Synthesis of unique scaffolds via diels alder cycloadditions of tetrasubstituted cyclohexadienes

Article abstract of DOI:10.1021/ol100318f

Chemical Reaction Reprentation Diels -Alder cycloadditions of highly substituted cyclohexadienes derived from rhodium-mediated [2 + 2 + 2] cyclizations are reported. Reactive heterodienophlles, Including singlet oxygen (¹O₂), 4-subst

Full text of DOI:10.1021/ol100318f

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1592-1595
Synthesis of Unique Scaffolds via
Diels-Alder Cycloadditions of
Tetrasubstituted Cyclohexadienes
Amanda L. Jones and John K. Snyder*
Department of Chemistry and the Center for Chemical Methodology and Library
DeVelopment (CMLD-BU), Boston UniVersity, Boston, Massachusetts 02215
jsnyder@bu.edu
Received February 6, 2010
ABSTRACT
Diels-Alder cycloadditions of highly substituted cyclohexadienes derived from rhodium-mediated [2 + 2 + 2] cyclizations are reported.
Reactive heterodienophiles, including singlet oxygen (1O2), 4-substituted-1,2,4-triazoline-3,5-diones (TADs), and aryl- and acylnitroso compounds
were employed, yielding novel heterocyclic products.
Reactivity in Diels-Alder (DA) cycloadditions of cyclo-
hexadienes is strongly influenced by steric constraints, often
requiring forceful conditions or catalysis to promote the
desired annulation.1,2 Unactivated, highly substituted cyclo-
hexadienes, which can be accessed via transition-metal-
catalyzed [2 + 2 + 2] cyclizations, are relatively unreactive
in intermolecular cycloadditions.2b,3
Previously, we reported the rhodium-mediated intramo-
lecular [2 + 2 + 2] cyclizations of tethered diyne-enone
substrates to produce cyclohexadiene systems which were
subsequently aromatized with DDQ, giving highly substituted
benzene rings.4 Other groups have also reported the use of
[2 + 2 + 2] cyclizations to generate cyclohexadienes with
quaternized allylic centers which cannot aromatize.5 We
became interested in the reactivity of these highly substituted,
electronically unactivated diene systems in DA cycloaddi-
tions, particularly with heterodienophiles, as this would allow
the creation of unique, densely functionalized scaffolds.
The preparation of three model substrates 4a-c was
straightforward employing methodology we previously re-
ported (Scheme 1).4 Diynyl esters 1a and 1b, prepared from
sequential SN2 displacements of 1,4-dibromobutyne,4,6 were
subjected to Weinreb amidations followed by isopropenyl
Grignard additions to give enediynes 3a and 3b. The desired
[2 + 2 + 2] cyclizations were achieved under Rh(I)-
catalyzed, microwave-promoted conditions to give racemic
cyclohexadienes 4a and 4b in 90% and 91% yields, respec-
tively.4 Pyrrolidine substrate 4c was easily prepared from
[2 + 2 + 2] cyclization of diyne 57 with excess methyl
methacrylate 6.5b
(1) For recent reviews of Diels-Alder reactions in synthesis, see: (a)
Nicolau, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew.
Chem., Int. Ed. 2002, 41, 1668. (b) Tietze, L. F.; Kettschau, G. Top. Curr.
Chem. 1997, 189, 1
.
(2) For work on catalytic Diels-Alder reactions, see: (a) Reymond, S.;
Cossy, J. Chem. ReV. 2008, 108, 5359. (b) Jung, M. E.; Ho, D.; Chu, H. V.
Org. Lett. 2005, 7, 1649, footnote 2. (c) Hayashi, Y. Cycloaddit. React.
Org. Synth. 2002, 5. (d) Dias, L. C. J. Braz. Chem. Soc. 1997, 8, 289
.
(5) (a) Geny, A.; Gaudrel, S.; Slowinsky, F.; Amatore, M.; Choraqui,
G.; Malacria, M.; Aubert, C.; Gandon, V. AdV. Synth. Catal. 2009, 351,
271. (b) Shibata, T.; Tsuchikama, K. Org. Biomol. Chem. 2008, 6, 1317,
and references therein.
(3) (a) Ren, S.; Igarashi, E.; Nakajima, K.; Kanno, K.-i.; Takahashi, T.
J. Am. Chem. Soc. 2009, 131, 7492. (b) Nishikawa, T.; Kakiya, H.;
Shinokubo, H.; Oshima, K. J. Am. Chem. Soc. 2001, 123, 4629. (c) Grigg,
R.; Scott, R.; Stevenson, P. J. Chem. Soc., Perkin Trans. 1 1988, 1365
(4) Jones, A. L.; Snyder, J. K. J. Org. Chem. 2009, 74, 2907.
.
(6) Blond, G.; Bour, C.; Salem, B.; Suffert, G. Org. Lett. 2008, 10, 1075.
(7) Nishida, M.; Shiga, H.; Mori, M. J. Org. Chem. 1998, 63, 8606.
10.1021/ol100318f  2010 American Chemical Society
Published on Web 03/08/2010

configuration was determined by NOE studies,13 with the
1
major stereoisomer resulting from O2 addition to the face
Scheme 1. Synthesis of Model Cyclohexadiene Substrates
opposite the angular methyl group. Although the ozone-
phosphite adduct reaction underwent complete conversion
(entry 1), several other products were also formed. These
byproducts were reduced by lowering the amount of (PhO)3P
used and ensuring all exogenous ozone was purged (entry
3). The photochemical reaction was limited by low conver-
sion of 4a even after extended reaction times (entry 4),
though the yield and dr remained comparable to the
ozone-phosphite procedure.
The singlet oxygen cycloaddition was then extended to
cyclohexadienes 4b and 4c (Table 2, entries 1 and 2),
a
1
Table 2. Cycloaddition of Dienes 4b-d with O2
With the tetrasubstituted cyclohexadienes in hand, we turned
to the cycloadditions of highly substituted cyclohexadiene 4a.
We began with singlet oxygen (1O2), generated in situ via
photochemical excitation,8 or degradation of the 1:1 ozone/
(PhO)3P adduct.9 Successful cycloaddition of 4a with 1O2 would
produce an endoperoxide, an intriguing class of compounds that
display antimalarial and other therapeutic properties.10
1
Table 1. Cycloaddition of O2 with Cyclohexadiene 4a
a Conditions: (PhO)3P (2 equiv), O3, -70 to 0 °C, 1.5 h. b Isolated yield.
c Determined by NMR.
yielding endoperoxides 7b and 7c. The high diastereoselec-
tivity of 7c likely results from the unfavorable electronic
repulsion that would exist between the angular ester group
and the approaching oxygen dienophile in leading to the other
diastereomer. Aromatizable cyclohexadiene 4d4 (entry 3)
could also be trapped with 1O2 at low temperature, yielding
diastereomeric endoperoxides 7d and 7e in a 4:3 ratio.14 The
low selectivity was attributed to the equatorial orientation
of the ester group in 4d, which reduces competition between
addition to the two faces of the diene.
conditionsa
(equiv of (PhO)3P)
entry
yieldb (%)
drc
1
2
3
4
A (10)
A (5)
A (2)
B
25
21
17:1
>20:1
>20:1
13:1
36
37(30)d
a Conditions: (A) (PhO)3P, O3, DCM, -70 to 0 °C, 1.5 h; (B) Rose
Bengal (1 mol %), O2 (1 atm), hν, EtOH, 0-10 °C, 7 h. b Isolated yields.
c Determined by NMR. d Percentage of (()-4a recovered.
With these promising results in hand, reactive nitrogen-
containing heterodienophiles were screened with cyclohexa-
diene 4c, which is easily prepared in large quantities. These
included 1,2,4-triazoline-1,4-diones (TADs) 9 (Table 3,
entries 1 and 2),15 arylnitroso 10 (entries 3-6),16,17 and
acylnitroso compounds 11 (entries 7-9), which are generated
1
Both methods of O2 generation produced endoperoxide
cycloadduct 7a in modest yield (Table 1).11 The high
diastereoselectivity was unexpected considering the small
size and limited steric bias of the dienophile.12 The relative
(8) Adam, W.; Bosio, S.; Bartoschek, A.; Griesbeck, A. G. Photoox-
ygenation of 1,3-dienes. In CRC Handbook of Organic Photochemistry and
Photobiology, 2nd ed.; Horspol, W., Lenci, F., Eds.; CRC Press: Boca Raton,
FL, 2004; pp 25/1-25/19.
(9) Murray, R. W.; Kaplan, M. L. J. Am. Chem. Soc. 1968, 90, 537.
(10) (a) Begue, J.-P.; Bonnet-Delpon, D. Drugs Future 2005, 30, 509.
(b) Woerdenberg, H. J.; Moskal, T. A.; Pras, N.; Malingre, T. M.; El-Farely,
F. S.; Harm, H.; Konnings, A. W. T. J. Nat. Prod. 1993, 56, 849.
(11) For related examples, see: (a) Wijeratne, E. M. K.; Liu, M. X.;
Kantipudi, N. B.; Brochini, C. B.; Gunatilaka, A. A. L.; Canfield, L. M.
Bioorg. Med. Chem. 2006, 14, 7875. (b) Harwood, L. M.; Robertson, J.;
Swallow, S. Synlett 1999, 9, 1359.
(12) Adam, W.; Prein, M. Acc. Chem. Res. 1996, 29, 275.
(13) See the Supporting Information for details on NOE studies.
(14) The structures of 7d and 7e were confirmed after O-O bond
cleavage. See the Supporting Information for complete details.
Org. Lett., Vol. 12, No. 7, 2010
1593

in situ by hydroxamic acid oxidation18 and have been
extensively used by Miller and co-workers to prepare a
variety of biologically active compounds.18a-c,e
the cycloadditions were analogous to those of 1O2 additions,
in which the major diastereomer resulted from dienophile
addition to the face away from the ester group. This was
supported by NOE studies13 and, for the triazoline dieno-
philes, confirmed by X-ray crystal structure analysis of PTAD
cycloadduct 8b (Figure 1). The para-substituted arylnitroso
Table 3. Dienophile Screening with Cyclohexadiene 4c
Figure 1. ORTEP diagram of cycloadduct (()-8b.
compounds 10a,b,d and acylnitroso precursors 11a-c ex-
hibited good regioselectivity in favor of the bulkier N-
substituted group adding remote to the ester-containing
quaternary center.19 Introduction of an ortho bromine sub-
stituent (10c, Table 3, entry 5) reduced both the reactivity
and regioselectivity.
While acylnitroso adducts 8g-i are stable in solution for
several days, arylnitroso adducts 8c,d,f undergo 10-25%
cycloreversion to 4c within 24 h in CDCl3.20 In order to
address this instability, reductive cleavage of the N-O bond
of 8g with Zn/AcOH21 was carried out (Scheme 2, eq 1),
Scheme 2. N-O Bond Cleavage of Nitroso Cycloadducts
a Conditions: (A) 9a,b (1.1 equiv), DCM, 0 °C; (B) 10a-d (2.0 equiv),
DCM, 0 °C; (C) 11a (1.5 equiv), NaIO4 (1.6 equiv), BnEt3NCl (1.6 equiv),
DCM, 0 °C; (D) 11b,c (1.5 equiv), Bu4NIO4 (1.5 equiv), DCM, 0 °C.
b Isolated yield. c Determined by NMR, identity of minor product unknown
unless otherwise noted. d Diastereomeric ratio. e Regioisomeric ratio.
The resulting racemic heterocyclic cycloadducts 8a-i were
produced in yields ranging from 64 to 87% and isomeric
ratios of up to >20:1 (Table 3). The diastereoselectivities of
producing amido alcohol 12a in excellent yield. The com-
paratively electron rich N-O bond of arylnitroso cycloadduct
8c was resistant to these and other reductive conditions,
including SmI2,22 Na/SiO2,23 and Pd/C-H2 (1 atm),24 leading
only to recovery of a mixture of cycloadduct and cyclor-
(15) (a) Fujia, M.; Matsushima, H.; Sugimura, T.; Tai, A.; Okuyama,
T. J. Am. Chem. Soc. 2001, 123, 2946. (b) Jensen, F.; Foote, C. S. J. Am.
Chem. Soc. 1987, 109, 6376.
(16) Priewisch, B.; Ru¨ck-Braun, K. J. Org. Chem. 2005, 70, 2353.
(17) (a) Bentley, K. W.; Horsewood, P.; Kirby, G. W. J. Chem. Soc.,
Chem. Commun. 1969, 23, 1411. (b) Hamer, J.; Ahmad, M.; Holliday, R. E.
J. Org. Chem. 1963, 28, 3034.
(18) (a) Yan, S.; Miller, M. J.; Wencewicz, T. A.; Mo¨llmann, U. Bioorg.
Med. Chem. Lett. 2010, 20, 1302. (b) Yang, B.; Zo¨llner, T.; Gebhardt, P.;
Mo¨llmann, U.; Miller, M. J. Org. Biomol. Chem. 2010, 8, 691. (c) Yang,
B.; Miller, P. A.; Mo¨llmann, U.; Miller, M. J. Org. Lett. 2009, 11, 2828.
(d) Iwasa, S.; Fakhruddin, A.; Nishiyama, H. Mini-ReV. Org. Chem. 2005,
2, 157. (e) Vogt, P. F.; Miller, M. J. Tetrahedron 1998, 54, 1317. (f) Keck,
G. E.; Romer, D. F. J. Org. Chem. 1993, 58, 6083.
(19) See the Supporting Information for details of regioselectivity
determination.
(20) Cycloadduct 10e was more stable in solution, possibly due to the
bulky o-Br substituent forcing the aromatic ring to rotate out of the plane
of the N-O bond, slowing the cycloreversion.
(21) Hall, A.; Bailey, P. D.; Ress, D. C.; Rosair, G. M.; Wightman,
R. H. J. Chem. Soc., Perkin Trans. 1 2000, 329.
1594
Org. Lett., Vol. 12, No. 7, 2010

eversion product 4c. By increasing the H2 pressure to 40
bar using an H-Cube hydrogenation reactor, the desired N-O
cleavage was achieved for 8c and 8f, yielding stable amino
alcohols 12b and 12c, respectively (Scheme 2, eq 2). Aryl
bromide cycloadducts 8d and 8e underwent dehalogenation
in addition to N-O bond cleavage under these conditions,
yielding only 12b.
Scheme 4
.
Acylnitroso Cycloadditions of Cyclohexadienes
4a,b,da
Scheme 3
.
Cycloadditions of Cyclohexadienes 4a,b,d-g with
TADs 9a and 9ba
a See the Supporting Information for complete reaction details and
compound characterization.
a See the Supporting Information for complete reaction details and
compound characterization
with the more sterically demanding N-substituted portion of
the unsymmetrical acylnitroso dienophiles adding away from
the Me-bearing quaternary center. Aromatizable cyclohexa-
dienes 4d-g (Scheme 3, eq 2) formed TAD cycloadducts
in which the dienophile added to the face opposite the ethyl
ester.
In conclusion, cycloadditions of highly substituted, unac-
tivated cyclohexadienes were achieved using several classes
of heterodienophiles under mild conditions. The substrates
are easily prepared by Rh(I)-catalyzed [2 + 2 + 2]
cyclizations previously reported.4 The resulting novel het-
erocyclic cycloadducts were generally isolated in good yields
and high selectivities. Future work is focused on diversifica-
tion of the cycloadducts. Development of an asymmetric
version of the [2 + 2 + 2] cyclization as well as studies to
better understand the origin of selectivity in these cycload-
ditions are also being investigated and will be reported in
due course.
The reactivity of racemic tricyclic cyclohexadienes with
select heterodienophiles from Table 3 was also investigated
(Schemes 3 and 4). Substrates 4a and 4b underwent
cycloadditions with TADs 9a and 9b (Scheme 3, eq 1),
providing four novel heterocyclic cycloadducts, 13a-14b,
in good to excellent yields and high diastereoselectivities.
Aromatizable cyclohexadienes 4d-g were also successfully
trapped with 9a and 9b, yielding cycloadducts 15a-18a and
15b-18b, respectively, also in good yields and diastereo-
selectivities (Scheme 3, eq 2).
Acylnitroso dienophiles also underwent cycloadditions
with 4a and 4b (Scheme 4, eqs 1 and 2). Subsequent N-O
cleavage of the pyridinyl-containing cycloadducts yielded
amido alcohols 13c and 14c. (Scheme 4, eq 1). Low regio-
and diastereoselectivities were observed in the analogous
cycloaddition of aromatizable cyclohexadiene 4d with 11a
(Scheme 4, eq 3), similar to what was observed for the
Acknowledgment. We thank the NIGMS CMLD initiative
(P50 GM067041) for financial support and the NSF for
supporting the purchase of the NMR (CHE 0619339) and
HRMS (CHE 0443618) spectrometers. We thank Dr. Emil
Lobkovsky (Cornell University) for X-ray structure analysis
and Professors John Porco and Aaron Beeler (Boston
University) for helpful discussions.
1
cycloaddition of 4d with O2.
Overall, the regio- and diastereoselectivities of all cy-
cloadducts derived from tricyclic cyclohexadienes were
consistent with previous observations. For nonaromatizable
tricyclic dienes 4a and 4b (Scheme 3, eq 1 and Scheme 4,
eqs 1 and 2), major products resulted from approach of the
dienophile from the face opposite the angular methyl group
Supporting Information Available: Full experimental
1
procedures, characterization data, and copies of H and 13C
(22) (a) McAuley, B. J.; Nieuwenhuyzen, M.; Sheldrake, G. N. Org.
Lett. 2000, 2, 1457. (b) Keck, G. E.; Wager, T. T.; McHardy, S. F.
Tetrahedron 1999, 55, 11755.
spectra of all new products, and X-ray crystallographic data
for 8b and 15b (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
(23) Dye, J. L.; Cram, K. D.; Urbin, S. A.; Redko, M. Y.; Jackson,
J. E.; Lefenfeld, M. J. Am. Chem. Soc. 2005, 127, 9338.
(24) Von Nussbaum, F.; Hanke, R.; Fahrig, T.; Benet-Buchholz, J. Eur.
J. Org. Chem. 2004, 2783.
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