Conformational effects in diastereoselective aryne diels-alder reactions: synthesis of benzo-fused [2.2.1] heterobicycles

Article abstract of DOI:10.1021/ol9019869

It was found that the diastereoselectivity of the Dials-Alder reaction between arynes and substituted furans Is highly sensitive to substitution, which affects the reactive conformation. By varying the location of the groups on the diene partner, It Is po

Full text of DOI:10.1021/ol9019869

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4688-4691
Conformational Effects in
Diastereoselective Aryne Diels-Alder
Reactions: Synthesis of Benzo-Fused
[2.2.1] Heterobicycles
Robert Webster and Mark Lautens*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario, Canada M5S 3H6
mlautens@chem.utoronto.ca
Received August 26, 2009
ABSTRACT
It was found that the diastereoselectivity of the Diels-Alder reaction between arynes and substituted furans is highly sensitive to substitution,
which affects the reactive conformation. By varying the location of the groups on the diene partner, it is possible to obtain both excellent
chemical yields and high stereoselectivity. This methodology offers rapid and convenient access to enantiomerically pure bicyclic scaffolds
which are difficult to prepare by other means.
Arynes have attracted considerable interest from the synthetic
community as reactive intermediates;1 however, asymmetric
Scheme 1.
ADA Cycloaddition with Acyclic Dienes3c
reactions involving them are exceedingly rare and remain a
challenge in the field.3a We previously reported the first
diastereoselective aryne Diels-Alder (ADA) reaction to yield
enantiomerically enriched products with acyclic dienes
bearing Oppolzer’s sultam as a chiral auxiliary, which gives
convenient entry into the biologically privileged 1,4-dihy-
dronaphthalene core (Scheme 1).3c
While excellent selectivites were obtained (>19:1), yields
were more modest, ranging from 40-60%, presumably due
to the acyclic scaffold’s thermodynamic preference to occupy
the s-trans conformation. During the course of our investiga-
tion to prepare enantiomerically enriched unsymmetrical
(1) For recent reviews on arynes see: (a) Pelissier, H.; Santelli, M.
Tetrahedron 2003, 59, 701–730. (b) Wenk, H.; Winkler, M.; Sander, W.
Angew. Chem., Int. Ed. 2003, 42, 502–527. (c) Dyke, A.; Hester, A.; Lloyd-
Jones, G. Synthesis 2006, 24, 4093–4112. (d) Pen˜a, D.; Pe´rez, D.; Guitia´n,
E. Heterocycles 2007, 74, 89–100. (e) Sanz, R. Org. Prep. Proced. Int.
2008, 40, 215–291.
(3) Only three reports of stereoselective reactions of arynes to yield
enantiomerically enriched products have appeared in the literature: (a) Diego,
P.; Pe´rez, D.; Guitia´n, E. Chem. Rec. 2007, 7, 326–333. (b) Caeiro, J.; Diego,
P.; Cobas, A.; Pe´rez, D.; Guitia´n, E. AdV. Synth. Catal. 2006, 348, 2466–
2474. (c) Dockendorff, C.; Sahli, S.; Olsen, M.; Milhau, L.; Lautens, M.
J. Am. Chem. Soc. 2005, 127, 15028–15029.
(2) For aryne trapping with furan, see: (a) Wittig, G.; Pohmer, L. Angew.
Chem. 1955, 67, 348. (b) Gilman, H.; Gorsich, R. J. Am. Chem. Soc. 1957,
79, 2625–2629. (c) Stiles, M.; Miller, R. J. Am. Chem. Soc. 1960, 82, 3802.
(d) Harrison, H.; Heaney, H.; Lees, P. Tetrahedron 1968, 24, 2625–2629.
(e) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211–
1214. (f) Kitamura, T.; Wasai, K.; Todaka, M.; Fujiwara, Y. Synlett 1999,
6, 731–732.
(4) Webster, R.; Bo¨ing, C.; Lautens, M. J. Am. Chem. Soc. 2009, 131,
444–445.
10.1021/ol9019869 CCC: $40.75
Published on Web 09/24/2009
 2009 American Chemical Society

oxabenzonorbornenes to study their behavior in ring-opening
chemistry,4 it was found that the analogous ADA reaction
with heterocyclic dienes fixed in the s-cis state gave much
improved yields, but a fluctuation of diastereoslectivity was
observed depending on the diene substrate. We felt this
phenomenon warranted further study.
When chiral pyrroles were treated with the silylaryl triflate
aryne precursors pioneered by Kobayashi,2e in the presence
of CsF and acetonitrile at room temperature, it was discov-
ered that 4 is an excellent substrate which reacts with a
variety of arynes in a highly efficient and diastereoselective
manner (Table 1). The use of Boc as a protecting group
the Boc group. This removal was accomplished by treating
the products with acetyl chloride in methanol to cleanly
afford the HCl salts which gave adequately resolved 1H NMR
spectra. In addition, it was possible to use the 19F NMR of
the crude 4c to confirm the dr was >20:1. Somewhat lower
yields were observed for the formation of 4d and 4e (Table
1, entries 4 and 5), presumably due to the relatively slow
formation of naphthyne and electron-rich arynes, respec-
tively.5 The absolute configuration of adducts 4b and 4d was
determined by deprotection followed by X-ray analysis of
its HCl salt and shows the same facial selectivity observed
for the acyclic dienes.
To our surprise, the ADA reaction of simple furan
substrates showed a large decrease in diastereoselectivity
(Scheme 2). The absolute configuration of the products 8
Table 1. ADA Reaction of N-Boc-pyrroles
Scheme 2. Steric Buttressing of the Chiral Auxiliary
and 13 were confirmed by single-crystal X-ray analysis. The
facial selectivity of the major diastereomer of the furan
cycloaddition was observed to be the same as that arising
from cycloaddition with the acyclic diene. Presumably, for
5 the oxygen of the furan and the sulfonamide moiety may
experience electrostatic repulsion,6 making the reactive
conformer significantly different than in the acyclic scaffold.
Various Lewis acid additives (BF3·Et2O, Cu(OTf)2, Zn(OTf)2,
Ti(OiPr)4) were employed in an attempt to influence the
dominant conformation in the transition state, but all proved
to have a negative impact on the yield and little effect on
the selectivity of the cycloaddition.7
a NMR peak broadening due to Boc groups was observed. Products
were deprotected using acetyl chloride in methanol, and the dr was assigned
from the crude 1H NMR of the corresponding HCl salt. b Absolute
configuration proven using X-ray analysis of deprotected HCl salt. c 4.5
equiv of the aryne precursor was used. d Assignment of dr confirmed by
19F NMR.
Overall, the stereoselectivity proved to be relatively
insensitive to temperature, as reactions between benzyne at
affords a favorable balance of reactivity, as the N-tosylpyrrole
was completely unreactive under these conditions and the
N-methylpyrrole was quickly consumed to yield an intrac-
table mixture of products. Due to line broadening in the H
NMR spectra of the N-Boc-azabicycles 4a-e, it was not
(5) Zhijian, L.; Larock, R. J. Org. Chem. 2007, 72, 4689–4691.
(6) The use of Oppolzer’s sultam as a chiral auxiliary in thermal reactions
has been thoroughly reviewed: Kim, B.; Curran, D. Tetrahedron 1993, 49,
293–318.
1
possible to unambiguously report a dr without first removing
(7) See the Supporting Information for the data table.
Org. Lett., Vol. 11, No. 20, 2009
4689

60 °C with 5 and 11 as the diene component gave similar
product ratios. We suspected the large excess of cesium
cations present might have some effect; however, using
alternate methods of benzyne generation in the absence of
cesium gave similar results,8 suggesting that a cesium chelate
is not responsible for the changes in selectivity. Furthermore,
auxiliary relative to the methyl group in 11 and may twist the
π system into adopting the opposite rotamer as the major
reactive conformation in solution. It remains unclear if the
dramatic increase in stereoselectivity in the azabicycle series
(Table 1) is due to a similar conformational change in the
orientation of the chiral auxiliary or perhaps owing to facial
shielding by the Boc group directed by the auxiliary.9
1
1D and 2D H NMR spectra of various dienes showed no
observable change with the addition of CsF. The use of other
chiral auxiliaries led to lower observed selectivity,7 in accord
with our previous report on the reactions of acyclic dienes.3b
We considered that adding a bulky substituent to the
3-position of the furan ring (Scheme 2) may overcome the
presumed electrostatic repulsion and force the π system to adopt
a reactive conformation similar to that of the acyclic dienes.
Compound 11 with a methyl group substituted at the 3-position
of the furan showed a significant increase in diastereoselectivity
(10:1) relative to the parent substrate when exposed to the same
reaction conditions. Replacement of the methyl with bromine
in 12 gives even higher selectivity (17:1).
The ADA conditions are amenable to gram scale production
and upon scale-up require as little as 1.3 equiv of aryne
precursor. For example, 8 can be conveniently isolated by
dissolution of the crude product in ethyl acetate followed by
precipitation using a small amount of pentane, giving a 60%
yield of the major diastereomer (98% de) without recourse to
chromatography. This constitutes a major improvement com-
pared to typical aryne trappings of this type, which commonly
employ a large excess of the furan (often 5-50 equiv).2
To demonstrate the utility of these substrates, post cycload-
dition transformations were performed (Scheme 3). Following
The chiral auxiliary can be easily removed under reductive
conditions (Scheme 2). HPLC analysis of 16 showed an er of
92:8 in agreement with the dr of 10:1 estimated from the H
1
Scheme 3
.
Synthesis of Optically Pure Bridged Benzazepine
and 1,2-Naphthalene Oxide Scaffolds
NMR of 13. Recrystallization of 16 gave 99% ee material
suitable for X-ray analysis. Tethering the chiral auxiliary to the
3-position of the furan shows similar, but less exaggerated,
effects on the stereochemical outcome. The absolute configu-
ration of 23 (Table 2) was also identified using X-ray analysis
and was shown to arise from the opposite facial selectivity
observed for both products 8 and 13. The methyl group at the
2-position in furan 22 is on the opposite side of the chiral
Table 2. Obtaining Opposite Facial Selectivity: Conformational
Control with the Auxiliary in the 3-Position
a dihydroxylation/oxidative cleavage/reductive amination pro-
tocol10 it was possible to convert the aza- and oxabenzonor-
bornenes into orthogonally protected aza- and oxa-bridged
(8) Reactions with benzenediazonium carboxylate at elevated temper-
atures gave similar yields and slightly lower selectivity.
(9) It would be expected that if the Boc group was simply acting as a
steric anchor at the 1-position of the pyrrole, the absolute configuration of
the azabicyclic products would be the opposite of that observed in the
reaction of furan substrate 11 which bears a methyl group on the opposite
side of the heterocycle relative to the chiral auxiliary.
(10) Brooks, P.; Caron, S.; Coe, J.; Ng, K.; Singer, R.; Vazquez, E.;
Vetelino, M.; Watson, H.; Whritenour, D.; Wirtz, M. Synthesis 2004, 11,
1755–1758.
a Ratio assinged from crude 1H NMR by relative peak integration.
b Absolute configuration proven using X-ray analysis. c Absolute configu-
ration of the major diastereomer is unknown.
4690
Org. Lett., Vol. 11, No. 20, 2009

benzazepines 27 and 28, respectively. Although such hetero-
cycles are rare, they show an interesting range of biological
activity, and currently no alternative simple methodology exists
for their preparation as single enantiomers.11 When 8 was
subjected to Tam’s Ru(II)-catalyzed isomerization conditions12
(Scheme 3), 29 was isolated as a 7:1 mixture of regioisomeric
epoxides with opposite selectivity expected based on Tam’s
original report, possibly due to a directing effect involving Ru
chelation by the sultam moiety. X-ray crystallography of 29
confirms the structure, but both regioisomers were found to
cocrystallize in an approximately 7:1 ratio.
tivites are obtainable and the absolute configuration at the
bridgehead junction can be controlled. These products allow
rapid access to enantiomerically pure aza-/oxa-bridged ben-
zazepines and 1,2-naphthalene oxides. Further mechanistic
and computational models are currently being investigated
to better understand the nature of the stereoselectivity in the
cycloaddition.
Acknowledgment. This work is supported by NSERC
(Canada), Merck-Frosst (IRC), and the University of Toronto.
R.W. thanks Dr. Christian Bo¨ing (Univeristy of Toronto) for
highly useful discussions and assistance with preliminary
parts of this work. We also thank Dr. A. Lough (University
of Toronto) for X-ray analysis.
In summary, a practical synthesis of optically pure [2.2.1]
benzo-fused oxa- and azabicyclic alkenes has been devel-
oped, and by careful choice of substituents to affect the
conformation of the substrates, both high yields and selec-
Supporting Information Available: Experimental pro-
cedures, characterization data for new compounds, and
additional data tables. This material is available free of charge
via the Internet at http://pubs.acs.org.
(11) For oxa-benzazepines as c-Met kinase inhibitors, see: Gulzar, A.;
Bohnstedt, A.; Breslin, H.; Burke, J.; Curry, M.; Diebold, J.; Dorsey, B.;
Dugan, B.; Feng, D.; Gingrich, D.; Guo, T.; Ho, K.; Learn, K.; Lisko, J.;
Liu, R.; Mesaros, E.; Milkiewicz, K.; Ott, G.; Parrish, J.; Theroff, J.; Thieu,
T.; Tripathy, R.; Underiner, T.; Wagner, J.; Weinberg, L.; Wells, G.; You,
M.; Zificsak, C. WO 2008051547, Oct 23, 2007. As ulcer treatments:
Wachter, M.; Karanewsky, D. US 4761413, Dec 22, 1986. For aza-
benzazepines as histamine H4 receptor ligands: Bell, A.; Lane, C.; Mowbray,
C.; Selby, M.; Swain, D.; Williams, N. WO 2007072163, June 28, 2007.
OL9019869
(12) Villeneuve, K.; Tam, W. J. Am. Chem. Soc. 2006, 128, 3514–3515.
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