Highly stereoselective formal [3 + 3] cycloaddition reactions of chiral vinylogous amides with α,β-unsaturated iminiums

Article abstract of DOI:10.1021/ol000049+

Highly stereoselective formal [3 + 3] cycloaddition reactions of chiral vinylogous amides with α,β-unsaturated iminiums are described. A mechanistic model is proposed to rationalize the observed stereoselectivity. The 6π-electron electrocyclic ring closure appears to be reversible, and a preferred rotation of the alkenyl group, one of the three 2π-components, during the ring closure step provides the thermodynamically favored diastereomer as the major product.

Full text of DOI:10.1021/ol000049+

ORGANIC
LETTERS
2000
Vol. 2, No. 8
1161-1164
Highly Stereoselective Formal [3 + 3]
Cycloaddition Reactions of Chiral
Vinylogous Amides with
r,â-Unsaturated Iminiums
Heather M. Sklenicka, Richard P. Hsung,* Lin-Li Wei, Michael J. McLaughlin,
Aleksey I. Gerasyuto,1 and Shane J. Degen1
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
hsung@chem.umn.edu
Received March 6, 2000
ABSTRACT
Highly stereoselective formal [3 + 3] cycloaddition reactions of chiral vinylogous amides with r,â-unsaturated iminiums are described. A
mechanistic model is proposed to rationalize the observed stereoselectivity. The 6π-electron electrocyclic ring closure appears to be reversible,
and a preferred rotation of the alkenyl group, one of the three 2π-components, during the ring closure step provides the thermodynamically
favored diastereomer as the major product.
We have been exploring reactions of R,â-unsaturated im-
iniums with 1,3-dicarbonyl equivalents to construct hetero-
cyclic structures.2-4 These reactions involve a sequence that
consists of a Knoevenagel condensation [an amine-assisted
C-1,2-addition-reversible â-elimination] followed by a 6π-
electron electrocyclic ring closure [Figure 1].2a,5,6 This process
constitutes a stepwise formal [3 + 3] cycloaddition protocol7
useful for synthesis of complex heterocycles. The net result
of this process is the formation of two σ-bonds in addition
to a new stereocenter adjacent to the heteroatom. This formal
(1) UMN Undergraduate Research Participants: 1998-1999. Recipients
of 1998 and 1999 LANDO-NSF REU Fellowships.
(2) (a) Hsung, R. P.; Shen, H. C.; Douglas, C. J.; Morgan, C. D.; Degen,
S. J.; Yao, L. J. J. Org. Chem. 1999, 64, 690. (b) Douglas, C. J.; Sklenicka,
H. M.; Shen, H. C.; Golding, G. M.; Mathias, D. S.; Degen, S. J.; Morgan,
C. D.; Shih, R. A.; Mueller, K. L.; Seurer, L. M.; Johnson, E. W.; Hsung,
R. P. Tetrahedron 1999, 55, 13683.
(3) (a) 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. (b)
Hsung, R. P.; Wei, L.-L.; Sklenicka, H. M.; Shen, H. C.; McLaughlin, M.
J.; Zehnder, L. R. In AdVances in Cycloaddition; Harmata, M., Ed.; JAI
Press: Greenwich, CT; in press.
(4) For our other efforts related to synthesis of heterocycles, see: (a)
Hsung, R. P. J. Org. Chem. 1997, 62, 7904. (b) Hsung, R. P. Heterocycles
1998, 48, 421. (c) Granum, K. G.; Merkel, G.; Mulder, J. A.; Debbins, S.
A.; Hsung, R. P. Tetrahedron Lett. 1998, 9597. (d) Hsung, R. P.; Zificsak,
C. A.; Wei, L.-L.; Zehnder, L. R.; Park, F.; Kim, M.; Tran, T.-T. T. J.
Org. Chem. 1999, 64, 8736. (e) Wei, L.-L.; Xiong, H.; Douglas, C. J.;
Hsung, R. P. Tetrahedron Lett. 1999, 6903. (f) Hsung, R. P.; Zificsak, C.
A.; Wei, L.-L.; Douglas, C. J.; Xiong, H.; Mulder, J. A. Org. Lett. 1999, 1,
1237. (g) Wei, L.-L.; Hsung, R. P.; Xiong, H.; Mulder, J. A.; Nkansah, N.
T. Org. Lett. 1999, 1, 2145.
Figure 1. Chiral vinylogous amide approach.
10.1021/ol000049+ CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/18/2000

[3 + 3] cycloaddition method can be classified as a sequential
anionic-pericyclic strategy for which the significance in
natural product synthesis has been elegantly summarized by
Tietze.8
the reaction of the vinylogous amide 2 with 3 was completely
stereorandom, leading to the cycloadduct 5 in 63% yield but
with a ratio of 55:45.
Uncertain of the mechanistic source of stereoinduction or
lack thereof, we screened several chiral vinylogous amides,
and compound 6 provided the best stereoselectivity [Scheme
2]. The reaction of 6 with R,â-unsaturated iminium 3 at 150
Our recent work using vinylogous amides has rendered
this strategy attractive for synthesis of piperidinyl hetero-
cycles.3 Having established its synthetic feasibility, we have
been exploring an asymmetric variant of this formal cyclo-
addition method. Specifically, we are interested in using
chiral vinylogous amides to control the stereocenter adjacent
to the nitrogen atom [Figure 1].9 We report here our first
realization of stereoselective formal [3 + 3] cycloaddition
reactions of chiral vinylogous amides with R,â-unsaturated
iminiums.
Scheme 2
Our initial choices of chiral vinylogous amides were
compounds 1 and 2 as shown in Scheme 1 because of their
Scheme 1
°C for 48 h afforded the desired cycloadduct 7 in 69% yield
as a single diastereomer. It is noteworthy that compound 7
possessed an unusually high specific optical rotation of -610.
Compound 7 could be readily desilylated using TBAF [80%
yield], leading to a crystalline alcohol intermediate that was
suitable for X-ray diffraction. The X-ray crystal structure of
desilylated 7 [Figure 2] revealed its absolute configuration
as shown in Scheme 2.
synthetic accessibility from simple condensation of the
corresponding chiral amines with 1,3-cyclohexanedione.
When the vinylogous amide 1 was reacted with R,â-
unsaturated iminium 3 [derived from 2-hexenal] at 150 °C
for 48 h, the desired formal cycloadduct 410 was obtained in
64% with a diastereomeric ratio of 75:25. On the other hand,
Under the same reaction conditions, the enantiomer of 6
provided ent-7 in 67% yield with an almost equally high
(5) For earlier studies in this area, see: (a) Hua, D. H.; Chen, Y.; Sin,
H.-S.; Maroto, M. J.; Robinson, P. D.; Newell, S. W.; Perchellet, E. M.;
Ladesich, J. B.; Freeman, J. A.; Perchellet, J.-P.; Chiang, P. K. J. Org.
Chem. 1997, 62, 6888. (b) Jonassohn, M.; Sterner, O.; Anke, H. Tetrahedron
1996, 52, 1473.
(6) (a) de March, P.; Moreno-Man˜as, M.; Casado, J.; Pleixats, R.; Roca,
J. L.; Trius, A. J. Heterocycl. Chem. 1984, 21, 1369. (b) Tietze, L. F.;
Kiedrowski, G. v.; Berger, B. Synthesis 1982, 683. (c) de Groot, A.; Jansen,
B. J. M. Tetrahedron Lett. 1975, 3407.
(7) Examples of [3 + 3] cycloaddition reactions in the truest sense are
extremely scarce, and there are only limited examples of metal-mediated
[3 + 3] cycloaddition reactions. For recent reviews, see: (a) Fru¨hauf, H.-
W. Chem. ReV. 1997, 97, 523. (b) Lautens, M.; Klute, W.; Tam, W. Chem.
ReV. 1996, 96, 49.
(8) For a review on synthetic methods involving sequential transforma-
tions, see: Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993,
32, 131.
(9) For a recent elegant study using chiral vinylogous amides to control
stereochemistry of a quaternary center using aza-annulation chemistry,
see: Benovsky, P.; Stephenson, G. A.; Stille, J. R. J. Am. Chem. Soc. 1998,
120, 2493.
(10) All new compounds are characterized by 1H NMR, 13C NMR, FTIR,
and mass spectroscopy. Details may be obtained from the Supporting
Information.
Figure 2. X-ray structure of desilylated 7.
Org. Lett., Vol. 2, No. 8, 2000
1162

diastereoselectivity. The type of protecting group on the
oxygen does not appear to affect the stereoselectivity of this
formal cycloaddition reaction. For example, the reaction of
chiral vinylogous amide 8, containing an acetyl group, led
to the desired heterocycle 9 in comparable yield and
stereoselectivity [Scheme 2].
Scheme 3
Having established the stereochemical assignment as well
as the synthetic feasibility of this stereoselective reaction,
reactions of 6, ent-6, or 8 with a variety of R,â-unsaturated
iminiums 10-14 were carried out. These reactions led to
the preparation of compounds 15-20 in good yields as well
as high stereoselectivity [Table 1]. Again, unusually high
Table 1. Generality of the Stereoselective [3 + 3]
Cycloaddition
diastereomeric ratio. These comparisons, along with those
unsuccessful examples shown in Scheme 1, prompted us to
explore a possible mechanistic model for this stereoselective
reaction. However, we first examined whether the observed
diastereoselectivity is a result of thermodynamic or kinetic
control, thereby providing insight into an important mecha-
nistic point regarding the reversibility of the 6π-electron
electrocyclic ring closure.
Toward this goal, we heated samples of the pure major
isomer of 5 [g95:5 major to minor] and an enriched minor
isomer of 7 [28:72 major to minor] at 150 °C in d8-toluene
for 36 h. The final isomeric ratios for 5 and 7 were 59:41
and 93:7, respectively. These experiments suggest that the
diastereoselectivity observed for these reactions is a result
of a thermodynamic control, and that the 6π-electron
electrocyclic ring closure step appears to be reversible.11 The
isomeric ratios were not affected when 5 and 7 were heated
at 85 °C for 10-15 h, and the ratios do not improve upon
heating at 240 °C for 24 h.
On the basis of these experiments, we proposed a
mechanistic model which is shown in Figure 3. The X-ray
specific optical rotations were also obtained for the major
isomers. It is noteworthy that tricycle 18 could also be
obtained with high stereoselectivity using the R,â-unsaturated
iminium derived from cyclohexencarboxaldehyde, albeit in
a slightly lower yield.
Reactions of chiral vinylogous amide 21 with R,â-
unsaturated iminium 10 also provided comparable stereo-
induction, leading to the formal cycloadduct 22 in 55% with
a ratio of 90:10 [Scheme 3]. However, the reaction of 23
with 3 led to 24 in similar yields but with a much depreciated
Figure 3. Proposed mechanistic model.
Org. Lett., Vol. 2, No. 8, 2000
1163

structure of desilylated 7 [Figure 2] reveals an interesting
conformational preference or orientation for the chiral groups
tethered to the nitrogen atom. That is, the two phenyl groups
are completely anti to one another and the one at C-1 appears
to π-stack with the vinyl carbon bearing the R group. In
addition, the imine nitrogen atom and the oxygen atom are
also anti to one another. If such a conformational preference
is viable prior to an electrocyclic ring closure, then there
can be two possible rotations for the vinyl strand of imine
intermediate 25 during the ring closure.12,13
Finally, the chiral-inducing unit tethered to the nitrogen
atom can be removed efficiently using hydrogenation
protocols. Compound ent-7 was first desilylated quantita-
tively using TBAF in CH2Cl2, and the corresponding
desilylated product was subsequently refluxed with am-
monium formate and 5% Pd-C in EtOH to provide
heterocycle 27 in 75% yield [Scheme 4]. The stereochemical
Scheme 4
The rotation-a of the vinyl strand should be favored leading
to the major isomer with the correct stereochemical assign-
ment, while the rotation-b is less favored owing to the severe
steric interaction between the R and phenyl groups. This
rotational preference essentially leads to the major product
with the least amount of steric congestion between the R
and phenyl groups, and thus, the major isomer of 26 is also
the thermodynamically more stable one. The reversibility of
the ring closure would allow the minor isomer of 26 to revert
back to the intermediate 25, and again through the more
favored rotation-a, the final diastereomeric ratio may be
attained. While this model appears to be suitable to the
observed diastereoselectivity, it does not fully compliment
with the result in which a relatively lower diastereoselectivity
was observed for larger R groups [entries 1 and 6 versus
entries 2, 3, and 5 in Table 1].
integrity at C-2 in 27 was not eroded because hydrogenation
occurred readily for the olefin at C3-C4, preventing any
electrocyclic ring opening to occur. Since the stereochemistry
at C-2 of 27 is the same as the corresponding one in
pumilotoxin C,15 we are pursuing an asymmetric synthesis
of members of the pumiliotoxin family of alkaloids using
this methodology.16
The proposed conformational preference is the key to the
observed stereoselectivity and unique to this particular chiral
vinylogous amide in which the phenyl ring at C-1 can reside
close to the vinyl strand bearing the R group, thereby
ensuring the rotational preference.14 To support the close
proximity of the C-1 phenyl group to the R group, we
We have described here the first highly stereoselective
reactions of chiral vinylogous amides with R,â-unsaturated
iminiums. We have also proposed a mechanistic model that
would rationalize the observed stereoselectivity as a result
of a preferred rotation during a reversible electrocyclic
ring closure step, leading to the thermodynamically more
stable product. Studies related to reactions of other chiral
vinylogous amides as well as synthetic applications of this
stereoselective reaction are currently underway.
1
observed in H NMR that, when applicable, resonance of
the methyl, methylene, or methine protons of formal cyclo-
adducts are shifted toward high field in an unusual manner
[-0.11 to 0.27 ppm], presumably owing to the anisotropic
effect of the phenyl ring. Hence, perturbations of this
conformational preference may lead to loss of stereoselec-
tivity as demonstrated in reactions of 1 and 2.
Acknowledgment. The authors thank University of
Minnesota for financial support in the form of Start-up Funds
and Grant-in-Aid of Research, Artistry and Scholarship
[CUFS 1003-519-5984] and the American Cancer Society
for an institutional grant [IRG-58-001-40-IRG-26]. R.P.H.
especially thanks R. W. Johnson Pharmaceutical Institutes
for a generous grant from the Focused Giving Program.
Authors also thank William B. Brennessel and Dr. Victor
Young for solving the X-ray structure.
In addition, the carbon R to the imine group in 25 may
also play a role in providing the required conformation. The
phenyl group at C-1 would likely prefer to be far away from
this sp3 methylene unit to avoid potential steric interaction.
However, in compound 23, this carbon is sp2, thereby
providing less steric interaction with the C-1 phenyl group.
Thus, reactions of 23 also led to lower diastereoselectivity.
We are currently pursuing calculations to determine whether
any π-π interactions may exist between the phenyl ring at
C-1 and the vinyl strand bearing the R group.
Supporting Information Available: General procedures
1
and characterization data for all new compounds and H
(11) For another precedent, see: Moorhoff, C. M. Synthesis 1997, 685.
(12) We are assuming that the imine nitrogen rather than an iminium
species is involved in the ring closure because of the presence of excess
piperidine. For a related reference, see: Kametani, T.; Kajiwara, M.;
Fukumoto, K. Tetrahedron 1974, 30, 1053.
(13) Shishido, K.; Ito, M.; Shimada, S.-I.; Fukumoto, K.; Kametani, T.
Chem. Lett. 1984, 1943.
NMR [13 pages]. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL000049+
(14) For a related example of such a rotational preference during a 6π-
electron electrocyclic ring closure, see: 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.
(15) Paulvannan, K.; Stille, J. R. Tetrahedron Lett. 1993, 6677.
(16) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In The Alkaloids; Cordell,
G. A., Ed.; Academic Press: New York, 1993; Vol. 43, p 185.
1164
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