Effect of counterion structure on rates and diastereoselectivities in α,β-unsaturated iminium-ion diels-alder reactions

Article abstract of DOI:10.1021/ol201448h

The use of cyclic α,β-unsaturated iminium-ion dienophiles is documented in two highly diastereoselective Diels-Alder (DA) reactions. The dienophilic counterion was found to have a significant effect on reactivity.

Full text of DOI:10.1021/ol201448h

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3758–3761
Effect of Counterion Structure on Rates and
Diastereoselectivities in r,β-Unsaturated
Iminium-Ion DielsÀAlder Reactions
€
David Marcoux, Pascal Bindschadler, Alexander W. H. Speed, Anna Chiu,
Joseph E. Pero, George A. Borg, and David A. Evans*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge,
Massachusetts 02138, United States
evans@chemistry.harvard.edu
Received May 28, 2011
ABSTRACT
The use of cyclic R,β-unsaturated iminium-ion dienophiles is documented in two highly diastereoselective DielsÀAlder (DA) reactions. The
dienophilic counterion was found to have a significant effect on reactivity.
Iminium-ion LUMO-lowering activation1 has been ex-
tensively studied in the context of DielsÀAlder (DA)
reactions and related organocatalyzed transformations.2
In some cases, the nature of the achiral counterion has
been demonstrated to have an important effect on the
selectivity of a given reaction, although its effect on
reactivity has not been explicitly studied.3
The purpose of this communication is to document the
counterion-dependent rate acceleration of endoselective
iminium ion DA reactions vide supra.
As illustrated in Figure 1, spiroimine-containing alka-
loids such as 1 and 2 each contain the prominent DA
Figure 1. Examples of spiro-imine containing natural products.
retron of interest (blue, dienophile; red, diene).
These marine natural products have attracted attention
(1) For seminal publications, see: (a) Ahrendt, K. A.; Borths, C. J.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243–4244. (b)
Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
2458–2460.
as a consequence of their architecture and biological
properties.4 These structures contain congested [6,6]-
or [7,6]-aza-spirocycles. As none of the published ap-
proaches to these illustrated structures has employed an
€
(2) For selected reviews, see: (a) Erkkila, A.; Majander, I.; Pihka,
P. M. Chem. Rev. 2007, 107, 5416–5470. (b) MacMillan, D. W. C.;
Lelais, G. In New Frontiers in Asymmetric Catalysis; Mikami, K., Lautens,
M., Eds.; John Wiley & Sons: Hoboken, NJ, 2007. (c) Enders, D.; Grondal,
C.; H€uttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570–1581. (d) Lelais,
G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79–87. (e)
MacMillan, D. W. C. Nature 2008, 455, 304–308.
(3) Ogilvie has observed an effect of counterion on yields. For
additional information, see: (a) Lemay, M.; Ogilvie, W. W. Org. Lett.
2005, 7, 4141–4144. (b) Lemay, M.; Ogilvie, W. W. J. Org. Chem. 2006,
71, 4663–4666. (c) Lakhdar, S.; Mayr, H. Chem. Commun. 2011, 47,
1866–1868.
(4) (a) Lu, C.-K.; Lee, G.-H.; Huang, R.; Chou, H.-N. Tetrahedron
Lett. 2001, 42, 1713–1716. (b) Stewart, M.; Blunt, J. W.; Munro,
M. H. G.; Robinson, W. T.; Hannah, D. J. Tetrahedron Lett. 1997,
384889–4890. (c) Uemura, D.; Chou, T.; Haino, T.; Nagatsu, A.; Fukuzawa,
S.; Zheng, S.; Chen, H. J. Am. Chem. Soc. 1995, 117, 1155–1156. (d) Hu, T.;
Burton, I. W.; Cembella, A. D.; Curtis, J. M.; Quilliam, M. A.; Walter, J. A.;
ꢀ
Wright, J. L. C. Nat. Prod. 2001, 64, 308–312. (e) Gueret, S. M.; Brimble,
M. A. Nat. Prod. Rep. 2010, 27, 1350–1366.
r
10.1021/ol201448h
Published on Web 06/16/2011
2011 American Chemical Society

iminium ion retron,5 we have focused our attention on the
development of these DA variants.
were observed in MeCN, MeOH, and i-PrOH. The use of
chlorinated solvents (CH2Cl2, CHCl3) led to diene poly-
merization while dienophile insolubility was noted in
other instances (PhH and PhMe).
The proposed approach to a generic [7,6]-aza-spiro-
cycle involves the cycloaddition between iminium-ion 3
and diene 4a (Scheme 1). This initial study involved
achiral dienophiles so that endo/exo diastereoselection
might be readily monitored without the intervention of
additional diastereomers. Previous literature examples
have revealed a significant range of endo/exo stereoÀ
selectivities for these reactions.6À8
We then submitted other dienes (4bÀd) to the DA
reaction with dienophile 3 and its six-membered counter-
part 6. We were pleased to observe good diastereoselec-
tivities and yields in all cases (Table 1). We also found that
the six-membered iminium-ion 6 was qualitatively more
reactive. In some cases, a decrease in temperature was
shown to be beneficial to reaction selectivity with 6 (entry
6). The greater reactivity of the six-membered dienophile
6 compared to its seven-membered counterpart 3 is high-
lighted in the illustrated competition experiment (eq 1).
Scheme 1. Counterion-Dependent DA Rate Acceleration
We have also evaluated the impact of the dienophilic
nitrogen substituent on reaction rate in a related competi-
tion experiment where an N-benzyl was employed as a
proton surrogate (eq 2). Dienophile 3 (X = SbF6) proved
to react 20Àtimes faster than its N-benzylated counter-
part 8 (X = SbF6) in the cycloaddition reaction with
diene 4a.
From this data set, it is believed that the benzylic CÀH
bonds stabilize, rather that destabilize, iminium-ion 8,
possibly through hyperconjugation. This reactivity trend
was not anticipated. This observation negates our initial
premise that the relative electronegativies of the N-sub-
stituents (H vs C) would influence electrophilic reactivity.
Conterion Effects. The results of the reaction of 3fi,9 (X =
OTs) with diene 4a are summarized in Scheme 1. When it
was found that this lead reaction required four days to
reach completion at rt, the subsequent counterion study
was undertaken. With the SbF6 and ClO4 counterions,
the reaction is complete in 15 and 17 h respectively.10
Consistently good endo diastereoselection (>90:10) was
observed for all cases. Polar solvents failed to reveal any
dramatic effects as similar rates and diastereoselectivities
(5) (a) Stivala, C. E.; Zakarian, A. J. Am. Chem. Soc. 2008, 130, 3774–
3776. (b) Nakamura, S.; Kikuchi, F.; Hashimoto, S. Angew. Chem., Int.
Ed. 2008, 47, 7091–7094. (c) McCauley, J. A; Nagasawa, K.; Lander,
P. A.; Mischke, S. G.; Semones, M. A.; Kishi, Y. J. Am. Chem. Soc. 1998,
120, 7647–7648. (d) Sakamoto, S.; Sakazaki, H.; Hagiwara, K.; Kamada,
K.; Ishii, K.; Noda, T.; Inoue, M.; Hirama, M. Angew. Chem., Int. Ed. 2004,
43, 6505–6510. (e) Beaumont, S.; Ilardi, E. A.; Tappin, N. D. C.; Zakarian,
A. Eur. J. Org. Chem. 2010, 5743–5765.
ꢀ
ꢀ
(6) For a recent review, see: Merino, P.; Marques-Lopez, E.; Tejero,
T.; Herrera, R. P. Synthesis 2010, 1–26.
(7) Johannes, J. W.; Wenglowsky, S.; Kishi, Y. Org. Lett. 2005, 7,
3997–4000.
(8) For other iminium-ion dienophiles in DielsÀAlder rections, see:
(a) Kim, J.; Thomson, R. J. Angew. Chem., Int. Ed. 2007, 46, 3104–3106.
(b) Zou, Y.; Che, Q.; Snider, B. B. Org. Lett. 2006, 8, 5605–5608. (c)
€
O’Connor, P. D.; Korber, K.; Brimble, M. A. Synlett 2008, 1036–1038.
(d) Boeckman, R. K., Jr.; Miller, Y.; Ryder, T. R. Org. Lett. 2010, 12,
4524–4527.
(9) See Supporting Information for experimental details.
(10) BArF (tetrakis(3,5-bis(trifluoromethyl)phenyl)borate) and BF4
have also been investigated. BArF gives results similar to ClO4 while BF4
is related to OTf. They have been omitted for clarity. See Supporting
Information for more details.
Org. Lett., Vol. 13, No. 14, 2011
3759

Table 1. Scope of Iminium-Ions 3 and 6 in DielsÀAlder Cycloadditions
a Reaction times in h are provided in parentheses. b Determined by 1H NMR analysis of the unpurified reaction mixture. c Combined isolated yield.
Yields in parentheses refer to the isolated free imine.
Scheme 2. Synthesis of Seven-membered Iminium Ion 3
Chiral Azadienes. Equations 3 and 4 illustrate two chiral
cyclic iminium ions of interest to several spiroimine
natural products (cf. Figure 1). In the case of the more
reactive 6-membered iminium-ion 10, we anticipated that
the resident methyl substituent would be sufficient to
control the facial selectivity of the reaction. Indeed, high
facial selectivity was observed when 10 reacted with
alkene 4a under the optimal reaction conditions (eq 3),
as only two of the four possible DA adducts were
observed. In contrast, the facial selectivity of the 7-mem-
bered iminium ion 12 represents a more ambiguous
case. In this instance, with the illustrated diene, face
selectivity is poor. In both instances, endo selectivities
were impressive.
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Org. Lett., Vol. 13, No. 14, 2011

Dienophile Syntheses. The synthesis of iminium ion dieno-
phile 3 is summarized in Scheme 2.11 The point of interest
in the synthesis of 3 is the transformation of the protected
ketoamine 14 to its derived cyclization product. As illu-
strated, cyclization precursor 14a is presented with the
options of kinetic or thermodynamic control. The com-
peting 7-endoÀ or 7-exoÀcyclization modes are pre-
sented (eq 5, eq 6). In accord with Baldwins Rules,12 it
is tempting to speculate that thermodynamic control
might dominate this process (eq 5); nevertheless, kinetic
selection for the 7-exoÀcyclization mode is clearly re-
vealed under kinetic cyclization conditions (CHCl3 reflux
for one h) (eq 6). After prolonged heating under these
conditions (∼18 h), the thermodynamic product was
observed. It is noteworthy that the gem-dimethyl moiety
is required for kinetic control (Thorpe-Ingold) in this
instance in spite of the fact that this control element is
present in both cyclization modes (Scheme 2) It is also
interesting that the vicinal dimethyl substitution pattern
in iminium ion 12 also promotes the desired kinetic
cyclization pathway.
The iminium ion DA cycloadditions included in this
study afford uniformly good endo diastereoselection.
Counterion effects may be relied upon to provide synthe-
tically useful rate accelerations for large non- coordinat-
ing counterions (X = SbF6) versus their chloride ion
counterparts. These observations should be relevant to
the further development of a variety of organocatalytic
and diastereoselective reactions involving iminium ion
reactants.
Acknowledgment. Financial support has been provided
by the National Institutes of Health (GM-33328-24).
Fellowships were provided to D.M. and A.W.H.S. by
NSERC (Canada) and to P.B. by the SNSF (Switzerland)
and Novartis Foundation.
Supporting Information Available. Complete experi-
mental details, proton and carbon NMR spectra for all
new compounds, and stereochemical determination. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) The synthesis of the six-membered dienophile 6 proceeds along
the same lines.
(12) Baldwin, J. E. J. Chem. Soc. Chem. Commun. 1976, 734–735 and
subsequent literature citations.
Org. Lett., Vol. 13, No. 14, 2011
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