Chiral cycloalkylidene α,β-unsaturated iminium approach to stereoselective formal [3+3] cycloaddition reaction in spiroheterocycle synthesis

Article abstract of DOI:10.1016/S0040-4039(00)02018-9

An approach to stereoselective formal [3+3] cycloaddition reaction using chiral cycloalkylidene α,β-unsaturated iminiums is described here leading to preparations of spiroheterocycles in modest stereoselectivity. The reversibility of 6π-electron electrocyclic ring closure did not always lead to the thermodynamically more favored product. These observations led to other useful mechanistic understanding of electrocyclic ring closure of 1-oxatrienes.

Full text of DOI:10.1016/S0040-4039(00)02018-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 609–613
Chiral cycloalkylidene a,b-unsaturated iminium approach to
stereoselective formal [3+3] cycloaddition reaction in
spiroheterocycle synthesis
Michael J. McLaughlin, Hong C. Shen and Richard P. Hsung*
Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA
Received 1 August 2000; revised 6 November 2000; accepted 7 November 2000
Abstract—An approach to stereoselective formal [3+3] cycloaddition reaction using chiral cycloalkylidene a,b-unsaturated
iminiums is described here leading to preparations of spiroheterocycles in modest stereoselectivity. The reversibility of 6p-electron
electrocyclic ring closure did not always lead to the thermodynamically more favored product. These observations led to other
useful mechanistic understanding of electrocyclic ring closure of 1-oxatrienes. © 2001 Elsevier Science Ltd. All rights reserved.
Reactions of a,b-unsaturated carbonyl systems with
1,3-diketo equivalents involve a tandem process consist-
ing of a Knoevenagel condensation followed by a 6p-
electron electrocyclic ring closure.1–3 The net result of
this step-wise or formal [3+3] cycloaddition reaction4,5
is the formation of two s-bonds in addition to a new
stereocenter adjacent to the heteroatom. Our work in
this area specifically using a,b-unsaturated iminiums6
has provided a general solution to the regiochemical
problems that occurred in previous studies,1,2 and led to
the development of an attractive approach for con-
structing complex heterocycles from simple intermedi-
ates.7,8 Having established its synthetic feasibility, we
have been exploring asymmetric variants of this formal
cycloaddition. Recently, we successfully utilized chiral
vinylogous amides as diketo equivalents to achieve high
diastereomeric control at the stereocenter adjacent to
the nitrogen atom.9 These studies led us to explore
another approach to stereoselective formal [3+3]
cycloaddition using chiral cycloalkylidene a,b-unsatu-
rated iminiums 2 (Scheme 1). This could lead to a novel
concept in achieving stereocontrol at the spirocenter of
heterocycles such as 4.10 We report here our studies of
formal [3+3] cycloaddition reactions of chiral
cycloalkylidene a,b-unsaturated iminiums with 4-
hydroxy-pyrones.
Chiral cycloalkylidene a,b-unsaturated iminiums were
generated in EtOAc at 85°C from corresponding alde-
hydes 5–911,12 using 1.0 equiv. of piperidine and 1.0
equiv. of Ac2O (Table 1).6 Mixtures of E and Z were
used throughout these reactions, but isomerization of
the Z isomer to E was very fast under the reactions
conditions. Subsequent reactions of these iminiums
with 6-methyl-4-hydroxy-2-pyrone led to isomeric
spiroheterocycles 10–14 in good yields (entries 1–5).
However, the diastereomeric ratio was at best 70:30
(determined by 1H NMR) for the compound 10 in
favor of the isomer a as assigned by nOe experiments.13
There is a noticeable inverse relationship between the
ratio and size of the R groups. When R is changed
from a Me to a t-Bu group, the ratio switched to 44:55
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02018-9

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M. J. McLaughlin et al. / Tetrahedron Letters 42 (2001) 609–613
Table 1.
in favor of the isomer 13b (entry 4). In addition, there
appears to be no heteroatom effect on the stereochem-
istry since the compound 14a with R being a MeO
group was obtained with a ratio of 55:45 in favor of the
isomer a (entry 5), but only 14a and 14b can be
separated via column chromatography.
240°C for 72 h, the ratio remained the same at 45:55 in
favor of 13b which is the relatively much less stable
isomer (see discussions later in Scheme 3).
Solvent polarities appear to have a minimum effect on
the stereoselectivity of this reaction (entries 6–10).
However, there is a noticeable temperature effect on the
stereoselectivity. The reaction of 6-methyl-4-hydroxy-2-
pyrone with the iminium generated from aldehyde 5
could proceed at lower temperatures such as 0 and
25°C (entries 11 and 12), although the conversion rate
is slower as indicated by the lower isolated yields
(starting materials were recovered). However,
diastereomeric ratios were found to be eroded from
70:30 observed at 85°C (entry 1) to 20:80 and 25:75 at
0 and 25°C, respectively (entries 11 and 12). These
observations suggest that the less stable isomer 10b can
be accessed via a kinetic ring closure at lower tempera-
tures. Such a dependence on temperature during a
6p-electron electrocyclic ring closure has not been well
noted for heteroatom substituted trienes.14–16
Our previous study using chiral vinylogous amides sug-
gests that the observed stereoinduction is in part a
result of thermodynamic control due to the reversibility
of the 6p-electron electrocyclic ring closure.9 To exam-
ine if these isomeric ratios also represent thermody-
namic ratios, a mixture of 10a/b (R=Me; 70:30) was
heated at 220–240°C in toluene. The ratio only changed
to 65:35 after heating for 72 h without noticeable
material depreciation. When trying to obtain a single
crystal of the pure 14a, it was found that after storing
at −10 to −20°C in ether/pentane for over 21 days, 14a
had actually epimerized presumably via iterative ring
opening and closure at a very low temperature, leading
to a mixture of 14a and 14b with a ratio of 1:1. These
control experiments suggest that ratios in entries 1–3
and 5 closely represent thermodynamic ratios. How-
ever, when compound 13a/b (R=t-Bu) was heated at
Finally, as shown in Scheme 2, utilizing chiral cy-
cloalkylidene a,b-unsaturated iminiums (15) possessing
Scheme 2.

M. J. McLaughlin et al. / Tetrahedron Letters 42 (2001) 609–613
611
Scheme 3.
either a remote stereocenter, two stereocenters, or a
more conformationally rigid decalin template did not
lead to improved diastereoselectivities, although yields
were quite high and compounds 16–18 are structurally
interesting and potentially useful spiroheterocycles.
equatorial face of a cyclohexane template during peri-
cyclic reactions,18 a working model is proposed here to
account for the observed stereoselectivity difference in
10 and 13. This model is also based on the assumption
that the more dominant intermediate in the equilibrium
leads to the major isomer.
Although the stereoselectivities observed here are mod-
est, it is still remarkable and deserves further com-
ments. As shown in Scheme 3, the stereochemistry is
likely determined after the Knoevenagel condensation
involving the iminium 19-E and during the 6p-electron
electrocyclic ring closure.14,15 Two possible 1-oxatriene
intermediates, 20 and 21, may be present in an equi-
librium that could either favor the intermediate 20
when A1,3 strain is minimum with small R1 groups, or
may lean toward 21 when A1,3 strain is more severe,
although the R1 group is now also axial leading to less
desired 1,3-diaxial interactions.
When R1=Me, the equilibrium should more distinctly
favor the intermediate 20 with minimum A1,3 strain.
Thus, an equatorial approach of the oxygen atom
during the ring closure via 20 would lead to the major
isomer 22a as observed for 10a. On the other hand,
when R1=t-Bu, both 20 and 21 suffer from severe A1,3
strain and 1,3-diaxial interactions, respectively. Thus,
the position of the equilibrium could shift toward the
intermediate 21 by alleviating the A1,3 strain,18b thereby
leading to 20 and 21 in relatively equal amount. Subse-
quent equatorial approach of the oxygen atom during
the ring closure could then afford both isomers 22a and
22b either in equal amount or slightly in favor of 22b as
observed for 13b.
If a simple rotation (or a torque action) of the vinyl
strand (exocyclic to the cyclohexane ring) in either
direction during the ring closure can account for the
formation of either the isomer 22a or 22b, then the
observed stereoinduction is quite surprising since there
is no apparent reason for any torquoselectivity or for
the rotation in one direction to be favored over the
other.9,16,17 In addition, based on the reversibility of the
6p-electron electrocyclic ring closure,9 the observed
stereoselectivity here should simply be a result of ther-
modynamic distributions of final cycloadducts as indi-
cated in the control studies. However, it does not agree
well with the observation that when R1=t-Bu, the
relatively much less stable isomer 13b (by about 0.71
kcal mol−1 using Spartan™ AM1 calculations) became
favored.
We have demonstrated that chiral cycloalkylidene a,b-
unsaturated iminiums can be used in stereoselective
formal [3+3] cycloaddition reactions leading to modest
stereoinduction at the spirocenter. Despite the re-
versibility of 6p-electron electrocyclic ring closure, the
thermodynamic product was not always favored. These
observations led to understandings of other factors in
the electrocyclic ring closure involving heteroatom sub-
stituted triene systems.
Acknowledgements
These observations suggest that there must be other
factors in addition to simple thermodynamic equilibra-
tion in the stereochemical control during the ring clo-
sure of heteroatom substituted trienes.14,15 Given the
understanding that the direction in the ring closure of
1-oxatrienes or 1-azatrienes starts with the lone pair of
the heteroatom,14,15 and by applying Stork’s postula-
tion that heteroatoms prefer to approach toward the
R.P.H. also thanks R. W. Johnson Pharmaceutical
Institute for financial support.
References
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M. J. McLaughlin et al. / Tetrahedron Letters 42 (2001) 609–613
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1995, 60, 1763. (b) Okamura, W. H.; de Lera, A. R.;
Reischl, W. J. Am. Chem. Soc. 1988, 110, 4462.
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3. Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993,
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4. For reviews on metal mediated [3+3] cycloaddition reac-
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5. For a recent review on step-wise [3+3] carbocyclizations
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6. (a) Hsung, R. P.; Shen, H. C.; Douglas, C. J.; Morgan, C.
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R. A.; Mueller, K. L.; Seurer, L. M.; Johnson, E. W.;
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R.; Dahl, J. W.; Hsung, R. P. Tetrahedron Lett. 2000, 41,
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7. Hsung, R. P.; Wei, L.-L.; Sklenicka, H. M.; Douglas, C.
J.; McLaughlin, M. J.; Mulder, J. A.; Yao, L. J. Org. Lett.
1999, 1, 509.
8. (a) Zehnder, L. R.; Hsung, R. P.; Wang, J.-S.; Golding, G.
M. Angew. Chem., Int. Ed. Eng. 2000, 39, 3876. (b)
McLaughlin, M. J.; Hsung, R. P. J. Org. Chem. 2000, 65,
in press.
16. For
a review on rotational preferences leading to
diastereomeric induction during a 6p-electron electro-
cyclic ring closure, see: Okamura, W. H.; de Lera, A. R.
Comprehensive Organic Synthesis; Trost, B. M.; Fleming,
I., Eds.; Paquette, L. A., volume editor; Pergamon:
Oxford, 1991; Vol. 5, pp. 699–750.
17. For some examples involving torquoselective processes,
see: (a) Giese, S.; Kastrup, L.; Stiens, D.; West, F. G.
Angew. Chem., Int. Ed. Engl. 2000, 39, 1970. (b) Hsung,
R. P.; Quinn, J. F.; Weisenberg, B. A.; Wulff, W. D.;
Yap, G. P. A.; Rheingold, A. L. J. Chem. Soc., Chem.
Commun. 1997, 615.
18. (a) Cvetovich, R. J. Diss. Abstr. Int. B 1979, 39(8), 3837;
Chem. Abstr. 1979, 90, 186758q. (b) Tanner, D.; Hag-
berg, L.; Poulsen, A. Tetrahedron 1999, 55, 1427.
19. Characterizations of selected new compounds: 10: mp=
91–92°C, Rf=0.40 (silica gel, 25% ethyl acetate/hexane);
1H NMR (300 MHz, CDCl3): isomer a l 6.41 (d, 1H,
J=10.2 Hz), 5.85 (s, 1H), 5.20 (d, 1H, J=10.2 Hz), 2.21
(s, 3H), 2.17 (m, 1H), 1.43–1.79 (m, 6H), 1.21–1.39 (m,
2H), 0.93 (d, 3H, J=3.3 Hz); isomer b l 6.49 (d, 1H,
J=10.2 Hz), 5.62 (s, 1H), 5.58 (d, 1H, J=10.2 Hz), 2.21
(s, 3H), 2.19 (m, 1H), 1.43–1.79 (m, 6H), 1.21–1.39 (m,
2H), 0.91 (d, 3H, J=3.3 Hz); 13C NMR (75 MHz,
CDCl3): isomer a l 164.6, 162.3, 124.7, 116.9, 100.3, 86.0,
83.6, 41.1, 40.5, 37.0, 30.6, 28.9, 25.4, 20.2, 16.6; isomer b
l 165.1, 162.5, 119.3, 118.0, 110.3, 100.2, 97.9, 40.1, 38.7,
28.4, 25.0, 22.0, 20.1, 18.3, 16.2; IR (thin film) cm−1
2932(s), 2855(s), 1716(s), 1646(s), 1560(s), 1447(m),
1387(m); mass spectrum (EI): m/e (% relative intensity)
246 (50) M+, 203 (25), 190 (16), 189 (100), 176 (14);
HRMS (EI): m/e calculated for C15H18O3: 246.3042, mea-
sured 246.1257; anal. calcd for C15H18O3: C, 73.15; H,
7.37; found: C, 72.99; H, 7.24. 13: Rf=0.54 (silica gel,
9. Sklenicka, H. M.; Hsung, R. P.; Wei, L.-L.; McLaughlin,
M. J.; Gerasyuto, A. I.; Degen, S. J.; Mulder, J. A. Org.
Lett. 2000, 2, 1161.
10. For a related review, see: Kotera, M. Bull. Soc. Chim. Fr.
1989, 370.
11. The cycloalkylidene a,b-unsaturated aldehydes 5–7 and 9
were prepared from their corresponding cyclohexanones
in three steps: (1) Wittig olefination using (EtO)2PCH2-
COOEt, (2) Dibal-H reduction, and (3) Ley’s TPAP or
Dess–Martin oxidation. The aldehyde 8 was prepared
from 2-t-Bu-cyclohexanone in two steps: (1) vinylmagne-
siumbromide, and (2) PCC oxidation.
1
50% ethyl acetate/hexane); H NMR (300 MHz, CDCl3):
isomer a l 6.38 (d, 1H, J=10.2 Hz), 5.80 (s, 1H), 5.78 (d,
1H, J=10.2 Hz), 2.20 (s, 3H), 2.04 (m, 1H), 1.58–1.77
(m, 2H), 1.53–1.58 (m, 2H), 1.40–1.43 (m, 2H), 1.24–1.30
(m, 2H), 0.94 (s, 9H); isomer b 6.22 (d, 1H, J=10.2 Hz),
5.70 (s, 1H), 5.46 (d, 1H, J=10.2 Hz), 2.21 (s, 3H), 2.04
(m, 1H), 1.58–1.77 (m, 2H), 1.53–1.58 (m, 2H), 1.40–1.43
(m, 2H), 1.24–1.30 (m, 2H), 0.98 (s, 9H); 13C NMR (75
MHz, CDCl3): isomer a l 171.1, 163.8, 162.5, 162.5,
121.1, 115.8, 100.4, 86.8, 55.0, 54.4, 42.9, 29.7, 29.4, 27.6,
26.8, 26.3, 22.1, 20.3; isomer b l 168.5, 163.1, 162.6,
162.1, 129.1, 112.7, 100.4, 84.4, 55.0, 53.9, 39.8, 30.4,
27.8, 26.1, 25.6, 23.5, 20.2; IR (neat) cm−1 2938(s),
2866(s), 2360(w), 1716(s), 1645(s), 1563(s), 1447(m),
1321(m); mass spectrum (EI): m/e (% relative intensity)
288 (22) M+, 273 (5), 231 (12), 190 (15), 189 (100); anal.
calcd for C18H24O3: C, 74.97; H, 8.39; found: C, 74.74; H,
8.50. 14: isomer a: mp=65–67°C, Rf=0.71 (silica gel,
50% ethyl acetate/hexane); isomer b: mp=85°C, Rf=0.60
(silica gel, 50% ethyl acetate/hexane); 1H NMR (300
1
12. All new compounds are characterized by H NMR, 13C
NMR, FTIR, and mass spectroscopy. See Ref. 19 for
spectroscopic and physical characterization of selected new
compounds.
13. nOe experiments were carried out on pure isomers 14a and
14b. The following observations were made. Compounds

M. J. McLaughlin et al. / Tetrahedron Letters 42 (2001) 609–613
613
MHz, CDCl3): isomer a l 6.52 (d, 1H, J=10.2 Hz), 5.82
(s, 1H), 5.65 (d, 1H, J=10.2 Hz), 3.38 (s, 3H), 3.34 (dd,
1H, J=4.2, 10.5 Hz), 2.23 (s, 3H), 1.90–1.99 (m, 2H),
1.47–1.71 (m, 4H), 1.29–1.44 (m, 2H); isomer b l 6.51 (d,
1H, J=10.2 Hz), 5.88 (s, 1H), 5.35 (d, 1H, J=10.2 Hz),
3.41 (s, 3H), 3.11 (dd, 1H, J=4.2, 10.5 Hz), 2.10 (s, 3H),
1.90–1.99 (m, 2H), 1.47–1.71 (m, 4H), 1.29–1.44 (m, 2H);
13C NMR (75 MHz, CDCl3): isomer a l 171.1, 164.0,
162.4, 122.6, 120.5, 118.0, 117.7, 100.1, 82.3, 57.7, 35.3,
25.8, 21.7, 20.6, 20.1; isomer b l 168.5, 163.0, 162.3,
131.3, 131.0, 117.7, 117.4, 100.4, 83.6, 58.0, 35.6, 25.2,
23.3, 21.7, 19.7; IR (thin film) cm−1 2936(s), 2864(m),
1718(s), 1646(s), 1561(s), 1447(s), 1423(m), 1324(s),
1230(m); mass spectrum (EI): m/e (% relative intensity)
262 (47) M+, 247 (37), 189 (100), 176 (20), 163 (17); anal.
calcd for C15H18O4: C, 68.69; H, 6.92; found: C, 68.88; H,
6.88. 17: Rf=0.65 (silica gel, 50% ethyl acetate/hexane),
[h]D=−22.0° (c=0.1, CHCl3); 1H NMR (300 MHz,
CDCl3): isomer a l 6.40 (d, 1H, J=10.5 Hz), 5.75 (s,
1H), 5.18 (d, 1H, J=10.5 Hz), 2.17 (s, 3H), 1.79 (m, 4H),
1.41–1.58 (m, 3H), 1.06–1.20 (m, 2H), 0.88 (d, 3H, J=7.8
Hz), 0.82 (d, 3H, J=6.3 Hz), 0.76 (d, 3H, J=6.9 Hz);
isomer b l 6.40 (d, 1H, J=10.5 Hz), 5.75 (s, 1H), 5.66 (d,
1H, J=10.5 Hz), 2.17 (s, 3H), 1.79 (m, 4H), 1.41–1.58
(m, 3H), 1.06–1.20 (m, 2H), 0.88 (d, 3H, J=7.8 Hz), 0.82
(d, 3H, J=6.3 Hz), 0.76 (d, 3H, J=6.9 Hz); 13C NMR
(75 MHz, CDCl3): isomer a l 166.0, 163.8, 162.3, 125.1,
113.0, 100.4, 85.3, 51.5, 50.4, 49.2, 34.5, 28.0, 26.4, 23.4,
21.9, 20.2, 20.1, 17.9; isomer b l 168.0, 164.7, 162.4,
121.1, 116.6, 97.6, 86.3, 52.9, 51.5, 50.7, 46.6, 33.6, 28.3,
27.4, 23.5, 22.1, 19.6, 28.6; IR (neat) cm−1 2953(s),
2869(m), 1717(s), 1646(s), 1560(s), 1447(m), 1424(m),
1326(m); mass spectrum (EI): m/e (% relative intensity)
288 (15) M+, 273 (9), 203 (100); anal. calcd for C18H24O3:
C, 74.70; H, 8.39; found: C, 74.44; H, 8.19. 18: Rf=0.62
(silica gel, 50% ethyl acetate/hexane); 1H NMR (300
MHz, CDCl3): isomer a l 6.37 (d, 1H, J=10.2 Hz), 5.80
(s, 1H), 5.12 (d, 1H, J=10.2 Hz), 2.18 (s, 3H), 1.48–1.74
(m, 6H), 1.40–1.44 (m, 2H), 1.03–1.29 (m, 4H), 0.86–1.06
(m, 4H); isomer b l 6.43 (d, 1H, J=10.2 Hz), 5.74 (s,
1H), 5.57 (d, 1H, J=10.2 Hz), 2.18 (s, 3H), 1.48–1.74 (m,
6H), 1.40–1.44 (m, 2H), 1.03–1.29 (m, 4H), 0.86–1.06 (m,
4H); 13C NMR (75 MHz, CDCl3): isomer a l 168.9,
165.2, 162.6, 124.5, 124.4, 100.4, 85.8, 51.9, 50.9, 49.6,
39.7, 39.6, 36.1, 33.3, 26.7, 26.6, 21.1, 20.1; isomer b l
171.7, 164.5, 162.4, 120.1, 117.1, 100.2, 83.5, 51.8, 51.0,
45.5, 38.0, 37.9, 37.4, 33.3, 27.1, 26.2, 20.2, 19.9; IR
(neat) cm−1 2926(s), 2852(s), 1718(s), 1646(s), 1560(s),
1448(s), 1424(m), 1324(m); mass spectrum (EI): m/e (%
relative intensity) 286 (65) M+, 243 (53), 176 (25), 163
(240, 147 (18); anal. calcd for C18H22O3: C, 75.50; H,
7.74; found: C, 75.48; H, 7.71.
.
.