided
22
wards C-2 might predominate. We imagined that the remote alk-
ene might be exerting an effect on the conformational preferences,
and to evaluate this possibility, we subjected dienone 7 lacking that
unsaturation to the standard conditions (Table 3, entry 6). In the
event, this substrate was found to undergo efficient electrocycliza-
tion and exclusive exocyclic elimination to give 8 in high yield. Fur-
ther computational studies to evaluate transition state energies for
the various elimination pathways may help elucidate this high selec-
tivity. Regardless of its origin, this general regioselectivity is wel-
come, especially as it preserves the two adjacent stereocenters at C-8
and C-9, set in the electrocyclization, in contrast with the outcome
had C or D predominated.
2
1
exclusively the 9,10-syn diastereomer. In this case, we presume
that the conformational restrictions of a somewhat strained
hydrindanone skeleton exerted a strong preference for a syn rela-
tionship at the two bridgehead carbons. In all cases, we observed
the expected 8,9-anti relative configuration, established in the
initial 4␲ conrotatory electrocyclization.
Conclusion
We have described above an efficient and succinct route to gener-
ate fused bicyclic 8-5 ring systems, a common substructure in a vari-
ety of natural products. This method generates three new
stereocenters, two of which form stereospecifically and the other
stereoselectively. The cyclization is effected by several common
Lewis acids. Finally, products 4a−4e and 8 portend synthetic utility,
as the elimination occurs with high regioselectivity and the remain-
ing olefins are situated for further elaboration to more complex
natural products. The origins of this regioselectivity are under cur-
rent investigation. Domino transannulation to afford triquinane sys-
tems was not observed for 3a−3e, suggesting the need for structural
augmentation of the proposed trapping alkene.
There are at least three regiochemical options for the elimination
event: (i) endocyclic (relative to the newly formed cyclopentenyl cation)
towards C-8 to afford the ring-fusing alkene isomer C, (ii) endocyclic
towards C-9 to give cyclopentenone D, or (iii) exocyclic into the cy-
clooctene ring, the observed pathway that provides 4a−4c and 4e
(Scheme 3). Exocyclic elimination from C-10 is also an option for
all but 3c, giving alkylidene cyclopentenone E. The high regioselec-
tivity seen in these cases was surprising, prompting us to consider
Published by NRC Research Press

Matier et al.
61
Scheme 3. Possible regiochemical outcomes of elimination step.
1
993, 34, 4583. doi:10.1016/S0040-4039(00)60630-5; (b) Fleming, M.;
Supplementary material
Fisher, P. V.; Gunawardena, G. U.; Jin, Y.; Zhang, C.; Zhang, W.; Arif, A. M.;
West, F. G. Synthesis 2001, 1268. doi:10.1055/s-2001-15067.
(14) Grunewald, G.; Grindel, J. J. Med. Chem. 1976, 19, 10. doi:10.1021/
jm00223a003.
15) Mayer, W.; Meier, H. Chem. Ber. 1989, 122, 509. doi:10.1002/cber.19891220319.
16) For other recent examples of Nazarov-type reactions using catalytic
Supplementary information including experimental proce-
dure, characterization data, and NMR spectra and spectral data
are available with the article through the journal Web site at
http://nrcresearchpress.com/doi/suppl/10.1139/cjc-2013-0456.
(
(
Sc(OTf)
3
, see (a) Malona, J. A.; Colbourne, J. M.; Frontier, A. J. Org. Lett. 2006,
Acknowledgements
8
, 5661. doi:10.1021/ol062403v; (b) Rieder, C. J.; Winberg, K. J.; West, F. G.
We thank the Natural Sciences and Engineering Research Council
of Canada for funding this research and for an Undergraduate Sum-
mer Research Award (CDM). We also thank the X-ray crystallo-
graphic, analytical, mass spectrometry, and NMR services at the
University of Alberta, Department of Chemistry for their essential
assistance.
J. Am. Chem. Soc. 2009, 131, 7504. doi:10.1021/ja9023226; (c) Singh, R.;
Panda, G. Org. Biomol. Chem. 2011, 9, 4782. doi:10.1039/c0ob00892c.
(
(
(
17) Syntheses: (a) Kinney, W. A.; Coghlan, M. J.; Paquette, L. A. J. Am. Chem. Soc.
1984, 106, 6868. doi:10.1021/ja00334a081; (b) Mehta, G.; Murty, A. N. J. Chem.
Soc. Chem. Commun. 1984, 1058. doi:10.1039/C39840001058; (c) Petasis, N. A.;
Patane, M. A. Tetrahedron Lett. 1990, 31, 6799. doi:10.1016/S0040-4039(00)
9
7175-2; (d) Inouye, Y.; Shirai, M.; Michino, T.; Kakisawa, H. Bull. Chem. Soc. Jpn.
993, 66, 324. doi:10.1246/bcsj.66.324; (e) MacDougall, J. M.; Turnbull, P.;
Verma, S. K.; Moore, H. W. J. Org. Chem. 1997, 62, 3792. doi:10.1021/jo970644y;
f) Takenaka, Y.; Ito, H.; Igushi, K. Tetrahedron 2006, 63, 510. doi:10.1016/j.tet.
006.10.072.
18) Syntheses: (a) Gadwood, R. C.; Lett, R. M.; Wissinger, J. E. J. Am. Chem. Soc.
986, 108, 6343. doi:10.1021/ja00280a035; (b) Paquette, L. A.; Ham, W. H.
1
References
(
2
(
1) For recent reviews: (a) Pellisier, H. Tetrahedron 2005, 61, 6479. doi:10.1016/j.
tet.2005.04.014; (b) Tius, M. A. Eur. J. Org. Chem. 2005, 2193. doi:10.1002/ejoc.
2
00500005; (c) Frontier, A. J.; Collison, C. Tetrahedron 2005, 61, 7577. doi:10.
1
1
016/j.tet.2005.05.019; (d) Nakanishi, W.; West, F. G. Curr. Opin. Drug Discov.
J. Am. Chem. Soc. 1987, 109, 3025. doi:10.1021/ja00244a026; (c) Feldman, K. S.;
Wu, M. J.; Rotella, D. P. J. Am. Chem. Soc. 1989, 111, 6457. doi:10.1021/
ja00198a087; (d) Molander, G. A.; Eastwood, P. R. J. Org. Chem. 1995, 60, 4559.
doi:10.1021/jo00119a038; (e) Fürstner, A.; Langemann, K. J. Org. Chem. 1996, 61
2
2
009, 12, 732; (e) Vaidya, T.; Eisenberg, R.; Frontier, A. J. ChemCatChem
011, 3, 1531. doi:10.1002/cctc.201100137.
(
2) Review: (a) Spencer, W. T., III; Vaidya, T.; Frontier, A. J. Eur. J. Org. Chem. 2013,
8, 3621. doi:10.1002/ejoc.201300134; Recent example: (b) Bonderoff, S. A.;
1
8746. doi:10.1021/jo961600c; (f) Harmata, M.; Rashatasakhon, P. Org. Lett.
Grant, T. N.; West, F. G.; Tremblay, M. Org. Lett. 2013, 15, 2888. doi:10.1021/
ol4012663.
3) Review: (a) Shimada, N.; Stewart, C.; Tius, M. Tetrahedron 2011, 67, 5851.
doi:10.1016/j.tet.2011.05.062; Recent examples: (b) Hutson, G. E.;
Türkmen, Y. E.; Rawal, V. H. J. Am. Chem. Soc. 2013, 135, 4988. doi:10.1021/
ja401908m; (c) Sadiya, R.; Winai, I.; Vadim, K.; Rueping, M. Chem. Asian J.
2
000, 2, 2913. doi:10.1021/ol006390b; (g) Dowling, M. S.; Vanderwal, C. D.
J. Org. Chem. 2010, 75 6908. doi:10.1021/jo101439h.
(
19) Syntheses: (a) Gibbons, E. G. J. Am. Chem. Soc. 1982, 104, 1767. doi:10.1021/
ja00370a067; (b) Boeckman, R. K., Jr.; Springer, D. M.; Alessi, T. R. J. Am.
Chem. Soc. 1989, 111, 8284. doi:10.1021/ja00203a043; (c) Fazakerley, N. J.;
Helm, M. D.; Procter, D. J. Chem. Eur. J. 2013, 19, 6718. doi:10.1002/chem.
2
012, 7, 2361. doi:10.1002/asia.201200391.
2
(
2
01300968. For a review on unnatural pleuromutilin derivatives, see
d) Tang, Y.-Z.; Liu, Y.-H.; Chen, J.-X. Mini-Rev. Med. Chem. 2012, 12, 53. doi:10.
174/138955712798868968.
(
4) Review: (a) Grant, T. N.; Rieder, C. J.; West, F. G. Chem. Commun. 2009, 5676.
doi:10.1039/b908515g; Recent example: (b) Kwon, Y.; McDonald, R.;
West, F. G.; Angew. Chem. Int. Ed. 2013, 52, 8616. doi:10.1002/anie.201303996.
5) Bender, J. A.; Blize, A. E.; Browder, C. C.; Giese, S.; West, F. G. J. Org. Chem.
(
20) Synthetic approach: Molander, G. A.; Quirmbach, M. S.; Silva, L. F., Jr.;
Spencer, K. C.; Balsells, J. Org. Lett. 2001, 3, 2257. doi:10.1021/ol015763l.
21) Relative stereochemistry of 4e was unambiguously determined via single
crystal X-ray diffraction analysis. CCDC 964321 contains the supplementary
crystallographic data for this paper. These data can be obtained, free of
charge, from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif (or 12 Union Road, Cambridge CB2
1EZ, U.K. (fax: 44-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk)).
(22) Nazarov cyclizations to form 5-5, 6-5, 7-5, and 12-5 bicyclic skeletons
typically furnish cyclopentenones with the new C=C bond at the ring-fusion
as the predominant or exclusive product. Representative examples:
(a) Braude, E. A.; Coles, J. A. J. Chem. Soc. 1952, 1430. doi:10.1039/
JR9520001430; (b) Braude, E. A.; Forbes, W. F. J. Chem. Soc. 1953, 2208. doi:
10.1039/JR9530002208; (c) Fristad, W. E.; Dime, D. S.; Bailey, T. R.;
Paquette, L. A. Tetrahedron Lett. 1979, 1999. doi:10.1016/S0040-4039(01)86247-X;
(d) Marino, J. P.; Linderman, R. J. J. Org. Chem. 1981, 46, 3696. doi:10.1021/
jo00331a023; (e) Goure, W. F.; Wright, M. E.; Davis, P. D.; Labadie, S. S.;
Stille, J. K. J. Am. Chem. Soc. 1984, 106, 6417. doi:10.1021/ja00333a054.
(
1
998, 63, 2430. doi:10.1021/jo9803030.
(
(
(
6) Browder, C. C.; West, F. G. Synlett 1999, 9, 1363. doi:10.1055/s-1999-32132.
7) Wender, P. A.; Correia, C. R. D. J. Am. Chem. Soc. 1987, 109, 2523. doi:10.1021/
ja00242a053.
(
8) Mehta, G.; Rao, K. S. J. Am. Chem. Soc. 1986, 108, 8015. doi:10.1021/
ja00285a023.
(
9) (a) Hiyama, T.; Shinoda, M.; Nozaki, H. Tetrahedron Lett. 1978, 771. doi:10.1016/
S0040-4039(01)85392-2; (b) Hiyama, T.; Shinoda, M.; Tsukanaka, M.;
Nozaki, H. Bull. Chem. Soc. Jpn. 1980, 53, 1010. doi:10.1246/bcsj.53.1010.
(
(
10) Hiyama, T.; Shinoda, M.; Saimoto, H.; Nozaki, H. Bull. Chem. Soc. Jpn. 1981, 54,
747. doi:10.1246/bcsj.54.2747.
11) (a) Jackson, D. A.; Rey, M.; Dreiding, A. S. Tetrahedron Lett. 1983, 24, 4817.
doi:10.1016/S0040-4039(00)94015-2; (b) Jackson, D. A.; Rey, M.;
Dreiding, A. S. Helv. Chim. Acta 1985, 68, 439. doi:10.1002/hlca.19850680217.
12) DeShong, P.; Sidler, D. R. J. Org. Chem. 1988, 53, 4894. doi:10.1021/
jo00255a052.
2
(
(
13) (a) West, F. G.; Fisher, P. V.; Gunawardena, G. U.; Mitchell, S. Tetrahedron Lett.
Published by NRC Research Press