Formal intermolecular 4 + 4 approach to cyclooctanoids: 4 + 3 Capture of the Nazarov oxyallyl intermediate with simple 1,3-dienes

Article abstract of DOI:10.1021/ol034985b

(Matrix presented) Simple 1,4-dien-3-ones and 1,3-dienes react in the presence of BF₃·OEt₂ via a domino Nazarov electrocyclization/intermolecular [4 + 3]-cycloaddition sequence to furnish keto-bridged cyclooctenes in good yield. Most

Full text of DOI:10.1021/ol034985b

ORGANIC
LETTERS
2
003
Vol. 5, No. 15
747-2750
Formal Intermolecular 4 + 4 Approach
to Cyclooctanoids: 4 + 3 Capture of
the Nazarov Oxyallyl Intermediate with
Simple 1,3-Dienes
2
†
,†
Yong Wang, Brenden D. Schill, Atta M. Arif, and F. G. West*
Department of Chemistry, UniVersity of Utah, 315 S. 1400 East, Rm. 2020,
Salt Lake City, Utah 84112-0850
frederick.west@ualberta.ca
Received June 2, 2003
ABSTRACT
Simple 1,4-dien-3-ones and 1,3-dienes react in the presence of BF
3
‚OEt
2
via a domino Nazarov electrocyclization/intermolecular
[4 + 3]-cycloaddition sequence to furnish keto-bridged cyclooctenes in good yield. Most cases showed high diastereofacial selectivity and/or
endo/exo selectivity, and surprising levels of regioselectivity were observed when isoprene was used as the diene partner.
5
The unique challenges associated with synthesis of the
cyclooctanoid system have prompted the development of
many clever synthetic approaches. Among these, methods
[4 + 4]-cycloaddition of 2-pyrones, and [4 + 3]-cyclo-
6
addition of cyclopentenyl cations with 1,3-dienes. For the
most part, these strategies have been limited to intramolecular
cases, due to the need for rapid capture of short-lived reactive
intermediates or excited states. Our observation of efficient
domino processes involving intermolecular trapping of the
Nazarov oxyallyl intermediate by silyl hydride and allyl-
1
that construct the eight-membered ring through a 4 + 4
cycloaddition process are especially attractive, since they
often involve the combination of two relatively simple and
comparably sized fragments.2 Recent examples include
7,8
3
9
the Ni-mediated coupling of 1,3-dienes, photochemical
silanes prompted an examination of the bimolecular version
of the [4 + 3]-cycloaddition process, which has enjoyed
[
4
+
4]-dimerization of 2-pyridones4 or crossed
considerable attention. Described here are the preliminary
†
Current address: Department of Chemistry, University of Alberta, W5-
6
7 Chemistry Centre, Edmonton, Alberta T6G 2G2, Canada.
(5) (a) Chase, C. E.; Bender, J. A.; West, F. G. Synlett 1996, 1173-
1175. (b) West, F. G.; Chase, C. E.; Arif, A. M. J. Org. Chem. 1993, 58,
3794-3795.
(
1) Review: Mehta, G.; Singh, V. Chem. ReV. 1999, 99, 881-930.
(2) Recent reviews of cycloaddition approaches to cyclooctanoid sys-
tems: (a) Rigby, J. H Tetrahedron 1999, 55, 4521-4538. (b) Sieburth, S.
McN.; Cunard, N. T. Tetrahedron 1996, 52, 6251-6282. (c) Lautens, M.;
Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49-92.
(6) (a) Harmata, M.; Rashatasakhon, P. Org. Lett. 2000, 2, 2913-2915.
(b) Wang, Y.; Arif, A. M.; West, F. G. J. Am. Chem. Soc. 1999, 121, 876-
877. (c) Cha, J. K.; Jin, S.-J.; Choi, J.-R.; Oh, J.; Lee, D. J. Am. Chem.
Soc. 1995, 117, 10914-10921. (d) Harmata, M.; Elahmad, S.; Barnes, C.
L. J. Org. Chem. 1994, 59, 1241-1242. (e) West, F. G.; Hartke-Karger,
C.; Koch, D. J.; Kuehn, C. E.; Arif, A. M. J. Org. Chem. 1993, 58, 6795-
6803. [4 + 3]-Cycloaddition reviews: (f) Harmata, M. Acc. Chem. Res.
2001, 34, 595-605. (g) Rigby, J. H.; Pigge, F. C. Org. React. 1997, 51,
351-478. (h) Harmata, M. Tetrahedron 1997, 53, 6235-6279. (i) Hosomi,
A.; Tominaga, Y. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds., Pergamon: Oxford, 1991; Vol. 5, pp 593-615.
(7) For an important exception describing intermolecular crossed
[4 + 4]-photocycloadditions of 2-pyridones, see: Sieburth, S. McN.; McGee,
K. F., Jr.; Zhang, F.; Chen, Y. J. Org. Chem. 2000, 65, 1972-1977.
(3) (a) Wender, P. A.; Nuss, J. M.; Smith, D. B.; Su a´ rez-Sobrino, A.;
Vågberg, J.; Decosta, D.; Bordner, J. J. Org. Chem. 1997, 62, 4908-4909.
For other recent examples of transition metal-mediated 4 + 4 processes,
see: (b) Murakami, M.; Itami, K.; Ito, Y. Synlett 1999, 951-953. (c)
Takahashi, T.; Sun, W.-H.; Liu, Y.; Nakajima, K.; Kotora, M. Organome-
tallics 1998, 17, 3841-3843.
(4) (a) Lee, Y.; McGee, K. F., Jr.; Chen, J.; Rucando, D.; Sieburth, S.
McN. J. Org. Chem. 2000, 65, 6676-6681. (b) Sieburth, S. McN.; McGee,
K. F., Jr.; Al-Tel, T. H. Tetrahedron Lett. 1999, 40, 4007-4010. (c)
Review: Sieburth, S. McN. In AdVances in Cycloaddition; Harmata, M.,
Ed.; JAI Press: Greenwich, CT, 1999; Vol. 5, pp 85-118.
1
0.1021/ol034985b CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/19/2003

Table 1. Domino Nazarov/Intermolecular [4 + 3]-Cycloaddition Reactions of Dienones with Simple Dienesa
entry
dienone
R1
R2
R3
R4
1,3-dieneb
X
R5
R6
temperature/time
products (% yield)c
1
2
3
4
5
6
7
8
9
0
1
2
3
4
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1d
1e
1e
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
Et
Et
Et
(CH2)4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
H
H
H
H
H
H
H
furan
DMB
isoprene
furan
C5H6
DMB
isoprene
furan
C5H6
DMB
O
-78 °C/0.5 h
-78 °C/3 hd
-25 °C/2.5 hd
-50 °C/2 h
-20 °C/2 h
-20 °C/2 h
-20 °C/2 h
-50 °C/3 h
-20 °C/2 h
-20 °C/2 h
-20 °C/2 h
-20 °C/1.5 h
40 °C/1 hg
2a (70)
3a (50)
4a (20)
2b (71)
8b (62)
3b (91)
Me
Me
Me
H
O
CH2
Me
Me
Me
H
e
4b + 5b (84; 5:1)
f
O
CH2
2c (72)
8c (64)
3c (93)
1
1
1
1
1
Me
Me
Me
Me
Me
Me
H
Me
Me
H
H
H
H
H
isoprene
DMB
DMB
4c + 5c (84; 4.2:1)e
3d (92)
3e (67)
4e + 5e (55; 1.4:3)e
(CH2)3
(CH2)3
isoprene
40 °C/1 hg
a
Standard Procedure. To a solution of dienone 1 and 1,3-diene (2.0 equiv) in CH2Cl2 at -20 °C was added BF3‚OEt2 (1.0 equiv), and the reaction was
maintained at that temperature for 2 h. Saturated aqueous NaHCO3 was added, and the mixture was allowed to warm to room temperature. Following
extraction of the aqueous phase with CH2Cl2, the combined organic phases were washed with brine, dried over MgSO4, and concentrated, and the resulting
crude product was purified by flash chromatography. Abbreviations: DMB ) 2,3-dimethylbutadiene; C5H6 ) cyclopentadiene. Isolated yields after
chromatography. In entries 2 and 3, 10 equiv of diene was used. Regioisomers 4 and 5 were isolated as an inseparable mixture and the ratios determined
by integration of H NMR signals. Cycloadduct 2c was isolated as a 1.3:1 ratio of diastereomers epimeric at R . Reactions carried out in ClCH2CH2Cl
using 0.1 equiv of BF3‚OEt2.
b
c
d
e
1
f
1 g
results of that study, a remarkably general and efficient
method for the convergent assembly of functionalized, keto-
bridged cyclooctenes from simple 1,3-diene and 1,4-dien-
of the simple cyclopentenone resulting from elimination was
observed. The product was assigned as the endo isomer
(cycloaddition via the compact transition state) based upon
1
0
3-one building blocks.
literature precedent and spectral data, and none of the
corresponding exo product (via the extended transition state)
Initial efforts focused on dibenzylidenepentanone 1a and
1
1
furan due to the exceptional reactivity of 1a toward elec-
was isolated.
9
trocyclic closure even at low temperature and the well
Given the initial success with 1a and furan, a range of
reaction partners was then surveyed (Table 1). Dienone 1a
also underwent domino electrocyclization/[4 + 3]-cyclo-
addition with 2,3-dimethylbutadiene and isoprene to give 3a
and 4a, albeit in moderate yields (entries 2 and 3). The
isolation of only isomer 4a upon reaction with isoprene
6,8
precedented efficiency of furan in the capture of oxyallyls.
In the event, treatment of 1a with 1.25 equiv of BF ‚OEt
78 °C in the presence of 2 equiv of furan, followed by
3
2
at
-
warming to 0 °C, furnished a single cycloadduct 2a in 70%
yield (Scheme 1). The efficiency of the bimolecular trapping
(
structure unambiguously established by X-ray crystal-
lography) deserves comment. The presumed oxyallyl inter-
mediate possesses C symmetry, so that approach of the diene
2
Scheme 1
(
8) Efficient intermolecular [4 + 3]-cycloadditions of cyclic oxyallyls
with reactive cyclic dienes are precedented: (a) Harmata, M.; Bohnert, G.
J. Org. Lett. 2003, 5, 59-61. (b) Harmata, M.; Rashatasakhon, P. Org.
Lett. 2001, 3, 2533-2525. (c) Leitch, J.; Heise, I. Eur. J. Org. Chem. 2001,
2
707-2718. (d) Harmata, M.; Shao, L.; K u¨ rti, L.; Abeywardane, A.
Tetrahedron Lett. 1999, 40, 1075-1078. (e) Cha, J. K.; Oh, J. Curr. Org.
Chem. 1998, 2, 217-232. (f) F o¨ hlisch, B.; Joachimi, R. Chem. Ber. 1987,
1
20, 1951-1960.
(
9) (a) Giese, S.; West, F. G. Tetrahedron 2000, 56, 10221-10228. (b)
Giese, S.; Kastrup, L.; Stiens, D.; West, F. G. Angew. Chem. 2000, 1970-
973.
10) There is ample precedent for preferred compact approach of furan
1
(
6
to oxyallyl partners. See Supporting Information for a discussion of the
structural assignments.
(
11) For a recent discussion of the theoretical basis of endo/exo
process is surprising, given the availability of the typical
eliminative pathway of the Nazarov reaction; however, none
preferences in [4 + 3]-cycloadditions, see: Cramer, C. J.; Harmata, M.;
Rashatasakhon, P. J. Org. Chem. 2001, 66, 5641-5644.
2748
Org. Lett., Vol. 5, No. 15, 2003

from either face is energetically comparable. While 4a and
the unseen isomer 5a are diastereomers, the origin of the
selectivity also can be viewed from a regiochemical perspec-
tive (Scheme 2). Transition state 6 entails bonding between
temperature was found to effect the Nazarov electrocycliza-
tion, but Lewis acid-catalyzed polymerization of the diene
was a serious complication. Eventually, use of catalytic
amounts (0.1 equiv) of BF
3 2
‚OEt at 40 °C in 1,2-dichloro-
ethane was found to be optimal. To our knowledge, this is
one of only two examples of Nazarov processes successfully
9
a
employing catalytic quantities of Lewis acid.
Scheme 2
Use of 1b,c,e together with isoprene explicitly introduced
the issue of regiochemistry in the cycloaddition process
(entries 7, 11, and 14). Significant regiocontrol was not
expected a priori, given the similar substitution pattern at
the oxyallyl termini and the low regioselectivity usually
observed for [4 + 3]-cycloadditions employing isoprene and
1
5
related monosubstituted dienes. However, in the event,
regioisomeric mixtures of 4.2:1f5:1 were obtained in all
three cases. Provisional regiochemical assignment of the
major isomers was possible in two cases (Figure 1). The
C-1 of isoprene and the oxyallyl terminus in which the
adjacent phenyl is syn to the approaching diene, while
transition state 7 involves the other possible orientation. The
12
origins of the high selectivity seen in this case are obscure.
Unsymmetrically substituted dienones 1b-e were exam-
ined with several 1,3-dienes, giving good to excellent yields
of the [4 + 3]-adducts. Optimal general conditions employed
1.0 equiv of BF
3
‚OEt and 2 equiv of diene at -20 °C. As
2
in the case with 1a and furan, cyclic dienes furan and
cyclopentadiene (entries 4, 5, 8, and 9) reacted via a compact
10
transition state to provide the endo isomers. In most cases,
the diene approached selectively from the less hindered face
Figure 1. Regiochemical assignments of 4b and 5e.
1
of the cyclic oxyallyl (anti to R ), although in one instance
low facial selectivity was observed (entry 8).13 This is
consistent with the excellent facial selectivity previously
major isomer from the reaction of 1b with isoprene was
assigned as 4b on the basis of the observation of a NOE
interaction between the benzylic methine and one of the
allylic protons and a strong vicinal coupling of the same
allylic proton to the adjacent alkene proton. In the case of
1e + isoprene, a NOE interaction between the protons of
the angular methyl and the allylic methylene adjacent to the
alkene proton supported the assignment of the major isomer
as 5e. Although a similar analysis was not possible for the
cycloadducts derived from 1c and isoprene, the major isomer
was tentatively assigned as 4c due to its analogy to 4b. In
all cases, the minor isomer was presumed to be a regioisomer
rather than a stereoisomer, since the analogous reactions with
dimethylbutadiene gave a single product. Formation of 4e
in preference to 5e is especially significant, as this adduct
possesses most of the carbon skeleton of the cyclooctanoid
natural products dactylol and poitediol.
6
b
reported in the intramolecular version of this process. The
generally high yields obtained from dimethylbutadiene and
isoprene (entries 6, 7, and 10-14) are gratifying in light of
the paucity of examples of efficient intermolecular [4 +
6
f
3
]-cycloadditions involving acyclic 1,3-dienes, especially
8
with cyclic oxyallyls. Moreover, complete diastereofacial
selectivity was obtained in all of the cases employing acyclic
dienes.
The cyclopentenyl substrate 1e was unreactive under the
standard conditions. We attribute this to a higher barrier to
Nazarov electrocyclization in this case due to the strain
associated with the resulting bicyclo[3.3.0]octenyl cation. A
similar result was seen in a series of fused bicyclic pyran-
4-ones, in which those fused to a six-membered or larger
ring underwent photochemical ring contraction via a Naz-
arov-like process, while the cyclopenteno-fused example was
inert to extended irradiation.14 In the case of 1e, higher
This methodology provides access to keto-bridged cy-
clooctenes in a single step from simple dienone and diene
(
12) Intervention of a competing stepwise cycloaddition mechanism in
unsymmetrical cases cannot be ruled out as a possible contributor to the
regioselectivity. We thank one of the reviewers for this suggestion.
(15) (a) Aungst, R. A., Jr.; Funk, R. L. Org. Lett. 2001, 3, 3553-3555.
(b) Harmata, M.; Sharma, U. Org. Lett. 2000, 2, 2703-2705. (c) Shimizu,
N.; Tanaka, M.; Tsuno, Y. J. Am. Chem. Soc. 1982, 104, 1330-1340. (d)
Sakurai, H.; Shirahata, A.; Hosomi, A. Angew. Chem., Int. Ed. Engl. 1979,
18, 163-164. (e) Shimizu, N.; Tsuno, Y. Chem. Lett. 1979, 103-106. (f)
Hoffmann, H. M. R.; Chidgey, R. Tetrahedron Lett. 1978, 85-88.
(
13) See Supporting Information for a discussion of the stereochemical
assignments of 2c.
14) Fleming, M.; Fisher, P. V.; Gunawardena, G. U.; Jin, Y.; Zhang,
(
C.; Zhang, W.; Arif, A. M.; West, F. G. Synthesis 2001, 1268-1274.
Org. Lett., Vol. 5, No. 15, 2003
2749

reactants. The conditions are relatively mild, and the yields
are generally good to excellent. Efficient intermolecular
trapping with acyclic dienes such as dimethylbutadiene and
isoprene is especially notable. In general, high diastereofacial
selectivity is seen with approach of the diene away from the
larger substituent on the cyclopentenyl cation, and complete
selectivity for the compact transition state was observed with
cyclic dienes. Oxyallyl cations with comparable R substit-
uents but differential â substitution display a surprising
degree of regioselectivity with isoprene. The origins of the
regioselectivity, the scope of this process with more elaborate
diene and dienone partners, and its potential application to
natural product targets are under current study, and the results
will be described in due course.
Acknowledgment. We thank the National Institutes of
Health for support of this work, and the University of Utah
Department of Chemistry for a Henry Eyring Research
Fellowship (B.D.S.).
Supporting Information Available: Experimental pro-
cedures and physical data for dienones 1b-e and all [4 +
1
3
]-cycloadducts, H NMR spectra for 1c-e, 2a, 4a, 3b, 8b,
and 5c, and X-ray data for 4a and 2b. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL034985B
2750
Org. Lett., Vol. 5, No. 15, 2003